HK1239758B - Compositions and method for treating compliment-associated conditions - Google Patents

Description

Compositions and methods for treating complement-related disorders

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application Nos. 61/864,941 filed on August 12, 2013, 61/866,651 filed on August 16, 2013, 61/872,098 filed on August 30, 2013, 61/988,012 filed on May 2, 2014, and 62/021,487 filed on July 7, 2014, the contents of which are incorporated herein by reference in their entireties.

Field of the Invention

The present invention relates to methods and compositions for treating various complement-related disorders (e.g., age-related macular degeneration) using Factor D inhibitors (e.g., anti-Factor D antibodies or antigen-binding fragments thereof). Also provided are methods for selecting or identifying patients for treatment with Factor D inhibitors. The methods include the use of prognostic and/or predictive biomarkers.

background

The complement system plays an important role in the clearance of immune complexes and in the immune response to infectious agents, foreign antigens, virus-infected cells, and tumor cells. However, complement is also involved in pathological inflammation and autoimmune diseases. Therefore, inhibition of excessive or uncontrolled activation of the complement cascade could provide clinical benefits to patients suffering from these diseases or conditions.

The complement system comprises two distinct activation pathways, designated the classical and alternative pathways (V. M. Holers, in Clinical Immunology: Principles and Practice, ed. R. R. Rich, Mosby Press; 1996, 363-391). The classical pathway is a calcium/magnesium-dependent cascade that is typically activated by the formation of an antigen-antibody complex. The alternative pathway is a magnesium-dependent cascade that is activated by the deposition and activation of C3 on specific sensitive surfaces (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymers). Activation of the complement pathway produces biologically active fragments of complement proteins, such as C3a, C4a, and C5a anaphylatoxins and the C5b-9 membrane attack complex (MAC), which regulate inflammatory events involving leukocyte chemotaxis, macrophage activation, neutrophils, platelets, mast cells and endothelial cells, vascular permeability, cell lysis, and tissue damage.

Factor D is a highly specific serine protease essential for activation of the alternative complement pathway. It cleaves factor B bound to C3b to produce the enzyme C3b/Bb, which is the active component of the alternative pathway C3/C5 convertase. Factor D may be a suitable target for inhibition because its plasma concentration in humans is very low (1.8 μg/ml) and it has been shown to be the rate-limiting enzyme for activation of the alternative complement pathway (P.H. Lesavre and H.J. Müller-Eberhard. J. Exp. Med., 1978; 148: 1498-1510; J.E. Volanakis et al., New Eng. J. Med., 1985; 312: 395-401).

Downregulation of complement activation has been demonstrated in animal models and in vitro studies to be effective for the treatment of several disease indications, such as systemic lupus erythematosus and glomerulonephritis (Y. Wang et al., Proc. Natl. Acad. Sci.; 1996, 93:8563-8568), rheumatoid arthritis (Y. Wang et al., Proc. Natl. Acad. Sci., 1995; 92:8955-8959), cardiopulmonary bypass and hemodialysis (C. S. Rinder, J. Clin. Invest., 1995; 96:1564-1572), hyperacute rejection in organ transplantation (HSP) and inflammatory bowel disease (AIDS). transplantation) (T. J. Kroshus et al., Transplantation, 1995; 60: 1194-1202), myocardial infarction (J. W. Homeister et al., J. Immunol., 1993; 150: 1055-1064; H. F. Weisman et al., Science, 1990; 249: 146-151), reperfusion injury (E. A. Amsterdam et al., Am. J. Physiol., 1995; 268: H448-H457), and adult respiratory distress syndrome (R. Rabinovici et al., J. Immunol., 1992; 149: 1744-1750). In addition, other inflammatory disorders and autoimmune/immune complex diseases are also closely related to germline activation (V.M. Holers, supra, B.P. Morgan. Eur. J. Clin. Invest., 1994: 24: 219-228), including heat injury, severe asthma, anaphylactic shock, bowel inflammation, urticaria, angioedema, vasculitis, multiple sclerosis, myasthenia gravis, membranoproliferative glomerulonephritis and Sjögren's syndrome.

Age-related macular degeneration (AMD), when untreated, is the leading cause of irreversible blindness in people over 50 years of age in developed countries (Friedman et al., Arch Opthalmol, 122:564-72 (2004)). Approximately 8 million Americans have intermediate AMD, characterized by the presence of large drusen in the macula (center of the retina), which puts them at risk for developing advanced disease and vision loss. Advanced AMD is divided into two clinical forms: geographic atrophy (GA) and an exudative or wet form characterized by choroidal neovascularization (CNV) (Age-Related Eye Disease Study [AREDS] Research Group, Arch Ophthalmol, 121:1621-24 (2003)). GA refers to confluent areas of retinal pigment epithelial (RPE) cell death, with superimposed photoreceptor atrophy. GA has a substantial impact on visual function: approximately 40% of a subgroup of patients have been shown to lose at least three visual Snellen equivalent lines within 2 years (Sunness et al., Retina, 7: 204-10 (2007)). Although the cause of AMD is still largely unknown, age, smoking, diet, and genetics have been proposed as risk factors for AMD (Amabti et al., Surv Opthalmol, 48(3): 257-93 (2003); Gorin et al., Mol Aspects Med, 33: 467-486 (2012)), and the alternative complement pathway (ACP) has been implicated in AMD (de Jong, N. Engl J. Med., 355: 1474-1485 (2006)). Increased ACP activation is found in drusen, lipoprotein-like deposits in the space between the RPE and Bruch's membrane, which are a hallmark of AMD. Moreover, the role of ACP activation in AMD has been supported by human genetics (Yates et al., New Engl J Med, 357: 553-61 (2007)). Complement factor D is a rate-limiting enzyme that plays a key role in the activation of the alternative complement pathway (ACP). Evidence for the involvement of factor D in the pathogenesis of AMD includes a protective effect against oxidative stress-mediated photoreceptor degeneration in a mouse model of genetically deficient factor D (Rohrer et al., Invest Ophtalmol Vis Sci, 48: 5282-89 (2007)), and increased systemic activation of complement (including factor D) detected in the serum of AMD patients relative to controls, suggesting that AMD may be a systemic disease with local manifestations in the aging macula (Scholl et al., PLoS ONE, 3 (7): e2593 (2008)). Furthermore, multiple papers on the heritability of AMD have independently demonstrated that a single nucleotide polymorphism in complement factor H (CFH), Y402H, is strongly associated with an increased risk of developing both early and late AMD (Edwards et al., Science, 308(5720):421-4 (2005); Hageman et al., PNAS, 102(20):7227-32 (2005); Haines et al., Science, 208(5720):419-21 (2005); Klein et al., Science, 308(5720):385-9 (2005); Prosser et al., J. Exp. Med., 204(10):2277-83 (2007); Zareparsi et al., Am J. Hum. Genet, 77: 149-153 (2005). Other risk alleles include polymorphisms in the complement factor H (CFH) risk locus (rs10737680), the complement factor I (CFI) risk locus (rs4698775), the complement component 2/complement factor B (C2/CFB) risk locus (rs429608), and the complement component (C3) risk locus (rs2230199) (Fritsche et al., Nat Genet, 77: 149-153 (2005). Genet, 45: 433-439 (2013). CFI, CFH, C2, CFB and C3 are additional members of the complement pathway. For example, PCT publications WO2011/017229, WO2009/146204 and WO2009/134709 have been involved in additional SNPs associated with genes in the complement pathway and their association with AMD. However, none of these references disclose or suggest the correlation of the identified SNPs with how the patient's disease progresses over time or how well the patient responds to AMD treatment. In a prospective study of the genetic role of AMD progression, genetic variants in the complement pathway, such as SNPs, were associated with progression from medium-sized drusen to large drusen and from large drusen to GA or NY. Yu et al., Invest. Ophthalm. & Visual Sci., 53: 1548-56 (2012). The results suggest that genes associated with AMD may be involved in the transition between distinct AMD stages during progression. However, whether the identified genes are associated with the rate of disease progression (e.g., in late stages such as GA) is still unknown.

Currently, anti-VEGF (vascular endothelial growth factor) is the standard of care for the majority of cases of wet late-stage AMD. There is currently no effective treatment that halts or slows the progression of GA. There are no approved treatments that prevent the progression of GA, creating a significant unmet need for GA patients. Therefore, there is a need for improved methods to identify effective treatments for GA and to understand how to treat GA patients. Specifically, diagnostic methods for identifying patients who are at risk for an increased rate of GA progression and who may benefit from treatment with anti-Factor D antibodies would greatly benefit the clinical management of these patients. The present invention addresses these and other needs.

All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety for any purpose.

SUMMARY OF THE INVENTION

The present invention is based in part on the novel and surprising discovery gleaned from clinical trials that certain polymorphisms associated with genes in the complement pathway are reliable predictors of the rate of progression in AMD patients and their response to anti-Factor D therapy. The methods of treatment, diagnosis/prognosis, and prediction of response to treatment provided herein can be used for patients suffering from age-related macular degeneration.

One embodiment of the present invention provides identification with the AMD progress risk of increase (for example, mid-term or late AMD, such as wet (neovascular/exudative) AMD or geographic atrophy) individual method, described method comprises determining individual genotype, wherein will determine that carrying risk allele (for example, the polymorphism that degenerative disease-is relevant, the polymorphism that AMD-is relevant) individual identification is as the individual of AMD progress risk with increase (for example, mid-term or late AMD, such as wet (neovascular/exudative) AMD or geographic atrophy).In some embodiments, the AMD progress risk of increase comprises the progress from early stage to mid-term AMD and/or the progress from mid-term to late AMD.In some embodiments, described risk allele is the minor allele of selected SNP.In some embodiments, described risk allele is the main allele of selected SNP. In some embodiments, the increased risk of AMD progression includes progression from early to more advanced disease in various AMD stages, including early AMD, intermediate AMD, and late AMD, wherein early AMD is characterized by multiple small (<63 μm), or ≥1 medium drusen (≥63 μm and <125 μm); intermediate AMD is characterized by multiple medium or ≥1 large drusen (≥125 μm), often with hyperpigmentation or hypopigmentation of the retinal pigment epithelium; and late AMD is characterized by geographic atrophy (GA) or neovascular (wet) AMD. In some embodiments, the risk allele can be a complement factor I (CFI) risk allele, a complement factor H (CFH) risk allele, a complement component 2 (C2) risk allele, a complement factor B (CFB) risk allele, and/or a complement component 3 (C3) risk allele. In some embodiments, the CFI risk allele is the rs4698775:G allele, or an equivalent allele thereof, or a G comprised within the selected SNP rs4698775, or an alternative SNP in linkage disequilibrium with rs4698775. In some embodiments, the CFI risk allele is the rs17440077:G allele, or an equivalent allele thereof, or a G comprised within the selected SNP rs17440077, or an alternative SNP in linkage disequilibrium with rs17440077. In some embodiments, the CFH risk allele is the rs10737680:A allele, or an equivalent allele thereof, or an A comprised within the SNP rs10737680, or an alternative SNP in linkage disequilibrium with rs10737680. In some embodiments, the CFH risk allele is the rs1329428:G allele, or an equivalent allele thereof, or a G encompassed by SNP rs1329428, or an alternative SNP in linkage disequilibrium with rs1329428. In some embodiments, the C2 risk allele is the rs429608:G allele, or an equivalent allele thereof, or a G encompassed by SNP rs429608, or an alternative SNP in linkage disequilibrium with rs429608. In some embodiments, the CFB risk allele is the rs429608:G allele, or an equivalent allele thereof, or a G encompassed by SNP rs429608, or an alternative SNP in linkage disequilibrium with rs429608. In some embodiments, the C3 risk allele is the rs2230199:G allele, or an equivalent allele thereof, or an alternative SNP contained within the G of SNP rs2230199 or in linkage disequilibrium with rs2230199. In some embodiments, the linkage disequilibrium is a D' measure or an ^r2 measure. In some embodiments, the D' measure between the selected SNP and the alternative SNP is ≥0.60. In some embodiments, the D' measure between the selected SNP and the alternative SNP is ≥0.70, 0.80, or 0.90. In some embodiments, the D' measure between the selected SNP and the alternative SNP is 1.0. In some embodiments, the ^r2 measure between the selected SNP and the alternative SNP is ≥0.60. In some embodiments, the ^r2 measure between the selected SNP and the alternative SNP is ≥0.70, 0.80, or 0.90. In some embodiments, the ^r2 measure between the selected SNP and the surrogate SNP is 1.0. In some embodiments, the surrogate SNP is the SNP specified in Tables 4-7. In some embodiments, SNP rs4698775 is located at position 110590479 on human chromosome 4 (Genomic Reference Sequence Association GRCh37; UCSC Genome HG19 Assembly; February 2009). The G allele changes the nucleotide sequence from T to G. In some embodiments, SNP rs17440077 is located at position 110537567 on human chromosome 4 (Genomic Reference Sequence Association GRCh37; UCSC Genome HG19 Assembly; February 2009). The G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs10737680 is located at position 196679455 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009). The A allele changes the nucleotide sequence from C to A. In some embodiments, SNP rs1329428 is located at position 196702810 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009). The G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs429608 is located at position 31930462 on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009). The G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs2230199 is located at position 6718387 on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009). The G allele changes the nucleotide sequence from C to G and the encoded amino acid from arginine to glycosylamine. In some embodiments, the alternative SNP is located between the SEC24B gene and the EGF gene on human chromosome 4 (regarding rs4698775) (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009), between the SEC24B gene and the EGF gene on human chromosome 4 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs17440077), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs10 737680), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs1329428), between the SLC44A4 gene and the TNXB gene on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs429608), between the TNFSF14 gene and the VAV1 gene on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs2230199). In some embodiments, the alternative SNP is located within 500,000 base pairs upstream or downstream of the selected SNP. In some embodiments, a patient is determined to carry a CFI risk allele and/or a CFH risk allele and/or a C2 risk allele and/or a CFB risk allele and/or a C3 risk allele. In some embodiments, an individual is determined to carry 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., risk alleles for AMD. In some embodiments, the presence of risk alleles in an individual comprises determining the nature of nucleotides in a polymorphism in nucleic acid provided by a sample from the individual. In some embodiments, the nucleic acid sample comprises DNA. In some embodiments, the nucleic acid sample comprises RNA. In some embodiments, the nucleic acid sample is amplified. In some embodiments, the nucleic acid sample is amplified by polymerase chain reaction. In some embodiments, polymorphisms are detected by polymerase chain reaction or sequencing. In some embodiments, polymorphisms are detected by amplifying a target region comprising at least one polymorphism, hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions, and detecting the hybridization. In some embodiments, the polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (denaturing gradient gel electrophoresis (DGGE)), time temperature gradient electrophoresis (time temperature gradient electrophoresis (TTGE)), Zn (II) -cyclen polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high throughput SNP genotyping platform, molecular beacons , 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification. In some embodiments, the sample is from any biological sample from which genomic DNA can be isolated, for example, but not limited to, a tissue sample, a saliva sample, a cheek swab sample, blood, or other biological fluid containing genomic DNA. In some embodiments, the sample comprises DNA. In some embodiments, the sample comprises RNA. In some embodiments, the nature of the nucleotides that are polymorphic in the patient is determined by genotyping. In some embodiments, genotyping is performed by PCR analysis, sequence analysis, or LCR analysis. In some embodiments, when there is at least one allele comprising a nucleotide selected from the group consisting of: a G nucleotide at SNP rs4698775, a G nucleotide at SNP rs17440077, an A nucleotide at SNP rs10737680, a G nucleotide at SNP rs1329428, a G nucleotide at SNP rs429608, or a G nucleotide at SNP rs2230199, the patient is identified as having an increased risk of AMD progression (e.g., intermediate or late AMD, such as wet (neovascular/exudative) AMD or geographic atrophy). Patients were identified as being at increased risk for progression of AMD if they had one or two copies of the G allele of rs4698775 or rs17440077 associated with CH, or its equivalent allele, rs1329428 associated with CFH, or its equivalent allele, or rs429608 associated with C2/CFB, or its equivalent allele, or rs2230199 associated with C3, or one or two copies of the A allele of rs10737680 associated with CFH, or its equivalent allele. Patients were identified as being at reduced risk for progression of AMD if they did not have one or two copies of the G allele of rs4698775 or rs17440077 associated with CFI, or its equivalent allele, rs1329428 associated with CFH, or its equivalent allele, or rs429608 associated with C2/CFB, or its equivalent allele, or rs2230199 associated with C3, or one or two copies of the A allele of rs10737680 associated with CFH, or its equivalent allele.

One embodiment of the present invention provides the method for predicting AMD progress (for example, mid-term or late AMD, such as wet (neovascular/exudative) AMD or geographic atrophy), described method comprises determining the patient's genotype, wherein determining that the patient carrying risk allele (for example the polymorphism that AMD-is relevant) is accredited as the patient of the danger (for example mid-term or late AMD, such as wet (neovascular/exudative) AMD or geographic atrophy) of the AMD progress with increase.In some embodiments, the AMD progress risk of increase comprises the progress from early stage AMD to mid-term AMD and from mid-term to late AMD.In some embodiments, described risk allele is the minor allele of selected SNP.In some embodiments, described risk allele is the main allele of selected SNP. In some embodiments, the increased risk of AMD progression includes progression from early to more advanced disease in various AMD stages, including early AMD, intermediate AMD, and late AMD, wherein early AMD is characterized by multiple small (<63 μm), or ≥1 medium drusen (≥63 μm and <125 μm); intermediate AMD is characterized by multiple medium or ≥1 large drusen (≥125 μm), often with hyperpigmentation or hypopigmentation of the retinal pigment epithelium; and late AMD is characterized by geographic atrophy (GA) or neovascular (wet) AMD. In some embodiments, the risk allele can be a complement factor I (CFI) risk allele, a complement factor H (CFH) risk allele, a complement component 2 (C2) risk allele, a complement factor B (CFB) risk allele, and/or a complement component 3 (C3) risk allele. In some embodiments, the CFI risk allele is the rs4698775:G allele, or an equivalent allele thereof, or a G contained in the selected SNP rs4698775, or an alternative SNP contained in linkage disequilibrium with rs4698775. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs4698775. In some embodiments, the CFI risk allele is the rs17440077 G: allele, or an equivalent allele thereof, or a G contained in the selected SNP rs17440077, or an alternative SNP contained in linkage disequilibrium with rs17440077. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs17440077. In some embodiments, the CFH risk allele is the rs10737680:A allele, or an equivalent allele thereof, or an A contained within SNP rs10737680, or an alternative SNP contained in linkage disequilibrium with rs10737680. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the selected risk allele of SNP rs10737680. In some embodiments, the CFH risk allele is the rs1329428:G allele, or an equivalent allele thereof, or a G contained within SNP rs1329428, or an alternative SNP contained in linkage disequilibrium with rs1329428. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the selected risk allele of SNP rs1329428. In some embodiments, the C2 risk allele is the rs429608:G allele, or an equivalent allele thereof, or a G contained in SNP rs429608, or an alternative SNP contained in linkage disequilibrium with rs429608. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs429608. In some embodiments, the CFB risk allele is the rs429608:G allele, or an equivalent allele thereof, or a G contained in SNP rs429608, or an alternative SNP contained in linkage disequilibrium with rs429608. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs429608. In some embodiments, the C3 risk allele is the rs2230199:G allele, or an equivalent allele thereof, or a G contained in SNP rs2230199, or an alternative SNP contained in linkage disequilibrium with rs2230199. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs2230199. In some embodiments, the linkage disequilibrium is a D' measure or an ^r2 measure. In some embodiments, the D' measure between the selected SNP and the alternative SNP is ≥ 0.60. In some embodiments, the D' measure between the selected SNP and the alternative SNP is ≥ 0.70, 0.80, or 0.90. In some embodiments, the D' measure between the selected SNP and the alternative SNP is 1.0. In some embodiments, the ^r2 measure between the selected SNP and the alternative SNP is ≥ 0.60. In some embodiments, the ^r2 measure between the selected SNP and the alternative SNP is ≥0.70, 0.80 or 0.90. In some embodiments, the ^r2 measure between the selected SNP and the alternative SNP is 1.0. In some embodiments, the alternative SNP is the SNP specified in Tables 4-7. In some embodiments, SNP rs4698775 is located at position 110590479 on human chromosome 4 (Genome Reference Sequence Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009), and the G allele changes the nucleotide sequence from T to G. In some embodiments, SNP rs17440077 is located at position 110537567 on human chromosome 4 (Genome Reference Sequence Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs10737680 is located at position 196679455 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the A allele changes the nucleotide sequence from C to A. In some embodiments, SNP rs1329428 is located at position 196702810 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs429608 is located at position 31930462 on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs2230199 is located at position 6718387 on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009), and the G allele changes the nucleotide sequence from C to G and the encoded amino acid from arginine to glycine. In some embodiments, the alternative SNP is located between the SEC24B gene and the EGF gene on human chromosome 4 (regarding rs4698775) (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009), between the SEC24B gene and the EGF gene on human chromosome 4 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs17440077), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs10 737680), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs1329428), between the SLC44A4 gene and the TNXB gene on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs429608), between the TNFSF14 gene and the VAV1 gene on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs2230199). In some embodiments, the alternative SNP is located within 500,000 base pairs upstream and downstream of the selected SNP. In some embodiments, the alternative SNP is located within 500,000 base pairs upstream or downstream of the selected SNP. In some embodiments, the patient is determined to carry a CFI risk allele and/or a CFH risk allele and/or a C2 risk allele and/or a CFB risk allele and/or a C3 risk allele. In some embodiments, the patient is determined to carry 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., AMD risk alleles. In some embodiments, the presence of risk alleles in the patient includes determining the nature of the nucleotides in a polymorphism from a nucleic acid provided by a patient sample. In some embodiments, the nucleic acid sample comprises DNA. In some embodiments, the nucleic acid sample comprises RNA. In some embodiments, the nucleic acid sample is amplified. In some embodiments, the nucleic acid sample is amplified by polymerase chain reaction. In some embodiments, polymorphisms are detected by polymerase chain reaction or sequencing. In some embodiments, polymorphisms are detected by amplifying a target region comprising at least one polymorphism, hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions, and detecting the hybridization. In some embodiments, the polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platform, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification. In some embodiments, the sample is any biological sample from which genomic DNA can be isolated, such as, but not limited to, a tissue sample, a saliva sample, a cheek swab sample, blood, or other biological fluid containing genomic DNA. In some embodiments, the nature of the polymorphic nucleotides in the patient is determined by genotyping. In some embodiments, genotyping is performed by PCR analysis, sequence analysis, or LCR analysis. In some embodiments, when there is at least one allele comprising a nucleotide selected from the group consisting of: a G nucleotide at SNP rs4698775, a G nucleotide at SNP rs17440077, an A nucleotide at SNP rs10737680, a G nucleotide at SNP rs1329428, a G nucleotide at SNP rs429608, or a G nucleotide at SNP rs2230199, the patient is identified as having an increased risk of AMD progression (e.g., intermediate or late AMD, such as wet (neovascular/exudative) AMD or geographic atrophy). Patients were identified as being at increased risk for progression to more advanced AMD if they had one or two copies of the G allele of rs4698775 or rs17440077 associated with CFI, or its equivalent allele, rs1329428 associated with CFH, or its equivalent allele, or rs429608 associated with C2/CFB, or its equivalent allele, or rs2230199 associated with C3, or one or two copies of the A allele of rs1329428 associated with CFH, or its equivalent allele. If the patient does not have one or two copies of the G allele of rs4698775 associated with CFI or its equivalent allele, rs1329428 associated with CFH or its equivalent allele, or rs429608 associated with C2/CFB or its equivalent allele, or rs2230199 associated with C3 or its equivalent allele, or does not have one or two copies of the A allele of rs10737680 associated with CFH or its equivalent allele, then the patient is identified as being at reduced risk of progression to more advanced AMD.

The present invention relates, at least in part, to methods for treating degenerative diseases (e.g., AMD) in patients using anti-Factor D antibodies or antigen-binding fragments thereof. In one aspect, the present invention relates to methods and compositions for treating a variety of degenerative conditions (e.g., age-related macular degeneration) using complement inhibitors. In one embodiment, the degenerative disease is an ocular degenerative disease. In one embodiment, the ocular degenerative disease is age-related macular degeneration. In any one of the embodiments disclosed herein, the complement inhibitor is an anti-Factor D antibody, or an antigen-binding fragment thereof. In some embodiments, the antibody is lampalizumab. Therefore, one embodiment of the present invention provides a method for treating age-related macular degeneration in a patient, the method comprising administering an effective amount of an anti-Factor D antibody, or an antigen-binding fragment thereof, to a patient diagnosed with age-related macular degeneration, wherein the patient carries one or more risk alleles for age-related macular degeneration (e.g., AMD-associated polymorphisms). In some embodiments, the risk allele is a minor allele of a selected SNP. In some embodiments, the risk allele is a major allele of a selected SNP. In some embodiments, the risk allele can be a CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB risk allele and/or a C3 risk allele. In some embodiments, the risk allele is a CFI risk allele. In some embodiments, the CFI risk allele is the rs4698775:G allele, or an equivalent allele thereof, or a G contained in the selected SNP rs4698775, or an alternative SNP in linkage disequilibrium with rs4698775. In some embodiments, the alternative SNP comprises a minor allele or an allele located in the same haplotype as the risk allele of the selected SNP rs4698775. In some embodiments, the CFI risk allele is the rs17440077G: allele, or an equivalent allele thereof, or a G comprised within the selected SNP rs17440077, or an alternative SNP comprised in linkage disequilibrium with rs17440077. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs17440077. In some embodiments, the CFH risk allele is the rs10737680A: allele, or an equivalent allele thereof, or an A comprised within the SNP rs10737680, or an alternative SNP comprised in linkage disequilibrium with rs10737680. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs10737680. In some embodiments, the CFH risk allele is the rs1329428:G allele, or an equivalent allele thereof, or a G comprised within SNP rs1329428, or an alternative SNP in linkage disequilibrium with rs1329428. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the selected risk allele of SNP rs1329428. In some embodiments, the C2 risk allele is the rs429608:G allele, or an equivalent allele thereof, or a G comprised within SNP rs429608, or an alternative SNP in linkage disequilibrium with rs429608. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the selected risk allele of SNP rs429608. In some embodiments, the CFB risk allele is the rs429608:G allele, or an equivalent allele thereof, or a G contained in SNP rs429608, or an alternative SNP contained in linkage disequilibrium with rs429608. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs429608. In some embodiments, the C3 risk allele is the rs2230199:G allele, or an equivalent allele thereof, or a G contained in SNP rs2230199, or an alternative SNP contained in linkage disequilibrium with rs2230199. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs2230199. In some embodiments, the linkage disequilibrium is a D' measure or an ^r2 measure. In some embodiments, the D' between the selected SNP and the alternative SNP measures ≥0.60. In some embodiments, the D' between the selected SNP and the alternative SNP measures ≥0.70, 0.80 or 0.90. In some embodiments, the D' between the selected SNP and the alternative SNP measures ≥1.0. In some embodiments, the r ² between the selected SNP and the alternative SNP measures ≥0.60. In some embodiments, the r ² between the selected SNP and the alternative SNP measures ≥0.70, 0.80 or 0.90. In some embodiments, the r ² between the selected SNP and the alternative SNP measures ≥1.0. In some embodiments, the alternative SNP is the SNP specified in Tables 4-7. In some embodiments, SNPrs4698775 is located at position 110590479 on human chromosome 4 (Genome Reference Sequence Consortium GRCh37; UCSC genome HG19 assembly; February 2009). The G allele changes the nucleotide sequence from T to G. In some embodiments, SNPrs17440077 is located at position 110537567 on human chromosome 4 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009). The G allele changes the nucleotide sequence from A to G. In some embodiments, SNPrs10737680 is located at position 196679455 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009). The A allele changes the nucleotide sequence from C to A. In some embodiments, SNPrs1329428 is located at position 196702810 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009). The G allele changes the nucleotide sequence from A to G. In some embodiments, SNPrs429608 is located at position 31930462 on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009). The G allele changes the nucleotide sequence from A to G. In some embodiments, SNPrs2230199 is located at position 6718387 on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009). The G allele changes the nucleotide sequence from C to G, and the encoded amino acid from arginine to glycine. In some embodiments, the alternative SNP is located between the SEC24B gene and the EGF gene on human chromosome 4 (regarding rs4698775) (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009), between the SEC24B gene and the EGF gene on human chromosome 4 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs17440077), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs10 737680), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (about rs1329428), between the SLC44A4 gene and the TNXB gene on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (about rs429608), between the TNFSF14 gene and the VAV1 gene on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (about rs2230199). In some embodiments, the alternative SNP is located within 500,000 base pairs upstream and downstream of the selected SNP. In some embodiments, the alternative SNP is located within 500,000 base pairs upstream or downstream of the selected SNP. In some embodiments, the patient is determined to carry a CFI risk allele and/or a CFH risk allele and/or a C2 risk allele and/or a CFB risk allele and/or a C3 risk allele. In some embodiments, the patient is determined to carry 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., AMD risk alleles. In some embodiments, the presence of risk alleles in the patient includes determining the nature of the nucleotides in a polymorphism from a nucleic acid provided by a patient sample. In some embodiments, the nucleic acid sample comprises DNA. In some embodiments, the nucleic acid sample comprises RNA. In some embodiments, the nucleic acid sample is amplified. In some embodiments, the nucleic acid sample is amplified by polymerase chain reaction. In some embodiments, polymorphisms are detected by polymerase chain reaction or sequencing. In some embodiments, polymorphisms are detected by amplifying a target region comprising at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions, and detecting the hybridization. In some embodiments, the polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platforms, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification. In some embodiments, described sample is from any biological sample that can separate genomic DNA, for example, but not limited to, tissue sample, saliva sample, cheek swab sample, blood, or other biological fluids that comprise genomic DNA.In some embodiments, determine the character of the nucleotide that is in polymorphism in the patient by genotyping.In some embodiments, genotyping is carried out by PCR analysis, sequence analysis or LCR analysis.In some embodiments, when there is at least one allelotrope that comprises the nucleotide that is selected from the group consisting of: at the G nucleotide of SNP rs4698775, at the G nucleotide of SNPrs17440077, at the A nucleotide of SNP rs10737680, at the G nucleotide of SNP rs1329428, at the G nucleotide of SNPrs429608 or at the G nucleotide of SNP rs2230199, described patient is accredited as having increased AMD progress danger and more likely to respond and comprise the treatment of anti-factor D antibody or its Fab. Patients are identified as having an increased risk of progression to AMD and as being more likely to respond to a treatment comprising an anti-Factor D antibody or antigen-binding fragment thereof if they have one or two copies of the G allele of rs4698775 or rs17440077 associated with CFI, or its equivalent allele, rs1329428 associated with CFH, or its equivalent allele, or rs429608 associated with C2/CFB, or its equivalent allele, or rs2230199 associated with C3, or one or two copies of the A allele of rs10737680 associated with CFH, or its equivalent allele. If the patient does not have one or two copies of the G allele of rs4698775 associated with CFI or its equivalent allele, rs1329428 associated with CFH or its equivalent allele, or rs429608 associated with C2/CFB or its equivalent allele, or rs2230199 associated with C3 or its equivalent allele, or does not have one or two copies of the A allele of rs10737680 associated with CFH or its equivalent allele, the patient is identified as having a reduced risk of AMD progression and is less likely to respond to treatment comprising an anti-D antibody or its antigen-binding fragment. In one embodiment, the patient's studied eye has a BCVA of 20/25-20/400. In one embodiment, the patient's studied eye has a BCVA of 20/25-20/100. In one embodiment, the patient's studied eye has a BCVA of 20/50-20/400. In one embodiment, the eye of the patient being studied has a BCVA of 20/50-20/100. In one embodiment, the eye of the patient being studied has a BCVA of better than 20/25 or worse than 20/400. In one embodiment, BCVA is determined using an ETDRS table. In some embodiments, the antibody or its antigen-binding fragment is administered intravitreally. In some embodiments, the age-related macular degeneration is dry AMD. In some embodiments, the dry AMD is late dry AMD. In some embodiments, the late dry AMD is geographic atrophy. In some embodiments, compared with control patients not receiving antibody treatment, after administering the antibody, the patient has the average change in the geographic atrophy (GA) area that decreases. In some embodiments, the average change in GA area is determined by measuring the GA area via standard imaging methods (e.g., fundus autofluorescence (FAF) or color fundus photography (CFP)). In some embodiments, the age-related macular degeneration is early AMD or mid-term AMD. In some embodiments, patients with early AMD or intermediate AMD have a reduction or delay in the appearance of clinical signs (e.g., can include measuring the number and size of drusen (for early and intermediate AMD) and monitoring hypopigmentation and hyperpigmentation associated with drusen (for intermediate AMD)). In some embodiments, the method further comprises administering a second drug to the subject. In some embodiments, the second drug is a VEGF inhibitor.

Other embodiments of the present invention provide methods for identifying patients with degenerative diseases (e.g., AMD patients) who may benefit from and/or respond to treatment with anti-Factor D antibodies, the method comprising determining the patient's genotype, wherein patients carrying risk alleles are identified as patients who may benefit from treatment with anti-Factor D antibodies or their antigen-binding fragments. In some embodiments, the method further comprises selecting a treatment comprising an anti-Factor D antibody or its antigen-binding fragment. In some embodiments, the antibody is lampalizumab. In one embodiment, the degenerative disease is an ocular degenerative disease. In one embodiment, the ocular degenerative disease is age-related macular degeneration. In some embodiments, the risk allele is a minor allele of a selected SNP. In some embodiments, the risk allele is a major allele of a selected SNP. In some embodiments, the risk allele (e.g., an AMD-associated polymorphism) can be a CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB risk allele, and/or a C3 risk allele. In some embodiments, the risk allele is a CFI risk allele. In some embodiments, the CFI allele is rs4698775:G allele or an equivalent allele thereof, or a G contained in the selected SNP rs4698775, or an alternative SNP contained in linkage disequilibrium with rs4698775. In some embodiments, the alternative SNP contains a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs4698775. In some embodiments, the CFI allele is rs17440077:G allele or an equivalent allele thereof, or a G contained in the selected SNP rs17440077, or an alternative SNP contained in linkage disequilibrium with rs17440077. In some embodiments, the alternative SNP contains a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs17440077. In some embodiments, the CFH risk allele is rs10737680:A allele or an equivalent allele thereof, or an A contained in the selected SNP rs10737680, or an alternative SNP contained in linkage disequilibrium with rs10737680. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs10737680. In some embodiments, the CFH risk allele is rs1329428:G allele or an equivalent allele thereof, or a G contained in the selected SNP rs1329428, or an alternative SNP contained in linkage disequilibrium with rs1329428. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs1329428. In some embodiments, the C2 risk allele is the rs429608:G allele, or an equivalent allele thereof, or a G contained in the selected SNP rs429608, or an alternative SNP contained in linkage disequilibrium with rs429608. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs429608. In some embodiments, the CFB risk allele is the rs429608:G allele, or an equivalent allele thereof, or a G contained in the selected SNP rs429608, or an alternative SNP contained in linkage disequilibrium with rs429608. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs429608. In some embodiments, the C3 risk allele is the rs2230199:G allele or an equivalent allele thereof, or is comprised of the G allele of the selected SNP rs2230199, or is comprised of an alternative SNP in linkage disequilibrium with rs2230199. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs2230199. In some embodiments, the linkage disequilibrium is a D' measure or an ^r2 measure. In some embodiments, the D' measure between the selected SNP and the alternative SNP is ≥0.60. In some embodiments, the D' measure between the selected SNP and the alternative SNP is ≥0.70, 0.80, or 0.90. In some embodiments, the D' measure between the selected SNP and the alternative SNP is 1.0. In some embodiments, the ^r2 measure between the selected SNP and the alternative SNP is ≥0.60. In some embodiments, the ^r2 measure between the selected SNP and the surrogate SNP is ≥0.70, 0.80 or 0.90. In some embodiments, the ^r2 measure between the selected SNP and the surrogate SNP is 1.0. In some embodiments, the surrogate SNP is the SNP specified in Tables 4-7. In some embodiments, SNP rs4698775 is located at position 110590479 on human chromosome 4 (Genome Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from T to G. In some embodiments, SNPrs17440077 is located at position 110537567 on human chromosome 4 (Genome Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs10737680 is located at position 196679455 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the A allele changes the nucleotide sequence from C to A. In some embodiments, SNP rs1329428 is located at position 196702810 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs429608 is located at position 31930462 on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs2230199 is located at position 6718387 on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009), and the G allele changes the nucleotide sequence from C to G and the encoded amino acid from arginine to glycine. In some embodiments, the alternative SNP is located between the SEC24B gene and the EGF gene on human chromosome 4 (regarding rs4698775) (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009), between the SEC24B gene and the EGF gene on human chromosome 4 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs17440077), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs10 737680), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs1329428), between the SLC44A4 gene and the TNXB gene on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs429608), between the TNFSF14 gene and the VAV1 gene on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs2230199). In some embodiments, the alternative SNP is located within 500,000 base pairs upstream or downstream of the selected SNP. In some embodiments, the patient is determined to carry a CFI risk allele and/or a CFH risk allele and/or a C2 risk allele and/or a CFB risk allele and/or a C3 risk allele. In some embodiments, the patient is determined to carry 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., AMD risk alleles. In some embodiments, the presence of risk alleles in the patient includes determining the nature of the nucleotides in a polymorphism from a nucleic acid provided by a patient sample. In some embodiments, the nucleic acid sample comprises DNA. In some embodiments, the nucleic acid sample comprises RNA. In some embodiments, the nucleic acid sample is amplified. In some embodiments, the nucleic acid sample is amplified by polymerase chain reaction. In some embodiments, polymorphisms are detected by polymerase chain reaction or sequencing. In some embodiments, polymorphisms are detected by amplifying a target region comprising at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to at least one polymorphism under stringent conditions, and detecting the hybridization. In some embodiments, the polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platform, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification. In some embodiments, the sample is any biological sample from which genomic DNA can be isolated, such as, but not limited to, a tissue sample, a saliva sample, a cheek swab sample, blood, or other biological fluid containing genomic DNA. In some embodiments, the sample comprises DNA. In some embodiments, the sample comprises RNA. In some embodiments, the properties of the polymorphic nucleotides in the patient are determined by genotyping. In some embodiments, genotyping is performed by PCR analysis, sequence analysis, or LCR analysis. In some embodiments, when there is at least one allele comprising a nucleotide selected from the group consisting of: a G nucleotide at SNP rs4698775, a G nucleotide at SNP rs17440077, an A nucleotide at SNP rs10737680, a G nucleotide at SNP rs1329428, a G nucleotide at SNP rs429608, or a G nucleotide at SNP rs2230199, the patient is identified as having an increased risk of AMD progression and being more likely to benefit from and/or respond to a treatment comprising an anti-Factor D antibody or an antigen-binding fragment thereof. Patients were identified as being at increased risk for progression of AMD if they had one or two copies of the G allele of rs4698775 associated with CFI, or its equivalent allele, rs1329428 associated with CFH, or its equivalent allele, or rs429608 associated with C2/CFB, or its equivalent allele, or rs2230199 associated with C3, or one or two copies of the A allele of rs10737680 associated with CFH, or its equivalent allele. If the patient does not have one or two copies of the G allele of rs4698775 relevant to CFI or the allele equivalent thereof, the rs1329428 relevant to CFH or the allele equivalent thereof, or the rs429608 relevant to C2/CFB or the allele equivalent thereof, or the rs2230199 relevant to C3 or the allele equivalent thereof, or does not have one or two copies of the A allele of rs10737680 relevant to CFH or the allele equivalent thereof, then the patient is identified as having a reduced risk of progressing to more late stage AMD. In one embodiment, the patient's studied eyes have a BCVA of 20/25-20/400. In one embodiment, the patient's studied eyes have a BCVA of 20/25-20/100. In one embodiment, the patient's studied eyes have a BCVA of 20/50-20/400. In one embodiment, the patient's studied eyes have a BCVA of 20/50-20/100. In one embodiment, the eye of the patient being studied has a BCVA that is better than 20/25 or worse than 20/400. In one embodiment, BCVA is determined using an ETDRS table. In some embodiments, the antibody or its antigen-binding fragment is administered intravitreally. In some embodiments, the age-related macular degeneration is dry AMD. In some embodiments, the dry AMD is late stage dry AMD. In some embodiments, the late stage dry AMD is geographic atrophy. In some embodiments, the age-related macular degeneration is early stage AMD or mid-stage AMD. In some embodiments, the patient suffering from early stage AMD or mid-stage AMD has a reduction or delay in the appearance of clinical signs (for example, the number and size of measuring drusen (for early and mid-stage AMD) and monitoring the hypopigmentation and hyperpigmentation (for mid-stage AMD) associated with drusen can be included).

Another embodiment of the present invention is to provide a method for optimizing the therapeutic efficacy of a degenerative disease (e.g., AMD) treatment, the method comprising determining the patient's genotype, wherein it is determined that patients carrying a risk allele (e.g., an AMD-associated polymorphism) are more likely to respond to treatment with an anti-Factor D antibody or its antigen-binding fragment. In one embodiment, the degenerative disease is an ocular degenerative disease. In one embodiment, the ocular degenerative disease is age-related macular degeneration. In some embodiments, the antibody is lampalizumab. In some embodiments, the risk allele is the minor allele of a selected SNP. In some embodiments, the risk allele is the major allele of a selected SNP. In some embodiments, the risk allele can be a CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB allele, and/or a C3 risk allele. In some embodiments, the risk allele is a CFI risk allele. In some embodiments, the CFI risk allele is the rs4698775:G allele, or an equivalent allele thereof, or a G contained in the selected SNP rs4698775, or an alternative SNP contained in linkage disequilibrium with rs4698775. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs4698775. In some embodiments, the CFI risk allele is the rs17440077:G allele, or an equivalent allele thereof, or a G contained in the selected SNP rs17440077, or an alternative SNP contained in linkage disequilibrium with rs17440077. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs17440077. In some embodiments, the CFH risk allele is the rs10737680:A allele, or an equivalent allele thereof, or an A contained within the selected SNP rs10737680, or an alternative SNP contained in linkage disequilibrium with rs10737680. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs10737680. In some embodiments, the CFH risk allele is the rs1329428:G allele, or an equivalent allele thereof, or a G contained within the selected SNP rs1329428, or an alternative SNP contained in linkage disequilibrium with rs1329428. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs1329428. In some embodiments, the C2 risk allele is the rs429608:G allele, or an equivalent allele thereof, or a G contained in the selected SNP rs429608, or an alternative SNP contained in linkage disequilibrium with rs429608. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs429608. In some embodiments, the CFB risk allele is the rs429608:G allele, or an equivalent allele thereof, or a G contained in the selected SNP rs429608, or an alternative SNP contained in linkage disequilibrium with rs429608. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs429608. In some embodiments, the C3 risk allele is the rs2230199:G allele, or an equivalent allele thereof, or an alternative SNP that is included in the G of the selected SNP rs2230199 or is included in linkage disequilibrium with rs2230199. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs2230199. In some embodiments, the linkage disequilibrium is a D' measure or an ^r2 measure. In some embodiments, the D' measure between the selected SNP and the alternative SNP is ≥0.60. In some embodiments, the D' measure between the selected SNP and the alternative SNP is ≥0.70, 0.80, or 0.90. In some embodiments, the D' measure between the selected SNP and the alternative SNP is 1.0. In some embodiments, the ^r2 measure between the selected SNP and the alternative SNP is ≥0.60. In some embodiments, the ^r2 measure between the selected SNP and the alternative SNP is ≥0.70, 0.80 or 0.90. In some embodiments, the ^r2 measure between the selected SNP and the alternative SNP is 1.0. In some embodiments, the alternative SNP is the SNP specified in Tables 4-7. In some embodiments, SNP rs4698775 is located at position 110590479 on human chromosome 4 (Genome Reference Sequence Association GRCh37; UCSC Genome HG19 Assembly; February 2009), and the G allele changes the nucleotide sequence from T to G. In some embodiments, SNP rs17440077 is located at position 110537567 on human chromosome 4 (Genome Reference Sequence Association GRCh37; UCSC Genome HG19 Assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rsI0737680 is located at position 196679455 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the A allele changes the nucleotide sequence from C to A. In some embodiments, SNP rs1329428 is located at position 196702810 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs429608 is located at position 31930462 on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs2230199 is located at position 6718387 on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009), and the G allele changes the nucleotide sequence from C to G and the encoded amino acid from arginine to glycine. In some embodiments, the alternative SNP is located between the SEC24B gene and the EGF gene on human chromosome 4 (regarding rs4698775) (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009), between the SEC24B gene and the EGF gene on human chromosome 4 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs17440077), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs10 737680), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs1329428), between the SLC44A4 gene and the TNXB gene on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs429608), between the TNFSF14 gene and the VAV1 gene on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs2230199). In some embodiments, the alternative SNP is located within 500,000 base pairs upstream or downstream of the selected SNP. In some embodiments, the alternative SNP is located within 500 base pairs upstream and downstream of the selected SNP. In some embodiments, the patient is determined to carry a CFI risk allele and/or a CFH risk allele and/or a C2 risk allele and/or a CFB risk allele and/or a C3 risk allele. In some embodiments, the patient is determined to carry 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., AMD risk alleles. In some embodiments, the presence of risk alleles in the patient comprises determining the properties of nucleotides in a polymorphic nucleic acid provided by a patient sample. In some embodiments, the nucleic acid sample comprises DNA. In some embodiments, the nucleic acid sample comprises RNA. In some embodiments, the nucleic acid sample is amplified. In some embodiments, the nucleic acid sample is amplified by polymerase chain reaction. In some embodiments, polymorphisms are detected by polymerase chain reaction or sequencing. In some embodiments, polymorphisms are detected by amplifying a target region comprising at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to at least one polymorphism under stringent conditions, and detecting the hybridization. In some embodiments, the polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platform, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification. In some embodiments, the sample is any biological sample from which genomic DNA can be separated, such as, but not limited to, a tissue sample, a saliva sample, a cheek swab sample, blood, or other biological fluids comprising genomic DNA. In some embodiments, the sample comprises DNA. In some embodiments, the sample comprises RNA. In some embodiments, the character of the nucleotides in the polymorphism is determined in the patient by genotyping. In some embodiments, genotyping is carried out by PCR analysis, sequence analysis or LCR analysis. In some embodiments, when there is at least one allele comprising the nucleotides selected from the group consisting of: at the G nucleotides of SNP rs4698775, at the G nucleotides of SNP rs17440077, at the A nucleotides of SNP rs10737680, at the G nucleotides of SNP rs1329428, at the G nucleotides of SNP rs429608 or at the G nucleotides of SNP rs2230199, the patient is identified as having increased AMD progression risk, and is more likely to benefit from the treatment comprising anti-factor D antibodies or their antigen-binding fragments. In one embodiment, the patient is accredited as being in the danger of AMD progress of increase if the patient has one or two copies of the rs4698775 relevant to CFI or the G allele of rs17440077 or the allele of its equivalent, the rs1329428 relevant to CFH or the allele of its equivalent, or the rs429608 relevant to C2/CFB or the allele of its equivalent, or the rs2230199 relevant to C3 or the allele of its equivalent, or have one or two copies of the A allele of rs10737680 relevant to CFH or the allele of its equivalent, described patient is accredited as being in the danger of AMD progress of increase.In one embodiment, the eye that patient is studied has the BCVA of 20/25-20/400.In one embodiment, the eye that patient is studied has the BCVA of 20/25-20/100.In one embodiment, the eye that patient is studied has the BCVA of 20/50-20/400. In one embodiment, the eye studied by the patient has a BCVA of 20/50-20/100. In one embodiment, the eye studied by the patient has a BCVA better than 20/25 or worse than 20/400. In one embodiment, BCVA is determined using an ETDRS table. In some embodiments, the antibody or its antigen-binding fragment is administered intravitreally. In some embodiments, the age-related macular degeneration is dry AMD. In some embodiments, the dry AMD is late dry AMD. In some embodiments, the late dry AMD is geographic atrophy. In some embodiments, compared with control patients not receiving antibody treatment, after applying the antibody, the patient has the average change in the geographic atrophy (GA) area that decreases. In some embodiments, the average change in GA area is determined by measuring the GA area via standard imaging methods (e.g., fundus autofluorescence (FAF) or color fundus photography (CFP)). In some embodiments, the age-related macular degeneration is early AMD or mid-term AMD. In some embodiments, patients with early AMD or intermediate AMD have a reduction or delay in the appearance of clinical signs (e.g., can include measuring the number and size of drusen (for early and intermediate AMD) and monitoring hypopigmentation and hyperpigmentation associated with drusen (for intermediate AMD)). In some embodiments, the method further comprises administering a second drug to the subject. In some embodiments, the second drug is a VEGF inhibitor.

Another embodiment of the present invention provides a method for predicting the response of a patient with a degenerative disease (e.g., AMD) to treatment with an anti-factor D antibody or its antigen-binding fragment, the method comprising determining the patient's genotype, wherein the patient carrying the risk allele is identified as having an increased risk of AMD progression (e.g., AG progression) and is more likely to respond to treatment with an anti-factor D antibody or its antigen-binding fragment. In one embodiment, the degenerative disease is an ocular degenerative disease. In one embodiment, the ocular degenerative disease is age-related macular degeneration. In some embodiments, the antibody is lampalizumab. In some embodiments, the risk allele is the minor allele of the selected SNP. In some embodiments, the risk allele is the major allele of the selected SNP. In some embodiments, the risk allele (e.g., AMD-associated polymorphism) can be a CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB risk allele, and/or a C3 risk allele. In some embodiments, the risk allele is a CFI risk allele. In some embodiments, the CFI risk allele is the rs4698775:G allele, or an equivalent allele thereof, or a G contained in the selected SNP rs4698775, or an alternative SNP contained in linkage disequilibrium with rs4698775. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs4698775. In some embodiments, the CFI risk allele is the rs17440077:G allele, or an equivalent allele thereof, or a G contained in the selected SNP rs17440077, or an alternative SNP contained in linkage disequilibrium with rs17440077. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs17440077. In some embodiments, the CFH risk allele is the rs10737680:A allele, or an equivalent allele thereof, or an A contained in the selected SNP rs10737680, or an alternative SNP contained in linkage disequilibrium with rs10737680. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs10737680. In some embodiments, the CFH risk allele is the rs1329428:G allele, or an equivalent allele thereof, or a G contained in the selected SNP rs1329428, or an alternative SNP contained in linkage disequilibrium with rs1329428. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs1329428. In some embodiments, the C2 risk allele is the rs429608:G allele, or an equivalent allele thereof, or a G contained in the selected SNP rs429608, or an alternative SNP contained in linkage disequilibrium with rs429608. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs429608. In some embodiments, the CFB risk allele is the rs429608:G allele, or an equivalent allele thereof, or a G contained in the selected SNP rs429608, or an alternative SNP contained in linkage disequilibrium with rs429608. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs429608. In some embodiments, the C3 risk allele is the rs2230199:G allele, or an equivalent allele thereof, or an alternative SNP that is included in the G of the selected SNP rs2230199 or is included in linkage disequilibrium with rs2230199. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs2230199. In some embodiments, the linkage disequilibrium is a D' measure or an ^r2 measure. In some embodiments, the D' measure between the selected SNP and the alternative SNP is ≥0.60. In some embodiments, the D' measure between the selected SNP and the alternative SNP is ≥0.70, 0.80, or 0.90. In some embodiments, the D' measure between the selected SNP and the alternative SNP is 1.0. In some embodiments, the ^r2 measure between the selected SNP and the alternative SNP is ≥0.60. In some embodiments, the ^r2 measure between the selected SNP and the surrogate SNP is ≥0.70, 0.80 or 0.90. In some embodiments, the ^r2 measure between the selected SNP and the surrogate SNP is 1.0. In some embodiments, the surrogate SNP is the SNP specified in Tables 4-7. In some embodiments, SNP rs4698775 is located at position 110590479 on human chromosome 4 (Genome Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from T to G. In some embodiments, SNP rs17440077 is located at position 110537567 on human chromosome 4 (Genome Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs10737680 is located at position 196679455 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the A allele changes the nucleotide sequence from C to A. In some embodiments, SNP rs1329428 is located at position 196702810 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs429608 is located at position 31930462 on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs2230199 is located at position 6718387 on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009), and the G allele changes the nucleotide sequence from C to G and the encoded amino acid from arginine to glycine. In some embodiments, the alternative SNP is located between the SEC24B gene and the EGF gene on human chromosome 4 (regarding rs4698775) (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009), between the SEC24B gene and the EGF gene on human chromosome 4 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs17440077), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs10 737680), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs1329428), between the SLC44A4 gene and the TNXB gene on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs429608), between the TNFSF14 gene and the VAV1 gene on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs2230199). In some embodiments, the alternative SNP is located within 500,000 base pairs upstream and downstream of the selected SNP. In some embodiments, the patient is determined to carry a CFI risk allele and/or a CFH risk allele and/or a C2 risk allele and/or a CFB risk allele and/or a C3 risk allele. In some embodiments, the patient is determined to carry 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., AMD risk alleles. In some embodiments, the presence of risk alleles in the patient includes determining the nature of the nucleotides in a polymorphism from a nucleic acid provided by a patient sample. In some embodiments, the nucleic acid sample comprises DNA. In some embodiments, the nucleic acid sample comprises RNA. In some embodiments, the nucleic acid sample is amplified. In some embodiments, the nucleic acid sample is amplified by polymerase chain reaction. In some embodiments, polymorphisms are detected by polymerase chain reaction or sequencing. In some embodiments, polymorphisms are detected by amplifying a target region comprising at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to at least one polymorphism under stringent conditions, and detecting the hybridization. In some embodiments, the polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platforms, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification. In some embodiments, the sample is any biological sample from which genomic DNA can be separated, such as, but not limited to, tissue sample, saliva sample, cheek swab sample, blood, or other biological fluids that comprise genomic DNA. In some embodiments, the blood sample comprises whole blood, blood-derived cell, blood plasma, serum and a combination thereof. In some embodiments, the character of the nucleotide that is in the polymorphism in the patient is determined by genotyping. In some embodiments, genotyping is carried out by PCR analysis, sequence analysis or LCR analysis. In some embodiments, when there is at least one allelotrope comprising the nucleotide selected from the group consisting of: at the G nucleotide of SNPrs4698775, at the G nucleotide of SNPrs17440077, at the A nucleotide of SNPrs10737680, at the G nucleotide of SNPrs1329428, at the G nucleotide of SNPrs429608 or at the G nucleotide of SNPrs2230199, the patient is identified as having increased AMD progression risk and is more likely to benefit from the treatment comprising anti-factor D antibodies or its Fab. If the patient has one or two copies of the G allele of rs4698775 or rs17440077 relevant to CFI or the allele thereof, the rs1329428 relevant to CFH or the allele thereof, or the rs429608 relevant to C2/CFB or the allele thereof, or the rs2230199 relevant to C3 or the allele thereof, or there is one or two copies of the A allele of rs10737680 relevant to CFH or the allele thereof, the patient is accredited as being in the AMD progress danger of increase. In one embodiment, the eye studied by the patient has a BCVA of 20/25-20/400. In one embodiment, the eye studied by the patient has a BCVA of 20/25-20/100. In one embodiment, the eye studied by the patient has a BCVA of 20/50-20/400. In one embodiment, the eye in which the patient is studied has a BCVA of 20/50-20/100. In one embodiment, the eye in which the patient is studied has a BCVA of better than 20/25 or worse than 20/400. In one embodiment, BCVA is determined using the ETDRS table. In some embodiments, the antibody or its antigen-binding fragment is administered intravitreally. In some embodiments, the age-related macular degeneration is dry AMD. In some embodiments, the dry AMD is late dry AMD. In some embodiments, the late dry AMD is geographic atrophy. In some embodiments, the age-related macular degeneration is early AMD or mid-term AMD. In some embodiments, patients with early AMD or mid-term AMD have a reduction or delay in the appearance of clinical signs (for example, the number and size of measuring drusen (for early and mid-term AMD) and monitoring the hypopigmentation and hyperpigmentation associated with drusen (for mid-term AMD)). In some embodiments, the method further comprises administering a second drug to the experimenter. In some embodiments, the second drug is a VEGF inhibitor.

Another embodiment of the present invention provides a method for determining that AMD patients will benefit from the possibility of treatment using anti-factor D antibodies or its antigen-binding fragment, the method comprising determining the patient's genotype, wherein the patient carrying the risk allele is identified as having increased AMD progression risk and is more likely to respond to the patient using anti-factor D antibodies or its antigen-binding fragment for treatment. In some embodiments, the antibody is lampalizumab. In some embodiments, the risk allele is the minor allele of selected SNP. In some embodiments, the risk allele is the major allele of selected SNP. In some embodiments, the risk allele (such as the polymorphism associated with AMD-) can be a CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB risk allele and/or a C3 risk allele. In some embodiments, the risk allele is a CFI risk allele. In some embodiments, the CFI risk allele is the rs4698775:G allele or an equivalent allele thereof, or a G comprised within the selected SNP rs4698775, or an alternative SNP comprised in linkage disequilibrium with rs4698775. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs4698775. In some embodiments, the CFI risk allele is the rs17440077:G allele or an equivalent allele thereof, or a G comprised within the selected SNP rs17440077, or an alternative SNP comprised in linkage disequilibrium with rs17440077. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs17440077. In some embodiments, the CFH risk allele is the rs10737680:A allele, or an equivalent allele thereof, or an A contained within the selected SNP rs10737680, or an alternative SNP contained in linkage disequilibrium with rs10737680. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs10737680. In some embodiments, the CFH risk allele is the rs1329428:G allele, or an equivalent allele thereof, or a G contained within the selected SNP rs1329428, or an alternative SNP contained in linkage disequilibrium with rs1329428. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs1329428. In some embodiments, the C2 risk allele is the rs429608:G allele, or an equivalent allele thereof, or a G comprised within the selected SNP rs429608, or an alternative SNP comprised in linkage disequilibrium with rs429608. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs429608. In some embodiments, the CFB allele is the rs429608:G allele, or an equivalent allele thereof, or a G comprised within the selected SNP rs429608, or an alternative SNP comprised in linkage disequilibrium with rs429608. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs429608. In some embodiments, the C3 risk allele is the rs2230199:G allele, or an equivalent allele thereof, or an alternative SNP comprising the G of the selected SNP rs2230199 or comprising linkage disequilibrium with rs2230199. In some embodiments, the alternative SNP comprises a minor allele or an allele located on the same haplotype as the risk allele of the selected SNP rs2230199. In some embodiments, the linkage disequilibrium is a D' measure or an ^r2 measure. In some embodiments, the D' measure between the selected SNP and the alternative SNP is ≥0.60. In some embodiments, the D' measure between the selected SNP and the alternative SNP is ≥0.70, 0.80, or 0.90. In some embodiments, the D' measure between the selected SNP and the alternative SNP is 1.0. In some embodiments, the ^r2 measure between the selected SNP and the alternative SNP is ≥0.60. In some embodiments, the ^r2 measure between the selected SNP and the alternative SNP is ≥0.70, 0.80 or 0.90. In some embodiments, the ^r2 measure between the selected SNP and the alternative SNP is 1.0. In some embodiments, the alternative SNP is the SNP specified in Tables 4-7. In some embodiments, SNP rs4698775 is located at position 110590479 on human chromosome 4 (Genome Reference Sequence Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009), and the G allele changes the nucleotide sequence from T to G. In some embodiments, SNP rs17440077 is located at position 110537567 on human chromosome 4 (Genome Reference Sequence Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs10737680 is located at position 196679455 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the A allele changes the nucleotide sequence from C to A. In some embodiments, SNP rs1329428 is located at position 196702810 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs429608 is located at position 31930462 on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009), and the G allele changes the nucleotide sequence from A to G. In some embodiments, SNP rs2230199 is located at position 6718387 on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 Assembly; February 2009), and the G allele changes the nucleotide sequence from C to G and the encoded amino acid from arginine to glycine. In some embodiments, the alternative SNP is located between the SEC24B gene and the EGF gene on human chromosome 4 (regarding rs4698775) (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009), between the SEC24B gene and the EGF gene on human chromosome 4 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs17440077), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009) (regarding rs10 737680), between the KCNT2 gene and the LHX9 gene on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs1329428), between the SLC44A4 gene and the TNXB gene on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs429608), between the TNFSF14 gene and the VAV1 gene on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 assembly; February 2009) (regarding rs2230199). In some embodiments, the alternative SNP is located within 500,000 base pairs upstream and downstream of the selected SNP. In some embodiments, the patient is determined to carry a CFI risk allele and/or a CFH risk allele and/or a C2 risk allele and/or a CFB risk allele and/or a C3 risk allele. In some embodiments, the patient is determined to carry 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., risk alleles for AMD. In some embodiments, the presence of risk alleles in the patient comprises determining the nature of the nucleotides in a polymorphism from a nucleic acid provided by a patient sample. In some embodiments, the nucleic acid sample comprises DNA. In some embodiments, the nucleic acid sample comprises RNA. In some embodiments, the nucleic acid sample is amplified. In some embodiments, the nucleic acid sample is amplified by polymerase chain reaction. In some embodiments, polymorphisms are detected by polymerase chain reaction or sequencing. In some embodiments, polymorphisms are detected by amplifying a target region comprising at least one polymorphism, hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions, and detecting the hybridization. In some embodiments, the polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platforms, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification. In some embodiments, the sample is any biological sample from which genomic DNA can be separated, such as, but not limited to, tissue sample, saliva sample, cheek swab sample, blood, or other biological fluids that comprise genomic DNA. In some embodiments, the character of the nucleotide that is in polymorphism in the patient is determined by genotyping. In some embodiments, genotyping is carried out by PCR analysis, sequence analysis or LCR analysis. In some embodiments, when there is at least one allelotrope that comprises the nucleotide that is selected from the group consisting of: at the G nucleotide of SNP rs4698775, at the G nucleotide of SNPrs17440077, at the G nucleotide of SNP rs10737680, at the G nucleotide of SNP rs1329428, at the G nucleotide of SNPrs429608 or at the G nucleotide of SNP rs2230199, the patient is accredited as having increased AMD progress danger and more likely to benefit from the treatment comprising anti-factor D antibody or its Fab. If the patient has one or two copies of the G allelotrope of rs4698775 or rs17440077 relevant to CFI or the allelotrope thereof, the rs1329428 relevant to CFH or the allelotrope thereof, or the rs429608 relevant to C2/CFB or the allelotrope thereof, or the rs2230199 relevant to C3 or the allelotrope thereof, or there is one or two copies of the A allelotrope of rs10737680 relevant to CFH or the allelotrope thereof, then the patient is accredited as being in the danger of AMD progress increased. In one embodiment, the eye studied by the patient has a BCVA of 20/25-20/400. In one embodiment, the eye studied by the patient has a BCVA of 20/25-20/100. In one embodiment, the eye studied by the patient has a BCVA of 20/50-20/400. In one embodiment, the eye in which the patient is studied has a BCVA of 20/50-20/100. In one embodiment, the eye in which the patient is studied has a BCVA of better than 20/25 or worse than 20/400. In one embodiment, BCVA is determined using an ETDRS table. In some embodiments, the antibody or its antigen-binding fragment is administered intravitreally. In some embodiments, the age-related macular degeneration is dry AMD. In some embodiments, the dry AMD is late dry AMD. In some embodiments, the late dry AMD is geographic atrophy. In some embodiments, the age-related macular degeneration is early AMD or mid-term AMD. In some embodiments, the patient suffering from early AMD or mid-term AMD has a reduction or delay in the appearance of clinical signs (for example, the number and size of measuring drusen can be included (for early and mid-term AND) and monitoring the hypopigmentation and hyperpigmentation associated with drusen (for mid-term AMD)). In some embodiments, the method further comprises administering a second drug to the experimenter. In some embodiments, the second drug is a VEGF inhibitor.

Another embodiment of the present invention provides a method for treating a degenerative disease (e.g., AMD) in a patient, the method comprising administering an effective amount of an anti-Factor D antibody or an antigen-binding fragment thereof to a patient diagnosed with a degenerative disease, wherein the patient has reduced AMD progression after treatment compared to a control. In some embodiments, the antibody is lampalizumab. In one embodiment, the degenerative disease is an ocular degenerative disease. In one embodiment, the ocular degenerative disease is age-related macular degeneration. In one embodiment, the patient's eye studied has a BCVA of 20/25-20/400. In one embodiment, the patient's eye studied has a BCVA of 20/25-20/100. In one embodiment, the patient's eye studied has a BCVA of 20/50-20/400. In one embodiment, the patient's eye studied has a BCVA of 20/50-20/100. In one embodiment, the patient's eye studied has a BCVA of better than 20/25 or worse than 20/400. In one embodiment, BCVA is determined using the ETDRS table. In some embodiments, the antibody or its antigen-binding fragment is administered intravitreally. In some embodiments, the age-related macular degeneration is dry AMD. In some embodiments, the dry AMD is late dry AMD. In some embodiments, the late dry AMD is geographic atrophy. In some embodiments, compared with control patients who do not receive antibody treatment, after administering the antibody, the patient has a reduced average change in geographic atrophy (GA) area. In some embodiments, the average change in GA area is determined by measuring the GA area via standard imaging methods (e.g., fundus autofluorescence (FAF) or color fundus photography (CFP)). In some embodiments, the age-related macular degeneration is early AMD or mid-stage AMD. In some embodiments, patients with early AMD or mid-stage AMD have a reduction or delay in the appearance of clinical signs (e.g., can include measuring the number and size of drusen (for early and mid-stage AMD) and monitoring the hypopigmentation and hyperpigmentation associated with drusen (for mid-stage AMD)). In some embodiments, the method also includes administering a second drug to the subject. In some embodiments, the second drug is a VEGF inhibitor.

Another embodiment of the present invention provides a method for identifying a patient with a degenerative disease (e.g., an AMD patient) who may benefit from treatment with an anti-Factor D antibody or an antigen-binding fragment thereof, the method comprising determining the patient's baseline GA area, wherein a patient with a baseline GA area requiring clinical intervention is identified as a patient who may benefit from treatment with an anti-Factor D antibody. In one embodiment, the degenerative disease is an ocular degenerative disease. In one embodiment, the ocular degenerative disease is age-related macular degeneration. In some embodiments, the antibody is lampalizumab. In one embodiment, the patient's eye studied has a BCVA of 20/25-20/400. In one embodiment, the patient's eye studied has a BCVA of 20/25-20/100. In one embodiment, the patient's eye studied has a BCVA of 20/50-20/400. In one embodiment, the patient's eye studied has a BCVA of 20/50-20/100. In one embodiment, the patient's eye studied has a BCVA of better than 20/25 or worse than 20/400. In one embodiment, BCVA is determined using the ETDRS table. In some embodiments, the antibody or its antigen-binding fragment is administered intravitreally. In some embodiments, the age-related macular degeneration is dry AMD. In some embodiments, the dry AMD is late dry AMD. In some embodiments, the late dry AMD is geographic atrophy. In some embodiments, compared with control patients who do not receive antibody treatment, after administering the antibody, the patient has a reduced average change in geographic atrophy (GA) area. In some embodiments, the average change in GA area is determined by measuring the GA area via standard imaging methods (e.g., fundus autofluorescence (FAF) or color fundus photography (CFP)). In some embodiments, the age-related macular degeneration is early AMD or mid-term AMD. In some embodiments, patients with early AMD or mid-term AMD have a reduction or delay in the appearance of clinical signs (e.g., can include measuring the number and size of drusen (for early and mid-term AMD) and monitoring the hypopigmentation and hyperpigmentation associated with drusen (for mid-term AMD)). In some embodiments, the method also includes administering a second drug to the experimenter. In some embodiments, the second drug is a VEGF inhibitor.

In some embodiments, the complement inhibitor in the methods described herein is an anti-Factor D antibody, or an antigen-binding fragment thereof. In some embodiments, the antibody specifically binds Factor D. In some embodiments, the antibody comprises: a light chain comprising: HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1), HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2), and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising: HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4); HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5), and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In some embodiments, the antibody comprises a heavy chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; and/or a light chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody is lampalizumab having CAS Registry Number 1278466-20-8. In some embodiments, the anti-Factor D antibody can be a monoclonal antibody, an antibody fragment, a chimeric antibody, a humanized antibody, a single chain antibody, or an antibody that competitively inhibits binding of an anti-Factor D antibody to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an anti-Factor D antibody to its corresponding antigenic epitope, wherein the anti-Factor D antibody comprises: a light chain comprising: HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1); HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2); and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising: HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4); HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5); and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:7 and/or a light chain variable region sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:8 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:15 and/or a light chain sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:16 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:8 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:15 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:16 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits the binding of lampalizumab, CAS Registry Number 1278466-20-8, to its corresponding antigenic epitope. In some embodiments, the anti-Factor D antibody binds to the same epitope on Factor D that is bound by another Factor D antibody. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D that is bound by an anti-Factor D antibody comprising a light chain comprising HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1), HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2), and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4); HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5), and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15 and/or a light chain sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 15 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D that is bound by lampalizumab, CAS Registry No. 1278466-20-8.

In some embodiments, the anti-Factor D antibody or antigen-binding fragment thereof is administered intraocularly or intravitreally. In some embodiments, the antibody is administered at a flat dose of 10 mg. In some embodiments, the antibody is administered at a flat dose of 10 mg per month or 10 mg every other month. In some embodiments, the antibody is administered intravitreally at a flat dose of 10 mg per month or 10 mg every other month. In some embodiments, the preparation or drug delivery mode of the anti-Factor D antibody or antigen-binding fragment thereof may include a dose less than or greater than 10 mg. In some embodiments, if administered via a long-acting delivery (LAD) device, the anti-Factor D antibody or antigen-binding fragment thereof is administered at a dose less than 10 mg. For example, the anti-Factor D antibody or antigen-binding fragment thereof is administered at a dose of 9, 8, 7, 6, 5, 4, 3, 2, or 1 mg. In some embodiments, if used intravitreally, the anti-Factor D antibody or antigen-binding fragment thereof is administered at a dose greater than 10 mg. For example, the anti-Factor D antibody or antigen-binding fragment thereof is administered at a dose of 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg.

In some embodiments, administration of the antibody is effective for one or more of: (1) reducing the area of GA, (2) reducing vision loss. In some embodiments, the methods described herein further comprise administering to the patient a second drug. In some embodiments, the second drug is a VEGF inhibitor. In some embodiments, the second drug is a standard of care for AMD.

In another aspect, the present invention provides a therapeutic regimen for treating patients who carry a risk allele and who need it, comprising administering a factor D inhibitor. In some embodiments, the complement inhibitor is an anti-factor D antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is administered at a fixed dose of 5-30 mg. In some embodiments, the antibody is administered at a fixed dose of 5-15 mg per month or 10-30 mg every other month. In some embodiments, the antibody is administered intraocularly or intravitreally. In some embodiments, the antibody is administered intravitreally at a fixed dose of 5 mg or 15 mg per month. In some embodiments, the antibody comprises: a light chain comprising: HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1), HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2), and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising: HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5), and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In some embodiments, the antibody comprises a heavy chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; and/or a light chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 (EVQLVQSGPELKKPGASVKVSCKAS GYTFTNYGMN WVRQAPGQGLEWMG WI NTYTGETTYADDFKG RFVFSLDTSVSTAYLQISSLKAEDTAVYYCER EGGVNN WGQGTLVTVSS; HVRs are underlined and in bold); and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8 (DIQVTQSPSSLSASVGDRVTITC ITSTDIDDDMN WYQQKPGKVPKLLIS GGNTLRP GVPSRFSGSGSGTDFTLTISSLQPEDVATYYC LQSDSLP YT FGQGTKVEIK; HVRs are underlined and in bold). In some embodiments, the antibody is lampalizumab with CAS Registry No. 1278466-20-8. In some embodiments, the anti-Factor D antibody can be a monoclonal antibody, an antibody fragment, a chimeric antibody, a humanized antibody, a single-chain antibody, or an antibody that competitively inhibits the binding of an anti-Factor D antibody to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits the binding of an anti-Factor D antibody to its corresponding antigenic epitope, wherein the anti-Factor D antibody comprises: a light chain comprising: HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1); HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2); and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising: HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4); HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5); and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:7 and/or a light chain variable region sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:8 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:15 and/or a light chain sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:16 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:8 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:15 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:16 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits the binding of lampalizumab, CAS Registry Number 1278466-20-8, to its corresponding antigenic epitope. In some embodiments, the anti-Factor D antibody binds to the same epitope on Factor D that is bound by another Factor D antibody. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D that is bound by an anti-Factor D antibody comprising a light chain comprising HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1), HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2), and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4); HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5), and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15 and/or a light chain sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 15 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D that is bound by lampalizumab, CAS Registry No. 1278466-20-8.

In another aspect, the present invention provides a method for identifying an AMD patient who can benefit from treatment with a factor D inhibitor, the method comprising determining a genotype by a sample of the patient, wherein a patient carrying a risk allele is identified as a patient who can benefit from treatment with a factor D inhibitor by a genotyping assay. In another aspect, the present invention provides a method for predicting the responsiveness of an AMD patient to treatment with a factor D inhibitor, the method comprising determining a genotype by a sample of the patient, wherein a patient carrying a risk allele is identified as a patient who may respond to treatment with the factor D inhibitor. In some embodiments, genotyping is performed using SNP arrays, Taqman (Hui et al., Current Protocol in Human Genetics, Supp 56:2.10.1-2.10.8 (2008)), fluorescence polarization, Sequenom or other methods described herein for analyzing SNPs. In some embodiments, genotyping is performed using PCR or sequencing.

In another aspect, the present invention provides a method for treating a degenerative disease, comprising administering an anti-Factor D antibody or antigen-binding fragment thereof comprising HVRH1, HVRH2, HVRH3, HVRL1, HVRL2, HVRL3, and HVRL3 to a patient suffering from the degenerative disease at a monthly dose of 10 mg, wherein the HVRs have the amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively. In one embodiment, the degenerative disease is an ocular degenerative disease. In one embodiment, the ocular degenerative disease is age-related macular degeneration. In one embodiment, the age-related macular degeneration is early, intermediate, or late AMD. In one embodiment, the late AMD is geographic atrophy. In some embodiments, a second drug is administered. In some embodiments, the second drug is a VEGF inhibitor. In one embodiment, the VEGF inhibitor is ranibizumab. In one embodiment, the anti-Factor D antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof comprising a VH comprising SEQ ID NO: 7 and a VL comprising SEQ ID NO: 8. In one embodiment, treatment results in a change in GA area of greater than 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 In one embodiment, treatment results in a decrease in GA area by more than 80% compared to baseline GA area. In one embodiment, treatment results in a decrease in GA area by more than 75% compared to baseline GA area. In one embodiment, treatment results in a decrease in GA area by more than 70% compared to baseline GA area. In one embodiment, treatment results in a decrease in GA area by more than 65% compared to baseline GA area. In one embodiment, treatment results in a decrease of greater than 60% in the change in GA area compared to baseline GA area. In one embodiment, treatment results in a decrease of greater than 55% in the change in GA area compared to baseline GA area. In one embodiment, treatment results in a decrease of greater than 50% in the change in GA area compared to baseline GA area. In one embodiment, treatment results in a decrease of greater than 45% in the change in GA area compared to baseline GA area. In one embodiment, treatment results in a decrease of greater than 40% in the change in GA area compared to baseline GA area. In one embodiment, treatment results in a decrease of greater than 35% in the change in GA area compared to baseline GA area. In one embodiment, treatment results in a decrease of greater than 30% in the change in GA area compared to baseline GA area. In one embodiment, treatment results in a decrease of greater than 25% in the change in GA area compared to baseline GA area. In one embodiment, treatment results in a decrease of greater than 20% in the change in GA area compared to baseline GA area. In one embodiment, treatment results in a decrease of greater than 15% in the change in GA area compared to baseline GA area. In one embodiment, treatment results in a decrease of greater than 10% in the change in GA area compared to baseline GA area. In one embodiment, treatment results in a decrease of greater than 5% in the change in GA area compared to baseline GA area. In one embodiment, the patient has geographic atrophy secondary to AMD. In one embodiment, the patient's eye has a BCVA of 20/25-20/400. In one embodiment, the patient's eye has a BCVA of 20/25-20/100. In one embodiment, the patient's eye has a BCVA of 20/50-20/400. In one embodiment, the patient's eye has a BCVA of 20/50-20/100. In one embodiment, the patient's eye has a BCVA better than 20/25 or worse than 20/400. In one embodiment, BCVA is determined using an ETDRS table. In one embodiment, the patient's eye has not received any previous intravitreal treatment, retinal surgery, or other retinal treatment procedures.

In one aspect, the present invention provides a kit for genotyping a biological sample from a patient with a degenerative disease, wherein the kit includes oligonucleotides for polymerase chain reaction or sequencing for detecting risk alleles. In another aspect, the present invention provides a kit for determining the presence of at least one degenerative disease-associated polymorphism in a biological sample, the kit including reagents for detecting the genotype of the biological sample and instructions for use to determine at least one degenerative disease-associated polymorphism, wherein the polymorphism is a risk allele selected from the group consisting of CFI allele, CFH allele, C2 allele, CFB allele, or C3 allele. In one embodiment, the biological sample is a blood sample, saliva, cheek swab, tissue sample, or body fluid sample. In one embodiment, the biological sample is a nucleic acid sample. In one embodiment, the nucleic acid sample comprises DNA. In one embodiment, the nucleic acid sample comprises RNA. In one embodiment, the nucleic acid sample is amplified. In one embodiment, the biological sample is obtained from a patient diagnosed with a degenerative disease, such as AMD, including early, intermediate, and late AMD. In one embodiment, the late AMD is GA. In one embodiment, the kit further comprises a packaging insert for determining whether a patient with a degenerative disease is likely to respond to an anti-Factor D antibody or an antigen-binding fragment thereof. In one embodiment, the kit is used to detect the presence of a CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB risk allele, or a C3 risk allele. In one embodiment, the kit is used to detect the presence of one or both alleles of the G genotype at SNP rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608, or SNP rs2230199, or both alleles of the A genotype at SNP rs10737680. In one embodiment, the reagents of the kit include a set of oligonucleotides specifically for detecting polymorphisms in the CFI, C2, CFB, C3, or CFH alleles. The oligonucleotides of the present invention can be forward primers and reverse primers suitable for amplifying a region of the CFI, C2, CFB, C3, or CFH gene, wherein the region contains a polymorphism in CFI, C2, CFB, C3, or CFH, respectively, selected from the group consisting of: a G genotype at SNPrs4698775, SNPrs17440077, SNPrs1329428, SNPrs429608, or SNPrs2230199, or an A genotype at SNPrs10737680. The kit can also include an oligonucleotide probe for detecting the polymorphism. Oligonucleotides useful as primers and probes of the present invention include those listed in Table 9, such as SEQ ID NOs: 17-41. In one aspect, the reagents of the kit include: (i) a forward primer of SEQ ID NO: 17 or 18 in combination with a reverse primer of SEQ ID NO: 19 or 20 and a labeled probe selected from SEQ ID NOs. 21 to 24; (ii) a forward primer of SEQ ID NO: 25 or 26 in combination with a reverse primer of SEQ ID NO: 27 or 28 and a labeled probe selected from SEQ ID NOs. 29 to 33; or (iii) a forward primer of SEQ ID NO: 34 or 35 in combination with a reverse primer of SEQ ID NO: 36 or 37 and a labeled probe selected from SEQ ID NOs. 38 to 41. In one embodiment, the reagents of the kit combine the primers and probes listed above in (i), (ii), and (iii).

In another aspect, the present invention provides a kit for predicting whether a patient has an increased likelihood of benefiting from treatment with an anti-Factor D antibody or antigen-binding fragment thereof, the kit comprising a first oligonucleotide and a second oligonucleotide specific for a polymorphism in CFI, C2, CFB, C3, or CFH. In one embodiment, the first oligonucleotide and the second oligonucleotide can be used to amplify a region of the CFI, C2, CFB, C3, or CFH gene, the region comprising a polymorphism in CFI, C2, CFB, C3, or CFH, respectively, selected from the group consisting of: a G genotype at SNP rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608, or SNP rs2230199, or an A genotype at SNP rs10737680. In one embodiment, the anti-Factor D antibody or antigen-binding fragment thereof comprises HVRH1, HVRH2, HVRH3, HVRL1, HVRL2, HVRL3 and HVRL3, wherein the HVRs have the amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.

In one aspect of the invention, the anti-Factor D antibody or antigen-binding fragment thereof comprises the variable heavy chain of SEQ ID NO:7 and/or the variable light chain of SEQ ID NO:8.

In one aspect of the invention, the polymorphism is a CFI polymorphism. In one embodiment, the CFI polymorphism is present in combination with one or more additional polymorphisms selected from the group consisting of a CFH polymorphism, a C2 polymorphism, a C3 polymorphism or a CFB polymorphism.

In one aspect, the present invention provides use of a reagent that specifically binds to at least one degenerative disease-associated polymorphism in the preparation of a diagnostic agent for diagnosing a degenerative disease, wherein the polymorphism is a minor allele selected from the group consisting of a CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB risk allele, or a C3 risk allele. In one embodiment, the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof. In one embodiment, the CFI allele comprises a G at SNP rs4698775 or rs17440077, the CFH allele comprises an A at SNP rs10737680 or a G at SNP rs1329428, the C2 allele comprises a G at SNP rs429608, the CFB allele comprises a G at SNP rs429608, and the C3 allele comprises a G at SNP rs2230199. In one embodiment, at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platforms, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification. In one embodiment, at least one polymorphism is by detecting like this: amplification comprises the target region of at least one polymorphism, and with at least one sequence-specific oligonucleotide hybridization with at least one polymorphism under stringent condition, and detects described hybridization.In one embodiment, in individuality, there is one or two allelomorphs of the G genotype of SNP rs4698775, SNPrs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or one or two allelomorphs of the A genotype of SNP rs10737680 that represent the danger of degenerative disease progression that increases.In one embodiment, detect the polymorphism in the linkage disequilibrium with at least one SNP of the group being formed by being selected from: SNP (SNP) rs4698775, rs17440077, rs10737680, rs1329428, rs429608 and rs2230199. In one embodiment, the degenerative disease is age-related macular degeneration. In one embodiment, the age-related macular degeneration is early, intermediate or late AMD. In one embodiment, the late AMD is geographic atrophy.

In one aspect, the present invention provides for the in vitro use of a reagent that binds to at least one polymorphism associated with a degenerative disease for identifying patients with a degenerative disease who are likely to respond to a treatment comprising an anti-Factor D antibody or an antigen-binding fragment thereof, wherein the polymorphism is a risk allele selected from the group consisting of a CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB risk allele, or a C3 risk allele, wherein the presence of the polymorphism identifies the patient as being more likely to respond to the treatment. In one embodiment, the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof. In one embodiment, the CFI allele comprises a G at SNP rs4698775 or rs17440077, the CFH allele comprises an A at SNP rs10737680 or a G at SNP rs1329428, the C2 allele comprises a G at SNP rs429608, the CFB allele comprises a G at SNP rs429608, and the C3 allele comprises a G at SNP rs2230199. In one embodiment, at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high throughput SNP genotyping platform, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass spectrometry. In one embodiment, the at least one polymorphism is detected by amplifying a target region comprising the at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions, and detecting the hybridization. In one embodiment, the presence of a SNP in an individual One or two alleles of the G genotype of rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608 or SNPrs2230199 or one or two alleles of the A genotype of SNP rs10737680 represent increased degenerative disease progression risk. In one embodiment, a polymorphism in the linkage disequilibrium with at least one SNP polymorphism selected from the group consisting of: SNP (SNP) rs4698775, rs17440077, rs10737680, rs1329428, rs429608 and rs2230199 is detected. In one embodiment, the degenerative disease is an ocular degenerative disease. In one embodiment, the ocular degenerative disease is age-related macular degeneration. In one embodiment, the age-related macular degeneration is early, mid-term or late AMD. In one embodiment, the late AMD is geographic atrophy.

In one aspect, the present invention provides the in vitro use of polymorphisms associated with degenerative diseases for selecting patients with degenerative diseases who may respond to treatment comprising an anti-Factor D antibody or its antigen-binding fragment, wherein, when the polymorphism associated with the degenerative disease is detected in a sample from the patient, the patient is identified as being more likely to respond to the treatment. In one embodiment, the polymorphism associated with the degenerative disease is a polymorphism associated with AMD. In one embodiment, the polymorphism associated with AMD is a risk allele selected from the group consisting of: CFI risk allele, CFH risk allele, C2 risk allele, CFB risk allele or C3 risk allele, which is used to identify patients with degenerative diseases who may respond to treatment comprising an anti-Factor D antibody or its antigen-binding fragment, wherein the presence of the polymorphism identifies the patient as being more likely to respond to the treatment. In one embodiment, the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof. In one embodiment, the CFI allele comprises a G at SNP rs4698775 or rs17440077, the CFH allele comprises an A at SNP rs10737680 or a G at SNP rs1329428, the C2 allele comprises a G at SNP rs429608, the CFB allele comprises a G at SNP rs429608, and the C3 allele comprises a G at SNP rs2230199. In one embodiment, at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platforms, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification. In one embodiment, at least one polymorphism is by detecting like this: amplification comprises the target region of at least one polymorphism, and with at least one sequence-specific oligonucleotide hybridization with at least one polymorphism under stringent condition, and detects described hybridization.In one embodiment, in individuality, there is one or two allelomorphs of the G genotype of SNP rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or one or two allelomorphs of the A genotype of SNP rs10737680 and represents the danger of degenerative disease progression that increases.In one embodiment, detect the polymorphism in the linkage disequilibrium with at least one SNP of the group being formed by being selected from: SNP (SNP) rs4698775, rs17440077, rs10737680, rs1329428, rs429608 and rs2230199. In one embodiment, the degenerative disease is an ocular degenerative disease. In one embodiment, the ocular degenerative disease is age-related macular degeneration. In one embodiment, the age-related macular degeneration is early, intermediate or late AMD. In one embodiment, the late AMD is geographic atrophy.

In one aspect, the present invention provides the use of polymorphisms associated with degenerative diseases in the preparation of diagnostic agents for assessing the likelihood that a patient with a degenerative disease will respond to a treatment comprising an anti-Factor D antibody or its antigen-binding fragment. In one embodiment, the polymorphism associated with the degenerative disease is an AMD-associated polymorphism. In one embodiment, the AMD-associated polymorphism is a risk allele selected from the group consisting of a CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB risk allele, or a C3 risk allele, for identifying a patient with a degenerative disease who is likely to respond to a treatment comprising an anti-Factor D antibody or its antigen-binding fragment, wherein the presence of the polymorphism identifies the patient as being more likely to respond to the treatment. In one embodiment, the CFI allele is its equivalent allele, the CFH allele is its equivalent allele, the C2 allele is its equivalent allele, the CFB allele is its equivalent allele, or the C3 allele is its equivalent allele. In one embodiment, the CFI allele comprises a G at single nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH allele comprises an A at single nucleotide polymorphism (SNP) rs10737680 or a G at single nucleotide polymorphism (SNP) rs1329428, the C2 allele comprises a G at single nucleotide polymorphism (SNP) rs429608, the CFB allele comprises a G at single nucleotide polymorphism (SNP) rs429608, and the C3 allele comprises a G at single nucleotide polymorphism (SNP) rs2230199. In one embodiment, at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platforms, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification. In one embodiment, at least one polymorphism is by detecting like this: amplification comprises the target region of at least one polymorphism, and with at least one sequence-specific oligonucleotide hybridization with at least one polymorphism under stringent condition, and detects described hybridization.In one embodiment, in individuality, there is one or two allelomorphs of the G genotype of SNP rs4698775, SNP rs17440077, SNP rs1329428, SNPrs429608 or SNP rs2230199 or one or two allelomorphs of the A genotype of SNP rs10737680 and represents the degenerative disease progress danger that increases.In one embodiment, detect the polymorphism in the linkage disequilibrium with at least one SNP of the group being formed by being selected from: SNP (SNP) rs4698775, rs17440077, rs10737680, rs1329428, rs429608 and rs2230199. In one embodiment, the degenerative disease is an ocular degenerative disease. In one embodiment, the ocular degenerative disease is age-related macular degeneration. In one embodiment, the age-related macular degeneration is early, intermediate or late AMD. In one embodiment, the late AMD is geographic atrophy.

In one aspect, the present invention provides oligonucleotides for detecting polymorphisms at one or more nucleotide positions in a complement-related locus. In one embodiment, the complement-related locus is selected from the group consisting of CFH, CFI, C3, C2, and CFB risk loci. In one embodiment, the nucleotide position is selected from the group consisting of nucleotide positions associated with rs4698775, rs17440077, rs10737680, rs1329428, rs429608, and rs2230199. In one embodiment, the oligonucleotide is at least 90% identical to one or more sequences selected from the group consisting of SEQ ID NOs: 17-41 and has the 3'-terminal nucleotide of said sequence. The oligonucleotide may contain three or fewer mismatches with one of the sequences, excluding the 3'-terminal nucleotide and/or at least one mismatch between the last five nucleotides at the 3'-terminus. The oligonucleotide may also contain at least one modified nucleotide between the last five nucleotides at the 3'-terminus. In some embodiments, the oligonucleotide is suitable for detecting one or more of the alleles of rs4698775, rs17440077, rs10737680, rs1329428, rs429608, and rs2230199.

In one aspect, the present invention is a diagnostic method for detecting SNPs in a CFH, CFI, C3, C2, or CFB risk locus. In one embodiment, the SNP is selected from rs4698775, rs17440077, rs10737680, rs1329428, rs429608, and rs2230199. In one embodiment, the SNP is detected using an oligonucleotide selected from SEQ ID NOs: 17-41, or a variant thereof that is at least 90% identical thereto and has a 3'-terminal nucleotide of the oligonucleotide. In one embodiment, the method comprises contacting a biological sample containing nucleic acid with one or more of the oligonucleotides in the presence of corresponding downstream primers and a detection probe. Advantageously, detection of several SNPs can be performed in a single reaction. In some embodiments, several closely located polymorphisms can be detected in a single reaction comprising two or more allele-specific oligonucleotides, for example, selected from the sequences listed in Table 9, which can be combined in a single reaction mixture with a single downstream primer and, optionally, a single detection probe. In another embodiment, the method comprises contacting a test sample comprising nucleic acid with one or more oligonucleotides that serve as SNP-specific probes in the presence of corresponding forward and reverse primers (i.e., primers capable of hybridizing to opposite strands of a target DNA nucleic acid, thereby allowing exponential amplification), nucleoside triphosphates, and a nucleic acid polymerase, such that the one or more allele-specific primers are effectively extended only when a mutation is present in the sample; and detecting the presence or absence of a mutation by directly or indirectly detecting the presence or absence of primer extension.

In a specific embodiment, the presence of primer extension is detected using a probe. The probe can be labeled with a radioactive or chromophore (fluorophore) label, for example, a label incorporating a FAM, JA270, CY5 family dye, or HEX dye. As an example of detection using a fluorescently labeled probe, mutations can be detected by real-time polymerase chain reaction (rt-PCR), in which hybridization of the probe causes enzymatic digestion of the probe and detection of the resulting fluorescence (TaqMan ^™ probe method, Holland et al. (1991) PNAS USA 88: 7276-7280). Alternatively, the presence of extension products and amplification products can be detected by gel electrophoresis followed by staining or by blotting and hybridization, as described, for example, in Sambrook, J. and Russell, DW (2001) Molecular Cloning, 3rd edition, CSHL Press, Chapters 5 and 9.

In some embodiments, the Factor D inhibitor described herein and in the uses described herein is an anti-Factor D antibody. The antibody specifically binds Factor D. In some embodiments, the antibody comprises: a light chain comprising: HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1), HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2), and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising: HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5), and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In some embodiments, the antibody comprises a heavy chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; and/or a light chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody is lampalizumab having CAS Registry Number 1278466-20-8. In some embodiments, the anti-Factor D antibody can be a monoclonal antibody, an antibody fragment, a chimeric antibody, a humanized antibody, a single chain antibody, or an antibody that competitively inhibits binding of an anti-Factor D antibody to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an anti-Factor D antibody to its corresponding antigenic epitope, wherein the anti-Factor D antibody comprises: a light chain comprising HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1), HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2), and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5), and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:7 and/or a light chain variable region sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:8 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:15 and/or a light chain sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:16 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:8 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:15 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:16 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits the binding of lampalizumab, CAS Registry Number 1278466-20-8, to its corresponding antigenic epitope. In some embodiments, the anti-Factor D antibody binds to the same epitope on Factor D that is bound by another Factor D antibody. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D that is bound by an anti-Factor D antibody comprising a light chain comprising HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1), HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2), and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5), and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15 and/or a light chain sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 15 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D that is bound by lampalizumab, CAS Registry No. 1278466-20-8.

In another aspect, the present invention provides an article of manufacture comprising an IVT administration device that delivers a fixed dose of an anti-Factor D antibody or antigen-binding fragment thereof to a patient, wherein the fixed dose is in the microgram-milligram range. In some embodiments, the fixed dose is 10 mg monthly or 10 mg every other month. In some embodiments, the concentration of the antibody in the device is about 10 mg. In another aspect, the present invention provides an article of manufacture comprising an anti-Factor D antibody or antigen-binding fragment thereof at a concentration of 10 mg. In some embodiments, the antibody comprises: a light chain comprising: HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1), HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2), and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising: HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5), and HVR-H3 comprising the amino acid sequence of EGGVNP (SEQ ID NO: 6). In some embodiments, the antibody comprises a heavy chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; and/or a light chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody is lampalizumab having CAS Registry Number 1278466-20-8.

In another aspect, the present invention provides a kit for identifying patients with degenerative diseases who may benefit from treatment with a factor D inhibitor, the kit comprising a vial for collecting a blood sample from a patient with a degenerative disease, and instructions for use for determining whether the patient with the degenerative disease carries a risk allele. In some embodiments, the presence of at least one SNP selected from the group consisting of complement factor I (CFI), complement factor H (CFH), complement factor B (CFB), complement component 3 (C3), and complement component 2 (C2) is used to determine whether the patient with the degenerative disease carries a risk allele. In one embodiment, the degenerative disease is an ocular degenerative disease. In some embodiments, the ocular degenerative disease is AMD. In some embodiments, the factor D inhibitor is an anti-factor D antibody, or an antigen-binding fragment thereof.

In another aspect, the present invention provides a stable lyophilized composition comprising, upon reconstitution with sterile water for injection: an anti-Factor D antibody or antigen-binding fragment thereof in an amount of about 80 to about 120 mg/mL, sodium chloride in an amount of about 8 to about 40 mM, sucrose in an amount of about 80 mM to about 240 mM, L-histidine in an amount of about 10 to about 60 mM, polysorbate 20 in an amount of about 0.01 to about 0.08% w/v, wherein the composition has a pH of about 5.0 to about 6.0.

It should be understood that one, some or all of the characteristics of the multiple embodiments described herein can be combined to form other embodiments of the present invention. These and other aspects of the present invention will be clear to those skilled in the art. These and other embodiments of the present invention are further described in the detailed description below.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts a diagram of the study design for the MAHALO trial described in Example 1 below.

FIG2A is a table summarizing the baseline characteristics of all efficacy-evaluable patients (n=123) from the Phase II component of the study described in Example 1. "Efficacy-evaluable patients" as used herein are defined as all randomized patients who received at least one treatment injection and had at least one post-baseline GA area measurement. FIG2B is a table summarizing the baseline characteristics of patients assessed based on CFI status, where risk allele carriers are defined as individuals who are heterozygous or homozygous for the risk allele at the tested SNP. VA = visual acuity. GA = geographic atrophy. DA = optic disc area (1DA = 2.54 mm ² ).

Figures 3A and 3B show preliminary efficacy results after locking the primary database of the MAHALO Phase II study with all visitor numbers; in the monthly lampalizumab group, the study met its primary endpoint of mean change from baseline in GA area (measured by fundus autofluorescence (FAF)) over 18 months and met its secondary endpoint of mean change from baseline in GA area (measured by color fundus photography (CFP)) over 18 months. In the monthly group, a positive treatment effect was observed in slowing the progression of GA area growth, with both primary (FAF) and secondary (CFP) imaging endpoints, starting at 6 months and continuing through 18 months. Figure 3A shows that based on the unadjusted mean with LOCF data, the monthly lampalizumab group had a 23.1% reduction in GA area growth progression relative to the pooled sham group. Figure 3B shows the least squares means of the stratified analysis of variance (LOCF) data (Henry Scheffe. Chapter 1.2 "Mathematical Models" in The Analysis of Variance, New York: John Wiley & Sons, Inc., 1999, pp. 4-7, stratified by lesion size type at baseline, <4 DA vs. >4 DA). The monthly lampalizumab group had a 20.4% reduction in GA area growth progression relative to the pooled sham group. The results demonstrate a clinically meaningful and statistically significant effect of monthly lampalizumab on reducing GA area growth during the 18-month study treatment period. "Sham pooled" refers to the treatment group that received sham monthly or every other month. "afD1m" refers to the treatment group that received lampalizumab monthly. "afD2m" refers to the treatment group that received lampalizumab every other month. The LOCF method refers to the last-observation-carried-forward method for imputing missing data (David Streiner. "Last-Observation-Carried-Forward Method" in Encyclopedia of Research Design, Vol. 2, Neil Salkind, Ed. Thousand Oaks, California: Sage Publications, Inc., 2010, p. 681-745).

FIG4 compares the changes in autofluorescence (DDAF) determined to be reduced in the sham and lampalizumab monthly treatment groups (DDAF changes in GA area are used herein to refer to changes in lesion size (in mm2) from baseline to 18 months). The total number of patients in the sham and lampalizumab monthly treatment groups is represented as "All". The number of patients who carried the CFH risk allele (rs1329428), C2/CFB risk allele (rs429608), C3 risk allele (rs2230199) or CFI risk allele (rs17440077) in the sham and lampalizumab monthly treatment groups is represented. All patients carried the C2/CFB risk allele (except 1 patient in the sham group). All patients also carried the CFH risk allele (excluding 2 patients in the sham group).

Fig. 5 shows the DDAF change (mean value of sham minus mean value of monthly treatment) and GA area reduction % (mean value of sham minus mean value of monthly treatment divided by mean value of sham) in the 18th month group. The total number of patients in the sham and lampalizumab monthly treatment groups is expressed as "all". It represents the number of patients who are heterozygous or homozygous for CFH risk alleles, C2 risk alleles, CFB risk alleles, C3 risk alleles or CFI risk alleles in the sham and lampalizumab monthly treatment groups. Patients heterozygous for CFI risk alleles (these patients also carry C2/CFB and CFH risk alleles) show -2.29mm ² of sham relative to the average GA area change of monthly treatment and 52.66% of the monthly treatment relative to sham % reduction, which shows that, relative to sham control, the damage progression rate in the monthly treatment group is significantly reduced. "DDAF" refers to GA area when used in this article. "DDAF changes" refers to the change from baseline when used in this article.

Figure 6 shows the least squares mean of the change in GA area measured by FAF from baseline DDAF in patients carrying the CFH, C2/CFB, and CFI risk alleles in the sham and lampalizumab monthly treatment groups. The data in this figure were adjusted for baseline lesion size as a continuous variable and baseline lesion size classification (<4 DA and ≥4 DA). The treatment effect and remission rate were calculated at month 18 (primary efficacy time point); the absolute treatment effect at month 18 was 1.837 mm2, which corresponds to a remission rate of 44%. The vertical bars are 95% confidence intervals for the least squares means. Asterisks (*) indicate unadjusted p-values <0.005 based on a mixed effects model with observed data.

Figure 7 shows the least squares mean change in GA area, measured by RAF, from baseline DDAF in patients with CFH, C2/CFB, and CFI risk alleles, compared with patients with CFH and C2/CFB risk alleles but without CFI risk alleles in the sham and lampalizumab monthly treatment groups. Data in this figure were adjusted for baseline lesion size and baseline lesion size category (<4 DA and ≥4 DA) as continuous variables. Treatment effect and remission rate were calculated at month 18 (primary efficacy time point). The absolute treatment effect at month 18 was 1.837 mm2, corresponding to a 44% remission rate, as shown in Figure 6; however, no treatment effect was observed in patients without CFI risk alleles who were treated with lampalizumab. In addition, patients with CFI risk alleles exhibited more rapid progression in the sham control group relative to the sham group without CFI risk alleles. These findings suggest that the CFI biomarker is both prognostic for AMD (e.g., GA) progression and predictive of lampalizumab treatment response. Vertical bars are 95% confidence intervals for the least squares means. Asterisks (*) indicate unadjusted p-values < 0.005 based on a mixed-effects model with observed data.

Figure 8 shows the least squares mean of the change in GA area measured by FAF from baseline DDAF in patients with CFH, C2/CFB, and CFI risk alleles and a baseline BCVA of 20/50-20/100 in the sham and lampalizumab monthly treatment groups. The data in this figure were adjusted for baseline lesion size as a continuous variable and baseline lesion size classification (<4 DA and ≥4 DA). The treatment effect and remission rate were calculated at month 18 (primary efficacy time point); the absolute treatment effect at month 18 was 2.827 mm2, corresponding to a remission rate of 54%. The vertical bars are 95% confidence intervals for the least squares means. Asterisks (*) indicate unadjusted p-values <0.005 based on a mixed-effects model with observed data.

Figure 9 shows that mRNA levels are highest in liver tissue, as measured by CFI (CFI nRPKM) from the publicly available Cancer Genome Atlas (TCGA) database. (RPKM = reads/Kb transcript length/hundreds of reads plotted; nRPKM is a normalized value to account for the fact that some regions of the genomic sequence are more efficient than others).

Figure 10 shows the levels of CFI mRNA for the rs4698775 SNP genotype in normal liver tissue. In normal TCGA liver samples, the rs698775 SNP genotype was significantly associated with CFI mRNA levels (p = 0.02). Homozygotes for the risk allele (GG) had less CFI mRNA than heterozygotes (GT), which in turn had less CFI mRNA than homozygotes for the non-risk allele (TT).

Figure 11 shows enrichment of CFI rare missense variants in samples from the MAHALO clinical trial compared to controls (P = 0.015).

FIG12 shows that CFI- (CFI- based on rs17440077) rare missense variant carriers had similar progression rates (mean change from baseline in GA area) as CFI+ (CFI+ based on rs17440077).

Details

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology, 2nd ed., J. Wiley & Sons (New York, N.Y. 1994), and March, Advanced Organic Chemistry Reactions, Mechanisms and Structure, 4th ed., John Wiley & Sons (New York, N.Y. 1992), provide those skilled in the art with a general guidance on various terms used herein.

I. Introduction

The invention particularly provides methods of treating patients with AMD (e.g., GA, wet (neovascular/exudative), early AMD, or intermediate AMD) using anti-Factor D antibodies or antigen-binding fragments thereof, methods of identifying patients who may benefit from such treatment (e.g., patient stratification), and methods of diagnosing patients at risk for progression of AMD.

II. Definitions

For purposes of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular will also include the plural, and vice versa. In the event that any definition set forth below conflicts with any document incorporated herein by reference, the definition set forth below will control.

When used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a protein" followed by "an antibody" includes a plurality of proteins or antibodies, respectively; reference to "a cell" includes a mixture of cells, and so forth.

The term "complement-associated disorders" is used in the broadest sense and includes disorders associated with excessive or uncontrolled complement activation. These include complement activation during cardiopulmonary bypass surgery; complement activation due to ischemia-reperfusion following acute myocardial infarction, aneurysm, stroke, hemorrhagic shock, crush injury, multiple organ failure, hypobolemic shock, intestinal ischemia, or other ischemic events. Complement activation has also been shown to be associated with inflammatory conditions such as severe burns, endotoxemia, septic shock, adult respiratory distress syndrome, hemodialysis, anaphylactic shock, severe asthma, angioedema, Crohn's disease, sickle cell anemia, post-streptococcal glomerulonephritis, and pancreatitis. These conditions may be the result of adverse drug reactions, drug allergies, IL-2-induced vascular leakage syndrome, or radiographic contrast media allergies. It also includes autoimmune diseases such as systemic lupus erythematosus, myasthenia gravis, rheumatoid arthritis, Alzheimer's disease and multiple sclerosis. Complement activation is also associated with transplant rejection. Complement activation is also associated with ocular diseases such as age-related macular degeneration, diabetic retinopathy and other ischemia-related retinopathies, choroidal neovascularization (CNV), geographic atrophy (GA), uveitis, diabetic macular edema, pathological myopia, von Hippel-Lindau disease, histoplasmosis of the eye, Central Retinal Vein Occlusion (CRVO), corneal neovascularization, and retinal neovascularization.

The term "complement-associated eye disorder" is used in the broadest sense and includes all eye disorders in which complement (including the classical and alternative pathways, particularly the alternative pathway of complement) is involved in the pathology. Complement-associated eye disorders include, but are not limited to, macular degenerative diseases, such as all stages of age-related macular degeneration (AMD), including dry and wet (non-exudative and exudative) forms, choroidal neovascularization (CNV), geographic atrophy (GA), uveitis, diabetic and other ischemia-related retinopathy, and other intraocular neovascular diseases, such as diabetic macular edema, pathological myopia, Hippel-Lindau disease, histoplasmosis of the eye, central retinal vein occlusion (CRVO), corneal neovascularization and retinal neovascularization. In one example, complement-associated eye disorders include age-related macular degeneration (AMD), including non-exudative (dry or atrophic) and exudative (wet) AMD, choroidal neovascularization (CNV), diabetic retinopathy (DR), geographic atrophy (GA), and endophthalmitis.

"Age-related macular degeneration," also referred to herein as "AMD," as used herein, is a condition of the eye caused by degeneration of cells in the macula, the part of the retina responsible for central vision. AMD can be: (1) wet (exudative), characterized by abnormal growth of blood vessels under the retina, which results in leakage of fluid or blood that ultimately damages the photoreceptors, or (2) dry (non-exudative), characterized by the accumulation of cellular debris called drusen between the retina and the choroid.

"Geographic atrophy," also referred to herein as "GA," as used herein, is a disease involving degeneration of the retinal pigment epithelium (RPE) associated with loss of photoreceptors. GA is an advanced form of dry AMD.

"GA area," as used herein, refers to a discrete area representing loss of retinal anatomy (e.g., photoreceptors and retinal pigment epithelium (RPE)). GA area is measured by standard imaging techniques, such as fundus autofluorescence (FAF) and digital color fundus photography (CFP).

"Early AMD," as used herein, is disease characterized by multiple small (<63 μm) or ≥1 intermediate drusen (≥63 μm and <125 μm).

"Medium drusen AND," as used herein, is disease characterized by multiple medium drusen or >1 large drusen (>125 μm), often with hyper- or hypo-pigmentation of the retinal pigment epithelium.

"Advanced AMD," as used herein, refers to disease characterized by geographic atrophy (GA) or cardiovascular (wet) AMD.

A "prognostic biomarker," as used herein, is a marker that is indicative of the likely course of a disease in an untreated individual.

"Predictive biomarker," as used herein, identifies a subpopulation of patients who are more likely to respond to a given treatment.

"Affinity" refers to the strength of the sum of all non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen-binding arm). The affinity of a molecule X for its partner Y can typically be expressed in terms of a dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

An "affinity matured" antibody is one with one or more alterations in one or more hypervariable regions (HVRs) compared to a parent antibody which does not possess said alterations, which alterations result in an improvement in the affinity of the antibody for antigen.

The terms "anti-target antibody" and "antibody that binds to a target" refer to an antibody that is capable of binding to a target (e.g., Factor D) with sufficient affinity to allow the antibody to be effectively used as a diagnostic and/or therapeutic agent targeting the target (e.g., Factor D). In one embodiment, the extent to which an anti-target antibody binds to an unrelated, non-target protein is about 10% less than the binding of the antibody to the target as measured, for example, by radioimmunoassay (RIA) or biacore assay. In specific embodiments, the antibody that binds to the target has a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10-8 M or less, e.g., 10-8 M to 10-13 M, e.g., 10-9 M to 10-13 M). In specific embodiments, the anti-target antibody binds to an epitope of the target that is conserved between different species.

The term "antibody" is used herein in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies (eg, bispecific antibodies), and antibody fragments so long as they exhibit the desired biological activity.

"Antibody fragments" comprise a portion of an intact antibody, preferably comprising its antigen-binding region. Examples of antibody fragments include Fab, Fab', F(ab') ₂ , and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

An "antibody that binds to the same epitope as a reference antibody" is an antibody that blocks more than 50% of the binding of the reference antibody to its antigen in a competition assay, whereas the reference antibody blocks more than 50% of the binding of the antibody to its antigen in a competition assay. In one aspect, the antigen binding activity of the antibodies of the invention is tested, for example, by known methods such as ELISA, Western blot, etc. In some embodiments, competition assays can be used to identify antibodies that compete with the reference antibody for binding to Factor D. In specific embodiments, the competing antibody binds to the same epitope (e.g., a linear or conformational epitope) as the reference anti-Factor D antibody referred to herein. Detailed exemplary methods for mapping epitopes bound by antibodies are provided in Morris (1996A) "Epitope Mapping Protocols," in Methods in Molecular Biology, Vol. 66 (Humana Press, Totowa, NJ). In an exemplary competitive assay, fixed factor D is incubated in a solution comprising an antibody (e.g., lampalizumab) binding factor D of a first label and a second unlabeled antibody, wherein the second unlabeled antibody is detected for its ability to compete with the first antibody for binding to factor D. The second antibody may be present in a hybridoma supernatant. As a control, fixed factor D is incubated in a solution comprising an antibody (e.g., lampalizumab) binding factor D of a first label but not comprising the second unlabeled antibody. After incubation under conditions allowing the first antibody to bind to factor D, excess unbound antibody is removed, and the amount of the label associated with fixed factor D is measured. If the amount of the label associated with fixed factor D is reduced in a large amount relative to the control sample in the test sample, this represents that the second antibody competes with the first antibody (e.g., lampalizumab) for binding to factor D. See Harlow and Lane (1988) Antibodies: A Laboratory Manual, Chapter 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

"Acceptor human framework" for the purpose of this article is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may include the same amino acid sequence, or it may include amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to a VL human immunoglobulin framework sequence or a human consensus framework sequence.

For the purposes herein, an "intact antibody" is an antibody comprising heavy and light chain variable domains and an Fc region.

As used herein, "anti-human Factor D antibody" means an antibody that specifically binds to human Factor D in such a way as to inhibit or substantially reduce complement activation.

As used herein, the term "Factor D" is used herein to refer to a native sequence or variant Factor D polypeptide.

"Native sequence" factor D is a polypeptide having an amino acid sequence identical to that of a natural factor D polypeptide, and has nothing to do with its preparation method. Therefore, native sequence factor D can be separated from nature, or can be prepared by recombinant and/or synthetic means. In addition to mature factor D protein, such as mature human factor D protein (NM_001928), the term "native sequence factor D" particularly includes naturally occurring factor D precursor forms (e.g., inactive preprotein, which is proteolytically cleaved and produces an active form), naturally occurring variant forms of factor D (e.g., alternatively spliced forms) and naturally occurring allelic variants, and structural conformational variants of factor D molecules with an amino acid sequence identical to that of a natural factor D polypeptide. Factor D polypeptides of non-human animals (including higher primates and non-human mammals) are particularly included within this definition.

By "Factor D variant" is meant an active Factor D polypeptide as defined below that has about 80% amino acid sequence identity to a native sequence Factor D polypeptide, such as a native sequence human Factor D polypeptide (NM_001928). Generally, a Factor D variant has at least about 80% amino acid sequence identity, or at least about 85% amino acid sequence identity, or at least about 90% amino acid sequence identity, or at least about 95% amino acid sequence identity, or at least about 98% amino acid sequence identity, or at least about 99% amino acid sequence identity to the mature human amino acid sequence (NM_001928).

The term "Factor D inhibitor" as used herein refers to a molecule that has the ability to inhibit the biological function of wild-type or mutant Factor D. Thus, the term "inhibitor" is defined in the context of the biological action of Factor D. In one embodiment, the Factor D inhibitors referred to herein specifically inhibit the alternative pathway of complement. The Factor D inhibitor can be in any form, as long as it is capable of inhibiting Factor D activity; inhibitors include antibodies (e.g., monoclonal antibodies as defined below and described in U.S. Patent Nos. 8,067,002 and 8,273,352), small organic/inorganic molecules, antisense oligonucleotides, aptamers, inhibitory peptides/polypeptides, inhibitory RNAs (e.g., small interfering RNAs), combinations thereof, and the like. In the context of a Factor D antagonist or inhibitor, "active" or "activity" or "biological activity" is the ability to antagonize (partially or completely inhibit) the biological activity of Factor D. An example of a biological activity of a Factor D antagonist is the ability to achieve a measurable improvement in the condition (e.g., pathology) of a Factor D-associated disease or disorder (such as, for example, a complement-associated eye disorder). Activity can be determined in in vitro or in vivo assays, including binding assays, alternative pathway hemolytic assays, using relevant animal models, or human clinical trials.

The term "biomarker" as used herein generally refers to a molecule, including a single nucleotide polymorphism (SNP), protein, carbohydrate structure, or glycolipid, whose expression in or on a mammalian tissue or cell can be detected by standard methods (or methods disclosed herein) and predicts, diagnoses, and/or prognoses the sensitivity of the mammalian cell or tissue to a therapeutic regimen based on inhibition of complement (e.g., the alternative pathway of complement). Alternatively, a SNP biomarker is determined when the SNP (a binary entity) divides a group of individuals into responders and non-responders. For example, a SNP of two nucleotides is identified: G and A, where A is the risk allele, carriers of the A allele (e.g., AA or GA individuals) respond to treatment, while individuals without the A allele (e.g., GG individuals) do not respond.

The term "single nucleotide polymorphism" is also referred to as "SNP" in this article and is used herein to refer to a single base substitution in a DNA sequence that causes genetic variability. The nucleotide position in a genome that may have more than one sequence in a colony is referred to as a "polymorphic site" or "polymorphism" in this article. For example, a polymorphic site can be a nucleotide sequence of more than two nucleotides, an inserted nucleotide or nucleotide sequence, a deleted nucleotide or nucleotide sequence, or a microsatellite. A polymorphic site that is more than two nucleotides in length can be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, more than 15, more than 20, more than 30, more than 50, more than 75, more than 100, more than 500, or about 1000 nucleotides in length, wherein all or some of the nucleotide sequence are different in the region. A polymorphic site that is a single nucleotide in length is referred to as a SNP herein. When there are two, three, or four alternative nucleotide sequences in a polymorphic site, every kind of nucleotide sequence is referred to as a "polymorphic variant" or "nucleic acid variant." Every possible variant in the DNA sequence is referred to as an "allele." When there are two polymorphic variants, the polymorphic variant that is present in most samples from the population is called the "prevalent allele" or "major allele", and the polymorphic variant that is less prevalent in the population is called the "uncommon allele" or "minor allele". An individual carrying two prevalent alleles or two uncommon alleles is "homozygous" for the polymorphism. An individual carrying one prevalent allele and one uncommon allele is "heterozygous" for the polymorphism. For C/G or A/T SNPs, the allele is uncertain and depends on the chain used to obtain data from the genotyping platform. For these C/G or A/T SNPs, the C or G nucleotide or the A or T nucleotide can be the risk allele, respectively, and is determined by the correlation of allele frequencies. Alleles associated with increased disease risk or associated with an odds ratio or relative risk of >1 are called "risk alleles" or "effect alleles". " risk allele " or " effect allele " can be minor allele or main allele.For example, in the individual colony suffering from age-related macular degeneration (for example, determining the main and minor allele state of allele in the individual colony suffering from age-related macular degeneration), described risk allele is the minor allele of SNPs rs4698775, rs17440077 and rs2230199, and described risk allele is the major allele of SNPs rs10737680, rs1329428 and rs429608.Term " risk locus " is that genome carries the zone of the risk allele relevant to specific disease (for example AMD).In some respects, one or more risk loci and one or more risk alleles are represented by themselves and the dependency of the specific gene (for example, the gene in the complement pathway) participating in specific disease (for example AMD). For example, "CFH risk allele" or "CFH allele" used interchangeably herein refer to the risk allele associated with the CFH risk locus; "CFI risk allele" or "CFI allele" used interchangeably herein refer to the risk allele associated with the CFI risk locus, "C3 risk allele" or "C3 allele" used interchangeably herein refer to the risk allele associated with the C3 risk locus; "C2 risk allele" or "C2 allele" used interchangeably herein refer to the risk allele associated with the C2 risk locus; "CFB risk allele" or "CFB allele" used interchangeably herein refer to the risk allele associated with the CFB risk locus; and, "C2/CFB risk allele" or "C2/CFB allele" used interchangeably herein refer to the risk allele associated with the C2/CFB risk locus. "Equivalent allele" or "alternative allele" as used herein refers to an allele that is expected to behave similarly to a published risk allele and is selected based on allele frequency compared to a published risk allele and/or a selected SNP as defined herein and a high ^r² (≥0.6) and/or high D' (≥0.6). In one embodiment, the high ^r² is ≥0.6, 0.7, 0.8, 0.9 or 1.0. In one embodiment, the high D' is ≥0.6, 0.7, 0.8, 0.9 or 1.0. SNPs associated with age-related macular degeneration include SNPs in loci of components of the complement cascade, including, but not limited to, CFH, CFI, C3, C2, CFB risk loci (Fritsche et al. (Nature Genetics, 45(4): 435-441 (2013)). The SNPs associated with age-related macular degeneration are referred to herein as "AMD-associated polymorphisms". "Degenerative disease associated polymorphism" refers to a polymorphism or SNP associated with a degenerative disease, and includes polymorphisms and/or SNPs associated with age-related macular degeneration. "Linkage disequilibrium" or "LD" as used herein refers to alleles at different loci that are randomly unrelated (i.e., unrelated in proportion to their frequencies). If alleles are in positive linkage disequilibrium, then the alleles are more likely to be statistically independent than expected assuming In some embodiments, the alleles of the present invention are more commonly present together if the alleles are in negative linkage disequilibrium (statistical independence). In contrast, if the alleles are in negative linkage disequilibrium, the alleles are less commonly present together than the predicted putative statistical independence. "Odds ratio" or "OR" as used herein refers to the ratio of the disease likelihood of an individual with a marker (allele or polymorphism) relative to the disease likelihood of an individual without the marker (allele or polymorphism). "Haplotype" as used herein refers to a group of alleles on a single chromosome that are sufficiently tightly linked to be inherited as a unit. SNPs rs4698775 and rs17440077 are located at the CFI risk locus, rs10737680 and rs1329428 are located at the CFH risk locus, rs429608 is located at the C2/CFB risk locus, and rs2230199 is located at the C3 risk locus (Genomic Reference Sequence Consortium GRCh37; UCSC Genome H19 Assembly; February 2009). SNP SNP rs4698775 is located at position 110590479 on human chromosome 4 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009). This G allele changes the nucleotide sequence from T to G. SNP rs17440077 is located at position 110537567 on human chromosome 4 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009). This G allele changes the nucleotide sequence from A to G. SNP rs10737680 is located at position 196679455 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009). This A allele changes the nucleotide sequence from C to A. SNP SNP rs1329428 is located at position 196702810 on human chromosome 1 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009). This G allele changes the nucleotide sequence from A to G. SNP rs429608 is located at position 31930462 on human chromosome 6 (Genomic Reference Sequence Consortium GRCh37; UCSC Genome HG19 assembly; February 2009). This G allele changes the nucleotide sequence from A to G. Rs2230199 is located at position 6718387 on human chromosome 19 (Genomic Reference Sequence Consortium GRCh37; UCSC Genomic HG19 Assembly; February 2009). The G allele changes the nucleotide sequence from C to G, and the encoded amino acid changes from arginine to glycine. Polymorphic variants can be detected on either or both chains of a double-stranded nucleic acid. In addition, polymorphic variants can be located within introns or exons of a gene or within a regulatory region portion, such as a promoter, 5' untranslated region (UTR), 3'UTR, and are located in DNA (e.g., genomic DNA (gDNA) and complementary DNA (cDNA)), RNA (e.g., mRNA, tRNA, and rRNA), or within a polypeptide. Polymorphic variants may or may not result in detectable differences in gene expression, polypeptide structure, or polypeptide function.

The term "selected SNP" as used herein refers to a SNP selected from the group consisting of rs4698775, rs17440077, rs10737680, rs1329428, rs429608, rs2230199.

The term "surrogate SNP" as used herein refers to a SNP that is predicted to behave similarly to a selected SNP and is selected based on similar allele frequencies and has linkage disequilibrium measured by r ² ≥ 0.6 and/or D' ≥ 0.6 with the selected SNP. Surrogate SNPs include the SNPs listed in Tables 4-7 that are in linkage disequilibrium (with D' or r ² ≥ 0.6) with the SNPs described herein (including SNPrs1329428, SNP rs2230199, SNP rs17440077, or SNP rs429608). Surrogate SNPs include those that are in linkage disequilibrium (with D' or r ² ≥ 0.6) with the SNPs described herein (including SNP rs2230199 or SNP rs4698775). The terms used in Tables 4-7 are defined as follows: (i) MAHALO_SNP refers to the SNP used in the anti-Factor D studies described in Examples 1-4; (ii) LD_SNP refers to the SNP that is in LD with the MAHALO_SNP (rsID designation from NCBI dbSNP build 137 (June 6, 2012) or International Nomenclature designation (e.g., X-XXXXX)), wherein the MAHALO_SNP includes the chromosome and base pair position (first number = chromosome number, second number after hyphen = base pair position) from genome build hg18 (UCSC HG18 genome assembly; March 2006); (iii) CHR refers to the chromosome position of the LD_SNP (genome build hg19; UCSC HG19 genome assembly; February 2009); (iv) BP refers to the DNA base pair position of the LD_SNP (genome build hg19; UCSC HG19 genome assembly; February 2009). R2 refers to the r-squared value of MAhALO_SNP and LD_SNP; (v) D' refers to the D' value of MAHALO_SNP and LD_SNP; (vi) Ancestry or "ANC" refers to the ancestry of the population used to determine the r2 and D'values; (vii) Source or "SRC" refers to a database listing common variants in the human genome (internal data or "GID" refers to a non-public database, 1000GP or "GP" refers to the 1000 Genomes Project public database (1000 Genomes Project Consortium et al., Nature, 467(7319): 1061-73 (2010)), and Hapmap or "HM" refers to the HapMap public database (International HapMap Consortium, Nature, 437(7063): 1299-320 (2005)). Population descriptions include: Caucasian (CAU); Southwest (Southwest) =African ancestry (ASW(A)) in the USA; Utah residents with Northern and Western European ancestry from the CEPHcollection (CEU(C)); Han Chinese in Beijing, China (CHB(H)); Central Indians in metropolitan Denver, Colorado (CHD(D)); Gujarati Indians in Houston, Texas (GIH(G)); Japanese in Tokyo, Japan (JPT(J)); Luhya in Webuye, Kenya (LWK(L)); Mexican ancestry (MEX(M)) in Los Angeles, California; Maasai in Kinyawa, Kenya (MKK(K)); Tuscans in Italy (TSI(T)); Yoruba in Ibadan, Nigeria (YRI(Y)). Table 4 shows the LD_SNPs in linkage disequilibrium (LD) with MAHALO_SNP rs17440077. Table 5 shows the LD_SNPs in linkage disequilibrium (LD) with MAHALO_SNP rs17440077. rs2230199 linkage disequilibrium (LD) LD_SNPs. Table 6 shows LD_SNPs in linkage disequilibrium (LD) with MAHALO_SNP rs429608. Table 7 shows LD_SNPs in linkage disequilibrium (LD) with MAHALO_SNP rs1329428.

The present invention provides methods for using the SNPs or other gene-based mechanisms as predictive biomarkers to predict response to treatment and as prognostic biomarkers to assess the progression of AMD, methods for using the SNPs or other gene-based mechanisms to select treatment strategies, and methods for using the SNPs or other gene-based mechanisms to stratify patients (including, but not limited to, selecting patients for clinical studies) or making clinical treatment decisions. "Patient stratification" as used herein refers to genotyping an individual to determine the likelihood of responding to treatment. Genotyping is performed to identify whether the individual carries a SNP. There are various methods for measuring specific SNP genotyping. Individuals carrying mutations in one or more SNPs can be detected at the DNA level by various techniques, including, but not limited to, SNP arrays, Taqman, fluorescence polarization, Sequenom (or other methods for analyzing SNPs described herein). Nucleic acids used for diagnosis can be obtained from the patient's cells, such as from blood, urine, saliva, tissue biopsy, and autopsy material.

" danger of increase " refers to when being used in this article, when in individual genome, there is specific base (relative to the colony that does not have described base in this genomic position, the possibility of AMD of the generation that increases more late form is relevant to) the time, think that described individuality is in " the danger of increase " of the AMD of the generation more late form, that is, there is the susceptibility of increase.In the present case, when base is present in individual one or another or two allelotrope, there is the possibility of described increase.In addition, when base is present in two allelotropes of individuality rather than being present in an allelotrope of described individuality, described possibility increases.

" the danger of reduction " refers to when being used in this article, when in individual genome, there is specific base (relative to the colony that does not have described base in this genomic position, the possibility of the generation of the AMD of later forms that described individual reduces is relevant) time, think that described individual is in " the danger of reduction " that the AMD of later forms that occurs, that is, there is the possibility of reduction.Described allele is sometimes referred to as " protective " in this area.As the danger that increases, it also may be characterized as dominant or recessive by the risk of reduction.

"Altered risk" means an increased or decreased risk.

Genomic DNA can be directly used for detection, or can be amplified by using PCR before analyzing genomic DNA or transcript.For example, by hybridization of the single-stranded DNA from individual fragmentation with the array comprising thousands of fixed unique nucleotide probe sequences.Design the nucleotide probe sequence so that it is combined with the target DNA sequence (for example, for SNP, allele-specific probe is used to identify and analyze the presence or absence of the SNP).Use detection system to record and explain the hybridization signal (probe or DNA detection and measurement fluorophore labeling) between the DNA of individual. Detection of specific DNA sequences can be achieved by a variety of methods, including, but not limited to, hybridization, RNase protection, chemical cleavage, direct DNA sequencing or use of restriction enzymes, Southern blotting of genomic DNA, in situ analysis, hybridization of sample and control nucleic acids to high-density arrays containing thousands of oligonucleotide probes (Cronin et al., Hum Mutat, 7(3):244-55 (1996) (or other methods for analyzing SNPs described herein). For example, genetic mutations can be identified using microarrays (Shen et al., Mutat Res, 573(1-2):70-82 (2005)). These genetic tests can be used to separate a population of individuals into subgroups with different responsiveness to anti-Factor D therapy.

The term "genotyping" as used herein refers to methods for determining differences in the genetic makeup ("genotype") of an individual, including, but not limited to, detecting the presence of DNA insertions or deletions, polymorphisms (SNPs or other), alleles (including minor or major or risk alleles in the form of SNPs, by examining the DNA sequence of an individual using an assay or bioassay (or other methods for analyzing SNPs described herein). For example, the DNA sequence of an individual determined by sequencing or other methods (e.g., other methods for analyzing SNPs described herein) can be compared to the sequence of another individual or a reference sequence. Methods for genotyping are generally known in the art (e.g., other methods for analyzing SNPs described herein) and include, but are not limited to, restriction fragment length polymorphism detection (RFLP) of genomic DNA, random amplified polymorphism detection (RAPD) of genomic DNA, amplified fragment length polymorphism detection (AFLPD), polymerase chain reaction (PCR), DNA sequencing, allele-specific oligonucleotide (ASO) probes, and hybridization to DNA microarrays or beads. Similarly, these technologies can be applied to the transcripts of analysis coding SNPs or other genetic factors.Use polymerase chain reaction (PCR) analysis, array hybridization or use DNA SNP chip microarray (it is commercially available, including DNA microarray snapshot) to conveniently measure the SNP of sample.Microarray can be used to determine whether SNP exists or does not exist in nucleic acid samples. Microarrays can include oligonucleotides, and methods for making and using oligonucleotide arrays suitable for diagnostic applications are disclosed in U.S. Patent Nos. 5,492,806; 5,525,464; 5,589,330; 5,695,940; 5,849,483; 6,018,041; 6,045,996; 6,136,541; 6,152,681; 6,156,501; 6,197,506; 6,223,127; 6,225,625; 6,229,911; 6,239,273; WO 00/52625; WO 01/25485; and WO 01/29259.

In some embodiments, clinicians can use genetic analysis to guide the appropriate treatment program for individuals who are most in need of such a treatment program. For example, the subjects in the study are genotyped and classified into: (1) a group that responds favorably to the treatment, and (2) a group that does not respond significantly to the treatment, and (3) a group that responds unfavorably to the treatment. Based on the results, the subjects are genotyped to predict whether the subjects will respond favorably, unfavorably, or unfavorably to the treatment. Potential participants in a clinical trial of a treatment can be screened to identify those participants who are most likely to respond favorably to the treatment and to exclude those participants who may experience side effects. Thus, the efficacy of a drug treatment can be measured in individuals who respond positively to the drug. Therefore, one embodiment is a method for selecting individuals to be included in a clinical trial of a treatment, the method comprising the steps of: (a) obtaining a nucleic acid sample from the individual, (b) determining the presence of a polymorphic variant associated with a positive response to the treatment or a polymorphic variant associated with a negative response to the treatment. In another embodiment, the invention includes a method for selecting an individual for treatment, comprising the steps of: (a) obtaining a nucleic acid sample from the individual, (b) determining the presence of a polymorphic variant associated with a positive response to the treatment, and (c) treating the individual by implementing the therapy.

The term "allele-specific primer" or "AS primer" refers to a primer that hybridizes to more than one variant of a target sequence, but is capable of distinguishing between multiple variants of the target sequence because, under appropriate conditions, the primer is efficiently extended by a nucleic acid polymerase only when hybridized to one of the variants. When hybridized to other variants of the target sequence, the primer is extended less efficiently or ineffectively. When the extension efficiency is poor or ineffective, the signal intensity is substantially low, or preferably, below the detection limit.

The term "allele-specific probe" or "AS probe" refers to a probe that hybridizes to more than one variant of a target sequence, but is able to distinguish between variants of the target sequence because a detectable signal is generated only upon hybridization to one of the variants. Upon hybridization to other variants of the target sequence, the signal is substantially less intense, or, preferably, below the limit of detection.

The term "primary sequence" refers to the order of nucleotides in a polynucleotide or oligonucleotide. Nucleotide modifications, such as nitrogen base modifications, sugar modifications, or other backbone modifications, are not part of the primary sequence. Labels conjugated to oligonucleotides, such as chromophores, are also not part of the primary sequence. Thus, two oligonucleotides can share the same primary sequence but differ in modifications and labels.

The term "primer" refers to a sequence that hybridizes to a target nucleic acid and is capable of serving as a starting point for synthesis of a complementary strand along the nucleic acid under conditions suitable for synthesis. As used herein, the term "probe" refers to an oligonucleotide that hybridizes to a sequence in a target nucleic acid and is typically detectably labeled. The probe may have modifications, such as 3'-end modifications that prevent the probe from being extended by nucleic acid polymerases, and one or more chromophores. Oligonucleotides with the same sequence may serve as primers in one assay and as probes in a different assay.

The term "modified nucleotides" refers to nucleic acid polymers that contain modified bases, sugar or phosphate groups or units that incorporate non-natural structural moieties in their structure. Examples of non-natural nucleotides include nucleotides with modified nitrogen bases, such as alkylated or other substituents with groups that are not present in the conventional nitrogen bases that participate in Watson-Crick pairing. By way of illustration, and without limitation, modified nucleotides include those with methyl, ethyl, benzyl or butyl-benzyl substituted bases. In allele-specific PCR, at least one primer is allele-specific so that primer extension occurs (or preferentially occurs) only when the specific primer for the sequence exists, and when another variant exists, primer extension does not occur (or occurs with lower effectiveness, i.e., with basic ΔCt). The design of successful allele-specific primers is an unpredictable technique. Although designing primers of known sequences is conventional, there is no formula for designing primers that can distinguish very similar sequences. Such differentiation is particularly challenging when one or more allele-specific primers targeting one or more polymorphic sites are present in the same reaction mixture.

The terms "complementary" or "complementarity" are used with reference to the reverse strands of polynucleotides as related to the Watson-Crick base pairing rules. The terms "completely complementary" or "100% complementary" refer to complementary sequences with Watson-Crick pairing of all bases between the reverse strands, i.e., there are no mismatches between any two bases in the polynucleotide duplex. However, duplexes are formed between the reverse strands even in the absence of complete complementarity. The terms "partially complementary" or "incompletely complementary" refer to any base alignment between reverse polynucleotide strands that is less than 100% completely matched (e.g., there is at least one mismatch or unmatched base between the polynucleotide duplexes). Duplexes between partially complementary strands are generally not as stable as duplexes between completely complementary strands.

A "phenotype" is a characteristic that can be compared between individuals, such as the presence or absence of a condition, eg, the development of intermediate or advanced AMD.

Nucleic acid samples are separated from biological samples obtained from a subject. "Biological samples" include, but are not limited to, blood, saliva, sputum, cell scrapings, and tissue biopsies. Nucleic acid samples can be separated from biological samples using standard techniques. Nucleic acid samples can be used in methods for determining the presence of polymorphic variants. The presence or absence of polymorphic variants can be determined using one or two chromosome complements unique to the nucleic acid sample. Determining the presence or absence of the polymorphic variant in two chromosome complements unique to the nucleic acid sample can be used to determine the zygosity of an individual to the polymorphic variant.

The "stringency" of a hybridization reaction can be easily determined by one of ordinary skill in the art and is typically calculated empirically based on probe length, wash temperature, and salt concentration. Typically, longer probes require higher temperatures for proper annealing, while shorter probes require lower temperatures. Hybridization typically relies on the ability of denatured DNA to reanneal when the complementary strand is present in an environment below its melting temperature. The higher the desired degree of homology between the probe and the hybridizable sequence, the higher the relative humidity that can be used. Therefore, it can be assumed that higher relative humidity will tend to make the reaction conditions more stringent, while lower temperatures will be less stringent. For further details and explanations of the stringency of hybridization reactions, see Ausubel et al., Current Protocols in Molecular Blology, Wiley Interscience Publishers, (1995).

"Stringent conditions" or "high stringency conditions" as defined herein can be determined by: (1) using low ionic strength and high temperature for washing, e.g., 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50°C; (2) using a denaturing agent during hybridization, such as formamide, e.g., 50% (v/v) formamide and 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer, pH 6.5, containing 750 mM sodium chloride, 75 mM sodium citrate at 42°C; or (3) using 50% formamide, 5xSSC (0.75 M The hybridization was carried out overnight at 42°C in a solution of 50 mM NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5x Denhardt's solution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10% dextran sulfate, and washed in 0.2xSSC (sodium chloride/sodium citrate) at 42°C for 10 minutes, followed by a high-stringency wash in 0.1xSSC containing EDTA at 55°C for 10 minutes.

"Moderately stringent conditions" can be identified as described in Sambrook et al., Molecular Cloning: A Laboratory Manual , New York: Cold Spring Harbor Press, 1989, and include the use of wash solutions and hybridization conditions (e.g., temperature, ionic strength, and % SDS) that are less stringent than those described above. An example of moderately stringent conditions is an overnight incubation at 37° C. in a solution containing 20% formamide, 5×SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5×Denhardt's solution, 10% dextran sulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed by washing the filters in 1×SSC at approximately 37-50° C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc., as needed to accommodate factors such as probe length.

The term "sample" or "test sample" as used herein refers to a composition obtained from or derived from a subject of interest, comprising cells and/or other molecular entities to be characterized and/or identified, for example, based on physical, biochemical, chemical and/or physiological characteristics. In one embodiment, the definition includes blood and other liquid samples and tissue samples of biological origin, such as biopsy samples, or tissue cultures or cells derived therefrom. The source of a tissue sample can be solid tissue, such as an organ or tissue sample or biopsy or aspirate derived from fresh, frozen and/or preserved; blood or any blood substitute; body fluid; and cells or plasma from any time of pregnancy or subject development. The term "sample", "biological sample" or "test sample" includes biological samples that have been processed in any way after their acquisition, such as by treatment with a reagent, solubilization, or enrichment for a specific component (such as a protein or polypeptide), or embedded in a semi-solid or solid matrix for sectioning purposes. For the purposes of this article, a "section" of a tissue sample means a single portion or single piece of a tissue sample, for example, a thin slice of tissue or cells cut from a tissue section. Samples include, but are not limited to, whole blood, blood-derived cells, serum, plasma, lymph fluid, synovial fluid, cell extracts, and combinations thereof. In one embodiment, the sample is a clinical sample. In another embodiment, the sample is used for diagnostic assays.

In one embodiment, the sample is obtained from the subject or patient prior to treatment with the complement inhibitor. In another embodiment, the sample is obtained from the subject or patient after at least one treatment with the complement inhibitor.

" reference sample " is used in this article to refer to any sample, standard or level for comparison purposes. In one embodiment, the reference sample is obtained from a healthy and/or non-diseased body part (e.g., tissue or cell) of the same subject or patient. In another embodiment, the reference sample is obtained from untreated tissue and/or cells of the same subject or patient's body. In another embodiment, the reference sample is obtained from a healthy and/or non-diseased part (e.g., tissue or cell) of an individual body that is not the subject or patient. In another embodiment, the reference sample is obtained from an untreated tissue and/or cell part of an individual body that is not the subject or patient.

In a specific embodiment, a reference sample is a single sample or a combination of multiple samples from the same subject or patient, and the multiple samples are obtained at one or more time points different from obtaining the test sample. For example, a reference sample is obtained from the same subject or patient at an earlier time point than obtaining the test sample. In a specific embodiment, a reference sample includes all types of biological samples defined above under the term "sample" obtained from one or more individuals that are not a subject or patient. In a specific embodiment, a reference sample is obtained from one or more individuals that are not the subject or patient who suffer from a degenerative disease (e.g., age-related macular degeneration).

In a specific embodiment, the reference sample is a combined multiple samples from one or more healthy individuals who are not the subject or patient. In a specific embodiment, the reference sample is a combined multiple samples from one or more individuals who are not the subject or patient and have a disease or condition (e.g., a degenerative disease, such as, for example, age-related macular degeneration). In a specific embodiment, the reference sample is a pooled RNA sample or pooled plasma or plasma sample from normal tissue of one or more individuals who are not the subject or patient.

The term "Fc receptor" or "FcR" is used to describe a receptor that binds to the Fc region of an antibody. Preferred FcRs are native sequence human FcRs. In addition, preferred FcRs are FcRs (gamma receptors) that bind to IgG antibodies, and include receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibiting receptor"), which have similar amino acid sequences and differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (see Dahron Annu. Rev. Immunol. 15: 203-234 (1997)). For a review of FcRs, see Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and deHaas et al., J. Lab. Clin. Med. 126:330-41 (1995). The term "FcR" herein encompasses other FcRs, including those to be identified in the future. The term also includes the neonatal receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

"Native antibodies" are typically heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced interchain disulfide bond. Each heavy chain has a variable domain ( _VH ) at one end followed by a number of constant domains. Each light chain has a variable domain ( _VL ) at one end and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the variable domain of the light chain is aligned with the variable domain of the heavy chain. Specific amino acid residues are believed to form the interface between the light and heavy chain variable domains.

The term "variable" refers to the fact that certain portions of the variable domains of antibodies differ extensively in sequence and are used for the binding and specificity of each particular antibody for its particular antigen. However, variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called hypervariable regions in the light and heavy chain variable domains. The more highly conserved portions of the variable domains are called framework regions (FRs). The variable domains of native heavy and light chains each contain four FRs, which mostly adopt a β-sheet configuration, connected by three hypervariable regions that form loops connecting and, in some cases, forming part of the β-sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRs and, together with the hypervariable regions of the other chain, contribute to the formation of the antibody's antigen-binding site (see Kabab et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in ADCC.

Papain digestion of antibodies produces two identical antigen-binding fragments (called "Fab" fragments, each with a single antigen-binding site) and a residual "Fc" (whose name reflects its ability to crystallize readily). Pepsin treatment produces an F(ab') ₂ fragment, which has two antigen-binding sites and is still capable of cross-linking antigen.

"Fv" is the smallest antibody fragment that contains a complete antigen recognition and antigen binding site. This region consists of a dimer of one heavy-chain variable domain and one light-chain variable domain in tight, non-covalent association. It is in this configuration that the three hypervariable regions of each variable domain interact to define an antigen-binding site on the surface of the _VH - _VL dimer. Collectively, these six hypervariable regions confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three hypervariable regions specific for an antigen) has the ability to recognize and bind antigen, although with lower affinity than the entire binding site.

Fab fragments also contain the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residues of the constant domains bear at least one free thiol group. F(ab') ₂ antibody fragments were originally generated as paired Fab' fragments with hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

The "light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

Depending on the amino acid sequence of the constant domain of the antibody heavy chain, antibodies can be divided into different classes. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG and IgM, and several of these classes can be further divided into subclasses (isotypes), for example, IgG1, IgG2, IgG3, IgG4, IgA and IgA2. The heavy chain constant domains corresponding to the different classes of antibodies are called α, δ, ε, γ and μ, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known.

"Single-chain Fv" or "scFv" antibody fragments comprise the _VH and _VL domains of an antibody, wherein these domains are present in a single polypeptide chain. Preferably, the Fv polypeptide further comprises a polypeptide linker between the _VH and _VL domains that enables the scFv to form the desired antigen-binding structure. For a review of scFv, see Plückthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore, eds., Springer-Verlag, New York, pp. 269-315 (1994).

The term "diabodies" refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain ( _VL ) on the same polypeptide chain ( _{VH - VL} ). By making the linker too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are more fully described in, e.g., EP 404,097; WO 93/11161; and Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

The term "monoclonal antibody" as used herein refers to an antibody obtained from a group of substantially homogeneous antibodies, i.e., the individual antibodies comprising the group are identical and/or bind to the same epitope, except for possible variants that may arise during the production of the monoclonal antibody (such variants are generally present in small amounts). Compared to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous because they are not contaminated by other immunoglobulins. The modifier "monoclonal" indicates the characteristic that the antibody is obtained from a substantially homogeneous group of antibodies and should not be construed as requiring the antibody to be produced by any particular method. For example, the monoclonal antibodies used in accordance with the present invention can be prepared by the hybridoma method first described by Kohler et al., Nature, 256: 495 (1975), or can be prepared by recombinant DNA methods (e.g., see U.S. Patent No. 4,816,567). For example, "monoclonal antibodies" can also be isolated from phage antibody libraries using the techniques described by Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991).

The monoclonal antibodies herein specifically include "chimeric" antibodies (immunoglobulins), and fragments of such antibodies, so long as the fragments exhibit the desired biological activity (U.S. Pat. No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984)). In such chimeric antibodies, a portion of the heavy and/or light chain is identical or homologous to the corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass. Chimeric antibodies of interest herein include "primatized" antibodies comprising variable domain antigen-binding sequences derived from non-human primates (e.g., Old World Monkeys, such as baboon, rhesus monkeys, or cynomolgus monkeys) and human constant region sequences (U.S. Pat. No. 5,693,780).

In some embodiments, the humanized antibody is a chimeric antibody comprising a minimum sequence from a non-human immunoglobulin (Ig). For the largest part, a humanized antibody is a human immunoglobulin (Ig) (acceptor antibody), wherein the residue from the acceptor hypervariable region is replaced by the residue from the hypervariable region (donor antibody) with the specificity, affinity and ability required of a non-human species (such as mouse, rat, rabbit or non-human primate). In some cases, the human immunoglobulin framework region (FR) residues are replaced by corresponding non-human residues. In addition, the humanized antibody can be included in the acceptor antibody or in the non-existent residues of the donor antibody. These modifications are carried out to further optimize antibody performance. Generally, the humanized antibody will comprise substantially all, at least one and typically two variable domains, wherein all or substantially all of the corresponding non-human immunoglobulins of the hypervariable ring, and all or substantially all of the FRs are those of human immunoglobulin sequences, except that the FR shown above replaces. The humanized antibody optionally also comprises at least a portion of an immunoglobulin constant region, typically at least a portion of a human immunoglobulin constant region. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).

"Framework" or "FR" refers to the variable domain residues excluding the hypervariable region (HVR) residues. The FR of a variable domain is generally composed of four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences generally appear in the following order in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

The term "hypervariable region" or "HVR" as used herein refers to each region of an antibody variable domain whose sequence is hypervariable and/or forms structurally defined loops ("hypervariable loops"). Typically, a natural four-chain antibody comprises six HVRs; three in VH (H1, H2, H3) and three in VL (L1, L2, L3). HVRs typically comprise amino acid residues from hypervariable loops and/or "complementarity determining regions" (CDRs), the latter of which have the highest sequence variability and/or are involved in antigen recognition. As used herein, an HVR comprises any number of residues located at the following positions: 24-36 (for L1), 46-56 (for L2), 89-97 (for L3), 26-35B (for H1), 47-65 (for H2) and 93-102 (for H3). Thus, an HVR comprises residues at the aforementioned positions:

A) 24-34 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987);

B) 24-34 of L1, 50-56 of L2, 89-97 of L3, 31-35B of H1, 50-65 of H2, and 95-102 of H3 (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991);

C) 30-36 (L1), 46-55 (L2), 89-96 (L3), 30-35 (H1), 47-58 (H2), 93-100a-j (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996).

Unless otherwise indicated, HVR residues and other residues (e.g., FR residues) in the variable domain are numbered herein according to Kabat et al. (see above). Typically, the Kabat numbering system is used when referring to residues in the variable domain (roughly residues 1-107 of the light chain and residues 1-113 of the heavy chain). 5th edition. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), explicitly incorporated herein by reference). Typically, when referring to residues in the immunoglobulin heavy chain constant region, the "EU numbering system" or "EU index" is used (e.g., Kabat et al., as reported above in the EU index; the hinge region in the heavy chain constant region is roughly residues 216-230 (EU numbering) of the heavy chain). "EU index as in Kabat" refers to the residue numbering of human IgG1 EU antibodies. Unless otherwise indicated herein, referring to the residue number in the antibody variable domain means the residue numbering according to the Kabat numbering system. Unless otherwise indicated herein, references to residue numbers in an antibody constant domain mean residue numbering according to the EU numbering system (eg, see U.S. Provisional Application No. 60/640,323, the accompanying drawings for EU numbering).

A "naked antibody" is an antibody (as defined herein) that is not conjugated to a heterologous molecule (such as a cytotoxic moiety or radiolabel).

An "isolated" antibody is one that has been identified and separated and/or recovered from a component of its natural environment. Contaminating components of an antibody's natural environment are substances that would interfere with its diagnostic or therapeutic use and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the antibody is purified to (1) greater than 95% by weight of the antibody, and most preferably greater than 99% by weight of the antibody, as determined, for example, by the Lowry method, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence using a spinning-cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using, for example, Coomassie blue or, preferably, silver stain. Isolated antibodies include antibodies in situ within recombinant cells, since at least one component of the antibody's natural environment will not be present. However, isolated antibodies are typically prepared by at least one purification step.

"Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after alignment and, if necessary, introduction of gaps to obtain maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment can be performed using a variety of methods within the skill in the art to determine percent amino acid sequence identity, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. One skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm required to achieve maximum alignment over the full length of the compared sequences. However, for this purpose, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The author of the ALIGN-2 sequence comparison computer program is Genentech, Inc., and the source code has been submitted with user documentation to the U.S. Copyright Office (Washington D.C., 20559) under U.S. copyright registration number TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc. (South San Francisco, California) or can be compiled from source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and are not changed.

In the case of amino acid sequence comparison using ALIGN-2, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (or in other words: a given amino acid sequence A has or contains a specific % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:

Multiply the X/Y ratio by 100,

where X is the number of amino acid residues scored as identical matches using the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be understood that when amino acid sequence A is not of equal length to amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless otherwise indicated, all % amino acid sequence identity values used herein are obtained as described in the preceding paragraph using the ALIGN-2 computer program.

The term "least squares" as used herein refers to the use of the least squares method, which minimizes the sum of the squares of the differences between each observed value and its estimated value (Plackett, R.L. Biometrics, 59: 239-251 (1972)). The least squares means described herein are based on an estimate of the mean DDAF change in GA area from baseline using a linear mixed efficacy model (Garret Fitzmaurice, Nan Laird, James Ware, Applied Longitudinal Analysis, 2nd Edition, Chapter 8, Publisher (John Wiley & Sons) (August 2011)), which was used to fit the relationship between GA area change relative to baseline GA lesion size (continuous), baseline GA lesion size category (<4 DA vs. ≥4 DA), time, treatment, and time-by-treatment interaction. See Figures 5 and 6.

The term "pharmaceutical formulation" refers to a preparation that is in form permitting the biological activity of the active ingredient contained therein to be effective, and that contains no additional ingredients that are unacceptably toxic to a subject to which the formulation would be administered.

"Pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

A "neutralizing antibody" is an antibody molecule that is able to eliminate or significantly reduce the effector function of the target antigen to which it binds. Thus, a "neutralizing" anti-Factor D antibody or antigen-binding fragment thereof is able to eliminate or significantly reduce the effector function of Factor D, such as spared complement activity.

An exemplary assay is one that monitors the ability of an anti-Factor D antibody or antigen-binding fragment thereof to neutralize the alternative complement activity of Factor D. See, for example, the hemolysis inhibition assay described in PCT/US2007/083172, published May 8, 2008, in which neutralization is measured by the ability of a candidate antibody to inhibit hemolysis of rabbit red blood cells using C1q-deficient human serum as a source of complement.

Alternatively, the ability of anti-Factor D antibodies to neutralize the cellular response induced by Factor D can be assayed by the C3 fluid phase invertase assay as described by Wiesmann et al., Nature, 444:217-220 (2006).

By "significant" reduction is meant a reduction in target antigen (e.g., Factor D) effector function (e.g., alternative complement activity) of at least about 60%, or at least about 70%, preferably at least about 75%, more preferably at least about 80%, even more preferably at least about 85%, more preferably at least about 90%, more preferably at least about 95%, and most preferably at least about 99%. Preferably, a "neutralizing" antibody as defined herein is capable of neutralizing at least about 60%, or at least about 70%, preferably at least about 75%, more preferably at least about 80%, even more preferably at least about 85%, more preferably at least about 90%, more preferably at least about 95%, and most preferably at least about 99% of the anti-alternative pathway activity of Factor D as measured by the hemolytic assay described in PCT/US2007/083172, published May 8, 2008.

"Subject" or "patient" herein is a human subject or patient. Typically, the subject or patient is suitable for the treatment of geographic atrophy. In one embodiment, the suitable subject or patient is a subject or patient who experiences or has experienced one or more signs, symptoms or other indications of geographic atrophy, or has been diagnosed with geographic atrophy, for example, whether newly diagnosed, previously diagnosed or in danger of developing geographic atrophy. In another embodiment, the patient to be treated can be screened with an assay for the presence of SNPs associated with AMD. A "stable" formulation is one in which the protein substantially retains its physical stability and/or chemical stability and/or biological activity upon storage. Preferably, upon storage, the formulation substantially retains its physical and chemical stability, as well as its biological activity. The storage period is typically selected based on the predetermined shelf life of the formulation. A variety of analytical techniques for measuring protein stability are available in the art and are summarized, for example, in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, New York, Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10: 29-90 (1993). Stability can be measured after a selected period of stability. Preferably, the formulation is stable at about 40°C for at least about 2-4 weeks, and/or at about 5°C and/or 15°C for at least 3 months, and/or at about -20°C for at least 3 months, or at least 1, 2, 3, or 4 years. Furthermore, the formulation is preferably stable after freezing (e.g., freezing to -70°C) and thawing the formulation, for example, after 1, 2, or 3 cycles of freezing and thawing. Stability can be assessed qualitatively and/or quantitatively in a variety of ways, including assessing aggregate formation (e.g., using size exclusion chromatography, by measuring turbidity, and/or by visual inspection); assessing charge heterogeneity by using cation exchange chromatography or capillary zone electrophoresis; amino-terminal or carboxyl-terminal sequence analysis; mass spectrometry analysis; SDS-PAGE analysis to compare reduced and intact antibodies; peptide mapping (e.g., trypsin or LYS-C) analysis; assessing the biological activity or antigen binding function of the antibody; etc. Instability can be related to any one or more of the following: aggregation, deamidation (e.g., Asn deamidation), oxidation (e.g., Met oxidation), isomerization (e.g., Asp isomerization), scission/hydrolysis/cleavage (e.g., hinge region cleavage), succinimide formation, unpaired cysteines, N-terminal extension, C-terminal processing, glycosylation differences, etc.

"Histidine buffer" is a buffer comprising histidine particles. Examples of histidine buffer include histidine chloride, histidine acetate, histidine phosphate, histidine sulfate. It is found that the preferred histidine buffer identified in the examples herein is histidine chloride. In one embodiment, the histidine chloride buffer is prepared by titrating L-histidine (free base, solid) with hydrochloric acid (liquid). In another embodiment, the histidine buffer is prepared by mixing histidine with histidine hydrochloride to obtain the required pH. Preferably, the histidine buffer or histidine chloride buffer is pH 5.0-6.0, preferably pH 5.2-5.8.

The "sugar" herein includes the general composition ( _CH2O )n and its derivatives, including monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, etc. Examples of sugars herein include glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, dextran, erythritol, glycerol, arabitol, sylitol, sorbitol, mannitol, mellibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, glucitol, maltitol, lactitol, isomaltulose, and the like.

As used herein, "surfactant" refers to a surface active agent, preferably a nonionic surfactant. Examples of surfactants herein include polysorbates (e.g., polysorbate 20 and polysorbate 80); poloxamers (e.g., poloxamer 188); Triton; sodium dodecyl sulfate (SDS); sodium laurate sulfate; sodium octyl glycoside (sodium octyl glycoside); octylglycoside); lauryl-, myristyl-, linoleyl-, or stearoyl-sulfobetaine; lauryl-, myristyl-, linoleyl-, or stearoyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl); myristamidopropyl-, palmamidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl taurate, or disodium methyl oleyl tartrate; and the MONAQUAT ^™ series (Mona Industries, Inc., Paterson, New Jersey); polyethylene glycol, polypropylene glycol, and copolymers of ethylene glycol and propylene glycol (e.g., Pluronics, PF68, etc.); etc. The preferred surfactant herein is polysorbate 20.

The diagnosis of GA can be made based on clinical history, clinical examination, and established imaging modalities.

As used herein, "treatment" of a subject refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already suffering from GA as well as those in whom GA is to be prevented. Thus, the subject may have already been diagnosed with GA or may be susceptible to or be susceptible to GA.

A "symptom" of GA is any pathological phenomenon or deviation from normal in structure, function, or sensation experienced by a subject and indicative of the disease.

The expression "effective amount" refers to an amount of an antibody effective for preventing, improving or treating GA.

"Antibody exposure" refers to contact with or exposure to an antibody herein at one or more doses administered over a period of about 1 day to about 5 weeks. The dose can be administered once or at fixed or irregular intervals during the exposure period, for example, once a week for four weeks, or two doses separated by about 13-17 days. The initial and subsequent antibody exposures are separated in time from each other as described in detail herein.

A "Factor D inhibitor" herein is an agent that inhibits, to some extent, the biological function of Factor D, typically by binding to or neutralizing the activity of Factor D. An example of a Factor D inhibitor specifically contemplated herein is lampalizumab.

"Package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications, other therapeutic products in combination with the packaged product, and/or warnings concerning the use of the therapeutic product.

An exposure that is not administered or provided until a specified time "from the initial exposure" or from any prior exposure means that, if more than one dose is administered in the exposure, the time of the second or subsequent exposure is measured from the time of administration of any dose in the prior exposure. For example, when two doses are administered in the initial exposure, the second exposure is not given until at least about 16-54 weeks has passed since the time of administration of the first and second doses within the prior exposure. Similarly, when three doses are administered, the second exposure can be measured from the time of the first, second, or third dose within the prior exposure. Preferably, "from the initial exposure" is measured from the time of the first dose.

A "drug" is an active medication that treats geographic atrophy or its symptoms or side effects.

The term "administration" is used herein in the broadest sense and specifically includes enteral, topical, and "parenteral administration." "Parenteral administration" and "administered parenterally" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intrasternal injection, infusion, ocular, intraocular, intravitreal, juxtascleral, subconjunctival, and superchoroidal. "IVT or ITV" as used herein means intravitreal.

Term " assessing AMD " is used to represent that method described in the present invention will assist medical expert (for example, including physician) to assess whether individuality is in the risk that AMD occurs in mid-term or late period or prognosis is to mid-term or late period AMD.The existence of the risk allele about CFI, CFH, C3, C2 or CFB in sample represents that described individuality is in the risk that AMD occurs in mid-term or late period or prognosis is to late period AMD.

The result from prognosis detection can be combined with other testing results, thereby diagnose the progress to AMD in more late period.In some embodiments, the result from tendency analysis can be combined with other detections, and described other testing results are epidemiology or genetics in nature, indicate the progress to AMD in more late period.In these embodiments, the combination of prognosis detection result and other testing results can be demonstrable or progress into AMD in more late period, and this combination can be used as AMD diagnosis.

The term "progression" is used herein to refer to the worsening of a disease over time. "Progression rate" or "rate of progression" refers to how fast or slow a disease progresses over time in a patient diagnosed with the disease. Diseases are typically chronic, and the timeframe can be weeks, months, or years. The progression rate of a disease can be represented by the measurable changes in a disease-specific characteristic over time. For example, the progression rate of a patient suffering from GA can be represented by the growth rate of the GA lesion area from baseline to the 18th month, as measured by standard imaging methods such as fundus autofluorescence (FAF) or color fundus photography (CFP). If its disease state progresses faster than those patients without the genetic signature, it is believed that the patient carrying the specific genetic signature has or is more likely to have a "progression rate that is improved." On the other hand, if its disease progression slows down after treatment compared to its disease state before treatment or compared to other patients not treated, it is believed that the patient responding to treatment has or is more likely to have a "slowed progression rate."

" more likely to respond " is used in this article and refers to the patient that more likely shows that AMD progress slows down or prevents.About GA, " more likely to respond " refers to the patient that more likely shows the GA area loss that FAF or CFP measure reduces with treatment.About mid-term AMD, " more likely to respond " refers to the patient that more likely shows the slowing down of late AMD progress.About early stage AMD, " more likely to respond " refers to the patient that more likely shows the slowing down of mid-term AMD progress.Word " response " represents in situation of the present invention and suffers from, suspects and suffers from or tends to suffer from or diagnoses the patient that suffers from illness as herein described and shows the response for anti-factor D treatment.

An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys and rabbits), and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human.

"Patient" or "subject" is any single human subject suitable for treatment herein, and it experiences or has experienced a kind of or or signs, symptoms or other indications of AMD.To be included as a subject is any subject who does not show any clinical signs of disease in a clinical research trial, or a subject who participates in an epidemiological study or a subject who was once used as a control.The subject may have been treated with an anti-factor D antibody or its antigen-binding fragment or another drug before, or not treated like this.When the treatment herein begins, the subject may be first-time experimented with respect to the other drug mentioned, that is, the subject may not have been treated with, for example, the anti-factor D therapy except "baseline" (that is, in the therapeutic method herein, the time set point before the anti-factor D of the first dose is applied, such as the day when the subject was screened before the treatment began). The "first-time experimented" subject is generally considered to be a candidate for the treatment of the other drug.

Word " providing assessment " is used in this article and refers to the information or data about the existence of the risk allele in patient sample that use is produced to assess the AMD in the described patient.Described information or data can be any form, written, oral or electronic.In some embodiments, use the information or data that are produced to comprise communicating, introducing (presenting), reporting, storing, sending, transmitting, providing, transmitting, spreading or their combination.In some embodiments, communicating, introducing, reporting, storing, sending, transmitting, providing, transmitting, spreading or their combination are carried out by computing device, analyzer unit or their combination.In some other embodiments, communicating, introducing, reporting, storing, sending, transmitting, providing, transmitting, spreading or their combination are carried out by laboratory or medical expert.In some embodiments, information or data comprise the indication of the presence or absence of risk allele in the sample.In some embodiments, information or data comprise the indication that assessment patient suffers from mid-term or late period AMD.

The term "sample" refers to a bodily fluid sample, a sample of isolated cells, or a sample from a tissue or organ. Bodily fluid samples can be obtained by known techniques and include samples of blood, plasma, serum, urine, lymph, sputum, ascites, bronchial lavage fluid, or any other bodily secretion or derivative thereof. Tissue or organ samples can be obtained from any tissue or organ, for example, by biopsy. Isolated cells can be obtained from bodily fluids or tissues or organs using separation techniques such as centrifugation or cell sorting. For example, cell-, tissue-, or organ samples can be obtained from cells, tissues, or organs that express or produce a biomarker. Samples can be frozen, fresh, fixed (e.g., formalin-fixed), centrifuged, and/or embedded (e.g., paraffin-embedded), etc. Of course, cell samples can be subjected to a variety of known post-processing preparation and storage techniques (e.g., nucleic acid and/or protein extraction, fixation, storage, freezing, ultrafiltration, concentration, evaporation, centrifugation, etc.) prior to assessing the amount of marker in the sample. Similarly, tissue biopsy samples can also be prepared and stored after collection, for example, fixing.Sample can be gathered before treatment, during treatment or after treatment.Sample can be gathered from the patient who suspects suffering from or diagnoses AMD and therefore may need treatment, or from the normal individual who is not suspected of suffering from any disease.

The phrase "selecting patients" or "identifying patients" is used in this article to refer to using the information or data generated about the presence of risk alleles in patient samples to identify or select patients who are more likely to benefit from a treatment that includes anti-factor D antibodies. The information or data used or generated can be in any form, written, oral or electronic. In some embodiments, using the information or data generated includes communicating, introducing, reporting, storing, sending, transmitting, providing, transmitting, disseminating or a combination thereof. In some embodiments, communicating, introducing, reporting, storing, sending, transmitting, providing, transmitting, disseminating or a combination thereof is carried out by a computing device, an analyzer unit or a combination thereof. In some other embodiments, communicating, introducing, reporting, storing, sending, transmitting, providing, transmitting, disseminating or a combination thereof is carried out by a laboratory or a medical expert. In some embodiments, the information or data include an indication of the presence or absence of the risk allele in the sample. In some embodiments, the information or data include an indication that the assessment patient is more likely to respond to a treatment that includes anti-factor D.

The phrase "select a treatment" as used herein refers to the use of information or data generated about the presence of risk alleles in a patient sample to identify or select a treatment for a patient. In some embodiments, the treatment may include anti-factor D. In some embodiments, the phrase "identify/select a treatment" includes identifying a patient who needs to adjust the effective amount of anti-factor D administered. In some embodiments, recommending a treatment includes recommending adjustment of the amount of anti-factor D administered. The phrase "recommend a treatment" as used herein may also refer to the use of information or data generated to propose or select a treatment including anti-factor D for a patient identified or selected as more likely to respond to a treatment including anti-factor D. The information or data used or generated may be in any form, written, oral, or electronic. In some embodiments, the use of the information or data generated includes communicating, introducing, reporting, storing, sending, transmitting, providing, transmitting, disseminating, or a combination thereof. In some embodiments, the communication, introduction, reporting, storing, sending, transmitting, providing, transmitting, disseminating, or a combination thereof is performed by a computing device, an analyzer unit, or a combination thereof. In some other embodiments, communication, introduction, reporting, storage, sending, transmission, providing, transmitting, dissemination or their combination are carried out by laboratory or medical expert.In some embodiments, information or data comprise the indication of the presence or absence of risk allele in the sample.In some embodiments, information or data comprise the indication that the treatment comprising anti-factor D is suitable for the patient.

III. Methods

The present invention provides compositions and methods for treating, prognosing, diagnosing and/or selecting AMD patient colonies that will be good candidates for the treatment of complement inhibitors. In one embodiment, the present invention provides methods for predicting the progress of a degenerative disease (e.g., AMD (including GA and CNV)) in a patient, comprising determining the presence of a risk allele in the patient. In one embodiment, the present invention provides methods for treating a degenerative disease (e.g., AMD (including GA and CNV)) in a patient, comprising administering an effective amount of an antibody combining factor D, wherein the patient carries a risk allele associated with AMD. In some embodiments, the present invention provides methods for treating a degenerative disease (e.g., AMD (including GA and CNV)) in a patient, comprising administering an effective amount of an antibody combining factor D according to a specific dosing regimen. In some embodiments, the present invention provides methods for treating a degenerative disease (e.g., AMD (including GA and CNV)) in a patient, comprising administering an effective amount of an antibody combining factor D or its Fab, wherein the patient is heterozygous or homozygous for a risk allele associated with a degenerative disease (e.g., AMD (including GA and CNV)). In some embodiments, the patient carries a risk allele in one, or all, or a combination of CFH, CFI, C3, C2, and CFB. In one embodiment, the antibody or antigen-binding fragment thereof is lampalizumab. In one embodiment, the present invention provides methods for predicting the response of a patient with a degenerative disease to treatment with an anti-Factor D antibody or antigen-binding fragment thereof. In one embodiment, the present invention provides methods for optimizing the therapeutic efficacy of treatment of a patient with a degenerative disease using an anti-Factor D antibody or antigen-binding fragment thereof.

The present invention is based, in part, on the use of specific genes (e.g., one or more of complement factor I (CFI), complement factor H (CFH), complement component 2 (C2), complement component 3 (C3), and complement factor B (CFB), and combinations thereof) or biomarkers (e.g., SNPs of complement factor I (CFI), complement factor H (CFH), complement component 2 (C2), complement component 3 (C3), and complement factor B (CFB)) that correlate with the efficacy of a factor D inhibitor (e.g., an anti-factor D antibody or an antigen-binding fragment thereof). Thus, the disclosed methods provide a convenient, efficient, and potentially cost-effective way to obtain data and information that can be used to assess whether a treatment for a patient is appropriate or effective. For example, a sample can be obtained from an AMD patient and the sample can be tested using a variety of in vitro assays to determine the presence or absence of expression levels of one or more biomarkers compared to a reference sample. In one embodiment, if a patient carries the risk allele -, then the patient may benefit from treatment with a factor D inhibitor (e.g., an anti-factor D antibody, or an antigen-binding fragment thereof, such as, for example, lampalizumab). The presence of a gene or biomarker or SNP can be determined based on any appropriate criteria known in the art, including, but not limited to, mRNA, cDNA, protein, protein fragment, and/or gene copy number.

Analysis of SNPs in a sample can be performed in blood, tissue, or other body fluids by a variety of methods, many of which are well known in the art and understood by those skilled in the art, including, but not limited to, DNA sequencing, RNA sequencing, polymerase chain reaction analysis of DNA, polymerase chain reaction analysis of RNA, oligonucleotide-based hybridization, in situ hybridization, oligonucleotide-based primer extension, electrophoresis, and HPLC. Additional technologies for detecting SNPs include, but are not limited to, the following: scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time-temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platforms, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), isothermal intelligent amplification. (Methods in Molecular Biology, Single Nucleotide Polymorphisms, 2nd ed., editor Anton Komar, Humana Press 2009; Chapters 7-28), PCR amplification of simple sequence length polymorphisms (SSLPs), ligase chain reaction (LCR), RNase A cleavage, chemical cleavage of heteroduplex DNA, single-strand conformation polymorphism (SSCP) analysis (Warren et al., Current Protocol in Human Genetics, Supp 15:7.4.1-7.4.23 (2001), bead-chip microarray (Lambert et al., Current Protocol in Human Genetics, Supp 78:2.9.1-2.9.3 (2013)), single-strand conformation polymorphism (SSCP) analysis, primer single base extension (SBE) (Deshpande et al., Current Protocol in Human Genetics, Supp 34: 13.4.1-13.4.11 (2005)), primer extension assay (Kwok et al., Current Protocol in Human Genetics, Supp 39: 2.11.1-2.11.10 (2003). The presence of SNPs can also be deduced by protein-based analysis techniques (e.g., examining protein expression levels or function), including immunoassays (e.g., ELISA, ELIFA, immunohistochemistry and/or Western blot analysis, immunoprecipitation, molecular binding assays, fluorescence-activated cell sorting (FACS), etc., quantitative blood-based assays (e.g., serum ELISA), in situ hybridization, or functional assays, including biochemical enzyme activity assays or cell-based systems, as well as any of a wide variety of assays that can be performed by gene and/or tissue array analysis. For example, common protocols for evaluating the status of genes and gene products can be found in Ausubel et al., eds., 1995, Current Protocols In Molecular Biology, Units 2 (Northern Blotting), 4 (Southern Blotting), 15 (Immunoblotting) and 18 (PCR Analysis). Multiplex immunoassays, such as those available from Rules Based Medicine, bead-based immunoassays, for example Luminex, ELISA or Meso Scale Discovery (MSD) can also be used.

One technique that is sensitive and suitable for SNP analysis of the present invention is allele-specific PCR (AS-PCR), as described, for example, in U.S. Patent No. 6,627,402. This technique detects mutations or polymorphisms in a nucleic acid sequence in the presence of wild-type variants of the sequence. In successful allele-specific PCR, the desired variant of the target nucleic acid is amplified, while other variants are not amplified, at least to a level that is not detectable.

One distinguishing measure of allele-specific PCR is the difference between the Ct values (ΔCt) in the amplification reactions involving two alleles. Each amplification reaction is characterized by a "growth curve" or "amplification curve", which, in the case of nucleic acid amplification, is a function graph in which the independent variable is the number of amplification cycles, and the dependent variable is the measurement parameter of the amplification dependency measured at each amplification cycle, such as the fluorescence emitted by a fluorophore. Typically, the measurement parameter of amplification dependency is the amount of fluorescence emitted by the probe during hybridization or when the probe is hydrolyzed by the nuclease activity of a nucleic acid polymerase, see Holland et al., (1991) Proc. Natl. Acad. Sci. 88: 7276-7280 and U.S. Patent number 5,210,015. The growth curve is characterized by a "threshold value" (or Ct value), which is the number of cycles that achieves a predetermined amplitude of the measurement parameter. A lower Ct value indicates faster amplification, while a higher Ct value indicates slower amplification. In the case of an allele-specific reaction, the difference between the Ct values of the two templates represents the allelic discrimination in the reaction.

In allele-specific PCR, at least one primer is allele-specific, so that primer extension occurs only (or preferentially) when there is a specific variant of the sequence, and when there is another variant, does not occur (or the effectiveness of occurrence is poor, that is, with an objective ΔCt). The design of successful allele-specific primers is an unpredictable technology. Although designing primers of known sequences is conventional, there is no formula for designing primers that can distinguish very similar sequences. When there are one or more allele-specific primers targeting one or more polymorphic sites in the same reaction mixture, the distinction is particularly challenging.

Typically, the distinguishing nucleotides in the primer, that is, the nucleotides that only match a variant of the target sequence, are 3'-end nucleotides. However, the 3' end of the primer is only one of the multiple determinants of specificity. For example, other mispairings may also affect differentiation. See U.S. Patent Application Serial No. 12/582,068 (published as US20100099110) filed on October 20, 2009. Another method is to include non-natural or modified nucleotides (U.S. Patent No. 6,001,611, which is fully incorporated herein by reference) that change the base pairing between the primer and the target sequence. The reduced extension kinetics of the primer and the specificity thereof are affected by multiple factors, including the overall sequence situation of the mispairing and other nucleic acids present in the reaction. The impact of these external factors on each other mispairing and each separate or combined other non-natural nucleotides is unpredictable. The applicant has detected a variety of primer variants and found that some variants are surprisingly significantly different in their ability to distinguish closely related target sequences.

In one embodiment, the present invention includes oligonucleotides specifically for determining polymorphisms in CFI, C2, CFB, C3, or CFH, respectively. In one embodiment, the present invention includes oligonucleotides selected from SEQ ID NOs: 17-41 (Table 9) and variants thereof that are at least 90% identical to said oligonucleotides and have the 3'-terminal nucleotide of said oligonucleotide for specific detection of risk alleles in CFI SNP rs4698775, CFH SNP rs1329428, and C2/CFB SNP rs429608, respectively. As shown in Table 9, mismatches and non-natural nucleotides are typically present in the 3'-terminal portion of the oligonucleotide used as a primer, particularly within the 5 penultimate nucleotides. However, some oligonucleotides having 90% identity to a given oligonucleotide also include those having 1, 2, or 3 mismatches elsewhere in the oligonucleotide, for example, mismatches in the 5'-portion of the oligonucleotide.

In a specific embodiment, the presence of the polymorphism is detected using a probe. The probe can be labeled with a radioactive or chromophore (fluorophore) label, for example, a label incorporating a FAM, JA270, CY5 family dye, or HEX dye. As an example of detection using a fluorescently labeled probe, the mutation can be detected by real-time polymerase chain reaction (rt-PCR), in which hybridization of the probe causes enzymatic digestion of the probe and detection of the resulting fluorescence (TaqMan ^™ probe method, Holland et al. (1991) PNAS USA 88: 7276-7280). Table 9 lists probes for detecting the risk alleles in CFI SNPrs4698775, CFH SNPrs1329428, and C2/CFB SNPrs429608, respectively. Alternatively, the polymorphism and the presence of the amplification product can be detected by gel electrophoresis followed by staining or by blotting and hybridization as described, for example, in Sambrook, J. and Russell, DW (2001) Molecular Cloning, 3rd edition, CSHL Press, Chapters 5 and 9.

"Fluorescent dyes" or "fluorophores" are compounds or moieties, e.g., attached to nucleic acids, that are capable of emitting light when excited by light of an appropriate wavelength. Typical fluorescent dyes include rhodamine dyes, cyanine dyes, fluorescein dyes, and dyes. Fluorophores are fluorescent chromophores. "FRET" or "fluorescence resonance energy transfer" or "Foerster resonance energy transfer" is the transfer of energy between at least two chromophores, a donor chromophore and an acceptor chromophore (called a quencher). When the donor is excited with light of an appropriate wavelength, the donor typically transfers energy to the acceptor. When the acceptor is a "dark" quencher, it causes the transferred energy to dissipate in a form other than light. Commonly used dark quenchers are BlackHoleQuenchers ^™ (BHQ), Biosearch Technologies, Inc. (Novato, Calif.), IowaBlack ^™ , Integrated DNA Tech., Inc. (Coralville, Iowa), and BlackBerry ^™ Quencher 650 (BBQ-650), Berry & Assoc., (Dexter, Mich.). Commonly used donor-quencher pairs include FAM-BHQ, CY5-BHQ, and HEX-BHQ.

Samples containing biomarkers or SNPs can be obtained by methods known in the art. See the definition section. In addition, by detecting SNPs in the body sample, the progress of treatment can be more easily monitored.

Genotyping arrays can be used to analyze DNA or RNA to detect the presence of SNPs or other genetically based mechanisms. One such example is based on Illumina's array technology, a commercially available microarray system that includes >700K loci (Oliphant et al., Biotechniques, Supp: 56-8, 60-1 (2002)) and is a commonly used DNA and RNA analysis method (e.g., identifying SNPs in nucleic acid samples). Illumina microarray technology uses 3 micron silica beads that are self-assembled in microwells on either of two substrates: optical fibers or planar silica slides. Each bead is covered with thousands of copies of a specific oligonucleotide that serves as a capture sequence.

The expression of selected genes or biomarkers in tissue or cell samples can also be examined by functional or activity-based assays. For example, if the biomarker is an enzyme, one can perform assays known in the art to determine or detect the presence of a given enzyme activity in a tissue or cell sample.

The SNP status of the patient based on the test results can be provided in a report. The report can be in the form of any written material (e.g., paper or digital form, or on the Internet) or oral statement (e.g., in person (live) or recorded). The report can also indicate to a health professional (e.g., a physician) that the patient may benefit from or may respond to treatment with a factor D inhibitor.

The kit of the present invention has various embodiments. In a specific embodiment, the kit includes a container, a label on the container, and a composition contained in the container, wherein the composition includes one or more primary antibodies that bind to one or more target polypeptide sequences corresponding to autoantibodies to SNPs, and a label on the container indicating that the composition can be used to evaluate the presence of one or more target proteins in at least one type of mammalian cells, and instructions for using the antibodies to evaluate the presence of one or more target proteins in at least one type of mammalian cells. The kit can also include a set of instructions and materials for preparing tissue samples and applying antibodies and probes to the same part of the tissue sample. The kit also includes primary and secondary antibodies, wherein the secondary antibodies are conjugated to a label, for example, an enzyme label.

In one embodiment, the subject has never been treated with a medicine (such as an immunosuppressant) for the treatment of AMD, and/or has never been treated with an antibody or its antigen-binding fragment for factor D. In another embodiment, the subject has been treated with one or more medicines for the treatment of a degenerative disease and/or has been treated with the antibody before. In another embodiment, the anti-factor D antibody or its antigen-binding fragment is the only medicine administered to the subject for the treatment of a degenerative disease. In another embodiment, the anti-factor D antibody or its antigen-binding fragment is one of the medicines for the treatment of AMD.

The antibody is administered by appropriate means, including parenteral, topical, subcutaneous, intraperitoneal, intrapulmonary, intranasal, intralesional and/or intravitreal administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. Intrathecal administration is also included. In addition, the antibody may be suitably administered by pulse infusion, for example, with decreasing doses of the antibody. Preferably, administration is by intravenous or subcutaneous administration, and more preferably by intravenous infusion. Each exposure may be provided using the same or different modes of administration. In one embodiment, each exposure is performed by IVT administration.

One can administer a second agent, such as a VEGF antagonist or antibody, together with the anti-Factor D antibody or antigen-binding fragment thereof.

For example, the antibody can be combined with an anti-VEGF drug such as AVASTIN (bevacizumab) or LUCENTIS (ranibizumab) or another Factor D antagonist/antibody or antigen-binding fragment thereof.

If the anti-Factor D antibody or antigen-binding fragment thereof is referred to as the first drug, more specific examples of the second drug include a VEGF antagonist or antibody.

These second drugs are generally used in the same dosage and by the same route of administration as previously used or at about 1-99% of the dosage previously used. If the second drug is used at all, it is preferably used in an amount lower than that in the absence of the anti-Factor D antibody or antigen-binding fragment thereof, particularly in subsequent administrations after the initial administration of the antibody, to eliminate or reduce side effects caused by the treatment.

When an effective amount of a second drug is administered with an antibody exposure, it can be administered with any exposure, for example, only with one exposure, or with more than one exposure. In one embodiment, the second drug is administered with the initial exposure. In another embodiment, the second drug is administered with the initial and second exposures. In another embodiment, the second drug is administered with all exposures.

Administration in combination includes co-administration (simultaneous administration), use of separate formulations or a single pharmaceutical formulation, and sequential administration in any order, wherein, preferably, there is a time period when both (or all) active agents simultaneously exert their biological activities. In a preferred embodiment, after the initial exposure, the amount of the agent is reduced or eliminated, thereby reducing the subject's exposure to agents with side effects, such as prednisone and cyclophosphamide, especially when the agent is a corticosteroid. In another embodiment, the amount of the second drug is not reduced or eliminated.

IV. Antibodies to Factor D Antibodies or Antigen-Binding Fragments thereof

Any factor D antibody or fragment thereof known in the art can be used in the methods described herein. For example, in one embodiment, the anti-factor D antibodies that can be used in the present invention are any of those disclosed in U.S. Pat. No. 8,067,002 or U.S. Pat. No. 8,273,352, and can also include chimeric, humanized or human versions of these antibodies (if not chimeric, humanized or human versions), and can also include fragments or derivatives thereof.

In some embodiments, the anti-human factor D monoclonal antibody or its antigen-binding fragment binds to and neutralizes at least the biological activity of human factor D. In specific embodiments, the human factor D monoclonal antibody or its antigen-binding fragment can significantly reduce or eliminate the biological activity of the human factor D in question. In one embodiment, the human factor D monoclonal antibody or its antigen-condensed fragment is capable of neutralizing at least 60%, or at least 70%, preferably at least 75%, more preferably at least 80%, even more preferably at least 85%, more preferably at least 90%, more preferably at least 95%, and most more preferably at least 99% of the biological activity of human factor D in a subject. Binding and neutralization assays are well known in the art. For example, see U.S. Patent No. 7,087,726 for assays for screening antibodies with desired binding and neutralization properties.

In certain embodiments, the anti-Factor D antibody or antigen-binding fragment thereof is capable of reducing alternative pathway hemolysis caused by Factor D by at least about 60%, or at least 70%, preferably at least 75%, more preferably at least 80%, even more preferably at least 85%, more preferably at least 90%, more preferably at least 95%, and most preferably at least 99%, as determined by an alternative pathway hemolysis assay.

In some embodiments, the anti-Factor D monoclonal antibody comprises the following HVRs:

(a) L1 of the formula ITSTDDDMM (SEQ ID NO: 1);

(b) L2 of formula GGNTLRP (SEQ ID NO: 2); and

(c) L3 of formula LQSDSLPYT (SEQ ID NO: 3); and/or

(d) H1 of the formula GYTFTNYGMN (SEQ ID NO: 4);

(e) H2 of the formula WINTYTGETTYADDFKG (SEQ ID NO: 5); and

(f) H3 of the formula EGGVNN (SEQ ID NO: 6).

In a specific embodiment, the anti-human Factor D monoclonal antibody comprises the following amino acid sequences in its heavy and light chain variable domains, respectively:

EVQLVQSGPELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGETTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCEREGGVNNWGQGTLVTVSS (SEQ ID NO: 7) and

DIQVTQSPSSSLSASVGDRVTITCITSTDIDDDMNWYQQKPGKVPKLLISGGNTLRPGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLQSDSLPYTFGQGTKVEIK (SEQ ID NO: 8).

In a specific embodiment, the anti-Factor D antibody comprises SEQ ID NO: 15 and SEQ ID NO: 16 shown below, wherein 238-1 refers to the specific humanized anti-Factor D Fab described in U.S. Patent No. 8,273,352:

Heavy chain sequence of humanized anti-Factor D Fab (238-1):

EVQLVQSGPELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGETTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCEREGGVNNWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT(SEQ ID NO：15)

Humanized anti-Factor D Fab light chain sequence (238-1):

DIQVTQSPSSSLSASVGDRVTITCITSTDIDDDMNWYQQKPGKVPKLLISGGNTLRPGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLQSDSLPYTFGQGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:16)

In another embodiment, the antibody comprises the variable region sequences of SEQ ID NO: 15 and SEQ ID NO: 16. In another embodiment, the antibody comprises the HVR sequences of SEQ ID NO: 15 and SEQ ID NO: 16. In another embodiment, the antibody comprises HVR sequences that are greater than 95% identical to the HVR sequences of SEQ ID NO: 15 and SEQ ID NO: 16 and/or comprises HVR sequences that are 95% identical to the HVR sequences of SEQ ID NO: 15 and SEQ ID NO: 16.

In any of the above embodiments, the anti-Factor D antibody can be humanized. In one embodiment, the anti-Factor D antibody comprises the HVRs described in any of the above embodiments and further comprises an acceptor human framework, e.g., a human immunoglobulin framework or a human consensus framework.

In another aspect, an anti-Factor D antibody comprises a heavy chain variable domain (VH) sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 15. In specific embodiments, a VH sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the reference sequence comprises substitutions (e.g., conservative substitutions), insertions, or deletions, but the Factor D antibody comprising said sequence retains the ability to bind Factor D. In specific embodiments, a total of 1-10 amino acids are substituted, inserted, and/or deleted in SEQ ID NO: 15. In specific embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-Factor D antibody comprises the VH sequence in SEQ ID NO: 15, including post-translational modifications of that sequence.

In another aspect, the anti-Factor D antibody comprises a light chain variable domain (VL) sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 16. In specific embodiments, the VL sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the reference sequence comprises substitutions (e.g., conservative substitutions), insertions, or deletions, but the Factor D antibody comprising the sequence retains the ability to bind Factor D. In specific embodiments, a total of 1-10 amino acids are substituted, inserted, and/or deleted in SEQ ID NO: 16. In specific embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-Factor D antibody comprises the VH sequence in SEQ ID NO: 16, including post-translational modifications of that sequence.

In another aspect, a Factor D antibody is provided, wherein the antibody comprises a VH as in any one of the embodiments provided above, and a VL as in any one of the embodiments provided above.

In another aspect, the invention provides antibodies that bind to the same epitope as another Factor D antibody. In one embodiment, the invention provides antibodies that bind to the same epitope as the Factor D antibodies provided herein. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an anti-Factor D antibody comprising a light chain comprising: HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1); HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2); and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising: HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4); HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5); and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15 and/or a light chain sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain sequence having the amino acid sequence of SEQ ID NO: 15 and/or a light chain sequence having the amino acid sequence of SEQ ID NO: 16. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D that is bound by lampalizumab, CAS Registry No. 1278466-20-8.

In another aspect, the present invention provides antibodies that competitively inhibit the binding of an anti-Factor D antibody to its corresponding antigenic epitope. For example, in certain embodiments, an anti-Factor D antibody competitively inhibits the binding of the anti-Factor D antibody to its corresponding antigenic epitope, wherein the anti-Factor D antibody comprises: a light chain comprising: HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1), HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2), and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising: HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5), and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:7 and/or a light chain variable region sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:8 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:8 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:15 and/or a light chain sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:16. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:15 and/or a light chain comprising the amino acid sequence of SEQ ID NO:16. In one embodiment, the anti-Factor D antibody competitively inhibits the binding of lampalizumab, CAS Registry Number 1278466-20-8, to its corresponding epitope.

In another aspect of the invention, the Factor D antibody described in any of the above embodiments is a monoclonal antibody, including chimeric, humanized or human antibodies. In one embodiment, the Factor D antibody is an antibody fragment, e.g., Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, e.g., a complete IgG1 or IgG4 antibody or other antibody class or isotype defined herein. In another embodiment, the antibody is a bispecific antibody.

In another aspect, the Factor D antibody of any of the preceding embodiments of the invention may incorporate any of the features, individually or in combination, as described in this Section IV and in Section V below.

In some embodiments, the anti-Factor D monoclonal antibody or its antigen-binding fragment has the same amino acid sequence as the anti-human Factor D monoclonal antibody designated Lampalizumab, a nonproprietary name adopted by the USAN Council. In other embodiments, the anti-human Factor D monoclonal antibody or its antigen-binding fragment has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% amino acid sequence identity to Lampalizumab. See U.S. Patent No. 8,067,002 or US 8.273,352. In specific embodiments, the anti-human Factor D monoclonal antibody is Lampalizumab. In some embodiments, the anti-human Factor D monoclonal antibody has the amino acid sequence disclosed in CAS Registry No. 1278466-20-8.

In some embodiments, the anti-human Factor D monoclonal antibody comprises HVRs encoded by the following sequences:

(a) L1 of the formula ATTACCAGCACTGATATTGATGATGATATGAAC (SEQ ID NO: 9);

(b) L2 of formula GGAGGCAATACTCTTCGTCCT (SEQ ID NO: 10);

(c) L3 of the formula TTGCAAAGTGATTCTTTGCCGTACACG (SEQ ID NO: 11);

(d) H1 of the formula GGATACACCTTCACTAACTATGGAATGAAC (SEQ ID NO: 12);

(e) H2 of the formula TGGATTAACACCTACACTGGAGAGACAACATATGCTGACGACTTCAAGGGA (SEQ ID NO: 13); and

(f) H3 of formula GAGGGGGGGGTTAATAAC (SEQ ID NO: 14).

V. Preparation of Antibodies

The preparation methods and articles of manufacture of the present invention may use or incorporate antibodies that bind to Factor D. Thus, methods for generating such antibodies will be described herein.

The factor D antigen used to prepare or screen for antibodies can be, for example, a soluble form of factor D, or a portion thereof containing the desired epitope. Alternatively, or in addition, cells expressing factor D on their cell surface can be used to produce or screen for antibodies. Other forms of factor D for generating antibodies are well known to those skilled in the art.

The following description relates to exemplary techniques for preparing antibodies for use in accordance with the present invention.

(i) Polyclonal antibodies

Polyclonal antibodies are preferably raised in animals by multiple subcutaneous (sc) or intraperitoneal (ip) injections of the relevant antigen and the agent. It may be useful to conjugate the relevant antigen to a protein that is immunogenic in the species to be immunized, such as keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, or soybean trypsin, using bifunctional reagents or derivatizing agents, for example, maleimidobenzoylsulfosuccinimide ester (conjugation through cysteine residues), N-hydroxybenzoylsulfosuccinimide (conjugation through lysine residues), glutaraldehyde, succinic anhydride, SOCl ₂ , or R ¹ N═C═NR, wherein R ^and R 1 are different alkyl groups.

For example, by combining 100 μg or 5 μg of protein or conjugate (for rabbits or mice, respectively) with 3 volumes of Freund's complete adjuvant, and by intradermal injection into multiple sites, the animal is immunized against the antigen, immunogenic conjugate or derivative. One month later, the animal is reinforced with 1/5 to 1/10 of the initial amount of peptide or conjugate in complete Freund's adjuvant by subcutaneous injection at multiple sites. After 7-14 days, the animal is bled and the antibody titer of the serum is measured. The animal is reinforced until the titer plateau value is reached. Preferably, the animal is reinforced with the same antigen but conjugated to different proteins and/or conjugated by different cross-linking agents. Conjugates can also be prepared as protein fusions in recombinant cell culture. In addition, aggregating agents, such as alum, are suitably used to enhance the immune response.

(ii) Monoclonal antibodies

A monoclonal antibody is obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind to the same epitope, except for possible variants that may arise during production of the monoclonal antibody (such variants generally exist in minor amounts). Thus, the modifier "monoclonal" indicates the character of the antibody as not being a mixture of dispersed or polyclonal antibodies.

For example, the monoclonal antibodies can be made by the hybridoma method first described by Kohler et al., Nature, 256:495 (1975), or can be made by recombinant DNA methods (U.S. Patent No. 4,816,567).

In the hybridoma method, a mouse or other suitable host animal, such as a hamster, is immunized as described above to elicit lymphocytes that produce or are capable of producing antibodies that specifically bind to the protein used for immunization. Alternatively, lymphocytes can be immunized in vitro. The lymphocytes are then fused with myeloma cells using a suitable fusing agent, such as polyethylene glycol, to form hybridoma cells (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)).

The hybridoma cells thus prepared are seeded and grown in an appropriate culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells. For example, if the parental myeloma cells lack the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT or HPRT), the culture medium for the hybridomas will typically contain hypoxanthine, aminopterin, and thymidine (HAT medium), which prevent the growth of HGPRT-deficient cells.

Preferred myeloma cells are those that fuse efficiently, support stable, high-level antibody production by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. Of these, preferred myeloma cell lines are murine myeloma lines, such as those derived from MOPC-21 and MPC-11 mouse tumors available from the Salk Institute Cell Distribution Center, San Diego, California, USA, and SP-2 or X63-Ag8-653 cells available from the American Type Culture Collection, Rockville, Maryland, USA. Human myeloma and mouse-human heteromyeloma cell lines have also been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987)).

The culture medium in which the hybridoma cells are grown is assayed for the production of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of the monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA).

For example, the binding affinity of a monoclonal antibody can be determined by Scatchard analysis of Munson et al., Anal. Biochem., 107:220 (1980).

After identifying hybridoma cells that produce antibodies of the desired specificity, affinity, and/or activity, the clones can be subcloned by limiting dilution and grown by standard methods (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986). Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640 medium. Alternatively, hybridomas can be grown in vivo as ascites tumors in animals.

The monoclonal antibodies secreted by the subclones are suitably separated from the culture medium, ascites fluid, or serum by conventional immunoglobulin purification procedures such as, for example, protein A-SEPHAROSE ^™ cross-linked agarose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

DNA encoding the monoclonal antibody is readily isolated and sequenced using conventional methods (e.g., by using oligonucleotide probes that specifically bind to genes encoding the heavy and light chains of murine antibodies). Hybridoma cells are a preferred source of such DNA. Once isolated, the DNA can be placed in an expression vector and then transferred to an otherwise non-immunoglobulin-producing host cell, such as an Escherichia coli (E. coli) cell, a simian COS cell, a Chinese hamster ovary (CHO) cell, or a myeloma cell, to obtain synthesis of the monoclonal antibody in the recombinant host cell. Review articles on recombinant expression of DNA encoding the antibody in bacteria include Skerra et al., Curr. Opinion in Immunol., 5: 256-262 (1993) and Plückthun, Immunol. Revs., 130: 151-188 (1992).

In another embodiment, antibodies or antibody fragments can be isolated from antibody phage libraries generated using the techniques described in McCafferty et al., Nature, 348: 552-554 (1990). Clackson et al., Nature, 352: 624-628 (1991) and Marks et al., J. Mol. Biol., 222: 581-597 (1991) describe the isolation of murine and human antibodies, respectively, using phage libraries. Subsequent publications describe the generation of high-affinity (nM range) human antibodies by chain shuffling (Marks et al., Bio/Technology, 10: 779-783 (1992)), as well as combinatorial infection and in vivo recombination as a strategy for constructing very large phage libraries (Waterhouse et al., Nuc. Acids. Res., 21: 2265-2266 (1993)). Therefore, these techniques are useful alternatives to traditional monoclonal antibody hybridoma techniques for isolating monoclonal antibodies.

The DNA also can be modified, for example, by substituting the coding sequences for human heavy and light chain constant domains for the homologous murine sequences (U.S. Pat. No. 4,816,567; Morrison, et al., Proc. Natl Acad. Sci. USA, 81:6851 (1984)), or by covalently linking the immunoglobulin coding sequence to all or part of the coding sequence for a non-immunoglobulin polypeptide.

Typically, the non-immunoglobulin polypeptides replace the constant domains of an antibody, or they replace the variable domains of one antigen combining site of an antibody, thereby creating a chimeric bivalent antibody comprising one antigen combining site with specificity for one antigen and another antigen combining site with specificity for a different antigen.

(iii) Humanized antibodies

Methods for humanizing non-human antibodies have been described in the art. Preferably, a humanized antibody has one or more amino acid residues from a non-human source introduced therein. These non-human amino acid residues are generally referred to as "import" residues, which are typically taken from an "import" variable domain. Humanization can be performed essentially according to the method of Winter and colleagues (Jones et al., Nature, 321: 522-525 (1986); Riechmann et al., Nature, 332: 323-327 (1988); Verhoeyen et al., Science, 239: 1534-1536 (1988)) by replacing the corresponding sequence of a human antibody with a hypervariable region sequence. Thus, the "humanized" antibody is a chimeric antibody (U.S. Patent No. 4,816,567), in which substantially less than a complete human variable domain has been replaced by a corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some hypervariable region residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.

The selection of human variable domains (light and heavy chains) for preparing humanized antibodies is very important for reducing antigenicity. According to the so-called "best-fit" method, the sequence of the variable domain of a rodent antibody is screened against a complete library of known human variable domain sequences. The human sequence that is closest to the rodent sequence is then accepted as the human framework region (FR) for the humanized antibody (Sims et al., J. Immunol., 151: 2296 (1993); Chothia et al., J. Mol. Biol., 196: 901 (1987)). Another method uses a specific framework region derived from the consensus sequence of all human antibodies of a specific subgroup of light or heavy chain variable regions. The same framework can be used for several different humanized antibodies (Carter et al., Proc. Natl. Acad. Sci. USA, 89: 4285 (1992); Presta et al., J. Immunol., 151: 2623 (1993)).

It is also important that antibodies should be humanized to retain high affinity for antigens and other favorable biological properties. To achieve this goal, according to a preferred method, humanized antibodies are prepared by analyzing the maternal sequence and a variety of conceptually humanized products using a three-dimensional model of the maternal and humanized sequences. Three-dimensional immunoglobulin models are commercially available and are familiar to those skilled in the art. Computer programs are available that illustrate and display the possible three-dimensional conformational structures of selected candidate immunoglobulin sequences. These displayed inspections allow analysis of the possible role of residues in the function of candidate immunoglobulin sequences, that is, analysis of the residues that affect the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from an acceptor, and the sequence can be imported to obtain desired antibody characteristics, such as increased affinity for the target antigen. Typically, hypervariable region residues directly and most substantially participate in the combination that affects the antigen.

(iv) Human antibodies

As an alternative to humanization, human antibodies can be produced. For example, it is now possible to produce transgenic animals (e.g., mice) that are capable of producing the entire repertoire of human antibodies in the absence of endogenous immunoglobulin production upon immunization. For example, it has been documented that homozygous deletion of the antibody heavy chain-joining region ( _JH ) gene in chimeric germline mutant mice results in complete inhibition of endogenous antibody production. Transferring the human germline immunoglobulin gene array into such germline mutant mice will result in the production of human antibodies upon antigen stimulation. For example, see Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90: 2551 (1993); Jakobovits et al., Nature, 362: 255-258 (1993); Bruggermann et al., Year in Immuno., 7: 33 (1993); and U.S. Pat. Nos. 5,591,669, 5,589,369, and 5,545,807.

Alternatively, phage display technology (McCafferty et al., Nature 348:552-553 (1990)) can be used to produce human antibodies and antibody fragments in vitro from the repertoire of immunoglobulin variable (V)-domain genes from unimmunized donors. According to this technology, antibody V-domain genes are cloned in frame into a major or minor coat protein gene of a filamentous bacteriophage (such as M13 or fd) and displayed as functional antibody fragments on the surface of the phage particle. Because the filamentous particle contains a single-stranded DNA copy of the phage genome, selection based on the functional characteristics of the antibody also results in selection of genes encoding antibodies that exhibit these properties. Thus, phage mimic some of the characteristics of B cells. Phage display can be performed in a variety of formats; for their review, see, for example, Johnson, Kevin S. and Chiswell, David J., Current Opinion in Structural Biology 3:564-571 (1993). Some sources of V gene segments can be used for phage display. Clackson et al., Nature, 352: 624-628 (1991) isolated a diversity array of anti-oxazolone antibodies from a small random combinatorial library of V genes from the spleens of immunized mice. A repertoire of V genes from unimmunized human donors can be constructed, and a diversity array of antigens (including self-antigens) can be isolated essentially according to the techniques described in Marks et al., J. Mol. Biol. 222: 581-597 (1991) or Griffith et al., EMBO J. 12: 725-734 (1993). See also U.S. Patent Nos. 5,565,332 and 5,573,905.

Human antibodies can also be generated by in vitro activated B cells (see US Pat. Nos. 5,567,610 and 5,229,275).

(v) Antibody fragments

A variety of techniques have been used to prepare antibody fragments. Traditionally, these fragments were produced by proteolytic digestion of intact antibodies (see Morimoto et al., Journal of Biochemical and Biophysical Methods 24: 107-117 (1992) and Brennan et al., Science, 229: 81 (1985)). However, these fragments can now be produced directly by recombinant host cells. For example, the antibody fragments can be isolated from the antibody phage library discussed above. Alternatively, Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab') ₂ fragments (Carter et al., Bio/Technology 10: 163-167 (1992)). According to another method, F(ab') ₂ fragments can be directly recovered from recombinant host cell cultures. Practitioners in this field are aware of other techniques for preparing antibody fragments. In other embodiments, the antibody of choice is a single-chain Fv fragment (scFv). See WO 1993/16185 and US Patent Nos. 5,571,894 and 5,587,458. The antibody fragment may also be a "linear antibody," as described, for example, in US Patent No. 5,641,870. The linear antibody fragment may be monospecific or bispecific.

(vi) Bispecific Antibodies

Bispecific antibodies are antibodies with binding specificity for at least two different epitopes. Exemplary bispecific antibodies can bind to two different epitopes of factor D antigen. Alternatively, the anti-factor D-binding arm can be combined with an arm that binds to a triggering molecule on a leukocyte, such as a T cell receptor molecule (e.g., CD2 or CD3), or an Fc receptor (FcγR) for IgG, such as FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16). Bispecific antibodies can also be used to locate cytotoxic agents. These antibodies have a factor D binding arm and an arm that binds to the cytotoxic agent (e.g., saporin, vinca alkaloids, ricin A chain, methotrexate, or a radioactive isotope hapten). Bispecific antibodies can be prepared as full-length antibodies or antibody fragments (e.g., F(ab') ₂ bispecific antibodies).

Methods for preparing bispecific antibodies are known in the art. Traditional preparation of full-length bispecific antibodies is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where the two chains have different specificities (Millstein et al., Nature, 305: 537-539 (1983)). Due to the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a possible mixture of 10 different antibody molecules, of which only one has the correct bispecific structure. Purification of the correct molecule is usually carried out by affinity chromatography steps, which is quite tedious and the product yield is low. Similar methods are disclosed in WO 1993/08829 and Traunecker et al., EMBO J., 10: 3655-3659 (1991).

According to different methods, antibody variable domains with required binding specificity (antibody-antigen combination site) are fused to immunoglobulin constant domain sequences. The fusion preferably has an immunoglobulin heavy chain constant domain, which comprises at least a portion of a hinge, CH2, and CH3 region. It preferably has a first heavy chain constant region (CH1) present in at least one fusion, which comprises the site required for light chain binding. DNAs encoding immunoglobulin heavy chain fusions and immunoglobulin light chains (if necessary) are inserted into independent expression vectors and co-transfected into appropriate host organisms. When the three peptide chains of unequal ratios used in the construction process provide optimal yields, this provides great flexibility for adjusting the mutual properties of the three polypeptide fragments in an embodiment. However, when expressing at least two polypeptide chains in equal ratios results in high yields or when the ratios have no particular significance, it is feasible to insert the coding sequences of two or all three polypeptide chains into one expression vector.

In a preferred embodiment of this method, the bispecific antibody is composed of a hybrid immunoglobulin with a first binding specificity on one arm and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) on the other arm. It was found that this asymmetric structure facilitates the separation of the desired bispecific compound from the unwanted immunoglobulin chain combination because the presence of the immunoglobulin light chain in only half of the bispecific molecule provides an easy means of separation. This method is disclosed in WO 1994/04690. For further details on the generation of bispecific antibodies, see, for example, Suresh et al., Methods in Enzymology, 121: 210 (1986).

According to another method described in U.S. Patent No. 5,731,168, the junction between a pair of antibody molecules can be modified to maximize the percentage of heterodimers recovered from recombinant cell culture. Preferably, the junction comprises at least a portion of the _CH3 domain of an antibody constant domain. In this way, one or more small amino acid side chains at the junction of the first antibody molecule are replaced by larger side chains (e.g., tyrosine or tryptophan). By replacing the larger amino acid side chains with smaller amino acid side chains (e.g., alanine or threonine), compensatory "cavities" of the same or similar size as the large side chains are produced at the junction of the second antibody molecule. This provides a mechanism for increasing the yield of heterodimers compared to other unwanted end products (e.g., homodimers).

Bispecific antibodies include cross-linked or "heteroconjugate" antibodies. For example, one antibody in the heteroconjugate can be coupled to avidin and the other antibody to biotin. For example, it has been proposed that such antibodies target immune system cells to unwanted cells (U.S. Patent number 4,676,980) and are used to treat HIV infection (WO 1991/00360, WO 1992/200373, and EP 03089). Heteroconjugate antibodies can be prepared using any convenient cross-linking method. Suitable cross-linking agents are well known in the art and, for example, are disclosed in U.S. Patent number 4,676,980, as well as a variety of cross-linking techniques.

Techniques for producing bispecific antibodies from antibody fragments have also been described in the literature. For example, bispecific antibodies can be prepared using chemical cross-linking. Brennan et al., Science, 229:81 (1985) describe a method in which intact antibody proteins are hydrolyzed and cleaved to produce F(ab') ₂ fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize nearby dithiols and prevent intermolecular disulfide formation. The resulting Fab' fragments are then converted into thionitrobenzoate (TNB) derivatives. One of the Fab'-TNB derivatives is then converted to a Fab'-thiol by reduction with mercaptoethylamine and mixed with an equimolar amount of another Fab'-TNB derivative to form a bispecific antibody. The resulting bispecific antibody can be used as a reagent for selective enzyme immobilization.

Various techniques for preparing and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies are produced using leucine zippers. Kostelny et al., J. Immunol., 148(5):1547-1553 (1992). Leucine zipper peptides from Fos and Jun proteins are linked to the Fab' portions of two different antibodies by gene fusion. The antibody homodimers are reduced at the hinge region to form monomers and then oxidized to form antibody heterodimers. This method can also be used to produce antibody homodimers. The "diabody" technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993) provides an alternative mechanism for preparing bispecific antibody fragments. The fragments comprise a heavy chain variable domain ( _VH ) connected to a light chain variable domain ( _VL ) by a linker that is too short to allow pairing between the two domains on the same chain. Thus, the _VH and _VL domains of one fragment are forced to pair with the complementary _VL and _VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for preparing bispecific antibody fragments by dimerizing single-chain Fv (sFv) fragments has also been reported. See Gruber et al., J. Immunol., 152: 5368 (1994).

Antibodies with more than two valencies are included. For example, trispecific antibodies can be prepared. Tutt et al. J. Immunol. 147:60 (1991).

VI. Conjugates and Other Modifications of Antibodies

The antibodies used in the methods herein or contained in the articles herein are optionally conjugated to a cytotoxic agent. For example, the (Factor D) antibody can be conjugated to a drug as described in WO2004/032828.

Chemotherapeutic agents useful in producing the antibody-cytotoxic agent conjugates have been described above.

Also conjugated herein are antibodies to one or more small molecule toxins (e.g., calicheamicin, maytansine (U.S. Pat. No. 5,208,020), trichothene, and CC1065). In one embodiment of the invention, the antibody is conjugated to one or more maytansine molecules (e.g., about 1 to about 10 maytansine molecules per antibody molecule). For example, maytansine can be converted to May-SS-Me, which can be reduced to May-SH3 and reacted with a modified antibody (Chari et al. Cancer Research 52: 127-131 (1992)) to produce a maytansinoid-antibody conjugate.

Alternatively, the antibody is conjugated to one or more calicheamicin molecules. The calicheamicin family of antibiotics is capable of producing double-stranded DNA breaks at sub-picomolar concentrations. Structural analogs of calicheamicin that can be used include, but are not limited to, γ ₁ ^I , α ₂ ^I , α ₃ ^I , N-acetyl-γ ₁ ^I , PSAG, and θ _{1 I} ⁽ Hinman et al. Cancer Research 53: 3336-3342 (1993) and Lode et al. Cancer Research 58: 2925-2928 (1998)).

Enzymatically active toxins and fragments thereof that can be used to treat tuberculosis include diphtheria A chain, nontuberculosis active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis toxin, scutellaria baicalensis toxin, scutellaria serrata ... officinalis inhibitors, gelonin, mitogellin, restrictocin, phenotypecin, enomycin, and the tricothecenes. See, for example, WO 1993/21232 published October 28, 1993.

The invention also encompasses antibodies conjugated to a compound having nucleolytic activity (eg, a ribonuclease or a DNA endonuclease, such as a deoxyribonuclease; DNase).

A variety of radioactive isotopes are available for the production of radioconjugated antibodies. Examples include At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² and radioactive isotopes of Lu.

Conjugates of the antibody and cytotoxic agent can be prepared using a variety of bifunctional protein coupling agents, such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate, iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (such as bis(p-diazoniumbenzoyl)ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate) and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14 labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugating radionucleotides to antibodies. See WO 1994/11026. The structure can be a "cleavable linker" that facilitates release of the cytotoxic drug in the cell. For example, an acid-labile linker, a peptidase-sensitive linker, a dimethyl linker, or a disulfide-containing linker can be used (Chari et al., Cancer Research 52:127-131 (1992)).

Alternatively, a fusion protein comprising the antibody and the cytotoxic agent can be prepared, for example, by recombinant techniques or peptide synthesis.

In another embodiment, the antibody is conjugated to a "receptor" (such as streptavidin) for tumor pre-targeting, wherein the antibody-receptor conjugate is administered to the individual, followed by the use of a clearing agent to clear unbound conjugate from the circulation, and then the "ligand" (such as avidin) coupled to a cytotoxic agent (such as a radionucleotide) is administered.

The antibodies of the invention may also be conjugated to prodrug activating enzymes that convert prodrugs (e.g., peptidyl chemotherapeutic agents, see WO 1981/01145) into active anticancer drugs. See, for example, WO 1988/07378 and U.S. Pat. No. 4,975,278.

The enzyme component of the conjugate includes any enzyme capable of acting on the prodrug in such a way as to convert it into its more active, cytotoxic form.

Enzymes useful in the methods of the invention include, but are not limited to, alkaline phosphatase for converting phosphate-containing prodrugs into free drug; arylsulfatase for converting sulfate-containing prodrugs into free drug; cytosine deaminase for converting non-toxic 5-fluorocytosine into an anticancer drug; proteases, such as serratia protease, thermolysin, subtilisin, carboxypeptidases, and cathepsins (such as cathepsins B and L), which are useful for converting peptide-containing prodrugs into free drug; D-alanylcarboxypeptidase, which is useful for converting prodrugs containing D amino acid substituents; carbohydrate-cleaving enzymes, such as β-galactosidase and neuraminidase, which are useful for converting glycosylated prodrugs into free drug; β-lactamase, which is useful for converting a drug derivatized with a β-lactam into free drug; and penicillin amidases, such as penicillin V amidase or penicillin G amidase, which are useful for converting a drug derivatized with a phenoxyacetyl group or a phenylacetyl group, respectively, on its amine nitrogen into free drug. Alternatively, the prodrugs of the present invention can be converted into free active drugs using antibodies with enzymatic activity (also known in the art as "abzymes") (e.g., see Massey, Nature 328: 457-458 (1987)). Antibody-abzyme conjugates can be prepared as described herein for delivery of the abzyme to tumor cell populations.

The enzyme of the invention can be covalently bound to the antibody by techniques well known in the art, such as using heterobifunctional cross-linkers as discussed above. Alternatively, a fusion protein comprising at least the antigen-binding region of an antibody of the invention linked to at least a functionally active portion of an enzyme of the invention can be constructed using recombinant DNA techniques well known in the art (e.g., see Neuberger et al., Nature, 312: 604-608 (1984)).

Other modifications of antibodies are contemplated herein. For example, the antibody can be linked to one of a variety of non-proteinaceous polymers, such as polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol. Antibody fragments, such as Fab', linked to one or more PEG molecules are particularly preferred embodiments of the present invention.

The antibodies disclosed herein can also be formulated as liposomes. Liposomes containing antibodies are prepared by methods known in the art, such as, for example, Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl. Acad. Sci. USA, 77: 4030 (1980); U.S. Patent Nos. 4,485,045 and 4,544,545; and WO 1997/38731 published on October 23, 1997. Liposomes with increased circulation time are disclosed in U.S. Patent No. 5,013,556.

Particularly useful liposomes can be produced by reverse phase evaporation using a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter of defined pore size to produce liposomes having the desired diameter. Fab' fragments of the antibodies of the present invention can be conjugated to the liposomes by disulfide-exchange reactions as described in Martin et al. J. Biol. Chem. 257: 286-288 (1982). A chemotherapeutic agent can optionally be included within the liposomes. See Gabizon et al. J. National Cancer Inst. 81 (19) 1484 (1989).

Amino acid sequence modifications of proteins or peptide antibodies as described herein are included. For example, they can ideally improve the binding affinity and/or other biological properties of the antibody. Amino acid sequence variants of antibodies are prepared by introducing appropriate nucleotide changes into the antibody nucleic acid or by peptide synthesis. The modifications include, for example, deletions, and/or insertions and/or substitutions of residues in the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions is performed to obtain the final construct, provided that the final construct has the desired characteristics. Amino acid changes can also alter the post-translational processing of the antibody, such as changing the number and position of glycosylation sites.

The method for identifying specific residues or regions as preferred locations for mutagenesis is called "alanine scanning mutagenesis," as described by Cunningham and Wells Science, 244: 1081-1085 (1989). Here, a residue or a group of target residues (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and replaced with neutral or negatively charged amino acids (most preferably alanine or polyalanine) to affect the interaction of the amino acids with the antigen. These amino acid positions that demonstrate functional sensitivity to the replacement are then refined by introducing additional or other variants at or against the replacement site. Thus, while the site for introducing amino acid sequence changes is predetermined, the nature of the mutation itself does not need to be predetermined. For example, to analyze the performance of a mutation at a given site, alanine scanning or random mutagenesis is performed at the target codon or region, and the expressed antibody variants are screened for the desired activity.

Amino acid sequence insertions include amino-terminal and/or carboxyl-terminal fusions ranging in length from one base to polypeptides containing more than one hundred residues, as well as intrasequence insertions of single or multiple amino acid residues. Terminal insertions include antibodies with an N-terminal methionyl residue or antibodies fused to cytotoxic polypeptides. Other insertional variants of the antibody molecule include the fusion of an enzyme to the N-terminus or C-terminus of the antibody, or a polypeptide that increases the serum half-life of the antibody.

The variant of another type is amino acid substitution variant. These variants have at least one amino acid residue that is replaced by different residues in the antibody molecule. The most interesting site about the substitution mutagenesis of antibody includes hypervariable region, but also includes that FR changes. Table 1 has shown conservative substitution under the title of " preferred substitution ". If the substitution causes biological activity to change, more substantial variation can be introduced so, it is named " exemplary substitution " in Table 1, or as further described below with reference to amino acid species, and screened product.

Table 1

Substantial modification of the biological properties of an antibody is achieved by selecting substitutions that differ significantly in their effect on maintaining: (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Amino acids can be grouped according to the similarity of their side chain properties (as described in A. L. Lehninger, Biochemistry, 2nd ed., pp. 73-75, Worth Publishers, New York (1975)):

(1) Non-polar: Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M)

(2) Uncharged polarity: Gly(G), Ser(S), Thr(T), Cys(C), Tyr(Y), Asn(N), Gln(Q)

(3) Acidic: Asp (D), Glu (E)

(4) Basic: Lys(K), Arg(R), His(H)

Alternatively, naturally occurring residues can be divided into the following groups based on common side-chain properties:

(1) Hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile;

(2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln;

(3) Acidic: Asp, Glu;

(4) Basic: His, Lys, Arg;

(5) Residues that affect chain orientation: Gly, Pro;

(6) Aromatic: Trp, Tyr, Phe.

Non-conservative substitutions will entail exchanging a member of one of these classes for a member of another class.

Any cysteine residue not involved in maintaining the correct conformation of the antibody may also be substituted, usually with serine, to improve the oxidative stability of the molecule and prevent abnormal cross-linking. Conversely, cysteine bond(s) may be added to the antibody to improve its stability (particularly when the antibody is an antibody fragment, such as an Fv fragment).

Particularly preferred substitution variant types involve replacing one or more hypervariable region residues of the parent antibody. Typically, the resulting selection variants for further development have improved biological properties relative to the parent antibody they produce. A convenient method for producing the substitution variants is to mature the affinity of phage display. In short, several hypervariable region sites (e.g., 6-7 sites) are mutated to produce all possible amino acid substitutions at each site. The resulting antibody variants are displayed on filamentous phage particles in a monovalent form as a fusion with the gene III product of the M13 packaged within each particle. The phage-displayed variants are then screened for their biological activity (e.g., binding affinity), as disclosed herein. In order to identify candidate hypervariable region sites for modification, alanine scanning mutagenesis can be performed to identify hypervariable region residues that significantly contribute to antigen binding. Alternatively, or additionally, the crystal structure of the antigen-antibody complex can be advantageously analyzed to identify the contact points between the antibody and the antigen. The contact residues and adjacent residues are replacement candidates according to the technology described in detail herein. Once such variants are generated, the panel of variants is screened as described herein, and antibodies with superior properties in one or more relevant assays can be selected for further development.

Another type of amino acid variant of an antibody alters the original glycosylation pattern of the antibody, such alterations comprising deleting one or more carbohydrate moieties present in the antibody, and/or adding one or more glycosylation sites not present in the antibody.

Glycosylation of polypeptides is typically either N-linked or O-linked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a cyanoamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.

Addition of glycosylation sites to antibodies is conventionally accomplished by altering the amino acid sequence so that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). Alterations can also be made by adding or substituting one or more serine or threonine residues into the sequence of the original antibody (for O-linked glycosylation sites).

When an antibody comprises an Fc region, the carbohydrate to which it is connected can be changed. For example, US 2003/0157108 (Presta, L.) describes an antibody having a mature carbohydrate structure lacking the fucose connected to the Fc region of an antibody. Also referring to US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd.). Antibodies having a bisecting N-acetylglucosamine (GlcNAc) in the carbohydrate connected to the Fc region of an antibody are described in WO 2003/011878, Jean-Mairet et al. and U.S. Patent number 6,602,684, Umana et al. WO 1997/30087, Patel et al. describe antibodies having at least one galactose residue in the oligosaccharide connected to the Fc region of an antibody. See also WO 1998/58964 (Raju, S.) and WO 1999/22764 (Raju, S.) relating to antibodies with altered carbohydrates attached to their Fc regions.

Preferred glycosylation variants herein comprise an Fc region wherein the carbohydrate structure attached to the Fc region lacks fucose. Such variants have improved ADCC function. Optionally, the Fc region further comprises one or more amino acid substitutions therein to further improve ADCC, for example, substitutions at positions 298, 333, and/or 334 (Eu numbering of residues) in the Fc region. Examples of publications relating to "defucosylated" or "fucose-deficient" antibodies include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; Okazaki et al., J. Mol. Biol. 336: 1239-1249 (2004); and Yamane-Ohnuki et al., Biotech. Bioeng. 87: 614 (2004). Examples of cell lines that produce defucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al., Arch. Biochem. Biophys. 249:533-545 (1986); US 2003/0157108, Presta, L; and WO 2004/056312, Adams et al., particularly Example 11), and knockout cell lines, such as CHO cells knocked out for the α-1,6-fucosyltransferase gene, FUT8 (Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004)).

Nucleic acid molecules encoding amino acid sequence variants of the antibody are prepared by a variety of methods known in the art, including, but not limited to, isolation from natural sources (in the case of naturally occurring amino acid sequence variants) or by oligonucleotide-mediated (or site-directed) mutagenesis, PCR mutagenesis, and cassette mutagenesis of a previously prepared variant or non-variant version of the antibody.

It may be desirable to modify the antibodies of the invention with respect to effector function, for example, to enhance ADCC and/or CDC of the antibody. This can be achieved by introducing one or more amino acid substitutions into the Fc region of the antibody. Alternatively or additionally, one or more cysteine residues can be introduced into the Fc region, thereby allowing interchain disulfide bond formation within this region. The homodimeric antibodies thus formed may have improved internalization capacity and/or increased complement-mediated cell killing and ADCC. See Caron et al., J. Exp Med. 176: 1191-1195 (1992) and Shopes, B. J. Immunol. 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers, as described in Wolff et al. Cancer Research 53: 2560-2565 (1993). Alternatively, antibodies can be engineered to have dual Fc regions and thus potentially have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design 3:219-230 (1989).

WO 2000/42072 (Presta, L.) describes antibodies with improved ADCC function in the presence of human effector cells, wherein the antibodies comprise amino acid substitutions in their Fc regions. Preferably, the antibodies with improved ADCC comprise substitutions at Fc region positions 298, 333, and/or 334. Preferably, the altered Fc region is an IgG1 Fc region comprising substitutions at one, two, or three of these positions or consisting of substitutions at one, two, or three of these positions.

Antibodies with altered C1q binding and/or CDC are described in WO 1999/51642 and U.S. Patent Nos. 6,194,551, 6,242,195, 6,528,624 and 6,538,124 (Idusogie et al.) The antibodies comprise amino acid substitutions at one or more of amino acid positions 270, 322, 326, 327, 329, 313, 333 and/or 334 of the Fc region.

To increase the serum half-life of an antibody, one can incorporate a salvage receptor binding epitope into the antibody (particularly an antibody fragment), for example, as described in U.S. Patent No. 5,739,277. As used herein, the term "salvage receptor binding epitope" refers to an epitope in the Fc region of an IgG molecule (e.g., IgG ₁ , IgG ₂ , IgG ₃ or IgG ₄ ) that is responsible for increasing the in vivo serum half-life of the IgG molecule. Antibodies with substitutions in their Fc region and increased serum half-life are also described in WO 2000/42072 (Presta, L.).

Also included are engineered antibodies having three or more (preferably four) functional antigen binding sites (US 2002/0004587 A1, Miller et al.).

VII. Pharmaceutical Preparations

Therapeutic formulations of the antibodies used in accordance with the present invention are prepared by mixing the antibody having the desired degree of purity with optional pharmaceutical carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. Ed. (1980)) in the form of lyophilized formulations or aqueous solutions. Suitable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations used and include buffers such as phosphate, histidine, citrate, and other organic acids; salts such as sodium chloride, calcium chloride and ammonium sulfate; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl alcohol or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight proteins, such as serum albumin, albuterol, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, glycosidase, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, glycosidase, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc-protein complexes); and/or nonionic surfactants, such as TWEEN ^™ , PLURONICS ^™ , or PEG.

Exemplary anti-Factor D antibody or antigen-binding fragment formulations are described in U.S. Patent Nos. 8,067,002, 8,193,329, 8,187,604, 8,372,403, 8,273,352, 6,954,107, 7,943,135, 7,439,331, 7,112,327, 8,124,090, and 8,236,317.

For example, lyophilized formulations suitable for subcutaneous administration are described in U.S. Patent No. 6,267,958 (Andya et al.). For example, lyophilized formulations suitable for intravitreal administration are described in U.S. Patent Nos. 7,807,164 and 8,481,046. Such lyophilized formulations can be reconstituted with appropriate diluents to a high protein concentration (e.g., as described in U.S. Patent No. 8,142,776), and the reconstituted formulation can be administered subcutaneously or intravitreally to the mammal to be treated herein.

Crystallized forms of antibodies are also contemplated. See, for example, US 2002/0136719A1 (Shenoy et al.).

The formulations herein may also contain more than one active compound (second drug) when necessary for the specific indication being treated, preferably compounds with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide a VEGF inhibitor in the formulation. For example, the type or effective amount of such other agent (referred to herein as a second drug, where the first drug is an anti-Factor D antibody) depends on the amount of antibody present in the formulation, the type of degenerative disease being treated, and the clinical parameters of the subject.

In colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions, the active ingredient can also be entrapped in microcapsules, for example, microcapsules prepared by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or alum-microcapsules and poly-(methyl methacrylate) microcapsules, respectively. Such techniques are disclosed, for example, in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release formulations can be prepared. Examples of suitable sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which are present in the form of shaped articles, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactic acid (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and gamma ethyl-L-glutamic acid, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers, such as LUPRON DEPOT ^™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

Formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.

VIII. Products

A variety of articles of manufacture are included within the scope of the present invention. In another embodiment of the present invention, an article of manufacture comprising a substance for the treatment of the above-mentioned degenerative diseases is provided. Preferably, the article of manufacture comprises (a) a container comprising a composition comprising an anti-Factor D antibody or an antigen-binding fragment thereof and a pharmaceutical carrier or diluent; and (b) a package insert with instructions for treating the degenerative disease in a subject, wherein the instructions indicate an amount of the antibody to be administered to the subject that is effective to provide an initial antibody exposure of about 0.5-4 grams, followed by a second antibody exposure of about 0.5-4 grams, wherein the second antibody exposure is provided about 16-54 weeks after the initial exposure, and each antibody exposure is provided to the subject as a single dose of the antibody or as two or three separate doses.

The package insert is on or connected to the container. Suitable containers include, for example, bottles, vials, syringes, etc. The container can be made of a variety of materials, such as glass or plastic. The container holds or contains such a composition that is effective for treating AMD and may have a sterile access port (for example, the container can be an intravenous solution bag or vial with a stopper that can be pierced by a hypodermic needle). At least one active agent in the composition is an antibody. The label or package insert indicates that the composition is used to treat a degenerative disease in a subject suitable for treatment, with specific instructions on the amount and time interval of the dosage of the antibody and any other drug provided. The product can also include a second container that includes a pharmaceutical dilution buffer, such as antibacterial water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and glucose solution. The product can also include a second or third container that includes a second drug, wherein the anti-factor D antibody or its antigen-binding fragment is a first drug, and wherein the product also includes a package insert for treating the subject with the second drug. Exemplary second drugs include chemotherapeutic agents, immunosuppressants, antimalarial agents, cytotoxic agents, integrin antagonists, cytokine antagonists, or hormones. In some embodiments, the second drug is a chemotherapeutic agent, antimalarial agent or immunosuppressant, including, for example, hydroxychloroquine, chloroquine, quinacrine, cyclophosphamide, prednisone, mycophenolate mofetil, methotrexate, azathiprine, or 6-mercaptopurine; a corticosteroid such as prednisone (with optional methotrexate, hydroxychloroquine, chloroquine, quinacrine, MMF, or azathioprine with or without 6-mercaptopurine); or a corticosteroid such as prednisone and MMF or cyclophosphamide. The article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

In another aspect, the present invention provides an article of manufacture comprising an IVT or long-acting delivery device that delivers a fixed dose of an anti-Factor D antibody or antigen-binding fragment thereof to a patient, wherein the fixed dose is in the range of micrograms to milligrams of the anti-Factor D antibody or antigen-binding fragment thereof. In some embodiments, the fixed dose is about 10 mg monthly or about 10 mg every other month. In some embodiments, the concentration of the antibody in the device is about 10 mg. In another aspect, the present invention provides an article of manufacture comprising an anti-Factor D antibody or antigen-binding fragment thereof at a concentration of about 10 mg. In some embodiments, the anti-Factor D antibody comprises a light chain comprising HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1), HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2), and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5), and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In some embodiments, the antibody comprises a heavy chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody is lampalizumab, CAS Registry No. 1278466-20-8. In some embodiments, the anti-Factor D antibody can be a monoclonal antibody, an antibody fragment, a chimeric antibody, a humanized antibody, a single-chain antibody, or an antibody that competitively inhibits binding of the anti-Factor D antibody to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an anti-Factor D antibody to its corresponding antigenic epitope, wherein the anti-Factor D antibody comprises: a light chain comprising HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1), HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2), and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5), and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:7 and/or a light chain variable region sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:8 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:15 and/or a light chain sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:16 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:8 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits binding of an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:15 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:16 to its corresponding antigenic epitope. In one embodiment, the anti-Factor D antibody competitively inhibits the binding of lampalizumab, CAS Registry Number 1278466-20-8, to its corresponding antigenic epitope. In some embodiments, the anti-Factor D antibody binds to the same epitope on Factor D that is bound by another Factor D antibody. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D that is bound by an anti-Factor D antibody comprising a light chain comprising HVR-L1 comprising the amino acid sequence of ITSTDIDDDMN (SEQ ID NO: 1), HVR-L2 comprising the amino acid sequence of GGNTLRP (SEQ ID NO: 2), and HVR-L3 comprising the amino acid sequence of LQSDSLPYT (SEQ ID NO: 3); and/or a heavy chain comprising HVR-H1 comprising the amino acid sequence of GYTFTNYGMN (SEQ ID NO: 4), HVR-H2 comprising the amino acid sequence of WINTYTGETTYADDFKG (SEQ ID NO: 5), and HVR-H3 comprising the amino acid sequence of EGGVNN (SEQ ID NO: 6). In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15 and/or a light chain sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D as bound by an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 15 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In one embodiment, the anti-Factor D antibody binds to the same epitope on Factor D that is bound by lampalizumab, CAS Registry No. 1278466-20-8.

IX. Exemplary Implementations

1. A method of treating a patient suffering from a degenerative disease, the method comprising:

(a) determining the presence of at least one degenerative disease-associated polymorphism in a sample from said patient;

(i) by providing a nucleic acid sample from the patient;

(ii) genotyping the presence of at least one degenerative disease-associated polymorphism, wherein the polymorphism is a risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele;

(b) identifying the patient as being more likely to respond to a treatment comprising an anti-Factor D antibody or antigen-binding fragment thereof in the presence of at least one risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele; and

(c) administering an anti-Factor D antibody or an antigen-binding fragment thereof to the patient when at least one risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a C3B allele, or a C3 allele is present.

2. The method of claim 1, wherein the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof.

3. The method of claim 1, wherein the CFI allele is contained in a G at a single nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH allele is contained in an A at a single nucleotide polymorphism (SNP) rs10737680 or a G at a single nucleotide polymorphism (SNP) rs1329428, the C2 allele is contained in a G at a single nucleotide polymorphism (SNP) rs429608, the CFB allele is contained in a G at a single nucleotide polymorphism (SNP) rs429608, and the C3 allele is contained in a G at a single nucleotide polymorphism (SNP) rs2230199.

4. The method of claim 1, wherein the sample is a blood sample, saliva, cheek swab, tissue sample, or body fluid sample.

5. The method of claim 1, wherein the nucleic acid sample comprises DNA.

6. The method of claim 1, wherein the nucleic acid sample comprises RNA.

7. The method of claim 5 or 6, wherein the nucleic acid sample is amplified.

8. The method of claim 5 or 6, wherein the nucleic acid sample is amplified by polymerase chain reaction.

9. The method of claim 5 or 6, wherein at least one polymorphism is detected by polymerase chain reaction.

10. The method of claim 5 or 6, wherein at least one polymorphism is detected by sequencing.

11. The method of claim 9 or 10, wherein at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, a high-throughput SNP genotyping platform, molecular beacons, a 5' nuclease reaction, a Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, a genotyping platform (such as Invader), a single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification.

12. The method of claim 1, wherein the at least one polymorphism is detected by amplifying a target region comprising the at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions and detecting the hybridization.

13. The method of claim 1, wherein the presence in the patient of one or both alleles of the G genotype of SNP rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608, or SNP rs2230199 or one or both alleles of the A genotype of SNP rs10737680 indicates an increased likelihood of responding to anti-Factor D antibody treatment.

14. The method of claim 3, wherein a polymorphism in linkage disequilibrium with at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs4698775, rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is detected.

15. The method of claim 1, wherein the degenerative disease is age-related macular degeneration.

16. The method of claim 15, wherein the age-related macular degeneration is early, intermediate or late AMD.

17. The method of claim 16, wherein the late stage AMD is geographic atrophy.

18. The method of claim 1, wherein the anti-Factor D antibody or antigen-binding fragment thereof is lampalizumab.

19. A method of identifying a patient suffering from a degenerative disease who is more likely to respond to a treatment comprising an anti-Factor D antibody or an antigen-binding fragment thereof, the method comprising:

(a) determining the presence of at least one degenerative disease-associated polymorphism in a sample from said patient;

(i) by providing a nucleic acid sample from the patient;

(ii) genotyping the presence of at least one degenerative disease-associated polymorphism, wherein the polymorphism is a risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele;

(b) designating the patient as more likely to respond to a treatment comprising an anti-Factor D antibody or antigen-binding fragment thereof in the presence of at least one risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele; and

(c) selecting a treatment comprising an anti-Factor D antibody or antigen-binding fragment thereof.

20. The method of claim 19, wherein the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof.

21. The method of claim 19, wherein the CFI allele is contained in a G at SNP rs4698775 or rs17440077, the CFH allele is contained in an A at SNP rs10737680 or a G at SNP rs1329428, the C2 allele is contained in a G at SNP rs429608, the CFB allele is contained in a G at SNP rs429608, and the C3 allele is contained in a G at SNP rs2230199.

22. The method of claim 19, wherein the sample is a blood sample, saliva, cheek swab, tissue sample, or body fluid sample.

23. The method of claim 19, wherein the nucleic acid sample comprises DNA.

24. The method of claim 19, wherein the nucleic acid sample comprises RNA.

25. The method of claim 19, wherein the nucleic acid sample is amplified.

26. The method of claim 19, wherein the nucleic acid sample is amplified by polymerase chain reaction.

27. The method of claim 19, wherein at least one polymorphism is detected by polymerase chain reaction.

28. The method of claim 19, wherein at least one polymorphism is detected by sequencing.

29. The method of claim 19, wherein the at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high throughput SNP genotyping platforms, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification.

30. The method of claim 19, wherein the at least one polymorphism is detected by amplifying a target region comprising the at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions and detecting the hybridization.

31. The method of claim 19, wherein the presence in the patient of one or two alleles of the G genotype of SNP rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608, or SNP rs2230199 or one or two alleles of the A genotype of SNPrs10737680 indicates an increased likelihood of responding to anti-factor D antibody treatment (qualifies as an increased likelihood).

32. The method of claim 21, wherein a polymorphism in linkage disequilibrium with at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs4698775, rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is detected.

33. The method of claim 19, wherein the degenerative disease is age-related macular degeneration.

34. The method of claim 33, wherein the age-related macular degeneration is early, intermediate or late AMD.

35. The method of claim 34, wherein the late stage AMD is geographic atrophy.

36. The method of claim 19, wherein the anti-Factor D antibody or fragment thereof is lampalizumab.

37. A method for optimizing the therapeutic efficacy of treatment of a patient suffering from a degenerative disease using an anti-Factor D antibody or antigen-binding fragment thereof, the method comprising:

(a) determining the presence of at least one degenerative disease-associated polymorphism in a sample from said patient;

(i) by providing a nucleic acid sample from the patient;

(ii) genotyping the presence of at least one degenerative disease-associated polymorphism, wherein the polymorphism is a risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele;

(b) identifying the patient as being more likely to respond to a treatment comprising an anti-Factor D antibody or antigen-binding fragment thereof in the presence of at least one risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele; and

(c) selecting a treatment comprising an anti-Factor D antibody or antigen-binding fragment thereof.

38. The method of claim 37, wherein the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof.

39. The method of claim 37, wherein the CFI allele is contained in a G at SNP rs4698775 or rs17440077, the CFH allele is contained in an A at SNP rs10737680 or a G at SNP rs1329428, the C2 allele is contained in a G at SNP rs429608, the CFB allele is contained in a G at SNP rs429608, and the C3 allele is contained in a G at SNP rs2230199.

40. The method of claim 37, wherein the sample is a blood sample, saliva, cheek swab, tissue sample, or body fluid sample.

41. The method of claim 37, wherein the nucleic acid sample comprises DNA.

42. The method of claim 37, wherein the nucleic acid sample comprises RNA.

43. The method of claim 37, wherein the nucleic acid sample is amplified.

44. The method of claim 37, wherein the nucleic acid sample is amplified by polymerase chain reaction.

45. The method of claim 37, wherein at least one polymorphism is detected by polymerase chain reaction.

46. The method of claim 37, wherein at least one polymorphism is detected by sequencing.

3b5b. The method of claim 37, wherein at least one polymorphism is detected by a technique selected from the group consisting of: scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platform, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification.

47. The method of claim 37, wherein the at least one polymorphism is detected by amplifying a target region comprising the at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions and detecting the hybridization.

48. The method of claim 37, wherein the presence in the patient of one or both alleles of the G genotype of SNP rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608, or SNP rs2230199 or one or both alleles of the A genotype of SNP rs10737680 indicates an increased likelihood of responding to anti-Factor D antibody treatment.

49. The method of claim 39, wherein a polymorphism in linkage disequilibrium with at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs4698775, rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is detected.

50. The method of claim 37, wherein the degenerative disease is age-related macular degeneration.

51. The method of claim 50, wherein the age-related macular degeneration is early, intermediate or late AMD.

52. The method of claim 37, wherein the late stage AMD is geographic atrophy.

53. The method of claim 37, wherein the anti-Factor D antibody or antigen-binding fragment thereof is lampalizumab.

54. A method of predicting the responsiveness of a patient with a degenerative disease to treatment with an anti-Factor D antibody or antigen-binding fragment thereof, the method comprising:

(a) determining the presence of at least one degenerative disease-associated polymorphism in a sample from said patient;

(i) by providing a nucleic acid sample from the patient;

(ii) genotyping the presence of at least one degenerative disease-associated polymorphism, wherein the polymorphism is a risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele;

(b) identifying the patient as more likely to respond to a treatment comprising an anti-Factor D antibody or antigen-binding fragment thereof in the presence of at least one risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele.

55. The method of claim 55, wherein the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof.

56. The method of claim 55, wherein the CFI allele is contained in a G at a single nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH allele is contained in an A at a single nucleotide polymorphism (SNP) rs10737680 or a G at a single nucleotide polymorphism (SNP) rs1329428, the C2 allele is contained in a G at a single nucleotide polymorphism (SNP) rs429608, the CFB allele is contained in a G at a single nucleotide polymorphism (SNP) rs429608, and the C3 allele is contained in a G at a single nucleotide polymorphism (SNP) rs2230199.

57. The method of claim 55, wherein the sample is a blood sample, saliva, cheek swab, tissue sample, or body fluid sample.

58. The method of claim 55, wherein the nucleic acid sample comprises DNA.

59. The method of claim 55, wherein the nucleic acid sample comprises RNA.

60. The method of claim 55, wherein the nucleic acid sample is amplified.

61. The method of claim 55, wherein the nucleic acid sample is amplified by polymerase chain reaction.

62. The method of claim 55, wherein at least one polymorphism is detected by polymerase chain reaction.

63. The method of claim 55, wherein at least one polymorphism is detected by sequencing.

64. The method of claim 55, wherein the at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high throughput SNP genotyping platforms, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification.

65. The method of claim 55, wherein the at least one polymorphism is detected by amplifying a target region comprising the at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions and detecting the hybridization.

66. The method of claim 55, wherein the presence in the patient of one or both alleles of the G genotype of SNP rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608, or SNP rs2230199 or one or both alleles of the A genotype of SNP rs10737680 indicates an increased likelihood of responding to anti-Factor D antibody treatment.

4d1. The method of claim 4a2, wherein a polymorphism in linkage disequilibrium with at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs4698775, rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is detected.

67. The method of claim 56, wherein the degenerative disease is age-related macular degeneration.

68. The method of claim 67, wherein the age-related macular degeneration is early, intermediate or late AMD.

69. The method of claim 55, wherein the late stage AMD is geographic atrophy.

70. The method of claim 55, wherein the anti-Factor D antibody or antigen-binding fragment thereof is lampalizumab.

71. A method of determining the likelihood that a patient with a degenerative disease will benefit from treatment with an anti-Factor D antibody or antigen-binding fragment thereof, the method comprising:

(a) determining the presence of at least one degenerative disease-associated polymorphism in a sample from said patient;

(i) by providing a nucleic acid sample from the patient;

(ii) genotyping the presence of at least one degenerative disease-associated polymorphism, wherein the polymorphism is a risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele;

(b) identifying the patient as more likely to respond to a treatment comprising an anti-Factor D antibody or antigen-binding fragment thereof in the presence of at least one risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele.

72. The method of claim 71, wherein the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof.

73. The method of claim 71, wherein the CFI allele is contained in a G at single nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH allele is contained in an A at single nucleotide polymorphism (SNP) rs10737680 or a G at single nucleotide polymorphism (SNP) rs1329428, the C2 allele is contained in a G at single nucleotide polymorphism (SNP) rs429608, the CFB allele is contained in a G at single nucleotide polymorphism (SNP) rs429608, and the C3 allele is contained in a G at single nucleotide polymorphism (SNP) rs2230199.

74. The method of claim 71, wherein the sample is a blood sample, saliva, cheek swab, tissue sample, or body fluid sample.

75. The method of claim 71, wherein the nucleic acid sample comprises DNA.

76. The method of claim 71, wherein the nucleic acid sample comprises RNA.

77. The method of claim 71, wherein the nucleic acid sample is amplified.

78. The method of claim 71, wherein the nucleic acid sample is amplified by polymerase chain reaction.

79. The method of claim 71, wherein at least one polymorphism is detected by polymerase chain reaction.

80. The method of claim 71, wherein at least one polymorphism is detected by sequencing.

81. The method of claim 71, wherein at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, a high throughput SNP genotyping platform, molecular beacons, a 5' nuclease reaction, a Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, a genotyping platform (such as Invader), a single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification.

82. The method of claim 71, wherein the at least one polymorphism is detected by amplifying a target region comprising the at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions and detecting the hybridization.

83. The method of claim 71, wherein the presence in the patient of one or both alleles of the G genotype of SNP rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608, or SNP rs2230199 or one or both alleles of the A genotype of SNPrs10737680 indicates an increased likelihood of responding to anti-Factor D antibody treatment.

84. The method of claim 73, wherein a polymorphism that is linkage disequilibrium with at least one single nucleotide polymorphism selected from the group consisting of single nucleotide polymorphisms (SNPs) rs4698775, rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is detected.

85. The method of claim 71, wherein the degenerative disease is Age-related macular degeneration.

86. The method of claim 85, wherein the age-related macular degeneration is early, intermediate or late AMD.

87. The method of claim 73, wherein the late stage AMD is geographic atrophy.

88. The method of claim 3, wherein the anti-Factor D antibody or antigen-binding fragment thereof is lampalizumab.

89. A method of assessing a degenerative disease in an individual, the method comprising:

(a) determining the presence of at least one degenerative disease-associated polymorphism in a sample from a patient;

(i) by providing a nucleic acid sample from the patient;

(ii) genotyping the presence of at least one degenerative disease-associated polymorphism, wherein the polymorphism is a risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele;

(b) providing an assessment of a degenerative disease when at least one risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele is present in the sample from the individual.

90. The method of claim 89, wherein the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof.

91. The method of claim 89, wherein the CFI allele is contained in a G at a single nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH allele is contained in an A at a single nucleotide polymorphism (SNP) rs10737680 or a G at a single nucleotide polymorphism (SNP) rs1329428, the C2 allele is contained in a G at a single nucleotide polymorphism (SNP) rs429608, the CFB allele is contained in a G at a single nucleotide polymorphism (SNP) rs429608, and the C3 allele is contained in a G at a single nucleotide polymorphism (SNP) rs2230199.

92. The method of claim 89, wherein the sample is a blood sample, saliva, cheek swab, tissue sample, or body fluid sample.

93. The method of claim 6, wherein the nucleic acid sample comprises DNA.

94. The method of claim 89, wherein the nucleic acid sample comprises RNA.

95. The method of claim 89, wherein the nucleic acid sample is amplified.

96. The method of claim 89, wherein the nucleic acid sample is amplified by polymerase chain reaction.

97. The method of claim 89, wherein at least one polymorphism is detected by polymerase chain reaction.

98. The method of claim 89, wherein at least one polymorphism is detected by sequencing.

99. The method of claim 89, wherein at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high throughput SNP genotyping platforms, molecular beacons, 5' nuclease reactions, Taqman assays, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assays, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification.

100. The method of claim 89, wherein the at least one polymorphism is detected by amplifying a target region comprising the at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions and detecting the hybridization.

101. The method of claim 89, wherein patients having one or both alleles of the G genotype of SNP rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608, or SNP rs2230199 or one or both alleles of the A genotype of SNP rs10737680 are more likely to respond to anti-Factor D antibody treatment.

102. The method of claim 91, wherein a polymorphism in linkage disequilibrium with at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs4698775, rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is detected.

103. The method of claim 689, wherein the degenerative disease is age-related macular degeneration.

104. The method of claim 103, wherein the age-related macular degeneration is early, intermediate or late stage AND.

105. The method of claim 104, wherein the late stage AMD is geographic atrophy.

106. A method of identifying an individual at increased risk for developing a more advanced form of age-related macular degeneration, the method comprising:

(a) determining the presence of at least one degenerative disease-associated polymorphism in a sample from the individual;

(a) determining the presence of at least one degenerative disease-associated polymorphism in a sample from the individual;

(i) by providing a nucleic acid sample from the individual;

(ii) genotyping the presence of at least one degenerative disease-associated polymorphism, wherein the polymorphism is a risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele;

(b) the individual is identified as being more likely to develop a more advanced form of AMD in the presence of at least one risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele.

107. (p11) The method of claim 106, wherein the individual is more likely to respond to a treatment comprising an anti-Factor D antibody or an antigen-binding fragment thereof in the presence of at least one risk allele from the group consisting of a free CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele; and further comprising selecting a treatment comprising an anti-Factor D antibody or an antigen-binding fragment thereof.

108. The method of claim 106, wherein the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof.

109. The method of claim 106, wherein the CFI allele is contained in a G at single nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH allele is contained in an A at single nucleotide polymorphism (SNP) rs10737680 or a G at single nucleotide polymorphism (SNP) rs1329428, the C2 allele is contained in a G at single nucleotide polymorphism (SNP) rs429608, the CFB allele is contained in a G at single nucleotide polymorphism (SNP) rs429608, and the C3 allele is contained in a G at single nucleotide polymorphism (SNP) rs2230199.

110. The method of claim 106, wherein the sample is a blood sample, saliva, cheek swab, tissue sample, or body fluid sample.

111. The method of claim 106, wherein the nucleic acid sample comprises DNA.

112. The method of claim 106, wherein the nucleic acid sample comprises RNA.

113. The method of claim 106, wherein the nucleic acid sample is amplified.

114. The method of claim 106, wherein the nucleic acid sample is amplified by polymerase chain reaction.

115. The method of claim 106, wherein at least one polymorphism is detected by polymerase chain reaction.

116. The method of claim 106, wherein at least one polymorphism is detected by sequencing.

117. The method of claim 106, wherein at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high throughput SNP genotyping platforms, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification.

118. The method of claim 106, wherein the at least one polymorphism is detected by amplifying a target region comprising the at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions and detecting the hybridization.

119. The method of claim 106, wherein patients having one or both alleles of the G genotype of SNP rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608, or SNP rs2230199 or one or both alleles of the A genotype of SNP rs10737680 are more likely to respond to anti-Factor D antibody treatment.

120. The method of claim 108, wherein a polymorphism in linkage disequilibrium with at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs4698775, rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is detected.

121. The method of claim 106, wherein the degenerative disease is age-related macular degeneration.

122. The method of claim 121, wherein the age-related macular degeneration is early, intermediate, or late AMD.

123. The method of claim 106, wherein the late stage AMD is geographic atrophy.

124. The method of claim 106, wherein the anti-Factor D antibody or antigen-binding fragment thereof is lampalizumab.

125. A method of predicting the progression of AMD in an individual, the method comprising:

(a) determining the presence of at least one degenerative disease-associated polymorphism in a sample from the individual;

(i) by providing a nucleic acid sample from the individual;

(ii) genotyping the presence of at least one degenerative disease-associated polymorphism, wherein the polymorphism is a risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele;

(b) the individual is identified as being more likely to develop a more advanced form of AMD in the presence of at least one risk allele selected from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele.

126. The method of claim 7, wherein the individual is more likely to respond to a treatment comprising an anti-Factor D antibody or an antigen-binding fragment thereof in the presence of at least one risk allele from the group consisting of a CFI allele, a CFH allele, a C2 allele, a CFB allele, or a C3 allele; and further comprising selecting a treatment comprising an anti-Factor D antibody or an antigen-binding fragment thereof.

127. The method of claim 7, wherein the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof.

128. The method of claim 7, wherein the CFI allele is contained in a G at a single nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH allele is contained in an A at a single nucleotide polymorphism (SNP) rs10737680 or a G at a single nucleotide polymorphism (SNP) rs1329428, the C2 allele is contained in a G at a single nucleotide polymorphism (SNP) rs429608, the CFB allele is contained in a G at a single nucleotide polymorphism (SNP) rs429608, and the C3 allele is contained in a G at a single nucleotide polymorphism (SNP) rs2230199.

129. The method of claim 7, wherein the sample is a blood sample, saliva, cheek swab, tissue sample, or body fluid sample.

130. The method of claim 7, wherein the nucleic acid sample comprises DNA.

131. The method of claim 7, wherein the nucleic acid sample comprises RNA.

132. The method of claim 7, wherein the nucleic acid sample is amplified.

133. The method of claim 7, wherein the nucleic acid sample is amplified by polymerase chain reaction.

134. The method of claim 7, wherein at least one polymorphism is detected by polymerase chain reaction.

135. The method of claim 7, wherein at least one polymorphism is detected by sequencing.

136. The method of claim 7, wherein at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis by homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, a high-throughput SNP genotyping platform, molecular beacons, a 5' nuclease reaction, a Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, a genotyping platform (such as Invader), a single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification.

137. The method of claim 7, wherein the at least one polymorphism is detected by amplifying a target region comprising the at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions and detecting the hybridization.

138. The method of claim 7, wherein the patient has one or both alleles of the G genotype of SNP rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608, or SNP rs2230199 or one or both alleles of the A genotype of SNP rs10737680 is more likely to respond to anti-Factor D antibody treatment.

139. The method of claim 7a2, wherein a polymorphism in linkage disequilibrium with at least one single nucleotide polymorphism (SNP) selected from the group consisting of r54698775, rs17440077, rs10737680, rs1329428, rs429608, and r52230199 is detected.

140. The method of claim 7, wherein the degenerative disease is age-related macular degeneration.

141. The method of claim 7e, wherein the age-related macular degeneration is early, intermediate or late AMD.

142. The method of claim 7, wherein the late stage AMD is geographic atrophy.

143. The method of claim 7, wherein the anti-Factor D antibody or antigen-binding fragment thereof is lampalizumab.

144. A method of determining the risk of progression of a degenerative disease in an individual suffering from a degenerative disease, the method comprising:

(a) determining the presence of at least one degenerative disease-associated polymorphism in a sample from the individual;

(i) by providing a nucleic acid sample from the individual;

(ii) genotyping the presence of at least one degenerative disease-associated polymorphism, wherein the polymorphism is a risk allele selected from the group consisting of a CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB risk allele, or a C3 risk allele;

(b) the individual is identified as having an increased risk of progression of the degenerative disease when the risk allele polymorphism is present, wherein the increased risk is relative to the risk when the major allele of the polymorphism is present.

145. The method of claim 144, wherein the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof.

146. The method of claim 144, wherein the CFI allele comprises a G at single nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH allele comprises an A at single nucleotide polymorphism (SNP) rs10737680 or a G at single nucleotide polymorphism (SNP) rs1329428, the C2 allele comprises a G at single nucleotide polymorphism (SNP) rs429608, the CFB allele comprises a G at single nucleotide polymorphism (SNP) rs429608, and the C3 allele comprises a G at single nucleotide polymorphism (SNP) rs2230199.

147. The method of claim 144, wherein the sample is a blood sample, saliva, cheek swab, tissue sample, or body fluid sample.

148. The method of claim 144, wherein the nucleic acid sample comprises DNA.

149. The method of claim 144, wherein the nucleic acid sample comprises RNA.

150. The method of claim 144, wherein the nucleic acid sample is amplified.

151. The method of claim 144, wherein the nucleic acid sample is amplified by polymerase chain reaction.

152. The method of claim 144, wherein at least one polymorphism is detected by polymerase chain reaction.

153. The method of claim 144, wherein at least one polymorphism is detected by sequencing.

154. The method of claim 144, wherein at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high throughput SNP genotyping platforms, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification.

155. The method of claim 144, wherein the at least one polymorphism is detected by amplifying a target region comprising the at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions and detecting the hybridization.

156. The method of claim 144, wherein the presence of two alleles of the G genotype of SNP rs4698775, SNPrs17440077, SNP rs1329428, SNP rs429608, or SNP rs2230199 or one or two alleles of the A genotype of SNP rs10737680 in the individual indicates an increased risk of progression of the degenerative disease.

157. The method of claim 146, wherein a polymorphism in linkage disequilibrium with at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs4698775, rs17440077, rs10737680, rs1329428, rs429608, and rs2230199 is detected.

158. The method of claim 144, wherein the degenerative disease is age-related macular degeneration.

150. The method of claim 158, wherein the age-related macular degeneration is early, intermediate, or late AMD.

160. The method of claim 144, wherein the late stage AMD is geographic atrophy.

161. A method for treating a degenerative disease, the method comprising administering to a patient suffering from the degenerative disease an anti-Factor D antibody or an antigen-binding fragment thereof at a dose of 10 mg per month, the anti-Factor D antibody or antigen-binding fragment thereof comprising HVRH1, HVRH2, HVRH3, HVRL1, HVRL2, HVRL3 and HVRL3, wherein the HVRs have the amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.

162. The method of claim 161, wherein the age-related macular degeneration is early, intermediate or late AMD.

163. The method of claim 162, wherein the late stage AMD is geographic atrophy.

164. The method of claim 161, wherein a second drug is administered.

165. The method of claim 164, wherein the second drug is a VEGF inhibitor.

166. The method of claim 165, wherein the VEGF inhibitor is ranibizumab.

167. The method of claim 161, wherein the anti-Factor D antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof comprising a VH comprising SEQ ID NO:7 and a VL comprising SEQ ID NO:8.

168. The method of claim 161, wherein the treatment results in a decrease in GA area change from baseline GA area of greater than or equal to 20%.

169. The method of claim 161, wherein the treatment results in a decrease in GA area change from baseline GA area of greater than or equal to 15%.

170. The method of claim 161, wherein the treatment results in a decrease in GA area change from baseline GA area of greater than or equal to 10%.

171. The method of claim 161, wherein the treatment results in a decrease in GA area change from baseline GA area of greater than or equal to 5%.

172. The method of claim 161, wherein the patient has geographic atrophy secondary to AMD.

173. The method of claim 161, wherein the patient's studied eye has a BCVA of 20/25-20/400.

174. The method of claim 161, wherein the patient's studied eye has a BCVA of 20/25-20/100.

175. The method of claim 161, wherein the patient's studied eye has a BCVA of 20/50-20/400.

176. The method of claim 161, wherein the patient has a BCVA of better than 20/25 or worse than 20/400 in the eye being studied.

177. The method of claim 161, wherein the patient's studied eye has not received any prior intravitreal therapy, retinal surgery, or other retinal therapeutic procedure.

178. A kit for genotyping a biological sample from a patient with a degenerative disease, wherein the kit comprises oligonucleotides for polymerase chain reaction or sequencing to detect risk alleles.

179. The kit of claim 178, wherein the biological sample is a blood sample, saliva, cheek swab, tissue sample, or body fluid sample.

180. The kit of claim 178, wherein the biological sample is a nucleic acid sample.

181. The kit of claim 180, wherein the nucleic acid sample comprises DNA.

182. The kit of claim 1181, wherein the nucleic acid sample comprises RNA.

183. The kit of claim 180, wherein the nucleic acid sample is amplified.

184. The kit of claim 178, wherein the kit further comprises a package insert for determining whether a patient with a degenerative disease is likely to respond to an anti-Factor D antibody or antigen-binding fragment thereof.

185. The kit of claim 178, wherein the kit is used to detect the presence of a CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB risk allele, or a C3 risk allele.

186. The kit of claim 10, wherein the kit is used to detect the presence of one or both alleles of the G genotype of SNP rs4698775, SNPrs17440077, SNP rs1329428, SNP rs429608, or SNP rs2230199, or both alleles of the A genotype of SNP rs10737680.

187. A kit for predicting whether a patient has an increased likelihood of benefiting from treatment with an anti-Factor D antibody or antigen-binding fragment thereof, the kit comprising a first oligonucleotide and a second oligonucleotide specific for a polymorphism in CFI, C2, CFB, C3 or CFH.

188. The kit of claim 187, wherein the first oligonucleotide and the second oligonucleotide can be used to amplify a region of the CFI, C2, CFB, C3 or CFH gene comprising a polymorphism in CFI, C2, CFB, C3 or CFH, respectively, selected from the group consisting of the G genotype of SNP rs4698775, SNP rs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or the A genotype of SNP rs10737680.

189. The method of any one of claims 1-5 and 7, wherein the anti-Factor D antibody or antigen-binding fragment thereof comprises HVRH1, HVRH2, HVRH3, HVRL1, HVRL2, HVRL3, and HVRL3, wherein the HVRs have the amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively.

190. The method of any one of claims 1-60, wherein the anti-Factor D antibody, or antigen-binding fragment thereof, comprises the variable heavy chain of SEQ ID NO:7 and/or the variable light chain of SEQ ID NO:8.

191. The method of any one of claims 1-160, wherein the polymorphism is a CFI polymorphism.

192. The method of claim 191, wherein the CFI polymorphism is present in combination with one or more additional polymorphisms selected from the group consisting of a CFH polymorphism, a C2 polymorphism, a C3 polymorphism, or a CFB polymorphism.

193. Use of a reagent that specifically binds to at least one degenerative disease-associated polymorphism in the preparation of a diagnostic agent for diagnosing a degenerative disease, wherein the polymorphism is a risk allele selected from the group consisting of CFI risk allele, CFH risk allele, C2 risk allele, CFB risk allele or C3 risk allele.

194. The use of claim 193, wherein the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof.

195. The use of claim 193, wherein the CFI allele comprises a G at single nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH allele comprises an A at single nucleotide polymorphism (SNP) rs10737680 or a G at single nucleotide polymorphism (SNP) rs1329428, the C2 allele comprises a G at single nucleotide polymorphism (SNP) rs429608, the CFB allele comprises a G at single nucleotide polymorphism (SNP) rs429608, and the C3 allele comprises a G at single nucleotide polymorphism (SNP) rs2230199.

196. The use of claim 193, wherein at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zn(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platforms, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multi-primer extension (MPEX), and isothermal intelligent amplification.

197. The use of claim 193, wherein the at least one polymorphism is detected by amplifying a target region comprising the at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions, and detecting the hybridization.

198. The use of claim 193, wherein the presence in the individual of one or both alleles of the G genotype of SNP rs4698775, SNPrs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or one or both alleles of the A genotype of SNP rs10737680 indicates an increased risk of progression of a degenerative disease.

199. The use of claim 195, wherein a polymorphism in linkage disequilibrium with at least one single nucleotide polymorphism selected from the group consisting of single nucleotide polymorphisms (SNPs) rs4698775, rs17440077, rs10737680, rs1329428, rs429608 and rs2230199 is detected.

200. The use of claim 193, wherein the degenerative disease is age-related macular degeneration.

201. The use of claim 200, wherein the age-related macular degeneration is early, intermediate or late AMD.

202. The use of claim 201, wherein the late AMD is geographic atrophy.

203. An in vitro use of a reagent that binds to at least one polymorphism associated with a degenerative disease for identifying patients with a degenerative disease who are likely to respond to a therapy comprising an anti-Factor D antibody or an antigen-binding fragment thereof, wherein the polymorphism is a risk allele selected from the group consisting of a CFI risk allele, a CFH risk allele, a C2 risk allele, a CFB risk allele, or a C3 risk allele, wherein the presence of the polymorphism identifies the patient as more likely to respond to the therapy.

204. The use of claim 203, wherein the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof.

205. The method of claim 203, wherein the CFI allele comprises a G at SNP rs4698775 or rs17440077, the CFH allele comprises an A at SNP rs10737680 or a G at SNP rs1329428, the C2 allele comprises a G at SNP rs429608, the CFB allele comprises a G at SNP rs429608, and the C3 allele comprises a G at SNP rs2230199.

206. The use of claim 203, wherein at least one polymorphism is detected by a technique selected from the group consisting of scanning probe and nanopore DNA sequencing, pyrosequencing, denaturing gradient gel electrophoresis (DGGE), time temperature gradient electrophoresis (TTGE), Zr(II)-cyclanine polyacrylamide gel electrophoresis, single nucleotide polymorphism analysis based on homogeneous fluorescent PCR, phosphate-affinity polyacrylamide gel electrophoresis, high-throughput SNP genotyping platform, molecular beacons, 5' nuclease reaction, Taqman assay, MassArray (single base primer extension coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry), trityl mass tags, genotyping platforms (such as Invader), single base primer extension (SBE) assay, PCR amplification (e.g., PCR amplification on magnetic nanoparticles (MNPs)), restriction enzyme analysis of PCR products (RFLP method), allele-specific PCR, multiple primer extension (MPEX), and isothermal intelligent amplification.

16b6. The method of claim 16, wherein the at least one polymorphism is detected by amplifying a target region comprising the at least one polymorphism and hybridizing with at least one sequence-specific oligonucleotide that hybridizes to the at least one polymorphism under stringent conditions, and detecting the hybridization.

207. The use of claim 203, wherein the presence in the individual of one or both alleles of the G genotype of SNP rs4698775, SNPrs17440077, SNP rs1329428, SNP rs429608 or SNP rs2230199 or one or both alleles of the A genotype of SNP rs10737680 indicates an increased risk of progression of a degenerative disease.

208. The use of claim 204, wherein a polymorphism in linkage disequilibrium with at least one single nucleotide polymorphism selected from the group consisting of single nucleotide polymorphisms (SNPs) rs4698775, rs17440077, rs10737680, rs1329428, rs429608 and rs2230199 is detected.

209. The use of claim 203, wherein the degenerative disease is age-related macular degeneration.

210. The use of claim 209, wherein the age-related macular degeneration is early, intermediate or late AMD.

211. The use of claim 210, wherein the late stage AMD is geographic atrophy.

212. A method of selecting a patient with a degenerative disease who is likely to respond to a treatment comprising anti-Factor D or an antigen-binding fragment thereof by detecting a polymorphism associated with a degenerative disease in vitro, wherein when the polymorphism associated with the degenerative disease is detected in a sample from the patient, the patient is identified as being more likely to respond to the treatment.

213. The use of claim 212, wherein the degenerative disease-associated polymorphism is an AMD-associated polymorphism.

214. The use of claim 212, wherein the polymorphism is a risk allele selected from the group consisting of CFI risk allele, CFH risk allele, C2 risk allele, CFB risk allele or C3 risk allele, which is used to prepare a diagnostic agent for diagnosing a degenerative disease.

215. The use of claim 214, wherein the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof.

216. The use of claim 214, wherein the CFI allele comprises a G at single nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH allele comprises an A at single nucleotide polymorphism (SNP) rs10737680 or a G at single nucleotide polymorphism (SNP) rs1329428, the C2 allele comprises a G at single nucleotide polymorphism (SNP) rs429608, the CFB allele comprises a G at single nucleotide polymorphism (SNP) rs429608, and the C3 allele comprises a G at single nucleotide polymorphism (SNP) rs2230199.

217. Use of a degenerative disease-associated polymorphism in the preparation of a diagnostic agent for assessing the likelihood of a patient suffering from a degenerative disease to respond to a treatment comprising an anti-Factor D antibody or an antigen-binding fragment thereof.

218. The use of claim 217, wherein the degenerative disease-associated polymorphism is an AMD-associated polymorphism.

219. The use of claim 217, wherein the polymorphism is a risk allele selected from the group consisting of CFI risk allele, CFH risk allele, C2 risk allele, CFB risk allele or C3 risk allele, which is used to prepare a diagnostic agent for diagnosing a degenerative disease.

220. The use of claim 219, wherein the CFI allele is an equivalent allele thereof, the CFH allele is an equivalent allele thereof, the C2 allele is an equivalent allele thereof, the CFB allele is an equivalent allele thereof, or the C3 allele is an equivalent allele thereof.

221. The use of claim 219, wherein the CFI allele comprises a G at single nucleotide polymorphism (SNP) rs4698775 or rs17440077, the CFH allele comprises an A at single nucleotide polymorphism (SNP) rs10737680 or a G at single nucleotide polymorphism (SNP) rs1329428, the C2 allele comprises a G at single nucleotide polymorphism (SNP) rs429608, the CFB allele comprises a G at single nucleotide polymorphism (SNP) rs429608, and the C3 allele comprises a G at single nucleotide polymorphism (SNP) rs2230199.

In specific embodiments, for example, the AMD danger of more late stage AMD (for example, mid-term AMD or CNV or map-like atrophy) based on their progress assessed by the method described herein, to the individuality that can benefit most from detection, prevention and/or treatment regimen, specially prescribe and/or implement described detection, prevention and/or treatment regimen.Thus be provided for identifying the patient with AMD progress danger then to the method for prescribing detection, treatment or prevention regimen to the individuality that is accredited as in the AMD progress danger of increase. This specific embodiment relates to the AMD in the treatment experimenter, alleviate the progress of AMD in the experimenter, or detect the AMD progress in the experimenter in early stage, it comprises: detect the presence or absence of the polymorphic variant relevant to AMD or AMD progress at SNP place in the nucleotide sequence, (comprising SNP rs4698775, rs17440077, rs10737680, rs1329428, rs429608, rs2230199) (Genome Reference Sequence Association GRCh37; UCSC genome HG19 assembly; February, 2009), and the experimenter derived from described sample is prescribed or implements AMD treatment regimen, prevention program and/or detection program, wherein, in described sample, detect the presence of the polymorphic variant relevant to the progress of AMD or AMD at one or more SNPs place in the nucleotide sequence.In these methods, genetic result can be used in conjunction with other test results, to diagnose AMD or AMD, as described herein.

In other embodiments, the pharmacogenomics method can be used to analyze and predict the response for AMD treatment or medicine.If the pharmacogenomics analysis indicates that the individual positive response uses the possibility of the AMD treatment of specific drugs (for example, anti-factor D antibody, or its Fab), then the medicine can be administered to the individual.If the analysis indicates that the individual possible negative response uses the treatment of specific drugs, then an alternative treatment course can be prescribed.Negative response can be defined as not having effective response or having toxic side effects.Can predict the response to therapeutic treatment in background studies, in described background studies, to any one but not limited to the experimenter of following colony as following colony, carry out genotyping: advantageously the colony of response treatment regimen, not obviously the colony of response treatment regimen and unfavorably the colony (for example, showing one or more side effects) of response treatment regimen.Can carry out genotyping to individual, to predict which colony they belong to.

Method as herein described is also applicable to clinical drug trials.Indication can be identified at one or more SNPs places to the response of the medicament for the treatment of AMD or to the polymorphic variant of the side effect of the medicament for the treatment of AMD.Then, the potential participant of the clinical trial of this medicament can be screened, thereby identify those individualities of most likely advantageously responding to said medicine, and get rid of those individualities of more unlikely response or experience side effect.Thus, can measure therapeutic efficacy in the individuality of the described medicine of positive response, and can not reduce said measurement owing to comprising the individuality of the described treatment of impossibly positive response.Therefore, another embodiment is the method for the individuality of selection to be included in the clinical trial for the treatment of, and said method comprises the steps: (a) obtains about individual nucleic acid sample, (b) determine and the polymorphic variant relevant to described treatment positive response or the character of the polymorphic variant relevant to the negative response for described treatment, and (c) if described nucleic acid sample comprises the polymorphic variant relevant to the positive response for described treatment, then in described clinical trial, comprise described individuality. Step (c) may further comprise administering the treatment to the individual if the nucleic acid sample comprises a polymorphic variant associated with a positive response to the treatment and/or if the nucleic acid sample lacks a polymorphic variant associated with a negative response to the treatment.

Further details of the invention are illustrated by the following non-limiting examples.The disclosures of all citations in the specification are expressly incorporated herein by reference.

Example

Example 1 - Geographic Atrophy Clinical Trial

Overview

Carry out 1b/II phase randomization, unilateral concealment, sham injection-controlled multicenter study, to evaluate the safety, tolerability and activity evidence of lampalizumab intravitreal (ITV) injection used monthly or every other month during the 18-month treatment period for patients with geographic atrophy (GA). Safety operation assessment was carried out before randomization study. Primary, secondary and exploratory results were assessed at the end of the 18-month treatment period. After the last ITV or sham injection was used for the research patients who were unqualified or chose not to continue the open-label extension study (OLE), a 3-month safety follow-up period began. For safety operation assessment, before starting the randomization phase of the study, multiple monthly 10mg lampalizumab ITV administrations were carried out. All patients in the safety operation assessment received at least 3 monthly doses of lampalizumab to obtain safety data from 10 evaluable patients. Evaluable patients are patients who have received at least three study drug injections.

For the four-arm randomization phase, patients were randomized with the use of an interactive web response system (IWRS) in a drug:sham allocation ratio of 2:1:2:1, so that 43 patients received monthly injections of lampalizumab, 21 patients received monthly injections of sham for 18 injections, 44 patients received injections of lampalizumab every other month, and 21 patients received injections of sham every other month for 9 injections.

Table 2 summarizes the experimental design.

Table 2

The patient population in this study included 57% women with a mean age of 79 years. The majority of patients in this study were white (>98%) and not Hispanic or Latino (>98%). Demographic and baseline characteristics were generally assessed across treatment groups. Fifty-eight percent of all efficacy-evaluable patients had a baseline geographic atrophic lesion area of <4 DA (1DA = 2.54 mm2), and the distribution was generally similar across treatment groups.

A running assessment of the safety and tolerability of multiple monthly 10mg lampalizumab ITV administrations was performed prior to commencing the randomized phase of the study. All patients in the safety running assessment received a minimum of 3 monthly lampalizumab doses (Fig. 1, to obtain safety data from 10 evaluable patients. All evaluable patients were patients who received at least three study drug injections. Eligible patients who enrolled in the safety running assessment followed the process described for the randomized phase of this study (see below), except for the BCVA inclusion criteria (see below; 3.1.1.b.1)).

For safety operation assessment, each patient receives study drug injection at day 0, and is assessed on the 1st day, 7 (± 2) day and 30 (± 7) day after each injection, until dose interruption is started. After the tenth evaluable patient finishes the follow-up visit on the 90th (± 7) day after the third study drug administration, it is followed by a dose interruption of about 1 week. During this interruption, (assessment) safety and tolerance of multiple drug administrations. The safety operation assessment proves the acceptable safety and tolerance of the 10-mg lampalizumab dosage that meets the dose limit criteria (DLC; see below), and starts the randomization phase. After interruption and determination of the acceptable safety and tolerance of the 10mg lampalizumab dosage, the patients participating in the safety operation assessment continue to use the study drug of 10mg once a month. These patients receive up to 18 lampalizumab treatments during this study.

Patients who discontinued study treatment early were encouraged to undergo regular monthly assessments until the end of their study period. If monthly assessments were not possible, patients were evaluated at least every 3 months and completed 12-month and 18-month follow-up. Patients who discontinued study treatment early were not allowed to participate in the OLE study.

Patients who withdraw from the study before completion will be asked to return for an early termination evaluation 30 (± 7) days after their last study treatment to monitor for adverse events and final study follow-up assessment. Patients who withdraw from the study before completion will not be allowed to enroll in the OLE study.

If ≥2 patients experience the same dose-limiting toxicity (DLT) during the safety run evaluation process (e.g., ≥2 patients have vitritis that meets the DLT criteria), the 10-mg dose group will be paused and all patients in the group will be discontinued from the study, and the early termination evaluation process will follow. A new group will be added to obtain 10 evaluable patients at the 5-mg dose; the same safety run evaluation process and rules as described for the 10-mg group will be used for patients in the 5-mg group. If a dose-reduction plan using 5 mg is initiated, successful completion of this group according to the DLC is required to start the randomization phase (Figure 1).

Single DLTs were defined as any of the following adverse events occurring during the safety operational assessment period and believed to be study drug related:

1. Vitritis or uveitis, defined as a change of 2 units on the marker grading scale after study drug injection (grading scale for anterior chamber flare or cells and vitreous cells). According to this definition, the study exclusion criteria determined that the baseline grade was 0, and an increase to 2+ or more would constitute a DLT. A grade of 4+ in the anterior chamber or vitreous cell count would be considered a major toxicity, requiring interruption of enrollment and further evaluation by the Internal Safety Review Committee to determine whether further enrollment/treatment is appropriate.

2. Endophthalmitis

3. Continuous evaluation of intraocular pressure (IOP) ≥30 mmHg (at three consecutive regular follow-up measurements)

4. A persistent decrease in visual acuity (VA) of ≥15 letters after study drug injection that is not attributable to the injection procedure or progression of GA.

Patients undergoing safety were assessed for DLTs at follow-up visits on Day 1, Day 7 (± 2), and Day 30 (± 7) after each study drug injection. This regimen continued until the tenth evaluable patient received the third study drug injection and completed Day 90 (± 7) follow-up.

The research drug dosage of 10mg that shows the acceptable safety that meets the DLC that limits in the safety operation assessment and tolerability is used for the randomization phase of this research.129 patients who suffer from GA secondary to AMD have joined this randomization phase.This research is by the screening phase of up to 14 days (day-14 to day-1) and to the treatment phase of 18 months of all randomized patients and to the patient's last study drug or the fake thing that are used after 3 months of safety follow-up phase composition of the extension research disclosed by unqualified or selecting not to continue to add label.

At screening and Day 0 follow-up, patients met all eligibility criteria, including having images taken at all screening visits by a central reading center. As part of the screening process, the central reading center evaluated fundus autofluorescence (FAF) images, digital fundus photographs (FP), and fluorescein angiograms (FA) to provide an objective, masked assessment of patient eligibility for GA. Eligible patients were enrolled on Day 0 and randomized using an interactive web response system (IWRS) in a 2:1:2:1 drug:sham allocation ratio, so that 43 patients received monthly lampalizumab injections, 21 patients received monthly sham injections for 18 injections, 44 patients received every other month lampalizumab injections, and 21 patients received every other month sham injections for 9 injections (Figure 1). Eligible patients were stratified based on GA lesion size. Patients were enrolled on the day treatment started (Day 0).

Only one eye was selected as the eye to be studied. If both eyes were not eligible, the eye with the worse vision (worse VA and/or minimal function) was selected for study treatment (the eye to be studied). The researchers and other on-site staff were not masked to the patients' treatment assignments. Only the patients were masked to their treatment assignments. All patients were followed up regularly every month for the duration of the study. On Day 0, the enrolled patients had their first ITV injection of lampalizumab or sham administered by the researchers. Patients in the randomized phase underwent safety and eye assessments 7 (± 2) days after the first injection. During subsequent follow-up visits (once a month), patients in the monthly treatment group were evaluated for safety by the researchers before receiving the study drug or sham injection. Patients in the alternate-monthly treatment group also underwent a safety assessment every month, but only received the study drug or sham during the alternate-monthly visits. Patients in the randomized phase were contacted by on-site personnel 7 (± 2) days after each injection to report decreased vision, eye pain, abnormal redness, or any other new eye symptoms in the eye to be studied. Patients were also asked to demonstrate that they took their prescribed, self-administered, and post-injection antibiotics. Patients who were eligible and chose to continue in the OLE study had their final safety visit at the 18-month follow-up. Patients who were ineligible or chose not to continue in the OLE study had their subsequent safety visit at the 19-month follow-up (for the alternate-month treatment group) or at the 20-month follow-up (for the monthly treatment group). Missed doses were not made up.

Patients who discontinued study treatment prematurely were encouraged to undergo regular monthly assessments until the end of their study period. If monthly assessments were not possible, patients were assessed at least every 3 months and completed 12-month and 18-month follow-up visits. Patients who discontinued study treatment prematurely were not permitted to continue in the OLE study. Patients who withdrew from the study before completion were asked to return for an early termination assessment 30 (± 7) days after their last study treatment to monitor for adverse events and the final study follow-up assessment. Patients who withdrew from the study before completion were not permitted to continue in the OLE study.

2. Outcome Measurement

2.1 Primary outcome measures

The primary efficacy outcome for evidence of activity in the Phase 1b/II study was the anatomical endpoint, rate of growth in GA lesion area as measured by FAF from baseline to Month 18. The anatomical primary endpoint provides a more sensitive measure of GA progression and serves as a surrogate for visual acuity loss.

2.2 Secondary outcome measures

Secondary efficacy outcome measures were the rate of growth of GA lesion area from baseline to month 18, assessed by digital stereoscopic color fundus photography, and the change in mean BCVA from baseline to month 18, measured using the ETDRS VA chart.

2.3 Additional outcome measures

Additional exploratory outcome measures included the following: a) rate of growth in GA area from baseline as assessed by spectral domain-optical coherence tomography (SD-OCT); b) change in drusen volume as assessed by SD-OCT; c) conversion rate to intermediate wet AMD in study eyes treated with lampalizumab relative to sham controls; d) change from baseline in words read per minute on the Submacular Surgery Trial (SST) reading speed assessment; (e) change from baseline in words read per minute binocularly on the Minnesota Reading Speed Assessment (MNRead); (f) change from baseline in contrast sensitivity as measured by corrected number of letters read on a Pelli-Robson chart; (g) change from baseline in the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25_composite score and 12 subscale scores); (h) change from baseline in the Functional Reading Independence Index (FNII). (i) Clinical genotyping to assess the relationship between genetic polymorphisms associated with AMD, disease characteristics, and response to lampalizumab administration.

2.4 Pharmacokinetic and pharmacodynamic outcome measures

The PK profile of serum concentration-time data following lampalizumab administration was determined. Derived PK parameters included the following: (a) exposure after the first dose (AUC); (b) maximum observed serum concentration (Cmax); (c) observed concentration steady-state; (d) time to steady-state; and (e) accumulation rate based on trough concentration. Anterior chamber (aqueous humor) aspirates were collected to assess PK and PD relationships. Additional PK and PD analyses were performed.

2.5 Exploratory outcome measures

a. GA area growth rate from baseline assessed by spectral domain-optical coherence tomography (SD-OCT)

b. Changes in drusen volume assessed by SD-OCT

c. Conversion rate to wet AMD in study eyes treated with lampalizumab relative to sham controls

d. Change from baseline in words per minute on the Submacular Surgery Test (SST) reading speed assessment

e. Change from baseline in words per minute read by both eyes on the Minnesota Reading Speed Assessment (MNRead)

f. Change from baseline in contrast sensitivity measured by correcting for the number of letters read on the Pelli-Robson chart

g. Change from baseline in the National Eye Institute Visual Energy Questionnaire-25 (NEIVFQ-25 composite score and 12 subscale scores)

h. Change from baseline in the Functional Reading Independence Index (FRII)

i. Clinical genotyping to assess the relationship between genetic polymorphisms associated with AMD, disease characteristics, and response to lampalizumab administration

2.5 Security Plan

Potential safety issues related to the route of administration or the pharmacology of lampalizumab include decreased BCVA; conjunctival hemorrhage; uveitis or vitritis (see Definitions of Uveitis and Vitritis (above for definitions; grading scale for evaluating anterior chamber scintillation or anterior chamber cells and vitreous cells and grading scale for vitreous inflammation)); intraocular infection; transient and/or persistent IOP elevation; cataract development or progression; retinal or vitreous hemorrhage, macular edema; and retinal break or detachment. All adverse events (serious and non-serious) occurring during the duration of this study were recorded on electronic case report forms (eCRFs).

Systemic lampalizumab levels are predicted to be low after multiple ITV administrations. However, monitor patients for evidence of systemic inhibition of ACP activity, such as a lowered infection threshold, particularly for encapsulated bacteria (i.e., Neisseria meningitidis, Streptococcus pneumonia, and Haemophilus influenzae).

Evaluate the occurrence and characteristics of adverse events, serious adverse events, and laboratory abnormalities. Perform ongoing safety monitoring.

Safety Operation Period: Conduct timely safety monitoring and examine safety data after study drug treatment to determine whether DLCs are met. Report all DLTs that occur within the pre-specified study drug administration window and review the reports.

Following the Day 0 study drug injection, all patients returned for safety assessment visits on Day 1, Day 7 (± 2), and Day 30 (± 7) after each monthly injection until dose interruption began. Safety run-in patients underwent the same safety assessments as those listed for patients in the randomized phase below.

Randomization phase: All patients returned for a safety assessment visit 7 days (± 2 days) after the first injection. For subsequent injections, randomized patients were contacted by study site personnel 7 (± 2) days after each injection to elicit reports of any decreased vision, eye pain, unusual redness, or any other new eye symptoms in the studied eye. Patients were asked whether they had taken prescribed, self-administered, post-injection antibacterial medications. Patients were instructed to contact the investigator at any time if they had any health-related concerns. Patients were asked to return to the clinic for a safety assessment visit as soon as possible if there was a legitimate reason.

Within 15 minutes after study treatment, the physician performed a finger count test on each patient; hand movements or light perception were tested as needed. Patients remained in the clinic for at least 60 (±10) minutes after study treatment. Intraocular pressure was measured in both eyes before treatment and 60 (±10) minutes after study treatment in the study eye only. If there were no safety concerns at 60 (±10) minutes, the patient was allowed to leave the clinic. If at 60 (±10) minutes, the IOP increased by ≥10 mmHg compared to the pre-injection measurement, the study eye was measured again at 120 (±10) minutes after injection. If there were no safety concerns at the time of the repeat measurement, the patient was allowed to leave the clinic. If the IOP was still elevated by ≥10 mmHg compared to the pre-injection measurement and the investigator had concerns after the repeat measurement, the patient remained in the clinic and was treated according to the investigator's clinical discretion before the patient left. Complete the Adverse Event eCRF page.

Detailed ophthalmologic examinations, including indirect funduscopy and slit-lamp examinations, were performed during the study. Routine bleeding, serum chemistry, coagulation, and urinalysis patterns were obtained from all patients, as well as blood samples for serum study drug concentrations, CH50 and AH50 determinations, and antibodies to lampalizumab. Aqueous humor aspirates were also obtained from patients who consented to the procedure and sample collection.

Unlike patients who continued in the OLE study at the 18-month follow-up visit, patients who withdrew from the study before completion (month 19 for the alternate-monthly treatment group and month 20 for the monthly treatment group) were asked to return for an early termination follow-up assessment 30 (± 7) days after the last study treatment visit. The follow-up included an assessment of all adverse events (serious and non-serious; ocular and non-ocular).

3. Materials and Methods

3.1 Patient selection and gender distribution

Written informed consent was obtained before commencing any study procedures. Screening evaluations were performed at any time within 14 days prior to Day 0 (the day of first study treatment). Patient selection criteria were the same as for the safety run-in phase and the randomization phase, with the exception of the eye selection criteria; patients with less severe visual impairment were enrolled in the randomization phase.

Both men and women were allowed to join, provided they met the inclusion criteria. However, pregnancy or breastfeeding were listed as exclusion criteria; therefore, pregnant or breastfeeding women were excluded from the trial.

The remaining inclusion/exclusion criteria applied to both male and female patients and pertained to patient health performance issues and safety concerns.

Randomization was not performed based on sex; therefore, patient enrollment was expected to reflect the demographic characteristics of the disease under study.

3.1.1.b.1

3.1.1 Inclusion criteria

Patients must meet the following criteria to be eligible for inclusion in the study:

a. General inclusion criteria

1. Willingness and ability to provide informed consent and comply with the research process as defined in the protocol.

2. Aged 60-89

3. For sexually active women of childbearing potential, they agree to use an appropriate form of contraception (or abstinence) for the duration of the study. If a woman is postmenopausal or has undergone a hysterectomy and/or bilateral oophorectomy, she is not considered to be of childbearing potential. Sexually active men need to use contraception (condoms) to ensure that their female partners do not become pregnant, unless they have undergone a successful vasectomy.

4. Ability and willingness to undergo all scheduled follow-up visits and assessments

b. Inclusion criteria for the eyes studied

Designate one eye as the study eye. If both eyes are eligible, the eye with the worse VA and/or worst function will be selected for study treatment (the study eye).

1. Visual acuity

(a) Regarding the safety operational phase: BCVA was 20/125 to 20/400, inclusive (Snellen equivalents), using the ETDRS table

(b) Regarding the randomization phase: BCVA of 20/50 to 20/400, inclusive (Snellen equivalents), using the ETDRS table

2. Re-divided area of GA secondary to AMD in the absence of choroidal neovascularization (CNV)

3.GA≥1 optic disc area (DA) (2.5 mm ² )

4. If GA is multifocal, at least one lesion has a lesion size ≥ 0.5DA (1.25 mm ² )

5. Total lesion size ≤ 7DA (17.5 mm ² ) and completely within the FAF imaging field of view

6. Percentage of high autofluorescence adjacent to GA regions (e.g., banded or diffuse junctional FAF patterns; Holz et al., Am J Qphthalmol, 143:463-472 (2007))

7. Sufficiently clear ocular media, adequate pupil dilation, and fixation to allow for satisfactory fundus imaging

c. Eye inclusion criteria for eyes not to be studied

1. GA secondary to AMD in the absence of CNV

3.1.2 Exclusion criteria

Patients who met any of the following criteria were excluded from the study:

1. History of vitrectomy, submacular surgery, or other surgical intervention for AMD in the studied eye

2. Previous subfoveal focal laser photocoagulation in the studied eye

3. Laser photocoagulation (juxtafoveal or extrafoveal) in the studied eye

4. Previous treatment with external beam irradiation or transpupillary thermal therapy in the studied eye

5. Previous treatment with fenretinide or participation in fenretinide research

6. Previous treatment with eculizumab or participation in eculizumab research

7. Prior ITV drug delivery in the study eye (e.g., ITV corticosteroid injection, anti-angiogenic drug, anti-complement agent, or device implant), with the exception of patients previously treated with lampalizumab. Single-operative administration of anti-VEGF agents during cataract surgery for cystoid macular edema prophylaxis at least 3 months prior to screening was permitted.

a.GA Features

1. GA in the studied eye extends beyond the FAF procedure field of view or does not meet the criteria for single or multifocal lesions

2. Absent or minimal hyperautofluorescence adjacent to the GA in the studied eyes (e.g., focal FAF pattern; Holz et al. 2007)

3. GA in either eye due to causes other than AMD (e.g., Stargardt disease, pattern dystophies, cone-rod dystrophy, or chloroquine/hydroxychloroquine toxicity)

b. Concurrent eye diseases

1. RPE tears involving the macula in the studied eye

2. History of retinal tears in the studied eye

3. Any concurrent ocular or intraocular disorder (e.g., cataract or epiretinal membrane) in the studied eye that, in the opinion of the Investigator, could:

(a) requires medical or surgical intervention during the study to prevent or treat vision loss that may result from the condition; or

(b) If allowed to progress without treatment during the study period, it would result in a loss of BCVA of at least 2 Snellen lines

4. Contraindications to the use of study drugs or a history of other eye or intraocular conditions that may affect the interpretation of study results or may put the patient at high risk of treatment complications

5. Active uveitis and/or vitritis (Grade 2 or above) in either eye (see Uveitis and Vitritis and for definitions of the Uveitis and Vitritis Grading Scale)

6. Current vitreous hemorrhage in the studied eye

7. History of retinal detachment or macular hole (grade 3 or 4) in the studied eye

8. Aphakia or absence of the posterior capsule in the studied eye

(a) Previous posterior capsule invasion in the study eye was also excluded unless it occurred due to yttrium aluminum garnet (YAG) laser posterior capsulotomy associated with previous posterior chamber intraocular lens implantation.

9. Spherical lens equivalent showing a myopic error greater than 8 diopters in the studied eye

10. For patients who have had previous refractive or cataract surgery in the study eye, the pre-operative refractive error in the study eye should not have exceeded 8 diopters of myopia

11. Intraocular surgery (including cataract surgery) in the study eye within 3 months prior to Day 0

12. Uncontrolled glaucoma in the study eye (defined as an IOP ≥ 30 mmHg despite treatment with anti-glaucoma medication)

13. History of glaucoma-filtration surgery in the studied eye

14. History of corneal transplantation in the studied eye

15. Diabetic retinopathy in either eye

16. History of active or wet AMD in either eye

17. History of primary or autoimmune-related uveitis in either eye

18. Active infection of conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye

19. History of infectious or inflammatory eye disease in either eye

c. Concurrent systemic diseases

1. Uncontrolled blood pressure (defined as systolic blood pressure >180 mmHg and/or diastolic blood pressure >110 mmHg when the patient is sitting)

(a) If the patient's initial measurement exceeds these values, a second reading may be taken 30 minutes or more later. If the patient's blood pressure must be controlled by antihypertensive medication, the patient is eligible if the medication has been taken continuously for at least 30 days before Day 0.

2. Medical conditions that may be associated with a clinically significant risk of bleeding

3. A history of other diseases, metabolic dysfunction, physical examination findings, or clinical laboratory findings that provide reasonable contraindications to the use of study drugs or that may affect the interpretation of study results or put the patient at high risk of treatment complications.

4. Treatment of active systemic infection

5. Predisposition or history of increased risk of infection

6. Known deficiency of complement factor D or alternative complement pathway activity

7. Active malignancy or history of malignancy within the past 5 years (except completely cured basal cell carcinoma of the skin)

8. History of allergy to fluorescein or history of non-compliance with treatment

9. Failure to obtain FP, FAF, FA, SD-OCT, or NI images of sufficient quality to allow analysis and grading by a central reading center

10. Failure to comply with study or follow-up procedures

11. Participation in any study of study drug within 3 months before Day 0 (excluding vitamins and minerals)

12. Requires continued use of any medications/treatments listed in the "Excluded Treatments" section (see Section 3.4.2)

3.3 Study Treatment

3.3.1 Trial Drugs

preparation

Lampalizumab drug product is provided as a sterile, white to off-white lyophilized powder in a 6-cc USP/Ph.1 type glass vial intended for ITV use. Each glass vial contains nominal 40mg lampalizumab. This drug product needs to be reconstituted in sterile water for injection (SWFI) (USP/Ph.Eur.). After reconstitution, the drug product is formulated into 100mg/mL lampalizumab in 40mM L-histidine hydrochloride, 20mM sodium chloride, 180mM sucrose, 0.04% (w/v) polysorbate 20, pH 5.5. The drug product does not contain a preservative and is only suitable for single use.

Dosage, administration and storage

About administration during the safety run-in phase : All safety run-in patients were administered an open-label 10-mg lampalizumab dose once a month. Follow-up visits for study drug treatment were regularly conducted every 30 (± 7) days, relative to the date of the first injection (Day 0), until the tenth evaluable patient completed a follow-up visit on Day 90 (± 7) after the third study drug treatment (when a dose interruption lasting approximately 7 days ensued). During the interruption process, the safety of multiple doses was tested. Because the safety run-in evaluation demonstrated acceptable multiple-dose safety and tolerability of lampalizumab (as described in the DLC (see Section 3.1.2)), the randomization phase began.

Following the interruption, patients who were safe and unsuccessful continued monthly study drug administration at the same dose as those in the randomized phase for the remainder of their 18-month treatment period, with the same frequency of follow-up visits and assessments as those in the randomized phase's monthly dosing group. These patients received a maximum of 18 doses of lampalizumab during the study. Doses were not repeated more than 22 days after the previous dose. Missed doses were not made up.

Regarding dosing during the randomized phase : As determined in the safety operational assessments, patients in the study drug group were dosed with lampalizumab either monthly or every other month, starting at the Day 0 visit, for a total of 18 injections in the monthly treatment group and 9 injections in the every other month treatment group.

In the sham group, patients were given sham injections either monthly or every other month, starting at the Day 0 visit, for a total of 18 injections in the monthly treatment group and 9 injections in the every other month treatment group. Doses were not repeated more than 22 days after the previous dose. Missed doses were not made up.

Administration : Lampalizumab is reconstituted with Sterile Water for Injection (SWFI) to form a dose formulation. Lampalizumab vials are for single use only. A vial used for one patient should not be used for any other patient.

Prior to the injection, patients were required to demonstrate that they had self-administered their antibiotics 4 times a day for 3 days, and were instructed to self-administer their antibiotics again 4 times a day for 3 days after the injection. Prior to the 18-month follow-up visit, patients who elected to continue in the OLE study were asked to sign the OLE study informed consent form and take the protocol-specified antibiotics as instructed. For these patients, eligibility for the OLE study was determined at their 18-month follow-up visit. Patients who were ineligible or chose not to continue in the OLE study continued safety follow-up in the study and had their final safety visit at the 19-month follow-up visit (for the alternate-month treatment group) or at the 20-month follow-up visit (for the monthly treatment group).

Storage : When receiving lampalizumab, refrigerate the vial at 2°C-8°C (36°F-46°F) until use. Do not use the lampalizumab vial after the expiration date provided by the supplier. No preservative is used in the lampalizumab drug product; therefore, this vial is for single use only. Do not freeze or shake the contents of the vial and protect from direct sunlight. Administer lampalizumab within 2 hours of dose preparation (reconstitution); the prepared dose may be kept at room temperature until administration.

3.4 Other treatments

3.4.1 Concomitant therapy

Concomitant medications were any prescription or over-the-counter medications other than protocol-specified procedural medications (e.g., dilating drops or fluorescein dye) and pre- and post-injection medications (e.g., proparacaine or antibacterials) used by the patient within the 7 days prior to Day 0 and during the patient's enrollment or early discontinuation visit.

Patients taking other medications should continue their use. Patients requiring the use of excluded medications are not eligible for inclusion in this study. All concomitant medications should be reported to the investigator and recorded on the appropriate eCRF.

During the patient's study participation, glaucoma episodes in the study eye were treated as clinically indicated.

Patients who developed mild non-proliferative diabetic retinopathy (eg, incidental hemorrhage or microaneurysm) in either eye during study participation were allowed to continue study treatment after consultation with a medical monitor.

Cataracts or posterior capsular opacification that developed in either eye during the patient's study participation were treated as clinically indicated. Dose retention criteria were applied for cataract surgery or YAG laser treatment.

Laser photocoagulation of a newly developed CNV in any eye during the patient's study participation was permitted, provided that the CNV was sufficiently distal to the GA lesion, as determined by the reading center, to be curable with a single laser treatment, and was approved by the medical monitoring device. Dose retention criteria applied to laser photocoagulation treatment.

3.4.2 Excluded therapies

At the investigator's discretion, patients are allowed to continue receiving medications and standard treatments for other conditions. However, the following medications/treatments are prohibited during the patient's participation in this study:

1. Systemic anti-VEGF agents

2. ITV anti-VEGF agent in either eye

3. ITV, subconjunctival, or topical (ocular) corticosteroids in either eye (short-term use of topical corticosteroids after cataract surgery is permitted)

4. Oral corticosteroids (prednisone or equivalent) at a dose >10 mg/day

5. Intra-articular or intramuscular corticosteroids may be used in a restricted manner after consultation with medical monitoring equipment

6. Intravenous corticosteroids

7. Systemic or IV immunomodulatory therapy (eg, azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, cyclophosphamide, anti-TNFs, eculizumab)

8. Treatment in either eye with

Other experimental therapies (except those using vitamins and minerals)

3.5 Research Evaluation

3.5.1 Definition of Research Evaluation

Study assessments are described in detail below and were performed at each study visit.

During the study, patients enrolled in the safety run-in phase had approximately 29 follow-up visits, and patients enrolled in the randomized phase had up to 22 study visits (excluding the screening visit). With the exception of patients who continued into the OLE study at Month 18, any patient who discontinued the Factor D study early (before the Month 19 visit for the alternate-monthly treatment group and before the Month 20 visit for the monthly treatment group) completed an Early Termination (ET) visit 30 days (±7) after their last study treatment.

Study treatment visits were conducted regularly every 30 (± 7) days relative to the Day 0 visit.

Routine hematology, serum chemistry, coagulation, urinalysis, and complement assessment (CH50 and AH50) were evaluated by a central laboratory. Other sample evaluations (PK, anti-lampalizumab antibodies, aqueous humor, and genotyping) were performed at Genentech.

a. Patient-Reported Outcomes

The NEIVFQ-25 questionnaire was administered by site personnel (excluding VA examiners) before patients completed any other study procedures for the visit.

The FRII questionnaire (for patients who entered the randomized phase and were English-reading) was administered by site personnel (except VA examiners) before patients completed any other study procedures for that visit.

b. Eye Assessment

BCVA on the ETDRS chart at a starting distance of 4 meters (performed before pupil dilation)

Contrast sensitivity measured by correcting the number of letters read on a Pelli-Robson chart; performed before the pupil is dilated

SST reading speed assessment; performed on patients reading English before pupil dilation

MNRead binocular reading rate assessment (for patients who entered the randomized phase and read English; pre-injection before pupil dilation)

IOP measurement (performed before the pupil is dilated; the method used for patients remained consistent throughout the study)

Slit lamp examination (grading scale for cells)

Indirect high-power ophthalmoscopy of both eyes with dilated pupils

Within 15 minutes after the injection, the physician will perform a finger counting test, hand movement test, or light perception test on only the studied eye.

IOP was measured in both eyes before injection and in the study eye 60 (±10) minutes after injection; if the pre-injection increase in IOP was ≥10 mmHg, it was measured again 120 (±10) minutes after injection; the method used for patients remained consistent throughout the study.

c. Eye imaging

The central reading center provides the sites with study manuals and training materials for designated study eye images. Before obtaining any study images, the reading center certifies/validates the site personnel, test images, systems, and software (where appropriate) as specified in the study manual. All eye images are obtained by trained field personnel at the study site and transmitted to the central reading center for independent analysis and/or storage.

The acquired eye images include the following:

Three-dimensional, digital color fundus photographs of both eyes

Fluorescein angiography images of both eyes (performed after obtaining laboratory samples)

FAF, NI, and SD-OCT images of both eyes

Additional details about obtaining these images are included in the Central Reading Center's brochure.

d. Laboratory evaluation

Samples were collected at regularly scheduled follow-up visits prior to treatment of the study eye and FA assessment (if applicable). No fasting was required prior to sample collection. All samples were shipped to a central laboratory for processing. Analysis was performed at the central laboratory or shipped to Genentech for analysis. Instructions for obtaining, handling, storing, and shipping all samples were provided in the laboratory manual. Laboratory supply kits were provided to sites by the central laboratory.

Conduct the following assessments:

1. Hematology: Hemoglobin, hematocrit, quantitative platelet count, red blood cells (RBC), white blood cells (WBC), and differentials, including neutrophils, bands, lymphocytes, basophils, eosinophils, and monocytes (absolute values and percentages)

2. Serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (BUN), creatinine, calcium, phosphorus, total and direct bilirubin, total protein, albumin, AST, ALT, lactate dehydrogenase (LDH), alkaline phosphatase, and uric acid

3. Urinalysis: specific gravity, pH, blood, protein, ketones, glucose, bilirubin, urobilinogen, microscopy (if any of the above urinalysis tests other than glucose and ketones are abnormal)

4. Coagulation: aPTT and PT5

5. Serum pregnancy test (β-human chorionic gonadotropin): For women of childbearing potential, including those who have had tubal ligation, if positive, study drug will not be administered.

6. Complement Assessment: AH50 and CH50

7.PK assay:

(a) Obtaining serum samples to measure lampalizumab concentrations

(b) Obtaining serum samples to measure anti-lampalizumab antibodies

(c) Collect anterior chamber (aqueous humor) aspirates to assess PK and PD relationships

e. Clinical genotyping samples

In the study of overshoot, a single whole blood sample was collected from the patient for genetic marker analysis. This sample was not required to be collected for all patients who joined the randomized phase of the study and who resided in the U.S., with the exception of the research centers located in Alaska and Oregon, where it was prohibited by law and where local policy prohibited the collection of samples for genetic marker analysis. Genetic marker samples were used to evaluate the relationship between genetic polymorphisms associated with AMD, baseline disease characteristics, and the response to lampalizumab.

f. Determination method

The drug concentration in serum was determined by ELISA. Anti-therapeutic antibodies (ATA) in serum were detected by bridging ELISA.

3.5.2 Safety Operation Phase: Evaluation During Treatment

When a patient meets all eligibility criteria at the Screening and Day 0 visits (the day of initial study drug administration), including receipt and evaluation of select images (FAF, NI, FP, FA, and SD-OCT obtained at the Screening visit) at a central reading center, the patient is assigned an identification number (different from the patient's screening number) and medication kit by the IWRS on Day 0. Patient medication kit assignment occurs after the pre-treatment assessment and prior to the administration of study treatment on Day 0.

a. Day 0

Day 0 is the day of the first injection of lampalizumab. The following assessments are performed on Day 0:

1. NEI VFQ-25 questionnaire; administered by site personnel (different from VA examiners) before patients complete any other study procedures

2. Vital signs (blood pressure, respiration, pulse, and temperature; performed before injection)

3. Eye Assessment

(i) BCVA at a starting distance of 4 meters (performed before the pupil is dilated and before injection)

(ii) Contrast sensitivity measured as the number of letters read corrected on the Pelli-Robson chart (performed before injection with the pupil dilated)

(iii) SST reading speed assessment (performed before injection with pupil dilated)

(iv) IOP measurement (obtained before injection in both eyes before pupil dilation; the method used for each patient must remain consistent throughout the study)

(v) Slit lamp examination (performed before injection)

(vi) Indirect high-power ophthalmoscopy of both eyes with dilated pupils (performed before injection)

4. Summary of Inclusion and Exclusion Criteria

5. Contact IWRS for patient identification number and study drug kit allocation before starting treatment

6. Reconstitution of Study Drug (See Pharmacy Binder)

7. Lampalizumab injection in the study eye

(a) Before the injection, ensure that patients have self-administered their antibiotics 4 times a day for 3 days, and instruct them to re-administer their antibiotics 4 times a day for 3 days after the injection.

8. Post-injection eye assessment

(a) Within 15 minutes after injection, a physician will perform a finger count test on the eye being studied only, followed by a hand movement test or light perception test (if necessary).

(b) IOP measurement should be performed in the study eye only, 60 (±10) minutes after injection; the method used for patients throughout the study must remain consistent.

9. Clinical Evaluation

(a) Monitor and record all adverse events

(b) Record the concomitant medications used by the patient in the 7 days before day 0

(c) Recording simultaneous eye procedures

b. Safety assessment follow-up on Day 1 and Day 7

Patients were evaluated for safety by outpatient examination on day 1 (±0) and day 7 (±2) after each study drug treatment until the start of discontinuation. The following assessments were performed:

1. Clinical Evaluation

(a) Vital signs (blood pressure, respiration, pulse and temperature)

(b) Record concomitant medications

(c) Recording simultaneous eye procedures

(d) Monitor and record all adverse events

2. Eye Assessment

(a) BCVA test at a starting distance of 4 meters (performed before pupil dilation). Note: If necessary, perform a finger counting test followed by hand movement and light perception tests.

(b) IOP measurement (obtained in both eyes; the method used for each patient must remain consistent throughout the study)

(c) Slit lamp examination (performed before injection)

(d) Indirect high-power ophthalmoscopy of both eyes with dilated pupils (performed before injection)

3. Serum samples for lampalizumab concentration measurement were collected only on day 1 and day 7 after the first study drug treatment.

4. Whole blood samples were collected for genetic marker analysis only on day 1 after the first study drug treatment.

c. Safety Month X

Patients undergoing safety follow-up will be followed up regularly every 30 (± 7) days relative to Day 0 until the start of study drug discontinuation. The following assessments will be made:

1. Vital signs (blood pressure, respiration, pulse, and temperature)

2. Eye Assessment

(a) BCVA measurement at a starting distance of 4 meters (performed before pupil dilation)

(b) IOP measurement (obtained in both eyes before pupil dilation; the method used for each patient must remain consistent throughout the study)

(c) Slit-lamp examination with dilated pupils and indirect high-power ophthalmoscopy of both eyes

3. Eye imaging

(a) SD-OCT for both eyes

4. Contact IWRS for study drug kit distribution before starting treatment

5. Study Drug Reconstitution (See Pharmacy Binder)

6. Administer lampalizumab injection in the studied eye

(a) Before the injection, ensure that patients have self-administered their antibiotics 4 times a day for 3 days, and instruct them to re-administer their antibiotics 4 times a day for 3 days after the injection.

7. Post-injection eye assessment

(a) A finger count test performed by a physician within 15 minutes after injection, performed on the eye being studied only, followed by a hand movement test or light perception test (if applicable)

(b) IOP measurement in the study eye only 60 (± 10) minutes after injection; (the method used for patients throughout the study must remain consistent)

8 Clinical Evaluation

(a) Monitor and record all adverse events

(b) Record concomitant medications

(c) Recording simultaneous eye procedures

9. Laboratory samples to be collected at each study treatment until discontinuation:

(a) Serum samples will be obtained to measure lampalizumab concentrations

(b) Serum samples will be obtained for measurement of anti-lampalizumab antibodies

(c) Complement AH50 and CH50

(d) Hematology

(e) Serum chemistry

(f) Coagulation: aPTT and PT

(g) Urinalysis

3.5.3 Randomization Phase: On-Treatment Assessment

When a patient meets all eligibility criteria at the Screening and Day 0 visits (the first day of study drug administration), including receipt and evaluation of select images (FAF, NI, FP, FA, and SD-OCT obtained at the Screening visit) at a central reading center, the patient is assigned an identification number (different from the patient's screening number) and medication kit by the IWRS on Day 0. Patient medication kit assignment occurs after the pre-treatment assessment and prior to the administration of study treatment on Day 0.

a. Day 0

Day 0 is the day of the first study treatment injection. The following assessments are performed on Day 0:

1. NEI VFQ-25 questionnaire; administered by site personnel (different from VA examiners) before patients complete any other study procedures; FRII questionnaire (for patients who enroll in the randomized phase and who read English) administered by site personnel (different from VA examiners) before the patient completes any other study procedures for this visit

2. Vital signs (blood pressure, respiration, pulse, and temperature; performed before injection)

3. Eye Assessment

(a) BCVA measurement at a starting distance of 4 meters (performed before injection with pupil dilated)

(b) Contrast sensitivity measured by corrected number of letters read on the Pelli-Robson chart (performed before injection with pupil dilated)

(c) SST reading speed assessment (performed before injection with pupil dilated)

(d) MNRead binocular reading rate assessment (for patients who entered the randomized phase and read English); performed before injection with pupils dilated)

(e) IOP measurement (obtained in both eyes before injection, before pupil dilation; the method used for each patient must remain consistent throughout the study)

(f) Slit lamp examination (performed before injection)

(g) Indirect high-power ophthalmoscopy of both eyes with dilated pupils (performed before injection)

4. Summary of Inclusion and Exclusion Criteria

5. Contact IWRS for patient identification number and study drug kit allocation before starting treatment

6. If applicable, reconstitute the study drug

7. Administer study drug injection in the study eye (drug or sham as per randomization)

(a) Before the injection, ensure that patients have self-administered the antibiotic prescribed to them and instruct them to re-administer the antibiotic after the injection, four times a day for three days.

8. Post-injection eye assessment

(a) Within 15 minutes after injection, a physician will perform a finger count test on the eye being studied only, followed by a hand movement test or light perception test (if necessary).

(b) IOP measurement should be performed in the study eye only, 60 (±10) minutes after injection; the method used for patients throughout the study must remain consistent.

9. Clinical Evaluation

(a) Monitor and record all adverse events

(b) Record the concomitant medications used by the patient in the 7 days before day 0

(c) Recording simultaneous eye procedures

b. Follow-up on Day 7

1. Clinical Evaluation

(a) Vital signs (blood pressure, temperature, respiration, and pulse)

(b) Record concomitant medications

(c) Recording simultaneous eye procedures

(d) Monitor and record all adverse events

2. Eye Assessment

(a) BCVA on the ETDRS chart at a starting distance of 4 m (performed before pupil dilation).

(b) IOP measurement (performed before the pupil is dilated; the method used for each patient must remain consistent throughout the study)

(c) Slit lamp examination

(d) Indirect high-power ophthalmoscopy of both eyes with dilated pupils

3. Sample Collection

(a) Serum PK samples for measuring lampalizumab concentrations

c. Follow-up from 1st to 18th month

Month 18 was the final study visit for eligible patients who elected to continue in the OLE study. Prior to the Month 18 visit, these patients were asked to sign the OLE informed consent form and were instructed to take their protocol-specified countermeasure. Eligibility for the OLE study was determined at the Month 18 visit.

1. NEI VFQ-25 questionnaire administered by site personnel (different from VA examiners) at 6, 12, and 18 months before patients completed any other study procedures

2. FRII questionnaires administered by site personnel (different from VA examiners) at the 6, 12, and 18 month visits (for patients who were randomized and who read English) before the patient completed any other study procedures at that visit.

3. Vital signs (blood pressure, respiration, pulse, and temperature; performed before injection)

4. Physical examination at 12 and 18 months follow-up

5. Eye Assessment

(a) BCVA measurement at a starting distance of 4 meters (performed before injection with pupil dilated)

(b) Contrast sensitivity measured by number of letters read corrected on the Pelli-Robson chart at 6, 12, and 18 months follow-up (performed before injection with the pupils dilated)

(c) SST reading speed assessment at 6, 12, and 18 months follow-up (performed before injection with pupils dilated)

(d) MNRead binocular reading rate assessment at 6, 12, and 18 months follow-up (for patients who entered the randomized phase and read English) (performed before injection with pupils dilated)

(e) IOP measurement (obtained before injection in both eyes before pupil dilation; the method used for each patient must remain consistent throughout the study)

(f) Slit lamp examination (performed before injection)

(g) Indirect high-power ophthalmoscopy of both eyes with dilated pupils (performed before injection)

6-eye imaging (transmits images to a central reading center)

(a) FAF and NI of both eyes at 6, 12, and 18 months follow-up

(b) Fundus photographs of both eyes at the 6th, 12th, and 18th month follow-up

(c) SD-OCT images of both eyes starting at month 1 and continuing monthly until the 12-month follow-up; thereafter, images will be taken only at the 15- and 18-month follow-up visits.

(d) Fluorescein angiography at 6, 12, and 18 months of follow-up

7. Implementation of study treatment:

(a) Monthly treatment group: follow-up from month 1 to month 17

(b) Alternate-month treatment group: 2nd, 4th, 6th, 8th, 10th, 12th, 14th, and 16th month follow-up

(c) Contact IWRS for patient study treatment kit allocation (if applicable) prior to starting treatment

(d) Reconstitution of study drug (see Pharmacy Binder for details)

8. Administer study treatment injection (drug or sham as per randomization) into the studied eye

(a) Before the injection, ensure that patients have self-administered their prescribed antibiotics and instruct them to self-administer their antibiotics again after the injection, 4 times a day for 3 days. Before the 18-month follow-up visit, patients who choose to continue in the OLE study will be asked to sign the OLE study informed consent form and take the prescribed antibiotics as instructed.

9. Post-injection eye assessment

(a) Within 15 minutes after injection, a physician will perform a finger count test on the eye being studied only, followed by a hand movement test or light perception test (if necessary).

(b) IOP measurement should be performed in the study eye only, 60 (±10) minutes after injection; the method used for patients throughout the study must remain consistent.

10. Clinical Evaluation

(a) Monitor and record all adverse events

(b) Record concomitant medications

(c) Recording simultaneous eye procedures

11 Central Laboratory Evaluation

(a) Central laboratory evaluation is performed before FA evaluation; patients do not need to fast before sample collection.

(b) Hematology, serum chemistry, coagulation, aPTT and PT, serum chemistry, urinalysis at 6-month, 12-month, and 18-month follow-up

(c) Serum pregnancy test at the 12th and 18th month follow-up

(d) Serum lampalizumab concentrations at 1, 2, 3, 6, 9, 12, 15, and 18 months of follow-up

(e) Serum anti-lampalizumab antibodies at 1, 2, 3, 6, 9, 12, 15, and 18 months of follow-up

(f) Complement assessment: AH50 and CH50 at 3, 6, 9, 12, 15, and 18 months

(g) Whole blood samples were collected at the 1st month follow-up for genetic marker determination

(h) On-site collection of anterior chamber (aqueous humor) aspiration samples at day 0, month 6, and month 12 follow-up to assess PK and PD relationships

12. For a complete list of laboratory tests, see the laboratory manual.

13. After the initial treatment visit, patients treated with study drug or sham received a telephone call 7 (± 2) days after each treatment visit to inquire about adverse events.

d. Follow-up was terminated at the 19th and 20th months or earlier

Safety follow-up at Months 19 (for the alternate-month treatment group) and 20 (for the monthly treatment group) was performed only for Factor D study patients who were ineligible or chose not to continue in the OLE study.

Unless otherwise specified, the following assessments were performed at Month 19, Month 20, and at the early termination visit:

1. NEI VFQ-25 questionnaire administered only at the early termination visit; administered by site personnel (different from VA examiners) before patients complete any other study procedures

2. FRII questionnaire administered only at the Early Termination Visit; administered by site personnel (different from VA examiners) before the patient completes any other study procedures for that visit (for patients who were enrolled in the randomized phase and who read English)

3. Clinical Evaluation

(a) Vital signs (blood pressure, respiration, pulse and temperature)

(b) Physical examination: only performed when follow-up is terminated early

(c) Monitor and record all adverse events

(d) Record concomitant medications

(e) Recording simultaneous eye procedures

4. Eye Assessment

(a) BCVA test at a starting distance of 4 meters

(b) Contrast sensitivity at the early termination visit only; measured by the number of letters read corrected on the Pelli-Robson chart (performed before pupil dilation)

(c) SST reading speed assessment only at the early termination visit (performed before pupil dilation)

(d) MNRead binocular reading rate assessment at the early termination visit only (for patients who entered the randomized phase and read English) (performed before pupil dilation)

(e) IOP measurement; the method used for patients must be consistent throughout the study

(f) Slit lamp examination (grading scale for scintillation/cells)

(g) Indirect high-power ophthalmoscopy of both eyes with dilated pupils

5Central laboratory evaluation only if follow-up is terminated early

(a) Central laboratory evaluation is performed before FA evaluation; patients do not need to fast before sample collection.

(b) Hematology

(c) Serum chemistry

(d) Coagulation: aPTT and PT

(e) Urinalysis

(f) Serum pregnancy test

(g) Serum lampalizumab concentration

(h) Serum anti-lampalizumab antibodies

(i) Complement assessment: AH50 and CH50

3.5.4 Study End/Early Termination of Follow-up

If a patient experienced eye pain, decreased vision, unusual redness, or any other new eye symptoms in the study eye, the investigator determined whether the patient should return to the clinic for a safety assessment. If a follow-up visit was necessary, an assessment was performed.

3.6 Determination method

The drug concentration in serum was determined by ELISA. ATAs in serum were detected by bridging ELISA.

3.7 Statistical methods

When all patients completed or terminated the treatment and safety follow-up period, the database was collated and locked. Only the patients and the researchers who scored the patients' visual acuity were masked to the treatment allocation. Two analyses were planned during the study: 1) a primary analysis after all patients in the randomized phase completed the 18-month treatment period; and 2) a final analysis at month 20 of patients who did not participate in the OLE study and completed the Factor D safety follow-up period.

Efficacy analyses were based on the mitigated voluntary treatment population, defined as all randomized patients who received at least one treatment dose and had at least one post-baseline primary efficacy measurement. For efficacy analyses, patients were grouped according to their randomly assigned treatment.

Safety analyses were based on all patients who received at least one treatment dose. Patients were divided into groups according to the treatment they received.

All statistical tests were two-sided with a type I error rate of 0.2. To understand the clinical significance of the estimated treatment effects and to aid in the interpretation of formal hypothesis testing, two-sided 80% confidence intervals are provided.

Descriptive summaries included mean, standard error, median, and range for continuous variables and counts and percentages for categorical variables. All analyses, summaries, and tabulations were performed using SAS software (version 9.1 or higher). Detailed statistical methods are described in the Data Analysis Plan (DAP).

3.7.1 Comparability Analysis of Treatment Groups

Demographic and baseline characteristics - such as age, sex, race, total lesion size, and baseline VA score - were summarized for all randomized patients by treatment group using descriptive statistics.

3.7.2 Efficacy Analysis

a. Primary efficacy endpoint

The primary efficacy endpoint was the mean GA area increase from baseline at month 18, as measured by FAF; the primary efficacy endpoint was analyzed at month 18. The primary analysis was performed using a hierarchical ANOVA with baseline lesion size as the stratification variable. Confidence intervals for the treatment effect size are provided, along with descriptive summary statistics for each treatment group.

b. Secondary efficacy endpoints

Similar analysis methods were used for the primary endpoints for the following secondary endpoints:

1. The average growth rate of GA area (D) from baseline at month 18 was measured by digital stereoscopic color fundus photographs

2. Mean change in BCVA from baseline at 18 months using the ETDRS system

3.8 Pharmacokinetic and Pharmacodynamic Analysis

The R individual and mean serum lampalizumab concentration-time data are tabulated and plotted according to the dose level. The serum pharmacokinetics of lampalizumab are summarized by estimating exposure between dose intervals, observing the maximum serum concentration ( _Cmax ) and the time to steady state and the parameter estimation of the accumulation rate. The estimated values for these parameters are tabulated and summarized by descriptive statistics. Anterior chamber (aqueous humor) puncture samples are collected to assess the relationship between PK and PD. Other PK, PD and biomarker studies are carried out.

3.9 Handling Missing Data

Every effort was made to minimize missing data. For the primary efficacy analysis, all patients in the ITT population who were alleviated were included in the analysis. If the primary efficacy measurement at month 18 was missing, the last observation imputed data before month 18 were used. If deemed appropriate, additional imputation methods were used to further characterize the results. Detailed information on the missing data handling method is provided in the DAP.

Example 2: Efficacy Analysis

Figures 3-7 below depict the treatment effect at month 18 for patients who received IVT administration of lampalizumab relative to sham injections as described in Example 1. Figures 3-7 depict the treatment effect as measured by the mean change in GA area (mm2) from baseline at month 18.

Figures 3A and 3B are shown in the preliminary efficacy results immediately after the primary database lock for the MAHALO Phase II study of all participant populations. In the lampalizumab monthly treatment group, the study met the primary endpoint of the mean change in GA area from baseline at month 18, as measured by fundus autofluorescence (FAF), and met the secondary endpoint of the mean change in GA area from baseline at month 18, as measured by color fundus photography (CFP). In the monthly treatment group, a positive treatment effect of slowing down the progression of GA area growth was observed: starting at 6 months and extending to 18 months. Based on the unadjusted mean of the LOCF data, the lampalizumab monthly treatment group had a 23.1% reduction in GA area growth progression relative to the combined sham group (Figure 3A). Based on least squares means from a stratified analysis of variance (Henry Scheffe. Chapter 1.2 "Mathematical Models," in The Analysis of Variance, New York: John Wiley & Sons, Inc., 1999, pp. 4-7), stratified by baseline lesion size category (<4DA vs. >4DA) with LOCF data, the monthly lampalizumab group had a 20.4% reduction in GA area growth progression relative to the pooled sham group ( FIG3B ). The results demonstrate a clinically meaningful and statistically significant effect of monthly lampalizumab on reducing GA area growth over the 18-month study treatment period. "Pooled sham" refers to the pooled monthly sham and alternate-month sham control treatment groups. "afD1m" refers to the monthly lampalizumab treatment group. "afD2m" refers to the alternate-month lampalizumab treatment group. The LOCF method refers to the last observation carried forward method for imputing missing data.

Figure 7 summarizes the least squares mean change in GA area, as measured by FAF, from baseline DDAF in patients with CFH, C2/CFB, and CFI risk alleles, compared with patients with CFH and C2/CFB risk alleles but without CFI risk alleles in the sham and lampalizumab monthly treatment groups. The data in this figure were adjusted for baseline lesion size and baseline lesion size category (<4DA and >=4DA) as continuous variables. Treatment effect and remission rate were calculated at month 18 (primary efficacy time point). The absolute treatment effect at month 18 was 1.837 mm2, corresponding to a 44% remission rate. In contrast, no treatment effect was observed in lampalizumab-treated patients without CFI risk alleles. Furthermore, patients with CFI risk alleles exhibited more rapid progression in the sham control group relative to the sham group without CFI risk alleles.

These findings suggest that the CFI biomarker is both prognostic for AMD progression and predictive of response to lampalizumab treatment.

Example 3: Genotyping analysis results

Participants in the anti-factor D study (n=93) were genotyped using the Illumina Omni 2.5M SNP chip. For genotyping, a single whole blood sample was collected from each patient. Genomic DVAs were extracted from each sample and analyzed using the Illumina Omni 2.5M SNP chip (Oliphant et al., Biotechniques, Suppl: 56-8, 60-1 (2002)). We applied the following quality control measures to the genome-wide data, such as the following removals: samples with >5% missing SNPs (n=44,180), samples with >5% missing SNPs (n=0), SNPs with a minor allele frequency <0.1 (n=831,590), Hardy-Weinberg equilibrium <1e-8 (n=1,678), duplicated/related samples (n=0), SNPs not located on the correct chromosome (n=3,624), SNPs without rs markers (n=56,333). After quality control measures, this left a total of 1,442,450 SNPs.

From this set of 1,442,450 SNPs, we selected four indicator SNPs (rs10737680 (CFH); rs429608 (C2/CFB); rs2230199 (C3); rs4698775 (CFI)) associated with five genes (CFH, C2, CFB, C3, and CFI) from the paper by Fritsche et al. (Nature Genetics, 45(4):435-441 (2013)) (or alternative SNPs if the indicator SNP identified in the paper was not present in our data set ( ^r2 > 0.8)). The alternative SNPs were rs1329428 (CFH) and rs17440077 (CFI)). C2 and CFB are located adjacent to each other on chromosome row, and therefore are both marked by rs429608 SNP, and this risk locus is referred to as " C2 / CFB risk locus " in this article, and it comprises two genes, C2 and CFB. The C2 / CFB locus marked by rs429608 is associated with the risk of age-related macular degeneration. Due to limited sample size in this study, we grouped individuals into "risk allele carriers" (being heterozygous or homozygous about the risk allele) or "non-risk allele carriers" (being homozygous about the non-risk allele) according to each SNP. For all SNPs (rs1329428, rs17440077, rs429608 and rs2230199), in our data set, the risk allele is guanine ridge (G). "Indicator SNP" is used in this article to refer to the SNP with the strongest p value in a specific region of a given study. For example, the index SNP for CFH, CFI, C2/CFB or C3 is the SNP with the strongest p-value in the Fritche Nature Genetics (Fritsche et al., Nature Genetics, 45(4):435-441 (2013)) study on the CFH, CFI, C2/CFB or C3 risk locus, respectively.

We compared differences in FAF measures of lesion size in ^mm2 from baseline to 18 months using the observed data sets.

The difference between anti-Factor D monthly and sham (pooled) was calculated as follows: mean DDAF of the pooled sham groups - DDAF of the anti-Factor D monthly groups / mean DDAF of the pooled sham groups.

We found that all individuals in our study (except two in the sham group) carried the CFH risk allele (Figure 4). All individuals (except one in the sham group) carried the C2/CFB risk allele (Figure 4). Therefore, we cannot determine whether carrying the risk alleles for these two genes has any effect on anti-factor D efficacy. We observed no differences between carriers of the C3 risk allele and non-risk alleles. Regarding CFI, we observed that patients in the treatment group with CFI risk alleles (n = 16) had a 44% reduction in lesion growth at month 18 compared with patients in the sham group with CFI risk alleles (n = 12) (Figure 6; data are least squares means). Compared with patients in the sham group without CFI risk alleles (n = 17) (Figure 5), patients in the treatment group without CFI risk alleles (n = 8) had a negligible 9% progression in lesion growth (Figure 5, lower row). Furthermore, we observed that patients in the treatment group with CFI risk alleles and a baseline BCVA of 20/50-20/100 (n=9) had a 54% reduction in lesion growth at month 18 compared with patients in the sham group with CFI risk alleles and a baseline BCVA of 20/50-20/100 (n=6) (Figure 8; data are least squares means).

Since the rs4698775 SNP (CFI SNP) is not on the Illumina Omni 2.5M SNP chip, we then also directly used Taqman assay to genotype the same patient samples from the anti-factor D study for the rs4698775 SNP (identified in the paper by Fritsche et al. (Fritsche et al., Nature Genetics, 45(4): 435-441 (2013)). The results using SNP rs4698775 were not significantly different from those using SNP rs17440077. Specifically, due to the linkage disequilibrium between SNP rs17440077 and SNP rs4698775, these two SNPs provided almost identical genotypic information in the patient samples. In addition, an effect on lesion growth comparable to that observed using the rs17440077 SNP (Figure 6) was also observed using the rs4698775 SNP.

These data show that, owing to compared with the patient without CFI risk allele, the patient with CFI risk allele has greater minimization in damage growth, therefore, CFI risk allele can be used for predicting the responsiveness for lampalizumab.These data also show that, owing to compared with the patient not carrying CFI risk allele, the patient with CFI risk allele has worse prognosis (for example, AMD progress), therefore, CFI risk allele can be used for predicting AMD progress.Alternative SNPs (for example, those listed about rs17440077 in table 4-7) with selected CFISNPs (rs4698775 and/or rs17440077) linkage disequilibrium (LD) can also be used for predicting the responsiveness for lampalizumab of patient, and can be used for predicting AMD progress. Alternative SNPs in linkage disequilibrium (LD) with selected CFHSNPs (rs10737680 and/or rs1329428), C2 or CFB SNPs (rs429608), and/or C3 SNP (rs2230199) can also be used to predict patient responsiveness to lampalizumab and can be used to predict AMD progression.

Example 4: Adverse Events

The most common adverse event (AE) was conjunctival hemorrhage: 2.4% in the sham group, 48.8% in the monthly lampalizumab group, and 34.1% in the alternate-monthly lampalizumab group (see Table 8). The most common anti-Factor D-related adverse event (AE) was increased intraocular pressure (IOP), which occurred in 1 patient in the monthly lampalizumab group (1 of 43 patients; 2.3% in the monthly group) and 3 patients in the alternate-monthly lampalizumab group (3 of 44 patients, 6.8%) (Table 8 shows all AEs, whether drug-related or not; see notes to Table 8).

The proportion of patients who discontinued treatment due to ocular adverse events in the study eye was 7% and 2.3% for patients receiving anti-Factor D antibody (monthly and every other month, respectively), and 2.4% for patients receiving sham injections. A summary of adverse events is shown in Table 3. There were no deaths, no ocular SAEs suspected to be caused by study drug, and no ocular SAEs in the study eye that led to treatment discontinuation. The safety profile for lampalizumab remains acceptable at this stage of development.

Table 3: Overall adverse event pattern

Table 8: Ocular AEs in Study Eyes (occurring in ≥3 patients in any group)

*Note: One patient in the monthly lampalizumab group and three patients in the every-other-month lampalizumab group were reported to have elevated intraocular pressure suspected to be related to study drug.

Example 5: eQTL Analysis

Although SNP rs4698775 is located in an intron of gene CCDC109B, CFI is currently the most attractive candidate gene at this locus based on genetic and biological evidence.We examined whether this rs4698775 SNP could be an expression quantitative trait locus (eQTL) affecting CFI mRNA levels in liver.

For eQTL analysis, TCGA RNA-seq data were obtained from the Cancer Genomics Hub (The Cancer Genome Atlas (TCGA) database) at UC Santa Cruz (Cancer Genome Atlas Research Network, Nature, Comprehensive Genomic Characterization Defines Human Gioblasoma Genes and Core Pathways, 455(7216): 1061-8 (Oct, 23 2008); Collins et al., Sci Am, Mapping the Cancer Genome. Pinpointing the Genes Involved in Cancer Will Help Chart a New Course Across the Complex Landscape of Human Malignancies, 296(3): 50-7 (March 2007)). TCGA contains RNA-seq and genotype data for tumor and normal samples from multiple tissues of the body. For this study, we used 34 normal liver tissue samples. The RNAseq data for these were analyzed using HTSeqGenie (Pau, G.B. et al., HTSeqGenie: a software package to analyse high-throughput sequencing experiments (2012)) as follows: First, reads with low nucleotide quality were removed (70% of the bases had a quality of <23). The passed reads were then aligned to the reference genome GRCh37 (Genome Research Consortium 37) using GSNAP (Genomic Short-read Nucleotide Alignment Program) (Wu, TD. et al., Bioinformatics, Fast and SNP-tolerant detection of complex variants and splicing in short reads, 26(7): 873-81 (4/1/2010). Alignments of reads reported as “uniquely mapping” by GSNAP were used for subsequent analysis. Then, RPKM = number of reads aligned to CFI genes/(total number of uniquely mapped reads for a sample x CFI gene length), and the CFI gene expression level of each sample was quantified. The genotypes for these samples were obtained through the Database of Genotypes and Phenotypes (dbGaP; dbGaP is a website owned by NCBI that archives and publishes the results of studies on the interaction between genotype and phenotype), and included genotypes for the Affymetrk6.0 (1 million) SNP array. As the SNP of interest, rs4698775 was not directly measured by the array, and the following workflow was used for genotype imputation, which included pre-phasing using SHAPEIT (Delaneau, O., Nature Methods, Improved whole-chromosome phasing for disease and population genetic studies, 10: 5-6 (2013)), and then using IMPUTE2 (Howie, B.N. et al., PLoS Genet, A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies, 5(6):e1000529(2009)) and a collection of reference haplotypes from the 1000 Genomes Project (1000 Genomes Project Consortium, Abecasis GR. et al., Nature, A map of human genome variation from population-scale sequencing, 467(7319):1061-73(2010)). Then, a correlation analysis was performed, which included log(CFI RPKM) linear regression of the additionally encoded rs4698775 genotypes (i.e., 0, 1, 2 copies of the "T" allele).

The results showed that CFI expression was highest in the body's liver tissue, which is the site of CFI synthesis (Figure 9). When grouped by genotype for rs4698775, we observed a significant reduction in CFI mRNA levels in normal TCGA liver samples (p = 0.02). In short, the rs4698775 genotype was significantly associated with CFI mRNA levels in normal TCGA liver samples (P = 0.02). Homozygotes for the risk allele (GG) had less CFI mRNA than heterozygotes (GT), who in turn had less CFI mRNA than homozygotes for the non-risk allele (TT) (Figure 10). These results are consistent with our hypothesis that CFI is a negative regulator of the alternative complement pathway and that carriers of the risk allele have lower CFI levels that can be used to regulate the alternative complement pathway. Using these results, we demonstrated the possible functional role of the common GWAS-associated SNP (rs4689775) used in our Phase II MAHALO analysis.

Example 6: CFI rare variant analysis

A recent report showed that rare missense variants (7.8%) were significantly overrepresented (p=1.7x10-8) in the CFI gene in AMD patients compared to controls (2.3%) (Seddon, et al. Nat Genet. 2013 45: 1366-70). A second report, focusing on a specific rare variant G119R within the CFI gene, showed that these types of variants had a significant effect on AMD risk (p=3.79x10-6; OR 22.20) (van de Ven, et al. Nat. Genet. 2013 45: 813-7).

Using available DNA, all patients in the MAHALO study were resequenced for exons in the CFI gene using Sanger dideoxy sequencing. Polymerase chain reaction (PCR) amplification was performed using standard PCR techniques using AmpliTaq Gold PCR Master Mix (Applied Biosystems), which contains all the chemical components required to amplify samples by PCR except primers and template, and an Applied Biosystems 3730./3730xl DNA Analyzer, an automated, high-throughput capillary electrophoresis system for analyzing fluorescently labeled DNA fragments. A two-step "boost/nested" PCR strategy was used, which involves first amplifying the bulk of the genomic DNA template to produce a boost product, which is then used as a template to amplify a smaller region for sequencing. Using this "boost/nested" strategy, we amplified a large region of the CFI gene from genomic DNA of patients in the MAHALO study using "boost" primers, thereby producing a product that was used as a template in subsequent nested reactions. The "nested" primers were used in subsequent nested PCR reactions to amplify a smaller region. The products of the nested reactions are used as templates for sequencing using standard sequencing techniques.

We resequenced all exons of CFI in our MAHALO patients using available DNA and found that 6 of them (6.9%) carried rare missense variants (Figure 11). We observed that CFI rare missense variants were significantly enriched in our MAHALO test samples from patients with GA compared to controls (P = 0.015). These patients carrying rare missense variants were evenly divided into our sham, every other month, and monthly groups. In the sham group, two individuals with rare variants (290E>D and 553P>S in the CFI gene) were carriers of non-risk alleles of rs17440077 (CFI-based on rs17440077). We observed that rare variant-positive individuals who were non-risk allele carriers of the rs17440077 SNP (CFI-based on rs17440077) used in the MAHALO study had similar differences in lesion area growth (e.g., GA progression rate) from baseline to 18 months as risk allele carriers (CFI+based on rs17440077) ( Figure 12 ).

Because the growth rate of these non-risk allele carriers with rare variants is similar to that of those with risk alleles, GA patients carrying these rare missense variants may progress at a rate similar to that of risk allele carriers, regardless of whether they are classified as risk or non-risk allele carriers based on the common rs17440077 SNP in CFI.

Example 7: Selection of Patients for Anti-Factor D Therapy

Patients diagnosed with GA are genotyped for the presence of polymorphisms associated with genes encoding selected complement factors. The presence of identified risk alleles and their combinations indicates the likelihood that the patient will respond to treatment with anti-Factor D, such as lampalizumab.

Specifically, the patient's genotype was detected by TaqMan real-time PCR. Each reaction included 0.4 μM of each forward and reverse primer and 0.15-0.3 μM of the detection probe (Table 9), uracil-N-glycosylase, 0.04-0.32 mM dNTPs (including dUTP), DNA polymerase, and appropriate DNA polymerase buffer (including aptamer). The reaction was performed on a 4800 instrument (Roche Molecular Diagnostics, Indianapolis, Ind.) in the following thermal cycling mode: 50°C for 5 minutes, followed by 2 cycles of 95°C (10 seconds) to 62°C (30 seconds), and 55 cycles of 93°C (10 seconds) to 62°C (30 seconds), followed by 37°C (10 minutes) and 25°C (10 minutes). Fluorescence data were collected at the beginning of each 62°C step.

Table 9. Oligonucleotides used for TaqMan RT-PCR

L＝N6-tert-butyl-benzyl dA

F = threoninol-FAM

Q＝BHQ2

P = 3'-phosphate

H＝threonine-HEX

S＝7-deazadG

E＝CY5.5

Once the GA patient's genotype is determined using the above-described TaqMan RT-PCR, the presence of specific risk alleles at the complement loci CFI, C2/CFB, and CFH is analyzed to derive the CFI pattern status, as described in Table 10. Patients with a CFI pattern+ are further evaluated as likely to respond to treatment with anti-Factor D. One selection method is illustrated in Table 10. A "+" indicates that the patient is "biomarker positive," and therefore more likely to respond to anti-Factor D therapy; while a "-" indicates that the patient is "biomarker negative," and therefore less likely to respond to anti-Factor D therapy. As shown in Table 10, patients with at least one CFI allele (G) in combination with at least one C2/CFB allele (G) or CFH allele (C on the complementary strand) are likely to respond to anti-Factor D therapy. In another example, patients with at least one CFI allele (G) are likely to respond to anti-Factor D therapy. Other similar selection criteria involving these SNPs and SNPs at other complement loci can be generated.

Table 10 Definition of genotype and CFI pattern status at selected complement loci

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALOSNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 4: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs17440077

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs2230199

Table 5: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNIP rs2230199

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 6: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs429608

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Table 7: LD_SNPs in linkage disequilibrium (LD) with MAHALO SNP rs1329428

Claims (14)

1. The use of a reagent for detecting the presence of at least one dry AMD-related polymorphism in a nucleic acid sample in the preparation of (a) a kit for predicting an increased rate of progression of dry age-related macular degeneration (AMD) in a patient with dry AMD, or (b) a kit for identifying a patient with dry AMD as more likely to respond to a therapy containing an anti-factor D antibody or its antigen-binding fragment, wherein the nucleic acid sample is isolated from a biological sample obtained from the patient, wherein, in the presence of the dry AMD-related polymorphism, the genotype of at least one single nucleotide polymorphism (SNP) rs4698775 or rs17440077 of the CFI allele in the nucleic acid sample is detected, wherein when the CFI allele contains G in the single nucleotide polymorphism (SNP) rs4698775 or rs17440077, the patient is identified as (1) more likely to have an increased rate of progression of dry AMD or (2) more likely to respond to a therapy containing an anti-factor D antibody or its antigen-binding fragment. 2. The application of claim 1, wherein the kit further comprises reagents for determining the genotype of a single nucleotide polymorphism (SNP) of the CFH allele, C2 allele, CFB allele, or C3 allele. 3. The application of claim 2, wherein the CFH allele is contained in A of single nucleotide polymorphism (SNP) rs10737680 or in G of single nucleotide polymorphism (SNP) rs1329428, the C2 allele is contained in G of single nucleotide polymorphism (SNP) rs429608, the CFB allele is contained in G of single nucleotide polymorphism (SNP) rs429608, and the C3 allele is contained in G of single nucleotide polymorphism (SNP) rs2230199. 4. The application of claim 1, wherein the biological sample is a body fluid sample. 5. The application of claim 1, wherein the biological sample is a blood sample, saliva, buccal swab, or tissue sample. 6. The application of claim 1, wherein the nucleic acid sample comprises DNA or RNA. 7. The application of claim 6, wherein the nucleic acid sample is amplified by polymerase chain reaction. 8. The application of any one of claims 1-7, wherein the polymorphism is detected by polymerase chain reaction. 9. The application of claim 7, wherein the polymorphism is detected by sequencing. 10. The application of claim 1, wherein the dry age-related macular degeneration is early, intermediate, or late AMD. 11. The application of claim 10, wherein the late AMD is map-like atrophy (GA). 12. The application of claim 1, wherein the anti-factor D antibody or its antigen-binding fragment comprises HVRH1, HVRH2, HVRH3, HVRL1, HVRL2 and HVRL3, wherein the HVRs have the amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively. 13. The application of claim 12, wherein the anti-factor D antibody or its antigen-binding fragment comprises the variable heavy chain of SEQ ID NO:7 and/or the variable light chain of SEQ ID NO:8. 14. The application of claim 12, wherein the anti-factor D antibody or its antigen-binding fragment is lambalizumab.