AU2017285763B2 - Anti-C5 antibodies and methods of use - Google Patents

Abstract

The invention provides anti-C5 antibodies and methods of using the same. In some embodiments, an isolated anti-C5 antibody of the present invention binds to an epitope within the beta chain of C5 with a higher affinity at neutral pH than at acidic pH. The invention also provides isolated nucleic acids encoding an anti-C5 antibody of the present invention. The invention also provides host cells comprising a nucleic acid of the present invention. The invention also provides a method of producing an antibody comprising culturing a host cell of the present invention so that the antibody is produced. The invention further provides a method of producing an anti-C5 antibody comprising immunizing an animal against a polypeptide which comprises the MG1-MG2 domain of the beta chain of C5. Anti-C5 antibodies of the present invention may be for use as a medicament.

Description

Description Title of Invention: ANTI-C5 ANTIBODIES AND METHODS OF USE Technical Field

[0001] The present invention relates to anti-C5 antibodies and methods of using the same. Background Art

[0002] The complement system plays a central role in the clearance of immune complexes and in immune responses to infectious agents, foreign antigens, virus-infected cells and tumor cells. There are about 25-30 complement proteins, which are found as a complex collection of plasma proteins and membrane cofactors. Complement components achieve their immune defensive functions by interacting in a series of intricate enzymatic cleavages and membrane binding events. The resulting complement cascades lead to the production of products with opsonic, immunoregulatory, and lytic functions.

[0003] Currently, it is widely accepted that the complement system can be activated through three distinct pathways: the classical pathway, the lectin pathway, and the alternative pathway. These pathways share many components, and while they differ in their initial steps, they converge and share the same terminal complement components (C5 through C9) responsible for the activation and destruction of target cells.

[0004] The classical pathway is normally activated by the formation of antigen-antibody complexes. Independently, the first step in activation of the lectin pathway is the binding of specific lectins such as mannan-binding lectin (MBL), H-ficolin, M-ficolin, L-ficolin and C-type lectin CL-11. In contrast, the alternative pathway spontaneously undergoes a low level of turnover activation, which can be readily amplified on foreign or other abnormal surfaces (bacteria, yeast, virally infected cells, or damaged tissue). These pathways converge at a point where complement component C3 is cleaved by an active protease to yield C3a and C3b.

[0005] C3a is an anaphylatoxin. C3b binds to bacterial and other cells, as well as to certain viruses and immune complexes, and tags them for removal from the circulation (the role known as opsonin). C3b also forms a complex with other components to form C5 convertase, which cleaves C5 into C5a and C5b.

[0006] C5 is a 190 kDa protein found in normal serum at approximately 80 micro g/ml (0.4 micro M). C5 is glycosylated with about 1.5-3% of its mass attributed to carbohydrate. Mature C5 is a heterodimer of 115 kDa alpha chain that is disulfide linked to 75 kDa beta chain. C5 is synthesized as a single chain precursor protein (pro-C5 precursor) of 1676 amino acids (see, e.g., PTL 1 and PTL 2). The pro-C5 precursor is cleaved to yield the beta chain as an amino terminal fragment and the alpha chain as a carboxyl terminal fragment. The alpha chain and the beta chain polypeptide fragments are connected to each other via a disulfide bond and constitute the mature C5 protein.

[0007] Mature C5 is cleaved into the C5a and C5b fragments during activation of the complement pathways. C5a is cleaved from the alpha chain of C5 by C5 convertase as an amino terminal fragment comprising the first 74 amino acids of the alpha chain. The remaining portion of mature C5 is fragment C5b, which contains the rest of the alpha chain disulfide bonded to the beta chain. Approximately 20% of the 11 kDa mass of C5a is attributed to carbohydrate.

[0008] C5a is another anaphylatoxin. C5b combines with C6, C7, C8 and C9 to form the membrane attack complex (MAC, C5b-9, terminal complement complex (TCC)) at the surface of the target cell. When sufficient numbers of MACs are inserted into target cell membranes, MAC pores are formed to mediate rapid osmotic lysis of the target cells.

[0009] As mentioned above, C3a and C5a are anaphylatoxins. They can trigger mast cell de granulation, which releases histamine and other mediators of inflammation, resulting in smooth muscle contraction, increased vascular permeability, leukocyte activation, and other inflammatory phenomena including cellular proliferation resulting in hypercel lularity. C5a also functions as a chemotactic peptide that serves to attract granulocytes such as neutrophils, eosinophils, basophils and monocytes to the site of complement activation.

[0010] The activity of C5a is regulated by the plasma enzyme carboxypeptidase N that removes the carboxy-terminal arginine from C5a forming C5a-des-Arg derivative. C5a-des-Arg exhibits only 1% of the anaphylactic activity and polymorphonuclear chemotactic activity of unmodified C5a.

[0011] While a properly functioning complement system provides a robust defense against infecting microbes, inappropriate regulation or activation of complement has been im plicated in the pathogenesis of a variety of disorders including, e.g., rheumatoid arthritis (RA); lupus nephritis; ischemia-reperfusion injury; paroxysmal nocturnal hemoglobinuria (PNH); atypical hemolytic uremic syndrome (aHUS); dense deposit disease (DDD); macular degeneration (e.g., age-related macular degeneration (AMD)); hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; Pauci-immune vasculitis; epidermolysis bullosa; recurrent fetal loss; multiple sclerosis (MS); traumatic brain injury; and injury resulting from myocardial infarction, cardiopulmonary bypass and hemodialysis (see, e.g., NPL 1). Therefore, inhibition of excessive or uncontrolled ac tivations of the complement cascade can provide clinical benefits to patients with such disorders.

[0012] Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon blood disorder, wherein red blood cells are compromised and are thus destroyed more rapidly than normal red blood cells. PNH results from the clonal expansion of hematopoietic stem cells with somatic mutations in the PIG-A (phosphatidylinositol glycan class A) gene which is located on the X chromosome. Mutations in PIG-A lead to an early block in the synthesis of glycosylphosphatidylinositol (GPI), a molecule which is required for the anchor of many proteins to cell surfaces. Consequently, PNH blood cells are deficient in GPI-anchored proteins, which include complement-regulatory proteins CD55 and CD59. Under normal circumstances, these complement-regulatory proteins block the formation of MAC on cell surfaces, thereby preventing erythrocyte lysis. The absence of the GPI-anchored proteins causes complement-mediated hemolysis in PNH.

[0013] PNH is characterized by hemolytic anemia (a decreased number of red blood cells), hemoglobinuria (the presence of hemoglobin in urine, particularly evident after sleeping), and hemoglobinemia (the presence of hemoglobin in the bloodstream). PNH-afflicted individuals are known to have paroxysms, which are defined here as in cidences of dark-colored urine. Hemolytic anemia is due to intravascular destruction of red blood cells by complement components. Other known symptoms include dysphasia, fatigue, erectile dysfunction, thrombosis and recurrent abdominal pain.

[0014] Eculizumab is a humanized monoclonal antibody directed against the complement protein C5, and the first therapy approved for the treatment ofparoxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) (see, e.g., NPL 2). Eculizumab inhibits the cleavage of C5 into C5a and C5b by C5 convertase, which prevents the generation of the terminal complement complex C5b-9. Both C5a and C5b-9 cause the terminal complement-mediated events that are characteristic of PNH and aHUS (see also, PTL 3, PTL 4, PTL 5, and PTL 6).

[0015] Several reports have described anti-C5 antibodies. For example, PTL 7 described an anti-C5 antibody which binds to the alpha chain of C5 but does not bind to C5a, and blocks the activation of C5, while PTL 8 described an anti-C5 monoclonal antibody which inhibits C5a formation. On the other hand, PTL 9 described an anti-C5 antibody which recognizes the proteolytic site for C5 convertase on the alpha chain of C5, and inhibits the conversion of C5 to C5a and C5b. PTL 10 described an anti-C5 antibody which has an affinity constant of at least 1 x10 7 M-.

[0016] Antibodies (IgGs) bind to neonatal Fc receptor (FcRn), and have long plasma retention times. The binding of IgGs to FcRn is typically observed under acidic conditions (e.g., pH 6.0), and it is rarely observed under neutral conditions (e.g., pH 7.4). Typically, IgGs are nonspecifically incorporated into cells via endocytosis, and return to the cell surfaces by binding to endosomal FcRn under the acidic conditions in the endosomes. Then, IgGs dissociate from FcRn under the neutral conditions in plasma. IgGs that have failed to bind to FcRn are degraded in lysosomes. When the FcRn binding ability of an IgG under acidic conditions is eliminated by introducing mutations into its Fc region, the IgG is not recycled from the endosomes into the plasma, leading to marked impairment of the plasma retention of the IgG. To improve the plasma retention of IgGs, a method that enhances their FcRn binding under acidic conditions has been reported. When the FcRn binding of an IgG under acidic conditions is improved by introducing an amino acid substitution into its Fc region, the IgG is more efficiently recycled from the endosomes to the plasma, and thereby shows improved plasma retention. Meanwhile, it has also been reported that an IgG with enhanced FcRn binding under neutral conditions does not dissociate from FcRn under the neutral conditions in plasma even when it returns to the cell surface via its binding to FcRn under the acidic conditions in the endosomes, and consequently its plasma retention remains unaltered, or rather, is worsened (see, e.g., NPL 3; NPL 4; NPL 5).

[0017] Recently, antibodies that bind to antigens in a pH-dependent manner have been reported (see, e.g., PTL land PTL 12). These antibodies strongly bind to antigens under the plasma neutral conditions and dissociate from the antigens under the endosomal acidic conditions. After dissociating from the antigens, the antibodies become capable once again of binding to antigens when recycled to the plasma via FcRn. Thus, a single antibody molecule can repeatedly bind to multiple antigen molecules. In general, the plasma retention of an antigen is much shorter than that of an antibody that has the above-mentioned FcRn-mediated recycling mechanism. Therefore, when an antigen is bound to an antibody, the antigen normally shows prolonged plasma retention, resulting in an increase of the plasma concentration of the antigen. On the other hand, it has been reported that the above-described antibodies, which bind to antigens in a pH-dependent manner, eliminate antigens from plasma more rapidly than typical antibodies because they dissociate from the antigens within the endosomes during the FcRn-mediated recycling process. PTL 13 also described computer modeling analysis showing that an antibody with pH-dependent binding directed against C5 could extend antigen knockdown. Citation List Patent Literature

[0018] [PTL 1] U.S. Patent No. 6,355,245

[PTL 2] U.S. Patent No. 7,432,356

[PTL 3] WO 2005/074607

[PTL 4] WO 2007/106585

[PTL 5] WO 2008/069889

[PTL 6] WO 2010/054403

[PTL 7] WO 95/29697

[PTL 8] WO 02/30985

[PTL 9] WO 2004/007553

[PTL 10] WO 2010/015608

[PTL 11] WO 2009/125825

[PTL 12] WO 2011/122011

[PTL 13] WO 2011/111007 Non Patent Literature

[0019] [NPL 1] Holers et al., Immunol. Rev. 223:300-316 (2008)

[NPL 2] Dmytrijuk et al., The Oncologist 13(9):993-1000 (2008)

[NPL 3] Yeung et al., J Immunol. 182(12): 7663-7671 (2009)

[NPL 4] Datta-Mannan et al., J Biol. Chem. 282(3):1709-1717 (2007)

[NPL 5] Dall'Acqua et al., J. Immunol. 169(9):5171-5180 (2002)

[0019a] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field. Summary of Invention

[0019b] Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

[0020] An aspect of the invention is to provide anti-C5 antibodies and methods of using the same.

[0021] The invention provides anti-C5 antibodies and methods of using the same.

[0021a] In a first aspect, the present invention provides an anti-C5 antibody, comprising: (a) a VH sequence of SEQ ID NO: 106 and a VL sequence of SEQ ID NO: 111; (b) a VH sequence of SEQ ID NO: 107 and a VL sequence of SEQ ID NO: 111; (c) a VH sequence of SEQ ID NO: 108 and a VL sequence of SEQ ID NO: 111; (d) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 111; (e) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 112; (f) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 113; or (g) a VH sequence of SEQ ID NO: 110 and a VL sequence of SEQ ID NO: 113, when used in treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5.

[0021b] In a second aspect, the present invention provides an anti-C5 antibody, comprising: (a) a VH sequence of SEQ ID NO: 106 and a VL sequence of SEQ ID NO: 111;

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(b) a VH sequence of SEQ ID NO: 107 and a VL sequence of SEQ ID NO: 111; (c) a VH sequence of SEQ ID NO: 108 and a VL sequence of SEQ ID NO: 111; (d) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 111; (e) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 112; (f) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 113; or (g) a VH sequence of SEQ ID NO: 110 and a VL sequence of SEQ ID NO: 113, when used in enhancing the clearance of C5 from plasma.

[0021c] In a third aspect, the present invention provides an anti-C5 antibody, comprising any one of (i) to (iv) below: (i) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (ii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (iii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and

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(f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125, when used in treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5.

[0021d] In a fourth aspect, the present invention provides an anti-C5 antibody, comprising any one of (i) to (iv) below: (i) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (ii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (iii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125, when used in enhancing the clearance of C5 from plasma.

[0021e] In a fifth aspect, the present invention provides an isolated antibody that specifically binds to C5 when used in treating a complement-mediated disease or condition which

5c

involves excessive or uncontrolled activation of C5, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

[0021f] In a sixth aspect, the present invention provides an isolated antibody that specifically binds to C5 when used in enhancing the clearance of C5 from plasma, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

[0021g] In a seventh aspect, the present invention provides an isolated antibody that specifically binds to C5p when used in treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

[0021h] In an eighth aspect, the present invention provides an isolated antibody that specifically binds to C5p when used in enhancing the clearance of C5 from plasma, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

[0021i] In a ninth aspect, the present invention provides use of an anti-C5 antibody in the manufacture of a medicament for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, wherein the anti C5 antibody comprises: (a) a VH sequence of SEQ ID NO: 106 and a VL sequence of SEQ ID NO: 111; (b) a VH sequence of SEQ ID NO: 107 and a VL sequence of SEQ ID NO: 111; (c) a VH sequence of SEQ ID NO: 108 and a VL sequence of SEQ ID NO: 111; (d) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 111; (e) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 112; (f) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 113; or (g) a VH sequence of SEQ ID NO: 110 and a VL sequence of SEQ ID NO: 113.

[0021j] In a tenth aspect, the present invention provides use of an anti-C5 antibody in the

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manufacture of a medicament for enhancing the clearance of C5 from plasma, wherein the anti-C5 antibody comprises: (a) a VH sequence of SEQ ID NO: 106 and a VL sequence of SEQ ID NO: 111; (b) a VH sequence of SEQ ID NO: 107 and a VL sequence of SEQ ID NO: 111; (c) a VH sequence of SEQ ID NO: 108 and a VL sequence of SEQ ID NO: 111; (d) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 111; (e) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 112; (f) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 113; or (g) a VH sequence of SEQ ID NO: 110 and a VL sequence of SEQ ID NO: 113:

[0021k] In an eleventh aspect, the present invention provides use of an anti-C5 antibody in the manufacture of a medicament for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, wherein the anti C5 antibody comprises any one of (i) to (iv) below: (i) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (ii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (iii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv)

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(a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

[00211] In a twelfth aspect, the present invention provides use of an anti-C5 antibody in the manufacture of a medicament for enhancing the clearance of C5 from plasma, wherein the anti-C5 antibody comprises any one of (i) to (iv) below: (i) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (ii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (iii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and

5f

(f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

[0021m]In a thirteenth aspect, the present invention provides use of an antibody that specifically binds to C5 in the manufacture of a medicament for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

[0021n] In a fourteenth aspect, the present invention provides use of an antibody that specifically binds to C5 in the manufacture of a medicament for enhancing the clearance of C5 from plasma, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

[0021o] In a fifteenth aspect, the present invention provides use of an antibody that specifically binds to C5p in the manufacture of a medicament for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

[0021p] In a sixteenth aspect, the present invention provides use of an antibody that specifically binds to C5p in the manufacture of a medicament for enhancing the clearance of C5 from plasma, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

[0021q] In a seventeenth aspect, the present invention provides a method for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 in an individual, wherein the method comprises administering to the individual having the complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 an effective amount of an anti-C5 antibody, wherein the anti-C5 antibody comprises: (a) a VH sequence of SEQ ID NO: 106 and a VL sequence of SEQ ID NO: 111; (b) a VH sequence of SEQ ID NO: 107 and a VL sequence of SEQ ID NO: 111; (c) a VH sequence of SEQ ID NO: 108 and a VL sequence of SEQ ID NO: 111;

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(d) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 111; (e) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 112; (f) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 113; or (g) a VH sequence of SEQ ID NO: 110 and a VL sequence of SEQ ID NO: 113.

[0021r] In an eighteenth aspect, the present invention provides a method for enhancing the clearance of C5 from plasma in an individual, wherein the method comprises administering to the individual an effective amount of an anti-C5 antibody, wherein the anti-C5 antibody comprises: (a) a VH sequence of SEQ ID NO: 106 and a VL sequence of SEQ ID NO: 111; (b) a VH sequence of SEQ ID NO: 107 and a VL sequence of SEQ ID NO: 111; (c) a VH sequence of SEQ ID NO: 108 and a VL sequence of SEQ ID NO: 111; (d) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 111; (e) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 112; (f) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 113; or (g) a VH sequence of SEQ ID NO: 110 and a VL sequence of SEQ ID NO: 113.

[0021s] In a nineteenth aspect, the present invention provides a method for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 in an individual, wherein the method comprises administering to the individual having the complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 an effective amount of an anti-C5 antibody, wherein the anti-C5 antibody comprises any one of (i) to (iv) below: (i) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (ii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (iii)

5h

(a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

[0021t] In a twentieth aspect, the present invention provides a method for enhancing the clearance of C5 from plasma in an individual, wherein the method comprises administering to the individual an effective amount of an anti-C5 antibody, wherein the anti-C5 antibody comprises any one of (i) to (iv) below: (i) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (ii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (iii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122;

5i

(e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

[0021u] In a twenty-first aspect, the present invention provides a method for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 in an individual, wherein the method comprises administering to the individual having the complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 an effective amount of an antibody that specifically binds to C5, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

[0021v] In a twenty-second aspect, the present invention provides a method for enhancing the clearance of C5 from plasma in an individual, wherein the method comprises administering to the individual an effective amount of an antibody that specifically binds to C5, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

[0021w]In a twenty-third aspect, the present invention provides a method for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 in an individual, wherein the method comprises administering to the individual having the complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 an effective amount of an antibody that specifically binds to C5P, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

[0021x] In a twenty-fourth aspect, the present invention provides a method for enhancing the clearance of C5 from plasma in an individual, wherein the method comprises

5j

administering to the individual an effective amount of an antibody that specifically binds to C5P, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

[0022] In some embodiments, an isolated anti-C5 antibody of the present invention binds to an epitope within the beta chain of C5. In some embodiments, an isolated anti-C5 antibody of the present invention binds to an epitope within the MG1-MG2 domain of the beta chain of C5. In some embodiments, an isolated anti-C5 antibody of the present invention binds to an epitope within a fragment consisting of amino acids 33-124 of the beta chain (SEQ ID NO: 40) of C5. In some embodiments, an isolated anti-C5 antibody of the present invention binds to an epitope within the beta chain (SEQ ID NO: 40) of C5 which comprises at least one fragment selected from the group consisting of amino acids 47-57, 70-76, and 107-110. In some embodiments, an isolated anti-C5 antibody of the present invention binds to an epitope within a fragment of the beta chain (SEQ ID NO: 40) of C5 which comprises at least one amino acid residue selected from the group consisting of Glu48, Asp51, His70, His72, Lys109, and HisI10 of SEQ ID NO: 40. In further embodiments, the antibody binds to C5 with a higher affinity at neutral pH than at acidic pH. In further embodiments, the antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8. In another embodiment, an isolated anti-C5 antibody of the present invention binds to the same epitope as an antibody described in Table 2. In further embodiments, the antibody binds to the same epitope as an antibody described in Table 2 with a higher affinity at pH7.4 than at pH5.8. In a further embodiment, the anti-C5 antibody of the present invention binds to the same epitope as an antibody described in Tables 7 or 8. In further embodiments, the antibody binds to the same epitope as an antibody described in Tables 7 or 8 with a higher affinity at pH7.4 than at pH5.8.

[0023] In certain embodiments, an anti-C5 antibody of the present invention competes for binding C5 with an antibody comprising a VH and VL pair selected from: (a) a VH of SEQ ID NO:1 and a VL of SEQ ID NO:11; (b) a VH of SEQ ID NO: 5 and a VL of SEQ ID NO:15; (c) a VH of SEQ ID NO:4 and a VL of SEQ ID NO:14; (d) a VH of SEQ ID NO: 6 and a VL of SEQ ID NO: 16; (e) a VH of SEQ ID NO:2 and a VL of SEQ ID NO:12; (f) a VH of SEQ ID NO: 3 and a VL of SEQ ID NO: 13; (g) a VH of SEQ ID NO:9 and a VL of SEQ ID NO:19; (h) a VH of SEQ ID NO:7 and a VL of SEQ ID NO: 17; (i) aVH of SEQ ID NO:8 and a VL of SEQ ID NO:18; and (j) a VH of SEQ ID NO:10 and a VL of SEQ ID NO:20. In further embodiments, the anti-C5 antibody binds to C5 with a higher affinity at neutral pH than at acidic pH. In further embodiments, the anti-C5 antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8.

[0024] In some embodiments, an isolated anti-C5 antibody of the present invention has a characteristic selected from the group consisting of: (a) the antibody contacts amino acids D51 and K109 of C5 (SEQ ID NO:39); (b) the affinity of the antibody for C5 (SEQ ID NO:39) is greater than the affinity of the antibody for a C5 mutant consisting of an E48A substitution of SEQ ID NO:39; or (c) the antibody binds to a C5 protein consisting of the amino acid sequence of SEQ ID NO:39 at pH7.4, but does not bind to a C5 protein consisting of the amino acid sequence of SEQ ID NO:39 with a H72Y substitution at pH7.4. In further embodiments, the antibody binds to C5 with a higher affinity at neutral pH than at acidic pH. In further embodiments, the antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8.

[0025] In some embodiments, an isolated anti-C5 antibody of the present invention inhibits activation of C5. In some embodiments, an isolated anti-C5 antibody of the present invention inhibits activation of C5 variant R885H. In some embodiments, an isolated anti-C5 antibody of the present invention is a monoclonal antibody. In some em bodiments, an isolated anti-C5 antibody of the present invention is a human, humanized, or chimeric antibody. In some embodiments, an isolated anti-C5 antibody of the present invention is an antibody fragment that binds to C5. In some em bodiments, an isolated anti-C5 antibody of the present invention is a full length IgG1 or IgG4 antibody.

[0026] In some embodiments, an isolated anti-C5 antibody of the present invention comprises (a) a HVR-H3 comprising the amino acid sequence DXGYX 2 X 3 PTHAMX 4 X 5, wherein X 1is G or A, X2 is V, Q or D, X 3 is T or Y, X4 is Y or H, X 5 is L or Y

(SEQ ID NO: 128), (b) a HVR-L3 comprising the amino acid sequence QXTX 2 VGSSYGNX 3, wherein X1 is S, C, N or T, X2 is F or K, X3 is A, T or H (SEQ ID NO: 131), and (c) a HVR-H2 comprising the amino acid sequence X1IX 2 TGSGAXYX 3 4 AX

WX 6KG, wherein X 1 is C, Aor G, X 2 is Yor F, X 3 is T, Dor E, X 4 is Y, Kor Q, X5 is S, D or E, X6 is A or V (SEQ ID NO: 127).

[0027] In some embodiments, an isolated anti-C5 antibody of the present invention comprises (a) a HVR-H1 comprising the amino acid sequence SSYYXX 2 , wherein X1 is M or V, X2 is C or A (SEQ ID NO: 126), (b) a HVR-H2 comprising the amino acid sequence X1IX 2 TGSGAX 3 YX 4 AXWXKG, wherein X1 is C, A or G, X 2 is Y or F, X3 is T, D or E, X4 is Y, K or Q, X5 is S, D or E, X6 is A or V (SEQ ID NO: 127), and (c)

a HVR-H3 comprising the amino acid sequence DXGYX 2 X 3 PTHAMX4X 5 , wherein X 1 is G or A, X 2 is V, Q or D, X 3 is T or Y, X 4 is Y or H, X5 is L or Y (SEQ ID NO: 128). In further embodiments, the antibody comprises (a) a HVR-L1 comprising the amino acid sequence X 1 ASQX 2 IX3 SX 4 LA, wherein X1 is Qor R, X2 is N, Q or G, X3 is G or S, X4 is D, K or S (SEQ ID NO: 129); (b) a HVR-L2 comprising the amino acid sequence GASXX 2 X3 S, wherein X1 is K, E or T, X2 is Lor T, X3 is A, H, Eor Q(SEQ ID NO: 130); and (c) a HVR-L3 comprising the amino acid sequence QXTX 2 VGSSYGNX 3, wherein X1 is S, C, N or T, X2 is F or K, X3 is A, T or H (SEQ ID NO: 131).

[0028] In some embodiments, an isolated anti-C5 antibody of the present invention comprises (a) a HVR-L1 comprising the amino acid sequence X 1 ASQXIX 2 3 SX 4 LA,

wherein X 1is Q or R, X 2 is N, Q or G, X 3 is G or S, X 4 is D, K or S (SEQ ID NO: 129); (b) a HVR-L2 comprising the amino acid sequence GASXX 2 X 3 S, wherein X 1 is K, E or T, X 2 is L or T, X3 is A, H, E or Q (SEQ ID NO: 130); and (c) a HVR-L3 comprising the amino acid sequence QX1 TX 2VGSSYGNX 3 , wherein X 1is S, C, N or T, X 2 is F or K, X 3 is A, T or H (SEQ ID NO: 131).

[0029] In some embodiments, an isolated anti-C5 antibody of the present invention comprises a heavy chain variable domain framework FR1 comprising the amino acid sequence of any one of SEQ ID NOs: 132-134; FR2 comprising the amino acid sequence of any one of SEQ ID NOs: 135-136; FR3 comprising the amino acid sequence of any one of SEQ ID NOs: 137-139; and FR4 comprising the amino acid sequence of any one of SEQ ID NOs: 140-141. In some embodiments, an isolated anti C5 antibody of the present invention comprises a light chain variable domain framework FRI comprising the amino acid sequence of any one of SEQ ID NOs: 142-143; FR2 comprising the amino acid sequence of any one of SEQ ID NOs: 144-145; FR3 comprising the amino acid sequence of any one of SEQ ID NOs: 146-147; and FR4 comprising the amino acid sequence of SEQ ID NO: 148.

[0030] In some embodiments, an isolated anti-C5 antibody of the present invention comprises (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 10, 106-110; (b) a VL sequence having at least 95% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 20, 111-113; or (c) a VH sequence as in (a) and a VL sequence as in (b). In further em bodiments, the antibody comprises a VH sequence of any one of SEQ ID NOs: 10, 106-110. In further embodiments, the antibody comprises a VL sequence of any one of SEQ ID NOs: 20, 111-113.

[0031] The invention provides an antibody comprising a VH sequence of any one of SEQ ID NOs: 10, 106-110 and a VL sequence of any one of SEQ ID NOs: 20, 111-113.

[0032] The invention also provides isolated nucleic acids encoding an anti-C5 antibody of the present invention. The invention also provides host cells comprising a nucleic acid of the present invention. The invention also provides a method of producing an antibody comprising culturing a host cell of the present invention so that the antibody is produced.

[0033] The invention further provides a method of producing an anti-C5 antibody. In some embodiments, the method comprises immunizing an animal against a polypeptide which comprises the MG1-MG2 domain (SEQ ID NO: 43) of the beta chain of C5. In some embodiments, the method comprises immunizing an animal against a polypeptide which comprises the region corresponding to amino acids at positions 33 to 124 of the beta chain (SEQ ID NO: 40) of C5. In some embodiments, the method comprises immunizing an animal against a polypeptide which comprises at least one fragment selected from amino acids 47-57, 70-76, and 107-110 of the beta chain (SEQ ID NO: 40) of C5. In some embodiments, the method comprises immunizing an animal against a polypeptide which comprises a fragment of the beta chain (SEQ ID NO: 40) of C5, which comprises at least one amino acid selected from Glu48, Asp51, His70, His72, Lys109, and HisI10.

[0034] The invention also provides a pharmaceutical formulation comprising an anti-C5 antibody of the present invention and a pharmaceutically acceptable carrier.

[0035] Anti-C5 antibodies of the present invention may be for use as a medicament. Anti-C5 antibodies of the present invention may be for use in treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5. Anti C5 antibodies of the present invention may be for use in enhancing the clearance of C5 from plasma.

[0036] Anti-C5 antibodies of the present invention may be used in the manufacture of a medicament. In some embodiments, the medicament is for treatment of a complement mediated disease or condition which involves excessive or uncontrolled activation of C5. In some embodiments, the medicament is for enhancing the clearance of C5 from plasma.

[0037] The invention also provides a method of treating an individual having a complement mediated disease or condition which involves excessive or uncontrolled activation of C5. In some embodiments, the method comprises administering to the individual an effective amount of an anti-C5 antibody of the present invention. The invention also provides a method of enhancing the clearance of C5 from plasma in an individual. In some embodiments, the method comprises administering to the individual an effective amount of an anti-C5 antibody of the present invention to enhance the clearance of C5 from plasma. Brief Description of Drawings

[0038] [fig.l]Figure 1 illustrates epitope binning of anti-C5 antibodies, as described in Example 2.2. Antibodies grouped into the same epitope bin are boxed with a thick line.

[0039] [fig.2A]Figure 2A illustrates BIACORE (registered trademark) sensorgrams of anti-C5 antibodies at pH7.4 (solid line) and pH5.8 (dashed line) to assess pH-dependency, as described in Example 3.2. CFA0305, CFA0307, CFA0366, CFA0501, CFA0538, and CFA0599 are antibodies grouped into epitope C, as described in Example 2.2.

[0040] [fig.2B]Figure 2B illustrates BIACORE (registered trademark) sensorgrams of anti-C5 antibodies at pH7.4 (solid line) and pH5.8 (dashed line) to assess pH-dependency, as described in Example 3.2. CFA0666, CFA0672, and CFA0675 are antibodies grouped into epitope C, and CFA0330 and CFA0341 are antibodies grouped into epitope B, as described in Example 2.2. 305LO5 is a humanized antibody of CFA0305, as described in Example 2.3.

[0041] [fig.3]Figure 3 illustrates Western Blot analysis against C5 beta-chain-derived fragments (amino acids 19-180, 161-340, 321-500, and 481-660 of SEQ ID NO:40) fused to GST-tag, as described in Example 4.1. CFA0305, CFA0307, CFA0366, CFA0501, CFA0538, CFA0599, CFA0666, CFA0672, and CFA0675 are antibodies grouped into epitope C. Anti-GST antibody is a positive control. The position of the GST-fused C5 fragments (46-49 kDa) is marked with an arrow.

[0042] [fig.4]Figure 4 illustrates BIACORE (registered trademark) sensorgrams of anti-C5 an tibodies towards MG1-MG2 domain of C5 beta-chain, as described in Example 4.3. The upper panel shows the results of CFA0305 (solid line), CFA0307 (dashed line), CFA0366 (dash-dot line), and eculizumab (dotted line). The middle panel shows the results of CFA0501 (solid line), CFA0599 (dashed line), CFA0538 (dash-dot line), and eculizumab (dotted line). The lower panel shows the results of CFA0666 (solid line), CFA0672 (dashed line), CFA0675 (dash-dot line), and eculizumab (dotted line). CFA0305, CFA0307, CFA0366, CFA0501, CFA0538, CFA0599, CFA0666, CFA0672, and CFA0675 are antibodies grouped into epitope C. Eculizumab is a control anti-C5 antibody.

[0043] [fig.5A]Figure 5A illustrates Western Blot analysis against MG1-MG2 domain-derived peptide fragments (amino acids 33-124, 45-124, 52-124, 33-111, 33-108, and 45-111 of SEQ ID NO:40) fused to GST-tag, as described in Example 4.4. Anti-GST antibody is used as an antibody for reaction. The position of the GST-fused C5 fragments (35-37kDa) is marked with an arrow.

[0044] [fig.5B]Figure 5B illustrates Western Blot analysis against MG1-MG2 domain-derived peptide fragments (amino acids 33-124, 45-124, 52-124, 33-111, 33-108, and 45-111 of SEQ ID NO:40) fused to GST-tag, as described in Example 4.4. CFA0305 is used as an antibody for reaction.

[0045] [fig.5C]Figure 5C summarizes binding reactions of anti-C5 antibodies to C5 beta chain-derived fragments, as described in Example 4.4. The fragments to which the anti-C5 antibodies grouped into epitope C (CFA0305, CFA0307, CFA0366, CFA0501, CFA0538, CFA0599, CFA0666, CFA0672, and CFA0675) bind are shown in gray, and the fragments to which they don't bind are shown in white.

[0046] [fig.6]Figure 6 illustrates Western Blot analysis against C5 point mutants in which E48, D51, and K109 of the beta-chain is substituted with alanine (E48A, D51A, and K109A, respectively), as described in Example 4.5. In the left panel, eculizumab (anti-C5 antibody, alpha-chain binder) is used as an antibody for reaction and the position of the alpha-chain of C5 (approx.1l3kDa) is marked with an arrow. In the right panel, CFA0305 (grouped into epitope C, beta-chain binder) is used as an antibody for reaction and the position of the beta-chain of C5 (approx. 74kDa) is marked with an arrowhead.

[0047] [fig.7]Figure 7 presents BIACORE (registered trademark) sensorgrams showing the in teraction of eculizumab-F760G4 (upper panel) or 305LO5 (lower panel) with C5 mutants, as described in Example 4.6. Sensorgrams were obtained by injection of C5-wt (thick solid curve), C5-E48A (short-dashed curve), C5-D51A (long-dashed curve), and C5-K109A (thin solid curve), respectively, over sensor surface im mobilized with eculizumab-F760G4 or 305LO5. Eculizumab is a control anti-C5 antibody. 305LO5 is a humanized antibody of CFA0305 (grouped into epitope C), as described in Example 2.3.

[0048] [fig.8]Figure 8 presents BIACORE (registered trademark) sensorgrams showing the in teraction of 305LO5 with C5 His mutants to assess pH-dependency, as described in Example 4.7. Sensorgrams were obtained by injection of C5-wt (thick solid curve), C5-H70Y (long-dashed curve), C5-H72Y (short-dashed curve), C5-Hi1OY (dotted curve), and C5-H70Y+H1lOY (thin solid curve), respectively, over sensor surface im mobilized with 305LO5. The antibody/antigen complexes were allowed to dissociate at pH7.4, followed by additional dissociation at pH5.8 (pointed by an arrow) to assess the pH-dependent interactions.

[0049] [fig.9A]Figure 9A illustrates inhibition of complement-activated liposome lysis by anti-C5 antibodies, as described in Example 5.1. The results of CFA0305, CFA0307, CFA0366, CFA0501, CFA0538, CFA0599, CFA0666, CFA0672, and CFA0675 grouped into epitope C, as described in Example 2.2, are shown.

[0050] [fig.9B]Figure 9B illustrates inhibition of complement-activated liposome lysis by anti-C5 antibodies, as described in Example 5.1. The results of antibodies CFA0330 and CFA0341 grouped into epitope B, as described in Example 2.2, are shown.

[0051] [fig.1OA]Figure IA illustrates inhibition of C5a generation by anti-C5 antibodies, as described in Example 5.2. C5a concentrations were quantified in the supernatants obtained during the liposome lysis assay described in Figure 9A.

[0052] [fig.1OB]Figure 1OB illustrates inhibition of C5a generation by anti-C5 antibodies, as described in Example 5.2. C5a concentrations were quantified in the supernatants obtained during the liposome lysis assay described in Figure 9B.

[0053] [fig.11]Figure 11 illustrates inhibition of complement-activated hemolysis by anti-C5 antibodies, as described in Example 5.3. Complements were activated via the classical pathway.

[0054] [fig.12]Figure 12 illustrates inhibition of complement-activated hemolysis by anti-C5 antibodies, as described in Example 5.4. Complements were activated via the al ternative pathway.

[0055] [fig.13]Figure 13 illustrates the time course of plasma human C5 concentration after intravenous administration of human C5 alone or human C5 and an anti-human C5 antibody in mice assessing C5 clearance, as described in Example 6.2. CFA0305, CFA0307, CFA0366, CFA0501, CFA0538, CFA0599, CFA0666, CFA0672, and CFA0675 are antibodies grouped into epitope C and CFA0330 and CFA0341 are an tibodies grouped into epitope B, as described in Example 2.2.

[0056] [fig.14]Figure 14 illustrates the time course of plasma anti-human C5 antibody con centration after intravenous administration of human C5 and an anti-human C5 antibody in mice assessing antibody pharmacokinetics, as described in Example 6.3. CFA0305, CFA0307, CFA0366, CFA0501, CFA0538, CFA0599, CFA0666, CFA0672, and CFA0675 are antibodies grouped into epitope C and CFA0330 and CFA0341 are antibodies grouped into epitope B, as described in Example 2.2.

[0057] [fig.15]Figure 15 illustrates inhibition of complement-activated liposome lysis by anti C5 antibodies, as described in Example 9.1. The results of antibodies 305LO15-SG422, 305LO16-SG422, 305LO18-SG422, 305LO19-SG422, 305LO20-SG422, and 305LO20-SG115 are shown.

[0058] [fig.16]Figure 16 illustrates inhibition of complement-activated liposome lysis by anti C5 antibodies, as described in Example 9.1. The results of antibodies 305LO15-SG115 and 305LO23-SG429 are shown.

[0059] [fig.17]Figure 17 illustrates inhibition of complement-activated liposome lysis by anti C5 antibodies, as described in Example 9.1. The results of antibodies 305LO22-SG115, 305LO22-SG422, 305LO23-SG115, and 305LO23-SG422 are shown.

[0060] [fig.18]Figure 18 illustrates inhibition of C5a generation by anti-C5 antibodies, as described in Example 9.2. C5a concentrations were quantified in the supernatants obtained during the liposome lysis assay described in Figure 15.

[0061] [fig.19]Figure 19 illustrates inhibition of C5a generation by anti-C5 antibodies, as described in Example 9.2. C5a concentrations were quantified in the supernatants obtained during the liposome lysis assay described in Figure 16.

[0062] [fig.20]Figure 20 illustrates inhibition of complement activity in monkey plasma by anti-C5 antibodies, as described in Example 9.3. Anti-C5 antibodies were administered into cynomolgus monkeys, and complement activities in plasma of the monkeys were measured in hemolysis assay.

[0063] [fig.21]Figure 21 illustrates inhibition of biological activity of wild type C5 (WT) and C5 variants (V145I, R449G, V8021, R885H, R928Q, D966Y, S13iON, and E1437D) by an anti-C5 antibody (eculizumab), as described in Example 9.4.

[0064] [fig.22]Figure 22 illustrates inhibition of biological activity of wild type C5 (WT) and C5 variants (V1451, R449G, V8021, R885H, R928Q, D966Y, S13iON, and E1437D) by anti-C5 antibody (a 305 variant), as described in Example 9.4.

[0065] [fig.23]Figure 23 illustrates inhibition of complement-activated liposome lysis by anti C5 antibodies (BNJ441 and a 305 variant), as described in Example 9.5.

[0066] [fig.24]Figure 24 illustrates the time course of plasma cynomolgus C5 concentration after intravenous administration of an anti-human C5 antibody in cynomolgus monkeys assessing C5 clearance, as described in Example 10.2.

[0067] [fig.25]Figure 25 illustrates the time course of plasma anti-human C5 antibody con centration after intravenous administration of an anti-human C5 antibody in cynomolgus monkeys assessing antibody pharmacokinetics, as described in Example 10.3.

[0068] [fig.26]Figures 26A and 26B illustrate the crystal structure of the 305 Fab bound to the human C5 (hC5)-MG1 domain, as described in Example 11.6. Figure 26A illustrates an asymmetric unit. MGi is shown in surface representation and the 305 Fab is shown as ribbons (dark gray: heavy chain, light gray: light chain). Figure 26B illustrates molecules 1 and 2 superimposed (dark gray: molecule 1, light gray: molecule 2).

[0069] [fig.27A]Figure 27A illustrates the epitope of the 305 Fab contact region on the MGi domain, as described in Example 11.6. Figure 27A illustrates epitope mapping in the MG Iamino acid sequence (dark gray: closer than 3.0 Angstrom, light gray: closer than 4.5 Angstrom).

[0070] [fig.27B]Figure 27B illustrates the epitope of the 305 Fab contact region on the MG1 domain, as described in Example 11.6. Figure 27B illustrates epitope mapping in the crystal structure (dark gray spheres: closer than 3.0 Angstrom, light gray sticks: closer than 4.5 Angstrom).

[0071] [fig.28A]Figure 28A illustrates a close-up view of the interactions E48, D51, and K109 (stick representation) with the 305 Fab (surface representation), as described in Example 11.7.

[0072] [fig.28B]Figure 28B illustrates interactions between E48 and its environment (dark gray dotted line: hydrogen bond with the Fab, light gray dotted line: water-mediated hydrogen bond), as described in Example 11.7.

[0073] [fig.28C]Figure 28C illustrates interactions between D51 and its environment (dark gray dotted line: hydrogen bond with the Fab), as described in Example 11.7.

[0074] [fig.28D]Figure 28D illustrates interactions between K109 and its environment (dark gray dotted line: hydrogen bond with the Fab, light gray dotted line: salt bridge with H CDR3_D95), as described in Example 11.7.

[0075] [fig.29A]Figure 29A illustrates a close-up view of the interactions of H70, H72, and HI10 (stick representation) with the 305 Fab (surface representation), as described in Example 11.8, in the same orientation as Figure 28A.

[0076] [fig.29B]Figure 29B illustrates interactions between H70 and its environment, as described in Example 11.8. This histidine residue is indicated in stick and mesh repre sentation. The hydrogen bond is indicated by dotted line.

[0077] [fig.29C]Figure 29C illustrates interactions between H72 and its environment, as described in Example 11.8. This histidine residue is indicated in stick and mesh repre sentation. The hydrogen bond is indicated by dotted line.

[0078] [fig.29D]Figure 29D illustrates interactions between HI10 and its environment, as described in Example 11.8. This histidine residue is indicated in stick and mesh repre sentation. The distance between HI10 and H-CDR3_HI00c is shown by dotted line. Description of Embodiments

[0079] The techniques and procedures described or referenced herein are generally well un derstood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J.

Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.I. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J. P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Im munology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); An tibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993).

[0080] I. DEFINITIONS 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 one skilled in the art with a general guide to many of the terms used in the present application. All references cited herein, including patent ap plications and publications, are incorporated by reference in their entirety.

[0081] For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. In the event that any definition set forth below conflicts with any document incorporated herein by reference, the definition set forth below shall control.

[0082] An "acceptor human framework" for the purposes herein is a framework comprising 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 comprise the same amino acid sequence thereof, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes are 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 the VL human immunoglobulin framework sequence or human consensus framework sequence.

[0083] "Affinity" refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, "binding affinity" refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific il lustrative and exemplary embodiments for measuring binding affinity are described in the following.

[0084] An "affinity matured" antibody refers to an antibody with one or more alterations in one or more hypervariable regions (HVRs), compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen.

[0085] The terms "anti-C5 antibody" and "an antibody that binds to C5" refer to an antibody that is capable of binding C5 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting C5. In one embodiment, the extent of binding of an anti-C5 antibody to an unrelated, non-C5 protein is less than about 10% of the binding of the antibody to C5 as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to C5 has a dissociation constant (Kd) of 1 micro M or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10-8 M or less, e.g., from 10-8 M to 10-13 M, e.g., from 109 M to 10-13 M). In certain embodiments, an anti-C5 antibody binds to an epitope of C5 that is conserved among C5 from different species.

[0086] The term "antibody" herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal an tibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.

[0087] An "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(ab') 2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0088] An "antibody that binds to the same epitope" as a reference antibody refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay, and/or conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay. An exemplary competition assay is provided herein.

[0089] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.

[0090] The "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1, and IgA 2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively.

[0091] The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At211, 1131, 1125, Y90, Re86, Re8 , Sm 153 , Bi 2 12 , 32 , Pb2 12 and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof; and the various antitumor or anticancer agents disclosed below.

[0092] "Effector functions" refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[0093] An "effective amount" of an agent, e.g., a pharmaceutical formulation, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.

[0094] The term "epitope" includes any determinant capable of being bound by an antibody. An epitope is a region of an antigen that is bound by an antibody that targets that antigen, and includes specific amino acids that directly contact the antibody. Epitope determinants can include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and can have specific three dimensional structural characteristics, and/or specific charge characteristics. Generally, antibodies specific for a particular target antigen will preferentially recognize an epitope on the target antigen in a complex mixture of proteins and/or macromolecules.

[0095] The term "Fc region" herein is used to define a C-terminal region of an im munoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0096] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FRI, FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FRI-HI(L)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0097] The terms "full length antibody," "intact antibody," and "whole antibody" are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.

[0098] The terms "host cell," "host cell line," and "host cell culture" are used inter changeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

[0099] A "human antibody" is one which possesses an amino acid sequence which cor responds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.

[0100] A "human consensus framework" is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Im munological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one embodiment, for the VL, the subgroup is subgroup kappa I as in Kabat et al., supra. In one embodiment, for the VH, the subgroup is subgroup III as in Kabat et al., supra.

[0101] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization. The term "hypervariable region" or "HVR" as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence ("complementarity determining regions" or "CDRs") and/or form structurally defined loops ("hypervariable loops") and/or contain the antigen-contacting residues ("antigen contacts"). Generally, antibodies comprise six HVRs: three in the VH (HI, H2, H3), and three in the VL (L, L2, L3). Exemplary HVRs herein include: (a) hypervariable loops occurring at amino acid residues 26-32 (LI), 50-52 (L2), 91-96 (L3), 26-32 (HI), 53-55 (H2), and 96-101 (H3) (Chothia, J. Mol. Biol. 196:901-917 (1987));(b) CDRs occurring at amino acid residues 24-34 (LI), 50-56 (L2), 89-97 (L3), 31-35b (HI), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, NIH, Bethesda, MD (1991));(c) antigen contacts occurring at amino acid residues 27c-36 (LI), 46-55 (L2), 89-96 (L3), 30-35b (HI), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and(d) combinations of (a), (b), and/or (c), including HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (HI), 26-35b (HI), 49-65 (H2), 93-102 (H3), and 94-102 (H3).

[0102] Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.

[0103] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.

[0104] An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human.

[0105] An "isolated" antibody is one which has been separated from a component of its natural environment. In some embodiments, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC) methods. For review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0106] An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0107] "Isolated nucleic acid encoding an anti-C5 antibody" refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.

[0108] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.

[0109] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical formulation.

[0110] "Native antibodies" refer to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glyco proteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CHI, CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (kappa) and lambda (lambda), based on the amino acid sequence of its constant domain.

[0111] The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the in dications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.

[0112] "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 with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative sub stitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any al gorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the US Copyright Office, Washington D.C., 20559, where it is registered under US Copyright Reg istration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0113] In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X/Y, where X is the number of amino acid residues scored as identical matches by 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 ap preciated that where the length of amino acid sequence A is not equal to the length of 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 specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the im mediately preceding paragraph using the ALIGN-2 computer program.

[0114] The term "pharmaceutical formulation" refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

[0115] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject., A pharma ceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0116] The term "C5", as used herein, encompasses any native C5 from any vertebrate source, including mammals such as primates (e.g., humans and monkeys) and rodents (e.g., mice and rats). Unless otherwise indicated, the term "C5" refers to a human C5 protein having the amino acid sequence shown in SEQ ID NO: 39 and containing the beta chain sequence shown in SEQ ID NO: 40. The term encompasses "full-length," unprocessed C5 as well as any form of C5 that results from processing in the cell. The term also encompasses naturally occurring variants of C5, e.g., splice variants or allelic variants. The amino acid sequence of an exemplary human C5 is shown in SEQ ID NO: 39 ("wild-type" or "WT" C5). The amino acid sequence of an exemplary beta chain of human C5 is shown in SEQ ID NO: 40. The amino acid sequences of exemplary MG1, MG2 and MG1-MG2 domains of the beta chain of human C5 are shown in SEQ ID NO: 41, 42, and 43, respectively. The amino acid sequences of exemplary cynomolgus monkey and murine C5 are shown in SEQ ID NO: 44 and 105, respectively. Amino acid residues 1-19 of SEQ ID NOs: 39, 40, 43, 44, and 105 correspond to a signal sequence that is removed during processing in the cell and is thus missing from the corresponding exemplary amino acid sequence.

[0117] As used herein, "treatment" (and grammatical variations thereof such as "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, di minishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some em bodiments, antibodies of the invention are used to delay development of a disease or to slow the progression of a disease.

[0118] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of com plementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0119] The term "vector," as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors".

[0120] II. COMPOSITIONS AND METHODS In one aspect, the invention is based, in part, on anti-C5 antibodies and uses thereof. In certain embodiments, antibodies that bind to C5 are provided. Antibodies of the invention are useful, e.g., for the diagnosis or treatment of a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5.

[0121] A. Exemplary Anti-C5 Antibodies In one aspect, the invention provides isolated antibodies that bind to C5. In certain embodiments, an anti-C5 antibody of the present invention binds to an epitope within the beta chain of C5. In certain embodiments, the anti-C5 antibody binds to an epitope within the MG1-MG2 domain of the beta chain of C5. In certain embodiments, the anti-C5 antibody binds to an epitope within a fragment consisting of amino acids 19-180 of the beta chain of C5. In certain embodiments, the anti-C5 antibody binds to an epitope within the MG1 domain (amino acids 20-124 of SEQ ID NO: 40 (SEQ ID NO: 41)) of the beta chain of C5. In certain embodiments, the anti-C5 antibody binds to an epitope within a fragment consisting of amino acids 33-124 of the beta chain of C5 (SEQ ID NO: 40). In another embodiment, the antibody does not bind to a fragment shorter than the fragment consisting of amino acids 33-124 of the beta chain of C5, e.g., a fragment consisting of amino acids 45-124, 52-124, 33-111, 33-108, or 45-111 of the beta chain of C5 (SEQ ID NO: 40).

[0122] In another aspect, the invention provides anti-C5 antibodies that exhibit pH dependent binding characteristics. As used herein, the expression "pH-dependent binding" means that the antibody exhibits "reduced binding to C5 at acidic pH as compared to its binding at neutral pH" (for purposes of the present disclosure, both ex pressions may be used interchangeably). For example, antibodies "with pH-dependent binding characteristics" include antibodies that bind to C5 with higher affinity at neutral pH than at acidic pH. In certain embodiments, the antibodies of the present invention bind to C5 with at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more times higher affinity at neutral pH than at acidic pH. In some embodiments, the antibodies bind to C5 with higher affinity at pH7.4 than at pH5.8. In further embodiments, the antibodies of the present invention bind to C5 with at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more times higher affinity at pH7.4 than at pH5.8.

[0123] The "affinity" of an antibody for C5, for purposes of the present disclosure, is expressed in terms of the KD of the antibody. The KD of an antibody refers to the equilibrium dissociation constant of an antibody-antigen interaction. The greater the KD value is for an antibody binding to its antigen, the weaker its binding affinity is for that particular antigen. Accordingly, as used herein, the expression "higher affinity at neutral pH than at acidic pH" (or the equivalent expression "pH-dependent binding") means that the KD for the antibody binding to C5 at acidic pH is greater than the KD for the antibody binding to C5 at neutral pH. For example, in the context of the present invention, an antibody is considered to bind to C5 with a higher affinity at neutral pH than at acidic pH if the KD of the antibody binding to C5 at acidic pH is at least 2 times greater than the KD of the antibody binding to C5 at neutral pH. Thus, the present invention includes antibodies that bind to C5 at acidic pH with a KD that is at least2,3,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100, 200, 400, 1000, 10000, or more times greater than the KD of the antibody binding to C5 at neutral pH. In another embodiment, the KD value of the antibody at neutral pH can be 10-7 M, 10-1 M, 10-9 M, 1010 M, 10-11 M, 10-12 M, or less. In another em bodiment, the KD value of the antibody at acidic pH can be 10-9 M, 10-1 M, 10-7 M, 106 M, or greater.

[0124] In further embodiments an antibody is considered to bind to C5 with a higher affinity at neutral pH than at acidic pH if the KD of the antibody binding to C5 at pH5.8 is at least 2 times greater than the KD of the antibody binding to C5 at pH7.4. In some em bodiments the provided antibodies bind to C5 at pH5.8 with a KD that is at least 3, 5,

10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,200,400, 1000, 10000, or more times greater than the KD of the antibody binding to C5 at pH7.4. In another embodiment, the KD value of the antibody at pH7.4 can be 10-7 M, 10-8 M, 10-9 M, 10-10 M, 10-11 M, 10-12 M, or less. In another embodiment, the KD value of the antibody at pH5.8 can be 10-9 M, 10-8 M, 10-7 M, 10-6 M, or greater.

[0125] The binding properties of an antibody for a particular antigen may also be expressed in terms of the kd of the antibody. The kd of an antibody refers to the dissociation rate constant of the antibody with respect to a particular antigen and is expressed in terms of reciprocal seconds (i.e., sec-'). An increase in kd value signifies weaker binding of an antibody to its antigen. The present invention therefore includes antibodies that bind to C5 with a higher kd value at acidic pH than at neutral pH. The present invention includes antibodies that bind to C5 at acidic pH with a kd that is at least 2, 3, 5, 10, 15, 20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,200,400,1000, 10000, or more times greater than the kd of the antibody binding to C5 at neutral pH. In another embodiment, the kd value of the antibody at neutral pH can be 10-2 1/s, 10-1 1/s, 10-4 1/s, 10-5 1/s, 10-6 1/s, or less. In another embodiment, the kd value of the antibody at acidic pH can be 10-1 I/s, 10-2 1/s, 10-1 1/s, or greater. The invention also includes antibodies that bind to C5 with a higher kd value at pH5.8 than at pH7.4. The present invention includes antibodies that bind to C5 at pH5.8 with a kd that is at least 3,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,200,400, 1000, 10000, or more times greater than the kd of the antibody binding to C5 at pH7.4. In another embodiment, the kd value of the antibody at pH7.4 can be 10-2 1/s, 10-3 1/s, 10-4 1/s, 10-5 1/s, 10-6 1/s, or less. In another embodiment, the kd value of the antibody at pH5.8 can be 10-3 1/s, 10-2 1/s, 10-1 1/s, or greater.

[0126] In certain instances, a "reduced binding to C5 at acidic pH as compared to its binding at neutral pH" is expressed in terms of the ratio of the KD value of the antibody binding to C5 at acidic pH to the KD value of the antibody binding to C5 at neutral pH (or vice versa). For example, an antibody may be regarded as exhibiting "reduced binding to C5 at acidic pH as compared to its binding at neutral pH", for purposes of the present invention, if the antibody exhibits an acidic/neutral KD ratio of 2 or greater. In certain exemplary embodiments, the pH5.8/pH7.4 KD ratio for an antibody of the present invention is 2 or greater. In certain exemplary embodiments, the acidic/neutral KD ratio for an antibody of the present invention can be 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or greater. In another embodiment, the KD value of the antibody at neutral pH can be 10-7 M, 10- 8M, 10-9 M, 10-10 M, 10-11 M, 10-12 M, or less. In another embodiment, the KD value of the antibody at acidic pH can be 10-9 M, 10- 8M, 10-7 M, 10-6 M, or greater. In further instances an antibody may be regarded as exhibiting "reduced binding to C5 at acidic pH as compared to its binding at neutral pH", for purposes of the present invention, if the antibody exhibits an pH5.8/pH7.4 KD ratio of 2 or greater. In certain exemplary embodiments, the pH5.8/pH7.4 KD ratio for an antibody of the present invention can be 3,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,200, 400, 1000, 10000, or greater. In another embodiment, the KD value of the antibody at pH7.4 can be 10-7 M, 10-8 M, 10-9 M, 10-10 M, 10-1 M, 10-12 M, or less. In another em bodiment, the KD value of the antibody at pH5.8 can be 10-9 M, 10-8 M, 10-7 M, 10-6 M, or greater.

[0127] In certain instances, a "reduced binding to C5 at acidic pH as compared to its binding at neutral pH" is expressed in terms of the ratio of the kd value of the antibody binding to C5 at acidic pH to the kd value of the antibody binding to C5 at neutral pH (or vice versa). For example, an antibody may be regarded as exhibiting "reduced binding to C5 at acidic pH as compared to its binding at neutral pH", for purposes of the present invention, if the antibody exhibits an acidic/neutral kd ratio of 2 or greater. In certain exemplary embodiments, the pH5.8/pH7.4 kd ratio for an antibody of the present invention is 2 or greater. In certain exemplary embodiments, the acidic/neutral kd ratio for an antibody of the present invention can be 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or greater. In further exemplary embodiments, the pH 5.8/pH 7.4 kd ratio for an antibody of the present invention can be 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or greater. In another embodiment, the kd value of the antibody at neutral pH can be 10-2 1/s, 10-3 1/s, 10-4 1/s, 10-5 1/s, 10-6 1/s, or less. In a further embodiment, the kd value of the antibody at pH 7.4 can be 10-2 1/s, 10-3 1/s, 10-4 1/s, 10-5 1/s, 10-6 1/s, or less. In another embodiment, the kd value of the antibody at acidic pH can be 10-3 1/s, 10-2 1/s, 10-1 1/s, or greater. In a further embodiment, the kd value of the antibody at pH5.8 can be 10 s,12 /s, 10-1 /s, or greater.

[0128] As used herein, the expression "acidic pH" means a pH of 4.0 to 6.5. The expression "acidic pH" includes pH values of any one of 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, and 6.5. In particular aspects, the "acidic pH" is 5.8.

[0129] As used herein, the expression "neutral pH" means a pH of 6.7 to about 10.0. The ex pression "neutral pH" includes pH values of any one of 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, and 10.0. In particular aspects, the "neutral pH" is 7.4.

[0130] KD values, and kd values, as expressed herein, may be determined using a surface plasmon resonance-based biosensor to characterize antibody-antigen interactions. (See, e.g., Example 3, herein). KD values, and kd values can be determined at 25 degrees C or 37 degrees C.

[0131] In certain embodiments, an anti-C5 antibody of the present invention binds to an epitope within the beta chain of C5 which consists of the MG1 domain (SEQ ID NO:41). In certain embodiments, an anti-C5 antibody of the present invention binds to an epitope within the beta chain (SEQ ID NO: 40) of C5 which comprises at least one fragment selected from the group consisting of amino acids 47-57, 70-76, and 107-110. In certain embodiments, an anti-C5 antibody of the present invention binds to an epitope within a fragment of the beta chain (SEQ ID NO: 40) of C5 which comprises at least one amino acid selected from the group consisting of Thr47, Glu48, Ala49, Phe50, Asp5l, Ala52, Thr53, Lys57, His70, Val7l, His72, Ser74, Glu76, Val107, Ser108, Lys109, and His110. In certain embodiments, an anti-C5 antibody of the present invention binds to an epitope within a fragment of the beta chain (SEQ ID NO: 40) of C5 which comprises at least one amino acid selected from the group consisting of Glu48, Asp5l, His70, His72, Lys109, and Hisl10. In certain embodiments, binding of an anti-C5 antibody of the present invention to a C5 mutant is reduced compared to its binding to wild type C5, wherein the C5 mutant has at least one amino acid sub stitution at a position selected from the group consisting of Glu48, Asp51, His72, and Lys109. In another embodiment, pH-dependent binding of an anti-C5 antibody of the present invention to a C5 mutant is reduced compared to its pH-dependent binding to wild type C5, wherein the C5 mutant has at least one amino acid substitution at a position selected from the group consisting of His70, His72, and His110. In a further embodiment, an amino acid at a position selected from Glu48, Asp51, and Lys109 is substituted with alanine, and an amino acid at a position selected from His70, His72, and HisI10 is substituted with tyrosine in the C5 mutant.

[0132] In certain embodiments, an anti-C5 antibody of the present invention competes for binding C5 with an antibody comprising a VH and VL pair selected from: (a) a VH of SEQ ID NO:1 and a VL of SEQ ID NO:11; (b) a VH of SEQ ID NO: 22 and a VL of SEQ ID NO:26; (c) a VH of SEQ ID NO:21 and a VL of SEQ ID NO:25; (d) a VH of SEQ ID NO: 5 and a VL of SEQ ID NO:15; (e) a VH of SEQ ID NO:4 and a VL of SEQ ID NO:14; (f) a VH of SEQ ID NO: 6 and a VL of SEQ ID NO: 16; (g) a VH of SEQ ID NO:2 and a VL of SEQ ID NO:12; (h) a VH of SEQ ID NO: 3 and a VL of SEQ ID NO: 13; (i) a VH of SEQ ID NO:9 and a VL of SEQ ID NO:19; (j) a VH of SEQ ID NO:7 and a VL of SEQ ID NO: 17; (k) aVH of SEQ ID NO:8 and a VL of SEQ ID NO:18; (1) a VH of SEQ ID NO: 23 and a VL of SEQ ID NO:27; and (m) a VH of SEQ ID NO: 10 and a VL of SEQ ID NO:20.

[0133] In certain embodiments, an anti-C5 antibody of the present invention binds C5 and contacts amino acid Asp51 (D51) of SEQ ID NO:39. In additional embodiments, an anti-C5 antibody of the present invention binds C5 and contacts amino acid Lys109 (K109) of SEQ ID NO:39. In a further embodiment, an anti-C5 antibody of the present invention binds C5 and contacts amino acid Asp51 (D51) and amino acid Lys109 (K109) of SEQ ID NO:39.

[0134] In certain embodiments, binding of an anti-C5 antibody of the present invention to a C5 mutant is reduced compared to its binding to wild type C5, wherein the C5 mutant has a Glu48Ala (E48A) substitution of SEQ ID NO:39. In another embodiment, pH dependent binding of an anti-C5 antibody of the present invention to a C5 mutant is reduced compared to its pH-dependent binding to wild type C5, wherein the C5 mutant has a Glu48Ala (E48A) substitution of SEQ ID NO:39.

[0135] In a further embodiment, an anti-C5 antibody binds to a C5 protein consisting of the amino acid sequence of SEQ ID NO:39, but does not bind to a C5 protein consisting of the amino acid sequence of SEQ ID NO:39 with a H72Y substitution, wherein the C5 protein and the H72Y substituted C5 protein are prepared and screened under the same conditions. In a further embodiment, the anti-C5 antibody binds to a C5 protein consisting of the amino acid sequence of SEQ ID NO:39 at pH7.4, but does not bind to the H72Y substituted C5 protein at pH7.4.

[0136] Without being restricted to a particular theory, it can be speculated that the binding of an anti-C5 antibody to C5 is reduced (or almost lost) when an amino acid residue on C5 is substituted with another amino acid, which means that the amino acid residue on C5 is critical for the interactions between the anti-C5 antibody and C5, and that the antibody may recognize an epitope around the amino acid residue on C5.

[0137] It has been discovered in the present invention that a group of anti-C5 antibodies that compete with one another or bind to the same epitope can exhibit pH-dependent binding characteristics. Among amino acids, histidine, with a pKa value of ap proximately 6.0 to 6.5, can have different proton dissociation states between neutral and acidic pH. Therefore, a histidine residue on C5 can contribute to the pH-dependent interactions between an anti-C5 antibody and C5. Without being restricted to a particular theory, it can be speculated that an anti-C5 antibody may recognize a confor mational structure around a histidine residue on C5, which is variable depending on pH. That speculation can be consistent with the experimental results described below: that the pH-dependency of an anti-C5 antibody is reduced (or almost lost) when a histidine residue on C5 is substituted with another amino acid (i.e., an anti-C5 antibody with pH-dependent binding characteristics binds to a histidine mutant of C5 with similar affinity to wild type C5 at neutral pH, while the same antibody binds to the histidine mutant of C5 with higher affinity than wild type C5 at acidic pH).

[0138] In certain embodiments, an anti-C5 antibody of the present invention binds to C5 from more than one species. In further embodiments, the anti-C5 antibody binds to C5 from human and a non-human animal. In further embodiments, the anti-C5 antibody binds to C5 from human and monkey (e.g., cynomolgus, rhesus macaque, marmoset, chimpanzee, or baboon).

[0139] In one aspect, the invention provides anti-C5 antibodies that inhibit activation of C5. In certain embodiments, anti-C5 antibodies are provided which prevent the cleavage of C5 to form C5a and C5b, thus preventing the generation of anaphylatoxic activity as sociated with C5a, as well as preventing the assembly of the C5b-9 membrane attack complex (MAC) associated with C5b. In certain embodiments, anti-C5 antibodies are provided which block the conversion of C5 into C5a and C5b by C5 convertase. In certain embodiments, anti-C5 antibodies are provided which block access of the C5 convertase to the cleavage site on C5. In certain embodiments, anti-C5 antibodies are provided which block hemolytic activity caused by the activation of C5. In further em bodiments, anti-C5 antibodies of the present invention inhibit the activation of C5 via classical pathway and/or alternative pathway.

[0140] In one aspect, the invention provides anti-C5 antibodies that inhibit activation of a C5 variant. A C5 variant means a genetic variant of C5 which is due to genetic variation such as a mutation, polymorphism or allelic variation. A genetic variation may comprise a deletion, substitution or insertion of one or more nucleotides. A C5 variant may comprise one or more genetic variations in C5. In certain embodiments, the C5 variant has biological activity similar to wild type C5. Such C5 variant may comprise at least one variation selected from the group consisting of V145, R449G, V8021, R885H, R928Q, D966Y, S1310N, and E1437D. Herein, R885H, for example, means a genetic variation where arginine at position 885 is substituted by histidine. In certain embodiments, an anti-C5 antibody of the present invention inhibits activation of both wild type C5 and at least one C5 variant selected from the group consisting of V1451, R449G, V8021, R885H, R928Q, D966Y, S1310N, and E1437D.

[0141] In one aspect, the invention provides an anti-C5 antibody comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) a HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 45-54; (b) a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55-64; (c) a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65-74; (d) a HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-84; (e) a HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 85-94; and (f) a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95-104.

[0142] In one aspect, the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) a HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 45-54; (b) a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55-64; and (c) a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65-74. In one embodiment, the antibody comprises a HVR-H3 comprising the amino acid sequence of any one of SEQ

ID NOs: 65-74. In another embodiment, the antibody comprises a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65-74 and a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95-104. In a further embodiment, the antibody comprises a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65-74, a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95-104, and a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55-64. In a further embodiment, the antibody comprises (a) a HVR HI comprising the amino acid sequence of any one of SEQ ID NOs: 45-54; (b) a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55-64; and (c) a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65-74.

[0143] In another aspect, the invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) a HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-84; (b) a HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 85-94; and (c) a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95-104. In one embodiment, the antibody comprises (a) a HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-84; (b) a HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 85-94; and (c) a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95-104.

[0144] In another aspect, an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) a HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 45-54, (ii) a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55-64, and (iii) a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65-74; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) a HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-84, (ii) a HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 85-94, and (c) a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95-104.

[0145] In another aspect, the invention provides an antibody comprising (a) a HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 45-54; (b) a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55-64; (c) a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65-74; (d) a HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-84; (e) a HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 85-94; and (f) a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95-104.

[0146] In one aspect, the invention provides an anti-C5 antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) a HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 45, 54, 117, 126; (b) a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55, 64, 118-120, 127; (c) a HVR H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65, 74, 121, 128; (d) a HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 75, 84, 122, 129; (e) a HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 85, 94, 123-124, 130; and (f) a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95, 104, 125, 131.

[0147] In one aspect, the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) a HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 45, 54, 117, 126; (b) a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55, 64, 118-120, 127; and (c) a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65, 74, 121, 128. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65, 74, 121, 128. In another em bodiment, the antibody comprises a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65, 74, 121, 128 and a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95, 104, 125, 131. In a further embodiment, the antibody comprises a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65, 74, 121, 128, a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95, 104, 125, 131, and a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55, 64, 118-120, 127. In a further embodiment, the antibody comprises (a) a HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 45, 54, 117, 126; (b) a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55, 64, 118-120, 127; and (c) a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65, 74, 121, 128.

[0148] In another aspect, the invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) a HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 75, 84, 122, 129; (b) a HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 85, 94, 123-124, 130; and (c) a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95, 104, 125, 131. In one embodiment, the antibody comprises (a) a HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 75, 84, 122, 129; (b) a HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 85, 94, 123-124, 130; and (c) a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95, 104,125,131.

[0149] In another aspect, an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) a HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 45, 54,

117, 126, (ii) a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55, 64, 118-120, 127, and (iii) a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65, 74, 121, 128; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) a HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 75, 84, 122, 129, (ii) a HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 85, 94, 123-124, 130, and (c) a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95, 104, 125, 131.

[0150] In another aspect, the invention provides an antibody comprising (a) a HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 45, 54, 117, 126; (b) a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55, 64, 118-120, 127; (c) a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65, 74, 121, 128; (d) a HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 75, 84, 122, 129; (e) a HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 85, 94, 123-124, 130; and (f) a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95, 104, 125, 131.

[0151] In certain embodiments, any one or more amino acids of an anti-C5 antibody as provided above are substituted at the following HVR positions: (a) in HVR-H1 (SEQ ID NO: 45), at positions 5, and 6; (b) in HVR-H2 (SEQ ID NO: 55), at positions 1, 3, 9, 11, 13, and 15; (c) in HVR-H3 (SEQ ID NO: 65), at positions 2, 5, 6, 12, and 13; (d) in HVR-L1 (SEQ ID NO: 75), at positions 1, 5, 7, and 9; (e) in HVR-L2 (SEQ ID NO: 85), at positions 4, 5, and 6; and (f) in HVR-L3 (SEQ ID NO: 95), at positions 2, 4, and 12.

[0152] In certain embodiments, the substitutions are conservative substitutions, as provided herein. In certain embodiments, any one or more of the following substitutions may be made in any combination: (a) in HVR-H1 (SEQ ID NO: 45), M5V or C6A; (b) in HVR-H2 (SEQ ID NO: 55), CIA or G, Y3F, T9D or E, Y11K or Q, S13D or E, or A15V; (c) in HVR-H3 (SEQ ID NO: 65), G2A, V5Q or D, T6Y, Y12H, or L13Y; (d) in HVR-L1 (SEQ ID NO: 75), QIR, N5Q or G, G7S, D9K or S; (e) in HVR-L2 (SEQ ID NO: 85), K4T or E, L5T, or A6H, A6 E, or A6Q; (f) in HVR-L3 (SEQ ID NO: 95) C2S, C2N, or C2T, F4K; or A12T or A12H.

[0153] All possible combinations of the above substitutions are encompassed by the consensus sequences of SEQ ID NOs: 126, 127, 128, 129, 130, and 131 for HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3, respectively.

[0154] In any of the above embodiments, an anti-C5 antibody is humanized. In one em bodiment, an anti-C5 antibody comprises HVRs as 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 embodiment, an anti-C5 antibody comprises HVRs as in any of the above embodiments, and further comprises a VH or VL comprising an FR sequence, wherein the FR sequences are as follows. For the heavy chain variable domain, the FRI comprises the amino acid sequence of any one of SEQ ID NOs: 132-134, FR2 comprises the amino acid sequence of any one of SEQ ID NOs: 135-136, FR3 comprises the amino acid sequence of any one of SEQ ID NOs: 137-139, FR4 comprises the amino acid sequence of any one of SEQ ID NOs: 140-141. For the light chain variable domain, FRI comprises the amino acid sequence of any one of SEQ ID NOs: 142-143, FR2 comprises the amino acid sequence of any one of SEQ ID NOs: 144-145, FR3 comprises the amino acid sequence of any one of SEQ ID NOs: 146-147, FR4 comprises the amino acid sequence of SEQ ID NO: 148.

[0155] In another aspect, an anti-C5 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 1-10. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., con servative substitutions), insertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in any one of SEQ ID NOs: 1-10. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VH sequence in any one of SEQ ID NOs: 1-10, including post-translational modifications of that sequence. In a particular em bodiment, the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 45-54, (b) HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55-64, and (c) HVR H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65-74.

[0156] In another aspect, an anti-C5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains sub stitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in any one of SEQ ID NOs: 11-20. In certain em bodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VL sequence in any one of SEQ ID NOs: 11-20, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-84; (b) HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 85-94; and (c) HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95-104.

[0157] In another aspect, an anti-C5 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the em bodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in any one of SEQ ID NOs: 1-10 and any one of SEQ ID NOs: 11-20, respectively, including post-translational modifications of those sequences.

[0158] In another aspect, an anti-C5 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 10, 106-110. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in any one of SEQ ID NOs: 10, 106-110. In certain embodiments, sub stitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VH sequence in any one of SEQ ID NOs: 10, 106-110, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) a HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 45, 54, 117, 126, (b) a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55, 64, 118-120, 127, and (c) a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65, 74, 121, 128.

[0159] In another aspect, an anti-C5 antibody comprises a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 10, 106-110. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in any one of SEQ ID NOs: 10, 106-110. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VH sequence in any one of SEQ ID NOs: 10, 106-110, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) a HVR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 45, 54, 117, 126, (b) a HVR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 55, 64, 118-120, 127, and (c) a HVR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 65, 74, 121, 128.

[0160] In another aspect, an anti-C5 antibody comprises a VH sequence having 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:10. In certain embodiments, the VH sequence is the amino acid sequence of SEQ ID NO:10. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 10. In certain embodiments, sub stitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VH sequence in SEQ ID NO: 10 including post-translational modifications of that sequence. In a particular em bodiment, the VH comprises one, two or three HVRs selected from: (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 54, (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 64, and (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 74.

[0161] In another aspect, an anti-C5 antibody comprises a VH sequence having 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: 106. In certain embodiments, the VH sequence is the amino acid sequence of SEQ ID NO:106. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 106. In certain embodiments, sub stitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VH sequence in SEQ ID NO: 106, including post-translational modifications of that sequence. In a particular em bodiment, the VH comprises one, two or three HVRs selected from: (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117, (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118, and (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121.

[0162] In another aspect, an anti-C5 antibody comprises a VH sequence having 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: 107. In certain embodiments, the VH sequence is the amino acid sequence of SEQ ID NO:107. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 107. In certain embodiments, sub stitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VH sequence in SEQ ID NO: 107, including post-translational modifications of that sequence. In a particular em bodiment, the VH comprises one, two or three HVRs selected from: (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117 (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119, and (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121.

[0163] In another aspect, an anti-C5 antibody comprises a VH sequence having 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: 108. In certain embodiments, the VH sequence is the amino acid sequence of SEQ ID NO:108. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 108. In certain embodiments, sub stitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VH sequence in SEQ ID NO: 108, including post-translational modifications of that sequence. In a particular em bodiment, the VH comprises one, two or three HVRs selected from: (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117 (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118, and (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121.

[0164] In another aspect, an anti-C5 antibody comprises a VH sequence having 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: 109. In certain embodiments, the VH sequence is the amino acid sequence of SEQ ID NO:109. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 109. In certain embodiments, sub stitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VH sequence in SEQ ID NO: 109, including post-translational modifications of that sequence. In a particular em bodiment, the VH comprises one, two or three HVRs selected from: (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117 (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118, and (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121.

[0165] In another aspect, an anti-C5 antibody comprises a VH sequence having 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: 110. In certain embodiments, the VH sequence is the amino acid sequence of SEQ ID NO:110. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 110. In certain embodiments, sub stitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VH sequence in SEQ ID NO: 110, including post-translational modifications of that sequence. In a particular em bodiment, the VH comprises one, two or three HVRs selected from: (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117 (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120, and (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121.

[0166] In another aspect, an anti-C5 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 20, 111-113. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains sub stitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in any one of SEQ ID NOs: 20, 111-113. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VL sequence in any one of SEQ ID NOs: 20, 111-113, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) a HVR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 75, 84, 122, 129; (b) a HVR-L2 comprising the amino acid sequence of any one of SEQ ID NOs: 85, 94, 123-124, 130; and (c) a HVR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 95, 104, 125, 131.

[0167] In another aspect, an anti-C5 antibody is provided, wherein the antibody comprises a VL having 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: 20. In certain em bodiments, the VL sequence is the amino acid sequence of SEQ ID NO:20. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), in sertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 20. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VL sequence in SEQ ID NO: 20, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 84; (b) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 94; and (c) a HVR L3 comprising the amino acid sequence of SEQ ID NO: 104.

[0168] In another aspect, an anti-C5 antibody is provided, wherein the antibody comprises a VL having 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: 111. In certain em bodiments, the VL sequence is the amino acid sequence of SEQ ID NO:111. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), in sertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 111. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VL sequence in SEQ ID NO: 111, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (b) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (c) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

[0169] In another aspect, an anti-C5 antibody is provided, wherein the antibody comprises a VL having 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: 112. In certain em bodiments, the VL sequence is the amino acid sequence of SEQ ID NO:112. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), in sertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 112. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VL sequence in SEQ ID NO: 112, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (b) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (c) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

[0170] In another aspect, an anti-C5 antibody is provided, wherein the antibody comprises a VL having 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: 113. In certain em bodiments, the VL sequence is the amino acid sequence of SEQ ID NO:113. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), in sertions, or deletions relative to the reference sequence, but an anti-C5 antibody comprising that sequence retains the ability to bind to C5. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 113. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-C5 antibody comprises the VL sequence in SEQ ID NO: 113, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (b) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (c) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

[0171] In another aspect, an anti-C5 antibody is provided wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the em bodiments provided above. In one embodiment, the antibody comprises the VH and VL sequences in any one of SEQ ID NOs: 10, 106-110 and any one of SEQ ID NOs: 20, 111-113, respectively, including post-translational modifications of those sequences.In one embodiment, the antibody comprises a VH sequence of SEQ ID NO:10 and a VL sequence of SEQ ID NO: 20. In one embodiment, the antibody comprises a VH sequence of SEQ ID NO:106 and a VL sequence of SEQ ID NO: 111.

In another embodiment, the antibody comprises a VH sequence of SEQ ID NO:107 and a VL sequence of SEQ ID NO: 111. In an additional embodiment, the antibody comprises a VH sequence of SEQ ID NO:108 and a VL sequence of SEQ ID NO: 111. In another embodiment, the antibody comprises a VH sequence of SEQ ID NO:109 and a VL sequence of SEQ ID NO: 111. In another embodiment, the antibody comprises a VH sequence of SEQ ID NO:109 and a VL sequence of SEQ ID NO: 112. In another embodiment, the antibody comprises a VH sequence of SEQ ID NO:109 and a VL sequence of SEQ ID NO: 113. In another embodiment, the antibody comprises a VH sequence of SEQ ID NO:110 and a VL sequence of SEQ ID NO: 113.

[0172] In one aspect, an anti-C5 antibody is provided wherein the antibody comprises a VH sequence containing (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 54, (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 64, and (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 74, and a VL sequence containing (a) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 84; (b) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 94; and (c) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 104.

[0173] In another aspect, an anti-C5 antibody is provided wherein the antibody comprises a VH sequence containing (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117, (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118, and (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121, and a VL sequence containing (a) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (b) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (c) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

[0174] In another aspect, an anti-C5 antibody is provided wherein the antibody comprises a VH sequence containing (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117, (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119, and (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121, and a VL sequence containing (a) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (b) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (c) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

[0175] In another aspect, an anti-C5 antibody is provided wherein the antibody comprises a VH sequence containing (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117, (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118, and (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121, and a VL sequence containing (a) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (b) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (c) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

[0176] In another aspect, an anti-C5 antibody is provided wherein the antibody comprises a

VH sequence containing (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117, (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120, and (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121, and a VL sequence containing (a) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (b) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (c) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

[0177] In certain embodiments, an anti-C5 antibody of the present invention comprises a VH as in any of the embodiments provided above and a heavy chain constant region comprising the amino acid sequence of any one of SEQ ID NOs: 33, 34, 35, 114, 115, and 116. In certain embodiments, an anti-C5 antibody of the present invention comprises a VL as in any of the embodiments provided above and a light chain constant region comprising the amino acid sequence of any one of SEQ ID NOs: 36, 37, and 38.

[0178] In another aspect, the invention provides an antibody that binds to the same epitope as an anti-C5 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an antibody described in Table 2. As demonstrated by the working examples below, all the anti-C5 antibodies described in Table 2 are grouped into the same epitope bin of C5 and exhibit pH dependent binding characteristics.

[0179] In an additional aspect, the invention provides an antibody that binds to the same epitope as an antibody provided herein. In a further aspect, the invention provides an antibody that binds to the same epitope as an antibody described in Tables 7 or 8. In certain embodiments, an antibody is provided that binds to an epitope within a fragment consisting of amino acids 33-124 of the beta chain of C5 (SEQ ID NO: 40). In certain embodiments, an antibody is provided that binds to an epitope within the beta chain of C5 (SEQ ID NO: 40) which comprises at least one fragment selected from the group consisting of amino acids 47-57, 70-76, and 107-110. In certain em bodiments, an antibody is provided that binds to an epitope within a fragment of the beta chain of C5 (SEQ ID NO: 40) which comprises at least one amino acid selected from the group consisting of Thr47, Glu48, Ala49, Phe50, Asp51, Ala52, Thr53, Lys57, His70, Val71, His72, Ser74, Glu76, Val107, Ser1O8, Lys109, and His110. In another embodiment, an epitope of an anti-C5 antibody of the present invention is a conformational epitope.

[0180] In a further aspect of the invention, an anti-C5 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-C5 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab') 2 fragment. In another embodiment, the antibody is a full length antibody, e.g., an intact IgG Ior IgG4 antibody or other antibody class or isotype as defined herein.

[0181] In a further aspect, an anti-C5 antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described in Sections 1-7 below:

[0182] 1. Antibody Affinity In certain embodiments, an antibody provided herein has a dissociation constant (Kd) of 1 micro M or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10-1 M or less, e.g., from 10-1 M to 10-13 M, e.g., from 10- M to 10-13 M).

[0183] In one embodiment, Kd is measured by a radiolabeled antigen binding assay (RIA). In one embodiment, an RIA is performed with the Fab version of an antibody of interest and its antigen. For example, solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of ( 125 I)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol. 293:865-881(1999)). To establish conditions for the assay, MICROTITER (registered trademark) multi-well plates (Thermo Scientific) are coated overnight with 5 micro g/ ml of a capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23 degrees C). In a non-adsorbent plate (Nunc #269620), 100 pM or 26 pM [ 125 I]-antigen are mixed with serial dilutions of a Fab of interest (e.g., consistent with assessment of the anti-VEGF antibody, Fab-12, in Presta et al., Cancer Res. 57:4593-4599 (1997)). The Fab of interest is then incubated overnight; however, the incubation may continue for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate washed eight times with 0.1% polysorbate 20 (TWEEN-20 (registered trademark)) in PBS. When the plates have dried, 150 micro 1/ well of scintillant (MICROSCINT-20TM; Packard) is added, and the plates are counted onaTOPCOUNT TM gamma counter (Packard) for ten minutes. Concentrations of each Fab that give less than or equal to 20% of maximal binding are chosen for use in com petitive binding assays.

[0184] According to another embodiment, Kd is measured using a BIACORE (registered trademark) surface plasmon resonance assay. For example, an assay using a BIACORE (registered trademark)-2000 or a BIACORE (registered trademark)-3000 (BIACORE (registered trademark), Inc., Piscataway, NJ) is performed at 25 degrees C with im mobilized antigen CM5 chips at -10 response units (RU). In one embodiment, car boxymethylated dextran biosensor chips (CM5, BIACORE (registered trademark),

Inc.) are activated with N-ethyl-N'- (3-dimethylaminopropyl)-carbodiimide hy drochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's in structions. Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 micro g/ml (-0.2 micro M) before injection at a flow rate of 5 micro /minute to achieve ap proximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics mea surements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20 TM) surfactant (PBST) at 25 degrees C at a flow rate of approximately 25 micro1/minute. Association rates (k,) and dissociation rates (kff) are calculated using a simple one-to-one Langmuir binding model (BIACORE (registered trademark) Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams. The equilibrium dissociation constant (Kd) is calculated as the ratio kff/k 0a. See, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999). If the on-rate exceeds 106 M- s-1 by the surface plasmon resonance assay above, then the on-rate can be determined by using a fluorescent quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm band-pass) at 25 degrees C of a 20 nM anti-antigen antibody (Fab form) in PBS, pH 7.2, in the presence of in creasing concentrations of antigen as measured in a spectrometer, such as a stop-flow equipped spectrophotometer (Aviv Instruments) or a 8000-series SLM-AMINCO TM

spectrophotometer (ThermoSpectronic) with a stirred cuvette.

[0185] 2. Antibody Fragments In certain embodiments, an antibody provided herein is an antibody fragment. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab') 2, Fv, and scFv fragments, and other fragments described below. For a review of certain antibody fragments, see Hudson et al., Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93/16185; and US Patent Nos. 5,571,894 and 5,587,458. For discussion of Fab and F(ab') 2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see US Patent No. 5,869,046.

[0186] Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

[0187] Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., US Patent No. 6,248,516).

[0188] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage), as described herein.

[0189] 3. Chimeric and Humanized Antibodies In certain embodiments, an antibody provided herein is a chimeric antibody. Certain chimeric antibodies are described, e.g., in US Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a "class switched" antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

[0190] In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs, e.g., CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corre sponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0191] Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described, e.g., in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); US Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity de termining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing "resurfacing"); Dall'Acqua et al., Methods 36:43-60 (2005) (describing "FR shuffling"); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer 83:252-260 (2000) (describing the "guided selection" approach to FR shuffling).

[0192] Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the "best-fit" method (see, e.g., Sims et al., J. Immunol. 151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al., Proc. Natl. Acad. Sci. USA 89:4285 (1992); and Presta et al., J. Immunol. 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)).

[0193] 4. Human Antibodies In certain embodiments, an antibody provided herein is a human antibody. Human antibodies can be produced using various techniques known in the art. Human an tibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharma. 5:368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

[0194] Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the en dogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal's chromosomes. In such transgenic mice, the endogenous im munoglobulin loci have generally been inactivated. For review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, e.g., US Patent Nos. 6,075,181 and 6,150,584 de scribing XENOMOUSE TM technology; US Patent No. 5,770,429 describing HUMAB (registered trademark) technology; US Patent No. 7,041,870 describing K-M MOUSE (registered trademark) technology, and US Patent Application Publication No. US 2007/0061900, describing VELOCIMOUSE (registered trademark) technology). Human variable regions from intact antibodies generated by such animals may be further modified, e.g., by combining with a different human constant region.

[0195] Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor, J. Immunol. 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol. 147:86 (1991).) Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA 103:3557-3562 (2006). Additional methods include those described, for example, in US Patent No. 7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (Trioma technology) is also described in Vollmers, Histology and Histopathology 20(3):927-937 (2005) and Vollmers, Methods and

Findings in Experimental and Clinical Pharmacology 27(3):185-191 (2005).

[0196] Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.

[0197] 5. Library-Derived Antibodies Antibodies of the invention may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are reviewed, e.g., in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001) and further described, e.g., in McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Marks, Meth.Mol. Biol. 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al., J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004).

[0198] In certain phage display methods, repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol. 12:433-455 (1994). Phage typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments. Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas. Alternatively, the naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self antigens without any immunization as described by Griffiths et al., EMBO J, 12:725-734 (1993). Finally, naive libraries can also be made syn thetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom, J. Mol. Biol. 227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example: US Patent No. 5,750,373, and US Publ.Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.

[0199] Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.

[0200] 6. Multispecific Antibodies

In certain embodiments, an antibody provided herein is a multispecific antibody, e.g., a bispecific antibody. Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites. In certain embodiments, one of the binding specificities is for C5 and the other is for any other antigen. In certain em bodiments, bispecific antibodies may bind to two different epitopes of C5. Bispecific antibodies may also be used to localize cytotoxic agents to cells which express C5. Bispecific antibodies can be prepared as full length antibodies or antibody fragments.

[0201] Techniques for making multispecific antibodies include, but are not limited to, re combinant co-expression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, Nature 305:537 (1983)), WO 93/08829, and Traunecker et al., EMBO J. 10:3655 (1991)), and "knob-in-hole" engineering (see, e.g., US Patent No. 5,731,168). Multi-specific antibodies may also be made by en gineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (W02009/089004A1); cross-linking two or more antibodies or fragments (see, e.g., US Patent No. 4,676,980, and Brennan et al., Science 229:81 (1985)); using leucine zippers to produce bi-specific antibodies (see, e.g., Kostelny et al., J. Immunol. 148(5):1547-1553 (1992)); using "diabody" technology for making bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993)); and using single-chain Fv (scFv) dimers (see, e.g., Gruber et al., J. Immunol. 152:5368 (1994)); and preparing trispecific antibodies as described, e.g., in Tutt et al., J. Immunol. 147:60 (1991).

[0202] Engineered antibodies with three or more functional antigen binding sites, including "Octopus antibodies," are also included herein (see, e.g., US 2006/0025576).

[0203] The antibody or fragment herein also includes a "Dual Acting FAb" or "DAF" comprising an antigen binding site that binds to C5 as well as another, different antigen (see, US2008/0069820, for example).

[0204] 7. Antibody Variants In certain embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modi fications include, for example, deletions from, and/or insertions into and/or sub stitutions of residues within the amino acid sequences of the antibody. Any com bination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding.

[0205] a. Substitution, Insertion, and Deletion Variants

In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the HVRs and FRs. Conservative substitutions are shown in Table 1 under the heading of "preferred substitutions." More substantial changes are provided in Table 1 under the heading of "exemplary substitutions," and as further described below in reference to amino acid side chain classes. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.

[Table 1] Original Exemplary Preferred Residue Substitutions Substitutions Ala (A) Val; Leu; Ile Val Arg (R) Lys; Gln; Asn Lys Asn (N) Gin; His; Asp, Lys; Arg Gin Asp (D) Glu; Asn Glu Cys (C) Ser; Ala Ser Gln (Q) Asn; Glu Asn Glu (E) Asp; Gin Asp Gly (G) Ala Ala His (H) Asn; Gin; Lys; Arg Arg Ile (I) Leu; Val; Met; Ala; Phe; Norleucine Leu Leu (L) Norleucine; Ile; Val; Met; Ala; Phe Ile Lys (K) Arg; Gin; Asn Arg Met (M) Leu; Phe; Ile Leu Phe (F) Trp; Leu; Val; Ile; Ala; Tyr Tyr Pro (P) Ala Ala Ser(S) Thr Thr Thr (T) Val; Ser Ser Trp (W) Tyr; Phe Tyr Tyr (Y) Trp; Phe; Thr; Ser Phe Val (V) Ile; Leu; Met; Phe; Ala; Norleucine Leu

[0206] Amino acids may be grouped according to common side-chain properties: (1) hy drophobic: 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 influence chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.

[0207] Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

[0208] One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have modifications (e.g., im provements) in certain biological properties (e.g., increased affinity, reduced immuno- genicity) relative to the parent antibody and/or will have substantially retained certain biological properties of the parent antibody. An exemplary substitutional variant is an affinity matured antibody, which may be conveniently generated, e.g., using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and the variant antibodies displayed on phage and screened for a particular biological activity (e.g., binding affinity).

[0209] Alterations (e.g., substitutions) may be made in HVRs, e.g., to improve antibody affinity. Such alterations may be made in HVR "hotspots," i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or residues that contact antigen, with the resulting variant VH or VL being tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al., in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001).) In some embodiments of affinity maturation, diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method to introduce diversity involves HVR-directed approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mu tagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.

[0210] In certain embodiments, substitutions, insertions, or deletions may occur within one or more HVRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative alterations (e.g., conservative sub stitutions as provided herein) that do not substantially reduce binding affinity may be made in HVRs. Such alterations may, for example, be outside of antigen contacting residues in the HVRs. In certain embodiments of the variant VH and VL sequences provided above, each HVR either is unaltered, or contains no more than one, two or three amino acid substitutions.

[0211] A useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called "alanine scanning mutagenesis" as described by Cunningham, Science 244:1081-1085 (1989). In this method, a residue or group of target residues (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with antigen is affected. Further substitutions may be introduced at the amino acid locations demon strating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of an antigen-antibody complex to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties.

[0212] Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antibody.

[0213] b. Glycosylation variants In certain embodiments, an antibody provided herein is altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of gly cosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

[0214] Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al., TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in an antibody of the invention may be made in order to create antibody variants with certain improved properties.

[0215] In one embodiment, antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e. g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in W02008/077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (Eu numbering of Fc region residues); however, Asn297 may also be located about +/- 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g.,

US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to "defucosylated" or "fucose-deficient" antibody variants 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; WO 2005/053742; WO 2002/031140; Okazaki et al., J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al., Biotech. Bioeng. 87:614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells deficient in protein fu cosylation (Ripka et al., Arch. Biochem. Biophys. 249:533-545 (1986); US 2003/0157108, Presta, L; and W02004/056312, Adams et al., especially at Example 11), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al., Biotech. Bioeng. 87:614 (2004); Kanda et al., Biotechnol. Bioeng. 94(4):680-688 (2006); and W02003/085107).

[0216] Antibodies variants are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003/011878 (Jean-Mairet et al.); US Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).

[0217] c. Fc region variants In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g., a substitution) at one or more amino acid positions.

[0218] In certain embodiments, the invention contemplates an antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half life of the antibody in vivo is important yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/ depletion of CDC and/or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks Fc gamma R binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express Fe gamma RIII only, whereas monocytes express Fe gamma RI, Fe gamma RII and Fe gamma RIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in US Patent No. 5,500,362 (see, e.g., Hellstrom et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); US Pat. No. 5,821,337 (see Bruggemann et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-ra dioactive assays methods may be employed (see, for example, ACTIT non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA); and CytoTox 96 (registered trademark) non-radioactive cytotoxicity assay (Promega, Madison, WI)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or addi tionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al., Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). Clq binding assays may also be carried out to confirm that the antibody is unable to bind Clq and hence lacks CDC activity. See, e.g., Clq and C3c binding ELISA in W02006/029879 and W02005/100402. To assess complement ac tivation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg et al., Blood 101:1045-1052 (2003); and Cragg et al., Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half life determinations can also be performed using methods known in the art (see, e.g., Petkova et al., Int'l. Immunol. 18(12):1759-1769 (2006)).

[0219] Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (US Patent No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called "DANA" Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581).

[0220] Certain antibody variants with improved or diminished binding to FcRs are described. (See, e.g., US Patent No. 6,737,056; WO 2004/056312, and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).)

[0221] In certain embodiments, an antibody variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).

[0222] In some embodiments, alterations are made in the Fc region that result in altered (i.e., either improved or diminished) Cl binding and/or Complement Dependent Cyto toxicity (CDC), e.g., as described in US Patent No. 6,194,551, WO1999/51642, and Idusogie et al., J. Immunol. 164:4178-4184 (2000).

[0223] Antibodies with increased half lives and improved binding to the neonatal Fc 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)), are described in US2005/0014934 (Hinton et al.). Those antibodies comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (US Patent No. 7,371,826).

[0224] See also Duncan, Nature 322:738-40 (1988); US Patent No. 5,648,260; US Patent No. 5,624,821; and WO 1994/29351 concerning other examples of Fc region variants.

[0225] d. Cysteine engineered antibody variants In certain embodiments, it may be desirable to create cysteine engineered antibodies, e.g., "thioMAbs," in which one or more residues of an antibody are substituted with cysteine residues. In particular embodiments, the substituted residues occur at ac cessible sites of the antibody. By substituting those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further herein. In certain em bodiments, any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain; Al18 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine engineered an tibodies may be generated as described, e.g., in US Patent No. 7,521,541.

[0226] e. Antibody Derivatives In certain embodiments, an antibody provided herein may be further modified to contain additional nonproteinaceous moieties that are known in the art and readily available. The moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1, 3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, polypropylene glycol ho mopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc.

[0227] In another embodiment, conjugates of an antibody and nonproteinaceous moiety that may be selectively heated by exposure to radiation are provided. In one embodiment, the nonproteinaceous moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102:11600-11605 (2005)). The radiation may be of any wavelength, and includes, but is not limited to, wavelengths that do not harm ordinary cells, but which heat the nonproteinaceous moiety to a temperature at which cells proximal to the antibody-nonproteinaceous moiety are killed.

[0228] B. Recombinant Methods and Compositions Antibodies may be produced using recombinant methods and compositions, e.g., as described in US Patent No. 4,816,567. In one embodiment, isolated nucleic acid encoding an anti-C5 antibody described herein is provided. Such nucleic acid may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody (e.g., the light and/or heavy chains of the antibody). In a further embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acid are provided. In a further embodiment, a host cell comprising such nucleic acid is provided. In one such embodiment, a host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is eukaryotic, e.g., a Chinese Hamster Ovary (CHO) cell or lymphoid cell (e.g., YO, NSO, Sp20 cell). In one embodiment, a method of making an anti-C5 antibody is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally re covering the antibody from the host cell (or host cell culture medium).

[0229] For recombinant production of an anti-C5 antibody, nucleic acid encoding an antibody, e.g., as described above, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).

[0230] Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed. For expression of antibody fragments and polypeptides in bacteria, see, e.g., US Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, describing expression of antibody fragments in E. coli.) After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.

[0231] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been "humanized," resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).

[0232] Suitable host cells for the expression of glycosylated antibody are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

[0233] Plant cell cultures can also be utilized as hosts. See, e.g., US Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES TM technology for producing antibodies in transgenic plants).

[0234] Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as YO, NSO and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248

(B.K.C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

[0235] Polyclonal antibodies are preferably raised in animals by multiple subcutaneous (sc) or intraperitoneal (ip) injections of the relevant antigen and an adjuvant. It may be useful to conjugate the relevant antigen to a protein that is immunogenic in the species to be immunized, e.g., keyhole limpet hemocyanin, serum albumin, bovine thy roglobulin, or soybean trypsin inhibitor using a bifunctional or derivatizing agent, for example, maleimidobenzoyl sulfosuccinimide ester (conjugation through cysteine residues), N-hydroxysuccinimide (through lysine residues), glutaraldehyde, succinic anhydride, SOCl 2 , or RIN=C=NR, where R and R1 are different alkyl groups.

[0236] Animals (usually non-human mammals) are immunized against the antigen, im munogenic conjugates, or derivatives by combining, e.g., 100 micro g or 5 micro g of the protein or conjugate (for rabbits or mice, respectively) with 3 volumes of Freund's complete adjuvant and injecting the solution intradermally at multiple sites. One month later the animals are boosted with 1/5 to 1/10 the original amount of peptide or conjugate in Freund's complete adjuvant by subcutaneous injection at multiple sites. Seven to 14 days later the animals are bled and the serum is assayed for antibody titer. Animals are boosted until the titer plateaus. Preferably, the animal is boosted with the conjugate of the same antigen, but conjugated to a different protein and/or through a different cross-linking reagent. Conjugates also can be made in recombinant cell culture as protein fusions. Also, aggregating agents such as alum are suitably used to enhance the immune response.

[0237] Monoclonal antibodies are obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and/or post-translational modifications (e.g., isomerizations, amidations) that may be present in minor amounts. Thus, the modifier "monoclonal" indicates the character of the antibody as not being a mixture of discrete antibodies.

[0238] For example, the monoclonal antibodies may be made using the hybridoma method first described by Kohler et al. Nature 256(5517):495-497 (1975). In the hybridoma method, a mouse or other appropriate host animal, such as a hamster, is immunized as hereinabove described to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization. Alter natively, lymphocytes may be immunized in vitro.

[0239] The immunizing agent will typically include the antigenic protein or a fusion variant thereof. Generally either peripheral blood lymphocytes (PBLs) are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press (1986), pp. 59-103).

[0240] Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells thus prepared are seeded and grown in a suitable 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 phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which are substances that prevent the growth of HGPRT-deficient cells.

[0241] Preferred immortalized myeloma cells are those that fuse efficiently, support stable high-level production of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. Among these, preferred 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 cells (and derivatives thereof, e.g., X63-Ag8-653) available from the American Type Culture Collection, Manassas, Virginia USA. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor et al., J Immunol. 133(6):3001-3005 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York (1987), pp. 51-63).

[0242] Culture medium in which hybridoma cells are growing is assayed for production of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of monoclonal antibodies produced by hybridoma cells is determined by immunopre cipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme linked immunosorbent assay (ELISA). Such techniques and assays are known in the art. For example, binding affinity may be determined by the Scatchard analysis of Munson, Anal Biochem. 107(1):220-239 (1980).

[0243] After hybridoma cells are identified that produce antibodies of the desired specificity, affinity, and/or activity, the clones may be subcloned by limiting dilution procedures and grown by standard methods (Goding, supra). Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640 medium. In addition, the hybridoma cells may be grown in vivo as tumors in a mammal.

[0244] 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, hydroxyapatite chro matography, gel electrophoresis, dialysis, or affinity chromatography.

[0245] Antibodies may be produced by immunizing an appropriate host animal against an antigen. In one embodiment, the antigen is a polypeptide comprising a full-length C5. In one embodiment, the antigen is a polypeptide comprising the beta chain (SEQ ID NO: 40) of C5. In one embodiment, the antigen is a polypeptide comprising the MG1-MG2 domain (SEQ ID NO: 43) of the beta chain of C5. In one embodiment, the antigen is a polypeptide comprising the MG1 domain (SEQ ID NO: 41) of the beta chain of C5. In one embodiment, the antigen is a polypeptide comprising the region corresponding to the amino acids at positions 19 to 180 of the beta chain of C5. In one embodiment, the antigen is a polypeptide comprising the region corresponding to the amino acids at positions 33 to 124 of the beta chain of C5. In one embodiment, the antigen is a polypeptide comprising at least one fragment selected from amino acids 47-57, 70-76, and 107-110 of the beta chain (SEQ ID NO: 40) of C5. In one em bodiment, the antigen is a polypeptide comprising a fragment of the beta chain of C5 which comprises at least one amino acid selected from the group consisting of Thr47, Glu48, Ala49, Phe50, Asp5l, Ala52, Thr53, Lys57, His70, Val71, His72, Ser74, Glu76, Val107, Ser108, Lys109, and His110. In one embodiment, the antigen is a polypeptide comprising a fragment of the beta chain of C5 which comprises at least one amino acid selected from the group consisting of Glu48, Asp51, His70, His72, Lys109, and His110. Also included in the present invention are antibodies produced by immunizing an animal against the antigen. The antibodies may incorporate any of the features, singly or in combination, as described in "Exemplary Anti-C5 Antibodies" above.

[0246] C. Assays Anti-C5 antibodies provided herein may be identified, screened for, or characterized for their physical/chemical properties and/or biological activities by various assays known in the art.

[0247] 1. Binding assays and other assays In one aspect, an antibody of the invention is tested for its antigen binding activity, e.g., by known methods such as ELISA, Western blot, BIACORE (registered trademark), etc.

[0248] In another aspect, competition assays may be used to identify an antibody that competes for binding to C5 with an anti-C5 antibody described herein. In certain em bodiments, when such a competing antibody is present in excess, it blocks (e.g., reduces) the binding of a reference antibody to C5 by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more. In some instances, binding is inhibited by at least 80%, 85%, 90%, 95%, or more. In certain embodiments, such a competing antibody binds to the same epitope (e.g., a linear or a conformational epitope) that is bound by an anti-C5 antibody described herein (e.g., an anti-C5 antibody described in Table 2). Detailed exemplary methods for mapping an epitope to which an antibody binds are provided in Morris, "Epitope Mapping Protocols," in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, NJ) (1996).

[0249] In an exemplary competition assay, immobilized C5 is incubated in a solution comprising a first labeled (reference) antibody that binds to C5 and a second unlabeled antibody that is being tested for its ability to compete with the first antibody for binding to C5. The second antibody may be present in a hybridoma supernatant. As a control, immobilized C5 is incubated in a solution comprising the first labeled antibody but not the second unlabeled antibody. After incubation under conditions permissive for binding of the first antibody to C5, excess unbound antibody is removed, and the amount of label associated with immobilized C5 is measured. If the amount of label associated with immobilized C5 is substantially reduced in the test sample relative to the control sample, then that indicates that the second antibody is competing with the first antibody for binding to C5. See, Harlow and Lane, An tibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY) (1988).

[0250] In another exemplary competition assay, BIACORE (registered trademark) analysis is used to determine the ability of a test anti-C5 antibody to compete with the binding to C5 by a second (reference) anti-C5 antibody. In a further aspect in which a BIACORE (registered trademark) instrument (for example, the BIACORE (registered trademark) 3000) is operated according to the manufacturer's recommendations, C5 protein is captured on a CM5 BIACORE (registered trademark) chip using a standard technique known in the art to generate a C5-coated surface. Typically 200-800 resonance units of C5 would be coupled to the chip (an amount that gives easily measurable levels of binding but that is readily saturable by the concentrations of test antibody being used). The two antibodies (i.e., the test and reference antibody) to be assessed for their ability to compete with each other are mixed at a 1:1 molar ratio of binding sites in a suitable buffer to create a test mixture. When calculating the concen trations on a binding site basis the molecular weight of an a test or reference antibody is assumed to be the total molecular weight of the corresponding antibody divided by the number of C5-binding sites on the antibody. The concentration of each antibody (i.e., test and reference antibody) in the test mixture should be high enough to readily saturate the binding sites for that antibody on the C5 molecules captured on the BIACORE (registered trademark) chip. The test and reference antibodies in the mixture are at the same molar concentration (on a binding basis), typically between 1.00 and 1.5 micromolar (on a binding site basis). Separate solutions containing the test antibody alone and the reference antibody alone are also prepared. Test antibody and reference antibody in these solutions should be in the same buffer and at the same concentration and conditions as in the test mixture. The test mixture containing the test antibody and reference antibody is passed over the C5-coated BIACORE (registered trademark) chip and the total amount of binding is recorded. The chip is then treated in such a way as to remove the bound test or reference antibody without damaging the chip-bound C5. Typically, this is done by treating the chip with 30 mM HC1 for 60 seconds. The solution of test antibody alone is then passed over the C5-coated surface and the amount of binding recorded. The chip is again treated to remove all of the bound antibody without damaging the chip-bound C5. The solution of reference antibody alone is then passed over the C5-coated surface and the amount of binding recorded. The maximum theoretical binding of the mixture of test antibody and reference antibody is next calculated, and is the sum of the binding of each antibody (i.e. test and reference) when passed over the C5 surface alone. If the actual recorded binding of the mixture is less than this theoretical maximum then test antibody and reference antibody are competing with each other for binding C5. Thus, in general, a competing test anti-C5 antibody is one which will bind to C5 in the above BIACORE (registered trademark) blocking assay such that during the assay and in the presence of the reference anti-C5 antibody the recorded binding is between 80% and 0.1% (e.g., 80% > to 4%) of the maximum theoretical binding, specifically between 75% and 0.1 % (e.g., 75% to 4%) of the maximum theoretical binding, and more specifically between 70% and 0.1% (e.g., 70% to 4%) of maximum theoretical binding (as defined above) of the test antibody and reference antibody in combination.

[0251] In certain embodiments, an anti-C5 antibody of the present invention competes for binding C5 with an antibody comprising a VH and VL pair selected from antibody CFA0341 and CFA0330. In some embodiments, an anti-C5 antibody competes for binding C5 with an antibody selected from: CFA0538, CFA0501, CFA0599, CFA0307, CFA0366, CFA0675, and CFA0672. In some embodiments, an anti-C5 antibody competes for binding C5 with antibody CFA0329. In some embodiments, an anti-C5 antibody competes for binding C5 with antibody CFA0666.

[0252] In certain embodiments, an anti-C5 antibody of the present invention competes for binding C5 with an antibody comprising a VH and VL pair of antibody CFA0305 or 305LO5.

[0253] In further embodiments, the anti-C5 antibody binds to C5 with a higher affinity at neutral pH than at acidic pH. In certain embodiments, an anti-C5 antibody of the present invention competes for binding C5 with an antibody comprising a VH and VL pair selected from: CFA0538, CFA0501, CFA0599, CFA0307, CFA0366, CFA0675, and CFA0672. In some embodiments, an anti-C5 antibody competes for binding C5 with antibody CFA0666. In further embodiments, the anti-C5 antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8.

[0254] In further embodiments, the anti-C5 antibody binds to C5 with a higher affinity at neutral pH than at acidic pH. In certain embodiments, an anti-C5 antibody of the present invention competes for binding C5 with an antibody comprising a VH and VL pair of antibody CFA0305 or 305LO5. In further embodiments, the anti-C5 antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8.

[0255] In certain embodiments, an anti-C5 antibody of the present invention competes for binding C5 with an antibody comprising a VH and VL pair selected from a VH of SEQ ID NO:22 and a VL of SEQ ID NO:26, or a VH of SEQ ID NO:21 and a VL of SEQ ID NO:25. In some embodiments, an anti-C5 antibody competes for binding C5 with an antibody comprising a VH and VL pair selected from: (a) a VH of SEQ ID NO: 5 and a VL of SEQ ID NO: 15; (b) a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 14; (c) a VH of SEQ ID NO:6 and a VL of SEQ ID NO:16; (d) aVH of SEQ ID NO:2 and a VL of SEQ ID NO:12; (e) a VH of SEQ ID NO: 3 and a VL of SEQ ID NO: 13; (f) a VH of SEQ ID NO: 1 and a VL of SEQ ID NO: 11; (g) a VH of SEQ ID NO:9 and a VL of SEQ ID NO:19; (h) aVH of SEQ ID NO:7 and a VL of SEQ ID NO:17; and (i) aVH of SEQ ID NO:8 and a VL of SEQ ID NO:18. In some embodiments, an anti-C5 antibody competes for binding C5 with antibody comprising a VH of SEQ ID NO:23 and a VL of SEQ ID NO:27. In some embodiments, an anti-C5 antibody competes for binding C5 with antibody comprising a VH of SEQ ID NO:7 and a VL of SEQ ID NO:17.

[0256] In certain embodiments, an anti-C5 antibody of the present invention competes for binding C5 with an antibody comprising a VH and VL pair selected from: (a) a VH of SEQ ID NO:1 and a VL of SEQ ID NO:11; (b) a VH of SEQ ID NO: 22 and a VL of SEQ ID NO:26; (c) a VH of SEQ ID NO:21 and a VL of SEQ ID NO:25; (d) a VH of SEQ ID NO: 5 and a VL of SEQ ID NO:15; (e) a VH of SEQ ID NO:4 and a VL of SEQ ID NO:14; (f) a VH of SEQ ID NO: 6 and a VL of SEQ ID NO: 16; (g) a VH of SEQ ID NO:2 and a VL of SEQ ID NO:12; (h) a VH of SEQ ID NO: 3 and a VL of SEQ ID NO: 13; (i) a VH of SEQ ID NO:9 and a VL of SEQ ID NO:19; (j) a VH of SEQ ID NO:7 and a VL of SEQ ID NO: 17; (k) aVH of SEQ ID NO:8 and a VL of SEQ ID NO:18; (1) a VH of SEQ ID NO: 23 and a VL of SEQ ID NO:27; and (m) a VH of SEQ ID NO:10 and a VL of SEQ ID NO:20.

[0257] In certain embodiments, an anti-C5 antibody of the present invention competes for binding C5 with an antibody comprising a VH and VL pair selected from: (a) a VH of SEQ ID NO: 22 and a VL of SEQ ID NO:26; (b) a VH of SEQ ID NO:21 and a VL of SEQ ID NO:25; (c) a VH of SEQ ID NO: 5 and a VL of SEQ ID NO:15; (d) a VH of SEQ ID NO:4 and a VL of SEQ ID NO:14; (e) a VH of SEQ ID NO: 6 and a VL of SEQ ID NO: 16; (f) a VH of SEQ ID NO:2 and a VL of SEQ ID NO:12; (g) a VH of SEQ ID NO: 3 and a VL of SEQ ID NO: 13; (h) a VH of SEQ ID NO:9 and a VL of

SEQ ID NO:19; (i) a VH of SEQ ID NO:7 and a VL of SEQ ID NO: 17; (j) aVH of SEQ ID NO:8 and a VL of SEQ ID NO:18; (k) a VH of SEQ ID NO: 23 and a VL of SEQ ID NO:27.

[0258] In certain embodiments, an anti-C5 antibody of the present invention competes for binding C5 with an antibody comprising a VH and VL pair selected from a VH of SEQ ID NO:1 and a VL of SEQ ID NO:11, or a VH of SEQ ID NO:10 and a VL of SEQ ID NO:20.

[0259] In further embodiments, the anti-C5 antibody binds to C5 with a higher affinity at neutral pH than at acidic pH. In certain embodiments, an anti-C5 antibody binds to C5 with a higher affinity at neutral pH than at acidic pH and competes for binding C5 with an antibody comprising a VH and VL pair selected from: (a) a VH of SEQ ID NO:1 and a VL of SEQ ID NO:11; (b) a VH of SEQ ID NO: 5 and a VL of SEQ ID NO:15; (c) a VH of SEQ ID NO:4 and a VL of SEQ ID NO:14; (d) a VH of SEQ ID NO: 6 and a VL of SEQ ID NO: 16; (e) a VH of SEQ ID NO:2 and a VL of SEQ ID NO:12; (f) a VH of SEQ ID NO: 3 and a VL of SEQ ID NO: 13; (g) a VH of SEQ ID NO:9 and a VL of SEQ ID NO:19; (h) a VH of SEQ ID NO:7 and a VL of SEQ ID NO: 17; (i) aVH of SEQ ID NO:8 and a VL of SEQ ID NO:18; and (j) a VH of SEQ ID NO:10 and a VL of SEQ ID NO:20. In further embodiments, the anti-C5 antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8.

[0260] In some embodiments, the anti-C5 antibody binds to C5 with a higher affinity at neutral pH than at acidic pH and competes for binding C5 with an antibody comprising a VH and VL pair selected from: (a) a VH of SEQ ID NO: 5 and a VL of SEQ ID NO: 15; (b) a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 14; (c) a VH of SEQ ID NO:6 and a VL of SEQ ID NO:16; (d) aVH of SEQ ID NO:2 and a VL of SEQ ID NO:12; (e) a VH of SEQ ID NO: 3 and a VL of SEQ ID NO: 13; (f) a VH of SEQ ID NO: 1 and a VL of SEQ ID NO: 11; (g) a VH of SEQ ID NO:9 and a VL of SEQ ID NO:19; (h) aVH of SEQ ID NO:7 and a VL of SEQ ID NO:17; and (i) aVH of SEQ ID NO:8 and a VL of SEQ ID NO:18. In further embodiments, the anti-C5 antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8.

[0261] In some embodiments, the anti-C5 antibody binds to C5 with a higher affinity at neutral pH than at acidic pH and competes for binding C5 with an antibody comprising a VH and VL pair selected from a VH of SEQ ID NO:1 and a VL of SEQ ID NO:11, or a VH of SEQ ID NO:10 and a VL of SEQ ID NO:20. In further embodiments, the anti-C5 antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8.

[0262] In certain embodiments, whether an anti-C5 antibody of the present invention binds to a certain epitope can be determined as follows: C5 point mutants in which an amino acid (except for alanine) on C5 is substituted with alanine are expressed in 293 cells, and binding of an anti-C5 antibody to the C5 mutants is tested via ELISA, Western blot or BIACORE (registered trademark); wherein a substantial reduction or elimination of binding of the anti-C5 antibody to the C5 mutant relative to its binding to wild type C5 indicates that the anti-C5 antibody binds to an epitope comprising that amino acid on C5. In certain embodiments, the amino acid on C5 to be substituted with alanine is selected from the group consisting of Glu48, Asp51, His70, His72, Lys109, and HisI10 of the beta chain of C5 (SEQ ID NO:40). In further embodiments, the amino acid on C5 to be substituted with alanine is Asp51 or Lys109 of the beta chain of C5 (SEQ ID NO:40).

[0263] In another embodiment, whether an anti-C5 antibody with pH-dependent binding characteristics binds to a certain epitope can be determined as follows: C5 point mutants in which a histidine residue on C5 is substituted with another amino acid (e.g., tyrosine) are expressed in 293 cells, and binding of an anti-C5 antibody to the C5 mutants is tested via ELISA, Western blot or BIACORE (registered trademark); wherein a substantial reduction of binding of the anti-C5 antibody to wild type C5 at acidic pH relative to its binding to the C5 mutant at acidic pH, indicates that the anti C5 antibody binds to an epitope comprising that histidine residue on C5. In further em bodiments, binding of the anti-C5 antibody to wild type C5 at neutral pH is not sub stantially reduced relative to its binding to the C5 mutant at neutral pH. In certain em bodiments, the histidine residue on C5 to be substituted with another amino acid is selected from the group consisting of His70, His72, and HisI10 of the beta chain of C5 (SEQ ID NO:40). In a further embodiment, the histidine residue His70 is substituted with tyrosine.

[0264] 2. Activity assays In one aspect, assays are provided for identifying anti-C5 antibodies thereof having biological activity. Biological activity may include, e.g., inhibiting the activation of C5, preventing the cleavage of C5 to form C5a and C5b, blocking the access of C5 convertase to the cleavage site on C5, blocking hemolytic activity caused by the ac tivation of C5, etc. Antibodies having such biological activity in vivo and/or in vitro are also provided.

[0265] In certain embodiments, an antibody of the invention is tested for such biological activity.

[0266] In certain embodiments, whether a test antibody inhibits the cleavage of C5 into C5a and C5b, is determined by methods described in, e.g., Isenman et al., J Immunol. 124(1):326-331 (1980). In another embodiment, this is determined by methods for specific detection of cleaved C5a and/or C5b proteins, e.g., ELISAs or Western blots. Where a decreased amount of a cleavage product of C5 (i.e., C5a and/or C5b) is detected in the presence of (or following contact with) the test antibody, the test antibody is identified as an antibody that can inhibit the cleavage of C5. In certain em- bodiments, the concentration and/or physiologic activity of C5a can be measured by methods, e.g., chemotaxis assays, RIAs, or ELISAs (See, e.g., Ward and Zvaifler J. Clin. Invest. 50(3):606-616 (1971)).

[0267] In certain embodiments, whether a test antibody blocks the access of C5 convertase to C5 is determined by methods for the detection of protein interactions between the C5 convertase and C5, e.g., ELISAs or BIACORE (registered trademark). Where the interactions are decreased in the presence of (or following contact with) the test antibody, the test antibody is identified as an antibody that can block the access of C5 convertase to C5.

[0268] In certain embodiments, C5 activity can be measured as a function of its cell-lysing ability in a subject's body fluids. The cell-lysing ability, or a reduction thereof, of C5 can be measured by methods well known in the art, for example, a conventional hemolytic assay, such as the hemolysis assay described by Kabat and Mayer (eds), Ex perimental Immunochemistry, 2nd Edition, 135-240, Springfield, IL, CC Thomas (1961), pages 135-139, or a conventional variation of that assay, such as the chicken erythrocyte hemolysis method as described in, e.g., Hillmen et al., N. Engl. J. Med. 350(6): 552-559 (2004). In certain embodiments, C5 activity, or inhibition thereof, is quantified using a CH50eq assay. The CH50eq assay is a method for measuring the total classical complement activity in serum. This test is a lytic assay, which uses antibody-sensitized erythrocytes as the activator of the classical complement pathway, and various dilutions of the test serum to determine the amount required to give 50% lysis (CH50). The percentage of hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measure of terminal complement complex (TCC) formation, since the TCC themselves are directly re sponsible for the hemolysis measured. Inhibition of C5 activation can also be detected and/or measured using the methods set forth and exemplified in the working examples. Using assays of these or other suitable types, candidate antibodies capable of inhibiting the activation of C5 can be screened. In certain embodiments, inhibition of C5 ac tivation includes at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% or greater decrease in the C5 activation in an assay as compared to the effect of a negative control under similar conditions. In some embodiments, it refers to inhibition of C5 activation by at least 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or greater.

[0269] D. Immunoconjugates The invention also provides immunoconjugates comprising an anti-C5 antibody herein conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.

[0270] In one embodiment, an immunoconjugate is an antibody-drug conjugate (ADC) in which an antibody is conjugated to one or more drugs, including but not limited to a maytansinoid (see, US Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see, US Patent Nos. 5,635,483 and 5,780,588, and 7,498,298); a dolastatin; a calicheamicin or derivative thereof (see, US Patent Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. 58:2925-2928 (1998)); an anthracycline such as daunomycin or doxorubicin (see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and US Patent No. 6,630,579); methotrexate; vindesine; a taxane such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; a trichothecene; and CC1065.

[0271] In another embodiment, an immunoconjugate comprises an antibody as described herein conjugated to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, nonbinding 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 inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.

[0272] In another embodiment, an immunoconjugate comprises an antibody as described herein conjugated to a radioactive atom to form a radioconjugate. A variety of ra dioactive isotopes are available for the production of radioconjugates. Examples include At 2 1 1, 1131, 112 5, y9o, Re' 6, Re 188, Sm 15 3 , Bi2 12 , 32, Pb2 1 2 and radioactive isotopes of Lu. When the radioconjugate is used for detection, it may comprise a radioactive atom for scintigraphic studies, for example tc99m or 1123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123 again, iodine-131, indium-I11, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

[0273] Conjugates of an antibody and cytotoxic agent may be made using a variety of bi functional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), 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), diiso cyanates (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-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See W094/11026. The linker may be a "cleavable linker" facilitating release of a cytotoxic drug in the cell. For example, an acid-labile linker, peptidase-sensitive linker, pho tolabile linker, dimethyl linker or disulfide-containing linker (Chari et al., Cancer Res. 52:127-131 (1992); US Patent No. 5,208,020) may be used.

[0274] The immunoconjugates or ADCs herein expressly contemplate, but are not limited to such conjugates prepared with cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzoate) which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL., U.S.A).

[0275] E. Methods and Compositions for Diagnostics and Detection In certain embodiments, any of the anti-C5 antibodies provided herein is useful for detecting the presence of C5 in a biological sample. The term "detecting" as used herein encompasses quantitative or qualitative detection. In certain embodiments, a bi ological sample comprises a cell or tissue, such as serum, whole blood, plasma, biopsy sample, tissue sample, cell suspension, saliva, sputum, oral fluid, cerebrospinal fluid, amniotic fluid, ascites fluid, milk, colostrums, mammary gland secretion, lymph, urine, sweat, lacrimal fluid, gastric fluid, synovial fluid, peritoneal fluid, ocular lens fluid and mucus.

[0276] In one embodiment, an anti-C5 antibody for use in a method of diagnosis or detection is provided. In a further aspect, a method of detecting the presence of C5 in a biological sample is provided. In certain embodiments, the method comprises contacting the biological sample with an anti-C5 antibody as described herein under conditions permissive for binding of the anti-C5 antibody to C5, and detecting whether a complex is formed between the anti-C5 antibody and C5. Such method may be an in vitro or in vivo method. In one embodiment, an anti-C5 antibody is used to select subjects eligible for therapy with an anti-C5 antibody, e.g., where C5 is a biomarker for selection of patients.

[0277] In another embodiment, a method of selecting an individual having a complement mediated disease or condition which involves excessive or uncontrolled activation of C5 as suitable for a therapy comprising an anti-C5 antibody of the present invention is provided. In certain embodiments, the method comprises (a) detecting a genetic variation in C5 derived from the individual, and (b) selecting the individual as suitable for the therapy comprising an anti-C5 antibody of the present invention when the genetic variation is detected in C5 derived from the individual. In another embodiment, a method of selecting a therapy for an individual having a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 is provided. In certain embodiments, the method comprises (a) detecting a genetic variation in C5 derived from the individual, and (b) selecting a therapy comprising an anti-C5 antibody of the present invention for the individual when the genetic variation is detected in C5 derived from the individual.

[0278] In another embodiment, a method of treating an individual having a complement mediated disease or condition which involves excessive or uncontrolled activation of C5 is provided. In certain embodiments, the method comprises (a) detecting a genetic variation in C5 derived from the individual, (b) selecting the individual as suitable for the therapy comprising an anti-C5 antibody of the present invention when the genetic variation is detected in C5 derived from the individual, and (c) administering an anti C5 antibody of the present invention to the individual.

[0279] In another embodiment, an anti-C5 antibody of the present invention for use in treating an individual having a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 is provided. In certain em bodiments, the individual is treated with an anti-C5 antibody of the present invention when the genetic variation is detected in C5 derived from the individual.

[0280] In another embodiment, in vitro use of a genetic variation in C5 for selecting an in dividual having a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 as suitable for a therapy comprising an anti-C5 antibody of the present invention is provided. In certain embodiments, the individual is selected as being suitable for the therapy when the genetic variation is detected in C5 derived from the individual. In another embodiment, in vitro use of a genetic variation in C5 for selecting a therapy for an individual having a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 is provided. In certain embodiments, a therapy comprising an anti-C5 antibody of the present invention is selected for the individual when the genetic variation is detected in C5 derived from the individual.

[0281] It has been reported that some patients who have genetic variation in C5 show poor response to a therapy comprising an existing anti-C5 antibody (Nishimura et al., N. Engl. J. Med. 370:632-639 (2014)). It is recommended that such a patient be treated with a therapy comprising an anti-C5 antibody of the present invention, because such an antibody has an inhibitory activity on the activation of C5 variants as well as wild type C5, as demonstrated in the working examples below.

[0282] Detection of a genetic variation in C5 can be carried out by using a method known in the prior art. Such a method may include sequencing, PCR, RT-PCR, and a hy bridization-based method such as southern blot or northern blot, but is not limited thereto. C5 variants may comprise at least one genetic variation. The genetic variation may be selected from a group consisting of V1451, R449G, V8021, R885H, R928Q, D966Y, S13ION, and E1437D. Herein, R885H, for example, means a genetic variation where arginine at position 885 is substituted by histidine. In certain embodiments, a C5 variant has biological activity similar to wild type C5.

[0283] Exemplary disorders that may be diagnosed using an antibody of the invention include rheumatoid arthritis (RA); systemic lupus erythematosus (SLE); lupus nephritis; ischemia reperfusion injury (IRI); asthma; paroxysmal nocturnal hemoglobinuria (PNH); hemolytic uremic syndrome (HUS) (e.g., atypical hemolytic uremic syndrome (aHUS)); dense deposit disease (DDD); neuromyelitis optica (NMO); multifocal motor neuropathy (MMN); multiple sclerosis (MS); systemic sclerosis; macular degeneration (e.g., age-related macular degeneration (AMD)); hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; epidermolysis bullosa; recurrent fetal loss; pre-eclampsia; traumatic brain injury; myasthenia gravis; cold ag glutinin disease; Sjogren's syndrome; dermatomyositis; bullous pemphigoid; phototoxic reactions; Shiga toxin E. coli-related hemolytic uremic syndrome; typical or infectious hemolytic uremic syndrome (tHUS); C3 Glomerulonephritis; Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis; humoral and vascular transplant rejection; acute antibody mediated rejection (AMR); graft dysfunction; myocardial in farction; an allogenic transplant; sepsis; coronary artery disease; hereditary an gioedema; dermatomyositis; Graves'disease; atherosclerosis; Alzheimer's disease (AD); Huntington's disease; Creutzfeld-Jacob disease; Parkinson's disease; cancers; wounds; septic shock; spinal cord injury; uveitis; diabetic ocular diseases; retinopathy of prematurity; glomerulonephritis; membranous nephritis; immunoglobulin A nephropathy; adult respiratory distress syndrome (ARDS); chronic obstructive pulmonary disease (COPD); cystic fibrosis; hemolytic anemia; paroxysmal cold hemoglobinuria; anaphylactic shock; allergy; osteoporosis; osteoarthritis; Hashimoto's thyroiditis; type I diabetes; psoriasis; pemphigus; autoimmune hemolytic anemia (AIHA); idiopathic thrombocytopenic purpura (ITP); Goodpasture syndrome; Degos disease; antiphospholipid syndrome (APS); catastrophic APS (CAPS); a cardiovascular disorder; myocarditis; a cerebrovascular disorder; a peripheral vascular disorder; a ren ovascular disorder; a mesenteric/enteric vascular disorder; vasculitis; Henoch Schonlein purpura nephritis; Takayasu's disease; dilated cardiomyopathy; diabetic an- giopathy; Kawasaki's disease (arteritis); venous gas embolus (VGE), restenosis following stent placement; rotational atherectomy; membraneous nephropathy; Guillain-Barre syndrome (GBS); Fisher syndrome; antigen-induced arthritis; synovial inflammation; viral infections; bacterial infections; fungal infections; and injury resulting from myocardial infarction, cardiopulmonary bypass and hemodialysis.

[0284] In certain embodiments, labeled anti-C5 antibodies are provided. Labels include, but are not limited to, labels or moieties that are detected directly (such as fluorescent, chromophoric, electron-dense, chemiluminescent, and radioactive labels), as well as moieties, such as enzymes or ligands, that are detected indirectly, e.g., through an enzymatic reaction or molecular interaction. Exemplary labels include, but are not limited to, the radioisotopes 32p, 14C, 1251, 3H, and 131I, fluorophores such as rare earth chelates or fluorescein and its derivatives, rhodamine and its derivatives, dansyl, um belliferone, luceriferases, e.g., firefly luciferase and bacterial luciferase (US Patent No. 4,737,456), luciferin, 2,3-dihydrophthalazinediones, horseradish peroxidase (HRP), alkaline phosphatase, beta-galactosidase, glucoamylase, lysozyme, saccharide oxidases, e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehy drogenase, heterocyclic oxidases such as uricase and xanthine oxidase, coupled with an enzyme that employs hydrogen peroxide to oxidize a dye precursor such as HRP, lac toperoxidase, or microperoxidase, biotin/avidin, spin labels, bacteriophage labels, stable free radicals, and the like.

[0285] F. Pharmaceutical Formulations Pharmaceutical formulations of an anti-C5 antibody as described herein are prepared by mixing such antibody having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; re sorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or im munoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, dis accharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharma ceutically acceptable carriers herein further include interstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX (registered trademark), Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Publ. Nos. 2005/0260186 and 2006/0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.

[0286] Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958. Aqueous antibody formulations include those described in US Patent No. 6,171,586 and WO 2006/044908, the latter formulations including a histidine-acetate buffer.

[0287] The formulation herein may also contain more than one active ingredients as necessary for the particular indication being treated, preferably those with com plementary activities that do not adversely affect each other. Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.

[0288] Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethyl cellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, re spectively, in colloidal drug delivery systems (for example, liposomes, albumin mi crospheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0289] Sustained-release preparations may be prepared. Suitable examples of sustained release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules.

[0290] The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

[0291] G. Therapeutic Methods and Compositions Any of the anti-C5 antibodies provided herein may be used in therapeutic methods.

[0292] In one aspect, an anti-C5 antibody for use as a medicament is provided. In further aspects, an anti-C5 antibody for use in treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 is provided. In certain embodiments, an anti-C5 antibody for use in a method of treatment is provided. In certain embodiments, the invention provides an anti-C5 antibody for use in a method of treating an individual having a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, comprising administering to the individual an effective amount of the anti-C5 antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent. An "individual" according to any of the above embodiments is preferably a human.

[0293] When the antigen is a soluble protein, the binding of an antibody to its antigen can result in an extended half-life of the antigen in plasma (i.e., reduced clearance of the antigen from plasma), since the antibody itself has a longer half-life in plasma and serves as a carrier for the antigen. This is due to the recycling of the antigen-antibody complex by FcRn through the endosomal pathway in cell (Roopenian, Nat. Rev. Immunol. 7(9):715-725 (2007)). However, an antibody with pH-dependent binding characteristics, which binds to its antigen in neutral extracellular environment while releasing it into acidic endosomal compartments following entry into cells, is expected to have superior properties in terms of antigen neutralization and clearance relative to its counterpart that binds in a pH-independent manner (Igawa et al., Nat. Biotech.. 28(11):1203-1207 (2010); Devanaboyina et al., mAbs 5(6):851-859 (2013); WO 2009/125825).

[0294] In further embodiments, the invention provides an anti-C5 antibody for use in enhancing the clearance of C5 from plasma. In certain embodiments, the invention provides an anti-C5 antibody for use in a method of enhancing the clearance of C5 from plasma in an individual comprising administering to the individual an effective amount of the anti-C5 antibody to enhance the clearance of C5 from plasma. In one embodiment, an anti-C5 antibody enhances the clearance of C5 from plasma, compared to a conventional anti-C5 antibody which does not have pH-dependent binding characteristics. An "individual" according to any of the above embodiments is preferably a human.

[0295] In further embodiments, the invention provides an anti-C5 antibody for use in sup pressing the accumulation of C5 in plasma. In certain embodiments, the invention provides an anti-C5 antibody for use in a method of suppressing the accumulation of C5 in plasma in an individual, comprising administering to the individual an effective amount of the anti-C5 antibody to suppress the accumulation of C5 in plasma. In one embodiment, the accumulation of C5 in plasma is the result of the formation of an antigen-antibody complex. In another embodiment, an anti-C5 antibody suppresses the accumulation of C5 in plasma, compared to a conventional anti-C5 antibody which does not have pH-dependent binding characteristics. An "individual" according to any of the above embodiments is preferably a human.

[0296] An anti-C5 antibodiy of the present invention may inhibit the activation of C5. In further embodiments, the invention provides an anti-C5 antibody for use in inhibiting the activation of C5. In certain embodiments, the invention provides an anti-C5 antibody for use in a method of inhibiting the activation of C5 in an individual, comprising administering to the individual an effective amount of the anti-C5 antibody to inhibit the activation of C5. In one embodiment, the cytotoxicity mediated by C5 is suppressed by inhibiting the activation of C5. An "individual" according to any of the above embodiments is preferably a human.

[0297] In a further aspect, the invention provides the use of an anti-C5 antibody in the man ufacture or preparation of a medicament. In one embodiment, the medicament is for treatment of a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5. In a further embodiment, the medicament is for use in a method of treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, comprising administering to an individual having a complement-mediated disease or condition which involves excessive or un controlled activation of C5 an effective amount of the medicament. In one such em bodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent. An "individual" according to any of the above embodiments is preferably a human.

[0298] In a further embodiment, the medicament is for enhancing the clearance of C5 from plasma. In a further embodiment, the medicament is for use in a method of enhancing the clearance of C5 from plasma in an individual comprising administering to the in dividual an effective amount of the medicament to enhance the clearance of C5 from plasma. In one embodiment, an anti-C5 antibody enhances the clearance of C5 from plasma, compared to a conventional anti-C5 antibody which does not have pH dependent binding characteristics. An "individual" according to any of the above em bodiments may be a human.

[0299] In a further embodiment, the medicament is for suppressing the accumulation of C5 in plasma. In a further embodiment, the medicament is for use in a method of sup pressing the accumulation of C5 in plasma in an individual, comprising administering to the individual an effective amount of the medicament to suppress the accumulation of C5 in plasma. In one embodiment, the accumulation of C5 in plasma is a result of the formation of an antigen-antibody complex. In another embodiment, an anti-C5 antibody suppresses the accumulation of C5 in plasma, compared to a conventional anti-C5 antibody which does not have pH-dependent binding characteristics. An "in dividual" according to any of the above embodiments may be a human.

[0300] An anti-C5 antibodiy of the present invention may inhibit the activation of C5. In a further embodiment, the medicament is for inhibiting the activation of C5. In a further embodiment, the medicament is for use in a method of inhibiting the activation of C5 in an individual, comprising administering to the individual an effective amount of the medicament to inhibit the activation of C5. In one embodiment, the cytotoxicity mediated by C5 is suppressed by inhibiting the activation of C5. An "individual" according to any of the above embodiments may be a human.

[0301] In a further aspect, the invention provides a method for treating a complement mediated disease or condition which involves excessive or uncontrolled activation of C5. In one embodiment, the method comprises administering to an individual having such a complement-mediated disease or condition which involves excessive or un controlled activation of C5 an effective amount of an anti-C5 antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent. An "individual" according to any of the above embodiments may be a human.

[0302] In a further aspect, the invention provides a method for enhancing the clearance of C5 from plasma in an individual. In one embodiment, the method comprises admin istering to the individual an effective amount of an anti-C5 antibody to enhance the clearance of C5 from plasma. In one embodiment, an anti-C5 antibody enhances the clearance of C5 from plasma, compared to a conventional anti-C5 antibody which does not have pH-dependent binding characteristics. In one embodiment, an "individual" is a human.

[0303] In a further aspect, the invention provides a method for suppressing the accumulation of C5 in plasma in an individual. In one embodiment, the method comprises admin istering to the individual an effective amount of an anti-C5 antibody to suppress the ac cumulation of C5 in plasma. In one embodiment, the accumulation of C5 in plasma is a result of the formation of an antigen-antibody complex. In another embodiment, an anti-C5 antibody suppresses the accumulation of C5 in plasma, compared to a con ventional anti-C5 antibody which does not have pH-dependent binding characteristics. In one embodiment, an "individual" is a human.

[0304] An anti-C5 antibodiy of the present invention may inhibit the activation of C5. In a further aspect, the invention provides a method for inhibiting the activation of C5 in an individual. In one embodiment, the method comprises administering to the individual an effective amount of an anti-C5 antibody to inhibit the activation of C5. In one em bodiment, the cytotoxicity mediated by C5 is suppressed by inhibiting the activation of C5. In one embodiment, an "individual" is a human.

[0305] In a further aspect, the invention provides pharmaceutical formulations comprising any of the anti-C5 antibodies provided herein, e.g., for use in any of the above therapeutic methods. In one embodiment, a pharmaceutical formulation comprises any of the anti-C5 antibodies provided herein and a pharmaceutically acceptable carrier. In another embodiment, a pharmaceutical formulation comprises any of the anti-C5 an tibodies provided herein and at least one additional therapeutic agent.

[0306] In a further aspect, the pharmaceutical formulation is for treatment of a complement mediated disease or condition which involves excessive or uncontrolled activation of C5. In a further embodiment, the pharmaceutical formulation is for enhancing the clearance of C5 from plasma. In one embodiment, an anti-C5 antibody enhances the clearance of C5 from plasma, compared to a conventional anti-C5 antibody which does not have pH-dependent binding characteristics. In a further embodiment, the pharma ceutical formulation is for suppressing the accumulation of C5 in plasma. In one em bodiment, the accumulation of C5 in plasma is a result of the formation of an antigen antibody complex. In another embodiment, an anti-C5 antibody suppresses the accu mulation of C5 in plasma, compared to a conventional anti-C5 antibody which does not have pH-dependent binding characteristics. An anti-C5 antibodiy of the present invention may inhibit the activation of C5. In a further embodiment, the pharma ceutical formulation is for inhibiting the activation of C5. In one embodiment, the cy totoxicity mediated by C5 is suppressed by inhibiting the activation of C5. In one em bodiment, the pharmaceutical formulation is administered to an individual having a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5. An "individual" according to any of the above embodiments is preferably a human.

[0307] In one aspect, an individual has wild type C5. In another aspect, an individual has a C5 variant. In certain embodiments, a C5 variant has biological activity similar to wild type C5. Such a C5 variant may comprise at least one variation selected from the group consisting of V145I, R449G, V802I, R885H, R928Q, D966Y, S1310N, and E1437D. Herein, R885H, for example, means a genetic variation where arginine at position 885 is substituted by histidine.

[0308] In a further aspect, the invention provides methods for preparing a medicament or a pharmaceutical formulation, comprising mixing any of the anti-C5 antibodies provided herein with a pharmaceutically acceptable carrier, e.g., for use in any of the above therapeutic methods. In one embodiment, the methods for preparing a medicament or a pharmaceutical formulation further comprise adding at least one additional therapeutic agent to the medicament or pharmaceutical formulation.

[0309] In certain embodiments, the complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 is selected from the group consisting of rheumatoid arthritis (RA); systemic lupus erythematosus (SLE); lupus nephritis; ischemia reperfusion injury (IRI); asthma; paroxysmal nocturnal hemoglobinuria (PNH); hemolytic uremic syndrome (HUS) (e.g., atypical hemolytic uremic syndrome (aHUS)); dense deposit disease (DDD); neuromyelitis optica (NMO); multifocal motor neuropathy (MMN); multiple sclerosis (MS); systemic sclerosis; macular degeneration (e.g., age-related macular degeneration (AMD)); hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; epidermolysis bullosa; recurrent fetal loss; pre-eclampsia; traumatic brain injury; myasthenia gravis; cold ag glutinin disease; Sjogren's syndrome; dermatomyositis; bullous pemphigoid; phototoxic reactions; Shiga toxin E. coli-related hemolytic uremic syndrome; typical or infectious hemolytic uremic syndrome (tHUS); C3 Glomerulonephritis; Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis; humoral and vascular transplant rejection; acute antibody mediated rejection (AMR); graft dysfunction; myocardial in farction; an allogeneic transplant; sepsis; coronary artery disease; hereditary an gioedema; dermatomyositis; Graves'disease; atherosclerosis; Alzheimer's disease (AD); Huntington's disease; Creutzfeld-Jacob disease; Parkinson's disease; cancers; wounds; septic shock; spinal cord injury; uveitis; diabetic ocular diseases; retinopathy of prematurity; glomerulonephritis; membranous nephritis; immunoglobulin A nephropathy; adult respiratory distress syndrome (ARDS); chronic obstructive pulmonary disease (COPD); cystic fibrosis; hemolytic anemia; paroxysmal cold hemoglobinuria; anaphylactic shock; allergy; osteoporosis; osteoarthritis; Hashimoto's thyroiditis; type I diabetes; psoriasis; pemphigus; autoimmune hemolytic anemia (AIHA); idiopathic thrombocytopenic purpura (ITP); Goodpasture syndrome; Degos disease; antiphospholipid syndrome (APS); catastrophic APS (CAPS); a cardiovascular disorder; myocarditis; a cerebrovascular disorder; a peripheral vascular disorder; a ren ovascular disorder; a mesenteric/enteric vascular disorder; vasculitis; Henoch Schonlein purpura nephritis; Takayasu's disease; dilated cardiomyopathy; diabetic an giopathy; Kawasaki's disease (arteritis); venous gas embolus (VGE), restenosis following stent placement; rotational atherectomy; membranous nephropathy; Guillain-Barre syndrome (GBS); Fisher syndrome; antigen-induced arthritis; synovial inflammation; viral infections; bacterial infections; fungal infections; and injury resulting from myocardial infarction, cardiopulmonary bypass and hemodialysis.

[0310] In certain embodiments, the complement-mediated disease or condition is an ocular disease condition. In further embodiments, the ocular condition is macular de generation. In further embodiments the macular degeneration is AMD. In further em bodiments, the AMD is the dry form of AMD.

[0311] In certain embodiments, the complement-mediated disease or condition is PNH.

[0312] In certain embodiments, the complement-mediated disease or condition is a my ocardial infarction.

[0313] In certain embodiments, the complement-mediated disease or condition is RA.

[0314] In certain embodiments, the complement-mediated disease or condition is os teoporosis or osteoarthritis.

[0315] In certain embodiments, the complement-mediated disease or condition is in- flammation.

[0316] In certain embodiments, the complement-mediated disease or condition is cancer.

[0317] Antibodies of the invention can be used either alone or in combination with other agents in a therapy. For instance, an antibody of the invention may be co-administered with at least one additional therapeutic agent.

[0318] Such combination therapies noted above encompass combined administration (where two or more therapeutic agents are included in the same or separate formulations), and separate administration, in which case, administration of the antibody of the invention can occur prior to, simultaneously, and/or following, administration of the additional therapeutic agent or agents. In one embodiment, administration of the anti-C5 antibody and administration of an additional therapeutic agent occur within about one month, or within about one, two or three weeks, or within about one, two, three, four, five, or six days, of each other.

[0319] An antibody of the invention (and any additional therapeutic agent) can be ad ministered by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous ad ministration. Dosing can be by any suitable route, e.g., by injections, such as in travenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. Various dosing schedules including but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein.

[0320] Antibodies of the invention would be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The antibody need not be, but is op tionally formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. These are generally used in the same dosages and with admin istration routes as described herein, or about from 1 to 99% of the dosages described herein, or in any dosage and by any route that is empirically/clinically determined to be appropriate.

[0321] For the prevention or treatment of disease, the appropriate dosage of an antibody of the invention (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician. The antibody is suitably administered to the patient at one time or over a series of treatments. Depending on the type and severity of the disease, about 1 micro g/kg to 15 mg/kg (e.g., 0.lmg/kg-10mg/kg) of antibody can be an initial candidate dosage for ad ministration to the patient, whether, for example, by one or more separate adminis trations, or by continuous infusion. One typical daily dosage might range from about 1 micro g/kg to 100 mg/kg or more, depending on the factors mentioned above. For repeated administrations over several days or longer, depending on the condition, the treatment would generally be sustained until a desired suppression of disease symptoms occurs. One exemplary dosage of the antibody would be in the range from about 0.05 mg/kg to about 10 mg/kg. Thus, one or more doses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg or 10 mg/kg (or any combination thereof) may be administered to the patient. Such doses may be administered intermittently, e.g., every week or every three weeks (e.g., such that the patient receives from about two to about twenty, or e.g., about six doses of the antibody). An initial higher loading dose, followed by one or more lower doses may be administered. The progress of this therapy is easily monitored by conventional techniques and assays.

[0322] It is understood that any of the above formulations or therapeutic methods may be carried out using an immunoconjugate of the invention in place of or in addition to an anti-C5 antibody.

[0323] H. Articles of Manufacture In another aspect of the invention, an article of manufacture containing materials useful for the treatment, prevention and/or diagnosis of the disorders described above is provided. The article of manufacture comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an antibody of the invention. The label or package insert indicates that the composition is used for treating the condition of choice. Moreover, the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the com position comprises an antibody of the invention; and (b) a second container with a composition contained therein, wherein the composition comprises a further cytotoxic or otherwise therapeutic agent. The article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the compositions can be used to treat a particular condition. Alternatively, or additionally, the article of man ufacture may further comprise a second (or third) container comprising a pharma ceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0324] It is understood that any of the above articles of manufacture may include an im munoconjugate of the invention in place of or in addition to an anti-C5 antibody. Examples

[0325] The following are examples of methods and compositions of the invention. It is un derstood that various other embodiments may be practiced, given the general de scription provided above. Example 1

[0326] Preparation of C5 1.1. Expression and purification of recombinant human and cynomolgus monkey C5 Recombinant human C5 (NCBI GenBank accession number: NP_001726.2, SEQ ID NO: 39) was expressed transiently using FreeStyle293-F cell line (Thermo Fisher, Carlsbad, CA, USA). Conditioned media expressing human C5 was diluted with equal volume of milliQ water, then applied to a Q-sepharose FF or Q-sepharose HP anion exchange column (GE healthcare, Uppsala, Sweden), followed by elution with a NaCl gradient. Fractions containing human C5 were pooled, then salt concentration and pH was adjusted to 80mM NaCl and pH6.4, respectively. The resulting sample was applied to a SP-sepharose HP cation exchange column (GE healthcare, Uppsala, Sweden) and eluted with a NaCl gradient. Fractions containing human C5 were pooled and subjected to CHT ceramic Hydroxyapatite column (Bio-Rad Laboratories, Hercules, CA, USA). Human C5 eluate was then applied to a Superdex 200 gel filtration column (GE healthcare, Uppsala, Sweden). Fractions containing human C5 were pooled and stored at -150 degrees C.

[0327] Expression and purification of recombinant cynomolgus monkey C5 (NCBI GenBank accession number: XP_005580972, SEQ ID NO: 44) was performed the same way as the human counterpart.

[0328] 1.2. Purification of cynomolgus monkey C5 (cynoC5) from plasma Plasma sample from cynomolgus monkey was applied to SSL7-agarose (Invivogen, San Diego, CA, USA) followed by elution with 100mM NaAcetate, pH3.5. Fractions containing cynoC5 were immediately neutralized and subjected to a Protein A HP column (GE healthcare, Uppsala, Sweden) in tandem to a Peptide M agarose (Invivogen, San Diego, CA, USA). The flow through fraction was then applied to a Superdex 200 gel filtration column (GE healthcare, Uppsala, Sweden). Fractions containing cynoC5 were pooled and stored at -80 degrees C. Example 2

[0329] Generation of anti-C5 antibodies 2.1. Antibody screening Anti-C5 antibodies were prepared, selected and assayed as follows:

[0330] Twelve to sixteen week old NZW rabbits were immunized intradermally with human C5 and/or monkey C5 (50-100 micro g/dose/rabbit). This dose was repeated 4-5 times over a 2 month period. One week after the final immunization, the spleen and blood were collected from the immunized rabbits. Antigen-specific B-cells were stained with labelled antigen, sorted with FCM cell sorter (FACS aria III, BD), and plated in 96-well plates at one cell/well density together with 25,000 cells/well of EL4 cells (European Collection of Cell Cultures) and activated rabbit T-cell conditioned medium diluted 20 times, and were cultured for 7-12 days. EL4 cells were treated with mitomycin C (Sigma, Cat No. M4287) for 2 hours and washed 3 times in advance. The activated rabbit T-cell conditioned medium was prepared by culturing rabbit thymocytes in RPMI-1640 containing Phytohemagglutinin-M (Roche, Cat No. 1 1082132-001), phorbol 12-myristate 13-acetate (Sigma, Cat No. P1585) and 2% FBS. After cultivation, B-cell culture supernatants were collected for further analysis and pellets were cryopreserved.

[0331] An ELISA assay was used to test the specificity of antibodies in a B-cell culture su pernatant. Streptavidin (GeneScript, Cat No. Z02043) was coated onto a 384-well MAXISorp (Nunc, Cat No. 164688) at 50nM in PBS for 1 hour at room temperature. Plates were then blocked with Blocking One (Nacalai Tesque, Cat No. 03953-95) diluted 5 times. Human or monkey C5 was labelled with NHS-PEG4-Biotin (PIERCE, Cat No. 21329) and was added to the blocked ELISA plates, incubated for 1 hour and washed. B-cell culture supernatants were added to the ELISA plates, incubated for 1 hour and washed. Binding was detected by goat anti-rabbit IgG-Horseradish peroxidase (BETHYL, Cat No. A120-111P) followed by the addition of ABTS (KPL, Cat No. 50-66-06).

[0332] An ELISA assay was used to evaluate pH-dependent binding of antibodies against C5. Goat anti-rabbit IgG-Fc (BETHYL, Cat No. A120-111A) diluted to 1 micro g/ml with PBS(-) was added to a 384-well MAXISorp (Nunc, Cat No. 164688), incubated for 1 hour at room temperature, and blocked with Blocking One (Nacalai Tesque, Cat No. 03953-95) diluted 5 times. After incubation, plates were washed and B-cell culture supernatants were added. Plates were incubated for 1 hour, washed, and 500pM of bi otinylated human or monkey C5 was added and incubated for 1 hour. After incubation, plates were washed and incubated with either pH7.4 MES buffer (20 mM MES, 150 mM NaCl and 1.2 mM CaCl 2) or pH5.8 MES buffer (20 mM MES, 150 mM NaCl and 1 mM EDTA) for 1 hour at room temperature. After incubation, binding of bi otinylated C5 was detected by Streptavidin-Horseradish peroxidase conjugate (Thermo Scientific, Cat No. 21132) followed by the addition of ABTS (KPL, Cat No. 50-66-06).

[0333] Octet RED384 system (Pall Life Sciences) was used to evaluate affinity and pH dependent binding of antibodies against C5. Antibodies secreted in the B-cell culture supernatant were loaded onto a Protein A biosensor tip (Pall Life Sciences) and dipped into 50 nM of human or monkey C5 in pH7.4 MES buffer to analyze association kinetics. Dissociation kinetics was analyzed in both pH7.4 MES buffer and pH5.8 MES buffer.

[0334] A total of 41,439 B-cell lines were screened for affinity and pH-dependent binding to human or monkey C5 and 677 lines were selected and designated CFA0001-0677. RNA of the selected lines was purified from cryopreserved cell pellets using ZR-96 Quick-RNA kits (ZYMO RESEARCH, Cat No. R1053). DNA encoding antibody heavy chain variable regions in the selected lines was amplified by reverse tran scription PCR and recombined with DNA encoding F760G4 (SEQ ID NO: 33) or F939G4 (SEQ ID NO: 34) heavy chain constant region. DNA encoding antibody light chain variable regions was amplified by reverse transcription PCR and recombined with DNA encoding kOMTC light chain constant region (SEQ ID NO: 36). Separately, the heavy and light chain genes of an existing humanized anti-C5 antibody, eculizumab (EcuH-G2G4, SEQ ID NO: 29 and EcuL-k, SEQ ID NO: 30), were syn thesized. DNA encoding VH (EcuH, SEQ ID NO: 31) was fused in-frame to DNA encoding a modified human IgG4 CH (F760G4, SEQ ID NO: 33), and DNA encoding VL (EcuL, SEQ ID NO: 32) was fused in-frame to DNA encoding a k0 light chain constant region (SEQ ID NO: 37). Each of the fused coding sequences was also cloned into an expression vector. The antibodies were expressed in FreeStyleTM 293-F Cells (Invitrogen) and purified from culture supernatant to evaluate functional activity. Neu tralizing activities of the antibodies were evaluated by testing inhibition of complement activity using a liposome lysis assay as described in Example 5.1.

[0335] 2.2. Epitope binning by sandwich ELISA Anti-C5 antibodies with high affinity, pH dependency or neutralizing activity were selected for further analysis. A sandwich ELISA assay was used to group the selected antibodies into different epitope bins binding to the same or overlapping epitopes of the C5 protein. Unlabelled capture antibodies were diluted to 1 micro g/ml with PBS

(-) and added to 384-well MAXISorp plates (Nunc, Cat No. 164688). Plates were incubated for 1 hour at room temperature and blocked with Blocking One (Nacalai Tesque, Cat No. 03953-95) diluted 5 times. Plates were incubated for 1 hour, washed, and 2 nM of human C5 was added and incubated for 1 hour. After incubation, plates were washed and labelled detection antibodies (Imicro g/mL, biotinylated by NHS PEG4-Biotin) were added. After 1 hour incubation, binding of biotinylated antibody was detected by Streptavidin-Horseradish peroxidase conjugate (Thermo Scientific, Cat No. 21132) followed by the addition of ABTS (KPL, Cat No. 50-66-06).

[0336] All anti-C5 antibodies were used as both a capture antibody and a detection antibody, and paired comprehensively. As shown in Figure 1, mutually competitive antibodies were grouped into 7 epitope bins: CFA0668, CFA0334 and CFA0319 were grouped into epitope A, CFA0647, CFA0589, CFA0341, CFA0639, CFA0635, CFA0330 and CFA0318 were grouped into epitope B, CFA0538, CFA0501, CFA0599, CFA0307, CFA0366, CFA0305, CFA0675, CFA0666 and CFA0672 were grouped into epitope C, eculizumab and CFA0322 were grouped into epitope D, CFA0329 was grouped into epitope E, CFA0359 and CFA0217 were grouped into epitope F, and CFA0579, CFA0328 and CFA0272 were grouped into epitope G. Figure 1 shows epitope binning of some of the anti-C5 chimeric antibodies. The sequences of the VH and VL anti-C5 antibodies grouped into epitope C are listed in Table 2.

[Table 2] Anti-C5 antibodies grouped into epitope C

SEQIDNO: Antibody VH A HVR-H1 HVR-HZ HVR-H3 HVR-L1 HVR-L2 VR-L3 CFA0305 1 11 45 55 65 75 85 95 CFA0307 2 12 46 56 66 76 86 96 CFA0366 3 13 47 57 67 77 87 97 CFA0501 4 14 48 58 68 78 88 98 CFA0538 5 15 49 59 69 79 89 99 CFA0599 6 16 50 60 70 80 90 100 CFA0666 7 17 51 61 71 81 91 101 CFA0672 8 18 52 62 72 82 92 102 CFA0675 9 19 53 63 73 83 93 103

[0337] 2.3. Humanization and optimization Humanization of the variable region of some of the anti-C5 antibodies was performed in order to reduce the potential immunogenicity of the antibodies. Comple mentarity-determining regions (CDRs) of the anti-C5 rabbit antibody were grafted onto homologous human antibody frameworks (FRs) using a conventional CDR grafting approach (Nature 321:522-525 (1986)). The genes encoding the humanized VH and VL were synthesized and combined with a modified human IgG4 CH (SG402, SEQ ID NO: 35) and a human CL (SKI, SEQ ID NO: 38), respectively, and each of the combined sequences was cloned into an expression vector.

[0338] A number of mutations and mutation combinations were examined to identify mutations and mutation combinations that improved the binding properties of some of the lead antibodies. Multiple mutations were then introduced to the humanized variable regions to enhance the binding affinity to C5 at a neutral pH or to reduce the binding affinity to C5 at an acidic pH. One of the optimized variants, 305LO5 (VH, SEQ ID NO: 10; VL, SEQ ID NO: 20; HVR-H1, SEQ ID NO: 54; HVR-H2, SEQ ID NO: 64; HVR-H3, SEQ ID NO: 74; HVR-L1, SEQ ID NO: 84; HVR-L2, SEQ ID NO: 94; and HVR-L3, SEQ ID NO: 104), was hence generated from CFA0305.

[0339] Antibodies were expressed in HEK293 cells co-transfected with a mixture of heavy and light chain expression vectors and were purified by protein A. Example 3

[0340] Binding characterization of anti-C5 antibodies 3.1. Expression and purification of recombinant antibodies Recombinant antibodies were expressed transiently using FreeStyle293-F cell line (Thermo Fisher, Carlsbad, CA, USA). Purification from the conditioned media ex pressing antibodies was performed using a conventional method using protein A. Gel filtration was further conducted if needed.

[0341] 3.2. Assessment of pH dependency The kinetic parameters of anti-C5 antibodies against recombinant human C5 were assessed at pH7.4 and pH5.8, at 37 degrees C using BIACORE (registered trademark) T200 instrument (GE Healthcare). ProA/G (Pierce) was immobilized onto a CM4 sensorchip using amine coupling kit (GE Healthcare) according to the recommended settings by GE Healthcare. Antibodies and analytes were diluted into the respective running buffers, ACES pH7.4 and pH5.8 (20 mM ACES, 150 mM NaCl, 1.2 mM CaCl 2, 0.05% Tween 20, 0.005% NaN). Each antibody was captured onto the sensor surface by ProA/G. Antibody capture levels were typically 60-90 resonance units (RU). Then, recombinant human C5 was injected at concentrations of 10 and 20 nM or 20 and 40 nM followed by dissociation. The surface was regenerated using 25 mM NaOH. Kinetic parameters at both pH conditions were determined by fitting the sen sorgrams with 1:1 binding model using BIACORE (registered trademark) T200 Evaluation software, version 2.0 (GE Healthcare). The sensorgrams of all antibodies are shown in Figures 2A and 2B. The association rate (ka), dissociation rate (kd), and binding affinity (KD) of the antibodies are listed in Table 3. All antibodies except CFA0330 (VH, SEQ ID NO: 21 and VL, SEQ ID NO: 25) and CFA0341 (VH, SEQ ID NO: 22 and VL, SEQ ID NO: 26) showed a relatively faster dissociation rate at pH 5.8 than pH7.4.

[Table 3] Kinetic parameters of anti-C5 antibodies under pH7.4 and pH5.8 conditions

Antibody pH7.4 pH5.8 Name ka kd KD ka kd KD CFA0305 3.82E+04 5.89E-04 1.54E-08 4.27E+04 1.83E-02 4.30E-07 CFA0307 3.24E+05 2.63E-03 8.13E-09 2.04E+05 3.34E-02 1.64E-07 CFA0366 1.04E+06 9.34E-03 8.99E-09 9.35E+05 7.03E-02 7.52E-08 CFA0501 4.74E+05 1.69E-03 3.56E-09 1.50E+05 2.62E-02 1.74E-07 CFA0538 4.73E+05 1.85E-03 3.91E-09 1.22E+05 3.01E-02 2.46E-07 CFA0599 4.74E+05 2.81E-03 5,93E-09 4.54E+05 3.73E-02 8.21E-08 CFA0666 3.65E+05 6.26E-04 1.71E-09 2.82E+05 9.39E-03 3.33E-08 CFA0672 5.23E+05 1.83E-04 3.51E-10 7.11E+04 9.78E-03 1.38E-07 CFA0675 3.83E+05 4.12E-04 1.08E-09 3.89E+05 6.61E-03 1.70E-08 305-LO5 4.48E+05 2.11E-04 4.71E-10 2.03E+06 2.85E-02 1.40E-08 CFA0330 1.66E+06 2.02E-04 1.22E-10 1.22E+06 2.24E-04 1.84E-10 CFA0341 6.28E+05 9.77E-05 1.55E-10 1.24E+06 7.39E-05 5,95E-11

[0342] 3.3. Cross reactivity check To observe the cross-reactivity of anti-C5 antibodies against human C5 (hC5) and cynomolgus monkey C5 (cynoC5), BIACORE (registered trademark) kinetics analysis was performed. The assay setting was the same as described in Example 3.2, Re combinant cynoC5 was injected at concentrations of 2, 10, and 50 nM. Kinetic pa rameters were determined by the same data fitting as described in Example 3.2. Binding kinetics and affinity at pH7.4 are listed in Table 4. The kinetic parameters against hC5 presented in Table 4 are the results of Example 3.2. All anti-C5 antibodies except CFA0672 showed comparable KD toward hC5 and cynoC5. KD of CFA0672 toward cynoC5 was 8 times weaker than toward hC5.

[Table 4] Binding kinetics and affinity of anti-C5 antibodies against hC5 and cynoC5 at pH7.4

Antibody affinity against hC5 affinity against cynoC5 Name ka kd KD ka kd KD CFA0305 3.82E+04 5.89E-04 1.54E-08 1.21E+04 6.70E-04 5.54E-09 CFA0307 3,24E+05 2.63E-03 8.13E-09 290E+05 2.23E-03 7.68E-09 CFA0366 1.04E+06 9.34E-03 8.99E-09 5.04E+05 9.04E-03 1.79E-08 CFA0501 4.74E+05 1.69E-03 3.56E-09 2.66E+05 1.56E-03 5.88E-09 CFA0538 4.73E+05 1.85E-03 3.91E-09 3.05E+05 1.66E-03 544E-09 CFA0599 4.74E+05 2.81E-03 5.93E-09 5A2E+05 2.35E-03 4.33E-09 CFA0666 3.65E+05 6.26E-04 1.71E-09 3.14E+05 4.93E-04 1.57E-09 CFA0672 5.23E+05 1.83E-04 3.51E-10 6.41E+05 1.85E-03 2.88E-09 CFA0675 3.83E+05 4.12E-04 1,08E-09 2,94E+05 3.78E-04 1.29E-09 Example 4

[0343] Epitope mapping of anti-C5 antibodies 4.1. Binding of anti-C5 MAbs to C5 beta-chain-derived peptides

Anti-C5 monoclonal antibodies (MAbs) were tested for binding to C5 beta chain-derived peptides in Western blot analysis. The C5 peptides: 19-180, 161-340, 321-500, and 481-660, fused to GST-tag (pGEX-4T-1, GE Healthcare Life Sciences, 28-9545-49) were expressed in E. coli (DH5alpha, TOYOBO, DNA-903). The E. coli samples were harvested after incubation with 1 mM Isopropyl beta D-1-thiogalactopyranoside (IPTG) for 5 hours at 37 degrees C, and centrifuged at 20000 x g for 1 min to obtain pellets. The pellets were suspended with a sample buffer solution (2ME+) (Wako, 191-13272), and used for Western blot analysis. Expression of each peptide was confirmed with anti-GST antibody (Abcam, ab9085) (Figure 3). The arrow indicates GST-fused C5 peptides (46-49kDa). Anti-C5 MAbs: CFA0305, CFA0307, CFA0366, CFA0501, CFA0538, CFA0599, CFA0666, CFA0672, and CFA0675, bound to 19-180 of C5 (Figure 3).

[0344] 4.2. Expression and purification of MG1-MG2 domain (1-225) of human C5 Recombinant MG1-MG2 domain (SEQ ID NO: 43) of human C5 beta-chain was expressed transiently using FreeStyle293-F cell line (Thermo Fisher, Carlsbad, CA, USA). Conditioned media expressing the MG1-MG2 domain was diluted with 1/2 vol of milliQ water, followed by application to a Q-sepharose FF anion exchange column (GE healthcare, Uppsala, Sweden). The flow through fraction from the anion exchange column was adjusted to pH 5.0 and applied to a SP-sepharose HP cation exchange column (GE healthcare, Uppsala, Sweden) and eluted with a NaCl gradient. Fractions containing the MG1-MG2 domain were collected from the eluent and subsequently subjected to a Superdex 75 gel filtration column (GE healthcare, Uppsala, Sweden) equilibrated with 1x PBS. The fractions containing the MG1-MG2 domain were then pooled and stored at -80 degrees C.

[0345] 4.3. Binding ability to MG1-MG2 domain The binding ability of anti-C5 antibodies towards the MG1-MG2 domain was measured using the same assay settings as described in Example 3.2, except that mea surements were only performed under pH7.4 conditions. The MG1-MG2 domain was injected at concentrations of 20 nM and 40 nM. As shown in Figure 4, all antibodies except eculizumab-F760G4 showed an increase of the binding response, indicating these antibodies are MG1-MG2 binders. Eculizumab-F760G4, which is a known alpha-chain binder, did not show binding to MG1-MG2 domain.

[0346] 4.4. Binding of anti-C5 MAbs to C5 MG1-MG2 domain-derived peptides The anti-C5 MAbs were tested for binding to MG1-MG2 domain-derived peptides in Western blot analysis. The C5 peptides: 33-124, 45-124, 52-124, 33-111, 33-108, and 45-111 (SEQ ID NO:40), fused to GST-tag, were expressed in E. coli. The E. coli samples were harvested after incubation with 1 mM IPTG for 5 hours at 37 degrees C, and centrifuged at 20000 x g for 1 min to obtain pellets. The pellets were suspended with the sample buffer solution (2ME+), and used for Western blot analysis. Ex pression of C5-derived peptides was confirmed with anti-GST antibody (Figure 5A). CFA0305 bound to only the peptide of 33-124 (Figure 5B). CFA0305 bound to beta chain of recombinant human C5 (rhC5) (approx.70kDa), which was used as a control. Figure 5C summarizes the reaction of anti-C5 MAbs to C5-derived peptides.

[0347] 4.5. Binding of anti-C5 MAbs to C5 mutants Since three amino acid residues in the C5 beta-chain: E48, D51, and K109, were predicted to be involved in the binding between C5 and the anti-C5-MAbs by crystal structure analysis, the anti-C5 MAbs were tested for binding to human C5 point mutants in Western blot analysis. C5 point mutants, in which any one of E48, D51, and K109 was substituted with alanine, were expressed in FS293 cells by lipofection. Culture media was harvested 5 days after lipofection, and thereafter used for Western blot. SDS-PAGE was conducted under reducing conditions. The results are shown in Figure 6. Eculizumab bound to alpha-chain of wild type (WT) C5 and three C5 point mutants, whereas CFA0305 bound to the beta-chain of WT C5 strongly, the E48A C5 mutant weakly, and did not bind to the beta-chain of the D5IA and K109A C5 mutants, indicating that these 3 amino acid residues are involved in the antibody/ antigen interactions. Table 5 presents a summary of Western blot analysis of the anti C5 MAbs (CFA0305, CFA0307, CFA0366, CFA0501, CFA0538, CFA0599, CFA0666, CFA0672, and CFA0675). The anti-C5 MAbs are grouped into the same epitope C, but binding patterns are slightly different between the antibodies, suggesting that the binding regions of C5 to the anti-C5 MAbs are close to each other but not identical.

[Table 5] Summary of anti-C5 MAbs reaction to C5 mutants

E48A AWT D51A_ K109A_ Eculizumab + + + +

CFA0305 + + CFA0307 + - CFA0366 + - - CFA0501 + - CFA0538 + - - CFA0599 + - - +

CFA0666 + - - +

CFA0672 + - - +

CFA0675 + + - +

[0348] 4.6. BIACORE (registered trademark) binding analysis of anti-C5 antibodies with C5 mutants To test if residues E48, G51, and K109 are indeed involved in antibody/antigen in teractions, BIACORE (registered trademark) binding analysis was performed. Three

C5 mutants were prepared: E48A, G51A, and K109A, as described in Example 4.5. Culture supernatant samples containing the mutant C5 over-expressed in FS293 cells were prepared at 40 micro g/ml of the mutant C5. For BIACORE (registered trademark) binding analysis, the sample was diluted 1x with BIACORE (registered trademark) running buffer (ACES pH7.4, 10 mg/ml BSA, 1 mg/ml carboxymethyl dextran) to a final sample concentration of 4 micro g/ml of the mutant C5.

[0349] The interactions of the three C5 mutants with anti-C5 antibodies were assessed at 37 degrees C with BIACORE (registered trademark) T200 instrument (GE Healthcare), using the assay condition described in Example 3.2. ACES pH 7.4 buffer containing 10 mg/ml BSA, 1 mg/ml carboxymethyl dextran was used as running buffer. Eculizumab F760G4 and 305LO5 were captured on different flow cells by monoclonal mouse anti human IgG, Fc fragment specific antibody (GE Healthcare). Flow cell 1 was used as the reference surface. Wild type and mutant C5 proteins were injected over sensor surface at 4 micro g/ml concentration to interact with the captured antibodies. At the end of each analysis cycle, the sensor surface was regenerated with 3M MgC 2 . The results were analyzed with Bia Evaluation software, version 2.0 (GE Healthcare). Curves of reference flow cell (flow cell 1) and blank injections of running buffer were subtracted from curves of the flow cell with captured antibodies.

[0350] As shown in Figure 7, all three C5 mutants could bind to eculizumab with a similar binding profile compared to wild type C5. For the 305LO5, all three mutants showed lower binding response to 305LO5 compared to wild type C5. The D51A and K109A mutants reduced the binding of C5 by 305LO5 to the baseline level.

[0351] 4.7. Identification of His residues on C5 that contribute to pH dependent interactions between anti-C5 antibody and C5 The crystal structure analysis revealed that 3 histidine residues on human C5 are located at the antibody/antigen interface. A histidine residue with a typical pKa of ap proximately 6.0 is known to contribute to pH dependent protein-protein interactions (Igawa et al., Biochim Biophys Acta 1844(11):1943-1950 (2014)). To investigate which of the His residues on the antibody/antigen interface contribute to pH dependent interactions between anti-C5 antibody and C5, BIACORE (registered trademark) binding analysis was performed. Three human C5 mutants with a single His mutation (H70Y, H72Y, and H1OY) and a mutant with a double-His mutation (H70Y +

HI1OY) were prepared as follows: single His mutants in which any one of H70, H72, and HI10 is substituted with tyrosine, and a double His mutant in which both H70 and HI10 are substituted with tyrosine, were expressed in FS293 cells by lipofection. The antigen binding properties of the C5 His mutants to 305LO5, a pH-dependent anti-C5 antibody, were determined by a modified BIACORE (registered trademark) assay as described in Example 4.6. Briefly, an additional dissociation phase at pH5.8 was in- tegrated into the BIACORE (registered trademark) assay immediately after the dis sociation phase at pH7.4 to assess the pH-dependent dissociation between the antibody and the antigen from the complexes formed at pH7.4. The dissociation rate at pH5.8 was determined by processing and fitting data using Scrubber 2.0 (BioLogic Software) curve fitting software.

[0352] As shown in Figure 8, the C5 single His mutation at H70 or HI10 and the double His mutation (H70 + HI10) did not affect the binding of C5 to the 305LO5 at neutral pH. Meanwhile, the single His mutation at H72 exhibited a significant impairment of binding of C5 to 305LO5. The dissociation rates at pH5.8 for the C5 His mutants and the C5-wt protein are shown in Table 6. As shown in Table 6, the C5-wt showed fastest dissociation from 305LO5 at pH5.8 among the C5 antigens tested. The single His mutation at H70 exhibited an almost two-fold slower dissociation rate at pH5.8 and the single His mutation at HI10 resulted in a slightly slower dissociation rate at pH5.8 compared to C5-wt. The double His mutation at both H70 and H110 resulted in larger effect on pH-dependent binding with a dissociation rate at pH5.8 almost three fold slower than C5-wt.

[Table 6] pH5.8 dissociation rate value for C5 His mutants binding to 305LO5 Antigens kd (1/s) C5-wt 1.1E-2 C5-H70Y 5.3E-3 C5-H1OY 9.3E-3 C5-H70Y, HIIOY 3.9E-3

Example 5

[0353] Inhibitory activity of anti-C5 antibodies on C5 activation 5.1. Inhibition of complement-activated liposome lysis by anti-C5 MAbs The anti-C5 MAbs were tested for inhibition of complement activity by a liposome lysis assay. Thirty microliters of normal human serum (6.7%) (Biopredic, SER018) was mixed with 20 micro L of the diluted MAb in a 96-well plate and incubated on a shaker for 30 min at 25 degrees C. Liposomes sensitized with the antibodies against dinitrophenyl (Autokit CH50, Wako, 995-40801) were transferred into each well and the plate was placed on a shaker for 2 min at 25 degrees C. Fifty microliters of substrate solution (Autokit CH50) was added to each well and mixed by shaking for 2 min at 25 degrees C. The final mixture was incubated at 37 degrees C for 40 minutes, and thereafter OD at 340 nm of the mixture was measured. The percent of liposome lysis was defined as 100x [(OD Ab - OD serum andliposomebackground)] [(OD withoutMAb - OD serum

Figure 9A shows that anti-C5 Mabs: CFA0305, 0307, 0366, 0501, and liposomebackground)].

0538, 0599, 0666, 0672, and 0675, inhibited the liposome lysis. Two non- pH-dependent antibodies: CFA0330 and 0341, also inhibited the lysis (Figure 9B).

[0354] 5.2. Inhibition of C5a generation by anti-C5 MAbs The anti-C5 MAbs were tested for C5a generation during liposome lysis to confirm that the anti-C5 MAbs inhibit cleavage of C5 into C5a and C5b. The C5a level in the supernatants from liposome lysis assay was quantified using a C5a ELISA kit (R&D systems, DY2037). All MAbs inhibited C5a generation in the supernatants dose dependently (Figures IA and 10B).

[0355] 5.3. Inhibition of complement-activated hemolysis by anti-C5 MAbs The anti-C5 MAbs were tested for inhibition of the classical complement activity in a hemolytic assay. Chicken red blood cells (cRBCs) (Innovative research, IC05-0810) were washed with gelatin/veronal-buffered saline containing 0.5 mM MgCl 2 and 0.15 mM CaCl 2 (GVB++) (Boston BioProducts, IBB-300X), and thereafter sensitized with anti-chicken RBC antibody (Rockland 103-4139) at 1micro g/ml for 15 minutes at 4 degrees C. The cells were then washed with GVB++ and suspended in the same buffer at 5x10 7 cells/ml. In a separate round-bottom 96-well microtest plate, 50 micro 1 of normal human serum (20%) (Biopredic, SER019) was mixed with 50 micro 1 of diluted Mab and incubated on a shaker at 37 degrees C for 30 minutes. Sixty microliters of the sensitized cRBCs suspension was then added to the wells containing the serum, and the antibody mixture was incubated at 37 degrees C for 30 minutes. After the incubation, the plate was centrifuged at 1000 x g for 2 minutes at 4 degrees C. Supernatants (100 micro 1) were transferred to wells on a flat-bottom 96-well microtest plate for mea surement of OD at 415 nm with a reference wavelength at 630 nm. The percent of hemolysis was defined as 100x [(OD Ab - OD serum and cRBCs)]/ [(OD without MAb - OD serum and

cRBCs background)]. Figure 11 shows that anti-C5 Mabs: CFA0305 and 305LO5, inhibited the hemolysis of cRBCs.

[0356] 5.4. Inhibition of alternative complement pathway by anti-C5 MAbs A hemolytic assay for the alternative pathway was performed in a similar way to the classical pathway haemolytic assay. Blood collected from a New Zealand White rabbit (InVivos) was mixed with the same volume of Alsever's solution (Sigma, A3551), and the mixture was used as rabbit RBCs (rRBCs). rRBCs were washed with GVB sup plemented with 2 mM MgCl 2 and 10 mM EGTA and suspended in the same buffer at 7x10 cells/ml. In a round-bottom 96-well microtest plate, 40 micro 1 of normal human serum (25%) (Biopredic, SER019) was mixed with 40 micro 1 of diluted Mab and incubated on a shaker at 37 degrees C for 30 minutes. Twenty microliters of the rRBCs suspension was then added to the wells containing the serum, and the antibody mixture was incubated at 37 degrees C for 60 minutes. After the incubation, the plate was cen trifuged at 1000 x g for 2 minutes at 4 degrees C. Supernatants (70 micro 1) were transferred to wells on a flat-bottom 96-well microtest plate for measurement of OD at

415 nm with a reference wavelength at 630 nm. Figure 12 shows that anti-C5 Mabs: CFA0305 and CFA0672, inhibited the hemolysis of rRBCs, indicating that these an tibodies inhibit the alternative complement pathways. Example 6

[0357] Pharmacokinetic study of anti-C5 monoclonal antibodies with human C5 in mice 6.1. In vivo test using C57BL/6 mice The in vivo kinetics of human C5 (Calbiochem) and anti-human C5 antibody was assessed after administering human C5 alone or human C5 and anti-human C5 antibody to C57BL/6 mice (In Vivos or Biological Resource Centre, Singapore). A human C5 solution (0.01 mg/ml) or a solution of mixture containing human C5 and anti-human C5 antibody (0.01 mg/ml and 2 mg/ml (CFA0305-F760G4, CFA0307-F760G4, CFA0366-F760G4, CFA0501-F760G4, CFA0538-F760G4, CFA0599-F760G4, CFA0666-F760G4, CFA0672-F760G4, and CFA0675-F760G4) or 0.2 mg/ml (CFA0330-F760G4, and CFA0341-F760G4), respectively) was ad ministered once at a dose of 10 ml/kg into the caudal vein. In this case, the anti-human C5 antibody is present in excess over human C5, and therefore almost every human C5 is assumed to be bound to the antibody. Blood was collected 5 minutes, seven hours, one day, two days, three days, and seven days after administration. The collected blood was immediately centrifuged at 14,000 rpm and 4 degrees C for 10 minutes to separate the plasma. The separated plasma was stored in a refrigerator at -80 degrees C before assay. The anti-human C5 antibodies used are: above-described CFA0305-F760G4, CFA0307-F760G4, CFA0330-F760G4, CFA0341-F760G4, CFA0366-F760G4, CFA0501-F760G4, CFA0538-F760G4, CFA0599-F760G4, CFA0666-F760G4, CFA0672-F760G4, and CFA0675-F760G4.

[0358] 6.2. Measurement of total human C5 plasma concentration by electrochemilumi nescence (ECL) assay The concentration of total human C5 in mouse plasma was measured by ECL.

[0359] In the presence of CFA0330-F760G4, CFA0341-F760G4, or human C5 alone in the plasma sample, the following method was used. Anti-human C5 antibody (Santa Cruz) was dispensed onto a MULTI-ARRAY 96-well bare plate (Meso Scale Discovery) and allowed to stand overnight at 4 degrees C to prepare anti-human C5-immobilized plates. Calibration curve samples and mouse plasma samples diluted 100-fold or more with 1 micro g/ml injected antibody (CFA0330-F760G4 or CFA0341-F760G4) were prepared and incubated for 30 minutes at 37 degrees C. Subsequently, the samples were dispensed onto the anti-human C5-immobilized plates, and allowed to stand for one hour at room temperature. Then, SULFO-TAG labelled anti-human IgG antibody (Meso Scale Discovery) was added to react for one hour at room temperature, and washing was performed. Immediately thereafter, Read Buffer T (x4) (Meso Scale Discovery) was dispensed and measurement was performed using a Sector Imager 2400 (Meso Scale Discovery).

[0360] In the presence of CFA0305-F760G4, CFA0307-F760G4, CFA0366-F760G4, CFA0501-F760G4, CFA0538-F760G4, CFA0599-F760G4, CFA0666-F760G4, CFA0672-F760G4, or CFA0675-F760G4 in the plasma sample, the following method was used. Anti-human C5 antibody (CFA0329-F939G4; VH, SEQ ID NO: 23 and VL, SEQ ID NO: 27) was dispensed onto a MULTI-ARRAY 96-well bare plate (Meso Scale Discovery) and allowed to stand overnight at 4 degrees C to prepare anti-human C5-immobilized plates. Calibration curve samples and mouse plasma samples diluted 100-fold or more with acidic solution (pH 5.5) were prepared and incubated for 30 minutes at 37 degrees C. Subsequently, the samples were dispensed onto the anti human C5-immobilized plates, and allowed to stand for one hour at room temperature. Then, SULFO-TAG labelled anti-human C5 antibody (CFA0300-F939G4; VH, SEQ ID NO: 24 and VL, SEQ ID NO: 28) was added to react for one hour at room tem perature, and washing was performed. Immediately thereafter, Read Buffer T (x4) (Meso Scale Discovery) was dispensed and measurement was performed using a Sector Imager 2400 (Meso Scale Discovery).

[0361] The human C5 concentration was calculated based on the response of the calibration curve using the analytical software SOFTmax PRO (Molecular Devices). The time course of plasma human C5 concentration after intravenous administration as measured by this method is shown in Figure 13. Data are plotted as the percentage remaining compared to the plasma human C5 concentration at 5 minutes.

[0362] 6.3. Measurement of anti-human C5 antibody plasma concentration by ECL assay The concentration of anti-human C5 antibody in mouse plasma was measured by ECL. Anti-human IgG (gamma-chain specific) F(ab')2 antibody fragment (Sigma) or anti-human IgG kappa chain antibody (Antibody Solutions) was dispensed onto a MULTI-ARRAY 96-well bare plate (Meso Scale Discovery) and allowed to stand overnight at 4 degrees C to prepare anti-human IgG-immobilized plates. Calibration curve samples and mouse plasma samples diluted 100-fold or more were prepared. Subsequently, the samples were dispensed onto the anti-human IgG-immobilized plates, and allowed to stand for one hour at room temperature. Then, biotinylated Anti Human IgG Antibody (Southembiotech) or SULFO-TAG labelled anti-human IgG Fc antibody (Southernbiotech) was added to react for one hour at room temperature, and washing was performed. Subsequently, only when biotinylated Anti-Human IgG Antibody was used, SULFO-TAG labelled streptavidin (Meso Scale Discovery) was added to react for one hour at room temperature, and washing was performed. Im mediately therafter, Read Buffer T (x4) (Meso Scale Discovery) was dispensed and measurement was performed using a Sector Imager 2400 (Meso Scale Discovery). The anti-human C5 antibody concentration was calculated based on the response of the cal ibration curve using the analytical software SOFTmax PRO (Molecular Devices). The time course of plasma anti-human C5 antibody concentration after intravenous admin istration as measured by this method is shown in Figure 14. Data are plotted as the percentage remaining compared to the plasma anti-human C5 antibody concentration at 5 minutes.

[0363] 6.4. Effect of pH dependent anti-human C5 antibody binding upon clearance of human C5 in vivo The pH dependent anti-human C5 antibodies (CFA0305-F760G4, CFA0307-F760G4, CFA0366-F760G4, CFA0501-F760G4, CFA0538-F760G4, CFA0599-F760G4, CFA0666-F760G4, CFA0672-F760G4, and CFA0675-F760G4) and non pH dependent anti-human C5 antibodies (CFA0330-F760G4, and CFA0341-F760G4) were tested in vivo and the resulting plasma anti-human C5 antibody concentration and plasma human C5 concentration were compared. As shown in Figure 14, the antibody exposure was comparable. Meanwhile, the clearance of human C5 simultaneously administered with the pH dependent anti-human C5 an tibodies was accelerated compared to that with the nonpH dependent anti-human C5 antibodies (Figure 13). Example 7

[0364] Optimization of anti-C5 monoclonal antibodies (305 variants) A number of mutations were introduced to the optimized variable region of the anti C5 antibody 305LO5 to further improve its properties, and the optimized variable regions 305LO15, 305LO16, 305LO18, 305LO19, 305LO20, 305LO22, and 305LO23 were generated. Amino acid sequences of VH and VL of the 305 variants are listed in Tables 7 and 8, respectively. The genes encoding the humanized VH were combined with a modified human IgG ICH variant SG115 (SEQ ID NO: 114), and modified human IgG4 CH variants SG422 (SEQ ID NO: 115) or SG429 (SEQ ID NO: 116). The genes encoding the humanized VL were combined with a human CL (SKI, SEQ ID NO: 38). Separately, heavy and light chain genes encoding a humanized anti-C5 antibody, BNJ441 (BNJ441H, SEQ ID NO: 149; BNJ441L, SEQ ID NO: 150), were synthesized and each was cloned into an expression vector.

[0365] Antibodies were expressed in HEK293 cells co-transfected with a combination of heavy and light chain expression vectors, and were purified by protein A.

[Table 7] VH amino acid sequences of the 305 variants Antibody VH HVR-H1 HVR-H2 HVR-H3

SEQ ID NO: 54 SEQ ID NO: 64 SEQ ID NO: 74 305LO5 SEQ ID NO: 10 SSYYVA AIYTGSGATYKASWAKG DGGYDYPTHAMHY

SEQIDNO:117 SEQIDNO:118 SEQIDNO:121 305LO15 SEQIDNO:106 SSYYMA AIFTGSGAEYIKAEWAKG DAGYDYPTHAMHY

SEQIDNO:117 SEQIDNO:119 SEQIDNO:121 305LO16 SEQIDNO:107 SSYYMA AIFTGSGAEYKAEWVKG DAGYDYPTHAMHY

SEQIDNO:117 SEQIDNO:118 SEQIDNO:121 305LO18 SEQIDNO:108 SSYYMA AIFTGSGAEYKAEWAKG DAGYDYPTHAMHY

SEQIDNO:117 SEQIDNO:118 SEQIDNO:121 305LO19 SEQIDNO:109 SSYYMA AIFTGSGAEYKAEWAKG DAGYDYPTHAMHY

SEQ ID NO: 117 SEQ ID NO: 118 SEQ ID NO: 121 305LO20 SEQ ID NO: 109 SSYYMA AIFTGSGAEYKAEWAKG DAGYDYPTHAMHY

SEQ ID NO: 117 SEQ ID NO: 118 SEQ ID NO: 121 305LO22 SEQ ID NO: 109 SSYYMA AIFTGSGAEYI(AEWAKG DAGYDYPTHAMHY

SEQ ID NO: 117 SEQ ID NO: 120 SEQ ID NO: 121 305LO23 SEQ ID NO: 110 SSYYMA GIFTGSGATYKAEWAKG DAGYDYPTHAMHY

[Table 8] VL amino acid sequences of the 305 variants Antibody VL HVR-L1 HVR-L2 HVR-L3

SEQ ID NO: 84 SEQ ID NO: 94 SEQ ID NO: 104 305LO5 SEQ ID NO: 20 QASQNIGSSLA GASKTHS QSTKVGSSYGNH

SEQ ID NO: 122 SEQ ID NO: 123 SEQ ID NO: 125 305LO15 SEQ ID NO: 111 RASQGISSSLA GASETES QNTIKVGSSYGNT

SEQ ID NO: 122 SEQ ID NO: 123 SEQ ID NO: 125 305LO16 SEQID NO: 111 RASQGISSSLA GASETES QNTIKVGSSYGNT

SEQ ID NO: 122 SEQ ID NO: 123 SEQ ID NO: 125 305LO18 SEQID NO: 111 RASQGISSSLA GASETES QNTKVGSSYGNT SEQ ID NO: 122 SEQ ID NO: 123 SEQ ID NO: 125 305LO19 SEQID NO: 111 RASQGISSSLA GASETES QNTKVGSSYGNT SEQ ID NO: 122 SEQ ID NO: 123 SEQ ID NO: 125 305LO20 SEQID NO: 112 RASQGISSSLA GASETES QNTKVGSSYGNT

SEQ ID NO: 122 SEQ ID NO: 124 SEQ ID NO: 125 305LO22 SEQID NO: 113 RASQGISSSLA GASTTQS QNTKVGSSYGNT

SEQ ID NO: 122 SEQ ID NO: 124 SEQ ID NO: 125 305LO23 SEQID NO: 113 RASQGISSSLA GASTTQS QNTKVGSSYGNT

Example 8

[0366] Binding characterization of anti-C5 antibodies (305 variants) The kinetic parameters of anti-C5 antibodies against recombinant human C5 were assessed at 37 degrees C using BIACORE (registered trademark) T200 instrument (GE Healthcare) at three different conditions; (1) both association and dissociation were at pH7.4, (2) both association and dissociation were at pH5.8, and (3) association was at pH7.4 but dissociation was at pH5.8. ProA/G (Pierce) was immobilized onto a CM1 sensorchip using amine coupling kit (GE Healthcare) according to the recommended settings by GE Healthcare. Antibodies and analytes for condition (1) and (3) were diluted in ACES pH7.4 buffer (20 mM ACES, 150 mM NaCl, 1.2 mM CaC 2, 0.05% Tween 20, 0.005% NaN) and for condition (2) they were diluted in ACES pH5.8 buffer (20 mM ACES, 150 mM NaCl, 1.2 mM CaC 2, 0.05% Tween 20,0.005% NaN ). Each antibody was captured onto the sensor surface by ProA/G. Antibody capture levels were typically 60-90 resonance units (RU). Then, recombinant human C5 was injected at 3 to 27 nM or 13.3 to 120 nM prepared by three-fold serial dilution, followed by dissociation. The surface was regenerated using 25 mM NaOH. Kinetic parameters at condition (1) and (2) were determined by fitting the sensorgrams with a 1:1 binding model and the dissociation rate at condition (3) was determined by fitting the sensorgrams with a 1:1 dissociation for MCK model using BIACORE (registered trademark) T200 Evaluation software, version 2.0 (GE Healthcare). pH dependency of all antibodies were shown as ratio of dissociation rate of condition (2) and (1).

[0367] Association rate (ka), dissociation rate (kd), binding affinity (KD), and pH de pendency are listed in Table 9. All antibodies showed a faster dissociation rate at pH 5.8 than pH7.4 and their pH dependency was around 20 fold.

[Table 9] Kinetics parameters of anti-C5 antibody variants under pH7.4 and pH5.8 conditions 7.4_7.4 5.8_5.8 7.4_5.8 pH ka (1/Ms) kd (/s) KD (M) ka (1/Ms) kd (1/s) KD (M) kd (1/s) dependency L015-SG422 1.40E+06 4.19E-04 300E-10 1.34E+05 8.79E-03 6.57E-08 1.61E-02 21.0 L015-SG115 1.31E+06 3.54E-04 2.70E-10 9.49E+04 8.27E-03 8.72E-08 1.67E-02 23.4 LO16-SG422 1.28E+06 4.12E-04 3.21E-10 1.09E+05 8.69E-03 7.95E-08 1.61E-02 21.1 L018-SG422 1.36E+06 4.26E-04 3.14E-10 1.39E+05 8.65E-03 6.24E-08 1.69E-02 20.3 L019-SG422 1.37E+06 4.76E-04 3.46E-10 1.38E+05 8.30E-03 6,OOE-08 1.61E-02 17.4 L020-SG115 1.44E+06 4.67E-04 3.24E-10 1.41E+05 8.18E-03 5.81E-08 1.61E-02 17.5 L020-SG422 1.35E+06 4.70E-04 3.49E-10 1.36E+05 8.15E-03 5.99E-08 1.55E-02 17.3 L022-SG115 1.46E+06 3.82E-04 2.62E-10 1.71E+05 9.30E-03 5.45E-08 1.46E-02 24.3 L023-SG115 1 53E+06 4.23E-04 2.77E-10 1 33E+05 8.55E-03 6.41E-08 1,73E-02 20.2

[0368] The binding affinity of anti-C5 antibodies (BNJ441, eculizumab, and a 305 variant) to recombinant human C5 at pH7.4 and pH5.8 were determined at 37 degrees C using a BIACORE (registered trademark) T200 instrument (GE Healthcare) to assess the effect of pH upon antigen binding. Goat anti-human IgG (Fc) polyclonal antibody (KPL #01-10-20) was immobilized onto a CM4 sensorchip using an amine coupling kit (GE Healthcare) according to the recommended settings by manufacturer. Antibodies and analytes were diluted either in ACES pH7.4 buffer or ACES pH5.8 buffer containing 20 mM ACES, 150 mM NaCl, 1.2 mM CaCl 2,0.05% Tween 20, and 0.005% NaN. Antibodies were captured on the sensor surface using the anti-Fc method, capture levels were typically 50-80 resonance units (RU). Recombinant human C5 was prepared by three-fold serial dilution starting from 27 nM for pH7.4 assay conditions, or 135 nM for pH 5.8 assay conditions. The surface was regenerated using 20 mM HCl, 0.01% Tween 20. The data were processed and fit with a 1:1 binding model using BiaEvaluation 2.0 software (GE Healthcare).

[0369] The binding affinity (KD) of BNJ441, eculizumab, and the 305 variant to re combinant human C5 at pH7.4 and pH5.8 is shown in Table 10. The 305 variant showed a ratio of (KD at pH 5.8)/(KD at pH 7.4) of almost 800, 8 fold higher than BNJ441 which only showed a ratio of (KD at pH 5.8)/(KD at pH 7.4) of 93.

[Table 10]

Antibody KD (M) ratio of KD at pH 7.4 pH 5.8 pH 5.8/pH 7.4 305L05 variant 1.66E-10 1.32E-07 795 Eculizumab 1.42E-10 2.64E-09 19 BNJ441 1.38E-09 1.28E-07 93

Example 9

[0370] Inhibitory activity of anti-C5 antibodies (305 variants) on C5 activation 9.1. Inhibition of complement-activated liposome lysis by anti-C5 MAbs The anti-C5 MAbs were tested for inhibition of complement activity by a liposome lysis assay. Thirty microliters of normal human serum (6.7%) (Biopredic, SER019) was mixed with 20micro L of diluted MAb in a 96-well plate and incubated on a shaker for 30 min at room temperature. Liposome solution sensitized with antibodies against dinitrophenyl (Autokit CH50, Wako, 995-40801) was transferred into each well and placed on a shaker for 2 min at 37 degrees C. Fifty microliters of substrate solution (Autokit CH50) was added to each well and mixed by shaking for 2 min at 37 degrees C. The final mixture was incubated at 37 degrees C for 40 minutes, and thereafter OD at 340 nm was measured. The percent of liposome lysis was defined as 100x [(OD MAb - OD serum and iposome background)]! [(OD withoutMAb - OD serum and liposome background)].

Figure 15 shows that the anti-C5 Mabs: 305LO15-SG422, 305LO16-SG422, 305LO18-SG422, 305LO19-SG422, 305LO20-SG422, and 305LO20-SG115, inhibited liposome lysis. Two antibodies with Fc variants: 305LO15-SG115 and 305LO23-SG429, also inhibited lipisome lysis (Figure 16).

[0371] The anti-C5 MAbs were tested for inhibition of recombinant human C5 (SEQ ID NO: 39). Ten microliters of C5-deficient human serum (Sigma, C1163) was mixed with 20micro L of diluted MAb and 20micro L of recombinant C5 (0.1micro g/mL) in a 96-well plate and incubated on a shaker for 1 hour at 37 degrees C. Liposomes (Autokit CH50) were transferred into each well and placed on a shaker for 2 min at 37 degrees C. Fifty microliters of substrate solution (Autokit CH50) was added to each well and mixed by shaking for 2 min at 37 degrees C. The final mixture was incubated at 37 degrees C for 180 minutes, and thereafter OD at 340 nm was measured. The percent of liposome lysis was defined as above. Figure 17 shows that anti-C5 Mabs: 305LO22-SG115, 305LO22-SG422, 305LO23-SG115, and 305LO23-SG422, inhibited liposome lysis.

[0372] 9.2. Inhibition of C5a generation by anti-C5 MAbs Anti-C5 MAbs were tested for C5a generation during liposome lysis to confirm that anti-C5 MAbs inhibit cleavage of C5 into C5a and C5b. C5a levels in the supernatants from a liposome lysis assay were quantified using a C5a ELISA kit (R&D systems, DY2037). All MAbs inhibited C5a generation in the supernatants in a dose-dependent manner (Figures 18 and 19).

[0373] 9.3. Measurement of complement activity in cynomolgus monkey plasma Anti-C5 MAbs were tested for inhibition of complement activity in cynomolgus monkey plasma. The anti-C5 Mabs were intra administered to the monkeys (20mg/kg), and plasma samples were collected periodically until day 56. Chicken red blood cells (cRBCs) (Innovative research, IC05-0810) were washed with gelatin/veronal-buffered saline containing 0.5 mM MgCl 2 and 0.15 mM CaCl 2 (GVB++) (Boston BioProducts, IBB-300X), and thereafter sensitized with anti-chicken RBC antibody (Rockland 103-4139) at Imicro g/ml for 15 minutes at 4 degrees C. The cells were then washed with GVB++ and suspended in the same buffer at 1x108 cells/ml. In a separate round bottom 96-well microtest plate, monkey plasma was incubated with the sensitized cRBCs at 37 degrees C for 20 minutes. After the incubation, the plate was centrifuged at 1000 x g for 2 minutes at 4 degrees C. Supernatants were transferred to wells on a flat-bottom 96-well microtest plates for measurement of OD at 415 nm with a reference wavelength at 630 nm. The percent of hemolysis was defined as lOOx [(OD Post administration - OD plasma and cRBCs background)] [(OD Pre administration - OD plasma and cRBCs background)]

Figure 20 shows that anti-C5 MAbs: 305LO15-SG422, 305LO15-SG115, 305LO16-SG422, 305LO18-SG422, 305LO19-SG422, 305LO20-SG422, 305LO20-SG115, and 305LO23-SG115, inhibited the complement activity in the plasma.

[0374] 9.4. Inhibition of biological activity of C5 variants by anti-C5 MAbs Anti-C5 MAbs were tested for the inhibition of recombinant human C5 variants: V1451, R449G, V8021, R885H, R928Q, D966Y, S131ON, and E1437D. It has been reported that PNH patients who have a R885H mutation in C5 show poor response to eculizumab (see, e.g., Nishimura et al., New Engl. J. Med. 370:632-639 (2014)). Each of the human C5 variants was expressed in FS293 cells, and the supernatants were used for the following study. Ten microliters of C5-deficient human serum (Sigma, C1163) was mixed with 20micro L of diluted MAb and 20micro L of cell culture media containing a recombinant C5 variant (2-3micro g/mL) in a 96-well plate and incubated on a shaker for 0.5 hour at 37 degrees C. Liposomes (Autokit CH50) were transferred into each well and placed on a shaker for 2 min at 37 degrees C. Fifty mi croliters of substrate solution (Autokit CH50) was added to each well and mixed by shaking for 2 min at 37 degrees C. The final mixture was incubated at 37 degrees C for 90 minutes, and thereafter OD at 340 nm was measured. The percent of liposome lysis was defined as above. Figure 21 shows that an anti-C5 MAb (eculizumab) did not inhibit the R885H C5 variant, but inhibited the other variants tested. Figure 22 shows that the anti-C5 MAb (a 305 variant) inhibited all variants of C5 tested.

[0375] 9.5. Inhibition of complement-activated liposome lysis by anti-C5 MAbs

Anti-C5 MAbs were tested for inhibition of complement activity by a liposome lysis assay. Thirty microliters of normal human serum (6.7%) (Biopredic, SER019) was mixed with 20micro L of diluted MAb in a 96-well plate and incubated on a shaker for 30 min at room temperature. Liposome solution sensitized with antibodies against dini trophenyl (Autokit CH50, Wako, 995-40801) was transferred into each well and placed on a shaker for 2 min at 25 degrees C. Fifty microliters of substrate solution (Autokit CH50) was added to each well and mixed by shaking for 2 min at 25 degrees C. The final mixture was incubated at 37 degrees C for 45 minutes, and thereafter OD at 340 nm was measured. The percent inhibition of liposome lysis was defined as 100x [(OD MAb - OD serum andliposome background)] [(OD without MAb - OD serum and liposome background)]. Figure 23 shows that the anti-C5 MAbs, BNJ441 and the 305 variant inhibited liposome lysis, and that the 305 variant has stronger inhibitory activity than BNJ441. Example 10

[0376] Pharmacokinetic study of anti-C5 monoclonal antibodies (305 variants) in cynomolgus monkey 10.1. In vivo test using cynomolgus monkey The in vivo kinetics of anti-human C5 antibody was assessed after administering anti-human C5 antibody in cynomolgus monkey (Shin Nippon Biomedical Labo ratories, Ltd., Japan). A solution of anti-human C5 antibody (2.5 mg/ml) was ad ministered once at a dose of approximately 8 ml/kg into the cephalic vein of the forearm by 30 minutes infusion. Blood was collected at pre-administration and 5 minutes, seven hours, one day, two days, three days, seven days, fourteen days, twenty one days, twenty eight days, thirty five days, forty two days, forty nine days, and fifty six days after administration. The collected blood was immediately centrifuged at 1,700 x g and 4 degrees C for 10 minutes to separate the plasma. The separated plasma was stored in a refrigerator at -70 degrees C or below before assay. The anti-human C5 antibodies were prepared as described in Example 7.

[0377] 10.2. Measurement of total cynomolgus monkey C5 plasma concentration by ELISA assay The concentration of total cynomolgus monkey C5 in cynomolgus monkey plasma was measured by ELISA. Anti-human C5 antibody (in-house antibody generated using the method described in Example 2) was dispensed onto Nunc-ImmunoPlate MaxiSorp (Nalge Nunc International) and allowed to stand overnight at 4 degrees C to prepare anti-cynomolgus monkey C5-immobilized plates. Calibration curve samples and cynomolgus monkey plasma samples diluted 20000-fold with 0.4micro g/ml injected antibody were prepared and incubated for 60 minutes at 37 degrees C. Subsequently, the samples were dispensed onto the anti-cynomolgus monkey C5-immobilized plates, and allowed to stand for one hour at room temperature. Then, HRP-labelled anti human IgG Antibody (SouthemBiotech) was added to react for thirty minutes at room temperature, and washing was performed. Subsequently, ABTS ELISA HRP Substrate (KPL) was added. The signal was measured by a plate reader at a wavelength of 405 nm. The cynomolgus monkey C5 concentration was calculated based on the response of the calibration curve using the analytical software SOFTmax PRO (Molecular Devices). The time course of plasma cynomolgus monkey C5 concentration after in travenous administration as measured by this method is shown in Figure 24. Data are plotted as the percentage remaining compared to plasma cynomolgus monkey C5 con centration at pre-administration. The pH dependent anti-human C5 antibodies (305LO15-SG422, 305LO15-SG115, 305LO16-SG422, 305LO18-SG422, 305LO19-SG422, 305LO20-SG422, 305LO20-SG115, 305LO22-SG422, 305LO23-SG422, and 305LO23-SG115) showed lower accumulation of plasma C5 compared to non pH dependent anti-human C5 antibodies.

[0378] 10.3. Measurement of anti-human C5 antibody plasma concentration by ELISA assay The concentration of anti-human C5 antibody in cynomolgus monkey plasma was measured by ELISA. Anti-human IgG kappa chain antibody (Antibody Solutions) was dispensed onto Nunc-ImmunoPlate MaxiSorp (Nalge Nunc International) and allowed to stand overnight at 4 degrees C to prepare anti-human IgG-immobilized plates. Cal ibration curve samples and cynomolgus monkey plasma samples diluted 100-fold or more were prepared. Subsequently, the samples were dispensed onto the anti-human IgG-immobilized plates, and allowed to stand for one hour at room temperature. Then, HRP-labelled anti-human IgG antibody (SouthernBiotech) was added to react for thirty minutes at room temperature, and washing was performed. Subsequently, ABTS ELISA HRP Substrate (KPL) was added. The signal was measured by a plate reader at a wavelength of 405 nm. The anti-human C5 antibody concentration was calculated based on the response of the calibration curve using the analytical software SOFTmax PRO (Molecular Devices). The time course of plasma anti-human C5 antibody con centration after intravenous administration as measured by this method is shown in Figure 25. The pH dependent anti-human C5 antibodies (305LO15-SG422, 305LO15-SG115, 305LO16-SG422, 305LO18-SG422, 305LO19-SG422, 305LO20-SG422, 305LO20-SG115, 305LO22-SG422, 305LO23-SG422, and 305LO23-SG115) displayed longer half-life compared to non pH dependent anti human C5 antibodies. Example 11

[0379] X-ray crystal structure analysis of a 305 variant Fab and human C5-MG1 domain complex

11.1. Expression and purification of the MG1 domain (20-124) of human C5 The MG1 domain (amino acid residues 20-124 of SEQ ID NO:39) fused to a GST-tag via thrombin cleavable linker (GST-MG1) was expressed in the E. coli strain BL21 DE3 pLysS (Promega) using a pGEX-4T-1 vector (GE healthcare). Protein expression was induced with 0.1 mM Isopropyl beta-D-1-thiogalactopyranoside (IPTG) at 25 degrees C for 5 hours. The bacterial cell pellet was lysed with Bugbuster (Merck) sup plemented with lysonase (Merck) and complete protease inhibitor cocktail (Roche), followed by the purification of GST-MG1 from the soluble fraction using a GSTrap column (GE healthcare) according to the manufacturer's instruction. The GST tag was cleaved with thrombin (Sigma), and the resulting MG1 domain was further purified with a Superdex 75 gel filtration column (GE healthcare). Fractions containing MG1 domain were pooled and stored at -80 degrees C.

[0380] 11.2. Preparation of Fab fragment of a 305 variant Fab fragments of one of the optimized variants from 305 were prepared by the con ventional method using limited digestion with papain (Roche Diagnostics, Cat No.1047825), followed by loading onto a protein A column (MabSlect SuRe, GE Healthcare) to remove Fc fragments, a cation exchange column (HiTrap SP HP, GE Healthcare), and a gel filtration column (Superdex200 16/60, GE Healthcare). Fractions containing Fab fragment were pooled and stored at -80 degrees C.

[0381] 11.3. Preparation of a 305 variant Fab and human C5-MG1 domain complex Purified recombinant human C5-MG1 domain was mixed with a purified 305 variant Fab fragment in a 1:1 molar ratio. The complex was purified by gel filtration chro matography (Superdex200 10/300 increase, GE Healthcare) using a column equi librated with 25 mM HEPES pH 7.5, 100 mM NaCl.

[0382] 11.4. Crystallization The purified complexes were concentrated to about 10 mg/mL, and crystallization was carried out by the sitting drop vapor diffusion method in combination with the seeding method at 4 degrees C. The reservoir solution consisted of 0.2 M magnesium formate dehydrate, 15.0% w/v polyethylene glycol 3350. This succeeded in yielding plate-like crystals in a few days. The crystal was soaked in a solution of 0.2 M magnesium formate dehydrate, 25.0% w/v polyethylene glycol 3350, and 20% glycerol.

[0383] 11.5. Data collection and structure determination X-ray diffraction data were measured by BL32XU at SPring-8. During the mea surement, the crystal was constantly placed in a nitrogen stream at -178 degrees C to maintain a frozen state, and a total of 180 X-ray diffraction images were collected using an MX-225HS CCD detector (RAYONIX) attached to a beam line, while rotating the crystal 1.0 degrees at a time. Determination of the cell parameters, indexing the diffraction spots, and processing the diffraction data obtained from the diffraction images were performed using the Xia2 program (J. Appl. Cryst. 43:186-190 (2010), XDS Package (Acta. Cryst. D66:125-132 (2010)), and Scala (Acta. Cryst. D62:72-82 (2006)), and finally the diffraction intensity data up to 2.11 Angstrom resolution was obtained. The crystallography data statistics are shown in Table 11.

[Table 11] X-ray data collection and refinement statistics

Data collection Space group P1 Unit Cell a, b,c (A) 39.79, 55.10, 127.76 a,y (°) 89.18, 86.24, 78.20 Resolution(A) 49.49-2.11 Total reflections 112,102 Unique reflections 56,154 Completeness (highest resolution shell) (%) 92.1(95.8) Emerge "(highest resolution shell)(%) 7.2 (31.7) Refinement Resolution(A) 25.00-2.11 Reflections 53,398 R factor ) (Rfeee) (%) 20.42 (26.44) rms deviation from ideal Bond lengths (A) 0.0088 Bond angles (°) 1.3441

a;Rerge =Zhklj[j (hkli) - KJ(hki)) |/YhklYj|Ij (hk)|, where Ij (hkl) and (K(hkl)) are the intensity of measurements and the mean intensity for the reflection with indices hkl, respectively. b; R factor = ZhkllFeatc(hkl)| - Fob. (hkl)/Zhkl|Foss(hkl), where F bs 0 and Fcaic are the observed and calculated structure factor amplitudes, respectively. c; Ree is calculated with 5% of the reflection randomly set aside.

[0384] The structure was determined by molecular replacement with the program Phaser (J. Appl. Cryst. 40:658-674 (2007)). The search model of the Fab domain was derived from the published human IgG4 Fab crystal structure (PDB code:1BBJ), and the search model of the MG1 domain was from the published human C5 crystal structure (PDB code: 3CU7, Nat.Immunol. 9:753-760 (2008)). A model was built with the Coot program (Acta Cryst. D66:486-501 (2010)) and refined with the program Refmac5 (Acta Cryst. D67:355-367 (2011)). The crystallographic reliability factor (R) for the diffraction intensity data from 25-2.11 Angstrom was 20.42%, with a Free R value of 26.44%. The structure refinement statistics are shown in Table 11.

[0385] 11.6. Overall structure of a 305 variant Fab and C5-MG1 domain complex

The Fab fragment of an optimized variant from 305 ("305 Fab") bound to the human C5-MG1 domain ("MG") in a 1:1 ratio, and the asymmetric unit of the crystal structure contained two complexes, Molecules 1 and 2, as depicted in Figure 26A. Molecules 1 and 2 can be aligned well at 0.717 Angstrom RMSD with the C alpha atom position in all the residues, as shown in Figure 26B. The figures discussed below were prepared using Molecule 1.

[0386] In Figures 27A and 27B, the epitope of the 305 Fab contact region is mapped in the MG1 amino acid sequence and in the crystal structure, respectively. The epitope includes the amino acid residues of MG1 that contain one or more atoms located within 4.5 Angstrom distance from any part of the 305 Fab in the crystal structure. In addition, the epitope within 3.0 Angstrom is highlighted in Figure 27A.

[0387] 11.7. Interactions of E48, D51, and K109 As described in Examples 4.5 and 4.6, the anti-C5 Mabs that include the 305 antibody series were tested for binding to three human C5 point mutants, E48A, D51A, and K109A, by Western blot and BIACORE (registered trademark) binding analyses. While the 305 variants bound WT C5 strongly, they bound the E48A C5 mutant only weakly and did not bind to the D51A and K109A mutants. The crystal structure of the 305 Fab and MG1 complex revealed that the three amino acids E48, D51, and K109, are all within 3.0 Angstrom distance from the 305 Fab, forming a number of hydrogen bonds with the Fab, as shown in Figure 28A. On more detailed examination, the K109 residue of MG1 is buried in a groove formed at the interface of the heavy chain of the Fab and tightly interacts with the Fab by three hydrogen bonds with H-CDR3_G97, H CDR3_Y100, and H-CDR3_TiOb, and by a salt bridge with H-CDR3_D95 (Figure 28D). D51 is located between MG1 and the heavy chain of the 305 Fab and makes two hydrogen bonds with H-CDR1_Ser32 and H-CDR2_Ser54 to fill the space (Figure 28C). These indicate that K109 and D51 of C5 are both critical residues for binding of the 305 antibody series. On the other hand, E48 is located closer to the surface and forms only one hydrogen bond with the Fab, suggesting that its contribution to the antibody binding would be less than those of K109 and E51 (Figure 28B). These rela tionships are consistent with the results of the Western blot and BIACORE (registered trademark) binding analyses of human C5 mutants (Examples 4.5 and 4.6). Sup plementary note: residue numbering for the Fab amino acids is based on the Kabat numbering scheme. (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991)

[0388] 11.8. Interactions of H70, H72, and HI10 of human C5 and 305 antibody series The crystal structure analysis revealed that three histidine residues on human C5, namely, H70, H72, and HI10, are included in the epitope of the 305 variant Fab, as shown in Figure 27A and Figure 29A. A BIACORE (registered trademark) binding analysis was performed to investigate the contribution of these histidine residues to the pH-dependent protein-protein interaction between human C5 and the 305 variant Fab using the human C5 mutants H70Y, H72Y, H110Y, and H70Y+H1OY (Example 4.7). H72Y resulted in the complete loss of the binding of the 305 variant Fab to C5. This residue of C5 is located in the pocket formed by the CDR2 loop of the heavy chain of the 305 Fab and the loop of MG1 (L73, S74, and E76) and fills this space tightly, as shown in Figure 29C. In addition, the H72 residue of C5 makes a hydrogen bond with H-CDR2_Y58. The H72Y mutation would not be expected to be tolerated as there is not enough space to accommodate the bulkier side chain of tyrosine. Also a hydrogen bond with H-CDR2_Y58 cannot be maintained. With regards to the contribution of H70 and HI10 to pH dependency, H70Y and HIOY mutations resulted in slower dis sociation of the 305 variant Fab from C5 at pH 5.8. H70 forms an intra-molecular hydrogen bond with T53 of MG1, which is believed to be disrupted at pH 5.8 when protonation of H70 of C5 causes a conformational change in the corresponding part of the interaction interface of MG1 (Figure 29B). For HI10, protonation of this C5 residue would be expected to cause a charge repulsion to the 305 Fab, which may be augmented by the protonation of the neighboring histidine residue, H-CDR3_H1Oc (Figure 29D).

[0389] Although the foregoing invention has been described in some detail by way of il lustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The dis closures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.t SEQUENCE LISTING SEQUENCE LISTING <110> <110> CHUGAI SEI CHUGAI SEIYAKU KABUSHIKI YAKU KABUSHI KAISHA KI KAISHA

<120> <120> ANTI-C5 ANTI -C5 ANTIBODIES AND METHODS ANTI BODIES AND METHODSOFOFUSE USE

<130> <130> C1-A1606P C1-A1606P

<150> <150> JP 2016-120325 JP 2016-120325 <151> <151> 2016-06-17 2016-06-17

<160> <160> 150 150 <170> <170> PatentIn versi PatentIn version 3.5 on 3. 5

<210> <210> 1 1 <211> <211> 121 121 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 1 1

Gln Ser Gln Ser Leu LeuGlu GluGlu Glu SerSer GlyGly Gly Gly Asp Asp Leu Lys Leu Val Val Pro LysGly ProALGly Ala Ser a Ser 1 1 5 5 10 10 15 15

Leu Ala Val Leu Ala ValThr ThrCys Cys Thr Thr AlaAla SerSer Gly Gly Phe Phe Ser Ser Ser Ser SerSer SerSer Ser Ser Tyr Tyr 20 20 25 25 30 30

Tyr Met Tyr Met Cys CysTrp TrpVal Val ArgArg GlnGln Ala Ala Pro Pro Gly Gly Gly Lys Lys Leu GlyGlu LeuTrp Glu lleTrp Ile 35 35 40 40 45 45

Gly Cys Gly Cys lle IleTyr TyrThr Thr GlyGly SerSer Gly Gly Ala Ala Thr Tyr Thr Tyr Tyr Al Tyr Ala Trp a Ser SerAITrp a Ala 50 50 55 55 60 60

Lys Gly Arg Lys Gly ArgPhe PheThr Thr lleIle SerSer Lys Lys Thr Thr Ser Ser Ser Thr Ser Thr ThrVal ThrThr Val LeuThr Leu

70 70 75 75 80 80

Gln Met Thr Gln Met ThrSer SerLeu LeuThrThr ValVal Ala Al a AspAsp ThrThr Ala Ala Thr Thr Tyr Cys Tyr Phe PheAICys a Ala 85 85 90 90 95 95

Ser Asp Gly Ser Asp GlyGly GlyTyr Tyr ValVal ThrThr Pro Pro Thr Thr His His Al a Ala Met Met Tyr Trp Tyr Leu LeuGITrp Gly 100 100 105 105 110 110

Pro Gly Thr Pro Gly ThrLeu LeuVal Val Thr Thr ValVal Ser Ser Ser Ser 115 115 120 120

<210> <210> 2 2 <211> <211> 117 117 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> Page Page 11

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt <223> <223> AnAnartificially artificially synthesized synthesi sequence zed sequence

<400> <400> 2 2

Gln Ser Gln Ser Leu LeuGlu GluGlu Glu SerSer GlyGly Gly Gly Gly Gly Leu Lys Leu Val Val Pro LysGly ProAla Gly SerAla Ser 1 1 5 5 10 10 15 15

Leu Thr Leu Leu Thr LeuThr ThrCys Cys LysLys AlaAla Ser Ser Gly Gly lle Ile Asp Ser Asp Phe PheAsn SerPhe AsnTyrPhe Tyr 20 20 25 25 30 30

Tyr lle Tyr Ile Cys Cys Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Asp Asp Leu Leu lle Ile 35 35 40 40 45 45

Alaa Cys AI Cys Ile Tyr Thr lle Tyr ThrVal ValSer SerGlyGly TyrTyr Thr Thr Tyr Tyr Tyr Ser Tyr Ala Ala Trp SerAlTrp a Ala 50 50 55 55 60 60

Lys Gly Arg Lys Gly ArgLeu LeuThr Thr lleIle SerSer Lys Lys Thr Thr Ser Ser Ser Thr Ser Thr ThrVal ThrThr Val LeuThr Leu

70 70 75 75 80 80

Gln Met Gln Met Thr ThrSer SerLeu LeuThrThr AlaAla Ala Ala Asp Asp Thr Thr Thr Ala Ala Tyr ThrPhe TyrCys Phe AlaCys Ala 85 85 90 90 95 95

Arg Asp Arg Asp Leu LeuHis HisAlAla Glylle a Gly Ile ThrThr AsnAsn Leu Leu Trp Trp Gly Gly Pro Thr Pro Gly GlyLeu Thr Leu 100 100 105 105 110 110

Val Thr Val Thr Val ValSer SerSer Ser 115 115

<210> <210> 3 3 <211> <211> 122 122 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An arti An artificially synthesized ficially synthesi sequence zed sequence

<400> <400> 3 3

Gln Ser Leu Gln Ser LeuGlu GluGlu Glu SerSer GlyGly Gly Gly Asp Asp Leu Lys Leu Val Val Pro LysGly ProAla Gly SerAla Ser 1 1 5 5 10 10 15 15

Leu Ser Leu Leu Ser LeuThr ThrCys Cys Thr Thr Al Ala Ala a Ala GlyGly LeuLeu Asp Asp Phe Phe Ser Ser Ser Ser SerTyr Ser Tyr 20 20 25 25 30 30

Tyr Met Tyr Met Cys Cys Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp lle Ile 35 35 40 40 45 45

Alaa Cys AI Cys Ile Tyr Ala lle Tyr AlaGly GlySer SerSerSer GlyGly Ile I le lleIle TyrTyr Tyr Tyr Ala Ala Asn Trp Asn Trp 50 50 55 55 60 60

Alaa Lys AI Lys Gly Arg Phe Gly Arg PheThr Thrlle Ile SerSer ArgArg Pro Pro Ser Ser Ser Thr Ser Thr Thr Val ThrThr Val Thr Page Page 22

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.txt

70 70 75 75 80 80

Leu Gln Met Leu Gln MetThr ThrSer Ser Leu Leu ThrThr AlaAla Ala Ala Asp Asp Thr Thr Thr Ala AlaTyr ThrPhe Tyr CysPhe Cys 85 85 90 90 95 95

Alaa Thr AI Thr Tyr Pro Thr Tyr Pro ThrTyr TyrGly Gly AspAsp GlyGly Gly Gly His His Ala Ala Phe Leu Phe Asn AsnTrp Leu Trp 100 100 105 105 110 110

Gly Pro Gly Pro Gly GlyThr ThrLeu Leu ValVal ThrThr Val Val Ser Ser Ser Ser 115 115 120 120

<210> <210> 4 4 <211> <211> 117 117 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 4 4

Gln Ser Gln Ser Val Val Glu Glu Glu Glu Ser Ser Gly Gly Gly Gly Arg Arg Leu Leu Val Val Thr Thr Pro Pro Gly Gly Thr Thr Pro Pro 1 1 5 5 10 10 15 15

Leu Thr Leu Leu Thr LeuThr ThrCys Cys ThrThr AL Ala Ser a Sen GlyGly PhePhe Ser Ser Leu Leu Ser Tyr Ser Ser SerTyr Tyr Tyr 20 20 25 25 30 30

Met Asn Met Asn Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp lle Ile Gly Gly 35 35 40 40 45 45

Met lle Met Ile Tyr TyrGly GlySer Ser GlyGly AI Ala a ThrThr TyrTyr Tyr Tyr Al aAla SerSer Trp Trp Al aAla Lys Lys Gly Gly 50 50 55 55 60 60

Arg Phe Arg Phe Thr Thrlle IleSer Ser LysLys ThrThr Ser Ser Ser Ser Thr Val Thr Thr Thr Asp ValLeu AspLys Leu MetLys Met

70 70 75 75 80 80

Thr Ser Thr Ser Leu LeuThr ThrThr ThrGluGlu AspAsp Thr Thr Ala Ala Thr Phe Thr Tyr Tyr Cys PheAICys AlaGln a Arg Arg Gln 85 85 90 90 95 95

Ile Tyr Ser lle Tyr SerGly GlyAsp Asp Asn Asn AsnAsn AspAsp Asn Asn Phe Phe Trp Pro Trp Gly GlyGly ProThr Gly LeuThr Leu 100 100 105 105 110 110

Val Thr Val Thr Val ValSer SerSer Ser 115 115

<210> <210> 5 5 <211> <211> 117 117 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> Page Page 33

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt <223> <223> AnAnarti artificially synthesized ificially synthesi sequence zed sequence

<400> <400> 5 5

Gln Ser Val Gln Ser ValGlu GluGlu Glu SerSer GlyGly Gly GI y ArgArg LeuLeu Val Val Thr Thr Pro Thr Pro Gly GlyPro Thr Pro 1 1 5 5 10 10 15 15

Leu Thr Leu Leu Thr LeuThr ThrCys Cys Thr Thr Al.Ala SerGly a Ser GlyPhe Phe SerSer LeuLeu Ser Ser Ser Ser Tyr Tyr Tyr Tyr 20 20 25 25 30 30

Met Asn Met Asn Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp lle Ile Gly Gly 35 35 40 40 45 45

Met lle Met Ile Tyr TyrGly GlySer Ser GlyGly Al Ala a ThrThr TyrTyr Tyr Tyr AI aAla SerSer Trp Trp Al aAla Lys Lys Gly Gly 50 50 55 55 60 60

Arg Phe Arg Phe Thr Thrlle IleSer Ser LysLys ThrThr Ser Ser Ser Ser Thr Val Thr Thr Thr Asp ValLeu AspLys Leu MetLys Met

70 70 75 75 80 80

Thr Ser Thr Ser Leu LeuThr ThrThr ThrGluGlu AspAsp Thr Thr Al aAla Thr Thr Tyr Tyr Phe Phe Cysa Ala Cys Al Argr Gln Arg GI 85 85 90 90 95 95

Ile Tyr Ser lle Tyr SerGly GlyAsp Asp Asn Asn AsnAsn AspAsp Asn Asn Phe Phe Trp Pro Trp Gly GlyGly ProThr Gly Thr Leu Leu 100 100 105 105 110 110

Val Thr Val Thr Val ValSer SerSer Ser 115 115

<210> <210> 6 6 <211> <211> 117 117 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An arti An artificially synthesized ficially synthesi sequence zed sequence

<400> <400> 6 6

Gln Ser Val Gln Ser ValGlu GluGlu Glu SerSer GlyGly Gly Gly Arg Arg Leu Thr Leu Val Val Pro ThrGly ProThr Gly ProThr Pro 1 1 5 5 10 10 15 15

Leu Thr Leu Leu Thr LeuThr ThrCys Cys Thr Thr ValVal SerSer Gly Gly Leu Leu Ser Ser Ser Leu LeuAsp SerAsn Asp Asn Thr Thr 20 20 25 25 30 30

Met Thr Met Thr Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp lle Ile Gly Gly 35 35 40 40 45 45

Ile Ile Ser lle lle SerPhe PheGly Gly Gly Gly AspAsp AlaAla Tyr Tyr Tyr Tyr AI a Ala Ser Ser Trp Lys Trp Ala AlaGly Lys Gly 50 50 55 55 60 60

Arg Phe Arg Phe Pro Prolle IleSer Ser LysLys ThrThr Ser Ser Thr Thr Thr Asp Thr Val Val Leu AspArg Leulle Arg ThrIle Thr Page Page 44

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.txt

70 70 75 75 80 80

Ser Pro Thr Ser Pro ThrThr ThrGlu GluAspAsp ThrThr Ala Ala Thr Thr Tyr Tyr Phe AI Phe Cys Cys Ala Val a Arg ArgGly Val Gly 85 85 90 90 95 95

Alaa Gly AI Gly Asn Ile Phe Asn lle PheTrp TrpTyr Tyr PhePhe AspAsp Leu Leu Trp Trp Gly Gly Pro Thr Pro Gly GlyLeu Thr Leu 100 100 105 105 110 110

Val Thr Val Thr Val ValSer SerSer Ser 115 115

<210> <210> 7 7 <211> <211> 116 116 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 7 7

Gln Ser Gln Ser Val Val Glu Glu Glu Glu Ser Ser Gly Gly Gly Gly Arg Arg Leu Leu Val Val Thr Thr Pro Pro Gly Gly Thr Thr Pro Pro 1 1 5 5 10 10 15 15

Leu Thr Leu Leu Thr LeuThr ThrCys Cys Thr Thr ValVal Sen Ser Gly Gly Phe Phe Ser Ser Ser Leu LeuThr SerTyr ThrAlaTyr Ala 20 20 25 25 30 30

Met Gly Met Gly Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp lle Ile Gly Gly 35 35 40 40 45 45

Thr lle Thr Ile Asp AspThr ThrGly Gly AspAsp AsnAsn Ser Ser Phe Phe Tyra Ala Tyr AI Asn Asn Trpa Ala Trp AI Lys Gly Lys Gly 50 50 55 55 60 60

Arg Phe Arg Phe Thr Thrlle IleSer Ser LysLys ThrThr Ser Ser Thr Thr Thr Asp Thr Val Val Leu AspLys Leulle Lys ThrIle Thr

70 70 75 75 80 80

Ser Pro Thr Ser Pro ThrAlAla GluAsp a Glu AspThr Thr AI Ala ThrTyr a Thr Tyr PhePhe CysCys AI aAla ArgArg Asn Asn Asp Asp 85 85 90 90 95 95

Gly Ser Gly Ser Val ValTyr TyrAsn Asn LeuLeu PhePhe Asn Asn Leu Leu Trp Pro Trp Gly Gly Gly ProThr GlyLeu Thr ValLeu Val 100 100 105 105 110 110

Thr Val Thr Val Ser SerSer Ser 115 115

<210> <210> 8 8 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> Page Page 55

JPOXMLDOC01-seql.txt JPOXMLDOC01-segl. txt <223> <223> AnAnartificially artificially synthesized synthesi sequence zed sequence

<400> <400: 8 8

Gln Ser Val Gln Ser ValGlu GluGlu Glu SerSer GlyGly Gly GI y ArgArg LeuLeu Val Val Thr Thr Pro Thr Pro Gly GlyPro Thr Pro 1 1 5 5 10 10 15 15

Leu Thr Leu Leu Thr LeuThr ThrCys Cys Thr Thr AlaAla SenSer Gly Gly Phe Phe Ser Ser Ser Leu LeuGly SerAsn GlyAlaAsn Ala 20 20 25 25 30 30

Ile Asn Trp lle Asn TrpVal ValArg Arg Gln Gln AlaAla ProPro Gly Gly Lys Lys Gly Glu Gly Leu LeuTrp Glulle Trp GlyIle Gly 35 35 40 40 45 45

Cys lle Cys Ile Tyr TyrThr ThrGly Gly SerSer AspAsp Thr Thr Thr Thr Tyr AI Tyr Tyr Tyra Ala Thr Al Thr Trp Trp Ala Lys a Lys 50 50 55 55 60 60

Gly Arg Gly Arg Phe PheThr Thrlle Ile SerSer LysLys Thr Thr Ser Ser Thr Val Thr Thr Thr Asp ValLeu AspLys Leu lleLys Ile

70 70 75 75 80 80

Alaa Ser Al Ser Pro Thr Thr Pro Thr ThrGlu GluAsp Asp ThrThr Al Ala Thr a Thr TyrTyr PhePhe Cys Cys Al aAla Arg Arg Gly Gly 85 85 90 90 95 95

Ser Gly Leu Ser Gly LeuTrp TrpGly Gly ProPro GlyGly Thr Thr Leu Leu Val Val Thr Ser Thr Val ValSer Ser Ser 100 100 105 105 110 110

<210> <210> 9 9 <211> <211> 116 116 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 9 9 Gln Ser Gln Ser Val Val Glu Glu Glu Glu Ser Ser Gly Gly Gly Gly Arg Arg Leu Leu Val Val Thr Thr Pro Pro Gly Gly Thr Thr Pro Pro 1 1 5 5 10 10 15 15

Leu Thr Leu Leu Thr LeuThr ThrCys Cys Thr Thr ValVal SerSer Gly Gly Phe Phe Ser Ser Ser Leu LeuThr SerTyr Thr Tyr Ala Ala 20 20 25 25 30 30

Met Gly Met Gly Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp lle Ile Gly Gly 35 35 40 40 45 45

Thr lle Thr Ile Asp AspThr ThrGly Gly AspAsp AsnAsn Ser Ser Phe Phe Tyra Ala Tyr AI Asn Asn Trp Lys Trp Ala AlaGly Lys Gly 50 50 55 55 60 60

Arg Phe Arg Phe Thr Thrlle IleSer Ser ArgArg ThrThr Ser Ser Thr Thr Thr Asp Thr Val Val Leu AspLys Leulle Lys ThrIle Thr

70 70 75 75 80 80

Ser Pro Thr Ser Pro ThrAlAla GluAsp a Glu AspThr Thr Ala Ala ThrThr TyrTyr Phe Phe Cys Cys Ala aAla ArgArg Asn Asn Asp Asp Page Page 66

JPOXMLDOC01-seql.txt JPOXMLDOC01-segl. txt 85 85 90 90 95 95

Gly Ser Gly Ser Val ValTyr TyrAsn Asn LeuLeu PhePhe Asn Asn Leu Leu Trp Pro Trp Gly Gly Gly ProThr GlyLeu Thr ValLeu Val 100 100 105 105 110 110

Thr Val Thr Val Ser SerSer Ser 115 115

<210> <210> 10 10 <211> <211> 123 123 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 10 10

Gln Val Gln Val Gln Gln Leu Leu Val Val Glu Glu Ser Ser Gly Gly Gly Gly Gly Gly Leu Leu Val Val Gln Gln Pro Pro Gly Gly Gly Gly 1 1 5 5 10 10 15 15

Ser Leu Arg Ser Leu ArgLeu LeuSer Ser CysCys Al Ala a Al Ala SerGly a Ser Gly PhePhe ThrThr Ser Ser His His Ser Ser Ser Ser 20 20 25 25 30 30

Tyr Tyr Tyr Tyr Val Val Ala Ala Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp 35 35 40 40 45 45

Val Gly Val Gly Ala Ala lle Ile Tyr Tyr Thr Thr Gly Gly Sen Ser Gly Gly Ala Ala Thr Thr Tyr Tyr Lys Lys Ala Ala Ser Ser Trp Trp 50 50 55 55 60 60

Alaa Lys AI Lys Gly Arg Phe Gly Arg PheThr Thrlle Ile SerSer LysLys Asp Asp Thr Thr Ser Ser Lys Gln Lys Asn AsnVal Gln Val

70 70 75 75 80 80

Val Leu Val Leu Thr ThrMet MetThr ThrAsnAsn MetMet Asp Asp Pro Pro Val Thr Val Asp Asp Ala ThrThr AlaTyr Thr TyrTyr Tyr 85 85 90 90 95 95

Cys Al Cys Alaa Ser Asp Gly Ser Asp GlyGly GlyTyr Tyr Asp Asp TyrTyr Pro Pro Thr Thr His His Al a Ala Met Met His Tyr His Tyr 100 100 105 105 110 110

Trp Gly Trp Gly Gln GlnGly GlyThr Thr LeuLeu ValVal Thr Thr Val Val Ser Ser Ser Ser 115 115 120 120

<210> <210> 11 11 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 11 11

Page Page 77

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.txt Asp Val Asp Val Val ValMet MetThr Thr GlnGln ThrThr Pro Pro AI aAla Ser Ser Val Val Ser Ser Al a Ala AI aAla Val Val Gly Gly 1 1 5 5 10 10 15 15

Gly Thr Gly Thr Val ValThr Thr11Ile LysCys e Lys Cys Gln Gln AI Ala Ser a Ser GlnGln AsnAsn lle Ile Gly Gly Ser Asp Ser Asp 20 20 25 25 30 30

Leu Ala Trp Leu Ala TrpTyr TyrGln Gln Gln Gln LysLys ProPro Gly Gly Gln Gln Pro Arg Pro Pro ProLeu ArgLeu Leu lleLeu Ile 35 35 40 40 45 45

Tyr Gly Tyr Gly Al Ala Ser Lys a Ser LysLeu LeuAIAla SerGly a Ser Gly Val Val SerSer SerSer Arg Arg Phe Phe Ser Gly Ser Gly 50 50 55 55 60 60

Ser Gly Ser Ser Gly SerGly GlyLys Lys GI Glu Phe u Phe Thr Thr LeuLeu ThrThr lle Ile Ser Ser Asp Glu Asp Leu LeuCys Glu Cys

70 70 75 75 80 80

Alaa Asp AI Asp Ala AI a Val Val Thr Tyr Tyr Thr Tyr TyrCys CysGln Gln Cys Cys ThrThr PhePhe Val Val Gly Gly Ser Ser Ser Ser 85 85 90 90 95 95

Tyr Gly Tyr Gly Asn AsnAIAla PheGly a Phe GlyGly Gly GlyGly ThrThr Glu Glu Val Val Val Val Val Lys Val Lys 100 100 105 105 110 110

<210> <210> 12 12 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An artificially An artificially synthesi synthesized sequence sequence <400> < 400 12 12

Ala Ile Glu Ala lle GluMet MetThr Thr GlnGln ThrThr Pro Pro Phe Phe Ser Ser Ser Val Val Al Ser Ala Val a Ala AlaGly Val Gly 1 1 5 5 10 10 15 15

Gly Thr Gly Thr Val ValThr ThrllIle LysCys e Lys Cys Gln Gln AlaAla Sen Ser Gln Gln Asn Asn Ile Sen lle Tyr TyrAsn Ser Asn 20 20 25 25 30 30

Leu Alaa Trp Leu AI Tyr Gln Trp Tyr GlnGln GlnLys Lys Pro Pro GlyGly GlnGln Arg Arg Pro Pro Lys Leu Lys Leu Leulle Leu Ile 35 35 40 40 45 45

Tyr Gly Tyr Gly Ala Ala Ser Ser Asn Asn Leu Leu Glu Glu Ser Ser Gly Gly Val Val Pro Pro Ser Ser Arg Arg Phe Phe Lys Lys Gly Gly 50 50 55 55 60 60

Ser Gly Ser Gly Ser SerGly GlyThr Thr GluGlu TyrTyr Thr Thr Leu Leu Thr Ser Thr lle Ile Asp SerLeu AspGlu Leu CysGlu Cys

70 70 75 75 80 80

Alaa Asp AI Asp Ala Al a Ala AI aThr Thr Tyr Tyr Tyr Cys Leu Tyr Cys LeuGln GlnGly GlyTyr Tyr SerSer TyrTyr Ser Ser Asn Asn 85 85 90 90 95 95

Val Asp Val Asp Asp AspAIAla PheGly a Phe GlyGly Gly GlyGly ThrThr Glu Glu Val Val Val Lys Val Val Val Lys Page Page 88

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt 100 100 105 105 110 110

<210> <210> 13 13 <211> <211> 112 112 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 13 13

Ala Gln Ala Gln Val ValLeu LeuThr Thr GlnGln ThrThr Pro Pro Ser Ser Ser Ser Ser Val Val Ala SerAla AlaVal Ala GlyVal Gly 1 1 5 5 10 10 15 15

Gly Thr Gly Thr Val ValThr Thrlle Ile AsnAsn CysCys Gln Gln Ser Ser Ser Ser Ser Gln Gln Val SerTyr ValSer TyrSerSer Ser 20 20 25 25 30 30

Asp Tyr Asp Tyr Leu LeuSer SerTrp Trp TyrTyr GlnGln Gln Gln Lys Lys Pro Gln Pro Gly Gly Pro GlnPro ProLys Pro LeuLys Leu 35 35 40 40 45 45

Leu Ile Tyr Leu lle TyrGlu GluAla Ala SerSer LysLys Leu Leu Al aAla SerSer Gly Gly Val Val Pro Arg Pro Pro ProPhe Arg Phe 50 50 55 55 60 60

Ser Gly Ser Ser Gly SerGly GlySen Ser GlyGly ThrThr Gln Gln Phe Phe Thr Thr Thr Leu Leu lle ThrSer IleGly Ser ValGly Val

70 70 75 75 80 80

Gln Cys Gln Cys Asp AspAsp AspAla AlaAlaAla ThrThr Tyr Tyr Tyr Tyr Cys Gly Cys Gln Gln Thr GlyTyr ThrTyr Tyr SerTyr Ser 85 85 90 90 95 95

Ser Gly Trp Ser Gly TrpTyr TyrPhe Phe AlaAla PhePhe Gly Gly Gly Gly Gly Glu Gly Thr Thr Val GluVal ValVal Val LysVal Lys 100 100 105 105 110 110

<210> <210> 14 14 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 14 14

Ala Al a Tyr Tyr Asp Met Thr Asp Met ThrGln GlnThr Thr Pro Pro AL Ala Ser a Ser ValVal GluGlu Val Val Ala Ala Val Gly Val Gly 1 1 5 5 10 10 15 15

Gly Thr Gly Thr Val ValThr Thrlle Ile AsnAsn CysCys Gln Gln Ala Ala Ser Ser Ser Glu Glu lle SerSer IleAsn SerTrpAsn Trp 20 20 25 25 30 30

Leu Ala Trp Leu Ala TrpTyr TyrGln Gln GlnGln LysLys Pro Pro Gly Gly Gln Gln Arg Lys Arg Pro ProLeu LysLeu Leu lleLeu Ile 35 35 40 40 45 45

Page Page 99

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql. txt Tyr Arg Tyr Arg Ala AlaSer SerThr Thr LeuLeu Al Ala a SerSer GlyGly Val Val Ser Ser Ser Ser Arg Lys Arg Phe PheGly Lys Gly 50 50 55 55 60 60

Ser Gly Ser Ser Gly SerGly GlyThr Thr GlnGln PhePhe Thr Thr Leu Leu Thr Ser Thr lle Ile Gly SerVal GlyGlu Val CysGlu Cys

70 70 75 75 80 80

Asp Asp Asp Asp Al Ala Alaa Thr a AI Tyr Tyr Thr Tyr TyrCys CysGln Gln Gln Gln AspAsp TyrTyr Ser Ser Ser Ser Ser Asn Ser Asn 85 85 90 90 95 95

Val Asp Val Asp Asn Asn Thr Thr Phe Phe Gly Gly Gly Gly Gly Gly Thr Thr Lys Lys Val Val Val Val Val Val Glu Glu 100 100 105 105 110 110

<210> <210> 15 15 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 15 15

Ala AL a Tyr Tyr Asp Met Thr Asp Met ThrGln GlnThr Thr Pro Pro AI Ala Ser a Ser ValVal GluGlu Val Val Ala Ala Val Gly Val Gly 1 1 5 5 10 10 15 15

Gly Thr Gly Thr Val Val Thr Thr lle Ile Asn Asn Cys Cys Gln Gln Ala Ala Ser Ser Glu Glu Ser Ser lle Ile Ser Ser Asn Asn Trp Trp 20 20 25 25 30 30

Leu Ala aTrp Leu Ala Trp Tyr Tyr Gln Gln Lys Gln Gln LysPro ProGly GlyGln Gln ArgArg ProPro Lys Lys Leu Leu Leu Ile Leu lle 35 35 40 40 45 45

Tyr Arg Tyr Arg AI Ala Ser Thr a Ser ThrLeu LeuAla AlaSerSer GlyGly Val Val Ser Ser Ser Ser Arg Lys Arg Phe PheGly Lys Gly 50 50 55 55 60 60

Ser Gly Ser Sen Gly SerGly GlyThr Thr Gln Gln PhePhe Thr Thr Leu Leu Thr Thr Ile Gly lle Ser SerVal GlyGlu Val CysGlu Cys

70 70 75 75 80 80

Asp Asp Asp Asp AI Ala Ala aThr a Ala Thr Tyr Tyr Tyr Cys Gln Tyr Cys GlnGln GlnAsp AspTyr Tyr SerSer SerSer Ser Ser Asn Asn 85 85 90 90 95 95

Val Asp Val Asp Asn Asn Thr Thr Phe Phe Gly Gly Gly Gly Gly Gly Thr Thr Thr Thr Val Val Val Val Val Val Glu Glu 100 100 105 105 110 110

<210> <210> 16 16 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 16 16 Page 10 Page 10

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt

Alaa Tyr Al Tyr Asp Met Thr Asp Met ThrGln GlnThr Thr Pro Pro AlaAla SerSer Val Val Glu Glu Val Val Val Ser SerGly Val Gly 1 1 5 5 10 10 15 15

Gly Thr Val Gly Thr ValThr ThrIIIle LysCys e Lys Cys Gln Gln Al Ala Ser a Ser GluGlu SerSer lle Ile Tyr Tyr Ser Ala Ser Ala 20 20 25 25 30 30

Leu Ala Trp Leu Ala TrpTyr TyrGln Gln Gln Gln LysLys ProPro Gly Gly Gln Gln Pro Lys Pro Pro ProLeu LysLeu Leu lleLeu Ile 35 35 40 40 45 45

Tyr Ser Tyr Ser Al Ala Ser Thr a Ser ThrLeu LeuAIAla SerGIGly a Ser ValPro y Val ProSer Ser ArgArg PhePhe Lys Lys Gly Gly 50 50 55 55 60 60

Ser Gly Ser Ser Gly SerGly GlyThr Thr GluGlu TyrTyr Thr Thr Leu Leu Thr Ser Thr lle Ile Asp SerLeu AspGlu Leu CysGlu Cys

70 70 75 75 80 80

Alaa Asp AI Asp Ala AI a Ala AI aThr Thr Tyr Tyr Tyr Cys Gln Tyr Cys GlnGln GlnTyr TyrTyr Tyr SerSer SerSer Thr Thr Asn Asn 85 85 90 90 95 95

Val His Val His Asn Asn Ser Ser Phe Phe Gly Gly Gly Gly Gly Gly Thr Thr Thr Thr Val Val Val Val Val Val Glu Glu 100 100 105 105 110 110

<210> <210> 17 17 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An arti An artificially synthesized ficially synthesi sequence zed sequence

<400> <400> 17 17

Asp Val Asp Val Val ValMet MetThr Thr GlnGln ThrThr Pro Pro AI aAla Ser Ser Val Val Ser Ser Alaa Ala Ala Al Val Gly Val Gly 1 1 5 5 10 10 15 15

Gly Thr Gly Thr Val ValThr Thrlle Ile LysLys CysCys Gln Gln AL aAla Ser Ser Glu Glu Asn Asn Ile Ser lle Tyr TyrAla Ser Ala 20 20 25 25 30 30

Leu Ser Trp Leu Ser TrpTyr TyrGln Gln GlnGln LysLys Pro Pro Gly Gly Leu Leu Arg Arg Arg Pro ProLeu ArgLeu Leu lleLeu Ile 35 35 40 40 45 45

Tyr Tyr Tyr Tyr Ala AlaSer SerThr Thr LeuLeu Al Ala a SerSer GlyGly Val Val Pro Pro Ser Ser Arg Lys Arg Phe PheGly Lys Gly 50 50 55 55 60 60

Ser Arg Ser Ser Arg SerGly GlyThr Thr GluGlu PhePhe Thr Thr Leu Leu Thr Thr Ile Asp lle Ser SerLeu AspGlu Leu CysGlu Cys

70 70 75 75 80 80

Alaa Asp AI Asp Ala AI a Ala AI aThr Thr Tyr Tyr Tyr Cys Gln Tyr Cys GlnGln GlnTyr TyrTyr Tyr AspAsp lleIle Asn Asn Ser Ser 85 85 90 90 95 95

Page 11 Page 11

JPOXMLDOC01-seql.txt JPOXMLDOC01-segl. txt Val Asp Val Asp Asn Asn Thr Thr Phe Phe Gly Gly Gly Gly Gly Gly Thr Thr Lys Lys Val Val Val Val Val Val Glu Glu 100 100 105 105 110 110

<210> <210> 18 18 <211> <211> 111 111 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 18 18

Asp Val Asp Val Val Val Met Met Thr Thr Gln Gln Thr Thr Pro Pro Ala Ala Ser Ser Val Val Ser Ser Ala Ala Pro Pro Val Val Gly Gly 1 1 5 5 10 10 15 15

Gly Thr Gly Thr Val ValThr Thrlle Ile LysLys CysCys Gln Gln Ala Ala Ser Asn Ser Gln Gln lle AsnTyr IleSer TyrLeuSer Leu 20 20 25 25 30 30

Leu Alaa Trp Leu Al Tyr Gln Trp Tyr GlnGln GlnLys Lys Pro Pro GlyGly Gl Gln r ProPro ProPro Lys Lys Leu Leu Leu Ile Leu lle 35 35 40 40 45 45

Tyr His Tyr His Thr ThrSer SerAsp Asp LeuLeu AlaAla Ser Ser GI yGly Val Val Pro Pro Ser Ser Arg Arg Arg Phe PheGly Arg Gly 50 50 55 55 60 60

Ser Gly Ser Ser Gly SerGly GlyThr Thr GluGlu PhePhe Thr Thr Leu Leu Thr Ser Thr lle Ile Asp SerLeu AspGlu Leu CysGlu Cys

70 70 75 75 80 80

Alaa Asp AI Asp Ala Alaa Thr Ala AL Tyr Tyr Thr Tyr TyrCys CysGln Gln Cys Cys ThrThr AlaAla Tyr Tyr Gly Gly Ser Ser Ser Ser 85 85 90 90 95 95

Asp Val Asp Val Gly GlyGly GlyThr Thr PhePhe GlyGly Gly Gly Gly Gly Thr Val Thr Thr Thr Val ValVal ValGlu Val Glu 100 100 105 105 110 110

<210> <210> 19 19 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 19 19

Asp Val Asp Val Val ValMet MetThr Thr GlnGln ThrThr Pro Pro Ala Ala Ser Ser Ser Val Val Ala SerAla AlaVal Ala GlyVal Gly 1 1 5 5 10 10 15 15

Gly Thr Gly Thr Val ValThr Thrlle Ile LysLys CysCys Gln Gln Ala Ala Ser Asn Ser Glu Glu lle AsnTyr IleSer TyrAlaSer Ala 20 20 25 25 30 30

Leu Ser Trp Leu Ser TrpTyr TyrGln Gln GlnGln LysLys Pro Pro Gly Gly Leu Leu Arg Arg Arg Pro ProLeu ArgLeu Leu lleLeu Ile 35 35 40 40 45 45

Page 12 Page 12

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt

Tyr Tyr Tyr Tyr Al Ala Ser Thr a Ser ThrLeu LeuAlAla SerGly a Ser Gly Val Val ProPro SerSer Arg Arg Phe Phe Lys Gly Lys Gly 50 50 55 55 60 60

Ser Arg Ser Ser Arg SerGly GlyThr Thr GluGlu PhePhe Thr Thr Leu Leu Thr Ser Thr lle Ile Asp SerLeu AspGlu Leu CysGlu Cys

70 70 75 75 80 80

Alaa Asp Al Asp Ala AI a Ala Ala Ser Tyr Tyr Ser Tyr TyrCys CysGln Gln Gln Gln TyrTyr TyrTyr Asp Asp lle Ile Asn Ser Asn Ser 85 85 90 90 95 95

Val Asp Val Asp Asn AsnThr ThrPhe Phe GlyGly GlyGly Gly Gly Thr Thr Lys Val Lys Val Val Val ValGIVal u Glu 100 100 105 105 110 110

<210> <210> 20 20 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An arti An artificially synthesized ficially synthesi sequence zed sequence

<400> <400> 20 20 Asp Val Asp Val Val Val Met Met Thr Thr Gln Gln Ser Ser Pro Pro Ser Ser Ser Ser Leu Leu Ser Ser Ala Ala Ser Ser Val Val Gly Gly 1 1 5 5 10 10 15 15

Asp Arg Asp Arg Val ValThr Thrlle Ile ThrThr CysCys Gln Gln Ala Ala Ser Asn Ser Gln Gln lle AsnGly IleSer GlySerSer Ser 20 20 25 25 30 30

Leu Alaa Trp Leu AI Tyr Gln Trp Tyr GlnGln GlnLys Lys Pro Pro GlyGly GlnGln Ala Ala Pro Pro Arg Leu Arg Leu Leulle Leu Ile 35 35 40 40 45 45

Tyr Gly Tyr Gly Al Ala Ser Lys a Ser LysThr ThrHis HisSerSer GlyGly Val Val Pro Pro Ser Ser Arg Ser Arg Phe PheGly Ser Gly 50 50 55 55 60 60

Ser Gly Ser Ser Gly SerGly GlyThr Thr AspAsp PhePhe Thr Thr Leu Leu Thr Ser Thr lle Ile Ser SerLeu SerGln Leu ProGln Pro

70 70 75 75 80 80

Glu Asp Glu Asp Val ValAlAla ThrTyr a Thr TyrTyr Tyr CysCys GlnGln Ser Ser Thr Thr Lys Lys Val Ser Val Gly GlySer Ser Ser 85 85 90 90 95 95

Tyr Gly Tyr Gly Asn AsnHiHis PheGly s Phe GlyGly Gly GlyGly ThrThr Lys Lys Val Val Glu Glu Ile Lys lle Lys 100 100 105 105 110 110

<210> <210> 21 21 <211> <211> 117 117 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

Page 13 Page 13

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt <400> 21 <400 21 Gln Ser Leu Gln Ser LeuGlu GluGlu Glu SerSer GlyGly Gly Gly Asp Asp Leu Glu Leu Val Val Pro GluGly ProAlGly Ala Ser a Ser 1 1 5 5 10 10 15 15

Leu Thr Leu Leu Thr LeuThr ThrCys Cys ThrThr AlaAla Ser Ser Gly Gly Phe Phe Ser Asn Ser Trp TrpSer AsnGly SerTyrGly Tyr 20 20 25 25 30 30

Asp Met Asp Met Cys Cys Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp lle Ile 35 35 40 40 45 45

Alaa Cys AI Cys Ile Tyr Thr lle Tyr ThrGly GlySer SerSerSer Al Ala Asn a Asn ThrThr AlaAla Tyr Tyr Al aAla Asn Asn Trp Trp 50 50 55 55 60 60

Alaa Lys AI Lys Gly Arg Phe Gly Arg PheThr Thrlle Ile SerSer LysLys Thr Thr Ser Ser Ser Ser Thr Val Thr Thr ThrThr Val Thr

70 70 75 75 80 80

Leu Gln Met Leu Gln MetThr ThrGly GlyLeuLeu ThrThr Ala Al a AlaAla AspAsp Thr Thr Ala Ala Thr Phe Thr Tyr TyrCys Phe Cys 85 85 90 90 95 95

Alaa Arg Al Arg His Hi s Asp Asp Asp Tyr Phe Asp Tyr PhePhe PheAsp Asp Leu Leu TrpTrp GlyGly Pro Pro Gly Gly Thr Leu Thr Leu 100 100 105 105 110 110

Val Thr Val Thr Val ValSer SerSer Ser 115 115

<210> <210> 22 22 <211> <211> 115 115 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 22 22 Gln Ser Gln Ser Val ValGlu GluGlu Glu SerSer GlyGly GI yGly ArgArg Leu Leu Val Val Thr Thr Pro Thr Pro Gly GlyPro Thr Pro 1 1 5 5 10 10 15 15

Leu Thr Leu Leu Thr LeuThr ThrCys Cys Thr Thr ValVal SerSer Gly Gly lle Ile Asp Ser Asp Leu LeuSer SerTyr Ser Tyr Thr Thr 20 20 25 25 30 30

Met Gly Met Gly Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Cys Cys lle Ile Gly Gly 35 35 40 40 45 45

Tyr lle Tyr Ile Hi His Ser Phe s Ser PheGly GlySer SerThrThr TyrTyr Tyr Tyr AI aAla SerSer Trp Trp Al aAla Lys Lys Gly Gly 50 50 55 55 60 60

Arg Phe Arg Phe Thr Thrlle IleSer Ser LysLys ThrThr Ser Ser Thr Thr Thr Asp Thr Val Val Leu AspGlu Leulle Glu ThrIle Thr

70 70 75 75 80 80

Page 14 Page 14

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.txt Ser Pro Thr Ser Pro ThrThr ThrGlu GluAspAsp ThrThr Ala Al a ThrThr TyrTyr Phe Phe Cys Cys Al a Ala Arg Arg Asp Val Asp Val 85 85 90 90 95 95

Gly Gly Gly Gly Ser SerSer SerGly Gly TrpTrp AspAsp Leu Leu Trp Trp Gly Gly Gly Gln Gln Thr GlyLeu ThrVal Leu ThrVal Thr 100 100 105 105 110 110

Val Ser Val Ser Ser Ser 115 115

<210> <210> 23 23 <211> <211> 116 116 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 23 23 Gln Gl r Ser Ser Leu Glu Glu Leu Glu GluSer SerGly Gly Gly Gly GlyGly LeuLeu Val Val Lys Lys Pro Ala Pro Gly GlySer Ala Ser 1 1 5 5 10 10 15 15

Leu Thr Leu Leu Thr LeuThr ThrCys Cys ThrThr AI Ala Ser a Ser GlyGly PhePhe Ser Ser Phe Phe Ser Gly Ser Ser SerTyr Gly Tyr 20 20 25 25 30 30

Tyr Met Tyr Met Cys Cys Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp lle Ile 35 35 40 40 45 45

Gly Cys Gly Cys lle IleGly GlyThr Thr lleIle SerSer Asp Asp Ser Ser Thr Tyr Thr Tyr Tyr Ala TyrSer AlaTrp Ser Al Trp a Ala 50 50 55 55 60 60

Lys Gly Arg Lys Gly ArgPhe PhePro Pro lleIle SerSer Lys Lys Al aAla SerSer Ser Ser Thr Thr Thr Thr Thr Val ValLeu Thr Leu

70 70 75 75 80 80

Gln Met Gln Met Thr ThrSer SerLeu LeuThrThr AlaAla AI aAla AspAsp Thr Thr Ala Ala Thr Thr Tyr Cys Tyr Phe PheAlCys a Ala 85 85 90 90 95 95

Arg Asp Arg Asp Pro ProTyr TyrSer Ser TyrTyr GlyGly Asp Asp Leu Leu Trp Pro Trp Gly Gly Gly ProThr GlyLeu Thr ValLeu Val 100 100 105 105 110 110

Thr Val Thr Val Ser SerSer Ser 115 115

<210> <210> 24 24 <211> <211> 125 125 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

Page 15 Page 15

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt <400> < 400 > 24 24 Gln Glu Gln Glu Gln GlnLeu LeuGlu Glu GluGlu SerSer Gly Gly Gly Gly Asp Val Asp Leu Leu Lys ValPro LysGlu Pro GlyGlu Gly 1 1 5 5 10 10 15 15

Ser Leu Thr Ser Leu ThrLeu LeuThr Thr CysCys ThrThr Ala AI a SerSer GlyGly Phe Phe Ser Ser Phe Ser Phe Sen SerGly Ser Gly 20 20 25 25 30 30

Asn Trp Asn Trp lle Ile Cys Cys Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp 35 35 40 40 45 45

Ile Alaa Cys lle AI Ile Tyr Cys lle TyrGly GlyGly GlySer Ser ValVal GlyGly Gly Gly Thr Thr Asp Al Asp Tyr Tyr Ala Ser a Ser 50 50 55 55 60 60

Trp Al Trp Alaa Lys Gly Arg Lys Gly ArgPhe PheThr Thr ValVal SerSer Lys Lys Thr Thr Ser Ser Ser Thr Ser Thr ThrVal Thr Val

70 70 75 75 80 80

Thr Leu Thr Leu Gln GlnMet MetThr ThrSerSer LeuLeu Thr Thr Ala Ala AI a Ala Asp Asp Thr Thr Ala Tyr Ala Thr ThrPhe Tyr Phe 85 85 90 90 95 95

Cys AI Cys Alaa Arg Met Glu Arg Met GluAsp AspGly Gly Tyr Tyr GlyGly Tyr Tyr Gly Gly Tyr Tyr Asp Tyr Asp Thr ThrPhe Tyr Phe 100 100 105 105 110 110

Lys Leu Trp Lys Leu TrpGly GlyPro Pro GlyGly ThrThr Leu Leu Val Val Thr Thr Val Ser Val Ser Ser Ser 115 115 120 120 125 125

<210> <210> 25 25 <211> <211> 114 114 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 25 25 Asp Val Asp Val Val ValMet MetThr Thr GlnGln ThrThr Pro Pro Al aAla Ser Ser Val Val Ser Ser Glu Val Glu Ser SerGly Val Gly 1 1 5 5 10 10 15 15

Gly Thr Gly Thr Val ValThr Thrlle Ile AsnAsn CysCys Gln Gln AI aAla Ser Ser Gln Gln Ser Ser Ile Asn lle Gly GlyAsn Asn Asn 20 20 25 25 30 30

Leu Alaa Trp Leu Al Tyr Gln Trp Tyr GlnGln GlnLys Lys Pro Pro GlyGly GI Gln n ProPro ProPro Lys Lys Leu Leu Leu Ile Leu lle 35 35 40 40 45 45

Tyr Asp Tyr Asp AI Ala Ser Asn a Ser AsnLeu LeuAla AlaSerSer GlyGly Val Val Pro Pro Ser Phe Ser Arg Arg Lys PheGly Lys Gly 50 50 55 55 60 60

Ser Arg Ser Ser Arg SerGly GlyThr Thr GluGlu ProPro Thr Thr Leu Leu Thr Thr Thr Asn Asn Leu ThrThr Leulle Thr SerIle Ser

70 70 75 75 80 80

Page 16 Page 16

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt

Gly Val Gly Val Gln GlnCys CysAlAla AspVal a Asp Val Ala Ala ThrThr TyrTyr Tyr Tyr Cys Cys Gln Gly Gln Ser SerTrp Gly Trp 85 85 90 90 95 95

Tyr Gly Tyr Gly Asn AsnSer SerTyr Tyr ValVal AlaAla Ala Ala Phe Phe Gly Gly Gly Gly Gly Thr GlyGlu ThrVal Glu ValVal Val 100 100 105 105 110 110

Val Lys Val Lys

<210> <210> 26 26 <211> <211> 112 112 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 26 26 Asp Val Asp Val Val ValMet MetThr Thr GlnGln ThrThr Pro Pro Ser Ser Ser Ser Ser Val Val Ala SerAlAla AlaGly a Val Val Gly 1 1 5 5 10 10 15 15

Gly Thr Gly Thr Val ValThr Thrlle Ile LysLys CysCys Gln Gln Ala Ala Ser Asn Ser Glu Glu lle AsnTyr IleSer TyrAsnSer Asn 20 20 25 25 30 30

Leu Alaa Trp Leu AI Tyr Gln Trp Tyr GlnGln GlnLys Lys Pro Pro GlyGly GlnGln Pro Pro Pro Pro Lys Leu Lys Arg Arglle Leu Ile 35 35 40 40 45 45

Tyr Asp Tyr Asp AI Ala Ser Asp a Ser AspLeu LeuAla AlaSerSer GlyGly Val Val Pro Pro Ser Ser Arg Ser Arg Phe PheGly Ser Gly 50 50 55 55 60 60

Ser Gly Tyr Ser Gly TyrGly GlyThr Thr GlnGln PhePhe Thr Thr Leu Leu Thr Ser Thr lle Ile Gly SerVal GlyGln Val CysGln Cys

70 70 75 75 80 80

Glu Asp Glu Asp Al Ala Ala Thr a Ala ThrTyr TyrTyr Tyr Cys Cys GlnGln Ala Ala Asn Asn Tyr Tyr Asp Thr Asp Ser SerSer Thr Ser 85 85 90 90 95 95

Ser Ser Phe Ser Ser PheGly GlyAsn Asn ValVal PhePhe Gly Gly Gly Gly Gly Gly Thr Val Thr Glu GluVal ValVal Val LysVal Lys 100 100 105 105 110 110

<210> <210> 27 27 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 27 27

Asp Leu Asp Leu Val Val Met Met Thr Thr Gln Gln Thr Thr Pro Pro Ala Ala Ser Ser Val Val Ser Ser Glu Glu Pro Pro Val Val Gly Gly 1 1 5 5 10 10 15 15 Page 17 Page 17

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Gly Thr Gly Thr Val ValThr Thrlle Ile LysLys CysCys Gln Gln Ala Ala Ser Ser Ser Gln Gln lle SerGly IleThr GlyTyrThr Tyr 20 20 25 25 30 30

Leu Alaa Trp Leu AI Tyr Gln Trp Tyr GlnGln GlnLys Lys Pro Pro GlyGly GlnGln Pro Pro Pro Pro Lys Leu Lys Leu Leulle Leu Ile 35 35 40 40 45 45

Tyr Arg Tyr Arg AI Ala Ser Thr a Ser ThrLeu LeuAIAla SerGIGly a Ser ValPro y Val ProSer Ser ArgArg PhePhe Lys Lys Gly Gly 50 50 55 55 60 60

Ser Gly Ser Ser Gly SerGly GlyThr Thr GlnGln PhePhe Thr Thr Leu Leu Thr Ser Thr lle Ile Asp SerLeu AspGlu Leu CysGlu Cys

70 70 75 75 80 80

Alaa Asp AI Asp Ala AI a Ala Al aThr Thr Tyr Tyr Tyr Cys Leu Tyr Cys LeuGly GlyGly GlyTyr Tyr TyrTyr GlyGly Phe Phe Ser Ser 85 85 90 90 95 95

Tyr Gly Tyr Gly Asn AsnAlAla PheGly a Phe GlyGly Gly GlyGly ThrThr Glu Glu Val Val Val Val Val Lys Val Lys 100 100 105 105 110 110

<210> <210> 28 28 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An arti An artificially synthesized ficially synthesi sequence zed sequence

<400> <400> 28 28 Asp lle Asp Ile Val ValMet MetThr Thr GlnGln ThrThr Pro Pro Al aAla Ser Ser Val Val Glu Glu Alaa Ala Ala Al Val Gly Val Gly 1 1 5 5 10 10 15 15

Gly Thr Gly Thr Val ValThr Thrlle Ile LysLys CysCys Gln Gln Al aAla Ser Ser Gln Gln Ser Ser Ile Ser lle Thr ThrTrp Ser Trp 20 20 25 25 30 30

Leu Ala Trp Leu Ala TrpTyr TyrGln Gln GlnGln LysLys Leu Leu Gly Gly GI nGln Pro Pro Pro Pro Lys Leu Lys Leu Leulle Leu Ile 35 35 40 40 45 45

Tyr Lys Tyr Lys Al Ala Ser Thr a Ser ThrLeu LeuAlAla SerGly a Ser Gly Val Val SerSer SerSer Arg Arg Phe Phe Lys Gly Lys Gly 50 50 55 55 60 60

Ser Gly Ser Ser Gly SerGly GlyThr Thr GluGlu PhePhe Thr Thr Leu Leu Thr Ser Thr lle Ile Asp SerLeu AspGlu Leu CysGlu Cys

70 70 75 75 80 80

Alaa Asp AI Asp Ala AI a Ala AI aThr Thr Tyr Tyr Tyr Cys Gln Tyr Cys GlnGly GlyTyr TyrTyr Tyr AspAsp SerSer Ser Ser Thr Thr 85 85 90 90 95 95

Ser Ser Tyr Ser Ser TyrVal ValPhe Phe GlyGly GlyGly Gly Gly Thr Thr Glu Val Glu Val Val Val ValLys Val Lys 100 100 105 105 110 110

Page 18 Page 18

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

<210> <210> 29 29 <211> <211> 448 448 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> :400: 29 29 Gln Val Gln Val Gln GlnLeu LeuVal Val GlnGln SerSer Gly Gly Al aAla GluGlu Val Val Lys Lys Lys Gly Lys Pro ProAla Gly Ala 1 1 5 5 10 10 15 15

Ser Val Lys Ser Val LysVal ValSer Ser CysCys LysLys Ala AI a SerSer GlyGly Tyr Tyr lle Ile Phe Asn Phe Ser SerTyr Asn Tyr 20 20 25 25 30 30

Trp lle Trp Ile Gln GlnTrp TrpVal Val ArgArg GlnGln Ala Ala Pro Pro Gly Gly Gly Gln Gln Leu GlyGlu LeuTrp Glu MetTrp Met 35 35 40 40 45 45

Gly Glu Gly Glu lle IleLeu LeuPro Pro GlyGly SerSer Gly Gly Ser Ser Thr Tyr Thr Glu Glu Thr TyrGlu ThrAsn Glu PheAsn Phe 50 50 55 55 60 60

Lys Asp Arg Lys Asp ArgVal ValThr Thr MetMet ThrThr Arg Arg Asp Asp Thr Thr Ser Ser Ser Thr ThrThr SerVal Thr TyrVal Tyr

70 70 75 75 80 80

Met Glu Met Glu Leu LeuSer SerSer SerLeuLeu ArgArg Ser Ser Glu Glu Asp Ala Asp Thr Thr Val AlaTyr ValTyr Tyr CysTyr Cys 85 85 90 90 95 95

Alaa Arg AI Arg Tyr Phe Phe Tyr Phe PheGly GlySer Ser SerSer ProPro Asn Asn Trp Trp Tyr Asp Tyr Phe Phe Val AspTrp Val Trp 100 100 105 105 110 110

Gly Gln Gly Gln Gly GlyThr ThrLeu Leu ValVal ThrThr Val Val Ser Ser Sera Ala Ser Al Ser Ser Thr Gly Thr Lys LysPro Gly Pro 115 115 120 120 125 125

Ser Val Phe Ser Val PhePro ProLeu Leu AlaAla ProPro Cys Cys Ser Ser Arg Thr Arg Ser Ser Ser ThrGlu SerSer Glu ThrSer Thr 130 130 135 135 140 140

Alaa Ala AI Al aLeu Leu Gly Gly Cys Leu Val Cys Leu ValLys LysAsp Asp Tyr Tyr PhePhe ProPro Glu Glu Pro Pro Val Thr Val Thr 145 145 150 150 155 155 160 160

Val Ser Val Ser Trp TrpAsn AsnSer Ser GlyGly AI Ala a LeuLeu ThrThr Ser Ser Gly Gly Vals His Val Hi Thr Thr Phe Pro Phe Pro 165 165 170 170 175 175

Alaa Val AI Val Leu Gln Ser Leu Gln SerSer SerGly Gly LeuLeu TyrTyr Ser Ser Leu Leu Ser Ser Ser Val Ser Val ValThr Val Thr 180 180 185 185 190 190

Val Pro Val Pro Ser Ser Ser Ser Asn Asn Phe Phe Gly Gly Thr Thr Gln Gln Thr Thr Tyr Tyr Thr Thr Cys Cys Asn Asn Val Val Asp Asp 195 195 200 200 205 205

Page 19 Page 19

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt Hiss Lys Hi Lys Pro Ser Asn Pro Ser AsnThr ThrLys Lys Val Val AspAsp Lys Lys Thr Thr Val Val Glu Lys Glu Arg ArgCys Lys Cys 210 210 215 215 220 220

Cys Val Glu Cys Val GluCys CysPro Pro ProPro CysCys Pro Pro Ala Ala Pro Val Pro Pro Pro Al Val Ala Pro a Gly GlySer Pro Ser 225 225 230 230 235 235 240 240

Val Phe Val Phe Leu Leu Phe Phe Pro Pro Pro Pro Lys Lys Pro Pro Lys Lys Asp Asp Thr Thr Leu Leu Met Met lle Ile Ser Ser Arg Arg 245 245 250 250 255 255

Thr Pro Thr Pro Glu GluVal ValThr Thr CysCys ValVal Val Val Val Val Asp Ser Asp Val Val Gln SerGlu GlnAsp Glu ProAsp Pro 260 260 265 265 270 270

Glu Val Glu Val Gln GlnPhe PheAsn Asn TrpTrp TyrTyr Val Val Asp Asp Gly Glu Gly Val Val Val GluHiVal HisAlAsn s Asn a Ala 275 275 280 280 285 285

Lys Thr Lys Lys Thr LysPro ProArg Arg GluGlu GluGlu Gln Gln Phe Phe Asn Thr Asn Ser Ser Tyr ThrArg TyrVal Arg ValVal Val 290 290 295 295 300 300

Ser Val Leu Ser Val LeuThr ThrVal Val LeuLeu Hi His Gln s Gln AspAsp TrpTrp Leu Leu Asn Asn Gly Glu Gly Lys LysTyr Glu Tyr 305 305 310 310 315 315 320 320

Lys Cys Lys Lys Cys LysVal ValSer Ser AsnAsn LysLys Gly Gly Leu Leu Pro Pro Ser 11 Ser Ser Ser Ile Lys e Glu GluThr Lys Thr 325 325 330 330 335 335

Ile Ser Lys lle Ser LysAIAla LysGly a Lys GlyGln GlnPro Pro ArgArg GluGlu Pro Pro Gl rGln Val Val Tyr Tyr Thr Leu Thr Leu 340 340 345 345 350 350

Pro Pro Ser Pro Pro SerGln GlnGlu Glu GluGlu MetMet Thr Thr Lys Lys Asn Asn Gln Ser Gln Val ValLeu SerThr Leu CysThr Cys 355 355 360 360 365 365

Leu Val Lys Leu Val LysGly GlyPhe Phe TyrTyr ProPro Ser Ser Asp Asp lle Ile AI a Ala Val Val Glu Glu Glu Trp TrpSer Glu Ser 370 370 375 375 380 380

Asn Gly Asn Gly Gln Gln Pro Pro Glu Glu Asn Asn Asn Asn Tyr Tyr Lys Lys Thr Thr Thr Thr Pro Pro Pro Pro Val Val Leu Leu Asp Asp 385 385 390 390 395 395 400 400

Ser Asp Gly Ser Asp GlySer SerPhe Phe PhePhe LeuLeu Tyr Tyr Ser Ser Arg Thr Arg Leu Leu Val ThrAsp ValLys Asp SerLys Ser 405 405 410 410 415 415

Arg Trp Arg Trp Gln GlnGlu GluGly Gly AsnAsn ValVal Phe Phe Ser Ser Cys Val Cys Ser Ser Met ValHiMet HisAlGlu s Glu a Ala 420 420 425 425 430 430

Leu Hiss Asn Leu Hi His Tyr Asn His TyrThr ThrGln Gln Lys Lys SerSer LeuLeu Ser Ser Leu Leu Ser Gly Ser Leu LeuLys Gly Lys 435 435 440 440 445 445

<210> <210> 30 30 <211> <211> 214 214 <212> <212> PRT PRT Page 20 Page 20

JPOXMLDOC01-seql.txt JPOXMLDOC01-segl. txt <213> Artificial sequence <213> Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 30 30 Asp lle Asp Ile Gln Gln Met Met Thr Thr Gln Gln Ser Ser Pro Pro Ser Ser Ser Ser Leu Leu Ser Ser Ala Ala Ser Ser Val Val Gly Gly 1 1 5 5 10 10 15 15

Asp Arg Asp Arg Val ValThr ThrIIIle ThrCys e Thr Cys GlyGly AlaAla Ser Ser Glu Glu Asn Asn Ile Gly lle Tyr TyrAla Gly Ala 20 20 25 25 30 30

Leu Asn Trp Leu Asn TrpTyr TyrGln Gln GlnGln LysLys Pro Pro Gly Gly Lys Lys Al a Ala Pro Pro Lys Leu Lys Leu Leulle Leu Ile 35 35 40 40 45 45

Tyr Gly Tyr Gly Ala Ala Thr Thr Asn Asn Leu Leu Ala Ala Asp Asp Gly Gly Val Val Pro Pro Ser Ser Arg Arg Phe Phe Ser Ser Gly Gly 50 50 55 55 60 60

Ser Gly Ser Ser Gly SerGly GlyThr Thr AspAsp PhePhe Thr Thr Leu Leu Thr Ser Thr lle Ile Ser SerLeu SerGln Leu ProGln Pro

70 70 75 75 80 80

Glu AspPhe GI Asp Phe Al Ala Thr a Thr TyrTyr TyrTyr Cys Cys Gln Gln Asn Asn Val Asn Val Leu LeuThr AsnPro Thr LeuPro Leu 85 85 90 90 95 95

Thr Phe Thr Phe Gly GlyGln GlnGly Gly ThrThr LysLys Val Val Glu Glu Ile Arg lle Lys Lys Thr ArgVal ThrAla Val AlaAla Ala 100 100 105 105 110 110

Pro Ser Val Pro Ser ValPhe Phelle Ile PhePhe ProPro Pro Pro Ser Ser Asp Asp Glu Leu Glu Gln GlnLys LeuSer Lys GlySer Gly 115 115 120 120 125 125

Thr AI Thr Alaa Ser Val Val Ser Val ValCys CysLeu Leu LeuLeu AsnAsn Asn Asn Phe Phe Tyr Tyr Pro Glu Pro Arg ArgAla Glu Ala 130 130 135 135 140 140

Lys Val Gln Lys Val GlnTrp TrpLys Lys ValVal AspAsp Asn Asn AI aAla LeuLeu Gln Gln Ser Ser Gly Ser Gly Asn AsnGln Ser Gln 145 145 150 150 155 155 160 160

Glu Ser Glu Ser Val ValThr ThrGlu Glu GlnGln AspAsp Ser Ser Lys Lys Asp Thr Asp Ser Ser Tyr ThrSer TyrLeu Ser SerLeu Ser 165 165 170 170 175 175

Ser Thr Leu Ser Thr LeuThr ThrLeu Leu SerSer LysLys Ala Al a AspAsp TyrTyr Glu Glu Lys Lys Hi s His Lys Lys Val Tyr Val Tyr 180 180 185 185 190 190

Alaa Cys AI Cys Glu Val Thr Glu Val ThrHis HisGln Gln GlyGly LeuLeu Ser Ser Ser Ser Pro Thr Pro Val Val Lys ThrSer Lys Ser 195 195 200 200 205 205

Phe Asn Arg Phe Asn ArgGly GlyGlu Glu Cys Cys 210 210

Page 21 Page 21

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt <210> <210> 31 31 <211> <211> 122 122 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 31 31

Gln Val Gln Val Gln GlnLeu LeuVal Val GlnGln SerSer Gly Gly Al aAla GluGlu Val Val Lys Lys Lys Gly Lys Pro ProAla Gly Ala 1 1 5 5 10 10 15 15

Ser Val Lys Ser Val LysVal ValSer Ser CysCys LysLys Ala Al a SerSer GlyGly Tyr Tyr lle Ile Phe Asn Phe Ser SerTyr Asn Tyr 20 20 25 25 30 30

Trp lle Trp Ile Gln GlnTrp TrpVal Val ArgArg GlnGln Ala Ala Pro Pro Gly Gly Gly Gln Gln Leu GlyGlu LeuTrp Glu MetTrp Met 35 35 40 40 45 45

Gly Glu Gly Glu lle IleLeu LeuPro Pro GlyGly SerSer Gly Gly Ser Ser Thr Tyr Thr Glu Glu Thr TyrGlu ThrAsn Glu PheAsn Phe 50 50 55 55 60 60

Lys Asp Arg Lys Asp ArgVal ValThr Thr MetMet ThrThr Arg Arg Asp Asp Thr Thr Ser Ser Ser Thr ThrThr SerVal Thr TyrVal Tyr

70 70 75 75 80 80

Met Glu Leu Met Glu LeuSer SerSer SerLeuLeu ArgArg Ser Ser Glu Glu Asp Ala Asp Thr Thr Val AlaTyr ValTyr Tyr CysTyr Cys 85 85 90 90 95 95

Alaa Arg AI Arg Tyr Phe Phe Tyr Phe PheGly GlySer Ser SerSer ProPro Asn Asn Trp Trp Tyr Tyr Phe Val Phe Asp AspTrp Val Trp 100 100 105 105 110 110

Gly Gln Gly Gln Gly GlyThr ThrLeu Leu ValVal ThrThr Val Val Ser Ser Ser Ser 115 115 120 120

<210> <210> 32 32 <211> <211> 107 107 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An arti An artificially synthesized ficially synthesi sequence zed sequence

<400> <400> 32 32 Asp lle Asp Ile Gln GlnMet MetThr Thr GlnGln SerSer Pro Pro Ser Ser Ser Ser Ser Leu Leu Al Ser Ala Val a Ser SerGly Val Gly 1 1 5 5 10 10 15 15

Asp Arg Asp Arg Val ValThr Thrlle Ile ThrThr CysCys Gly Gly AI aAla Ser Ser Glu Glu Asn Asn Ile Gly lle Tyr TyrAla Gly Ala 20 20 25 25 30 30

Leu Asn Trp Leu Asn TrpTyr TyrGln Gln GlnGln LysLys Pro Pro Gly Gly Lys Lys AI a Ala Pro Pro Lys Leu Lys Leu Leulle Leu Ile 35 35 40 40 45 45

Page 22 Page 22

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Tyr Gly Tyr Gly AI Ala Thr Asn a Thr AsnLeu LeuAIAla AspGly a Asp Gly Val Val ProPro SerSer Arg Arg Phe Phe Ser Gly Ser Gly 50 50 55 55 60 60

Ser Gly Ser Ser Gly SerGly GlyThr Thr AspAsp PhePhe Thr Thr Leu Leu Thr Ser Thr lle Ile Ser SerLeu SerGln Leu ProGln Pro

70 70 75 75 80 80

Glu Asp Glu Asp Phe PheAIAla ThrTyr a Thr TyrTyr Tyr CysCys GlnGln Asn Asn Val Val Leu Leu Asn Pro Asn Thr ThrLeu Pro Leu 85 85 90 90 95 95

Thr Phe Thr Phe Gly GlyGln GlnGly Gly ThrThr LysLys Val Val Glu Glu Ile Lys lle Lys 100 100 105 105

<210> <210> 33 33 <211> <211> 325 325 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 33 33

Alaa Ser Al Ser Thr Lys Gly Thr Lys GlyPro ProSer Ser ValVal PhePhe Pro Pro Leu Leu Al aAla Pro Pro Cys Cys Ser Arg Ser Arg 1 1 5 5 10 10 15 15

Ser Thr Ser Thr Ser SerGlu GluSer Ser ThrThr AI Ala a AI Ala Leu a Leu Gly Gly CysCys LeuLeu Val Val Lys Lys Asp Tyr Asp Tyr 20 20 25 25 30 30

Phe Pro Glu Phe Pro GluPro ProVal Val ThrThr ValVal Ser Ser Trp Trp Asn Gly Asn Ser Ser Ala GlyLeu AlaThr Leu SerThr Ser 35 35 40 40 45 45

Gly GI y Val Val His Hi s Thr Thr Phe Pro AI Phe Pro Ala Val Leu a Val Leu Gln GlnSer SerSer SerGlyGly LeuLeu Tyr Tyr Ser Ser 50 50 55 55 60 60

Leu Ser Ser Leu Ser SerVal ValVal Val ThrThr ValVal Pro Pro Ser Ser Ser Ser Ser Gly Ser Leu LeuThr GlyLys Thr ThrLys Thr

70 70 75 75 80 80

Tyr Thr Tyr Thr Cys CysAsn AsnVal ValAspAsp HisHis Lys Lys Pro Pro Ser Thr Ser Asn Asn Lys ThrVal LysAsp Val LysAsp Lys 85 85 90 90 95 95

Arg Val Arg Val Glu GluSer SerLys Lys TyrTyr GlyGly Pro Pro Pro Pro Cys Pro Cys Pro Pro Cys ProPro CysAIPro Ala Pro a Pro 100 100 105 105 110 110

Glu GI u Phe Phe Arg Gly Gly Arg Gly GlyPro ProLys Lys Val Val PhePhe LeuLeu Phe Phe Pro Pro Pro Pro Pro Lys LysLys Pro Lys 115 115 120 120 125 125

Asp Thr Asp Thr Leu LeuMet Metlle Ile SerSer ArgArg Thr Thr Pro Pro Glu Thr Glu Val Val Cys ThrVal CysVal Val ValVal Val 130 130 135 135 140 140

Page 23 Page 23

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt Asp Val Asp Val Ser Ser Gln Gln Glu Glu Asp Asp Pro Pro Glu Glu Val Val Gln Gln Phe Phe Asn Asn Trp Trp Tyr Tyr Val Val Asp Asp 145 145 150 150 155 155 160 160

Gly Val Gly Val Glu Glu Val Val His His Asn Asn Ala Ala Lys Lys Thr Thr Lys Lys Pro Pro Arg Arg Glu Glu Glu Glu Gln Gln Phe Phe 165 165 170 170 175 175

Asn Ser Asn Ser Thr ThrTyr TyrArg Arg ValVal ValVal Ser Ser Val Val Leu Val Leu Thr Thr Leu ValHiLeu HisAsp s Gln Gln Asp 180 180 185 185 190 190

Trp Leu Trp Leu Asn AsnGly GlyLys Lys GluGlu TyrTyr Lys Lys Cys Cys Lys Ser Lys Val Val Asn SerLys AsnGly Lys LeuGly Leu 195 195 200 200 205 205

Pro Ser Ser Pro Ser Serlle IleGlu Glu LysLys ThrThr lle Ile Ser Ser Lys Lys AI a Ala Lys Lys Gly Pro Gly Gln GlnArg Pro Arg 210 210 215 215 220 220

Glu Pro Glu Pro Gln GlnVal ValTyr Tyr ThrThr LeuLeu Pro Pro Pro Pro Ser Glu Ser Gln Gln Glu GluMet GluThr Met LysThr Lys 225 225 230 230 235 235 240 240

Asn Gln Asn Gln Val Val Ser Ser Leu Leu Thr Thr Cys Cys Leu Leu Val Val Lys Lys Gly Gly Phe Phe Tyr Tyr Pro Pro Ser Ser Asp Asp 245 245 250 250 255 255

Ile II e Ala ValGlu Al Val GluTrp Trp Glu Glu SerSer AsnAsn Gly Gly Gln Gln Pro Asn Pro Glu GluAsn AsnTyr Asn Tyr Lys Lys 260 260 265 265 270 270

Thr Thr Thr Thr Pro ProPro ProVal Val LeuLeu AspAsp Ser Ser Asp Asp Gly Phe Gly Ser Ser Phe PheLeu PheTyr Leu SerTyr Ser 275 275 280 280 285 285

Arg Leu Arg Leu Thr ThrVal ValAsp Asp LysLys SerSer Arg Arg Trp Trp Gln Gly Gln Glu Glu Asn GlyVal AsnPhe Val SerPhe Ser 290 290 295 295 300 300

Cys Ser Cys Ser Val ValMet MetHis His GluGlu AlaAla Leu Leu His His AsnS His Asn Hi Tyr Tyr Thr Lys Thr Gln GlnSer Lys Ser 305 305 310 310 315 315 320 320

Leu Ser Leu Leu Ser LeuSer SerLeu Leu 325 325

<210> <210> 34 34 <211> <211> 325 325 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 34 34 Alaa Ser AI Ser Thr Lys Gly Thr Lys GlyPro ProSer Ser ValVal PhePhe Pro Pro Leu Leu AI aAla Pro Pro Cys Cys Ser Arg Ser Arg 1 1 5 5 10 10 15 15

Ser Thr Ser Ser Thr SerGlu GluSer Ser ThrThr AlaAla Ala Ala Leu Leu Gly Leu Gly Cys Cys Val LeuLys ValAsp Lys TyrAsp Tyr Page 24 Page 24

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt 20 20 25 25 30 30

Phe Pro Glu Phe Pro GluPro ProVal Val Thr Thr ValVal SerSer Trp Trp Asn Asn Ser AL Ser Gly Gly Ala Thr a Leu LeuSer Thr Ser 35 35 40 40 45 45

Gly Val Gly Val Hi His Thr Phe s Thr PhePro ProAla AlaValVal LeuLeu Gln Gln Ser Ser Ser Ser Gly Tyr Gly Leu LeuSer Tyr Ser 50 50 55 55 60 60

Leu Ser Ser Leu Ser SerVal ValVal Val ThrThr ValVal Pro Pro Ser Ser Ser Ser Ser Gly Ser Leu LeuThr GlyLys Thr ThrLys Thr

70 70 75 75 80 80

Tyr Thr Tyr Thr Cys CysAsn AsnVal ValAspAsp HisHis Lys Lys Pro Pro Ser Thr Ser Asn Asn Lys ThrVal LysAsp Val LysAsp Lys 85 85 90 90 95 95

Arg Val Arg Val Glu Glu Ser Ser Lys Lys Tyr Tyr Gly Gly Pro Pro Pro Pro Cys Cys Pro Pro Pro Pro Cys Cys Pro Pro Ala Ala Pro Pro 100 100 105 105 110 110

Glu Phe Arg GI Phe ArgGly GlyGly GlyPro ProLys LysVal ValPhe PheLeu LeuPhe PhePro ProPro ProLys LysPro ProLys Lys 115 115 120 120 125 125

Asp Thr Asp Thr Leu LeuTyr Tyrlle Ile SerSer ArgArg Thr Thr Pro Pro GI u Glu Val Val Thr Thr Cys Val Cys Val ValVal Val Val 130 130 135 135 140 140

Asp Val Asp Val Ser Ser Gln Gln Glu Glu Asp Asp Pro Pro Glu Glu Val Val Gln Gln Phe Phe Asn Asn Trp Trp Tyr Tyr Val Val Asp Asp 145 145 150 150 155 155 160 160

Gly Val Gly Val Glu GluVal ValHiHis AsnAla s Asn Ala Lys Lys ThrThr Lys Lys Pro Pro Arg Arg Glu Gln Glu Glu GluPhe Gln Phe 165 165 170 170 175 175

Asn Ser Asn Ser Thr Thr Tyr Tyr Arg Arg Val Val Val Val Ser Ser Val Val Leu Leu Thr Thr Val Val Leu Leu His His Gln Gln Asp Asp 180 180 185 185 190 190

Trp Leu Trp Leu Asn Asn Gly Gly Lys Lys Glu Glu Tyr Tyr Lys Lys Cys Cys Lys Lys Val Val Ser Ser Asn Asn Lys Lys Gly Gly Leu Leu 195 195 200 200 205 205

Pro Ser Ser Pro Ser Serlle IleGlu Glu LysLys ThrThr lle Ile Ser Ser Lys Lys AI a Ala Lys Lys Gly Pro Gly Gln GlnArg Pro Arg 210 210 215 215 220 220

Glu Pro Gln Glu Pro GlnVal ValTyr Tyr ThrThr LeuLeu Pro Pro Pro Pro Ser Glu Ser Gln Gln Glu GluMet GluThr Met LysThr Lys 225 225 230 230 235 235 240 240

Asn Gln Asn Gln Val Val Ser Ser Leu Leu Thr Thr Cys Cys Leu Leu Val Val Lys Lys Gly Gly Phe Phe Tyr Tyr Pro Pro Ser Ser Asp Asp 245 245 250 250 255 255

Ile Ala Val lle Ala ValGlu GluTrp Trp Glu Glu SerSer AsnAsn Gly Gly Gln Gln Pro Asn Pro Glu GluAsn AsnTyr Asn LysTyr Lys 260 260 265 265 270 270

Page 25 Page 25

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt Thr Thr Thr Thr Pro ProPro ProVal Val LeuLeu AspAsp Ser Ser Asp Asp Gly Phe Gly Ser Ser Phe PheLeu PheTyr Leu SerTyr Ser 275 275 280 280 285 285

Arg Leu Arg Leu Thr ThrVal ValAsp Asp LysLys SerSer Arg Arg Trp Trp Gln Gly Gln Glu Glu Asn GlyVal AsnPhe Val SerPhe Ser 290 290 295 295 300 300

Cys Ser Val Cys Ser ValMet MetHis His GI Glu Ala u Ala Leu Leu HisHis TyrTyr Hi sHis ValVal Thr Thr Gln Gln Lys Ser Lys Ser 305 305 310 310 315 315 320 320

Leu Ser Leu Leu Ser LeuSer SerLeu Leu 325 325

<210> <210> 35 35 <211> <211> 325 325 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 35 35 Alaa Ser Al Ser Thr Lys Gly Thr Lys GlyPro ProSer Ser ValVal PhePhe Pro Pro Leu Leu AI aAla Pro Pro Cys Cys Ser Arg Ser Arg 1 1 5 5 10 10 15 15

Ser Thr Ser Ser Thr SerGlu GluSer Ser ThrThr AlaAla Ala Al a LeuLeu GlyGly Cys Cys Leu Leu Val Asp Val Lys LysTyr Asp Tyr 20 20 25 25 30 30

Phe Pro Glu Phe Pro GluPro ProVal Val ThrThr ValVal Ser Ser Trp Trp Asn Gly Asn Ser Ser AI Gly Ala Thr a Leu LeuSer Thr Ser 35 35 40 40 45 45

Gly Val Gly Val Hi His Thr Phe s Thr PhePro ProAIAla ValLeu a Val Leu Gln Gln SerSer SerSer Gly Gly Leu Leu Tyr Ser Tyr Ser 50 50 55 55 60 60

Leu Ser Ser Leu Ser SerVal ValVal Val ThrThr ValVal Pro Pro Ser Ser Ser Ser Ser Gly Ser Leu LeuThr GlyLys Thr ThrLys Thr

70 70 75 75 80 80

Tyr Thr Tyr Thr Cys Cys Asn Asn Val Val Asp Asp His His Lys Lys Pro Pro Ser Ser Asn Asn Thr Thr Lys Lys Val Val Asp Asp Lys Lys 85 85 90 90 95 95

Arg Val Arg Val GI Glu Ser Lys u Ser LysTyr TyrGly Gly ProPro ProPro Cys Cys Pro Pro Pro Pro Pro Cys Cys Ala ProPro Ala Pro 100 100 105 105 110 110

Gluu Phe GI Phe Arg Gly Gly Arg Gly GlyPro ProLys Lys Val Val PhePhe Leu Leu Phe Phe Pro Pro Pro Pro Pro Lys LysLys Pro Lys 115 115 120 120 125 125

Asp Thr Asp Thr Leu LeuMet Met11Ile SerArg e Ser Arg ThrThr ProPro Glu Glu Val Val Thr Thr Cys Val Cys Val ValVal Val Val 130 130 135 135 140 140

Asp Val Asp Val Ser Ser Gln Gln Glu Glu Asp Asp Pro Pro Glu Glu Val Val Gln Gln Phe Phe Asn Asn Trp Trp Tyr Tyr Val Val Asp Asp Page 26 Page 26

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql. txt 145 145 150 150 155 155 160 160

Gly Val Gly Val Glu GluVal ValHis His AsnAsn AlaAla Lys Lys Thr Thr Lys Arg Lys Pro Pro Glu ArgGlu GluGln Glu PheGln Phe 165 165 170 170 175 175

Asn Ser Asn Ser Thr ThrTyr TyrArg Arg ValVal ValVal Ser Ser Val Val Leu Val Leu Thr Thr Leu ValHiLeu HisAsp s Gln Gln Asp 180 180 185 185 190 190

Trp Leu Trp Leu Asn AsnGly GlyLys Lys GluGlu TyrTyr Lys Lys Cys Cys Lys Ser Lys Val Val Asn SerLys AsnGly Lys LeuGly Leu 195 195 200 200 205 205

Pro Ser Ser Pro Ser Serlle IleGlu Glu LysLys ThrThr lle Ile Ser Ser Lys Lys AI a Ala Lys Lys Gly Pro Gly Gln GlnArg Pro Arg 210 210 215 215 220 220

Glu Pro Glu Pro Gln GlnVal ValTyr Tyr ThrThr LeuLeu Pro Pro Pro Pro Ser Glu Ser Gln Gln Glu GluMet GluThr Met LysThr Lys 225 225 230 230 235 235 240 240

Asn Gln Asn Gln Val Val Ser Ser Leu Leu Thr Thr Cys Cys Leu Leu Val Val Lys Lys Gly Gly Phe Phe Tyr Tyr Pro Pro Ser Ser Asp Asp 245 245 250 250 255 255

Ile Alaa Val lle Al Glu Trp Val Glu TrpGlu GluSer Ser Asn Asn GlyGly GlnGln Pro Pro Glu Glu Asn Tyr Asn Asn AsnLys Tyr Lys 260 260 265 265 270 270

Thr Thr Thr Thr Pro ProPro ProVal Val LeuLeu AspAsp Ser Ser Asp Asp Gly Phe Gly Ser Ser Phe PheLeu PheTyr Leu SerTyr Ser 275 275 280 280 285 285

Lys Leu Thr Lys Leu ThrVal ValAsp Asp LysLys SerSer Arg Arg Trp Trp Gln Gly Gln Glu Glu Asn GlyVal AsnPhe Val SerPhe Ser 290 290 295 295 300 300

Cys Ser Cys Ser Val ValMet MetHis His GluGlu AlaAla Leu Leu His His Asn Tyr Asn His His Thr TyrGln ThrLys Gln SerLys Ser 305 305 310 310 315 315 320 320

Leu Ser Leu Leu Ser LeuSer SerPro Pro 325 325

<210> <210> 36 36 <211> <211> 107 107 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 36 36 Arg Thr Arg Thr Val ValAla AlaAla Ala ProPro SerSer Val Val Phe Phe Ile Pro lle Phe Phe Pro ProSer ProAsp Ser GluAsp Glu 1 1 5 5 10 10 15 15

Gln Leu Gln Leu Lys LysSer SerGly Gly ThrThr AlaAla Ser Ser Val Val Val Leu Val Cys Cys Leu LeuAsn LeuAsn AsnPheAsn Phe 20 20 25 25 30 30 Page 27 Page 27

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Tyr Pro Tyr Pro Arg ArgGlu GluAla Ala LysLys ValVal Gln Gln Trp Trp Lys Asp Lys Val Val Asn AspAlAsn AlaGILeu Gln a Leu 35 35 40 40 45 45

Ser Gly Asn Ser Gly AsnSer SerGIGln GluSer n Glu Ser Val Val ThrThr GluGlu Gln Gln Asp Asp Ser Asp Ser Lys LysCys Asp Cys 50 50 55 55 60 60

Thr Tyr Thr Tyr Ser SerLeu LeuSer Ser SerSer ThrThr Leu Leu Thr Thr Leu Lys Leu Ser Ser Ala LysAsp AlaTyr Asp GI Tyr u Glu

70 70 75 75 80 80

Lys His Lys Lys His LysVal ValTyr TyrAI Ala Cys a Cys GI Glu ValThr u Val Thr Hi His Gln s Gln GlyGly LeuLeu Ser Ser Ser Ser 85 85 90 90 95 95

Pro Val Thr Pro Val ThrLys LysSer Ser Phe Phe AsnAsn Arg Arg Gly Gly Glu Glu Cys Cys 100 100 105 105

<210> <210> 37 37 <211> <211> 107 107 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 37 37 Arg Thr Arg Thr Val ValAla AlaAla Ala ProPro SerSer Val Val Phe Phe Ile Pro lle Phe Phe Pro ProSer ProAsp Ser GluAsp Glu 1 1 5 5 10 10 15 15

Gln Leu Gln Leu Lys LysSer SerGly Gly ThrThr Al Ala Ser a Ser ValVal ValVal Cys Cys Leu Leu Leu Asn Leu Asn AsnPhe Asn Phe 20 20 25 25 30 30

Tyr Pro Tyr Pro Arg ArgGlu GluAla Ala LysLys ValVal Gln Gln Trp Trp Lys Asp Lys Val Val Asn AspAlAsn AlaGILeu a Leu n Gln 35 35 40 40 45 45

Ser Gly Asn Ser Gly AsnSer SerGln Gln GluGlu SerSer Val Val Thr Thr Glu Asp Glu Gln Gln Ser AspLys SerAsp Lys SerAsp Ser 50 50 55 55 60 60

Thr Tyr Thr Tyr Ser Ser Leu Leu Ser Ser Ser Ser Thr Thr Leu Leu Thr Thr Leu Leu Ser Ser Lys Lys Ala Ala Asp Asp Tyr Tyr Glu Glu

70 70 75 75 80 80

Lys Hiss Lys Lys Hi Val Tyr Lys Val TyrAIAla CysGIGlu a Cys Val Thr u Val ThrHiHis GlnGly s Gln GlyLeu Leu SerSer SerSer 85 85 90 90 95 95

Pro Val Thr Pro Val ThrLys LysSer Ser PhePhe AsnAsn Arg Arg Gly Gly Glu Glu Cys Cys 100 100 105 105

<210> <210> 38 38 <211> <211> 107 107 <212> <212> PRT PRT Page 28 Page 28

JPOXMLDOC01-seql.txt JPOXMLDOC01-segl. txt <213> Artificial sequence <213> Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 38 38 Arg Thr Arg Thr Val ValAlAla Ala a Al Pro Ser a Pro SerVal ValPhe Phe Ile lle PhePhe ProPro Pro Pro Ser Ser Asp Glu Asp Glu 1 1 5 5 10 10 15 15

Gln Leu Gln Leu Lys LysSer SerGly Gly ThrThr AlaAla Ser Ser Val Val Val Leu Val Cys Cys Leu LeuAsn LeuAsn AsnPheAsn Phe 20 20 25 25 30 30

Tyr Pro Tyr Pro Arg Arg Glu Glu Ala Ala Lys Lys Val Val Gln Gln Trp Trp Lys Lys Val Val Asp Asp Asn Asn Ala Ala Leu Leu GI Glnn 35 35 40 40 45 45

Ser Gly Asn Ser Gly AsnSer SerGln Gln GluGlu SerSer Val Val Thr Thr Glu Asp Glu Gln Gln Ser AspLys SerAsp Lys SerAsp Ser 50 50 55 55 60 60

Thr Tyr Thr Tyr Ser SerLeu LeuSer Ser SerSer ThrThr Leu Leu Thr Thr Leu Lys Leu Ser Ser Ala LysAsp AlaTyr Asp GluTyr Glu

70 70 75 75 80 80

Lys Hiss Lys Lys Hi Val Tyr Lys Val TyrAla AlaCys Cys Glu Glu ValVal ThrThr Hi sHis GlnGln Gly Gly Leu Leu Ser Ser Ser Ser 85 85 90 90 95 95

Pro Val Thr Pro Val ThrLys LysSer Ser PhePhe AsnAsn Arg Arg Gly Gly Glu Glu Cys Cys 100 100 105 105

<210> <210> 39 39 <211> <211> 1676 1676 <212> <212> PRT PRT <213> <213> Homo sapiens Homo sapiens <400> <400> 39 39 Met Gly Met Gly Leu LeuLeu LeuGly Gly lleIle LeuLeu Cys Cys Phe Phe Leu Phe Leu lle Ile Leu PheGly LeuLys Gly ThrLys Thr 1 1 5 5 10 10 15 15

Trp Gly Trp Gly Gln Gln Glu Glu Gln Gln Thr Thr Tyr Tyr Val Val lle Ile Ser Ser Ala Ala Pro Pro Lys Lys lle Ile Phe Phe Arg Arg 20 20 25 25 30 30

Val Gly Val Gly Al Ala Ser Glu a Ser GluAsn Asnlle Ile ValVal lleIle Gln Gln Val Val Tyr Tyr Tyr Gly Gly Thr TyrGlu Thr Glu 35 35 40 40 45 45

Alaa Phe AI Phe Asp Alaa Thr Asp AI Ile Ser Thr lle Serlle IleLys Lys Ser Ser TyrTyr ProPro Asp Asp Lys Lys Lys Phe Lys Phe 50 50 55 55 60 60

Ser Tyr Ser Ser Tyr SerSer SerGly Gly HisHis ValVal His Hi s LeuLeu SerSer Ser Ser Glu Glu Asn Phe Asn Lys LysGln Phe Gln

70 70 75 75 80 80

Asn Ser Asn Ser Al Ala Ile Leu a lle LeuThr Thrlle Ile GlnGln ProPro Lys Lys Gln Gln Leu Leu Pro Gly Pro Gly GlyGln Gly Gln Page 29 Page 29

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt 85 85 90 90 95 95

Asn Pro Asn Pro Val ValSer SerTyr Tyr ValVal TyrTyr Leu Leu Glu Glu Val Ser Val Val Val Lys SerHiLys HisSer s Phe Phe Ser 100 100 105 105 110 110

Lys Ser Lys Lys Ser LysArg ArgMet Met ProPro lleIle Thr Thr Tyr Tyr Asp Gly Asp Asn Asn Phe GlyLeu PhePhe Leu llePhe Ile 115 115 120 120 125 125

Hiss Thr Hi Thr Asp Lys Pro Asp Lys ProVal ValTyr Tyr ThrThr ProPro Asp Asp Gln Gln Ser Ser Val Val Val Lys LysArg Val Arg 130 130 135 135 140 140

Val Tyr Val Tyr Ser SerLeu LeuAsn Asn AspAsp AspAsp Leu Leu Lys Lys Proa Ala Pro Al Lys Glu Lys Arg Arg Thr GluVal Thr Val 145 145 150 150 155 155 160 160

Leu Thr Phe Leu Thr Phelle IleAsp Asp ProPro GluGlu Gly Gly Ser Ser Glu Glu Val Met Val Asp AspVal MetGlu Val GI Glu u Glu 165 165 170 170 175 175

Ile Asp Hi lle Asp His Ile Gly s lle Glylle Ilelle IleSer Ser PhePhe ProPro Asp Asp Phe Phe Lys Pro Lys lle IleSer Pro Ser 180 180 185 185 190 190

Asn Pro Asn Pro Arg ArgTyr TyrGly Gly MetMet TrpTrp Thr Thr lle Ile Lysa Ala Lys AI Lys Lys Lys Tyr Tyr Glu LysAsp Glu Asp 195 195 200 200 205 205

Phe Ser Thr Phe Ser ThrThr ThrGly Gly ThrThr AlaAla Tyr Tyr Phe Phe GI uGlu Val Val Lys Lys Glu Val Glu Tyr TyrLeu Val Leu 210 210 215 215 220 220

Pro His Phe Pro His PheSer SerVal Val SerSer lleIle Glu Glu Pro Pro Glu Asn Glu Tyr Tyr Phe Asnlle PheGly Ile TyrGly Tyr 225 225 230 230 235 235 240 240

Lys Asn Phe Lys Asn PheLys LysAsn Asn PhePhe GluGlu lle Ile Thr Thr lle Ile Lys Arg Lys Ala AlaTyr ArgPhe Tyr TyrPhe Tyr 245 245 250 250 255 255

Asn Lys Asn Lys Val ValVal ValThr Thr GluGlu Al Ala a AspAsp ValVal Tyr Tyr lle Ile Thr Gly Thr Phe Phe lle GlyArg Ile Arg 260 260 265 265 270 270

Glu Asp Glu Asp Leu LeuLys LysAsp Asp AspAsp GlnGln Lys Lys Glu Glu Met Gln Met Met Met Thr GlnAlThr AlaGIMet a Met n Gln 275 275 280 280 285 285

Asn Thr Asn Thr Met MetLeu Leulle Ile AsnAsn GlyGly lle Ile Ala Ala Gln Thr Gln Val Val Phe ThrAsp PheSer Asp GluSer Glu 290 290 295 295 300 300

Thr Al Thr Alaa Val Lys Glu Val Lys GluLeu LeuSer Ser TyrTyr TyrTyr Ser Ser Leu Leu Glu Glu Asp Asn Asp Leu LeuAsn Asn Asn 305 305 310 310 315 315 320 320

Lys Tyr Leu Lys Tyr LeuTyr Tyrlle Ile AlaAla ValVal Thr Thr Val Val Ile Ser lle Glu Glu Thr SerGly ThrGly Gly PheGly Phe 325 325 330 330 335 335

Page 30 Page 30

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt Ser Glu Glu Ser Glu GluAlAla Glulle a Glu IlePro Pro Gly Gly lleIle LysLys Tyr Tyr Val Val Leu Pro Leu Ser SerTyr Pro Tyr 340 340 345 345 350 350

Lys Leu Asn Lys Leu AsnLeu LeuVal Val AI Ala Thr a Thr Pro Pro LeuLeu PhePhe Leu Leu Lys Lys Pro lle Pro Gly GlyPro Ile Pro 355 355 360 360 365 365

Tyr Pro Tyr Pro II Ile Lys Val e Lys ValGln GlnVal Val LysLys AspAsp Ser Ser Leu Leu Asp Leu Asp Gln Gln Val LeuGly Val Gly 370 370 375 375 380 380

Gly Val Gly Val Pro ProVal ValThr Thr LeuLeu AsnAsn Ala AI a GlnGln ThrThr lle Ile Asp Asp Val Gln Val Asn AsnGlu Gln Glu 385 385 390 390 395 395 400 400

Thr Ser Thr Ser Asp Asp Leu Leu Asp Asp Pro Pro Ser Ser Lys Lys Ser Ser Val Val Thr Thr Arg Arg Val Val Asp Asp Asp Asp Gly Gly 405 405 410 410 415 415

Val Al Val Alaa Ser Phe Val Ser Phe ValLeu LeuAsn Asn LeuLeu ProPro Ser Ser Gly Gly Val Val Val Thr Thr Leu ValGlu Leu Glu 420 420 425 425 430 430

Phe Asn Val Phe Asn ValLys LysThr Thr AspAsp AI Ala Pro a Pro AspAsp LeuLeu Pro Pro Glu Glu Glu Gln Glu Asn AsnAlGln a Ala 435 435 440 440 445 445

Ile Ala Tyr Ser Ser Leu Ser Gln Ser Tyr Arg Glu Gly Tyr Arg Ala lle 450 450 455 455 460 460

Leu Tyr II Leu Tyr Ile Asp Trp e Asp TrpThr ThrAsp Asp Asn Asn HisHis LysLys AI aAla LeuLeu Leu Leu Val Val Glyu Glu Gly GI 465 465 470 470 475 475 480 480

Hiss Leu Hi Leu Asn Ile lle Asn lle IleVal ValThr Thr Pro Pro LysLys SerSer Pro Pro Tyr Tyr Ile Lys lle Asp Asplle Lys Ile 485 485 490 490 495 495

Thr His Thr His Tyr TyrAsn AsnTyr Tyr LeuLeu lleIle Leu Leu Ser Ser Lys Lys Lys Gly Gly lle Lyslle IleHis Ile PheHis Phe 500 500 505 505 510 510

Gly Thr Gly Thr Arg ArgGlu GluLys Lys PhePhe SerSer Asp Asp Al aAla Ser Ser Tyr Tyr Gln Gln Ser Asn Ser lle Ilelle Asn Ile 515 515 520 520 525 525

Pro Val Thr Pro Val ThrGln GlnAsn Asn MetMet ValVal Pro Pro Ser Ser Ser Leu Ser Arg Arg Leu LeuVal LeuTyr Val TyrTyr Tyr 530 530 535 535 540 540

Ile Val Thr lle Val ThrGly GlyGlu Glu GlnGln ThrThr Ala Al a GluGlu LeuLeu Val Val Ser Ser Asp Val Asp Ser SerTrp Val Trp 545 545 550 550 555 555 560 560

Leu Asn lle Leu Asn IleGlu GluGlu Glu LysLys CysCys Gly Gly Asn Asn GI nGln Leu Leu Gln Gln Vals His Val Hi Leu Ser Leu Ser 565 565 570 570 575 575

Pro Asp AI Pro Asp Ala Asp Al a Asp Ala Tyr Ser a Tyr SerPro ProGly GlyGln Gln ThrThr ValVal Ser Ser Leu Leu Asn Met Asn Met 580 580 585 585 590 590

Page 31 Page 31

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt

Alaa Thr AI Thr Gly Met Asp Gly Met AspSer SerTrp Trp ValVal AI Ala Leu a Leu Al Ala a AlAla ValAsp a Val Asp SerSer AlaAla 595 595 600 600 605 605

Val Tyr Val Tyr Gly GlyVal ValGln Gln ArgArg GlyGly AI aAla LysLys Lys Lys Pro Pro Leu Arg Leu Glu Glu Val ArgPhe Val Phe 610 610 615 615 620 620

Gln Phe Gln Phe Leu LeuGlu GluLys Lys SerSer AspAsp Leu Leu Gly Gly Cys AI Cys Gly Glya Ala Gly Gly Gly Gly GlyLeu Gly Leu 625 625 630 630 635 635 640 640

Asn Asn Asn Asn AI Ala Asn Val a Asn ValPhe PheHis His LeuLeu AI Ala Gly a Gly LeuLeu ThrThr Phe Phe Leu Leu Thr Asn Thr Asn 645 645 650 650 655 655

Alaa Asn AI Asn Ala AI a Asp Asp Asp Ser Gln Asp Ser GlnGlu GluAsn Asn Asp Asp GluGlu ProPro Cys Cys Lys Lys Glu Ile Glu lle 660 660 665 665 670 670

Leu Arg Pro Leu Arg ProArg ArgArg Arg ThrThr LeuLeu Gln Gln Lys Lys Lys Lys Ile Glu lle Glu Glulle GluAla Ile AlaAla Ala 675 675 680 680 685 685

Lys Tyr Lys Lys Tyr LysHis HisSer Ser ValVal ValVal Lys Lys Lys Lys Cys Cys Cys Asp Cys Tyr TyrGly AspAIGly Ala Cys a Cys 690 690 695 695 700 700

Val Asn Val Asn Asn AsnAsp AspGlu Glu ThrThr CysCys GI uGlu GlnGln Arg Arg Al aAla Al Ala a ArgArg lleIle Ser Ser Leu Leu 705 705 710 710 715 715 720 720

Gly Pro Gly Pro Arg ArgCys Cyslle Ile LysLys Al Ala Phe a Phe ThrThr Glu Glu Cys Cys Cys Cys Val Ala Val Val ValSer Ala Ser 725 725 730 730 735 735

Gln Leu Gln Leu Arg ArgAIAla Asnlle a Asn IleSer Ser Hi His Lys s Lys Asp Asp MetMet GlnGln Leu Leu Gly Gly Arg Leu Arg Leu 740 740 745 745 750 750

His Hi s Met Met Lys Thr Leu Lys Thr LeuLeu LeuPro Pro Val Val SerSer LysLys Pro Pro Glu Glu Ile Ser lle Arg ArgTyr Ser Tyr 755 755 760 760 765 765

Phe Pro Glu Phe Pro GluSer SerTrp Trp LeuLeu TrpTrp Glu GI u ValVal HisHis Leu Leu Val Val Pro Arg Pro Arg ArgLys Arg Lys 770 770 775 775 780 780

Gln Leu Gln Leu Gln Gln Phe Phe Ala Ala Leu Leu Pro Pro Asp Asp Ser Ser Leu Leu Thr Thr Thr Thr Trp Trp Glu Glu lle Ile Gln Gln 785 785 790 790 795 795 800 800

Gly Val Gly Val Gly Glylle IleSer Ser AsnAsn ThrThr Gly Gly lle Ile Cys Ala Cys Val Val Asp AlaThr AspVal Thr LysVal Lys 805 805 810 810 815 815

Alaa Lys AI Lys Val Phe Lys Val Phe LysAsp AspVal Val PhePhe LeuLeu Glu Glu Met Met Asn Asn Ile Tyr lle Pro ProSer Tyr Ser 820 820 825 825 830 830

Val Val Val Val Arg ArgGly GlyGlu Glu GlnGln lleIle Gln Gln Leu Leu Lys Thr Lys Gly Gly Val ThrTyr ValAsn Tyr TyrAsn Tyr 835 835 840 840 845 845 Page 32 Page 32

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Arg Thr Arg Thr Ser SerGly GlyMet Met GlnGln PhePhe Cys Cys Val Val Lys Ser Lys Met Met Al Ser Ala Glu a Val ValGly Glu Gly 850 850 855 855 860 860

Ile Cys Thr lle Cys ThrSer SerGlu Glu Ser Ser ProPro ValVal lle Ile Asp Asp His Gly His Gln GlnThr GlyLys Thr Lys Ser Ser 865 865 870 870 875 875 880 880

Ser Lys Cys Ser Lys CysVal ValArg Arg GlnGln LysLys Val Val Glu Glu Gly Ser Gly Ser Ser Ser SerHiSer HisVal s Leu Leu Val 885 885 890 890 895 895

Thr Phe Thr Phe Thr ThrVal ValLeu Leu ProPro LeuLeu Glu Glu lle Ile Gly His Gly Leu Leu Asn Hislle AsnAsn Ile PheAsn Phe 900 900 905 905 910 910

Ser Leu Glu Ser Leu GluThr ThrTrp Trp PhePhe GlyGly Lys Lys Glu Glu Ile Val lle Leu Leu Lys ValThr LysLeu Thr ArgLeu Arg 915 915 920 920 925 925

Val Val Val Val Pro ProGlu GluGly Gly ValVal LysLys Arg Arg Glu Glu Ser Ser Ser Tyr Tyr Gly SerVal GlyThr Val LeuThr Leu 930 930 935 935 940 940

Asp Pro Asp Pro Arg ArgGly Glylle Ile TyrTyr GlyGly Thr Thr lle Ile Ser Arg Ser Arg Arg Lys ArgGlu LysPhe Glu ProPhe Pro 945 945 950 950 955 955 960 960

Tyr Arg Tyr Arg lle IlePro ProLeu Leu AspAsp LeuLeu Val Val Pro Pro Lys Glu Lys Thr Thr lle GluLys IleArg Lys lleArg Ile 965 965 970 970 975 975

Leu Ser Val Leu Ser ValLys LysGly Gly LeuLeu LeuLeu Val Val GI yGly GluGlu lle Ile Leu Leu Ser Val Ser Ala AlaLeu Val Leu 980 980 985 985 990 990

Ser Ser Gln Gln Glu Glu Gly Gly Ile lle Asn Ile Leu Asn lle Leu Thr ThrHis HisLeu LeuPro ProLys LysGly Gly Ser Ser Ala Ala 995 995 1000 1000 1005 1005

Glu Ala Glu Ala Glu GluLeu LeuMet MetSer SerVal ValVal Val Pro Pro Val Val Phe Phe Tyr Tyr Val Val Phe Phe His Hi s 1010 1010 1015 1015 1020 1020

Tyr Leu Tyr Leu Glu GluThr ThrGly GlyAsn AsnHi His TrpAsn s Trp Asnlle IlePhe PheHi His SerAsp s Ser AspPro Pro 1025 1025 1030 1030 1035 1035

Leu Leu Ile Glu Lys lle Glu Lys Gln Gln Lys LysLeu LeuLys Lys Lys Lys Lys Lys Leu Leu Lys Lys GluGlu GlyGly MetMet 1040 1040 1045 1045 1050 1050

Leu Leu Ser Ile Met Ser lle Met Ser Ser Tyr Tyr Arg Arg Asn Asn AIAla AspTyr a Asp TyrSer SerTyr Tyr Ser Ser Val Val 1055 1055 1060 1060 1065 1065

Trp Lys Trp Lys Gly GlyGly GlySer SerAl Ala Ser Thr a Ser ThrTrp TrpLeu LeuThr ThrAla AlaPhe Phe AI Ala Leu a Leu 1070 1070 1075 1075 1080 1080

Arg Val Arg Val Leu LeuGly GlyGln GlnVal ValAsn AsnLys Lys Tyr Tyr Val Val Glu Glu Gln Gln Asn Asn Gln Gln Asn Asn Page 33 Page 33

JPOXMLDOC01-seql.txt UPOXMLDOC01-segl.txt 1085 1085 1090 1090 1095 1095

Ser Ser Ile CysAsn lle Cys AsnSer SerLeu LeuLeu LeuTrp Trp Leu Leu Val Val Glu Glu Asn Asn TyrTyr GlnGln LeuLeu 1100 1100 1105 1105 1110 1110

Asp Asn Asp Asn Gly GlySer SerPhe PheLys LysGlu GluAsn Asn Ser Ser Gln Gln Tyr Tyr Gln Gln Pro Pro lle Ile Lys Lys 1115 1115 1120 1120 1125 1125

Leu Leu Gln GlyThr Gln Gly ThrLeu LeuPro ProVal ValGIGlu Ala u Al a Arg Arg Glu Glu Asn SerLeu Asn Ser LeuTyr Tyr 1130 1130 1135 1135 1140 1140

Leu Leu Thr AlaPhe Thr Ala PheThr ThrVal Vallle IleGly Gly Ile lle Arg Arg Lys Lys AIAla Phe a Phe Asp Asp Ile lle 1145 1145 1150 1150 1155 1155

Cys Pro Cys Pro Leu LeuVal ValLys Lyslle IleAsp AspThr Thr Ala Ala Leu Leu Ile lle Lys Lys Ala AI a Asp Asp Asn Asn 1160 1160 1165 1165 1170 1170

Phe Phe Leu Leu GI Leu Leu Glu u Asn Asn Thr Thr Leu Pro Al Leu Pro Ala a Gln Gln Ser Ser Thr PheThr Thr Phe ThrLeu Leu 1175 1175 1180 1180 1185 1185

Ala lle Ala Ile Ser SerAla AlaTyr TyrAI Ala a Leu Ser Leu SerLeu LeuGly GlyAsp AspLys LysThr Thr Hi His Pro s Pro 1190 1190 1195 1195 1200 1200

Gln Phe Gln Phe Arg ArgSer Serlle IleVal ValSer SerAI Ala LeuLys a Leu LysArg ArgGlu GluAl Ala LeuVal a Leu Val 1205 1205 1210 1210 1215 1215

Lys Lys Gly AsnPro Gly Asn ProPro Prolle IleTyr TyrArg Arg Phe Phe Trp Trp Lys Lys Asp Asp AsnAsn LeuLeu GlnGln 1220 1220 1225 1225 1230 1230

His Hi sLys Lys Asp Asp Ser Ser Val Ser Ser Val Pro Pro Asn AsnThr ThrGly GlyThr ThrAla AlaArg Arg Met Met Val Val 1235 1235 1240 1240 1245 1245

Glu ThrThr GI Thr Thr Ala Ala Tyr Tyr AIAla LeuLeu a Leu Leu Thr Thr Ser Ser Leu Leu Asn Asn LeuLeu LysLys AspAsp 1250 1250 1255 1255 1260 1260

Ile lle Asn Tyr Val Asn Tyr Val Asn Asn Pro Pro Val Val lle Ile Lys Lys Trp Trp Leu Leu Ser Ser GluGlu GluGlu GlnGln 1265 1265 1270 1270 1275 1275

Arg Tyr Arg Tyr Gly GlyGly GlyGly GlyPhe PheTyr TyrSer Ser Thr Thr Gln Gln Asp Asp Thr Thr lle Ile Asn Asn Ala Al a 1280 1280 1285 1285 1290 1290

Ile lle Glu Gly Leu Glu Gly Leu Thr Thr Glu Glu Tyr Tyr Ser Ser Leu Leu Leu Leu Val Val Lys Lys GlnGln LeuLeu ArgArg 1295 1295 1300 1300 1305 1305

Leu Leu Ser MetAsp Ser Met Asplle IleAsp AspVal ValSer Ser Tyr Tyr Lys Lys HiHis LysGly s Lys Gly AIAla Leu a Leu 1310 1310 1315 1315 1320 1320

Page 34 Page 34

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt His Hi sAsn Asn Tyr Tyr Lys Lys Met Thr Asp Met Thr Asp Lys LysAsn AsnPhe PheLeu LeuGly GlyArg Arg Pro Pro Val Val 1325 1325 1330 1330 1335 1335

Glu Val Glu Val Leu LeuLeu LeuAsn AsnAsp AspAsp AspLeu Leu IleVal I le ValSer SerThr ThrGly Gly Phe Phe Gly Gly 1340 1340 1345 1345 1350 1350

Ser Gly Leu Ser Gly Leu Al Ala Thr a Thr ValVal Hi His S Val Val Thr Thr Thr Val Thr Val ValHiVal His s Lys Lys Thr Thr 1355 1355 1360 1360 1365 1365

Ser Ser Thr SerGlu Thr Ser GluGlu GluVal ValCys CysSer Ser Phe Phe Tyr Tyr Leu Leu Lys Lys lleIle AspAsp ThrThr 1370 1370 1375 1375 1380 1380

Gln Asp Gln Asp lle IleGlu GluAI Ala Ser His a Ser His Tyr TyrArg ArgGly GlyTyr TyrGI Gly AsnSer y Asn SerAsp Asp 1385 1385 1390 1390 1395 1395

Tyr Lys Tyr Lys Arg ArgI Ile ValAl e Val Ala Cys Al a Cys Ala Ser Tyr a Ser Tyr Lys Lys Pro Pro Ser SerArg ArgGlu Glu 1400 1400 1405 1405 1410 1410

Glu Ser Glu Ser Ser SerSer SerGly GlySer SerSer SerHis His Al Ala Val Val Met Met Asp Asp Ile Leu lle Ser Ser Leu 1415 1415 1420 1420 1425 1425

Pro Pro Thr GlyIIle Thr Gly SerAla e Ser AlaAsn AsnGIGlu GluAsp u Glu AspLeu LeuLys LysAIAla LeuVal a Leu Val 1430 1430 1435 1435 1440 1440

Glu Gly Glu Gly Val ValAsp AspGln GlnLeu LeuPhe PheThr Thr Asp Asp Tyr Tyr Gln Gln Ile lle Lys Lys Asp Asp Gly Gly 1445 1445 1450 1450 1455 1455

His Val His Val lle IleLeu LeuGln GlnLeu LeuAsn AsnSer Ser Ile lle Pro Pro Ser Ser Ser Ser Asp Asp Phe Phe Leu Leu 1460 1460 1465 1465 1470 1470

Cys Val Cys Val Arg ArgPhe PheArg Arglle IlePhe PheGlu Glu Leu Leu Phe Phe Glu Glu Val Val Gly GI y Phe Phe Leu Leu 1475 1475 1480 1480 1485 1485

Ser Ser Pro Ala Pro Al a Thr Thr Phe Phe Thr Thr Val TyrGlu Val Tyr GluTyr TyrHis HisArg ArgPro Pro Asp Asp Lys Lys 1490 1490 1495 1495 1500 1500

Gln Cys Gln Cys Thr ThrMet MetPhe PheTyr TyrSer SerThr Thr Ser Ser Asn Asn Ile lle Lys Lys lle Ile Gln Gln Lys Lys 1505 1505 1510 1510 1515 1515

Val Cys Val Cys Glu GluGly GlyAla AlaAla AlaCys CysLys Lys Cys Cys Val Val Glu Glu Ala Ala Asp Asp Cys Cys Gly Gly 1520 1520 1525 1525 1530 1530

Gln Met Gln Met Gln GlnGlu GluGlu GluLeu LeuAsp AspLeu Leu Thr Thr Ile lle Ser Ser Al Ala Glu a Glu Thr Thr Arg Arg 1535 1535 1540 1540 1545 1545

Lys Lys Gln ThrAL Gln Thr Ala Cys Cys Lys Lys Pro Pro GluGlu lleIle Ala Al a Tyr Tyr AlAla Tyr a Tyr Lys Lys Val Val 1550 1550 1555 1555 1560 1560

Page 35 Page 35

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Ser Ser Ile ThrSer lle Thr SerII Ile e Thr Thr Val Glu Val GI Asn Val u Asn Val Phe Phe Val Val Lys LysTyr TyrLys Lys 1565 1565 1570 1570 1575 1575

Ala Thr Ala Thr Leu LeuLeu LeuAsp Asplle IleTyr TyrLys Lys Thr Thr Gly Gly Glu Glu Ala Ala Val Val Ala AI a Glu Glu 1580 1580 1585 1585 1590 1590

Lys Lys Asp SerGlu Asp Ser Glulle IleThr ThrPhe Phelle Ile Lys Lys Lys Lys Val Val Thr Thr CysCys ThrThr AsnAsn 1595 1595 1600 1600 1605 1605

Ala Glu Ala Glu LeuLeu ValVal LysLys Gly Gly Arg Arg GlnLeu Gln Tyr Tyr lleLeu IleGIMet e Met Gly y Lys GluLys Glu 1610 1610 1615 1615 1620 1620

Ala Leu Ala Leu Gln Glnlle IleLys LysTyr TyrAsn AsnPhe Phe Ser Ser Phe Phe Arg Arg Tyr Tyr lle Ile Tyr Tyr Pro Pro 1625 1625 1630 1630 1635 1635

Leu Leu Asp SerLeu Asp Ser LeuThr ThrTrp Trplle IleGlu Glu Tyr Tyr Trp Trp Pro Pro Arg Arg AspAsp ThrThr ThrThr 1640 1640 1645 1645 1650 1650

Cys Ser Cys Ser Ser SerCys CysGln GlnAla AlaPhe PheLeu Leu AIAla AsnLeu a Asn LeuAsp AspGI Glu PheAl u Phe Ala 1655 1655 1660 1660 1665 1665

Glu Asp Glu Asp lle IlePhe PheLeu LeuAsn AsnGly GlyCys Cys 1670 1670 1675 1675

<210> <210> 40 40 <211> <211> 673 673 <212> <212> PRT PRT <213> <213> Homo sapiens Homo sapiens

<400> <400> 40 40 Met Gly Met Gly Leu LeuLeu LeuGly Gly lleIle LeuLeu Cys Cys Phe Phe Leu Phe Leu lle Ile Leu PheGly LeuLys Gly ThrLys Thr 1 1 5 5 10 10 15 15

Trp Gly Trp Gly Gln GlnGlu GluGln Gln ThrThr TyrTyr Val Val lle Ile Ser Pro Ser Ala Ala Lys Prolle LysPhe IleArgPhe Arg 20 20 25 25 30 30

Val Gly Val Gly AI Ala Ser Glu a Ser GluAsn Asnlle Ile ValVal lleIle Gln Gln Val Val Tyr Tyr Tyr Gly Gly Thr TyrGlu Thr Glu 35 35 40 40 45 45

Alaa Phe AI Phe Asp Alaa Thr Asp AI Ile Ser Thr lle Serlle IleLys Lys Ser Ser TyrTyr ProPro Asp Asp Lys Lys Lys Phe Lys Phe 50 50 55 55 60 60

Ser Tyr Ser Ser Tyr SerSer SerGly Gly HisHis ValVal His His Leu Leu Ser Glu Ser Ser Ser Asn GluLys AsnPhe Lys GI Phe n Gln

70 70 75 75 80 80

Asn Ser Asn Ser Ala Alalle IleLeu LeuThrThr lleIle Gln Gln Pro Pro Lys Leu Lys Gln Gln Pro LeuGly ProGly Gly GlnGly Gln 85 85 90 90 95 95

Page 36 Page 36

JPOXMLDOC01-seql.txt JPOXMLDOC01-segl. txt

Asn Pro Asn Pro Val ValSer SerTyr Tyr ValVal TyrTyr Leu Leu Glu Glu Val Ser Val Val Val Lys SerHiLys HisSer s Phe Phe Ser 100 100 105 105 110 110

Lys Ser Lys Lys Ser LysArg ArgMet Met ProPro lleIle Thr Thr Tyr Tyr Asp Gly Asp Asn Asn Phe GlyLeu PhePhe Leu llePhe Ile 115 115 120 120 125 125

His Hi s Thr Thr Asp Lys Pro Asp Lys ProVal ValTyr Tyr Thr Thr ProPro AspAsp Gln Gln Ser Ser Val Val Val Lys LysArg Val Arg 130 130 135 135 140 140

Val Tyr Val Tyr Ser SerLeu LeuAsn Asn AspAsp AspAsp Leu Leu Lys Lys Proa Ala Pro AI Lys Glu Lys Arg Arg Thr GluVal Thr Val 145 145 150 150 155 155 160 160

Leu Thr Phe Leu Thr Phelle IleAsp Asp ProPro GluGlu Gly Gly Ser Ser Glu Glu Val Met Val Asp AspVal MetGlu Val GI Glu u Glu 165 165 170 170 175 175

Ile Asp Hi lle Asp His Ile Gly s lle Glylle Ilelle IleSer Ser PhePhe ProPro Asp Asp Phe Phe Lys Pro Lys lle IleSer Pro Ser 180 180 185 185 190 190

Asn Pro Asn Pro Arg ArgTyr TyrGly Gly MetMet TrpTrp Thr Thr lle Ile Lysa Ala Lys AI Lys Lys Lys Tyr Tyr Glu LysAsp Glu Asp 195 195 200 200 205 205

Phe Ser Thr Phe Ser ThrThr ThrGly Gly ThrThr AlaAla Tyr Tyr Phe Phe GI uGlu Val Val Lys Lys Glu Val Glu Tyr TyrLeu Val Leu 210 210 215 215 220 220

Pro His Phe Pro His PheSer SerVal Val SerSer lleIle Glu Glu Pro Pro Glu Asn Glu Tyr Tyr Phe Asn11Phe IleTyr e Gly Gly Tyr 225 225 230 230 235 235 240 240

Lys Asn Phe Lys Asn PheLys LysAsn Asn PhePhe GluGlu lle Ile Thr Thr Ile Al lle Lys Lysa Ala Arg Phe Arg Tyr TyrTyr Phe Tyr 245 245 250 250 255 255

Asn Lys Asn Lys Val Val Val Val Thr Thr Glu Glu Al Alaa Asp Asp Val Val Tyr Tyr Ile Thr Phe le Thr Phe Gly Gly lle Ile Arg Arg 260 260 265 265 270 270

Gluu Asp GI Asp Leu Lys Asp Leu Lys AspAsp AspGln Gln Lys Lys GI Glu Met u Met MetMet GlnGln Thr Thr AI aAla Met Met GI nGln 275 275 280 280 285 285

Asn Thr Asn Thr Met Met Leu Leu lle Ile Asn Asn Gly Gly le IleAla AlaGl Gln Val Thr r Val Thr Phe Phe Asp Asp Ser Ser Glu Glu 290 290 295 295 300 300

Thr Al Thr Alaa Val Lys Glu Val Lys GluLeu LeuSer Ser TyrTyr TyrTyr Ser Ser Leu Leu Glu Glu Asp Asn Asp Leu LeuAsn Asn Asn 305 305 310 310 315 315 320 320

Lys Tyr Leu Lys Tyr LeuTyr Tyrlle Ile AlaAla ValVal Thr Thr Val Val Ile Ser lle Glu Glu Thr SerGly ThrGly Gly PheGly Phe 325 325 330 330 335 335

Ser Glu Glu Ser Glu GluAla AlaGlu Glu lleIle ProPro Gly Gly lle Ile Lys Val Lys Tyr Tyr Leu ValSer LeuPro Ser TyrPro Tyr 340 340 345 345 350 350 Page 37 Page 37

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Lys Leu Asn Lys Leu AsnLeu LeuVal Val AlaAla ThrThr Pro Pro Leu Leu Phe Lys Phe Leu Leu Pro LysGly Prolle Gly ProIle Pro 355 355 360 360 365 365

Tyr Pro Tyr Pro lle IleLys LysVal Val GlnGln ValVal Lys Lys Asp Asp Ser Asp Ser Leu Leu Gl Asp Gln Val r Leu LeuGly Val Gly 370 370 375 375 380 380

Gly Val Gly Val Pro ProVal ValThr Thr LeuLeu AsnAsn Ala Ala Gln Gln Thr Asp Thr lle Ile Val AspAsn ValGln Asn GluGln Glu 385 385 390 390 395 395 400 400

Thr Ser Thr Ser Asp Asp Leu Leu Asp Asp Pro Pro Ser Ser Lys Lys Ser Ser Val Val Thr Thr Arg Arg Val Val Asp Asp Asp Asp Gly Gly 405 405 410 410 415 415

Val AI Val Alaa Ser Phe Val Ser Phe ValLeu LeuAsn Asn LeuLeu ProPro Ser Ser Gly Gly Val Val Val Thr Thr Leu ValGlu Leu Glu 420 420 425 425 430 430

Phe Asn Val Phe Asn ValLys LysThr Thr AspAsp Al Ala Pro a Pro AspAsp LeuLeu Pro Pro Glu Glu Glu Gln Glu Asn AsnALGln a Ala 435 435 440 440 445 445

Arg Glu Arg Glu Gly Gly Tyr Tyr Arg Arg Ala Ala lle Ile Ala Ala Tyr Tyr Ser Ser Ser Ser Leu Leu Ser Ser Gln Gln Ser Ser Tyr Tyr 450 450 455 455 460 460

Leu Tyr lle Leu Tyr IleAsp AspTrp Trp ThrThr AspAsp Asn Asn Hi sHis LysLys AI aAla LeuLeu Leu Leu Val Val Gly Glu Gly Glu 465 465 470 470 475 475 480 480

His Leu His Leu Asn Asnlle Ilelle Ile ValVal ThrThr Pro Pro Lys Lys Ser Tyr Ser Pro Pro lle TyrAsp IleLys Asp lleLys Ile 485 485 490 490 495 495

Thr Hi Thr Hiss Tyr Asn Tyr Tyr Asn TyrLeu Leulle Ile Leu Leu SerSer Lys Lys Gly Gly Lys Lys Ile His lle lle IlePhe His Phe 500 500 505 505 510 510

Gly Thr Gly Thr Arg ArgGlu GluLys Lys PhePhe SerSer Asp Asp AL aAla Ser Ser Tyr Tyr Gln Gln Ser Asn Ser lle Ilelle Asn Ile 515 515 520 520 525 525

Pro Val Thr Pro Val ThrGln GlnAsn Asn MetMet ValVal Pro Pro Ser Ser Ser Ser Arg Leu Arg Leu LeuVal LeuTyr Val TyrTyr Tyr 530 530 535 535 540 540

Ile Val Thr lle Val ThrGly GlyGlu Glu Gln Gln ThrThr Ala Al a GluGlu LeuLeu Val Val Ser Ser Asp Val Asp Ser SerTrp Val Trp 545 545 550 550 555 555 560 560

Leu Asn lle Leu Asn IleGlu GluGlu Glu LysLys CysCys Gly Gly Asn Asn Gln Gln Leu Val Leu Gln GlnHis ValLeu His SerLeu Ser 565 565 570 570 575 575

Pro Asp AI Pro Asp Ala Asp Ala a Asp AlaTyr TyrSer Ser Pro Pro GlyGly GlnGln Thr Thr Val Val Ser Asn Ser Leu LeuMet Asn Met 580 580 585 585 590 590

Alaa Thr AI Thr Gly Met Asp Gly Met AspSer SerTrp Trp ValVal AI Ala Leu a Leu AlaAla AlaAla Val Val Asp Asp Ser Ala Ser Ala Page 38 Page 38

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt 595 595 600 600 605 605

Val Tyr Val Tyr Gly GlyVal ValGln Gln ArgArg GlyGly Ala Ala Lys Lys Lys Leu Lys Pro Pro Glu LeuArg GluVal Arg PheVal Phe 610 610 615 615 620 620

Gln Phe Gln Phe Leu LeuGlu GluLys Lys SerSer AspAsp Leu Leu Gly Gly Cys Ala Cys Gly Gly Gly AlaGly GlyGly Gly LeuGly Leu 625 625 630 630 635 635 640 640

Asn Asn Asn Asn AI Ala Asn Val a Asn ValPhe PheHis His LeuLeu AlaAla Gly Gly Leu Leu Thr Thr Phe Thr Phe Leu LeuAsn Thr Asn 645 645 650 650 655 655

Alaa Asn AI Asn Ala AI a Asp Asp Asp Ser Gln Asp Ser GlnGlu GluAsn Asn Asp Asp GluGlu ProPro Cys Cys Lys Lys Glu Ile Glu lle 660 660 665 665 670 670

Leu Leu

<210> <210> 41 41 <211> <211> 105 105 <212> <212> PRT PRT <213> <213> Homo sapiens Homo sapiens <400> <400> 41 41

Glu Gln Glu Gln Thr ThrTyr TyrVal Val lleIle SerSer Ala Al a ProPro LysLys lle Ile Phe Phe Arg Gly Arg Val ValAla Gly Ala 1 1 5 5 10 10 15 15

Ser Glu Asn Ser Glu Asnlle IleVal Val 11 Ile Gln e Gln Val Val TyrTyr GlyGly Tyr Tyr Thr Thr Glua Ala Glu AL Phe Asp Phe Asp 20 20 25 25 30 30

Alaa Thr Al Thr Ile Ser lle lle Ser IleLys LysSer Ser Tyr Tyr ProPro AspAsp Lys Lys Lys Lys Phe Tyr Phe Ser SerSer Tyr Ser 35 35 40 40 45 45

Ser Gly Hi Ser Gly His Val His s Val HisLeu LeuSer Ser Ser Ser GluGlu AsnAsn Lys Lys Phe Phe Gln Ser Gln Asn AsnAlSer a Ala 50 50 55 55 60 60

Ile Leu Thr lle Leu Thrlle IleGln Gln Pro Pro LysLys GlnGln Leu Leu Pro Pro Gly Gln Gly Gly GlyAsn GlnPro Asn Pro Val Val

70 70 75 75 80 80

Ser Tyr Val Ser Tyr ValTyr TyrLeu LeuGluGlu ValVal Val Val Ser Ser Lys Phe Lys His His Ser PheLys SerSer Lys LysSer Lys 85 85 90 90 95 95

Arg Met Arg Met Pro Pro lle Ile Thr Thr Tyr Tyr Asp Asp Asn Asn Gly Gly 100 100 105 105

<210> <210> 42 42 <211> <211> 101 101 <212> <212> PRT PRT <213> <213> Homo sapiens Homo sapiens

Page 39 Page 39

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt <400> < 400 42 42 Phe Leu Phe Phe Leu Phelle IleHiHis ThrAsp s Thr AspLys Lys ProPro ValVal Tyr Tyr Thr Thr Pro Gln Pro Asp AspSer Gln Ser 1 1 5 5 10 10 15 15

Val Lys Val Lys Val ValArg ArgVal Val TyrTyr SerSer Leu Leu Asn Asn Asp Leu Asp Asp Asp Lys LeuPro LysAIPro Ala Lys a Lys 20 20 25 25 30 30

Arg Glu Arg Glu Thr Thr Val Val Leu Leu Thr Thr Phe Phe lle Ile Asp Asp Pro Pro Glu Glu Gly Gly Ser Ser Glu Glu Val Val Asp Asp 35 35 40 40 45 45

Met Val Met Val Glu Glu Glu Glu lle Ile Asp Asp His His lle Ile Gly Gly le Ilelle IleSer SerPhe PhePro ProAsp AspPhe Phe 50 50 55 55 60 60

Lys Ile Pro Lys lle ProSer SerAsn Asn ProPro ArgArg Tyr Tyr Gly Gly Met Met Trp lle Trp Thr ThrLys IleAILys Ala Lys a Lys

70 70 75 75 80 80

Tyr Lys Tyr Lys Glu Glu Asp Asp Phe Phe Ser Ser Thr Thr Thr Thr Gly Gly Thr Thr Ala Ala Tyr Tyr Phe Phe Glu Glu Val Val Lys Lys 85 85 90 90 95 95

Gluu Tyr GI Tyr Val Leu Pro Val Leu Pro 100 100

<210> <210> 43 43 <211> <211> 225 225 <212> <212> PRT PRT <213> <213> Homo sapiens Homo sapiens

<400> <400> 43 43

Met Gly Met Gly Leu LeuLeu LeuGly Gly 11 Ile Leu e Leu CysCys PhePhe Leu Leu lle Ile Phe Phe Leu Lys Leu Gly GlyThr Lys Thr 1 1 5 5 10 10 15 15

Trp Gly Trp Gly Gln GlnGlu GluGIGln ThrTyr n Thr Tyr ValVal lleIle Ser Ser AI aAla ProPro Lys Lys lle Ile Phe Arg Phe Arg 20 20 25 25 30 30

Val Gly Val Gly AI Ala Ser Glu a Ser GluAsn Asnlle Ile ValVal lleIle Gln Gln Val Val Tyr Tyr Tyr Gly Gly Thr TyrGIThr u Glu 35 35 40 40 45 45

Alaa Phe AI Phe Asp Alaa Thr Asp AI Ile Ser Thr lle Serlle IleLys Lys Ser Ser TyrTyr ProPro Asp Asp Lys Lys Lys Phe Lys Phe 50 50 55 55 60 60

Ser Tyr Ser Ser Tyr SerSer SerGly Gly HisHis ValVal His His Leu Leu Ser Glu Ser Ser Ser Asn GluLys AsnPhe Lys GI Phe n Gln

70 70 75 75 80 80

Asn Ser Asn Ser Al Ala Ile Leu a lle LeuThr Thrlle Ile GlnGln ProPro Lys Lys Gln Gln Leu Leu Pro Gly Pro Gly GlyGIGly n Gln 85 85 90 90 95 95

Asn Pro Asn Pro Val ValSer SerTyr Tyr ValVal TyrTyr Leu Leu Glu Glu Val Ser Val Val Val Lys SerHiLys HisSer s Phe Phe Ser 100 100 105 105 110 110 Page 40 Page 40

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Lys Ser Lys Lys Ser LysArg ArgMet Met ProPro lleIle Thr Thr Tyr Tyr Asp Gly Asp Asn Asn Phe GlyLeu PhePhe Leu llePhe Ile 115 115 120 120 125 125

Hiss Thr Hi Thr Asp Lys Pro Asp Lys ProVal ValTyr Tyr Thr Thr ProPro AspAsp GI nGln SerSer Val Val Lys Lys Val Arg Val Arg 130 130 135 135 140 140

Val Tyr Val Tyr Ser SerLeu LeuAsn Asn AspAsp AspAsp Leu Leu Lys Lys Pro Lys Pro Ala Ala Arg LysGlu ArgThr Glu ValThr Val 145 145 150 150 155 155 160 160

Leu Thr Phe Leu Thr Phelle IleAsp Asp Pro Pro GluGlu Gly Gly Ser Ser Glu Glu Val Met Val Asp AspVal MetGlu Val GI Glu Glu u 165 165 170 170 175 175

Ile II e Asp Asp His Hi s Ile lle Gly Ile lle Gly lle Ile Ser SerPhe PhePro Pro AspAsp PhePhe Lys Lys lle Ile Pro Ser Pro Ser 180 180 185 185 190 190

Asn Pro Asn Pro Arg ArgTyr TyrGly Gly MetMet TrpTrp Thr Thr lle Ile Lysa Ala Lys AI Lys Lys Tyr Glu Tyr Lys LysAsp Glu Asp 195 195 200 200 205 205

Phe Ser Thr Phe Ser ThrThr ThrGly Gly ThrThr AlaAla TyrPhe a Tyr PheGIGlu ValLys u Val Lys GluGlu TyrTyr Val Val Leu Leu 210 210 215 215 220 220

Pro Pro 225 225

<210> <210> 44 44 <211> <211> 1676 1676 <212> <212> PRT PRT <213> <213> Macaca fascicularis Macaca fascicularis

<400> <400> 44 44 Met Gly Met Gly Leu LeuLeu LeuGly Gly II Ile Leu e Leu CysCys PhePhe Leu Leu lle Ile Phe Phe Leu Lys Leu Gly GlyThr Lys Thr 1 1 5 5 10 10 15 15

Trp Gly Trp Gly Gln Gln Glu Glu Gln Gln Thr Thr Tyr Tyr Val Val lle Ile Ser Ser Ala Ala Pro Pro Lys Lys lle Ile Phe Phe Arg Arg 20 20 25 25 30 30

Val Gly Val Gly Al Ala Ser Glu a Ser GluAsn Asnlle Ile ValVal lleIle Gln Gln Val Val Tyr Tyr Gly Thr Gly Tyr TyrGlu Thr Glu 35 35 40 40 45 45

Alaa Phe AI Phe Asp Alaa Thr Asp AI Ile Ser Thr lle Serlle IleLys Lys Ser Ser TyrTyr ProPro Asp Asp Lys Lys Lys Phe Lys Phe 50 50 55 55 60 60

Ser Tyr Ser Ser Tyr SerSer SerGly Gly HisHis ValVal His Hi s LeuLeu SerSer Ser Ser Glu Glu Asn Phe Asn Lys LysGln Phe Gln

70 70 75 75 80 80

Asn Ser Asn Ser Al Ala Val Leu a Val LeuThr Thrlle Ile GlnGln ProPro Lys Lys Gln Gln Leu Leu Pro Gly Pro Gly GlyGIGly n Gln 85 85 90 90 95 95 Page 41 Page 41

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Asn Gln Asn Gln Val ValSer SerTyr Tyr ValVal TyrTyr Leu Leu Glu Glu Val Ser Val Val Val Lys SerHiLys HisSer s Phe Phe Ser 100 100 105 105 110 110

Lys Ser Lys Lys Ser LysLys Lyslle Ile ProPro lleIle Thr Thr Tyr Tyr Asp Gly Asp Asn Asn Phe GlyLeu PhePhe Leu llePhe Ile 115 115 120 120 125 125

His Hi s Thr Thr Asp Lys Pro Asp Lys ProVal ValTyr Tyr Thr Thr ProPro AspAsp Gln Gln Ser Ser Val Val Val Lys LysArg Val Arg 130 130 135 135 140 140

Val Tyr Val Tyr Ser SerLeu LeuAsn Asn AspAsp AspAsp Leu Leu Lys Lys Pro Lys Pro Ala Ala Arg LysGlu ArgThr Glu ValThr Val 145 145 150 150 155 155 160 160

Leu Thr Phe Leu Thr Phelle IleAsp Asp ProPro GluGlu Gly Gly Ser Ser Glu Glu Ile Met lle Asp AspVal MetGlu Val GluGlu Glu 165 165 170 170 175 175

Ile Asp Hi lle Asp His Ile Gly s lle Glylle Ilelle IleSer Ser PhePhe ProPro Asp Asp Phe Phe Lys Pro Lys lle IleSer Pro Ser 180 180 185 185 190 190

Asn Pro Asn Pro Arg Arg Tyr Tyr Gly Gly Met Met Trp Trp Thr Thr lle Ile Gln Gln Ala Ala Lys Lys Tyr Tyr Lys Lys Glu Glu Asp Asp 195 195 200 200 205 205

Phe Ser Thr Phe Ser ThrThr ThrGly Gly ThrThr Al Ala Phe a Phe PhePhe GluGlu Val Val Lys Lys Glu Val Glu Tyr TyrLeu Val Leu 210 210 215 215 220 220

Pro His Phe Pro His PheSer SerVal Val SerSer ValVal Glu Glu Pro Pro Glu Glu Ser Phe Ser Asn Asnlle PheGly Ile TyrGly Tyr 225 225 230 230 235 235 240 240

Lys Asn Phe Lys Asn PheLys LysAsn Asn PhePhe GluGlu lle Ile Thr Thr lle Ile Lysa Ala Lys Al Arg Phe Arg Tyr TyrTyr Phe Tyr 245 245 250 250 255 255

Asn Lys Asn Lys Val Val Val Val Thr Thr Glu Glu Ala Ala Asp Asp Val Val Tyr Tyr lle Ile Thr Thr Phe Phe Gly Gly lle Ile Arg Arg 260 260 265 265 270 270

Glu GI u Asp Asp Leu Lys Asp Leu Lys AspAsp AspGln Gln Lys Lys GluGlu MetMet Met Met Gln Gln Thra Ala Thr Al Met Gln Met Gln 275 275 280 280 285 285

Asn Thr Asn Thr Met MetLeu Leulle Ile AsnAsn GlyGly lle Ile Al aAla Glu Glu Val Val Thr Asp Thr Phe Phe Ser AspGlu Ser Glu 290 290 295 295 300 300

Thr Al Thr Alaa Val Lys GI Val Lys Glu Leu Ser u Leu SerTyr TyrTyr Tyr Ser Ser LeuLeu GluGlu Asp Asp Leu Leu Asn Asn Asn Asn 305 305 310 310 315 315 320 320

Lys Tyr Leu Lys Tyr LeuTyr Tyrlle Ile AlaAla ValVal Thr Thr Val Val I leIle Glu Glu Ser Ser Thr Gly Thr Gly GlyPhe Gly Phe 325 325 330 330 335 335

Ser Glu Glu Ser Glu GluAla AlaGlu Glu lleIle ProPro Gly Gly lle Ile Lys Val Lys Tyr Tyr Leu ValSer LeuPro Ser TyrPro Tyr Page 42 Page 42

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt 340 340 345 345 350 350

Lys Leu Asn Lys Leu AsnLeu LeuVal Val AI Ala Thr a Thr Pro Pro LeuLeu PhePhe Leu Leu Lys Lys Pro lle Pro Gly GlyPro Ile Pro 355 355 360 360 365 365

Tyr Ser Tyr Ser lle IleLys LysVal Val GlnGln ValVal Lys Lys Asp Asp AI a Ala Leu Leu Asp Asp Gln Val Gln Leu LeuGly Val Gly 370 370 375 375 380 380

Gly Val Gly Val Pro ProVal ValThr Thr LeuLeu AsnAsn Ala AI a GlnGln Thr Thr lle Ile Asp Asp Val Gln Val Asn AsnGlu Gln Glu 385 385 390 390 395 395 400 400

Thr Ser Thr Ser Asp Asp Leu Leu Glu Glu Pro Pro Arg Arg Lys Lys Ser Ser Val Val Thr Thr Arg Arg Val Val Asp Asp Asp Asp Gly Gly 405 405 410 410 415 415

Val AI Val Alaa Ser Phe Val Ser Phe ValVal ValAsn Asn LeuLeu ProPro Ser Ser Gly Gly Val Val Val Thr Thr Leu ValGlu Leu Glu 420 420 425 425 430 430

Phe Asn Val Phe Asn ValLys LysThr Thr AspAsp AI Ala Pro a Pro AspAsp LeuLeu Pro Pro Asp Asp Glu Gln Glu Asn AsnAla Gln Ala 435 435 440 440 445 445

Arg Glu Arg Glu Gly GlyTyr TyrArg Arg AlaAla lleIle Ala Ala Tyr Tyr Ser Leu Ser Ser Ser Ser LeuGln SerSer Gln TyrSer Tyr 450 450 455 455 460 460

Leu Tyr lle Leu Tyr IleAsp AspTrp Trp ThrThr AspAsp Asn Asn His His Lys Lys Ala Leu Ala Leu LeuVal LeuGly Val GI Gly u Glu 465 465 470 470 475 475 480 480

Tyr Leu Tyr Leu Asn Asn lle Ile lle Ile Val Val Thr Thr Pro Pro Lys Lys Ser Ser Pro Pro Tyr Tyr lle Ile Asp Asp Lys Lys lle Ile 485 485 490 490 495 495

Thr Hi Thr Hiss Tyr Asn Tyr Tyr Asn TyrLeu Leulle Ile Leu Leu SerSer LysLys Gly Gly Lys Lys Ile His lle lle IlePhe His Phe 500 500 505 505 510 510

Gly Thr Gly Thr Arg ArgGlu GluLys Lys LeuLeu SerSer Asp Asp AI aAla Ser Ser Tyr Tyr Gln Gln Ser Asn Ser lle Ilelle Asn Ile 515 515 520 520 525 525

Pro Val Thr Pro Val ThrGln GlnAsn Asn MetMet ValVal Pro Pro Ser Ser Ser Ser Arg Leu Arg Leu LeuVal LeuTyr Val TyrTyr Tyr 530 530 535 535 540 540

Ile Val Thr lle Val ThrGly GlyGlu Glu GI Gln Thr n Thr AI Ala GluLeu a Glu Leu ValVal SerSer Asp Asp Ser Ser Val Trp Val Trp 545 545 550 550 555 555 560 560

Leu Asn 11 Leu Asn Ile Glu Glu e Glu GluLys LysCys Cys Gly Gly AsnAsn GlnGln Leu Leu Gln Gln Vals His Val Hi Leu Ser Leu Ser 565 565 570 570 575 575

Pro Asp AI Pro Asp Ala Asp Thr a Asp ThrTyr TyrSer Ser Pro Pro GlyGly Gln GI n ThrThr ValVal Ser Ser Leu Leu Asn Met Asn Met 580 580 585 585 590 590

Page 43 Page 43

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql. txt Val Thr Val Thr Gly GlyMet MetAsp Asp SerSer TrpTrp Val Val Ala Ala Leu Al Leu Thr Thra Ala Val Ser Val Asp AspAlSer a Ala 595 595 600 600 605 605

Val Tyr Val Tyr Gly Gly Val Val Gln Gln Arg Arg Arg Arg Ala Ala Lys Lys Lys Lys Pro Pro Leu Leu Glu Glu Arg Arg Val Val Phe Phe 610 610 615 615 620 620

Gln Phe Leu Gln Phe LeuGlu GluLys Lys SerSer AspAsp Leu Leu Gly Gly Cys AI Cys Gly Glya Ala Gly Gly Gly Gly GlyLeu Gly Leu 625 625 630 630 635 635 640 640

Asn Asn Asn Asn AI Ala Asn Val a Asn ValPhe PheHis His LeuLeu AlaAla Gly Gly Leu Leu Thr Thr Phe Thr Phe Leu LeuAsn Thr Asn 645 645 650 650 655 655

Alaa Asn AI Asn Ala Al a Asp Asp Asp Ser Gln Asp Ser GlnGlu GluAsn Asn Asp Asp GluGlu ProPro Cys Cys Lys Lys Glu Ile Glu lle 660 660 665 665 670 670

Ile Arg Pro lle Arg ProArg ArgArg Arg Met Met LeuLeu GlnGln Glu Glu Lys Lys Ile Glu lle Glu Glulle GluAla Ile Al Ala a Ala 675 675 680 680 685 685

Lys Tyr Lys Lys Tyr LysHis HisLeu Leu ValVal ValVal Lys Lys Lys Lys Cys Cys Cys Asp Cys Tyr TyrGly AspVal Gly ArgVal Arg 690 690 695 695 700 700

Ile Asn His lle Asn HisAsp AspGlu Glu Thr Thr CysCys Glu Glu Gln Gln Arg Arg AI a Ala AI aAla Arg Arg lle Ile Ser Val Ser Val 705 705 710 710 715 715 720 720

Gly Pro Gly Pro Arg ArgCys CysVal Val LysLys Al Ala Phe a Phe ThrThr Glu GI u CysCys CysCys Val Val Val Val AI a Ala Ser Ser 725 725 730 730 735 735

Gln Leu Gln Leu Arg ArgAIAla AsnAsn a Asn AsnSer Ser HisHis LysLys Asp Asp Leu Leu Gln Gly Gln Leu Leu Arg GlyLeu Arg Leu 740 740 745 745 750 750

Hiss Met Hi Met Lys Thr Leu Lys Thr LeuLeu LeuPro Pro Val Val SerSer Lys Lys Pro Pro Glu Glu Ile Ser lle Arg ArgTyr Ser Tyr 755 755 760 760 765 765

Phe Pro Glu Phe Pro GluSer SerTrp Trp LeuLeu TrpTrp Glu GI u ValVal HisHis Leu Leu Val Val Pro Arg Pro Arg ArgLys Arg Lys 770 770 775 775 780 780

Gln Leu Gln Leu Gln GlnPhe PheAIAla LeuPro a Leu Pro AspAsp SerSer Val Val Thr Thr Thr Thr Trp lle Trp Glu GluGln Ile Gln 785 785 790 790 795 795 800 800

Gly Val Gly Val Gly Glylle IleSer Ser AsnAsn SerSer Gly Gly lle Ile Cys Ala Cys Val Val Asp AlaThr Asplle Thr LysIle Lys 805 805 810 810 815 815

Alaa Lys AI Lys Val Phe Lys Val Phe LysAsp AspVal Val PhePhe LeuLeu Glu Glu Met Met Asn Asn 11 e Ile Pro Pro Tyr Ser Tyr Ser 820 820 825 825 830 830

Val Val Val Val Arg ArgGly GlyGlu Glu GlnGln ValVal Gln Gln Leu Leu Lys Thr Lys Gly Gly Val ThrTyr ValAsn Tyr TyrAsn Tyr 835 835 840 840 845 845

Page 44 Page 44

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Arg Thr Arg Thr Ser SerGly GlyMet Met GlnGln PhePhe Cys Cys Val Val Lys Ser Lys Met Met AI Ser Ala Glu a Val ValGly Glu Gly 850 850 855 855 860 860

Ile Cys Thr lle Cys ThrSer SerGlu Glu Ser Ser ProPro ValVal lle Ile Asp Asp Hi s His Gln Gln Gly Lys Gly Thr ThrSer Lys Ser 865 865 870 870 875 875 880 880

Ser Lys Cys Ser Lys CysVal ValArg Arg GlnGln LysLys Val Val Glu Glu Gly Ser Gly Ser Ser Asn SerHiAsn HisVal s Leu Leu Val 885 885 890 890 895 895

Thr Phe Thr Phe Thr ThrVal ValLeu Leu ProPro LeuLeu Glu Glu lle Ile Gly Gln Gly Leu Leu Asn Glnlle AsnAsn Ile PheAsn Phe 900 900 905 905 910 910

Ser Leu Glu Ser Leu GluThr ThrSer Ser PhePhe GlyGly Lys Lys Glu Glu lle Ile Leu Lys Leu Val ValSer LysLeu Ser ArgLeu Arg 915 915 920 920 925 925

Val Val Val Val Pro Pro Glu Glu Gly Gly Val Val Lys Lys Arg Arg Glu Glu Ser Ser Tyr Tyr Ser Ser Gly Gly lle Ile Thr Thr Leu Leu 930 930 935 935 940 940

Asp Pro Asp Pro Arg Arg Gly Gly lle Ile Tyr Tyr Gly Gly Thr Thr lle Ile Ser Ser Arg Arg Arg Arg Lys Lys Glu Glu Phe Phe Pro Pro 945 945 950 950 955 955 960 960

Tyr Arg Tyr Arg lle Ile Pro Pro Leu Leu Asp Asp Leu Leu Val Val Pro Pro Lys Lys Thr Thr Glu Glu lle Ile Lys Lys Arg Arg lle Ile 965 965 970 970 975 975

Leu Ser Val Leu Ser ValLys LysGIGly LeuLeu y Leu Leu Val Val GlyGly GluGlu lle Ile Leu Leu Ser Val Ser Ala AlaLeu Val Leu 980 980 985 985 990 990

Ser Ser Arg Arg Glu Glu Gly Gly Ile lle Asn Ile Leu Asn lle Leu Thr ThrHi His Leu Pro s Leu Pro Lys Lys Gly GlySer SerAla Ala 995 995 1000 1000 1005 1005

Glu Ala Glu Ala Glu GluLeu LeuMet MetSer SerVal ValVal Val Pro Pro Val Val Phe Phe Tyr Tyr Val Val Phe Phe His Hi s 1010 1010 1015 1015 1020 1020

Tyr Leu Tyr Leu Glu GluThr ThrGly GlyAsn AsnHis HisTrp Trp Asn Asn 11 Ile PheHi e Phe His SerAsp s Ser AspPro Pro 1025 1025 1030 1030 1035 1035

Leu Leu Ile GluLys lle Glu LysArg ArgAsn AsnLeu LeuGlu Glu Lys Lys Lys Lys Leu Leu Lys Lys GluGlu GlyGly MetMet 1040 1040 1045 1045 1050 1050

Val Ser Val Ser lle IleMet MetSer SerTyr TyrArg ArgAsn Asn AI Ala AspTyr a Asp TyrSer SerTyr Tyr Ser Ser Val Val 1055 1055 1060 1060 1065 1065

Trp Lys Trp Lys Gly GlyGly GlySer SerAl Ala Ser Thr a Ser ThrTrp TrpLeu LeuThr ThrAl Ala PheAl a Phe Ala Leu Leu 1070 1070 1075 1075 1080 1080

Arg Val Arg Val Leu LeuGly GlyGln GlnVal ValHi His LysTyr s Lys TyrVal ValGlu GluGln GlnAsn Asn Gln Gln Asn Asn 1085 1085 1090 1090 1095 1095 Page 45 Page 45

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.txt

Ser Ile Cys Ser lle CysAsn AsnSer SerLeu LeuLeu LeuTrp Trp Leu Leu Val Val Glu Glu Asn Asn TyrTyr GlnGln LeuLeu 1100 1100 1105 1105 1110 1110

Asp Asn Asp Asn Gly GlySer SerPhe PheLys LysGI Glu AsnSer u Asn SerGln GlnTyr TyrGln GlnPro Pro Ile lle Lys Lys 1115 1115 1120 1120 1125 1125

Leu Leu Gln GlyThr Gln Gly ThrLeu LeuPro ProVal ValGlu Glu AIAla ArgGlu a Arg GluAsn AsnSer Ser Leu Leu Tyr Tyr 1130 1130 1135 1135 1140 1140

Leu Leu Thr Ala Thr Al a Phe Phe Thr Thr Val Val Ile Glylle lle Gly IleArg ArgLys LysAl Ala PheAsp a Phe Asplle Ile 1145 1145 1150 1150 1155 1155

Cys Pro Cys Pro Leu LeuVal ValLys Lyslle IleAsn AsnThr Thr AlAla LeuLeu lleIle Lys Lys Al a Ala Asp Asp Thr Thr 1160 1160 1165 1165 1170 1170

Phe Phe Leu LeuGlu Leu Leu GluAsn AsnThr ThrLeu LeuPro Pro Ala Ala Gln Gln Ser Ser Thr Thr PhePhe ThrThr LeuLeu 1175 1175 1180 1180 1185 1185

Ala lle Ala Ile Ser SerAla AlaTyr TyrAI Ala Leu Ser a Leu SerLeu LeuGly GlyAsp AspLys LysThr Thr His His Pro Pro 1190 1190 1195 1195 1200 1200

Gln Phe Gln Phe Arg Arg SerSer lleIle Val Val Ser Ser Ala Lys Al a Leu LeuArg LysGIArg u AlGlu Ala a Leu ValLeu Val 1205 1205 1210 1210 1215 1215

Lys Lys Gly AsnPro Gly Asn ProPro Prolle IleTyr TyrArg Arg Phe Phe Trp Trp Lys Lys Asp Asp SerSer LeuLeu GlnGln 1220 1220 1225 1225 1230 1230

His Lys His Lys Asp AspSer SerSer SerVal ValPro ProAsn Asn Thr Thr Gly Gly Thr Thr Ala Ala Arg Arg Met Met Val Val 1235 1235 1240 1240 1245 1245

Glu Thr Glu Thr Thr ThrAla AlaTyr TyrAl Ala Leu Leu a Leu LeuThr ThrSer SerLeu LeuAsn AsnLeu Leu Lys Lys Asp Asp 1250 1250 1255 1255 1260 1260

Ile lle Asn Tyr Val Asn Tyr Val Asn Asn Pro Pro lle Ile lle Ile Lys Lys Trp Trp Leu Leu Ser Ser GluGlu GluGlu GlnGln 1265 1265 1270 1270 1275 1275

Arg Tyr Arg Tyr Gly GlyGly GlyGly GlyPhe PheTyr TyrSer Ser Thr Thr Gln Gln Asp Asp Thr Thr lle Ile Asn Asn Ala Ala 1280 1280 1285 1285 1290 1290

Ile lle Glu Gly Leu Glu Gly Leu Thr Thr Glu Glu Tyr Tyr Ser Ser Leu Leu Leu Leu Val Val Lys Lys GlnGln LeuLeu ArgArg 1295 1295 1300 1300 1305 1305

Leu Leu Asn MetAsp Asn Met AspII Ile e Asp Asp Val Ala Val AI a Tyr Tyr Lys Lys His His Lys GlyPro Lys Gly ProLeu Leu 1310 1310 1315 1315 1320 1320

His Hi sAsn Asn Tyr Tyr Lys Lys Met Met Thr Thr Asp LysAsn Asp Lys AsnPhe PheLeu LeuGly GlyArg Arg Pro Pro Val Val Page 46 Page 46

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt 1325 1325 1330 1330 1335 1335

Glu Val Glu Val Leu LeuLeu LeuAsn AsnAsp AspAsp AspLeu Leu Val Val Val Val Ser Ser Thr Thr Gly Gly Phe Phe Gly Gly 1340 1340 1345 1345 1350 1350

Ser Ser Gly LeuAla Gly Leu AlaThr ThrVal ValHis HisVal Val Thr Thr Thr Thr Val Val Val Hi Val His s Lys Thr Lys Thr 1355 1355 1360 1360 1365 1365

Ser Ser Thr SerGlu Thr Ser GluGlu GluVal ValCys CysSer Ser Phe Phe Tyr Tyr Leu Leu Lys Lys lleIle AspAsp ThrThr 1370 1370 1375 1375 1380 1380

Gln Asp Gln Asp lle IleGlu GluAla AlaSer SerHi His TyrArg s Tyr ArgGly GlyTyr TyrGly GlyAsn Asn Ser Ser Asp Asp 1385 1385 1390 1390 1395 1395

Tyr Lys Tyr Lys Arg Arg lleIle ValVal Al aAla CysCys Al a Ala Ser Ser Tyr Pro Tyr Lys LysSer ProLysSer GI uLys Glu 1400 1400 1405 1405 1410 1410

Glu Ser Glu Ser Ser SerSer SerGly GlySer SerSer SerHis His AI Ala Val Val Met Met Asp Asp Ile Leu lle Ser Ser Leu 1415 1415 1420 1420 1425 1425

Pro Pro Thr Glylle Thr Gly IleAsn AsnAI Ala a Asn GluGlu Asn Glu GluAsp AspLeu LeuLys LysAlAla LeuVal a Leu Val 1430 1430 1435 1435 1440 1440

Glu Gly Glu Gly Val ValAsp AspGln GlnLeu LeuPhe PheThr Thr Asp Asp Tyr Tyr Gln Gln Ile lle Lys Lys Asp Asp Gly Gly 1445 1445 1450 1450 1455 1455

His Hi sVal Ile Leu Val lle Leu Gln Gln Leu Leu Asn Asn Ser Serlle IlePro ProSer SerSer SerAsp Asp Phe Phe Leu Leu 1460 1460 1465 1465 1470 1470

Cys Val Cys Val Arg ArgPhe PheArg Arglle IlePhe PheGIGlu LeuPhe u Leu PheGlu GluVal ValGly Gly Phe Phe Leu Leu 1475 1475 1480 1480 1485 1485

Ser Ser Pro Ala Pro Al a Thr Thr Phe Phe Thr Thr Val TyrGlu Val Tyr GluTyr TyrHis HisArg ArgPro Pro Asp Asp Lys Lys 1490 1490 1495 1495 1500 1500

Gln Gln Cys ThrMet Cys Thr MetPhe PheTyr TyrSer SerThr Thr Ser Ser Asn Asn Ile lle Lys Lys lleIle GlnGln LysLys 1505 1505 1510 1510 1515 1515

Val Cys Val Cys Glu GluGly GlyAl Ala Thr Cys a Thr Cys Lys LysCys Cyslle IleGlu GluAla AlaAsp Asp Cys Cys Gly Gly 1520 1520 1525 1525 1530 1530

Gln Met Gln Met Gln GlnLys LysGlu GluLeu LeuAsp AspLeu Leu Thr Thr ll Ile SerAla e Ser AlaGlu Glu Thr Thr Arg Arg 1535 1535 1540 1540 1545 1545

Lys Lys Gln ThrAla Gln Thr AlaCys CysAsn AsnPro ProGlu Glu Ile lle Ala Ala Tyr Tyr AlAla Tyr a Tyr Lys Lys Val Val 1550 1550 1555 1555 1560 1560

Page 47 Page 47

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt Ile Ile Helle ThrThr SerSer lleIle ThrThr ThrThr GI uGlu AsnAsn ValVal PhePhe ValVal Lys Lys Tyr Tyr Lys Lys 1565 1565 1570 1570 1575 1575

Ala Thr Ala Thr Leu LeuLeu LeuAsp Asplle IleTyr TyrLys Lys Thr Thr Gly Gly Glu Glu Ala Ala ValVal Ala AI a Glu Glu 1580 1580 1585 1585 1590 1590

Lys Lys Asp Ser Glu Asp Ser Glu lle Ile Thr Thr Phe Phe lle Ile Lys Lys Lys Lys Val Val Thr Thr CysCys ThrThr AsnAsn 1595 1595 1600 1600 1605 1605

Ala Glu Ala Glu Leu LeuVal ValLys LysGly GlyArg ArgGI Gln TyrLeu n Tyr Leulle IleMet MetGly Gly Lys Lys Glu Glu 1610 1610 1615 1615 1620 1620

AlaaLeu Al Gln lle Leu Gln Ile Lys Lys Tyr Tyr Asn Asn Phe PheThr ThrPhe PheArg ArgTyr Tyrlle Ile Tyr Tyr Pro Pro 1625 1625 1630 1630 1635 1635

Leu Leu Asp SerLeu Asp Ser LeuThr ThrTrp Trplle IleGlu Glu Tyr Tyr Trp Trp Pro Pro Arg Arg AspAsp ThrThr ThrThr 1640 1640 1645 1645 1650 1650

Cys Ser Cys Ser Ser SerCys CysGln GlnAl Ala Phe Leu a Phe LeuAl Ala Asn Asn Leu Leu Asp Asp Glu GI u Phe Phe AI Ala a 1655 1655 1660 1660 1665 1665

Glu Asp Glu Asp lle IlePhe PheLeu LeuAsn AsnGly GlyCys Cys 1670 1670 1675 1675

<210> <210> 45 45 <211> <211> 6 6 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 45 45 Ser Ser Tyr Ser Ser TyrTyr TyrMet Met CysCys 1 1 5 5

<210> <210> 46 46 <211> <211> 6 6 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 46 46 Asn Phe Asn Phe Tyr TyrTyr Tyrlle Ile CysCys 1 1 5 5

<210> <210> 47 47 <211> <211> 6 6 <212> <212> PRT PRT Page 48 Page 48

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql. txt <213> Artificial sequence <213> Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 47 47

Ser Ser Tyr Ser Ser TyrTyr TyrMet Met CysCys 1 1 5 5

<210> <210> 48 48 <211> <211> 6 6 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 48 48

Ser Ser Tyr Ser Ser TyrTyr TyrMet Met AsnAsn 1 1 5 5

<210> <210> 49 49 <211> <211> 6 6 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 49 49 Ser Ser Tyr Ser Ser TyrTyr TyrMet Met AsnAsn 1 1 5 5

<210> <210> 50 50 <211> <211> 5 5 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 50 50 Asp Asn Asp Asn Thr ThrMet MetThr Thr 1 1 5 5

<210> <210> 51 51 <211> <211> 5 5 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> An artificially <223> An artificially synthesized synthesized sequence sequence

<400> <400> 51 51

Page 49 Page 49

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.txt Thr Tyr Thr Tyr AI Ala Met Gly a Met Gly 1 1 5 5

<210> <210> 52 52 <211> <211> 5 5 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 52 52 Gly Asn Gly Asn Ala Alalle IleAsn Asn 1 1 5 5

<210> <210> 53 53 <211> <211> 5 5 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 53 53 Thr Tyr Thr Tyr Ala Ala Met Met Gly Gly 1 1 5 5

<210> <210> 54 54 <211> <211> 6 6 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 54 54 Ser Ser Tyr Ser Ser TyrTyr TyrVal Val AlaAla 1 1 5 5

<210> <210> 55 55 <211> <211> 17 17 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 55 55 Cys lle Cys Ile Tyr TyrThr ThrGly Gly SerSer GlyGly Ala Ala Thr Thr Tyr Al Tyr Tyr Tyra Ala Ser AI Ser Trp Trp Ala Lys a Lys 1 1 5 5 10 10 15 15

Gly Gly

Page 50 Page 50

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.t txt

<210> <210> 56 56 <211> <211> 17 17 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 56 56 Cys lle Cys Ile Tyr TyrThr ThrVal Val SerSer GlyGly Tyr Tyr Thr Thr Tyr Ala Tyr Tyr Tyr Ser AlaTrp SerAla Trp LysAla Lys 1 1 5 5 10 10 15 15

Gly Gly

<210> <210> 57 57 <211> <211> 18 18 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 57 57 Cys lle Cys Ile Tyr TyrAla AlaGly Gly SerSer SerSer Gly Gly lle Ile Ile Tyr lle Tyr Tyr Ala TyrAsn AlaTrp Asn AlaTrp Ala 1 1 5 5 10 10 15 15

Lys Gly Lys Gly

<210> <210> 58 58 <211> <211> 16 16 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> AnAn artificially arti synthesized ificially synthesi sequence zed sequence

<400> <400> 58 58

Met lle Met Ile Tyr Tyr Gly Gly Ser Ser Gly Gly Ala Ala Thr Thr Tyr Tyr Tyr Tyr Ala Ala Ser Ser Trp Trp Ala Ala Lys Lys Gly Gly 1 1 5 5 10 10 15 15

<210> <210> 59 59 <211> <211> 16 16 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 59 59 Met lle Met Ile Tyr Tyr Gly Gly Ser Ser Gly Gly Ala Ala Thr Thr Tyr Tyr Tyr Tyr Ala Ala Ser Ser Trp Trp Ala Ala Lys Lys Gly Gly 1 1 5 5 10 10 15 15 Page 51 Page 51

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

<210> <210> 60 60 <211> <211> 16 16 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 60 60 Ile Ile Ser lle lle SerPhe PheGly Gly Gly Gly AspAsp AlaAla Tyr Tyr Tyr Tyr Ala Trp Ala Ser SerAla TrpLys Ala Lys Gly Gly 1 1 5 5 10 10 15 15

<210> <210> 61 61 <211> <211> 16 16 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 61 61

Thr lle Thr Ile Asp Asp Thr Thr Gly Gly Asp Asp Asn Asn Ser Ser Phe Phe Tyr Tyr Ala Ala Asn Asn Trp Trp Ala Ala Lys Lys Gly Gly 1 1 5 5 10 10 15 15

<210> <210> 62 62 <211> <211> 17 17 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 62 62 Cys lle Cys Ile Tyr TyrThr ThrGly Gly SerSer AspAsp Thr Thr Thr Thr Tyr Ala Tyr Tyr Tyr Thr AlaTrp ThrAla Trp LysAla Lys 1 1 5 5 10 10 15 15

Gly Gly

<210> <210> 63 63 <211> <211> 16 16 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 63 63 Thr lle Thr Ile Asp Asp Thr Thr Gly Gly Asp Asp Asn Asn Ser Ser Phe Phe Tyr Tyr Ala Ala Asn Asn Trp Trp Ala Ala Lys Lys Gly Gly 1 1 5 5 10 10 15 15

<210> <210> 64 64 Page 52 Page 52

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt <211> <211> 17 17 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 64 64 Ala lle Ala Ile Tyr TyrThr ThrGly Gly SerSer GlyGly Ala Ala Thr Thr Tyr AI Tyr Lys Lysa Ser Ala Trp Ser Ala TrpLys Ala Lys 1 1 5 5 10 10 15 15

Gly Gly

<210> <210> 65 65 <211> <211> 13 13 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 65 65 Asp Gly Asp Gly Gly Gly Tyr Tyr Val Val Thr Thr Pro Pro Thr Thr His His Ala Ala Met Met Tyr Tyr Leu Leu 1 1 5 5 10 10

<210> <210> 66 66 <211> <211> 9 9 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 66 66 Asp Leu Asp Leu Hi His Ala Gly s Ala Glylle IleThr Thr AsnAsn LeuLeu 1 1 5 5

<210> <210> 67 67 <211> <211> 13 13 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 67 67

Tyr Pro Tyr Pro Thr Thr Tyr Tyr Gly Gly Asp Asp Gly Gly Gly Gly His His Ala Ala Phe Phe Asn Asn Leu Leu 1 1 5 5 10 10

<210> <210> 68 68 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence Page 53 Page 53

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 68 68 Gln lle Gln Ile Tyr TyrSer SerGly Gly AspAsp AsnAsn Asn Asn Asp Asp Asn Phe Asn Phe 1 1 5 5 10 10

<210> <210> 69 69 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 69 69 Gln Ile Tyr Gln lle TyrSer SerGly Gly AspAsp AsnAsn Asn Asn Asp Asp Asn Phe Asn Phe 1 1 5 5 10 10

<210> <210> 70 70 <211> <211> 12 12 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 70 70

Val Gly Val Gly Ala Ala Gly Gly Asn Asn lle Ile Phe Phe Trp Trp Tyr Tyr Phe Phe Asp Asp Leu Leu 1 1 5 5 10 10

<210> <210> 71 71 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 71 71

Asn Asp Asn Asp Gly Gly Ser Ser Val Val Tyr Tyr Asn Asn Leu Leu Phe Phe Asn Asn Leu Leu 1 1 5 5 10 10

<210> <210> 72 72 <211> <211> 4 4 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> AnAn artificially arti synthesized ficially synthesi sequence zed sequence

<400> <400> 72 72 Gly Ser Gly Ser Gly GlyLeu Leu Page 54 Page 54

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql. txt 1 1

<210> <210> 73 73 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 73 73

Asn Asp Asn Asp Gly Gly Ser Ser Val Val Tyr Tyr Asn Asn Leu Leu Phe Phe Asn Asn Leu Leu 1 1 5 5 10 10

<210> <210> 74 74 <211> <211> 13 13 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 74 74 Asp Gly Asp Gly Gly GlyTyr TyrAsp Asp TyrTyr ProPro Thr Thr His His Ala His Ala Met Met Tyr His Tyr 1 1 5 5 10 10

<210> <210> 75 75 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 75 75

Gln Ala Gln Ala Ser SerGln GlnAsn Asn lleIle GlyGly Ser Ser Asp Asp Leu Ala Leu Ala 1 1 5 5 10 10

<210> <210> 76 76 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesized synthesized sequence sequence

<400> <400> 76 76

Gln Ala Gln Ala Ser SerGln GlnAsn Asn lleIle TyrTyr Ser Ser Asn Asn Leu Ala Leu Ala 1 1 5 5 10 10

<210> <210> 77 77 <211> <211> 13 13 <212> <212> PRT PRT <213> <213> Artificialsequence Artifici sequence Page 55 Page 55

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 77 77 Gln Ser Gln Ser Ser SerGln GlnSer Ser ValVal TyrTyr Ser Ser Ser Ser Asp Leu Asp Tyr Tyr Ser Leu Ser 1 1 5 5 10 10

<210> <210> 78 78 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 78 78 Gln Al Gln Alaa Ser Glu Ser Ser Glu Serlle IleSer Ser Asn Asn TrpTrp LeuLeu Ala Ala 1 1 5 5 10 10

<210> <210> 79 79 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 79 79

Gln Ala Gln Ala Ser SerGlu GluSer Ser lleIle SerSer Asn Asn Trp Trp Leu Ala Leu Ala 1 1 5 5 10 10

<210> <210> 80 80 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 80 80 Gln Ala Gln Ala Ser SerGlu GluSer Ser lleIle TyrTyr Ser Ser Ala Ala Leu a Leu AlaAla 1 1 5 5 10 10

<210> <210> 81 81 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 81 81

Gln Ala Ser Gln Ala SerGlu GluAsn Asn lleIle TyrTyr Ser Ser Ala Ala Leu Ser Leu Ser Page 56 Page 56

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt 1 1 5 5 10 10

<210> <210> 82 82 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 82 82 Gln Ala Gln Ala Ser SerGln GlnAsn Asn lleIle TyrTyr Ser Ser Leu Leu Leu Ala Leu Ala 1 1 5 5 10 10

<210> <210> 83 83 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 83 83 Gln Ala Gln Ala Ser SerGlu GluAsn Asn lleIle TyrTyr Ser Ser Ala Ala Leu Ser Leu Ser 1 1 5 5 10 10

<210> <210> 84 84 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 84 84 Gln Ala Gln Ala Ser SerGln GlnAsn Asn lleIle GlyGly Ser Ser Ser Ser Leu Ala Leu Ala 1 1 5 5 10 10

<210> <210> 85 85 <211> <211> 7 7 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 85 85

Gly Al Gly Alaa Ser Lys Leu Ser Lys LeuAlAla Ser a Ser 1 1 5 5

<210> <210> 86 86 <211> <211> 7 7 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence Page 57 Page 57

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.txt

<220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 86 86 Gly Al Gly Alaa Ser Asn Leu Ser Asn LeuGlu GluSer Ser 1 1 5 5

<210> <210> 87 87 <211> <211> 7 7 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 87 87 Glu Ala Ser Glu Ala SerLys LysLeu Leu Al Ala Ser a Ser 1 1 5 5

<210> <210> 88 88 <211> <211> 7 7 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 88 88

Arg Al Arg Alaa Ser Thr Leu Ser Thr LeuAlAla Ser a Ser 1 1 5 5

<210> <210> 89 89 <211> <211> 7 7 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 89 89 Arg Ala Arg Ala Ser SerThr ThrLeu Leu AI Ala Ser a Ser 1 1 5 5

<210> <210> 90 90 <211> <211> 7 7 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 90 90 Ser Ala Ser Ser Ala SerThr ThrLeu Leu AlaAla SerSer Page 58 Page 58

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt 1 1 5 5

<210> <210> 91 91 <211> <211> 7 7 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 91 91

Tyr Ala Tyr Ala Ser SerThr ThrLeu Leu Al Ala Ser a Ser 1 1 5 5

<210> <210> 92 92 <211> <211> 7 7 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 92 92 His Thr Ser His Thr SerAsp AspLeu Leu Al Ala Ser a Ser 1 1 5 5

<210> <210> 93 93 <211> <211> 7 7 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 93 93 Tyr Ala Tyr Ala Ser SerThr ThrLeu Leu AlaAla SerSer 1 1 5 5

<210> <210> 94 94 <211> <211> 7 7 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> AnAn artificially arti synthesized ficially synthesi sequence zed sequence

<400> <400> 94 94

Gly Ala Gly Ala Ser SerLys LysThr Thr HisHis SerSer 1 1 5 5

<210> <210> 95 95 <211> <211> 12 12 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence Page 59 Page 59

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.txt <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 95 95 Gln Cys Gln Cys Thr ThrPhe PheVal Val GlyGly SerSer Ser Ser Tyr Tyr Gly Ala Gly Asn Asn Ala 1 1 5 5 10 10

<210> <210> 96 96 <211> <211> 12 12 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 96 96 Leu Gln Gly Leu Gln GlyTyr TyrSer Ser Tyr Tyr SerSer Asn Asn Val Val Asp Asp Asp Ala Asp Ala 1 1 5 5 10 10

<210> <210> 97 97 <211> <211> 12 12 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 97 97

Gln Gly Gln Gly Thr ThrTyr TyrTyr Tyr SerSer SerSer Gly Gly Trp Trp Tyr AL Tyr Phe Phea Ala 1 1 5 5 10 10

<210> <210> 98 98 <211> <211> 12 12 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 98 98 Gln Gln Gln Gln Asp AspTyr TyrSer Ser SerSer SerSer Asn Asn Val Val Asp Thr Asp Asn Asn Thr 1 1 5 5 10 10

<210> <210> 99 99 <211> <211> 12 12 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 99 99 Gln Gln Gln Gln Asp Asp Tyr Tyr Ser Ser Ser Ser Ser Ser Asn Asn Val Val Asp Asp Asn Asn Thr Thr Page 60 Page 60

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.txt 1 1 5 5 10 10

<210> <210> 100 100 <211> <211> 12 12 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An arti An artificially ificially synthesized sequence synthesi zed sequence

<400> <400> 100 100 Gln Gln Gln Gln Tyr TyrTyr TyrSer Ser SerSer ThrThr Asn Asn Val Val His Ser His Asn Asn Ser 1 1 5 5 10 10

<210> <210> 101 101 <211> <211> 12 12 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 101 101

Gln Gln Gln Gln Tyr TyrTyr TyrAsp Asp lleIle AsnAsn Ser Ser Val Val Asp Thr Asp Asn Asn Thr 1 1 5 5 10 10

<210> <210> 102 102 <211> <211> 13 13 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An artificially An artificially synthesized synthesized sequence sequence

<400> <400> 102 102

Gln Cys Gln Cys Thr ThrAla AlaTyr Tyr GlyGly SerSer Ser Ser Asp Asp Val Gly Val Gly Gly Thr Gly Thr 1 1 5 5 10 10

<210> <210> 103 103 <211> <211> 12 12 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesized synthesized sequence sequence

<400> <400> 103 103 Gln Gln Gln Gln Tyr TyrTyr TyrAsp Asp lleIle AsnAsn Ser Ser Val Val Asp Thr Asp Asn Asn Thr 1 1 5 5 10 10

<210> <210> 104 104 <211> <211> 12 12 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence Page 61 Page 61

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 104 104 Gln Ser Thr Gln Ser ThrLys LysVal Val GlyGly SerSer Ser Ser Tyr Tyr Gly His Gly Asn Asn His 1 1 5 5 10 10

<210> <210> 105 105 <211> <211> 1680 1680 <212> <212> PRT PRT <213> <213> Mus muscul Mus musculus us <400> <400> 105 105 Met Gly Met Gly Leu LeuTrp TrpGly Gly 11 Ile Leu e Leu CysCys LeuLeu Leu Leu lle Ile Phe Phe Leu Lys Leu Asp AspThr Lys Thr 1 1 5 5 10 10 15 15

Trp Gly Trp Gly Gln GlnGlu GluGln Gln ThrThr TyrTyr Val Val lle Ile Ser Pro Ser Ala Ala Lys Prolle LysLeu IleArgLeu Arg 20 20 25 25 30 30

Val Gly Val Gly Ser SerSer SerGlu Glu AsnAsn ValVal Val Val lle Ile Gln His Gln Val Val Gly HisTyr GlyThr Tyr GluThr Glu 35 35 40 40 45 45

Alaa Phe AI Phe Asp Alaa Thr Asp Al Leu Ser Thr Leu SerLeu LeuLys Lys Ser Ser TyrTyr ProPro Asp Asp Lys Lys Lys Val Lys Val 50 50 55 55 60 60

Thr Phe Thr Phe Ser SerSer SerGly Gly TyrTyr ValVal Asn Asn Leu Leu Ser Glu Ser Pro Pro Asn GluLys AsnPhe Lys Gl Phe r Gln

70 70 75 75 80 80

Asn AI Asn Alaa Ala Leu Leu Ala Leu LeuThr ThrLeu Leu GlnGln ProPro Asn Asn Gln Gln Val Arg Val Pro Pro Glu ArgGIGlu u Glu 85 85 90 90 95 95

Ser Pro Val Ser Pro ValSer SerHiHis ValTyr s Val Tyr Leu Leu GluGlu ValVal Val Val Ser Ser Lyss His Lys Hi Phe Ser Phe Ser 100 100 105 105 110 110

Lys Ser Lys Lys Ser LysLys Lyslle Ile ProPro lleIle Thr Thr Tyr Tyr Asn Gly Asn Asn Asn lle GlyLeu IlePhe Leu llePhe Ile 115 115 120 120 125 125

Hiss Thr Hi Thr Asp Lys Pro Asp Lys ProVal ValTyr Tyr Thr Thr ProPro Asp Asp Gln Gln Ser Ser Val lle Val Lys LysArg Ile Arg 130 130 135 135 140 140

Val Tyr Val Tyr Ser SerLeu LeuGly Gly AspAsp AspAsp Leu Leu Lys Lys Proa Ala Pro Al Lys Glu Lys Arg Arg Thr GluVal Thr Val 145 145 150 150 155 155 160 160

Leu Thr Phe Leu Thr Phelle IleAsp Asp Pro Pro GluGlu GlyGly Ser Ser Glu Glu Val lle Val Asp AspVal IleGlu Val GI Glu u Glu 165 165 170 170 175 175

Asn Asp Asn Asp Tyr TyrThr ThrGly Gly lleIle lleIle Ser Ser Phe Phe Pro Phe Pro Asp Asp Lys Phelle LysPro Ile SerPro Ser 180 180 185 185 190 190 Page 62 Page 62

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Asn Pro Asn Pro Lys Lys Tyr Tyr Gly Gly Val Val Trp Trp Thr Thr lle Ile Lys Lys Ala Ala Asn Asn Tyr Tyr Lys Lys Lys Lys Asp Asp 195 195 200 200 205 205

Phe Thr Thr Phe Thr ThrThr ThrGly Gly Thr Thr Al Ala Tyr a Tyr PhePhe GluGlu lle Ile Lys Lys Glu Val Glu Tyr TyrLeu Val Leu 210 210 215 215 220 220

Pro Arg Phe Pro Arg PheSer SerVal Val SerSer lleIle Glu Glu Leu Leu Glu Glu Arg Phe Arg Thr Thrlle PheGly Ile TyrGly Tyr 225 225 230 230 235 235 240 240

Lys Asn Phe Lys Asn PheLys LysAsn Asn PhePhe GluGlu lle Ile Thr Thr Val Val Lysa Ala Lys Al Arg Phe Arg Tyr TyrTyr Phe Tyr 245 245 250 250 255 255

Asn Lys Asn Lys Val Val Val Val Pro Pro Asp Asp Ala Ala Glu Glu Val Val Tyr Tyr Ala Ala Phe Phe Phe Phe Gly Gly Leu Leu Arg Arg 260 260 265 265 270 270

Glu GI u Asp Asp Ile Lys Asp lle Lys AspGlu GluGlu Glu Lys Lys GlnGln MetMet Met Met His His Lysa Ala Lys AI Thr Gln Thr Gln 275 275 280 280 285 285

Alaa Ala Al AI aLys Lys Leu Leu Val Asp Gly Val Asp GlyVal ValAla Ala Gln Gln lleIle SerSer Phe Phe Asp Asp Ser Glu Ser Glu 290 290 295 295 300 300

Thr Al Thr Alaa Val Lys Glu Val Lys GluLeu LeuSer Ser TyrTyr AsnAsn Ser Ser Leu Leu Glu Glu Asp Asn Asp Leu LeuAsn Asn Asn 305 305 310 310 315 315 320 320

Lys Tyr Leu Lys Tyr LeuTyr Tyrlle Ile AlaAla ValVal Thr Thr Val Val Thr Ser Thr Glu Glu Ser SerGly SerGly Gly PheGly Phe 325 325 330 330 335 335

Ser Glu Glu Ser Glu GluALAla Glulle a Glu IlePro Pro Gly Gly ValVal LysLys Tyr Tyr Val Val Leu Pro Leu Ser SerTyr Pro Tyr 340 340 345 345 350 350

Thr Leu Thr Leu Asn Asn Leu Leu Val Val Ala Ala Thr Thr Pro Pro Leu Leu Phe Phe Val Val Lys Lys Pro Pro Gly Gly lle Ile Pro Pro 355 355 360 360 365 365

Phe Ser lle Phe Ser IleLys LysAIAla GlnVal a Gln Val Lys Lys AspAsp SerSer Leu Leu Glu Glu Gln Val Gln Ala AlaGly Val Gly 370 370 375 375 380 380

Gly Val Gly Val Pro ProVal ValThr Thr LeuLeu MetMet Ala Ala Gln Gln Thr Asp Thr Val Val Val AspAsn ValGln Asn GluGln Glu 385 385 390 390 395 395 400 400

Thr Ser Thr Ser Asp Asp Leu Leu Glu Glu Thr Thr Lys Lys Arg Arg Ser Ser lle Ile Thr Thr His His Asp Asp Thr Thr Asp Asp Gly Gly 405 405 410 410 415 415

Val AI Val Alaa Val Phe Val Val Phe ValLeu LeuAsn Asn LeuLeu ProPro Ser Ser Asn Asn Val Val Val Thr Thr Leu ValLys Leu Lys 420 420 425 425 430 430

Phe Glu lle Phe Glu IleArg ArgThr Thr AspAsp AspAsp Pro Pro Glu Glu Leu Leu Pro Glu Pro Glu GluAsn GluGln Asn AlaGln Ala Page 63 Page 63

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt 435 435 440 440 445 445

Ser Lys Glu Ser Lys GluTyr TyrGlu Glu AlaAla ValVal Ala AL a TyrTyr SerSer Ser Ser Leu Leu Ser Ser Ser Gln GlnTyr Ser Tyr 450 450 455 455 460 460

Ile Tyr lle lle Tyr IleAla AlaTrp Trp Thr Thr GluGlu AsnAsn Tyr Tyr Lys Lys Pro Leu Pro Met MetVal LeuGly Val Gly Glu Glu 465 465 470 470 475 475 480 480

Tyr Leu Tyr Leu Asn Asnlle IleMet Met ValVal ThrThr Pro Pro Lys Lys Ser Tyr Ser Pro Pro lle TyrAsp IleLys Asp lleLys Ile 485 485 490 490 495 495

Thr His Thr His Tyr TyrAsn AsnTyr Tyr LeuLeu lleIle Leu Leu Ser Ser Lys Lys Lys Gly Gly lle LysVal IleGln Val TyrGln Tyr 500 500 505 505 510 510

Gly Thr Gly Thr Arg ArgGlu GluLys Lys LeuLeu PhePhe Ser Ser Ser Ser Thr Gln Thr Tyr Tyr Asn Glnlle AsnAsn Ile lleAsn Ile 515 515 520 520 525 525

Pro Val Thr Pro Val ThrGln GlnAsn Asn MetMet ValVal Pro Pro Ser Ser AI aAla Arg Arg Leu Leu Leu Tyr Leu Val ValTyr Tyr Tyr 530 530 535 535 540 540

Ile Val Thr lle Val ThrGly GlyGlu Glu Gln Gln ThrThr AlaAla Glu Glu Leu Leu Vala Ala Val AI Aspa Ala Asp AI Val Trp Val Trp 545 545 550 550 555 555 560 560

Ile Asn 11 lle Asn Ile Glu Glu e Glu GluLys LysCys CysGly Gly AsnAsn GlnGln Leu Leu Gln Gln Vals His Val Hi Leu Ser Leu Ser 565 565 570 570 575 575

Pro Asp Glu Pro Asp GluTyr TyrVal Val TyrTyr SerSer Pro Pro Gly Gly Gln Gln Thr Ser Thr Val ValLeu SerAsp Leu MetAsp Met 580 580 585 585 590 590

Val Thr Val Thr Glu GluAlAla AspSer a Asp SerTrp Trp ValVal AI Ala Leu a Leu SerSer Ala AI a ValVal AspAsp Arg Arg Al aAla 595 595 600 600 605 605

Val Tyr Val Tyr Lys LysVal ValGln Gln GlyGly AsnAsn AI aAla LysLys Arg Arg AI aAla MetMet Gln Gln Arg Arg Val Phe Val Phe 610 610 615 615 620 620

Gln Ala Gln Ala Leu Leu Asp Asp Glu Glu Lys Lys Ser Ser Asp Asp Leu Leu Gly Gly Cys Cys Gly Gly Ala Ala Gly Gly Gly Gly Gly Gly 625 625 630 630 635 635 640 640

Hiss Asp Hi Asp Asn Alaa Asp Asn AI Val Phe Asp Val PheHiHis LeuAI s Leu Ala Gly Leu a Gly LeuThr ThrPhe Phe LeuLeu ThrThr 645 645 650 650 655 655

Asn AI Asn Alaa Asn Alaa Asp Asn AI Asp Ser Asp Asp SerHis HisTyr Tyr Arg Arg AspAsp AspAsp Ser Ser Cys Cys Lys Glu Lys GI 660 660 665 665 670 670

Ile Leu Arg lle Leu ArgSer SerLys Lys Arg Arg AsnAsn LeuLeu His His Leu Leu Leu Gln Leu Arg ArgLys Glnlle Lys Ile Glu Glu 675 675 680 680 685 685

Page 64 Page 64

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.txt Glu Gln Glu Gln Ala AlaAIAla LysTyr a Lys TyrLys Lys Hi His Ser s Ser Val Val ProPro LysLys Lys Lys Cys Cys Cys Tyr Cys Tyr 690 690 695 695 700 700

Asp Gly Asp Gly Ala AlaArg ArgVal Val AsnAsn PhePhe Tyr Tyr Glu Glu Thr Glu Thr Cys Cys Glu GluArg GluVal Arg Al Val a Ala 705 705 710 710 715 715 720 720

Arg Val Arg Val Thr Thrlle IleGly Gly ProPro LeuLeu Cys Cys lle Ile Arga Ala Arg Al Phe Phe Asn Cys Asn Glu GluCys Cys Cys 725 725 730 730 735 735

Thr lle Thr Ile AI Ala Asn Lys a Asn Lys11Ile ArgLys e Arg LysGlu Glu Ser Ser ProPro HisHis Lys Lys Pro Pro Val Gln Val Gln 740 740 745 745 750 750

Leu Gly Arg Leu Gly Arglle IleHiHis IleLys s lle Lys Thr Thr LeuLeu LeuLeu Pro Pro Val Val Met Al Met Lys Lys Ala Asp a Asp 755 755 760 760 765 765

Ile Arg Ser lle Arg SerTyr TyrPhe Phe Pro Pro GluGlu SerSer Trp Trp Leu Leu Trp lle Trp Glu GluHis IleArg His ValArg Val 770 770 775 775 780 780

Pro Lys Arg Pro Lys ArgLys LysGln Gln LeuLeu GlnGln Val Val Thr Thr Leu Asp Leu Pro Pro Ser AspLeu SerThr Leu ThrThr Thr 785 785 790 790 795 795 800 800

Trp Glu Trp Glu lle IleGln GlnGly Gly lleIle GlyGly lle Ile Ser Ser Asp Gly Asp Asn Asn lle GlyCys IleVal Cys AlaVal Ala 805 805 810 810 815 815

Asp Thr Asp Thr Leu LeuLys LysAlAla LysVal a Lys Val PhePhe LysLys Glu GI u ValVal PhePhe Leu Leu Glu Glu Met Asn Met Asn 820 820 825 825 830 830

Ile Pro Tyr lle Pro TyrSer SerVal Val Val Val ArgArg GlyGly Glu Glu Gln Gln Ile Leu lle Gln GlnLys LeuGly Lys ThrGly Thr 835 835 840 840 845 845

Val Tyr Val Tyr Asn AsnTyr TyrMet Met ThrThr SerSer Gly Gly Thr Thr Lys Cys Lys Phe Phe Val CysLys ValMet Lys SerMet Ser 850 850 855 855 860 860

Alaa Val AI Val Glu Gly lle Glu Gly IleCys CysThr Thr SerSer GlyGly Ser Ser Ser Ser AI aAla Al aAla SerSer Leu Leu His His 865 865 870 870 875 875 880 880

Thr Ser Arg Thr Ser ArgPro ProSer Ser ArgArg CysCys Val Val Phe Phe Gln lle Gln Arg Arg Glu IleGly GluSer Gly SerSer Ser 885 885 890 890 895 895

Ser Hiss Leu Ser Hi Val Thr Leu Val ThrPhe PheThr Thr Leu Leu LeuLeu ProPro Leu Leu Glu Glu Ile Leu lle Gly GlyHiLeu s His 900 900 905 905 910 910

Ser lle Ser Ile Asn AsnPhe PheSer Ser LeuLeu GluGlu Thr Thr Ser Ser Phe Lys Phe Gly Gly Asp Lyslle AspLeu Ile ValLeu Val 915 915 920 920 925 925

Lys Thr Leu Lys Thr LeuArg ArgVal Val ValVal ProPro Glu Glu Gly Gly Val Val Lys Glu Lys Arg ArgSer GluTyr Ser AlaTyr Ala 930 930 935 935 940 940

Page 65 Page 65

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt

Gly Val Gly Val lle IleLeu LeuAsp Asp ProPro LysLys Gly Gly lle Ile Arg lle Arg Gly Gly Val IleAsn ValArg Asn ArgArg Arg 945 945 950 950 955 955 960 960

Lys Glu Phe Lys Glu PhePro ProTyr Tyr ArgArg lleIle Pro Pro Leu Leu Asp Asp Leu Pro Leu Val ValLys ProThr Lys LysThr Lys 965 965 970 970 975 975

Val Glu Val Glu Arg Arg lle Ile Leu Leu Ser Ser Val Val Lys Lys Gly Gly Leu Leu Leu Leu Val Val Gly Gly Glu Glu Phe Phe Leu Leu 980 980 985 985 990 990

Ser Thr Val Ser Thr ValLeu LeuSer Ser LysLys GluGlu Gly Gly Ile11Asn lle Asn Ile Thr e Leu LeuHiThr His s Leu ProLeu Pro 995 995 1000 1000 1005 1005

Lys Lys Gly SerAla Gly Ser AlaGlu GluAla AlaGlu GluLeu Leu Met Met Ser Ser Ile lle Ala Ala ProPro ValVal PhePhe 1010 1010 1015 1015 1020 1020

Tyr Val Tyr Val Phe PheHi His Tyr Leu s Tyr Leu Glu Glu AI Ala Gly Asn a Gly Asn His His Trp Trp Asn AsnII Ile Phe e Phe 1025 1025 1030 1030 1035 1035

Tyr Pro Tyr Pro Asp AspThr ThrLeu LeuSer SerLys LysArg Arg Gl Gln SerLeu r Ser LeuGlu GluLys Lys Lys Lys Ile lle 1040 1040 1045 1045 1050 1050

Lys Lys Gln GlyVal Gln Gly ValVal ValSer SerVal ValMet Met Ser Ser Tyr Tyr Arg Arg Asn Asn Ala AI a Asp Asp Tyr Tyr 1055 1055 1060 1060 1065 1065

Ser Ser Tyr SerMet Tyr Ser MetTrp TrpLys LysGly GlyAlAla SerAl a Ser Ala Ser Thr a Ser Thr Trp TrpLeu LeuThr Thr 1070 1070 1075 1075 1080 1080

Alaa Phe AI Alaa Leu Phe AI Leu Arg Arg Val Val Leu Gly Gln Leu Gly Gln Val Val AI Alaa Lys Tyr Val Lys Tyr Val Lys Lys 1085 1085 1090 1090 1095 1095

Gln Asp Gln Asp Glu GluAsn AsnSer Serlle IleCys CysAsn Asn Ser Ser Leu Leu Leu Leu Trp Trp Leu Leu Val Val Glu Glu 1100 1100 1105 1105 1110 1110

Lys Lys Cys GlnLeu Cys Gln LeuGlu GluAsn AsnGI Gly SerPhe y Ser PheLys LysGlu GluAsn AsnSer Ser Gln Gln Tyr Tyr 1115 1115 1120 1120 1125 1125

Leu Leu Pro IleLys Pro lle LysLeu LeuGln GlnGly GlyThr Thr Leu Leu Pro Pro Ala Ala Glu Glu AlaAla GlnGln GluGlu 1130 1130 1135 1135 1140 1140

Lys Lys Thr LeuTyr Thr Leu TyrLeu LeuThr ThrAl Ala PheSer a Phe SerVal Val11 Ile Gly lle e Gly IleArg ArgLys Lys 1145 1145 1150 1150 1155 1155

Alaa Val AI Asp lle Val Asp Ile Cys Cys Pro Pro Thr Thr Met MetLys Lyslle IleHis HisThr ThrAI Ala LeuAsp a Leu Asp 1160 1160 1165 1165 1170 1170

Lys Lys Ala AspSer Ala Asp SerPhe PheLeu LeuLeu LeuGlu Glu Asn Asn Thr Thr Leu Leu Pro Pro SerSer LysLys SerSer 1175 1175 1180 1180 1185 1185 Page 66 Page 66

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt

Thr Phe Thr Phe Thr ThrLeu LeuAla Alalle IleVal ValAI Ala TyrAl a Tyr Ala Leu Ser a Leu Ser Leu LeuGly GlyAsp Asp 1190 1190 1195 1195 1200 1200

Arg Thr Arg Thr Hi His Pro Arg s Pro Arg Phe Phe Arg Arg Leu Leulle IleVal ValSer SerAla AlaLeu Leu Arg Arg Lys Lys 1205 1205 1210 1210 1215 1215

Glu Ala Glu Ala Phe PheVal ValLys LysGly GlyAsp AspPro Pro Pro Pro II Ile TyrArg e Tyr ArgTyr Tyr Trp Trp Arg Arg 1220 1220 1225 1225 1230 1230

Asp Thr Asp Thr Leu LeuLys LysArg ArgPro ProAsp AspSer Ser Ser Ser Val Val Pro Pro Ser Ser Ser Ser Gly Gly Thr Thr 1235 1235 1240 1240 1245 1245

Alaa Gly Al MetVal Gly Met ValGlu Glu ThrThr ThrThr AI a Ala Tyr Tyr Al a Ala Leu Leu Leua Ser Leu Al AlaLeu Ser Leu 1250 1250 1255 1255 1260 1260

Lys Lys Leu LysAsp Leu Lys AspMet MetAsn AsnTyr TyrAIAla AsnPro a Asn Prolle Ilelle IleLys Lys Trp Trp Leu Leu 1265 1265 1270 1270 1275 1275

Ser Ser Glu GluGln Glu Glu GlnArg ArgTyr TyrGly GlyGly Gly Gly Gly Phe Phe Tyr Tyr Ser Ser ThrThr GlnGln AspAsp 1280 1280 1285 1285 1290 1290

Thr lle Thr Ile Asn AsnAla Alalle IleGlu GluGly GlyLeu Leu Thr Thr Glu Glu Tyr Tyr Ser Ser Leu Leu Leu Leu Leu Leu 1295 1295 1300 1300 1305 1305

Lys Gln lle Lys Gln Ile Hi His Leu s Leu AspAsp MetMet Asp Asn Asp lle IleVal AsnAIVal AlaLysTyr a Tyr Lys His Hi s 1310 1310 1315 1315 1320 1320

Glu Gly Glu Gly Asp AspPhe PheHis HisLys LysTyr TyrLys Lys Val Val Thr Thr Glu Glu Lys Lys His His Phe Phe Leu Leu 1325 1325 1330 1330 1335 1335

Gly Arg Gly Arg Pro ProVal ValGlu GluVal ValSer SerLeu Leu Asn Asn Asp Asp Asp Leu Asp Val Val Leu Val Val Ser Ser 1340 1340 1345 1345 1350 1350

Thr Gly Thr Gly Tyr TyrSer SerSer SerGly GlyLeu LeuAI Ala ThrVal a Thr ValTyr TyrVal ValLys Lys Thr Val Thr Val 1355 1355 1360 1360 1365 1365

Val Hi Val Hiss Lys Lys 11 Ilee Ser Ser Val Val Ser Glu Glu Ser Glu Glu Phe Phe Cys Cys Ser Ser Phe PheTyr TyrLeu Leu 1370 1370 1375 1375 1380 1380

Lys Lys Ile AspThr lle Asp ThrGln GlnAsp Asplle IleGlu Glu AlAla SerSer a Ser SerHi His PheArg s Phe ArgLeu Leu 1385 1385 1390 1390 1395 1395

Ser Ser Asp SerGly Asp Ser GlyPhe PheLys LysArg Arglle Ile Ile lle AIAla CysAI a Cys Ala SerTyr a Ser TyrLys Lys 1400 1400 1405 1405 1410 1410

Pro Pro Ser LysGlu Ser Lys GluGI Glu Ser Ser Thr Thr SerSer GlyGly SerSer SerSer Hi His s AlaAla ValVal MetMet Page 67 Page 67

JPOXMLDOC01-seql.txt JPOXMLDOC01-segl.txt 1415 1415 1420 1420 1425 1425

Asp lle Asp Ile Ser SerLeu LeuPro ProThr ThrGly Glylle Ile Gly Gly Ala Ala Asn Asn Glu Glu Glu Glu Asp Asp Leu Leu 1430 1430 1435 1435 1440 1440

Arg Al Arg Alaa Leu Leu Val Val Glu Glu Gly Gly Val Val Asp AspGI Gln Leu Leu Leu Leu Thr Thr Asp Asp Tyr Tyr Gln Gln 1445 1445 1450 1450 1455 1455

Ile lle Lys Asp Gly Lys Asp Gly His His Val Val lle Ile Leu Leu Gln Gln Leu Leu Asn Asn Ser Ser lleIle ProPro SerSer 1460 1460 1465 1465 1470 1470

Arg Asp Arg Asp Phe PheLeu LeuCys CysVal ValArg ArgPhe Phe Arg Arg Ile I e Phe Phe GI Glu Leu u Leu Phe Phe Gln Gln 1475 1475 1480 1480 1485 1485

Val Gly Val Gly Phe PheLeu LeuAsn AsnPro ProAI Ala ThrPhe a Thr PheThr ThrVal ValTyr TyrGlu Glu Tyr Tyr Hi His s 1490 1490 1495 1495 1500 1500

Arg Pro Arg Pro Asp AspLys LysGln GlnCys CysThr ThrMet Met Ile lle Tyr Tyr Ser Ser Ile lle Ser Ser Asp Asp Thr Thr 1505 1505 1510 1510 1515 1515

Arg Leu Arg Leu Gln GlnLys LysVal ValCys CysGlu GluGly Gly Ala Ala Ala Ala Cys Cys Thr Thr Cys Cys Val Val Glu Glu 1520 1520 1525 1525 1530 1530

Alaa Asp AI CysAlAla Asp Cys GlnLeu a Gln LeuGIGln n Al Ala a GIGlu Val Val Asp Asp Leu lle Leu Ala Ala SerIle Ser 1535 1535 1540 1540 1545 1545

Alaa Asp AI Ser Arg Asp Ser Arg Lys Lys GI Gluu Lys Alaa Cys Lys AI Cys Lys Lys Pro Pro Glu Thr Ala Glu Thr Ala Tyr Tyr 1550 1550 1555 1555 1560 1560

Alaa Tyr AI Lys Val Tyr Lys Val Arg Arg lle Ile Thr Thr Ser SerAI Ala Thr Glu a Thr Glu Glu Glu Asn AsnVal ValPhe Phe 1565 1565 1570 1570 1575 1575

Val Lys Val Lys Tyr TyrThr ThrAla AlaThr ThrLeu LeuLeu Leu Val Val Thr Thr Tyr Tyr Lys Lys Thr Thr Gly Gly Glu Glu 1580 1580 1585 1585 1590 1590

Alaa Ala Al Asp Glu Ala Asp Glu Asn Asn Ser Ser Glu Glu Val ValThr ThrPhe Phelle IleLys LysLys Lys Met Met Ser Ser 1595 1595 1600 1600 1605 1605

Cys Thr Cys Thr Asn AsnAl Ala Asn Leu a Asn Leu Val Val Lys LysGly GlyLys LysGln GlnTyr TyrLeu Leu Ile lle Met Met 1610 1610 1615 1615 1620 1620

Gly Lys Gly Lys Glu GluVal ValLeu LeuGln Glnlle IleLys Lys Hi His AsnPhe s Asn PheSer SerPhe Phe Lys Lys Tyr Tyr 1625 1625 1630 1630 1635 1635

Ile lle Tyr Pro Leu Tyr Pro Leu Asp Asp Ser Ser Ser Ser Thr Thr Trp Trp Ile lle Glu Glu Tyr Tyr TrpTrp ProPro ThrThr 1640 1640 1645 1645 1650 1650

Page 68 Page 68

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.txt Asp Thr Asp Thr Thr ThrCys CysPro ProSer SerCys CysGln Gln AlaAla Phe Phe ValVal Glu Glu Asn Asn Leu Leu Asn Asn 1655 1655 1660 1660 1665 1665

Asn Phe Asn Phe Al Ala Glu Asp a Glu Asp Leu Leu Phe Phe Leu LeuAsn AsnSer SerCys CysGI Glu 1670 1670 1675 1675 1680 1680

<210> <210> 106 106 <211> <211> 123 123 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 106 106 Gln Val Gln Val Gln GlnLeu LeuVal Val GluGlu SerSer Gly Gly Gly Gly Gly Val Gly Leu Leu Gln ValPro GlnGly Pro ArgGly Arg 1 1 5 5 10 10 15 15

Ser Leu Arg Ser Leu ArgLeu LeuSer Ser CysCys AlaAla Ala Ala Ser Ser Gly Thr Gly Phe Phe Val ThrHiVal HisSer s Ser Ser Ser 20 20 25 25 30 30

Tyr Tyr Tyr Tyr Met Met Ala Ala Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp 35 35 40 40 45 45

Val Gly Val Gly Ala Ala lle Ile Phe Phe Thr Thr Gly Gly Ser Ser Gly Gly Ala Ala Glu Glu Tyr Tyr Lys Lys Ala Ala Glu Glu Trp Trp 50 50 55 55 60 60

Alaa Lys AI Lys Gly Arg Val Gly Arg ValThr Thrlle Ile SerSer LysLys Asp Asp Thr Thr Ser Ser Lys Gln Lys Asn AsnVal Gln Val

70 70 75 75 80 80

Val Leu Val Leu Thr ThrMet MetThr ThrAsnAsn MetMet Asp Asp Pro Pro Val Thr Val Asp Asp Ala ThrThr AlaTyr Thr TyrTyr Tyr 85 85 90 90 95 95

Cys Al Cys Alaa Ser Asp Ala Ser Asp AlaGly GlyTyr Tyr AspAsp TyrTyr Pro Pro Thr Thr His His Ala Hi Ala Met Met His Tyr s Tyr 100 100 105 105 110 110

Trp Gly Trp Gly Gln GlnGly GlyThr Thr LeuLeu ValVal Thr Thr Val Val Ser Ser Ser Ser 115 115 120 120

<210> <210> 107 107 <211> <211> 123 123 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 107 107 Gln Val Gln Val Gln GlnLeu LeuVal Val GluGlu SerSer Gly Gly Gly Gly Gly Val Gly Leu Leu Gln ValPro GlnGly Pro ArgGly Arg 1 1 5 5 10 10 15 15

Page 69 Page 69

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt

Ser Leu Arg Ser Leu ArgLeu LeuSer Ser CysCys AI Ala Ala a Ala SenSer GlyGly Phe Phe Thr Thr Val Ser Val His HisSer Ser Ser 20 20 25 25 30 30

Tyr Tyr Tyr Tyr Met Met Ala Ala Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp 35 35 40 40 45 45

Val Gly Val Gly Ala Alalle IlePhe Phe ThrThr GlyGly Ser Ser Gly Gly AI a Ala Glu Glu Tyr Ala Tyr Lys Lys Glu AlaTrp Glu Trp 50 50 55 55 60 60

Val Lys Val Lys Gly Gly Arg Arg Phe Phe Thr Thr lle Ile Ser Ser Arg Arg Asp Asp Asn Asn Ser Ser Lys Lys Asn Asn Thr Thr Leu Leu

70 70 75 75 80 80

Tyr Leu Tyr Leu Gln GlnMet MetAsn AsnSerSer LeuLeu Arg Arg Ala Ala Glu Thr Glu Asp Asp Ala ThrVal AlaTyr Val TyrTyr Tyr 85 85 90 90 95 95

Cys AI Cys Alaa Ser Asp Al Ser Asp Ala Gly Tyr a Gly TyrAsp AspTyr Tyr Pro Pro ThrThr HisHis Ala Ala Met Met His Tyr His Tyr 100 100 105 105 110 110

Trp Gly Trp Gly Arg ArgGly GlyThr Thr LeuLeu ValVal Thr Thr Val Val Ser Ser Ser Ser 115 115 120 120

<210> <210> 108 108 <211> <211> 123 123 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 108 108 Gln Val Gln Val Gln GlnLeu LeuVal Val GluGlu SerSer Gly Gly Gly Gly Gly Val Gly Leu Leu Gln ValPro GlnGly Pro ArgGly Arg 1 1 5 5 10 10 15 15

Ser Leu Arg Ser Leu ArgLeu LeuSer Ser CysCys AI Ala Ala a Ala SerSer GlyGly Phe Phe Thr Thr Vals His Val Hi Ser Ser Ser Ser 20 20 25 25 30 30

Tyr Tyr Tyr Tyr Met MetAlAla TrpVal a Trp ValArg Arg GlnGln Al Ala Pro a Pro GlyGly LysLys Gly Gly Leu Leu Glu Trp Glu Trp 35 35 40 40 45 45

Val Gly Val Gly Ala Alalle IlePhe Phe ThrThr GlyGly Ser Ser Gly Gly AI a Ala Glu Glu Tyr AI Tyr Lys Lysa Ala Glu Trp Glu Trp 50 50 55 55 60 60

Alaa Lys Al Lys Gly Arg Val Gly Arg ValThr Thrlle Ile SerSer LysLys Asp Asp Thr Thr Ser Ser Lys Gln Lys Asn AsnVal Gln Val

70 70 75 75 80 80

Val Leu Val Leu Thr ThrMet MetThr ThrAsnAsn MetMet Asp Asp Pro Pro Val Thr Val Asp Asp AI Thr Ala Tyr a Thr ThrTyr Tyr Tyr 85 85 90 90 95 95

Page 70 Page 70

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt Cys Al Cys Alaa Ser Asp Ala Ser Asp AlaGly GlyTyr Tyr Asp Asp TyrTyr ProPro Thr Thr Hi sHis Al aAla MetMet His His Tyr Tyr 100 100 105 105 110 110

Trp Gly Trp Gly Arg ArgGly GlyThr Thr LeuLeu ValVal Thr Thr Val Val Ser Ser Ser Ser 115 115 120 120

<210> <210> 109 109 <211> <211> 123 123 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 109 109 Gln Val Gln Val Gln GlnLeu LeuVal Val GluGlu SerSer Gly Gly Gly Gly Gly Val Gly Leu Leu Gln ValPro GlnGly Pro GlyGly Gly 1 1 5 5 10 10 15 15

Ser Leu Arg Ser Leu ArgLeu LeuSer Ser CysCys AlaAla Ala Ala Ser Ser Gly Thr Gly Phe Phe Val ThrHiVal HisSer s Ser Ser Ser 20 20 25 25 30 30

Tyr Tyr Tyr Tyr Met Met Ala Ala Trp Trp Val Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp 35 35 40 40 45 45

Val Gly Val Gly Ala Alalle IlePhe Phe ThrThr GlyGly Ser Ser Gly Gly Al a Ala Glu Glu Tyr Ala Tyr Lys Lys Glu AlaTrp Glu Trp 50 50 55 55 60 60

Alaa Lys AI Lys Gly Arg Val Gly Arg ValThr Thrlle Ile SerSer LysLys Asp Asp Thr Thr Ser Ser Lys Gln Lys Asn AsnVal Gln Val

70 70 75 75 80 80

Val Leu Val Leu Thr ThrMet MetThr ThrAsnAsn MetMet Asp Asp Pro Pro Val Thr Val Asp Asp Ala ThrThr AlaTyr Thr TyrTyr Tyr 85 85 90 90 95 95

Cys AI Cys Alaa Ser Asp Ala Ser Asp AlaGly GlyTyr Tyr Asp Asp TyrTyr Pro Pro Thr Thr Hi sHis Ala Ala Met Met Hi s His Tyr Tyr 100 100 105 105 110 110

Trp Gly Trp Gly Gln GlnGly GlyThr Thr LeuLeu ValVal Thr Thr Val Val Ser Ser Ser Ser 115 115 120 120

<210> <210> 110 110 <211> <211> 123 123 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 110 110 Gln Val Gln Val Gln GlnLeu LeuVal Val GluGlu SerSer Gly Gly Gly Gly Gly Val Gly Leu Leu GI Val Gln Gly n Pro ProGly Gly Gly 1 1 5 5 10 10 15 15

Page 71 Page 71

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Ser Leu Arg Ser Leu ArgLeu LeuSer Ser CysCys Al Ala Ala a Ala SerSer GlyGly Phe Phe Thr Thr Vals His Val Hi Ser Ser Ser Ser 20 20 25 25 30 30

Tyr Tyr Tyr Tyr Met MetAlAla TrpVal a Trp ValArg Arg GlnGln AlaAla Pro Pro Gly Gly Lys Lys Gly Glu Gly Leu LeuTrp Glu Trp 35 35 40 40 45 45

Val Ser Val Ser Gly Glylle IlePhe Phe ThrThr GlyGly Ser Ser Gly Gly AI a Ala Thr Thr Tyr Ala Tyr Lys Lys Glu AlaTrp Glu Trp 50 50 55 55 60 60

Alaa Lys AI Lys Gly Arg Val Gly Arg ValThr Thrlle Ile SerSer LysLys Asp Asp Thr Thr Ser Ser Lys Gln Lys Asn AsnVal Gln Val

70 70 75 75 80 80

Val Leu Val Leu Thr ThrMet MetThr ThrAsnAsn MetMet Asp Asp Pro Pro Val Thr Val Asp Asp AI Thr Ala Tyr a Thr ThrTyr Tyr Tyr 85 85 90 90 95 95

Cys AI Cys Alaa Ser Asp AI Ser Asp Ala Gly Tyr a Gly TyrAsp AspTyr Tyr Pro Pro ThrThr HisHis Ala Ala Met Met His Tyr His Tyr 100 100 105 105 110 110

Trp Gly Trp Gly Gln GlnGly GlyThr Thr LeuLeu ValVal Thr Thr Val Val Ser Ser Ser Ser 115 115 120 120

<210> <210> 111 111 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 111 111

Asp lle Asp Ile Gln Gln Met Met Thr Thr Gln Gln Ser Ser Pro Pro Ser Ser Ser Ser Leu Leu Ser Ser Ala Ala Ser Ser Val Val Gly Gly 1 1 5 5 10 10 15 15

Asp Arg Asp Arg Val ValThr Thrlle Ile ThrThr CysCys Arg Arg AI aAla Ser Ser Gln Gln Gly Gly Ile Ser lle Ser SerSer Ser Ser 20 20 25 25 30 30

Leu Alaa Trp Leu Al Tyr Gln Trp Tyr GlnGln GlnLys Lys Pro Pro GlyGly LysLys AI aAla ProPro Lys Lys Leu Leu Leu Ile Leu lle 35 35 40 40 45 45

Tyr Gly Tyr Gly Ala Ala Ser Ser Glu Glu Thr Thr Glu Glu Ser Ser Gly Gly Val Val Pro Pro Ser Ser Arg Arg Phe Phe Ser Ser Gly Gly 50 50 55 55 60 60

Ser Gly Ser Ser Gly SerGly GlyThr Thr AspAsp PhePhe Thr Thr Leu Leu Thr Ser Thr lle Ile Ser SerLeu SerGln Leu ProGln Pro

70 70 75 75 80 80

Glu Asp Phe Glu Asp PheAIAla ThrTyr a Thr TyrTyr Tyr Cys Cys GlnGln AsnAsn Thr Thr Lys Lys Val Ser Val Gly GlySer Ser Ser 85 85 90 90 95 95

Page 72 Page 72

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt Tyr Gly Tyr Gly Asn Asn Thr Thr Phe Phe Gly Gly Gly Gly Gly Gly Thr Thr Lys Lys Val Val Glu Glu lle Ile Lys Lys 100 100 105 105 110 110

<210> <210> 112 112 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 112 112 Asp lle Asp Ile Gln Gln Met Met Thr Thr Gln Gln Ser Ser Pro Pro Ser Ser Ser Ser Leu Leu Ser Ser Ala Ala Ser Ser Val Val Gly Gly 1 1 5 5 10 10 15 15

Asp Arg Asp Arg Val ValThr Thrlle Ile ThrThr CysCys Arg Arg Ala Ala Ser Gly Ser Gln Gln 11 Gly Ile Ser e Ser SerSer Ser Ser 20 20 25 25 30 30

Leu Alaa Trp Leu Al Tyr Gln Trp Tyr GlnGln GlnLys Lys Pro Pro GlyGly GlnGln Ala Ala Pro Pro Arg Leu Arg Leu Leulle Leu Ile 35 35 40 40 45 45

Tyr Gly Tyr Gly Ala Ala Ser Ser Glu Glu Thr Thr Glu Glu Ser Ser Gly Gly Val Val Pro Pro Ser Ser Arg Arg Phe Phe Ser Ser Gly Gly 50 50 55 55 60 60

Ser Gly Ser Ser Gly SerGly GlyThr Thr AspAsp PhePhe Thr Thr Leu Leu Thr Ser Thr lle Ile Ser SerLeu SerGln Leu ProGln Pro

70 70 75 75 80 80

Glu Asp Glu Asp Phe PheAlAla ThrTyr a Thr TyrTyr Tyr Cys Cys GlnGln AsnAsn Thr Thr Lys Lys Val Ser Val Gly GlySer Ser Ser 85 85 90 90 95 95

Tyr Gly Tyr Gly Asn AsnThr ThrPhe Phe GlyGly GlyGly Gly Gly Thr Thr Lys Glu Lys Val Val lle GluLys Ile Lys 100 100 105 105 110 110

<210> <210> 113 113 <211> <211> 110 110 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 113 113 Asp lle Asp Ile Gln Gln Met Met Thr Thr Gln Gln Ser Ser Pro Pro Ser Ser Ser Ser Leu Leu Ser Ser Ala Ala Ser Ser Val Val Gly Gly 1 1 5 5 10 10 15 15

Asp Arg Asp Arg Val ValThr Thrlle Ile ThrThr CysCys Arg Arg Ala Ala Ser Gly Ser Gln Gln lle GlySer IleSer SerSerSer Ser 20 20 25 25 30 30

Leu Ala Trp Leu Ala TrpTyr TyrGln Gln GlnGln LysLys Pro Pro Gly Gly Gl rGln n AlAla ProArg a Pro ArgLeu Leu LeuLeu lleIle 35 35 40 40 45 45

Page 73 Page 73

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Tyr Gly Tyr Gly AI Ala Ser Thr a Ser ThrThr ThrGln GlnSerSer GlyGly Val Val Pro Pro Ser Ser Arg Ser Arg Phe PheGly Ser Gly 50 50 55 55 60 60

Ser Gly Ser Ser Gly SerGly GlyThr Thr AspAsp PhePhe Thr Thr Leu Leu Thr Ser Thr lle Ile Ser SerLeu SerGln Leu ProGln Pro

70 70 75 75 80 80

Glu Asp Glu Asp Phe PheAIAla ThrTyr a Thr TyrTyr Tyr CysCys GlnGln Asn Asn Thr Thr Lys Lys Val Ser Val Gly GlySer Ser Ser 85 85 90 90 95 95

Tyr Gly Tyr Gly Asn AsnThr ThrPhe Phe GlyGly GlyGly Gly Gly Thr Thr Lys Glu Lys Val Val lle GluLys Ile Lys 100 100 105 105 110 110

<210> <210> 114 114 <211> <211> 328 328 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An arti An artificially synthesized ficially synthesi sequence zed sequence

<400> <400> 114 114 Alaa Ser AI Ser Thr Lys Gly Thr Lys GlyPro ProSer Ser ValVal PhePhe Pro Pro Leu Leu Al aAla Pro Pro Ser Ser Ser Lys Ser Lys 1 1 5 5 10 10 15 15

Ser Thr Ser Thr Ser SerGly GlyGly Gly ThrThr AI Ala a AI Ala Leu a Leu Gly Gly CysCys LeuLeu Val Val Lys Lys Asp Tyr Asp Tyr 20 20 25 25 30 30

Phe Pro Glu Phe Pro GluPro ProVal Val ThrThr ValVal Ser Ser Trp Trp Asn Gly Asn Ser Ser Ala GlyLeu AlaThr Leu SerThr Ser 35 35 40 40 45 45

Gly GI y Val Val His Hi s Thr Thr Phe Pro AI Phe Pro Ala Val Leu a Val Leu Gln GlnSer SerSer SerGlyGly LeuLeu Tyr Tyr Ser Ser 50 50 55 55 60 60

Leu Ser Ser Leu Ser SerVal ValVal Val ThrThr ValVal Pro Pro Ser Ser Ser Ser Ser Gly Ser Leu LeuThr GlyGln Thr ThrGln Thr

70 70 75 75 80 80

Tyr lle Tyr Ile Cys CysAsn AsnVal ValAsnAsn HisHis Lys Lys Pro Pro Ser Thr Ser Asn Asn Lys ThrVal LysAsp Val LysAsp Lys 85 85 90 90 95 95

Lys Val Glu Lys Val GluPro ProLys Lys SerSer CysCys Asp Asp Lys Lys Thr Thr Hi s His Thr Thr Cys Pro Cys Pro ProCys Pro Cys 100 100 105 105 110 110

Pro Alaa Pro Pro AI Glu Leu Pro Glu LeuArg ArgArg Arg Gly Gly ProPro LysLys Val Val Phe Phe Leu Pro Leu Phe PhePro Pro Pro 115 115 120 120 125 125

Lys Pro Lys Lys Pro LysAsp AspThr Thr LeuLeu MetMet lle Ile Ser Ser Arg Arg Thr Glu Thr Pro ProVal GluThr Val CysThr Cys 130 130 135 135 140 140

Page 74 Page 74

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.t txt Val Val Val Val Val ValAsp AspVal Val SerSer HisHis Glu Glu Asp Asp Prou Glu Pro GI Val Val Lys Asn Lys Phe PheTrp Asn Trp 145 145 150 150 155 155 160 160

Tyr Val Tyr Val Asp AspGly GlyVal Val GluGlu ValVal His His Asn Asn Al a Ala Lys Lys Thr Thr Lys Arg Lys Pro ProGIArg L Glu 165 165 170 170 175 175

Glu Gln Glu Gln Tyr TyrAsn AsnSer Ser ThrThr TyrTyr Arg Arg Val Val Val Val Val Ser Ser Leu ValThr LeuVal Thr LeuVal Leu 180 180 185 185 190 190

His Hi : Gln Asp S Gln AspTrp TrpLeu Leu Asn Asn Gly Lys Glu Gly Lys Glu Tyr TyrLys LysCys Cys LysLys ValVal Ser Ser Asn Asn 195 195 200 200 205 205

Lys Gly Leu Lys Gly LeuPro ProSer Ser SerSer lleIle Glu Glu Lys Lys Thr Thr Ile Lys lle Ser SerAILys AlaGly a Lys Lys Gly 210 210 215 215 220 220

Gln Pro Gln Pro Arg ArgGlu GluPro Pro GlnGln ValVal Tyr Tyr Thr Thr Leu Pro Leu Pro Pro Ser ProArg SerGlu Arg GI Glu u Glu 225 225 230 230 235 235 240 240

Met Thr Met Thr Lys LysAsn AsnGln Gln ValVal SerSer Leu Leu Thr Thr Cys Val Cys Leu Leu Lys ValGly LysPhe Gly TyrPhe Tyr 245 245 250 250 255 255

Pro Ser Asp Pro Ser Asplle IleAla Ala ValVal GluGlu Trp Trp Glu Glu Ser Ser Asn Gln Asn Gly GlyPro GlnGlu Pro AsnGlu Asn 260 260 265 265 270 270

Asn Tyr Asn Tyr Lys Lys Thr Thr Thr Thr Pro Pro Pro Pro Val Val Leu Leu Asp Asp Ser Ser Asp Asp Gly Gly Ser Ser Phe Phe Phe Phe 275 275 280 280 285 285

Leu Tyr Ser Leu Tyr SerLys LysLeu Leu Thr Thr ValVal Asp Asp Lys Lys Ser Ser Arg Gln Arg Trp TrpGln GlnGly Gln AsnGly Asn 290 290 295 295 300 300

Val Phe Val Phe Ser SerCys CysSer Ser ValVal LeuLeu His His Glu Glu Al a Ala Leu Leu His His His Ala Ala Tyr HisThr Tyr Thr 305 305 310 310 315 315 320 320

Arg Lys Arg Lys Glu Glu Leu Leu Ser Ser Leu Leu Ser Ser Pro Pro 325 325

<210> <210> 115 115 <211> <211> 325 325 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 115 115 Alaa Ser AI Ser Thr Lys Gly Thr Lys GlyPro ProSer Ser ValVal PhePhe Pro Pro Leu Leu Al aAla Pro Pro Cys Cys Ser Arg Ser Arg 1 1 5 5 10 10 15 15

Ser Thr Ser Ser Thr SerGly GlyGly Gly ThrThr AlaAla Ala Ala Leu Leu Gly Leu Gly Cys Cys Val LeuLys ValAsp Lys TyrAsp Tyr Page 75 Page 75

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql. txt 20 20 25 25 30 30

Phe Pro Glu Phe Pro GluPro ProVal Val Thr Thr ValVal SerSer Trp Trp Asn Asn Ser Al Ser Gly Gly Ala Thr a Leu LeuSer Thr Ser 35 35 40 40 45 45

Gly Val Gly Val Hi His Thr Phe s Thr PhePro ProAlAla ValLeu a Val Leu Gln Gln SerSer SerSer Gly Gly Leu Leu Tyr Ser Tyr Ser 50 50 55 55 60 60

Leu Ser Ser Leu Ser SerVal ValVal Val ThrThr ValVal Pro Pro Ser Ser Ser Ser Ser Gly Ser Leu LeuThr GlyLys Thr ThrLys Thr

70 70 75 75 80 80

Tyr Thr Tyr Thr Cys CysAsn AsnVal ValAspAsp HisHis Lys Lys Pro Pro Ser Thr Ser Asn Asn Lys ThrVal LysAsp Val LysAsp Lys 85 85 90 90 95 95

Arg Val Arg Val Glu GluSer SerLys Lys TyrTyr GlyGly Pro Pro Pro Pro Cys Pro Cys Pro Pro Cys ProPro CysAlPro Ala Pro a Pro 100 100 105 105 110 110

Glu Phe Arg GI Phe Arg Arg ArgGly GlyPro ProLys LysVal ValPhe PheLeu LeuPhe PhePro ProPro ProLys LysPro ProLys Lys 115 115 120 120 125 125

Asp Thr Asp Thr Leu LeuMet Metlle Ile SerSer ArgArg Thr Thr Pro Pro GI u Glu Val Val Thr Thr Cys Val Cys Val ValVal Val Val 130 130 135 135 140 140

Asp Val Asp Val Ser Ser His His Glu Glu Asp Asp Pro Pro Glu Glu Val Val Lys Lys Phe Phe Asn Asn Trp Trp Tyr Tyr Val Val Asp Asp 145 145 150 150 155 155 160 160

Gly Val Gly Val Glu GluVal ValHiHis AsnAla s Asn Ala Lys Lys ThrThr LysLys Pro Pro Arg Arg Glu Gln Glu Glu GluTyr Gln Tyr 165 165 170 170 175 175

Asn Ser Asn Ser Thr ThrTyr TyrArg Arg ValVal ValVal Ser Ser Val Val Leu Val Leu Thr Thr Leu ValHiLeu HisAsp s Gln Gln Asp 180 180 185 185 190 190

Trp Leu Trp Leu Asn Asn Gly Gly Lys Lys Glu Glu Tyr Tyr Lys Lys Cys Cys Lys Lys Val Val Ser Ser Asn Asn Lys Lys Gly Gly Leu Leu 195 195 200 200 205 205

Pro Ser Ser Pro Ser Serlle IleGlu Glu LysLys ThrThr lle Ile Ser Ser Lys Lys AI a Ala Lys Lys Gly Pro Gly Gln GlnArg Pro Arg 210 210 215 215 220 220

Glu Pro Gln Glu Pro GlnVal ValTyr Tyr ThrThr LeuLeu Pro Pro Pro Pro Ser Ser Arg Glu Arg Glu GluMet GluThr Met LysThr Lys 225 225 230 230 235 235 240 240

Asn Gln Asn Gln Val Val Ser Ser Leu Leu Thr Thr Cys Cys Leu Leu Val Val Lys Lys Gly Gly Phe Phe Tyr Tyr Pro Pro Ser Ser Asp Asp 245 245 250 250 255 255

Ile 11 e Ala Ala Val Glu Trp Val Glu TrpGlu GluSer Ser Asn Asn GlyGly GlnGln Pro Pro Glu Glu Asn Tyr Asn Asn AsnLys Tyr Lys 260 260 265 265 270 270

Page 76 Page 76

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt Thr Thr Thr Thr Pro ProPro ProVal Val LeuLeu AspAsp Ser Ser Asp Asp Gly Phe Gly Ser Ser Phe PheLeu PheTyr Leu SerTyr Ser 275 275 280 280 285 285

Lys Leu Thr Lys Leu ThrVal ValAsp Asp LysLys SerSer Arg Arg Trp Trp Gln Gly Gln Gln Gln Asn GlyVal AsnPhe Val SerPhe Ser 290 290 295 295 300 300

Cys Ser Cys Ser Val ValLeu LeuHis His GI Glu Ala u Ala Leu Leu HisHis AlaAla Hi sHis TyrTyr Thr Thr Arg Arg Lysu Glu Lys GI 305 305 310 310 315 315 320 320

Leu Ser Leu Leu Ser LeuSer SerPro Pro 325 325

<210> <210> 116 116 <211> <211> 325 325 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 116 116 Alaa Ser Al Ser Thr Lys Gly Thr Lys GlyPro ProSer Ser ValVal PhePhe Pro Pro Leu Leu AI aAla Pro Pro Cys Cys Ser Arg Ser Arg 1 1 5 5 10 10 15 15

Ser Thr Ser Ser Thr SerGly GlyGly Gly ThrThr Al Ala a AI Ala LeuGly a Leu Gly CysCys LeuLeu Val Val Lys Lys Asp Tyr Asp Tyr 20 20 25 25 30 30

Phe Pro Glu Phe Pro GluPro ProVal Val ThrThr ValVal Ser Ser Trp Trp Asn Gly Asn Ser Ser AL Gly Ala Thr a Leu LeuSer Thr Ser 35 35 40 40 45 45

Gly Val Gly Val His HisThr ThrPhe Phe ProPro Al Ala a ValVal LeuLeu Gln Gln Ser Ser Ser Ser Gly Tyr Gly Leu LeuSer Tyr Ser 50 50 55 55 60 60

Leu Ser Ser Leu Ser SerVal ValVal Val ThrThr ValVal Pro Pro Ser Ser Ser Ser Ser Gly Ser Leu LeuThr GlyLys Thr ThrLys Thr

70 70 75 75 80 80

Tyr Thr Tyr Thr Cys CysAsn AsnVal ValAspAsp HisHis Lys Lys Pro Pro Ser Thr Ser Asn Asn Lys ThrVal LysAsp Val LysAsp Lys 85 85 90 90 95 95

Arg Val Arg Val Glu Glu Ser Ser Lys Lys Tyr Tyr Gly Gly Pro Pro Pro Pro Cys Cys Pro Pro Pro Pro Cys Cys Pro Pro Ala Ala Pro Pro 100 100 105 105 110 110

Gluu Phe GI Phe Arg Arg Gly Arg Arg GlyPro ProLys Lys Val Val PhePhe Leu Leu Phe Phe Pro Pro Pro Pro Pro Lys LysLys Pro Lys 115 115 120 120 125 125

Asp Thr Asp Thr Leu LeuMet Met11Ile SerArg e Ser Arg ThrThr ProPro Glu Glu Val Val Thr Thr Cys Val Cys Val ValVal Val Val 130 130 135 135 140 140

Asp Val Asp Val Ser Ser His His Glu Glu Asp Asp Pro Pro Glu Glu Val Val Lys Lys Phe Phe Asn Asn Trp Trp Tyr Tyr Val Val Asp Asp Page 77 Page 77

JPOXMLDOC01-seql.txt JPOXMLDOC01-segl. txt 145 145 150 150 155 155 160 160

Gly Val Gly Val Glu GluVal ValHiHis AsnAla s Asn Ala LysLys ThrThr Lys Lys Pro Pro Arg Arg Glu Gln Glu Glu GluTyr Gln Tyr 165 165 170 170 175 175

Asn Ser Asn Ser Thr ThrTyr TyrArg Arg ValVal ValVal Ser Ser Val Val Leu Val Leu Thr Thr Leu ValHiLeu HisAsp s Gln Gln Asp 180 180 185 185 190 190

Trp Leu Trp Leu Asn AsnGly GlyLys Lys GluGlu TyrTyr Lys Lys Cys Cys Lys Ser Lys Val Val Asn SerLys AsnGly Lys LeuGly Leu 195 195 200 200 205 205

Pro Ser Ser Pro Ser Serlle IleGlu Glu LysLys ThrThr lle Ile Ser Ser Lys Lys Al a Ala Lys Lys Gly Pro Gly Gln GlnArg Pro Arg 210 210 215 215 220 220

Glu Pro Gln Glu Pro GlnVal ValTyr Tyr ThrThr LeuLeu Pro Pro Pro Pro Ser Glu Ser Arg Arg Glu GluMet GluThr Met LysThr Lys 225 225 230 230 235 235 240 240

Asn Gln Asn Gln Val Val Ser Ser Leu Leu Thr Thr Cys Cys Leu Leu Val Val Lys Lys Gly Gly Phe Phe Tyr Tyr Pro Pro Ser Ser Asp Asp 245 245 250 250 255 255

Ile Ala Val lle Ala ValGlu GluTrp Trp GluGlu SerSer Asn Asn Gly Gly Gln Gln Pro Asn Pro Glu GluAsn AsnTyr Asn LysTyr Lys 260 260 265 265 270 270

Thr Thr Thr Thr Pro ProPro ProVal Val LeuLeu AspAsp Ser Ser Asp Asp Gly Phe Gly Ser Ser Phe PheLeu PheTyr Leu SerTyr Ser 275 275 280 280 285 285

Arg Leu Arg Leu Thr ThrVal ValAsp Asp LysLys SerSer Arg Arg Trp Trp Gln Gly Gln Gln Gln Asn GlyVal AsnPhe Val SerPhe Ser 290 290 295 295 300 300

Cys Ser Cys Ser Val Val Leu Leu His His Glu Glu Ala Ala Leu Leu His His Ala Ala His His Tyr Tyr Thr Thr Arg Arg Lys Lys GI Glu 305 305 310 310 315 315 320 320

Leu Ser Leu Leu Ser LeuSer SerPro Pro 325 325

<210> <210> 117 117 <211> <211> 6 6 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 117 117 Ser Ser Tyr Ser Ser TyrTyr TyrMet Met AI Ala a 1 1 5 5

<210> <210> 118 118 <211> <211> 17 17 Page 78 Page 78

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.txt <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence <400> <400> 118 118

Ala lle Ala Ile Phe Phe Thr Thr Gly Gly Ser Ser Gly Gly Ala Ala Glu Glu Tyr Tyr Lys Lys Ala Ala Glu Glu Trp Trp Ala Ala Lys Lys 1 1 5 5 10 10 15 15

Gly Gly

<210> <210> 119 119 <211> <211> 17 17 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 119 119 Ala lle Ala Ile Phe PheThr ThrGly Gly SerSer GlyGly Ala Ala Glu Glu Tyr AI Tyr Lys Lysa Ala Glu Val Glu Trp TrpLys Val Lys 1 1 5 5 10 10 15 15

Gly Gly

<210> <210> 120 120 <211> <211> 17 17 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 120 120 Gly lle Gly Ile Phe PheThr ThrGly Gly SerSer GlyGly Ala Ala Thr Thr Tyr Ala Tyr Lys Lys Glu AlaTrp GluAla Trp LysAla Lys 1 1 5 5 10 10 15 15

Gly Gly

<210> <210> 121 121 <211> <211> 13 13 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 121 121

Asp Al Asp Alaa Gly Tyr Asp Gly Tyr AspTyr TyrPro Pro ThrThr HisHis Ala Ala Met Met His His Tyr Tyr Page Page 7979

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql. txt 1 1 5 5 10 10

<210> <210> 122 122 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 122 122

Arg Ala Arg Ala Ser SerGln GlnGly Gly lleIle SerSer Ser Ser Ser Ser Leu Ala Leu Ala 1 1 5 5 10 10

<210> <210> 123 123 <211> <211> 7 7 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 123 123 Gly Ala Gly Ala Ser SerGlu GluThr Thr GluGlu SerSer 1 1 5 5

<210> <210> 124 124 <211> <211> 7 7 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 124 124 Gly Ala Gly Ala Ser SerThr ThrThr Thr GlnGln SerSer 1 1 5 5

<210> <210> 125 125 <211> <211> 12 12 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An arti An artificially ificially synthesized sequence synthesized sequence

<400> <400> 125 125

Gln Asn Gln Asn Thr ThrLys LysVal Val GlyGly SerSer Ser Ser Tyr Tyr Gly Thr Gly Asn Asn Thr 1 1 5 5 10 10

<210> <210> 126 126 <211> <211> 6 6 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence Page 80 Page 80

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt

<220> <220> <223> <223> AnAn artificially arti synthesized ficially synthesi sequence zed sequence

<220> <220> <221> <221> misc_feature miisc_feature <222> <222> (5)..(5) (5)..(5) <223> <223> Xaa is Met Xaa is MetororVal Val

<220> <220> <221> <221> misc_feature mi sc_feature <222> <222> (6)..(6) (6) (6) <223> <223> Xaa is Cys Xaa is CysororAla Ala

<400> <400> 126 126 Ser Ser Ser Ser Tyr TyrTyr TyrXaa Xaa XaaXaa 1 1 5 5

<210> <210> 127 127 <211> <211> 17 17 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<220> <220> <221> <221> misc_feature sc_feature <222> <222> (1)..(1) (1)..(1) <223> <223> Xaa is Xaa is Cys, Cys,Ala Alaoror GlyGly

<220> <220> <221> <221> misc_feature misc_feature <222> <222> (3)..(3) (3)..(3) <223> <223> Xaa is Tyr Xaa is TyrororPhe Phe <220> <220> <221> <221> misc_feature mi sc_feature <222> <222> (9)..(9) (9) (9) <223> Xaais <223> Xaa isThr, Thr,Asp Aspor orGlu Glu <220> <220> <221> <221> misc_feature mi sc_feature <222> <222> (11)..(11) (11)..(11) <223> <223> Xaa is Xaa is Tyr, Tyr,Lys Lysoror GlnGln <220> <220> <221> <221> misc_feature isc_feature <222> <222> (13)..(13) (13)..(13) <223> <223> Xaa is Xaa is Ser, Ser,Asp Asporor Glu Glu

<220> <220> <221> <221> misc_feature isc_feature <222> <222> (15)..(15) (15)..(15) <223> <223> Xaa is Xaa is Ala AlaororVal Val <400> <400> 127 127 Xaa lle Xaa Ile Xaa XaaThr ThrGly Gly SerSer GlyGly Ala Ala Xaa Xaa Tyr Ala Tyr Xaa Xaa Xaa AlaTrp XaaXaa Trp LysXaa Lys Page 81 Page 81

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.txt 1 1 5 5 10 10 15 15

Gly Gly

<210> <210> 128 128 <211> <211> 13 13 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> An artificially <223> An artificially synthesized synthesized sequence sequence

<220> <220> <221> <221> misc_feature mi sc_feature <222> <222> (2)..(2) (2) (2) <223> <223> Xaa is Xaa is Gly Gly or or Ala Ala <220> <220> <221> <221> misc_feature mi isc_feature <222> <222> (5)..(5) (5)..(5) <223> <223> Xaa is Xaa is Val, Val,Gln Glnoror Asp Asp <220> <220> <221> <221> misc_feature mi sc_feature <222> <222> (6)..(6) (6)..(6) <223> <223> Xaa is Xaa is Thr ThrororTyr Tyr

<220> <220> <221> <221> misc_feature mi isc_feature <222> <222> (12)..(12) (12)..(12) <223> <223> Xaa is Xaa is Tyr TyrororHiHis s

<220> <220> <221> <221> misc_feature mi sc_feature <222> <222> (13)..(13) (13)..(13) <223> <223> Xaa is Xaa is Leu LeuororTyr Tyr

<400> <400> 128 128 Asp Xaa Asp Xaa Gly GlyTyr TyrXaa Xaa XaaXaa ProPro Thr Thr Hi sHis Ala Ala Met Met Xaa Xaa Xaa Xaa 1 1 5 5 10 10

<210> <210> 129 129 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<220> <220> <221> <221> misc_feature mi isc_feature <222> <222> (1)..(1) (1)..(1) <223> <223> Xaa is Xaa is Gln GlnororArg Arg

<220> <220> <221> <221> misc_feature mi sc_feature Page 82 Page 82

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt <222> (5)..(5) <222> (5) . (5) <223> Xaa is <223> Xaa is Asn, Asn, Gln Gln or or Gly Gly

<220> <220> <221> <221> misc_feature misc_feature <222> <222> (7)..(7) (7)..(7) <223> <223> Xaa is Xaa is Gly GlyororSer Ser <220> <220> <221> <221> misc_feature mi isc_feature <222> <222> (9)..(9) (9) (9) <223> <223> Xaa is Xaa is Asp, Asp,Lys Lysoror SerSer

<400> <400> 129 129 Xaa Ala Xaa Ala Ser SerGln GlnXaa Xaa lleIle XaaXaa Ser Ser Xaa Xaa Leu Ala Leu Ala 1 1 5 5 10 10

<210> <210> 130 130 <211> <211> 7 7 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<220> <220> <221> <221> misc_feature mi isc_feature <222> <222> (4)..(4) (4)..(4) <223> <223> Xaa is Xaa is Lys, Lys,Glu Gluoror ThrThr

<220> <220> <221> <221> misc_feature mi sc_feature <222> <222> (5)..(5) (5)..(5) <223> <223> Xaa is Xaa is Leu LeuororThr Thr

<220> <220> <221> <221> misc_feature mi sc_feature <222> <222> (6)..(6) (6). (6) <223> <223> Xaa is Xaa is Ala, Ala,HiHis, GluororGIGln S, Glu

<400> <400> 130 130

Gly Ala Gly Ala Ser SerXaa XaaXaa Xaa XaaXaa SerSer 1 1 5 5

<210> <210> 131 131 <211> <211> 12 12 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<220> <220> <221> <221> misc_feature mi isc_feature <222> <222> (2)..(2) (2)..(2) <223> <223> Xaa is Xaa is Ser, Ser,Cys, Cys,Asn Asn or or ThrThr

Page 83 Page 83

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql.tx <220> <220> <221> <221> misc_feature mi sc_feature <222> <222> (4)..(4) (4) (4) <223> <223> Xaa is Xaa is Phe PheororLys Lys <220> <220> <221> <221> misc_feature misc_feature <222> <222> (12)..(12) (12)- (12) <223> <223> Xaa is Xaa is Ala, Ala,Thr Throror His His <400> <400> 131 131

Gln Xaa Thr Gln Xaa ThrXaa XaaVal Val GlyGly SerSer Ser Ser Tyr Tyr Gly Xaa Gly Asn Asn Xaa 1 1 5 5 10 10

<210> <210> 132 132 <211> <211> 30 30 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 132 132 Gln Val Gln Val Gln Gln Leu Leu Val Val Glu Glu Ser Ser Gly Gly Gly Gly Gly Gly Leu Leu Val Val Gln Gln Pro Pro Gly Gly Gly Gly 1 1 5 5 10 10 15 15

Ser Leu Arg Ser Leu ArgLeu LeuSer Ser CysCys Al Ala Ala a Ala SerSer GlyGly Phe Phe Thr Thr Ser His Ser His 20 20 25 25 30 30

<210> <210> 133 133 <211> <211> 30 30 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 133 133 Gln Val Gln Val Gln GlnLeu LeuVal Val GluGlu SerSer Gly Gly Gly Gly Gly Val Gly Leu Leu Gln ValPro GlnGly Pro ArgGly Arg 1 1 5 5 10 10 15 15

Ser Leu Arg Ser Leu ArgLeu LeuSer Ser CysCys AlaAla Ala Ala Ser Ser Gly Thr Gly Phe Phe Val ThrHiVal s His 20 20 25 25 30 30

<210> <210> 134 134 <211> <211> 30 30 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 134 134 Gln Val Gln Val Gln GlnLeu LeuVal Val GluGlu SerSer Gly Gly Gly Gly Gly Val Gly Leu Leu Gln ValPro GlnGly Pro GlyGly Gly Page 84 Page 84

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.t txt 1 1 5 5 10 10 15 15

Ser Leu Arg Ser Leu ArgLeu LeuSer Ser CysCys AlaAla Ala Ala Ser Ser Gly Thr Gly Phe Phe Val ThrHiVal s His 20 20 25 25 30 30

<210> <210> 135 135 <211> <211> 14 14 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 135 135 Trp Val Trp Val Arg Arg Gln Gln Ala Ala Pro Pro Gly Gly Lys Lys Gly Gly Leu Leu Glu Glu Trp Trp Val Val Gly Gly 1 1 5 5 10 10

<210> <210> 136 136 <211> <211> 14 14 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 136 136 Trp Val Trp Val Arg ArgGln GlnAla Ala ProPro GlyGly Lys Lys Gly Gly Leu Trp Leu Glu Glu Val TrpSer Val Ser 1 1 5 5 10 10

<210> <210> 137 137 <211> <211> 32 32 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 137 137 Arg Phe Arg Phe Thr Thrlle IleSer Ser LysLys AspAsp Thr Thr Ser Ser Lys Gln Lys Asn Asn Val GlnVal ValLeu Val ThrLeu Thr 1 1 5 5 10 10 15 15

Met Thr Met Thr Asn AsnMet MetAsp Asp ProPro ValVal Asp Asp Thr Thr Ala Tyr Ala Thr Thr Tyr TyrCys TyrAlCys Ala Ser a Ser 20 20 25 25 30 30

<210> <210> 138 138 <211> <211> 32 32 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> AnAn artificially artificially synthesized synthesi sequence zed sequence

<400> <400> 138 138

Page 85 Page 85

JPOXMLDOC01-seql.txt UPOXMLDOC01-seql. txt Arg Val Arg Val Thr Thr lle Ile Ser Ser Lys Lys Asp Asp Thr Thr Ser Ser Lys Lys Asn Asn Gln Gln Val Val Val Val Leu Leu Thr Thr 1 1 5 5 10 10 15 15

Met Thr Met Thr Asn AsnMet MetAsp Asp ProPro ValVal Asp Asp Thr Thr Ala Tyr Ala Thr Thr Tyr TyrCys TyrAla CysSerAla Ser 20 20 25 25 30 30

<210> <210> 139 139 <211> <211> 32 32 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 139 139 Arg Phe Arg Phe Thr Thrlle IleSer Ser ArgArg AspAsp Asn Asn Ser Ser Lys Thr Lys Asn Asn Leu ThrTyr LeuLeu Tyr GlnLeu Gln 1 1 5 5 10 10 15 15

Met Asn Met Asn Ser SerLeu LeuArg Arg Al Ala Glu a Glu AspAsp ThrThr Ala Ala Val Val Tyr Tyr Tyr Al Tyr Cys Cys Ala Ser a Ser 20 20 25 25 30 30

<210> <210> 140 140 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 140 140 Trp Gly Trp Gly Gln GlnGly GlyThr Thr LeuLeu ValVal Thr Thr Val Val Ser Ser Ser Ser 1 1 5 5 10 10

<210> <210> 141 141 <211> <211> 11 11 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 141 141

Trp Gly Trp Gly Arg ArgGly GlyThr Thr LeuLeu ValVal Thr Thr Val Val Ser Ser Ser Ser 1 1 5 5 10 10

<210> <210> 142 142 <211> <211> 23 23 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 142 142 Page 86 Page 86

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt Asp Val Asp Val Val Val Met Met Thr Thr Gln Gln Ser Ser Pro Pro Ser Ser Ser Ser Leu Leu Ser Ser Ala Ala Ser Ser Val Val Gly Gly 1 1 5 5 10 10 15 15

Asp Arg Asp Arg Val ValThr Thrlle Ile ThrThr CysCys 20 20

<210> <210> 143 143 <211> <211> 23 23 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 143 143 Asp lle Asp Ile Gln Gln Met Met Thr Thr Gln Gln Ser Ser Pro Pro Ser Ser Ser Ser Leu Leu Ser Ser Ala Ala Ser Ser Val Val Gly Gly 1 1 5 5 10 10 15 15

Asp Arg Asp Arg Val ValThr Thrlle Ile ThrThr CysCys 20 20

<210> <210> 144 144 <211> <211> 15 15 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 144 144 Trp Tyr Trp Tyr Gln GlnGln GlnLys Lys ProPro GlyGly Gln Gln Ala Ala Pro Leu Pro Arg Arg Leu Leulle LeuTyr Ile Tyr 1 1 5 5 10 10 15 15

<210> <210> 145 145 <211> <211> 15 15 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 145 145 Trp Tyr Trp Tyr Gln GlnGln GlnLys Lys ProPro GlyGly Lys Lys Ala Ala Pro Leu Pro Lys Lys Leu Leulle LeuTyr Ile Tyr 1 1 5 5 10 10 15 15

<210> <210> 146 146 <211> <211> 32 32 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

Page 87 Page 87

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql.txt <400> < 400> 146 146 Gly Val Gly Val Pro ProSer SerArg Arg PhePhe SerSer Gly Gly Ser Ser Gly Gly Gly Ser Ser Thr GlyAsp ThrPhe Asp ThrPhe Thr 1 1 5 5 10 10 15 15

Leu Thr lle Leu Thr IleSer SerSer Ser LeuLeu GlnGln Pro Pro Glu Glu Asp Asp Val Thr Val Ala AlaTyr ThrTyr TyrCysTyr Cys 20 20 25 25 30 30

<210> <210> 147 147 <211> <211> 32 32 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> <400> 147 147 Gly Val Gly Val Pro ProSer SerArg Arg PhePhe SerSer Gly Gly Ser Ser Gly Gly Gly Ser Ser Thr GlyAsp ThrPhe Asp ThrPhe Thr 1 1 5 5 10 10 15 15

Leu Thr lle Leu Thr IleSer SerSer Ser Leu Leu GlnGln ProPro Glu Glu Asp Asp Phea Ala Phe Al Thr Tyr Thr Tyr TyrCys Tyr Cys 20 20 25 25 30 30

<210> <210> 148 148 <211> <211> 10 10 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence

<220> <220> <223> <223> An arti An artificially synthesized ficially synthesi sequence zed sequence

<400> <400> 148 148 Phe Gly Gly Phe Gly GlyGly GlyThr Thr Lys Lys ValVal Glu Glu lle Ile Lys Lys 1 1 5 5 10 10

<210> <210> 149 149 <211> <211> 448 448 <212> <212> PRT PRT <213> <213> Artificial sequence Artificial sequence

<220> <220> <223> <223> An arti An artificially synthesized ficially synthesi sequence zed sequence

<400> <400> 149 149 Gln Val Gln Val Gln GlnLeu LeuVal Val GlnGln SerSer Gly Gly Ala Ala Glu Lys Glu Val Val Lys LysPro LysGly Pro Al Gly a Ala 1 1 5 5 10 10 15 15

Ser Val Lys Ser Val LysVal ValSer Ser CysCys LysLys Ala Ala Ser Ser Glys His Gly Hi lle Ile Phe Asn Phe Ser SerTyr Asn Tyr 20 20 25 25 30 30

Trp lle Trp Ile Gln GlnTrp TrpVal Val ArgArg GlnGln Ala Ala Pro Pro Gly Gly Gly Gln Gln Leu GlyGlu LeuTrp Glu MetTrp Met 35 35 40 40 45 45

Page 88 Page 88

JPOXMLDOC01-seql.txt JPOXMLDOC01-segl. txt

Gly Glu Gly Glu lle IleLeu LeuPro Pro GlyGly SerSer Gly Gly His His Thr Tyr Thr Glu Glu Thr TyrGlu ThrAsn Glu PheAsn Phe 50 50 55 55 60 60

Lys Asp Arg Lys Asp ArgVal ValThr Thr MetMet ThrThr Arg Arg Asp Asp Thr Thr Thr Ser Ser Ser ThrThr SerVal Thr TyrVal Tyr

70 70 75 75 80 80

Met Glu Met Glu Leu LeuSer SerSer SerLeuLeu ArgArg Ser Ser Glu Glu Asp AI Asp Thr Thra Val Ala Tyr Val Tyr TyrCys Tyr Cys 85 85 90 90 95 95

Alaa Arg AI Arg Tyr Phe Phe Tyr Phe PheGly GlySer Ser SerSer ProPro Asn Asn Trp Trp Tyr Asp Tyr Phe Phe Val AspTrp Val Trp 100 100 105 105 110 110

Gly Gln Gly Gln Gly GlyThr ThrLeu Leu ValVal ThrThr Val Val Ser Ser Sera Ala Ser AI Ser Ser Thr Gly Thr Lys LysPro Gly Pro 115 115 120 120 125 125

Ser Val Phe Ser Val PhePro ProLeu Leu AI Ala Pro a Pro Cys Cys SerSer ArgArg Ser Ser Thr Thr Ser Ser Ser Glu GluThr Ser Thr 130 130 135 135 140 140

Alaa Ala Al AI aLeu Leu Gly Gly Cys Leu Val Cys Leu ValLys LysAsp Asp Tyr Tyr PhePhe ProPro Glu Glu Pro Pro Val Thr Val Thr 145 145 150 150 155 155 160 160

Val Ser Val Ser Trp TrpAsn AsnSer Ser GlyGly AI Ala a LeuLeu ThrThr Ser Ser Gly Gly Vals His Val Hi Thr Thr Phe Pro Phe Pro 165 165 170 170 175 175

Alaa Val Al Val Leu Gln Ser Leu Gln SerSer SerGly Gly LeuLeu TyrTyr Ser Ser Leu Leu Ser Val Ser Ser Ser Val ValThr Val Thr 180 180 185 185 190 190

Val Pro Val Pro Ser Ser Ser Ser Asn Asn Phe Phe Gly Gly Thr Thr Gln Gln Thr Thr Tyr Tyr Thr Thr Cys Cys Asn Asn Val Val Asp Asp 195 195 200 200 205 205

Hiss Lys Hi Lys Pro Ser Asn Pro Ser AsnThr ThrLys Lys Val Val AspAsp Lys Lys Thr Thr Val Val GI u Glu Arg Arg Lys Cys Lys Cys 210 210 215 215 220 220

Cys Val Cys Val Glu GluCys CysPro Pro ProPro CysCys Pro Pro AI aAla Pro Pro Pro Pro Val Val Ala Pro Ala Gly GlySer Pro Ser 225 225 230 230 235 235 240 240

Val Phe Val Phe Leu LeuPhe PhePro Pro ProPro LysLys Pro Pro Lys Lys Asp Leu Asp Thr Thr Met Leulle MetSer Ile ArgSer Arg 245 245 250 250 255 255

Thr Pro Thr Pro Glu GluVal ValThr Thr CysCys ValVal Val Val Val Val Asp Ser Asp Val Val Gln SerGlu GlnAsp Glu ProAsp Pro 260 260 265 265 270 270

Glu GI u Val Val Gln Phe Asn Gln Phe AsnTrp TrpTyr Tyr Val Val AspAsp GlyGly Val Val Glu Glu Val: His Val Hi S AsnAsn Al Ala 275 275 280 280 285 285

Lys Thr Lys Lys Thr LysPro ProArg Arg GluGlu GluGlu Gln Gln Phe Phe Asn Thr Asn Ser Ser Tyr ThrArg TyrVal Arg ValVal Val 290 290 295 295 300 300 Page 89 Page 89

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Ser Val Leu Ser Val LeuThr ThrVal Val LeuLeu HisHis Gln Gln Asp Asp Trp Asn Trp Leu Leu Gly AsnLys GlyGlu Lys TyrGlu Tyr 305 305 310 310 315 315 320 320

Lys Cys Lys Lys Cys LysVal ValSer Ser AsnAsn LysLys Gly GI y LeuLeu ProPro Ser Ser Ser Ser 11 e Ile Glu Glu Lys Thr Lys Thr 325 325 330 330 335 335

Ile Ser Lys lle Ser LysAIAla LysGly a Lys GlyGln Gln Pro Pro ArgArg GluGlu Pro Pro Gln Gln Val Thr Val Tyr TyrLeu Thr Leu 340 340 345 345 350 350

Pro Pro Ser Pro Pro SerGln GlnGlu Glu Glu Glu MetMet Thr Thr Lys Lys Asn Asn Gln Ser Gln Val ValLeu SerThr Leu CysThr Cys 355 355 360 360 365 365

Leu Val Lys Leu Val LysGly GlyPhe Phe TyrTyr ProPro Ser Ser Asp Asp lle Ile Ala Glu Ala Val ValTrp GluGlu Trp SerGlu Ser 370 370 375 375 380 380

Asn Gly Asn Gly Gln Gln Pro Pro Glu Glu Asn Asn Asn Asn Tyr Tyr Lys Lys Thr Thr Thr Thr Pro Pro Pro Pro Val Val Leu Leu Asp Asp 385 385 390 390 395 395 400 400

Ser Asp Gly Ser Asp GlySer SerPhe Phe PhePhe LeuLeu Tyr Tyr Ser Ser Arg Thr Arg Leu Leu Val ThrAsp ValLys Asp SerLys Ser 405 405 410 410 415 415

Arg Trp Arg Trp Gln GlnGlu GluGly Gly AsnAsn ValVal Phe Phe Ser Ser Cys Val Cys Ser Ser Leu ValHiLeu HisAla s Glu Glu Ala 420 420 425 425 430 430

Leu His Ser Leu His SerHis HisTyr Tyr ThrThr GlnGln Lys Lys Ser Ser Leu Leu Ser Ser Ser Leu LeuLeu SerGly Leu LysGly Lys 435 435 440 440 445 445

<210> <210> 150 150 <211> <211> 214 214 <212> <212> PRT PRT <213> <213> Artificialsequence Artificial sequence <220> <220> <223> <223> An artificially An artificiallysynthesi synthesized sequence zed sequence

<400> :400: 150 150 Asp lle Asp Ile Gln Gln Met Met Thr Thr Gln Gln Ser Ser Pro Pro Ser Ser Ser Ser Leu Leu Ser Ser Ala Ala Ser Ser Val Val Gly Gly 1 1 5 5 10 10 15 15

Asp Arg Asp Arg Val ValThr Thr11Ile ThrCys e Thr Cys GlyGly Al Ala Ser a Ser GluGlu AsnAsn lle Ile Tyr Tyr Gly Ala Gly Ala 20 20 25 25 30 30

Leu Asn Trp Leu Asn TrpTyr TyrGln Gln GlnGln LysLys Pro Pro Gly Gly Lys Lys Al a Ala Pro Pro Lys Leu Lys Leu Leulle Leu Ile 35 35 40 40 45 45

Tyr Gly Tyr Gly Al Ala Thr Asn a Thr AsnLeu LeuAla AlaAspAsp GlyGly Val Val Pro Pro Ser Ser Arg Ser Arg Phe PheGly Ser Gly 50 50 55 55 60 60

Page 90 Page 90

JPOXMLDOC01-seql.txt JPOXMLDOC01-seql. txt

Ser Gly Ser Ser Gly SerGly GlyThr Thr AspAsp PhePhe Thr Thr Leu Leu Thr Ser Thr lle Ile Ser SerLeu SerGln Leu ProGln Pro

70 70 75 75 80 80

Glu Asp Glu Asp Phe PheAIAla ThrTyr a Thr TyrTyr Tyr Cys Cys GlnGln Asn Asn Val Val Leu Leu Asn Pro Asn Thr ThrLeu Pro Leu 85 85 90 90 95 95

Thr Phe Thr Phe Gly GlyGln GlnGly Gly ThrThr LysLys Val Val Glu Glu Ile Arg lle Lys Lys Thr ArgVal ThrAIVal a AlAla a Ala 100 100 105 105 110 110

Pro Ser Val Pro Ser ValPhe Phelle Ile PhePhe ProPro Pro Pro Ser Ser Asp Asp Glu Leu Glu Gln GlnLys LeuSer Lys GlySer Gly 115 115 120 120 125 125

Thr Ala Thr Ala Ser SerVal ValVal Val CysCys LeuLeu Leu Leu Asn Asn Asn Tyr Asn Phe Phe Pro TyrArg ProGIArg u AlGlu a Ala 130 130 135 135 140 140

Lys Val Gln Lys Val GlnTrp TrpLys Lys ValVal AspAsp Asn Asn Ala Ala Leu Leu Gln Gly Gln Ser SerAsn GlySer Asn GI Ser n Gln 145 145 150 150 155 155 160 160

Glu Ser Glu Ser Val ValThr ThrGlu Glu GlnGln AspAsp Ser Ser Lys Lys Asp Thr Asp Ser Ser Tyr ThrSer TyrLeu Ser SerLeu Ser 165 165 170 170 175 175

Ser Thr Leu Ser Thr LeuThr ThrLeu Leu SerSer LysLys Ala Al a AspAsp TyrTyr Glu Glu Lys Lys His Val His Lys LysTyr Val Tyr 180 180 185 185 190 190

Alaa Cys AI Cys Glu Val Thr Glu Val ThrHis HisGln Gln GlyGly LeuLeu Ser Ser Ser Ser Pro Pro Val Lys Val Thr ThrSer Lys Ser 195 195 200 200 205 205

Phe Asn Arg Phe Asn ArgGly GlyGlu Glu CysCys 210 210

Page 91 Page 91

Claims (42)

CLAIMS:

1. An anti-C5 antibody, comprising: (a) a VH sequence of SEQ ID NO: 106 and a VL sequence of SEQ ID NO: 111; (b) a VH sequence of SEQ ID NO: 107 and a VL sequence of SEQ ID NO: 111; (c) a VH sequence of SEQ ID NO: 108 and a VL sequence of SEQ ID NO: 111; (d) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 111; (e) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 112; (f) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 113; or (g) a VH sequence of SEQ ID NO: 110 and a VL sequence of SEQ ID NO: 113, when used in treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5.

2. An anti-C5 antibody, comprising: (a) a VH sequence of SEQ ID NO: 106 and a VL sequence of SEQ ID NO: 111; (b) a VH sequence of SEQ ID NO: 107 and a VL sequence of SEQ ID NO: 111; (c) a VH sequence of SEQ ID NO: 108 and a VL sequence of SEQ ID NO: 111; (d) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 111; (e) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 112; (f) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 113; or (g) a VH sequence of SEQ ID NO: 110 and a VL sequence of SEQ ID NO: 113, when used in enhancing the clearance of C5 from plasma.

3. An anti-C5 antibody, comprising any one of (i) to (iv) below: (i) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (ii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122;

(e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (iii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125, when used in treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5.

4. An anti-C5 antibody, comprising any one of (i) to (iv) below: (i) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (ii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (iii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117;

(b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125, when used in enhancing the clearance of C5 from plasma.

5. The antibody of any one of claims 1 to 4, further comprising

[I] a heavy chain constant region comprising the amino acid sequence of any one of SEQ ID NOs: 33, 34, 35, 114, 115, and 116; and

[II] a light chain constant region comprising the amino acid sequence of any one of SEQ ID NOs: 36, 37, and 38.

6. The antibody of claim 5, comprising a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 114; and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 38.

7. An isolated antibody that specifically binds to C5 when used in treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

8. An isolated antibody that specifically binds to C5 when used in enhancing the clearance of C5 from plasma, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

9. An isolated antibody that specifically binds to C5p when used in treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

10. An isolated antibody that specifically binds to C5p when used in enhancing the clearance of C5 from plasma, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

11. The antibody of any one of claims 1 to 10, wherein the antibody inhibits activation of C5.

12. The antibody of any one of claims 1 to 11, wherein the antibody inhibits activation of C5 variant R885H.

13. The antibody of any one of claims I to 12, wherein the antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8.

14. The antibody of any one of claims I to 13, which is a full length IgGIor IgG4 antibody.

15. Use of an anti-C5 antibody in the manufacture of a medicament for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, wherein the anti-C5 antibody comprises: (a) a VH sequence of SEQ ID NO: 106 and a VL sequence of SEQ ID NO: 111; (b) a VH sequence of SEQ ID NO: 107 and a VL sequence of SEQ ID NO: 111; (c) a VH sequence of SEQ ID NO: 108 and a VL sequence of SEQ ID NO: 111; (d) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 111; (e) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 112; (f) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 113; or (g) a VH sequence of SEQ ID NO: 110 and a VL sequence of SEQ ID NO: 113.

16. Use of an anti-C5 antibody in the manufacture of a medicament for enhancing the clearance of C5 from plasma, wherein the anti-C5 antibody comprises: (a) a VH sequence of SEQ ID NO: 106 and a VL sequence of SEQ ID NO: 111; (b) a VH sequence of SEQ ID NO: 107 and a VL sequence of SEQ ID NO: 111; (c) a VH sequence of SEQ ID NO: 108 and a VL sequence of SEQ ID NO: 111; (d) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 111; (e) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 112; (f) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 113; or (g) a VH sequence of SEQ ID NO: 110 and a VL sequence of SEQ ID NO: 113.

17. Use of an anti-C5 antibody in the manufacture of a medicament for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, wherein the anti-C5 antibody comprises any one of (i) to (iv) below:

(i) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (ii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (iii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; or

(iv) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

18. Use of an anti-C5 antibody in the manufacture of a medicament for enhancing the clearance of C5 from plasma, wherein the anti-C5 antibody comprises any one of (i) to (iv) below:

(i) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (ii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (iii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120;

(c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

19. The use of any one of claims 15 to 18, wherein the anti-C5 antibody further comprises

[I] a heavy chain constant region comprising the amino acid sequence of any one of SEQ ID NOs: 33, 34, 35, 114, 115, and 116; and

[II] a light chain constant region comprising the amino acid sequence of any one of SEQ ID NOs: 36, 37, and 38.

20. The use of claim 19, wherein the anti-C5 antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 114; and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 38.

21. Use of an antibody that specifically binds to C5 in the manufacture of a medicament for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

22. Use of an antibody that specifically binds to C5 in the manufacture of a medicament for enhancing the clearance of C5 from plasma, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

23. Use of an antibody that specifically binds to C5p in the manufacture of a medicament for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

24. Use of an antibody that specifically binds to C5p in the manufacture of a medicament for enhancing the clearance of C5 from plasma, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

25. The use of any one of claims 15 to 24, wherein the antibody inhibits activation of C5.

26. The use of any one of claims 15 to 25, wherein the antibody inhibits activation of C5 variant R885H.

27. The use of any one of claims 15 to 26, wherein the antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8.

28. The use of any one of claims 15 to 27, wherein the antibody is a full length IgG Ior IgG4 antibody.

29. A method for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 in an individual, wherein the method comprises administering to the individual having the complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 an effective amount of an anti-C5 antibody, wherein the anti-C5 antibody comprises: (a) a VH sequence of SEQ ID NO: 106 and a VL sequence of SEQ ID NO: 111; (b) a VH sequence of SEQ ID NO: 107 and a VL sequence of SEQ ID NO: 111; (c) a VH sequence of SEQ ID NO: 108 and a VL sequence of SEQ ID NO: 111; (d) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 111; (e) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 112; (f) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 113; or (g) a VH sequence of SEQ ID NO: 110 and a VL sequence of SEQ ID NO: 113.

30. A method for enhancing the clearance of C5 from plasma in an individual, wherein the method comprises administering to the individual an effective amount of an anti-C5 antibody, wherein the anti-C5 antibody comprises: (a) a VH sequence of SEQ ID NO: 106 and a VL sequence of SEQ ID NO: 111; (b) a VH sequence of SEQ ID NO: 107 and a VL sequence of SEQ ID NO: 111;

(c) a VH sequence of SEQ ID NO: 108 and a VL sequence of SEQ ID NO: 111; (d) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 111; (e) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 112; (f) a VH sequence of SEQ ID NO: 109 and a VL sequence of SEQ ID NO: 113; or (g) a VH sequence of SEQ ID NO: 110 and a VL sequence of SEQ ID NO: 113.

31. A method for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 in an individual, wherein the method comprises administering to the individual having the complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 an effective amount of an anti-C5 antibody, wherein the anti-C5 antibody comprises any one of (i) to (iv) below:

(i) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (ii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (iii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120;

(c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

32. A method for enhancing the clearance of C5 from plasma in an individual, wherein the method comprises administering to the individual an effective amount of an anti-C5 antibody, wherein the anti-C5 antibody comprises any one of (i) to (iv) below:

(i) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (ii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 119; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; (iii) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 118; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and (f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 117; (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 120; (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122; (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 124; and

(f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 125.

33. The method of any one of claims 29 to 32, wherein the anti-C5 antibody further comprises

[I] a heavy chain constant region comprising the amino acid sequence of any one of SEQ ID NOs: 33, 34, 35, 114, 115, and 116; and

[II] a light chain constant region comprising the amino acid sequence of any one of SEQ ID NOs: 36, 37, and 38.

34. The method of claim 33, wherein the anti-C5 antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 114; and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 38.

35. A method for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 in an individual, wherein the method comprises administering to the individual having the complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 an effective amount of an antibody that specifically binds to C5, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

36. A method for enhancing the clearance of C5 from plasma in an individual, wherein the method comprises administering to the individual an effective amount of an antibody that specifically binds to C5, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

37. A method for treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 in an individual, wherein the method comprises administering to the individual having the complement-mediated disease or condition which involves excessive or uncontrolled activation of C5 an effective amount of an antibody that specifically binds to C5p, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

38. A method for enhancing the clearance of C5 from plasma in an individual, wherein the method comprises administering to the individual an effective amount of an antibody that specifically binds to C5p, wherein the antibody has a VH sequence consisting of SEQ ID NO: 106, a VL sequence consisting of SEQ ID NO: 111, a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 114, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO: 38.

39. The method of any one of claims 29 to 38, wherein the antibody inhibits activation of C5.

40. The method of any one of claims 29 to 39, wherein the antibody inhibits activation of C5 variant R885H.

41. The method of any one of claims 29 to 40, wherein the antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8.

42. The method of any one of claims 29 to 41, wherein the antibody is a full length IgGI or IgG4 antibody.

Chugai Seiyaku Kabushiki Kaisha

Patent Attorneys for the Applicant/Nominated Person

SPRUSON&FERGUSON

Max (1.59) Min (0.07)

1.06 0.52 0.84 0.74 0.62 0.58 0.71 0.89 0.95 0.82 0.84 0.69 0.92 0.86 0.54 1.02 1.28 1.23 1.23 1.32 0.36 1.3 0.8 0.8 0.5 0.4

1.28 1.29 1.11 1.21 0.93 0.99 1.36 1.03 1.09 1.13 0.98 0.88 0.91 0.91 1.21 1.16 0.65 1.57 1.3 1.39 APPLICATION 1.3 1.1 1.2 1.2 REPRESENTATIVE 1.15 1.18 1.08 1.08 0.99 0.73 0.95 1.11 0,91 1.16 1.17 1.08 1.02 0.92 0.96 1.32 1.27 0.99 0.91 1.19 1.34 1.08 1.35 0.9 REQUIREMENTS 04306707089088088097113114088117101 0.070.0802031 1.25 1.38 1.13 1.22 1.22 1.33 1.08 1.37 1.15 0.97 0.99 1.02 0.94 0.75 1,26 1.13 1.33 1.17 1.42 0.43 0.8 1.3 0.3

1.17 1.41 1.34 1.35 1.28 1.38 1.13 1.36 1,37 1.17 1.17 1.25 1.13 1.11 0.95 1.31 1.36 1.29 1.47 1.26 0.41 1.38 1.29 1.2 0.7 REPRESENTATIVE 1.33 1.29 1.25 1.09 1.19 1.28 0.79 1.21 1.08 1.16 1.19 1.14 1.05 1.36 1.34 1.26 1.43 1.31 1.39 1.14 1.2 1.2 1.3 13 1.33 1.36 1.27 1.28 1.33 1.34 1.03 1.35 1.04 1.16 1.14 1.19 1.14 1.01 1.08 1.28 1.24 0.39 1.41 1.29 1.38 1.02 1.2 0.3 1.2

0.98 1.17 1.14 1.13 0.96 1.28 1.24 0.28 1.22 1.43 1.19 REQUIREMENTS 1.32 1.32 1.14 1.21 1.33 1.38 1.29 1.16 1.2

1.13 1.17 0.97 1.18 1.12 0.98 0.72 0.56 0.59 0.51 0.52 1.31 1.27 1.15 1.28 1.02 1.1 0.4 0.2 REPRESENTATIVE 1.27 1.24 1.01 1.08 0.94 1.08 0.71 1.27 1.06 0.56 1.45 1.27 1.19 1.33 1.29 1.19 0.4 1,2 0.8

Capture antibody

1.27 1.26 1.14 1.06 1.02 1.16 0.79 1.31 0.55 0.43 0.57 0.41 0.18 0.62 1.25 1.48 1.29 1.24 1.36 1.32 1.29 1.1

1.27 1.35 1.18 1.07 1.03 1.13 0.73 0.33 0.25 1.54 1.27 1.21 1.33 1.33 1.28 0.99 1.21

1.43 1.17 0.61 0.89 0.92 0,61 1.04 0.59 0.58 0,37 0.19 1.49 1.41 1.17 1.31 1.25 1.28 1.07

0.59 1.13 1.22 0.78 0.57 0.95 0.95 0.47 0.55 0.55 0.36 0.15 1.45 1.21 1.03 1.23 1.23 1.07 0.71 0.5 1.2

0.95 0.96 0.44 0.57 0.41 0.41 0,68 0.63 0.42 0.43 0.39 0.49 0.35 0.15 0.56 1.07 1.08 0.88 1.21 0.96 0.3 0.5

0.45 0.44 0.46 0.25 0.32 0.35 0.38 0.29 0.14 0.42 0.39 1.16 1.03 0.76 1.02 1.03 0.8 0.6 0.3 0.4

0.65 0.66 0.31 0.33 0.29 0.39 0.18 0.44 0.44 0.28 0.27 0.26 0.31 0.22 0.11 0.36 0.33 1.01 0.64 0.96 0.91 0.3

1.17 1.19 0.12 1.21 1.25 1.13 1.36 1 1.26 1.16 1.44 1.29 1.28 REQUIREMENT 1.1 MEMBERSHIP 1.29 1 1.18 1.32 0.13 0.07 0.08 0.08 0.09 1.1 0.89 1.28 1.22 1.29 1.18 1.59 1.28 1.18 1.49 1.31 1.3 DECLARATION 0.75 1.06 0.12 0.07 0.07 0.07 0.08 0.79 0.98 0.64 1.14 1.08 1.22 1.17 1.11 1.39 1.24 1.12 0.1 0.1 1.2 1.4 0.9

0.09 0.23 0.08 0.08 0.08 0.08 0.44 0.26 0.19 0.68 0.85 0.89 0.96 0.73 REPLACEMENTS 0.07 0.08 0.79 1.05 0.81 0.3 0.1

0.16 0.12 0.19 0.11 0.07 0.08 0.08 0.07 0.08 0.09 0.82 0.76 0.75 0.57 0.59 1.12 0.95 1.27 1.53 1.42 1.18 1.28 1.22 0.82 INFORMATION 1.1 1.5

0.63 0.11 0.08 0.62 0.29 0.26 0.82 0.75 1.05 1.22 1.22 1.02 1.35 1.05 0.95 0.57 0.5

1.29 0.68 1.27 1.28 1.36 1.22 MEDICATIONS 0.12 0.08 0.08 0.07 0.07 0.08 0.93 0.91 0.75 1.23 1.07 1.51 1.45 1.37 1.27 0.9

1 0.12 0.11

0.09 0.69 0.15 0.32 0.83 0.62 0.52 0.55 0.52 0.52 0.08 0.29 0.86 0.73 0.89 0.89 1.17 0.79 1.16 0.91 0.88 0.6 0.6 1.36 1139 0 1.28 11.07 (

0.08 0.09 0.08 0.97 0.59 1.06 0.96 1.04 1.09 0.86 1.28 1.21 1.26 1.28 1 1.42 11.47 1.34 11.33 1.28 1.25

1.46 1.3

0.08 0.11 0.77 0.72 0.29 0.42 1.16 1.06 1.26 1.21 1.25 1.28 0.62 1.33 1.26 1.21 1.28 1.45 1.33 0.1 0.5 CFA0318-F760G4 CFA0272-F760G4 CFA0307-F760G4 CFA0217-F760G4 CFA0328-F760G4 CFA0635-F760G4 CFA0330-F760G4 CFA0305-F760G4 CFA0501-F760G4 CFA0579-F760G4 CFA0319-F760G4 CFA0322-F760G4 CFA0341-F760G4 CFA0647-F760G4 CFA0639-F760G4 CFA0366-F760G4 CFA0675-F760G4 CFA0672-F760G4 CFA0329-F760G4 CFA0666-F760G4 Eculizumab-F760G4 CFA0359-F760G4 CFA0599-F760G4 CFA0538-F760G4 CFA0589-F760G4 CFA0668-F760G4 CFA0334-F760G4

420 420

pH7.4 pH5.8 S pH7.4 pH5.8 S pH7.4 pH5.8 S

360 360 360

baseline) = (0 Time 300 300 300

baseline) = (0 Time baseline) = (0 Time sensorgram Adjusted sensorgram Adjusted sensorgram Adjusted 240 240 240

180 180 180

120 120 120

CFA0538

CFA0501

CFA0599

60 60 60

RU RU 200 150 100 50 0 -50 200 150 100 50 0 -50 RU 200 150 100 50 0 -50

0 0 0

420 420 420

pH7.4 pH5.8 S pH7.4 pH5.8 S pH7.4 pH5.8 S

360 360 360

baseline) = (0 Time baseline) = (0 Time baseline) = (0 Time 300 300 300 sensorgram Adjusted sensorgram Adjusted sensorgram Adjusted 240 240 240

180 180 180

120 120 120

CFA0307

CFA0366

CFA0305

60 60 60

RU 200 150 100 50 0 -50 RU 200 150 100 50 0 -50 RU 200 150 100 50 0 -50

0 0 0 pH7.4 pH5.8

420 420 420 pH7.4 pH5.8

S pH7.4 pH5.8 S S

360 360 360

baseline) = (0 Time baseline) = (0 Time 300

baseline) = (0 Time 300 300

sensorgram Adjusted sensorgram Adjusted sensorgram Adjusted 240 240 240

180 180 180

120 120 120

CFA0341

CFA0330

305-L05

60 60 60

RU 200 150 100 50 -50 0 RU 200 150 100 50 -50 0 RU 200 150 100 50 -50 0 0 0 0

420 420 420

pH7.4 pH5.8 S pH7.4 pH5.8 S pH7.4 pH5.8 S

360 360 360

baseline) = (0 Time 300 baseline) = (0 Time baseline) = (0 Time 300 300 sensorgram Adjusted sensorgram Adjusted sensorgram Adjusted 240 240 240

180 180 180

120 120 120

CFA0666

CFA0675

CFA0672

60 60 60

RU 200 150 100 50 -50 0 RU 200 150 100 50 -50 0 RU 200 150 100 -50 0 50 0 0 0

CFA0675

CFA0501

kDa 250 150 100 75 50 37 25 20 15 kDa 250 150 100 75 50 37 25 20 15 CFA0672

CFA0366

250kD

150 100 kDa 250 150 100 75 50 37 25 20 15 75 50 37 25 20 15 CFA0666

CFA0307

kDa 250 150 100 250 150 100 75 50 37 25 20 15 kDa 75 50 37 25 20 15

CFA0599 CFA0305

250kD

150 100 kDa 250 150 100 75 50 37 25 20 15 75 50 37 25 20 15

CFA0538 Anti-GST

kDa 250 150 100 150 100 75 50 37 25 20 15 kDa 250 75 50 37 25 20 15