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WO2010057242A2 - Vaccin - Google Patents

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Publication number
WO2010057242A2
WO2010057242A2 PCT/AT2009/000452 AT2009000452W WO2010057242A2 WO 2010057242 A2 WO2010057242 A2 WO 2010057242A2 AT 2009000452 W AT2009000452 W AT 2009000452W WO 2010057242 A2 WO2010057242 A2 WO 2010057242A2
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WO
WIPO (PCT)
Prior art keywords
seq
peptide
vaccine
antibodies
pcsk9
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/AT2009/000452
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German (de)
English (en)
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WO2010057242A3 (fr
Inventor
Sylvia Brunner
Pola Linzmayer-Hirt
Walter Schmidt
Bettina Wanko
Gabriele Winsauer
Christina Woess
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Affiris AG
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Affiris AG
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Publication date
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Publication of WO2010057242A2 publication Critical patent/WO2010057242A2/fr
Publication of WO2010057242A3 publication Critical patent/WO2010057242A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0012—Lipids; Lipoproteins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6081—Albumin; Keyhole limpet haemocyanin [KLH]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a vaccine for the treatment or prevention of health problems which may be caused by atherosclerosis, in particular stroke, cardiovascular diseases (which may lead to myocardial infarction), and peripheral vascular disease.
  • Atherosclerosis is characterized, among other things, by the deposition of lipid particles in large arteries. In a multi-stage process that continues for many years to decades, atherosclerosis leads to narrowing of the affected vessels. Depending on the location of the vessels cardiovascular diseases (heart attack), stroke and peripheral vascular diseases may result.
  • a major cause of atherosclerosis is lifestyle-related (low-exercise, high-fat diet, smoking) and / or genetic factors related to lipid metabolism, i. Too high total cholesterol or in particular to high levels of LDLc ("low density lipoprotein cholesterol”) in combination with low HDLc values ("High Density Lipoprotein Cholesterol").
  • ADH autosomal dominant hypercholesterolemia
  • LDLR LDL receptor
  • apolipoprotein B-100 the ligand for the LDLR
  • PCSK9 protein convertingase PCSK9
  • PC secretory proprotein
  • subtilisin-like serine proteases "subtilisin-like serine proteina- ses w”
  • PCl / 3 PC2, furin, PC4, PC5 / 6, PACE4 and PC7
  • SKI-1 / S1P and PCSK9 also called NARC-I ("neural apoptosis-regulated convertase 1"
  • the convertases are expressed in the brain and peripheral organs. You have different radio For example, for the production of neuropeptides, growth factors, cytokines, receptors, in cell adhesion and cell migration as well as growth and differentiation of progenitor cells. Many convertases are known to play a role in diseases such as cancer or viral infections. Conditional shedding of PC5 / 6 in mice leads to malformations and bone defects in embryos, which is probably due to lack of processing of growth differentiation factor 11 ("growth differentiation factor 11").
  • Some members of the convertase family also affect the lipid metabolism:
  • PCSK9 inactivates the Low Density Lipoprotein Receptor (LDLR).
  • LDLR Low Density Lipoprotein Receptor
  • the gene for the human PCSK9 protein is located on chromosome Ip32.3.
  • the gene is approximately 22 kilo base pairs long and encodes a 692 amino acid (AS) long glycoprotein.
  • the expression of PCSK9 is regulated by sterol regulatory element binding proteins (SREBPs) and statins, which is also the case for other genes important in cholesterol metabolism.
  • SREBPs sterol regulatory element binding proteins
  • statins which is also the case for other genes important in cholesterol metabolism.
  • PCSK9 is mainly expressed in the liver but also in the small intestine and kidney and secreted.
  • the 74 kDa pro-protein is autocatalytically processed in the endoplasmic reticulum, producing the approximately 60 kDa protein.
  • PCSK9 consists of
  • PCSK9 plays a crucial role in cholesterol metabolism as it directly regulates the amount of LDLR present on liver cells.
  • the LDLR is a glycoprotein located in the plasma membrane that removes cholesterol-rich LDLc particles from the plasma by endocytosis.
  • the binding of PCSK9 leads to the uptake of LDLR into liver cells and subsequently its degradation into lysosomes as opposed to recycling to the cell surface that would occur without the binding of PCSK9.
  • PCSK9 seems to have an influence on the receptors for ApoE (ApoER2) and VLDL (Very Low Density Lipoprotein).
  • LDLc hypercholesterolemia
  • atherosclerotic coronary heart disease coronary artery disease
  • LDLLR Low-density lipoprotein
  • Nonsense” mutations are common in some populations, eg, about 2% of African Americans have one of two mutations leading to a -30% reduction in LDLc levels, and a "missense” mutation is known in Caucasians which lowers the LDLc by ⁇ 15%. These lower LDLc levels lead to a significantly reduced incidence of CHD.
  • PCSK9 knock-out mice have more LDLR on their liver cells and reduced levels of plasma LDLc, and the inhibition of PCSK9 also leads to a significant reduction in total cholesterol and LDLc in mice fed on high-fat foods the amount of LDLR in the liver is doubled.
  • PCSK9 Congenital homozygous "knock-out" of PCSK9 leads in humans to extremely low levels of LDLc with no noticeable side effects.
  • the inhibition of PCSK9, for example, by antisense oligonucleotides, small molecule inhibitors or antibodies, is therefore an attractive target to reduce the effects of atherosclerosis, particularly cardiovascular disease, as a stand-alone therapy as well in combination with, for example, statins (which upregulate the PCSK9 protein) or with drugs that affect HDLc levels.
  • the present invention relates to a vaccine comprising at least one peptide with a minimum length of 7 amino acids derived from the amino acid sequence TLGTNFGRCVDLFAPGEDII- GASSDCSTCFVSQSGTSQAAAHVAGIA (SEQ ID NO: 1), wherein the peptide has the amino acid sequence DIIGA (SEQ ID NO: 2) and / or CFVSQSG (SEQ ID No. 3) of SEQ ID NO: 1.
  • peptides of at least 7 amino acid residues derived from SEQ ID NO: 1 and comprising either SEQ ID NO: 2 or SEQ ID NO: 3 are capable of forming in a mammal and in a human of antibodies directed against PCSK9.
  • the antibodies produced by administration are capable of binding to a portion of PCKS9 responsible for the binding of PCKS9 to the LDL receptor. This is to prevent the PCSK9-mediated degradation of LDLR and reduce the amount of LDLc, which in turn means that diseases that are the result of an elevated LDLc level (eg cardiovascular diseases), can be treated or treated as a preventive measure could be.
  • the peptide according to the invention which comprises both SEQ ID No. 2 and SEQ ID No. 3, likewise has the amino acid residues located between the two sequences and derived from SEQ ID No. 1.
  • derived peptide refers to peptide fragments of SEQ ID NO: 1 which are at least 7 amino acid residues in length, which peptides may also have a minimum length of 8, 9, 10, 11 or 12 amino acids
  • the peptides of the invention comprise at most 47, 45, 43, 40 or 35 amino acids
  • Preferred peptides have a length of 8 to 20, more preferably 9 to 17, in particular 10 to 15, amino acids.
  • the peptide is selected from the group consisting of IIGASSDCSTCFVSQSG (SEQ ID NO: 5), DLFAPGEDIIGASSDC (SEQ ID NO: 6), STCFVSQSGTSQAAAH (SEQ ID NO: 7), LFAPGEDIIGASSDC (SEQ ID NO: 5).
  • FAPGEDIIGASSDC SEQ ID NO: 9
  • APGEDIIGASSDC SEQ ID NO: 10
  • PGEDIIGAC SEQ ID NO: 11
  • GEDIIGASSDC SEQ ID NO: 12
  • EDIIGASSDC SEQ ID NO: 13
  • DIIGASSDC SEQ ID NO: 14
  • STCFVSQSGTSQAAA SEQ ID NO: 15
  • STCFVSQSGTSQAA SEQ ID NO: 16
  • STCFVSQSGTSQA SEQ ID NO: 17
  • STCFVSQSGTSQ SEQ ID NO: 18
  • STCFVSQSGTS SEQ ID NO: 17
  • STCFVSQSGT SEQ ID NO: 20
  • STCFVSQSG SEQ ID NO: 21
  • TCFVSQSGT SEQ ID NO: 22
  • CFVSQSG SEQ ID NO: 23
  • the peptide STCFVSQSGTSQAAAH SEQ ID NO: 7
  • its C-terminal deletion derivatives having at least 9 amino acids SEQ ID NO: 21
  • the peptide according to the invention preferably has a cysteine residue at the C-terminus and / or at the N-terminus, a cysteine residue can e.g. also be added at the N and / or C terminus.
  • Cysteine residues can be used, for example, for the cyclization of the peptides.
  • further substances can be coupled to the SH groups of the cysteine residues, preferably to the N- or C-terminal cysteine residues.
  • the cysteine residue may be a naturally occurring cysteine residue at this site or it may be attached at the N or C terminus of a sequence derived from the native sequence. Of course, it is also possible to couple via an internal cysteine.
  • the peptide according to the invention is coupled to a pharmaceutically acceptable carrier, preferably to KLH (keyhole limpet hemocyanin) (eg with NHS-PEO4 maleimides or other to those skilled in the art known suitable linkers)), tetanus toxoid, albumin binding protein, serum albumin, a dendrimer (MAP, Biol., Chem. 358: 581), peptide linkers (or flanking regions), and adjuvant substances described in Singh et al. , Nat. Biotech. 17 (1999): 1075-1081 (especially those in Table 1 of this document) and O 'Hagan et al. , Nature Reviews Drug Discovery 2 (9) (2003): 727-735 (in particular, the endogenous immunopotentiating compounds and delivery systems described therein) or mixtures thereof.
  • KLH keyhole limpet hemocyanin
  • MAP Biol., Chem. 358: 581
  • peptide linkers or flanking regions
  • the vaccine composition can be formulated with an adjuvant, preferably a sparingly soluble aluminum composition, especially aluminum hydroxide.
  • adjuvants such as MF59, aluminum phosphate, calcium phosphate, cytokines (eg IL-2, IL-12, GM-CSF), saponins (eg QS21), MDP derivatives, CpG oligos, LPS, MPL, polyphosphazenes, emulsions can also be used (eg, Freund's adjuvant, SAF), liposomes, virosomes, iscome, cochleates, PLG microparticles, poloxamer particles, virus-like particles, heat-labile enterotoxin (LT), cholera toxin (CT), mutant toxins (eg LTK63 and LTR72) , Microparticles and / or polymerized liposomes.
  • Suitable adjuvants may be, for example, Purcell W et al. (Nature Reviews Drug Discovery 6 (2007): 404-414), especially Box 2.
  • the compound of the present invention is preferably linked to the carrier or adjuvant via a linker selected from the group consisting of NHS-poly (ethylene oxide) (PEO) (eg, NHS-PEO 4 -maleimide).
  • PEO poly (ethylene oxide)
  • the conjugation chemistry eg via heterobifunctional compounds, such as GMBS, and of course also others, as described, for example, in "Bioconjugate Techniques", Greg T. Hermanson
  • Conjugation is preferably established via the N- or C-terminal cysteine residue (s).
  • the peptide is formulated for intradermal, subcutaneous or intramuscular administration to humans.
  • a vaccine comprising the peptide of the invention may be administered in any suitable manner, for example, id, iV, ip, im, intranasally, orally, subcutaneously, etc., and with any suitable delivery device (O'Hagan et al., Nature Reviews Drug Discovery 2 (9) (2003): 727-735).
  • the peptide The present invention is particularly preferably formulated for intravenous, subcutaneous, intradermal or intramuscular administration (see, for example, "Handbook of Pharmaceutical Manufacturing Formulations", Sarfaraz Niazi, CRC Press Ine, 2004).
  • the vaccine will contain the peptide of the invention in an amount of 0.1 ng to 10 mg, preferably 10 ng to 1 mg, especially 100 ng to 100 ⁇ g, or alternatively, e.g. 100 fmol to 10 .mu.mol, preferably 10 pmol to 1 .mu.mol, in particular 100 pmol to 100 nmol.
  • the vaccine may also contain adjuvant substances, e.g. Buffers, stabilizers, etc. included.
  • the vaccine according to the invention is suitable for the treatment and / or prevention of cardiovascular diseases and other disorders caused by atherosclerosis, in particular cardiovascular diseases, strokes and peripheral vascular diseases (see Pschyrembel, Clinical Dictionary, 261).
  • Another aspect of the present patent application relates to a peptide as defined above.
  • the present invention relates not only to a vaccine of the type described above but also the peptides contained therein.
  • the peptides according to the invention are suitable for the treatment and / or prevention of diseases caused by atherosclerosis, in particular stroke, cardiovascular diseases and disorders of peripheral vessels.
  • Another aspect of the present invention relates to an isolated antibody directed against a peptide of the invention.
  • antibodies which are capable of binding to these peptides are also possible to use antibodies which are capable of binding to these peptides. Such antibodies not only bind to the peptides but also to the PCSK9 protein present in the body.
  • the antibodies according to the present invention are preferably monoclonal antibodies.
  • Such antibodies which are homogeneous populations of antibodies to a particular antigen, can be obtained by any technique that allows the production of antibody molecules. These include, for example, the hybridoma technique of Kohler and Milstein (Nature 256 (1975): 495-497 and US Pat. No. 4,376,110), the human B-cell hybridoma technique (Kosbor et al., Immunology Today 4 (1983): 72; CoIe et al. , Proc. Natl. Acad. Be. USA 80 (1983): 2026-2030) and the EBV hybridoma technique (CoIe et al., Monoclonal Antibodies and Cancer Therapy, Alan R.
  • Such antibodies may belong to any immunoglobulin class, including IgG, IgM, IgE, IgA, IgD, and any subclass thereof.
  • the hybridoma producing the mAb of this invention can be cultured in vitro or in vivo.
  • monoclonal antibodies by recombinant technologies in eukaryotic, yeast, insect and plant cells and in plants. These expression systems as well as the methods for isolating these antibodies from the cells are well known in the art.
  • humanized monoclonal antibodies or functional parts thereof Fab, single-chain antibodies, etc., which are able to recognize the peptides according to the invention are particularly preferred.
  • a further aspect of the present invention relates to the use of a peptide or antibody according to the invention for the manufacture of a medicament for the treatment and / or prevention of disorders caused by atherosclerosis, in particular stroke, cardiovascular diseases and diseases of the peripheral vessels.
  • Fig. 1 shows the detection of PCK9-specific antibodies in mice after administration of a peptide having the amino acid sequence SEQ ID NO. 6 by ELISA.
  • Fig. 2 shows the detection of PCK9-specific antibodies in mice after administration of a peptide having the amino acid sequence SEQ ID NO: 27 by ELISA.
  • Figures 3 to 9 show the detection of PCK9-specific antibodies in mice after administration of a peptide having the amino acid sequences SEQ ID NOS: 8 to 14 by ELISA.
  • Fig. 10 shows the detection of PCK9-specific antibodies in mice after administration of a peptide having the amino acid sequence SEQ ID NO: 24 by ELISA.
  • Fig. 11 shows the detection of PCK9-specific antibodies in mice after administration of a peptide having the amino acid sequence SEQ ID NO: 7 by means of ELISA.
  • Figures 12 to 20 show the detection of PCK9-specific antibodies in mice after administration of a peptide having the amino acid sequence SEQ ID Nos. 15 to 23 by means of EDISA.
  • Figure 21 shows the detection of PCK9-specific antibodies in mice after administration of a peptide having the amino acid sequence SEQ ID NO: 25 by ELISA.
  • Fig. 22 shows an ELISA in which purified mouse monoclonal antibodies generated after immunization with SEQ ID NO: 7 were added to the immunized peptide sequence as well as to truncations of this peptide (SEQ ID NOs: 21, 22, 23 and 25).
  • the table shows the raw ELISA data of Figure 22.
  • the binding of monoclonal anti-PCSK9 antibodies to various peptides was tested in order to further determine the binding site of the antibodies.
  • An antibody should preferably not only bind to the C-terminus, therefore all antibodies that recognize the tested peptides are in principle suitable.
  • the raw ELISA data are Figure 23 shown.
  • the signal strengths of defined amounts of monoclonal anti-PCSK9 antibodies to recombinantly produced PCSK9 protein were compared in the ELISA, the signal strengths being reduced to a dilution of 15.6 ng / ml of antibody.
  • Figures 24 and 25 show the detection of antibodies to the administered peptides (STCFVSQSGT-C, IIGASSDCSTCFVSQS, CIGIGDCSTCFVSQS, and IIGASSDCSTCFVSQS-C) in mice after peptide injection by peptide ELISA to measure antibody titers ( Figure 24) ) and the detection of PCSK9-specific antibodies by PCSK9 protein ELISA in these sera (the sera were diluted 1: 100 and 1: 400, Fig. 25).
  • the peptides were coupled to KLH via GMBS 4-maleimidobutyric acid N-hydroxysuccinimide ester. 30 ⁇ g of these conjugates (the amount refers to the peptide) were mixed with aluminum hydroxide (final Alum concentration 0.2%). The buffer used was PBS.
  • mice Balb / c or C57B1 / 6 mice were immunized subcutaneously (in the flank). Number of injections 2 to 4 times. The interval between immunizations was 1 week to 6 weeks. The injection volume per mouse was between 200 ⁇ l and 1 ml. Blood was drawn 2 weeks after immunization.
  • Serum or plasma of the immunized mice was tested by ELISA for antibodies against the immunized peptide and for antibodies to the PCSK9 protein.
  • microtiter plates were coated with peptide (coupled to BSA) or protein
  • the said peptides were coupled to BSA and coated on ELISA plates. Subsequently, the monoclonal antibodies were added to the plates. The binding of antibodies to the peptides was standardized by means of biotinylated polyclonal anti-mouse IgG antibody (detection antibody) and subsequent parabolic reaction (streptavidin-HRP ("Horse Raddish peroxidase *); ABTS (2,2'-azino-bis (3 ethylbenzothiazoline-6-sulfonic acid) for the color reaction, measured at OD 405 nm).
  • the monoclonal mouse anti-hu PCSK9 antibodies shown in Figure 22 were applied in different amounts (7.8 to 500 ng / ml respectively) to an ELISA plate coated with recombinantly produced PCSK9 protein.
  • the detection of bound antibodies was carried out with biotinylated anti-mouse IgG and streptavidin-HRP. After addition of the substrate (ABTS), the OD was measured at 405 nm.
  • the signal strength of the different antibodies was compared. The higher the signal, the stronger the antibody being tested binds to the PCSK9 protein.
  • This ELISA can be used to select for subsequent experiments those antibodies which bind as strongly as possible to the target protein.
  • Example 3 As strongly binding antibodies in this ELISA those were designated, which exhibit an OD of more than 1.2 even with a dilution of 15.6 ng / ml, OD between 0.4 and 1.2 is designated as medium signal, among them as weak signal. Preferably, antibodies with the highest possible signal were used in further experiments.
  • Example 3 As strongly binding antibodies in this ELISA those were designated, which exhibit an OD of more than 1.2 even with a dilution of 15.6 ng / ml, OD between 0.4 and 1.2 is designated as medium signal, among them as weak signal. Preferably, antibodies with the highest possible signal were used in further experiments.
  • Example 3 Example 3:
  • mice each were vaccinated with the peptides described in FIGS. 24 and 25 (coupled to KLH and mixed with alum) and the sera were analyzed after 1, 2, and 3 injections by means of peptide ELISA for the measurement of the antibody titer.
  • the sera with comparably high anti-peptide titers were subsequently tested for PCSK9-specific antibodies by means of PCSK9 protein ELISA. investigated for the ability of the peptides to induce PCSK9-specific antibodies.

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Abstract

L'invention concerne un vaccin comportant au moins un peptide dérivé de la séquence d'acide aminé TLGTNFGRCVDLFAPGEDII- GASSDCSTCFVSQSGTSQAAAHVAGIA (SÉQ ID N°1) et présentant une longueur minimale de 7 acides aminés, le peptide comportant également la séquence d'acide aminé DIIGA (SÉQ ID N°2) et/ou CFVSQSG (SÉQ ID N°3) de la SÉQ ID Nr. 1.
PCT/AT2009/000452 2008-11-19 2009-11-19 Vaccin Ceased WO2010057242A2 (fr)

Applications Claiming Priority (2)

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ATA1800/2008 2008-11-19
AT0180008A AT507604A1 (de) 2008-11-19 2008-11-19 Behandlung von atherosklerose

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WO2010057242A2 true WO2010057242A2 (fr) 2010-05-27
WO2010057242A3 WO2010057242A3 (fr) 2010-09-16

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
WO2011117401A1 (fr) * 2010-03-25 2011-09-29 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.R.L. Utilisation de pcsk9 en tant que vaccin permettant d'abaisser le niveau de cholestérol
EP2450382A1 (fr) * 2010-11-04 2012-05-09 Affiris AG Peptide immunogène
EP2532359A1 (fr) 2011-06-10 2012-12-12 Affiris AG Fragments de CETP
EP2570135A1 (fr) * 2011-09-13 2013-03-20 Affiris AG Vaccin
US8889144B2 (en) 2009-09-03 2014-11-18 Pfizer Vaccines Llc PCSK9 vaccine
WO2015123291A1 (fr) * 2014-02-11 2015-08-20 The Usa, As Represented By The Secretary, Dept. Of Health And Human Services Vaccin à base de pcsk9 et méthodes d'utilisation dudit vaccin
US10557129B2 (en) * 2015-01-30 2020-02-11 Pronasci Inc. Peptides derived from human PCSK9 catalytic domain and uses thereof for promoting LDL-R activity

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US7572618B2 (en) * 2006-06-30 2009-08-11 Bristol-Myers Squibb Company Polynucleotides encoding novel PCSK9 variants
EP2083861A4 (fr) * 2006-11-07 2010-11-24 Merck Sharp & Dohme Antagonistes de pcsk9
WO2008125623A2 (fr) * 2007-04-13 2008-10-23 Novartis Ag Molécules et procédés de modulation de proprotéine convertase subtilisine/kexine de type 9 (pcsk9)

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COLE ET AL.: "Monoclonal Antibodies and Cancer Therapy", 1985, ALAN R. LISS, INC., pages: 77 - 96
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KOSBOR ET AL., IMMUNOLOGY TODAY, vol. 4, 1983, pages 72
O'HAGAN ET AL., NATURE REVIEWS DRUG DISCOVERY, vol. 2, no. 9, 2003, pages 727 - 735
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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8889144B2 (en) 2009-09-03 2014-11-18 Pfizer Vaccines Llc PCSK9 vaccine
US9987341B2 (en) 2009-09-03 2018-06-05 Pfizer Vaccines Llc PCSK9 vaccine
US9481875B2 (en) 2009-09-03 2016-11-01 Pfizer Vaccines Llc PCSK9 vaccine
WO2011117401A1 (fr) * 2010-03-25 2011-09-29 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.R.L. Utilisation de pcsk9 en tant que vaccin permettant d'abaisser le niveau de cholestérol
EP2450382A1 (fr) * 2010-11-04 2012-05-09 Affiris AG Peptide immunogène
WO2012059573A1 (fr) * 2010-11-04 2012-05-10 Affiris Ag Peptide immunogène
WO2012168486A1 (fr) 2011-06-10 2012-12-13 Affiris Ag Fragments de cetp
EP2532359A1 (fr) 2011-06-10 2012-12-12 Affiris AG Fragments de CETP
WO2013037889A3 (fr) * 2011-09-13 2013-05-10 Affiris Ag Vaccin
JP2014527078A (ja) * 2011-09-13 2014-10-09 アフィリス・アクチェンゲゼルシャフト ワクチン
WO2013037889A2 (fr) 2011-09-13 2013-03-21 Affiris Ag Vaccin
US9220762B2 (en) 2011-09-13 2015-12-29 Affiris Ag PCSK9 peptide combination vaccine and method of use
EP2570135A1 (fr) * 2011-09-13 2013-03-20 Affiris AG Vaccin
US9669079B2 (en) 2011-09-13 2017-06-06 Affiris Ag PCSK9 peptide combination vaccine and method of use
WO2015123291A1 (fr) * 2014-02-11 2015-08-20 The Usa, As Represented By The Secretary, Dept. Of Health And Human Services Vaccin à base de pcsk9 et méthodes d'utilisation dudit vaccin
US10279019B2 (en) 2014-02-11 2019-05-07 Stc.Unm PCSK9 peptide vaccine conjugated to a Qbeta carrier and methods of using the same
US10925938B2 (en) 2014-02-11 2021-02-23 The Usa, As Represented By The Secretary, Dept. Of Health And Human Services Composition comprising PCSK9 peptide conjugated to a Qbeta carrier and methods of using the same
US11696941B2 (en) 2014-02-11 2023-07-11 The Usa, As Represented By The Secretary, Dept. Of Health And Human Services Compositions comprising a PCSK9 peptide conjugated to a qbeta carrier and methods of using the same
US10557129B2 (en) * 2015-01-30 2020-02-11 Pronasci Inc. Peptides derived from human PCSK9 catalytic domain and uses thereof for promoting LDL-R activity

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