IES20140321A2

IES20140321A2 - An injectable antibody preparation for use in reducing or maintaining previously reduced cholesterol level

Info

Publication number: IES20140321A2
Application number: IES20140321A
Authority: IE
Inventors: Jasper Clube
Original assignee: Kymab Ltd
Priority date: 2014-07-15
Filing date: 2014-12-22
Publication date: 2016-01-27
Also published as: IES86623B2

Abstract

An injectable preparation comprising an antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human. The antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO: 1. The antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an amino acid selected from the group consisting of an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42. The human comprises an IGHG1*01 human heavy chain constant region gene segment or the human expresses antibodies comprising a human gamma-1 heavy chain constant region that comprises said amino acid. The human further comprises a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation in SEQ ID NO: 1.

Description

| LOOPED [liman TARGETS III TECHNICAL FIELD id="p-1" id="p-1"

[0001] The technology described herein relates to ligands, e.g., antibodies for the treatment of disease.

BACKGROUND id="p-2" id="p-2"

[0002] It is recognized that individual humans differ in their sequence and recently several individuals have had their genomes sequenced, for instance James Watson and Craig Venter. Comparison of the genome sequence of individuals has revealed differences in their sequences in both coding and non-coding parts of the genome. Some of these variations in humans are significant and contribute to phenotypic differences between individuals. In extreme cases these will result in genetic disease. The 1000 Genomes Project has the objective of cataloguing sequences in the human genome, involving sequencing the genomes of a very large sampling of individuals from diverse art-recognized human ethnic populations. [0003] Proprotein convertase subtilisin kexin type 9 (PCSK9) is a serine protease involved in regulating the levels of the low density lipoprotein receptor (LDLR) protein (Horton et al., 2007; Seidah and Prat, 2007). In vitro experiments have shown that adding PCSK9 to HepG2 cells lowers the levels of cell surface LDLR (Benjannet et al., 2004; Lagace et al., 2006; Maxwell et al., 2005; Park et al., 2004). Experiments with mice have shown that increasing PCSK9 protein levels decreases levels of LDLR protein in the liver (Benjannet et al., 2004; Lagace et al., 2006; Maxwell et al., 2005; Park et al., 2004), while PCSK9 knockout mice have increased levels of LDLR in the liver (Rashid et al., 2005). Additionally, various human PCSK9 mutations that result in either increased or decreased levels of plasma LDL have been identified (Kotowski et al., 2006; Zhao et al., 2006). PCSK9 has been shown to directly interact with the LDLR protein, be endocytosed along with the LDLR, and co-immunofluoresce with the LDLR throughout the endosomal pathway (Lagace et al., 2006). id="p-4" id="p-4"

[0004] PCSK9 is a prohormone-proprotein convertase in the subtilisin (S8) family of serine proteases (Seidah et al., 2003). Humans have nine prohormone-proprotein convertases that can be divided between the S8A and S8B subfamilies (Rawlings et al., 2006). Furin, PC1/PC3, PC2, PACE4, PC4, PC5/PC6 and PC7/PC8/LPC/SPC7 are classified in subfamily S8B. Crystal and NMR structures of different domains from mouse furin and PCI reveal subtilisinlike pro- and catalytic domains, and a P domain directly C-terminal to the catalytic domain (Henrich et al., 2003; Tangrea et al., 2002). Based on the amino acid sequence similarity within this subfamily, all seven members are predicted to have similar structures (Henrich et 18936261 1 al., 2005). SKI-1/S1P and PCSK9 are classified in subfamily S8A. Sequence comparisons with these proteins also suggest the presence of subtilisin-like pro- and catalytic domains (Sakai et al., 1998; Seidah et al., 2003; Seidah et al., 1999). In these proteins the amino acid sequence C-terminal to the catalytic domain is more variable and does not suggest the presence of a P domain. id="p-5" id="p-5"

[0005] Prohormone-proprotein convertases are expressed as zymogens and they mature through a multi step process. The function of the pro-domain in this process is twofold. The pro-domain first acts as a chaperone and is required for proper folding of the catalytic domain (Ikemura et al., 1987). Once the catalytic domain is folded, autocatalysis occurs between the pro-domain and catalytic domain. Following this initial cleavage reaction, the pro-domain remains bound to the catalytic domain where it then acts as an inhibitor of catalytic activity (Fu et al., 2000). When conditions are correct, maturation proceeds with a second autocatalytic event at a site within the pro-domain (Anderson et al., 1997). After this second cleavage event occurs the pro-domain and catalytic domain dissociate, giving rise to an active protease. id="p-6" id="p-6"

[0006] Autocatalysis of the PCSK9 zymogen occurs between Glnl52 and Serl53 (VFAQ|SIP (SEQ ID NO: 67))(Naureckiene et al., 2003), and has been shown to be required for its secretion from cells (Seidah et al., 2003). A second autocatalytic event at a site within PCSK9's pro-domain has not been observed. Purified PCSK9 is made up of two species that can be separated by non-reducing SDS-PAGE; the pro-domain at 17 Kd, and the catalytic plus C-terminal domains at 65 Kd. PCSK9 has not been isolated without its inhibitory pro-domain, and measurements of PCSK9's catalytic activity have been variable (Naureckiene et al., 2003; Seidah et al., 2003). id="p-7" id="p-7"

[0007] In certain embodiments, a PCSK9 polypeptide includes terminal residues, such as, but not limited to, leader sequence residues, targeting residues, amino terminal methionine residues, lysine residues, tag residues and/or fusion protein residues. PCSK9 has also been referred to as FH3, NARC1, HCHOLA3, proprotein convertase subtilisin/kexin type 9, and neural apoptosis regulated convertase 1. The PCSK9 gene encodes a proprotein convertase protein that belongs to the proteinase K subfamily of the secretory subtilase family. The term PCSK9 denotes both the proprotein and the product generated following autocatalysis of the proprotein. When only the autocatalyzed product is being referred to (such as for an antigen binding protein or ligand that binds to the cleaved PCSK9), the protein can be referred to as the mature, cleaved, processed or active PCSK9. When only the inactive form is being referred to, the protein can be referred to as the inactive, pro-form, 18936261-1 or unprocessed form of PCSK9. The term PCSK9 also encompasses PCSK9 molecules incorporating post-translational modifications of the PCSK9 amino acid sequence, such as PCSK9 sequences that have been glycosylated, PCSK9 sequences from which its signal sequence has been cleaved, PCSK9 sequence from which its pro domain has been cleaved from the catalytic domain but not separated from the catalytic domain (see, e.g., FIGS. 1A and IB of US20120093818A1).

SUMMARY |0008] Through the application of human genetic variation analysis and rationallydesigned sequence selection the present invention provides for improved human patient diagnosis and therapy based on human PCSK9 variation. Importantly, the invention enables tailored medicines that address individual human patient genotypes or phenotypes. id="p-9" id="p-9"

[0009] The inventor's analysis of large numbers of naturally-occurring genomic human PCSK9 sequences reveals that there is significant variation across diverse human populations and provides for the ability for correlation between individual human patients and tailored medical and diagnostic approaches addressing the target. The technical applications of these findings, as per the present invention, thus contribute to better treatment, prophylaxis and diagnosis in humans and provides for patient benefit by enabling personalized medicines and therapies. This provides advantages of better prescribing, less wastage of medications and improved chances of drug efficacy and better diagnosis in patients. id="p-10" id="p-10"

[0010] Furthermore, the inventor surprisingly realised that some rarer natural forms, although present in humans at much lower frequencies than the common form, nevertheless are represented in multiple and ethnically-diverse human populations and usually with many human examples per represented ethnic population. Thus, the inventor realised that targeting such rarer forms would provide for effective treatment, prophylaxis or diagnosis across many human ethnic populations, thereby extending the utility of the present invention and better serving patients in those populations. id="p-11" id="p-11"

[0011] With this, the inventor realised that there is significant industrial and medical application for the invention in terms of guiding the choice of an anti-PCSK9 ligand for administration to human patients for therapy and/or prophylaxis of PCSK9-mediated or associated diseases and conditions. In this way, the patient receives drugs and ligands that are tailored to their needs - as determined by the patient's genetic or phenotypic makeup. Hand-in-hand with this, the invention provides for the genotyping and/or phenotyping of patients in connection with such treatment, thereby allowing a proper match of drug to 18936261-1 3 patient. This increases the chances of medical efficacy, reduces the likelihood of inferior treatment using drugs or ligands that are not matched to the patient (eg, poor efficacy and/or side-effects) and avoids pharmaceutical mis-prescription and waste. id="p-12" id="p-12"

[0012] To this end, the invention provides:[0013] In a First Configuration id="p-14" id="p-14"

[0014] An anti-human PCSK9 ligand for use in a method of treating and/or preventing a PCSK9-mediated disease or condition in a human whose genome comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37, wherein the method comprises administering the ligand to the human. id="p-15" id="p-15"

[0015] In a Second Configuration id="p-16" id="p-16"

[0016] A ligand that binds a human PCSK9 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-27 for use in a method comprising the step of using the ligand to target said PCSK9 in a human to treat and/or prevent a disease or condition mediated by PCSK9, the method comprising administering the ligand to the human. (0017] In a Third Configuration id="p-18" id="p-18"

[0018] A pharmaceutical composition or kit for treating and/or preventing a PCSK9mediated condition or disease. id="p-19" id="p-19"

[0019] In a Fourth Configuration id="p-20" id="p-20"

[0020] A method of producing an anti-human PCSK9 antibody binding site, the method comprising obtaining a plurality of anti-PCSK9 antibody binding sites, screening the antibody binding sites for binding to a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, ay and <7 or a catalytic or C-terminal domain or a peptide thereof that comprises amino acid variation from the corresponding sequence of SEQ ID NO: 1, 2 or 3 and isolating an antibody binding site that binds in the screening step, and optionally producing a form f, p r, p, m, e, h, ajar q PCSK9-binding fragment or derivative of the isolated antibody. (0021] In a Fifth Configuration id="p-22" id="p-22"

[0022] A method of producing an anti-human PCSK9 antibody, the method comprising immunising a non-human vertebrate (eg, a mouse or a rat) with a human PCSK9 comprising an amino acid sequence selected from the group consisting of the amino acid sequences of forms f, p r, p, m, e, h, aj and q or a catalytic or C-terminal domain or a peptide thereof that comprises amino acid variation from the corresponding sequence of SEQ ID NO: 1, 2 or 3 and isolating an antibody that binds a human PCSK9 comprising selected from the group consisting of forms f, p r, p, m, e, h, ay and <7 or a catalytic or C-terminal domain or a peptide thereof that comprises amino acid variation from the corresponding 18936261-1 sequence of SEQ ID NO: 1, 2 or 3, and optionally producing a form f, c, r, p, m, e, h, ajar q PCSK9-binding fragment or derivative of the isolated antibody. (0023] In a Sixth Configuration id="p-24" id="p-24"

[0024] A kit for PCSK9 genotyping a human, wherein the kit comprises a nucleic acid (i) comprising a sequence of contiguous nucleotides that specifically hybridises to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof, or specifically hybridises to an antisense sequence or an RNA transcript of said sequence, wherein said sequence of contiguous nucleotides hybridises to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridises to an antisense sequence or an RNA transcript thereof; and/or (ii) comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or comprising an antisense sequence or RNA version of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28. id="p-25" id="p-25"

[0025] In a Seventh Configuration id="p-26" id="p-26"

[0026] Use of an anti-PCSK9 ligand that binds a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, a/and q in the manufacture of a medicament for treating and/or preventing a PCSK9-mediated disease or condition in a human whose genome comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37. id="p-27" id="p-27"

[0027] In a Eighth Configuration id="p-28" id="p-28"

[0028] Use of an anti-PCSK9 ligand that binds a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, ajand q in the manufacture of a medicament for targeting said PCSK9 in a human to treat and/or prevent a disease or condition mediated by PCSK9. id="p-29" id="p-29"

[0029] In a Ninth Configuration id="p-30" id="p-30"

[0030] A method of targeting a PCSK9 for treating and/or preventing a PCSK9mediated disease or condition in a human, the method comprising administering an antiPCSK9 ligand to a human comprising a nucleotide sequence selected from the group consisting SEQ ID NOs: 29-37, whereby a PCSK9 encoded by said nucleotide sequence is targeted. id="p-31" id="p-31"

[0031] In a Tenth Configuration id="p-32" id="p-32"

[0032] A method of treating and/or preventing a disease or condition mediated by PCSK9 in a human, the method comprising targeting a human PCSK9 selected from the group 18936261-1 consisting of forms f, c, r, p, m, e, h, ajand q by administering to the human a ligand that binds said PCSK9 thereby treating and/or preventing said disease or condition in the human. id="p-33" id="p-33"

[0033] In a Eleventh Configuration id="p-34" id="p-34"

[0034] A method of PCSK9 genotyping a nucleic add sample of a human, the method comprising identifying in the sample the presence of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or the catalytic- or C-terminal domainencoding sequence thereof. id="p-35" id="p-35"

[0035] In a Twelfth Configuration id="p-36" id="p-36"

[0036] A method of PCSK9 typing a protein sample of a human, the method comprising identifying in the sample the presence of a human PCSK9 selected from the group consisting of forms / c, r, p, m, e, h, ajand q. id="p-37" id="p-37"

[0037] In a Thirteenth Configuration id="p-38" id="p-38"

[0038] A method of treating and/or preventing in a human patient a cardiovascular disease or condition, or a disease or condition that is associated with elevated LDL cholesterol (eg, hypercholesterolaemia), wherein the patient is receiving or has previously received statin treatment for said disease or condition, the method comprising typing the patient using a method of the invention and administering a ligand according to the invention whereby the human is treated or said disease or condition is prevented; optionally also reducing or stopping statin treatment. id="p-39" id="p-39"

[0039] In a Fourteenth Configuration id="p-40" id="p-40"

[0040] An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 or a Leu corresponding to position 206 of SEQ ID NO: 42, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGHGl*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-1 constant regions comprising such an Asp and Leu. id="p-41" id="p-41"

[0041] In a Fifteenth Configuration id="p-42" id="p-42"

[0042] A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said 18936261-1 human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 or a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (i) an IGHGl*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-1 heavy chain constant regions comprising such an Asp and Leu and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1. id="p-43" id="p-43"

[0043] In a Sixteenth Configuration id="p-44" id="p-44"

[0044] An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody comprises a human gamma-2 heavy chain constant region that comprises an amino acid selected from the group consisting of a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGHG2*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-2 constant regions comprising such a Pro, Asn, Phe, Val and Ala. id="p-45" id="p-45"

[0045] In a Seventeenth Configuration id="p-46" id="p-46"

[0046] A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-2 heavy chain constant region that comprises an amino acid selected from the group consisting of a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of 18936261-1 SEQ ID NO: 44 and wherein said human comprises (i) an IGHG2*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-2 heavy chain constant regions comprising such a Pro, Asn, Phe, Val and Ala and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1. id="p-47" id="p-47"

[0047] In a Eighteenth Configuration id="p-48" id="p-48"

[0048] An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 or a Cys corresponding to position 87 of SEQ ID NO: 50, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGKC*01 human light chain constant region gene segment, or the human expresses antibodies comprising human kappa light chain constant regions comprising such an Val and Cys. id="p-49" id="p-49"

[0049] In a Nineteenth Configuration id="p-50" id="p-50"

[0050] A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 or a Cys corresponding to position 87 of SEQ ID NO: 50 and wherein said human comprises (i) an IGKC*01 human light chain constant region gene segment, or the human expresses antibodies comprising human kappa light chain constant regions comprising such an Val and Cys and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-termina! domain comprising said mutation I474V or E670G in SEQ ID NO: 1. id="p-51" id="p-51"

[0051] In a Twentieth Configuration id="p-52" id="p-52"

[0052] An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human IGLC2*01 lambda light chain 18936261-1 constant region, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises a human IGLC2*01 lambda light chain constant region gene segment, or the human expresses antibodies comprising human IGLC2*01 lambda light chain constant regions. id="p-53" id="p-53"

[0053] In a Twenty-First Configuration id="p-54" id="p-54"

[0054] A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human IGLC2*01 lambda light chain constant region and wherein said human comprises (i) an IGLC2*01 human light chain constant region gene segment, or the human expresses antibodies comprising a human IGLC2*01 lambda light chain constant regions and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1. [0055] In a Twenty-Second Configuration id="p-56" id="p-56"

[0056] An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human variable domain that is derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, wherein the VH gene segment is derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, wherein the VH gene segment is selected from the group consisting of (i) IGHV1-18*O1 and the genome of the human comprises a human IGHV1-18*O1 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV1-18*O1; or (ii) IGVH1-46*O1 and the genome of the human comprises a human IGHV1-46*O1 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV1-46*O1, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence, and comprises said VH gene segment or expresses antibodies comprising VH 18936261-1 domains that are derived from the recombination of said human VH gene segment, a human D gene segment and a human JH gene segment. id="p-57" id="p-57"

[0057] In a Twenty-Third Configuration id="p-58" id="p-58"

[0058] A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein (i) the antibody or fragment comprises a human variable domain that is derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, wherein the VH gene segment is selected from the group consisting of (a) IGHV1-18*O1 and the genome of the human comprises a human IGHV1-18*O1 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV1-18*O1; and (b) IGVH1-46*O1 and the genome of the human comprises a human IGHV1-46*O1 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV1-46*O1, and wherein said human comprises (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1. id="p-59" id="p-59"

[0059] In a Twenty-Fourth Configuration id="p-60" id="p-60"

[0060] A method for treating a PCSK9-mediated disease or condition in a human by targeting a PCSK9 that comprises a C-terminal domain amino acid polymorphism (compared to SEQ ID NO: 1), the method comprising administering to the human a ligand (eg, an antibody or fragment) that has been determined to specifically bind to a PCSK9 comprising a C-terminal domain comprising I474V or 670G (numbering according to SEQ ID NO:1); wherein the human expresses said PCSK9 or the genome of the human comprises a nucleotide sequence encoding said PCSK9; wherein said human is treated for said disease or condition. id="p-61" id="p-61"

[0061] In a Twenty-Fifth Configuration id="p-62" id="p-62"

[0062] A method of reducing cholesterol level or maintaining a previously reduced cholesterol level in a human in need thereof, the method comprising:- a. Carrying out an initial treatment of said human for an initial treatment period by administering an anti-human PCSK9 ligand (eg, an antibody or fragment) to said human, wherein (i) the ligand has been determined to specifically bind to a PCSK9 comprising a C-terminal domain comprising I474V or 670G (numbering according 18936261-1 to SEQ ID NO:1); (ii) the human expresses said PCSK9 or the genome of the human comprises a nucleotide sequence encoding said PCSK9 and (iii) the human has received or is receiving statin treatment to lower or maintain cholesterol level; wherein the initial treatment comprises the administration of a single or multiple doses of the ligand to the human; b. Determining to (i) terminate statin treatment (ii) keep the human off statin treatment; or (iii) reduce statin treatment after said initial treatment period; and c. Continuing to administer the ligand to said patient after said time period has expired, thereby reducing cholesterol level or maintaining a previously reduced cholesterol level in said human. id="p-63" id="p-63"

[0063] In a Twenty-Sixth Configuration id="p-64" id="p-64"

[0064] An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human (eg, gamma) heavy chain constant region that comprises a first amino acid that is encoded by a human (eg, gamma) heavy chain constant region gene segment SNP, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation 1474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said PCSK9 amino acid sequence and comprises a human (eg, gamma) heavy chain constant region gene segment comprising said SNP, or the human expresses antibodies comprising human (eg, gamma) constant regions comprising said first amino acid. id="p-65" id="p-65"

[0065] In a Twenty-Seventh Configuration [0066| An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human (eg, kappa or lambda) light chain constant region that comprises a first amino acid that is encoded by a human (eg. kappa or lambda respectively) light chain constant region gene segment SNP, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said PCSK9 amino acid sequence and comprises a human (eg, kappa or lambda respectively) light chain constant region gene segment comprising said SNP, or the human expresses antibodies 18936261-1 comprising human (eg, kappa or lambda respectively) constant regions comprising said first amino acid. id="p-67" id="p-67"

[0067] In a Twenty-Eighth Configuration id="p-68" id="p-68"

[0068] An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human variable (eg, VH, Vk or VA) domain that comprises a first amino acid that is encoded by a V (eg, VH, Vk or VA respectively) gene segment SNP, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said PCSK9 amino acid sequence and comprises a human V (eg, VH, Vk or VA respectively) gene segment comprising said SNP, or the human expresses antibodies comprising V (eg, VH, Vk or VA respectively) domains comprising said first amino acid.

BRIEF DESCRIPTION OF THE DRAWINGS id="p-69" id="p-69"

[0069] Figure 1 shows in silico modeling of PCSK9 surface variant residues. id="p-70" id="p-70"

[0070] Figure 2 depicts the cumulative allele frequency distribution across the 1000 Genomes Project databse of human VH3-23 alleles comprising SNP rs56069819 (such alleles denonted C and the most frequent allele (which does not comprise this SNP) denoted A). [0071] Figure 3 depicts frameworks and CDRs encoded by VH3-23*04 as obtained from the IMGT database (available on the World Wide Web at www.IMGT.org). Figure 3 discloses the nucleotide sequences as SEQ ID NOS 69, 69, 69, 71, 71, 71, 72, 74, 76, 39 and 77, respectively, in order of appearance. Figure 3 discloses the coded amino acid sequences as SEQ ID NOS 70, 70, 70, 70, 70, 70, 73, 75, 75, 38 and 78, respectively, in order of appearance. id="p-72" id="p-72"

[0072] Figure 4 depicts sequences of VH3-23*04. The portion of VH3-23*04 comprising the FW1 residue change of rs56069819 (SEQ ID NO: 38). The portion of the nucleic acid sequence encoding rs56069819 is depicted (SEQ ID NO: 39). The FW1 encoded by VH3-23*04 is depicted (SEQ ID NO: 40).

DETAILED DESCRIPTION 18936261-1 id="p-73" id="p-73"

[0073] The skilled person will know that SNPs or other changes that translate into amino acid variation can cause variability in conformation or activity of human targets to be addressed. This has spawned great interest in personalized medicine where genotyping and knowledge of protein and nucleotide variability is used to tailor medicines and diagnosis of patients more effectively. The present invention provides for tailored pharmaceuticals and testing that specifically addresses rarer variant forms of a human target of interest (TOI), that target being human PCSK9. id="p-74" id="p-74"

[0074] The present invention harnesses the power of human genetic variation analysis and rationally-designed sequence selection. The technical applications of these approaches, as per the present invention, contribute to better treatment, prophylaxis and diagnosis in humans and provides for patient benefit by providing choice and enabling personalized medicines and therapies. This provides advantages of better prescribing, less wastage of medications and improved chances of drug efficacy and better diagnosis in patients. id="p-75" id="p-75"

[0075] As sources of genomic sequence variation data, the skilled person will be aware of the available databases and resources (including updates thereof) provided by the following:- 1. HapMap (The International HapMap Consortium. 2003; http://hapmap.ncbi.nlm.nih.gov/index.html.en). The HapMap Project is an international project that aims to compare the genetic sequences of different individuals to identify chromosomal regions containing shared genetic variants. The HapMap www site provides tools to identify chromosomal regions and the variant therein, with options to drill down to population level frequency data. 2. 1000 Genomes Project (The 1000 Genomes Project Consortium 2010; available on the World Wide Web at http://www.1000genomes.org/). This resource provides complete genomic sequence for at least 2500 unidentified individuals from one of 25 distinct population groups. 3. Japanese SNP Database( H.Haga et al. 2002; available on the World Wide Web at http://snp.ims.u-tokyo.ac.jp/index.html). Based on a study identifying 190,562 human genetic variants. id="p-76" id="p-76"

[0076] The present invention involves the identification and cataloguing of naturally-occurring human genomic target sequence variants, including those found to be relatively low-frequency or rare variants that segregate with specific human ethnic populations and in many individual humans. 18936261-1 id="p-77" id="p-77"

[0077] An aspect of the invention is based on rational design of sequence selection addressing the desirability to tailor medicaments and diagnostics to rarer, but yet still significant groups of human individuals that suffer from, or have the potential to suffer from (ie, who are at risk of), a disease or condition mediated or associated with the target of interest. In devising this rational design of the present aspect of the invention, the inventor included considerations of the spread of prevalence of naturally-occurring target variant sequences across multiple, diverse human ethnic populations, as well as the importance of addressing such populations where many individuals are likely to display a genotype and/or phenotype of one or more of the variants being analysed. As part of this design, the inventor saw the importance of adopting the art-recognised classifications of human ethnic populations, and in this respect the inventor based the analysis and design on the recognised human ethnic populations adopted by the 1000 Genomes Project, since this is a resource that is, and will continue to be, widely adopted by the scientific and medical community. id="p-78" id="p-78"

[0078] Figure 2 shows the cumulative allele frequency distribution across the 1000 Genomes Project databse of human VH3-23 alleles comprising SNP rs56069819 (such alleles denonted C and the most frequent allele (which does not comprise this SNP) denoted A). The figure shows that VH3-23 alleles comprising SNP rs56069819 are present at a cumulative frequency of 11% across all human ethnic populations taken as a whole, whereas in certain specific human ethnic sub-populations (ASW, LWK, YRI, CEU and GBR) such alleles are present at an above-average cumulative frequency. Indicated in the figure are those human PCSK9 variant forms (marked Variants) that are found in the various sub-populations with above-average occurrence of human VH3-23 alleles comprising SNP rs56069819. ]0079] Thus, in this aspect of the invention, the inventor designed the following variant sequence selection criteria, these being criteria that the inventor realised would provide for useful medical drugs and diagnostics to tailored need in the human population. id="p-80" id="p-80"

[0080] Selection Criteria id="p-81" id="p-81"

[0081] Three or four of the following:- • Naturally-occurring human PCSK9 variant sequences having a cumulative human allele frequency of 35% or less; • Naturally-occurring human PCSK9 variant sequences having a total human genotype frequency of 40% or less; • Naturally-occurring human PCSK9 variant sequences found in many different human ethnic populations (using the standard categorisation of the 1000 Genomes Project; see Table 4 below); and 18936261-1 • Naturally-occurring human PCSK9 variant sequences found in many individuals distributed across such many different ethnic populations. id="p-82" id="p-82"

[0082] The inventor's selection included, as a consideration, selection for nucleotide variation that produced amino acid variation in corresponding PCSK9 forms (ie, non-synonymous variations), as opposed to silent variations that do not alter amino acid residues in the target protein. id="p-83" id="p-83"

[0083] Optionally, further sequence analysis and 3D in siiico modelling (eg, see Figure 1) can also be used as an additional selection criterion: variants whose variant amino acid residues (versus the most common form of human PCSK9) are surface-exposed on the target are desirable for selection, since the inventor saw these as contributing to determining the topography of the target and potentially contributing to how and where ligand binding on the target occurs. id="p-84" id="p-84"

[0084] In an embodiment, the cumulative human allele frequency is 30, 25, 20, 15, or 5% or less, eg, in the range from 1 to 20% or 1 to 15% or 1 to 10%. id="p-85" id="p-85"

[0085] In an embodiment, the total human genotype frequency is 35, 30, 25, 20, , 10 or 5% or less, eg, in the range from 1 to 25%, 1 to 20%, 1 to 15%, 1 to about 15%, 1 to 10%, 1 to about 10% or 1 to 5% or 1 to about 5%. id="p-86" id="p-86"

[0086] In an embodiment, the naturally-occurring human target variant sequences are found in at least 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 different human ethnic populations (using the standard categorisation of the 1000 Genomes Project). |0087] In an embodiment, the naturally-occurring human target variant sequences are found in at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 130, 140 or 150 individuals distributed across such many different ethnic populations. id="p-88" id="p-88"

[0088] In an example, the following criteria are applied:- • Naturally-occurring human PCSK9 variant sequences having a cumulative human allele frequency of 15% or less; • Naturally-occurring human PCSK9 variant sequences having a total human genotype frequency of 20% or less; • Naturally-occurring human PCSK9 variant sequences found in at least 5 different human ethnic populations (using the standard categorisation of the 1000 Genomes Project); and • Naturally-occurring human PCSK9 variant sequences found in many individuals distributed across such many different ethnic populations. 18936261-1 id="p-89" id="p-89"

[0089] In any aspect, configuration, example, embodiment, clause or concept herein, frequencies may be determined using bioinformatics. id="p-90" id="p-90"

[0090] In any aspect, configuration, example, embodiment, clause or concept herein, frequencies may be determined by reference to a database comprising at least 1000 or 2000 human sequences. id="p-91" id="p-91"

[0091] In any aspect, configuration, example, embodiment, clause or concept herein heterozygous human genotype frequency means the cumulative frequency of all genotypes in the sample or database or in humans having one occurrence of the rare variant allele and one occurrence of another allele (heterozygous state), eg, genotype in 1000 Genomes database. id="p-92" id="p-92"

[0092] In any aspect, configuration, example, embodiment, clause or concept herein homozygous human genotype frequency means the cumulative frequency of two occurrences of the variant allele (homozygous state), eg, genotype in 1000 Genomes Project database. id="p-93" id="p-93"

[0093] In any aspect, configuration, example, embodiment, clause or concept herein total human genotype frequency means the total of heterozygous plus homozygous human genotype frequencies. id="p-94" id="p-94"

[0094] In any aspect, configuration, example, embodiment, clause or concept herein cumulative human allele frequency refers to the total of all occurrences of the variant allele in the sample or database or in humans, eg, in the 1000 Genomes Project database. id="p-95" id="p-95"

[0095] In an example, the criteria are applied with reference to one or more human genomic sequence databases as described herein. For example, the criteria are those as applied to the 1000 Genomes database. id="p-96" id="p-96"

[0096] For example in any aspect example, embodiment or configuration of the invention, the 1000 Genomes database release 13. For example, the 1000 Genomes database in its most recent version as at 1 October 2013. id="p-97" id="p-97"

[0097] The following bioinformatics protocol is envisaged to indentify human sequences for use in the present invention: (a) Identify a genomic region containing a PCSK9 target sequence of interest (Target genomic region') and calculate the genomic coordinates, using coordinates that match the sequence assembly build used by either the 1000 Genomes Project or International HapMap project (or another selected human gene database of choice). (b) Identify genomic variants mapped to the genomic region previously identified in (a). Retrieve allele frequencies for variants for each super population and preferably sub- 18936261-1 population where such data is available. The VWC tools for the 1000 Genomes Project can be used for this step. (c) Filter list of genomic variants from target genomic region to contain only variants classed as either 'non-synonymous' single nucleotide polymorphisms (SNPs) or genomic 'insertions or detections' (indels). Filter further to include those that are present in exonic sequences only. Non-synonymous refers to nucleotide variation that produces amino acid variation (ie, excluding silent mutations). (d) Correlate population frequency data for each of the identified variants for each of the super populations (for example 'European Ancestry', 'East Asian ancestry', 'West African ancestry', 'Americas', and 'South Asian ancestry') to identify those variants that segregate with less than two super-populations. Further correlate all identified variants with each of the sub-populations (for example, 'European ancestry' superpopulation might be subdivided into groups such as 'CEU - Utah residents with Northern or Western European ancestry', 'TSI Toscani in Italia' and 'British from England and Scotland') and produce a second score for rarity of variants within a super-population. (e) Collect one or more sequences that show segregation to specific sub-populations for use in the present invention, eg, according to selection criteria as described herein. id="p-98" id="p-98"

[0098] Human Populations id="p-99" id="p-99"

[0099] Optionally the ethnic populations are selected from those identified in the 1000 Genomes Project database. In this respect, see Table 4 which provides details of the ethnic populations on which the 1000 Genomes Project database is based. id="p-100" id="p-100"

[00100] N A Rosenberg et at (Science 20 December 2002: vol. 298 no. 5602 2342- 2343) studied the genetic structure of human populations of differing geographical ancestry. In total, 52 populations were sampled, these being populations with: id="p-101" id="p-101"

[00101] African ancestry (Mbuti Pygmies, Biaka Pygmies, San peoples, and speakers of Niger-Kordofanian languages (Bantu, Yoruba or Mandenka populations), ]00102] Eurasian ancestry (European ancestry (Orcadian, Adygei, Basque, French, Russians, Italians, Sardinian, Tuscan), Middle Eastern ancestry (Mozabite, Bedouin, Druze, Palestinians), Central/South Asian ancestry (Balochi, Brahul, Makrani, Sindhi, Pathan, Burusho, Hazara, Uygur, Kalash)), 18936261-1 id="p-103" id="p-103"

[00103] East Asian ancestry (Han, Dal, Daur, Hezhen, Lahu, Miao, Oroqen, She, Tujia, Tu, Xibo, Yi, Mongola, Naxi, Cambodian, Japanese, Yakut), Oceanic ancestry (Melanesian, Papuan); or id="p-104" id="p-104"

[00104] Americas ancestry (Karitiana, Surui, Colombian, Maya, Pima). 100105] The International HapMap Project, Nature, 2003 Dec 18;426(6968):789-96, discloses that goal of the HapMap Project: to determine the common patterns of DNA sequence variation in the human genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The relevant human populations of differing geographical ancestry include Yoruba, Japanese, Chinese, Northern European and Western European populations. More specifically:[00106] Utah population with Northern or Western European ancestry (samples collected in 1980 by the Centre d'Etude du Polymorphisme Humain (CEPH)); population with ancestry of Yoruba people from Ibadan, Nigeria; population with Japanese ancestry; and population with ancestry of Han Chinese from China. id="p-107" id="p-107"

[00107] The authors, citing earlier publications, suggest that ancestral geography is a reasonable basis for sampling human populations. id="p-108" id="p-108"

[00108] A suitable sample of human populations used in the present invention is as follows:- (a) European ancestry (b) Northern European ancestry; Western European ancestry; Toscani ancestry; British ancestry, Finnish ancestry or Iberian ancestry. (c) More specifically, population of Utah residents with Northern and/or Western European ancestry; Toscani population in Italia; British population in England and/or Scotland; Finnish population in Finland; or Iberian population in Spain. (a) East Asian ancestry (b) Japanese ancestry; Chinese ancestry or Vietnamese ancestry. (c) More specifically, Japanese population in Toyko, Japan; Han Chinese population in Beijing, China; Chinese Dai population in Xishuangbanna; Kinh population in Ho Chi Minh City, Vietnam; or Chinese population in Denver, Colorado, USA. (a) West African ancestry (b) Yoruba ancestry; Luhya ancestry; Gambian ancestry; or Malawian ancestry. 18936261-1 (c) More specifically, Yoruba population in Ibadan, Nigeria; Luhya population in Webuye, Kenya; Gambian population in Western Division, The Gambia; or Malawian population in Blantyre, Malawi. (a) Population of The Americas (b) Native American ancestry; Afro-Caribbean ancestry; Mexican ancestry; Puerto Rican ancestry; Columbian ancestry; or Peruvian ancestry. (c) More specifically, population of African Ancestry in Southwest US; population of African American in Jackson, MS; population of African Caribbean in Barbados; population of Mexican Ancestry in Los Angeles, CA; population of Puerto Rican in Puerto Rico; population of Colombian in Medellin, Colombia; or population of Peruvian in Lima, Peru. (a) South Asian ancestry (b) Ahom ancestry; Kayadtha ancestry; Reddy ancestry; Maratha; or Punjabi ancestry. (c) More specifically, Ahom population in the State of Assam, India; Kayadtha population in Calcutta, India; Reddy population in Hyderabad, India; Maratha population in Bombay, India; or Punjabi population in Lahore, Pakistan. id="p-109" id="p-109"

[00109] In any configuration ofthe invention, in one embodiment, each human population is selected from a population marked (a) above. id="p-110" id="p-110"

[00110] In any configuration of the invention, in another embodiment, each human population is selected from a population marked (b) above. (00111] In any configuration ofthe invention, in another embodiment, each human population is selected from a population marked (c) above. id="p-112" id="p-112"

[00112] In one embodiment the ethnic populations are selected from the group consisting of an ethnic population with European ancestry, an ethnic population with East Asian, an ethnic population with West African ancestry, an ethnic population with Americas ancestry and an ethnic population with South Asian ancestry. id="p-113" id="p-113"

[00113] In one embodiment the ethnic populations are selected from the group consisting of an ethnic population with Northern European ancestry; or an ethnic population with Western European ancestry; or an ethnic population with Toscani ancestry; or an ethnic population with British ancestry; or an ethnic population with Icelandic ancestry; or an ethnic population with Finnish ancestry; or an ethnic population with Iberian ancestry; or an ethnic population with Japanese ancestry; or an ethnic population with Chinese ancestry; or an ethnic population Vietnamese ancestry; or an ethnic population with Yoruba ancestry; or an ethnic population with Luhya ancestry; or an ethnic population with Gambian ancestry; or an 18936261-1 ethnic population with Malawian ancestry; or an ethnic population with Native American ancestry; or an ethnic population with Afro-Caribbean ancestry; or an ethnic population with Mexican ancestry; or an ethnic population with Puerto Rican ancestry; or an ethnic population with Columbian ancestry; or an ethnic population with Peruvian ancestry; or an ethnic population with Ahom ancestry; or an ethnic population with Kayadtha ancestry; or an ethnic population with Reddy ancestry; or an ethnic population with Maratha; or an ethnic population with Punjabi ancestry. id="p-114" id="p-114"

[00114] Anti-Target Ligands id="p-115" id="p-115"

[00115] The invention provides useful anti-target ligands for addressing humans suffering from or likely to suffer from a disease or condition mediated or associated with PCSK9. For example, the ligand specifically binds to a PCSK9 variant as per the invention. The ligand may inhibit or antagonise the activity of the PCSK9 target, eg, the ligand neutralises the target. The skilled person will be familiar with neutralising ligands in general, such as antibodies or antibody fragments, and can readily test suitable ligands for specific binding and/or neutralisation of a target in vitro or in an in vivo assay. id="p-116" id="p-116"

[00116] In an example, the ligand is (or has been determined as) a neutraliser of the PCSK9. In an example, determination is carried out in a human (eg, in a clinical trial). In an example, determination is carried out in a non-human, eg, in a mouse, rat, rabbit, pig, dog, sheep or non-human primate (eg, Cynomolgous monkey, rhesus monkey or baboon). (00117] An antibody fragment comprises a portion of an intact antibody, preferably the antigen binding and/or the variable region of the intact antibody. Examples of antibody fragments include dAb, Fab, Fab', F(ab')2 and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules and multispecific antibodies formed from antibody fragments. id="p-118" id="p-118"

[00118] In an embodiment, the ligand of the invention is or comprises an antibody or antibody fragment, for example an antibody or fragment comprising human variable regions (and optionally also human constant regions). Anti-PCSK9 or PCSK9-binding or targeting antibodies and fragments can be prepared according to any known method, eg, using transgenic mice (eg, the Kymouse™ or Velocimouse™, or Omnimouse™ , Xenomouse™, HuMab Mouse™ or MeMo Mouse™), rats (eg, the Omnirat™), camelids, sharks, rabbits, chickens or other non-human animals immunised with the PCSK9 followed optionally by humanisation of the constant regions and/or variable regions to produce human or humanised antibodies. In an example, display technologies can be used, such as yeast, phage or ribosome display, as will be apparent to the skilled person. Standard affinity maturation, eg, 18936261-1 using a display technology, can be performed in a further step after isolation of an antibody lead from a transgenic animal, phage display library or other library. Representative examples of suitable technologies are described in US20120093818 (Amgen, Inc), which is incorporated by reference herein in its entirety, eg, the methods set out in paragraphs [0309] to [0346]. id="p-119" id="p-119"

[00119] Generally, a VELOCIMMUNE™ or other mouse or rat can be challenged with the antigen of interest, and lymphatic cells (such as B-cells) are recovered from the mice that express antibodies. The lymphatic cells may be fused with a myeloma cell line to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the variable regions of the heavy chain and light chain may be isolated and linked to desirable isotypic constant regions of the heavy chain and light chain. Such an antibody protein may be produced in a cell, such as a CHO cell. Alternatively, DNA encoding the antigen-specific chimaeric antibodies or the variable domains of the light and heavy chains may be isolated directly from antigen-specific lymphocytes. (00120] Initially, high affinity chimaeric antibodies are isolated having a human variable region and a mouse constant region. As described below, the antibodies are characterized and selected for desirable characteristics, including affinity, selectivity, epitope, etc. The mouse constant regions are replaced with a desired human constant region to generate the fully human antibody of the invention, for example wild-type or modified IgGl or IgG4 (for example, SEQ ID NO: 751, 752,753 in US2011/0065902 (which is incorporated by reference herein in its entirety), which sequences are incorporated herein by reference for use in the ligands of the present invention). While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region. id="p-121" id="p-121"

[00121] In an example, the ligand of the invention is or comprises a nucleic acid, eg, RNA, eg, siRNA that hybridises under stringent condition to the PCSK9 variant sequence, eg, hybridises a nucleotide sequence comprising one or more nucleotides that are variant (versus the most common PCSK9 sequence, eg, with reference to the 1000 Genomes Project database). id="p-122" id="p-122"

[00122] For example, the nucleic acid hybridises to a region immediately flanking a nucleotide that is variant compared to the corresponding nucleotide of the PCSK9 nucleotide sequence having the highest cumulative human allele frequency and/or the highest total human genotype frequency. In an example, the nucleic acid hybridises to at two or more such variant nucleotides. 18936261-1 id="p-123" id="p-123"

[00123] Specific hybridisation is under stringent conditions, as will be apparent to the skilled person, eg, conditions of 5xSSC, 5xDenhardt's reagent, and 0.5% SDS at 65° C. id="p-124" id="p-124"

[00124] Target binding ability, specificity and affinity (Kd, Koff and/or Kon) can be determined by any routine method in the art, eg, by surface plasmon resonance (SPR). The term Kd, as used herein, is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction. id="p-125" id="p-125"

[00125] In one embodiment, the surface plasmon resonance (SPR) is carried out at °C. In another embodiment, the SPR is carried out at 37°C. 100126] In one embodiment, the SPR is carried out at physiological pH, such as about pH7 or at pH7.6 (eg, using Hepes buffered saline at pH7.6 (also referred to as HBSEP)). id="p-127" id="p-127"

[00127] In one embodiment, the SPR is carried out at a physiological salt level, eg, 150mM NaCl. id="p-128" id="p-128"

[00128] In one embodiment, the SPR is carried out at a detergent level of no greater than 0.05% by volume, eg, in the presence of P20 (polysorbate 20; eg, Tween-20™) at 0.05% and EDTA at 3mM. id="p-129" id="p-129"

[00129] In one example, the SPR is carried out at 25°C or 37°C in a buffer at pH7.6, 150mM NaCl, 0.05% detergent (eg, P20) and 3mM EDTA. The buffer can contain lOmM Hepes. In one example, the SPR is carried out at 25QC or 37°C in HBS-EP. HBS-EP is available from Teknova Inc (California; catalogue number H8022). id="p-130" id="p-130"

[00130] In an example, the affinity of the ligand (eg, antibody) is determined using SPR by 1. Coupling anti-mouse (or other relevant human, rat or non-human vertebrate antibody constant region species-matched) IgG (eg, Biacore™ BR-1008-38) to a biosensor chip (eg, GLM chip) such as by primary amine coupling; 2. Exposing the anti-mouse IgG (or other matched species antibody) to a test IgG antibody to capture test antibody on the chip; 3. Passing the test antigen over the chip's capture surface at 1024nM, 256nM, 64nM, 16nM, 4nM with a OnM (i.e. buffer alone); and 4. And determining the affinity of binding of test antibody to test antigen using surface plasmon resonance, eg, under an SPR condition discussed above (eg, at 25°C in physiological buffer). SPR can be carried out using any standard SPR apparatus, such as by Biacore™ or using the ProteOn XPR36™ (Bio-Rad®). 18936261-1 id="p-131" id="p-131"

[00131] Regeneration of the capture surface can be carried out with lOmM glycine at pH1.7. This removes the captured antibody and allows the surface to be used for another interaction. The binding data can be fitted to 1:1 model inherent using standard techniques, eg, using a model inherent to the ProteOn XPR36™ analysis software. id="p-132" id="p-132"

[00132] In an example, the ligand of the invention is contained in a medical container, eg, a vial, syringe, IV container or an injection device (eg, an intraocular or intravitreal injection device). In an example, the ligand is in vitro, eg, in a sterile container. In an example, the invention provides a kit comprising the ligand of the invention, packaging and instructions for use in treating or preventing or diagnosing in a human a disease or condition mediated by the PCSK9. In an example, the instructions indicate that the human should be genotyped for a PCSK9 variant sequence of the invention before administering the ligand to the human. In an example, the instructions indicate that the human should be phenotyped for a PCSK9 variant of the invention before administering the ligand to the human. In an example, the human is of Chinese (eg, Han or CHS) ethnicity and the instructions are in Chinese (eg, Mandarin). In an example, the instructions comprise directions to administer alirocumab or evolocumab to said human. (001331 The invention addresses the need to treat humans having naturallyoccurring rarer natural PCSK9 alleles, genotypes and phenotypes (rarer protein forms). In this respect, the invention provides the following aspects. 100134] In a First Aspect: An anti-human PCSK9 ligand for use in a method of treating and/or preventing a PCSK9-mediated disease or condition in a human whose genome comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37, wherein the method comprises administering the ligand to the human. id="p-135" id="p-135"

[00135] In an example, the nucleotide sequence is selected from the group consisting of SEQ ID NOs: 29-35 and 37; or selected from the group consisting of SEQ ID NOs: 29-32 and 34-37; or selected from the group consisting of SEQ ID NOs: 29-32, 34, 35 and 37. These are naturally-occurring allele (haplotype) sequences that do not encode 46L and which meet the criteria set out above. These groups comprise variants that are associated with elevated LDL-C. id="p-136" id="p-136"

[00136] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated LDL-C (Pisciotta et a/2006). 18936261-1 id="p-137" id="p-137"

[00137] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen et a/2005). id="p-138" id="p-138"

[00138] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35, 36 and 37; or selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35 and 37. These are allele (haplotype) sequences that have a naturallyoccurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-139" id="p-139"

[00139] In an example, the nucleotide sequence is SEQ ID NO:29. id="p-140" id="p-140"

[00140] In an example, the nucleotide sequence is SEQ ID NO:30. |00141] In an example, the nucleotide sequence is SEQ ID NO:31. id="p-142" id="p-142"

[00142] In an example, the nucleotide sequence is SEQ ID NO:32. id="p-143" id="p-143"

[00143] In an example, the nucleotide sequence is SEQ ID NO:33. id="p-144" id="p-144"

[00144] In an example, the nucleotide sequence is SEQ ID NO:34. id="p-145" id="p-145"

[00145] In an example, the nucleotide sequence is SEQ ID NO:35. id="p-146" id="p-146"

[00146] In an example, the nucleotide sequence is SEQ ID NO:36. id="p-147" id="p-147"

[00147] In an example, the nucleotide sequence is SEQ ID NO:37. id="p-148" id="p-148"

[00148] The PCSK9 variant is not the most frequent. id="p-149" id="p-149"

[00149] In an embodiment of any configuration, example, embodiment or aspect herein, the ligand, antibody, fragment or binding site of the invention is recombinant. id="p-150" id="p-150"

[00150] In a Second Aspect: The ligand of aspect 1, wherein the ligand has been or is determined as capable of binding a human PCSK9 selected from the group consisting forms f, c, r, p, m, e, h, ay and q. [00151 ] In an example of any aspect, the ligand binds (or has been determined to bind) two, three, four or more human PCSK9 selected from the group consisting forms f, c, r, p, m, e, h, aja/ q. id="p-152" id="p-152"

[00152] In an example of any aspect, the ligand comprises a protein domain that specifically binds to PCSK9, eg, a human PCSK9 selected from the group consisting forms f, c, r, p, m, e, h, ajand q. ]00153] The term specifically binds, or the like, means that a ligand, eg, an antibody or antigen-binding fragment thereof, forms a complex with an antigen that is relatively stable under physiologic conditions. Specific binding can be characterized by an equilibrium dissociation constant of at least about IxlO-6 M or less (e.g., a smaller KD denotes a tighter binding). Methods for determining whether two molecules specifically bind 18936261-1 are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. An isolated antibody that specifically binds a human PCSK9 may, however, exhibit cross-reactivity to other antigens such as a PCSK9 molecule from another species. Moreover, multi-specific antibodies (e.g., bispecifics) that bind to human PCSK9 and one or more additional antigens are nonetheless considered antibodies that specifically bind'' PCSK9, as used herein. id="p-154" id="p-154"

[00154] In an example of any aspect, the ligand comprises or consists of a protein that mimics the EGFA domain of the LDL receptor and specifically binds to PCSK9, eg, a human PCSK9 selected from the group consisting forms f, c, r, p, m, e, h, ay and q. id="p-155" id="p-155"

[00155] In an example of any aspect, the ligand antagonises PCSK9, eg, a human PCSK9 selected from the group consisting forms f, c, r, p, m, e, h, ay and q. [00156| In an example of any aspect, the method comprises (before administering the ligand) the step of determining that the ligand is capable of binding a human PCSK9 selected from the group consisting forms f, c, r, p, m, e, h, ay and q. id="p-157" id="p-157"

[00157] In an example of any aspect, binding is determined by SPR. In an example of any aspect, binding is determined by ELISA. id="p-158" id="p-158"

[00158] In an example of any aspect, said forms are the mature forms. id="p-159" id="p-159"

[00159] In an example of any aspect, said forms are the pro-forms. id="p-160" id="p-160"

[00160] The terms is determined, is genotyped or is phenotyped and the like herein mean that the method comprises a step of such determining, genotyping or phenotyping, |00161] In a Third Aspect: A ligand that binds a human PCSK9 comprising an amino add sequence selected from the group consisting of SEQ ID NOs: 4-27 for use in a method comprising the step of using the ligand to target said PCSK9 in a human to treat and/or prevent a disease or condition mediated by PCSK9, the method comprising administering the ligand to the human. id="p-162" id="p-162"

[00162] In an example, the disease or condition is mediated by a human PCSK9 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-27. [00163] In an example, the amino acid sequence selected from the group consisting of SEQ ID NOs: 4-23, 26 and 27; or selected from the group consisting of SEQ ID NOs: 4-14 and 18-27; or selected from the group consisting of SEQ ID NOs: 4-14, 18-23, 26 and 27.

These are naturally-occurring sequences that do not comprise 46L and which meet the criteria set out above. These groups comprise variants that are associated with elevated LDL-C. 18936261-1 id="p-164" id="p-164"

[00164] In an example, the amino acid sequence is SEQ ID NO: 18, 19 or 20, that comprises a 425S, which is associated with elevated LDL-C (Pisciotta et al 2006). id="p-165" id="p-165"

[00165] In an example, the amino acid sequence selected from the group consisting of SEQ ID NOs: 10,11, 12, 26 and 27, that comprise 670G which is a marker for severity of coronary atherosclerosis (Chen et al 2005). id="p-166" id="p-166"

[00166] In an example, the amino acid sequence selected from the group consisting of SEQ ID NOs: 10-14 and 18-27; or selected from the group consisting of SEQ ID NOs: 1014, 18-23, 26 and 27. These are sequences that have a naturally-occurring combination of differences from SEQ ID NOs: 1-3 (form a) and which meet the criteria set out above. id="p-167" id="p-167"

[00167] In an example, the amino acid sequence is SEQ ID NO: 4. [00168] In an example, the amino acid sequence is SEQ ID NO: 5. [00169] In an example, the amino acid sequence is SEQ ID NO: 6. [00170] In an example, the amino acid sequence is SEQ ID NO: 7. [00171] In an example, the amino acid sequence is SEQ ID NO: 8. 15 [00172] In an example, the amino acid sequence is SEQ ID NO: 9. [00173] In an example, the amino acid sequence is SEQ ID NO: 10. [00174] In an example, the amino acid sequence is SEQ ID NO: 11. [00175] In an example, the amino acid sequence is SEQ ID NO: 12. [00176] In an example, the amino acid sequence is SEQ ID NO: 13. 20 [00177] In an example, the amino acid sequence is SEQ ID NO: 14. [00178] In an example, the amino acid sequence is SEQ ID NO: 15. [001791 In an example, the amino acid sequence is SEQ ID NO: 16. [00180] In an example, the amino acid sequence is SEQ ID NO: 17. [00181] In an example, the amino acid sequence is SEQ ID NO: 18. 25 [00182] In an example, the amino acid sequence is SEQ ID NO: 19. [00183] In an example, the amino acid sequence is SEQ ID NO: 20. [00184] In an example, the amino acid sequence is SEQ ID NO: 21. [00185] In an example, the amino acid sequence is SEQ ID NO: 22. [00186] In an example, the amino acid sequence is SEQ ID NO: 23. 30 [00187] In an example, the amino acid sequence is SEQ ID NO: 24. [00188] In an example, the amino acid sequence is SEQ ID NO: 25. [00189] In an example, the amino acid sequence is SEQ ID NO: 26. [00190] In an example, the amino acid sequence is SEQ ID NO: 27. 18936261-1 id="p-191" id="p-191"

[00191] In a Fourth Aspect: The ligand of aspect 3, wherein the genome of the human comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37. id="p-192" id="p-192"

[00192] In an example, the nucleotide sequence is selected from the group consisting of SEQ ID NOs: 29-35 and 37; or selected from the group consisting of SEQ ID NOs: 29-32 and 34-37; or selected from the group consisting of SEQ ID NOs: 29-32, 34, 35 and 37. These are naturally-occurring allele (haplotype) sequences that do not encode 46L and which meet the criteria set out above. These groups comprise variants that are associated with elevated LDL-C. id="p-193" id="p-193"

[00193] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated LDL-C (Pisciotta ei a/2006). id="p-194" id="p-194"

[00194] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen efa/2005). id="p-195" id="p-195"

[00195] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35, 36 and 37; or selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35 and 37. These are allele (haplotype) sequences that have a naturallyoccurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. |00196] In an example, the nucleotide sequence is SEQ ID NO: 29. id="p-197" id="p-197"

[00197] In an example, the nucleotide sequence is SEQ ID NO: 30. id="p-198" id="p-198"

[00198] In an example, the nucleotide sequence is SEQ ID NO: 31. id="p-199" id="p-199"

[00199] In an example, the nucleotide sequence is SEQ ID NO: 32. id="p-200" id="p-200"

[00200] In an example, the nucleotide sequence is SEQ ID NO: 33. id="p-201" id="p-201"

[00201] In an example, the nucleotide sequence is SEQ ID NO: 34. id="p-202" id="p-202"

[00202] In an example, the nucleotide sequence is SEQ ID NO: 35. 100203] In an example, the nucleotide sequence is SEQ ID NO: 36. id="p-204" id="p-204"

[00204] In an example, the nucleotide sequence is SEQ ID NO: 37. id="p-205" id="p-205"

[00205] In a Fifth Aspect: The ligand of any preceding aspect, wherein the human has been or is genotyped as positive for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domainencoding sequence thereof. id="p-206" id="p-206"

[00206] In an example, the nucleotide sequence is selected from the group consisting of SEQ ID NOs: 29-35 and 37; or selected from the group consisting of SEQ ID 18936261-1 NOs: 29-32 and 34-37; or selected from the group consisting of SEQ ID NOs: 29-32, 34, 35 and 37. id="p-207" id="p-207"

[00207] These are naturally-occurring allele (haplotype) sequences that do not encode 46L and which meet the criteria set out above. These groups comprise variants that are associated with elevated LDL-C. (00208] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated LDL-C (Pisciotta efa/2006). id="p-209" id="p-209"

[00209] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen et a! 2005). 100210] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35, 36 and 37; or selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35 and 37. These are allele (haplotype) sequences that have a naturallyoccurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-211" id="p-211"

[00211] In an example, the nucleotide sequence is SEQ ID NO: 29. id="p-212" id="p-212"

[00212] In an example, the nucleotide sequence is SEQ ID NO: 30. {00213] In an example, the nucleotide sequence is SEQ ID NO: 31. id="p-214" id="p-214"

[00214] In an example, the nucleotide sequence is SEQ ID NO: 32. id="p-215" id="p-215"

[00215] In an example, the nucleotide sequence is SEQ ID NO: 33. id="p-216" id="p-216"

[00216] In an example, the nucleotide sequence is SEQ ID NO: 34. id="p-217" id="p-217"

[00217] In an example, the nucleotide sequence is SEQ ID NO: 35. [00218| In an example, the nucleotide sequence is SEQ ID NO: 36. id="p-219" id="p-219"

[00219] In an example, the nucleotide sequence is SEQ ID NO: 37. 100220] In a Sixth Aspect: The ligand of any preceding aspect, wherein the human has been or is phenotyped as positive for a human PCSK9 selected from the group consisting of forms f, p r, p, m, e, h, a/and <7or at least the catalytic or C-terminal domain thereof. {00221] In an example, said forms are the mature forms. (00222] In an example, said forms are the pro-forms. id="p-223" id="p-223"

[00223] In a Seventh Aspect: The ligand of any preceding aspect, wherein the method comprises genotyping the human as positive for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof. 18936261-1 id="p-224" id="p-224"

[00224] In an example, the nucleotide sequence is selected from the group consisting of SEQ ID NOs: 29-35 and 37; or selected from the group consisting of SEQ ID NOs: 29-32 and 34-37; or selected from the group consisting of SEQ ID NOs: 29-32, 34, 35 and 37. These are naturally-occurring allele (haplotype) sequences that do not encode 46L and which meet the criteria set out above. These groups comprise variants that are associated with elevated LDL-C. id="p-225" id="p-225"

[00225] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated LDL-C (Pisciotta eta/2006). |00226] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen eia/2005). id="p-227" id="p-227"

[00227] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35, 36 and 37; or selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35 and 37. These are allele (haplotype) sequences that have a naturallyoccurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-228" id="p-228"

[00228] [00229] [00230] [00231] [00232] [00233] [00234] [00235] In an example, the nucleotide sequence is SEQ ID NO: 29. In an example, the nucleotide sequence is SEQ ID NO: 30. In an example, the nucleotide sequence is SEQ ID NO: 31. In an example, the nucleotide sequence is SEQ ID NO: 32. In an example, the nucleotide sequence is SEQ ID NO: 33. In an example, the nucleotide sequence is SEQ ID NO: 34. In an example, the nucleotide sequence is SEQ ID NO: 35. In an example, the nucleotide sequence is SEQ ID NO: 36. [00236] In an example, the nucleotide sequence is SEQ ID NO: 37. [00237] In an Eight Aspect: The ligand of any preceding aspect, wherein the method comprises phenotyping the human has positive for a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, ajand q or at least the catalytic or C-terminal domain thereof. id="p-238" id="p-238"

[00238] [00239] [00240] In an example, said forms are the mature forms. In an example, said forms are the pro-forms. In a Ninth Aspect: The ligand of any preceding aspect, wherein the human has been or is genotyped as heterozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain18936261-1 encoding sequence thereof; optionally wherein the human has been or is genotyped as comprising the nucleotide sequence of SEQ ID NO: 28 or at least the catalytic domain- or Cterminal domain-encoding sequence thereof and a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domainencoding sequence thereof. |00241] Heterozygous here means that in the human's genotype one allele comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof and other allele can be any PCSK9 (eg, form a, a'or an allele comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof). id="p-242" id="p-242"

[00242] In an example, the method comprises (before administering the ligand) genotyping the human as heterozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domainencoding sequence thereof; optionally also genotyping the human as comprising the nucleotide sequence of SEQ ID NO: 28 or at least the catalytic domain- or C-terminal domainencoding sequence thereof and a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof. id="p-243" id="p-243"

[00243] In an example, the nucleotide sequence is selected from the group consisting of SEQ ID NOs: 29-35 and 37; or selected from the group consisting of SEQ ID NOs: 29-32 and 34-37; or selected from the group consisting of SEQ ID NOs: 29-32, 34, 35 and 37. These are naturally-occurring allele (haplotype) sequences that do not encode 46L and which meet the criteria set out above. These groups comprise variants that are associated with elevated LDL-C. id="p-244" id="p-244"

[00244] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated LDL-C (Pisciotta efa/2006). id="p-245" id="p-245"

[00245] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen eta!2005). id="p-246" id="p-246"

[00246] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35, 36 and 37; or selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35 and 37. These are allele (haplotype) sequences that have a naturally18936261-1 occurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-247" id="p-247"

[00247] In an example, the nucleotide sequence is SEQ ID NO: 29. id="p-248" id="p-248"

[00248] In an example, the nucleotide sequence is SEQ ID NO: 30. (00249] In an example, the nucleotide sequence is SEQ ID NO: 31. id="p-250" id="p-250"

[00250] In an example, the nucleotide sequence is SEQ ID NO:32. id="p-251" id="p-251"

[00251] In an example, the nucleotide sequence is SEQ ID NO:33. id="p-252" id="p-252"

[00252] In an example, the nucleotide sequence is SEQ ID NO:34. id="p-253" id="p-253"

[00253] In an example, the nucleotide sequence is SEQ ID NO:35. id="p-254" id="p-254"

[00254] In an example, the nucleotide sequence is SEQ ID NO:36. 100255] In an example, the nucleotide sequence is SEQ ID NO:37. id="p-256" id="p-256"

[00256] In a Tenth Aspect: The ligand of any one of aspects 1 to 9, wherein the genome of the human has been or is genotyped as homozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof. ]00257] Homozygous here means that in the human's genotype each allele comprises the same nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof. id="p-258" id="p-258"

[00258] In an example, the method comprises genotyping the human as homozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 2937 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof. id="p-259" id="p-259"

[00259] In an example, the nucleotide sequence is selected from the group consisting of SEQ ID NOs: 29-35 and 37; or selected from the group consisting of SEQ ID NOs: 29-32 and 34-37; or selected from the group consisting of SEQ ID NOs: 29-32, 34, 35 and 37. These are naturally-occurring allele (haplotype) sequences that do not encode 46L and which meet the criteria set out above. These groups comprise variants that are associated with elevated LDL-C. (00260] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated LDL-C (Pisciotta et a/2006). id="p-261" id="p-261"

[00261] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen et a/2005). id="p-262" id="p-262"

[00262] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35, 36 and 37; or selected from the group consisting of SEQ ID 18936261-1 NOs: 31, 32, 34, 35 and 37. These are allele (haplotype) sequences that have a naturallyoccurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-263" id="p-263"

[00263] In an example, the nucleotide sequence is SEQ ID NO: 29. id="p-264" id="p-264"

[00264] In an example, the nucleotide sequence is SEQ ID NO: 30. |00265] In an example, the nucleotide sequence is SEQ ID NO: 31. id="p-266" id="p-266"

[00266] In an example, the nucleotide sequence is SEQ ID NO: 32. id="p-267" id="p-267"

[00267] In an example, the nucleotide sequence is SEQ ID NO: 33. id="p-268" id="p-268"

[00268] In an example, the nucleotide sequence is SEQ ID NO: 34. id="p-269" id="p-269"

[00269] In an example, the nucleotide sequence is SEQ ID NO: 35. id="p-270" id="p-270"

[00270] In an example, the nucleotide sequence is SEQ ID NO: 36. id="p-271" id="p-271"

[00271] In an example, the nucleotide sequence is SEQ ID NO: 37. id="p-272" id="p-272"

[00272] In an Eleventh Aspect: The ligand of any preceding aspect, wherein the ligand comprises an antibody binding site that binds a human PCSK9 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-27 and optionally has been or is determined as capable of such binding. id="p-273" id="p-273"

[00273] In an example, the method comprises (before administering the ligand) the step of determining that the ligand is capable of binding to said human PCSK9. id="p-274" id="p-274"

[00274] In an example, the binding is specific binding. In an example, the ligand binds (or has been determined as binding) to the PCSK9 with an affinity (Kd) of ImM, lOOnM, lOnM or InM or less. In an embodiment, the affinity is no less than 10, 100 or 1000 fM. 100275] In an example, binding or affinity is determined by SPR or ELISA. id="p-276" id="p-276"

[00276] In an example, the disease or condition is mediated by a human PCSK9 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-27. [00277] In an example, the amino acid sequence selected from the group consisting of SEQ ID NOs: 4-23, 26 and 27; or selected from the group consisting of SEQ ID NOs: 4-14 and 18-27; or selected from the group consisting of SEQ ID NOs: 4-14, 18-23, 26 and 27.

These are naturally-occurring sequences that do not comprise 46L and which meet the criteria set out above. These groups comprise variants that are associated with elevated LDL-C. id="p-278" id="p-278"

[00278] In an example, the amino acid sequence is SEQ ID NO: 18, 19 or 20, that comprises a 425S, which is associated with elevated LDL-C (Pisciotta et al 2006). id="p-279" id="p-279"

[00279] In an example, the amino acid sequence selected from the group consisting of SEQ ID NOs: 10,11,12, 26 and 27, that comprise 670G which is a marker for severity of coronary atherosclerosis (Chen et al 2005). 18936261-1 id="p-280" id="p-280"

[00280] In an example, the amino acid sequence selected from the group consisting of SEQ ID NOs: 10-14 and 18-27; or selected from the group consisting of SEQ ID NOs: 1014, 18-23, 26 and 27. These are sequences that have a naturally-occurring combination of differences from SEQ ID NOs: 1-3 (form a) and which meet the criteria set out above. id="p-281" id="p-281"

[00281] In an example, the amino acid sequence is SEQ ID NO: 4. [00282] In an example, the amino acid sequence is SEQ ID NO: 5. [00283] In an example, the amino acid sequence is SEQ ID NO: 6. [00284] [00285] [00286] [00287] In an example, the amino acid sequence is SEQ ID NO: 7. In an example, the amino acid sequence is SEQ ID NO: 8. In an example, the amino acid sequence is SEQ ID NO: 9. In an example, the amino acid sequence is SEQ ID NO; 10. [00288] [00289] [00290] In an example, the amino acid sequence is SEQ ID NO: 11. In an example, the amino acid sequence is SEQ ID NO: 12. In an example, the amino acid sequence is SEQ ID NO: 13. [00291] [00292] [00293] [00294] In an example, the amino acid sequence is SEQ ID NO: 14. In an example, the amino acid sequence is SEQ ID NO: 15. In an example, the amino acid sequence is SEQ ID NO: 16. In an example, the amino acid sequence is SEQ ID NO: 17. 100295] [00296] [00297| In an example, the amino acid sequence is SEQ ID NO: 18. In an example, the amino acid sequence is SEQ ID NO: 19. In an example, the amino acid sequence is SEQ ID NO: 20. [00298] 100299] In an example, the amino acid sequence is SEQ ID NO; 21. In an example, the amino acid sequence is SEQ ID NO: 22. 100300] In an example, the amino add sequence is SEQ ID NO: 23. (00301] In an example, the amino acid sequence is SEQ ID NO: 24. [00302] In an example, the amino acid sequence is SEQ ID NO: 25. [00303] [00304] [00305] In an example, the amino acid sequence is SEQ ID NO: 26. In an example, the amino acid sequence is SEQ ID NO: 27. In a Twelfth Aspect: The ligand of aspect 11, wherein the ligand is an antibody or antibody fragment. For example, the antibody or antibody fragment is a PCSK9 antagonist, eg, neutralises PCSK9. Examples of such antibodies are disclosed, for instance, in WO 2008/057457, WO2008/057458, WO 2008/057459, WO 2008/063382, WO 2008/133647, WO 2009/100297, WO 2009/100318, WO 201 1/037791, WO 201 1/053759, WO 201 1/053783, WO 2008/125623, WO 2011/072263, WO 2009/055783, WO 2010/029513, WO 18936261-1 2011/11 1007, WO 2010/077854, the disclosures and sequences of such antibodies being incorporated herein in their entireties by refere for use in the invention. One specific example is AMG 145 (Amgen), LY3015014 (Eli Lilly) or alirocumab, or a PCSK9-binding derivative thereof. Advantageously, the ligand is or comprises alirocumab. id="p-306" id="p-306"

[00306] Alternatively, the ligand is or comprises evolocumab. id="p-307" id="p-307"

[00307] In an example, the ligand is SAR236553/REGN727 (Sanofi Aventis/Regeneron) or a PCSK9-binding derivative thereof. id="p-308" id="p-308"

[00308] In an example, the ligand comprises or consists of a neutralizing antibody that binds to the PCSK9, wherein the antibody binds to PCSK9 and reduces the likelihood that PCSK9 binds to LDLR. id="p-309" id="p-309"

[00309] The ligand of aspect 11, wherein the ligand is a PCSK9 antagonist, eg, neutralises PCSK9. 100310] In an example of any aspect of the invention, the ligand comprises or consists a ligand selected from evolocumab, lD05-IgG2 (Merck &Co.), ALN-PCS02 (Alnylam), RN316 (Pfizer-Rinat), LY3015014 (Eli Lilly) and alirocumab, or a PCSK9-binding derivative thereof. In an example, the ligand is SAR236553/REGN727 (Sanofi Aventis/Regeneron) or a PCSK9-binding derivative thereof. id="p-311" id="p-311"

[00311] In a Thirteenth Aspect: The ligand of any one of aspects 1 to 10, wherein (i) the ligand comprises a sequence of contiguous nucleotides that specifically hybridises to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof, or specifically hybridises to an antisense sequence or an RNA transcript of said sequence, wherein said sequence of contiguous nucleotides hybridises to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridises to an antisense sequence or an RNA transcript thereof respectively; and/or (ii) the ligand comprises a sequence of at least 10 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or is an antisense sequence or RNA version of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28. id="p-312" id="p-312"

[00312] In an example, the nucleotide sequence is selected from the group consisting of SEQ ID NOs: 29-35 and 37; or selected from the group consisting of SEQ ID NOs: 29-32 and 34-37; or selected from the group consisting of SEQ ID NOs: 29-32, 34, 35 and 37. These are naturally-occurring allele (haplotype) sequences that do not encode 46L 18936261-1 and which meet the criteria set out above. These groups comprise variants that are associated with elevated LDL-C. id="p-313" id="p-313"

[00313] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated LDL-C (Pisciotta et a/2006). id="p-314" id="p-314"

[00314] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen et al 2005). id="p-315" id="p-315"

[00315] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35, 36 and 37; or selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35 and 37. These are allele (haplotype) sequences that have a naturallyoccurring combination of differences from SEQ ID NO: 28 (form a} and which meet the criteria set out above. id="p-316" id="p-316"

[00316] In an example, the nucleotide sequence is SEQ ID NO:29. id="p-317" id="p-317"

[00317] In an example, the nucleotide sequence is SEQ ID NO:30. (00318] In an example, the nucleotide sequence is SEQ ID NO:31. id="p-319" id="p-319"

[00319] In an example, the nucleotide sequence is SEQ ID NO:32. id="p-320" id="p-320"

[00320] In an example, the nucleotide sequence is SEQ ID NO:33. id="p-321" id="p-321"

[00321] In an example, the nucleotide sequence is SEQ ID NO:34. id="p-322" id="p-322"

[00322] In an example, the nucleotide sequence is SEQ ID NO:35. id="p-323" id="p-323"

[00323] In an example, the nucleotide sequence is SEQ ID NO:36. id="p-324" id="p-324"

[00324] In an example, the nucleotide sequence is SEQ ID NO:37. id="p-325" id="p-325"

[00325] In an embodiment, the ligand comprises at least 10, 11, 12, 13, 14,15, 20, , 30, 35, 40, 45, 50 or 100 contiguous nucleotides of said nucleotide sequence. id="p-326" id="p-326"

[00326] In a Fourteenth Aspect: The ligand of any preceding aspect, wherein said disease or condition is hyperlipidaemia, hypercholesterolaemia (eg, familial hypercholesterolaemia), heart attack, stroke, coronary heart disease, atherosclerosis or a cardiovascular disease or condition. id="p-327" id="p-327"

[00327] The ligand of any preceding aspect, wherein the disease or condition is hypercholesterolemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, cholestatic liver disease, nephrotic syndrome, hypothyroidism, obesity, atherosclerosis or a cardiovascular disease. id="p-328" id="p-328"

[00328] In an example, said disease or condition is hypercholesterolaemia. The term hypercholesterolaemia, as used herein, refers to a condition in which cholesterol levels are elevated above a desired level. In some embodiments, this denotes that serum cholesterol 18936261-1 levels are elevated. In some embodiments, the desired level takes into account various risk factors that are known to one of skill in the art (and are described or referenced in US2O120093818). [00329] The ligand of any preceding aspect, wherein the human is identified as 5 heterozygous for Familial Hypercholesterolemia, statin intolerant, statin uncontrolled, or at risk for developing hypercholesterolemia, dyslipidemia, cholestatic liver disease, nephrotic syndrome, hypothyroidism, obesity, atherosclerosis or a cardiovascular disease. [00330] In a Fifteenth Aspect: The ligand of any preceding aspect, wherein said disease or condition is associated with elevated LDL cholesterol. 10 [00331] Cholesterol levels are measured in milligrams (mg) of cholesterol per deciliter (dL) of blood in the United States and some other countries. Canada and most European countries measure cholesterol in millimoles (mmol) per liter (L) of blood. Below are general guideline ideal ranges and elevated ranges. Total cholesterol Total cholesterol* (U.S. and some other countries) (Canada and most of Europe) Below 200 mg/dL Below 5.2 mmol/L Ideal 200-239 mg/dL 5.2-6.2 mmol/L Borderline high 240 mg/dL and above Above 6.2 mmol/L High LDL cholesterol LDL cholesterol* (U.S. and some other countries) (Canada and most of Europe) 100-129 mg/dL 2.6-3.3 mmol/L Ideal 130-159 mg/dL 3.4-4.1 mmol/L Borderline high 160-189 mg/dL 4.1-4.9 mmol/L High 190 mg/dL and above Above 4.9 mmol/L Very high 15 ♦Canadian and European guidelines differ slightly from U.S. guidelines. These conversions are based on U.S. guidelines. 18936261-1 id="p-332" id="p-332"

[00332] Elevated LDL cholesterol is, therefore, 160 mg/dL or above (4.1 mmol/L or above). id="p-333" id="p-333"

[00333] In a Sixteenth Aspect: The ligand of any preceding aspect, wherein the ligand inhibits human PCSK9 binding to human LDL receptor and optionally has been or is determined as capable of such inhibition. id="p-334" id="p-334"

[00334] In an example, the method comprises (before administering the ligand) determining that the ligand is capable of such inhibition. [0033S] Inhibition determination is eg, inhibition in a blood or serum sample, at rtp, at pH7, at 37 degrees centigrade and/or under the physiological conditions of a human body. [00336] In a Seventeenth Aspect: The ligand of any preceding aspect, wherein the human is resistant or substantially resistant to statin (eg, avorstatin and/or fluvastatin) treatment of said disease or condition. ]00337] In an Eighteenth Aspect: The ligand of any preceding aspect, wherein the ligand is for treating and/or preventing a PCSK9-mediated disease or condition in a human (i) whose genome comprises SEQ ID NO: 29 and wherein the human is of ASW,YRI,GBR,TSI, CLM,LWK,MXL,JPT,PUR,IBS,FIN or CEU ancestry; or (ii) whose genome comprises SEQ ID NO: 30 and wherein the human is of ASW,YRI,GBR,TSI,CLM, CHB,LWK,CHS,JPT,PUR,FIN or CEU ancestry; or (iii) whose genome comprises SEQ ID NO: 32 and wherein the human is of ASW,GBR,TSI,CLM, JPT,PUR,IBS,FIN or CEU ancestry; or (iv) whose genome comprises SEQ ID NO: 33 and wherein the human is of LWK,ASW,YRI or CLM ancestry; or (v) whose genome comprises SEQ ID NO: 34 and wherein the human is of LWK,ASW or YRI ancestry; or (vi) whose genome comprises SEQ ID NO: 35 and wherein the human is of PUR,TSI,FIN or CEU ancestry; or (vii) whose genome comprises SEQ ID NO: 36 and wherein the human is of LWK,ASW or YRI ancestry; or (viii) whose genome comprises SEQ ID NO: 37 and wherein the human is of CHS,ASW,JPT,PUR or CHB ancestry. id="p-338" id="p-338"

[00338] In a Nineteenth Aspect: The ligand of any preceding aspect, wherein the ligand is for treating and/or preventing a PCSK9-mediated disease or condition in a human (i) that expresses PCSK9 form fand wherein the human is of ASW,YRI,GBR,TSI,CLM,LWK,MXL,JPT,PUR,IBS,FIN or CEU ancestry; or 18936261-1 (ii) that expresses PCSK9 form cand wherein the human is of ASW,YRI,GBR,TSI,CLM,CHB,LWK,CHS,JPT,PUR,FIN or CEU ancestry; or (iii) that expresses PCSK9 form pand wherein the human is of ASW,GBR,TSI,CLM,JPT,PUR,IBS,FIN or CEU ancestry; or (iv) that expresses PCSK9 form m and wherein the human is of LWK,ASW,YRI or CLM ancestry; or (v) that expresses PCSK9 form eand wherein the human is of LWK,ASW or YRI ancestry; or (vi) that expresses PCSK9 form h and wherein the human is of PUR,TSI,FIN or CEU ancestry; or (vii) that expresses PCSK9 form a/and wherein the human is of LWK,ASW or YRI ancestry; or (viii) that expresses PCSK9 form <7 and wherein the human is of CHS, ASW, JPT, PUR or CHB ancestry. id="p-339" id="p-339"

[00339] In an example, said forms are the mature forms. id="p-340" id="p-340"

[00340] In an example, said forms are the pro-forms. id="p-341" id="p-341"

[00341] In a Twentieth Aspect: A pharmaceutical composition or kit for treating and/or preventing a PCSK9-mediated condition or disease (eg, as recited in aspect 14 or 15), the composition or kit comprising a ligand of any preceding aspect and optionally a statin (eg, cerovastatin, atorvastatin, simvastatin, pitavastin, rosuvastatin, fluvastatin, lovastatin or pravastatin); and optionally in combination with a label or instructions for use to treat and/or prevent said disease or condition in a human (eg, covering treatment of a human as recited in aspect 18 or 19); optionally wherein the label or instructions comprise a marketing authorisation number (eg, an FDA or EMA authorisation number); optionally wherein the label or instructions comprise directions to administer alirocumab or evolocumab to said human; optionally wherein the kit comprises an IV or injection device that comprises the ligand (and, eg, also a statin). id="p-342" id="p-342"

[00342] In a Twenty-first Aspect: A method of producing an anti-human PCSK9 antibody binding site, the method comprising obtaining a plurality of anti-PCSK9 antibody binding sites, screening the antibody binding sites for binding to a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, ajawd qor a catalytic or C-terminal domain or a peptide thereof that comprises amino acid variation from the corresponding sequence of SEQ ID NO: 1, 2 or 3 and isolating an antibody binding site that binds in the screening step, and optionally producing a form f, c, r, p, m, e, h, ajor q PCSK9-binding fragment or derivative of the isolated antibody. id="p-343" id="p-343"

[00343] In an example, said forms are the mature forms. 18936261-1 id="p-344" id="p-344"

[00344] In an example, said forms are the pro-forms. id="p-345" id="p-345"

[00345] In an example of this and the next aspect, the plurality of binding sites comprises or consists of a plurality of 4-chain antibodies or fragments thereof, eg, dAbs, Fabs or scFvs. Suitable methods for producing pluralities of binding sites for screening include phage display (producing a phage display library of antibody binding sites), ribosome display (producing a ribosome display library of antibody binding sites), yeast display (producing a yeast display library of antibody binding sites), or immunisation of a non-human vertebrate (eg, a rodent, eg, a mouse or rat, eg, a Velocimouse™, Kymouse™, Xenomouse™, Aliva Mouse™, HuMab Mouse™, Omnimouse™, Omnirat™ or MeMo Mouse™) with a PCSK9 epitope and isolation of a repertoire of antibody-producing cells (eg, a B-cell, plasma cell or plasmablast repertoire) and/or a repertoire of isolated antibodies. id="p-346" id="p-346"

[00346] In an example, the method comprises selecting one or more antibody binding sites that each specifically binds to a human PCSK9 epitope comprising amino acid variation from the corresponding sequence of SEQ ID NO: 1, 2 or 3. id="p-347" id="p-347"

[00347] For example, the ligand specifically binds to an epitope comprising an amino acid that is variant compared to the corresponding amino acid of the PCSK9 encoded by SEQ ID NO: 1, 2 or 3. In an example, the ligand specifically binds to an epitope comprising two or more such variant amino acids. In an example, specific binding means binding with an affinity (Kd) of ImM, lOOnM, lOnM or InM or less, eg, as determined by SPR.. [00348] The term epitope is a region of an antigen that is bound by an antibody.

Epitopes may be defined as structural or functional. Functional epitopes are generally a subset of the structural epitopes and have those residues that directly contribute to the affinity of the interaction. Epitopes may also be conformational, that is, composed of non-linear amino acids. In certain embodiments, epitopes may include determinants that are chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics, and/or specific charge characteristics. id="p-349" id="p-349"

[00349] In a Twenty-second Aspect: A method of producing an anti-human PCSK9 antibody, the method comprising immunising a non-human vertebrate (eg, a mouse or a rat) with a human PCSK9 comprising an amino acid sequence selected from the group consisting of the amino acid sequences of forms f, c, r, p, m, e, h, a/and q or a catalytic or C-terminal domain or a peptide thereof that comprises amino acid variation from the corresponding sequence of SEQ ID NO: 1, 2 or 3 and isolating an antibody that binds a human PCSK9 comprising selected from the group consisting of forms f, c, r, p, m, e, h, a/and q or 18936261-1 a catalytic or C-terminal domain or a peptide thereof that comprises amino acid variation from the corresponding sequence of SEQ ID NO: 1, 2 or 3, and optionally producing a form f, c, r, p, m, e, h, 5/or <7PCSK9-binding fragment or derivative of the isolated antibody. id="p-350" id="p-350"

[00350] In an example, said forms are the mature forms. id="p-351" id="p-351"

[00351] In an example, said forms are the pro-forms. id="p-352" id="p-352"

[00352] In a Twenty-third Aspect: The method of aspect 21 or 22, comprising the step of obtaining a nucleic acid encoding the antibody, fragment, derivative or binding site and optionally inserting the nucleic acid in an expression vector. id="p-353" id="p-353"

[00353] For example, the method comprises isolating a cell (eg, B-cell, plasmablast, plasma cell or memory cell) comprising the nucleic acid, wherein the cell is obtained from a non-human vertebrate that has been immunised with the PCSK9 epitope. id="p-354" id="p-354"

[00354] In a Twenty-fourth Aspect: A kit for PCSK9 genotyping a human, wherein the kit comprises a nucleic acid (i) comprising a sequence of 10 or more (eg, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more) contiguous nucleotides that specifically hybridises to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof, or specifically hybridises to an antisense sequence or an RNA transcript of said sequence, wherein said sequence of contiguous nucleotides hybridises to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridises to an antisense sequence or an RNA transcript thereof; and/or (ii) comprising a sequence of at least 10 or more (eg, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more) nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or comprising an antisense sequence or RNA version of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28. id="p-355" id="p-355"

[00355] In an example, the nucleotide sequence is selected from the group consisting of SEQ ID NOs: 29-35 and 37; or selected from the group consisting of SEQ ID NOs: 29-32 and 34-37; or selected from the group consisting of SEQ ID NOs: 29-32, 34, 35 and 37. These are naturally-occurring allele (haplotype) sequences that do not encode 46L and which meet the criteria set out above. These groups comprise variants that are associated with elevated LDL-C. id="p-356" id="p-356"

[00356] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated LDL-C (Pisciotta ef a/2006). 18936261-1 id="p-357" id="p-357"

[00357] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen et a/2005). id="p-358" id="p-358"

[00358] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35, 36 and 37; or selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35 and 37. These are allele (haplotype) sequences that have a naturallyoccurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-359" id="p-359"

[00359] In an example, the nucleotide sequence is SEQ ID NO:29. id="p-360" id="p-360"

[00360] In an example, the nucleotide sequence is SEQ ID NO:30. id="p-361" id="p-361"

[00361] In an example, the nucleotide sequence is SEQ ID NO:31. id="p-362" id="p-362"

[00362] In an example, the nucleotide sequence is SEQ ID NO:32. id="p-363" id="p-363"

[00363] In an example, the nucleotide sequence is SEQ ID NO:33. id="p-364" id="p-364"

[00364] In an example, the nucleotide sequence is SEQ ID NO:34. id="p-365" id="p-365"

[00365] In an example, the nucleotide sequence is SEQ ID NO:35. id="p-366" id="p-366"

[00366] In an example, the nucleotide sequence is SEQ ID NO:36. [00367| In an example, the nucleotide sequence is SEQ ID NO:37. id="p-368" id="p-368"

[00368] In a Twenty-fifth Aspect: id="p-369" id="p-369"

[00369] A kit for PCSK9 genotyping or phenotyping a human, wherein the kit comprises a ligand according to any one of aspects 1 to 19 or an antibody, fragment or derivative produced by the method of any one of aspects 21 to 23. [00370| In a Twenty-sixth Aspect: Use of an anti-PCSK9 ligand that binds a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, ay and q in the manufacture of a medicament for treating and/or preventing a PCSK9-mediated disease or condition in a human whose genome comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37, optionally for treating and/or preventing a PCSK9mediated disease or condition in a human as recited in aspect 18 or 19. id="p-371" id="p-371"

[00371] In an example, said forms are the mature forms. 100372] In an example, said forms are the pro-forms. {00373] In a Twenty-seventh Aspect: Use of an anti-PCSK9 ligand that binds a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, ay and q in the manufacture of a medicament for targeting said PCSK9 in a human to treat and/or prevent a disease or condition mediated by PCSK9, optionally for targeting PCSK9 in a human as recited in aspect 18 or 19. 18936261-1 id="p-374" id="p-374"

[00374] In an example, said forms are the mature forms. id="p-375" id="p-375"

[00375] In an example, said forms are the pro-forms. {00376] In an example, the nucleotide sequence is selected from the group consisting of SEQ ID NOs: 29-35 and 37; or selected from the group consisting of SEQ ID NOs: 29-32 and 34-37; or selected from the group consisting of SEQ ID NOs: 29-32, 34, 35 and 37. These are naturally-occurring allele (haplotype) sequences that do not encode 46L and which meet the criteria set out above. These groups comprise variants that are associated with elevated LDL-C. id="p-377" id="p-377"

[00377] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated LDL-C (Pisciotta et a/2006). id="p-378" id="p-378"

[00378] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen eia/2005). id="p-379" id="p-379"

[00379] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35, 36 and 37; or selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35 and 37. These are allele (haplotype) sequences that have a naturallyoccurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-380" id="p-380"

[00380] [00381] [00382] [00383] [00384] In an example, the nucleotide sequence is SEQ ID NO: 29. In an example, the nucleotide sequence is SEQ ID NO: 30. In an example, the nucleotide sequence is SEQ ID NO: 31, In an example, the nucleotide sequence is SEQ ID NO: 32. In an example, the nucleotide sequence is SEQ ID NO: 33. [00385| [00386] [00387] [00388] [00389] [00390] In an example, the nucleotide sequence is SEQ ID NO: 34. In an example, the nucleotide sequence is SEQ ID NO: 35. In an example, the nucleotide sequence is SEQ ID NO: 36. In an example, the nucleotide sequence is SEQ ID NO: 37. The ligand can be any anti-PCSK9 ligand disclosed herein. In a Twenty-eighth Aspect: The use of aspect 26 or 27, wherein the ligand, human, disease or condition is according to any one of aspects 1 to 19. id="p-391" id="p-391"

[00391] In a Twenty-ninth Aspect: A method of targeting a PCSK9 for treating and/or preventing a PCSK9-mediated disease or condition in a human, the method comprising administering an anti-PCSK9 ligand to a human comprising a nucleotide sequence selected 18936261-1 from the group consisting SEQ ID NOs: 29-37, whereby a PCSK9 encoded by said nucleotide sequence is targeted. id="p-392" id="p-392"

[00392] The ligand can be any anti-PCSK9 ligand disclosed herein. id="p-393" id="p-393"

[00393] In a Thirtieth Aspect: The method of aspect 29, wherein the method comprises targeting a human PCSK9 selected from the group consisting of forms f, cf r, p, m, e, h, aj and q with said ligand to treat and/or prevent said disease or condition in said human. [00394] In an example, said forms are the mature forms. id="p-395" id="p-395"

[00395] In an example, said forms are the pro-forms. id="p-396" id="p-396"

[00396] In a Thirty-first Aspect: A method of treating and/or preventing a disease or condition mediated by PCSK9 in a human, the method comprising targeting a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, ajand q by administering to the human a ligand that binds said PCSK9 thereby treating and/or preventing said disease or condition in the human. id="p-397" id="p-397"

[00397] In an example, said forms are the mature forms. 100398] In an example, said forms are the pro-forms. id="p-399" id="p-399"

[00399] The ligand can be any anti-PCSK9 ligand disclosed herein. id="p-400" id="p-400"

[00400] In a Thirty-second Aspect: The method of aspect 31, wherein the genome of the human comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37.

J00401] In an example, the nucleotide sequence is selected from the group consisting of SEQ ID NOs: 29-35 and 37; or selected from the group consisting of SEQ ID NOs: 29-32 and 34-37; or selected from the group consisting of SEQ ID NOs: 29-32, 34, 35 and 37. These are naturally-occurring allele (haplotype) sequences that do not encode 46L and which meet the criteria set out above. These groups comprise variants that are associated with elevated LDL-C. id="p-402" id="p-402"

[00402] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated LDL-C (Pisciotta ef 5/2006). id="p-403" id="p-403"

[00403] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen eia/2005). , [00404] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35, 36 and 37; or selected from the group consisting of SEQ ID NOs: 31, 32, 34, 35 and 37. These are allele (haplotype) sequences that have a naturally18936261-1 occurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. [00405] In an example, the nucleotide sequence is SEQ ID NO: 29. [00406] In an example, the nucleotide sequence is SEQ ID NO: 30. 5 [00407] In an example, the nucleotide sequence is SEQ ID NO: 31. [00408] In an example, the nucleotide sequence is SEQ ID NO: 32. 100409] In an example, the nucleotide sequence is SEQ ID NO: 33. [00410] In an example, the nucleotide sequence is SEQ ID NO: 34. [00411] In an example, the nucleotide sequence is SEQ ID NO: 35. 10 [00412] In an example, the nucleotide sequence is SEQ ID NO: 36. [00413| In an example, the nucleotide sequence is SEQ ID NO: 37. [00414| In a Thirty-third Aspect: The method of any one of aspects 29 to 32, wherein the human has been or is genotyped as positive for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or the catalytic- or C-terminal domain- 15 encoding sequence thereof. [00415] In a Thirty-fourth Aspect: The method of any one of aspects 29 to 33, wherein the human has been or is phenotyped as positive for a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, ay and q. |00416] In an example, said forms are the mature forms. 20 [00417] In an example, said forms are the pro-forms. [00418| In a Thirty-fifth Aspect: The method of any one of aspects 29 to 34, wherein the method comprises genotyping the human as positive for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or the catalytic- or C-terminal domain-encoding sequence thereof. 25 [00419] In a Thirty-sixth Aspect: The method of any one of aspects 29 to 35, wherein the method comprises phenotyping the human as positive for a human PCSK9 sequence selected from the group consisting of forms f, c, r, p, m, e, h, ajand q. [00420] In an example, said forms are the mature forms. [00421] In an example, said forms are the pro-forms. 30 [00422] In a Thirty-seventh Aspect: The method of any one of aspects 29 to 36, wherein the human has been or is genotyped as heterozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or the catalytic- or C-terminal domain-encoding sequence thereof; optionally wherein the human has been or is genotyped as comprising the nucleotide sequence of SEQ ID NO: 28 or the catalytic- or C-terminal 18936261-1 domain-encoding sequence thereof and a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or the catalytic- or C-terminal domain-encoding sequence thereof. id="p-423" id="p-423"

[00423] In a Thirty-eighth Aspect: The method of any one of aspects 29 to 37, wherein the genome of the human has been or is genotyped as homozygous for a nucleotide sequence selected from the group consisting of of SEQ ID NOs: 29-37 or the catalytic- or Cterminal domain-encoding sequence thereof. id="p-424" id="p-424"

[00424] In a Thirty-ninth Aspect: The method of any one of aspects 29 to 38, wherein the method comprises genotyping the human for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or the catalytic- or C-terminal domainencoding sequence thereof before administering the ligand to the human, wherein the ligand is determined to be capable of binding to a PCSK9 encoded by said selected sequence. id="p-425" id="p-425"

[00425] In a Fortieth Aspect: The method of any one of aspects 29 to 39, wherein the ligand, human, disease or condition is according to any one of aspects 1 to 19. [00426] In a Forty-first Aspect: A method according to any one of aspects 29 to for treating and/or preventing a condition or disease as recited in aspect 14 or 15, the method comprising administering said ligand and a statin (eg, cerovastatin, atorvastatin, simvastatin, pitavastin, rosuvastatin, fluvastatin, lovastatin or pravastatin) to the human. id="p-427" id="p-427"

[00427] In a Forty-second Aspect: The method of aspect 41, wherein the ligand and statin are administered separately. id="p-428" id="p-428"

[00428] In a Forty-third Aspect: The method of aspect 41, wherein the ligand and statin are administered simultaneously. [00429| In a Forty-fourth Aspect: The method of any one of aspects 29 to 43, wherein the ligand is administered by subcutaneous injection. id="p-430" id="p-430"

[00430] In a Forty-fifth Aspect: A method of PCSK9 genotyping a nucleic acid sample of a human, the method comprising identifying in the sample the presence of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or the catalyticor C-terminal domain-encoding sequence thereof. id="p-431" id="p-431"

[00431] In a Forty-sixth Aspect: A method of PCSK9 typing a protein sample of a human, the method comprising identifying in the sample the presence of a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, aj and q. id="p-432" id="p-432"

[00432] In an example, said forms are the mature forms. id="p-433" id="p-433"

[00433] In an example, said forms are the pro-forms. 18936261-1 id="p-434" id="p-434"

[00434] In an example, the method comprises obtaining a PCSK9 protein sample from the human and then carrying out the identifying step. id="p-435" id="p-435"

[00435] In a Forty-seventh Aspect: The method of aspect 45 or 46, comprising obtaining a sample of serum, blood, faeces, hair, tissue, cells, urine or saliva from a human, whereby the nucleic acid or protein sample is obtained and used in the step of identifying said sequence, id="p-436" id="p-436"

[00436] In a Forty-eight Aspect: The method of any one of aspects 45 to 47, comprising using a ligand according to any one of aspects 1 to 19 to carry out said identifying step. id="p-437" id="p-437"

[00437] In a Forty-ninth Aspect: A method of treating and/or preventing in a human patient a cardiovascular disease or condition, or a disease or condition that is associated with elevated LDL cholesterol (eg, hypercholesterolaemia), wherein the patient is receiving or has previously received statin treatment for said disease or condition, the method comprising typing the patient using a method of any one of aspects 45 to 48 and administering a ligand according to one of aspects 1 to 19 whereby the human is treated or said disease or condition is prevented; optionally also reducing or stopping statin treatment. [00438] In an example, said reducing or stopping comprises reducing the dose and/or dosing frequency of statin. id="p-439" id="p-439"

[00439] In a Fiftieth Aspect: A diagnostic, therapeutic or prophylactic kit comprising a ligand that is capable of binding to or has been or is determined as capable of binding to an amino acid sequence selected from SEQ ID NOs: 4-27 and instructions for carrying out the method of any one of aspects 46 to 49 and/or a label or instructions indicating or covering administration of the ligand to a human as defined in any one of aspects 1 to 19. id="p-440" id="p-440"

[00440] In a Fifty-first Aspect: A diagnostic, therapeutic or prophylactic kit comprising a nucleic acid probe comprising a nucleotide sequence that specifically hybridises to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or an antisense sequence or RNA transcript thereof and instructions for carrying out the method of aspect 45, 47 or 48. id="p-441" id="p-441"

[00441] In embodiments of any of the aspects described herein, optionally, the PCSK9 is human PCSK9, eg, a mature, cleaved, autocatalysed or active PCSK9. In an example, the disease is a cardiovascular disease such as hyperlipidaemia. 18936261-1 |00442| In examples of the present invention, the ligand specifically binds to human PCSK9, eg, one or more of the rare PCSK9 variants disclosed herein (eg, one, two, three, more or all mature forms f, c, r, p, m, e, h, ay and q) and optionally also the a and/or a'form.

For example, the ligand specifically binds to mature form /and/or cas well as form a. id="p-443" id="p-443"

[00443] Determination of such binding can be performed by any antibody binding test as known in the art, eg, by surface plasmon resonance. Binding to each such form is, for example, respectively with a Kd of at least ImM, ΙΟΟηΜ, InM, ΙΟΟρΜ, lOpM or lpM. id="p-444" id="p-444"

[00444] In an example, the ligand binds form a and a PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, a/and q, wherein the ligand binding to said selected form is with a Kd (determined by SPR) that is at least 60, 70, 80, 90 or 95% of the Kd for binding to form a. In an embodiment, both forms are mature forms. In an embodiment, both forms are pro-forms. id="p-445" id="p-445"

[00445] In an example, the ligand binds form a and form f, wherein the ligand binding to form Ais with a Kd (determined by SPR) that is at least 60, 70, 80, 90 or 95% of the Kd for binding to form a. In an embodiment, both forms are mature forms. In an embodiment, both forms are pro-forms. id="p-446" id="p-446"

[00446] In an example, the ligand binds form a and form c, wherein the ligand binding to form cis with a Kd (determined by SPR) that is at least 60, 70, 80, 90 or 95% of the Kd for binding to form a. In an embodiment, both forms are mature forms. In an embodiment, both forms are pro-forms. id="p-447" id="p-447"

[00447] In an example, the ligand binds form a and form r, wherein the ligand binding to form ris with a Kd (determined by SPR) that is at least 60, 70, 80, 90 or 95% of the Kd for binding to form a. In an embodiment, both forms are mature forms. In an embodiment, both forms are pro-forms. id="p-448" id="p-448"

[00448] In an example, the ligand binds form a and form p, wherein the ligand binding to form p is with a Kd (determined by SPR) that is at least 60, 70, 80, 90 or 95% of the Kd for binding to form a. In an embodiment, both forms are mature forms. In an embodiment, both forms are pro-forms. id="p-449" id="p-449"

[00449] In an example, the ligand binds form a and form m, wherein the ligand binding to form m is with a Kd (determined by SPR) that is at least 60, 70, 80, 90 or 95% of the Kd for binding to form a. In an embodiment, both forms are mature forms. In an embodiment, both forms are pro-forms. id="p-450" id="p-450"

[00450] In an example, the ligand binds form a and form e, wherein the ligand binding to form e is with a Kd (determined by SPR) that is at least 60, 70, 80, 90 or 95% of 18936261-1 the Kd for binding to form a. In an embodiment, both forms are mature forms. In an embodiment, both forms are pro-forms. id="p-451" id="p-451"

[00451] In an example, the ligand binds form id="p-452" id="p-452"

[00452] In an example, the ligand binds form a and form aj, wherein the ligand binding to form ajis with a Kd (determined by SPR.) that is at least 60, 70, 80, 90 or 95% of the Kd for binding to form a. In an embodiment, both forms are mature forms. In an embodiment, both forms are pro-forms. ]00453] In an example, the ligand binds form a and form q, wherein the ligand binding to form q is with a Kd (determined by SPR) that is at least 60, 70, 80, 90 or 95% of the Kd for binding to form a. In an embodiment, both forms are mature forms. In an embodiment, both forms are pro-forms. id="p-454" id="p-454"

[00454] In examples ofthe present invention, the ligand neutralises human PCSK9, eg, one or more of the rare PCSK9 variants disclosed herein (eg, one, two, three, more or all mature forms f,c,r,p, m, e, h, ajand q) and optionally also the a and/or a'form. For example, the ligand neutralises mature form f and/or c as well as form a. Determination of neutralisation can be performed, for example, by any neutralisation assay method disclosed in US20120093818A1 (Amgen, Inc) or US20110065902A1 (Regeneron Pharmaceuticals, Inc). Ligands of the invention that bind or target PCSK9 are useful, for example, for therapeutic and prophylactic applications disclosed in US20120093818A1 and US20110065902A1, these specific disclosures being incorporated herein by reference in their entirety for use in the present invention and for possible inclusion in claims herein. id="p-455" id="p-455"

[00455] In embodiments where the ligand is used for therapeutic applications, an antigen binding protein can inhibit, interfere with or modulate one or more biological activities of a PCSK9 (eg, one or more of the rare variants disclosed herein and optionally also the a and/or a'form). In one embodiment, ligand binds specifically to human PCSK9 (eg, one or more of the rare variants disclosed herein and optionally also the a and/or a'form) and/or substantially inhibits binding of human PCSK9 (eg, said one or more ofthe rare variants disclosed herein and optionally also the a and/or a'form) to LDLR by at least 20%, eg, 20%40%, 40-60%, 60-80%, 80-85%, or more (for example, by measuring binding in an in vitro competitive binding assay). In an example, the ligand is an antibody. 18936261-1 id="p-456" id="p-456"

[00456] In an embodiment, the ligand has a Kd of less (binding more tightly) than -7, IO-8, 10~9, IO-10, IO-11, 10"12, 10-13 M for binding to one, two or more of the rare variants disclosed herein and optionally also the a and/or a'form. In an example, Kd is determined using SPR. id="p-457" id="p-457"

[00457] In an embodiment, the ligand has an IC50 for blocking the binding of LDLR to one or more of the rare PCSK9 variants disclosed herein (and optionally also the a and/or a' form) of less than 1 microM, 1000 nM to 100 nM, 100 nM to 10 nM, 10 nM to 1 nM, 1000 pM to 500 pM, 500 pM to 200 pM, less than 200 pM, 200 pM to 150 pM, 200 pM to 100 pM, 100 pM to 10 pM, 10 pM to 1 pM. id="p-458" id="p-458"

[00458] In an embodiment, the ligand has an IC50 for blocking the binding of LDLR to the a and/or a'form of PCSK9 that is no more than 1000, 100, 90, 80, 70, 60, 50, 40, 30, 20 or 10-fold more (ie, more inhibitor/) than the IC50 for blocking the binding of LDLR to one or more of the rare PCSK9 variants disclosed herein (eg, one or more PCSK9 proteins comprising a sequence selected from SEQ ID NOs: 4 to 27). Additionally or alternatively, for example, the ligand has an IC50 for blocking the binding of LDLR to (i) the a and/or a'form of less than 1 microM, 1000 nM to 100 nM, 100 nM to 10 nM, 10 nM to 1 nM, 1000 pM to 500 pM, 500 pM to 200 pM, less than 200 pM, 200 pM to 150 pM, 200 pM to 100 pM, 100 pM to 10 pM, 10 pM to 1 pM, eg, in the range of ImM to IpM (eg, ImM to lOOpM; lOnM to lOOpM; InM to lOpM; or lOOpM to IpM) and (ii) one or more PCSK9 proteins comprising a sequence selected from SEQ ID NOs: 4 to 27 of less than 1 microM, 1000 nM to 100 nM, 100 nM to 10 nM, 10 nM to 1 nM, 1000 pM to 500 pM, 500 pM to 200 pM, less than 200 pM, 200 pM to 150 pM, 200 pM to 100 pM, 100 pM to 10 pM, 10 pM to 1 pM, eg, in the range of ImM to IpM (eg, ImM to lOOpM; lOnM to lOOpM; InM to lOpM; or lOOpM to IpM). id="p-459" id="p-459"

[00459] In an embodiment, the ligand binds to the a and/or a'form of PCSK9 with a binding affinity (Kd) that is greater than up to 10%, greater than up to 20%, greater than up to 40%, greater than up to 50%, greater than up to 55%, greater than up to 60%, greater than up to 65%, greater than up to 70%, greater than up to 75%, greater than up to 80%, greater than up to 85%, greater than up to 90%, greater than up to 95% or greater than up to 100% (ie, is double) relative to binding to a PCSK9 comprising a sequence selected from SEQ ID NOs: 4 to 27. Such binding measurements can be made using a variety of binding assays known in the art, eg, using surface plasmon resonance (SPR), such as by Biacore™ or using the ProteOn XPR36™ (Bio-Rad®), or using KinExA® (Sapidyne Instruments, Inc). (00460] In one embodiment, the surface plasmon resonance (SPR) is carried out at °C. In another embodiment, the SPR is carried out at 37°C. 18936261-1 id="p-461" id="p-461"

[00461] In one embodiment, the SPR is carried out at physiological pH, such as about pH7 or at pH7.6 (eg, using Hepes buffered saline at pH7.6 (also referred to as HBSEP))· id="p-462" id="p-462"

[00462] In one embodiment, the SPR is carried out at a physiological salt level, eg, 150mM NaCI. id="p-463" id="p-463"

[00463] In one embodiment, the SPR is carried out at a detergent level of no greater than 0.05% by volume, eg, in the presence of P20 (polysorbate 20; eg, Tween-20TM) at 0.05% and EDTAat3mM. id="p-464" id="p-464"

[00464] In one example, the SPR is carried out at 25°C or 37°C in a buffer at pH7.6, 150mM NaCI, 0.05% detergent (eg, P20) and 3mM EDTA. The buffer can contain lOmM Hepes. In one example, the SPR is carried out at 25°C or 37°C in HBS-EP. HBS-EP is available from Teknova Inc (California; catalogue number H8022). id="p-465" id="p-465"

[00465] In an example, the affinity of the ligand which is an antibody is determined using SPR by 1. Coupling anti-mouse (or other relevant vertebrate) IgG (eg, Biacore BR-1008-38) to a biosensor chip (eg, GLM chip) such as by primary amine coupling; 2. Exposing the anti-mouse IgG (vertebrate antibody) to a test IgG antibody to capture test antibody on the chip; 3. Passing the test antigen over the chip's capture surface at 1024nM, 256nM, 64nM, 16nM, 4nM with a OnM (i.e. buffer alone); and 4. And determining the affinity of binding of test antibody to test antigen using surface plasmon resonance, eg, under an SPR condition discussed above (eg, at 25°C in physiological buffer). SPR can be carried out using any standard SPR apparatus, such as by BiacoreTM or using the ProteOn XPR36TM (Bio-Rad®), [00466] Regeneration of the capture surface can be carried out with lOmM glycine at pH1.7. This removes the captured antibody and allows the surface to be used for another interaction. The binding data can be fitted to 1:1 model inherent using standard techniques, eg, using a model inherent to the ProteOn XPR36™ analysis software. id="p-467" id="p-467"

[00467] In an embodiment, assaying or testing of a ligand of the invention is carried out at or substantially at pH7 (eg, for in vitro tests and assays,) and at or substantially at rtp. [00468] One example of an IgG2 heavy chain constant domain of an anti-PCSK9 antibody of the present invention has the amino acid sequence as shown in SEQ ID NO: 154, FIG. 3KK of US20120093818A1, which sequence is incorporated herein by reference. 18936261-1 id="p-469" id="p-469"

[00469] One example of an IgG4 heavy chain constant domain of an anti-PCSK9 antibody of the present invention has the amino acid sequence as shown in SEQ ID NO: 155, FIG. 3KK of US20120093818A1, which sequence and disclosure is incorporated herein by reference in its entirety. id="p-470" id="p-470"

[00470] One example of a kappa light chain constant domain of an anti-PCSK9 antibody has the amino acid sequence as shown in SEQ ID NO: 157, FIG. 3KK of US20120093818A1, which sequence and disclosure is incorporated herein by reference in its entirety. id="p-471" id="p-471"

[00471] One example of a lambda light chain constant domain of an anti-PCSK9 antibody has the amino acid sequence as shown in SEQ ID NO: 156, FIG. 3KK of US20120093818A1, which sequence and disclosure is incorporated herein by reference in its entirety. id="p-472" id="p-472"

[00472] In examples of the present invention, the ligand binds mature PCSK9, eg, a mature form of one or more of the rare variants disclosed herein and optionally also the a and/or a'form. 100473] In examples of the present invention, the ligand binds the catalytic domain of PCSK9, eg, of a mature form of one or more of the rare variants disclosed herein and optionally also the a and/or a'form. id="p-474" id="p-474"

[00474] In examples of the present invention, the ligand binds the prodomain of PCSK9, eg, of a mature form of one or more of the rare variants disclosed herein and optionally also the a and/or a'form. id="p-475" id="p-475"

[00475] In some embodiments, the ligand binds to the V domain of PCSK9, eg, of a mature form of one or more of the rare variants disclosed herein and optionally also the a and/or a'form. In some embodiments, the ligand binds to the V domain of PCSK9 (eg, of a mature form of one or more of the rare variants disclosed herein and optionally also the a and/or a'form) and prevents (or reduces, eg, by at least 10%) PCSK9 from binding to LDLR. In some embodiments, the ligand binds to the V domain of PCSK9 (eg, of a mature form of one or more of the rare variants disclosed herein and optionally also the a and/or a'form), and while it does not prevent (or reduce) the binding of PCSK9 to LDLR, the ligand prevents or reduces (eg, by at least 10%) the adverse activities mediated through PCSK9 on LDLR. [00476] In examples of the present invention, the ligand is or comprises a fully human antibody. In an example, the ligand comprises human variable regions or humanised variable regions. 18936261-1 id="p-477" id="p-477"

[00477] In an example, the ligand of the invention specifically binds to an epitope of a human PCSK9 selected from the group consisting of forms f, p r, p, m, e, h, ay and q, wherein the epitope comprises at least one amino acid that is not found in form a. For example, the amino acid is selected from the group consisting of 46L, 53V, 425S, 443T, 474V, 619P and 670G (numbering as used in SEQ ID NO:1). For example, the amino acid is selected from the group consisting of 425S, 443T, 474V, 619P and 670G (numbering as used in SEQ ID NO:1). For example, the amino acid is selected from the group consisting of 425S and 443T (numbering as used in SEQ ID NO:1), For example, the amino acid is selected from the group consisting of 474V, 619P and 670G (numbering as used in SEQ ID NO:1). In an example, the PCSK9 form is the mature form. In an example, the PCSK9 form is the pro-form. In an example, the ligand also specifically binds to form a and/or a'. In an embodiment, the ligand specifically binds to an epitope of form YPCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to an epitope of form cPCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to an epitope of form r PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to an epitope of form p PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to an epitope of form m PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to an epitope of form e PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to an epitope of form h PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to an epitope of form aj PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to an epitope of form q PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. id="p-478" id="p-478"

[00478] In an embodiment, ligand binds specifically to the pro-domain of a human PCSK9 selected from the group consisting of forms f, p r, p, m, e, h, ay and q. In an example, the ligand also specifically binds to the pro-domain of form a and/or a'. In an embodiment, the ligand specifically binds to the pro-domain of form APCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the pro-domain of form cPCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the pro18936261-1 domain of form rPCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the pro-domain of form p PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the pro-domain of form m PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the pro-domain of form e PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the pro-domain of form h PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the prodomain of form aj PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the pro-domain of form q PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. [00479] In an embodiment, ligand binds specifically to the catalytic domain of a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, aj and q. In an example, the ligand also specifically binds to the catalytic domain of form a and/or a'. In an embodiment, the ligand specifically binds to the catalytic domain of form /PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the catalytic domain of form cPCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the catalytic domain of form cPCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the catalytic domain of form pPCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the catalytic domain of form m PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the catalytic domain of form ePCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the catalytic domain of form h PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the catalytic domain of form a/PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the catalytic domain of form 7PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. id="p-480" id="p-480"

[00480] In an embodiment, ligand binds specifically to the C-terminal domain of a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, Λ, ay and q. In an 18936261-1 example, the ligand also specifically binds to the C-terminal domain'of form a and/or a'. In an embodiment, the ligand specifically binds to the C-terminal domain of form 7PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the C-terminal domain of form cPCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the C-terminal domain of form r PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the C-terminal domain of form p PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the C-terminal domain of form m PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the C-terminal domain of form e PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the C-terminal domain of form h PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the C-terminal domain of form aj PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the C-terminal domain of form 7PCSK9Z wherein the epitope comprises at least one amino acid that is not found in form a. id="p-481" id="p-481"

[00481] In an embodiment, ligand binds specifically to the substrate-binding groove of a human PCSK9 selected from the group consisting of forms f, p r, p, m, e, h, ay and q (see Cunningham et al., Nat Struct Mol Biol. 2007 May; 14(5):413-9. Epub 2007 Apr 15, Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia, incorporated herein in its entirety by reference). In an example, the ligand also specifically binds to the substrate-binding groove of form a and/or a'. In an embodiment, the ligand specifically binds to the Substrate-binding groove of form 7PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the Substrate-binding groove of form cPCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the Substrate-binding groove of form rPCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the Substrate-binding groove of form p PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the Substrate-binding groove of form m PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand 18936261-1 specifically binds to the Substrate-binding groove of form e PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the Substrate-binding groove of form h PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the Substrate-binding groove of form aj PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the Substrate-binding groove of form q PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. id="p-482" id="p-482"

[00482] Reference is made to US20120093818A1 (Amgen, Inc), the entire disclosure of which is incorporated herein by reference. This patent application discloses relevant ligands for use in the present invention, as well as examples and methods of producing and testing ligands that can be used with reference to the present invention. [00483] In an example, the ligand is or comprises an antibody disclosed in Table 2 of US20120093818A1 (Amgen, Inc) or is a PCSK9-binding derivative thereof. id="p-484" id="p-484"

[00484] In an embodiment, the PCSK9-binding ligand of the invention is selected from the antigen binding proteins disclosed in US20120093818A1 (Amgen, Inc), eg, in paragraphs [0009] to [0014] and [0058] to [0063] of US20120093818A1; all of these disclosures (including the sequences of such proteins) are incorporated herein by reference as though explicitly recited herein and for possible inclusion in one or more claims or for use in the present invention. id="p-485" id="p-485"

[00485] In this paragraph SEQ ID NOs are those as appearing in US20120093818A1 (Amgen, Inc) and these sequences are incorporated herein by reference as though explicitly recited herein and for possible inclusion in one or more claims or for use in the present invention. In some aspects, the ligand of the invention comprises an isolated antigen binding protein that binds PCSK9 comprising: A) one or more heavy chain complementary determining regions (CDRHs) selected from the group consisting of: (i) a CDRH1 from a CDRH1 in a sequence selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60; (ii) a CDRH2 from a CDRH2 in a sequence selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60; (iii) a CDRH3 from a CDRH3 in a sequence selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60; and (iv) a CDRH of (i), (ii), and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more 18936261-1 than 4 amino acids; B) one or more light chain complementary determining regions (CDRLs) selected from the group consisting of: (i) a CDRLI from a CDRLI in a sequence selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46; (ii) a CDRL2 from a CDRL2 in a sequence selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46; (iii) a CDRL3 from a CDRL3 in a sequence selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46; and (iv) a CDRL of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 4 amino acids; or C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B). In some embodiments, the isolated antigen binding protein comprises at least one CDRH of A) and at least one CDRL of B). In some embodiments, the isolated antigen binding protein comprises at least two CDRH of A) and at least two CDRL of B). In some embodiments, the isolated antigen binding protein comprises said CDRH1, CDRH2, CDRH3, CDRLI, CDRL2 and CDRL3. In some embodiments, the CDRH of A) is selected from at least one of the group consisting of: (i) a CDRH1 amino acid sequence selected from the CDRH1 in a sequence selected from the group consisting of SEQ ID NO: 67, 79, 89, and 49; (ii) a CDRH2 amino acid sequence selected from the CDRH2 in a sequence selected from the group consisting of SEQ ID NO: 67, 79, 89, and 49; (iii) a CDRH3 amino acid sequence selected from the CDRH3 in a sequence selected from the group consisting of SEQ ID NO: 67, 79, 89, and 49; and (iv) a CDRH of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 2 amino acids. In addition, the CDRL of B) is selected from at least one of the group consisting of: (i) a CDRLI amino acid sequence selected from the CDRLI in a sequence selected from the group consisting of SEQ ID NO: 12, 35, 32, and 23; (ii) a CDRL2 amino acid sequence selected from the CDRL2 in a sequence selected from the group consisting of SEQ ID NO: 12, 35, 32, and 23; (iii) a CDRL3 amino acid sequence selected from the CDRL3 in a sequence selected from the group consisting of SEQ ID NO: 12, 35, 32, and 23; and (iv) a CDRL of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 2 amino acids; or C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B. In some embodiments, the CDRH of A) is selected from at least one of the group consisting of: (i) a CDRH1 amino acid sequence of the CDRH1 amino acid sequence in SEQ ID NO: 67; (ii) a CDRH2 amino acid sequence of the CDRH2 amino acid sequence in SEQ ID NO: 67; (iii) a CDRH3 amino acid sequence of the CDRH3 amino acid sequence in SEQ ID NO: 67; 18936261-1 and (iv) a CDRH of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 2 amino acids; said CDRL of B) is selected from at least one of the group consisting of: (i) a CDRL1 amino acid sequence of the CDRL1 amino acid sequence in SEQ ID NO: 12; (ii) a CDRL2 amino acid sequence of the CDRL2 amino acid sequence in SEQ ID NO: 12; (iii) a CDRL3 amino acid sequence of the CDRL3 amino acid sequence in SEQ ID NO: 12; and (iv) a CDRL of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 2 amino acids; or C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B). In some embodiments, the antigen binding protein comprises A) a CDRH1 of the CDRH1 sequence in SEQ ID NO: 67, a CDRH2 of the CDRH2 sequence in SEQ ID NO: 67, and a CDRH3 of the CDRH3 sequence in SEQ ID NO: 67, and B) a CDRL1 of the CDRL1 sequence in SEQ ID NO: 12, a CDRL2 of the CDRL2 sequence in SEQ ID NO: 12, and a CDRL3 of the CDRL3 sequence in SEQ ID NO: 12. In some embodiments, the antigen binding protein comprises a heavy chain variable region (VH) having at least 80% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60, and/or a light chain variable region (VL) having at least 80% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46. In some embodiments, the VH has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60, and/or the VL has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46. In some embodiments, the VH is selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60, and/or the VL is selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46. id="p-486" id="p-486"

[00486] In an example of any aspect of the invention, the PCSK9-targeting or binding ligand comprises or consists of AMG145 or 31H4, 16F12, 11F1, 8A3 or 21B12 disclosed in US20120093818A1 (Amgen, Inc) or an antibody comprising the variable domains of AMG145, 31H4, 16F12, 11F1, 8A3 or 21B12, the disclosures of which (including sequences) are incorporated herein by reference as though explicitly recited herein and for possible 18936261-1 inclusion in one or more claims or for use in the present invention. Preferably, the PCSK9targeting or binding ligand comprises or consists of AMG145. id="p-487" id="p-487"

[00487] In an example, the AMG145 or other ligand of the invention is glycosylated, eg, has human glycosylation (eg, produced by a CHO, Cos or Hek293 cell). In an example, the ligand of the invention is produced in CHO, id="p-488" id="p-488"

[00488] Reference is made to US20110065902A1 (Regeneron Pharmaceuticals, Inc), the entire disclosure of which is incorporated herein by reference. This patent application discloses relevant ligands for use in the present invention, as well as examples and methods of producing and testing ligands and determining medical efficacy that can be used with reference to the present invention. id="p-489" id="p-489"

[00489] Reference is made to the following PCT applications, the entire disclosures of which are incorporated herein by reference. These disclose relevant ligands for use in the present invention, as well as examples and methods of producing and testing ligands and determining medical efficacy that can be used with reference to the present invention.

WO2008057457 WO2008057458 WO2008057459 WO2008063382 WO2008133647 WO2009100297 WO2009100318 WO2011037791 WO2011053759 WO2011053783 WO2008125623 WO2011072263 WO2009055783 WO2010029513 WO2011111007 WO2010077854 Antibody ligands to PCSK9 are described in, for example, WO 2008/057457, WO 2008/057458, WO 2008/057459, WO 2008/063382, WO 2008/125623, and US 2008/0008697. [00490] In an example, the ligand is or comprises an antibody disclosed in the Examples of US20110065902A1 (eg, 316P or 300N) or is a PCSK9-binding derivative thereof. 18936261-1 All of these disclosures (including the sequences of such proteins and corresponding nucleotide sequences) are incorporated herein by reference as though explicitly recited herein and for possible inclusion in one or more claims or for use in the present invention. In an embodiment, the ligand is or comprises the variable domains of antibody 316P or 300N disclosed in US20110065902A1 or is (or comprises) such antibody or a PCSK9-binding derivative thereof. The foregoing reference is incorporated by reference herein in its entirety. [00491] In an embodiment, the ligand is or comprises the variable domains of antibody alirocumab or SAR236553/REGN727 (Sanofi Aventis/Regeneron) or is (or comprises) such antibody or a PCSK9-binding derivative thereof. In an example, the antibody is glycosylated, eg, has human glycosylation (eg, produced by a CHO, Cos or Hek293 cell). Preferably, the ligand is alirocumab or SAR236553/REGN727. id="p-492" id="p-492"

[00492] In an embodiment, the ligand is or comprises the variable domains of antibody evolocumab or or is (or comprises) such antibody or a PCSK9-binding derivative thereof. In an example, the antibody is glycosylated, eg, has human glycosylation (eg, produced by a CHO, Cos or Hek293 cell). Preferably, the ligand is evolocumab. (00493] In an embodiment, the ligand is selected from evolocumab, lD05-IgG2 (Merck & Co.), ALN-PCS02 (Alnylam), RN316 (Pfizer-Rinat) and alirocumab. id="p-494" id="p-494"

[00494] In an embodiment, the ligand is selected from the following (sequences and definitions as per US2011/0065902, incorporated herein by reference in its entirety):1. An antibody or antigen-binding fragment thereof which specifically binds hPCSK9, wherein the antibody or antigen-binding fragment comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair having SEQ ID NOs: 218/226. 2. The antibody or antigen-binding fragment of concept 1 comprising heavy and light chain CDR amino acid sequences having SEQ ID NOs: 220, 222, 224, 228, 230 and 232. 3. The antibody or antigen-binding fragment of concept 2 comprising an HCVR having the amino acid sequence of SEQ ID NO: 218 and an LCVR having the amino acid sequence of SEQ ID NO: 226. 4. An antibody or antigen-binding fragment thereof which binds to the same epitope on hPCSK9 as an antibody comprising heavy and light chain CDR amino acid sequences having SEQ ID NOs: 220, 222, 224, 228, 230 and 232.

. An antibody or antigen-binding fragment thereof which competes for binding to hPCSK9 with an antibody comprising heavy and light chain CDR amino acid sequences having SEQ ID NOs: 220, 222, 224, 228, 230 and 232. 18936261-1 id="p-495" id="p-495"

[00495] In an embodiment, the ligand is selected from the following (sequences and definitions as per US2012/0093818, incorporated herein by reference herein in its entirety):1. An isolated neutralizing antigen binding protein that binds to a PCSK9 protein comprising the amino acid sequence of SEQ ID NO: 1, wherein the neutralizing antigen binding protein decreases the LDLR lowering effect of PCSK9 on LDLR, wherein the antigen binding protein comprises a light chain comprising an amino acid sequence of SEQ ID NO: 46, and wherein the antigen binding protein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 60. 2. The isolated neutralizing antigen binding protein of concept 2, wherein the antigen binding protein is a LDLR non-competitive neutralizing antigen binding protein. 3. The isolated neutralizing antigen binding protein of concept 2, wherein the antigen binding protein is a LDLR competitive neutralizing antigen binding protein. 4. An antigen binding protein that selectively binds to PCSK9, wherein said antigen binding protein binds to PCSK9 with a Kd that is less than 100 pM.

. An antigen binding protein that binds to a PCSK 9 protein of SEQ ID NO: 303 in a first manner, wherein the antigen binding protein binds to a variant of PCSK9 in a second manner, wherein said PCSK9 variant has at least one point mutation at a position selected from the group consisting of: 207, 208, 185, 181, 439, 513, 538, 539, 132, 351, 390, 413, 582, 162, 164, 167, 123, 129, 311, 313, 337, 519, 521, and 554 of SEQ ID NO: 303, wherein the first manner comprises a first EC50, a first Bmax, or a first EC50 and a first Bmax, wherein the second manner comprises a second EC50, a second Bmax, or a second EC50 and a second Bmax, and wherein a value for the first manner is different from a value for the second manner, and wherein the antigen binding protein comprises a light chain comprising an amino acid sequence of SEQ ID NO: 46, and wherein the antigen binding protein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 60. 6. The antigen binding protein of concept 6, wherein the first manner comprises a first Bmax, wherein the second manner comprises a second Bmax that is different from the first Bmax, and wherein said PCSK9 variant has at least one point mutation selected from the group consisting of: D162R, R164E, E167R, S123R, E129R, A311R, D313R, D337R, R519E, H521R, and Q554R. 7. The antigen binding protein of concept 6, wherein the antigen binding protein binds to PCSK9 at a location that overlaps with a location that LDLR binds to PCSK9. 8. A method of making an antigen binding protein that binds to a PCSK9 protein comprising the amino acid sequence of SEQ ID NO: 1, wherein the antigen binding protein decreases the 18936261-1 LDLR lowering effect of PCSK9 on LDLR, said method comprising:providing a host cell comprising a nucleic acid sequence that encodes the antigen binding protein; andmaintaining the host cell under conditions in which the antigen binding protein is expressed, wherein the antigen binding protein comprises a light chain comprising an amino acid sequence of SEQ ID NO: 46, and wherein the antigen binding protein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 60. 9. A method for treating or preventing a condition associated with elevated serum cholesterol levels in a subject, said method comprising administering to a subject in need thereof an effective amount of an isolated neutralizing antigen binding protein simultaneously or sequentially with an agent that elevates the availability of LDLR protein, wherein the isolated antigen binding protein binds to a PCSK9 protein comprising the amino acid sequence of SEQ ID NO: 1, wherein the neutralizing antigen binding protein decreases the LDLR lowering effect of PCSK9 on LDLR, wherein the antigen binding protein comprises a light chain comprising an amino acid sequence of SEQ ID NO: 46, and wherein the antigen binding protein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 60.

. The method of concept 10, wherein the agent that elevates the availability of LDLR protein comprises a statin. 11. An antigen binding protein that binds to PCSK9, wherein when the antigen binding protein is bound to PCSK9, the antibody is positioned 8 angstroms or less from at least one of the following residues of PCSK9: S153, S188, 1189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, F379, 1154, T187, H193, E195, 1196, M201, V202, C223, T228, S235, G236, A239, G244, M247, 1369, S372, C375, or C378, wherein the antigen binding protein comprises a light chain comprising an amino acid sequence of SEQ ID NO: 46, and wherein the antigen binding protein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 60. id="p-496" id="p-496"

[00496] The ligand can be used for the treatment, therapy, prophylaxis and/or diagnosis of one or more diseases or conditions or susceptibility thereto, wherein such diseases or conditions comprise those disclosed in US20120093818A1 (Amgen, Inc) and US20110065902A1 (Regeneron Pharmaceuticals, Inc), eg, a disease or condition disclosed in paragraphs [0375] to [0383] of US20120093818A1, which disclosure is incorporated herein by reference in its entirety for inclusion in one more claims herein. id="p-497" id="p-497"

[00497] The ligand can be administered to a human characterised as described in US20120093818A1 (Amgen, Inc) or US20110065902A1; each of which is incorporated by reference herein in its entirety. 18936261-1 id="p-498" id="p-498"

[00498] The ligand can be administered in a form or combination disclosed in US20120093818A1 (Amgen, Inc) or US20110065902A1, which disclosure is incorporated herein by reference. For example, the ligand with a drug, excipient, diluent or carrier as described in US20120093818A1 (Amgen, Inc) or US20110065902A1 (eg, as disclose in paragraphs [0384] to [0412] of US20120093818A1), which disclosure is incorporated herein by reference, and the present invention also relates to the corresponding pharmaceutical compositions comprising the combination of a ligand of the invention and such a further agent. Each of the foregoing references is incorporated by reference herein in its entirety. [00499] The ligand can be used in a method of diagnosis as set out in US20120093818A1 (Amgen, Inc) or US20110065902A1, eg, in paragraphs [0413] to [0415] of US20120093818A1 which disclosure is incorporated herein by reference. Each of the foregoing references is incorporated by reference herein in its entirety. id="p-500" id="p-500"

[00500] Diagnostic Applications 100501] In some embodiments, the ligand of the invention is a diagnostic tool. The ligand can be used to assay the amount of PCSK9 present in a sample and/or subject. As will be appreciated by one of skill in the art, such ligands need not be neutralizing ligands. In some embodiments, the diagnostic ligand is not a neutralizing ligand. In some embodiments, the diagnostic ligand binds to a different epitope than a neutralizing ligand binds to. In some embodiments, the two ligands do not compete with one another. id="p-502" id="p-502"

[00502] In some embodiments, the ligands of the invention are used or provided in an assay kit and/or method for the detection of PCSK9 in mammalian tissues or cells in order to screen/diagnose for a disease or disorder associated with changes in levels of PCSK9. The kit comprises a ligand that binds PCSK9 and means for indicating the binding of the ligand with PCSK9, if present, and optionally PCSK9 protein levels. Various means for indicating the presence of a ligand can be used. For example, fluorophores, other molecular probes, or enzymes can be linked to the ligand and the presence of the ligand can be observed in a variety of ways. The method for screening for such disorders can involve the use of the kit, or simply the use of one of the disclosed ligands and the determination of whether the ligand binds to PCSK9 in a sample. As will be appreciated by one of skill in the art, high or elevated levels of PCSK9 will result in larger amounts of the ligand binding to PCSK9 in the sample. Thus, degree of ligand binding can be used to determine how much PCSK9 is in a sample.

Subjects or samples with an amount of PCSK9 that is greater than a predetermined amount (e.g., an amount or range that a person without a PCSK9 related disorder would have) can be characterized as having a PCSK9 mediated disorder. In some embodiments, the invention 18936261-1 provides a method wherein the ligand is administered to a subject taking a statin, in order to determine if the statin has increased the amount of PCSK9 in the subject. id="p-503" id="p-503"

[00503] In some embodiments, the ligand is a non-neutralizing ligand and is used to determine the amount of PCSK9 in a subject receiving an ABP and/or statin treatment. [00504| In some embodiments, the ligand of the invention can specifically bind human PCSK9 (eg, one, two or more rare variant forms disclosed herein) and is characterized by at least one of: (i) capable of reducing serum total cholesterol at least about 25-35% and sustaining the reduction over at least a 24 day period relative to a predose level; (ii) capable of reducing serum LDL cholesterol at least about 65-80% and sustaining the reduction over at least a 24 day period relative to a predose level; (iii) capable of reducing serum LDL cholesterol at least about 40-70% and sustaining the reduction over at least a 60 or 90 day period relative to a predose level; (iv) capable of reducing serum triglyceride at least about 25-40% relative to predose level; (v) does not reduce serum HDL cholesterol or reduces serum HDL cholesterol no more than 5% relative to predose level. In some embodiments, an isolated nucleic acid molecule is provided and it encodes the ligand. In some embodiments an expression vector is provided and comprises the nucleic acid molecule. In some embodiments, a pharmaceutical composition is provided and it can comprise the ligand and a pharmaceutically acceptable carrier. In some embodiments, a method is provided for treating a disease or condition which is ameliorated, improved, inhibited or prevented with a PCSK9 antagonist ligand of the invention. The method can comprise administering a therapeutic amount of the pharmaceutical composition or ligand to a subject in need thereof. In some embodiments, the subject is a human subject suffering from hypercholesterolemia, hyperlipidemia, indicated for LDL apheresis, identified as heterozygous for Familial Hypercholesterolemia, statin intolerant, statin uncontrolled, at risk for developing hypercholesterolemia, dyslipidemia, cholestatic liver disease, nephrotic syndrome, hypothyroidism, obesity, atherosclerosis and cardiovascular diseases. In some embodiments, a method of providing a treatment or therapy is provided to a subject. In some embodiments, the method comprises reducing serum cholesterol at least about 40-70% over at least 60 to 90 days. In some embodiments, a method of receiving treatment or therapy is provided, the method can comprise receiving a ligand thereof at a frequency of once every 60 to 90 days. [00505[ In one aspect, the invention provides a ligand of the invention which is or comprises an human antibody or antigen-binding fragment of a human antibody that specifically binds and inhibits human proprotein convertase subtilisin/kexin type 9 (hPCSK9, eg, one, two or more rare variant forms disclosed herein and optionally form a and/or form 18936261-1 a), characterized by the ability to reduce serum LDL cholesterol in a human by 40-80% over a 24, 60 or 90 day period relative to predose levels, with little or no reduction in serum HDL cholesterol and/or with little or no measurable effect on liver function, as determined by ALT and AST measurements. id="p-506" id="p-506"

[00506] In one embodiment, the ligand of the invention comprises an antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9 and is characterized by at least one of; (i) capable of reducing serum total cholesterol at least about 25-35% and sustaining the reduction over at least a 24 day period relative to a predose level, preferably the reduction in serum total cholesterol is at least about 30-40%; (ii) capable of reducing serum LDL cholesterol at least about 65-80% and sustaining the reduction over at least a 24 day period relative to a predose level; (iii) capable of reducing serum triglyceride at least about 25-40% relative to predose level; (iv) does not reduce serum HDL cholesterol or reduces serum HDL cholesterol no more than 5% relative to predose level.

See US2011/0065902 for definitions of these terms and optional features, the disclosure of which are incorporated herein by reference in its entirety. [00507| In one embodiment, the invention comprises an antibody or antigenbinding fragment of an antibody that specifically binds hPCSK9 and is characterized by at least one of: (i) capable of reducing serum LDL cholesterol at least about 40-70% and sustaining the reduction over at least a 60 or 90 day period relative to a predose level; (ii) capable of reducing serum triglyceride at least about 25-40% relative to predose level; (iii) does not reduce serum HDL cholesterol or reduces serum HDL cholesterol no more than 5% relative to predose level. id="p-508" id="p-508"

[00508] In one embodiment, the antibody or antigen-binding fragment is characterized as exhibiting an enhanced binding affinity (KD) for hPCSK9 at pH 5.5 relative to the KD at pH 7.4, as measured by plasmon surface resonance. In a specific embodiment, the antibody or fragment thereof exhibits at least a 20-fold, at least a 40-fold or at least a 50-fold enhanced affinity for PCSK9 at an acidic pH relative to a neutral pH, as measured by surface plasmon resonance. id="p-509" id="p-509"

[00509] In one embodiment, the antibody or antigen-binding fragment is characterized as not exhibiting an enhanced binding affinity for PCSK9 at an acidic pH relative 18936261-1 to a neutral pH, as measured by surface plasmon resonance. In a specific embodiment, the antibody or fragment thereof exhibits a decreased binding affinity at an acidic pH. id="p-510" id="p-510"

[00510] In another embodiment, the antibody or antigen-binding fragment binds human, human GOF mutation D374Y, cynomolgus monkey, rhesus monkey, mouse, rat and hamster PCSK9. id="p-511" id="p-511"

[00511] In one embodiment, the antibody or antigen-binding fragment binds human and monkey PCSK9, but does not bind mouse, rat or hamster PCSK9. id="p-512" id="p-512"

[00512] In one embodiment, the invention comprises an antibody or antigenbinding fragment of an antibody comprising one or more of a heavy chain variable region (HCVR.), light chain variable region (LCVR), HCDR1, HCDR2, HCDR3 disclosed in any of paragraphs [023]-[037] of US2011/0065902, the disclosure of which is incorporated herein by reference in its entirety. id="p-513" id="p-513"

[00513] In a related embodiment, the invention comprises an antibody or antigenbinding fragment of an antibody which specifically binds hPCSK9, wherein the antibody or fragment comprises heavy and light chain CDR domains contained within heavy and light chain sequence pairs selected from the group consisting of SEQ ID NO (using the sequence numbering in US2011/0065902): 2/10, 18/20, 22/24, 26/34, 42/44, 46/48, 50/58, 66/68, 70/72, 74/82, 90/92, 94/96, 98/106, 114/116, 118/120, 122/130, 138/140, 142/144, 146/154, 162/164, 166/168, 170/178, 186/188, 190/192, 194/202, 210/212, 214/216, 218/226, 234/236, 238/240, 242/250, 258/260, 262/264, 266/274, 282/284, 286/288, 290/298, 306/308, 310/312, 314/322, 330/332, 334/336, 338/346, 354/356, 358/360, 362/370, 378/380, 382/384, 386/394, 402/404, 406/408, 410/418, 426/428, 430/432, 434/442, 450/452, 454/456, 458/466, 474/476, 478/480, 482/490, 498/500, 502/504, 506/514, 522/524, 526/528, 530/538, 546/548, 550/552, 554/562, 570/572, 574/576, 578/586, 594/596, 598/600, 602/610, 618/620, 622/624, 626/634, 642/644, 646/648, 650/658, 666/668, 670/672, 674/682, 690/692, 694/696, 698/706, 714/716, 718/720, 722/730, 738/740 and 742/744. In one embodiment, the CDR sequences are contained within HCVR and LCVR selected from the amino acid sequence pairs of SEQ ID NO: 50/58, 66/68, 70/72, 74/82, 90/92, 94/96, 122/130, 138/140, 142/144, 218/226, 234/236, 238/240, 242/250, 258/260, 262/264, 314/322, 330/332 and 334/336. In more specific embodiments, the CDR sequences are comprised within HCVR/LCVR sequences selected from SEQ ID NO: 90/92 or 218/226. Each of the foregoing references is incorporated by reference herein in its entirety. id="p-514" id="p-514"

[00514] In an example, the invention features a pharmaceutical composition comprising a ligand of the invention, wherein the ligand comprises or consists of a 18936261-1 recombinant human antibody or fragment thereof which specifically binds hPCSK9 and a pharmaceutically acceptable carrier. In one embodiment, the invention features a composition which is a combination of a ligand of the invention (eg, an antibody or antigen-binding fragment of an antibody), and a second therapeutic agent. The second therapeutic agent may be any agent that is advantageously combined with the ligand of the invention, for example, an agent capable of inducing a cellular depletion of cholesterol synthesis by inhibiting 3hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase, such as, for example, cerovastatin, atorvastatin, simvastatin, pitavastin, rosuvastatin, fluvastatin, lovastatin, pravastatin, etc; capable of inhibiting cholesterol uptake and or bile acid re-absorption; capable of increasing lipoprotein catabolism (such as niacin); and/or activators of the LXR transcription factor that plays a role in cholesterol elimination such as 22-hydroxycholesterol. [00515] In an example, the invention provides a method for inhibiting hPCSK9 activity using the anti-PCSK9 ligand of the invention (eg, an antibody or antigen-binding portion of the antibody of the invention), wherein the therapeutic methods comprise administering a therapeutically effective amount of a pharmaceutical composition comprising an antibody or antigen-binding fragment of an antibody of the invention. The disorder treated is any disease or condition which is improved, ameliorated, inhibited or prevented by removal, inhibition or reduction of PCSK9 activity. Specific populations treatable by the therapeutic methods of the invention include subjects indicated for LDL apheresis, subjects with PCSK9activating mutations (gain of function mutations, GOF), subjects with heterozygous Familial Hypercholesterolemia (heFH); subjects with primary hypercholesterolemia who are statin intolerant or statin uncontrolled; and subjects at risk for developing hypercholesterolemia who may be preventably treated. Other indications include dyslipidemia associated with secondary causes such as Type 2 diabetes mellitus, cholestatic liver diseases (primary biliary cirrhosis), nephrotic syndrome, hypothyroidism, obesity; and the prevention and treatment of atherosclerosis and cardiovascular diseases. id="p-516" id="p-516"

[00516] In specific embodiments of the method of the invention, the ligand of the invention (eg, anti-hPCSK9 antibody or antibody fragment of the invention) is useful to reduce elevated total cholesterol, non-HDL cholesterol, LDL cholesterol, and/or apolipoprotein B (apolipoprotein B100). id="p-517" id="p-517"

[00517] The ligand (eg, antibody or antigen-binding fragment) of the invention may be used alone or in combination with a second agent, for example, an HMG-CoA reductase inhibitor and/or another lipid lowering drug. 18936261-1 id="p-518" id="p-518"

[00518] The term isolated with reference to a ligand, antibody or protein, for example in any aspect, configuration, example or emodiment, means that a subject ligand, antibody, protein etc (1) is free of at least some other proteins with which it would normally be found, (2) is essentially free of other proteins from the same source, e.g., from the same species, (3) is expressed by a cell from a different species, (4) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is associated in nature, (5) is operably associated (by covalent or noncovalent interaction) with a polypeptide with which it is not associated in nature, or (6) does not occur in nature. Typically, an isolated ligand, antibody, protein etc constitutes at least about 5%, at least about 10%, at least about 25%, or at least about 50% of a given sample. Genomic DNA, cDNA, mRNA or other RNA, of synthetic origin, or any combination thereof can encode such an isolated ligand, antibody protein etc. Preferably, the isolated ligand, antibody protein etc is substantially free from proteins or polypeptides or other contaminants that are found in its natural environment that would interfere with its therapeutic, diagnostic, prophylactic, research or other use. id="p-519" id="p-519"

[00519] For example, an isolated antibody is one that has been identified, separated and/or recovered from a component of its production environment (eg, naturally or recombinantly). Preferably, the isolated polypeptide is free of association with all other components from its production environment, eg, so that the antibody has been isolated to an FDA-approvable or approved standard. Contaminant components of its production environment, such as that resulting from recombinant transfected cells, are materials that would typically interfere with research, diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the polypeptide will be purified: (1) to greater than 95% by weight of antibody as determined by, for example, the Lowry method, and in some embodiments, to greater than 99% by weight; (2) to a degree sufficient to obtain at least 15 residues of Nterminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, an isolated polypeptide or antibody will be prepared by at least one purification step. id="p-520" id="p-520"

[00520] Immunoconjugates 18936261-1 id="p-521" id="p-521"

[00521] The invention encompasses the ligand (eg, antibody) conjugated to a therapeutic moiety (immunoconjugate), such as a cytotoxin, a chemotherapeutic drug, an immunosuppressant or a radioisotope. Cytotoxin agents include any agent that is detrimental to cells. Examples of suitable cytotoxin agents and chemotherapeutic agents for forming immunoconjugates are known in the art, see for example, WO 05/103081, which is incorporated by reference herein in its entirety. |00522] Bispecifics (00523] The antibodies of the present invention may be monospecific, bispecific, or multispecific. Multispecific mAbs may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for more than one target polypeptide. See, e.g., Tutt et al. (1991) J. Immunol. 147:60-69. The human anti-PCSK9 (eg, anti-PCSK9) mAbs can be linked to or co-expressed with another functional molecule, e.g., another peptide or protein. For example, an antibody or fragment thereof can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment, to produce a bispecific or a multispecific antibody with a second binding specificity. (00524] An exemplary bi-specific antibody format that can be used in the context of the present invention involves the use of a first immunoglobulin (Ig) CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bispecific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second CH3 may further comprise a Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second CH3 include: D16E, L18M, N44S, K52N, V57M, and V821 (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of IgGl antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N3845, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of IgG4 antibodies.

Variations on the bi-specific antibody format described above are contemplated within the scope of the present invention. id="p-525" id="p-525"

[00525] Treatment Population 18936261-1 id="p-526" id="p-526"

[00526] The invention provides therapeutic methods for treating a human patient in need of a composition or ligand of the invention. While modifications in lifestyle and conventional drug treatment are often successful in reducing cholesterol levels, not all patients are able to achieve the recommended target cholesterol levels with such approaches. Various conditions, such as familial hypercholesterolemia (FH), appear to be resistant to lowering of LDL-C levels in spite of aggressive use of conventional therapy. Homozygous and heterozygous familial hypercholesterolemia (hoFH, heFH) is a condition associated with premature atherosclerotic vascular disease. However, patients diagnosed with hoFH are largely unresponsive to conventional drug therapy and have limited treatment options.

Specifically, treatment with statins, which reduce LDL-C by inhibiting cholesterol synthesis and upregulating the hepatic LDL receptor, may have little effect in patients whose LDL receptors are non-existent or defective. A mean LDL-C reduction of only less than about 20% has been recently reported in patients with genotype-confirmed hoFH treated with the maximal dose of statins. The addition of ezetimibe 10 mg/day to this regimen resulted in a total reduction of LDL-C levels of 27%, which is still far from optimal. Likewise, many patients are statin nonresponsive, poorly controlled with statin therapy, or cannot tolerate statin therapy; in general, these patients are unable to achieve cholesterol control with alternative treatments. There is a large unmet medical need for new treatments that can address the short-comings of current treatment options. id="p-527" id="p-527"

[00527] Specific populations treatable by the therapeutic methods of the invention include patients indicated for LDL apheresis, subjects with PCSK9-activating (GOF) mutations, heterozygous Familial Hypercholesterolemia (heFH); subjects with primary hypercholesterolemia who are statin intolerant or statin uncontrolled; and subjects at risk for developing hypercholesterolemia who may be preventably treated. id="p-528" id="p-528"

[00528] Therapeutic Administration and Formulations id="p-529" id="p-529"

[00529] The invention provides therapeutic compositions comprising the anti-PCSK9 ligands, antibodies or antigen-binding fragments thereof of the present invention. The administration of therapeutic compositions in accordance with the invention will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTINT™), DNA conjugates, anhydrous 18936261-1 absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. Compendium of excipients for parenteral formulations PDA (1998) J Pharm Sci Technol 52:238-311. id="p-530" id="p-530"

[00530] The dose may vary depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like. When the ligand, eg, antibody, of the present invention is used for treating various conditions and diseases associated with PCSK9, including hypercholesterolemia, disorders associated with LDL and apolipoprotein B, and lipid metabolism disorders, and the like, in an adult patient, it is advantageous to intravenously administer the ligand or antibody of the present invention normally at a single dose of about 0.01 to about 20 mg/kg body weight, more preferably about 0.02 to about 7, about 0.03 to about 5, or about 0.05 to about 3 mg/kg body weight. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. id="p-531" id="p-531"

[00531] Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, thus the composition invention provides the ligand by e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al. (1987) J. Biol. Chern. 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. id="p-532" id="p-532"

[00532] The pharmaceutical composition can be also delivered in a vesicle, in particular a liposome (see Langer (1990) Science 249:1527-1533; Treat et al. (1989) in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez Berestein and Fidler (eds.), Liss, New York, pp. 353-365; Lopez-Berestein, ibid., pp. 317-327; see generally ibid.). id="p-533" id="p-533"

[00533] In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton (1987) CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974). In yet another embodiment, a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of 18936261-1 the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138, 1984). [00534| The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule. A pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all ofthe pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded. id="p-535" id="p-535"

[00535] Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present invention. Examples include, but certainly are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Burghdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, Ind.), NOVOPEN™!, II and III (Novo Nordisk, Copenhagen, Denmark), 18936261-1 NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), ΟΡΊΊΡΕΝΤ™, ΟΡΉΡΕΝ PRO™, ΟΡΉΡΕΝ STARLET™, and OPTICLIKT™ (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present invention include, but certainly are not limited to the SOLOSTAR™ pen (sanofiaventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly). [00536| Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the aforesaid antibody contained is generally about 5 to about 500 mg per dosage form in a unit dose; especially in the form of injection, it is preferred that the aforesaid antibody is contained in about 5 to about 100 mg and in about 10 to about 250 mg for the other dosage forms. id="p-537" id="p-537"

[00537] The invention provides therapeutic methods in which the ligand, eg, antibody or antibody fragment, of the invention is useful to treat hypercholesterolemia associated with a variety of conditions involving hPCSK9. The anti-PCSK9 ligands, eg, antibodies or antibody fragments, of the invention are particularly useful for the treatment of hypercholesterolemia and the like. Combination therapies may include the anti-PCSK9 ligand of the invention with, for example, one or more of any agent that (1) induces a cellular depletion of cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase, such as cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin; (2) inhibits cholesterol uptake and or bile acid reabsorption; (3) increase lipoprotein catabolism (such as niacin); and activators of the LXR transcription factor that plays a role in cholesterol elimination such as 22-hydroxycholesterol or fixed combinations such as ezetimibe plus simvastatin; a statin with a bile resin (e.g., cholestyramine, colestipol, colesevelam), a fixed combination of niacin plus a statin (e.g., niacin with lovastatin); or with other lipid lowering agents such as omega-3-fatty acid ethyl esters (for example, omacor). [00538J Ligands of the invention are useful, for instance, in specific binding assays, for genotyping or phenotyping humans, affinity purification of the PCSK9 and in screening assays to identify other antagonists of PCSK9 activity. Some of the ligands of the invention are useful for inhibiting binding of PCSK9 to a congnate human receptor or protein, or inhibiting PCSK9-mediated activities. 18936261-1 100539] The invention encompasses anti-PCSK9 (eg, PCSK9) antibody ligands having a modified glycosylation pattern. In some applications, modification to remove undesirable glycosylation sites may be useful, or e.g., removal of a fucose moiety to increase antibody dependent cellular cytotoxicity (ADCC) function (see Shield et al. (2002) JBC 277:26733). In other applications, modification of galactosylation can be made in order to modify complement dependent cytotoxicity (CDC). id="p-540" id="p-540"

[00540] In an example, the invention features a pharmaceutical composition comprising a ligand of the invention, wherein the ligand is or comprises a recombinant human antibody or fragment thereof which specifically binds the PCSK9 (eg, a rare variant as described herein) and a pharmaceutically acceptable carrier. In one embodiment, the invention features a composition which is a combination of an antibody ligand or antigenbinding fragment of an antibody of the invention, and a second therapeutic agent. The second therapeutic agent may be any of an anti-inflammatory agent, an anti-angiogenesis agent, a painkiller, a diuretic, a chemotherapeutic agent, an anti-neoplastic agent, a vasodilator, a vasoconstrictor, a statin, a beta blocker, a nutrient, an adjuvant, an anti-obesity agent and an anti-diabetes agent. id="p-541" id="p-541"

[00541] Pharmaceutically acceptable refers to approved or approvable by a regulatory agency of the USA Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans. A pharmaceutically acceptable carrier, excipient, or adjuvant refers to an carrier, excipient, or adjuvant that can be administered to a subject, together with an agent, e.g., any antibody or antibody chain described herein, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the agent. id="p-542" id="p-542"

[00542] In an example, the invention features a method for inhibiting PCSK9 activity using the anti-PCSK9 ligand of the invention (eg, an antibody or antigen-binding portion of the antibody of the invention), wherein the therapeutic method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising the ligand. The disorder treated is any disease or condition which is improved, ameliorated, inhibited or prevented by removal, inhibition or reduction of PCSK9 activity. id="p-543" id="p-543"

[00543] By the phrase therapeutically effective amount is meant an amount that produces the desired effect for which it is administered. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known 18936261-1 techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding). id="p-544" id="p-544"

[00544] Genotyping & Phenotyping id="p-545" id="p-545"

[00545] The skilled person will be familiar with techniques that can be used for accurate genotyping and application to the invention. These include the following.

Hybridization-based methods 1.1 Dynamic allele-specific hybridization 1.2 Molecular beacons 1.3 SNP microarrays Enzyme-based methods 2.1 Restriction fragment length polymorphism 2.2 PCR-based methods 2.3 Flap endonuclease 2.4 Primer extension 2.5 5'- nuclease 2.6 Oligonucleotide Ligation Assay Other post-amplification methods based on physical properties of DNA 3.1 Single strand conformation polymorphism 3.2 Temperature gradient gel electrophoresis 3.3 Denaturing high performance liquid chromatography 3.4 High-resolution melting of the entire amplicon 3.5 Use of DNA mismatch-binding proteins 3.6 SNPlex (SNPlex™ is a proprietary genotyping platform sold by Applied Biosystems). (00546] Next-generation sequencing technologies such as pyrosequencing is also useful. (00547] Reference is also made to GB2444410A and the genotyping method disclosed therein, which is incorporated herein by reference in its entirety. id="p-548" id="p-548"

[00548] Miniaturized assays, such as microarrays with oligonucleotide reagents immobilized on small surfaces, are frequently proposed for large-scale mutation analysis and high-throughput genotyping (Large-scale identification, mapping, and genotyping of singlenucleotide polymorphisms in the human genome (Wang DG, Fan JB, Siao CJ, Berno A, Young P, Sapolsky R, Ghandour G, Perkins N, Winchester E, Spencer J, Kruglyak L, Stein L, Hsie L, Topaloglou T, Hubbell E, Robinson E, Mittmann M, Morris MS, Shen N, Kilburn D, Rioux J, Nusbaum C, Rozen S, Hudson TJ, Lipshutz R, Chee M, Lander ES, Science. 1998 May 15; 18936261-1 280(5366):1077-82). Other high-throughput methods discriminate alleles by differential hybridization, primer extension, ligation and cleavage of an allele-specific probe (Review Accessing genetic variation: genotyping single nucleotide polymorphisms, Syvanen AC, Nat Rev Genet. 2001 Dec; 2(12):930-42; Review Techniques patents for SNP genotyping, Twyman RM, Primrose SB, Pharmacogenomics. 2003 Jan; 4(1):67-79). [00549| An approach for a fully automated, large-scale SNP analysis is the 'homogeneous' assay, i.e. a single-phase assay without separation steps, permitting continual monitoring during amplification. The TaqMan™ assay (Applied Biosystems), originally designed for quantitative real-time PCR, is a homogeneous, single-step assay also used in determination of mutation status of DNA (see, eg, A.A. Komar (ed.), Single Nucleotide Polymorphisms, Methods in Molecular Biology 578, DOI 10.1007/978-1-60327-411-1_19, Humana Press, a part of Springer Science+ Business Media, LLC; and Single Nucleotide Polymorphisms, Methods in Molecular Biology™ Volume 578, 2009, pp 293-306, The TaqMan Method for SNP Genotyping, Gong-Qing Shen eta!)· The TaqMan SNP Genotyping Assay exploits the 5'-exonuclease activity of AmpliTaq Gold™ DNA polymerase to cleave a doubly labeled probe hybridized to the SNP-containing sequence of ssDNA. Cleavage separates a 5'fluorophore from a 3'-quencher leading to detectable fluorescent signal. The use of two allelespecific probes carrying different fluorophores permits SNP determination in the same tube without any post-PCR processing. Genotype is determined from the ratio of intensities of the two fluorescent probes at the end of amplification. Thus, rather than taking advantage of the full set of real-time PCR data as in quantitative studies, only end-point data are used. [00550) TaqMan SNP genotyping in a high-throughput, automated manner is facilitated by the use of validated Pre-made TaqMan® Genotyping assays, but Custom TaqMan® Assays may also be used (High-throughput genotyping with single nucleotide polymorphisms, Ranade K, Chang MS, Ting CT, Pei D, Hsiao CF, Olivier M, Pesich R, Hebert J, Chen YD, Dzau VJ, Curb D, Olshen R, Risch N, Cox DR, Botstein D, Genome Res. 2001 Jul; 11(7): 1262-8; Assessment of two flexible and compatible SNP genotyping platforms: TaqMan SNP Genotyping Assays and the SNPlex Genotyping System, De la Vega FM, Lazaruk KD, Rhodes MD, Wenz MH, Mutat Res. 2005 Jun 3; 573(1-2):111-35). The results of the assay can be automatically determined by genotyping software provided with real-time thermal cyclers (e.g. IQ software of Bio-Rad, Sequence Detection Software of Applied Biosystems). [00551] Single nucleotide polymorphisms (SNPs) can be determined using TaqMan™ real-time PCR assays (Applied Biosystems) and commercial software that assigns genotypes based on reporter probe signals at the end of amplification. An algorithm for automatic 18936261-1 genotype caling of SNPs using the full course of TaqMan real-time data is available for use (A. Callegaro et al, Nucleic Acids Res. 2006; 34(7): e56, Published online 2006 April 14. doi: 10.1093/nar/gkll85, PMCID: PMC1440877). The algorithm is unique in that it classifies samples according to the behavior of blanks (no DNA samples), which cluster with heterozygous samples. This method of classification eliminates the need for positive controls and permits accurate genotyping even in the absence of a genotype class, for example when one allele is rare. id="p-552" id="p-552"

[00552] The skilled person will be familiar with techniques that can be used for accurate phenotyping and application to the invention. These include the use of amino acid sequencing of isolated target protein and comparison of sequences from different variants (eg, with the most common variant). An antibody that specifically and selectively binds in the area of a SNP under stringent conditions can also be used to identify a particular variant. In another method, the genotype is determined and a corresponding amino acid sequence (phenotype) determined, eg, by in silico translation. id="p-553" id="p-553"

[00553] For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims, are provided below. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. Unless otherwise defined, all 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. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided within the specification shall prevail. (00554] For convenience, certain terms employed herein, in the specification, examples and appended claims are collected here. id="p-555" id="p-555"

[00555] The terms decrease, reduced, or reduction are all used herein to mean a decrease by a statistically significant amount. In some embodiments, reduce, reduction or decrease typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , or more. As used herein, reduction does not encompass a complete reduction as 18936261-1 compared to a reference level. A decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder. However, for example, for the purposes of lowering or reducing cholesterol level, for example, a reduction by about -10 points can be considered a decrease or reduction. id="p-556" id="p-556"

[00556] In certain aspects of all embodiments of the invention, the term inhibition is used. Inhibition refers and refers to decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , or more including 100% inhibition as compared to a reference level. Complete inhibition refers to a 100% inhibition as compared to a reference level. [00557] The terms increased, increase, enhance, or activate are all used herein to mean an increase by a statically significant amount. In some embodiments, the terms increased, increase, enhance, or activate can mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. In the context of a marker or symptom, an increase is a statistically significant increase in such level. id="p-558" id="p-558"

[00558] As used herein, the term substantially refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term substantially is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena. For the removal of doubt, substantially can refer to at least a 90% extent or degree of a characteristic or property of interest, e.g. at least 90%, at least 92%, at least 95%, at least 98%, at least 99% or greater. 18936261-1 id="p-559" id="p-559"

[00559] As used herein, a subject means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters. In some embodiments, the subject is a mammal, e.g., a primate, e.g., a human. The terms, individual, patient and subject are used interchangeably herein. In some embodiments, the subject can be a non-human vertebrate, e.g. a primate, a rodent, a mouse, a rat, a pig, a sheep, a zebrafish, a frog, etc. id="p-560" id="p-560"

[00560] Preferably, the subject is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of a disease or condition, e.g., a cardiovascular condition. A subject can be male or female. id="p-561" id="p-561"

[00561] A subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment or one or more complications related to such a condition, and optionally, have already undergone treatment for the condition or the one or more complications related to the condition. Alternatively, a subject can also be one who has not been previously diagnosed as having the condition or one or more complications related to the condition. For example, a subject can be one who exhibits one or more risk factors for the condition or one or more complications related to the condition or a subject who does not exhibit risk factors. id="p-562" id="p-562"

[00562] A subject in need or human in need of treatment for a particular condition can be a subject having that condition, such as increased cholesterol levels, diagnosed as having that condition, or at risk of developing that condition. id="p-563" id="p-563"

[00563] As used herein, the terms protein and polypeptide are used interchangeably herein to designate a series of amino acid residues, connected to each other by peptide bonds between the alpha-amino and carboxy groups of adjacent residues. The terms protein, and polypeptide refer to a polymer of amino acids with natural amino acids. When referring to modified polypeptides one refers to polypeptides that include modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc.) and amino acid analogs, regardless of its size or function. Protein and polypeptide are often used in reference to relatively large polypeptides, whereas the term peptide is often used in reference to small polypeptides, but usage of these terms in the art overlaps. The terms protein and polypeptide are used interchangeably herein when referring to a gene product and fragments thereof. Thus, exemplar/ polypeptides or proteins include gene products, naturally occurring proteins with 18936261-1 the specified sequence, One can also use peptide homologs, peptide orthologs, peptide paralogs, peptide fragments and other equivalents, variants, fragments, and analogs of the peptides as these terms are understood by one of ordinary skill in the art. id="p-564" id="p-564"

[00564] As used herein, the term nucleic acid or nucleic acid sequence refers to any molecule, preferably a polymeric molecule, incorporating units of ribonucleic acid, deoxyribonucleic acid. The nucleic acid can be either single-stranded or double-stranded. A single-stranded nucleic acid can be one nucleic acid strand of a denatured double- stranded DNA. Alternatively, it can be a single-stranded nucleic acid not derived from any doublestranded DNA. In one aspect, the nucleic acid can be DNA, In another aspect, the nucleic acid can be RNA. Suitable nucleic acid molecules are DNA, including genomic DNA or cDNA. Other suitable nucleic acid molecules are RNA, including mRNA. In some aspects one can also use analogs of nucleic acids. id="p-565" id="p-565"

[00565] As used herein, the term nucleic acid probe refers to an isolated oligonucleotide molecule having a nucleic acid sequence which can hybridize to a target nucleic acid sequence, e.g. specifically hybridize to the target sequence. In some embodiments, a nucleic acid probe can further comprise a detectable label. In some embodiments, a nucleic acid probe can be attached to a solid surface. In some embodiments, a nucleic acid from is from about 5 nt to about 100 nt in length. id="p-566" id="p-566"

[00566] As used herein, the term siRNA refers to a nucleic acid that forms an RNA molecule comprising two individual strands of RNA which are substantially complementary to each other. Typically, the siRNA is at least about 15-40 nucleotides in length (e.g., each complementary sequence of the double stranded siRNA is about 15-40 nucleotides in length, and the double stranded siRNA is about 15-40 base pairs in length, preferably about 19-25 base nucleotides, e.g., 19, 20, 21, 22, 23, 24, or 25 nucleotides in length). In some embodiments, a siRNA can be blunt-ended. In some embodiments, a siRNA can comprise a 3' and/or 5' overhang on each strand having a length of about 0, 1, 2, 3, 4, or 5 nucleotides. The length of the overhang is independent between the two strands, i.e., the length of the overhang on one strand is not dependent on the length of the overhang on the second strand. The siRNA molecules can also comprise a 3' hydroxyl group. In some embodiments, the siRNA can comprise a 5' phosphate group. A siRNA has the ability to reduce or inhibit expression of a gene or target RNA when the siRNA is present or expressed in the same cell as the target gene, e.g. the target RNA. siRNA-dependent post-transcriptional silencing of gene expression involves cutting the target RNA molecule at a site guided by the siRNA. 18936261-1 id="p-567" id="p-567"

[00567] As used herein, PCSK9 or proprotein convertase subtilisin/kexin type 9 refers to a serine protease involved in regulating the levels of the low density lipoprotein receptor (LDLR) protein (Horton et al., 2007; Seidah and Prat, 2007). PCSK9 has been shown to directly interact with the LDLR protein, be endocytosed along with the LDLR, and coimmunofluoresce with the LDLR throughout the endosomal pathway (Lagace et al., 2006). PCSK9 is a prohormone-proprotein convertase in the subtilisin (S8) family of serine proteases (Seidah et al., 2003). The sequence of PCSK9 for a variety of species is known, e.g., human PCSK9 (NCBI Gene ID No: 255738). Nucleotide and polypeptide sequences for a number of PCSK9 isoforms are provided herein, e.g., SEQ ID NOs: 1-37. id="p-568" id="p-568"

[00568] PCSK9 exists as both a pro-form and a mature form. Autocatalysis of the PCSK9 proform occurs between Glnl52 and Serl53 (VFAQ|SIP (SEQ ID NO: 67)) (Naureckiene et al., 2003), and has been shown to be required for its secretion from cells (Seidah et al., 2003). The inactive form prior to this cleavage can be referred to herein as the inactive, pro-form, or unprocessed form of PCSK9. The C-terminal fragment generated by the autocatalysis event can be referred to herein as the mature, cleaved, processed or active PCSK9. Examples of pro-form and mature PCSK9 isoforms are provided herein, see, e.g. SEQ ID NOs: 1-27. id="p-569" id="p-569"

[00569] As used herein, the catalytic domain of PCSK9 refers to the portion of a PCSK9 polypeptide corresponding to positions 153 to 449 of PCSK9, e.g. of SEQ ID NO: 1. As used herein, the C-terminal domain of PCSK9 refers to the portion of a PCSK9 polypeptide corresponding to positions 450-692 of PCSK9, e.g., of SEQ ID NO: 1. id="p-570" id="p-570"

[00570] As used herein, a disease or condition mediated by PCSK9 refers to a disease or condition which is caused by or characterized by a change in PCSK9, e.g. a change in expression level, a change in activity, and/or the presence of a variant or mutation of PCSK9. Non-limiting examples of such diseases or conditions can include, for example, a lipid disorder, hyperlipoproteinemia, hyperlipidemia; dyslipidemia; hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication, type II diabetes, high blood pressure, and a cardiovascular disease or condition. Claudication mentioned herein can be claudication associated with elevated cholesterol. In an example, the disease or condition is an inflammatory or autoimmune disease or condition. Methods of identifying and/or diagnosing such diseases and conditions are well known to medical practitioners of ordinary skill. id="p-571" id="p-571"

[00571] A subject at risk of having or developing a disease or condition mediated by PCSK9 can be a subject exhibiting one or more signs or symptoms of such a disease or condition or 18936261-1 having one or more risk factors for such a disease or condition, e.g. being overweight, having elevated cholesterol level, comprising one or more genetic polymorphisms known to predispose to the disease or condition, e.g., elevated cholesterol level, such as having a mutation in the LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B) or in the PCSK9 gene and/or having a family history of such a disease or condition. id="p-572" id="p-572"

[00572] As used herein, ligand refers to a molecule which can bind, e.g., specifically bind, to a second molecule or receptor. In some embodiments, a ligand can be, e.g., an antibody, antibody fragment, antibody portion, and/or affibody. ]00573] The term variant as used herein refers to a peptide or nucleic acid that differs from the polypeptide or nucleic acid (eg, the most common one in humans, eg, most frequent in a database as disclosed herein, such as the 1000 Genomes Project database) by one or more amino acid or nucleic acid deletions, additions, yet retains one or more specific functions or biological activities of the naturally occurring molecule. Amino acid substitutions include alterations in which an amino acid is replaced with a different naturally-occurring amino acid residue. Such substitutions may be classified as conservative, in which case an amino acid residue contained in a polypeptide is replaced with another naturally occurring amino acid of similar character either in relation to polarity, side chain functionality or size. Such conservative substitutions are well known in the art. Substitutions encompassed by the present invention may also be non-conservative, in which an amino acid residue which is present in a peptide is substituted with an amino acid having different properties, such as naturally-occurring amino acid from a different group (e.g., substituting a charged or hydrophobic amino; acid with alanine), or alternatively, in which a naturally-occurring amino acid is substituted with a non- conventional amino acid. In some embodiments amino acid substitutions are conservative. Also encompassed within the term variant when used with reference to a polynucleotide or polypeptide, refers to a polynucleotide or polypeptide that can vary in primary, secondary, or tertiary structure, as compared to a reference polynucleotide or polypeptide, respectively (e.g., as compared to a wild- type polynucleotide or polypeptide). id="p-574" id="p-574"

[00574] Variants of PCSK9 are provided elsewhere herein. Variants of PCSK9 can include the forms described herein as a, f, c, r, p, m, e h, aj, and q. Sequences of these variants are provided herein, see, e.g, SEQ ID NOs: 1-27 and in Tables 1, 2 and 5. id="p-575" id="p-575"

[00575] In some aspects, one can use synthetic variants, recombinant variants, or chemically modified polynucleotide variants or polypeptide variants isolated or generated 18936261-1 using methods well known in the art. Modified variants can include conservative or nonconservative amino acid changes, as described below. Polynucleotide changes can result in amino acid substitutions, additions, deletions, fusions and truncations in the polypeptide encoded by the reference sequence. Some aspects use include insertion variants, deletion variants or substituted variants with substitutions of amino acids, including insertions and substitutions of amino acids and other molecules) that do not normally occur in the peptide sequence that is the basis of the variant, for example but not limited to insertion of ornithine which do not normally occur in human proteins. The term conservative substitution, when describing a polypeptide, refers to a change in the amino acid composition of the polypeptide that does not substantially alter the polypeptide's activity. For example, a conservative substitution refers to substituting an amino acid residue for a different amino acid residue that has similar chemical properties. Conservative amino acid substitutions include replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, or a threonine with a serine. id="p-576" id="p-576"

[00576] Conservative amino acid substitutions result from replacing one amino acid with another having similar structural and/or chemical properties, such as the replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, or a threonine with a serine. Thus, a conservative substitution of a particular amino acid sequence refers to substitution of those amino acids that are not critical for polypeptide activity or substitution of amino acids with other amino acids having similar properties (e.g., acidic, basic, positively or negatively charged, polar or non-polar, etc.) such that the substitution of even critical amino acids does not reduce the activity of the peptide, (i.e. the ability of the peptide to penetrate the blood brain barrier (BBB)). Conservative substitution tables providing functionally similar amino acids are well known in the art. For example, the following six groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Serine (S), Threonine (T); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W). (See also Creighton, Proteins, W. H.

Freeman and Company (1984), incorporated by reference in its entirety.) In some embodiments, individual substitutions, deletions or additions that alter, add or delete a single amino acid or a small percentage of amino acids can also be considered conservative substitutions if the change does not reduce the activity of the peptide. Insertions or deletions are typically in the range of about 1 to 5 amino acids. The choice of conservative amino acids may be selected based on the location of the amino acid to be substituted in the peptide, for 18936261-1 example if the amino acid is on the exterior of the peptide and expose to solvents, or on the interior and not exposed to solvents. 100577] In alternative embodiments, one can select the amino acid which will substitute an existing amino acid based on the location ofthe existing amino acid, i.e. its exposure to solvents (i.e. if the amino acid is exposed to solvents or is present on the outer surface of the peptide or polypeptide as compared to internally localized amino acids not exposed to solvents). Selection of such conservative amino acid substitutions are well known in the art, for example as disclosed in Dordo et al, J. Mol Biol, 1999, 217, 721-739 and Taylor et al, J. Theor. Biol. 119(1986);205-218 and S. French and B. Robson, J. Mol. Evol. 19(1983)171. Accordingly, one can select conservative amino acid substitutions suitable for amino acids on the exterior of a protein or peptide (i.e. amino acids exposed to a solvent), for example, but not limited to, the following substitutions can be used: substitution of Y with F, T with S or K, P with A, E with D or Q, N with D or G, R with K, G with N or A, T with S or K, D with N or E, I with L or V, F with Y, S with T or A, R with K, G with N or A, K with R, A with S, K or P. [00578] In alternative embodiments, one can also select conservative amino acid substitutions encompassed suitable for amino acids on the interior of a protein or peptide, for example one can use suitable conservative substitutions for amino acids is on the interior of a protein or peptide (i.e. the amino acids are not exposed to a solvent), for example but not limited to, one can use the following conservative substitutions: where Y is substituted with F, T with A or S, I with L or V, W with Y, M with L, N with D, G with A, T with A or S, D with N, I with L or V, F with Y or L, S with A or T and A with S, G, T or V. In some embodiments, nonconservative amino acid substitutions are also encompassed within the term of variants. [00579] As used herein an antibody refers to IgG, IgM, IgA, IgD or IgE molecules or antigen-specific antibody fragments thereof (including, but not limited to, a Fab, F(ab')2, Fv, disulphide linked Fv, scFv, single domain antibody, closed conformation multispecific antibody, disulphide-linked scfv, diabody), whether derived from any species that naturally produces an antibody, or created by recombinant DNA technology; whether isolated from serum, B-cells, hybridomas, transfectomas, yeast or bacteria. Antibodies can be humanized using routine technology. id="p-580" id="p-580"

[00580] As described herein, an antigen is a molecule that is bound by a binding site on an antibody agent. Typically, antigens are bound by antibody ligands and are capable of raising an antibody response in vivo. An antigen can be a polypeptide, protein, nucleic acid or other molecule or portion thereof. The term antigenic determinant refers to an epitope on 18936261-1 the antigen recognized by an antigen-binding molecule, and more particularly, by the antigenbinding site of said molecule. id="p-581" id="p-581"

[00581] As used herein, the term antibody fragment refers to a polypeptide that includes at least one immunoglobulin variable domain or immunoglobulin variable domain sequence and which specifically binds a given antigen. An antibody fragment can comprise an antibody or a polypeptide comprising an antigen-binding domain of an antibody. In some embodiments, an antibody fragment can comprise a monoclonal antibody or a polypeptide comprising an antigen-binding domain of a monoclonal antibody. For example, an antibody can include a heavy (H) chain variable region (abbreviated herein as VH), and a light (L) chain variable region (abbreviated herein as VL). In another example, an antibody includes two heavy (H) chain variable regions and two light (L) chain variable regions. The term antibody fragment encompasses antigen-binding fragments of antibodies (e.g., single chain antibodies, Fab and sFab fragments, F(ab')2, Fd fragments, Fv fragments, scFv, and domain antibodies (dAb) fragments (see, e.g. de Wildt et al., Eur J. Immunol. 1996; 26(3):629-39; which is incorporated by reference herein in its entirety)) as well as complete antibodies. An antibody can have the structural features of IgA, IgG, IgE, IgD, IgM (as well as subtypes and combinations thereof). Antibodies can be from any source, including mouse, rabbit, pig, rat, and primate (human and non-human primate) and primatized antibodies. Antibodies also include midibodies, humanized antibodies, chimeric antibodies, and the like. |00582] As used herein, antibody variable domain refers to the portions of the light and heavy chains of antibody molecules that include amino acid sequences of Complementarity Determining Regions (CDRs; ie., CDR1, CDR2, and CDR3), and Framework Regions (FRs). VH refers to the variable domain of the heavy chain. VL refers to the variable domain of the light chain. According to the methods used in this invention, the amino acid positions assigned to CDRs and FRs may be defined according to Kabat (Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987 and 1991)) or according to IMGT nomenclature. id="p-583" id="p-583"

[00583] D domain or region refers to the diversity domain or region of an antibody chain. J domain or region refers to the joining domain or region of an antibody chain. |00584] An antibody gene segment, e.g. a VH gene segment, D gene segment, or JH gene segment refers to oligonucleotide having a nucleic acid sequence that encodes that portion of an antibody, e.g. a VH gene segment is an oligonucleotide comprising a nucleic acid sequence that encodes a polypeptide VH domain. id="p-585" id="p-585"

[00585] The VH and VL regions can be further subdivided into regions of hypervariability, 18936261-1 termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). The extent of the framework region and CDRs has been precisely defined (see, IMGT or Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242, and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; which are incorporated by reference herein in their entireties). Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. id="p-586" id="p-586"

[00586] The terms antigen-binding fragment or antigen-binding domain, which are used interchangeably herein are used to refer to one or more fragments of a full length antibody that retain the ability to specifically bind to a target of interest. Examples of binding fragments encompassed within the term antigen-binding fragment of a full length antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment including two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CHI domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546; which is incorporated by reference herein in its entirety), which consists of a VH or VL domain; and (vi) an isolated complementarity determining region (CDR) that retains specific antigen-binding functionality. [00587] As used herein, the term antibody binding site refers to a polypeptide or domain that comprises one or more CDRs of an antibody and is capable of binding an antigen. For example, the polypeptide comprises a CDR3 (eg, HCDR3). For example the polypeptide comprises CDRs 1 and 2 (eg, HCDR1 and 2) or CDRs 1-3 of a variable domain of an antibody (eg, HCDRsl-3). In an example, the antibody binding site is provided by a single variable domain (eg, a VH or VL domain). In another example, the binding site comprises a VH/VL pair or two or more of such pairs. ]00588] As used herein, the term specific binding refers to a chemical interaction between two molecules, compounds, cells and/or particles wherein the first entity binds to the second, target entity with greater specificity and affinity than it binds to a third entity which is a non-target. For example, in an diagnostic test the specific binding of a ligand can distinguish between two variant PCSK9 proteins as described herein. In some embodiments, specific binding can refer to an affinity of the first entity for the second target entity which is at least 10 times, at least 50 times, at least 100 times, at least 500 times, at least 1000 times or greater than the affinity for the third nontarget entity. In the context of oligonucleotide 18936261-1 strands which interact via hybridization, specific binding can be specific hybridization. [00589] Additionally, and as described herein, a recombinant human(ized) antibody can be further optimized to decrease potential immunogenicity, while maintaining functional activity, for therapy in humans. In this regard, functional activity means a polypeptide capable of displaying one or more known functional activities associated with a recombinant antibody or antibody reagent thereof as described herein. Such functional activities include, e.g. the ability to bind to a target molecule. id="p-590" id="p-590"

[00590] The term immunizing refers to the step or steps of administering one or more antigens to an animal so that antibodies can be raised in the animal Generally, immunizing comprises injecting the antigen or antigens into the animal. Immunization can involve one or more administrations of the antigen or antigens. Suitable methods are prime-boost and RIMMS procedures as known to the skilled person in the art. 100591] As used herein, an affibody refers to a relatively small synthetic protein molecule that has high binding affinity for a target protein (e.g. for PCSK9 or a variant thereto).

Affibodies are composed of a three-helix bundle domain derived from the IgG-binding domain of staphylococcal protein A. The protein domain consists of a 58 amino acid sequence, with 13 randomized amino acids affording a range of affibody variants. Despite being significantly smaller than an antibody (an affibody weighs about 6 kDa while an antibody commonly weighs about 150 kDa), an affibody molecule works like an antibody since its binding site is approximately equivalent in surface area to the binding site of an antibody. [00592| As used herein, VH3-23*04 refers to a human VH domain variant comprising the polypeptide sequence of SEQ ID NO: 38. As opposed to the reference sequence, VH3-23*04 has a valine residue instead of a leucine residue (see Figures 3 and 4; L24V, numbering including signal sequence; valine at position 5 shown in Figure 4) as a result of the presence of the rs56069819 SNP in the nucleic acid sequence encoding the VH domain. As used herein, rs56069819 refers to a mutation or variant in a VH gene segment from adenosine to cytosine (or thymine to guanine, depending upon the strand of DNA which is being read), resulting in the VH domain encoding VH3-23*04. Rs56069819 is depicted in Figure 4 and SEQ ID NO: 39, which demonstrate the T->G mutation (it is noted that the dbSNP entry for RS5606819 depicts the other strand, which comprises the A->C mutation). Further description of VH3-23*04 can be found, e.g., in US Patent Publication 2013/0071405; which is incorporated by reference herein in its entirety. id="p-593" id="p-593"

[00593] As used herein, determine or determining refers to ascertaining, e.g., by a quantitative or qualitative analysis. As used herein, has been determined can refer to 18936261-1 ascertaining on the basis of previously obtained information or simultaneously obtained information. id="p-594" id="p-594"

[00594] In some aspects of all embodiments of the invention selecting can include automation such as a computer implemented software program that upon input of the relevant data such as ethnicity or a panel of SNP data can make the determination based on the instructions set forth herein. id="p-595" id="p-595"

[00595] As used herein, assaying refers to assessing, evaluating, quantifying, measuring, or characterizing an analyte, e.g., measuring the level of an analyte in a sample, identifying an analyte, or detecting the presence or absence of an analyte in a sample. In some embodiments, assaying refers to detecting a presence or absence of the analyte of interest. In some embodiments, assaying refers to quantifying an amount of an analyte, e.g., providing a measure of concentration or degree of analyte abundance. In some embodiments, assaying refers to enumerating the number of molecules of analyte present in a sample and/or specimen, e.g., to determine an analyte copy number. id="p-596" id="p-596"

[00596] As used herein multiplex refers to the carrying out of a method or process simultaneously and in the same reaction vessel on two or more, typically three or more, different target sequences, e.g. on two or more isoforms of PCSK9, or PCSK9 and an additional target. A multiplex analysis typically includes analysis of 10-50; 10-100; 10-1000, 10-5000, 10-10000 reactions in a multiplex format, such as a multiwail, an array, or a multichannel reaction. id="p-597" id="p-597"

[00597] Often the analysis or multiplex analysis is also automated using robotics and typically software executed by a computer and may include a robotic handling of samples, automatic or robotic selection of positive or negative results, assaying for presence of absence of a target, such as a nucleic add polymorphism or a protein variant. |00598] The term biological sample or test sample as used herein denotes a sample taken or isolated from a biological organism, e.g., a sample from a subject.

Exemplary biological samples include, but are not limited to, a biofluid sample; serum; plasma; urine; saliva; hair, epithelial cells, skin, a tumor biopsy and/or tissue sample etc. The term also includes a mixture of the above-mentioned samples. The term test sample or biological sample also includes untreated or pretreated (or pre-processed) biological samples. For the analysis of nucleic acids, the biological sample should typically comprise at least one cell comprising nucleic acids. id="p-599" id="p-599"

[00599] The test sample can be obtained by removing a sample of cells from a subject, but can also be accomplished by using previously isolated cells (e.g. isolated at a 18936261-1 prior time point and isolated by the same or another person). In addition, the test sample can be freshly collected or a previously collected, refrigerated, frozen or otherwise preserved sample. |00600] In some embodiments, the test sample can be an untreated test sample.

As used herein, the phrase untreated test sample refers to a test sample that has not had any prior sample pre-treatment except for dilution and/or suspension in a solution. Exemplary methods for treating a test sample include, but are not limited to, centrifugation, filtration, sonication, homogenization, heating, freezing and thawing, and combinations thereof. In some embodiments, the test sample can be a frozen test sample, e.g., a frozen tissue. The frozen sample can be thawed before employing methods, assays and systems described herein. After thawing, a frozen sample can be centrifuged before being subjected to methods, assays and systems described herein. In some embodiments, the test sample is a clarified test sample, for example, by centrifugation and collection of a supernatant comprising the clarified test sample. In some embodiments, a test sample can be a pre-processed test sample, for example, supernatant or filtrate resulting from a treatment selected from the group consisting of centrifugation, filtration, thawing, purification, and any combinations thereof. In some embodiments, the test sample can be treated with a chemical and/or biological reagent. Chemical and/or biological reagents can be employed to protect and/or maintain the stability of the sample, including biomolecules (e.g., nucleic acid and protein) therein, during processing. One exemplary reagent is a protease inhibitor, which is generally used to protect or maintain the stability of protein during processing. The skilled artisan is well aware of methods and processes appropriate for pre-processing of biological samples required for determination of the level of an expression product as described herein. id="p-601" id="p-601"

[00601] As used herein, genotyping refers to a process of determining the specific allelic composition of a cell and/or subject at one or more position within the genome, e.g. by determining the nucleic add sequence at that position. Genotyping refers to a nucleic acid analysis and/or analysis at the nucleic acid level. As used herein, phenotyping refers a process of determining the identity and/or composition of an expression product of a cell and/or subject, e.g. by determining the polypeptide sequence of an expression product, Phenotyping refers to a protein analysis and/or analysis at the protein level. id="p-602" id="p-602"

[00602] As used herein, the term nucleic acid amplification'' refers to the production of additional copies of a nucleic acid sequence and is typically carried out using polymerase chain reaction (PCR) or ligase chain reaction (LCR) technologies well known in the art (Dieffenbach, C. W. and G. S. Dveksler (1995) PCR Primer, a Laboratory Manual, Cold 18936261-1 Spring Harbor Press, Plainview, N. Y.). Other methods for amplification are also contemplated in aspects of the invention. id="p-603" id="p-603"

[00603] The term allele-specific amplification refers to a reaction (e.g., PCR reaction) in which at least one of the primers (e.g., allele-specific primer) is chosen from a polymorphic area of gene (e.g., single nucleotide polymorphism), with the polymorphism located at or near the primer's 3'-end. A mismatched primer will not initiate amplification, whereas a matched primer will initiate amplification. The appearance of an amplification product is indicative of the presence of the polymorphism. id="p-604" id="p-604"

[00604] As used herein, sequencing refers to the determination of the exact order of nucleotide bases in a strand of DNA (deoxyribonucleic acid) or RNA (ribonucleic acid) or the exact order of amino acids residues or peptides in a protein. Nucleic acid sequencing can be done using Sanger sequencing or next-generation high-throughput sequencing. ]00605] As used herein next-generation sequencing refers to oligonucleotide sequencing technologies that have the capacity to sequence oligonucleotides at speeds above those possible with conventional sequencing methods (e.g. Sanger sequencing), due to performing and reading out thousands to millions of sequencing reactions in parallel. Nonlimiting examples of next-generation sequencing methods/platforms include Massively Parallel Signature Sequencing (Lynx Therapeutics); 454 pyro-sequencing (454 Life Sciences/ Roche Diagnostics); solid-phase, reversible dye-terminator sequencing (Solexa/Illumina): SOLID technology (Applied Biosystems); Ion semiconductor sequencing (ION Torrent); DNA nanoball sequencing (Complete Genomics); and technologies available from Pacific Biosciences, Intelligen Bio-systems, Oxford Nanopore Technologies, and Helicos Biosciences. Nextgeneration sequencing technologies and the constraints and design parameters of associated sequencing primers are well known in the art (see, e.g. Shendure, et al., Next-generation DNA sequencing, Nature, 2008, vol. 26, No. 10,1135-1145; Mardis, The impact of nextgeneration sequencing technology on genetics, Trends in Genetics, 2007, vol. 24, No. 3, pp. 133-141; Su, et al., Next-generation sequencing and its applications in molecular diagnostics" Expert Rev Mol Diagn, 2011, ll(3):333-43; Zhang et al., The impact of next-generation sequencing on genomics, J Genet Genomics, 2011, 38(3):95-109; (Nyren, P. et al. Anal Biochem 208: 17175 (1993); Bentley, D. R. Curr Opin Genet Dev 16:545-52 (2006); Strausberg, R. L., etal. Drug Disc Today 13:569-77 (2008); U.S. Pat. No. 7,282,337; U.S. Pat. No. 7,279,563; U.S. Pat. No. 7,226,720; U.S. Pat. No. 7,220,549; U.S. Pat. No. 7,169,560; U.S. Pat. No. 6,818,395; U.S. Pat. No. 6,911,345; US Pub. Nos. 2006/0252077; 18936261-1 2007/0070349; and 20070070349; which are incorporated by referene herein in their entireties). id="p-606" id="p-606"

[00606] As used herein, nucleic acid hybridization refers to the pairing of complementary RNA and DNA strands as well as the pairing of complementary DNA single strands. In some embodiments, nucleic acid hybridization can refer to a method of determining a nucleic acid sequence and/or identity by hybridizing a nucleic acid sample with a probe, e.g. Northern or Southern blot analysis or microarray analysis. id="p-607" id="p-607"

[00607] As used herein, the terms treat, treatment, treating, or amelioration refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a condition associated with a disease or disorder. The term treating includes reducing or alleviating at least one adverse effect or symptom of a condition, disease or disorder. Treatment is generally effective if one or more symptoms or clinical markers are reduced. Alternatively, treatment is effective if the progression of a disease is reduced or halted. That is, treatment includes not just the improvement of symptoms or markers, but also a cessation of, or at least slowing of, progress or worsening of symptoms compared to what would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), and/or decreased mortality, whether detectable or undetectable. The term treatment of a disease also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment). For treatment to be effective a complete cure is not contemplated. The method can in certain aspects include cure as well. 100608] As used herein, the term pharmaceutical composition refers to the active agent in combination with a pharmaceutically acceptable carrier e.g. a carrier commonly used in the pharmaceutical industry. The phrase pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. id="p-609" id="p-609"

[00609] As used herein, the term administering, refers to the placement of a compound as disclosed herein into a subject by a method or route which results in at least partial delivery of the agent at a desired site. Pharmaceutical compositions comprising the 18936261-1 compounds disclosed herein can be administered by any appropriate route which results in an effective treatment in the subject. [00610) Multiple compositions can be administered separately or simultaneously.

Separate administration refers to the two compositions being administered at different times, e.g. at least 10, 20, 30, or 10-60 minutes apart, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 hours apart. One can also administer compositions at 24 hours apart, or even longer apart. Alternatively, two or more compositions can be administered simultaneously, e.g. less than 10 or less than 5 minutes apart. Compositions administered simultaneously can, in some aspects, be administered as a mixture, with or without similar or different time release mechanism for each of the components. id="p-611" id="p-611"

[00611] As used herein, contacting refers to any suitable means for delivering, or exposing, an agent to at least one complex, enzyme, or cell. Exemplary delivery methods include, but are not limited to, direct delivery to cell culture medium, perfusion, injection, or other delivery method well known to one skilled in the art. id="p-612" id="p-612"

[00612] As used herein, obtain refers to any method of acquiring, securing, procuring, or coming into the possession of, e.g. a sample. Obtaining a biological sample from a subject can comprise physical removing a sample from a subject (e.g. drawing blood or taking a hair or saliva sample) without or without active participation from the subject; receiving a sample from a subject (e.g. the subject collects a saliva or hair sample themselves and provides it, e.g. in a container provided for the purpose); or procuring a sample from a storage facility, medical facility, or medical provider. Obtain from the human or subject, refers to an active step of, e.g., drawing blood or taking a tissue or cell sample. 100613] As used herein, cholesterol level refers to a level of one or more of total cholesterol, LDL cholesterol, HDL cholesterol, and/or triglycerides. Cholesterol levels can be the level of cholesterol in the blood of a subject. id="p-614" id="p-614"

[00614] As used herein in reference to cholesterol levels, maintain refers to preventing the level from worsening (e.g. increasing). In some embodiments, maintaining a particular level refers to a process that results in the cholesterol level not increasing by more than 10% over time. Maintaining may also refer to maintaining a previously achieved level. For example, if a human has received statin treatment, one can maintain the cholesterol level achieved using the statin treatment. id="p-615" id="p-615"

[00615] In some embodiments, the subject treated according to the methods described herein has previously had their cholesterol level reduced. As used herein, previously reduced indicates that at a prior point in time, the subject experienced a decrease 18936261-1 in cholesterol levels. The decrease can be due to administration of a pharmaceutical composition (e.g. administration of a composition as described herein or another composition, e.g. a statin) or due to another cause, e.g. a change in diet and/or exercise. id="p-616" id="p-616"

[00616] An existing treatment for high cholesterol levels is the administration of a statin. As referred to herein, a statin (also known as HMG-CoA reductase inhibitors) are inhibitors of the enzyme HMG-coA reductase, which mediates cholesterol production in the liver. Statins, by competitively binding HMG-CoA reductase, prevent the binding of HMG-CoA to the enzyme and thereby inhibit the activity of the reductase (e.g. the production of mevalonate). Non-limiting examples of statins can include atorvastatin (LIPITOR™), fluvastatin (LESCOL™), lovastatin (MEVACOR™, ALTOCOR™), pitavastatin (LIVALO™), pravastatin (PRAVACHOL™), rosuvastatin (CRESTOR™), and simvastatin (ZOCOR™). Statins can be administered in combination with other agents, e.g. the combination of ezetimibe and simvastatin. (00617] Some subjects are, or become, resistant to statin treatment. As used herein, resistant to statin treatment or reduced responsiveness to statin treatment refers to a subject exhibiting a statistically significantly lower response to the administration of a statin as compared to a reference level. The reference level can be, e.g., the average response for a population of subjects or the level of the individual subject at an earlier date. A response to statin treatment is readily measured by one of skill in the art, e.g., measurement of cholesterol levels, changes in cholesterol levels, and/or HMG-CoA reductase activity. id="p-618" id="p-618"

[00618] As used herein, the term detectable label refers to a molecule or moiety that can be detected, e.g. measured and/or determined to be present or absent. Detectable labels can comprise, for example, a light-absorbing dye, a fluorescent dye, or a radioactive label. Detectable labels, methods of detecting them, and methods of incorporating them into reagents (e.g. antibodies and nucleic acid probes) are well known in the art. id="p-619" id="p-619"

[00619] In some embodiments, detectable labels can include labels that can be detected by spectroscopic, photochemical, biochemical, immunochemical, electromagnetic, radiochemical, or chemical means, such as fluorescence, chemifluoresence, or chemiluminescence, or any other appropriate means. The detectable labels used in the methods described herein can be primary labels (where the label comprises a moiety that is directly detectable or that produces a directly detectable moiety) or secondary labels (where the detectable label binds to another moiety to produce a detectable signal, e.g., as is common in immunological labeling using secondary and tertiary antibodies). The detectable 18936261-1 label can be linked by covalent or non-covalent means to the reagent. Alternatively, a detectable label can be linked such as by directly labeling a molecule that achieves binding to the reagent via a ligand-receptor binding pair arrangement or other such specific recognition molecules. Detectable labels can include, but are not limited to radioisotopes, bioluminescent compounds, chromophores, antibodies, chemiluminescent compounds, fluorescent compounds, metal chelates, and enzymes. id="p-620" id="p-620"

[00620] In other embodiments, the detectable label can be a fluorescent compound.

When the fluorescently label is exposed to light of the proper wavelength, its presence can then be detected due to fluorescence. In some embodiments, a detectable label can be a fluorescent dye molecule, or fluorophore including, but not limited to fluorescein, phycoerythrin, phycocyanin, o-phthaldehyde, fluorescamine, Cy3™, Cy5™, allophycocyanine, Texas Red, peridenin chlorophyll, cyanine, tandem conjugates such as phycoerythrin-Cy5™, green fluorescent protein, rhodamine, fluorescein isothiocyanate (FITC) and Oregon Green™, rhodamine and derivatives (e.g., Texas red and tetrarhodimine isothiocynate (TRITC)), biotin, phycoerythrin, AMCA, CyDyes™, 6-carboxyfhiorescein (commonly known by the abbreviations FAM and F), 6-carboxy-2',4',7',4,7-hexachlorofiuorescein (HEX), 6-carboxy-4',5'-dichloro-2',7'dimethoxyfiuorescein (JOE or J), N,N,N',N'-tetramethyl-6carboxyrhodamine (TAMRA or T), 6carboxy-X-rhodamine (ROX or R), 5-carboxyrhodamine-6G (R6G5 or G5), 6carboxyrhodamine-6G (R6G6 or G6), and rhodamine 110; cyanine dyes, e.g. Cy3, Cy5 and Cy7 dyes; coumarins, e.g umbelliferone; benzimide dyes, e.g. Hoechst 33258; phenanthridine dyes, e.g. Texas Red; ethidium dyes; acridine dyes; carbazole dyes; phenoxazine dyes; porphyrin dyes; polymethine dyes, e.g. cyanine dyes such as Cy3, Cy5, etc; BODIPY dyes and quinoline dyes. In some embodiments, a detectable label can be a radiolabel including, but not limited to 3H, 125I, 35S, 14C, 32P, and 33P. In some embodiments, a detectable label can be an enzyme including, but not limited to horseradish peroxidase and alkaline phosphatase. An enzymatic label can produce, for example, a chemiluminescent signal, a color signal, or a fluorescent signal. Enzymes contemplated for use as a detectable label can include, but are not limited to, malate dehydrogenase, staphylococcal nuclease, delta-V-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-VI-phosphate dehydrogenase, glucoamylase and acetylcholinesterase. In some embodiments, a detectable label is a chemiluminescent label, including, but not limited to lucigenin, luminol, luciferin, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester. In some 18936261-1 embodiments, a detectable label can be a spectral colorimetric label including, but not limited to colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, and latex) beads. id="p-621" id="p-621"

[00621] In some embodiments, reagents can also be labeled with a detectable tag, such as c-Myc, HA, VSV-G, HSV, FLAG, V5, HIS, or biotin. Other detection systems can also be used, for example, a biotin-streptavidin system. In this system, the antibodies immunoreactive (i. e. specific for) with the biomarker of interest is biotinylated. Quantity of biotinylated antibody bound to the biomarker is determined using a streptavidin-peroxidase conjugate and a chromagenic substrate. Such streptavidin peroxidase detection kits are commercially available, e. g. from DAKO; Carpinteria, CA. A reagent can also be detectably labeled using fluorescence emitting metals such as 152Eu, or others of the lanthanide series. These metals can be attached to the reagent using such meta! chelating groups as diethylenetriaminepentaacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA). [00622] As used herein, authorization number or marketing authorization number refers to a number issued by a regulatory agency upon that agency determining that a particular medical product and/or composition may be marketed and/or offered for sale in the area under the agency's jurisdiction. As used herein regulatory agency refers to one of the agencies responsible for evaluating, e.g, the safety and efficacy of a medical product and/or composition and controlling the sales/marketing of such products and/or compositions in a given area. The Food and Drug Administration (FDA) in the US and the European Medicines Agency (EPA) in Europe are but two examples of such regulatory agencies. Other non-limiting examples can include SDA, MPA, MHPRA, IMA, ANMAT, Hong Kong Department of Health-Drug Office, CDSCO, Medsafe, and KFDA. id="p-623" id="p-623"

[00623] As used herein, injection device refers to a device that is designed for carrying out injections, an injection including the steps of temporarily fluidically coupling the injection device to a person's tissue, typically the subcutaneous tissue. An injection further includes administering an amount of liquid drug into the tissue and decoupling or removing the injection device from the tissue. In some embodiments, an injection device can be an intravenous device or IV device, which is a type of injection device used when the target tissue is the blood within the circulatory system, e.g., the blood in a vein. A common, but non-limiting example of an injection device is a needle and syringe. id="p-624" id="p-624"

[00624] As used herein, a buffer refers to a chemical agent that is able to absorb a certain quantity of acid or base without undergoing a strong variation in pH. id="p-625" id="p-625"

[00625] As used herein, packaging refers to how the components are organized and/or restrained into a unit fit for distribution and/or use. Packaging can include, e.g., 18936261-1 boxes, bags, syringes, ampoules, vials, tubes, clamshell packaging, barriers and/or containers to maintain sterility, labeling, etc. {00626] As used herein, instructions refers to a display of written, printed or graphic matter on the immediate container of an article, for example the written material displayed on a vial containing a pharmaceutically active agent, or details on the composition and use of a product of interest included in a kit containing a composition of interest. Instructions set forth the method of the treatment as contemplated to be administered or performed. id="p-627" id="p-627"

[00627] As used herein, a solid surface refers to an object suitable for the attachment of biomolecules. Non-limiting examples of a solid surface can include a particle (including, but not limited to an agarose or latex bead or particle or a magnetic particle), a bead, a nanoparticle, a polymer, a substrate, a slide, a coverslip, a plate, a dish, a well, a membrane, and/or a grating. The solid surface can include many different materials including, but not limited to, polymers, plastics, resins, polysaccharides, silicon or silica based materials, carbon, metals, inorganic glasses, and membranes. id="p-628" id="p-628"

[00628] As used herein, classification of a subject, e.g., classification of the subject's ancestry refers to determining if the subject has biological ancestors who originated in a particular geographical area, and are therefore likely to have particular genetic variants found in the populations which have historically occupied that area. Classification can comprise, e.g. obtaining information on the subject's family, interviewing the subject or a family member regarding their biological family's ancestry, and/or genetic testing. Classification can be on the basis used for the 1000 Genomes Project, as will be familiar to the skilled person in the art. In some embodiments, the subject can be classified as being of a particular ancestry if at least the subject's genome comprises a substantial number of different alleles in common with other humans of that ancestry (eg, determined by reference to the 1000 Genomes Project database), for example, at least 10, 20, 30, 40, 50 or 100 or more alleles in common. Abbreviations for particular ancestral groups are provided in Table 4. id="p-629" id="p-629"

[00629] The term statistically significant or significantly refers to statistical significance and generally means a two standard deviation (2SD) or greater difference. [00630] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term about.The term about when used in connection with percentages can mean ±1%. id="p-631" id="p-631"

[00631] As used herein the term comprising or comprises is used in reference to compositions, methods, and respective component(s) thereof, that are essential to the 18936261-1 method or composition, yet open to the inclusion of unspecified elements, whether essential or not. id="p-632" id="p-632"

[00632] The term consisting of refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment. id="p-633" id="p-633"

[00633] As used herein the term consisting essentially of refers to those elements required for a given embodiment. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment. id="p-634" id="p-634"

[00634] The singular terms a, an, and the include plural referents unless context clearly indicates otherwise. Similarly, the word or is intended to include and unless the context dearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The abbreviation, e.g. is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation e.g. is synonymous with the term for example. id="p-635" id="p-635"

[00635] Definitions of common terms in cell biology and molecular biology can be found in The Merck Manual of Diagnosis and Therapy, 19th Edition, published by Merck Research Laboratories, 2006 (ISBN 0-911910-19-0); Robert S. Porter et al. (eds.), The Encyclopedia of Molecular Biology, published by Blackwell Science Ltd., 1994 (ISBN 0-63202182-9); Benjamin Lewin, Genes X, published by Jones & Bartlett Publishing, 2009 (ISBN10: 0763766321); Kendrew et al. (eds.),, Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-5698) and Current Protocols in Protein Sciences 2009, Wiley Intersciences, Coligan et al., eds. [00636] Unless otherwise stated, the present invention was performed using standard procedures, as described, for example in Sambrook et al., Molecular Cloning: A Laboratory Manual (4 ed.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (2012); Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (1995); or Methods in Enzymology: Guide to Molecular Cloning Techniques Vol. 152, S. L. Berger and A. R. Kimmel Eds., Academic Press Inc., San Diego, USA (1987); Current Protocols in Protein Science (CPPS) (John E. Coligan, et. aL, ed., John Wiley and Sons, Inc.), Current Protocols in Cell Biology (CPCB) (Juan S. Bonifacino et. al. ed., John Wiley and Sons, Inc.), and Culture of Animal Cells: A Manual of Basic Technique by R. Ian Freshney, Publisher: Wiley-Uss; 5th edition (2005), Animal Cell Culture Methods (Methods in Cell Biology, Vol. 57, 18936261-1 Jennie P. Mather and David Barnes editors, Academic Press, 1st edition, 1998) which are all incorporated by reference herein in their entireties. id="p-637" id="p-637"

[00637] Other terms are defined herein within the description of the various aspects of the invention. id="p-638" id="p-638"

[00638] All patents and other publications; including literature references, issued patents, published patent applications, and co-pending patent applications; cited throughout this application are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the technology described herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

J00639] The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts of the above references and application to provide yet further embodiments of the disclosure.

Moreover, due to biological functional equivalency considerations, some changes can be made in protein structure without affecting the biological or chemical action in kind or amount.

These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims. id="p-640" id="p-640"

[00640] Specific elements of any of the foregoing embodiments can be combined or substituted for elements in other embodiments. Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all 18936261-1 embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure. id="p-641" id="p-641"

[00641] It will be understood that particular configurations, aspects, examples, clauses and embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine study, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims. All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The use of the word a or an when used in conjunction with the term comprising in the claims and/or the specification may mean one, but it is also consistent with the meaning of one or more, at least one, and one or more than one. The use of the term or in the claims is used to mean and/or unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and and/or. Throughout this application, the term about is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects. id="p-642" id="p-642"

[00642] As used in this specification and claim(s), the words comprising (and any form of comprising, such as comprise and comprises), having (and any form of having, such as have and has), including (and any form of including, such as includes and include) or containing (and any form of containing, such as contains and contain) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps [00643] Any part of this disclosure may be read in combination with any other part of the disclosure, unless otherwise apparent from the context. id="p-644" id="p-644"

[00644] All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All 18936261-1 such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims. id="p-645" id="p-645"

[00645] The present invention is described in more detail in the following non limiting Examples. id="p-646" id="p-646"

[00646] The invention addresses the need to treat humans having naturallyoccurring rarer natural PCSK9 alleles, genotypes and phenotypes (rarer protein forms). In this respect, the invention provides the following aspects. id="p-647" id="p-647"

[00647] In a First Aspect: A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof comprising a. selecting a human comprising (i) a proprotein convertase subtilisin/kexin type 9 (PCSK9) nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37; and/or (ii) a nucleotide sequence thereof encoding the catalytic domain or C-terminal domain of a PCSK9 protein; and b. administering to said human an antibody or antibody fragment that specifically binds one or more a PCSK9 amino acid sequence encoded by said nucleotide sequence comprised by the human. id="p-648" id="p-648"

[00648] In an example, step (a) comprises selecting a human comprising a PCSK9 protein encoded by the nucleotide sequence of (i) or (ii). id="p-649" id="p-649"

[00649] In an example, the antibody or antibody fragment specifically binds said PCSK9 amino acid sequence. In an example, the antibody or antibody fragment binds a second PCSK9 protein comprising an amino acid sequence encoded by (i) a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37; and/or (ii) a nucleotide sequence thereof encoding the catalytic domain or C-terminal domain of a PCSK9 protein. In an example, the antibody comprises a VH domain derived from the recombination of a human VH gene segment, human D gene segments and a human JH segment, the VH gene segment comprising a nucleotide sequence that comprises a single nucleotide polymorphism with nucleotide C as indicated in rs56069819 (CTGTACCAAGCCTCCCCCAGACTCCA[A/C]CAGCTGCACCTCACACTGGACACCT) (SEQ ID NO: 68). In an example, the VH gene segment is VH3-23*04 (SEQ ID NO: 38) encoded by a sequence comprising SEQ ID NO: 39. In an example, the antibody comprises a VH domain, wherein the VH domain comprises the framework 1 sequence of SEQ ID No. 40. id="p-650" id="p-650"

[00650] In an example, the human has been determined to comprise the nucleotide sequence of (i) and/or (ii). In an example, the human has been determined to comprise a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the 18936261 1 nucleotide sequence of (i) and/or (ii). In an example, the method further comprises the step of determining that the human comprises the nucleotide sequence of (i) and/or (ii). id="p-651" id="p-651"

[00651] In an example, the determining step is performed before administration of the antibody to the human. In an example, the method further comprises the step of determining that the human comprises a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of (i) and/or (ii). In an example, the determining step is performed before administration of the antibody to the human. In an example, the step of determining comprises assaying a biological sample from the human for (i) a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37; and/or (ii) a nucleotide sequence encoding the catalytic domain or C-terminal domain of the PCSK9 variant protein. In an example, the assaying comprises contacting the biological sample with c. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domainencoding sequence thereof, or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof is present; and/or d. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 variant protein. 18936261-1 100 id="p-652" id="p-652"

[00652] In an example, the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification. In an example, the assaying is performed in a multiplex format. In an example the method further comprises obtaining the biological sample from the human. In an example, said biological sample comprises serum, blood, feces, tissue, a cell, urine and/or saliva of said human. id="p-653" id="p-653"

[00653] In an example, said human is or has been further determined to be substantially resistant to statin treatment. In an example, the human is receiving or has received statin treatment or has reduced responsiveness to statin treatment. id="p-654" id="p-654"

[00654] In an example, the human is further administered a statin. In an example, said antibody or antibody fragment and said statin are administered separately or simultaneously. id="p-655" id="p-655"

[00655] In an example, said human is indicated as heterozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 and/or the nucleotide sequence thereof encoding the catalytic domain- or C-terminal domain-encoding sequence of a PCSK9 protein. In an example, said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28 and/or the catalytic domain- or C-terminal domain-encoding sequence thereof. id="p-656" id="p-656"

[00656] In an example, said human is indicated as homozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 and/or the catalytic domain- or C-terminal domain-encoding sequence thereof. id="p-657" id="p-657"

[00657] In an example, said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia; dyslipidemia; hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication, type II diabetes, high blood pressure, and a cardiovascular disease or condition. id="p-658" id="p-658"

[00658] In an example, said method treats or prevents in said human at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia; dyslipidemia; hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication, type II diabetes, high blood pressure, and a cardiovascular disease or condition. id="p-659" id="p-659"

[00659] Some embodiments of the technology described herein can be defined according to any of the following numbered paragraphs: 18936261-1 101 1. A method of treating and/or preventing a disease or condition mediated by proprotein convertase subtilisin/kexin type 9 (PCSK9) in a human who has been determined to comprise and/or selected as comprising a PCSK9 variant protein, the method comprising administering to the human a ligand that binds the PCSK9 variant protein to treat and/or prevent said disease or condition.

In an alternative, paragraph 1 provides: A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation as defined herein (eg, I474V or E670G) in SEQ ID NO: 1, wherein the antibody comprises a VH domain derived from the recombination of a human VH segment, a human D gene segment and a human JH segment, the human VH segment encoding a valine at the amino acid corresponding to position 5 of SEQ ID NO: 40 and wherein said human comprises (i) a VH gene segment encoding the framework 1 of SEQ ID NO: 40 and (ii) a nucleotide sequence encoding a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation in SEQ ID NO: 1.

In an alternative, paragraph 1 provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation as defined herein (eg, I474V or E670G) in SEQ ID NO: 1, wherein the antibody comprises a VL domain derived from the recombination of a human VL segment and a human JL segment, the human VL segment is a VA or Vk disclosed herein and wherein said human comprises (i) said VL gene segment and (ii) a nucleotide sequence encoding a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation in SEQ ID NO: 1. 18936261-1 102 In an alternative, paragraph 1 provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation as defined herein (eg, I474V or E670G) in SEQ ID NO: 1, wherein the antibody comprises a C domain encoded by a human CH, CA or Ck gene segment disclosed herein and wherein said human comprises (i) said C gene segment and (ii) a nucleotide sequence encoding a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation in SEQ ID NO: 1. 2. The method of paragraph 1, wherein said PCSK9 variant protein is selected from the group consisting of PCSK9 variant protein forms f, c, r, p, m, e, h, aj and q. 3. The method of paragraph 2, wherein the variant is mature PCSK9. 4. The method of paragraph 1, 2 or 3 further comprising assaying a biological sample from the human for the PCSK9 variant protein form.

. A method of treating and/or preventing a disease or condition mediated by proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by (i) a nucleotide sequence selected from the group consisting of SEQ ID NOs: 2937; and/or (ii) a nucleotide sequence encoding the catalytic domain or C-terminal domain thereof in a human who has been determined as comprising and/or selected as comprising (i) the nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37; and/or (ii) the nucleotide sequence thereof encoding the catalytic domain or C-terminal domain of a PCSK9 protein, the method comprising administering to said human a ligand that binds said PCSK9 variant protein to treat and/or prevent said disease or condition. 6. The method of paragraph 5 further comprising assaying a biological sample from the human for (i) a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37; and/or (ii) a nucleotide sequence thereof encoding the catalytic domain or C-terminal domain of a PCSK9 protein. 7. The method of paragraph 6, wherein the assaying comprises nucleic acid amplification and/or one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification. 18936261-1 103 8. The method of paragraph 6, wherein the assaying is performed in a multiplex format. 9. The method of any one of paragraphs 1-8, further comprising obtaining the biological sample from the human.

. The method of any one of paragraphs 1-9, wherein said human has been further determined to be and/or selected as substantially resistant to statin treatment of said disease or condition. 11. The method of any one of paragraphs 1-10, wherein the ligand is selected from an antibody, an antibody portion, an antibody fragment or an affibody. 12. The method of paragraph 11, wherein the ligand is an antibody or antibody fragment that specifically binds to a human PCSK9 selected from forms f, c, m, e, h, p, q and aj, wherein the antibody or fragment comprises a VH domain derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, the VH gene segment comprising a nucleotide sequence that comprises SNP rs56069819 (SEQ ID NO: 41). 13. The ligand of paragraph 12, wherein the VH gene segment is VH3-23*04. 14. The method of any one of the paragraphs 1-13, wherein said administering further comprises administering a statin to the human.

. The method of any one of paragraphs 1-14, wherein said ligand and said statin are administered separately or simultaneously. 16. The method of any one of paragraphs 1-15, wherein said biological sample comprises serum, blood, feces, hair, tissue, cells, urine and/or saliva of said human. 17. The method of any one of the paragraphs 1-16, wherein said human is indicated as heterozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 and/or the nucleotide sequence thereof encoring a catalytic domain- or C-terminal domain-encoding sequence of a PCSK9 protein. 18. The method of any one of paragraphs 1-17, wherein said human is indicated as comprising the nucleotide sequence of SEQ ID NO: 28 and/or the catalytic domain- or C-terminal domain-encoding sequence thereof. 19. The method of any one of paragraphs 1-18, wherein said human is indicated as homozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 and/or the nucleotide sequence thereof encoding a catalytic domain- or C-terminal domain-encoding sequence of a PCSK2 protein. 18936261-1 104 . The method of any one of paragraphs 1-19, wherein when said human is determined to comprise and/or selected as comprising: a. SEQ ID NO: 29 and is classified as of ASW, YRI, GBR, TSI, CLM, LWK, MXL, JPT, PUR, IBS, FIN or CEU ancestry, then administering to said human a ligand that specifically binds said PCSK9 variant protein comprising a variant encoded by SEQ ID NO: 29; or b. SEQ ID NO: 30 and is classified as of ASW, YRI, GBR, TSI, CLM, CHB, LWK, CHS, JPT, PUR, FIN or CEU ancestry then administering to said human a ligand that specifically binds said PCSK9 variant protein comprising a variant encoded by SEQ ID NO: 30; or c. SEQ ID NO: 32, and is classified as of ASW, GBR, TSI, CLM, JPT, PUR, IBS, FIN or CEU ancestry then administering to said human a ligand that specifically binds said PCSK9 variant protein comprising a variant encoded by SEQ ID NO: 32; or d. SEQ ID NO: 33, and is classified as of LWK, ASW, YRI or CLM ancestry then administering to said human a ligand that specifically binds said PCSK9 variant protein comprising a variant encoded by SEQ ID NO: 33; or e. SEQ ID NO: 34, and is classified as of LWK, ASW or YRI ancestry then administering to said human a ligand that specifically binds said PCSK9 variant protein comprising a variant encoded by SEQ ID NO: 34; or f. SEQ ID NO: 35, and is classified as of PUR, TSI, FIN or CEU ancestry then administering to said human a ligand that specifically binds said PCSK9 variant protein comprising a variant encoded by SEQ ID NO: 35; or g. SEQ ID NO: 36, and is classified as of LWK, ASW or YRI ancestry then administering to said human a ligand that specifically binds said PCSK9 variant protein comprising a variant encoded by SEQ ID NO: 36; or h. SEQ ID NO: 37, and is classified as of CHS, ASW, JPT, PUR or CHB ancestry then administering to said human a ligand that specifically binds said PCSK9 variant protein comprising a variant encoded by SEQ ID NO: 37. 21. The method of any one of paragraphs 1-19, wherein when said human is determined to comprise and/or selected as comprising: a. PCSK9 protein form f, and is classified as of ASW, YRI, GBR, TSI, CLM, LWK, MXL, JPT, PUR, IBS, FIN or CEU ancestry then administering a ligand that specifically binds said PCSK9 protein form f for a time and in an amount 18936261-1 105 effective to treat and/or prevent said disease or condition in said human, thereby to treat and/or prevent said disease or condition in said human; or b. PCSK9 protein form c, and is classified as of ASW, YRI, GBR, TSI, CLM, CHB, LWK, CHS, JPT, PUR, FIN or CEU ancestry then administering a ligand that specifically binds said PCSK9 protein form c for a time and in an amount effective to treat and/or prevent said disease or condition in said human, thereby to treat and/or prevent said disease or condition in said human; or c. PCSK9 protein form p, and is classified as of ASW, GBR, TSI, CLM, JPT, PUR, IBS, FIN or CEU ancestry then administering a ligand that specifically binds said PCSK9 protein form p for a time and in an amount effective to treat and/or prevent said disease or condition in said human, thereby to treat and/or prevent said disease or condition in said human; or d. PCSK9 protein form m, and is classified as of LWK, ASW, YRI or CLM ancestry then administering a ligand that specifically binds said PCSK9 protein form m for a time and in an amount effective to treat and/or prevent said disease or condition in said human, thereby to treat and/or prevent said disease or condition in said human; or e. PCSK9 protein form e, and is classified as of LWK, ASW or YRI ancestry then administering a ligand that specifically binds said PCSK9 protein form e for a time and in an amount effective to treat and/or prevent said disease or condition in said human, thereby to treat and/or prevent said disease or condition in said human; or f, PCSK9 protein form h, and is classified as of PUR, TSI, FIN or CEU ancestry then administering a ligand that specifically binds said PCSK9 protein form h for a time and in an amount effective to treat and/or prevent said disease or condition in said human, thereby to treat and/or prevent said disease or condition in said human; or g. PCSK9 protein form aj, and is classified as of LWK, ASW or YRI ancestry then administering a ligand that specifically binds said PCSK9 protein form aj for a time and in an amount effective to treat and/or prevent said disease or condition in said human, thereby to treat and/or prevent said disease or condition in said human; or h. PCSK9 protein form q, and is classified as of CHS, ASW, JPT, PUR or CHB ancestry then administering a ligand that specifically binds said PCSK9 protein 18936261-1 106 form q for a time and in an amount effective to treat and/or prevent said disease or condition in said human, thereby to treat and/or prevent said disease or condition in said human. 22. The method of any one of paragraphs 1-21, wherein said ligand is capable of specifically binding said PCSK9 variant protein or a nucleic acid encoding said PCSK9 variant protein. 23. The method of any one of paragraphs 1-21, wherein said ligand specifically binds two or more human PCSK9 variant proteins or fragment thereof selected from the group consisting of SEQ ID NOs: 4-27. 24. The method of paragraph 23, wherein said ligand specifically binds two or more human PCSK9 proteins or fragment thereof, wherein at least one of the protein fragments comprise an amino acid sequence selected from SEQ ID NOs: 4-14,1823, 26 and 27.

. The method of any one of paragraphs 4 and 6-23, wherein said human PCSK9 protein assayed in said sample is in the mature form. 26. The method of any one of paragraphs 4 and 6-24, wherein said human PCSK9 protein assayed in said sample is in the pro-form. 27. The method of paragraph 1-26, wherein said disease or condition is selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia; dyslipidemia; hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication, type II diabetes, high blood pressure, and a cardiovascular disease or condition. 28. A kit for genotyping a proprotein convertase subtilisin/kexin type 9 (PCSK9) gene variant in a nucleic acid sample of a human being affected with or at risk of a PCSK9 mediated disease, the kit comprising a. at least one nucleic acid probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in a biological sample the presence of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 and the sequence thereof encoding a catalytic domain- or C-terminal domain of a PCSK9 protein, or can specifically hybridize to and identify in a biological sample the presence of an antisense of said nucleotide sequence, wherein said nucleic acid probe hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or an antisense sequence thereof; and/or 18936261-1 107 b. at least two nucleic acid probes comprising at least two sequences, each of at least 10 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or comprising an antisense sequence of said contiguous nucleotides, wherein at least one of said oligonucleotide probes comprises at least one nucleotide present in said selected nucleotide sequence which is not present in SEQ ID NO: 28 or an antisense sequence thereof, and c. optionally at least one of the following: one or more buffers, packaging, label, and/or instructions for PCSK9 genotyping in a biological sample comprising nucleic acids obtained from a human- 29. The kit of paragraph 28, wherein the nucleic acid probe is attached to a solid surface.

. The kit of any of paragraphs 28-29, further comprising a detectable label attached to said nucleic acid probe. 31. A kit for phenotyping proprotein convertase subtilisin/kexin type 9 (PCSK9) protein in a biological sample, the kit comprising a plurality of antibodies or antibody portions or fragments, wherein each antibody or antibody fragment or portion is specific for a PCSK9 variant protein selected from the group consisting of forms f, c, r, p, m, e, h, aj and q or a catalytic or C-terminal domain or a peptide thereof that comprises amino acid variation from the corresponding sequence of SEQ ID NO: 1, 2 or 3; and optionally at least one of the following: one or more buffers, packaging and/or label or instructions or a label for PCSK9 phenotyping in a biological sample comprising PCSK9 obtained from a human. 32. The kit of paragraph 31, further comprising a statin. 33. A pharmaceutical composition comprising a ligand capable of specifically binding proprotein convertase subtilisin/kexin type 9 (PCSK9) variants selected from the group consisting of forms f, c, r, p, m, e, h, aj and q or a catalytic or C-terminal domain or a peptide thereof that comprises amino acid variation from the corresponding sequence of SEQ ID NO: 1, 2 or 3. 34. The pharmaceutical composition of paragraph 33, wherein the ligand is an antibody, antibody portion, antibody fragment or an affibody specific for the PCSK9 variant selected from the group consisting of forms f, c, r, p, m, e, h, aj and q or a catalytic or C-terminal domain or a peptide thereof that comprises amino acid variation from the corresponding sequence of SEQ ID NO: 1, 2 or 3. 18936261-1 108 . The pharmaceutical composition of any of paragraphs 33-34, further comprising a statin. 36. The pharmaceutical composition of paragraph 35, wherein the statin is atorvastatin. 37. A drug delivery system comprising the pharmaceutical composition of paragraph 33 or 34 and an injection or IV device. 38. A kit comprising the pharmaceutical composition of paragraph 33, packaging and instructions or label for administering the ligand to a human affected with or at risk of a PCSK9-mediated disease or condition, wherein the human expresses a variant PCSK9 protein form selected from the group consisting of forms f, c, r, p, m, e, h, aj and q or a catalytic or C-terminal domain or a peptide thereof. 39. The kit of paragraph 38, wherein the instructions or label indicate administration with a statin and/or to a human who is indicated for statin treatment or has been administered a statin or has reduced responsiveness to statin treatment. 40. The kit of paragraph 38 or 39, wherein the human has been determined to be and/or selected as resistant to treatment with statins. 41. The kit of paragraph 39 or 40, wherein the instructions or label indicate administration to a human who has received statin and further instruct reducing statin administration to the human. 42. The kit of paragraph 38, further comprising at least one buffer, packaging and/or instructions or label for PCSK9 genotyping in a biological sample obtained from a human. 43. The kit of paragraph 38 wherein the label comprises a marketing authorization number issued by a regulatory agency. 44. The kit of paragraph 43, wherein the regulatory agency is selected from the FDA or EMA. 45. The kit of paragraph 38, wherein the label or instructions further comprise directions to administer alirocumab or evolocumab to said human. 46. The kit of any one of paragraphs 38-45, further comprising an IV or injection device that optionally comprises alirocumab or evolocumab. 47. A kit for treating and/or preventing a disease or condition mediated by proprotein convertase subtilisin/kexin type 9 (PCSK9) in a human who has been determined to comprise and/or selected as comprising a PCSK9 variant protein the kit comprising (a) a alirocumab or evolocumab in a sealed container, and (b) a label 18936261-1 109 or instructions indicating administration of the alirocumab or evolocumab to a human who expresses a variant PCSK9 protein form selected from the group consisting of forms f, c, r, p, m, e, h, aj and q or a catalytic or C-terminal domain or a peptide thereof. 48. The kit of paragraph 47, wherein the label further indicates that if the human has been or is administered statin, the statin treatment should be continued. 49. The kit of paragraph 47, wherein the label further indicates that if the human has been or is administered statin, the statin treatment should be reduced or discontinued. 50. A method of treating and/or preventing a disease or condition mediated by proprotein convertase subtilisin/kexin type 9 (PCSK9) in a human, the method comprising a. assaying a biological sample from the human for the presence of one or more PCSK9 protein variants selected from the group consisting of PCSK9 forms f, c, r, p, m, e, h, aj and q; and b. administering a therapeutically effective amount of a human PCSK9 binding ligand to the human when one or more of the PCSK9 forms f, c, r, p, m, e, h, aj and q is detected. 51. The method of paragraph 50, wherein the ligand specifically binds one or more of the PCSK9 forms f, c, r, p, m, e, h, aj and q. 52. A method of treating and/or preventing a disease or condition mediated by proprotein convertase subtilisin/kexin type 9 (PCSK9) in a human, the method comprising a. assaying a biological sample from the human for the presence or one or more PSCK9 nucleic acid variants selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof; and b. administering a therapeutically effective amount of a human PCSK9 binding ligand to the human when one or more of the PCSK9 nucleic acid variants are detected. 53. The method of paragraph 52, wherein the ligand specifically binds one or more of the PCSK9 forms f, c, r, p, m, e, h, aj and q. 18936261-1 110 54. A method of selecting a human for treatment and/or prevention of a disease mediated by a proprotein convertase subtilisin/kexin type 9 (PCSK9) protein with a human PCSK9 binding ligand comprising: a. assaying a biological sample taken from the human for the presence of a PCSK9 protein variant selected from the group consisting of forms f, c, r, p, m, e, h, aj and q, and b. selecting the human for treatment with the human PCSK9 binding ligand when at least one of the PCSK9 protein variants selected from the group consisting of forms f, c, r, p, m, e, h, aj and q is detected. 55. The method of paragraph 54, wherein the human is indicated for statin treatment or has been administered statin. 56. The method of paragraph 54 or 55, wherein the human has been identified as substantially resistant to statin treatment or has reduced responsiveness to statin treatment. 57. The method of any one of paragraphs 54-56, wherein the disease or condition is selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia; dyslipidemia; hypercholesterolemia, heart attack, stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication, type II diabetes, high blood pressure, and a cardiovascular disease or condition. 58. The method of any one of paragraphs 54-57, wherein the administered human PCSK9 binding ligand is specific for the detected PCSK9 form. 59. The method of any one of paragraphs 54-58, wherein said PCSK9 protein form comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-27. 60. The method of any one of paragraphs 54-59, wherein said PCSK9 protein form comprises the mature PCSK9 form. 61. An assay for selecting a human affected with a proprotein convertase subtilisin/kexin type 9 (PCSK9) protein mediated disease or condition as eligible for treatment with human PCSK9 binding ligand, the method comprising a. contacting a biological sample from said human with at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding 18936261-1 111 sequence thereof, or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof is present; and/or b. detecting the presence or absence of the complex; and c. selecting the human as eligible for treatment with the human PCSK9 binding ligand when presence of at least one complex comprising a PCSK9 form encoded by SEQ ID NOs: 29-37 or the catalytic domain- or C-terminal domainencoding sequence thereof is detected. 62. An assay for selecting a human as eligible for treatment with human proprotein convertase subtilisin/kexin type 9 (PCSK9) binding ligand, the method comprising a. contacting a biological sample from a human with PCSK9 mediated disease or condition with one or more antibody, antibody portion or antibody fragment capable of binding to a PCSK9 variant form selected from the group consisting of PCSK9 form f, c, r, p, m, e, h, aj and q thereby forming a complex when one or more PCSK9 form f, c, r, p, m, e, h, aj and q is present; b. detecting the presence or absence or the complex; and c. selecting the human as eligible for treatment with the human PCSK9 binding ligand when presence of at least one complex comprising PCSK9 form f, c, r, p, m, e, h, aj and q is detected. 63. The assay of paragraphs 61 or 62, wherein the disease or condition is selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia; dyslipidemia; hypercholesterolemia, heart attack, stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication, type II diabetes, high blood pressure, and a cardiovascular disease or condition. 64. The assay of any one of paragraphs 61-63, wherein the human PSCK9 binding ligand is specific for the detected PCSK9 form. 65. The assay of any one of paragraphs 61-64, further comprising amplifying nucleic acids from the biological sample. 66. The assay of any one of paragraphs 61-65, further comprising isolating nucleic acids from the biological sample. 18936261-1 112 67. The assay of any one of paragraphs 61-66, further comprising administering to said human the PCSK9-binding ligand. 68. A method of producing an anti-human proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody binding site, the method comprising obtaining a plurality of anti-PCSK9 antibody binding sites, screening the antibody binding sites for binding to a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, aj and q or a catalytic or C-terminal domain or a peptide thereof that comprises amino acid variation from the corresponding sequence of SEQ ID NO: 1, 2 or 3 and isolating an antibody binding site that binds in the screening step, and optionally producing a form f, c, r, p, m, e, h, aj or q PCSK9-binding fragment or derivative of the isolated antibody. 69. A method of producing an anti-human proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody, the method comprising immunising a non-human vertebrate with a human PCSK9 comprising an amino acid sequence selected from the group consisting of the amino acid sequences of forms f, c, r, p, m, e, h, aj and q or a catalytic or C-terminal domain or a peptide thereof that comprises amino acid variation from the corresponding sequence of SEQ ID NO: 1, 2 or 3 and isolating an antibody that binds a human PCSK9 comprising selected from the group consisting of forms f, c, r, p, m, e, h, aj and q or a catalytic or C-terminal domain or a peptide thereof that comprises amino acid variation from the corresponding sequence of SEQ ID NO: 1, 2 or 3, and optionally producing a form f, c, r, p, m, e, h, aj or q PCSK9-binding fragment or derivative of the isolated antibody. 70. The method of paragraphs 68-69, wherein the non-human vertebrate is a mouse or a rat. 71. The method of any of paragraphs 68-70, comprising the step of obtaining a nucleic acid encoding the antibody, fragment, derivative or binding site and optionally inserting the nucleic acid in an expression vector. 72. A kit for proprotein convertase subtilisin/kexin type 9 (PCSK9) genotyping a human, wherein the kit comprises a nucleic acid (i) comprising a sequence of contiguous nucleotides that specifically hybridises to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof, or specifically hybridises to an antisense sequence or an RNA transcript of said sequence, wherein said sequence of contiguous nucleotides hybridises to at least one 18936261-1 113 nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridises to an antisense sequence or an RNA transcript thereof; and/or (ii) comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or comprising an antisense sequence or RNA version of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28. 73. A kit for proprotein convertase subtilisin/kexin type 9 (PCSK9) genotyping or phenotyping a human, wherein the kit comprises a ligand antibody that binds a human PCSK9 comprising selected from the group consisting of forms f, c, r, p, m, e, h, aj and q or a catalytic or C-terminal domain or a peptide thereof that comprises amino acid variation from the corresponding sequence of SEQ ID NO: 1, 2 or 3, or an antibody, fragment or derivative produced by the method of any one of paragraphs 68-71. 74. A method of targeting a proprotein convertase subtilisin/kexin type 9 (PCSK9) for treating and/or preventing a PCSK9-mediated disease or condition in a human, the method comprising administering an anti-PCSK9 ligand to a human comprising a nucleotide sequence selected from the group consisting SEQ ID NOs: 29-37, whereby a PCSK9 encoded by said nucleotide sequence is targeted. 75. The method of paragraph 74, wherein the method comprises targeting a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, aj and q with said ligand to treat and/or prevent said disease or condition in said human. 76. A method of treating and/or preventing a disease or condition mediated by proprotein convertase subtilisin/kexin type 9 (PCSK9) in a human, the method comprising targeting a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, aj and q by administering to the human a ligand that binds said PCSK9 thereby treating and/or preventing said disease or condition in the human. 77. The method of paragraph 76, wherein the genome of the human comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37. 78. The method of any one of paragraphs 74 to 77, wherein the human has been or is genotyped as positive for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or the catalytic- or C-terminal domain-encoding sequence thereof. 18936261-1 114 79. The method of any one of paragraphs 74 to 78, wherein the human has been or is phenotyped as positive for a human PCSK9 selected from the group consisting of forms f, c, r, p, m, e, h, aj and q. 80. The method of any one of paragraphs 74-79, wherein the method comprises genotyping the human as positive for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or the catalytic- or C-terminal domainencoding sequence thereof. 81. The method of any one of paragraphs 74-80, wherein the method comprises phenotyping the human as positive for a human PCSK9 sequence selected from the group consisting of forms f, c, r, p, m, e, h, aj and q. 82. The method of any one of paragraphs 74 to 81, wherein the human has been or is genotyped as heterozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or the catalytic- or C-terminal domain-encoding sequence thereof; optionally wherein the human has been or is genotyped as comprising the nucleotide sequence of SEQ ID NO: 28 or the catalytic- or Cterminal domain-encoding sequence thereof and a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or the catalytic- or C-terminal domain-encoding sequence thereof. 83. The method of any one of paragraphs 74 to 82, wherein the genome of the human has been or is genotyped as homozygous for a nucleotide sequence selected from the group consisting of of SEQ ID NOs: 29-37 or the catalytic- or Cterminal domain-encoding sequence thereof. 84. The method of any one of paragraphs 74 to 83, wherein the method comprises genotyping the human for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or the catalytic- or C-terminal domain-encoding sequence thereof before administering the ligand to the human, wherein the ligand is determined to be capable of binding to a PCSK9 encoded by said selected sequence. 85. The method according to any one of paragraphs 74 to 84 further comprising administering said ligand and a statin (eg, atorvastatin) to the human. 86. The method of paragraph 85, wherein the ligand and statin are administered separately. 87. The method of paragraph 85, wherein the ligand and statin are administered simultaneously. 18936261-1 115 88. The method of any one of paragraphs 74 to 87, wherein the ligand is administered by subcutaneous injection. 89. A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof comprising a. selecting a human comprising (i) a proprotein convertase subtilisin/kexin type 9 (PCSK9) nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37; and/or (ii) a nucleotide sequence thereof encoding the catalytic domain or C-terminal domain of a PCSK9 protein; and b. administering to said human an antibody or antibody fragment that specifically binds one or more a PCSK9 amino acid sequence encoded by said nucleotide sequence comprised by the human. 90. The method of paragraph 89, wherein step (a) comprises selecting a human comprising a PCSK9 protein encoded by the nucleotide sequence of (i) or (ii). 91. The method of paragraph 89 or 90, wherein the antibody or antibody fragment specifically binds said PCSK9 amino acid sequence. 92. The method of paragraph 89 or 90, wherein the antibody or antibody fragment binds a second PCSK9 protein comprising an amino acid sequence encoded by (i) a nucleotide sequence selected from the group consisting of SEQ ID NOs; 29-37; and/or (ii) a nucleotide sequence thereof encoding the catalytic domain or Cterminal domain of a PCSK9 protein. 93. The method of paragraph 89 or 90, wherein the antibody comprises a VH domain derived from the recombination of a human VH gene segment, human D gene segments and a human JH segment, the VH gene segment comprising a nucleotide sequence that comprises a single nucleotide polymorphism with nucleotide C as indicated in rs56069819 (SEQ ID NO 41). 94. The method of paragraph 93, wherein the VH gene segment is VH3-23*04. 95. The method of any one of paragraphs 89-93, wherein the antibody comprises a VH domain, wherein the VH domain comprises the framework 1 sequence of SEQ ID NO: 38. 96. The method of any one of paragraphs 89-95, wherein the human has been determined to comprise the nucleotide sequence of (i) and/or (ii). 97. The method of any one of paragraphs 89-96, wherein the human has been determined to comprise a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of (i) and/or (ii). 18936261-1 116 The method of any one of paragraphs 89-97, comprising the step of determining that the human comprises the nucleotide sequence of (i) and/or (ii). 98. The method of paragraph 98, wherein the determining step is performed before administration of the antibody to the human. 99. The method of any one of paragraphs 89-99, comprising the step of determining that the human comprises a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of (i) and/or (ii). 100. The method of paragraph 100, wherein the determining step is performed before administration of the antibody to the human. 101. The method of paragraph 100 or 101, wherein the step of determining comprises assaying a biological sample from the human for (i) a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37; and/or (ii) a nucleotide sequence encoding the catalytic domain or C-terminal domain of the PCSK9 variant protein. 102. The method of paragraph 102, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domainencoding sequence thereof, or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when a nucleotide 18936261-1 117 sequence selected from the group consisting of SEQ ID NOs: 29-37 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 variant protein. 103. The method of paragraph 102 or 103, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification. 104, The method of any one of paragraphs 102-104, wherein the assaying is performed in a multiplex format. 105. The method of any one of paragraphs 102-105, further comprising obtaining the biological sample from the human. 106. The method of any one of paragraphs 89-106, wherein said human is or has been further determined to be substantially resistant to statin treatment. 107. The method of any one of paragraphs 89-107, wherein the human is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 108. The method of any one of paragraphs 89-108, wherein the human is further administered a statin. 109. The method of any one of paragraphs 89-108, wherein said antibody or antibody fragment and said statin are administered separately or simultaneously, 110. The method of any one of paragraphs 106-110, wherein said biological sample comprises serum, blood, feces, tissue, a cell, urine and/or saliva of said human. 111. The method of any one of paragraphs 89-111, wherein said human is indicated as heterozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 and/or the nucleotide sequence thereof encoding the catalytic domain- or C-terminal domain-encoding sequence of a PCSK9 protein. 112. The method of any one of paragraphs 89-112, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28 and/or the catalytic domain- or C-terminal domain-encoding sequence thereof. 113. The method of any one of paragraphs 89-113, wherein said human is indicated as homozygous for a nucleotide sequence selected from the group 18936261-1 118 consisting of SEQ ID NOs: 29-37 and/or the catalytic domain- or C-terminal domain-encoding sequence thereof. 114. The method of any one of paragraphs 89-114, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia; dyslipidemia; hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication, type II diabetes, high blood pressure, and a cardiovascular disease or condition. 115. The method of any one of paragraphs 89-115, wherein said method treats or prevents in said human at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia; dyslipidemia; hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication, type II diabetes, high blood pressure, and a cardiovascular disease or condition. id="p-660" id="p-660"

[00660] Additional Tailoring of Ligands to Genotype and/or Phenotype of the Human Patient As described herein, the present invention contemplates ligands (eg, antibodies and fragments) whose binding site specificities have been matched to one or more variant human PCSK9s. Human PCSK9 is referred to as TOI elsewhere herein. Additionally or alternatively (and as further illustrated in the non-limiting Examples below), an optional aspect of the invention provides for matching of other features of the ligand to the patient's genotype or phenotype. In this respect, for example, the invention includes the ability to match amino acid sequence variation in a human patient to one or more ligand sequences or domains outside of the binding sites. For example, where the ligand comprises or consists of a human PCSK9-binding antibody or an anti-human PCSK9 receptor Fc fusion, this aspect of the invention provides for more tailored matching of one or more constant region domains (eg, the Fc) to the patient genotype or phenotype. Additionally or alternatively, it is contemplated that sequence variation in the binding site can be similarly matched to the patient's genotype or phenotype. The present inventor has done this by considering the SNP occurrences in sequences encoding one or more parts of the ligand, eg, SNP occurrences in one, more or all of the gene segments from which the variable domain(s) and/or constant region domain(s) are derived. The inventor realised that it would be desirable to match the ligand to one or more corresponding variant SNPs found in the patient to be treated therapeutically and/or 18936261-1 119 prophylactically. Matching could involve designing the ligand specifically for a patient of known phenotype and/or genotype, or matching could involve choosing a ligand by determining that there is correspondence between variation in the patient's phenotype or genotype with the variation in the ligand amino acid and/or corresponding nucleotides. id="p-661" id="p-661"

[00661] A key consideration for the inventor was the desire to promote compatibility of the ligand with the patient's body, and in particular, the possible patient immune system responses to administered ligands. For example, it has been observed that human patients receiving human or humanised antibody drugs may mount an immune response against the incoming antibody (a so-called HAHA response) which results in the patient producing antidrug antibodies as a result ofthe patient's immune system recognising the drug as foreign. For example, studies have suggested that some patients receiving HUMIRA™ (adalimumab), currently the biggest selling antibody medicine, mount a HAHA immune response against the medicine, and this may impact treatment adversely. Reference is made to JAMA. 2011;305(14): 1460-1468. doi:10.1001/jama.2011.406: Development of Antidrug Antibodies Against Adalimumab and Association With Disease Activity and Treatment Failure During Long-term Follow-up, GM Bartelds etat. The authors concluded that results of this study showed that development of antidrug antibodies was associated with a negative outcome of adalimumab treatment in human RA patients. It was reported that not only did patients with anti-adalimumab antibodies discontinue treatment more often and earlier than patients without anti-adalimumab antibodies, they also had a higher disease activity during treatment and only rarely came into remission. In addition, reportedly the data showed that two-thirds of the anti-adalimumab antibody-positive patients developed these antibodies in the first 28 weeks of treatment and that the presence of anti-adalimumab antibodies substantially influenced serum adalimumab concentrations. id="p-662" id="p-662"

[00662] This HAHA theme is, therefore, a significant concern and this has been considered by the regulatory authorities. For example, the European Medicines Agency (EMA) has issued a Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use (available on the world wide web at ema.europa.eu/docs/en_GB/document_library/Sdentific_guideline/2012/06/WC500128688.pdf ; EMA/CHMP/BMWP/86289/2010, addendum to EMEA/CHMP/BMWP/14327/2006), which came into force on 1st December 2012. As such, it is good practice for researchers to identify and assess risk of anti-antibody drug occurrence and effects. id="p-663" id="p-663"

[00663] The present aspect of the invention, by more closely tailoring the ligand itself (as well as its specificity) to the patient, helps to address these considerations when 18936261-1 120 designing and administering anti-human PCSK9 medicines for treating and/or preventing human PCSK9-related diseases and conditions. id="p-664" id="p-664"

[00664] The inventor also considered the desirability to tailor the variation in the ligand constant region (eg, for an antibody or Fc-containing ligand), mindful that then the constant region being administered to the patient would be tuned to the various components, such as patient's Fc receptors, that would interact with the constant region in the patient. Good Fc/Fc receptor interactions can be important for drug recycling (via the FcRn) to provide for useful half-lives in vivo or for use in cell killing, eg, for cancer indications. In this way it is possible, therefore, to tune the effector function of the constant region (eg, Fc) to the patient more closely, to promote efficacy. For example, more efficacious drugs are desirable for better patient treatment and may provide the possibility of lowered dosing and/or dosing frequencies. (00665] Thus, in examples of this aspect, the invention provides the following (set out as clauses):- 1. The ligand, method, use, kit or composition of the invention, wherein (i) the ligand (eg, antibody or fragment) comprises (a) a variable domain that is encoded by a human V region nucleotide sequence, wherein the V nucleotide sequence is derived from recombination of human VH, D and JH gene segments or human VL and JL gene segments; or (b) a constant region domain encoded by a C region gene segment; Wherein a first gene segment of said gene segments of (a), or said C region gene segment of (b) comprises a first single nucleotide polymorphism (SNP) encoding a first amino acid polymorphism; and (ii) the genome of said human comprises said first SNP or wherein said human expresses (a') an antibody variable domain comprising said first amino acid polymorphism or (b') an antibody constant domain comprising said first amino acid polymorphism. 18936261-1 121 2. The ligand, method, use, kit or composition of clause 1, wherein blood of said human comprises substantially no antibodies that specifically bind to the domain comprising said first amino acid polymorphism as determined in an in vitro binding assay. 3. The ligand, method, use, kit or composition of clause 2, wherein SPR is used to carry out said assay.

In an alternative, ELISA is used. 4. The ligand, method, use, kit or composition of any one of clauses 1 to 3, wherein the genome of said human comprises said first gene segment (when (a) applies) or said C region gene segment (when (b) applies).

. The ligand, method, use, kit or composition of any one of clauses 1 to 4, wherein said first segment or a second segment of said segments of (a), or said C region gene segment of (b), comprises a second SNP encoding a second amino acid polymorphism; and wherein the genome of said human comprises said second SNP or wherein said human expresses (a) an antibody variable domain comprising said second amino acid polymorphism or (b) an antibody constant region domain comprising said first and second amino acid polymorphisms. 6. The ligand, method, use, kit or composition of clause 5, wherein said human expresses an antibody variable domain comprising said first and second amino acid polymorphisms. 7. The ligand, method, use, kit or composition of clause 5 or 6, wherein the first and second SNPs of said genome are comprised by the same antibody gene segment, For example, the first and second SNPs of the genome are comprised by an IGHGl*01 gene segment and said first segment of (a) is an IGHGl*01 gene segment.

For example, the first and second SNPs of the genome are comprised by an IGHG2*01 gene segment and said first segment of (a) is an IGHG2*01 gene segment. 18936261-1 122 8. The ligand, method, use, kit or composition of any one of clauses 1 to 7, wherein each SNP is a variable region gene segment SNP. 9. The ligand, method, use, kit or composition of any one of clauses 1 to 7, wherein each SNP is a constant region gene segment SNP, eg each SNP is a gamma-1 constant region gene segment SNP, or a gamma-2 constant region gene segment SNP, or a gamma-3 constant region gene segment SNP or a gamma-4 constant region gene segment SNP.

. The ligand, method, use, kit or composition of clause 9, wherein the first SNP is a CHI, CH2, CH3 or CH4 gene segment SNP and/or the second SNP is a CHI, CH2, CH3 or CH4 gene segment SNP. 11. The ligand, method, use, kit or composition of any one of clauses 1 to 8, wherein each SNP is a variable domain SNP, eg, a VH domain SNP, or a Vk domain SNP, or a VA SNP. 12. The ligand, method, use, kit or composition of any one of clauses 1 to 11, wherein said constant region domain of (b) is comprised by an antibody Fc region. 13. The ligand, method, use, kit or composition of any one of clauses 1 to 12, wherein the ligand (eg, antibody or fragment) has been determined to specifically bind one or more human PCSK9 variants as disclosed herein, for example, with a KD of InM or less (eg, 100 or lOpM or less) as determined by SPR. 14. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 13), wherein the ligand comprises or consists of an antibody or fragment that comprises a human antibody variable domain derived from the recombination of a human V gene segment and a human J gene segment (and optionally a human D gene segment when the variable domains are VH domains); and wherein the genome of the human comprises said human V gene segment and/or the human expresses antibodies comprising antibody variable domains derived from the recombination of said human V gene segment and a human J gene segment (and optionally a human D gene segment).

In an example, the V gene segment is any of the V gene segments disclosed in WO2013041844, a 1000 Genomes database and/or www.imgt.org, the disclosures of 18936261-1 123 which (including disclosure relating to sequence) is explicitly incorporated herein by reference for use in the present invention.

. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 14), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused human PCSK9 receptor) comprises a human heavy chain constant domain encoded by a first constant region nucleotide sequence; and wherein the genome of the human comprises a heavy chain constant region nucleotide sequence that is identical to said first constant region nucleotide sequence and/or the human expresses antibodies comprising said human constant domain. 16. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 15), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused human PCSK9 receptor) comprises a human gamma heavy chain CHI domain encoded by a CHI nucleotide sequence; and wherein the genome of the human comprises a gamma heavy chain constant region nucleotide sequence that is identical to said CHI nucleotide sequence and/or the human expresses antibodies comprising said human gamma CHI domain. 17. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 16), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused human PCSK9 receptor) comprises a human gamma heavy chain CH2 domain encoded by a CH2 nucleotide sequence; and wherein the genome of the human comprises a gamma heavy chain constant region nucleotide sequence that is identical to said CH2 nucleotide sequence and/or the human expresses antibodies comprising said human gamma CH2 domain. 18. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 17), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused human PCSK9 receptor) comprises a human gamma heavy chain CH3 domain encoded by a CH3 nucleotide sequence; and wherein the genome of the human comprises a gamma heavy chain constant region nucleotide sequence that is identical to said CH3 nucleotide sequence and/or the human expresses antibodies 18936261-1 124 comprising said human gamma CH3 domain. 19. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 18), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused human PCSK9 receptor) comprises a human gamma heavy chain CH4 domain encoded by a CH4 nucleotide sequence; and wherein the genome of the human comprises a gamma heavy chain constant region nucleotide sequence that is identical to said CH4 nucleotide sequence and/or the human expresses antibodies comprising said human gamma CH4 domain.

. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 19), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused human PCSK9 receptor) comprises a human gamma heavy chain Fc region encoded by a Fc nucleotide sequence; and wherein the genome of the human comprises a gamma heavy chain constant region nucleotide sequence that is identical to said Fc nucleotide sequence and/or the human expresses antibodies comprising said human gamma Fc region. 21. The ligand, method, use, kit or composition of any one of clauses 16 to 20, wherein said human gamma heavy chain is a human gamma-1 heavy chain. 22. The ligand, method, use, kit or composition of any one of clauses 16 to 20, wherein said human gamma heavy chain is a human gamma-2 heavy chain. 23. The ligand, method, use, kit or composition of any one of clauses 16 to 20, wherein ligand comprises a human IGHGl*01 gamma-1 heavy chain constant region. 24. The ligand, method, use, kit or composition of any one of clauses 16 to 20, wherein ligand comprises a human IGHG2*01 gamma-1 heavy chain constant region.

. The ligand, method, use, kit or composition of any one of clauses 15 to 24, wherein the human has been or is genotyped as positive for said heavy chain constant region nucleotide sequence. 18936261-1 125 26. The ligand, method, use, kit or composition of clause 23, wherein the human has been or is genotyped as positive for human IGHG1*O1 nucleotide sequence. 27. The ligand, method, use, kit or composition of clause 24, wherein the human has been or is genotyped as positive for human IGHG2*01 nucleotide sequence. 28. The ligand, method, use, kit or composition of any one of clauses 16 to 24, wherein the human has been or is phenotyped as positive for said gamma heavy chain constant domain, CHI, CH2, CH3, CH4 or Fc. 29. The ligand, method, use, kit or composition of clause 28, (i) when dependent from clause 23, wherein the human has been or is phenotyped as positive for a human IGHGl*01 gamma heavy chain constant domain, CHI, CH2, CH3, CH4 or Fc or (ii) when dependent from clause 24, wherein the human has been phenotyped as positive for a human IGHG2*01 gamma heavy chain constant domain, CHI, CH2, CH3, CH4 or Fc.

. The method or use of any one of clauses 16 to 24 and 26 to 29, comprising genotyping the human as positive for said gamma heavy chain constant region nucleotide sequence, eg, positive for said gamma heavy chain constant domain, CHI, CH2, CH3, CH4 or Fc nucleotide sequence; positive for said human IGHG1*O1 gamma heavy chain constant region, CHI, CH2, CH3, CH4 or Fc nucleotide sequence; or positive for said human IGHG2*01 gamma heavy chain constant region, CHI, CH2, CH3, CH4 or Fc nucleotide sequence. 31. The method or use of any one of clauses 16 to 24 and 26 to 30, comprising phenotyping the human as positive for said gamma heavy chain constant region, eg, positive for said gamma heavy chain constant domain, CHI, CH2, CH3, CH4 or Fc; positive for said human IGHGl*01 gamma heavy chain constant domain, CHI, CH2, CH3, CH4 or Fc; or positive for said human IGHG2*01 gamma heavy chain constant domain, CHI, CH2, CH3, CH4 or Fc. [00666| Examples of Tailored Ligands 18936261-1 126 [00667J The inventor analysed amino acid variability and distribution amongst large representative human samples. The result of the analysis for example antibody gene segments is shown in Table 8, J00668] In a first example, the inventor identified the possibility of addressing the rarer IGH-gamma-1 SNPs 204D (observed cumulative frequency of 0.296) and 206L (observed cumulative frequency of 0.283) individually or in combination. These residues are part of the CH3 domain, and as such they form part of antibody Fc regions, Thus, matching of these CH3 variations with the patient is especially beneficial for reasons as discussed above. Thus, this example provides aspects set out in the following clauses. 32. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 31), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused TOI receptor) comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 or a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein the genome of the human comprises a gamma-1 heavy chain constant region nucleotide sequence that encodes such an Asp or Leu or the human expresses antibodies comprising human gamma-1 constant regions comprising such an Asp or Leu.

The skilled person will be familiar with techniques for determining genome sequences of a human, eg, by using a sample containing genomic DNA and/or RNA, sequencing and comparing using bioinformatics or other computer tools to compare the sampled sequence with sequences of human alleles (eg, as shown in the IMGT, 100 genomes or other database as disclosed herein). In an example, the sample is a blood or saliva or cheek swab sample. 33. The ligand, method, use, kit or composition of clause 32,wherein the ligand comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42. 34. The ligand, method, use, kit or composition of clause 32 or 33,wherein the genome of the human comprises a gamma-1 heavy chain constant region nucleotide sequence that encodes such an Asp and Leu or the human expresses antibodies comprising human 18936261-1 127 gamma-1 constant regions comprising such an Asp and Leu.

. The ligand, method, use, kit or composition of clause 32, 33 or 34, wherein the ligand comprises a human IGHGl*01 gamma-1 heavy chain constant region, eg, an Fc, CHI, CH2 and/or CH3 domain encoded by human IGHGl*01. 36. The ligand, method, use, kit or composition of any one of clauses 32 to 35, wherein the genome of the human comprises a human IGHGl*01 nucleotide sequence or the human expresses antibodies comprising human constant domains encoded by a human IGHGl*01 nucleotide sequence. 37. The ligand, method, use, kit or composition of any one of clauses 32 to 36, wherein the ligand comprises a hinge region encoded by human IGHG1*O1. 38. The ligand, method, use, kit or composition of any one of clauses 32 to 37, wherein the ligand comprises or consists of an antibody, wherein the antibody comprises heavy chains that comprise SEQ ID NO: 61. 39. The ligand, method, use, kit or composition of any one of clauses 32 to 38, wherein the human is of European ancestry.

As shown in Table 8, 204D and 206L are found in such humans. 40. The ligand, method, use, kit or composition of any one of clauses 32 to 39, wherein the human has been or is genotyped as positive for said Asp and/or Leu. 41. The ligand, method, use, kit or composition of any one of clauses 32 to 40, wherein the human has been or is genotyped as positive for human IGHGl*01. 42. The ligand, method, use, kit or composition of any one of clauses 32 to 41, wherein the human has been or is phenotyped as positive for a human IGHGl*01 CH3. 43. The method or use of any one of clauses 32 to 42, comprising selecting a said human whose genome comprises a codon(s) encoding said Asp and/or Leu; comprises human 18936261-1 128 IGHGl*01; or comprises a human IGHGl*01 CH3. 44. The method or use of any one of clauses 32 to 43, comprising selecting a said human whose phenotype comprises said Asp and/or Leu; a human IGHGl*01 region ; or a human IGHG1*O1 CH3. 44a. The ligand, method, use, kit or composition of any one of clauses 32 to 44, wherein the human expresses antibodies comprising human gamma-1 constant regions comprising such an Asp and Leu. id="p-669" id="p-669"

[00669] In a second example, the inventor identified the possibility of addressing IGH-gamma-2 SNPs. This included consideration of Fc region variation - in this respect, the inventor focused on positions 161 and 257 which are in the Fc region. Thus, this example provides aspects set out in the following clauses. 45. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 31), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused TOI receptor) comprises a human gamma-2 heavy chain constant region that comprises an amino acid selected from the group consisting of a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44; and wherein the genome of the human comprises a gamma-2 heavy chain constant region nucleotide sequence that encodes such a selected amino acid or the human expresses antibodies comprising human gamma-2 constant regions comprising such a selected amino acid. 46. The ligand, method, use, kit or composition of clause 45, wherein the ligand comprises a human gamma-2 heavy chain constant region that comprises (i) a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44 and optionally (ii) a Val corresponding to position 161 of SEQ ID NO: 44 and/or an Ala corresponding to position 257 of SEQ ID 18936261-1 129 NO: 44; and wherein the genome of the human comprises a gamma-2 heavy chain constant region nucleotide sequence that encodes such amino acids of (i) or the human expresses antibodies comprising human gamma-2 constant regions comprising such amino acids of (i).

This example focuses on CHI variation. 47. The ligand, method, use, kit or composition of clause 45 or 46, wherein the ligand comprises a human gamma-2 heavy chain constant region that comprises (i) a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44 and optionally (ii) an amino acid selected from the group consisting of a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44 and a Phe corresponding to position 76 of SEQ ID NO: 44; and wherein the genome of the human comprises a gamma-2 heavy chain constant region nucleotide sequence that encodes such amino acids of (i) or the human expresses antibodies comprising human gamma-2 constant regions comprising such amino acids of (i).

This example focuses on Fc variation. 48. The ligand, method, use, kit or composition of any one of clauses 45 to 47, wherein the ligand comprises a human IGHG2*01 gamma-2 heavy chain constant region, eg, an Fc, CHI, CH2 and/or CH3 domain encoded by human IGHG2*01. 49. The ligand, method, use, kit or composition of any one of clauses 45 to 48, wherein the genome of the human comprises a human IGHG2*01 nucleotide sequence or the human expresses antibodies comprising human constant domains encoded by a human IGHG2*01 nucleotide sequence. 50. The ligand, method, use, kit or composition of any one of clauses 45 to 49, wherein the ligand comprises a hinge region encoded by human IGHG2*01. 51. The ligand, method, use, kit or composition of any one of clauses 45 to 50, wherein the ligand comprises or consists of an antibody, wherein the antibody comprises heavy chains 18936261-1 130 that comprise SEQ ID NO: 63 or 65. 52. The ligand, method, use, kit or composition of any one of clauses 45 to 51, wherein the human is of European, African American, or European American ancestry. 53. The ligand, method, use, kit or composition of any one of clauses 45 to 52, wherein the human has been or is genotyped as positive for one, more or all of said Pro, Asn, Phe, Val and Ala. 54. The ligand, method, use, kit or composition of any one of clauses 45 to 53, wherein the human has been or is genotyped as positive for human IGHG2*01. 55. The ligand, method, use, kit or composition of any one of clauses 45 to 54, wherein the human has been or is phenotyped as positive for a human IGHG2*01 CHI. 56. The ligand, method, use, kit or composition of any one of clauses 45 to 55, wherein the human has been or is phenotyped as positive for a human IGHG2*01 CH2. 57. The ligand, method, use, kit or composition of any one of clauses 45 to 56, wherein the human has been or is phenotyped as positive for a human IGHG2*01 CH3. 58. The method or use of any one of clauses 45 to 57, comprising selecting a said human whose genome comprises a codon(s) encoding one, more or all of said Pro, Asn, Phe, Val and Ala; comprises human IGHG2*01; or comprises a human IGHG2*01 CHI, CH2 and/or CH3. 59. The method or use of any one of clauses 45 to 58, comprising selecting a said human whose phenotype comprises one, more or all of said Pro, Asn, Phe, Val and Ala; a human IGHG2*01 region; or a human IGHG2*01 CHI, CH2 and/or CH3. 60. The ligand, method, use, kit or composition of any one of clauses 45 to 59, wherein the human expresses antibodies comprising human gamma-2 constant regions comprising such a Pro, Asn, Phe, Val and Ala. 18936261-1 131 id="p-670" id="p-670"

[00670] In a third example, the inventor addressed human kappa constant region variation. Thus, the present aspect of the invention also provides the following. 61. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 60), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused TOI receptor) comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 or a Cys corresponding to position 87 of SEQ ID NO: 50; and wherein the genome of the human comprises a kappa light chain constant region nucleotide sequence that encodes such a Val or Cys or the human expresses antibodies comprising human kappa light chain constant regions comprising such a Val or Cys. 62. The ligand, method, use, kit or composition of clause 61, wherein the ligand comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 and a Cys corresponding to position 87 of SEQ ID NO: 50. 63. The ligand, method, use, kit or composition of clause 61 or 62, wherein the genome of the human comprises a kappa light chain constant region nucleotide sequence that encodes such a Val and Cys or the human expresses antibodies comprising human kappa constant regions comprising such a Val and Cys. 64. The ligand, method, use, kit or composition of any one of clauses 61 to 63, wherein the antibody or fragment comprises a human IGKC*01 kappa light chain constant region. 65. The ligand, method, use, kit or composition of any one of clauses 61 to 64, wherein the ligand comprises or consists of an antibody, wherein the antibody comprises light chains that comprise SEQ ID NO: 62 or 66. 66. The ligand, method, use, kit or composition of any one of clauses 61 to 65, wherein the ligand comprises or consists of an antibody, wherein the antibody comprises a light chain variable domain derived from recombination of a human Vk gene segment and a human Jk gene segment, wherein the Jk gene segment is IGKJ2*01 (SEQ ID NO: 57). 18936261-1 132 67. The ligand, method, use, kit or composition of any one of clauses 61 to 66, wherein the human has been or is phenotyped as positive for said Val and/or Cys. 68. The ligand, method, use, kit or composition of any one of clauses 61 to 67, wherein the human has been or is genotyped as positive for human IGKC*01. 69. The ligand, method, use, kit or composition of any one of clauses 61 to 68, wherein the human has been or is phenotyped as positive for a human IGKC*01 domain. 70. The method or use of any one of clauses 61 to 69, comprising selecting a said human whose genome comprises a codon(s) encoding said Val and/or Cys; or comprises human IGKC*01. 71. The method or use of any one of clauses 61 to 70, comprising selecting a said human whose phenotype comprises such a Val and/or Cys; or comprises a human IGKC*01 domain. 72. The ligand, method, use, kit or composition of any one of clauses 61 to 71, wherein the human expresses antibodies comprising human kappa constant domains comprising such a Val and Cys, eg, expresses human IGKC*01 constant domains. |00671] In a fourth example, the inventor addressed human lambda constant region variation. Thus, this example provides aspects set out in the following clauses. 73. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 60), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused TOI receptor) comprises a human IGLC2*01 light chain constant region; and wherein the genome of the human comprises a human IGLC2*01 nucleotide sequence or the human expresses antibodies comprising human light chain IGLC2*01 constant regions. 18936261-1 133 74. The ligand, method, use, kit or composition of clause 73, wherein the antibody comprises light chains that comprise SEQ ID NO: 64. 75. The ligand, method, use, kit or composition of clause 73 or 74, wherein the human has been or is genotyped as positive for human IGLC2*01. 76. The ligand, method, use, kit or composition of any one of clauses 73 to 75, wherein the human has been or is phenotyped as positive for a human IGLC2*01 domain. 77. The method or use of any one of clauses 73 to 76, comprising selecting a said human whose genome comprises human IGLC2*01. 78. The method or use of any one of clauses 73 to 77, comprising selecting a said human whose phenotype comprises a human IGLC2*01 domain. 79. The ligand, method, use, kit or composition of any one of clauses 73 to 78, wherein the human expresses antibodies comprising human lambda IGLC2*01 constant domains. id="p-672" id="p-672"

[00672] In a fifth example, the inventor addressed human heavy chain variable region variation. Thus, this example provides aspects set out in the following clauses. 80. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 79), wherein the ligand comprises or consists of an antibody or fragment, wherein the antibody or fragment comprises a VH domain that is derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, wherein the VH gene segment is selected from the group consisting of (i) IGHV1-18*O1 and the genome of the human comprises a human IGHV1-18*O1 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV1-18*O1; or (ii) IGVH1-46*O1 and the genome of the human comprises a human IGHV1-46*O1 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV1- 18936261-1 134 46*01. 81. The ligand, method, use, kit or composition of clause 80, wherein the antibody or fragment comprises a one more or all of a CHI domain, CH2 domain, CH3 domain, hinge or Fc encoded by human IGHG2*01. 82. The ligand, method, use, kit or composition of clause 80 or 81, wherein the antibody or fragment comprises heavy chains that comprise SEQ ID NO: 63 or 65. 83. The ligand, method, use, kit or composition of any one of clauses 80 to 82, wherein the human has been or is genotyped as positive for said selected VH gene segment, positive for human IGHV1-18*O1 or IGVH1-46*O1. 84. The method or use of any of clauses 80 to 83, comprising genotyping the human as positive for said selected VH gene segment, eg, positive for human IGHVl-18*01 or IGVH 1-46*01. id="p-673" id="p-673"

[00673] In a sixth example, the inventor addressed human light chain variable region variation. Thus, this example provides aspects set out in the following clauses. [00674] 85. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 84), wherein the ligand comprises or consists of an antibody or fragment, wherein the antibody or fragment comprises a VL domain that is derived from the recombination of a human VL gene segment and a human JL gene segment, wherein the VL gene segment is selected from the group consisting of (i) IGKV4-l*01 and the genome of the human comprises a human IGKV4-l*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV4-l*01; (ii) IGLV2-14*01 and the genome of the human comprises a human IGLV2-14*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGLV2-14*01; or (iii) IGKV1-13*O2 and the genome of the human comprises a human IGKV1-13*O2 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV1-13*O2. 18936261-1 135 86. The ligand, method, use, kit or composition of clause 85, wherein the antibody comprises light chains that comprise SEQ ID NO: 62, 64 or 66. 87. The ligand, method, use, kit or composition of clause 85 or 86, wherein the antibody or fragment comprises a light chain variable domain derived from recombination of a human Vk gene segment and a human Jk gene segment, wherein the Jk gene segment is IGKJ2*01 (SEQ ID NO: 57; wherein (i) or (iii) applies. 88. The ligand, method, use, kit or composition of any one of clauses 85 to 87, wherein the human has been or is genotyped as positive for said selected VL gene segment, eg, positive for human IGKV4-l*01, IGLV2-14*01 or IGKV1-13*O2. 89. The method or use of clause 88, comprising genotyping the human as positive for said selected VL gene segment, eg, genotyping the human as positive for human IGKV4-l*01, IGLV2-14*01 or IGKV1-13*O2. 90. The ligand, method, use, kit or composition of any one of clauses 1 to 89, wherein the ligand (eg, antibody or fragment) binds said human PCSK9 with a dissociation constant (Kd) of InM or less as determined by SPR, (eg, 100, 10 or lpM or less). id="p-675" id="p-675"

[00675] Further exemplary ligands are in the paragraphs 1-17 as follows. 1. An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human gamma heavy chain constant region that comprises a first amino acid that is encoded by a human gamma heavy chain constant region gene segment SNP, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said PCSK9 amino acid sequence and comprises a human gamma heavy chain constant region gene segment comprising said SNP, or the human expresses antibodies comprising human gamma constant regions comprising said first amino acid.

In an alternative, paragraph 1 provides:18936261-1 136 An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 or a Leu corresponding to position 206 of SEQ ID NO: 42, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGHGl*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-1 constant regions comprising such an Asp and Leu.

In an embodiment, said mutation is I474V. In another embodiment, said mutation is E670G.

An example provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGHGl*01 human heavy chain constant region gene segment. Optionally, the antibody or fragment comprises an IGHGl*01 human heavy chain constant region.

Another example provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42, and the antibody or fragment 18936261-1 137 specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGHG1*O1 human heavy chain constant region gene segment. Optionally, the antibody or fragment comprises an IGHGl*01 human heavy chain constant region.

In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a Cterminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (i) an IGHGl*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1. 2. The antibody or antibody fragment of paragraph 1, wherein the antibody comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42. 3. The antibody or antibody fragment of paragraph 1 or 2, wherein the antibody comprises an IGHGl*01 human heavy chain constant region. 4. The antibody or antibody fragment of any one of paragraphs 1 to 3, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30.

. The antibody or antibody fragment of any one of paragraphs 1 to 4, the method comprising the step of determining that the human comprises the nucleotide sequence 18936261-1 138 that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the human. 6. The antibody or antibody fragment of paragraph 5, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 7. The antibody or antibody fragment of paragraph 6, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the Cterminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 18936261-1 139 8, The antibody or antibody fragment of paragraph 6 or 7, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 9. The antibody or antibody fragment of any one of paragraphs 1 to 8, wherein said antibody or antibody fragment is for administration to a human that is or has been further determined to be substantially resistant to statin treatment.

. The antibody or antibody fragment of any one of paragraphs 1 to 9, wherein antibody or antibody fragment is for administration to a human that is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 11. The antibody or antibody fragment of paragraph 9 or 10, wherein said antibody or antibody fragment is for administration to the human separately or simultaneously with said statin treatment. 12. The antibody or antibody fragment of any one of paragraphs 6 to 10, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 13. The antibody or antibody fragment of any one of paragraphs 1 to 12, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 Cterminal domain comprising a mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising a mutation I474Vor E670G in SEQ ID NO: 1. 14. The antibody or antibody fragment of any one of paragraphs 1 to 13, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 18936261-1 140 . The antibody or antibody fragment of any one of paragraphs 1 to 14, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 16. The antibody or antibody fragment of any one of paragraphs 1 to 15, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 17. The antibody or antibody fragment of any one of paragraphs 1 to 16, wherein said antibody or antibody fragment is for administration by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-676" id="p-676"

[00676] Further exemplary methods are in the paragraphs 1-18 as follows. 1. A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 or a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (i) an IGHGl*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-1 heavy chain constant regions comprising such an Asp and Leu and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1.

An example provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase 18936261-1 141 subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (i) an IGHGl*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V in SEQ ID NO: 1. Optionally, the antibody or fragment comprises a IGHGl*01 human heavy chain constant region.

Another example provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (i) an IGHGl*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation E670G in SEQ ID NO: 1. Optionally, the antibody or fragment comprises an IGHGl*01 human heavy chain constant region.

In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (i) an IGHGl*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1. 18936261-1 142 2. The method of paragraph 1, comprising, before said administering, selecting a human comprising said nucleotide sequence of (ii), wherein the human is the human of paragraph 1. 3. The method of paragraph 1 or 2, wherein the antibody comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42, 4. The method of paragraph 1, 2 or 3, wherein the antibody comprises an IGHGl*01 human heavy chain constant region.

. The method of any one of paragraphs 1 to 4, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30. 6. The method of any one of paragraphs 1 to 5, comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the human. 7, The method of paragraph 6, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 8. The method of paragraph 7, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain 18936261-1 143 comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b, at least one oligonucleotide probe comprising a sequence of at ieast 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 9. The method of paragraph 7 or 8, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format, . The method of any one of paragraphs 1 to 9, wherein said human is or has been further determined to be substantially resistant to statin treatment. 11. The method of any one of paragraphs 1 to 10, wherein said human is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 12. The method of paragraph 10 or 11, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with said statin treatment. 18936261-1 144 13. The method of any one of paragraphs 7 to 9, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 14. The method of any one of paragraphs 1 to 13, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474Vor E670G in SEQ ID NO: 1.

. The method of any one of paragraphs 1 to 14, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 16. The method of any one of paragraphs 1 to 15, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 17. The method of any one of paragraphs 1 to 16, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 18. The method of any one of paragraphs 1 to 17, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-677" id="p-677"

[00677] Further exemplary ligands are in the paragraphs 1-17 as follows. 1. An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody comprises a human gamma-2 heavy chain constant region that comprises an amino acid selected from the group consisting of a Pro corresponding to position 72 of 18936261-1 145 SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGHG2*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-2 constant regions comprising such a Pro, Asn, Phe, Val and Ala.

An example provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody comprises a human gamma-2 heavy chain constant region that comprises a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGHG2*01 human heavy chain constant region gene segment. Optionally, the antibody or fragment comprises an IGHG2*01 human heavy chain constant region.

Another example provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody comprises a human gamma-2 heavy chain constant region that comprises a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding 18936261-1 146 to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGHG2*01 human heavy chain constant region gene segment. Optionally, the antibody or fragment comprises an IGHG2*01 human heavy chain constant region.

In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-2 heavy chain constant region that comprises a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44 and wherein said human comprises (i) an IGHG2*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1. 2. The antibody or antibody fragment of paragraph 1, wherein the antibody comprises a human gamma-2 heavy chain constant region that comprises a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44. 3. The antibody or antibody fragment of paragraph 1 or 2, wherein the antibody comprises an IGHG2*01 human heavy chain constant region. 4. The antibody or antibody fragment of any one of paragraphs 1 to 3, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded 18936261-1 147 by the nucleotide sequence of SEQ ID NO: 29 or 30.

. The antibody or antibody fragment of any one of paragraphs 1 to 4, the method comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the human. 6. The antibody or antibody fragment of paragraph 5, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 7. The antibody or antibody fragment of paragraph 6, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and 18936261-1 148 detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 8. The antibody or antibody fragment of paragraph 6 or 7, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 9. The antibody or antibody fragment of any one of paragraphs 1 to 8, wherein said antibody or antibody fragment is for administration to a human that is or has been further determined to be substantially resistant to statin treatment.

. The antibody or antibody fragment of any one of paragraphs 1 to 9, wherein antibody or antibody fragment is for administration to a human that is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 11. The antibody or antibody fragment of paragraph 9 or 10, wherein said antibody or antibody fragment is for administration to the human separately or simultaneously with said statin treatment. 12. The antibody or antibody fragment of any one of paragraphs 6 to 8, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 13. The antibody or antibody fragment of any one of paragraphs 1 to 12, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising a mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising a mutation I474Vor E670G in SEQ ID NO: 1. 14. The antibody or antibody fragment of any one of paragraphs 1 to 13, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, 18936261-1 149 hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure.

. The antibody or antibody fragment of any one of paragraphs 1 to 14, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 16. The antibody or antibody fragment of any one of paragraphs 1 to 15, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 17. The antibody or antibody fragment of any one of paragraphs 1 to 16, wherein said antibody or antibody fragment is for administration by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-678" id="p-678"

[00678] Further exemplary methods are in the paragraphs 1-18 as follows. 1. A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-2 heavy chain constant region that comprises an amino acid selected from the group consisting of a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44 and wherein said human comprises (i) an IGHG2*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-2 heavy chain constant regions comprising such a Pro, Asn, Phe, Val and Ala and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1. 18936261-1 150 In an embodiment, said mutation is I474V. In another embodiment, said mutation is E670G.

An example provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-2 heavy chain constant region that comprises a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44 and wherein said human comprises (i) an IGHG2*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V in SEQ ID NO: 1. Optionally, the antibody or fragment comprises an IGHG2*01 human heavy chain constant region.

Another example provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-2 heavy chain constant region that comprises a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44 and wherein said human comprises (i) an IGHG2*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation E670G in SEQ ID NO: 1. Optionally, the antibody or fragment comprises an IGHG2*01 human heavy chain constant region. 18936261-1 151 In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-2 heavy chain constant region that comprises a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44 and wherein said human comprises (i) an IGHG2*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1. 2. The method of paragraph 1, comprising, before said administering, selecting said human comprising said nucleotide sequence of (ii). 3. The method of paragraph 1 or 2, wherein the antibody comprises a human gamma-1 heavy chain constant region that comprises a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44. 4. The method of paragraph 1, 2 or 3, wherein the antibody comprises an IGHG2*01 human heavy chain constant region.

. The method of any one of paragraphs 1 to 4, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30. 6. The method of any one of paragraphs 1 to 5, comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal 18936261-1 152 domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the human, 7. The method of paragraph 6, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 8. The method of paragraph 7, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 18936261-1 153 9. The method of paragraph 7 or 8, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format.

. The method of any one of paragraphs 1 to 9, wherein said human is or has been further determined to be substantially resistant to statin treatment. 11. The method of any one of paragraphs 1 to 10, wherein said human is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 12. The method of paragraph 10 or 11, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with said statin treatment. 13. The method of any one of paragraphs 7 to 9, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 14. The method of any one of paragraphs 1 to 13, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474Vor E670G in SEQ ID NO: 1.

. The method of any one of paragraphs 1 to 14, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 16. The method of any one of paragraphs 1 to 15, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, 18936261-1 154 claudication and high blood pressure. 17. The method of any one of paragraphs 1 to 16, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 18. The method of any one of paragraphs 1 to 17, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. 100679) Further exemplary ligands are in the paragraphs 1-17 as follows. 1. An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 or a Cys corresponding to position 87 of SEQ ID NO: 50, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGKC*01 human light chain constant region gene segment, or the human expresses antibodies comprising human kappa light chain constant regions comprising such an Val and Cys.

An example provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 and a Cys corresponding to position 87 of SEQ ID NO: 50, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a Cterminal domain comprising a mutation I474V in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGKC*01 human light chain constant region gene segment. Optionally, the antibody or 18936261-1 155 fragment comprises an IGKC*01 human light chain constant region.

Another example provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 and a Cys corresponding to position 87 of SEQ ID NO: 50, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a Cterminal domain comprising a mutation E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGKC*01 human light chain constant region gene segment. Optionally, the antibody or fragment comprises an IGKC*01 human light chain constant region.

In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 and a Cys corresponding to position 87 of SEQ ID NO: 50 and wherein said human comprises (i) an IGKC*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1. 2. The antibody or antibody fragment of paragraph 1, wherein the antibody comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 or a Cys corresponding to position 87 of SEQ ID NO: 50. 3. The antibody or antibody fragment of paragraph 1 or 2, wherein the antibody comprises an IGKC*01 human kappa chain constant region. 4. The antibody or antibody fragment of any one of paragraphs 1 to 3, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 18936261-1 156 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30.

. The antibody or antibody fragment of any one of paragraphs 1 to 4, the method comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the human. 6. The antibody or antibody fragment of paragraph 5, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 7. The antibody or antibody fragment of paragraph 6, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and 18936261-1 157 detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the Cterminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 8, The antibody or antibody fragment of paragraph 6 or 7, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 9. The antibody or antibody fragment of any one of paragraphs 1 to 8, wherein said antibody or antibody fragment is for administration to a human that is or has been further determined to be substantially resistant to statin treatment.

. The antibody or antibody fragment of any one of paragraphs 1 to 9, wherein antibody or antibody fragment is for administration to a human that is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 11. The antibody or antibody fragment of paragraph 9 or 10, wherein said antibody or antibody fragment is for administration to the human separately or simultaneously with said statin treatment. 12. The antibody or antibody fragment of any one of paragraphs 6 to 10, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 13. The antibody or antibody fragment of any one of paragraphs 1 to 12, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising a mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising a mutation I474Vor E670G in SEQ ID NO: 1. 14. The antibody or antibody fragment of any one of paragraphs 1 to 13, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, 18936261-1 158 hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure.

. The antibody or antibody fragment of any one of paragraphs 1 to 14, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 16. The antibody or antibody fragment of any one of paragraphs 1 to 15, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 17. The antibody or antibody fragment of any one of paragraphs 1 to 16, wherein said antibody or antibody fragment is for administration by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-680" id="p-680"

[00680] Further exemplary methods are in the paragraphs 1-18 as follows. 1. A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 or a Cys corresponding to position 87 of SEQ ID NO: 50 and wherein said human comprises (i) an IGKC*01 human light chain constant region gene segment, or the human expresses antibodies comprising human kappa light chain constant regions comprising such an Val and Cys and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1.

In an embodiment, said mutation is I474V. In another embodiment, said mutation is E670G. 18936261-1 159 An example provides: A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 in SEQ ID NO; 1, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 and a Cys corresponding to position 87 of SEQ ID NO: 50 and wherein said human comprises (i) an IGKC*01 human light chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V in SEQ ID NO: 1. Optionally, the antibody or fragment comprises an IGKC*01 human light chain constant region.

Another example provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 and a Cys corresponding to position 87 of SEQ ID NO: 50 and wherein said human comprises (i) an IGKC*01 human light chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation E670G in SEQ ID NO: 1. Optionally, the antibody or fragment comprises an IGKC*01 human light chain constant region.

In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 and a Cys corresponding to position 87 of 18936261-1 160 SEQ ID NO: 50 and wherein said human comprises (i) an IGKC*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1. 2. The method of paragraph 1, comprising, before said administering, selecting said human comprising said nucleotide sequence of (ii). 3. The method of paragraph 1 or 2, wherein the antibody comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 or a Cys corresponding to position 87 of SEQ ID NO: 50. 4. The method of paragraph 1, 2 or 3, wherein the antibody comprises an IGKC*01 human kappa chain constant region.

. The method of any one of paragraphs 1 to 4, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30. 6. The method of any one of paragraphs 1 to 5, comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the human. 7. The method of paragraph 6, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 18936261-1 161 8. The method of paragraph 1, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucieotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 9. The method of paragraph 7 or 8, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format.

. The method of any one of paragraphs 1 to 9, wherein said human is or has been further determined to be substantially resistant to statin treatment, 18936261-1 162 11. The method of any one of paragraphs 1 to 10, wherein said human is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 12. The method of paragraph 10 or 11, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with said statin treatment. 13. The method of any one of paragraphs 7 to 9, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 14. The method of any one of paragraphs 1 to 13, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474Vor E670G in SEQ ID NO: 1.

. The method of any one of paragraphs 1 to 14, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 16. The method of any one of paragraphs 1 to 15, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 17. The method of any one of paragraphs 1 to 16, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 18. The method of any one of paragraphs 1 to 17, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is 18936261-1 163 comprised in an injectable preparation. id="p-681" id="p-681"

[00681] Further exemplary ligands are in the paragraphs 1-15 as follows. 1. An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human IGLC2*01 lambda light chain constant region, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises a human IGLC2*01 lambda light chain constant region gene segment, or the human expresses antibodies comprising human IGLC2*01 lambda light chain constant regions.

An example provides: An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human IGLC2*01 lambda light chain constant region, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation 1474V in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises a human IGLC2*01 lambda light chain constant region gene segment. Optionally, the antibody or fragment comprises a human IGLC2*01 lambda light chain constant region.

Another example provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human IGLC2*01 lambda light chain constant region, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a 18936261-1 164 mutation E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises a human IGLC2*01 lambda light chain constant region gene segment. Optionally, the antibody or fragment comprises a human IGLC2*01 lambda light chain constant region.

In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human IGLC2*01 lambda light chain constant region and wherein said human comprises (i) an IGLC2*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1. 2. The antibody or antibody fragment of paragraph 1, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a Cterminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30. 3. The antibody or antibody fragment of paragraphs 1 or 2, the method comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the human. 4. The antibody or antibody fragment of paragraph 3, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 18936261-1 165 . The antibody or antibody fragment of paragraph 4, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the Cterminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 6. The antibody or antibody fragment of paragraph 4 or 5, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 7. The antibody or antibody fragment of any one of paragraphs 1 to 6, wherein said antibody or antibody fragment is for administration to a human that is or has been further determined to be substantially resistant to statin treatment. 18936261-1 166 8. The antibody or antibody fragment of any one of paragraphs 1 to 7, wherein antibody or antibody fragment is for administration to a human that is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 9. The antibody or antibody fragment of paragraph 7 or 8, wherein said antibody or antibody fragment is for administration to the human separately or simultaneously with said statin treatment.

. The antibody or antibody fragment of any one of paragraphs 4 to 8, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 11. The antibody or antibody fragment of any one of paragraphs 1 to 10, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising a mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising a mutation I474Vor E670G in SEQ ID NO: 1. 12. The antibody or antibody fragment of any one of paragraphs 1 to 11, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 13. The antibody or antibody fragment of any one of paragraphs 1 to 12, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 14. The antibody or antibody fragment of any one of paragraphs 1 to 13, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 18936261-1 167 . The antibody or antibody fragment of any one of paragraphs 1 to 14, wherein said antibody or antibody fragment is for administration by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-682" id="p-682"

[00682] Further exemplary methods are in the paragraphs 1-16 as follows. 1. A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human IGLC2*01 lambda light chain constant region and wherein said human comprises (i) an IGLC2*01 human light chain constant region gene segment, or the human expresses antibodies comprising a human IGLC2*01 lambda light chain constant regions and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1.

An example provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 in SEQ ID NO: 1, wherein the antibody or fragment comprises a human IGLC2*01 lambda light chain constant region and wherein said human comprises (i) an IGLC2*01 human light chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V in SEQ ID NO: 1. Optionally, the antibody or fragment comprises an IGLC2*01 human light chain constant region.

Another example provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level 18936261-1 168 in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human IGLC2*01 lambda light chain constant region and wherein said human comprises (i) an IGLC2*01 human light chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation E670G in SEQ ID NO: 1. Optionally, the antibody or fragment comprises an IGLC2*01 human light chain constant region.

In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human IGLC2*01 lambda light chain constant region and wherein said human comprises (i) an IGLC2*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 2. The method of paragraph 1, comprising, before said administering, selecting said human comprising said nucleotide sequence of (ii). 3. The method of paragraph 1 or 2, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30. 4. The method of any one of paragraphs 1 to 3, comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before administration of the 18936261-1 169 antibody to the human.

. The method of paragraph 4, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 6. The method of paragraph 5, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 7. The method of paragraph 5 or 6, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next 18936261-1 170 generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 8. The method of any one of paragraphs 1 to 7, wherein said human is or has been further determined to be substantially resistant to statin treatment. 9. The method of any one of paragraphs 1 to 8, wherein said human is receiving or has received statin treatment or has reduced responsiveness to statin treatment.

. The method of paragraph 8 or 9, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with said statin treatment. 11. The method of any one of paragraphs 5 to 7, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 12. The method of any one of paragraphs 1 to 11, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474Vor E670G in SEQ ID NO: 1. 13. The method of any one of paragraphs 1 to 12, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 14. The method of any one of paragraphs 1 to 13, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 18936261-1 171 . The method of any one of paragraphs 1 to 14, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 16. The method of any one of paragraphs 1 to 15, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-683" id="p-683"

[00683] Further exemplary ligands are in the paragraphs 1-15 as follows. 1. An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human variable domain that is derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, wherein the VH gene segment is as defined in any one of clauses 80 to 90, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence, and comprises said VH gene segment or expresses antibodies comprising VH domains that are derived from the recombination of said human VH gene segment, a human D gene segment and a human JH gene segment, In an embodiment, said mutation is I474V. In another embodiment, said mutation is E670G. 2. The antibody or antibody fragment of paragraph 1, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a Cterminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30. 3. The antibody or antibody fragment of paragraphs 1 or 2, the method comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before 18936261-1 172 administration of the antibody to the human. 4. The antibody or antibody fragment of paragraph 3, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1.

. The antibody or antibody fragment of paragraph 4, wherein the assaying comprises contacting the biological sample with a, at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the Cterminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 6. The antibody or antibody fragment of paragraph 4 or 5, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, 18936261-1 173 next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 7. The antibody or antibody fragment of any one of paragraphs 1 to 6, wherein said antibody or antibody fragment is for administration to a human that is or has been further determined to be substantially resistant to statin treatment. 8. The antibody or antibody fragment of any one of paragraphs 1 to 7, wherein antibody or antibody fragment is for administration to a human that is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 9. The antibody or antibody fragment of paragraph 7 or 8, wherein said antibody or antibody fragment is for administration to the human separately or simultaneously with said statin treatment.

. The antibody or antibody fragment of any one of paragraphs 4 to 8, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 11. The antibody or antibody fragment of any one of paragraphs 1 to 10, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising a mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising a mutation I474Vor E670G in SEQ ID NO: 1. 12. The antibody or antibody fragment of any one of paragraphs 1 to 11, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 13. The antibody or antibody fragment of any one of paragraphs 1 to 12, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one 18936261-1 174 condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 14. The antibody or antibody fragment of any one of paragraphs 1 to 13, wherein the nucleotide sequence is SEQ ID NO: 29 or 30.

. The antibody or antibody fragment of any one of paragraphs 1 to 14, wherein said antibody or antibody fragment is for administration by intravenous or subcutaneous administration and/or is comprised in an injectable preparation.

Further exemplary methods are in the paragraphs 1-16 as follows. 1. A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human variable domain that is derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, wherein the VH gene segment is as defined in any one of clauses 80 to 90 and wherein said human comprises (i) comprises said VH gene segment or expresses antibodies comprising VH domains that are derived from the recombination of said human VH gene segment, a human D gene segment and a human JH gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1.

In an embodiment, said mutation is I474V. In another embodiment, said mutation is E670G. 2, The method of paragraph 1, comprising, before said administering, selecting said human comprising said nucleotide sequence of (ii). 18936261-1 175 3. The method of paragraph 1 or 2, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30. 4. The method of any one of paragraphs 1 to 3, comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the human.

. The method of paragraph 4, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 6. The method of paragraph 5, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is 18936261-1 176 not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the 5 complex determines that the human comprises the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 7. The method of paragraph 5 or 6, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 8. The method of any one of paragraphs 1 to 7, wherein said human is or has been further determined to be substantially resistant to statin treatment. 9. The method of any one of paragraphs 1 to 8, wherein said human is receiving or has received statin treatment or has reduced responsiveness to statin treatment.

. The method of paragraph 8 or 9, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with said statin treatment. 11, The method of any one of paragraphs 5 to 7, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human, 12, The method of any one of paragraphs 1 to 11, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474Vor E670G in SEQ ID NO: 1. 13. The method of any one of paragraphs 1 to 12, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, 18936261-1 177 hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 14. The method of any one of paragraphs 1 to 13, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure, . The method of any one of paragraphs 1 to 14, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 16. The method of any one of paragraphs 1 to 15, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-684" id="p-684"

[00684] Regimens id="p-685" id="p-685"

[00685] A: The invention further provides the following regimens, ligands and kits. 1. A method for treating a human PCSK9-mediated disease or condition in a human by targeting a rare variant human PCSK9, the method comprising administering to the human a ligand (eg, an antibody or fragment) that has been determined to specifically bind to said PCSK9variant; wherein the human expresses said PCSK9 variant or the genome of the human comprises a nucleotide sequence encoding said PCSK9 variant; wherein said human is treated for said disease or condition.

The variant PCSK9 can, for example, be any rare variant as described herein.

For example, there is provided: la. A method for treating a PCSK9-mediated disease or condition in a human by targeting a PCSK9 that comprises a C-terminal domain amino acid polymorphism (compared to SEQ ID 18936261-1 178 NO: 1), the method comprising administering to the human a ligand (eg, an antibody or fragment) that has been determined to specifically bind to a PCSK9 comprising a C-terminal domain comprising I474V or 670G (numbering according to SEQ ID NO:1); wherein the human expresses said PCSK9 or the genome ofthe human comprises a nucleotide sequence encoding said PCSK9; wherein said human is treated for said disease or condition.

In an embodiment, determination of said specific binding is by reference to binding assay data, eg, as determined using SPR or ELISA. Determination may, for example, be by reference to information in a printed publication, eg, with knowledge of data presented in the present or another patent application or in a journal article. Once armed with such knowledge (eg, in the absence of further testing of binding), the skilled person is able - by direction of the present invention - to treat a relevant human whose genotype or phenotype matches the binding specificity of the ligand.

The antibody or fragment can be according to any configuration, example, embodiment, aspect, clause or paragraph herein.

In an embodiment, the method comprises, before said administering, selecting a human comprising said nucleotide sequence encoding the PCSK9, wherein the human is said human in clause 1 (eg, la). 2. The method of clause 1, comprising before said administering the step of determining that the ligand specifically binds to said PCSK9, eg, using SPR or ELISA. 3. The method of clause 1 or 2, wherein the specific binding to said PCSK9 is binding with a dissociation constant (Kd) of InM or less, eg, 100, 10 or lpM or less. 4. The method of any of clauses 1 to 3 (eg, clause la), wherein the condition is elevated LDL-cholesterol or is caused by elevated LDL-cholesterol.

. The method of clause 4 (eg, when dependent from clause la), wherein the condition is selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, 18936261-1 179 peripheral vascular disease, claudication and high blood pressure. 6. The method of any one of clauses 1 to 5 (eg, when dependent from clause la), wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30. 7, The method of any one of clauses 1 to 6 (eg, when dependent from clause la), comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the human. 8. The method of clause 7, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 9. The method of clause 8, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous 18936261-1 180 . nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1.

. The method of clause 8 or 9, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 11. The method of any one of clauses 1 to 10, wherein said human is or has been further determined to be substantially resistant to statin treatment. 12. The method of any one of clauses 1 to 11, wherein said human is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 13. The method of clauses 11 or 12, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with said statin treatment. 14. The method of any one of clauses 8 to 10, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human.

. The method of any one of clauses 1 to 14, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474Vor E670G in SEQ ID NO: 1. 18936261-1 181 16. The method of any one of clauses 1 to 15, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 17. The method of any one of clauses 1 to 16, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure, 18. The method of any one of clauses 1 to 17, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 19. The method of any one of clauses 1 to 18, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation.

. A ligand (eg, an antibody or fragment) for use in the method of any one of clauses 1 to 19, wherein the ligand specifically binds the PCSK9. 21. A kit comprising the ligand of clause 20 and instructions for carrying out the method of any one of clauses 1 to 19. 100686] B; The invention further provides the following regimens, ligands and kits. 1. A method of reducing cholesterol level or maintaining a previously reduced cholesterol level in a human in need thereof, the method comprising:- a. Carrying out an initial treatment of said human for an initial treatment period by administering an anti-human PCSK9 ligand (eg, an antibody or fragment) to said human, wherein (i) the ligand has been determined to specifically bind to a PCSK9 comprising a C-terminal domain comprising I474V or 670G (numbering according to SEQ ID NO:1); (ii) the human expresses said PCSK9 or the genome of the 18936261-1 182 human comprises a nucleotide sequence encoding said PCSK9 and (iii) the human has received or is receiving statin treatment to lower or maintain cholesterol level; wherein the initial treatment comprises the administration of a single or multiple doses of the ligand to the human; b. Determining to (i) terminate statin treatment (ii) keep the human off statin treatment; or (iii) reduce statin treatment after said initial treatment period; and c. Continuing to administer the ligand to said patient after said time period has expired, thereby reducing cholesterol level or maintaining a previously reduced cholesterol level in said human.

A pharmaceutically-effective amount of said ligand is administered.

In an embodiment, the method comprises, before said administering, selecting a human comprising said nucleotide sequence encoding the PCSK9, wherein the human is said human recited in clause 1.

In an example, the initial treatment period is 7 days, 14 days, 21 days, 28 days, a month, two months, three months, four months, five months, six months, seven months, eight months, nine months or a year. 2. The method of clause 1, wherein the human has or is suffering from statin-associated memory loss or a statin-associated neurodegenerative condition, or has or is at increased 18936261-1 183 risk of diabetes (eg, statin-associated diabetes). 3. The method of clause 1 or 2, comprising, before said initial treatment, the step of determining that the human has or is suffering from statin-associated memory loss or a statin-associated neurodegenerative condition, or has or is at increased risk of diabetes (eg, statin-associated diabetes). 4. The method of clause 2 or 3, comprising, after step (b) (eg, during step (c)) determining that the memory loss or said neurodegenerative condition has improved.

. The method of any one of clauses 1 to 4, wherein said human is over 40 years of age (eg, 50 or over, 55 or over, 60 or over, 65 or over, or 70 or over). 6. The method of any one of clauses 1 to 5, wherein step (c) comprises determining to increase the doses of said ligand to be administered after said initial treatment period and administering said increased doses to said human. 7. The method of any one of clauses 1 to 6, wherein step (b) comprises determining that the human is intolerant or refactory to treatment by a statin. 8. The method of any one of clauses 1 to 7, wherein the initial treatment comprises the administration of a statin, fenofibrate (eg, Tricor™ or Lofibra™) or ezetimibe to the human in addition to the ligand. 9. The method of any one of clauses 1 to 8, wherein step (b) comprises terminating or reducing statin, fenofibrate (eg, Tricor™ or Lofibra™) or ezetimibe treatment during step (c).

. The method of any one of clauses 1 to 9, comprising increasing (ie, increasing compared to the initial treatment dose) the ligand dose during step (c). 11. The method of any one of clauses 1 to 10, wherein the human has received high dose statin treatment prior to the initial treatment, and wherein step (c) comprises administering a lower (eg, a medium or low) dose statin treatment in addition to said 18936261-1 184 ligand.

The skilled person is familiar with the meaning of high, medium and low dose treatments (and how to determine according to each patient, eg, the patient's body mass). For example, the statin is selected from rosuvastatin, atorvastatin and simvastatin.

For example daily statin doses are as follows:- Low 10 to 20mg (eg, lOmg); medium >20 and <60mg (eg, 40mg); high 60-100mg (eg, 80mg). 12. The method of any one of clauses 1 to 10, wherein the human has received medium dose statin treatment prior to the initial treatment, and wherein step (c) comprises administering a lower (eg, a low) dose statin treatment or no statin in addition to said ligand. 13. The method of any one of clauses 1 to 10, wherein the human has received low dose statin treatment prior to the initial treatment, and wherein step (c) comprises administering no statin in addition to said ligand. 14. The method of any one of clauses 1 to 13, comprising, before the initial treatment, the step of determining that the ligand specifically binds to said PCSK9, eg, using SPR or ELISA.

. The method of any one of clauses 1 to 14, wherein the specific binding to said PCSK9 is binding with a dissociation constant (Kd) of InM or less, eg, 100, 10 or IpM or less. 16. The method of any of clauses 1 to 15, wherein the human is at risk of or suffering from a condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 17. The method of clause 16, wherein step (c) treats or reduces the risk of said condition in the human. 18936261-1 185 18. The method of any one of clauses 1 to 17, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30. 19. The method of any one of clauses 1 to 18, comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-termina! domain comprising said mutation I474V or E670G and/or □ proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the human.

. The method of clause 19, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 21. The method of clause 20, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence 18936261-1 186 encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 22. The method of clause 20 or 21, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 23. The method of any one of clauses 1 to 22, wherein said human is or has been further determined to be substantially resistant to statin treatment. 24. The method of any one of clauses 20 to 22, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human.

. The method of any one of clauses 1 to 24, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474Vor E670G in SEQ ID NO: 1. 26. The method of any one of clauses 1 to 25, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 27. The method of any one of clauses 1 to 26, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 18936261-1 187 28. The method of any one of clauses 1 to 27, wherein said ligand (eg, antibody or antibody fragment) is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. 29. A ligand (eg, an antibody or fragment) for use in the method of any one of clauses 1 to 28, wherein the ligand specifically binds the PCSK9.

. A kit comprising the ligand of clause 29 and instructions for carrying out the method of any one of clauses 1 to 28. id="p-687" id="p-687"

[00687] In an example of any aspect of the invention, the ligand (eg, antibody or fragment, eg, alirocumab, bocovizumab or evolocumab, or an antibody or fragment comprising the variable domains of 316P or 31H4) is administered to the human at a twoweekly dose of from 75 to 150mg (eg, from 75 to 150mg administered once or twice over a 15 two-week period). In an example, the ligand is for such administration to the human. 18936261-1 188 EXAMPLES Example 1: Rare PCSK9 Variants id="p-688" id="p-688"

[00688] The present invention provides anti-PCSK9 ligands; and PCSK9-binding or targeting ligands as described herein. The ligands have a variety of utilities. Some of the ligands, for instance, are useful in specific binding assays, for genotyping or phenotyping humans, affinity purification of PCSK9, in particular human PCSK9 or its ligands and in screening assays to identify other antagonists of PCSK9 activity. Some of the ligands of the invention are useful for inhibiting binding of PCSK9 to LDLR, or inhibiting PCSK9-mediated activities. 100689] Anti-PCSK9 ligands (eg, antibodies and anti-sense RNA) have been developed based on targeting and neutralising so-called wild-type human PCSK9, which is a commonly-occurring form (see, eg, US20120093818A1 and US20110065902A1). While such therapies are useful for human patients harbouring this form of human PCSK9, the inventor considered it useful to investigate the possibility of targeting much rarer - but still naturallyoccurring - forms of PCSK9 amongst human populations. In this way, the inventor arrived at insight into the natural occurrences and distributions of rarer human PCSK9 forms that can serve as useful targets (at the protein or nucleic acid level) for human treatment, prophylaxis and diagnosis pertinent to diseases and conditions mediated or associated with PCSK9 activity. This particularly provides for tailored therapies, prophylaxis and diagnosis in humans that are devoid of the common PCSK9 gene or protein (ie, the form a or a'as used in US20120093818A1 and US20110065902A1 to generate antibodies). id="p-690" id="p-690"

[00690] The skilled person will know that SNPs or other changes that translate into amino acid variation can cause variability in activity and/or conformation of human targets to be addressed. This has spawned great interest in personalized medicine where genotyping and knowledge of protein and nucleotide variability is used to more effectively tailor medicines and diagnosis of patients. The invention, therefore, provides for tailored pharmaceuticals and testing that specifically addresses rarer PCSK9 polymorphic variant forms. Such forms or alleles (at the nucleotide level), in many of the examples determined by the inventor, comprise multiple changes at the nucleotide and amino acid levels from the corresponding common form nucleotide and amino acids sequences, ie, there are multiple non-synonymous changes at the nucleotide level that translate into multiple corresponding changes in the protein target in humans. 18936261-1 189 id="p-691" id="p-691"

[00691] Furthermore, the inventor surprisingly realised that the rarer natural forms, although present in humans at much lower frequencies than the common form, nevertheless are represented in multiple and ethnically-diverse human populations and usually with many human examples per represented ethnic population. Thus, the inventor realised that targeting such rarer forms would provide for effective treatment, prophylaxis or diagnosis across many human ethnic populations, thereby extending the utility of the present invention. [00692| With this realisation, the inventor realised that there is significant industrial and medical application for the invention in terms of guiding the choice of anti-PCSK9 ligand for administration to human patients for therapy and/or prophylaxis of PCSK9-mediated or associated diseases or conditions. In this way, the patient receives drugs and ligands that are tailored to their needs - as determined by the patient's genetic or phenotypic makeup. Handin-hand with this, the invention provides for the genotyping and/or phenotyping of patients in connection with such treatment, thereby allowing a proper match of drug to patient. This increases the chances of medical efficacy, reduces the likelihood of inferior treatment using drugs or ligands that are not matched to the patient (eg, poor efficacy and/or side-effects) and avoids pharmaceutical mis-prescription and waste. id="p-693" id="p-693"

[00693] In developing this thinking, in this non-limiting example the present inventor decided to determine a set of human PCSK9 variants on the basis of the following criteria, these being criteria that the inventor realised would provide for useful medical drugs and diagnostics to tailored need in the human population. The inventor selected variants having at least 3 of the 4 following criteria:- • PCSK9 variants having a cumulative human allele frequency in the range from 1 to 10%; • PCSK9 variants having a total human genotype frequency in the range from 1 to about 15%; • PCSK9 variants found in many different human ethnic populations (using the standard categorisation of the 1000 Genomes Project, which is an accepted standard in the art; see Table 4 below); and • PCSK9 variants found in many individuals distributed across such many different ethnic populations. id="p-694" id="p-694"

[00694] On the basis of these criteria, the inventor identified the variants listed in Table 1 below (excluding form a). 18936261 1 190 id="p-695" id="p-695"

[00695] The inventor's selection included, as a consideration, selection for nucleotide variation that produced amino acid variation in corresponding PCSK9 forms (ie, non-synonymous variations), as opposed to silent variations that do not alter amino acid residues in the target protein. 18936261-1 191 id="p-696" id="p-696"

[00696] Variant Allele Nucleotide Sequences id="p-697" id="p-697"

[00697] Thus, (i) The nucleotide sequence of allele fis identical to SEQ ID NO: 28 except that the nucleotide sequence of allele /comprises a GTC codon instead of an ATC codon at the position labelled I474V in SEQ ID NO: 28; (ii) The nucleotide sequence of allele cis identical to SEQ ID NO: 28 except that the nucleotide sequence of allele c comprises a GGG codon instead of an GAG codon at the position labelled E670G in SEQ ID NO: 28; (iii) The nucleotide sequence of allele ris identical to SEQ ID NO: 28 except that the nucleotide sequence of allele r comprises a GTC codon instead of an ATC codon at the position labelled I474V in SEQ ID NO: 28; and a GGG codon instead of an GAG codon at the position labelled E670G in SEQ ID NO: 28; (iv) The nucleotide sequence of allele p is identical to SEQ ID NO: 28 except that the nucleotide sequence of allele p comprises a GTC codon instead of a GCC codon at the position labelled A53V in SEQ ID NO: 28; and a GTC codon instead of an ATC codon at the position labelled I474V in SEQ ID NO: 28; (v) The nucleotide sequence of allele m is identical to SEQ ID NO: 28 except that the nucleotide sequence of allele m comprises a ACC codon instead of a GCC codon at the position labelled A443T in SEQ ID NO: 28; (vi) The nucleotide sequence of allele e is identical to SEQ ID NO: 28 except that the nucleotide sequence of allele e comprises a AGT codon instead of an AAT codon at the position labelled N425S in SEQ ID NO: 28; and a GTC codon instead of an ATC codon at the position labelled I474V in SEQ ID NO: 28; (vii) The nucleotide sequence of allele h is identical to SEQ ID NO: 28 except that the nucleotide sequence of allele h comprises a ACC codon instead of a GCC codon at the position labelled A443T in SEQ ID NO: 28; and a CCG codon instead of a CAG codon at the position labelled Q619P in SEQ ID NO: 28; (viii) The nucleotide sequence of allele ayis identical to SEQ ID NO: 28 except that the nucleotide sequence of allele ay comprises a CTT codon instead of an CGT codon at the position labelled R46L in SEQ ID NO: 28; and a GTC codon instead of an ATC codon at the position labelled I474V in SEQ ID NO: 28; and (ix) The nucleotide sequence of allele q is identical to SEQ ID NO: 28 except that the nucleotide sequence of allele ¢7 comprises a GTC codon instead of a GCC codon at the 204 18936261-1 position labelled A53V in SEQ ID NO: 28; and a GGG codon instead of an GAG codon at the position labelled E670G in SEQ ID NO: 28. id="p-698" id="p-698"

[00698] Variant Pro-Form Amino Acid Sequences (Numbering is as per SEQ ID NO: 1 recited above) (A) The amino acid sequence of form Ais identical to the amino acid sequence from amino acid number 31 to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form /comprises a valine at position 474; (B) The amino acid sequence of form cis identical to the amino acid sequence from amino acid number 31 to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form ccomprises a glycine at position 670; (C) The amino acid sequence of form cis identical to the amino acid sequence from amino acid number 31 to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form /-comprises a valine at position 474 and a glycine at position 670; (D) The amino acid sequence of form pis identical the amino acid sequence from amino acid number 31 to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form p comprises a valine at position 53 and a valine at position 474; (E) The amino acid sequence of form m is identical to the amino acid sequence from amino acid number 31 to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form m comprises a threonine at position 443; (F) The amino acid sequence of form e is identical to the amino acid sequence from amino acid number 31 to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form e comprises a serine at position 425 and a valine at position 474; (G) The amino acid sequence of form h is identical to the amino acid sequence from amino acid number 31 to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form h comprises a threonine at position 443 and a proline at position 619; (H) The amino acid sequence of form a/is identical to the amino acid sequence from amino acid number 31 to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form ajcomprises a leucine at position 46 and a valine at position 474; and (I) The amino acid sequence of form q is identical to the amino acid sequence from amino acid number 31 to (and including) amino acid number 692 of SEQ ID NO: 1 except that 205 18936261-1 the amino acid sequence of form g comprises a valine at position 53 and a glycine at position 670. id="p-699" id="p-699"

[00699] Variant Mature Form Amino Acid Sequences (Numbering is as per SEQ ID NO: 1 recited above) (A') The amino acid sequence of form Ais identical to SEQ ID NO: 2 except that the amino acid sequence of form ^comprises a valine at position 474; (B1) The amino acid sequence of form cis identical to SEQ ID NO: 2 except that the amino acid sequence of form ccomprises a glycine at position 670; (C) The amino acid sequence of form ris identical to SEQ ID NO: 2 except that the amino acid sequence of form /-comprises a valine at position 474 and a glycine at position 670; (D1) The amino acid sequence of form p is identical to SEQ ID NO: 2 except that the amino acid sequence of form p comprises a valine at position 474; (E') The amino acid sequence of form m is identical to SEQ ID NO: 2 except that the amino acid sequence of form m comprises a threonine at position 443; (F1) The amino acid sequence of form e is identical to SEQ ID NO: 2 except that the amino acid sequence of form e comprises a serine at position 425 and a valine at position 474; (G') The amino acid sequence of form h is identical to SEQ ID NO: 2 except that the amino acid sequence of form h comprises a threonine at position 443 and a proline at position 619; (H') The amino acid sequence of form ay is identical to SEQ ID NO: 2 except that the amino acid sequence of form ay comprises valine at position 474; and (Γ) The amino acid sequence of form q is identical to SEQ ID NO: 2 except that the amino acid sequence of form qcomprises a glycine at position 670. id="p-700" id="p-700"

[00700] The mature form of p is identical to the mature form of /and aj. id="p-701" id="p-701"

[00701] The mature form of cis identical to the mature form of q. id="p-702" id="p-702"

[00702] Further sequence analysis and 3D in silico modelling (see Figure 1) revealed that selected variants also fulfilled the following additional selection criteria:- • PCSK9 variants whose variant amino acid residues (versus the common form of human PCSK9) are found in the mature form of the target (ie, outside the pro-domain); and • PCSK9 variants whose variant amino acid residues (versus the common form of human PCSK9) are surface-exposed on the target, which the inventor saw as contributing to determining the topography of the target and potentially contributing to how and where ligand binding on the target occurs. id="p-703" id="p-703"

[00703] As shown in Figure 1, identified positions 425, 443, 474, 619 and 670 (found in the selected variants of the invention) are all surface-exposed and outside of the 206 18936261-1 pro-domain. Variant positions 425 and 443 are surface-exposed on the catalytic domain, while variant positions 474, 619 and 670 are surface-exposed on the C-terminal domain. id="p-704" id="p-704"

[00704] The inventor, thus, applied the novel selection criteria to determine rare variant forms of human PCSK9, realising the utility of their nucleotide and amino acid sequences in the various configurations, aspects, clauses, embodiments and example ofthe invention herein, and thereby providing for novel personalized medical and diagnostic applications as described above. 100705] Tailoring Antibodies to Rare PCSK9 Variant Profile |00706] As outlined above, the invention includes the possibility to tailor treatment of humans further by selecting antibody-based ligands with variable domains based on gene segments commonly found in humans of the ethnic populations where the variant PCSK9 forms are found to meet the selection criteria of the invention. An example is provided below for ligands comprising antibody VH domains derived from recombination of human VH3-23. [00707] The inventor analysed the frequencies and distribution of various human VH3-23 alleles and realised the desirability of using ligands based on human VH3-23 alleles comprising SNP rs56069819. This SNP corresponds to a change from leucine at position 24 in the encoded protein sequence to a valine at that position (L24V change) and the SNP is at coordinate 106268889 on human chromosome 14. id="p-708" id="p-708"

[00708] Figure 2 shows the cumulative allele frequency distribution across the 1000 Genomes Project database of human VH3-23 alleles comprising SNP rs56069819 (such alleles denonted C and the most frequent allele (which does not comprise this SNP) denoted A). The figure shows that VH3-23 alleles comprising SNP rs56069819 are present at a cumulative frequency of 11% across all human ethnic populations taken as a whole, whereas in certain specific human ethnic sub-populations (ASW, LWK, YRI, CEU and GBR) such alleles are present at an above-average cumulative frequency. Indicated in the figure are those human PCSK9 variant forms (marked Variants) that are found in the various sub-populations with above-average occurrence of human VH3-23 alleles comprising SNP rs56069819. Table 6 shows the VH3-23 variants and the SNPs that they comprise, as well as their cumulative allele frequencies as found in the 1000 Genomes Project database. id="p-709" id="p-709"

[00709] Notably, human VH3-23 alleles comprising SNP rs56069819 were found in the CEU population at a frequency that is almost double the frequency of 11% for all populations. For the ASW and YRI populations the frequency was over a quarter of the 207 18936261-1 population. Thus, the invention advantageously enables one to select a ligand comprising an antibody or antibody fragment, wherein the antibody or fragment comprises a VH domain derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, the VH gene segment comprising a nucleotide sequence that comprises SNP rs56069819 (dbSNP numbering, build number as recited above). id="p-710" id="p-710"

[00710] In an example, one can tailor the treatment further by selecting such a ligand that specifically binds to a human PCSK9 selected from forms : / c, m, e, h, p, q and aj, such forms being those appearing in human populations AS\N, LWK, YRI, CEU and GBR. [00711] In an example, the VH gene segment is VH3-23*04, which is a commonly found variant that comprises SNP rs56069819 in human populations ASW, LWK, YRI, CEU and GBR. id="p-712" id="p-712"

[00712] In an example, the ligand is for treating and/or preventing a PCSK9mediated disease or condition in a human that expresses a human PCSK9 selected from forms : f, c, m, e, h, p, q and aj. [00713J In an example, the ligand is for treating and/or preventing a PCSK9mediated disease or condition in a human of ASW, LWK, YRI, CEU or GBR ancestry. [00714J In an embodiment, the ligand is for treating and/or preventing a PCSK9mediated disease or condition in a human of ASW ancestry, wherein the human expresses a PCSK9 selected from f, c, m, e, h, pand qor the human comprises a corresponding nucleotide or amino acid sequence as set out in Table 5. Optionally this ligand comprises a VH domain derived from recombination of human VH3-23*04. id="p-715" id="p-715"

[00715] In an embodiment, the ligand is for treating and/or preventing a PCSK9mediated disease or condition in a human of LWK ancestry, wherein the human expresses a PCSK9 selected from f, c, m, eand h or the human comprises a corresponding nucleotide or amino acid sequence as set out in Table 5. Optionally this ligand comprises a VH domain derived from recombination of human VH3-23*04. 100716] In an embodiment, the ligand is for treating and/or preventing a PCSK9mediated disease or condition in a human of YRI ancestry, wherein the human expresses a PCSK9 selected from f, c, m, e and h or the human comprises a corresponding nucleotide or amino acid sequence as set out in Table 5. Optionally this ligand comprises a VH domain derived from recombination of human VH3-23*04. id="p-717" id="p-717"

[00717] In an embodiment, the ligand is for treating and/or preventing a PCSK9mediated disease or condition in a human of CEU ancestry, wherein the human expresses a PCSK9 selected from f, c, pand ajor the human comprises a corresponding nucleotide or 208 18936261-1 amino acid sequence as set out in Table 5. Optionally this ligand comprises a VH domain derived from recombination of human VH3-23*04. id="p-718" id="p-718"

[00718] In an embodiment, the ligand is for treating and/or preventing a PCSK9mediated disease or condition in a human of GBR ancestry, wherein the human expresses a PCSK9 selected from f, cand por the human comprises a corresponding nucleotide or amino acid sequence as set out in Table 5. Optionally this ligand comprises a VH domain derived from recombination of human VH3-23*04. id="p-719" id="p-719"

[00719] For example in any aspect, example, embodiment or configuration of the invention, the anti-TOI (eg, PCSK9 or IL4Ra) ligand (eg, trap, antibody or fragment) comprises a VH domain derived from the recombination of a human VH segment (eg, human VH3-23*04), a human D gene segment and a human JH segment, the human VH segment encoding the framework 1 of SEQ ID NO: 40 and wherein said human comprises a VH gene segment encoding the framework 1 of SEQ ID NO: 40 , or the human expresses VH domains that comprise the framework 1 of SEQ ID NO: 40. In an alternative, the ligand comprises a VH domain derived from the recombination of a human VH segment (eg, human VH3-23*04), a human D gene segment and a human JH segment, the human VH segment comprising SNP rs56069819 and wherein said human comprises a VH gene segment comprising SNP rs56069819. id="p-720" id="p-720"

[00720] SNP rs56069819 is present in humans at an average cumulative frequency of 11% according to the 1000 Genomes Phase I database, but is higher in AFR (23%), EUR (13%), ASW (27%), LWK (15%), YRI (28%), CEU (19%) and GBR (15%) populations, thus in an embodiment when an anti-TOI (eg, PCSK9 or IL4Ra) antibody or fragment comprises framework 1 of SEQ ID NO: 40 or comprises a VH domain derived from the recombination of a human VH segment (eg, human VH3-23*04), a human D gene segment and a human JH segment, the human VH segment comprising SNP rs56069819, the human is of an ancestry selected from the group consisting of AFR, EUR, ASW, LWK, YRI, CEU and GBR ancestry. For example, the human is of AFR ancestry. For example, the human is of EUR ancestry. For example, the human is of ASW ancestry. For example, the human is of LWK ancestry. For example, the human is of YRI ancestry. For example, the human is of CEU ancestry. For example, the human is of GBR ancestry. In an example, the selected ancestry of the human is one of these listed ancestries and the TOI comprises an amino acid variation (mutation) that is encoded by a SNP that is also present in such a human population at a higher than average cumulative frequency according to the 1000 Genomes. For example, the ligand (eg, antibody or fragment) specifically binds an IL4R protein that comprises a mutation S752A and 209 18936261-1 the human is of YRI ancestry. In this case, the SNP encoding the mutation, as well as SNP rs56069819 are present in the YRI population at an above average cumulative frequency. This general aspect of the invention is therefore particularly useful for tailoring to the genomic profiles of members of such a population. id="p-721" id="p-721"

[00721] In an example the ligand specifically binds to human PCSK9 form f. id="p-722" id="p-722"

[00722] In an example the human expresses a human PCSK9 selected from forms: f, e, p, and aj. id="p-723" id="p-723"

[00723] In an example the human is of ASW, LWK, YRI, CEU or GBR ancestry. id="p-724" id="p-724"

[00724] In an example the human is of ASW ancestry and the human expresses a human PCSK9 selected from forms: f, e, pand aj; optionally the ligand comprises a VH domain derived from recombination of human VH3-23*04. id="p-725" id="p-725"

[00725] In an example the human is of LWK ancestry and the human expresses a human PCSK9 selected from forms: f, e, pand aj; cptionally the ligand comprises a VH domain derived from recombination of human VH3-23*04. id="p-726" id="p-726"

[00726] In an example the human is of YRI ancestry and the human expresses a human PCSK9 selected from forms: f, e, pand aj; optionally the ligand comprises a VH domain derived from recombination of human VH3-23*04. id="p-727" id="p-727"

[00727] In an example the human is of CEU ancestry and the human expresses a human PCSK9 selected from forms: f, e, pand aj; optionally the ligand comprises a VH domain derived from recombination of human VH3-23*04. 100728] In an example the human is of GBR ancestry and the human expresses a human PCSK9 selected from forms: j e, pand aj, optionally the ligand comprises a VH domain derived from recombination of human VH3-23*04. id="p-729" id="p-729"

[00729] In an example the genome of the human comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29, 32, 34 and 36, wherein the antibody or fragment specifically binds to a human PCSK9 selected from forms : f, e, pand ajrespectively, wherein the antibody or fragment comprises a VH domain derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, the VH gene segment comprising a nucleotide sequence that comprises SEQ ID NO: 39 or its complement. Optionally wherein VH gene segment is VH3-23*04 (SEQ ID NO: 38). id="p-730" id="p-730"

[00730] In an example, the ligand is alirocumab. 210 18936261-1 id="p-731" id="p-731"

[00731] In other embodiments, as explained more fully above, the invention provides for ligands which are tailored to the human recipient's genotype and/or phenotype based on alternative human VH gene segments, or on Vk, VA or constant region gene segments (see further Table 8 for representative variants). id="p-732" id="p-732"

[00732] For example, the ligand of the invention comprises or consists of an antibody that comprises a VH domain that is derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, wherein the VH gene segment is selected from the group consisting of (i) IGHV1-18*O1 and the genome of the human comprises a human IGHV1-18*O1 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV118*01; or (ii) IGVH 1-46*01 and the genome of the human comprises a human IGHV1-46*O1 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination ofhuman IGHV1-46*O1. |00733] For example, the ligand of the invention comprises or consists of an antibody that comprises a VL domain that is derived from the recombination of a human VL gene segment and a human JL gene segment, wherein the VL gene segment is selected from the group consisting of (i) IGKV4-l*01 and the genome of the human comprises a human IGKV4-l*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV4-l*01; (ii) IGLV2-14*01 and the genome of the human comprises a human IGLV2-14*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGLV2-14*01; or (Hi) IGKV1-13*O2 and the genome of the human comprises a human IGKV113*02 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV1-13*O2. id="p-734" id="p-734"

[00734] For example, the inventor identified the possibility of addressing the rarer IGH-gamma-1 SNPs 204D (observed cumulative frequency of 0.296) and 206L (observed cumulative frequency of 0.283) individually or in combination. These residues are part of the CH3 domain, and as such they form part of antibody Fc regions. Thus, matching of these CH3 variations with the patient is especially beneficial for reasons as discussed above. Thus, in this example the ligand of the invention comprises or consists of an antibody that comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 or a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein the genome of the human comprises a gamma-1 heavy chain constant region nucleotide sequence that encodes such an Asp or Leu or the human expresses antibodies comprising 211 18936261-1 human gamma-1 constant regions comprising such an Asp or Leu. An example of such a ligand is alirocumab. id="p-735" id="p-735"

[00735] In another example, the inventor identified the possibility of addressing IGH-gamma-2 SNPs. This included consideration of Fc region variation - in this respect, the inventor focused on positions 161 and 257 which are in the Fc region. Thus, in this example the ligand of the invention comprises or consists of an antibody that comprises a human gamma-2 heavy chain constant region that comprises an amino acid selected from the group consisting of a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44; and wherein the genome of the human comprises a gamma-2 heavy chain constant region nucleotide sequence that encodes such a selected amino acid or the human expresses antibodies comprising human gamma-2 constant regions comprising such a selected amino acid. An example of such a ligand is evolocumab or bococizumab. id="p-736" id="p-736"

[00736] In another example, the inventor addressed human kappa constant region variation. Thus, in this example the ligand of the invention comprises or consists of an antibody that comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 or a Cys corresponding to position 87 of SEQ ID NO: 50; and wherein the genome of the human comprises a kappa light chain constant region nucleotide sequence that encodes such a Val or Cys or the human expresses antibodies comprising human kappa light chain constant regions comprising such a Val or Cys. An example of such a ligand is alirocumab or bococizumab. {00737] In another example, the inventor addressed human lambda constant region variation. Thus, in this example the ligand of the invention comprises or consists of an antibody that comprises a human IGLC2*01 light chain constant region; and wherein the genome of the human comprises a human IGLC2*01 nucleotide sequence or the human expresses antibodies comprising human light chain IGLC2*01 constant regions. An example of such a ligand is evolocumab.

Example 2: Determination of Specific Binding of Ligands of the Invention to PCSK9 Variants 212 18936261-1 id="p-738" id="p-738"

[00738] Method of SPR Determination of Binding Binding of the antibodies to the PCSK9 variants was carried out by SPR using the ProteOn XPR36™ Array system (BioRad). An anti-human IgG surface (Jackson Labs 109-005-008) was created on a GLC Biosensor chip by primary amine coupling. Test antibodies were captured on this surface as ligands. The PCSK9 variants were used as analytes and passed over the captured antibodies at 256nM, 64nM, 16nM, 4nM and InM. Binding curves were double referenced using a buffer injection (i.e. OnM) to remove baseline drift and injection artefacts. Regeneration of the capture surface was with lOOmM phosphoric acid which removed the captured antibody allowing another cycle of capture and binding. The binding sensorgrams generated were analysed using the 1:1 model inherent to the ProteOn XPR36 Array system analysis software. The assay was performed at 25 °C and using lxHBS-EP (Teknova) as running buffer. 100739] Data Three antibodies were tested and the resulting binding data are presented below (Table 3). Antibodies 316P and 31H4 are antibodies disclosed in US20110065902A1 (the sequences of these antibodies and their variable domains are incorporated herein by reference for possible use in the present invention and possible inclusion in claims herein). Antibody 316P comprises heavy chain variable domains derived from recombination of human VH3-23*04 and JH2*01 (with a D), and light chain variable domains derived from recombination of human Vk4-1*01 and Jk2*01. id="p-740" id="p-740"

[00740] Evolocumab comprises a human IGHG2*01 heavy chain and a human IGLC2*01 lambda light chain, a VH derived from recombination of human IGHV1-18*O1 and IGHJ6*01 (with a D segment) and a VA derived from recombination of human IGLV2-14*01 and IGU2*01.

Table 3: SPR Determination of Ligand Binding Specificity for PCSK9 Variants Variant/Anti body ka (1/Ms) kd (1/s) KD (nM) PCSK9 a 316P 1.37E+06 2.75E-04 0.201 31H4 1.14E+06 6.38E-05 0.056 Evolocumab 1.14E+05 2.62E-05 0.229 PCSK9 a' 316P 1.50E+06 2.72E-04 0.181 213 18936261-1 31H4 1.23E+06 6.06E-05 0.049 Evolocumab 1.24E+05 2.29E-05 0.185 PCSK9 c 316P 1.49E+06 2.75E-04 0.184 31H4 1.22E+06 5.69E-05 0.047 Evolocumab 1.20E+05 2.20E-05 0.183 PCSK9 r 316P 1.40E+06 2.76E-04 0.197 31H4 1.15E+06 5.82E-05 0.051 Evolocumab 1.16E+05 2.67E-05 0.230 PCSK9 f 316P 1.39E+06 2.82E-04 0.203 31H4 1.13E+06 5.95E-05 0.053 Evolocumab 1.16E+05 2.66E-05 0.229 PCSK9 D 316P 1.39E+06 2.73E-04 0.196 31H4 1.14E+06 6.12E-05 0.054 Evolocumab 1.14E+05 2.50E-05 0.219 id="p-741" id="p-741"

[00741] Results The results showed that ah antibodies tested bound to PCSK9 variants equally, with any binding variation seen being within experimental error for such a strong affinity interaction. id="p-742" id="p-742"

[00742] Thus, the invention determines that an antibody with the following profile can specifically bind one or more variants of the invention:- 1. An antibody (eg, 316P or alirocumab) that comprises heavy chain variable domains derived from recombination of human IGHV3-23*04 and IGHJH2*01 (with a D), and light chain variable domains derived from recombination of human IGKV4-l*01 and IGKJ2*01; or 2. An antibody (eg, evolocumab) that comprises human heavy chain variable domains derived from recombination of human IGHV1-18*O1 and IGHJ6*01 (with a D segment) and light chain 214 18936261-1 variable domains derived from recombination of human IGLV2-14*01 and IGU2*01. id="p-743" id="p-743"

[00743] Thus, according to the invention, the skilled person is hereby provided with the required determination of specific binding of the ligand to PCSK9 variants. Applications of this determination are set out above in the context of methods and other aspects of the invention. id="p-744" id="p-744"

[00744] References: The references cited herein are incorporated by reference in their entirety. 1) Horton etal, Trends Biochem Sci. 2007 Feb;32(2):71-7. Epub 2007 Jan 9, Molecular biology of PCSK9: its role in LDL metabolism. 2) Seidah and Prat, J Mol Med (Berl). 2007 Jul;85(7):685-96. Epub 2007 Mar 10, The proprotein convertases are potential targets in the treatment of dyslipidemia. 3) Benjannet etal, J Biol Chern. 2004 Nov 19;279(47):48865-75. Epub 2004 Sep 9, NARC1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. 4) Lagace etal, J Clin Invest. 2006 Nov;116(ll):2995-3005, Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.

) Maxwell et al, Proc Natl Acad Sci USA. 2005 Feb 8; 102(6) :2069-74. Epub 2005 Jan 27, Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. 6) Park etat, J Biol Chern. 2004 Nov 26;279(48):50630-8. Epub 2004 Sep 22, Posttranscriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. 7) Rashid etal, Proc Natl Acad Sci USA. 2005 Apr 12;102(15):5374-9. Epub 2005 Apr 1, Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. 8) Kotowski et al, Am J Hum Genet. 2006 Mar;78(3):410-22. Epub 2006 Jan 20, A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. 9) Chen etal, J Am Coll Cardiol. 2005 May 17;45(10): 1611-9. Epub 2005 Apr 21, A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis. 215 18936261-1 ) Pisciotta etat, Atherosclerosis. 2006 Jun;186(2):433-40. Epub 2005 Sep 23, Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia. 11) Zhao et al, Am J Hum Genet. 2006 Sep;79(3):514-23. Epub 2006 Jul 18, Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. 12) Seidah et al, Proc Natl Acad Sci USA. 2003 Feb 4; 100(3) :928-33. Epub 2003 Jan 27, The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. 216 18936261-1 Table 4: 1000 GENOMES PROJECT HUMAN POPULATIONS Below is a summary of the ethnic populations as per the 1000 Genomes Project sequences.

Population European ancestry Utah residents (CEPH) with Northern and Western European ancestry (CEU) Toscani in Italia (TSI) British from England and Scotland (GBR) Finnish from Finland (FIN) Iberian populations in Spain (IBS) East Asian ancestry Han Chinese in Beijing, China (CHB) Japanese in Toyko, Japan (JPT) Han Chinese South (CHS) Chinese Dai in Xishuangbanna (CDX) Kinh in Ho Chi Minh City, Vietnam (KHV) Chinese in Denver, Colorado (CHD) (pilot 3 only) West African ancestry 217 18936261-1 Population Yoruba in Ibadan, Nigeria (YRI) Luhya in Webuye, Kenya (LWK) Gambian in Western Division, The Gambia (GWD) Malawian in Blantyre, Malawi (MAB) West African Population (TBD) Americas African Ancestry in Southwest US (ASW) African American in Jackson, MS (AJM) African Caribbean in Barbados (ACB) Mexican Ancestry in Los Angeles, CA (MXL) Puerto Rican in Puerto Rico (PUR) Colombian in Medellin, Colombia (CLM) Peruvian in Lima, Peru (PEL) South Asian ancestry Ahom in the State of Assam, India Kayadtha in Calcutta, India Reddy in Hyderabad, India Maratha in Bombay, India 218 18936261-1 Population Punjabi in Lahore, Pakistan 219 18936261-1 in LU u LU σ LU in s (/) in .«3 Ό Γ-- 03 7 fc Q fc Cc rt rij 01 ΟΊ X & 7 Fl C -J 1 Η Lu (5 J> LLi Χ· > ο > · 0 η. 0 u ι < Π U..I fl ι) 7J cL χ $ί £ Q f- Ο - ί θ < Μ uji £ d g1 <χ <, <- rt f Ο Q_ < Ε± -ί (5 CL Ή LU σι Q- χ 0 X LU 0 < 7 < cn X 0 £ £ δ 3 £ y y ί g i 0 & yg £ 8 P y g fc ί υ b q 0 '0 tn c. < CL < ? 3 s χ t; XT < ·η ci x Ln -- 0 Ltί ίΧ 1 q -' LU UJ Q 0 (X 0 5l g fc S b 7 u c 7 :-: t- q. -i -rt 0 > X rj 0 & 7 9 fc s k / S « fl fc Φ 0 ci. 0 Cl -0 n. i.J > -1 0 \ U in T l >· or '< H > ύ $ £ q < ΪΠ H UJ j=i Cq CT X. rn p 0 g Έ g fc > U fc g ώ & S’ * w* fc 03 -^ Q. > 11 fc 7 > s fc fc b ’X I ,U 0 rt m bn 01 i.rj - ~-J , W .55 L J ± p1 7 90 g S ί •j-: §? fe fc -% £S ό ϋ ‘4 cf- l. oc t. s 1. t? m ,j > > tn tai S t ^1 fc 7 s S’ o 3 fc : ; o Φ Η Γ *rt S J^· e s s' > 7 :η gl £ 1 2 Ό bo U in CX m Lu CL H I O c σ u I 2 ω 1 s <7 * § s? n 8 s £ £ s x: Φ φ Ρί *C 0 GH S > g go % g £ a £ σ J X L> £> Έ Su 0 § feo δ 0 ° « η >. rz L5 0 cc < < > ™ kFP 3 J CL l.} 0 > l: 0 u ‘0 r ’ bt» ® x ru r) on ,-» m uij '-^ । i 0 ft. 0 H > d·1 -7 LL '> c .C lj -j ci. -7. l· Un > 'L, rr: 0 Φ 0 S rt £ --. rt’ — _· C ... oj — 7, μ Λ Du d» W a C c s $ ' Cl c cv c> C_ 'f - η > L j ul kp -^- »-0. b- >1 00 ™ ·- S § § § k S g 4 0 fl 0 d *h h > x Th 0 O] U cu Lu ijj Ul (Ί P ύη 0 5Z < jr : fc : rt g j g ! 1 π '> to fc fl Cl U U > g H· <..' ,ή ri W > (IJ fc y ϋ « S ψ S’ S fc 7 fc H F rt i_ ; 7 7 I'' ! i $ 5 L ii! 5 fc. ή f p o cu LU u ;?1 hl hi Ό cq oj ΓΊ f-\ 0' I? 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CT ri th S3 Cj ’·. ι ID LJ TO fa fa th c) O th F< ?n th ri m th ri ri Γm 2 G 0G GAG GT T GT C T GGCAC 0 TACGTGGTGGTGT TGAAGGAGGAGAC CCaC CT Ct CGCAG T CAGAGCG· GACTGCCGGCCSTCTGCAGGCCCAGGCTGCCCGCCGGGGATACCTeACCAAGATCCTG^CATGTCTTCC AT tG C C TT C t r J C T GGC TT C C T GGT GAAGAT GAGT GgCoAC C TGC T □Ά—·' C T C τ T GAAgT T0C C 0 CATGT'?GAGTACA.TCGAGGAGG^.CTCCTCTGTCTTTGCCCAGagCStCCCg7'ggaaccggagCggarracccctt2ca jgg7accggfcgga,:gaa':accagccccocgacggaggcagcctggtggaggt,gTaTc:cc':agacaccagca:.acagag7gaccaccgggaa a;c£agggcaggg7ca~g£X^ccgacitcgagaatgtgcccgaggaggacgggacccgcT:.x^ ggcacccacct^cagggetggrcagcggccgggatgccggcgtggccaagggxgccapca-gcgcagcsTgcgcgigctcaactgccaaggE aagggMCgg^agcggcacccicazaggcctggagtttattcggaaaagccagaggtccagCGgiggggcoac:gg:gg:gcTgGgcccci ggcgggtggg’acagccgcgrccTcaacgccgcctgccagcgccLggcgagggcrggggLCgrgragrcaccgc-gccggcaacr.cc.gggac ga:gcc:gcc:c:ac:ccccagcc:cagctcccgaggtcatcacagttg^gccaccaatgcccaagaccagccgg7gaccc:ggggacntggg saccaactxggccgegtgTggacctctttgccccaggggaggacatcattggtgcciccagcgacrgca.gcaccjgc^tgt'gTcacagagtgg gaca-rcacaggccccgcccacgzggaggcattgcagccaigatgc^tGgccgagccggagxcaccxggccgagzxgaggcagagactg " K425SAATt3A3T 444:T 3X t; «% . . . a:cca ata a g cca a a gaT grca*· caaTgaggccTggttcccTgaggaccagcgggTa erga ccccca a ca:XCarGGGGCAGGTTGGCAGCTGTnTGCAGGACTGTATGGTCAGCACACTCGGGGCCTACACGGATGGCC - 3A acagccgtcgcccgctgcgccccagatgaggagctgctgagctgctccagtttctccaggagtgggaagcgg CGGGGCGAGCGCATGGAGGCCCAAGGGGGCAAGCrGGTCTGCCGGGCCCACAACGCTTTTGGGGGTGAGGG TG TCTA C G C CATTG C CA G GTG CTGCCTGCTA CCCCAG GCCAA CTG CAGCGTC C A C AC AG CTC C A C CA G CTG A G GCCAGCATGGGGACCC.GTGTCCACTGCCA.CCAACAGGGCCACGTCCTCACA.GGCTGCAGCTCCCACTGGGAG GTGGAGGACCTTGGCACCCACAAGCCGCCTGTGCTGAGGCCACGAGGTCAGCCCAACCAGTGCGTGGGCCAC agggaggccagcatccacgcttcctgctgccatgccccaggtctggaatgcaaagtcaaggagcatggaa QF75P 2-3 T3 2CG ES22G SA-3 to GGG TCCC G G C C CCT CAG GAGCAG GTGACCGTGGCCTGCGAGGAGG GCTGGACCCT G AlTGG CTGCAGTGlCCTCC CTGGGAC-TCCCACGTCCTGGGGGCCTACGCCGTAGACAACACGTG’-GTAGTCAGGAGCCGGGACGTC.AGCA EE 7 j G 3.AG tc GGG .:tacaggcagcaccagcgaagaggccgtgacagccgttgcca.tctgctgccggagccggcacctggcgcagg CCTCCCAG GAGCTCl AGTG AC kJ γΊ Ei rt U h L Η ω o 0 b $ O ri B 0 fl p | tn Ei i3 T <’ 8 η y f? rt ri o ri b C Pl e) E< m no h rt Τι Γ.ι O rt1 f ο Ο η □ " o f( b n ° rt 1 ' f 1 f 1 > l! 0 W ft ;* 1 Ο Λή 11 «Λ ι·λ b : Γι A' η rr. rt rt o p d <' rt rT b rt q 0 O 3 ri] in r< , ’’ $ ^-1 u fc o in tJ fc in fc ft y fc ο β b Η fc fc β fc ft ft d fc P· Ai CD fc p’ ft l.> β CD ! 7 f t β (-j η n r । H 0 0 0 o Ci (π n ?n f j 0 Qj ο ή ri 0 O rX ri D («J 7-1 0 n rt r Q rt rt p Q 0 rt 0 o Ei F< ra re ho bo ho re 0 Fi i i bo bo up ra bo ao hti co to bn to ra ra hu re ra ua ua 4 un ra CJ ho bn up ra bo ra eh ra bl) ra ho bo bq bo UQ ra btl fl bp bn o bn S’ w bo fl by fl hl) tie ho QO tip UQ tin ho tn fl by ra hp i i OJ ω by tin re uo fl bp be bp ho ho fl bp bn tip ra up tp to un bo bn up re bn t ra , hu ra , ho . ra re QO M ho uo Uli be B bn bn ttj tin 0 I— 0 0 (j i.O fi 0 O 0 0 Fi $ 0 Fi ire E< r) r ί Γ· Γ· ί I r i 0 Fi Ci 0 Fi Fi Fi O Fl 0 Fi tn S8 re bQ Up bq o ra up ra ω fan to tin fl bo ra to ba fl bn Q° tn uq fl bp cu bo ω o bo ra S’ ao ra UJ fl un ra bo ho tin bo bn ra bn „ gg I 88 S’ 8 S. C Cm bo TO bO up cn be re to UQ bn hi) ho UG un bn cu ho UO un an bn re bn bo bo ITI UH re ho bp ra ra ra ra bo ., o ί: up ra by by no bq .¾0 bo ra bn bo bO ra a »iu UO re JAI cm bO bn bo re re o bo bo o' uu on ho QO tin tin tip Sa x S2 bo W bp ti ΰ bp ω ft Uq fl Q P3 bp fl ra ra bp fl ti to bo ra bo bn J ra ί bo ra bo bo bn ra ra ho bn UO Uh xi 02 ho Uo bn bo i ► ra bn ra §8 bq fl bn in cm re CO ire era δ? on UO fl bo < 0 0 re bo 5 u bn ho to to OLI bo m bn tn ho fl tin un ra bn bo bo ra bo un re ra LXi < 0 0 < 0 < 0 0 0 (D 0 h f.o 0 0 cu 0 0 0 7 0 ^.-r r.j 0 < 0 0 0 A J 0 < b 0 < 3 0 0 0 0 0 0 0 0 F < Cj 0 0 rei 0 0 CU TO.» cu l_J < F0 f j 0 r^.i cu 0 Lj 0 < 0 0 t J I. J 19 < 0 OJ 0 CU 0 0 0 CU 0 *wJ tU 0 0 J < < 0 0 CU H < < 0' 0 F| < <1, CU 01 Eh 0 <1 0 0 0 *~j 0 0 0 '.J < F 0 A u 0 0 ύ < 1— CD 0 F- l J < CU 3 0 0 h: y 0 0 < ό tu 0 0 3 0 0 ’a; 0 0 h H 0 0 cu H 0 0 0 < 0 H0 0 O 3 $ 0 0 Lj < t I O 0 0 0 < r ί 0 |= 0 OJ < 0 0 0 0 0 ο 0 < 0 b (_j 0 0 0 £ 0 < 0 H H 0 < 1— < L J o 0 0 0 0 0 0 < Q 1— 0 0 0 0 9 did jie: re 02 re 01 $ 0 U 0 < C J < 0 0 0 < tU 0 0 < i, J < 0 0 0 0 1= L .J 3 Cr I 0 1. t ra CTCAG CCCAC 0 A ) cu I rJ 0 r 0 1— 0 h< 0 CU 0 G . p j cT cu 0 < 0 < < (U < 0 ( 1 0 cu -L 0 t-L1 < t.J 1 J 0 0 ) 0 <1 0 l·· 0 1., J 1- 1— 1 1 f,’J 0 1 - ( 1 ί. 1 Γ j ο ’(Λ Ο Ε Π3 X 0J L_ Ο to to «J co CM I CO ID Φ <Λ Φ Φ to E SNPs rs61750837 j rs61752504 σ> R in in 2 LD 1— rs61752504 m co o lo rτ—1 LD in X— TS1064090 rsl055799 rsl064091 rsl064091 rsl064090 rs56069819 rs56069819 rs56069819 6186909SSJ rs56069819 rs56069819 cn co Ch kO o ID Ln in u. Cumulative allele :freguency ____ 0.0983 _______ CO o o o l0.0046______________ 0.0009 ______ SOOO’O in o o o o SOOO'O 0.114 VH3-23 haplotype a (=VH3-23*04) "O Φ ·'—) =5 in TOTAL: Table 7: Exemplary anti-PCSK9 antibodies and/or antibody fragments useful in any and all aspects of the invention SEQ ID NOs comprising an anti-PCSK9 monoclonal antibody or fragment thereof which are incorporated by reference from the patent application publication numbers recited in the abutting column. Patent or patent Publication which is incorporated by reference in its entirety, and specifically with respect to the SEQ ID Nos. comprising an anti-PCSK9 monoclonal antibody or fragment thereof cited in the abutting column. Light chain complementary determining regions (CDRL) SEQ ID NO: 5, 7, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, 46, 270, 271, 272, 273, 275, 277, 286, 287, 288, 297, 299, 301, 405, 407, 409, 411, 413, 415, 417, 421, 425, 429, 433, 437, 441, 445, 449, 453, 457, 461, 465, 469, 473, 477, 481, 485; Heavy chain complementary determining regions (CDRH) SEQ ID NO: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 61, 62, 64, 65, 67, 69, 71, 72, 74, 76, 77, 78, 79, 80, 81, 83, 85, 87, 89, 91, 278, 289, 290, 291, 292, 298, 300, 302, 401, 404, 406, 408, 410, 412, 414, 416, 419, 423, 427, 431, 435, 439, 443, 447, 451, 455, 459, 463, 467, 471, 475, 479, 483; US20120020975 Al CDRL SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, 46, 405, 407, 409, 411, 413, 415, 417, 465; CDRH SEQ ID NO: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 62, 64, 65, 67, 69, 71, 72, 74, 76, 77, 78, 79, 80, 81, 83, 85, 87, 89, 91, 404, 406, 408, 410, 412, 414, 416, 463; US20120027765A1 243 SEQ ID NOs comprising an anti-PCSK9 monoclonal antibody or fragment thereof which are incorporated by reference from the patent application publication numbers recited in the abutting column. Patent or patent Publication which is incorporated by reference in its entirety, and specifically with respect to the SEQ ID Nos. comprising an anti-PCSK9 monoclonal antibody or fragment thereof cited in the abutting column. CDRL SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, 46, 405, 407, 409, 411, 413, 415, 417, 465; CDRH SEQ ID NO: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 62, 64, 65, 67, 69, 71, 72, 74, 76, 77, 78, 79, 80, 81, 83, 85, 87, 89, 91, 404, 406, 408, 410, 412, 414, 416, 463; US8168762B2 CDRL SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, 46, 222, 229, 238, 405, 407, 409, 411, 413, 415, 417; CDRH SEQ ID NO: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 62, 64, 65, 67, 69, 71, 72, 74, 76, 77, 78, 79, 80, 81, 83, 85, 87, 89, 91, 247, 256, 265, 404, 406, 408, 410, 412, 414, 416; US20120020976A1 CDRL SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, 46, 405, 407, 409, 411, 413, 415, 417, 461, 465, 485; CDRH SEQ ID NO: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 62, 64, 65, 67, 69, 71, 72, 74, 76, 77, 78, 79, 80, 81, 83, 85, 87, 89, 91, 404, 406, 408, 410, 412, 414, 416, 459, 463, 483; US20130085265A1 244 SEQ ID NOs comprising an anti-PCSK9 monoclonal antibody or fragment thereof which are incorporated by reference from the patent application publication numbers recited in the abutting column. Patent or patent Publication which is incorporated by reference in its entirety, and specifically with respect to the SEQ ID Nos. comprising an anti-PCSK9 monoclonal antibody or fragment thereof cited in the abutting column. CDRL SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, 46, 405, 407, 409, 411, 413, 415, 417, 461, 465, 485; CDRH SEQ ID NO: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 62, 64, 65, 67, 69, 71, 72, 74, 76, 77, 78, 79, 80, 81, 83, 85, 87, 89, 91, 404, 406, 408, 410, 412, 414, 416, 459, 463, 483; US20130079501A1 CDRL SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, 46, 405, 407, 409, 411, 413, 415, 417, 158, 162, 395, 473, 477; CDRH SEQ ID NO: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 62, 64, 65, 67, 69, 71, 72, 74, 76, 77, 78, 79, 80, 81, 83, 85, 87, 89, 91, 404, 406, 408, 410, 412, 414, 416, 180, 175, 308, 368, 471, 475; US20120213797A1 CDRL SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, 46, 405, 407, 409, 411, 413, 415, 417; CDRH SEQ ID NO: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 62, 64, 65, 67, 69, 71, 72, 74, 76, 77, 78, 79, 80, 81, 83, 85, 87, 89, 91, 404, 406, 408, 410, 412, 414, 416; US20120251544A1 245 SEQ ID NOs comprising an anti-PCSK9 monoclonal antibody or fragment thereof which are incorporated by reference from the patent application publication numbers recited in the abutting column. Patent or patent Publication which is incorporated by reference in its entirety, and specifically with respect to the SEQ ID Nos. comprising an anti-PCSK9 monoclonal antibody or fragment thereof cited in the abutting column. CDRL SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, 46, 405, 407, 409, 411, 413, 415, 417, 461, 465, 485; CDRH SEQ ID NO: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 62, 64, 65, 67, 69, 71, 72, 74, 76, 77, 78, 79, 80, 81, 83, 85, 87, 89, 91, 404, 406, 408, 410, 412, 414, 416, 459, 463, 483; US20130052201A1 CDRL SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, 46, 405, 407, 409, 411, 413, 415, 417, 461, 465, 485; CDRH SEQ ID NO: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 62, 64, 65, 67, 69, 71, 72, 74, 76, 77, 78, 79, 80, 81, 83, 85, 87, 89, 91, 404, 406, 408, 410, 412, 414, 416, 459, 463, 483; US20130058944A1 CDRL SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, 46, 405, 407, 409, 411, 413, 415, 417; CDRH SEQ ID NO: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 62, 64, 65, 67, 69, 71, 72, 74, 76, 77, 78, 79, 80, 81, 83, 85, 87, 89, 91, 404, 406, 408, 410, 412, 414, 416; US20130079502A1 246 SEQ ID NOs comprising an anti-PCSK9 monoclonal antibody or fragment thereof which are incorporated by reference from the patent application publication numbers recited in the abutting column. Patent or patent Publication which is incorporated by reference in its entirety, and specifically with respect to the SEQ ID Nos. comprising an anti-PCSK9 monoclonal antibody or fragment thereof cited in the abutting column. CDRL SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, 46, 405, 407, 409, 411, 413, 415, 417; CDRH SEQ ID NO: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 62, 64, 65, 67, 69, 71, 72, 74, 76, 77, 78, 79, 80, 81, 83, 85, 87, 89, 91, 404, 406, 408, 410, 412, 414, 416; US20130245235A1 247 σι c ο § c ra σι £ I (Λ C Ο ra σ ο. ο ο. ra Ε Cum Freq9 0.296 0.704 0.283 Ε 'V ΐ Ε "V Ο « Φ Ο φ r t ι = 2 0.096 (0.496) 0.504 (0.904) 0.104 (0.462) Het Freq6 0.400 0.400 0.358 i No. Individs5 m LO 366 Human Populations4 A (European ancestry) A (European ancestry A (European Variant Nucleotide Position 14:106208086 (forward strand) 14:106208086 (forward strand) 14:106208082 (forward strand) Nucleotide Variation2 (NCBI dbSNP reference number)3 GAT GAG (rsl045853) CTG Amino Acid Position & Variation 204D (CH3 variation)___1 204E (CH3 variation) 206L Example Human Allele1 IGHGl*01 IGHG1*O3 IGHGl*01 Human Gene Segment Type IGHG1 ό CO o o 0.292 0.997 co ro lo 896) .540 .876) rsj Ί---1 rn cr cr ό o o ci ό 358 336 .336 .007 o o o o c ra Φ f cn 8 c ra < CL 2 ZJ Hi ω Φ o c ra co co < 106208082 /vard strand) 106110914 Λ/a rd strand) 106110914 ward strand) :106110904 ward strand) 14: ,p 14: ,p 14: £ 14: ,p __ ATG ofc in rd r—1 rd co t—< i—1 2 ς CCC ACC ip cr lo rd co i—1 t—i Uri j— ____j AAC (CH3 variation) 206M (CH3 variation) 72P (CHI variation) \ 72T (CHI variation) 75N (CHI variation) IGHG1*O3 Ί—1 o * rd ID X O 1—1 IGHG2*02 IGHG2*01 IGHG2 0.004 i—1 O 0.289 0.539 (0.881) 0.118 (0.46) 0.007 0.342 0.342 < co QQ 14:106110904 (forward strand) 14:10611013 (forward strand) _ ________-_____ 14:10611013 (forward strand) AGC (rs201590297) GTG ATG (rs8009156) 75S (CHI variation) ____i 76F (CHI variation) 76L (CHI variation) 161V (CH2 variation) 161M IGHG2*04 ι—1 o * r\J ID X ID ι IGHG2*04 IGHG2*01 IGHG2*02 C\J ch la i_n CD o o 00 Ln o o o ο ό co οι r\i cr> σι CD CD CD \r co ch ch ο ο ό o co b? NG? o o o o m Ln ο o o ό o ch rm Ch o τ-i O o o Ch rm Ch o θ o o O Q U Q variation. 14:106109752 (forward strand) 14:106109752 (forward strand) 1 Table Footnotes: 1. IMGT notation (ww.imgt.org); refer to figures for other alleles comprising this 2. SNP Underlined in Codon. 3. NCBI dbSNP Build 138 released on Apr 25, 2013. 4. Human population used for representative variant frequency analysis. ODD__ TCC (rs4983499) (CH2 variation) 257A (CH3 variation) 257S (CH3 variation) IGHG2*01 1 IGHG2*06 LT) Populations Φ I φ Ο ο φ C ο ο G Φ CD 8 ra Φ φ ra CD Φ ra ra φ ra ΐο ω ZJ Ο CD >· Μ Ο ε Φ Φ ra cn Φ ra φ 'θ’ φ C ο CD ro 'ι_ ra φ L0 ra cn Φ ο £Σ φ ο ra ο c φ σι ra ε φ υ cn Φ ra ο Φ > ra ο & c φ cn σ ο CD Ν Ο Ε ο ω φ ra υη ra φ η. ο ra ra ιυ ο ω ra ra ο 4—J ra ο £Ζ Φ ra ZJ Ε cn σ Ο σ ΝΙ kO m jn Φ cn ra η 13 ra ra Ο GO Φ cn £ σϊ φ φ CD σ c 'in <η Φ Ε ο C φ ID ra ra φ CL ο LU ω ra φ cn ra ε φ 4-J 13 ιη cn σ ο S Ν 2 ω φ ο C φ CD Ο ra Q LP Ο ο. ω LU LH LD CL cn UJ cn σ ο ΝΙ <υ Φ Φ ra u_ φ ο C co ο kO ra ε cn σ ο σ> & ο ε ο ο 4-J ra φ £ c φ Ο C φ CD ra Ε ra ρ ra ο φ φ 75 ra ε ra Table 9: FURTHER SEQUENCES SE Q ID NO Human Allele Nucleotide/Amino Acid Sequence HEAVY CHAIN ALLELES__ 41 IGHG1*O1 (CHl+Hinge+C H2+CH3+CHS) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccc aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactgg tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg ctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtgg cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtaaa 42 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSS GLYSLSSVVTVPSSSLGTQIYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APELLGG PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYN STYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK D=position 204 L= position 206 43 IGHG2*01 (CHl+Hinge+C H2+CH3+CHS) gcctccaccaagggcccatcggtcttccccctggcgccctgctccaggagcacctccgag agcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg tggaactcaggcgctctgaccagcggcgtgcacaccttcccagctgtcctacagtcctca ggactctactccctcagcagcgtggtgaccgtgccctccagcaacttcggcacccagacc tacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagacagttgagcgc aaatgttgtgtcgagtgcccaccgtgcccagcaccacctgtggcaggaccgtcagtcttc ctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacgtgc gtggtggtggacgtgagccacgaagaccccgaggtccagttcaactggtacgtggacggc 18936261-1 253 gtggaggtgcataatgccaagacaaagccacgggaggagcagttcaacagcacgttccgt gtggtcagcgtcctcaccgttgtgcaccaggactggctgaacggcaaggagtacaagtgc aaggtctccaacaaaggcctcccagcccccatcgagaaaaccatctccaaaaccaaaggg cagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgg gagagcaatgggcagccggagaacaactacaagaccacacctcccatgctggactccgac ggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaac gtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctc tccctgtctccgggtaaa 44 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSS GLYSLSSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAP PVAGPSVF LFPPKPKDTLMISRTPEVTCWVDVSHEDPEVQFNWYVDGVEVHNAKTKPR EEQFNSTFR WSVLTWHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPP SREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVD KSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK P=position 72 N=position 75 F=position 76 V=position 161 A=position 257 45 i IGHV1-18*O1 caggttcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtc tcctgcaaggcttctggttacacctttaccagctatggtatcagctgggtgcgacaggcc cctggacaagggcttgagtggatgggatggatcagcgcttacaatggtaacacaaactat gcacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagcctac atggagctgaggagcctgagatctgacgacacggccgtgtattactgtgcgagaga 46 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAP GQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDD TAVYYCAR 47 IGHV1-46*O1 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtt tcctgcaaggcatctggatacaccttcaccagctactatatgcactgggtgcgacaggcc cctggacaagggcttgagtggatgggaataatcaaccctagtggtggtagcacaagctac gcacagaagttccagggcagagtcaccatgaccagggacacgtccacgagcacagtctac atggagctgagcagcctgagatctgaggacacggccgtgtattactgtgcgagaga 48 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAP GQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTA VYYCAR LIGH T CHAIN ALLELES 18936261-1 254 49 IGKC*01 cgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatct ggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacag tggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggac agcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgag aaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaag agcttcaacaggggagagtgt 50 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC V=position 84 Opposition 87 51 IGLC2*01 ggtcagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaa gccaacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtg gcttggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaa caaagcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaag tcccacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtg gcccctacagaatgttca 52 GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAG Vt 111PSK QSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 53 Xi" IGKV4-l*01 atggtgttgcagacccaggtcttcatttctctgttgctctggatctctggtgcctacggg gacatcgtgatgacccagtctccagactccctggctgtgtctctgggcgagagggccacc atcaactgcaagtccagccagagtgttttatacagctccaacaataagaactacttagct tggtaccagcagaaaccaggacagcctcctaagctgctcatttactgggcatctacccgg gaatccggggtccctgaccgattcagtggcagcgggtctgggacagatttcactctcacc atcagcagcctgcaggctgaagatgtggcagtttattactgtcagcaatattatagtact cctcc _____i DIVMTQSPDSUWSLGERATINCKSSQSVLYSSNNKNYLA WYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLBSSLQAEDVAVY YCQQYYST P 18936261 1 255 55 IGKV1-13*O2 atgg acatg agggtccccgctcagctcctgggg cttctg ctgctctggctcccagca ggt gccagatgtgccatccagttgacccagtctccatcctccctgtctgcatctgtaggagac agagtcaccatcacttgccgggcaagtcagggcattagcagtgctttagcctggtatcag cagaaaccagggaaagctcctaagctcctgatctatgatgcctccagtttggaaagtggg gtcccatcaaggttcagcggcagtggatctgggacagatttcactctcaccatcagcagc ctgcagcctgaagattttgcaacttattactgtcaacagtttaatagttaccctcagtgc cagatgtgccatccagttgacccagtctccatcctccctgtctgcatctgtaggagacag agtcaccatcacttgccgggcaagtcagggcattagcagtgctttagcctggtatcagca gaaaccagggaaagctcctaagctcctgatctatgatgcctccagtttggaaagtggggt cccatcaaggttcagcggcagtggatctgggacagatttcactctcaccatcagcagcct gcagcctgaagattttgcaacttattactgtcaacagtttaatagttaccctca 57 IGKJ2*01 tgtacacttttggccaggggaccaagctggagatcaaac 58 YTFGQGTKLEIK 59 IGU2*01 tgtggtattcggcggagggaccaagctgaccgtcctag 60 WFGGGTKLTVL 61 An IGHGl*01 Heavy Chain Constant Region ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNST YRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 62 An IGKC*01 Kappa Light Chain Constant Region RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC 63 An IGHG2*01 Heavy Chain Constant Region ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVE CPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVQFNWY VDGVEVHNAKTKPREEQFNSTFRWSVLTWHQDWLNGKEYKCKVSNKGLP APIEfCTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK 18936261-1 256 64 An IGLC2*01 Lambda Light Chain Constant Region QPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVE 1 1 1PSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 65 An IGHG2*01 Heavy Chain Constant Region ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVE CPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVQFNWY VDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLP SSIEK7ISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK 66 An IGKC*01 Kappa Light Chain Constant Region RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC 18936261-1 257 STATEMENTS OF INVENTION: A. A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 or a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (i) an IGHGl*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising an Asp corresponding to position 204 of SEQ ID NO: 42 and Leu corresponding to position 206 of SEQ ID NO: 42 and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1.

B. The method of statement A, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42.

C. The method of statement A, wherein said antibody or antibody fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (i) an IGHGl*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation in SEQ ID NO: 1.

D. The method of any preceding statement, wherein the antibody or fragment comprises an IGHGl*01 human heavy chain constant region.

E. The method of any preceding statement, comprising, before said administering, selecting a human comprising said nucleotide sequence of (ii), wherein the human is the human of statement A.

F. The method of any preceding statement, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain 18936261-1 258 comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30.

G. The method of any preceding statement, comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the human.

H. The method of statement G, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1.

I. The method of statement H, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and 18936261-1 259 detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1.

J. The method of statement H, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format.

K. The method of any preceding statement, wherein said human is or has been further determined to be substantially resistant to statin treatment.

L. The method of any preceding statement, wherein said human is receiving or has received statin treatment or has reduced responsiveness to statin treatment.

M. The method of any preceding statement, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with said statin treatment.

N. The method of statement H, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 0. The method of any preceding statement, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474Vor E670G in SEQ ID NO: 1.

P. The method of any preceding statement, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication (e.g. claudication associated with elevated cholesterol) and high blood pressure.

Q. The method of any preceding statement, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication (e.g. claudication associated with elevated cholesterol) and high blood pressure. 18936261-1 260 R. The method of any preceding statement, wherein the nucleotide sequence is SEQ ID NO: 29 or 30.

S. The method of any preceding statement, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation.

Further Statements of Invention are as follows: 1. An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO: 1 and wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an amino acid selected from the group consisting of: an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (i) an IGHGl*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising a human gamma-1 heavy chain constant region that comprises said amino acid and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation in SEQ ID NO: 1. 2. The antibody or antibody fragment of statement 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42. 3. The antibody or antibody fragment of statement 1, wherein said antibody or antibody fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (i) an IGHGl*01 human heavy chain constant region gene segment and (ii) a nucleotide 18936261-1 261 sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation in SEQ ID NO: 1. 4. The antibody or antibody fragment of any preceding statement, wherein the antibody or fragment comprises an IGHGl*01 human heavy chain constant region.

. The antibody or antibody fragment of any preceding statement, wherein the method comprises, before administration of said antibody or fragment, selecting a human comprising said nucleotide sequence of (ii), wherein the human is the human of statement 1. 6. The antibody or antibody fragment of any preceding statement, wherein (i) the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30 or (ii) wherein the method comprises the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the human. 7. The antibody or antibody fragment of statement 6, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 8. The antibody or antibody fragment of statement 7, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or 18936261-1 262 b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the C-terminal domain comprising the mutation 1474V or E670G in SEQ ID NO: l.The antibody or antibody fragment of statement 7, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 9. The antibody or antibody fragment of any preceding statement, wherein the antibody or antibody fragment is for administration to a human that is is or has been further determined to be substantially resistant to statin treatment.

. The antibody or antibody fragment of any preceding statement, wherein the antibody or antibody fragment is for administration to a human that is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 11. The antibody or antibody fragment of any preceding statement, wherein said antibody or antibody fragment is for administration to the human separately or simultaneously with said statin treatment. 12. The antibody or antibody fragment of any one of statements 7-9, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 13. The antibody or antibody fragment of any preceding statement, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474V or E670G, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28, or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474Vor E670G in SEQ ID NO: 1. 18936261-1 263 Attorney Docket No: 069496-080093-US Table 1: Human PCSK9 variants distributed over several human ethnic populations & having a total human genotype frequency in the range of 1 to about 15% (a) Amino acid variability, population distributions and frequencies 0.64815 . . Cum Freq6 0.0855 0.0729 0.4506 (0.8457) Hom Freq4 (Het + Hom freq5) 0.009 (0.162) 0.0081 (0.1377) 0.3951 Het Freq3 0.153 0.1296 14 No. Unique Pops2 rxi ZT 939 No. Individs1 180 153 m " ri tn (J Η co fc Σ T ri- ri υ £ 3 | g ξ fc Human Populations Z cn £ £ $ § % ξ 5 p 5 C? ο E o > ι-ί ω ω j < Η X - U- CD CD -i- 5 2 Σ 3' 3 tn cn < H 670E Amino Acid Position & Variation 670G L .___ X 619Q 619P 4741 474V i ____ X 443A 443T \ 425N cn in rN ri 53A 53V 46R 46L Form a Varian t Form M- u Attorney Docket No: 069496-080093-US f g 0 0 0.0292 0.0221 0.0149 0.0068 0.0045 1 0 0 0 0.0032 acid being st all other posit 0.009 (0.0324) (0.0441) (0.0225) (0.0135) (0.009) (0.0081) (0.0063) the variant amino 2; amino acids at 0.0234 0.0441 0.0225 0.0135 600’0 Τ800Ό 0.0063 at that position in form a, in the first row of the tabk cn m CO tn 49 2915 10 cn e amino acid being shown fc 2 2 gu E 1 * £ § => cd U CD H u s S Z tn 2 H " <£ U 1—1 LWK,ASW,YRI, CLM 1—1 Cd ί < § LWK,ASW,YRI PUR,TSI,FIN,CE U CHS,ASW,JPT, PUR,CHB is different from th form a amino acid — X X — X he variant form ie table and the X X X X cid for tl n" of th X X amino ai Zariatio X hat the : tion & \ X X es: icates t d Posit X )otnot jox indi no Acii L. Ο. E Φ £ ra σ Table F< x in a t in Amii of each variant form are identical to those found in form a.

Attorney Docket No: 069496-080093-US position . (b) Nucleotide Sequence Variations of Selected Alleles < \ Nucleotide Position1 1:55529187 Non-Synonymous Nucleotide Variation2 CD < 1:55527222 O < 1:55524237 ID 1:55523855 ______1 < < 1:55523802 ID O 1:55505668 H CD 1:55505647 H Allele a Variant Allele Attorney Docket No: 069496-080093-US Variant ID3 rs505151 ing Amino Acid Variation 670G X X X rs28362277 619P X rs562556 474V X X X X X rs28362263 443T X X Ί----1 co CM rsl CO 00 rsj in u. v C O a ιλ u u O o 4255 X rs!1583680 53V X X τ—1 OS Ln 1—J Ί---1 ΙΛ u. 46L X u- u L. a E (D £ m* σ CD E 0 c CD O rn 0 rsl 1— CD JO E CD Cl CD in rn 5 (D g in ra jz CD CD i_n 1— 0) £ E CD B c LU ro X- u CD TO cz JO E • =3 c £Z o CD ‘4—1 4-) ra ra '1— c ra > Έ 0 TO 0 0 O CD τH U CD Σ3 c E 0 in in ZJ O O E E 0 1— c: JZ O u c c 1 ro E cz 0 c 0 Φ jz c 0 4—* 2 in CD ra .in tn '1— c Cl 0 E 4—) O 'in u O CD Cl CD "ra "ra 4-) fe c JO ra *S_ E ra Z3 > C ra CD 4-) ra JZ 4-) E 0 in O in Φ E 4-» 0 ra • · j= TO in B u c in 0 X c c 2 g 0 ra LL ra 4-J c CD JO 0 z: 2x T—| LT) assembly: GRCh37 (GCA_000001405.13); Attorney Docket No: 069496-080093-US Attorney Docket No: 069496-080093-US Μ 8 c 0) Ai cu 3 ju «5 Hi 1'1 Lv1 01 /j X Ul Uu i Ί id n N rx Cl: id Ui OO (ϋ (Ό 4-J CID V ώ '4..c <2 CT k . ω _l O Li I iD Q (D (0 ϋΠ E E co S 'do ¢0 > iX F~ n, U on X < on <ΰ O1 (Γ) X LU σ .. .1 I_1J O' CO hi! ‘U ‘X n;.

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CJ CJ CJ 09 cj ijj 'G J J -r ¢9 qj "j ID i— CD QJ CD CD CD 09 ro u u u ra QJ QJ CD QJ QJ CD 09 09 CD CD 1= CD U QJ Κω CD < CD CD CD U £ QJ CD CD CD CD 09 CD CD CD < u < (J CJ CD ra Courier = nucleotide sequence encoding pro peptide (nucleotides 91-456) lower case = nucleotide sequence encoding catalytic domain (nucleotides 457-1346) Attorney Docket No: 069496-080093-US tn 14. The antibody or antibody fragment of any preceding statement, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication mediated by PCSK9 and high blood pressure.

. The antibody or antibody fragment of any preceding statement, wherein said antibody or antibody fragment is for treating or reducing the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication mediated by PCSK9 and high blood pressure. 16. The antibody or antibody fragment of any preceding statement, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 17. The antibody or antibody fragment of any preceding statement, wherein said antibody or antibody fragment is for administration by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. 18. The antibody or antibody fragment of any preceding statement, wherein the antibody is a human antibody. 18936261-1 264 sequence listing as filed P17140.IES SEQUENCE LISTING <110> CLUBE, JASPER R. <120> HUMAN TARGETS III <130> 069496/080093 <140> <141> <160> 78 <170> Patentin version 3.5 <210> 1 <211> 692 <212> PRT <213> Homo sapiens <400> 1 Met Gly 1 Thr Val Ser 5 Ser Arg Arg ser Trp 10 T rp Pro Leu Pro Leu 15 Leu Leu Leu Leu Leu 20 Leu Leu Leu Gly Pro 25 Al a Gly Ala Arg Al a 30 Gl n Glu Asp Glu Asp 35 Gly Asp Tyr Glu Glu 40 Leu val Leu Ala Leu 45 Arg Ser Glu Glu Asp 50 Gly Leu Ala Glu Al a 55 Pro Glu Hi s Gly Thr 60 Thr Ala Thr Phe Hi s 65 Arg cys Al a Lys Asp 70 Pro Trp Arg Leu Pro 75 Gly Thr Tyr val Val 80 Val Leu Lys Glu Glu 85 Thr Hi s Leu Ser Gin 90 Ser Glu Arg Thr Ala 95 Arg Arg Leu Gin Al a 100 Gin Al a Al a Arg Arg 105 Gly Tyr Leu Thr Lys 110 lie Leu His val Phe 115 Hi s Gly Leu Leu pro 120 Gly Phe Leu val Lys 125 Met Ser Gly Asp Leu 130 Leu Glu Leu Al a Leu 135 Lys Leu Pro Hi s Val 140 Asp Tyr lie Gl u Glu 145 Asp ser Ser Val Phe 150 Al a Gin Ser lie Pro 155 Trp Asn Leu Glu Arg 160 lie Thr Pro Pro Arg 165 Tyr Arg Al a Asp Glu 170 Tyr Gl n Pro Pro Asp 175 Gly Gly Ser Leu val 180 Glu Val Tyr Leu Leu 185 Asp Thr Ser He Gin 190 Ser Asp Page 1 P17140.IES sequence listing as filed Hi s Arg Glu 195 lie Glu Gly Arg val 200 Met val Thr Asp Phe 205 Glu Asn val Pro Glu Glu 210 Asp Gly Thr Arg Phe 215 Hi s Arg Gin Ala 220 Ser Lys cys Asp Ser His Gly 225 Thr Hi s Leu 230 Ala Gly Val val Ser Gly 235 Arg Asp Al a Gly 240 val Ala Lys Gly Al a 245 Ser Met Arg Ser Leu 250 Arg val Leu Asn cys 255 G1 n Gly Lys Gly Thr 260 Val ser Gly Thr Leu 265 lie Gly Leu Glu Phe 270 lie Arg Lys Ser G1 n 275 Leu Val Gin Pro val 280 Gly Pro Leu val val 285 Leu Leu Pro Leu Ala Gly 290 Gly Tyr Ser Arg Val 295 Leu Asn Ala Ala 300 Cys G1 n Arg Leu Ala Arg Ala 305 Gly val val 310 Leu Val Thr Ala Ala Gly 315 Asn Phe Arg Asp 320 Asp Ala cys Leu Tyr 325 Ser Pro Ala Ser Ala 330 Pro Glu Val lie Thr 335 Val Gly Ala Thr Asn 340 Ala Gin Asp Gin Pro 345 Val Thr Leu Gly Thr 350 Leu Gly Thr Asn Phe 355 Gly Arg cys val Asp 360 Leu Phe Ala Pro Gly 365 Glu Asp He lie Gly Ala 370 Ser Ser Asp Cys Ser 375 Thr cys Phe val 380 ser Gin Ser Gly Thr ser Gin 385 Ala Ala Ala 390 His Val Ala Gly lie Ala 395 Ala Met Met Leu 400 Ser Ala Glu Pro Glu 405 Leu Thr Leu Al a Glu 410 Leu Arg Gin Arg Leu 415 He His Phe Ser Ala 420 Lys Asp val lie Asn 425 Glu Ala Trp Phe Pro 430 Glu Asp Gin Arg val 435 Leu Thr Pro Asn Leu 440 Val Ala Ala Leu Pro 445 Pro ser Thr His Gly Ala Gly Trp Gin Leu Phe cys Arg Thr val Trp Ser Ala Hi s 450 455 460 Page 2 P17140.IES sequence listing as filed ser Gly Pro Thr Arg 465 Met Ala 470 Thr Al a IIe Ala Arg Cys 475 Al a Pro ASp 480 Glu Glu Leu Leu Ser 485 cys Ser ser Phe ser Arg Ser Gly 490 Lys Arg 495 Arg Gly Glu Arg Met Glu 500 Ala Gin Gly Gly Lys Leu Val cys 505 Arg 510 Ala Hi s Asn Ala Phe Gly Gly 515 Glu Gly val 520 Tyr Ala lie Ala Arg 525 cys cys Leu Leu Pro Gin Ala Asn 530 cys Ser 535 val His Thr Ala Pro Pro 540 Ala Glu Ala Ser Met Gly Thr Arg 545 Val His 550 Cys ms Gin Gin Gly His 555 Val Leu Thr 560 Gly Cys Ser ser His 565 Trp Glu Val Glu Asp Leu Gly Thr 570 His Lys 575 Pro Pro Val Leu Arg Pro 580 Arg Gly Gin Pro Asn Gin Cys Val 585 Gly 590 Hi s Arg Glu Ala Ser lie His 595 Ala Ser Cys 600 cys His Ala Pro Gly 605 Leu Glu cys Lys Val Lys Glu His 610 Gly lie 615 Pro Ala Pro Gin Glu Gin 620 val Thr val Ala Cys Glu Glu Gly 625 Trp Thr 630 Leu Thr Gly cys Ser Ala 635 Leu Pro Gly 640 Thr ser His val Leu 645 Gly Ala Tyr Ala Val Asp Asn Thr 650 Cys val 655 val Arg Ser Arg Asp Val 660 Ser Thr Thr Gly Ser Thr Ser Glu 665 Glu 670 Al a val Thr Ala val Ala lie 675 cys Cys Arg 680 Ser Arg His Leu Ala 685 Gin Al a Ser Gin Glu Leu Gin 690 <210> 2 <211> 662 <212> PRT <213> Homo sapiens <400> 2 Gin Glu Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Page 3 Leu Ala Leu Arg P17140.IES 1 5 - sequence listing as filed Ser Glu Glu Asp Gly Leu Ala Glu 20 Ala Pro Glu His Gly Thr Thr Ala 25 30 Thr Phe His Arg cys Ala Lys Asp 35 40 Pro Trp Arg Leu Pro Gly Thr Tyr 45 val val val Leu Lys Glu Glu Thr 55 His Leu Ser Gin ser Glu Arg Thr 60 Ala Arg Arg Leu Gin Ala Gin Ala 65 70 Ala Arg Arg Gly Tyr Leu Thr Lys 75 80 lie Leu His Val Phe His Gly Leu 85 Leu Pro Gly Phe Leu val Lys Met 95 Ser Gly Asp Leu Leu Glu Leu Ala 100 Leu Lys Leu Pro His val Asp Tyr 105 110 lie Glu Glu Asp ser ser Val Phe 115 120 Ala Gin ser lie Pro Trp Asn Leu 125 Glu Arg lie Thr Pro Pro Arg Tyr 130 135 Arg Ala Asp Glu Tyr Gin Pro Pro 140 Asp Gly Gly Ser Leu Val Glu val 145 150 Tyr Leu Leu Asp Thr ser lie Gin 155 160 Ser Asp His Arg Glu lie Glu Gly 165 Arg Val Met Val Thr Asp Phe Glu 170 175 Asn val Pro Glu Glu Asp Gly Thr 180 Arg Phe His Arg Gin Ala Ser Lys 185 190 Cys Asp Ser His Gly Thr His Leu 195 200 Ala Gly Val Val ser Gly Arg Asp 205 Ala Gly Val Ala Lys Gly Ala ser 210 215 Met Arg ser Leu Arg Val Leu Asn 220 Cys Gin Gly Lys Gly Thr Val Ser 225 230 Gly Thr Leu Ue Gly Leu Glu Phe 235 240 lie Arg Lys Ser Gin Leu val Gin 245 Pro Val Gly Pro Leu val Val Leu 250 255 Leu Pro Leu Ala Gly Gly Tyr ser 260 Arg Val Leu Asn Ala Ala cys Gin 265 270 Arg Leu Ala Arg Ala Gly Val val Leu Val Thr Ala Ala Gly Asn Phe Page 4 P17140.IES 275 280 - sequence listing as filed 285 Arg Asp Asp Ala Cys Leu Tyr Ser 290 295 Pro Ala ser Ala Pro Glu val lie 300 Thr Val Gly Ala Thr Asn Ala Gin 305 310 Asp Gin Pro Val Thr Leu Gly Thr 315 320 Leu Gly Thr Asn Phe Gly Arg Cys 325 Val Asp Leu Phe Ala Pro Gly Glu 330 335 Asp lie lie Gly Ala Ser ser Asp 340 Cys ser Thr Cys Phe Val ser Gin 345 350 Ser Gly Thr Ser Gin Ala Ala Ala 355 360 His Val Ala Gly lie Ala Ala Met 365 Met Leu Ser Ala Glu Pro Glu Leu 370 375 Thr Leu Ala Glu Leu Arg Gin Arg 380 Leu lie His Phe Ser Ala Lys Asp 385 390 val lie Asn Glu Ala Trp Phe Pro 395 400 Glu Asp Gin Arg Val Leu Thr Pro 405 Asn Leu Val Ala Ala Leu Pro Pro 410 415 Ser Thr His Gly Ala Gly Trp Gin 420 Leu Phe Cys Arg Thr Val Trp ser 425 430 Ala His ser Gly Pro Thr Arg Met 435 440 Ala Thr Ala lie Ala Arg Cys Ala 445 Pro Asp Glu Glu Leu Leu ser cys 450 455 Ser Ser Phe Ser Arg ser Gly Lys 460 Arg Arg Gly Glu Arg Met Glu Ala 465 470 Gin Gly Gly Lys Leu Val Cys Arg 475 480 Ala His Asn Ala Phe Gly Gly Glu 485 Gly val Tyr Ala lie Ala Arg cys 490 495 cys Leu Leu Pro Gin Ala Asn Cys 500 Ser Val His Thr Ala Pro Pro Ala 505 510 Glu Ala Ser Met Gly Thr Arg Val 515 520 His Cys His Gin Gin Gly His val 525 Leu Thr Gly Cys Ser Ser His Trp 530 535 Glu val Glu Asp Leu Gly Thr His 540 Lys Pro Pro val Leu Arg Pro Arg Gly Gin Pro Asn Gin Cys Val Gly Page 5 545 P17140.IES - sequence listing as filed 550 555 560 His Arg Glu Ala Ser 565 lie His Ala Ser Cys Cys His Ala Pro Gly Leu 570 575 Glu cys Lys Val Lys 580 Glu His Gly lie Pro Ala Pro Gin Glu Gin Val 585 590 Thr Val Ala cys Glu 595 Glu Gly Trp Thr Leu Thr Gly cys Ser Ala Leu 600 605 Pro Gly Thr Ser His 610 Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys 615 620 val val Arg Ser Arg 625 Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Glu 630 635 640 Ala Val Thr Ala Val 645 Ala lie Cys cys Arg Ser Arg His Leu Ala Gin 650 655 Ala Ser Gin Glu Leu 660 Gin <210> 3 <211> 540 <212> PRT <213> Homo sapiens <400> 3 Ser lie Pro Trp Asn 1 5 Leu Glu Arg lie Thr pro Pro Arg Tyr Arg Ala 10 15 Asp Glu Tyr Gin Pro 20 Pro Asp Gly Gly Ser Leu val Glu Val Tyr Leu 25 30 Leu Asp Thr Ser Tie 35 Gin Ser Asp His Arg Glu lie Glu Gly Arg val 40 45 Met val Thr Asp Phe 50 Glu Asn val Pro Glu Glu Asp Gly Thr Arg Phe 55 60 His Arg Gin Ala Ser 65 Lys Cys Asp ser His Gly Thr His Leu Ala Gly 70 75 80 Val Val ser Gly Arg 85 Asp Ala Gly Val Ala Lys Gly Ala Ser Met Arg 90 95 Ser Leu Arg val Leu 100 Asn Cys Gin Gly Lys Gly Thr Val Ser Gly Thr 105 110 Leu lie Gly Leu Glu 115 Phe lie Arg Lys Ser Gin Leu val Gin Pro Val 120 125 Page 6 P17140.IES - sequence listing as filed Gly Pro Leu Val 130 Val Leu Leu Pro Leu Ala Gly Gly Tyr ser Arg val 135 140 Leu 145 Asn Ala Ala cys Gin 150 Arg Leu Al a Arg Ala 155 Gly Val val Leu Val 160 Thr Ala Ala Gly Asn 165 Phe Arg Asp Asp Ala 170 cys Leu Tyr ser Pro 175 Al a Ser Al a Pro Glu 180 Val lie Thr val Gly 185 Ala Thr Asn Al a Gin 190 Asp Gin Pro Val Thr 195 Leu Gly Thr Leu Gly 200 Thr Asn Phe Gly Arg 205 cys Val Asp teu phe 210 Al a Pro Gly Glu Asp 215 lie Il e Gly Al a Ser 220 Ser Asp cys ser Thr 225 Cys Phe Val Ser Gin 230 Ser Gly Thr Ser Gin 235 Al a Al a Al a Hi s val 240 Ala Gly 11 e Al a Al a 245 Met Met Leu Ser Ala 250 Glu Pro Glu Leu Thr 255 Leu Al a Glu Leu Arg 260 Gin Arg Leu He Hi s 265 Phe Ser Al a Lys Asp 270 Val lie Asn Glu Ala 275 Trp Phe Pro Glu Asp 280 Gl n Arg val Leu Thr 285 Pro Asn Leu Val Al a 290 Ala Leu Pro Pro Ser 295 Thr Hi s Gly Ala Gly 300 Trp Gin Leu Phe Cys 305 Arg Thr val Trp ser 310 Al a Hi s Ser Gly Pro 315 Thr Arg Met Ala Thr 320 Al a 11 e Al a Arg Cys 325 Al a Pro Asp Glu Glu 330 Leu Leu ser cys ser 335 Ser Phe Ser Arg Ser 340 Gly Lys Arg Arg Gly 345 Glu Arg Met Glu Ala 350 Gin Gly Gly Lys Leu 355 val cys Arg Al a Hi s 360 Asn Ala Phe Gly Gly 365 Glu Gly Val Tyr Ala 370 lie Ala Arg Cys Cys 375 Leu Leu pro Gin Ala 380 Asn cys Ser Val Hi s 385 Thr Ala Pro Pro Ala 390 Glu Al a Ser Met Gly 395 Thr Arg Val Hi s Cys 400 Page 7 Hi s Gin Gin Gly His 405 P17140 • IES Thr - sequence Gly Cys Ser 410 1i sti ng as filed Trp Glu 415 Val Val Leu Ser His Glu Asp Leu Gly 420 Thr Hi s Lys Pro Pro 425 Val Leu Arg Pro Arg 430 Gly Gin Pro Asn Gin 435 cys Val Gly His Arg 440 Glu Ala Ser lie Hi s 445 Ala Ser Cys cys Hi s 450 Al a Pro Gly Leu Glu 455 Cys Lys Val Lys G1 u 460 Hi s Gly lie Pro Al a 465 Pro Gin Glu Gin val 470 Thr val Al a cys Glu 475 Glu Gly T rp Thr Leu 480 Thr Gly cys Ser Al a 485 Leu Pro Gly Thr Ser 490 Hi s Val Leu Gly Ala 495 Tyr Al a Val Asp Asn 500 Thr cys val val Arg 505 Ser Arg Asp val Ser 510 Thr Thr Gly ser Thr 515 Ser Glu Glu Ala Val 520 Thr Al a val Al a lie 525 cys cys Arg Ser Arg 530 Hi s Leu Ala Gin Ala 535 Ser Gin Glu Leu Gin 540 <210> 4 <211> 692 <212> PRT <213> Homo sapiens <400> 4 Met Gly 1 Thr Val Ser 5 Ser Arg Arg ser Trp 10 T rp Pro Leu pro Leu 15 Leu Leu Leu Leu Leu 20 Leu Leu Leu Gly Pro 25 Al a Gly Ala Arg Ala 30 Gin G1 u Asp Glu Asp 35 Gly Asp Tyr Glu Glu 40 Leu val Leu Ala Leu 45 Arg Ser G1 u Glu Asp 50 Gly Leu Ala Glu Al a 55 pro Glu Hi s Gly Thr 60 Thr Ala Thr Phe Hi s 65 Arg cys Ala Lys Asp 70 Pro Trp Arg Leu pro 75 Gly Thr Tyr val Val 80 val Leu Lys Glu Glu 85 Thr Hi s Leu Ser Gin 90 Ser Glu Arg Thr Al a 95 Arg Arg Leu Gin Ala Gin Ala Al a Arg Arg Gly Tyr Leu Thr Lys lie Leu Page 8 100 P17140.IES - sequence 105 li sti ng as fi1ed 110 His Val Phe 115 Hi s Gly Leu Leu Pro 120 Gly Phe Leu Val Lys 125 Met Ser Gly Asp Leu Leu 130 Glu Leu Ala Leu Lys 13 5 Leu Pro His Val Asp 140 Tyr lie Glu Glu Asp Ser 145 Ser Val Phe Ala Gin 150 Ser lie Pro 155 Trp Asn Leu Glu Arg 160 lie Thr Pro Pro Arg Tyr Arg Ala 165 Asp Glu Tyr 170 Gin Pro Pro Asp Gly 175 Gly Ser Leu val 180 Glu val Tyr Leu Leu Asp Thr 185 Ser lie Gin ser Asp 190 His Arg Glu 195 lie Glu Gly Arg Val 200 Met Val Thr Asp Phe 205 Glu Asn Val Pro Glu Glu 210 Asp Gly Thr Arg Phe 215 His Arg Gin Ala Ser 220 Lys cys Asp Ser His Gly 225 Thr His Leu Ala Gly 230 Val Val Ser 235 Gly Arg Asp Al a Gly 240 val Ala Lys Gly Ala Ser Met Arg 245 Ser Leu Arg 250 val Leu Asn cys Gin 255 Gly Lys Gly Thr 260 Val Ser Gly Thr Leu lie Gly 265 Leu Glu Phe lie Arg 270 Lys Ser Gin 275 Leu val Gin Pro Val 280 Gly Pro Leu val val 285 Leu Leu Pro Leu Ala Gly 290 Gly Tyr Ser Arg val 295 Leu Asn Ala Ala cys 300 Gin Arg Leu Ala Arg Ala 305 Gly Val Val Leu Val 310 Thr Ala Ala 315 Gly Asn Phe Arg Asp 320 Asp Ala Cys Leu Tyr ser Pro Ala 325 Ser Ala Pro 330 Glu Val lie Thr Val 335 Gly Ala Thr Asn 340 Ala Gin Asp Gin Pro Val Thr 345 Leu Gly Thr Leu Gly 350 Thr Asn Phe 355 Gly Arg Cys Val Asp 360 Leu Phe Ala Pro Gly 365 Glu Asp lie lie Gly Ala ser ser Asp Cys ser Thr Cys Phe Page 9 val ser Gin Ser Gly P17140.IES - sequence listing as filed 370 375 380 Thr ser 385 Gin Ala Al a Ala 390 Hi s Val Ala Gly He Ala 395 Al a Met Met Leu 400 Ser Ala Glu Pro Glu 405 Leu Thr Leu Al a Glu 410 Leu Arg Gin Arg Leu 415 lie Hi s Phe Ser Ala 420 Lys Asp val lie Asn 425 Glu Al a Trp Phe Pro 430 Glu Asp Gin Arg Val 435 Leu Thr Pro Asn Leu 440 Val Ala Al a Leu Pro 445 Pro ser Thr Hi s Gly 450 Al a Gly T rp Gin Leu 455 Phe cys Arg Thr Val 460 Trp Ser Al a Hi s Ser 465 Gly Pro Thr Arg Met 470 Al a Thr Ala Val Ala 475 Arg cys Al a Pro Asp 480 Gl U Glu Leu Leu Ser 485 Cys Ser Ser Phe ser 490 Arg ser Gly Lys Arg 495 Arg Gly Glu Arg Met 500 Glu Al a Gin Gly Gly 505 Lys Leu Val Cys Arg 510 Al a Hi s Asn Ala Phe 515 Gly Gly Glu Gly Val 520 Tyr Ala He Ala Arg 525 cys cys Leu Leu Pro 530 Gin Ala Asn Cys Ser 535 Val Hi s Thr Ala Pro 540 Pro Al a G1U Al a Ser 545 Met Gly Thr Arg val 550 Hi s cys Hi s Gl n Gin 555 Gly Hi s Val Leu Thr 560 Gly Cys Ser Ser His 565 Trp Gl u val Glu Asp 570 Leu Gly Thr Hi s Lys 575 Pro pro val Leu Arg 580 Pro Arg Gly Gin Pro 585 Asn Gin cys val Gly 590 Hi s Arg Glu Al a ser 595 He Hi s Al a Ser cys 600 cys Hi s Ala Pro Gly 605 Leu Gl u cys Lys Val 610 Lys Glu Hi s Gly lie 615 Pro Al a Pro Gin Glu 620 Gin Val Thr val Ala 625 cys Glu Glu Gly Trp 630 Thr Leu Thr Gly cys 635 ser Ala Leu Pro Gly 640 Thr Ser Hi s val Leu Gly Ala Tyr Ala val Asp Asn Thr cys val Val Page 10 P17140.IES - sequence listing as filed 645 650 655 Arg Ser Arg Asp val 660 Ser Thr Thr Gly Ser Thr 665 Ser Glu Glu Ala Val 670 Thr Ala Val Ala lie Cys Cys Arg Ser Arg His 675 680 Leu Ala Gin Ala Ser 685 Gin Glu Leu Gin 690 <210> 5 <211> 662 <212> PRT <213> Homo sapiens <400> 5 Gin Glu 1 ASp Glu Asp 5 Gly Asp Tyr Glu Glu 10 Leu val Leu Al a Leu 15 Arg Ser Glu Glu Asp 20 Gly Leu Ala Glu Ala 25 pro Glu Hi s Gly Thr 30 Thr Al a Thr Phe His 35 Arg Cys Ala Lys Asp 40 Pro Trp Arg Leu Pro 45 Gly Thr Tyr Val val 50 val Leu Lys Glu Glu 55 Thr His Leu Ser Gin 60 Ser Glu Arg Thr Al a 65 Arg Arg Leu Gin Al a 70 Gin Ala Ala Arg Arg 75 Gly Tyr Leu Thr Lys 80 Il e Leu Hi s val Phe 85 Hi s Gly Leu Leu Pro 90 Gly Phe Leu Val Lys 95 Met Ser Gly Asp Leu 100 Leu Glu Leu Al a Leu 105 Lys Leu Pro Hi s val 110 Asp Tyr il e Glu Glu 115 Asp Ser Ser Val Phe 120 Al a Gl n Ser lie Pro 125 T rp Asn Leu Glu Arg 130 lie Thr Pro Pro Arg 135 Tyr Arg Al a Asp Glu 140 Tyr Gl n pro Pro Asp 145 Gly Gly Ser Leu val 150 Glu val Tyr Leu Leu 155 Asp Thr Ser lie Gin 160 ser Asp Hi s Arg Glu 165 He Glu Gly Arg val 170 Met Val Thr Asp Phe 175 Glu Asn Val Pro Glu 180 Glu Asp Gly Thr Arg 185 Phe Hi s Arg Gin Ala 190 ser Lys Page 11 P17140.IES - sequence listing as filed Cys Asp Ser Hi s Gly Thr His Leu Ala 200 Gly val val Ser Gly 205 Arg Asp 195 Ala Gly 210 Val Ala Lys Gly Ala 215 Ser Met Arg Ser Leu 220 Arg val Leu Asn cys 225 Gin Gly Lys Gly Thr 230 Val Ser Gly Thr Leu 235 lie Gly Leu Glu Phe 240 lie Arg Lys Ser Gin 245 Leu Val Gin Pro val 250 Gly Pro Leu val Val 255 Leu Leu Pro Leu Ala 260 Gly Gly Tyr ser Arg 265 val Leu Asn Ala Al a 270 cys Gin Arg Leu Al a 275 Arg Al a Gly Val Val 280 Leu val Thr Ala Ala 285 Gly Asn Phe Arg Asp 290 Asp Al a Cys Leu Tyr 295 Ser Pro Ala Ser Ala 300 Pro Glu Val He Thr 305 Val Gly Ala Thr Asn 310 Ala Gl n Asp Gin Pro 315 val Thr Leu Gly Thr 320 Leu Gly Thr Asn Phe 325 Gly Arg cys val Asp 330 Leu Phe Ala Pro Gly 335 Glu Asp lie lie Gly 340 Al a Ser Ser Asp cys 345 Ser Thr cys Phe val 350 Ser Gin Ser Gly Thr 355 ser Gin Ala Al a Ala 360 Hi s val Al a Gly ll e 365 Al a Al a Met Met Leu 370 Ser Al a Gl u Pro Glu 375 Leu Thr Leu Ala Glu 380 Leu Arg Gin Arg Leu 385 lie Hi s Phe Ser Ala 390 Lys Asp Val lie Asn 395 Glu Ala T rp Phe Pro 400 Glu Asp Gin Arg Val 405 Leu Thr Pro Asn Leu 410 Val Al a Al a Leu Pro 415 Pro Ser Thr His Gly 420 Al a Gly Trp Gin Leu 425 Phe cys Arg Thr val 430 Trp Ser Ala Hi s ser 435 Gly Pro Thr Arg Met 440 Al a Thr Ala Val Ala 445 Arg cys Ala Pro Asp 450 Glu Glu Leu Leu Ser 455 cys Ser Ser Phe Ser 460 Arg Ser Gly Lys Page 12 P17140.IES sequence listing as filed Arg Arg Gly Glu Arg Met Glu Ala 465 470 Gin Gly Gly Lys Leu Val Cys Arg 475 480 Ala His Asn Ala Phe Gly Gly Glu 485 Gly Val Tyr Ala lie Ala Arg Cys 490 495 Cys Leu Leu Pro Gin Ala Asn Cys 500 Ser Val His Thr Ala Pro Pro Ala 505 510 Glu Ala ser Met Gly Thr Arg val 515 520 His cys His Gin Gin Gly His val 525 Leu Thr Gly Cys Ser Ser His Trp 530 535 Glu Val Glu Asp Leu Gly Thr His 540 Lys Pro Pro Val Leu Arg Pro Arg 545 550 Gly Gin Pro Asn Gin Cys Val Gly 555 560 His Arg Glu Ala ser lie His Ala 565 ser cys cys His Ala pro Gly Leu 570 575 Glu Cys Lys Val Lys Glu His Gly 580 lie Pro Ala Pro Gin Glu Gin Val 585 590 Thr Val Ala Cys Glu Glu Gly Trp 595 600 Thr Leu Thr Gly Cys Ser Ala Leu 605 Pro Gly Thr ser His val Leu Gly 610 615 Ala Tyr Ala val Asp Asn Thr cys 620 Val Val Arg Ser Arg Asp Val Ser 625 630 Thr Thr Gly Ser Thr Ser Glu Glu 635 640 Ala val Thr Ala val Ala lie Cys 645 Cys Arg Ser Arg His Leu Ala Gin 650 655 Ala ser Gin Glu Leu Gin 660 <210> 6 <211> 540 <212> PRT <213> Homo sapiens <400> 6 Ser lie Pro Trp Asn Leu Glu Arg Asp Glu Tyr Gin Pro Pro Asp Gly 20 Leu Asp Thr Ser lie Gin Ser Asp lie Thr Pro Pro Arg Tyr Arg Ala 1015 Gly Ser Leu Val Glu Val Tyr Leu 2530 His Arg Glu lie Glu Gly Arg val Page 13 P17140.IES 35 40 - sequence listing as filed 45 Met val Thr Asp Phe Glu Asn Val 50 55 Pro Glu Glu Asp Gly Thr Arg Phe 60 His Arg Gin Ala Ser Lys Cys Asp 65 70 Ser His Gly Thr His Leu Ala Gly 80 Val Val Ser Gly Arg Asp Ala Gly 85 Val Ala Lys Gly Ala ser Met Arg 95 ser Leu Arg Val Leu Asn Cys Gin 100 Gly Lys Gly Thr val Ser Gly Thr 105 110 Leu lie Gly Leu Glu Phe lie Arg 115 120 Lys ser Gin Leu Val Gin Pro val 125 Gly Pro Leu Val val Leu Leu Pro 130 135 Leu Ala Gly Gly Tyr ser Arg Val 140 Leu Asn Ala Ala Cys Gin Arg Leu 145 150 Ala Arg Ala Gly Val Val Leu Val 155 160 Thr Ala Ala Gly Asn Phe Arg Asp 165 Asp Ala cys Leu Tyr Ser Pro Ala 170 175 Ser Ala Pro Glu val lie Thr val 180 Gly Ala Thr Asn Ala Gin Asp Gin 185 190 pro val Thr Leu Gly Thr Leu Gly 195 200 Thr Asn Phe Gly Arg Cys Val Asp 205 Leu Phe Ala Pro Gly Glu Asp lie 210 215 lie Gly Ala ser Ser Asp Cys Ser 220 Thr Cys Phe val ser Gin ser Gly 225 230 Thr Ser Gin Ala Ala Ala His Val 235 240 Ala Gly lie Ala Ala Met Met Leu 245 Ser Ala Glu Pro Glu Leu Thr Leu 250 255 Ala Glu Leu Arg Gin Arg Leu lie 260 His Phe ser Ala Lys Asp Val lie 265 270 Asn Glu Ala Trp phe Pro Glu Asp 275 280 Gin Arg Val Leu Thr Pro Asn Leu 285 val Ala Ala Leu Pro Pro Ser Thr 290 295 His Gly Ala Gly Trp Gin Leu Phe 300 Cys Arg Thr val Trp ser Ala His Ser Gly Pro Thr Arg Met Ala Thr Page 14 P17140.IES - sequence listing as filed 305 310 315320 Ala val Ala Arg Cys Ala Pro Asp Glu Glu Leu 325330 Leu Ser Cys Ser Ser 335 Phe Ser Arg Ser Gly Lys Arg Arg Gly Glu Arg Met Glu Ala Gin Gly 340 345350 Gly Lys Leu Val 355 Cys Arg Ala Hi s 360 Asn Ala Phe Gly Gly 365 Glu Tyr Ala 370 lie Ala Arg Cys Cys 375 Leu Leu Pro Gin Al a 380 Asn Cys His Thr 385 Ala Pro Pro Ala Glu 390 Al a Ser Met Gly 395 Thr Arg Val His Gin Gin Gly His Val Leu 405 Thr Gly Cys 410 ser Ser Hi s Trp Glu Asp Leu Gly 420 Thr His Lys Pro Pro Val 425 Leu Arg Pro Arg 430 Pro Asn Gin cys 435 val Gly His Arg 440 Glu Ala ser lie His 445 Al a Cys His 450 Ala Pro Gly Leu Glu 455 cys Lys val Lys Glu 460 Hi s Gly Gly Val Ser Val His Cys 400 Glu val 415 Gly Gin Ser Cys lie Pro Ala Pro Gin 465 Glu Gin val 470 Thr val Al a Cys Glu Glu 475 Gly T rp Thr Leu 480 Thr Gly Cys Ser Ala Leu Pro Gly Thr Ser His Val Leu Gly Ala Tyr 485 490 495 Thr Al a val Asp Asn 500 Thr Cys Val val Arg 505 Ser Arg Asp val Ser 510 Gly ser Thr Ser Glu Glu Al a val Thr Al a val Ala lie Cys 515 520 525 Ser Arg Hi s Leu Ala Gin Ala Ser Gin Glu Leu Gin 530 535 540 Cys Thr Arg <210> 7 <211> 692 <212> PRT <213> Homo sapiens <400> 7 Met Gly Thr val Ser ser Arg Arg ser Trp Trp Pro 15 10 Leu Pro Leu Leu Page 15 P17140.IES - sequence listing as filed Leu Leu Asp Glu Glu Asp 50 Hi s 65 Arg Val Leu Arg Leu Hi s val Asp Leu 130 Glu 145 Asp e Thr Gly ser Hi s Arg Pro Glu 210 Ser 225 Hi s val Al a Gly Lys Lys ser Gin 275 Leu Gly cys Lys Gin Leu ser Pro Leu Glu Gly Lys Gly Phe 115 Glu 195 Asp 35 Leu 20 Leu Leu Leu Gly Pro 25 Ala Gly Ala Arg Al a 30 G1 n Glu Gly Asp Tyr Glu Glu 40 Leu Val Leu Ala Leu 45 Arg Ser Glu Leu Ala Glu Ala 55 Pro Glu His Gly Thr 60 Thr Al a Thr Phe Ala Lys Asp 70 Pro τ rp Arg Leu Pro 75 Gly Thr Tyr Val Val 80 Glu Glu 85 Thr Hi s Leu Ser Gin 90 Ser G1 u Arg Thr Al a 95 Arg Ala 100 Gin Ala Ala Arg Arg 105 Gly Tyr Leu Thr Lys 110 lie Leu Hi s Gly Leu Leu pro 120 Gly Phe Leu Val Lys 125 Met Ser Gly Glu Leu Ala Leu 135 Lys Leu Pro Hi s val 140 Asp Tyr lie Glu ser val Phe 150 Ala Gin Ser lie Pro 155 T rp Asn Leu Glu Arg 160 Pro Arg 165 Tyr Arg Al a Asp Glu 170 Tyr Gin Pro Pro Asp 175 Gly val 180 Glu Val Tyr Leu Leu 185 Asp Thr ser lie Gin 190 ser Asp lie Glu Gly Arg Val 200 Met val Thr Asp Phe 205 Glu Asn val Asp Gly Thr Arg 215 phe Hi s Arg Gin Al a 220 ser Lys cys Asp Thr Hi s Leu 230 Ala Gly val Val Ser 235 Gly Arg Asp Al a Gly 240 Gly Ala 245 ser Met Arg Ser Leu 250 Arg Val Leu Asn cys 255 G1 n Thr 260 val Ser Gly Thr Leu 265 lie Gly Leu Glu Phe 270 lie Arg Leu val Gin pro Val Gly Pro Leu val Val Leu Leu Pro 280 285 Page 16 P17140.IES - sequence listing as filed Leu Ala Gly 290 Gly Tyr Ser Arg val 295 Leu Asn Ala Ala Cys 300 Gin Arg Leu Ala 305 Arg Ala Gly val val Leu Val 310 Thr Ala Ala Gly Asn 315 Phe Arg Asp 320 Asp Ala Cys Leu Tyr Ser Pro Ala 325 Ser Ala 330 Pro Glu val lie Thr 335 Val Gly Ala Thr Asn Ala Gin Asp Gin 340 Pro Val 345 Thr Leu Gly Thr 350 Leu Gly Thr Asn Phe 355 Gly Arg cys Val Asp 360 Leu Phe Ala Pro Gly 365 Glu Asp lie lie Gly Ala 370 ser Ser Asp cys ser 375 Thr Cys Phe val ser 380 Gin Ser Gly Thr 385 Ser Gin Ala Al a Ala Hi s Val 390 Ala Gly lie Ala Ala 395 Met Met Leu 400 Ser Ala Glu Pro Glu Leu Thr Leu 405 Ala Glu 410 Leu Arg Gin Arg Leu 415 lie Hi s Phe Ser Ala Lys Asp val lie 420 Asn Glu 425 Ala Trp Phe Pro 430 Glu Asp Gin Arg Val 435 Leu Thr Pro Asn Leu 440 Val Ala Ala Leu Pro 445 Pro ser Thr Hi s Gly Ala 450 Gly Trp Gin Leu Phe 455 cys Arg Thr val Trp 460 Ser Al a Hi s ser 465 Gly Pro Thr Arg Met Ala Thr 470 Ala lie Ala Arg cys 475 Al a Pro Asp 480 Glu Glu Leu Leu Ser cys ser Ser 485 Phe Ser 490 Arg Ser Gly Lys Arg 495 Arg Gly Glu Arg Met Glu Ala Gin Gly 500 Gly Lys 505 Leu Val Cys Arg 510 Al a Hi s Asn Ala Phe 515 Gly Gly Glu Gly val 520 Tyr Al a lie Ala Arg 525 cys Cys Leu Leu Pro Gin 530 Ala Asn Cys Ser Val 535 His Thr Ala Pro Pro 540 Ala Glu Ala Ser 545 Met Gly Thr Arg val His Cys 550 His Gin Gin Gly His 555 Val Leu Thr 560 Page 17 P17140.IES - sequence listing as filed Gly Cys Ser ser His Trp Glu Val 565 Glu Asp Leu Gly Thr His Lys Pro 570 575 Pro val Leu Arg Pro Arg Gly Gin 580 Pro Asn Gin cys val Gly His Arg 585 590 Glu Ala Ser lie His Ala ser Cys 595 600 Cys His Ala Pro Gly Leu Glu Cys 605 Lys Val Lys Glu His Gly lie Pro 610 615 Ala Pro Gin Glu Gin Val Thr val 620 Ala Cys Glu Glu Gly Trp Thr Leu 625 630 Thr Gly Cys ser Ala Leu Pro Gly 635 640 Thr Ser His val Leu Gly Ala Tyr 645 Ala val Asp Asn Thr cys val Val 650 655 Arg Ser Arg Asp Val Ser Thr Thr 660 Gly Ser Thr Ser Glu Gly Ala Val 665 670 Thr Ala Val Ala lie cys cys Arg 675 680 Ser Arg His Leu Ala Gin Ala ser 685 Gin Glu Leu Gin 690 <210> 8 <211> 662 <212> PRT <213> Homo sapiens <400> 8 Gin Glu Asp Glu Asp Gly Asp Tyr Glu Glu Leu val Leu Ala Leu Arg ser Glu Glu Asp Gly Leu Ala Glu 20 Ala Pro Glu His Gly Thr Thr Ala 25 30 Thr Phe His Arg Cys Ala Lys Asp 40 Pro Trp Arg Leu Pro Gly Thr Tyr 45 Val Val val Leu Lys Glu Glu Thr 55 His Leu Ser Gin ser Glu Arg Thr 60 Ala Arg Arg Leu Gin Ala Gin Ala 65 70 Ala Arg Arg Gly Tyr Leu Thr Lys 75 80 lie Leu His val Phe His Gly Leu 85 Leu Pro Gly Phe Leu val Lys Met 95 Ser Gly Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr Page 18 P17140.IES - sequence listing as filed 100 105110 lie Glu Glu Asp Ser Ser Val Phe Ala Gin ser lie Pro Trp Asn Leu 115 120125 Glu Arg lie Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gin Pro Pro 130 135140 Asp Gly Gly Ser Leu val Glu val Tyr Leu Leu Asp Thr ser lie Gin 145 150 155160 Ser Asp His Arg Glu lie Glu Gly Arg Val Met Val Thr Asp Phe Glu 165 170175 Asn val Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gin Ala ser Lys 180 185190 Cys Asp Ser His Gly Thr His Leu Ala Gly Val val ser Gly Arg Asp 195 200205 Ala Gly val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn 210 215220 cys Gin Gly Lys Gly Thr Val Ser Gly Thr Leu lie Gly Leu Glu Phe 225 230 235240 lie Arg Lys Ser Gin Leu val Gin Pro Val Gly Pro Leu val Val Leu 245 250255 Leu Pro Leu Ala Gly Gly Tyr Ser Arg val Leu Asn Ala Ala Cys Gin 260 265270 Arg Leu Ala Arg Ala Gly Val Val Leu Val Thr Ala Ala Gly Asn Phe 275 280285 Arg Asp Asp Ala Cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu Val lie 290 295300 Thr Val Gly Ala Thr Asn Ala Gin Asp Gin Pro Val Thr Leu Gly Thr 305 310 315320 Leu Gly Thr Asn Phe Gly Arg Cys val Asp Leu Phe Ala Pro Gly Glu 325 330335 Asp lie lie Gly Ala Ser ser Asp cys Ser Thr cys Phe val ser Gin 340 345350 Ser Gly Thr Ser Gin Ala Ala Ala His Val Ala Gly lie Ala Ala Met 355 360365 Met Leu Ser Ala Glu Pro Glu Leu Thr Leu Ala Glu Leu Arg Gin Arg Page 19 P17140.IES 370 375 - sequence listing as filed 380 Leu lie His Phe Ser Ala Lys Asp 385 390 Val lie Asn Glu Ala Trp Phe Pro 395 400 Glu Asp Gin Arg Val Leu Thr Pro 405 Asn Leu val Ala Ala Leu Pro Pro 410 415 ser Thr His Gly Ala Gly Trp Gin 420 Leu Phe Cys Arg Thr Val Trp Ser 425 430 Ala His ser Gly Pro Thr Arg Met 435 440 Ala Thr Ala lie Ala Arg cys Ala 445 Pro Asp Glu Glu Leu Leu ser cys 450 455 Ser Ser Phe Ser Arg ser Gly Lys 460 Arg Arg Gly Glu Arg Met Glu Ala 465 470 Gin Gly Gly Lys Leu Val Cys Arg 475 480 Ala His Asn Ala Phe Gly Gly Glu 485 Gly val Tyr Ala lie Ala Arg cys 490 495 Cys Leu Leu Pro Gin Ala Asn Cys 500 Ser Val His Thr Ala Pro Pro Ala 505 510 Glu Ala Ser Met Gly Thr Arg Val 515 520 His Cys His Gin Gin Gly His Val 525 Leu Thr Gly Cys Ser Ser His Trp 530 535 Glu val Glu Asp Leu Gly Thr His 540 Lys Pro pro val Leu Arg Pro Arg 545 550 Gly Gin pro Asn Gin cys Val Gly 555 560 His Arg Glu Ala ser lie His Ala 565 Ser Cys cys His Ala Pro Gly Leu 570 575 Glu Cys Lys Val Lys Glu His Gly 580 lie Pro Ala Pro Gin Glu Gin val 585 590 Thr val Ala Cys Glu Glu Gly Trp 595 600 Thr Leu Thr Gly Cys ser Ala Leu 605 Pro Gly Thr ser His Val Leu Gly 610 615 Ala Tyr Ala val Asp Asn Thr cys 620 Val Val Arg Ser Arg Asp Val Ser 625 630 Thr Thr Gly Ser Thr Ser Glu Gly 635 640 Ala val Thr Ala val Ala lie Cys Cys Arg Ser Arg His Leu Ala Gin Page 20 P17140.IES - sequence listing as filed 645 650 655 Ala Ser Gin Glu Leu Gin 660 <210> 9 <211> 540 <212> PRT <213> Homo sapiens <400> 9 Ser lie 1 Pro Trp Asn 5 Leu Glu Arg lie Thr 10 Pro Pro Arg Tyr Arg 15 Al a Asp Glu Tyr Gl n 20 pro Pro Asp Gly Gly 25 ser Leu val Gl u val 30 Tyr Leu Leu Asp Thr 35 Ser Il e Gl n Ser Asp 40 Hi s Arg Glu lie Glu 45 Gly Arg Val Met val 50 Thr ASp Phe Glu Asn 55 Val Pro Glu Glu Asp 60 Gly Thr Arg Phe His 65 Arg Gin Al a ser Lys 70 cys Asp Ser Hi s Gly 75 Thr Hi s Leu Al a Gly 80 Val Val Ser Gly Arg 85 Asp Al a Gly val Al a 90 Lys Gly Ala Ser Met 95 Arg Ser Leu Arg Val 100 Leu Asn cys Gin Gly 105 Lys Gly Thr Val Ser 110 Gly Thr Leu lie Gly 115 Leu Glu Phe lie Arg 120 Lys Ser Gin Leu val 125 Gl n Pro val Gly Pro 130 Leu val Val Leu Leu 135 Pro Leu Al a Gly Gly 140 Tyr Ser Arg Val Leu 145 Asn Al a Al a Cys Gin 150 Arg Leu Al a Arg Al a 155 Gly Val Val Leu Val 160 Thr Al a Al a Gly Asn 165 Phe Arg Asp Asp Ala 170 cys Leu Tyr Ser Pro 175 Ala Ser Al a Pro Glu 180 Val lie Thr Val Gly 185 Al a Thr Asn Ala Gin 190 Asp Gin Pro val Thr 195 Leu Gly Thr Leu Gly 200 Thr Asn Phe Gly Arg 205 cys Val Asp Leu Phe 210 Ala Pro Gly Glu Asp 215 lie lie Gly Ala Ser 220 ser Asp cys ser Page 21 P17140.IES - sequence listing as filed Thr 225 Cys Phe Val Ser Gin 230 Ser Gly Thr Ser Gin 235 Ala Ala Ala His Val 240 Al a Gly He Ala Ala 245 Met Met Leu Ser Ala 250 Glu Pro Glu Leu Thr 255 Leu Ala Glu Leu Arg 260 Gin Arg Leu lie His 265 Phe Ser Al a Lys Asp 270 Val lie Asn Glu Ala Trp 275 Phe Pro Glu Asp Gin 280 Arg Val Leu Thr 285 Pro Asn Leu val Al a 290 Ala Leu Pro Pro ser Thr His 295 Gly Al a Gly 300 Trp Gin Leu Phe cys 305 Arg Thr val Trp Ser 310 Ala His Ser Gly Pro 315 Thr Arg Met Al a Thr 320 Ala Il e Al a Arg cys 325 Al a Pro Asp Glu Glu 330 Leu Leu ser cys Ser 335 Ser Phe Ser Arg Ser 340 Gly Lys Arg Arg Gly 345 Glu Arg Met Glu Ala 350 Gin Gly Gly Lys Leu val 355 cys Arg Ala His Asn 360 Al a Phe Gly Gly 365 Glu Gly val Tyr Al a 370 He Ala Arg cys Cys Leu Leu 375 Pro Gl n Al a 380 Asn cys Ser Val Hi s 385 Thr Ala Pro Pro Al a 390 Glu Ala Ser Met Gly 395 Thr Arg val Hi s cys 400 Hi s Gin Gin Gly Hi s 405 Val Leu Thr Gly cys 410 Ser Ser Hi s τ rp Glu 415 val Gl U Asp Leu Gly 420 Thr Hi s Lys Pro Pro 425 Val Leu Arg pro Arg 430 Gly Gin Pro Asn Gin Cys 435 val Gly His Arg Glu 440 Al a ser lie Hi s 445 Ala Ser cys cys His 450 Ala Pro Gly Leu Glu cys Lys 455 Val Lys Glu 460 His Gly lie Pro Ala 465 Pro Gin Glu Gin Val 470 Thr Val Ala cys Glu 475 Glu Gly Trp Thr Leu 480 Thr Gly cys ser Ala 485 Leu Pro Gly Thr ser 490 His Val Leu Gly Al a 495 Tyr Page 22 Ala val Asp Asn 500 Ρ17140 Thr cys Val .IES - sequence listing Asp Val as filed Val Arg 505 Ser Arg ser 510 Thr Thr Gly Ser Thr 515 Ser Arg His 530 <210> 10 <211> 692 <212> PRT <213> Homo ! <400> 10 ser Glu Leu Ala sapi ens Gly Gin Al a Al a 535 val 520 Ser Thr Gin Ala Glu val Leu Ala Gin 540 He 525 cys cys Arg Met 1 Gly Thr Val Ser 5 Ser Arg Arg Ser Trp 10 Trp Pro Leu pro Leu 15 Leu teu Leu Leu Leu 20 Leu Leu Leu Gly Pro 25 Al a Gly Al a Arg Al a 30 G1 n Glu Asp Glu Asp 35 Gly Asp Tyr Glu Glu 40 Leu val Leu Ala Leu 45 Arg ser Glu Glu Asp 50 Gly Leu Al a Glu Ala 55 Pro Glu Hi s Gly Thr 60 Thr Al a Thr Phe Hi s 65 Arg Cys Al a Lys Asp 70 Pro Trp Arg Leu Pro 75 Gly Thr Tyr Val Val 80 val Leu Lys G1 u Glu 85 Thr Hi s Leu Ser Gin 90 Ser Glu Arg Thr Al a 95 Arg Arg Leu Gin Al a 100 Gin Al a Al a Arg Arg 105 Gly Tyr Leu Thr Lys 110 He Leu Hi s Val Phe 115 Hi s Gly Leu Leu Pro 120 Gly Phe Leu val Lys 12 5 Met Ser Gly Asp Leu 130 Leu Glu Leu Al a Leu 135 Lys Leu Pro His val 140 Asp Tyr lie G1 u Glu 145 Asp Ser ser Val Phe 150 Al a Gin Ser He Pro 155 Trp Asn Leu Glu Arg 160 He Thr Pro pro Arg 165 Tyr Arg Ala Asp Glu 170 Tyr G1 n Pro Pro Asp 175 Gly Gly ser Leu val 180 Glu Val Tyr Leu Leu 185 Asp Thr Ser lie Gin 190 ser Asp Hi s Arg Glu lie Glu Gly Arg val Met Val Thr Asp phe Glu Asn val Page 23 P17140.IES 195 200 - sequence listing as filed 205 Pro Glu Glu Asp Gly Thr Arg Phe 210 215 His Arg Gin Ala Ser Lys Cys Asp 220 Ser His Gly Thr His Leu Ala Gly 225 230 val Val Ser Gly Arg Asp Ala Gly 235 240 Val Ala Lys Gly Ala Ser Met Arg 245 Ser Leu Arg val Leu Asn Cys Gin 250 255 Gly Lys Gly Thr val Ser Gly Thr 260 Leu lie Gly Leu Glu Phe lie Arg 265 270 Lys Ser Gin Leu val Gin Pro val 275 280 Gly Pro Leu Val val Leu Leu pro 285 Leu Ala Gly Gly Tyr Ser Arg Val 290 295 Leu Asn Ala Ala cys Gin Arg Leu 300 Ala Arg Ala Gly val Val Leu Val 305 310 Thr Ala Ala Gly Asn Phe Arg Asp 315 320 Asp Ala Cys Leu Tyr Ser Pro Ala 325 ser Ala Pro Glu val lie Thr val 330 335 Gly Ala Thr Asn Ala Gin Asp Gin 340 Pro val Thr Leu Gly Thr Leu Gly 345 350 Thr Asn phe Gly Arg Cys val Asp 355 360 Leu Phe Ala Pro Gly Glu Asp lie 365 lie Gly Ala Ser Ser Asp cys ser 370 375 Thr Cys Phe Val ser Gin ser Gly 380 Thr Ser Gin Ala Ala Ala His val 385 390 Ala Gly lie Ala Ala Met Met Leu 395 400 ser Ala Glu Pro Glu Leu Thr Leu 405 Ala Glu Leu Arg Gin Arg Leu lie 410 415 His Phe ser Ala Lys Asp val lie 420 Asn Glu Ala Trp Phe Pro Glu Asp 425 430 Gin Arg Val Leu Thr Pro Asn Leu 435 440 Val Ala Ala Leu Pro Pro Ser Thr 445 His Gly Ala Gly Trp Gin Leu Phe 450 455 Cys Arg Thr Val Trp Ser Ala His 460 Ser Gly Pro Thr Arg Met Ala Thr Ala Val Ala Arg cys Ala Pro Asp Page 24 P17140.IES - sequence listing as filed 465 470 475 480 Glu Glu Leu Leu ser Cys 485 ser ser Phe Ser 490 Arg Ser Gly Lys Arg 495 Arg Gly Glu Arg Met 500 Glu Ala Gin Gly Gly 505 Lys Leu val Cys Arg 510 Al a Hi s Asn Ala Phe 515 Gly Gly Glu Gly val 520 Tyr Al a lie Al a Arg 525 cys Cys Leu Leu Pro 530 Gin Ala Asn cys Ser 535 Val Hi s Thr Al a Pro 540 Pro Al a Glu Al a Sen 545 Met Gly Thr Arg val 550 Hi s cys Hi s Gin Gin 555 Gly Hi s val Leu Thr 560 Gly cys Ser ser Hi s 565 Trp Glu val Glu Asp 570 Leu Gly Thr Hi s Lys 575 Pro pro Val Leu Arg 580 Pro Arg Gly Gin pro 585 Asn Gin Cys Val Gly 590 Hi s Arg Glu Ala Ser 595 He Hi s Al a Ser Cys 600 cys Hl s Al a Pro Gly 605 Leu G1 u Cys Lys val 610 Lys Glu Hi s Gly lie 615 Pro Ala Pro Gin Glu 620 Gin Val Thr Val Al a 625 cys Glu Glu Gly Trp 630 Thr Leu Thr Gly cys 63 5 Ser Ala Leu Pro Gly 640 Thr Ser Hi s Val Leu 645 Gly Ala Tyr Al a val 650 Asp Asn Thr cys Val 655 Val Arg ser Arg Asp 660 Val Ser Thr Thr Gly 665 ser Thr Ser Glu Gly 670 Al a Val Thr Al a val 675 Al a lie Cys cys Arg 680 Ser Arg Hi s Leu Al a 685 Gin Al a Ser Gin Glu Leu Gin 690 <210> 11 <211> 662 <212> PRT <213> Homo sapiens <400> 11 Gin Glu Asp Glu Asp Gly Asp Tyr Glu Glu Leu val 1 5 10 Leu Ala Leu Arg Page 25 P17140.IES Ser Glu Glu Asp Gly Leu Ala Glu 20 - sequence listing as filed Ala Pro Glu His Gly Thr Thr Ala 25 30 Thr Phe His Arg cys Ala Lys Asp 35 40 Pro Trp Arg Leu Pro Gly Thr Tyr 45 Val val Val Leu Lys Glu Glu Thr 50 55 His Leu ser Gin Ser Glu Arg Thr 60 Ala Arg Arg Leu Gin Ala Gin Ala 65 70 Ala Arg Arg Gly Tyr Leu Thr Lys 75 80 lie Leu His Val Phe His Gly Leu 85 Leu Pro Gly Phe Leu val Lys Met 95 Ser Gly Asp Leu Leu Glu Leu Ala 100 Leu Lys Leu Pro His val Asp Tyr 105 110 lie Glu Glu Asp Ser ser Val Phe 115 120 Ala Gin Ser lie Pro Trp Asn Leu 125 Glu Arg lie Thr Pro Pro Arg Tyr 130 135 Arg Ala Asp Glu Tyr Gin Pro Pro 140 Asp Gly Gly Ser Leu val Glu Val 145 150 Tyr Leu Leu Asp Thr ser lie Gin 155 160 Ser Asp His Arg Glu lie Glu Gly 165 Arg Val Met Val Thr Asp Phe Glu 170 175 Asn Val Pro Glu Glu Asp Gly Thr 180 Arg Phe His Arg Gin Ala ser Lys 185 190 Cys Asp ser His Gly Thr His Leu 195 200 Ala Gly val val Ser Gly Arg Asp 205 Ala Gly Val Ala Lys Gly Ala Ser 210 215 Met Arg Ser Leu Arg val Leu Asn 220 Cys Gin Gly Lys Gly Thr Val ser 225 230 Gly Thr Leu lie Gly Leu Glu Phe 235 240 lie Arg Lys Ser Gin Leu val Gin 245 Pro val Gly Pro Leu val val Leu 250 255 Leu Pro Leu Ala Gly Gly Tyr Ser 260 Arg Val Leu Asn Ala Ala Cys Gin 265 270 Arg Leu Ala Arg Ala Gly Val val 275 280 Leu val Thr Ala Ala Gly Asn Phe 285 Page 26 Arg Asp 290 Asp Ala Cys P17140.IES - sequence listing as filed Leu Tyr ser 295 Pro Ala ser Ala 300 Pro Glu val lie Thr 305 Val Gly Ala Thr Asn 310 Al a Gl n Asp Gin Pro 315 val Thr Leu Gly Thr 320 Leu Gly Thr Asn Phe 325 Gly Arg Cys Val Asp 330 Leu Phe Al a Pro Gly 335 Glu Asp lie Il e Gly 340 Al a Ser Ser Asp Cys 345 ser Thr cys Phe val 350 Ser Gin ser Gly Thr 355 Ser Gin Al a Al a Al a 360 Hi s Val Al a Gly lie 365 Al a Al a Met Met Leu 370 Ser Al a Glu Pro Glu 375 Leu Thr Leu Al a Glu 380 Leu Arg Gin Arg Leu 385 il e His Phe Ser Ala 390 Lys Asp Val il e Asn 395 Glu Al a Trp Phe Pro 400 Glu Asp Gin Arg Val 405 Leu Thr Pro Asn Leu 410 Val Ala Ala Leu Pro 415 pro Ser Thr Hi s Gly 420 Ala Gly Trp Gl n Leu 425 Phe cys Arg Thr Val 430 Trp Ser Ala Hl s Ser 435 Gly Pro Thr Arg Met 440 Ala Thr Ala Val Ala 445 Arg cys Ala Pro Asp 450 Glu Glu Leu Leu Ser 455 cys ser Ser phe Ser 460 Arg Ser Gly Lys Arg 465 Arg Gly Gl U Arg Met 470 Glu Al a Gin Gly Gly 475 Lys Leu Val cys Arg 480 Al a Hl s Asn Al a Phe 485 Gly Gly Glu Gly val 490 Tyr Al a Il e Ala Arg 495 Cys cys Leu Leu Pro 500 Gin Ala Asn Cys ser 505 Val Hi s Thr Ala Pro 510 Pro Ala Glu Al a Ser 515 Met Gly Thr Arg val 520 Hi s Cys Hi s Gin Gin 525 Gly Hi s Val Leu Thr 530 Gly cys Ser ser Hi s 535 Trp Glu val Glu Asp 540 Leu Gly Thr Hi s Lys 545 Pro Pro val Leu Arg 550 Pro Arg Gly Gin Pro 555 Asn Gin Cys Val Gly 560 Page 27 P17140.IES sequence listing as filed Hi s Arg Glu Ala ser 565 lie Hi s Ala ser Cys 570 cys Hi s Ala Pro Gly 575 Leu Glu cys Lys val 580 Lys Glu Hi s Gly lie 585 Pro Ala Pro Gin Glu 590 Gin Val Thr Val Ala 595 Cys Glu Glu Gly Trp 600 Thr Leu Thr Gly cys 605 Ser Ala Leu Pro Gly 610 Thr Ser Hi s val Leu 615 Gly Al a Tyr Ala val 620 Asp Asn Thr cys Val 625 Val Arg Ser Arg Asp 630 Val Ser Thr Thr Gly 635 Ser Thr ser Glu Gly 640 Ala val Thr Al a Val 645 Ala lie Cys cys Arg 650 Ser Arg His Leu Al a 655 Gin Al a ser Gin Glu 660 Leu Gin <210> 12 <211> 540 <212> PRT <213> Homo sapiens <400> i; Ser lie 1 ! Pro Trp Asn 5 Leu Glu Arg Il e Thr 10 pro Pro Arg Tyr Arg 15 Ala Asp Glu Tyr Gin 20 Pro Pro Asp Gly Gly 25 ser Leu val Glu Val 30 Tyr Leu Leu Asp Thr 35 Ser lie Gin Ser Asp 40 Hi s Arg Glu lie Glu 45 Gly Arg val Met Val 50 Thr Asp Phe Glu Asn 55 val Pro Glu Glu Asp 60 Gly Thr Arg Phe Hi s 65 Arg Gl n Al a Ser Lys 70 cys Asp Ser His Gly 75 Thr His Leu Ala Gly 80 Val val ser Gly Arg 85 Asp Ala Gly val Ala 90 Lys Gly Ala ser Met 95 Arg ser Leu Arg Val 100 Leu Asn Cys Gin Gly 105 Lys Gly Thr val Ser 110 Gly Thr Leu He Gly 115 Leu Glu Phe lie Arg 120 Lys Ser Gin Leu val 125 Gin Pro Val Gly Pro Leu Val val Leu Leu Pro Leu Ala Gly Page 28 Gly Tyr Ser Arg Val P17140.IES 130 135 - sequence listing as filed 140 Leu Asn Ala Ala Cys Gin Arg Leu 145 150 Ala Arg Ala Gly Val val Leu val 155 160 Thr Ala Ala Gly Asn Phe Arg Asp 165 Asp Ala Cys Leu Tyr Ser Pro Ala 170 175 Ser Ala Pro Glu val lie Thr Val 180 Gly Ala Thr Asn Ala Gin Asp Gin 185 190 pro val Thr Leu Gly Thr Leu Gly 195 200 Thr Asn Phe Gly Arg cys Val Asp 205 Leu Phe Ala Pro Gly Glu Asp lie 210 215 lie Gly Ala Ser ser Asp Cys Ser 220 Thr Cys Phe val Ser Gin Ser Gly 225 230 Thr Ser Gin Ala Ala Ala His Val 235 240 Ala Gly lie Ala Ala Met Met Leu 245 Ser Ala Glu Pro Glu Leu Thr Leu 250 255 Ala Glu Leu Arg Gin Arg Leu lie 260 His Phe Ser Ala Lys Asp Val lie 265 270 Asn Glu Ala Trp Phe Pro Glu Asp 275 280 Gin Arg Val Leu Thr Pro Asn Leu 285 Val Ala Ala Leu Pro Pro Ser Thr 290 295 His Gly Ala Gly Trp Gin Leu Phe 300 Cys Arg Thr Val Trp Ser Ala His 305 310 Ser Gly Pro Thr Arg Met Ala Thr 315 320 Ala val Ala Arg cys Ala Pro Asp 325 Glu Glu Leu Leu Ser Cys ser ser 330 335 Phe Ser Arg Ser Gly Lys Arg Arg 340 Gly Glu Arg Met Glu Ala Gin Gly 345 350 Gly Lys Leu Val Cys Arg Ala His 355 360 Asn Ala Phe Gly Gly Glu Gly val 365 Tyr Ala lie Ala Arg Cys Cys Leu 370 375 Leu Pro Gin Ala Asn Cys ser val 380 His Thr Ala Pro Pro Ala Glu Ala 385 390 Ser Met Gly Thr Arg val His Cys 395 400 His Gin Gin Gly His val Leu Thr Gly cys ser ser His Trp Glu val Page 29 P17140.IES - sequence listing as filed 405 410 415 Glu Asp Leu Gly 420 Thr His Lys Pro Pro 425 val Leu Arg Pro Arg 430 Gly Gin Pro Asn Gin cys Val Gly Hi s Arg Glu Al a Ser lie Hl S Al a Ser cys 435 440 445 cys His Al a Pro Gly Leu Glu Cys Lys Val Lys Glu Hi s Gly lie Pro 450 455 460 Ala Pro Gin Glu G1 n val Thr val Al a cys Glu Glu Gly Trp Thr Leu 465 470 475 480 Thr Gly Cys Ser Al a Leu Pro Gly Thr ser Hi s val Leu Gly Ala Tyr 485 490 495 Ala Val Asp Asn Thr Cys val Val Arg Ser Arg Asp Val Ser Thr Thr 500 505 510 Gly ser Thr ser Glu Gly Al a Val Thr Al a Val Al a lie cys cys Arg 515 520 525 Ser Arg His Leu Al a Gin Al a Ser Gin Glu Leu Gin 530 535 540 <210> 13 <211> 692 <212> PRT <213> Homo sapiens <400> 13 Met Gly Thr val ser Ser Arg Arg ser Trp Trp Pro Leu Pro Leu Leu Leu Leu Leu Leu Leu Leu Leu Gly 20 Pro Ala Gly Ala Arg Ala Gin Glu 25 30 Asp Glu Asp Gly Asp Tyr Glu Glu 3 5 40 Leu val Leu Ala Leu Arg ser Glu Glu Asp Gly Leu val Glu Ala Pro 55 Glu His Gly Thr Thr Ala Thr Phe 60 His Arg Cys Ala Lys Asp Pro Trp 70 Arg Leu Pro Gly Thr Tyr val val 80 Val Leu Lys Glu Glu Thr His Leu 85 Ser Gin Ser Glu Arg Thr Ala Arg 95 Arg Leu Gin Ala Gin Ala Ala Arg 100 Arg Gly Tyr Leu Thr Lys lie Leu 105 110 Page 30 P17140.IES sequence listing as filed His Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met ser Gly 115 120125 Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr lie Glu 130 135140 Glu Asp ser Ser val Phe Ala Gin Ser lie Pro Trp Asn Leu Glu Arg 145 150 155160 lie Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gin Pro pro Asp Gly 165 170175 Gly Ser Leu val Glu val Tyr Leu Leu Asp Thr ser lie Gin ser Asp 180 185190 His Arg Glu lie Glu Gly Arg Val Met val Thr Asp Phe Glu Asn val 195 200205 Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gin Ala ser Lys Cys Asp 210 215220 ser His Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp Ala Gly 225 230 235240 Val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg val Leu Asn Cys Gin 245 250255 Gly Lys Gly Thr Val ser Gly Thr Leu lie 265 Gly Leu Glu Phe 270 lie Arg 260 Lys Ser Gin Leu 275 val Gin pro Val Gly Pro 280 Leu Val val 285 Leu Leu Pro Leu Ala Gly Gly Tyr Ser Arg val Leu Asn Al a Al a cys Gl n Arg Leu 290 ' 295 300 Ala Arg Ala Gly Val val Leu Val Thr Ala Ala Gly Asn Phe Arg Asp 305 310 315320 Asp Ala Cys Leu Tyr ser Pro Ala Ser Ala Pro Glu val lie Thr val 325 330335 Gly Ala Thr Asn Ala Gin Asp Gin Pro val Thr Leu Gly Thr Leu Gly 340 345350 Thr Asn Phe Gly Arg cys Val 355 Asp Leu Phe Ala Pro Gly Glu Asp lie 360365 lie Gly Ala Ser Ser Asp Cys Ser Thr Cys Phe Val 370 375380 Ser Gin ser Gly Page 31 P17140.IES Thr ser Gin Ala Ala Ala His Val 385 390 - sequence listing as filed Ala Gly lie Ala Ala Met Met Leu 395 400 Ser Ala Glu Pro Glu Leu Thr Leu 405 Ala Glu Leu Arg Gin Arg Leu lie 410 415 His Phe Ser Ala Lys Asp val lie 420 Asn Glu Ala Trp Phe Pro Glu Asp 425 430 Gin Arg val Leu Thr Pro Asn Leu 435 440 Val Ala Ala Leu Pro Pro Ser Thr 445 His Gly Ala Gly Trp Gin Leu Phe 450 455 Cys Arg Thr val Trp Ser Ala His 460 Ser Gly Pro Thr Arg Met Ala Thr 465 470 Ala val Ala Arg Cys Ala Pro Asp 475 480 Glu Glu Leu Leu Ser Cys Ser ser 485 Phe Ser Arg Ser Gly Lys Arg Arg 490 495 Gly Glu Arg Met Glu Ala Gin Gly 500 Gly Lys Leu Val cys Arg Ala His 505 510 Asn Ala Phe Gly Gly Glu Gly Val 515 520 Tyr Ala lie Ala Arg Cys cys Leu 525 Leu Pro Gin Ala Asn Cys Ser val 530 535 His Thr Ala Pro Pro Ala Glu Ala 540 Ser Met Gly Thr Arg val His cys 545 550 His Gin Gin Gly His Val Leu Thr 555 560 Gly Cys Ser Ser His Trp Glu Val 565 Glu Asp Leu Gly Thr His Lys Pro 570 575 Pro val Leu Arg Pro Arg Gly Gin 580 Pro Asn Gin Cys val Gly His Arg 585 590 Glu Ala Ser lie His Ala ser cys 595 600 Cys His Ala pro Gly Leu Glu Cys 605 Lys Val Lys Glu His Gly lie Pro 610 615 Ala Pro Gin Glu Gin Val Thr val 620 Ala Cys Glu Glu Gly Trp Thr Leu 625 630 Thr Gly Cys ser Ala Leu Pro Gly 635 640 Thr Ser His Val Leu Gly Ala Tyr 645 Ala Val Asp Asn Thr Cys val Val 650 655 Page 32 P17140.IES sequence listing as filed Arg Ser Arg Asp val 660 ser Thr Thr Gly ser Thr Ser Glu Glu Ala Val 665 670 Thr Ala Val Ala lie Cys Cys Arg Ser Arg His 675 680 Leu Ala Gin Ala Ser 685 Gin Glu Leu Gin 690 <210> 14 <211> 662 <212> PRT <213> Homo sapiens <400> 14 Gin 1 Glu Asp Glu Asp 5 Gly Asp Tyr Glu Glu 10 Leu Val Leu Al a Leu 15 Arg Ser Glu Glu Asp Gly Leu val Glu Ala Pro Glu His Gly Thr Thr Ala Thr Phe Hi s 20 Arg Cys Ala Lys Asp 25 Pro Trp Arg Leu Pro 30 Gly Thr Tyr val Val 35 Val Leu Lys Glu Glu 40 Thr His Leu Ser Gin 45 ser Glu Arg Thr Al a 50 Arg Arg Leu Gin Ala 55 Gin Ala Ala Arg Arg 60 Gly Tyr Leu Thr Lys 65 He Leu Hi s Val Phe 70 Hi s Gly Leu Leu Pro 75 Gly Phe Leu val Lys 80 Met Ser Gly Asp Leu 85 Leu Gl u Leu Al a Leu 90 Lys Leu Pro Hi s Val 95 Asp Tyr lie Gl u Glu 100 ASp Ser Ser val Phe 105 Al a Gl n Ser lie Pro 110 τ rp Asn Leu Glu Arg 115 lie Thr Pro Pro Arg 120 Tyr Arg Al a Asp Gl u 125 Tyr Gl n pro Pro Asp 130 Gly Gly Ser Leu Val 135 Glu Val Tyr Leu Leu 140 Asp Thr Ser He Gl n 145 Ser Asp Hi s Arg Glu 150 lie Glu Gly Arg Val 155 Met val Thr Asp Phe 160 Glu Asn val Pro Glu 165 Glu Asp Gly Thr Arg 170 Phe His Arg Gin Ala 175 Ser Lys cys Asp Ser 180 Hi s Gly Thr His Leu 185 Ala Gly Val Val Ser 190 Gly Arg ASp Page 33 P17140.IES - sequence listing as filed 195 200 205 Al a Gly 210 val Ala Lys Gly Ala 215 Ser Met Arg Ser Leu 220 Arg val Leu Asn cys 225 Gin Gly Lys Gly Thr 230 val ser Gly Thr Leu 235 lie Gly Leu Glu Phe 240 He Arg Lys Ser Gin 245 Leu Val Gin Pro val 250 Gly Pro Leu val val 255 Leu Leu pro Leu Al a 260 Gly Gly Tyr Ser Arg 265 val Leu Asn Al a Al a 270 Cys Gin Arg Leu Al a 275 Arg Al a Gly Val val 280 Leu Val Thr Ala Ala 285 Gly Asn Phe Arg Asp 290 Asp Al a cys Leu Tyr 295 Ser Pro Ala Ser Ala 300 Pro Glu val lie Thr 305 val Gly Al a Thr Asn 310 Al a Gin Asp Gin Pro 315 val Thr Leu Gly Thr 320 Leu Gly Thr Asn Phe 325 Gly Arg cys Val Asp 330 Leu Phe Ala Pro Gly 335 Glu Asp He lie Gly 340 Al a Ser Ser Asp Cys 345 Ser Thr Cys Phe val 350 ser Gin Ser Gly Thr 355 Ser Gl n Al a Al a Ala 360 Hi s Val Ala Gly lie 365 Al a Al a Met Met Leu 370 Ser Al a Glu Pro Glu 375 Leu Thr Leu Ala Glu 380 Leu Arg Gin Arg Leu 385 lie Hi s Phe ser Al a 390 Lys Asp val lie Asn 395 Gl u Al a T rp Phe Pro 400 Glu Asp Gin Arg Val 405 Leu Thr Pro Asn Leu 410 Val Al a Al a Leu Pro 415 Pro ser Thr Hi s Gly 420 Al a Gly Trp Gin Leu 425 Phe cys Arg Thr Val 430 Trp Ser Ala His Ser 435 Gly Pro Thr Arg Met 440 Al a Thr Al a Val Al a 445 Arg Cys Ala Pro Asp 450 Glu Glu Leu Leu Ser 455 cys ser Ser Phe Ser 460 Arg Ser Gly Lys Arg Arg Gly Glu Arg Met Glu Ala Gin Gly Gly Lys Leu val cys Arg Page 34 465 P17140.IES 470 - sequence 475 listing as filed 480 Ala His Asn Ala Phe 485 Gly Gly Glu Gly val Tyr 490 Ala lie Ala Arg 495 Cys cys Leu Leu Pro Gin 500 Ala Asn Cys Ser val His 505 Thr Ala Pro Pro 510 Ala Glu Ala ser Met Gly 515 Thr Arg Val 520 His Cys His Gin Gin 525 Gly His val Leu Thr Gly Cys ser 530 Ser His Trp 535 Glu val Glu Asp Leu 540 Gly Thr Hi s Lys Pro Pro val Leu 545 Arg Pro Arg 550 Gly Gin Pro 555 Asn Gin Cys Val Gly 560 His Arg Glu Ala Ser 565 lie His Ala Ser Cys cys 570 His Ala Pro Gly 575 Leu Glu Cys Lys Val Lys 580 Glu His Gly Ile Pro Ala 585 Pro Gin Glu Gin 590 Val Thr Val Ala Cys Glu 595 Glu Gly Trp 600 Thr Leu Thr Gly Cys 605 Ser Ala Leu Pro Gly Thr Ser His 610 Val Leu Gly 615 Ala Tyr Ala Val Asp 620 Asn Thr Cys val val Arg Ser Arg 625 Asp Val Ser 630 Thr Thr Gly 635 Ser Thr Ser Glu Glu 640 Ala Val Thr Ala Val 645 Ala ser Gin Glu Leu 660 <210> 15 <211> 692 <212> PRT <213> Homo sapiens <400> 15 Ala lie Cys Gl n Cys Arg Ser 650 Arg His Leu Ala 655 Gl n Met Gly Thr Val ser 1 5 Ser Arg Arg ser Trp Trp 10 Pro Leu Pro Leu 15 Leu Leu Leu Leu Leu Leu 20 Leu Leu Gly Pro Ala Gly 25 Ala Arg Ala Gin 30 Glu Asp Glu Asp Gly Asp Tyr Glu Glu Leu val Leu Ala Leu Arg Ser Glu 40 45 Page 35 P17140.IES - sequence listing as filed Glu ASp 50 Gly Leu Ala Glu Al a 55 Pro Glu Hi s Gly Thr 60 Thr Ala Thr Phe His 65 Arg cys Ala Lys Asp 70 Pro Trp Arg Leu pro 75 Gly Thr Tyr Val Val 80 val Leu Lys Glu Glu 85 Thr Hi s Leu Ser Gin 90 Ser Glu Arg Thr Al a 95 Arg Arg Leu Gin Al a 100 Gl n Al a Al a Arg Arg 105 Gly Tyr Leu Thr Lys 110 11 e Leu Hi s Val Phe 115 Hi s Gly Leu Leu pro 120 Gly Phe Leu val Lys 12 5 Met Ser Gly Asp Leu 130 Leu Glu Leu Al a Leu 135 Lys Leu Pro Hi s val 140 Asp Tyr Il e Glu Glu 145 Asp Ser Ser val Phe 150 Ala Gin ser Il e Pro 155 Trp Asn Leu Glu Arg 160 lie Thr Pro Pro Arg 165 Tyr Arg Ala Asp Glu 170 Tyr Gin Pro Pro Asp 175 Gly Gly Ser Leu Val 180 Glu Val Tyr Leu Leu 185 Asp Thr Ser lie Gin 190 Ser Asp Hi s Arg Glu 195 lie G1U Gly Arg val 200 Met Val Thr Asp Phe 205 Gl u Asn Val Pro Gl u 210 Glu ASp Gly Thr Arg 215 Phe Hi s Arg Gin Al a 220 Ser Lys Cys Asp ser 225 Hi s Gly Thr Hi s Leu 230 Ala Gly Val Val Ser 235 Gly Arg Asp Ala Gly 240 Val Ala Lys Gly Al a 245 Ser Met Arg ser Leu 250 Arg val Leu Asn cys 255 Gl n Gly Lys Gly Thr 260 Val ser Gly Thr Leu 265 lie Gly Leu Glu Phe 270 lie Arg Lys Ser Gin 275 Leu Val Gin Pro val 280 Gly Pro Leu Val val 285 Leu Leu Pro Leu Ala 290 Gly Gly Tyr Ser Arg 295 val Leu Asn Ala Ala 300 cys Gin Arg Leu Ala 305 Arg Ala Gly Val val 310 Leu val Thr Ala Al a 315 Gly Asn Phe Arg Asp 320 Page 36 P17140.IES Asp Ala Cys Leu Tyr Ser Pro Ala 325 - sequence listing as filed Ser Ala Pro Glu Val lie Thr Val 330 335 Gly Ala Thr Asn Ala Gin Asp Gin 340 Pro val Thr Leu Gly Thr Leu Gly 345 350 Thr Asn Phe Gly Arg Cys Val Asp 355 360 Leu Phe Ala Pro Gly Glu Asp lie 365 lie Gly Ala Ser Ser Asp cys Ser 370 375 Thr Cys Phe val ser Gin Ser Gly 380 Thr Ser Gin Ala Ala Ala His val 385 390 Ala Gly lie Ala Ala Met Met Leu 395 400 Ser Ala Glu Pro Glu Leu Thr Leu 405 Ala Glu Leu Arg Gin Arg Leu lie 410 415 His Phe Ser Ala Lys Asp val lie 420 Asn Glu Ala Trp Phe Pro Glu Asp 425 430 Gin Arg Val Leu Thr Pro Asn Leu 435 440 val Ala Thr Leu Pro Pro Ser Thr 445 His Gly Ala Gly Trp Gin Leu Phe 450 455 cys Arg Thr val Trp ser Ala His 460 ser Gly Pro Thr Arg Met Ala Thr 465 470 Ala lie Ala Arg Cys Ala Pro Asp 475 480 Glu Glu Leu Leu ser cys Ser Ser 485 Phe ser Arg Ser Gly Lys Arg Arg 490 495 Gly Glu Arg Met Glu Ala Gin Gly 500 Gly Lys Leu Val Cys Arg Ala His 505 510 Asn Ala Phe Gly Gly Glu Gly Val 515 520 Tyr Ala lie Ala Arg Cys Cys Leu 525 Leu Pro Gin Ala Asn cys Ser Val 530 535 His Thr Ala Pro Pro Ala Glu Ala 540 Ser Met Gly Thr Arg Val His cys 545 550 His Gin Gin Gly His val Leu Thr 555 560 Gly Cys Ser Ser His Trp Glu Val 565 Glu Asp Leu Gly Thr His Lys Pro 570 575 Pro Val Leu Arg Pro Arg Gly Gin 580 Pro Asn Gin Cys Val Gly His Arg 585 590 Page 37 P17140.IES sequence listing as filed Glu Ala Ser He His Ala Ser Cys 595 600 Cys His Ala Pro Gly Leu Glu Cys Lys val Lys Glu His Gly lie Pro 610 615 Ala Pro Gin Glu Gin Val Thr val 620 Ala Cys Glu Glu Gly Trp Thr Leu 625 630 Thr Gly Cys Ser Ala Leu pro Gly 635 640 Thr Ser His Val Leu Gly Ala Tyr 645 Ala Val Asp Asn Thr cys val val Arg Ser Arg Asp val Ser Thr Thr 660 Gly ser Thr Ser Glu Glu Ala Val 665 670 Thr Ala Val Ala lie cys Cys Arg 675 680 Ser Arg His Leu Ala Gin Ala ser 685 Gin Glu Leu Gin 690 <210> 16 <211> 662 <212> PRT <213> Homo sapiens <400> 16 Gin Glu Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg 15 1015 Ser Glu Glu Asp Gly Leu Ala Glu Ala pro Glu His Gly Thr Thr Ala 20 2530 Thr Phe His Arg Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr 35 4045 Val Val Val Leu Lys Glu Glu Thr His Leu ser Gin Ser Glu Arg Thr 50 5560 Ala Arg Arg Leu Gin Ala Gin Ala Ala Arg Arg Gly Tyr Leu Thr Lys 65 70 7580 lie Leu His Val Phe His Gly Leu Leu Pro Gly Phe Leu val Lys Met 85 9095 Ser Gly Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr 100 105110 lie Glu Glu Asp Ser Ser Val Phe Ala Gin Ser lie Pro Trp Asn Leu 115 120125 Glu Arg lie Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gin Pro Pro Page 38 P17140.IES 130 135 - sequence listing as filed 140 Asp Gly Gly Ser Leu Val Glu Val 145 150 Tyr Leu Leu Asp Thr ser lie Gin 155 160 Ser Asp His Arg Glu lie Glu Gly 165 Arg val Met val Thr Asp Phe Glu 170 175 Asn Val Pro Glu Glu Asp Gly Thr 180 Arg Phe His Arg Gin Ala Ser Lys 185 190 Cys Asp Ser His Gly Thr His Leu 195 200 Ala Gly val val ser Gly Arg Asp 205 Ala Gly val Ala Lys Gly Ala Ser 210 215 Met Arg ser Leu Arg val Leu Asn 220 Cys Gin Gly Lys Gly Thr Val Ser 225 230 Gly Thr Leu lie Gly Leu Glu Phe 235 240 lie Arg Lys ser Gin Leu val Gin 245 Pro val Gly Pro Leu Val Val Leu 250 255 Leu Pro Leu Ala Gly Gly Tyr Ser 260 Arg Val Leu Asn Ala Ala Cys Gin 265 270 Arg Leu Ala Arg Ala Gly Val Val 275 280 Leu Val Thr Ala Ala Gly Asn Phe 285 Arg Asp Asp Ala Cys Leu Tyr Ser 290 295 Pro Ala ser Ala Pro Glu val lie 300 Thr val Gly Ala Thr Asn Ala Gin 305 310 Asp Gin Pro Val Thr Leu Gly Thr 315 320 Leu Gly Thr Asn Phe Gly Arg Cys 325 Val Asp Leu Phe Ala Pro Gly Glu 330 335 Asp lie lie Gly Ala Ser ser Asp 340 Cys ser Thr Cys Phe Val Ser Gin 345 350 Ser Gly Thr ser Gin Ala Ala Ala 355 360 His Val Ala Gly lie Ala Ala Met 365 Met Leu Ser Ala Glu Pro Glu Leu 370 375 Thr Leu Ala Glu Leu Arg Gin Arg 380 Leu lie His Phe ser Ala Lys Asp 385 390 Val lie Asn Glu Ala Trp Phe Pro 395 400 Glu Asp Gin Arg val Leu Thr Pro Asn Leu Val Ala Thr Leu Pro Pro page 39 P17140.IES - sequence listing as filed 405 410415 Ser Thr Hi s Gly 420 Ala Gly Trp Gin Leu 425 Phe cys Arg Thr val 430 Trp Ser Ala Hi s Ser 435 Gly Pro Thr Arg Met 440 Ala Thr Ala He Ala 445 Arg Cys Ala Pro Asp 450 Glu Glu Leu Leu Ser 455 Cys ser Ser Phe ser 460 Arg ser Gly cys Arg 465 Arg Gly Glu Arg Met 470 Glu Al a Gin Gly Gly Lys 475 Leu Val cys Arg 480 Al a Hi s Asn Al a Phe 485 Gly Gly G1 u Gly val Tyr Ala 490 lie Al a Arg 495 Cys cys Leu Leu Pro 500 Gin Ala Asn cys ser 505 Val His Thr Al a Pro 510 Pro Ala Glu Ala ser 515 Met Gly Thr Arg val 520 Hi s cys His Gin G1 n 525 Gly Hi s Val Leu Thr Gly cys Ser Ser Hi s T rp Glu Val Glu Asp Leu Gly Thr Hi s 530 535 540 Lys Pro Pro val Leu Arg Pro Arg Gly Gin Pro Asn Gin Cys val Gly 545 550 555560 His Arg Glu Ala Ser lie His Ala Ser Cys Cys His Ala Pro Gly Leu 565 570575 Glu cys Lys val Lys Glu His Gly lie Pro Ala Pro Gin Glu Gin val 580 585590 Thr Val Ala cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu 595 600605 Pro Gly Thr ser His Val Leu Gly Ala Tyr Ala Val Asp Asn Thr cys 610 615620 Val val Arg Ser Arg Asp val Ser Thr Thr Gly Ser Thr Ser Glu Glu 625 630 635640 Ala Val Thr Ala val Ala He Cys Cys Arg ser Arg His Leu Ala Gin 645 650655 Ala Ser Gin Glu Leu Gin 660 <210> 17 Page 40 P17140.IES sequence listing as filed <211> 540 <212> PRT <213> Homo sapiens <400> 17 Ser 1 lie Pro Trp Asn 5 Leu Glu Arg lie Thr 10 Pro Pro Arg Tyr Arg 15 Ala Asp Glu Tyr Gin 20 Pro Pro Asp Gly Gly 25 Ser Leu Val Glu Val 30 Tyr Leu Leu Asp Thr 35 Ser lie Gin Ser Asp 40 Hi s Arg Gl U lie Glu 45 Gly Arg val Met val 50 Thr Asp Phe Glu Asn 55 val Pro Glu G1U Asp 60 Gly Thr Arg Phe Hi s 65 Arg Gin Ala Ser Lys 70 cys Asp Ser Hi s Gly 75 Thr Hi s Leu Al a Gly 80 val Val ser Gly Arg 85 Asp Al a Gly val Ala 90 Lys Gly Ala Ser Met 95 Arg Ser Leu Arg Val 100 Leu Asn cys Gin Gly 105 Lys Gly Thr val Ser 110 Gly Thr Leu lie Gly 115 Leu Glu Phe lie Arg 120 Lys Ser Gin Leu val 125 Gin Pro Val Gly pro 130 Leu val Val Leu Leu 135 Pro Leu Al a Gly Gly 140 Tyr Ser Arg val Leu 145 Asn Al a Al a cys Gin 150 Arg Leu Ala Arg Al a 155 Gly Val val Leu val 160 Thr Al a Al a Gly Asn 165 Phe Arg Asp Asp Ala 170 cys Leu Tyr Ser Pro 175 Al a ser Al a Pro Glu 180 Val lie Thr Val Gly 185 Al a Thr Asn Al a Gin 190 Asp Gl n Pro Val Thr 195 Leu Gly Thr Leu Gly 200 Thr Asn Phe Gly Arg 205 cys Val Asp Leu phe 210 Ala Pro Gly Glu Asp 215 lie lie Gly Al a Ser 220 Ser Asp Cys Ser Thr 225 Cys Phe Val Ser Gin 230 Ser Gly Thr ser Gin 235 Ala Ala Ala Hi s Val 240 Ala Gly lie Ala Ala 245 Met Met Leu Ser Ala 250 Glu Pro Glu Leu Thr 255 Leu Page 41 P17140.IES Ala Glu Leu Arg Gin Arg Leu lie 260 - sequence listing as filed His Phe Ser Ala Lys Asp Val lie 265 270 Asn Glu Ala Trp Phe Pro Glu Asp 275 280 Gin Arg Val Leu Thr Pro Asn Leu 285 Val Ala Thr Leu Pro Pro Ser Thr 290 295 His Gly Ala Gly Trp Gin Leu Phe 300 Cys Arg Thr Val Trp Ser Ala His 305 310 Ser Gly Pro Thr Arg Met Ala Thr 315 320 Ala lie Ala Arg cys Ala Pro Asp 325 Glu Glu Leu Leu ser Cys Ser ser 330 335 Phe Ser Arg Ser Gly Lys Arg Arg 340 Gly Glu Arg Met Glu Ala Gin Gly 345 350 Gly Lys Leu Val Cys Arg Ala His 355 360 Asn Ala Phe Gly Gly Glu Gly Val 365 Tyr Ala lie Ala Arg cys Cys Leu 370 375 Leu Pro Gin Ala Asn Cys Ser Val 380 His Thr Ala Pro Pro Ala Glu Ala 385 390 Ser Met Gly Thr Arg val His Cys 395 400 His Gin Gin Gly His Val Leu Thr 405 Gly Cys Ser Ser His Trp Glu Val 410 415 Glu Asp Leu Gly Thr His Lys Pro 420 Pro Val Leu Arg Pro Arg Gly Gin 425 430 Pro Asn Gin Cys Val Gly His Arg 435 440 Glu Ala ser lie His Ala Ser Cys 445 ' cys His Ala Pro Gly Leu Glu Cys 450 455 Lys Val Lys Glu His Gly lie Pro 460 Ala Pro Gin Glu Gin val Thr Val 465 470 Ala Cys Glu Glu Gly Trp Thr Leu 475 480 Thr Gly Cys ser Ala Leu Pro Gly 485 Thr ser His Val Leu Gly Ala Tyr 490 495 Ala val Asp Asn Thr Cys Val Val 500 Arg Ser Arg Asp Val Ser Thr Thr 505 510 Gly Ser Thr Ser Glu Glu Ala Val 515 520 Thr Ala Val Ala lie Cys Cys Arg 525 Page 42 P17140.IES sequence listing as filed Ser Arg His Leu Ala Gin Ala ser Gin Glu Leu Gin 530 535 540 <210> 18 <211> 692 <212> PRT <213> Homo sapiens <400> 18 Leu Pro Leu 15 Leu Met 1 Gly Thr Val Ser Ser 5 Arg Arg Ser Trp 10 Trp Pro Leu Leu Leu Leu 20 Leu Leu Leu Gly Pro 25 Al a Gly Al a Arg Al a 30 Gin Glu Asp G1 u Asp 35 Gly Asp Tyr Glu Glu 40 Leu val Leu Ala Leu 45 Arg ser Glu Glu Asp 50 Gly Leu Ala Glu Ala 55 Pro Glu Hi s Gly Thr 60 Thr Al a Thr Phe His 65 Arg cys Ala Lys Asp 70 Pro Trp Arg Leu Pro 75 Gly Thr Tyr val val 80 val Leu Lys Glu Glu 85 Thr Hi s Leu Ser Gin 90 Ser Glu Arg Thr Ala 95 Arg Arg Leu Gin Ala 100 Gin Ala Al a Arg Arg 105 Gly Tyr Leu Thr Lys 110 Il e Leu Hi s val Phe 115 Hl s Gly Leu Leu Pro 120 Gly Phe Leu Val Lys 125 Met Ser Gly ASp Leu 130 Leu Glu Leu Al a Leu 135 Lys Leu pro His Val 140 Asp Tyr il e Glu Glu 145 Asp Ser Ser Val Phe 150 Al a Gin ser lie Pro 155 Trp Asn Leu Glu Arg 160 lie Thr pro Pro Arg 165 Tyr Arg Ala Asp Glu 170 Tyr Gin Pro Pro Asp 175 Gly Gly ser Leu val 180 Glu Val Tyr Leu Leu 185 ASp Thr Ser lie Gl n 190 Ser Asp Hi s Arg Glu 195 lie Glu Gly Arg val 200 Met Val Thr ASp Phe 205 Glu Asn val Pro Glu 210 Glu Asp Gly Thr Arg 215 Phe Hi s Arg Gin Ala 220 Ser Lys Cys Asp ser Hi s Gly Thr His Leu Ala Gly val Val Ser Gly Arg ASp Al a Gly Page 43 P17140.IES - sequence listing as filed 225 230 235 240 Val Ala Lys Gly Ala Ser 245 Met Arg Ser Leu Arg 250 Val Leu Asn cys 255 Gin Gly Lys Gly Thr 260 val Ser Gly Thr Leu 265 lie Gly Leu Glu Phe 270 lie Arg Lys Ser Gin 275 Leu val Gin pro val 280 Gly Pro Leu val Val 285 Leu Leu Pro Leu Al a 290 Gly Gly Tyr Ser Arg 295 Val Leu Asn Al a Al a 300 Cys Gin Arg Leu Al a 305 Arg Al a Gly Val val 310 Leu val Thr Ala Al a 315 Gly Asn phe Arg Asp 320 Asp Al a cys Leu Tyr 325 Ser Pro Ala Ser Al a 330 pro Gl u Val lie Thr 335 Val Gly Al a Thr Asn 340 Al a Gin Asp Gin Pro 345 val Thr Leu Gly Thr 350 Leu Gly Thr Asn Phe 355 Gly Arg cys val Asp 360 Leu Phe Ala Pro Gly 365 Glu Asp lie lie Gly 370 Al a Ser Ser Asp cys 375 ser Thr Cys phe Val 380 Ser Gin Ser Gly Thr 385 Ser Gl n Al a Al a Al a 390 Hi s val Al a Gly ll e 395 Al a Al a Met Met Leu 400 Ser Al a Gl u Pro Glu 405 Leu Thr Leu Al a Glu 410 Leu Arg Gin Arg Leu 415 lie Hi s Phe ser Al a 420 Lys Asp val lie Ser 425 Glu Al a τ rp Phe Pro 430 Glu Asp Gin Arg Val 435 Leu Thr Pro Asn Leu 440 Val Al a Al a Leu Pro 445 Pro Ser Thr Hi s Gly 450 Al a Gly T rp Gin Leu 455 Phe cys Arg Thr Val 460 Trp ser Ala Hi s Ser 465 Gly Pro Thr Arg Met 470 Ala Thr Ala Val Ala 475 Arg cys Al a Pro Asp 480 Glu Glu Leu Leu Ser 485 Cys Ser Ser Phe Ser 490 Arg Ser Gly Lys Arg 495 Arg Gly Glu Arg Met Glu Ala Gin Gly Gly Lys Leu Val Cys Arg Ala Hi s Page 44 500 P17140.IES - sequence listing as filed 505 510 Asn Ala Phe Gly Gly Glu Gly val 515520 Leu Pro Gin Ala Asn Cys ser Val 530535 Ser Met Gly Thr Arg val His Cys 545550 Tyr Ala lie Ala Arg Cys Cys Leu 525 His Thr Ala Pro Pro Ala Glu Ala 540 His Gin Gin Gly His Val Leu Thr 555 560 Gly cys Ser Ser His Trp Glu val Glu Asp Leu Gly Thr His Lys Pro 565 570 575 Pro Val Leu Arg Pro Arg Gly Gin 580 Pro Asn Gin Cys Val Gly His Arg 585 590 Glu Ala Ser lie His Ala Ser Cys 595 600 cys His Ala Pro Gly Leu Glu cys 605 Lys val Lys Glu His Gly lie Pro 610 615 Ala Pro Gin Glu Gin Val Thr Val 620 Ala Cys Glu Glu Gly Trp Thr Leu 625 630 Thr Gly Cys Ser Ala Leu Pro Gly 635 640 Thr Ser His Val Leu Gly Ala Tyr 645 Ala Val Asp Asn Thr Cys val Val 650 655 Arg Ser Arg Asp Val Ser Thr Thr 660 Gly Ser Thr Ser Glu Glu Ala Val 665 670 Thr Ala val Ala 675 lie Cys cys Arg Ser Arg His 680 Leu Ala Gin Ala ser 685 Gin Glu Leu Gin 690 <210> 19 <2U> 662 <212> PRT <213> Homo sapiens <400> 19 Gin Glu Asp Glu Asp Gly Asp Tyr Glu Glu Leu 1 5 10 val Leu Ala Leu Arg Ser Glu Glu Asp Gly Leu Ala Glu Ala Pro Glu 20 25 Thr Phe His Arg Cys Ala Lys Asp Pro Trp Arg 35 40 His Gly Thr Thr Ala 30 Leu Pro Gly Thr Tyr 45 Page 45 P17140.IES - sequence listing as filed Val Val 50 val Leu Lys Glu Glu 55 Thr Hi s Leu Ser Gin Ser 60 Glu Arg Thr Ala 65 Arg Arg Leu Gin Ala 70 Gin Ala Al a Arg Arg Gly Tyr 75 Leu Thr Lys 80 lie Leu Hi s val Phe Hi s 85 Gly Leu Leu Pro 90 Gly Phe Leu val Lys 95 Met Ser Gly Asp Leu 100 Leu Glu Leu Al a Leu 105 Lys Leu Pro His val 110 Asp Tyr He Glu Glu 115 Asp ser ser Val Phe 120 Al a Gin Ser lie Pro 125 Trp Asn Leu Glu Arg 130 He Thr Pro Pro Arg 135 Tyr Arg Ala Asp Glu Tyr 140 Gin Pro Pro Asp 145 Gly Gly Ser Leu val 150 Glu Val Tyr Leu Leu Asp Thr 155 ser lie Gin 160 Ser Asp Hi s Arg Glu lie 165 Glu Gly Arg Val 170 Met val Thr Asp Phe 175 Glu Asn Val Pro Glu 180 Glu Asp Gly Thr Arg 185 Phe His Arg Gin Al a 190 Ser Lys Cys Asp Ser 195 Hi s Gly Thr Hi s Leu 200 Ala Gly Val val ser 205 Gly Arg Asp Ala Gly 210 Val Al a Lys Gly Ala 215 Ser Met Arg Ser Leu Arg 220 val Leu Asn cys 225 Gl n Gly Lys Gly Thr ' 230 Val ser Gly Thr Leu lie Gly 235 Leu Glu Phe 240 lie Arg Lys Ser Gin Leu 245 Val Gin Pro val 250 Gly Pro Leu val val 255 Leu Leu Pro Leu Al a 260 Gly Gly Tyr Ser Arg 265 Val Leu Asn Ala Al a 270 cys Gl n Arg Leu Al a 275 Arg Ala Gly Val Val 280 Leu Val Thr Ala Ala 285 Gly Asn Phe Arg Asp 290 Asp Ala Cys Leu Tyr 295 Ser Pro Ala Ser Ala Pro 300 Gl U Val lie Thr 305 Val Gly Al a Thr Asn 310 Al a Gin Asp Gin pro val Thr 315 Leu Gly Thr 320 Page 46 P17140.IES - sequence listing as filed Leu Gly Thr Asn Phe 325 Gly Arg Cys val Asp Leu Phe Ala 330 Pro Gly 335 Glu Asp lie lie Gly 340 Al a Ser Ser Asp cys 345 ser Thr cys Phe val 350 Ser Gin Ser Gly Thr 355 Ser Gin Ala Ala Al a 360 Hi s val Al a Gly lie 365 Al a Ala Met Met Leu 370 Ser Ala Glu Pro Gl u 375 Leu Thr Leu Ala Glu 380 Leu Arg Gin Arg Leu 385 11 e Hi s Phe ser Al a 390 Lys Asp val lie ser 395 Glu Al a T rp phe Pro 400 Glu Asp Gl n Arg Val 405 Leu Thr Pro Asn Leu 410 Val Al a Al a Leu Pro 415 Pro Ser Thr Hi s Gly 420 Ala Gly Trp Gin Leu 425 Phe cys Arg Thr Val 430 T rp ser Ala Hi s Ser 435 Gly pro Thr Arg Met 440 Al a Thr Al a val Ala 445 Arg cys Ala Pro Asp 450 Glu Glu Leu Leu Ser 455 cys Ser Ser Phe Ser 460 Arg Ser Gly Lys Arg 465 Arg Gly Glu Arg Met 470 Glu Al a Gl n Gly Gly 475 Lys Leu Val cys Arg 480 Al a Hi s Asn Ala phe 485 Gly Gly Glu Gly val 490 Tyr Ala lie Ala Arg 495 cys cys Leu Leu Pro 500 Gin Al a Asn cys Ser 505 Val Hi s Thr Al a Pro 510 Pro Al a Glu Al a Ser 515 Met Gly Thr Arg val 520 Hi s cys Hi s Gl n Gin 525 Gly Hi s val Leu Thr 530 Gly Cys Ser Ser Hi s 535 Trp Glu val Glu Asp 540 Leu Gly Thr Hi s Lys 545 Pro pro Val Leu Arg 550 Pro Arg Gly Gin Pro 555 Asn Gin cys Val Gly 560 Hi s Arg Glu Ala Ser 565 lie Hi s Ala Ser cys 570 cys Hi s Ala Pro Gly 575 Leu Gl u Cys Lys Val 580 Lys Glu Hi s Gly lie 585 Pro Al a Pro Gin Glu 590 Gin Val Page 47 P17140.IES sequence listing as filed Thr Val Ala cys Glu 595 Glu Gly Trp 600 Thr Leu Thr Gly cys 605 ser Ala Leu Pro Gly 610 Thr Ser His val Leu 615 Gly Ala Tyr Ala val 620 Asp Asn Thr cys val 625 val Arg Ser Arg Asp 630 Val Ser Thr Thr Gly 635 Ser Thr Ser Glu Glu 640 Ala Val Thr Ala Val 645 Al a lie Cys cys Arg 650 Ser Arg Hi s Leu Ala 655 Gin Al a ser Gin Glu 660 Leu Gin <210> 20 <211> 540 <212> PRT <213> Homo sapiens <400> 2( Ser lie 1 ) Pro Trp Asn 5 Leu Glu Arg lie Thr 10 Pro Pro Arg Tyr Arg 15 Ala Asp Glu Tyr Gin 20 Pro Pro Asp Gly Gly 25 Ser Leu val Glu Val 30 Tyr Leu Leu Asp Thr 35 Ser lie Gin Ser Asp 40 Hi s Arg Glu lie Glu 45 Gly Arg val Met val 50 Thr Asp Phe Glu Asn 55 Val Pro G1U Glu Asp 60 Gly Thr Arg Phe Hi s 65 Arg Gin Ala Ser Lys 70 cys Asp ser His Gly 75 Thr Hi s Leu Al a Gly 80 Val Val ser Gly Arg 85 Asp Ala Gly Val Ala 90 Lys Gly Ala ser Met 95 Arg Ser Leu Arg Val 100 Leu Asn Cys Gin Gl y 105 Lys Gly Thr val Ser 110 Gly Thr Leu lie Gly 115 Leu Glu Phe il e Arg 120 Lys Ser Gin Leu Val 125 Gl n pro Val Gly Pro 130 Leu Val val Leu Leu 135 pro Leu Al a Gly Gly 140 Tyr Ser Arg val Leu 145 Asn Ala Al a Cys Gin 150 Arg Leu Al a Arg Ala 155 Gly Val Val Leu val 160 Thr Ala Ala Gly Asn Phe Arg Asp Asp Ala Cys Page 48 Leu Tyr Ser Pro Ala - sequence listing as filed P17140.IES 165 170 175 Ser Ala Pro Glu 180 val lie Thr val Gly Ala 185 Thr Asn Ala Gin Asp Gin 190 Pro Val Thr Leu 195 Gly Thr Leu Gly Thr Asn 200 Phe Gly Arg Cys val Asp 205 Leu Phe Ala Pro 210 Gly Glu Asp He lie Gly 215 Ala Ser Ser Asp Cys Ser 220 Thr cys Phe Val 225 Ser Gin Ser Gly Thr Ser 230 Gin Ala Ala Ala His Val 235 240 Ala Gly lie Ala Al a 245 Met Met Leu Ser Ala 250 Glu Pro Glu Leu Thr Leu 255 Ala Glu Leu Arg 260 Gin Arg Leu lie His Phe 265 ser Ala Lys Asp val lie 270 Ser Glu Ala Trp 275 Phe Pro Glu Asp Gin Arg 280 Val Leu Thr Pro Asn Leu 285 Val Ala Ala Leu 290 Pro Pro ser Thr His Gly 295 Ala Gly Trp Gin Leu Phe 300 Cys Arg Thr val 305 Trp ser Ala His ser Gly 310 Pro Thr Arg Met Ala Thr 315 320 Ala val Ala Arg cys 325 Ala Pro Asp Glu Glu 330 Leu Leu Ser Cys Ser Ser 335 Phe Ser Arg Ser 340 Gly Lys Arg Arg Gly Glu 345 Arg Met Glu Ala Gin Gly ' 350 Gly Lys Leu val 355 cys Arg Al a His Asn Al a 360 Phe Gly Gly Glu Gly Val 365 Tyr Ala lie Ala 370 Arg Cys Cys Leu Leu Pro 375 Gin Ala Asn Cys Ser Val 380 His Thr Ala Pro 385 Pro Ala Glu Ala Ser Met 390 Gly Thr Arg Val His Cys 395 400 His Gin Gin Gly Hi s 405 val Leu Thr Gly cys 410 ser Ser His Trp Glu val 415 Glu Asp Leu Gly 420 Thr His Lys Pro Pro Val 425 Leu Arg Pro Arg Gly Gin 430 Pro Asn Gin Cys Val Gly His Arg Glu Ala Ser lie His Ala Ser Cys Page 49 435 P17140.IES - sequence listing as filed 440 445 Cys His Ala Pro Gly Leu Glu cys 450 455 Lys val Lys Glu His Gly lie Pro 460 Ala pro Gin Glu Gin val Thr Val 465 470 Ala Cys Glu Glu Gly Trp Thr Leu 475 480 Thr Gly Cys Ser Ala Leu Pro Gly 485 Thr Ser His val Leu Gly Ala Tyr 490 495 Ala val Asp Asn Thr Cys val val 500 Arg ser Arg Asp Val Ser Thr Thr 505 510 Gly Ser Thr ser Glu Glu Ala Val 515 520 Thr Ala val Ala lie Cys Cys Arg 525 Ser Arg His Leu Ala Gin Ala Ser 530 535 Gin Glu Leu Gin 540 <210> 21 <211> 692 <212> PRT <213> Homo sapiens <400> 21 Met Gly Thr Val ser ser Arg Arg 1 5 Ser Trp Trp Pro Leu Pro Leu Leu Leu Leu Leu Leu Leu Leu Leu Gly 20 pro Ala Gly Ala Arg Ala Gin Glu Asp Glu Asp Gly Asp Tyr Glu Glu 35 40 Leu Val Leu Ala Leu Arg Ser Glu 45 Glu Asp Gly Leu Ala Glu Ala Pro 55 Glu His Gly Thr Thr Ala Thr Phe 60 His Arg Cys Ala Lys Asp Pro Trp 65 70 Arg Leu pro Gly Thr Tyr Val val 75 80 Val Leu Lys Glu Glu Thr His Leu 85 Ser Gin ser Glu Arg Thr Ala Arg 95 Arg Leu Gin Ala Gin Ala Ala Arg 100 Arg Gly Tyr Leu Thr Lys lie Leu 105 110 His val Phe His Gly Leu Leu Pro 115 120 Gly Phe Leu Val Lys Met ser Gly 125 Asp Leu Leu Glu Leu Ala Leu Lys 130 135 Leu Pro His val Asp Tyr lie Glu 140 Page 50 Glu 145 Asp Ser Ser Val P17140.IES - sequence listing as filed Phe 150 Al a Gin Ser lie Pro 155 Trp Asn Leu Glu Arg 160 lie Thr Pro Pro Arg 165 Tyr Arg Al a Asp Glu 170 Tyr Gin Pro Pro Asp 175 Gly Gly Ser Leu val 180 Glu Val Tyr Leu Leu 185 ASp Thr Ser lie Gin 190 Ser Asp Hi s Arg Glu 195 lie Glu Gly Arg val 200 Met Val Thr Asp Phe 205 Gl u Asn val Pro Glu 210 Glu Asp Gly Thr Arg 215 Phe Hi s Arg Gl n Ala 220 ser Lys Cys Asp Ser 225 Hi s Gly Thr Hi s Leu 230 Al a Gly val val Ser 235 Gly Arg Asp Al a Gly 240 val Al a Lys Gly Ala 245 ser Met Arg Ser Leu 250 Arg Val Leu Asn Cys 255 Gin Gly Lys Gly Thr 260 Val Ser Gly Thr Leu 265 lie Gly Leu Glu Phe 270 lie Arg Lys Ser Gl n 275 Leu val Gin Pro Val 280 Gly pro Leu Val Val 285 Leu Leu Pro Leu Ala 290 Gly Gly Tyr ser Arg 295 Val Leu Asn Al a Ala 300 Cys Gin Arg Leu Al a 305 Arg Al a Gly val Val 310 Leu val Thr Al a Al a 315 Gly Asn Phe Arg Asp 320 Asp Al a Cys Leu Tyr 325 Ser Pro Al a Ser Al a 330 Pro Glu Val He Thr 335 Val Gly Al a Thr Asn 340 Al a Gin ASp Gl n Pro 345 val Thr Leu Gly Thr 350 Leu Gly Thr Asn Phe 355 Gly Arg cys Val Asp 360 Leu Phe Ala pro Gly 365 Glu Asp lie He Gly 370 Al a ser ser Asp Cys 375 Ser Thr cys Phe Val 380 Ser Gin Ser Gly Thr 385 ser Gin Al a Ala Ala 390 Hl s val Al a Gly He 395 Ala Ala Met Met Leu 400 Ser Ala Glu Pro Glu 405 Leu Thr Leu Al a Glu 410 Leu Arg Gin Arg Leu 415 lie Page 51 P17140.IES sequence listing as filed Hi s Phe Ser Al a 420 Lys Asp val lie Asn 425 Glu Al a Trp Phe Pro 430 Glu Asp Gin Arg Val 435 Leu Thr Pro Asn Leu 440 val Ala Thr Leu Pro 445 Pro Ser Thr Hi s Gly 450 Ala Gly Trp Gin Leu 455 Phe cys Arg Thr val 460 Trp ser Ala Hi s Ser 465 Gly Pro Thr Arg Met 470 Al a Thr Al a lie Ala 475 Arg cys Al a Pro Asp 480 Glu Glu Leu Leu Ser 485 cys Ser Ser Phe Ser 490 Arg Ser Gly Lys Arg 495 Arg Gly Glu Arg Met 500 Glu Ala Gl n Gly Gly 505 Lys Leu val cys Arg 510 Al a Hi s Asn Al a Phe 515 Gly Gly Glu Gly val 520 Tyr Al a lie Ala Arg 525 cys cys Leu Leu Pro 530 Gin Ala Asn cys Ser 535 Val Hi s Thr Ala Pro 540 Pro Ala Glu Ala Ser 545 Met Gly Thr Arg val 550 Hi s Cys His Gin Gin 555 Gly Hi s val Leu Thr 560 Gly Cys Ser Ser Hi s 565 Trp Glu val Glu Asp 570 Leu Gly Thr Hi s Lys 575 Pro Pro Val Leu Arg 580 Pro Arg Gly Gin Pro 585 Asn Gin Cys Val Gly 590 Hi s Arg Glu Al a Ser 595 lie His Al a Ser Cys 600 cys Hi s Al a Pro Gly 605 Leu Glu Cys Lys val 610 Lys Glu Hi s Gly lie 615 Pro Al a Pro Pro Gl u 620 Gin val Thr val Ala 625 cys Glu Glu Gly τ rp 630 Thr Leu Thr Gly Cys 635 Ser Ala Leu Pro Gly 640 Thr Ser Hi S val Leu 645 Gly Al a Tyr Al a val 650 Asp Asn Thr cys Val 655 Val Arg ser Arg Asp 660 Val ser Thr Thr Gly 665 Ser Thr Ser Glu Glu 670 Ala val Thr Ala Val 675 Ala lie cys cys Arg 680 Ser Arg Hi s Leu Ala 685 Gin Al a Ser Page 52 P17140.IES sequence listing as filed Gin Glu Leu Gin 690 <210> 22 <211> 662 <212> PRT <213> Homo sapiens <400> 22 Gin Glu Asp Glu Asp Gly 1 5 Ser Glu Glu Asp Gly Leu 20 Thr Phe His Arg Cys Ala 35 Asp Tyr Glu Glu Leu Val 10 Ala Glu Ala Pro Glu His 25 Lys Asp Pro Trp Arg Leu 40 Leu Ala Leu Arg Gly Thr Thr Ala Pro Gly Thr Tyr 45 Val Val val Leu Lys Glu Glu Thr His Leu Ser Gin ser Glu Arg Thr 50 5560 Ala Arg Arg Leu Gin Ala Gin Ala Ala Arg Arg Gly Tyr Leu Thr Lys 65 70 7580 lie Leu His Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met 9095 ser Gly Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr 100 105110 lie Glu Glu Asp Ser Ser Val Phe Ala Gin ser lie Pro Trp Asn Leu 115 120125 Glu Arg lie Thr Pro pro Arg Tyr Arg Ala Asp Glu Tyr Gin Pro Pro 130 135140 Asp Gly Gly ser Leu Val Glu val Tyr Leu Leu Asp Thr ser lie Gin 145 150 155160 Ser Asp His Arg Glu lie Glu Gly Arg Val Met val Thr Asp Phe Glu 165 170175 Asn Val Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gin Ala ser Lys 180 185190 cys Asp Ser His Gly Thr His Leu Ala Gly Val val ser Gly Arg Asp 195 200205 Ala Gly val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn 210 215220 Cys Gin Gly Lys Gly Thr Val Ser Gly Thr Leu lie Gly Leu Glu Phe Page 53 225 P17140.IES 230 - sequence listing 235 as filed 240 lie Arg Lys Ser Gin 245 Leu Val Gin Pro Val Gly Pro Leu 250 Val Val 255 Leu Leu Pro Leu Ala Gly 260 Gly Tyr ser Arg val Leu Asn Ala 265 Ala cys 270 Gin Arg Leu Ala Arg Ala 275 Gly Val val 280 Leu val Thr Ala Ala 285 Gly Asn Phe Arg Asp Asp Ala Cys 290 Leu Tyr Ser 295 Pro Ala Ser Ala Pro 300 Glu Val lie Thr val Gly Ala Thr 305 Asn Ala Gin 310 Asp Gin Pro val Thr 315 Leu Gly Thr 320 Leu Gly Thr Asn Phe 325 Gly Arg cys Val Asp Leu Phe Ala 330 Pro Gly 335 Glu Asp lie lie Gly Ala 340 Ser ser Asp Cys Ser Thr cys Phe 345 Val Ser 3 50 Gin ser Gly Thr Ser Gin 355 Ala Ala Ala 360 His val Ala Gly lie 365 Ala Ala Met Met Leu Ser Ala Glu 370 Pro Glu Leu 375 Thr Leu Ala Glu Leu 380 Arg Gln Arg Leu lie His Phe Ser 385 Ala Lys Asp 390 val lie Asn Glu Ala 395 Trp Phe Pro 400 Glu Asp Gin Arg val 405 Leu Thr Pro Asn Leu val Ala Thr 410 Leu Pro 415 Pro ser Thr His Gly Ala 420 Gly Trp Gin Leu Phe Cys Arg Thr 425 Val Trp 430 Ser Ala His Ser Gly Pro 435 Thr Arg Met 440 Ala Thr Ala lie Ala 445 Arg Cys Ala Pro Asp Glu Glu Leu 450 Leu ser Cys 455 Ser ser Phe Ser Arg 460 ser Gly Lys Arg Arg Gly Glu Arg 465 Met Glu Ala 470 Gin Gly Gly Lys Leu 475 Val Cys Arg 480 Ala His Asn Ala Phe 485 Gly Gly Glu Gly val Tyr Ala He 490 Ala Arg 495 cys Cys Leu Leu Pro Gin Ala Asn Cys Ser val His Thr Ala Page 54 pro Pro Ala 500 P17140 .IES - sequence listing 505 as filed 510 Glu Ala Ser Met Gly Thr Arg val Hi s cys Hi s Gin Gin Gly His Val 515 520 525 Leu Thr Gly cys Ser Ser Hi s Trp Glu Val Glu Asp Leu Gly Thr His 530 535 540 Lys Pro Pro val Leu Arg Pro Arg Gly Gin Pro Asn Gin cys val Gly 545 550 555 560 Hi s Arg Glu Al a ser lie Hi s Al a Ser cys cys Hi s Al a pro Gly Leu 565 570 575 Glu Cys Lys val Lys Glu Hi s Gly lie Pro Al a Pro pro Glu Gin val 580 585 590 Thr Val Ala cys Gl u Glu Gly T rp Thr Leu Thr Gly Cys Ser Al a Leu 595 600 605 Pro Gly Thr Ser Hi s Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys 610 615 620 val val Arg Ser Arg Asp Val ser Thr Thr Gly Ser Thr Ser Glu Glu 625 630 635 640 Ala Val Thr Al a Val Ala lie cys cys Arg Ser Arg Hi s Leu Al a Gin 645 650 655 Ala ser Gin Gl u Leu Gin 660 <210> 23 <211> 540 <212> PRT <213> Homo sapiens <400> 23 ser lie Pro Trp Asn Leu Glu Arg lie Thr 510 Asp Glu Tyr Gin Pro Pro Asp Gly Gly Ser 2025 Leu Asp Thr Ser lie Gin Ser Asp His Arg 3540 Met val Thr Asp Phe Glu Asn val Pro Glu 5055 His Arg Gin Ala Ser Lys Cys Asp Ser His 6570 Pro Pro Arg Tyr Arg 15 Al a Leu Val Glu Val 30 Tyr Leu Glu Il e Glu 45 Gly Arg Val Gl u Asp 60 Gly Thr Arg Phe Gly Thr Hi s Leu Ala Gly 80 Page 55 P17140.IES sequence listing as filed Val Val Ser Gly Arg Asp Ala Gly val Ala Lys Gly Ala Ser Met Arg 85 9095 Ser Leu Arg Val Leu Asn Cys Gin Gly Lys Gly Thr Val ser Gly Thr 100 105110 Leu lie Gly Leu Glu Phe lie Arg Lys Ser Gin Leu Val Gin Pro val 115 120125 Gly Pro Leu Val Val Leu Leu Pro Leu Ala Gly Gly Tyr Ser Arg val 130 135140 Leu Asn Ala Ala cys Gin Arg Leu Ala Arg Ala Gly val Val Leu Val 145 150 155160 Thr Ala Ala Gly Asn 165 Phe Arg ASp Asp Al a 170 cys Leu Tyr Ser Pro 175 Ala Ser Ala Pro Glu val lie Thr Val Gly Al a Thr Asn Ala Gin Asp Gin 180 185 190 Pro Val Thr Leu Gly Thr Leu Gly Thr Asn Phe Gly Arg Cys Val Asp 195 200205 Leu Phe Ala Pro Gly Glu Asp lie lie Gly Ala ser ser Asp Cys ser 210 215220 Thr 225 cys Phe val Ser Gin 230 ser Gly Thr Ser Gin Ala 235 Al a Al a Hi s Val 240 Al a Gly lie Ala Ala Met 245 Met Leu Ser Al a 250 Glu Pro G1 u Leu Thr 255 Leu Al a Glu Leu Arg 260 Gin Arg Leu lie His 265 Phe Ser Ala Lys Asp 270 Val il e Asn Glu Ala Trp 275 Phe Pro Glu Asp Gin 280 Arg val Leu Thr 285 Pro Asn Leu val Ala 290 Thr Leu pro Pro Ser Thr His 295 Gly Ala Gly 300 Trp Gin Leu Phe cys 305 Arg Thr val Trp Ser 310 Ala His ser Gly Pro Thr 315 Arg Met Ala Thr 320 Al a lie Ala Arg Cys Ala 325 Pro Asp Glu Glu 330 Leu Leu Ser cys Ser 335 Ser Phe Ser Arg Ser 340 Gly Lys Arg Arg Gly 345 Glu Arg Met Glu Al a 350 Gin Gly Page 56 P17140.IES sequence listing as filed Gly Lys Leu 355 val cys Arg Al a Hi s 360 Asn Ala Phe Gly Gly 365 Glu Gly Val Tyr Ala 370 lie Ala Arg Cys Cys 375 Leu Leu Pro Gin Ala 380 Asn cys ser Val Hi s 385 Thr Ala Pro pro Ala 390 Glu Al a Ser Met Gly 395 Thr Arg Val Hi s Cys 400 Hi s Gin Gin Gly Hi s 405 Val Leu Thr Gly cys 410 Ser Ser Hi s T rp Glu 415 Val G1 u Asp Leu Gly 420 Thr His Lys Pro Pro 425 Val Leu Arg Pro Arg 430 Gly G1 n Pro Asn Gin 435 cys val Gly Hi s Arg 440 G1 u Ala Ser lie Hi s 445 Ala Ser cys Cys Hi s 450 Ala Pro Gly Leu Glu 455 Cys Lys Val Lys Glu 460 Hi s Gly lie Pro Al a 465 Pro pro Glu Gin val 470 Thr Val Al a Cys Glu 475 Glu Gly Trp Thr Leu 480 Thr Gly Cys ser Al a 485 Leu Pro Gly Thr Ser 490 Hi s Val Leu Gly Ala 495 Tyr Al a val Asp Asn 500 Thr cys val val Arg 505 Ser Arg Asp val Ser 510 Thr Thr Gly Ser Thr 515 Ser Glu Glu Al a Val 520 Thr Al a val Al a lie 525 cys Cys Arg ser Arg 530 His Leu Al a Gin Ala 535 ser Gin Glu Leu G1 n 540 <210> 24 <211> 692 <212> PRT <213> Homo sapiens <400> 24 Met 1 Gly Thr Val Ser 5 Ser Arg Arg ser Trp Trp 10 Pro Leu Pro Leu 15 Leu Leu Leu Leu Leu 20 Leu Leu Leu Gly Pro 25 Ala Gly Al a Arg Ala 30 Gin Glu Asp Glu Asp 35 Gly Asp Tyr Glu Glu Leu 40 val Leu Al a Leu 45 Leu ser Glu Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala Thr Phe Page 57 P17140.IES - sequence listing as filed 55 60 His 65 Arg cys Ala Lys Asp 70 Pro Trp Arg Leu pro 75 Gly Thr Tyr val val 80 val Leu Lys Glu Glu 85 Thr Hi s Leu Ser Gin 90 Ser Glu Arg Thr Ala 95 Arg Arg Leu Gin Ala 100 Gin Ala Al a Arg Arg 105 Gly Tyr Leu Thr Lys 110 He Leu Hi s Val Phe 115 Hi s Gly Leu Leu Pro 120 Gly Phe Leu val Lys 125 Met ser Gly Asp Leu 130 Leu Glu Leu Ala Leu 135 Lys Leu Pro Hi s Val 140 Asp Tyr lie Glu Glu 145 Asp Ser Ser Val Phe 150 Al a Gin Ser lie Pro 155 Trp Asn Leu Glu Arg 160 lie Thr Pro Pro Arg 165 Tyr Arg Al a Asp Glu 170 Tyr Gin Pro Pro Asp 175 Gly Gly Ser Leu Val 180 Glu Val Tyr Leu Leu 185 Asp Thr Ser lie Gin 190 Ser Asp Hi s Arg Glu 195 He Glu Gly Arg Val 200 Met val Thr Asp Phe 205 Glu Asn Val Pro Glu 210 Glu Asp Gly Thr Arg 215 Phe Hi s Arg Gin Al a 220 ser Lys cys Asp ser 225 Hi s Gly Thr Hi s Leu 230 Al a Gly val Val Ser 235 Gly Arg Asp Al a Gly 240 val Ala Lys Gly Al a 245 Ser Met Arg Ser Leu 250 Arg Val Leu Asn cys 255 Gin Gly Lys Gly Thr 260 Val Ser Gly Thr Leu 265 lie Gly Leu Glu Phe 270 lie Arg Lys Ser Gin 275 Leu Val Gin Pro Val 280 Gly Pro Leu Val val 285 Leu Leu Pro Leu Ala 290 Gly Gly Tyr Ser Arg 295 Val Leu Asn Al a Ala 300 cys Gin Arg Leu Al a 305 Arg Ala Gly Val val 310 Leu val Thr Ala Ala 315 Gly Asn Phe Arg Asp 320 Asp Ala cys Leu Tyr Ser Pro Ala Ser Al a Pro Glu Val He Thr val Page 58 - sequence listing as filed P17140.IES 325 330 335 Gly Ala Thr Asn 340 Ala Gin Asp Gl n Pro 345 val Thr Leu Gly Thr 350 Leu Gly Thr Asn Phe 355 Gly Arg Cys val Asp 360 Leu Phe Ala Pro Gly 365 Glu ASp He lie Gly 370 Ala Ser Ser Asp cys 375 Ser Thr cys Phe Val 380 ser Gin Ser Gly Thr 385 Ser Gin Ala Al a Ala 390 Hi s Val Ala Gly lie 395 Ala Ala Met Met Leu 400 Ser Ala Glu Pro Glu 405 Leu Thr Leu Al a Glu 410 Leu Arg Gin Arg Leu 415 lie Hi s Phe Ser Ala 420 Lys Asp Val lie Asn 425 Glu Ala T rp Phe Pro 430 Glu Asp Gin Arg val 435 Leu Thr Pro Asn Leu 440 Val Al a Ala Leu Pro 445 Pro ser Thr Hi s Gly 450 Al a Gly Trp Gin Leu 455 Phe Cys Arg Thr Val 460 Trp Ser Ala Hi s ser 465 Gly Pro Thr Arg Met 470 Ala Thr Al a Val Ala 475 Arg cys Al a Pro Asp 480 Glu Glu Leu Leu Ser 485 Cys Ser ser Phe Ser 490 Arg Ser Gly Lys Arg 495 Arg Gly Gl u Arg Met 500 Glu Al a Gin Gly Gly 505 Lys Leu Val cys Arg 510 Al a Hi s Asn Al a Phe 515 Gly Gly Glu Gly val 520 Tyr Al a He Al a Arg 525 Cys cys Leu Leu Pro 530 Gin Ala Asn Cys Ser 535 val His Thr Ala Pro 540 Pro Al a Glu Al a Ser 545 Met Gly Thr Arg val 550 Hi s cys Hi s Gin Gin 555 Gly Hi s val Leu Thr 560 Gly cys Ser Ser Hi s 565 Trp Glu val Glu Asp 570 Leu Gly Thr Hi s Lys 575 Pro Pro val Leu Arg 580 Pro Arg Gly Gin Pro 585 Asn Gin cys Val Gly 590 Hi s Arg Glu Ala Ser lie Hi s Ala ser Cys Cys His Ala Page 59 Pro Gly Leu Glu cys P17140.IES - sequence listing as filed 595 Lys val Lys Glu His 610 Gly He Pro Ala Pro Gin Glu Gin Val Thr val 615 620 Ala Cys Glu Glu Gly 625 Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly 630 635 640 Thr Ser His Val Leu 645 Gly Ala Tyr Ala Val Asp Asn Thr Cys Val val 650 655 Arg ser Arg Asp val 660 ser Thr Thr Gly Ser Thr Ser Glu Glu Ala val 665 670 Thr Ala val Ala lie Cys cys Arg Ser Arg His Leu Ala Gin Ala Ser 680 685 Gin Glu Leu Gin 690 <210> 25 <211> 662 <212> PRT <213> Homo sapiens <400> 25 Gin Glu Asp Glu Asp 1 5 Gly Asp Tyr Glu Glu Leu val Leu Ala Leu Leu ser Glu Glu Asp Gly 20 Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala 25 30 Thr Phe His Arg cys 35 Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr 40 45 Val val Val Leu Lys 50 Glu Glu Thr His Leu ser Gin Ser Glu Arg Thr 55 60 Ala Arg Arg Leu Gin 65 Ala Gin Ala Ala Arg Arg Gly Tyr Leu Thr Lys 70 75 80 lie Leu His val Phe His Gly Leu Leu Pro Gly Phe Leu val Lys Met 90 95 Ser Gly Asp Leu Leu 100 Glu Leu Ala Leu Lys Leu Pro His val Asp Tyr 105 110 lie Glu Glu Asp Ser 115 Ser val Phe Ala Gin ser lie pro Trp Asn Leu 120 125 Glu Arg lie Thr Pro 130 Pro Arg Tyr Arg Ala Asp Glu Tyr Gin Pro Pro 135 140 Page 60 P17140.IES - sequence listing as filed Asp Gly Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser lie Gin 145 150 155160 Ser Asp His Arg Glu lie Glu Gly Arg Val Met val Thr Asp Phe Glu 165 170175 Asn Val Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gin Ala ser Lys 180 185190 cys Asp Ser His Gly Thr His Leu Ala Gly Val val ser Gly Arg Asp 195 200205 Ala Gly val Ala Lys Gly Ala ser Met Arg ser Leu Arg val Leu Asn 210 215220 Cys Gin Gly Lys 225 Gly Thr 230 Val Ser Gly Thr Leu 235 He Gly Leu Glu Phe 240 lie Arg Lys Ser Gin Leu 245 Val Gin Pro Val 250 Gly Pro Leu val Val 255 Leu Leu Pro Leu Ala 260 Gly Gly Tyr Ser Arg 265 Val Leu Asn Ala Ala Cys 270 Gin Arg Leu Ala Arg 275 Ala Gly Val Val Leu 280 val Thr Ala Ala 285 Gly Asn Phe Arg Asp Asp Ala 290 Cys Leu Tyr 295 Ser pro Al a Ser Ala Pro 300 Glu Val lie Thr Val Gly Ala 305 Thr Asn 310 Al a Gin Asp Gin pro 315 Val Thr Leu Gly Thr 320 Leu Gly Thr Asn Phe Gly 325 Arg Cys Val ASp 330 Leu Phe Ala Pro Gly 335 Glu Asp lie lie Gly 340 Ala Ser Ser Asp Cys 345 Ser Thr Cys Phe Val Ser 350 Gl n Ser Gly Thr Ser 355 Gin Ala Al a Al a Hi s 360 Val Ala Gly He 365 Ala Ala Met Met Leu Ser Ala 370 Glu Pro Glu 375 Leu Thr Leu Ala Glu Leu 380 Arg Gin Arg Leu lie His Phe 385 Ser Ala 390 Lys Asp Val lie Asn 395 Glu Ala Trp Phe Pro 400 Glu Asp Gin Arg Val Leu Thr Pro Asn Leu val Al a Ala Leu Pro Pro 405 410 415 Page 61 P17140.IES sequence listing as filed Ser Thr Hi s Gly 420 Ala Gly Trp Gin Leu 425 Phe cys Arg Thr val 430 Trp Ser Ala Hl s Ser 435 Gly Pro Thr Arg Met 440 Ala Thr Ala Val Al a 445 Arg cys Al a Pro Asp 450 Glu Glu Leu Leu Ser 455 Cys Ser ser Phe Ser 460 Arg Ser Gly Lys Arg 465 Arg Gly Glu Arg Met 470 Glu Ala Gin Gly Gly 475 Lys Leu Val Cys Arg 480 Al a Hi s Asn Al a Phe 485 Gly Gly Glu Gly Val 490 Tyr Ala il e Al a Arg 495 Cys Cys Leu Leu Pro 500 Gin Al a Asn Cys Ser 505 val Hl S Thr Al a Pro 510 Pro Al a Glu Ala Ser 515 Met Gly Thr Arg val 520 His cys Hi s Gin Gin 525 Gly Hl s val Leu Thr 530 Gly Cys Ser Ser Hi s 535 Trp Glu Val Glu Asp 540 Leu Gly Thr Hi s Lys 545 Pro Pro val Leu Arg 550 Pro Arg Gly Gin pro 555 Asn Gin Cys val Gly 560 Hl s Arg Glu Ala Ser 565 lie His Ala Ser cys 570 cys Hi s Al a Pro Gly 575 Leu Glu cys Lys val 580 Lys Glu Hi s Gly lie 585 Pro Ala Pro Gin G1 u 590 G1 n Val Thr Val Ala 595 Cys Glu Glu Gly T rp 600 Thr Leu Thr Gly Cys 605 Ser Al a Leu Pro Gly 610 Thr Ser Hi s Val Leu 615 Gly Ala Tyr Ala Val 620 Asp Asn Thr cys Val 625 Val Arg Ser Arg Asp 630 val ser Thr Thr Gly 635 Ser Thr Ser Glu Glu 640 Al a Val Thr Ala val 645 Al a lie cys Cys Arg 650 ser Arg Hi s Leu Al a 655 Gin Ala Ser Gin Glu Leu Gin <210> 26 <211> 692 <212> PRT 660 Page 62 P17140.IES sequence listing as filed <213> Homo sapiens <400> 26 Met 1 Gly Thr Val Ser Ser 5 Arg Arg Ser Trp Trp 10 Pro Leu Pro Leu 15 Leu Leu Leu Leu Leu 20 Leu Leu Leu Gly Pro Ala Gly 25 Al a Arg Ala 30 Gin Glu Asp Glu Asp 35 Gly Asp Tyr Glu Glu 40 Leu Val Leu Al a Leu 45 Arg Ser Glu Gl u Asp Gly 50 Leu val Glu Ala Pro 55 Glu His Gly Thr 60 Thr Al a Thr Phe Hi s 65 Arg Cys Al a Lys Asp 70 Pro Trp Arg Leu Pro 75 Gly Thr Tyr Val Val 80 Val Leu Lys Glu Glu Thr 85 His Leu Ser Gin Ser 90 Glu Arg Thr Al a 95 Arg Arg Leu Gin Al a 100 Gin Ala Ala Arg Arg Gly Tyr 105 Leu Thr Lys 110 lie Leu Hi s Val Phe 115 His Gly Leu Leu Pro 120 Gly Phe Leu Val Lys 125 Met Ser Gly Asp Leu Leu 130 Glu Leu Ala Leu Lys 135 Leu Pro His val 140 Asp Tyr lie Glu Glu 145 Asp ser Ser val Phe 150 Ala Gin Ser lie Pro 155 Trp Asn Leu Glu Arg 160 lie Thr Pro Pro Arg Tyr 165 Arg Ala Asp Glu Tyr 170 Gin Pro Pro Asp 175 Gly Gly Ser Leu val 180 Glu Val Tyr Leu Leu Asp Thr 185 Ser lie Gin 190 Ser ASp Hi s Arg Glu 195 lie Glu Gly Arg Val 200 Met Val Thr Asp Phe 205 Glu Asn val Pro Glu Glu 210 Asp Gly Thr Arg Phe 215 His Arg Gin Ala 220 Ser Lys Cys Asp Ser His Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp Ala Gly 225 230 235 240 val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg val Leu Asn cys Gin 245 250 255 Gly Lys Gly Thr val Ser Gly Thr Leu lie Gly Leu Glu Phe lie Arg page 63 P17140.IES 260 - sequence listing as filed 265 270 Lys Ser Gin Leu Val Gin Pro Val 275 280 Gly Pro Leu Val val Leu Leu Pro 285 Leu Ala Gly Gly Tyr ser Arg Val 290 295 Leu Asn Ala Ala Cys Gin Arg Leu 300 Ala Arg Ala Gly val Val Leu Val 305 310 Thr Ala Ala Gly Asn Phe Arg Asp 315 320 Asp Ala Cys Leu Tyr Ser Pro Ala 325 Ser Ala Pro Glu val lie Thr val 330 335 Gly Ala Thr Asn Ala Gin Asp Gin 340 Pro val Thr Leu Gly Thr Leu Gly 345 350 Thr Asn Phe Gly Arg cys Val Asp 355 360 Leu phe Ala Pro Gly Glu Asp lie 365 lie Gly Ala ser Ser Asp cys ser 370 375 Thr Cys Phe Val ser Gin ser Gly 380 Thr ser Gin Ala Ala Ala His Val 385 390 Ala Gly lie Ala Ala Met Met Leu 395 400 Ser Ala Glu Pro Glu Leu Thr Leu 405 Ala Glu Leu Arg Gin Arg Leu lie 410 415 His Phe Ser Ala Lys Asp Val lie 420 Asn Glu Ala Trp Phe Pro Glu Asp 425 430 Gin Arg val Leu Thr Pro Asn Leu 435 440 Val Ala Ala Leu Pro Pro ser Thr 445 His Gly Ala Gly Trp Gin Leu Phe 450 455 Cys Arg Thr Val Trp Ser Ala His 460 Ser Gly Pro Thr Arg Met Ala Thr 465 470 Ala lie Ala Arg cys Ala Pro Asp 475 480 Glu Glu Leu Leu Ser cys ser Ser 485 Phe Ser Arg Ser Gly Lys Arg Arg 490 495 Gly Glu Arg Met Glu Ala Gin Gly 500 Gly Lys Leu val Cys Arg Ala His 505 510 Asn Ala Phe Gly Gly Glu Gly val 515 520 Tyr Ala lie Ala Arg Cys cys Leu 525 Leu Pro Gin Ala Asn cys Ser Val His Thr Ala Pro Pro Ala Glu Ala Page 64 530 P17140.IES 535 sequence listing as filed 540 ser Met Gly Thr Arg val His Cys His Gin Gin Gly His Val Leu Thr Gly Cys Ser Ser His Trp Glu Val Glu Asp Leu Gly Thr His Lys Pro 565 570575 Pro Val Leu Arg Pro Arg Gly Gin Pro Asn Gin cys Val Gly His Arg 580 585590 Glu Ala Ser lie His Ala Ser Cys Cys His Ala Pro Gly Leu Glu Cys 595 600605 Lys Val Lys Glu His Gly lie Pro Ala Pro Gin Glu Gin Val Thr val 610 615620 Ala 625 cys Glu Glu Gly Trp Thr Leu Thr Gly Cys ser Al a Leu Pro Gly 640 630 635 Thr Ser His Val Leu 645 Gly Ala Tyr Ala Val Asp 650 Asn Thr cys Val 655 Val Arg Ser Arg Asp 660 Val Ser Thr Thr Gly ser Thr 665 Ser Glu Gly 670 Al a Val Thr Ala Val Ala 675 lie cys Cys Arg Ser Arg His 680 Leu Al a 685 Gin Ala Ser Gin Glu Leu Gin 690 <210> 27 <211> 662 <212> PRT <213> Homo sapiens <400> 27 Gin Glu Asp Glu Asp Gly Asp Tyr 1 5 Glu Glu Leu Val Leu Ala Leu Arg Ser Glu Glu Asp Gly Leu val Glu 20 Ala Pro Glu His Gly Thr Thr Ala 25 30 Thr Phe His Arg Cys Ala Lys Asp 35 40 Pro Trp Arg Leu Pro Gly Thr Tyr Val Val val Leu Lys Glu Glu Thr 50 55 His Leu Ser Gin ser Glu Arg Thr 60 Ala Arg Arg Leu Gin Ala Gin Ala 65 70 Ala Arg Arg Gly Tyr Leu Thr Lys 75 80 Page 65 P17140.IES sequence listing as filed lie Leu His Val Phe His Gly Leu Leu Pro 85 90 Ser Gly Asp Leu Leu Glu Leu Ala Leu Lys 100 105 lie Glu Glu Asp Ser ser Val Phe Ala Gin 115 120 Glu Arg lie Thr Pro Pro Arg Tyr Arg Ala 130 135 Asp Gly Gly ser Leu val Glu Val Tyr Leu 145 150 Ser Asp His Arg Glu lie Glu Gly Arg Val 165 170 Asn Val Pro Glu Glu Asp Gly Thr Arg Phe 180 185 cys Asp Ser His Gly Thr His Leu Ala Gly 195 200 Ala Gly Val Ala Lys Gly Ala ser Met Arg 210 215 Cys Gin Gly Lys Gly Thr Val Ser Gly Thr 225 230 lie Arg Lys ser Gin Leu val Gin Pro val 245 250 Leu Pro Leu Ala Gly Gly Tyr Ser Arg val 260 265 Arg Leu Ala Arg Ala Gly Val Val Leu Val 275 280 Arg Asp Asp Ala Cys Leu Tyr Ser Pro Ala 290 295 Thr val Gly Ala Thr Asn Ala Gin Asp Gin 305 310 Leu Gly Thr Asn Phe Gly Arg Cys Val Asp 325 330 Asp lie lie Gly Ala Ser Ser Asp Cys Ser 340 345 Phe Leu val Lys 95 Met pro His val Asp Tyr 110 lie pro Trp Asn Leu 125 Glu Tyr Gl n Pro Pro 140 Asp Thr ser lie Gin 160 Val Thr Asp Phe Gl u 175 Arg Gin Ala Ser Lys 190 Val Ser Gly Arg Asp 205 Leu Arg Val Leu Asn 220 lie Gly Leu Glu Phe 240 Pro Leu val Val Leu 255 Asn A1 a Al a Cys Gl n 270 Al a Al a Gly Asn Phe 285 Ala Pro Glu Val lie 300 Val Thr Leu Gly Thr 320 Phe Ala Pro Gly Glu 335 Cys Phe val Ser Gin 350 Page 66 Ser Gly Thr ser Gin P17140.IES - sequence listing as filed Ala Ala Ala 360 Hi s Val Ala Gly He 365 Ala Ala Met 355 Met Leu 370 Ser Ala Glu Pro Glu 375 Leu Thr Leu Ala Glu 380 Leu Arg Gin Arg Leu 385 lie Hi s Phe Ser Ala 390 Lys Asp Val lie Asn 395 Gl u Ala Trp Phe Pro 400 Glu Asp Gl n Arg Val 405 Leu Thr Pro Asn Leu 410 val Al a Al a Leu Pro 415 Pro ser Thr Hi s Gly 420 Al a Gly Trp Gl n Leu 425 Phe cys Arg Thr Val 430 Trp Ser Al a Hi s Ser 435 Gly Pro Thr Arg Met 440 Al a Thr Al a lie Al a 445 Arg cys Ala Pro Asp 450 Glu Glu Leu Leu Ser 455 Cys ser ser Phe Ser 460 Arg Ser Gly Lys Arg 465 Arg Gly Glu Arg Met 470 Glu Ala Gin Gly Gly 475 Lys Leu Val cys Arg 480 Al a His Asn Ala Phe 485 Gly Gly Glu Gly val 490 Tyr Al a lie Al a Arg 495 cys cys Leu Leu Pro 500 Gin Ala Asn cys ser 505 val Hi s Thr Ala Pro 510 Pro Ala Gl U Al a ser 515 Met Gly Thr Arg val 520 Hi s cys Hi s Gin Gin 525 Gly Hl s val Leu Thr 530 Gly cys Ser Ser Hi s 535 Trp Glu Val Glu Asp 540 Leu Gly Thr Hi s Lys 545 Pro Pro val Leu Arg 550 Pro Arg Gly Gin Pro 555 Asn Gin cys Val Gly 560 Hl S Arg Glu Al a Ser 565 lie His Ala Ser cys 570 cys Hi s Ala Pro Gly 575 Leu Glu cys Lys Val 580 Lys Glu Hi s Gly lie 585 Pro Ala Pro Gin Glu 590 Gin Val Thr Val Ala 595 cys Glu Glu Gly Trp 600 Thr Leu Thr Gly cys 605 Ser Ala Leu pro Gly 610 Thr Ser Hi s Val Leu 615 Gly Ala Tyr Ala val 620 Asp Asn Thr cys Page 67 P17140.IES - sequence listing as filed Val Val Arg ser Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Gly 625 630 635 640 Ala Val Thr Ala val Ala lie cys Cys Arg Ser Arg His Leu Ala Gin 645 650 655 Ala Ser Gin Glu Leu Gin 660 <210> 28 <211> 2080 <212> DNA <213> Homo sapiens <400> 28 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg 60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag 120 ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc 180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg 240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc 300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct 360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc 420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg 480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg 540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc 600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc 660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc 720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg 780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg 840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc 900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac 960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat 1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac 1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg 1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg 1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc 1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg 1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta 1380 tggtcagcac actcggggcc tacacggatg gccacagcca tcgcccgctg cgccccagat 1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga Page 68 agcggcgggg cgagcgcatg 1500 P17140.IES - sequence listing as filed gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 29 <211> 2080 <212> DNA <213> Homo sapiens <400> 29 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 Page 69 P17140.IES - sequence listing as filed tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc 1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagccg tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 30 <211> 2080 <212> DNA <213> Homo sapiens <400> 30 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg 60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 Page 70 P17140.IES - sequence listing as filed gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagcca tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaaggg gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 31 <211> 2080 <212> DNA <213> Homo sapiens <400> 31 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 Page 71 P17140.IES - sequence listing as filed agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc 720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagccg tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaaggg gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 32 <211> 2080 <212> DNA <213> Homo sapiens <400> 32 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggtcg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 Page 72 P17140.IES - sequence listing as filed gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagccg tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 33 <211> 2080 <212> DNA <213> Homo sapiens <400> 33 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg 60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag 120 Page 73 ctggtgctag ccttgcgttc P17140.IES cgaggaggac - sequence ggcctggccg listing as aagcacccga filed gcacggaacc 180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg 240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc 300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct 360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc 420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg 480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg 540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc 600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc 660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc 720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg 780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg 840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc 900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac 960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat 1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac 1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg 1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg 1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc 1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg 1320 gtggccaccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta 1380 tggtcagcac actcggggcc tacacggatg gccacagcca tcgcccgctg cgccccagat 1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg 1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc 1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca 1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca 1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg 1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc 1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag 1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg 1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac 1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg 2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac 2080 <210> 34 Page 74 P17140.IES sequence listing as filed <211> 2080 <212> DNA <213> Homo sapiens <400> 34 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcagtgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagccg tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 Page 75 P17140.IES - sequence listing as filed acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 35 <211> 2080 <212> DNA <213> Homo sapiens <400> 35 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccaccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagcca tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 page 76 P17140.IES - sequence listing as filed ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca 1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctccggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 36 <211> 2080 <212> DNA <213> Homo sapiens <400> 36 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg 60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgctttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 Page 77 P17140.IES - sequence listing as filed tggtcagcac actcggggcc tacacggatg gccacagccg tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 37 <211> 2080 <212> DNA <213> Homo sapiens <400> 37 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggtcg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 Page 78 P17140.IES - sequence listing as filed ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg 1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg 1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc 1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg 1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta 1380 tggtcagcac actcggggcc tacacggatg gccacagcca tcgcccgctg cgccccagat 1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg 1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc 1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca 1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca 1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg 1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc 1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag 1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg 1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac 1980 gtcagcacta agccggcacc <210> 38 <211> 98 <212> PRT <213> Homo <400> 38 caggcagcac cagcgaaggg gccgtgacag tggcgcaggc ctcccaggag ctccagtgac sapi ens ccgttgccat ctgctgccgg 2040 2080 Glu val Gin 1 Leu val Glu Ser Gly Gly Gly Leu 5 10 Val Gin Pro Gly Gly 15 Ser Leu Arg Leu Ser Cys Ala Ala ser Gly Phe 20 25 ' Thr Phe Ser 30 Ser Tyr Ala Met ser 35 Trp Val Arg Gin Ala Pro Gly Lys 40 Gly Leu Glu 45 Trp val ser Ala lie 50 Ser Gly Ser Gly Gly Ser Thr Tyr 55 Tyr Ala Asp 60 Ser Val Lys Gly Arg 65 Phe Thr lie Ser Arg Asp Asn Ser 70 75 Lys Asn Thr Leu Tyr 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr 85 90 Ala Val Tyr Tyr cys 95 Ala Lys Page 79 P17140.IES sequence listing as filed <210> 39 <211> 296 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(294) <400> 39 gag gtg cag etg gtg gag tet ggg Glu val Gin Leu Val Glu Ser Gly tcc etg aga etc tcc tgt gca gcc ser Leu Arg Leu Ser cys Ala Ala gcc atg age tgg gtc ege cag get Ala Met ser Trp val Arg Gin Ala 3540 tea get att agt ggt agt ggtggt Ser Ala lie Ser Gly Ser GlyGly 5055 aag ggc egg ttc acc ate tccaga Lys Gly Arg Phe Thr lie SerArg 6570 etg caa atg aac age etg agagcc Leu Gin Met Asn Ser Leu Arg Ala geg aaa ga Ala Lys gga ggc ttg gta cag cct ggg ggg Gly Gly Leu val Gin Pro Gly Gly 1015 tet gga ttc acc ttt age agetat Ser Gly Phe Thr Phe Ser SerTyr 2530 cca ggg aag ggg etg gag tgggtc Pro Gly Lys Gly Leu Glu Trpval age aca tac tac gca gac tccgtg Ser Thr Tyr Tyr Ala Asp serVal gac aat tcc aag aac acg etgtat Asp Asn ser Lys Asn Thr LeuTyr 7580 gag gac acg gcc gta tat tactgt Glu Asp Thr Ala val Tyr Tyrcys 9095 144 192 240 288 296 <210> 40 <211> 25 <212> PRT <213> Homo sapiens <400> 40 Glu Val Gin Leu val Glu Ser Gly Ser Leu Arg Leu Ser cys Ala Ala 20 Gly Gly Leu Val Gin Pro Gly Gly ser 25 <210> 41 <211> 990 <212> DNA <213> Homo sapiens <400> 41 gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gaeggtgteg tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc Page 80 120 180 240 P17140.IES - sequence listing as filed tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac agcacgtacc gggtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 300 360 420 480 540 600 660 720 780 840 900 960 990 <210> 42 <211> 330 <212> PRT <213> Homo sapiens <400> 42 Ala Ser Thr Lys Gly Pro Ser Val 1 5 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 20 Leu Gly Cys Leu val Lys Asp Tyr 25 30 phe Pro Glu Pro val Thr Val ser 40 Trp Asn Ser Gly Ala Leu Thr Ser 45 Gly val His Thr Phe Pro Ala Val 50 55 Leu Gin Ser ser Gly Leu Tyr Ser Leu Ser Ser val val Thr Val Pro 65 70 Ser Ser Ser Leu Gly Thr Gin Thr 75 80 Tyr lie Cys Asn val Asn His Lys 85 Pro Ser Asn Thr Lys val Asp Lys 95 Lys Val Glu Pro Lys ser Cys Asp 100 Lys Thr His Thr Cys Pro Pro Cys 105 110 Pro Ala Pro Glu Leu Leu Gly Gly 115 120 Pro Ser Val Phe Leu Phe Pro Pro 125 Lys Pro Lys Asp Thr Leu Met lie 130 135 Ser Arg Thr Pro Glu Val Thr Cys 140 Page 81 P17140.IES sequence listing as filed Val Val Val Asp val Ser His Glu 145 150 Asp Pro Glu val Lys Phe Asn Trp 155 160 Tyr Val Asp Gly Val Glu val His 165 Asn Ala Lys Thr Lys Pro Arg Glu 170 175 Glu Gin Tyr Asn Ser Thr Tyr Arg 180 Val val Ser val Leu Thr Val Leu 185 190 His Gin Asp Trp Leu Asn Gly Lys 195 200 Glu Tyr Lys cys Lys Val ser Asn 205 Lys Ala Leu Pro Ala Pro lie Glu 210 215 Lys Thr lie Ser Lys Ala Lys Gly 220 Gin Pro Arg Glu Pro Gin Val Tyr 225 230 Thr Leu Pro Pro Ser Arg Asp Glu 235 240 Leu Thr Lys Asn Gin val Ser Leu 245 Thr Cys Leu val Lys Gly Phe Tyr 250 255 Pro Ser Asp lie Ala Val Glu Trp 260 Glu Ser Asn Gly Gin Pro Glu Asn 265 270 Asn Tyr Lys Thr Thr Pro Pro val 275 280 Leu Asp Ser Asp Gly Ser Phe Phe 285 Leu Tyr Ser Lys Leu Thr Val Asp 290 295 Lys Ser Arg Trp Gin Gin Gly Asn 300 val Phe Ser Cys Ser val Met His 305 310 Glu Ala Leu His Asn His Tyr Thr 315 320 Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 43 <211> 978 <212> DNA <213> Homo sapiens <400> 43 gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 120 180 240 300 360 Page 82 P17140.IES - sequence listing as filed ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 420 480 540 600 660 720 780 840 900 960 978 <210> 44 <211> 326 <212> PRT <213> Homo sapiens <400> 44 Ala ser Thr Lys Gly Pro Ser Val 1 5 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 25 30 Phe Pro Glu Pro val Thr val ser 40 Trp Asn Ser Gly Ala Leu Thr ser 45 Gly val His Thr Phe Pro Ala Val 50 55 Leu Gin ser ser Gly Leu Tyr Ser 60 Leu Ser Ser Val Val Thr Val Pro 70 ser Ser Asn Phe Gly Thr Gin Thr 75 80 Tyr Thr Cys Asn val Asp His Lys 85 Pro Ser Asn Thr Lys val Asp Lys 95 Thr val Glu Arg Lys Cys Cys Val 100 Glu cys Pro Pro Cys Pro Ala Pro 105 110 Pro Val Ala Gly Pro Ser Val Phe 115 120 Leu Phe Pro Pro Lys Pro Lys Asp 125 Thr Leu Met lie Ser Arg Thr Pro 130 135 Glu val Thr Cys Val val val Asp 140 val Ser His Glu Asp Pro Glu Val 145 150 Gin Phe Asn Trp Tyr val Asp Gly 155 160 Page 83 P17140.IES - sequence listing as filed Val Glu val His Asn 165 Ala Lys Thr Lys Pro Arg Glu 170 Glu Gl n Phe 175 Asn Ser Thr Phe Arg Val 180 val Ser Val Leu 185 Thr val val Hi s Gin 190 Asp Trp Leu Asn Gly 195 Lys Glu Tyr Lys cys 200 Lys Val ser Asn Lys 205 Gly Leu Pro Ala Pro 210 lie Glu Lys Thr lie ser 215 Lys Thr Lys Gly 220 Gin Pro Arg G1U Pro 225 Gin val Tyr Thr Leu 230 Pro Pro ser Arg Glu Glu 235 Met Thr Lys Asn 240 Gin Val Ser Leu Thr 245 Cys Leu Val Lys Gly Phe Tyr 250 Pro Ser Asp 255 He Ala val Glu Trp Glu 260 Ser Asn Gly Gl n 265 Pro Glu Asn Asn Tyr 270 Lys Thr Thr Pro Pro 275 Met Leu Asp Ser Asp 280 Gl y Ser Phe Phe Leu 285 Tyr ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn val Phe Ser Cys 290 295 300 Ser val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu 305 310 315 320 Ser Leu Ser Pro Gly Lys 325 <210> 45 <211> 296 <212> DNA <213> Homo sapiens <400> 45 caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggtta cacctttacc agctatggta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactat 180 gcacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240 atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagaga 296 <210> 46 <211> 98 <212> PRT <213> Homo sapiens <400> 46 Page 84 P17140.IES - sequence listing as filed Gin val Gin Leu Val Gin ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15 Ser Val Lys Val ser cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 25 30 Gly lie Ser Trp Val Arg Gin Ala 35 40 Pro Gly Gin Gly Leu Glu Trp Met 45 Gly Trp lie Ser Ala Tyr Asn Gly 50 55 Gin Gly Arg val Thr Met Thr Thr 65 70 Met Glu Leu Arg Ser Leu Arg ser 85 Asn Thr Asn Tyr Ala Gin Lys Leu 60 Asp Thr Ser Thr ser Thr Ala Tyr 75 80 Asp Asp Thr Ala Val Tyr Tyr Cys 90 95 Ala Arg <210> 47 <211> 296 <212> DNA <213> Homo sapiens <400> 47 caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt tcctgcaagg catctggata caccttcacc agctactata tgcactgggt gcgacaggcc cctggacaag ggcttgagtg gatgggaata atcaacccta gtggtggtag cacaagctac gcacagaagt tccagggcag agtcaccatg accagggaca cgtccacgag cacagtctac atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaga 120 180 240 296 <210> 48 <211> 98 <212> PRT <213> Homo sapiens <400> 48 Gin Val 1 Gin Leu Val 5 Gin Ser Gly Ala Glu 10 val Lys Lys Pro Gly 15 Al a Ser Val Lys val Ser Cys Lys Ala ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Met Hi s Trp val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 40 45 Gly lie lie Asn Pro ser Gly Gly Ser Thr ser Tyr Ala Gin Lys Phe 50 55 60 Gin Gly Arg val Thr Met Thr Arg Asp Thr ser Thr Ser Thr Val Tyr Page 85 P17140.IES - sequence listing as filed 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg <210> 49 <211> 321 <212> DNA <213> Homo sapiens <400> 49 cgaactgtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 120 180 240 300 321 <210> 50 <211> 107 <212> PRT <213> Homo sapiens <400> 50 Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro ser Asp Glu 15 1015 Gin Leu Lys Ser Gly Thr Ala ser Val Val Cys Leu Leu Asn Asn Phe 20 2530 Tyr Pro Arg Glu Ala Lys val Gin Trp Lys val Asp Asn Ala Leu Gin 35 4045 Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp ser Lys Asp Ser 50 5560 Thr Tyr Ser Leu ser Ser Thr Leu Thr Leu ser Lys Ala Asp Tyr Glu 65 70 7580 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu ser Ser 85 9095 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu cys 100105 <210> 51 <211> 318 <212> DNA <213> Homo sapiens Page 86 P17140.IES sequence listing as filed <400> 51 ggtcagccca aggctgcccc ctcggtcact ctgttcccgc cctcctctga ggagcttcaa 60 gccaacaagg ccacactggt gtgtctcata agtgacttct acccgggagc cgtgacagtg 120 gcttggaaag cagatagcag ccccgtcaag gcgggagtgg agaccaccac accctccaaa 180 caaagcaaca acaagtacgc ggccagcagc tatctgagcc tgacgcctga gcagtggaag 240 tcccacagaa gctacagctg ccaggtcacg catgaaggga gcaccgtgga gaagacagtg 300 gcccctacag aatgttca 318 <210> 52 <211> 106 <212> PRT <213> Homo sapiens <400> 52 Gly Gin Pro Lys Ala Ala Pro Ser val Thr Leu Phe Pro Pro ser Ser Glu Glu Leu Gin Ala Asn Lys Ala Thr Leu Val Cys Leu lie Ser Asp 20 2530 Phe Tyr Pro Gly Ala val Thr Val Ala Trp Lys Ala Asp Ser ser Pro 35 4045 Val Lys Ala Gly val Glu Thr Thr Thr Pro Ser Lys Gin Ser Asn Asn 50 5560 Lys Tyr Ala Ala ser Ser Tyr Leu ser Leu Thr Pro Glu Gin Trp Lys 65 70 7580 Ser His Arg Ser Tyr ser cys Gin val Thr His Glu Gly Ser Thr val 85 9095 Glu Lys Thr Val Ala Pro Thr Glu cys ser 100105 <210> 53 <211> 365 <212> DNA <213> Homo sapiens <400> 53 atggtgttgc agacccaggt cttcatttct ctgttgctct ggatctctgg tgcctacggg60 gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc120 atcaactgca agtccagcca gagtgtttta tacagctcca acaataagaa ctacttagct180 tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctacccgg240 gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc300 atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtact360 cctcc365 Page 87 P17140.IES sequence listing as filed <210> 54 <211> 101 <212> PRT <213> Homo sapiens <400> 54 Asp lie val 1 Met Thr Gin Ser 5 pro Asp Ser 10 Leu Ala Val Ser Leu 15 Gly Glu Arg Ala Thr 20 lie Asn cys Lys Ser ser 25 Gin ser val Leu 30 Tyr ser Ser Asn Asn 35 Lys Asn Tyr Leu Ala 40 Trp Tyr Gin Gin Lys 45 Pro Gly Gin Pro Pro Lys 50 Leu Leu lie Tyr 55 Trp Ala Ser Thr Arg 60 Glu Ser Gly Val Pro Asp Arg 65 Phe ser Gly ser 70 Gly Ser Gly Thr 75 Asp Phe Thr Leu Thr 80 lie Ser ser Leu Gin Ala Glu 85 Asp Val Ala 90 Val Tyr Tyr cys Gin 95 Gin Tyr Tyr ser Thr Pro 100 <210> 55 <211> 654 <212> DNA <213> Homo sapi ens <400> 55 atggacatga gggtccccgc tcagctcctg gggcttctgc tgctctggct cccagcaggt gccagatgtg ccatccagtt gacccagtct ccatcctccc tgtctgcatc tgtaggagac agagtcacca tcacttgccg ggcaagtcag ggcattagca gtgctttagc ctggtatcag cagaaaccag ggaaagctcc taagctcctg atctatgatg cctccagttt ggaaagtggg gtcccatcaa ggttcagcgg cagtggatct gggacagatt tcactctcac catcagcagc ctgcagcctg aagattttgc aacttattac tgtcaacagt ttaatagtta ccctcagtgc cagatgtgcc atccagttga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc acttgccggg caagtcaggg cattagcagt gctttagcct ggtatcagca gaaaccaggg aaagctccta agctcctgat ctatgatgcc tccagtttgg aaagtggggt cccatcaagg ttcagcggca gtggatctgg gacagatttc actctcacca tcagcagcct gcagcctgaa gattttgcaa cttattactg tcaacagttt aatagttacc ctca 120 180 240 300 360 420 480 540 600 654 <210> 56 <400> 56 Page 88 P17140.IES sequence listing as filed 000 <210> 57 <211> 39 <212> DNA <213> Homo sapiens <400> 57 tgtacacttt tggccagggg accaagctgg agatcaaac 39 <210> 58 <211> 12 <212> PRT <213> Homo sapiens <400> 58 Tyr Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys 10 <210> 59 <211> 38 <212> DNA <213> Homo sapiens <400> 59 tgtggtattc ggcggaggga ccaagctgac cgtcctag 38 <210> 60 <211> 12 <212> PRT <213> Homo sapiens <400> 60 val val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 10 <210> 61 <211> 329 <212> PRT <213> Homo sapiens <400> 61 Ala ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 2530 Phe Pro Glu Pro val Thr val ser Trp Asn Ser Gly Ala Leu Thr ser 35 4045 Gly val His Thr Phe Pro Ala Val Leu Gin ser Ser Gly Leu Tyr Ser 50 5560 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr 65 70 7580 Tyr lie cys Asn val Asn His Lys Pro Ser Asn Thr Lys val Asp Lys Page 89 P17140.IES Lys val Glu Pro Lys 100 sequence listing as filed 90 95 Pro Ala Pro Glu Leu 115 Lys Pro Lys Asp Thr 130 Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 105110 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 120125 Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys 135140 val val Val Asp Val 145 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 150 155 160 Tyr Val Asp Gly val 165 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 170 175 Glu Gin Tyr Asn Ser 180 Thr Tyr Arg val val ser val Leu Thr val Leu 185 190 His Gin Asp Trp Leu 195 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 200 205 Lys Ala Leu Pro Ala 210 pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly 215 220 Gin Pro Arg Glu Pro 225 Gin Val Tyr Thr Leu Pro Pro ser Arg Asp Glu 230 235 240 Leu Thr Lys Asn Gin 245 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 250 255 Pro Ser Asp lie Ala 260 val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn 265 270 Asn Tyr Lys Thr Thr 275 Pro Pro Val Leu Asp ser Asp Gly ser Phe Phe 280 285 Leu Tyr ser Lys Leu 290 Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn 295 300 val Phe ser cys ser 305 val Met His Glu Ala Leu His Asn His Tyr Thr 310 315 320 Gin Lys Ser Leu Ser 325 Leu Ser Pro Gly <210> 62 <211> 107 <212> PRT <213> Homo sapiens Page 90 P17140.IES - sequence listing as filed <400> 62 Arg Thr Val Ala Ala Pro Ser val Phe lie Phe Pro Pro Ser Asp Glu 15 1015 Gin Leu Lys ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 2530 Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys val Asp Asn Ala Leu Gin 35 4045 Ser Gly Asn Ser Gin Glu ser Val Thr Glu Gin Asp Ser Lys Asp ser 50 5560 Thr Tyr ser Leu ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 7580 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu ser ser 85 9095 Pro Val Thr Lys ser Phe Asn Arg Gly Glu Cys 100105 <210> 63 <211> 326 <212> PRT <213> Homo sapiens <400> 63 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 15 1015 ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 2530 Phe Pro Glu Pro val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 4045 Gly Val His Thr Phe Pro Ala Val Leu Gin Ser ser Gly Leu Tyr Ser 50 5560 Leu Ser Ser Val Val Thr Val Pro ser ser Asn Phe Gly Thr Gin Thr 65 70 7580 Tyr Thr Cys Asn val Asp His Lys Pro Ser Asn Thr Lys val Asp Lys 85 9095 Thr Val Glu Arg Lys Cys Cys Val Glu cys Pro Pro Cys Pro Ala Pro 100 105110 Pro val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120125 Thr Leu Met lie ser Arg Thr Pro Glu Val Thr cys val val val Asp Page 91 130 P17140.IES - sequence listing as filed 135 140 Val Ser His Glu Asp Pro Glu Val 145 150 Gin Phe Asn Trp Tyr val Asp Gly 155 160 val Glu Val His Asn Ala Lys Thr 165 Lys Pro Arg Glu Glu Gin Phe Asn 170 175 Ser Thr Phe Arg val val ser val 180 Leu Thr Val val His Gin Asp Trp 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys 195 200 Lys val ser Asn Lys Gly Leu Pro 205 Ala Pro lie Glu Lys Thr lie ser 210 215 Lys Thr Lys Gly Gin Pro Arg Glu 220 Pro Gin val Tyr Thr Leu Pro Pro 225 230 ser Arg Glu Glu Met Thr Lys Asn 235 240 Gin Val ser Leu Thr Cys Leu Val 245 Lys Gly Phe Tyr Pro Ser Asp lie 250 255 Ala val Glu Trp Glu ser Asn Gly 260 Gin Pro Glu Asn Asn Tyr Lys Thr 265 270 Thr Pro Pro Met Leu Asp Ser Asp 275 280 Gly Ser Phe Phe Leu Tyr Ser Lys 285 Leu Thr Val Asp Lys Ser Arg Trp 290 295 Gin Gin Gly Asn Val Phe Ser cys 300 ser val Met His Glu Ala l.eu His 305 310 Asn His Tyr Thr Gin Lys Ser Leu 3.15 320 Ser Leu ser Pro Gly Lys 325 <210> 64 <211> 105 <212> PRT <213> Homo sapiens <400> 64 Gin Pro Lys Ala Ala Pro Ser Val Thr 1 5 Leu Phe Pro Pro Ser Ser Glu Glu Leu Gin Ala Asn Lys Ala Thr Leu 20 25 val Cys Leu lie ser Asp Phe 30 Tyr Pro Gly Ala val Thr Val Ala Trp 35 40 Lys Ala Asp Ser ser Pro Val 45 Page 92 P17140.IES sequence listing as filed Lys Ala Gly Val Glu Thr Thr Thr 55 Tyr Ala Ala ser Ser Tyr Leu ser 65 70 His Arg Ser Tyr Ser Cys Gin Val 85 Pro ser Lys Gin Ser Asn Asn Lys 60 Leu Thr Pro Glu Gin Trp Lys Ser 75 80 Thr His Glu Gly Ser Thr Val Glu 90 95 Lys Thr Val Ala Pro Thr Glu Cys Ser 100 105 <210> 65 <211> 326 <212> PRT <213> Homo sapiens <400> 65 Ala Ser Thr Lys Gly Pro Ser val Phe Pro Leu Ala Pro Cys Ser Arg 15 1015 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 2530 Phe Pro Glu Pro val Thr Val Ser Trp Asn ser Gly Ala Leu Thr ser 35 4045 Gly val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 50 5560 Leu ser ser Val Val Thr val Pro ser ser Asn Phe Gly Thr Gin Thr 65 70 7580 Tyr Thr Cys Asn val Asp His Lys Pro Ser Asn Thr Lys val Asp Lys 85 9095 Thr Val Glu Arg Lys Cys cys Val Glu Cys Pro Pro Cys Pro Ala Pro 100 105110 Pro val Ala Gly Pro Ser Val Phe Leu Phe pro Pro Lys Pro Lys Asp 115 120125 Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr cys val val val Asp 130 135140 val ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly 145 150 155160 val Glu val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn 165 170175 Ser Thr Phe Arg val val Ser Val Leu Thr val val His Gin Asp Trp Page 93 180 Leu Asn Gly Lys Glu 195 P17140.IES - sequence listing as filed 185 190 Tyr Lys Cys Lys val Ser Asn Lys Gly Leu Pro 200 205 Ser Ser lie Glu Lys 210 Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu 215 220 Pro Gin Val Tyr Thr 225 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 230 235 240 Gin val Ser Leu Thr 245 cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie 250 255 Ala Val Glu Trp Glu 260 Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr 265 270 Thr Pro Pro Met Leu 275 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 280 285 Leu Thr Val Asp Lys 290 Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys 295 300 Ser Val Met His Glu 305 Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu 310 315 320 Ser Leu Ser Pro Gly 325 Lys <210> 66 <211> 107 <212> PRT <213> Homo sapiens <400> 66 Arg Thr Val Ala Ala 1 5 Pro ser Val Phe lie Phe Pro Pro Ser Asp Glu 10 15 Gin Leu Lys Ser Gly 20 Thr Ala Ser val val cys Leu Leu Asn Asn Phe 25 30 Tyr Pro Arg Glu Ala 35 Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 45 ser Gly Asn Ser G1n 50 Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 55 60 Thr Tyr Ser Leu Ser 65 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 70 75 80 Lys His Lys Val Tyr 85 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 90 95 Page 94 P17140.IES - sequence listing as filed Pro val Thr Lys ser Phe Asn Arg Gly Glu cys 100 105 <210> 67 <211> 7 <212> PRT <213> Homo sapiens <400> 67 val Phe Ala Gin Ser lie Pro <210> 68 <211> 52 <212> DNA <213> Homo sapiens <400> 68 ctgtaccaag cctcccccag actccamcag ctgcacctca cactggacac ct <210> 69 <211> 296 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(294) <400> 69 gag gtg cag ctg ttg gag tct gqg gga gqc ttg gta cag cct gqg ggg Glu val Gin Leu Leu Glu Ser Gly Gly Gly Leu val Gin Pro Gly Gly 1015 tcc ctg aga etc tcc tgt gca gcc tct gga ttc acc ttt age agetat Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser serTyr 2530 gcc atg age tgg gtc ege cag get cca gqg aag gqg ctg gag tgggtc Ala Met Ser Trp val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trpval 4045 tea get att agt ggt agt ggt ggt age aca tac tac gca gac tccgtg ser Ala lie Ser Gly ser Gly Gly ser Thr Tyr Tyr Ala Asp SerVal 5560 aag gqc egg ttc acc ate tcc aga gac aat tcc aag aac acg ctgtat Lys Gly Arg Phe Thr lie ser Arg Asp Asn ser Lys Asn Thr LeuTyr 70 7580 ctg caa atg aac age ctg aga gcc gag gac acg gcc gta tat tactgt Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala val Tyr Tyrcys 9095 geg aaa ga Ala Lys 144 192 240 288 296 <210> 70 <211> 98 <212> PRT <213> Homo sapiens Page 95 P17140.IES sequence listing as filed <400> 70 Glu val Gin Leu Leu Glu Ser Gly 1 5 Gly Gly Leu val Gin Pro Gly Gly Ser Leu Arg Leu ser cys Ala Ala 20 Ser Gly Phe Thr Phe Ser Ser Tyr 25 30 Ala Met Ser Trp val Arg Gin Ala 35 40 Pro Gly Lys Gly Leu Glu Trp Val 45 ser Ala lie Ser Gly Ser Gly Gly 55 Ser Thr Tyr Tyr Ala Asp ser val 60 Lys Gly Arg Phe Thr lie ser Arg 65 70 Asp Asn ser Lys Asn Thr Leu Tyr 75 80 Leu Gin Met Asn Ser Leu Arg Ala 85 Glu Asp Thr Ala Val Tyr Tyr cys 90 95 Ala Lys <210> 71 <211> 294 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(294) <400> 71 gag gtg cag ctg ttg gag tet ser ggg gga ggc ttg Leu gta val cag Gin cct Pro ggg Gly 15 ggg Gly 48 Glu 1 Val Gin Leu Leu Glu 5 Gly Gly Gly 10 tcc ctg aga etc tcc tgt gca gcc tet gga ttc acc ttt age age tat 96 Ser Leu Arg Leu 20 Ser cys Al a Al a Ser 25 Gly Phe Thr Phe Ser 30 Ser Tyr gcc atg age tgg gtc ege cag get cca ggg aag ggg ctg gag tgg gtc 144 Ala Met ser 35 T rp Val Arg Gl n Al a 40 Pro Gly Lys Gly Leu 45 Gl u Trp val tea get att agt ggt agt ggt ggt age aca tac tac gca gac tcc gtg 192 Ser Al a 50 lie Ser Gly ser Gly 55 Gly ser Thr Tyr Tyr 60 Ala Asp Ser val aag ggc egg ttc acc ate tcc aga gac aat tcc aag aac acg ctg tat 240 Lys 65 Gly Arg Phe Thr lie 70 Ser Arg Asp Asn Ser 75 Lys Asn Thr Leu Tyr 80 ctg caa atg aac age ctg aga gcc gag gac acg gcc gta tat tac tgt 288 Leu geg Ala Gin aaa Lys Met Asn ser 85 Leu Arg Al a Glu Asp 90 Thr Ala val Tyr Tyr 95 cys 294 Page 96 P17140.IES sequence listing as filed <210> 72 <211> 296 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(294) <400> 72 gag gtg cag etg ttg gag tet ggg gga ggc ttg gta cag cct ggg ggg48 Glu val Gin Leu Leu Glu ser Gly Gly Gly Leu val Gin Pro Gly Gly 15 1015 tcc etg aga etc tcc tgt gca gcc tet gga ttc acc ttt age age tat96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser SerTyr 2530 gcc atg age tgg gtc ege cag get cca ggg aag ggg etg gag tgg gtc144 Ala Met Ser Trp val Arg Gin Ala Pro Gly Lys Gly Leu Glu TrpVal 4045 tea get att agt ggt agt ggt ggt age aca tac tac gga gac tcc gtg192 Ser Ala lie ser Gly ser Gly Gly ser Thr Tyr Tyr Gly Asp SerVal 5560 aag ggc egg ttc acc ate tea aga gac aat tcc aag aac acg etg tat240 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr LeuTyr 70 7580 etg caa atg aac age etg aga gcc gag gac acg gcc gta tat tac tgt288 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr TyrCys 9095 gcg aaa ga296 Ala Lys <2L0> 73 <211> 98 <212> PRT <213> Homo sapiens <400> 73 Glu Val Gin Leu Leu Glu Ser Gly 1 5 Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 20 Ser Gly Phe Thr Phe Ser Ser Tyr 25 30 Ala Met ser Trp val Arg Gin Ala 35 40 Pro Gly Lys Gly Leu Glu Trp Val 45 Ser Ala lie Ser Gly Ser Gly Gly 55 Ser Thr Tyr Tyr Gly Asp Ser val 60 Lys Gly Arg Phe Thr lie Ser Arg 65 70 Asp Asn Ser Lys Asn Thr Leu Tyr 80 Page 97 Leu Gin Met Asn Ser 85 P17140.IES - sequence listing as filed Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 90 95 Ala Lys <210> <211> <212> <213> 294 DNA Homo sapiens <220> <221> <222> CDS Cl).·(294) <400> gag G1 U 1 gtg val cag G1 n ctg Leu ttg Leu 5 gag tet ggg Gly gga ggc ttg gta val cag G1 n cct ggg ggg 48 G1 u ser Gly Gly 10 Leu Pro Gly 15 Gly tcc ctg aga etc tcc tgt gca gcc tet gga ttc acc ttt age age tat 96 Ser Leu Arg Leu Ser Cys Ala Al a Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 gcc atg age tgg gtc ege cag get cca ggg aag ggg ctg gag tgg gtc 144 Al a Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp val 35 40 45 tea gtt att tat age ggt ggt agt age aca tac tat gca gac tcc gtg 192 Ser val lie Tyr ser Gly Gly ser ser Thr Tyr Tyr Al a Asp Ser val 50 55 60 aag ggc egg ttc acc ate tcc aga gat aat tcc aag aac acg ctg tat 240 Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg aga gcc gag gac acg gcc gta tat tac tgt 288 Leu G1 n Met Asn Ser Leu Arg Al a Glu Asp Thr Ala Val Tyr Tyr cys 85 90 95 294 geg Al a aaa cys <210> <211> <212> <213> PRT Homo sapiens <400> Glu 1 Val Gin Leu Leu 5 Glu Ser Gly Gly Gly 10 Leu val G1 n Pro Gly 15 Gly Ser Leu Arg Leu 20 Ser cys Ala Al a Ser 25 Gly Phe Thr Phe Ser 30 Ser Tyr Al a Met Ser 35 Trp val Arg Gin Ala 40 Pro Gly Lys Gly Leu 45 Glu Trp Val Ser Val 50 lie Tyr Ser Gly Gly 55 Ser Ser Thr Tyr Tyr 60 Ala Asp Ser val Page 98 P17140.IES sequence listing as filed Lys Gly Arg Phe Thr lie Ser Arg Asp Asn ser Lys Asn Thr Leu Tyr 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 85 90 Tyr Tyr Cys 95 Ala Lys <210> 76 <211> 296 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(294) <400> 76 gag gtg cag ctg ttg gag tct ggg gga ggc ttg gta cag cct ggg ggg Glu val Gin Leu Leu Glu Ser Gly Gly Gly Leu val Gin Pro Gly Gly 1015 tcc ctg aga etc tcc tgt gca gcc tct gga ttc acc ttt age agetat Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser SerTyr 2530 gcc atg age tgg gtc ege cag get cca ggg aag ggg ctg gag tgggtc Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu TrpVal 4045 tea gtt att tat age ggt ggt agt age aca tac tat gca gac tccgtg Ser Val lie Tyr Ser Gly Gly ser ser Thr Tyr Tyr Ala Asp Serval 5560 aag ggc egg ttc acc ate tcc aga gat aat tcc aag aac acg ctgtat Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr LeuTyr 70 7580 ctg caa atg aac age ctg aga gcc gag gac acg gcc gta tat tactgt Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala val Tyr Tyrcys 9095 geg aaa ga Ala Lys 144 192 240 288 296 <210> 77 <211> 294 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(294) <400> 77 gag gtg cag ctg ttg gag tct ggg gga ggc ttg gta cag cct ggg ggg Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 Page 99 P17140.IES - sequence listing as filed tcc etg aga etc tcc tgt gca gcc tet gga Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 2025 gcc atg age tgg gtc ege cag get ccaggg Ala Met Ser Trp Val Arg Gin Ala ProGly 3540 tea get att tat age agt ggt agt ageaca Ser Ala lie Tyr ser Ser Gly Ser SerThr 5055 aag ggc egg ttc acc ate tcc aga gacaat Lys Gly Arg phe Thr lie Ser Arg AspAsn 6570 etg caa atg aac age etg aga gcc gaggac Leu Gin Met Asn Ser Leu Arg Ala GluAsp 8590 geg aaa Ala Lys ttc acc ttt age age tat96 Phe Thr Phe ser ser Tyr 30 aag ggg etg gag tgg gtc144 Lys Gly Leu Glu Trp Val 45 tac tat gca gac tcc gtg192 Tyr Tyr Ala Asp Ser val 60 tcc aag aac acg etg tat240 Ser Lys Asn Thr Leu Tyr 7580 acg gcc gta tat tac tgt288 Thr Ala Val Tyr Tyr Cys 294 <210> 78 <211> 98 <212> PRT <213> Homo sapiens <400> 78 Glu Val Gin 1 Leu Leu 5 Glu Ser Gly Gly Gly 10 Leu val Gin pro Gly Gly 15 Ser Leu Arg Leu 20 Ser cys Al a Al a Ser 25 Gly Phe Thr Phe Ser 30 Ser Tyr Al a Met Ser 35 Trp val Arg Gin Al a 40 Pro Gly Lys Gly Leu 45 Gl u T rp val Ser Ala 50 Il e Tyr Ser Ser Gly 55 Ser ser Thr Tyr Tyr 60 Al a ASp ser Val Lys 65 Gly Arg Phe Thr lie 70 Ser Arg Asp Asn Ser 75 Lys Asn Thr Leu Tyr 80 Leu Gin Met Asn Ser 85 Leu Arg Al a Glu Asp 90 Thr Al a Val Tyr Tyr 95 cys Ala Lys

Claims

1. An injectable preparation comprising an antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO: 1 and wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an amino acid selected from the group consisting of: an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (iii) an IGHGl*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising a human gamma-1 heavy chain constant region that comprises said amino acid and (iv) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation in SEQ ID NO: 1.

2. , The preparation of claim 1, wherein the antibody is a human antibody.

3. The preparation of claim 1 or claim 2, wherein the antibody or fragment comprises an IGHG1*O1 human heavy chain constant region.

4. The preparation of any preceding claim, wherein the antibody or antibody fragment is for administration to a human that is receiving or has received statin treatment or has reduced responsiveness to statin treatment.

5. The preparation of any preceding claim, wherein said antibody or antibody fragment is for treating or reducing the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication mediated by PCSK9 and high blood pressure.