IES86597B2 - An injectable antibody preparation for use in treating or reducing the risk of atopic dermatitis or asthma - Google Patents

Abstract

An injectable preparation comprising an antibody or antibody fragment for use in a method of treating or reducing the risk of atopic dermatitis or asthma in humans is described. The antibody or antibody fragment of the preparation specifically binds to a human IL4Ra protein that comprises a selected mutation from the group consisting of 175V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO. 67. The antibody or antibody fragment comprises a human gamma-4 heavy chain constant region that comprises an amino acid selected from the group consisting of a Leu at position 189 shown in SEQ ID NO 73 and an Arg at position 289 shown in SEQ ID NO. 73. The human comprises an IGHG4*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-4 heavy chain constant regions comprising said selected amino acid. The human further comprises a nucleotide sequence encoding said IL4Ra protein comprising said selected mutation.

Description

AN INJECTABLE ANTIBODY PREPARATION FOR USE IN TREATING OR REDUCING THE RISK OF ATOPIC DERMATITIS OR ASTHMA CROSS-REFERENCE TO RELATED APPLICATIONS TECHNICAL FIELD [0001] The technology described herein relates to ligands, e.g., antibodies for the treatment of disease.

BACKGROUND [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 arerecognized human ethnic populations SUMMARY [0003] Through the application of human genetic variation analysis and rationally-designed sequence selection the present invention provides for improved human patienet diagnosis and therapy. Importantly, the invention enables tailored medicines that address individual human patient genotypes or phenotypes. id="p-4" id="p-4"

[0004] The inventor's analysis of large numbers of naturally-occurring genomic human TOI 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-5" id="p-5"

[0005] Furthermore, the inventor surprisingly realised tbtff 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 utlitl9ity of the present invention and better serving patients in those populations.

MCG28801 [0006] 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-TOI ligand for administration to human patients for therapy and/or prophylaxis of TOI-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 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. |0007] To this end, the invention provides:[0008] In a First Configuration [0009] A method of treating or preventing a disease or condition in a human, wherein the disease or condition is mediated by a Target of Interest (TOI), wherein the TOI is present in humans as different polymorphic variants, the method comprising a. Administering to the human an anti-TOI ligand to target a TOI variant in the human and treat or prevent said disease or condition, wherein the TOI in said human is encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or wherein the TOI in said human is encoded by a nucleotide sequence having a total human genotype frequency of less than 50%; wherein b. Before step (a) said human has been or is genotyped as positive for said nucleotide sequence or phenotyped as positive for said TOI variant. id="p-10" id="p-10"

[0010] In a Second Configuration [0011] A method of treating or preventing a disease or condition in a human, wherein the disease or condition is mediated by a Target of Interest (TOI), wherein the TOI is present in humans as different polymorphic variants, the method comprising a. Administering to the human an anti- TOI ligand to target a TOI variant in the human and treat or prevent said disease or condition, wherein the TOI in said human is encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or wherein the TOI in said human is encoded by a nucleotide sequence having a total human genotype frequency of less than 50%; wherein b. before step (a) the ligand has been or is determined as capable of binding to said TOI variant. id="p-12" id="p-12"

[0012] In a Third Configuration |0013] A method of treating or preventing a disease or condition in a human, wherein the disease or condition is mediated by a Target of Interest (TOI), wherein the TOI is present in humans as different polymorphic variants, the method comprising a. Administering to the human an anti-TOI ligand to target a TOI variant in the human and treat or prevent said disease or condition, wherein the TOI in said human is a variant encoded by a nucleotide sequence having a cumulative human allele frequency of more than 50% and/or having a total human genotype frequency of more than 50%; wherein b. Before step (a) said human has been or is genotyped as negative for a variant nucleotide sequence having a cumulative human allele frequency of fess than 50% and/or having a total human genotype frequency of less than 50%; or phenotyped as negative for a TOI variant encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. id="p-14" id="p-14"

[0014] In a Fourth Configuration [0015] An anti-human TOI ligand for use in a method of treating and/or preventing a TOImediated disease or condition in a human, wherein the TOI is present in humans as different polymorphic variants and wherein the genome of said human comprises a TOI nucleotide sequence having a cumulative human aileie frequency of less than 50% and/or a total human genotype frequency of less than 50%, the method comprising administering the ligand to the human. id="p-16" id="p-16"

[0016] In a Fifth Configuration [0017] A ligand that binds a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, for use in a method comprising the step of using the ligand to target said TOI in a human to treat and/or prevent a disease or condition mediated by TOI. the method comprising administering the ligand to the human. |0018] In a Sixth Configuration [0019] A pharmaceutical composition or kit for treating or preventing a condition or disease mediated by a TOI. id="p-20" id="p-20"

[0020] In a Seventh Configuration [0021] A method of producing an anti-human TOI antibody binding site, the method comprising obtaining a plurality of anti-TOI antibody binding sites, screening the antibody binding sites for binding to a TOI comprising an amino acid sequence encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, or to a peptide thereof that comprises an amino acid variation from the corresponding sequence encoded by the TOI-encoding nucleotide sequence having the highest cumulative human aileie frequency and/or the highest totai human genotype frequency, and isolating an antibody binding site that binds in the screening step. id="p-22" id="p-22"

[0022] In a Eighth Configuration [0023] A method of producing an anti-human TOI antibody, the method comprising immunising a non-human vertebrate (eg, a mouse or a rat) with a TOI comprising an amino acid sequence encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, or to a peptide thereof that comprises an amino acid variation from the corresponding sequence encoded by the TOI-encoding nucleotide sequence having the highest cumulative human allele frequency and/or the highest total human genotype frequency, and isolating an antibody that binds a TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, and optionally producing a TOI-binding fragment or derivative of the isolated antibody. id="p-24" id="p-24"

[0024] In a Ninth Configuration [0025] A kit for TOI genotyping a human, wherein the kit comprises a nucleic acid comprising a nucleotide sequence that specifically hybridises to a TOI nucleotide sequence selected having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% or an RNA transcript thereof; and/or the nucleic acid comprises a nucleotide sequence that comprises at least 10 contiguous nucleotides of a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% oils an antisense sequence thereof. id="p-26" id="p-26"

[0026] In a Tenth Configuration [0027] Use of an anti-TOI ligand that binds a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%. in the manufacture of a medicament for treating and/or preventing a TOI-mediated disease or condition in a human whose genome comprises a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. |0028] In a Eleventh Configuration (0029] Use of an anti-TOI ligand that binds a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, in the manufacture of a medicament for targeting said TOI in a human to treat and/or prevent a disease or condition mediated by TOI. id="p-30" id="p-30"

[0030] In a Twelfth Configuration [0031] A method of targeting a TOI for treating and/or preventing a TOI-mediated disease or condition in a human, the method comprising administering an anti-TOI ligand lo a human comprising a TOI nucleotide sequence selected having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, whereby a TOI encoded by said nucleotide sequence is targeted. id="p-32" id="p-32"

[0032] In a Thirteenth Configuration [0033] A method of ΤΟΪ genotyping a nucleic acid sample of a human, the method comprising identifying in the sample the presence of a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. id="p-34" id="p-34"

[0034] In a Fourteenth Configuration [0035] A method of TOI typing a protein sample of a human, the method comprising identifying in the sample the presence of a TOI amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. [0036[ hi an example, the TOI is a human TOI selected from the group consisting of PCSK9. VEGF-A and IL6 receptor. id="p-37" id="p-37"

[0037] A Fifteenth Configuration provides a 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 (tr) an antibody constant domain comprising said first amino acid polymorphism. id="p-38" id="p-38"

[0038] A Sixteenth Configuration provides the ligand, method, use, kit or composition of the invention, 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). [0039] A Sixteenth Configuration provides the ligand, method, use, kit or composition of the invention, wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused human PCSK.9 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. [0040J A Seventeenth Configuration provides the ligand, method, use, kit or composition of the invention, wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused TO1 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. id="p-41" id="p-41"

[0041] A Eighteenth Configuration provides the ligand, method, use. kit or composition of the invention, 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. id="p-42" id="p-42"

[0042] A Ninteenth Configuration provides the ligand, method, use, kit or composition of the invention, 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 Sight chain constant regions comprising such a Val or Cys. id="p-43" id="p-43"

[0043] A Twentieth Configuration provides the ligand, method, use, kit or composition of the invention, 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) IGHVl-18*01 and the genome of the human comprises a human 1GHV1-I8*O1 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHVl-18*01; or (ii) IGVH1-46*O1 and the genome of the human comprises a human IGHV 1-46*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV 1 -46*01. [0044] A Twenty-First Configuration provides the ligand, method, use, kit or composition of the invention, 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 IGKV4-1 *01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV4-1 *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) IGKV 1-13*02 and the genome of the human comprises a human IGKV 1-13 *02 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV 1-13*02. [0045] A Twenty-Second Configuration provides a method of treating or reducing the risk of an IL4Ra-mediated disease or condition in a human in need thereof the method comprising administering to said human a ligand (eg. an antibody or antibody fragment) that specifically binds a human 1L4RA protein that comprises a mutation selected from the group consisting of 175 V. Ε400Λ. C43 1R. S503P, Q576R and S752A in SEQ ID NO: 67. As explained further below·; these amino acid variations are found in naturally-occurring IL-4Ra variants in humans found in many populations.

Said human comprises a nucleotide sequence encoding said 1L4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576Rand S752A in SEQ ID NO; 67. id="p-46" id="p-46"

[0046] A Twenty-Third Configuration provides a ligand (eg, an antibody or antibody fragment) for treating or reducing the risk of an IL4Ra-mediated disease or condition in a human in need thereof, the method comprising administering to said human said ligand, wherein the ligand specifically binds a human IL4RA protein that comprises a mutation selected from the group consisting of 175V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO; 67. Said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A. C43 1R, S503P, Q576R and S752A in SEQ ID NO: 67. [0047] Λ Twenty-Fourth Configuration provides provides a method of targeting lL4Ra in a human, the method comprising administering to said human a ligand (eg, an antibody or antibody fragment) that specifically binds a human IL4RA protein that comprises a mutation selected from the group consisting of 175 V, E400A, C431R, S503P. Q576R and S752A in SEQ ID NO: 67. Said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67. In an example, the human is suffering from or at riskof an IL4Ra-mediated disease or condition. In an example, the method treats or reduces the risk of an IL4Ra-mediated disease or condition in the human. id="p-48" id="p-48"

[0048] A Twenty-Fifth Configuration provides a ligand (eg, an antibody or antibody fragment) for targeting IL4Ra in a human, the method comprising administering to said human said ligand, wherein the ligand specifically binds a human IL4RA protein that comprises a mutation selected from the group consisting of I75V, E400A, C431R, S5O3P, Q576R and S752A in SEQ ID NO: 67. Said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C43 1 R, S503P. Q576R and S752A in SEQ ID NO: 67. In an example, the human is suffering from or at riskof an IL4Ra-mediated disease or condition. In an example, the method treats or reduces the risk of an IL4Ra-mediated disease or condition in the human. id="p-49" id="p-49"

[0049] In an embodiment of any of the 21-25*’' configurations, (i) the antibody or fragment 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 the framework I 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 ; and wherein (ii) said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67. id="p-50" id="p-50"

[0050] Additionally or alternatively, in an embodiment of any of the 21 -25th configurations, (i) the antibody or fragment comprises a human gamma-4 heavy chain constant region that comprises a Leu at position 189 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73 and wherein said human comprises an IGHG4*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-4 heavy chain constant regions comprising a Leu at position 189 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73; and wherein (ii) said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of 175V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67. id="p-51" id="p-51"

[0051] 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 I of SEQ ID NO: 40 , or tine human expresses VH domains that comprise the framework 1 of SEQ ID NO: 40. In an alternative, the ligand comprises a VI I 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 rs5606981 9 and wherein said human comprises a VH gene segment comprising SNP rs560698l9. id="p-52" id="p-52"

[0052] SNP rs560698l 9 is present in humans at an average cumulative frequency of I 1% 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 1L4R protein that comprises a mutation S752A and 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.

BRIEF DESCRIPTION OF THE DRAWINGS [0053] This patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee, [0054] Figure 1 shows in silico modeling of PCSK9 surface variant residues. id="p-55" id="p-55"

[0055] 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). The figure shows that VH3-23 alleles comprising SNP rs56069819 are present at a cumulative frequency of ! 1% 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 VFI3-23 alleles comprising SNP rs56069819. id="p-56" id="p-56"

[0056] Figure 3 depicts frameworks and CDRs encoded by VI 13-23*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 76, 76, 76, 78, 78. 78, 79, 81, 83, 39 and 84, respectively, in order of appearance. Figure 3 discloses the coded amino acid sequences as SEQ ID NOS 77, 77. 77. 77. 77, 77, 80, 82, 82, 38 and 85, respectively, in order of appearance. id="p-57" id="p-57"

[0057] figure 4 depicts sequences of VH3-23*04. The portion of VI 13-23*04 comprising the FW1 residue change of rs56069819 (SEQ ID NO: 38). The portion of the nucleic acid sequence encoding rs560698 19 is depicted (SEQ ID NO: 39). The FW1 encoded by VH3-23*04 is depicted (SEQ ID NO: 40).

DETAILED DESCRIPTION [0058] 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). id="p-59" id="p-59"

[0059] I he 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.

As sources of genomic sequence variation data, the skilled person wili be aware of the available databases and resources (including updates thereof) provided by the following:1. HapMap (The International HapMap Consortium. 2003; available on the World Wide Web at 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 1 000genomes.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.Ifaga et al. 2002; available on the World Wide Web at snp.ims.utokyo.ac.jp/index.html), Based on a study identifying 190,562 human genetic variants. id="p-60" id="p-60"

[0060] 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. id="p-61" id="p-61"

[0061] 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-62" id="p-62"

[0062] 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-63" id="p-63"

[0063] Selection Criteria [0064] Three or four of the following:• Naturally-occurring human target variant sequences having a cumulative human allele frequency of 35% or less; • Naturally-occurring human target variant sequences having a total human genotype frequency of 40% or less; • Naturally-occurring human target variant sequences found in many different human ethnic populations (using the standard categorisation of the 1000 Genomes Project: see Table 4 below): and • Naturally-occurring human target variant sequences found in many individuals distributed across such many different ethnic populations. id="p-65" id="p-65"

[0065] The inventor's selection included, as a consideration, selection for nucleotide variation that produced amino acid variation in corresponding TOI forms (ie, non-synonymous variations), as opposed to silent variations that do not alter amino acid residues in the target protein. id="p-66" id="p-66"

[0066] In an embodiment, the cumulative human allele frequency is 30, 25, 20. 15, 10 or 5% or less, eg, in the range from I to 20% or 1 to 1 5% or 1 to 10%. id="p-67" id="p-67"

[0067] In an embodiment, the total human genotype frequency is 35, 30, 25, 20, 15,10 or 5% or less, eg, in the range from 1 to 25%, 1 to 20%. 1 to 15%, I to about 15%, I to 10%, 1 to about 10% or 1 to 5% or 1 to about 5%.

J0068] In an embodiment, the naturally-occurring human target variant sequences are found in at least 9. 10. 1 1, 12, 13. 14, 15. 16, 17, 18, 19 or 20 different human ethnic populations (using the standard categorisation ofthe 1000 Genomes Project). id="p-69" id="p-69"

[0069] 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-70" id="p-70"

[0070] In an example, the following criteria are applied:• Naturally-occurring human target variant sequences having a cumulative human allele frequency of 15% or less; • Naturally-occurring human target variant sequences having a total human genotype frequency of 20% or less; • Naturally-occurring human target variant sequences found in at least 5 different human ethnic populations (using the standard categorisation of the 1000 Genomes Project); and • Naturally-occurring human target variant sequences found in many individuals distributed across such many different ethnic populations. id="p-71" id="p-71"

[0071] 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-72" id="p-72"

[0072] 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-73" id="p-73"

[0073] Optionally, further sequence analysis and 3D in silico modelling (eg. see Figure I) can also be used as an additional selection criterion: variants whose variant amino acid residues (versus the most common form of human TOI) 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-74" id="p-74"

[0074] The following bioinformatics protocol is envisaged to indentify human sequences for use in the present invention: (a) Identify a genomic region containing a 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 subpopulation 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 delections’ (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’ super-population 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. [0075) Human Populations |0076| 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-77" id="p-77"

[0077] N A Rosenberg et al (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-78" id="p-78"

[0078] African ancesny [0079] (Mbuti Pygmies. Biaka Pygmies. San peoples, and speakers ol’Niger-Kordofanian languages (Bantu, Yoruba or Mandenka populations), [0080] Eurasian ancestry [0081] (European ancestry (Orcadian, Adygei, Basque, French, Russians, Italians, Sardinian, Tuscan), [0082] Middle Eastern ancestry (Mozabite, Bedouin, Druze, Palestinians), [0083] Central/South Asian ancestry (Balochl, Brahul, Makrani, Sindhi, Pathan, Burusho, Hazara, Uygur, Kalash)), [0084] East Asian ancestry [0085] (Han, Dal, Daur, Hezhen, Lahu, Miao, Oroqen, She, Tujia, Tu, Xibo, Yi. Mongola, Naxi, Cambodian, Japanese, Yakut), Oceanic ancestry (Melanesian, Papuan); or [0086] Americas ancestry 10087] (Karitiana, Surui. Colombian. Maya. Pima). id="p-88" id="p-88"

[0088] 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:[0089] Utah population with Northern or Western European ancestry (samples collected in 1980 by the Centre d’Etude du Polymorphisms 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-90" id="p-90"

[0090] The authors, citing earlier publications, suggest that ancestral geography is a reasonable basis for sampling human populations. [00911 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 cmceshy (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. (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-92" id="p-92"

[0092] In any configuration of the invention, in one embodiment, each human population is selected from a population marked "(a)" above. id="p-93" id="p-93"

[0093] In any configuration of the invention, in another embodiment, each human population is selected from a population marked "(b)" above. id="p-94" id="p-94"

[0094] In any configuration of the invention, in another embodiment, each human population is selected from a population marked "(c)" above. id="p-95" id="p-95"

[0095] 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-96" id="p-96"

[0096] 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 ancestiy; or an ethnic population with Luhya ancestry; or an ethnic population with Gambian ancestry; or an 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 Kavadtha ancestry; or an ethnic population with Reddy ancestry; or an ethnic population with Maratha; or an ethnic population with Punjabi ancestiy. id="p-97" id="p-97"

[0097] Anti-Target Ligands [0098] 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 the TOI. For example, the ligand specifically binds to the TOI variant as per the invention. The ligand may inhibit or antagonise the activity of the 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-99" id="p-99"

[0099] 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 antibodymolecules and multispecific antibodies formed from antibody fragments. |00100] 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-TOI or TOI-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 Mouse1171 or MeMo Mouse1171), rats (eg, the Omnirat™), camelids, sharks, rabbits, chickens or other non-human animals immunised with the TOI 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, 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 herein by reference, eg. the methods set out in paragraphs [0309] to [0346], Although this is with reference to PCSK9, the antibody-generating methods can be applied to other TOIs as per the broadest scopes of the present invention. id="p-101" id="p-101"

[00101] 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 ceil 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 Cl-IO 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. id="p-102" id="p-102"

[00102] 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 IgG 1 or lgG4 (for example, SEQ ID NO: 751,752,753 in US2011/0065902, 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-103" id="p-103"

[00103] 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 TOI variant sequence, eg, hybridises a nucleotide sequence comprising one or more nucleotides that are variant (versus the most common TOI sequence, eg, with reference to the 1000 Genomes Project database), [00104] Target binding ability, specificity and affinity (Kd, Kotr and/or KOI1) 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. 100105] In one embodiment, the surface plasmon resonance (SPR) is carried out at 25°C. In another embodiment, the SPR is carried out at 37°C. id="p-106" id="p-106"

[00106] In one embodiment, the SPR is carried out at physiological pH, such as about pI47 or at pH7.6 (eg, using Hepes buffered saline at pH7.6 (also referred to as HBS-EP)). id="p-107" id="p-107"

[00107] In one embodiment, the SPR is carried out at a physiological salt level, eg, l50mM NaCI, [00108] 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-109" id="p-109"

[00109] 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-110" id="p-110"

[00110] 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, at25°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®). id="p-111" id="p-111"

[00111] Regeneration of the capture surface can be carried out with lOmM glycine at pHl .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 XPR361M analysis software. id="p-112" id="p-112"

[00112] 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 TOI. In an example, the instructions indicate that the human should be genotyped for a TOI 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 TOI variant of the invention before administering the ligand to the human. In an example, the human is of Chinese (eg, Han) ethnicity and the instructions are in Chinese (eg, Mandarin). In an example, the instructions comprise directions to administer alirocumab or evolocumab to said human. id="p-113" id="p-113"

[00113] The invention relates to the concepts set out in the following clauses. id="p-114" id="p-114"

[00114] Clause 1 A method of treating or preventing a disease or condition in a human, wherein the disease or condition is mediated by a Target of Interest (TOI), wherein the TOI is present in humans as different polymorphic variants, the method comprising a. Administering to the human an anti-TOI ligand to target a TOI variant in the human and treat or prevent (eg, by at least 40, 50, 60, 70, 80, 90 or 95%) said disease or condition, wherein the TOI in said human is encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or wherein the TOI in said human is encoded by a nucleotide sequence having a total human genotype frequency of less than 50%; wherein Before step (a) said human has been or is genotyped as positive for said nucleotide sequence or phenotyped as positive for said TOI variant, or the method comprises before step (a) genotyping the human as positive for said nucleotide sequence or phenotyping the human as positive for said TOI variant. |00115] In any aspect configuration, example, embodiment, clause or concept herein, frequencies may be determined using bioinformatics. id="p-116" id="p-116"

[00116] 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. |00117] 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-118" id="p-118"

[00118] 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-119" id="p-119"

[00119] In any aspect, configuration, example, embodiment, clause or concept herein totai human genotype frequency means the total of heterozygous plus homozygous human genotype frequencies. id="p-120" id="p-120"

[00120] 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-121" id="p-121"

[00121] Clause 2: The method of clause 1, wherein before step (a) the ligand has been or is determined as being capable of binding to said TOI variant, eg, with an affinity (Kd) disclosed below. [00122] In an example, the ligand is (or has been determined as) a neutraliser of the TOI. 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). id="p-123" id="p-123"

[00123] Clause 3: A method of treating or preventing a disease or condition in a human, wherein the disease or condition is mediated by a Target of Interest (TOI), wherein the TOI is present in humans as different polymorphic variants, the method comprising a. Administering to the human an anti-TOI ligand to target a TOI variant in the human and treat or prevent (eg, by at least 40, 50, 60, 70, 80, 90 or 95%) said disease or condition. wherein the TOI in said human is encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or wherein the TOI in said human is encoded by a nucleotide sequence having a total human genotype frequency of less than 50%; wherein b. Before step (a) the ligand has been or is determined as capable of binding to said TOI variant, eg, with an affinity (Kd) disclosed below. id="p-124" id="p-124"

[00124] In an example, tlie ligand is (or lias been determined as) a neutraliser of the TOI. In an example, determination is carried out in a human (eg. in a clinical trial). In an exampie, 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). id="p-125" id="p-125"

[00125] Clause 4 : The method of clause 3, wherein the genome of said human comprises a nucleotide sequence encoding said TOI variant; and before step (a) said nucleotide sequence has been or is determined as having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. (00126] The TOI variant is not the most frequent. id="p-127" id="p-127"

[00127] Clause 5 : The method of clause 3 or 4, wherein said human has been or is genotyped as positive for said variant nucleotide sequence before step (a), or the method comprises genotyping the human as positive for said variant nucleotide sequence before step (a). id="p-128" id="p-128"

[00128] Clause 6: The method of any preceding clause, wherein the human has been or is phenotyped as positive for said TOI variant before step (a), or the method comprises phenotyping the human as positive for said variant nucleotide sequence before step (a). 100129) Clause 7: I he method of any preceding clause, wherein said frequency is less than 10 or 15% (eg. from 1 to 1 0%). id="p-130" id="p-130"

[00130] In an embodiment, the cumulative human allele frequency is 30, 25, 20, 15, 10 or 5% or less, eg, in the range from I to 20% or 1 to 15% or I to 10%. id="p-131" id="p-131"

[00131] In an embodiment, the total human genotype frequency is 35, 30, 25, 20. 15. 1 0 or 5% or less, eg, in the range from I to 25%, 1 to 20%, 1 to 15%, I to about 15%, 1 to 10%, I to about 10% or 1 to 5% or 1 to about 5%. id="p-132" id="p-132"

[00132] Clause 8: The method of any preceding clause, wherein the ligand is capable of binding to two or more different TOI variants, each being encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% (eg, from 1 to 10%) and/or having a total human genotype frequency of less than 50% (eg, from 1 to 20%). id="p-133" id="p-133"

[00133] In an embodiment, the cumulative human allele frequency of each TOI variant is 30, 25. 20, 15, 10 or 5% or less, eg, in the range from 1 to 20% or 1 to 1 5% or 1 to 10%. |00134] In an embodiment, the total human genotype frequency of each TOI variant is 35, 30, 25, 20, 15, 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-135" id="p-135"

[00135] Clause 9: A method of treating or preventing a disease or condition in a human, wherein the disease or condition is mediated by a Target of Interest (TOI), wherein the TOI is present in humans as different polymorphic variants, the method comprising a. Administering to the human an anti-TOI ligand to target a TOI variant in the human and treat or prevent (eg, by at least 40, 50, 60, 70, 80, 90 or 95%) said disease or condition, wherein the TOI in said human is a variant encoded by a nucleotide sequence having a cumulative human allele frequency of more than 50% (eg. the highest frequency) and/or having a total human genotype frequency of more than 50% (eg, tlie highest frequency): wherein b. Before step (a) said human has been or is genotyped as negative for a variant nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%; or phenotyped as negative for a TOI variant encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%: or Before step (a) said the method comprises genotyping the human as negative for a variant nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%; or phenotyping the human as negative for a TOI variant encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%.

JOO136] In an embodiment, in (a) the cumulative human allele frequency is 55, 60. 65. 70. 75. 80. or 90 or more but less than 95, 96. 97. 98, 99 or 100% (eg. in the range from 5 1 to 80%). |00137] In an embodiment, in (a) the total human genotype frequency is 55, 60, 65, 70, 75, 80. 85 or 90 or more but less than 95, 96, 97, 98, 99 or 100% (eg, in the range from 51 to 80%). id="p-138" id="p-138"

[00138] In an embodiment, in (b) the cumulative human allele frequency is 30, 25, 20, 15, 10 or 5% or less, eg, in the range from 1 to 20% or 1 to 15% or 1 to 10%. id="p-139" id="p-139"

[00139] In an embodiment, in (b) the total human genotype frequency is 35, 30, 25, 20, 15, 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 I to about 5%. id="p-140" id="p-140"

[00140] Clause 10: The method of clause 9, wherein before step (a), the human has been or is phenotyped as positive for the most frequent TO! variant or genotyped for the nucleotide sequence thereof. id="p-141" id="p-141"

[00141] In an embodiment, before step (a) the human has been or is genotyped as positive for TOI variant nucleotide sequence having a cumulative human allele frequency of 55, 60, 65, 70, 75, 80, 85 or 90 or more but less than 95, 96, 97, 98, 99 or 100% (eg, in the range from 51 to 80%) or phenotyped for the TOI variant thereof. id="p-142" id="p-142"

[00142] In an embodiment, before step (a) the human has been or is genotyped as positive for TO! variant nucleotide sequence having a total human genotype frequency of 55, 60, 65, 70, 75, 80, 85 or 90 or more but less than 95, 96, 97, 98, 99 or 100% (eg, in the range from 5 1 to 80%) or phenotyped for the TOI variant thereof. id="p-143" id="p-143"

[00143] Clause 11: The method of clause 9 or 10. wherein before step (a) the ligand has been or is determined as being capable of binding to the most frequent TOI variant. id="p-144" id="p-144"

[00144] Clause 12: The method of clause 9. 10 or ] 1, wherein before step (a) the ligand has been or is determined as being substantially incapable of neutralising or inhibiting said TOI variant recited in step (b). id="p-145" id="p-145"

[00145] By "substantially incapable or neutralising or inhibiting" is meant: Neutralisation or inhibition less than 50, 25, 10, 5 or 0.5% inhibition or neutralisation of the most frequent TOI variant. [00146] Clause 13: T he method of any one of clauses 9 to 12, wherein the ligand is capable of binding to the most frequent TOI variant. id="p-147" id="p-147"

[00147] Clause 14: The method of any one of clauses 9 to 13, wherein the ligand is capable of binding to two or more different TOI variants, each being encoded by a nucleotide sequence having a cumulative human allele frequency of more than 50%. id="p-148" id="p-148"

[00148] in an embodiment, each TOI variant is encoded by a nucleotide sequence having a cumulative human allele frequency of 55, 60, 65, 70, 75, 80, 85 or 90 or more hut less than 95. 96, 97, 98, 99 or 100% (eg, in the range from 5 1 to 80%). id="p-149" id="p-149"

[00149] In an embodiment, each ΤΌΙ variant is encoded by a nucleotide sequence having a total human genotype frequency of 55, 60, 65, 70, 75, 80, 85 or 90 or more but less than 95, 96, 97, 98. 99 or 100% (eg, in the range from 5 I to 80%). id="p-150" id="p-150"

[00150] Clause 15: The method of any preceding clause, wherein said variant nucleotide sequence recited in step (a) has been or is determined as being present in at least 2 different human ethnic populations, eg, at least 2, 3, 4, 5, 6, 7, 8 or 9 different human ethnic populations in fable 4. [00151] Clause 16: The method of any preceding clause, wherein said hitman frequency is the frequency in a database of naturally-occurring sequences sampled from at least 15, 20 or 25 different human ethnic populations and comprising at least 1000 sequences. In an embodiment, the database is the 1000 Genomes Project database as described herein. id="p-152" id="p-152"

[00152] Clause 17: An anti-human TOI ligand for use in a method of treating and/or preventing a TOI-mediated disease or condition in a human, wherein the TOI is present in humans as different polymorphic variants and wherein the genome of said human comprises a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, the method comprising administering the ligand to the human, [00153] In the alternative, clause 17 provides an anti-human TOI ligand for use in a method according to any one of clauses 1 to 16, the method comprising administering the ligand to the human. |00154| In an embodiment, the cumulative human allele frequency is 30. 25, 20, 15, 10 or 5% or less, eg, in the range from I to 20% or 1 to 15% or 1 to 10%. id="p-155" id="p-155"

[00155] In an embodiment, the total human genotype frequency is 35, 30, 25, 20, 15, 10 or 5% or less, eg, in the range from I to 25%, 1 to 20%, 1 to 15%, 1 to about 15%, I to 10%, 1 to about 1 0% or 1 to 5% or 1 to about 5%. id="p-156" id="p-156"

[00156] Clause 18: The ligand of clause 17, wherein the ligand has been or is determined as capable of binding the human TOI encoded by said nucleotide sequence. id="p-157" id="p-157"

[00157] In the alternative, clause 18 provides a ligand that binds a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, for use in a method comprising the step of using the ligand to target said TOI in a human to treat and/or prevent a disease or condition mediated by TOI, the method comprising administering the ligand to the human. [00158] Clause 19: A ligand that binds a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, for use in a method according to any one of clauses 1 to 16. the method comprising administering the ligand to the human. id="p-159" id="p-159"

[00159] Clause 20: The ligand of any one of clauses 17 to 19, wherein the human has been or is genotyped as positive for said TOI nucleotide sequence having a cumulative human allele frequency of less than 50%. [00160| The ligand of any one of clauses 17 to 19, wherein the human has been or is genotyped as positive for said TOI nucleotide sequence having a total human genotype frequency of less than 50%. [00161] Clause 21: The ligand of any one of clauses 17 to 20, wherein the human has been or is phenotyped as positive for a TOI encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. |00162] Clause 22: The ligand of any one of clauses 17 to 21, wherein the human has been or is genotyped as heterozygous for a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%; optionally wherein the human has been or is genotyped as comprising a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and a TOI nucleotide sequence having a cumulative human allele frequency of more than 50% (eg, having the highest cumulative human allele frequency) and/or having a total human genotype frequency of more than 50% (eg, having the highest total human genotype frequency). id="p-163" id="p-163"

[00163] Clause 23: The ligand of any one of clauses 17 to 22, wherein the genome of the human has been or is genotyped as homozygous for a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. |00164] Clause 24: The ligand of any one of clauses 17 to 23, wherein the ligand comprises an antibody binding site that binds a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%; and optionally has been or is determined as capable of such binding. [ 00165] Clause 25: The ligand of clause 24, wherein the ligand is an antibody or antibody fragment, (00166] Clause 26:The ligand of any one of clauses 17 to 23, wherein the ligand comprises a nucleotide sequence that specifically hybridises to a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50% or an RNA transcript thereof; and/or the ligand comprises a nucleotide sequence that comprises at least 10 contiguous nucleotides of a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50% or is an antisense sequence thereof [00167] In an embodiment, the ligand comprises a nucleotide sequence that comprises at least 10. 11, 12, 13. 14, 15. 20, 25, 30, 35, 40, 45, 50 or 100 contiguous nucleotides of a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50% or is an antisense sequence thereof. ]00168] Clause 27: The ligand of any one of clauses 17 to 26, wherein the genome of said human comprises a nucleotide sequence having a cumulative human allele frequency of less than 50% and the sequence is found in at least 2 different ethnic populations (eg. found in at least 9, 10, 11. 12. 13. 14, 15, 16, 17. 18, 19 or 20 different human ethnic populations (for example as per the populations in Table 4)). In an example, numbers are with reference to the 1000 Genomes Project database. id="p-169" id="p-169"

[00169] The ligand of any one of clauses 1 7 to 26, wherein the genome of said human comprises a nucleotide sequence having a cumulative human allele frequency of less than 50% and the sequence is found in at least 20 individuals distributed across at least 2 said different ethnic populations (eg, found in at least in at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90. 95, 100. 105, 1 10, 115, 120, 130, 140 or 150 individuals distributed across such many different ethnic populations). In an example, numbers are with reference to the 1000 Genomes Project database. id="p-170" id="p-170"

[00170] Clause 28: A pharmaceutical composition or kit for treating or preventing a condition or disease mediated by a TOI as recited in any preceding clause, the composition or kit comprising a ligand of any one of clauses 17 to 27; and optionally in combination with a label or instructions for use to treat and/or prevent said disease or condition in a human; optionally wherein the label or instructions comprise a marketing authorisation number (eg, an FDA or EMA authorisation number); optionally wherein the kit comprises an injection pen or IV container that comprises the ligand. [00171] In an example, the label or instructions cover or describe use for a human comprising a TOI variant encoded by a nucleotide sequence as recited in clause 17. id="p-172" id="p-172"

[00172] Clause 29: A method of producing an anti-human TOI antibody binding site, the method comprising obtaining a plurality of anti-TOI antibody binding sites, screening the antibody binding sites for binding to a TOI comprising an amino acid sequence encoded by a nucleotide sequence having a cumulative human allele frequency of' less than 50% and/or a total human genotype frequency of less than 50%, or to a peptide thereof that comprises an amino acid variation from the corresponding sequence encoded by the TOI-encoding nucleotide sequence having the highest cumulative human allele frequency and/or the highest total human genotype frequency, and isolating an antibody binding site that binds in the screening step. id="p-173" id="p-173"

[00173] In an embodiment of any aspect herein, the antibody, fragment or binding site is recombinant. id="p-174" id="p-174"

[00174] In the alternative, clause 29 provides: A method of producing an anti-human TOI antibody, the method comprising immunising a non-human vertebrate (eg, a mouse or a rat) with a TOI comprising an amino acid sequence encoded by a nucleotide sequence having a cumulative human aliele frequency of less than 50% and/or a total human genotype frequency of less than 50%. or to a peptide thereof that comprises an amino acid variation from the corresponding sequence encoded by the TOI-encoding nucleotide sequence having the highest cumulative human allele frequency and/or the highest total human genotype Frequency, and isolating an antibody that binds a TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%. and optionally producing a TOI-binding fragment or derivative of the isolated antibody. |00175] 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) lias 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. (00176] 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 exampie, the Lowry method, and in some embodiments, to greater than 99% by weight: (2) to a degree sufficient to obtain al least 15 residues of N-terminai 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 Cooinassie 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-177" id="p-177"

[00177] Immunoconj ugates [00178] 'fhe 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 05/10308 1. id="p-179" id="p-179"

[00179] Bispecifics [00180] The antibodies of the present invention may be monospecific, bispecific, or mullispecific. 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-TOI (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. id="p-181" id="p-181"

[00181] 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 Cl 43 domain, wherein the first and second Ig CI43 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 lg CH3 domain binds Protein A and the second lg CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an I495R 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 IgG 1 antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of IgG2 antibodies; and QI5R, N44S. K52N, V57M, R69K, E79Q, and V821 (by IMGT; Q355R.

N3845, K392N, V397M. R409K, E4I9Q, 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-182" id="p-182"

[00182] Clause 30: The method of clause 29. 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-183" id="p-183"

[00183] Clause 31: A kit for TOI genotyping a human, wherein the kit comprises a nucleic acid comprising a nucleotide sequence that specifically hybridises to a TOI nucleotide sequence selected having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% or an RNA transcript thereof; and/or the nucleic acid comprises a nucleotide sequence that comprises at least 10 (eg, at least 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50 or 100) contiguous nucleotides of a TO! nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% or is an antisense sequence thereof, [00184] For example, the nucleic acid hybridises to a region immediately flanking a nucleotide that is variant compared to the corresponding nucleotide of the TOI 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.

J DO 185] Specific hybridisation is under stringent conditions, as will be apparent to the skilled person, eg, conditions of 5 - SSC. S^Denhardt's reagent, and 0.5% SDS at 65° C. id="p-186" id="p-186"

[00186] Clause 32: A kit for TO] genotyping or phenotyping a human, wherein the kit comprises a ligand according to any one of clauses 17 to 27 or an antibody, fragment or derivative produced by the method of any one of clauses 29 to 31. id="p-187" id="p-187"

[00187] For example, the ligand specifically binds to an epitope comprising an amino acid that is variant compared to the corresponding amino acid of the TOI encoded by a nucleotide sequence having the highest cumulative human allele frequency and/or the highest total human genotype frequency. 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 1 mM, ΙΟΟηΜ, lOnM or InM or less, eg, as determined by SPR, [00188] 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. [00189] Clause 33: Use of an anti-TOI ligand that binds a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%. in the manufacture of a medicament for treating and/or preventing a TOI-mediated disease or condition in a human whose genome comprises a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. 1001901 Clause 34: Use of an anti-TOI ligand that binds a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, in the manufacture of a medicament for targeting said TOI in a human to treat and/or prevent a disease or condition mediated by TOI. [001911 The use of clause 33 or 34, wherein the ligand, human, disease or condition is according to any one of clauses 1 to 27. id="p-192" id="p-192"

[00192] Clause 35: A method of targeting a TOI for treating and/or preventing a TOI-mediated disease or condition in a human, the method comprising administering an anti-TOI ligand to a human comprising a TOI nucleotide sequence selected having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, whereby a TOI encoded by said nucleotide sequence is targeted. id="p-193" id="p-193"

[00193] Clause 36: The method of clause 35, wherein the method comprises targeting a human TOI comprising an amino acid sequence with said ligand to treat and/or prevent said disease or condition in said human, wherein said amino acid sequence is encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%. id="p-194" id="p-194"

[00194] Clause 37: A method of TOI genotyping a nucleic acid sample of a human, the method comprising identifying in the sample the presence of a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. id="p-195" id="p-195"

[00195] In an example, the method comprises obtaining a TOI nucleic acid sample from the human and then carrying out the identifying step. id="p-196" id="p-196"

[00196] Clause 38: A method of TOI typing a protein sample ofa human, the method comprising identifying in the sample the presence of a TOI amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. id="p-197" id="p-197"

[00197] In an example, the method comprises obtaining a TOI protein sample from the human and then carrying out the identifying step. id="p-198" id="p-198"

[00198] Clause 39: The method of clause 37 or 38, comprising obtaining a sample of serum, blood, faeces, hair, urine or saliva from a human, whereby the nucleic acid or protein sample is obtained for use in the step of identifying said sequence. id="p-199" id="p-199"

[00199] Clause 40: The method of any one of clauses 37 to 39, comprising using a ligand according to any one of clauses 17 to 27 to carry out said identifying step. id="p-200" id="p-200"

[00200] Clause 41: A diagnostic kit comprising a ligand that is capable of binding a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% and instructions for carrying out the method of clause 38 or 39. id="p-201" id="p-201"

[00201] Clause 42: A diagnostic kit comprising a nucleic acid probe comprising a nucleotide sequence that specifically hybridises a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% or an RNA transcript thereof and instructions for carrying out the method of clause 38 or 39. id="p-202" id="p-202"

[00202] Clause 43: The method, ligand, composition, kit or use of any preceding clause, wherein the TOI is encoded by a nucleotide sequence having a cumulative human allele frequency from 1 to 10% and/or a total human genotype frequency from ] to about 15% or from ] to 15%. id="p-203" id="p-203"

[00203] Clause 44: The method, ligand, composition, kit or use of any preceding clause wherein the TOI is a human TOI selected from Table 5; optionally for treating and/or preventing a corresponding disease or condition as set out in Table 5. id="p-204" id="p-204"

[00204] For example, the TOI is human PCSK9, eg, a mature, cleaved, autocatalysed or active PCSK9. In an example, the disease is a cardiovascular disease such as hyperlipidaemia. id="p-205" id="p-205"

[00205] Ligands of the invention are useful, for instance, in specific binding assays, for genotyping or phenotyping humans, affinity purification of the TOI and in screening assays to identify other antagonists of TOI activity. Some of the ligands of the invention are useful for inhibiting binding of TOI to a congnate human receptor or protein, or inhibiting TOI-mediated activities. id="p-206" id="p-206"

[00206] The invention encompasses anti-TOI (eg, PCSK.9) 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 ah (2002) JBC 277:26733). In other applications, modification of galactosylation can be made in order to modify complement dependent cytotoxicity (CDC). id="p-207" id="p-207"

[00207] 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 TOI (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 antigen-binding 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-208" id="p-208"

[00208] ‘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 earner, 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-209" id="p-209"

[00209] In an example, the invention features a method for inhibiting TOI activity using the antiTOI 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 TOI activity. id="p-210" id="p-210"

[00210] 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 techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding). id="p-211" id="p-211"

[00211] The term "specifically binds," or the like, means that a ligand, eg, an antibody or antigenbinding 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 1 x IO6 M or less (e.g., a smaller KD denotes a tighter binding). Methods for determining whether two molecules specifically bind 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 TOI may, however, exhibit cross-reactivity to other antigens such as a TOI molecule from another species. Moreover, multi-specific antibodies (e.g., bispecifics) that bind to human TOI and one or more additional antigens are nonetheless considered antibodies that "specifically bind" TOI, as used herein. |00212] Genotyping A Phenotyping 100213] 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). id="p-214" id="p-214"

[00214] Next-generation sequencing technologies such as pyrosequencing is also useful. id="p-215" id="p-215"

[00215] Reference is also made to GB24444I0A and the genotyping method disclosed therein, which is incorporated herein by reference in its entirety. 100216] 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 single-nucleotide 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; 280(5366):1077-82). Other high-throughput methods discriminate alleles by differential hybridization, primer extension, ligation and cleavage of an allelespecific 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). id="p-217" id="p-217"

[00217] 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 realtime 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 10.1007/978-1-60327-411-119, 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 ei al). The TaqMan SNP Genotyping Assay exploits the 5'-exonuclease activity of AmpliTaq Gold1®1 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 allele-specific 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. id="p-218" id="p-218"

[00218] 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, WenzMH, Mutat Res. 2005 Jun 3; 573(1-2):1 1 1-35). The results of the assay can be automatically determined by genotyping software provided with real-time thermal cyclers (e.g. 10 software of Bio-Rad. Sequence Detection Software of Applied Biosystems). [00219] 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 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/gkll 85, 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-220" id="p-220"

[00220] 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 sifico translation. [00221 ] Therapeutic Administration and Formulations [00222] The invention provides therapeutic compositions comprising the anti-TOI ligand, eg, 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 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 ah Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311. id="p-223" id="p-223"

[00223] 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 the TOI in an adult patient, it is advantageous to intravenously administer the 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. [00224| Various delivery systems are known and can be used to administer the ligand or pharmaceutical composition of the invention, for example a ligand provided 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. Chem, 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The ligand or 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-225" id="p-225"

[00225] The ligand or 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-226" id="p-226"

[00226] In certain situations, the ligand or 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 the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138, 1984). id="p-227" id="p-227"

[00227] T he 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 of the 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, fhe 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. 100228] Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a ligand or pharmaceutical composition of the present invention. Examples include, but certainly are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), D1SETRONIC™ 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), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), OPTIPENT™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPT1CEIKT™ (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 (sanofi-aventis), the FLEXPEN™ (Novo Nordisk), and the KW1KPEN™ (Eli Lilly). id="p-229" id="p-229"

[00229] 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 ligand(s). 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. [00230] Exemplary TOE [00231] For example in any configuration, aspect, concept, example or configuration of the invention, the or each TOI is selected from the group consisting of ABCF1; ACVR1; ACVR1B; ACVR2: ACVR2B: ACVRL1; ADORA2A; Aggrecan: AGR2; AICDA; AWl; A1G1: AKAP1; AKAP2; ΑΙΎΙΗ; amyloid-beta; AMHR2: ANGPT1; ANGPT2; ANGPTL3; ANGPTL4; ANPEP: APC; APOC1; AR; Axl; A2GPI (zinc-a-glycoprotein); B7.1; B7.2; BAD; BAFF; BAG1; BAIT BCL2; BCL6; BDNF; BLNK; BLR1 (MDR15); BlyS; BMP1; BMP2; BMP3B (GDF1O); BMP4; BMP6; BMP8; BMPR1A; BMPR1 B; BMPR2: BPAGI (plectin); BRCA1; CI9orflO (IL27w); C3; C4A; C5; C5R1; CANT1; CASP1; CASP4; CAV1; CB1; CCBP2 (D6/JAB61); CCL1 (1-309): CCL11 (eotaxin); CCL13 (MCP-4): CCL15 (MIP-id); CCL16 (HCC-4); CCLI7 (TARC); CCLI8 (PARC): CCL19 (MIP-3b); CCL2 (MCP-I); MCAF; CCL2O (MIP-3a); CCL21 (MIP-2); SLC; exodus-2; CCL22 (MDC / STC-1); CCL23 (MPIF-1); CCL24 (MPIF-2 I eotaxin-2); CCL25 (TECK): CCL26 (eotaxin-3): CCL27 (CTACK /ILC); CCL28; CCL3 (MIP-la); CCL4 (MIP-lb); CCL5 (RANTES); CCL7 (MCP-3); CCL8 (mcp-2); CCNA1; CCNA2; CCND1; CCNE1; CCNE2; CCR1 (CKR1 / HM145); CCR2 (mcp-lRB / RA):CCR3 (CKR3 / CMKBR3); CCR4; CCR5 (CMK.BR5 I ChemRB); CCR6 (CMKBR6 ICKR-L3 / STRL22 / DRY6); CCR7 (CKR7 / EBI1); CCR8 (CMKBR8 /TER1 / CKR-L1): CCR9 (GPR-9-6): CCRL1 (VSHKI): CCRI.2 (L-CCR); CD7, CD164; CDI9; CD1C; CD2O; CD200: CD-22; CD24: CD28: CD3; CD37: CD38: CD3E: CD3G: CD3Z; CD4; CD4O: CD4OL: CD44; CD45RB: CD52; CD69; CD72; CD74; CD79A; CD79B; CD8; CD8O: CDS I; CD83; CD86; CD96; CD207; CDH1 (E-cadherin); CDH10; CDH12; CDH13; CDH18; CDH19; CDH20; CDH5; CDH7; CDH8; CDH9; CDK2; CDK3; CDK4; CDK5; CDK.6; CDK7; CDK9; CDKNIA (p2IWapl/Cipl); CDKN1B (p27Kip 1); CDKNIC; CDKN2A (pl6INK4a); CDKN2B; CDKN2C; CDKN3; CEBPB; CELSR3; CER1; CHGA; CHGB; Chitinase; CHRNG; CHST10; CKLFSF2; CKLFSF3; CKLFSF4; CKLFSF5; CKLFSF6; CKLFSF7; CKLFSF8; CLDN3; CLDN7 (claudin-7); CLN3; CLU (clusterin); CMKLR1; CMKOR1 (RDC1); CNRI; COL18A1; COL1A1; COL4A3; COL6A1; CR2; CRP; CSF1 (M-CSF); CRLF2; CSF2 (GM-CSF); CSF3 (GCSF); CTLA4; CTNNB1 (b-catenin); CTSB (cathepsin B); CX3CL1 (SCYDi) ; CX3CR1 (V28); CXCR6; CXCL1 (GRO1); CXCL1O (IP-10); CXCL11 (I-TAC / IP-9); CXCL12 (SDF1); CXCL13; CXCL14; CXCL16; CXCL2 (GRO2); CXCL3 (GRO3); CXCL5 (ENA-78 1 LIX); CXCL6 (GCP-2): CXCL9 (MIG); CXCR3 (GPR9/CKR-L2); CXCR4; CXCR6 (TYMSTR ISTRL33 I Bonzo); CYB5: CYC1; CYSLTR1; DAB2IP; DAND5; DES: DKFZp451 JOI 18; DNCL1; DPP4; E2F1; ECGF1; EDG1; EFNAI; EENA3: EFNB2; EGF; EGFR; ELAC2; ENG; ENO1; ENO2; ENO3; EphA4: EPHB4; EPO; ERBB2 (Her-2); EREG; ERK8; ESR1; ESR2; F3 (TF); FADD; FasL: FASN; FCER1 A; FCER2; FCGR3A; FCRL4; FGF; FGF1 (aFGF); FGF1O; FGF11; FGF12; FGF12B; FGF13; FGFI4; FGFI6; FGF17; FGF18; FGF19; FGF2 (bFGF); FGF2O; FGF21; FGF22; FGF23; FGF3 (int-2); FGF4 (HST); FGF5; FGF6 (HST-2); FGF7 (KGF); FGF8; FGF9; FGFR3; FIGF (VEGFD); FIE1 (EPSILON); FIE1 (ZETA); FLJ12584; FLJ25530; FLRT1 (fibronectin); FLT1; FOS; FOSE! (FRA-I); FY (DARC): GABRP (GABAa); GAGEB1; GAGEC1; Galectin-3; GALNAC4S65T; GATA3; GDF5; GFI1: GGT1; GHR; GM-CSF; GNAS1; GNRH1: GPR2 (CCR1O); GPR3 1; GPR44; GPR81 (FKSG8O); GPR87; GPR137C; GRCCIO (CIO); GRP; GSN (Gelsolin); GSTP1; HAVCR1; HAVCR2; HDAC4; EDAC5; HDAC7A; HDAC9; hepcidin: hemojuvelin: HGF; HIF1A; HIP 1; histamine and histamine receptors; HLA-A; HLA-DRA; HM74; HMOX1; HUMCYT2A; ICEBERG; ICOS; 1D2; IFN-a; IFNA1; IFNA2; IFNA4; IFNA5; IFNA6; IFNA7; IFNB1; IFNgamma; TFNW1; IGBP1; IGF]; IGF1R; IGF2; IGFBP2; IGFBP3; IGFBP6; IL-1; IL10; IL10RA; IL10RB; IL11; IL11RA; IL-12; IL12A; IL12B: IL12RB1; ILI2RB2; IL13; IL13RA1; IL13RA2; 1L14; 1L15; IL15RA; IL 16; 1L17; 1L17B; IL17C; IL17R; 1L18; 1L18BP; IL18R1; 1L18RAP; 1L19; ILIA; IL1B; ILIF1O; IL1F5: IL1F6; IL1F7; IL1F8; IL1F9; IL1HY1; IL1R1; IL1R2; 1L1RAP; IL 1 RAPE E IL1RAPL2; IL I RL i ;IL 1 RL2 IE1RN; 1L2; 1L20; IL2ORA: IL2IR; 1 L22; 1L22R; IE22RA2; 1L23; 1L24: 1L25; 1L26; 1L27; 1L28A; 1L28B; 1L29; IL2RA; IL2RB: IL2RG; 1L3; 1L30: IL3RA: 1L4; 1L4R; 1L5; 1L5RA: IL6; IL6 receptor; IL6ST (glycoprotein 130); 1L7;TL7R; 1L8; IL8RA; IL8RB; IL8RB; 1L9: IE9R; ILK; INHA; 1NHBA; INSL3; 1NSL4: IRAKI; IRAK2; ITGA1; ITGA2; 1TGA3; ITGA6 (a6 integrin); 1TGAV; ITGB3; ITGB4 (b 4 integrin); JAG1; JAKE JAK3; JUN; K6HF; KAIL KDR; MTLG; KLF5 (GC Box BP); KLF6; KLK10; KLK12; KLK13; KLK14; KLK15; KLK3; KLK4: KLK5; KLK6; KLK9; KRT1; KRT19 (Keratin 19); KRT2A; KRTHB6 (hair-specific type II keratin): LAG3: LAMA5: LEP (leptin); LIGHT; Lingo-p75; LingoTroy; EPS: LRP5; LTA (TNF-b); LTB; LTB4R (GPR16); LTB4R2; LTBR; MACMARCKS: MAG or Omgp: MAP2K7 (c-Jun): MDK; MIBI: midkine; MIF; MIP-2: MKI67 (Ki-67); MMP2: MMP9; MS4AI; MSMB; MT3 (metallothionectin-ifi); MTSS 1; MUC I (mucin); MYC; MYD88; NCK2: neurocan; Nav1.7; Nav1.8; NFKB 1; NFKB2; NGFB (NGF); NGFR; NgR-Lingo; NgR-Nogo66 (Nogo); NgR-p75; NgR-Troy; NME1 (NM23A); NOX5; NPPB; NROB1; NROB2; NR1D1; NR1D2: NR1H2; NRII13; NRIH4; NR1I2; NRII3; NR2C1; NR2C2; NR2E1; NR2E3; NR2FLNR2F2: NR2F6; NR3C1; NR3C2; NR4A1; NR4A2; NR4A3; NR5A1; NR5A2; NR6A1; NRP1; NRP2; NT5E;NTN4; ODZ1; OPG; OPRD1; OX40L; 0X40; P2RX7; PAP; PARTI; PATE; PAWR; PCA3; PCNA; PCSK9, PD-1, PD-LI; PDGFA; PDGFB; PECAM1; PF4 (CXCL4); PGF; PGR; phosphacan; PIAS2; Placental Growth Factor (PIGF); PIK3CG; PLAU (uPA); PLG; PLXDC1; PPBP (CXCL7); PP1D; PR1; PRKCQ; PRKD1; PRF; PROC; PROK2; PSAP; PSCA; PTAFR; PTEN; PTGS2 (COX2); PTN; RAC2 (p21Rac2); RARB; RGS1; RGS13; RGS3; RNF1 1O(ZNF144); ROBO2; RORI; S100A2; SCGBID2 (lipophilin B); SCGB2AI (mammaglobin 2); SCGB2A2 (mammaglobin 1); SCYEI (endothelial Monocyte-activating cytokine); SDF2; SERP1NA1; SERPINIA3; SERPINB5 (maspin): SERPINE1 (PAT-i); SERPINF1; SHBG; SLA2; SLC2A2; SLC33A1; SLC43A1; SLIT2; SPP1; SPRR1 B (Spri); ST6GAL1; STAB1; STAT6; STEAP; STEAP2; TB4R2; TBX21; TCP 10; TDGF1: TEK; TGFA; TGFB1; TGFB1I1; TGFB2; TGFB3; TGFBI: TGFBR1; TGFBR2; TGFBR3; TH1L; THBS1 (thrombospondin-1); THBS2; THBS4; THPO; TIE (Tie-i); TIM3; TMP3; tissue factor; TLR1O; TLR2; TLR3; TLR4; TLR5; TLR6; TLR7; TLR8; TLR9; TMPRSS6; TNF; TNF-o; TNFAIP2 (B94); TNFAIP3; TNFRSF1 1 A; TNFRSF1A; TNFRSF1B; TNFRSF21; TNFRSF5; TNFRSF6 (Fas); TNFRSF7; TNFRSF8; TNFRSF9; TNFSF10 (TRAIL); TNFSF1 1 (TRANCE); TNFSF12 (APO3L); TNFSF13 (April); TNFSF13B; TNFSF14 (FIVEM-L); TNFSF1 5 (VEGI); TNFSF1 8; TNFSF4 (0X40 ligand); TNFSF5 (CD4O ligand); TNFSF6 (FasL); TNFSF7 (CD27 ligand); TNFSF8 (CD3O ligand); TNFSF9 (4-1BB ligand); TOLL1P; Toll-like receptors; TOP2A (topoisomerase lia); TP53; TPM1; TPM2; TRADD; TRAFI; TRAF2; TRAF3; TRAF4; TRAF5; TRAF6; TRAIL; TREM1; TREM2; TRPC6; TSLP; TWEAK; VEGFA; VFGFB; VEGFC; versican; VEIL C5; VLA-4; Wnt7A; XCIJ (lymphotactin); XCL2 (SCM-lb); XCR1 (GPR5 / CCXCR1); YY1; and ZFPM2. 100232] [00233] [00234] [00235] [00236] [00237] [002381 [00239] [00240] [00241] [00242] [00243] [00244] (00245) [00246] 100247] [00248] In an example, the TOI is a human TOI selected from Table 5. In an example, the TOI is 0X40 ligand.

In an example, the TOI is 0X40, In an example, the TOI is PCSK9, In an example, the TOI is IL6 receptor (IL-6R).

In an example, the TOI is LIGHT.

In an example, the TOI is VEGF-A.

In an example, the TOI is TNF alpha.

In an example, the TOI is PIGF. in an example, the TOI is IGF1R.

In an example, the TOI is OPG.

In an example, the TOI is ICOS In an example, the TOI is NGF.

In an example, the TOI is BMP6.

In an example, the TOI is ferroportin.

In an example, the TOI is TMPRSS6.

In an example, the TOI is hemojuvelin. id="p-249" id="p-249"

[00249] [00250] (00251] [00252] [00253] [002541 [00255] [00256| [00257( [00258] [00259] [00260| [00261] [00262] [00263] [00264] [00265] [00266] In an example, the TOI is VEGF receptor.

In an example, the TOI is PDGF receptor.

In an example, the TOI is stem cell factor receptor.

In an example, the TOI is hepcidin.

In an example, the TOI is IL-4 receptor alpha.

In an example, the TOI is sclerostin.

In an example, the TOI is IL-13 receptor.

In an example, the TOI is CD7.

In an example, the TOI is delta-like ligand-4 (DI14), In an example, the TOI is HGE.

In an example, the TOI is angiopoietin-2 (Ang2).

In an example, the TOI is GDF8.

In an example, the TOI is ERBB3.

In an example, the TOI is IL-17 receptor.

In an example, the TOI is CD40.

In an example, the TOI is CD40 ligand.

In an example, the TOI is EGFR, 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. 100267] For convenience, certain terms employed herein, in the specification, examples and appended claims are collected here. id="p-268" id="p-268"

[00268] 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 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 5-10 points can be considered a ’‘decrease" or "reduction." [00269] 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%. al 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. [00270] T he terms increased", "increase", enhance, or activate" are ail 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-fo!d 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. [0027 Ϊ ] 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 lo 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. id="p-272" id="p-272"

[00272] 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-273" id="p-273"

[00273] 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-274" id="p-274"

[00274] 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 tlie 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-275" id="p-275"

[00275] 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, [00276| 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., phosphorylaled, 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, exemplary polypeptides or proteins include gene products, naturally occurring proteins with 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, [00277] 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 singlestranded nucleic acid not derived from any double-stranded 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-278" id="p-278"

[00278] 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. [00279] 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 1 5-40 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. id="p-280" id="p-280"

[00280] 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 co-immunofluoresce with the LDLR throughout the endosomal pathway (Lagace et a!., 2006). PCSK9 is a prohormone-proprotein convertase in the subtilisin (S8) family of serine proteases (Seidah et al., 2003). fhe sequence of PCSK9 for a variety of species is known, e.g., human PCSK9 (NCB1 Gene ID No: 255738). Nucleotide and polypeptide sequences for a number of PCSK.9 isoforms are provided herein, e.g., SEQ IDNOs: 1-37. id="p-281" id="p-281"

[00281] PCSK9 exists as both a pro-form and a mature form. Autocatalysis of the PCSK9 proform occurs between Gin 152 and Seri 53 (VFAQ|SIP (SEQ ID NO: 75)) (Naureckiene et ah. 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-282" id="p-282"

[00282] As used herein, the "catalytic domain" of PCSK9 refers to the portion of a PCSK9 polypeptide corresponding to positions 153 to 449 of PCSK.9, e.g. of SEQ ID NO: 1. As used herein, the "C-terminal domain" ofPCSK9 refers to the portion of a PCSK9 polypeptide corresponding to positions 450-692 of PCSK9, e.g., of SEQ ID NO: 1. id="p-283" id="p-283"

[00283] As used herein, a disease or condition mediated by PCSK.9'* 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 11 diabetes, high blood pressure, and a cardiovascular disease or condition. 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-284" id="p-284"

[00284] 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 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 lowdensity 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-285" id="p-285"

[00285] 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. id="p-286" id="p-286"

[00286] 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-287" id="p-287"

[00287] Variants of PCSK9 are provided elsewhere herein. Variants of PCSK.9 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:l-27 and in Table I, 2 or 6. id="p-288" id="p-288"

[00288] In some aspects, one can use "synthetic variants, "recombinant variants", or "chemically modified" polynucleotide variants or polypeptide variants isolated or generated using methods well known in the art. Modified variants" can include conservative or non-conservative 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 lo 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-289" id="p-289"

[00289] 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 (1), 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 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. id="p-290" id="p-290"

[00290] In alternative embodiments, one can select the amino acid which will substitute an existing amino acid based on the location of the 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 witli 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. id="p-291" id="p-291"

[00291] 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, 1 with L or V, W with Y, M with L, N with D, G with A, T with A or S, D with N, ί 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, non-conservative amino acid substitutions are also encompassed within the term of variants. id="p-292" id="p-292"

[00292] As used herein an 'antibody" refers to IgG, IgM, IgA, IgD or IgE molecules or antigenspecific antibody fragments thereof (including, but nol limited to, a Fab. F(ab')2. Fv, disulphide linked Fv, scFv, single domain antibody, closed conformation multispecific antibody, disulphide-linked sefv, 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-293" id="p-293"

[00293] 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 the antigen recognized by an antigen-binding molecule, and more particularly, by the antigen-binding site of said molecule. id="p-294" id="p-294"

[00294] 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 ora 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 (14) 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. id="p-295" id="p-295"

[00295] 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 Rabat (Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987 and 1991)) or according to IMGT nomenclature. id="p-296" id="p-296"

[00296] 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. id="p-297" id="p-297"

[00297] 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-298" id="p-298"

[00298] The VH and VL regions can be further subdivided into regions of hypervariabiJily. 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 Rabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, L.S. Department of Health and Human Services. NIE1 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-299" id="p-299"

[00299] 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 341:544546; 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. |00300] 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 VII or VL domain). In another example, the binding site comprises a VH/VT pair or two or more of such pairs. id="p-301" id="p-301"

[00301] 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 PCSK.9 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 strands which interact via hybridization, specific binding can be '‘specific hybridization." [00302] Additionally, and as described herein, a recombinant human(ized) antibody can be further optimized to decrease potential immunogenicily, 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, [00303] 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. (00304] 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 therefo). 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. id="p-305" id="p-305"

[00305] 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 VI1323*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-306" id="p-306"

[00306] 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 ascertaining on the basis of previously obtained information or simultaneously obtained information. id="p-307" id="p-307"

[00307] 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-308" id="p-308"

[00308] 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, assay ing 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. 100309] 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. Λ multiplex analysis typically includes analysis of 10-50; 10-100: 10-1000, 10-5000. 10-10000 reactions in a multiplex format, such as a multiwall, an array, or a multichannel reaction. |00310] 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 acid polymorphism or a protein variant. (00311] 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. |00312] The test sample can be obtained by removing a sample of cells from a subject, but can atso be accomplished by using previously isolated cells (e.g. isolated at a 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. |00313] 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. Γη 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 preprocessing of biological samples required for determination of the level of an expression product as described herein. id="p-314" id="p-314"

[00314] 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 acid 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-315" id="p-315"

[00315] 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 Spring Harbor Press, Plainview. N. Y.). Other methods for amplification are also contemplated in aspects of the invention. id="p-316" id="p-316"

[00316] 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-317" id="p-317"

[00317] 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. id="p-318" id="p-318"

[00318] 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. Non-limiting examples of next-generation sequencing methods/platforms include Massively Parallel Signature Sequencing (Lynx Therapeutics): 454 pyra-sequencing (454 Life Sciences/ Roche Diagnostics): solid-phase, reversible dye-terminator sequencing (Solexa/lllumina): 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. Next-generation 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, 1 135-1145: Mardis, " I he impact of next-generation 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, 11(3):333-43; Zhang et ah. "The impact of next-generation sequencing on genomics, .1 Genet Genomics, 201 1, 38(3):95-109: (Nyren, P. et al. Anal Biochem 208: 17175 (1993); Bentley, D. R. CurrOpin Genet Dev 16:545-52 (2006); Strausberg, R. L., et al. 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; 2007/0070349; and 20070070349; which are incorporated by referene herein in their entireties). id="p-319" id="p-319"

[00319] 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-320" id="p-320"

[00320] 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. id="p-321" id="p-321"

[00321] 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-322" id="p-322"

[00322] 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 compounds disclosed herein can be administered by any appropriate route which results in an effective treatment in the subject. [00323] 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. |00324] 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 lo one skilled in the art. (00325] 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. id="p-326" id="p-326"

[00326] 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-327" id="p-327"

[00327] 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. [00328| 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 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-329" id="p-329"

[00329] 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. id="p-330" id="p-330"

[00330] 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-331" id="p-331"

[00331] 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-332" id="p-332"

[00332] 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), fhe detectable 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 olher such specific recognition molecules. Detectable labels can include, but are not limited to radioisotopes, biolumiiiesccnt compounds, chromophores, antibodies, chemiluminescent compounds, fluorescent compounds, metal chelates, and enzymes. [00333| In other embodiments, the detectable label can be a fluorescent compound. When the riuorescently 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, Cy3IM, Cy5IM, allophycocyanine, Texas Red, peridenin chlorophyll, cyanine, tandem conjugates such as phycoerythrin-Cy51M, 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™, 6earboxyfhiorescein (commonly known by the abbreviations FAM and E), 6-carboxy-2',4',7’,4,7hexachlorofiuorescein (HEX), 6-carboxy’4',5’-dichloro-2',7'-dimethoxyfiuorescein (JOE or J), N,N,N',N'-tetramethyl-6carboxyrhodamine (TAMRA or T), 6-carboxy-X-rhodamine (ROX or R), 5carboxyrhodamine-6G (R6G5 or G5), 6-carboxyrhodamine-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 Ή, ,25I. 35S, l4C, 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-Vl-phosphate dehydrogenase, glucoamylase and acetylcholinesterase, hi 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 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-334" id="p-334"

[00334] 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 delectably labeled using fluorescence emitting metals such as l52Eu. or others of the lanthanide series. These metals can be attached to the reagent using such metal chelating groups as diethylenetriaminepentaacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA). id="p-335" id="p-335"

[00335] 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-336" id="p-336"

[00336] 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. [0(1337] 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-338" id="p-338"

[00338] 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., boxes, bags, syringes, ampoules, vials, tubes, clamshell packaging, barriers and/or containers to maintain sterility, labeling, etc. id="p-339" id="p-339"

[00339] 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 activ e 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-340" id="p-340"

[00340] 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-341" id="p-341"

[00341] 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. or 100 or more alleles in common. Abbreviations for particular ancestral groups are provided in Table 4. id="p-342" id="p-342"

[00342] The term statistically significant or significantly'1 refers to statistical significance and generally means a two standard deviation (2SD) or greater difference. id="p-343" id="p-343"

[00343] 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-344" id="p-344"

[00344] As used herein the term comprising or comprises is used in reference to compositions, methods, and respective component^) thereof, that are essential to the method or composition, yet open to the inclusion of unspecified elements, whether essential or not. id="p-345" id="p-345"

[00345] 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-346" id="p-346"

[00346] 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-347" id="p-347"

[00347] 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 clearly 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-348" id="p-348"

[00348] 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 0-632-02182-9); Benjamin Lewin, Genes X, published by Jones & Bartlett Publishing, 2009 (ISBN-10: 0763766321); Kendrew et al. (eds.),, Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8) and Current Protocols in Protein Sciences 2009, Wiley Intersciences, Coligan et al.. eds. id="p-349" id="p-349"

[00349] 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-Eiss; 5th edition (2005), Animal Cell Culture Methods (Methods in Cell Biology, Vol. 57, Jennie P. Mather and David Barnes editors. Academic Press, 1 st edition, 1998) which are all incorporated by reference herein in their entireties. [00350| Other terms are defined herein within the description of the various aspects of the invention. [003511 Al! 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. [00352 ] 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 arc 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-353" id="p-353"

[00353] 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 embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure. id="p-354" id="p-354"

[00354] 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. Ail 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-355" id="p-355"

[00355] 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 openended and do not exclude additional, unrecited elements or method steps [00356] Any part of this disclosure may be read in combination with any other part of the disclosure, unless otherwise apparent front the context, [00357] 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 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-358" id="p-358"

[00358] The present invention is described in more detail in the following non limiting Examples, [00359] Some embodiments of the technology described herein can be defined according to any of the following numbered paragraphs: 1. A method of treating or preventing a disease or condition in a human, wherein the disease or condition is mediated by a Target of Interest (TOI), wherein the TOI is present in humans as different polymorphic variants, the method comprising a. selecting a human that is positive for the TOI polymorphic variant, wherein the TOI in said human is encoded by a nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or wherein the TOI in said human is encoded by a nucleotide sequence comprising an allele having total human genotype frequency of less than 50%; and b. administering to the human an anti-TOI ligand lo target tlie TOI in the human to treat or prevent said disease or condition.

In an alternative where the TOI is human PCSK9, paragraph ! 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 subtiIisin/kexin type 9 (PCSK.9) 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 subtil isin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation in SEQ ID NO: 1.

In an alternative where the TO! is human PCSK9, 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, 1474V 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 Vk 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.

In an alternative where the TOI is human PCSK9, 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: I, wherein the antibody comprises a C domain encoded by a human CH, CI 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 Cterminal domain comprising said mutation in SEQ ID NO: I. 2. 1'iie method of paragraph I. wherein before step (a) the ligand has been or is determined as being capable of specifically binding to said TOI variant. 3. The method of paragraph 1 or 2. comprising determining that the human is positive for the ΙΌ1 polymorphic variant, optionally wherein the step of determining comprises determining that the human is positive for a nucleotide variant encoding said TOI variant. 4. The method of paragraph 3, wherein the step of determining comprises assaying a biological sample obtained from said human for a nucleotide polymorphism encoding said TOI polymorphic variant.

. The method of paragraph 3 or 4, wherein the step of determining comprises assaying a biological sample obtained from said human for a protein corresponding to the TOI polymorphic variant. 6. The method of any preceding paragraph, wherein said frequency is less than 15%. 7. The method of any preceding paragraph, wherein said frequency is less than 10%. 8. The method of any preceding paragraph, wherein the ligand is capable of specifically binding to two or more different TOI variants, each being encoded by a nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. 9. A method of treating or preventing a disease or condition in a human, wherein the disease or condition is mediated by a Target of Interest (TOI), wherein the '101 is present in humans as different polymorphic variants, the method comprising a. selecting a human that is negative for a variant nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%; or that the human is negative for a TOI variant encoded by a nucleotide sequence comprising the allele having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%; and b. administering to the human an anti-TOI ligand to target the TOI variant in the human and treat or prevent said disease or condition, wherein the TOI in said human is a variant encoded by a nucleotide sequence comprising an allele having a cumulative human allele frequency of more than 50% and/or having a total human genotype frequency of more than 50%.

. The method of paragraph 9, comprising determining that the human is positive for the TO! polymorphic variant, optionally wherein the determining comprises that the human has been or is phenotyped as positive for the most frequent TOI variant or genotyped for the nucleotide sequence thereof. 11. The method of paragraph 10, wherein determining comprises assaying for the nucleotide sequence to determine the presence of said allele. 12. The method of paragraph 11, wherein the assaying comprises nucleic acid amplification. 13. The method of paragraph 11 or 12, wherein the assaying comprises hybridization, sequencing, or next generation sequencing. 14. The method of any of paragraphs 11-13, further comprising the step of obtaining a biological sample from the human.

. The method of any one of paragraphs 9-14, wherein the ligand has been or is determined as being capable of specifically binding to the most frequent TOI variant. 16, The method of any one of paragraphs 9-15, wherein the ligand has been or is determined as being substantially incapable of neutralising or inhibiting said TOI variant. ] 7. The method of any one of paragraphs 9-16, wherein the ligand is capable of specifically binding to the most frequent TOI variant. 8. The method of any one of paragraphs 9-1 7, wherein the ligand is capable of specifically binding to two or more different TOI variants, each being encoded by a nucleotide sequence comprising an allele having a cumulative human allele frequency of more than 50%. 19. The method of any preceding paragraph, wherein said TOI polymorphic variant has been or is determined as being present in al least two different human ethnic populations, . The method of any preceding paragraph, wherein said cumulative human allele frequency is the frequency in a database of naturally-occurring sequences sampled from at least 15 different human ethnic populations and comprising at least 1000 sequences. 21. The method of any ofthe preceding paragraphs, wherein the ligand is an antibody, antibody fragment or an affibody. 22. The method of any of the preceding paragraphs, wherein the ligand comprises a nucleotide sequence that specifically hybridises to a TOI nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50% or an RNA transcript thereof; and/or the ligand comprises a nucleotide sequence that comprises at least 10 contiguous nucleotides of a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50% or is an antisense sequence thereof. 23. The method of any of the preceding paragraphs, wherein the genome of said human comprises an allele having a cumulative human allele frequency of less than 50% and the allele is found in at least 2 different ethnic populations. 24. A composition comprising a ligand capable of binding a target of interest encoded by a nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and the allele is found in at least 2 different ethnic populations and optionally a pharmaceutically acceptable carrier and optionally a label or instructions for use to treat and/or prevent said disease or condition in a human; optionally wherein the label or instructions comprise a marketing authorisation number issued by a regulatory authority.

. A kit for treating or preventing a condition or disease mediated by a target of interest as recited in any preceding paragraph, the kit comprising a ligand capable of specifically binding a target of interest encoded by a nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and the allele is found in at least 2 different ethnic populations ; and optionally in combination with a label or instructions for use to treat and/or prevent said disease or condition in a human; optionally wherein the label or instructions comprise a marketing authorisation number issued by a regulatory agency; optionally wherein the kit comprises an injection pen or IV container that comprises the ligand. 26. The composition of paragraph 24 or the kit of paragraph 25, wherein the regulatory agency is FDA or EMA. 27. A method of producing an anti-human TOI antibody binding site, the method comprising obtaining a plurality of anti-TOI antibody binding sites, screening the antibody binding sites for binding to a TOI comprising an amino acid sequence encoded by a nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, or to a peptide thereof that comprises an amino acid variation from the corresponding sequence encoded by the TOI-encoding nucleotide sequence comprising an allele having the highest cumulative human allele frequency and/or the highest total human genotype frequency, and isolating an antibody binding site that binds in the screening step. 28. A method of producing an anti-human TOI antibody, the method comprising immunising a nonhuman vertebrate with a TOI comprising an amino acid sequence encoded by a nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, or to a peptide thereof that comprises an amino acid variation from the corresponding sequence encoded by the TOI-encoding nucleotide sequence comprising an allele having the highest cumulative human allele frequency and/or the highest total human genotype frequency, and isolating an antibody that binds a TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, and optionally producing a TOI-binding fragment or derivative of the isolated antibody. 29. The method of paragraph 28. wherein the non-human vertebrate is a mouse or a rat, . l he method of paragraph 29 or 30. 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, 31. A kit for TOI genotyping a human, wherein the kit comprises a nucleic acid comprising a nucleotide sequence that specifically hybridises to a TOI nucleotide sequence selected having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% or an RNA transcript thereof; and/or the nucleic acid comprises a nucleotide sequence that comprises at least 10 contiguous nucleotides of a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% or is an antisense sequence thereof. 32. A kit for TOi genotyping or phenotyping a human, wherein the kit comprises a ligand capable of binding a target of interest encoded by a nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% or an antibody, fragment or derivative produced by the method of any one of paragraphs 28 to 30. 33. The kit of paragraph 32. wherein the allele is found in at least 2 different ethnic populations. 34. Use of an anti-TOI ligand that specifically binds a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, in the manufacture of a medicament for treating and/or preventing a TOI-mediated disease or condition in a human whose genome comprises a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less titan 50%.

. Use of an anti-TOI ligand that specifically binds a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, in the manufacture of a medicament for targeting said TOI in a human to treat and/or prevent a disease or condition mediated by TOI. 36. A method of targeting a Target of Interest (TOI) for treating and/or preventing a TOI-mediated disease or condition in a human, the method comprising administering an anti-TOI ligand to a human comprising a TOI nucleotide sequence comprising an allele selected as having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, whereby a TOI encoded by said nucleotide sequence is targeted. 37. The method of paragraph 36, wherein the method comprises targeting a human TOI comprising an amino acid sequence with said ligand to treat and/or prevent said disease or condition in said human, wherein said amino acid sequence is encoded by a nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%. 38. A method of Target of interest (TOI) genotyping a nucleic acid sample of a human, the method comprising assaying in the sample the presence of a TOI nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. 39. A method of Target of Interest (TOI) typing a protein sample of a human, the method comprising assaying the sample the presence of a TOI amino acid sequence encoded by a TOI nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%, 40. The method of paragraph 38 or 39, comprising obtaining a sample of serum, blood, faeces, hair, urine or saliva from a human, whereby the nucleic acid or protein sample is obtained for use in the step of assaying said sequence. 41. The method of any one of paragraphs 38-40, comprising using a ligand capable of targeting a nucleic acid sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50% or a ligand capable of specifically binding the TOI encoded by said nucleic acid sequence to carry out said identifying step. 42. A diagnostic kit comprising a ligand that is capable of binding a human Target of Interest (TOI) comprising an amino acid sequence encoded by a TOI nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% and instructions for carrying out the method of atty one of paragraphs 38-41. 43. The diagnostic kit wherein the ligand is selected from an antibody, antibody fragment, antibody portion, affybody, oligonucleotide, modified oligonucleotide, antisense oligonucleotide, siRNA. and micro RNA. 44. A diagnostic kit comprising a nucleic acid probe comprising a nucleotide sequence that specifically hybridises a Target of Interest (TOI) nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% or an RNA transcript thereof and instructions for carrying out the method of paragraph 38 or 39. 45. The method, ligand, composition, kit or use of any preceding paragraph, wherein the TOI is encoded by a nucleotide sequence having a cumulative human allele frequency from 1 to 10% and/or a total human genotype frequency from I to about 15% or from 1 to 15%. 46. The method, ligand, composition, kit or use of any preceding paragraph wherein the TOI is a human TOI selected from Table 5; optionally for treating and/or preventing a corresponding disease or condition as set out in Table 5. 47. A method of treating or preventing a disease or condition in a human, wherein the disease or condition is mediated by a Target of Interest (TOI), wherein the TOI is present in humans as different polymorphic variants, the method comprising administering to the human determined to be positive for the TOI polymorphic variant, wherein the TOI in said human is encoded by a nucleotide sequence comprising an allele having a cumulative human allele frequency of less than 50% and/or wherein the TOI in said human is encoded by a nucleotide sequence comprising an allele having total human genotype frequency of less than 50% an anti-TOI ligand to target the ΊΌΙ in the human to treat or prevent said disease or condition. 48. The method of paragraph 47, wherein the anti-TOI ligand is selected from an antibody, an antibody portion, an antibody fragment, an affibody, an antisense oligonucleotide, an siRNA. and a microRNA. id="p-360" id="p-360"

[00360] Additional Tailoring of Ligands to Genotype and/or Phenotype of the Human Patient [00361] 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 TOIs (eg, PCSK9 or IL6R). Additionally or alternatively (and as further illustrated in the nonlimiting 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 TOI-binding antibody or an anti-human TOI 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 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. [00362| 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 anti-drug antibodies as a result of the 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. 201 1:305( 14): 1460-1468. doi: 10,1001/jama,201 1.406: Development of Antidrug Antibodies Against Adalimumab and Association With Disease Activity and Treatment Failure During Long-term Follow-up. GM Barteids et a!, l he authors concluded that results of this study showed that development of antidrug antibodies was associated witii a negative outcome of adatimiimab treatment in human RA patients. It was reported that not only did patients with antiadalimumab antibodies discontinue treatment more often and earlier than patients without antiadalimumab 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 ofthe 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. [00363] 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 tlie world wide web at ema.emOpa.eu/docs/en_GD/document !ibrary/Scientific_guideline/2012/06/WC500128688.pdf; EMA/CHMP/BMWP/86289/2010. addendum lo EMEA/CHMP/BMWP/14327/2006). which came into force on Is1 December 2012. As such, it is good practice for researchers to identify and assess risk of anti-antibodv drug occurrence and effects. id="p-364" id="p-364"

[00364] l he 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 designing and administering anti-human TOI medicines for treating and/or preventing human TOI -related diseases and conditions. id="p-365" id="p-365"

[00365] 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. id="p-366" id="p-366"

[00366] Thus, in examples of this aspect, the invention provides the following (set out as clauses):!, The ligand, method, use. kit or composition of the invention, wherein (i) the ligand (eg, antibody or fragment) comprises (c) 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 VI. and JL gene segments; or (d) 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. 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 I 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 1GHG I *01 gene segment and said first segment of (a) is an IGHGI *01 gene segment.

For example, the first and second SNPs of the genome are comprised by an 1GHG2*O1 gene segment and said first segment of (a) is an IGHG2*01 gene segment. 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 CH 1, 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 Vk 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 TOI variants as disclosed herein, for example, with a KD of InM or less (eg, 100 or ΙΟρΜ 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 WO201304I844. a 1000 Genomes database and/or www.imgt.org, the disclosures of 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 Ik fused human TOI 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 refused human TOI 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 Fcfused human TOI 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. ] 8. 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 refused human TOI 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 CFI3 nucleotide sequence and/or the human expresses antibodies comprising said human gamma CH3 domain, 19. fhe ligand, method, use, kit or composition of the invention (eg, according to any one of clauses I to 18), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fcfused human ΤΟΪ 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 I to 19), wherein the ligand (eg. comprising or consisting of an antibody or fragment or an Fcfused human ΊΌ1 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 IGI IGI *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. 26. The ligand, method, use, kit or composition of clause 23. wherein the human has been or is genotyped as positive for human 1GHGI *01 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, CH1, 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 IGHG1*OI gamma heavy chain constant domain, CHI, CII2, CI 13, CH4 or Fc or (ii) when dependent from clause 24, wherein the human has been phenotyped as positive fora human 1GHG2*OI gamma heavy chain constant domain, CHI, CH2, CH3, CH4 or Fc.

. The method or use of any one of clauses 1 6 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 1GI IG 1 *01 gamma heavy chain constant region, CH 1, CH2. CH3. CH4 or Fc nucleotide sequence; or positive for said human IGHG2*0l gamma heavy chain constant region. CHI, CH2, CH3, CH4 or Fc nucleotide sequence. 31. 'fhe 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 IGHG1 *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, CFI3, CH4 or Fc. id="p-367" id="p-367"

[00367] Examples of Tailored Ligands [00368] 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 9. (00369] In a fu st example, the inventor identified the possibility of addressing the rarer 1GI I-gamma-I SNPs 204D (observed cumulative frequency of 0.296) and 206E (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 refused TO! 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 witli 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 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 IG1 IG1*()1 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 IGHG1*O1 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 *01. 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: 6E 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 9, 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 1GHG 1*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 IGHG1 *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 1GHG1 *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 ; ora human IGHGl*01 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-370" id="p-370"

[00370] In a second example, the inventor identified the possibility of addressing 1GIIgamma-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 Fcfused 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 Vai 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 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 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 CHS 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 that comprise SEQ ID NO: 63 or 65. 52. The ligand, method, use, kit or composition of any one of clauses 45 to 5 I, 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 fora human IGHG2*0l CHE 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. [00371 j 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 I to 60). wherein the ligand (eg. comprising or consisting of an antibody or fragment or an Fcfused 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). 67. fhe ligand, method, use, kit or composition of any one of clauses 61 lo 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. Ihe ligand, method, use. kit or composition of any one of clauses 61 to 68. wherein the human has been or is phenotyped as positive fora human 1GKC*O1 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*OI. 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 !GKC*0l domain. 72. The ligand, method, use, kit or composition of any one of clauses 63 to 71, wherein the human expresses antibodies comprising human kappa constant domains comprising such a Val and Cys, eg, expresses human IGKC*03 constant domains. id="p-372" id="p-372"

[00372] 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 refused 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 (GLC2*01 constant regions. 74. 'l'he 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*O1. 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 fora 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. fhe 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, [00373] 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*01 and the genome of the human comprises a human IGHV1-18*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV 1-18*01; 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 IGHV 1-46*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*01 or IGVHI-46*0l. 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 IGHV] - J 8*01 or IGVH1 -46*01, [00374] In a sixth example, the inventor addressed human light chain variable region variation. Thus, this example provides aspects set out in the following clauses. id="p-375" id="p-375"

[00375] 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) IGKV4-1 *01 and the genome of the human comprises a human 1GKV4-1 *0, nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV4-1 *01; (ii) IGLV2-14*01 and the genome of the human comprises a human 1GLV2-14*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGLV2-14*01; or (iii) IGKV1-13*02 and the genome of the human comprises a human IGKV I13*02 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV 1-13*02. 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 1GKJ2*O1 (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 VE 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 IGK.V4-1*01.1GLV2-14*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 TOI with a dissociation constant (Kd) of InM or less as determined by SPR, (eg, 100, 10 or lpM or less). id="p-376" id="p-376"

[00376] In a specific embodiment, the ligand, antibody or fragment of present invention comprises an Fc region, wherein the Fc region comprises at least one non-native amino acid residue selected from the group consisting of 234D, 234E, 234N, 234Q. 234T. 234H. 234Y, 2341, 234V, 234F, 235A, 235D, 235R. 235W, 235P, 235S. 235N. 235Q, 235T, 235H. 235Y. 2351. 235V. 23517 236E, 239D, 239E, 239N. 239Q, 239F, 23917 239H, 239Y, 2401, 240A, 240T, 240M, 241W, 241 L, 241Y. 241 E. 241 R. 243W, 243L 243Y. 243R. 243Q, 244El. 245A. 247E, 247V. 247G. 25IE. 252Y. 254T. 255L. 256E, 256M, 2621. 262A. 262T. 262E, 2631, 263A. 263T, 263M. 264L. 2641, 264W. 264T. 264R. 264F. 264M. 264Y, 264E, 265G, 265N, 265Q, 265Y. 265F. 265V, 2651, 265L. 265H. 265T. 2661, 266A. 266T. 266M. 267Q. 267L. 268E, 269EI, 269Y. 269F, 269R, 270E. 280A. 284M. 292P, 292L, 296E. 296Q. 296D, 296N, 296S, 296T, 296L. 2961, 296FE 269G. 297S, 297D, 297E. 298EL 2981, 298T, 298F. 2991, 299L, 299A, 299S, 299V, 299H, 299F, 299E, 3051. 313E. 3 16D, 325Q. 325L, 3251, 325D, 325E, 325A, 325T, 325V, 325H, 327G, 327W, 327N, 327L, 328S, 328M, 328D, 328E, 328N, 328Q, 328F, 3281, 328V, 328T, 328H, 328A, 329F, 329H, 329Q, 330K. 330G, 330T, 330C, 330L, 330Y, 330V, 3301, 330F, 330R, 330H, 331G, 33 1 A, 331L, 331M, 33 IF, 33 1W. 33 IK, 33 IQ, 331E, 331S, 331V, 3311, 331C, 331Y, 33114, 331R, 33 IN, 33 ID, 331T, 332D, 332S, 332W, 332F, 332E, 332N, 332Q, 332T, 332H, 332Y, 332A, 339T, 370E, 370N, 378D, 392T, 396E, 416G, 419H, 421K, 440Yand 434W as numbered by the EU index as set forth in Rabat. Optionally, the Fc region may comprise additional and/or alternative non-native amino acid residues known to one skilled in the art (see, e.g., U.S. Patents 5,624,821 ; 6,277,375 ; 6,737,056 : PCT Patent Publications WO 01/58957 ; WO 02/06919 : WO 04/016750 ; WO 04/029207 : WO 04/035752 and WO 05/0402 I 7 ). id="p-377" id="p-377"

[00377] In an example the ligand, antibody or fragment comprises one or more human binding sites that specifically bind the TOI (eg, PCSK9, IL4Ra, 1L6R, VEGFA or Navi .7). In an embodiment, the binding sites comprise or consist of human antibody variable domains or human receptors for the TOI (eg, Human receptor binding sites for VEGFA). Furthermore, the ligand, antibody or fragment can be optionally fully human (eg. comprising human constant regions, eg, human Fc regions with or without human CL regions). In an example, the ligand is aflibercept, alirocumab, sarilumab or dupilumab. Fully human ligands maximise compatibility with the human patient when used in the context ofthe invention wherein the V and/or C regions are tailored to the human genotype and/or phenotype as per the description herein. id="p-378" id="p-378"

[00378] Some embodiments of the technology described herein can be defined according to any of the following numbered paragraphs: 1. A method of treating or preventing a disease or condition in a human, wherein the disease or condition is mediated by a Target of Interest (TOI). wherein the TOI is present in humans as different polymorphic variants, the method comprising a. Administering to the human an anti-TOI ligand to target a I'Ol variant in the human and treat or prevent said disease or condition, wherein the TOI in said human is encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or wherein the TOI in said human is encoded by a nucleotide sequence having a total human genotype frequency of less than 50%; wherein b. Before step (a) said human has been or is genotyped as positive for said nucleotide sequence or phenotyped as positive for said TOI variant, 2. The method of paragraph 1, wherein before step (a) the ligand has been or is determined as being capable of binding to said TO] variant. 3. A method of treating or preventing a disease or condition in a human, wherein the disease or condition is mediated by a Target of Interest (TOI), wherein the TOI is present in humans as different polymorphic variants, the method comprising a. Administering to the human an anti-TOI ligand to target a TOI variant in the human and treat or prevent said disease or condition, wherein the TOI in said human is encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or wherein the TOI in said human is encoded by a nucleotide sequence having a total human genotype frequency of less than 50%; wherein b. Before step (a) the ligand has been or is determined as capable of binding to said TOI variant. 4. The method of paragraph 3. wherein the genome of said human comprises a nucleotide sequence encoding said TOI variant: and before step (a) said nucleotide sequence has been or is determined as having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. . l he method of paragraph 3 or 4. wherein said human has been or is genotyped as positive for said variant nucleotide sequence before step (a). 6. The method of any preceding paragraph, wherein the human has been or is phenotyped as positive for said TOI variant before step (a). 7. The method of any preceding paragraph, wherein said frequency is less than 10 or 15%. 8. The method of any preceding paragraph, wherein the ligand is capable of binding to two or more different TO! variants, each being encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. 9. A method of treating or preventing a disease or condition in a human, wherein the disease or condition is mediated by a Target of Interest (TOI), wherein the TOI is present in humans as different polymorphic variants, the method comprising a. Administering to the human an anti-TOI ligand to target a TOI variant in the human and treat or prevent said disease or condition, wherein the TOI in said human is a variant encoded by a nucleotide sequence having a cumulative human allele frequency of more than 50% and/or having a total human genotype frequency of more than 50%: wherein b. Before step (a) said human has been or is genotyped as negative for a variant nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%; or phenotyped as negative for a TOI variant encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%.

. The method of paragraph 9, wherein before step (a), the human has been or is phenotyped as positive for the most frequent TOI variant or genotyped for the nucleotide sequence thereof. 11. The method of paragraph 9 or 10, wherein before step (a) the ligand has been or is determined as being capable of binding to the most frequent TOI variant. 12. The method of paragraph 9, 10 or 11, wherein before step (a) the ligand has been or is determined as being substantially incapable of neutralising or inhibiting said TOI variant recited in step (b). 13. The method of any one of paragraphs 9 to 12, wherein the ligand is capable of binding to the most frequent TOI variant. 14. The method of any one of paragraphs 9 to 13, wherein the ligand is capable of binding to two or more different TOI variants, each being encoded by a nucleotide sequence having a cumulative human allele frequency of more than 50%.

. The method of any preceding paragraph, wherein said variant nucleotide sequence recited in step (a) has been or is determined as being present in at least 2 different human ethnic populations. 16. The method of any preceding paragraph, wherein said human frequency is the frequency in a database of naturally-occurring sequences sampled from at least 1 5 different human ethnic populations and comprising at least 1000 sequences. 7. An anti-human TOI ligand for use in a method of treating and/or preventing a TOI-mediated disease or condition in a human, wherein the TOI is present in humans as different polymorphic variants and wherein the genome of said human comprises a TOI nucleotide sequence having a cumulative human allele frequency ofless than 50% and/or a total human genotype frequency of less than 50%, the method comprising administering the ligand to the human. 18. The ligand of paragraph 17, wherein the ligand has been or is determined as capable of binding the human TOI encoded by said nucleotide sequence. 19. A iigand that binds a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency ofless than 50%, for use in a method comprising the step of using the ligand to target said TOI in a human to treat and/or prevent a disease or condition mediated by TOI. the method comprising administering the ligand to the human.

. The ligand of any one of paragraphs 1 7 to 19, wherein the human has been or is genotyped as positive for said TOI nucleotide sequence having a cumulative human allele frequency ofless than 50%.

The ligand of any one of paragraphs 1 7 to 19, wherein the human has been or is genotyped as positive for said TOI nucleotide sequence having a total human genotype frequency ofless than 50%. 21. ’fhe ligand of any one of paragraphs 17 to 20, wherein the human has been or is phenotyped as positive for a TOI encoded by a nucleotide sequence having a cumulative human allele frequency ofless than 50% and/or having a total human genotype frequency ofless than 50%. 22. The ligand of any one of paragraphs 17 to 21, wherein the human has been or is genotyped as heterozygous for a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency ofless than 50%; optionally wherein the human has been or is genotyped as comprising a TOI nucleotide sequence having a cumulative human allele frequency ofless than 50% and a TOI nucleotide sequence having a cumulative human allele frequency of more than 50% and/or having a total human genotype frequency of more than 50%. 23. The ligand of any one of paragraphs 17 to 22, wherein the genome of the human has been or is genotyped as homozygous for a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. 24. The ligand of any one of paragraphs 17 to 23, wherein the ligand comprises an antibody binding site that binds a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%; and optionally has been or is determined as capable of such binding.

. The ligand of paragraph 24, wherein the ligand is an antibody or antibody fragment. 26. l he ligand of any one of paragraphs 17 to 23. wherein the ligand comprises a nucleotide sequence that specifically hybridises to a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50% or an RNA transcript thereof; and/or the ligand comprises a nucleotide sequence that comprises at least 10 contiguous nucleotides of a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50% or is an antisense sequence thereof, 27. The ligand of any one of paragraphs 17 to 26, wherein the genome of said human comprises a nucleotide sequence having a cumulative human allele frequency of less than 50% and the sequence is found in at least 2 different ethnic populations. 28. A pharmaceutical composition or kit for treating or preventing a condition or disease mediated by a TOI as recited in any preceding paragraph, the composition or kit comprising a ligand of any one of paragraphs 17 to 27: and optionally in combination with a label or instructions for use to treat and/or prevent said disease or condition in a human; optionally wherein the label or instructions comprise a marketing authorisation number (eg. an FDA or EMA authorisation number); optionally wherein the kit comprises an injection pen or IV container that comprises the ligand. 29. A method of producing an anti-human TOI antibody binding site, the method comprising obtaining a plurality' of anti-TOI antibody binding sites, screening the antibody binding sites for binding to a TOI comprising an amino acid sequence encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, or to a peptide thereof that comprises an amino acid variation from the corresponding sequence encoded by the TOI-encoding nucleotide sequence having the highest cumulative human allele frequency and/or the highest total human genotype frequency, and isolating an antibody binding site that binds in the screening step, , A method of producing an anti-human TOI antibody, the method comprising immunising a nonhuman vertebrate (eg, a mouse or a rat) with a TOI comprising an amino acid sequence encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, or to a peptide thereof that comprises an amino acid variation from the corresponding sequence encoded by the TOI-encoding nucleotide sequence having the highest cumulative human allele frequency and/or the highest total human genotype frequency, and isolating an antibody that binds a TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%. and optionally producing a TOI-binding fragment or derivative of the isolated antibody.

I. The method of paragraph 29 or 30, 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. 32. A kit for TO! genotyping a human, wherein the kit comprises a nucleic acid comprising a nucleotide sequence that specifically hybridises to a TOI nucleotide sequence selected having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% or an RNA transcript thereof; and/or the nucleic acid comprises a nucleotide sequence that comprises at least 10 contiguous nucleotides of a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% or is an antisense sequence thereof. 33. A kit for TOI genotyping or phenotyping a human, wherein the kit comprises a ligand according to any one of paragraphs 17 to 27 or an antibody, fragment or derivative produced by the method of any one of paragraphs 29 to 3 1. 34. Use of an anti-TOI ligand tiial binds a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a totai human genotype frequency of less than 50%. in the manufacture of a medicament for treating and/or preventing a TOI-mediated disease or condition in a human whose genome comprises a 'TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%.

. Use of an anti-TOI ligand that binds a human TOI comprising an amino acid sequence encoded by a TOi nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, in the manufacture of a medicament for targeting said TO! in a human to treat and/or prevent a disease or condition mediated by TOI. 36. A method of targeting a TOI for treating and/or preventing a TOI-mediated disease or condition in a human, the method comprising administering an anti-TOI ligand to a human comprising a TOI nucleotide sequence selected having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%, whereby a ΊΌΙ encoded by said nucleotide sequence is targeted. 37. The method of paragraph 36, wherein the method comprises targeting a human TOI comprising an amino acid sequence with said ligand to treat and/or prevent said disease or condition in said human, wherein said amino acid sequence is encoded by a nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50%. 38. A method of TOI genotyping a nucleic acid sample of a human, the method comprising identifying in the sample the presence of a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. 39. A method of TOI typing a protein sample of a human, the method comprising identifying in the sample the presence of a TOI amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or having a total human genotype frequency of less than 50%. 40. The method of paragraph 38 or 39, comprising obtaining a sample of serum, blood, faeces, hair, urine or saliva from a human, whereby the nucleic acid or protein sample is obtained for use in the step of identifying said sequence. 41. The method of any one of paragraphs 38 to 40, comprising using a ligand according to any one of paragraphs 17 to 27 to carry out said identifying step. 42. A diagnostic kit comprising a ligand that is capable of binding a human TOI comprising an amino acid sequence encoded by a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% and instructions for carrying out the method of paragraph 38 or 39. 43. A diagnostic kit comprising a nucleic acid probe comprising a nucleotide sequence that specifically hybridises a TOI nucleotide sequence having a cumulative human allele frequency of less than 50% and/or a total human genotype frequency of less than 50% or an RNA transcript thereof and instructions for carrying out the method of paragraph 38 or 39. 44. The method, ligand, composition, kit or use of any preceding paragraph, wherein the 401 is encoded by a nucleotide sequence having a cumulative human allele frequency from 1 to 10% and/or a total human genotype frequency from I to about 15% or from 1 to 15%. 45. The method, ligand, composition, kit or use of any preceding paragraph wherein the TOI is a human 4Ό1 selected from Table 5; optionally for treating and/or preventing a corresponding disease or condition as set out in table 5. 46. The ligand, method, use, kit or composition of any preceding paragraph, wherein (i) the ligand (eg, antibody or fragment) comprises (e) 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 (f) 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. 47. The ligand, method, use, kit or composition of paragraph 46, 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. 48. The ligand, method, use, kit or composition of paragraph 47, wherein SPR is used to cany out said assay. 49. The ligand, method, use, kit or composition of any one of paragraphs 46 to 48, wherein the genome of said human comprises said first gene segment (when (a) applies) or said C region gene segment (when (b) applies), 50. The ligand, method, use. kit or composition of any one of paragraphs 46 to 49, 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. i. The ligand, method, use, kit or composition of paragraph 50, wherein said human expresses an antibody variable domain comprising said first and second amino acid polymorphisms. 52. The ligand, method, use, kit or composition of paragraph 50 or 51, wherein the first and second SNPs of said genome are comprised by the same antibody gene segment, 53. The ligand, method, use. kit or composition of any one of paragraphs 46 to 52. wherein each SNP is a variable region gene segment SNP. 54. The ligand, method, use. kit or composition of any one of paragraphs 46 to 52. 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. 55. The ligand, method, use, kit or composition of paragraph 54, wherein the first SNP is a CHI, CH2, CH3 or CH4 gene segment SNP and/or the second SNP is a CHI, CH2, CPI3 or CH4 gene segment SNP. 56. The ligand, method, use, kit or composition of any one of paragraphs 46 to 53, wherein each SNP is a variable domain SNP, eg, a VH domain SNP, or a Vk domain SNP, or a VX SNP, 57. The ligand, method, use, kit or composition of any one of paragraphs 46 to 56, wherein said constant region domain of (b) is comprised by an antibody Fc region, 58. The ligand, method, use, kit or composition of any one of paragraphs 46 to 57. wherein the ligand (eg. antibody or fragment) has been determined to specifically bind one or more human TOI variants as disclosed herein, for example, with a KD of 1 nM or less (eg, 100 or 1 OpM or less) as determined by SPR. 59. The ligand, method, use, kit or composition of any preceding paragraph (eg, according to any one of paragraphs 46 to 58), wherein the ligand comprises or consists of an antibody or fragment that comprises a human antibody variable domain derived from the recombination ofa human V gene segment and a human J gene segment (and optionally a human D gene segment when the variable domains are VFI 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). 60. The ligand, method, use, kit or composition of any preceding paragraph (eg, according to any one of paragraphs 46 to 59), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused human TOI 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. 61. The ligand, method, use. kit or composition of any preceding paragraph (eg. according to any one of paragraphs 46 to 60). wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused human TOI 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. 62. The ligand, method, use, kit or composition of any preceding paragraph (eg, according to any one of paragraphs 46 to 61), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused human TOI 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. 63. The ligand, method, use, kit or composition of any preceding paragraph (eg, according to any one of paragraphs 46 to 62), wherein, wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused human TOI 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 comprising said human gamma CH3 domain. 64. The ligand, method, use, kit or composition of any preceding paragraph (eg, according to any one of paragraphs 46 to 63), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused human TOI 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 Cl 14 nucleotide sequence and/or the human expresses antibodies comprising said human gamma CH4 domain. 65. The ligand, method, use. kit or composition of any preceding paragraph (eg, according to any one of paragraphs 46 to 64), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fc-fused human TOI receptor) comprises a human gamma heavy chain Fe 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. 66. The ligand, method, use, kit or composition of any one of paragraphs 61 to 65, wherein said human gamma heavy chain is a human gamma-1 heavy chain. 67. The ligand, method, use, kit or composition of any one of paragraphs 61 to 65, wherein said human gamma heavy chain is a human gamma-2 heavy chain. 68. The ligand, method, use. kit or composition of any one of paragraphs 61 to 65. wherein ligand comprises a human IGHG1 *01 gamma-1 heavy chain constant region. 69. The ligand, method, use, kit or composition of any one of paragraphs 61 to 65, wherein ligand comprises a human IGHG2*0l gamma-1 heavy chain constant region. 70. fhe ligand, method, use. kit or composition of any one of paragraphs 60 lo 69. wherein the human has been or is genotyped as positive lor said heavy chain constant region nucleotide sequence. 71. The ligand, method, use, kit or composition of paragraph 68, wherein the human has been or is genotyped as positive for human IGHG1*O1 nucleotide sequence. 72. The ligand, method, use, kit or composition of paragraph 69, wherein the human has been or is genotyped as positive for human IGHG2*01 nucleotide sequence. 73. The ligand, method, use, kit or composition of any one of paragraphs 61 to 69, wherein the human has been or is phenotyped as positive for said gamma heavy chain constant domain, CH 1, CH2, CH3, CH4 or Fc. 74. The ligand, method, use, kit or composition of paragraph 63, (i) when dependent from clause 23. wherein the human has been or is phenotyped as positive for a human IGHG1 *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, CH1, CH2, CH3, CH4 or Fc. 75. The method or use of any one of paragraphs 61 to 69 and 71 to 74, 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 IGHG 1*01 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, CI-U, CH2, CH3, CH4 or Fc nucleotide sequence. 76. The method or use of any one of paragraphs 61 to 69 and 71 to 75, comprising phenotyping the human as positive for said gamma heavy chain constant region, eg, positive for said gamma heavy chain constant domain. CHI. CH2. CTI3. CH4 or Fc: positive for said human IGHGI *01 gamma heavy chain constant domain, CHI. CH2. CH3, CH4 or Fc: or positive for said human IGHG2*01 gamma heavy chain constant domain. CH 1, CH2. CH3. CH4 or Fc. 77. The ligand, method, use, kit or composition of any preceding paragraph (eg, according to any one of clauses 46 to 76), 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. 78. The ligand, method, use, kit or composition of paragraph 77,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. 79. Fhe ligand, method, use, kit or composition of paragraph 77 or 78,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 gamma-1 constant regions comprising such an Asp and Leu. 80. The ligand, method, use, kit or composition of paragraph 77. 78 or 79, 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 IGFIGl *01. 81. The ligand, method, use, kit or composition of any one of paragraphs 77 to 80, wherein the genome of the human comprises a human IGI IGI *01 nucleotide sequence or the human expresses antibodies comprising human constant domains encoded by a human IGHG1 *01 nucleotide sequence. 82. The ligand, method, use, kit or composition of any one of paragraphs 77 to 81, wherein the ligand comprises a hinge region encoded by human IGHGI *01. 83. The ligand, method, use, kit or composition of any one of paragraphs 77 to 82, wherein the ligand comprises or consists of an antibody, wherein the antibody comprises heavy chains that comprise SEQ ID NO: 61. 84. The ligand, method, use, kit or composition of any one of paragraphs 77 to 83, wherein the human is of European ancestry. 85. The ligand, method, use, kit or composition of any one of paragraphs 77 to 84, wherein the human has been or is genotyped as positive for said Asp and/or Leu. 86. The ligand, method, use, kit or composition of any one of paragraphs 77 to 85. wherein the human has been or is genotyped as positive for human IGHGl *01. 87. The ligand, method, use, kit or composition of any one of paragraphs 77 to 86, wherein the human has been or is phenotyped as positive for a human IGHG1 *01 CH3. 88. The method or use of any one of paragraphs 77 to 87. comprising selecting a said human whose genome comprises a codon(s) encoding said Asp and/or Leu: comprises human IGHG 1*01; or comprises a human IGHG1 *01 CH3. 89. The method or use of any one of paragraphs 77 to 88, comprising selecting a said human whose phenotype comprises said Asp and/or Leu; a human IGHG 1 *01 region ; or a human IGHGl *01 CH3. 90. The ligand, method, use, kit or composition of any preceding paragraph, 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. 91. The ligand, method, use. kit or composition of paragraph 90, 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 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). 92. The ligand, method, use, kit or composition of paragraph 90 or 91, 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). 93. The ligand, method, use. kit or composition of any one of paragraph 90 to 92, wherein the ligand comprises a human IGHG2*01 gamma-2 heavy chain constant region, eg. an Tc, CHI, CH2 and/or CH3 domain encoded by human IGHG2*01. 94. The ligand, method, use, kit or composition of any one of paragraphs 90 to 93, 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*0I nucleotide sequence. 95. The ligand, method, use. kit or composition of any one of paragraphs 90 to 94. wherein the ligand comprises a hinge region encoded by human IGHG2*01. 96. The ligand, method, use, kit or composition of any one of paragraphs 90 to 95, wherein the ligand comprises or consists of an antibody, wherein the antibody comprises heavy chains that comprise SEQ ID NO: 63 or 65. 97. The ligand, method, use, kit or composition of any one of paragraphs 90 to 96, wherein the human is of European, African American, or European American ancestry. 98. fhe ligand, method, use, kit or composition of any one of paragraphs 90 to 97. wherein the human has been or is genotyped as positive for one, more or all of said Pro. Asn, Phe, Val and Ala. 99. The ligand, method, use, kit or composition of any one of paragraphs 90 to 98. wherein the human has been or is genotyped as positive for human IGHG2*01. 100. The ligand, method, use, kit or composition of any one of paragraphs 90 to 99, wherein the human has been or is phenotyped as positive for a human !GHG2*01 CH I. 101. The ligand, method, use, kit or composition of any one of paragraphs 90 to 100. wherein the human has been or is phenotyped as positive for a human IGHG2*01 CH2. 102. The ligand, method, use. kit or composition of any one of paragraphs 90 to 101. wherein the human has been or is phenotyped as positive for a human IGHG2*01 CH3. 103. The method or use of any one of paragraphs 90 to 102, 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 1GHG2*O1 CHI, CH2 and/or CH3. 104. The method or use of any one of paragraphs 90 to 103, 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 CH1.CH2 and/or CH3. 105. The ligand, method, use, kit or composition of any one of paragraphs 90 to 104, wherein the human expresses antibodies comprising human gamma-2 constant regions comprising such a Pro. Asn, Phe, Val and Ala. 106. The ligand, method, use, kit or composition of any preceding paragraph, 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 Vat or Cys or the human expresses antibodies comprising human kappa light chain constant regions comprising such a Val or Cys. 107. The ligand, method, use, kit or composition of paragraph 106, 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. 108. The ligand, method, use, kit or composition of paragraph 106 or 107, 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. 109. The ligand, method, use, kit or composition of any one of paragraphs 106 to 108, wherein the antibody or fragment comprises a human 1GKC*O1 kappa light chain constant region.

. The ligand, method, use, kit or composition of any one of paragraphs 106 to 109, wherein the ligand comprises or consists of an antibody, wherein the antibody comprises light chains that comprise SEQ ID NO: 62 or 66. 111. The ligand, method, use, kit or composition of any one of paragraphs 106 to 110, 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*0] (SEQ ID NO: 57). 112. The ligand, method, use, kit or composition of any one of paragraphs 106 to 111, wherein the human has been or is phenotyped as positive for said Val and/or Cys. 113. The ligand, method, use, kit or composition of any one of paragraphs 106 to 112. wherein the human has been or is genotyped as positive for human 1GKC*O1. 114. The ligand, method, use, kit or composition of any one of paragraphs 106 to 113, wherein the human has been or is phenotyped as positive for a human IGKC*01 domain. 115. The method or use of any one of paragraphs 106 to 114, comprising selecting a said human whose genome comprises a codon(s) encoding said Val and/or Cys; or comprises human IGKC*01. 116. The method or use of any one of paragraphs 106 to 115, comprising selecting a said human whose phenotype comprises such a Val and/or Cys; or comprises a human IGKC*01 domain. 117, The ligand, method, use, kit or composition of any one of paragraphs 106 to 116, wherein the human expresses antibodies comprising human kappa constant domains comprising such a Val and Cys, eg, expresses human IGKC*01 constant domains.

I 1 8. The ligand, method, use, kit or composition of any preceding paragraph, 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. 119. The ligand, method, use, kit or composition of paragraph 118. wherein the antibody comprises light chains that comprise SEQ ID NO: 64, 120. The ligand, method, use, kit or composition of paragraph 118 or 119. wherein the human has been or is genotyped as positive for human IGLC2*0I. 121. The I igand, method, use, kit or composition of any one of paragraphs 11 8 to 120, wherein the human has been or is phenotyped as positive for a human 1GLC2*O1 domain. 122. The method or use of any one of paragraphs 118 to 212, comprising selecting a said human whose genome comprises human 1GLC2*O1. 123. 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. 124. The ligand, method, use, kit or composition of any one of paragraphs 108 to 123, wherein the human expresses antibodies comprising human lambda 1GLC2*O1 constant domains. 125. The ligand, method, use, kit or composition of any preceding paragraph, 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*01 and the genome of the human comprises a human IGHV 1 1 8*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHVl-l 8*01; or (ii) IGVH1-46*O1 and the genome of the human comprises a human IGHV 1 -46*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV 1-46*01, 126. The ligand, method, use, kit or composition of paragraph 125, wherein the antibody or fragment comprises a one more or all of a CHI domain, CH2 domain, CI 13 domain, hinge or Tc encoded by human 1GHG2*O1. 127. The ligand, method, use, kit or composition of paragraph 125 or 126, wherein the antibody or fragment comprises heavy chains that comprise SEQ ID NO: 63 or 65. 128. The ligand, method, use, kit or composition of any one of paragraphs 125 to 127, wherein the human has been or is genotyped as positive for said selected VH gene segment, positive for human 1GHVI-18*O1 or IGVH1-46*O1. 129. The method or use of any of paragraphs 125 to 128, comprising genotyping the human as positive for said selected VH gene segment, eg, positive for human IGHV1-18*01 or IGVH 1-46*01, 130. The ligand, method, use, kit or composition any preceding paragraph, 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) IGKV41*01 and the genome of the human comprises a human 1GK V4-I *0! nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV4-1 *01; (ii) IGLV2-14*0l and the genome ofthe 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*02 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 IGKVl-13*02. 1. The ligand, method, use, kit or composition of paragraph 130, wherein the antibody comprises light chains that comprise SEQ ID NO: 62, 64 or 66. 132. The ligand, method, use, kit or composition of paragraph 130 or 13 1, 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, 133. The ligand, method, use, kit or composition of any one of paragraphs 130 to 132, wherein the human has been or is genotyped as positive for said selected VI. gene segment, eg. positive for human 1GKV4-P01. 1GLV2-14*O1 orIGKV 1-13*02. 134. The method or use of paragraph 133, comprising genotyping the human as positive for said selected VL gene segment, eg, genotyping the human as positive for human IGKV4-1 *01, 1GLV2-14*O1 orIGKV 1-13*02. 135. The ligand, method, use, kit or composition of any preceding paragraph, wherein tlie ligand (eg, antibody or fragment) binds said human TOI with a dissociation constant (Kd) of InM or less as determined by SPR, (eg, 100, 10 or IpM or less). 136. The ligand, method, use, kit or composition of any preceding paragraph, wherein the TOI is human PCSK9 or human 1L-6R, 100379] EXAMPLES (00380] Example 1: Rare PCSK9 Variants (00381 ] Proprotcin convertase subtilisin kexin type 9 (PCSK.9) 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 ah, 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 endocvtosed along with the LDLR. and coimmunofluoresce with the LDLR throughout the endosomal pathway (Lagace et al., 2006). id="p-382" id="p-382"

[00382] PCSK9 is a prohormone-proprotein convertase in the subtilisin (S8) family of serine proteases (Seidah et a)., 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 subtilisin-Iike pro- and catalytic domains, and a P domain directly C-terminal to the catalytic domain (Henrich et ah, 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 al., 2005). SKI-1/S1P and PCSK.9 are classified in subfamily S8A. Sequence comparisons with these proteins also suggest the presence of subtilisin-Iike pro- and catalytic domains (Sakai etak, 1998; Seidah etak, 2003; Seidah etal., 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-383" id="p-383"

[00383] Prohormone-proprotein convertases are expressed as zymogens and they mature through a multi step process. 'Hie function of the pro-domain in this process is two-fold. 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-384" id="p-384"

[00384] Autocatalysis of the PCSK9 zymogen occurs between Glnl52 and Serl53 (VFAQjSIP (SEQ ID NO; 75)) (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-385" id="p-385"

[00385] In certain embodiments, a PCSK.9 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, NARCI, 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, or unprocessed form of PCSK.9. 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 US2012009381 SAI; which is incorporated by reference herein in its entirety). id="p-386" id="p-386"

[00386] 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. 100387] 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 IJS20I I0065902A1; each of which is incorporated by reference herein in its entirety). 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 naturally-occurring ~ 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-388" id="p-388"

[00388] 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 PCSK.9 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. |00389] 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. |00390] 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. 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 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-391" id="p-391"

[00391] in developing this thinking, 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 tlie 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 fable 4 below); and • PCSK9 variants found in many individuals distributed across such many different ethnic populations. id="p-392" id="p-392"

[00392] On the basis of these criteria, the inventor identified the variants listed in Table 1 below (excluding form a). id="p-393" id="p-393"

[00393] 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.

Table 1: Human PCSK9 variants distributed over several human ethnic populations & having a xo oN LTJ o _Q ra O Φ tie c ra u. Φ C > u c Φ □ □r OJ Φ ex > o c Φ tw c ra E _C ro +-» o iz> QJ U c cr a? T3 c ro IZ> c o 4—' z> _Q i— CO T3 C o q-» ΓΌ Q.

O CX _Q Π5 T3 Ό TO O C E < Π3 0.64815 U3 O’ Q LL E 3 U 0.0855 0.0729 I 1 0.0292 0.0221 0.0149 0.0068 0.0045 0.0041 | 0.0032 0.4506 {0.8457) XT cr a u LL E □ X E o h *— 4- 0.009 (0.162) 0.0081 (0.1377) 1: 0.009 i (0.0324) (0.0441) (0.0225) (0.0135) (600Ό) (0,0081) (0.0063) 0.3951 ΠΊ CT Φ LL 4-» Φ X 0.153 0.1296 , 0.0234 0.0441 0.0225 LO ΓΟ o ό 6000 0.0081 0.0063 'd- x—1 No. Unique 1 12 12 σι <4- co ro LQ 939 No. «Η V) C ;> ΐ c 180 153 L 49 cr C\l15 o —1 στ r-· or cd x ‘to co τ in 0 to to co —- to in ~ ct X X cr > to U X g u to 3 £ 1 to ΰ Human | Populations .. □c co CQ > * to 3 cr >' cl χ >- to l·— LU <: to LO LO —J _ < Η X lu ί s’2 ’-7 (i - CJ to IZI oc 5 x 2 > to u z g u si q; in n 5 to < 1— —1 a- FDD cr to (J CO H- to U to 2 5 2 £ to g < U s > ί LO < ί! cc > ί LO <£ —J ΕΞ >- ί LO < Σ3 LU u X LL LO ι- οί Ξ3 Q- H CL Co X < to to cr X X CD CL 670E 670G X X X 1 619Q ation 619P X 4741 n & Vari; > •sT Γ· «2-f> X X X X X < m *3· 1 Positioi 443T X X 2 LD CM lino Acid 425S X < ΓΟ ld fc < > m LD X X C£ o 46L X Form a I Variant E o LL M— u u Q_ E Φ _c ‘πΓ cr £ Q X (Λ og X x ’3 τ3 sO ΓΛ .2 +— (Λ © Cl E £ X «73 Cl t3 X Ci x '3 k3 © © © o X c £ r/j £ j© o E <1> OG ‘δ X © <υ X C4 .2 x © L-.

,© C <3 «73 J© X KJ c © U i_ © © o o io c © kJ > © © © ου .2 KJ x © CX Oi ex Ci □G oG Ci Ci s c 0G >, N © P δ _© Ci kJ > Ci Ci σ o «Λ X •w 1 UJ ΓΖ) <— <3 Ci oG _2 1" Ci © • ίΛ 73 73 X Ci -S w Ci 10 > CC Ci X <— C © S—’ C Ό δ i—1 5 O X o <4— o Ci o eZi — m cs Ci > Ci OG Ci ¢/) X <3 X Ci O o o o © c -t-» © o X H γ X X 7Ϊ X o r- , o © 3 0G co Ci 73 O x δ 73 fi .2 X <4— Ci 75 ' 1 Qi . .CD £ P c c δ 3 ex O ex δ 3 σ Ci o x .5 O r— 3 O σ X , 3 Μ—* o *,™. Ci s E « > o 4—> Ci r-» X o o X Ci ex >·. 4-» Ci =$J ~73 Ul © X O X Ci ex 3 3 3 Ci +-> 73 X ES © 3 Ci Γ2 .— 0G ω «Kt 3 P □ Γ OG 3 Ci X Ci E Ci 73 © ο- L. 73 U 1) ’> 3 σ’ 3 X .© x χ P u X Ξ X £ 3 3 τη 3 c \i X 3 C <4- o X- © O 0G X o X 73 o B g 3 .3 ’ c 03 X δ o3 u Ci X £ S-. Ci X £ Ζί N C δ c > 3 5 CJ A X · — z Z :r 7 CJ £ ‘x c 73 CJ < X r-i re © Cl >. © c Ci oG ofi © 'c? KJ «Λ (Λ So & Q Ci X Ci Ci X c © © c ο U — =3 © © o © © © O © Ci > © cr © <2 Ci ex © c Ci OG a E □ X X c Ci X O ?? * X X N O E o X © E © Ci O Ci CX >» © Ci 0G £ x © oG >, S' © c X kJ -a o Oi a o o o JU Ci > o oG >> s © >» © c Ci CT Ci Ci Cl © c Ci 0G g Ci Ci © ci © © c σ £ _2 Ci c kJ E Ci > — £ a < O0 oo re X o o Cl o C-l D Ci Qi o ΓΊ X o o ex S Ci £ © oG O -ί—' (b) Nucleotide Sequence Variations of Selected Alleles < 1:55529187 tu rs505151 o X LO X X X < 1:55527222 u r-*- x CM CM ID CO 00 CM ΙΛ I— CL σ> ί—i LO X < i-4 c 1:55524237 le Variation2 tu LO LO in CM LO m /1 u. 1 Variation 474V X X X X X tu icleotide Positio LD IT) CO CO CM Ln lZ) in T-1 mous Nucleotid < o +-» c 3 > CO LO CM CM LO m co ΓΜ /1 u. ding Amino Aci< 443T X X < ZJ Z 1:55523802 Non-Synony tu t—I LO CM CM LO co oa CM /1 Correspon 425S X <_> co LO LO un o lZj LD lZ) τ—1 H o co LO CO CO m r~1 tH LO > CO m X X tU 1:55505647 1- r* st v—1 τ—1 or LZJ 1 τΗ CZ> _j LO st X | Allele a Variant Allele *4- L> Q. E Φ X ’ro σ -σ u 4-1 X O > u X c JU υ C O U U > x o3 Q O .3 x o X o ?2 ‘3 cs o U 3 E Έ o CS P 1) o O Ό u co o CS ex CM E o u u X E E tuzo o. u oc 3 f 3 co r 3 > u y CO u u u . E — u X bD 3 P 3 U r* y CJ m ΓΕ «—X u L- 3 U X E O 3 3 e P 3 U f- -w 3 3 c o w O u_ U o y o X o SO '—- P > u P '5b Q u r- *- 3 3 I —[ r- 3 y 0 U U -ο 3 75 u p u 3 4—* 3 o 0-L a. co _u —t o 3 lo o 3 u. 3- U X £ o o ω *_ □ o r- o 3 o CL u 1 £ Ξ < δ o y U Q O O e bi) a x i—· u. CO 3 C/t U X X X o o o O c w o y 3 C o' a u X 4-J o o χ _x _u Ο- 2 X o Ι) o Ξ ZJ X 3 z u y y z •— 3 CM allele a); and 3. NCBI dbSNP reference number (NCBI dbSNP Build 138 released on Apr 25, 2013). (a) Human PCSK9 Form a Amino Acid Sequence (SEQ ID NO:1) - Pro-form with Signal Sequence L % i’gl to 3/ to rt| H H ('j to tto to rt, tort I ίΟ fl to to •ll -t rt. i Ί to to to to Γ 1 to O* 'to to x to: -to n 'to --j --j --j --j -.j --j --j to --j to •to to to £ Fto 's to to Ll tf 1— f/7 T3 'Ό Ί3 Ό 13 «/) to— _c DC LU 19 l2i toaUi 4 rtj U) ..NT /7 13 "C5 C_ O Qi cd LU LU I 1 to I 1 cr L~ _fp to— tf rn rn 4—1 fc> «Ό 4—' X y J_ r/0 1 1 f '1 tf rlj O rn cd r/0 LO L j fc' Ό ιυ ,li tf LU y y (-9 l·— 1 ί) i-1 to to to tol ii I 11 i: to to I i H to L-i t 1 f1 Ci to to rtj rt( toi rti toi ] 1 to rtl rti to to to to to to to £ to ci- to to u.

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CJ CJ (J nj o ]ID 1| 115 1.9 (rj III LU CO 'X cj t5 cj t5 C5 (, cj CJ '-X l I t5 C5 CJ C J 00 < 00 co CJ cj 05 1-C I 05 LJ o O'.

\O S' (J (J (O I I to IJ L_) to •s' t ) IJ CJ LO --X LJ LO CJ LO IL) L_) < I -X c ) (.) I ( J LO CJ CJ CJ L/C tZΟβ c O o O CT ¢/) b JU o zi Π * 0) Ή h o o o tZ w u s_ £ c id="p-394" id="p-394"

[00394] Variant Allele Nucleotide Sequences Thus, (i) The nucleotide sequence ol'allele/is 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 1474V In SEQ ID NO: 28; (ii) The nucleotide sequence of allele c is 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) fhe nucleotide sequence of allele r is 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 1474V 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 14 74 V 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 lo SEQ !D NO: 28 except that the nucleotide sequence of allele e comprises a AGT codon instead of an AAT codon at the posit ion labelled N425S in SEQ ID NO: 28: and a GTC codon instead of an ATC codon at the position labelled 1474V 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 Q6I9P in SEQ ID NO: 28; (viii) The nucleotide sequence of allele aj is identical to SEQ ID NO: 28 except that the nucleotide sequence of allele aj 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 q comprises a GTC codon instead of a GCC codon at the 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-395" id="p-395"

[00395] Variant Pro-Form Amino Acid Sequences (Numbering is as per SEQ ID NO: 1 recited above) 105 (A) The amino acid sequence of form/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/comprises a valine at position 474; (B) The amino acid sequence of form c is identical to the amino acid sequence from amino acid number 3 1 to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form c comprises a glycine at position 670; (C) The amino acid sequence of form r is identical to the amino acid sequence from amino acid number 3 1 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 p is identical the amino acid sequence from amino acid number 3 I 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 3 ! 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: I 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 aj is identical to the amino acid sequence from amino acid number 3 1 to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form aj comprises 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: I except that the amino acid sequence of form q comprises a valine at position 53 and a glycine at position 670. id="p-396" id="p-396"

[00396] Variant Mature Form Amino Acid Sequences (Numbering is as per SEQ ID NO: 1 recited above) (A') The amino acid sequence of form/is identical to SEQ ID NO: 2 except that the amino acid sequence of form/comprises a valine at position 474; (B') The amino acid sequence of form c is identical to SEQ ID NO: 2 except that the amino acid sequence of form c comprises a glycine at position 670; (C1) The amino acid sequence of form r is identical to SEQ ID NO: 2 except that the amino acid sequence of form r comprises a valine at position 474 and a glycine at position 670; (D') 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; 106 (E1) 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; (F') 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; (O') The amino acid sequence of form A 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: (IT) The amino acid sequence of form aj is identical to SEQ ID NO: 2 except that the amino acid sequence of form aj 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 q comprises a glycine at position 670. 100397] The mature form of p is identical to the mature form of/and cj. |00398] The mature form of c is identical to the mature form of q. id="p-399" id="p-399"

[00399] Further sequence analysis and 3D in silico modelling (see Figure 1) revealed that selected variants also fulfilled the following 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-400" id="p-400"

[00400] As shown in Figure I, identified positions 425, 443, 474, 619 and 670 (found in the selected variants of the invention) are all surface-exposed and outside of the 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-401" id="p-401"

[00401] In a first example, 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-402" id="p-402"

[00402] In a First Aspect; An anti-human PCSK.9 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-403" id="p-403"

[00403] 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 naturallyoccurring 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. 107 |00404| In an example, the nucleotide sequence is SEQ ID ND: 34, that encodes a 425S. which is associated with elevated LDL-C (Pisciotta el al 2006). id="p-405" id="p-405"

[00405] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 3 1 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen el al 2005). id="p-406" id="p-406"

[00406] 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 naturally-occurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-407" id="p-407"

[00407] In an [00408] In an (00409] In an 100410] In an |00411] In an |00412] In an [00413] In an 100414] In an mple, the nucleotide sequence is SEQ ID NO: 3 1 .mple, the nucleotide sequence is SEQ ID NO: 32 mple. the nucleotide sequence is SEQ ID NO: 33 In an example, the nucleotide sequence is SEQ ID NO: 34 [00415] In an example, the nucleotide sequence is SEQ ID NO: 37. id="p-416" id="p-416"

[00416] 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 / c, r, p, m, e, h, aj and q. id="p-417" id="p-417"

[00417] 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, aj and q. [00418] In an example of any aspect, the ligand comprises a protein domain that specifically binds to PCSK.9, eg. a human PCSK9 selected from the group consisting forms/' c. /·, p. m. e, A, aj and q. [00419] The term ’'specifically binds. or the like, means that a ligand, eg. an antibody or antigenbinding 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 I x 10 '' M or less (e.g., a smaller KD denotes a tighter binding). Methods for determining whether two molecules specifically bind 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 specie. 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" PCSK.9, as used herein. 108 [00420] 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 PCSK.9 selected from the group consisting forms / c, r, p, m, e, h, aj and q. id="p-421" id="p-421"

[00421] In an example of any aspect, the ligand antagonises PCSK9, eg, a human PCSK9 selected from the group consisting forms/ c, r, p, m, e, h, aj and q. id="p-422" id="p-422"

[00422] 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 / c. r. p, m, e, h, aj and q. [00423J In an example of any aspect, binding is determined by SPR. In an example of any aspect, binding is determined by ELISA. id="p-424" id="p-424"

[00424] In an example of any aspect, said forms are the mature forms. id="p-425" id="p-425"

[00425] In an example of any aspect, said forms are the pro-forms. id="p-426" id="p-426"

[00426] In a Third Aspect: 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. id="p-427" id="p-427"

[00427] In an example, the disease or condition is mediated by a human PCSK.9 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-27. id="p-428" id="p-428"

[00428] 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 naturallyoccurring 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-429" id="p-429"

[00429] 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-430" id="p-430"

[00430] 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). [0043 T] 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: 10-14. 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-432" id="p-432"

[00432] In an example, the amino acid sequence is SEQ ID NO: 4. id="p-433" id="p-433"

[00433] In an example, the amino acid sequence is SEQ ID NO: 5. id="p-434" id="p-434"

[00434] In an example, the amino acid sequence is SEQ ID NO: 6. id="p-435" id="p-435"

[00435] In an example, the amino acid sequence is SEQ ID NO: 7. id="p-436" id="p-436"

[00436] In an example, the amino acid sequence is SEQ ID NO: 8. 109 [00437] [00438] [00439] [00440] [00441] [00442] [00443] [00444] [00445] [00446] [00447] [00448] [00449] [00450] [00451] [00452] [00453] [00454] [00455] (00456J In an example, the amino acid sequence is SEQ ID NO: 9. In an example, the amino acid sequence is SEQ ID NO: 10. In an example, the amino acid sequence is SEQ ID NO: 1 1. In an example, the amino acid sequence is SEQ ID NO: 12. In an example, the amino acid sequence is SEQ ID NO: 13.

In an example In an example In an example In an example In an example In an example In an example In an example In an example In an example In an example the amino acid sequence is SEQ ID NO: 14. the amino acid sequence is SEQ ID NO: 15. the amino acid sequence is SEQ ID NO: 16. the amino acid sequence is SEQ ID NO: 17. the amino acid sequence is SEQ ID NO: 18. the amino acid sequence is SEQ ID NO: 19. the amino acid sequence is SEQ ID NO: 20. the amino acid sequence is SEQ ID NO: 21. the amino acid sequence is SEQ ID NO: 22. the amino acid sequence is SEQ ID NO: 23. the amino acid sequence is SEQ ID NO: 24.

In an example, the amino acid sequence is SEQ ID NO: 25.

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 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-457" id="p-457"

[00457] 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 naturallyoccurring 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 EDL-C. id="p-458" id="p-458"

[00458] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S. which is associated with elevated LDL-C (Pisciotta et ai 2006). id="p-459" id="p-459"

[00459] 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-460" id="p-460"

[00460] 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 naturally-occurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-461" id="p-461"

[00461] In an example, the nucleotide sequence is SEQ ID NO: 29 100462] In an example, the nucleotide sequence is SEQ ID NO: 30. 110 [00463] Jn an example, the nucleotide sequence is SEQ ID NO: 3 1. id="p-464" id="p-464"

[00464] In an example, the nucleotide sequence is SEQ ID NO: 32. id="p-465" id="p-465"

[00465] In an example, the nucleotide sequence is SEQ ID NO: 33 [00466] In an example, the nucleotide sequence is SEQ ID NO: 34 [00467] In an example, the nucleotide sequence is SEQ ID NO: 35. |00468] In an example, the nucleotide sequence is SEQ ID NO: 36. id="p-469" id="p-469"

[00469] In an example, the nucleotide sequence is SEQ ID NO: 37. |00470] 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 domain-encoding sequence thereof. |00471] In an example, the nucleotide sequence is selected from the group consisting of SEQ II) NOs: 29-35 and 37: or selected from the group consisting of SEQ ID NOs: 29-32 and 34-37; or selected from ihe group consisting of SEQ ID NOs: 29-32, 34, 35 and 37. These are naturallyoccurring 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-472" id="p-472"

[00472] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated LDL-C (Pisciotta el rz/2006). id="p-473" id="p-473"

[00473] 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). ]00474] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 3 1, 32, 34, 35. 36 and 37: or selected from the group consisting of SEQ ID NOs: 3 1. 32. 34. 35 and 37. These are allele (haplotype) sequences that have a naturally-occurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-475" id="p-475"

[00475] In an example, the nucleotide sequence is SEQ ID NO: 29. id="p-476" id="p-476"

[00476] In an example, the nucleotide sequence is SEQ ID NO: 30. id="p-477" id="p-477"

[00477] In an example, the nucleotide sequence is SEQ ID NO: .31. id="p-478" id="p-478"

[00478] In an example, the nucleotide sequence is SEQ ID NO: 32. id="p-479" id="p-479"

[00479] In an example, the nucleotide sequence is SEQ ID NO: 33. id="p-480" id="p-480"

[00480] in an example, the nucleotide sequence is SEQ ID NO: 34. id="p-481" id="p-481"

[00481] In an example, the nucleotide sequence is SEQ ID NO: 35. [004821 In an example, the nucleotide sequence is SEQ ID NO: 36. id="p-483" id="p-483"

[00483] In an example, the nucleotide sequence is SEQ ID NO: 37. id="p-484" id="p-484"

[00484] 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 c, r, p. m, e, h, aj and q or at least the catalytic or C-terminal domain thereof. id="p-485" id="p-485"

[00485] in an example, said forms are the mature forms.

Ill [00486] in an example, said forms are the pro-forms. id="p-487" id="p-487"

[00487] 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. 100488] 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 arc naturallyoccurring allele (hapiotype) 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-489" id="p-489"

[00489] In an example, the nucleotide sequence is SEQ ID NO: 34. that encodes a 425S, which is associated with elevated LDL-C (Pisciotta et al 2006). id="p-490" id="p-490"

[00490] In an example, the nucleotide sequence selected from tlie group consisting of SEQ ID NOs: 31 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen el id="p-492" id="p-492"

[00492] In an [00493] In an [00494] In an [00495] In an [00496] In an [00497] In an [00498] In an [00499] In an [00500] In an [00501] In an id="p-502" id="p-502"

[00502] [00503] [00504] £7/2005). id="p-491" id="p-491"

[00491] 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: 3 I, 32, 34, 35 and 37. These are allele (hapiotype) sequences that have a naturally-occurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above.

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, tiie nucleotide sequence is SEQ ID NO: 3 1.

In an example, tiie 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, In an example, the nucleotide sequence is SEQ ID NO: 37.

In an Eighth 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, aj and q or at least the catalytic or C-terminal domain thereof.

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 domain-encoding sequence thereof; optionally wherein the human has been or is genotyped as comprising the nucleotide sequence of SEQ 112 ID NO: 28 or at least the catalytic domain- or C-terminal 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 domain-encoding sequence thereof. id="p-505" id="p-505"

[00505] "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 PCSK.9 (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). [00506] In an example, tlie 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 domain-encoding 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 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 Cterminal domain-encoding sequence thereof. id="p-507" id="p-507"

[00507] 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. [00508J These are naturally-occurring allele (hapiotype) 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-509" id="p-509"

[00509] In an example, the nucleotide sequence is SEQ ID NO: 34. that encodes a 425S, which is associated with elevated LDL-C (Pisciotta el al 2006). id="p-510" id="p-510"

[00510] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 3 1 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen et allhftS}. id="p-511" id="p-511"

[00511] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs; 3 I, 32, 34, 35, 36 and 37; or selected from the group consisting of SEQ ID NOs: 3 1,32, 34, 35 and 37. These are allele (hapiotype) sequences that have a naturally-occurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-512" id="p-512"

[00512] In an example, the nucleotide sequence is SEQ ID NO: 29. id="p-513" id="p-513"

[00513] In an example, the nucleotide sequence is SEQ ID NO: 30. id="p-514" id="p-514"

[00514] In an example, the nucleotide sequence is SEQ ID NO: 31. id="p-515" id="p-515"

[00515] In an example, the nucleotide sequence is SEQ ID NO: 32. id="p-516" id="p-516"

[00516] In an example, the nucleotide sequence is SEQ ID NO: 33. id="p-517" id="p-517"

[00517] In an example, the nucleotide sequence is SEQ ID NO: 34, |00518] In an example, the nucleotide sequence is SEQ ID NO: 35. 113 [00519] In an example, the nucleotide sequence is SEQ ID NO: 36. id="p-520" id="p-520"

[00520] In an example, the nucleotide sequence is SEQ ID NO: 37. id="p-521" id="p-521"

[00521] 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 fora nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at ieast the catalytic domain- or C-terminal domain-encoding sequence thereof. id="p-522" id="p-522"

[00522] "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-523" id="p-523"

[00523] In an example, the method comprises genotyping the human as homozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or al least the catalytic domain- or C-terminal domain-encoding sequence thereof. {00524] 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 naturallyoccurring 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-525" id="p-525"

[00525] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated EDL-C (Pisciotta e/£7/2006). id="p-526" id="p-526"

[00526] 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-527" id="p-527"

[00527] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 3 1. 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 naturally-occurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-528" id="p-528"

[00528] In an example, the nucleotide sequence is SEQ ID NO: 29. )00529] In an example, the nucleotide sequence is SEQ ID NO: 30. id="p-530" id="p-530"

[00530] In an example, the nucleotide sequence is SEQ ID NO: 31. id="p-531" id="p-531"

[00531] In an example, the nucleotide sequence is SEQ ID NO: 32. id="p-532" id="p-532"

[00532] In an example, the nucleotide sequence is SEQ ID NO: 33. id="p-533" id="p-533"

[00533] In an example, the nucleotide sequence is SEQ ID NO: 34. id="p-534" id="p-534"

[00534] In an example, the nucleotide sequence is SEQ ID NO: 35. id="p-535" id="p-535"

[00535] In an example, the nucleotide sequence is SEQ ID NO: 36. id="p-536" id="p-536"

[00536] In an example, the nucleotide sequence is SEQ ID NO: 37. id="p-537" id="p-537"

[00537] In an Eleventh Aspect: The ligand of any preceding aspect, wherein the ligand comprises an antibody binding site that binds a human PCSK.9 comprising an amino acid sequence 114 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-538" id="p-538"

[00538] 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-539" id="p-539"

[00539] 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, ΙΟΟηΜ. lOnM or InM or less. In an embodiment, the affinity is no less than 10, 100 or 1000 fM. id="p-540" id="p-540"

[00540] In an example, binding or affinity is determined by SPR or ELISA. id="p-541" id="p-541"

[00541] 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. id="p-542" id="p-542"

[00542] 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 naturallyoccurring 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, [00543] 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-544" id="p-544"

[00544] In an example, the amino acid sequence selected from the group consisting of SEQ ID NOs: 10. 1 ], 12,26 and 27, that comprise 670G which is a marker for severity of coronary atherosclerosis (Chen et al 2005). id="p-545" id="p-545"

[00545] 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: 10-14, 18-23. 26 and 27, These are sequences that have a naturally-occurring combination of differences from SEQ ID NOs: I -3 (form a) and which meet the criteria set out above [00546] In an example, the amino acid sequence is SEQ ID NO: 4, [00547] In an example, the amino acid sequence is SEQ ID NO: 5. (00548] In an example, the amino acid sequence is SEQ ID NO: 6. 100549] In an example, the amino acid sequence is SEQ ID NO: 7. 100550] In an example, the amino acid sequence is SEQ ID NO: 8. id="p-551" id="p-551"

[00551] In an example, the amino acid sequence is SEQ ID NO: 9. 100552) In an example, the amino acid sequence is SEQ ID NO: 10. id="p-553" id="p-553"

[00553] In an example, the amino acid sequence is SEQ ID NO: 1 1. id="p-554" id="p-554"

[00554] In an example, the amino acid sequence is SEQ ID NO: 12. id="p-555" id="p-555"

[00555] In an example, the amino acid sequence is SEQ ID NO: 13, [00556] In an example, the amino acid sequence is SEQ ID NO: 14. id="p-557" id="p-557"

[00557] In an example, the amino acid sequence is SEQ ID NO: 15. id="p-558" id="p-558"

[00558] In an example, the amino acid sequence is SEQ ID NO: 16. 115 [00559] In an example, the amino acid sequence is SEQ ID NO: 17. id="p-560" id="p-560"

[00560] In an example, the amino acid sequence is SEQ ID NO: 18. id="p-561" id="p-561"

[00561] In an example, the amino acid sequence is SEQ ID NO: 19. [00562J In an example, the amino acid sequence is SEQ ID NO: 20. id="p-563" id="p-563"

[00563] In an example, the amino acid sequence is SEQ ID NO: 2!. [005641 In an example, the amino acid sequence is SEQ ID NO: 22. id="p-565" id="p-565"

[00565] In an example, the amino acid sequence is SEQ ID NO: 23. id="p-566" id="p-566"

[00566] In an example, the amino acid sequence is SEQ ID NO: 24. id="p-567" id="p-567"

[00567] In an example, the amino acid sequence is SEQ ID NO: 25. id="p-568" id="p-568"

[00568] In an example, the amino acid sequence is SEQ ID NO: 26. id="p-569" id="p-569"

[00569] In an example, the amino acid sequence is SEQ ID NO: 27. id="p-570" id="p-570"

[00570] 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 PCSK.9 antagonist, eg. neutralises PCSK9. id="p-571" id="p-571"

[00571] Examples of such antibodies are disclosed, for instance, in WO 2008/057457, W02008/057458, 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 201 1/11 1007. WO 2010/077854. the disclosures and sequences of such antibodies being incorporated herein for use in the invention in their entireties by reference. One specific example is AMG 145 (Amgen). LY3015014 (Eli Lilly) or alirocumab. Advantageously, the ligand is or comprises alirocumab. Alternatively, the ligand is or comprises evoiocumab. id="p-572" id="p-572"

[00572] In an example, the ligand is SAR236553/REGN727 (Sanofi Aventis/Regeneron) or a PCSK9-binding derivative thereof. id="p-573" id="p-573"

[00573] In an example, the ligand comprises or consists of a neutralizing antibody that binds to the PCSK9, wherein the antibody binds to PCSK.9 and reduces the likelihood that PCSK9 binds to LDLR, [00574] The ligand of aspect 11, wherein the ligand is a PCSK9 antagonist, eg, neutralises PCSK9. id="p-575" id="p-575"

[00575] In an example of any aspect of the invention, the ligand comprises or consists a ligand selected from evoiocumab, lD05-IgG2 (Merck & Co.), ALN-PCS02 (Alnylam), RN316 (PfizerRinat), EY3015014 (Eli Lilly) and alirocumab (SAR236553/REGN727: Sanofi Aventis/Regeneron). [00576] In 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 Cterminal 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 116 [00581| In an [00582| In an [00583] In an [005841 In an [00585] In an [00586| In an [00587| In an [00588] In an (00589] In an ]00590| In an 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. (00577] 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 front the group consisting of SEQ ID NOs: 29-32, 34, 35 and 37. These are naturallyoccurring 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. {00578] In an example, the nucleotide sequence is SEQ ID NO: 34. that encodes a 425S, which is associated with elevated LDL-C (Pisciotta ei al 2006), [00579] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 3 I and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen ei a/2005). id="p-580" id="p-580"

[00580] 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: 3 1,32. 34, 35 and 37. These are allele (haplotype) sequences that have a naturally-occurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above.

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: 3 I.

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.

In an example, the nucleotide sequence is SEQ ID NO: 37.

In an embodiment, the ligand comprises at least 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50 or 100 contiguous nucleotides of said nucleotide sequence. id="p-591" id="p-591"

[00591] 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, |00592] 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. 117 [00593] 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 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 US20120093818). id="p-594" id="p-594"

[00594] The ligand of any preceding aspect, wherein the human is identified as 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. id="p-595" id="p-595"

[00595] In a Fifteenth Aspect: The ligand of any preceding aspect, wherein said disease or condition is associated with elevated LDL cholesterol. id="p-596" id="p-596"

[00596] Cholesterol levels are measured in milligrams (mg) of cholesterol per deciliter (df) 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. Belov,' 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 LDU cholesterol* (U.S. and some other countries) (Canada and most of Eu rope) 100-129 mg/dE 2.6-3.3 mmol/L Ideal 130-159 mg/dE 3.4-4.1 mmol/L Borderline high 160-189 mg/dE 4.1-4.9 mmol/L High 190 mg/dL and above Above 4.9 mmol/L Very high *Canadian and European guidelines differ slightly from U.S. guidelines. These conversions are based on U.S. guidelines. id="p-597" id="p-597"

[00597] Elevated LDL cholesterol is, therefore, 160 mg/dL or above (4.1 mmol/E or above). [00598] 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-599" id="p-599"

[00599] In an example, the method comprises (before administering the ligand) determining that the ligand is capable of such inhibition. 118 [00600] 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. id="p-601" id="p-601"

[00601] In a Seventeeth 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. id="p-602" id="p-602"

[00602] 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 ASWfYRLGBR.TSl, 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,TS1.CEM. CHBJ.WK.CHSJPT.PUR.FIN or CEU ancestry: or (iii) whose genome comprises SEQ ID NO: 32 and wherein the human is of ASW.GBR,TS1,CEM. 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 CI.M 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.ASWJP I'.PUR or CHB ancestry. id="p-603" id="p-603"

[00603] In a Ninteenth Aspect: ihe 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 / and wherein the human is of ASW.YRI.GBR,TSLCLM,LWK,MXLJPT.PUR,IBS,FIN or CEU ancestry; or (ii) that expresses PCSK.9 form c and w herein the human is of ASW,YRI,GBR,TSI,CLM,CHB,LWK.CHSJPT,PUR,FIN or CEU ancestry; or (iii) that expresses PCSK9 form p and wherein the human is of ASW,GBR,TSI,CLMJPT,PUR,IBS,FIN or CEU ancestry; or (iv) that expresses PCSK9 form m and wherein the human is of LWK,ASW,YRI or CUM ancestry: or (v) that expresses PCSK9 form e and 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 aj and wherein the human is of LWK,ASW or YRI ancestry; or (viii) that expresses PCSK9 form q and wherein the human is of CHS,ASW,JPT,PUR or CHB ancestry. 119 [00604] In an example, said forms are the mature forms. id="p-605" id="p-605"

[00605] In an example, said forms are the pro-forms, [00606] 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-607" id="p-607"

[00607] 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/ 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-bitiding fragment or derivative of the isolated antibody. id="p-608" id="p-608"

[00608] in an example, said forms are the mature forms. id="p-609" id="p-609"

[00609] In an example, said forms are the pro-forms. id="p-610" id="p-610"

[00610] 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 scEvs. 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 VelocimouseIM. Kymouse1M. XenomouseIM, Aliva MouseIM. HuMab MouseIM. OmnimouseIM. OmniratIM or MeMo MouseIM) with a PCSK9 epitope and isolation of a repertoire of antibodyproducing cells (eg. a B-cell. plasma cell or plasmablast repertoire) and/or a repertoire of isolated antibodies. id="p-611" id="p-611"

[00611] 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-612" id="p-612"

[00612] 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 120 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; I. 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. id="p-613" id="p-613"

[00613] In an example, said forms are the mature forms. id="p-614" id="p-614"

[00614] In an example, said forms are the pro-forms. id="p-615" id="p-615"

[00615] 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, [00616] For example, the method comprises isolating a cell (eg, B-cell, plasmablast. plasma cell or memory cel!) comprising the nucleic acid, wherein the cell is obtained from a non-human vertebrate that has been immunised with the PCSK9 epitope. [00617j 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 Cterminal 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 ofa 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-618" id="p-618"

[00618] 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 naturallyoccurring allele (hapiotype) 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-619" id="p-619"

[00619] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated LDL-C (Pisciotta el al 2006). 121 100620] 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). 100621] In an example, the nucleotide sequence selected from Ihe group consisting of SEQ ID NOs: 3 1, 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 naturally-occurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. [00622| [00623] [00624] 100625) (00626] [00627] [00628] [00629] [00630] [00631] [006331 In [00634] In [00635] In 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.

In an example, the nucleotide sequence is SEQ ID NO: 37.

In a Twenty-fifth Aspect: 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. id="p-632" id="p-632"

[00632] In a Twenty-sixth Aspect: Use of an anti-PCSK.9 ligand that binds a human PCSK.9 selected from the group consisting of forms/ c, r, p, m, e, h, aj and q in the manufacture of a medicament for treating and/or preventing a PCSK9-niediated 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 PCSK9-mediated disease or condition in a human as recited in aspect 18 or 19.

In an example, said forms are the mature forms.

In an example, said forms are the pro-forms.

In a Twenty-seventh Aspect: Use of an anti-PCSK9 ligand that binds a human PCSK9 selected from the group consisting of forms/ c, r, p, m, e. h, aj 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 PCSK.9, optionally for targeting PCSK9 in a human as recited in aspect 18 or 19. id="p-636" id="p-636"

[00636] In an example, said forms are the mature forms. id="p-637" id="p-637"

[00637] In an example, said forms are the pro-forms. id="p-638" id="p-638"

[00638] 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 naturally122 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-639" id="p-639"

[00639] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S. which is associated with elevated LDL-C (Pisciotta et al 2006). 100640] in an example, the nucleotide sequence selected from the group consisting of SLQ ID NOs: 31 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen et «/2005). |00641] 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 arc allele (haplotype) sequences that have a naturally-occurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-642" id="p-642"

[00642] In an example, the nucleotide sequence is SEQ ID NO: 29. id="p-643" id="p-643"

[00643] In an example, the nucleotide sequence is SEQ ID NO; 30. id="p-644" id="p-644"

[00644] In an example, the nucleotide sequence is SEQ ID NO: 3 I. id="p-645" id="p-645"

[00645] In an example, the nucleotide sequence is SEQ ID NO: 32. id="p-646" id="p-646"

[00646] In an example, the nucleotide sequence is SEQ ID NO: 33. id="p-647" id="p-647"

[00647] In an example, the nucleotide sequence is SEQ ID NO: 34. id="p-648" id="p-648"

[00648] In an example, the nucleotide sequence is SEQ ID NO: 35. id="p-649" id="p-649"

[00649] In an example, the nucleotide sequence is SEQ ID NO: 36. id="p-650" id="p-650"

[00650] In an example, the nucleotide sequence is SEQ ID NO: 37. |006511 The ligand can be any anti-PCSK9 ligand disclosed herein. id="p-652" id="p-652"

[00652] In a Twenty-eight 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. [00653j 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 from the group consisting SEQ ID NOs: 29-37, whereby a PCSK.9 encoded by said nucleotide sequence is targeted. |00654] The ligand can be any anti-PCSK9 ligand disclosed herein. id="p-655" id="p-655"

[00655] 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 c, r, p, m, e, h, aj and q with said ligand to treat and/or prevent said disease or condition in said human. id="p-656" id="p-656"

[00656] In an example, said forms are the mature forms. id="p-657" id="p-657"

[00657] In an example, said forms are the pro-forms. |00658] 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, 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. 123 [00659] In an example, said forms are the mature forms. id="p-660" id="p-660"

[00660] In an example, said forms are the pro-forms. id="p-661" id="p-661"

[00661] The ligand can be any anti-PCSK9 ligand disclosed herein. |00662] 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. 100663] 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. T hese are naturallyoccurring 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-664" id="p-664"

[00664] In an example, the nucleotide sequence is SEQ ID NO: 34, that encodes a 425S, which is associated with elevated LDL-C (Pisciotta el al 2006). id="p-665" id="p-665"

[00665] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 3 1 and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen el al 2005). id="p-666" id="p-666"

[00666] 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: 3 1, 32, 34, 35 and 37. These are allele (haplotype) sequences that have a naturally-occurring combination of differences from SEQ ID NO: 28 (form a) and which meet the criteria set out above. id="p-667" id="p-667"

[00667] In an example, the nucleotide sequence is SEQ ID NO: 29. id="p-668" id="p-668"

[00668] In an example, the nucleotide sequence is SEQ ID NO: 30. |00669] In an example, the nucleotide sequence is SEQ ID NO: 3 I. 100670] In an example, the nucleotide sequence is SEQ ID NO: 32. 100671] In an example, the nucleotide sequence is SEQ ID NO: 33. id="p-672" id="p-672"

[00672] In an example, the nucleotide sequence is SEQ ID NO: 34. id="p-673" id="p-673"

[00673] In an example, the nucleotide sequence is SEQ ID NO: 35. id="p-674" id="p-674"

[00674] In an example, the nucleotide sequence is SEQ ID NO: 36. id="p-675" id="p-675"

[00675] In an example, the nucleotide sequence is SEQ ID NO: 37. |00676] 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-encoding sequence thereof. [00677] 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 PCSK.9 selected from the group consisting of forms ' c, r, p, m, e, h, aj and q. id="p-678" id="p-678"

[00678] In an example, said forms are the mature forms. id="p-679" id="p-679"

[00679] In an example, said forms are the pro-forms. 124 |00680] 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. [00681] 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 / c, r, p, m, e, h, aj and q. |00682] In an example, said forms are the mature forms. id="p-683" id="p-683"

[00683] In an example, said forms are the pro-forms. id="p-684" id="p-684"

[00684] 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 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. |00685] 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 C-terminal domain-encoding sequence thereof. )00686] 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 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. 100687 J In a Fortieth Aspect: fhe 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. |00688] In a Forty-first Aspect: A method according to any one of aspects 29 to 40 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, lovaslatin or pravastatin) to the human. id="p-689" id="p-689"

[00689] In a Forty-second Aspect: The method of aspect 41, wherein the ligand and statin are administered separately. id="p-690" id="p-690"

[00690] In a Forty-third Aspect: The method of aspect 41, wherein the ligand and statin are administered simultaneously. id="p-691" id="p-691"

[00691] In a Forty-fourth Aspect: The method of any one of aspects 29 to 43, wherein the ligand is administered by subcutaneous injection. 125 [00692] In a Forty-fifth Aspect: A method of PCSK.9 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 catalytic- or C-terminal domainencoding sequence thereof. id="p-693" id="p-693"

[00693] 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 ofa human PCSK9 selected from the group consisting of forms f c, r, p, m, e, h, aj and q. id="p-694" id="p-694"

[00694] In an exampie, said forms are the mature forms. id="p-695" id="p-695"

[00695] In an example, said forms are the pro-forms. id="p-696" id="p-696"

[00696] 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-697" id="p-697"

[00697] In a Forty-eighth 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 cany out said identifying step. id="p-698" id="p-698"

[00698] 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. id="p-699" id="p-699"

[00699] In an example, said reducing or stopping comprises reducing the dose and/or dosing frequency of statin. id="p-700" id="p-700"

[00700] 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-701" id="p-701"

[00701] 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, [00702] 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 / c, r, p, m, e, h, aj and q) and optionally also the a and/or a' form. For example, the ligand specifically binds to mature form / and/or c as well as form a. Determination of such binding can be performed by any antibody binding test as known in the art, eg, by surface plasmon resonance. 126 Binding to each such form is, for example, respectively with a Kd of at least 1 mM, 1 OOnM, 1 nM, ΙΟΟρΜ, ΙΟρΜ or lpM, [00703] In an example, the ligand binds form a and a PCSK9 selected from the group consisting of forms/ c, r. p, m, e, h, aj 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-704" id="p-704"

[00704] In an example, the ligand binds form a and form/ wherein the ligand binding to 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. [00705] In an example, the ligand binds form a and form c, wherein the ligand binding to form c 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. [00706) In an example, the ligand binds form a and form r, wherein the ligand binding lo form r 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. [007071 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. [00708| 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. [00709| 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 the Kd for binding to form a. In an embodiment, both forms are mature forms. In an embodiment, both forms are pro-forms. [00710] In an example, the ligand binds form a and form h, wherein the ligand binding to form h 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 arc mature forms, hi an embodiment, both forms are pro-forms. [00711] In an example, the ligand binds form a and form aj, wherein the ligand binding to form aj 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. [00712] 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. [00713] In examples of the 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/ c. r, p, m, e, h. aj and q) and optionally also the a and/or a' form. For example, the ligand neutralises mature form/and/or c as well as form a. Determination of neutralisation can be performed, for 127 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 US201 10065902A1, these specific disclosures being incorporated herein by reference for use in the present invention and for possible inclusion in claims herein. id="p-714" id="p-714"

[00714] 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 PCSK.9 (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 PCSK.9 (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 PCSK.9 (eg, said one or more of the 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. id="p-715" id="p-715"

[00715] In an embodiment, the ligand has a Kd of less (binding more tightly) than 10 7, 10 A 10 ί 10 l0, 10 , 1 0 l2. 10 1' 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-716" id="p-716"

[00716] 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-717" id="p-717"

[00717] In an embodiment, the ligand has an IC50 for blocking the binding of LDLR to the u and/or ct' form of PCSK9 that is no more than 1000, 100, 90, 80, 70. 60, 50, 40, 30. 20 or 10-fold more (ie, more inhibitory) 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. lOOnMto 10 nM, 10 nM to 1 nM, lOOOpM 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 lpM (eg, ImM to ΙΟΟρΜ; 1 OnM to ΙΟΟρΜ; InM to 10pM;or lOOpMto 1 pM) and (ii) one or more PCSK9 proteins comprising a sequence selected from SEQ ID NOs: 4 to 27 of less than 1 microM, lOOOnMto 100 nM, lOOnM to 1 OnM, 1 OnM 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 lpM (eg. ImM to 1 OOpM; 10nM to ΙΟΟρΜ; InM to ΙΟρΜ; or ΙΟΟρΜ to lpM). [00718] 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 128 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). id="p-719" id="p-719"

[00719] In one embodiment, the surface plasmon resonance (SPR) is carried out at 25°C. In another embodiment, the SPR is carried out at 37°C. [007201 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 HBS-EP)). id="p-721" id="p-721"

[00721] In one embodiment, the SPR is carried out at a physiological salt level, eg, 150mM NaCl. id="p-722" id="p-722"

[00722] 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) al 0.05% and EDTA at 3mM. id="p-723" id="p-723"

[00723] In one example, the SPR is carried out at 25°C or 37°C in a buffer at pH7.6, I 50mM NaCl, 0.05% detergent (eg, P20) and 3mM EDTA. The buffer can contain I OmM 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-724" id="p-724"

[00724] 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. GEM 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 lO24nM, 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®). id="p-725" id="p-725"

[00725] Regeneration of the capture surface can be carried out with 1 OmM glycine at pH 1.7. 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-726" id="p-726"

[00726] 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. 129 [00727] 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 US201200938 ISA I, which sequence is incorporated herein by reference. id="p-728" id="p-728"

[00728] One example of an IgG4 heavy chain constant domain of an anti-PC$K9 antibody of the present invention has the amino acid sequence as shown in SEQ ID NO: 155, FIG. 3K.K. of US20120093818A1. which sequence is incorporated herein by reference. id="p-729" id="p-729"

[00729] One example of a kappa light chain constant domain of an anti-PCSK.9 antibody has the amino acid sequence as shown in SEQ ID NO: 1 57, FIG. 3KK which sequence is incorporated herein by reference. id="p-730" id="p-730"

[00730] 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 is incorporated herein by reference. id="p-731" id="p-731"

[00731] 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 optional iy also the a and/or a' form. id="p-732" id="p-732"

[00732] 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-733" id="p-733"

[00733] In examples of the present invention, the ligand binds the prodomain of PCSK9, eg, ofa mature form of one or more of the rare variants disclosed herein and optionally also the a and/or a' form. id="p-734" id="p-734"

[00734] 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, ofa mature form of one or more of the rare variants disclosed herein and optional ly 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 PCSK.9 to LDLR, the ligand prevents or reduces (eg, by at least 10%) the adverse activities mediated through PCSK9 on LDLR. ]00735] 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. id="p-736" id="p-736"

[00736] In an example, the ligand of the invention specifically binds to an epitope of a human PCSK9 selected from the group consisting of forms/ c, r, p. m, e, h, aj 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 130 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/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 c 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 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-737" id="p-737"

[00737] In an embodiment, ligand binds specifically to the pro-domain of a human PCSK9 selected from the group consisting of forms /- c, r, p, m, e, h, aj 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 /PCSK.9. wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, lhe ligand specifically binds to the pro-domain of'form c PCSK9, wherein tlie 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 r PCSK9. wherein the epitope D x ^Yrises 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 prodomain 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 pro-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 pro-domain of form q PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. 131 [00738] In an embodiment, ligand binds specifically to the catalytic domain of a human PCSK9 selected from the group consisting of forms/ c, r, p, tn, 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 c 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 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 catalytic domain of form p PCSK.9, 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 e PCSK.9, 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 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 catalytic domain of form q PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. id="p-739" id="p-739"

[00739] In an embodiment, ligand binds specifically to the C-terminal domain ofa human PCSK9 selected from the group consisting of forms / c, r, p, m, e, h, aj and q. In an 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 /'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 Cterminal domain of form c PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. hi an embodiment, the ligand specifically hinds 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 PCSK.9, 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 Cterminal 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 132 specifically binds to the C-terminal domain of form q PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. (00740] In an embodiment, ligand binds specifically to the substrate-binding groove of a human PCSK.9 selected from the group consisting of forms / c, r, p, nt, e. h. qj and q (see Cunningham et al.. Nat Struct Mol Biol, 2007 May;14(5):4l3-9. Epub 2007 Apr 15, '‘Structural and biophysical studies ofPCSK9 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/PCSK.9, 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 c 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 r PCSK.9, 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 specifically binds to the Substratebinding groove of form e PCSK.9, 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 tlie 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-741" id="p-741"

[00741] Reference is made to US2012009381 8A1 (Amgen, Inc), the entire disclosure of which is incorporated herein. 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. id="p-742" id="p-742"

[00742] 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-743" id="p-743"

[00743] In an embodiment, the PCSI<9-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 US20I20093818A1; 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. 133 [00744] In this paragraph SEQ ID NOs are those as appearing in US20120093818AI (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 (CDREIs) 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 than 4 amino acids: 13) one or more light chain complementary determining regions (CDRLs) selected from the group consisting of: (i) a CDRLI from a CDRL1 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 IDNO: 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 CDREIs 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 CDRH I 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, 134 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 CDRI-ll 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; 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 CDRL I 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 CDRH 1 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 CDRL 5 of the CDRL1 sequence in SEQ ID NO: 12, a CDRL2 of the CDRE2 sequence in SEQ ID NO: 12, and a CDRE3 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 entity with an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 7. 9. 1 0. 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 IDNO: 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 VI, is selected from the group consisting of SEQ ID NO: 5, 7. 9, 10. 12. 13. , 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-745" id="p-745"

[00745] In an example of any aspect of the invention, the PCSK9-targeting or binding ligand comprises or consists of AMGI45 or 3IH4, 16F12, 11 FI, 8A3 or21B12 disclosed in US20120093818A1 (Amgen, Inc) or an antibody comprising the variable domains of AMG145, 135 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 inclusion in one or more claims or for use in the present invention. Preferably, the PCSK9-targeting or binding ligand comprises or consists of AMG145. id="p-746" id="p-746"

[00746] In an example, the AMG145 or other ligand of the invention is glycosylated, eg, has human glycosylation (eg, produced by a CHO, Cos or Hek.293 cell). In an example, the ligand of the invention is produced in CHO. id="p-747" id="p-747"

[00747] Reference is made to US201 1 0065902A1 (Regeneron Pharmaceuticals. Inc), the entire disclosure of which is incorporated herein. 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. |00748] Reference is made to the following PCT applications, the entire disclosures of which are incorporated herein. 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.

W02008057457 W02008057458 W02008057459 W02008063382 W02008133647 W02009100297 W02009100318 WO2011037791 WO2011053759 WO2011053783 W02008125623 WO2011072263 W02009055783 WO2010029513 WO201 111 1007 WO2010077854 [00749] 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; each of which is incorporated by reference herein in its entirety.. id="p-750" id="p-750"

[00750] In an example, the ligand is or comprises an antibody disclosed in the Examples of 1JS20110065902A1 (eg, 316P or 300N) or is a PCSK9-binding derivative thereof. All of these disclosures (including the sequences of such proteins and corresponding nucleotide sequences) are 136 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. id="p-751" id="p-751"

[00751] 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 alirocumab is glycosylated, eg, has human glycosylation (eg. produced by a CPIO. Cos or Hek293 cell). Preferably, the ligand is alirocumab or SAR236553/REGN727. id="p-752" id="p-752"

[00752] 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 CI-10, Cos or Hek293 cell). Preferably, the ligand is evolocumab. |00753] In an embodiment, the ligand is selected from evolocumab, 1 D05-lgG2 (Merck & Co,). ALN-PCS02 (Alnylam), RN3I6 (Pfizer-Rinat) and alirocumab. id="p-754" id="p-754"

[00754] In an embodiment, the ligand is selected from the following (sequences and definitions as per US2011/0065902, incorporated herein by reference):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: 2 18 and an L.CVR 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. id="p-755" id="p-755"

[00755] In an embodiment, the ligand is selected from the following (sequences and definitions as per LJS2012/0093818, incorporated herein by reference):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 137 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 PCSK9witha 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 al 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, Rl 64E, E167R, S123R, E129R, A3 11R, 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 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 138 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 ofPCSK9: SI53, SI 88, Il 89. Q190, S191, DI92. Rl94. El97, 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-756" id="p-756"

[00756] 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-757" id="p-757"

[00757] The ligand can be administered to a human characterised as described in US20120093818AI (Amgen, Inc) or US20110065902A1. id="p-758" id="p-758"

[00758] The ligand can be administered in a form or combination disclosed in US20I200938I8AI (Amgen. Inc) orUS20110065902A1, which disclosure is incorporated herein by reference. For example, the ligand with a drug, excipient, diluent or carrier as described in LJS2012009381 8A1 (Amgen, Inc) or US20I 10065902A1 (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 ofa ligand of the invention and such a further agent. id="p-759" id="p-759"

[00759] The ligand can be used in a method of diagnosis as set out in US20120093818AI (Amgen, Inc) or US20110065902A1, eg, in paragraphs [0413] to [0415] of US20120093818A1 which disclosure is incorporated herein by reference. id="p-760" id="p-760"

[00760] Diagnostic Applications |00761] 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 139 epitope than a neutralizing ligand binds to. In some embodiments, the two ligands do not compete with one another. [ 00762 J 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 PCSK.9 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 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-763" id="p-763"

[00763] In some embodiments, the ligand is a non-neutralizing ligand and is used to determine the amount of PCSK9 in a subject receiving an ARP and/or statin treatment. id="p-764" id="p-764"

[00764] 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. Jn 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 PCSK.9 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 140 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. |00765] 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 conveilase subtilisin/kexin type 9 (hPCSK9, eg, one, two or more rare variant forms disclosed herein and optionally form a and/or form a j, 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-766" id="p-766"

[00766] In one embodiment, the ligand of the invention comprises an antibody or antigen-binding fragment of an antibody that specifically binds hPCSK.9 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. id="p-767" id="p-767"

[00767] See US2011/0065902 for definitions of these terms and optional features, the disclosure of which is incorporated herein by reference in its entirety. |00768] In one embodiment, 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 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-769" id="p-769"

[00769] 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 141 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. |00770] 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 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-771" id="p-771"

[00771] In another embodiment, the antibody or antigen-binding fragment binds human, human GOF mutation D374Y, cynomolgus monkey, rhesus monkey, mouse, rat and hamster PCSK9. |00772] 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-773" id="p-773"

[00773] In one embodiment, the invention comprises an antibody or antigen-binding 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]-[03 7] of US2011/0065902, the disclosures of which are incorporated herein by reference, [00774] In a related embodiment, the invention comprises an antibody or antigen-binding 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, 3 10/3 12, 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, 61 8/620, 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. id="p-775" id="p-775"

[00775] In an example, the invention features a pharmaceutical composition comprising a ligand of the invention, wherein the ligand comprises or consists of a 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 142 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 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase, such as, for example, cerovastatin, atorvastatin. simvastatin, pitavastin, rosuvastatin, fluvastatin, lovaslatin, 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. id="p-776" id="p-776"

[00776] 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, lhe disorder treated is any disease or condition which is improved, ameliorated, inhibited or prevented by removal, inhibition or reduction of PCSK.9 activity. Specific populations treatable by the therapeutic methods of the invention include subjects indicated for LDL apheresis, subjects with PCSK9-activating 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. |00777] 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 BI 00). |00778j 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, [00779] Treatment Population [00780] 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 143 synthesis and upregulatingthe 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 non-responsive, 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-781" id="p-781"

[00781] 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 (hcFi I): 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-782" id="p-782"

[00782] Therapeutic Administration and Formulations [00783] 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 LlPOFEC'l’lNT™)- DNA conjugates, anhydrous 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 ai. Compendium of excipients for parenteral formulations PDA (1998) J Pharm Sci Technol 52:238-311. |00784] The dose may vary depending upon the age and the size ofa subject to be administered, target disease, conditions, route of administration, and the like. When the ligand, eg, antibody, ofthe 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 ofthe 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 ofthe treatment can be adjusted. id="p-785" id="p-785"

[00785] 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., 144 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. Chem. 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes, l’he 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-786" id="p-786"

[00786] 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. 3 1 7-327: see generally ibid,). id="p-787" id="p-787"

[00787] 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 the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138, 1984). (00788] 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 arc. 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 of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readiiy 145 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-789" id="p-789"

[00789] 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), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), OPTIPENT™, OPTIPEN PRO™, OPTIPEN 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 (sanofi-aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly). id="p-790" id="p-790"

[00790] 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 tlie 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. (00791] 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 exampie, one or more of any agent that (1) induces a cellular depletion of cholesterol synthesis by inhibiting 3-hydroxy-3methylglutaryl (HMG)-coenzyme A (CoA) reductase, such as cerivastatin, atorvastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin; (2) inhibits cholesterol uptake and or bile acid re-absorption; (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). 146 [00792] Tailoring Antibodies to Rare PCSK9 Variant Profile [00793] As outline 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 PCSK.9 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. id="p-794" id="p-794"

[00794] 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-795" id="p-795"

[00795] 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 7 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-796" id="p-796"

[00796] Notably, human VH3-23 alleles comprising SNP rs56069819 were found in the CEO population at a frequency that is almost double the frequency of 1 1% for all populations. For the ASW and YR1 populations the frequency was over a quarter of the population. Thus, the invention advantageously enables one to select a ligand comprising an antibody or antibody fragment, wherein the antibody or fragment comprises a VII 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-797" id="p-797"

[00797] 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 ASW, LWK, YRI. CEU and GBR. |00798] 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, [00799] In an example, the ligand is for treating and/or preventing a PCSK9-mediated disease or condition in a human that expresses a human PCSK9 selected from forms : / c, m, e, h, p, q and aj. 147 [00800] In an example, the ligand is for treating and/or preventing a PCSK9-mediated disease or condition in a human of ASW, LWK, YRf, CEU or GBR ancestry. id="p-801" id="p-801"

[00801] In an embodiment, the ligand is for treating and/or preventing a PCSK9-mediated disease or condition in a human of ASW ancestry, wherein the human expresses a PCSK9 selected from f q m, e, h, p and q or the human comprises a corresponding nucleotide or amino acid sequence as set out in Table 6. Optionally this ligand comprises a VH domain derived from recombination of human VH3-23*04. id="p-802" id="p-802"

[00802] In an embodiment, the ligand is for treating and/or preventing a PCSK9-mediated disease or condition in a human of LWK ancestry, wherein the human expresses a PCSK9 selected from/ c. m, e and h or the human comprises a corresponding nucleotide or amino acid sequence as set out in Table 6. Optionally this ligand comprises a VH domain derived from recombination of human VH323*04. id="p-803" id="p-803"

[00803] In an embodiment, the ligand is for treating and/or preventing a PCSK9-mediated 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 6. Optionally this ligand comprises a VH domain derived from recombination of human VH3-23*04. [00804] In an embodiment, the ligand is for treating and/or preventing a PCSK9-mediated disease or condition in a human of CEU ancestry, wherein the human expresses a PCSK9 selected from/ c. p and qj or the human comprises a corresponding nucleotide or amino acid sequence as set out in Table 6. Optionally this ligand comprises a VH domain derived from recombination of human VH3-23*04. |00805] In an embodiment, the ligand is for treating and/or preventing a PCSK9-mediated disease or condit ion in a human of GBR ancestry, wherein the human expresses a PCSK9 selected from/ c and p or the human comprises a corresponding nucleotide or amino acid sequence as set out in fable 6. Optionally this ligand comprises a VH domain derived from recombination of human VH3-23*04. )00806] In an example, the ligand is alirocumab. |00807] 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, VX or constant region gene segments (see further Table 9 for representative variants). 100808] 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*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV 1-18*01; or (ii) 1GVH1 -46*01 and the genome of the 148 human comprises a human IGHV 1-46*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV 1-46*01. id="p-809" id="p-809"

[00809] 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) IGKV4-1 *01 and the genome of the human comprises a human 1GKV4-1 *01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV4-1 *01; (ii) IGLV2-14*01 and the genome of the human comprises a human IGLV214*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGLV2-14*01: or (iii) IGKV 1-13*02 and the genome of the human comprises a human IGKV1-13*02 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV 1-13*02, [00810] For example, the inventor identified the possibility of addressing the rarer IGHgamma-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 human gamma-1 constant regions comprising such an Asp or Leu. An example of such a ligand is alirocumab. id="p-811" id="p-811"

[00811] In another example, the inventor identified the possibility of addressing IGHgamma-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. [00812| 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 149 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, [00813] 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. |00814] F urther exemplary ligands are in the paragraphs 1-1 7 as follows, 1. An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, or (b) targeting PCSK9 in a human, 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 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 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 embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

In an alternative, paragraph 1 provides:An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, or (b) targeting PCSK9 in a human. wherein the antibody or fragment comprises a human gamma-J 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 1474V or E670G in SEQ ID NO: 1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and 150 comprises an IGHG1 *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.

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

An example provides;An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, or (b) targeting PCSK.9 in a human. 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 IGHG1 *01 human heavy chain constant region gene segment. Optionally, the antibody or fragment comprises an 1GHG1*O1 human heavy chain constant region.

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in tlie human.

Another example provides:An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, or(b) targeting PCSK9 in a human, 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 E670G in SEQ 1DNO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGHG1 *01 human heavy chain constant region gene segment. Optionally, the antibody or fragment comprises an IGHG1 *01 human heavy chain constant region. 151 In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

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 IGLIGl*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. fhe antibody or antibody fragment of paragraph 1 or 2, wherein the antibody comprises an IGHGI *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 lo 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.

. 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 1474V or E67OG and/or a proprotein convertase subtilisin/kexin type 9 (PCSK.9) variant protein comprising said mutation J474V 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 1474V or E670G in SEQ ID 152 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 1 0 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 1474V 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 PCSK.9 that comprises the C-terminal domain comprising the mutation 1474V 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 1474V 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: I. 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. 153 . 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. 1. 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. lhe 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, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. . fhe 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. fhe antibody or antibody fragment of any one of paragraphs I to 16. wherein said antibody or antibody fragment is for administration by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. 154 [00815] Further exemplary methods are in the paragraphs 1 -18 as follows. 1. A method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (RCSK9) that comprises a Cterminal domain comprising a mutation 1474 or E670G in SEQ ID NO: I. 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 IGHG1 *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 (PCSK.9) 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.

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

An example provides:A method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human. 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 Cterminal 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 IGHG1 *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: I. Optionally, the antibody or fragment comprises a 1GHG1 *01 human heavy chain constant region.

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human. 155 Another example provides:A method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human, 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 Cterminal 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 IGHG I *01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein conveilase 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 1GHG1 *01 human heavy chain constant region, In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

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-! 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 IGHG1 *01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK.9) that comprises a C-terminal domain comprising said mutation 1474V or E670G in SEQ ID NO: 1, 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 I. 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 IGHG1 *01 human heavy chain constant region. 156 . 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 1474V 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 hitman 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 (PCSK.9) variant protein comprising said mutation 1474V 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 PCSK.9 that comprises the Cterminal domain comprising the mutation 1474V or E670G in SEQ ID NO: I. 8. The method of paragraph 7, wherein the assaying comprises contacting the biological sample w ith 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 PCSK.9 that comprises the C-terminal domain comprising the mutation 1474V 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 PCSK.9 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 PCSK.9 that comprises the C-terminal domain comprising the mutation 1474V 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 Cterminal 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 PCSK.9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 157 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. fhe 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 l474Vor 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. fhe method of any one of paragraphs I 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. 158 17. The method of any one of paragraphs 1 to ]6, 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-816" id="p-816"

[00816] further exemplary ligands are in the paragraphs 1 -1 7 as follows. 1. An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK.9 in a human, 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 Pile 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 Cterminal domain comprising a mutation 1474V 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.

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

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously7 reduced cholesterol level in the human.

An example provides:An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human, 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 (PCSK.9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V 159 in SEQ ID NO: I, 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 In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.region.

Another example provides:An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human, 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 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 embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

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 lo 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*0! 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, 160 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. fhe antibody or antibody fragment of paragraph 1 or 2, wherein the antibody comprises an 1GEIG2*O1 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 PCSK.9 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 that encodes a PCSK9 comprising a C-terminal domain comprising said mutation 1474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation 1474V 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 1474V 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: I 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 161 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 1474V 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 PCSK.9 that comprises a Cterminal domain comprising the mutation I474V or E670G in SEQ ID NO: I 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-tenninal 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, . Tiie antibody or antibody fragment of any one of paragraphs 1 io 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 162 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.

. 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-817" id="p-817"

[00817] Further exemplary methods are in the paragraphs 1-1 8 as follows, 1. A method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK.9 in a human. 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 Cterminal 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*O1 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 163 nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK.9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: I.

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

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

An example provides:A method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human. the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein conveilase subtilisin/kexin type 9 (PCSK9) that comprises a Cterminal domain comprising a mutation 1474 in SEQ ID NO: I. 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*0l 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 1474V in SEQ ID NO: 1. Optionally, the antibody or fragment comprises an IGHG2*01 human heavy chain constant region.

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

Another example provides:A method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human, 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 Cterminal domain comprising a mutation E670G in SEQ ID NO; I, 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 IDNO: 44 and an Ala corresponding to position 257 ofSEQ ID NO: 44 and wherein said human comprises (i) an IGHG2*0I human heavy chain constant region gene segment and (ii) 164 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.

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

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 (PCSK.9) 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*()1 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. 165 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 1474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation 1474V 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 fora nucleotide sequence encoding the PCSK9 that comprises the Ctermina! domain comprising the mutation 1474V 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: I 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-termina! domain comprising the mutation 1474V or E670G in SEQ ID NO: I 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 Cterminal domain comprising the mutation 1474V 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. 166 . 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. 1. 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 1474V 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 1474Vor E670G in SEQ ID NO: 1.

. The method of any one of paragraphs I 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 I to 15, wherein said antibody or antibody fragment treats or reduces the risk in said human of al 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 1 7, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. 167 [00818] Further exemplary ligands are in the paragraphs 1-17 as follows. 1. An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human. 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 1474V or E670G in SEQ ID NO: I, 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.

In an embodiment, said mutation is 1474V. In another embodiment, said mutation is E670G.

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

An example provides:An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human. 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 C-terminal domain comprising a mutation I474V in SEQ ID NO: i, 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 embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

Another example provides:168 An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human, 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 (PCSK.9) 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 IGKC*()1 human light chain constant region gene segment. Optionally, the antibody or fragment comprises an IGKC*0l human light chain constant region.

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human. 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: I. 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 I 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: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of 169 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 fora nucleotide sequence encoding the PCSK.9 that comprises the C-terminal domain comprising the mutation 1474V or E670G in SEQ II) 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 lire PCSK9 that comprises the C-terminal domain comprising the mutation 1474V 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 ofa 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 ofthe complex determines that the human comprises the PCSK9 that comprises the C-terminal 170 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. 1. 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-lerminal 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 l474Vor 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.

. 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 171 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-819" id="p-819"

[00819] Further exemplary methods are in the paragraphs 1-18 as follows. 1. A method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human, 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 Cterminal 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 1GKC*O1 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 1474V or E670G in SEQ ID NO: 1. in an embodiment, said mutation is 1474V. In another embodiment, said mutation is E670G, In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

An example provides:A method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human, 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 Cterminal domain comprising a mutation 1474 in SEQ ID NO: 1, wherein the antibody or fragment 172 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 (j) an IGKC*0I 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 1474V in SEQ ID NO: 1. Optionally, the antibody or fragment comprises an JGKC*01 human light chain constant region.

In an embodiment of (b). the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

Another example provides:A method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK.9) that comprises a Cterminal domain comprising a mutation E670G in SEQ ID NO: I, 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 (PCSK.9) that comprises a C-terminal domain comprising said mutation F:670G in SEQ ID NO: 1. Optionally, the antibody or fragment comprises an IGKC*01 human light chain constant region.

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

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 1474V or E670G in SEQ 173 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 I 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 I to 4, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK.9 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 1474V 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 Cterminal domain comprising the mutation 1474V or E670G in SEQ ID NO: 1. 8. l’he 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 174 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 Ctermina! 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 PCSK.9 that comprises the C-terminal domain comprising the mutation 1474V 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. 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 I to 13, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation 1474V 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 PCSK.9 C-terminal domain comprising said mutation I474Vor E670G in SEQ ID NO: 1, 175 . 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. I'he method of any one of paragraphs 1 lo 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. |00820] Further exemplary ligands are in the paragraphs 1-15 as follows. 1, An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human. 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 IGEC2*01 lambda light chain constant regions.

In an embodiment, said mutation is 1474V. In another embodiment, said mutation is E670G.

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

An example provides:An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or 176 maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human, 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 in SEQ ID NO:I, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises a human 1GLC2*O1 lambda light chain constant region gene segment. Optionally, the antibody or fragment comprises a human IGLC2*0l lambda light chain constant region.

In an embodiment of (b). the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

Another example provides:An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human, wherein the antibody or fragment comprises a human 1GLC2*OS 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 E670G in SEQ ID NO:1. wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises a human 1GLC2*O1 lambda light chain constant region gene segment, Optionally, the antibody or fragment comprises a human IGLC2*01 lambda light chain constant region.

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human.

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 1GLC2*O1 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK.9) that comprises a C-terminal domain comprising said mutation 1474V or E670G in SEQ ID NO: I. 177 2. The antibody or antibody fragment of paragraph 1, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK.9 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. 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 ofthe 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-terminai 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 1474V 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 ofa 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 178 encoding the PCSK9 that comprises a C-terminal domain comprising the mutation 1474V or E670G in SEQ ID NO: I 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: 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. 8. The antibody or antibody fragment of any one of paragraphs I 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.

I I. The antibody or antibody fragment of any one of paragraphs I 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 1474Vor E670G in SEQ ID NO: 1. 12. The antibody or antibody fragment of any one of paragraphs 1 to 1 I, 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 179 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.

. The antibody or antibody fragment of any one of paragraphs I to 14, wherein said antibody or antibody fragment is for administration by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. (00821] 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 1GLC2*O1 lambda light chain constant region and wherein said human comprises (i) an IGLC2*01 human light chain constant region gene segment, or tlie 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 1474V or E670G in SEQ ID NO: 1.

In an embodiment, said mutation is I474V, In another embodiment, said imitation is F.670G.

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 180 and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK.9) 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 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 I or 2, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminaf 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. fhe method of any one of paragraphs 1 to 3, comprising the step of determining that the human comprises the nucleotide sequence lhat 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. 181 . 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 Cterminal 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 w ith 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 PCSK.9 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 Cterminal domain comprising the mutation 1474V 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. Tlie 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. 182 . 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 PCSK.9 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.

. 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. (00822] Further exemplary ligands are in the paragraphs 1-15 as follows. 1. An antibody or antibody fragment for use in a method of (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human, 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 183 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 VII 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.

In an embodiment of (b). the antibody or fragment treats or reduces cholesterol level or maintains previously reduced cholesterol level in the human. 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 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. 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 ofthe antibody lo the human. 4. fhe 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 PCSK.9 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 184 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 TD NO: ! 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 PCSK.9 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 1474V 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 PCSK.9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: I. 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. fhe 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. 185 . 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, 1, 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 1474V 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.

. 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 (a) reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof or (b) targeting PCSK9 in a human, 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 Cterminal 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 186 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.

In an embodiment of (b), the antibody or fragment treats or reduces cholesterol ievel or maintains previously reduced cholesterol level in the human. 2. The method of paragraph I, 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 1474V 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 proprolein convertase subtilisin/kexin type 9 (PCSK.9) 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 Cterminal domain comprising the mutation I474V or E670G in SEQ ID NO: I. 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 PCSK.9 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 187 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 1474V 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 1474V 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 Cterminal 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: 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 I 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 1 1, 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 188 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.

. The method of any one of paragraphs I to 14, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 16. The method of any one of paragraphs I 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-823" id="p-823"

[00823] Regimens [00824] 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 fo 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.

In an alternative, clause 1 provides:A method for 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 189 comprises a nucleotide sequence encoding said PCSK9 variant. In an embodiment, 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: a. 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 PCSK.9 comprising a C-terminal domain comprising 1474V or 670G (numbering according to SEQ ID ΝΟ.Ί); 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.

For example, there is provided: b. A method for targeting a PCSK9 that comprises a C-terminal domain amino acid polymorphism (compared to SEQ ID NO: I), 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 Cterminal domain comprising 1474V 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: optionally 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. 190 In an embodiment, the method comprises, before said administering, selecting a human comprising said nucleotide sequence encoding the PCSK.9, wherein the human is said human in clause I (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 I or 2, wherein the specific binding to said PCSK9 is binding with a dissociation constant (Kd) of InM or less, eg, 100, 10 or 1 pM or less. 4. The method of any of clauses 1 to 3 (eg, clause la), wherein the condition is elevated LDLcholesterol 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, 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 Cterminal domain comprising said mutation I474V or E670G in SEQ ID NO: I 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 1474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation 1474V 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 1474V or E670G in SEQ ID NO: 1. 9. The method of clause 8, wherein the assaying comprises contacting the biological sample with 191 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, w herein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ fD 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 1474V 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, w herein 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 PCSK.9 that comprises a Cterminal 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-lerminal 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. I'he 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 1 1 or 12, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with said statin treatment. 192 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. 16. The method of any one of clauses 1 to 1 5. 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 o f 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 I ipid 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 J to 17, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 19. The method of any one of clauses 1 to ] 8. 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 iigand of clause 20 and instructions for carrying out the method of any one of clauses I to 19. id="p-825" id="p-825"

[00825] B: The invention further provides the following regimens, ligands and kits. 193 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 1474V or 670G (numbering according to SEQ ID NO: 1): (ii) the human expresses said PCSK9 or the genome of tlie 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.

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.

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. 194 2. The method of clause I, wherein 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). 3. The method of clause I 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 I 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, fenofibrale (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, fenofibratc (eg, Tricor™ or Lofibra™) or ezetimibe treatment during step (c).

. The method of any one of clauses I to 9, comprising increasing (ie, increasing compared to the initial treatment dose) the ligand dose during step (c).

I. 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 ligand.

The skilled person is familiar with the meaning of high, medium and low dose treatments (and 195 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 60-1 OOmg (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 PCSK.9, eg, using SPR or ELISA.

. The method of any one of clauses 1 to 14, wherein the specific binding to said PCSK.9 is binding with a dissociation constant (Kd) of InM or less, eg, 100. 10 or IpM or less. 6. The method of any of clauses 1 to 1 5, 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. 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 ofSEQ 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 PCSK.9 comprising a C-terminal domain 196 comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation 1474V 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-tcrminal domain comprising the mutation 1474V or E670G in SEQ ID NO: 1. 21. The method of clause 20. wherein the assaying comprises contacting the biological sample w ith 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 1474V 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 1474V 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 PCSK.9 that comprises the C-terminal domain comprising the mutation 1474V 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 Cterminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and detecting the presence or absence of the complex, w herein 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. 197 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, coronaty 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. 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 I to 28. [00826| 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 31EI4) is administered to the human at a two-weekly dose of from 75 to 150mg (eg, from 75 to 150mg administered once or twice over a two-week period). In an exampie, the ligand is for such administration to the human. 198 Determination of Specific Binding of Ligands of the Invention to PCSK9 Variants [00827] 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, !6nM, 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 UC and using I xHBS-EP (Teknova) as running buffer. id="p-828" id="p-828"

[00828] Data Three antibodies were tested and the resulting binding data are presented below (Table 3). Antibodies 3 I6P 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*0L |00829] Evolocumab comprises a human IGHG2*01 heavy chain and a human 1GLC2*O1 lambda light chain, a VH derived from recombination of human IGHV1-18*O1 and IGHJ6*01 (with a D segment) and a V?, derived from recombination of human IGLV2-14*01 and 1GLJ2*O1.

Table 3: SPR Determination of Ligand Binding Specificity for PCSK9 Variants Variant/Antibody ka (1 /Ms) kd (l/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 0.229 199 PCSK9 a’ 316P 1.50E+06 2.72E-04 0.181 31H4 1.23E+06 6.06E-05 0.049 Evolocumab I.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 2.82 E-04 0.203 31H4 1.13E+06 5.95 E-05 0.053 Evolocumab 14 6E+05 2.66E-05 0.229 PCSK9 p 316P 1.39E+06 2.73 E-04 0.196 3 1EI4 E14E-06 6.12E-05 0.054 Evolocumab 1.14E+05 2.50E-05 0.219 100830] Results The results showed that ali antibodies tested bound to PCSK9 variants equally, with any binding variation seen being within experimental error for such a strong affinity interaction. id="p-831" id="p-831"

[00831] Thus, the invention determines that an antibody with the following profile can specifically bind one or more variants of the invention:20 I, An antibody (eg, 3 16P or alirocunnab) that comprises heavy chain variable domains derived from recombination of human IGEIV3-23*04 and IGHJH2*01 (with a D), and light chain variable domains derived from recombination of human IGKV4-l*01 and 1GKJ2*O1; or 200 2. An antibody (eg, evoiocumab) that comprises human heavy chain variable domains derived from recombination of human IGHV1-18*01 and IGHJ6*01 (with a D segment) and light chain variable domains derived from recombination of human IGLV2-14*01 and IGLJ2*0l. |00832] 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. |00833] REFERENCES: Horton et al, Trends Biochem Sci. 2007 Feb;32(2):7l-7. Epub 2007 Jan 9. Molecular biology of PCSK9: its role in LDL metabolism.

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.

Benjannet et al, J Biol Chem. 2004 Nov 19;279(47):48865-75. Epub 2004 Sep 9, NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.

Lagace et al, J Clin invest. 2006 Nov;l 16(1 1):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 IJ S A. 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.

Park et al. J Biol Chem. 2004 Nov 26:279(48):50630-8. Epub 2004 Sep 22. Post-transcriptional regulation oilow density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver.

Rashid el al, Proc Natl Acad Sci USA. 2005 Apr 12:102(1 5):5374-9. Epub 2005 Apr 1. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.

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.

Chen et al, 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. Pisciotta et al, 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.

Zhao et al, Am J Hum Genet. 2006 Sep;79(3):5 14-23. Epub 2006 Jul 18, Molecular characterization of loss-of-function mutations in PCSK.9 and identification of a compound heterozygote. 201 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. id="p-834" id="p-834"

[00834] EXAMPLE 2: IL4 Receptor Alpha (IL4Ra; CD124) [00835] lnterleukin-4 (IL-4, also known as B cell stimulating factor or BSF-1) was originally characterized by its ability to stimulate the proliferation of B cells in response to low concentrations of antibodies directed to surface immunoglobulin. IL-4 has been shown to possess a broad spectrum of biological activities, including growth stimulation of f cells, mast cells, granulocytes, megakaryocytes and erythrocytes. IL-4 induces the expression of class 11 major histocompatibility complex molecules in resting B cells, and enhances the secretion of IgE and IgGl isotypes by stimulated B cells [00836] In an example, the invention provides a method of treating or reducing the risk of an IL4Ra-mediated disease or condition in a human in need thereof, the method comprising administering to said human a ligand (eg, an antibody or antibody fragment) that specifically binds a human IL4RA protein. The invention also provides a corresponding ligand. id="p-837" id="p-837"

[00837] The present invention provides anti-IL4Ra ligands; and II ARa-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 IE4Ra, in particular human IL4Ra or its ligands and in screening assays to identify other antagonists of IL4Ra activity. Some of the ligands of the invention are useful for inhibiting binding of IL4Ra to 11,4. or inhibiting if4Ra-mediated activities. |()08381 Anti-IL4Ra ligands (eg. antibodies and anti-sense RNA) have been developed based on targeting and neutralising so-called wild-type" human lL4Ra. which is a commonly-occurring form (see, eg, SEQ ID NO: 67). While such therapies are useful for human patients harbouring this form of human IL4RA, the inventor considered it useful to investigate the possibility of targeting rarer - but still naturally-occurring - forms of IL4Ra amongst human populations. In this way, the inventor arrived at insight into the natural occurrences and distributions of rarer human IL4Ra 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 1L4RA activity. This particularly provides for tailored therapies, prophylaxis and diagnosis in humans that are devoid of the common IL4Ra gene or protein. id="p-839" id="p-839"

[00839] 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 202 invention, therefore, provides for tailored pharmaceuticals and testing that specifically addresses rarer IL4Ra polymorphic variant forms. Such forms or "alleles" (at the nucleotide level), comprise one or more changes at the nucleotide and amino acid levels from the corresponding common form nucleotide and amino acids sequences, ie, there are one or more non-synonymous changes at the nucleotide level that translate into one or more corresponding changes in the protein target in humans. [00840] 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. |00841 j 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-IL4Ra ligand for administration to human patients for therapy and/or prophylaxis of IL4Ra-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. 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 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-842" id="p-842"

[00842] In developing this thinking, in this non-limiting example the present inventor decided to determine a set of human IL4Ra 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:[00843] Naturally-occurring human IL4Ra variation having a cumulative human allele frequency of 35% or less: 100844) Naturally-occurring human IT4Ra variation having a total human genotype frequency of about 50% or less: id="p-845" id="p-845"

[00845] Naturally-occurring human IL4Ra variation found in many different human ethnic populations (using the standard categorisation of the 1000 Genomes Project; see Table 2 below); and [00846] Naturally-occurring human IL4Ra variation found in many individuals distributed across such many different ethnic populations. id="p-847" id="p-847"

[00847] On the basis of these criteria, the inventor identified variants listed in Table 11 below.

The inventor's selection included, as an additional or alternative consideration, selection for nucleotide variation that produced amino acid variation in corresponding IL4Ra forms (ie, nonsynonyntous variations), as opposed to silent variations that do not alter amino acid residues in the target protein. 203 [00848] In an example, the invention provides a method of treating or reducing the risk of an IL4Ra-mediated disease or condition in a human in need thereof, the method comprising administering to said human a ligand (eg, an antibody or antibody fragment) that specifically binds a human IL4RA protein that comprises a mutation selected from the group consisting of 175 V, E40OA, C431R, S503P, Q576R and S752A in SEQ ID NO: 67. As explained further below, these amino acid variations are found in naturally-occurring IL-4Ra variants in humans found in many populations. Said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C43 1R, S503P, Q576R and S752A in SEQ ID NO: 67. id="p-849" id="p-849"

[00849] An example also provides a ligand (eg, an antibody or antibody fragment) for treating or reducing the risk of an IL4Ra-mediated disease or condition in a human in need thereof, the method comprising administering to said human said ligand, wherein the ligand specifically binds a human 1L4RA protein that comprises a mutation selected from the group consisting of 175V, E400A, C43) R. S503P, Q576R and S752A in SEQ ID NO: 67. Said human comprises a nucleotide sequence encoding said 1L4RA protein comprising said mutation selected from the group consisting of 175V, E400A, C43 IR, S503P, Q576R and S752A in SEQ ID NO: 67. id="p-850" id="p-850"

[00850] In an example, the invention provides a method of targeting IL4Ra in a human, the method comprising administering to said human a ligand (eg, an antibody or antibody fragment) that specifically binds a hitman IL4RA protein that comprises a mutation selected from the group consisting of 175V, E400A, C43 IR, S503P, Q576R and S752A in SEQ ID NO: 67. Said human comprises a nucleotide sequence encoding said 1L4RA protein comprising said mutation selected from the group consisting of 175V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67. In an example, the human is suffering from or at riskof an IL4Ra-mediated disease or condition. In an example, the method treats or reduces the risk of an IL4Ra-mediaied disease or condition in the human. id="p-851" id="p-851"

[00851] An example also provides a ligand (eg, an antibody or antibody fragment) for targeting lL4Ra in a human, the method comprising administering to said human said ligand, wherein the iigand specifically binds a human IL4RA protein that comprises a mutation selected from the group consisting of I75V, E400A. C431R, S5O3P, Q576R and S752A in SEQ ID NO: 67. Said human comprises a nucleotide sequence encoding said 1L4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67. In an example, the human is suffering from or at riskof an lL4Ra-mediated disease or condition. In an example, the method treats or reduces the risk of an IL4Ra-mediated disease or condition in the human, [00852] In an embodiment, (i) the antibody or fragment comprises a VH domain derived from the recombination ofa human VH segment, 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 204 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 ; and wherein (ii) said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of 175V, E400A, C431R, S503P, Q576Rand S752A in SEQ ID NO: 67, [00853] Additionally or alternatively, in an embodiment, (i) the antibody or fragment comprises a human gamma-4 heavy chain constant region that comprises a Leu at position 189 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73 and wherein said human comprises an IGHG4*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-4 heavy chain constant regions comprising a Leu at position 189 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73; and wherein (ii) said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of 175V, Ε400Λ, C431R, S5O3P, Q576R and S752A in SEQ ID NO: 67. |00854] The biological activities of IL-4 are mediated by specific cell surface receptors for IL-4. Human IL-4 receptor alpha (hlL-4Ra) is described in, for example, U.S. Patent No. 5,599,905, 5,767,065, and 5,840,869. Antibodies to hlL-4Rare described in U.S. Patent No. 5,717,072. |00855] Methods for using antibodies to hlL-4R are described in U.S, Patent Nos. 5.714,146; 5,985,280; and 6,716,587. id="p-856" id="p-856"

[00856] The human IE-4Ra (aka IE-4Rct) subunit (Swiss Prot accession number P24394) is a 140kDa type 1 membrane protein that binds human IL-4 with a high affinity (Andrews et al J. Biol. Chem (2002) 277:46073-46078). The IL-4/ IL-4Ra complex can dimerize with either the common gamma chain (yc, CD132) or the IL-13Ralphal (IL-13Ral) subunit, via domains on IL-4, to create two different signalling complexes, commonly referred to as Type I and Type II receptors, respectively. Alternatively. IL-13 can bind IL-13Ru.l to form an IL-13/IL-13 Ret I complex that recruits the IE-4Rc subunit to form a Type II receptor complex. Thus. IL-4Ra mediates the biological activities of both IL-4 and IL-13 (reviewed by Gessner et al, Immunobiology, 201:285. 2000). In vitro studies have shown that IE-4 and IL-13 activate effector functions in a number of cell types, for example in T cells. B cells, eosinophils, mast cells, basophils, airway smooth muscle cells, respiratory epithelial cells, lung fibroblasts, and endothelial cells (reviewed by Steinke et al, Resp Res, 2:66, 2001, and by Willis-Karp, Immunol Rev. 202:175. 2004), [00857] IL-4 by binding to its receptor (IL-4R) is essential for the development of airway inflammation present in asthma, through the induction of IgE synthesis in B cells and differentiation of T cells to a Th2 phenotype. Dupilumab is a monoclonal antibody designed for the treatment of atopic diseases. It binds to the alpha subunit of the interleukin-4 receptor. Through blockade of 1L-4R alpha, dupilumab modulates signaling of both the IL-4 and IL-13 pathway, which have been implicated in the pathophysiology of allergic disease. Anti-IL4Ra ligands, antibodies and fragments according to the invention can, for example, be used for treating or reducing the risk of allergic disease. 205 In an example, the ligand, antibody or fragment is for treating or reducing the risk of (or treats or reduces the risk of) allergic asthma, eosinophilic asthma or atopic dermatitis, optionally wherein the antibody is dupilumab, [00858] In addition to its role in asthma, IL-4Ra has been linked with a number of other pathologies, e.g. as follows (anti-!L4Ra ligands, antibodies and fragments according to the invention can. for example, be used for treating or reducing the risk of any one of these diseases or conditions): [00859] Chronic Obstructive Pulmonary Disease (COPD) includes patient populations with varying degrees of chronic bronchitis, small airway disease and emphysema and is characterised byprogressive irreversible lung function decline that responds poorly to current asthma based therapy. The underlying causes of COPD remain poorly understood. The Dutch hypothesis proposes that there is a common susceptibility to COPD and asthma and therefore, that similar mechanisms may contribute to the pathogenesis of both disorders (Sluiter et ah. Eur Respir J,). Zheng et al (J Clin Invest, 106(9): 1081-93, 2000) have demonstrated that overexpression ofIL-13 in the mouse lung caused emphysema, elevated mucus production and inflammation, reflecting aspects of human COPD. Furthermore, AHR, an IL-13 dependent response in murine models of allergic inflammation, has been shown to be predictive of lung function decline in smokers (Tashkin et ah. Am J Respir Crit Care Med, 153(6 Pt 1):1802-11, 1996). A link has also been established between an IL-13 promoter polymorphism and susceptibility to develop COPD (Van Der Pouw Kraan et al.. Genes Immun, 3(7): 436-9, 2002), The signs are therefore that 1E-4/IL-13 pathway, and in particular IL-13, plays an important role in the pathogenesis of COPD. id="p-860" id="p-860"

[00860] In addition to asthma, the IL-4/II-13 pathway has been linked to other fibrotic conditions, like systemic sclerosis (Ilasegawa et ah, J Rheumatol, 24(2):328-32, 1997), pulmonary fibrosis (Hancock et ah, Am J Respir Cell Mol Biol. 1 8(1): 60-5. 1998), parasite-induced liver fibrosis (Fallon etal., J Immunol, 164(5): 2585-91, 2000; Chiaramonte et al., J Clin Invest. 104(6): 777-85, 1999: Chiaramonte Hepatology 34(2):273-82, 2001), and cystic fibrosis (Hauber et al,. J. Cyst Fibr, 2:189, 2003), [00861] IL-4 and to some extent IL-13, are crucial for B cell mediated activities, such as B cell proliferation, immunoglobulin secretion, and expression of FcepsilonR, Clinical applications of an IL4Ra inhibitor include for example, use in allergy therapy to suppress IgE synthesis (including for example atopic dermatitis and food allergy), use in transplation therapy to prevent transplant rejection, as well as suppression of delayed-type hypersensitivity or contact hypersensitivity reactions. id="p-862" id="p-862"

[00862] II-4R antagonists may also find use as adjuvants to allergy immunotherapy and as vaccine adjuvants. ]00863| lL-4Ra polymorphisms in the human population have been described (reviewed by Gessner et al. Immunobiology, 201:285. 2000) and association with IgE levels or clinical atopy has been reported in some populations. For instance, V75R576 IL-4Rot is associated with allergic asthma and enhanced IL-4Ra function (Risma et al. J.Immunol. 169(3):1604-1610, 2002). 206 [00864] Anti-IL4Ra ligands, antibodies and fragments according to the invention optionally neutralise IL-4Ra with high potency, for example as described in more detail in the Examples of EP2604628. Neutralisation means inhibition of a biological activity mediated by IL-4Ra. Ligands, antibodies and fragments according to the invention may neutralise one or more activities mediated by lL-4Ra. The inhibited biological activity is likely mediated by prevention of IL-4Ra forming a signalling complex with gamma chain (or JL-13Ra) and either of the associated soluble ligands, e.g. IL-4 or IL-13. (00865] Neutralisation of IL-4 or IL-1 3 signalling through its lL-4Ra containing receptor complex may be measured by inhibition of IL-4 or IL-13 stimulated TF-1 cell proliferation. id="p-866" id="p-866"

[00866] The ligand, antibody or fragment according to the invention is, for example, dupilumab or any one disclosed in WO 08/054606 (Regeneron), EP2604628 (Medimmune), WO 01/92340 (immnunex) or WO 05/047331 (Immunex), the disclosures of which (including Ihe sequences, eg.

VH. VL and heavy and light chain sequences) are incorporated herein by reference for potential inclusion in one or more claims herein. According to a further aspect of the ligand, antibody or fragment according to the invention is capable of binding human interleukin-4 receptor alpha (hlL4Ra) and cynomolgus monkey interleukin-4 receptor alpha (cylL-4Ra). Cynomolgus IL-4Ra cDNA sequence is shown as SEQ ID NO: 455 EP2604628. In a particular embodiment the antibody or fragment is a human antibody or fragment. The ligand, antibody or fragment according to the invention is an antibody or fragment, for example, that comprises a VH and/or VL of dupilumab. or comprises a heavy and/or light chain of dupilumab. In one embodiment, the ligand, antibody or fragment comprises a VH domain comprising SEQ ID NO: 69. In one embodiment, the ligand, antibody or fragment comprises a VL domain comprising SEQ ID NO: 70. in one embodiment, the ligand, antibody or fragment comprises a heavy chain comprising SEQ ID NO: 71. In one embodiment, the ligand, antibody or fragment comprises a light chain comprising SEQ ID NO: 72. [00867] In a specific embodiment, the ligand, antibody or fragment of present invention comprises an Fc region, wherein the Fc region comprises at least one non-native amino acid residue selected from the group consisting of 234D, 234E, 234N, 234Q. 234T. 234H, 234Y, 2341, 234V. 234F, 235A, 235D. 235R, 235W, 235P. 235S, 235N. 235Q. 235T. 235H. 235Y. 2351, 235V, 235F. 236E. 239D, 239E, 239N, 239Q, 239E, 239T, 239H, 239Y, 2401, 240A, 240T, 240M, 241W, 241 L, 241Y, 241E. 241 R. 243W, 243L 243Y, 243R, 243Q, 244H, 245A, 247L, 247V, 247G, 251F, 252Y, 254T, 255L, 256E, 256M, 2621, 262A, 262T, 262E, 2631, 263A, 263T, 263M, 264L, 2641, 264W. 264T, 264R, 264F, 264M, 264Y, 264E, 265G, 265N, 265Q, 265Y, 265F, 265V, 2651, 265L, 265H. 265T, 2661, 266A, 266T, 266M, 267Q, 267L, 268E, 269H, 269Y, 269F, 269R, 270E. 280A, 284M. 292P, 292L, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 2961, 296H, 269G. 297S, 297D, 297E. 298H, 2981, 298T, 298F. 2991, 299L. 299A. 299S. 299V, 299H, 299F, 299E, 3051, 31 3F, 3 16D, 325Q, 325L, 3251, 325D. 325E, 325A, 325T, 325V, 325H. 327G, 327W, 327N, 327L, 328S, 328M, 328D, 328E, 328N, 328Q, 328F, 3281, 328V, 328T, 328H. 328A, 329F, 329H, 329Q, 330K, 330G. 207 330T, 330C, 33OL, 330Y, 330V, 3301, 33OF, 330R, 33OEI, 33 1G, 331 A, 331 L, 331M, 33 IF, 331W, IK, 33IQ, 33IE, 33 IS, 331V, 3311, 331C, 331Y, 331H, 331R, 33 IN, 331D, 331T, 332D, 332S, 332W, 332F, 332E, 332N, 332Q, 332T, 332H, 332Y, 332A, 339T, 370E, 370N, 378D, 392T, 396L, 416G, 419H, 421K, 440Yand 434W as numbered by the EC index as set forth in Rabat. Optionally, the Fc region may comprise additional and/or alternative non-native amino acid residues known to one skilled in the art (see, e.g., U.S. Patents 5,624,821 ; 6,277,375 ; 6,737,056 ; PCT Patent Publications WO 01/58957 : WO 02/06919 : WO 04/016750 : WO 04/029207 : WO 04/035752 and WO 05/0402 I 7 ). id="p-868" id="p-868"

[00868] Tlie ligand, antibody or fragment according to the invention is for treating or preventing or reducing the risk of (or treats or prevents or reduces the risk ol). for example, any disease or condition disclosed in any of WO 08/054606 (Regeneron), EP2604628 (Medimmune), WO 01/92340 (immnunex) and WO 05/047331 (Immunex), the disclosures of which diseases and conditions are incorporated herein by reference for potential inclusion in one or more claims herein. id="p-869" id="p-869"

[00869] Further encompassed by the invention is the use of the ligand, antibody or fragment of an in the manufacture of a medicament for use to attenuate or inhibit an IL-4Ra-mediated disease or disorder in a human. IL-4Ra-mediated or related disorders which are treated by the ligand, antibody or fragment of the invention include, for example, arthritis (including septic arthritis), herpetiformis, chronic idiopathic urticaria, scleroderma, hypertrophic scarring, Whipple's Disease, benign prostate hyperplasia, lung disorders, such as mild, moderate or severe asthma, inflammatory disorders such as inflammatory bowel disease, allergic reactions, Kawasaki disease, sickie cell disease, Churg-Strauss syndrome. Grave's disease, pre-eclampsia. Sjogren's syndrome, autoimmune lymphoproliferative syndrome, autoimmune hemolytic anemia, Barrett's esophagus, autoimmune uveitis, tuberculosis, and nephrosis. id="p-870" id="p-870"

[00870] Particular conditions for which a ligand, antibody or fragment of the invention may be used in treatment or diagnosis include: asthma. COPD (eg, chronic bronchitis, small airway disease or emphysema), inflammatory bowel disease, a fibrotic condition (eg, systemic sclerosis, pulmonary fibrosis, parasite-induced liver fibrosis, or cystic fibrosis), allergy (for example atopic dermatitis, dust mite allergy, pet allergy or food allergy), transplation therapy to prevent transplant rejection, suppression of a delayed-type hypersensitivity or a contact hypersensitivity reaction, as an adjuvant to allergy immunotherapy or as a vaccine adjuvant. id="p-871" id="p-871"

[00871] Thus, a ligand, antibody or fragment of the invention is useful as a therapeutic agent in the treatment ofa condition involving IL-4, IL-13 or IL-4Ra expression and/or activity. One embodiment, among others, is a method of treatment comprising administering an effective amount of a ligand, antibody or fragment of the invention to a patient in need thereof, wherein functional consequences of IL-4Ra activation are decreased. Another embodiment, among others, is a method of treatment comprising (i) identifying a patient demonstrating IL-4, IL-13 or IL-4Ra expression or activity, and (ii) administering an effective amount of a ligand, antibody or fragment of the invention 208 to the patient, wherein a functional consequence of IL-4Ra activation are attenuated. An effective amount according to the invention is an amount that modulates (e.g. decreases) the functional consequences of IL-4Ra activation so as to modulate (e.g. decrease or lessen) the severity of at least one symptom of the particular disease or disorder being treated, but not necessarily cure the disease or disorder. Accordingly, one embodiment of the invention is a method of treating or reducing the severity of at least one symptom of any of the disorders referred to herein, comprising administering to a patient in need thereof an effective amount of one or more ligands, antibodies or fragments of the present invention alone or in a combined therapeutic regimen with another appropriate medicament known in the art or described herein such that the severity of at least one symptom of any of the disorders is reduced. Another embodiment of the invention, among others, is a method of antagonizing at least one effect of IL-4Ra comprising contacting with or administering an effective amount of one or more ligands, antibodies or fragments of the present invention such that said at least one effect of lL-4Ra is antagonized, e.g. the ability of IL-4Ra to form a complex (the precursor to active signalling) with IL-4. id="p-872" id="p-872"

[00872] A ligand, antibody or fragment of the invention can, in an example, be used in combination with another therapeutic agent for the treatment of cancer. Suitable agents to be used in combination include those disclosed in EP2604628 (eg, in paragaraph [0287]), which disclosure is incorporated herein by reference. id="p-873" id="p-873"

[00873] Tailoring Antibodies to Rarer IL4Ra Variant Profile [00874] As outlined herein (for example, in the context ofPCSK9 in Example 1), the invention includes the possibility to tailor treatment of humans further by selecting antibody-based ligands with variable domains and/or constant domains based on gene segments found in many humans of the ethnic populations where the variant TOI forms are found to meet the selection criteria of the invention. This also applies mutaiis mutandis where the TOI is human IL4Ra, as in the present example. Thus, all disclosure herein relating to tailoring variable and/or constant domains apply to the present example, relating to Il,4Ra and is combinable for use in one or more claims herein, [00875] As described in Example 1, an example is provided for ligands comprising antibody VH domains derived from recombination of human IGHV gene segments comprising selected nucleotides at positions in the HCDR1 or FW3 where there is variability in humans (ie, where SNPs occur in humans). id="p-876" id="p-876"

[00876] Further information is provided in Table 4, which shows variation at these positions, as well as the variant distributions across the 1000 Genomes Project database relating to many human populations, [00877] 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 209 VH gene segments, or on Vk, Vk or constant region gene segments (see further Table 9 for representative variants). [00878| In an example, following this guidance, the chosen ligand is dupilumab. id="p-879" id="p-879"

[00879] Further examples, therefore are:(i) wherein 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 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, this example (i) provides:wherein the ligand comprises a VH domain derived from the recombination ofa human VH segment (eg, human VH3-23*04), a human D gene segment and a human JH segment, the human VII segment comprising SNP rs56069819 and wherein said human comprises a VH gene segment comprising SNP rs56069819. (ii) wherein the ligand comprises a VH domain derived from the recombination of human VH segment IGHV3-7*01, a human D gene segment and a human JH segment, and wherein said human comprises a IGI IV3-7*01 VH gene segment or the human expresses VH domains derived from the recombination of human VH segment IGHV3-7*0l, a human D gene segment and a human JH segment. (iii) wherein the ligand comprises a Vk domain derived from the recombination of human Vk segment IGKV1-12*O1 and a human Jk segment, and wherein said human comprises a IGKV1-12*O1 Vk gene segment or the human expresses Vk domains derived from the recombination of human Vk segment IGKV1-12*01 and a human Jk segment. (iv) wherein the ligand comprises a Vk domain derived from the recombination of a human Vk segment and a human Jk segment, the human Vk segment encoding (i) a CDR.3 comprising a Pro at position 7 shown in SEQ ID NO: 36 and wherein said human comprises a Vk gene segment encoding a CDR3 comprising a Pro at position 7 shown in SEQ ID NO: 36, or the human expresses Vk domains that comprise a CDR3 comprising a Pro at position 7 shown in SEQ ID NO: 36; or (ii) a FW3 comprising a Ser at position 15 shown in SEQ ID NO: 38 and w'herein said human comprises a Vk gene segment encoding a FW3 comprising a Ser at position 15 shown in SEQ ID NO: 38 or the human expresses Vk domains that comprise a FW3 comprising a Ser at position 15 shown in SEQ ID NO: 38. (v) wherein the ligand comprises a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 4 or a Leu at position 206 shown in SEQ ID NO: 4 and wherein said human comprises (i) an IGHG1 *01 human heavy chain constant region gene segment, or 210 the human expresses antibodies comprising human gamma-1 heavy chain constant regions comprising an Asp at position 204 shown in SEQ ID NO: 4 or a Leu at position 206 shown in SEQ ID NO: 4. (vi) wherein the ligand comprises a human gamma-2 heavy chain constant region that comprises an amino acid selected from the group consisting of a Pro at position 72 shown in SEQ ID NO: 6, an Asn at position 75 shown in SEQ ID NO: 6, a Phe at position 76 shown in SEQ ID NO: 6, a Val at position 161 shown in SEQ ID NO: 6 and an Ala at position 257 shown in SEQ ID NO: 6 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 said selected Pro at position 72 shown in SEQ ID NO: 6, Asn at position 75 shown in SEQ ID NO: 6, Phe at position 76 shown in SEQ ID NO: 6, Val at position 161 shown in SEQ ID NO: 6 or Ala at position 257 shown in SEQ ID NO: 6. (vii) wherein the ligand comprises a human kappa chain constant region that comprises a Val at position 84 shown in SEQ ID NO: 16 or a Cys at position 87 shown in SEQ ID NO: 1 6 and wherein said human comprises (i) an IGK.C1 *01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human kappa chain constant regions comprising a Val corresponding to position 84 shown in SEQ ID NO: 16 or a Cys at position 87 shown in SEQ ID NO: 16 and (ii) a nucleotide sequence encoding said IL4RA protein comprising said Asp358Ala or Val385Ile in SEQ ID NO: 1. (viii) wherein the ligand comprises a human IGLC1*O1 lambda chain constant region and wherein said human comprises (i) a human IGLC1 *01 lambda chain constant region gene segment, or the human expresses antibodies comprising human IGLCl*01 lambda chain constant regions. (ix) wherein the ligand comprises a human gamma-4 heavy chain constant region that comprises a Leu at position 1 89 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73 and wherein said human comprises (i) an 1GHG4*O1 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-4 heavy chain constant regions comprising a Leu at position 189 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73, 100880] For example, as per example (v). the inventor identified the possibility of addressing IGH-gamma-4 variation and identified utility for variations 189L and 289R individually or in combination, since these residues are part of the CH3 domain, and as such they form pail 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-4 heavy chain constant region that comprises a Leu corresponding to position 189 of SEQ ID NO: 73 or an Arg corresponding to position 289 of SEQ ID NO: 73 and wherein the genome of the human comprises a gamma-4 heavy chain constant region nucleotide sequence that encodes such a Leu and/or Arg or the human expresses antibodies 211 comprising human gamma-4 constant regions comprising such a Leu and/or Arg. An example of such a ligand is dupilumab. 100881 ] Determination of Specific Binding of Ligands of the Invention to IL4RA Variants [00882] The specific binding of Ligands of the invention to IL4Ra variants can be performed using the SPR method described in Example 1. id="p-883" id="p-883"

[00883] Embodiments are provided as follows:[00884] Methods with VH Tailoring 1. A method of treating or reducing the risk of an IL4Ra-mediated disease or condition in a human in need thereof, the method comprising administering to said human a ligand (eg. an antibody or antibody fragment) that specifically binds a human IL4Ra protein that comprises a mutation selected from the group consisting of 175 V. E400A, C431R, S5O3P, Q576R and S752A in SEQ ID NO: 67: wherein (i) the ligand 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 the framework I 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 ; and wherein (ii) said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of 175 V. E400A, C431R. S503P. Q576R and S752A in SEQ ID NO: 67.

In an alternative, clause 1 provides:A method of targeting lL4Ra in a human, the method comprising administering to said human a ligand (eg, an antibody or antibody fragment) that specifically binds a human IL4Ra protein that comprises a mutation selected from the group consisting of 175V, E400A, C431R, S5O3P. Q576R and S752A in SEQ ID NO: 67: wherein (i) the ligand 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 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 ; and wherein (ii) said human comprises a nucleotide sequence encoding said IL4RA protein 212 comprising said mutation selected front the group consisting of 175V, E400A, C431R, S503P. Q576R and S752A in SEQ ID NO: 67.

In an example, the human is suffering from or at riskofan IL4Ra-mediated disease or condition. In an example, the method treats or reduces the risk of an IL4Ra-mediated disease or condition in the human.

In an example of the method or ligand of the invention, the IE4Ra comprises mutation 175 V.

In an example of the method or ligand of the invention, the IL4Ra comprises mutation E400A.

In an example of the method or ligand of the invention, the IL4Ra comprises mutation C43 1 R.

In an example of the method or ligand of the invention, the IL4Ra comprises mutation S503P, In an example of the method or ligand of the invention, the IL4Ra comprises mutation Q576R.

In an example of the method or ligand of the invention, the IL4Ra comprises mutation S752A. 2. The method of clause 1, wherein the IL4Ra comprises mutations I75V and Q576R in SEQ ID NO: 67 and optionally the disease is asthma.

Q576R and 175V are associated with airway inflammation disease, eg. asthma. Por example, see Clin Exp Allergy. 2003 Aug;33(8): 1111-7. Polymorphisms in the interleukin-4 and interleukin-4 receptor alpha chain genes confer susceptibility to asthma and atopy in a Caucasian population. Beghe B el al (referring to I75V instead as I50V); J Asthma, 2010 Apr:47(3):238-44. doi: .3 109/02770900903509099, Association and gene-gene interactions of eight common singlenucleotide polymorphisms with pediatric asthma in middle china", Wu X et ah Clin Exp Allergy. 2004 Oct;34(l 0):1570-5. Haplotypes of the interleukin-4 receptor alpha chain gene associate with susceptibility to and severity of atopic asthma. Hytonen AM et ah all incorporated herein by reference. 3. The method of clause 1 or 2, wherein the nucleotide sequence of (ii) comprises nucleotide mutation -3223T (dB SNP numbering).

This variation is associated with airway inflammation disease, eg, asthma. 4. The method of any preceding clause, wherein each said human VI I gene segment comprises SEQ IDNO: 39. 213 . The method of any preceding clause, wherein the VH gene segment comprised by said human is a germline VH gene segment. 6. The method of any preceding clause comprising, before said administering, selecting a human comprising said nucleotide sequence of (ii), wherein the human is the human of clause 1, 7. The method of any preceding clause, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL4Ra protein comprising said mutation selected from the group consisting of 175V, Ε400Λ, C43 1 R. S503P, Q576R and S752A in SEQ ID NO: 67 and/or an JL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A. C431R, S503P. Q576R and S752A in SEQ ID NO: 67. 8. The method of any preceding clause, comprising the step of determining that the human comprises (a) the nucleotide sequence that encodes an IL4Ra protein comprising said mutation selected from the group consisting of 175V, E400A, C43 1R, S503P, Q576R and S752A in SEQ ID NO: 67 and/or (b) an lL4Ra protein comprising said mutation said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67, optionally, wherein the determining step is performed before administration of the antibody to the human. 9. The method of clause 8. wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL4Ra protein comprising said mutation selected from the group consisting oi?I75V, E400A. C43 1R. S503P, Q576R and S752A in SEQ ID NO: 67.

. The method of clause 9, wherein the assaying comprises contacting the biological sample with at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding an IL4Ra protein comprising said mutation selected from the group consisting of 175V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation selected from the group consisting of I75V, E400A, C43 I R, S5O3P, Q576R and S752A in SEQ ID NO: 67, thereby forming a complex when at least one nucleotide sequence encoding the lL4Ra protein comprising said mutation selected from the group consisting of 175 V, E400A, 214 C431R, S503P, Q576R and S752A in SEQ ID NO: 67 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67. 11. The method of clause 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. 12. The method of clause 9 or 11, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 13. The method of any preceding clause, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL4Ra protein comprising said mutation selected from the group consisting of 175V, E400A, C43 1R, S503P, Q576R and S752A in SEQ ID NO: 67, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 68, or said human is indicated as homozygous for a nucleotide sequence encoding the IL4Ra protein comprising said mutation selected from the group consisting of 175V, E400A, C431R, S503P, Q576Rand S752A in SEQ ID NO: 67. 14. The method of any preceding clause, wherein said human is or has been further determined to be substantially resistant to an asthma treatment.

. The method of any preceding clause, wherein said human is receiving or has received an asthma treatment or has reduced responsiveness to an asthma treatment. 16. The method of any preceding clause, wherein said disease or condition is an inflammatory disease or condition; an atopic disease or condition; a respiratory disease or condition; a disease or condition associated with elevated IgE: or a disease or condition associated with elevated 11,-4 and/or IL-13 activity. 215 17. The method of any preceding clause, wherein said disease or condition is selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia, environmental lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of the mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis, aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis, pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X. pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis. 18, The method of any preceding clause, wherein said human has been diagnosed with at least one condition selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia, environmental lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of tlie mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis. aspergilloma. aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis. pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X, pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis. 19. The method of any preceding clause, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia, environmental lung disease. 216 pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of the mediastinum, disorders ofthe diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis, aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis, pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X, pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis . The method of any preceding clause, wherein the nucleotide sequence comprises one or more SNPs selected from the group consisting of rsl 805010. rs 1 80501 I, rs 1 805012. rsl805015. i-sl801275 and rsl805016. 21. The method of any preceding clause, wherein said antibody or antibody fragment is administered by inhaled, intravenous or subcutaneous administration and/or is comprised in an inhalable or injectable preparation. 22. The method of any preceding clause, wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 69. id="p-885" id="p-885"

[00885] Ligands with VH Tailoring 1. A ligand (eg. an antibody or antibody fragment) for use in a method of treating or reducing the risk of an IL4Ra-mediated disease or condition (eg, asthma) in a human in need thereof, wherein the ligand specifically binds a human IL4RA protein that comprises a mutation selected from the group consisting of 175V, E400A, C43 IR, S503P, Q576R and S752A in SEQ ID NO: 67; wherein (i) the ligand comprises a VPI 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 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 217 the framework 1 of SEQ ID NO: 40 : and wherein (ii) said human comprises a nucleotide sequence encoding said IE4RA protein comprising said mutation selected from the group consisting of 175V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67.

In an alternative, paragraph I provides:A ligand (eg, an antibody or antibody fragment) for use in a method of targeting lL4Ra in a human, wherein the ligand specifically binds a human IL4RA protein that comprises a mutation selected from the group consisting of 175V. E400A, C431R. S503P, Q576R and S752A in SEQ ID NO: 67: wherein (i) the ligand comprises a VI1 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 the framework 1 of SEQ ID NO: 40 and wherein said human comprises a VH gene segment encoding the framework I of SEQ ID NO: 40, or the human expresses VH domains that comprise the framework 1 of SEQ ID NO: 40 : and wherein (ii) said human comprises a nucleotide sequence encoding said IE4RA protein comprising said mutation selected from the group consisting of I75V. E400A, C43 1 R, S503P. Q576R and S752A in SEQ ID NO: 67.

In an example, the human is suffering from or at riskof an lL4Ra-mediated disease or condition, In an example, the method treats or reduces the risk of an IL4Ra-mediated disease or condition in the human. 2. The ligand of paragraph 1. wherein the IL4Ra comprises mutations 175 V and Q576R in SEQ ID NO: 67 and optionally the disease is asthma, 3. fhe ligand of paragraph 1 or 2. wherein the nucleotide sequence of (ii) comprises nucleotide mutation -3223T (dB SNP numbering), 4. The ligand of any preceding paragraph, wherein each said human VH gene segment comprises SEQ ID NO: 39. 218 . The ligand of any preceding paragraph, wherein the VH gene segment comprised by said human is a germ line VH gene segment. 6. The ligand of any preceding paragraph, said method comprising, before said administering, selecting a human comprising said nucleotide sequence of (ii). wherein the human is the human of paragraph 1. 7. The ligand of any preceding paragraph, wherein the human lias been determined to comprise the nucleotide sequence that encodes an IL4Ra protein comprising said mutation selected from the group consisting of 175 V. E400A. C431R, S503P, Q576R and S752A in SEQ ID NO: 67 and/or an IL4Ra protein comprising said mutation selected from the group consisting of 175V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67. 8. The ligand of any preceding paragraph, said method comprising the step of determining that the human comprises (a) the nucleotide sequence that encodes an IL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A, C431 R, S503P, Q576R and S752A in SEQ ID NO: 67 and/or (b) an IL4Ra protein comprising said mutation said mutation selected from the group consisting of 175 V, E400A, C43 1R. S503P. Q576R and S752A in SEQ ID NO: 67, optionally, wherein the determining step is performed before administration of the antibody to the human. 9. The ligand of paragraph 8. wherein the step of determining comprises assaying a biological sample from the human fora nucleotide sequence encoding a IL4Ra protein comprising said mutation selected from the group consisting of 175V, E400A, C43 1R, S503P, Q576R and S752A in SEQ ID NO: 67.

. The ligand of paragraph 9, wherein the assaying comprises contacting the biological sample with at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides ofa nucleotide sequence encoding an IL4Ra protein comprising said mutation selected from the group consisting of 175V, E400A, C43 1 R, S5O3P, Q576R and S752A in SEQ ID NO: 67 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67, thereby forming a complex when al least one nucleotide sequence encoding 219 the lL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A, C43 1R, S5O3P, Q576R and S752A in SEQ ID NO: 67 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the !L4Ra protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67. 11. The ligand of paragraph 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. 12. The ligand of paragraph 9 or I 1, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 13. The ligand of any preceding paragraph, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A, C43 1R, S5O3P, Q576R and S752A in SEQ ID NO: 67, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 68, or said human is indicated as homozygous for a nucleotide sequence encoding the IL4Ra protein comprising said mutation selected from the group consisting of 175V. E400A, C431 R, S503P. Q576R and S752A in SEQ ID NO: 67. 14. The ligand of any preceding paragraph, wherein said human is or has been further determined to be substantially resistant to an asthma treatment.

. The ligand of any preceding paragraph, wherein said human is receiving or has received an asthma treatment or has reduced responsiveness to an asthma treatment. 16. The ligand of any preceding paragraph, wherein said disease or condition is an inflammatory disease or condition; an atopic disease or condition; a respiratory disease or condition; a disease or condition associated with elevated IgE; or a disease or condition associated with elevated 11,-4 and/or IL-13 activity. 220 17. The ligand of any preceding paragraph, wherein said disease or condition is selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia, environmental lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of the mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis, aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis. pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X, pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis. 18. The ligand of any preceding paragraph, wherein said human has been diagnosed with at least one condition selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia, environmental lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of the mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis. aspergilloma. aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis, pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X, pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis. 19. The ligand of any preceding paragraph, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia. environmental 221 lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of the mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis, aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis, pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X, pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis . The ligand of any preceding paragraph, wherein the nucleotide sequence comprises one or more SNPs selected from the group consisting of rsl805010, rsl 80501 1, rs 1805012, rs 1805015, rsl801275 and rsl805016. 21. The ligand of any preceding paragraph, wherein said antibody or antibody fragment is for inhaled, intravenous or subcutaneous administration and/or is comprised in an inhalable or injectable preparation. 22. I'he ligand of any preceding paragraph, wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 69. (00886] Methods with C Region Tailoring 1. A method of treating or reducing the risk of an IL4Ra-tnediated disease or condition in a human in need thereof, the method comprising administering to said human a ligand (eg, an antibody or antibody fragment) that specifically binds a human IL4Ra protein that comprises a mutation selected from the group consisting of 175V, E400A, C431R, S503P. Q576R and S752A in SEQ ID NO; 67; wherein the ligand comprises a human gamma-4 heavy chain constant region that comprises a Leu at position 189 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73 and wherein said human comprises (i) an IGHG4*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-4 heavy chain constant 222 regions comprising a Leu at position 189 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73; and wherein (ii) said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of 175V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67.

In an alternative, clause 1 provides:A method of targeting IL4Ra in a human, the method comprising administering to said human a ligand (eg, an antibody or antibody fragment) that specifically binds a human IL4Ra protein that comprises a mutation selected from the group consisting of 175V, E400A, C431R, S5O3P, Q576R and S752A in SEQ ID NO; 67: wherein the ligand comprises a human gamma-4 heavy chain constant region that comprises a Leu at position 189 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73 and wherein said human comprises (i) an IGHG4*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-4 heavy chain constant regions comprising a Leu at position 1 89 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73; and wherein (ii) said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R. S503P. Q576R and S752A in SEQ ID NO: 67.

In an example, the human is suffering from or at risk of an IL4Ra-mediated disease or condition. In an example, the method treats or reduces the risk of an IL4Ra-mediated disease or condition in the human.

In an example of the method or ligand of the invention, the IL4Ra comprises mutation 175 V.

In an example of the method or ligand of the invention, the IL4Ra comprises mutation E400A.

In an example of the method or ligand of the invention, the IL4Ra comprises mutation C43 1R, In an example of the method or ligand of the invention, the IL4Ra comprises mutation S503P.

In an example of the method or ligand of the invention, the IL4Ra comprises mutation Q576R.

In an example of the method or ligand of the invention, the IL4Ra comprises mutation S752A. 2. The method of clause 1, wherein the IL4Ra comprises mutations 175 V and Q576R in SEQ ID NO: 67 and optionally the disease is asthma. 223 3. The method of clause I or 2, wherein the nucleotide sequence of (ii) comprises nucleotide mutation -3223T (dB SNP numbering). 4. The method of any preceding clause, wherein said human gamma-4 heavy chain constant region that comprises SEQ ID NO: 73.

. The method of any preceding clause, wherein the human expresses antibodies comprising human IGHG4*01 heavy chain constant regions. 6. The method of any preceding clause comprising, before said administering, selecting a human comprising said nucleotide sequence of (ii), wherein tlie human is tlie human of clause 1. 7. The method of any preceding clause, wherein the human has been determined to comprise the nucleotide sequence that encodes an lL4Ra protein comprising said mutation selected from the group consisting of 175V, E400A, C431R, S503P. Q576R and S752A in SEQ ID NO: 67 and/or an !L4Ra protein comprising said mutation selected from the group consisting of 175V. Ε400Λ. C431R, S503P, Q576R and S752A in SEQ ID NO: 67. 8. The method of any preceding clause, comprising tlie step of determining that the human comprises (a) the nucleotide sequence that encodes an IL4Ra protein comprising said mutation selected from the group consisting of 175V, E400A, C43 1 R, S503P, Q576R and S752A in SEQ ID NO: 67 and/or (b) an IL4Ra protein comprising said mutation said mutation selected from the group consisting of 175V, E400A, C43 IR, S503P, Q576R and S752A in SEQ ID NO: 67, optionally, wherein the determining step is performed before administration ofthe antibody to tlie human. 9. The method of clause 8, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a lL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A. C43 1 R, S503P, Q576R and S752A in SEQ ID NO: 67.

. The method of clause 9, wherein the assaying comprises contacting the biological sample with at least one oligonucleotide probe comprising a sequence of 224 at least 10 contiguous nucleotides of a nucleotide sequence encoding an IL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S5O3P, Q576R and S752A in SEQ ID NO: 67 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation selected from the group consisting of 175V. E400A, C43 1 R, S503P. Q576R and S752A in SEQ ID NO: 67. thereby forming a complex when at least one nucleotide sequence encoding the IL4Ra protein comprising said mutation selected from the group consisting of 175V. E400A. C431R, S503P, Q576R and S752A in SEQ ID NO: 67 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL4Ra protein comprising said mutation selected from the group consisting of 175V, E400A, C43 1R, S503P, Q576R and S752A in SEQ ID NO: 67.

I I. The method of clause 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. 12. The method of clause 9 or 1 1, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 13. The method of any preceding clause, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL4Ra protein comprising said mutation selected from the group consisting of 175 V, E400A, C43 1 R, S503P, Q576R and S752A in SEQ ID NO: 67. optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 68. or said human is indicated as homozygous for a nucleotide sequence encoding the lL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67. 14. The method of any preceding clause, wherein said human is or has been further determined to be substantially resistant to an asthma treatment.

. The method of any preceding clause, wherein said human is receiving or has received an asthma treatment or has reduced responsiveness to an asthma treatment. 225 16. The method of any preceding clause, wherein said disease or condition is an inflammatory disease or condition; an atopic disease or condition; a respiratory disease or condition; a disease or condition associated with elevated IgE; or a disease or condition associated with elevated IL-4 and/or IL-13 activity. 17. The method of any preceding clause, wherein said disease or condition is selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia. environmental lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of the mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis, aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis, pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X, pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis. 18. The method of any preceding clause, wherein said human has been diagnosed with at least one condition selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia, environmental lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of the mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis, aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis, pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X, pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease. 226 rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis. 19. The method of any preceding clause, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia, environmental lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of the mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis, aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontubercuious mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis, pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X, pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis . The method of any preceding clause, wherein the nucleotide sequence comprises one or more SNPs selected from the group consisting of rsl 805010. rsl 80501 1, rsl805012, rs 1 805015. rsl 801275 and rs 1805016. 21. The method of any preceding clause, wherein said antibody or antibody fragment is administered by inhaled, intravenous or subcutaneous administration and/or is comprised in an inhalablc or injectable preparation. id="p-887" id="p-887"

[00887] Ligands with Constant Region Tailoring 1, A ligand (eg, an antibody or antibody fragment) for use in a method of treating or reducing the risk of an IL4Ra-mediated disease or condition (eg, asthma) in a human in need thereof, wherein the ligand specifically binds a human IL4RA protein that comprises a mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67: wherein (i) the ligand comprises a human gamma-4 heavy chain constant region that comprises a Leu at position 189 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73 227 and wherein said human comprises (i) an 1GHG4*O1 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-4 heavy chain constant regions comprising a Leu at position 189 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73; and wherein (ii) said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of 175V, E400A, C43 IR, S503P. Q576R and S752A in SEQ ID NO: 67.

In an alternative, paragraph 1 provides:A ligand (eg. an antibody or antibody fragment) for use in a method of targeting IL4Ra in a human, wherein the ligand specifically binds a human IL4RA protein that comprises a mutation selected from the group consisting of 175 V, E400A. C43 1 R. S503P. Q576R and S752A in SEQ ID NO: 67; w herein (i) the ligand comprises a human gamma-4 heavy chain constant region that comprises a Leu at position 189 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73 and wherein said human comprises (i) an IGHG4*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-4 heavy chain constant regions comprising a Leu at position 189 shown in SEQ ID NO: 73 or an Arg at position 289 shown in SEQ ID NO: 73; and wherein (ii) said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A. C431R, S503P, Q576R and S752A in SEQ ID NO: 67.

In an example, the human is suffering from or at risk of an IL4Ra-mediated disease or condition. In an example, the method treats or reduces the risk of an IL4Ra-mediated disease or condition in the human. 2. 'fhe ligand of paragraph 1. wherein the IL4Ra comprises mutations I75V and Q576R in SEQ ID NO: 67 and optionally the disease is asthma. 3. The ligand of paragraph 1 or 2, wherein the nucleotide sequence of (ii) comprises nucleotide mutation -3223T (dB SNP numbering). 228 4. The ligand of any preceding paragraph, wherein said human gamma-4 heavy chain constant region that comprises SEQ ID NO: 73.

. The ligand of any preceding paragraph, wherein the human expresses antibodies comprising human IGHG4*0l heavy chain constant regions. 6. The ligand of any preceding paragraph, said method comprising, before said administering, selecting a human comprising said nucleotide sequence of (ii), wherein the human is the human of paragraph 1. 7. The ligand of any preceding paragraph, wherein the human has been determined to comprise the nucleotide sequence that encodes an IE4Ra protein comprising said mutation selected from the group consisting of 175 V, E400A. C431R, S503P. Q576R and S752A in SEQ ID NO: 67 and/or an IL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A. C431R. S503P, Q576R and S752A in SEQ ID NO: 67. 8. The ligand of any preceding paragraph, said method comprising the step of determining that the human comprises (a) the nucleotide sequence that encodes an IL4Ra protein comprising said mutation selected from the group consisting of 175 V, E40GA, C43 1R, S503P, Q576R and S752A in SEQ ID NO: 67 and/or (b) an IL4Ra protein comprising said mutation said mutation selected from the group consisting of I75V. E400A, C431 R, S5O3P, Q576R and S752A in SEQ ID NO: 67. optionally, wherein the determining step is performed before administ ration of tiie antibody to the human. 9. The ligand of paragraph 8. wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL4Ra protein comprising said mutation selected from the group consisting of 175V, E400A, C43 1R. S5O3P. Q576R and S752A in SEQ ID NO: 67.

. The ligand of paragraph 9, wherein the assaying comprises contacting the biological sample with at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding an IL4Ra protein comprising said mutation selected from the group consisting of 175 V, E400A, C431R, S503P, Q576R and 229 S752A in SEQ ID NO: 67 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation selected from the group consisting of 175V, E400A, C431R, S503P. Q576R and S752A in SEQ ID NO: 67. thereby forming a complex when at least one nucleotide sequence encoding the IL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A. C431R, S503P, Q576R and S752A in SEQ ID NO: 67 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A. C431R. S503P, Q576R and S752A in SEQ ID NO: 67. 11. The ligand of paragraph 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. 12. The ligand of paragraph 9 or 1 1. wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human, 13. The ligand of any preceding paragraph, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL4Ra protein comprising said mutation selected from the group consisting of 175V. E400A. C431R, S503P, Q576R and S752A in SEQ ID NO: 67, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 68. or said human is indicated as homozygous for a nucleotide sequence encoding the IL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A.

C43 1 R, S5O3P, Q576R and S752A in SEQ ID NO: 67. 14. The ligand of any preceding paragraph, wherein said human is or has been further determined to be substantially resistant to an asthma treatment.

. The ligand of any preceding paragraph, wherein said human is receiving or has received an asthma treatment or has reduced responsiveness to an asthma treatment. 230 16. The ligand of any preceding paragraph, wherein said disease or condition is an inflammatory disease or condition; an atopic disease or condition; a respiratory disease or condition; a disease or condition associated with elevated IgE; or a disease or condition associated with elevated IL-4 and/or IL-13 activity. 7. The ligand of any preceding paragraph, wherein said disease or condition is selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia. environmental lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of the mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis, aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis, pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X. pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis. 8. The ligand of any preceding paragraph, wherein said human has been diagnosed with at least one condition selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia, environmental lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of the mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory' distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis, aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis, pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X. pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease. 231 rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis. 19. The ligand of any preceding paragraph, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia. environmental lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of the mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis, aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis, pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary' embolus, pulmonary inflammation, pulmonary histiocytosis X, pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis . The ligand of any preceding paragraph, wherein the nucleotide sequence comprises one or more SNPs selected from the group consisting of rs 1805010. rsl 80501 1, rsl 805012, rsl 80501 5, rsl 80 3 275 and rsl80501 6. 21. The ligand of any preceding paragraph, wherein said antibody or antibody fragment is for inhaled, intravenous or subcutaneous administration and/or is comprised in an inhalable or injectable preparation. id="p-888" id="p-888"

[00888] In an example of any other example or embodiment, clause or paragraph relating to lL4Ra. the IL4Ra mutation is 75 V and the human is of AFR or ASN ancestry, eg, the ancestry' of the human is selected from ASW, LWK, CHS or JPT. All of these ancestries have greater than the average of 47% frequency for 75V. |00889] In an example of any other example or embodiment, clause or paragraph relating to IL4Ra, the lL4Ra mutation is 400A and the human is of AFR ancestry, eg, the ancestry of the human 232 is selected from ASW, LWK and YRI. All of these ancestries have greater than the average frequency for 400A. id="p-890" id="p-890"

[00890] In an example of any other example or embodiment, clause or paragraph relating to IL4Ra, the IL4Ra mutation is 431R and the human is of AFR or AMR ancestry, eg, the ancestry of the human is selected from YRI, CLM, MXL, PUR or CEU. All of these ancestries have greater than the average frequency for 43 IR. 100891] In an example of any other example or embodiment, clause or paragraph relating to IL4Ra. the IL4Ra mutation is 752A and the human is of AFR ancestry, eg, the ancestry of the human is selected from ASW. LWK and YRI. All of these ancestries have 37-39% frequency, which is greater than the average frequency for 752A. 100892] Frequencies are with reference to the 1000 Genomes database (version 2011 052 1) here. id="p-893" id="p-893"

[00893] In an example of any other example or embodiment, clause or paragraph relating to lL4Ra. the IL4Ra mutation is 75V and the human is of AFR or ASN ancestry, eg, the ancestry of the human is selected from ASW, LWK, CHS or JPT. Allof these ancestries have greater than the average of 47% frequency for 75V. |00894] [00895] 233 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 (TS1) 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 (KFIV) Chinese in Denver. Colorado (CHD) (pilot 3 only) West African ancestry Yoruba in Ibadan. Nigeria (YRI) Luhya in Webuye, Kenya (LWK) Gambian in Western Division. The Gambia (GWD) Malawian in Blanlyre, 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) 234 Population 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 Punjabi in Lahore, Pakistan 235 Table 5: TOIs & Related Diseases, Conditions and Example Ligands Human TOI Example Disease or Condition Example Ligand 11-17a Inflammatory Disease Uveitis Rheumatoid Arthritis Psoriasis AIN457 Ixekizumab Angiotensin II Receptor Type 1 (ATi) Hypertension LCZ696 Neprilysin Hypertension LCZ696 Metabotropic Glutamate Receptor 5 (Mglur5) Fragile X Syndrome AFQ056 Mavoglurant A Histone Deacetylase Cancer. Eg. Multiple Myeloma LBH589 ί Panobinostat Diacylglycerol acyltransferase-Ι (DGAT-1) Familial Chylomicronaemia Syndrome I.CQ908 Pradigastat Smoothened (Smo) Basal cell carcinoma Solid tumour Myelofibrosis Medulloblastoma Solid tumour LDE225 Smoothened (Smo) receptor Basal ceil carcinoma Solid tumors LEQ506 ALK Non small cell lung carcinoma (NSCLC) LDK378 phosphatidyl inositol-3-kinase (P13K) m'lOR A KT Cancer, eg. solid tumour. breast cancer. Renal celt carcinoma (RCC). Endometrial cancer, Nonsmall cell lung cancer (NSCLC), prostate cancer, Glioblastoma multiforme (GBM) CRPC BKM120 236 GIST Myelofibrosis mTOR PI3K AKT Cancer, eg, solid tumour, breast cancer. Renal cell carcinoma (RCC), Endometrial cancer, Nonsmall cell lung cancer (NSCLC), prostate cancer. Glioblastoma multi forme (GBM) CRPC GIST Myelofibrosis BEZ235 Ρ13Κα mTOR P13K AKT Cancer, eg, solid tumour, breast cancer, Renal cell carcinoma (RCC). Endometrial cancer, Nonsmall cell lung cancer (NSCLC), prostate cancer. Glioblastoma multiforme (GBM) CRPC GIST Myelofibrosis BYL719 Mitogen-activated ERK kinase 1 (MEK1) Mitogen-activated ERK kinase 2 (MEK2) Cancer, eg, solid tumour. melanoma, pancreatic, colon, lung or thyroid cancer Metastasis MEK162 protein kinase Acute myeloid leukemia PKC412 protein kinase C FLf-3 c-KIT (AML) Myelodysplastic syndrome (MDS) Aggressive systemic mastocytosis (ASM) Midostaurin ActRIlB Sporadic inclusion body BYM338 237 myositis (sIBM) bimagrumab CD19 • Cancer, eg, Leukaemia, mast cell leukemia. Acute Lymphoblastic Leukemia, Chronic lymphocytic leukemia (CLL) or Hematological tumors CTLO19 (formerly CART- 19) 11 β-hydroxylase Cushing's syndrome LCI699 BRAE Cancer, eg, melanoma LGX818 Receptor Tyrosine Kinase FGFR • Cancer, eg, solid tumour • Breast Cancer • Endometrial cancer • Hepatocellular carcinoma • Renal cell carcinoma (RCC) • Bladder cancer • multiple myeloma (MM), hepatocellular carcinoma • endometrial cancer TKI258 (formerly CHIR- 258) Dovitinib DAC enzyme hematologic malignancy Multiple myeloma MyeEodysplastic syndrome (MDS) Myelofibrosis LBH589 panobinostat HSP90 • Cancer, eg, Breast Cancer, gastric AUY922 238 • cancer or Non - small cell lung cancer (NSCLC) FGFR • Cancer, eg, solid BGJ398 tumour • Breast Cancer i • Endometrial cancer • Hepatocellular carcinoma • Renal cell carcinoma (RCC) • Bladder cancer • multiple myeloma (MM), hepatocellular carcinoma • endometrial cancer clAPl • Cancer, eg, solid LCL161 cIAP2 tumour • Breast Cancer Endometrial cancer • Hepatocellular carcinoma • Renal ceil carcinoma (RCC) • Bladder cancer • multiple myeloma (MM), hepatocellular carcinoma • endometrial cancer Akt « Cancer, eg, Solid GDC-0068 tumour, gastric cancer(eg, castration-resistant RG7440 239 prostate cancer), prostate cancer, gastroesophageal junction cancer CD22 Hematologic malignancies Non-Hodgkin's lymphoma (eg, relapsed or refractory follicular non-Hodgkin's lymphoma) Diffuse large B-ecll lymphoma (eg. relapsed or refractory diffuse large B- cell lymphoma) DCDT2980S RG7593 CD79b Hematologic malignancies Non-Hodgkin's lymphoma (eg, relapsed or refractory follicular non-Hodgkin's lymphoma) Diffuse large B-cell lymphoma (eg, relapsed or refractory diffuse large B- cell lymphoma) DCDS4501A RG7596 endothelin B receptor (ETBR) Melanoma, eg. metastatic or unresectabJe melanoma DEDN6526A RG7636 HFR3 Cancer, eg, metastatic epithelial tumour, metastatic squamous cell carcinoma of the head and neck cancer, metastatic colorectal cancer MEIID7945A RG7597 1 EGFR Cancer, eg, metastatic epithelial tumour, metastatic squamous cell carcinoma of the head and neck cancer, metastatic MEHD7945A RG7597 Necitumumab 240 colorectal cancer MUCI6 Cancer, eg, ovarian cancer DMUC5754A (eg, platinum-resistant ovarian cancer) RG7458 sodium-dependent phosphate transport protein Cancer, eg, metastatic non- DNIB0600A 2b (NaPi2b) squamous non -small cell lung cancer, ovarian cancer (eg, platinum-resistant ovarian cancer) RG7599 PDL1 (programmed death ligand 1) Cancer, eg, solid tumour MPDL3280A metastatic melanoma RG7446 non-small cell lung cancer STEAP1 (six-transmembrane epithelial Cancer, eg, prostate cancer DSTP3086S antigen of the prostate 1) (eg, metastatic castration- resistant prostate cancer) RG7450 Bcl-2 Cancer, eg, leukaemia (eg, GDC-0199 chronic lymphocytic leukaemia), non-Hodgkin's lymphoma RG7601 Checkpoint kinase 1 (ChKl) GDC-0425 Cancer, eg, solid tumour, refractory solid tumour or RG7602 lymphoma GDC-0575 RG7741 mitogen activated protein kinase kinase GDC-0973 (MAPKK) Cancer, eg. solid tumour. RG7421 Cobimetinib melanoma (eg. metastatic MEK GDC-0623 melanoma) RG7420 epidermal growth factor domain-like-7 Cancer, eg, colorectal Parsatuzumab (EGFL7) cancer (eg, metastatic MEGF0444A colorectal cancer), NSCLC RG74I4 phosphatidylinositol-3-kinase (PI3K) Cancer, eg, prostate cancer, GDC-0032 renal cell carcinoma, RG7604 endometrial cancer, breast 241 cancer (eg, HER2-negative metastatic breast cancer, metastatic hormone receptor-positive breast cancer), solid tumour GDC-0084 RG7666 Pictilisib GDC-0941 RG732I ml OR Cancer, eg, prostate cancer, G DC-0980 TORC1 TORC2 PI3K renal cell carcinoma, endometrial cancer, breast cancer (eg, HER2-negative metastatic breast cancer, metastatic hormone receptor-positive breast cancer), solid tumour RG7422 IL17 Autoimmune disease Ankylosing spondylitis: Asthma; Multiple myeloma; Multiple sclerosis; Polymyalgia rheumatica; Psoriasis; Psoriatic arthritis: Rheumatoid arthritis: Uveitis Secukinumab ixekizumab M1 prime segment of membrane IgE Allergic Asthma Quilizumab ·, MEM PI 972A RG7449 IFN alpha Autoimmune disease Systemic lupus erythematosus Rontalizumab PCSK.9 (proprotein conveilase subtilisin/kexin coronary heart disease MPSK3169A type 9) (CHD) or high risk of CHD hyperlipidaemia hypercholesterolaemia stroke atherosclerosis a cardiovascular disease or RG7652 242 condition a condition associated with elevated LDL Vascular Endothelial Growth Factor-A Diabetic Macular Edema EYLEA® (VEGF-A) (DME), Branch Retinal Vein Aflibercept AVAST1N™ Placental Growth Factor (P1GF) Occlusion (BRVO) Wet age-related macular LUCENTIS™ degeneration (Wet AMD) IL-6 receptor Inflammatory disease, eg, rheumatoid arthritis Uveitis (eg, non-infectious uveitis) Ankylosing spondylitis; Sarilumab REGN88 Cancer PCSK9 (proprotein convertase subtilisin/kexin coronary' heart disease Alirocumab type 9) (CHD) or high risk of CHD hyperlipidaemia hypercholesterolaemia stroke atherosclerosis a cardiovascular disease or condition a condition associated with elevated LDL· REGN727 LY3015014 NGF Osteoarthritis Fasinumab Pain REGN475 IL-4 receptor alpha Allergic asthma eosinophilic asthma Dupilumab REGN668 IL-13 receptor Atopic dermatitis delta-like ligand-4 (DI14) Cancer Enoticumab REGN421 angiopoietin-2 (Ang2) Cancer Nesvacumab REGN910 GDF8 Metabolic disorder cancer, obesity, diabetes, REGN1O33 LY2495655 243 arthritis, multiple sclerosis, muscular dystrophy, amyotrophic lateral sclerosis, Parkinson's disease, osteoporosis. osteoarthritis, osteopenia. metabolic syndromes (including, but not limited to diabetes, obesity, nutritional disorders, organ atrophy, chronic obstructive pulmonary disease and anorexia) Disuse muscle atrophy cancer-related cachexia ERBB3 Cancer REGN1400 angiopoietin-1 (Angl) angiopoietin -1 (Ang2) Cancer, eg. ovarian cancer AMG386 VEGF receptor PDGF receptor Stem celt factor receptor Cancer NSCLC Breast cancer Thyroid cancer Motesanib AMG 706 type 1 insulin-like growth factor receptor (1GF1R) Cancer Breast cancer Pancreatic cancer Gaiiitumab Linsiti ni b ASP7487 hepatocyte growth factor (HGF) Cancer Breast cancer Pancreatic cancer Rilotumumab HER3 ErbB3 Cancer Breast cancer Pancreatic cancer AMG 888 U3-1287 ί IL-1 7 receptor Inflammatory disease Asthma Psoriasis AMG 827 brodalumab sclerostin Bone-related condition AMG 785 244 postmenopausal osteoporosis fracture healing CDP7851 glucokinase Diabetes AMG 151 ARRY-403 PCSK9 (proprotein convertase subtilisin/kexin coronary heart disease AMG 145 type 9) (CIID) or high risk of CHD hyperlipidaemia hypercholesterolaem ia stroke atherosclerosis a cardiovascular disease or condition a condition associated with elevated LDL Evolocumab VLA 2 Inflammatory bowel SAR3 39658 Integrin α.2β 1 disease IL-4 Idiopathic pulmonary SAR156597 IL-13 fibrosis lysophosphatidic acid receptor LPA-l LPA-3 Systemic sclerosis fibrosis SARI 00842 Androgen receptor Cancer, eg. prostate cancer. MDV3IOO breast cancer enzalulamide HER1 Erlotin ib EGFR Cancer, eg, NSCLC ERBITUX™ VECTiBIX™ VEGF receptor 1 V EGF receptor 2 VEGF receptor 3 Cancer, eg, colorectal cancer, breast cancer ASP4I30 tivozanib JAR Inflammatory disease, eg, ASP015K JAK1 rheumatoid arthritis Baricitinib JAK2 Diabetic nephropathy CD40 Prevention of organ transplant rejection ASP1240 GnRH Endometriosis ASP1707 245 Cancer, eg, prostate cancer degarelix PDE9 Lower unirary tract symptoms associated with benign prostatic hyperplasia ASP4901 TNF alpha Inflammatory disease, eg, rheumatoid arthritis, psoriasis, chrohn’s disease. IBD Ccrtolizumab pegol Programmed cell death protein 1 Cancer Nivolumab Chronic myelocytic ' MK-3475 leukemia: Hepatitis C virus infection; Hepatocellular carcinoma; Hodgkins disease; Melanoma; Multiple myeloma; NonHodgkin lymphoma; Nonsmall-cell lung cancer; Renal cell carcinoma; Solid tumor; Stage IV melanoma Hepatocyte growth factor MET Cancer Glioblastoma; I Iepatocellular carcinoma; Metastatic colorectal cancer: Metastatic non small cell lung cancer: Metastatic stomach cancel·: Non-small-cell lung cancer onartuzumab Angiopoietin ligand-1 Angiopoietin ligand-2 Tek tyrosine kinase receptor Breast tumor; Cancer: Colorectal tumor; Fallopian tube cancer; Gastrointestinal tumor: Glioblastoma; Hepatocellular carcinoma; Metastatic esophageal cancer; Metastatic trebananib 246 gastrointestinal cancer; Metastatic non small cell lung cancer; Metastatic ovary cancer; Metastatic renal cancer; Ovary tumor; Peritoneal tumor; Transitional cell carcinoma CD37 modulator Lymphocyte function antigen-3 receptor SLAM family member 7 Cancel' Multiple myeloma elotuzumab IL-2 IL-2 receptor alpha Multiple sclerosis daclizumab EGFR Cancer necitumumab Metastatic non small cell lung cancer; Solid tumor IL-5 Asthma; Eosinophilic esophagitis reslizumab B-lymphocyte cell adhesion molecule Inotuzumab CD22 Cancer, eg Acute lymphoblastic leukemia; Follicle center lymphoma; inotuzumab ozogamicin Non-Hodgkin lymphoma; Systemic lupus epratuzumab erythematosus. moxctumomab hairy ceil leukaemia moxelumomab pasudotox 1 1L1 beta Acne vulgaris; Atherosclerosis; Behcets disease; Cardiovascular disease; Dermatomyositis; Insulin dependent diabetes: Multiple myeloma; Osteoarthritis; Paraproteinemia; Polymyositis; Pyoderma gevokizumab 247 gangrenosum; Scleritis; Uveitis CD20 Cancer Ocrelizumab Multiple sclerosis ofatumumab follicular lymphoma (eg, refractory or relapsed) diffuse large B cell lymphoma (eg, relapsed) chronic Ivmphocvtic leukaemia (eg, first line therapy or relapsed) IL-23 Crohns disease; Inflammatory disease; Psoriasis tildrakizumab BAFF Neutrokine alpha Autoimmune disease systemic lupus erythematosus Multiple myeloma vasculitis Belimumab Benlysta™ Tabalumab 1L5 Asthma mepolizumah IL6 Inflammatory disease sirukumab rheumatoid arthritis Lp-PLA2 Atherosclerosis darapladib diabetic macular oedema CCR9 chemokine receptor Inflammatory disease Vercirnon rheumatoid arthritis 248 Crohn’s disease DOPA decarboxylase Parkinson's Disease Patrome Her2 Cancer, eg, gastric cancer. Tyverb™ EGFR breast cancer, head and Tykerb™ neck squamous cell cancer. lapatinib ADP receptor Cardiovascular disease or Brilinta condition Brilique Thrombosis, eg, arterial thrombosis VEGPR Cancer, eg, Caprelsa EGFR medullary thyroid cancer LABA LAMA Respiratory disease or condition.eg, COPD PT003 GFF Factor Xa thromboembolism apixaban Oxelumab 0X40 ligand Asthma Graft-versus-host disease Tremelimumab Ticilimumab ipilimumab CTLA-4 CD152 Cancer, eg, melanoma Autoimmune disease MPDL3280A Cancer, eg, solid tumour. MEDI4736 PD-L1 kidney cancer, lung cancer. melanoma. NSCLC. multiple myeloma Autoimmune disease Nivolumab Cancer, eg, solid tumour. AMP-514 kidney cancer, lung cancer. AMP-224 PD-1 melanoma. NSCLC, multiple myeloma Autoimmune disease 249 LIGHT TNFSFI4 CD40 ligand JAK Inflammatory disease, eg, rheumatoid arthritis, psoriasis, chrohn’s disease, IBD. ulcerative colitis, Psoriatic Arthritis tofacitinib Nerve Growth Factor Pain tanezumab Osteoarthritis pain Herl receptor Her2 receptor Cancer, eg, Non-Small Cell Lung Cancer dacomitinib Her4 receptor c-MET Cancer, eg, Non-Small Cell crizotinib ALK Lung Cancer Programmed cell death 1 receptor Cancer, eg, renal cell carcinoma Nivolumab SLAMF7 Cancer, eg, multiple Elotuzumab CD319 myeloma CD30 Cancer, eg, Hodgkin lymphoma, systemic Brentuximab anaplastic large cell lymphoma, T-cell Brentuximab vedolin lymphoma GPR40 Diabetes, eg. diabetes Fasiglifam DPP-4 mellitus trelagl ipti n VEFGR-1 receptor VEFGR-2 receptor Cancer, eg. non-squamous Motesanib VEFGR-3 receptor PDGFR cK.it non-small cell lung cancer Motesanib diphosphate amyloid β Alzheimer's disease Solanezumab TNF alpha Inflammatory disease, eg. SIMPONI™ rheumatoid arthritis. HDMIRA™ psoriasis, chrohn’s disease. REMICADE™ IBD, ulcerative colitis, ENBREL™ 250 Psoriatic Arthritis Adalimumab IL-21 Autoimmune disease or condition Agonist or antagonist antibody specific for human IL-21 Inflammatory disease or NNC01 14-0005 condition NNC0114-0006 Rheumatoid arthritis Crohn's disease NN8828 IBD Ulcerative colitis AIR-107 Systemic lupus erythematosus (SLE) Said or an anti-IL-21 antibody in combination with an agent selected from Graft versus host disease the group consisting of ipilimumab (eg, to treat Cancer Metastatic melanoma Renal cell carcinoma Melanoma Solid tumours Acute myeloid leukaemia Non-Hodgkin's lymphoma Ovarian cancer Colorectal cancer melanoma), an anti-PDl antibody (eg, to treat solid tumours), sunitinib (eg. to treat renal cell carcinoma). rituximab (eg. to treat Non- Hodgkin’s lymphoma). I sorafenib (eg. to treat renal cell carcinoma). doxorubicin (eg. Io treat ovarian cancer) and cetuximab (eg, to treat colorectal cancer). 251 Table 6: PCSK9 SEQUENCES 252 253 254 255 256 257 258 259 260 261 Γ'ί fc FJ fc ci cj <-·» fc tv Cj tr fc Cj s ID l·' C.9 Γ ) f 1 Fl n| C’ c,)| C> F-i H C) CJ rn d ΓτΕ f) tn H r.n C.n F-r r j cn I C rn cn r lj rn I -if F-E C J ci; C'J CJ $ C ) d F-i m c; C ) d cj c j CJ rn c.n Fi C 3 d 1 1* Fi cn d d c j Fi d 'ii Fi Fi cj C) cn m cj H F-i d rn Ci d ή it d d n CJ Cj Frl Μ in F-i r-i O () CJ CJ d Fl C) CJ c cj F-i r.n cj Π d rn it C) CJ ri Cj CJ 'd f) CJ ' t d d Γ-Ι C 1 c) ft Γ-Ι cj CJ tn cj cj d rn cj d CJ F-r it i,n F-J CJ cj ft C in cj d o F-i in cn r-lj r lj CJ Cl ft c.n d d o ,? π: η kO [> CM £ ‘ r< Γι7 t—I r-t m tot ΟΊ <11 ΣΣ1 Ό ΓΊΤ Φ cC C O ► ί[ s d rn m ll H-, 'U'l rn I1 ο 7Z o dU C* C ™ i'll -Β C i_i Tj ·ϊΊ CO I— c_ co /··'·: F;i tj Cj Cj Cj Cj VI V3 CJ C> U '-to Cto tT Fl n Fi cn tJ CJ cn Cj Ci t1) »-t C ] F-i C ) Cl d in C J 1-1 tj Ci CJ nt Cj Π Cl Ci d i'l H *d in n f J fi! tj F-i in o tj rn cn F-i CJ CJ d tl> ft d d ih C 3 Γ-Ι C j I·' C C) C J C j f) r n CJ F-i F tl d F-i C 3 I rn r j C ) C) tn C1 tn cl Π F-h t'l t'J C ) f j 1 1 F-i c 1 c Ϊ c ) CJ cn C i J n Π c 3 Fi in Fl f) r-i in cn cn CJ cj tn C) Π ' i, ft i „1 1 I in m ω C 3 C r n c C 3 F-i η m in cn CJ tn Ci tj d Fi -i! CJ C j it □ΙΪ L ϋ;. -0 □ll l_l till V. <· Ό -73 O G ‘C O NUCLEOTIDE SEQUENCES w u >11 :4 s ί ς- C Φ rjj J cr rr rn Ll Φ •H L| ;ί Cl CJ Ξ5 C < o C£l 111 Cl.

CL 262 263 TCCCGGCCCCTCAGGAGCAGC-TGACCGTGGCCTGCGAGGAGCC-CTCGACCCTGACTC-GCTGCAGTGCCCTCC 264 265 266 267 268 269 270 271 Table 7: Human VH3-23 Variant Alleles SNPs rs61750837 rs61752504 Os Os r- un un o | r$61752504 rs61750837 rs 1064090 Os O' r- un un O VI Qs o tot SO o ω u, rs 1064091 rs 1064090 Os oo & SO o so un to Os 00 Ό· SO o SC un <Λ rs56069819 Os co o·· so o SO un $λ Os co OS so O sO un tZ) Os. co Os SO o so un V) Os 00 Os sO o SO un /3 Cumulative allele frequency 0.0983 0.0087 0.0046 Os O o o o 0.0005 0.0005 0.0005 0.114 VH3-23 haplotype tot o * m rs m X > -σ 3 TOTAL: 272 Table 8: Exemplary anti-PCSK9 antibodies and/or antibody fragments fi .2 « © Ξ e rt c. s © -i— « 51m •n ΓΟΟ CS s CJ ©s © © CZ2 © o Λ . J_ fi ·** © c fi fi c an « fi ox J3 © aft u "© C- c P Λ © © fi «Λ fi o 13 z fi o JO X © O' fi w © Vi E C 9Π — O-— re JP Tt o' £ — re rrf 00 — CS -- CS SO fi — rS L. . ,Tt ci © £? c © o o p CS o t- Γ— CS o „ rs NO Tt oo rs , ΓCS co — cs Tt rs O re , rs ,- ¢7-1 η rs fi 'o « 2 E S 8 σ c ω o o Tt oo Γ CS O re rr ΓΟΟ rs re r η r- rre cs •n in» nF Tt —*' CS '·© o re — — o re r- Tt Tt ‘Eb in Γ—- O'·’ Tt Tt Tt __/ ^-. © c-f <©r ©n — t-' c-‘ CJ N£>4-1 9Π o 00 o CS Ό Tt Tt 0β P-r Tt Tt Tr- c r—» Γ- Γ-rr, Γ— Γ- 'r- n-» no ΟΟ rs re ee «η» rr o CS N© tJ- Tt p o in n re Tt Tt fi n O oo , O·' ,. in re © r ,. p O O in» ©· S re o — n Ti- Tt © Ό Tt N© oo re Tt Τ- re ©n’ >> OO CS r— OO sd η .—, Tt u Tt Ό 00 O — in Tt Tt fi r ,. p CJ Tt it Γ— —. or , ,—, n n © Tt NO oo CJ Tt — — Tt OO E p <© in Tt Tt Tt © o —7 o NO o Γ- CS Tt Tt ©Nr — Q- /-.r. .— CS Γ— O Tt 00 fi oo ΟΟ O' — Tt Tt Tt Tt δ 1—1 η» Γ— CS Tt Tt «J © O NO re Γ— Γ— Γ- o O' t-* Γ- o o' re re re Γ— o re r- fi in r- Ot 1-1 Tt 00 oo n? cs Tt Tt Tt fi co no NO cs Tt Tt Tt ,-1 re CS «η re re η» Γ— ON oo ©N ©N Γ— o re r- X 00 o re Γ- Γ- re cs Tt Tt Tt C2 n Tt cs Tt Tt Tt — re > n Γ- p.rr V— — on O fi Qr. p. 00 NO •n n NO rs Γ- o cs NO © C_) Tt cs Γ- o re r- re cs re Tt Tt X n C’ cs Tt Tt Tt 273 SEQ ID NOs comprising an anti-PCSK9 Patent or patent Pblication monoclonal antibody or fragment thereof < On S© Γ— c Cd o o Cd O ci JQ ni CO cd SO ΓΟΟ SO oo on ο Cd rn r-f , It m Cd r- o it — , on , It — f— on m Cd r- Qs —1 0Π on o o c Os rn m it ,— MJ <-O ·—1r. onr. r.r, 00 SO c r- Cd Cd o SO 00 mr. p. on r so SO itf on on T-t· o Cd it O sO 00 if cd on it it rn SO Os( Cd it so 00' sO 00 n{ it It r r c m o c Cd t— It o Cd vj- c- SO oo Mlr , ’—' it r r Cd Cb- it o δ Cd m 00 on δ z SO co oo cf Cd it Cd m it on c- Q Qr o [-f m r—- od O o Cd rn ’-f a LU on r- it LU cf so sO C rn on c- 00 -J co On It X on so o it —C rn on Γ- so’ o Q rn of O Q it if U rn it (J on it Cd un rn IC rn ci r- it o it O on c r ,—· it p r—« rn Cd Γ- OS p. on on r. o o os O m it — MJ OO ,, C- on r- co SO c C- cd Cd it O on so oo rn SO if on on SO o C| It ©S so oo it p. . c ^t it r· <- it Cl on rn Ό cf Cl It so oo sO oo — it It r If- m o cr Cd --- cd r- SO OO it of ci cf it it o o it j· Cl rn cf sO oo f onr cd ,—. 00 —· z OOr OS —' Q Cd rn it a on c- it co c rn C oo O σ Cd rn it o on c- It uu OS Ό* U-l so c p CZ) m -—' on Γ- OO -J 00 on It X on sc o it C4 rn a! on c r. a r~f m cf O a if It SO o o rn it <_> on c it 274 c w to Ξ ftK +-» c to G to w Λ Cfi < © ΓO' o CM o © CM CM CZ? < GO © CM go o o ΓΟ O CM ND ON ii! U Cl, fin O to fi to -fi s to fi 0£ Λ ώ o ’o o © Λ S3 « 0£> >s ‘3S X Cl ε c to fi Vj P « Z fi P O' W Z> OO CM © CM oT CM ro CM CM CM O'.

CM CM CM CM . · CM Hd oT oT .- GO θΤ — θΤ θΤ CM CO OT — OT oT d oT O θΤ o ro rO © CM o .

UI o Q d o CO © ,- or © ΓΟ <-O ,· © GO Ό ro , oo ro ro ro CM d CM θΤ Γ’Ί r- CM GO — ,—1 CM r- © '-Or f. o © © 00 NO p r- d d © <00 NO p p NO NO o © oo orr oT d O0 © oo θΤ r ,- CM d © 00 OTr. „ © o d © oo z 00 d Q NO Γ- — d ΟΟ σ NO r- uu © d y> NO r- X d d c4 o Γ- □ d d to NO r- © OT d CM oT © OT o or © © or or © or d © CM d go CM GO co CM o’ d d GO o z Q O UJ GC J cd Ω O f p or CM , p CM © rO Γ-rO C- orr. o 1/Ί P . r- © — — ro ro CM c- ON COr d GO r or O © . Γ P d © p ro © GO —i NO 00 ro p OO GO p nO 00 ©’ © c- γ- or CM © d NO οο p p p GO GO O\ © © © P d GO GO CM © © O' NO 00 orr p p or p .. © CM — P or ro NO CM © © 00 NO OO © or p p oT ro p CM •-1 p CM © r- d NO 00 orr p —™ or , ,— CM © or o d oT CM ro p r—-. M0 00 p GO 'o' CM .— 00 >—. z oo d — CM ro © Q GO r~ d d ro d oo' © CM ro or O GO Γ- or d M0 p UJ d d ro 1-- (Z> GO Γ- oor. p — p © 00 IO or X GO NO or — ro p cd GO Γ- p. p p. © co p p ·© r- ro o 1—1 or cT © —· ro or U GO Γ- or 275 SEQ ID NOs comprising an anti-PCSK9 T Patent or patent Pblication monoclonal antibody or fragment thereof I o C O' co CM cz> < r— & rCC CM CM CM tot C- tot cd CM CM o CM p Γ- p CM o Ό re r- re r- tot no re r- tot re I-- tot re o LCr. p . f p o ,- LC Γ r --- tot 1-. Ί-' re ,—1 tot re p — *— OO re CM c- o oc re P Γ- CM r- O' o C C p tot LC tot LC p re o o c/ p o o p O' O' p re tot LC V*— KO 00 re cc tot C 1-- NO 00 c oo LC p p NO p p o LC , P Γ— QQ NO tot c- r- tot oo KO re , C- r- — CM tot o ND oo ,, CM CM tot p o NO oo P C LC p O' p p CM LC ,. P o SO kO LC LC LC KO tot kD p LC LC oo CM tot tot O' NO 00 tot o CM tot On NO OO r—.4, pr p p p P p. tot .- P tot CM ,— tot cc NO tot CM oo p tot re NO CM KO NO oo — CM tot LC oo NO oo — tot tot pr. tot p p — tot P f- tot re O p CM — re o p P CM CM tot r- t-> KJD 00 tot CM tot r- c- KO oo tot ,— tot p. 1-1 ,. p tot p P -— CM ¢/ tot O o tot CM o tot O o tot CM re C o NO 00 cmT o CM re iC o NO oo cm ,—, 00 z oo O' z 0Q ·— oo O' •—1 CM re tot Q LC r- tot n CM re tot Q tc [-- tot O r- cc Γ- oo o o r-i re r-‘ oo o CM re tot o LC tot σ CM re tot a LC r- tot KD ω NO r-r LU On nd' P UJ KO C- P - r re ,—, LC r- cd — re <Λ LC c- oo Lc OC >c tot X LC NO 40 »4 od LC tot X C NO o tot Γ- tot re oi LC C~- oi —· re Z LC r- P r-^ re CN O Q tot tot 06 Q c-r re O' o a tot tot MD o r- re tot LC r~ tot o re tot u c r- tot tot 276 SEQ ID NOs comprising an anti-PCSK9 Patent or patent Pblication monoclonal antibody or fragment thereof < ED ED CH © CH © CH or CH CH ED © CD © CH EC .. r στ CH r P CH © X' m r- σ fo σ ED CD o σΤ ED CH Γ- © ED i/Df. © © & © cd CD σΤ -—' NO 00 <·,r. ED e. OO © r- Γ- cH CH σ © NO οο rr ED r. r- © σ ED ED CH σΤ © NO OO σΤ f. f. . <· CH CD © cr CH σΤ cd © oo — OΓ σΤ r r στ p-. CD © CH Γ CH σΤ r— Γ—' © 00 σΤ IjQ r.Γ — dT <- r —- CH ο·· στ © © σΤ δ CH CD ED*' δ © oo ΓΗ z >— QQ --1 z oo' © —· Q rq CD στ o ED Γ- σΤ © Γ—' cd* Γ- ΟΟ ο σ CH CD σΤ σ ED Γ— σΤ to O\ © UJ ©' Γ-’ tZ3 ,-- CD --· ED Γ- οο -1 00 ED σΤ rc ED \£> © στ — CD 5 ED Γ— Q r-^ CD ON © Q σΤ σΤ © Ο O --- CD σΤ U ED Γ- στ © CH CD r-* CD ci Γ— ^T wT o ED f r , « ,-- σΤr •— — CD UD CDf. CH Γ- © OOr ED ED ,r. σΤ © © , Γ-r. cr © CD CD σΤ ED .—. © OO CD OO ED f. © OO © σΤ Γ- Γ- σΤ CH CH σΤr. © © ΟΟ ,.r.f ED EDr. © © σΤ © ED ED ED Ο CH σΤ σΤ © © OO σΤr ,. C. σΤ <. <-· c σΤ ΓΗ --- σΤ CD © CH σΤ © 00 © 00 •—1r. ,, σΤ σΤ r, σΤ [-—. CD © CH ’—1 ί. CH σΤ Γ- r-i’ © OO σΤ tri CH QN σΤ σΤ o' σΤ δ cH CD ED δ © oo CH ζ — ΟΟ ζ OO ©r CH CD σΤ ED Γ- σΤ Q Ωr. θ' Γ- CD1—1 r- 00 Ο*' σ CH CD σ σ ED Γ- σΤ ω CT © m © r-' GO — CD — GO ED r- 00^ J 00 tn σΤ X ED ©' © σΤ c4 .—1 CDr. αί ED Γ-r. Q r-° CD © © Ω xT © © O — CD σΤ Ο ED Γ- σΤ 277 SEQ ID NOs comprising an anti-PCSK9 Patent or patent Pbiication monoclonal antibody or fragment thereof i < < tot cn tot o Os un OO o Un l*- O o o o m m o CN CN GO to — tot nt cn rN CN ,. ci o - m P~~ rto P~- totx,«i rn r~~ m c- tot o >/Ί ,_.c o un .—' tot .— — rn ,—. tot —1 r^, nJ P- Os oo un m Γ ΓΝ P- O' un un O' OS tot ,. un un o' O o o o O' rn nt un SO oo rn m rn tot --- SO 00r 00 un ,-r so un , C oo so tot p- P- tot oo SO P- P- CN tot o SO 00 ,- CN CN tot o SC oo un unrr. OSr. un r so tot so uO un un so tot un un o Cl tot tot Os SO oo tot o CN tot Os SO oo , tot tot tot CN tot rn sO tot CN ,, tot rn SO OS CN tot sO oo SO oo — Os CN tot 00 so 001—· tot tot< p tot ,. c tot ,. tot m O ci tot m O . r- CN — Γ' cN tot C-' p- so 00 CN tot p- P- sO oo tot un c-f O'1' tot tot o o tot un CN Os tot tot o o’ tot δ Cl m un rs, s> SO oo ci o CN m un o SO oo CN oo z od OS z — oo ’—· oo OS- Ci m un c- CN m tot un P- tot n Q f 1c.r Γ. p C Γ- rn1—1 r- oo o' o r- m c- oo O a Cl m tot a un p- tot σ CN rn tot o un P- tot UJ o- so X sO C-' UJ On so U2 so P- p GO cn .—. 00 un t*- oo GO >—< m — cz> un P- OO to QQ un tot X un so o tot _l oo un tot X un so o tot Cd m un t-~- cd --- m cd un Ρ~~ p Q P- m Os o Q tot tot 06 Ci r- rn Os O Q tot tot so o U rn tot U un p- M- U — m tot sJ un P- tot 278 SEQ ID NOs comprising an anti-PCSK9 Patent or patent Pblication monoclonal antibody or fragment thereof < un m cd on it Cd rn Cd on cdr o’ of cof ό Z □ o ω _] Cd Q O c if cd Cd o rn c rn r— itr o onr — it '— ,— rn ci r- σ on on p p O of σ ο rn it — sO 00 ,- on P oo •c r- Γ- CI It o s© ΟΟ p. on p P SO ifr on on CI It σ sC oo f. it p . f it ci it m sc CI it oO s© 00 »—· p It p P It rn o . p cd 1-· P CI it r- cf sc oo It p. ,. —' it ,. p —' CI σ- it o o It CI τη cn sC oo p p, of1s> p. p. cl .— 00 »— Z OO O’ 1—· CI m it on Γ- it L-1 o C- rn Γ- ΟΟ o CI m It Q όη Γ- it cf sO p -Ij s© c p — m r— on C- oo p,r 1-- I , Pr. o oo ΟΊ it X on \O it rn p Ci! on Γ- P P o Ci p. p sc r- rn o —1 It it o ,—, m it (J on r- It 279 £ a CJ O' Φ Table 9: Human variable & constant variants distributed over several human ethnic populations - useful for ligand tailoring c TO E X rσ οι in (/} O T3 c to ΙΛ C o Q.

O cl + 4-» Φ X 1 0.296 LO LO ON on O d d o tot o co Lf) τΗ ^τ 0 0 LO 02 d d tot d LO to CO c TO Φ Q.

O k_ >> to Φ U C TO c .5 Φ s c O 0 _φ ’to V O 3 Cl z φ ts c ‘M .2 O ‘£3 Φ TO u u- 3 TO z > 0_ z Φ uo MJ _Q c C Φ k CD £ u V z fri U Φ _Q E c LO co o CM L0 O tot τ—ί "Ο c TO +-> in "O TO g £_ o LO o cm NO o t—1 dt TO k+-1 t/Ί T3 t_ TO g L_ o Hl < o| < m LT) OQ LH tot o ί—I to O Ό < o c E < ΙΛ o Q. c o ‘4-» .2 *c TO > Q CO •rt X O tj c-J c -t—1 .TO TO > LU o CM c o TO ‘k.

TO > φ Q.

E to C ro E X Φ _QJ < CO o <3 X ^3 !GHG1*O1 ) 206L 1 CTG 14:106208082 ! A 0.358 | 0.104 0.283 c c TO C Φ Φ Φ £ E O. £ Φ > 3 X U? tXQ Φ ΙΛ H f c X 280 C\l on Γ\Ι ό <3· Γ\Ι LO m m O "C τ-Η c on ω O 4-> t-1 in rH Ό lo O (Ό t—ί 1 r·, Ο U <1 Μ σι in C\J LD cr on ό m on on ό o on o τ—I 3· in Γ9 L9 X CN o * CN cn X cn * r-J X 281 © ο ο ό ο >- σ> ΓΜ U § toi S © © ο ΓΜ t1 TTG Έ ή θ Τ +-* ο ΓΟ > V> L ~ £ 5 .2 ro > Ή LL © θ £ 5 ΓΟ > 76L =τ ο * ΓΊ to X to © Ο * ΓΜ Ο X ο >3· ο * C'J to X to C ο > ΓΟ ΓΟ > IGHG2*01 [ 161V GTG ! 14:10611013 Β I 0.342 0.539 0.711 282 283 Table Footnotes: 1. IMGT notation (ww.imgt.org); refer to figures lor other alleles comprising this variation. 2. SNP Underlined in Codon. 284 un rN < c o O ω (Λ ro o oo rn ro CD cl Z CO jro XJ CD U _>. ro cr o cn QJ CL TO CD V) ro ro a. o CL c ro Ξ ro X ro o δ ro c4 o X <υ Ρ δ χ ο ο _ro <υ Ε Ο ρΰ δ Ο ο ro _Ε > Ο δ' u Dcr <υ co e CJ o _e P δ ro CL o ω 'o ro |—1 ‘δ c-l sO •O> O ro a o CL -TO H Lj< O o _c rn < b/j bi) ro Ό c ro -C ro ro no cn E o ro O © © © ro o δ P < < o © un sO X CO ω co u un so r- ro o ro x o X o o >Ί O δ δ cr ro p cr roc p> Jt> o CL JU ro >% O ro C bi) P ro C -TO ro u E > ro -4-J ro _c Έ P δ 5 O oo σΐ 285 Table 10: FURTHER SEQUENCES SE Q Human Allele Nucleotide/Amino Acid Sequence ID NO HEAVY CHAIN ALLELES 41 i IGHG1*O1 (CH1+Hinge+ CH2+CH3+CHs) gcctccaccaagggcccatcggtcttccccctggcaccctcctccaaga gcacctctggg ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccgg tgacggtgtcg tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcc tacagtcctca ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgg gcacccagacc tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaaga aagttgagccc aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaac tcctgggggga ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatct cccggacccct gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtca agttcaactgg tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggagg agcagtacaac agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaag gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgaga aaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccat cccgggatgag ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatc ccagcgacatc gccgtggagtgggagagcaatgggcagccggagaacaactacaagacca cgcctcccgtg ctggactccgacggctccttcttcctctacagcaagctcaccgtggaca agagcaggtgg cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcaca accactacacg cagaagagcctctccctgtctccgggtaaa 42 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSS GLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL 286 YSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK D=position 204 Imposition 206 43 IGHG2*01 gcctccaccaagggcccatcggtcttccccctggcgccctgctccagga gcacctccgag (CH1+Hinge+ agcacagccgccctgggctgcctggtcaaggactacttccccgaacegg CH2+CH3+CH- tgacggtgtcg S) tggaactcaggcgctctgaccagcggcgtgcacaccttcccagctgtcc tacagtcctca ggactctactccctcagcagcgtggtgaccgtgccctccagcaacttcg gcacccagacc tacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaaga cagttgagcgc aaatgttgtgtcgagtgcccaccgtgcccagcaccacctgtggcaggac cgtcagtcttc ctcttccccccaaaacccaaggacaccctcatgatctcccggacccctg aggtcacgtgc gtggtggtggacgtgagccacgaagaccccgaggtccagttcaactggt acgtggacggc gtggaggtgcataatgccaagacaaagccacgggaggagcagttcaaca gcacgttccgt gtggtcagcgtcctcaccgttgtgcaccaggactggctgaacggcaagg agtacaagtgc aaggtctccaacaaaggcctcccagcccccatcgagaaaaccatctcca aaaccaaaggg cagccccgagaaccacaggtgtacaccctgcccccatcccgggaggaga tgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcg : ccgtggagtgg gagagcaatgggcagccggagaacaactacaagaccacacctcccatgc tggactccgac ggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggc agcaggggaac gtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgc agaagagcctc tccctgtctccgggtaaa 44 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSS GLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPC PAPPVAGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTK PREEQFNSTFR WSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYT LPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKL TVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK 287 P=position 72 N=position 75 F=position 76 V=position 161 A=position 257 45 IGHV1-18*O1 caggttcagctggtgcagtctggagctgaggtgaagaagcctggggcct cagtgaaggtc tcctgcaaggcttctggttacacctttaccagctatggtatcagctggg tgcgacaggcc cctggacaagggcttgagtggatgggatggatcagcgcttacaatggta acacaaactat gcacagaagctccagggcagagtcaccatgaccacagacacatccacga gcacagcctac atggagctgaggagcctgagatctgacgacacggccgtgtattactgtg cgagaga 46 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAP GQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDD TAVYYCAR 47 IGHV1-46*01 caggtgcagctggtgcagtctggggcrgaggtgaagaagcctggggcct cagtgaaggtt tcctgcaaggcatctggatacaccttcaccagctactatatgcactggg tgcgacaggcc j cctggacaagggcttgagtggatgggaataatcaaccctagtggtggta gcacaagctac gcacagaagttccagggcagagtcaccatgaccagggacacgtccacga gcacagtctac atggagctgagcagcctgagatctgaggacacggccgtgtattactgtg cgagaga 48 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAP GQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED TAVYYCAR LIGHT CHAIN ALLELES 49 IGKC*01 cgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagc agttgaaatct ggaactgcctctgttgtgtgcctgctgaataacttctatcccagagagg 288 ccaaagtacag tggaaggtggataacgccctccaatcgggtaactcccaggagagtgtca cagagcaggac agcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaag cagactacgag aaacacaaagtctacgcctgcgaagtcacccatcagggcctgagetcgc ccgtcacaaag agcttcaacaggggagagtgt 50 RTVAAPSVFIFPPSDEQLKSGTASVVCLLWNFYPREAKVQWKVDNALQS GNSQESVTEQD S KDSTYS LS STLTLS KADYEKHKVYACEVTHQGLS S PVTKSFNRGEC V=position 84 exposition 87 51 IGLC2*01 ggtcagcccaaggctgccccctcggtcactctgttcccgccctcctctg aggagcttcaa gccaacaaggccacactggtgtgtctcataagtgacttctacccgggag ccgtgacagtg gcttggaaagcagatagcagccccgtcaaggcgggagtggagaccacca caccctccaaa caaagcaacaacaagtacgcggccagcagctatctgagcctgacgcctg agcagtggaag 1 tcccacagaagctacagctgccaggtcacgcatgaagggagcaccgtgg agaagacagtg gcccctacagaatgttca 52 GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPV KAGVETTTPSK QSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 5 3 IGKV4-l*01 atggtgttgcagacccaggtctteatttctctgttgctctggatctctg gtgcctacggg gacatcgtgatgacccagtctccagactccctggctgtgtctctgggcg agagggccacc atcaactgcaagtccagccagagtgttttatacagctccaacaataaga actacttagct tggtaccagcagaaaccaggacagcctcctaagctgctcatttactggg catctacccgg gaatccggggtccctgaccgattcagtggcagcgggtctgggacagatt tcactctcacc atcagcagcctgcaggctgaagatgtggcagtttattactgtcagcaat attatagtact cctcc 289 54 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLA WYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQQYYST P 55 IGKV1-13*O2 atggacatgagggtccccgctcagctcctggggcttctgctgctctggc tcccagcaggt gccagatgtgccatccagttgacccagtctccatcctccctgtctgcat ctgtaggagac agagtcaccatcacttgccgggcaagtcagggcattagcagtgctttag cctggtatcag cagaaaccagggaaagctcctaagctcctgatctatgatgcctccagtt tggaaagtggg gtcccatcaaggttcagcggcagtggatctgggacagatttcactctca ccatcagcagc ctgcagcctgaagattttgcaacttattactgtcaacagtttaatagtt accctcagtgc cagatgtgccatccagttgacccagtctccatcctccctgtctgcatct gtaggagacag agtcaccatcacttgccgggcaagtcagggcattagcagtgctttagcc tggtatcagca gaaaccagggaaagctcctaagctcctgatctatgatgcctccagtttg gaaagtggggt cccatcaaggttcagcggcagtggatctgggacagatttcactctcacc atcagcagcct gcagcctgaagattttgcaacttattactgtcaacagtttaatagttac cctca 57 IGKJ2*01 tgtacacttttggccaggggaccaagctggagatcaaac 58 YTFGQGTKLEIK 59 IGLJ2*01 tgtggtattcggcggagggaccaagctgaccgtcctag 60 VVFGGGTKLTVL 61 An IGHGl*01 Heavy Chain Constant Region ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV EPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPEWNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 62 An IGKC*01 Kappa Light Chain Constant Region RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV TKSFNRGEC 63 An IGHG2*01 Heavy Chain Constant ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTV ERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTWHQDWLNGK 290 Region EYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 64 An IGLC2*01 Lambda Light Chain Constant Region QPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKT VAPTECS 6 5 An IGHG2*01 Heavy Chain Constant Region ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTV ERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCWVDVSH EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRWSVLTVVHQDWLNGK EYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDK.S RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 66 An IGKC*01 Kappa Light Chain Constant Region RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV TKSFNRGEC HUMAN IL4Ra SEQUENCES 67 Amino Acid Sequence MGWLCSGLLFPVSCLVLLQVASSGNMKVLQEPTCVSDYMSISTCEWKMNGPTNC STELRLLYQLVFLLSEAHTCIPENNGGAGCVCHLLMDDWSADNYTLDLWAGQQ LLWKGSFKPSEHVKPRAPGNLTVHTNVSDTLLLTWSNPYPPDNYLYNHLTYAVN IWSENDPADFRIYNVTYLEPSLRIAASTLKSGISYRARVRAWAQCYNTTWSEWS PSTKWHNSYREPFEQHLLLGVSVSCIVILAVCLLCYVSITKIKKEWWDQIPNPA RSRLVAIIIQDAQGSQWEKRSRGQEPAKCPHWKNCLTKLLPCFLEHNMKRDEDP HKAAKEMPFQGSGKSAWCPVEISKTVLWPESISWRCVELFEAPVECEEEEEVE EEKGSFCASPESSRDDFQEGREGIVARLTESLFLDLLGEENGGFCQQDMGESCL LPPSGSTSAHMPWDEFPSAGPKEAPPWGKEQPLHLEPSPPASPTQSPDNLTCTE TPLVIAGNPAYRSFSNSLSQSPCPRELGPDPLLARHLEEVEPEMPCVPQLSEPT TVPQPEPETWEQILRRNVLQHGAAAAPVSAPTSGYQEFVHAVEQGGTQASAWG LGPPGEAGYKAFSSLLASSAVSPEKCGFGASSGEEGYKPFQDLIPGCPGDPAPV PVPLFTFGLDREPPRSPQSSHLPSSSPEHLGLEPGEKVEDMPKPPLPQEQATDP LVDSLGSGIVYSALTCHLCGHLKQCHGQEDGGQTPVMASPCCGCCCGDRSSPPT TPLRAPDPSPGGVPLEASLCPASLAPSGISEKSKSSSSFHPAPGNAQSSSQTPK IVNFVSVGPTYMRVS l=position 75 E=position 400 exposition 431 S=position 503 Q=position 576 S=position 752 68 Nucleotide Sequence ATGGGGTGGCTTTGCTCTGGGCTCCTGTTCCCTGTGAGCTGCCTGGTCCTGCTG CAGGTGGCAAGCTCTGGGAACATGAAGGTCTTGCAGGAGCCCACCTGCGTCTCC GACTACATGAGCATCTCTACTTGCGAGTGGAAGATGAATGGTCCCACCAATTGC AGCACCGAGCTCCGCCTGTTGTACCAGCTGGTTTTTCTGCTCTCCGAAGCCCAC ACGTGTATCCCTGAGAACAACGGAGGCGCGGGGTGCGTGTGCCACCTGCTCATG GATGACGTGGTCAGTGCGGATAACTATACACTGGACCTGTGGGCTGGGCAGCAG 291 CTGCTGTGGAAGGGCTCCTTCAAGCCCAGCGAGCATGTGAAACCCAGGGCCCCA GGAAACCTGACAGTTCACACCAATGTCTCCGACACTCTGCTGCTGACCTGGAGC AACCCGTATCCCCCTGACAATTACCTGTATAATCATCTCACCTATGCAGTCAAC ATTTGGAGTGAAAACGACCCGGCAGATTTCAGAATCTATAACGTGACCTACCTA GAACCCTCCCTCCGCATCGCAGCCAGCACCCTGAAGTCTGGGATTTCCTACAGG GCACGGGTGAGGGCCTGGGCTCAGTGCTATAACACCACCTGGAGTGAGTGGAGC CCCAGCACCAAGTGGCACAACTCCTACAGGGAGCCCTTCGAGCAGCACCTCCTG CTGGGCGTCAGCGTTTCCTGCATTGTCATCCTGGCCGTCTGCCTGTTGTGCTAT GTCAGCATCAGCAAGATTTVAGAAAGAATGGTGGGATCAGATTCCCAACCCAGCC CGCAGCCGCCTCGTGGCTATAATAATCCAGGATGCTCAGGGGTCACAGTGGGAG AAGCGGTCCCGAGGCCAGGAACCAGCCAAGTGCCCACACTGGAAGAATTGTCTT ACCAAGCTCTTGCCCTGTTTTCTGGAGCACAACATGAAAAGGGATGAAGATCCT CACAAGGCTGCCAAAGAGATGCCTTTCCAGGGCTCTGGAAAATCAGCATGGTGC CCAGTGGAGATCAGCAAGACAGTCCTCTGGCCAGAGAGCATCAGCGTGGTGCGA TGTGTGGAGTTGTTTGAGGCCCCGGTGGAGTGTGAGGAGGAGGAGGAGGTAGAG GAAGAAAAAGGGAGCTTCTGTGCATCGCCTGAGAGCAGCAGGGATGACTrCCAG GAGGGAAGGGAGGGCATTGTGGCCCGGCTAACAGAGAGCCTGTTCCTGGACCTG CTCGGAGAGGAGAATGGGGGCTTTTGCCAGCAGGACATGGGGGAGTCATGCCTT CTTCCACCTTCGGGAAGTACGAGTGCTCACATGCCCTGGGATGAGTTCCCAAGT GCAGGGCCCAAGGAGGCACCTCCCTGGGGCAAGGAGCAGCCTCTCCACCTGGAG CCAAGTCCTCCTGCCAGCCCGACCCAGAGTCCAGACAACCTGACTTGCACAGAG ACGCCCCTCGTCATCGCAGGCAACCCTGCTTACCGCAGCTTCAGCAACTCCCTG AGCCAGTCACCGTGTCCCAGAGAGCTGGGTCCAGACCCACTGCTGGCCAGACAC CTGGAGGAAGTAGAACCCGAGATGCCCTGTGTCCCCCAGCTCTCTGAGCCAACC ACTGTGCCCCAACCTGAGCCAGAAACCTGGGAGCAGATCCTCCGCCGAAATGTC CTCCAGCATGGGGCAGCTGCAGCCCCCGTCTCGGCCCCCACCAGTGGCTATCAG GAGTTTGTACATGCGGTGGAGCAGGGTGGCACCCAGGCCAGTGCGGTGGTGGGC TTGGGTCCCCCAGGAGAGGCTGGTTACAAGGCCTTCTCAAGCCTGCTTGCCAGC AGTGCTGTGTCCCCAGAGAAATGTGGGTTTGGGGCTAGCAGTGGGGAAGAGGGG TATAAGCCTTTCCAAGACCTCATTCCTGGCTGCCCTGGGGACCCTGCCCCAGTC CCTGTCCCCTTGTTCACCTTTGGACTGGACAGGGAGCCACCTCGCAGTCCGCAG AGCTCACATCTCCCAAGCAGCTCCCCAGAGCACCTGGGTCTGGAGCCGGGGGAA AAGGTAGAGGACATGCCAAAGCCCCCACTTCCCCAGGAGCAGGCCACAGACCCC CTTGTGGACAGCCTGGGCAGTGGCATTGTCTACTCAGCCCTTACCTGCCACCTG TGCGGCCACCTGAAACAGTGTCATGGCCAGGAGGATGGTGGCCAGACCCCTGTC ATGGCCAGTCCTTGCTGTGGCTGCTGCTGTGGAGACAGGTCCTCGCCCCCTACA ACCCCCCTGAGGGCCCCAGACCCCTCTCCAGGTGGGGTTCCACTGGAGGCCAGT CTGTGTCCGGCCTCCCTGGCACCCTCGGGCATCTCAGAGAAGAGTAAATCCTCA TCATCCTTCCATCCTGCCCCTGGCAATGCTCAGAGCTCAAGCCAGACCCCCAAA ATCGTGAACTTTGTCTCCGTGGGACCCACATACATGAGGGTCTCTTAG 292 ANTI-HUMAN IL4Ra ANTIBODY SEQUENCES 69 VH EVQLVESGGG leqpggslrlscagsgftfr dyamtwvrqa pgkglewvss ISGSGGNTYY ADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCAKDR L SITIRPRYYGLDVWGQGTTVTVSS 70 VL DTVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQ LLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTP YTFGQGTKLEIK 71 HEAVY CHAIN EVQLVESGGG LEQPGGSLRL SCAGSGFTFR DYAMTWVRQA PGKGLEWVSS ISGSGGNTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKDR LSITIRPRYY GLDVWGQGTT VTVSSASTKG PSVFPLAPCS RSTSESTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSWTVPSSS LGTKTYTCNV DHKPSNTKVD KRVESKYGPP CPPCPAPEFL GGPSVFLFPP KPKDTLMISR TPEVTCWVD VSQEDPEVQF NWYVDGVEVH NAKTKPREEQ FNSTYRWSV LTVLHQDWLN GKEYKCKVSN KGLPSSIEKT ISKAKGQPRE PQVYTLPPSQ EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSRLTVDKS RWQEGNVFSC SVMHEALHNH YTQKSLSLSL G 72 LIGHT CHAIN DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQ LLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTP YTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSF HUMAN IGHG4 SEQUENCES 73 IGHG4*01 AMINO ACID SEQUENCE ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPE FLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNA KTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK exposition 189 R-poslJon 289 74 IGHG4*01 NUCLEOTIDE SEQUENCE GCTTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCAC CTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCT TCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACC GTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACA AGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCC ATGCCCATCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGT TCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACG TGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGT ACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGC AGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC 293 TGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGT CCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACA GGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGC CTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGG AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA CTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGT GGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAA CCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAATGA exposition 565 (CTG encodes 189V) G=position 866 (AGG encodes 289R) Reference to sequence positions throughout this specification are to the sequence positions as identified in the description and tables. For example, positions 75, 400, 431. 503, 576 and 752 of SEQ ID NO:67 are the positions identified in SEQ ID NO:67 in Table 10. 294 Table 11: Human IL4Ra variants distributed over several human ethnic populations & > u c V σ QJ u 4o a > o c QJ ω c ra E O © ‘35 © "3 tXQ c ’> ra c cr QJ k_ LL E □ u 0.533 0.467 i 0.777 0.223 1 T c i_ T LO II. σ _ + a> E i o 0.302 (0.764) 0.235 (0.697) 0.648 (0.904) 0.095 (0.351) ΓΛ V 01 U. Ή 01 X 0.462 0.462 0.256 kO LH PS 0 0) 3 O- PJ co c a ZD o , Q, □ z Tt rH T i—1 r*1 ΙΛ Ό I / -o c LT) ro oo rs ND Γ- 988 tT CO m Human Populations LO i r< x ^ =; Λ CD ZD u _ cD or _T x co x cr U Q X > u 1 § i LO U CL < —i x 'd υ Ξ9 =? m bc X X co x q; u a 2 H 5 § P g U 751 75V 400E < o o Tt Most common Variant Most common Variant 295 296 0.118 σ> ο. 0.030 (0.206) 0.176 225 ί-Ό ,Λ Γι'' χ GO Π CC 33 W CQ QC _? X 03 χ cr Ο L9 ^ >- 3 Ζ | Η ιη ο α- <3* ~> 752Α common Variant 297 φ £ o c Φ C TO (b) Nucleotide Sequence Variations of Selected Alieies 1- Nucleotide Position1 16:27363606 Non-Synonymous Nucleotide Variation2 j o fit s +» c to TO > NO r—1 O Lf) O 00 tH •St L Corresponding Amino Acid Variation 752A < 16:27363079 o z CH t—1 O 00 x—1 LO 576R H ©I Z 00 CH NO crj T— CH NO χ—1 cr Z C\l NC CO Τ'- CH NO t—1 L> rsl805015 503 P 1- L> CH τ- Ο z o 00 Ή •Si DC <—1 co σΤ < 16:27362551 s— o z o 00 rH L/J 400A < 16:27344882 O O τ—1 o z o oo t— IZI > z r> Common Allete Variant Allele O CH v_ Φ _Q £ φ -f—' Cl Φ Z co Φ uo TO _Φ Φ _Ω £ φ ι/t C Φ X £ □ c φ +-» ro c T3 i_ o o Φ Φ £ o to O E o x u c TO £ Ξ5 C O Φ LTO ΙΛ C o 4-J ζ/Ί O Cl Φ x £ C3 C Φ £ o υο O £ o _Φ _Φ To c O £ E o u 4-> 1/Ί O £ o ~O φ i_ TO Cl £ O Φ c TO TO > Φ Φ ω c TO m <—ι o CH LO γη L_ CL < C o Ό Φ to TO _Φ Φ s_ Ώ '5 CQ Cl Z X Ό CQ u Φ JO £ Z3 C 0) Φ c Φ Z X "C u cc Ό Φ 4-/ TO SuO Q. i_ O u r JU x M— o Φ Φ c Φ Ξ3 cr Φ cn Φ L> I/» C TO JD Q_ £ TO X Φ c < 298 SNP rsl 805010 (encoding 75V; see Table 11) is present in humans at an average cumulative frequency of 47% according to the 1000 Genomes Phase 1 database, but is higher in AFR, ASN, ASW, LWK, MXL, CHS and JPT populations; thus in an embodiment, the human is of AFR or ASN ancestry, eg, of ASW, LWK, MXL, CHS or JPT ancestry. In an embodiment, therefore, when the wherein the ligand (eg, antibody or fragment) specifically binds an IL4R protein that comprises a mutation 175V, the human comprises SNP rsl 805010; and optionally the human is of AFR or ASN ancestry, eg, of ASW, LWK, MXL, CHS or JPT ancestry. For example, the human is of AFR ancestry. For example, the human is of ASN ancestry. For example, the human is of ASW ancestry. For example, the human is of LWK ancestry. For example, the human is of ASW ancestry. For example, the human is of MXL ancestry. For example, the human is of CHS ancestry. For example, the human is of JPT ancestry.

SNP rsl 80501 1 (encoding 400A; see Table 11) is present in humans at an average cumulative frequency of 22% according to the 1000 Genomes Phase I database, but is higher in AFR, ASW.

LWK and YR1 populations; thus in an embodiment, the human is of AFR ancestry, eg, of ASW. LWK and YRI ancestry. In an embodiment, therefore, when the wherein the ligand (eg, antibody or fragment) specifically binds an IL4R protein that comprises a mutation E400A, the human comprises SNP rsl 805011; and optionally the human is of AFR ancestry, eg, of ASW, LWK and YRI ancestry. For example, the human is of AFR 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.

SNP rsl 8050 12 (encoding 43 1 R; see Table 1 I) is present in humans at an average cumulative frequency of 10% according to the 1000 Genomes Phase I database, but is higher in AFR, AMR.

EUR, YRI. CLM. MXL, PUR, CEU and GBR populations: thus in an embodiment, the human is of AFR, AMR or EUR, ancestry, eg, of YRI, CLM, MXL, PUR, CEU or GBR ancestry. In an embodiment, therefore, when the wherein the ligand (eg. antibody or fragment) specifically binds an IL4R protein that comprises a mutation C431R, the human comprises SNP rs 1805012: and optionally the human is of A AFR, AMR or EUR. ancestry, eg, of YRI, CLM, MXL. PUR, CEU or GBR ancestry. For example, the human is of AFR ancestry. For example, the human is of AMR ancestry. For example, the human is of EUR ancestry. For example, the human is of YRI ancestry. For example, the human is of CLM ancestry. For example, the human is of MXL ancestry. For example, the human is of PUR ancestry . For example, the human is of CEU ancestry. For example, the human is of GBR ancestry .

SNP rs 1805015 (encoding 5O3P; see Table 1 1) is present in humans at an average cumulative frequency of 21% according to the 1000 Genomes Phase I database, but is higher in AFR, ASW. LWK. YRI, PUR and GBR populations; thus in an embodiment, the human is of AFR, or ASW ancestry, eg. of LW K. YRI. PUR or GBR ancestry. In an embodiment, therefore, when the wherein the ligand (eg, antibody or fragment) specifically binds an IJ.4R protein that comprises a mutation S503P, the human comprises SNP rs 1805015; and optionally the human is of APR. or ASW ancestry, eg, of LWK. YRI, PUR or GBR ancestry. For example, the human is of AFR ancestry. For example, the human is of ASW ancestry. For example, the human is of LWK ancestry. For example, the 299 human is of YRI ancestry. For example, the human is of PUR ancestry. For example, the human is of GBR ancestry.

SNP rsl801275 (encoding 576R; see Table 11) is present in humans at an average cumulative frequency of 35% according to the 1000 Genomes Phase I database, but is higher in AFR, ASW, LWK and YRI populations: thus in an embodiment, the human is of AFR ancestry, eg, of ASW. LWK or YRI ancestry. In an embodiment, therefore, when the wherein the ligand (eg. antibody or fragment) specifically binds an 11.4R protein that comprises a mutation Q576R. the human comprises SNP rsl 801275; and optionally the human is of AFR ancestry, eg, of ASW, LWK orYRI ancestry. For example, the human is of AFR 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.

SNP rs 1805016 (encoding 752A; see Table I I) is present in humans at an average cumulative frequency of 12% according to the 1000 Genomes Phase 1 database, but is higher in AFR, ASW, LWK and YRI populations; thus in an embodiment, the human is of AFR ancestry, eg, of ASW, LWK or YRI ancestry. In an embodiment, therefore, when the wherein the ligand (eg, antibody or fragment) specifically binds an 1L4R protein that comprises a mutation S752A, the human comprises SNP rsl 805016; and optionally the human is of AFR ancestry, eg, of ASW, LWK or YRI ancestry.

IGHV3-23 SNP rs56069819 is present in humans at an average cumulative frequency of 1 1% according to the 1000 Genomes Phase I database, but is higher in AFR (23%). FUR (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 I of SEQ ID NO: 40 or comprises a VI I domain derived from the recombination of a human VI I segment (eg, human VH3-23*04), a human D gene segment and a human JH segment, the human VH segment comprising SNP rs5606981 9. the human is of AFR. EUR. ASW. LWK. YRI, CEU or 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.

STATEMENTS OF INVENTION: A. A method of treating or reducing the risk of an IL4Ra-mediated disease or condition in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a human IL4RA protein that comprises a mutation selected from the group consisting of I75V. F400A, C43 I R, S5O3P, Q576R and S752A in SEQ ID NO: 67: wherein (i) the antibody or fragment comprises a VH domain derived from the recombination of a human VII segment, a human D gene segment and a human JH segment, the human VH segment encoding the 300 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; and wherein (ii) said human comprises a nucleotide sequence encoding said IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431 R, S503P, Q576R and S752A in SEQ ID NO: 67.

B. The method of statement A. wherein the IL4Ra comprises mutations 175V and Q576R in SEQ ID NO: 67 and optionally the disease is asthma.

C. The method of statement A or B. wherein the nucleotide sequence of(ii) comprises nucleotide mutation -3223T (dB SNP numbering).

D. The method of any preceding statement, wherein each said human VH gene segment comprises SEQ ID NO: 39.

E. The method of any preceding statement, wherein the VH gene segment comprised by said human is a germline VH gene segment.

F 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 clause 1.

G. The method of any preceding statement, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL4RA protein comprising said mutation selected from the group consisting of I75V. E400A. C43 1 R. S503P, Q576R and S752A in SEQ ID NO: 67 and/or an IL4RA protein comprising said mutation selected from the group consisting of 175V, E400A, C431 R. S503P, Q576R and S752A in SEQ ID NO: 67, IT The method of any preceding statement, comprising the step of determining that the human comprises (a) the nucleotide sequence that encodes an IL4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67 and/or (b) an IL4RA protein comprising said mutation said mutation selected from the group consisting of I75V, E400A, C431R, S5O3P, Q576R and S752A in SEQ ID NO: 67, optionally, wherein the determining step is performed before administration of the antibody to the human.

I. The method of statement H, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL4RA protein comprising said mutation selected from the group consisting of 175V, E400A, C43 IR, S503P, Q576R and S752A in 301 SEQ ID NO: 67.

J. The method of statement I, wherein the assaying comprises contacting the biological sample with at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding an IL4RA protein comprising said mutation selected from the group consisting of 175V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation selected from the group consisting of I75V. E400A, C431R. S503P. Q576R and S752A in SEQ ID NO: 67. thereby forming a complex when at least one nucleotide sequence encoding the IL4RA protein comprising said mutation selected from the group consisting of 175V. E400A. C431R, S503P, Q576R and S752A in SEQ ID NO: 67 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IE4RA protein comprising said mutation selected from the group consisting of I75V, E400A, C431R. S503P. Q576R and S752A in SEQ ID NO: 67.

K. The method of statement I or J, 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.

L. The method of statement I. J or K. wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human.

M. fhe method of an\ preceding statement, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the 1L4RA protein comprising said mutation selected from the group consisting of 175V, E400A, C43IR, S503P, Q576R and S752A in SEQ ID NO: 67, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 68. or said human is indicated as homozygous for a nucleotide sequence encoding the IL4RA protein comprising said mutation selected from the group consisting of 175V, E400A, C431R, S503P. Q576R and S752A in SEQ ID NO: 67.

N. The method of any preceding statement, wherein said human is or has been further determined to be substantially resistant to an asthma treatment. 302 Ο.

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

P. The method of any preceding statement, wherein said disease or condition is an inflammatory disease or condition: an atopic disease or condition; a respiratory disease or condition; a disease or condition associated with elevated IgE; or a disease or condition associated with elevated IL-4 and/or IL-13 activity.

Q. The method of any preceding statement, wherein said disease or condition is selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia, environmental lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders ofthe pleura, disorders of the mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis, aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis, pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X, pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis.

R. The method of any preceding statement, wherein said human lias been diagnosed with at least one condition selected from the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia. environmental lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of the mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis, aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis, pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X, pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener’s 303 granulomatosis.

S. 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 the group consisting of an airway inflammatory disease or condition, chronic obstructive pulmonary disease, asthma, pneumonia, hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia, environmental lung disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, primary pulmonary hypertension, pulmonary thromboembolism, disorders of the pleura, disorders of the mediastinum, disorders of the diaphragm, hypoventilation, hyperventilation, sleep apnea, acute respiratory distress syndrome, mesothelioma, sarcoma, graft rejection, graft versus host disease, lung cancer, allergic rhinitis, allergy, asbestosis. aspergilloma, aspergillosis, bronchiectasis, chronic bronchitis, emphysema, eosinophilic pneumonia, idiopathic pulmonary fibrosis, invasive pneumococcal disease, influenza, nontuberculous mycobacteria, pleural effusion, pneumoconiosis, pneumocytosis. pneumonia, pulmonary actinomycosis, pulmonary alveolar proteinosis, pulmonary anthrax, pulmonary edema, pulmonary embolus, pulmonary inflammation, pulmonary histiocytosis X. pulmonary hypertension, pulmonary nocardiosis, pulmonary tuberculosis, pulmonary veno-occlusive disease, rheumatoid lung disease, sarcoidosis, and Wegener's granulomatosis T, The method of any preceding statement, wherein the nucleotide sequence comprises one or more SNPs selected from the group consisting of rsl 805010, rsl 805011, rsl 805012, rsl 805015, rsl 801275 and rsl805016.

U. The method of any preceding statement, wherein said antibody or antibody fragment is administered by inhaled, intravenous or subcutaneous administration and/or is comprised in an inhalable or injectable preparation, V, The method of any preceding statement, wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 69, Further Statements of Invention are as follows: I. An antibody or antibody fragment for use in a method of treating or reducing the risk of atopic dermatitis or asthma in a human in need thereof, wherein the antibody or antibody fragment specifically binds a human lL4Ra protein that comprises a mutation selected from the group consisting of 175V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67; wherein (i) the antibody or fragment 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 304 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 ofSEQ ID NO: 40; and wherein (ii) said human comprises a nucleotide sequence encoding said IE4Ra protein comprising said selected mutation. 2. The antibody or antibody fragment of statement I, wherein the IL4Ra comprises mutations 175 V and Q576R in SEQ ID NO: 67 and optionally the disease is asthma. 3. The antibody or antibody fragment of statement I or statement 2, wherein the nucleotide sequence of (ii) comprises nucleotide mutation -3223T (dB SNP numbering). 4. The antibody or antibody fragment of any preceding statement, wherein each said human VH gene segment comprises SEQ ID NO: 39.

. The antibody or antibody fragment of any preceding statement, wherein the VII gene segment comprised by said human is a germline VH gene segment. 6. The antibody or antibody fragment of any preceding statement comprising, before administration of said antibody or antibody fragment, selecting a human comprising said nucleotide sequence of (ii), wherein the human is the human of statement 1. 7. The antibody or antibody fragment of any preceding statement, wherein (i) the human has been determined to comprise the nucleotide sequence that encodes an IL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A. C43 I R, S503P, Q576R and S752A in SEQ ID NO: 67 and/or an JL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A, C43 1R, S503P, Q576R and S752A in SEQ ID NO: 67 or (ii) comprising the step of determining that the human comprises (a) the nucleotide sequence that encodes an IL4Ra protein comprising said mutation selected from the group consisting of 175 V, E400A, C43IR. S5O3P, Q576R and S752A in SEQ ID NO: 67 and/or (b) an lL4Ra protein comprising said mutation said mutation selected from the group consisting of 175 V, E400A.

C431R, S503P, Q576R and S752A in SEQ ID NO: 67, optionally, wherein the determining step is performed before administration of the antibody to the human. 8. The antibody or antibody fragment of statement 7, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL4Ra protein 305 comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67. 9. The antibody or antibody fragment of statement 8, wherein the assaying comprises contacting the biological sample with at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding an IL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A, C43 1R, S503P, Q576R and S752A in SEQ ID NO: 67 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation selected from the group consisting of 175V, E400A, C43 1R, S503P, Q576R and S752A in SEQ ID NO: 67, thereby forming a complex when at least one nucleotide sequence encoding the IL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A, C43 1R, S5O3P, Q576R and S752A in SEQ ID NO: 67 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL4Ra protein comprising said mutation selected from the group consisting of 175V, E400A, C431R, S503P. Q576R and S752A in SEQ ID NO: 67.

. The antibody or antibody fragment of statement 8 or statement 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 antibody or antibody fragment of any one of statements 8-10, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 12. The antibody or antibody fragment of any preceding statement, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL4Ra protein comprising said mutation selected from the group consisting of I75V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ IDNO: 68, or said human is indicated as homozygous fora nucleotide sequence encoding the IL4Ra protein comprising said mutation selected from the group consisting of 175 V, E400A, C431 R, S5O3P, Q576R and S752A in SEQ ID NO: 67. 13. The antibody or antibody fragment of any preceding statement, wherein said human is or has been further determined to be substantially resistant to an asthma treatment. 306 14. The antibody or antibody fragment of any preceding statement, wherein said human is receiving or has received an asthma treatment or has reduced responsiveness to an asthma treatment.

. The antibody or antibody fragment of any preceding statement, wherein the nucleotide sequence comprises one or more SNPs selected from the group consisting of rs 1805010, rs I 805011, rs 1805012, rs 1805015. rs 1801275 and rs 1805016. 16. The antibody or antibody fragment of any preceding statement, wherein said antibody or antibody fragment is for administration by inhaled, intravenous or subcutaneous administration and/or is comprised in an inhalable or injectable preparation. 17. The antibody or antibody fragment of any preceding statement, wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 69. ] 8. The antibody or antibody fragment of any preceding statement, wherein the antibody is a human antibody. 307 SEQUENCE LISTING <110> CLUBE, JASPER R. <120> HUMAN TARGETS VIII <130> 069496-082412-CIP <140> <141> <150> 14/331,730 <151> 2014-07-15 <160> 85 <170> Patenlln version 3,5 <210> 1 <211> 692 <212> PRT <213> Homo sapiens <400> 1 ser 5 Ser Arg Arg Ser Trp 10 Trp Pro L.eu Pro Leu 15 Leu Met 1 Gly Thr Val Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gin Glu 20 25 30 Asp Glu Asp Gly Asp Tyr Glu Glu Leu val Leu Ala Leu Arg Ser Glu 35 40 45 Gl u Asp Gly Leu Ala Glu Ala Pro Glu Hi s Gly Thr Thr Ala Thr Phe 50 55 60 Hi s Arg cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr val val 65 70 75 80 Val Leu Lys Glu Glu Thr Hi s Leu ser Gin Ser Glu Arg Thr Ala Arg 85 90 95 Arg Leu Gl n Ala Gin Al a Al a Arg Arg Gly Tyr Leu Thr Lys lie Leu 100 105 110 Hi s Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met Ser Gly 115 120 125 Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His val Asp Tyr Ile Glu 130 135 140 Gl u Asp Ser Ser val Phe Ala Gl n Ser lie Pro Trp Asn Leu Glu Arg 145 150 155 160 ile Thr Pro Pro Arg Tyr Arg Al a Asp Glu Tyr Gin Pro Pro ASP Gly 165 170 175 Gly Ser Leu val Glu val Tyr Leu Leu Asp Thr Ser ile Gin ser Asp 180 185 190 # His ; Arg i 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 Al a 220 Ser L.ys 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 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 He Gly Leu Glu Phe 270 lie Arg Lys Ser Gl n 275 Leu val Gl n 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 Ala 315 Gly Asn Phe Arg A5p 320 Asp Ala Cys Leu Tyr 325 Ser Pro Ala Ser Al a 330 Pro Glu Val He Thr 335 val Gly Al a 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 Il e lie 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 Al a 390 Hi s val Al a Gly lie 395 Al a Ala Met Met Leu 400 Ser Al a Glu Pro Glu 405 Leu Thr Leu Ala Glu 410 Leu Arg Gin Arg Leu 415 He His Phe Ser Al a 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 Hi s i Gly . 450 Ala ' Gly Trp Gin Leu 455 Phe Cys Arg Thr Val 460 Trp Ser Ala Hi s 308 Ser Gly 465 Pro Thr Arg Met Ala Thr Ala lie Ala Arg Cys Ala Pro Asp 480 470 475 Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys Arg Arg 485 490 495 Gly Glu Arg Met Glu Ala Gl n Gly Gly Lys Leu val Cys Arg Al a Hi s 500 505 510 Asn Al a Phe Gly Gly Gl U Gly val Tyr Ala lie Al a Arg cys Cys Leu 515 520 525 Leu Pro Gl n Ala Asn Cys Ser val Hi s Thr Ala Pro pro a'I a Glu Ala 530 53 5 540 ser Met Gly Thr Arg val Hi s Cys Hi s Gin Gin Gly Hi s Val Leu Thr 545 550 555 560 Gly cys ser Ser Hi s Trp Gl u Val Glu Asp Leu Gly Thr His Lys Pro 565 570 575 Pro val Leu Arg Pro Arg Gly Gin Pro Asn Gl n Cys val Gly Hi s Arg 580 585 590 Glu Ala Ser lie Hi s Ala Ser Cys Cys Hi s Ala Pro Gly Leu Gl u Cys 595 600 605 Lys Val Lys Glu Hi s Gly lie Pro Ala pro Gin Glu Gl n Val Thr val 610 615 620 Al a cys Glu Glu Gly Trp Thr Leu Thr Gly Cys ser Ala Leu Pro Gly 625 630 635 640 Thr Ser Hi s Val Leu Gly Ala Tyr Al a Val Asp Asn Thr cys Val Val 645 650 655 Arg Ser Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Glu Al a val 660 665 670 Thr Ala val Ala lie cys cys Arg ser Arg His Leu Ala Gin Ala Ser 675 680 685 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 Leu Ala Leu Arg 15 10 15 310 Ser Gli i Gib 1 Asp • Gly ' Leu i Ala Glu Al a Pro Glu His Gly Thr Thr Al a 20 25 30 Thr Phe His Arg i Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr 35 40 45 Val val Val Leu Lys Glu Glu Thr Hi s Leu Ser Gin Ser Glu Arg Thr 50 55 60 Ala Arg Arg Leu Gin Al a Gin Ala a! a Arg Arg Gly Tyr Leu Thr Lys 65 70 75 80 lie Leu Hi s Val Phe Hi s dy Leu Leu Pro Gl y Phe Leu Val Lys Met 85 90 95 Ser Gly Asp Leu Leu Glu Leu Al a Leu Lys Leu Pro Hi s Val Asp Tyr 100 105 110 lie Glu Glu Asp ser Ser Val Phe Ala Gin Ser lie Pro Trp Asn Leu 115 120 125 Glu Arg ll e Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gl n Pro pro 130 135 140 Asp Gly Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser lie Gin 145 150 155 160 Ser Asp His Arg Glu lie Glu Gly Arg Val Met Val Thr Asp Phe Glu 165 170 175 Asn Val Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gin Ala Ser Lys 180 185 190 cys Asp Ser Hi s Gly Thr Hi s Leu Al a Gly val val Ser Gly Arg Asp 195 200 205 Ala Gly Val Ala Lys Gly Ala Ser Met Arg ser Leu Arg val Leu Asn 210 215 220 Cys Gin Gly Lys Gly Thr val ser Gly Thr Leu He Gly Leu Glu Phe 225 230 235 240 lie Arg Lys Ser Gin Leu Val Gin pro val Gly Pro Leu val Val Leu 245 250 255 Leu Pro Leu Ala Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala Cys Gl n 260 265 270 Arg Leu Ala Arg Ala Gly Val val Leu Val Thr Ala Ala Gly Asn Phe 275 280 285 Arg Asp , Asp , Ala cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu val lie 290 295 300 Thr Val Gly Ala Thr Asn Ala Gin Asp Gin Pro Val Thr Leu Gly Thr 305 310 315 320 Leu Gly Thr Asn Phe Gly Arg cys Val Asp Leu Phe Ala Pro Gly Glu 325 330 335 Asp lie lie Gly Ala ser Ser Asp Cys Ser Thr cys Phe Val Ser Gin 340 345 350 Ser Gly Thr Ser Gin Al a Al a Ala Hl S val Ala Gly lie Ala Al a Met 355 360 365 Met Leu Ser Ala Glu Pro Gl U Leu Thr Leu Ala Glu Leu Arg Gin Arg 370 375 380 Leu lie His Phe Ser Ala Lys Asp val lie Asn Glu Al a T rp Phe Pro 385 390 395 400 Glu Asp Gin Arg Val Leu Thr Pro Asn Leu val Ala Ala Leu Pro Pro 405 410 415 Ser Thr His Gly Ala Gly Trp Gin Leu Phe cys Arg Thr Val Trp Ser 420 425 430 Al a Hi s Ser Gly Pro Thr Arg Met Al a Thr Al a lie Al a Arg Cys Al a 435 440 445 Pro Asp Glu Glu Leu Leu Ser cys Ser ser Phe Ser Arg Ser Gly Lys 450 455 460 Arg Arg Gly Glu Arg Met Glu Al a Gl n Gly Gly Lys Leu val cys Arg 465 470 475 480 Al a Hi s Asn Ala Phe Gl y Gly Glu Gly Val Tyr Ala lie Al a Arg Cys 485 490 495 Cys Leu Leu Pro Gin Al a Asn cys Ser Val Hi s Thr Ala Pro Pro Ala 500 505 510 Gl u Ala Ser Met Gly Thr Arg val His Cys Hi s Gin Gin Gly Hi s Val 515 520 525 Leu Thr Gly Cys Ser Ser His 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 HIS , Arg ' Glu Ala Ser lie Hi s Al a Ser cys cys Hi s Ala Pro Gly Leu 565 570 575 31^ Glu cys Lys val Lys Glu Hi s Gly lie Pro Al a Pro Gin Glu Gl n Val 580 585 590 Thr val Ala cys Glu Glu Gly T rp Thr Leu Thr Gly Cys Ser Ala Leu 595 600 605 Pro Gly Thr Ser Hi s Val Leu Gly Al a 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 Ala val Ala lie Cys cys Arg Ser Arg Hi s Leu Al a Gl n 645 650 655 Ala ser Gl n Gl u Leu Gin 660 <210> 3 <211> 540 <212> PRT <213> Homo sapiens <400> 3 Ser lie 1 Pro Trp Asn 5 Leu Gl U 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 ser 35 ll e Gl n Ser Asp 40 Hi s Arg Glu lie Glu 45 Gly Arg Val Met val 50 Thr Asp Phe Gl u Asn 55 val Pro Glu Glu Asp 60 Gly Thr Arg Phe Hi 5 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 Gl n Gly 105 Lys Gly Thr Val Ser 110 Gly Thr Leu lie Gly Leu 115 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 Ala Gly Gly 140 Tyr ser Arg val Leu 145 Asn Ala Ala cys Gin 150 Arg Leu Ala Arg Ala 155 Gly Val Val Leu Val 160 2D Thr Ala ί Ala Gly • Asn Phe Arg Asp Asp Ala Cys Leu Tyr Ser Pro Ala 165 170 175 Ser • Ala . Pro Glu val lie Thr val Gly Ala Thr Asn Ala Gin Asp Gin 180 185 190 Pro val Thr Leu cly Thr Leu Gly Thr Asn Phe Gly Arg Cys Val Asp 195 200 205 Leu Phe Ala Pro Gly Glu Asp He lie Gly Ala Ser Ser Asp Cys Ser 210 215 220 Thr cys Phe val Ser Gl n Ser Gly Thr Ser Gin Al a Al a Ala Hi s Val 225 230 235 240 Ala Gly He Ala Ala Met Met Leu Ser Ala Glu Pro Gl U Leu Thr Leu 245 250 255 Ala Glu Leu Arg Gin Arg Leu lie His Phe ser Ala Lys Asp val lie 260 265 270 Asn Glu Ala Trp Phe Pro Gl u Asp Gin Arg val Leu Thr Pro Asn Leu 275 280 285 val Ala Ala Leu Pro Pro Ser Thr Hi s Gly Ala Gly Trp Gin Leu Phe 290 295 300 Cys Arg Thr val Trp Ser Al a His Ser Gly pro Thr Arg Met Ala Thr 305 310 315 320 Al a lie Ala Arg cys Ala Pro Asp Glu Glu Leu Leu ser Cys Ser Ser 325 330 335 Phe Ser Arg Ser Gly Lys Arg Arg Gly Glu Arg Met GlU Ala Gl n Gly 340 345 350 Gly Lys Leu val cys Arg Ala Hi s Asn Al a Phe Gly Gly Glu Gly Val 355 360 365 Tyr Ala lie Ala Arg cys cys Leu Leu Pro Gin Ala Asn cys ser Val 370 375 380 Hi s Thr Ala Pro Pro Al a Gl u Ala Ser Met Gly Thr Arg val Hi s Cys 385 390 395 400 His Gin Gin Gly His val Leu Thr Gly cys Ser Ser Hi s Trp Glu Val 405 410 415 Glu . Asp Leu Gly Thr His Lys Pro Pro val Leu Arg Pro Arg Gly Gin 420 425 430 Pro < Asn ' Gin Cys Val Gly Hi s Arg Glu Ala ser lie Hi s Ala ser Cys 435 440 445 <319 Cys Hi s 450 Al a Pro Gly Leu Glu 455 cys Lys val Lys Glu 460 Hi s Gly lie pro Ala Pro Gin Gl u Gin Val Thr val Ala cys Glu Glu Gly Trp Thr Leu 465 470 475 480 Thr Gly Cys Ser Ala Leu Pro Gly Thr ser Hl 5 Val Leu Gly Ala Tyr 485 490 495 Al a Val Asp Asn Thr cys val val Arg Ser Arg Asp val Ser Thr Thr 500 505 510 Gly Ser Thr ser Glu Glu Ala val Thr Al a val Ala lie Cys cys Arg 515 520 525 ser Arg Hi s Leu Ala Gin Al a ser Gl n Gl u Leu Gl n 530 535 540 <210> 4 <211> 692 <212> PRT <213> Homo sapiens <400> 4 Met 1 Gly Thr Val Ser Ser Arg 5 Arg Ser Trp 10 T rp Pro Leu pro Leu 15 Leu Leu Leu Leu Leu Leu Leu Leu Gl y Pro Ala Gly Al a Arg Al a Gl n Gl U 20 25 30 ASP Gl u Asp Gly Asp Tyr Glu Glu Leu Val Leu Al a Leu Arg Ser Glu 35 40 45 Glu Asp Gly Leu Ala Glu Al a Pro Glu Hi s Gly Thr Thr Al a Thr Phe 50 55 60 HI S Arg Cys Al a Lys Asp Pro T rp Arg Leu Pro Gly Thr Tyr val Val 65 70 75 80 Val Leu Lys Glu Glu Thr Hi s Leu Ser Gl n ser Glu Arg Thr Ala Arg 85 90 95 Arg Leu Gin Ala Gin Ala Ala Arg Arg Gly Tyr Leu Thr Lys He Leu 100 105 110 His val Phe Hi s Gly Leu Leu Pro Gly Phe Leu val Lys Met Ser Gly 115 120 125 Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro Hi s val Asp Tyr He Glu 130 135 140 Glu Asp ser ser Val phe Ala Gin Ser lie Pro Trp Asn Leu Glu Arg 145 150 155 160 lie : Thr Pro1 Pro - Arg Tyr Arg Ala Asp Glu Tyr Gin Pro Pro ASp Gly 165 170 175 Gly Ser Leu Val Glu val Tyr Leu Leu ASp Thr Ser lie Gin ser Asp 180 185 190 Hi s Arg Glu lie Glu Gly Arg val Met Val Thr ASp Phe Gl u Asn Val 195 200 205 Pro Glu Glu Asp Gly Thr Arg Phe Hi s Arg Gin Al a Ser Lys Cys Asp 210 215 220 Ser His Gly rhr Hi s Leu Al a 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 260 265 270 Lys Ser Gin Leu Val Gin Pro Val Gly Pro Leu Val val Leu Leu Pro 275 280 285 Leu Ala Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala Cys Gin Arg Leu 290 295 300 Ala Arg Ala Gly Val Val Leu Val Thr Al a Ala Gly Asn Phe Arg Asp 305 310 315 320 Asp Ala Cys Leu Tyr Ser Pro Al a Ser Ala Pro Glu Val He Thr Val 325 330 335 Gly Ala Thr Asn Al a Gin Asp Gl n pro Val Thr Leu Gly Thr Leu Gly 340 345 350 Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Gl u Asp lie 355 360 365 lie Gly Ala Ser Ser Asp Cys Ser Thr cys Phe Val Ser Gin Ser Gly 370 375 380 Thr Ser Gin Ala Ala Ala His Val Ala Gly lie Ala Ala Met Met Leu 385 390 395 400 Ser Ala Glu Pro Gl u Leu Thr Leu Ala Glu Leu Arg Gin Arg Leu He 405 410 415 Hi s Phe ser . Ala Lys Asp Val lie Asn Glu Ala Trp Phe Pro Glu Asp 420 425 430 Gin Arg Val Leu Thr Pro Asn Leu Val Ala Ala Leu Pro Pro Ser Thr 435 440 445 Hi s Gly Al a Gly T rp Gl n Leu Phe Cys Arg Thr Val Trp Ser Ala His 450 455 460 Ser Gly Pro Thr Arg Met Ala Thr Ala Val Ala Arg cys Al a Pro Asp 465 470 475 480 Glu Glu Leu Leu Ser Cys Ser Ser Phe ser Arg ser Gly 1.. ys Arg Arg 485 490 495 Gly Glu Arg Met Gl u Ala Gin Gly Gly Lys Leu val cys Arg Ala Hi s 500 505 510 Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala lie Al a Arg Cys Cys Leu 515 520 525 Leu Pro Gin Ala Asn cys Ser val Hi s Thr Ala Pro Pro Ala Glu Ala 530 535 540 Ser Met Gly Thr Arg Val Hi s Cys Hi s Gin Gin Gly His val Leu Thr 545 550 555 560 Gly cys ser Ser Hi s Trp Glu val Glu Asp Leu Gly Thr Hi s Lys Pro 565 570 575 Pro val Leu Arg Pro Arg Gly Gin Pro Asn Gin cys val Gly Hi s Arg 580 585 590 Glu Ala ser ile Hi s Al a Ser Cys Cys Hi s Al a Pro Gl y Leu Glu Cys 595 600 605 Lys Val Lys Glu Hi s Gly Ile Pro Al a Pro Gin Glu Gin val Thr val 610 615 620 Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly cys Ser Al a Leu Pro Gly 625 630 635 640 Thr Ser Hi s Val Leu Gly Ala Tyr Al a Val Asp Asn Thr cys val val 645 650 655 Arg Ser . Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Glu Ala val 660 665 670 Thr , Ma ' val . Ala Ile Cys Cys Arg Ser Arg Hi s Leu Al a Gl n Ala Ser 675 680 685 Gin Glu Leu Gin 690 <210> 5 <211> 662 η <212> PRT <213> Homo sapiens <400> 5 Gin Glu Asp Glu 1 Asp Gly Asp 5 Tyr Glu Glu 10 Leu Val Leu Ala Leu 15 Arg Ser Glu Glu Asp Gly Leu Al a Glu Ala pro Glu Hi s Gly Thr Thr Al a 20 25 30 Thr Phe Hi s Arg Cys Ala Lys Asp pro Trp Arg Leu Pro Gly Thr Tyr 35 40 45 Val Val Val Leu Lys Glu Gl U Thr Hi s Leu ser Gl n Ser Glu Arg Thr 50 55 60 Ala Arg Arg Leu Gin Ala Gin Al a Al a Arg Arg Gly Tyr Leu Thr Lys 65 70 75 80 Tie Leu Hi s Val Phe Hi s Gly Leu Leu Pro Gly Phe Leu Val Lys Met 85 90 95 ser Gly ASp Leu Leu Gl u Leu Ala Leu Lys Leu Pro Hi s Val Asp Tyr 100 105 110 lie Glu Glu Asp Ser Ser val Phe Ala Gin Ser lie Pro Trp Asn Leu 115 120 125 Glu Arg lie Thr pro Pro Arg Tyr Arg Al a Asp Glu Tyr Gl n Pro Pro 130 135 140 Asp Gly Gly Ser Leu val Glu Val Tyr Leu Leu Asp Thr Ser lie Gl n 145 150 155 160 Ser Asp Hi s Arg Glu ll e Glu Gly Arg Val Met Val Thr Asp Phe Glu 165 170 175 Asn val Pro Glu Glu Asp Gl y Thr Arg Phe Hi s Arg Gin Ala Ser Lys 180 185 190 Cys Asp ser His Gly Thr Hi s Leu Ala Gly Val val ser Gly Arg Asp 195 200 205 Ala Gly val Al a Lys Gly Ala Ser Met Arg ser Leu Arg val Leu Asn 210 215 220 cys Gin Gly Lys Gly Thr Val Ser Gly Thr Leu lie Gly Leu Glu Phe 225 230 235 240 lie Arg Lys Ser Gin Leu Val Gin Pro Val Gly Pro Leu Val Val Leu 245 250 255 Leu Pro Leu Ala Gly Gly Tyr ser Arg Val Leu Asn Al a Ala Cys Gl n 260 265 270 Arg I Leu ι Ala Arg Ala . Gly val val Leu Val Thr Ala Ala Gly Asn Phe 275 280 285 Arg ι Asp Asp Ala cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu Val lie 290 295 300 Thr val Gly Ala Thr Asn Ala Gl n ASp Gin Pro Val Thr Leu Gl y rhr 305 310 315 320 Leu Gly Thr Asn Phe Gly Arg Cys val Asp Leu Phe Ala Pro Gly Glu 325 330 335 Asp lie lie Gly Ala Ser Ser Asp cys ser Thr Cys Phe val Ser Gin 340 34 5 350 ser Gly Thr Ser Gin Ala Al a Al a Hi s Val Ala Gly lie Al a Ala Met 355 360 365 Met Leu ser Ala Glu Pro Glu Leu Thr Leu Ala Glu Leu Arg Gin Arg 370 375 380 Leu lie His Phe Ser Ala Lys Asp val lie Asn Glu Ala Trp Phe Pro 385 390 395 400 Glu Asp Gin Arg val Leu Thr Pro Asn Leu Val Ala Ala Leu Pro Pro 405 410 415 ser Thr His Gly Al a Gly T rp Gl n Leu phe cys Arg Thr Val T rp ser 420 425 430 Ala Hi s Ser Gly Pro Thr Arg Met Al a Thr Ala val Ala Arg cys Ala 435 440 445 Pro Asp Glu Glu Leu Leu ser cys Ser Ser Phe Ser Arg Ser Gly Lys 450 455 460 Arg Arg Gly Glu Arg Met Glu Ala Gl n Gly Gly Lys Leu val cys Arg 465 470 475 480 Ala His Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala lie Ala Arg Cys 485 490 495 cys Leu Leu Pro Gin Ala Asn Cys Ser val His Thr Ala Pro Pro Ala 500 505 510 Glu . Ala ser Met Gly Thr Arg Val Hi s cys Hi s Gin Gin Gly Hi s val 515 520 525 Leu Thr ι Gly cys Ser Ser Hi s T rp Glu Val Glu Asp Leu Gly Thr Hi s 530 535 540 3H Lys Pro Pro Val Leu 545 Arg pro Arg Gly 550 Gin Pro 555 Asn Gin Cys Val Gly 560 His Arg Glu Ala Ser lie His Ala Ser Cys Cys His Ala pro Gly Leu 565 570 575 Glu Cys Lys Val Lys Glu His Gly lie Pro Ala Pro Gin Glu Gin Val 580 585 590 Thr Val Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu 595 600 605 Pro Gly Thr Ser His Val Leu Gly Ala Tyr A 1 a Val Asp Asn Thr cys 610 615 620 Val Val Arg Ser Arg Asp Val Ser Thr Thr Gly ser Thr Ser Gl u Glu 625 630 635 640 Ala Val Thr Ala val Ala lie cys Cys Arg Ser Arg His Leu Al a Gin 645 650 655 Ala Ser Gin Glu Leu Gl n 660 <210> 6 <211> 540 <212> PRT <213> Homo sapiens <400> 6 Ser lie Pro Trp Asn Leu Glu Arg Tie Thr Pro Pro Arg Tyr Arg Al a 1 5 10 15 Asp Glu Tyr Gin Pro Pro Asp Gly Gly Ser Leu val Glu val Tyr Leu 20 25 30 Leu Asp Thr Ser lie Gin Ser Asp His Arg Glu lie Glu Gly Arg val 35 40 45 Met Val Thr Asp Phe Glu Asn val Pro Gl u Gl U Asp Gly Thr Arg Phe 50 55 60 His Arg Gin Ala Ser Lys Cys Asp Ser Hi s Gly Thr Hi s Leu Al a Gly 65 70 75 80 val val ser Gly Arg Asp Ala Gly val Ala Lys Gly Ala Ser Met Arg 85 90 95 ser Leu Arg val Leu Asn Cys Gin Gly Lys Gly Thr Val Ser Gly Thr 100 105 110 Leu lie Gly Leu Glu Phe lie Arg Lys Ser Gin Leu val Gin Pro val 115 120 125 Gly Pro Leu Val 130 Val Leu Leu Pro Leu 135 Al a Gly Gly Tyr Ser 140 Arg val Leu Asn Ala Ala i Cys Gl n Arg Leu Ala Arg Al a Gly val val Leu Val 145 150 155 160 Thr Ala Ala Gly Asn Phe Arg Asp Asp Ala Cys Leu Tyr Ser Pro Al a 165 170 175 Ser Ala Pro Glu Val lie Thr Val Gly Ala Thr Asn Ala Gin Asp Gin 180 185 190 pro val Thr Leu Gl y Thr Leu Gly Thr Asn Phe Gly Arg cys Val Asp 195 200 205 Leu Phe Ala Pro Gly Glu Asp lie lie Gly Ala Ser Ser Asp Cys Ser 210 215 220 Thr Cys Phe val Ser Gl n Ser Gly Thr Ser Gin Ala Ala Ala Hi s Val 225 230 235 240 Ala Gly lie Ala Ala Met Met Leu Ser Ala Glu Pro Glu Leu Thr Leu 245 250 255 Ala Glu Leu Arg Gl n Arg Leu lie Hi s Phe Ser Ala Lys Asp val lie 260 265 270 Asn Glu Ala Trp Phe pro Glu Asp Gin Arg val Leu Thr pro Asn Leu 275 280 285 Val Ala Ala Leu Pro Pro Ser Thr Hi s Gly Al a Gly T rp Gin Leu Phe 290 295 300 Cys Arg Thr val Trp Ser Al a His Ser Gly Pro Thr Arg Met Ala Thr 305 310 315 320 Ala Val Ala Arg Cys Ala Pro Asp Glu Gl u Leu Leu Ser Cys Ser Ser 325 330 335 Phe ser Arg ser Gly Lys Arg Arg Gly Glu Arg Met Glu Al a Gin Gly 340 345 350 Gly Lys Leu Val cys Arg Ala Hi s Asn Ala Phe Gly Gl y Glu Gly Val 355 360 365 Tyr Ala lie Ala Arg Cys Cys Leu Leu Pro Gin Ala Asn Cys Ser val 370 375 380 His Thr Ala Pro Pro Al a Glu Ala Ser Met Gly Thr Arg Val Hi s cys 385 390 395 400 His Gin Gin Gly Hi s Val Leu Thr Gly cys Ser Ser His Trp Glu Val 405 410 415 3Π Glu Asp Leu Gly Thr 420 Hi s Lys Pro Pro 425 Val Leu Arg Pro Arg 430 Gly Gin pro Asn Gin Cys Val Gly His Arg Glu Ala Ser lie His Ala Ser cys 435 440 445 Cys Hi s Ala Pro Gly Leu Glu Cys Lys Val Lys Glu Hi s Gly lie Pro 450 455 460 Al a Pro Gin Gl u Gin Val Thr val Ala Cys Gl U Gl u Gly T rp Thr Leu 465 470 475 480 Thr Gly Cys Ser Ala Leu Pro Gly Thr Ser His 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 Gl u Glu Ala val Thr Al a val Al a lie cys cys Arg 515 520 525 Ser Arg His Leu Ala Gl n Ala Ser Gl n Glu Leu Gl n 530 535 540 <210> 7 <211> 692 <212> PRT <213> Homo sapiens <400> 7 ser 5 Ser Arg Arg Ser Trp 10 Trp Pro Leu pro Leu 15 Leu Met 1 Gly Thr val Leu Leu Leu Leu 20 Leu Leu Leu Gly Pro 25 Al a Gly Ala Arg Ala 30 Gin Glu ASp Glu Asp Gly 35 Asp Tyr Glu Glu 40 Leu val Leu Al a Leu 45 Arg Sen Glu Glu Asp 50 Gly Leu Ala Glu Ala Pro 55 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 His Leu Ser Gin 90 Ser Glu Arg Thr Al a 95 Arg Arg Leu Gin Ala 100 Gl n Ala Ala Arg Arg 105 Gly Tyr Leu Thr Lys 110 lie Leu Hi s val Phe His Gly Leu Leu Pro Gly phe Leu Val Lys Met Ser Gly 115 120 125 3ΖΛ Asp Leu Leu Glu 130 i Leu i Ala . Leu 135 Lys Leu Pro Hi s val 140 Asp Tyr lie Glu Glu Asp Ser ser 145 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 Gl n 190 Ser Asp His Arg Glu lie 195 Glu Gly Arg val Met 200 val Thr ASp Phe 205 Gl u Asn Val Pro Glu Glu Asp 210 Gly Thr Arg 215 Phe His Arg Gin Al a 220 Ser iys cys Asp Ser His Gly Thr 225 Hi S Leu 230 Ala Gly val val ser 235 Gly Arg ASP Ala Gly 240 val Ala 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 Gin Leu 275 val Gl n Pro Val Gly 280 Pro Leu Val Val 285 Leu Leu Pro Leu Ala Gly Gly 290 Tyr ser Arg 295 val Leu Asn Ala Ala 300 cys Gl n Arg Leu Ala Arg Ala Gly 305 val Val 310 L.eu val Thr Ala Ala 315 Gly Asn Phe Arg Asp 320 Asp Ala cys Leu Tyr 325 Ser Pro Ala Ser Al a 330 Pro Glu Val He Thr 335 Val Gly Ala Thr Asn 340 Al a Gin Asp Gin Pro 345 val Thr Leu Gly Thr 350 Leu Gly Thr Asn Phe Gly 355 Arg cys Val Asp Leu 360 phe Ala Pro Gly 365 Glu Asp lie lie Gly Ala Ser 370 Ser Asp Cys 375 Ser Thr cys Phe Val 380 Ser Gin Ser Gly Thr Ser Gin Ala . 385 Ala Ala 390 Hi s Val Ala Gly lie 395 Ala Ala Met Met Leu 400 3t3 Ser Ala Glu Pro Glu 405 Leu Thr Leu Ala Glu 410 Leu Arg Gin Arg Leu 415 He His Phe Ser Ala Lys 420 Asp Val lie Asn 425 Gl u Ala Trp phe Pro 430 Glu Asp Gin Arg val Leu Thr 435 Pro Asn Leu 440 val Ala Al a Leu Pro 445 Pro Ser Thr His Gly Ala Gly Trp 450 Gl n Leu 455 Phe Cys Arg Thr Val 460 Trp Ser Al a Hi s Ser Gly Pro Thr Arg 465 Met 470 Ala Thr Ala lie Ala 475 Arg Cys Ala pro Asp 480 Glu Glu Leu Leu Ser 485 Cys Ser ser Phe Ser 490 Arg ser Gl y Lys Arg 495 Arg Gly Glu Arg Met Glu 500 Ala Gin Gly Gly 505 Lys Leu Val Cys Arg 510 Ala His Asn Ala Phe Gly Gly 515 Glu Gly val 520 Tyr Ala He Al a Arg 525 Cys Cys Leu Leu Pro Gin Ala Asn 530 cys Ser 535 Val Hi s Thr Ala Pro 540 Pro Al a Glu Ala Ser Met Gly Thr Arg 545 Val 550 Hi s Cys Hi s Gin Gl n 555 Gly His val Leu Thr 560 Gly cys Ser Ser His 565 Trp Glu Val Gl u Asp 570 Leu Gly Thr His Lys 575 Pro Pro val Leu Arg Pro 580 Arg Gly Gl n Pro 585 Asn Gin Cys Val Gly 590 Hi s Arg Glu Ala Ser lie Hi s 595 Ala Ser Cys 600 Cys Hi s Al a Pro Gly 605 Leu Glu Cys Lys Val Lys Glu His 610 Gly He 615 Pro Ala pro Gin Gl u 620 Gin val Thr Val Ala Cys Glu Glu Gly 625 Trp 630 Thr Leu Thr Gly cys 635 Ser Ala Leu Pro Gly 640 Thr Ser His Val Leu 645 Gly Ala Tyr Al a val 650 Asp Asn Thr Cys Val 655 val Arg ser Arg Asp val 660 Ser Thr Thr Gly 665 Ser Thr Ser Gl u Gly 670 Ala val Thr Ala Val Ala lie 675 cys Cys Arg 680 Ser Arg His Leu Ala 685 Gin a! a Ser Gin Glu Leu Gin 690 <210> 8 <211> 662 <212> PRT <213> Homo sapiens <400> 8 Glr 1 Glu ASp i Glu Asp Gl y Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg 1 5 10 15 Ser ' Glu Gl U Asp Gly Leu Al a Glu Al a Pro Glu Hi s Gly Thr Thr Ala 20 25 30 Thr Phe Hi s Arg cys Al a Lys Asp Pro T rp Arg Leu Pro Gly Thr ryr 3 5 40 45 Val Val Val Leu Lys Gl u Gl u Thr His Leu Ser Gin Ser Glu Arg Thr 50 55 60 Ala Arg Arg Leu Gin Ala Gin Ala Ala Arg Arg Gly Tyr Leu Thr Lys 65 70 75 80 lie Leu Hi s Val Phe Hi s Gly Leu Leu Pro Gly Phe Leu Val Lys Met 85 90 95 Ser Gly Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro Hi s Val Asp Tyr 100 105 110 Tie Glu Glu Asp Ser Ser val phe Ala Gl n ser il e Pro Trp Asn Leu 115 120 125 Glu Arg Ile Thr Pro Pro Arg Tyr Arg Al a Asp Glu Tyr Gin Pro Pro 130 135 140 Asp Gly Gly ser Leu val Glu Val Tyr Leu Leu Asp Th r Ser Ile Gl n 145 150 155 160 Ser Asp Hi s Arg Glu lie Glu Gl y Arg val Met val Thr Asp Phe Glu 165 170 175 Asn val pro Gl u Glu Asp Gly Thr Arg Phe Hi s Arg Gin Ala Ser Lys 180 185 190 Cys Asp Ser Hi s Gly Thr Hi s Leu Ala Gly val Val Ser Gly Arg Asp 195 200 205 Al a Gly val Ala Lys Gly Ala Ser Met Arg ser Leu Arg val Leu Asn 210 215 220 Cys Gin ' Gly Lys Gly Thr val ser Gly Thr Leu ile Gly Leu Gl u Phe 225 230 235 240 lie : Arg Lys Ser Gin Leu Val Gin Pro val Gly pro Leu Val Val Leu 245 250 255 Leu Pro Leu Ala Gly Gly Tyr ser Arg val Leu Asn Ala Al a Cys Gl n 260 265 270 Arg Leu Al a Arg Ala Gly val Val Leu val Thr Al a Ala Gly Asn Phe 275 280 285 Arg Asp ASp Ala Cys Leu Tyr Ser Pro Ala Ser Al a Pro Gl u val lie 290 295 300 Thr Val Gly Ala Thr Asn Ala Gin ASp Gin Pro Val Thr Leu Gly Thr 305 310 315 320 Leu Gly Thr Asn Phe Gly Arg cys val Asp Leu Phe Al a Pro Gly Gl u 325 330 335 Asp lie lie Gly Ala Ser Ser Asp Cys Ser Thr cys Phe val Ser Gl n 340 345 350 Ser Gly Thr Ser Gin Ala Ala Ala Hi s Val Ala Gly lie Ala Ala Met 355 360 365 Met Leu Ser Ala Glu Pro Glu Leu Thr Leu Ala Gl u Leu Arg Gin Arg 370 375 380 Leu lie His Phe Ser Al a Lys ASP val lie Asn Glu Al a Trp Phe Pro 385 390 395 400 Glu Asp Gin Arg val Leu Thr Pro Asn Leu Val Al a Ala Leu Pro Pro 405 410 415 Ser Thr Hi s Gly Ala Gly Trp Gl n Leu Phe cys Arg Thr val T rp Ser 420 425 430 Ala Hl s Ser Gly Pro Thr Arg Met Al a Thr a! a lie Al a Arg Cys Al a 435 440 445 Pro Asp Glu Glu Leu Leu Ser cys Ser Ser Phe ser Arg Ser Gly Lys 450 455 460 Arg Arg Gly Glu Arg Met Glu Al a Gin Gly Gly Lys Leu Val cys Arg 465 470 475 480 Ala Hi s Asn Ala Phe Gly Gl y Glu Gly val Tyr Al a lie Ala Arg Cys 485 490 495 cys Leu Leu Pro Gin Ala Asn cys Ser Val Hi s Thr Al a Pro Pro Al a 500 505 510 3^ Glu Ala Ser Met 515 Gly Thr Arg val 520 His cys His Gin Gl n 525 Gly His val Leu Thr Gly Cys 530 Ser Ser His Trp 535 Glu Val Glu Asp 540 Leu Gly Thr Hi s Lys Pro Pro Val 545 Leu Arg 550 Pro Arg Gly Gin Pro Asn 555 Gin cys val Gly 560 His Arg Glu Ala Ser 565 He His Ala Ser Cys 570 Cys Hi s Al a Pro Gl y 575 Leu Glu Cys Lys Val 580 Lys Glu His Gly Tie Pro 585 Ala Pro Gin Glu 590 Gin Val Thr Val Ala Cys 595 Glu Glu Gly Trp 600 Thr Leu Thr Gly cys 605 Ser Al a Leu Pro Gly Thr Ser 610 Hi s val Leu Gly 615 Ala Tyr Ala Val 620 Asp Asn Thr Cys val val Arg Ser 62 5 Arg Asp 630 Val ser thr Thr Gly Ser 635 Thr Ser Glu Gly 640 Ala val Thr Ala Val 645 Al a lie Cys Cys Arg 650 Ser Arg His Leu Ala 655 Gl n Ala Ser Gin Glu 660 Leu Gin <210> 9 <211> 540 <212> PRT <213> Homo sapiens <400> 9 Ser lie Pro Trp 1 Asn 5 Leu Glu Arg lie Thr 10 Pro Pro Arg Tyr Arg 15 Al a Asp Glu Tyr Gin 20 Pro Pro Asp Gly Gly Ser 25 Leu val Glu Val 30 Tyr Leu Leu Asp Thr Ser 35 lie Gin Ser Asp 40 His Arg Glu lie Glu 45 Gly Arg Val Met Val Thr Asp 50 Phe Glu Asn Val 55 Pro Glu Glu Asp 60 Gly Thr Arg Phe Hi5 Arg Gin Ala 65 Ser Lys 70 Cys Asp ser His Gly Thr 75 Hi s Leu Ala Gly 80 Val Val ser Gly , Arg Asp Ala Gly Val Ala Lys Gly Al a ser Met Arg 90 95 3V\ Ser ’ Leu i Arg I val Leu i Asn Cys Gin Gly Lys Gly Thr Val Ser Gly Thr 100 105 110 Leu i lie1 Gly Leu Glu Phe lie Arg Lys Ser Gin Leu Val Gin Pro val 115 120 125 Gly Pro Leu Val val Leu Leu Pro Leu Al a Gly Gly Tyr ser Arg val 130 135 140 Leu Asn Al a Al a Cys Gl n Arg Leu Al a Arg Ala Gly Val Val Leu Val 145 150 15 5 160 rhr Ala Ala Gly Asn Phe Arg Asp Asp Al a cys Leu 'ryr ser Pro Al a 165 170 17 5 Ser Ala Pro Glu val lie Thr val Gl y Ala 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 195 200 205 Leu Phe Al a Pro Gly Glu ASD He lie Gly Al a Ser Ser Asp Cys Ser 210 215 220 Thr Cys Phe Val Ser Gl n Ser Gly Thr Ser Gin Al a Ala Ala Hi s Val 225 230 235 240 Al a Gly lie Ala Ala Met Met Leu ser Ala Gl u Pro Gl u Leu Thr Leu 245 250 255 Ala Glu Leu Arg Gl n Arg Leu lie Hi s Phe Ser Al a Lys Asp val lie 260 265 270 Asn Glu Ala Trp Phe Pro Glu Asp Gin Arg Val Leu Thr Pro Asn Leu 275 280 285 val a! a Ala Leu Pro Pro Ser Thr Hi s Gly Ala Gly Trp Gin Leu Phe 290 295 300 Cys Arg Thr val T rp Ser Ala Hi s Ser Gly Pro Thr Arg Met Al a Thr 305 310 315 320 Ala lie Ala Arg Cys Ala Pro ASp Glu Glu Leu Leu Ser Cys ser Ser 325 330 335 Phe Ser Arg ser Gly Lys Arg Arg Gly Gl u Arg Met Glu Al a Gin Gly 340 345 350 Gly Lys Leu Val cys Arg Ala Hi s Asn Ala Phe Gly Gly Gl u Gly val 355 360 365 Tyr . Al a lie . Ala Arg Cys Cys Leu Leu Pro Gl n Ala Asn Cys Ser val 370 375 380 Hi s Thr Ala Pro Pro Al a Gl u Ala Ser Met Gly Thr Arg val Hi s Cys 385 390 395 400 Hi s Gin Gl n Gly Hi s val Leu Thr Gly cys Sen Sen Hi s Trp Glu val 405 410 415 Glu Asp Leu Gly Thr Hi s Lys Pro Pro val Leu Arg Pro Arg Gly Gl n 420 425 430 pro Asn Gl n Cys Val Gl y Hi s Arg Gl U Al a Sen lie His Ala Ser Cys 43 5 440 44 5 Cys Hi s Al a Pro Gly Leu Gl u Cys Lys val Lys Glu Hl s Gly lie Pro 450 455 460 Ala pro Gin Glu Gl n Val Thr val Ala Cys Gl u Glu Gly τ rp Th r Leu 465 470 475 480 Thr Gly Cys Ser Ala Leu Pro Gly Thr ser Hi s Val Leu Gly Ala Tyr 485 490 495 Ala Val Asp Asn Thr cys Val val Arg Sen Arg Asp Val Ser Thr Thr 500 505 510 Gly Ser Thr Ser Glu Gly Ala Val Thr Ala Val Ala He cys Cys Arg 515 520 525 ser Arg Hi s Leu Ala Gl n Al a Ser Gin Glu Leu Gin 530 535 540 <210> 10 <211> 692 <212> PRT <213> Homo sapiens <400> 10 Met 1 Gly Thr Val Ser 5 Ser Arg Arg Ser Trp 10 Trp Pro Leu Pro Leu 15 Leu Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Al a Arg Al a Gin Glu 20 25 30 Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg Ser Glu 35 40 45 Glu Asp Gly Leu Ala Glu Al a Pro Glu Hi s Gly Thr Thr Ala Thr Phe 50 55 60 Hi s Arg cys Al a Lys Asp pro T rp Arg Leu Pro Gly Thr Tyr Val Val 65 70 75 80 Val Leu Lys Glu Glu Thr Hi s Leu Ser Gin Ser Glu Arg Thr Al a Arg 90 95 213 Arg t Leu i Gin i Ala Gl n Al a Ala Arg Arg Gly Tyr Leu Thr Lys lie Leu 100 105 110 Hi s Val Phe Hi s Gly Leu Leu pro Gly Phe Leu Val Lys Met ser Gl y 115 120 125 Asp Leu Leu Gl u Leu Al a Leu Lys Leu pro His val Asp Tyr Tie Glu 130 135 140 Glu ASp Ser Ser Val Phe Ala Gin Ser lie Pro τ rp Asn Leu Glu Arg 145 150 .155 160 lie Thr pro Pro Arg Tyr Arg Al a Asp Glu Tyr Gin pro Pro Asp Gly 165 170 175 Gly Ser Leu Val Gl u val Tyr Leu Leu Asp Thr ser lie Gin Ser Asp 180 185 190 Hi s Arg Gl u lie Glu Gly Arg val Met val Thr Asp Phe Gl u Asn Val 195 200 205 Pro Glu Glu Asp Gly Thr Arg Phe Hi s Arg Gin Ala ser Lys cys Asp 210 215 220 Ser Hi s Gly Thr Hi s Leu Al a Gly val val Ser Gly Arg Asp Al a 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 Il e Gly Leu Gl U Phe lie Arg 260 265 270 Lys Ser Gin Leu Val Gl n Pro val Gly Pro Leu Val Val Leu Leu pro 275 280 285 Leu Al a Gly Gly Tyr Ser Arg val Leu Asn Ala Ala cys Gin Arg Leu 290 295 300 Ala Arg Al a Gly Val Val Leu Val Thr Ala Ala Gly Asn Phe Arg ASp 305 310 315 320 Asp Ala cys Leu Tyr Ser Pro Al a ser Ala Pro Glu val lie Thr val 325 330 335 Gly . Ala Thr Asn Ala Gin Asp Gin Pro Val Thr Leu Gly Thr Leu Gly 340 345 350 Thr . Asn phe Gl y Arg cys val Asp Leu Phe Ala Pro Gly Glu Asp lie 355 360 365 530 lie Gly Ala Ser Ser Asp 3701 cys ser Thr cys Phe 375 Val 380 Ser Gin Ser Gly Thr Ser Gin Ala Ala Ala His val Ala Gly lie Ala Ala Met Met Leu 385 390 395 400 Ser Ala Glu pro Glu Leu Thr Leu Ala Glu Leu Arg Gin Arg Leu lie 405 410 415 His Phe Ser Ala Lys Asp Val lie Asn Glu Ala T rp Phe Pro Glu Asp 420 425 430 Gin Arg val Leu Thr Pro Asn Leu val Ala Ala Leu Pro Pro Ser T h γ- 435 440 445 His Gly Ala Gly Trp Gin Leu Phe Cys Arg Thr val Trp Ser Al a η! s 450 455 460 Ser Gly Pro Thr Arg Met Ala Thr Ala val Ala Arg Cys Ala Pro Asp 465 470 475 480 Glu Glu Leu Leu Ser Cys ser ser Phe ser Arg ser Gly Lys Arg Arg 485 490 495 Gly Glu Arg Met Glu Ala Gin Gly Gly Lys Leu val Cys Arg Ala His 500 505 510 Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala Tie Ala Arg Cys cys Leu 515 520 525 Leu Pro Gin Ala Asn Cys Ser Val His Thr Ala Pro pro Ala Glu Al a 530 535 540 Ser Met Gly Thr Arg Val His Cys His Gin Gin Gly His Val Leu Thr 545 550 555 560 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 Pro Asn Gin cys Val Gly Hi s Arg 580 585 590 Glu Ala ser lie His Ala Ser Cys Cys His Ala pro Gly Leu Glu cys 595 600 605 Lys Val Lys Glu His Gly lie Pro Ala Pro Gin Glu Gin Val Thr Val 610 615 620 Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly cys ser Ala Leu Pro Gly 625 630 635 640 Thr Ser His val Leu Gly , Ala Tyr Ala Val Asp Asn Thr Cys val val 645 650 655 Arg Ser Arg Asp val Ser Thr Thr Gly Ser Thr ser Glu Gly Ala Val 660 665 ' 670 Thr Ala Val Ala lie Cys Cys Arg ser Arg His Leu Ala Gin Ala Ser 675 680 685 Gin Glu Leu Gin 690 <210> 11 <211> 662 <212> PRT <213> Homo sapiens <400> 11 Gin Gl U Asp Glu Asp Gly Asp Tyr Gl U Gl u Leu val Leu Al a Leu Arg 1 5 10 15 Ser Glu Glu Asp Gly Leu Al a Glu Ala pro Gl u Hi s Gly Thr Thr Ala 20 25 30 Thr Phe His Arg Cys Ala Lys Asp Pro Trp Arg Leu pro Gly Thr Tyr 35 40 45 val Val Val Leu Lys Glu Glu Thr His Leu Ser Gin ser Glu Arg Thr 50 55 60 Al a Arg Arg Leu Gin Ala Gin Ala Al a Arg Arg Gly Tyr Leu Thr Lys 65 70 75 80 Il e Leu Hi 5 Val Phe Hi s Gly Leu Leu Pro Gly Phe Leu val Lys Met 85 90 95 Ser Gly Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro Hi s Val Asp Tyr 100 105 110 lie Gl u Glu Asp ser ser val phe Al a Gl n Ser lie Pro T rp Asn Leu 115 120 125 Glu Arg ile Thr Pro Pro Arg Tyr Arg Al a Asp Glu Tyr Gin pro pro 130 135 140 Asp Gly Gly Ser Leu val Gl u val Tyr Leu Leu Asp Thr Ser lie Gin 145 150 155 160 Ser Asp Hi s Arg Glu lie Glu Gly Arg val Met Val Thr Asp phe Glu 165 170 175 Asn Val Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gin Al a Ser Lys 180 185 190 Cys Asp Ser Hi s Gly Thr Hi s Leu Al a Gly val val Ser Gly Arg Asp 195 200 205 Al a Gly Val Ala Lys Gly Al a Ser Met Arg Ser Leu Arg val L.eu Asn 210 215 220 Cys Gl n Gl y Lys Gly Thr val Ser Gly Thr Leu lie Gly Leu Gl u Phe 225 230 235 240 He Arg Lys Ser Gin Leu val Gl n Pro val Gly Pro Leu Val val Leu 245 250 255 Leu pro Leu Al a Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala Cys Gl n 260 265 270 Arg Leu Al a Arg Ala Gly Val Val Leu Val Thr Al a Ala Gly Asn Phe 275 280 285 Arg Asp Asp Al a Cys Leu Tyr Ser pro Al a Ser Al a pro Glu val il e 290 295 300 Thr Val Gly Al a Thr Asn Ala Gin Asp Gin Pro Val Thr Leu Gly Thr 305 310 315 320 Leu Gly Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gl y Glu 325 330 335 Asp lie lie Gly Al a Ser Ser Asp Cys Ser Thr cys Phe val Ser Gin 340 345 350 Ser Gly Thr Ser Gl n Al a Ala Al a Hi s val Ala Gly il e Ala Al a Met 355 360 365 Met Leu Ser Al a Glu Pro Gl u Leu Thr Leu Al a Glu Leu Arg Gin Arg 370 375 380 Leu Il e Hi s Phe Ser Al a Lys Asp Val il e Asn Glu Ala τ rp Phe Pro 385 390 395 400 Glu Asp Gin Arg val Leu Thr pro Asn Leu val Ala Ala Leu Pro Pro 405 410 415 Ser Thr Hi s Gly Al a Gly T rp Gl n Leu Phe cys Arg Thr val T rp Ser 420 425 430 Ala His Ser Gly Pro Thr Arg Met Ala Thr Ala val Ala Arg Cys Ala 435 440 445 Pro Asp Gl u Glu Leu Leu Ser cys Ser Ser Phe Ser Arg Ser Gly Lys 450 455 460 Arg Arg Gly Glu Arg Met Glu Al a Gin Gly Gly Lys Leu Val Cys Arg 465 470 475 480 333 Al a Hl S Asn Al a Phe Gly Gly Gl u Gly val Tyr Ala lie Ala Arg Cys 485 490 495 cys Leu Leu Pro Gl n Ala Asn Cys Ser Val Hi s Thr Al a Pro Pro Al a 500 505 510 Glu Al a Ser Met Gl y Thr Arg Val Hi s cys Hi s Gin Gin Gly Hi s Val 515 520 525 Leu Thr Gly Cys Ser Ser Hi s T rp Glu val Glu Asp Leu cly Thr Hi s 530 535 540 Lys Pro Pro val Leu Arg Pro Arg Gly Gin Pro Asn Gin Cys Val Gl y 545 550 555 560 Hi s Arg Glu Al a Ser lie Hi s Ala ser Cys Cys Hi s Ala pro Gly Leu 565 570 575 Glu Cys Lys val Lys Glu His Gly lie Pro Ala Pro Gin Glu Gin val 580 585 590 Thr val Ala cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu 595 600 605 Pro Gly Thr Ser Hi s Val Leu Gly Ala Tyr Al a Val Asp Asn Thr cys 610 615 620 val Val Arg Ser Arg Asp val ser Thr Thr Gly Ser Thr ser Glu Gly 625 630 635 640 Al a val Thr Ala val Ala lie cys Cys Arg Ser Arg Hi s Leu Ala Gin 645 650 655 Al a Ser Gl n Glu Leu Gl n 660 <210> 12 <211> 540 <212> PRT <213> Homo sapiens <400> 12 Ser lie Pro Trp Asn Leu Glu Arg lie Thr Pro Pro Arg Tyr Arg Ala 1 5 10 15 Asp Glu Tyr Gin Pro Pro ASp cly Gly ser Leu Val Glu Val Tyr Leu 20 25 30 Leu ASp Thr ser U e Gin Ser Asp Hi s Arg Glu lie Glu Gly Arg val 35 40 45 Met Val Thr Asp Phe Glu Asn Val Pro Gl u Glu Asp Gly Thr Arg Phe 55 60 314 Hi £ ; Arg 1 Glr 1 Al 3 i Ser Lys Cys Asp ' Ser His Gly Thr His Leu Ala Gly 65 70 75 80 val val Ser ' Gly ‘ Arg ASP Ala Gly val Ala Lys Gly Ala Ser Met Arg 85 90 95 Ser Leu Arg val Leu Asn Cys Gin Gly Lys Gly Thr val ser Gly Thr 100 105 110 Leu lie Gly Leu Gl U Phe lie Arg cys Ser Gin Leu val Gl n pro val 115 120 12 5 Gly Pro Leu val val Leu Leu pro Leu Ala Gly Gly Tyr Ser Arg val 130 135 140 Leu Asn Al a Al a Cys Gin Arg Leu Al a Arg Ala Gly Val val Leu val 145 150 155 160 Thr Al a Ala Gly Asn Phe Arg Asp ASp Ala Cys Leu Tyr Ser Pro Al a 165 170 175 Ser Ala Pro Gl u val lie Thr Val Gly Ala Thr Asn Ala Gl n Asp Gin 180 185 190 Pro val Thr Leu Gly Thr Leu Gly Thr Asn Phe Gly Arg cys val Asp 195 200 205 Leu Phe Ala pro Gly Glu Asp ll e lie Gly Ala Ser Ser ASp cys ser 210 2.15 220 Thr Cys Phe Val Ser Gl n ser Gly Thr Ser Gin Al a Ala Al a His val 225 230 235 240 Al a Gly lie Ala Ala Met Met Leu Ser Ala Glu Pro Glu Leu Thr Leu 245 250 255 Ala Gl u Leu Arg Gl n Arg Leu ll e Hi 5 Phe Ser Al a Lys Asp Val He 260 265 270 Asn Glu Al a T rp Phe Pro Gl u Asp Gin Arg Val Leu Thr pro Asn Leu 275 280 285 val Ala Al a Leu Pro Pro ser Thr Hi s Gly Ala Gly Trp Gl n Leu Phe 290 295 300 Cys Arg Thr val τ rp Ser Ala His Ser Gly Pro Thr Arg Met Ala Thr 305 310 315 320 Ala Val , Ala Arg Cys Al a Pro ASp Glu Glu Leu Leu Ser cys Ser Ser 325 330 335 Phe Ser Arg Ser 1 Gly Lys Arg Arg Gly Glu Arg Met Glu Al a Gin Gly 340 345 350 -5 Gly Lys Leu val cys Arg Ala Hi s Asn Ala Phe Gly Gly Glu Gly val 355 360 365 Tyr Al a Xie Ala Arg Cys cys Leu Leu Pro Gin Al a Asn Cys Ser val 370 375 380 Hi s Th r Al a Pro Pro Ala Glu Al a Ser Met Gly Thr Arg val Hi s Cys 385 390 395 400 Hi s Gin Gl n Gly Hi s Val Leu Thr Gly Cys Ser Ser His τ rp Gl u Val 405 410 415 Gl u Asp leu Gly Thr Hi 5 lys Pro Pro Val Leu Arg Pro Arg Gly Gin 420 425 430 Pro Asn Gin cys val Gly Hi s Arg Gl u Ala Ser lie Hi s Al a ser Cys 435 440 445 cys Hi s Ala Pro Gly Leu Glu cys Lys Val Lys Glu Hi s Gly lie Pro 450 455 460 Ala Pro Gin Glu Gl n Val Thr val Ala Cys Glu Glu Gly Trp Thr Leu 465 470 475 480 Thr Gly Cys Ser Ala Leu Pro Gly Thr Ser His 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 Ala val Thr Ala Val Ala lie Cys cys Arg 515 520 525 Ser Arg His Leu Al a Gl n Al a ser Gl n Glu Leu Gin 530 535 540 <210> 13 <211> 692 <212> PRT <213> Homo sapiens <40i d> i: I Met Gly Thr Val Ser Ser Arg Arg ser Trp Trp Pro Leu Pro Leu Leu 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gin Glu 20 25 30 Asp Glu Asp Gly Asp Tyr Glu Glu Leu val Leu Al a Leu Arg Ser Glu 35 40 45 Glu ASp Gly Leu val Gl u Ala Pro Glu Hi s Gly Thr Thr Ala Thr Phe 55 60 336 His Arg Cys 65 Ala Lys : Asp 70 1 Pre i Trp1 Arg Leu pro Gly 75 Thr Tyr Val Val Leu Lys Glu Glu 85 Thr Hi s Leu Ser Gin 90 Ser Glu Arg Thr Ala 95 Arg Leu Gin Ala Gin 100 Ala Ala Arg Arg 105 Gly Tyr Leu Thr Lys 110 lie His Val Phe 115 His Gly Leu Leu Pro 120 Gly Phe Leu Val Lys 125 Met Ser Asp Leu Leu 130 Glu Leu Ala Leu 135 Lys Leu Pro His val 140 ASP Ty r lie Glu Asp Ser 145 Ser Val Phe 150 Al a Gin ser lie Pro Trp 155 Asn Leu Gl u lie Thr Pro Pro Arg 165 Tyr Arg Ala Asp Glu 170 Tyr Gin Pro Pro Asp 175 Gly Ser Leu val Glu 180 val Tyr Leu Leu 185 Asp Thr Ser Il e Gin 190 Ser His Arg Glu 195 lie Glu Gly Arg Val 200 Met Val Thr Asp Phe 205 Gl u Asn Pro Glu Glu 210 Asp Gly Thr Arg 215 Phe His Arg Gin Ala 220 Ser Lys Cys Ser His Gly 225 Thr His Leu 230 Ala Gly val val Sen Gly 235 Arg Asp Al a Val Ala Lys Gl y Ala 245 Ser Met Arg ser Leu 250 Arg val Leu Asn Cys 255 Gly Lys Gly Thr Val 260 Ser Gl y Thr Leu 265 He Gly Leu Gl U phe 270 lie Lys Ser Gin 275 Leu Val Gin Pro val 280 Gly Pro Leu val Val 285 Leu Leu Leu Ala Gly 290 Gly Tyr Ser Arg 295 Val Leu Asn Ala Ala 300 cys Gl n Arg Ala Arg Ala ' 305 Gly val val 310 Leu Val Thr Ala Ala Gly 315 Asn Phe Arg Asp Ala Cys Leu Tyr 325 ser Pro . Ala Ser Al a 330 Pro Glu Val lie Thr 335 Val Arg Leu Gly G IU Arg 160 Gly Asp Val Asp Gly 240 Gin Arg Pro Leu Asp 320 Val 331 Gly Ala i Thr1 Asn 340 Ala Gin 1 ASp1 Gin Pro 345 val Thr Leu Gly Thr 350 Leu Gly Thr Asn Phe 355 ! Gly Arg cys Val Asp 360 Leu Phe Al a Pro Gly 365 Glu Asp lie lie Gly 370 Ala Ser ser Asp Cys 375 Ser Thr cys Phe val 380 ser Gin ser Gly Thr ser 385 Gin Ala Ala Ala 390 Hi s val Ala Gly lie 395 Al a Ala Met Met Leu 400 Ser Ala Glu Pro Glu L.eu 405 Thr Leu Al a Glu 410 Leu Arg Gin Arg Leu 415 lie His Phe Ser Ala 420 Lys Asp val lie Asn 425 Gl u Ala Trp Phe Pro 430 Gl u Asp Gin Arg val 435 Leu Thr Pro Asn Leu 440 Val Ala Al a Leu Pro 445 Pro Ser Thr His Gly 450 Ala Gly Trp Gin Leu 455 Phe cys Arg Thr Val 460 Trp Ser Ala His Ser Gly 465 Pro Thr Arg Met 470 Ala Thr Ala val Ala 475 Arg Cys Ala Pro Asp 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 Gl n 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 Al a Asn Cys ser 535 Val Hi s Thr Al a Pro 540 Pro Al a Glu Al a Ser Met 545 Gl y Thr Arg val 550 Hi s Cys Hi s Gl n Gin 555 Gl y His val Leu Thr 560 Gly Cys Ser Ser His Trp 565 Glu Val Gl u 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 lie Hi s Al a Ser Cys 600 Cys His Ala Pro Gly 605 Leu Glu Cys Lys Val l 610 Lys i Glu His Gly He 615 Pro Ala Pro Gin Glu 620 Gin val Thr val 33S Ala cys > Gl u Gl L i Gly1 Trp Thr Leu Thr Gly cys Ser Ala Leu Pro Gly 625 630 635 640 Thr Ser ' His ; val Leu Gly Ala Tyr Ala val Asp Asn Thr Cys Val Val 645 650 655 Arg Ser ' Arg 1 Asp Val Ser Thr Thr Gly Ser Thr Ser Gl u Gl u Ala Val 660 665 670 Thr Ala Val Ala lie Cys Cys Arg Ser Arg His i.eu Ala Gin Ala Ser 675 680 685 Gin Glu Leu Gl n 690 <210> 1 4 <211> 6 62 <212> P RT <213> rt omo sapT ens <400> Ι- 4 ΟΙ n Glu ASp Glu Asp Gly ASp Tyr Glu Glu Leu Val Leu Al a Leu Arg 1 5 10 15 Ser Glu Glu Asp Gly Leu val Gl u Ala Pro Glu Hi s Gly Thr Thr Ala 20 25 30 Thr Phe Hi s Arg Cys Ala Lys Asp Pro T rp Arg Leu Pro Gly Thr Tyr 35 40 45 Val Val val Leu Lys Glu Gl u Thr Hi s Leu Ser Gin Ser Glu Arg Thr 50 55 60 Ala Arg Arg Leu Gin Al a Gl n Al a Ala Arg Arg Gly Tyr Leu Thr Lys 65 70 75 80 Ile Leu Hi s Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met 85 90 95 Ser Gly Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His val Asp Tyr 100 105 110 Ile Glu Glu Asp Ser Ser Val Phe Ala Gin Ser lie Pro Trp Asn Leu 115 120 125 Glu Arg Ile Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gin Pro Pro 130 135 140 Asp Gly Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser Ile Gin 145 150 155 160 Ser Asp Hi s Arg Glu lie Glu Gly Arg val Met Val Thr ASp phe Glu 165 170 175 33 q Asn ι val Pro Glu ι Glu Asp > Gly Thr Arg Phe Hi s Arg Gin Ala Ser Lys 180 185 190 Cys Asp ser His Gly Thr Hi s Leu Al a Gly val val ser Gly Arg Asp 195 200 205 Ala Gly val Ala Lys Gly Ala Ser Met Arg ser Leu Arg Val Leu Asn 210 215 220 Cys Gl n Gly Lys Gly Thr Val Ser Gly Thr Leu lie Gly Leu Glu Phe 225 230 235 240 lie Arg Lys Ser Gin Leu val Gin Pro val Gly Pro Leu val val Leu 245 250 255 Leu Pro Leu Ala Gly Gly Tyr Ser Arg Val Leu Asn Ala Al a Cys Gin 260 265 270 Arg Leu Al a Arg Ala Gly val val Leu val Thr Ala Ala Gly Asn Phe 275 280 285 Arg Asp ASp Ala Cys Leu Tyr ser Pro Ala ser Ala Pro Glu val il e 290 295 300 Thr val Gly Ala Thr Asn Al a Gin Asp Gin Pro Val Thr Leu Gly Thr 305 310 315 320 Leu Gly Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Glu 325 330 335 Asp lie lie Gly Al a Ser Ser Asp cys Ser Thr cys Phe Val Ser Gl n 340 345 350 Ser Gly Thr Ser Gin Ala Al a Ala Hi s Val Ala Gly lie Al a Ala Met 355 360 365 Met Leu Ser Al a Gl u Pro Glu Leu Thr Leu Ala Glu Leu Arg Gin Arg 370 375 380 Leu lie Hi s Phe Ser Al a Lys Asp val lie Asn Glu Ala Trp Phe Pro 385 390 395 400 Glu ASp Gin Arg Val Leu Thr Pro Asn Leu Val Al a Ala Leu Pro Pro 405 410 415 Ser Thr Hi s Gly Al a Gly Trp Gl n Leu Phe Cys Arg Thr val T rp Ser 420 425 430 Ala i Hi s : 5er Gly Pro Thr Arg Met Al a Thr Al a Val Al a Arg Cys Al a 435 440 445 Pro ι Asp Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys 450 455 460 Arg Arg Gly Glu Arg Met Glu Al a Gl n Gly Gly Lys Leu Val Cys Arg 465 470 475 480 Al a Hi s Asn Ala Phe Gly cly Glu Gly Val Tyr Ala lie Ala Arg Cys 485 490 495 Cys Leu Leu Pro Gin Ala Asn Cys Ser val Hi s Thr Ala Pro Pro Ala 500 505 510 Glu Al a Ser Met Gly Thr Arg Val Hi s cys His Gl n Gl n Gly Hi s val 515 520 525 Leu Thr Gly Cys Ser Ser Hi s Trp Glu Val Glu A5p Leu cly Thr Hi s 530 535 540 Lys Pro Pro Val Leu Arg Pro Arg Gly Gl n Pro Asn Gin Cys val Gly 545 550 555 560 Hi s Arg Glu a! a Ser lie Hi s Ala ser cys cys His Ala pro Gly Leu 565 570 575 Glu Cys Lys Val Lys Glu His Gly lie Pro Ala Pro Gin Gl u Gl n Val 580 585 590 Thr Val Ala cys Gl u Glu Gly Trp Thr Leu Thr Gly cys Ser Al a Leu 595 600 605 Pro Gl y Thr Ser Hi s Val Leu Gly Al a Tyr Al a val Asp Asn Thr cys 610 615 620 Val Val Arg Ser Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Gl u Glu 625 630 635 640 Ala Val Th r Al a Val Al a lie Cys cys Arg Ser Arg Hi s Leu Al a Gl n 645 650 655 Ala Ser ' Gl n Glu Leu Gin 660 <210> 15 <211> 692 <212> PRT <213> Homo sapiens <400> 15 Met Gly Thr val ser ser Arg Arg ser Trp Trp Pro Leu Pro Leu Leu 15 10 15 Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gin Glu 20 25 30 Asp Glu Asp Gly 35 ' ASp • Tyr • Glu i Glu 40 Leu val Leu Ala Leu 45 Arg Ser Glu Glu Asp Gly Leu 50 Ala Glu Al a 55 Pro Glu Hl s Gly Thr 60 Thr Ala Thr Phe His Arg cys Ala 65 Lys Asp 70 Pro Trp Arg Leu Pro 75 Gly Thr Tyr val Val 80 Val Leu Lys Glu Glu 85 Thr His Leu Ser Gin 90 Ser Glu Arg Thr Al a 95 Arg Arg Leu Gin Ala 100 Gl n Ala Ala- Arg Arg 105 Gly Tyr Leu Thr Lys 110 Il e Leu His val Phe His 115 Gly Leu Leu Pro 120 Gly Phe Leu Val Lys 125 Met Ser Gly Asp Leu Leu Glu 130 Leu Al a Leu 135 Lys Leu Pro Hi s val 140 Asp Tyr Il e Glu Glu Asp Ser Ser 145 val Phe 150 Ala Gl n Ser lie pro 155 Trp Asn Leu Gl u 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 Gl u val Tyr Leu Leu 185 Asp Thr Ser He Gl n 190 Ser Asp His Arg Glu lie 195 Glu Gly Arg Val 200 Met val Thr Asp Phe 205 Gl u Asn val Pro Glu Glu Asp 210 Gl y Thr Arg 215 Phe Hi s Arg Gin Ala 220 Ser Lys Cys Asp ser His Gly Thr 225 Hi s Leu 230 Al a Gly val Val Ser 235 Gly Arg ASp Al a Gly 240 Val Ala 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 Gin Leu 275 Val Gl n pro val 280 Gly Pro Leu Val Val 285 Leu Leu Pro Leu Ala Gly Gly 290 Tyr Ser Arg 295 val Leu Asn Ala Ala 300 Cys Gin Arg Leu Ala Arg Ala Gly ' 305 Val val 310 Leu val Thr Al a Ala 315 Gly Asn Phe Arg Asp 320 Asp Ala Cys Leu i Tyr Ser Pro Ala Ser Ala pro Glu val Π e Thr Val 325 330 335 Gly Ala Thr Asn Ala Gin Asp Gin pro Val Thr Leu Gly Thr Leu Gly 340 345 350 Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala pro Gly Glu Asp lie 355 360 365 lie Gly Ala Ser Ser Asp Cys Ser Thr Cys Phe Val Ser Gl n ser Gly 370 375 380 Thr Ser Gin Ala Ala Ala Hi s val Ala Gly He Ala Al a Met Met Leu 385 390 395 400 Ser Ala Glu Pro Glu Leu Thr Leu Ala Gl u Leu Arg Gin Arg Leu lie 405 410 415 His Phe Ser Ala Lys Asp Val He Asn Glu Ala Trp Phe Pro Glu ASp 420 425 430 Gin Arg Val Leu Thr Pro Asn Leu val Ala Thr Leu Pro Pro Ser Thr 435 440 445 Hi s Gly Al a Gly Trp Gl n Leu Phe cys Arg Thr val T rp ser Al a His 450 455 460 ser Gly pro Thr Arg Met Ala Thr Ala lie Ala Arg Cys Ala pro Asp 465 470 475 480 Glu Glu Leu Leu Ser cys Ser Ser Phe Ser Arg Ser Gly Lys Arg Arg 485 490 495 Gly Glu Arg Met Glu Al a Gin Gly Gly Lys Leu val cys Arg Al a Hi s 500 505 510 Asn Ala Phe Gly Gly Glu Gly Val Tyr Al a He Al a Arg Cys Cys Leu 515 520 525 Leu Pro Gin Ala Asn cys ser Val Hi s Thr Ala Pro Pro Ala Glu Ala 530 535 540 Ser Met Gly Thr Arg Val Hi s cys Hi s Gin Gin Gly Hi s Val Leu Thr 545 550 555 560 Gly cys ser Ser Hi s Trp Glu Val Glu Asp Leu Gly Thr His Lys Pro 565 570 575 Pro Val Leu Arg Pro Arg Gly Gin Pro Asn Gin Cys val Gly Hi s Arg 580 585 590 3W Glu Ala Ser 595 lie Hi s Ala Ser Cys Cys His 600 Al a Pro Gly 605 Leu Glu Cys Lys Val Lys Glu Hi s Gly lie pro Ala Pro Gin Glu Gin Val Thr Val 610 615 620 Al a cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Al a Leu Pro Gly 625 630 635 640 Thr1 Ser Hi s Val Leu Gly Al a Tyr Ala val Asp Asn Thr Cys val val 645 650 655 Arg ser Arg Asp Val Ser Thr Thr Gly Ser Th Γ- ser Gl u Glu Ala Val 660 665 670 Thr Ala val Ala lie Cys Cys Arg Ser Arg Η! s Leu Ala Gin Ala Ser 675 680 ' 685 Gin Glu Leu Gin 690 <210> 16 <211> 662 <212> PRT <213> Homo sapiens <40 0> 1 6 Gin Glu Asp Gl U Asp Gly Asp Tyr Gl u Glu Leu Val Leu Al a Leu Arg 1 5 10 15 Ser Glu Gl u Asp Gly Leu Ala Glu Ala Pro Glu Hi s Gly Thr Thr Ala 20 25 30 Thr Phe His Arg Cys Ala Lys ASp Pro Trp Arg L.eu Pro Gly Thr Tyr 35 40 45 Val val val Leu Lys Glu Glu Thr Hi s Leu Ser Gin Ser Glu Arg Thr 50 55 60 Ala Arg Arg Leu Gl n Al a Gin Ala Ala Arg Arg Gly Tyr Leu Thr Lys 65 70 75' 80 He Leu Hi s Val Phe Hi s Gly Leu Leu Pro Gly Phe Leu Val Lys Met 85 90 95 ser Gly Asp Leu Leu Gl u Leu Ala Leu Lys Leu Pro Hl S Val Asp Tyr 100 105 110 He Gl u Glu ASp ser ser val Phe Ala Gl n Ser lie Pro Trp Asn Leu 115 120 125 Glu Arg He Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gin Pro Pro 130 135 140 Asp Gly Gly Ser Leu Val Glu Val Tyr Leu Leu ASp Thr Ser lie Gin 145 150 155 160 Ser Asp i His Arg Glu lie Glu Gly Arg Val Met val Thr ASp Phe Glu 165 170 175 Asn Val Pro Glu Glu Asp Gly Thr Arg Phe Hi s Arg Gin Al a Ser Lys 180 185 190 Cys Asp ser Hi s Gly Thr Hi s Leu Ala Gly val val Ser Gl y Arg ASp 195 200 205 Ala Gly val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn 210 215 220 Cys Gin Gly Lys Gly Thr Val Ser cly Thr leu lie Gly Leu Gl u Phe 225 230 235 240 lie Arg Lys Ser Gin Leu Val Gin Pro val Gly Pro Leu Val Val Leu 245 250 255 Leu Pro Leu Ala Gly Gly Tyr ser Arg val Leu Asn Ala Al a Cys Gin 260 265 270 Arg Leu Ala Arg Ala Gly Val Val Leu Val Thr Al a Al a Gly Asn Phe 275 280 285 Arg Asp Asp Ala Cys Leu Tyr ser pro Al a Ser Ala Pro Glu val lie 290 295 300 Thr val Gly Ala Thr Asn Ala Gl n Asp Gin Pro Val Thr Leu Gly Thr 305 310 315 320 Leu Gly Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Al a Pro Gly Gl u 325 330 335 Asp lie lie Gly Ala Ser Ser Asp Cys ser Thr cys phe Val Ser Gl n 340 345 350 Ser Gly Thr Ser Gin Ala Ala Al a Hi s val Al a Gly lie Al a Ala Met 355 360 365 Met Leu Ser Ala Glu Pro Glu Leu Thr Leu Al a Glu Leu Arg Gl n Arg 370 375 380 Leu lie His Phe Ser Ala Lys Asp val lie Asn Glu Ala Trp Phe Pro 385 390 395 400 Glu Asp Gin Arg val Leu Thr Pro Asn Leu Val Ala Thr Leu Pro Pro 405 410 415 Ser Thr His Gly Ala Gly Trp Gin Leu Phe cys Arg Thr val Trp Ser 420 425 430 3R5 Ala Hi s Ser Gly Pro Thr Arg Met Ala Thr Al a lie Ala Arg Cys Ala 435 440 445 pro Asp Gl u Glu Leu Leu Ser Cys ser Ser Phe Ser Arg Ser Gly Lys 450 455 460 Arg Arg Gly Glu Arg Met Glu Al a Gin Gly Gly Lys Leu Val cys Arg 465 470 475 480 Al a Hi s Asn Ala Phe Gl y Gly Gl u Gly Val Tyr Al a Tie Al a Arg Cys 485 490 495 Cys Leu Leu Pro Gin Ala Asn cys Ser Val Hi s Thr a! a Pro Pro Ala 500 505 510 Glu Al a Ser Met Gly Thr Arg val Hi s cys Hi s Gl n Gin Gly Hi s val 515 520 525 Leu Thr Gly Cys Ser Ser His Trp Gl u Val Gl u Asp Leu Gly Thr Hi s 530 535 540 Lys pro Pro Val Leu Arg Pro Arg Gly Gin Pro Asn Gl n cys val Gly 545 550 555 560 Hi s Arg Glu Ala Ser il e Hi s Ala Ser cys cys Hi s Al a pro Gly Leu 565 570 575 Glu Cys Lys val Lys Gl u Hi s Gly lie Pro Ala pro Gl n Glu Gin val 580 585 590 Thr val Al a Cys Glu Glu Gly Trp Thr Leu Thr Gly cys Ser Ala Leu 595 600 605 Pro Gly Thr Ser Hi s Val Leu Gly Al a 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 Gl U 62 5 630 635 640 Al a Val Thr Al a val Ala Ile Cys Cys Arg ser Arg Hi s Leu Ala Gl n 645 650 655 Al a Ser Gin Glu Leu Gin 660 <210> 17 <211> 540 <212> PRT <213> Homo sapiens <400> 17 Ser Ile Pro Trp Asn Leu Glu Arg lie Thr Pro Pro Arg Tyr Arg Ala 15 10 15 ASp Gil ι Tyr Gin ι Pro ι pro ASp Gly Gly Ser Leu Val Glu Val Tyr Leu 20 25 30 Leu Asp ι Thr ser ’ lie Gin Ser Asp Hi s Arg Gl u Tie Glu Gly Arg val 35 40 45 Met Val Thr Asp Phe Glu Asn val pro Gl u Gl u Asp Gly Thr Arg Phe 50 55 60 His Arg Gin Ala Ser Lys cys Asp ser Hi s Gly Thr His Leu Ala Gly 65 70 75 80 val Val Ser Gly Arg Asp Ala Gly val Ala Lys Gly Al a Ser Met Arg 85 90 95 Ser Leu Arg Val Leu Asn cys Gl n Gly Lys Gly Thr val Ser Gly Thr 100 105 110 Leu lie Gly Leu Glu Phe lie Arg Lys Ser Gin Leu val Gin Pro Val 115 120 125 Gly pro Leu Val val Leu Leu Pro Leu Al a Gly Gly Tyr Ser Arg val 130 135 140 Leu Asn Ala Ala Cys Gin Arg Leu Al a Arg Ala Gly Val Val Leu val 145 150 155 160 Thr Ala Ala Gly Asn Phe Arg Asp ASp Ala cys Leu Tyr ser Pro Ala 165 170 175 Ser Al a Pro Glu Val lie Thr Val Gl y Al a Thr Asn a! a Gl n ASp Gin 180 185 190 Pro val Thr Leu Gly Thr Leu Gly Thr Asn Phe Gly Arg Cys val Asp 195 200 205 Leu Phe Ala Pro Gly Gl u ASp lie Il e Gly Al a Ser Ser Asp Cys ser 210 215 220 Thr Cys Phe Val Ser Gl n Ser Gly Thr ser Gin Ala Ala Al a Hi s Val 225 230 235 240 Ala Gly lie Ala Ala Met Met Leu Ser Ala Glu Pro Glu Leu Thr Leu 245 250 255 Ala Glu Leu Arg Gin Arg Leu He Hi s Phe Ser Ala Lys Asp val lie 260 265 270 Asn ' Glu Ala Trp Phe Pro Glu Asp Gin Arg Val Leu Thr Pro Asn Leu 275 280 285 3n Val Ala 290 Thr 1 Leu Pro pro Ser 295 Thr Hi s Gly Al a Gly 300 Trp Gin Leu Phe Cys Arg 305 Thr val Trp Ser 310 Ala Hi s Ser Gly Pro 315 Thr Arg Met Ala Thr 320 Ala lie Ala 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 Gl u Al a 350 Gin Gl y Gly Lys Leu 355 Val Cys Arg A1 a Hi s 360 Asn Al a Phe Gly Gl y 365 Gl u Gl y Va 1 Tyr Ala 370 He Al a Arg Cys Cys 375 Leu Leu Pro Gin Ala 380 As π Cys ser val His Thr 385 Al a pro Pro Al a 390 Glu Ala Ser Met Gly 395 Thr Arg Val Hi s Cys 400 His Gin Gin Gly His 405 Val Leu Thr Gly Cys 410 Ser Ser Hi s Trp Glu 415 Val Glu ASp Leu Gly 420 Thr His Lys Pro Pro 425 Val Leu Arg Pro Arg 430 Gly Gin Pro Asn Gin 435 Cys Val Gly Hi s Arg 440 Glu Al a Ser lie Hi s 445 Ala Ser cys Cys His 450 Ala pro Gly Leu Gl u 455 Cys Lys val Lys Glu 460 Hi s Gly lie Pro Ala Pro 465 Gl n Gl U Gl n Val 470 Thr val Al a Cys Glu 475 Gl u Gly Trp Thr Leu 480 Thr Gly Cys ser Ala 485 Leu Pro Gly Thr Ser 490 Hi s val Leu Gly Al a 495 Tyr Ala Val Asp Asn 500 Thr Cys Val Val Arg 505 Ser Arg Asp Val Ser 510 Thr Thr Gly Ser Thr 515 Ser Glu Gl u Al a val 520 Thr Al a Val Al a He 525 cys Cys Arg Ser Arg 530 Hi s Leu Al a Gin Ala 535 ser Gin Glu Leu Gl n 540 <210> 18 <211> 692 <212> PRT <213> Homo sapiens <400> 18 3^% Met Gly 1 • Thr val Ser 5 Ser Arg l Arg Ser Trp 10 Trp pro Leu Pro Leu 15 Leu Leu Leu Leu Leu 20 Leu Leu Leu Gly Pro 25 Ala Gly Ala Arg Ala 30 Gin 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 Ala 55 Pro Glu Hi s Gly Thr 60 Thr Ala Thr Phe His Arg 65 Cys Al a Lys Asp 70 pro Trp Arg Leu Pro 75 Gl y Thr Tyr Val Val 80 Val Leu Lys Glu Gl u 85 Thr HIS Leu Ser Gl n 90 Ser Glu Arg Thr Ala 95 Arg Arg Leu Gin Ala 100 Gin Al a Ala 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 Gl y Asp Leu 130 Leu Glu Leu Ala Leu 135 Lys Leu Pro Hi s val 140 ASp Tyr lie Glu Glu Asp 145 Ser ser val Phe 150 Ala Gin Ser lie Pro 155 Trp Asn Leu Gl u 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 Gl n 190 Ser ASP His 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 Gin Ala 220 Ser Lys cys Asp Ser His 225 Gly Thr Hi s Leu 230 Al a Gly Val Val Ser 235 Gly Arg ASp Al a Gly 240 Val Ala 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 · Gin 275 Leu Val Gl n Pro val 280 Gly Pro Leu Val val 285 Leu Leu pro 333 Leu i Ala Gly ' Gly Tyr Ser Arg val Leu Asn Al a Al a cys Gl n Arg Leu 290 295 300 Al a Arg Ala Gly val val Leu val Thr Ala Al a Gly Asn phe Arg Asp 305 310 315 320 Asp Ala Cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu val Tie Thr Val 325 330 335 Gly Ala Thr Asn Ala Gin Asp Gl n pro Val Thr Leu Gly Thr Leu Gly 340 345 350 Thr Asn Phe Gly Arg cys val ASp Leu Phe Al a Pro Gly Glu Asp lie 355 360 365 il e Gly Ala ser ser ASp Cys Ser Thr cys Phe val Ser Gin ser Gly 370 375 380 Thr Ser Gin Ala Ala Al a Hi s Val Ala Gly He Al a Ala Met Met Leu 385 390 395 400 Ser Ala Glu Pro Glu Leu Thr Leu Ala Glu Leu Arg Gin Arg Leu lie 405 410 415 Hi s Phe Ser Al a Lys A5p Val lie ser Glu Ala Trp Phe pro Gl u Asp 420 425 430 Gin Arg val Leu Thr Pro Asn Leu Val Ala Ala Leu Pro pro Ser Thr 435 440 445 Hi s Gly Ala Gly T rp Gl n Leu Phe cys Arg Thr val Trp ser Al a Hi s 450 455 460 Ser Gly Pro Thr Arg Met Ala Thr Ala val Ala Arg cys Al a Pro Asp 465 470 475 480 Glu Glu Leu Leu Ser cys Ser Ser Phe Ser Arg ser Gly Lys Arg Arg 485 490 495 Gly Glu Arg Met Gl u Ala Gin Gly Gl y Lys Leu val Cys Arg Ala Hi s 500 505 510 Asn , Ala Phe Gly Gly Glu Gly Val Tyr Ala lie Al a Arg Cys cys Leu 515 520 525 Leu Pro Gin Ala . Asn Cys Ser val Hi s Thr Ala Pro Pro Ala Glu Ala 530 535 540 Ser 1 Met Gly ' Thr , Arg val Hi s cys Hi s Gin Gin Gly Hi s Val Leu Thr 545 550 555 560 360 Gly Cys Ser Ser His 565 T rp Glu Val Gl u Asp 570 Leu Gly Thr Hi s Lys 575 pro Pro val Leu Arg Pro Arg Gly Gin Pro Asn Gin Cys Val Gly Hi s Arg 580 585 590 Glu Ala Ser lie Hi s Ala Ser Cys cys His Ala Pro Gly Leu Glu cys 595 600 605 Lys val Lys Gl U His Gly lie Pro Ala Pro Gl n Glu Gl n val Thr val 610 615 620 Ala Cys GlU Glu Gly Trp Thr Leu rh r Gly Cys Ser Ala Leu Pro Gl y 625 630 635 640 Thr Ser Hi 5 val Leu Gly Al a Tyr Ala Val Asp Asn Thr Cys Val Val 645 650 655 Arg Ser Arg Asp val Ser Thr Thr Gly Ser Thr Ser Glu Glu Ala Val 660 665 670 Thr Al a val Ala lie cys cys Arg Ser Arg Hi s Leu Ala Gin Ala Ser 675 680 685 Gin Glu Leu Gin 690 <210> 19 <211> 662 <212> PRT <213> Homo sapiens <400> 19 Asp Gly 5 Asp Tyr Glu Glu 10 Leu val Leu Ala Leu 15 Arg Gl n 1 Glu Asp Glu Ser Gl u Glu Asp cly Leu Al a Gl u Al a Pro Gl u Hi s Gly Thr Thr Ala 20 25 30 Thr Phe Hi s Arg cys Al a Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr 35 40 45 Val Val val Leu Lys Gl u Glu Thr Hi s Leu Ser Gl n Ser Gl u Arg Thr 50 55 60 Al a Arg Arg Leu Gin Ala Gin Al a Ala Arg Arg Gly Tyr Leu Thr Lys 65 70 75 80 lie Leu Hi s Val Phe Hi s Gly Leu Leu Pro Gly Phe Leu Val Lys Met 85 90 95 Ser Gly Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro Hi s val Asp Tyr 100 105 110 Ml lie Glu Glu Asp Ser 115 ’ Ser val Phe 120 ; Ala 1 Gin Ser il e Pro 125 Trp Asn Leu Glu Arq lie Thr Pro 130 i Pro Arg 135 Tyr Arg Ala Asp Glu 140 Tyr Gin Pro Pro Asp Gly Gly Ser Leu 145 Val 150 Glu val Tyr Leu Leu 155 Asp Thr ser il e Gl n 160 Ser Asp His Arg Glu 165 lie Gl u Gly Arg val 170 Met val Thr Asp Phe 175 Gl u Asn val pro Glu Glu 180 Asp Gly Thr Arg 185 Phe Hi s Arg Gl n Ala 190 Ser Lys Cys Asp ser His Gly 195 Thr Hi s Leu 200 Al a Gly Val val Ser 205 Gly Arg Asp Ala Gly val Ala Lys 210 Gly Ala 215 ser Met Arg Ser Leu 220 Arg Val Leu Asn Cys Gin Gly Lys Gly 225 Thr 230 Val ser Gly Thr Leu 235 lie Gly Leu Gl u Phe 240 lie Arg Lys Ser Gin 245 Leu val Gin Pro val 250 Gl y Pro Leu Val val 255 Leu Leu Pro Leu Ala Gly 260 Gly Tyr Ser Arg 265 val Leu Asn Al a Ala 270 cys Gin Arg Leu Ala Arg Ala 275 Gly Val Val 280 Leu val Thr Al a Al a 285 Gly Asn Phe Arg Asp Asp Ala Cys 290 Leu Tyr 295 ser Pro Al a Ser Ala 300 Pro Gl u val He Thr val Gly Ala Thr 305 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 Ala 340 ser ser Asp cys 345 Ser Thr Cys Phe Val 350 Ser Gin Ser Gly Thr Ser Gin 355 Ala Al a Ala 360 Hi s Val Al a Gly lie 365 Ala Al a Met Met Leu ser Ala Glu 370 Pro Glu 375 Leu Thr Leu Ala Glu 380 Leu Arg Gin Arg Leu lie His Phe Ser 385 Ala 390 Lys Asp Val lie Ser 395 Glu Ala Trp Phe Pro 400 '452.

Gl u 1 Asp i Gin Arg Val Leu Thr Pro Asn Leu val Al a Ala Leu Pro Pro 405 410 415 Ser Thr Hi s Gly Ala Gly T rp Gin Leu Phe cys Arg Thr Val Trp Ser 420 425 430 Al a Hi s Ser Gly Pro Thr Arg Met Al a Thr Al a Val Ala Arg Cys Ala 435 440 445 Pro Asp Gl u Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys 450 455 460 Arg Arg Gly Glu Arg Met Gl u Ala Gin Gly Gly Lys Leu Val cys Arg 465 470 475 480 Ala Hi s Asn Ala phe Gl y Gly Glu cl y Val Tyr Al a Il e Al a Arg cys 485 490 495 Cys Leu Leu Pro Gl n Ala Asn Cys Ser Val Hi s Thr Ala Pro pro Ala 500 505 510 Gl u Ala ser Met Gly Thr Arg Val Hi s Cys Hi s Gin Gin Gly Hi s Val 515 520 525 Leu Thr Gly cys Ser ser Hi s τ rp Gl u Val Glu Asp Leu Gly Thr His 530 535 540 Lys Pro Pro val Leu Arg Pro Arg Gl y Gin Pro Asn Gl n Cys val Gly 545 550 555 560 Hi s Arg Gl u Al a ser ile Hi s Al a ser cys cys Hi s Al a Pro Gly Leu 565 570 575 Glu cys Lys Val Lys Gl u Hi s Gly lie pro Ala Pro Gl n Gl u Gin Val 580 585 590 Thr val Al a Cys Gl u Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala 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 . Ala Val Ala lie cys cys Arg Ser Arg Hi s Leu Al a Gl n 645 650 655 Ala Ser Gin Glu Leu Gin 660 333 <210> 20 <211> 540 <212> PRT <213> Homo sapiens <400> 20 Ser lie Pro Trp 1 Asn 5 Leu Glu Arg He Thr 10 Pro Pro Arg Tyr Arg 15 Al a Asp - Glu Tyr Gin Pro Pro Asp Gly Gly Ser Leu Val Glu val Tyr Leu 20 25 30 Leu Asp Thr ser lie Gin ser ASp Hi s Arg Glu lie Glu Gly Arg val 35 40 45 Met val Thr Asp Phe Glu Asn val Pro Gl u Glu Asp Gly rh r Arg Phe 50 55 60 Hi s Arg Gl n a! a ser Lys Cys Asp Ser Hi s Gly Thr Hi s Leu Al a Gly 65 70 75 80 Val Val Ser Gly Arg Asp Al a Gly Val Al a Lys Gly Al a Ser Met Arg 85 90 95 Ser Leu Arg Val Leu Asn Cys Gin Gly Lys Gly Thr Val Ser Gly Thr 100 105 110 Leu lie Gly Leu Glu Phe lie Arg Lys Ser Gin Leu Val Gin Pro val 115 120 125 Gly Pro Leu Val Val Leu Leu Pro Leu Ala Gly Gly Tyr ser Arg val 130 13 5 140 Leu Asn Ala Al a cys Gl n Arg Leu Al a Arg Ala Gly val val Leu Val 145 150 155 160 Thr Al a Al a Gly Asn Phe Arg Asp Asp Al a cys Leu Tyr Ser Pro Al a 165 170 175 ser Ala Pro Glu val lie Thr val Gly Ala Thr Asn Al a Gl n Asp Gl n 180 185 190 pro Val Thr Leu Gly Thr Leu Gly Thr Asn Phe Gly Arg cys Val Asp 195 200 205 Leu phe Ala pro Gly Glu ASp lie lie Gly Ala Ser Ser Asp Cys Ser 210 215 220 Thr cys Phe val Ser Gin Ser Gly Thr Ser Gin Ala Al a Al a Hi s Val 225 230 235 240 Al a Gly lie Al a Ala Met Met Leu Ser Ala Glu Pro Glu Leu Thr Leu 245 250 255 (Τ5Λ Ala Glu Leu Arg 260 Gin Arg Leu lie Hi s 265 Phe Ser Ala Lys Asp 270 Val He Ser Glu Ala Trp Phe Pro Gl u Asp Gin Arg val Leu Thr Pro Asn Leu 275 280 285 val Al a Ala Leu Pro Pro Ser Thr Hi s Gly Ala Gly Trp Gl n Leu Phe 290 295 300 cys Arg Thr Val Trp Ser Al a Hi s ser Gly Pro Thr Arg Met Ala Thr 305 310 315 320 Al a Val Ala Arg cys Ala Pro Asp Gl u Glu Leu Leu Ser Cys Ser Ser 325 330 335 Phe Ser Arg Ser Gly Lys Arg Arg Gl y Glu Arg Met Glu Ala Gin Gly 340 345 350 Gly Lys Leu Val Cys Arg Ala Hi s Asn Ala Phe Gly Gly Glu Gly Val 355 360 365 Tyr Ala He Ala Arg cys cys Leu Leu pro Gl n Ala Asn Cys ser val 370 375 380 Hi s Thr Ala Pro Pro Ala Glu Ala ser Met Gly Thr Arg val Hi s cys 385 390 395 400 Hi s Gin Gin Gly Hi s Val Leu Thr Gly cys Ser Ser Hi s Trp Glu val 405 410 415 Glu Asp Leu Gly Thr Hi s Lys Pro Pro val Leu Arg Pro Arg Gly Gin 420 425 430 Pro Asn Gin cys Val Gly Hi s Arg Gl u Al a Ser lie Hi s Al a Ser Cys 435 440 445 Cys Hi s Al a pro Gly Leu Glu Cys Lys val Lys Gl u Hi s Gly lie Pro 450 455 460 Al a Pro Gin Glu Gin Val Thr Val Al a Cys Glu Gl u Gly Trp Thr Leu 465 470 475 480 Thr Gly cys Ser Ala Leu Pro Gly Thr Ser Hi s Val Leu Gly Ala Tyr 485 490 495 Ala Val ASp Asn Thr 500 cys val Val Arg Ser Arg 505 ASp val Ser 510 Thr Thr Gly Ser Thr Ser Gl u Glu Ala Val Thr Ala val Ala lie Cys cys Arg 515 520 525 Ser Arg Hi s Leu Ala Gin Ala Ser Gin Glu Leu Gin 530 535 540 555<210> 21 <211> 692 <212> PRT <213> Homo sapiens <400> 21 Met Gly Thr Val 1 Ser Ser Arg 5 Arg Ser Trp 10 T rp pro Leu Pro Leu 15 Leu Leu Leu Leu Leu Leu Leu Leu Gly Pro Al a Gly Al a Arg Ala Gin Glu 20 25 30 Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg ser Glu 35 40 45 Glu Asp Gly Leu Ala Glu Ala Pro Glu Hi s Gly Thr Thr Al a Thr Phe 50 55 60 His Arg Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr Val val 65 70 75 80 Val Leu Lys Glu Glu Thr His Leu ser Gin Ser Glu Arg Thr Ala Arg 85 90 95 Arg Leu Gin Ala Gin Ala Ala Arg Arg Gly Tyr Leu Thr Lys lie Leu 100 105 110 His Val Phe His Gly Leu Leu Pro Gl y Phe Leu Val Lys Met Ser Gly 115 120 125 Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr ll e Glu 130 135 140 Glu Asp Ser Ser Val Phe Ala Gin Ser lie Pro T rp Asn Leu Glu Arg 145 150 155 160 lie Thr pro Pro Arg Tyr Arg Al a Asp Glu Tyr Gin pro Pro ASp Gly 165 170 175 Gly Ser Leu val Glu val Tyr Leu Leu Asp Thr Ser lie Gl n Ser Asp 180 185 190 His Arg Glu lie Glu Gly Arg val Met val Thr Asp Phe Glu Asn val 195 200 205 Pro Glu Glu Asp Gly Thr Arg Phe Hi s Arg Gin Ala Ser Lys cys ASp 210 215 220 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 b Gly Lys Gly Thr val Ser sly Thr Leu lie Gly Leu Glu Phe lie Arg 260 265 270 Lys Ser Gin Leu val Gl n pro val Gly Pro Leu val val Leu Leu pro 275 280 285 Leu Ala dy Gly Tyr Ser Arg val Leu Asn Ala Al a Cys Gin Arg Leu 290 295 300 Ala Arg Ala Gly val Val Leu Val Thr Ala Al a Gly As η Phe Arg Asp 305 310 315 320 Asp Ala Cys Leu Tyr Ser Pro Ala Ser Ala Pro GlU val He Thr Val 325 330 335 Gly Ala Thr Asn Al a Gl n Asp Gin Pro Val Thr Leu Gly Thr Leu Gly 340 345 350 Thr Asn Phe Gly Arg cys val Asp Leu phe Ala Pro Gly Gl u ASp lie 355 360 365 lie Gly Ala Ser ser ASp Cys Ser Thr cys Phe Val Ser Gin Ser Gly 370 375 380 Thr Ser Gin Al a Al a Ala Hi s Val Al a Gly lie Ala Ala Met Met Leu 385 390 395 400 Ser Ala Gl u Pro Gl U Leu Thr Leu Ala Gl ll Leu Arg Gin Arg Leu lie 405 410 415 His Phe Ser Al a Lys Asp val lie Asn Glu Al a τ rp phe Pro Glu Asp 420 425 430 Gin Arg Val Leu Thr Pro Asn Leu Val Ala Thr Leu Pro Pro Ser Thr 435 440 445 His Gly Al a Gly Trp Gin Leu Phe cys Arg Thr val T rp Ser Ala Hi s 450 455 460 Ser Gly Pro Thr Arg Met Ala Thr Ala lie Ala Arg Cys Al a Pro Asp 465 470 475 480 Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg ser Gly Lys Arg Arg 485 490 495 Gly Glu Arg Met Glu Al a Gin Gly Gly Lys Leu val cys Arg Ala Hi s 500 505 510 Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala He Ala Arg cys cys Leu 515 520 525 <3ST L.eL i Pro > Gin i Ala Asn Cys Ser val His Thr Al a Pro pro Ala Gl u Ala 530 535 540 Ser ' Met Gly1 Thr Arg Val His cys His Gin Gl n Gly Hi s val Leu Thr 545 550 555 560 Gly Cys ser ser Hi s Trp Glu val Glu Asp Leu Gly Thr Hi s Lys Pro 565 570 575 Pro val Leu Arg Pro Arg G'ly Gin Pro Asn Gl n Cys Val Gly Hi s Arg 580 58 5 590 Glu Ala ser Il e Hl S Al a Ser Cys Cys His A1 a Pro Gly Leu Glu Cys 595 600 605 Lys val Lys Gl u His Gly lie Pro Ala Pro pro Glu Gin val Thr Vai 610 615 620 Al a Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly 625 630 635 640 Thr Ser Hi s val Leu Gly Ala Tyr Ala Val ASp Asn Thr Cys val Val 645 650 655 Arg Ser Arg Asp Val Ser Thr Thr Gly ser Thr Ser Glu Gl u Ala val 660 665 670 Thr Ala val Ala lie Cys Cys Arg Ser Arg Hi s Leu Al a Gin Ala Ser 675 680 685 Gl n Glu Leu Gl n 690 <21C i> 22 <211 > 66 2 <212 > PR T <213 > Ho mo s api e :ns <400 > 22 Gl n Glu ASp Gl u Asp Gly Asp Tyr Glu Glu Leu Val Leu Al a Leu Arg 1 5 10 15 Ser Gl u Glu ASp Gly Leu Ala Glu Ala Pro Glu Hi s Gl y Thr Th r Al a 20 25 30 Thr Phe Hi s Arg Cys Al a Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr 35 40 45 val val ' 7 a 1 Leu Lys Glu Glu Thr His Leu Ser Gin Ser Glu Arg Thr 50 55 60 Ala < Arg Arg Leu Gin Ala Gin Ala Ala Arg Arg Gly Tyr Leu Thr Lys 70 75 80 33% lie Leu His ; Val Phe His 85 Gly Leu Leu Pro 90 Gly Phe Leu val Lys 95 Met Ser Gly Asp ' Leu Leu Glu Leu Ala Leu Lys Leu Pro Hi s val ASp Tyr 100 105 110 lie Glu Glu ASp Ser Ser val Phe Al a Gin Ser H e pro Trp Asn Leu 115 120 12 5 Glu Arg lie Thr Pro Pro Arg Tyr Arg Al a Asp Gl U Tyr Gl n Pro Pro 130 135 140 Asp Gly Gly Ser Leu Val Glu Val Tyr Leu Leu ASp Thr ser lie Glri 145 150 155 160 Ser Asp His Arg Glu lie Glu Gly Arg val Met. val Thr Asp Phe Glu 165 170 175 Asn Val Pro Glu Glu Asp Gly Thr Arg Phe Hi s Arg Gin Ala Ser Lys 180 185 190 cys Asp ser Hi s Gly Thr His Leu Al a Gly Val val ser Gly Arg ASp 195 200 205 Ala Gly val Al a Lys Gly Ala ser Met Arg ser Leu Arg Val Leu Asn 210 215 220 Cys Gin Gly Lys Gly Thr val Ser Gly Thr Leu Il e Gly Leu Gl u Phe 225 230 235 240 lie Arg Lys Ser Gin Leu Val Gin Pro val Gl y Pro Leu val Val Leu 245 250 255 Leu Pro Leu Al a Gly Gly Tyr Ser Arg Val Leu Asn Al a Al a Cys Gl n 260 265 270 Arg Leu Ala Arg Ala Gly Val Val Leu Val Thr Ala Ala Gly Asn Phe 275 280 285 Arg Asp Asp Ala Cys Leu Tyr Ser Pro Ala Ser Al a Pro Glu val He 290 295 300 Thr val Gly Al a Thr Asn Ala Gin Asp Gin Pro val Thr Leu Gly Thr 305 310 315 320 Leu Gly Thr Asn phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Glu 325 330 335 Asp lie lie Gly Ala Ser Ser Asp cys Ser Thr cys Phe val Ser Gin 340 345 350 Ser Gly Thr : Ser - Gin Ala Ala Ala Hi s val Ala Gly lie Ala Ala Met 355 360 365 153 Met Leu ser Ala 370 Glu Pro Glu 375 Leu Thr Leu Ala Glu 380 Leu Arg Gl n Arg Leu lie His Phe Ser Ala Lys Asp val lie Asn Gl U Ala Trp Phe Pro 385 390 395 400 Glu Asp Gin Arg Val Leu Thr Pro Asn Leu Val Al a Thr Leu pro Pro 405 410 415 Ser Thr His Gly Ala Gly Trp G1 n Leu Phe cys Arg Thr Val Trp Ser 420 425 430 Ala His ser Gly Pro Thr1 Arg Met Ala Thr Ala lie Ala Arg Cys Al a 435 440 445 Pro Asp Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys 450 455 460 Arg Arg Gly Glu Arg Met Glu Al a Gin Gly Gly Lys Leu Val cys Arg 465 470 475 480 Ala His Asn Ala Phe Gly Gly Glu Gly val Tyr Ala Ile Ala Arg cys 485 490 495 Cys Leu Leu Pro Gin Ala Asn Cys Ser val Hi s Thr Al a pro Pro Ala 500 505 510 Glu Ala Ser Met Gly Thr Arg val His cys His Gl n Gin Gly Hi s Val 515 520 525 Leu Thr Gly Cys Ser Ser Hi s T rp Glu val Gl U Asp Leu Gl y Thr Hi s 530 535 540 Lys pro Pro val Leu Arg Pro Arg Gly Gin Pro Asn Gin cys Val Gly 545 550 555 560 His Arg Glu Ala Ser lie Hi s Ala Ser Cys Cys Hi s Al a Pro Gly Leu 565 570 575 Glu cys Lys val Lys Glu Hi s Gly lie Pro Ala Pro Pro Glu Gin val 580 585 590 Thr Val Ala Cys Glu Glu Gly T rp Thr Leu Thr Gly Cys Ser Ala Leu 595 600 605 Pro Gly Thr Ser Hi s Val Leu Gly Al a Tyr Ala val ASp Asn Thr cys 610 615 620 Val val Arg ser , Arg Asp val ser Thr Thr Gl y Ser Thr Ser Glu Glu 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> 23 <211> 540 <212> PRT <213> Homo sapiens <400> 23 Asn 5 Leu Gl u Arg lie Thr Pro Pro Arq Tyr Arg Ala Ser 1 lie Pro Trp 10 15 Asp Glu Tyr Gin Pro Pro Asp Gly Gly Ser Leu val Glu val Tyr Leu 20 25 30 Leu Asp Thr Ser lie Gin Ser A5p Hi s Arg Glu lie Gl U Gly Arg Val 35 40 45 Met Val Thr Asp Phe Glu Asn Val Pro Glu Glu Asp Gly Thr Arg Phe 50 55 60 Hi s Arg Gin Ala Ser Lys cys Asp Ser Hi s Gl y Thr Hi s Leu Ala Gly 65 70 75 80 Val Val Ser Gly Arg Asp Al a Gly Val Ala Lys Gl y Ala Ser Met Arg 85 90 95 Ser Leu Arg Val Leu Asn Cys Gin Gly Lys Gly Thr val Ser Gly Thr 100 105 110 Leu lie Gly Leu Glu Phe lie Arg Lys Ser Gin Leu Val Gl n Pro val 115 120 12 5 Gly Pro Leu val Val Leu Leu Pro Leu Al a Gl y Gly Tyr Ser Arg val 130 135 140 Leu Asn Ala Ala Cys Gin Arg Leu Ala Arg Al a Gly val Val Leu Val 145 150 155 160 Thr Ala Ala Gly Asn Phe Arg Asp Asp Al a Cys Leu Tyr Ser Pro Ala 165 170 175 Ser Al a pro Glu val lie Thr val Gly Ala Thr Asn Al a Gin Asp Gin 180 185 190 Pro val Thr Leu Gl y Thr Leu Gly Thr Asn Phe Gly Arg cys Val Asp 195 200 205 Leu Phe Ala Pro Gly Glu Asp lie lie Gly Al a Ser Ser Asp Cys Ser 210 215 220 361 Thr cys Phe val ser 225 Gin 230 ι Ser 1 Gly ' Thr Ser Gin 235 Ala Al a Ala His val 240 Ala Gly lie Ala Ala 245 Met Met Leu Ser Ala 250 Gl u Pro Glu Leu Thr 255 Leu Ala Glu Leu Arg Gin 260 Arg Leu lie Hi s 265 Phe Ser Ala Lys Asp 270 Val lie Asn Glu Ala Trp Phe 275 Pro Gl U ASp 280 Gin Arg Val Leu Thr 285 Pro Asn Leu Val Ala Thr Leu Pro 290 Pro Ser 295 Thr Hi s Gly Al a Gly 300 Trp Gl n Leu Phe Cys Arg Thr Val Trp 305 Ser 310 Al a Hi s Ser Gly pro 315 Thr Arg Met Ala Thr 320 Ala lie Ala Arg cys 325 Ala Pro Asp Gl u Gl u 330 Leu Leu Ser cys Ser 335 Ser Phe Ser Arg Ser Gly 340 Lys Arg Arg Gly 345 Glu Arg Met Gl u Ala 350 Gl n Gly Gly Lys Leu Val cys 355 Arg Ala His 360 Asn Ala phe Gly Gly 365 Glu Gly Val Tyr Ala lie Ala Arg 370 Cys Cys 375 Leu Leu Pro Gl n Al a 380 Asn cys Ser Val His Thr Ala Pro pro 385 Al a 390 Glu Ala Ser Met Gly 395 Thr Arg val His cys 400 His Gin Gin Gly His 405 Val Leu Thr cly Cys 410 ser Ser Hi s T rp Gl u 415 Val Glu Asp Leu Gly Thr 420 Hi s Lys Pro Pro 425 Val Leu Arg pro Arg 430 Gl y Gl n Pro Asn Gin Cys val 435 Gly Hi 5 Arg 440 Glu Ala Ser lie His 44 5 Al a Ser Cys Cys His Ala Pro Gly 450 Leu Glu 455 Cys Lys val Lys Glu 460 Hi s Gly Il e Pro Ala Pro Pro Glu Gin 465 val 470 Thr Val Ala Cys Gl u 475 Glu Gly Trp Thr Leu 480 Thr Gly Cys Ser Ala 485 Leu pro Gly Thr Ser 490 Hi s Val Leu Gly Al a 495 Tyr Ala Val Asp Asn Thr 500 Cys Val Val Arg 505 Ser Arg Asp val Ser 510 Thr Thr Gly Ser Thr Ser Glu Glu Ala Val Thr Ala Val Ala lie Cys Cys Arg 515 520 525 Ser Arg His Leu Ala Gin Ala Sen Gin Glu Leu Gin 530 535 540 <210> 24 <211> 692 <212> PRT <213> Homo sapiens <4C IO> 2 4 Met : Gly Thr val Ser Ser Arg Arg Ser Trp T rp pro Leu pro Leu Leu 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala G1 y Ala Arg Al a Gin Gl U 20 25 30 Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Leu ser Gl u 35 40 45 Glu Asp Gly Leu Ala Glu Ala pro Glu Hi s Gly Thr Thr Ala Thr Phe 50 55 60 Hi s Arg Cys Al a Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr Val Val 65 70 75 80 val Leu Lys Glu Glu Thr Hi s Leu Ser Gin Ser Glu Arg Thr Ala Arg 85 90 95 Arg Leu Gl n Ala Gl n Al a Al a Arg Arg Gly Tyr Leu Thr Lys Il e Leu 100 105 110 His Val Phe Hi s Gly Leu Leu Pro Gly Phe Leu val Lys Met Ser Gly 115 120 125 ASp Leu Leu Glu Leu Al a Leu Lys Leu Pro Hi s val ASp Tyr lie Gl u 130 135 140 Glu ASp Ser Ser val Phe Al a Gin Ser lie Pro Trp Asn Leu Gl u Arg 145 150 155 160 lie Thr pro Pro Arg Tyr Arg Al a Asp Glu Tyr Gin Pro Pro Asp Gl y 165 170 175 Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser lie Gin Ser Asp 180 185 190 Hi s Arg Glu lie Glu Gly Arg val Met Val Thr Asp Phe Glu Asn Val 195 200 205 Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gin Ala Ser Lys Cys ASp 210 215 220 Ser His Gly Thr His Leu Al a 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 Gl n 245 250 255 Gly Lys Gly Thr Val ser Gly Thr Leu lie Gly Leu Glu Phe lie Arg 260 265 270 Lys Ser Gin Leu val Gl n pro val Gly Pro Leu Val val Leu Leu Pro 275 280 285 Leu Ala Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala cys Gin Arg Leu 290 295 300 Ala Arg Ala Gly Val val Leu val Thr Ala Al a Gly Asn Phe Arg ASp 305 310 315 320 Asp Ala cys Leu Tyr ser Pro Ala Ser Ala Pro Glu Val lie Thr val 325 330 335 Gly Ala Thr Asn Ala Gl n Asp Gin Pro Val Thr Leu Gly Thr Leu Gly 340 345 350 Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Al a Pro Gly Glu Asp He 355 360 365 lie Gly Ala ser ser ASp cys Ser Thr Cys Phe Val ser Gin Ser Gly 370 375 380 Thr ser Gin Ala Ala Ala Hi s Val Al a Gly lie Al a Al a Met Met Leu 385 390 395 400 Ser Ala Glu Pro Glu Leu Thr Leu Ala Gl u Leu Arg Gin Arg teu il e 405 410 415 His Phe Ser Ala Lys Asp Val lie Asn Glu Al a Trp Phe Pro Glu ASp 420 425 430 Gin Arg Val Leu Thr Pro Asn Leu val Ala Al a Leu Pro Pro ser Thr 435 440 445 His Gly Ala Gly Trp Gin Leu Phe Cys Arg Thr Val Trp Ser Ala Hi s 450 455 460 Ser Gly Pro Thr Arg Met Ala Thr Ala val Ala Arg Cys Ala pro ASp 465 470 475 480 Glu Glu Leu Leu ser cys ser Ser Phe Ser Arg Ser Gly Lys Arg Arg 485 490 495 3£>q Gly Glu Arg Met Gl u Al a Gin Gly Gly Lys Leu val Cys Arg Ala Hi s 500 505 510 Asn Ala Phe Gly Gly Glu Gly Val Tyr Al a Il e Al a Arg Cys Cys Leu 515 520 525 Leu Pro Gin Ala Asn cys Ser Val Hi s Thr Ala pro pro Ala Glu Ala 530 535 540 Ser Met Gl y Thr Arg Val Hi s Cys His Gin Gl n ciy Hi s Val Leu Thr 545 550 555 560 Gly Cys Ser Ser Hi s Trp Glu Val Gl u Asp Leu Gly Thr Hi s Lys Pro 565 570 575 Pro val Leu Arg Pro Arg Gly Gin Pro Asn Gin Cys Val Gly Hi s Arg 580 585 590 Glu Al a Ser He Hi s Ala Ser Cys Cys Hi s Al a Pro Gly Leu Glu Cys 595 600 605 Lys val Lys Glu His Gly lie Pro Ala Pro Gl n Gl u Gin Val Thr val 610 615 620 Ala cys Glu Glu Gly Trp Thr Leu Thr Gly Cys ser Ala Leu Pro Gly 625 630 635 640 Thr Ser Hi s Val Leu Gly Ala Tyr Ala val Asp Asn Thr cys val val 645 650 655 Arg Ser Arg Asp val Ser Thr Thr Gly Ser Thr Ser Glu Glu Al a Val 660 665 670 Thr Ala val Al a il e cys Cys Arg Ser Arg Hi s Leu Al a Gin Al a Ser 675 680 685 Gin Glu Leu Gin 690 <210> 25 <211> 662 <212> PRT <213> Homo sapiens <400> 25 Gl n Glu ASP Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Leu 1 5 10 15 Ser Glu Glu Asp Gly Leu Ala Glu Al a Pro Glu Hi s Gly Thr Thr Ala 20 25 30 Thr Phe Hi s Arg Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr 40 45 Val Val 50 Val Leu Lys Glu Glu Thr His 55 Leu Ser Gin Ser 60 Glu Arg Thr Ala Arg Arg Leu i Gl n Ala Gl n Ala Ala Arg Arg Gly Tyr Leu Thr Lys 65 70 75 80 lie Leu Hi s val Phe His Gly Leu Leu Pro Gly phe Leu Val Lys Met. 85 90 95 Ser Gly Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro Hi s Val Asp Tyr 100 105 110 lie Glu Gl u Asp Ser Ser Val Phe Ala Gin Ser Il e Pro Trp Asn Leu 115 120 12 5 Glu Arg lie Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gin Pro Pro 130 13 5 140 Asp Gly Gly ser Leu val Gl u val Tyr Leu Leu Asp Thr Ser lie Gin 145 150 155 160 Ser Asp His Arg Glu lie Glu Gly Arg val Met val Thr Asp Phe Gl u 165 170 175 Asn Val Pro Glu Gl u Asp cly Thr Arg Phe Hi s Arg Gin Al a Ser Lys 180 185 190 Cys Asp ser Hi s Gl y Thr Hi s Leu Ala Gly Val val Ser Gly Arg Asp 195 200 205 Ala Gly Val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn 210 215 220 Cys Gin Gly Lys Gly Thr Val Ser Gly Thr Leu lie Gly Leu Glu Phe 225 230 235 240 lie Arg Lys Ser Gin Leu val Gin Pro val Gly Pro Leu Val val Leu 245 250 255 Leu Pro Leu Al a Gly Gly Tyr Ser Arg val Leu Asn Ala Ala cys Gin 260 265 270 Arg Leu Ala Arg Ala Gly Val val Leu val Thr Ala Ala Gly Asn Phe 275 280 285 Arg Asp Asp Ala Cys Leu Tyr ser Pro Al a Ser Al a Pro Glu val lie 290 295 300 Thr Val Gly . Ala Thr Asn Ala Gin Asp Gl n Pro Val Thr Leu Gly Thr 305 310 315 320 Leu Gly Thr , Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Gl u 325 330 335 3GG Asp i Ile lie Gly Ala . ser ser Asp Cys Ser Thr Cys Phe Val ser Gin 340 345 350 Ser Gly Thr Ser Gl n Ala Al a Ala Hi s Val Ala Gly He Ala Al a Met 355 360 365 Met Leu Ser Ala Glu Pro Glu Leu Thr Leu Al a Glu Leu Arg Gin Arg 370 375 380 Leu He Hi 5 Phe Ser Ala cys Asp Val ile Asn Glu Ala Trp Phe Pro 385 390 395 400 Gl u Asp Gin Arg Val Leu Thr Pro Asn Leu val Ala Ala L.eu Pro Pro 405 410 415 Ser Thr Hi s Gly Ala Gly Trp Gin Leu Phe Cys Arg Thr val Trp ser 420 425 430 Ala Hi s Ser Gly Pro Thr Arg Met Al a Thr Ala val Al a Arg Cys Al a 435 440 445 Pro Asp Glu Gl u Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys 450 455 460 Arg Arg Gly Glu Arg Met Glu Al a Gin Gly Gly Lys Leu Val Cys Arg 465 470 475 480 Ala His Asn Al a Phe Gly Gly Gl u Gly Val Tyr Ala He Al a Arg Cys 485 490 495 cys Leu Leu pro Gl n Al a Asn cys Ser val Hi s Thr Al a Pro Pro Al a 500 505 510 Gl u Ala Ser Met Gly Thr Arg val Hi s Cys His Gin Gl n Gly Hi s val 515 520 525 Leu Thr Gly cys Ser Ser Hi s T rp Glu Val Glu Asp Leu Gly Thr His 530 535 540 Lys Pro Pro val Leu Arg Pro Arg Gly Gin Pro Asn Gl n Cys Val Gl y 545 550 555 560 Hi s Arg Glu Ala Ser lie His Al a Ser cys Cys His Ala Pro Gly Leu 565 570 575 Glu Cys Lys val Lys Glu Hi s Gly lie pro Ala pro Gin Glu Gin val 580 585 590 Thr ' val . Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Al a Leu 595 600 605 3&L 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 62 5 630 635 640 Ala val Thr Ala Val Ala lie Cys Cys Arg Ser Arg Hi s Leu Al a Gl n 645 650 655 Al a Ser Gl n Glu Leu Gl n 660 <210> 26 <211> 692 <212> PRT <213> Homo sapiens <40 O> 2 6 Met Gly Thr Val Ser Ser Arg Arg Ser r rp Trp Pro Leu pro Leu L.eu 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gl y Ala Arg Al a Gin Gl u 20 25 30 Asp Gl u Asp Gly Asp Tyr Gl u Gl u Leu val Leu Al a Leu Arg Ser Glu 35 40 45 Glu Asp Gly Leu Val Glu Ala Pro Glu Hi s Gly Thr Thr Ala Thr Phe 50 55 60 Hi s Arg Cys Ala Lys Asp Pro T rp Arg Leu Pro dy Thr Tyr Val val 65 70 75 80 Val Leu Lys Gl u Glu Thr Hi s Leu Ser Gin Ser Gl u Arg Thr Al a Arg 85 90 95 Arg Leu Gl n Ala Gin Al a Al a Arg Arg Gly Tyr Leu Thr Lys Il e Leu 100 105 110 Hl s val Phe Hi s Gly Leu Leu Pro Gly Phe Leu val Lys Met ser Gly 115 120 125 Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro Hi s val Asp Tyr lie Glu 130 135 140 Glu Asp Ser Ser Val phe Al a Gin ser lie Pro Trp Asn Leu Glu Arg 145 150 155 160 Il e Thr Pro Pro Arg Tyr Arg Al a Asp Glu Tyr Gin Pro Pro Asp Gly 165 170 175 Gly ser Leu Val Glu val Tyr Leu Leu Asp Thr Ser lie Gin Ser Asp 180 185 190 36? His Arg Glu lie Glu Gly Arg Val 200 Met val Thr Asp Phe 205 Glu Asn val 195 Pro Glu Glu Asp Gly Thr Arg Phe Hi s Arg Gl n Ala Ser Lys cys Asp 210 215 220 ser His Gl y Thr Hi s 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 Gl n 245 250 255 Gly Lys Gly Thr val Ser Gly Thr Leu Il e Gly Leu Glu Phe lie Arg 260 265 270 Lys ser Gin Leu Val Gl n Pro Val Gly Pro Leu Val Val Leu Leu Pro 275 280 285 Leu Al a Gly Gly Tyr Ser Arg Val Leu Asn Al a Al a Cys Gin Arg Leu 290 295 300 Ala Arg Ala Gl y val val Leu val Thr Ala Ala Gly Asn Phe Arg Asp 305 310 315 320 Asp Ala cys Leu Tyr ser Pro Al a Ser Ala Pro Glu val lie Thr Val 325 330 335 Gly Ala Thr Asn Ala Gin Asp Gin Pro val Thr Leu Gly Thr Leu Gly 340 345 350 Thr Asn Phe Gly Arg Cys Val Asp L.eu Phe Ala Pro Gl y Glu Asp lie 355 360 365 lie Gly Al a Ser Ser ASp cys Ser Thr cys Phe val 5er Gin ser Gly 370 375 380 Thr Ser Gin Ala Al a Ala Hi s val Ala Gl y lie Al a Ala Met Met Leu 385 390 395 400 Ser Al a Gl u Pro Glu Leu Thr Leu Al a Glu Leu Arg Gl n Arg Leu lie 405 410 415 His Phe Ser Ala Lys ASp val lie Asn Gl U Ala Trp Phe pro Glu Asp 420 425 430 Gl n Arg Val Leu Thr Pro Asn Leu Val Ala Ala Leu Pro Pro Ser Thr 435 440 445 His Gly Ala Gly Trp Gin Leu Phe Cys Arg Thr val Trp Ser Ala His 450 455 460 ser Gly Pro Thr Arg Met Al a Thr Al a lie Al a Arg Cys Ala Pro Asp 465 470 475 480 363 Glu Glu Leu Leu Ser 485 Cys Ser Ser Phe Ser Arg ser Gly 490 Lys Arg 495 Arg Gly Glu Arg Met Glu Al a Gl n Gly Gly Lys Leu Val Cys Arg Ala Hi s 500 505 510 Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala lie Ala Arg Cys cys Leu 515 520 525 Leu Pro Gin Ala Asn cys ser Val Hi s Thr Al a Pro Pro Ala Glu Ala 530 535 540 Ser Met Gly Thr Arg val Hi s Cys Hi s Gl n Gin Gly His val Leu Thr 545 550 555 560 Gly cys ser Ser His Trp Glu val Gl u Asp L.eu Gly Thr His Lys Pro 565 570 575 Pro Val Leu Arg pro Arg Gly Gin Pro Asn Gin Cys val Gly Hi s Arg 580 585 590 Glu Ala Ser lie His Ala ser Cys Cys Hi s Ala Pro Gly Leu Glu Cys 595 600 605 Lys Val Lys Glu Hi s Gly lie Pro Ala Pro Gl n Gl u Gl n val Thr val 610 615 620 Ala Cys Glu Gl u Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly 62 5 630 635 640 Th r Ser Hi s Val Leu Gly Al a Tyr Ala Val Asp Asn Thr Cys val Val 645 650 655 Arg Ser Arg Asp val ser Thr Thr Gly Ser Thr Ser Glu Gly Al a val 660 665 670 Thr Ala Val Al a lie Cys cys Arg ser Arg Hi s Leu Al a Gin Ala Ser 675 680 68 5 Gin Glu Leu Gin 690 <210> 27 <211> 662 <212> PRT <213> Homo sapiens <400> 27 Gin Glu Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg 15 10 15 Ser Glu Glu Asp Gly Leu Val Glu Ala Pro Glu His Gly Thr Thr Ala 20 25 30 340 Thr ’ Phe ' His ; Arg I cys Ala , Lys ASp Pro Trp Arg Leu Pro Gly Thr Tyr 35 40 45 Val Val Val Leu Lys Glu Glu Thr Hi s Leu Ser Gl n Ser Glu Arg Thr 50 55 60 Ala Arg Arg Leu Gl n Ala Gin Ala Al a Arg Arg Gly Tyr Leu Thr Lys 65 70 75 80 lie Leu Hi s val Phe Hi s Gly Leu Leu pro Gly Phe Leu Val Lys Met 85 90 95 Ser Gl y Asp Leu Leu Gl u Leu Ala Leu Lys Leu Pro Hi s Val ASp Tyr 100 105 110 lie Glu Gl u Asp Ser Ser Val Phe Al a Gin Ser He Pro Trp Asn Leu 115 120 12 5 Gl u Arg lie Thr pro Pro Arg Tyr Arg Al a Asp Gl U Tyr Gl n Pro Pro 130 135 140 Asp Gly Gly Ser Leu Val Glu Val Tyr Leu Leu ASp Thr Ser lie Gl n 145 150 155 160 ser Asp Hi s Arg Gl u lie Glu Gly Arg val Met val Thr Asp Phe Glu 165 170 17 5 Asn Val Pro Gl u Glu Asp Gl y Thr Arg Phe Hi s Arg Gl n Al a Ser Lys 180 185 190 Cys Asp Ser His Gly Thr His Leu Al a Gly Val Val Ser Gly Arg Asp 195 200 205 Ala Gly Val Ala Lys Gly Al a Ser Met Arg Ser Leu Arg Val Leu Asn 210 215 220 cys Gl n Gly Lys Gly Thr val Ser Gly Thr Leu lie Gly Leu Glu Phe 225 230 235 240 lie Arg Lys Ser Gin Leu Val Gl n pro val Gly Pro Leu val val Leu 245 250 255 Leu Pro Leu Ala Gly Gly Tyr Ser Arg val Leu Asn Ala Ala Cys Gin 260 265 270 Arg Leu . Ala Arg Al a Gly val val Leu val Thr Al a Ala Gly Asn Phe 275 280 285 Arg . Asp , Asp . Ala cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu Val lie 290 295 300 31( Thr val Gly ' Ala . Thr1 Asn Ala Gin Asp Gin pro val Thr Leu Gly Thr 305 310 315 320 Leu Gly Thr Asn Phe Gly Arg cys Val Asp Leu Phe Ala Pro Gly Gl u 325 330 335 ASp lie He Gly Ala Ser Ser ASp Cys Ser Thr cys phe val Ser Gl n 340 345 350 Ser Gly Thr Ser Gl n Al a Al a Ala His Val Al a Gly lie A1 a Ala Met 355 360 365 Met Leu Ser Ala Glu Pro Gl u Leu Thr Leu Al a Glu Leu Arg Gl n Arg 370 375 380 Leu lie His Phe Ser Ala Lys Asp Val lie Asn Glu Al a Trp Phe Pro 385 390 395 400 Glu Asp Gin Arg Val Leu Thr Pro Asn Leu Val Ala Al a Leu Pro Pro 405 410 415 Ser Thr His Gly Ala Gly τ rp Gl n Leu Phe Cys Arg Thr val Trp Ser 420 425 430 Al a His Ser Gly Pro Thr Arg Met Al a Thr Ala lie Ala Arg Cys Ala 435 440 445 Pro Asp Glu Glu Leu Leu Ser Cys Ser Ser Phe ser Arg Ser Gly Lys 450 455 460 Arg Arg Gly Gl U Arg Met Gl u Al a Gl n Gly Gly Lys Leu val cys Arg 465 470 475 480 Al a His Asn Ala Phe Gl y Gly Gl u Gly val Tyr Al a lie Ala Arg Cys 485 490 495 cys Leu Leu pro Gl n Al a Asn cys Ser val Hi 5 Thr Ala Pro Pro Al a 500 505 510 Glu Ala Ser Met Gly Thr Arg Val Hi s cys HIS Gin Gl n Gl y Hi s 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 Gl y Gin Pro Asn Gl n cys Val Gly 545 550 555 560 His Arg Glu Ala 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 Ala Pro Gin Glu Gin Val 580 585 590 Π Thr Val Ala 595 Cys Glu Glu Gly Trp 600 Thr Leu Thr Gly Cys 605 Ser Ala Leu Pro Gly Thr Ser His Val Leu Gly Al a Tyr Ala Val Asp Asn Thr Cys 610 615 620 Val Val Arg Ser Arg Asp Val Ser Thr Thr Gl y Ser Thr 5er Glu Gly 625 630 635 640 Al a 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 Gl n 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 i 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 caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg 2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac 2080 <210> 29 <211> 2080 <212> DNA <213> Homo sapiens <400> 29 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 <394 ctctttgccc : caggggagga . catcattggt gcctccagcg actgcagcac ctgctttgtg 1140 tcacagagtg I 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 gccacagccg 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> 30 <211> 2080 <212> DNA <213> Homo sapiens <400> 30 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 i gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg 780 gttagcggca i ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg 840 <3 Π gggccactgg ι 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 ccecaacctg 1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta 1380 tggtcagcac actcggggcc tacacggatg gccacagcca tcgcccgctg cgccccagat 1440 gaggagctgc tgagctgctc cagtttcccc 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 cagcgaaggg gccgtgacag ccgttgccat ctgctgccgg 2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac 2080 <210> 31 <211> 2080 <212> DNA <213> Homo sapi ens <400> 31 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 gccacagccg 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 cagcgaaggg gccgtgacag ccgttgccat ctgctgccgg 2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac 2080 <210> 32 <211> 2080 <212> DNA <213> Homo sapiens <400> 32 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg 60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag 120 ctggtgctag ccttgcgttc cgaggaggac ggcctggtcg 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 420 341 gactacatcg i 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 gccacagccg 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> 33 <211> 2080 <212> DNA <213> Homo sapi ens <400> 33 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 3Π gtgctgaagg I 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 <211> 2080 <212> DNA <213> Homo sapiens <400> 34 atgggcaccc l tcagctccag I gcggtcctgg tggccgctgc cactgctgct gctgctgctg 60 ctgctcctgc i gtcccgcggg I 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 tt0999acca 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 tcagtgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg 1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta 1380 tggtcagcac actcggggcc tacacggatg gccacagccg 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 i caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg 2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac 2080 350 <210> 35 <211> 2080 <212> DNA <213> Homo sapiens <400> 35 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac. ctgctttgtg tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg gtggccaccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta tggtcagcac actcggggcc tacacggatg gccacagcca tcgcccgctg cgccccagat gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctccggag caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 acctcccacg 1 tcctgggggc : ctacgccgta gacaacacgt gtgtagtcag gagccgggac 1980 gtcagcacta ; caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg 2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac 2080 <210> 36 <211> 2080 <212> DNA <213> Homo sapi ens <400> 36 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct. gctgctgctg 60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag 120 ctggtgctag ccttgctttc 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 gccacagccg 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> 37 <211> 2080 <212> DNA <213> Homo sapiens <400> 37 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg 60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag 120 ctggtgctag ccttgcgttc cgaggaggac ggcctggtcg 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 agcggcgggg cgagcgcatg 1500 3^ 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 cagcgaaggg gccgtgacag ccgttgccat ctgctgccgg 2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac 2080 <210> 38 <211> 98 <212> PRT <213> Homo sapiens <400> 38 Gl U 1 val Gin Leu Val 5 Glu Ser Gly Gly Gly 10 Leu Val Gin Pro Gly 15 Gly Ser Leu Arg Leu Ser cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met ser Trp val Arg Gl n Ala pro Gly Lys Gly Leu Glu Trp val 35 40 45 ser Ala lie ser Gly Ser Gly Gly Ser Thr Tyr Ty r Al a Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gl n Met Asn ser Leu Arg Al a Gl U Asp Thr A1 a val Tyr Tyr Cys 90 95 Ala Lys <210> 39 <211> 296 <212> DNA <213> Homo sapiens <220> <221> CDS <222> ¢1).. (294) <400> 39 gag gtq cag Gl u Val Gl n ctg gtq Leu Val gag Gl u tct ggg Ser Gly gga Gly ggc Gly ttg Leu gta Val cag Gl n cct gqg ggg Pro Gly Gly 1 5 10 15 tcc Ser ctg aga etc tcc tgt gca gcc tet gga ttc acc ttt age Ser 30 age Ser tat Tyr 96 Leu Arg Leu 20 Ser cys Al a Ala Ser 25 Gly Phe Thr Phe gcc atg age tgg gtc ege cag get cca ggg aag ggg Gly ctg gag tgg gtc 144 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Leu Glu Trp Val 35 40 45 tea get att agt ggt agt ggt ggt age aca tac tac gca gac tcc gtg 192 Ser Ala lie Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala ASp Ser val 50 55 60 aag ggc Gly egg ttc acc ate tcc aga gac aat tcc aag aac aeg ctg tat 240 Lys Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg aga gcc gag gac aeg gcc gta tat tac tgt 288 Leu Gin Met Α5Π Ser Leu Arg Al a Glu Asp Thr Ala Val Tyr Tyr cys 85 90 95 gcg aaa ga 296 Ala Lys <210> 40 <211> 25 <212> PRT <213> Homo sapiens <400> 40 Glu Val Gin Leu val Glu Ser Gly Gly Gly Leu val Gin Pro Gly Gly 15 10 15 Ser Leu Arg Leu Ser Cys Ala Ala ser 20 25 <210> 41 <211> 990 <212> DNA <213> Homo sapiens <400> 41 gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540 agcacgtacc gggtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 720 ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960 cagaagagcc tctccctgtc tccgggtaaa 990 <210> 42 <211> 330 <212> PRT <213> Homo sapiens <400> 42 Al a 1. . Ser Thr Lys Gly 5 ' Pro Ser1 Val Phe pro 10 Leu Al a Pro Ser Ser 15 Lys ser Thr ser ’ Gly 20 Gly Thr Al a Al a Leu 25 Gly cys Leu val Lys 30 ASp Tyr Phe Pro Glu 35 Pro val Thr Val Ser 40 Trp Asn Ser Gly Ala 45 Leu Thr Ser Gly Val His 50 Thr Phe Pro Ala 55 Val Leu Gin Ser Ser 60 Gly Leu Tyr Ser Leu 65 ser ser val Val Thr 70 Val Pro ser Ser Ser 75 Leu Gly Thr Gin Thr 80 Tyr lie Cys Asn val 85 Asn His Lys Pro Ser 90 Asn Thr Lys val Asp 95 Lys Lys val Glu Pro 100 Lys Ser cys Asp Lys 105 Thr Hi s Thr cys Pro 110 pro cys Pro Ala Pro 115 Gl U Leu Leu Gly Gly 120 Pro Ser Val phe L.eu 12 5 Phe Pro Pro Lys Pro Lys 130 ASp Thr Leu Met 135 Ile Ser Arg Thr Pro 140 Glu val Th r Cys val 145 val Val Asp Val Ser 150 Hi s Glu Asp Pro Glu 155 Val Lys Phe Asn Trp 160 Tyr val Asp Gly Val 165 Glu Val Hi s Asn Al a 170 Lys Thr Lys Pro Arg 175 Glu Gl u Gin Tyr Asn 180 ser Thr Tyr Arg val 185 Val Ser Val Leu Thr 190 val Leu Hi s Gin Asp 195 Trp Leu Asn Gly Lys 200 Glu Tyr Lys cys Lys 205 val ser Asn Lys , Ala Leu Pro . Ala Pro lie Glu Lys Thr He Ser Lys Al a Lys Gly 210 215 220 Gl n 225 Pro Arg Gl u Pro Gin 230 val Tyr Thr Leu Pro 235 Pro Ser Arg Asp Glu 240 Leu Thr Lys Asn Gl n Val Ser Leu Thr Cys Leu val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp lie Al a Val Glu T rp Glu Sen Asn Gly Gin Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe phe 275 280 285 Leu Tyr Ser Lys Leu Thr val Asp Lys ser Arg Trp Gl n Gl n Gl y Asn 290 295 300 Val Phe Sen Cys Ser Val Met His Gl u Ala Leu His Asn Hi s Tyr Thr· 305 310 315 320 Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 43 <211> 978 <212> DNA <213> Homo <400> 43 gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 60 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120 tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 240 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 300 aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 360 ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 420 gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 480 gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 540 gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc 600 aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 660 cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 720 caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 780 gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 840 ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 900 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 960 tccctgtctc cgggtaaa 978 381 <210> 44 <211> 326 <212> PRT <213> Homo sapiens <400> 44 Ala ser Thr 1 Lys Gly Pro Ser Val 5 phe Pro 10 Leu Ala Pro Cys ser 15 Arg Ser Thr1 Ser Glu ser Thr Al a Ala Leu Gly cys Leu val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro val Thr Val Ser T rp Asn Ser Gly A 1 a Leu Thr Ser 35 40 45 Gly Val Hi s Thr Phe Pro Ala val Leu Gin Ser Ser Gly Leu ryr Ser 50 55 60 Leu Ser Ser val val Thr val Pro Ser Ser Asn Phe Gly Thr Gl n Thr 65 70 75 80 Tyr Thr cys Asn val Asp Hi s Lys Pro Ser Asn Thr Lys val Asp Lys 85 90 95 Thr val Glu Arg Lys cys cys val Gl u Cys Pro Pro cys Pro Al a Pro 100 105 110 pro val Ala Gly Pro Ser val Phe Leu Phe pro pro Lys pro Lys Asp 115 120 125 Thr Leu Met lie Ser Arg Thr pro Gl u val Thr cys val val Val Asp 130 135 140 Val Ser Hi s Glu Asp Pro Glu val Gl n Phe Asn Trp Tyr val ASp cly 145 150 155 160 val Glu val Hi s Asn Al a Lys Thr Lys Pro Arg Glu Gl u Gin Phe Asn 165 170 175 Ser Thr Phe Arg Val val Ser val Leu Thr Val Val Hi s Gin Asp T rp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys cys Lys val Ser Asn Lys Gly Leu Pro 195 200 205 Ala Pro lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu 210 215 220 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gin Val Ser Leu Thr cys Leu val Lys Gly Phe Tyr Pro ser Asp He 245 250 255 Ala val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr 260 265 270 Thr pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr ser Lys 275 280 285 Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys 290 295 300 ser Val Met Hl S Glu Al a Leu Hi s Asn Hi 5 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 Gin val 1 Gl n Leu Val 5 Gl n Ser Gly A 1 a 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 Gly lie ser Trp val Arg Gin Al a Pro Gly Gin Gly Leu Gl u T rp Met 35 40 45 Gly τ rp lie Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gin Lys Leu 50 55 60 Gin Gly Arg Val Thr Met Thr Thr Asp Thr ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 90 95 Ala Arg 381 <210> 47 <211> 296 <212> DNA <213> Homo sapiens <400> 47 caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60 tcctgcaagg catctggata caccttcacc agctactata tgcactgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaata atcaacccta gtggtggtag cacaagctac 180 gcacagaagt tccagggcag agtcaccatg accagggaca cgtccacgag cacagtctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaga 296 <210> 48 <211> 98 <212> PRT <213> Homo sapiens <400> 48 Gin Val Gl n Leu Val Gin Ser Gly Ala Glu val Lys Lys Pro Gl y Al a 1 5 10 15 Ser Val Lys val Ser cys cys Ala ser Gly Tyr Thr phe Thr Ser Tyr 20 25 30 Tyr Met Hi s Trp Val Arg Gl n Al a Pro Gly Gl n Gly Leu Glu Trp Met 35 40 45 Gly lie lie Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gin Lys Phe 50 55 60 Gl n Gly Arg val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr val Tyr 65 70 75 80 Met Gl U Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala val Tyr Tyr Cys 90 95 Ala Arg <210> 49 <211> 321 <212> DNA <213> Homo sapi ens <400> 49 cgaactgtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60 ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120 tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180 agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 240 aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 300 agcttcaaca ggggagagtg t 321 <210> 50 <211> 107 <212> PRT <213> Homo sapiens <40 0> 5i 0 Arg Thr val Ala Ala pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 1 5 10 15 Gl n Leu Lys Ser Gly Thr Al a ser val val cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu a! a Lys val Gin Trp Lys val Asp Asn Ala Leu Gl n 35 40 45 Ser Gly Asn Ser Gin Glu Ser val Thr Glu Gin ASp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala ASP Tyr Gl u 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu val Thr His Gin Gly Leu Ser Ser 85 90 95 pro Val Thr Lys ser Phe Asn Arg Gly Glu Cys 100 105 <210> 51 <211> 318 <212> DNA <213> Homo <400> 51 ggtcagccca aggctgcccc c tcggtcact 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 1 Gin Pro Lys Ala 5 Ala pro Ser val Thr 10 Leu Phe Pro Pro Ser 15 Ser Gl u Gl u Leu Gl n Ala Asn Lys Al a Thr Leu Val Cys Leu lie Ser Asp 20 25 30 331 Phe Tyr Pro 35 Gly Ala val Thr Val 40 Ala Trp Lys Ala Asp 45 Ser Ser Pro Val Lys Ala Gly val Gl u Thr Thr Thr Pro Ser Lys Gin Ser Asn Asn 50 55 60 Lys Tyr Al a Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gin T rp Lys 65 70 75 80 Ser Hl S Arg ser Tyr Ser cys Gl n Val Thr Hi s Gl u Gly Ser Thr val 85 90 95 Gill Lys Thr val Ala pro Thr Glu Cys Ser 100 105 <210> 53 <211> 365 <212> DNA <213> Homo sapiens <400> 53 atggtgttgc agacccaggt cttcatttct ctgttgctct ggatctctgg tgcctacggg 60 gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 120 atcaactgca agtccagcca gagtgtttta tacagctcca acaataagaa ctacttagct 180 tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctacccgg 240 gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 300 atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtact 360 cctcc 365 <210> 54 <211> 101 <212> PRT <213> Homo sapiens <400> 54 Asp 1 Tie Val Met Thr 5 G 1 n Ser Pro Asp Ser 10 Leu Al a Val Ser Leu 15 Gly Glu Arg Al a Thr rle Asn Cys Lys Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Al a ser Thr Arg Glu ser Gly val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Al a Glu Asp Val Al a Val Tyr Tyr Cys Gin Gin 90 95 3^ Tyr Tyr Ser Thr Pro 100 <210> 55 <211> 654 <212> DNA <213> Homo sapiens <400> 55 atggacatga gggtccccgc tcagctcctg gggcttctgc tgctctggct cccagcaggt 60 gccagatgtg ccatccagtt gacccagtct ccatcctccc tgtctgcatc tgtaggagac 120 agagtcacca tcacttgccg ggcaagtcag ggcattagca gtgctttagc ctggtatcag 180 cagaaaccag ggaaagctcc taagctcctg atctatgatg cctccagttt ggaaagtggg 240 gtcccatcaa ggttcagcgg cagtggatct gggacagatt tcactctcac catcagcagc 300 ctgcagcctg aagattttgc aacttattac tgtcaacagt ttaatagtta ccctcagtgc 360 cagatgtgcc atccagttga cccagtctcc atcctccctg tctgcatctg taggagacag 420 agtcaccatc acttgccggg caagtcaggg cattagcagt gctttagcct ggtatcagca 480 gaaaccaggg aaagctccta agctcctgat ctatgatgcc tccagtttgg aaagtggggt 540 cccatcaagg ttcagcggca gtggatctgg gacagatttc actctcacca tcagcagcct 600 gcagcctgaa gattttgcaa cttattactg tcaacagttt aatagttacc ctca 654 <210> 56 <400> 56 000 <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 1 5 10 <210> 59 <211> 38 <212> DNA <213> Homo sapiens <400> 59 tgtggtattc ggcggaggga ccaagctgac cgtcctag 38 <210> 60 <211> 12 3^3 <212> PRT <213> Homo sapiens <400> 60 val val Phe Gly Gly1 Gly Thr Lys Leu Thr val Leu 1 5 10 <210> 61 <211> 329 <212> PRT <213> Homo sapi ens <400> 61 Ala Ser Thr Lys Gly Pro Ser Val Phe pro Leu Al a Pro Ser ser cys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asri Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gl n ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr val Pro ser ser Ser Leu Gly Thr Gl n Thr 65 70 75 80 Tyr lie Cys Asn val Asn His Lys Pro ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser cys Asp Lys Thr Hi s Thr cys pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro ser val phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met lie ser Arg Thr pro Glu Val Thr cys 130 135 140 val val val Asp Val Ser His Glu Asp Pro Gl u Val Lys Phe Asn T rp 145 150 155 160 Tyr Val Asp Gly Val Glu val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gin Tyr Asn Ser Thr Tyr Arg val val Ser Val Leu Thr Val Leu 180 185 190 HIS Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Tie Glu Lys Thr Tie Ser Lys Al a Lys Gly 210 215 220 Gin 225 Pro Arg Glu Pro Gl n 230 val Tyr Thr Leu Pro 235 Pro Ser Arg Asp Glu 240 Leu Thr Lys Asn Gl n Val Ser Leu Thr Cys Leu val Lys Gl y Phe Tyr 245 250 255 Pro Ser Asp lie Ala Val Gl u Trp Gl u Ser Asn Gly Gin Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro val Leu Asp Ser Asp Gly Ser Phe phe 275 280 285 Leu Tyr Ser Lys L eu Thr val Asp Lys Ser Arg Trp Gin Gin Gly Asn 290 295 300 Val Phe ser cys ser val Met Hi s Glu Ala Leu Hi s Asn Hi s Tyr Thr 305 310 315 320 Gin Lys Ser Leu Ser Leu Ser Pro Gly 325 <210> 62 <211> 107 <212> PRT <213> Homo sapiens <40: 0> 6 2 Arg Thr val Ala Al a pro ser val Phe lie Phe Pro Pro Ser Asp Glu 1 5 10 15 Gin Leu Lys Ser Gly Thr Al a Ser val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Gl u Al a Lys val Gl n τ rp Lys Val Asp Asn Ala Leu Gl n 35 40 45 Ser Gly Asn Ser Gin Glu Ser val Thr Glu Gin Asp Ser Lys ASp ser 50 55 60 Thr Tyr Ser Leu Ser ser Thr Leu Th r Leu Ser Lys Al a Asp Tyr Gl u 65 70 75 80 Lys Hi 5 Lys Val Tyr Ala cys Gl u val Thr Hi s Gl n Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu cys 100 105 <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 1 5 10 15 115 ser Thr Ser ' Glu ι Ser Thr Al a Al a Leu Gly cys Leu val Lys Asp Tyr 20 25 30 Phe ! Pro ι Glu Pro Val Thr val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly val Hi s Thr Phe Pro Al a Val Leu Gin Ser Ser Gl y Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr' val Pro Ser Ser Asn Phe Gly Thr Gin Thr 65 70 75 80 Tyr Thr Cys Asn val ASp Hi s Lys pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Thr val Gl u Arg Lys Cys cys val Glu Cys Pro Pro Cys pro Ala pro 100 105 110 Pro Val Al a Gly Pro Ser val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met lie Ser Arg Thr Pro Glu val Thr cys Val Val val Asp 130 135 140 val Ser His Gl u Asp Pro Gl u val Gin Phe Asn Trp Tyr val Asp Gly 145 150 155 160 val Gl u Val His Asn Al a Lys Thr Lys Pro Arg Glu Gl u Gin Phe Asn 165 170 175 Ser Thr Phe Arg val val Ser val Leu Thr val val Hi s Gin Asp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys val Ser Asn Lys Gly Leu Pro 195 200 205 Ala Pro lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu 210 215 220 Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gin val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie 245 250 255 Ala val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr 260 265 270 Thr Pro Pro Met Leu Asp Ser Asp Gly ser Phe Phe Leu Tyr Ser Lys 275 280 285 Leu Thr 290 Val Asp Lys Ser Arg 295 Trp Gin Gin Gly Asn 300 val Phe Ser Cys Ser Val Met Hi s Glu Ala Leu Hi s Asn His Tyr Thr Gl n Lys Ser Leu 305 310 315 320 Ser Leu Ser Pro Gly Lys 325 <210> 64 <211> 105 <212> PRT <21 3> H omo sapi ens <40 0> 6 4 Gin Pro Lys Ala Ala Pro Ser val Thr Leu Phe Pro Pro Ser Ser Gl u 1 5 10 15 Glu Leu Gin Ala Asn Lys Ala Thr Leu Val Cys Leu lie Ser Asp Phe 20 25 30 Tyr Pro Gly Ala val Thr Val Al a Trp Lys Ala Asp Ser Ser Pro Val 35 40 45 Lys Ala Gly val Glu Thr Thr Thr Pro ser Lys Gin ser Asn Asn Lys 50 55 60 Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Gl u Gl n T rp Lys Ser 65 70 75 80 His Arg ser Tyr Ser Cys Gin Val Thr Hi s Glu Gly ser Thr val Glu 85 90 95 Lys Thr val Al a Pro Thr Gl u Cys Ser 100 105 <210> 65 <211> 326 <212> PRT <213> Homo sapiens <401 0> 6! 5 Ala Ser Thr Lys Gly Pro Ser val Phe Pro Leu Ala Pro cys ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Al a Leu Gly cys Leu val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Al a Leu Thr Ser 35 40 45 Gly Val Hi s Thr phe Pro Ala val Leu Gin ser ser Gly Leu Tyr ser 50 55 60 Leu ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr 70 75 80 nr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Thr val Glu Arg Lys Cys cys Val Glu cys Pro Pro cys Pro a! a pro 100 105 110 Pro val Ala Gly Pro Ser val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met Il e ser Arg Thr Pro Glu Val Thr cys Va 1 val val ASp 130 13 5 140 Val Ser Hi s Glu Asp pro Glu val Gin Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 Val Gl u Val Hi s Asn Al a Lys Thr Lys pro Arg Glu Gl u Gin Phe Asn 165 170 17 5 ser Thr Phe Arg Val Val Ser val Leu Thr Val Val Hi s Gl n Asp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205 Ser Ser lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu 210 215 220 Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Gl u Gl U Met Thr Lys Asn 225 230 235 240 Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp He 245 250 255 Al a val Gl u Trp Glu Ser Asn Gly Gin pro Glu Asn Asn Tyr Lys Thr 260 265 270 Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr ser Lys 275 280 285 Leu Thr val Asp Lys Ser Arg Trp Gl n Gl n Gly Asn val Phe Ser Cys 290 295 300 Ser Val Met Hi s Glu Ala Leu Hi s Asn Hi s Tyr Thr Gl n Lys ser Leu 305 310 315 320 ser Leu ser pro Gly Lys <210> 66 <211> 107 <212> PRT <213> Homo sapiens <33? 325 <400> 66 Arg Thr Val 1! Ala Ala Pro ser val 5 Phe lie Phe 10 Pro Pro Ser Asp Glu 15 Gin Leu Lys ; Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg i Glu Ala Lys val Gin Trp Lys val ASp Asn Ala Leu Gin 3 5 40 45 Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin ASp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys Hi s Lys val Tyr Ala Cys Glu val Thr His Gin Gly Leu Ser ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 67 <211> 825 <212> PRT <213> Homo : sapi ens <400> 67 Met Gly Trp Leu cys ser Gly Leu Leu Phe Pro val ser cys Leu val 1 5 10 15 Leu Leu Gin Val Ala Ser Ser Gly Asn Met Lys Val Leu Gl n Glu Pro 20 25 30 Thr Cys val Ser Asp Tyr Met Ser ile Ser Thr Cys Glu Trp Lys Met: 35 40 45 Asn Gly pro Thr Asn Cys Ser Thr Glu Leu Arg Leu Leu Tyr Gin Leu 50 55 60 Val Phe Leu Leu Ser Glu Ala Hi s Thr cys lie Pro Glu Asn Asn Gly 65 70 75 80 Gly Ala Gly Cys Val Cys His Leu Leu Met Asp Asp Val val Ser Ala 85 90 95 Asp Asn Tyr Thr Leu Asp Leu Trp Ala Gly Gin Gin Leu Leu Trp Lys 100 105 110 Gly Ser Phe Lys Pro Ser Glu His val Lys Pro Arg Ala pro Gly Asn 115 120 12 5 Leu Thr val His Thr Asn Val Ser Asp Thr Leu Leu Leu Thr Trp Ser 130 135 140 cm Asr 145 ι Pre » Tyr Pre ι Pro - ASp 150 Asn Tyr Leu Tyr Asn 155 Hi s Leu Thr Tyr Ala 160 val Asn lie Trp ser 165 Glu Asn Asp Pro Ala 170 ASp Phe Arg lie Tyr 175 Asn val Thr Tyr Leu 180 Glu Pro Ser Leu Arg 185 lie Ala Ala Ser Thr 190 Leu Lys Ser Gly lie 195 Ser Tyr Arg Ala Arg 200 Val Arg Ala Trp Ala 205 Gin Cys Tyr Asn Thr 210 Thr T rp Ser Glu Trp 215 ser Pro Ser Thr Lys 220 Trp Hi s Asn Ser Tyr 225 Arg Glu pro Phe Glu 230 Gl n Hi s Leu Leu Leu 235 Gly val ser Val Ser 240 cys il e Val lie Leu 245 Al a val cys Leu Leu 250 Cys Tyr val Ser lie 255 Thr Lys lie Lys Lys 260 Glu Trp Trp ASp Gin 265 He Pro Asn pro Al a 270 Arg Ser Arg Leu Val 275 Ala lie lie He Gl n 280 ASp Ala Gl n Gly Ser 285 Gin Trp Glu Lys Arq 290 Ser Arg Gly Gin Glu 295 Pro Ala Lys cys Pro 300 His Trp Lys Asn Cys 305 Leu Thr Lys L.eu Leu 310 Pro Cys Phe Leu Glu 315 Hi s Asn Met Lys Arg 320 Asp Glu Asp Pro Hl s 325 Lys Al a Al a Lys Gl u 330 Met Pro Phe Gin Gly 335 Ser Gly Lys Ser Ala 340 Trp Cys Pro Val GlU 345 lie Ser Lys Thr Val 350 Leu Trp pro GlU ser 355 lie ser val val Arg 360 Cys Val Gl u Leu Phe 365 Glu Ala Pro val Glu 370 Cys Glu Glu Glu Glu 375 Glu Val Glu Glu Glu 380 Lys Gly ser Phe cys 385 Al a Ser pro Gl u Ser 390 Ser Arg Asp Asp Phe 395 Gin Glu Gly Arg Glu 400 Gly lie ' val Ala . Arg 405 Leu Thr Glu Ser Leu 410 phe Leu Asp Leu Leu 415 Gly 900 Glu Glu Asr ι Gly Gly ' Phe ! Cys Gin Gin Asp Met Gly Glu Ser cys Leu 420 425 430 Leu Pro Pro ι Ser Gly Ser Thr Ser Al a Hi s Met Pro Trp ASp Glu Phe 435 440 445 pro Ser1 Al a Gly Pro Lys Gl u Al a Pro Pro Trp Gly Lys Gl u Gin Pro 450 455 460 Leu His Leu Glu Pro Ser Pro Pro Ala Ser pro Thr Gin Ser Pro Asp 465 470 475 480 Asn Leu Thr Cys Thr Gl u Thr Pro Leu Val II e A1 a Gly Asn Pro Ala 485 490 495 Tyr Arg Ser Phe ser Asn Ser Leu Ser Gl n ser Pro cys Pro Arg Glu 500 505 510 Leu Gly Pro Asp Pro Leu Leu Ala Arg Hi s Leu Glu Glu val Glu Pro 515 520 525 Glu Met pro Cys val pro Gin Leu Ser Glu Pro Thr Thr val Pro Gin 530 535 540 Pro Glu Pro Glu Thr Trp Glu Gl n lie Leu Arg Arg Asn Val Leu Gin 545 550 555 560 His Gly Ala Ala Ala Ala Pro val Ser Al a Pro Thr Ser Gly Tyr Gin 565 570 575 Glu Phe val His Ala val Glu Gl n Gly Gly Thr Gl n Ala Ser Al a val 580 585 590 Val Gly Leu Gly Pro Pro Gly Gl u Al a Gly Tyr Lys Al a Phe Ser ser 595 600 605 Leu Leu Al a Ser Ser Al a val Ser pro Glu Lys cys Gly Phe Gly Ala 610 615 620 Ser Ser Gly Gl U Gl U Gly Tyr Lys pro Phe Gin ASp Leu lie pro Gly 625 630 635 640 Cys Pro Gly Asp Pro Ala pro val Pro Val Pro Leu Phe Thr Phe Gly 645 650 655 Leu Asp Arg Glu pro pro Arg Ser Pro Gin Ser Ser Hi s Leu Pro Ser 660 665 670 Ser Ser Pro Gl u Hi s Leu Gl y Leu Glu Pro Gly Glu Lys val Glu Asp 675 680 685 Met Pro Lys Pro Pro Leu Pro Gin Glu Gin Ala Thr Asp Pro Leu Val 690 695 700 U 01 Asp Sen Leu Gly Ser Gly lie Val Tyr Ser Ala Leu Thr Cys Hi s Leu 705 710 715 720 Cys Gly Hi s Leu Lys Gl n cys Hi s Gl y Gl n Glu Asp Gly Gly Gl n Thr 725 730 735 Pro val Met Al a ser Pro Cys cys Gly Cys Cys Cys Gly Asp Arg Ser 740 745 750 Sen Pro Pro Thr Thr Pro Leu Arg Ala Pro Asp Pro Ser Pro Gly Gly 755 760 765 Val Pro Leu Glu Ala Ser Leu Cys Pro Ala Ser Leu Ala Pro Ser Gly 770 775 780 He ser Glu L.ys ser Lys ser Ser ser Ser Phe Hi s Pro Al a Pro Gly 785 790 795 800 Asn Ala Gin ser ser Ser Gin Thr pro Lys lie Val Asn Phe Val Ser 805 810 815 Val Gly Pro Thr Tyr Met Arg val ser 820 825 <210> 68 <211> 2478 <212> DNA <213> Homo sapiens <400> 68 atggggtggc tttgctctgg gctcctgttc cctgtgagct gcctggtcct gctgcaggtg 60 gcaagctctg ggaacatgaa ggtcttgcag gagcccacct gcgtctccga ctacatgagc 120 atctctactt gcgagtggaa gatgaatggt cccaccaatt gcagcaccga gctccgcctg 180 ttgtaccagc tggtttttct gctctccgaa gcccacacgt gtatccctga gaacaacgga 240 ggcgcggggt gcgtgtgcca cctgctcatg gatgacgtgg tcagtgcgga taactataca 300 ctggacctgt gggctgggca gcagctgctg tggaagggct ccttcaagcc cagcgagcat 360 gtgaaaccca gggccccagg aaacctgaca gttcacacca atgtctccga cactctgctg 420 ctgacctgga gcaacccgta tccccctgac aattacctgt ataatcatct cacctatgca 480 gtcaacattt ggagtgaaaa cgacccggca gatttcagaa tctataacgt gacctaccta 540 gaaccctccc tccgcatcgc agccagcacc ctgaagtctg ggatttccta cagggcacgg 600 gtgagggcct gggctcagtg ctataacacc acctggagtg agtggagccc cagcaccaag 660 tggcacaact cctacaggga gcccttcgag cagcacctcc tgctgggcgt cagcgtttcc 720 tgcattgtca tcctggccgt ctgcctgttg tgctatgtca gcatcaccaa gattaagaaa 780 gaatggtggg atcagattcc caacccagcc cgcagccgcc tcgtggctat aataatccag 840 gatgctcagg ggtcacagtg ggagaagcgg tcccgaggcc aggaaccagc caagtgccca 900 cactggaaga attgtcttac caagctcttg ccctgttttc tggagcacaa catgaaaagg 960 gatgaagatc ctcacaaggc tgccaaagag atgcctttcc agggctctgg aaaatcagca 1020 tggtgcccag tggagatcag caagacagtc ctctggccag agagcatcag cgtggtgcga 1080 tgtgtggagt tgtttgaggc cccggtggag tgtgaggagg aggaggaggt agaggaagaa 1140 aaagggagct tctgtgcatc gcctgagagc agcagggatg acttccagga gggaagggag 1200 ggcattgtgg cccggctaac agagagcctg ttcctggacc tgctcggaga ggagaatggg 1260 ggcttttgcc agcaggacat gggggagtca tgccttcttc caccttcggg aagtacgagt 1320 gctcacatgc cctgggatga gttcccaagt gcagggccca aggaggcacc tccctggggc 1380 aaggagcagc ctctccacct ggagccaagt cctcctgcca gcccgaccca gagtccagac 1440 aacctgactt gcacagagac gcccctcgtc atcgcaggca accctgctta ccgcagcttc 1500 agcaactccc tgagccagtc accgtgtccc agagagctgg gtccagaccc actgctggcc 1560 agacacctgg aggaagtaga acccgagatg ccctgtgtcc cccagctctc tgagccaacc 1620 actgtgcccc aacctgagcc agaaacctgg gagcagatcc tccgccgaaa tgtcctccag 1680 catggggcag ctgcagcccc cgtctcggcc cccaccagtg gctatcagga gtttgtacat 1740 gcggtggagc agggtggcac ccaggccagt gcggtggtgg gcttgggtcc cccaggagag 1800 gctggttaca aggccttctc aagcctgctt gccagcagtg ctgtgtcccc agagaaatgt 1860 gggtttgggg ctagcagtgg ggaagagggg tataagcctt tccaagacct cattcctggc 1920 tgccctgggg accctgcccc agtccctgtc cccttgttca cctttggact ggacagggag 1980 ccacctcgca gtccgcagag ctcacatctc ccaagcagct ccccagagca cctgggtctg 2040 gagccggggg aaaaggtaga ggacatgcca aagcccccac ttccccagga gcaggccaca 2100 gacccccttg tggacagcct gggcagtggc attgtctact cagcccttac ctgccacctg 2160 tgcggccacc tgaaacagtg tcatggccag gaggatggtg gccagacccc tgtcatggcc 2220 agtccttgct gtggctgctg ctgtggagac aggtcctcgc cccctacaac ccccctgagg 2280 gccccagacc cctctccagg tggggttcca ctggaggcea gtctgtgtcc ggcctccctg 2340 gcaccctcgg gcatctcaga gaagagtaaa tcctcatcat ccttccatcc tgcccctggc 2400 aatgctcaga gctcaagcca gacccccaaa atcgtgaact ttgtctccgt gggacccaca 2460 tacatgaggg tctcttag 2478 <210> 69 <211> 125 <212> PRT <213> Homo sapiens <400> 69 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Glu Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr phe Arg Asp Tyr 20 25 30 Ala Met Thr T rp Val Arg Gin Ala pro Gly Lys Gly Leu Gl u Trp Val 903 40 45 ser Ser lie Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gl n Met Asn Ser Leu Arg Al a Glu ASP Thr Ala Val Tyr Tyr cys 85 90 95 Al a lys Asp Arg leu Ser lie Thr lie Arg Pro Arg Ty r Tyr Gl y Leu 100 105 110 A5p val T rp Gly Gl n Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 70 <211> 112 <212> PRT <213> Homo sapiens <400> 70 Thr Pro 15 Gly Asp 1 He Val Met Thr 5 Gl n Ser Pro Leu Ser 10 Leu Pro val Glu Pro Ala Ser 20 He Ser cys Arg Ser 25 Ser Gin Ser Leu Leu 30 Tyr Ser lie Gly Tyr 35 Asn Tyr Leu ASp Trp 40 Tyr Leu Gin Lys Ser 45 Gly Gin Ser Pro Gl n 50 Leu Leu He Tyr Leu 55 Gly Ser Asn Arg Ala 60 Ser Gly val Pro Asp 65 Arg Phe ser Gly ser 70 Gly Ser Gl y Thr Asp 75 Phe rhr Leu Lys lie 80 Ser Arg Val Glu Ala 85 Glu Asp val Gly Phe 90 Tyr Tyr Cys Met Gin 95 Al a Leu Gin Thr Pro Tyr Thr Phe Gly Gin Gly Thr Lys Leu Glu He Lys 100 105 HO <210> 71 <211> 451 <212> PRT <213> Homo sapiens <400> 71 Glu val Gin Leu Val Glu Ser Gly Gly Gly Leu Glu Gin Pro Gly Gly 1 5 10 15 . Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr 20 25 30 904 Ala Met Thr Trp 35 * val Arg Gin Ala Pro 40 Gl y Lys Gly Leu 45 Glu Trp Val Ser ’ Ser lie Ser 50 Gly Ser Gl y 55 Gly Asn Thr Tyr Tyr 60 Ala 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 Ala Glu Asp 90 Thr Al a Val Tyr Tyr 95 Cys Al a Lys Asp Arg 100 Leu Ser il e Thr lie 105 Arg Pro Arg Tyr Tyr 110 Gly Leu ASp val Trp Gly 115 Gl n G1 y Thr Thr val 120 Thr val ser Ser 125 A'I a ser Thr Lys Gly Pro Ser 130 Val Phe Pro 135 Leu Ala Pro cys Ser 140 Arg Ser Thr Ser Gl U 145 ser Thr Ala Ala Leu 150 Gly Cys Leu val Lys 155 Asp Tyr Phe Pro Glu 160 Pro Val Thr Val ser 165 T rp Asn Ser Gly Ala 170 Leu Thr Ser Gly Val 175 Hi s Thr Phe Pro Ala 180 Val Leu Gin Ser Ser 185 Gly Leu Tyr Ser Leu 190 Ser Ser val val Thr val 195 pro Ser Ser Ser Leu 200 Gly Thr Lys Thr 205 Tyr Thr Cys Asn Val Asp His 210 Lys Pro Ser 215 Asn Thr Lys Val Asp 220 Lys Arg Val Glu ser 225 Lys Tyr Gly Pro Pro 230 Cys Pro Pro Cys Pro 235 Ala Pro Gl u Phe Leu 240 Gly Gly Pro Ser val 245 Phe Leu Phe Pro Pro 250 Lys pro Lys Asp Thr 255 Leu Met lie Ser Arg 260 Thr Pro Glu Val Thr 265 cys Val Val val Asp 270 Val ser Gin Glu Asp Pro 275 Glu val Gin Phe Asn 280 τ rp Tyr val Asp 285 Gly val Glu val His Asn Ala 290 Lys Thr Lys 295 Pro Arg Glu Glu Gin 300 Phe Asn Ser Thr Tyr , Arg Val val 5er val Leu Thr val Leu Hi s Gin Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys 325 cys Lys val Ser Asn Lys Gly 330 Leu Pro Ser 335 Ser lie Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin 340 345 350 val Tyr Thr Leu Pro pro Ser Gin Glu Glu Met Thr Lys Asn Gl n Val 355 360 365 ser Leu Thr cys Leu val Lys Gly phe Tyr Pro Ser Asp lie Al a val 370 375 380 Glu Trp Gl u Ser Asn Gly Gin Pro Glu Asn Asn ryr Lys Thr Th r Pro 385 390 395 400 Pro val Leu Asp Ser Asp Gly Ser phe phe Leu Tyr Ser Arg Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gin Glu Gly Asn Val Phe Ser cys Ser Val 420 425 430 Met Hi s Glu Al a Leu Hi s Asn His Tyr Thr Gin Lys Ser Leu Ser Leu 435 440 445 Ser Leu Gly 450 <210> 72 <211> 214 <212> PRT <213> Homo sapiens <400> 72 Asp 1 lie Val Met Thr 5 Gin Ser Pro Leu Ser 10 Leu Pro Val Th r Pro 15 Gly Gl u Pro Al a Ser lie Ser Cys Arg Ser Ser Gl n ser Leu Leu Tyr Ser 20 25 30 Ile Gly Tyr Asn Tyr Leu Asp T rp Tyr Leu Gl n Lys ser Gly Gl n Ser 35 40 45 Pro Gin Leu Leu lie Tyr Leu Gly Ser Asn Arg Al a Ser Gly val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr ASp Phe Thr Leu Lys lie 65 70 75 80 ser Arg val Glu Al a Glu ASp val Gly Phe Tyr Tyr cys Met Gin Al a 85 90 95 Leu Gin Thr Pro Tyr Thr Phe Gly Gl n Gly Thr Lys Leu Gl u Ile Lys 100 105 110 Arg Thr val Ala Ala Pro ser val 120 Phe lie phe pro pro 125 ser Asp Glu 115 Gl n Leu Lys Ser Gly Thr Al a Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Gl u Ala Lys val Gl n Trp Lys Val Asp Asn Al a Leu Gin 145 150 155 160 Ser Gly Asn Ser Gin Gl u Ser Val Thr Glu Gl n Asp Ser Lys Asp Ser 165 170 17 5 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu 180 185 190 Lys Hi s Lys val Tyr Ala cys Glu val Thr Hi s Gl n Gly Leu Ser ser 195 200 205 Pro Val Thr Lys Ser Phe 210 <210> 73 <211> 327 <212> PRT <213> Homo sapiens <400> 73 Phe Pro 10 Leu A1 a Pro Cys Ser 15 Arg Ala 1 Ser Thr Lys Gly 5 Pro Ser Val Ser Thr Ser Glu 20 Ser Thr Ala Ala Leu 25 Gly Cys Leu Val Lys 30 Asp Tyr Phe Pro Glu 35 Pro Val Thr val Ser 40 τ rp Asn Ser Gly Al a 45 Leu Thr Ser Gly Val 50 Hi s Thr Phe Pro Al a 55 Val Leu Gin Ser Ser 60 Gly Leu Tyr Ser Leu 65 Ser Ser Val Val Thr 70 Val Pro Ser ser Ser 75 Leu Gly Thr Lys Thr 80 Tyr Thr cys Asn val 85 Asp Hi s Lys Pro Ser 90 Asn Thr Lys val Asp 95 Lys Arg val Glu Ser 100 Lys Tyr Gly Pro Pro 105 Cys Pro Ser Cys Pro 110 Al a Pro Gl u Phe Leu 115 Gly Gly Pro Ser Val 120 Phe Leu Phe Pro Pro 125 Lys Pro Lys ASp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr cys Val val Val 901 130 135 140 Asp Val 145 Ser Gin Glu Asp 150 Pro Glu Val Gl n phe 155 Asn τ rp Tyr val Asp 160 Gly val Glu val Hi 5 Asn Al a Lys Thr Lys Pro Arg Gl u Glu Gl n Phe 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser val Leu Thr Val Leu His Gl n Asp 180 185 190 T rp Leu Asn Gly Lys Glu Tyr Lys cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser lie Gl u Lys Thr He Ser Lys Ala Lys cly Gl n Pro Arg 210 215 220 Glu Pro Gl n val Tyr Thr Leu Pro Pro Ser Gin Glu Glu Met Thr Lys 225 230 235 240 Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 rle Al a Val Glu T rp Gl U Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp ser ASp Gly ser Phe phe Leu Tyr ser 275 280 285 Arg Leu Thr Val Asp Lys Ser Arg Trp Gl n Glu Gly Asn val phe Ser 290 295 300 Cys Ser Val Met Hi s Glu Ala Leu Hl s Asn Hi s Tyr Thr Gin Lys ser 305 310 315 320 Leu Ser Leu Ser Leu Gly Lys 325 <210> 74 <211> 984 <212> DNA <213> Homo sapiens <400> 74 gcttccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 60 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 240 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 300 aaatatggtc ccccatgccc atcatgccca gcacctgagt tcctgggggg accatcagtc 360 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 420 90S tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 480 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 540 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 600 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 660 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 720 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 780 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 840 gacggctcct tcttcctcta cagcaggctc accgtggaca agagcaggtg gcaggagggg 900 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 960 ctctccctgt ctctgggtaa atga 984 <210> 75 <211> 7 <212> PRT <213> Artificial Sequence <22O> <223> Description of Artificial Sequence: Synthetic pepti de <400> 75 val Phe Ala Gin Ser lie Pro <210> 76 <211> 296 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1),.(294) <400> 76 gag Gl U 1 gtq val cag Gin ctg Leu ttg gag tet Ser ggg Gly gga Gly ggc ttg gta val cag Gl n cct Pro ggg Gly 15 ggg Gl y 48 Leu 5 Glu Gly 10 Leu tcc ctg aga etc tcc tgt gca gcc tet gga ttc acc ttt age age tat 96 ser Leu Arg Leu Ser Cys Al a 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 Al a Pro Gly Lys Gly Leu Gl u Trp val 35 40 45 tea get att agt ggt agt ggt ggt age aca tac tac gca gac tcc gtg 192 Ser Ala lie ser Gly ser Gly Gly Ser Thr Tyr Tyr Ala A5p Ser val 50 55 60 aag ggc egg ttc acc ate tcc aga gac aat tcc aag aac aeg ctg tat 240 Lys Gly Arg phe Thr lie Ser Arg Asp Asn ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg aga gcc gag gac aeg gcc gta tat tac tgt 288 Leu Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Ala val Tyr Tyr Cys 85 90 95 405 gcg aaa ga Ala Lys 296 <210> 77 <211> 98 <212> PRT <213> Homo sapiens <400> 77 Gl U 1 val Gl n Leu Leu 5 Glu Sen Gly Gly GlνΙΟ Leu Val Gin Pro Gly 15 Gly Sen Leu Arg Leu Ser Cys a! a Al a Sen Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Tnp Val Arg Gin Ala Pro Gly Lys Gly Leu Gl u Trp Val 35 40 45 Sen Ala lie Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala A5p Ser val 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Gl u Asp Thr Ala Val Tyr Tyr cys 90 95 Ala Lys <210> 78 <211> 294 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(294) <400> 78 gag Glu 1 gtg Val cag Gin ctg Leu ttg gag tet Ser gqg gga Gly Gly gqc Gly 10 ttg Leu gta val cag Gin cct Pro ggg Gly 15 ggg Gly 48 Leu 5 Glu 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 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp val 35 40 45 tea get att agt ggt agt ggt ggt age aca tac tac gca gac tcc gtg val 192 Ser Al a lie Ser Gly ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser 50 55 60 aag ggc egg ttc acc ate tcc aga gac aat tcc aag aac aeg ctg tat 240 Lys Gly Arg Phe Thr lie ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg Leu caa atg Gin Met aac age ctg Leu aga Arg gcc Ala gag Gl u gac aeg Asp Thr 90 gcc Ala gta Val tat Tyr tac Tyr 95 tgt cys 288 Asn Ser 85 gcg aaa 294 Ala Lys <210> 79 <211> 296 <212> DNA <213> Homo sapiens <22Ο> <221> CDS <22 2> ( 1).. (294 3 <40 0> 7 9 gag gtg cag ctg ttg gag tct ggg gga ggc ttg gta cag cct ggg ggg 48 Gl u Val Gin Leu Leu Gl u Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 tcc ctg aga etc tcc tgt gca gee tct gga ttc acc ttt age age cat 96 Ser Leu Arg Leu Ser cys Al a Al a Ser ciy 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 Ala Met ser T rp val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp val 35 40 45 tea get att agt ggt agt ggt ggt age aca tac tac gga gac tcc gtg 192 ser Ala lie ser Gly Ser Gly Gly Ser Thr Tyr Tyr Gly ASp Ser Val 50 55 60 aag ggc egg ttc acc ate tea aga gac aat tee aag aac aeg ctg tat 240 cys Gly Arg Phe Thr lie ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg aga gcc gag gac aeg gcc gta tat tac tgt 288 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val iyr Tyr cys 85 90 95 geg aaa ga 296 Ala Lys <210> 80 <211> 98 <212> PRT <213> Homo sapi ens <400> 80 Glu val Gin 1 Leu Leu 5 Glu Ser Gly Gly Gly 10 Leu val Gin Pro Gly 15 Gly Ser Leu Arg Leu 20 Ser cys Ala Al a Ser 25 Gly Phe Thr Phe Ser 30 Ser Tyr Ala Met Ser 35 Trp Val Arg Gin Al a 40 Pro Gly Lys Gly Leu 45 Glu Trp val Ser Ala lie Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Gly Asp Ser val 55 60 Ml Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala val Tyr Tyr Cys 85 90 95 Ala Lys <210> 81 <211> 294 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(294) <400> 81 gag Glu 1 gtg Val cag Gl n ctg Leu ttg gag tet Ser ggg gga ggc ttg gta cag cct Pro ggg Gly 15 ggg Gly 48 Leu 5 Gl u Gly Gly Gly Leu 10 Val Gin tcc ctg aga etc tcc tgt gca gcc tet gga ttc acc ttt age age tat 96 Ser Leu Arg Leu ser cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 gcc atg age tgg gtc ege cag get cca ggg aag ggg Gly ctg gag tgg gtc 144 Ala Met ser τ rp Val Arg Gin Ala Pro Gly Lys 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 Ala ASp Ser val 50 55 60 aag ggc egg ttc acc ate tcc aga gat aat tcc aag aac aeg ctg tat 240 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg Let El atg aac age ctg aga gcc gag gac aeg gcc gta tat tac tgt 288 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 geg 3. cl El 294 Ala Lys <210> 82 <211> 98 <212> PRT <213> Homo sapiens <400> 82 Glu 1 Val Gin Leu Leu Glu ser Gly Gly Gly Leu val Gl n Pro Gly Gly 15 5 10 ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp val 40 45 ser val lie Tyr Ser Gl y Gly Ser Ser Thr Tyr Tyr Ala ASp Ser Val 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Al a Val Tyr Tyr Cys 85 90 95 Ala Lys <210> 83 <211> 296 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(294) <400> 83 gag Gl u 1 gtg Val cag Gin ctg Leu ttg gag tct Ser ggg gga Gly Gly ggc ttg gta cag cct Pro ggg Gly 15 ggg cly 48 Leu 5 Gl u Gly 10 Leu Val Gl n tcc ctg aga etc tcc tgt gca gcc tct 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 Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu τ rp val 35 40 45 tea gtt att tat age ggt ggt cly agt age aca tac tat gca gac tcc gtg 192 Ser val lie Tyr Ser 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 aeg ctg tat 240 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Α5Π Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg aga gcc gag gac aeg gcc gta tat tac tgt 288 Leu Gl n Met Asn Ser Leu Arg Ala Glu ASp Thr Ala Val Tyr Tyr Cys 85 90 95 gcg aaa ga 296 Ala Lys <210> 84 <211> 294 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(294) <400> 84 gag gtg cag ctg ttg gag tct ggg gga ggc ttg gta cag cct ggg ggg 48 LU Glu 1 val Gin Leu Leu 5 Glu ser Gly Gly Gly 10 Leu val Gl n 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 Ala Met ser T rp val Arg Gl n Ala Pro Gly Lys cly Leu Glu T rp Val 35 40 45 tea get att tat age agt ggt agt age aca tac tat gca gac tcc gtg 192 Ser Al a lie Tyr ser Ser Gly Ser Ser Thr Tyr Tyr Ala Asp ser val 50 55' 60 aag 99 c egg ttc acc ate tcc aga gac aat tee aag aac aeg ctg tat 240 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 ctg caa atg aac age ctg aga gee gag gac aeg gcc gta tat tac tgt 288 Leu Gl n Met Asn Ser Leu Arg Ala Glu Asp Thr Al a Val Tyr Tyr Cys 85 90 95 gcg aaa 294 Ala Lys <210> 85 <211> 98 <212> PRT <213> Homo sapiens <400> 85 Leu 5 Glu ser Gly Gly Gly 10 Leu Val Gin Pro Gly 15 Gly Glu 1 val Gin Leu Ser Leu Arg Leu Ser cys Ala Al a Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met ser T rp val Arg Gl n Ala Pro Gly Lys Gly Leu Gl u Trp val 35 40 45 Ser Ala lie Tyr Ser Ser Gly Ser Ser Thr Tyr Tyr Ala Asp ser val 50 55 60 Lys Gly Arg Phe Thr il e Ser Arg Asp Asn ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gl n Met Asn Ser Leu Arg Ala Gl u Asp Thr Ala Val Tyr Tyr cys 85 90 95 Ala Lys ON

Claims (5)

1. An injectable preparation comprising an antibody or antibody fragment for use in a method of treating or reducing the risk of atopic dermatitis or asthma in a human in need thereof, wherein the antibody or antibody fragment specifically binds a human IL4Ra 5 protein that comprises a mutation selected from the group consisting of 175V, E400A, C431R, S503P, Q576R and S752A in SEQ ID NO: 67; wherein (i) the antibody or fragment comprises a VH domain derived from the recombination ofa human VH segment, a human D gene segment and a human JH 10 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; and 15 wherein (ii) said human comprises a nucleotide sequence encoding said IL4Ra protein comprising said selected mutation.

2. The preparation of claim 1, wherein the IL4Ra comprises mutations 175 V and Q576R in SEQ ID NO; 67 and/or the nucleotide sequence of (ii) comprises nucleotide mutation 20 3223 T (dB SNP numbering) and optionally the method is a method of treating or reducing the risk of asthma.

3. The preparation of claim 1 or claim 2, wherein each said human VH gene segment comprises SEQ ID NO; 39.

4. The preparation of any preceding claim, wherein said human is receiving or has received an asthma treatment or has reduced responsiveness to an asthma treatment.

5. The preparation of any preceding claim, wherein the antibody is a human antibody.