IES86646B2 - An injectable antibody preparation for use in treating or reducing the risk of rheumatoid arthritis - Google Patents

Abstract

An injectable preparation comprising an antibody or antibody fragment, for use in a method of treating or reducing the risk of rheumatoid arthritis in a human. The antibody or fragment specifically binds an IL6R protein that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO. 78 and 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 encodes a CDR1 comprising a Phe at position 4 shown in SEQ ID NO. 109. In this case, the human comprises a VH gene segment encoding a CDR1 comprising a Phe at position 4 shown in SEQ ID NO. 109, or the human expresses VH domains that comprise a CDR1 comprising a Phe at position 4 shown in SEQ ID No. 109. Alternatively, the human VH segment encodes a FW3 comprising a Thr at position 33 shown in SEQ ID NO. 111. In this alternative case, the human comprises a VH gene segment encoding a FW3 comprising a Thr at position 33 shown in SEQ ID NO. 111 or the human expresses VH domains that comprise a FW3 comprising a Thr at position 33 shown in SEQ ID No. 111. In both cases, the human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val385Ile in SEQ ID NO. 78.

Description

AN INJECTCTABLE ANTIBODY PREPARATION FOR USE IN TREATING OR REDUCING THE RISK OF RHEUMATOID ARTHRITIS SEQUENCE LISTING [00011 The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on August 11, 2014, is named 069496-0824 IO-US_SL.txt and is 260,517 bytes in size.

TECHNICAL FIELD id="p-2" id="p-2"

[0002] The technology described herein relates to anti-IL-6 receptor (IL6R) ligands, e.g., antibodies for the treatment of disease.

BACKGROUND [0003| It is recognized that individual humans differ in their sequence and recently several individuals have had their genomes sequenced, for instance James Watson and Craig Venter. Comparison of the genome sequence of individuals has revealed differences in their sequences in both coding and non-coding parts of the genome. Some of these variations in humans are significant and contribute to phenotypic differences between individuals. In extreme cases these will result in genetic disease. The 1000 Genomes Project has the objective of cataloguing sequences in the human genome, involving sequencing the genomes of a very large sampling of individuals from diverse art-recognized human ethnic populations. id="p-4" id="p-4"

[0004] Interleukin-6 (IL-6) is a complex cytokine, which plays a critical role in the regulation of inflammatory responses. Interleukin-6 (IL-6) signals through a ligand-binding IL-6 receptor (IL-6R; also known as CD 126) chain and a common signal-transducing chain glycoprotein 130 (gp 130; also known as CD130), which is also engaged by receptors specific for IL-11, IL-27, leukaemia inhibitory factor, oncostatin M (OSM). ciliary neurotrophic factor (CNTF) and cardiotrophin 1 (CT1). A soluble form of the IL-6R (sIL~6R) can be generated by proteolytic cleavage of mlL-6R by the metalloproteinases TNFa-converting enzyme (TACE; also known as ADAM 17) and ADAM 10 or alternatively spliced mRNA. IL-6 responses can be induced classically in cells expressing mIL-6R through a high-affinity tetrameric complex consisting of IL-6, IL-6R and two gp 130 molecules (or a hexameric complex consisting of two IL-6, two mIL-6R and two gp 130 molecules). Alternatively, a sIL-6ML-6R complex directly binds to and signals through gpl30 in cells lacking mIL-6R in a process that has been termed trans-signalling. High levels of IL-6 and sIL-6R have been reported in several chronic inflammatory diseases and in cancer. Several drugs that target different components of the IL-6 and IL-6R system have been described, including IL-6-speciflc monoclonal antibodies (mAbs) (for example, CNTO 328), IL-6R-specific mAbs (for example, tocilizumab) and soluble gpl30"Fc, an antagonist of IL-6R trans-signalling. See a review at "Averting inflammation by targeting the cytokine environment", Manfred Kopf, Martin F. Bachmann & S 866 46 Benjamin J. Marsland, Nature Reviews Drug Discovery 9, 703-718 (September 2010), doi:10.1038/nrd2805 (incorporated herein by reference). id="p-5" id="p-5"

[0005] Genetic variation in the IL-6 receptor gene is associated with the risk of several human diseases with an inflammatory component, including coronary heart disease, rheumatoid arthritis, and asthma. A non-synonymous variant in the IL-6 receptor gene (1L6R Asp358Ala: rs2228145 A>C) is associated with the increased susceptibility to asthma. It is thought that the variant exerts its functional mechanism by regulating the balance between sIL6R (generated through cleavage of the cell surface receptor and by alternative splicing of a soluble 1L6R isoform) and membrane-bound IL-6R (involved in classic IL6R signalling). Ferreira et al reportedly showed for the first time that the minor allele of this non-synonymous variant (AIa358) directly controls the surface levels of IL-6R on individual immune cells and that these differences in protein levels translate into a functional impairment in IL6R signaling. |0006] Ferreira et al noted that while classic IL6R signalling appears responsible for regulatory T-cell suppression, IL6R trans-signalling (via sIL6R) seems to promote T helper 2 cell polarization in the lung. IL6R has been shown to be expressed in the epithelium, smooth muscle and vascular endothelium of human airways, and in macrophages and granulocytes of bronchoalveolar lavage fluid (BALF). Soluble IL6R levels in BALF are elevated in asthmatic patients compared to controls, and are elevated further upon allergen challenge, indicating an important role of slL6R in the context of the lung and associated tissues. Consistent with these findings, as noted above 358Ala is also associated with an increased severity of asthma. The authors also provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D) in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble 1L6R (slL6R) levels (reportedly 34.6% increase in sIL6R per copy of the minor allele 3 5 8 A la: rs2228145 [C]). The authors provided evidence that the non-synonymous variant rs2228145 regulates the balance of surface and sIL6R, and also affects the responsiveness of immune cells io IL6 stimulation. This mechanism underpins the effect of 358Ala on the IL-6/IL-6R pathway. |0007] Revez et al comments that the main genetic determinant of soluble interleukin 6 receptor levels is the variant rs2228145 that maps to the cleavage site of 1L6R. Reportedly, for each Ala allele, slL6R serum levels increase by about 20 ng ml and asthma risk by 1.09-fold. However, the authors conclude that this variant does not explain the total heritability for slL6R levels.

Additional independent variants in IL6R may therefore contribute to variation in sIL6R levels and influence asthma risk. The authors imputed 471 variants in IL6R and tested these for association with sIL6R serum levels in 360 individuals. An intronic variant (rs 12083537) was associated with slL6R levels independently of rs4129267 (P=0.0005), a proxy single-nucleotide polymorphism for rs2228145. A significant and consistent association for rs 12083537 was observed in a replication panel of 354 individuals (P=0.033). Each rs12083537:A allele increased sIL6R serum levels by 2.4 ng ml. Analysis of mRNA levels in two cohorts did not identify significant associations between rs 12083537 and IL6R transcription levels. On the other hand, results from 16705 asthmatics and 30809 controls showed that the rs!2083537:A allele increased asthma risk by 1.04-fold (P=0.0419). [0008] J C Galicia et al investigated the association of the IL6R polymorphisms with the serum levels of soluble IL6 receptor. In total, 115 healthy volunteers were genotyped, with 70 of them analyzed for sIL6R levels. Using the PCR/RFLP methods, two important polymorphic sites were selected for genotyping: the 48892A/C (D358A) in exon 9 and the -183G/A in the promoter region. In exon 9. C allele carriers had higher sIL6R level (P<0.0001) showing that this sequence variation, which corresponds to the proteolytic cleavage site of IL-6Ralpha, strongly influences the serum slL6R levels. In the promoter region, G allele carriers had lower slL6R levels (P<0.0082) compared with the A allele carriers. id="p-9" id="p-9"

[0009] Esparza-Gordillo et a! examined the results of all genome-wide association studies from a public repository and selected 318 genetic markers that were significantly associated with any inflammatory trait. These markers were considered candidates and tested for association with atopic dermatitis (AD) in a 3-step approach including 7 study populations with 7130 patients with AD and 9253 control subjects. Reportedly a functional amino acid change in the IL-6 receptor (IL-6R Asp358Ala; rs2228145) was significantly associated with AD. investigation of 2 independent population-based birth cohorts showed that IL-6R 358Ala specifically predisposes to the persistent form of AD. Carriers of 358Ala had increased serum levels of soluble IL6R, with homozygote carriers showing a 2-fold increase. Moreover, the authors reported that slL6R levels were higher in patients with AD than in control subjects. The authors conclude that the study supports the importance of genetic variants influencing inflammation in the aetiology' of AD. Moreover, they identified a functional genetic variant in II 6R influencing disease prognosis and specifically predisposing io persistent AD. id="p-10" id="p-10"

[0010] Antibodies to human 1L6R are described in US804361 7. US 56 703 73. US581 7790.

EP409607 and those publications in Table 13 below. Therapeutic methods are described in US58885 10, US80436I 7, US67233 19 and those publications in Table 13 below. Actemra™ (tocilizumab) is a humanised example of an anti-IL-6R agent that blocks both classic and transsignaling. When directed to antibodies, the invention instead is directed to antibodies with fully human (not humanised) variable regions (and optionally also human constant regions). id="p-11" id="p-11"

[0011] Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of synovial tissue, leading to destruction of the joint architecture. It is recognized that cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) play a role in joint inflammation and cartilage damage observed in RA. IL-6 is a pleiotropic cytokine with biological effects on many cell types. IL-6 is often regarded as being downstream of TNF or IL-1 in inflammatory cytokine cascades and may therefore represent a common pathway factor in a wide range of inflammatory processes. Blockade of IL-6 signaling therefore offers the potential to ameliorate multiple pathogenic features of RA and other inflammatory diseases. id="p-12" id="p-12"

[0012] Therapeutic methods using IL-6R antagonists are mentioned in U.S. Pat. Nos. ,888,510; 6,723,319; and 2001/0001663. Exemplary anti-IL-6R antibodies are described in U.S. Pat. Nos. 7,582,298; 6,410,691; 5,817,790; 5,795,695; 6,670,373; and 7,582,298. id="p-13" id="p-13"

[0013] In certain embodiments, an IL6R 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. "IL6R" has also been referred to as interleukin-6 receptor subunit alpha, GDI26; IL-6R-1; IL-6RA; IL6Q; IL6RA; IL6RQ; and gp80.

SUMMARY id="p-14" id="p-14"

[0014] Through the application of human genetic variation analysis and rationallydesigned sequence selection the present invention provides for improved human patient diagnosis and therapy based on human IL6R variation. Importantly, the invention enables tailored medicines that address individual human patient genotypes or phenotypes. id="p-15" id="p-15"

[0015] 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-16" id="p-16"

[0016] Furthermore, the inventor surprisingly realised that some rarer natural forms, although present in humans at much lower frequencies than the common form, nevertheless are represented in multiple and ethnically-diverse human populations and usually with many human examples per represented ethnic population. Thus, the inventor realised that targeting such rarer forms would provide for effective treatment, prophylaxis or diagnosis across many human ethnic populations, thereby extending the utility of the present invention and better serving patients in those populations. [0017] 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 TOl-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. [0018| To this end, the invention provides:|0019J In a First Configuration id="p-20" id="p-20"

[0020] 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.

J0021 ] In a Second Configuration id="p-22" id="p-22"

[0022] 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. (0023} In a Third Configuration id="p-24" id="p-24"

[0024] 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-ΊΌΙ ligand to target a Ί Ο1 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%. id="p-25" id="p-25"

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

[0026] 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 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. |0027] In a Fifth Configuration id="p-28" id="p-28"

[0028] 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. |0029] In a Sixth Configuration |0030] A pharmaceutical composition or kit for treating or preventing a condition or disease mediated by a TOI. |0031 ] In a Seventh Configuration id="p-32" id="p-32"

[0032] 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 TOJ 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 TOl-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-33" id="p-33"

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

[0034] 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 101 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 TOJ-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 TOl-binding fragment or derivative of the isolated antibody. id="p-35" id="p-35"

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

[0036] 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. id="p-37" id="p-37"

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

[0038] 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%. id="p-39" id="p-39"

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

[0040] 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-41" id="p-41"

[0041] In a Twelfth Configuration [0042} 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-43" id="p-43"

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

[0044] 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-45" id="p-45"

[0045] In a Fourteenth Configuration [0046) A method of TOI typing a protein sample of a human, the method comprising identifying in the sample the presence of a 101 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-47" id="p-47"

[0047] In an example, the TOI is a human TOI selected from the group consisting of PCSK9, VEGF-A and IL6 receptor. id="p-48" id="p-48"

[0048] 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 ainino 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 ainino acid polymorphism. (0049] 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). |0050] 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 PCSK9 receptor) comprises a human heavy chain constant domain encoded by a first constant region nucleotide sequence; and wherein the genome of the human comprises a heavy chain constant region nucleotide sequence that is identical to said first constant region nucleotide sequence and/or the human expresses antibodies comprising said human constant domain. |0051] 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 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. (0052] 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. 100531 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: 127 or a Cys corresponding to position 87 of SEQ ID NO: 127: 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. id="p-54" id="p-54"

[0054] 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) IGHV1-1 8*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 ofhuman IGHV 1 -1 8*01: or(ii) IGVH 1-46*01 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 ofhuman IGHV 1-46*01. [0055] 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-I *01 and the genome of the human comprises a human 1GKV4-I*O1 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination ofhuman IGKV4-l*01; (ii) IGLV2-14*01 and the genome of the human comprises a human IGLV2-14*0l nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination ofhuman IGLV2-I4*O 1; or (iii) IGKVl-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 1GKV1-I3*O2. |0056] Furthermore, the inventor’s analysis of large numbers of naturally-occurring genomic human IL6R 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. (0057] furthermore, the inventor surprisingly realised that some rarer natural forms, although present in humans at much lower frequencies than the common form, nevertheless are represented in multiple and ethnically-diverse human populations and usually with many human examples per represented ethnic population. Thus, the inventor realised that targeting such rarer forms would provide for effective treatment, prophylaxis or diagnosis across many human ethnic populations, thereby extending the utility of the present invention and belter serving patients in those populations. id="p-58" id="p-58"

[0058] 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-IL6R ligand for administration to human patients for therapy and/or prophylaxis of IL6R-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. Th is 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-59" id="p-59"

[0059] In addition to binding specificity for IL6R variant(s). the invention also relates to tailoring of the ligand (eg, antibody) sequence per se to the recipient human patient. id="p-60" id="p-60"

[0060] To this end, the invention provides:[0061] In a First Configuration id="p-62" id="p-62"

[0062] A method of treating or reducing the risk of an IL6R-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 an IL6R protein that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78; wherein the genome of said human comprises a nucleotide sequence encoding said 1L6R protein comprising said Asp358Ala or Val3 851 Ie in SEQ ID NO: 78. id="p-63" id="p-63"

[0063] In a first embodiment, 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 (i) a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109 and wherein said human comprises a VH gene segment encoding a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109, or the human expresses VH domains that comprise a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109; or (ii) a FW3 (framework 3) comprising a Thr at position 33 shown in SEQ ID NO: 1 11 and wherein said human comprises a VH gene segment encoding a FW3 comprising a Thr at position 1 10 shown in SEQ ID NO: 111 or the human expresses VH domains that comprise a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 111. |0064] In a second embodiment, 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 1GHV3-7*O1 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. |0065| In a third embodiment, the ligand comprises a Vk domain derived from the recombination of human Vk segment 1GKV1 -12*01 and a human Jk segment, and wherein said human comprises a 1GKV 1-12*0] 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. id="p-66" id="p-66"

[0066] In a fourth embodiment, 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 CDR3 comprising a Pro at position 7 shown in SEQ ID NO: 113 and wherein said human comprises a Vk gene segment encoding a CDR3 comprising a Pro at position 7 shown in SEQ ID NO: 1 13, or the human expresses Vk domains that comprise a CDR3 comprising a Pro at position 7 shown in SEQ ID NO: 113; or (ii) a FW3 comprising a Ser at position 15 shown in SEQ ID NO: 115 and wherein said human comprises a Vk gene segment encoding a FW3 comprising a Ser at position 15 shown in SEQ ID NO: 1 15 or the human expresses Vk domains that comprise a FW3 comprising a Ser at position 15 shown in SEQ ID NO: 115. |0067| In a fifth embodiment, the ligand comprises a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 or a Leu at position 206 shown in SEQ ID NO: 81 and wherein said human comprises an IGHG 1*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-1 heavy chain constant regions comprising an Asp at position 204 shown in SEQ ID NO: 81 or a Leu at position 206 shown in SEQ ID NO: 81. id="p-68" id="p-68"

[0068] In a sixth embodiment, 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: 83, an Asn at position 75 shown in SEQ ID NO: 83, a Phe at position 76 shown in SEQ ID NO: 83, a Val at position 161 shown in SEQ ID NO: 83 and an Ala at position 257 shown in SEQ ID NO: 83 and wherein said human comprises 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: 83, Asn at position 75 shown in SEQ ID NO: 83, Phe at position 76 shown in SEQ ID NO: 83, Val at position 161 shown in SEQ ID NO: 83 or Ala at position 257 shown in SEQ ID NO: 83. id="p-69" id="p-69"

[0069] In a seventh embodiment, the ligand comprises a human kappa chain constant region that comprises a Val at position 84 shown in SEQ ID NO: 93 or a Cys at position 87 shown in SEQ ID NO: 93 and wherein said human comprises an IGKC1 *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: 93 or a Cys at position 87 shown in SEQ ID NO: 93. |0070] In an eighth embodiment, the ligand comprises a human IGLCl*01 lambda chain constant region and wherein said human comprises a human IGLC1*O1 lambda chain constant region gene segment, or the human expresses antibodies comprising human IGLCI *01 lambda chain constant regions. |0071] These eight embodiments are also individually combinable with any of the other configurations disclosed herein. |0072] In a Second Configuration |0073] Corresponding anti-IL6R ligands (eg, an antibody or fragment) for treating or reducing the risk of an lL6R-mediated disease or condition in a human in need thereof, wherein the ligands specifically bind an IL6R protein that comprises a mutation Asp358Ala or Val3 851 Ie in SEQ ID NO: 78. id="p-74" id="p-74"

[0074] In a Third Configuration id="p-75" id="p-75"

[0075] A pharmaceutical composition or kit for treating, reducing the risk of, or preventing an IL6R-mediated condition or disease. id="p-76" id="p-76"

[0076] In a Fourth Configuration id="p-77" id="p-77"

[0077] A method of producing an anti-human IL6R antibody binding site, the method comprising obtaining a plurality of anti-IL6R antibody binding sites, screening the antibody binding sites for binding to a human IL6R that comprises a mutation Asp358Ala or Va 13851le in SEQ ID NO: 78 and isolating an antibody binding site that binds in the screening step, and optionally producing an )L6R-binding fragment or derivative of the isolated antibody. id="p-78" id="p-78"

[0078] In a Fifth Configuration id="p-79" id="p-79"

[0079] A method of producing an anti-human IL6R antibody, the method comprising immunising a non-human vertebrate (eg, a mouse or a rat that expresses human variable domains) with a human 1L6R comprising a mutation Asp358Ala or Val385He in SEQ ID NO: 78 or a peptide thereof that comprises a mutation Asp358Ala or Val3 85Ue in SEQ ID NO: 78 and isolating an antibody that binds a human IL6R comprising said mutation or a peptide thereof that said mutation, and optionally producing an lL6R~binding fragment or derivative of the isolated antibody. id="p-80" id="p-80"

[0080] In a Sixth Configuration id="p-81" id="p-81"

[0081] A kit for IE6R genotyping a human, wherein the kit comprises a nucleic acid (i) comprising a sequence of contiguous nucleotides that specifically hybridises to a nucleotide sequence encoding an IL6R protein that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78, or specifically hybridises to an antisense sequence or an RNA transcript of said sequence, wherein said sequence of contiguous nucleotides hybridises to the nucleotide present in said selected sequence which encodes said mutation or hybridises to an antisense sequence or an RNA transcript thereof; and/or (ii) comprising a sequence of at least 10 contiguous nucleotides of an IL6R nucleotide sequence wherein said contiguous nucleotides encode said mutation or comprising an antisense sequence or RNA version of said contiguous nucleotides. id="p-82" id="p-82"

[0082] In a Seventh Configuration [0083| Use of an anti-IL6R ligand that specifically binds a human 1L6R that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78 in the manufacture of a medicament for treating, reducing the risk of, or preventing an IL6R-mediated disease or condition in a human whose genome comprises an 1L6R nucleotide sequence encoding said mutation. |0084] In a Eighth Configuration id="p-85" id="p-85"

[0085] Use of an anti-IL6R ligand that specifically binds a human 1L6R that comprises a mutation Asp358Ala or Val3 851 Ie in SEQ ID NO: 78 in the manufacture of a medicament for targeting said 1L6R in a human to treat, reduce the risk of, or prevent a disease or condition mediated by IL6R. |0086| In a Ninth Configuration |0087| A method of targeting an IL6R for treating, reducing the risk of or preventing an IL6R-mediated disease or condition in a human, the method comprising administering an anti-IL6R ligand to a human comprising a nucleotide sequence that encodes a mutation Asp358Ala or VaL3 851 Ie in SEQ ID NO: 78, whereby an IL6R encoded by said nucleotide sequence is targeted. id="p-88" id="p-88"

[0088] In a Tenth Configuration id="p-89" id="p-89"

[0089] A method of treating, reducing the risk of, or preventing a disease or condition mediated by IL6R in a human, the method comprising targeting a human 1L6R that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78 by administering to the human a ligand that specifically binds said IL6R thereby treating, reducing the risk of, or preventing said disease or condition in the human.

J0090] In a Eleventh Configuration id="p-91" id="p-91"

[0091] A method of 1L6R genotyping a nucleic acid sample of a human, the method comprising identifying in the sample the presence of an IL6R nucleotide sequence that encodes a mutation Asp358Ala or Val3851 Ie in SEQ ID NO: 78. |0092] In a Twelfth Configuration |0093] A method of IL6R typing a protein sample of a human, the method comprising identifying in the sample the presence of a human IL6R comprising a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. (0094] In a Thirteenth Configuration |0095] A method of treating, reducing the risk o.f or preventing in a human patient a disease or condition selected from the group consisting of an inflammatory bowel disease (IBD), Crohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen's syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease, optionally wherein the patient is receiving or has previously received an anti-TNF alpha treatment for said disease or condition, the method comprising typing the patient using a method of the invention and administering a ligand according to the invention whereby the human is treated or said disease or condition is prevented; optionally also reducing or stopping said anti-TNF alpha treatment. id="p-96" id="p-96"

[0096] In an embodiment of any configuration, the disease or condition is severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. id="p-97" id="p-97"

[0097] in an example, the ligand or method • Reduces T helper 2 cell polarization in the lung; ♦ Treats or reduces the risk of a lung disease, eg. asthma: ♦ Treats or reduces the risk of type 1 diabetes; • Treats or reduces the risk of atopic dermatitis; or is a ligand or method for said purpose.

Optionally the ligand specifically binds an IL6R protein that comprises a mutation Asp358Ala in SEQ ID NO: 78. In addition, optionally, the human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358AIa in SEQ ID NO: 78.

BRIEF DESCRIPTION OF THE DRAWINGS id="p-98" id="p-98"

[0098] 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. |0099| Figure I shows in silica modeling of PCSK9 surface variant residues. id="p-100" id="p-100"

[00100] 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 ς*Α). 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. id="p-101" id="p-101"

[00101] Figure 3 depicts frameworks and CDRs encoded by VH3-23*04 as obtained from the IMGT database (available on the World Wide Web at www.IMGT.org). Figure 3 discloses the nucleotide sequences as SEQ ID NOS 68. 68. 68. 70. 70. 70. 71. 73. 75. 39 and 76, respectively, in order of appearance. Figure 3 discloses the coded amino acid sequences as SEQ ID NOS 69, 69, 69. 69, 69. 69, 72, 74, 74. 38 and 77, respectively, in order of appearance. [001021 Figure 4 depicts sequences of VH3-23*04. The portion of VH3-23*04 comprising the FW1 residue change of rs56069819 (SEQ ID NO: 38). The portion of the nucleic acid sequence encoding rs56069819 is depicted (SEQ ID NO: 39). The FW1 encoded by VH3-23*04 is depicted (SEQ ID NO: 40).

DETAILED DESCRIPTION id="p-103" id="p-103"

[00103] The skilled person will know that SNPs or other changes that translate into amino acid variation can cause variability in conformation or activity of human targets to be addressed. This has spawned great interest in personalized medicine where genotyping and knowledge of protein and nucleotide variability is used to tailor medicines and diagnosis of patients more effectively. The present invention provides for tailored pharmaceuticals and testing that specifically addresses rarer variant forms of a human target of interest (TOI), that target being human IL6R. id="p-104" id="p-104"

[00104] The present invention harnesses the power of human genetic variation analysis and rationally-designed sequence selection. The technical applications of these approaches, as per the present invention, contribute to better treatment, prophylaxis and diagnosis in humans and provides for patient benefit by providing choice and enabling personalized medicines and therapies. This provides advantages of better prescribing, less wastage of medications and improved chances of drug efficacy and better diagnosis in patients. id="p-105" id="p-105"

[00105] As sources of genomic sequence variation data, the skilled person will be aware of the available databases and resources (including updates thereof) provided by the following:1. HapMap (The International HapMap Consortium, 2003; http://hapmap.ncbi.nlm.nih.gov/index.html.en). The HapMap Project is an international project that aims to compare the genetic sequences of different individuals to identify chromosomal regions containing shared genetic variants. The HapMap www site provides tools to identify chromosomal regions and the variant therein, with options to drill down to population level frequency data. 2. 1000 Genomes Project (The 1000 Genomes Project Consortium 201 0; available on the World Wide Web at www.1000genomes.org/). This resource provides complete genomic sequence for at least 2500 unidentified individuals from one of 25 distinct population groups. For the purposes of the present invention, for example, the 100 Genomes database release 20130502 (see available at ftp.1000genomes.ebi.ac.uk/voll/ftp/reiease/20130502/) can be used, which is incorporated herein by refrence. 3. Japanese SNP Database( H.Haga 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. |00106] I he present invention involves the identification and cataloguing of naturallyoccurring human genomic target sequence variants, including those found to be relatively lowfrequency or rare variants that segregate with specific human ethnic populations and in many individual humans. |00107] 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. 100108] Thus, in this aspect of the invention, the inventor designed the follow ing variant sequence selection criteria, these being criteria that the inventor realised wOiild provide for useful medical drugs and diagnostics to tailored need in the human population. id="p-109" id="p-109"

[00109] Selection Criteria [001101 Three or four of the following:- • Naturally-occurring human target variation sequences, e.g., IL6R variation, having a cumulative human allele frequency of 35% or less; • Naturally-occurring human target variation sequences, e.g., IL6R variation, having a total human genotype frequency of about 50% or less; • Naturally-occurring human target variation sequences, e.g., 1L6R variation, found in many different human ethnic populations (using the standard categorisation of the 1000 Genomes Project; see Table 12 below); and ♦ Naturally-occurring human target variation sequences, e.g., IL6R variation, found in many individuals distributed across such many different ethnic populations. [00111| The inventor's selection included, as a consideration, selection for nucleotide variation that produced amino acid variation in corresponding TOI forms, e.g., IL6R forms, (ie, non5 synonymous variations), as opposed to silent variations that do not alter amino acid residues in the target protein. id="p-112" id="p-112"

[00112] In an embodiment, the cumulative human allele frequency is 30. 25, 20, 15, 10 or % or less, eg, in the range from 1 to 20% or 1 tol 5% or 1 to 10%. [00113| In an embodiment, the total human genotype frequency is 35. 30, 25, 20, 15. 10 or % 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 % or 1 to 5% or I to about 5%. id="p-114" id="p-114"

[00114] In an embodiment, the cumulative human allele frequency is 32, 30, 25. 20. 15. 10 or 5% or less, eg, in the range from I to 32% or 5 to 32% or 1 to 10%. |00115] In an embodiment, the total human genotype frequency is 51, 50, 40, 35, 30, 25. , 15, 10 or 5% or less, eg, in the range from 1 to 51%, 1 to 25%, 1 to 20%. 1 to 15%, 1 to about %, 1 to 10%, 1 to about 10% or 1 to 5% or 1 to about 5%. id="p-116" id="p-116"

[00116] In an embodiment, the naturally-occurring human target variant sequences are found in at least 9, 10, 11, 12, 13, 14, 1 5, 16, 17, 18, 19 or 20 different human ethnic populations (using the standard categorisation of the 1000 Genomes Project). id="p-117" id="p-117"

[00117] 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, 150. 200, 300, 400 or 500 individuals distributed across such many different ethnic populations. [00118| In an example, the following criteria are applied:- · Naturally-occurring human target, e.g. IL6R. variant sequences having a cumulative human allele frequency of 1 5% or less; • Naturally-occurring human target, e.g.. IL6R. variant sequences having a total human genotype frequency of 20% or less; • Naturally-occurring human target, e.g., IL6R, variant sequences found in at least 5 (4 for IL6R) different human ethnic populations (using the standard categorisation of the 1000 Genomes Project); and • Naturally-occurring human target, e.g., IL6R, variant sequences found in many individuals distributed across such many different ethnic populations. |00119] In any aspect, configuration, example, embodiment, clause or concept herein, frequencies may be determined using bioinformatics. |00Ι20| 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. (00121 ] 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-122" id="p-122"

[00122] 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 a 1000 Genomes Project database. id="p-123" id="p-123"

[00123] In any aspect, configuration, example, embodiment, clause or concept herein total human genotype frequency" means the total of heterozygous plus homozygous human genotype frequencies. id="p-124" id="p-124"

[00124] 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 a 1000 Genomes Project database.

JOO 125) 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-126" id="p-126"

[00126] 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 or at 1 August 2014. In an example, the version is 20110521. In another example it is version 20130502. id="p-127" id="p-127"

[00127] Optionally, further sequence analysis and 3D in silico modelling (eg, see Figure 1) can also be used as an additional selection criterion: variants whose variant amino acid residues (versus the most common form of human 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-128" id="p-128"

[00128] 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, e.g., an 1L6R target sequence of interest, (Target genomic region’) and calculate the genomic coordinates, using coordinates that match the sequence assembly build used by either the 1000 Genomes Project or International HapMap project (or another selected human gene database of choice). (b) Identify genomic variants mapped to the genomic region previously identified in (a). Retrieve allele frequencies for variants for each super population and preferably sub population where such data is available. The VWC tools for the 1000 Genomes Project can be used for this step. (c) Filter list of genomic variants from target genomic region to contain only variants classed as either 'non-synonymous’ single nucleotide polymorphisms (SNPs) or genomic 'insertions or 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 Iwo 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. id="p-129" id="p-129"

[00129] Human Populations id="p-130" id="p-130"

[00130] Optionally the ethnic populations are selected from those identified in the 1000 Genomes Project database. In this respect, see Table 12 which provides details of the ethnic populations on which the 1000 Genomes Project database is based. [00131| 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-132" id="p-132"

[00132] Afincan ancestry (Mbuli Pygmies. Biaka Pygmies, San peoples, and speakers of Niger-Kordofan ian languages (Bantu. Yoruba or Mandenka populations), [00133] Eurasian ancestry (European ancestry (Orcadian, Adygei, Basque, French, Russians. Italians, Sardinian, Tuscan). Middle Eastern ancestry (Mozabite, Bedouin, Druze, Palestinians), Central/South Asian ancestry (Balochi. BrahuL Makrani. Sindhi. Pathan. Burusho, Hazara. Uygur. Kalash)), [00134] East Asian ancestry (Han, Dal, Daur, Hezhen, Laho, Miao, Oroqen, She, Tujia, Tu, Xibo, Yi, Mongola, Naxi, Cambodian, Japanese, Yakut), Oceanic ancestry (Melanesian, Papuan); or [00135] Americas ancestry (Karitiana, Surui, Colombian, Maya, Pima). id="p-136" id="p-136"

[00136] 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:[00137] Utah population with Northern or Western European ancestiy (samples collected in ! 980 by the Centre d’Etude du Polymorphisme Humain (CEPH)); population with ancestry of Yoruba people from Ibadan, Nigeria; population with Japanese ancestry; and population with ancestry of Han Chinese from China. id="p-138" id="p-138"

[00138] The authors, citing earlier publications, suggest that ancestral geography is a reasonable basis for sampling human populations. id="p-139" id="p-139"

[00139] 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 ancestiy. (c) More specifically, population of Utah residents with Northern and/or Western European ancestry; Toscani population in Italia; British population in England and/or Scotland; Finnish population in Finland; or Iberian population in Spain. (a) East Asian ancestry (b) Japanese ancestiy; 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 ancestiy; Luhya ancestiy; 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 Bl an tyre, 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-140" id="p-140"

[00140] In any configuration of the invention, in one embodiment, each human population is selected from a population marked (a) above. id="p-141" id="p-141"

[00141] In any configuration of the invention, in another embodiment, each human population is selected from a population marked (b)" above. id="p-142" id="p-142"

[00142] In any configuration of the invention, in another embodiment, each human population is selected from a population marked (c) above. id="p-143" id="p-143"

[00143] 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. [00144J In one embodiment the ethnic populations are selected from the group consisting of an ethnic population with Northern European ancestry; or an ethnic population with Western European ancestry; or an ethnic population with Toscani ancestry; or an ethnic population with British ancestry; or an ethnic population with Icelandic ancestry; or an ethnic population with Finnish ancestry; or an ethnic population with Iberian ancestry; or an ethnic population with Japanese ancestry; or an ethnic population with Chinese ancestry; or an ethnic population Vietnamese ancestry: or an ethnic population with Yoruba ancestry; or an ethnic population with Luhya ancestry; or an ethnic population with Gambian ancestry; or an ethnic population with Malawian ancestry; or an ethnic population with Native American ancestry; or an ethnic population with Afro-Caribbean ancestry: or an ethnic population with Mexican ancestry; or an ethnic population with Puerto Rican ancestry; or an ethnic population with Columbian ancestry; or an ethnic population with Peruvian ancestry'; or an ethnic population with Ahom ancestry; or an ethnic population with Kayadtha ancestry; or an ethnic population with Reddy ancestry; or an ethnic population with Maratha; or an ethnic population with Punjabi ancestry. id="p-145" id="p-145"

[00145] Anti-Target Ligands id="p-146" id="p-146"

[00146] 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, e.g., 1L6R. For example, the ligand specifically binds to a TOI, e.g., IL6R variant as per the invention. The ligand may inhibit or antagonise the activity of the TOI, e.g., 1L6R 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. |00147] In an example, the ligand is (or has been determined as) a neutraliser of the TOL e.g., IL6R. 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). 100148] An antibody "fragment" comprises a portion of an intact antibody, preferably the antigen binding and/or the variable region of the intact antibody. Examples of antibody fragments include dAb. Fab, Fab', F(ab')2 and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules and muItispecific antibodies formed from antibody fragments. [00149| 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-TOl or TOl-binding or targeting, e.g., anti-IL6R or IL6R-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™ , XenomouseIM, HuMab Mouse™ or MeMo Mouse™), rats (eg, the Omnirat™), camelids, sharks, rabbits, chickens or other non-human animals immunised with the TOI, e.g., 1L6R, 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 below herein. 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. (001501 Generally, a VELOCIMMUNE™ or other mouse or rat can be challenged with the antigen of interest, and lymphatic cells (such as B-cells) are recovered from the mice that express antibodies. The lymphatic cells may be fused with a myeloma cell line to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the variable regions of the heavy chain and light chain may be isolated and linked to desirable isotypic constant regions of the heavy chain and light chain. Such an antibody protein may be produced in a cell, such as a CHO cell. Alternatively, DNA encoding the antigen-specific chimaeric antibodies or the variable domains of the light and heavy chains may be isolated directly from antigen-specific lymphocytes. |00151J 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 IgG4 (for example, SEQ ID NO: 751, 752,753 in US2011/0065902 (which is incorporated by reference herein in its entirety), which sequences are incorporated herein by reference for use in the ligands of the present invention). While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region. id="p-152" id="p-152"

[00152] 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, e.g., IL6R, variant sequence, eg, hybridises a nucleotide sequence comprising one or more nucleotides that are variant (versus the most 10 common IL6R sequence, eg, with reference to the 1000 Genomes Project database). id="p-153" id="p-153"

[00153] for example, the nucleic acid hybridises to a region immediately flanking a nucleotide that is variant compared to the corresponding nucleotide of the 1L6R 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. id="p-154" id="p-154"

[00154] Specific hybridisation is under stringent conditions, as will be apparent to the skilled person, eg, conditions of 5*SSC, 5*Denhardfs reagent, and 0.5% SDS at 65° C. id="p-155" id="p-155"

[00155] Target binding ability, specificity and affinity (Kd, Koff and/or Kon) can be determined by any routine method in the art, eg, by surface plasmon resonance (SPR). The term "Kd", as used herein, is intended to refer to the equilibrium dissociation constant of a particular 20 antibody-antigen interaction. id="p-156" id="p-156"

[00156] In one embodiment, the surface plasmon resonance (SPR) is carried out al 25°C.

In another embodiment, the SPR is carried out at 37°C. id="p-157" id="p-157"

[00157] 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-158" id="p-158"

[00158] In one embodiment, the SPR is carried out at a physiological salt level, eg. !50mM NaCI. |00159| 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-20IM) at 0.05% and EDTA at 3mM. id="p-160" id="p-160"

[00160] 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 1 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-161" id="p-161"

[00161] In an example, the affinity of the ligand (eg, antibody) is determined using SPR by 1. Coupling anti-mouse (or other relevant human, rat or non-human vertebrate antibody constant region species-matched) IgG (eg, Biacore™ BR-1008-38) to a biosensor chip (eg, GLM chip) such as by primary amine coupling; 2, Exposing the anti-mouse IgG (or other matched species antibody) to a test IgG antibody to capture test antibody on the chip; 3. Passing the test antigen over the chip’s capture surface at 1024nM, 256nM, 64nM, 16nM, 4nM with a OnM (i.e. buffer alone); and 4. And determining the affinity of binding of test antibody to test antigen using surface plasmon resonance, eg, under an SPR condition discussed above (eg, at 25°C in physiological buffer). SPR can be carried out using any standard SPR apparatus, such as by BiacoreIM or using the ProteOn XPR36™ (Bio-Rad®). id="p-162" id="p-162"

[00162] Regeneration of the capture surface can be carried out with lOmM 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 XPR361M analysis software. id="p-163" id="p-163"

[00163] 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, e g., 1L6R. In an example, the instructions indicate that the human should be genotyped for a TOI, e.g., IL6R, 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, e.g., IL6R, variant of the invention before administering the ligand to the human. In an example, the human is of Chinese (eg, Han or CHS) ethnicity and the instructions are in Chinese (eg. Mandarin). In an example, the instructions comprise directions to administer alirocumab or evolocumab to said human. In an example, the TOI is IL6R and the instructions comprise directions to administer sarilumab to said human. [00164| In an example, the ligand is or comprises soluble human gpl30-Fc. id="p-165" id="p-165"

[00165] The invention relates to the concepts set out in the following clauses. id="p-166" id="p-166"

[00166] 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. [00167J In any aspect, configuration, example, embodiment, clause or concept herein, frequencies may be determined using bioinformatics. id="p-168" id="p-168"

[00168] 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.

J00169] 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-170" id="p-170"

[00170] 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-171" id="p-171"

[00171] In any aspect, configuration, example, embodiment, clause or concept herein total human genotype frequency" means the total of heterozygous plus homozygous human genotype frequencies. id="p-172" id="p-172"

[00172] 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-173" id="p-173"

[00173] 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. [00174] 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, determinalion 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-175" id="p-175"

[00175] 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-176" id="p-176"

[00176] 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-177" id="p-177"

[00177] 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%. 100178] The TOI variant is not the most frequent. |00179| Clauses: 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-180" id="p-180"

[00180] 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 phenolyping the human as positive for said variant nucleotide sequence before step (a). id="p-181" id="p-181"

[00181] Clause 7: The method of any preceding clause, wherein said frequency is less than 10 or 15% (eg, from I to 10%). 100182] In an embodiment, the cumulative human allele frequency is 30. 25, 20. 1 5. 10 or 5% or less, eg, in the range from 1 to 20% or 1 to 1 5% or 1 to 10%. id="p-183" id="p-183"

[00183] 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%, 1 to about 15%, 1 to 10%. 1 to about 10% or 1 to 5% οι* 1 to about 5%. id="p-184" id="p-184"

[00184] 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 I to 20%). id="p-185" id="p-185"

[00185] 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 15% or I to 10%. |00186] In an embodiment, the total human genotype frequency of each TOI variant is 35, 30, 25. , 15,10 or 5% or less, eg, in the range from I to 25%, 1 to 20%, 1 to 1 5%, I to about 15%, 1 to 10%, 1 to about 10% or 1 to 5% or 1 to about 5%. id="p-187" id="p-187"

[00187] 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, the 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%. 100188] In an embodiment, in (a) the cumulative human allele 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 5 1 to 80%). |00189] 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 5 I to 80%). id="p-190" id="p-190"

[00190] 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 1 5% or 1 to 10%. id="p-191" id="p-191"

[00191] 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 1 to about 5%. id="p-192" id="p-192"

[00192] Clause 10: The method of clause 9. wherein before step (a), the human has been or is phenotyped as positive for the most frequent TOJ variant or genotyped for the nucleotide sequence thereof. id="p-193" id="p-193"

[00193] 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-194" id="p-194"

[00194] In an embodiment, before step (a) the human has been or is genotyped as positive for TOI 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-195" id="p-195"

[00195] 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-196" id="p-196"

[00196] Clause 12: The method of clause 9. 10 or I 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-197" id="p-197"

[00197] 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. [00198] Clause 13: The method of any one of clauses 9 to 12, wherein the ligand is capable of binding to the most frequent TOI variant. id="p-199" id="p-199"

[00199] 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-200" id="p-200"

[00200] 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 but less than 95, 96, 97, 98. 99 or 100% (eg, in the range from 51 to 80%). id="p-201" id="p-201"

[00201] In an embodiment, each TOI 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 1 to 80%). |00202] 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 14. (00203] Clause 16: The method of any preceding clause, wherein said human 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-204" id="p-204"

[00204] 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. id="p-205" id="p-205"

[00205] 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. id="p-206" id="p-206"

[00206] In an embodiment, 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-207" id="p-207"

[00207] 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%, I to 15%, I to about 15%, 1 to 10%, 1 to about 10% or 1 to 5% or 1 to about 5%. id="p-208" id="p-208"

[00208] 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-209" id="p-209"

[00209] 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 TOL the method comprising administering the ligand to the human. |002101 Clause 19: A ligand that binds a human ΊΌΙ comprising an ainino 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. (00211] 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%. id="p-212" id="p-212"

[00212] 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%. [00213] 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%. [00214] 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-215" id="p-215"

[00215] 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%. [00216] 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. id="p-217" id="p-217"

[00217] Clause 25: The ligand of clause 24, wherein the ligand is an antibody or antibody fragment. id="p-218" id="p-218"

[00218] 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. [00219| In an embodiment, the ligand comprises a nucleotide sequence that comprises al least 10, II, 12, 13, 14, 1 5, 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. id="p-220" id="p-220"

[00220] 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 14)). In an example, numbers are with reference to the 1000 Genomes Project database. id="p-221" id="p-221"

[00221] 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 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. 1 20. 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. (00222} 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. id="p-223" id="p-223"

[00223] 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-224" id="p-224"

[00224] 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-225" id="p-225"

[00225] In an embodiment of any aspect herein, the antibody, fragment or binding site is recombinant. id="p-226" id="p-226"

[00226] 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 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 ofless than 50%. and optionally producing a TOI-binding fragment or derivative of the isolated antibody. |00227] 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-228" id="p-228"

[00228] 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 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. id="p-229" id="p-229"

[00229] 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-230" id="p-230"

[00230] 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 ofless than 50% and/or a total human genotype frequency ofless 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 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. |00231] 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. id="p-232" id="p-232"

[00232] Specific hybridisation is under stringent conditions, as will be apparent to the skilled person, eg, conditions of SxSSC, 5*Denhardt's reagent, and 0.5% SDS at 65° C. |00233| Clause 32: A kit for TOI genotyping or phenotyping a human, wherein the kit comprises a ligand according to any one of clauses 1 7 to 27 or an antibody, fragment or derivative produced by the method of any one of clauses 29 to 31. id="p-234" id="p-234"

[00234] 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 I mM. ΙΟΟηΜ. lOnM or InM or less, eg, as determined by SPR. [002351 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. [00236] 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%. id="p-237" id="p-237"

[00237] Clause 34: Use of an anti-ΊΌΙ 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-238" id="p-238"

[00238] 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-239" id="p-239"

[00239] Clause 35: A method of targeting a TOI for treating and/or preventing a TOI-mcdialed disease or condition in a human, the method comprising administering an anti-TOI ligand to a human comprising a TO) nucleotide sequence selected having a cumulative human allele frequency ofless than 50% and/or a total human genotype frequency of less than 50%. whereby a TOI encoded by said nucleotide sequence is targeted. |00240] Clause 36: The method of clause 35, w herein 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, wTerein said amino acid sequence is encoded by a nucleotide sequence having a cumulative human allele frequency ofless than 50% and/or a total human genotype frequency of less than 50%. |00241 ] 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 ofless than 50%. id="p-242" id="p-242"

[00242] In an example, the method comprises obtaining a TOI nucleic acid sample from the human and then carrying out the identifying step. [00243| Clause 38: 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%. id="p-244" id="p-244"

[00244] In an example, the method comprises obtaining a TOJ protein sample from the human and then carrying out the identifying step. id="p-245" id="p-245"

[00245] 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. [00246J 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-247" id="p-247"

[00247] 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-248" id="p-248"

[00248] 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-249" id="p-249"

[00249] 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 1 to about 15% or from 1 to 15%. id="p-250" id="p-250"

[00250] 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. [002511 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-252" id="p-252"

[00252] 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-253" id="p-253"

[00253] The invention encompasses anti-TOI (eg, PCSK9 or IL6R) antibody ligands having a modified glycosylation pattern. In some applications, modification to remove undesirable glycosylation sites may be useful, or e.g., removal of a fucose moiety to increase antibody dependent cellular cytotoxicity (ADCC) function (see Shield et al. (2002) JBC 277:26733). In other applications, modification of galactosylation can be made in order to modify complement dependent cytotoxicity (CDC). id="p-254" id="p-254"

[00254] The invention addresses the need to treat humans having naturally-occurring rarer natural 1L6R alleles, genotypes and phenotypes (rarer protein forms). In this respect, the invention provides the configurations and embodiments described above, as well as the following examples. [00255) In an embodiment of any configuration, example, embodiment or aspect herein, the ligand, antibody, fragment or binding site of the invention is recombinant. id="p-256" id="p-256"

[00256] In an example, the ligand has been or is determined as capable of specifically binding a human IL6R that comprises a mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78. [00257] In an example, the ligand binds (or has been determined to bind) a first human IL6R that comprises a mutation Asp358Ala and a second human IL6R that comprises a mutation Va!385He in SEQ ID NO: 78, wherein the IL6Rs are different. In an embodiment, the ligand binds said 1L6R wTen in complex with human gp 130 and/or human 1L6. The complex can be a cell-surface bound on human cells or it can be in solution. id="p-258" id="p-258"

[00258] In an example, the ligand comprises a protein domain that specifically binds to a human 1L6R that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78 id="p-259" id="p-259"

[00259] The term "specifically binds," or the like, means that a ligand, eg, an antibody or antigen-binding fragment thereof, forms a complex with an antigen that is relatively stable under physiologic conditions. Specific binding can be characterized by an equilibrium dissociation constant of at least about I χ 10 6 M or less (e.g., a smaller KD denotes a tighter binding). Methods for determining whether two tiles 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 IL6R may, however, exhibit cross-reactivity to other antigens such as an IL6R molecule from another species. Moreover, multi-specific antibodies (e.g., bispecifics) that bind to human IL6R and one or more additional antigens are nonetheless considered antibodies that 'specifically bind" IL6R, as used herein. id="p-260" id="p-260"

[00260] In an example, the ligand comprises or consists of a protein that mimics human IL6 orgpI30. [00261 ] In an example, the ligand antagonises said human 1L6R that comprises a mutation Asp358Ala or Val3 851 Ie in SEQ ID NO: 78. |00262] In an example, the method comprises (before administering the ligand) the step of determining that the ligand is capable of binding said human IL6R that comprises a mutation Asp358Ala or Val3 851 Ie in SEQ ID NO: 78. id="p-263" id="p-263"

[00263] In an example, binding is determined by SPR. In an example, binding is determined by ELISA. id="p-264" id="p-264"

[00264] In an example, said said IL6R is soluble IL6R. id="p-265" id="p-265"

[00265] In another example, said IL6R is human cell-surface bound IL6R. [00266| The terms ‘is determined", ’is genotyped" or ‘is phenotyped" and the like herein mean that the method comprises a step of such determining, genotyping or phenotyping. id="p-267" id="p-267"

[00267] In an example, the human has been or is genotyped as positive for an IL6R nucleotide sequence encoding said mutation Asp358Ala or Val385He in SEQ ID NO: 78. id="p-268" id="p-268"

[00268] In an example, the human has been or is phenotyped as positive for a human IL6R that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78. [00269| In an example, the method comprises genotyping the human as positive for a nucleotide sequence encoding said mutation Asp358Ala or Val385ile in SEQ ID NO: 78. [00270| In an example, the method comprises phenotyping the human has positive for a human 1L6R that comprises a mutation Asp358Ala or Val3851le in SEQ ID NO: 78. id="p-271" id="p-271"

[00271] In an example, the human has been or is genotyped as heterozygous for a nucleotide sequence encoding said mutation Asp358Ala or VaI38511e in SEQ ID NO: 78. id="p-272" id="p-272"

[00272] '‘Heterozygous" here means that in the human’s genotype one allele comprises a nucleotide sequence encoding said mutation Asp358Ala or Val385He in SEQ ID NO: 78 and other allele can be any IL6R (eg, the most common form, SEQ ID NO:79, or an allele comprising a nucleotide sequence encoding said mutation Asp358Ala or Val385He in SEQ ID NO: 78 that is different from the other allele). id="p-273" id="p-273"

[00273] In an example, the method comprises (before administering the ligand) genotyping the human as heterozygous for a nucleotide sequence encoding said mutation Asp358Ala or Val3851le in SEQ ID NO: 78; optionally also genotyping the human as comprising the nucleotide sequence of SEQ ID NO: 9. id="p-274" id="p-274"

[00274] In an example, the genome of the human has been or is genotyped as homozygous for a nucleotide sequence selected encoding said mutation Asp358Ala or Val385lie in SEQ ID NO: 78. id="p-275" id="p-275"

[00275] Homozygous’' here means that in the human’s genotype each allele comprises the same nucleotide sequence selected encoding said mutation Asp358Ala or Val385He in SEQ ID NO: 78. id="p-276" id="p-276"

[00276] In an example, the method comprises genotyping the human as homozygous for a nucleotide sequence encoding said mutation Asp358Ala or Val385lie in SEQ ID NO: 78. id="p-277" id="p-277"

[00277] In an example, the ligand comprises an antibody binding site that binds a human IL6R comprising a mutation Asp358Ala or Val3851le in SEQ ID NO: 78 and optionally has been or is determined as capable of such binding. [00278| In an example, the method comprises (before administering the ligand) the step of determining that the ligand is capable of binding to said human IL6R. id="p-279" id="p-279"

[00279] In an example, the binding is specific binding. In an example, the ligand binds (or has been determined as binding) to the IL6R with an affinity (Kd) of ImM, lOOnM, lOnM or InM or less. In an embodiment, the affinity is no less than 10, 100 or 1000 AM. id="p-280" id="p-280"

[00280] In an example, binding or affinity’ is determined by SPR or ELISA. id="p-281" id="p-281"

[00281] In an example, the disease or condition is mediated by a human IL6R comprising a mutation Asp.358Ala or VaJ385IJe in SEQ ID NO: 78. id="p-282" id="p-282"

[00282] In an example, in any context herein the IL6R is complexed with a human gp 130, eg, soluble gp 130 or human cell surface-bound gp 130. id="p-283" id="p-283"

[00283] In an example, the IL6R is bound to human IL6. id="p-284" id="p-284"

[00284] In an example, the ligand is an antibody or antibody fragment. For example, the antibody or antibody fragment is an IL6R antagonist, eg, neutralises IL6R (eg, when in such a complex with human gp 130 or bound to human IL6 as described above). Examples of such antibodies are disclosed, for instance, in US80436I7 or any other reference listed in fable 13, the disclosures and sequences of such antibodies being incorporated herein in their entireties by refere for use in the invention, One specific example is sarilumab. or an IL6R-binding derivative thereof. id="p-285" id="p-285"

[00285] Advantageously, the ligand is or comprises sarilumab. id="p-286" id="p-286"

[00286] In an example, the ligand comprises or consists of a neutralizing antibody that binds to the IL6R, wherein the antibody binds to IL6R and reduces the likelihood that IL6R binds to human IL6 and/or human gp!30. id="p-287" id="p-287"

[00287] In an example, the ligand is an IL6R antagonist, eg, neutralises IL6R. id="p-288" id="p-288"

[00288] An example is provided wherein (i) the ligand comprises a sequence of contiguous nucleotides that specifically hybridises to a nucleotide sequence that encodes said mutation(s), or specifically hybridises to an antisense sequence or an RNA transcript of said sequence, wherein said sequence of contiguous nucleotides hybridises to a nucleotide sequence that encodes said mutation(s) 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 that encodes said mutation(s) or is an antisense sequence or RNA version of said contiguous nucleotides, wherein said sequence of contiguous nucleotides encodes said mutation(s). |00289] In an example, said human is or has been further determined to be substantially resistant to an anti-TNF alpha treatment. |00290| "An anti-TNF alpha treatment’* is optionally selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®), certolizumab pegol (eg, Cimzia®), golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate.

For example it is adalimumab treatment. For example, it is etanercept treatment. For example, it is infliximab treatment. |002911 Reference to "IL6R protein that comprises a mutation Asp358Aia or Val385He in SEQ ID NO: 78" refers to an alanine at a position in an IL6R protein corresponding to position 358 as noted in SEQ ID NO: 78 (see Table 15) herein or an isoleucine at a position in an IL6R protein corresponding to position 385 as noted in SEQ ID NO: 78 (in Table 15). Similarly, phrases such as "a Pro at position 72 shown in SEQ ID NO: 83" mean a proline at a position corresponding to position number 72 as in SEQ ID NO: 83 in Table 15. |00292] In an example, said human is receiving or has received an anti-TNF alpha treatment or has reduced responsiveness to an anti-TNF alpha treatment. id="p-293" id="p-293"

[00293] In an example, said antibody or antibody fragment is administered to the human separately or simultaneously with methotrexate and/or an anti- I NF alpha treatment. id="p-294" id="p-294"

[00294] In an example, said disease or condition is an inflammatory disease or condition. [00295) In an example, said disease or condition is selected from the group consisting of an inflammatory bowel disease (1BD), Crohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvFID). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. [00296| In an example, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. id="p-297" id="p-297"

[00297] In an example, said disease or condition is cancer. (00298] In an example, said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD). Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graftversus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. For example, the human has been diagnosed with moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. id="p-299" id="p-299"

[00299] In an example, 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 inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation.

Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. id="p-300" id="p-300"

[00300] In an example, the antibody or fragment comprises constant domains that are rabbit, chicken or murine, eg, mouse or rat constant domains. id="p-301" id="p-301"

[00301] In an example, the antibody or fragment constant domains are human. The presence of human variable and constant domains is particularly advantageous for matching to human patients, and thus in an emobidiment the ligand is or comprises an antibody or fragment whose variable and constant domains are human. id="p-302" id="p-302"

[00302] In an example, the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736. These endode for the Asp358Ala or Val385lie mutations. Thus, the human can comprise one or both of these SNPs. [00303| In an example, said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation, or is for said administration. id="p-304" id="p-304"

[00304] In an example, the ligand inhibits human IL6R binding to human IL6 and/or human gp!30 and optionally has been or is determined as capable of such inhibition. |00305] In an example, the method comprises (before administering the ligand) determining that the ligand is capable of such inhibition. id="p-306" id="p-306"

[00306] Inhibition determination is eg, inhibition in a blood or serum sample, at rtp. al pH7, at 37 degrees centigrade and/or under the physiological conditions of a human body. id="p-307" id="p-307"

[00307] In an example, the ligand is for treating, reducing the risk of or preventing an IL6R-mediated disease or condition in a human (i) whose genome comprises a nucleotide sequence encoding said IL6R protein comprising mutation Asp358Ala in SEQ ID NO: 78 and wherein the human is of KHV, GBR. CHB, CDX. CLM. MXL. CHS. JPT, GIH, PUR. ESN. FIN, ACB. BEB. YRL ASW, ITU, PJL. TSI. PEL. MSL, LWK. STU. GWD. IBS or CEU ancestry, eg, the human is of YRI, ASW, GBR. TSI. CLM, CHB. LWK. CHS. MXL, PUR, JPT, IBS, FIN or CEU ancestry; or (ii) whose genome comprises a nucleotide sequence encoding said IL6R protein comprising mutation Va)385Ile in SEQ ID NO: 78 and wherein the human is of ASW, YRI, PEL, MSL, LWK, GWD, PUR, IBS, ESN or ACB ancestry eg, the human is of EWK, ASW, YRI or PUR ancestry. id="p-308" id="p-308"

[00308] SNP rs2228145 (encoding Ala 358; see Table 11) is present in humans at an average cumulative frequency of 32% according to the 1000 Genomes Phase I database, but is higher in AMR, ASN, EUR, CLM, MXL, PUR, CHB, CHS, JPT, CEU, GBR, IBS and TSI populations; thus in an embodiment, the human is of AMR, ASN or EUR ancestry, eg, of CLM, MXL. PUR, CHB, CHS, JPT. CEU, GBR, IBS or TSI ancestry. In an embodiment, therefore, when the wherein the ligand (eg. antibody or fragment) specifically binds an IL6R protein that comprises a mutation Asp358Ala, the human comprises SNP rs2228145; and optionally the human is of AMR, ASN or EUR ancestry, eg, of CLM, MXL, PUR. CHB, CHS. JPT, CEU, GBR, IBS or LSI ancestry. |00309] SNP rs28730736 (encoding He 385; see Table 1 1) is present in humans at an average cumulative frequency of 5% 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 IL6R protein that comprises a mutation Val385Ile, the human comprises SNP rs28730736; and optionally the human is of AFR ancestry, eg, of ASW, LWK or YRI ancestry. id="p-310" id="p-310"

[00310] In an example, the invention provides pharmaceutical composition or kit for treating, reducing the risk of or preventing an IL6R-mediated condition or disease (eg, as recited above), the composition or kit comprising a ligand of the invention and optionally methotrexate and/or an anti-TNF alpha treatment: and optionally in combination with a label or instructions for use to treat, reduce the risk of or prevent said disease or condition in a human (eg, covering treatment of a human as recited herein); 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 sarilumab to said human; optionally wherein the kit comprises an IV or injection device that comprises the ligand (and, eg. also methotrexate or said antiTNF alpha treatment). For example, the invention provides pharmaceutical composition or kit for treating, reducing the risk of or preventing an IL6R-mediated condition or disease (eg. as recited above), the composition or kit comprising a ligand of the invention in combination with a label or instructions for use to treat arthritis in a human, wherein the label or instructions comprise a marketing authorisation number (eg, an FDA or EMA authorisation number), wherein the label or instructions comprise directions covering administration of sarilumab to said human; optionally wherein the kit comprises an IV or injection device that comprises the ligand (and, eg. also methotrexate or said anti-TNF alpha treatment). [003111 In an example, the invention provides a method of producing an anti-human IL6R antibody binding site, the method comprising obtaining a plurality of anti-IL6R antibody binding sites, screening the antibody binding sites for binding to a human IL6R that comprises a mutation Asp358Ala or Val3 8 5 He in SEQ ID NO: 78 or a peptide thereof that comprises mutation Asp358Ala or Val3 851 Ie in SEQ ID NO: 78 and isolating an antibody binding site that binds in the screening step, and optionally producing an IL6R-binding fragment or derivative of the isolated antibody. id="p-312" id="p-312"

[00312] In an enbodiment of this and the next example, the plurality of binding sites comprises or consists of a plurality of 4-chain antibodies or fragments thereof, eg, dAbs, Fabs or scFvs. Suitable methods for producing pluralities of binding sites for screening include phage display (producing a phage display library of antibody binding sites), ribosome display (producing a ribosome display library of antibody binding sites), yeast display (producing a yeast display library of antibody binding sites), or immunisation of a non-human vertebrate (eg, a rodent, eg, a mouse or rat, eg. a Velocimouse™, Kymousc™, Xenomouse™. Aliva Mouse™. HuMab Mouse,M. Omnimouse,M. Omnirat™ or MeMo Mouse™) with an IL6R 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-313" id="p-313"

[00313] In an example, the method comprises selecting one or more antibody binding sites or a derivative thereof that each specifically binds to a human IL6R epitope comprising a mutation Asp358Ala or Val385He in SEQ ID NO: 78. id="p-314" id="p-314"

[00314] In an example, specific binding means binding with an affinity (Kd) of ImM, lOOnM, 10nM or InM or less, eg, as determined by SPR. id="p-315" id="p-315"

[00315] 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. [00316] In an example the invention provides a method of producing an anti-human I LAR antibody, the method comprising immunising a non-human vertebrate (eg, a mouse or a rat that expresses human antibody variable domains) with a human IL6R comprising a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78 or a peptide thereof that comprises a mutation Asp358Ala or Val38511e in SEQ ID NO: 1 and isolating an antibody that binds a human IL6R comprising a mutation Asp358Ala or Val385He in SEQ ID NO: 78 or a peptide thereof that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78, and optionally producing an lL6R-binding fragment or derivative of the isolated antibody. id="p-317" id="p-317"

[00317] In an example the method further comprises 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-318" id="p-318"

[00318] In an example the method further comprises isolating a cell (eg, B-cell, plasmablast, plasma cell or memory cell) comprising the nucleic acid, wherein the cell is obtained from a non-human vertebrate that has been immunised with the 1L6R epitope. id="p-319" id="p-319"

[00319] In an example the method provides a kit for IL6R 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 encoding a human IL6R comprising a mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78, 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 encoding said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78 or hybridises to an antisense sequence or an RNA transcript thereof; and/or (ii) comprising a sequence of at least 1 0 or more (eg. 10, 15, 20, 30. 40. 50, 60. 70. 80. 90, 100 or more) nucleotides of a nucleotide sequence encoding an 1L6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val3851 le in SEQ ID NO: 78. id="p-320" id="p-320"

[00320] In an example the invention provides a kit for IL6R genotyping or phenotyping a human, wherein the kit comprises a ligand according to the invention or an antibody, fragment or derivative produced by the method of the invention. [003211 In an example the invention provides the use of an anti-IL6R ligand that binds a human IL6R comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78 in the manufacture of a medicament for treating, reducing the risk of or preventing an !L6R-mediated disease or condition in a human whose genome comprises a nucleotide sequence encoding said IL6R protein comprising said Asp.358Ala or Val38511 e in SEQ ID NO: 78. optionally for treating, reducing the risk of or preventing an IL6R-mediated disease or condition in a human as recited herein. [00322| In an example the invention provides the use of an anti-IL6R ligand that binds a human IL6R comprising said mutation Asp358Ala and/or Val385lle in SEQ ID NO: 78 in the manufacture of a medicament for targeting said IL6R in a human to treat, reduce the risk of or prevent a disease or condition mediated by IE6R, optionally for targeting IL6R in a human as recited above. [00323] In an example the invention provides a method of targeting an IL6R for treating, reducing the risk of or preventing an IE6R-mediated disease or condition in a human, the method comprising administering an anti-IL6R ligand to a human comprising a nucleotide sequence encoding an IL6R protein comprising a mutation Asp358Ala or Val385He in SEQ ID NO: 78, whereby an IL6R encoded by said nucleotide sequence is targeted. id="p-324" id="p-324"

[00324] The ligand can be any anti-IL6R ligand disclosed herein. id="p-325" id="p-325"

[00325] In an example the invention provides a method of treating, reducing the risk of or preventing a disease or condition mediated by IL6R in a human, the method comprising targeting a human IL6R comprising a mutation Asp358Ala or Val385He in SEQ ID NO: 78 by administering to the human a ligand that binds said IL6R thereby treating, reducing the risk of or preventing said disease or condition in the human. id="p-326" id="p-326"

[00326] The ligand can be any anti-IL6R ligand disclosed herein. id="p-327" id="p-327"

[00327] In an example the human has been or is phenotyped as positive for a human IL6R comprising a mutation Asp358Ala or Val385He in SEQ ID NO: 78. In an example the human has been or is genotyped as positive for a nucleotide sequence encoding a human 1E6R comprising a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. id="p-328" id="p-328"

[00328] In an example the method comprises genotyping the human as positive for a nucleotide sequence encoding an IL6R protein comprising a mutation Asp358Ala or Val3851 Ie in SEQ ID NO: 78. |00329] In an example the method comprises phenotyping the human as positive for an IL6R protein comprising a mutation Asp358Ala or Va!3851 Ie in SEQ ID NO: 78. id="p-330" id="p-330"

[00330] In an example the human has been or is genotyped as heterozygous for a nucleotide sequence encoding an IL6R protein comprising a mutation Asp358Ala or Val3851 Ie in SEQ ID NO: 78; optionally wherein the human has been or is also genotyped as comprising the nucleotide sequence of SEQ ID NO; 79. id="p-331" id="p-331"

[00331] In an example the genome of the human has been or is genotyped as homozygous for a nucleotide sequence selected encoding an IL6R protein comprising a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. id="p-332" id="p-332"

[00332] In an example the method comprises genotyping the human for a nucleotide sequence encoding an IL6R protein comprising a mutation Asp358Ala or Val385He in SEQ ID NO: 78 before administering the ligand to the human, wherein the ligand is determined to be capable of binding to an IL6R encoded by said selected sequence. id="p-333" id="p-333"

[00333] In an example the method comprises administering said ligand and methotrexate and/or an anti-TNF alpha treatment (eg, infliximab (eg. Remicade®), adalimumab (eg. I lumira®). certolizumab pegol (eg, Cimzia®), golimurnab (eg, Simponi®), or etanercept (eg, Enbrcl®) treatment) to the human. In an example the method comprises administering said ligand and adalimumab. In an example the method comprises administering said ligand and etanercept. In an example the method comprises administering said ligand and infliximab. id="p-334" id="p-334"

[00334] In an example the ligand and anti-TNF alpha treatment are administered separately. ]00335] In an example the ligand and anti-TNF alpha treatment are administered simultaneously. id="p-336" id="p-336"

[00336] In an example the ligand is administered by subcutaneous injection. id="p-337" id="p-337"

[00337] The invention also provides a method of IL6R genotyping a nucleic acid sample of a human, the method comprising identifying in the sample the presence of a nucleotide sequence encoding an IL6R protein comprising a mutation Asp358Ala or VaI385Ile in SEQ ID NO: 78, and optionally administering to the human a ligand of the invention. id="p-338" id="p-338"

[00338] The invention also provides a method of IL6R typing a protein sample of a human, the method comprising identifying in the sample the presence of a human 1L6R comprising a mutation Asp358Ala or Val3 851 Ie in SEQ ID NO: 78, and optionally administering to the human a ligand of the invention. id="p-339" id="p-339"

[00339] In an example, the method comprises obtaining an 11,6R protein sample from the human and then carrying out the identifying step. For example the sample is obtained by 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. In an example a ligand according of the invention is used to carry out said identifying step. id="p-340" id="p-340"

[00340] The invention als provides a method of treating, reducing the risk of, or preventing in a human patient an IL6R-mediated disease or condition (eg, rheumatoid arthritis), wherein the patient is receiving or has previously received an anti-I NF alpha treatment for said disease or condition, the method comprising typing the patient using a method of the invention as described above and administering a ligand of the invention to the human, whereby the human is treated or said disease or condition is prevented; optionally also reducing or stopping anti-TNF alpha treatment. In an embodiment, the ligand is co-administered with methotrexate. |00341] In an example, said reducing or stopping comprises reducing the dose and/or dosing frequency of anti-TNF alpha treatment. id="p-342" id="p-342"

[00342] The invention also provides 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 IL6R comprising a mutation Asp358Ala or Val385He in SEQ ID NO: 78 and instructions for carrying out a method of the invention and/or a label or instructions indicating or covering administration of the ligand to a human as per the invention (eg, a human comprising a nucleotide sequence encoding an IL6R comprising a mutation Asp358Ala or VaJ3851 Ie in SEQ ID NO: 78). id="p-343" id="p-343"

[00343] The invention also provides a diagnostic, therapeutic or prophylactic kit comprising a nucleic acid probe comprising a nucleotide sequence that specifica 1 ly hybridises to a nucleotide sequence encoding an 1L6R protein comprising a mutation Asp358Ala or Val385He in SEQ ID NO: 78 or an antisense sequence or RNA transcript thereof and instructions for carrying out a method of the invention. id="p-344" id="p-344"

[00344] In embodiments of any of the configuration, examples or aspects described herein, optionally, the IL6R is human IL6R, eg, a soluble or cell-surface bound human IL6R. In an example, the disease is an inflammatory disease such as rheumatoid arthritis. id="p-345" id="p-345"

[00345] In examples of the present invention, the ligand specifically binds to human IL6R that comprises a mutation Asp358Ala in SEQ ID NO: 78, In examples of the present invention, the ligand specifically binds to human IL6R that comprises a mutation Val385lie in SEQ ID NO: 78. id="p-346" id="p-346"

[00346] Determination of such binding can be performed by any antibody binding test as known in the art, eg, by surface plasmon resonance. Binding to each such form is, for example, respectively with a Kd of at least ImM. ΙΟΟηΜ, InM, ΙΟΟρΜ, ΙΟρΜ or IpM. [00347| In an example, the ligand binds human 1L6R that comprises a mutation Asp358Ala in SEQ ID NO: 78, wherein the ligand binding to said IL6R is with a Kd (determined by SPR) that is at least 60, 70, 80, 90 or 95% of the Kd for binding to human 1L6R comprising SEQ ID NO: 78. (00348] In an example, the ligand binds human 1L6R that comprises a mutation Val3851 le in SEQ ID NO: 78. wherein the ligand binding to said IL6R is with a Kd (determined by SPR) that is at least 60. 70, 80. 90 or 95% of the Kd for binding to human 1L6R comprising SEQ ID NO: 78, [00349] In examples of the present invention, the ligand neutralises human IL6R that comprises a mutation Asp358Ala in SEQ ID NO: 78 and optionally also human 1L6R comprising SEQ ID NO: 78. In examples of the present invention, the ligand neutralises human IL6R that comprises a mutation Val3851le in SEQ ID NO: 78 and optionally also human IL6R comprising SEQ ID NO: 78. Determination of neutralisation can be performed, for example, by any neutralisation assay method disclosed in US8043617 (Regeneron Pharmaceuticals, Inc), eg, as disclosed in Example 4 therein, or disclosed in any of the patents or applications in Table 13. Ligands of the invention that bind or target IL6R are useful, for example, for therapeutic and prophylactic applications disclosed in US804361 7 or disclosed in any of the patents or applications in Table 13, these specific disclosures being incorporated herein by reference in their entirety for use in the present invention and for possible inclusion in claims herein. id="p-350" id="p-350"

[00350] In embodiments where the ligand is used for therapeutic applications, ligand of the invention can inhibit, interfere with or modulate one or more biological activities of an IL6R (eg. human IL6R that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78 and optionally also human 1L6R comprising SEQ ID NO: 78). In one embodiment, ligand binds specifically to human IL6R (eg, human IL6R that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78 and optionally also human 1L6R comprising SEQ ID NO: 78) and/or substantially inhibits binding of human IL6R (eg, human 1L6R that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78 and optionally also human IL6R comprising SEQ ID NO:78) to human 116 and/or human gp 1.30 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 or comprises an antibody or IL6R-binding fragment thereof (eg, a Fab or scFv). id="p-351" id="p-351"

[00351] In an embodiment, the ligand has a Kd of less (binding more tightly) than 10 7. -s, 10°, 10"'°, 10H, 1012, 10 13 M for binding to one or more of a human IL6R that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78 and optionally also human IL6R comprising SEQ ID NO: 78. In an example, Kd is determined using SPR. |00352] In an embodiment, the ligand has an IC50 for blocking the binding of human IL6 to one or more of a human IL6R that comprises a mutation Asp358Ala or Val385Ue in SEQ ID NO. 78 (and optionally also human IL6R comprising SEQ ID NO: 78) of less than 1 microM, 1000 nM to 100 nM. 100 nM to 10 nM, 10 nM to I 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. )00353] In an embodiment, the ligand has an IC50 for blocking the binding of human gp 130 to one or more of a human IL6R that comprises a mutation Asp358Ala or Val385 lie in SEQ ID NO: 78 (and optionally also human IL6R comprising SEQ ID NO: 78) of less than 1 microM. 1000 nM to 100 nM. 100 nM to 10 nM, 10 nM to 1 nM, 1000 pM to500 pM, 500 pM to 200 pM, less than 200 pM, 200 pM to 150pM, 200pM to 100 pM, lOOpM to lOpM, lOpMto 1 pM. |00354] In an embodiment, the ligand has an 1C50 for blocking the binding of human IL6 to human IL-6R comprising SEQ ID NO: 78 that is no more than 1000, 100, 90, 80, 70, 60, 50, 40, 30, 20 or 10-fold (ie, more inhibitory) than the IC50 for blocking the binding of human IL6 to one or more of a human 1L6R that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78.

Additionally or alternatively, for example, the ligand has an IC50 for blocking the binding of human IL6 to (i) human IL6R comprising SEQ ID NO: 78 of less than I microM, 1000 nM to 100 nM. 100 nM to 10 nM, 10 nM to 1 nM, 1000 pM to 500 pM, 500 pM to 200 pM. less than 200 pM. 200 pM to 150 pM. 200 pM to 100 pM, 100 pM to 10 pM. 10 pM to 1 pM, eg. in the range of ImM to IpM (eg. ImM to lOOpM; lOnMtolOOpM; InM to I OpM; or lOOpM to 1 pM) and (ii) one or more more of a human IL6R that comprises a mutation Asp358Ala or Val38511e in SEQ ID NO: 78 of less than 1 microM. 1000 nM to 100 nM, 100 nM to 10 nM, 10 nM to 1 nM. 1000 pM to 500 pM. 500 pM to 200 pM, less than 200 pM, 200 pM to 150 pM, 200 pM to 100 pM, 100 pM to 10 pM, 10 pM to 1 pM. eg, in the range of ImM to IpM (eg, ImM to lOOpM; lOnM to 100pM: InM to 10pM: or 100pM to IpM). id="p-355" id="p-355"

[00355] In an embodiment, the ligand has an IC50 for blocking the binding of human gp 130 to human IL6R comprising SEQ ID NO: 78 that is no more than 1000, 100, 90, 80, 70, 60, 50. 40, 30, 20 or 10-fold (ie, more inhibitory) than the IC50 for blocking the binding of human gp 130 to one or more of a human IL6R that comprises a mutation Asp358Ala or Val3 85Ue in SEQ ID NO: 78. Additionally or alternatively, for example, the ligand has an IC50 for blocking the binding of human gpl30 to (i) human IL6R comprising SEQ ID NO: 78 of less than 1 microM, 1000 nM to lOOnM, 100 nM to 10 nM, 10 nM to I nM. 1000 pM to 500 pM, 500 pM to 200 pM, less than 200 pM. 200 pM to 1 50 pM. 200 pM to 100 pM, 100 pM to 10 pM, 10 pM to 1 pM. eg. in the range of ImM to IpM (eg, ImM to ΙΟΟρΜ: lOnM to lOOpM; InM to lOpM; or lOOpM to IpM) and (ii) one or more more of a human IL6R that comprises a mutation Asp358Ala or Val3851le in SEQ ID NO: 78 of less than 1 microM. 1000 nM to 100 nM. 100 nM to 10 nM, 10 nM to I nM, 1000 pM to 500 pM, 500 pM to 200 pM, less than 200 pM, 200 pM to 150 pM, 200 pM to 100 pM, 100 pM to 10 pM, 10 pM to 1 pM, eg, in the range of ImM to IpM (eg, ImM to lOOpM; lOnM to lOOpM; InM to lOpM; or lOOpM to IpM). |00356] In an embodiment, the ligand binds to human IL6R comprising SEQ ID NO: 78 with a binding affinity that is greater than up to 10%, greater than up to 20%. greater than up to 40%. greater than up to 50%, greater than up to 55%, greater than up to 60%. greater than up to 65%, greater than up to 70%, greater than up to 75%, greater than up to 80%, greater than up to 85%, greater than up to 90%, greater than up to 95% or greater than up to 100% (ie. affinity is double, so Kd is half) relative to binding to a human IL6R that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78. 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 Biacore1 M or using the ProteOn XPR36™ (Bio-Rad®), or using KinExA® (Sapidyne Instruments, Inc). id="p-357" id="p-357"

[00357] 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-358" id="p-358"

[00358] 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-359" id="p-359"

[00359] In one embodiment, the SPR is carried out at a physiological salt level, eg. 150mMNaCk id="p-360" id="p-360"

[00360] In one embodiment, the SPR is carried out al a detergent level of no greater than 0.05% by volume, eg, in the presence of P20 (polysorbate 20: eg, Tween-20TM) at 0.05% and EDTA at 3mM. [00361 ] In one example, the SPR is carried out at 25L)C or 37°C in a buffer at pl 17,6, 50mM NaCl, 0.05% detergent (eg, P20) and 3mM EDTA. The buffer can contain 1 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-362" id="p-362"

[00362] In an example, the affinity of the ligand, which is an antibody, is determined using SPR by J. Coupling anti-mouse (or other relevant vertebrate) IgG (eg, Biacore BR-1008-38) to a biosensor chip (eg, GLM chip) such as by primary amine coupling; 2. Exposing the anti-mouse IgG (vertebrate antibody) to a test IgG antibody to capture test antibody on the chip; 3. Passing the test antigen over the chip’s capture surface at IO24nM, 256nM, 64nM, 16nM, 4nM with a OnM (i.e. buffer alone); and 4. And determining the affinity of binding of test antibody to test antigen using surface plasmon resonance, eg, under an SPR condition discussed above (eg. at 25°C in physiological buffer). SPR can be carried out using any standard SPR apparatus, such as by Biacore™ or using the ProteOn XPR36™ (Bio-Rad®). id="p-363" id="p-363"

[00363] 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 XPR36IM analysis software. id="p-364" id="p-364"

[00364] 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 assaysj and at or substantially at rtp. id="p-365" id="p-365"

[00365] In one example an anti-IL6R antibody ligand of the present invention has of an IgG2 heavy chain constant region comprising or consisting of the amino acid sequence as shown in SEQ ID NO: 1 54. FIG. 3KK of US20120093818AI. which sequence is incorporated herein by reference. id="p-366" id="p-366"

[00366] In one example an anti-IL6R antibody ligand of the present invention has of an lgG4 heavy chain constant region comprising or consisting of the amino acid sequence as shown in SEQ ID NO: 155, FIG. 3KK of L/S20I200938I8A1, which sequence is incorporated herein by reference. id="p-367" id="p-367"

[00367] In an example, the antibody of the invention comprises a human IGHG 1*01 or IGHG2*01 heavy chain constant region. Additionally or alternatively, the antibody of the invention comprises a human IGKC*01 or IGLC1 *01 light chain constant region. In an example, the antibody of the invention comprises a human IGHGI *01 heavy chain constant region and a human IGKC*01 light chain constant region. id="p-368" id="p-368"

[00368] In an example, the antibody of the invention comprises the heavy chain constant region ofSEQIDNO: 104 or 106. 100369] In an example, the antibody of the invention comprises the light chain constant region of SEQ ID NO: 1 05 or 107. )00370] In an example, the antibody of the invention comprises SEQ ID NO: 104 or 106.

In an example, the antibody of the invention comprises SEQ ID NO: 105 or 107. [00371( In examples of the present invention, the ligand is or comprises a fully human antibody (ie, the variable domains and constant domains are human). id="p-372" id="p-372"

[00372] In an example, the ligand of the invention specifically binds to an epitope of a human 1L6R comprising at least one amino acid that is not found in SEQ ID NO: 78. For example, the amino acid is 358Ala or 385Ue (numbering as used in SEQ ID NO:78), For example, the ligand of the invention specifically binds to an epitope comprising 358Ala and to an epitope comprising 385He. Optionally, the ligand also specifically binds to a human IL6R comprising SEQ ID NO: 78. [00373] Reference is made to US8043617 (Regeneron, Inc) the entire disclosure of which is incorporated herein by reference. This patent application discloses relevant ligands for use in the present invention, as well as examples and methods of producing and testing ligands that can be used with reference to the present invention. For example, in one embodiment, the antibody or antigenbinding portion of the antibody of the invention comprises a heavy chain variable region (HCVR) selected from the group consisting of SEQ 1DNO:3, 227, 19, 231,35, 51,67, 83, 99, 115, 131, 147, 239, 241, 163, 179,235, 195 and 211, or substantially similar sequence thereof. In a more specific embodiment, the antibody or antigen-binding fragment thereof further comprises a light chain variable region (LCVR) selected from the group consisting of SEQ ID NO: I 1,229, 27, 233, 43, 59, 75, 91, 107, 123, 139, 155, 171, 187, 203 and 219, or a substantially similar sequence thereof. In specific embodiments, the antibody or antigen-binding fragment thereof comprise HCVR/LCVR pairs selected from the group consisting of SEQ ID NO:3/11; 227/229; 19/27: 23 1/233; 35/43; 51/59; 67/75: 83/91; 99/107; 115/123; 131/139; 147/155; 239/155; 241; 155; 163/171: 179/187: 235/237; 195/203: and 211/219, or substantially similar sequences thereof (these sequences, SEQ ID NOs and pairs being those disclosed in LJS8568721. which is incorporated herein by reference as though written herein and for potential inclusion the invention and claims herein). In an example, the human antibody or antigen-binding fragment comprises the complementarity determining region (CDR) sequences of a heavy chain variable region (HCVR) and light chain variable region (LCVR) pair (HCVR/LCVR) set forth in SEQ ID NO: 19/27 of US856872L which are incorporated herein by reference as though written herein and for potential inclusion the invention and claims herein. In an example, the ligand of the invention comprises or consists of an antibody disclosed in any of Tables I to 4 of US856872I, the associated disclosures (including sequences) of which are incorporated herein by reference. id="p-374" id="p-374"

[00374] In an example, the ligand is or comprises sarilumab or is an lL6R-binding derivative thereof. |00375] In an example, the antibody or other ligand of the invention is glycosylated, eg, has human glycosylation (eg, produced by a CHO, Cos or Hek293 cell). In an example, the ligand of the invention is produced in CHO. |00376] 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 US8043617 (Regeneron Pharmaceuticals. Inc), which disclosure is incorporated herein by reference in its entirety for inclusion in one more claims herein or one or more disease or conditions disclosed herein. id="p-377" id="p-377"

[00377] The ligand can be administered to a human characterised as described in US8043617 (Regeneron Pharmaceuticals, Inc) which disclosure is incorporated by reference herein in its entirety. id="p-378" id="p-378"

[00378] The ligand can be administered in a form or combination disclosed in US804361 7 (Regeneron Pharmaceuticals, Inc), which disclosure is incorporated herein by reference. id="p-379" id="p-379"

[00379] The ligand can be used in a method of diagnosis. id="p-380" id="p-380"

[00380] Diagnostic Applications id="p-381" id="p-381"

[00381] In some embodiments, the ligand of the invention is a diagnostic tool. The ligand can be used to assay the amount of IL6R present in a sample and/or subject. As will be appreciated by one of skill in the art, such ligands need not be neutralizing ligands. In some embodiments, the diagnostic ligand is not a neutralizing ligand. In some embodiments, the diagnostic ligand binds to a different epitope than a neutralizing ligand binds to. In some embodiments, the two ligands do not compete with one another. id="p-382" id="p-382"

[00382] In some embodiments, the ligands of the invention are used or provided in an assay kit and/or method for the detection of IL6R in mammalian tissues or cells in order to screen/diagnose for a disease or disorder associated with changes in levels of 1L6R. The kit comprises a ligand that binds IL6R and means for indicating the binding of the ligand with IL6R, if present, and optionally JL6R 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 IL6R in a sample. As will be appreciated by one of skill in the art. high or elevated levels of IL6R will result in larger amounts of the ligand binding to IL6R in the sample. Thus, degree of ligand binding can be used to determine how much IL6R is in a sample. Subjects or samples with an amount of IL6R that is greater than a predetermined amount (e.g., an amount or range that a person without an 1L6R related disorder would have) can be characterized as having an IL6R mediated disorder. id="p-383" id="p-383"

[00383] In some embodiments, the ligand is a non-neutralizing ligand and is used to determine the amount of IL6R in a subject receiving an anti-TNF alpha treatment. id="p-384" id="p-384"

[00384] In some embodiments, an isolated nucleic acid molecule is provided and it encodes the ligand. In some embodiments an expression vector is provided and comprises the nucleic acid molecule. In some embodiments, a pharmaceutical composition is provided and comprises 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 an IL6R 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 an inflammatory disease, eg. rheumatoid arthritis. 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. id="p-385" id="p-385"

[00385] 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 a human IL6R comprising a mutation Asp358Ala or Val3 851 Ie in SEQ ID NO: 78 (and optionally a human IL6R comprising SEQ ID NO: 781), characterized by the ability to reduce human IL6 activity in a human by 40-80% over a 24. 60 or 90 day period relative to predose levels, eg. as determined using the assay set out in Example 4 of US8043617 (incorportated herein by reference). [00386] In one embodiment, the antibody or antigen-binding fragment is characterized as exhibiting an enhanced binding affinity (Kd) for hIL6R at pH 5.5 relative to the Kd at pH 7.4, as measured by plasmon surface resonance. In a specific embodiment, the antibody or fragment thereof exhibits at least a 20-fold, at least a 40-fold or at least a 50-fold enhanced affinity for IL6R at an acidic pH relative to a neutral pH, as measured by surface plasmon resonance. id="p-387" id="p-387"

[00387] In one embodiment, the antibody or antigen-binding fragment is characterized as not exhibiting an enhanced binding affinity for IE6R 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-388" id="p-388"

[00388] In another embodiment, the antibody or antigen-binding fragment specifically binds a human IL6R comprising a mutation Asp358Ala or Val385lie in SEQ ID NO: 78 and also specifically binds one or more of cynomolgus monkey, rhesus monkey, mouse, rat and hamster IL6R (eg, binds human and mouse IL6R, or binds human and cynomolgus monkey IL6R or binds human and rhesus monkey IL6R). id="p-389" id="p-389"

[00389] In one embodiment, the antibody or antigen-binding fragment binds human and cyno and/or rhesus monkey IL6R, but does not bind mouse, rat or hamster IL6R. id="p-390" id="p-390"

[00390] 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), HCDRI, HCDR2, and HCDR3 disclosed in US8043617, the disclosure of which is incorporated herein by reference in its entirety. |00391] 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 hIL6R and a pharmaceutically acceptable carrier. In one embodiment, the invention features a composition which is a combination of a ligand of the invention (eg, an antibody or antigen-binding fragment of an antibody), and a second therapeutic agent. The second therapeutic agent may be any agent that is advantageously combined with the ligand of the invention, for example, an anti-inflammatory agent, eg, an anti-TNF alpha agent (eg, antibody) or methotrexate. [00392| In an example, the invention provides a method for inhibiting hIL6R activity using the anti-IL6R ligand of the invention (eg, an antibody or antigen-binding portion of the antibody of the invention), wherein the therapeutic methods comprise administering a therapeutically effective amount of a pharmaceutical composition comprising an antibody or antigen-binding fragment of an antibody of the invention. The disorder treated is any disease or condition which is improved, ameliorated, inhibited or prevented by removal, inhibition or reduction of 1L6R activity. id="p-393" id="p-393"

[00393] The term isolated" with reference to a ligand, antibody or protein, for example in any aspect, configuration, example or emodiment, means that a subject ligand, antibody, protein etc (1) is free of at least some other proteins with which it would normally be found, (2) is essentially free of other proteins from the same source, e.g., from the same species, (3) is expressed by a cell from a different species, (4) has been separated from at least about 50 percent of polynucleotides, lipids. carbohydrates, or other materials with which it is associated in nature, (5) is operably associated (by covalent or noncovalent interaction) with a polypeptide with which it is not associated in nature, or (6) does not occur in nature. Typically, an "isolated" ligand, antibody, protein etc constitutes at least about 5%, at least about 10%, at least about 25%, or at least about 50% of a given sample. Genomic DNA. cDNA, mRNA or other RNA. of synthetic origin, or any combination thereof can encode such an isolated ligand, antibody protein etc. Preferably, the isolated ligand, antibody protein etc is substantially free from proteins or polypeptides or other contaminants that are found in its natural environment that would interfere with its therapeutic, diagnostic, prophylactic, research or other use. [00394] 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: (I) to greater than 95% by weight of antibody as determined by, for example, the Lowry method, and in some embodiments, to greater than 99% by weight; (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator. or (3) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or. preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant cells since al least one component ofthe antibody's natural environment will not be present. Ordinarily, however, an isolated polypeptide or antibody will be prepared by at least one purification step. 1003951 I mm unoconjugates id="p-396" id="p-396"

[00396] The invention encompasses the ligand (eg, antibody) conjugated to a therapeutic moiety ("immunoconjugate"), such as a cytotoxin, a chemotherapeutic drug, an immunosuppressant or a radioisotope. Cytotoxin agents include any agent that is detrimental to cells. Examples of suitable cytotoxin agents and chemotherapeutic agents for forming immunoconjugates are known in the art, see for example. WO 05/103081. which is incorporated by reference herein in its entirety. 100397] Bispecifics id="p-398" id="p-398"

[00398] The antibodies of the present invention may be monospecific, bispecific, or multispeci fic. 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 anti-TOI (e.g., anti-!L6R) mAbs can be linked to or coexpressed 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-399" id="p-399"

[00399] An exemplary bi-specific antibody format that can be used in the context of the present invention involves the use of a first immunoglobulin (Ig) CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bi specific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second CH3 may further comprise a Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second CH3 include: D16E, L18M, N44S, K52N, V57M, and V821 (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of IgG 1 antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N. and V422I by EU) in the case of IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N3845, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of IgG4 antibodies. Variations on the bi-specific antibody format described above are contemplated within the scope of the present invention. id="p-400" id="p-400"

[00400] Therapeutic Administration and Formulations id="p-401" id="p-401"

[00401] The invention provides therapeutic compositions comprising the anti-TOI ligand, eg, antibodies or antigen-binding fragments thereof, of the present invention. The invention provides therapeutic compositions comprising the anti-IL6R 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 lo 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 al. ‘Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-31 I. id="p-402" id="p-402"

[00402] 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 IL6R in an adult patient, it is advantageous to intravenously administer the ligand or antibody of the present invention normally at a single dose of about 0.01 to about 20 mg/kg body weight, more preferably about 0.02 to about 7, about 0.03 to about 5, or about 0.05 to about 3 mg/kg body weight. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. id="p-403" id="p-403"

[00403] Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, thus the composition invention provides the ligand by e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see. e.g., Wu et al. (1987) J. Biol. Chern. 262:4429-4432). Methods of introduction include, but are not limited to. intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. id="p-404" id="p-404"

[00404] 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-405" id="p-405"

[00405] 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. Ela. (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 (sec. e.g.. Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138. 1984). |00406} The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule. A pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all 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. 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-407" id="p-407"

[00407] 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, NJ.), 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). [00408| Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the aforesaid antibody contained is generally about 5 to about 500 mg per dosage form in a unit dose; especially in the form of injection, it is preferred that the aforesaid antibody is contained in about 5 to about 100 mg and in about 10 to about 250 mg for the other dosage forms. 100409] The invention provides therapeutic methods in which the ligand, eg, antibody or antibody fragment, of the invention is useful to treat an inflammatory disease or condition associated with elevated hIL6R and/or IL6R activity. The anti-IL6R ligands, eg, antibodies or antibody fragments, of the invention are particularly useful for the treatment of arthritis. id="p-410" id="p-410"

[00410] Ligands of the invention are useful, for instance, in specific binding assays, for genotyping or phenotyping humans, affinity purification of the TOI, e.g., IL6R, and in screening assays to identify other antagonists of TOI, e.g., IL6R, activity. Some of the ligands of the invention are useful for inhibiting binding of TOI, e.g.. IL6R, to a congnate human receptor or protein, or inhibiting TOI, e.g., IL6R, -mediated activities. id="p-411" id="p-411"

[00411] The invention encompasses anti-TOI (eg, anti-lL6R) antibody ligands having a modified glycosylation pattern. In some applications, modification to remove undesirable glycosylation sites may be useful, or e.g., removal of a fucose moiety to increase antibody dependent cellular cytotoxicity (ADCC) function (see Shield et al. (2002) JBC 277:26733). In other applications, modification of galactosylation can be made in order to modify complement dependent cytotoxicity (CDC). id="p-412" id="p-412"

[00412] 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 a TOI (e.g., a rare variant as described herein) (e.g., IL6R) 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-413" id="p-413"

[00413] "Pharmaceutically acceptable" refers to approved or approvable by a regulatory agency of the USA Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans. A "pharmaceutically acceptable carrier, excipient, or adjuvant" refers to an carrier, excipient, or adjuvant that can be administered to a subject, together with an agent, e.g., any antibody or antibody chain described herein, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the agent. |00414] In an example, the invention features a method for inhibiting TOL e.g.. 1L6R. activity using the anti TOL e.g.. anti-IL6R. 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 TOL e.g., 1L6R, activity. id="p-415" id="p-415"

[00415] 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 Ait, Science and Technology of Pharmaceutical Compounding). id="p-416" id="p-416"

[00416] 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. [00417J Genotyping & Phenotyping id="p-418" id="p-418"

[00418] 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,M is a proprietary genotyping platform sold by Applied Biosystems). id="p-419" id="p-419"

[00419] Next-generation sequencing technologies such as pyrosequencing is also useful. [00420| Reference is also made to GB2444410A and the genotyping method disclosed therein, which is incorporated herein by reference in its entirety. id="p-421" id="p-421"

[00421] Miniaturized assays, such as microarrays with oligonucleotide reagents immobilized on small surfaces, are frequently proposed for large-scale mutation analysis and highthroughput genotyping (Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome (Wang DG, Fan JB. Siao C.L Berno A. Young P. Sapolsky R. GhandourG. 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 G, 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 allele-specific probe (Review Accessing genetic variation: genotyping single nucleotide polymorphisms, Syvanen AC, Nat Rev Genet. 2001 Dec; 2(12):930-42; Review Techniques patents for SNP genotyping, Twyman RM, Primrose SB, Pharmacogenomics. 2003 Jan; 4(1):67-79). id="p-422" id="p-422"

[00422] 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 TaqMan1 M 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 pail of Springer Science-HBusiness Media. LLC; and Single Nucleotide Polymorphisms, Methods in Molecular Biology™ Volume 578. 2009. pp 10 293-306, The TaqMan Method for SNP Genotyping, Gong-Qing Shen el al). The TaqMan SNP Genotyping Assay exploits the 5'-exonuclease activity of AmphTaq Gold1M DNA polymerase to cleave a doubly labeled probe hybridized to the SNP-containing sequence of ssDNA, Cleavage separates a 5'-fhiorophore 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-423" id="p-423"

[00423] 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 20 be used (High-throughput genotyping with single nucleotide polymorphisms, Ranade K, Chang MS, Ting CT, Pei D, Hsiao CF, Olivier M, Pesich R, Hebert J, Chen YD, Dzau VJ, Curb D, Olshen R, Risch N. Cox DR, Botstein D, Genome Res. 2001 Jul; 11(7): 1262-8; Assessment of two flexible and compatible SNP genotyping platforms: TaqMan SNP Genotyping Assays and the SNPlex Genotyping System, De la Vega FM. Lazaruk KD. Rhodes MD, Wenz MH, Mutat Res. 2005 Jun 3: 573(1-2):1 1 I25 35). The results of the assay can be automatically determined by genotyping software provided with real-time thermal cyclers (e.g. IQ software of Bio-Rad, Sequence Detection Software of Applied Biosystems). id="p-424" id="p-424"

[00424] Single nucleotide polymorphisms (SNPs) can be determined using TaqManIM real-time PCR assays (Applied Biosystems) and commercial software that assigns genotypes based on 30 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 el ah Nucleic Acids Res. 2006: 34(7): e56, Published online 2006 April 14. doi: 10.1093/nar/gkl 1 85, PMCID: PMC 1440877). The algorithm is unique in that it classifies samples according to the behavior of blanks (no DNA samples), which cluster w ith heterozygous samples. This method of classification 35 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-425" id="p-425"

[00425] 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 silica translation. id="p-426" id="p-426"

[00426] Exemplary TOls [00427| 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; ACVRI; ACVR1B; ACVR2; ACVR2B: ACVRLI; ADORA2A; Aggiecan; AGR2; AICDA; AW1; AIGI; AKAPI: AKAP2; AIYIH; amyloid-beta: AMHR2; ANGPTI; ANGPT2; ANGPTL3; ANGPTL4; ANPEP; APC: APOCI: AR; Axl; AZGPI (zinc-a-glycoprotein); B7.I; B7.2; BAD; BAIT; BAG I; BAI1; BCL2; BCL6; BDNF; BLNK; BLR1 (MDRI5); BlyS; BMP1: BMP2; BMP3B (GDF1O); BMP4; BMP6; BMP8; BMPR1 A; BMPRIB: BMPR2; BPAG1 (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); CCL17 (TARC); CCLI8 (PARC); CCLI9 (MIP-3b); CCL2 (MCP-1); MCAF; CCL2O (MIP-3a); CCL2I (MIP-2); SLC; exodus-2; CCL22 (MDC / STC-1); CCL23 (MPIF-I); CCL24 (MP1F-2 I eotaxin-2); CCL25 (TECK): CCL26 (eotaxin-3); CCL27 (CTACK /ILC); CCL28; CCL3 (MIP-la); CCL4 (MIP-1 b); CCL5 (RANTES): CCL7(MCP-3): CCL8 (mcp-2); CCNAI; CCNA2; CCNDI; CCNE1; CCNE2: CCR1 (CKR1 / HM145); CCR2 (mcp-l RB / RA);CCR3 (CKR3 /CMKBR3): CCR4; CCR5 (CMKBR5 I ChemRI 3); CCR6 (CMKBR6 / CKR-L3 i STRL22 / DRY6); CCR7 (CKR7 / EBI I); CCR8 (CMKBR8 / TERI / CKR-LI); CCR9 (GPR-9-6); CCRL1 (VSHK1); CCRL2 (L-CCR); CD7, CDI64; CDI9; CDIC; 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; CD81; CD83: CD86; CD96: CD207; CDH1 (E-cadherin); CDH10; CDH12: CDH13; CDHI8: CDH19; CDH20; CDH5: CDH7; CDI-I8; CDH9; CDK2; CDK3; CDK4; CDK5; CDK6; CDK7; CDK9; CDKN1A (p2IWapl/Cipl); CDKN1B (p27Kipl); CDKN1C; CDKN2A (p!61NK4a); 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); CMKLRI; CMKOR1 (RDC1); CNR1; COLI8A1; COLIA1; COL4A3; COL6A1; CR2; CRP; CSF1 (M-CSF); CRLF2; CSF2 (GM-CSF); CSF3 (GCSF); CTLA4; CTNNB1 (b-catenin); CTSB (cathepsin B); CX3CL1 (SCYDi); CX3CRI (V28); CXCR6; CXCL1 (GROI); CXCI. 10 (IP-10); CXCL11 (I-TAC / IP-9); CXCL12 (SDFI); CXCL13; CXCL14; CXCL 16; 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; DKFZp45 I JOI 18; DNCL1; DPP4; E2FI; ECGF1; EDGl; EFNAI; EFNA3; EFNB2; EGF; EGFR; ELAC2; ENG; ENO I; ENO2; ENO3; EphA4; EPHB4; EPO; ERBB2 (Her-2); EREG; ERK8; ESRI; ESR2; F3 (TF); FADD; FasL; FASN; FCER1A; FCER2; FCGR3A; FCRL4; FGF; FGF1 (aFGF); FGF1O; FGF11; FGF12; FGF12B; FGF13; FGF14; FGF16; 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); FILI (EPSILON); FILI (ZETA); FLJ12584; FLJ25530; FLRTI (fibronectin); FLTI; I OS: FOSL1 (FRA-1): FY (DARC): GABRP (GABAa): GAGEB1; GAGECI: Galeclin-3: GALNAC4S65T; GAI A3: GDF5: GFII: GG IΊ : GUR: GM-CSF: GN ASI: GNRI11: GPR2 (CCRIO): GPR31: GPR44; GPR81 (FKSG8O): GPR87; GPRI37C; GRCCIO (CIO); GRP: GSN (Gelsolin): GSTPI; HAVCRI; HAVCR2: HDAC4: EDAC5; HDAC7A; HDAC9: hepcidin; heinojuvelin: HGF: HIHA: HIP 1; histamine and histamine receptors: HLA-Λ; HLA-DRA; HM74; HMOX1; HUMCYT2A; ICEBERG: ICOS: 1D2; IFN-a; IFNAI; IFNA2; 1FNA4; 1FNA5; IFNA6: IFNA7; 1FNBI; IFNgamma; TFNW1; IGBP1; IGFI; 1GFIR; IGF2; IGFBP2; IGFBP3; IGFBP6; IL-1; IL10: ILIORA: 1LI0RB; IL11; IL11RA; IL-12; ILI2A; IL12B; IL12RB1; IL12RB2; 1LI3; IL13RA1; 1LI3RA2; 1L14; 1LI5; ILI5RA; IL16; 1L17; IL17B; 1LI7C; 1L17R: I LI 8; IL18BP: ILI8RI; IL18RAP; 1LI9; ILIA; ILI B; IL1F1O; IL1F5; IL1F6; ILI F7; IL1F8; IL1F9; ILI HY1; 1L1R1; 1L1R2; IL1RAP; ILIRAPL1; IL1RAPL2; IL 1 RLI;ILIRL2 IL1RN; 1L2; IL20; IL2ORA; IL21R; IL22; 1L22R; 1L22RA2; 1L23; IL24; IL25; IL26; 1L27; 1L28A; IL28B; 1L29; 1L2RA; IL2RB; IL2RG; 1L3; 1L30; IL3RA; 1L4; 1L4R; 1L5; 1L5RA; I L6; IL6 receptor; IL6ST (glycoprotein 130); 1L7; TL7R; 1L8; IL8RA: IL8RB: IL8RB: 1L9: IL9R: ILK; INF1A; INHBA; INSL3; INSL4; IRAKI; IRAK2; ITGAI; ITGA2: ITGA3: II GA6 (a6 integrin): ITGAV: ITGB3; HGB4 (b 4 integrin); JAG I; JAKI; JAK3; JUN: K6HF; KAll; KDR; M'l LG; KLF5 (GC Box BP): KLF6: KLK10; KLKI2; KLK13: KLK14: KLKI5; KLK3; KLK4: KLK5: KLK6: KLK9: KRT1; KRT19 (Keratin 19): KRT2A; KRTI IB6 (hair-specific type II keratin): LAGS: LAMA5; LEP (leptin); LIGHT: Lingo-p75; LingoTroy: LPS; LRP5; ETA (TNF-b); L I B: LTB4R (GPRI6): LTB4R2; LTBR; MACMARCKS; MAG or Omgp; MAP2K7 (c-Jun); MDK; MIBI; midkine; MIF; MIP-2; MK167 (Ki-67); MMP2; MMP9; MS4A1; MSMB: MT3 (metallothionectin-ifi); MTSS 1; MUC 1 (mucin): MYC; MYD88: NCK2: neurocan: NavL7; NavL8; NFKB 1; NFKB2; NGFB (NGF): NGFR; NgR-Lingo; NgR-Nogo66 (Nogo); NgR-p75; NgR-Troy; NMEI (NM23A); NOX5; NPPB; NROBI; NROB2; NRID1; NRID2; NR1H2; NRIH3; NR1H4; NR1I2; NRI13; NR2C1; NR2C2; NR2E1;NR2E3; NR2F1; NR2F2; NR2F6; NR3CI; NR3C2; NR4AI; NR4A2; NR4A3; NR5AI; NR5 A2; NR6A1; NRPI; NRP2: NT5E; NTN4; ODZ1; OPG; OPRD1; OX40L; 0X40; P2RX7; PAP; PARTI; PATE; PAWR; PCA3; PCNA; PCSK9, PD-I, PD-LI; PDGFA; PDGFB; PECAM1; PF4 (CXCL4); PGF; PGR; phosphacan; PIAS2; Placental Growth Factor (PIGF); PIK3CG; PLAU (uPA); PLG; PLXDC1; PPBP (CXCL7); PPID; PRI; PRKCQ; PRKD1; PRL; PROC; PROK2; PSAP; PSCA; PTAFR; PTEN; PTGS2 (COX2); PTN; RAC2 (P21Rac2); RARB; RGS1; RGSI3; RGS3: RNFI 1O(ZNFI44); ROBO2; RORI; S100A2; SCGB1D2 (lipophilin B); SCGB2A1 (mammaglobin 2); SCGB2A2 (mammaglobin 1); SCYEI (endothelial Monocyte-activating cytokine); SDF2; SERP1NA1; SERPINIA3; SERPINB5 (maspin); SERP1NE1 (PAT-i); SERPINF1; SHBG; SLA2; SLC2A2; SLC33AI; SLC43A1; SL1T2; SPPI; SPRR1B (Spri); ST6GAL1; STAB 1; STAT6; STEAP; STEAP2; TB4R2; TBX2I; TCP 10; TDGF1; TEK; TGFA; TGFBI; TGFB III; TGFB2; TGFB3; TGFBI; TGFBR1; TGFBR2; TGFBR3; TH IL: 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-«; TNFAIP2 (B94); TNFAIP3; TNFRSFI I A; TNFRSFIA; TNFRSFIB; TNFRSF21: TNFRSF5: TNFRSF6 (Fas); TNFRSF7; TNFRSF8; TNFRSF9; TNFSFIO (TRAIL): TNFSF1 1 (TRANCE): TNFSF12 (APO3L); TNFSF13 (April); TNFSFI3B; TNFSF14 (HVEM-L); TNFSFI 5 (VEG1): TNFSFI 8: TNFSF4 (0X40 ligand); TNFSF5 (CD4O ligand): TNFSF6 (FasL): TNFSF7 (CD27 ligand); TNFSF8 (CD3O ligand): TNFSF9 (4-1BB ligand); Ί OLLIP; Toll-like receptors; TOP2A (topoisomerase lia): TP53; TPM1:TPM2; TRADD: TRAFI; TRAF2; TRAF3: TRAF4: TRAF5: TRAF6; TRAIL; I REMI; TREM2; TRPC6; TSLP; TWEAK; VEGFA; VEGFB; VEGFC; versican: VI IL C5; VLA-4; Wnt7A; XCL1 (lymphotactin); XCL2 (SCM-lb); XCR1 (GPR5 / CCXCRI); YY1: and ZFPM2. |00428] In an example, the TO] is a human TOI selected from Table 5. id="p-429" id="p-429"

[00429] In an example, the TOI is OX40 ligand. id="p-430" id="p-430"

[00430] In an example, the TO) is OX40. id="p-431" id="p-431"

[00431] In an example, the TOI is PCSK9. id="p-432" id="p-432"

[00432] In an example, the TOI is 1L6 receptor (IL-6R). id="p-433" id="p-433"

[00433] In an example, the TOI is LIGHT. id="p-434" id="p-434"

[00434] In an example, the TOI is VEGF-A. |00435] In an example, the TOI is I NF alpha. |00436] In an example, the TOI is PIGF. |00437] In an example, the TOI isIGFIR. |00438] In an example, the TOI is OPG. |00439] In an example, the TOI is ICOS |00440] In an example, the TOI is NGF. (00441] In an example, the TOI is BMP6. id="p-442" id="p-442"

[00442] In an example, the TOI is fenOportin. id="p-443" id="p-443"

[00443] In an example, the TOI is TMPRSS6. id="p-444" id="p-444"

[00444] In an example, the TOI is hemojuvelin. (00445] In an example, the TOI is VEGF receptor. id="p-446" id="p-446"

[00446] In an example, the TOI is PDGF receptor. id="p-447" id="p-447"

[00447] In an example, the TOI is stem cell factor receptor. id="p-448" id="p-448"

[00448] In an example, the TOI is hepcidin. id="p-449" id="p-449"

[00449] In an example, the TOI is IL-4 receptor alpha. id="p-450" id="p-450"

[00450] In an example, the TOI is sclerostin. |00451] In an example, the TOI is IL-13 receptor. |00452] In an example, the TOI is CD7. |00453] In an example, the TOI is delta-like ligand-4 (DII4). |00454| In an example, the TOI is HGF. |00455] In an example, the TOI is angiopoietin-2 (Ang2). id="p-456" id="p-456"

[00456] In an example, the TOI is GDF8. id="p-457" id="p-457"

[00457] In an example, the TOI is ERBB3. id="p-458" id="p-458"

[00458] In an example, the TOI is IL-17 receptor. id="p-459" id="p-459"

[00459] In an example, the TOI is CD40. id="p-460" id="p-460"

[00460] In an example, the TOI is CD40 ligand. 1004611 In an example, the TO! is EGFR. id="p-462" id="p-462"

[00462] 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 ail to which this invention belongs. If there is an apparent discrepancy between the usage of a term in the ait and its definition provided herein, the definition provided within the specification shall prevail. 100463] For convenience, certain terms employed herein, in the specification, examples and appended claims are collected here. 100464] 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 al 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." id="p-465" id="p-465"

[00465] In certain aspects of all embodiments of the invention, the term "inhibition" is used. Inhibition refers and refers to decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment) and can include, for example, a decrease by at least about 10%. at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , or more including 100% inhibition as compared to a reference level. Complete inhibition" refers to a 100% inhibition as compared to a reference level. id="p-466" id="p-466"

[00466] The terms increased", increase", "enhance", or activate" are all used herein to mean an increase by a statically significant amount. In some embodiments, the terms increased, increase", "enhance", or ‘‘activate" can mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%. or at least about 50%. or at least about 60%, or at least about 70%. or at least about 80%. or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or al least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. In the context of a marker or symptom, an "increase" is a statistically significant increase in such level. id="p-467" id="p-467"

[00467] As used herein, the term substantially" refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term substantially" is therefore used herein to capture the potential lack of completeness inherent in many bio logical 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. (00468] 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." lipatient" 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. In an alternative embodiment, where administration to a human is mentioned in the context of the invention herein, the alternative is that administration is to a different, non-human, subject. Similarly, alternative to a human comprising said nucleotide sequence, such a sequence may be comprised by a non-human subject. This may be useful for the assaying, treatment, prevention or diagnosis in a non-human animal (eg, non-human primate) that comprises one or both of the, e.g., 1L6R mutations. id="p-469" id="p-469"

[00469] 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-470" id="p-470"

[00470] A subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment or one or more complications related to such a condition, and optionally, have already undergone treatment for the condition or the one or more complications related to the condition. Alternatively, a subject can also be one who has not been previously diagnosed as having the condition or one or more complications related to the condition. For example, a subject can be one who exhibits one or more risk factors for the condition or one or more complications related to the condition or a subject who does not exhibit risk factors. id="p-471" id="p-471"

[00471] 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. |00472| As used herein, the terms protein and polypeptide are used interchangeably herein to designate a series of amino acid residues, connected to each other by peptide bonds between the alpha-amino and carboxy groups of adjacent residues, The terms protein, and polypeptide refer to a polymer of amino acids with natural amino acids. When referring to modified polypeptides" one refers to polypeptides that include modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc,) and amino acid analogs, regardless of its size or function. Protein" and polypeptide" are often used in reference to relatively large polypeptides, whereas the term peptide is often used in reference to small polypeptides, but usage of these terms in the art overlaps. The terms protein" and ’’polypeptide are used interchangeably herein when referring to a gene product and fragments thereof Thus, 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. [00473| 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-474" id="p-474"

[00474] 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. (00475] As used herein, the term "siRNA" refers to a nucleic acid that forms an RNA molecule comprising two individual strands of RNA which are substantially complementary to each other, Typically, the siRNA is at least about 15-40 nucleotides in length (e.g.. each complementary sequence of the double stranded siRNA is about 15-40 nucleotides in length, and the double stranded siRNA is about 15-40 base pairs in length, preferably about 19-25 base nucleotides, e.g., 19. 20, 21. 22, 23, 24. or 25 nucleotides in length). In some embodiments, a siRNA can be blunt-ended. In some embodiments, a siRNA can comprise a 3’ and/or 5’ overhang on each strand having a length of about 0, 1,2, 3, 4, or 5 nucleotides. The length of the overhang is independent between the two strands, i.e.. the length of the overhang on one strand is not dependent on the length of the overhang on the second strand, The siRNA molecules can also comprise a 3’ hydroxyl group. In some embodiments, the siRNA can comprise a 5’ phosphate group, A siRNA has the ability to reduce or inhibit expression of a gene or target RNA when the siRNA is present or expressed in the same cell as the target gene, e.g. the target RNA. siRNA-dependent post-transcriptional silencing of gene expression involves cutting the target RNA molecule at a site guided by the siRNA. id="p-476" id="p-476"

[00476] 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 el 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 cl aL, 2006). PCSK9 is a prohormone-proprotein convertase in the subtilisin (S8) family of serine proteases (Seidah et aL, 2003). The sequence of PCSK9 for a variety of species is known, e.g., human PCSK9 (NCBI Gene ID No: 255738). Nucleotide and polypeptide sequences for a number of PCSK9 isoforms are provided herein, e.g., SEQ ID NOs: 1-37. id="p-477" id="p-477"

[00477] 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: 67)) (Naureckiene et aL, 2003), and has been shown to be required for its secretion from cells (Seidah et al,. 2003). The inactive form prior to this cleavage can be referred to herein as the "inactive", "pro-form", or "unprocessed" form of PCSK9. The C-terminal fragment generated by the autocatalysis event can be referred to herein as the "mature," "cleaved", "processed" or "active" PCSK9. Examples of pro-form and mature PCSK9 isoforms are provided herein, see, e.g. SEQ ID NOs: 1-27. id="p-478" id="p-478"

[00478] As used herein, the "catalytic domain" of PCSK9 refers to the portion of a PCSK9 polypeptide corresponding to positions 153 to 449 of PCSK9, e.g. of SEQ ID NO: 1. As used herein, the "C-terminal domain" of PCSK9 refers to the portion of a PCSK9 polypeptide corresponding to positions 450-692 of PCSK9, e.g., of SEQ ID NO: 1. id="p-479" id="p-479"

[00479] As used herein, a disease or condition "mediated by PCSK9" refers to a disease or condition which is caused by or characterized by a change in PCSK9, e.g. a change in expression level, a change in activity, and/or the presence of a variant or mutation of PCSK9. Non-limiting examples of such diseases or conditions can include, for example, a lipid disorder, hyperlipoproteinemia, hyperlipidemia; dyslipidemia; hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication, type II diabetes, high blood pressure, and a cardiovascular disease or condition. 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-480" id="p-480"

[00480] 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-481" id="p-481"

[00481] As used herein, a disease or condition "mediated by IL6R" refers to a disease or condition which is caused by or characterized by a change (eg, increase) in IL6R, e.g. a change in expression level, a change in activity, and/or the presence of a variant or mutation of IL6R. Nonlimiting examples of such diseases or conditions include, for example, an inflammatory bowel disease (IBD). Crohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation.

Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. For example, moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. Methods of identifying and/or diagnosing such diseases and conditions are well known to medical practitioners of ordinary skill. |00482] A subject at risk of having or developing a disease or condition mediated by IL6R 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. comprising one or more genetic polymorphisms known to predispose to the disease or condition, e.g., comprising a nucleotide sequence encoding an IL6R protein comprising a mutation Asp358Ala and/or VaI3851 Ie in SEQ ID NO: 1, or comprising such an 1L6R. id="p-483" id="p-483"

[00483] 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-484" id="p-484"

[00484] 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 a 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-485" id="p-485"

[00485] Variants ofPCSK9 are provided elsewhere herein. Variants of PCSK9 can include the forms described herein as a, f, c, r. p, m, e h. aj, and q. Sequences of these variants are provided herein, see. e.g. SEQ ID NOs:I-27 and in Table I. 2 or 6. id="p-486" id="p-486"

[00486] hi 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. (00487] The invention contemplates chemically modified synthetic or recombinant ligand (or ligand-encoding nucleotide sequences) derivatives isolated or generated using methods well known in the art. Modified derivatives" 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. id="p-488" id="p-488"

[00488] The invention contemplates chemically modified, synthetic or recombinant ligand (or ligand-encoding nucleotide sequences) derivatives isolated or generated using methods well known in the art. ^Modified derivatives" 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 include insertion variants, deletion variants or substituted variants with substitutions of amino acids, including insertions and substitutions of amino acids and other molecules) that do not normally occur in the peptide sequence that is the basis of the variant, for example but not limited to insertion of ornithine which do not normally occur in human proteins. The term conservative substitution. when describing a polypeptide, refers to a change in the amino acid composition of the polypeptide that does not substantially alter the polypeptide’s activity. For example, a conservative substitution refers to substituting an amino acid residue for a different amino acid residue that has similar chemical properties. Conservative amino acid substitutions include replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, or a threonine with a serine. 100489) 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 follow ing six groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A). Serine (S), Threonine (T): 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q): 4) Arginine (R). Lysine (K); 5) Isoleucine (I). Leucine (L), Methionine (M). Valine (V); and 6) Phenylalanine (F). Tyrosine (Y), Tryptophan (W). (Sec 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-490" id="p-490"

[00490] 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 with S or K, D with N or E, I with L or V, F with Y, S with T or A, R with K, G with N or A, K with R, A with S, K or P. id="p-491" id="p-491"

[00491] In alternative embodiments, one can also select conservative amino acid substitutions encompassed suitable for amino acids on the interior of a protein or peptide, for example one can use suitable conservative substitutions for amino acids is on the interior of a protein or peptide (i.e. the amino acids are not exposed to a solvent), for example but not limited to. one can use the following conservative substitutions: where Y is substituted with F. T with A or S, I with L or V. W with Y. M with 1.. N with D. G with A. T with A or S. D with N. ] 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-492" id="p-492"

[00492] As used herein an antibody" includes an IgG (eg, IgG 1, 2, 3 or 4), IgM, IgA. IgD or IgE or antigen-specific antibody fragments thereof (including, but not limited to, a Fab, F(ab')2, Fv, disulphide linked Fv, scFv, single domain antibody, closed conformation multispecific antibody; disulphide-linked 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. [00493] 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-494" id="p-494"

[00494] 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 antigem An antibody fragment can comprise an antibody or a polypeptide comprising an antigen-binding domain of an antibody. In some embodiments, an antibody fragment can comprise a monoclonal antibody or a polypeptide comprising an antigenbinding domain of a monoclonal antibody. For example, an antibody can include a heavy (H) chain variable region (abbreviated herein as VI I), 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 Wild! 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 or 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, human antibodies, humanized antibodies, chimeric antibodies, and the like. id="p-495" id="p-495"

[00495] As used herein, antibody variable domain refers to the portions of the light and heavy chains of antibody molecules that include amino acid sequences of Complementarity Determining Regions (CDRs: ie.. CDR1. CDR2. and CDR3), and Framework Regions (FRs). VH refers to the variable domain of the heavy chain. VL refers to the variable domain of the light chain. According to the methods used in this invention, the amino acid positions assigned to CDRs and FRs may be defined according to Kabat (Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987 and 1991)) or according to 1MGT nomenclature. id="p-496" id="p-496"

[00496] 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. (00497] 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-498" id="p-498"

[00498] The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions" (FR" or "FW"). The extent of the framework region and CDRs has been precisely defined (see, 1MGT or Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition. U.S. Department of Health and Human Services, NIH Publication No. 91-3242. and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917: which are incorporated by reference herein in their entireties). Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FRL CDR1, FR2, CDR2, FR3, CDR3, FR4. id="p-499" id="p-499"

[00499] 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 CH 1 domains; (iv) an Fv fragment consisting of the VL and VII domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546; which is incorporated by reference herein in its entirety), which consists of a VH or VL domain; and (vi) an isolated complementarity determining region (CDR) that retains specific antigen-binding functionality. 100500] 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, HCDRI and 2) or CDRs 1-3 of a variable domain of an antibody (eg, FICDRsl-3). In an example, the antibody binding site is provided by a single variable domain (eg, a VH or VL domain). In another example, the binding site comprises a VH/VL pair or two or more of such pairs. id="p-501" id="p-501"

[00501] As used herein, the term "specific binding" refers to a chemical interaction between two molecules, coinpounds, 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 a diagnostic test the specific binding of a ligand can distinguish between two variant 1L6R 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." id="p-502" id="p-502"

[00502] Additionally, and as described herein, a recombinant human(ized) antibody can be further optimized to decrease potential immunogenicity, while maintaining functional activity, for therapy in humans. In this regard, functional activity means a polypeptide capable of displaying one or more known functional activities associated with a recombinant antibody or antibody reagent thereof as described herein. Such functional activities include, e.g. the ability to bind to a target molec ule, id="p-503" id="p-503"

[00503] 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. |00504] 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, IL6R, 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-505" id="p-505"

[00505] 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 ofthe presence ofthe 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 VH323*04. Rs56069819 is depicted in Figure 4 and SEQ ID NO: 39, which demonstrate the Ί ->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-506" id="p-506"

[00506] As used herein, "determine' or "determining refers to ascertaining, e.g.. by a quantitative or qualitative analysis. As used herein, "lias been determined can refer to ascertaining on the basis of previously obtained information or simultaneously obtained information. |00507] In some aspects of all embodiments of the invention selecting can include automation such as a computer implemented software program that upon input ofthe relevant data such as ethnicity or a panel of SNP data can make the determination based on the instructions set forth herein. id="p-508" id="p-508"

[00508] As used herein, "assaying" refers to assessing, evaluating, quantifying, measuring, or characterizing an analyte, e.g., measuring the level of an analyte in a sample, identifying an analyte, or detecting the presence or absence of an analyte in a sample. In some embodiments, assaying refers to detecting a presence or absence of the analyte of interest. In some embodiments, assaying refers to quantifying an amount of an analyte, e.g.. providing a measure of concentration or degree of analyte abundance. In some embodiments, assaying refers to enumerating the number of molecules of analyte present in a sample and/or specimen, e.g.. to determine an analyte copy number. id="p-509" id="p-509"

[00509] 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, tvapically three or more, different target sequences, e.g. on two or more variants of PCSK9 or IL6R. or PCSK9 or II.6R and an additional target. A multiplex analysis typically includes analysis of 19-50: 10-100: 10-1000. 105000. 10-10000 reactions in a multiplex format, such as a multiwall, an array, or a multichannel reaction. id="p-510" id="p-510"

[00510] 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. id="p-511" id="p-511"

[00511] 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 abovementioned samples. The term "test sample" or "biological sample" also includes untreated or pretreated (or pre-processed) biological samples. For the analysis of nucleic acids, the biological sample should typically comprise at least one cell comprising nucleic acids. id="p-512" id="p-512"

[00512] The test sample can be obtained by removing a sample of cells from a subject, but can also be accomplished by using previously isolated cells (e.g. isolated at a 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. |005131 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 pretreatment 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 (issue. The frozen sample can be thawed before employing methods, assays and systems described herein. After thawing, a frozen sample can be centrifuged before being subjected to methods, assays and systems described herein. In some embodiments, the test sample is a clarified test sample, for example, by centrifugation and collection of a supernatant comprising the clarified test sample. In some embodiments, a test sample can be a pre-processed test sample, for example, supernatant or filtrate resulting from a treatment selected from the group consisting of centrifugation, filtration, thawing, purification, and any combinations thereof, in some embodiments, the test sample can be treated with a chemical and/or biological reagent. Chemical and/or biological reagents can be employed to protect and/or maintain the stability of the sample, including biomolecules (e.g.. nucleic acid and protein) therein, during processing. One exemplary reagent is a protease inhibitor, which is generally used to protect or maintain the stability of protein during processing. The skilled artisan is well aware of methods and processes appropriate for pre-processing of biological samples required for determination of the level of an expression product as described herein. |00514] 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-515" id="p-515"

[00515] 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-516" id="p-516"

[00516] The term ’’allele-specific amplification" refers to a reaction (e.g., PCR reaction) in which at least one of the primers (e.g., allele-speci fic 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-517" id="p-517"

[00517] 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-518" id="p-518"

[00518] 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 method s/pl at forms include Massively Parallel Signature Sequencing (Lynx Therapeutics); 454 pyro-sequencing (454 Life Sciences/ Roche Diagnostics); solid-phase, reversible dye-terminator sequencing (Solexa/Illumina): SOLiD technology (Applied Biosystems); Ion semiconductor sequencing (ION Torrent); DNA nanoball sequencing (Complete Genomics); and technologies available from Pacific Biosciences, Intelligen Bio-systems, Oxford Nanopore Technologies, and Helicos Biosciences. 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/1 Nature. 2008. vol. 26, No. 10. 1 135-1145: Mardis. "The 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. 201 1. 1 1 (3):333-43: Zhang et al., "The impact of next-generation sequencing on genomics", J Genet Genomics. 2011,38(3):95-109; (Nyren, P. et al. Anal Biochem 208: 17175 (1993): Bentley, D. R. Curr Opin Genet Dev 16:545-52 (2006); Strausberg, R. L., 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. 6.91 1,345: US Pub. Nos. 2006/0252077; 2007/0070349; and 20070070349: which are incorporated by referene herein in their entireties). id="p-519" id="p-519"

[00519] 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-520" id="p-520"

[00520] 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 slop 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. [00521| 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. |005221 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. |00523] Multiple compositions can be administered separately or simultaneously. Separate administration refers to the two compositions being administered at different times, e.g. at least 10. 20, 30, or 10-60 minutes apart, or 1.2. 3, 4, 5, 6. 7, 8. 9, 10, 12 hours apart. One can also administer compositions at 24 hours apart, or even longer apart. Alternatively, two or more compositions can be administered simultaneously, e.g. less than 10 or less than 5 minutes apart. Compositions administered simultaneously can, in some aspects, be administered as a mixture, with or without similar or different time release mechanism for each of the components. id="p-524" id="p-524"

[00524] As used herein, "contacting" refers to any suitable means for delivering, or exposing, an agent to at least one complex, enzyme, or cell. Exemplary delivery methods include, but are not limited to, direct delivery to cell culture medium, perfusion, injection, or other delivery method well known to one skilled in the art. id="p-525" id="p-525"

[00525] 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-526" id="p-526"

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

[00527] 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. [00528] 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-529" id="p-529"

[00529] 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 (MEV ACOR™, 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. [005301 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-531" id="p-531"

[00531] Some subjects are, or become, resistant to anti-TNF alpha treatment. As used herein, "resistant to anti-TNF alpha treatment" or "reduced responsiveness to anti-TNF alpha treatment" or similar refers to a subject exhibiting a statistically significantly lower response to the administration of an anti-TNF alpha treatment as compared to a reference level, t he 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. 100532] 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-533" id="p-533"

[00533] In some embodiments, detectable labels can include labels that can be detected by spectroscopic, photochemical, biochemical, immunochemical, electromagnetic, radiochemical, or chemical means, such as fluorescence, chemifluoresence, or chemiluminescence, or any other appropriate means. The detectable labels used in the methods described herein can be primary labels (where the label comprises a moiety that is directly detectable or that produces a directly detectable moiety) or secondary labels (where the detectable label binds to another moiety to produce a detectable signal, e.g., as is common in immunological labeling using secondary and tertiary antibodies). The detectable label can be linked by covalent or non~covalent means to the reagent, Alternatively, a delectable label can be linked such as by directly labeling a molecule that achieves binding to the reagent via a ligand-receptor binding pair arrangement or other such specific recognition molecules. Detectable labels can include, but arc not limited to radioisotopes, bioluminescent compounds, chromophores, antibodies, chemiluminescent compounds, fluorescent compounds, metal chelates, and enzymes. [00534) In other embodiments, the detectable label can be a fluorescent compound. When the fluorescently label is exposed to light of the proper wavelength, its presence can then be detected due to fluorescence. In some embodiments, a detectable label can be a fluorescent dye molecule, or fluorophore including, but not limited to fluorescein, phycoerythrin, phycocyanin, o-phthaldehyde, fluorescamine, Cy3™, Cy5™, allophycocyanine, Texas Red, peridenin chlorophyll, cyanine, tandem conjugates such as phycoeiythrin-Cy51M, green fluorescent protein, rhodamine, fluorescein isothiocyanate (FJTC) and Oregon Green1 M, rhodamine and derivatives (e.g., Texas red and tetrarhodimine isothiocynate (TRITC)), biotin, phycoerythrin, AMCA, CyDyes™, 6carboxyfhiorescein (commonly known by the abbreviations FAM and F), b-carboxy^kTJ'A?hexachlorofluorescein (HEX), 6-carboxy-4,,5,-dichloro-2\7’-dimethoxyfltiorescein (JOE or J), Ν,Ν,Ν’,Ν -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 1 10; cyanine dyes, e.g. Cy3, Cy5 and Cy7 dyes; coumarins, e.g umbelliferone; benzimide dyes, e.g.

Hoechst 33258; phenanthridine dyes, e.g. Texas Red; ethidium dyes; acridine dyes; carbazole dyes; phenoxazine dyes; porphyrin dyes; polymethine dyes, e.g. cyanine dyes such as Cy3? Cy5. etc: BODIPY dyes and quinoline dyes. In some embodiments, a detectable label can be a radiolabel including, but not limited to 3H, 125L ?:,S. 14C, 22P, and 3T. 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. In some embodiments, a detectable label is a chemiluminescent label, including, but not limited to lucigenin, luminol, luciferin, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester. In some 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. 100535) In some embodiments, reagents can also be labeled with a detectable lag. 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 l)2Eu, 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-536" id="p-536"

[00536] 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 saies/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. 100537] 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. [00538] As used herein, a buffer'1 refers to a chemical agent that is able to absorb a certain quantity of acid or base without undergoing a strong variation in pH. 100539J 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. |00540] As used herein, "instructions" refers to a display of written, printed or graphic matter on the immediate container of an article, for example the written material displayed on a vial containing a pharmaceutically active agent, or details on the composition and use of a product of interest included in a kit containing a composition of interest. Instructions set forth the method of the treatment as contemplated to be administered or performed. id="p-541" id="p-541"

[00541] 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. 100542] As used herein, classification of a subject, e.g.. classification of the subject’s ancestry refers to determining if the subject has biological ancestors who originated in a particular geographical area, and are therefore likely to have particular genetic variants found in the populations which have historically occupied that area. Classification can comprise, e.g. obtaining information on the subject’s family, interviewing the subject or a family member regarding their biological family’s ancestry, and/or genetic testing. Classification can be on the basis used for the 1000 Genomes Project, as will be familiar to the skilled person in the art. In some embodiments, the subject can be classified as being of a particular ancestry if at least the subject's genome comprises a substantial number of different alleles in common with other humans of that ancestry (eg, determined by reference to the 1000 Genomes Project database), for example, at least 10, 20, 30, 40, 50 or 100 or more alleles in common. Abbreviations for particular ancestral groups are provided in Table 12. id="p-543" id="p-543"

[00543] The term statistically significant" or significantly" refers to statistical significance and generally means a two standard deviation (2SD) or greater difference. id="p-544" id="p-544"

[00544] 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%. |00545] As used herein the term ’’comprising or ’’comprises is used in reference to compositions, methods, and respective component(s) thereof, that are essential to the method or composition, yet open to the inclusion of unspecified elements, whether essential or not. [005461 The term consisting oPr 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-547" id="p-547"

[00547] 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-548" id="p-548"

[00548] 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. (00549) 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 0-91 1910-19-0); Robert S. Porter ct 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 1-5608L569-8) and Current Protocols in Protein Sciences 2009. Wiley Intersciences, Coligan et al., eds. id="p-550" id="p-550"

[00550] 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-Liss; 5th edition (2005), Animal Cell Culture Methods (Methods in Cell Biology, Vol. 57, Jennie P. Mather and David Barnes editors. Academic Press, 1st edition, 1998) which are all incorporated by reference herein in their entireties. id="p-551" id="p-551"

[00551] Other terms are defined herein within the description of the various aspects of the invention. id="p-552" id="p-552"

[00552] AH 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. id="p-553" id="p-553"

[00553] The description of embodiments ofthe disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts of the above references and application to provide yet further embodiments of the disclosure. Moreover, due to biological functional equivalency considerations, some changes can be made in protein structure without affecting the biological or chemical action in kind or amount. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims. id="p-554" id="p-554"

[00554] 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 ofthe 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-555" id="p-555"

[00555] It will be understood that particular configurations, aspects, examples, clauses and embodiments described herein are shown by way of illustration and not as limitations ofthe invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine study, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims. All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are hemin 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. [00556| 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 [00557 J Any part of this disclosure may be read in combination with any other part of the disclosure, unless otherwise apparent from the context. id="p-558" id="p-558"

[00558] 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-559" id="p-559"

[00559] The present invention is described in more detail in the following non limiting Examples. [00560] 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-TOl ligand to target the TOI in the human to treat or prevent said disease or condition.

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

In an alternative 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: 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 Υλ 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: 1, wherein the antibody comprises a C domain encoded by a human CH, Cl 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 Clerminal domain comprising said mutation in SEQ ID NO: I. 2. The method of paragraph 1, wherein before step (a) the ligand has been or is determined as being capable of specifically binding lo said TOI variant. 3. The method of paragraph 1 or 2, comprising determining that the human is positive for the TOI polymorphic variant optionally wherein the step of determining comprises determining that the human is positive fora 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 TOI 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 tola) 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 TOI 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. fhe 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. 17. 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 9-17, 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 at 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 of the preceding paragraphs, wherein the ligand is an antibody, antibody fragment or an affibody. 22. I‘he 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 ofless 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 ofless 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 ofless 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 ofless 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 TOl-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 TOl-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.

. 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. 1. 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 than 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 Jess 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%. 8. 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 any 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 microRNA. 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 1 to about 15% or from 1 to I 5%. 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 TOJ 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 TOI 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-561" id="p-561"

[00561] The present invention is described in more detail in the following non limiting Examples. id="p-562" id="p-562"

[00562] The invention addresses the need to treat humans having naturally-occurring rarer natural 1L6R SNPs, alleles, genotypes and phenotypes (rarer protein forms). In this respect, the invention provides a method of treating or reducing the risk of an IL6R-mediated disease or condition in a human in need thereof comprising a. selecting a human comprising a nucleotide sequence encoding said 1L6R protein comprising said Asp358Ala or Val385He in SEQ ID NO: 78; and b. administering to said human an antibody or antibody fragment that specifically binds an JL6R amino acid sequence encoded by said nucleotide sequence comprised by the human. id="p-563" id="p-563"

[00563] In an example, step (a) comprises selecting a human comprising an 1L6R protein encoded by the nucleotide sequence. |00564] In an example, the antibody or antibody fragment specifically binds said IL6R amino acid sequence. In an example, the antibody or antibody fragment binds a second IL6R protein comprising an amino acid sequence encoded by a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val385He in SEQ ID NO: 78. In an example, the antibody comprises a VH domain derived from the recombination of a human VH gene segment, human D gene segments and a human JI 1 segment, the VI1 gene segment being as defined herein. id="p-565" id="p-565"

[00565] In an example, the human has been determined to comprise the nucleotide sequence. In an example, the human has been determined to comprise an IL6R encoded by the nucleotide sequence. In an example, the method further comprises the step of determining that the human comprises the nucleotide sequence. [00566| In an example, the determining step is performed before administration of the antibody to the human. In an example, the method further comprises the step of determining that the human comprises an IL6R encoded by the nucleotide sequence. In an example, the determining step is performed before administration of the antibody to the human. In an example, the step of determining comprises assaying a biological sample from the human for said nucleotide sequence. |00567] Additional Tailoring of Ligands to Genotype and/or Phenotype of the Human Patient [00568| 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. e.g.. lL6Rs. The term TOI" used elsewhere herein encompasses human PCSK9 and/or 1L6R. Additionally or alternatively (and as further illustrated in the non-limiting Examples below), an optional aspect of the invention provides for matching of other features of the ligand to the patient’s genotype or phenotype. In this respect, for example, the invention includes the ability to match amino acid sequence variation in a human patient to one or more ligand sequences or domains outside of the binding sites. For example, where the ligand comprises or consists of a human TOI, e.g. IL6Rbinding antibody or an anti-human TOI, e.g., IL6R receptor (eg, gp 130) 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) arc 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. id="p-569" id="p-569"

[00569] 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.2011.406: Development of Antidrug Antibodies Against Adalimumab and Association With Disease Activity and Treatment Failure During Long-term Follow-up’’, GM Bartelds el aL The authors concluded that results of this study showed that development of antidrug antibodies was associated with a negative outcome of adalimumab treatment in human RA patients. It was reported that not only did patients with 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 of the anti-adalimumab antibody-positive patients developed these antibodies in the first 28 weeks of treatment and that the presence of anti-adalimumab antibodies substantially influenced serum adalimumab concentrations. (00570] Ί his HAHA theme is. therefore, a significant concern and this has been considered by the regulatory authorities, l or example, the European Medicines Agency (EMA) has issued a Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use (available on the World Wide Web at wvvw.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128688.pdf; EMA/CHMP/BMWP/86289/2010. addendum to 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-antibody drug occurrence and effects. |00571] The present aspect of the invention, by more closely tailoring the ligand itself (as well as its specificity) to the patient, helps to address these considerations when designing and administering anti-human TOI, e.g., IL6R medicines for treating, reducing the risk of, and/or preventing human IL6R-related diseases and conditions. id="p-572" id="p-572"

[00572] 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 and/or inflammatory 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-573" id="p-573"

[00573] 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 ofhuman VH, D and JH gene segments or human VE 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 (a5) an antibody variable domain comprising said first amino acid polymorphism or (b*) an antibody constant domain comprising said first amino acid polymorphism.

In an example, the first gene segment is any of the 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 and possible inclusion in one or more claims herein. 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 cany out said assay.

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

. The ligand, method, use. kit or composition of any one of clauses 1 io 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 IGHGI *01 gene segment and said first segment of (a) is an IGHG1 *01 gene segment.

For example, the first and second SNPs of the genome are comprised by an IGHG2*01 gene segment and said first segment of (a) is an IGHG2*01 gene segment. 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 I. 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 VX SNP. 12. The ligand, method, use, kit or composition of any one of clauses 1 to 1 1, 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 TOL e.g..

II AR, variants as disclosed herein, for example, with a KD of InM or less (eg. 100 or 1 OpM 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 WO20I3041844, 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 Fcfused human TOI, e.g., IL6R 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 Fcfused human TOI, e.g.. IL6R. receptor) comprises a human gamma heavy chain CHI domain encoded by a CH I 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 I to 16), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Refused human TOL e.g., IL6R 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. Ihe ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 1 7), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fcfused human TOI, e.g., 1L6R 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. 19. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses 1 to 18), wherein the ligand (eg, comprising or consisting of an antibody or fragment or an Fcfused human TOI, e.g., IL6R 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 Refused human TOI. e.g., 1L6R 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 IGHG1 *01 gamma-1 heavy chain constant region. 24. The ligand, method, use, kit or composition of any one of clauses 16 to 20, w herein ligand comprises a human 1GHG2*O1 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*O1 nucleotide sequence. 27. The ligand, method, use, kit or composition of clause 24, wherein the human has been or is genotyped as positive for human IGHG2*01 nucleotide sequence. 28. The ligand, method, use, kit or composition of any one of clauses 16 to 24. wherein the human has been or is phenotyped as positive for said gamma heavy chain constant domain, CH 1. CU2. 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 IGHG 1*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*0l gamma heavy chain constant domain. CH I. CH2. CH3. CH4 or Fc.

. The method or use of any one of clauses 16 to 24 and 26 to 29. comprising genotyping the human as positive for said gamma heavy chain constant region nucleotide sequence, eg, positive for said gamma heavy chain constant domain, CHI, CH2, CH3, CH4 or Fc nucleotide sequence; positive for said human 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. CHI, CH2. CH3, CH4 or Fc nucleotide sequence. 1. The method or use of any one of clauses 16 to 24 and 26 to 30, comprising phenotyping the human as positive for said gamma heavy chain constant region, eg, positive for said gamma heavy chain constant domain, CHI, CH2, CH3, CH4 or Fc; positive for said human IGHG 1*01 gamma heavy chain constant domain, CH 1, CH2, CH3, CH4 or Fc; or positive for said human IGHG2*01 gamma heavy chain constant domain. CHI, CH2, CH3, CH4 or Fc. id="p-574" id="p-574"

[00574] Examples ofTailored Ligands The inventor analysed amino acid variability and distribution amongst large representative human samples. The result of the analysis for antibody gene segments is shown in Tables 4 and 9. |00575) In a first example, the inventor identified the possibility of addressing the rarer IGH-gamma-l SNPs 204D (observed cumulative frequency of 0.296) and 206L (observed cumulative frequency of 0.283) individually or in combination. These residues are part of the CH3 domain, and as such they form part of antibody Fc regions. Thus, matching of these CH3 variations with the patient is especially beneficial for reasons as discussed above. Thus, this example provides aspects set out in the following clauses. 32. The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses to 3 1), wherein the ligand (eg. comprising or consisting of an antibody or fragment or an Fcfused TOI receptor) comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 4 or a Leu corresponding to position 206 of SEQ ID NO: 4 and wherein the genome of the human comprises a gamma-1 heavy chain constant region nucleotide sequence that encodes such an Asp or Leu or the human expresses antibodies comprising human gamma-1 constant regions comprising such an Asp or Leu.

The skilled person will be familiar with techniques for determining genome sequences of a human, eg, by using a sample containing genomic DNA and/or RNA, sequencing and comparing using bioinformatics or other computer tools to compare the sampled sequence with sequences of human alleles (eg, as shown in the IMGT, 100 genomes or other database as disclosed herein). In an example, the sample is a blood or saliva or cheek swab sample. 33. The ligand, method, use. kit or composition of clause 32.wherein the ligand comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 81 and a Leu corresponding to position 206 of SEQ ID NO: 81. 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 IGHGI *01 gamma-1 heavy chain constant region, eg, an Fc, CHI, CH2 and/or CH3 domain encoded by human IGHGI *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 IGHGI *01 nucleotide sequence or the human expresses antibodies comprising human constant domains encoded by a human IGHGI*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 IGHGI *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: 104. 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 14, 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 IGHG 1*01: or comprises a human IGHG 1*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 IGHG 1 *01 region ; or a human IGHG 1 *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-576" id="p-576"

[00576] In a second 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, 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 3 1), 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: 83, an Asn corresponding to position 75 of SEQ ID NO: 83, a Phe corresponding to position 76 of SEQ ID NO: 83, a Val corresponding to position 161 of SEQ ID NO: 83 and an Ala corresponding to position 257 of SEQ ID NO: 83; 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: 83, an Asn corresponding to position 75 of SEQ ID NO: 83, a Phe corresponding to position 76 of SEQ ID NO: 83 and optionally (ii) a Val corresponding to position 161 of SEQ ID NO: 83 and/or an Ala corresponding to position 257 of SEQ ID NO: 83; 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: 83 and an Ala corresponding to position 257 of SEQ ID NO: 83 and optionally (ii) an amino acid selected from the group consisting of a Pro corresponding to position 72 of SEQ ID NO: 83. an /\sn corresponding to position 75 of SEQ ID NO: 83 and a Phe corresponding to position 76 of SEQ ID NO: 83; and w'herein 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. w'herein the ligand comprises a human IGHG2*01 gamma-2 heavy chain constant region, eg, an Fc, CHI, CH2 and/or CH3 domain encoded by human IGHG2*01. 49. fhe ligand, method, use. kit or composition of any one of clauses 45 to 48. wherein the genome of the human comprises a human IGHG2*0l nucleotide sequence or the human expresses antibodies comprising human constant domains encoded by a human IG1 IG2*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: 104. 52. The ligand, method, use, kit or composition of any one of clauses 45 to 51, wherein the human is of European, African American, or European American ancestry. 53. The ligand, method, use, kit or composition of any one of clauses 45 to 52, wherein the human has been or is genotyped as positive for one, more or all of said Pro. Asn. Phe, Val and Ala. 54. The ligand, method, use. kit or composition of any one of clauses 45 to 53, wherein the human has been or is genotyped as positive for human IGHG2*01. 55. The ligand, method, use, kit or composition of any one of clauses 45 to 54. wherein the human has been or is phenotyped as positive for a human IGHG2*01 CHI. 56. The ligand, method, use. kit or composition of any one of clauses 45 to 55. wherein the human has been or is phenotyped as positive fora human 1GHG2*OI 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 fora 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 ail 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 1GHG2*O1 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. [00577( 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 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: 93 or a Cys corresponding to position 87 of SEQ ID NO: 93; 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: 93 and a Cys corresponding to position 87 of SEQ ID NO: 93. 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: 105. 66. The ligand, method, use, kit or composition of any one of clauses 61 to 65. w herein 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 JKgene segment is IGKJ2*01 (SEQ ID NO: 100). 67. The ligand. method, use, kit or composition of any one of clauses 61 to 66, wherein the human has been or is phenotyped as positive for said Val and/or Cys. 68. The ligand, method, use, kit or composition of any one of clauses 61 to 67, wherein the human has been or is genotyped as positive for human IGKC*01. 69. The ligand, method, use. kit or composition of any one of clauses 61 to 68. wherein the human has been or is phenotyped as positive for a human ]GKC*01 domain. 70. The method or use of any one of clauses 61 to 69, comprising selecting a said human whose genome comprises a codon(s) encoding said Val and/or Cys; or comprises human IGKC*01. 100 71. The method or use of any one of clauses 61 to 70, comprising selecting a said human whose phenotype comprises such a Val and/or Cys; or comprises a human IGKC*0l domain. 72. The ligand, method, use, kit or composition of any one of clauses 61 to 71, wherein the human expresses antibodies comprising human kappa constant domains comprising such a Val and Cys, eg, expresses human IGKC*0l constant domains. (00578] 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 I c fused TOI receptor) comprises a human 1GLC2*O1 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. 74. The ligand, method, use, kit or composition of clause 73, wherein the antibody comprises light chains that comprise SEQ ID NO: 105. 75. The ligand, method, use. kit or composition of clause 73 or 74, w herein the human has been or is genotyped as positive for human IGI..C2*01. 76. The ligand, method, use, kit or composition of any one of clauses 73 to 75, wherein the human has been or is phenotyped as positive for a human IGLC2*01 domain. 77. The method or use of any one of clauses 73 to 76. comprising selecting a said human whose genome comprises human 1GLC2*O1. 78. The method or use of any one of clauses 73 to 77. comprising selecting a said human whose phenotype comprises a human IGLC2*01 domain. 79. The ligand, method, use, kit or composition of any one of clauses 73 to 78, wherein the human expresses antibodies comprising human lambda IGLC2*01 constant domains. id="p-579" id="p-579"

[00579] 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 35 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 101 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 I -18*01; or (ii) IGVH 1-46*01 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.

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) IGHV3-9*01 and the genome of the human comprises a human IGHV3-9*0l nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human 1GHV3-9*O1; or (ii) IGHV3-7*01and the genome of the human comprises a human IGHV3-7*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV3-7*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*0L 82. I'he ligand, method, use, kit or composition of clause 80 or 8 I. wherein the antibody or fragment comprises heavy chains that comprise SEQ ID NO: 104 or 106. 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 IGHV 1-1 8*01 or IGVHI-46*01.

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 IGHV3-9*01 or IGHV3-7*01. 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 IGHVI-1 8*01 or IGVH 1-46*01. 102 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 IGHV3-9*01 or 1GHV3-7*O I. (00580] In a sixth example, the inventor addressed human light chain variable region variation. Thus, this example provides aspects set out in the following clauses. 85. The ligand, method, use. kit or composition of the invention (eg, according to any one of clauses I 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 IGK V4-1 *01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination ofhuman IGKV4-1 *01; (ii) IGLV2-14*01 and the genome of the human comprises a human 1GLV2-I4*O1 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination ofhuman IGLV2-14*01; or (iii) IGKV1-13*02 and the genome of the human comprises a human IGKV113*02 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination ofhuman 1GKV1-13*02.

The ligand, method, use, kit or composition of the invention (eg, according to any one of clauses I 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) IGK V1-12*01and the genome of the human comprises a human IGKV 1-12*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination ofhuman IGKVLI2*0): or(ii) 1GKV3-1 1*01 and the genome of the human comprises a human 1GKV3-1 1*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV3-1 1*01. 86. The ligand, method, use, kit or composition of clause 85, wherein the antibody comprises light chains that comprise SEQ ID NO: 105 or 107. 87. The ligand, method, use, kit or composition of clause 85 or 86, wherein the antibody or fragment comprises a light chain variable domain derived from recombination of a human Vk gene segment and a human Jk gene segment, wherein the Jk gene segment is IGKJ2*01 (SEQ ID NO: 100) or IGKJ4*0l (SEQ ID NO: 102). 103 88. The ligand, method, use, kit or composition of any one of clauses 85 to 87, wherein the human has been or is genotyped as positive for said selected VL gene segment, eg, positive for human IGKV4-l*01, IGLV2-I4*O1 or IGKVE13*02. 89. The method or use of clause 88, comprising genotyping the human as positive for said selected VL gene segment, eg, genotyping the human as positive for human IGKV4-I *01, IGLV2-14*01 or IGKVl-13*02.

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 IGKV1-12*01 or IGKV311*01. 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 TOL e.g., human 1L6R that comprises a mutation Asp358Ala or Val3 851 Ie in SEQ ID NO: 78 with a dissociation constant (Kd) of InM or less as determined by SPR, (eg, 100, 10 or IpM or less). |00581] In an embodiment of the invention, there are provided methods as per the following clauses:- 1. A method of treating or reducing the risk of an IL6R-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 an IL6R protein that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78; wherein 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 (i) a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109 and wherein said human comprises a VH gene segment encoding a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109, or the human expresses VH domains that comprise a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109; or (ii) a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 111 and wherein said human comprises a VH gene segment encoding a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 1 1 1 or the human expresses VH domains that comprise a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 111; and wherein said human comprises a nucleotide sequence encoding said 1L6R protein comprising said Asp358AIa or Val3851le in SEQ ID NO: 78. 104 In an example, said ligand has been determined to specifically bind an IL6R protein that comprises a mutation Asp358Ala or Val3851 le in SEQ ID NO: 78.

In an example, said IL6R protein comprises a mutation Asp358Ala in SEQ ID NO: 78.

In an example, said IL6R protein comprises a mutation Val385He in SEQ ID NO: 78. 2. A method of treating or reducing the risk of an IL6R-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 an IL6R protein that comprises a mutation Asp358Ala or Val3851lc in SEQ ID NO: 78; wherein the ligand comprises a VH domain derived from the recombination of a human VH gene segment, a human D gene segment and a human JH segment, the human VH gene segment comprising (a) T at nucleotide number 86 shown in SEQ ID NO: 84 and wherein said human comprises a VH gene segment comprising T at nucleotide number 86 shown in SEQ ID NO: 84; or (b) C at nucleotide number 272 shown in SEQ ID NO: 84 and wherein said human comprises a VI I gene segment comprising C at nucleotide number 272 shown in SEQ ID NO: 84; and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val.385Hc in SEQ ID NO: 78. 3. The method of any preceding clause, wherein each said human VH gene segment comprises SEQ ID NO: 108. 4. The method of any preceding clause, wherein each said human VH gene segment comprises SEQ ID NO: 1 10.

. The method of any preceding clause, wherein said VH domain is derived from the recombination of human VH segment 1GHV3-9*O1, a human D gene segment and a human JH segment. 6. The method of any preceding clause, wherein said VH domain comprises the FW3 sequence of SEQ ID NO: 111. 105 7. The method of any preceding clause, wherein the VH gene segment comprised by said human is a germ line VH gene segment. 8, The method of any preceding clause, wherein the ligand comprises a human gamma-1 heavy chain comprising said VH domain and a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 and a Leu at position 206 shown in SEQ ID NO: 81 and wherein said human comprises an IGHGI*01 human heavy chain constant region gene segment. 9. The method of any preceding clause, wherein the antibody or fragment comprises an 1GHG1 *01 human heavy chain constant region.

. The method of any preceding clause, wherein the human is of AMR, ASN or EUR ancestry.

For example, the human is of CHB, CHS, JPT, CEU or FIN ancestry; These ancestries have very high (greater than 85%, for example greater than 90% or even 100%) cumulative frequencies for the SNP (FW3 SNP) and thus the ligand of the invention is well suited to treating or preventing a human IL6R-mediated disease or condition in such a human. 11. 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. 12. The method of any preceding clause, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78 and/or an IL6R protein comprising said mutation Asp358AIa and/or Val385Ile in SEQ ID NO: 78. 13. The method of any preceding clause, comprising the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385He and/or an IL6R protein comprising said mutation Asp358Ala and/or Val3851le, optionally, wherein the determining step is performed before administration of the antibody to the human. 14. The method of clause 13, wherein the step of determining comprises assaying a biological sample from the human fora nucleotide sequence encoding a IL6R protein comprising said mutation 106 Asp358Ala and/or Val385Ile in SEQ ID NO: 78.

. The method of clause 14, 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 IL6R protein comprising said mutation Asp358Ala and/or Va 13851le in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78. thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78. 16. The method of clause 14, 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. 17. The method of clause 14 or 16, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 18. The method of any preceding clause, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the 1L6R protein comprising said mutation Asp358Ala or Val3851le in SEQ ID NO: 78. optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. 19. The method of any preceding clause, wherein said human is or has been further determined to be substantially resistant to an anti-TNF alpha treatment.

In any embodiment herein an anti-TNF alpha treatment is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®). certolizumab pegol (eg, Cimzia®). golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate. 107 . The method of any preceding clause, wherein said human is receiving or has received an antiTNF alpha treatment or has reduced responsiveness to an anti-TNF alpha treatment. 21. The method of any preceding clause, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment. 22. The method of any preceding clause, w herein said disease or condition is an inflammatory disease or condition. 23. 1'he method of any preceding clause, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Crohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 24. The method of any preceding clause, wherein said human has been diagnosed w ith at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-hosl disease (GvHD). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis. Sjorgen’s syndrome, airway inflammation. Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. . fhe 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 inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 108 26. The method of any preceding clause, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736. 27. The method of any preceding clause, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. [00582) In an embodiment of the invention, there are provided methods as per the following paragraphs:- 1. An anti-IL6R ligand (eg. an antibody or fragment) for treating or reducing the risk of an 1L6Rmediated disease or condition in a human in need thereof, wherein the ligand specifically binds an IL6R protein that comprises a mutation Asp358Ala or Va!3851 le in SEQ ID NO: 78, wherein 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 (i) a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109 and wherein said human comprises a VH gene segment encoding a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109, or the human expresses VH domains that comprise a CDR1 comprising a Phe at position 4 shown in SEQ ID NO; 109; or (ii) a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 1 11 and wherein said human comprises a VH gene segment encoding a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 111 or the human expresses VH domains that comprise a FW3 comprising a Thr al position 33 shown in SEQ ID NO: I I 1: and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val3851 le in SEQ ID NO: 78.

In an example, said ligand has been determined to specifically bind an IL6R protein that comprises a mutation Asp358Ala or Va 1385lie in SEQ ID NO: 78 2. An anti-IL6R ligand (eg, an antibody or fragment) for treating or reducing the risk of an IL6Rmediated disease or condition in a human in need thereof, wherein the ligand specifically binds an IL6R protein that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78, wherein the ligand comprises a VH domain derived from the recombination of a human VH gene segment, a human D gene segment and a human JH segment, the human VH gene segment comprising (a) T at nucleotide number 86 shown in SEQ ID NO: 84 and wherein said human 109 comprises a VH gene segment comprising T at nucleotide number 86 shown in SEQ ID NO: 84; or (b) C at nucleotide number 272 shown in SEQ ID NO: 84 and wherein said human comprises a VH gene segment comprising C at nucleotide number 272 shown in SEQ ID NO: 84; and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val385lie in SEQ ID NO: 78.

In an example, said ligand has been determined to specifically bind an 1L6R protein that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78 3. The ligand of any preceding paragraph, wherein each said human VH gene segment comprises SEQ ID NO: 108. 4. The ligand of any preceding paragraph, wherein each said human VH gene segment comprises SEQ ID NO: 1 10.

. The ligand of any preceding paragraph, wherein said VH domain is derived from the recombination of human VH segment 1GHV3-9*O1, a human D gene segment and a human JH segment. 6. The ligand of any preceding paragraph, wherein said VH domain comprises the FW3 sequence of SEQ ID NO: 111. 7, The ligand of any preceding paragraph, wherein the VH gene segment comprised by said human is a germ line VH gene segment. 8. The ligand of any preceding paragraph, wherein the ligand comprises a human gamma· I heavy chain comprising said VH domain and a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 and a Leu at position 206 shown in SEQ ID NO: 81 and wherein said human comprises an IGHG I *01 human heavy chain constant region gene segment. 9. The ligand of any preceding paragraph, wherein the antibody or fragment comprises an IGHG 1*01 human heavy chain constant region.

. The ligand of any preceding paragraph, wherein the human is of AMR, ASN or EUR ancestry. 110 For example, the human is of CHB, CHS, JPT, CEU or FIN ancestry. 11. The ligand of any preceding paragraph, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val38511e in SEQ ID NO: 78; and/or an II 6R protein comprising said mutation Asp358Ala and/or Val38511e in SEQ ID NO: 78. 12. The ligand of any preceding paragraph, comprising the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val3 851 Ie: and/or an 1L6R protein comprising said mutation Asp358Ala and/or Val385 lie, optionally, wherein the determining step is performed before administration of the antibody to the human. 13. The ligand of paragraph 12, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a 1L6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78. 14. The ligand of paragraph 13, 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 1L6R protein comprising said mutation Asp358Ala and/or Vai385lie in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358A)a and/or Va!385He in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78 is present: and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL6R protein comprising said mutation Asp358AJa and/or Va)385He in SEQ ID NO: 78.

. The ligand of paragraph 13, 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.

Ill 16. The ligand of paragraph 13 or 15, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 7. The ligand of any preceding paragraph, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385)le in SEQ ID NO: 78.

I 8. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is or has been further determined to be substantially resistant an anti-TNF alpha treatment.

In any embodiment herein "an anti-TNF alpha treatment" is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®). certolizumab pegol (eg, Cimzia®). golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate. 19. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is receiving or has received an anti-TNF alpha treatment or has reduced responsiveness to an antiTNF alpha treatment.

. The ligand of any preceding paragraph, wherein said ligand is for administration to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment. 21. The ligand of any preceding paragraph, wherein said disease or condition is an inflammatory disease or condition. 22. The ligand of any preceding paragraph, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation. Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 112 23. The ligand of any preceding paragraph, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen's syndrome, airway inflammation. Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 24. The ligand of any preceding paragraph, wherein said ligand treats or reduces the risk in said human of at least one condition selected from the group consisting of an inflammatory bowel disease (IBD). Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen's syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

. The ligand of any preceding paragraph, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736 26. T he ligand of any preceding paragraph, wherein said ligand is for intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-583" id="p-583"

[00583] In an embodiment ofthe invention, there are provided methods as per the following clauses:- 1. A method of treating or reducing the risk of an IL6R-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 an IL6R protein that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78; wherein the ligand comprises a VH domain derived from the recombination of human VH segment IGHV3-7*0l, a human D gene segment and a human JH segment, and wherein said human comprises a IGHV3-7*01 VH gene segment or the human expresses VH domains derived from the recombination of human VH segment lGHV3-7*0l, a human D gene segment and a human JH segment; and 113 wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val38511e in SEQ ID NO: 78.

In an example, said ligand has been determined to specifically bind an IL6R protein that comprises a mutation Asp358Ala or Val3851le in SEQ ID NO: 78 2. The method of clause 1. wherein the ligand comprises a human gamma-1 heavy chain comprising said VH domain and a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 and a Leu at position 206 shown in SEQ ID NO: 81 and wherein said human comprises an IGHG1 *01 human heavy chain constant region gene segment. 3. The method of any preceding clause, wherein the antibody or fragment comprises an IGHG 1*01 human heavy chain constant region. 4. 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.

. The method of any preceding clause, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78 and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78. 6. The method of any preceding clause, comprising the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val3851le and/or an IL6R protein comprising said mutation Asp358Ala and/or Val3851 le, optionally, wherein the determining step is performed before administration of the antibody to the human. 7. The method of clause 6, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78. 114 8. The method of clause 7, 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 1L6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78. thereby forming a complex when at least one nucleotide sequence encoding the 1L6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78 is present: and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78. 9. The method of clause 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.

. The method of clause 7 or 9, wherein said biological sample comprises serum, blood, faeces, tissue, a cell· urine and/or saliva of said human. 1. The method of any preceding clause, wherein said human is indicated as heterozygous fora nucleotide sequence encoding the 1L6R protein comprising said mutation Asp358Ala or Val3851 le in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. 12. The method of any preceding clause, wherein said human is or has been further determined to be substantially resistant to an anti-TNF alpha treatment.

In any embodiment herein an anti-TNF alpha treatment" is optionally selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®), certolizumab pegol (eg, Cimzia®), golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or 115 without methotrexate. 13. The method of any preceding clause, wherein said human is receiving or has received an antiTNF alpha treatment or has reduced responsiveness to an anti-TNF alpha treatment. 14. The method of any preceding clause, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment.

. The method of any preceding clause, wherein said disease or condition is an inflammatory disease or condition. 16. The method of any preceding clause, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Crohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen's syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 17. The method of any preceding clause, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bow el disease (IBD). Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis. Sjorgen's syndrome, airway inflammation. Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 18. 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 inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative 116 colitis, Sjorgen’s syndrome, airway inflammation, Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 19. The method of any preceding clause, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736.

. The method of any preceding clause, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-584" id="p-584"

[00584] In an embodiment of the invention, there are provided methods as per the following paragraphs:- 1. An anti-IL6R ligand (eg. an antibody or fragment) for treating or reducing the risk of an IL6Rmediated disease or condition in a human in need thereof, wherein the ligand specifically binds an IL6R protein that comprises a mutation Asp358Ala or Val3851 le in SEQ ID NO: 78, wherein the ligand comprises a VH domain derived from the recombination ofhuman VH segment IGHV3-7*01, a human D gene segment and a human JH segment, and wherein said human comprises a IGHV3-7*01 VH gene segment or the human expresses VH domains derived from the recombination ofhuman VH segment 1GHV3-7*O1, a human D gene segment and a human JH segment; and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val3851le in SEQ ID NO: 78.

In an example, said ligand has been determined to specifically bind an IL6R protein that comprises a mutation Asp358Ala or Val385lle in SEQ ID NO: 78 2. (he ligand of any paragraph L wherein the ligand comprises a human gamma-1 heavy chain comprising said VII domain and a human gamma-] heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 and a Leu at position 206 shown in SEQ ID NO: 8) and wherein said human comprises an IGHGI *01 human heavy chain constant region gene segment. 117 3. The ligand of any preceding paragraph, wherein the antibody or fragment comprises an 1GHGP0I human heavy chain constant region. 4. The ligand of any preceding paragraph, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78; and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78.

. The ligand of any preceding paragraph, comprising the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385He; and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385He, optionally, wherein the determining step is performed before administration of the antibody to the human. 6, The ligand of paragraph 5, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78. 7. The ligand of paragraph 6, 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 IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or VaI3851 Ie in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL6R protein comprising said mutation Asp358Ala and/or Val3851 Ie in SEQ ID NO: 78. 8. The ligand of paragraph 6, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic 118 acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format, 9. The ligand of paragraph 6 or 8, wherein said biological sample comprises serum, blood, faeces, 5 tissue, a cell, urine and/or saliva of said human.

. The ligand of any preceding paragraph, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or VaI385He in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising 10 the nucleotide sequence of SEQ ID NO: 79. or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ilc in SEQ ID NO: 78. 11. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that 15 is or has been further determined to be substantially resistant an anti-TNF alpha treatment, In any embodiment herein "an anti-TNF alpha treatment" is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg. Humira®). certolizumab pegol (eg, Cimzia®). golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate, 20 12. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is receiving or has received an anti-TNF alpha treatment or has reduced responsiveness to an antiTNF alpha treatment. 13. The ligand of any preceding paragraph, wherein said ligand is for administration to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment. 14. The ligand of any preceding paragraph, wherein said disease or condition is an inflammatory disease or condition.

. The ligand of any preceding paragraph, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, 119 ulcerative colitis, Sjorgen's syndrome, airway inflammation, Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 16. The ligand of any preceding paragraph, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD). Chrohn's disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen's syndrome, airway inflammation. Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 17. The ligand of any preceding paragraph, wherein said ligand treats or reduces the risk in said human of at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen's syndrome, airway inflammation. Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 18. The ligand of any preceding paragraph, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736. 19. The ligand of any preceding paragraph, wherein said ligand is for intravenous or subcutaneous administration and/or is comprised in an injectable preparation. |00585] In an embodiment of the invention, there are provided methods as per the following clauses:- 1. A method of treating or reducing the risk of an IL6R-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 an JL6R protein that comprises a mutation Asp358Ala or Val3851le in SEQ ID NO: 78; 120 wherein the ligand comprises a Vk domain derived from the recombination of human Vk segment IGKV1-12*01 and a human Jk segment, and wherein said human comprises a IGKV 1-12*01 Vk gene segment or the human expresses Vk domains derived from the recombination of human Vk segment IGKV 1-12*01 and a human Jk segment; and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Va 13851le in SEQ ID NO: 78.

In an example, said ligand has been determined to specifically bind an IL6R protein that comprises a mutation Asp358AIa or Val385Ile in SEQ ID NO: 78 2. The method of clause 1, wherein the ligand comprises a human kappa chain comprising said Vk domain and a human kappa chain constant region that comprises a Val at position 84 shown in SEQ ID NO: 93 and a Cys shown in SEQ ID NO: 93 and wherein said human comprises an IGKC*01 human kappa chain constant region gene segment. 3. The method of any preceding clause, wherein the antibody or fragment comprises an IGKC*01 human kappa chain constant region. 4. 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.

. The method of any preceding clause, wherein the human has been determined to comprise the nucleotide sequence that encodes an IE6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78 and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ue in SEQ ID NO: 78. 6. The method of any preceding clause, comprising the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile and/or an IL6R protein comprising said mutation Asp358Ala and/or Val3851le, optionally, wherein the determining step is performed before administration of the antibody to the human. 7. The method of clause 6, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL6R protein comprising said mutation 121 Asp358Ala and/or Val3 85 lie in SEQ ID NO: 78. 8. I’he method of clause 7, 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 IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the 1L6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78 is present; and delecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises (he IL6R protein comprising said mutation Asp358Ala and/or Val3851 le in SEQ ID NO: 78. 9. The method of clause 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.

. The method of clause 7 or 9, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 1. The method of any preceding clause, wherein said human is indicated as heterozygous fora nucleotide sequence encoding the IL6R protein comprising said mutation A.sp358Ala or Val385He in SEQ ID NO: 78. optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79. or said human is indicated as homozygous for a nucleotide sequence encoding the 1L6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. 12. The method of any preceding clause, wherein said human is or has been further determined to be substantially resistant to an anti-TNF alpha treatment.

In any embodiment herein an anti-TNF alpha treatment" is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®), certolizumab pegol (eg, Cimzia®). golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate. 122 13. The method of any preceding clause, wherein said human is receiving or has received an antiTNF alpha treatment or has reduced responsiveness to an anti-TNF alpha treatment. 14. The method of any preceding clause, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment.

. The method of any preceding clause, wherein said disease or condition is an inflammatory disease or condition. 16. The method of any preceding clause, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD). Crohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis. Sjorgen’s syndrome, airway inflammation. Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 7. The method of any preceding clause, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation. Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 18. 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 inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 123 19. The method of any preceding clause, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736.

. The method of any preceding clause, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. (00586) In an embodiment of the invention, there are provided methods as per the following paragraphs:- 1. An anti’IL6R ligand (eg, an antibody or fragment) for treating or reducing the risk of an IL6Rmediated disease or condition in a human in need thereof, wherein the ligand specifically binds an IL6R protein that comprises a mutation Asp358Ala or Val3851 Ie in SEQ ID NO: 78. wherein the ligand comprises a Vk domain derived from the recombination of human Vk segment 1GK V1 -12*01 and a human Jk segment, and wherein said human comprises a IGKVI-12*01 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; and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val38511e in SEQ ID NO: 78.

In an example, said ligand has been determined to specifically bind an IL6R protein that comprises a mutation Asp358Ala or VaL385Ile in SEQ ID NO: 78 2. The ligand of any paragraph 1, wherein the ligand comprises a human kappa chain comprising said Vk domain and a human kappa chain constant region that comprises a Val at position 84 shown in SEQ ID NO: 93 and a Cys shown in SEQ ID NO: 93 and wherein said human comprises an iGKC*01 human kappa chain constant region gene segment. 3. The ligand of any preceding paragraph, wherein the antibody or fragment comprises an IGKC*01 human kappa chain constant region. 4. The ligand of any preceding paragraph, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val38511e in SEQ ID NO: 78; and/or an IL6R protein comprising said mutation Asp358Ala 124 and/or Val385He in SEQ ID NO: 78.

. The ligand of any preceding paragraph, comprising the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Va 13851le; and/or an IL6R protein comprising said mutation Asp358Ala and/or Val3851lc. optionally, wherein the determining step is performed before administration of the antibody to the human. 6. The ligand of paragraph 5. wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a 1L6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78. 7. The ligand of paragraph 6, wherein the assay ing 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 1L6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the 1L6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78. 8. Tiie ligand of paragraph 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. 9. The ligand of paragraph 6 or 8. wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human.

. The ligand of any preceding paragraph, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or 125 Val385He in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the 1L6R protein comprising said mutation Asp358Ala or Val385He in SEQ ID NO: 78. 1. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is or has been further determined to be substantially resistant an anti-TNF alpha treatment.

In any embodiment herein "an anti-TNF alpha treatment" is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®), certolizumab pegol (eg, Ciinzia®). golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate. 12. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is receiving or has received an anti-TNF alpha treatment or has reduced responsiveness to an antiTNF alpha treatment. 13. The ligand of any preceding paragraph, wherein said ligand is for administration to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment. 14. The ligand of any preceding paragraph, wherein said disease or condition is an inflammatory disease or condition.

. The ligand of any preceding paragraph, wherein said disease or condition is selected from the group consisting of an inflammatory bow'd disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD), asthma, adult respiratory' distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 16. The ligand of any preceding paragraph, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn's disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen's syndrome, airway inflammation. 126 Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 17. The ligand of any preceding paragraph, wherein said ligand treats or reduces the risk in said 5 human of at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, alopic dermatitis, systemic lupus erythematosus and coronary heart disease. 18. The ligand of any preceding paragraph, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736. 19. The ligand of any preceding paragraph, wherein said ligand is for intravenous or subcutaneous administration and/or is comprised in an injectable preparation. 127 id="p-587" id="p-587"

[00587] Jn an embodiment of the invention, there are provided methods as per the following clauses:- I. A method of treating or reducing the risk of an lL6R-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 an IL6R protein that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78; wherein the ligand comprises a Vk domain derived from the recombination of a human Vk segment and a human .Ik segment, the human Vk segment encoding (i) a CDR3 comprising a Pro at position 7 shown in SEQ ID NO: I 1 3 and wherein said human comprises a Vk gene segment encoding a CDR3 comprising a Pro at position 7 shown in SEQ ID NO: I 13, or the human expresses Vk domains that comprise a CDR3 comprising a Pro at position 7 shown in SEQ ID NO: 1 13; or (ii) a FW3 comprising a Ser at position 15 shown in SEQ ID NO: 11 5 and wherein said human comprises a Vk gene segment encoding a FW3 comprising a Ser at position 15 shown in SEQ ID NO: 115 or the human expresses Vk domains that comprise a FW3 comprising a Ser at position 15 shown in SEQ ID NO: 1 15; and wherein said human comprises a nucleotide sequence encoding said 1L6R protein comprising said Asp358Ala or Val385Ile in SEQ ID NO: 78.

In an example, said ligand has been determined to specifically bind an IL6R protein that comprises a mutation Asp358Ala or Val3851ie in SEQ ID NO: 78 2. A method of treating or reducing the risk of an IL6R-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 an IL6R protein that comprises a mutation Asp358Ala or Val3851le in SEQ ID NO: 78; wherein the ligand comprises a Vk domain derived from the recombination of a human Vk gene segment and a human Jk segment, the human Vk gene segment comprising (a) T at nucleotide number 199 shown in SEQ ID NO: 98 and wherein said human comprises a Vk gene segment comprising T at nucleotide number 199 shown in SEQ ID NO: 98; or (b) C at nucleotide number 284 shown in SEQ ID NO: 98 and wherein said human comprises a Vk gene segment comprising T at nucleotide number 284 shown in SEQ ID NO: 98; and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said 128 Asp358Ala or Val385lle in SEQ ID NO: 78. 3. The method of any preceding clause, wherein each said human Vk gene segment comprises SEQ ID NO: 1 12. 4. The method of any preceding clause, wherein each said human Vk gene segment comprises SEQ ID NO: 1 14.

. The method of any preceding clause, wherein said Vk domain is derived from the recombination of human Vk segment IGKV3-1 1*01 and a human Jk segment. 6. The method of any preceding clause, wherein said Vk domain comprises the FW3 sequence of SEQ ID NO:1 15. 7. The method of any preceding clause, wherein the Vk gene segment comprised by said human is a germline Vk gene segment. 8. The method of any preceding clause, wherein the ligand comprises a human kappa chain comprising said Vk domain and a human kappa chain constant region that comprises a Val al position 84 shown in SEQ ID NO: 93 and a Cys shown in SEQ ID NO: 93 and wherein said human comprises an IGKC*0) human kappa chain constant region gene segment.. 9. The method of any preceding clause, wherein die antibody or fragment comprises an 1GKC*O) human heavy chain constant region.

. 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.

I. The method of any preceding clause, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Va!385Ile in SEQ ID NO: 78 and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ue in SEQ ID NO: 78. 12. The method of any preceding clause, comprising the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile, optionally, wherein the determining step is performed before administration of the 129 antibody to the human. 13. The method of clause 12, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL6R protein comprising said mutation Asp358Ala and/or Val385lie in SEQ ID NO: 78. 14. The method of clause 13. 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 IL6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val385lie in SEQ ID NO: 78. thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78 is present: and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the 1E6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78.

. The method of clause 13, 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. 16. The method of clause 13 or 15. wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 7. The method of any preceding clause, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val3851le in SEQ ID NO: 78. optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. 18. The method of any preceding clause, wherein said human is or has been further determined to be substantially resistant to an anti-TNF alpha treatment. 130 In any embodiment herein "an anti-TNF alpha treatment is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®), certolizumab pegol (eg, Cimzia®), golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate. 19. Fhe method of any preceding clause, wherein said human is receiving or has received an antiTNF alpha treatment or has reduced responsiveness to an anti-TNF alpha treatment.

. The method of any preceding clause, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment. 21. The method of any preceding clause, wherein said disease or condition is an inflammatory disease or condition. 22. Fhe method of any preceding clause, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Crohn's disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, grafl-versushost disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 23. The method of any preceding clause, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation. Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 24. 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 inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic 131 dermatitis, systemic lupus erythematosus and coronary heart disease.

. The method of any preceding clause, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736. 26. The method of any preceding clause, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-588" id="p-588"

[00588] In an embodiment ofthe invention, there are provided methods as per the following paragraphs:- I. An anti-IL6R ligand (eg. an antibody or fragment) for treating or reducing the risk of an IL6Rmediated disease or condition in a human in need thereof, wherein the ligand specifically binds an IL6R protein that comprises a mutation Asp358Ala or Val385IIe in SEQ ID NO: 78. 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 CDR3 comprising a Pro at position 7 shown in SEQ ID NO: 113 and wherein said human comprises a Vk gene segment encoding a CDR3 comprising a Pro at position 7 shown in SEQ ID NO: 113, or the human expresses Vk domains that comprise a CDR3 comprising a Pro at position 7 shown in SEQ ID NO: 113: or (ii) a FW3 comprising a Ser at position 1 5 shown in SEQ ID NO: 1 15 and wherein said human comprises a Vk gene segment encoding a FW3 comprising a Ser at position 1 5 shown in SEQ ID NO: 1 I 5 or the human expresses Vk domains that comprise a FW3 comprising a Ser at position 15 shown in SEQ ID NO: 1 15; and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val3851le in SEQ ID NO: 78.

In an example, said ligand has been determined to specifically bind an IL6R protein that comprises a mutation Asp358Ala or Val3 851 Ie in SEQ ID NO: 78 2. An anti-IL6R ligand (eg, an antibody or fragment) for treating or reducing the risk of an IL6Rmediated disease or condition in a human in need thereof, wherein the ligand specifically binds an IL6R protein that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78. wherein the ligand comprises a Vk domain derived from the recombination of a human Vk gene segment and a human Jk segment, the human Vk gene segment comprising (a) T at nucleotide number 199 shown in SEQ ID NO: 98 and wherein said human comprises a Vk gene segment 132 comprising T at nucleotide number 199 shown in SEQ ID NO: 98; or (b) C at nucleotide number 284 shown in SEQ ID NO: 98 and wherein said human comprises a Vk gene segment comprising T at nucleotide number 284 shown in SEQ ID NO: 98; and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val385lie in SEQ ID NO: 78.

In an example, said ligand has been determined to specifically bind an 1L6R protein that comprises a mutation Asp358Ala or Va 1385lie in SEQ ID NO: 78 3. The ligand of paragraph 1 or 2, wherein each said human VII gene segment comprises single nucleotide polymorphism rs 182958807 and/or rs 191612627. 4. The ligand of any preceding paragraph, wherein each said human Vk gene segment comprises SEQ ID NO: 112.

. The ligand of any preceding paragraph, wherein each said human Vk gene segment comprises SEQ ID NO: 114. 6. T he ligand of any preceding paragraph, wherein said Vk domain is derived from the recombination of human Vk segment 1GKV3-11 *01 and a human Jk segment. 7. The ligand of any preceding paragraph, wherein said Vk domain comprises the FW3 sequence of SEQ ID NO: 1 15. 8. The ligand of any preceding paragraph, wherein the Vk gene segment comprised by said human is a germline Vk gene segment. 9. The ligand of any preceding paragraph, wherein the ligand comprises a human kappa chain comprising said Vk domain and a human kappa chain constant region that comprises a Val at position 84 shown in SEQ ID NO: 93 and a Cys shown in SEQ ID NO: 93 and wherein said human comprises an IGKC*01 human kappa chain constant region gene segment..

. The ligand of any preceding paragraph, wherein the antibody or fragment comprises an IGKC*01 human heavy chain constant region. 133 11. The ligand of any preceding paragraph, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78; and/or an IL6R protein comprising said mutation Asp358Ala and/or Val3 85 He in SEQ ID NO: 78. 12. fhe ligand of any preceding paragraph, comprising the step of determining that the human comprises the nucleotide sequence that encodes an 1L6R protein comprising said mutation Asp358Ala and/or Val385lie; and/or an IL6R protein comprising said mutation Asp358Ala and/or VaL3 8511e. optionally, wherein the determining step is performed before administration of the antibody to the human. 13. The ligand of paragraph 12, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78. 14. The ligand of paragraph 14, 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 IL6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val3851 le in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or VaL3851le in SEQ ID NO: 78 is present: and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78. . fhe ligand of paragraph 1 3. 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. 134 16. The ligand of paragraph 13 or 14. wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 17. The ligand of any preceding paragraph, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385lie in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. 18. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is or has been further determined to be substantially resistant an anti-TNF alpha treatment.

In any embodiment herein "an anti-TNF alpha treatment is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®), certolizumab pegol (eg, Cimzia®), golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate. 19. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is receiving or has received an anti-TNF alpha treatment or has reduced responsiveness to an antiTNF alpha treatment.

. The ligand of any preceding paragraph, wherein said ligand is for administration to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment. 21. The ligand of any preceding paragraph, wherein said disease or condition is an inflammatory disease or condition. 22. The ligand of any preceding paragraph, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 135 23. The ligand of any preceding paragraph, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation. Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 24. The ligand of any preceding paragraph, wherein said ligand treats or reduces the risk in said human of at least one condition selected from the group consisting of an inflammatory bowel disease (IBD). Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen's syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

. The ligand of any preceding paragraph, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736. 26. The ligand of any preceding paragraph, wherein said ligand is for intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-589" id="p-589"

[00589] In an embodiment of the invention, there are provided methods as per the following clauses:- 1, A method of treating or reducing the risk of an IL6R-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 an 1L6R protein that comprises a mutation Asp358A)a or Val385He in SEQ ID NO: 78. wherein the ligand comprises a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 ora Leu at position 206 shown in SEQ ID NO: 81 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 an Asp at position 204 shown in SEQ ID NO: 81 or a Leu at position 206 shown in SEQ ID NO: 81 and (ii) a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val3851le in SEQ ID NO: 78.

In an example, said ligand, antibody or antibody fragment has been determined to specifically 136 bind an IL6R protein that comprises a mutation Asp358Ala or Val3851le in SEQ ID NO: 78. 2. The method of clause 1, wherein the ligand comprises a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 and a Leu at position 206 shown in SEQ ID NO: 81. 3. The method of any preceding clause, wherein the ligand comprises a human gamma ! heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 and a Leu at position 206 shown in SEQ ID NO: 81 and wherein said human comprises (i) an IGHGI *01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said IL6R protein comprising said mutation Asp358Ala or Val3 85Ue in SEQ ID NO: 78. 4. The method of clause L 2 or 3, wherein the antibody or fragment comprises an IGHG 1*01 human heavy chain constant region.

. 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. 6. The method of any preceding clause, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Jie in SEQ ID NO: 78 and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ue in SEQ ID NO: 78. 7. The method of any one of clauses 1 to 6, comprising the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile and/or an 1L6R protein comprising said mutation Asp358Ala and/or Val385Ile, 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 a IL6R protein comprising said mutation Asp358Ala and/or Val385Ue in SEQ ID NO: 78. 9. The method of clause 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 1L6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ JD NO: 78 or comprising an antisense 137 sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val385lie in SEQ ID NO: 78 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL6R protein comprising said mutation Asp358A)a and/or Val385He in SEQ ID NO: 78.

. The method of clause 8, wherein the assay ing comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 11. The method of clause 8 or 10, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 12. The method of any preceding clause, w herein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Va!3851 Ie in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the 1L6R protein comprising said mutation Asp358Ala or Val3851le in SEQ ID NO: 78.

I 3. The method of any preceding clause, wherein said human is or has been further determined to be substantially resistant to an anti-TNF alpha treatment.

In any embodiment herein "an anti-TNF alpha treatment'’ is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®), certolizumab pegol (eg, Cimzia®). golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate. 14. The method of any preceding clause, wherein said human is receiving or has received an antiTNF alpha treatment or has reduced responsiveness to an anti-TNF alpha treatment.

. The method of any preceding clause, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment. 138 16. The method of any preceding clause, wherein said disease or condition is an inflammatory disease or condition. 17. The method of any preceding clause, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD). Crohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 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 inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis. Sjorgen’s syndrome, airway inflammation. Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 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 inflammatory bowel disease (IBD). Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. . fhe method of any preceding clause, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736. 21. The method of any preceding clause, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. 139 id="p-590" id="p-590"

[00590] In an embodiment of the invention, there are provided methods as per the following paragraphs:- I. An anti-IL6R ligand (eg, an antibody or fragment) for treating or reducing the risk of an IL6Rmediated disease or condition in a human in need thereof, wherein the ligand specifically binds an 1L6R protein that comprises a mutation Asp358Ala or Val3851le in SEQ ID NO: 78, wherein the ligand comprises a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 or a Leu at position 206 shown in SEQ ID NO: 81 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 an Asp at position 204 shown in SEQ ID NO: 81 or a Leu at position 206 shown in SEQ ID NO: 81 and (ii) a nucleotide sequence encoding said 1L6R protein comprising said Asp358Ala or Val3851le in SEQ ID NO: 78.

In an example, said ligand has been determined to specifically bind an IL6R protein that comprises a mutation Asp358Ala or Va!385He in SEQ ID NO: 78 2. The ligand of paragraph 1, wherein the ligand comprises a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 and a Leu at position 206 shown in SEQ ID NO: 8 I. 3. The ligand of any preceding paragraph, wherein said ligand comprises a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 and a Leu at position 206 shown in SEQ ID NO: 81 and wherein said human comprises (i) an IGHGl*0l human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said IL6R protein comprising said mutation Asp358A!a and/or Val385He in SEQ ID NO: 78. 4. The ligand of paragraph L 2 or 3, wherein the ligand comprises an IGHGI *01 human heavy chain constant region.

. The ligand of any preceding paragraph, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78; and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78. 6. The ligand of any one of paragraphs 1 to 5, comprising the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385lie; and/or an IL6R protein comprising said mutation Asp358Ala and/or 140 Val38511e, optionally, wherein the determining step is performed before administration of the antibody to the human. 7. The ligand of paragraph 6, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL6R protein comprising said mutation Asp358Ala and/or Val3851 le in SEQ ID NO: 78. 8. The ligand of paragraph 7. 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 IL6R protein comprising said mutation Asp358Ala and/or Val385fle in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val385lie in SEQ ID NO: 78 is present: and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78. 9. The ligand of paragraph 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 assay ing is performed in a multiplex format.

. The ligand of paragraph 7 or 9. wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 1. The ligand of any preceding paragraph, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385He in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. 141 12. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is or has been further determined to be substantially resistant an anti-TNF alpha treatment.

In any embodiment herein "an anti-TNF alpha treatment" is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®), certolizumab pegol (eg, Cimzia®), golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate. 13. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is receiving or has received an anti-Ί NF alpha treatment or has reduced responsiveness to an antiTNF alpha treatment. 14. The ligand of any preceding paragraph, wherein said ligand is for administration to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment.

I 5. The ligand of any preceding paragraph, wherein said disease or condition is an inflammatory disease or condition. 16. The ligand of any preceding paragraph, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 7. The ligand of any preceding paragraph, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD). Chrohn's disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation. Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 18. The ligand of any preceding paragraph, wherein said ligand treats or reduces the risk in said human of at least one condition selected from the group consisting of an inflammatory bowel 142 disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis. Sjorgen's syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 19. The ligand of any preceding paragraph, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736.

. The ligand of any preceding paragraph, wherein said ligand is for intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-591" id="p-591"

[00591] In an embodiment of the invention, there are provided methods as per the following clauses:- I. A method of treating or reducing the risk of an IL6R-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 an 1L6R protein that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78, 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: 83, an Asn at position 75 shown in SEQ ID NO: 83. a Phe at position 76 shown in SEQ ID NO: 83, a Val at position 161 shown in SEQ ID NO: 83 and an Ala al position 257 shown in SEQ ID NO: 83 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: 83, Asn at position 75 shown in SEQ ID NO: 83, Phe at position 76 shown in SEQ ID NO: 83, Val at position 161 shown in SEQ ID NO: 83 or Ala at position 257 shown in SEQ ID NO: 83 and (ii) a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val385He in SEQ ID NO: 78. 2. The method of clause I. wherein the ligand comprises a human gamma-2 heavy chain constant region that comprises (i) a Pro at position 72 shown in SEQ ID NO: 83, an Asn at position 75 shown in SEQ ID NO: 83, a Phe at position 76 shown in SEQ ID NO: 83 and optionally (ii) a Val at position 161 shown in SEQ ID NO: 83 and/or an Ala at position 257 shown in SEQ ID NO: 83: 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). 143 Jn an example, said ligand, antibody or antibody fragment has been determined to specifically bind an IL6R protein that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78. 3, The method of any preceding clause, wherein the ligand comprises a human gamma-2 heavy chain constant region that comprises (i) a Val at position 161 shown in SEQ ID NO: 83 and an Ala at position 257 shown in SEQ ID NO: 83 and optionally (ii) an amino acid selected from the group consisting of a Pro at position 72 showm in SEQ ID NO: 83. an Asn at position 75 shown in SEQ ID NO: 83 and a Phe at position 76 shown in SEQ ID NO: 83; 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), 4. The method of clause 1, 2 or 3, wherein the antibody or fragment comprises an IGHG2*0l human heavy chain constant region.

. 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. 6. The method of any preceding clause, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78 and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78. 7. The method of any one of clauses 1 to 6.. comprising the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or VaJ385ile and/or an IL6R protein comprising said mutation Asp358Ala and/or Val3 851le, 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 a IL6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78. 9. The method of clause 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 1L6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78 or comprising an antisense 144 sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL6R protein comprising said mutation Asp358Ala and/or Val3 85 lie in SEQ ID NO: 78.

. The method of clause 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. 11. The method of clause 8 or 10, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 12. The method of any preceding clause, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358A!a or Val385He in SEQ ID NO: 78. optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or VaL385Ile in SEQ ID NO: 78. 13. The method of any preceding clause, wherein said human is or has been further determined to be substantially resistant to an anti-TNF alpha treatment.

In any embodiment herein an anti-TNF alpha treatment" is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®), certolizumab pegol (eg. Cimzia®), golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate. 14. The method of any preceding clause, wherein said human is receiving or has received an antiTNF alpha treatment or has reduced responsiveness to an anti-TNF alpha treatment.

. The method of any preceding clause, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment. 145 16. The method of any preceding clause, wherein said disease or condition is an inflammatory disease or condition. 17. The method of any preceding clause, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Crohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis. Sjorgen’s syndrome, airway inflammation. Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 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 inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis. Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 19. The method of any preceding clause, wherein said antibod)·’ or antibody fragment treats or reduces the risk in said human of al least one condition selected from the group consisting of an inflammatory bowel disease (IBD). Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

. The method of any preceding clause, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736. 21. The method of any preceding clause, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. 146 |00592] In an embodiment of the invention, there are provided methods as per the following paragraphs:- 1. An anti-IL6R ligand (eg, an antibody or fragment) for treating or reducing the risk of an IL6Rmediated disease or condition in a human in need thereof, wherein the ligand specifically binds an IL6R protein that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78, wherein the ligand comprises a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 or a Leu at position 206 shown in SEQ ID NO: 81 and wherein said human comprises (i) an IGHGl*01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-1 heavy chain constant regions comprising an Asp at position 204 shown in SEQ ID NO: 81 or a Leu at position 206 shown in SEQ ID NO: 81 and (ii) a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val3851le in SEQ ID NO: 78.

In an example, said ligand has been determined to specifically bind an IL6R protein that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78 2. The ligand of paragraph 1, wherein the ligand comprises a human gamma-2 heavy chain constant region that comprises (i) a Pro at position 72 shown in SEQ ID NO: 83, an Asn at position 75 shown in SEQ ID NO: 83, a Phe at position 76 shown in SEQ ID NO: 83 and optionally (ii) a Val at position 161 shown in SEQ ID NO: 83 and/or an Ala at position 257 shown in SEQ ID NO:83; 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). 3. Lhe ligand of any preceding paragraph, wherein the ligand comprises a human gamma-2 heavy chain constant region that comprises (i) a Val at position 161 show n in SEQ ID NO: 83 and an Ala at position 257 showm in SEQ ID NO: 83 and optionally (ii) an amino acid selected from the group consisting of a Pro at position 72 shown in SEQ ID NO: 83, an Asn at position 75 shown in SEQ ID NO: 83 and a Phe at position 76 showm in SEQ ID NO: 83; 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). 4. The ligand of paragraph 1,2 or 3, wherein the ligand comprises an IGHG2*01 human heavy chain constant region. 147 . The ligand of any preceding paragraph, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78; and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78. 6. The ligand of any one of paragraphs 1 to 5, comprising the step of determining that the human comprises the nucleotide sequence that encodes an 1L6R protein comprising said mutation Asp358Ala and/or Val385He; and/or an IL6R protein comprising said mutation Asp358AIa and/or Val3 8 5 He. optionally, wherein the determining step is performed before administration of the antibody to the human. 7. The ligand of paragraph 6, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a 1L6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78. 8. The ligand of paragraph 7, 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 IL6R protein comprising said mutation Asp358AIa and/or Val385Ile in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val385lle in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or VaL385Ile in SEQ ID NO: 78 is present: and delecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL6R protein comprising said mutation Asp358Ala and/or Val385llc in SEQ ID NO: 78. 9. The ligand of paragraph 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. 148 . The ligand of paragraph 7 or 9, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 1. The ligand of any preceding paragraph, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the 1L6R protein comprising said mutation Asp358Ala or Val385Ue in SEQ ID NO: 78. 12. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is or has been further determined to be substantially resistant an anti-TNF alpha treatment.

In any embodiment herein an anti-TNF alpha treatment*’ is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg. Humira®). certolizumab pegol (eg, Cimzia®), golimumab (eg, Simponi®). and etanercept (eg, Enbrel®) treatment with or without methotrexate. 13. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is receiving or has received an anti-TNF alpha treatment or has reduced responsiveness to an antiTNF alpha treatment. 14. The ligand of any preceding paragraph, wherein said ligand is for administration to the human separately or simultaneously with methotrexate or an anti-TNF’ alpha treatment.

, The ligand of any preceding paragraph, wherein said disease or condition is an inflammatory disease or condition. 16. The ligand of any preceding paragraph, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn's disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD). asthma, adult respirator}' distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 149 17. The ligand of any preceding paragraph, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD). Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen's syndrome, airway inflammation. Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 8. The ligand of any preceding paragraph, wherein said ligand treats or reduces the risk in said human of at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen's syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 19. The ligand of any preceding paragraph, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736.

, The ligand of any preceding paragraph, wherein said ligand is for intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-593" id="p-593"

[00593] In an embodiment of the invention, there are provided methods as per the following clauses:- 1. A method of treating or reducing the risk of an IL6R-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 an IL6R protein that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78, wherein the ligand comprises a human kappa chain constant region that comprises a Val al position 84 shown in SEQ ID NO: 93 or a Cys at position 87 shown in SEQ ID NO: 93 and wherein said human comprises (i) an IGKC1 *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: 93 ora Cys at position 87 shown in SEQ ID NO: 93 and (ii) a nucleotide sequence encoding said 1L6R protein comprising said Asp358Ala or Val385He in SEQ ID NO: 78.

In an example, said ligand, antibody or antibody fragment has been determined to specifically 150 bind an IL6R protein that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78. 2. The method of clause 1, wherein the ligand comprises a human kappa chain constant region that comprises a Val at position 84 shown in SEQ ID NO: 93 and a Cys al position 87 shown in SEQ ID NO: 93. 3. The method of any preceding clause, wherein the ligand comprises a human kappa constant region that comprises a Val at position 84 shown in SEQ ID NO: 93 and a Cys at position 87 shown in SEQ ID NO: 93 and wherein said human comprises (i) an IGKC^Ol human kappa chain constant region gene segment and (ii) a nucleotide sequence encoding said IL6R protein comprising said mutation Asp358Ala or Val385lle in SEQ ID NO: 78. 4. The method of clause L 2 or 3. wherein the ligand comprises an IGKC1*O1 human kappa chain constant region.

. 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. 6. The method of any preceding clause, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78 and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78. 7. The method of any one of clauses 1 to 6. comprising the step of determining that the human comprises the nucleotide sequence that encodes an 1L6R protein comprising said mutation Asp358Ala and/or Val385lie and/or an IL6R protein comprising said mutation Asp358Ala and/or Val3 85Ue. optionally, wdierein 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 a IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78. 9. The method of clause 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 IL6R protein comprising said mutation Asp358Ala and/or Val3851 Ie in SEQ ID NO: 78 or comprising an antisense 151 sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the 1L6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78.

. The method of clause 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.

] I. 1 he method of clause 8 or 10, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 12. The method of any preceding clause, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val3851le in SEQ ID NO: 78. optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79. or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385lle in SEQ ID NO: 78. 13. The method of any preceding clause, wherein said human is or has been further determined to be substantially resistant to an anti-TNF alpha treatment.

In any embodiment herein an anti-TNF alpha treatment" is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®), certolizumab pegol (eg, Cimzia®). golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate. 14. The method of any preceding clause, wherein said human is receiving or has received an antiTNF alpha treatment or has reduced responsiveness to an anti-TNF alpha treatment.

. The method of any preceding clause, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment. 152 16. The method of any preceding clause, wherein said disease or condition is an inflammatory disease or condition. 17. The method of any preceding clause, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Crohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 8. The method of any preceding clause, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 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 inflammatory bowel disease (IBD). Chrohn's disease, rheumatoid arthritis, psoriasis, bronchiolitis. gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis. Sjorgen’s syndrome, airway inflammation. Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

. The method of any preceding clause, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736. 21. The method of any preceding clause, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. 153 id="p-594" id="p-594"

[00594] In an embodiment of the invention, there are provided methods as per the following paragraphs:- 1. An anti-lL6R ligand (eg, an antibody or fragment) for treating or reducing the risk of an IL6Rmediated disease or condition in a human in need thereof, wherein the ligand specifically binds an IL6R protein that comprises a mutation Asp358Ala or Val3851le in SEQ ID NO: 78, wherein the ligand comprises a human kappa chain constant region that comprises a Val at position 84 shown in SEQ ID NO: 93 or a Cys at position 87 shown in SEQ ID NO: 93 and wherein said human comprises (i) an IGKC1 *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: 93 or a Cys at position 87 shown in SEQ ID NO: 93 and (ii) a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val38511e in SEQ ID NO: 78.

In an example, said ligand has been determined to specifically bind an IL6R protein that comprises a mutation Asp358Ala or Va!3851le in SEQ ID NO: 78 2. The ligand of paragraph 1, wherein the ligand comprises a human kappa chain constant region that comprises a Val at position 84 shown in SEQ ID NO: 93 and a Cys at position 87 shown in SEQ ID NO: 93. 3. The ligand of any preceding paragraph, wherein the ligand comprises a human kappa constant region that comprises a Val at position 84 shown in SEQ ID NO: 93 and a Cys at position 87 shown in SEQ ID NO: 93 and wherein said human comprises (i) an 1GKC*O1 human kappa chain constant region gene segment and (ii) a nucleotide sequence encoding said IL6R protein comprising said mutation Asp358Ala or Va!3851le in SEQ ID NO: 78. 4. The ligand of paragraph 1,2 or 3. wherein the ligand comprises an IGKC1 *01 human kappa chain constant region.

. The ligand of any preceding paragraph, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or VaI3851le in SEQ ID NO: 78; and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78. 6. The ligand of any one of paragraphs 1 to 5, comprising the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation 154 Asp358Ala and/or Val385lie; and/or an IL6R protein comprising said mutation Asp358Ala and/or Val3 8 51 le, optionally, wherein the determining step is performed before administration of the antibody to the human. 7. The ligand of paragraph 6, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a JL6R protein comprising said mutation Asp358Ala and/or Va 1385lie in SEQ ID NO: 78. 8. The ligand of paragraph 7. 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 IL6R protein comprising said mutation Asp358Ala and/or Val385IIe in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val3851 le in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78 is present: and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78. 9. The ligand of paragraph 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. . 1 he ligand of paragraph 7 or 9. wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. ] 1. The ligand of any preceding paragraph, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or 155 Val385Ile in SEQ ID NO: 78. 12. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is or has been further determined to be substantially resistant an anti-TNF alpha treatment.

In any embodiment herein "an anti-TNF alpha treatment" is selected from the group consisting of an infliximab (eg. Remicade®), adalimumab (eg, Humma®), certolizumab pegol (eg, Cimzia®), golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate. 13. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is receiving or has received an anti-TNF alpha treatment or has reduced responsiveness to an antiI NF alpha treatment. 14. The ligand of any preceding paragraph, wherein said ligand is for administration to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment.

. The ligand of any preceding paragraph, wherein said disease or condition is an inflammatory disease or condition. 16. The ligand of any preceding paragraph, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis. psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 7. The ligand of any preceding paragraph, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation. Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 156 18. The ligand of any preceding paragraph, wherein said ligand treats or reduces the risk in said human of at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis. Sjorgen's syndrome, airway inflammation. Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease, 19. The ligand of any preceding paragraph, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736.

. The ligand of any preceding paragraph, wherein said ligand is for intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-595" id="p-595"

[00595] In an embodiment of the invention, there are provided methods as per the following clauses:- 1. A method of treating or reducing the risk of an IL6R-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 an IL6R protein that comprises a mutation Asp358AIa or Va!385Ile in SEQ ID NO: 78. wherein the ligand comprises a human IGLC1 *01 lambda chain constant region and wherein said human comprises (i) a human IGLC I *01 lambda chain constant region gene segment, or the human expresses antibodies comprising human IGLC 1 *01 lambda chain constant regions and (ii) a nucleotide sequence encoding said 1L6R protein comprising said Asp358Ala or Val3 851 Ie in SEQ ID NO: 78.

In an example, said ligand, antibody or antibody fragment has been determined to specifically bind an IL6R protein that comprises a mutation Asp358Ala or Val3851 Ie in SEQ ID NO: 78. 2. 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. 3. The method of any preceding clause, wherein the human has been determined to comprise the nucleotide sequence that encodes an 1L6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78 and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385lle in SEQ ID NO: 78. 157 4. The method of any one of clauses 1 to 3, comprising the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile. optionally, wherein the determining step is performed before administration of the antibody to the human.

. The method of clause 4. wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78. 6. The method of clause 5. wherein the assay ing 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 IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the 1L6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78. 7, The method of clause 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. 8. The method of clause 5 or 7, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 9. The method of any preceding clause, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385He in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79. or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or 158 Val385Ile in SEQ ID NO: 78.

. The method of any preceding clause, wherein said human is or has been further determined to be substantially resistant to an anti-TNF alpha treatment.

In any embodiment herein "an anti-TNF alpha treatment" is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®), certolizumab pegol (eg, Cimzia®), golimumab (eg. Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexate. 1. The method of any preceding clause, wherein said human is receiving or has received an antiTNF alpha treatment or has reduced responsiveness to an anti-TNF alpha treatment. 12. The method of any preceding clause, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment. 13. The method of any preceding clause, wherein said disease or condition is an inflammatory disease or condition. 14. The method of any preceding clause, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Crohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis.

. The method of any preceding clause, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 159 16. 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 inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. ] 7. The method of any preceding clause, wherein the nucleotide sequence comprises SNP rs2228145 10 and/or SNP rs28730736. 22. The method of any preceding clause, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation, f00596] In an embodiment of the invention, there are provided methods as per the following paragraphs;- 1. An anti-IL6R ligand (eg, an antibody or fragment) for treating or reducing the risk of an IL6Rmediated disease or condition in a human in need thereof, wherein the ligand specifically binds an 1L6R protein that comprises a mutation Asp358Ala or Val38511e in SEQ ID NO: 78. wherein the 20 ligand comprises a human IGLC1 *01 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 IGLCP01 lambda chain constant regions and (ii) a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val3851 le in SEQ ID NO: 78.

In an example, said ligand has been determined to specifically bind an IL6R protein that comprises a mutation Asp358Ala or Va 13851le in SEQ ID NO: 78 2. fhe ligand of paragraph I, wherein the human has been determined to comprise the nucleotide 30 sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78; and/or an IL6R protein comprising said mutation Asp358Ala and/or Val3851 le in SEQ ID NO: 78. 3. The ligand of paragraph 1 or 2, comprising the step of determining that the human comprises the 35 nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385He; and/or an IL6R protein comprising said mutation Asp358Ala and/or Val3851le, 160 optional ly, wherein the determining step is performed before administration of the antibody to the human. 4. The ligand of paragraph 3, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL6R protein comprising said mutation Asp358Ala and/or Val385lle in SEQ ID NO: 78.

. The ligand of paragraph 4, 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 IL6R protein comprising said mutation Asp358Ala and/or Val38511e in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78. thereby forming a complex when at least one nucleotide sequence encoding the ILAR protein comprising said mutation Asp358Ala and/or Val3 851 Ie in SEQ ID NO: 78 is present: and detecting the presence or absence of the complex, wherein detecting the presence ofthe complex determines that the human comprises the IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78. 6. The ligand of paragraph 4, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allcle-specific amplification and/or wherein the assaying is performed in a multiplex format. 7. The ligand of paragraph 4 or 6. wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 8. The ligand of any preceding paragraph, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the 1L6R protein comprising said mutation Asp358Ala or Val385lle in SEQ ID NO: 78. 161 9. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is or has been further determined to be substantially resistant an anti-TNF alpha treatment.

In any embodiment herein "an anti-TNF alpha treatment" is selected from the group consisting of an infliximab (eg, Remicade®), adalimumab (eg, Humira®), certolizumab pegol (eg, Cimzia®). golimumab (eg, Simponi®), and etanercept (eg, Enbrel®) treatment with or without methotrexaie.

. The ligand of any preceding paragraph, wherein said ligand is for administration to a human that is receiving or has received an anti-TNF alpha treatment or has reduced responsiveness to an antiTNF alpha treatment. 11. The ligand of any preceding paragraph, wherein said ligand is for administration to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment. 12. The ligand of any preceding paragraph, wherein said disease or condition is an inflammatory disease or condition. 13. The ligand of any preceding paragraph, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IRD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versushost disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis. Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 14. The ligand of any preceding paragraph, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, grafi-versus-host disease (GvHD). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation. Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

. The ligand of any preceding paragraph, wherein said ligand treats or reduces the risk in said human of at least one condition selected from the group consisting of an inflammatory bowel 162 disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. ό. The ligand of any preceding paragraph, wherein the nucleotide sequence comprises SNP rs2228!45 and/or SNP rs28730736. 7. The ligand of any preceding paragraph, wherein said ligand is for intravenous or subcutaneous administration and/or is comprised in an injectable preparation. id="p-597" id="p-597"

[00597] Regimens |00598] A: The invention further provides the following regimens, ligands and kits. 1. A method for treating a human IL6R-mediated disease or condition in a human by targeting a rare variant human IL6R, the method comprising administering to the human a ligand (eg, an antibody or fragment) that has been determined to specifically bind to said IL6Rvariant; wherein the human expresses said 1L6R variant or the genome of the human comprises a nucleotide sequence encoding said 11,6R variant: w herein said human is treated for said disease or condition.

Phe variant IL6R can. for example, be an 1L6R protein that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. In an example, the IL6R comprises a mutation Asp358Ala in SEQ ID NO: 78. In an example, the IL6R comprises a mutation Val385Ile in SEQ ID NO: 78.

In an example, the 1L6R is a a human soluble IL6R.

In an example, the IL6R is a a human cell-suface IL6R.

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

In an embodiment, the method comprises, before said administering, selecting a human comprising said nucleotide sequence encoding the IL6R, wherein the human is said human in clause 1 (eg. la). 2. The method of clause J, comprising before said adminislering the step of determining that the ligand specifically binds to said IL6R, eg, using SPR or ELISA. 3. The method of clause I or 2, wherein the specific binding to said 1L6R is binding with a dissociation constant (Kd) of 1 nM or less, eg, 100, 10 or I pM or less. 4. The method of any of clauses I to 3 (eg, clause la), wherein said disease or condition is an inflammatory disease or condition.

. The method of clause 4 (eg, when dependent from clause la), wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Crohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD). asthma, adult respiratory distress syndrome (ARDS), septic shock, ulc-erative colitis. Sjorgen’s syndrome, airway inflammation. Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

In any embodiment herein, the arthritis is moderate to severe rheumatoid arthritis or Systemic juvenile idiopathic arthritis. 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 an IL6R comprising a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78 and/or a 1L6R protein comprising a mutation Asp358Ala or Val385He in SEQ ID NO: 78. 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 an 1L6R comprising a mutation Asp358Ala or Val3851 Ie in SEQ ID NO: 78 and/or a IL6R protein comprising a mutation Asp358Ala or Val3851 Ie in SEQ ID NO: 78, optionally, wherein the 164 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 IL6R that encodes an 1L6R comprising a mutation Asp358Ala or Val385Jle in SEQ ID NO: 78. 9. The method of clause 8, wherein the assaying comprises contacting the biological sample with al least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding an IL6R protein comprising said mutation Asp358Ala and/or Val3851 le in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358AJa and/or Va)385He in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the . 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.

I 1. The method of any one of clauses 1 to 10. wherein said human is or has been further determined to be substantially resistant to an anti-TNF alpha treatment. 12. The method of any one of clauses 1 to 11, wherein said human is receiving or has received an anti-TNF alpha treatment or has reduced responsiveness to an anti-TNF alpha 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 anti-TNF alpha treatment. 14. The method of any one of clauses 8 to 10, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human.

. The method of any one of clauses 1 to 14, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or 165 Val38511e in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the 1L6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. 16. The method of any one of clauses 1 to 15, wherein said human has been diagnosed with at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation. Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 17. The method of any one of clauses 1 to 16, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 18. The method of any one of clauses 1 to 17, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736. 19. The method of any one of clauses J to 18. wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation.

. A ligand (eg, an antibody or fragment) for use in the method of any one of clauses 1 to 19. wherein the ligand specifically binds the IL6R. 21. A kit comprising the ligand of clause 20 and instructions for carrying out the method of any one of clauses 1 to 19. 166 id="p-599" id="p-599"

[00599] B: The invention further provides the following regimens, ligands and kits. 1. A method of treating or reducing the risk of an IL6R-mediated disease or condition 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 IL6R ligand (eg, an antibody or fragment) to said human, wherein (i) the ligand has been determined to specifically bind to an IL6R protein that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78: (ii) the human expresses said 1L6R or the genome of the human comprises a nucleotide sequence encoding said 1L6R and (iii) the human has received or is receiving an anti-1NF alpha treatment for treating or reducing the risk of an IL6R-mediated disease or condition; wherein the initial treatment comprises the administration of a single or multiple doses of the ligand to the human: b. Determining to (i) terminate anti-TNF alpha treatment (ii) keep the human off anti-TNF alpha treatment: or (iii) reduce anti-TNF alpha treatment after said initial treatment period; and c. Continuing to administer the ligand to said patient after said time period has expired, thereby treating or reducing the risk of an IL6R-mediated disease or condition 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 IL6R, 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 ora 167 year. 2. The method of clause I, wherein the human has or is suffering from an anti-TNF alpha treatmentassociated side effect.

An example of a side effect is selected from the group consisting of hepatitis B infection in a carrier of the virus, an allergic reaction, a nervous system condition, a blood condition, heart failure, an immune reaction (eg, lupus-like syndrome), a liver condition, and new or worsening psoriasis. In an example, the treatment is adalimumab treatment. 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 an anti-TNF alpha treatment-associated side effect. 4. The method of clause 2 or 3. comprising, after step (b) (eg, during step (¢)) determining that the side effect has lessened.

. 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 oven 60 or over, 65 or over, or 70 or over). 6. The method of any one of clauses 1 to 5, wherein step (c) comprises determining to increase the doses of said ligand to be administered after said initial treatment period and administering said increased doses to said human. 7. The method of any one of clauses 1 to 6, wherein step (b) comprises determining that the human is intolerant or refactory to treatment by an anti-TNF alpha treatment. 8. The method of any one of clauses 1 to 7, wherein the initial treatment comprises the administration of infliximab (eg, Remicade®), adalimumab (eg, Humira®). certolizumab pegol (eg, Cimzia®). golimumab (eg, Simponi®), or etanercept (eg. Enbrel®) treatment, with or without methotrexate, 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 infliximab (eg, Remicade®), adalimumab (eg, Humira®), certolizumab pegol (eg. Cimzia®), golimumab (eg, Simponi®), or etanercept (eg, Enbrel®) treatment during step (c). 168 . The method of any one of clauses 1 to 9, comprising increasing (ie, increasing compared to the initial treatment dose) the ligand dose during step (c). 1. The method of any one of clauses 1 to 10, wherein the human has received high dose anti-TNF alpha treatment prior to the initial treatment, and wherein step (c) comprises administering a lower (eg. a medium or low) dose anti-TNF alpha treatment in addition to said ligand.

The skilled person is familiar with the meaning of high, medium and low dose treatments (and how to determine according to each patient, eg, the patient’s body mass). 12. The method of any one of clauses 1 to 10, wherein the human has received medium dose antiTNF alpha treatment prior to the initial treatment and wherein step (c) comprises administering a lower (eg, a low) dose statin treatment or no anti-TNF alpha in addition to said ligand. 13. The method of any one of clauses 1 to 10, wherein the human has received low dose anti-TNF alpha treatment prior to the initial treatment, and wherein step (c) comprises administering no anti-TNF alpha 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 IL6R, eg. using SPR or ELISA.

. The method of any one of clauses I to 14, wherein the specific binding to said IL6R is binding with a dissociation constant (Kd) of 1 nM or less, eg, 100, 10 or 1 pM or less. 16. The method of any of clauses I to 15. wherein the human is at risk of or suffering from a condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis. Sjorgen’s syndrome, airway inflammation. Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

I 7. 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 an IL6R comprising a mutation Asp358Ala or Val3851le in 169 SEQ ID NO: 78 and/or an 1L6R protein comprising a mutation Asp358Ala or Val3851le in SEQ ID NO: 78. 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 an IL6R comprising a mutation Asp358Ala or Val3851le in SEQ ID NO: 78 and/or an IL6R protein comprising a mutation Asp358Aia or Val3851 le in SEQ ID NO: 78, 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 IL6R that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. 21. The method of clause 20, 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 IL6R protein comprising said mutation Asp358Ala and/or Val385Ue in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val385Ue in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the 116R protein comprising said mutation Asp358Ala and/or Val385lie in SEQ ID NO; 78 is present: and delecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 78. 22. The method of clause 20 or 2 k wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 23. The method of any one of clauses 1 to 22, wherein said human is or has been further determined to be substantially resistant to an anti-TNF alpha (eg, adalimubab, infliximab or etanercept) treatment. 170 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 1L6R protein comprising said mutation Asp358Ala or Val385He in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. 26. The method of any one of clauses 1 to 25, wherein said human has been diagnosed with al least one condition selected from the group consisting of an inflammaloiy bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen's syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease. 27. The method of any one of clauses 1 to 26, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736. 28. The method of any one of clauses I lo 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 lo 28, wherein the ligand specifically binds the IL6R.

. A kit comprising the ligand of clause 29 and instructions for carrying out the method of any one of clauses ! to 28. id="p-600" id="p-600"

[00600] In an example of any aspect of the invention, the ligand (eg, antibody or fragment, eg, sarilumab) is administered to the human at a two-weekly dose of from 75 to 200mg (eg, from 150 to 1200mg administered once or twice over a two-week period, eg, 150mg or 200mg once a week or once every other week). In an example, the ligand is for such administration to the human. |00601| 171 |00602] is 12083537 |00603] With reference to any configuration, aspect, embodiment or example of the invention described herein, in an embodiment the human comprises an IL6R nucleotide sequence comprising mutation 2913A>G (SEQ ID NO: 79) (ie, wherein the human comprises SNP rsl 2083537). In an example, the human has been genotyped for said mutation. In an example, the method comprises genotyping the human for said mutation (eg, prior to the administration of the ligand). In an example, the human is suffering from or at risk of suffering from asthma. In an example, the ligand or method is for treating, preventing, or reducing the risk of asthma in the human. In an example, the ligand or method treats or reduces the risk of asthma in the human. |00604] Thus, in an alternative to any configuration, aspect, embodiment or example of the invention herein, instead of the phrase wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val3 851 ie in SEQ ID NO: 78", it can instead be read wherein said human comprises a nucleotide sequence encoding an IL6R protein, wherein the nucleotide sequence comprises a mutation 2913A>G in SEQ ID NO: 79" or "wherein said human comprises a nucleotide sequence encoding an IL6R protein, wherein the nucleotide sequence comprises SNP rsl 2083537" or ^wherein the genome of said human comprises SNP rs 12083537". Additionally, in an example, said IL6R protein comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. id="p-605" id="p-605"

[00605] Some embodiments of the technology described herein can be defined according to any of the following numbered paragraphs: I. 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. 2. The method of paragraph I, wherein before step (a) the ligand has been or is determined as being capable of binding to said TOI 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 172 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 1Ό1 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%.

. The 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 1 5%. 8. The method of any preceding paragraph, 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% 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 ΓΌ1 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. 173 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. 6. 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 TOl-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. 18. I he 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 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.

. The ligand of any one of paragraphs 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%. fhe ligand of any one of paragraphs 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%. 21. The 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 of less than 50% and/or having a total human genotype frequency of less than 50%. 22. The ligand of any one of paragraphs I 7 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 174 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% and/or having a total human genotype frequency of more than 50%. 23. The ligand of any one of paragraphs I 7 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. The ligand of any one of paragraphs I 7 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 175 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 genoty pe frequency of less than 50%, or to a peptide thereof that comprises an amino acid variation from the corresponding sequence encoded by the TOl-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 TOl-binding fragment or derivative of the isolated antibody. 1. 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 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 ofless 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 ofless 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 1 7 to 27 or an antibody, fragment or derivative produced by the method of any one of paragraphs 29 to 31. 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 ofless 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 ofless than 50% and/or a total human genotype frequency ofless than 50%, in the manufacture of a medicament for targeting said ΊΌ1 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 176 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. 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 ofless than 50% and/or having a total human genotype frequency ofless 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 1 7 to 27 to cany 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 ofless than 50% and/or a total human genotype frequency ofless 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 TOI is encoded by a nucleotide sequence having a cumulative human allele frequency from I to 10% and/or a total human genotype frequency from 1 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 TOI 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 177 (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 carry 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. 178 55. The ligand, method, use, kit or composition of paragraph 54, wherein the first SNP is a CH 1, CH2, CH3 orCH4 gene segment SNP and/or the second SNP is a CHI, CH2, CH3 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 ΙΟρΜ 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), w herein 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). 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 CH 1 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 CH 1 nucleotide sequence and/or the human expresses antibodies comprising said human gamma CH I 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 179 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 Cl 13 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 CFI4 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. 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 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. 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 IGHG I *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 to 69. wherein the human has been or is genotyped as positive for 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 IGHG 1*01 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 phenolyped as positive for said gamma heavy chain constant domain, CHI, CH2, CH3, CH4 or Fc. 180 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 fora human IGHG2*01 gamma heavy chain 5 constant domain, CH 1, 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] *01 gamma heavy chain constant region. CHI. 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. 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, CI 13, CH4 or Fc; positive for said human 1GHG1 *01 gamma heavy chain constant domain, CHI, CH2, CH3, CH4 or Fc; or positive for said human 1GHG2*O1 gamma heavy chain constant domain, CHI, 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 ofthe 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-J 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. The ligand, method, use, kit or composition of paragraph 77 or 78.wherein the genome ofthe 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 1GHG1*OI gamma-1 heavy chain constant region, eg, an Fc. CHI, CH2 and/or CH3 domain encoded by human IGHG 1*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 IGHG 1 *01 nucleotide sequence or the human expresses 181 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 IGHG 1*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 lo 83, wherein the human is of European ancestry. 85. fhe 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 IGHG 1 *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 IGHG 1*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 IGHG! *01 CH3. 89. The method or use of any one of paragraphs 77 to 88. comprising selecting a said human w hose phenotype comprises said Asp and/or Leu: a human IGHG 1*01 region ; or a human IGHG1 *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 182 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 JD 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 Fc, CH 1, CFI2 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*01 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*0I. 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. The 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 IGHG2*01 CH 1. 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 1GHG2*O1 CH3. 183 103. 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 IGHG2*01 CHI, CI 12 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 CHLCH2 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 Val 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 I 06, 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 IGKC*01 kappa light chain constant region. ] 10. 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.

I 1 1. Fhe 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*01 (SEQ ID NO: 57).

I 12. The ligand, method, use, kit or composition of any one of paragraphs 106 to 1 11, 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 1 12, wherein the human has been or is genotyped as positive for human IGKC*01. 184 114. 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 lGKC*01 constant domains. 118. 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 1GLC2*OI 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*0l constant regions. 19. The ligand, method, use, kit or composition of paragraph 1 1 8, wherein the antibody comprises light chains that comprise SEQ ID NO: 64. 120. The ligand, method, use, kit or composition of paragraph 11 8 or 119. wherein the human has been or is genotyped as positive for human IGLC2*01. 121. The ligand, method, use, kit or composition of any one of paragraphs 1 18 to 120. wherein the human has been or is phenotyped as positive for a human IGLC2*01 domain. 122. The method or use of any one of paragraphs 118 to 212, comprising selecting a said human whose genome comprises human IGLC2*01.

I 23. The method or use of any one of clauses 73 to 77. comprising selecting a said human whose phenotype comprises a human IGEC2*01 domain. 124. J he ligand, method, use. kil or composition of any one of paragraphs 108 lo 123. wherein the human expresses antibodies comprising human lambda IGLC2*0l 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*O1 and the genome of the human comprises a human IGHV118*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination ofhuman IGHV 1-1 8*01; or (ii) IGVH 1-46*01 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 ofhuman IGHV I-46*01. 185 126. 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, CH3 domain, hinge or Fc encoded by human IGHG2*0L 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 IGHV1-18*01 or 1GVH 1-46*01. 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 IGHV 1-18*01 or IGVH1 -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) IGKV4I *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*0] and the genome of the human comprises a human IGLV2-I4*O1 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGLV2-14*01; or (iii) IGKVl-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 IGKV1-13*O2. 131. The ligand, method, use, kit or composition of paragraph 130, w herein 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 131. 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. 133. The ligand, method, use. kit or composition of any one of paragraphs 130 to 132. w herein the human has been or is genotyped as positive for said selected VL. gene segment, eg, positive for human IGKV4-P0L IGLV2-14*01 or 1GKV 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, IGLV2-14*01 or IGKV1-I3*O2. 135. The ligand, method, use, kit or composition of any preceding paragraph, w'herein 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 IpM or less). 186 136. The ligand, method, use, kit or composition of any preceding paragraph, wherein the TOI is human PCSK9 or human IL-6R.

EXAMPLES [00606) Example 1: Rare PCSK9 Variants id="p-607" id="p-607"

[00607] Proprotein convertase subtilisin kexin type 9 (PCSK9) is a serine protease involved in regulating the levels of the low density lipoprotein receptor (LDLR) protein (Horton et al.. 2007: Seidah and Prat, 2007). In vitro experiments have shown that adding PCSK9 to HepG2 cells lowers the levels of cell surface LDLR (Benjannet et al., 2004; Lagace et al., 2006; Maxwell et al.. 2005; Park et al., 2004), Experiments with mice have shown that increasing PCSK9 protein levels decreases levels of LDLR protein in the liver (Benjannet et al., 2004; Lagace et al., 2006; Maxwell et al., 2005; Park et al., 2004), while PCSK9 knockout mice have increased lex'els of LDLR in the liver (Rashid et al., 2005). Additionally, various human PCSK9 mutations that result in either increased or decreased levels of plasma LDL have been identified (Kotowski et al., 2006; Zhao et al., 2006). PCSK9 has been shown to directly interact with the LDLR protein, be endocytosed along with the LDLR, and coimmunofluoresce with the LDLR throughout the endosomal pathway (Lagace et al., 2006). id="p-608" id="p-608"

[00608] PCSK9 is a prohormone-proprotein convertase in the subtilisin (S8) family of serine proteases (Seidah et al., 2003). Humans have nine prohormone-proprotein convertases that can be divided between the S8A and S8B subfamilies (Rawlings et al., 2006). Furin. PCI/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-like pro- and catalytic domains, and a P domain directly C-terminal to the catalytic domain (Henrich et al., 2003; Tangrea et al., 2002). Based on the amino acid sequence similarity within this subfamily, all seven members are predicted to have similar structures (Henrich et al., 2005), SKI-1 /S1P and PCSK9 are classified in subfamily S8A. Sequence comparisons will) these proteins also suggest the presence of subtilisin-like pro- and catalytic domains (Sakai et al., 1998; Seidah et al., 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-609" id="p-609"

[00609] Prohormone-proprotein convertases are expressed as zymogens and they mature through a multi step process. The function of the pro-domain in this process is 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. 187 id="p-610" id="p-610"

[00610] Autocatalysis of the PCSK9 zymogen occurs between Glnl52 and Seri 53 (VFAQ|SIP (SEQ ID NO: 67)) (Naureckiene et al., 2003), and has been shown to be required for its secretion from cells (Seidah et al., 2003). A second autocatalytic event at a site within PCSK9’s pro-domain has not been observed. Purified PCSK9 is made up of two species that can be separated by non-reducing SDS-PAGE: the pro-domain at 17 Kd. and the catalytic plus C-terminal domains at 65 Kd. PCSK9 has not been isolated without its inhibitory pro-domain, and measurements of PCSK9's catalytic activity have been variable (Naureckiene et al.. 2003; Seidah et al.. 2003). id="p-611" id="p-611"

[00611] In certain embodiments, a PCSK9 polypeptide includes terminal residues, such as. but not limited to, leader sequence residues, targeting residues, amino terminal methionine residues, lysine residues, tag residues and/or fusion protein residues. "PCSK9" has also been referred to as FI 13.

NARC1, HCHOLA3, proprotein convertase subtilisin/kexin type 9, and neural apoptosis regulated convertase 1. The PCSK9 gene encodes a proprotein convertase protein that belongs to the proteinase K subfamily of the secretory subtilase family. The term "PCSK9" denotes both the proprotein and the product generated following autocatalysis of the proprotein. When only the autocatalyzed product is being referred to (such as for an antigen binding protein or ligand that binds to the cleaved PCSK9), the protein can be referred to as the "mature," "cleaved", "processed" or "active" PCSK9. When only the inactive form is being referred to, the protein can be referred to as the "inactive", "pro-form, or "unprocessed" form of PCSK9. The term PCSK9 also encompasses PCSK9 molecules incorporating post-translational modifications of the PCSK9 amino acid sequence, such as PCSK9 sequences that have been glycosylated. PCSK9 sequences from which its signal sequence has been cleaved, PCSK9 sequence from which its pro domain has been cleaved from the catalytic domain but not separated from the catalytic domain (see. e.g.. FIGS. IA and IB of US20 12009381 8A L which is incorporated by reference herein in its entirety). id="p-612" id="p-612"

[00612] fhe 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. id="p-613" id="p-613"

[00613] 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 andUS201 10065902A1; 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 188 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 US2012009381 8A1 and US20110065902A1 to generate antibodies), id="p-614" id="p-614"

[00614] The skilled person will know that SNPs or other changes that translate into amino acid variation can cause variability in activity and/or conformation of human targets to be addressed. This has spawned great interest in personalized medicine where genotyping and knowledge of protein and nucleotide variability is used to more effectively tailor medicines and diagnosis of patients. The invention, therefore, provides for tailored pharmaceuticals and testing that specifically addresses rarer PCSK9 polymorphic variant forms. Such forms or "alleles" (at the nucleotide level), in many of the examples determined by the inventor, comprise multiple changes at the nucleotide and amino acid levels from the corresponding common form nucleotide and amino acids sequences, ie, there are multiple non-synonymous changes at the nucleotide level that translate into multiple corresponding changes in the protein target in humans. id="p-615" id="p-615"

[00615] 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. 100616] 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 w ith 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 w'aste. |00617] 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 the 4 following criteria:- • PCSK9 variants having a cumulative human allele frequency in the range from I to 10%; • PCSK9 variants having a total human genotype frequency in the range from 1 to about 1 5%: 189 • PCSK9 variants found in many different human ethnic populations (using the standard categorisation of the 1000 Genomes Project, which is an accepted standard in the art; see Table 4 below); and • PCSK9 variants found in many individuals distributed across such many different ethnic populations. id="p-618" id="p-618"

[00618] On the basis of these criteria, the inventor identified the variants listed in Table 1 below (excluding form a). id="p-619" id="p-619"

[00619] The inventor's selection included, as a consideration, selection for nucleotide variation that produced amino acid variation in corresponding PC/SK9 forms (ie. non-synonymous variations). as opposed lo silent variations that do not alter amino acid residues in the target protein. 190 Table 1: Human PCSK9 variants distributed over several human ethnic populations & having a total human genotype frequency in the range of 1 to about 15% (a) Amino acid variability, population distributions and frequencies 0.64815 g § £ U h 0.0855 0.0729 0.0292 0.0221 0.0149 | 0.0068 1 0.0045 I 0.0041 0.4506 (0.8457) Hom Freq4 (Het + Hom freq5) 0.009 (0.162) 0.0081 ! (0.1377) 0.009 (0.0324) (0.0441) (0.0225) | (0.0135) | (0.009) 1 (0.0081) 0.395! Het Freq3 0.153 0.1296 0.0234 o 1 0.0225 i i | 0.0135 cr 1 o i 1 4 ; 0.0081 1______L. .................... No. Unique Fops2 C4 cr 939 No. Individs1 180 153 617 29 in O O' £ m X F, I 2 O q A co _r . —< x 2 4 oi Human Populations ASW,YRI,GBR, TSI,CLM,LWK, MXL,JPT,PUR, IBS, FIN,CEU % 02 H 2 c. o c4 2 X Z > q E cc > □ < H j CU ω O Sr £ 5 CO < □ E9 LWK,ASW,YRI CLM ! LWK,ASW,YRI | LWK,ASW,YRI U g U- 00 670E Amino Acid Position & Variation________ 670G x — — 0619 6191’ 4741 474V X _________________ __l X 1 X X X 443 A 443T ! X X 425N 425S X 53A 53V X 46R 19F X Form a Varian t Form u ex E Λ5 191 c £ ο X CO Οβ ’ C <— Ε 3 cd x 4— :> g s— χ Μ— .2 •4—^ ω Ο 4— ,Γ4— Ε ο ,u4-J δ Lg . — <υ .Ε 2* <4ο co c ο σι ο Cu <υ X 4— Ο 4— 3 <Λ Ο 03 Ο 3 Ε 03 αί χ cd C έ Q ο 0β r; 'δ X) E E , P x 4— X 4—· o CD CD ,p £ c GO οβ o X rCD 0β .E c <υ x E □ c X ‘q 03 O .S P < x O Ο Ο Ο X) Ο κ 2 3 Ο ο ο α> C ο 3 (D cu o 3 •3 3 03 0β CD D ο3 27 s to 3 C 3 ' £ 3 > CD X ο co 3 O Οβ & G 3 O r-; 2 σ 3 cX go 3 £ QJ (U X CD X £ CD co 3 3 3 ο δ U. 3 Ο Ο CD 3 — Οβ .Ε 3 CO D ο- ο § 0β Έ ο θ' δ G0 3 X 3 3 Ό CD G ο 3 CD 3 CD CD Q. 3 3 3 3 3 3 Q cd δ δ Ο ο ο ο 3 co 3 ο 3 δ 3 σ' CD > 3 3 Ο ,2 δΊ Ε ο δ Ο ο ο ο ο § δ 0β δ 3 2 3 3 δ’ o’ 3 3 00 >> CD O X 3 'all occurrences of the var r~ o r- δ o 3 C- ο. 1D £2 <υ δ σ’ <υ Cu οβ CD 27 4— Λ 4—' δ 3 σο CD CD 3 cD 3 D CT u .£ ω 3 3 rs > Ό .E <4o 5— (D X E 3 Z C 03 Ε X <υ 2 Έ 3 X Ο Uh ο 3 (D 0β 3 3 Ε 3 X co 3 Ο Οβ ν ο Uh Ο <υ X CO CO 3 Q Οβ n‘ ο Uh Q Ο X, Ο δ Οβ 3 3 3 3 X co 3 Ο 0β ν' ο Ε ο X c 3 δ GO 3 X 3 3 Ό GO CD 3 Ο 3 CD Ο S CD Ql. o 3 CD 00 3 3 E 3 X s 0> CD 3 3 E 3 X > 3 3 E 3 U — CM m 3 3 A \6 co o 192 (b) Nucleotide Sequence Variations of Selected Alleles < < o u o _________________________________________ Nucleotide Position1 1 1:55529187 Ie Variation2 I O ________ Variant ID3 1 rs505151 1 Corresponding Amino Acid Variation 670G X X i ΐ X icates that a variant allele comprises the nomsynonymous nucleotide variation indicated in the 5th row. 1:55527222 O rs28362277 619P X 1:55524237 o o LCD CO ! ir> m xO CO co \O m 00 CJ CO s_ 474V XT X 1 X X X 1:55523855 Non-Synonymous Nucleotid < 443T I X X 1:55523802 o rs2836226I | 1 425S X X 1:55505668 rsl 1583680 53V X 1:55505647 rsl 1591 147 | 46L | X c a box ind (/> o c c o i2 .2 φ c o 2 ra > 3 u ex E Λ ’c? σ x i υ p o p p '3 C3 c c E ra c ra c <υ co c οΛ c 'Sb o rd ra qj <υ ra NCB1 dbSNP reference number (NCB1 dbSNP Build 138 released on Apr 25, 2013). ra H 193 (a) Human PCSK9 Form a Amino Acid Sequence (SEQ ID NO:1) - Pro-form" with Signal Sequence l-U X I -*-i LH ( j x GJ Lu ,-r1 x: A d ' 1 K-i.

►' X I I Ί n Ο co I ιΊ X O Xi Op Ό O .V ’Zl CT v_ ‘.—J Π w x Γ ί J a I ι-Ί L? w w "0 Φ Φ CL C Φ M— Ό -4^ E tlO ro Π A n XI 'A n. Φ -,j —j —j -~j --j -, j —j --j —j CL ~-j Cl. £ Cr\ ci: co A l·O Ή A L x । Ί H x H i J X O X r’j^ C X । Ί A A A t-f X A 7'J CX U J I Ί A bi A A 1-1 % H O A X Oil· Φ φ L. Ί0 υθ σ- % 4-1 "0 Φ 00 "0 rj CJcf ί Ό ex ’ l_ c> c a A A > i<) 8) I 1 w w H 1-n ri ΓΛ Ti £1.

Si CL σ’ σ- CO C7> CT 0 c X y E tn ro Π3 nj -0 v_ uD I ω JZ 4—' Φ no rj nj *-4— o M— jii 00 CL CT Ό CT itj l_ 4-1 on φ Cl rc Ld Cl < HX o •Ώ C> •Π ID A UJ A A u LU o Cl % A C J C ) 00 < A < LU A A O > o σ CL o A Cl I-·.

T> σ A σ A A ij o ϊί t; < A] A hCO c X H— Q A CT) A ϋ I— Q 3J Q QJ A <0 LC <— SO A· II r^, tn ri tn m 4—' A O L< A II s— ’ u. □ O u C3 o 1—1 c cS P o c3 c ’p QJ ύ I! < A A ω A A A 194 The pro-form is the sequence from amino acid number 3 I to (and including) amino acid number 692 of SEQ ID NO: 1. The mature form is the sequence from amino acid number 153 to (and including) amino acid number 692 of SEQ ID NO E ,φ ώ φ C5 s X Q cd i5 o J3 u-, CL C .2 u co O c X c cd QJJ .2 P Z no X rc no ω "O u iZ) cd cr ru: Ό O) Φ Cl no •D 41 iZ) 4-) •Z) ώ fC E CT ω (D X c £ no no x cl no cl o' D- CD op >Z) tu: CT o co E CD X Ό no lO no ru CL z> CD CT CT) Π3 z> ro o.

CD ·-+— 4-) tu: V. ru: 4-) CD C 4—> ro no f-i (D C| "O CO r- I Π ch n _L LU C ) LLl -J o CJ co < CL GO LU CL CL LU σ ci' _L CL CO CL ς) rj o I •Ώ '--f t; G LU| Lu Hon O H I— cp Q CL on □L 195 (c) Human PCSK9 Allele a Nucleotide Sequence (SEQ ID NO: 28) - Encoding Pro-form Plus Signal Sequence I0 Cj IC.J 0 I0 i0 0 I0 I0 1-0 0 1-0 0 1-0 Lj C j H 0i (J 0 H H Cj CJ CJ < j A H (j 1-1 d 0 $ ( ) (J Cl o ( 'J H ( j Cj Cj C) d o H H O 0 d (j C.i «ί! (. j •C (..I ( I 7 ί J ( J .I1 C.J Cj (.. j (j L'J (j * k LJ CO ή-Ί in •-I' O CJ s • L CD o (J Cj Cj H U U Cj Cj o r'd 0 Cj . 11 c> c j Cj Cj (j H 7 (J co Lj H LJ H 0 LJ -4 (J LJ L) ’ΐ| CJ 7 (J CJ 7 Cj h (j (‘j H ('J ( J H CJ (h H CJ CJ ,ί] H Cj O <Ί< 0 Cj cj H Lj Lj (JJ H A 0 CJ r'i1 H 0 CJ ( j ' J H H ( J H 0 H i! f j 0 H LJ C H c; u h! LJ o i'C (j H Q ( j .i| H i Ί J ( 'j ί <1 0 Ci ( J ( J ( J ·: j ( .» ( j (J l·» (J ( ’J 0 il! LJ (J ( j CJ CJ •'ll o CJ H (j (j 0 (J L) 0 (J O H O rT] LJ (J (J ( ) Cj Hi H CJ :i CJ H H (j O 0 0 H Lj Cj ri! CJ 0 H 0 CJ H ( j (.j ri] (!’ ( j 0 Lj A L J i'J H Cj CJ H C.J ί j A H 0 0 0 H O o H ί J A H O L) 0 Cj H •C L» ID ID ft Γ0 HO uo l* UO re tic uo 4-J LJ LJ co (0 UO uo 4-4 UO o o 4-» CD u tio to H H H ( .· | I ('J H ( J H ( j U H CJ CJ 7 0 4! 0 0 CJ H c! u A CJ r-ll 0 CJ H 0 H c! Cj ID ίϋ uo LO LO (0 ω tiO 4—1 HQ to HO (0 •J (0 4—1 (0 lj 110 (0 LJ (0 LJ (0 bO to CO ·-» 4— HO CD CD bO 4-» bo CO CO CO co bO CO to co bo to co bu bO bO CD co HO CD μ 4—1 bO 4—1 no bij L·» CO 4-> L> O no 4-1 L> ώ Li HO ► OO bo HO to no 4—1 co HO HO UO i_> ft CD CD ID HO UO uo uo uo E Li to uo uo uo uo uo uo to fO UO to L» co ID 4UO 4-4 UO UO CD UO ru HO CD ID HO UO CD UO ·-> 4—1 ·-» 4—' to 4-1 CIO En tio '0 QO tiO uo CIO ft bO no ro til bo CO bo bO CO bO bO co HO bJj HO Hj HO HQ UjO HO bO to lj to to Γ0 HO tlO HO HO UO no (0 to HO (0 HO CD HO ft ώ HD co to tio 4—· co tiO HO ClO CO bO bO LIO co tiO co CD l.l bo Ll bO 4-J CD l_l no co i_J no 4—· bO bd bO CO CD 0J bO HO 4— bii bO no CD 1-1 bO HO uo HO 4bO 4-> ·-> L· HO CD <_j i_) 4-i HO bO ft HO rO I I HO CD ro <0 <0 HO bO no w to HO HO bQ D £ QO CO bO bO 4-1 uo ID CO ii UO 4ID UO μ uo uo uo uo 4-1 uo uo bCi co bO i_l bO uo bCi co 0’ uo co UO uo uo LJ o uo co (0 uo CD CD ID uo I-4 CD ω I I LD co L' ru LJ uo Γ0 IJ UO 4-4 CU no L1 no re tD UO L· D UO UO 4-4 no HQ LI HO to ω to bO 4—1 HO UO HO HO no no 4-4 co L· 4-i t_l CD LJ HO HO LJ LJ ro Li HO UO ‘D UO CD ft UO UO co LJ LJ LJ CO L» HO HO cd KJ UO uo uo »0 rO HQ LI i I UO ID CD CO l_l 4-4 LJ ID th ID uo •D UO UO HO uo uo uo 4-4 •1-4 uo ru co to uo cu UO 4-4 UO ω ID 4-4 Li lj UO to Li Li L> i_> LJ CD 4-4 o 4-4 ID LJ UO 4-4 L> LJ UO 4-» CO UO uo 4-4 uo uo CD lb eij CD HO HO rij UO uo uo uo I'D l· ID CD ‘D ft UO CD uo bo L< no CD bO l_l bd uo 4-.

HO CD MO 4CD L_ i UO 4-4 £ ID -4-4 •D ID UO uo 4-» HO UO 4-4 ID UO ‘J LJ UO uo £ LI CO CD L' Li CD uo ID ub I J 4-4 10 ti UO 4—1 ίϊϋ uo $ CD uo 4-4 LJ uo 4-4 L· uo uo CD L« co ID 4-4 CD Li to uo 196 UO ω CJ CJ (Q no 1 DO no ώ no -+CU CU IJ cu no CU Ko no no tiO Φ ω no no nj no CD I < O cd o ICJ co 09 co 09 C) IC_) '-X (J < (J 09 '-i. (J I·· CO co ι '‘ll I CO I I J Cl I •Ί J co C ) co < £' cd co co I II co cj I(J co I co <£ CD I co co < (0 <£' CO I < co < o tj co co I cj o o 09. tj 09 cj o c j CJ CJ I co •J I ι ) (0 < < ij CD co co (0 co < (J < CD 09 I -. <£ ( J cd cj co < 09 CJ 09 co CD 09 cj co I (J co < o CJ < CJ (J l·cj co < cj <£’ (J < cj C) I05’ (J co CJ co I(J CJ c_j CO co X ¢-) C) CD I09 I— 09 । 0 G i_r.' ICJ cj IJ CJ Iij 09 -X CJ CD lCJ 09 CD CJ I U CJ ICD (J 'il (J C J (0 CO co <0 CJ '-•0 '.‘i {J Lj tj OD CD U I CD CJ CD I 09 < tj (J < < CJ CJ CJ OD cj I CO <9 < CO cj CJ CD CD <0 co I ' o ID I co I CJ CD co < Ο < cj <0 co CD I < cj CO <£ CD 09 <’ < CJ l~ 09 I < CO ίο I CD CD <* O CJ CJ CJ co I< J) o O I L_) 09 Icj I I CJ co O < CJ CJ I< CJ OD < CD 09 CJ •4 c9 U t> r I U> UJ Cj O •-ί Lien -I CJ cj ( ) I CJ (J Ο CD I CO < CJ CD ΙΟ CD 09 ICJ <£ CD l·cj CJ cj < 09 CD ΙΟ CD CD CD < CD CD 'i CD O CD ι (J o CD CD I CD CD ICD CD < CJ OD < CD CD Ί O ΙΟ CJ CJ cj CD CD cj CJ O o CD CJ I CD CD CD 09 (J o CD < o IICD ICD I- t CJ < I- CJ CD CJ 1-CJ o 1 (J (J < CJ CJ o ΙΟ OD 05 09 ΙΟ r '1 Cj 1.9 I 9 UJ LU CD O CD (J CD CD ι CJ o < o 09 CD cj O OD CJ o CJ 09 < 09 O < 09 1-09 < cj cj I o CD CD 09 O o CJ ICJ (J 09 The pro-form is encoded by nucleotide sequence from nucleotide 91 to (and including) nucleotide 2076.

The mature form is encoded by nucleotide sequence from nucleotide 457 to (and including) nucleotide 2076. 197 id="p-620" id="p-620"

[00620] Variant Allele Nucleotide Sequences Thus, (i) The nucleotide sequence of al lele/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 1474 V 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) The 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 I474V in SEQ ID NO: 28; and a GGG codon instead of an GAG codon at the position labelled E670G in SEQ ID NO: 28: (iv) The nucleotide sequence of allele p is identical to SEQ ID NO: 28 except that the nucleotide sequence of allele p comprises a GTC codon instead of a GCC codon at the position labelled A53 V in SEQ ID NO: 28; and a GTC codon instead of an ATC codon at the position labelled 1474V 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 ’Ά443Τ in SEQ ID NO: 28; (vi) The nucleotide sequence of allele e is identical to SEQ ID NO: 28 except that the nucleotide sequence of allele e comprises a AGT codon instead of an AAT codon at the position labelled "Ν4255 in SEQ ID NO: 28; and a GTC codon instead of an ATC codon at the position labelled I474V in SEQ ID NO: 28; (vii) The nucleotide sequence of allele h is identical to SEQ ID NO: 28 except that the nucleotide sequence of allele h comprises a ACC codon instead of a GCC codon at the position labelled A443T in SEQ ID NO: 28; and a CCG codon instead of a CAG codon al the position labelled Q619P 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 CGI 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 UA53V 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-621" id="p-621"

[00621] Variant Pro-Form Amino Acid Sequences (Numbering is as per SEQ ID NO: 1 recited above) 198 (A) The amino acid sequence of form/is identical to the amino acid sequence from amino acid number 3 I to (and including) amino acid number 692 of SEQ ID NO: I 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 r 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 1 to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form m comprises a threonine at position 443; (F) The amino acid sequence of form e is identical to the amino acid sequence from amino acid number 31 to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form e comprises a serine at position 425 and a valine at position 474; (G) The amino acid sequence of form h is identical to the amino acid sequence from amino acid number 31 to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form h comprises a threonine at position 443 and a proline at position 619; (11) The amino acid sequence of form aj is identical to 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 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 3 I to (and including) amino acid number 692 of SEQ ID NO: 1 except that the amino acid sequence of form q comprises a valine at position 53 and a glycine at position 670. (00622] Variant Mature Form Amino Acid Sequences (Numbering is as per SEQ ID NO: 1 recited above) (Ar) 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; (B1) 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; (C) 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; 199 (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: (Fr) The amino acid sequence of form e is identical to SEQ ID NO: 2 except that the amino acid sequence of form e comprises a serine at position 425 and a valine at position 474; (G’) rhe amino acid sequence of form h is identical to SEQ ID NO: 2 except that the amino acid sequence of form h comprises a threonine at position 443 and a proline at position 619; (Ff) 1 he 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. 100623] I he mature form ofp is identical to the mature form of/and aj. id="p-624" id="p-624"

[00624] The mature form ofc is identical to the mature form ofq. id="p-625" id="p-625"

[00625] Further sequence analysis and 3D in silica 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. |00626] 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-627" id="p-627"

[00627] 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-628" id="p-628"

[00628] In a First Aspect: An anti-human PCSK9 ligand for use in a method of treating and/or preventing a PCSK9-mediated disease or condition in a human whose genome comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37, wherein the method comprises administering the ligand to the human. id="p-629" id="p-629"

[00629] 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. 200 id="p-630" id="p-630"

[00630] 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). [00631| 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). [00632( 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. [00633[ hi an example, the nucleotide sequence is SEQ ID NO: 29. /00634] In an example, the nucleotide sequence is SEQ ID NO: 30. id="p-635" id="p-635"

[00635] In an example, the nucleotide sequence is SEQ ID NO: 3 I. id="p-636" id="p-636"

[00636] In an example, the nucleotide sequence is SEQ ID NO: 32. id="p-637" id="p-637"

[00637] In an example, the nucleotide sequence is SEQ ID NO: 33. |00638] In an example, the nucleotide sequence is SEQ ID NO: 34. id="p-639" id="p-639"

[00639] In an example, the nucleotide sequence is SEQ ID NO: 35. id="p-640" id="p-640"

[00640] In an example, the nucleotide sequence is SEQ ID NO: 36. [00641| In an example, the nucleotide sequence is SEQ ID NO: 37. |00642] In a Second Aspect: The ligand of aspect 1. wherein the ligand has been or is determined as capable of binding a human PCSK.9 selected from the group consisting forms / c. r. p. m, e. h. aj and q. 100643( 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, tn, e, h, aj and q. [00644] In an example of any aspect, the ligand comprises a protein domain that specifically binds lo PCSK9, eg, a human PCSK9 selected from the group consisting forms/ c, r, p, in, e, h, aj and q. [00645] 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 10"6 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., bispccifics) that bind to human PCSK9 and one or more additional antigens are nonetheless considered antibodies that "specifically bind" PCSK9. as used herein. 201 id="p-646" id="p-646"

[00646] In an example of any aspect, the ligand comprises or consists of a protein that mimics the EGFA domain of the LDL receptor and specifically binds to PCSK9, eg, a human PCSK9 selected from the group consisting forms/ c, r, p, m, e, h, aj and q. id="p-647" id="p-647"

[00647] In an example of any aspect, the ligand antagonises PCSK.9, eg, a human PCSK9 selected from the group consisting forms f c, r, p, m, e, h, aj and q. |00648] 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, Λ, aj and q. |00649] In an example of any aspect, binding is determined by SPR. In an example of any aspect, binding is determined by ELISA. id="p-650" id="p-650"

[00650] In an example of any aspect, said forms are the mature forms. id="p-651" id="p-651"

[00651] In an example of any aspect, said forms are the pro-forms. id="p-652" id="p-652"

[00652] 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-653" id="p-653"

[00653] 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-654" id="p-654"

[00654] 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, 1 8-23, 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. 1006551 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). [00656| In an example, the amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 11, 12, 26 and 27, that comprise 670G which is a marker for severity of coronary atherosclerosis (Chen et al 2005). id="p-657" id="p-657"

[00657] 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-658" id="p-658"

[00658] In an example, the amino acid sequence is SEQ ID NO:4. id="p-659" id="p-659"

[00659] In an example, the amino acid sequence is SEQ ID NO:5. id="p-660" id="p-660"

[00660] In an example, the amino acid sequence is SEQ ID NO:6. id="p-661" id="p-661"

[00661] In an example, the amino acid sequence is SEQ ID NO:7. id="p-662" id="p-662"

[00662] In an example, the amino acid sequence is SEQ ID NO:8. 202 id="p-663" id="p-663"

[00663] In an example, the amino acid sequence is SEQ ID NO: 9. id="p-664" id="p-664"

[00664] In an example, the amino acid sequence is SEQ ID NO: 10. id="p-665" id="p-665"

[00665] In an example, the amino acid sequence is SEQ ID NO: 11. id="p-666" id="p-666"

[00666] In an example, the amino acid sequence is SEQ ID NO: 12. id="p-667" id="p-667"

[00667] In an example, the amino acid sequence is SEQ ID NO: 13. |00668] In an example, the amino acid sequence is SEQ ID NO: 14. (00669] In an example, the amino acid sequence is SEQ ID NO: 15. id="p-670" id="p-670"

[00670] In an example, the amino acid sequence is SEQ ID NO: 16. [00671| In an example, the amino acid sequence is SEQ ID NO: 17. [00672| In an example, the amino acid sequence is SEQ ID NO: 18. id="p-673" id="p-673"

[00673] In an example, the amino acid sequence is SEQ ID NO: 19. id="p-674" id="p-674"

[00674] In an example, the amino acid sequence is SEQ ID NO: 20. id="p-675" id="p-675"

[00675] In an example, the amino acid sequence is SEQ ID NO: 21. id="p-676" id="p-676"

[00676] In an example, the amino acid sequence is SEQ ID NO: 22. id="p-677" id="p-677"

[00677] In an example, the amino acid sequence is SEQ ID NO: 2.3. id="p-678" id="p-678"

[00678] In an example, the amino acid sequence is SEQ ID NO: 24. id="p-679" id="p-679"

[00679] In an example, the amino acid sequence is SEQ ID NO: 25. id="p-680" id="p-680"

[00680] In an example, the amino acid sequence is SEQ ID NO: 26. id="p-681" id="p-681"

[00681] In an example, the amino acid sequence is SEQ ID NO: 27. |00682] 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-683" id="p-683"

[00683] 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-684" id="p-684"

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

[00685] 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). [00686| 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-687" id="p-687"

[00687] In an example, the nucleotide sequence is SEQ ID NO: 29 id="p-688" id="p-688"

[00688] In an example, the nucleotide sequence is SEQ ID NO: 30. 203 id="p-689" id="p-689"

[00689] In an example, the nucleotide sequence is SEQ ID NO: 3 I. id="p-690" id="p-690"

[00690] In an example, the nucleotide sequence is SEQ ID NO: 32. [00691 ] In an example, the nucleotide sequence is SEQ ID NO: 33 (00692] In an example, the nucleotide sequence is SEQ ID NO: 34 id="p-693" id="p-693"

[00693] In an example, the nucleotide sequence is SEQ ID NO: 35. id="p-694" id="p-694"

[00694] In an example, the nucleotide sequence is SEQ ID NO: 36. id="p-695" id="p-695"

[00695] In an example, the nucleotide sequence is SEQ ID NO: 37. id="p-696" id="p-696"

[00696] In a Fifth Aspect: T‘he 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 al least the catalytic domain- or C-terminal domain-encoding sequence thereof. |00697] 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. |00698] 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). 100699| 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-700" id="p-700"

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

[00701] in an example, the nucleotide sequence is SEQ ID NO: 29. [00702| In an example, the nucleotide sequence is SEQ ID NO: 30. [00703| In an example, the nucleotide sequence is SEQ ID NO: 31. id="p-704" id="p-704"

[00704] In an example, the nucleotide sequence is SEQ ID NO: 32. id="p-705" id="p-705"

[00705] In an example, the nucleotide sequence is SEQ ID NO: 33. id="p-706" id="p-706"

[00706] In an example, the nucleotide sequence is SEQ ID NO: 34. id="p-707" id="p-707"

[00707] In an example, the nucleotide sequence is SEQ ID NO: 35. id="p-708" id="p-708"

[00708] In an example, the nucleotide sequence is SEQ ID NO: 36. |00709] In an example, the nucleotide sequence is SEQ ID NO: 37. id="p-710" id="p-710"

[00710] In a Sixth Aspect: The ligand of any preceding aspect, wherein the human has been or is phenotyped as positive fora human PCSK9 selected from the group consisting of forms / c, r, p, m, e, h, aj and q or at least the catalytic or C-terminal domain thereof. id="p-711" id="p-711"

[00711] In an example, said forms are the mature forms. 204 |00712] In an example, said forms are the pro-forms. id="p-713" id="p-713"

[00713] 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. id="p-714" id="p-714"

[00714] 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-715" id="p-715"

[00715] In an example, the nucleotide sequence is SEQ ID NO: 34. that encodes a 425S, which is associated with elevated EDL-C (Pisciotta et al 2006). |00716| 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 el a/2005). 100717] 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 ¢7) and which meet the criteria set out above. id="p-718" id="p-718"

[00718] In an example, the nucleotide sequence is SEQ ID NO:29. id="p-719" id="p-719"

[00719] In an example, the nucleotide sequence is SEQ ID NO;30. id="p-720" id="p-720"

[00720] In an example, the nucleotide sequence is SEQ ID NO:31. [00721) In an example, the nucleotide sequence is SEQ ID NO:32. id="p-722" id="p-722"

[00722] In an example, the nucleotide sequence is SEQ ID NO:33. [00723J In an example, the nucleotide sequence is SEQ ID NO:34, id="p-724" id="p-724"

[00724] In an example, the nucleotide sequence is SEQ ID NO:35. id="p-725" id="p-725"

[00725] In an example, the nucleotide sequence is SEQ ID NO:36. [00726| In an example, the nucleotide sequence is SEQ ID NO:37. [00727| 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, nt e, h, aj and q or at least the catalytic or C-terminal domain thereof |00728] In an example, said forms are the mature forms. id="p-729" id="p-729"

[00729] In an example, said forms are the pro-forms. id="p-730" id="p-730"

[00730] 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 205 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-731" id="p-731"

[00731] Heterozygous here means that in the human’s genotype one allele comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof and other allele can be any PCSK9 (eg, form a, a' or an allele comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof). id="p-732" id="p-732"

[00732] In an example, the method comprises (before administering the ligand) genotyping the human as heterozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal 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. [00733) 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. id="p-734" id="p-734"

[00734] These are naturally-occurring allele (haplotype) sequences that do not encode 46L and which meet the criteria set out above. These groups comprise variants that are associated with elevated LDL-C. id="p-735" id="p-735"

[00735] In an example, the nucleotide sequence is SEQ ID NO: 34. that encodes a 425S. which is associated wath elevated LDL-C (Pisciotta et a! 2006). id="p-736" id="p-736"

[00736] 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 6//2005). id="p-737" id="p-737"

[00737] 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; 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. |00738] In an example, the nucleotide sequence is SEQ ID NO: 29. id="p-739" id="p-739"

[00739] In an example, the nucleotide sequence is SEQ ID NO: 30. id="p-740" id="p-740"

[00740] In an example, the nucleotide sequence is SEQ ID NO: 3 I. id="p-741" id="p-741"

[00741] In an example, the nucleotide sequence is SEQ ID NO: 32. id="p-742" id="p-742"

[00742] In an example, the nucleotide sequence is SEQ ID NO: 33. id="p-743" id="p-743"

[00743] In an example, the nucleotide sequence is SEQ ID NO: 34. 206 id="p-744" id="p-744"

[00744] In an example, the nucleotide sequence is SEQ ID NO;35. id="p-745" id="p-745"

[00745] In an example, the nucleotide sequence is SEQ ID NO:36. id="p-746" id="p-746"

[00746] In an example, the nucleotide sequence is SEQ ID NO:37. id="p-747" id="p-747"

[00747] In a Tenth Aspect: The ligand of any one of aspects I to 9, wherein the genome of the human has been or is genotyped as homozygous for a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C-terminal domain-encoding sequence thereof. [00748) 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. (00749) 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 at least the catalytic domain- or C-terminal domain-encoding sequence thereof. id="p-750" id="p-750"

[00750] 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-751" id="p-751"

[00751] 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-752" id="p-752"

[00752] 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 ei al 2005). |00753j 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-754" id="p-754"

[00754] In an example, the nucleotide sequence is SEQ ID NO:29. id="p-755" id="p-755"

[00755] In an example, the nucleotide sequence is SEQ ID NO:30. |00756] In an example, the nucleotide sequence is SEQ ID NO:3 1. id="p-757" id="p-757"

[00757] In an example, the nucleotide sequence is SEQ ID NO:32. |00758] In an example, the nucleotide sequence is SEQ ID NO:33. [00759| In an example, the nucleotide sequence is SEQ ID NO;34. id="p-760" id="p-760"

[00760] In an example, the nucleotide sequence is SEQ ID NO:35. id="p-761" id="p-761"

[00761] In an example, the nucleotide sequence is SEQ ID NO:36. id="p-762" id="p-762"

[00762] In an example, the nucleotide sequence is SEQ ID NO:37. 207 id="p-763" id="p-763"

[00763] In an Eleventh Aspect: The ligand of any preceding aspect, wherein the ligand comprises an antibody binding site that binds a human PCSK9 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4-27 and optionally has been or is determined as capable of such binding. id="p-764" id="p-764"

[00764] 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. 100765] 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 I mM. 1 OOnM. 1 OnM or 1 nM or less. In an embodiment, the affinity is no less than 10. 100 or 1000 fM. |00766] In an example, binding or affinity is determined by SPR or ELISA. id="p-767" id="p-767"

[00767] 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. |00768] 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 1 8-27; or selected from the group consisting of SEQ ID NOs: 4-14, 18-23, 26 and 27. These arc 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-769" id="p-769"

[00769] 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-770" id="p-770"

[00770] In an example, the amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 11. 12, 26 and 27. that comprise 670G which is a marker for severity of coronary atherosclerosis (Chen et al 2005). id="p-771" id="p-771"

[00771] 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 |00772] In an example, the amino acid sequence is SEQ ID NO: 4. id="p-773" id="p-773"

[00773] In an example, the amino acid sequence is SEQ ID NO: 5. id="p-774" id="p-774"

[00774] In an example, the amino acid sequence is SEQ ID NO: 6. id="p-775" id="p-775"

[00775] In an example, the amino acid sequence is SEQ ID NO: 7. id="p-776" id="p-776"

[00776] In an example, the amino acid sequence is SEQ ID NO: 8. id="p-777" id="p-777"

[00777] In an example, the amino acid sequence is SEQ ID NO: 9. id="p-778" id="p-778"

[00778] In an example, the amino acid sequence is SEQ ID NO: 10. |00779] In an example, the amino acid sequence is SEQ ID NO: 1 I. )00780] In an example, the amino acid sequence is SEQ ID NO: 1 2. id="p-781" id="p-781"

[00781] In an example, the amino acid sequence is SEQ ID NO: 13 100782] In an example, the amino acid sequence is SEQ ID NO: 14. 208 id="p-783" id="p-783"

[00783] Jn an example, the amino acid sequence is SEQ ID NO: 15. id="p-784" id="p-784"

[00784] In an example, the amino acid sequence is SEQ ID NO: 16. id="p-785" id="p-785"

[00785] In an example, the amino acid sequence is SEQ ID NO: 17. id="p-786" id="p-786"

[00786] In an example, the amino acid sequence is SEQ ID NO: 18. id="p-787" id="p-787"

[00787] In an example, the amino acid sequence is SEQ ID NO: 19. id="p-788" id="p-788"

[00788] In an example, the amino acid sequence is SEQ ID NO: 20. [00789| In an example, the amino acid sequence is SEQ ID NO: 21. id="p-790" id="p-790"

[00790] In an example, the amino acid sequence is SEQ ID NO: 22. [007911 In an example, the amino acid sequence is SEQ ID NO: 23. id="p-792" id="p-792"

[00792] In an example, the amino acid sequence is SEQ ID NO: 24. [00793| In an example, the amino acid sequence is SEQ ID NO: 25. id="p-794" id="p-794"

[00794] In an example, the amino acid sequence is SEQ ID NO: 26. id="p-795" id="p-795"

[00795] in an example, the amino acid sequence is SEQ ID NO: 27. id="p-796" id="p-796"

[00796] In a Twelfth Aspect: The ligand of aspect 1 1, wherein the ligand is an antibody or antibody fragment. For example, the antibody or antibody fragment is a PCSK9 antagonist, eg, neutralises PCSK9. |00797| Examples of such antibodies are disclosed, for instance, in WO 2008/057457, WO2008/057458, WO 2008/057459, WO 2008/063382, WO 2008/133647, WO 2009/100297, WO 2009/100318, WO 201 1/037791, WO 201 1/053759, WO 201 1/053783, WO 2008/125623, WO 2011/072263, WO 2009/055783, WO 2010/029513, WO 2011/11 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). LY30I 5014 (Eli Lilly) or alirocumab. Advantageously, the ligand is or comprises alirocumab. Alternatively, the ligand is or comprises evolocumab. 100798] In an example, the ligand is SAR236553/REGN727 (Sanofi Aventis/Regeneron) or a PCSK9-binding derivative thereof. id="p-799" id="p-799"

[00799] In an example, the ligand comprises or consists of a neutralizing antibody that binds to the PCSK9, wherein the antibody binds to PCSK9 and reduces the likelihood that PCSK9 binds to LDLR. (00800] The ligand of aspect 11, wherein the ligand is a PCSK9 antagonist, eg, neutralises PCSK9. id="p-801" id="p-801"

[00801] In an example of any aspect of the invention, the ligand comprises or consists a ligand selected from evolocumab, I D05-IgG2 (Merck & Co.), ALN-PCS02 (Alnylam), RN3 16 (PfizerRinat), LY3015014 (Eli Lilly) and alirocumab (SAR236553/REGN727; Sanofi Aventis/Regeneron). [00802] In Thirteenth Aspect: The ligand of any one of aspects I to 10, wherein (i) the ligand comprises a sequence of contiguous nucleotides that specifically hybridises to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or at least the catalytic domain- or C 209 terminal domain-encoding sequence thereof, or specifically hybridises to an antisense sequence or an RNA transcript of said sequence, wherein said sequence of contiguous nucleotides hybridises to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridises to an antisense sequence or an RNA transcript thereof respectively; and/or (ii) the ligand comprises a sequence of at least 10 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or is an antisense sequence or RNA version of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28. |00803] 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. [00804| 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). [00805( 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 all^S). |00806| 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. |00807] In an example, the nucleotide sequence is SEQ ID NO:29. 100808] In an example, the nucleotide sequence is SEQ ID NO:30. |00809] In an example, the nucleotide sequence is SEQ ID NO:3 I. (00810] In an example, the nucleotide sequence is SEQ ID NO:32. [008111 In an example, the nucleotide sequence is SEQ ID NO:33. id="p-812" id="p-812"

[00812] In an example, the nucleotide sequence is SEQ ID NO:34. id="p-813" id="p-813"

[00813] In an example, the nucleotide sequence is SEQ ID NO:35. |00814] In an example, the nucleotide sequence is SEQ ID NO:36. (00815] In an example, the nucleotide sequence is SEQ ID NO:37. 100816] Inan embodiment, the ligand comprises at least 10, 11, 12, 13, 14. 1 5, 20, 25, 30, 35. 40. 45, 50 or 100 contiguous nucleotides of said nucleotide sequence. id="p-817" id="p-817"

[00817] In a Fourteenth Aspect: The ligand of any preceding aspect, wherein said disease or condition is hyperlipidaemia, hyperchoiesterolaemia (eg, familial hypercholesterolaemia), heart attack, stroke, coronary heart disease, atherosclerosis or a cardiovascular disease or condition. 210 |00818| 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. [008191 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 ait (and are described or referenced in US2012009381 8). id="p-820" id="p-820"

[00820] 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-821" id="p-821"

[00821] In a Fifteenth Aspect: The ligand of any preceding aspect, wherein said disease or condition is associated with elevated LDL cholesterol. id="p-822" id="p-822"

[00822] Cholesterol levels are measured in milligrams (mg) of cholesterol per deciliter (dL) of blood in the United States and some other countries. Canada and most European countries measure cholesterol in millimoles (mmol) per liter (L) of blood. Below are general guideline ideal ranges and elevated ranges.

Total cholesterol Total cholesterol* (U.S. and some other countries) (Canada and most of Europe) Below 200 mg/dL Below 5.2 mmol/L Ideal 200-239 mg/dL 5.2-6.2 mmol/L Borderline high 240 mg/dL and above Above 6.2 mmol/L High LDL cholesterol LDL cholesterol* (U.S. and some other countries) (Canada and most of Europe) 100-129 mg/dL 2.6-3.3 mmol/L Ideal 130-159 mg/dL 3.4-4.1 mmol/L Borderline high )60-189 mg/dL 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. |00823] Elevated LDL cholesterol is, therefore, 160 mg/dL or above (4.1 mmol/L or above). id="p-824" id="p-824"

[00824] 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. 211 id="p-825" id="p-825"

[00825] in an example, the method comprises (before administering the ligand) determining that the ligand is capable of such inhibition. id="p-826" id="p-826"

[00826] 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-827" id="p-827"

[00827] 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-828" id="p-828"

[00828] 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 AS W,YRI,GBR,TSL CLM.LWK,MXLJPT,PUR,IBS,FIN or CEU ancestry; or (ii) whose genome comprises SEQ ID NO: 30 and wherein the human is of ASW,YR1,GBR,TSLCLM, CHB,LWK,CHS ,JPT,PUR,FIN or CEU ancestry; or (iii) whose genome comprises SEQ ID NO: 32 and wherein the human is of ASW,GBR,TSI,CLM, JPT,PUR,IBS,FIN or CEU ancestry; or (iv) whose genome comprises SEQ ID NO: 33 and wherein the human is of LWK,ASW.YRI or CLM ancestry; or (v) whose genome comprises SEQ ID NO: 34 and wherein the human is of LWK,ASW or YRI ancestry: or (vi) whose genome comprises SEQ ID NO: 35 and wherein the human is of PUR,TSI,FIN or CEU ancestry; or (vii) whose genome comprises SEQ ID NO: 36 and wherein the human is of LWK,ASW or YRI ancestry: or (viii) whose genome comprises SEQ ID NO: 37 and wherein the human is of CHS_ASW.JPT.PUR or CHB ancestry. id="p-829" id="p-829"

[00829] In a Ninteenth Aspect: The ligand of any preceding aspect, wherein the ligand is for treating and/or preventing a PCSK9-mediated disease or condition in a human (i) that expresses PCSK9 form /and wherein the human is of ASW,YRLGBR,TSLCLM,LWK,MXL,JPT,PUR,1BS,FIN or CEU ancestry; or (ii) that expresses PCSK9 form c and wherein the human is of ASW,YRI,GBR,TSLCLM.CHB,LWK.CHSJPT,PUR.FIN or CEU ancestry: or (iii) that expresses PCSK9 formp and wherein the human is of ASW,GBR,TSI,CLMJPT,PUR,IBS.EIN or CEU ancestry; or (iv) that expresses PCSK9 form w and wherein the human is of LWK,ASW,YRI or CLM 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 eij and wherein the human is of LWK,ASW or YRI ancestry; or 212 (viii) that expresses PCSK9 form q and wherein the human is of CHS,ASW,JPT,PUR or CHB ancestry. id="p-830" id="p-830"

[00830] In an example, said forms are the mature forms. [00831| In an example, said forms are the pro-forms. [008321 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). 100833] 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 /, c, r, p, m. e, h, aj or q PCSKQ-binding fragment or derivative of the isolated antibody. id="p-834" id="p-834"

[00834] In an example, said forms are the mature forms. [00835| In an example, said forms are the pro-forms. [00836| 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, labs or scFvs. Suitable methods for producing pluralities of binding sites for screening include phage display (producing a phage display library of antibody binding sites), ribosome display (producing a ribosome display library of antibody binding sites), yeasl display (producing a yeast display library of antibody binding sites), or immunisation of a non-human vertebrate (eg, a rodent eg, a mouse or rat, eg, a Velocimouse™, Kymouse™, Xenomouse™, Aliva Mouse™, HuMab Mouse™, Omnimouse™, Omnirat2 M or MeMo Mouse1 M) 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-837" id="p-837"

[00837] 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. 213 id="p-838" id="p-838"

[00838] In a Twenty-second Aspect: A method of producing an anti-human PCSK9 antibody, the method comprising immunising a non-human vertebrate (eg, a mouse or a rat) with a human PCSK9 comprising an amino acid sequence selected from the group consisting of the amino acid sequences of forms / 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 / 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: L 2 or 3, and optionally producing a form f c. r, p, nt. e, h aj or q PCSK9-binding fragment or derivative of the isolated antibody. id="p-839" id="p-839"

[00839] In an example, said forms are the mature forms, id="p-840" id="p-840"

[00840] In an example, said forms are the pro-forms. id="p-841" id="p-841"

[00841] In a Twenty-third Aspect: The method of aspect 21 or 22, comprising the step of obtaining a nucleic acid encoding the antibody, fragment, derivative or binding site and optionally inserting the nucleic acid in an expression vector. id="p-842" id="p-842"

[00842] For example, the method comprises isolating a cell (eg, B-cell, plasmablast, plasma cell or memory cell) comprising the nucleic acid, wherein the cell is obtained from a non-human vertebrate that has been immunised with the PCSK9 epitope. id="p-843" id="p-843"

[00843] 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 Cterminai domain-encoding sequence thereof, or specifically hybridises to an antisense sequence or an RNA transcript of said sequence, w herein said sequence of contiguous nucleotides hybridises to al least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridises to an antisense sequence or an RNA transcript thereof; and/or (ii) comprising a sequence of at least 10 or more (eg, 10, 15, 20. 30, 40, 50, 60, 70, 80, 90, 100 or more) nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or comprising an antisense sequence or RNA version of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28. id="p-844" id="p-844"

[00844] 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 sei out above. These groups comprise variants that are associated with elevated LDL-C. 214 id="p-845" id="p-845"

[00845] 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-846" id="p-846"

[00846] 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 el al 2005). id="p-847" id="p-847"

[00847] 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. |00848] In an example, the nucleotide sequence is SEQ ID NO:29. id="p-849" id="p-849"

[00849] In an example, the nucleotide sequence is SEQ ID NO:30. id="p-850" id="p-850"

[00850] In an example, the nucleotide sequence is SEQ ID NO:31. id="p-851" id="p-851"

[00851] In an example, the nucleotide sequence is SEQ ID NO:32. 100852] In an example, the nucleotide sequence is SEQ ID NO:33. id="p-853" id="p-853"

[00853] In an example, the nucleotide sequence is SEQ ID NO:34. id="p-854" id="p-854"

[00854] in an example, the nucleotide sequence is SEQ ID NO:35. id="p-855" id="p-855"

[00855] In an example, the nucleotide sequence is SEQ ID NO:36. |00856] In an example, the nucleotide sequence is SEQ ID NO:37. id="p-857" id="p-857"

[00857] Jn 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-858" id="p-858"

[00858] In a Twenty-sixth Aspect: Use of an anti-PCSK.9 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 treating and/or preventing a PCSK9-mediatcd 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. [00859| In an example, said forms are the mature forms. id="p-860" id="p-860"

[00860] In an example, said forms are the pro-forms. id="p-861" id="p-861"

[00861] 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 PCSK9, optionally for targeting PCSK.9 in a human as recited in aspect 18 or 19. id="p-862" id="p-862"

[00862] In an example, said forms are the mature forms. id="p-863" id="p-863"

[00863] In an example, said forms are the pro-forms. id="p-864" id="p-864"

[00864] 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 215 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-865" id="p-865"

[00865] 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-866" id="p-866"

[00866] In an example, the nucleotide sequence selected from the group consisting of SEQ ID NOs: 3 ] and 37, that encode 670G which is a marker for severity of coronary atherosclerosis (Chen el 4// 2005). |00867| 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 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-868" id="p-868"

[00868] In an example, the nucleotide sequence is SEQ ID NO: 29, id="p-869" id="p-869"

[00869] In an example, the nucleotide sequence is SEQ ID NO: 30. [00870| In an example, the nucleotide sequence is SEQ ID NO: 3 1. id="p-871" id="p-871"

[00871] In an example, the nucleotide sequence is SEQ ID NO: 32. id="p-872" id="p-872"

[00872] In an example, the nucleotide sequence is SEQ ID NO: 33. id="p-873" id="p-873"

[00873] In an example, the nucleotide sequence is SEQ ID NO: 34. id="p-874" id="p-874"

[00874] In an example, the nucleotide sequence is SEQ ID NO: 35. id="p-875" id="p-875"

[00875] In an example, the nucleotide sequence is SEQ ID NO: 36. id="p-876" id="p-876"

[00876] In an example, the nucleotide sequence is SEQ ID NO: 37. |00877| The ligand can be any anti-PCSK9 ligand disclosed herein. [00878| 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. (00879| 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 PCSK9 encoded by said nucleotide sequence is targeted. [00880] The ligand can be any anti-PCSK9 ligand disclosed herein. id="p-881" id="p-881"

[00881] 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, tn, e, h, aj and q w ith said ligand to treat and/or prevent said disease or condition in said human. id="p-882" id="p-882"

[00882] In an example, said forms are the mature forms. id="p-883" id="p-883"

[00883] In an example, said forms are the pro-forms. id="p-884" id="p-884"

[00884] 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 216 group consisting of forms/ c, r, p, m, e, h, qj 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. |00885] In an example, said forms are the mature forms. |00886] In an example, said forms are the pro-forms. id="p-887" id="p-887"

[00887] The ligand can be any anti-PCSK9 ligand disclosed herein. (00888] In a Thirty-second Aspect: The method of aspect 3 1, wherein the genome of the human comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37. id="p-889" id="p-889"

[00889] 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 arc associated with elevated LDL-C. id="p-890" id="p-890"

[00890] 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-891" id="p-891"

[00891] 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 el al 2005). (00892J 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, [00893] In an example, the nucleotide sequence is SEQ ID NO: 29. 100894] In an example, the nucleotide sequence is SEQ ID NO:30. |00895] In an example, the nucleotide sequence is SEQ ID NO:31. id="p-896" id="p-896"

[00896] In an example, the nucleotide sequence is SEQ ID NO:32. [00897| In an example, the nucleotide sequence is SEQ ID NO:33. id="p-898" id="p-898"

[00898] In an example, the nucleotide sequence is SEQ ID NO:34. id="p-899" id="p-899"

[00899] In an example, the nucleotide sequence is SEQ ID NO:35. |00900| In an example, the nucleotide sequence is SEQ ID NO:36. 1009011 In an example, the nucleotide sequence is SEQ ID NO:37. id="p-902" id="p-902"

[00902] 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. (00903] Tn a Thirty-fourth Aspect: The method of any one of aspects 29 to 33. wherein the human has been or is phenotyped as positive for a human PCSK9 selected from the group consisting of forms / c, r, p, m, e, h, aj and q. 100904] In an example, said forms are the mature forms. 217 id="p-905" id="p-905"

[00905] In an example, said forms are the pro-forms. id="p-906" id="p-906"

[00906] 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. [00907) In a Thirty-sixth Aspect: The method of any one of aspects 29 to 35. wherein the method comprises phenotyping the human as positive fora human PCSK9 sequence selected from the group consisting of forms f c, r, p, m, e. h. aj and q. [00908| In an example, said forms are the mature forms. id="p-909" id="p-909"

[00909] In an example, said forms are the pro-forms. (00910] 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. id="p-911" id="p-911"

[00911] 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. id="p-912" id="p-912"

[00912] In a Thirty-ninth Aspect: The method of any one of aspects 29 to 38. wherein the method comprises genotyping the human fora 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 lo a PCSK9 encoded by said selected sequence. id="p-913" id="p-913"

[00913] In a Fortieth Aspect: The method of any one of aspects 29 to 39, w herein the ligand, human, disease or condition is according to any one of aspects 1 to 19. id="p-914" id="p-914"

[00914] 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, atorvastatim simvastatin, pitavastin, rosuvastatin, fluvastatin, lovastatin or pravastatin) to the human. id="p-915" id="p-915"

[00915] In a Forty-second Aspect: The method of aspect 41. wherein the ligand and statin are administered separately. id="p-916" id="p-916"

[00916] In a Forty-third Aspect: The method of aspect 41, wherein the ligand and statin are administered simultaneously. id="p-917" id="p-917"

[00917] In a Forty-fourth Aspect: The method of any one of aspects 29 to 43, wherein the ligand is administered by subcutaneous injection. 218 id="p-918" id="p-918"

[00918] In a Forty-fifth Aspect: A method of PCSK9 genotyping a nucleic acid sample of a human, the method comprising identifying in the sample the presence of a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or the catalytic- or C-terminal domainencoding sequence thereof id="p-919" id="p-919"

[00919] In a Forty-sixth Aspect: A method of PCSK9 typing a protein sample of a human, the method comprising identifying in the sample the presence of a human PCSK9 selected from the group consisting of forms / c. r. p, m, e. / aj and q. id="p-920" id="p-920"

[00920] In an example, said forms are the mature forms. id="p-921" id="p-921"

[00921] In an example, said forms are the pro-forms. id="p-922" id="p-922"

[00922] 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-923" id="p-923"

[00923] 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-924" id="p-924"

[00924] 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 I to 19 whereby the human is treated or said disease or condition is prevented: optionally also reducing or stopping statin treatment. |00925| In an example, said reducing or stopping comprises reducing the dose and/or dosing frequency of statin. |00926] 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-927" id="p-927"

[00927] In a Fifty-first Aspect: A diagnostic, therapeutic or prophylactic kit comprising a nucleic acid probe comprising a nucleotide sequence that specifically hybridises to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 29-37 or an antisense sequence or RNA transcript thereof and instructions for carrying out the method of aspect 45, 47 or 48. id="p-928" id="p-928"

[00928] In examples of the present invention, the ligand specifically binds to human PCSK.9. eg, one or more ofthe rare PCSK9 variants disclosed herein (eg, one. two, three, more or all mature forms/ c, r, py m, et h, aj and q) and optionally also the a and/or a ’ form. For example, the ligand specifically binds to mature form f 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. 219 Binding to each such form is, for example, respectively with a Kd of at least 1 mM, lOOnM, 1 nM. ΙΟΟρΜ, lOpMor IpM. id="p-929" id="p-929"

[00929] 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, [00930| 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. [00931| 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. [00932) In an example, the ligand binds form a and form r, wherein the ligand binding to 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. id="p-933" id="p-933"

[00933] In an example, the ligand binds form a and formp, wherein the ligand binding to form p is with a Kd (determined by SPR) that is at least 60, 70, 80, 90 or 95% of the Kd for binding to form a. In an embodiment, both forms are mature forms. In an embodiment, both forms are pro-forms. id="p-934" id="p-934"

[00934] In an example, the ligand binds form a and form w, wherein the ligand binding to form m is with a Kd (determined by SPR) that is at least 60, 70, 80, 90 or 95% of the Kd for binding to form a. In an embodiment, both forms are mature forms. In an embodiment, both forms are pro-forms. id="p-935" id="p-935"

[00935] 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. id="p-936" id="p-936"

[00936] 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) thal 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-937" id="p-937"

[00937] 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. id="p-938" id="p-938"

[00938] In an example, the ligand binds form a and form q, wherein the ligand binding to form q is with a Kd (determined by SPR) that is at least 60, 70, 80, 90 or 95% of the Kd for binding to form a. In an embodiment, both forms are mature forms. In an embodiment, both forms are pro-forms. id="p-939" id="p-939"

[00939] 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 a1 form. For example, the ligand neutralises mature form/ and/or c as well as form a. Determination of neutralisation can be performed, for 220 example, by any neutralisation assay method disclosed in US20120093818A1 (Amgen, Inc) or US20110065902A1 (Regeneron Pharmaceuticals, Inc). Ligands of the invention that bind or target PCSK9 are useful, for example, for therapeutic and prophylactic applications disclosed in US20120093818A1 and US20110065902A1, these specific disclosures being incorporated herein by reference for use in the present invention and for possible inclusion in claims herein. |00940] In embodiments where the ligand is used for therapeutic applications, an antigen binding protein can inhibit, interfere with or modulate one or more biological activities of a PCSK9 (eg, one or more of the rare variants disclosed herein and optionally also the a and/or a' form), hi one embodiment, ligand binds specifically to human PCSK9 (eg, one or more of the rare variants disclosed herein and optionally also the a and/or a ’ form) and/or substantially inhibits binding of human PCSK9 (eg. said one or more 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-941" id="p-941"

[00941] In an embodiment, the ligand has a Kd of less (binding more tightly) than 10 , 10 10Λ -10, IO11, IO12, 10"13 M for binding to one, two or more of the rare variants disclosed herein and optionally also the a and/or a ' form. In an example, Kd is determined using SPR. id="p-942" id="p-942"

[00942] In an embodiment, the ligand has an 1C50 for blocking the binding of LDLR to one or more of the rare PCSK9 variants disclosed herein (and optionally also the a and/or cd 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 I pM. id="p-943" id="p-943"

[00943] In an embodiment, the ligand has an IC50 for blocking the binding of LDLR to the a and/or a ’ form of PCSK9 that is no more than 1000, 100. 90. 80. 70, 60, 50, 40, 30. 20 or 10-fold more (ie. more inhibitory) than the 1C50 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 1C50 for blocking the binding of LDLR to (i) the a and/or o' form of less than 1 microM, 1000 nM to 100 nM. lOOnMto lOnM, lOnMto 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 IpM (eg, ImM to lOOpM; lOnMto ΙΟΟρΜ; InMto lOpM; or lOOpM to IpM) and (ii) one or more PCSK9 proteins comprising a sequence selected from SEQ ID NOs: 4 to 27 of less than 1 microM, 1000 nM to 100 nM, 100 nM to 10 nM, 10 nM to 1 nM, 1000 pM to 500 pM, 500 pM to 200 pM, less than 200 pM, 200 pM to 150 pM, 200 pM to 100 pM, 100 pM to 10 pM, 10 pM to 1 pM, eg, in the range of ImM to IpM (eg, ImM to ΙΟΟρΜ; lOnM to lOOpM; InM to lOpM; or lOOpM to IpM). id="p-944" id="p-944"

[00944] 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 221 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,M or using the ProteOn XPR361M (Βίο-Rad®), or using KinExA® (Sapidyne Instruments. Inc). id="p-945" id="p-945"

[00945] In one embodiment, the surface plasmon resonance (SPR) is carried out al 25C1C. In another embodiment, the SPR is carried out at 37°C. id="p-946" id="p-946"

[00946] 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)'). |00947] In one embodiment, the SPR is carried out at a physiological salt level, eg. 1 50mM NaCl. id="p-948" id="p-948"

[00948] 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. (00949] In one example, the SPR is carried out at 25°C or 37°C in a buffer at pH7.6, 150mM NaCl, 0.05% detergent (eg, P20) and 3mM EDTA. The buffer can contain lOmM Hepes. In one example, the SPR is carried out at 25°C or 37°C in HBS-EP. HBS-EP is available from Teknova Inc (California; catalogue number H8022). id="p-950" id="p-950"

[00950] In an example, the affinity of the ligand which is an antibody is determined using SPR by 1. Coupling anti-mouse (or other relevant vertebrate) IgG (eg. Biacore BR-1008-38) to a biosensor chip (eg, GLM chip) such as by primary amine coupling; 2. Exposing the anti-mouse IgG (vertebrate antibody) to a test IgG antibody to capture test antibody on the chip; 3. Passing the test antigen over the chip’s capture surface at IO24nM, 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®). [009511 Regeneration of the capture surface can be carried out with 1 OmM glycine a.t 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-952" id="p-952"

[00952] 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. 222 |00953] 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: 1 54, FIG. 3KK of US20120093818ΛI, which sequence is incorporated herein by reference. id="p-954" id="p-954"

[00954] One example of an IgG4 heavy chain constant domain of an anti-PCSK9 antibody of the present invention has the amino acid sequence as shown in SEQ ID NO: 155. FIG. 3KK of US20120O93818A1, which sequence is incorporated herein by reference. id="p-955" id="p-955"

[00955] One example of a kappa light chain constant domain of an anti-PCSK9 antibody has the amino acid sequence as shown in SEQ ID NO: 157, FIG. 3KK which sequence is incorporated herein by reference. id="p-956" id="p-956"

[00956] 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-957" id="p-957"

[00957] In examples ofthe present invention, the ligand binds mature PCSK9, eg, a mature form of one or more of the rare variants disclosed herein and optionally also the a and/or a ' form. (00958] 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-959" id="p-959"

[00959] In examples of the present invention, the ligand binds the prodomain of PCSK9, eg, of a mature form of one or more of the rare variants disclosed herein and optionally also the a and/or a' form. id="p-960" id="p-960"

[00960] In some embodiments, the ligand binds to the V domain of PCSK9, eg, of a mature form of one or more of the rare variants disclosed herein and optionally also the a and/or a ’ form. In some embodiments, the ligand binds to the V domain of PCSK9 (eg. of a mature form of one or more of the rare variants disclosed herein and optionally also the a and/or a ’ form) and prevents (or reduces, eg, by at least 10%) PCSK9 from binding to LDLR. In some embodiments, the ligand binds to the V domain of PCSK9 (eg, of a mature form of one or more of the rare variants disclosed herein and optionally also the a and/or a’ form), and while it does not prevent (or reduce) the binding of PCSK9 to LDLR, the ligand prevents or reduces (eg, by at least 10%) the adverse activities mediated through PCSK9 on LDLR. id="p-961" id="p-961"

[00961] In examples ofthe 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-962" id="p-962"

[00962] 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, 53 V, 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:I). For example, the amino acid is selected 223 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 ar. 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. [00963| In an embodiment, iigand 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/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 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 pro-domain of form r PCSK9, wherein the epitope comprises al 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 iigand 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. 224 id="p-964" id="p-964"

[00964] Jn an embodiment, ligand binds specifically to the catalytic domain of a human PCSK9 selected from the group consisting of forms f c, r, p, m, e, h, aj and q. In an example, the ligand also specifically binds to the catalytic domain of form a and/or a’. In an embodiment, the ligand specifically binds to the catalytic domain of form/PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the catalytic domain of form 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 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 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 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 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. (009651 In an embodiment, ligand binds specifically to the C-terminal 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 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. In an embodiment, the ligand specifically binds to the C-terminal domain of form r PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the C-terminal domain of form p PCSK9, w herein 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 ainino 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 225 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. id="p-966" id="p-966"

[00966] In an embodiment ligand binds specifically to the substrate-binding groove of a human PCSK9 selected from the group consisting of forms / c, r, p, m, e, h, aj and q (see Cunningham et al., Nat Struct Mol Biol. 2007 May; 14(5):413-9. Epub 2007 Apr 15, "Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia", incorporated herein in its entirety by reference). In an example, the ligand also specifically binds to the substrale-binding groove of form a and/or a', hi an embodiment, the ligand specifically binds to the Substrate-binding groove of form / PCS K9, 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 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 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 PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the Substrate-binding groove of form h PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds to the Substrate-binding groove of form aj PCSK9, wherein the epitope comprises at least one amino acid that is not found in form a. In an embodiment, the ligand specifically binds lo 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-967" id="p-967"

[00967] Reference is made to US20120093818A1 (Amgen. Inc), the entire disclosure of which is incorporated herein. I his 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-968" id="p-968"

[00968] In an example, the ligand is or comprises an antibody disclosed in fable 2 of US20120093818A1 (Amgen, Inc) or is a PCSK9-binding derivative thereof. id="p-969" id="p-969"

[00969] In an embodiment, the PCSK9-binding ligand of the invention is selected from the antigen binding proteins disclosed in US20120093818A1 (Amgen, Inc), eg, in paragraphs [0009] to [0014] and [0058] to [0063] of US20120093 818A1; all of these disclosures (including the sequences of such proteins) are incorporated herein by reference as though explicitly recited herein and for possible inclusion in one or more claims or for use in the present invention. id="p-970" id="p-970"

[00970] In this paragraph SEQ ID NOs are those as appearing in US20120093818A1 (Amgen, Inc) and these sequences are incorporated herein by reference as though explicitly recited herein and 226 for possible inclusion in one or more claims or for use in the present invention. In some aspects, the ligand of the invention comprises an isolated antigen binding protein that binds PCSK9 comprising: A) one or more heavy chain complementary determining regions (CDRHs) selected from the group consisting of: (i) a CDRH 1 from a CDRH 1 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, 5 1, 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; B) one or more light chain complementary determining regions (CDRLs) selected from the group consisting of: (i) a CDRL1 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 ofSEQ ID NO: 5,7,9, 10, 12. 13, 1 5, 16, 17. 18, 19, 20,21,22,23, 24, 26,28,30.31,32, 33, 35, 36, 37, 38, 39, 40, 42. 44. and 46; and (iv) a CDRL of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 4 amino acids; or C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B). In some embodiments, the isolated antigen binding protein comprises at least one CDRH of A) and at least one CDRL of B). In some embodiments, the isolated antigen binding protein comprises at least two CDRH of A) and at least two CDRL of B). In some embodiments, the isolated antigen binding protein comprises said CDRH], CDRH2, CDRH3. CDRL1, 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 1 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 CDRL1 amino acid sequence selected from the CDRLI in a sequence selected from the group consisting of SEQ ID NO: 12, 35, 32, and 23; (ii) a CDRL2 amino acid sequence selected from the CDRL2 in a sequence selected from the group consisting of SEQ ID NO: 12, 35, 32, and 23; (iii) a CDRL3 amino acid sequence selected from the CDRL3 in a sequence selected from the group consisting of SEQ ID NO: 12, 35, 32, and 23; and (iv) a CDRL of (i), (ii) and (iii) that contains 227 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 CDRH 1 amino acid sequence of the CDRH 1 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 CDRL1 amino acid sequence of the CDRJL1 amino acid sequence in SEQ ID NO: 12; (ii) a CDRL2 amino acid sequence of the CDRL2 amino acid sequence in SEQ ID NO: 12; (iii) a CDRL3 amino acid sequence of the CDRL3 amino acid sequence in SEQ ID NO: 12: and (iv) a CDRL of (i). (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 2 amino acids; or C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B). In some embodiments, the antigen binding protein comprises A) a CDRH1 of the CDRH1 sequence in SEQ ID NO: 67, a CDRH2 of the CDRH2 sequence in SEQ ID NO: 67, and a CDRH3 of the CDRH3 sequence in SEQ ID NO: 67, and B) a CDRL1 of the CDRLI sequence in SEQ ID NO: 12, a CDRL2 of the CDRL2 sequence in SEQ ID NO: 12. and a CDRL3 of the CDRL3 sequence in SEQ ID NO: 12. In some embodiments, the antigen binding protein comprises a heavy chain variable region (VH) having al 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, 5 1. 53, 48, 54, 55, 56, 49, 57, 50, 91,64, 62, 89. 65, 79. 80, 76. 77. 78. 83. 69, 81, and 60, and/or a light chain variable region (VL) having at least 80% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 5. 7, 9, 10. 12, 13, 15, 16, 17, 18, 19, 20,21,22,23,24, 26,28, 30,31,32,33,35,36,37.38,39,40, 42, 44. and 46. In some embodiments, the VII has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87. 58, 52, 51. 53, 48, 54, 55. 56. 49, 57. 50, 91, 64. 62, 89, 65, 79, 80, 76. 77, 78, 83, 69, 81, and 60, and/or the VL has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 5. 7, 9, 10, 12, 13. 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39.40, 42, 44, and 46. In some embodiments, the VH is selected from the group consisting of SEQ ID NO: 74. 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91.64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60, and/or the VL is selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, , 16, 1 7, 18, 19, 20, 2 I, 22, 23, 24. 26. 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46. [00971 ] In an example of any aspect of the invention, the PCSK9-targeting or binding ligand comprises or consists of AMG 145 or 31H4, I6F12, 1 1 F1, 8A3 or 21 B12 disclosed in US20120093818A1 (Amgen, Inc) or an antibody comprising the variable domains of AMG 145, 31H4, 16F12, 11 Fl, 8A3 or 2 IB 12, the disclosures of which (including sequences) are incorporated herein by reference as though explicitly recited herein and for possible inclusion in one or more 228 claims or for use in the present invention. Preferably, the PCSK9-targeting or binding ligand comprises or consists of AMG145. id="p-972" id="p-972"

[00972] In an example, the AMG145 or other ligand of the invention is glycosylated, eg, has human glycosylation (eg, produced by a CHO, Cos or Hek293 cell). In an example, the ligand of the invention is produced in CHO. (00973] Reference is made to US20I10065902A1 (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. [00974| 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.

WO2008057457 WO2008057458 WO2008057459 WO2008063382 WO2008133647 WO2009100297 WO2009100318 WO201 1037791 WO2011053759 WO201 1053783 WO2008125623 WO201 1072263 WO2009055783 WO2010029513 WO201 111 1007 WO2010077854 id="p-975" id="p-975"

[00975] 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-976" id="p-976"

[00976] In an example, the ligand is or comprises an antibody disclosed in the Examples of US20110065902A1 (eg, 316P or 300N) or is a PCSK9-binding derivative thereof. All of these disclosures (including the sequences of such proteins and corresponding nucleotide sequences) are incorporated herein by reference as though explicitly recited herein and for possible inclusion in one or more claims or for use in the present invention. In an embodiment, the ligand is or comprises the 229 variable domains of antibody 316P or 300N disclosed in US20110065902AI or is (or comprises) such antibody or a PCSK9-binding derivative thereof. id="p-977" id="p-977"

[00977] 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 CHO, Cos or Hek293 cell). Preferably, the ligand is alirocumab or SAR236553/REGN727. |00978] In an embodiment, the ligand is or comprises the variable domains of antibody evolocumab or or is (or comprises) such antibody or a PCSK9-binding derivative thereof. In an example, the antibody is glycosylated, eg. has human glycosylation (eg. produced by a CHO. Cos or Hek293 cell). Preferably, the ligand is evolocumab. |00979] In an embodiment, the ligand is selected from evolocumab, )D05~lgG2 (Merck & Co.). ALN-PCS02 (Alnylam), RN316 (Pfizer-Rinat) and alirocumab. |00980] In an embodiment, the ligand is selected from the following (sequences and definitions as per US201 1/0065902, 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: 218 and an LCVR having the amino acid sequence of SEQ ID NO: 226. 4. An antibody or antigen-binding fragment thereof w hich 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. 100981 ] In an embodiment, the ligand is selected from the following (sequences and definitions as per US2012/0093818, 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 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 230 is a LDLR non-competitive neutralizing antigen binding protein. 3. The isolated neutralizing antigen binding protein of concept 2, wherein the antigen binding protein is a LDLR competitive neutralizing antigen binding protein. 4. An antigen binding protein that selectively binds to PCSK9, wherein said antigen binding protein binds to PCSK9 with a Kd that is less than 100 pM.

. An antigen binding protein that binds to a PCSK 9 protein of SEQ ID NO: 303 in a first manner, wherein the antigen binding protein binds to a variant of PCSK9 in a second manner, wherein said PCSK9 variant has at least one point mutation at a position selected from the group consisting of: 207, 208, 185, 181,439,513, 538, 539, 132,351,390,413, 582, 162, 164, 167, 123, 129,311.3 13,337, 5 19, 521, and 554 of SEQ ID NO: 303, wherein the first manner comprises a first EC50, a first Umax, or a first EC50 and a first Bmax. wherein the second manner comprises a second EC50, a second Bmax. or a second EC50 and a second Bmax. and wherein a value for the first manner is different from a value for the second manner, and wherein the antigen binding protein comprises a light chain comprising an amino acid sequence of SEQ ID NO: 46, and wherein the antigen binding protein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 60. 6. The antigen binding protein of concept 6, wherein the first manner comprises a first Bmax, wherein the second manner comprises a second Bmax that is different from the first Bmax, and wherein said PCSK9 variant has at least one point mutation selected from the group consisting of: D162R, R164E, E167R, S123R, E129R. A3 1 1 R, D3 13R, D337R, R519E. H521 R, 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 ing 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: I, wherein the neutralizing antigen binding protein decreases the LDLR lowering effect of PCSK9 on LDLR, wherein the antigen binding protein comprises a light chain comprising an amino acid sequence of SEQ ID NO: 46, and wherein the antigen binding protein comprises a heavy chain comprising an amino acid sequence of 231 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, 1189, QI90, SI91, D192, R194, EI97, G198, RI99, V200. D224, R237. D238. K243, S373. D374. S376. Γ377, F379, 1154, TI87, HI93. El95. 1196, M20I. V202. C223. T228. S235. G236, Λ239, 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-982" id="p-982"

[00982] 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 f0375] to [0383] of US20120093818A1. which disclosure is incorporated herein by reference in its entirety for inclusion in one more claims herein. id="p-983" id="p-983"

[00983] The ligand can be administered to a human characterised as described in US20120093818A1 (Amgen, Inc) or US20110065902A1. id="p-984" id="p-984"

[00984] The ligand can be administered in a form or combination disclosed in US20120093818A1 (Amgen, Inc) or US2011O065902A I, which disclosure is incorporated herein by reference. For example, the ligand with a drug, excipient, diluent or carrier as described in US2012009381 8A1 (Amgen, Inc) or US20I 10065902A1 (eg, as disclose in paragraphs [0384] to [0412] of US201 20093818A1). which disclosure is incorporated herein by reference, and the present invention also relates to the corresponding pharmaceutical compositions comprising the combination of a ligand of the invention and such a further agent. id="p-985" id="p-985"

[00985] The ligand can be used in a method of diagnosis as set out in US20120093818A1 (Amgen, Inc) or US20110065902Al, eg, in paragraphs [0413] to [0415] of US20120093818A1 which disclosure is incorporated herein by reference. id="p-986" id="p-986"

[00986] Diagnostic Applications id="p-987" id="p-987"

[00987] In some embodiments, the ligand of the invention is a diagnostic tool. The ligand can be used to assay the amount of PCSK9 present in a sample and/or subject. As will be appreciated by one of skill in the art, such ligands need not be neutralizing ligands. In some embodiments, the diagnostic ligand is not a neutralizing ligand. In some embodiments, the diagnostic ligand binds to a different epitope than a neutralizing ligand binds to. In some embodiments, the two ligands do not compete with one another. 232 (00988} 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, fkiorophores, other molecular probes, or enzymes can be linked to the ligand and the presence of the ligand can be observed in a variety of ways. The method for screening for such disorders can involve the use of the kit or simply the use of one of the disclosed ligands and the determination of whether the ligand binds to PCSK9 in a sample. As will be appreciated by one of skill in the art, high or elevated levels of PCSK9 will result in larger amounts of the ligand binding to PCSK9 in the sample. Thus, degree of ligand binding can be used to determine how much PCSK9 is in a sample. Subjects or samples with an amount of PCSK9 that is greater than a predetermined amount (e.g., an amount or range that a person without a PCSK9 related disorder would have) can be characterized as having a PCSK9 mediated disorder. In some embodiments, the invention 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. |00989| In some embodiments, the ligand is a non-neutralizing ligand and is used to determine the amount of PCSK9 in a subject receiving an ABP and/or statin treatment. id="p-990" id="p-990"

[00990] In some embodiments, the ligand of the invention can specifically bind human PCSK9 (eg, one, two or more rare variant forms disclosed herein) and is characterized by at least one of: (i) capable of reducing serum total cholesterol at least about 25-35% and sustaining the reduction over at least a 24 day period relative to a predose level; (ii) capable of reducing serum LDL· cholesterol at least about 65-80% and sustaining the reduction over at least a 24 day period relative to a predose level; (iii) capable of reducing serum LDL cholesterol at least about 40-70% and sustaining the reduction over at least a 60 or 90 day period relative to a predose level; (iv) capable of reducing serum triglyceride at least about 25-40% relative to predose level; (v) does not reduce serum HDL cholesterol or reduces serum HDL cholesterol no more than 5% relative to predose level. In some embodiments, an isolated nucleic acid molecule is provided and it encodes the ligand. In some embodiments an expression vector is provided and comprises the nucleic acid molecule. In some embodiments, a pharmaceutical composition is provided and it can comprise the ligand and a pharmaceutically acceptable carrier. In some embodiments, a method is provided for treating a disease or condition which is ameliorated, improved, inhibited or prevented with a PCSK9 antagonist ligand of the invention. The method can comprise administering a therapeutic amount of the pharmaceutical composition or ligand to a subject in need thereof. In some embodiments, the subject is a human subject suffering from hypercholesterolemia, hyperlipidemia, indicated for LDL apheresis, identified as heterozygous for Familial Hypercholesterolemia, statin intolerant, statin uncontrolled, at risk for developing hypercholesterolemia, dyslipidemia, cholestatic liver disease, nephrotic syndrome, 233 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. id="p-991" id="p-991"

[00991] 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 proprotcin convertase subtilisin/kexin type 9 (hPCSK9, eg, one, two or more rare variant forms disclosed herein and optionally form a and/or form a ’), characterized by the ability to reduce serum LDL cholesterol in a human by 40-80% over a 24. 60 or 90 day period relative to predose levels, with little or no reduction in serum HDL cholesterol and/or w ith little or no measurable effect on liver function, as determined by ALT and AST measurements. id="p-992" id="p-992"

[00992] In one embodiment, the ligand ofthe invention comprises an antibody or antigen-binding fragment of an antibody that specifically binds hPCSK9 and is characterized by at least one of: (i) capable of reducing serum total cholesterol at least about 25-35% and sustaining the reduction over at least a 24 day period relative to a predose level, preferably the reduction in scrum 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-993" id="p-993"

[00993] See US20I 1/0065902 for definitions of these terms and optional features, the disclosure of wTich is incorporated herein by reference in its entirety. id="p-994" id="p-994"

[00994] 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 al least about 40-70% and sustaining the reduction over at least a 60 or 90 day period relative to a predosc 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-995" id="p-995"

[00995] In one embodiment, the antibody or antigen-binding fragment is characterized as exhibiting an enhanced binding affinity (KD) for I1PCSK9 at pH 5.5 relative to the KD at pH 7.4, as measured by plasmon surface resonance. In a specific embodiment, the antibody or fragment thereof exhibits at least a 20-fold, at least a 40-fold or at least a 50-fold enhanced affinity for PCSK9 at an acidic pH relative to a neutral pH, as measured by surface plasmon resonance. 234 id="p-996" id="p-996"

[00996] 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-997" id="p-997"

[00997] In another embodiment, the antibody or antigen-binding fragment binds human, human GOP mutation D374Y, cynomolgus monkey, rhesus monkey, mouse, rat and hamster PCSK9. id="p-998" id="p-998"

[00998] In one embodiment, the antibody or antigen-binding fragment binds human and monkey PCSK.9, but does not bind mouse, rat or hamster PCSK9. (00999] 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]-|037] of US2011/0065902, the disclosures of which are incorporated herein by reference. [001000( In a related embodiment, the invention comprises an antibody or antigen-binding fragment of an antibody which specifically binds I1PCSK9, wherein the antibody or fragment comprises heavy and light chain CDR domains contained within heavy and light chain sequence pairs selected from the group consisting of SEQ ID NO (using the sequence numbering in US2011/0065902): 2/10, 18/20, 22/24, 26/34, 42/44, 46/48, 50/58, 66/68, 70/72, 74/82, 90/92, 94/96, 98/106, 114/116, 118/120, 122/130, 138/140, 142/144, 146/154, 162/164, 166/168, 170/178, 186/188, 190/192, 194/202, 210/212, 214/216, 218/226, 234/236, 238/240, 242/250, 258/260. 262/264. 266/274, 282/284. 286/288. 290/298, 306/308. 310/312, 314/322. 330/332, 334/336, 338/346, 354/356, 358/360. 362/370, 378/380. 382/384, 386/394. 402/404. 406/408. 410/418. 426/428, 430/432. 434/442, 450/452. 454/456. 458/466. 474/476. 478/480. 482/490. 498/500. 502/504. 506/514. 522/524. 526/528. 530/538. 546/548. 550/552. 554/562. 570/572. 574/576. 578/586. 594/596, 598/600, 602/610, 618/620. 622/624, 626/634, 642/644, 646/648, 650/658, 666/668. 670/672, 674/682, 690/692, 694/696, 698/706, 714/716, 718/720, 722/730, 738/740 and 742/744. In one embodiment, the CDR sequences are contained within HCVR and LCVR selected from the amino acid sequence pairs of SEQ ID NO: 50/58, 66/68, 70/72, 74/82, 90/92, 94/96. 122/130, 138/140, 142/144, 218/226, 234/236, 238/240, 242/250, 258/260, 262/264, 3 14/322, 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. [0010011 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 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 235 inhibiting 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase, such as, for example, cerovastatin, atorvastatin, simvastatin, pitavastin. rosuvastatin, fluvastatin, lovastatin, pravastatin, etc; capable of inhibiting cholesterol uptake and or bile acid re-absorption; capable of increasing lipoprotein catabolism (such as niacin); and/or activators of the LXR transcription factor that plays a role in cholesterol elimination such as 22-hydroxycholesterol. |001002] In an example, the invention provides a method for inhibiting hPCSK9 activity using the anti-PCSK9 ligand of the invention (eg, an antibody or antigen-binding portion of the antibody of the invention), wherein the therapeutic methods comprise administering a therapeutically effective amount of a pharmaceutical composition comprising an antibody or antigen-binding fragment of an antibody of the invention. The disorder treated is any disease or condition which is improved, ameliorated, inhibited or prevented by removal, inhibition or reduction of PCSK9 activity. Specific populations treatable by the therapeutic methods of the invention include subjects indicated for LDL apheresis, subjects with PCSK9-activating mutations (gain of function mutations, "GOF"), subjects with heterozygous Familial Hypercholesterolemia (heFI I); subjects with primary hypercholesterolemia who are statin intolerant or statin uncontrolled; and subjects at risk for developing hypercholesterolemia who may be preventably treated. Other indications include dyslipidemia associated with secondary causes such as Type 2 diabetes mellitus, cholestatic liver diseases (primary biliary cirrhosis), nephrotic syndrome, hypothyroidism, obesity; and the prevention and treatment of atherosclerosis and cardiovascular diseases. id="p-1003" id="p-1003"

[001003] 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 Bl00). [001004] 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. [ 001005] Treat meat Population id="p-1006" id="p-1006"

[001006] The invention provides therapeutic methods for treating a human patient in need of a composition or ligand of the invention. While modifications in lifestyle and conventional drug treatment are often successful in reducing cholesterol levels, not all patients are able to achieve the recommended target cholesterol levels with such approaches. Various conditions, such as familial hypercholesterolemia (FH), appear to be resistant to lowering of LDL-C levels in spite of aggressive use of conventional therapy. Homozygous and heterozygous familial hypercholesterolemia (hoFH, heFH) is a condition associated with premature atherosclerotic vascular disease. However, patients diagnosed with hoFH are largely unresponsive to conventional drug therapy and have limited treatment options. Specifically, treatment with statins, which reduce LDL-C by inhibiting cholesterol synthesis and upregulating the hepatic LDL receptor, may have little effect in patients whose LDL receptors are non-existent or defective. A mean LDL-C reduction of only less than about 20% has 236 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-1007" id="p-1007"

[001007] Specific populations treatable by the therapeutic methods of the invention include patients indicated for LDL apheresis, subjects with PCSK9-activating (GOF) mutations, heterozygous Familial Hypercholesterolemia (heFH); subjects with primary hypercholesterolemia who are statin intolerant or statin uncontrolled: and subjects at risk for developing hypercholesterolemia who may be preventably treated. |Ό01008] Therapeutic Administration and Formulations id="p-1009" id="p-1009"

[001009] The invention provides therapeutic compositions comprising the anti-PCSK9 ligands, antibodies or antigen-binding fragments thereof of the present invention. The administration of therapeutic compositions in accordance with the invention will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTINT™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations*' PDA (1998) J Pharm Sci Techno! 52:238-3 11. id="p-1010" id="p-1010"

[001010] The dose may vary depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like. When the ligand, eg. antibody, of the present invention is used for treating various conditions and diseases associated with PCSK9. including hypercholesterolemia, disorders associated with LDL and apolipoprotein B, and lipid metabolism disorders, and the like, in an adult patient, it is advantageous to intravenously administer the ligand or antibody of the present invention normally at a single dose of about 0.01 to about 20 mg/kg body weight, more preferably about 0.02 to about 7, about 0.03 to about 5, or about 0.05 to about 3 mg/kg body weight. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. id="p-1011" id="p-1011"

[001011] Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, thus the composition invention provides the ligand by e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al. (1987) J. Biol. Chem. 237 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., ora! mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. id="p-1012" id="p-1012"

[001012] The pharmaceutical composition can be also delivered in a vesicle, in particular a liposome (see Langer (1990) Science 249:1 527-1533; 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 17-327; see generally ibid.). id="p-1013" id="p-1013"

[001013] 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 materialscan be used: sec. 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-1014" id="p-1014"

[001014] The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g.. by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oi 1)), 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. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable 238 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. |001015] 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 111 (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-1016" id="p-1016"

[001016] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the aforesaid antibody contained is generally about 5 to about 500 mg per dosage form in a unit dose; especially in the form of injection, it is preferred that the aforesaid antibody is contained in about 5 to about 100 mg and in about 10 to about 250 mg for the other dosage forms. id="p-1017" id="p-1017"

[001017] I he 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 anli-PCSK9 ligands, eg, antibodies or antibody fragments, of the invention are particularly useful for the treatment of hypercholesterolemia and the like. Combination therapies may include the anti-PCSK9 ligand of the invention with, for example, one or more of any agent that (1) induces a cellular depletion of cholesterol synthesis by inhibiting 3-hydroxy-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-hydroxycho)esterol 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). id="p-1018" id="p-1018"

[001018] Tailoring Antibodies to Rare PCSK9 Variant Profile 239 id="p-1019" id="p-1019"

[001019] As outline above, the invention includes the possibility to tailor treatment of humans further by selecting anti body-based ligands with variable domains based on gene segments commonly found in humans of the ethnic populations where the variant PCSK9 forms are found to meet the selection criteria of the invention. An example is provided below for ligands comprising antibody VH domains derived from recombination of human VH3-23. id="p-1020" id="p-1020"

[001020] The inventor analysed the frequencies and distribution of various human VH3-23 alleles and realised the desirability of using ligands based on human VI13-23 alleles comprising SNP r$560698 19. 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-1021" id="p-1021"

[001021] Figure 2 shows the cumulative allele frequency distribution across the 1000 Genomes Project database of human VH3-23 alleles comprisingSNPrs56069819 (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 I 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 VH3-23 alleles comprising SNP rs560698J9. 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-1022" id="p-1022"

[001022] Notably, human VH3-23 alleles comprising SNP rs56069819 were found in the CEU 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 VH domain derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, the VII gene segment comprising a nucleotide sequence that comprises SNP rs56069819 (dbSNP numbering, build number as recited above). id="p-1023" id="p-1023"

[001023] 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. id="p-1024" id="p-1024"

[001024] 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, CEL and GBR. [0010251 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. [001026] In an example, the ligand is for treating and/or preventing a PCSK9-mediated disease or condition in a human of ASW, LWK, YRI, CEU or GBR ancestry. 240 id="p-1027" id="p-1027"

[001027] 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/ c. 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 V 143-23*04. id="p-1028" id="p-1028"

[001028] 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-1029" id="p-1029"

[001029] 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/ c. in. e and h 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. [001030] 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 aj 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. [001031] in an embodiment, the ligand is for treating and/or preventing a PCSK9-mediated disease or condition 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 Table 6. Optionally this ligand comprises a VH domain derived from recombination of human VH3-23*04. 1001032) In an example, the ligand is alirocumab. id="p-1033" id="p-1033"

[001033] 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, νλ or constant region gene segments (see further Table 9 for representative variants). 1001034) 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) IGHV 1-18*01 and the genome of the human comprises a human IGHV 1-18*01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGHV 1 -18*01; or (ii) IGVH 1 -46*01 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 I-46*01. 1001035] 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 241 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 IGKV4-I *01 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV4-l*01; (ii) IGLV2-I4*O1 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*0I; or (iii) IGKV 1-13*02 and the genome of the human comprises a human IGKV 1 -1 3*02 nucleotide sequence or the human expresses antibodies comprising variable domains derived from the recombination of human IGKV LI 3*02. [0010361 For example, the inventor identified the possibility of addressing the rarer 1GHgamma-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-1037" id="p-1037"

[001037] 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. 1001038] In another example, the inventor addressed human kappa constant region variation. Thus, in this example the ligand of the invention comprises or consists of an antibody that comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 or a Cys corresponding to position 87 of SEQ ID NO: 50; and wherein the genome of the human comprises a kappa light chain constant region nucleotide sequence that encodes such a Val or Cys or the human expresses antibodies comprising human kappa light chain constant regions comprising such a Val or Cys. An example of such a ligand is alirocumab or bococizumab. 242 id="p-1039" id="p-1039"

[001039] 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 ofthe human comprises a human IGLC2*01 nucleotide sequence or the human expresses antibodies comprising human light chain IGLC2*0I constant regions. An example of such a ligand is evolocumab. [001040] Further exemplary ligands are in the paragraphs 1-17 as follows. 1. An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human gamma heavy chain constant region that comprises a first amino acid that is encoded by a human gamma heavy chain constant region gene segment SNP. and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said PCSK9 amino acid sequence and comprises a human gamma heavy chain constant region gene segment comprising said SNP, or the human expresses antibodies comprising human gamma constant regions comprising said first amino acid.

In an alternative, paragraph 1 provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 or a Leu corresponding to position 206 of SEQ ID NO: 42. and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation 1474V or E670G in SEQ ID NO: I. wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGHGP01 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 1474V. In another embodiment, said mutation is E670G. An example provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a 243 C-terminal domain comprisinga mutation I474V in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGHG 1 *01 human heavy chain constant region gene segment. Optionally, the antibody or fragment comprises an IGHG I *01 human heavy chain constant region.

Another example provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42. and the antibody or fragment 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 IGHG I *01 human heavy chain constant region gene segment. Optionally, the antibody or fragment comprises an IGHG I *01 human heavy chain constant region.

In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (i) an IGHG1 *01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotcin convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation 1474V or E670G in SEQ ID NO: I. 2. The antibody or antibody fragment of paragraph 1. wherein the antibody comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO; 42. 3. The antibody or antibody fragment of paragraph 1 or 2, wherein the antibody comprises an IGHG 1*01 human heavy chain constant region. 4. The antibody or antibody fragment of any one of paragraphs 1 to 3, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a Cterminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a 244 proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30.

. The antibody or antibody fragment of any one of paragraphs 1 to 4, the method comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation 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 1474 V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ iD NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 thereby forming a complex when the nucleotide sequence encoding the PCSK9 that comprises a C-terminal domain comprising the mutation 1474V or E670G in SEQ ID NO: 1 is present; and 245 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: 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.

. 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, I. 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 scrum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 13. The antibody or antibody fragment of any one of paragraphs 1 to 12, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising a mutation 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. 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 246 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, 7. The 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. id="p-1041" id="p-1041"

[001041] Further exemplary methods are in the paragraphs 1-18 as follows. 1. A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1. wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 or a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (i) an IGHGI *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 proprotcin convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: I. in an embodiment, said mutation is 1474V. In another embodiment, said mutation is E670G.

An example provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 in SEQ ID NO: L 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 IGHGI*01 human heavy chain 247 constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V in SEQ ID NO: 1. Optionally, the antibody or fragment comprises a IGHG 1*01 human heavy chain constant region.

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

In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-1 heavy chain constant region that comprises an Asp corresponding to position 204 of SEQ ID NO: 42 and a Leu corresponding to position 206 of SEQ ID NO: 42 and wherein said human comprises (i) an IGHG 1*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 ID NO: 1. 2. I he 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. 248 4. The method of paragraph I, 2 or 3, wherein the antibody comprises an IGHG 1 *01 human heavy chain constant region.

. The method of any one of paragraphs 1 to 4, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30. 6. The method of any one of paragraphs 1 to 5. comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation 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 PCSK9 that comprises the Cterminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 8. The method of paragraph 7, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation 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, 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: 1 is present; and 249 detecting the presence or absence ofthe complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 9. The method of paragraph 7 or 8, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format.

. The method of any one of paragraphs 1 to 9, wherein said human is or has been further determined to be substantially resistant to statin treatment. 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 SPLQ ID NO: I.

. The method of any one of paragraphs 1 to 14, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 16. The method of any one of paragraphs 1 to 15, wherein said antibody or antibody fragment treats or reduces the risk in said human of at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a 250 stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 7. The method of any one of paragraphs 1 to 16, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 8. 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. id="p-1042" id="p-1042"

[001042] Further exemplary ligands are in the paragraphs 1-17 as follows. 1. An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody comprises a human gamma-2 heavy chain constant region that comprises an amino acid selected from the group consisting of a Pro corresponding to position 72 of 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 io position 257 of SEQ ID NO: 44, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an 1GHG2*OI 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 1474V. In another embodiment, said mutation is E670G.

An example provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody 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 1474V in SEQ ID NO: I. wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGHG2*0l human heavy chain constant region gene segment. Optionally, the 251 antibody or fragment comprises an IGHG2*0l human heavy chain constant region.

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

In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human gamma-2 heavy chain constant region that comprises a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44. a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44 and wherein said human comprises (i) an 1GHG2*O1 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 ID NO: 1. 2. The antibody or antibody fragment of paragraph I. wherein the antibody comprises a human gamma-2 heavy chain constant region that comprises a Pro corresponding to position 72 of SEQ ID NO: 44. an Asn corresponding to position 75 of SEQ ID NO: 44. a Phe corresponding to position 76 of SEQ ID NO: 44. a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44. 3. The antibody or antibody fragment of paragraph I or 2, wherein the antibody comprises an IGHG2*01 human heavy chain constant region. 252 4. The antibody or antibody fragment of any one of paragraphs I to 3, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30.

. The antibody or antibody fragment of any one of paragraphs I 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 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 I474V or E670G in SEQ ID NO: 1. 7, The antibody or antibody fragment of paragraph 6, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation 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 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 253 detecting the presence cr 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. 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. 2. The antibody or anlibody fragment of any one of paragraphs 6 lo 8. wherein said biological sample comprises scrum, 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 I2; 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. 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. 254 . The antibody or antibody fragment of any one of paragraphs I 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-1043" id="p-1043"

[001043] Further exemplary methods are in the paragraphs 1-18 as follows. 1. A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: I. 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*(H human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-2 heavy chain constant regions comprising such a Pro. Asn. Phe. Val and Ala and (ii) a nucleotide sequence encoding said proprotcin 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.

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: I, wherein the 255 antibody or fragment comprises a human gamma-2 heavy chain constant region that comprises a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44 and wherein said human comprises (i) an IGHG2*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V in SEQ ID NO: 1. Optionally, the antibody or fragment comprises an IGHG2*0l human heavy chain constant region.

Another example provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation E670G in SEQ ID NO: L wherein the antibody or fragment comprises a human gamma-2 heavy chain constant region that comprises a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44 and wherein said human comprises (i) an IGHG2*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation E670G in SEQ ID NO: I. Optionally, the antibody or fragment comprises an IGHG2*0l human heavy chain constant region.

In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: L wherein the antibody or fragment comprises a human gamma-2 heavy chain constant region that comprises a Pro corresponding to position 72 of SEQ ID NO: 44, an Asn corresponding to position 75 of SEQ ID NO: 44, a Phe corresponding to position 76 of SEQ ID NO: 44, a Val corresponding to position 161 of SEQ ID NO: 44 and an Ala corresponding to position 257 of SEQ ID NO: 44 and wherein said human comprises (i) an IGHG2*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: I. 256 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 1GHG2*O1 human heavy chain constant region.

. The method of any one of paragraphs 1 to 4, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30. 6. The method of any one of paragraphs 1 to 5, comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation 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 for a nucleotide sequence encoding the PCSK9 that comprises the Cterminal 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 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 I474V or E670G in SEQ ID NO: I is present; and/or 257 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 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 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. 1. The method of any one of paragraphs I 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 1 L wherein said antibody or antibody fragment is administered to the human separately or simultaneously with said statin treatment. 3. 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 I474Vor E670G in SEQ ID NO: 1. 258 . 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. 6. 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. 7. fhe method of any one of paragraphs 1 to 16, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 18. fhe 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. 1001044] Further exemplary ligands arc in the paragraphs 1-17 as follows. 1. An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Vai corresponding to position 84 of SEQ ID NO: 50 or a Cys corresponding to position 87 of SEQ ID NO: 50, and the 3011000)-7 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 I474V. In another embodiment, said mutation is E670G.

An example provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val 259 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 1474V in SEQ ID NO:1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises an IGKC*01 human light chain constant region gene segment. Optionally, the antibody or fragment comprises an 1GKC*OI human light chain constant region.

Another example provides:An antibod}' or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 and a Cys corresponding to position 87 of SEQ ID NO: 50, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a 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*0l human light chain constant region gene segment. Optionally, the antibody or fragment comprises an IGKC*01 human light chain constant region.

In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 and a Cys corresponding to position 87 of SEQ ID NO: 50 and wherein said human comprises (i) an IGKC*01 human heavy chain constant region gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation 1474V or E670G in SEQ ID NO: E 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. I'he antibody or antibody fragment of paragraph 1 or 2, wherein the antibody comprises an IGKC*01 human kappa chain constant region. 260 4. The antibody or antibody fragment of any one of paragraphs I 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 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.

. 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 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 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 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 1474V or E670G in SEQ ID NO: 1 is present: and 261 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. 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 io 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 ceil, urine and/or saliva of said human. 13. The antibody or antibody fragment of any one of paragraphs 1 to 12. wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising a mutation I474V or E670G. optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 28. or said human is indicated as homozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising a mutation I474Vor E670G in SEQ ID NO: 1. 14. The antibody or antibody fragment of any one of paragraphs 1 to 13, wherein said human has been diagnosed with at least one condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 262 . 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.

I 7. 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. 1001045] further exemplary methods are in the paragraphs 1-1 8 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: 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 or a Cys corresponding to position 87 of SEQ ID NO: 50 and wherein said human comprises (i) an IGKC*01 human light chain constant region gene segment, or the human expresses antibodies comprising human kappa light chain constant regions comprising such an Val and Cys and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-tcrminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1.

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

An example provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 in SEQ ID NO: 1, wherein the antibody or fragment comprises a human 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 263 gene segment and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation I474V in SEQ ID NO: 1. Optionally, the antibody or fragment comprises an IGKC*01 human light chain constant region.

Another example provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation E670G in SEQ ID NO: k 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 ty pe 9 (PCSK9) that comprises a C-terminal domain comprising said mutation E670G in SEQ ID NO: 1. Optionally, the antibody or fragment comprises an 1GKC*OI human light chain constant region.

In an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1, wherein the antibody or fragment comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 and a Cys corresponding to position 87 of SEQ ID NO: 50 and wherein said human comprises (i) an IGKC*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 I474V or E670G in SEQ ID NO: 1. 2. The method of paragraph 1. comprising, before said administering, selecting said human comprising said nucleotide sequence of (ii). 3. The method of paragraph 1 or 2. wherein the antibody comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 50 or a Cys corresponding to position 87 of SEQ ID NO: 50. 264 4. The method of paragraph 1,2 or 3, wherein the antibody comprises an IGKC*01 human kappa chain constant region.

. The method of any one of paragraphs 1 to 4. wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotcin 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 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 PCSK9 that comprises the Cterminal 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: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to at least one nucleotide present in said selected sequence which is not present in SEQ ID NO: 28 or hybridizes to an antisense sequence thereby forming a complex when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 is present; and/or b. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides of a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation 1474V or E670G in SEQ ID NO; I or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises al 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 265 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. I'he method of paragraph 7 or 8. wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format.

. The method of any one of paragraphs 1 to 9, wherein said human is or has been further determined to be substantially resistant to statin treatment. 11. The method of any one of paragraphs 1 to 10, wherein said human is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 12. The method of paragraph 10 or 11, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with said statin treatment. 13. The method of any one of paragraphs 7 to 9. wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 14. The method of any one of paragraphs 1 to 13, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation 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 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. The method of any one of paragraphs 1 to 1 5, 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 266 stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 17. The method of any one of paragraphs I 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. [001046| f urther exemplary ligands are in the paragraphs 1-15 as follows.

I. An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human 1GEC2*O1 lambda light chain constant region, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation 1474V or E670G in SEQ ID NO: 1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises a human IGLC2*01 lambda light chain constant region gene segment, or the human expresses antibodies comprising human IGLC2*01 lambda light chain constant regions.

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

An example provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human IGLC2*0l lambda light chain constant region, and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation 1474V in SEQ ID NO: 1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence and comprises a human 1GLC2*O1 lambda light chain constant region gene segment. Optionally, the antibody or fragment comprises a human 1GLC2*O1 lambda light chain constant region.

Another example provides:An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human IGLC2*01 lambda light chain constant region, and the antibody 267 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*0l lambda light chain constant region. in an example, said antibody or antibody fragment has been determined to specifically bind a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1. wherein the antibody or fragment comprises a human 1GLC2*O1 lambda light chain constant region and wherein said human comprises (i) an IGLC2*0i 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 ID NO: 1. 2. The antibody or antibody fragment of paragraph I, 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: 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. 3. The antibody or antibody fragment of paragraphs I or 2. the method comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G. optionally, wherein the determining step is performed before administration of the antibody to the human. 4. The antibody or antibody fragment of paragraph 3. wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation 1474V 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 268 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 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 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 I474V or E670G in SEQ ID NO: 1. 6. The antibody or antibody fragment of paragraph 4 or 5, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 7. The antibody or antibody fragment of any one of paragraphs 1 to 6. wherein said antibody or antibody fragment is for administration to a human that is or has been further determined to be substantially resistant to statin treatment. 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 269 treatment.

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

. 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. 1001047] 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: I. wherein the antibody or fragment comprises a human IGLC2*01 lambda light chain constant 270 region and wherein said human comprises (i) an IGLC2*0l human light chain constant region gene segment, or the human expresses antibodies comprising a human IGLC2*01 lambda light chain constant regions and (ii) a nucleotide sequence encoding said proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising said mutation 1474V or E670G in SEQ ID NO: 1.

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

An example provides:A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 in SEQ ID NO: 1, wherein the antibody or fragment comprises a human 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 1474V 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 1GLC2*OI 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*0l 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 271 comprises a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 2. The method of paragraph 1, comprising, before said administering, selecting said human comprising said nucleotide sequence of (ii). 3. The method of paragraph 1 or 2, wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30. 4. The method of any one of paragraphs 1 to 3, comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation I474V or E670G. optionally, wherein the determining step is performed before administration of the 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 1474V or E670G in SEQ ID NO: 1. 6. The method of paragraph 5. wherein the assay ing comprises contacting the biological sample with a. al 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 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 272 detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 7. The method of paragraph 5 or 6, wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 8. I he method of any one o f paragraphs 1 to 7. wherein said human is or has been further determined to be substantially resistant to statin treatment. 9. The method of any one of paragraphs 1 to 8, wherein said human is receiving or has received statin treatment or has reduced responsiveness to statin treatment.

. The method of paragraph 8 or 9, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with said statin treatment. 11. The method of any one of paragraphs 5 to 7, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 12. The method of any one of paragraphs 1 to 1 1. wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PGSK9 C-terminal domain comprising said mutation 1474V or E670G. optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ JD 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 273 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. 1001048] Further exemplary ligands are in the paragraphs 1-1 5 as follows.

I. An antibody or antibody fragment for use in a method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof, wherein the antibody or fragment comprises a human variable domain that is derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, wherein the VH gene segment is as defined in any one of clauses 80 to 90. and the antibody or fragment specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) amino acid sequence that comprises a C-terminal domain comprising a mutation I474V or E670G in SEQ ID NO: 1, wherein the human comprises a nucleotide sequence encoding said amino acid sequence, and comprises said VH gene segment or expresses antibodies comprising VH domains that are derived from the recombination of said human VH gene segment, a human D gene segment and a human JI I gene segment.

In an embodiment, said mutation is 1474V. In another embodiment. said mutation is E670G. 2. The antibody or antibody fragment of paragraph 1. wherein the human has been determined to comprise the nucleotide sequence that encodes a PCSK9 comprising a 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. 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 1474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the 274 human. 4. The antibody or antibody fragment of paragraph 3, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1.

. The antibody or antibody fragment of paragraph 4. wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 1 or that specifically hybridizes to an antisense of said sequence, wherein said nucleic acid hybridizes to al 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 1 0 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: I 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 ofthe complex, wherein detecting the presence ofthe 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. 275 7. The antibody or antibody fragment of any one of paragraphs 1 to 6, wherein said antibody or antibody fragment is for administration to a human that is or has been further determined to be substantially resistant to statin treatment. 8. The antibody or antibody fragment of any one of paragraphs 1 to 7, wherein antibody or antibody fragment is for administration to a human that is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 9. The antibody or antibody fragment of paragraph 7 or 8, wherein said antibody or antibody fragment is for administration to the human separately or simultaneously with said statin treatment.

. The antibody or antibody fragment of any one of paragraphs 4 to 8. wherein said biological sample comprises serum, blood, faeces, tissue, a celI. 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 PCSK.9 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: I. 12. The antibody or antibody fragment of any one of paragraphs 1 to 1 1, 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 I 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. 276 . The antibody or antibody fragment of any one of paragraphs J 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.

I. A method of reducing cholesterol level or maintaining previously reduced cholesterol level in a human in need thereof the method comprising administering to said human an antibody or antibody fragment that specifically binds a proprotein convertase subtilisin/kexin type 9 (PCSK9) that comprises a C-terminal domain comprising a mutation 1474 or E670G in SEQ ID NO: 1. wherein the antibody or fragment comprises a human variable domain that is derived from the recombination of a human VH gene segment a human D gene segment and a human JI 1 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 1474V or E670G in SEQ ID NO: 1.

In an embodiment, said mutation is I474V. In another embodiment, said mutation is E670G. 2. The method of paragraph 1, comprising, before said administering, selecting said human comprising said nucleotide sequence of (ii). 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-terminal domain comprising said mutation I474V or E670G in SEQ ID NO: 1 and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein encoded by the nucleotide sequence of SEQ ID NO: 29 or 30. 4. The method of any one of paragraphs 1 to 3, comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation 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. 277 . 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 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-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, 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 1474V or E670G in SEQ ID NO: I. 7. The method of paragraph 5 or 6. wherein the assaying comprises nucleic acid amplification and optionally one or more methods selected from sequencing, next generation sequencing, nucleic acid hybridization, and allele-specific amplification and/or wherein the assaying is performed in a multiplex format. 8. The method of any one of paragraphs 1 to 7, wherein said human is or has been further determined to be substantially resistant to statin treatment. 9. The method of any one of paragraphs 1 to 8. wherein said human is receiving or has received statin treatment or has reduced responsiveness to statin treatment. 278 . 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. 1. 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. I’he method of any one of paragraphs 1 to 1 I, 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: I. 13. The method of any one of paragraphs I 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 1 to 15, wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. |001049] Regimens 1001050] A: The invention further provides the following regimens, ligands and kits. 22. 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 279 antibody or fragment) that has been determined to specifically bind to said PCSK9variant; wherein the human expresses said PCSK9 variant or the genome of the human comprises a nucleotide sequence encoding said PCSK9 variant; wherein said human is treated for said disease or condition.

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

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

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

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

In an embodiment, the method comprises, before said administering, selecting a human comprising said nucleotide sequence encoding the PCSK9, wherein the human is said human in clause 1 (eg, la). 23. 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. 280 24. The method of clause I or 2, wherein the specific binding to said PCSK9 is binding with a dissociation constant (Kd) of 1 nM or less, eg, 100, 10 or 1 pM or less.

. 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. 26. 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. 27. The method of any one of clauses I 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: 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. 28. The method of any one of clauses 1 to 6 (eg, when dependent from clause la), comprising the step of determining that the human comprises the nucleotide sequence that encodes a PCSK9 comprising a C-terminal domain comprising said mutation I474V or E670G and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) variant protein comprising said mutation 1474V or E670G, optionally, wherein the determining step is performed before administration of the antibody to the human. 29. 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.

. The method of clause 8, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E670G in SEQ ID NO: 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 281 when at least one nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation I474V or E67OG 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. 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. 32. The method of any one of clauses I to 10, wherein said human is or has been further determined to be substantially resistant to statin treatment. 33. 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. 34. The method of clauses I 1 or 12, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with said statin treatment.

. 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. 36. 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 282 the PCSK9 C-terminal domain comprising said mutation I474Vor E670G in SEQ ID NO: 1. 37. 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. 38. The method of any one of clauses 1 to 16, wherein said antibody or antibody fragment treats or reduces the risk in said human of at feast 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. 39. The method of any one of clauses 1 to 1 7, wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 40. The method of any one of clauses I to 18. wherein said antibody or antibody fragment is administered by intravenous or subcutaneous administration and/or is comprised in an injectable preparation. 41. A ligand (eg, an antibody or fragment) for use in the method of any one of clauses I to 19. wherein the ligand specifically binds the PCSK9. 42. A kit comprising the ligand of clause 20 and instructions for carrying out the method of any one of clauses I to 19. id="p-1051" id="p-1051"

[001051] B: The invention further provides the following regimens, ligands and kits. 21. A method of reducing cholesterol level or maintaining a previously reduced cholesterol level in a human in need thereof, the method comprising:- a. Carrying out an initial treatment of said human for an initial treatment period by administering an anti-human PCSK9 ligand (eg, an antibody or fragment) to said human, wherein (i) the ligand has been determined to specifically bind to a PCSK9 comprising a C-terminal domain comprising I474V or 670G (numbering according to SEQ ID NO: I); (ii) the human expresses said PCSK9 or the genome of the human comprises a nucleotide 283 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. 22. The method of clause 1, wherein the human has or is suffering from statin-associated memory loss or a statin-associated neurodegenerative condition, or has or is at increased risk of diabetes (eg, statin-associated diabetes). 23. The method of clause 1 or 2. comprising, before said initial treatment, the step of determining that the human has or is suffering from statin-associated memory loss or a statin-associated neurodegenerative condition, or has or is at increased risk of diabetes (eg, statin-associated 284 diabetes). 24. 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). 26. The method of any one of clauses I io 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. 27. The method of any one of clauses 1 to 6, wherein step (b) comprises determining that the human is intolerant or refactory to treatment by a statin. 28. The method of any one of clauses 1 to 7, wherein the initial treatment comprises the administration of a statin, fenofibrate (eg, Tricor™ or Lofibra™) or ezetimibe to the human in addition to the ligand. 29. The method of any one of clauses 1 to 8, wherein step (b) comprises terminating or reducing statin, fenofibrate (eg. Tricor™ or Lofibra™) or ezetimibe treatment during step (c).

. The method of any one of clauses 1 to 9. comprising increasing (ie. increasing compared to the initial treatment dose) the ligand dose during step (c). 31. 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 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, 10mg); medium >20 and <60mg (eg. 40mg): high 60-1 OOmg (eg, 80mg). 285 32. 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. 33. 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. 34. The method of any one of clauses 1 to 13. comprising, before the initial treatment, the step of determining that the ligand specifically binds to said PCSK9, eg, using SPR or ELISA.

. The method of any one of clauses 1 to 14, wherein the specific binding to said PCSK9 is binding with a dissociation constant (Kd) of 1 nM or less, eg, 100, 10 or IpM or less. 36. The method of any of clauses 1 to 15, wherein the human is at risk of or suffering from a condition selected from a lipid disorder, hyperlipoproteinemia, hyperlipidemia, dyslipidemia, hypercholesterolemia, a heart attack, a stroke, coronary heart disease, atherosclerosis, peripheral vascular disease, claudication and high blood pressure. 37. The method of clause 16. wherein step (c) treats or reduces the risk of said condition in the human. 38. The method of any one of clauses i 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 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. 39. The method of any one of clauses I to 18. 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. 40. The method of clause 19, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding the PCSK9 that comprises the C-terminal 286 domain comprising the mutation I474V or E670G in SEQ ID NO: 1. 41. The method of clause 20, wherein the assaying comprises contacting the biological sample with a. at least one oligonucleotide probe comprising a sequence of at least 10 contiguous nucleotides that can specifically hybridize to and identify in the biological sample a nucleotide sequence encoding the PCSK9 that comprises the C-terminal domain comprising the mutation 1474V 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-terminal domain comprising the mutation 1474V or E670G in SEQ ID NO: 1 is present: and/or b, al 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 1474V or E670G in SEQ ID NO: I. 42. 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. 43. 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. 44. 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. 45, The method of any one of clauses I to 24, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the PCSK9 C-terminal domain comprising said mutation I474V or 287 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. 46. The method of any one of clauses 1 to 25, wherein said human has been diagnosed with 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. 47. The method of any one of clauses 1 to 26. wherein the nucleotide sequence is SEQ ID NO: 29 or 30. 48. 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. 49. 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. 50. A kit comprising the ligand of clause 29 and instructions for carrying out the method of any one of clauses 1 to 28. id="p-1052" id="p-1052"

[001052] 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 3 16P or 3 1114) is administered to the human at a two-weekly dose of from 75 to 150mg (eg, from 75 to 1 50mg administered once or twice over a two-week period). In an example, the ligand is for such administration to the human.

Determination of Specific Binding of Ligands of the Invention to PCSK9 Variants id="p-1053" id="p-1053"

[001053] 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, 288 64nM, 16nM, 4nM and InM. Binding curves were double referenced using a buffer injection (i.e. OnM) to remove baseline drift and injection artefacts. Regeneration of the capture surface was with 1 OOmM phosphoric acid which removed the captured antibody allowing another cycle of capture and binding. The binding sensorgrains generated were analysed using the 1:1 model inherent to the ProteOn XPR36 Array system analysis software. The assay was performed at 25 °C and using IxHBS-EP (Teknova) as running buffer. 1001054] Data Three antibodies were tested and the resulting binding data are presented below' (Table 3). Antibodies 3I6P and 31H4 are antibodies disclosed in US20110065902A1 (the sequences of these antibodies and their variable domains are incorporated herein by reference for possible use in the present invention and possible inclusion in claims herein). Antibody 316P comprises heavy chain variable domains derived from recombination of human VH3-23*04 and JH2*01 (with a D), and light chain variable domains derived from recombination of human Vk4-1 *01 and Jk2*01 . 1001055] Evoiocumab comprises a human IGHG2*01 heavy chain and a human IGLC2*01 lambda light chain, a VH derived from recombination of human IGHV1-18*01 and IGHJ6*0l (with a D segment) and a VZ derived from recombination of human 1GLV2-14*OI and IGEJ2*0L Table 3: SPR Determination of Ligand Binding Specificity for PCSK9 Variants Variant/Antibody ka (l/Ms) kd(1/s) KD(nM) PCSK9 a 316P I.37E+06 2.75E-04 0.201 3 1H4 1.14E+06 6.38E-05 0.056 Evoiocumab 1.14E+05 2.62E-05 0.229 PCSK9 a’ 3I6P 1.50E+06 2.72E-04 0.181 31H4 1.23E+06 6.06E-05 0.049 Evoiocumab 1.24E+05 2.29E-05 ___ 0.185 PCSK9 c 3I6P 1.49E+06 2.75E-04 0.184 3 1H4 1.22E+06 5.69E-05 0.047 Evolocu mab I.20E+05 2.20E-05 0.183 PCSK9 r __i 316P 1.40E+06 2.76E-04 0.197 3ΪΗ4 1.15E+06 5.82E-05 0.051 Evoiocumab 1.16E+05 2.67E-05 0.230 PCSK9 f 316P E39E+06 2.82E-04 0.203 31H4 1.13E+06 5.95E-05 0.053 289 Evolocumab 1.16E+05 2.66E-05 0.229 PCSK9 p 316P I.39E+06 2.73E-04 0.196 3 1 H4 I.14E+06 6.12E-05 0.054 Evolocumab 1.14E+05 2.50E-05 0.219 ---------------------- J id="p-1056" id="p-1056"

[001056] Results The results showed that all antibodies tested bound to PCSK9 variants equally, with any binding variation seen being within experimental error for such a strong affinity interaction. id="p-1057" id="p-1057"

[001057] Thus, the invention determines that an antibody with the follow ing profile can specifically bind one or more variants of the invention:L An antibody (eg, 3 16P or alirocumab) that comprises heavy chain variable domains derived from recombination ofhuman IGHV3-23*04 and IGHJH2*()1 (with a D), and light chain variable domains derived from recombination ofhuman IGKV4-P01 and IGKJ2*01: or 2. An antibody (eg. evolocumab) that comprises human heavy chain variable domains derived from recombination ofhuman IGHV 1-18*01 and 1GHJ6*O1 (with a D segment) and light chain variable domains derived from recombination ofhuman IGLV2-14*0l and IGLJ2*0L id="p-1058" id="p-1058"

[001058] Thus, according to the invention, the skilled person is hereby provided with the required determination of specific binding of the ligand to PCSK9 variants. Applications of this determination are set out above in the context of methods and other aspects of the invention. id="p-1059" id="p-1059"

[001059] REFERENCES: Horton e! al, Trends Biochem Sci. 2007 Feb;32(2):71-7. 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. 290 Benjannet el 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(11):2995-3005, Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.

Maxwell etal, Proc Natl Acad Sci USA. 2005 Feb 8:102(6):2069-74. Epub 2005 Jan 27, Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.

Park el aK J Biol Chern. 2004 Nov 26:279(48):50630-8. Epub 2004 Sep 22. Post-transcriptional regulation of low density lipoprotein receptor protein by prop rote in convertase subtilisin/kexin type 9a in mouse liver.

Rashid et al, Proc Natl Acad Sci U S A. 2005 Apr 12; 102( 15):53 74-9. Epub 2005 Apr I. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.

Kotowski el 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 etal, J Am Col! 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 el 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 el aL Am J Hum Genet. 2006 Sep:79(3):5 14-23. Epub 2006 Jul 18. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.

Seidah el aL Proc Natl Acad Sci U S A. 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.

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 (CEPFI) with Northern and Western European ancestry (CEU) Toscani in Italia (TSI) British from England and Scotland (GBR) 291 Population Finnish from Finland (FIN) Iberian populations in Spain (IBS) East Asian ancestry Han Chinese in Beijing, China (CHB) Japanese in Toyko, Japan (JPT) Han Chinese South (CHS) Chinese Dai in Xishuangbanna (CDX) Kinh in Ho Chi Minh City, Vietnam (KHV) Chinese in Denver, Colorado (CHD) (pilot 3 only) West African ancestry Yoruba in Ibadan, Nigeria (YRI) Luhya in Webuye, Kenya (LWK) Gambian in Western Division, The Gambia (GWD) Malawian in Blantyre, Malawi (MAB) West African Population (TBD) Americas African Ancestry in Southwest US (ASW) African American in Jackson. MS (AJM) African Caribbean in Barbados (ACB) Mexican Ancestry in Los Angeles, CA (MXL) Puerto Rican in Puerto Rico (PUR) Colombian in Medellin, Colombia (CLM) Peruvian in Lima, Peru (PEL) South Asian ancestry Ahom in the State of Assam, India Kayadtha in Calcutta, India Reddy in Hyderabad, India Maratha in Bombay, India 292 Population Punjabi in Lahore, Pakistan 293 Table 5: TOI$ & Related Diseases, Conditions and Example Ligands Human TOI Example Disease or Condition Example Ligand II-17a Inflammatory Disease Uveitis Rheumatoid Arthritis Psoriasis AIN457 Ixekizumab Angiotensin II Receptor Type 1 (ATi) Hypertension LCZ696 Neprilysin Hypertension LCZ696 i Metabotropic Glutamate Receptor 5 (Mglur5) Fragile X Syndrome AFQ056 Mavoglurant A Histone Deacetylase Cancer, Eg. Multiple Myeloma LBH589 Panobinostat DiacyJglycerol acyl transferase-1 (DGAT-1) Familial Chylomicronacmia Syndrome LCQ908 Pradigastat Smoothened (Smo) Basal cell carcinoma Solid tumour Myelofibrosis Medulloblastoma Solid tumour LDE225 Smoothened (Smo) receptor Basal cell carcinoma Solid tumors ITQ506 ! ALK Non small cell lung carcinoma (NSCLC) ___________________________________________________________( 1.DK378 phosphalidylinositol-3-kinase (P13K) m l OR AKT Cancer, eg, solid tumour, breast cancer, Renal cell carcinoma (RCC), Endometrial cancer, Nonsmall cell lung cancer (NSCLC), prostate cancer. Glioblastoma multiforme (GBM) CRPC BKM120 294 GIST Myelofibrosis mTOR PI3K AKT Cancer, eg, solid tumour, breast cancer, Renal cell carcinoma (RCC), Endometrial cancer. Nonsmall cell lung cancer (NSCLC), prostate cancel*. Glioblastoma multi forme (GBM) CRPC GIST Myelofibrosis BEZ235 ΡΙ3Κα 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 BYL719 Mitogen-activated ERK kinase 1 (MEK1) Mitogen-activated ERK kinase 2 (MEK2) Cancer, eg, solid tumour, melanoma, pancreatic, colon, king or thyroid cancer 1 Metastasis MEK162 ! 1 protein kinase protein kinase C FLT-3 c-KIT Acute myeloid leukemia (AML) Myelodysplastic syndrome (MDS) Aggressive systemic mastocytosis (ASM) PKC412 Midostaurin ActRIlB Sporadic inclusion body BYM338 295 myositis (sIBM) bimagruinab CD19 • Cancer, eg. Leukaemia, mast cell leukemia. Acute Lymphoblastic 1 Leukemia, Chronic j lymphocytic i leukemia (CEL) or Hematological tumors CTLO19 (formerly CART19) I 11 β-hydroxylase Cushing's syndrome LC1699 BRAF 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 Myelodysplastic syndrome (MDS) Myelofibrosis LBH589 panobi nostat HSP90 • Cancer, eg, Breast Cancer, gastric AUY922 296 cancer or Nonsmall cell lung cancer (NSCLC) • FGFR I • Cancer, eg, solid tumour • Breast Cancer • Endometrial cancer • Hepatocellular carcinoma • Renal cell carcinoma (RCC) • Bladder cancer • multiple myeloma (MM), hepatocellular carcinoma • endometrial cancer BGJ398 cIAPJ C1AP2 I 1 I • Cancer, eg, solid tumour • Breast Cancer • Endometrial cancer • Hepatocellular carcinoma • Renal cell carcinoma (RCC) • Bladder cancer • multiple myeloma (MM), hepatocellular carcinoma • endometrial cancer LCL16I Akt • Cancer, eg, Solid tumour, gastric cancer (eg. castration-resistant G DC-0068 RG7440 20Ί prostate cancer), prostate cancer, gastroesophageal junction cancer CD22 Hematologic malignancies Non-Hodgkin's lymphoma (eg, relapsed or refractory follicular non-Hodgkin's i lymphoma) Diffuse large Bed 1 lymphoma (eg, relapsed or refractory diffuse large Bcell lymphoma) DCDT2980S RG7593 I 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 Bcell lymphoma) DCDS450IA RG7596 endothelin B receptor (ETBR) I I 1 HER3 ; Melanoma, eg. metastatic or unrescctable melanoma Cancer, eg, metastatic epithelial tumour, metastatic squamous cell carcinoma of the head and neck cancer, metastatic colorectal cancer DEDN6526A | RG7636 MEHD7945A j RG7597 EGFR Cancer, eg, metastatic epithelial tumour, metastatic squamous cell carcinoma of the head and neck cancer, metastatic MEHD7945A RG7597 Necitumumab 298 colorectal cancer MUC16 Cancer, eg, ovarian cancer (eg, platinum-resistant ovarian cancer) DMUC5754A RG7458 sodium-dependent phosphate transport protein 2b (NaPi2b) i Cancer, eg, metastatic nonsquamous non-small cell lung cancer, ovarian cancer (eg, platinum-resistant ovarian cancer) DNIB0600A RG7599 PDL1 (programmed death ligand 1) STRAP 1 (six-transmembrane epithelial antigen of the prostate 1) Cancer, eg, solid tumour metastatic melanoma non-small cell lung cancer Cancer, eg. prostate cancer (eg, metastatic castrationresistant prostate cancer) MPDL3280A i RG7446 DSTP3086S RG7450 Bcl-2 Cancer, eg, leukaemia (eg, chronic lymphocytic leukaemia), non-Hodgkin's lymphoma G DC-0199 RG7601 Checkpoint kinase 1 (ChKl) 1 Cancer, eg, solid tumour, refractory solid tumour or lymphoma G DC-0425 RG7602 GDC-0575 ; RG7741 GDC-0973.......... ’ RG742I Cobimetinib G DC-0623 RG7420 i mitogen activated protein kinase kinase (MAPKK) MEK Cancer, eg, solid tumour, melanoma (eg. metastatic melanoma) epidermal growth factor domain-like-7 (EGFL7) Cancer, eg, colorectal cancer (eg, metastatic colorectal cancer), NSCLC Parsatuzumab MEGF0444A RG74I4 phosphatidylinositol-3-kinase (PI3K) Cancer, eg, prostate cancer, renal cell carcinoma, endometrial cancer, breast GDC-0032 RG7604 299 cancer (eg, HER2-negative metastatic breast cancer, metastatic hormone receptor-positive breast cancer), solid tumour G DC-0084 RG7666 Pictilisib GDC-0941 RG732I mTOR roRCi TORC2 i P13K j Cancer, eg, prostate cancer, renal cell carcinoma, endometrial cancer, breast cancer (eg, HER2-negative metastatic breast cancer, metastatic hormone receptor-positive breast cancer), solid tumour GDC-0980 RG7422 IE17 Autoimmune disease Ankylosing spondylitis; Asthma; Multiple myeloma; Multiple sclerosis; Polymyalgia rheumatica; Psoriasis; Psoriatic arthritis; Rheumatoid arthritis; Uveitis Secukinumab ixekizumab Ml prime segment of membrane IgE IFN alpha Allergic Asthma Autoimmune disease Systemic lupus erythematosus Quilizumab MEMPI972A RG7449 Rontalizumab PCSK9 (proprotein convertase subtilisin/kexin type 9) coronary heart disease (CHD) or high risk of CHD hyperlipidaemia hypercholesterolaemia stroke atherosclerosis a cardiovascular disease or MPSK3169A RG7652 300 condition a condition associated with elevated LDL Vascular Endothelial Growth Factor-A (VEGF-A) Placental Growth Factor (P1GF) Diabetic Macular Edema (DME), Branch Retinal Vein Occlusion (BRVO) Wet age-related macular degeneration (Wet AMD) EYLEA® Aflibercept AVASTIN™ LUCENT1S™ IL-6 receptor Inflammatory disease, eg. rheumatoid arthritis Uveitis (eg, non-infectious uveitis) Ankylosing spondylitis; Cancer Sarilumab i REGN88 PCSK9 (proprotein convertase subtilisin/kexin type 9) coronary heart disease (CHD) or high risk ofCHD hyperlipidaemia hypercholesterolaemia stroke atherosclerosis a cardiovascular disease or condition a condition associated with elevated LDL Alirocumab REGN727 LY3015014 I i NGF 1 L~4 receptor alpha IL-13 receptor delta-like ligand-4 (DI14) Osteoarthritis Pain Allergic asthma eosinophilic asthma Atopic dermatitis Cancer Fasinumab 1 REGN475 Dupilumab REGN668 Enoticumab REGN421 angiopoietin-2 (Ang2) Cancer Nesvacumab REGN9I0 GDF8 Metabolic disorder cancer, obesity, diabetes, REGN1033 LY2495655 301 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 REGNI400 angiopoietin -1 (Angl) angiopoietin -1 (Ang2) Cancer, eg. ovarian cancer AMG386 VEGF receptor PDGF receptor Stem cell factor receptor Cancer NSCLC Breast cancer Thyroid cancer Molesan ib AMG 706 type 1 insulin-like growth factor receptor | (1GF1R) Cancer Breast cancer Pancreatic cancer Ganitumab Linsilinib ASP7487 hepatocyte growth factor (I IGF) Cancer Breast cancer Pancreatic cancer Rilotumumab ! HER3 ErbB3 Cancer Breast cancer Pancreatic cancer AMG 888 U3-1287 IL17 receptor Inflammatory disease Asthma Psoriasis AMG 827 brodalumab sclerostin Bone-related condition AMG 785 302 postmenopausal osteoporosis fracture healing CDP7851 glucokinase Diabetes AMG 151 ARRY-403 PCSK9 (proprotein convertase subtilisin/kexin type 9) coronary heart disease (CHD) or high risk of CUD hyperlipidaemia hypercholesterolaemia stroke atherosclerosis a cardiovascular disease or condition a condition associated with elevated LDL AMG 145 Evolocumab VLA2 Integrin α2β! Inflammatory bowel disease SAR339658 IL-4 IL-13 Idiopathic pulmonary fibrosis SAR156597 lysophosphatidic acid receptor LPA-I LPA-3 Systemic sclerosis fibrosis SARI 00842 Androgen receptor Cancer, eg. prostate cancer, breast cancer MDV3100 enzahitamide HER] EGER Cancer, eg, NSCLC Erlotinib ERBITUX™ VECTIBIX™ VEGF receptor 1 VEGF receptor 2 VEGF receptor 3 Cancer, eg, colorectal cancer, breast cancer ASP4I30 tivozanib JAK JAKI JAK2 Inflammatory disease, eg, rheumatoid arthritis Diabetic nephropathy ASP0I5K Baricitinib CD40 Prevention of organ transplant rejection ASP 1240 GnRH Endometriosis ASP 1707 303 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 Certolizumab pegol Programmed cell death protein 1 Cancer Chronic myelocytic 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 Nivokimab MK-3475 Hepatocyte growth factor MET Cancer j Glioblastoma; Hepatocellular carcinoma; Metastatic colorectal cancer; Metastatic non j I small cell lung cancer; Metastatic stomach cancer: Non-small-cell lung cancer onarluzumab 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 304 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 Cancer Multiple myeloma elotuzumab ' IL 2 : 1L-2 receptor alpha Multiple sclerosis daclizumab : EGFR Cancer Metastatic non small cell lung cancer; Solid tumor necitumumab IL-5 Asthma; Eosinophilic esophagitis reslizumab B-lymphocyte cell adhesion molecule CD22 Cancer, eg Acute lymphoblastic leukemia; Follicle center lymphoma; Non-Hodgkin lymphoma; Systemic lupus 5 erythematosus, hairy cell leukaemia Inotuzumab inotuzumab ozogamicin epratuzumab moxetumomab moxetumomab pasudotox IL1 beta Acne vulgaris; Atherosclerosis; Behcets disease; Cardiovascular disease; Dermatomyositis; Insulin dependent diabetes; Multiple myeloma; Osteoarthritis; Paraproteinemia; Polymyositis; Pyoderma gevokizumab 305 gangrenosum; Scleritis; Uveitis CD20 1 Cancer Multiple sclerosis follicular lymphoma (eg, refractory or relapsed) diffuse large B cell lymphoma (eg, relapsed) chronic lymphocytic leukaemia (eg, first line therapy or relapsed) Oerel izumab ofatumumab IL-23 1_________________________________________________________________________________________________________________________________________________________________________________ ___________________________________________________________________________________________________________________ Crohns disease; Inflammatory disease; Psoriasis tildrakizumab BAFF Neutrokinc alpha 1 Autoimmune disease systemic lupus erythematosus Multiple myeloma vasculitis Belimumab Bcnlysta™ Tabalumab IL5 Asthma mepolizumab __________ . . ------------. __________________ _ ....... ..........—____ _______________________________________________ ___________- --------------...----------- ···— 11.6 Inflammatory disease 1 rheumatoid arthritis sirukumab Lp-PLA2 Atherosclerosis diabetic macular oedema darapladib CCR9 chemokine receptor Inflammatory disease rheumatoid arthritis Vercirnon 306 Crohn’s disease DOPA decarboxylase Parkinson's Disease Patrome Her2 EGFR Cancer, eg, gastric cancer, breast cancer, head and neck squamous cell cancer, Tyverb™ Tykerb™ lapatini b A DP receptor Cardiovascular disease or condition Thrombosis, eg, arterial thrombosis Brilinta Brilique ____________________________1 VEGFR EGFR Cancer, eg, medullary thyroid cancer Caprclsa LABA LAMA Respiratory disease or condition,eg, COPD PT003 GFF Factor Xa thromboembolism apixaban Oxekimab 0X40 ligand Asthma Graft-versus-host disease Tremelimumab Ticilimumab ipi 1 im umab CTLA-4 CD 152 Cancer, eg, melanoma Autoimmune disease MPDL3280A MED14736 PD-L1 Cancer, eg. solid tumour, kidney cancer, lung cancer, melanoma. NSCLC. multiple myeloma Autoimmune disease Nivolumab AMP-514 AMP-224 PD-1 Cancer, eg. solid tumour, kidney cancer, lung cancer, melanoma, NSCLC, multiple myeloma Autoimmune disease 307 LIGHT TNFSF14 CD40 ligand JAK Inflammatory disease, eg. rheumatoid arthritis, psoriasis, chrohn’s disease, IBD, ulcerative colitis. Psoriatic Arthritis tofacitinib Nerve Growth Factor Pain Osteoarthritis pain tanezumab Herl receptor Her2 receptor Her4 receptor Cancer, eg, Non-Small Cell Lung Cancer dacomitinib c-MET ALK Cancer, eg, Non-Small Cell Lung Cancer crizotinib ____________________________________________________________________________| Programmed cell death 1 receptor Cancer, eg. renal cell carcinoma Nivolumab SLAMF7 CD319 Cancer, eg, multiple myeloma Elotuzumab CD30 Cancer, eg, Hodgkin lymphoma, systemic anaplastic large cell lymphoma, T-cell lymphoma Brentuximab Brentuximab vedotin ' GPR40 DPP-4 Diabetes, eg, diabetes mellitus Fasiglifam 1 trelagliptin VEFGR-I receptor VEFGR-2 receptor VEFGR-3 receptor PDGFR cKit Cancer, eg, non-squamous non-small cell lung cancer Motesanib Motesanib diphosphate amyloid β Alzheimer’s disease Inflammatory disease, eg. rheumatoid arthritis, psoriasis, chrohn’s disease, IBD, ulcerative colitis, Solanezumab TNF alpha SIMPONI™ HUM IRA™ REMICADE™ ENBREL™ 308 Psoriatic Arthritis Adalimumab IL-21 1 Autoimmune disease or condition Inflammatory disease or condition Rheumatoid arthritis Crohn's disease IBD Ulcerative colitis Systemic lupus erythematosus (SLE) Graft versus host disease Cancer Metastatic melanoma Renal cell carcinoma Melanoma Solid tumours Acute myeloid leukaemia Non-Hodgkin’s lymphoma Ovarian cancer Colorectal cancer Agonist or antagonist antibody specific for human IL-2] NNCOI 14-0005 WCii! bl-0006 \\8828 ATR-107 Said or an anti-IL-21 antibody in combination with an agent selected from the group consisting of ipilimumab (eg, to treat melanoma), an anti-PDl antibody (eg, to treat solid tumours), sunilinib (eg, to treat renal cell carcinoma), rituximab (eg, to treat NonHodgkin*s lymphoma), 1 sorafenib (eg. to treat renal cell carcinoma), doxorubicin (eg. to treat ovarian cancer) and cetuximab (eg, to treat colorectal cancer). 309 Table 6: PCSK9 SEQUENCES 310 311 312 cn Η Ll > ra < M? π: d q r u ι O · :-· iD I.U > g- rr: > T - $ y £ « T )7 1 J '-^ l/Ί 1 l'c ra .J m ω । । J Ο ιι^ i'll ύ»Ί LJ X ra 1— Lj LZi l,_J 1- J ।____ C iD > A £ V H c G (J Q a H •jit μ η- 11J * < ϋ o s / <. / g S- ' 2 b U o S' > S ? £ ri < σ > Γι < 1--- < J '-’ Cf 14 '1 τ -C < 6 V A ra. 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Qt QU QU TO o' •j ου -I QU QU QU QU i_i QU QO QU C1 :r kJ kJ ID OU -I OU '* Cj I. 1' in Ok c trJ F< 0 tn ID b in ίΓ| Fi ΓΙ • i; k ,J I. J uu ί: TO Ui DU -1 I Γ-Ι > I 0 0 QU LJ < 0' lD < b LD < 3 LD lD H X iD k— O 1— LD 0) ID LD ID H LD < LD u r ί H 11! «X 0 0 r-X QU Lu QU Lu QU OU QU QU □U t□U OU TO QU TO QU Ou Ou QU OU QU □0 CO OU QU ί C Q QU QU QU QU QU QU QU o QU O OU TO Lu uu TO m o in ΰδ ί? TO on QU on QU r TO OU QO » 1= tn 0 Fi 0 tn Eth H 19 in Fi m tn Fi in 0 0 ( ) 328 329 Table 7: Human VH3-23 Variant Alleles rs61750837 SNPs rs61752504 rsl 055799 rs61752504 rs61750837 rsl064090 rsl055799 rsl 064091 rsl 064091 rsl064090 o OQ o o o rs56069819 ; rs56069819 rs56069819 rs560698l 9 rs56069819 rs56069819 Cumulative allele frequency 0.0983 ____________ 0.0087 0.0046______________ o o o o o 0.0005 0.0005 SOOOO 0.114 VH3-23 haplotype o * 1 X Λ Ό 3 £Λ TOTAL: 330 CJ OJD co 0 z. 1) C CJ E ox ci ci CJ cz> CU Ob 1) a cu Ό c cd 4-J ΓCJ 4D 4—> x: oo tT', cn cj tn -J cd cr CJ Ln tC Ό nt Dij tn O' rn nr oo cj \O CJ cn NO nt no OJJ CJ »n \D o oo •—<· Ή Cl nr nt oo NO rn rn OO oo cj OO rJ rm \O □o tn tn o c- o cj cn tn . r m oo oo NO QJ 2? cd 4-4 cu E cd JD CJ O' ω rno oo Γη CJ ND nT \O oo NO oo r' o CD oo Γ* tn nr tn nr nr O NO oo oc o CJ CJ — nt 5 . ·' X. ΓΛ r> ♦ C o o m m tn r^ σ> r— nT oo CJ nt nr ^r NO o e Τ' r r in r- o> 00 ON er o oo o m O' tn nr CJ nT nr nr m r oo NO tn m nr CJ O' o m tn r- CJ nr nT nt 331 SEQ ID NOs comprising an anti-PCSK9 Patent or patent Pblication monoclonal antibody or fragment thereof \O B2 CM C4 O O CD 00 O> O • * CD 00 60 —\ 0 xb 0b ri , ri O - D 0b Ό CC Γ' xb 0 m r- Γ— — o in . . O in r t 0b f— ‘ . — 0t r· — *k i/0 rr r ci r- Ch in cr .. CD Γ— o — on I/Ί . __ < ICi in * 6 . o O Ο O r- =F' *0^ rn m 0b .—· o 00 rc 0b »——· 0 0Φ *—· IC < rv — - * in r cc O .. Γ- Γ- oc 0 0 oc CD rD O O ΟΟ cD 0b 0 . r V. O xt IC < r in s O xb in c m r O o CD 0b Ch O oc 0 CJ 0F Ch O 00 0b 0b ci in rn 0 — xf ci in xr 0b ,. O cr CD 0b O . 0b OC VO 0b r 00 0b CT CD 0F O e . 0T 00 0b 0 co e 0b [-^ m O > > * 0b cr O . CD 0b r— CD r—- e Cl r r- o 00 O 0© xb in r CA _ * o 0F 3 0 o' 0T in CD O 0b 0b O r O —1 Q C4 f. r IQ /-> \O 00 H 0 CD . c . in O O oo ci z CO Z oc z — co — Z OC co £ cd m 0b in Γ- 0b 0 P .. Q P rx .. r 6 Γ- rn >— 00 0 Ο Γ- rn •— r^- 00 0 o ω co cr rc — O < 0 UJ \d Γ- 0b EQ cd m — 00 .. 0 ω in O r7 0b UQ rc — in Γ- 00 60 —1 m m QO X oc tri 0b X in Ο 0 0b X qo on 0b X in 0 0 0b *n m < m Γ—' Γ 0 c> rc O A χ xt 0 0 0 .. Ch r— m 0 0 0b 0b 0 0 U — m xb O un r- 0b O — m 0b tn r— 0b 332 ο ίΕ q C5 \Ο cd Γ^. Γ· o Cd CT ·’ cd 0 Cd : ; Ο cdr 0^ CT un Cd 0- . 'T < . r σ Ο CJ — Cd cd o Ό i in XT ri · Γ- Ch CO Cd <. TT .. in in n Ϊ1 ΤΓ cz? £ C~J Cd - r ch o o O Ch Ch υ a. -Ε η cn oo Cl 'T in O Γ' 00 414 CT r> oo Tt dd <01 oo vr <0 \O R 00 ( 0^ ct Ό 5 cd cd •T o O r oo Cd ci cd 'T r> in o sO r oo i Ch' C Ε ►κΓ, s© »*» ' 0> <0r 1— \P kO in in in Λ cd Cd 'T Tt ch o oo 'Τ- d cd Ό oo 0Γ Ε Λ WL Λ Cd CT 'sf r> re ο' C' cd 'T 1' cn r Ό 0Χ Cd Tt OO o 00 ·—’ O- Cd od O oo OJD '· 0Γ , c ττ Γχ tT Tf Γ ,Ξ CT O Cd •—1 0-t rT o CJ ·—- r C Cd T — O oo oo 01 ^- r- l^' \O 00 ’T Έ ΙΥ> Th Γ· c o n - r _«- * « 73 cd o Tt o o ’st cd Ch M o o oo α€ Ο -C δ Cd Ch ό so oo dD O cd CT ud ό Ό ri ζ • 00 z OO Ch o z 1 oo' z CO Ch ο Ε ί*— 0 Cd cn 1' Tt Q >0 oo tT A cd CT 'T 0 m n 0Γ ςΛ Λ o' [< ^- O r< CT R oo o ο ’S ο cd cr O 10 0- o xft o cd CT Tt o m 0- tT ζ. Ε ω Ch o' X o' r< ω Ob dd UJ dd S' a ΗΗ Ο υ ο LS r ’ « co CT <0 in o TT 00 X 10 10 dC υτ o Cd 00 X oo CT in . ’T GO X in in oo o tT Ο c CT 4. ct 10 0~ 56, oi r—< CT - in 0^ . 0 fed © Ε Q r< CT OO a vt 0 [< CT Ob o a τΤ TT Ό Ό cn Ο >* * CT Cd u 10 0~ cd U ·—‘ CT 'T u in 0- 333 SEQ ID NOs comprising an anti-PCSK9 Patent or patent Pblication monoclonal antibody or fragment thereof in Ch O C0 o ’Th on m o' Ch in al o' 01 Ch s <0 ‘0 0Γ 0© xr 0*-r roo Ch. oo C' r r0f.

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ND OO Γ* t— oo oo tn '0 oo 0oo O' 0o 0F O MΛ NO 1>0 O' cn — cn in ^r sD ·—* co in O' \D 0^ in oo OO i0 A O' oo roo OO o' o rn QO rn ¢0 \cT rn in rn GC al Ό ND OO OO 0NO r 00 in 0~ 334 patent Pblication < 52201 Al o 5 cu CJ pi .—j US201300 1 i 1 1 I SEQ ID NOs comprising an anti-PCSK9 | monoclonal antibody or fragment thereof I i _____1 CDRL SEQ ID NO: 5, 7,9, 10, 12, 13, 15, 16, 17, 18. 19, 20,21,22, 23,24,26, 28,30,31,32, 33. 35, 36, 37, 38, 39. 40, 42. 44, 46. 405. 407, 409,411,413,415,417; ci ’—1 ΙΖΊ O in Cb cr OQ CT 9 cr O Z Q O ω oo 2 Q U 54, 55, 56, 57, 58, 60, 62, 64, 65, 67, 69, 71, 72, । 74, 76, 77, 78, 79, 80, 81, 83, 85, 87, 89, 91,404, 406. 408,410,412,414,416; CDRL SEQ ID NO: 5,7,9, 10, 12, 13, 15, 16, 17, 18, 19,20,21,22,23,24,26,28,30,31, 32, 33. 35, 36, 37, 38, 39, 40, 42, 44, 46, 405, 407, 409,41 1,413,415,417,461,465,485: cn in ci Ln o’ on O cr 00 cT o z Q o LU OC X cd a o 54, 55, 56. 57, 58, 60, 62, 64, 65, 67, 69. 71, 72, 74, 76. 77, 78, 79, 80, 81,83. 85, 87, 89. 91,404. ! . r rc oc cr cn cf O O> cr r Ct ^r c4 o 00 o cr o cT 335 SEQ ID NOs comprising an anti-PCSK9 | Patent or patent Pblication monoclonal antibody or fragment thereof nr in r4 nF . ri 04 O CM -- r nO rn Co nr \D CO r ro m nF nF -— —1 m » » nF , .— — m CD p- oo in C^t oq' ON on in Γ A. nF m in Ch o o nr c Ch Ch r o o r. cf m GO I 1 1 1 NO 00 CO cn ro nr NO 00 •— oc N© CO nF 1/3 Γ Γ. NO nF oo \D in Γ r- Γ- CD CM nF O NO oc CD 04 nF o xD oo Λ m i/3 r- c Ch o in e NO nF nd Ch GO in m NO nF in I/O o CD nt nF NO oo nt o Cl nF O' NO oo —' vt γ- ΓΟ nF nr m NO nr CM nr nF co NO ch CD NO co nF NO oo e ’—· nF - CM nF oo' ND oo nT m o' CM »— f oT co o' . · CD '—1 r CO nF r- ND OO Cl nT f*»*- r- NO 00 nr m cd cK nF nr o' o nr in CD Ch nr nr o o' nr o CD rn GO O ND oo 74 o CM rn in A w NO 00 CM z CO » z: 00 o< -— z OO Z 00 Ch 0 CD co Vt 0 GO Γ nr Γ Q CD CO nr 0 in Γ r> ^r <> o' p-. CO r- oo o o' p- co p- CO o O CO CG nF o in Γ nr o CD m nT o in n- nr υϋ Ch NO LU DC ω Ch no r> UJ NO r^ r 00 m ^-· CZ) in oo 00 < co oo in p- 00 -) oo in nr X in O o -J oo in nT X in NO o nr r/. V—< m in r- f < co 4> in Γ' a c/ o Q nF in N© o 0 Γ-' m ch o 0 nr NO o o ’— s nr U nr U r— ro nr u in c- nr 336 SEQ ID NOs comprising an anti-PCSK9 Patent or patent Pblication monoclonal antibody or fragment thereof < oo CM X CM bn CM sn —· un ri o r- nt r * Γ- o cr o oo cm CM CM CM f — CM CM o' m OO in .

O c> 00 Γ' r— * o r- cn CM — O MD . oo Z nr « < r . O Γ~- rn O — cn rt o Z Q O □J (Z) \C oo «. r un in Ό oo vt cn so 00 cm' — Ό OO o' o MD 00 oo C> c* n r- oo un MD iZ in rX tri Z in rP z z U r· . Γ so ci — oo o rt C' MD O ^r 337 Table 9: Human variable & constant variants distributed over several human ethnic populations - useful for ligand tailoring Cum Freq9 0.296 o o 0.283 0.717 © « ί I = £ x x ώ 0.096 (0.496) 0.504 (0.904) 0.104 (0.462) [ 0.538 (0.896) 1 1 Het Freq6 0.400 0.400 0.358 I 0.358 J__ No. Individs31 £91 Human Populations4 A (European ancestry) A (European ancestry i___________ A (European j ancestry) 1 1 Λ (European ancestry) Variant Nucleotide Position 14:106208086 (forward strand) 14:106208086 (forward strand) i 14:106208082 (forward strand) 14:106208082 (forward strand) Nucleotide Variation2 (NCBI dbSNP reference number)3 GAT GAG (rsl 045853) i .......... r-i Gi 1 ATG 1 — (rsl 1621259) Example Amino Human Acid Allele1 Position & Variation IGHGI *01 ; 204D | i ! (CH 3 variation) IGHGI *03 ί 204E i I : (CH3 variation) IGHGI *01 I 2061. j (CH3 1 : variation) IGHGI *03 206M i 1 : (CH3 variation) Human Gene Segment Type IGHGI 338 oo CM o O o o CM n o o d d d o S' m nr m CM O' in oo ·—· O' d d d d _______— _____________ MD so r- CD o cn rn o o d d d d i CO CD < < nr S' o 1= — c _ , r- CD ib GT c3 o 03 O ?3 cr o d o d o d — X CZ 1 ZPi r— "η T^ SO Έ so Έ SO ί- CD oJ o S O ch Ο X ? i X — X ? X <2 S fP CM iGHG2*04 I 76L TTG > CM C4 o * CM so C4 o o cm O X o CM u X 339 o 0.289 Ch GJ io Ό d C © 0.408 0.005 i 0.539 (0.881) oo rC C? Cl Ch O Ch Ch Ch cr o Ch ch ό o- o o 00 r- NO o o o o rc m CD Ο 1 Ο O, 0 O ! i ΖΚΌ 0.342 cs Ch. o — o o o Ch r- Ch o o o o QQ U Q u o Table Footnotes: 1. 1MGT notation (ww.imgt.org); refer to figures for other alleles comprising this variation. 2. SNP Underlined in Codon. 14:10611013 (forward strand) 14:1061 1013 (forward strand) 14:106109752 (forward strand) 14:106109752 (forward strand) oin............ ATG (rs8009I 56) GCC TCC (rs4983499) variation) 161V (CH2 variation) 161M (CH2 variation) 257A (CH 3 variation) 257S (CH3 variation) IGHG2*01 IGHG2*02 1 1 1 i .. | IGHG2*01 I 1 1 i i i IGHG2*06 NCBI dbSNP Build 138 released on Apr 25. 2013. 340 Human population used for representative variant frequency analysis. xD r- oc ch 341 Table 10: FURTHER SEQUENCES SE Q ID NO Human Allele Nudeotide/Amino Acid Sequence HEAVY CHAIN ALLELES ___ ___ __________ 41 1GHGP0I (CH l+Hinge+C H2+CH3+CFI- S) I gcctccaccaagggcccatcggtcttccccctggcaccctcclccaagagcacctctggg i ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggigacggigtcg । tggaactcaggcgccctgaccagcggcgtgcacaccttcccggclglcctacagtcctca ggactctactccctcagcagcgtggigaccgtgccctccagcagcllgggcacccagacc tacatclgcaacgtgaalcacaagcccagcaacaccaaggtggacaagaaagttgagccc j aaatcttgtgacaaaactcacacalgcccaccgtgcccagcacctgaactcclgggggga 1 ccgtcagtcttcclcttccccccaaaacccaaggacaccctcatgatctcccggacccct i gaggtcacatgcglggtggtggacgtgagccacgaagaccctgaggtcaagncaactgg I tacgtggacggcglggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac j agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag 1 gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg ctggactccgacggctccttcttcctctacagcaagctcaccg'tggacaagagcaggtgg cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtaaa 42 I astkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsga LTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK , THTCPPCPAPELLGG PSVFLFPPKPKDTLM1SRTPEVTCVVVDVSHEDPEVKFNWYVDGV I EVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSRDE LTKNQVSL'FCL.VKGFYPSDIAVEWESNGQPENNYKTTPPVEOSDG SFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK D=position 204 L=position 206 43 1GHG2*OI (CHI+Hinge+C H2+CH3+CH- S) gcctccaccaagggcccatcggtcttccccctggcgccctgctccaggagcacclccgag agcacagccgccctgggctgcctggtcaaggactactlccccgaaccggtgacggtgtcg tggaactcaggcgctctgaccagcggcgtgcacaccttcccagctgtcctacagtcctca ggactctactccctcagcagcgtggtgaccgtgccctccagcaacttcggcacccagacc tacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagacagttgagcgc aaatgttgtgtcgagtgcccaccgtgcccagcaccacctgtggcaggaccgtcagtcttc ctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacgtgc gtggtggtggacgtgagccacgaagaccccgaggtccagttcaactggtacgtggacggc gtggaggtgcataatgccaagacaaagccacgggaggagcagttcaacagcacgttccgt gtggtcagcgtcctcaccgttgtgcaccaggactggctgaacggcaaggagtacaagtgc aaggtctccaacaaaggcctcccagcccccatcgagaaaaccatctccaaaaccaaaggg cagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaac 342 caggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgg gagagcaatgggcagccggagaacaactacaagaccacacctcccatgctggactccgac ggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaac gtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctc tccctgtctccgggtaaa 44 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSS GLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV ECPPCPAPPVAGPSVF ; LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTFR VVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREP QVYTLPPSREEMTKN QVSLTCLVKGFYPSD1AVEWESNGQPENNYK TTPPMLDSDGSFFL YSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSESLSPGK P-position 72 N=position 75 F=position 76 V=position )61 A=position 257 ! 45 IGHV1-18*O1 caggttcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtc tcctgcaaggcttctggtlacacctttaccagctatggtatcagctgggtgcgacaggcc cctggacaagggettgagtggaigggatggatcagcgcttacaatggtaacacaaactat gcacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagcctac alggagctgaggagcctgagatctgacgacacggccgtgtattactgtgcgagaga 46 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAP GQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSIAYMELR । SLRSDDTAVYYCAR . ϊ 47 IGHVI-46*0l caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtt tcctgcaaggcatctggatacaccttcaccagctactatatgcactgggtgcgacaggcc cctggacaagggcttgaglggatgggaataatcaaccctagtggtggtagcacaagctac gcacagaagttccagggcagagtcaccaigaccagggacacgtccacgagcacagtctac atggagctgagcagcctgagatcigaggacacggccgtgtattactglgcgagaga 48 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAP GQGLEWMGI1NPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSL RSEDTAVYYCAR LIGHT CHAIN ALLELES 49 IGKC*OI cgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatct ggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacag tggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggac agcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgag aaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaag agcttcaacaggggagagtgt 343 50 RTVAAPSVF1FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC V=position 84 C=position 87 51 1GLC2*O1 ggtcagcccaaggctgccccctcggtcactctgttcccgccctcctclgaggagcttcaa gccaacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtg gcttggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaa caaagcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaag tcccacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtg gcccctacagaatgttca 52 GQPKAAPSVTLFPPSSEELQANKATI.VCL1SDFYPGAVTVAWKAD SSPVKAGVEFTTPSK QSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTEC S 53 IGKV4-l*01 atggtgttgcagacccaggtcttcatttctctgltgctctggatctctgglgcctacggg gacatcgtgatgacccagtctccagactccctggctgtgtctctgggcgagagggccacc atcaactgcaagtccagccagagtgttttatacagctccaacaataagaactacttagct tggtaccagcagaaaccaggacagcctcctaagctgctcatttactgggcatctacccgg gaatccggggtccctgaccgattcagtggcagcgggtctgggacagatttcactctcacc atcagcagcctgcaggctgaagatgtggcagtttattactgtcagcaatattatagtact cctcc 54 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNMKNYLA WYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQA EDVAVYYCQQYYST P 344 55 IGKV1 -13*02 atggacatgagggtccccgctcagctcctggggcttctgctgctctggctcccagcaggt gccagatgtgccatccagttgacccagtctccatcctccetgtctgcatctgtaggagac agagtcaccatcacttgccgggcaagtcagggcattageagtgctttagcctggtatcag cagaaaccagggaaagctcctaagctcctgatctatgatgcctccagtttggaaagtggg gtcccatcaaggttcagcggcagtggatctgggacagatttcactctcaccatcagcagc ctgcagcctgaagattttgcaacttattactgtcaacagtttaatagttaccctcagtgc cagatglgccatccagttgacccagtctccatcctccctgtctgcatctgtaggagacag agtcaccatcacttgccgggcaagtcagggcattagcagtgctttagcctggtatcagca gaaaccagggaaagctectaagctcctgatctatgatgcctccagtttggaaagtggggt cccatcaaggttcagcggcagtggatctgggacagatttcactctcaccatcagcagcct gcagcctgaagattttgcaacttattactgtcaacagtttaatagttaccctca 57 IGKJ2*01 tgtacacttttggccaggggaccaagctggagatcaaac YTFGQGTKLEIK 59 IGLJ2*01 tgtggtattcggcggagggaccaagctgaccgtcctag 60 VVFGGGTKLTVL 61 An IGHGRO] Heavy Chain Constant Region ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA ' LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLM1SRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP1EKT1SKAKGQP REPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHN11YTQKSLSLSPG i 62 An IGKC*01 Kappa Light Chain Constant Region RTVAAPSVF1FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC 63 An IGHG2*01 Heavy Chain Constant Region ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSN TKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFR VVSVLTVVHQDWLNGKEYKCKVSNKGLPAP1EKTISKTKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK 64 An 1GLC2*O1 Lambda Light QPKAAPSVTLFPPSSEELQANKATLVCL1SDFYPGAVTVAWKADS SPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTH 345 Chain Constant Region EGSTVEKTVAPTECS 65 An 1GHG2*O1 Heavy Chain Constant Region astkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgal TSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSN TKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPE vtcvvvdvshedpevqfnwyvdgvevhnaktkpreeqfnstfr vvsvltvvhqdwlngkeykckvsnkglpssiektisktkgqprep QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPMLDSDGSFFLYSKLrVDKSRWQQGNVFSCSVMHEAI.HNH YTQKSLSLSPGK 66 An IGKC*OI Kappa Light Chain Constant Region RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC 346 Example!: Rarer IL6R Variants id="p-1060" id="p-1060"

[001060] The present invention provides anti-IL6R ligands; and lL6R-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 (L6R. in particular human IL6R or its ligands and in screening assays to identify other antagonists of IL6R activity. Some of the ligands of the invention are useful for inhibiting binding of IL6R to IL6 and/or gp 130. or inhibiting IL6R-mediated activities. [0010611 Anii-1L6R ligands (eg, antibodies and anti-sense RNA) have been developed based on targeting and neutralising so-called wild-type" human IL6R, which is a commonlyoccurring form (see, eg, SEQ ID NO: 78). While such therapies are useful for human patients harbouring this form of human 1L6R, the inventor considered it useful to investigate the possibility of targeting rarer but still naturally-occurring - forms of IL6R amongst human populations. In this way, the inventor arrived at insight into the natural occurrences and distributions of rarer human 1L6R 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 IL6R activity. This particularly provides for tailored therapies, prophylaxis and diagnosis in humans that are devoid of the common IL6R gene or protein. id="p-1062" id="p-1062"

[001062] 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 IL-6R 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. [001063] 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. 1001064] 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-IL6R ligand for administration to human patients for therapy and/or prophylaxis of IL6R-mediated or associated diseases or conditions. In this way, the patient receives drugs and ligands that are tailored to their 347 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. |001065] In developing this thinking, in this non-limiting example the present inventor decided to determine a set of human 1L6R 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 follow ing criteria: - • Naturally-occurring human IL6R variation having a cumulative human allele frequency of 35% or less; • Naturally-occurring human IL6R variation having a total human genotype frequency of about 50% or less; • Naturally-occurring human IL6R variation found in many different human ethnic populations (using the standard categorisation of the 1000 Genomes Project; see Table 12 below); and • Naturally-occurring human IL6R variation found in many individuals distributed across such many different ethnic populations. id="p-1066" id="p-1066"

[001066] On the basis of these criteria, the inventor identified the variants listed in Table 1 I below. The inventor’s selection included, as a consideration, selection for nucleotide variation that produced amino acid variation in corresponding IL6R forms (ie, non-synonymous variations), as opposed to silent variations that do not alter amino acid residues in the target protein. id="p-1067" id="p-1067"

[001067] SNP rs2228145 (encoding Ala 358: see Table 11) is present in humans at an average cumulative frequency of 32% according to the 1000 Genomes Phase I database, but is higher in AMR. ASN. EUR. CLM. MXL, PUR. CHB. CHS. JPT. CEU. GBR. IBS and TSI populations: thus in an embodiment, the human is of AMR. ASN or EUR ancestry, eg, of CLM, MXL, PUR. CHB, CHS, JPT, CEU, GBR, IBS or TSI ancestry. In an embodiment, therefore, when the wherein the ligand (eg, antibody or fragment) specifically binds an IL6R protein that comprises a mutation Asp358Ala, the human comprises SNP rs2228145; and optionally the human is of AMR, ASN or EUR ancestry, eg, of CLM, MXL, PUR, CHB, CHS, JPT. CEU. GBR, IBS or TSI ancestry. id="p-1068" id="p-1068"

[001068] SNP rs28730736 (encoding lie 385; see Table 11) is present in humans at an average cumulative frequency of 5% 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 348 wherein the ligand (eg, antibody or fragment) specifically binds an IL6R protein that comprises a mutation Va)385Ile, the human comprises SNP rs28730736; and optionally the human is of AFR. ancestry, eg, of ASW, LWK or YRI ancestry. 349 Table 11: Human IL6R variants distributed over several human ethnic populations & £ o Of c Λ E 5 -C C ’> S3 4= Cum Freq6 0.680 0.320 1 _____ 0.947 0.053 Hom Freq4 (Het + Hom freq5) 0.489 (0.872) 0.128 (0.511) '4 A? c> o — - 0.010 (0.096) Het Freq3 0.383 0.383 0.086 0.086 No. Unique Pops2 cF — ct No. Individs1 557 kN o Human Populations - T . zu : " z s 1 OQ > Γ X q Ο H z 4 c > X Z X - £ X U Z £ Z U cu — £ ri? x cd ί X > U 2 I.WK.ASW.YRI.PUR (see note 8) 358D 358A 385V 3851 Most common Variant Most common Variant 350 Number of individuals in 1000 Genomes database (201 10521 . found to have the allele; Number of unique human ethnic populations in 1000 Genomes database in which the allele was found to occur, Heterozygous human genotype frequency, ie, cumulative frequency of all genotypes having one occurrence of the variant allele and one occurrence of o oo o — o Cd c 351 o Ξ o c O o Έ S3 X ω <υ S3 CM Jj P o <9 QC v-> QJ Qi S3 r> P Q rc ,o ^r.E > <υ r~ o CM -j * «— Q P S3 c S3 O Q — DU E > OJj Q CM ΙΟ cZ S3 GO Tj y o +—* O G0 CZ δ P E Q o ω cu z GC _c T3 u z δ X c c tZ cd c GO £ £ cu Z CQ u z 352 id="p-1069" id="p-1069"

[001069] Example 3: Tailoring Antibodies to Rarer IL6R Variant Profile id="p-1070" id="p-1070"

[001070] As outlined above, the invention includes the possibility to tailor treatment of humans further by selecting antibody-based ligands with variable and/or constant domains based on gene segments found in many humans of the ethnic populations where the variant IL6R forms are found to meet the selection criteria of the invention. 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 HCDRI or FW3 where there is variability in humans (ie, where SNPs occur in humans). id="p-1071" id="p-1071"

[001071] The inventor analysed human IGHV variation and used this to choose ligands based on human IGHV alleles comprising said selected nucleotides and for matching to human recipient genotypes and/or phenotypes. The inventor identified utility in using gene VH gene segments encoding (i) a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109 and wherein said human comprises a VH gene segment encoding a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109, or the human expresses VH domains that comprise a CDR I comprising a Phe at position 4 shown in SEQ ID NO: 109; or (ii) a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 111 and wherein said human comprises a VH gene segment encoding a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 111 or the human expresses VH domains that comprise a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 11 I. Further information is provided in Table 14, which shows variation at these positions, as well as the variant distributions across the 1000 Genomes Project database relating to many human populations. id="p-1072" id="p-1072"

[001072] In other embodiments, as explained more fully above, the invention provides for ligands which arc tailored to the human recipient's genotype and/or phenotype based on alternative human VH gene segments, or on Vk. VZ or constant region gene segments (see further Table 14 for representative variants). id="p-1073" id="p-1073"

[001073] In an example, following this guidance, the chosen ligand can be sarilumab. id="p-1074" id="p-1074"

[001074] Further examples, therefore are:- (i) wherein the ligand comprises a VH domain derived from the recombination cf human VH segment IGHV3~7*0l, a human D gene segment and a human JH segment, and wherein said human comprises a IGHV3-7*OI VH gene segment or the human expresses VH domains derived from the recombination of human VI I segment IGHV3-7*0l, a human D gene segment and a human JH segment. (ii) wherein the ligand comprises a Vk domain derived from the recombination of human Vk segment IGKV I -12*01 and a human Jk segment, and wherein said human comprises a IGKV I -12*01 Vκ gene segment or the human expresses Vk domains derived from the recombination of human Vk segment IGKV 1-12*01 and a human Jk segment. 353 (iii) 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 CDR3 comprising a Pio al position 7 shown in SEQ ID NO: 113 and wherein said human comprises a Vk gene segment encoding a CDR3 comprising a Pro at position 7 shown in SEQ ID NO: 1 13, or the human expresses Vk domains that comprise a CDR3 comprising a Pro at position 7 shown in SEQ ID NO: 1 13; or (ii) a FW3 comprising a Ser at position 15 shown in SEQ ID NO: 115 and wherein said human comprises a Vk gene segment encoding a FW3 comprising a Ser at position 15 shown in SEQ ID NO: 1 15 or the human expresses Vk domains that comprise a FW3 comprising a Ser at position 1 5 shown in SEQ ID NO: 0 5. (iv) wherein the ligand comprises a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 or a Leu at position 206 shown in SEQ ID NO: 81 and wherein said human comprises (i) an IGHG I *01 human heavy chain constant region gene segment, or the human expresses antibodies comprising human gamma-1 heavy chain constant regions comprising an Asp at position 204 shown in SEQ ID NO: 81 or a Leu at position 206 shown in SEQ ID NO: 81. (v) 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: 83, an Asn at position 75 shown in SEQ ID NO: 83, a Phe at position 76 shown in SEQ ID NO: 83, a Val at position 161 shown in SEQ ID NO: 83 and an Ala at position 257 shown in SEQ ID NO: 83 and wherein said human comprises (i) an IG11G2*O I 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: 83, Asn at position 75 shown in SEQ ID NO: 83. Phe at position 76 shown in SEQ ID NO: 83. Val at position 16 I shown in SEQ ID NO: 83 or Ala al position 257 shown in SEQ ID NO: 83. (vi) wherein the ligand comprises a human kappa chain constant region that comprises a Val at position 84 shown in SEQ ID NO: 93 or a Cys at position 87 shown in SEQ ID NO: 93 and wherein said human comprises (i) an IGKC1 *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: 93 or a Cys at position 87 shown in SEQ ID NO: 93 and (ii) a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val38511e in SEQ ID NO: 78. (vii) wherein the ligand comprises a human IGLC1*O1 lambda chain constant region and wherein said human comprises (i) a human 1GLC1 *01 lambda chain constant region gene segment, or the 354 human expresses antibodies comprising human IGLC1 *01 lambda chain constant regions. 1001075] For example, as per example (iv), the inventor identified the possibility of addressing the rarer IGH-gamma-1 SNPs 204D (observed cumulative frequency of 0.296) and 2061. (observed cumulative frequency of 0.283) individually or in combination. These residues are pail 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: 81 or a Leu corresponding to position 206 of SEQ ID NO: 81 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 sarilumab. id="p-1076" id="p-1076"

[001076] in another example, as per example (v), the inventor identified the possibility of addressing IGH-gamma-2 SNPs. This included consideration of Fc region variation - in this respect, the inventor focused on positions 161 and 257 which are in the Fc region. Thus, in this example the ligand of the invention comprises or consists of an antibody that comprises a human gamma-2 heavy chain constant region that comprises an amino acid selected from the group consisting of a Pro corresponding to position 72 of SEQ ID NO: 83, an Asn corresponding to position 75 of SEQ ID NO: 83, a Phe corresponding to position 76 of SEQ ID NO: 83, a Val corresponding to position 161 of SEQ ID NO: 83 and an Ala corresponding to position 257 of SEQ ID NO: 83; 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-1077" id="p-1077"

[001077] In another example, as per example (vi), the inventor addressed human kappa constant region variation. Thus, in this example the ligand of the invention comprises or consists of an antibody that comprises a human kappa light chain constant region that comprises a Val corresponding to position 84 of SEQ ID NO: 93 or a Cys corresponding to position 87 of SEQ ID NO: 93: 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 sarilumab. [001078] In another example, as per example (vii), 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. 355 Example 4: Determination of Specific Binding of Ligands of the Invention to 1L6R Variants The specific binding of ligands of the invention to IL6R variants can be performed using the following method. [001079J Method of SPR Determination of Binding Binding of the antibodies to the IL6R variants is 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 are captured on this surface as ligands. The IL6R variants are used as analytes and passed over the captured antibodies at 256nM. 64nM, 16nM. 4nM and 1 nM. Binding curves are double referenced using a buffer injection (i.e. OnM) to remove baseline drift and injection artefacts. Regeneration of the capture surface is with 100mM phosphoric acid which removes the captured antibody allowing another cycle of capture and binding. The binding sensorgrams generated are analysed using the 1:1 model inherent to the ProteOn XPR36 Array system analysis software. The assay is performed at 25 °C and using IxHBS-EP (Teknova) as running buffer. id="p-1080" id="p-1080"

[001080] References: The references cited herein arc incorporated by reference in their entirety 1. Ferreira el al (PLoS Genet. 2013 Apr: 9(4):e1003444. doi: 10.1 371/journaLpgen. 1003444. Epub 2013 Apr 4, Functional IL6R 358Ala allele impairs classical IL’6 receptor signaling [sic] and influences risk of diverse in flammatory diseases"; 2. Rantala A et aL Hum Immunol. 201 I Jan;72( I ):63-8. doi: 10.1016/j.humimm.2010.10.010. Epub 2010 Oct 15. Association of IL-6 and 1L-6R gene polymorphisms with susceptibility to respiratory tract infections in young Finnish men": 3. Zhang HY el al. Oral Dis. 2014 Jan;20(l ):69-75. doi: 10.1 I 11 /odi. 12075. Epub 2013 Feb 24. The association of IL-6 and IL-6R gene polymorphisms with chronic periodontitis in a Chinese population’*; 4. J C Galicia et al, Genes and Immunity (2004) 5, 513-516. doi: 10.1038/sj.gene.6364120 Published online 12 August 2004, "Polymorphisms in the IL-6 receptor (IL-6R) gene: strong evidence that serum levels of soluble IL-6R are genetically influenced"; 356 . Esparza-Gordillo J e! al, J Allergy Clin Immunol. 2013 Aug; 132(2):371-7. doi: .10!6/j.jaci.2013.01.057. Epub 2013 Apr 9, "A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis. 357 Table 12; 1000 GENOMES PROJECT HUMAN POPULATIONS Below is a summary of the ethnic populations as per the 1000 Genomes Project sequences. (a) 100 Genome Populations Population Code Population Description Super Population Code CHB Han Chinese in Bejing. China ASN J PT Japanese in Tokyo, Japan ASN CMS Southern Han Chinese ASN CDX Chinese Dai in Xishuangbanna, China ASN KI IV Kinh in Ho Chi Minh City, Vietnam ASN CEU Utah Residents (CEPH) with Northern and Western European ancestry EUR TSI Toscani in Italia EUR FIN Finnish in Finland EUR GBR British in England and Scotland EUR IBS Iberian population in Spain EUR YRI Yoruba in Ibadan, Nigera AFR LWK Luhya in Webuye, Kenya AFR GWD Gambian in Western Divisors in The Gambia AFR MSL Mcnde in Sierra Leone AFR ESN Esan in Nigera AFR ASW Americans of African Ancestry in SW USA AFR ACB African Carribbeans in Barbados AFR MXL Mexican Ancestry from Los Angeles USA AMR PUR Puerto Ricans from Puerto Rico AMR CLM Colombians from Medellin, Colombia AMR PEL Peruvians from Lima. Peru AMR GIH Gujarati Indian from Houston. Texas SAN P.IL Punjabi from Lahore. Pakistan SAN BEB Bengali from Bangladesh SAN STU Sri Lankan Tamil from the UK SAN ITU Indian Telugu from the UK SAN (b) Super Populations AFR, African AMR, Ad Mixed American ASN, East Asian EUR, European 358 SAN, South Asian (c) Population Ancestries European ancestry Utah residents (CEPH) with Northern and Western European ancestry (CEU) Toscani in Italia (TSI) British from England and Scotland (GBR) Finnish from Finland (FIN) Iberian populations in Spain (IBS) East Asian ancestry Han Chinese in Beijing, China (CHB) Japanese in Toyko. Japan (JPT) Han Chinese South (CHS) Chinese Dai in Xishuangbanna (CDX) Kinh in Ho Chi Minh City, Vietnam (KHV) Chinese in Denver. Colorado (CHD) (pilot 3 only) West African ancestry Yoruba in Ibadan, Nigeria (YRI) Luhya in Webuye, Kenya (LWK) Gambian in Western Division. The Gambia (GWD) 359 Malawian in Blantyre, Malawi (MAB) West African Population (TBD) Americas African Ancestry in Southwest US (ASW) African American in Jackson, MS (AJM) African Caribbean in Barbados (ACB) Mexican Ancestry in Los Angeles. CA (MXL) Puerto Rican in Puerto Rico (PUR) Colombian in Medellin, Colombia (CLM) Peruvian in Lima, Peru (PEL) South Asian ancestry Ahom in the State of Assam. India Kayadtha in Calcutta. India Reddy in Hyderabad. India Maratha in Bombay, India Punjabi in Lahore. Pakistan 360 Table 13: Exemplary anti-IL6R disclosures, eg of antibodies and/or antibody fragments, assays, treatments, formulations, kits, methods and indications, useful in any and all aspects of the invention Patent or patent application which is incorporated by reference in its entirety, and specifically, eg, with respect to the SEQ ID Nos. comprising an anti-IL6R monoclonal antibody or fragment thereof US856872I.

US20130157313AI.

US20130149310A J, US20130I22003A1, US8I92741.

US8I83014, US20I20003697AI, US8080248.

US8043617.

US20I 10171241A I, US20100316636AL US20100316627AI, US 75 82298 Table 14: Human antibody gene segment variants distributed over several human ethnic populations - useful for ligand tailoring Cum Freq10 0.888 00 + — /—S 0- Ch cr E ’T 04 © o Q OO Ch χ Μ M i O aj 01 O' 00 1) 0 Fr 0 ^ΕΛ -σ 10 © z -5 •— ! c G E C 71 E d X 3 s X ©. © fe0 CT to -σ c 0) *z c ID .2 eo iii 2 Έ C3 X © O to > = — Z X £ fe Q •or*L· Z qj -r E & 3 ,2 x> G O O © © * ° t e H pl UI ri BI fe in t— < © Z 73 Π ± > U U C Z X—Z *. - - ______ ·- -7? C Tt CM - op 'CJ ct 33 © c £ < Coordinate2 & Variation 1 J s 1 0/ Z Y -= a q r 3 "O' £ £ 5 30S MG ! nurnberi CDR] variatk 1 1OT hr al position i 0 0 0 φ Q. e - Cl * Ch * ch * Ch E E 3 CT CT CT Λ □ > X E X X X X 0 O >—i 0 Ή ε a * W Human Gene Segmen Type 0 c< > Ί 5 —. ____ 362 0.112 9960 o d I960 0.039 rar oo rq S' rar 00 CM MD ί/ύ m o O sO CM O'' o o — o p p p I O' o^ o o d d d s o s °> s ° e CM xj- rat nr OO sO so E^- o p p O o d d d d d o O'' CM O' cn MD o oo i 02 00 CD o S ~rj Ό n CH = Χί" rn ra s© ra vO ra tn cc un ra rq d > μ? d 03 sZl o V3 ND to md -γ-j X CM -y CM CM -p o ra 9· s d E d ra S ra - £ oo ? oo oo oo £ rar Q CM <2 CM O Fl £ '—- o s o oo O [ , ^« H 23 o 02( Ui u TC Zl ~ OO OO «— - - U—» (— R s Γ £ § MD OO Z 0. cn q o . ri 0 P z ’d ra OM ariat C A ,ra AZ 5 ’d MD g ο Ο E S Z d r- cc E 7P 'ariat . - oo o X OO b o i cn — ix d cn » o 2 n at pi Ώ I! W3 X LU 09 —' U. (Pro SE (Cl (Ser SE (F j) ! ,—. 5-9*02 -11*0 -1 1*0 i 1 I d p. V3 X y: o O o -- V3 o 363 ό 0.757 0.296 o o 0.283 1 0.717 ο ο \Ο θ 0.584 (0.929) 0.096 (0.496) 0.504 (0.904) 0.104 (0.462) 0.538 (0.896) ο 0.345 I 0.400 i ! _____ o o I ! 0.358 0.358 J___________ 454 o 153 | 366 ω < (European ancestry) < (European ancestry A (European ancestry) < (European 2:89156948 (forward strand) 2:89156948 (forward strand) 2:89156939 (forward strand) 2:89156939 1 (forward strand) i 14:106208086 1 1 (forward strand) 14:106208086 j (forward strand) 14:106208082 (forward strand) 14:106208082 (forward strand) GTC i— UI (rs232230) TGC GGC (rs200765 148) HI rn DVD i (rs 1045853) CTG <1 84 V (Val at position 84 in SEQ ID NO: 16) w__ 87C (Cys at position 87 in SEQ ID NO: 16) 1 028 204D (CH3 variation) 204E (CH3 variation) 206L (CH3 variation) 206M ___________________ Ο * Ο Ο o * u o IGKC*01 o * IGHG 1*01 s * δ X !0*lDH91 IGHG I *03 IGKC IGHG1 364 IGHG2*01 1 72P I CCC ! 14:106110914 I B I I 0.336 I 0.540 I 0.708 365 CM CN in IT) O o o 0.408 0.005 ation. org) unless otherwise indicated (0.46) CO c7 CM CT Q\ 0s CN CN xF o o o o oo r- cm er o o o o m on ο o ο ο, ό o ο r-' er o θ o ! 0.199 0.007 O Q υ X' (forward strand) 14:106109752 (forward strand) 14:106109752 (forward strand) Table Footnotes: 10. IMGT notation (ww.imgt.org); refer to figures for other alleles comprising this vari. 11. Numbering as indicated in Ensembl (available on the World Wide Web at ensembL 12. SNP Underlined in Codon. (rs8009J56) (CH2 variation) 257A GCC (CH3 variation) i 25 7S TCC (rs4983499) . . ! (CH3 variation) IGHG2*01 1GHG2*O6 ©ο CO '5 CQ Q, Z 00 ,£> X o z cd CZ) G5 rd o cz V) CD a rd ex o ex rd rP X X oo C .2 t5 CX O ex 0) E o X E o c a> O CQ ESP6500:African American. 366 CD cd o G. O u« 2 UJ k© x (/: (D G a Cd (D CD > G G CD CD □0 > cd j=2 CD cd N O CD CD cd CD 1) CD CD CD O0 CD CD O £ JO E G 'N G G Po g CD o a CD OJO G cd S CZ) 3 o OJO N -w O g cP CD CZ) cd O 5d OD >0 cP tD CD CD Q G (D fa (D CD CJ CD CU cz; O OJO O 5— CD cd -1—· CD cd OJO G cd E <4-< CD CZ) •fc-» N* O E o 4—* o G CD 00 o G CD 00 § E G Έ 1-> oo G cd s CD cd ON 367 Table 15: SEQUENCES SE Q ID NO: Human Allele Nucleotide/Amino Acid Sequence 78 79 i 1 IH-6R MLAVGCALL·AALLAAPGAALAPRRCPAQEVARGVLTSLPGDSVTLTCPG VEPEDNATVHWVLR.KPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSC YRAGRPAG TVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKA VLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLAVPEGDSSFYIVSMCVAS SVGSKFSKTQTFQGCG1LQPDPPANITVTAVARNPRWLSVTWQDPHSWN SSFYRLRFELRYRAERSKTFTTWMVKDLQHHCV1HDAWSGLRHVVQLR AQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDD NILFRDSANATSLPVQDSSSVPLPTFLVAGGSEAFGTLLCIAIVLRFKKTW KLRAEKEGKTSMHPPYSLGQLVPERPRPTPVFVPLISPPVSPSSEGSDNTSS HNRPDARDPRSPYDISNTDYFFPR Deposition 358 Veposilion 385 ATGCTGGCCGTCGGCTGCGCGCTGCTGGCTGCCCTGCTGGCCGCGCCG GGAGCGGCGCTGGCCCCAAGGC GCTGCCCTGCGCAGGAGGTGGCGAGAGGCGTGCTGACCAGTCTGCCA GGAGACAGCGTGACTCTGACCTG CCCGGGGGTAGAGCCGGAAGACAATGCCACTGTTCACTGGGTGCTCA GGAAGCCGGCTGCAGGCTCCCAC CCCAGCAGATGGGCTGGCATGGGAAGGAGGCTGCTGCTGAGGTCGGT GCAGCTCCACGACTCTGGAAACT ATTCATGCTACCGGGCCGGCCGCCCAGCTGGGACTGTGCACTTGCTGG TGGATGTTCCCCCCGAGGAGCC CCAGCTC I CC JGCTTCCGGAAGAGCCCCCTCAGCAATGTTGTTTGT GA GTGGGGTCCTCGGAGCACCCCA TCCCTGACGACAAAGGCTGTGC I CI I GGTGAGGAAGTTTCAGAACAG TCCGGCCGAAGACTTCCAGGAGC ' CGTGCCAGTATTCCCAGGAGTCCCAGAAGTTCTCCTGCCAGTTAGCAG TCCCGGAGGGAGACAGCTCTTT CTACATAGTGTCCATGTGCGTCGCCAGTAGTGTCGGGAGCAAGTTCA GCAAAACTCAAACCTTTCAGGGT TGTGGAATCITGCAGCCTGATCCGCCTGCCAACATCACAGTCACTGCC GTGGCCAGAAACCCCCGCTGGC TCAGTGTCACCTGGCAAGACCCCCACTCCTGGAACTCATCTTTCTACA GACTACGGTTTGAGC I CAGA'i A TCGGGOOAACXKSTCAAAG CACAACATGGA TGGTCAAGGACC rCCAGCATCACTGTGTCATCCAC GACGCCTGGAGCGGCCTGAGGCACG ^ rGCAGCTTCGTGCCCAGGA GGAGTTCGGGCAAGGCGAGTGGA GCGAGTGGAGCCCGGAGGCCATGGGCACGCCTTGGACAGAA 1 CCAGG AGTCC TCCAGCTGAGAACGAGGT GTCCACCCCCATGCAGGCACTTACTACTAATAAAGACGATGATAATA TTCTCTTCAGAGATTCTGCAAAT GCGACAAGCCTCCCAGTGCAAGATTCTTCTTCAGTACCACTGCCCACA ITCCTGGTTGCTGGAGGGAGCC TGGCCTTCGGAACGCTCCTCTGCATTGCCATTGTTCTGAGGTTCAAGA AGACGTGGAAGCTGCGGGCTCT GAAGGAAGGCAAGACAAGCATGCATCCGCCGTACTCTTTGGGGCAGC TGGTCCCGGAGAGGCCTCGACCC ACCCCAGTGC'ITGTTCCTCTCATCTCCCCACCGGTGTCCCCCAGCAGC CTGGGGTCTGACAATACCTCGA 368 GCCACAACCGACCAGATGCCAGGGACCCACGGAGCCCTTATGACATC AGCAATACAGACTACTTCTTCCC CAGATAG HEAVY CHAIN ALLELES 80 IGHGI *01 (CI-H+Hinge+CH24 CH3+CH-S) gccLccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca ggactciaclccctcagcagcgtggtgaccgtgccctccagcagctlgggcacccagacc tacatctgcaacglgaatcacaagcccagcaacaccaaggtggacaagaaagilgagccc aaatcttgtgacaaaactcacacatgcccaccgTgcccagcacclgaactcclgggggga ccglcagtcitcctcttccccccaaaacccaaggacaccctcalgatctcccggacccct gaggicacalgcgtggtggtggacgtgagccacgaagaccctgagglcaagttcaactgg Lacgtggacggcglggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac agcacgiaccggglggtcagcgtccicaccgtcctgcaccaggactggctgaaiggcaag gagtacaagtgcaaggtctccaacaaagccctcccagcccccalcgagaaaaccaictcc aaagccaaagggcagccccgagaacxacaggtgtacaccctgcccccalcccgggatgag ctgaccaagaaceaggtcagcctgacctgcctggtcaaaggcttctaicccagcgacatc gccgtggagtgggagagcaatgggcagccggagaacaaclacaagaccacgcctcccglg ctggactccgacggctccttcttcctctacagcaagclcaccgtggacaagagcaggtgg cagcaggggaacgtcttctcalgctccgtgalgcatgaggctclgcacaaccaclacacg cagaagagcctctccctgtctccgggtaaa i ; 8) ASTKGRS\WLAASSKSTSGGTAA1.GCLVKI)YITLPVTVSWNSGA VLQSS GLYSLSSVVTVPSSSIGTQTYICNVNHKPSN IKVDKKVliPKSCDK ΓΙ iTCEPCPAP]· I.I.GG PSVFLTTPKPKDTLMISRTPEVTCVVVDVSHEDPi-VKFNWYVDGVr· ViiNAKlKPR EEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAIAEKTISKAKGQPRETQVYTLP PSRDE LTKNQVSLTCLVKGFYPSDlAVEWESNGQPENNYKTTPPVLLSDGSFFLYSKLrV DKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK Deposition 204 Imposition 206 82 1GHG2*OI (CH HHinge-Cl 12- i CH3+CH-S) gcctccaccaagggcccatL’gglcUccccciggcgcccigctccaggagcaeclccgag agcacagccgccctgggctgectggicaaggactacuccccgaaccggigacggtgtcg : tggaaclcaggcgciugaccagcggcgtgcacaccttcccagctgicclacagtcclca ggactctactccctcagcagcglggtgaccgtgccctccagcaacticggcacccagacc tacacctgcaacgtagalcacaagcccagcaacaccaaggtggacaagacagligagcgc aaatgtlgigtcgagtgcccaccgtgcccagcaccacctgtggcaggaccgtcagtctlc ctcttccccccaaaacccaaggacaccctcatgatclcccggacccctgaggtcacgtgc giggtggtggacgtgagccacgaagaccccgaggiccagitcaacigglacgtggacggc glggaggtgcataatgccaagacaaagccacgggaggagcagttcaacagcacgltccgt glggtcagcgtcctcaccgugtgcaccaggactggclgaacggcaaggagiacaagtgc aaggtciccaacaaaggcclcccagcccccatcgagaaaaccatciccaaaaccaaaggg cagccccgagaaccacagglgtacaccctgcccccaicccgggaggagatgaccaagaac caggtcagcctgacctgcctggicaaaggcttctaccccagcgacaicgccgtggagigg gagagcaaigggcagccggagaacaaciacaagaccacaccicccalgciggaclccgac ggciccnciicciciacagcaagctcaccgtggacaagagcaggtggcagcaggggaac glcttcicatgclccglgalgcalgaggclctgcacaaccaclacacgcagaagagcclc iccctgictccggglaaa 83 ASTKGPSVEPI.APCSRSTSESTAALGCLVKDYm-.PVTVSWNSGAl.TSGVHTFPAV LQSS GLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVF.RKCCVF.CPPCPAPPVA GPSVF LFPPKPKDTLMISRTPEV'rCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTFR vvsvltvviiqowlngkeykckvsnkglpapiekhsktkgqprepqvytlppsre EMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLbSDGSFFl.YSKLTVDKSR WQQGN VFSCSVMHEALHNHYTQKSLSLSPGK 369 Reposition 72 ^-position 75 Exposition 76 V=position 161 Apposition 257 84 1GHV3-9*O1 1 1 gaagtgcagctggtggagtctgggggaggctlggtacagcctggcagglccctgagactctcctgtgcagcctctg gattcacctttgatga.ttatgccatgcactgggtccggcaagctccagggaagggcctggagtgggtctcaggtat1 agttggaatagtggragcataggclatgcggactctgtgaagggccgattcaccatctccagagacaacgccaaga actccctgtatctgcaaatgaacagtctgagagctgaggacacggccttgtattactglgcaaaagata (^nucleotide number 86 c=nucleotide number 272 85 EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMH WVRQAPGKGLEW VSG1SWN SGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKD F position 30 (1MGT nomenclature) T= position 1 10 (dbSNP nomenclature) 86 1GHV3-7*OI gaggtgcagctggtggagtctgggggaggcttggtccagcciggggggtccctgagactc tcctgtgcagcctctggattcacctttagtagctattggatgagctgggtccgccaggct ccagggaaggggctggagtgggtggccaacataaagcaagatggaagtgagaaatactal gtggactcigtgaagggccgattcaccatctccagagacaacgccaagaactcactgiat ctgcaaatgaacagcctgagagccgaggacacggctgtglattactgtgcgagaga 87 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWV ANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AR 88 IGHJ3*02 T GAT GCT TIT GAT ATC TGG GGC CAA GGG ACA ATG GTC ACC GTC TCT 1 CA G 89 D A F D 1 W G Q G Τ Μ V Τ V S S 90 1GH.I6T1 AT TAC TAC TAC TAC TAC GGT ATG GAC GTC TGG GGG CAA GGG ACC ACG G TC ACC GTC TCC TCA G 91 YYYYYGMDVWGQGT Τ V Τ V S S LIGIT 1 CHAIN ALL El.ES __Γ 92 IGKC*01 cgaactgtggctgcaccatctgtcltcatcttcccgccaiclgatgagcagugciaaici ggaactgcctctgugigigcclgcigaataacltctatcceagagaggccaaagiacag iggaaggtggataacgccctccaalcggglaactcccaggagagtgtcacagagcaggac agcaaggacagcacctacagcctcagcagcacectgacgctgagcaaagcagaciacgag aaacacaaagtclacgccxgcgaagtcacccatcagggcclgagctcgcccgtcacaaag agcltcaacaggggagagtgl 93 RTVAAPSV14FPPSDEQIXSGTASWCUJWFYl^F^KVQ\\d 94 IGLCPOI cccaaggccaaccccacggtcactclgttcccgcWcctctgaggagctccaagccaac aaggccacactagtgtgtctgatcagtgacuctacccgggagctgtgacaglggcttgg aaggcagatggcagccccglcaaggcgggagtggagacgaccaaaccclccaaacagagc aacaacaagtacgcggccagcagctacctgagcctgacgcccgagcagtggaagtcccac agaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcccct acagaatgttca 95 PKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKA GVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV 370 APTECS 96 IGKVL12*01 gacatccagatgacccagtctccatcttccgtgtctgcatctgtaggagacagagtcacc atcacttgtcgggcgagtcagggtattagcagctggttagcctggtatcagcagaaacca gggaaagcccctaagctcclgatctalgctgcatccagmgcaaaglgggglcccatca aggilcagcggcagrggatctgggacagatttcactctcaccalcagcagcctgcagcct gaagauagcaacttactattgicaacaggclaacagtitccctcc ___ __ 97 DIQMTQSPSSVSASVGDRV'I'I rCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFP 98 IGKV3-11*01 gaaaltglgttgacacagtctccagccaccctgictttgtciccaggggaaagagccacc ctcicetgcagggccagtcagagigttagcagctacttagcctgglaccaacagaaacct ggccaggctcccaggclccicalclalgatgcatccaacagggccactggcalcccagcc aggttcagtggcagtgggtctgggacagacucacicicaccatcagcagcctagagcci gaagattttgcagtitanactgtcagcagegtagcaactggccicc t^nucleotide number 199 c=nucleotide number 284_______________i 99 EIVLTQSPAl'LSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRIJJYDASNRA'r GIPARFSGSGSGTDFTl/riSSLFPFOFAVYYCQQRSNWP S=position 87 P=position 115 100 IGKJ2*01 tgiacactttiggccaggggaccaagctggagatcaaac 101 YTFGQGTKLEIK 102 1GKJ4*91 G CTC ACT 'FTC GGC GGA GGG ACC AAG GTG GAG ATC AAA C 103 L TFGGGTKVEIK 104 An IGHGPO! Heavy Chain EVQLVESGGG LVQPGRSLRL SCAASRFTFD DYAMHWVRQA PGKGLEWVSG ISWNSGRIGY ADSVKGRFTI SRDNAENSLF LQMNGLRAED TALYYCAKGR DSFD1WGQGT MVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVI.QSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKKVF.PKSCD KTHTCPPCPA PELLGGPSVF i LFPPKPKDTL M1SRTPEVTC VVVDVSHF.DP EVKFNWYVDG VEVHNAKTKP REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP lEKTISKAKG QPREPQVTYL PPSRDELTKN QVSLTCLVKG FYPSD1AVEW ESNGQPENNY KTTPPVLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNIIYTQKSL SLSPGK 105 An IGKC*01 Kappa Ligli! Chain DIQMTQSPSS VSASVGDRVT [TCRASQGIS SWLAWYQQKP GKAPKLLIYG ASSLESGVPS RFSGSGSG1D FTLT1SSLQP EDFASYYCQQ ANSFPYTFGQ CTREE)KRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVT1IQG LSSPVTKSFN RGEC 106 An IGHGM01 Heavy Chain EVQLVESGGGLVQPGGSLRLSCAASGFTFSPFAMSWVRQAPGKGLEWV AKISPGGSWTYY SDTVTGRniSRDNAKNSLYLQMNSLRAEDTAVYYCARQLWGYYAl.DI WGQGTTVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL1SGVH TFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPELLGGP SVFLFPPKPKDTLMISRTPF.VTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDEL 371 TKNQVSLTCLVKGFYPSD1AVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 107 An IGKC*01 Kappa Light Chain EIVLTQSPATLSLSPGERATLSCSAS1SVSYMYWYQQKPGQAPRLL1YDMS NLASGIPAR FSGSGSGTDFTLTISSLEPEDFAVYYCMQWSGYPY TFGGGTKVEIKRTVA APSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTL SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 108 IGHV3-9*01 CDR1 (IMGT nomenclature) ggattcacctttgatgattatgcc Imposition 1 1 109 G F T F D D Y A F=position 4____ _______________________ i 1 10 ]GHV3-9*01 FW3 (IMGT nomenclature) ggc tat geg gac tct gtg aag ggc ega ttc acc ate tcc aga gac aac gcc aag aac tcc cig tat ctg caa atg aac agt ctg aga get gag gac acg gcc ttg tat tac tgt exposition 98 ___________ ________ 111 G Y A D S V K G R F T I S R D N A K N S L Y L QMNSLRAEDTALYYC Imposition 33_____ 112 1GKV3-1 1*01 CDR3 (IMGT Nomcncalture) CAG CAG CGT AGC AAC TGG CCT CC C=nucleotide 20 113 QQRSNWP Imposition 7 114 IGKV3-11 *01 FW3 (IMGT Nomencalturc) aacagggccactggcatcccagccaggttcagtggcagtgggtctgggacagacttcactctcaccalcagcagcctagagcct gaagatlttgcagttlattactgt T=nucleotide 43 j 1 15 NRATGIPARFSGSGSGTDI I LTISSLEPFDFAVYYC j S=posilion 15 _________________ _ ___ 1 Reference to sequence positions throughout this specification are to the sequence positions as identified in the description and tables. For example, positions 204 and 206 of SEQ ID NO:81 arc the positions identified in SEQ ID NO:81 in Table 1 5. 372 STATEMENTS OF INVENTION: A. A method of treating or reducing the risk of an IL6R-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 an IL6R protein that comprises a mutation Asp358Ala or Val38511e in SEQ ID NO: 1; wherein the antibody or fragment comprises a VI I 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 (i) a CDRI comprising a Phe at position 4 shown in SEQ ID NO: 32 and wherein said human comprises a VH gene segment encoding a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 32. or the human expresses λζΗ domains that comprise a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 32; or (ii) a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 34 and wherein said human comprises a VH gene segment encoding a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 34 or the human expresses VH domains that comprise a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 34; and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val385Ile in SEQ ID NO: 1.

B. A method of treating or reducing the risk of an lL6R-mediated disease or condition in a human in need thereof, the method comprising administering to said human an antibody or fragment that specifically binds an IL6R protein that comprises a mutation Asp358Ala or Val385llc in SEQ ID NO: 1: wherein the antibody or fragment comprises a VH domain derived from the recombination of a human VH gene segment, a human D gene segment and a human JH segment, the human VH gene segment comprising (a) T at nucleotide number 86 shown in SEQ ID NO: 7 and wherein said human comprises a VH gene segment comprising T at nucleotide number 86 shown in SEQ ID NO: 7; or (b) C at nucleotide number 272 shown in SEQ ID NO: 7 and wherein said human comprises a VH gene segment comprising Cal nucleotide number 272 shown in SEQ ID NO: 7; and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val385Ile in SEQ ID NO: 1. 373 C. The method of statement B, wherein each said human VH gene segment comprises SEQ ID NO: 31.

C. The method of statement B, wherein each said human VH gene segment comprises SEQ ID NO: 33.

D. fhe method of any preceding statement, wherein said VH domain is derived from the recombination of human VH segment IGHV3-9*01. a human D gene segment and a human JH segment; and said human comprises human VH segment 1GH\Z3-9*O1 or expresses VH domains derived from the recombination of human VII gene segment IGHV3-9*01, a human D gene segment and a human JH segment.

E. The method of any preceding statement, wherein said VH domain comprises the FW3 sequence of SEQ ID NO: 34.

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

H. The method of any preceding statement, wherein the antibody or fragment comprises a human gamma-1 heavy chain comprising said VI1 domain and a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 4 and a Leu at position 206 shown in SEQ ID NO: 4 and wherein said human comprises an IGHG! *01 human heavy chain constant region gene segment. 1. The method of any preceding statement, wherein the antibody or fragment comprises an IGHGl*01 human heavy chain constant region.

J. The method of any preceding statement, wherein the human is of AMR, ASN or EUR ancestry. 374 K, The method of any preceding statement comprising, before said administering, selecting a human comprising said nucleotide sequence of (ii), wherein the human is the human of statement 1.

L. The method of any preceding statement comprising, before said administering, selecting a human comprising said nucleotide sequence of (ii), wherein the human is the human of statement 2.

M. The method of any preceding statement, wherein the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 1 and/or an IL6R protein comprising said mutation Asp358Ala and/or Val3851 le in SEQ ID NO: 1.

O. The method of any preceding statement, comprising the step of determining that the human comprises the nucleotide sequence that encodes an 1L6R protein comprising said mutation Asp358Ala and/or Val385Ile and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile, optionally, wherein the determining step is performed before administration of the antibody to the human.

P. The method of statement O. wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL6R protein comprising said mutation Asp358Ala and/or Val385Ilc in SEQ ID NO: 1.

Q. I’he method of statement P, 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 IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 1 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val3851 le in SEQ ID NO: 1, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 1 is present; and detecting the presence or absence of the complex, wherein detecting the presence of the 375 complex determines that the human comprises the IL6R protein comprising said mutation Asp358Ala and/or Val385He in SEQ ID NO: 1.

R. The method of statement P or Q, 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.

S. The method of statement P, Q or R, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human.

T. The method of any preceding statement, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 1, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 2. or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 1.

U. The method of statement any preceding, wherein said human is or has been further determined to be substantially resistant to an anti-TNF alpha treatment.

V. The method of any preceding statement, wherein said human is receiving or has received an anti-TNF alpha treatment or has reduced responsiveness to an anti-TNF alpha treatment.

W. The method of any preceding statement, wherein said antibody or antibody fragment is administered to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment.

X. The method of any preceding statement, wherein said disease or condition is an inflammatory disease or condition. 376 Y. The method of any preceding statement, wherein said disease or condition is selected from the group consisting of an inflammatory bowel disease (IBD), Crohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis. Sjorgen’s syndrome, airway inflammation. Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

Z. The method of any preceding statement, wherein said human has been diagnosed with al least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graft-versus-host disease (GvHD), asthma, adull respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman’s disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

AA. The method of any preceding statement, wherein said antibody or antibody fragmen! treats or reduces the risk in said human of at least one condition selected from the group consisting of an inflammatory bowel disease (IBD), Chrohn’s disease, rheumatoid arthritis, psoriasis, bronchiolitis, gingivitis, transplant rejection, allogenic transplant rejection, graftversus-host disease (GvHD), asthma, adult respiratory distress syndrome (ARDS), septic shock, ulcerative colitis, Sjorgen’s syndrome, airway inflammation, Castleman's disease, periodontitis, atopic dermatitis, systemic lupus erythematosus and coronary heart disease.

AB. The method of any preceding statement, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736.

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

Further Statements of Invention are as follows: 377 1. An antibody or antibody fragment for use in a method of treating or reducing the risk of rheumatoid arthritis in a human in need thereof, wherein the antibody or fragment specifically binds an IL6R protein that comprises a mutation Asp358Ala or Val385He in SEQ ID NO: 78 and 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 (i) a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109. wherein said human comprises a VII gene segment encoding a CDR! comprising a Phe al position 4 shown in SEQ ID NO: 109, or the human expresses VH domains that comprise a CDR] comprising a Phe at position 4 shown in SEQ ID NO: 109; or (ii) a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 111, wherein said human comprises a VH gene segment encoding a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 111 or the human expresses VH domains that comprise a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 111; and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or VaI385Ile in SEQ ID NO: 78. 2. An antibody or antibody fragment for use in a method of treating or reducing the risk of rheumatoid arthritis in a human in need thereof, wherein the antibody or fragment specifically binds an IL.6R protein that comprises a mutation Asp358AIa or Val385Ile in SEQ ID NO: 78 and comprises a VH domain derived from the recombination of a human VH gene segment, a human D gene segment and a human JH segment, the human VH gene segment comprising (a) T at nucleotide number 86 shown in SEQ ID NO: 84 and wherein said human comprises a VH gene segment comprising T at nucleotide number 86 shown in SEQ ID NO: 84: or (b) C at nucleotide number 272 shown in SEQ ID NO: 84 and wherein said human comprises a VH gene segment comprising C at nucleotide number 272 shown in SEQ ID NO: 84; and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val385Ile in SEQ ID NO: 78. 378 3. The antibody or antibody fragment of statement 2, wherein said human VH gene segment comprises SEQ ID NO: 108 or SEQ ID NO: 110. 4. The antibody or antibody fragment of any preceding statement, wherein said VH domain is derived from the recombination of human VH segment IGHV3-9*01, a human D gene segment and a human JH segment; and said human comprises human VH segment IGHV3-9*01 or expresses VH domains derived from the recombination of human VII gene segment IGHV3-9*01. a human D gene segment and a human JH segment.

. The antibody or antibody fragment of any preceding statement, wherein said VH domain comprises the FW3 sequence of SEQ ID NO: 111. 6. The antibody or antibody fragment of any preceding statement, wherein the VH gene segment comprised by said human is a germline VH gene segment. 7. The antibody or antibody fragment of any preceding statement, wherein the antibody or fragment comprises a human gamma-1 heavy chain comprising said VH domain and a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 and a Leu al position 206 shown in SEQ ID NO: 81 and wherein said human comprises an 1GHG1*O1 human heavy chain constant region gene segment. 8. The antibody or antibody fragment of any preceding statement, wherein the antibody or fragment comprises an IGHGP01 human heavy chain constant region. 9. The antibody or antibody fragment of any preceding statement, wherein the human is of AMR, ASN or EUR ancestry and/or wherein the method comprises, before administration of said antibody or fragment, selecting a human comprising said nucleotide sequence, wherein the human is the human of statement 1 or statement 2.

. The antibody or antibody fragment of any preceding statement, wherein (i) the human has been determined to comprise the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val38511e in SEQ ID NO: 78 and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78 or (ii) 379 wherein the method comprises the step of determining that the human comprises the nucleotide sequence that encodes an IL6R protein comprising said mutation Asp358Ala and/or Val385Ile and/or an IL6R protein comprising said mutation Asp358Ala and/or Val385IIe, optionally, wherein the determining step is performed before administration of the antibody to the human. 11. The antibody or antibody fragment of statement 10, wherein the step of determining comprises assaying a biological sample from the human for a nucleotide sequence encoding a IL6R protein comprising said mutation Asp358Ala and/or Val3851le in SEQ ID NO: 78. 12. The antibody or antibody fragment of statement 11. 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 IL6R protein comprising said mutation Asp358Ala and/or Val385Ue in SEQ ID NO: 78 or comprising an antisense sequence of said contiguous nucleotides, wherein said sequence of contiguous nucleotides comprises a nucleotide sequence encoding said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78, thereby forming a complex when at least one nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78 is present: and detecting the presence or absence of the complex, wherein detecting the presence of the complex determines that the human comprises the IL6R protein comprising said mutation Asp358Ala and/or Val385Ile in SEQ ID NO: 78. 13. The antibody or antibody fragment of statement I I or statement 12. 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. 14. The antibody or antibody fragment of any one of statements 11-13, wherein said biological sample comprises serum, blood, faeces, tissue, a cell, urine and/or saliva of said human. 380 . The antibody or antibody fragment of any preceding statement, wherein said human is indicated as heterozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385lle in SEQ ID NO: 78, optionally, wherein said human is further indicated as comprising the nucleotide sequence of SEQ ID NO: 79, or said human is indicated as homozygous for a nucleotide sequence encoding the IL6R protein comprising said mutation Asp358Ala or Val385Ile in SEQ ID NO: 78. 16. The antibody or antibody fragment of any preceding statement, wherein said human is or has been further determined to be substantially resistant to an anti-TNF alpha treatment. 17. Fhe antibody or antibody fragment of any preceding statement, wherein said human is receiving or has received an anti-TNF alpha treatment or has reduced responsiveness to an anti-TNF alpha treatment. 18. The antibody or antibody fragment of any preceding statement, wherein said antibody or antibody fragment is for administration to the human separately or simultaneously with methotrexate or an anti-TNF alpha treatment. 19. The antibody or antibody fragment of any preceding statement, wherein the nucleotide sequence comprises SNP rs2228145 and/or SNP rs28730736. . l'he antibody or antibody fragment of any preceding statement, wherein said antibody or antibody fragment is for administration by intravenous or subcutaneous administration or is comprised in an injectable preparation. 21. The antibody or antibody fragment of any preceding statement, wherein the antibody is a human antibody. 381 SEQUENCE LISTING <110> CLUBE, JASPER R. <12 0> HUMAN TARGETS VI <130> 069496/082410-US <140> <141> <150> 14/331,730 <151> 2014-07-15 <160> 115 <170> Patentin version 3.5 <210> 1 <211> 692 <212> PRT <213> Homo sapiens <400> 1 Met Gly Thr Val Ser Ser Arg Arg Ser Trp Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val 35 40 Glu Asp Gly Leu Ala Glu Ala Pro Glu His 50 55 His Arg Cys Ala Lys Asp Pro Trp Arg Leu 65 70 Val Leu Lys Glu Glu Thr His Leu Ser Gin 85 90 Arg Leu Gin Ala Gin Ala Ala Arg Arg Gly 100 105 His Val Phe His Gly Leu Leu pro Gly Phe 115 120 Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro 130 135 Glu Asp ser Ser Val Phe Ala Gin Ser lie 145 150 lie Thr pro Pro Arg Tyr Arg Ala Asp Glu 165 170 Gly Ser Leu val Glu Val Tyr Leu Leu Asp 180 185 Pro Leu Pro Leu Leu Ala Arg Ala Gin Glu 30 Ala Leu Arg Ser Glu 45 Thr Thr Ala Thr Phe 60 Gly Thr Tyr val Val 80 Glu Arg Thr Ala Arg 95 Leu Thr Lys lie Leu 110 val Lys Met Ser Gly 125 Val Asp Tyr lie Glu 140 Trp Asn Leu GliFArg 160 Gin Pro Pro Asp Gly 175 Ser lie Gin Ser Asp 190 Hi s Arg Glu 195 lie Glu Gly Arg val 200 Met val Thr Asp Phe 205 Glu Asn val pro Glu 210 Glu Asp Gl y Thr Arg 215 Phe His Arg Gin Ala 220 ser Lys Cys Asp Ser 225 His 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 lie Gly Leu Glu Phe 270 lie Arg Lys Ser Gin 275 Leu Val Gin Pro val 280 Gly pro Leu val val 285 Leu Leu pro Ala 305 Asp Leu Ala Gly Gly Tyr 290 ser Arg 295 Val Leu Asn Ala Ala 300 Arg Ala Gly val Val Leu Val Thr Ala Ala Gly Cys Asn 310 315 Ala Cys Leu Tyr 325 Ser Pro Ala Ser Ala 330 Pro Glu val Gl n Phe lie Arg Arg Thr 335 Leu Asp 320 val Gly Ala Thr Asn 340 Ala Gin Asp Gin Pro 345 Val Thr Leu Gly Thr 350 Leu Gly Thr Asn Phe 355 Gly Arg Cys Val Asp 360 Leu Phe Ala Pro Gly 365 Glu Asp lie He Gly 370 Al a Ser Ser Asp cys 375 Ser Thr Cys Phe val 380 Ser Gin Ser Gly Thr 385 ser Gin Ala Ala Al a 390 Hi s Val Al a Gly lie 395 Ala Ala Met Met Leu 400 Ser Al a Glu Pro Glu 405 Leu Thr Leu Ala Gl U 410 Leu Arg Gin Arg Leu 415 lie Hi s Phe Ser Ala 420 Lys Asp val He 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 Gly 450 Ala Gly Trp Gl n Leu 455 Phe cys Arg Thr Val 460 Trp ser Ala His Ser Gly Pro Thr Arg Met Ala Thr Ala lie 465 470 Glu Glu Leu Leu ser cys ser ser Phe Ser 485 490 Gly Glu Arg Met Glu Ala Gin Gly Gly Lys 500 505 Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala 515 520 Leu Pro Gin Ala Asn Cys Ser Val His Thr 530 535 Ser Met Gly Thr Arg Val His Cys His Gin 545 550 Gly Cys ser ser His Trp Glu val Glu Asp 565 570 Pro val Leu Arg Pro Arg Gly Gin Pro Asn 580 585 Glu Ala Ser lie His Ala Ser Cys cys His 595 600 Lys Val Lys Glu His Gly lie Pro Ala Pro 610 615 Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly 625 630 Thr ser His val Leu Gly Ala Tyr Ala val 645 650 Arg ser Arg Asp Val ser Thr Thr Gly Ser 660 665 Thr Ala Val Ala lie Cys Cys Arg ser Arg 675 680 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 15 10 Arg Cys Ala Pro Asp 480 Ser Gly Lys Arg Arg 495 Val cys Arg Ala His 510 Ala Arg Cys Cys Leu 525 Pro Pro Ala Glu Ala 540 Gly His Val Leu Thr 560 Gly Thr His Lys Pro 575 Cys Val Gly His Arg 590 Pro Gly Leu Glu Cys 605 Glu Gin val Thr val 620 Ser Ala Leu Pro Gly 640 Asn Thr cys val val 655 Ser Glu Glu Ala val 670 Leu Ala Gin Ala Ser 685 val Leu Ala Leu Arg Ser Glu Glu ASp 20 Gly Leu Ala Glu Ala 25 Pro Glu His Gly Thr 30 Thr Ala Thr Phe Hi s 35 Arg Cys Al a Lys Asp 40 Pro Trp Arg Leu Pro 45 Gly Thr Tyr val Val 50 val Leu Lys Glu Glu 55 Thr Hi s Leu ser Gin 60 Ser Glu Arg Thr Ala 65 Arg Arg Leu Gin Al a 70 Gin Ala Ala Arg Arg 75 Gly Tyr Leu Thr Lys 80 lie Leu Hi s Vai Phe 85 Hi s Giy Leu Leu pro 90 Gly Phe Leu Val Lys 95 Met Ser Gly Asp Leu 100 Leu Gl u Leu Ala Leu 105 Lys Leu pro Hi s val 110 Asp Tyr lie Glu Glu 115 ASp Ser Ser val Phe 120 Ala Gin Ser lie Pro 125 Trp Asn Leu Glu Arg 130 lie Thr pro pro Arg 135 Tyr Atg Ala Asp Glu 140 Tyr Gin pro Pro ASp 145 Gly Gly Ser Leu val 150 Glu Val Tyr Leu Leu 155 Asp Thr Ser He Gl n 160 ser Asp His Arg Glu 165 lie Glu Gly Arg Val 170 Met val Thr Asp Phe 175 Glu Asn Val Pro Glu 180 Glu Asp Giy Thr Arg 185 phe His Arg Gin Ala 190 ser Lys Cys Asp Ser 195 Hi s Gly Thr Hi s Leu 200 Ala Gly val val Ser 205 Gly Arg ASp Ala Gly 210 Val Al a Lys Gly Ala 215 Ser Met Arg ser Leu 220 Arg Val Leu Asn cys 225 Gin Gly Lys Gly Thr 230 val Ser Gly Thr Leu 235 lie Gly Leu Glu Phe 240 lie Arg Lys ser Gin 245 Leu val Gin Pro val 250 Gly Pro Leu val val 255 Leu Leu Pro Leu Al a 260 Gly Gly Tyr Ser Arg 265 val Leu Asn Ala Ala 270 Cys Gin Arg Leu Ala 275 Arg Ala Gly Val val 280 Leu val Thr Ala Ala 285 Gly Asn Phe Arg ASP 290 Asp Ala cys Leu Tyr 295 Ser Pro Ala Ser Ala 300 Pro Glu val lie Thr 305 val Gly Ala Thr Asn 310 Ala Gin Asp Gin pro 315 val Thr Leu Gly Thr 320 Leu Gly Thr Asn Phe 325 Gly Arg Cys val Asp 330 Leu Phe Ala Pro Gly 335 Glu Asp He He Gly 340 Ala ser Ser Asp Cys 345 Ser Thr cys Phe val 350 ser Gin Ser Gly Thr 355 Ser Gin Al a Ala Ala 360 Hi s val Ala Gly lie 365 Ala Ala Met Met Leu 370 Ser Al a Glu Pro Glu 375 Leu Thr Leu Ala Glu 380 Leu Arg Gin Arg Leu 385 lie Hl S Phe ser Al a 390 cys Asp Val Il e Asn 395 Glu Ala Trp Phe Pro 400 Glu Asp Gin Arg val 405 Leu Thr pro Asn Leu 410 Val Ala Ala Leu Pro 415 Pro Ser Thr Hi s Gly 420 Ala Gly Trp Gin Leu 425 Phe cys Arg Thr Val 430 Trp Ser Al a Hi s Ser 435 Gly pro Thr Arg Met 440 Al a Thr Ala lie Ala 445 Arg cys Al a Pro Asp 450 Glu Glu Leu Leu Ser 455 Cys Ser Ser Phe ser 460 Arg Ser Gly Lys Arg 465 Arg Gly Gl u Arg Met 470 Glu Ala Gl n Gly Gly 475 Lys Leu Val cys Arg 480 Al a Hi s Asn Al a Phe 485 Gly Gly Glu Gly val 490 Tyr Al a Il e Al a Arg 495 Cys cys Leu Leu Pro 500 Gin Ala Asn Cys Ser 505 Val Hi s Thr Al a pro 510 pro Ala Glu Ala ser 515 Met Gly Thr Arg Val 520 Hi s cys Hi s Gin Gin 525 Gly Hi s Val Leu Thr 530 Gly cys Ser Ser Hi s 535 Trp Glu Val Glu Asp 540 Leu Gly Thr His Lys 545 Pro pro val Leu Arg 550 Pro Arg Gly Gin Pro 555 Asn Gin Cys Val Gly 560 Hi s Arg Glu Ala ser 565 lie Hi s Ala Ser Cys 570 cys His Ala pro Gly 575 Leu Glu Cys Lys Val 580 Thr val Ala cys 595 Pro Gly Thr Ser 610 Val Val Arg Ser 625 Lys Glu His Gly Glu Glu Gly Trp 600 His Val Leu Gly 615 Arg Asp Val Ser 630 lie Pro Ala Pro 585 Thr Leu Thr Gly Ala Tyr Ala val 620 Thr Thr Gly Ser 635 Gin Glu Gin Val 590 Cys Ser Ala Leu 605 Asp Asn Thr cys Thr Ser Glu Glu 640 Ala Val Thr Ala Val Ala lie Cys Cys Arg Ser Arg His 645 650 Leu Ala Gin 655 Ala Ser Gin Glu Leu Gin 660 <210> 3 <211> 540 <212> PRT <213> Homo sapiens <400> 3 Ser lie Pro Trp Asn Asp Glu Tyr Gin Pro 20 Leu Asp Thr Ser lie 35 Leu Glu Arg lie Thr Pro Pro Arg Tyr Arg Ala 1015 Pro Asp Gly Gly Ser Leu Val Glu Val Tyr Leu 2530 Gin Ser Asp His Arg Glu lie Glu Gly Arg Val 4045 Met Val Thr Asp Phe Glu Asn Val 55 Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gin Ala Ser Lys Cys Asp 65 70 Ser His Gly Thr His Leu Ala Gly 80 val val Ser Gly Arg Asp Ala Gly 85 val Ala Lys Gly Ala Ser Met Arg 95 Ser Leu Arg val Leu Asn Cys Gin 100 Gly Lys Gly Thr val Ser Gly Thr 105 110 Leu lie Gly Leu Glu Phe lie Arg 115 120 Lys ser Gin Leu val Gin Pro val 125 Gly Pro Leu val Val Leu Leu Pro 130 135 Leu Ala Gly Gly Tyr Ser Arg Val 140 Leu Asn Ala Ala Cys Gin Arg Leu 145 150 Ala Arg Ala Gly val Val Leu val 155 160 Thr Ala Ala Gly Asn Phe Arg Asp Asp Ala 165 170 ser Ala Pro Glu val He Thr val Gly Ala 180 185 Pro val Thr Leu Gly Thr Leu Gly Thr Asn 195 200 Leu Phe Ala Pro Gly Glu Asp lie lie Gly 210 215 Thr cys Phe val ser Gin ser Gly Thr ser 225 230 Ala Gly lie Ala Ala Met Met Leu ser Ala 245 250 Ala Glu Leu Arg Gin Arg Leu lie His Phe 260 265 Asn Glu Ala Trp Phe Pro Glu Asp Gin Arg 275 280 Val Ala Ala Leu Pro Pro Ser Thr His Gly 290 295 Cys Arg Thr val Trp Ser Ala His Ser Gly 305 310 Ala lie Ala Arg Cys Ala Pro Asp Glu Glu 325 330 Phe ser Arg Ser Gly Lys Arg Arg Gly Glu 340 345 Gly Lys Leu Val Cys Arg Ala His Asn Ala 355 360 Tyr Ala lie Ala Arg Cys Cys Leu Leu Pro 370 375 His Thr Ala Pro Pro Ala Glu Ala ser Met 385 390 His Gin Gin Gly His val Leu Thr Gly cys 405 410 Glu Asp Leu Gly Thr His Lys Pro Pro val 420 425 Pro Asn Gin cys val Gly His Arg Glu Ala 435 440 Leu Tyr Ser Pro Ala 175 Asn Ala Gin Asp Gin 190 Gly Arg Cys val Asp 205 Ser Ser Asp Cys Ser 220 Ala Ala Ala His val 240 pro Glu Leu Thr Leu 255 Ala Lys Asp Val lie 270 Leu Thr Pro Asn Leu 285 Gly Trp Gin Leu Phe 300 Thr Arg Met Ala Thr 320 Leu Ser Cys Ser ser 335 Met Glu Ala Gin Gly 350 Gly Gly Glu Gly val 365 Ala Asn Cys ser val 380 Thr Arg val His Cys 400 Ser His Trp Glu Val 415 Arg pro Arg Gly Gin 430 lie His Ala ser cys 445 Cys His Ala Pro Gly Leu Glu Cys Lys 450 455 Ala Pro Gin Glu Gin val Thr Val Ala 465 470 Thr Gly Cys Ser Ala Leu Pro Gly Thr 485 Ala val Asp Asn Thr Cys Val Val Arg 500 505 Gly Ser Thr Ser Glu Glu Ala val Thr 515 520 Ser Arg His Leu Ala Gin Ala Ser Gin 530 535 <210> 4 <211> 692 <212> PRT <213> Homo sapiens <400> 4 Met Gly Thr val Ser Ser Arg Arg Ser 1 5 Leu Leu Leu Leu Leu Leu Leu Gly Pro 20 25 Asp Glu Asp Gly Asp Tyr Glu Glu Leu 35 40 Glu Asp Gly Leu Ala Glu Ala Pro Glu 55 Lys Glu His Gly lie Pro 460 Glu Glu Gly Trp Thr Leu 475 480 His val Leu Gly Ala Tyr 495 Arg Asp val Ser Thr Thr 510 Val Ala lie Cys Cys Arg 525 Leu Gin 540 Trp Pro Leu Pro Leu Leu 15 Gly Ala Arg Ala Gin Glu 30 Leu Ala Leu Arg Ser Glu 45 Gly Thr Thr Ala Thr Phe 60 His Arg cys Ala Lys Asp Pro Trp Arg 65 70 pro Gly Thr Tyr val Val 75 80 Val Leu Lys Glu Glu Thr His Leu Ser 85 Ser Glu Arg Thr Ala Arg 95 Arg Leu Gin Ala Gin Ala Ala Arg Arg 100 105 Tyr Leu Thr Lys lie Leu 110 His val Phe His Gly Leu Leu Pro Gly 115 120 Leu val Lys Met Ser Gly 125 Asp Leu Leu Glu Leu Ala Leu Lys Leu 130 135 His val Asp Tyr lie Glu 140 Glu Asp Ser ser val Phe Ala Gin ser 145 150 Pro Trp Asn Leu Glu Arg 155 160 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 He Gin 190 Ser Asp Hi s Arg Glu 195 He Glu Gly Arg Val 200 Met val Thr Asp Phe 205 Glu Asn Val Pro Glu 210 Glu Asp Gly Thr Arg 215 Phe Hi s Arg Gin Ala 220 Ser Lys cys ASP ser 225 His Gly Thr His 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 Gin 275 Leu val Gin pro val 280 Gly pro Leu Val val 285 Leu Leu Pro Leu Ala 290 Gly Gly Tyr ser Arg 295 val Leu Asn Ala Ala 300 cys Gin Arg Leu Al a 305 Arg Ala Gly val val 310 Leu Val Thr Ala Ala 315 Gly Asn phe Arg Asp 320 Asp Ala Cys Leu Tyr 325 ser Pro Ala Ser Ala 330 pro Glu Val lie Thr 335 Val Gl y Ala Thr Asn 340 Ala Gl n Asp Gin pro 345 Val Thr Leu Gly Thr 350 Leu Gl y Thr Asn Phe 355 Gly Arg Cys val Asp 360 Leu Phe Al a Pro Gly 365 Glu Asp Il e He Gly 370 Al a Ser Ser Asp cys 375 Ser Thr Cys Phe Val 380 Ser Gin Ser Gly Thr 385 Ser Gin Ala Ala Al a 390 Hi s val Ala Gly lie 395 Ala Ala Met Met Leu 400 ser Ala Glu Pro Glu 405 Leu Thr Leu Ala Glu 410 Leu Arg Gin Arg Leu 415 lie Hi s Phe ser Ala 420 Lys Asp Val lie Asn 425 Glu Ala Trp Phe Pro 430 Glu Asp 350 Gin Arg Val Leu Thr pro Asn Leu Val 435 440 His Gly Ala Gly Trp Gin Leu Phe cys 450 455 Ser Gly pro Thr Arg Met Ala Thr Ala 465 470 Glu Glu Leu Leu Ser Cys Ser Ser Phe 485 Gly Glu Arg Met Glu Ala Gin Gly Gly 500 505 Asn Ala Phe Gly Gly Glu Gly val Tyr 515 520 Leu Pro Gin Ala Asn cys ser Val His 530 535 Ser Met Gly Thr Arg val His Cys His 545 550 Gly Cys Ser Ser His Trp Glu Val Glu 565 Pro Val Leu Arg Pro Arg Gly Gin Pro 580 585 Glu Ala Ser lie His Ala ser Cys Cys 595 600 Lys val Lys Glu His Gly lie Pro Ala 610 615 Ala Cys Glu Glu Gly Trp Thr Leu Thr 625 630 Thr Ser His Val Leu Gly Ala Tyr Ala 645 Arg ser Arg Asp val ser Thr Thr Gly 660 665 Thr Ala val Ala lie cys Cys Arg Ser 675 680 Ala Leu Pro Pro Ser Thr 445 Thr val Trp ser Ala His 460 Ala Arg cys Ala Pro Asp 475 480 Arg Ser Gly Lys Arg Arg 495 Leu val Cys Arg Ala His 510 lie Ala Arg cys Cys Leu 525 Ala Pro Pro Ala Glu Ala 540 Gin Gly His val Leu Thr 555 560 Leu Gly Thr His Lys Pro 575 Gin cys Val Gly His Arg 590 Ala Pro Gly Leu Glu Cys 605 Gin Glu Gin val Thr val 620 Cys Ser Ala Leu Pro Gly 635 640 Asp Asn Thr Cys val Val 655 Thr ser Glu Glu Ala val 670 His Leu Ala Gin Ala ser 685 Gin Glu Leu Gin 690 <210> 5 <211> 662 '531 <212> PRT <213> Homo sapiens <400> 5 Gin Glu Asp Glu Asp Gly Asp Tyr 1 5 Glu Glu Leu val Leu Ala Leu Arg Ser Glu Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala 25 30 Thr Phe His Arg Cys Ala Lys Asp 35 40 Pro Trp Arg Leu Pro Gly Thr Tyr 45 Val Val val Leu Lys Glu Glu Thr 50 55 His Leu Ser Gin Ser Glu Arg Thr 60 Ala Arg Arg Leu Gin Ala Gin Ala 65 70 Ala Arg Arg Gly Tyr Leu Thr Lys 75 80 lie Leu His val Phe His Gly Leu 85 Leu Pro Gly Phe Leu val Lys Met 95 Ser Gly Asp Leu Leu Glu Leu Ala 100 Leu Lys Leu pro His val Asp Tyr 105 110 lie Glu Glu Asp Ser Ser Val Phe 115 120 Ala Gin Ser lie Pro Trp Asn Leu 125 Glu Arg lie Thr Pro Pro Arg Tyr 130 135 Arg Ala Asp Glu Tyr Gin Pro Pro 140 Asp Gly Gly Ser Leu Val Glu val 145 150 Tyr Leu Leu Asp Thr Ser lie Gin 155 160 Ser Asp His Arg Glu lie Glu Gly 165 Arg val Met Val Thr Asp Phe Glu 170 175 Asn Val Pro Glu Glu Asp Gly Thr 180 Arg Phe His Arg Gin Ala Ser Lys 185 190 Cys Asp Ser His Gly Thr His Leu 195 200 Ala Gly Val val Ser Gly Arg Asp 205 Ala Gly val Ala Lys Gly Ala ser 210 215 Met Arg Ser Leu Arg val Leu Asn 220 Cys Gin Gly Lys Gly Thr Val Ser 225 230 Gly Thr Leu lie Gly Leu Glu Phe 235 240 lie Arg Lys set Gin Leu val Gin 245 Pro Val Gly Pro Leu val val Leu 250 255 Leu Pro Leu Ala Gly Gly Tyr Ser 260 Arg Val Leu Asn Ala Ala Cys Gin 265 270 Arg Leu Ala 275 Arg Ala Gly Val val 280 Leu val Thr Al a Al a 285 Gly Asn Phe Arg Asp 290 Asp Ala Cys Leu Tyr 295 ser Pro Ala Ser Al a 300 pro Glu val lie Thr 305 Val Gly Ala Thr Asn 310 Ala Gin Asp Gin Pro 315 Val Thr Leu Gly Thr 320 Leu Gly Thr Asn Phe 325 G1 y Arg cys val ASp 330 Leu Phe Ala Pro Gly 335 Glu Asp He lie Gly 340 Al a Ser Ser Asp cys 345 Ser Thr Cys Phe val 350 Ser Gin Ser Gly Thr 355 Ser Gin Al a Ala Al a 360 Hi s val Ala Gly lie 365 Al a Ala Met Met Leu 370 Ser Ala Glu Pro Glu 375 Leu Thr Leu Ala Glu 380 Leu Arg Gin Arg Leu 385 lie His Phe ser Ala 390 Lys ASp Val lie Asn 395 Glu Ala Trp Phe Pro 400 Glu ASp Gin Arg Val 405 Leu Thr Pro Asn Leu 410 val Ala Ala Leu Pro 415 Pro Ser Thr His Gly 420 Al a Gly Trp Gin Leu 425 Phe Cys Arg Thr Val 430 Trp Ser Ala Hi s ser 435 Gly Pro Thr Arg Met 440 Ala Thr Ala val Ala 445 Arg Cys Ala Pro Asp 450 Glu Glu Leu Leu Ser 455 Cys Ser Ser Phe Ser 460 Arg ser Gly Lys Arg 465 Arg Gly G1U Arg Met 470 Glu Ala Gin Gly Gly 475 Lys Leu Val Cys Arg 480 Ala Hi s Asn Ala Phe 485 Gly Gly Glu Gly val 490 Tyr Ala lie Ala Arg 495 cys cys Leu Leu Pro 500 Gin Al a Asn cys ser 505 Val Hi s Thr Ala Pro 510 pro Ala Glu Ala Ser 515 Met Gly Thr Arg Val 520 Hi s Cys Hi s Gin Gin 525 Gly Hi s val Leu Thr 530 Gly cys Ser Ser Hi s 535 Trp Glu val Glu Asp 540 Leu Gly Thr His 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 His 565 Ala Ser Cys 570 cys His Ala Pro Gly 575 Leu Glu Cys Lys Val Lys Glu His 580 Gly lie Pro 585 Ala Pro Gin Glu 590 Gin val Thr Val Ala 595 Cys Glu Glu Gly Trp Thr Leu 600 Thr Gly cys 605 Ser Ala Leu Pro Gly Thr 610 ser His val Leu 615 Gly Ala Tyr Ala val 620 Asp Asn Thr cys val val Arg 625 ser Arg Asp Val 630 Ser Thr Thr Gly 635 Ser Thr ser Glu Glu 640 Ala Val Thr Ala Ser Gin Ala Val Ala lie 645 Glu Leu Gin 660 Cys Cys Arg 650 Ser Arg Hi s Leu Ala 655 Gin <210> 6 <211> 540 <212> PRT <213> Homo sapiens <400> 6 Ser lie Pro Trp Asn Leu Glu Arg lie Thr Pro Pro Arg Tyr Arg Ala 1015 Asp Glu Tyr Gin Pro Pro Asp Gly Gly ser Leu Val Glu val Tyr Leu 20 2530 Leu Asp Thr Ser lie Gin Ser Asp His Arg Glu lie Glu Gly Arg Val 35 4045 Met val Thr Asp Phe Glu Asn Val Pro Glu Glu Asp Gly Thr Arg Phe 50 5560 His Arg Gin Ala Ser Lys Cys Asp Ser His Gly Thr His Leu Ala Gly 65 70 7580 Val val ser Gly Arg Asp Ala Gly val Ala Lys Gly Ala Ser Met Arg 85 9095 ser Leu Arg val Leu Asn cys Gin Gly Lys Gly Thr Val Ser Gly Thr 100 105110 Leu lie Gly Leu Glu Phe lie Arg Lys ser Gin Leu val Gin Pro val 115 120125 Gly Pro Leu Val Val Leu Leu Pro Leu 135 Ala Gly Gly Tyr 140 Ser Arg val 130 Leu Asn Ala Ala cys Gin Arg Leu Ala 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 Ala Pro Glu val He Thr Val Gly Ala Thr Asn Al a Gin Asp Gin 190 180 185 pro val Thr 195 Leu Gly Thr Leu Gly 200 Thr Asn phe Gly Arg 205 Cys val Asp Leu Phe 210 Ala pro Gly Glu Asp 215 lie lie Gly Ala Ser 220 Ser Asp Cys Ser Thr 225 cys Phe val Ser Gin 230 Ser Gly Thr Ser Gin 235 Ala Ala Ala His Val 240 Ala Gly lie Ala Ala 245 Met Met Leu Ser Ala 250 Glu Pro Glu Leu Thr 255 Leu Ala Glu Leu Arg 260 Gin Arg Leu lie Hi s 265 Phe Ser Ala Lys Asp 270 val He Asn Glu Ala 275 Trp Phe Pro Glu Asp 280 Gin Arg val Leu Thr 285 Pro Asn Leu Val Ala 290 Ala Leu pro Pro ser 295 Thr His Gly Ala Gly 300 Trp Gin Leu Phe Cys 305 Arg Thr val Trp Ser 310 Ala Hi s Ser G1 y Pro 315 Thr Arg Met Ala Thr 320 Al a val 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 Glu Ala 350 Gin Gly Gly Lys Leu 355 Val cys Arg Ala His 360 Asn Ala Phe Gly Gly 365 Glu Gly val Tyr Ala 370 lie Ala Arg Cys Cys 375 Leu Leu Pro Gin Ala 380 Asn Cys Ser val Hi s 385 Thr Ala Pro Pro Al a 390 Glu Ala Ser Met Gly 395 Thr Arg val Hi s Cys 400 Hi s Gin Gin Gly Hi s 405 Val Leu Thr Gly Cys 410 ser Ser Hi s Trp Glu 415 Val Glu Asp Leu Gly Thr His Lys Pro 420 Pro Val Leu Arg Pro Arg Gly Gin 425 430 pro Asn Gin Cys Val Gly His Arg 435 440 Glu Ala Ser lie His Ala ser Cys 445 cys His Ala Pro Gly Leu Glu cys 450 455 Lys Val Lys Glu His Gly lie Pro 460 Ala Pro Gin Glu Gin val Thr val 465 470 Ala Cys Glu Glu Gly Trp Thr Leu 475 480 Thr Gly Cys Ser Ala Leu Pro Gly 485 Thr Ser His Val Leu Gly Ala Tyr 490 495 Ala Val Asp Asn Thr Cys Val Val 500 Arg ser Arg Asp Val Ser Thr Thr 505 510 Gly Ser Thr ser Glu Glu Ala val Thr Ala val 515 520 Ala lie Cys cys Arg 525 Ser Arg His Leu Ala Gin Ala Ser Gin Glu Leu Gin 530 535 540 <210> 7 <211> 692 <212> PRT <213> Homo sapiens <400> 7 Met Gly Thr val 1 Ser Ser Arg Arg Ser Trp Trp Pro Leu Pro Leu Leu 5 10 15 Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gin Glu 25 30 Asp Glu Asp Gly Asp Tyr Glu Glu 35 40 Leu Val Leu Ala Leu Arg Ser Glu Glu Asp Gly Leu Ala Glu Ala Pro 55 Glu His Gly Thr Thr Ala Thr Phe 60 His Arg cys Ala Lys Asp Pro Trp 65 70 Arg Leu Pro Gly Thr Tyr val Val 75 80 Val Leu Lys Glu Glu Thr His Leu 85 ser Gin Ser Glu Arg Thr Ala Arg 95 Arg Leu Gin Ala Gin Ala Ala Arg 100 Arg Gly Tyr Leu Thr Lys lie Leu 105 110 His Val Phe His Gly Leu Leu Pro 115 120 Gly Phe Leu Val Lys Met Ser Gly 125 Asp Leu 130 Leu Glu Leu Ala Leu 135 Lys Leu pro Hi s Val 140 Asp Tyr lie Glu Glu 145 Asp Ser Ser val Phe 150 Ala Gin Ser He Pro 155 Trp Asn Leu Glu Arg 160 He 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 He Gin 190 Ser Asp His Arg G1U 195 lie Glu G1 y Arg Val 200 Met Val Thr Asp Phe 205 Glu Asn val pro G1 u 210 Glu Asp Gly Thr Arg 215 phe Hi s Arg Gin Ala 220 ser Lys Cys Asp ser 225 His Gly Thr Hi s Leu 230 Al a Gly val val ser 235 Gly Arg Asp Ala G1 y 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 He Arg Lys Ser G1 n 275 Leu Val Gin Pro Val 280 Gly Pro Leu Val Val 285 Leu Leu Pro Leu Ala 290 Gly Gly Tyr Ser Arg 295 Val Leu Asn 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 Asp 320 Asp Ala cys Leu Tyr 325 Ser Pro Ala Ser Ala 330 pro Glu val lie Thr 335 val Gly Ala Thr Asn 340 Ala Gin Asp Gin Pro 345 val Thr Leu Gly Thr 350 Leu Gly Thr Asn Phe 355 Gly Arg Cys Val Asp 360 Leu Phe Ala Pro Gly 365 Glu Asp lie lie Gly 370 Ala Ser Ser Asp Cys 375 Ser Thr Cys Phe Val 380 Ser Gin Ser Gly Thr 385 ser Gin Ala Ala Al a 390 Hi s Val Ala Gly lie 395 Ala Al a Met Met Leu 400 Ser Ala Glu Pro Glu Leu Thr Leu 405 Ala Glu Leu Arg Gin Arg Leu lie 410 415 His Phe Ser Ala Lys Asp val lie 420 Asn Glu Ala Trp Phe Pro Glu Asp 425 430 Gin Arg Val Leu Thr Pro Asn Leu 435 440 val Ala Ala Leu Pro Pro Ser Thr 445 His Gly Ala Gly Trp Gin Leu Phe 450 455 Cys Arg Thr val Trp ser Ala His 460 Ser Gly Pro Thr Arg Met Ala Thr 465 470 Ala lie Ala Arg Cys Ala Pro Asp 475 480 Glu Glu Leu Leu Ser Cys Ser Ser 485 Phe Ser Arg Ser Gly Lys Arg Arg 490 495 Gly Glu Arg Met Glu Ala Gin Gly 500 Gly Lys Leu Val Cys Arg Ala His 505 510 Asn Ala Phe Gly Gly Glu Gly Val 515 520 Tyr Ala lie Ala Arg cys Cys Leu 525 Leu Pro Gin Ala Asn cys Ser Val 530 535 His Thr Ala Pro Pro Ala Glu Ala 540 Ser Met Gly Thr Arg val His cys 545 550 His Gin Gin Gly His val Leu Thr 555 560 Gly Cys Ser Ser His Trp Glu val 565 Glu Asp Leu Gly Thr His Lys pro 570 575 Pro val Leu Arg Pro Arg Gly Gin 580 Pro Asn Gin Cys val Gly His Arg 585 590 Glu Ala Ser lie His Ala ser Cys 595 600 Cys His Ala Pro Gly Leu Glu Cys 605 Lys val Lys Glu His Gly lie Pro 610 615 Ala Pro Gin Glu Gin val Thr Val 620 Ala Cys Glu Glu Gly Trp Thr Leu 625 630 Thr Gly Cys ser Ala Leu Pro Gly 635 640 Thr ser His val Leu Gly Ala Tyr 645 Ala val Asp Asn Thr cys val val 650 655 Arg Ser Arg Asp Val Ser Thr Thr 660 Gly ser Thr ser Glu Gly Ala val 665 670 Thr Ala Val Ala lie Cys Cys Arg 675 680 ser Arg His Leu Ala Gin Ala ser 685 sex Val Leu Ala Leu Arg Gin Glu Leu Gin 690 <210> 8 <211> 662 <212> PRT <213> Homo sapiens <400> 8 Gin Glu Asp Glu Asp Gly Asp Tyr Glu Glu 10 Ser Glu Glu Asp Gly Leu Ala Glu Ala Pro 20 25 His Gly Thr Thr Ala 30 Thr Phe His Arg Cys Ala Lys Asp Pro Trp 35 40 Leu Pro Gly Thr Tyr Val Val Val Leu Lys Glu Glu Thr His Leu 55 Gin ser Glu Arg Thr 60 Ala Arg Arg Leu Gin Ala Gin Ala Ala Arg 65 70 Gly Tyr Leu Thr Lys 80 lie Leu His val Phe His Gly Leu Leu Pro 90 Phe Leu val Lys Met 95 Ser Gly Asp Leu Leu Glu Leu Ala Leu Lys 100 105 Pro His val Asp Tyr 110 lie Glu Glu Asp Ser Ser Val Phe Ala Gin 115 120 lie Pro Trp Asn Leu 125 Glu Arg He Thr Pro Pro Arg Tyr Arg Ala 130 135 Glu Tyr Gin Pro Pro 140 Asp Gly Gly Ser Leu Val Glu val Tyr Leu 145 150 Asp Thr Ser lie Gin 160 Ser Asp His Arg Glu lie Glu Gly Arg val 165 170 Val Thr Asp Phe Glu 175 Asn Val Pro Glu Glu Asp Gly Thr Arg Phe 180 185 Arg Gin Ala Ser Lys 190 Cys Asp Ser His Gly Thr His Leu Ala Gly 195 200 Val Ser Gly Arg Asp 205 Ala Gly Val Ala Lys Gly Ala Ser Met Arg 210 215 Leu Arg val Leu Asn 220 Cys Gin Gly Lys Gly Thr Val Ser Gly Thr 225 230 lie Gly Leu Glu Phe 240 lie Arg Lys Ser Gin Leu val Gin 245 Pro Val Gly pro Leu Val val Leu 250 255 Leu Pro Leu Ala Gly Gly Tyr ser 260 Arg Val Leu Asn Ala Ala cys Gin 265 270 Arg Leu Ala Arg Ala Gly val val 275 280 Leu val Thr Ala Ala Gly Asn phe 285 Arg Asp Asp Ala Cys Leu Tyr Ser 290 295 Pro Ala Ser Ala Pro Glu val lie 300 Thr Val Gly Ala Thr Asn Ala Gin 305 310 Asp Gin Pro Val Thr Leu Gly Thr 315 320 Leu Gly Thr Asn Phe Gly Arg cys 325 val Asp Leu Phe Ala Pro Gly Glu 330 335 Asp lie lie Gly Ala ser ser Asp 340 Cys Ser Thr Cys Phe Val Ser Gin 345 350 Ser Gly Thr Ser Gin Ala Ala Ala 355 360 His val Ala Gly lie Ala Ala Met 365 Met Leu Ser Ala Glu Pro Glu Leu 370 375 Thr Leu Ala Glu Leu Arg Gin Arg 380 Leu lie His Phe Ser Ala Lys Asp 385 390 Val lie Asn Glu Ala Trp Phe pro 395 400 Glu Asp Gin Arg Val Leu Thr pro 405 Asn Leu Val Ala Ala Leu Pro pro 410 415 Ser Thr His Gly Ala Gly Trp Gin 420 Leu Phe cys Arg Thr val Trp Ser 425 430 Ala His Ser Gly Pro Thr Arg Met 435 440 Ala Thr Ala lie Ala Arg Cys Ala 445 Pro Asp Glu Glu Leu Leu Ser Cys 450 455 Ser Ser Phe ser Arg Ser Gly Lys 460 Arg Arg Gly Glu Arg Met Glu Ala 465 470 Gin Gly Gly Lys Leu Val Cys Arg 475 480 Ala His Asn Ala Phe Gly Gly Glu 485 Gly Val Tyr Ala lie Ala Arg Cys 490 495 Cys Leu Leu Pro Gin Ala Asn Cys 500 Ser val His Thr Ala Pro Pro Ala 505 510 400 Glu Ala Ser 515 Met Gly Thr Arg val 520 Hi s Cys Hi s Gin Gin 525 Gly His Val Leu Thr 530 Gly cys Ser ser Hi s 535 T rp Glu val Glu Asp 540 Leu Gly Thr Hi s Lys 545 pro Pro Val Leu Arg 550 Pro Arg Gly Gin Pro 555 Asn G1 n cys Val Gly 560 Hi s Arg Glu Ala Ser 565 He Hi s Al a Ser cys 570 Cys Hi s Al a Pro Gly 575 Leu Glu Cys Lys val 580 Lys G1 u Hi s Gly lie 585 Pro Ala Pro G1 n Glu 590 Gin Val Thr val Al a 595 Cys Glu Glu Gly Trp 600 Thr Leu Thr Gly cys 605 Ser Ala Leu Pro Gly 610 Thr Ser Hi s val Leu 615 Gly Ala Tyr Al a val 620 Asp Asn Thr cys Val 625 Val Arg ser Arg Asp 630 val Ser Thr Thr Gly 635 Ser Thr Ser Glu Gly 640 Ala Val Thr Ala Val 645 Ala He cys Cys Arg 650 Ser Arg Hi s Leu Ala 655 Gin Al a Ser Gin Glu 660 Leu Gin <210> 9 <211> 540 <212> PRT <213> Homo sapiens <400> 9 Ser lie 1 Pro T rp 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 25 ser Leu val Glu Val 30 Tyr Leu Leu Asp Thr 35 Ser lie G1 n Ser Asp 40 Hi s Arg Glu He Glu 45 Gly Arg Val Met Val 50 Thr Asp Phe G1 u Asn 55 val pro Glu Glu Asp 60 Gly Thr Arg phe Hi s 65 Arg Gin Ala Ser Lys 70 cys Asp Ser Hi s Gly 75 Thr Hi s Leu Ala Gly 80 Val Val Ser Gly Arg 85 Asp Ala Gly val Ala 90 Lys Gly Ala ser Met 95 Arg 101 Ser Leu Arg Val 100 Leu Asn Cys Gin Gly Lys 105 Gly Thr val Ser 110 Gly Thr Leu lie Gly 115 Leu Glu Phe lie Arg Lys Ser 120 Gin Leu Val 125 Gin Pro Val Gly pro Leu 130 val val Leu Leu Pro Leu Ala 135 Gly Gly 140 Tyr Ser Arg Val Leu 145 Asn Ala Ala Cys G1 n 150 Arg Leu Ala Arg Ala Gly 155 val Val Leu val 160 Thr Ala Ala Gly Asn 165 Phe Arg Asp Asp Ala 170 Cys Leu Tyr Ser Pro 175 Ala ser Ala Pro Glu 180 val He Thr Val Gly Ala 185 Thr Asn Al a Gin 190 Asp Gin Pro val Thr 195 Leu Gly Thr Leu Gly Thr Asn 200 Phe Gly Arg 205 cys Val Asp Leu phe Ala 210 Pro Gly Glu Asp lie lie Gly 215 Ala ser 220 Ser Asp cys ser Thr 225 Cys Phe Val Ser Gin 230 Ser Gly Thr Ser Gin Ala 235 Al a Ala His val 240 Ala Gly He Ala Ala 245 Met Met Leu Ser Ala 250 Glu Pro Glu Leu Thr 255 Leu Ala Glu Leu Arg 260 G1 n Arg Leu lie His Phe 265 Ser Ala Lys Asp 270 Val He Asn Glu Ala Trp Phe Pro Glu Asp Gin Arg val Leu Thr Pro Asn Leu 275 280285 Val Ala Ala Leu Pro Pro Ser Thr His Gly Ala Gly Trp Gin Leu Phe 290 295300 Cys Arg Thr Val Trp Ser Ala His Ser Gly Pro Thr Arg Met Ala Thr 305 310 315320 Ala lie Ala Arg cys Ala Pro Asp Glu Glu Leu Leu ser cys ser Ser 325 330335 Phe ser Arg Ser Gly Lys Arg Arg Gly Glu Arg Met Glu Ala Gin Gly 340 345350 Gly Lys Leu val cys Arg Ala His Asn Ala Phe Gly Gly Glu Gly val 355 360365 Tyr Ala He Ala Arg Cys cys Leu Leu pro Gin Ala Asn Cys Ser Val 370 375380 His Thr Ala pro Pro Ala Glu Ala Ser Met 385 390 His Gin Gin Gly His val Leu Thr Gly Cys 405 410 Glu Asp Leu Gly Thr His Lys Pro Pro val 420 425 Pro Asn Gin Cys val Gly His Arg Glu Ala 435 440 Cys His Ala Pro Gly Leu Glu Cys Lys Val 450 455 Ala Pro Gin Glu Gin val Thr Val Ala cys 465 470 Thr Gly Cys ser Ala Leu Pro Gly Thr Ser 485 490 Ala val Asp Asn Thr cys val val Arg ser 500 505 Gly Ser Thr Ser Glu Gly Ala Val Thr Ala 515 520 Ser Arg His Leu Ala Gin Ala ser Gin Glu 530 535 <210> 10 <211> 692 <212> PRT <213> Homo sapiens <400> 10 Ser 5 Ser Arg Arg Ser Trp 10 Met 1 Gly Thr Val Leu Leu Leu Leu 20 Leu Leu Leu Gly Pro 25 Al a ASp Glu Asp 35 Gly Asp Tyr Glu Glu 40 Leu val G1 u Asp Gly 50 Leu Ala G1 u Al a 55 Pro Glu Hi s Hi s 65 Arg Cys Ala Lys Asp 70 Pro Trp Arg Leu val Leu Lys Glu Glu 85 Thr Hi s Leu Ser Gin 90 Thr Arg Val His Cys 400 ser His Trp Glu val 415 Arg Pro Arg Gly Gin 430 lie His Ala Ser Cys 445 Glu His Gly lie Pro 460 Glu Gly Trp Thr Leu 480 Val Leu Gly Ala Tyr 495 Asp Val Ser Thr Thr 510 Ala lie Cys Cys Arg 525 Gin 540 pro Leu Pro Leu Leu 15 Ala Arg Ala Gin Glu 30 Ala Leu Arg ser Glu 45 Thr Thr Ala Thr Phe 60 Gly Thr Tyr val val 80 Glu Arg Thr Ala Arg Arg Leu Gin Al a 100 Gin Ala Ala Arg Arg 105 Gly Tyr Leu Thr Lys 110 lie Leu Hi s Val Phe 115 His Gly Leu Leu Pro 120 Gly Phe Leu val Lys 125 Met Ser Gly Asp Leu 130 Leu Glu Leu Ala Leu 135 Lys Leu pro His val 140 Asp Tyr lie Glu Glu 145 Asp Ser Ser Val Phe 150 Ala Gin Ser lie Pro 155 Trp Asn Leu Glu Arg 160 lie Thr Pro Pro Arg 165 Tyr Arg Al a Asp Glu 170 Tyr Gin Pro Pro Asp 175 Gly Gly Ser Leu val 180 Glu val Tyr Leu Leu 185 Asp Thr ser lie Gin 190 Ser Asp Hi s Arg Glu 195 He Glu Gly Arg Val 200 Met val Thr Asp Phe 205 Glu Asn Val pro Glu 210 Glu Asp Gly Thr Arg 215 Phe His Arg Gin Al a 220 ser Lys cys ASp Ser 225 Hi s Gly Thr Hi s Leu 230 Ala Gly val val Ser 235 Gly Arg Asp Ala Gly 240 Val Ala Lys Gly Ala 245 Ser Met Arg Ser Leu 250 Arg Val Leu Asn cys 255 G1 n Gly Lys Gly Thr 260 Val Ser Gly Thr Leu 265 lie Gly Leu Glu Phe 270 lie Arg Lys ser Gin 275 Leu val G1 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 Al a Ala 300 cys G1 n Arg Leu Ala 305 Arg Ala Gly Val val 310 Leu val Thr Ala Ala 315 Gly Asn Phe Arg Asp 320 Asp Ala cys Leu Tyr 325 Ser Pro Ala Ser Ala 330 Pro Glu val lie Thr 335 val Gly Ala Thr Asn 340 Ala Gin Asp Gin pro 345 val Thr Leu Gly Thr 350 Leu Gly Thr Asn Phe 355 Gly Arg Cys Val ASp 360 Leu Phe Ala pro Gly 365 Glu ASP lie /fc lie Gly 370 Ala Ser ser Asp cys 375 Ser Thr cys Phe Val 380 ser Gl η Ser Gly Thr 385 Ser Gin Ala Ala Ala 390 Hi s Val Ala Gly lie 395 Ala Ala Met Met Leu 400 Ser Ala Glu Pro Glu 405 Leu Thr Leu Ala Glu 410 Leu Arg Gin Arg Leu 415 lie Hi s Phe ser Al a 420 Lys Asp Val lie Asn 425 Glu Ala Trp Phe Pro 430 G1U Asp Gin Arg Val 435 Leu Thr Pro Asn Leu 440 Val Ala Ala Leu Pro 445 Pro Ser Thr Hi s Gly 450 Ala Gly Trp Gin Leu 455 Phe cys Arg Thr Val 460 T rp Ser Ala Hl S Ser 465 Gly Pro Thr Arg Met 470 Ala Thr Ala Val Ala 475 Arg cys Ala Pro Asp 480 Glu Glu Leu Leu Ser 485 cys Ser ser Phe Ser 490 Arg Ser Gly Lys Arg 495 Arg Gly Glu Arg Met 500 Glu Ala Gin Gly Gly 505 Lys Leu Val Cys Arg 510 Ala His Asn Ala Phe 515 Gly Gly Glu Gly Val 520 Tyr Ala lie Ala Arg 525 Cys cys Leu Leu Pro 530 Gin Al a Asn cys Ser 535 val His Thr Ala Pro 540 Pro Ala Glu Ala Ser 545 Met Gly Thr Arg Val 550 His cys Hi s Gin Gin 555 Gly Hi s val Leu Thr 560 Gly cys ser ser Hi s 565 T rp G1U val G1U ASp 570 Leu Gly Thr Hi s Lys 575 Pro Pro val Leu Arg 580 Pro Arg Gly Gl n Pro 585 Asn Gl n 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 610 Lys Glu Hi s Gly lie 615 Pro Ala Pro Gin Glu 620 Gin val Thr Val Ala 625 Cys Glu Glu Gly Trp 630 Thr Leu Thr Gly cys 635 Ser Ala Leu Pro Gly 640 Thr Ser Hi s Val Leu 645 Gly Ala Tyr Ala Val 650 Asp Asn Thr cys val 655 val Arg Ser Arg Asp Val 660 Ser Thr Thr Gly Ser Thr ser Glu Gly Ala val 665 670 Thr Ala Val Ala lie Cys Cys Arg Ser Arg His 675 680 Leu Ala Gin Ala Ser 685 Gin Glu Leu Gin 690 <210> 11 <211> 662 <212> PRT <213> Homo sapiens <400> 11 Gin Glu Asp 1 Glu Asp 5 Gly Asp Tyr Glu Glu 10 Leu Val Leu Al a Leu 15 Arg Ser Glu Glu Asp 20 Gly Leu Ala Glu Al a 25 Pro Glu Hi s Gly Thr 30 Thr Ala Thr Phe Hi s 35 Arg Cys Ala Lys Asp 40 Pro Trp Arg Leu Pro 45 Gly Thr Tyr val Val 50 Val Leu Lys Glu Glu 55 Thr Hi s Leu Ser Gin 60 Ser Glu Arg Thr Ala 65 Arg Arg Leu Gin Ala 70 Gin Ala Ala Arg Arg 75 Gly Tyr Leu Thr Lys 80 lie Leu Hi s val Phe 85 His Gly Leu Leu Pro 90 Gly Phe Leu Val Lys 95 Met Ser Gly Asp Leu 100 Leu Glu Leu Al a Leu 105 Lys Leu pro Hi s val 110 Asp Tyr lie Glu Gl u 115 Asp Ser Ser Val Phe 120 Al a Gin Ser lie Pro 12 5 T rp Asn Leu Glu Arg 130 He Thr Pro Pro Arg 135 Tyr Arg Ala Asp Glu 140 Tyr Gin Pro Pro Asp 145 Gly Gly Ser Leu Val 150 Glu Val Tyr Leu Leu 155 Asp Thr Ser lie Gin 160 Ser Asp Hi s Arg Glu 165 lie Glu Gly Arg val 170 Met Val Thr Asp Phe 175 Glu Asn val Pro Glu 180 Glu Asp Gly Thr Arg 185 Phe Hi s Arg Gin Al a 190 Ser Lys cys Asp Ser 195 His Gly Thr His Leu 200 Ala Gly Val Val Ser 205 Gly Arg Asp Ala Gly 210 Val Ala Lys Gly Ala 215 ser Met Arg Ser Leu 220 Arg val Leu Asn cys 225 Gin Gly Lys Gly Thr 230 val Ser Gly Thr Leu 235 lie Gly Leu Glu Phe 240 lie Arg Lys Ser G1 n 245 Leu val Gin Pro Val 250 Gly Pro Leu val Val 255 Leu Leu Pro Leu Ala 260 Gly Gly Tyr Ser Arg 265 Val Leu Asn Ala Ala 270 Cys Gin Arg Leu Ala 275 Arg Al a Gly val Val 280 Leu Val Thr Ala Ala 285 Gly Asn Phe Arg Asp 290 Asp Al a cys Leu Tyr 295 Ser Pro Al a Ser Ala 300 Pro Glu Val lie Thr 305 val Gly Ala Thr Asn 310 Ala Gin Asp Gin Pro 315 val Thr Leu Gly Thr 320 Leu Gly Thr Asn Phe 325 Gly Arg cys val ASP 330 Leu Phe Ala Pro Gly 335 Glu Asp He He Gly 340 Al a Ser ser Asp Cys 345 Ser Thr Cys Phe val 350 ser Gin Ser Gly Thr 355 Ser Gin Ala Ala Al a 360 Hi s Val Ala Gly He 365 Ala Ala Met Met Leu 370 Ser Ala Glu pro Glu 375 Leu Thr Leu Ala Glu 380 Leu Arg Gin Arg Leu 385 lie Hi s Phe ser Ala 390 Lys Asp val lie Asn 395 Glu Ala Trp Phe Pro 400 Glu ASp Gin Arg Val 405 Leu Thr Pro Asn Leu 410 Val Ala Ala Leu Pro 415 Pro ser Thr His Gly 420 Ala Gly Trp Gin Leu 425 Phe Cys Arg Thr Val 430 Trp ser Ala Hi s Ser 435 Gly Pro Thr Arg Met 440 Ala Thr Ala Val Ala 445 Arg Cys Ala pro Asp 450 Glu Glu Leu Leu ser 455 cys Ser ser phe Ser 460 Arg Ser Gly Lys Arg 465 Arg Gly Glu Arg Met 470 Glu Al a Gin Gly Gly 475 Arg 480 Lys Leu val Cys Ala His Asn Ala Phe Gly Gly Glu 485 Gly Val Tyr Ala lie Ala Arg Cys 490 495 Cys Leu Leu Pro Gin Ala Asn cys 500 ser val His Thr Ala Pro pro Ala 505 510 Glu Ala Ser Met Gly Thr Arg Val 515 520 His Cys His Gin Gin Gly His val 525 Leu Thr Gly Cys Ser Ser His Trp 530 535 Glu val Glu Asp Leu Gly Thr His 540 Lys Pro Pro Val Leu Arg Pro Arg 545 550 Gly Gin Pro Asn Gin Cys Val Gly 555 560 His Arg Glu Ala Ser lie His Ala 565 ser cys Cys His Ala Pro Gly Leu 570 575 Glu cys Lys val Lys Glu His Gly 580 lie Pro Ala Pro Gin Glu Gin val 585 590 Thr Val Ala Cys Glu Glu Gly Trp 595 600 Thr Leu Thr Gly Cys Ser Ala Leu 605 pro Gly Thr Ser His val Leu Gly 610 615 Ala Tyr Ala val Asp Asn Thr Cys 620 Val Val Arg Ser Arg Asp Val Ser 625 630 Thr Thr Gly Ser Thr Ser Glu Gly 635 640 Ala val Thr Ala val Ala He Cys 645 Cys Arg Ser Arg His Leu Ala Gin 650 655 Ala Ser Gin Glu Leu Gin 660 <210> 12 <211> 540 <212> PRT <213> Homo sapiens <400> 12 Ser 1 He pro Trp Asn 5 Leu Glu Arg lie Thr 10 Pro Pro Arg Tyr Arg 15 Ala Asp Glu Tyr Gin Pro 20 Pro Asp Gly Gly Ser 25 Leu val Glu Val 30 Tyr Leu Leu Asp Thr Ser He 35 Gin Ser Asp His Arg 40 Glu lie Glu 45 Gly Arg val Met val Thr Asp Phe Glu Asn Val Pro Glu Glu Asp Gly Thr Arg Phe 55 60 His Arg Gin Ala Ser Lys Cys Asp 65 70 Ser His Gly Thr His Leu Ala Gly 75 80 Val val ser Gly Arg Asp Ala Gly 85 Val Ala Lys Gly Ala Ser Met Arg 95 Ser Leu Arg val Leu Asn Cys Gin 100 Gly Lys Gly Thr val Ser Gly Thr 105 110 Leu lie Gly Leu Glu Phe lie Arg 115 120 Lys Ser Gin Leu Val Gin Pro Val 125 Gly Pro Leu val Val Leu Leu Pro 130 135 Leu Ala Gly Gly Tyr Ser Arg val 140 Leu Asn Ala Ala Cys Gin Arg Leu 145 150 Ala Arg Ala Gly val val Leu val 155 160 Thr Ala Ala Gly Asn Phe Arg Asp 165 Asp Ala Cys Leu Tyr ser Pro Ala 170 175 ser Ala Pro Glu val He Thr val 180 Gly Ala Thr Asn Ala Gin Asp Gin 185 190 Pro Val Thr Leu Gly Thr Leu Gly 195 200 Thr Asn Phe Gly Arg Cys val Asp 205 Leu Phe Ala Pro Gly Glu Asp lie 210 215 lie Gly Ala ser Ser Asp Cys Ser 220 Thr cys Phe Val Ser Gin Ser Gly 225 230 Thr Ser Gin Ala Ala Ala His Val 235 240 Ala Gly lie Ala Ala Met Met Leu 245 Ser Ala Glu Pro Glu Leu Thr Leu 250 255 Ala Glu Leu Arg Gin Arg Leu lie 260 His Phe ser Ala Lys Asp Val lie 265 270 Asn Glu Ala Trp Phe Pro Glu Asp 275 280 Gin Arg Val Leu Thr Pro Asn Leu 285 Val Ala Ala Leu Pro Pro Ser Thr 290 295 His Gly Ala Gly Trp Gin Leu Phe 300 cys Arg Thr val Trp Ser Ala His 305 310 Ser Gly pro Thr Arg Met Ala Thr 315 320 Ala Val Ala Arg Cys Ala Pro Asp 325 Glu Glu Leu Leu ser cys Ser ser 330 335 Phe ser Arg ser Gly Lys Arg Arg 340 Gly Glu Arg Met Glu Ala Gin Gly 345 350 Gly Lys Leu Val cys Arg Ala 355 Tyr Ala lie Ala Arg Cys Cys 370 375 His Asn Ala Phe Gly Gly Glu Gly val 360 365 Leu Leu pro Gin Ala Asn Cys ser val 380 His Thr Ala Pro Pro Ala Glu 385 390 Ala ser Met Gly Thr Arg Val His Cys 395 400 His Gin Gin Gly His Val Leu 405 Thr Gly Cys Ser Ser His Trp Glu Val 410 415 Glu Asp Leu Gly Thr His Lys 420 Pro Pro Val Leu Arg pro Arg Gly Gin 425 430 Pro Asn Gin Cys val Gly His 435 Arg Glu Ala Ser lie His Ala ser Cys 440 445 Cys His Ala Pro Gly Leu Glu 450 455 Cys Lys val Lys Glu His Gly lie Pro 460 Ala Pro Gin Glu Gin val Thr 465 470 Val Ala Cys Glu Glu Gly Trp Thr Leu 475 480 Thr Gly Cys Ser Ala Leu Pro 485 Gly Thr Ser His Val Leu Gly Ala Tyr 490 495 Ala val Asp Asn Thr cys Val 500 Val Arg Ser Arg Asp Val Ser Thr Thr 505 510 Gly ser Thr Ser Glu Gly Ala 515 Val Thr Ala Val Ala lie Cys Cys Arg 520 525 Ser Arg His Leu Ala Gin Ala 530 535 Ser Gin Glu Leu Gin 540 <210> 13 <211> 692 <212> PRT <213> Homo sapiens <400> 13 Met Gly Thr Val 1 Ser Ser Arg Arg ser Trp Trp pro Leu 5 10 Pro Leu Leu Leu Leu Leu Leu Leu Leu 20 Asp Glu Asp Gly Asp Tyr 35 Glu Asp Gly Leu Val Glu 50 Leu Gly Pro Ala Gly Ala Arg 25 Glu Glu Leu Val Leu Ala Leu 45 Ala Pro Glu His Gly Thr Thr 55 60 Ala Gin Glu 30 Arg Ser Glu Ala Thr phe Hi s 65 Arg cys Ala Lys Asp 70 pro Trp Arg Leu Pro 75 Gly Thr Tyr val Val 80 val Leu Lys Glu Glu 85 Thr Hi s Leu Ser Gin 90 Ser Glu Arg Thr Ala 95 Arg Arg Leu Gin Ala 100 Gin Ala Ala Arg Arg 105 Gly Tyr Leu Thr Lys 110 He Leu His val Phe 115 Hi s Gly Leu Leu Pro 120 Gly Phe Leu Val Lys 125 Met Ser Gly Asp Leu 130 Leu Glu Leu Al a Leu 135 Lys Leu pro Hi s Val 140 Asp Tyr ll e Glu Glu 145 Asp ser ser val Phe 150 Ala Gin ser lie Pro 155 Trp Asn Leu Gl U Arg 160 He Thr Pro Pro Arg 165 Tyr Arg Ala Asp Glu 170 Tyr Gl n Pro Pro ASp 175 Gly Gly ser Leu Val 180 Glu Val Tyr Leu Leu 185 Asp Thr Ser lie Gin 190 Ser Asp Hi s Arg Glu 195 lie Glu Gly Arg val 200 Met val Thr Asp Phe 205 Glu Asn val Pro Glu 210 Glu Asp Gly Thr Arg 215 phe Hi s Arg Gin Ala 220 Ser Lys Cys Asp Ser 225 Hi s Gly Thr His Leu 230 Ala Gly val Val Ser 235 Gly Arg Asp Ala Gly 240 Val Al a Lys Gly Ala 245 Ser Met Arg ser Leu 250 Arg Val Leu Asn Cys 255 Gin Gly Lys Gly Thr 260 val ser Gly Thr Leu 265 lie Gly Leu Glu Phe 270 He Arg Lys Ser Gin 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 Asp 320 Asp Ala cys Leu Tyr 325 Ser Pro Ala Ser Al a 330 Pro Glu val lie Thr 335 val Gly Ala Thr Asn 340 Ala Gin Asp Thr Asn phe Gly 355 lie Gly 370 Ala Ser Thr Ser 385 Gin Ala ser Ala Glu Pro Hi s Phe Ser Ala 420 Gin Arg Val Leu 435 Arg Ser Al a Glu 405 Lys Thr Cys val Asp cys 375 Ala His 390 Leu Thr Asp Val Pro Asn Hi s Gly 450 Ala Gly ser Gly 465 Pro Thr Glu Glu Gly Glu Asn Ala Leu Pro 530 ser Met 545 Gly Cys pro Val Glu Ala Lys Val 610 Leu Leu Arg Met 500 Phe Gly 515 Gin Ala Gly Thr ser Ser Leu Arg 580 Ser lie 595 Lys Glu Trp Arg Ser 485 Glu Gly Asn Arg His 565 Pro Hi s Hi s Gin Leu 455 Met Ala 470 Cys Ser Ala Gin Glu Gly Cys Ser 535 val His 550 Trp Glu Arg Gly Gin Pro 345 Asp teu 360 Ser Thr Val Ala Leu Ala lie Asn 425 Leu val 440 Phe Cys Thr Ala Ser Phe Gly Gly 505 val Tyr 520 val His Cys His Val Glu Gin Pro 585 Val Thr Phe Ala Cys Phe Gly lie 395 Glu Leu 410 Glu Ala Ala Ala Arg Thr Val Ala 475 ser Arg 490 Lys Leu Ala He Thr Ala Gin Gin 555 Asp Leu 570 Asn Gin Leu Gly pro Gly 365 val Ser 380 Ala Ala Arg Gin Trp Phe Leu Pro 445 val Trp 460 Arg Cys Ser Gly val Cys Ala Arg 525 Pro Pro 540 Gly His Gly Thr Cys Val Al a ser Gly lie 615 cys cys 600 His Ala pro Gly 605 Pro Ala pro Gin Glu Gin 620 Thr 350 Glu Gin Met Arg Pro 430 Pro Ser Ala Arg 510 Cys Al a val Hi s Gly 590 Leu Val Leu Gly Asp lie Ser Gly Met Leu 400 Leu lie 415 Glu Asp Ser Thr Ala His pro Asp 480 Arg Arg 495 Ala His Cys Leu Glu Ala Leu Thr 560 Lys Pro 575 His Arg Glu cys Thr val Ala 625 Cys Glu Glu Gly Trp 630 Thr Leu Thr Gly cys 635 Ser Ala Leu Pro Gly 640 Thr Ser Hl S val Leu 645 Gly Ala Tyr Al a Val 650 ASp Asn Thr cys Val 655 val Arg Ser Arg Asp 660 val Ser Thr Thr Gly 665 Ser Thr Ser Glu Glu 670 Ala Val Thr Ala Val 675 Al a lie Cys cys Arg 680 Ser Arg Hi s Leu Ala 685 Gin Al a Ser Gin Glu 690 Leu G1 n <210> 14 <211> 662 <212> PRT <213> Homo sapiens <400> 14 Gin Glu Asp Glu 1 Ser Glu Glu Asp 20 Thr Phe His Arg 35 val val Val Leu 50 Asp Gly Asp 5 Gly Leu val Cys Ala Lys Lys Glu Glu 55 Tyr Glu Glu Leu Val 10 Glu Ala Pro Glu His Asp Pro Trp Arg Leu 40 Thr His Leu Ser Gin 60 Leu Ala Leu Arg Gly Thr Thr Ala 30 Pro Gly Thr Tyr 45 ser Glu Arg Thr Ala Arg Arg 65 Leu Gin Ala Gin Ala Ala Arg Arg Gly Tyr Leu Thr Lys 70 75 80 lie Leu His Val Phe His Gly Leu 85 Ser Gly Asp Leu Leu Glu Leu Ala 100 Leu Pro Gly Phe Leu Val Lys Met 95 Leu Lys Leu Pro His Val Asp Tyr 105 110 lie Glu Glu Asp Ser Ser Val 115 Phe Ala Gin Ser lie Pro Trp Asn Leu 120 125 Glu Arg lie Thr 130 Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gin 135 140 Pro Pro 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 165 lie Glu Gly Arg val Met val Thr Asp 170 Phe Glu 175 Asn val pro Glu 180 Glu Asp Gly Thr Arg 185 Phe His Arg Gin Ala 190 Ser Lys cys Asp Ser 195 Hi s Gly Thr Hi s Leu 200 Ala Gly Val Val Ser 205 Gly Arg Asp Ala Gly 210 val Ala Lys Gly Ala 215 Ser Met Arg Ser Leu 220 Arg val Leu Asn Cys 225 Gin Gly Lys Gly Thr 230 val Ser Gly Thr Leu 235 lie Gly Leu Glu Phe 240 He Arg Lys Ser Gin 245 Leu Val Gin Pro val 250 Gly Pro Leu Val val 255 Leu Leu Pro Leu Ala 260 Gly Gly Tyr Ser Arg 265 val Leu Asn Al a Ala 270 cys G1 n Arg Leu Ala 275 Arg Ala Gly Val Val 280 Leu Val Thr Al a Ala 285 Gly Asn Phe Arg Asp 290 Asp Ala cys Leu Tyr 295 ser pro Ala ser Ala 300 pro Glu val lie Thr 305 val Gly Ala Thr Asn 310 Ala Gin Asp Gin pro 315 val Thr Leu Gly Thr 320 Leu Gly Thr Asn Phe 325 Gly Arg Cys Val ASp 330 Leu Phe Al a Pro Gly 335 G1 u Asp lie lie Gly 340 Ala Ser Ser Asp cys 345 Ser Thr Cys Phe val 350 Ser Gin Ser Gly Thr 355 Ser Gin Ala Al a Ala 360 Hi s Val Al a Gly lie 365 Ala Ala Met Met Leu 370 Ser Ala Glu Pro Glu 375 Leu Thr Leu Al a Glu 380 Leu Arg Gin Arg Leu 385 lie Hi s Phe Ser Ala 390 Lys Asp val lie Asn 395 Glu Ala Trp Phe Pro 400 Glu Asp Gin Arg Val 405 Leu Thr Pro Asn Leu 410 val Ala Ala Leu Pro 415 Pro Ser Thr Hi s Gly 420 Ala Gly Trp G1 n Leu 425 Phe Cys Arg Thr Val 430 Trp Ser Ala Hi s Ser 435 Gly Pro Thr Arg Met 440 Ala Thr Ala val Ala 445 Arg cys Ala 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 465 470 Gin Gly Gly Lys Leu val Cys Arg 475 480 Ala His Asn Ala Phe Gly Gly Glu 485 Gly val Tyr Ala lie Ala Arg Cys 490 495 Cys Leu Leu Pro Gin Ala Asn cys 500 ser val His Thr Ala pro Pro Ala 505 510 Glu Ala Ser Met Gly Thr Arg Val 515 520 His Cys His Gin Gin Gly His val 525 Leu Thr Gly Cys Ser Ser His Trp 530 535 Glu Val Glu Asp Leu Gly Thr His 540 Lys Pro Pro Val Leu Arg pro Arg 545 550 Gly Gin Pro Asn Gin cys val Gly 555 560 His Arg Glu Ala Ser lie His Ala 565 Ser Cys Cys His Ala Pro Gly Leu 570 575 Glu Cys Lys Val Lys Glu His Gly 580 lie Pro Ala Pro Gin Glu Gin val 585 590 Thr Val Ala Cys Glu Glu Gly Trp 595 600 Thr Leu Thr Gly Cys ser Ala Leu 605 Pro Gly Thr Ser His val Leu Gly 610 615 Ala Tyr Ala val Asp Asn Thr Cys 620 Val val Arg Ser Arg Asp val Ser 625 630 Thr Thr Gly Ser Thr Ser Glu Glu 635 640 Ala Val Thr Ala val Ala lie Cys 645 Cys Arg Ser Arg His Leu Ala Gin 650 655 Ala ser Gin Glu Leu Gin 660 <210> 15 <211> 692 <212> PRT <213> Homo sapiens <400> 15 Met Gly Thr Val 1 Ser Ser Arg Arg 5 Leu Leu Leu Leu 20 Leu Leu Leu Gly Ser Trp Trp Pro Leu Pro Leu Leu Pro Ala Gly Ala Arg Ala Gin Glu Asp Glu Asp Gly Asp Tyr Glu Glu 40 Leu Val Leu Ala Leu Arg Ser Glu 45 Glu Asp Gly Leu Ala Glu Ala Pro 50 55 Glu His Gly Thr Thr Ala Thr Phe 60 His Arg Cys Ala Lys Asp Pro Trp 65 70 Arg Leu Pro Gly Thr Tyr val val 80 Val Leu Lys Glu Glu Thr His Leu Ser Gin Ser Glu Arg Thr Ala Arg 95 Arg Leu Gin Ala Gin Ala Ala Arg 100 Arg Gly Tyr Leu Thr Lys lie Leu 105 110 His Val Phe His Gly Leu Leu Pro 115 120 Gly Phe Leu Val Lys Met Ser Gly 125 Asp Leu Leu Glu Leu Ala Leu Lys 130 135 Leu Pro His Val Asp Tyr lie Glu 140 Glu Asp Ser Ser val Phe Ala Gin 145 150 Ser lie Pro Trp Asn Leu Glu Arg 155 160 lie Thr Pro Pro Arg Tyr Arg Ala 165 Asp Glu Tyr Gin Pro Pro Asp Gly 170 175 Gly Ser Leu Val Glu val Tyr Leu 180 Leu Asp Thr Ser He Gin ser Asp 185 190 His Arg Glu lie Glu Gly Arg val 195 200 Met val Thr Asp Phe Glu Asn val 205 Pro Glu Glu Asp Gly Thr Arg Phe 210 215 His Arg Gin Ala ser Lys cys Asp 220 Ser His Gly Thr His Leu Ala Gly 225 230 Val Val Ser Gly Arg Asp Ala Gly 235 240 val Ala Lys Gly Ala Ser Met Arg 245 ser Leu Arg Val Leu Asn Cys Gin 250 255 Gly Lys Gly Thr val ser Gly Thr 260 Leu lie Gly Leu Glu Phe lie Arg 265 270 Lys Ser Gin Leu val Gin Pro val 275 280 Gly Pro Leu Val val Leu Leu Pro 285 Leu Ala Gly Gly Tyr Ser Arg Val 290 295 Leu Asn Ala Ala Cys Gin Arg Leu 300 Ala Arg Ala Gly val val Leu val 305 310 Thr Ala Ala Gly Asn Phe Arg Asp 315 320 Asp Ala cys Leu Tyr 325 Ser Pro Ala Ser Ala 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 355 Gly Arg cys Val Asp 360 Leu Phe Ala 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 385 Ser Gin Ala Ala Al a 390 Hi s val Ala Gly Il e 395 Ala Ala Met Met Leu 400 ser Ala G1U Pro Glu 405 Leu Thr Leu Ala Glu 410 Leu Arg Gin Arg Leu 415 lie Hi s phe Ser Ala 420 Lys Asp Val He Asn 425 Glu Ala Trp Phe Pro 430 Glu Asp Gin Arg val 435 Leu Thr Pro Asn Leu 440 val Ala Thr Leu Pro 445 Pro Ser Thr Hi s Gly 450 Al a Gly T rp Gl n Leu 455 Phe Cys Arg Thr Val 460 Trp Ser Ala Hi s Ser 465 Gly pro Thr Arg Met 470 Al a Thr Ala He Ala 475 Arg Cys Ala Pro Asp 480 Glu Glu Leu Leu Ser 485 cys Ser Ser Phe Ser 490 Arg ser Gly Lys Arg 495 Arg Gly Glu Arg Met 500 Glu Ala Gin Gly Gly 505 Lys Leu Val Cys Arg 510 Ala Hi s Asn Ala Phe 515 Gly Gly Glu Gly val 520 Tyr Ala e Ala Arg 525 cys cys Leu Leu pro 530 Gl n Ala Asn cys Ser 535 Val Hi s Thr Ala Pro 540 Pro Ala Glu Ala Ser 545 Met Gly Thr Arg val 550 His cys His Gin Gin 555 Gly Hi s val Leu Thr 560 Gly cys Ser Ser Hi s 565 Trp Glu Val Glu Asp 570 Leu Gly Thr His Lys 575 Pro Pro Val Leu Arg 580 Pro Arg Gl y Gin Pro 585 Asn Gl n Cys Val Gly 590 Hi s Arg Glu Ala Ser lie His Ala Ser Cys 595 600 Cys His Ala Pro Gly Leu Glu Cys 605 Lys Val Lys Glu His Gly lie Pro 610 615 Ala Pro Gin Glu Gin Val Thr val 620 Ala Cys Glu Glu Gly Trp Thr Leu 625 630 Thr Gly Cys Ser Ala Leu Pro Gly 635 640 Thr Ser His Val Leu Gly Ala Tyr 645 Ala val Asp Asn Thr cys Val val 650 655 Arg Ser Arg Asp val Ser Thr Thr 660 Gly Ser Thr Ser Glu Glu Ala val 665 670 Thr Ala Val Ala lie Cys Cys Arg 675 680 Ser Arg His Leu Ala Gin Ala Ser 685 Gin Glu Leu Gin 690 <210> 16 <211> 662 <212> PRT <213> Homo sapiens <400> 16 Gin Glu Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg Ser Glu Glu Asp Gly Leu Ala Glu 20 Ala Pro Glu His Gly Thr Thr Ala 25 30 Thr Phe His Arg cys Ala Lys Asp 40 Pro Trp Arg Leu Pro Gly Thr Tyr 45 Val val val Leu Lys Glu Glu Thr 55 His Leu Ser Gin Ser Glu Arg Thr 60 Ala Arg Arg Leu Gin Ala Gin Ala 65 70 Ala Arg Arg Gly Tyr Leu Thr Lys 75 80 lie Leu His val Phe His Gly Leu 85 Leu Pro Gly Phe Leu Val Lys Met 95 Ser Gly Asp Leu Leu Glu Leu Ala 100 Leu Lys Leu Pro His val Asp Tyr 105 110 lie Glu Glu Asp ser ser val Phe 115 120 Ala Gin Ser lie Pro Trp Asn Leu 125 Glu Arg lie Thr Pro Pro Arg Tyr 130 135 Arg Ala Asp Glu Tyr Gin Pro Pro 140 ASp 145 Gly Gly Ser Leu val 150 Glu Val Tyr Leu Leu 155 Asp Thr Ser lie Gin 160 ser Asp His Arg Glu 165 lie Glu Gly Arg Val 170 Met val Thr Asp Phe 175 Glu Asn val pro Glu 180 Glu Asp Gly Thr Arg 185 Phe Hi s Arg Gin Ala 190 Ser Lys cys Asp ser 195 His Gly Thr Hi s Leu 200 Ala Gly Val val ser 205 Gly Arg Asp Al a Gly 210 val Ala Lys Gly Ala 215 Ser Met Arg ser Leu 220 Arg Val Leu Asn Cys 225 Gin Gly Lys Gly Thr 230 val Ser Gly Thr Leu 235 lie Gly Leu Glu Phe 240 He Arg Lys ser Gin 245 Leu val Gin pro Val 250 Gly Pro Leu Val val 255 Leu Leu Pro Leu Ala 260 Gly Gly Tyr ser Arg 265 Val Leu Asn Ala Ala 270 Cys Gin Arg Leu Ala 275 Arg Al a Gly val Val 280 Leu Val Thr Ala Ala 285 Gly Asn phe Arg Asp 290 ASp Ala cys Leu Tyr 295 Ser Pro Al a Ser Ala 300 Pro Glu val He Thr 305 val Gly Ala Thr Asn 310 Ala Gin ASp Gin Pro 315 Val Thr Leu Gly Thr 320 Leu Gly Thr Asn Phe 325 Gly Arg cys val Asp 330 Leu Phe Ala Pro Gly 335 Glu Asp He lie Gly 340 Al a ser ser Asp cys 345 Ser Thr cys Phe val 350 ser Gin Ser Gly Thr 355 Ser Gin Al a Ala Ala 360 Hi s Val Ala Gly lie 365 Ala Al a Met Met Leu 370 Ser Ala Glu pro Glu 375 Leu Thr Leu Ala Glu 380 Leu Arg Gin Arg Leu 385 lie Hi s Phe Ser Ala 390 Lys Asp Val He Asn 395 Glu Ala Trp Phe Pro 400 Glu Asp Gin Arg Val 405 Leu Thr Pro Asn Leu 410 val Ala Thr Leu Pro 415 Pro Ser Thr His Gly 420 Ala Gly Trp Gin Leu 425 Phe Cys Arg Thr Val 430 Trp ser Ala His ser Gly Pro Thr Arg Met Ala 435 440 Pro Asp Glu Glu Leu Leu Ser Cys ser 450 455 Arg Arg Gly Glu Arg Met Glu Ala Gin 465 470 Ala His Asn Ala Phe Gly Gly Glu Gly 485 Cys Leu Leu Pro Gin Ala Asn Cys ser 500 505 Glu Ala Ser Met Gly Thr Arg Val His 515 520 Leu Thr Gly Cys Ser Ser His Trp Glu 530 535 Lys Pro Pro val Leu Arg Pro Arg Gly 545 550 His Arg Glu Ala ser lie His Ala Ser 565 Glu Cys Lys Val Lys Glu His Gly lie 580 585 Thr Val Ala Cys Glu Glu Gly Trp Thr 595 600 Pro Gly Thr Ser His val Leu Gly Ala 610 615 val Val Arg Ser Arg Asp val Ser Thr 625 630 Ala val Thr Ala val Ala lie Cys cys 645 Ala ser Gin Glu Leu Gin 660 <210> 17 <211> 540 <212> PRT <213> Homo sapiens <400> 17 Ser lie Pro Trp Asn Leu Glu Arg lie Ala lie Ala Arg Cys Ala 445 Phe Ser Arg Ser Gly Lys 460 Gly Lys Leu val Cys Arg 475 480 Tyr Ala lie Ala Arg cys 495 His Thr Ala Pro Pro Ala 510 His Gin Gin Gly His Val 525 Glu Asp Leu Gly Thr His 540 pro Asn Gin cys val Gly 555 560 Cys His Ala Pro Gly Leu 575 Ala Pro Gin Glu Gin Val 590 Thr Gly cys Ser Ala Leu 605 Ala Val Asp Asn Thr Cys 620 Gly ser Thr Ser Glu Glu 635 640 Ser Arg His Leu Ala Gin 655 Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gin 20 Pro Pro Asp Gly Gly 25 Ser Leu val Glu Val 30 Tyr Leu Leu Asp Thr 35 Ser lie Gin Ser Asp 40 Hi s Arg Glu lie Glu 45 Gly Arg Val Met val 50 Thr Asp Phe Glu Asn 55 val Pro Glu Glu Asp 60 Gly Thr Arg Phe Hi s 65 Arg Gin Ala ser Lys 70 cys Asp Ser Hi s Gly 75 Thr Hi s Leu Ala Gly 80 val val Ser Gly Arg 85 Asp Ala Gly Val Ala 90 Lys Gly Ala Ser Met 95 Arg Ser Leu Arg Val 100 Leu Asn cys Gin Gly 105 Lys Gly Thr val Ser 110 Gly Thr Leu lie Gly 115 Leu Glu Phe lie Arg 120 Lys Ser Gin Leu val 125 Gin pro Val Gly pro 130 Leu Val Val Leu Leu 135 Pro Leu Ala Gly Gly 140 Tyr Ser Arg val Leu 145 Asn Ala Ala cys G1 n 150 Arg Leu Ala Arg Al a 155 Gly Val val Leu Val 160 Thr Ala Ala Gly Asn 165 Phe Arg Asp Asp Ala 170 Cys Leu Tyr Ser Pro 175 Al a Ser Ala Pro Glu 180 val Il e Thr val Gly 185 Ala Thr Asn Ala Gin 190 Asp Gin Pro val Thr 195 Leu Gly Thr Leu Gly 200 Thr Asn phe Gly Arg 205 cys val Asp Leu Phe 210 Ala Pro Gly G1 U Asp 215 He lie Gly Al a ser 220 ser Asp cys Ser Thr 225 Cys Phe Val Ser Gin 230 ser Gly Thr Ser G1 n 235 Al a Al a Ala Hi s val 240 Ala Gly lie Ala Ala 245 Met Met Leu Ser Al a 250 Glu Pro Glu Leu Thr 255 Leu Ala Glu Leu Arg 260 Gin Arg Leu lie Hi s 265 Phe Ser Ala Lys Asp 270 Val lie Asn Glu Al a 275 Trp Phe Pro Glu Asp 280 Gin Arg val Leu Thr 285 Pro Asn Leu Val Ala 290 Thr Leu Pro Pro ser 295 Thr Hi s Gly Ala Gly 300 Trp Gin Leu Phe cys 305 Arg Thr val Trp Ser 310 Ala His Ser Gly Pro 315 Thr Arg Met Ala Thr 320 Al a 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 Glu Ala 350 Gin Gly Gly Lys Leu 355 val cys Arg Ala Hi s 360 Asn Ala Phe Gly Gly 365 Glu Gly val Tyr Ala 370 lie Ala Arg Cys cys 375 Leu Leu Pro Gin Ala 380 Asn Cys ser Val His 385 Thr Ala Pro Pro Ala 390 Glu Al a ser Met Gly 395 Thr Arg Val His cys 400 His Gin Gin Gly Hi s 405 Val Leu Thr Gly cys 410 Ser Ser Hi s Trp Glu 415 Val Glu Asp Leu Gly 420 Thr Hl s Lys Pro Pro 425 Val Leu Arg pro Arg 430 Gly Gin Pro Asn Gin 435 Cys Val Gly Hi s Arg 440 Glu Ala Ser He Hi s 445 Ala ser cys Cys Hi s 450 Ala Pro Gly Leu Glu 455 cys Lys val Lys Glu 460 Hi s Gly lie Pro Ala 465 Pro Gl n G1U Gin val 470 Thr Val Ala cys Glu 475 Glu Gly Trp Thr Leu 480 Thr Gly Cys Ser Ala 485 Leu Pro Gly Thr ser 490 Hi s val Leu Gly Al a 495 Tyr Al a Val Asp Asn 500 Thr cys Val Val Arg 505 Ser Arg Asp Val ser 510 Thr Thr Gly Ser Thr 515 Ser Glu Glu Ala Val 520 Thr Al a Val Ala lie 525 cys Cys Arg Ser Arg 530 His Leu Ala Gin Ala 535 Ser Gin Glu Leu Gin 540 <210> 18 <211> 692 <212> PRT <213> Homo sapiens <400> 18 Met 1 Gly Thr Val Ser 5 ser Arg 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 Gl n Glu Asp Glu Asp 35 Gly Asp Tyr Gl u Glu 40 Leu val Leu Ala Leu 45 Arg Ser Glu Glu ASp 50 Gly Leu Ala Glu Ala 55 Pro Glu His Gly Thr 60 Thr Ala Thr Phe His 65 Arg cys Al a Lys Asp 70 Pro Trp Arg Leu Pro 75 Gly Thr Tyr Val Val 80 val Leu Lys Glu Glu 85 Thr Hi s Leu set Gin 90 Ser Glu Arg Thr Ala 95 Arg Arg Leu Gin Ala 100 Gin Ala Ala Arg Arg 105 Gly Tyr Leu Thr Lys no lie Leu His Val Phe 115 Hi s Gly Leu Leu Pro 120 Gly Phe Leu val Lys 125 Met Ser Gly Asp Leu 130 Leu Glu Leu Ala Leu 135 Lys Leu Pro His val 140 Asp Tyr He Glu Glu 145 Asp ser Ser Val Phe 150 Ala Gin Ser lie pro 155 Trp Asn Leu Glu Arg 160 lie Thr Pro Pro Arg 165 Tyr Arg Al a Asp Glu 170 Tyr Gin Pro Pro ASp 175 Gly Gly Ser Leu Val 180 Glu val Tyr Leu Leu 185 Asp Thr Ser lie Gin 190 Ser Asp Hi s Arg Glu 195 He Glu Gly Arg val 200 Met val Thr Asp Phe 205 Glu Asn Val Pro Glu 210 Glu Asp Gly Thr Arg 215 Phe Hi s Arg Gin Al a 220 ser Lys Cys Asp Ser 225 Hi s Gly Thr Hi s Leu 230 Ala 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 He Gly Leu Glu Phe 270 He Arg Lys Ser Gin 275 Leu val Gin Pro Val 280 Gly Pro Leu Val val 285 Leu Leu pro Leu Ala Gly Gly Tyr ser Arg val 290 295 Leu Asn Ala Ala Cys Gin Arg Leu 300 Ala Arg Ala Gly val val Leu val 305 310 Thr Ala Ala Gly Asn Phe Arg Asp 315 320 Asp Ala Cys Leu Tyr Ser Pro Ala 325 Ser Ala Pro Glu val lie Thr val 330 335 Gly Ala Thr Asn Ala Gin Asp Gin 340 Pro val Thr Leu Gly Thr Leu Gly 345 350 Thr Asn Phe Gly Arg Cys Val Asp 355 360 Leu Phe Ala pro Gly Glu Asp lie 365 lie Gly Ala Ser Ser Asp Cys Ser 370 375 Thr Cys Phe Val Ser Gin Ser Gly 380 Thr Ser Gin Ala Ala Ala His val 385 390 Ala Gly lie Ala Ala Met Met Leu 395 400 ser Ala Glu pro Glu Leu Thr Leu 405 Ala Glu Leu Arg Gin Arg Leu lie 410 415 His Phe Ser Ala Lys Asp val lie 420 Ser Glu Ala Trp Phe Pro Glu Asp 425 430 Gin Arg Val Leu Thr Pro Asn Leu 435 440 val Ala Ala Leu Pro Pro ser Thr 445 His Gly Ala Gly Trp Gin Leu Phe 450 455 cys Arg Thr val Trp Ser Ala His 460 Ser Gly Pro Thr Arg Met Ala Thr 465 470 Ala Val Ala Arg cys Ala Pro Asp 475 480 Glu Glu Leu Leu Ser Cys Ser Ser 485 Phe Ser Arg Ser Gly Lys Arg Arg 490 495 Gly Glu Arg Met Glu Ala Gin Gly 500 Gly Lys Leu Val Cys Arg Ala His 505 510 Asn Ala Phe Gly Gly Glu Gly Val 515 520 Tyr Ala lie Ala Arg cys cys Leu 525 Leu Pro Gin Ala Asn Cys Ser Val 530 535 His Thr Ala Pro Pro Ala Glu Ala 540 Ser Met Gly Thr Arg val His Cys 545 550 His Gin Gin Gly His Val Leu Thr 555 560 Gly cys ser ser His Trp Glu val Glu Asp Leu Gly 570 Thr Hi s Lys 575 Pro 565 Pro Val Leu Arg Pro 580 Arg Gly Gin Pro Asn Gin Cys 585 Val Gly 590 Hi s Arg Glu Ala ser lie His 595 Ala Ser Cys Cys His Ala Pro 600 Gly 605 Leu Glu cys Lys Val Lys Glu His 610 Gly lie 615 Pro Ala Pro Gin G1u 620 Gin val Thr val Al a 625 Cys Glu Glu Gly T rp 630 Thr Leu Thr Gly cys ser 635 Ala Leu Pro Gly 640 Thr Ser His Val Leu 645 Gly Ala Tyr Ala val Asp Asn 650 Thr cys val 655 val Arg Ser Arg Asp Val 660 Ser Thr Thr Gly Ser Thr Ser 665 Glu Glu 670 Al a Val 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> 19 <211> 662 <212> PRT <213> Homo sapiens <400> 19 Gin Glu Asp Glu Asp Gly Asp Tyr 1 5 Glu Glu Leu val Leu Ala Leu Arg Ser Glu Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala 25 30 Thr Phe His Arg Cys Ala Lys Asp 40 pro Trp Arg Leu Pro Gly Thr Tyr Val Val Val Leu Lys Glu Glu Thr 55 His Leu Ser Gin Ser Glu Arg Thr 60 Ala Arg Arg Leu Gin Ala Gin Ala 65 70 Ala Arg Arg Gly Tyr Leu Thr Lys 75 80 lie Leu His val Phe His Gly Leu 85 Leu Pro Gly Phe Leu Val Lys Met 95 Ser Gly Asp Leu Leu Glu Leu Ala 100 Leu Lys Leu Pro His Val Asp Tyr 105 110 lie Glu Glu Asp Ser ser val Phe 115 120 Ala Gin Ser lie Pro Trp Asn Leu 125 Glu Arg lie Thr pro Pro Arg Tyr 130 135 Arg Ala Asp Glu Tyr Gin Pro Pro 140 Asp Gly Gly Ser Leu val Glu Val 145 150 Tyr Leu Leu Asp Thr ser lie Gin 155 160 Ser Asp His Arg Glu He Glu Gly 165 Arg Val Met val Thr Asp Phe Glu 170 175 Asn val Pro Glu Glu Asp Gly Thr 180 Arg Phe His Arg Gin Ala Ser Lys 185 190 cys Asp Ser His Gly Thr His Leu 195 200 Ala Gly Val val ser Gly Arg Asp 205 Ala Gly Val Ala Lys Gly Ala Ser 210 215 Met Arg Ser Leu Arg val Leu Asn 220 Cys Gin Gly Lys Gly Thr val Ser 225 230 Gly Thr Leu lie Gly Leu Glu Phe 235 240 lie Arg Lys ser Gin Leu val Gin 245 Pro Val Gly Pro Leu val val Leu 250 255 Leu Pro Leu Ala Gly Gly Tyr ser 260 Arg val Leu Asn Ala Ala cys Gin 265 270 Arg Leu Ala Arg Ala Gly Val Val 275 280 Leu val Thr Ala Ala Gly Asn phe 285 Arg Asp Asp Ala Cys Leu Tyr Ser 290 295 Pro Ala ser Ala Pro Glu val lie 300 Thr val Gly Ala Thr Asn Ala Gin 305 310 Asp Gin pro Val Thr Leu Gly Thr 315 320 Leu Gly Thr Asn Phe Gly Arg Cys 325 Val Asp Leu Phe Ala Pro Gly Glu 330 335 Asp lie lie Gly Ala Ser Ser Asp 340 Cys ser Thr Cys Phe Val ser Gin 345 350 Ser Gly Thr Ser Gin Ala Ala Ala 355 360 His Val Ala Gly lie Ala Ala Met 365 Met Leu Ser Ala Glu pro Glu Leu 370 375 Thr Leu Ala Glu Leu Arg Gin Arg 380 Leu lie His Phe Ser Ala Lys Asp 385 390 Val lie Ser Glu Ala Trp Phe pro 395 400 /fc G1 u Asp Gin Arg val 405 Leu Thr Pro Asn Leu 410 Val Ala Ala Leu Pro 415 Pro ser Thr Hi s Gly 420 Ala Gly Trp Gin Leu 425 Phe cys Arg Thr Val 430 Trp ser Ala Hi s Ser 435 Gly Pro Thr Arg Met 440 Ala Thr Ala Val Ala 445 Arg Cys Ala Pro Asp 450 Glu Glu Leu Leu ser 455 Cys Ser Ser Phe Ser 460 Arg Ser Gly Lys Arg 465 Arg Gly Glu Arg Met 470 Glu Ala Gin Gly Gly 475 Lys Leu val cys Arg 480 Ala Hi s Asn Ala Phe 485 Gly Gly Glu Gly val 490 Tyr Ala He Ala Arg 495 Cys cys Leu Leu Pro 500 Gin Ala Asn Cys Ser 505 Val His Thr Ala Pro 510 Pro Ala Glu Ala Ser 515 Met Gly Thr Arg val 520 His cys His Gin Gin 525 Gly His Val Leu Thr 530 Gly Cys Ser ser Hi s 535 Trp Glu val Glu Asp 540 Leu Gly Thr His Lys 545 Pro Pro val Leu Arg 550 Pro Arg Gly Gin Pro 555 Asn Gin cys val Gly 560 Hi s Arg G1 u Ala Ser 565 lie Hi s Ala Ser cys 570 cys Hi s Ala Pro Gly 575 Leu Glu cys Lys val 580 Lys Glu Hi s Gly lie 585 Pro Ala Pro Gin Glu 590 Gin val Thr val Ala 595 Cys Glu Glu Gly Trp 600 Thr Leu Thr Gly cys 605 Ser Ala Leu Pro Gly 610 Thr Ser His val Leu 615 Gly Ala Tyr Ala val 620 Asp Asn Thr cys Val 625 Val Arg Ser Arg Asp 630 val Ser Thr Thr Gly 635 ser Thr Ser Glu Glu 640 Al a Val Thr Al a val 645 Ala lie cys Cys Arg 650 Ser Arg His Leu Ala 655 Gin Al a ser Gin Glu 660 Leu Gin <210> 20 <211> 540 <212> PRT <213> Homo sapiens <400> 20 Ser lie Pro Trp Asn Leu Glu Arg lie Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gin Pro pro Asp Gly Gly ser Leu val Glu val Tyr Leu 25 30 Leu Asp Thr Ser lie Gin ser Asp 35 40 His Arg Glu lie Glu Gly Arg Val 45 Met val Thr Asp Phe Glu Asn Val 55 Pro Glu Glu Asp Gly Thr Arg Phe 60 His Arg Gin Ala Ser Lys Cys Asp 65 70 ser His Gly Thr His Leu Ala Gly 80 Val Val Ser Gly Arg Asp Ala Gly 85 val Ala Lys Gly Ala ser Met Arg 95 Ser Leu Arg val Leu Asn cys Gin 100 Gly Lys Gly Thr Val ser Gly Thr 105 110 Leu lie Gly Leu Glu Phe lie Arg 115 120 Lys Ser Gin Leu val Gin Pro Val 125 Gly Pro Leu val Val Leu Leu Pro 130 135 Leu Ala Gly Gly Tyr Ser Arg Val 140 Leu Asn Ala Ala Cys Gin Arg Leu 145 150 Ala Arg Ala Gly Val val Leu Val 155 160 Thr Ala Ala Gly Asn Phe Arg Asp 165 Asp Ala Cys Leu Tyr ser Pro Ala 170 175 Ser Ala Pro Glu Val lie Thr Val 180 Gly Ala Thr Asn Ala Gin Asp Gin 185 190 Pro Val Thr Leu Gly Thr Leu Gly 195 200 Thr Asn Phe Gly Arg Cys val Asp 205 Leu Phe Ala Pro Gly Glu Asp lie 210 215 lie Gly Ala Ser Ser Asp Cys Ser 220 Thr cys Phe val ser Gin Ser Gly 225 230 Thr ser Gin Ala Ala Ala His Val 235 240 Ala Gly lie Ala Ala Met Met Leu 245 ser Ala Glu Pro Glu Leu Thr Leu 250 255 Ala Glu Leu Arg Gin 260 Arg Leu lie His 265 Phe Ser Ala Lys Asp 270 Val lie ser Glu Ala Trp Phe 275 Pro Glu Asp 280 Gin Arg Val Leu Thr 285 Pro Asn Leu val Ala 290 Ala Leu Pro Pro ser 295 Thr Hl s Gly Ala Gly 300 Trp Gin Leu Phe Cys 305 Arg Thr val Trp Ser Ala 310 Hi s Ser Gly Pro Thr 315 Arg Met Ala Thr 320 Ala val 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 Gin Gly 340 345350 Gly Lys Leu val cys Arg Ala His Asn Ala Phe Gly Gly Glu Gly val 355 360365 Tyr Ala lie Ala Arg Cys Cys Leu Leu Pro Gin Ala Asn Cys Ser Val 370 375380 His Thr Ala Pro Pro Ala Glu Ala Ser Met Gly Thr Arg val His Cys 385 390 395400 His Gin Gin Gly His Val Leu Thr Gly Cys Ser ser His Trp Glu val 405 410415 Glu Asp Leu Gly Thr His Lys Pro Pro Val Leu Arg Pro Arg Gly Gin 420 425430 Pro Asn Gin Cys Val Gly His Arg Glu Ala Ser lie His Ala ser Cys 435 440445 cys His Ala Pro Gly Leu Glu cys Lys val Lys Glu His Gly lie Pro 450 455460 Ala Pro Gin Glu Gin Val Thr Val Ala Cys Glu Glu Gly Trp Thr Leu 465 470 475480 Thr Gly Cys Ser Ala Leu Pro Gly Thr ser His Val Leu Gly Ala Tyr 485 490495 Ala Val Asp Asn Thr Cys val val Arg Ser Arg Asp Val ser Thr Thr 500 505510 Gly Ser Thr Ser Glu Glu Ala val Thr Ala val Ala lie cys Cys Arg 515 520525 Ser Arg His Leu Ala Gin Ala Ser Gin Glu Leu Gin 530 535540 VA <210> 21 <211> 692 <212> PRT <213> Homo sapiens <400> 21 Arg Arg ser Trp Trp 10 Pro Leu Pro Leu 15 Leu Met Gly 1 Thr Val ser ser 5 Leu Leu Leu Leu 20 Leu Leu Leu Gly pro 25 Al a 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 Hi s 65 Arg Cys Ala Lys Asp 70 Pro Trp Arg Leu Pro 75 Gly Thr Tyr Val Val 80 val Leu Lys Glu Glu 85 Thr His Leu ser Gin 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 Gly Asp Leu 130 Leu G1 u Leu Al a Leu 135 Lys Leu pro Hi s Val 140 Asp Tyr lie Glu Glu 145 Asp Ser Ser Val Phe 150 Ala Gl n Ser lie pro 155 Trp Asn Leu Glu Arg 160 lie Thr Pro Pro Arg 165 Tyr Arg Ala Asp Glu 170 Tyr Gin Pro Pro Asp 175 Gly Gly Ser Leu Val 180 Glu val Tyr Leu Leu 185 Asp Thr ser lie Gin 190 Ser Asp Hi s Arg Glu 195 lie Glu Gly Arg Val 200 Met Val Thr Asp Phe 205 Glu Asn Val Pro G1 u 210 Glu Asp Gly Thr Arg 215 Phe His Arg Gin Al a 220 ser Lys cys Asp Ser 225 Hi s Gly Thr Hi s Leu 230 Ala Gly val val Ser 235 Gly Arg Asp Ala Gly 240 val Ala Lys Gly Ala 245 Ser Met Arg Ser Leu 250 Arg Val Leu Asn Cys 255 Gin Gly Lys Gly Thr val ser Gly Thr 260 Leu lie Gly Leu Glu Phe lie Arg 265 270 Lys Ser Gin Leu Val Gin Pro Val 275 280 Gly Pro Leu Val val Leu Leu Pro 285 Leu Ala Gly Gly Tyr ser Arg val 290 295 Leu Asn Ala Ala Cys Gin Arg Leu 300 Ala Arg Ala Gly Val Val Leu Val 305 310 Thr Ala Ala Gly Asn Phe Ang Asp 315 320 Asp Ala Cys Leu Tyr ser Pro Ala 325 Sen Ala Pno Glu Val lie Thr Val 330 335 Gly Ala Thr Asn Ala Gin Asp Gin 340 Pro Val Thr Leu Gly Thr Leu Gly 345 350 Thn Asn Phe Gly Arg Cys Val Asp 355 360 Leu Phe Ala Pro Gly Glu Asp lie 365 lie Gly Ala Ser Ser Asp Cys Ser 370 375 Thr Cys Phe val Ser Gin Ser Gly 380 Thr Ser Gin Ala Ala Ala His val 385 390 Ala Gly lie Ala Ala Met Met Leu 395 400 Ser Ala Glu Pro Glu Leu Thr Leu 405 Ala Glu Leu Arg Gin Arg Leu lie 410 415 His Phe Ser Ala Lys Asp val lie 420 Asn Glu Ala Tnp Phe Pro Glu Asp 425 430 Gin Ang val Leu Thr Pro Asn Leu 435 440 Val Ala Thr Leu Pro Pro Ser Thr 445 His Gly Ala Gly Tnp Gin Leu Phe 450 455 Cys Arg Thr Val Trp ser Ala His 460 Ser Gly Pro Thr Arg Met Ala Thr 465 470 Ala lie Ala Arg Cys Ala Pro Asp 475 480 Glu Glu Leu Leu Ser Cys Ser Ser 485 Phe Ser Arg ser Gly Lys Arg Arg 490 495 Gly Glu Arg Met Glu Ala Gin Gly 500 Gly Lys Leu Val Cys Arg Ala His 505 510 Asn Ala Phe Gly Gly Glu Gly val 515 520 Tyr Ala lie Ala Arg Cys cys Leu 525 Leu Pro Gin Ala Asn cys ser val His Thr Ala Pro pro Ala Glu Ala 530 535540 Ser wet Gly Thr Arg Val His Cys His Gin Gin Gly His Val Leu Thr 545 550 555560 Gly cys ser ser His Trp Glu val Glu Asp Leu Gly Thr His Lys Pro 565 570575 Pro Val Leu Arg Pro Arg Gly Gin Pro Asn Gin cys Val Gly His Arg 580 585590 Glu Ala ser He His Ala Ser cys Cys His Ala Pro Gly Leu Glu Cys 595 600605 Lys Val Lys Glu His Gly lie Pro Ala Pro Pro Glu Gin Val Thr Val 610 615620 Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly cys ser Ala Leu Pro Gly 625 630 635640 Thr ser His Val Leu Gly Ala Tyr Ala val Asp Asn Thr cys val val 645 650655 Arg Ser Arg Asp Val Ser Thr Thr Gly Ser Thr ser Glu Glu Ala val 660 665670 Thr Ala val Ala lie Cys Cys Arg Ser Arg His Leu Ala Gin Ala Ser 675 680685 Gin Glu Leu Gin 690 <210> 22 <211> 662 <212> PRT <213> Homo sapiens <400> 22 Gin Glu Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val 15 10 Leu Ala Leu Arg ser Glu Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala 25 30 Thr phe His Arg Cys Ala Lys Asp 40 Pro Trp Arg Leu pro Gly Thr Tyr 45 Val val Val Leu Lys Glu Glu Thr 55 His Leu Ser Gin Ser Glu Arg Thr 60 Ala Arg Arg Leu Gin Ala Gin Ala 65 70 Ala Arg Arg Gly Tyr Leu Thr Lys 75 80 lie Leu Hi s Val Phe 85 His Gly Leu Leu Pro 90 Gly Phe Leu val Lys 95 Met ser Gly Asp Leu 100 Leu Glu Leu Ala Leu 105 Lys Leu Pro His val 110 ASP Tyr lie Glu Glu 115 Asp Ser Ser Val Phe 120 Ala Gin Ser lie Pro 125 Trp Asn Leu Glu Arg 130 lie Thr Pro pro Arg 135 Tyr Arg Ala Asp Glu Tyr 140 Gin Pro Pro ASp 145 Gly Gly ser Leu val 150 Glu val Tyr Leu Leu 155 Asp Thr Ser lie Gin 160 Ser Asp Hi s Arg Glu 165 lie Glu Gly Arg Val 170 Met val Thr Asp Phe 175 Glu Asn Val Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gin Ala ser Lys 180 185190 Cys Asp ser His Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp 195 200205 Ala Gly Val Ala Lys Gly Ala ser Met Arg Ser Leu Arg val Leu Asn 210 215220 cys Gin Gly Lys Gly Thr Val Ser Gly Thr Leu lie Gly Leu Glu Phe 225 230 235240 lie Arg Lys ser Gin Leu val Gin Pro Val Gly Pro Leu Val Val Leu 245 250255 Leu Pro Leu Ala Gly Gly Tyr Ser Arg val Leu Asn Ala Ala cys Gin 260 265270 Arg Leu Ala Arg Ala Gly val Val Leu Val Thr Ala Ala Gly Asn Phe 275 280285 Arg Asp Asp Ala Cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu val lie 290 295300 Thr Val Gly Ala Thr Asn Ala Gin Asp Gin Pro Val Thr Leu Gly Thr 305 310 315320 Leu Gly Thr Asn Phe Gly Arg cys val Asp Leu Phe Ala Pro Gly Glu 325 330335 Asp lie lie Gly Ala ser ser Asp Cys Ser Thr Cys Phe Val Ser Gin 340 345350 Ser Gly Thr ser Gin Ala Ala Ala His val Ala Gly lie Ala Ala Met 355 360365 Met Leu 370 ser Ala Glu pro Glu 375 Leu Thr Leu Al a Glu 380 Leu Arg Gin Arg Leu 385 Tie Hi s Phe Ser Ala 390 Lys Asp val lie Asn 395 Glu Ala Trp Phe Pro 400 Glu Asp Gin Arg val 405 Leu Thr Pro Asn Leu 410 val Ala Thr Leu Pro 415 Pro Ser Thr Hi s Gly 420 Al a Gly Trp Gin Leu 425 Phe cys Arg Thr val 430 Trp Ser Ala Hi s Ser 435 Gly Pro Thr Arg Met 440 Ala Thr Al a He Al a 445 Arg Cys Ala Pro Asp 450 Glu Glu Leu Leu Ser 455 Cys Ser Ser Phe Ser 460 Arg Ser Gly Lys Arg 465 Arg Gly Glu Arg Met 470 Glu Al a Gin Gly Gly 475 Lys Leu Val cys Arg 480 Ala His Asn Ala Phe 485 Gly Gly Glu Gly val 490 Tyr Ala Il e Ala Arg 495 cys Cys Leu Leu Pro 500 Gin Ala Asn Cys ser 505 val Hi s Thr Al a Pro 510 Pro Ala Glu Ala Ser 515 Met Gly Thr Arg Val 520 His Cys Hi s G1 n Gin 525 Gly His val Leu Thr 530 Gly cys ser ser Hi s 535 Trp Glu val Gl u Asp 540 Leu Gly Thr Hi s Lys 545 Pro pro val Leu Arg 550 pro Arg Gly Gin Pro 555 Asn Gin cys val Gly 560 Hi s Arg Glu Ala Ser 565 lie Hi s Ala Ser cys 570 cys Hi s Ala Pro Gly 575 Leu Glu Cys Lys val 580 Lys Glu Hi s Gly lie 585 Pro Al a Pro Pro Glu 590 Gin val Thr Val Al a 595 Cys Glu Glu Gly Trp 600 Thr Leu Thr Gly cys 605 ser Al a Leu Pro Gly 610 Thr ser Hi s val Leu 615 Gly Ala Tyr Al a Val 620 Asp Asn Thr cys Val 625 val Arg Ser Arg Asp 630 val Ser Thr Thr Gly 635 Ser Thr Ser Glu Glu 640 Ala Val Thr Ala val 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 Ser lie Pro Trp Asn Leu Glu Arg lie Thr Pro Pro Arg Tyr Arg Ala 15 1015 Asp Glu Tyr Gin Pro Pro Asp Gly Gly Ser Leu Val Glu Val Tyr Leu 20 2530 Leu Asp Thr Ser lie Gin Ser Asp His Arg Glu lie Glu Gly Arg Val 35 4045 Met val Thr Asp Phe Glu Asn Val Pro Glu Glu Asp Gly Thr Arg Phe 50 5560 His Arg Gin Ala Ser Lys cys Asp ser His Gly Thr His Leu Ala Gly 65 70 7580 Val val ser Gly Arg Asp Ala Gly val Ala Lys Gly Ala ser Met Arg 85 9095 Ser Leu Arg Val Leu Asn Cys Gin Gly Lys Gly Thr Val Ser Gly Thr 100 105110 Leu lie Gly Leu Glu Phe lie Arg Lys ser Gin Leu val Gin pro Val 115 120125 Gly pro Leu Val val Leu Leu pro Leu Ala Gly Gly Tyr Ser Arg Val 130 135140 Leu Asn Ala Ala Cys Gin Arg Leu Ala Arg Ala Gly val val Leu val 145 150 155160 Thr Ala Ala Gly Asn Phe Arg Asp Asp Ala cys Leu Tyr ser Pro Ala 165 170175 ser Ala Pro Glu val lie Thr Val Gly Ala Thr Asn Ala Gin Asp Gin 180 185190 Pno val Thr Leu Gly Thr Leu Gly Thr Asn Phe Gly Arg Cys Val Asp 195 200205 Leu Phe Ala Pro Gly Glu Asp He lie Gly Ala ser ser Asp cys ser 210 215220 Thr 225 Cys Phe Val Ser Gin 230 Ser Gly Thr Ser Gin 235 Ala Ala Ala His val 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 lie His 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 Thr Leu Pro Pro ser Thr Hi s Gly Ala Gly Trp Gin Leu Phe 290 295 300 Cys Arg Thr Val Trp Ser Ala Hi s Ser Gly Pro Thr Arg Met Ala Thr 305 310 315 320 Ala lie Ala Arg cys Ala Pro Asp Glu Glu Leu Leu Ser Cys Ser Ser 335 330 325 Phe Ser Arg Ser 340 Gly Lys Arg Arg Gly 345 Glu Arg Met Glu Al a 350 Gin Gly Gly Lys Leu 355 Val cys Arg Ala Hi s 360 Asn Al a Phe Gly Gly 365 Glu Gly Val Tyr Ala 370 lie Ala Arg cys cys 375 Leu Leu Pro Gin Ala 380 Asn Cys Ser val Hi s 385 Thr Ala Pro Pro Ala 390 Glu Ala Ser Met Gly 395 Thr Arg val His cys 400 Hi s Gl n Gin Gly Hi s 405 Val Leu Thr Gly Cys 410 Ser Ser Hi s Trp Glu 415 val Glu Asp Leu Gly 420 Thr Hi s Lys Pro pro 425 val Leu Arg Pro Arg 430 Gly Gin Pro Asn Gin 435 Cys val Gly Hi s Arg 440 Glu Al a Ser lie Hi s 445 Al a Ser cys cys His 450 Ala Pro Gly Leu Glu 455 Cys Lys Val Lys Glu 460 His Gly lie Pro Ala 465 pro pro Glu Gin val 470 Thr val Ala cys Glu 475 Glu Gly Trp Thr Leu 480 Thr Gly Cys Ser Ala 485 Leu Pro Gly Thr ser 490 His val Leu Gly Ala 495 Tyr Ala Val Asp Asn 500 Thr 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 Ser Arg His Leu Ala Gin Ala Ser Gin Glu Leu Gin 530 535 540 <210> 24 <211> 692 <212> PRT <213> Homo sapiens <400> 24 Met Gly Thr Val Ser Ser Arg Arg Ser Trp Trp Pro Leu Pro Leu Leu 15 1015 Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gin Glu 20 2530 Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Leu ser Glu 35 4045 Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala Thr Phe 50 5560 His Arg Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr val Val 65 70 7580 val Leu Lys Glu Glu Thr His Leu ser Gin Ser Glu Arg Thr Ala Arg 85 9095 Arg Leu Gin Ala Gin Ala Ala Arg Arg Gly Tyr Leu Thr Lys lie Leu 100 105110 His Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met Ser Gly 115 120125 Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His val Asp Tyr lie Glu 130 135140 Glu Asp Ser Ser val Phe Ala Gin Ser lie Pro Trp Asn Leu Glu Arg 145 150 155160 lie Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gin Pro Pro Asp Gly 165 170175 Gly Ser Leu Val Glu val Tyr Leu Leu Asp Thr Ser lie Gin ser Asp 180 185190 His Arg Glu He Glu Gly Arg val Met val Thr Asp Phe Glu Asn val 195 200205 Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gin Ala Ser Lys cys Asp 210 215220 Ser 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 lie Gly Leu Glu Phe 270 He Arg Lys ser Gin 275 Leu Val Gin Pro Val 280 Gly Pro Leu val Val 285 Leu Leu Pro Leu Ala 290 Gly Gly Tyr Ser Arg 295 val Leu Asn Al a Ala 300 Cys Gin Arg Leu Al a 305 Arg Ala Gly Val val 310 Leu val Thr Ala Ala 315 Gly Asn Phe Arg Asp 320 Asp Ala cys Leu Tyr 325 Ser Pro Ala ser Ala 330 pro Glu Val lie Thr 335 Val Gly Ala Thr Asn 340 Ala Gin Asp Gin Pro 345 Val Thr Leu Gly Thr 350 Leu Gly Thr Asn Phe 355 Gly Arg cys val ASp 360 Leu Phe Al a Pro Gly 365 Glu Asp He He Gly 370 Ala ser ser Asp Cys 375 Ser Thr cys Phe Val 380 Ser Gin Ser Gly Thr 385 Ser Gin Ala Al a Al a 390 His Val Ala Gly lie 395 Ala Al a Met Met Leu 400 Ser Ala G1 u Pro G1 u 405 Leu Thr Leu Ala Glu 410 Leu Arg Gin Arg Leu 415 lie His Phe Ser Ala 420 Lys Asp Val Il e Asn 425 Glu Ala Trp Phe pro 430 Glu Asp Gin Arg Val 435 Leu Thr Pro Asn Leu 440 val Ala Ala Leu Pro 445 Pro Ser Thr His Gly 450 Al a Gly Trp Gin Leu 455 Phe Cys Arg Thr val 460 Trp Ser Ala Hi s Ser 465 Gly Pro Thr Arg Met 470 Ala Thr Ala val Ala 475 Arg cys Ala Pro Asp 480 Glu Glu Leu Leu Ser 485 Cys Ser Ser Phe Ser 490 Arg Ser Gly Lys Arg 495 Arg Gly Glu Arg Met Glu Ala Gin Gly Gly 500 505 Asn Ala Phe Gly Gly Glu Gly val Tyr 515 520 Leu Pro Gin Ala Asn Cys Ser Val His 530 535 Ser Met Gly Thr Arg Val His Cys His 545 550 Gly Cys Ser ser His Trp Glu Val Glu 565 Pro Val Leu Arg Pro Arg Gly Gin Pro 580 585 Glu Ala Ser lie His Ala Ser cys cys 595 600 Lys Val Lys Glu His Gly lie Pro Ala 610 615 Ala Cys Glu Glu Gly Trp Thr Leu Thr 625 630 Thr Ser His Val Leu Gly Ala Tyr Ala 645 Arg Ser Arg Asp Val Ser Thr Thr Gly 660 665 Thr Ala Val Ala lie cys Cys Arg ser 675 680 Gin Glu Leu Gin 690 <210> 25 <211> 662 <212> PRT <213> Homo sapiens <400> 25 Gin Glu Asp Glu Asp Gly Asp Tyr Glu Ser Glu Glu Asp Gly Leu Ala Glu Ala Thr Phe His Arg Cys Ala Lys Asp Pro 35 40 Leu val Cys Arg Ala His 510 lie Ala Arg Cys cys Leu 525 Ala Pro Pro Ala Glu Ala 540 Gin Gly His val Leu Thr 555 560 Leu Gly Thr His Lys Pro 575 Gin Cys val Gly His Arg 590 Ala Pro Gly Leu Glu cys 605 Gin Glu Gin val Thr Val 620 Cys Ser Ala Leu Pro Gly 635 640 Asp Asn Thr cys val val 655 Thr Ser Glu Glu Ala val 670 His Leu Ala Gin Ala Ser 685 Leu Val Leu Ala Leu Leu Glu His Gly Thr Thr Ala Arg Leu Pro Gly Thr Tyr 45 Val val 50 val Leu Lys Glu Glu 55 Thr Hi s Leu Ser Gin 60 Ser Glu Arg Thr Ala 65 Arg Arg Leu Gin Ala 70 Gin Ala Ala Arg Arg 75 Gly Tyr Leu Thr Lys 80 lie Leu His val phe 85 Hi s Gly Leu Leu Pro 90 Gly phe Leu Val Lys 95 Met ser Gly Asp Leu 100 Leu Glu Leu Ala Leu 105 Lys Leu Pro Hi s Val 110 Asp Tyr lie Glu Glu 115 Asp Ser Ser Val Phe 120 Ala Gin ser He Pno 125 Trp Asn Leu Glu Ang 130 lie Thr Pro Pro Arg 135 Tyr Arg Ala ASp Glu 140 Tyr Gin Pro Pro Asp 145 Gly Gly Ser Leu Val 150 Glu Val Tyr Leu Leu 155 Asp Thr ser lie Gin 160 Ser Asp His Arg Glu 165 lie Glu Gly Arg val 170 Met Val Thr Asp Phe 175 Glu Asn Val Pro Gl U 180 Glu ASP Gly Thr Arg 185 Phe His Arg Gin Ala 190 Ser Lys cys Asp Ser 195 Hi s Gly Thr His Leu 200 Al a Gly val val sen 205 Gly Arg Asp Al a Gly 210 val Al a Lys Gly Ala 215 Ser Met Ang Ser Leu 220 Arg Val Leu Asn cys 225 Gin Gly Lys Gly Thr 230 Val Ser Gly Thr Leu 235 lie Gly Leu Glu Phe 240 il e Arg Lys ser Gl n 245 Leu val Gin Pro Val 250 Gly Pro Leu Val Val 255 Leu Leu Pro Leu Ala 260 Gly Gly Tyr Ser Arg 265 Val Leu Asn Ala Ala 270 cys Gin Ang Leu Ala 275 Arg Ala Gly Val Val 280 Leu val Thr Ala Ala 285 Gly Asn Phe Arg Asp 290 Asp Ala cys Leu Tyr 295 Ser Pro Ala Ser Ala 300 Pro Glu Val Il e Thr 305 val Gly Ala Thr Asn 310 Al a Gin Asp Gin Pro 315 val Thr Leu Gly Thr 320 Leu Gly Thr Asn Phe 325 Gly Arg Cys val Asp 330 Leu Phe Ala Pro Gly 335 Glu Asp lie lie Gly Ala Ser Ser Asp 340 Cys ser Thr Cys Phe val Ser Gin 345 350 Ser Gly Thr Ser Gin Ala Ala Ala 355 360 His val Ala Gly lie Ala Ala Met 365 Met Leu Ser Ala Glu Pro Glu Leu 370 375 Thr Leu Ala Glu Leu Arg Gin Arg 380 Leu lie His Phe ser Ala Lys Asp 385 390 val lie Asn Glu Ala Trp Phe Pro 395 400 Glu Asp Gin Arg val Leu Thr Pro 405 Asn Leu val Ala Ala Leu Pro Pro 410 415 Ser Thr His Gly Ala Gly Trp Gin 420 Leu Phe Cys Arg Thr Val Trp Ser 425 430 Ala His Ser Gly Pro Thr Arg Met 435 440 Ala Thr Ala val Ala Arg cys Ala 445 Pro Asp Glu Glu Leu Leu Ser cys 450 455 ser ser Phe ser Arg Ser Gly Lys 460 Arg Arg Gly Glu Arg Met Glu Ala 465 470 Gin Gly Gly Lys Leu val Cys Arg 475 480 Ala His Asn Ala Phe Gly Gly Glu 485 Gly val Tyr Ala lie Ala Arg cys 490 495 Cys Leu Leu Pro Gin Ala Asn cys 500 Ser val His Thr Ala Pro Pro Ala 505 510 Glu Ala Ser Met Gly Thr Arg Val 515 520 His Cys His Gin Gin Gly His Val 525 Leu Thr Gly cys ser Ser His Trp 530 535 Glu val Glu Asp Leu Gly Thr His 540 Lys Pro Pro val Leu Arg Pro Arg 545 550 Gly Gin Pro Asn Gin Cys Val Gly 555 560 His Arg Glu Ala Ser lie His Ala 565 Ser Cys Cys His Ala Pro Gly Leu 570 575 Glu Cys Lys val Lys Glu His Gly 580 lie Pro Ala Pro Gin Glu Gin Val 585 590 Thr val Ala Cys Glu Glu Gly Trp 595 600 Thr Leu Thr Gly Cys Ser Ala Leu 605 Pro Gly Thr ser His val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys 610 615 620 val val Arg ser Arg Asp val ser Thr 625 630 Ala val Thr Ala val Ala lie Cys cys 645 Ala Ser Gin Glu Leu Gin 660 <210> 26 <211> 692 <212> PRT <213> Homo sapiens <400> 26 Met Gly Thr Val Ser Ser Arg Arg Ser Leu Leu Leu Leu Leu Leu Leu Gly Pro 20 25 Asp Glu Asp Gly Asp Tyr Glu Glu Leu 35 40 Glu Asp Gly Leu val Glu Ala Pro Glu 55 His Arg Cys Ala Lys Asp Pro Trp Arg 65 70 Val Leu Lys Glu Glu Thr His Leu ser 85 Arg Leu Gin Ala Gin Ala Ala Ang Ang 100 105 His Val Phe His Gly Leu Leu Pro Gly 115 120 Asp Leu Leu Glu Leu Ala Leu Lys Leu 130 135 Glu Asp Ser Ser Val Phe Ala Gin ser 145 150 lie Thr Pro Pro Arg Tyr Arg Ala Asp 165 Gly Ser Leu Val Glu Val Tyr Leu Leu 180 185 Gly Ser Thr ser Glu Glu 635 640 ser Arg His Leu Ala Gin 655 Trp Pro Leu Pro Leu Leu Gly Ala Arg Ala Gin Glu 30 Leu Ala Leu Arg ser Glu Gly Thr Thr Ala Thr Phe 60 Pro Gly Thr Tyr val Val 75 80 Ser Glu Arg Thr Ala Arg Tyr Leu Thr Lys Tie Leu 110 Leu val Lys Met ser Gly 125 His Val Asp Tyr lie Glu 140 Pro Trp Asn Leu Glu Arg 155 160 Tyr Gin Pro Pro Asp Gly 175 Thr Ser lie Gin Ser Asp 190 b Hi s Arg Glu 195 He Glu Gly Arg Val 200 Met val Thr Asp Phe 205 Glu Asn Val Pro Glu 210 Glu Asp Gly Thr Arg 215 Phe His Arg Gin Ala 220 ser Lys Cys Asp Ser 225 Hi s Gly Thr Hi s Leu 230 Ala Gly Val val Ser 235 Gly Arg Asp Ala Gly 240 val Ala Lys Gly 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 Gin 275 Leu val Gin Pro Val 280 Gly Pro Leu val val 285 Leu Leu Pro Leu Ala 290 Gly Gly Tyr Ser Arg 295 Val Leu Asn Ala Al a 300 cys G1 n Arg Leu Ala 305 Arg Al a Gly val val 310 Leu Val Thr Ala Ala 315 Gly Asn Phe Arg Asp 320 Asp Ala cys Leu Tyr 325 Ser Pro Ala Ser Ala 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 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 385 Ser Gin Al a Ala Al a 390 Hi s val Al a Gly lie 395 Ala Ala Met Met Leu 400 Ser Al a Glu Pro Glu 405 Leu Thr Leu Al a Glu 410 Leu Arg Gin Arg Leu 415 lie Hi s Phe Ser Ala 420 Lys Asp Val He Asn 425 Glu Ala Trp Phe Pro 430 Glu ASp G1 n Arg Val 435 Leu Thr Pro Asn Leu 440 val Ala Ala Leu Pro 445 Pro Ser Thr Hi s Gly 450 Ala Gly Trp Gin Leu 455 phe Cys Arg Thr Val 460 ser 465 Gly pro Thr Arg Met 470 Ala Thr Ala lie Ala 475 Arg cys Ala Pro Asp 480 Trp ser Ala Hi s Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser 485 490 Gly Glu Arg Met Glu Ala Gin Gly Gly Lys 500 505 Asn Ala Phe Gly Gly Glu Gly val Tyr Ala 515 520 Leu Pro Gin Ala Asn Cys Ser val His Thr 530 535 ser Met Gly Thr Arg Val His cys His Gin 545 550 Gly cys Ser ser His Trp Glu val Glu Asp 565 570 Pro Val Leu Arg Pro Arg Gly Gin Pro Asn 580 585 Glu Ala ser lie His Ala ser cys cys His 595 600 Lys Val Lys Glu His Gly lie Pro Ala Pro 610 615 Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly 625 630 Thr Ser His Val Leu Gly Ala Tyr Ala Val 645 650 Arg ser Arg Asp Val Ser Thr Thr Gly Ser 660 665 Thr Ala val Ala lie Cys Cys Arg Ser Arg 675 680 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 Ser Glu Glu Asp Gly Leu val Glu Ala Pro Ser Gly Lys Arg Arg 495 val Cys Arg Ala His 510 Ala Arg Cys Cys Leu 525 Pro Pro Ala Glu Ala 540 Gly His Val Leu Thr 560 Gly Thr His Lys Pro 575 Cys Val Gly His Arg 590 Pro Gly Leu Glu cys 605 Glu Gin Val Thr Val 620 Ser Ala Leu Pro Gly 640 Asn Thr cys Val val 655 Ser Glu Gly Ala val 670 Leu Ala Gin Ala Ser 685 Val Leu Ala Leu Arg His Gly Thr Thr Ala 30 Thr phe Hi s 35 Arg cys Ala Lys Asp 40 Pro Trp Arg Leu pro 45 Gly Thr Tyr Val val 50 Val Leu Lys G1 u Glu 55 Thr Hi s Leu Ser Gin 60 Ser Glu Arg Thr Ala 65 Arg Arg Leu Gin Ala 70 Gin Ala Ala Arg Arg 75 Gly Tyr Leu Thr Lys 80 il e Leu Hi s val Phe 85 Hi s Gly Leu Leu Pro 90 Gly Phe Leu Val Lys 95 Met ser Gly Asp Leu 100 Leu Glu Leu Ala Leu 105 Lys Leu Pro Hi s val 110 Asp Tyr lie Glu Glu 115 Asp Ser Ser val Phe 120 Al a Gin ser lie pro 125 Trp Asn Leu Glu Arg 130 lie Thr Pro Pro Arg 135 Tyr Arg Ala Asp Glu 140 Tyr Gin Pro Pro ASp 145 Gly Gly Ser Leu Val 150 Glu Val Tyr Leu Leu 155 Asp Thr ser He Gin 160 Ser Asp Hi s Arg Glu 165 He Glu Gly Arg val 170 Met Val Thr Asp Phe 175 Glu Asn Val Pro Glu 180 Glu Asp Gly Thr Arg 185 Phe His Arg Gin Ala 190 Ser Lys cys Asp Ser 195 Hi s Gly Thr Hi s Leu 200 Ala Gly Val Val ser 205 Gly Arg Asp Al a Gly 210 Val Ala Lys Gly Ala 215 Ser Met Arg Ser Leu 220 Arg val Leu Asn cys 225 Gin Gly Lys Gly Thr 230 Val Ser Gly Thr Leu 235 He Gly Leu Glu Phe 240 lie Arg Lys Ser Gin 245 Leu val Gin Pro val 250 Gly Pro Leu Val Val 255 Leu Leu Pro Leu Al a 260 Gly Gly Tyr ser Arg 265 val Leu Asn Ala Ala 270 cys Gin Arg Leu Ala 275 Arg Ala Gly Val Val 280 Leu Val Thr Ala Ala 285 Gly Asn Phe Arg Asp 290 Asp Ala Cys Leu Tyr 295 Ser Pro Ala Ser Ala 300 Pro Glu val lie Thr Val Gly Ala Thr Asn Ala Gin 305 310 Asp Gin Pro val Thr Leu Gly Thr 315 320 Leu Gly Thr Asn Phe Gly Arg Cys 325 Val Asp Leu Phe Ala Pro Gly Glu 330 335 Asp lie lie Gly Ala ser Ser Asp 340 Cys ser Thr Cys Phe Val Ser Gin 345 350 ser Gly Thr ser Gin Ala Ala Ala 355 360 His val Ala Gly lie Ala Ala Met 365 Met Leu Ser Ala Glu Pro Glu Leu 370 375 Thr Leu Ala Glu Leu Arg Gin Arg 380 Leu lie His Phe Ser Ala Lys Asp 385 390 Val lie Asn Glu Ala Trp Phe Pro 395 400 Glu Asp Gin Arg val Leu Thr Pro 405 Asn Leu Val Ala Ala Leu Pro Pro 410 415 Ser Thr His Gly Ala Gly Trp Gin 420 Leu Phe Cys Arg Thr val Trp Ser 425 430 Ala His Ser Gly Pro Thr Arg Met 435 440 Ala Thr Ala lie Ala Arg cys Ala 445 Pro Asp Glu Glu Leu Leu Ser Cys 450 455 Ser Ser Phe ser Arg Ser Gly Lys 460 Arg Arg Gly Glu Arg Met Glu Ala 465 470 Gin Gly Gly Lys Leu val Cys Arg 475 480 Ala His Asn Ala Phe Gly Gly Glu 485 Gly Val Tyr Ala lie Ala Arg Cys 490 495 Cys Leu Leu Pro Gin Ala Asn Cys 500 Ser val His Thr Ala Pro Pro Ala 505 510 Glu Ala Ser Met Gly Thr Arg Val 515 520 His Cys His Gin Gin Gly His Val 525 Leu Thr Gly Cys Ser ser His Trp 530 535 Glu Val Glu Asp Leu Gly Thr His 540 Lys Pro Pro Val Leu Arg Pro Arg 545 550 Gly Gin Pro Asn Gin Cys Val Gly 555 560 His Arg Glu Ala Ser lie His Ala 565 Ser cys Cys His Ala Pro Gly Leu 570 575 Glu Cys Lys Val Lys Glu His Gly 580 lie pro Ala Pro Gin Glu Gin val 585 590 Thr Val Ala Cys Glu Glu Gly Trp 595 600 Thr Leu Thr Gly Cys ser Ala Leu 605 pro Gly Thr Ser His Val Leu Gly 610 615 Ala Tyr Ala val Asp Asn Thr cys 620 Val Val Arg Ser Arg Asp val ser 625 630 Thr Thr Gly Ser Thr ser Glu Gly 635 640 Ala val Thr Ala val Ala lie cys 645 Cys Arg ser Arg His Leu Ala Gin 650 655 Ala Ser Gin Glu Leu Gin 660 <210> 28 <211> 2080 <212> DNA <213> Homo sapiens <400> 28 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagcca tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagrcag gagccgggac1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 29 <211> 2080 <212> DNA <213> Homo sapiens <400> 29 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagccg tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 30 <211> 2080 <212> DNA <213> Homo sapiens <400> 30 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg 60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagcca tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaaggg gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 31 <211> 2080 <212> DNA <213> Homo sapiens <400> 31 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg 60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 %0 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt. gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagccg tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaaggg gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 32 <211> 2080 <212> DNA <213> Homo sapiens <400> 32 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggtcg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagccg tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 33 <211> 2080 <212> DNA <213> Homo sapiens <400> 33 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 i/SL gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccaccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagcca tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 34 <211> 2080 <212> DNA <213> Homo sapiens <400> 34 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcagtgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagccg tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 Sf <210> 35 <211> 2080 <212> DNA <213> Homo sapiens <400> 35 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccaccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagcca tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctccggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 36 <211> 2080 <212> DNA <213> Homo sapiens <400> 36 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgctttc cgaggaggac ggcctggccg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagccg tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac1980 gtcagcacta caggcagcac cagcgaagag gccgtgacag ccgttgccat ctgctgccgg2040 agccggcacc tggcgcaggc ctcccaggag ctccagtgac2080 <210> 37 <211> 2080 <212> DNA <213> Homo sapiens <400> 37 atgggcaccg tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg60 ctgctcctgg gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag120 ctggtgctag ccttgcgttc cgaggaggac ggcctggtcg aagcacccga gcacggaacc180 acagccacct tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg240 gtgctgaagg aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc300 caggctgccc gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct360 ggcttcctgg tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc420 gactacatcg aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg480 attacccctc cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg540 gaggtgtatc tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc600 atggtcaccg acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc660 agcaagtgtg acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc720 gtggccaagg gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg780 gttagcggca ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg840 gggccactgg tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc900 tgccagcgcc tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac960 gatgcctgcc tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat1020 gcccaagacc agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac1080 ctctttgccc caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg1140 tcacagagtg ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg1200 tctgccgagc cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc1260 aaagatgtca tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg1320 gtggccgccc tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta1380 tggtcagcac actcggggcc tacacggatg gccacagcca tcgcccgctg cgccccagat1440 gaggagctgc tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg1500 gaggcccaag ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc 1560 tacgccattg ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca 1620 ccagctgagg ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca 1680 ggctgcagct cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg 1740 ccacgaggtc agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc 1800 tgccatgccc caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag 1860 caggtgaccg tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg 1920 acctcccacg tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac 1980 gtcagcacta agccggcacc <210> 38 <211> 98 <212> PRT <213> Homo <400> 38 caggcagcac cagcgaaggg gccgtgacag ccgttgccat ctgctgccgg tggcgcaggc ctcccaggag ctccagtgac sapiens 2040 2080 Glu Val Gin 1 Leu val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 5 10 15 Ser Leu Arg Leu Ser cys Ala Ala ser Gly phe Thr Phe Ser ser Tyr 20 25 30 Ala Met ser 35 Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 40 45 Ser Ala lie 50 Ser Gly ser Gly Gly ser Thr Tyr Tyr Ala Asp ser Val 55 60 Lys Gly Arg 65 Phe Thr lie ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 70 75 80 Leu Gin Met Ala Lys Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 <210> 39 <211> 296 <212> DNA <213> Homo sapiens <22O> <221> CDS <222> (1)..(294) <400> 39 gag gtg cag ctg gtg gag tct ggg gga ggc ttg gta cag cct ggg ggg 48 Glu val Gin Leu val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 tcc ctg aga etc tcc tgt gca ser Leu Arg Leu ser cys Ala 20 gcc atg age tgg gtc ege cag Ala Met Ser Trp Val Arg Gin tea get att agt ggt agt ggt Ser Ala lie Ser Gly Ser Gly 5055 aag gqc egg ttc acc atetcc Lys Gly Arg Phe Thr lieSer 6570 ctg caa atg aac age ctg aga Leu Gin Met Asn Ser Leu Arg geg aaa ga Ala Lys gcc tet gga ttc acc ttt age age tat Ala ser Gly Phe Thr Phe ser ser Tyr 2530 get cca ggg aag ggg ctg gag tgggtc Ala Pro Gly Lys Gly Leu Glu Trpval 4045 ggt age aca tac tac gca gac tccgtg Gly Ser Thr Tyr Tyr Ala Asp Serval aga gac aat tcc aag aac acg ctgtat Arg Asp Asn Ser Lys Asn Thr LeuTyr 7580 gcc gag gac acg gcc gta tat tactgt Ala Glu Asp Thr Ala Val Tyr Tyrcys 9095 <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 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gaeggtgteg tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc tacatctgca aegtgaatea caagcccagc aacaccaagg tggacaagaa agttgagccc aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggaegtgage cacgaagacc etgaggteaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc aagacaaagc egegggagga gcagtacaac agcacgtacc gggtggtcag cgtcctcacc gtcctgcacc aggaetgget gaatggcaag gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 144 192 240 288 296 120 180 240 300 360 420 480 540 600 660 720 ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa <210> 42 <211> 330 <212> PRT <213> Homo sapiens <400> 42 Ala Ser Thr Lys Gly Pro Ser val 1 5 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu val Lys Asp Tyr 25 30 Phe Pro Glu Pro Val Thr Val Ser 40 Trp Asn ser Gly Ala Leu Thr Ser 45 Gly val His Thr Phe Pro Ala val 55 Leu Gin ser Ser Gly Leu Tyr Ser 60 Leu Ser Ser Val val Thr val Pro 65 70 Ser Ser Ser Leu Gly Thr Gin Thr 80 Tyr lie Cys Asn val Asn His Lys 85 Pro Ser Asn Thr Lys Val Asp Lys 95 Lys Val Glu Pro Lys Ser Cys Asp 100 Lys Thr His Thr Cys Pro Pro Cys 105 110 Pro Ala Pro Glu Leu Leu Gly Gly 115 .120 Pro Ser val Phe Leu Phe Pro Pro .125 Lys Pro Lys Asp Thr Leu Met lie 130 135 Ser Arg Thr Pro Glu Val Thr Cys 140 Val val val Asp Val ser His Glu 145 150 Asp Pro Glu Val Lys Phe Asn Trp 155 160 Tyr Val Asp Gly Val Glu val His 165 Asn Ala Lys Thr Lys Pro Arg Glu 170 175 Glu Gin Tyr Asn Ser Thr Tyr Arg 180 Val val Ser val Leu Thr Val Leu 185 190 His Gin Asp Trp Leu Asn Gly Lys 195 200 Glu Tyr Lys Cys Lys Val Ser Asn 205 Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly 780 840 900 960 990 210 215 220 Gin Pro Arg Glu Pro Gin val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp lie Ala Val Glu Trp Glu 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 Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn 290 295 300 Val Phe Ser cys Ser val Met Hl s Glu 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 sapiens <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 tccctgtctc cgggtaaa actacacgca gaagagcctc 960 978 <210> 44 <211> 326 <212> PRT <213> Homo sapiens <400> 44 Ala Ser Thr Lys Gly Pro Ser Val Phe pro Leu Ala Pro Cys ser Arg 15 1015 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly cys Leu Val Lys Asp Tyr 20 2530 Phe Pro Glu Pro val Thr val ser Trp Asn Ser Gly Ala Leu Thr ser 35 40’ 45 Gly Val His Thr Phe Pro Ala Val Leu Gin Ser ser Gly Leu Tyr Ser 50 5 560 Leu Ser Ser val val Thr Val Pro ser Ser Asn Phe Gly Thr Gin Thr 65 70 7580 Tyr Thr Cys Asn val Asp His Lys Pro Ser Asn Thr Lys val Asp Lys 85 9095 Thr Val Glu Arg Lys cys Cys val Glu Cys Pro Pro Cys Pro Ala Pro 100 105110 Pro val Ala Gly Pro Ser val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120125 Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135140 Val Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr val Asp Gly 145 150 155160 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn 165 170175 Ser Thr Phe Arg val Val Ser Val Leu Thr val val His Gin Asp Trp 180 185190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200205 Ala Pro lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu 210 215220 Pro Gin Val Tyr Thr Leu Pro Pro ser Arg Glu Glu Met Thr Lys Asn 225 230 235240 Gin val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie 245 250255 Ala val Glu Trp 260 Glu Ser Asn Gly Gin 265 Pro Glu Asn Asn Tyr 270 Lys Thr Thr Pro Pro 275 Met Leu Asp Ser Asp 280 Gly Ser Phe Phe Leu 285 Tyr Ser Lys Leu Thr 290 val Asp i.ys ser Arg 295 Trp Gin Gin Gly Asn 300 val Phe Ser cys Ser 305 Val Met Hi s Glu Ala 310 Leu Hi s Asn Hl 5 Tyr 315 Thr Gin Lys Ser Leu 320 ser Leu ser Pro Gly 325 Lys <210> <211> <212> 296 DNA <213> Homo sapiens <400> 45 caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc tcctgcaagg cttctggtta cacctttacc agctatggta tcagctgggt gcgacaggcc cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactat gcacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagaga 120 180 240 296 <210> <211> <212> <213> PRT Homo sapiens <400> Gin 1 val Gin leu Val 5 Gin Ser Gly Ala Glu 10 val Lys Lys Pro Gly 15 Ala Ser val Lys val 20 ser Cys Lys Ala Ser 25 Gly Tyr Thr Phe Thr 30 Ser Tyr Gly lie Ser 35 Trp val Arg Gin Ala 40 Pro Gly Gl n Gly Leu 45 Glu Trp Met Gly Trp 50 lie Ser Ala Tyr Asn 55 Gly Asn Thr Asn Tyr 60 Ala Gin Lys Leu Gin 65 Gly Arg val Thr Met 70 Thr Thr Asp Thr Ser 75 Thr Ser Thr Ala Tyr 80 Met Glu Leu Arg Ser 85 Leu Arg Ser Asp Asp 90 Thr Ala val Tyr Tyr 95 Cys Ala Arg <210> 47 <211> 296 <212> DNA <213> Homo sapiens <400> 47 caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt tcctgcaagg catctggata caccttcacc agctactata tgcactgggt gcgacaggcc cctggacaag ggcttgagtg gatgggaata atcaacccta gtggtggtag cacaagctac gcacagaagt tccagggcag agtcaccatg accagggaca cgtccacgag cacagtctac atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaga <210> 48 <211> 98 <212> PRT <213> Homo sapiens <400> 48 Gin val Gin Leu Val Gin ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser val Lys val Ser Cys Lys Ala 20 Ser Gly Tyr Thr phe Thr ser Tyr 25 30 Tyr Met His Trp Val Arg Gin Ala 40 pro Gly Gin Gly Leu Glu Trp Met 45 Gly lie lie Asn Pro Ser Gly Gly 55 Ser Thr Ser Tyr Ala Gin Lys Phe 60 Gin Gly Arg Val Thr Met Thr Arg 65 70 Asp Thr Ser Thr ser Thr val Tyr 75 80 Met Glu Leu ser ser Leu Arg ser Glu Asp Thr Ala Val Tyr Tyr cys 95 120 180 2.40 296 Ala Arg <210> 49 <211> 321 <212> DNA <213> Homo sapiens <400> 49 cgaactgtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 120 180 240 300 agcttcaaca ggggagagtg t <210> 50 <211> 107 <212> PRT <213> Homo sapiens <400> 50 Arg Thr val Ala Ala Pro ser val 1 5 321 Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val val cys Leu Leu Asn Asn Phe 25 30 Tyr Pro Arg Glu Ala Lys Val Gin 35 40 Trp Lys val Asp Asn Ala Leu Gin Ser Gly Asn ser Gin Glu ser Val 55 Thr Glu Gin Asp Ser Lys Asp Ser 60 Thr Tyr Ser Leu Ser Ser Thr Leu 65 70 Thr Leu Ser Lys Ala Asp Tyr Glu 75 80 Lys His Lys val Tyr Ala Cys Glu 85 val Thr His Gin Gly Leu ser Ser 95 Pro val Thr Lys ser Phe Asn Arg 100 Gly Glu Cys 105 <210> 51 <211> 318 <212> DNA <213> Homo sapiens <400> 51 ggtcagccca aggctgcccc ctcggtcact ctgttcccgc cctcctctga ggagcttcaa gccaacaagg ccacactggt gt.gtct.cata agtgacttct acccgggagc cgtgacagtg gcttggaaag cagatagcag ccccgtcaag gcgggagtgg agaccaccac accctccaaa caaagcaaca acaagtacgc ggccagcagc tatctgagcc tgacgcctga gcagtggaag tcccacagaa gctacagctg ccaggtcacg catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgttca 120 180 240 300 318 <210> 52 <211> 106 <212> PRT <213> Homo sapiens <400> 52 Gly Gin Pro Lys Ala Ala Pro Ser val Thr Leu Phe Pro Pro Ser Ser 15 10 15 Glu Glu Leu Gin Ala Asn Lys Ala Thr Leu Val Cys Leu lie Ser Asp 20 25 30 Phe Tyr Pro Gly Ala Val Thr Val 40 Ala Trp Lys Ala Asp ser Ser Pro 45 val Lys Ala Gly Val Glu Thr Thr 55 Thr Pro ser Lys Gin ser Asn Asn 60 Lys Tyr Ala Ala Ser Ser Tyr Leu 65 70 Ser Leu Thr Pro Glu Gin Trp Lys 80 Ser His Arg Ser Tyr Ser Cys Gin 85 Val Thr His Glu Gly Ser Thr val 95 Glu Lys Thr Val Ala Pro Thr Glu 100 Cys Ser 105 <210> 53 <211> 365 <212> DNA <213> Homo sapiens <400> 53 atggtgttgc agacccaggt cttcatttct ctgttgctct ggatctctgg tgcctacggg60 gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc120 atcaactgca agtccagcca gagtgtttta tacagctcca acaataagaa ctacttagct180 tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctacccgg240 gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc300 atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtact360 cctcc365 <210> 54 <211> 101 <212> PRT <213> Homo sapiens <400> 54 Asp lie val Met Thr Gin ser Pro Asp ser Leu Ala val ser Leu Gly 1015 Glu Arg Ala Thr Tie Asn Cys Lys Ser Ser Gin ser Val Leu Tyr ser 20 2530 ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 4045 Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 5560 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 7580 lie Ser ser Leu Gin Ala Glu Asp val Ala val Tyr Tyr Cys Gin Gin 85 9095 Tyr Tyr Ser Thr Pro 100 <210> 55 <211> 654 <212> DNA <213> Homo sapiens <400> 55 atggacatga gggtccccgc tcagctcctg gggcttctgc tgctctggct cccagcaggt60 gccagatgtg ccatccagtt gacccagtct ccatcctccc tgtctgcatc tgtaggagac.120 agagtcacca tcacttgccg ggcaagtcag ggcattagca gtgctttagc ctggtatcag180 cagaaaccag ggaaagctcc taagctcctg atctatgatg cctccagttt ggaaagtggg240 gtcccatcaa ggttcagcgg cagtggatct gggacagatt tcactctcac catcagcagc300 ctgcagcctg aagattttgc aacttattac tgtcaacagt ttaatagtta ccctcagtgc360 cagatgtgcc atccagttga cccagtctcc atcctccctg tctgcatctg taggagacag420 agtcaccatc acttgccggg caagtcaggg cattagcagt gctttagcct ggtatcagca480 gaaaccaggg aaagctccta agctcctgat ctatgatgcc tccagtttgg aaagtggggt540 cccatcaagg ttcagcggca gtggatctgg gacagatttc actctcacca tcagcagcct600 gcagcctgaa gattttgcaa cttattactg tcaacagttt aatagttacc ctca654 <210> 56 <400> 56 000 <210> 57 <211> 39 <212> DNA <213> Homo sapiens <400> 57 tgtacacttt tggccagggg accaagctgg agatcaaac <210> 58 <211> 12 <212> PRT <213> Homo sapiens <400> 58 Tyr Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys <210> 59 <211> 38 <212> DNA <213> Homo sapiens <400> 59 tgtggtattc ggcggaggga ccaagctgac cgtcctag <210> 60 <211> 12 <212> PRT <213> Homo sapiens <400> 60 Val val Phe Gly Gly Gly Thr Lys <210> 61 <211> 329 <212> PRT <213> Homo sapiens <400> 61 Ala Ser Thr Lys Gly Pro Ser val .1 5 Leu Thr Val Leu Phe Pro Leu Ala Pro ser Ser Lys 1.0 15 Ser Thr Ser Gly Gly Thr Ala Ala 20 Leu Gly Cys Leu Val Lys Asp Tyr 25 ' 30 Phe Pro Glu pro Val Thr Val Ser 35 40 Trp Asn Ser Gly Ala Leu Thr ser Gly val His Thr Phe Pro Ala val 50 55 Leu Gin Ser Ser Gly Leu Tyr Ser 60 Leu Ser Ser Val Val Thr val Pro 65 70 Ser ser ser Leu Gly Thr Gin Thr 75 80 Tyr lie cys Asn val Asn His Lys 85 Pro Ser Asn Thr Lys Val Asp Lys 95 Lys Val Glu Pro Lys Ser cys Asp 100 Lys Thr His Thr cys Pro Pro Cys 105 110 Pro Ala Pro Glu Leu Leu Gly Gly 115 120 Pro ser Val Phe Leu Phe Pro Pro 125 Lys pro Lys Asp Thr Leu Met lie 130 135 Ser Arg Thr Pro Glu Val Thr Cys 140 val val Val Asp val Ser His Glu 145 150 Asp Pro Glu Val Lys Phe Asn Trp 155 160 Tyr Val Asp Gly val Glu val His 165 Asn Ala Lys Thr Lys Pro Arg Glu 170 175 Glu Gin Tyr Asn Ser Thr Tyr Arg 180 val Val Ser val Leu Thr val Leu 185 190 His Gin Asp Trp Leu Asn Gly Lys 195 200 Glu Tyr Lys Cys Lys val Ser Asn 205 Lys Ala Leu Pro Ala Pro lie Glu 210 215 Lys Thr lie Ser Lys Ala Lys Gly 220 Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu pro Pro Ser Arg Asp Glu X3 225 230 235 240 Leu Thr Lys Asn Gin Val Ser Leu 245 Thr Cys Leu val Lys Gly Phe Tyr 250 255 Pro Ser Asp lie Ala Val Glu Trp 260 Glu Ser Asn Gly Gin Pro Glu Asn 265 270 Asn Tyr Lys Thr Thr Pro Pro val 275 280 Leu Asp Ser Asp Gly Ser Phe Phe 285 Leu Tyr Ser Lys Leu Thr Val Asp 290 295 Lys Ser Arg Trp Gin Gin Gly Asn 300 ' val Phe Ser cys Ser Val Met His 305 310 Glu Ala Leu His Asn His Tyr Thr 315 320 Gin Lys Ser Leu Ser Leu Ser Pro ’ 325 Gly <210> 62 <211> 107 <212> PRT <213> Homo sapiens <400> 62 Arg Thr val Ala Ala Pro Ser val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala ser 20 val val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gin 35 40 Trp Lys Val Asp Asn Ala Leu Gin 45 Ser Gly Asn Ser Gin Glu Ser val 50 55 Thr Glu Gin Asp ser Lys Asp ser Thr Tyr Ser Leu ser Ser Thr Leu 65 70 Thr Leu ser Lys Ala Asp Tyr Glu 75 80 Lys His Lys Val Tyr Ala Cys Glu 85 val Thr His Gin Gly Leu Ser Ser 95 Pro val Thr Lys ser Phe Asn Arg 100 Gly Glu cys 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 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 Trp Asn Ser Gly Ala 45 Leu Thr Ser Gly val 50 His 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 Asn 75 Phe Gly Thr Gin Thr 80 Tyr Thr cys Asn Val 85 Asp His Lys Pro ser 90 Asn Th r Lys val ASp 95 Lys Thr val Glu Arg 100 Lys cys Cys val Glu 105 cys pro Pro cys Pro 110 Al a Pro Pro Val Ala 115 Gly Pro Ser Val phe 120 Leu Phe Pro Pro Lys 125 Pro Lys Asp Thr Leu 130 Met lie ser Arg Thr 135 pro Glu Val Thr cys 140 val val val Asp val 145 ser Hi s Glu Asp Pro 150 Glu val Gin Phe Asn 155 Trp Tyr val Asp Gly 160 Val Glu Val His Asn 165 Ala Lys Thr Lys Pro 170 Arg Glu Glu Gin Phe 175 Asn Ser Thr Phe Arg 180 val Val Ser Val Leu 185 Thr Val val Hi s Gin 1.90 Asp Trp Leu Asn Gly 195 Lys Glu Tyr Lys Cys 200 Lys Val Ser Asn Lys 205 Gly Leu Pro Ala Pro 210 il e Glu Lys Thr lie 215 Ser Lys Thr Lys Gly 220 Gin Pro Arg Glu Pro 225 Gin val Tyr Thr Leu 230 Pro Pro Ser Arg Glu 235 Glu Met Thr Lys Asn 240 Gin Val Ser Leu Thr 245 Cys Leu Val Lys Gly 250 Phe Tyr pro Ser Asp 255 lie Ala val Gl u Trp 260 Glu Ser Asn Gly Gin 265 Pro Glu Asn Asn Tyr 270 Lys Thr Thr Pro Pro 275 Met Leu Asp Ser Asp 280 Gly Ser Phe Phe Leu 285 Tyr Ser Lys Leu Thr val Asp Lys Ser Arg Trp Gin Gin Gly Asn val Phe Ser cys CFO 290 295 300 Ser Val 305 Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys ser Leu 310 315 320 Ser Leu Ser Pro Gly 325 Lys <210> 64 <211> 105 <212> PRT <213> Homo sapiens <400> 64 Gin Pro Lys 1 Ala Ala Pro Ser val 5 Thr Leu 10 Phe Pro Pro Ser Ser 15 Glu Glu Leu Gin Ala 20 Asn L.ys Ala Thr Leu 25 Val cys Leu Il e Ser 30 ASp Phe Tyr Pro Gly 35 Ala val Thr val Ala 40 Trp Lys Ala Asp Ser45 Ser Pro val Lys Ala 50 Gly Val Glu Thr Thr 55 Thr Pro ser Lys Gin 60 Ser Asn Asn Lys Tyr 65 Ala Ala Ser Ser Tyr 70 Leu Ser Leu Thr pro 75 Glu Gin Trp Lys Ser 80 Hi s Arg Ser Tyr ser 85 Lys Thr val Ala Pro 100 <210> 65 <211> 326 <212> PRT <213> Homo sapiens <400> 65 cys Thr Gin Glu val cys Thr Ser 105 Hi s 90 Glu Gly Ser Thr val 95 Glu Ala 1 Ser Thr Lys Gly 5 Pro ser val Phe Pro 10 Leu Ala Pro Cys ser 15 Arg 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 Trp Asn Ser Gly Ala 45 Leu Thr Ser Gly Val 50 His 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 Asn 75 Phe Gly Thr Gin Thr 80 Tyr Thr Cys Asn val 85 Asp His Lys pro ser 90 Asn Thr Lys Val ASP 95 Lys Thr val Glu Arg 100 Lys Cys cys val Glu 105 Cys Pro Pro Cys Pro 110 Ala Pro pro val Ala 115 Gly Pro Ser val phe 120 Leu Phe Pro Pro Lys 125 Pro Lys Asp Thr Leu 130 Met He Ser Arg Thr 135 pro Glu Val Thr cys 140 val val va 1 Asp Val 145 Sen Hi s Glu Asp Pro 150 Glu val Gin Phe Asn 155 Tnp ryr Val Asp Gl y 160 Val Glu val His Asn 165 Ala Lys Thr Lys Pro 170 Arg Gl u Glu Gin Phe 175 Asn Ser Thr Phe Arg 180 val Val ser Val Leu 185 Thr Val val Hi s Gin 190 Asp Trp Leu Asn Gly 195 Lys Glu Tyr Lys Cys 200 Lys Val Ser Asn Lys 205 Gly Leu pro Ser Ser 210 He Glu Lys Thr lie 215 Ser Lys Thr Lys Gly 220 Gin pro Arg Glu Pro 225 Gin Val Tyr Thr Leu 230 Pro Pro Ser Arg Glu 235 Glu Met Thr Lys Asn 240 Gin val Ser Leu Thr 245 cys Leu val Lys Gly 250 Phe tyr pro Ser Asp 255 He Ala Val Glu Trp 260 Glu sen Asn Gly Gin 265 Pro Glu Asn Asn Tyr 270 Lys Thr Thr Pro Pro 275 Met Leu Asp ser Asp 280 Gly ser Phe Phe Leu 285 Tyr Ser Lys Leu Thr 290 val ASp Lys Ser Arg 295 Trp Gin Gin Gly Asn 300 Val phe ser Cys Ser 305 val Met Hi s Glu Ala 310 Leu Hi s Asn Hi s Tyr 315 Thr Gin Lys Ser Leu 320 ser Leu Ser Pro Gly 325 Lys <210> 66 <211> 107 <212> PRT <213> Homo sapiens <400> 66 Arg Thr val Ala Ala Pro Ser Val 1 5 Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys ser Gly Thr Ala ser 20 Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys val Gin 35 40 Trp Lys val Asp Asn Ala Leu Gin 45 Ser Gly Asn ser Gin Glu Ser val 50 55 Thr Glu Gin Asp ser Lys Asp Ser 60 Thr Tyr ser Leu Ser Ser Thr Leu 65 70 Thr Leu Ser Lys Ala Asp Tyr Glu 75 80 Lys His Lys Val Tyr Ala Cys Glu val Thr His Gin Gly Leu Ser Ser 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 67 <211> 7 <212> PRT <213> Homo sapiens <400> 67 Val Phe Ala Gin Ser lie Pro <210> 68 <211> 296 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(294) <400> 68 gag gtg cag ctg ttg gag tet Glu Val Gin Leu Leu Glu Ser tcc ctg aga etc tcc tgt gca Ser Leu Arg Leu Ser Cys Ala gcc atg age tgg gtc ege cag Ala Met ser Trp val Arg Gin tea get att agt ggt agt ggt Ser Ala lie ser Gly Ser Gly 5055 aag gqc egg ttc acc atetcc Lys Gly Arg Phe Thr lieSer 6570 ggg gga gqc ttg gta cag cct ggg ggg Gly Gly Gly Leu Val Gin Pro Gly Gly gcc tet gga ttc acc ttt age age tat Ala Ser Gly Phe Thr Phe Ser Ser Tyr 2530 get cca ggg aag ggg ctg gag tgggtc Ala Pro Gly Lys Gly Leu Glu TrpVal 4045 ggt age aca tac tac gca gac tccgtg Gly Ser Thr Tyr Tyr Ala Asp Serval aga gac aat tcc aag aac acg ctgtat Arg Asp Asn ser Lys Asn Thr LeuTyr 7580 144 192 240 ctg caa atg aac age ctg Leu Gin Met Asn ser Leu aga gcc gag gac acg gcc gta Arg Ala Glu Asp Thr Ala Val 90 tat tac tgt 288 Tyr Tyr Cys 95 geg aaa ga Ala Lys 296 <210> 69 <211> 98 <212> PRT <213> Homo sapiens <400> 69 Glu Val Gin Leu Leu Glu Ser Gly 1 5 Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu ser Cys Ala Ala 20 ser Gly Phe Thr Phe ser ser Tyr 25 30 Ala Met Ser Trp Val Arg Gin Ala 35 40 Pro Gly Lys Gly Leu Glu Trp val 45 ser Ala lie ser Gly Ser Gly Gly 55 Ser Thr Tyr Tyr Ala Asp Ser val 60 Lys Gly Arg Phe Thr lie Ser Arg 65 70 Asp Asn Ser Lys Asn Thr Leu Tyr 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala val Tyr Tyr cys 95 Ala Lys <210> 70 <211> 294 <212> DNA <213> Homo sapiens <22O> <221> CDS <222> (1)..(294) <400> 70 gag gtg cag ctg ttg gag tet ggg gga ggc Glu Val Gin Leu Leu Glu Ser Gly Gly Gly 510 tcc ctg aga etc tcc tgt gca gcc tetgqa ser Leu Arg Leu ser cys Ala Ala SerGly 2025 gcc atg age tgg gtc ege cag get ccaggg Ala Met ser Trp Val Arg Gin Ala ProGly 3540 tea get att agt ggt agt ggt ggt ageaca Ser Ala lie Ser Gly Ser Gly Gly SerThr 5055 ttg gta cag cct ggg ggg48 Leu Val Gin Pro Gly Gly ttc acc ttt age age tat96 Phe Thr Phe ser ser Tyr 30 aag ggg ctg gag tgg gtc144 Lys Gly Leu Glu Trp Val 45 tac tac gca gac tcc gtg192 Tyr Tyr Ala Asp Ser Val aag ggc egg ttc acc ate tcc Lys Gly Arg Phe Thr lie Ser aga Arg gac Asp aat Asn tcc aag aac acg etg Leu tat Tyr 80 240 Ser 75 Lys Asn Thr 65 70 etg caa atg aac age etg aga gcc gag gac acg gcc gta tat tac tgt 288 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 294 gcg aaa Ala Lys <210> 71 <211> 296 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(294) <400> 71 gag gtg cag etg ttg Glu val Gin Leu Leu tcc etg aga etc tcc Ser Leu Arg Leu Ser gcc atg age tgg gtc Ala Met Ser Trp val 35 tea get att agt ggt ser Ala lie Ser Gly 50 aag ggc egg ttc acc Lys Gly Arg Phe Thr 65 etg caa atg aac age Leu Gin Met Asn ser gag tet ggg gga ggc ttg gta Glu Ser Gly Gly Gly Leu val 10 tgt gca gcc tet gga ttc acc cys Ala Ala Ser Gly Phe Thr 25 ege cag get cca ggg aag ggg Arg Gin Ala Pro Gly Lys Gly agt ggt ggt age aca tac tac ser Gly Gly Ser Thr Tyr Tyr 5560 ate tea aga gac aat tccaag lie Ser Arg Asp Asn SerLys 7075 etg aga gcc gag gac acggcc Leu Arg Ala Glu Asp ThrAla cag cct ggg ggg48 Gin Pro GlyGly ttt age age tat96 Phe Ser SerTyr etg gag tgg gtc144 Leu Glu Trpval gga gac tcc gtg192 Gly Asp serval aac acg etg tat240 Asn Thr LeuTyr gta tat tac tgt288 val Tyr Tyrcys gcg aaa ga Ala Lys 296 <210> 72 <211> 98 <212> PRT <213> Homo sapiens <400> 72 Glu Val Gin Leu Leu Glu 1 5 Ser Gly Gly Gly Leu Val 10 Gin Pro Gly Gly Ser Leu Arg Leu 20 ser Cys Ala Ala ser Gly Phe Thr Phe Ser ser Tyr 25 30 Ala Met ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp val 35 40 45 ser Ala lie Ser Gly 50 Ser Gly Gly Ser Thr Tyr Tyr Gly Asp ser val 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn 65 70 ser Lys Asn Thr Leu Tyr 80 Leu Gin Met Asn ser Leu Arg Ala Glu Asp Thr Ala val 85 90 Tyr ryr cys 95 Ala Lys <210> 73 <211> 294 <212> DNA <213> Homo sapiens <22O> <221> CDS <222> (1)..(294) <400> 73 gag gtq cag etg ttg gag tet ggg gga ggc ttg gta Glu Val Gin Leu Leu Glu Ser Gly Gly Gly LeuVal 1510 tcc etg aga etc tcc tgt gca gee tet gga ttcacc Ser Leu Arg Leu Ser cys Ala Ala ser Gly PheThr 2025 gee atg age tgg gtc ege cag get cca gqg aagggg Ala Met Ser Trp Val Arg Gin Ala Pro Gly LysGly 3540 tea gtt att tat age ggt ggt agt age aca tactat Ser Val lie Tyr Ser Gly Gly Ser Ser Thr TyrTyr 5560 aag ggc egg ttc acc ate tcc aga gat aat tccaag Lys Gly Arg Phe Thr lie Ser Arg Asp Asn SerLys 7075 etg caa atg aac age etg aga gee gag gac acggee Leu Gin Met Asn Ser Leu Arg Ala Glu Asp ThrAla 8590 cag cct ggg ggg Gin Pro Gly Gly 15 ttt age age tat Phe Ser Ser Tyr 30 etg gag tgg gtc Leu Glu Trp val 45 gca Ala gac Asp tcc Ser gtg val aac acg etg tat Asn Thr Leu Tyr 80 gta tat tac tgt val Tyr Tyr cys 95 144 192 240 288 geg aaa Ala Lys 294 <210> 74 <211> 98 <212> PRT <213> Homo sapiens <400> 74 Glu val Gin Leu 1 Ser Leu Arg Leu 20 Leu Glu Ser Gly 5 Ser cys Ala Ala Gly Gly Leu val Ser Gly Phe Thr 25 Gin Pro Gly Gly Phe Ser Ser Tyr 30 Ala Met ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp val 35 ' 40 45 ser val lie Tyr Ser Gly Gly ser 50 55 Lys Gly Arg Phe Thr lie ser Arg 65 70 Leu Gin Met Asn ser Leu Arg Ala 85 ser Thr Tyr Tyr Ala Asp Ser val 60 Asp Asn Ser Lys Asn Thr Leu Tyr 75 80 Glu Asp Thr Ala val Tyr Tyr Cys 90 95 Ala Lys <210> 75 <211> 296 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(294) <400> 75 gag gtg cag ctg ttg gag tct ggg gga ggc ttg gta cag cct ggg ggg Glu val Gin Leu Leu Glu Ser Gly Gly Gly Leu val Gin Pro Gly Gly 1015 tcc ctg aga etc tcc tgt gca gcc tct gga ttc acc ttt age agetat Ser Leu Arg Leu Ser cys Ala Ala Ser Gly Phe Thr Phe ser SerTyr 2530 gcc atg age tgg gtc ege cag get cca ggg aag ggg ctg gag tgggtc Ala Met Ser Trp val Arg Gin Ala Pro Gly Lys Gly Leu Glu TrpVal 4045 tea gtt att tat age ggt ggt agt age aca tac tat gca gac tecgtg Ser Val lie Tyr Ser Gly Gly Ser ser Thr Tyr Tyr Ala Asp SerVal 5560 aag ggc egg ttc. acc ate tcc aga gat aat tcc aag aac acg ctgtat Lys Gly Arg Phe Thr lie Ser Arg Asp Asn ser Lys Asn Thr LeuTyr 70 7580 ctg caa atg aac age ctg aga gcc gag gac acg gcc gta tat tactgt Leu Gin Met Asn ser Leu Arg Ala Glu Asp Thr Ala val Tyr Tyrcys 9095 geg aaa ga Ala Lys 144 192 240 288 296 <21O> 76 <211> 294 <212> DNA <213> Homo sapiens <22O> <221> CDS <222> (1)..(294) <400> 76 gag gtg cag ctg ttg gag tct ggg gga ggc ttg gta cag cct ggg ggg48 Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro GlyGly 1015 tcc ctg aga etc tcc tgt gca gcc tct gga ttc acc ttt age age tat96 Ser Leu Arg Leu Ser cys Ala Ala Ser Gly Phe Thr Phe Ser SerTyr 2530 gcc atg age tgg gtc ege cag get cca ggg aag gag ctg gag tgg gtc144 Ala Met Ser Trp val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trpval 4045 tea get att tat age agt ggt agt age aca tac tat gca gac tec gtg192 Ser Ala lie Tyr ser ser Gly Ser ser Thr Tyr Tyr Ala Asp setval 55 60’ aag ggc egg ttc acc ate tcc aga gac aat tcc aag aac acg ctg tat240 Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr LeuTyr 70 7580 ctg caa atg aac age ctg aga gcc gag gac acg gcc gta tat tac tgt288 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyrcys 9095 geg aaa294 Ala Lys <210> 77 <211> 98 <212> PRT <213> Homo sapiens <400> 77 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 Ala Ser 25 Gly Phe Thr Phe ser 30 Ser Tyr Ala Met Ser 35 Trp Val Arg Gin Ala 40 Pro Gly Lys Gly Leu 45 Glu Trp val Ser Ala 50 lie Tyr Ser Ser Gly 55 Ser Ser Thr Tyr Tyr 60 Ala Asp Ser val Lys 65 Gly Arg Phe Thr He 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 Ala val Tyr Tyr 95 Cys Ala Lys <210> 78 <211> 468 <212> PRT <213> Homo sapiens <400> 78 Met 1 Leu Ala val Gly 5 Cys Ala Leu Leu Ala 10 Ala Leu Leu Ala Ala 15 pro Gly Ala Ala Leu 20 Ala Pro Arg Arg Cys 25 pro Ala Gin Glu Val 30 Ala Arg Gly Val Leu 35 Thr Ser Leu Pro Gly 40 Asp Ser val Thr Leu 45 Thr Cys pro Gly Val 50 Glu Pro Glu Asp Asn 55 Ala Thr Val His Trp 60 Val Leu Arg Lys Pro 65 Ala Ala Gly Ser Hl S Pro Ser Arg Trp Ala 75 Gly Met Gly Arg Arg 80 Leu Leu Leu Arg ser 85 Val Gin Leu Hi s ASp 90 Ser Gly Asn Tyr Ser 95 Cys Tyr Arg Ala Gly 100 Arg Pro Ala Gly Thr 105 val His Leu Leu Val 110 Asp Val pro pro Glu 115 Glu Pro Gin Leu Ser 120 cys Phe Arg Lys Ser 125 Pro Leu Ser Asn val 130 val Cys Glu Trp Gly 135 Pro Arg Ser Thr Pro 140 Ser Leu Thr Thr Lys 145 Ala Val Leu Leu Val 150 Arg Lys Phe Gin Asn 155 Ser pro Ala Glu ASp 160 Phe Gin Glu Pro cys 165 Gin Tyr Ser Gin Glu .170 Ser Gin Phe ser 175 Cys Gin Leu val 180 Pro Glu Gly Asp ser 185 Ser Phe Tyr He val 190 ser Met cys Val Al a 195 Ser Ser Val Gly Ser 200 Lys Phe ser Lys Thr 205 Gin Thr Phe Gin Gly 210 Cys Gly He Leu Gin 215 Pro Asp Pro Pro Ala 220 Asn lie Thr val Thr 225 Ala val Ala Arg Asn 230 Pro Arg Trp Leu Ser 235 Val Thr Trp Gin Asp 240 Pro Hi s Ser Trp Asn 245 Ser Ser Phe Tyr Arg 250 Leu Arg Phe Glu Leu 255 Arg Tyr Arg Ala Glu 260 Arg Ser Lys Thr Phe 265 Thr Thr Trp Met Val 270 Lys Asp Leu Gin His His cys val lie His Asp Ala Trp Ser Gly Leu Arg Hi s 275 280 285 Val val Gin Leu Arg Ala Gin Glu Glu Phe Gly Gin Gly Glu Trp Ser 290 295300 Glu Trp Ser Pro Glu Ala Met Gly Thr Pro Trp Thr Glu Ser Arg ser 305 310 315320 Pro Pro Ala Glu Asn Glu val Ser Thr pro Met Gin Ala Leu Thr Thr 325 330335 Asn Lys Asp Asp Asp Asn lie Leu Phe Arg Asp Ser Ala Asn Ala Thr 340 345350 Ser Leu Pro val Gin Asp ser Ser Ser val Pro Leu Pro Thr Phe Leu 355 360365 Val Ala Gly Gly Ser Leu Ala Phe Gly Thr Leu Leu cys lie Ala lie 370 375380 Val Leu Arg Phe Lys Lys Thr Trp Lys Leu Arg Ala Leu Lys Glu Gly 385 390 395400 Lys Thr Ser Met His Pro Pro Tyr Ser Leu Gly Gin Leu Val Pro Glu 405 410415 Arg Pro Arg Pro Thr Pro val Leu val Pro Leu lie Ser Pro pro Val 420 425430 Ser Pro ser Ser Leu Gly Ser Asp Asn Thr Ser Ser His Asn Arg Pro 435 440445 Asp Ala Arg Asp Pro Arg Ser Pro Tyr Asp lie Ser Asn Thr Asp Tyr 450 455460 phe Phe pro Arg 465 <210> 79 <211> 1407 <212> DNA <213> Homo sapiens <400> 79 atgctggccg tcggctgcgc gctgctggct gccctgctgg ccgcgccggg agcggcgctg gccccaaggc gctgccctgc gcaggaggtg gcgagaggcg tgctgaccag tctgccagga gacagcgtga ctctgacctg cccgggggta gagccggaag acaatgccac tgttcactgg gtgctcagga agccggctgc aggctcccac cccagcagat gggctggcat gggaaggagg ctgctgctga ggtcggtgca gctccacgac tctggaaact attcatgcta ccgggccggc cgcccagctg ggactgtgca cttgctggtg gatgttcccc ccgaggagcc ccagctctcc tgcttccgga agagccccct cagcaatgtt gtttgtgagt ggggtcctcg gagcacccca 120 180 240 300 360 420 tccctgacga caaaggctgt gctcttggtg aggaagtttc agaacagtcc ggccgaagac480 ttccaggagc cgtgccagta ttcccaggag tcccagaagt tctcctgcca gttagcagtc540 ccggagggag acagctcttt ctacatagtg tccatgtgcg tcgccagtag tgtcgggagc600 aagttcagca aaactcaaac ctttcagggt tgtggaatct tgcagcctga tccgcctgcc660 aacatcacag tcactgccgt ggccagaaac ccccgctggc tcagtgtcac ctggcaagac720 ccccactcct ggaactcatc tttctacaga ctacggtttg agctcagata tcgggctgaa780 cggtcaaaga cattcacaac atggatggtc aaggacctcc agcatcactg tgtcatccac840 gacgcctgga gcggcctgag gcacgtggtg cagcttcgtg cccaggagga gttcgggcaa900 ggcgagtgga gcgagtggag cccggaggcc atgggcacgc cttggacaga atccaggagt960 cctccagctg agaacgaggt gtccaccccc atgcaggcac ttactactaa taaagacgat1020 gataatattc tcttcagaga ttctgcaaat gcgacaagcc tcccagtgca agattcttct1080 tcagtaccac tgcccacatt cctggttgct ggagggagcc tggccttcgg aacgctcctc1140 tgcattgcca ttgttctgag gttcaagaag acgtggaagc tgcgggctct gaaggaaggc1200 aagacaagca tgcatccgcc gtactctttg gggcagctgg tcccggagag gcctcgaccc1260 accccagtgc ttgttcctct catctcccca ccggtgtccc ccagcagcct ggggtctgac1320 aatacctcga gccacaaccg accagatgcc agggacccac ggagccctta tgacatcagc1380 aatacagact acttcttccc cagatag1407 <210> 80 <211> 990 <212> ONA <213> Homo sapiens <400> 80 gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg60 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg120 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc240 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc,300 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga360 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct420 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg480 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac540 agcacgtacc gggtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag600 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc660 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag720 ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc780 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg840 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 900 960 990 <210> <211> <212> <213> 330 PRT Homo sapiens <400> Ala 1 Ser Thr Lys Gly 5 Pro Ser val Phe Pro 10 Leu Ala Pro Ser ser Lys Ser Thr Ser Gly 20 Gly Thr Ala Ala Leu 25 Gly cys Leu val Lys 30 Asp Tyr Phe Pro Glu 35 Pro Val Thr Val Ser Trp Asn Ser Gly Ala 45 Leu Thr Ser Gly Val 50 Hi s Thr Phe Pro Ala 55 val Leu Gin Ser Ser 60 Gly Leu Tyr Ser Leu 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 Hi s Lys Pro Ser 90 Asn Thr Lys val ASp 95 Lys iys val Glu Pro 100 Lys Ser cys Asp Lys 105 Thr His Thr cys Pro 110 Pro cys Pro Ala Pro 115 G1 u Leu Leu Gly Gly 120 Pro ser val Phe Leu 125 Phe Pro Pro Lys Pro 130 Lys Asp Thr Leu Met 135 lie Ser Arg Thr Pro 140 Glu Val Thr 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 Ala 170 Lys Thr Lys Pro Arg 175 Glu Glu 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 210 Leu Pro Ala Pro lie 215 Glu Lys Thr lie Ser 220 Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Al Lys Ala Lys Gly 225 230 235 240 Leu Thr Lys Asn Gin Val 245 Ser Leu Thr cys Leu val Lys Gly Phe Tyr Pro Ser ASp lie 260 Ala Val Glu Trp Glu 265 Ser Asn Gly Gin Pro 270 Glu Asn Asn Tyr Lys 275 Thr Thr Pro Pro Val 280 Leu ASp Ser Asp Gly 285 ser Phe Phe Leu Tyr 290 ser Lys Leu Thr val 295 Asp Lys Ser Arg Trp 300 Gin Gin Gly Asn Val 305 Phe ser Cys Ser Val 310 Met His Glu Ala Leu 315 Hi s Asn His Tyr Thr 320 Gin Lys ser Leu Ser 325 Leu ser Pro Gly Lys 330 <210> 82 <211> 978 <212> DNA <213> Homo sapiens <400> 82 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 <210> 83 <211> 326 <212> PRT <213> Homo <400> 83 Ala Ser Thr 1 sapiens Lys Gly Pro 5 Ser Val Phe Pro 10 Leu Ala Pro Cys Ser 15 Arg ser Thr ser Glu 20 Ser Thr Al a Ala 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 50 Hi s 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 Asn 75 Phe Gly Thr Gin Thr 80 Tyr Thr Cys Asn val 85 ASP Hi s Lys Pro Ser 90 Asn Thr Lys Val Asp 95 Lys Thr Val Glu Arg 100 Lys cys cys Val Glu 105 Cys Pro Pro Cys Pro 110 Ala Pro Pro Val Ala 115 Gly pro ser val Phe 120 Leu Phe pro pro Lys 125 Pro Lys Asp Thr Leu 130 Met lie ser Arg Thr 135 Pro Glu Val Thr cys 140 val Val Val Asp Val 145 Ser Hi s Glu Asp Pro 150 Glu Val Gin Phe Asn 1.55 Trp Tyr val Asp Gly 160 Val Glu Val Hi s Asn 165 Ala Lys Thr Lys Pro 170 Arg Glu Glu Gin Phe. 175 Asn Ser Thr Phe Arg 180 val val Ser val Leu 185 Thr Val val His Gin 190 Asp Trp Leu Asn Gly 195 Lys Glu Tyr Lys cys 200 Lys val ser Asn Lys 205 Gly Leu Pro Ala Pro 210 lie Glu Lys Thr He 215 ser Lys Thr Lys Gly 220 Gin Pro Arg Glu Pro 225 Gin val Tyr Thr Leu 230 Pro pro Ser Arg Glu 235 Glu Met Thr Lys Asn 240 Gin Val Ser Leu Thr 245 cys Leu val Lys Gly 250 phe Tyr Pro Ser Asp 255 lie Ala ’ Val ' Glu Trp 260 Glu ser Asn Gly Gin 265 pro Glu Asn Asn Tyr 270 Lys Thr Thr Pro Leu Thr 290 ser val 305 pro Met 275 val Asp Met His Leu Asp Lys Ser Glu Ala 310 Ser Asp 280 Arg Trp 295 Leu His Gly ser Gin Gin Asn Hi s Phe Phe Gly Asn 300 Tyr Thr 315 Leu Tyr 285 val Phe Gin Lys Ser Lys Ser Cys Ser Leu 320 Ser Leu Ser Pro Gly Lys 325 <210> 84 <211> 298 <212> DNA <213> Homo sapiens <400> 84 gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagata 120 180 240 298 <210> 85 <211> 99 <212> PRT <213> Homo sapiens <400> 85 Glu val Gin Leu val Glu ser Gly 1 5 Gly Gly Leu Val Gin pro Gly Arg Ser Leu Arg Leu Ser cys Ala Ala 20 Ser Gly Phe Thr Phe Asp Asp Tyr 25 30 Ala Met His Trp val Arg Gin Ala 35 40 Pro Gly Lys Gly Leu Glu Trp val ‘ 45 Ser Gly lie Ser Trp Asn Ser Gly 50 55 Ser lie Gly Tyr Ala Asp ser val 60 Lys Gly Arg Phe Thr lie Ser Arg 65 70 Asp Asn Ala Lys Asn Ser Leu Tyr 75 80 Leu Gin Met Asn Ser Leu Arg Ala 85 Glu Asp Thr Ala Leu Tyr Tyr Cys 95 Ala Lys Asp <210> 86 /fc <211> 296 <212> DNA <213> Homo sapi ens <400> 86 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc tcctgtgcag cctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaatactat gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaga 120 180 240 296 <210> 87 <211> 98 <212> PRT <213> Homo sapiens <400> 87 Glu 1 val Gin Leu Val 5 Glu Ser Gly Gly Gly 10 Leu val Gin Pro Gly 15 Gly Ser Leu Arg Leu Ser 20 Cys Ala Ala Ser 25 Gly Phe Thr phe ser 30 Ser Tyr Trp Met Ser 35 Trp val Arg Gin Ala 40 pro Gly Lys Gly Leu Glu 45 Trp val Ala Asn 50 lie Lys Gin ASp Gly Ser 55 Glu Lys Tyr Tyr 60 Val Asp Ser Val Lys 65 Gly Arg Phe Thr lie 70 Ser Arg Asp Asn Ala Lys 75 Asn Ser Leu Tyr 80 Leu Gin Met Asn Ser 85 Leu Arg Ala G1 u Asp 90 rhr Ala Val Tyr Tyr 95 cys Ala Arg <210> 88 <211> 50 <212> DNA <213> Homo sapiens <400> 88 tgatgctttt gatatctggg gccaagggac aatggtcacc gtctcttcag <210> 89 <211> 16 <212> PRT <213> Homo sapiens <400> 89 Asp Ala Phe Asp lie Trp Gly Gin Gly Thr Met val Thr Val Ser Ser 15 10 15 <210> 90 <211> 63 <212> DNA <213> Homo sapiens <400> 90 attactacta ctactacggt atggacgtct gggggcaagg gaccacggtc accgtctcct cag <210> 91 <211> 20 <212> PRT <213> Homo sapiens <400> 91 Tyr Tyr Tyr Tyr Tyr Gly Met Asp val Trp Gly Gin Gly Thr Thr val Thr val ser Ser <210> 92 <211> 321 <212> DNA <213> Homo sapiens <400> 92 cgaactgtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct60 ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag120 tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac180 agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag240 aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag300 agcttcaaca ggggagagtg t321 <210> 93 <211> 107 <2L2> PRT <213> Homo sapiens <400> 93 Arg Thr Val Ala Ala Pro Ser val Phe lie Phe Pro Pro ser Asp Glu Gin Leu Lys ser Gly Thr Ala ser Val val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys val Asp Asn Ala Leu Gin 35 40 45 ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys val Tyr Ala cys Glu Val Thr His Gin Gly Leu ser Ser pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 94 <211> 312 <212> DNA <213> Homo <400> 94 cccaaggcca aaggccacac aaggcagatg aacaacaagt agaagctaca acagaatgtt sapiens accccacggt tagtgtgtct gcagccccgt acgcggccag gctgccaggt. ca cactctgttc. gatcagtgac caaggcggga cagctacctg cacgcatgaa ccgccctcct ttctacccgg gtggagacga agcctgacgc gggagcaccg ctgaggagct gagctgtgac ccaaaccctc ccgagcagtg tggagaagac ccaagccaac agtggcttgg caaacagagc gaagtcccac agtggcccct 120 180 240 300 312 <210> 95 <211> 104 <212> PRT <213> Homo sapiens <400> 95 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser ser Glu Glu 1015 Leu Gin Ala Asn Lys Ala Thr Leu val Cys Leu lie Ser Asp Phe Tyr 20 2530 Pro Gly Ala val Thr val Ala Trp Lys Ala Asp Gly ser Pro val Lys 35 4045 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gin Ser Asn Asn Lys Tyr 50 5560 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gin Trp Lys Ser His 65 70 7580 Arg ser Tyr ser cys Gin val Thr His Glu Gly ser Thr val Glu Lys 85 9095 Thr val Ala Pro Thr Glu Cys Ser 100 <210> 96 <211* 287 <212> DNA <213> Homo sapiens <400> 96 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120 Gt gggaaagccc ctaagctcct aggttcagcg gcagtggatc gaagattttg caacttacta gatctatgct gcatccagtt tgggacagat ttcactctca ttgtcaacag gctaacagtt tgcaaagtgg ggtcccatca ccatcagcag cctgcagcct tccctcc 180 240 287 <210> 97 <211> 95 <212> PRT <213> Homo sapiens <400> 97 Asp lie Gin Met Thr Gin Ser Pro 1 5 ser Ser val ser Ala ser val Gly Asp Arg Val Thr lie Thr Cys Arg ' Ala ser Gin Gly lie Ser ser Trp 25 30 Leu Ala Trp Tyr Gin Gin Lys Pro 40 Gly Lys Ala Pro Lys Leu Leu lie 45 Tyr Ala Ala Ser ser Leu Gin ser 50 55 Gly val Pro ser Arg Phe ser Gly Ser Gly ser Gly Thr Asp Phe Thr 65 70 Leu Thr lie Ser Ser Leu Gin Pro 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys 85 Gin Gin Ala Asn Ser Phe pro 95 <210> 98 <211> 287 <212> DNA <213> Homo sapiens <400> 98 gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctcc 120 180 240 287 <210> 99 <211> 95 <212> PRT <213> Homo sapiens <400> 99 Glu lie val Leu Thr Gin Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 15 1015 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Tyr 20 2530 Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie 35 4045 /5 Tyr Asp Ala ser Asn Arg Ala Thr Gly lie Pro Ala Arg Phe ser Gly 50 55 60 ser 65 Gly Ser Gly Thr Asp 70 Phe Thr Leu Thr lie Ser 75 Ser Leu Glu Pro 80 G1 u Asp Phe Ala Val Tyr Tyr Cys Gin Gin Arg Ser Asn Trp Pro 85 90 95 <210> 100 <211> 39 <212> DNA <213> Homo sapiens <400> 100 tgtacacttt tggccagggg accaagctgg agatcaaac <210> 101 <211> 12 <212> PRT <213> Homo sapiens <400> 101 Tyr Thr phe Gly Gin Gly Thr Lys Leu Glu He Lys 10 <210> 102 <211> 38 <212> DNA <213> Homo sapiens <400> 102 gctcactttc ggcggaggga ccaaggtgga gatcaaac <210> 103 <211> 12 <212> PRT <213> Homo sapiens <400> 103 Leu Thr phe Gly Gly Gly Thr Lys 1 5 Val Glu lie Lys <210> 104 <211> 446 <212> PRT <213> Homo sapiens <400> 104 Glu val Gin Leu val Glu ser Gly 1 5 Gly Gly Leu Val Gin Pro Gly Arg ser Leu Arg Leu ser cys Ala Ala 20 Ser Arg phe Thr Phe Asp Asp Tyr 25 30 Ala Met His Trp val Arg Gin Ala 35 40 pro Gly Lys Gly Leu Glu Trp val 45 iso Ser Gly He Ser Trp Asn Ser 55 Gly Arg lie Gly Tyr 60 Al a Asp Ser val Lys 65 Gly Arg Phe Thr He 70 Ser Arg Asp Asn Ala 75 Glu Asn Ser Leu Phe 80 Leu Gin Met Asn Gly 85 Leu Arg Ala Glu Asp 90 Thr Ala Leu Tyr Tyr 95 Cys Ala Lys Gly Arg 100 Asp Ser Phe Asp lie 105 Trp Gly Gin Gly Thr 110 Met Val Thr Val Ser 115 Ser Ala Ser Thr Lys 120 Gly Pro Ser Val Phe 125 Pro Leu Ala Pro Ser 130 Ser Lys Ser Thr ser 135 Gly Gly Thr Al a Ala 140 Leu Gly Cys Leu val 145 Lys Asp Tyr Phe Pro 150 Glu Pro val Thr val 155 Ser Trp Asn Ser Gly 160 Ala Leu Thr Ser Gly 165 Val His Thr Phe Pro 170 Ala val Leu Gin Ser 175 Ser Gly Leu Tyr ser 180 Leu ser Ser Val val 185 Thr val pro Ser Ser 190 Ser Leu Gly Thr Gin 195 Thr Tyr lie Cys Asn 200 val Asn His Lys Pro 205 ser Asn Thr Lys val 210 Asp Lys Lys val Glu 215 Pro Lys Ser Cys Asp 220 Lys Thr Hi s Thr Cys 225 Pro Pro Cys Pro a! a 230 Pro Glu Leu Leu Gly 235 Gly Pro Ser Val Phe 240 Leu Phe Pro Pro Lys 245 pro Lys Asp Thr Leu 250 Met Tie SetArg Thr 255 pro Glu val Thr cys 260 val Val val Asp val 265 Ser Hi s Glu ASP Pro 270 Glu Val Lys Phe Asn 275 Trp Tyr val Asp Gly 280 val Glu val Hi s Asn 285 Ala Lys Thr Lys Pro 290 Arg Glu Glu Gin Tyr 295 Asn ser Thr Tyr Arg 300 Val val ser val Leu 305 Thr val Leu His Gl n 310 Asp Trp Leu Asn Gly 315 Lys Glu Tyr Lys Cys 320 Lys val Ser Asn Lys 325 Al a Leu Pro Ala Pro 330 He Glu Lys Thr lie 335 Ser Lys Ala Lys Gly Gin Pro Arg Glu 340 Pro Gin Val Thr Tyr Leu Pro Pro 345 350 Ser Arg Asp Glu Leu Thr Lys Asn 355 360 Gin val Ser Leu Thr Cys Leu val 365 Lys Gly Phe Tyr pro Ser Asp lie 370 375 Ala val Glu Trp Glu ser Asn Gly 380 Gin Pro Glu Asn Asn Tyr Lys Thr 385 390 Thr Pro Pro Val Leu Asp ser Asp 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys 405 Leu Thr val Asp Lys Ser Arg Trp 410 415 Gin Gin Gly Asn Val Phe Ser Cys 420 Ser Val Met His Glu Ala Leu His 425 430 Asn His Tyr Thr Gin Lys Ser Leu 435 440 Ser Leu Ser pro Gly Lys 445 <210> 105 <211> 214 <212> PRT <213> Homo sapiens <400> 105 Asp lie Gin Met Thr Gin Ser Pro ser Ser val ser Ala ser val Gly 15 1015 Asp Arg val Thr Ue Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 2530 Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala pro Lys Leu Leu lie 35 4045 Tyr Gly Ala Ser Ser Leu Glu ser Gly Val Pro ser Arg Phe ser Gly 50 5560 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 7580 Glu Asp Phe Ala Ser Tyr Tyr Cys Gin Gin Ala Asn Ser Phe Pro Tyr 85 9095 Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg Thr val Ala Ala 100 105110 Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys ser Gly 115 120125 Thr Ala Ser Val val cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135140 Lys Val 145 Gin Trp Lys Val 150 Asp Asn Ala Leu Gin 155 ser Gly Asn Ser Gin 160 Glu ser val Thr Glu 165 Gin Asp ser Lys Asp 170 Ser Thr Tyr Ser Leu 175 ser Ser Thr Leu Thr 180 Leu Ser Lys Ala ASp 185 Tyr Glu Lys His Lys 190 Val Tyr Ala cys Glu 195 Val Thr His Gin Gly 200 Leu Ser Ser Pro val 205 Thr Lys ser Phe Asn 210 Arg Gly G1 u cys <210> 106 <211> 449 <212> PRT <213> Homo sapiens <400> 106 Glu Val Gin Leu val Glu ser Gly 1 5 Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu ser cys Ala Ala 20 Ser Gly Phe Thr Phe Ser Pro Phe 25 30 Ala Met Ser Trp Val Arg Gin Ala 35 40 Pro Gly Lys Gly Leu Glu Trp val Ala Lys lie Ser Pro Gly Gly Ser 50 55 Trp Thr Tyr Tyr Ser Asp Thr val 60 Thr Gly Arg phe Thr lie Ser Arg 65 70 Asp Asn Ala Lys Asn Ser Leu Tyr 75 80 Leu Gin Met Asn ser Leu Arg Ala 85 Glu Asp Thr Ala Val Tyr Tyr cys 90 95 Ala Arg Gin Leu Trp Gly Tyr Tyr 100 Ala Leu Asp lie Trp Gly Gin Gly 105 110 Thr Thr val Thr val ser ser Ala 115 120 Ser Thr Lys Gly Pro Ser val Phe 125 Pro Leu Ala Pro ser Ser Lys Ser 130 135 Thr set Gly Gly Thr Ala Ala Leu 140 Gly Cys Leu Val Lys Asp Tyr Phe 145 150 Pro Glu Pro Val Thr val Ser Trp 155 160 Asn Ser Gly Ala Leu Thr set Gly 165 Val His Thr Phe Pro Ala val Leu 170 175 Gin Ser Ser Gly Leu Tyr Ser Leu ser ser val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu 195 Gly Thr Gin Thr Tyr 200 lie Cys Asn Val Asn 205 Hi s Lys Pro ser Asn 210 Thr Lys Val Asp Lys 215 Lys val Glu pro Lys 220 Ser cys Asp Lys Thr 225 Hi s Thr Cys Pro Pro 230 cys Pro Ala Pro Glu 235 Leu Leu Gly Gly Pro 240 ser Val Phe Leu Phe 245 Pro Pro Lys Pro Lys 250 Asp Thr Leu Met lie 255 Ser Arg Thr Pro Glu 260 val Thr Cys val Val 265 Val Asp Val ser His 270 Glu Asp Pro Glu Val 275 Lys Phe Asn trp Tyr 280 Val Asp Gly val Glu 285 Val Hi s Asn Al a Lys 290 Thr Lys Pro Arg Glu 295 Glu Gin Tyr Asn ser 300 Thr Tyr Arg val Val 305 Ser Val Leu Thr val 310 Leu His Gin Asp Trp 315 Leu Asn Gly Lys Glu 320 Tyr Lys cys Lys Val 325 Ser Asn Lys Ala Leu 330 Pro Ala Pro lie Glu 335 Lys rhr He Ser Lys 340 Ala Lys Gly Gin Pro 345 Arg Glu Pro Gin Val 350 Tyr Thr Leu pro Pro 355 Ser Arg Asp Glu Leu 360 Th r Lys Asn Gin Val 365 ser Leu Thr cys Leu 370 val Lys Gly Phe ryr 375 Pro Ser Asp He Ala 380 Val Glu Trp Glu Ser 385 Asn Gly Gin Pro Gl u 390 Asn Asn Tyr Lys Thr 395 Thr Pro Pro Val Leu 400 Asp Ser ASp Gly Ser 405 Phe Phe Leu Tyr Ser 410 Lys Leu Thr Val Asp 415 Lys ser Arg Trp Gin 420 Gin Gly Asn val Phe 425 Ser cys Ser val Met 430 His Glu Ala Leu His 435 Asn His Tyr Thr Gin 440 Lys ser Leu ser Leu 445 ser Pro Gly Lys <210> 107 <211> 213 <212> PRT <213> Homo sapiens <400> 107 Glu lie Val Leu Thr Gin Ser Pro Ala Thr leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Ser Ala ser lie ser Val Ser Tyr Met 20 2530 Tyr Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie Tyr 35 40'45 Asp Met Ser Asn Leu Ala Ser Gly lie Pro Ala Arg Phe Ser Gly Ser 50 5560 Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Glu Pro Glu 65 70 7580 Asp Phe Ala Val Tyr Tyr Cys Met Gin Trp Ser Gly Tyr Pro Tyr Thr 85 9095 Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala Pro 100 105110 Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr 115 120125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135140 Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu 145 150 155160 Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170175 Thr Leu Thr Leu ser Lys Ala Asp Tyr Glu Lys His Lys val Tyr Ala 180 185190 Cys Glu val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200205 Asn Arg Gly Glu cys 210 <210> 108 <211> 24 <212> DNA <213> Homo sapiens <400> 108 ggattcacct ttgatgatta tgcc <210> 109 <211> 8 <212> PRT <213> Homo sapiens <400> 109 Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <2io> no <211> 114 <212> DNA <213> Homo sapiens <400> 110 ggctatgcgg actctgtgaa gggccgattc accatctcca gagacaacgc caagaactcc ctgtatctgc aaatgaacag tctgagagct gaggacacgg ccttgtatta ctgt 114 <210> 111 <211> 38 <212> PRT <213> Homo sapiens <400> 111 Gly Tyr Ala 1 Asp Ser Val 5 Lys Gly Arg Phe Thr 10 He Ser Arg Asp 15 Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp 30 Thr Ala Leu Tyr Tyr Cys 35 <210> 112 <211> 23 <212> DNA <213> Homo sapiens <400> 112 cagcagcgta gcaactggcc tcc <210> 113 <211> 7 <212> PRT <213> Homo sapiens <400> 113 Gin Gin Arg ser Asn Trp Pro 1 5 <210> 114 <211> 108 <212> DNA <213> Homo sapiens <400> 114 aacagggcca ctggcatccc agccaggttc agtggcagtg ggtctgggac agacttcact ctcaccatca gcagcctaga gcctgaagat tttgcagttt attactgt 108 <210> 115 <211> 36 <212> PRT <213> Homo sapiens <400> 115 Asn Arg Ala Thr Gly lie Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly 15 Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Glu Pro Glu Asp Phe Ala 20 25 30 Val Tyr Tyr Cys 35

Claims (5)

Claims:

1. An injectable preparation comprising an antibody or antibody fragment for use in a method of treating or reducing the risk of rheumatoid arthritis in a human in need thereof, wherein the antibody or fragment specifically binds an IL6R protein that comprises a mutation Asp.358Ala or Val385Ile in SEQ ID NO: 78 and 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 (i) a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109, wherein said human comprises a VH gene segment encoding a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109, or the human expresses VH domains that comprise a CDR1 comprising a Phe at position 4 shown in SEQ ID NO: 109; or (ii) a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 111, wherein said human comprises a VH gene segment encoding a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 111 or the human expresses VH domains that comprise a FW3 comprising a Thr at position 33 shown in SEQ ID NO: 111; and wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358AIa or Val385Ile in SEQ ID NO: 78.

2. An injectable preparation comprising an antibody or antibody fragment for use in a method of treating or reducing the risk of rheumatoid arthritis in a human in need thereof, wherein the antibody or fragment specifically binds an IL6R protein that comprises a mutation Asp358Ala or Val385Ile in SEQ ID NO: 78 and comprises a VH domain derived from the recombination of a human VH gene segment, a human D gene segment and a human JH segment, the human VH gene segment comprising (a) T at nucleotide number 86 shown in SEQ ID NO: 84 and wherein said human comprises a VH gene segment comprising T at nucleotide number 86 shown in SEQ ID NO: 84; or (b) C at nucleotide number 272 shown in SEQ ID NO: 84 and wherein said human comprises a VH gene segment comprising C at nucleotide number 272 shown in SEQ ID NO: 84; and 498 wherein said human comprises a nucleotide sequence encoding said IL6R protein comprising said Asp358Ala or Val385IIe in SEQ ID NO: 78.

3. The preparation of claim 1 or claim 2, wherein the antibody or fragment comprises a human gamma-1 heavy chain comprising said VH domain and a human gamma-1 heavy chain constant region that comprises an Asp at position 204 shown in SEQ ID NO: 81 and a Leu at position 206 shown in SEQ ID NO: 81 and wherein said human comprises an IGHGI *01 human heavy chain constant region gene segment

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

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