KR20230107696A - 저-점도 항원 결합 단백질 및 이의 제조 방법 - Google Patents
저-점도 항원 결합 단백질 및 이의 제조 방법 Download PDFInfo
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Abstract
본 발명은 감소된 점도를 갖는 항원 결합 단백질의 제조 방법에 관한 것이다. 이러한 방법은 고점도 가변 도메인 서브패밀리의 잔기를 상관관계가 있는 저점도 서브패밀리의 잔기로 대체함으로써 진행된다. 이러한 방법은 Fc 도메인 내의 잔기를 저점도와 연관된 잔기로 치환하고, 하전된 잔기를 Fc 도메인의 C-말단에 첨가하는 단계를 추가로 포함한다. 본 발명은 추가로, 이러한 방법에 의해 제조된 항원 결합 단백질에 관한 것이다.
Description
[관련 출원에 대한 교차 참조]
본 출원은 2017년 8월 16일에 출원된 미국 가출원 62/546,469; 2016년 12월 6일에 출원된 미국 가출원 62/430,773; 및 2016년 9월 29일에 출원된 미국 가출원 62/401,770의 우선권을 주장하며, 이들은 각각 그 전체가 모든 목적을 위해 원용에 의해 본 명세서에 포함된다.
[기술분야]
본 발명은 생물약제, 특히 치료적 항원 결합 단백질, 이의 사용 방법, 이의 약제학적 조성물 및 이들의 제조 방법에 관한 것이다. 특히, 본 발명은 점도를 감소시키도록 돌연변이화된 항원 결합 단백질, 특히 항체에 관한 것이다.
[서열 목록에 대한 간단한 설명]
서열번호: 1 내지 서열번호: 383을 포함하는 "A-2063-WO-PCT_ST25"라는 명칭의 서열 목록은 그 전체가 원용에 의해 본 명세서에 포함되며, 이러한 서열 목록은 본원에 개시된 핵산 및/또는 아미노산 서열을 포함한다. 서열 목록은 EFS를 통해 ASCII 텍스트 포맷으로 본 명세서에 제출되었으며, 따라서, 이의 종이 및 컴퓨터 판독 가능 형태를 둘 다 구성한다. 서열 목록은 처음에 2017년 8월 16일에 PatentIn을 사용하여 생성되었고, 그 크기는 4.32 MB이다.
현재, 모노클로날 항체(mAb)는, 판매중이고 개발 하에 있는 현대의 치료적 단백질의 가장 인기있는 양상이다. 항체들 사이의 차이는 주로 항원 결합 도메인 또는 상보성 결정 영역(CDR)에 있다. CDR에서의 이들 차이는, 일시적인 단백질-단백질 상호작용 경향의 차이를 초래하며, 이는 이들 자체를 벌크 용액 점도로서 나타내는 것으로 생각된다. 몇몇 그룹은 점성 항체 용액(주로 이량체) 내에서 항체의 가역적 클러스터의 존재를 기재하였다. 중합체 점도의 몇몇 이론적 설명은 이들 클러스터의 상호작용을 벌크 용액 점도 거동에 대한 기전으로서 설명하기 위해 제안되었다.
항체는 통상적으로 길항제로서 작용하며, 따라서, 요망되지 않는 상호작용을 차단하기 위해서는 종종 1회 용량 당 100 mg을 초과하는 다량이 필요하다. 환자의 편안함을 위해, 1 mL 부피의 단일 피하 주사가 가장 바람직한 투여 방식이다. 비교적 작은 부피로 다량의 mAb를 투여하는 필요성은 100 mg/ml 이상의 고농도 제제를 필요로 하였다. 항체는 분자량이 약 150 kDa인 큰 생물중합체이고, 이들의 고농도는 여과 및 주사 바늘을 통한 통과 중 피하 공간 내에서 단백질-단백질 및 단백질-벽 상호작용으로 인해 고전단응력 및 고점도를 초래한다. 고점도는 치료적 항원 결합 단백질의 제조뿐만 아니라 환자에게 이들 단백질의 투여 시, 주사 동안의 엄청나게 높은 배압으로 인해 주사 장치의 기능 부전, 수동 투여의 어려움, 저하된 생체이용률, 및 환자 불편의 초래를 포함한 문제점을 제시한다.
생물약제 제조 비용이 저하됨에 따라, 고농도 치료적 모노클로날 항체 용액의 개발 및 이용이 가속화되었다. 일부 경우, 이들 항체 용액은 의도된 용량 시도의 제조 및 투여를 가능하게 할 수 있는 점성 용액 속성을 가진다. 항체가 "점성" 또는 "비점성"인지 결정하는 것으로 보이는 CDR의 차이는, 단백질-단백질 상호작용을 추진시키는 CDR의 경향과 관련이 있는 것 같다.
고점도를 초래하는 상호작용의 성질을 이해하고 고점도 항체 제제의 점도를 감소시키기 위한 상당한 노력이 산업에서 이루어지고 있다. 항체 제제의 점도에 영향을 주는 가장 중요한 매개변수는 하기를 포함한다:
· 단백질의 pI 및 용액의 pH에 의해 정의되는 분자간 상호작용. 문헌[Cheng et al. (2013), "Linking the solution viscosity of an IgG2 monoclonal antibody to its structure as a function of pH and temperature," J. Pharm Sci . 102: 4291-4304].
· 전하 상호작용. 문헌[Yadav et al.(2012), "Viscosity behavior of high-concentration monoclonal antibody solutions: correlation with interaction parameter and electroviscous effects," J. Pharm Sci. 101: 998-1011; Yadav et al. (2012), "The influence of charge distribution on self-association and viscosity behavior of monoclonal antibody solutions." Mol Pharm 9(4): 791-802; Singh et al. (2014), "Dipole-Dipole Interaction in Antibody Solutions: Correlation with Viscosity Behavior at High Concentration," Pharm Res . 31(9): 2549-2558; Chaudhri et al. (2013), "The role of amino acid sequence in the self-association of therapeutic monoclonal antibodies: insights from coarse-grained modeling," J. Phys. Chem. B 117: 1269-1279].
· 소수성 상호작용. 문헌[Guo et al. (2012),"Structure-activity relationship for hydrophobic salts as viscosity-lowering excipients for concentrated solutions of monoclonal antibodies," Pharm Res 29: 3102-3109].
최고 용액 점도는 가장 음의(negative) 확산 상호작용 매개변수 kD, 최고 겉보기 반경 및 최저 순전하를 갖는 조건 하에 관찰되었다. 문헌[Neergaard et al. (2013), "Viscosity of high concentration protein formulations of monoclonal antibodies of the IgG1 and IgG4 subclass - prediction of viscosity through protein-protein interaction measurements," Eur. J. Pharm Sci . 49: 400-410]. 삼투 이차 비리얼 계수(B(2); osmotic second virial coefficient)의 구성성분인 확산 상호작용 매개변수(kD)는 농축된 mAb 용액의 점도와 양호한(R은 0.9 초과) 상관관계에 있는 한편, mAb 순전하는 약한(R은 0.6 미만) 상관관계에 있었으며, 이는, 약한 분자간 상호작용이 농축된 mAb 용액의 점탄성 거동을 지배하는 데 중요함을 가리킨다. 문헌[Connolly, et al. (2012), "Weak interactions govern the viscosity of concentrated antibody solutions: high-throughput analysis using the diffusion interaction parameter," Biophys. J . 103: 69-78]. 이 명세서에서 보고된 연구에서, 3D 구조에 연결된 일차 서열이 이용되었다. 문헌[Honegger et al. (2001), "Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool," J. Mol. Biol . 309: 657-670]을 참조한다. 몇몇 mAb 분자들의 점도값을 측정하여, 기계 학습 알고리즘(machine learning algorithm)을 통한 mAb의 점도 예측 모델을 개발하였다. 구조적 위치, 전하 및 소수성은 이러한 모델에 이용된 아미노산의 주요 매개변수였다.
모노클로날 항체의 점도는 하기 문헌의 분자 정보를 사용하여 평가되었다: 문헌[Li, L. et al. (2014), "Concentration dependent viscosity of monoclonal antibody solutions: explaining experimental behavior in terms of molecular properties," Pharm. Res . 31: 3161-3178; 및 Sharma et al. (2014), "In silico selection of therapeutic antibodies for development: viscosity, clearance, and chemical stability," Proc. Natl. Acad. Sci. U. S. A 111: 18601-6].
항체들 사이의 상호작용의 최종(net) 결과는, 점성 용액을 초래하는 상호작용의 연장된 일시적 네트워크(침투(percolating) 네트워크), 또는 이후에 더 큰 구조로서 용액 유동성(rheology)에 다소 영향을 주는 더 큰 올리고머의 형성이다. 이 명세서에서 보고된 연구에서는, 점성 항체 용액을 초래하게 될 특이적인 단백질-단백질 상호작용을 추론하려는 시도에서, 적은 수의 점성 항체가 생화학적 및 생물물리학적 분석을 위한 대상으로서 사용되었다.
안정성 및 다른 생물물리학적 특성을 개선하기 위해 Aho 넘버링 접근법이 과거에 이용되었다. 문헌[Ewert et al. (2003), "Structure-based improvement of the biophysical properties of immunoglobulin VH domains with a generalizable approach," Biochemistry 42: 1517-1528; Ewert et al. (2003), "Biophysical properties of human antibody variable domains," J. Mol. Biol . 325: 531-553; Ewert et al. (2004), "Stability improvement of antibodies for extracellular and intracellular applications: CDR grafting to stable frameworks and structure-based framework engineering," Methods 34: 184-199; 및 Rothlisberger et al. (2005), "Domain interactions in the Fab fragment: a comparative evaluation of the single-chain Fv and Fab format engineered with variable domains of different stability," J Mol. Biol . 347: 773-789]. Aho 넘버링 시스템은 또한 과거에, 응집 경향을 감소시키는 데 이용되었다. Borras et al. (2013), 미국 특허 8,545,849.
본 발명은 고점도와 연관이 있는 것으로 나타난 프레임워크 영역 및/또는 Fc 도메인 내의 서열을 변형시킴으로써 항원 결합 단백질의 점도를 감소시키는 방법에 관한 것이다.
후속하는 공정 상세 사항에서, 모든 가변 영역 아미노산은 Aho 넘버링에 의해 식별되고, 보존 영역으로부터의 모든 아미노산은 EU 넘버링에 의해 식별된다. Aho 넘버링은 정렬되고, EU(문헌[Edelman et al. (1969), "The covalent structure of an entire gamma immunoglobulin molecule," Proc. Natl. Acad. Sci. U. S. A . 63, 78-85]), Kabat(문헌[Kabat et al. (1991), Sequences of proteins of immunological interest, Fifth Edition. NIH Publication No. 91-3242]), Chothia(문헌[Chothia et al., (1992), "Structural repertoire of the human VH segments," J.Mol.Biol . 227: 799-817); (문헌[Tomlinson et al., (1995), "The structural repertoire of the human V kappa domain," EMBO J 14: 4628-4638])를 포함한 다른 주요 넘버링 체계와 상관관계된다. 4개의 넘버링 시스템 중 임의의 시스템은 상호교환적으로 사용되어, 본 명세서에서 기재된 바람직한 아미노산 치환을 식별할 수 있다.
항원 결합 단백질이 VH1|1-18 생식선(germline) 서브패밀리를 포함하는 경우, 본 방법은 82X1, 94X2 및 95X3으로부터 선택되는 하나 이상의 치환을 포함하도록 VH1 서열을 변형시키는 단계를 포함하며, 여기서, X1은 염기성 잔기(R, K 또는 H)이며, X2는 극성, 비하전된 잔기(S, T, N 또는 Q)이고, X3은 염기성 잔기(R, K 또는 H)이다. 모든 잔기는 Aho 넘버링 시스템에 의해 식별된다. VH1|1-18 생식선 서브패밀리에 바람직한 돌연변이는 82R, 94S 및 95R이다. VH1|1-18 생식선 서브패밀리에 적용된 바와 같은 방법은 치환 59X20을 추가로 포함할 수 있으며, 여기서, X20은 염기성 잔기(R, K 또는 H)이고, 이때 돌연변이 59K가 바람직하다.
항원 결합 단백질이 VH3|3-33 생식선 서브패밀리를 포함하는 경우, 본 방법은 1X4, 17X5 및 85X6으로부터 선택되는 하나 이상의 치환을 포함하도록 VH3 서열을 변형시키는 단계를 포함하며, 여기서, X4는 음전하성 잔기(D 또는 E)이며, X5는 작은 소수성 잔기(G, A, V, I, L 또는 M)이고, X6은 작은 소수성 잔기(G, A, V, I, L 또는 M)이다. 모든 잔기는 Aho 넘버링 시스템에 의해 식별된다. VH3|3-33 생식선 서브패밀리에 바람직한 돌연변이는 1E, 17G 및 85A이다.
항원 결합 단백질이 VK3|L16 생식선 서브패밀리를 포함하는 경우, 본 방법은 4X10, 13X11, 76X12, 78F, 95X13, 97X14 및 98P로부터 선택되는 하나 이상의 치환을 포함하도록 VK3 서열을 변형시키는 단계를 포함하며, 여기서, X10은 G, A, V, I, L 및 M으로부터 선택되며, X11은 G, A, V, I, L 및 M으로부터 선택되며, X12는 D 및 E로부터 선택되며, X13은 R, K 및 H로부터 선택되고, X14는 D 및 E로부터 선택된다. 모든 잔기는 Aho 넘버링 시스템에 의해 식별된다. VK3|L16 생식선 서브패밀리에 바람직한 돌연변이는 4L, 13L, 76D, 95R, 97E 및 98P이다.
항원 결합 단백질이 VK3|L6 생식선 서브패밀리를 포함하는 경우, 본 방법은 76X12 및 95X13으로부터 선택되는 하나 이상의 치환을 포함하도록 VK3 서열을 변형시키는 단계를 포함한다. VK3|L6 생식선 서브패밀리에 바람직한 돌연변이는 76D 및 95R이다.
본 발명의 방법은 253X15, 440X16 및 439X17로부터 선택되는 하나 이상의 치환을 포함하도록 Fc 도메인을 변형시키는 단계를 추가로 포함하며, 여기서, X15는 작은 소수성 잔기(G, A, V, I, L 또는 M)이며, X16은 염기성 잔기(R, K 또는 H)이고, X17은 음전하성 잔기(D 또는 E)이며, 여기서, Fc 도메인 서열은 440X16 및 439X17 중 하나만 포함한다. 모든 잔기는 EU 넘버링 시스템에 의해 식별된다. Fc 도메인의 바람직한 돌연변이는 253A, 440K 및 439E이다.
본 발명의 방법은 X18X19를 포함하도록 Fc 도메인 서열의 C-말단을 변형시키는 단계를 추가로 포함하며, 여기서, X18은 D 및 E로부터 또는 H, K 및 R로부터 선택되는 1 내지 4개의 아미노산을 포함하고, X19는 P, M, G, A, V, I, L, S, T, N, Q, F, Y 및 W로부터 선택되고, X18이 D 또는 E를 포함하는 경우 부재하며, X18이 이의 C-말단부에 K 또는 R을 포함하는 경우 존재하고, X18이 이의 C-말단부에 H를 포함하는 경우 존재하거나 부재한다. 바람직한 Fc C-말단 변형은 C-말단에 KP, KKP, KKKP(서열번호: 380), E 또는 EE를 포함한다.
상기 방법들은 바람직하게는, 이하 도 1a 및 도 1b에 보여진 고점도 항체에 적용된다. VH1|1-18 서열을 수반하는 방법 부분은 바람직하게는, 도 1b로부터의 항체 AF, AK, AL, AN 및 AO에 적용된다. VH3|3-33 서열을 수반하는 방법 부분은 바람직하게는, 도 1b로부터의 항체 AQ, AM, AI 및 AG에 적용된다. VK3|L16 서열을 수반하는 방법 부분은 바람직하게는, 도 1b로부터의 항체 AF 및 AQ에 적용된다. VK3|L6 서열을 수반하는 방법 부분은 바람직하게는, 항체 AJ에 적용된다.
본 발명의 방법은, 항원 결합 단백질 및 부모 항체가 동일한 농도로 투여된 경우, 부모 항체보다 빠르게 최대 혈청 농도에 도달하는 항원 결합 단백질의 제조 방법을 추가로 포함하며, 상기 방법은 부모 항체에 서열 변형 440X16을 도입하는 단계를 포함하며, 여기서, X16은 R, K 및 H로부터 선택된다. 바람직한 방법에서, 서열-변형된 항원 결합 단백질은 피하 주사 후, 부모 항체보다 적어도 2배 빠르게 최대 혈청 농도에 도달한다. 또한, 항원 결합 단백질 및 부모 항체가 동일한 농도로 투여된 경우, 피하 주사 후 부모 항체의 최대 혈청 농도보다 높은 최대 혈청 농도에 도달하는 항원 결합 단백질의 제조 방법이 본 발명에 포함되며, 상기 방법은 부모 항체에 서열 변형 440X16을 도입하는 단계를 포함하며, 여기서, X16은 R, K 및 H로부터 선택된다. 바람직한 방법에서, 서열-변형된 항원 결합 단백질은 부모 항체의 최대 혈청 농도보다 적어도 약 25% 더 높은 최대 혈청 농도에 도달한다. 이들 각각의 방법에서, 바람직한 X16은 K이고, 바람직한 부모 항체는 PCSK9 폴리펩타이드이다(항체 AK가 가장 바람직함).
본 발명은 추가로, 돌연변이체 항원 결합 단백질에 관한 것이며, 이러한 단백질은
a. 82X1, 94X2 및 95X3으로부터 선택되는 하나 이상의 치환을 포함하는 VH1|1-18 생식선 서브패밀리 서열로서, 여기서, X1은 R, K 및 H로부터 선택되며, X2는 S, T, N 및 Q로부터 선택되고, X3은 R, K 및 H로부터 선택되는, 서열;
b. 1X4, 17X5 및 85X6으로부터 선택되는 하나 이상의 치환을 포함하는 VH3|3-33 생식선 서브패밀리 서열로서, 여기서, X4는 D 및 E로부터 선택되며, X5는 G, A, V, I, L 및 M으로부터 선택되고, X6은 G, A, V, I, L 및 M으로부터 선택되는, 서열;
c. 4X10, 13X11, 76X12, 78F, 95X13, 97X14 및 98P로부터 선택되는 하나 이상의 치환을 포함하는 VK3|L16 생식선 서브패밀리로서, 여기서, X10은 G, A, V, I, L 및 M으로부터 선택되며, X11은 G, A, V, I, L 및 M으로부터 선택되며, X12는 D 및 E로부터 선택되며, X13은 R, K 및 H로부터 선택되고, X14는 D 및 E로부터 선택되며, 여기서, 돌연변이체 항원 결합 단백질이 치환 78F만 포함하는 것은 아닌, 서열;
d. 76X12 및 95X13으로부터 선택되는 하나 이상의 치환을 포함하는 VK3|IL6 생식선 서브패밀리;
e. 253X10, 440X11 및 439X12로부터 선택되는 하나 이상의 치환을 포함하는 Fc 도메인 서열로서, 여기서, X10은 G, A, V, I, L 및 M으로부터 선택되며, X11은 R, K 및 H로부터 선택되고, X12는 D 및 E로부터 선택되며, 여기서, X16이 K이고 X17이 E인 경우, 항원 결합 단백질은 253X15 또는 하위단락 a, b, c, d 및 f로부터 선택되는 변형 중 적어도 하나를 포함하며, 항원 결합 단백질은 CD20에 특이적으로 결합하는, 서열; 및
f. C-말단에 X18X19를 포함하는 Fc 도메인 서열로서, 여기서, X18은 D 및 E로부터 또는 H, K 및 R로부터 선택되는 1 내지 4개의 아미노산이고, X19는 P, M, G, A, V, I, L, S, T, N, Q, F, Y 및 W로부터 선택되고, X18이 D 또는 E를 포함하는 경우 부재하며, X18이 이의 C-말단부에 K 또는 R을 포함하는 경우 존재하고, X18이 이의 C-말단부에 H를 포함하는 경우 존재하거나 부재하고, PGKP(서열번호:381), PGKKP(서열번호:382), PGKKKP(서열번호:383) 또는 PGE가 C-말단에 보이는 경우, 항원 결합 단백질은 253X15 또는 하위단락 a 내지 e로부터 선택되는 치환 중 적어도 하나를 포함하며, 항원 결합 단백질은 CD20 또는 CD38에 특이적으로 결합한다. 바람직한 Fc C-말단 변형은 C-말단에 KP, KKP, KKKP(서열번호:380), E 또는 EE를 포함하는, 서열
로부터 선택되는 하나 이상의 서열을 포함하며,
가변 영역 아미노산은 Aho 넘버링 시스템에 따라 넘버링되고, Fc를 포함한 보존 영역으로부터의 모든 아미노산은 EU 넘버링에 따른 것이다.
본 발명에 따른 바람직한 항원 결합 단백질은, 상기 변형이 이하 도 1a 및 도 1b의 항체에 적용되는 것들이다. 또한 다음과 같은 항원 결합 단백질이 바람직하다:
VH1|1-18 생식선 서브패밀리 서열이 82R, 94S 및 95R로부터 선택되는 하나 이상의 치환을 포함하며, 이때 이러한 치환을 모두 갖는 것이 가장 바람직한, 항원 결합 단백질;
VH3|3-33 생식선 서브패밀리 서열이 치환 1E, 17G 및 85A 중 하나 이상을 포함하며, 이때 이러한 치환을 모두 갖는 것이 가장 바람직한, 항원 결합 단백질;
VK3|L16 생식선 서브패밀리 서열이 4L, 13L, 76D, 95R, 97E 및 98P로부터 선택되는 하나 이상의 치환을 포함하며, 이때 이러한 치환을 모두 갖는 것이 가장 바람직한, 항원 결합 단백질;
VK3|L6 생식선 서브패밀리 서열이 76D 및 95R로부터 선택되는 하나 이상의 치환을 포함하며, 이때 이러한 치환을 둘 다 갖는 것이 가장 바람직한, 항원 결합 단백질;
Fc 도메인 서열이 253A, 440K 및 439E로부터 선택되는 하나 이상의 치환을 포함하며, 이때 이러한 치환을 모두 갖는 것이 가장 바람직한, 항원 결합 단백질; 및
Fc 도메인 C-말단이 KP, KKP, KKKP(서열번호:380) 및 E로부터 선택되는 서열을 포함하는 항원 결합 단백질
이 바람직하다.
가변 영역에서 전술한 바람직한 아미노산 치환은 모두 Aho 넘버링 시스템에 의해 식별된다. Fc를 포함한 보존 영역 내의 모든 잔기는 EU 넘버링 시스템에 의해 식별된다.
본 발명에 따른 바람직한 항원 결합 단백질은 다음을 포함한다: 전술한 VH1|1-18 생식선 서브패밀리 치환 중 하나 이상, 가장 바람직하게는 모두를 갖는 도 1b로부터의 항체 AF, AK, AL, AN 및 AO; VH3|3-33 생식선 서브패밀리 치환 중 하나 이상, 가장 바람직하게는 모두를 갖는 도 1b로부터의 항체 AQ, AM, AI 및 AG; VK3|L16 생식선 서브패밀리 치환 중 하나 이상, 가장 바람직하게는 모두를 갖는 항체 AF 및 AQ; VK3|L6 생식선 서브패밀리 치환 중 하나 이상, 가장 바람직하게는 모두를 갖는 도 1b로부터의 항체 AJ; 및 상기 주지된 Fc 치환 중 하나 이상, 바람직하게는 모두를 갖는 도 1b로부터의 항체 BA, AH 및 AN.
전술한 서열 변형으로 인해, 본 발명은 추가로, 서열번호: 352, 353, 354, 366 및 368로부터 선택되는 중쇄 서열을 포함하고 바람직하게는 서열번호: 351의 경쇄 서열을 또한 포함하는, PCSK9에 특이적으로 결합하는 항원 결합 단백질에 관한 것이다.
전술한 서열 변형으로 인해, 본 발명은 또한, 서열번호: 356, 357 및 358로부터 선택되는 중쇄 서열을 포함하고 바람직하게는 서열번호: 355의 경쇄 서열을 추가로 포함하는, c-fms에 특이적으로 결합하는 항원 결합 단백질에 관한 것이다.
전술한 서열 변형으로 인해, 본 발명은 또한, 서열번호: 359, 361, 362, 364 및 368로부터 선택되는 중쇄 서열을 포함하고 바람직하게는 서열번호: 360, 363, 365 및 367로부터 선택되는 경쇄 서열을 추가로 포함하는, GIPR에 특이적으로 결합하는 항원 결합 단백질에 관한 것이다.
모든 변형된 항원 결합 단백질은 비변형된 항체에 대해 이전에 기재된 것과 동일한 적응증(indication)에 유용하다.
돌연변이화된 중쇄를 갖는 도 1a 및 도 1b로부터의 각각의 항원 결합 단백질은 도 1a 및 도 1b의 비변형된 부모 항체에서 기재된 바와 같은 경쇄 서열을 추가로 포함하는 것이 바람직하다. 돌연변이화된 경쇄를 갖는 각각의 전술한 항원 결합 단백질은 기재된 바와 같은 또는 도 1a 및 도 1b의 비변형된 부모 항체에서 나타나는 바와 같은 중쇄 서열을 추가로 포함하는 것이 바람직하다.
본 발명은 추가로, 개선된 약물동력학 특성을 갖는 상기 기재된 바와 같은 항원 결합 단백질을 포함한다. 본 발명은 상기 언급된 서열 변형 중 임의의 서열 변형을 선택적으로 갖는 항원 결합 단백질을 포함하며, 여기서:
a. 항원 결합 단백질은 440X16 서열 변형이 결여된 부모 항체에 비해, 서열 변형 440X16을 포함하며,
b. 항원 결합 단백질은, 항원 결합 단백질 및 부모 항체가 동일한 농도로 투여된 경우, 피하 주사 후 부모 항체보다 빠르게 최대 혈청 농도에 도달하고,
c. 항원 결합 단백질은, 항원 결합 단백질 및 부모 항체가 동일한 농도로 투여된 경우, 피하 주사 후 부모 항체의 최대 혈청 농도보다 높은 최대 혈청 농도에 도달한다.
이러한 항원 결합 단백질에 바람직한 부모 항체는 PCSK9 결합 폴리펩타이드이며, 이때 항체 AK가 가장 바람직하다. 이러한 항원 결합 단백질에서 바람직한 치환기 X16은 K이다. 이러한 항원 결합 단백질로 과콜레스테롤혈증을 치료하는 방법이 본 발명에 추가로 존재한다.
본 발명은 또한, 본 발명의 항원 결합 단백질을 인코딩하는 단리된 핵산, 뿐만 아니라 이러한 핵산을 포함하는 벡터, 이러한 벡터를 포함하는 숙주 세포, 및 이러한 항원 결합 단백질의 제조 방법 및 사용 방법에 관한 것이다.
다른 실시형태에서, 본 발명은 항원 결합 단백질을 포함하는 조성물 및 항원 결합 단백질을 포함하는 키트, 뿐만 아니라 항원 결합 단백질을 포함하는 제조 물품을 제공한다.
용어의 정의
후속하는 상세한 설명에서, 많은 용어들이 광범위하게 사용된다. 하기 정의는 본 발명의 이해를 용이하게 하기 위해 제공된다.
다르게 명시되지 않는 한, 단수형("a", "an", "the") 및 "적어도 하나"는 상호교환적으로 사용되고, 1개 이상을 의미한다.
"항원 결합 단백질"은, 이것이 결합하는 또 다른 분자(항원)에 대해 강한 친화성을 갖는 항원-결합 영역 또는 항원-결합 부분을 포함하는 단백질 또는 폴리펩타이드를 지칭한다. 항원-결합 단백질은 항체, 펩티바디, 항체 단편(예를 들어 Fab, Fab', F(ab')2, Fv, 단일 도메인 항체), 항체 유도체, 항체 유사체, 융합 단백질, 및 키메라 항원 수용체(CAR)를 포함한 항원 수용체를 포괄한다.
"항체"(Ab) 및 "면역글로불린"(Ig)은 동일한 구조적 특징을 갖는 당단백질이다. 항체는 특이적인 항원에 결합 특이성을 나타내는 한편, 면역글로불린은 항체 및 항원 특이성이 결여된 다른 항체-유사 분자를 둘 다 포함한다. 후자의 종류의 폴리펩타이드는 예를 들어, 림프계에 의해 낮은 수준으로, 및 골수종에 의해 증가된 수준으로 생성된다. 따라서, 본원에 사용된 바와 같이, 용어 "항체" 또는 "항체 펩타이드(들)"는 온전한 항체, 특이적인 결합에 대해 이 명세서에 개시된 항체와 경쟁하는 항체, 또는 특이적인 결합에 대해 온전한 항체와 경쟁하고 키메라, 인간화, 완전 인간 및 이중특이적 항체를 포함하는 이의 항원-결합 단편(예를 들어 Fab, Fab', F(ab')2, Fv, 단일 도메인 항체)을 지칭한다. 소정의 실시형태에서, 항원-결합 단편은 예를 들어, 재조합 DNA 기술에 의해 생성된다. 추가의 실시형태에서, 항원-결합 단편은 온전한 항체의 효소적 또는 화학적 절단에 의해 생성된다. 항원-결합 단편으로는, Fab, Fab', F(ab)2, F(ab')2, Fv 및 단일-사슬 항체가 있으나, 이들로 한정되는 것은 아니다. 본 발명에 사용하기에 적합한 항체의 예로는 비제한적으로, 도 1a 및 1b에 열거된 항체, 뿐만 아니라 아바고보맙(Abagovomab), 아브식시맙(Abciximab), 악톡수맙(Actoxumab), 아달리무맙(Adalimumab), 아펠리모맙(Afelimomab), 아푸투주맙(Afutuzumab), 알라시주맙(Alacizumab), 알라시주맙 페골(Alacizumab pegol), ALD518, 알렘투주맙(Alemtuzumab), 알리로쿠맙(Alirocumab), 알렘투주맙(Alemtuzumab), 알투모맙(Altumomab), 아마툭시맙(Amatuximab), 아나투모맙 마페나톡스(Anatumomab mafenatox), 안루킨주맙(Anrukinzumab), 아폴리주맙(Apolizumab), 아르시투모맙(Arcitumomab), 아셀리주맙(Aselizumab), 알티누맙(Altinumab), 아틀리주맙(Atlizumab), 아토롤리미우맙(Atorolimiumab), 토실리주맙(tocilizumab), 바피뉴주맙(Bapineuzumab), 바실릭시맙(Basiliximab), 바비툭시맙(Bavituximab), 벡투모맙(Bectumomab), 벨리무맙(Belimumab), 벤랄리주맙(Benralizumab), 베르틸리무맙(Bertilimumab), 베실레소맙(Besilesomab), 베바시주맙(Bevacizumab), 베즐로톡수맙(Bezlotoxumab), 비시로맙(Biciromab), 비바투주맙(Bivatuzumab), 비바투주맙 메르탄신(Bivatuzumab mertansine), 블리나투모맙(Blinatumomab), 블로소주맙(Blosozumab), 브렌툭시맙 베도틴(Brentuximab vedotin), 브리아키누맙(Briakinumab), 브로달루맙(Brodalumab), 카나키누맙(Canakinumab), 칸투주맙 메르탄신(Cantuzumab mertansine), 칸투주맙 메르탄신, 카플라시주맙(Caplacizumab), 카프로맙 펜데티드(Capromab pendetide), 카를루맙(Carlumab), 카투막소맙(Catumaxomab), CC49, 세델리주맙(Cedelizumab), 세르톨리주맙 페골(Certolizumab pegol), 세툭시맙(Cetuximab), 시타투주맙 보가톡스(Citatuzumab bogatox), 식수투무맙(Cixutumumab), 클라자키주맙(Clazakizumab), 클레놀릭시맙(Clenoliximab), 클리바투주맙 테트락세탄(Clivatuzumab tetraxetan), 코나투무맙(Conatumumab), 크레네주맙(Crenezumab), CR6261, 다세투주맙(Dacetuzumab), 다클리주맙(Daclizumab), 달로투주맙(Dalotuzumab), 다라투무맙(Daratumumab), 뎀시주맙(Demcizumab), 데노수맙(Denosumab), 데투모맙(Detumomab), 도를리모맙 아리톡스(Dorlimomab aritox), 드로지투맙(Drozitumab), 둘리고투맙(Duligotumab), 두필루맙(Dupilumab), 에크로멕시맙(Ecromeximab), 에쿨리주맙(Eculizumab), 에도바코맙(Edobacomab), 에드레콜로맙(Edrecolomab), 에팔리주맙(Efalizumab), 에푼구맙(Efungumab), 엘로투주맙(Elotuzumab), 엘실리모맙(Elsilimomab), 에나바투주맙(Enavatuzumab), 엔리모맙 페골(Enlimomab pegol), 에노키주맙(Enokizumab), 에노키주맙, 에노티쿠맙(Enoticumab), 에노티쿠맙, 엔시툭시맙(Ensituximab), 에피투모맙 시툭세탄(Epitumomab cituxetan), 에프라투주맙(Epratuzumab), 에레누맙(Erenumab), 에를리주맙(Erlizumab), 에르투막소맙(Ertumaxomab), 에타라시주맙(Etaracizumab), 에트롤리주맙(Etrolizumab), 에볼로쿠맙(evolocumab), 엑스비비루맙(Exbivirumab), 엑스비비루맙, 파놀레소맙(Fanolesomab), 파랄리모맙(Faralimomab), 파를레투주맙(Farletuzumab), 파시누맙(Fasinumab), FBTA05, 펠비주맙(Felvizumab), 페자키누맙(Fezakinumab), 피클라투주맙(Ficlatuzumab), 피기투무맙(Figitumumab), 플란보투맙(Flanvotumab), 폰톨리주맙(Fontolizumab), 포랄루맙(Foralumab), 포라비루맙(Foravirumab), 프레솔리무맙(Fresolimumab), 풀라누맙(Fulranumab), 푸툭시맙(Futuximab), 갈릭시맙(Galiximab), 가니투맙(Ganitumab), 간테네루맙(Gantenerumab), 가빌리모맙(Gavilimomab), 겜투주맙 오조가미신(Gemtuzumab ozogamicin), 게보키주맙(Gevokizumab), 기렌툭시맙(Girentuximab), 글렘바투무맙 베도틴(Glembatumumab vedotin), 골리무맙(Golimumab), 고밀릭시맙(Gomiliximab), GS6624, 이발리주맙(Ibalizumab), 이브리투모맙 티욱세탄(Ibritumomab tiuxetan), 이크루쿠맙(Icrucumab), 이고보맙(Igovomab), 임시로맙(Imciromab), 임가투주맙(Imgatuzumab), 인클라쿠맙(Inclacumab), 인다툭시맙 라브탄신(Indatuximab ravtansine), 인플릭시맙(Infliximab), 인테투무맙(Intetumumab), 이놀리모맙(Inolimomab), 이노투주맙 오조가미신(Inotuzumab ozogamicin), 이필리무맙(Ipilimumab), 이라투무맙(Iratumumab), 이톨리주맙(Itolizumab), 익세키주맙(Ixekizumab), 켈릭시맙(Keliximab), 라베투주맙(Labetuzumab), 레브리키주맙(Lebrikizumab), 레말레소맙(Lemalesomab), 레르델리무맙(Lerdelimumab), 렉사투마맙(Lexatumumab), 리비비루맙(Libivirumab), 리겔리주맙(Ligelizumab), 린투주맙(Lintuzumab), 리릴루맙(Lirilumab), 로르보투주맙 메르탄신(Lorvotuzumab mertansine), 루카투무맙(Lucatumumab), 루밀릭시맙(Lumiliximab), 마파투무맙(Mapatumumab), 마슬리모맙(Maslimomab), 마브릴리무맙(Mavrilimumab), 마투주맙(Matuzumab), 메폴리주맙(Mepolizumab), 메텔리무맙(Metelimumab), 밀라투주맙(Milatuzumab), 민레투모맙(Minretumomab), 미투모맙(Mitumomab), 모가물리주맙(Mogamulizumab), 모롤리무맙(Morolimumab), 모타비주맙(Motavizumab), 목세투모맙 파수도톡스(Moxetumomab pasudotox), 무로모납-CD3(Muromonab-CD3), 나콜로맙 타페나톡스(Nacolomab tafenatox), 나밀루맙(Namilumab), 납투모맙 에스타페나톡스(Naptumomab estafenatox), 나르나투맙(Narnatumab), 나탈리주맙(Natalizumab), 네바쿠맙(Nebacumab), 네시투무맙(Necitumumab), 네렐리모맙(Nerelimomab), 네스바쿠맙(Nesvacumab), 니모투주맙(Nimotuzumab), 니볼루맙(Nivolumab), 노페투모맙 메르펜탄(Nofetumomab merpentan), 오카라투주맙(Ocaratuzumab), 오크렐리주맙(Ocrelizumab), 오둘리모맙(Odulimomab), 오파투무맙(Ofatumumab), 올라라투맙(Olaratumab), 올로키주맙(Olokizumab), 오말리주맙(Omalizumab), 오나르투주맙(Onartuzumab), 오포투주맙 모나톡스(Oportuzumab monatox), 오레고보맙(Oregovomab), 오르티쿠맙(Orticumab), 오텔릭시주맙(Otelixizumab), 옥셀루맙(Oxelumab), 오자네주맙(Ozanezumab), 오조랄리주맙(Ozoralizumab), 파기박시맙(Pagibaximab), 팔리비주맙(Palivizumab), 파니투무맙(Panitumumab), 파노바쿠맙(Panobacumab), 파르사투주맙(Parsatuzumab), 파스콜리주맙(Pascolizumab), 파테클리주맙(Pateclizumab), 파트리투맙(Patritumab), 펨투모맙(Pemtumomab), 페라키주맙(Perakizumab), 페르투주맙(Pertuzumab), 펙셀리주맙(Pexelizumab), 피딜리주맙(Pidilizumab), 핀투모맙(Pintumomab), 플라쿨루맙(Placulumab), 포네주맙(Ponezumab), 프레잘루맙(Prezalumab), 프릴릭시맙(Priliximab), 프리투무맙(Pritumumab), PRO 140, 퀼리주맙(Quilizumab), 라코투모맙(Racotumomab), 라드레투맙(Radretumab), 라피비루맙(Rafivirumab), 라무시루맙(Ramucirumab), 라니비주맙(Ranibizumab), 락시바쿠맙(Raxibacumab), 레가비루맙(Regavirumab), 레슬리주맙(Reslizumab), 릴로투무맙(Rilotumumab), 리툭시맙(Rituximab), 로바투무맙(Robatumumab), 롤레두맙(Roledumab), 로모소주맙(Romosozumab), 론탈리주맙(Rontalizumab), 로벨리주맙(Rovelizumab), 루플리주맙(Ruplizumab), 사말리주맙(Samalizumab), 사릴루맙(Sarilumab), 사투모맙 펜데티드(Satumomab pendetide), 세쿠키누맙(Secukinumab), 세비루맙(Sevirumab), 시브로투주맙(Sibrotuzumab), 시팔리무맙(Sifalimumab), 실툭시맙(Siltuximab), 심투주맙(Simtuzumab), 시플리주맙(Siplizumab), 시루쿠맙(Sirukumab), 솔라네주맙(Solanezumab), 솔리토맙(Solitomab), 소넵시주맙(Sonepcizumab), 손투주맙(Sontuzumab), 스타물루맙(Stamulumab), 술레소맙(Sulesomab), 수비주맙(Suvizumab), 타발루맙(Tabalumab), 타카투주맙 테트락세탄(Tacatuzumab tetraxetan), 타도시주맙(Tadocizumab), 탈리주맙(Talizumab), 타네주맙(Tanezumab), 타플리투모맙 팝톡스(Taplitumomab paptox), 테피바주맙(Tefibazumab), 텔리모맙 아리톡스(Telimomab aritox), 테나투모맙(Tenatumomab), 테피바주맙(Tefibazumab), 텔리모맙 아리톡스(Telimomab aritox), 테나투모맙(Tenatumomab), 테넬릭시맙(Teneliximab), 테플리주맙(Teplizumab), 테프로투무맙(Teprotumumab), 테제펠루맙(Tezepelumab), TGN1412, 트레멜리무맙(Tremelimumab), 티실리무맙(Ticilimumab), 틸드라키주맙(Tildrakizumab), 티가투주맙(Tigatuzumab), TNX-650, 토실리주맙(Tocilizumab), 토랄리주맙(Toralizumab), 토시투모맙(Tositumomab), 트랄로키누맙(Tralokinumab), 트라스투주맙(Trastuzumab), TRBS07, 트레갈리주맙(Tregalizumab), 트레멜리무맙(Tremelimumab), 투코투주맙 셀모류킨(Tucotuzumab celmoleukin), 투비루맙(Tuvirumab), 유블리툭시맙(Ublituximab), 유렐루맙(Urelumab), 유르톡사주맙(Urtoxazumab), 유스테키누맙(Ustekinumab), 바팔릭시맙(Vapaliximab), 바텔리주맙(Vatelizumab), 베돌리주맙(Vedolizumab), 벨투주맙(Veltuzumab), 베팔리모맙(Vepalimomab), 베센쿠맙(Vesencumab), 비실리주맙(Visilizumab), 볼로식시맙(Volociximab), 보르세투주맙 마포도틴(Vorsetuzumab mafodotin), 보투무맙(Votumumab), 잘루투무맙(Zalutumumab), 자놀리무맙(Zanolimumab), 자툭시맙(Zatuximab), 지랄리무맙(Ziralimumab) 및 졸리모맙 아리톡스(Zolimomab aritox)가 있다.
본원에 사용된 바와 같이, 용어 "단리된 항체"는 이의 천연 환경의 구성성분으로부터 식별되고, 분리 및/또는 회수된 항체를 지칭한다. 이의 천연 환경의 오염 구성성분은 항체에 대한 진단적 또는 치료적 용도를 방해할 물질이고, 효소, 호르몬, 및 다른 단백질성 또는 비단백질성 용질을 포함할 수 있다. 바람직한 실시형태에서, 항체는 (1) 로리 방법(Lowry method)에 의해 결정된 바와 같이 항체의 95 중량% 초과, 가장 바람직하게는 99 중량% 초과까지, (2) 스피닝 컵 시쿼네이터(spinning cup sequenator)의 사용에 의해 N-말단 또는 내부 아미노산 서열 중 적어도 15개 잔기를 수득하기에 충분한 정도까지, 또는 (3) 환원 또는 비환원 조건 하에 쿠마시 블루 또는 바람직하게는 은(sliver) 염색을 사용하여 SDS-PAGE에 의해 균질성까지 정제될 것이다. 단리된 항체는 재조합 세포 내의 인 시추(in situ) 항체를 포함하는데, 이는 항체의 천연 환경의 적어도 하나의 구성성분이 존재하지 않을 것이기 때문이다. 그러나 통상적으로, 단리된 항체는 적어도 하나의 정제 단계에 의해 제조될 것이다.
용어 항원 또는 다른 폴리펩타이드의 "결합하다(하는)"은, 본 발명의 리간드 폴리펩타이드가 수용체에 결합하는 것; 본 발명의 수용체 폴리펩타이드가 리간드에 결합하는 것; 본 발명의 항체가 항원 또는 에피토프에 결합하는 것; 본 발명의 항원 또는 에피토프가 항체에 결합하는 것; 본 발명의 항체가 항-이디오타입(anti-idiotypic) 항체에 결합하는 것; 본 발명의 항-이디오타입 항체가 리간드에 결합하는 것; 본 발명의 항-이디오타입 항체가 수용체에 결합하는 것; 본 발명의 항-항-이디오타입 항체가 리간드, 수용체 또는 항체에 결합하는 것 등을 포함하지만, 이들로 한정되는 것은 아니다.
용어 "면역글로불린"은 면역글로불린 유전자에 의해 실질적으로 인코딩되는 하나 이상의 폴리펩타이드로 구성된 단백질을 지칭한다. 하나의 형태의 면역글로불린은 항체의 기본적인 구조 단위를 구성한다. 이러한 형태는 사량체이고, 2개의 동일한 쌍의 면역글로불린 사슬들로 구성되며, 각각의 쌍은 하나의 경쇄 및 하나의 중쇄를 가진다. 각각의 쌍에서, 경쇄 및 중쇄 가변 영역이 함께 항원에의 결합을 담당하고, 불변 영역은 항체 효과기 기능을 담당한다.
전장 면역글로불린 "경쇄"(약 25 Kd 또는 약 214개 아미노산)는 NH2-말단에서 가변 영역 유전자(약 110개 아미노산) 및 COOH-말단에서 카파 또는 람다 불변 영역 유전자에 의해 인코딩된다. 전장 면역글로불린 "중쇄"(약 50 Kd 또는 약 446개 아미노산)는 유사하게 가변 영역 유전자(약 116개 아미노산) 및 다른 상기 언급된 불변 영역 유전자들 중 하나(약 330개 아미노산)에 의해 인코딩된다. 중쇄는 감마, 뮤, 알파, 델타 또는 입실론으로서 분류되고, 항체의 이소타입을 각각 IgG(예컨대 IgG1, IgG2, IgG3 및 IgG4), IgM, IgA, IgD 및 IgE로서 한정한다(define). 경쇄 및 중쇄 내에서, 가변 및 불변 영역은 약 12개 이상의 아미노산으로 이루어진 "J" 영역에 의해 접합되며, 이때 중쇄는 약 10개 초과의 아미노산으로 이루어진 "D" 영역을 또한 포함한다. (일반적으로, 문헌[Fundamental Immunology (Paul, W., ed., 2nd Edition, Raven Press, NY (1989))], 챕터 7(그 전체가 모든 목적을 위해 원용에 의해 포함됨) 참조).
면역글로불린 경쇄 또는 중쇄 가변 도메인 또는 영역은 "상보성 결정 영역"(CDR)이 개재된(interrupted) "프레임워크 영역"(FR)을 포함한다. 문헌[Kabat et al. (1991), Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, Md. (1991); Chothia et al. (1987), J. Mol. Biol. 196: 901-917](이들은 둘 다 원용에 의해 본 명세서에 포함됨). FR 잔기는 본원에 정의된 바와 같은 CDR 영역 잔기 이외의 가변 도메인 잔기이다. 상이한 경쇄 또는 중쇄의 프레임워크 영역의 서열은 종(species) 내에서 비교적 보존된다. 따라서, "인간 프레임워크 영역"은 자연 발생 인간 면역글로불린의 프레임워크 영역과 실질적으로 동일한(약 85% 이상, 통상 90% 내지 95% 이상) 프레임워크 영역이다. 구성분 경쇄 및 중쇄의 조합된 프레임워크 영역인 항체의 프레임워크 영역은 CDR을 위치시키고 정렬하는 역할을 한다. CDR은 주로, 항원의 에피토프에 결합하는 역할을 한다. 이에, 용어 "인간화" 면역글로불린은 인간 프레임워크 영역, 및 비-인간(통상 마우스 또는 래트) 면역글로불린으로부터의 하나 이상의 CDR을 포함하는 면역글로불린을 지칭한다. CDR을 제공하는 비-인간 면역글로불린은 "공여체"로 불리고, 프레임워크를 제공하는 인간 면역글로불린은 "수여체(acceptor)"로 불린다. 불변 영역이 존재할 필요는 없지만, 이들이 존재한다면 이들 불변 영역은 인간 면역글로불린 불변 영역과 실질적으로 동일, 즉, 적어도 약 85% 내지 90%, 바람직하게는 약 95% 이상 동일해야 한다. 따라서, 가능하게는 CDR을 제외하고, 인간화 면역글로불린의 모든 부분은 천연 인간 면역글로불린 서열의 상응하는 부분과 실질적으로 동일하다. 나아가, 인간 프레임워크 영역 내의 하나 이상의 잔기는 최적의 항원-결합 친화성 및 특이성을 보유하기 위해 부모 서열로 역돌연변이화될 수 있다. 이러한 방식으로, 비-인간 부모 항체로부터의 소정의 프레임워크 잔기는 부모 항체의 면역원성을 최소화하면서도 이의 결합 특성을 보유하기 위해 이러한 인간화 항체에 보유된다. 본원에 사용된 바와 같이, 용어 "인간 프레임워크 영역"은 이러한 역돌연변이를 갖는 영역을 포함한다. "인간화 항체"는 인간화 경쇄 및 인간화 중쇄 면역글로불린을 포함하는 항체이다. 예를 들어, 인간화 항체는 예를 들어 하기 정의된 바와 같은 전형적인 키메라 항체를 포괄하지 않을 것인데, 왜냐하면 키메라 항체의 전체 가변 영역이 비-인간이기 때문이다.
본 발명의 모노클로날 항체 및 항체 구축물은 구체적으로 "키메라" 항체(면역글로불린)를 포함하며, 이러한 항체에서, 이들이 요망되는 생물학적 활성을 나타내는 한, 중쇄 및/또는 경쇄의 일부는 특정 종으로부터 유래되거나 특정 항체 클래스(class) 또는 서브클래스에 속하는 항체 내의 상응하는 서열과 동일하거나 상동성인 한편, 사슬(들)의 나머지는 또 다른 종으로부터 유래되거나 또 다른 항체 클래스 또는 서브클래스에 속하는 항체, 뿐만 아니라 이러한 항체의 단편 내의 상응하는 서열과 동일하거나 상동성이다(미국 특허 4,816,567; 문헌[Morrison et al. (1984), Proc. Natl. Acad. Sci. USA, 81: 6851-6855]). 본원에서 관심 키메라 항체는 비-인간 영장류(예를 들어 구대륙 원숭이(Old World Monkey), 유인원 등)로부터 유래된 가변 도메인 항원-결합 서열 및 인간 불변 영역 서열을 포함하는 "영장류화" 항체를 포함한다. 키메라 항체를 제조하기 위한 여러 가지 접근법들이 기재되어 있다. 예를 들어 문헌[Morrison et al . (1985), Proc. Natl. Acad. Sci. U.S.A. 81:6851; Takeda et al . (1985), Nature 314:452], Cabilly et al ., 미국 특허 4,816,567; Boss et al ., 미국 특허 4,816,397; Tanaguchi et al ., EP 0171496; EP 0173494; 및 GB 2177096을 참조한다.
용어 "인간 항체" 및 "완전 인간 항체"는 각각, 인간 면역글로불린 라이브러리로부터 또는 하나 이상의 인간 면역글로불린에 대해 트랜스제닉인 동물로부터 단리된 항체를 포함하여 인간 면역글로불린의 아미노산 서열을 갖고, 내인성 면역글로불린을 발현하지 않는 항체; 예를 들어, Xenomouse® 항체 및 미국 특허 5,939,598에서 Kucherlapati 등에 의해 기재된 바와 같은 항체를 지칭한다.
용어 "유전자 변경 항체"는, 아미노산 서열이 본래의 항체의 서열로부터 달라진 항체를 의미한다. 항체의 발생 시 재조합 DNA 기술의 적절성(relevance) 때문에, 당업자는 천연 항체에서 확인되는 아미노산 서열로 국한될 필요가 없으며; 항체는 요망되는 특징을 수득하도록 재설계될 수 있다. 가능한 변이(variation)는 많이 있으며, 단지 하나 또는 몇 개의 아미노산에 가해지는 변화로부터 예를 들어 가변 및/또는 불변 영역의 완전한 재설계에 이르기까지 다양하다. 불변 영역에서의 변화는 일반적으로, 보체 고정, 막과의 상호작용 및 다른 효과기 기능, 뿐만 아니라 제조 가능성(manufacturability) 및 점도와 같은 특징을 개선하거나 변경시키기 위해 이루어질 것이다. 가변 영역에서의 변화는 항원 결합 특징을 개선하기 위해 이루어질 것이다.
"Fab 단편"은 하나의 경쇄, 및 하나의 중쇄의 CH1 및 가변 영역으로 구성된다. Fab 분자의 중쇄는 또 다른 중쇄 분자와 이황화 결합을 형성할 수 없다.
"Fab' 단편"은 하나의 경쇄, 및 CH1과 CH2 도메인 사이에서 불변 영역을 더 함유하는 하나의 중쇄를 함유하여, 사슬간 이황화 결합이 2개의 중쇄들 사이에서 형성되어 F(ab')2 분자를 형성할 수 있다.
"F(ab')2 단편"은 2개의 경쇄, 및 CH1과 CH2 도메인 사이의 불변 영역의 일부를 함유하는 2개의 중쇄를 함유하여, 사슬간 이황화 결합이 2개의 중쇄들 사이에서 형성된다.
용어 "Fv 단편" 및 "단일 사슬 항체"는 중쇄 및 경쇄 둘 다로부터의 항체 가변 영역을 함유하지만 불변 영역이 결여된 폴리펩타이드를 지칭한다. 완전 항체와 같이, 이는 특이적인 항원에 선택적으로 결합할 수 있다. Fv 단편은 분자량이 단지 약 25 kDa으로서, 2개의 중쇄 단백질 및 2개의 경쇄로 구성된 보편적인 항체(150 내지 160 kD)보다 훨씬 작고, 심지어 Fab 단편(약 50 kDa, 하나의 경쇄 및 1/2의 중쇄)보다도 작다.
"단일 도메인 항체"는 단일 도메인 Fv 단위, 예를 들어 VH 또는 VL로 구성된 항체 단편이다. 완전 항체와 같이, 이는 특이적인 항원에 선택적으로 결합할 수 있다. 단일-도메인 항체는 분자량이 단지 12 내지 15 kDa으로서, 2개의 중쇄 단백질 및 2개의 경쇄로 구성된 보편적인 항체(150 내지 160 kD)보다 훨씬 작고, 심지어 Fab 단편(약 50 kDa, 하나의 경쇄 및 1/2의 중쇄) 및 단일-사슬 가변 단편(약 25 kDa, 2개의 가변 도메인, 하나는 경쇄로부터이고 하나는 중쇄로부터임)보다도 작다. 최초의 단일-도메인 항체는 낙타과에서 확인된 중쇄 항체로부터 조작되었다. 단일-도메인 항체에 대한 대부분의 연구가 현재로서는 중쇄 가변 도메인을 기반으로 하고 있지만, 경쇄 가변 도메인 및 경쇄로부터 유래된 나노바디 또한, 표적 에피토프에 특이적으로 결합하는 것으로 나타나 있다.
본원에 사용된 바와 같이, 용어 "모노클로날 항체"는 하이브리도마 기술을 통해 생성된 항체로 한정되지 않는다. 용어 "모노클로날 항체"는 이것이 생성되는 방법이 아니라, 임의의 진핵, 원핵 또는 파지 클론을 포함한 단일 클론으로부터 유래된 항체를 지칭한다.
일부 실시형태에서, 본 발명의 항원 결합 단백질은 이것이 유래되는 항체의 인간 항원을 선택적으로 저해한다. 예를 들어, 본원에 기재된 바와 같이 치환된 것과 같은 항체 AF의 서열을 갖는 항원 결합 단백질은 도 1b에서 항체 AF의 항원을 선택적으로 저해할 것이다. 항체 또는 이의 기능성 단편은, 특이적인 수용체의 저해 검정법에서 항체의 IC50이 또 다른 "참조" 리간드 또는 수용체의 저해 검정법에서의 IC50보다 적어도 50배 더 낮을 때, 다른 수용체 또는 리간드에 비해 특이적인 수용체 또는 리간드를 "선택적으로 저해한다". "IC50"은 생물학적 또는 생화학적 기능의 50% 저해를 달성하는 데 필요한 용량/농도이다. 방사성 리간드를 이용하는 경우, IC50은 이러한 방사성 리간드의 특이적인 결합 중 50%를 대체하는 경쟁 리간드의 농도이다. 임의의 특정 성분 또는 길항제의 IC50은, 용량-반응 곡선을 구축하고 특정 기능 검정법에서 효능제 활성을 역전시키는 데 대한 상이한 농도의 약물 또는 길항제의 효과를 검사함으로써 결정될 수 있다. 효능제의 최대 생물학적 반응의 1/2을 저해하는 데 필요한 농도를 결정함으로써, 주어진 길항제 또는 약물에 대한 IC50 값이 계산될 수 있다. 따라서, 임의의 항-PCSK9 항체 또는 이의 기능성 단편에 대한 IC50 값은 예를 들어, 임의의 기능 검정법에서 인간 PCSK9 수용체를 활성화시키는 데 있어서 PCSK9의 최대 생물학적 반응의 1/2을 저해하는 데 필요한 항체 또는 단편의 농도를 결정함으로써 계산될 수 있다. 특이적인 리간드 또는 수용체를 선택적으로 저해하는 항체 또는 이의 기능성 단편은 해당 리간드 또는 수용체에 대한 중화 항체 또는 중화 단편인 것으로 이해된다. 따라서 일부 실시형태에서, 항-PCSK9 항체 또는 기능성 단편은 인간 PCSK9의 중화 항체 또는 단편이다.
본 발명의 치환된 항원 결합 단백질은 이들이 유래되는 비치환된 항체를 교차-차단할 수 있다. 용어 "교차-차단하다," "교차-차단된," 및 "교차-차단성"은 본원에서, 다른 항원 결합 단백질(예를 들어 항체 또는 결합 단편)이 표적(예를 들어 인간 PCSK9)에 결합하는 것을 방해하는 항원 결합 단백질의 능력을 의미하는 데에 상호교환적으로 사용된다. 또 다른 항원 결합 단백질이 표적에 결합하는 것을 항체 또는 결합 단편이 방해할 수 있는 정도, 및 따라서 이것을 교차-차단이라고 할 수 있는지의 여부는 경쟁 결합 검정법을 사용하여 결정될 수 있다. 일부 실시형태에서, 본 발명의 교차-차단성 항원 결합 단백질은 참조 항체가 표적 항원에 결합하는 것을 약 40% 내지 100%, 예컨대 약 60% 내지 약 100%, 구체적으로 바람직하게는 약 70% 내지 100%, 보다 구체적으로 바람직하게는 약 80% 내지 100% 감소시킨다. 교차-차단을 검출하는 데 특히 적합한 정량적 검정법은, 표면 플라즈몬 공명 기술을 사용하여 상호작용의 정도를 측정하는 Biacore 기계를 사용한다. 또 다른 적합한 정량적 교차-차단 검정법은 표적 항원에의 항체들의 결합의 측면에서 이들 항체 사이의 경쟁을 측정하기 위해 FACS-기반 접근법을 사용한다.
용어 "핵산" 또는 "핵산 분자"는 폴리뉴클레오타이드, 예컨대 데옥시리보핵산(DNA) 또는 리보핵산(RNA), 올리고뉴클레오타이드, 중합효소 연쇄 반응(PCR)에 의해 발생된 단편, 및 연결, 절단, 엔도뉴클레아제 작용 및 엑소뉴클레아제 작용 중 임의에 의해 발생된 단편을 지칭한다. 핵산 분자는, 자연 발생 뉴클레오타이드(예컨대 DNA 및 RNA), 또는 자연 발생 뉴클레오타이드의 유사체(예를 들어 자연 발생 뉴클레오타이드의 α-거울상이성질체 형태), 또는 이들 둘 다의 조합인 단량체로 구성될 수 있다. 변형된 뉴클레오타이드는 당 모이어티 및/또는 피리미딘 또는 퓨린 염기 모이어티에 변경을 가질 수 있다. 당 변형은 예를 들어, 하나 이상의 하이드록실기를 할로겐, 알킬기, 아민 및 아지도기로 대체하는 것을 포함하거나, 당은 에테르 또는 에스테르로서 작용화될 수 있다. 더욱이, 완전 당 모이어티는 입체적으로 및 전자적으로 유사한 구조, 예컨대 아자-당 및 탄소환식 당 유사체로 대체될 수 있다. 염기 모이어티에서의 변형의 예는 알킬화된 퓨린 및 피리미딘, 아실화된 퓨린 또는 피리미딘, 또는 다른 잘 알려진 헤테로환식 치환기를 포함한다. 핵산 단량체는 포스포디에스테르 결합 또는 이러한 연결의 유사체에 의해 연결될 수 있다. 포스포디에스테르 연결의 유사체는 포스포로티오에이트, 포스포로디티오에이트, 포스포로셀레노에이트, 포스포로디셀레노에이트, 포스포로아닐로티오에이트, 포스포르아닐리데이트, 포스포르아미데이트 등을 포함한다. 용어 "핵산 분자"는 또한, 소위 "펩타이드 핵산"을 포함하며, 이는 폴리아미드 백본에 부착된 자연 발생 또는 변형된 핵산 염기를 포함한다. 핵산은 단일 가닥 또는 이중 가닥일 수 있다.
용어 "핵산 분자의 보체"는 참조 뉴클레오타이드 서열과 비교하여 상보적 뉴클레오타이드 서열 및 역배향을 갖는 핵산 분자를 지칭한다.
용어 "축퇴(degenerate) 뉴클레오타이드 서열"은 폴리펩타이드를 코딩하는 참조 핵산 분자와 비교하여 하나 이상의 축퇴 코돈을 포함하는 뉴클레오타이드의 서열을 나타낸다. 축퇴 코돈은 뉴클레오타이드의 상이한 트리플렛(triplet)을 함유하지만, 동일한 아미노산 잔기를 인코딩한다(즉, GAU 및 GAC 트리플렛은 각각 Asp을 인코딩함).
"단리된 핵산 분자"는 유기체의 게놈 DNA에 혼입되지 않은 핵산 분자이다. 예를 들어, 세포의 게놈 DNA로부터 분리된, 항체의 중쇄를 인코딩하는 DNA 분자는 단리된 DNA 분자이다. 단리된 핵산 분자의 또 다른 예는 유기체의 게놈에 혼입되지 않은 화학적으로-합성된 핵산 분자이다. 특정 종으로부터 단리된 핵산 분자는 해당 종으로부터의 염색체의 완전한 DNA 분자보다 작다.
"핵산 분자 구축물"은 자연상에 존재하지 않는 배열로 조합되고 병치된 핵산의 분절을 함유하도록 인간 개입을 통해 변형된 단일- 또는 이중-가닥의 핵산 분자이다.
"상보적 DNA(cDNA)"는 효소 역전사효소에 의해 mRNA 주형으로부터 형성된 단일-가닥 DNA 분자이다. 전형적으로, mRNA의 일부에 상보적인 프라이머가 역전사의 개시에 이용된다. 당업자는 또한 용어 "cDNA"를, 이러한 단일-가닥 DNA 분자 및 이의 상보적 DNA 가닥으로 구성된 이중-가닥 DNA 분자를 지칭하는 데 사용한다. 용어 "cDNA"는 또한, RNA 주형으로부터 합성된 cDNA 분자의 클론을 지칭한다.
"프로모터"는 구조 유전자의 전사를 지시하는 뉴클레오타이드 서열이다. 전형적으로, 프로모터는 유전자의 5' 비-코딩 영역에서 구조 유전자의 전사 시작 부위에 근접하게 위치한다. 전사의 개시에 작용하는 프로모터 내의 서열 요소는 종종 컨센서스(consensus) 뉴클레오타이드 서열을 특징으로 한다. 이들 프로모터 요소는 RNA 중합효소 결합 부위, TATA 서열, CAAT 서열, 분화-특이 요소(DSE(differentiation-specific element); 문헌[McGehee et al. (1993), Mol. Endocrinol., 7:551]), 환식 AMP 반응 요소(CRE), 혈청 반응 요소(SRE; 문헌[Treisman (1990), Seminars in Cancer Biol., 1:47]), 글루코코르티코이드 반응 요소(GRE), 및 다른 전사 인자를 위한 결합 부위, 예컨대 CRE/ATF(문헌[O'Reilly et al. (1992), J. Biol. Chem., 267:19938]), AP2(문헌[Ye et al. (1994), J. Biol. Chem., 269:25728]), SP1, cAMP 반응 요소 결합 단백질(CREB; 문헌[Loeken (1993), Gene Expr., 3:253]) 및 팔량체 인자(일반적으로 문헌[Watson et al. (1987), eds., Molecular Biology of the Gene, 4th Edition, The Benjamin/Cummings Publishing Company, Inc., 및 Lemaigre et al. (1994), Biochem. J., 303:1] 참조)를 포함한다. 프로모터가 유도성 프로모터인 경우, 전사 속도는 유도제에 반응하여 증가한다. 대조적으로, 프로모터가 구성적 프로모터인 경우, 전사 속도는 유도제에 의해 조절되지 않는다. 억제성 프로모터가 또한 공지되어 있다.
"조절 요소"는 코어 프로모터의 활성을 조정하는 뉴클레오타이드 서열이다. 예를 들어, 조절 요소는 특정 세포, 조직 또는 세포소기관에서 전사를 배타적으로 또는 우선적으로 가능하게 하는 세포 인자와 결합하는 뉴클레오타이드 서열을 함유할 수 있다. 이들 타입의 조절 요소는 보통, "세포-특이적", "조직-특이적" 또는 "세포소기관-특이적" 방식으로 발현되는 유전자와 연관이 있다.
"인핸서"는 전사의 시작 부위에 비해 인핸서의 거리 또는 배향과는 상관없이, 전사의 효율을 증가시킬 수 있는 조절 요소 타입이다.
"이종성 DNA"는 주어진 숙주 세포 내에 천연적으로 존재하지 않는 DNA 분자, 또는 DNA 분자 집단을 지칭한다. 숙주 DNA가 비-숙주 DNA(즉, 외인성 DNA)와 조합되는 한, 특정 숙주 세포에 이종성인 DNA 분자는 숙주 세포 종으로부터 유래된 DNA(즉, 내인성 DNA)를 함유할 수 있다. 예를 들어, 전사 프로모터를 포함하는 숙주 DNA 분절에 작동적으로 연결되는 폴리펩타이드를 인코딩하는 비-숙주 DNA 분절을 함유하는 DNA 분자는 이종성 DNA 분자인 것으로 여겨진다. 역으로, 이종성 DNA 분자는 외인성 프로모터에 작동적으로 연결된 내인성 유전자를 포함할 수 있다. 또 다른 예시로서, 야생형 세포로부터 유래된 유전자를 포함하는 DNA 분자는, 야생형 유전자가 결여된 돌연변이체 세포 내로 해당 DNA 분자가 도입된다면, 이종성 DNA인 것으로 여겨진다.
"발현 벡터"는 숙주 세포에서 발현되는 유전자를 인코딩하는 핵산 분자이다. 전형적으로, 발현 벡터는 전사 프로모터, 유전자 및 전사 종결자를 포함한다. 유전자 발현은 통상 프로모터의 제어 하에 놓이고, 이러한 유전자는 프로모터에 "작동적으로 연결된다"라고 한다. 유사하게는, 조절 요소 및 코어 프로모터는, 이러한 조절 요소가 상기 코어 프로모터의 활성을 조정한다면, 작동적으로 연결된 것이다.
"재조합 숙주"는 클로닝 벡터 또는 발현 벡터와 같은 이종성 핵산 분자를 함유하는 세포이다. 본 맥락에서, 재조합 숙주의 일례는 발현 벡터로부터 본 발명의 길항제를 생성하는 세포이다. 대조적으로, 이러한 길항제는 상기 길항제의 "천연 공급원"이며 발현 벡터가 결여된 세포에 의해 생성될 수 있다.
용어 "아미노-말단" 및 "카르복실-말단"은 본원에서 폴리펩타이드 내의 위치를 나타내는 데 사용된다. 문맥이 허용하는 경우, 이들 용어는 폴리펩타이드의 특정 서열 또는 일부와 관련하여, 근접성 또는 상대 위치를 나타내는 데 사용된다. 예를 들어, 폴리펩타이드 내의 참조 서열에 대해 카르복실-말단에 위치한 소정의 서열은 상기 참조 서열의 카르복실 말단에 근접하게 위치하지만, 완전한 폴리펩타이드의 카르복실 말단에 필수적으로 있는 것은 아니다.
"융합 단백질"은 적어도 2개의 유전자의 뉴클레오타이드 서열을 포함하는 핵산 분자에 의해 발현되는 하이브리드 단백질이다. 예를 들어, 융합 단백질은 친화성 매트릭스 또는 또 다른 관심 표적에 결합하는 폴리펩타이드와 융합된 항체 중쇄의 적어도 일부를 포함할 수 있다.
용어 "수용체"는 "리간드"라고 하는 생물활성(bioactive) 분자에 결합하는 세포-결합 단백질을 나타낸다. 이러한 상호작용은 세포 상에서 리간드의 효과를 매개한다. 수용체는 막-결합성, 세포액성(cytosolic) 또는 핵성(nuclear); 단량체성(예를 들어 갑상선 자극 호르몬 수용체, 베타-아드레날린성 수용체) 또는 다량체성(예를 들어 PDGF 수용체, 성장 호르몬 수용체, IL-3 수용체, GM-CSF 수용체, G-CSF 수용체, 에리스로포이에틴 수용체 및 IL-6 수용체)일 수 있다. 막-결합성 수용체는 세포외 리간드-결합 도메인, 및 전형적으로 신호 전달에 관여하는 세포내 효과기 도메인을 포함하는 다중(multi)-도메인 구조를 특징으로 한다. 소정의 막-결합성 수용체에서, 세포외 리간드-결합 도메인 및 세포내 효과기 도메인은 완전한 기능성 수용체를 포함하는 개별 폴리펩타이드에 위치한다. 일반적으로, 수용체에의 리간드의 결합은 수용체에서 형태 변화(conformational change)를 초래하여, 효과기 도메인과 세포 내의 다른 분자(들) 사이의 상호작용을 유발하며, 이는 다시 세포의 대사 변경을 초래한다. 수용체-리간드 상호작용과 종종 연결된 대사 과정(event)은 유전자 전사, 인산화, 탈인산화, 증가된 환식 AMP 생성, 세포내 칼슘의 동원, 막지질의 동원, 세포 접착, 이노시톨 지질의 가수분해 및 인지질의 가수분해를 포함한다.
용어 "발현"은 유전자 생성물의 생합성을 지칭한다. 예를 들어, 구조 유전자의 경우, 발현은 구조 유전자를 mRNA로 전사시키고, mRNA를 하나 이상의 폴리펩타이드로 번역하는 것을 수반한다.
용어 "보체/항-보체 쌍"은 적절한 조건 하에 비-공유 결합된, 안정한 쌍을 형성하는 비-동일한(non-identical) 모이어티를 나타낸다. 예를 들어, 비오틴과 아비딘(또는 스트렙타비딘)은 보체/항-보체 쌍의 원형적(prototypical) 구성원이다. 다른 예시적인 보체/항-보체 쌍은 수용체/리간드 쌍, 항체/항원(또는 합텐 또는 에피토프) 쌍, 센스/안티센스 폴리뉴클레오타이드 쌍 등을 포함한다. 보체/항-보체 쌍의 후속적인 해리가 바람직한 경우, 이러한 보체/항-보체 쌍은 바람직하게는 109 M-1 미만의 결합 친화성을 가진다.
"검출 가능 표지"는 진단에 유용한 분자를 생성하기 위해 항체 모이어티에 공액될 수 있는 분자 또는 원자이다. 검출 가능 표지의 예로는, 킬레이터, 광활성제(photoactive agent), 방사성 동위원소, 형광제, 상자성 이온 또는 다른 마커 모이어티가 있다.
용어 "친화성 태그"는 본원에서, 제2 폴리펩타이드의 정제 또는 검출을 제공하거나 기질에의 제2 폴리펩타이드의 부착을 위한 부위를 제공하기 위해 제2 폴리펩타이드에 부착될 수 있는 폴리펩타이드 분절을 나타내는 데 사용된다. 원칙적으로, 항체 또는 다른 특이적인 결합제가 이용 가능한 임의의 펩타이드 또는 단백질이 친화성 태그로서 사용될 수 있다. 친화성 태그는 폴리히스티딘 트랙트, 단백질 A(문헌[Nilsson et al. (1985), EMBO J. 4:1075; Nilsson et al. (1991), Methods Enzymol., 198:3]), 글루타티온 S 전이효소(문헌[Smith et al. (1988), Gene, 67:31]), Glu-Glu 친화성 태그(문헌[Grussenmeyer et al (1985)., Proc. Natl. Acad. Sci. USA 82:7952]), 성분 P, FLAG® 펩타이드(문헌[Hopp et al. (1988), Biotechnology 6:1204]), 스트렙타비딘 결합 펩타이드, 또는 다른 항원성 에피토프 또는 결합 도메인을 포함한다. 일반적으로, 문헌[Ford et al. (1991), Protein Expression and Purification, 2:95]를 참조한다. 친화성 태그를 인코딩하는 DNA 분자는 상업적 공급 회사(예를 들어 Pharmacia Biotech, 미국 뉴저지주 피스카타웨이 소재)로부터 입수 가능하다.
용어 "산성 잔기" 및 "음전하성 잔기"는 산성 기를 포함하는 측쇄를 갖는 아미노산 잔기를 지칭한다. 예시적인 산성 또는 음전하성 잔기는 D 및 E를 포함한다.
용어 "아미드 잔기"는 산성 기의 아미드 유도체를 포함하는 측쇄를 갖는 아미노산을 지칭한다. 예시적인 아미드 잔기는 N 및 Q를 포함한다.
용어 "방향족 잔기"는 방향족 기를 포함하는 측쇄를 갖는 아미노산 잔기를 지칭한다. 예시적인 방향족 잔기는 F, Y 및 W를 포함한다.
용어 "염기성 잔기" 및 "양전하성 잔기"는 염기성 기를 포함하는 측쇄를 갖는 아미노산 잔기를 지칭한다. 예시적인 염기성 또는 양전하성 잔기는 H, K 및 R을 포함한다.
용어 "친수성 잔기" 및 "극성 비하전된 잔기"는 극성 기를 포함하는 측쇄를 갖는 아미노산 잔기를 지칭한다. 예시적인 친수성 또는 극성 비하전된 잔기는 C, S, T, N 및 Q를 포함한다.
용어 "비-작용성 잔기" 및 "작은 소수성 잔기"는 산성, 염기성 또는 방향족 기가 결여된 측쇄를 갖는 아미노산 잔기를 지칭한다. 예시적인 비-작용성, 작은 소수성 잔기는 M, G, A, V, I, L 및 노르류신(Nle)을 포함한다.
본 발명의 일 양태는 PCSK9 결합 폴리펩타이드에 관한 것이다. "PCSK9-결합 폴리펩타이드"는 전구단백질 전환효소 서브틸리신(subtilisin)/켁신(kexin) 타입 9(PCSK9) 단백질에 결합하는 폴리펩타이드를 의미한다. 일부 경우, PCSK9-결합 폴리펩타이드는 PCSK9가 저밀도 지질 수용체(LDLR)에 결합하는 것을 차단한다. 이러한 차단성 PCSK9-결합 폴리펩타이드는 모노클로날 항체(mAb)일 수 있고, 다음 중 하나일 수 있다:
a. 서열번호: 136의 아미노산 서열을 갖는 중쇄 폴리펩타이드 및 서열번호: 134의 아미노산 서열을 갖는 경쇄 폴리펩타이드를 포함하는 mAb(항체 AK, 에볼로쿠맙) 또는 이의 항원-결합 단편;
b. PCSK9에의 결합에 대해 에볼로쿠맙과 경쟁하는 mAb;
c. 하기를 포함하는 mAb:
i. 하기 상보성 결정 영역(CDR)을 포함하는 중쇄 폴리펩타이드: 서열번호: 376 또는 378에서 CDR1인 중쇄 CDR1; 서열번호: 376 또는 378에서 CDR2인 중쇄 CDR2; 서열번호: 376 또는 378에서 CDR3인 중쇄 CDR3, 및
ii. 하기 CDR을 포함하는 경쇄 폴리펩타이드: 서열번호: 377 또는 379에서 CDR1인 경쇄 CDR1; 서열번호: 377 또는 379에서 CDR2인 경쇄 CDR2; 및 서열번호: 377 또는 379에서 CDR3인 경쇄 CDR3;
d. PCSK9의 잔기 S153, D188, I189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, 및 D238, K243, S373, D374, S376, T377, F379, I154, T1897, H193, E195, I196, M201, V202, C223, T228, S235, G236, A239, G244, M247, I369, S372, C375, C378, R237 및 D238 중 적어도 하나에 결합하는 mAb로서, 상기 PCSK9는 서열번호: 369의 아미노산 서열을 포함하는, mAb;
e. 하기를 포함하는 항체에 의해 결합되는 에피토프와 중첩되는 PCSK9 상의 에피토프에서 PCSK9에 결합하는 mAb:
i. 서열번호: 136에서 아미노산 서열의 중쇄 가변 영역; 및
ii. 서열번호: 134에서 아미노산 서열의 경쇄 가변 영역, 및
iii. 여기서, mAb의 에피토프는 저밀도 지질단백질 수용체(LDLR) 단백질의 상피 성장 인자-유사 반복부 A(EGF-A) 도메인이 결합하는 부위와 추가로 중첩됨(문헌[Horton, Cohen, & Hobbs (2007), Trends Biochem Sci, 32(2), 71-77. doi: 10.1016/j.tibs.2006.12.008; Seidah & Prat (2007), J Mol Med (Berl), 85(7), 685-696];
f. 하기 상보성 결정 영역(CDR)을 포함하는 중쇄 폴리펩타이드를 포함하는 mAb:
i. 서열번호: 373, 374 및 375의 아미노산 서열을 각각 갖는 중쇄 CDR1, CDR2 및 CDR3; 및
ii. 서열번호: 369, 370 및 371의 아미노산 서열을 각각 갖는 경쇄 CDR1, CDR2 및 CDR3; 또는
g. 서열번호: 378의 중쇄 변이체 영역 서열 및 서열번호: 379의 경쇄 변이체 영역 서열을 포함하는 mAb.
바람직한 실시형태
전반적인 서열 특징과 점도의 상관관계
본 명세서의 실시예 1에 보고된 연구의 주요 목적은 고농도 모노클로날 항체 제제의 점도를 감소시킬 목적으로, 점도와 IgG 모노클로날 항체의 아미노산 서열 또는 전반적인 서열 특징 사이의 연관성을 식별하는 것이었다. 이를 위해, 43개의 상이한 모노클로날 항체의 점도값을 150 mg/ml에서 측정하여, 5 내지 33 cP의 광범위한 값을 제공하였다(도 1a 및 도 1b). 모노클로날 항체의 주요 전반적인 서열 특징, 예컨대 경쇄 및 중쇄 유형, 이들의 서브타입(생식선), 및 pI는 계산되었으며 점도와 상관관계가 있었으나, 유의한 상관관계를 즉시 드러내지는 않았다(도 1a 및 도 1b). IgG 이소타입 내의 다형성(polymorphism)(알로타입으로 공지됨)은 인간으로부터 유래된 혈청학적 시약을 사용하여 기재되었고(문헌[Ropartz, C., Schanfield, M. S., and Steinberg, A. G. (1976), "Review of the notation for the allotypic and related markers of human immunoglobulins," WHO meeting on human immunoglobulin allotypic markers, held 16-19 July 1974, Rouen, France; report amended June 1976, J Immunogenet. 3, 357-362]), 중쇄 및 경쇄의 보존 영역 내의 몇몇 특이적인 위치에서 소정의 아미노산 잔기와 상관관계가 있었다(문헌[Jefferis and Lefranc (2009) Human immunoglobulin allotypes: possible implications for immunogenicity, mAbs 1, 332-338])(문헌[Vidarsson, G., Dekkers, G., and Rispens, T. (2014) IgG subclasses and allotypes: from structure to effector functions, Front Immunol. 5, 1-17]). 알로타입은 경쇄 및 중쇄의 다른 식의(otherwise) 보존 영역에 소수의 상이한 잔기(하기 기재됨)를 도입한다. 이러한 연구에 사용된 모든 카파 경쇄는 동일한(3) 알로타입(EU 넘버링에서 잔기 A153, V191을 특징화함)이었다. 모든 IgG2 중쇄 경쇄는 동일한 (n-) 알로타입이었다(P189를 특징화함). 4개의 IgG1 중쇄 알로타입이 기재되었다(EU 넘버링에서 하기 관련된 잔기를 포함함): f(R214); z(K214); a(D356, L358) 및 x(G431)(Jefferis & Lefranc, 2009)(Vidarsson et al., 2014). 위치 E356, M358 및 A431에 대안적인 잔기를 갖는 IgG1 중쇄는, 이들 아미노산 잔기가 다른 IgG 서브클래스에 존재하기 때문에 알로타입을 구성하지 않는다. IgG1 알로타입(x)은 이 연구에 존재하지 않았으며; 모든 IgG1 중쇄는 A431을 가졌다. IgG1 중쇄 알로타입(f), (z), (a) 및 관련된 잔기는 도 1a 및 도 1b에서 보여진다.
도 1a 및 도 1b에서 항체는 점도에 의해 분류된다. 도 1a 및 도 1b의 표는 모노클로날 항체 명칭, 측정된 농도, 측정된 점도값, 및 타입, 서브타입 및 계산된 pI를 포함한 전반적인 서열 매개변수를 포함한다. IgG1 타입, 람다 경쇄 및 VH1 중쇄 서브타입은 볼드체로 되어 있다.
IgG1과 IgG2 중쇄 및 카파와 람다 경쇄는 점도 범위에 걸쳐 보다 고르게 분포되었다. 서브타입의 서열 평가는 몇몇 고점도 및 저점도 서브타입 쌍: VH1|1-18 및 VH1|1-02; VH3|3-33 및 VH3|3-07; VK3|L16 및 VK3|A27을 드러내었으며, 이때 점도 잔기와 상관 시, 무작위 상관관계 확률은 각각 0.0002; 0.076 및 0.031에서였다(도 2). 이 연구는 D 및 J 영역 서열과 점도의 상관관계를 알아보았으나, 유의한 상관관계를 확인하지 못하였다.
도 2는 점도에 대한 무작위 상관관계 확률을 가리키는 p-값을 보여준다. 도 2는 또한, 고점도 서브타입에서의 잔기, Aho 넘버링에서의 위치, 및 저점도 서브타입에서의 잔기를 보여준다.
VH1 서브타입의 14개 IgG 분자 중에서, 고점도는 VH1 1-18 서브타입과 강하게 연관이 있었고, 저점도는 VH1 1-01 서브타입과 강하게 연관이 있었으며, 이때 이의 매우 낮은 확률은 우발 동시 계수(random coincidence)였다(도 9).
2개의 서브타입과 점도 사이의 상관관계를 평가하기 위해, 스튜던츠 t-테스트에 의한 동일한 집단 평균의 확률을, 양측 분포(two-tailed distribution)와 함께 t-테스트 2-표본 동일 변이체를 사용하여 VH1|1-02 대 VH1|1-18, VH3|3-33 대 VH3|3-07 및 VK3|L16 대 VK3|A27에 대해 계산하였다.
경쇄 VK3|L16과 고점도 및 VK3|A27과 저점도의 연관성(t-테스트, p=0.031)이 검출되었다(도 2, 도 12, 좌측면). VK3|L16 대 VK3|A27 및 VH3|3-33 대 VH3|3-07은 이 명세서에서 더 논의된다. VH1|1-18 및 VH1|1-02는 점도에 대한 강한 상관관계로 인해, 하기와 같이 더 평가되었다. 다음 단계로서, 43개의 항체 사슬 서열을 하기와 같이 정렬하고, 평가하였다.
서열 정렬 및 넘버링 시스템
하기를 포함한 몇몇 IgG 넘버링 시스템이 존재한다:
· EU--문헌[Edelman et al. (1969), "The covalent structure of an entire gamma immunoglobulin molecule," Proc. Natl. Acad. Sci. U. S. A . 63, 78-85];
· Kabat--문헌[Kabat et al. (1991), Sequences of proteins of immunological interest, Fifth Edition. NIH Publication No. 91-3242];
· Chothia--문헌[Chothia et al. (1992), "Structural repertoire of the human VH segments," J.Mol.Biol. 227: 799-817; Tomlinson et al., (1995), "The structural repertoire of the human V kappa domain. EMBO J. 14: 4628-4638];
· Aho--문헌[Hoenegger et al. (2001), "Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool," J. Mol. Biol . 309, 657-670];
및 기타. 상기 언급된 모든 4개의 넘버링 시스템은 도 9에 예시되어 있으며, 우측면은 VH1 서브타입의 중쇄의 프레임 영역 3에 대한 것이다. 상이한 항체의 가변 도메인의 400개 초과의 결정 구조로부터 유래된 아미노산 잔기의 공간 위치를 이용함으로써 Aho 체계를 구축하였다. A. Honegger(상기 인용)에 의해 정의된 Aho 넘버링 시스템이 3D 구조-기반 넘버링 시스템이기 때문에, 이 연구에 사용하였다. 이는 CDR 내의 잔기에 대해 특이적으로 이점을 생성하며: 동일한 숫자를 가진 잔기는 유사한 공간 영역에 위치하고, 상이한 IgG 서열에 걸쳐 비교될 만하다. Aho 넘버링 체계에서 잔기 위치가 3차 구조와 관련이 있기 때문에, 이들 위치는 생물물리학적 및 생화학적 특성, 및 가능하게는 점도와 더 연관될 것이다. Aho 넘버링은 이 명세서의 몇몇 표에 보여진 바와 같이 다른 주요 넘버링 체계와 함께 정렬되고 상관관계를 이룬다. 4개의 넘버링 시스템 중 임의의 시스템은 바람직한 아미노산 치환을 식별하기 위해 상호교환적으로 사용될 수 있다. 상이한 넘버링 시스템에 대해 중쇄 가변 영역은 하기 잔기: 149 Aho, 117 EU, 113 Kabat, 113 Chothia에서 종결된다. 경쇄 가변 영역은 149 Aho, 107 EU, 107 Kabat, 107 Chothia에서 종결된다. Aho 넘버링은, Kabat 및 Chothia에서와 같이 CDR 잔기에 문자를 사용하는 대신(예를 들어 Kabat 및 Chothia에 대해 82b), CDR 영역에 더 많은 수를 할당한다. 그 결과, 동일한 잔기에 대한 Aho 수는 종종 더 길다. 각각의 가변 영역은 하기 서열: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4에서 3개의 상보성 결정 영역(CDR) 및 4개의 프레임워크 영역(FR)을 포함한다. CDR이 항원에의 결합을 목적으로 큰 서열 다양성을 제공하는 한편(CDR3 영역이 가장 자주 결합함), FR 서열은 보다 보존되고, 단지 소수의 차이를 함유하며, 이들 차이 중 일부는 서브타입 특이적이다.
점도에 대한 서열의 상관관계
전반적인 서열 특징을 평가하는 것 외에도, 가변 영역의 서열을 정렬하여, 점도 차이의 원인이 되는 잔기를 식별하였다. 시각적 관찰 외에도, 소프트웨어 기계 학습 알고리즘을 개발하고, 적용하여, 점도에 가장 많이 영향을 주는 잔기를 식별하고 이들의 서열로부터 항체의 점도값을 예측하였다. Aho-정렬 위치에서 잔기의 전하 및 소수성을 사용하여 예측 모델을 구축하였다.
중쇄 VH1 서열 정렬, 및 고-점도 VH1 1-18 서브타입의 5개 서열 및 저-점도 VH1 1-02 서브타입 분자의 5개 서열의 평가는, 단지 4개의 잔기가 2개 서브타입들 사이에서 프레임에서 상이하였으며, 4개 모두 프레임워크 3에 위치하였음을 드러내었다(도 9, 우측면). CDR이 종종 항원에의 결합에 관여하고 점도를 감소시키려는 목적으로 CDR을 조작하는 것(CDR 내의 잔기를 돌연변이화하는 것)은 효능 상실이라는 유의한 위험을 가질 것이기 때문에, 다수의 서열 차이가 CDR에서 관찰되었으나 이들 차이는 연구 범위를 벗어났다. 점도와 FR3 내의 잔기에서 서브타입-관련 차이는, 하기 아미노산 치환: T82R, T86I, R94S 및 S95R이 Aho 넘버링에서 점도를 잠재적으로 감소시킬 수 있을 것임을 가리켰다. 소프트웨어 알고리즘은 4개의 치환을 지지하였고, 또한, 하기 2개의 치환: FR1에서 경쇄 G13V/L 및 CDR2의 엣지로부터 중쇄 S59R/K가 점도 감소와 상관관계가 있음을 제안하였으며: 후자의 상관관계는 VH3 서브타입에서 관찰되었다(도 9, 우측면).
제안된 아미노산 치환의 인 실리코(in silico) 평가
VH T82R. R82는 VH1-02에서 고빈도로 발생한다. IgG 구조 모델링은, 중쇄 Aho 위치 82가 글로불린 폴드(fold)의 상위(upper) 코어의 일부이고 항원과 전형적으로 접촉하지는 않지만 문헌[Ewert et al. (2003), "Biophysical properties of human antibody variable domains," J. Mol. Biol . 325: 531-553]에 따르면 CDR 백본과 직접적으로 접촉할 수 있음을 가리켰다. HC82는 CDR1 및 CDR2 백본 아미드와 매우 보존된 주쇄 - 측쇄 H-결합 상호작용을 가진다(상기 Honegger et al.). R82는 또한, CDR2 루프의 백본 산소 원자와 배위될 수 있다.
VH R94S 및 S95R. S94 및 R95는 VH1-02에서 고빈도로 발생한다. 이들 위치는 표면 상에서 항원 결합 도메인으로부터 멀리 위치하고, 하위 코어의 일부인 것으로 여겨진다.
T86I. I86은 VH1-02에서 고빈도로 발생한다. 데이터는 표면 상의 소수성 잔기(I)를 친수성 잔기(T)로 치환하는 것을 제안하며, 이러한 치환은 잠재적으로 응집을 초래할 수 있다.
VH S59R/K- VH1 및 VH3 내에서, 친수성 위치 59는 더 낮은 점도와 연관이 있다. VH S59R/K 위치는 높은 구조적 및 서열 가변성을 가지며, 용매에 꽤 노출되고, 상위 코어의 일부이며 결합에 영향을 줄 수 있는 잔기 58과 60 사이에 직접적으로 존재한다. 이러한 구조는 잔기 58 및 60(특히 묻힌다면(buried) 58)에서의 차이에 직접적으로 의존할 가능성이 있을 것이다. R/K59는 낮은 발생 빈도(2% 미만)을 가지고, 아미노산 잔기 빈도 분석에 따르면 VH1에서 관찰되지 않았다. 모든 R/K59는 1개(VH4)를 제외하고는 VH3 데이터세트 내에 수용된다.
VL G13V/L- 이 위치는 구조적으로 묻혀 있고, 상기 Ewert et al.에 따르면 가변 도메인의 하위 코어의 일부이다. 이러한 관점에서, 더 많은 소수성 잔기로의 G13V 돌연변이는 코어를 더 강하게 만들어야 한다.
요약하면, 인 실리코 서열 분석은, 제안된 돌연변이가 생리학적 또는 약한 산성 제제 조건 하에 임의의 추가의 글리코실화 부위 또는 신속한 분해에 취약한 부위를 도입하지 않음을 가리켰다(NG, NS, NT, DG, DH). VH T82R, T86I, R94S 및 S95R 돌연변이는 프레임 영역 3에서 서브타입 VH1-18로부터 VH1-02로의 스위치를 제공할 것이며, 따라서, 이들 돌연변이는 임의의 비통상적인 또는 희귀한 모티프를 도입하지 않아야 한다. VH S59R 및 VL G13V 돌연변이의 첨가는 VH1 외부의 VH3 서브타입으로부터 소프트웨어에 의해 제안되었다. HC CDR2의 엣지에 존재하는 S59R을 제외하고 돌연변이 부위 중 어느 것도 결합 영역에 가까이 위치하지 않으며, 따라서, 효능/결합을 방해할 약한 위험성을 나타낸다. 아르기닌은 위치 59에서 매우 낮은 빈도의 잔기(R59)이며, 따라서 이의 영향을 예측하기란 어렵다. T86I는 응집 위험이 높은 것으로 식별되었으며, 돌연변이 목록으로부터 제거되었다.
생성된 돌연변이체 및 이들의 발현, 효능, 화학적 변형, 글리코실화 및 점도.
상기 고려사항들을 참작하여, 효능을 유지하면서도 점도를 감소시킬 목적으로 고-점도 VH1-18 서브타입의 2개의 IgG2 항체 AK 및 AO에 대해 몇몇 돌연변이체를 생성하였다(도 9b). 도 9b는 모노클로날 항체 돌연변이체 기호 및 중쇄 및 경쇄 상에서의 관련 돌연변이를 포함한다.
S59R 치환을 함유하는 AK 돌연변이체 둘 다에서 매우 낮은 발현 수준이 관찰되었다(도 3에서 *로 표시되어 있음). 생존력 및 생존 세포 밀도 또한, 이들 중 하나인 AK(59 82 94 95 13)에서 낮았다. 한편, S59R 치환을 함유하는 항체 AO 돌연변이체는 AO 부모 분자의 역가와 비교될 만한 역가를 생성하였다. 중쇄 위치 59에 대한 일반적인 결론을 내리기에는 통계가 충분하지 않았지만, 이러한 사례는 단일 아미노산 치환이 발현을 급격하게 변경시킬 수 있음을 제안하였다. 산화, 탈아미드화, 이성질체화 및 글리코실화 패턴을 포함한 화학적 변형은 펩타이드 맵핑 LC-MS 분석에 의해 측정된 바와 같이 2개의 부모 및 이들의 돌연변이체 사이에서 유사하였다.
PCSK9에의 결합을 통해 측정된 부모 AK 항체 및 2개의 잘-발현된 돌연변이체의 효능값은 유사하였다(도 4). 마지막으로, AK 및 AO 돌연변이체의 측정된 점도값은 예측된 바와 같이 부모보다 유의하게 낮았다(도 5). 예를 들어, AK(82 94 95) 돌연변이체는 부모의 점도의 39%에 불과하였다. S59R 치환을 함유하는 AO 돌연변이체 둘 다의 점도는 훨씬 더 낮아서, 부모의 점도의 대략 28%였다(도 5). S59R 돌연변이체는 AK 항체에 대해서는 잘 발현되지 않았으며, 점도가 측정될 수 없었다. 비교를 위해 VH1|1-18 및 VH1|1-02 생식선 서브패밀리에 대한 평균 점도값을 부가하였다. CDR에서 8개 및 프레임 영역에서 4개를 포함하여 총 12개의 일관된 서열 차이를 VH1|1-18과 VH1|1-02 서브패밀리 사이에서 식별하였다(도 9). 모두 프레임 영역 3에 있는 3개의 부위를 고점도 VH1|1-18로부터 저점도 VH1|1-02로의 아미노산 치환을 위해 선택하였다. 프레임에서의 3개의 점 돌연변이를 VH1|1-18 서브패밀리의 2개의 mAb(AK 및 AO)에 도입하여, 이들 잔기만 VH1|1-02에 존재하는 잔기로 전환시켰다. 점도에서 가능한 2배 저하를 달성할 가능성이 이론적으로 낮긴(3/12) 하였지만, 이들 치환은 오히려 예상치 못하게 바람직한 결과를 낳았으며: 단지 3개의 치환으로도, 점도는 2개의 항체 분자 모두에서 대략 2배 저하되었다.
점도 대 pI
pI로부터의 점도 의존성이 43개의 mAb로 이루어진 전체 세트로부터 명확하지 않더라도, VH1 서브세트는, pH 5.2 제제에서 mAb의 pI 값이 pI 8.5로부터 pI 6.5까지 저하될 때, 점도는 꾸준히 증가하였음을 명확하게 보여주었다(도 6). 고-점도 VH1|1-18 mAb와 저-점도 VH1|1-02 mAb 사이의 시프트(shift) 또한 알 수 있다. 예측된 바와 같이, AK 및 AO 항체의 T82R, R94S 및 S95R 돌연변이체는 도면 상에서 VH1|1-18로부터 VH1|1-02 영역까지 점도 스케일을 따라 대략 2배 아래로 이동하였다(도 6). 돌연변이체 AO(59 82 94 95) 및 AO(59 82 94 95 13)는 훨씬 더 낮은 점도 및 약간 더 높은 pI까지 이동하였고, 이는 VH1 그룹의 외부로부터 채택된 S59R 치환이 점도를 더 감소시키는 데 효과적이었음을 가리켰다. 안타깝게도, R59를 함유하는 AK 돌연변이체는 잘 발현되지 않았으며, 이는 위치 59에서 저-빈도 아르기닌 잔기의 출현이 발현에 영향을 줄 수 있음을 제안하였다.
pH가 pI보다 낮은 제제(예를 들어 이 연구에서 사용된 약한 산성 제제)에서 항체에 대한 pI의 증가는 전형적으로, 점도 저하를 초래한다. 이러한 결과는, 양으로 하전된 항체 분자의 쿨롱 반발에 의해 설명될 수 있다. 항체를 포함한 단백질은 고농도에서 불량한 용해성 및 높은 침전율을 보여주며, 이는 점도에 영향을 주는 것으로 공지되어 있다. 프레임 영역 3에서 VH1|1-18로부터 VH1|1-02로의 치환이 점도에서 2배 저하 및 항체 pI 값에서 단지 미미한 증가를 초래하였으며, 이는, 전하 증가가 아니라 그보다는 일부 구조적 변화가 점도의 급격한 저하의 원인일 수 있음을 제안한다는 것이 흥미롭다.
수백 개의 Fab 도메인의 결정학 구조를 겹친 후, 모든 VH 및 VL 위치에 대한 수소 결합 상호작용이 식별되었다(문헌[Honegger et al. (2001), "Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool," J. Mol. Biol . 309: 657-670]). 데이터는, 식별된 위치가 주쇄 및 측쇄 수소 결합 상호작용을 통해 다른 잔기에 결합될 수 있음을 가리킨다(타입 III AK 및 AO 항체 분자에 대해). 예를 들어, 일부 VH 타입 III 면역글로불린 구조에서 94는 77에 결합되었고; 95 내지 18에; 59는 67, 66, 65, 61, 60에, 그리고 VL13은 146, 148에 결합되었다. 따라서, 이들 위치에서 잔기 치환은 상호작용 및 면역글로불린 폴드를 변화시킬 수 있다. AK 항체의 결정 구조(문헌[Jackson et al ., 2007), "The Crystal Structure of PCSK9: a Regulator of Plasma LDL-Cholesterol," Structure 15: 545-52])는, 모든 3개의 위치 82, 94 및 95가 Fab 영역의 바로 주변부 상에 존재하고, 용매 및 다른 항체 분자에 노출됨을 제안한다. VH3(도 11) 및 VK3(도 12)에서 FR3 위치의 변화가 또한, 점도와 상관관계가 있다. 점도에서 이들의 역할에 대한 한 가지 설명은, FR3에서 이들 위치가 분자의 주변부 상에 존재하고 주사 바늘을 통한 움직임과 연관된 전단 응력 및 점도 측정 동안 분자간 상호작용에 능동적으로 연계된다는 것이다.
더 낮은 점도 VK3|A27 및 더 높은 점도 VK3|L16 항체는 점도와 pI 사이에서 역의 상관관계를 보여주었다(도 8, 도 12).
pI는 매우 강하지는 않았지만 일부 경우에서는 점도의 유용한 예측자였음을 언급할 필요가 있다. 일반적으로, pI가 증가함에 따라 점도는 저하되었으며, pI를 고려할 것이다. 예를 들어, VH3|3-33의 점도값은 낮아졌으며, 더 높은 pI 항체 분자에 대해서는 VH3|3-07과 유사하였다(도 7). 따라서, VH3|3-33의 점도를 예측할 때, pI가 고려될 것이다.
VH3 및 VK3 생식선 패밀리에 대해 제안된 점도 감소
고-점도 VH3|3-33 및 저-점도 VH3|3-07 항체는 평균적으로, 큰 점도 차이를 갖는 한편, 유사한 pI 범위를 차지한다(도 7). 예상치 못하게 평균적으로, VH3|3-07은 더 낮은 점도 및 또한 더 낮은 pI를 가졌으며, 이는 문헌에서 보고된 전형적인 거동과 모순된다. 하기 VH3|3-33 분자의 점도값은 돌연변이: AQ, AM, AI, AG에 의해 감소될 수 있다.
고-점도 VK3|L16 및 저-점도 VK3|A27 경쇄를 갖는 모노클로날 항체가 또한, 큰 점도 차이를 보여준 한편, pI 값에서는 비교적 작은 차이를 보여주었고, 이는 다시, 서브패밀리들 사이에서의 구조적 차이를 제안한다(도 8). 하기 VK3|L16 분자의 점도값은 도 11에서 기재된 돌연변이: 항체 AQ 및 AF에 의해 감소될 수 있다.
전반적인 서열 특징의 분석은, 하기 고/저점도 쌍: VH1|1-18 / VH1|1-02; VK3|L16 / VK3|A27; 및 VH3|3-33 / VH3|3-07을 드러내었으며, 이때 상관관계의 p-값은 각각 0.0002, 0.031 및 0.076에서였다(도 2). 점도 차이와 상관관계가 있는 서열 위치 및 잔기가 식별되었으며, 점도 저하 점 돌연변이에 대한 후보로서 고려될 수 있다(도 2). VH 및 VL 패밀리와 점도의 수행된 상기 상관관계는, 이론적으로 하기 VH 및 VL 조합: VH에 대해 VH2, VH3|3-07, VH1|1-02 및 VL에 대해 VK3, VL1, VK3|A27을 갖는 항체가 최저 점도를 가질 것임을 가리킨다(도 13a 및 도 13b). VH1|1-02 및 VK3|A27 배열의 3개의 항체는 사실상 본 발명자들의 세트에서 발생하였고, 이들은 실제로 낮은 점도값: B(5.6 cP), J(8.2 cP), Y(12.1 cP)을 나타내었다.
화학적 가교 연구
점성 항체 용액에서 잠재적인 단백질-단백질 상호작용의 광범위한 조사는, 높은 단백질 농도에서 화학적 가교를 사용하여 시도되었다. 화학적 가교는, 단백질의 특이적인 부분이 서로 상호작용함을 입증하기 위해 사용되는 전형적인 생화학적 기술이다. 본 문헌에서, 본 발명자들은 고농도 점성 항체 용액에서 잠재적인 단백질-단백질 상호작용을 식별하기 위한 제로 길이(zero length) 화학적 가교 시약의 사용을 기재하고 있다. 점성 및 비-점성 항체의 화학적 가교 결과는 용액에서 잠재적인 단백질-단백질 상호작용의 모델을 구축하는 데 사용된다.
EDC를 이용한 화학적 가교는, 보편적인 화학적으로 가교 가능한 올리고머성 분포의 존재를 드러낸다. 올리고머성 패턴을 초래하는 화학적 가교는 놀랍게도, 분가간이 아니라 분자내 가교이다. Fc의 상부와 Fab의 하부 사이의 분자내 가교는 Fc-Fc 매개 항체 올리고머의 형성을 도울 수 있는 항체 형태를 초래한다. 1HZH 항체 결정 구조는, IgG1 육량체를 형성하는 데 중대한 Fc-Fc 상호작용을 용이하게 하기 위해 Fc 도메인에 기대어 고정된(pinned) 하나의 Fab 팔(arm)을 갖는 비대칭적 단위에서 항체 육량체를 함유한다. 이러한 형태의 출현은 단백질 결정에서 육량체의 형성에 중대할 수 있거나 그렇지 않을 수 있다. Fab-Fc 분자내 화학적 가교가 존재할 때, 용액 내에서 육량체를 형성하려는 증가된 경향은, Fc에 고정된 Fab 팔이 Fc-Fc 기반 항체 올리고머를 형성하려는 증가된 경향을 가질 수 있음을 제안한다.
Fc-Fc 상호작용의 저하는 용액 점도를 저하시킬 수 있다
과학적 문헌은, Clq1과의 상호작용 및 CDC 활성과 관련된 항체의 육량체 형성에 대한 연구를 포함한다. Diebolder 등은, K439E 및 S440K를 포함한 소정의 Fc 점 돌연변이를 갖는 항-CD20 항체가 CDC 활성을 무력화시켰으나, 연관된 K439E/S440K 이중 돌연변이체는 CDC 활성을 복구시켰음을 확인하였다. 또한, I253A 돌연변이는 CDC 활성을 저하시켰다. 문헌[Diebolder et al. (2014), "Complement is Activated by IgG Hexamers Assembled at the Cell Surface," Science 343: 1260-3]. Diebolder 등은 이들이 개시하는 돌연변이체를 항체 점도에 미치는 효과와 연관시키지 않았다. 유사하게는, van den Bremer 등(2015)은, 항체의 C-말단에 있는 하전된 잔기가 IgG 육량체 구조를 형성하는 능력의 저하로 인해 Clq1 상호작용을 저하시킬 수 있음을 확인하였다. 저자들은 IgG의 C-말단에 있는 하전된 잔기의 존재를 항체 용액 점도에 미치는 효과와 연관시키지는 않았다.
점성 항체 용액에서 항체의 육량체의 관찰은, 항체 육량체 결정 구조뿐만 아니라 Clq1(보체)의 모집(recruitment) 전에 형성되는 것으로 생각되는 구조에 존재하는 Fc-Fc 상호작용이 화학적 가교제 EDC의 부재 시 점성 항체 용액 내에 존재하는 가능성이 있음을 제안하였다. Fc-Fc 상호작용이 용액 점도에 기여할 것인지 테스트하기 위해, Diebolder 등에 의해 수행된 연구를 기반으로 한 Fc 돌연변이체를 Amgen사에서 발생시켰다. 그 후에, 콘 앤드 플레이트 유동학(cone and plate rheology)에 의해 항-PCSK9 제제 완충제 내에서 물질을 평가하였다. 부모 항-PCSK9 항체 AK와 Fc 돌연변이체 항-PCSK9 항체의 비교는, Fc에 대한 Fc의 친화성의 저하가 항체의 용액 점도를 저하시킨다는 것을 입증하였다. 점 돌연변이체는 FcRn 결합능을 보유하였고, 생물활성에 아무런 변화가 없었다. 야생형 점도로 되돌아가기 위해 야생형 보체 활성을 복구시킨 이중 돌연변이체의 능력은, Fc-Fc 상호작용 능력이 야생형 수준으로 복구된다면 점도 저하가 역전될 수 있음을 증명한다. 용액 점도를 증가시키는 Fc-Fc 매개 올리고머성 화학종의 관찰과 함께 고려하면, 항체 용액 점도에 기여하는 보편적인 Fc-매개 단백질-단백질 상호작용이 존재한다. Diebolder 등에 의해 CDC 활성을 감소시키는 것으로 식별되고 이 연구에서 점도에 대해 테스트된 5개의 돌연변이, S440K, I253A, K439E, H433A, N434A 중에서, 단지 처음 2개의 돌연변이만 고농도 항-PCSK9 제제에서 감소된 점도를 보여준 한편, K439E, H433A 및 N343A는 고농도 항-PCSK9 제제에서 점도를 감소시키지 않았으며, 이는 직접적인 상관관계가 존재하지 않고, 당업자는 Diebolder 등에 의해 제공된 정보로부터 더 낮은 점도를 올바르게 예상할 수 없을 것임을 가리킨다는 점에 주목할 필요가 있다. K439E 돌연변이체는 또한, 고 단백질 농도 수크로스 제제에서 평가되었으며, 동일한 농도에서 부모 항-PCSK9 돌연변이체보다 점성이 낮은 것으로 확인되었다. 항-PCSK9 제제에서 아르기닌의 존재는, Fc-Fc 상호작용을 저하시키기 위해 K439E 돌연변이체에 도입된 음전하의 유효성(effectiveness)을 저하시켰을 수 있는 전하 스크리닝에 영향을 끼쳤을 수 있다. H433A 및 N434A 돌연변이체는 K439E 돌연변이체처럼 명백한 전하 스크리닝 민감성을 갖지 않는다.
Fc-Fc 상호작용은 2가지 잠재적인 방식으로 가능한 잠재적인 상호작용의 수를 증가시킴으로써 용액 점도에 영향을 줄 수 있다. Fc-Fc 상호작용은 1개 항체 당 상호작용의 수를, 1개 항체 당 2개의 CDR 매개 상호작용으로부터 2개의 CDR 매개 상호작용 + 2개의 Fc 매개 상호작용까지 증가시킬 수 있거나, 용액에 존재하는 올리고머에서 이용 가능한 자유(free) CDR 말단의 수를 변화시킬 수 있을 것이다. IgG1, IgG2, IgG3 및 IgG4 항체의 Fc 도메인이 매우 유사하다는 사실을 고려하면, Fc-Fc 매개 상호작용은 모든 항체에 존재할 가능성이 있다. 비-점성 항체의 분석은, Fc-Fc 상호작용의 존재를 가리키는 분자내 가교가 동일한 농도에서 점성 항체와는 대조적으로 부재함을 보여준다. 이는, 비-점성 항체에서 Fc-Fc 상호작용이 이론적으로는 가능하더라도, 부재함을 제안한다. CDR 차근접 이웃(next nearest neighbor) 상호작용은 Fc-Fc 상호작용을 증강시키기 위해 Fc들 사이의 상대 거리뿐만 아니라 상대 배향에도 영향을 줄 수 있다. 이는, 점성 항체가 실온에서 Fc-Fc 상호작용을 갖는 한편 비-점성 항체는 그렇지 못한 이유를 설명해 줄 수 있다.
Fc-Fc 상호작용의 존재는 또한, 항체의 올리고머(이량체, 삼량체, 사량체 등)가 최대 수의 자유 CDR 말단을 함유할 가능성을 증가시킨다. 더 큰 수의 자유 CDR 말단은 CDR 차근접 이웃 상호작용의 수를 증가시킨다. 이는 다시, 보다 효율적인 "침투"의 결과, 네트워크 형성 경향을 증가시키고 용액 점도를 증가시킬 수 있다.
점도를 감소시키기 위한 C-말단 변형
항체 C-말단에서 소정의 변형은 C1q 결합 및 보체-의존적 세포독성(CDC)을 방해한다. 문헌[Van den Bremer et al. (2015), "Human IgG is produced in a pro-form that requires clipping of C-terminal lysines for maximal complement activation," mAbs 7(4): 672-80]. 저자들은, C-말단 라이신 및 C-말단 글루탐산이, Clq1와 가장 효율적으로 상호작용할 수 있는 항체의 육량체를 초래하는 Fc-Fc 상호작용의 경향을 저하시키는 가능성이 있음을 확인하였다. 저자들은, C-말단에 PGKP(서열번호:381), PGKKP(서열번호:382), PGKKKP(서열번호:383), 및 PGE를 갖는 CD20 항체 및 CD38 항체의 돌연변이체를 구축하였다. 이들은, 이들 돌연변이체가 유의하게 감소되거나 완전히 상실된 CDC 활성을 보여주었음을 확인하였다. 따라서, 저자들에 의해 이전에 CDC 활성과 상관관계된 육량체화를 상기 돌연변이가 차단했다고 결론내릴 수 있다. 육량체화와 점도의 본 상관관계를 고려하면, 이러한 돌연변이는 항원 결합 단백질의 점도도 감소시킬 것이다. 따라서, 기존의 C-말단 아미노산의 첨가 또는 치환에 의해 배치되는지 상관없이, 양으로 하전된 또는 음으로 하전된 아미노산을 C-말단에 배치하는 것은 항원 결합 단백질의 점도를 감소시킬 것으로 결론내리는 것이 타당하다.
약물동력학 매개변수를 개선하기 위한 서열 변형
본 발명은 또한, 점도도 감소시킬 수 있는 돌연변이를 갖는 항원 결합 단백질에서 개선된 약물동력학 특성의 발견을 포함한다. 특히, S440K 돌연변이는 Tmax(투약 후 최대 농도가 관찰될 때의 시간) 및 Cmax(투약 후 측정된 최대 관찰 농도)를 둘 다 개선하는 것으로 확인되었다. S440K를 선택적으로 다른 돌연변이와 함께 갖는 항체 AK의 돌연변이체는 돌연변이체 및 부모 항체를 동일한 농도에서 피하 주사 후, 부모 항체 AK의 Tmax의 1/2 초과만큼 감소된 Tmax를 갖는 것으로 확인되었다. 이러한 돌연변이체는 또한, 돌연변이체 및 부모 항체의 피하 주사 후, 28% 또는 42% 더 높은 Cmax를 갖는 것으로 확인되었다. 도 22를 참조한다.
핵산, 벡터, 숙주 세포
본 발명은 또한, 본 발명의 이중특이적 항체를 인코딩하는 단리된 핵산을 포함하며, 상기 항체는 예를 들어 본원에 개시된 이중특이적 항체의 경쇄, 경쇄 가변 영역, 경쇄 불변 영역, 중쇄, 중쇄 가변 영역, 중쇄 불변 영역, 링커, 및 이들의 모든 구성성분 및 조합을 포함한다. 본 발명의 핵산은 이러한 본 발명의 핵산과 적어도 80%, 보다 바람직하게는 적어도 약 90%, 보다 바람직하게는 적어도 약 95%, 가장 바람직하게는 적어도 약 98%의 상동성을 갖는 핵산을 포함한다. 특정 서열을 지칭할 때, 용어 "유사성 퍼센트", "동일성 퍼센트" 및 "상동성 퍼센트"는 위스콘신 대학교의 GCG® 소프트웨어 프로그램에서 설정된 바와 같이 사용된다. 본 발명의 핵산은 또한, 상보적 핵산을 포함한다. 일부 경우, 서열은 정렬되었을 때, 완전히 상보적일 것이다(미스매치가 없음). 다른 경우, 서열에 약 20% 이하의 미스매치가 있을 수 있다. 본 발명의 일부 실시형태에서, 본 발명의 항체의 중쇄 및 경쇄를 둘 다 인코딩하는 핵산이 제공된다.
본 발명의 핵산은 플라스미드, 코스미드, 바크미드(bacmid), 파지, 인공 염색체(BAC, YAC) 또는 바이러스와 같은 벡터 내로 클로닝될 수 있으며, 이러한 벡터 내로 또 다른 유전자 서열 또는 요소(DNA 또는 RNA)가 삽입되어, 부착된 서열 또는 요소의 복제가 유발될 수 있다. 일부 실시형태에서, 발현 벡터는 구성적으로 활성인 프로모터 분절(예컨대 비제한적으로 CMV, SV40, 신장 인자 또는 LTR 서열) 또는 유도성 프로모터 서열, 예컨대 스테로이드 유도성 pIND 벡터(Invitrogen)를 함유하며, 여기서, 핵산의 발현이 조절될 수 있다. 본 발명의 발현 벡터는 내부 리보솜 진입 부위(internal ribosomal entry site)와 같은 조절 서열을 추가로 포함할 수 있다. 발현 벡터는, 예를 들어 형질감염에 의해 세포 내로 도입될 수 있다.
또 다른 실시형태에서, 본 발명은 하기 작동적으로 연결된 요소: 전사 프로모터; 본 발명의 이중특이적 항원 결합 단백질, 항체 또는 항원-결합 단편의 중쇄를 인코딩하는 제1 핵산 분자; 본 발명의 이중특이적 항원 결합 단백질, 항체 또는 항원-결합 단편의 경쇄를 인코딩하는 제2 핵산 분자; 및 전사 종결자를 포함하는 발현 벡터를 제공한다. 또 다른 실시형태에서, 본 발명은 하기 작동적으로 연결된 요소: 제1 전사 프로모터; 본 발명의 이중특이적 항원 결합 단백질, 항체 또는 항원-결합 단편의 중쇄를 인코딩하는 제1 핵산 분자; 제1 전사 종결자; 제2 전사 프로모터; 본 발명의 이중특이적 항원 결합 단백질, 항체 또는 항원-결합 단편의 경쇄를 인코딩하는 제2 핵산 분자; 및 제2 전사 종결자를 포함하는 발현 벡터를 제공한다.
분비 신호 펩타이드 서열은 또한 선택적으로, 관심 코딩 서열에 작동적으로 연결된 발현 벡터에 의해 인코딩될 수 있으며, 따라서, 발현된 폴리펩타이드는 요망된다면 세포로부터 관심 폴리펩타이드의 보다 손쉬운 단리를 위해 재조합 숙주 세포에 의해 분비될 수 있다.
이러한 벡터를 포함하고 중쇄 및 경쇄를 발현하는 재조합 숙주 세포가 또한 제공된다.
정제
항체 정제 방법은 당업계에 공지되어 있고, 본 발명의 항체 및 이중특이적 항체의 제조와 함께 이용될 수 있다. 본 발명의 일부 실시형태에서, 항체 정제 방법은 여과, 친화성 컬럼 크로마토그래피, 양이온 교환 크로마토그래피, 음이온 교환 크로마토그래피 및 농축을 포함한다. 여과 단계는 바람직하게는 한외여과(ultrafiltration), 보다 바람직하게는 한외여과 및 투석여과(diafiltration)를 포함한다. 여과는 바람직하게는 적어도 약 5 내지 50회, 보다 바람직하게는 10 내지 30회, 가장 바람직하게는 14 내지 27회 수행된다. 친화성 컬럼 크로마토그래피는 예를 들어 PROSEP® 친화성 크로마토그래피(Millipore, 미국 메사추세츠주 빌레리카 소재)를 사용하여 수행될 수 있다. 바람직한 실시형태에서, 친화성 크로마토그래피 단계는 PROSEP®-vA 컬럼 크로마토그래피를 포함한다. 용출물은 용매 세제 내에서 세척될 수 있다. 양이온 교환 크로마토그래피는 예를 들어, SP-세파로스 양이온 교환 크로마토그래피를 포함할 수 있다. 음이온 교환 크로마토그래피는 예를 들어 비제한적으로 Q-세파로스 패스트 플로우 음이온 교환을 포함할 수 있다. 음이온 교환 단계는 바람직하게는 비-결합성이어서, DNA 및 BSA를 포함한 오염물질의 제거를 허용한다. 항체 생성물은 바람직하게는 예를 들어 Pall DV 20 나노필터를 사용하여 나노여과된다. 항체 생성물은 예를 들어 한외여과 및 투석여과를 사용하여 농축될 수 있다. 본 방법은 응집물을 제거하기 위해 크기 배제 크로마토그래피 단계를 추가로 포함할 수 있다. 정제의 추가의 매개변수는 이하 작업예에서 보인다.
이중특이적 항체, 항체 또는 항원-결합 단편은 또한, 당업계에 공지된 다른 방법에 의해, 예를 들어 항체 및 항체 단편의 화학적 커플링에 의해 생성될 수 있다.
본 명세서에서 인용된 각각의 원고, 연구 논문, 검토 기사, 요약서, 특허 출원, 특허 또는 다른 공개문헌은 그 전체가 원용에 의해 본 명세서에 포함된다.
본 발명은 감소된 점도를 갖는 항원 결합 단백질의 제조 방법을 제공한다. 이러한 방법은 고점도 가변 도메인 서브패밀리의 잔기를 상관관계가 있는 저점도 서브패밀리의 잔기로 대체함으로써 진행된다. 이러한 방법은 Fc 도메인 내의 잔기를 저점도와 연관된 잔기로 치환하고, 하전된 잔기를 Fc 도메인의 C-말단에 첨가하는 단계를 추가로 포함한다. 본 발명은 추가로, 이러한 방법에 의해 제조된 항원 결합 단백질을 제공한다.
도 1a 및 도 1b는 pH 5.2(폴리소르베이트 없음)에서 20 mM 아세테이트 및 9% 수크로스를 포함하는 제제 완충제에서 150 mg/mL에서 제제화된 IgG1 및 IgG2 모노클로날 항체에 대해 측정된 점도값의 표를 보여준다. 도 1a 및 도 1b는 연구된 항체의 표적뿐만 아니라 이들의 경쇄 및 중쇄 타입, 생식선 서브패밀리, 농도, pI 및 점도를 보여준다. 도 1a 및 도 1b에서 각각의 항체는 도면 및 서열 목록에 주지된 바와 같은 아미노산 서열을 가진다. 중쇄 및 경쇄 아미노산 서열은 서열 목록에서 이들 서열 바로 앞에 SEQ ID NO를 갖는 핵산에 의해 인코딩된다.
도 1c 및 도 1d는 도 1a 및 도 1b의 항체의 프레임워크 영역 및 Fc 영역에 대한 서열 식별 번호(SEQ ID NO)를 보여준다. 도 1d는 또한, 도 17에서 논의된 항체 BA를 보여준다.
도 2는 이 명세서에서 식별된 고점도 및 저점도 서브타입 쌍(pair)을 보여준다.
도 3은 7일간의 세포 배양 후 수합 시 역가에 대한 상대값, 최종 생존 세포 밀도(VCD; viable cell density) 및 생존력(viability)을 포함하여, AK 및 AO 항체 분자 및 이들의 돌연변이체에 대한 발현 결과를 보여준다. AK 값은 100%에서이다.
도 4는 AK 부모 항체(AK 대조군, AK) 및 이들의 돌연변이체의 효능(potency)을 보여준다.
도 5는 부모 AK 및 AO 항체에 비해 돌연변이체의 점도를 보여준다. 43개 항체의 세트로부터의 고점도 VH1|1-18 및 저점도 VH1|1-02의 평균 점도값이 또한, 비교를 위해 나타나 있다.
도 6은 고점도 VH1|1-18 및 저점도 VH1|1-02 서브타입의 mAb의 측정된 점도값 대 계산된 전체 분자 pI 값을 보여준다. AK 및 AO 항체의 저-점도 돌연변이체가 또한 나타나 있다.
도 7은 고점도 VH3|3-33 및 저점도 VH3|3-07 서브타입의 mAb의 측정된 점도값 대 계산된 전체 분자 pI를 보여준다. 저-점도 돌연변이체 AQ(1, 17, 85)가 또한 나타나 있다.
도 8은 고점도 VK3|L16 및 VK3|L6 서브패밀리 및 저점도 VK3|A27 서브패밀리의 mAb의 측정된 점도값 대 계산된 전체 분자 pI 값을 보여준다. 저-점도 돌연변이체 AQ(4 13 76 95 97 98)가 또한 나타나 있다.
도 9는 mAbs 고점도 VH1|1-18 및 저점도 VH1|1-02 서브타입(생식선)의 전반적인 서열 매개변수를 보여주는 표이다. 도 9에서 mAb는 점도에 의해 분류된다. 표는 이들의 mAb 기호, 측정된 점도값, 계산된 pI 값, 및 VL 및 VH 생식선을 포함한다. VH 생식선의 경우, 더 높은 점도 VH1|1-18은 굵은 글씨로 밑줄이 그어져 있다. 중쇄 프레임워크 3 서열이 나타나 있다. 고점도와 상관관계가 있는 잔기는 굵은 글씨로 밑줄이 그어져 있다. VBase 서열은, 상이한 잔기가 서브패밀리에 전형적인 잔기임을 예시하기 위해 비교를 위한 VH1|1-18 및 VH1|1-02 생식선 서브패밀리에 대해 첨가된다.
도 10은 AK 및 AO 항체의 생성되고 특징화된 돌연변이체를 보여주는 표이다.
도 11은 VH3 중쇄를 가진 13개의 mAb의 전반적인 서열 매개변수를 보여주는 표이다. 도 11은 mAb 기호, 측정된 점도값, 계산된 pI 값, HC 및 LC 타입, 및 VL 및 VH 서브타입(생식선)을 포함한다. 더 높은 점도의 VH3|3-33 서브패밀리는 굵은 글씨 및 밑줄로 나타나 있다. 고점도와 상관관계가 있는 잔기는 굵은 글씨로 밑줄이 그어져 있다. VBase 서열은, 상이한 잔기가 서브패밀리에 전형적인 것임을 예시하기 위해 비교를 위한 VH3|3-33 및 VH3|3-07 생식선 서브패밀리에 대해 첨가된다.
도 12는 VK3 경쇄를 가진 14개의 mAb의 전반적인 서열 매개변수를 보여주는 표이다. 도 12에서 mAb는 이들의 mAb 기호, 측정된 점도값, 계산된 pI 값, HC 및 LC 타입, 및 VL 및 VH 서브타입(생식선)을 포함하여 점도에 의해 분류된다. 더 높은 점도 VK3|L16 및 VK3|L6 서브패밀리는 굵은 글씨로 밑줄이 그어져 있다. VK3|A27 서브패밀리와 비교하여 VK3|L16과 VK3|L6 서브패밀리 사이에서 일관적으로 상이한 경쇄 잔기는 우측면에 나타나 있다. VK3|L16 및 VK3|L6 서브패밀리에서 고점도와 상관관계가 있는 잔기는 굵은 글씨로 밑줄이 그어져 있다. VBase 서열은, 상이한 잔기가 서브패밀리에 전형적인 잔기임을 예시하기 위해 비교를 위한 VK3|L16 및 VK3|A27 생식선 서브패밀리에 대해 첨가된다.
도 13a 및 도 13b는 명시된 중쇄 및 경쇄 생식선 패밀리 및 VH1, VH3 및 VK3의 생식선 서브패밀리를 함유하는 온전한 항체 분자에 대한 측정된 점도 및 계산된 pI 값에 대한 평균값을 보여준다. X-축은 패밀리, 및 각각의 패밀리와 서브패밀리 내의 구성원의 수를 함유한다.
도 14a는, Fc-Fc 상호작용 표면에서의 돌연변이가 용액 점도를 저하시킬 수 있음을 보여준다. 항체 AK, 및 항체 AK 돌연변이체 I253A 및 S440K의 농도의 점도가 나타나 있다.
도 14b는, 야생형 보체 활성을 복구시키는 이중 돌연변이체가 야생형 점도도 복구시킴을 보여준다. 이러한 도면은 항체 AK, 항체 AK 돌연변이체 I253A, 항체 AK 돌연변이체 S440K, 및 항체 AK 이중 돌연변이체 K439E/S440K의 농도의 점도를 보여준다. 상기 도면은 또한, 항체 AK 부모에 비해 점도를 저하시키지 않는 항체 AK 돌연변이체 K439E, 항체 AK 돌연변이체 H433A, 및 항체 AK 돌연변이체 N434A의 점도를 보여준다.
도 15는 부모 항체 AK 및 다양한 돌연변이체의 절대 및 상대 점도값을 보여주는 표이다. 부모 항체 AK 및 돌연변이체는 항체 AK 및 저점도 돌연변이체의 약물동력학 및 약력학의 비인간 영장류 연구에 사용된다.
도 16은 EDC 화학적 가교의 도식이다(실시예 2 참조).
도 17은 더 낮은 점도 변이체로의 Fc 돌연변이에 대해 선택된 단백질의 점도를 보여주는 표이다.
도 18은 항체 AH의 EDC 화학적 가교에 의한 항체 시스템 올리고머의 농도-의존적 형성을 보여준다.
도 19a는, Fc 영역에서 S440K 돌연변이가 항체 AQ에서 점도를 감소시킴을 보여준다. (돌연변이체의 농도는 실제로 150 mg/mL임을 주지함.) 도 19b는 지수 적합(exponential fit)과 함께 동일한 데이터의 산점도이다. 도 19b에서 다이아몬드형은 보여진 농도에서 비변형된 항체 AQ를 나타내고, 정사각형은 150 mg/mL에서 S440K 돌연변이체를 보여준다.
도 20a는 측정된 농도 및 점도를 포함하여, 항체 AQ의 생성되고 특징화된 돌연변이체를 보여주는 표이다.
도 20b는 GIP에 의해 활성화되고 항-GIPR 항체에 의해 차단되는 인간 GIP 수용체를 발현하는 293/huGIPR 세포의 cAMP 반응을 보여준다. 시험관내 cAMP 활성은 점도 돌연변이에 의해 동일하게 영향을 받지 않았다. 효능은 검정법의 오차 한계 내에서 여전히 동일하였다.
도 21은 이하 작업예에서 더 상세히 기재되는 바와 같이 수컷 시노몰구스 원숭이에서 단일-용량 피하 볼루스(bolus) 약물동력학 연구를 위한 실험 디자인의 요약을 보여준다.
도 22는 수컷 시노몰구스 원숭이(N = 4마리 수컷)에게 10 mg/kg을 피하 투여한 후, 항체 AK 또는 저점도 돌연변이체 동족체의 평균 약물동력학 매개변수 추정치를 보여준다. 점도를 감소시키는 Fc 영역에서 돌연변이의 도입은 Tmax를 감소시키고, Cmax를 증가시킨다.
도 23은 프리테스트(CLAB일)와 비교한 LDL-C의 퍼센트를 보여준다. *퍼센트 변화는 제1일 프리테스트 값으로 나눈 개별 동물의 투약-후 값으로서 표현된다. 모든 4개의 항체(부모 항체 AK, AK Fc 돌연변이체, AK Fab 돌연변이체 및 AK 이중 Fc/Fab 돌연변이체)는 모두 LDL-C에서 감소를 유도한다.
도 24a 및 도 24b는 약물동력학 프로파일(μg/mL)을 혈장 내 상응하는 저밀도 지질단백질(LDL) 농도(mg/dL) 프로파일과 함께 보여준다. LDL 농도 및 테스트 물품 혈청 농도는 4마리 동물에 대한 평균값으로서 제시된다. 실선과 함께 채워진 원형은 부모 항체 AK의 혈청 농도를 가리킨다. 파선과 함께 비워진(open) 정사각형은 Fab 돌연변이를 갖는 항체의 혈청 농도를 가리킨다. 실선과 함께 채워진 삼각형은 Fc 돌연변이를 갖는 항체의 혈청 농도를 가리킨다. 파선과 함께 비워진 다이아몬드형은 Fab 및 Fc 돌연변이를 둘 다 갖는 항체의 혈청 농도를 가리킨다. 이들 데이터는, 항체 제제의 점도를 감소시키는 Fc 영역 내에서 돌연변이의 존재가 Tmax까지의 감소된 시간 및 더 높은 Cmax를 초래함을 가리킨다. 부모 항체의 모든 돌연변이체 형태는 혈청 LDL-C를 낮추는 능력을 보유한다(하위 패널).
도 1c 및 도 1d는 도 1a 및 도 1b의 항체의 프레임워크 영역 및 Fc 영역에 대한 서열 식별 번호(SEQ ID NO)를 보여준다. 도 1d는 또한, 도 17에서 논의된 항체 BA를 보여준다.
도 2는 이 명세서에서 식별된 고점도 및 저점도 서브타입 쌍(pair)을 보여준다.
도 3은 7일간의 세포 배양 후 수합 시 역가에 대한 상대값, 최종 생존 세포 밀도(VCD; viable cell density) 및 생존력(viability)을 포함하여, AK 및 AO 항체 분자 및 이들의 돌연변이체에 대한 발현 결과를 보여준다. AK 값은 100%에서이다.
도 4는 AK 부모 항체(AK 대조군, AK) 및 이들의 돌연변이체의 효능(potency)을 보여준다.
도 5는 부모 AK 및 AO 항체에 비해 돌연변이체의 점도를 보여준다. 43개 항체의 세트로부터의 고점도 VH1|1-18 및 저점도 VH1|1-02의 평균 점도값이 또한, 비교를 위해 나타나 있다.
도 6은 고점도 VH1|1-18 및 저점도 VH1|1-02 서브타입의 mAb의 측정된 점도값 대 계산된 전체 분자 pI 값을 보여준다. AK 및 AO 항체의 저-점도 돌연변이체가 또한 나타나 있다.
도 7은 고점도 VH3|3-33 및 저점도 VH3|3-07 서브타입의 mAb의 측정된 점도값 대 계산된 전체 분자 pI를 보여준다. 저-점도 돌연변이체 AQ(1, 17, 85)가 또한 나타나 있다.
도 8은 고점도 VK3|L16 및 VK3|L6 서브패밀리 및 저점도 VK3|A27 서브패밀리의 mAb의 측정된 점도값 대 계산된 전체 분자 pI 값을 보여준다. 저-점도 돌연변이체 AQ(4 13 76 95 97 98)가 또한 나타나 있다.
도 9는 mAbs 고점도 VH1|1-18 및 저점도 VH1|1-02 서브타입(생식선)의 전반적인 서열 매개변수를 보여주는 표이다. 도 9에서 mAb는 점도에 의해 분류된다. 표는 이들의 mAb 기호, 측정된 점도값, 계산된 pI 값, 및 VL 및 VH 생식선을 포함한다. VH 생식선의 경우, 더 높은 점도 VH1|1-18은 굵은 글씨로 밑줄이 그어져 있다. 중쇄 프레임워크 3 서열이 나타나 있다. 고점도와 상관관계가 있는 잔기는 굵은 글씨로 밑줄이 그어져 있다. VBase 서열은, 상이한 잔기가 서브패밀리에 전형적인 잔기임을 예시하기 위해 비교를 위한 VH1|1-18 및 VH1|1-02 생식선 서브패밀리에 대해 첨가된다.
도 10은 AK 및 AO 항체의 생성되고 특징화된 돌연변이체를 보여주는 표이다.
도 11은 VH3 중쇄를 가진 13개의 mAb의 전반적인 서열 매개변수를 보여주는 표이다. 도 11은 mAb 기호, 측정된 점도값, 계산된 pI 값, HC 및 LC 타입, 및 VL 및 VH 서브타입(생식선)을 포함한다. 더 높은 점도의 VH3|3-33 서브패밀리는 굵은 글씨 및 밑줄로 나타나 있다. 고점도와 상관관계가 있는 잔기는 굵은 글씨로 밑줄이 그어져 있다. VBase 서열은, 상이한 잔기가 서브패밀리에 전형적인 것임을 예시하기 위해 비교를 위한 VH3|3-33 및 VH3|3-07 생식선 서브패밀리에 대해 첨가된다.
도 12는 VK3 경쇄를 가진 14개의 mAb의 전반적인 서열 매개변수를 보여주는 표이다. 도 12에서 mAb는 이들의 mAb 기호, 측정된 점도값, 계산된 pI 값, HC 및 LC 타입, 및 VL 및 VH 서브타입(생식선)을 포함하여 점도에 의해 분류된다. 더 높은 점도 VK3|L16 및 VK3|L6 서브패밀리는 굵은 글씨로 밑줄이 그어져 있다. VK3|A27 서브패밀리와 비교하여 VK3|L16과 VK3|L6 서브패밀리 사이에서 일관적으로 상이한 경쇄 잔기는 우측면에 나타나 있다. VK3|L16 및 VK3|L6 서브패밀리에서 고점도와 상관관계가 있는 잔기는 굵은 글씨로 밑줄이 그어져 있다. VBase 서열은, 상이한 잔기가 서브패밀리에 전형적인 잔기임을 예시하기 위해 비교를 위한 VK3|L16 및 VK3|A27 생식선 서브패밀리에 대해 첨가된다.
도 13a 및 도 13b는 명시된 중쇄 및 경쇄 생식선 패밀리 및 VH1, VH3 및 VK3의 생식선 서브패밀리를 함유하는 온전한 항체 분자에 대한 측정된 점도 및 계산된 pI 값에 대한 평균값을 보여준다. X-축은 패밀리, 및 각각의 패밀리와 서브패밀리 내의 구성원의 수를 함유한다.
도 14a는, Fc-Fc 상호작용 표면에서의 돌연변이가 용액 점도를 저하시킬 수 있음을 보여준다. 항체 AK, 및 항체 AK 돌연변이체 I253A 및 S440K의 농도의 점도가 나타나 있다.
도 14b는, 야생형 보체 활성을 복구시키는 이중 돌연변이체가 야생형 점도도 복구시킴을 보여준다. 이러한 도면은 항체 AK, 항체 AK 돌연변이체 I253A, 항체 AK 돌연변이체 S440K, 및 항체 AK 이중 돌연변이체 K439E/S440K의 농도의 점도를 보여준다. 상기 도면은 또한, 항체 AK 부모에 비해 점도를 저하시키지 않는 항체 AK 돌연변이체 K439E, 항체 AK 돌연변이체 H433A, 및 항체 AK 돌연변이체 N434A의 점도를 보여준다.
도 15는 부모 항체 AK 및 다양한 돌연변이체의 절대 및 상대 점도값을 보여주는 표이다. 부모 항체 AK 및 돌연변이체는 항체 AK 및 저점도 돌연변이체의 약물동력학 및 약력학의 비인간 영장류 연구에 사용된다.
도 16은 EDC 화학적 가교의 도식이다(실시예 2 참조).
도 17은 더 낮은 점도 변이체로의 Fc 돌연변이에 대해 선택된 단백질의 점도를 보여주는 표이다.
도 18은 항체 AH의 EDC 화학적 가교에 의한 항체 시스템 올리고머의 농도-의존적 형성을 보여준다.
도 19a는, Fc 영역에서 S440K 돌연변이가 항체 AQ에서 점도를 감소시킴을 보여준다. (돌연변이체의 농도는 실제로 150 mg/mL임을 주지함.) 도 19b는 지수 적합(exponential fit)과 함께 동일한 데이터의 산점도이다. 도 19b에서 다이아몬드형은 보여진 농도에서 비변형된 항체 AQ를 나타내고, 정사각형은 150 mg/mL에서 S440K 돌연변이체를 보여준다.
도 20a는 측정된 농도 및 점도를 포함하여, 항체 AQ의 생성되고 특징화된 돌연변이체를 보여주는 표이다.
도 20b는 GIP에 의해 활성화되고 항-GIPR 항체에 의해 차단되는 인간 GIP 수용체를 발현하는 293/huGIPR 세포의 cAMP 반응을 보여준다. 시험관내 cAMP 활성은 점도 돌연변이에 의해 동일하게 영향을 받지 않았다. 효능은 검정법의 오차 한계 내에서 여전히 동일하였다.
도 21은 이하 작업예에서 더 상세히 기재되는 바와 같이 수컷 시노몰구스 원숭이에서 단일-용량 피하 볼루스(bolus) 약물동력학 연구를 위한 실험 디자인의 요약을 보여준다.
도 22는 수컷 시노몰구스 원숭이(N = 4마리 수컷)에게 10 mg/kg을 피하 투여한 후, 항체 AK 또는 저점도 돌연변이체 동족체의 평균 약물동력학 매개변수 추정치를 보여준다. 점도를 감소시키는 Fc 영역에서 돌연변이의 도입은 Tmax를 감소시키고, Cmax를 증가시킨다.
도 23은 프리테스트(CLAB일)와 비교한 LDL-C의 퍼센트를 보여준다. *퍼센트 변화는 제1일 프리테스트 값으로 나눈 개별 동물의 투약-후 값으로서 표현된다. 모든 4개의 항체(부모 항체 AK, AK Fc 돌연변이체, AK Fab 돌연변이체 및 AK 이중 Fc/Fab 돌연변이체)는 모두 LDL-C에서 감소를 유도한다.
도 24a 및 도 24b는 약물동력학 프로파일(μg/mL)을 혈장 내 상응하는 저밀도 지질단백질(LDL) 농도(mg/dL) 프로파일과 함께 보여준다. LDL 농도 및 테스트 물품 혈청 농도는 4마리 동물에 대한 평균값으로서 제시된다. 실선과 함께 채워진 원형은 부모 항체 AK의 혈청 농도를 가리킨다. 파선과 함께 비워진(open) 정사각형은 Fab 돌연변이를 갖는 항체의 혈청 농도를 가리킨다. 실선과 함께 채워진 삼각형은 Fc 돌연변이를 갖는 항체의 혈청 농도를 가리킨다. 파선과 함께 비워진 다이아몬드형은 Fab 및 Fc 돌연변이를 둘 다 갖는 항체의 혈청 농도를 가리킨다. 이들 데이터는, 항체 제제의 점도를 감소시키는 Fc 영역 내에서 돌연변이의 존재가 Tmax까지의 감소된 시간 및 더 높은 Cmax를 초래함을 가리킨다. 부모 항체의 모든 돌연변이체 형태는 혈청 LDL-C를 낮추는 능력을 보유한다(하위 패널).
본 발명은 하기 실시예에 의해 더 예시되며, 이들 작업예는 예시하는 것이지만 본 발명의 범위를 제한하지 않는다.
실시예 1
Fab 돌연변이
재료
상이한 표적 및 상이한 서열을 갖는 43개의 인간 및 인간화 재조합 모노클로날 항체 분자 세트를 표준 절차에 따라 생성하고 정제하였다(도 1a 및 도 1b). 크기 배제 크로마토그래피(SEC)에 의해 등가 순도(equivalent purity)가 98% 초과인 세트를 수합하였다. 시료를 2℃ 내지 8℃에서 30±10 psi의 최대 압력에서 Amicon Ultrafiltration Stirred Cell Model 8003(Millipore, 미국 메사추세츠주 빌레리카 소재)을 사용하여 3 mL 최대 부피로 농축시켰다. 이들 시료를 pH 5.2에서 20 mM 아세테이트, 9% 수크로스를 함유하는(폴리소르베이트 없음) 제제 완충제 내에서 근사 부피 고갈(approximate volume depletion)에 따라 150 mg/mL까지 농축시키고, 최종 농도를 280 nm에서 단백질의 흡광도(희석 후 0.1 내지 1의 흡광 단위(AU) 내에서 끝나기 위해) 및 단백질-특이 소광 계수(extinction coefficient)를 사용하여 결정하였다(± 10%).
2개의 mAb의 몇몇 저점도 돌연변이체를 유사한 표준 절차에 따라 생성하며, 정제하고 제제화하였다. 이들 돌연변이체는 전구단백질 전환효소 서브틸리신/켁신 타입 9에 대한 항체(PCSK9, 항체 AK) 및 대식세포 콜로니-자극 인자에 대한 항체(M-CSF, AO)를 포함하였다.
점도 측정
점도 분석을, CP-40 스핀들 및 시료 컵을 사용하여 Brookfield LV-DVIII 콘 앤드 플레이트 장비(Brookfield Engineering, 미국 메사추세츠주 미들보로 소재) 상에서 수행하였다. 모든 측정을 시료 컵에 부착된 수조에 의해 제어되는 25℃에서 수행하였다. 다수의 점도 측정을, 한정된 토크 범위(10% 내지 90%) 내에서 스핀들의 RPM을 증가시킴으로써 수동으로 수합하였다. 생성된 비교 차트를 단순화하고자 1개 시료 당 1개의 점도값을 보고하기 위해 측정을 평균내었다.
서열 정렬
구조-기반 서열 정렬을, 취리히 대학교의 생화학부로부터 다운로드한 Excel Macros를 사용하여 개발된 Ab Initio 소프트웨어 툴에 의해 수행하였다.
실시예 2
Fc 돌연변이
돌연변이체의 발현 및 정제
재료 및 방법
· 항-C-키트 항체(서열번호: 173 및 175의 핵산에 의해 각각 인코딩된 항체 BA, 서열번호: 174 및 176), 항-스클레로스틴(sclerostin) 항체 AH 및 항-PCSK9 항체 AK
· 항-스트렙타비딘 IgG1 및 IgG2.
· 1-에틸-3-[3-디메틸아미노프로필] 카르보디이미드 하이드로클로라이드(EDC)
· n-메틸-2-피롤리돈을 이용한 용해
· 광 산란(LS)과 함께 크기 배제 고성능 액체 크로마토그래피(SE-HPLC)
· 환원 및 알킬화된 역상 고성능 액체 크로마토그래피(RA RP-HPLC)
· 전기 분무 이온화 질량 분광법(ESI-MS)과 함께 트립신 펩타이드 맵
· 콘 앤드 플레이트 점도계
결과
고농도 모노클로날 항체 용액의 EDC 가교의 SE-HPLC는 올리고머를 형성하는 경향을 드러낸다
화합물 1-에틸-3-[3-디메틸아미노프로필] 카르보디이미드 하이드로클로라이드(EDC)를 사용하여, 항체 내의 산성 잔기를 항체 내의 일차 아민(N-말단 및/또는 Lys 잔기)에 화학적으로 가교시키고, 다른 연구에도 사용하여 단백질-단백질 상호작용의 영역을 결정하였다. 일차 아민에 대한 카르복실기의 근접성은, 아미드 결합이 2개의 기들 사이에서 형성되기 때문에 중대하다(도 16). 형성되는 가교는 용액 내에 존재하는 염다리(salt bridge)일 가능성이 있다. 문헌[Carraway and Koshland, Jr. (1972). "Carbodiimide modification of proteins." Methods Enzymol 25: 616-623]. 항체 패널을 동일한 용액 조건 하에 EDC와 화학적으로 가교시켰다. 이전의 유동학 연구는, 패널 내의 항체 중 일부가 점성이고 일부는 그렇지 않음을 결정하였다(도 17). 비-점성 항체는 이량체 함량이 조금 증가하였으나, 더 높은 차수(order)는 다량으로 함유하지 않았다. 대조적으로, 점성 항체는 이량체뿐만 아니라 더 높은 차수의 올리고머를 다량으로 함유하였다. 요약은 도 17에 제공된다. 점성이 있는 것으로서 식별된 모든 항체는 이량체보다 큰 것으로 보인 EDC 가교 화학종을 함유하였다. 더 큰 올리고머 화학종의 출현은 농도 의존적이다(항체 AH는 도 18에서 실시예로서 보여짐). 추가 분석을 용이하게 하기 위해, 화학적 가교 조건을 변화시켜, 가교 반응을 완료시켰다. 200 mg/mL에서 화학적 가교 후 용액은 고체가 되었다. 고체를 완충제 또는 완충 3% NMP 용액을 이용하여 재-용해시켰다. 2개 시료 모두의 SE-HPLC 분석은, 시료들이 유사하였음을 보여주었다. 완충 3% NMP 용액은, 더 많은 물질을 용액 내로 넣음에 따라 단백질을 유의하게 더 빠르게 용해시켰다. 항체 AH를 재-용해시키고, 실시예로서 추가로 분석하였다.
온라인 LS와 함께 SE-HPLC에 의한 크기 분석
가교된 항체 용액을 온라인 광 산란과 함께 SE-HPLC에 의해 분석하여, 용출 화학종의 크기를 결정하였다. EDC 화학적 가교 및 3% NMP를 이용한 재용해 후, 항체 AH의 온라인 광 산란 분석과 함께 SE-HPLC를 수행하였다. SE-HPLC는 UV 및 RI에 존재하는 3개의 피크를 드러내었다. 첫 번째 피크는 질량이 840.5 kD인 화학종으로서 식별되었다. 이는 항체 AH의 육량체에 대해 예상된 질량 873.2 kD에 가깝다. 또 다른 화학종은 494.6 kD의 질량을 가졌으며, 이는 항체 AH의 삼량체에 대해 예측된 질량 436.6 kD에 가깝다. 세 번째 화학종은 139.9 kD의 질량을 보여주었으며, 이는 항체 AH의 단량체에 대해 예측된 질량 145.5 kD에 가깝다.
EDC 가교된 항체 AH의 환원 및 알킬화된 역상 HPLC
가교된 항체 용액을 환원 및 알킬화된 역상 고성능 액체 크로마토그래피에 의해 분석하였다. 경쇄(LC) 및 중쇄(HC)가 둘 다 대부분 회수되는 것은 예상치 못하였는데, 왜냐하면 HC 또는 LC는 서로 가교되어 본래의 것이 아닌(non-native) LC-HC 펩타이드 또는 본래의 것이 아닌 LC-LC 또는 HC-HC 펩타이드를 형성하며, 이는 SEC 분석에 의해 관찰된 가교된 올리고머를 반영하는 것으로 추정되었기 때문이다. 항체 AH의 경우, LC는 비-가교된 항체 AH LC와 정확하게 동일한 질량을 갖고 동일한 장소에서 용출되었다. 항체 AH 내의 HC에서 변화가 존재하였으며, 이는 농도 의존적이다. 100 kD의 식별된 질량을 가졌던 HC-HC 가교된 물질(약 33분째에 용출됨, 도 21)이 소량 존재한다. 150 mg/mL 및 200 mg/mL에서, HC 화학종의 분포는 유사하다. 더 낮은 단백질 농도에서, 분포는 약 28.5분째에 용출되는 화학종을 더 많이 포함한다. HC 화학종의 분포는 SEC에 의해 분석된 바와 같이 각각의 시료에 존재하는 올리고머의 양과 상관관계가 있으며, 이때 200 mg/mL 시료는 가장 많은 양의 육량체를 함유하고, 10 mg/mL 시료는 매우 적은 양의 올리고머를 함유하였다. 패턴은 다른 점성 항체 용액에서도 관찰되었다.
실시예 3
항-PCSK9 부모 항체 AK 및 저점도 돌연변이체의 약물동력학 및 약력학(PKPD)에 대한 비인간 영장류 연구
재료: 항체 AK 및 이의 돌연변이체. 모든 돌연변이는 중쇄에 있다.
Fab 돌연변이체: T82(72)R, R94(84)S, S95(85)R; Aho 넘버링(실제 넘버링)
Fc 돌연변이체 S(434)K(EU 넘버링에서 S440K):
이중 돌연변이체: T82(72)R, R94(84)S, S95(85)R; S(434)K:
4마리의 수컷 시노몰구스 원숭이로 이루어진 4개 그룹을 이 연구에 사용하였다. 각각의 그룹은 하기와 같이 10 mg/kg의 1회 피하(SC) 용량을 제공받았다. 그룹 1은 부모 항체 AK(140 mg/ml)를 제공받았으며; 그룹 2는 Fab 돌연변이체(210 mg/ml)를 제공받았으며; 그룹 3은 Fc 돌연변이체(210 mg/ml)를 제공받았고; 그룹 4는 Fab/Fc 돌연변이체(210 mg/ml)를 제공받았다. 그룹 1 및 2는 또한, 희석제 대조군 SC 용량을 가졌다. Fab 돌연변이체는 위치에서 하기 치환 T82(72)R, R94(84)S, S95(85)R을 포함하였다. Fc 돌연변이체는 위치에서 치환 S(434)K를 포함하였다.
210 mg/ml에서 점도를 측정하기 위해, 부모 및 모든 돌연변이체를 10 mM 아세테이트, 155 mM N-아세틸 아르기닌(NAR), 70 mM ArgHCl, pH 5.4, 0.01% 폴리소르베이트 80 내에서 210 mg/mL에서 제제화하였다. ARG2 콘/플레이트를 1000 sec-1 및 25C에서 사용하여 점도를 측정하였다. 도 15를 참조한다.
연구 설계 개요:
4마리의 수컷 시노몰구스 원숭이로 이루어진 4개 그룹
· 각각의 그룹은 1 SC 용량(10 mg/kg)의:
그룹 1: 부모 항체 AK(140 mg/ml)
그룹 2: Fab 돌연변이체(210 mg/ml)
그룹 3: Fc 돌연변이체(210 mg/ml)
그룹 4: Fab/Fc 돌연변이체(210 mg/ml)
를 제공받았다.
· 그룹 1 및 2는 또한, 희석제 대조군 피하 용량을 가졌다
· 투약 후 3일째에 주사 부위에서 피부 생검을 채취하였다
· 조직병리 분석을 수행하였다
· 혈장 LDL, HDL, 총 콜레스테롤 및 PK를 투약-후 6주 동안 이어나갔다
연구 결론
생성된 모든 4개의 동족체는 LDL을 낮추는 것으로 표시되었다
· 투약 후 2주째에 최대 감소: 부모에 대해 이전에 관찰된 것보다 1주 후에
· 효과의 최하점(nadir)은 Fab/Fc 돌연변이체의 경우 상당한(profound) 것만큼은 아니었다(약 78% vs 약 90%)
· 기준선으로의 회귀는 Fc 돌연변이체의 경우 약간 더 가속화된 것으로 보인다
· PK: 평균 노출은 모든 처리군 사이에서 (Cmax 및 AUClast를 기반으로) 유사하였다(1.4배 이내)
· 항-PCSK9 항체 AK에서 Fab 및/또는 Fc 돌연변이는 비인간 영장류(NHP)(시노몰구스 원숭이)에서 주사 부위 반응(ISR) 또는 약물동력학 및 약력학 (PKPD) 프로파일에 유의한 효과를 갖지 않았다.
Fab 돌연변이체: T82(72)R, R94(84)S, S95(85)R; Aho 넘버링(실제 넘버링).
Fc 돌연변이체: S(434)K(EU 넘버링에서 S440K).
실시예 4
GIPR(2G10.006) 항체 AQ의 저-점도 돌연변이체의 생성 및 특징화
항체 AQ의 저점도 돌연변이체의 클로닝, 발현, 정제 및 고농도 제제
GIPR(2G10.006) AQ 부모는 미국 가출원 62/387,486에서 2G10_LC1.006(인용된 특허 출원의 서열번호: 74)으로서 기재되어 있다. 상기 언급된 미국 특허 출원은 원용에 의해 본 명세서에 포함된다. 돌연변이 부위 Q1(1)E, R17(16)G, S85(75)A를 갖는 중쇄 돌연변이체 AQ(HC 1, 17, 85) 및 돌연변이 부위 M4(4)L, V13(13)L, A76(60)D, S95(77)R, Q97(79)E, S98(80)P를 갖는 경쇄 돌연변이체 AQ(LC 4 13 76 95 97 98)를 하기와 같이 생성하였다. GIPR(2G10.006)(항체 AQ) 저점도 돌연변이체를 위한 합성 유전자를 생성하고, 분해한 다음, 플라스미드 발현 벡터 내로 연결하였다. 구축물을 DNA 시퀀싱에 의해 입증하였다. 클로날 CHO 숙주 세포주의 전기천공에 의해 안정한 세포 풀을 만들었다. 이러한 풀을 선별 하에, 생존력이 85% 초과에 도달할 때까지 배양하였다. 풀을 유가식 생성 배양물 내로 10일 동안 접종하고, 원심분리된 배지를 수합하였다.
수합된 상층액을 멸균 여과하고, 이전에 기재된 공정과 유사한 단백질 A, 양이온 교환 및 음이온 교환으로 구성된 3개의 컬럼 크로마토그래피 공정을 통해 정제하였다(문헌[Shukla et al. (2007), "Downstream processing of monoclonal antibodies―Application of platform approaches," J. Chrom. B 848: 28-39]). 생성된 정제 풀을 pH 5.2에서 20 mM 아세테이트 및 9% 수크로스를 함유하는 제제 완충제(폴리소르베이트 없음) 내로 투석시켜, 약 5.2의 최종 pH를 달성하고, 원심분리 한외여과를 통해 30 kDa 컷오프 필터 위로 대략 150 mg/mL까지 농축시켰다(도 20a).
효능 측정
글루코스-의존적 인슐린 자극성 폴리펩타이드 수용체(GIPR; glucose-dependent insulinotropic polypeptide receptor)를 발현하는 포유류 세포 293/huGIPR을 이용하는 검정법에서 효능을 측정하였다. 증가하는 농도의 항-GIPR 부모 AQ 및 저-점도 돌연변이체는 GIP와 GIPR의 상호작용을 차단하고 있었으며, 이는 검정법 동안 모니터링된 cAMP 변화를 유도하였다. 검정법의 적용은 문헌[Tseng C.C. et al. (1996), "Postprandial stimulation of insulin release by glucose-dependent insulinotropic polypeptide (GIP). Effect of a specific glucose-dependent insulinotropic polypeptide receptor antagonist in the rat," J. Clin..Invest. 98: 2440-2445]에서 이미 기재되었다.
점도 측정
AQ 및 2개의 저점도 돌연변이체의 점도 분석을, CP25-1/TG 스핀들을 사용하여 Anton Paar 레오미터 상에서 수행하였다. 모든 측정을 시료 컵에 부착된 수조에 의해 제어되는 25℃에서 수행하였다. 점도 측정을, 전단 속도를 0 rpm 내지 2000 rpm에서 증가시키면서 수동으로 수합하였다. 전단 속도 1000 1/s에서 10개의 점도 측정 결과 및 전단 속도 2000 1/s에서 10개의 점도 측정 결과를 각각의 시료에 대해 수합하고, 1개 시료 당 1개의 점도값을 보고하기 위해 평균내었다.
점도 측정은 점도계의 상태, 실내 온도, 및 측정 시간에서의 일부 다른 미미한 매개변수와 같은 일부 매개변수에서 훨씬 미미한 변화에도 민감하기 때문에, 점도 측정의 정밀도가 해당 정확성보다 훨씬 더 양호함을 주지할 필요가 있다. 따라서, 모든 관심 시료를 하나의 세팅에서 측정하거나 관심 시료가 2개의 세팅에서 측정된다면 2개 세팅 모두에서 동일한 참조 표준을 갖는 것이 중요하다.
결과
항-GIPR(2G10.006) 항체 AQ는 중쇄 VH3|3-33 및 경쇄 VK3|L16의 고-점도 생식선 서브패밀리에 속한다. AQ의 점도를 감소시키기 위해 도 11 및 도 12로부터 유래된 몇몇 돌연변이를 프레임에서 만들었다. 하나의 점도계 세팅에서 측정된 부모 AQ 및 2개의 돌연변이체의 점도는 하기 값: AQ - 19.1 cP, AQ(HC 1, 17, 85) - 15.8 cP, AQ(LC 4 13 76 95 97 98) - 12.7 cP(도 20)을 드러내었다. 부모 AQ에 비해, 중쇄 돌연변이체 AQ(HC 1, 17, 85) 돌연변이체는 83%에 존재하였고, 경쇄 돌연변이체 AQ(LC 4 13 76 95 97 98)는 67%에 존재하였다. 도 7 및 8은 VH3 및 VK3 패밀리 구성원에 대한 점도 대 pI 도면 상에서 돌연변이체의 위치를 예시한다. 시험관내 cAMP 활성은 점도 돌연변이에 의해 동일하게 영향을 받지 않았다. 시험관내 세포-기반 검정법의 오차 한계 내에서 효능은 여전히 동일하였다(도 20b 참조). 요약하자면, 도입된 돌연변이는 효능 상실 없이 점도를 감소시켰다.
실시예 5
GIPR 저점도 돌연변이체 경쇄 V78F(Aho 넘버링에서는 LC V78F 및 선형 넘버링에서는 LC V62F)
GIPR(2G10.006) 항체 AQ는 A52Su 제제 내 150 mg/mL에서 23 cP의 고점도를 보여주었다. 이 항체는 카파 경쇄(LC V78 Aho) 내의 Aho 넘버링에서 저-빈도 잔기 V78(선형 넘버링에서는 V62)을 특징으로 하였다. V78의 발생 빈도는 1% 미만인 한편, F78은 카파 생식선과 관련된 경쇄 서열 내에서 98% 초과이다. 잔기 LC V78은 공분산 위반자(covariance violator)였기 때문에 관심을 끌었다. 공분산 분석은 항체의 가변 영역에서 잔기의 생리화학적 특성을 기반으로 쌍으로(pair-wise) 보존된-잔기 위치를 구축하여, 잘못 위치된 잔기(종종 비-생식선 잔기임)를 식별할 수 있게 한다. 공분산 분석은 추가로, 이탈(deviating) 위치의 아미노산을, 분자-동역학적 시뮬레이션에 의해 커버되지 않는(uncovered) 큰 형태 변화를 초래하는 보다 보편적인 생식선 서열로 대체하는 것을 제안할 수 있다(문헌[Kannan G., "Method of correlated mutational analysis to improve therapeutic antibodies,"] US Ser. No. 61/451929, PCT/US 2012/028596, WO 2012/125495). 공분산 위반을 제거하고 인간 서열의 퍼센트를 증가시키기 위해, LC V78F 돌연변이를 GIPR(2G10.006) 항체 AQ에 도입하였다.
뜻밖에도, 돌연변이체의 점도는 25%만큼 저하된 한편, cAMP(세포-기반) 검정법에 의해 측정된 바와 같이 인간 GIPR에 대해 유사한 효능을 유지하였다. 2개의 서열, GIPR(2G10.006) AQ 부모 및 이의 LC V78F 돌연변이체는 모두 미국 가출원 62/387,486에서 각각 2G10_LC1.006(인용된 출원의 서열번호: 74) 및 2G10_LC1.003(인용된 출원의 서열번호: 71)으로서 기재되어 있다. 이러한 미국 특허 출원은 원용에 의해 본 명세서에 포함된다. 본 발명에서 새로 발견된 것은, 이러한 치환이 LC V78F 돌연변이에 의해 약 25%의 점도 감소를 초래하였다는 것이다. GIPR_2G10.006 AQ 및 이의 V78F 돌연변이체의 점도 분석을, 20 mM 아세테이트, pH 5.2에서 9% 수크로스, 0.01% 폴리소르베이트 80을 함유하는 제제 내 150 mg/ml에서, 1000 전단 속도 및 25C에서 TA Instruments - Waters LLC사의 AR-G2 Magnetic Bearing 콘 앤드 플레이트 레오미터를 사용하여 수행하였다. 콘 플레이트 크기는 직경이 20 mm이고, 콘 각도가 1.988°이었으며, Steel -990918 Peltier 플레이트가 구비되었고, Flow Sweep 절차를 사용하여 작동되었다. 측정된 점도값은 GIPR_2G10.006의 경우 21 cP이고, GIPR (2G10.003) LC V78F 돌연변이체의 경우 15.3 cP였으며 25%의 점도 감소가 존재한다.
이전의 실시예에서 주지된 바와 같이, 점도 측정의 정밀도는 해당 정확성보다 훨씬 양호하다. 0.01% 폴리소르베이트가 있을 때 150 mg/mL에서의 점도는 전형적으로 폴리소르베이트가 없을 때보다 10% 낮으며, 이는 GIPR(2G10.006)의 경우에 관찰되었다. 이의 점도는 폴리소르베이트가 없을 때(모든 43개의 항체에서와 같이) 23 cP였고, 폴리소르베이트가 있을 때 21 cP였다.
실시예 6
시노몰구스 원숭이 연구
실시예 3에 보여진 AK(대조군으로서, AMG 145 및 에볼로쿠맙으로도 공지되어 있음)로서 지정된 항체, 및 Fab 돌연변이체, Fc 돌연변이체 및 이중 돌연변이체를 실시예 1 및 2에 개시된 방법을 사용하여 발생시켰다. 이들 항체의 약물동력학 특성을 생체내에서 수컷 시노몰구스 원숭이 내로의 단일 피하 볼루스 주사에 의해 테스트하였다.
연구 설계
연구를 수컷 시노몰구스 원숭이에서 수행하였다. 동물은 2.7 내지 3.8 연령이었고, 체중은 2.9 내지 3.8 kg이었다. 투약 개시 전에 동물을 7일 동안 실험실에 적응시켰다. 선별 기준은 치료전 콜레스테롤(LDL 및 HDL 포함) 수준으로부터 허용 가능한 결과를 포함하였다. 투약 개시 전, 모든 동물을 무작위로 나누고, 컴퓨터-기반 무작위화 절차를 사용하여 그룹으로 지정하였다.
제1일에 테스트 및 대조군 물품을 적절한 동물에게 등-중앙(mid-dorsal) 영역 내로 1회 피하 투여하였다. 투여 전에 주사 부위(들)를 면도하고, 만년 잉크(indelible ink)로 표시하였다. 용량 투여 동안 동물을 일시적으로 움직이지 못하게 하였으며, 진정제를 투여하지는 않았다. 각각의 동물에 대한 용량 부피는 가장 최근의 체중 측정을 기반으로 하였다. 그룹 1 및 2의 경우, 투약 용액을 각각의 동물의 등에 2회 피하 주사(1회는 테스트 물질로, 1회는 희석제로)를 통해 투여하였다. 주사 부위는 적어도 5 내지 6 cm 떨어져 있었다. 테스트 물질을 각각의 동물의 척추의 우측 상에 투여하였다. 희석제를 각각의 동물의 척추의 좌측 상에 전달하였다. 그룹 3 및 4의 경우, 투약 용액을 각각의 동물의 등에 단일 피하 주사를 통해 투여하였다. 각각의 동물에 대한 용량 수준 및 부피는 도 21에 요약되어 있다.
이 연구의 생전(in-life portion) 기간(43일)에 걸쳐 다양한 시점에서, 포타슘(K2) EDTA를 함유하는 튜브 내로 정맥 천자에 의해 혈액 시료를 수합하였다. 혈청 화학 채혈 전에 동물을 단식시키지 않았다.
채혈 후 시료를 냉각시키고, 혈청 또는 혈장 조제물용으로 나누었다. 시료를 부드럽게 혼합하고 원심분리하였다. 수합 직후 원심분리(1500 내지 2000 x g에서 대략 10분 동안)할 때까지 혈액 시료를 습식 아이스 상에서 대략 4℃에서 유지시켰다. 생성된 혈장 또는 혈청을 분리하고, 2개의 분취물(주된 것(primary) 및 백업)로 나누고, 적절하게 표지된 폴리프로필렌 튜브로 옮긴 다음, -80℃에서 유지되도록 설정된 냉동고에서 분석 시까지 보관하였다. 혈장 시료를 사용하여 약물동력학 평가를 위한 테스트 물품 농도를 결정하였으며, 혈청 시료를 콜레스테롤, HDL 및 LDL에 대해 분석하였다.
약물동력학 평가
효소-연결 면역흡착 검정법(ELISA)을 사용하여 혈장 시료를 각각의 테스트 항체(항체 AK, AK Fab 돌연변이체, AK S440K Fc 돌연변이체 및 AK Fab/S440K 이중 돌연변이체)의 농도에 대해 분석하였다. 이러한 검정법은 재조합 인간 PCSK9를 포착 시약으로서 사용하고, 인간 IgG1에 대한 홀스래디쉬 퍼옥시다제 표지 항체를 검출 시약으로서 사용한다. 항체 AK 또는 저점도 동족체를 100% 시노몰구스 원숭이 K2-EDTA 풀 내로 스파이킹(spiking)함으로써 표준 및 품질 관리 시료(QC)를 제조한다. Costar 96-웰 마이크로플레이트 웰(Corning Incorporated)을 재조합 인간 PCSK9로 코팅시킨다. 블록킹(blocking) 단계 후, TBS(Thermo Scientific) 중 Blocker™ BLOTTO에서 100의 희석 인자로 전처리한 후, 표준, 매트릭스 블랭크(NSB), QC(QC) 및 테스트 시료를 마이크로플레이트 웰 내로 로딩한다. 시료 내 항체 AK는 마이크로플레이트 상에 코팅된 고정된 재조합 인간 PCSK9에 의해 포착된다. 마이크로플레이트 웰을 세척함으로써, 비결합된 물질을 제거한다. 세척 후, 포착된 항체 AK를 결합시키기 위해, 마우스 항-인간 IgG, Ab35, HRP 공액 검출 항체를 마이크로플레이트 웰에 첨가한다. 마이크로플레이트 웰을 세척함으로써, 비결합된 검출 항체를 제거한다. 결합된 마우스 항-인간 IgG Ab35 HRP 공액체의 검출을 위해 1-구성성분 TMB 용액을 마이크로플레이트 웰에 첨가한다. TMB 기질 용액은 퍼옥시다제와 반응하고, HRP의 존재 시 비색 신호(colorimetric signal)를 생성하며, 이러한 신호는 포착 시약에 의해 결합된 항체 AK 또는 저점도 돌연변이체 동족체의 양과 비례한다. 2 N 황산을 사용하여 발색을 중단시키고, 색상 세기(광학 밀도 또는 OD)를 450 nm 마이너스 650 nm에서 측정한다. 1의 가중 인자와 함께 4 매개변수(Marquardt) 회귀 모델을 사용하는 Watson 버전 7.4 SP3(또는 이후의) 데이터 환원 패키지를 사용하여 데이터를 환원시킨다.
WinNonlin 약물동력학 소프트웨어를 사용하여 약물동력학 매개변수를 추정하였다. 피하 투여 경로와 일관되는 비-구획(non-compartmental) 접근법을 매개변수 추정에 사용하였다. 제1일로부터의 혈장 내 개별 농도로부터 모든 매개변수를 발생시켰다. 하기 매개변수를 확인하였다
Tmax(투약 후 최대 관찰 농도가 관찰되었을 때의 시간),
Cmax(투약 후 측정된 최대 관찰 농도),
AUC(0-t)(선형 또는 선형/로그 사다리꼴 방법을 사용한, 용량 투여 시작 시부터 투약 후 마지막으로 정량 가능한 농도가 관찰되었을 때까지의 농도 대 시간 곡선 아래의 영역),
AUC(0-t)/D(투여된 용량으로 나눈 AUC(0-t)), 및
RAUC(초기 투약 간격 동안 T1로부터 T2까지의 곡선 아래 면적으로 나눈, 정상 상태에서 T1로부터 T2까지의 곡선 아래 면적).
결과 및 논의
도시된 테스트 물품 농도 대 시간은 도 24a 및 도 24b에 보여진다(각각의 테스트 물품에 대한 평균 농도, 각각의 시점에서 n=4). 4개의 테스트 물품에 대한 약물동력학 매개변수는 도 22에 요약되어 있다. Fc 돌연변이 S440K를 함유하는 항체(항체 AK(Fc 돌연변이체) 및 항체 AK(Fc 및 Fab 이중 돌연변이체) 둘 다)는 항체 AK(대조군) 및 항체 AK(Fab 돌연변이체)에 비해 감소된 Tmax(각각 0.81 및 1일 대 2.5일) 및 증가된 Cmax(각각 125 및 112 μg/mL 대 87.8 μg/mL)를 보여주며, 이는, 점도를 감소시키는 Fc 돌연변이를 함유하는 항체가 피하 주사 후 보다 빠르게 순환계로 분포되고 있음을 가리킨다.
항체 AK의 모든 저점도 동족체의 투여는 예상된 약리학에서, 기준선(제-6일)과 비교하여 저하된 총 콜레스테롤 농도와 연관된 저밀도 지질단백질(LDL)의 약한 내지 중간 정도의 저하를 초래하였다. AK Fab 돌연변이체 및 AK S440K Fc 돌연변이체의 투여 후 총 콜레스테롤 및 저밀도 지질단백질 콜레스테롤에 대한 저하 규모는 일반적으로, 제25일에 AK S440K Fc 돌연변이체 및 제29일에 AK(대조군) 및 AK Fab 돌연변이체의 기준선으로의 회복 경향을 가진 대조군 동물과 유사하였다. AK Fab/S440K 이중 돌연변이체에 대한 총 콜레스테롤 및 저밀도 지질단백질 콜레스테롤에 대한 저하 규모는 일반적으로, 대조군(10 mg/kg에서 항체 AK)과 비교하여 덜 확연하였다. 임의의 AK 저점도 동족체에서 고밀도 지질단백질에서는 변화가 없었다. 기준선에 비해 LDL-C의 변화 퍼센트는 도 23에서 표로 제시되어 있고, 도 24a 및 도 24b에서 시간에 대해 도시되어 있다.
약어
본 명세서 전체에 걸쳐 사용된 약칭된 용어는 하기와 같이 정의된다.
AEI
대립유전자 발현 불균형
ANOVA
분산 분석
AUC
곡선 아래 면적
BSA
소 혈청 알부민
DMEM
둘베코스 모디파이드 이글 미디엄
DMSO
디메틸 설폭사이드
EDC
1-에틸-3-[3-디메틸아미노프로필] 카르보디이미드 하이드로클로라이드
EDTA
에틸렌디아민테트라아세트산
ELISA
효소-연결 면역흡착 검정법
eQTL
발현량 형질 위치(expression quantitative trait loci)
ESI-TOF
비행형 전기분무 이온화 시간(electrospray ionization time of flight)
FACS
형광-활성화 세포 분류
FBS
태아 소 혈청
FPLC
고속 단백질 액체 크로마토그래피
FVB
프렌드 백혈병 바이러스 1b(Fv1b) 대립유전자를 위해 근친 교배된 마우스 계통
H&E
헤마톡실린 및 에오신
HA
하이포크산틴
HIC
소수성 상호작용 크로마토그래피
HPLC
고성능 액체 크로마토그래피
HRP
홀스래디쉬 퍼옥시다제
HUVEC
인간 제대혈 상피 세포
IBD
염증성 장질환
IDMEM
글루타민이 없는 DMEM
IFN
인터페론
IL
인터루킨
MCP
단핵구 화학주성 단백질
MSD
거대분자 구조 데이터베이스
PBMC
말초 혈액 단핵구 세포
PBS
인산염-완충 식염수
PCR
중합효소 연쇄 반응
PEG
폴리에틸렌 글리콜
PEI
폴리에틸렌이민
QTL
양적 형질 위치
RPMI
Roswell Park Memorial Institute사에서 개발된 배지
SNP
단일 뉴클레오타이드 다형성
TFA
트리플루오로아세트산
TMB
3,3',5,5'-테트라메틸벤지딘
SEQUENCE LISTING
<110> AMGEN Inc.
<120> LOW-VISCOSITY ANTIGEN BINDING PROTEINS AND METHODS OF MAKING THEM
<130> IPA190564-US-D1
<150> US 62/401,770
<151> 2016-09-29
<150> US 62/430,773
<151> 2016-12-06
<150> US 62/546,469
<151> 2017-08-16
<160> 383
<170> PatentIn version 3.5
<210> 1
<211> 705
<212> DNA
<213> Homo sapiens
<400> 1
atggaaaccc cggcgcagct gctgtttctg ctgctgctgt ggctgccgga taccaccggc 60
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga cagagccacc 120
ctctcctgca gggccagtca gagtgttagt agcagctact ttgcctggta ccagcagaaa 180
cctggccagg ctcccaggct cctcatttat ggtgcatcca gtagggccac tggcatccca 240
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 300
cctgaagatt ttgcagtgta ttactgtcag cagtatgata ggtcacctcg gacgttcggc 360
caagggacca aggtggaaat caaacgtacg gtggctgcac catctgtctt catcttcccg 420
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 705
<210> 2
<211> 235
<212> PRT
<213> Homo sapiens
<400> 2
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Ser Tyr Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr
100 105 110
Asp Arg Ser Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 3
<211> 1389
<212> DNA
<213> Homo sapiens
<400> 3
atggattgga cctggcgtat tctgtttctg gtggcggcgg cgaccggcgc gcatagccag 60
gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg gggcctcagt gaaggtctcc 120
tgtaagtctt ctggatacac cttcaccggc tactatatgc actgggtgcg acaggcccct 180
ggacaagggc ttgagtggat gggatggatc aaccctaaca gtggtggcac aaactatgca 240
cagaagttta agggcagggt caccatgacc agggacacgt ccatcagcac agcctacatg 300
gagctgagca ggctgagatc tgacgacacg gccgtgtatt actgtgcgag agataagtgg 360
ctggacggct ttgactactg gggccaggga accctggtca ccgtctcctc agctagcacc 420
aagggcccat cggtcttccc cctggcgccc tgctccagga gcacctccga gagcacagcg 480
gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540
ggcgctctga ccagcggcgt gcacaccttc ccagctgtcc tacagtcctc aggactctac 600
tccctcagca gcgtggtgac cgtgccctcc agcaacttcg gcacccagac ctacacctgc 660
aacgtagatc acaagcccag caacaccaag gtggacaaga cagttgagcg caaatgttgt 720
gtcgagtgcc caccgtgccc agcaccacct gtggcaggac cgtcagtctt cctcttcccc 780
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacgtg cgtggtggtg 840
gacgtgagcc acgaagaccc cgaggtccag ttcaactggt acgtggacgg cgtggaggtg 900
cataatgcca agacaaagcc acgggaggag cagttcaaca gcacgttccg tgtggtcagc 960
gtcctcaccg ttgtgcacca ggactggctg aacggcaagg agtacaagtg caaggtctcc 1020
aacaaaggcc tcccagcccc catcgagaaa accatctcca aaaccaaagg gcagccccga 1080
gaaccacagg tgtacaccct gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc 1140
ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg ggagagcaat 1200
gggcagccgg agaacaacta caagaccaca cctcccatgc tggactccga cggctccttc 1260
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1320
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1380
ccgggtaaa 1389
<210> 4
<211> 463
<212> PRT
<213> Homo sapiens
<400> 4
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ser Ser Gly Tyr Thr Phe
35 40 45
Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala
65 70 75 80
Gln Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Asp Lys Trp Leu Asp Gly Phe Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
225 230 235 240
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
340 345 350
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 5
<211> 726
<212> DNA
<213> Homo sapiens
<400> 5
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60
cgctgtgata ttgtgatgac ccagactcca ctctccctgc ccgtcacccc tggagagccg 120
gcctccatct cctgcaggtc tagtcagagc ctcttgaata gtgttgatgg aagcaccaat 180
ttggactggt atctgcagaa gccagggcag tctccacagc tcctgatcta tacgctttcc 240
tatcgggcct ctggagtccc agacaggttc agtggcagtg ggtcaggcac tgacttcaca 300
ctgaaaatca gcagggtgga ggctgaggat gttggagttt attactgcat gcaacgtata 360
gagtttccgc tcactttcgg cggagggacc aaggtggaga tcaaacgtac ggtggctgca 420
ccatctgtct tcatcttccc gccatctgat gagcagttga aatctggaac tgcctctgtt 480
gtgtgcctgc tgaataactt ctatcccaga gaggccaaag tacagtggaa ggtggataac 540
gccctccaat cgggtaactc ccaggagagt gtcacagagc aggacagcaa ggacagcacc 600
tacagcctca gcagcaccct gacgctgagc aaagcagact acgagaaaca caaagtctac 660
gcctgcgaag tcacccatca gggcctgagc tcgcccgtca caaagagctt caacagggga 720
gagtgt 726
<210> 6
<211> 242
<212> PRT
<213> Homo sapiens
<400> 6
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Thr Pro Leu Ser
20 25 30
Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Leu Asn Ser Val Asp Gly Ser Thr Asn Leu Asp Trp Tyr
50 55 60
Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Thr Leu Ser
65 70 75 80
Tyr Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
85 90 95
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
100 105 110
Val Tyr Tyr Cys Met Gln Arg Ile Glu Phe Pro Leu Thr Phe Gly Gly
115 120 125
Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe
130 135 140
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val
145 150 155 160
Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp
165 170 175
Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
180 185 190
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
195 200 205
Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val
210 215 220
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
225 230 235 240
Glu Cys
<210> 7
<211> 1395
<212> DNA
<213> Homo sapiens
<400> 7
atggagttgg ggctgtgctg ggttttcctt gttgctattt tagaaggtgt ccagtgtgag 60
gtgcagctgg tggagtctgg gggaggcttg gtacagcctg gggggtccct gagactctcc 120
tgtgcagcct ctggattcac cttcagtagc tatagcatga actgggtccg ccaggctcca 180
gggaaggggc tggagtgggt ttcatacatt agtagtagtg gtagttccat atactacgca 240
gactctgtga agggccgatt caccatctcc agagacaatg ccaagaactc actgtatctg 300
caaatgaaca gcctgagaga cgaggacacg gctgtgtatt actgtgcgag agagaggtac 360
tacggtgaca cgccctttga ctactggggc cagggaaccc tggtcaccgt ctctagtgcc 420
tccaccaagg gcccatcggt cttccccctg gcgccctgct ccaggagcac ctccgagagc 480
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540
aactcaggcg ctctgaccag cggcgtgcac accttcccag ctgtcctaca gtcctcagga 600
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca acttcggcac ccagacctac 660
acctgcaacg tagatcacaa gcccagcaac accaaggtgg acaagacagt tgagcgcaaa 720
tgttgtgtcg agtgcccacc gtgcccagca ccacctgtgg caggaccgtc agtcttcctc 780
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacgtgcgtg 840
gtggtggacg tgagccacga agaccccgag gtccagttca actggtacgt ggacggcgtg 900
gaggtgcata atgccaagac aaagccacgg gaggagcagt tcaacagcac gttccgtgtg 960
gtcagcgtcc tcaccgttgt gcaccaggac tggctgaacg gcaaggagta caagtgcaag 1020
gtctccaaca aaggcctccc agcccccatc gagaaaacca tctccaaaac caaagggcag 1080
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1140
gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtgggag 1200
agcaatgggc agccggagaa caactacaag accacacctc ccatgctgga ctccgacggc 1260
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1320
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1380
ctgtctccgg gtaaa 1395
<210> 8
<211> 465
<212> PRT
<213> Homo sapiens
<400> 8
Met Glu Leu Gly Leu Cys Trp Val Phe Leu Val Ala Ile Leu Glu Gly
1 5 10 15
Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Ser Ile Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Arg Tyr Tyr Gly Asp Thr Pro Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
210 215 220
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
225 230 235 240
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Lys
465
<210> 9
<211> 699
<212> DNA
<213> Homo sapiens
<400> 9
atgtcgccat cacaactcat tgggtttctg ctgctctggg ttccagcctc caggggtgaa 60
attgtgctga ctcagtctcc agactttcag tctgtgactc caaaggagaa agtcaccatc 120
acctgccggg ccagtcagag cattggtagt agcttacact ggtaccagca gaaaccagat 180
cagtctccaa agctcctcat caagtatgct tcccagtcct tctcaggggt cccctcgagg 240
ttcagtggca gtggatctgg gacagatttc accctcacca tcaatagcct ggaagctgaa 300
gatgctgcag cgtattactg tcatcagagt agtagtttac ctctcacttt cggcggaggg 360
accaaggtgg agatcaaacg aactgtggct gcaccatctg tcttcatctt cccgccatct 420
gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 480
agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 540
agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 600
agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 660
agctcgcccg tcacaaagag cttcaacagg ggagagtgt 699
<210> 10
<211> 233
<212> PRT
<213> Homo sapiens
<400> 10
Met Ser Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Ala
1 5 10 15
Ser Arg Gly Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val
20 25 30
Thr Pro Lys Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile
35 40 45
Gly Ser Ser Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys
50 55 60
Leu Leu Ile Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser
85 90 95
Leu Glu Ala Glu Asp Ala Ala Ala Tyr Tyr Cys His Gln Ser Ser Ser
100 105 110
Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr
115 120 125
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
130 135 140
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
145 150 155 160
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
165 170 175
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
180 185 190
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
195 200 205
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
210 215 220
Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 11
<211> 1389
<212> DNA
<213> Homo sapiens
<400> 11
atggggtcaa ccgccatcct cgccctcctc ctggctgttc tccaaggagt ctgtgccgag 60
gtgcagctga tgcagtctgg agcagaggtg aaaaagcccg gggagtctct gaagatctcc 120
tgtaagggtt ctggatacag cttttccttc cactggatcg cctgggtgcg ccagatgccc 180
gggaaaggcc tggagtggat ggggatcatc catcctggtg cctctgatac cagatacagc 240
ccgtccttcc aaggccaggt caccatctca gccgacaact ccaacagcgc cacctacctg 300
cagtggagca gcctgaaggc ctcggacacc gccatgtatt tctgtgcgag acaaagggaa 360
ctcgactact ttgactactg gggccaggga accctggtca ccgtctctag tgcctccacc 420
aagggcccat cggtcttccc cctggcgccc tgctccagga gcacctccga gagcacagcg 480
gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540
ggcgctctga ccagcggcgt gcacaccttc ccagctgtcc tacagtcctc aggactctac 600
tccctcagca gcgtggtgac cgtgccctcc agcaacttcg gcacccagac ctacacctgc 660
aacgtagatc acaagcccag caacaccaag gtggacaaga cagttgagcg caaatgttgt 720
gtcgagtgcc caccgtgccc agcaccacct gtggcaggac cgtcagtctt cctcttcccc 780
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacgtg cgtggtggtg 840
gacgtgagcc acgaagaccc cgaggtccag ttcaactggt acgtggacgg cgtggaggtg 900
cataatgcca agacaaagcc acgggaggag cagttcaaca gcacgttccg tgtggtcagc 960
gtcctcaccg ttgtgcacca ggactggctg aacggcaagg agtacaagtg caaggtctcc 1020
aacaaaggcc tcccagcccc catcgagaaa accatctcca aaaccaaagg gcagccccga 1080
gaaccacagg tgtacaccct gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc 1140
ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg ggagagcaat 1200
gggcagccgg agaacaacta caagaccaca cctcccatgc tggactccga cggctccttc 1260
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1320
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1380
ccgggtaaa 1389
<210> 12
<211> 463
<212> PRT
<213> Homo sapiens
<400> 12
Met Gly Ser Thr Ala Ile Leu Ala Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Val Cys Ala Glu Val Gln Leu Met Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe
35 40 45
Ser Phe His Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu
50 55 60
Glu Trp Met Gly Ile Ile His Pro Gly Ala Ser Asp Thr Arg Tyr Ser
65 70 75 80
Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Asn Ser Asn Ser
85 90 95
Ala Thr Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met
100 105 110
Tyr Phe Cys Ala Arg Gln Arg Glu Leu Asp Tyr Phe Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
225 230 235 240
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
340 345 350
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 13
<211> 708
<212> DNA
<213> Homo sapiens
<400> 13
atggacatga gggtccccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60
cgctgtgata tccagatgac ccaatcccct tctagtctgt ccgcttctgt gggcgacagg 120
gttacaataa cttgcaaagc gagccaggac atcaacaaat atgtggcttg gtatcagcaa 180
aaacccggca aggcaccaaa attgctcatt tattacacgt catggctcca gcctggtgta 240
cctagcaggt tttccggctc cggctcaggt accgacttta ctttcactat ctcctcactg 300
cagccggagg acattgccac atactactgt ctccaatatg ataacttgtt gtatactttt 360
gggcaaggaa ctaagctcga gatcaaacgt acggtggctg caccatctgt cttcatcttc 420
ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac 480
ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 540
tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc 600
ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga agtcacccat 660
cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 708
<210> 14
<211> 236
<212> PRT
<213> Homo sapiens
<400> 14
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser
35 40 45
Gln Asp Ile Asn Lys Tyr Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Trp Leu Gln Pro Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln
100 105 110
Tyr Asp Asn Leu Leu Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 15
<211> 1401
<212> DNA
<213> Homo sapiens
<400> 15
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60
cgctgtgagg ttcagcttgt ggagtctggc ggcggcctgg tgcagccagg cggttcactc 120
aggctgagct gtgctgcatc agggttcacc ttcagccgtt actggatgaa ctgggtgcgg 180
caagcacccg ggaaaggcct ggagtgggtg gctcagattc gcttgaaaag tgacaattat 240
gccactcact atgcagaaag cgtgaagggg cgctttacaa tttctagaga caacgccaaa 300
aactcactgt acctgcagat gaacagcctc agagctgagg atacagctgt gtattattgt 360
actgaggggc tcgactattg gggacagggc acgacagtga ccgtctctag tgcctccacc 420
aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 480
gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540
ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 600
tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 660
aacgtgaatc acaagcccag caacaccaag gtggacaaga aagttgagcc caaatcttgt 720
gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 780
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 840
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 900
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 960
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1020
tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1080
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1140
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1200
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1260
gacggctcct tcttcctcta tagcaagctc accgtggaca agagcaggtg gcagcagggg 1320
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1380
ctctccctgt ctccgggtaa a 1401
<210> 16
<211> 467
<212> PRT
<213> Homo sapiens
<400> 16
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Arg Tyr Trp Met Asn Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr
65 70 75 80
Ala Thr His Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
85 90 95
Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
100 105 110
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Glu Gly Leu Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 17
<211> 708
<212> DNA
<213> Homo sapiens
<400> 17
atggacatga gggtcctcgc tcagctcctg gggctcctgc tgctctgttt cccaggtgcc 60
agatgtgaca tccagatgac ccagtctcca tcctcactgt ctgcatctgt aggagacaga 120
gtcaccatca cttgtcgggc gagtcagggt attagcaact ggttagcctg gtatcagcag 180
aaaccagaga aagcccctaa gtccctgatc tatgctgcat ccagtttgca aagtggggtc 240
ccatcaaggt tcagcggcag tggatctggg acagatttca ctctcaccat cagcagcctg 300
cagcctgaag attttgcaac ttattactgc caacagtatg atagttaccc tcggacgttc 360
ggccaaggga ccaaggtgga aatcaaacga actgtggctg caccatctgt cttcatcttc 420
ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac 480
ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 540
tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc 600
ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga agtcacccat 660
cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 708
<210> 18
<211> 236
<212> PRT
<213> Homo sapiens
<400> 18
Met Asp Met Arg Val Leu Ala Gln Leu Leu Gly Leu Leu Leu Leu Cys
1 5 10 15
Phe Pro Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Ser Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys
50 55 60
Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Tyr Asp Ser Tyr Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 19
<211> 1398
<212> DNA
<213> Homo sapiens
<400> 19
atggagttgg ggctgaactg ggttttcctt gttgctattt tagaaggtgt ccactgtgag 60
gtgcagctgg tggagtctgg gggaggcttg gtccagcctg gggggtccct gagactctcc 120
tgtgcagctt ctggatttac ctttagtagt tattggatga gttgggtccg ccaggctcca 180
gggaaagggc tggagtgggt ggcctacata aagcaagatg gaaatgagaa atactatgtg 240
gactctgtga agggccgatt caccatctcc agagacaacg ccaagaactc attgtatctg 300
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag ggaagggata 360
ctttggttcg gggacttacc gacgttctgg ggccagggaa ccctggtcac cgtctctagt 420
gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 480
agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540
tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 600
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 660
tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 720
aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 780
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 840
gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 900
gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 960
gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc 1020
aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 1080
cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1140
caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 1200
gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 1260
ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1320
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1380
tccctgtctc cgggtaaa 1398
<210> 20
<211> 466
<212> PRT
<213> Homo sapiens
<400> 20
Met Glu Leu Gly Leu Asn Trp Val Phe Leu Val Ala Ile Leu Glu Gly
1 5 10 15
Val His Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Tyr Ile Lys Gln Asp Gly Asn Glu Lys Tyr Tyr Val
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Gly Ile Leu Trp Phe Gly Asp Leu Pro Thr
115 120 125
Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu
145 150 155 160
Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn
210 215 220
Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg
225 230 235 240
Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Lys
465
<210> 21
<211> 723
<212> DNA
<213> Homo sapiens
<400> 21
atggacatga ggctccctgc tcagctcctg gggctgctaa tgctctgggt cccaggatcc 60
agtggggatg ttctgatgac tcagtctcca ctctccctgc ccgtcaccct tggacagccg 120
gcctccatct cctgcaggtc tagtcaaagc atcgtacaca gtaacggaaa cacctacttg 180
gagtggtatc tgcagaggcc aggccaatct ccaaagctcc taatttataa ggtttctaac 240
cggttctctg gggtcccaga cagattcagc ggcagtgggt caggcactga tttcacactg 300
aaaatcagca gggtggaggc tgaggatgtt ggggtttatt actgcttcca aggtagccac 360
gttcctctga cgttcggcgc agggaccaag ctggaaatca aacggactgt ggctgcacca 420
tctgtcttca tcttcccgcc atctgatgag cagttgaaat ctggaactgc ctctgttgtg 480
tgcctgctga ataacttcta tcccagagag gccaaagtac agtggaaggt ggataacgcc 540
ctccaatcgg gtaactccca ggagagtgtc acagagcagg acagcaagga cagcacctac 600
agcctcagca gcaccctgac gctgagcaaa gcagactacg agaaacacaa agtctacgcc 660
tgcgaagtca cccatcaggg cctgagctcg cccgtcacaa agagcttcaa caggggagag 720
tgt 723
<210> 22
<211> 241
<212> PRT
<213> Homo sapiens
<400> 22
Met Asp Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp
1 5 10 15
Val Pro Gly Ser Ser Gly Asp Val Leu Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu
50 55 60
Gln Arg Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn
65 70 75 80
Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Leu Thr Phe Gly Ala Gly
115 120 125
Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
Cys
<210> 23
<211> 1410
<212> DNA
<213> Homo sapiens
<400> 23
atggacacac tttgctccac gctcctgctg ctgaccatcc cttcatgggt cttgtcccag 60
gtcaccttga aggagtctgg tcctgcgctg gtgaaaccca cacagaccct cacgctgacc 120
tgcaccttct ctgggttctc actccgcact agtggaatgg gcgtgggctg gatccgtcag 180
cccccaggaa aggccctgga gtggcttgcc cacatttggt gggatgatga taagagctac 240
aacccatctc tgaagagcca gctcaccatc tctaaggaca cctccaaaaa ccaggtggtc 300
cttacaatga ccaacatgga ccctgtggac acagccacat attactgtgc acgcagaaac 360
tattactacg acgactactt cgcctactgg ggccagggca ccctggtcac cgtctctagt 420
gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 480
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 600
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 660
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 720
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 780
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 840
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 900
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 960
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 1020
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1080
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 1140
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1200
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1260
ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 1320
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1380
cagaagagcc tctccctgtc tccgggtaaa 1410
<210> 24
<211> 470
<212> PRT
<213> Homo sapiens
<400> 24
Met Asp Thr Leu Cys Ser Thr Leu Leu Leu Leu Thr Ile Pro Ser Trp
1 5 10 15
Val Leu Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys
20 25 30
Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu
35 40 45
Arg Thr Ser Gly Met Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys
50 55 60
Ala Leu Glu Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Ser Tyr
65 70 75 80
Asn Pro Ser Leu Lys Ser Gln Leu Thr Ile Ser Lys Asp Thr Ser Lys
85 90 95
Asn Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala
100 105 110
Thr Tyr Tyr Cys Ala Arg Arg Asn Tyr Tyr Tyr Asp Asp Tyr Phe Ala
115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
145 150 155 160
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
210 215 220
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
225 230 235 240
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
<210> 25
<211> 705
<212> DNA
<213> Homo sapiens
<400> 25
atggaaaccc cggcgcagct gctgtttctg ctgctgctgt ggctgccgga taccaccggc 60
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120
ctctcctgca gggccagtca gagtgttagc agcagctact tcgcctggta ccaacagaaa 180
cctggccagg ctcccaggct cctcatctat ggtacatcca gcagggccac tggcatccca 240
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccgtcag cagactggag 300
cctgaggatt ttgcagtgta ttactgtcag cagtatgata ggtcacctcg gacgttcggc 360
caagggacca aggtggaaat caaacgtacg gtggctgcac catctgtctt catcttcccg 420
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 705
<210> 26
<211> 235
<212> PRT
<213> Homo sapiens
<400> 26
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Ser Tyr Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Thr Ser Ser Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Val
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr
100 105 110
Asp Arg Ser Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 27
<211> 1389
<212> DNA
<213> Homo sapiens
<400> 27
atggattgga cctggcgtat tctgtttctg gtggcggcgg cgaccggcgc gcatagccag 60
gtgcagttgg tgcagtctgg ggctgcggtg aagaagcctg gggcctcagt gaaggtctcc 120
tgcaaggctt ctggatacac cttcaccggc tactatatac actgggtgcg acaggcccct 180
ggacaagggc ttgagtggat gggatggatc aaccctaaca gtggtggcac aaactatgca 240
caaaagtttc agggcagggt caccatgacc agggacacgt ccatcagcac agcctccatg 300
gaactgagca ggctgagatc tgacgacacg gccgtttatt tctgtgcgag agatcggtgg 360
ctggatgctt ttgatatctg gggccaaggg acaatggtca ccgtctcttc tgctagcacc 420
aagggcccat cggtcttccc cctggcgccc tgctccagga gcacctccga gagcacagcg 480
gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540
ggcgctctga ccagcggcgt gcacaccttc ccagctgtcc tacagtcctc aggactctac 600
tccctcagca gcgtggtgac cgtgccctcc agcaacttcg gcacccagac ctacacctgc 660
aacgtagatc acaagcccag caacaccaag gtggacaaga cagttgagcg caaatgttgt 720
gtcgagtgcc caccgtgccc agcaccacct gtggcaggac cgtcagtctt cctcttcccc 780
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacgtg cgtggtggtg 840
gacgtgagcc acgaagaccc cgaggtccag ttcaactggt acgtggacgg cgtggaggtg 900
cataatgcca agacaaagcc acgggaggag cagttcaaca gcacgttccg tgtggtcagc 960
gtcctcaccg ttgtgcacca ggactggctg aacggcaagg agtacaagtg caaggtctcc 1020
aacaaaggcc tcccagcccc catcgagaaa accatctcca aaaccaaagg gcagccccga 1080
gaaccacagg tgtacaccct gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc 1140
ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg ggagagcaat 1200
gggcagccgg agaacaacta caagaccaca cctcccatgc tggactccga cggctccttc 1260
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1320
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1380
ccgggtaaa 1389
<210> 28
<211> 463
<212> PRT
<213> Homo sapiens
<400> 28
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Ala Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Gly Tyr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala
65 70 75 80
Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
85 90 95
Thr Ala Ser Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Phe Cys Ala Arg Asp Arg Trp Leu Asp Ala Phe Asp Ile Trp Gly
115 120 125
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
225 230 235 240
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
340 345 350
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 29
<211> 705
<212> DNA
<213> Homo sapiens
<400> 29
atggaaaccc cagctcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120
ctctcctgca gggccagtca gagtgttagc agcggctact taacctggta ccagcagaaa 180
cctggccagg ctcccagact cctcatctat ggtgcatcca gcagggccac tggcatccca 240
gacaggttca gtggcagtgg gtctgggacg gacttcactc tcaccatcag cagactggag 300
cctgaagatt ttgcagtgta ttactgtcag cagtatggta actcactgag caggtttggc 360
caggggacca agctggagat caaacgtacg gtggctgcac catctgtctt catcttcccg 420
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 705
<210> 30
<211> 235
<212> PRT
<213> Homo sapiens
<400> 30
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Gly Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr
100 105 110
Gly Asn Ser Leu Ser Arg Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 31
<211> 1422
<212> DNA
<213> Homo sapiens
<400> 31
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60
cgctgtcagg tgcagctggt ggagtctggg ggaggcgtgg tccagcctgg gaggtccctg 120
agactctcct gtgcagcgtc tggattcacc ttcagtagct atggcatgca ctgggtccgc 180
caggctccag gcaaggggct ggagtgggtg gcagttatat ggtatgatgg aagtaataaa 240
tactatgcag actccgtgaa gggccgattc atcatctcca gagataaatc caagaacacg 300
ctgtatctgc aaatgaacag cctgagagcc gaggacacgg ctgtgtatta ctgtgcgaga 360
gcggggggta tagcagcagc tggcctctac tactactacg gtatggacgt ctggggccaa 420
gggaccacgg tcaccgtctc tagtgcctcc accaagggcc catcggtctt ccccctggcg 480
ccctgctcca ggagcacctc cgagagcaca gcggccctgg gctgcctggt caaggactac 540
ttccccgaac cggtgacggt gtcgtggaac tcaggcgctc tgaccagcgg cgtgcacacc 600
ttcccagctg tcctacagtc ctcaggactc tactccctca gcagcgtggt gaccgtgccc 660
tccagcaact tcggcaccca gacctacacc tgcaacgtag atcacaagcc cagcaacacc 720
aaggtggaca agacagttga gcgcaaatgt tgtgtcgagt gcccaccgtg cccagcacca 780
cctgtggcag gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 840
tcccggaccc ctgaggtcac gtgcgtggtg gtggacgtga gccacgaaga ccccgaggtc 900
cagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccacgggag 960
gagcagttca acagcacgtt ccgtgtggtc agcgtcctca ccgttgtgca ccaggactgg 1020
ctgaacggca aggagtacaa gtgcaaggtc tccaacaaag gcctcccagc ccccatcgag 1080
aaaaccatct ccaaaaccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 1140
tcccgggagg agatgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctac 1200
cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1260
acacctccca tgctggactc cgacggctcc ttcttcctct acagcaagct caccgtggac 1320
aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 1380
aaccactaca cgcagaagag cctctccctg tctccgggta aa 1422
<210> 32
<211> 474
<212> PRT
<213> Homo sapiens
<400> 32
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys
65 70 75 80
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Lys
85 90 95
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Ala Gly Gly Ile Ala Ala Ala Gly
115 120 125
Leu Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val
130 135 140
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
145 150 155 160
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
165 170 175
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
180 185 190
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
195 200 205
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe
210 215 220
Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
225 230 235 240
Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro
245 250 255
Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro
260 265 270
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
275 280 285
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp
290 295 300
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
305 310 315 320
Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val
325 330 335
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
340 345 350
Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly
355 360 365
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
370 375 380
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
385 390 395 400
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
405 410 415
Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe
420 425 430
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
435 440 445
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
450 455 460
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 33
<211> 806
<212> DNA
<213> Homo sapiens
<400> 33
atgacatcca ctttgccttt ctctccacag gtgtccactc ccaggtccaa gtttaaacgg 60
atctctagcg aattccctct agagtcgact agaccaccat ggacatgagg gtgcccgctc 120
agctcctggg gctcctgctg ctgtggctga gaggtgcgcg ctgttcttct gagctgactc 180
aggaccctac tgtgtctgtg gccttgggac agacagtcaa aatcacatgc caaggagaca 240
gcctcagaag tttttatgca agctggtacc agcagaagcc aggacaggcc cctgtacttg 300
tcttctatgg taaaaacaac cggccctcag ggatcccaga ccgattctct ggctccagct 360
caggaaacac agcttccttg accatcactg gggctcaggc ggaagatgag gctgactatt 420
attgtaattc ccgggacagc agtgtttacc atctggtact cggcggaggg accaagctga 480
ccgtcctagg tcagcccaag gccaacccca ctgtcactct gttcccgccc tcctctgagg 540
agctccaagc caacaaggcc acactagtgt gtctgatcag tgacttctac ccgggagctg 600
tgacagtggc ctggaaggca gatggcagcc ccgtcaaggc gggagtggag accaccaaac 660
cctccaaaca gagcaacaac aagtacgcgg ccagcagcta cctgagcctg acgcccgagc 720
agtggaagtc ccacagaagc tacagctgcc aggtcacgca tgaagggagc accgtggaga 780
agacagtggc ccctacagaa tgttca 806
<210> 34
<211> 236
<212> PRT
<213> Homo sapiens
<400> 34
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ser Ser Glu Leu Thr Gln Asp Pro Thr Val
20 25 30
Ser Val Ala Leu Gly Gln Thr Val Lys Ile Thr Cys Gln Gly Asp Ser
35 40 45
Leu Arg Ser Phe Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Val Leu Val Phe Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile
85 90 95
Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg
100 105 110
Asp Ser Ser Val Tyr His Leu Val Leu Gly Gly Gly Thr Lys Leu Thr
115 120 125
Val Leu Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro
130 135 140
Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile
145 150 155 160
Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly
165 170 175
Ser Pro Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser
180 185 190
Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln
195 200 205
Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser
210 215 220
Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230 235
<210> 35
<211> 1434
<212> DNA
<213> Homo sapiens
<400> 35
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60
cgctgtcagg tgcagttggt gcagtctggg gctgaggtga agaagcctgg ggcctcagtg 120
aaggtctcct gcaaggcttc tggatacacc ttcaccggct actatatgca ctgggtgcga 180
caggcccctg gacaagggct tgagtggatg ggatggatca accctaacag tggtggcaca 240
aactatgcac agaagtttca gggcagggtc accatgacca gggacacgtc catcagcaca 300
gcctacatgg agctgagcag gctgagatct gacgacacgg ccgtgtattt ctgtgcgaga 360
gatcaaatga gtattattat gcttcgggga gtttttcccc cttactatta cggtatggac 420
gtctggggcc aagggaccac ggtcaccgtc tctagtgcct ccaccaaggg cccatcggtc 480
ttccccctgg cgccctgctc caggagcacc tccgagagca cagcggccct gggctgcctg 540
gtcaaggact acttccccga accggtgacg gtgtcgtgga actcaggcgc tctgaccagc 600
ggcgtgcaca ccttcccagc tgtcctacag tcctcaggac tctactccct cagcagcgtg 660
gtgaccgtgc cctccagcaa cttcggcacc cagacctaca cctgcaacgt agatcacaag 720
cccagcaaca ccaaggtgga caagacagtt gagcgcaaat gttgtgtcga gtgcccaccg 780
tgcccagcac cacctgtggc aggaccgtca gtcttcctct tccccccaaa acccaaggac 840
accctcatga tctcccggac ccctgaggtc acgtgcgtgg tggtggacgt gagccacgaa 900
gaccccgagg tccagttcaa ctggtacgtg gacggcgtgg aggtgcataa tgccaagaca 960
aagccacggg aggagcagtt caacagcacg ttccgtgtgg tcagcgtcct caccgttgtg 1020
caccaggact ggctgaacgg caaggagtac aagtgcaagg tctccaacaa aggcctccca 1080
gcccccatcg agaaaaccat ctccaaaacc aaagggcagc cccgagaacc acaggtgtac 1140
accctgcccc catcccggga ggagatgacc aagaaccagg tcagcctgac ctgcctggtc 1200
aaaggcttct accccagcga catcgccgtg gagtgggaga gcaatgggca gccggagaac 1260
aactacaaga ccacacctcc catgctggac tccgacggct ccttcttcct ctacagcaag 1320
ctcaccgtgg acaagagcag gtggcagcag gggaacgtct tctcatgctc cgtgatgcat 1380
gaggctctgc acaaccacta cacgcagaag agcctctccc tgtctccggg taaa 1434
<210> 36
<211> 478
<212> PRT
<213> Homo sapiens
<400> 36
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Gln Ser Gly Ala Glu
20 25 30
Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly
35 40 45
Tyr Thr Phe Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Gln Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr
65 70 75 80
Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr
85 90 95
Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp
100 105 110
Thr Ala Val Tyr Phe Cys Ala Arg Asp Gln Met Ser Ile Ile Met Leu
115 120 125
Arg Gly Val Phe Pro Pro Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln
130 135 140
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
145 150 155 160
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
165 170 175
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
180 185 190
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
195 200 205
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
210 215 220
Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys
225 230 235 240
Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val
245 250 255
Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val
325 330 335
Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
355 360 365
Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
370 375 380
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp
420 425 430
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 37
<211> 723
<212> DNA
<213> Homo sapiens
<400> 37
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcc 60
agatgtgata ttgtgatgac tcagtctcca ctctccctgc ccgtcacccc tggagagccg 120
gcctccatct cctgcaggtc tagtcagagc ctcctgcata gtaatggata caactatttg 180
gattggtacc tgcagaagcc agggcagtct ccacagctcc tgatctattt gggttctaat 240
cgggcctccg gggtccctga caggttcagt ggcagtggat caggcacaga ttttacactg 300
aaaatcagca gagtggaggc tgaggatgtt ggggtttatt actgcatgca agctctacaa 360
actccgctca ctttcggcgg agggaccaag gtagagatca aacggactgt ggctgcacca 420
tctgtcttca tcttcccgcc atctgatgag cagttgaaat ctggaactgc ctctgttgtg 480
tgcctgctga ataacttcta tcccagagag gccaaagtac agtggaaggt ggataacgcc 540
ctccaatcgg gtaactccca ggagagtgtc acagagcagg acagcaagga cagcacctac 600
agcctcagca gcaccctgac gctgagcaaa gcagactacg agaaacacaa agtctacgcc 660
tgcgaagtca cccatcaggg cctgagctcg cccgtcacaa agagcttcaa caggggagag 720
tgt 723
<210> 38
<211> 241
<212> PRT
<213> Homo sapiens
<400> 38
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu
50 55 60
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn
65 70 75 80
Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Met Gln Ala Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly
115 120 125
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
Cys
<210> 39
<211> 1425
<212> DNA
<213> Homo sapiens
<400> 39
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcc 60
agatgtgagg tgcagctggt ggagtctggg ggaggcttgg tccagcctgg ggggtccctg 120
agactctcct gtgcagcctc cggattcacc tttagtagct attggatgag ctgggtccgc 180
caggctccag ggaaggggct ggagtgggtg gccagcataa aacaagatgg aagtgagaaa 240
tactatgtgg actctgtgaa gggccgattc accatctcca gagacaacgc caggaactca 300
ctgtatctgc aaatgaacag cctgagagcc gaggacacgg ctgtgtatta ctgtgcgaga 360
gatcttgtat taatggtgta tgatatagac tactactact acggtatgga cgtctggggc 420
caagggacca cggtcaccgt ctcctcagcc tccaccaagg gcccatcggt cttccccctg 480
gcgccctgct ccaggagcac ctccgagagc acagcggccc tgggctgcct ggtcaaggac 540
tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ctctgaccag cggcgtgcac 600
accttcccag ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgaccgtg 660
ccctccagca acttcggcac ccagacctac acctgcaacg tagatcacaa gcccagcaac 720
accaaggtgg acaagacagt tgagcgcaaa tgttgtgtcg agtgcccacc gtgcccagca 780
ccacctgtgg caggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 840
atctcccgga cccctgaggt cacgtgcgtg gtggtggacg tgagccacga agaccccgag 900
gtccagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccacgg 960
gaggagcagt tcaacagcac gttccgtgtg gtcagcgtcc tcaccgttgt gcaccaggac 1020
tggctgaacg gcaaggagta caagtgcaag gtctccaaca aaggcctccc agcccccatc 1080
gagaaaacca tctccaaaac caaagggcag ccccgagaac cacaggtgta caccctgccc 1140
ccatcccggg aggagatgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1200
taccccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1260
accacacctc ccatgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1320
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1380
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaa 1425
<210> 40
<211> 475
<212> PRT
<213> Homo sapiens
<400> 40
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Ser Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ala Ser Ile Lys Gln Asp Gly Ser Glu Lys
65 70 75 80
Tyr Tyr Val Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Arg Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Leu Val Leu Met Val Tyr Asp
115 120 125
Ile Asp Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
130 135 140
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
145 150 155 160
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
165 170 175
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
180 185 190
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
195 200 205
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
210 215 220
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
225 230 235 240
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
245 250 255
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
325 330 335
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
340 345 350
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
370 375 380
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 41
<211> 723
<212> DNA
<213> Homo sapiens
<400> 41
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcc 60
agatgtgata ttgtgatgac tcagtctcca ctctccctgc ccgtcacccc tggagagccg 120
gcctccatct cctgcaggtc tagtcagagc ctcctgcata gtaatgggta caactatttg 180
gattggtacc tgcagaagcc agggcagtct ccacagctcc tgatctattt gggttctaat 240
cgggcctccg gggtccctga caggttcagt ggcagtggat caggcacaca tcttacactg 300
aaaatcagca gagtggaggc tgaggatgtt ggagtttatt actgcatgca aactctacaa 360
actccgctca ctttcggcgg agggaccaag gtagagatca aacggactgt ggctgcacca 420
tctgtcttca tcttcccgcc atctgatgag cagttgaaat ctggaactgc ctctgttgtg 480
tgcctgctga ataacttcta tcccagagag gccaaagtac agtggaaggt ggataacgcc 540
ctccaatcgg gtaactccca ggagagtgtc acagagcagg acagcaagga cagcacctac 600
agcctcagca gcaccctgac gctgagcaaa gcagactacg agaaacacaa agtctacgcc 660
tgcgaagtca cccatcaggg cctgagctcg cccgtcacaa agagcttcaa caggggagag 720
tgt 723
<210> 42
<211> 241
<212> PRT
<213> Homo sapiens
<400> 42
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu
50 55 60
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn
65 70 75 80
Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
His Leu Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Met Gln Thr Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly
115 120 125
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
Cys
<210> 43
<211> 1425
<212> DNA
<213> Homo sapiens
<400> 43
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcc 60
agatgtgagg tgcagctggt ggagtctggg ggaggcttgg tccagcctgg ggggtccctg 120
agactctcct gtgcagcctc cggattcacc tttagtaact attggatgag ctgggtccgc 180
caggctccag ggaaggggct ggagtgggtg gccagcataa aacaagatgg aagtgagaaa 240
tactatgtgg actctgtgaa gggccgattc gccatctcca gagacaacgc caagaactca 300
ctgtttctgc aaatgaacag cctgagagcc gaggacacgg ctgtgtatta ctgtgcgaga 360
gatcttgtac taatggtgta tgatatagac tactactact acggtatgga cgtctggggc 420
caagggacca cggtcaccgt ctcctcagcc tccaccaagg gcccatcggt cttccccctg 480
gcgccctgct ccaggagcac ctccgagagc acagcggccc tgggctgcct ggtcaaggac 540
tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ctctgaccag cggcgtgcac 600
accttcccag ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgaccgtg 660
ccctccagca acttcggcac ccagacctac acctgcaacg tagatcacaa gcccagcaac 720
accaaggtgg acaagacagt tgagcgcaaa tgttgtgtcg agtgcccacc gtgcccagca 780
ccacctgtgg caggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 840
atctcccgga cccctgaggt cacgtgcgtg gtggtggacg tgagccacga agaccccgag 900
gtccagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccacgg 960
gaggagcagt tcaacagcac gttccgtgtg gtcagcgtcc tcaccgttgt gcaccaggac 1020
tggctgaacg gcaaggagta caagtgcaag gtctccaaca aaggcctccc agcccccatc 1080
gagaaaacca tctccaaaac caaagggcag ccccgagaac cacaggtgta caccctgccc 1140
ccatcccggg aggagatgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1200
taccccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1260
accacacctc ccatgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1320
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1380
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaa 1425
<210> 44
<211> 475
<212> PRT
<213> Homo sapiens
<400> 44
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Asn Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ala Ser Ile Lys Gln Asp Gly Ser Glu Lys
65 70 75 80
Tyr Tyr Val Asp Ser Val Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn
85 90 95
Ala Lys Asn Ser Leu Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Leu Val Leu Met Val Tyr Asp
115 120 125
Ile Asp Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
130 135 140
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
145 150 155 160
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
165 170 175
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
180 185 190
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
195 200 205
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
210 215 220
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
225 230 235 240
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
245 250 255
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
325 330 335
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
340 345 350
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
370 375 380
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 45
<211> 705
<212> DNA
<213> Homo sapiens
<400> 45
atgacttgtt ctccactgct gctgactctg ctgattcatt gtactggttc ttgggcgcag 60
tctgtgttga cgcagccgcc ctcagtgtct gcggccccag gacagaaggt caccatctcc 120
tgctctggaa gcagctccaa cattgggaat aattatgtat cctggtacca gcagctccca 180
ggaacagccc ccaaactcct catttatgac aataataagc gaccctcagg gattcctgac 240
cgattctctg gctccaagtc tggcacgtca accaccctgg gcatcaccgg actccagact 300
ggggacgagg ccgattatta ctgcggaaca tgggatagcc gcctgagtgc tgtggttttc 360
ggcggaggga ccaagctgac cgtcctaggt cagcccaagg ccaaccccac tgtcactctg 420
ttcccgccct cctctgagga gctccaagcc aacaaggcca cactagtgtg tctgatcagt 480
gacttctacc cgggagctgt gacagtggcc tggaaggcag atggcagccc cgtcaaggcg 540
ggagtggaga ccaccaaacc ctccaaacag agcaacaaca agtacgcggc cagcagctac 600
ctgagcctga cgcccgagca gtggaagtcc cacagaagct acagctgcca ggtcacgcat 660
gaagggagca ccgtggagaa gacagtggcc cctacagaat gttca 705
<210> 46
<211> 235
<212> PRT
<213> Homo sapiens
<400> 46
Met Thr Cys Ser Pro Leu Leu Leu Thr Leu Leu Ile His Cys Thr Gly
1 5 10 15
Ser Trp Ala Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala
20 25 30
Pro Gly Gln Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile
35 40 45
Gly Asn Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro
50 55 60
Lys Leu Leu Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Thr Thr Leu Gly Ile Thr
85 90 95
Gly Leu Gln Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp
100 105 110
Ser Arg Leu Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val
115 120 125
Leu Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser
130 135 140
Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser
145 150 155 160
Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser
165 170 175
Pro Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn
180 185 190
Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp
195 200 205
Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr
210 215 220
Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230 235
<210> 47
<211> 1425
<212> DNA
<213> Homo sapiens
<400> 47
atggaatttg gtctgtcttg ggtatttctg gttgctctgc tgcgtggcgt gcagtgccag 60
gtgcagctgg tggaatctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120
tgtgcagcct ctggattcac cttcagtagc tttggcatgc actgggtccg ccaggctcca 180
ggcaaggggc tggagtgggt ggcagttata tcatttgatg gaagtattaa gtattctgta 240
gactccgtga agggccgatt caccatctcc agagacaatt caaagaacac gctgtttctg 300
caaatgaaca gcctgcgagc cgaggacacg gctgtgtatt actgtgcgag agatcggctc 360
aattactatg atagtagtgg ttattatcac tacaaatact acggtatggc cgtctggggc 420
caagggacca cggtcaccgt ctctagtgcc tccaccaagg gcccatcggt cttccccctg 480
gcgccctgct ccaggagcac ctccgagagc acagcggccc tgggctgcct ggtcaaggac 540
tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ctctgaccag cggcgtgcac 600
accttcccag ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgaccgtg 660
ccctccagca acttcggcac ccagacctac acctgcaacg tagatcacaa gcccagcaac 720
accaaggtgg acaagacagt tgagcgcaaa tgttgtgtcg agtgcccacc gtgcccagca 780
ccacctgtgg caggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 840
atctcccgga cccctgaggt cacgtgcgtg gtggtggacg tgagccacga agaccccgag 900
gtccagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccacgg 960
gaggagcagt tcaacagcac gttccgtgtg gtcagcgtcc tcaccgttgt gcaccaggac 1020
tggctgaacg gcaaggagta caagtgcaag gtctccaaca aaggcctccc agcccccatc 1080
gagaaaacca tctccaaaac caaagggcag ccccgagaac cacaggtgta caccctgccc 1140
ccatcccggg aggagatgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1200
taccccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1260
accacacctc ccatgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1320
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1380
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaa 1425
<210> 48
<211> 475
<212> PRT
<213> Homo sapiens
<400> 48
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Phe Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Ser Phe Asp Gly Ser Ile Lys Tyr Ser Val
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Asp Arg Leu Asn Tyr Tyr Asp Ser Ser Gly Tyr
115 120 125
Tyr His Tyr Lys Tyr Tyr Gly Met Ala Val Trp Gly Gln Gly Thr Thr
130 135 140
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
145 150 155 160
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
165 170 175
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
180 185 190
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
195 200 205
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
210 215 220
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
225 230 235 240
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
245 250 255
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
325 330 335
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
340 345 350
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
370 375 380
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 49
<211> 702
<212> DNA
<213> Homo sapiens
<400> 49
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcc 60
agatgttatg agctgactca gccaccctca gtgtccgtgt ccccaggaca gacagccacc 120
atcacctgct ctggagataa attgggggaa agatatgcgt cttggtatca gcagaggcca 180
ggccagtccc ctgtactggt catctatcaa gatatcaagc ggccctcagg gatccctgag 240
cgattctctg gctccaactc tgggaacaca gccactctga ccatcagcgg gacccaggct 300
atggatgagg ctgactattt ctgtcaggcg tggtacagca gcaccaatgt gcttttcggc 360
ggagggacca agctgaccgt cctaggtcag cccaaggctg ccccctcggt cactctgttc 420
ccgccctcct ctgaggagct tcaagccaac aaggccacac tggtgtgtct cataagtgac 480
ttctacccgg gagccgtgac agtggcctgg aaggcagata gcagccccgt caaggcggga 540
gtggagacca ccacaccctc caaacaaagc aacaacaagt acgcggccag cagctatctg 600
agcctgacgc ctgagcagtg gaagtcccac agaagctaca gctgccaggt cacgcatgaa 660
gggagcaccg tggagaagac agtggcccct acagaatgtt ca 702
<210> 50
<211> 234
<212> PRT
<213> Homo sapiens
<400> 50
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser
20 25 30
Val Ser Pro Gly Gln Thr Ala Thr Ile Thr Cys Ser Gly Asp Lys Leu
35 40 45
Gly Glu Arg Tyr Ala Ser Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro
50 55 60
Val Leu Val Ile Tyr Gln Asp Ile Lys Arg Pro Ser Gly Ile Pro Glu
65 70 75 80
Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser
85 90 95
Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Phe Cys Gln Ala Trp Tyr
100 105 110
Ser Ser Thr Asn Val Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
115 120 125
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
130 135 140
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
145 150 155 160
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
165 170 175
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
180 185 190
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
195 200 205
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
210 215 220
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230
<210> 51
<211> 1398
<212> DNA
<213> Homo sapiens
<400> 51
atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60
gtgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120
tgtgcagcgt ctggattcac cttcagtagc tatggcatgc actgggtccg ccaggctcca 180
ggcaaggggc tggagtgggt ggcagttata tggtatgctg aaagtaataa atactacgca 240
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctg 300
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agcccaggag 360
ggtatagccc ctgacgcttt tgatatctgg ggccaaggaa caatggtcac cgtctcttca 420
gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 480
agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540
tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 600
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 660
tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 720
aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 780
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 840
gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 900
gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 960
gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc 1020
aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 1080
cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1140
caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 1200
gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 1260
ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1320
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1380
tccctgtctc cgggtaaa 1398
<210> 52
<211> 466
<212> PRT
<213> Homo sapiens
<400> 52
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Trp Tyr Ala Glu Ser Asn Lys Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ala Gln Glu Gly Ile Ala Pro Asp Ala Phe Asp
115 120 125
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu
145 150 155 160
Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn
210 215 220
Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg
225 230 235 240
Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Lys
465
<210> 53
<211> 702
<212> DNA
<213> Homo sapiens
<400> 53
atggggtcaa ccgccatcct tggcctcctc ctggctgtcc tgcagggagg gcgcgccgaa 60
attgtgttga cgcagtctcc aggcaccctg tctttgtctc caggggaaag agccaccctc 120
tcctgcaggg ccagtcagag tgttagcagc agctacttag cctggcacca gcagaaacct 180
ggccaggctc ccaggctcct catctatggt gcatccagca gggccactgg catcccagac 240
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag actggagcct 300
gaagattttg cagtgtatta ctgtcagcag tatggtagct caccgtggac gttcggccaa 360
gggaccaagg tggaaatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 420
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 480
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 540
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 600
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 660
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 702
<210> 54
<211> 234
<212> PRT
<213> Homo sapiens
<400> 54
Met Gly Ser Thr Ala Ile Leu Gly Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Gly Arg Ala Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
20 25 30
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val
35 40 45
Ser Ser Ser Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Gln Ala Pro
50 55 60
Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly
100 105 110
Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 55
<211> 1389
<212> DNA
<213> Homo sapiens
<400> 55
atggggtcaa ccgccatcct tggcctcctc ctggctgtcc tgcagggagg gcgcgccgag 60
gtgcagctat tggagtctgg gggaggcttg gtacagcctg gggggtccct gagactctcc 120
tgtgcagcct ctggattcac ctttagcacc tatgtcatga gctgggtccg ccaggctcca 180
gggaaggggc tggagtgggt ctcaagtatt agtggtagtg gtcttggctc atactacgca 240
gactccgtga agggccggtt caccatctcc agagacaatt ccaagaacac gctgtatctg 300
caaatgaaca gcctgagagc cgaggacacg gccgtatatt actgtgcgaa agaggcccat 360
cgggggccct ttgactactg gggccaggga accctggtca ccgtctcctc agctagcacc 420
aagggcccat cggtcttccc cctggcgccc tgctccagga gcacctccga gagcacagcg 480
gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540
ggcgctctga ccagcggcgt gcacaccttc ccagctgtcc tacagtcctc aggactctac 600
tccctcagca gcgtggtgac cgtgccctcc agcaacttcg gcacccagac ctacacctgc 660
aacgtagatc acaagcccag caacaccaag gtggacaaga cagttgagcg caaatgttgt 720
gtcgagtgcc caccgtgccc agcaccacct gtggcaggac cgtcagtctt cctcttcccc 780
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacgtg cgtggtggtg 840
gacgtgagcc acgaagaccc cgaggtccag ttcaactggt acgtggacgg cgtggaggtg 900
cataatgcca agacaaagcc acgggaggag cagttcaaca gcacgttccg tgtggtcagc 960
gtcctcaccg ttgtgcacca ggactggctg aacggcaagg agtacaagtg caaggtctcc 1020
aacaaaggcc tcccagcccc catcgagaaa accatctcca aaaccaaagg gcagccccga 1080
gaaccacagg tgtacaccct gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc 1140
ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg ggagagcaat 1200
gggcagccgg agaacaacta caagaccaca cctcccatgc tggactccga cggctccttc 1260
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1320
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1380
ccgggtaaa 1389
<210> 56
<211> 463
<212> PRT
<213> Homo sapiens
<400> 56
Met Gly Ser Thr Ala Ile Leu Gly Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Gly Arg Ala Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Thr Tyr Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Leu Gly Ser Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Lys Glu Ala His Arg Gly Pro Phe Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
225 230 235 240
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
340 345 350
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 57
<211> 721
<212> DNA
<213> Homo sapiens
<400> 57
atgaggctcc ttgctcagct tctggggctg ctaatgctct gggtccctgg atccagtggg 60
gatattgtga tgacccagac tccactctcc tcacctgtca cccttggaca gccggcctcc 120
atctcctgca ggtctagtca aagcctcgta cacagtgatg gaaacaccta cttgagttgg 180
cttcagcaga ggccaggcca gcctccaaga ctcctaattt ataagaaatt taaccggttc 240
tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac actgaaaatc 300
agcagggtgg aagctgagga tgtcggggtt tattactgca tgcaagctac acaaattcct 360
ctcactttcg gccctgggac caaagtggat atcaaacgaa ctgtggctgc accatctgtc 420
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 480
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 540
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 600
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 660
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttga 720
g 721
<210> 58
<211> 239
<212> PRT
<213> Homo sapiens
<400> 58
Met Arg Leu Leu Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Gly Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser Pro
20 25 30
Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
35 40 45
Leu Val His Ser Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg
50 55 60
Pro Gly Gln Pro Pro Arg Leu Leu Ile Tyr Lys Lys Phe Asn Arg Phe
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe
85 90 95
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
100 105 110
Cys Met Gln Ala Thr Gln Ile Pro Leu Thr Phe Gly Pro Gly Thr Lys
115 120 125
Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
130 135 140
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
145 150 155 160
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
165 170 175
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
180 185 190
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
195 200 205
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
210 215 220
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 59
<211> 1416
<212> DNA
<213> Homo sapiens
<400> 59
atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60
gtgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120
tgtgcagcgt ctggattcac cttcagtttc tatggcatgc actgggtccg ccaggctcca 180
ggcaaggggc tggagtgggt ggcagttata tggtatgatg gaagtaataa atactatgca 240
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctg 300
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agggggttat 360
gattacgttt gggggagtta tcgccgtaac tccgactttg actactgggg ccagggaacc 420
ctggtcaccg tctctagtgc ctccaccaag ggcccatcgg tcttccccct ggcgccctgc 480
tccaggagca cctccgagag cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 540
gaaccggtga cggtgtcgtg gaactcaggc gctctgacca gcggcgtgca caccttccca 600
gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 660
aacttcggca cccagaccta cacctgcaac gtagatcaca agcccagcaa caccaaggtg 720
gacaagacag ttgagcgcaa atgttgtgtc gagtgcccac cgtgcccagc accacctgtg 780
gcaggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 840
acccctgagg tcacgtgcgt ggtggtggac gtgagccacg aagaccccga ggtccagttc 900
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccacg ggaggagcag 960
ttcaacagca cgttccgtgt ggtcagcgtc ctcaccgttg tgcaccagga ctggctgaac 1020
ggcaaggagt acaagtgcaa ggtctccaac aaaggcctcc cagcccccat cgagaaaacc 1080
atctccaaaa ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1140
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctaccccagc 1200
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacacct 1260
cccatgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1320
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1380
tacacgcaga agagcctctc cctgtctccg ggtaaa 1416
<210> 60
<211> 472
<212> PRT
<213> Homo sapiens
<400> 60
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Phe Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gly Gly Tyr Asp Tyr Val Trp Gly Ser Tyr Arg
115 120 125
Arg Asn Ser Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
130 135 140
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys
145 150 155 160
Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys
165 170 175
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
180 185 190
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
195 200 205
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr
210 215 220
Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val
225 230 235 240
Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro
245 250 255
Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
260 265 270
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
275 280 285
Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
290 295 300
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
305 310 315 320
Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln
325 330 335
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
340 345 350
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro
355 360 365
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
370 375 380
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
385 390 395 400
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
405 410 415
Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
420 425 430
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
435 440 445
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
450 455 460
Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 61
<211> 705
<212> DNA
<213> Homo sapiens
<400> 61
atggaagccc cagctcagct tctcttcctc ctgctactct ggctcccaga taccactgga 60
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 120
ctctcctgca gggccagtca gagtgttgac agcaacttag cctggtaccg gcagaaacct 180
ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 240
aggttcagtg gcagtgggtc tgggactgag ttcactctca ccatcagcag cctgcagtct 300
gaagattttg cagtttatta ctgtcagcag tatattaact ggcctccgat caccttcggc 360
caagggacac gactggagat taaacgaact gtggctgcac catctgtctt catcttcccg 420
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 705
<210> 62
<211> 235
<212> PRT
<213> Homo sapiens
<400> 62
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Asp Ser Asn Leu Ala Trp Tyr Arg Gln Lys Pro Gly Gln Ala Pro
50 55 60
Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ile
100 105 110
Asn Trp Pro Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 63
<211> 1395
<212> DNA
<213> Homo sapiens
<400> 63
atgaaacacc tgtggttctt ccttctcctg gtggcagctc ccagatgggt cctgtcccag 60
gtgcagctgc aggagtcggg cccaggactg gtgaagcctt cggagaccct gtccctcacc 120
tgcactgtct ctggtggctc catcagtatt tactactgga gctggatccg gcagccccca 180
gggaagggac tggagtggat tgggtatgtc tattacagtg ggagcaccaa ttacaacccc 240
tccctcaaga gtcgagtcac catatcagta gacacgtcca agaaccagtt ctccctgaag 300
ctgaactctg tgaccgctgc ggacacggcc gtgtattact gtgcgagagg gggatacgat 360
ttttggagtg gttattttga ctactggggc cagggaaccc tggtcaccgt ctctagtgcc 420
tccaccaagg gcccatcggt cttccccctg gcgccctgct ccaggagcac ctccgagagc 480
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540
aactcaggcg ctctgaccag cggcgtgcac accttcccag ctgtcctaca gtcctcagga 600
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca acttcggcac ccagacctac 660
acctgcaacg tagatcacaa gcccagcaac accaaggtgg acaagacagt tgagcgcaaa 720
tgttgtgtcg agtgcccacc gtgcccagca ccacctgtgg caggaccgtc agtcttcctc 780
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacgtgcgtg 840
gtggtggacg tgagccacga agaccccgag gtccagttca actggtacgt ggacggcgtg 900
gaggtgcata atgccaagac aaagccacgg gaggagcagt tcaacagcac gttccgtgtg 960
gtcagcgtcc tcaccgttgt gcaccaggac tggctgaacg gcaaggagta caagtgcaag 1020
gtctccaaca aaggcctccc agcccccatc gagaaaacca tctccaaaac caaagggcag 1080
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1140
gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtgggag 1200
agcaatgggc agccggagaa caactacaag accacacctc ccatgctgga ctccgacggc 1260
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1320
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1380
ctgtctccgg gtaaa 1395
<210> 64
<211> 465
<212> PRT
<213> Homo sapiens
<400> 64
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys
20 25 30
Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile
35 40 45
Ser Ile Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Val Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro
65 70 75 80
Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln
85 90 95
Phe Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
100 105 110
Tyr Cys Ala Arg Gly Gly Tyr Asp Phe Trp Ser Gly Tyr Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
210 215 220
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
225 230 235 240
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Lys
465
<210> 65
<211> 723
<212> DNA
<213> Homo sapiens
<400> 65
atggtgctgc agacccaggt gtttattagc ctgctgctgt ggattagcgg cgcgtatggc 60
gacatcgtgc tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 120
atcaactgca agtccagcca gagtatttta tacagctcca gcaatgagaa cttcttaact 180
tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctacccgg 240
gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 300
atcagcagcc tgcagcctga agatgtggca gtttattact gtcagcaata ttttagtgtt 360
tttcggacgt tcggccaagg gaccagggtg gaaatcaaac gtacggtggc tgcaccatct 420
gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 480
ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 540
caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 600
ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 660
gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 720
tag 723
<210> 66
<211> 240
<212> PRT
<213> Homo sapiens
<400> 66
Met Val Leu Gln Thr Gln Val Phe Ile Ser Leu Leu Leu Trp Ile Ser
1 5 10 15
Gly Ala Tyr Gly Asp Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ala
20 25 30
Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser
35 40 45
Ile Leu Tyr Ser Ser Ser Asn Glu Asn Phe Leu Thr Trp Tyr Gln Gln
50 55 60
Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
65 70 75 80
Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Val Tyr
100 105 110
Tyr Cys Gln Gln Tyr Phe Ser Val Phe Arg Thr Phe Gly Gln Gly Thr
115 120 125
Arg Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
130 135 140
Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys
145 150 155 160
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
165 170 175
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
180 185 190
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
195 200 205
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
210 215 220
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235 240
<210> 67
<211> 1395
<212> DNA
<213> Homo sapiens
<400> 67
atggattgga cctggcgtat tctgtttctg gtggcggcgg cgaccggcgc gcatagccag 60
gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg gggcctcagt gaaggtctcc 120
tgcaaggctt ctggatacac cttcaccggc tactatatac actgggtgcg acaggcccct 180
ggacaagggc ttgagtggat gggatggatc aaccctaaca gtggtggcac aaactctgca 240
cagaagtttc ggggcagggt caccatgacc agggacacgt ccatcagcac agcctacatg 300
gagctgagca ggctgagatc tgacgacacg gccgtgtatt actgtgcgcg agagggtgga 360
tacagctatg gttactttga ctactggggc cagggaaccc tggtcaccgt ctcctcagct 420
agcaccaagg gcccatcggt cttccccctg gcgccctgct ccaggagcac ctccgagagc 480
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540
aactcaggcg ctctgaccag cggcgtgcac accttcccag ctgtcctaca gtcctcagga 600
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca acttcggcac ccagacctac 660
acctgcaacg tagatcacaa gcccagcaac accaaggtgg acaagacagt tgagcgcaaa 720
tgttgtgtcg agtgcccacc gtgcccagca ccacctgtgg caggaccgtc agtcttcctc 780
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacgtgcgtg 840
gtggtggacg tgagccacga agaccccgag gtccagttca actggtacgt ggacggcgtg 900
gaggtgcata atgccaagac aaagccacgg gaggagcagt tcaacagcac gttccgtgtg 960
gtcagcgtcc tcaccgttgt gcaccaggac tggctgaacg gcaaggagta caagtgcaag 1020
gtctccaaca aaggcctccc agcccccatc gagaaaacca tctccaaaac caaagggcag 1080
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1140
gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtgggag 1200
agcaatgggc agccggagaa caactacaag accacacctc ccatgctgga ctccgacggc 1260
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1320
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1380
ctgtctccgg gtaaa 1395
<210> 68
<211> 465
<212> PRT
<213> Homo sapiens
<400> 68
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Gly Tyr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Ser Ala
65 70 75 80
Gln Lys Phe Arg Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Gly Gly Tyr Ser Tyr Gly Tyr Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
210 215 220
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
225 230 235 240
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Lys
465
<210> 69
<211> 708
<212> DNA
<213> Homo sapiens
<400> 69
atggacatga gggtccccgc tcagctcctg gggctcctgc tgctctggtt cccaggtgcc 60
aggtgtgaca tccagatgac ccagtctcca tcctccctgt ctgcatctgt aggagacaga 120
gtcaccatca cttgccgggc aagtcagggc attagaaatg atttaggctg gtatcagcag 180
aaaccaggga aagcccctaa gcgcctgatc tatgctgcat ccagtttgca aagtggggtc 240
ccatcaaggt tcagcggcag tggatctggg acagaattca ctctcacaat cagcagtgtg 300
cagcctgaag attttgtaac ttattactgt ctacagcata atagtaaccc tctcactttc 360
ggcggaggga ccaaggtgga gatcaaacga actgtggctg caccatctgt cttcatcttc 420
ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac 480
ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 540
tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc 600
ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga agtcacccat 660
cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 708
<210> 70
<211> 236
<212> PRT
<213> Homo sapiens
<400> 70
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
85 90 95
Ile Ser Ser Val Gln Pro Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln
100 105 110
His Asn Ser Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 71
<211> 1419
<212> DNA
<213> Homo sapiens
<400> 71
atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60
gtgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120
tgtgcagcgt ctggattcac cttcagtagc tatggcatgc actgggtccg ccaggctcca 180
ggcaaggggc tggagtgggt ggcagttatg tggtatgatg gaagtaataa agactatgta 240
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctg 300
caaatgaacc gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agaaaaagat 360
cattacgaca ttttgactgg ttataactac tactacggtc tggacgtctg gggccaaggg 420
accacggtca ccgtctcctc agcctccacc aagggcccat cggtcttccc cctggcgccc 480
tgctccagga gcacctccga gagcacagcg gccctgggct gcctggtcaa ggactacttc 540
cccgaaccgg tgacggtgtc gtggaactca ggcgctctga ccagcggcgt gcacaccttc 600
ccagctgtcc tacagtcctc aggactctac tccctcagca gcgtggtgac cgtgccctcc 660
agcaacttcg gcacccagac ctacacctgc aacgtagatc acaagcccag caacaccaag 720
gtggacaaga cagttgagcg caaatgttgt gtcgagtgcc caccgtgccc agcaccacct 780
gtggcaggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 840
cggacccctg aggtcacgtg cgtggtggtg gacgtgagcc acgaagaccc cgaggtccag 900
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc acgggaggag 960
cagttcaaca gcacgttccg tgtggtcagc gtcctcaccg ttgtgcacca ggactggctg 1020
aacggcaagg agtacaagtg caaggtctcc aacaaaggcc tcccagcccc catcgagaaa 1080
accatctcca aaaccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1140
cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctacccc 1200
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccaca 1260
cctcccatgc tggactccga cggctccttc ttcctctaca gcaagctcac cgtggacaag 1320
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1380
cactacacgc agaagagcct ctccctgtct ccgggtaaa 1419
<210> 72
<211> 473
<212> PRT
<213> Homo sapiens
<400> 72
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Met Trp Tyr Asp Gly Ser Asn Lys Asp Tyr Val
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Arg Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Lys Asp His Tyr Asp Ile Leu Thr Gly Tyr
115 120 125
Asn Tyr Tyr Tyr Gly Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr
130 135 140
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
145 150 155 160
Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val
165 170 175
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
180 185 190
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
195 200 205
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly
210 215 220
Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys
225 230 235 240
Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys
245 250 255
Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
260 265 270
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
275 280 285
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
290 295 300
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
305 310 315 320
Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His
325 330 335
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
340 345 350
Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
355 360 365
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
370 375 380
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
385 390 395 400
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
405 410 415
Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
420 425 430
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
435 440 445
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
450 455 460
Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 73
<211> 705
<212> DNA
<213> Homo sapiens
<400> 73
atggaaaccc cggcgcagct gctgtttctg ctgctgctgt ggctgccgga taccaccggc 60
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120
ctctcctgca gggccagtca gtatattagc aacacctatt tagcctggtt ccagcagaaa 180
cctggccagg ctcccaggct cctcatctat ggtgcagcca ccagggccac tggcatccca 240
gacaggttca gtggcagtgg gtctgggaca gacttcactt tcaccatcag cagactggag 300
cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgtg gacgttcggc 360
caagggacca cggtggaaat caaacgtacg gtggctgcac catctgtctt catcttcccg 420
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 705
<210> 74
<211> 235
<212> PRT
<213> Homo sapiens
<400> 74
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Tyr
35 40 45
Ile Ser Asn Thr Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ala Thr Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr
100 105 110
Gly Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr Thr Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 75
<211> 1389
<212> DNA
<213> Homo sapiens
<400> 75
atggattgga cctggcgtat tctgtttctg gtggcggcgg cgaccggcgc gcatagccag 60
gtgcagttgg tgcagtctgg ggctgaggtg aagaagcctg gggcctcagt gaaggtctcc 120
tgcaaggctt ctggatacac cttcaccggc tactatatgc actgggtgcg acaggcccct 180
ggacaagggc ttgagtggat gggatggatc aaccctaaca gtggtggcac aaactatgca 240
cagaggtttc ggggcagggt caccatgacc agggacacgt ccatcagcac agcctacatg 300
gaactgagca ggctgagatc tgacgacacg gccgtgtatt actgtgcgag agccccgtat 360
gactggacct ttgactactg gggccaggga accctggtca ccgtctcctc agctagcacc 420
aagggcccat cggtcttccc cctggcgccc tgctccagga gcacctccga gagcacagcg 480
gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540
ggcgctctga ccagcggcgt gcacaccttc ccagctgtcc tacagtcctc aggactctac 600
tccctcagca gcgtggtgac cgtgccctcc agcaacttcg gcacccagac ctacacctgc 660
aacgtagatc acaagcccag caacaccaag gtggacaaga cagttgagcg caaatgttgt 720
gtcgagtgcc caccgtgccc agcaccacct gtggcaggac cgtcagtctt cctcttcccc 780
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacgtg cgtggtggtg 840
gacgtgagcc acgaagaccc cgaggtccag ttcaactggt acgtggacgg cgtggaggtg 900
cataatgcca agacaaagcc acgggaggag cagttcaaca gcacgttccg tgtggtcagc 960
gtcctcaccg ttgtgcacca ggactggctg aacggcaagg agtacaagtg caaggtctcc 1020
aacaaaggcc tcccagcccc catcgagaaa accatctcca aaaccaaagg gcagccccga 1080
gaaccacagg tgtacaccct gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc 1140
ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg ggagagcaat 1200
gggcagccgg agaacaacta caagaccaca cctcccatgc tggactccga cggctccttc 1260
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1320
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1380
ccgggtaaa 1389
<210> 76
<211> 463
<212> PRT
<213> Homo sapiens
<400> 76
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala
65 70 75 80
Gln Arg Phe Arg Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ala Pro Tyr Asp Trp Thr Phe Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
225 230 235 240
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
340 345 350
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 77
<211> 708
<212> DNA
<213> Homo sapiens
<400> 77
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60
cgctgtgaca tccagatgac ccagtctcca tcttccgtgt ctgcatctgt aggagacaga 120
gtcaccatca cttgtcgggc gagtcagggt attagcaact ggttagcctg gtatcagcag 180
aaaccaggga cagcccctaa actcctgatc tatgctgcat ccagtttgca aagtggggtc 240
ccatcaaggt tcagcggcag tggatctggg acagatttca ctctcaccat cagcagcctg 300
cagcctgaag attttgcaac ttactattgt caacaggcta acagtttccc attcactttc 360
ggccctggga ccaaagtgga tatcaaacgt acggtggctg caccatctgt cttcatcttc 420
ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac 480
ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 540
tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc 600
ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga agtcacccat 660
cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 708
<210> 78
<211> 236
<212> PRT
<213> Homo sapiens
<400> 78
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Ser Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Thr
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Ala Asn Ser Phe Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 79
<211> 1407
<212> DNA
<213> Homo sapiens
<400> 79
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60
cgctgtcagg tgcagttggt gcagtctggg actgaggtga agaagcctgg ggcctcaatg 120
aaggtttcct gcaaggcatc tggatacacc ttcaccagct attatatgca ctgggtgcga 180
caggcccctg gacaagggct tgagtggatg ggaataatca accctagtgg tgatagcaca 240
agctacgcac agaagttcca gggcagagtc accatgacca gggacacgtc cacgaacaca 300
gtctacatgg agctgagcag cctgagatct gaggacacgg ccatgtatta ctgtgcgaga 360
gatgtagagg ttcggggaat ttctcacttt gactactggg gccagggaac cctggtcacc 420
gtctctagtg cctccaccaa gggcccatcg gtcttccccc tggcgccctg ctccaggagc 480
acctccgaga gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 540
acggtgtcgt ggaactcagg cgctctgacc agcggcgtgc acaccttccc agctgtccta 600
cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag caacttcggc 660
acccagacct acacctgcaa cgtagatcac aagcccagca acaccaaggt ggacaagaca 720
gttgagcgca aatgttgtgt cgagtgccca ccgtgcccag caccacctgt ggcaggaccg 780
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 840
gtcacgtgcg tggtggtgga cgtgagccac gaagaccccg aggtccagtt caactggtac 900
gtggacggcg tggaggtgca taatgccaag acaaagccac gggaggagca gttcaacagc 960
acgttccgtg tggtcagcgt cctcaccgtt gtgcaccagg actggctgaa cggcaaggag 1020
tacaagtgca aggtctccaa caaaggcctc ccagccccca tcgagaaaac catctccaaa 1080
accaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1140
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1200
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacacc tcccatgctg 1260
gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1320
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1380
aagagcctct ccctgtctcc gggtaaa 1407
<210> 80
<211> 469
<212> PRT
<213> Homo sapiens
<400> 80
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Gln Ser Gly Thr Glu
20 25 30
Val Lys Lys Pro Gly Ala Ser Met Lys Val Ser Cys Lys Ala Ser Gly
35 40 45
Tyr Thr Phe Thr Ser Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Gln Gly Leu Glu Trp Met Gly Ile Ile Asn Pro Ser Gly Asp Ser Thr
65 70 75 80
Ser Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr
85 90 95
Ser Thr Asn Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp
100 105 110
Thr Ala Met Tyr Tyr Cys Ala Arg Asp Val Glu Val Arg Gly Ile Ser
115 120 125
His Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
130 135 140
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser
145 150 155 160
Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
165 170 175
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
180 185 190
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
195 200 205
Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr
210 215 220
Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr
225 230 235 240
Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro
245 250 255
Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
260 265 270
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
275 280 285
Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
290 295 300
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
305 310 315 320
Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu
325 330 335
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala
340 345 350
Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro
355 360 365
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
370 375 380
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly Lys
465
<210> 81
<211> 714
<212> DNA
<213> Homo sapiens
<400> 81
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccgac 60
atccagctga cccagtctcc atcatctctg agcgcatctg ttggagatag ggtcactatg 120
agctgtaagt ccagtcaaag tgttttatac agtgcaaatc acaagaacta cttggcctgg 180
taccagcaga aaccagggaa agcacctaaa ctgctgatct actgggcatc cactagggaa 240
tctggtgtcc cttcgcgatt ctctggcagc ggatctggga cagattttac tttcaccatc 300
agctctcttc aaccagaaga cattgcaaca tattattgtc accaatacct ctcctcgtgg 360
acgttcggtg gagggaccaa ggtgcagatc aaacgaactg tggctgcacc atctgtcttc 420
atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 480
aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 540
ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 600
agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 660
acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgt 714
<210> 82
<211> 238
<212> PRT
<213> Homo sapiens
<400> 82
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala
20 25 30
Ser Val Gly Asp Arg Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val
35 40 45
Leu Tyr Ser Ala Asn His Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys
50 55 60
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu
65 70 75 80
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
85 90 95
Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr
100 105 110
Cys His Gln Tyr Leu Ser Ser Trp Thr Phe Gly Gly Gly Thr Lys Val
115 120 125
Gln Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
130 135 140
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
165 170 175
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
195 200 205
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
210 215 220
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 83
<211> 1395
<212> DNA
<213> Homo sapiens
<400> 83
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactcccag 60
gtccagctgg tccaatcagg ggctgaagtc aagaaacctg ggtcatcagt gaaggtctcc 120
tgcaaggctt ctggctacac ctttactagc tactggctgc actgggtcag gcaggcacct 180
ggacagggtc tggaatggat tggatacatt aatcctagga atgattatac tgagtacaat 240
cagaacttca aggacaaggc cacaataact gcagacgaat ccaccaatac agcctacatg 300
gagctgagca gcctgaggtc tgaggacacg gcattttatt tttgtgcaag aagggatatt 360
actacgttct actggggcca aggcaccacg gtcaccgtct cctcagcctc caccaagggc 420
ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 480
ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 540
ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 600
agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 660
aatcacaagc ccagcaacac caaggtggac aagagagttg agcccaaatc ttgtgacaaa 720
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 780
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 840
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 900
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 960
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 1020
gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1080
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1140
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1200
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1260
tccttcttcc tctatagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1320
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1380
ctgtctccgg gtaaa 1395
<210> 84
<211> 465
<212> PRT
<213> Homo sapiens
<400> 84
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Trp Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Ile Asn Pro Arg Asn Asp Tyr Thr Glu Tyr Asn
65 70 75 80
Gln Asn Phe Lys Asp Lys Ala Thr Ile Thr Ala Asp Glu Ser Thr Asn
85 90 95
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe
100 105 110
Tyr Phe Cys Ala Arg Arg Asp Ile Thr Thr Phe Tyr Trp Gly Gln Gly
115 120 125
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
130 135 140
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
145 150 155 160
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
165 170 175
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
180 185 190
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
195 200 205
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
210 215 220
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
225 230 235 240
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Lys
465
<210> 85
<211> 705
<212> DNA
<213> Homo sapiens
<400> 85
atggaaaccc cagctcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120
ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 180
cctggccagg ctcccaggct cctcatatat ggtgcatcca gcagggccac tggcatccca 240
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 300
cctgaagatt ttgcagtgta ttactgtcag cggtctggtg gctcatcatt cactttcggc 360
cctgggacca aagtggatat caaacgaact gtggctgcac catctgtctt catcttcccg 420
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 705
<210> 86
<211> 235
<212> PRT
<213> Homo sapiens
<400> 86
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Ser
100 105 110
Gly Gly Ser Ser Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 87
<211> 1398
<212> DNA
<213> Homo sapiens
<400> 87
atggggtcaa ccgccatcct cgccctcctc ctggctgttc tccaaggagt ctgtgccgag 60
gtgcagctgg tacagtctgg agcagaggtg aaaaagcccg gggagtctct gaagatctcc 120
tgtaagggtt ctggatacaa ctttaccagc tactggatcg gctgggtgcg ccagatgccc 180
gggaaaggcc tggagttgat ggggatcatc tatcctggtg actctgatac cagatacagc 240
ccgtccttcc aaggccaggt caccatctca gccgacaagt ccatcagcac cgcctacctg 300
cagtggagca gcctgaaggc ctcggacacc gccatgtatt actgtggttc ggggagctac 360
ttttacttcg atctctgggg ccgtggcacc ctggtcaccg tctctagtgc ctccaccaag 420
ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 480
ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 540
gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 600
ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 660
gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 720
aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 780
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 840
gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 900
gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 960
gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 1020
aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1080
cagccccgag aaccacaggt gtacaccctg cccccatccc gggatgagct gaccaagaac 1140
caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1200
gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1260
ggctccttct tcctctatag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1320
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1380
tccctgtctc cgggtaaa 1398
<210> 88
<211> 466
<212> PRT
<213> Homo sapiens
<400> 88
Met Gly Ser Thr Ala Ile Leu Ala Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Val Cys Ala Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe
35 40 45
Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu
50 55 60
Glu Leu Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser
65 70 75 80
Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser
85 90 95
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met
100 105 110
Tyr Tyr Cys Gly Ser Gly Ser Tyr Phe Tyr Phe Asp Leu Trp Gly Arg
115 120 125
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
130 135 140
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
145 150 155 160
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
165 170 175
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
180 185 190
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
195 200 205
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
210 215 220
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
225 230 235 240
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Lys
465
<210> 89
<211> 723
<212> DNA
<213> Homo sapiens
<400> 89
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60
cgctgtgata ttgtgatgac tcagtctcca ctctccctgc ccgtcacccc tggagagccg 120
gcctccatct cctgcaggtc tagtcagagc ctcctgcata gtcatggata caactatttg 180
gattggtacc tgcagaagcc agggcagtct ccacagctcc tgatctattt gggttctaat 240
cgggcctccg gggtccctga caggttcagt ggcagtggat caggcacaga ttttacactg 300
aaaatcagca gagtggaggc tgaggatgtt ggggtttatt actgcatgca aggtacacac 360
tggcctccga cttttggcca ggggaccaag ctggagatca aacgtacggt ggctgcacca 420
tctgtcttca tcttcccgcc atctgatgag cagttgaaat ctggaactgc ctctgttgtg 480
tgcctgctga ataacttcta tcccagagag gccaaagtac agtggaaggt ggataacgcc 540
ctccaatcgg gtaactccca ggagagtgtc acagagcagg acagcaagga cagcacctac 600
agcctcagca gcaccctgac gctgagcaaa gcagactacg agaaacacaa agtctacgcc 660
tgcgaagtca cccatcaggg cctgagctcg cccgtcacaa agagcttcaa caggggagag 720
tgt 723
<210> 90
<211> 241
<212> PRT
<213> Homo sapiens
<400> 90
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Leu His Ser His Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu
50 55 60
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn
65 70 75 80
Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Met Gln Gly Thr His Trp Pro Pro Thr Phe Gly Gln Gly
115 120 125
Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
Cys
<210> 91
<211> 1410
<212> DNA
<213> Homo sapiens
<400> 91
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60
cgctgtgagg tccagctggt gcagtctggg ggaggcgtgg tccagcctgg gaggtccctg 120
agactctcct gtgcagcgtc tggattcacc ttcagtagct atggcatgca ctgggtccgc 180
caggctccag gcaaggggct ggagtgggtt tcatacatta gtagtagtgg tagtaccata 240
tactacgcag actctgtgaa gggccgattc accatctcca gggacaacgc caagaactca 300
ctatatctgc aaatgaacag cctgagagcc gaggacacgg ccgtgtatta ctgtgcgaga 360
gatctgttag attacgatct gttgactggt tatggctact ggggccaggg aaccctggtc 420
accgtctcta gtgcctccac caagggccca tcggtcttcc ccctggcgcc ctgctccagg 480
agcacctccg agagcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 540
gtgacggtgt cgtggaactc aggcgctctg accagcggcg tgcacacctt cccagctgtc 600
ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcaacttc 660
ggcacccaga cctacacctg caacgtagat cacaagccca gcaacaccaa ggtggacaag 720
acagttgagc gcaaatgttg tgtcgagtgc ccaccgtgcc cagcaccacc tgtggcagga 780
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 840
gaggtcacgt gcgtggtggt ggacgtgagc cacgaagacc ccgaggtcca gttcaactgg 900
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cacgggagga gcagttcaac 960
agcacgttcc gtgtggtcag cgtcctcacc gttgtgcacc aggactggct gaacggcaag 1020
gagtacaagt gcaaggtctc caacaaaggc ctcccagccc ccatcgagaa aaccatctcc 1080
aaaaccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1140
atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctaccc cagcgacatc 1200
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac acctcccatg 1260
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1320
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1380
cagaagagcc tctccctgtc tccgggtaaa 1410
<210> 92
<211> 470
<212> PRT
<213> Homo sapiens
<400> 92
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Gln Ser Gly Gly Gly
20 25 30
Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile
65 70 75 80
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Leu Leu Asp Tyr Asp Leu Leu
115 120 125
Thr Gly Tyr Gly Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
130 135 140
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
145 150 155 160
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
165 170 175
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
180 185 190
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
195 200 205
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
210 215 220
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
225 230 235 240
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
245 250 255
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
305 310 315 320
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
<210> 93
<211> 705
<212> DNA
<213> Homo sapiens
<400> 93
atggaaaccc cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120
ctctcctgca gggccagtca gggtattagt agaagctact tagcctggta ccagcagaaa 180
cctggccagg ctcccagcct cctcatctat ggtgcatcca gcagggccac tggcatccca 240
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 300
cctgaagatt ttgcagtgta ttactgtcaa caatttggta gttcaccgtg gacgttcggc 360
caagggacca aggtggaaat caaacgaact gtggctgcac catctgtctt catcttcccg 420
ccatctgatg agcagttgaa atctggaact gctagcgttg tgtgcctgct gaataacttc 480
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 705
<210> 94
<211> 235
<212> PRT
<213> Homo sapiens
<400> 94
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Gly
35 40 45
Ile Ser Arg Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Ser Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe
100 105 110
Gly Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 95
<211> 1413
<212> DNA
<213> Homo sapiens
<400> 95
atgaagcatc tgtggttctt cctcctgctg gtggcagctc ccagatgggt cctgtcccag 60
gtgcagctgc aggagtcggg cccaggactg gtgaagcctt cacagaccct gtccctcacc 120
tgcactgtct ctggtggctc catcagcagt ggtgattact tctggagctg gatccgccag 180
ctcccaggga agggcctgga gtggattggg cacatccata acagtgggac cacctactac 240
aatccgtccc tcaagagtcg agttaccata tcagtagaca cgtctaagaa gcagttctcc 300
ctgaggctga gttctgtgac tgccgcggac acggccgtat attactgtgc gagagatcga 360
gggggtgact actactatgg tatggacgtc tggggccaag ggaccacggt caccgtctcc 420
tcagcctcca ccaagggccc atccgtcttc cccctggcac cctcctccaa gagcacctct 480
gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 540
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 600
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 660
acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gagagttgag 720
cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 780
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 840
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 900
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 960
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 1020
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1080
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 1140
gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1200
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1260
gtgctggact ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 1320
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1380
acgcagaaga gcctctccct gtctccgggt aaa 1413
<210> 96
<211> 471
<212> PRT
<213> Homo sapiens
<400> 96
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys
20 25 30
Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile
35 40 45
Ser Ser Gly Asp Tyr Phe Trp Ser Trp Ile Arg Gln Leu Pro Gly Lys
50 55 60
Gly Leu Glu Trp Ile Gly His Ile His Asn Ser Gly Thr Thr Tyr Tyr
65 70 75 80
Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys
85 90 95
Lys Gln Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Arg Asp Arg Gly Gly Asp Tyr Tyr Tyr Gly Met
115 120 125
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
145 150 155 160
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
225 230 235 240
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
245 250 255
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
275 280 285
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
290 295 300
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
305 310 315 320
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
325 330 335
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
355 360 365
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
370 375 380
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
385 390 395 400
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
405 410 415
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
420 425 430
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 97
<211> 708
<212> DNA
<213> Homo sapiens
<400> 97
atggacatga gggtccctgc tcagctcctg gggctcctgc tgctctggct ctcaggtgcc 60
agatgtgaca tccagatgac ccagtctcca tcctccctgt ctgcatctgt aggagacaga 120
gtcaccatca cttgccaggc gagtcaggac atcagcaact atttaaattg gtatcagcag 180
aaaccaggga aagcccctaa actcctgatc tacgatgcat ccaatttgga aacaggggtc 240
ccatcaaggt tcagtggaag tggatctggg acagatttta ctttcaccat cagcagcctg 300
cagcctgaag atattgcaac atatttctgt caacactttg atcatctccc gctcgctttc 360
ggcggaggga ccaaggtgga gatcaaacga actgtggctg caccatctgt cttcatcttc 420
ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac 480
ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 540
tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc 600
ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga agtcacccat 660
cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 708
<210> 98
<211> 236
<212> PRT
<213> Homo sapiens
<400> 98
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Ser Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser
35 40 45
Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys Gln His
100 105 110
Phe Asp His Leu Pro Leu Ala Phe Gly Gly Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 99
<211> 1392
<212> DNA
<213> Homo sapiens
<400> 99
atgaaacacc tgtggttctt cctcctcctg gtggcagctc ccagatgggt cctgtcccag 60
gtacagctgc aggagtcggg cccaggactg gtgaagcctt cggagaccct gtccctcacc 120
tgcactgtct ctggtggctc cgtcagcagt ggtgattact actggacctg gatccggcag 180
tccccaggga agggactgga gtggattgga cacatctatt acagtgggaa caccaattat 240
aacccctccc tcaagagtcg actcaccata tcaattgaca cgtccaagac tcagttctcc 300
ctgaagctga gttctgtgac cgctgcggac acggccattt attactgtgt gcgagatcga 360
gtgactggtg cttttgatat ctggggccaa gggacaatgg tcaccgtctc ttcagctagc 420
accaagggcc catcggtctt ccccctggcg ccctgctcca ggagcacctc cgagagcaca 480
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 540
tcaggcgctc tgaccagcgg cgtgcacacc ttcccagctg tcctacagtc ctcaggactc 600
tactccctca gcagcgtggt gaccgtgccc tccagcaact tcggcaccca gacctacacc 660
tgcaacgtag atcacaagcc cagcaacacc aaggtggaca agacagttga gcgcaaatgt 720
tgtgtcgagt gcccaccgtg cccagcacca cctgtggcag gaccgtcagt cttcctcttc 780
cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac gtgcgtggtg 840
gtggacgtga gccacgaaga ccccgaggtc cagttcaact ggtacgtgga cggcgtggag 900
gtgcataatg ccaagacaaa gccacgggag gagcagttca acagcacgtt ccgtgtggtc 960
agcgtcctca ccgttgtgca ccaggactgg ctgaacggca aggagtacaa gtgcaaggtc 1020
tccaacaaag gcctcccagc ccccatcgag aaaaccatct ccaaaaccaa agggcagccc 1080
cgagaaccac aggtgtacac cctgccccca tcccgggagg agatgaccaa gaaccaggtc 1140
agcctgacct gcctggtcaa aggcttctac cccagcgaca tcgccgtgga gtgggagagc 1200
aatgggcagc cggagaacaa ctacaagacc acacctccca tgctggactc cgacggctcc 1260
ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1320
tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 1380
tctccgggta aa 1392
<210> 100
<211> 464
<212> PRT
<213> Homo sapiens
<400> 100
Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp
1 5 10 15
Val Leu Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys
20 25 30
Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val
35 40 45
Ser Ser Gly Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys
50 55 60
Gly Leu Glu Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr
65 70 75 80
Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys
85 90 95
Thr Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala
100 105 110
Ile Tyr Tyr Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp
115 120 125
Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
130 135 140
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
145 150 155 160
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
165 170 175
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
180 185 190
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
195 200 205
Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp
210 215 220
His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys
225 230 235 240
Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser
245 250 255
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
260 265 270
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
275 280 285
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
290 295 300
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val
305 310 315 320
Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
325 330 335
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr
340 345 350
Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
355 360 365
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
370 375 380
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
385 390 395 400
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp
405 410 415
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
420 425 430
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
435 440 445
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 101
<211> 708
<212> DNA
<213> Homo sapiens
<400> 101
atggaaaccc cagcgcagct tctcttcctc ctgctactct ggctcccaga taccgctagc 60
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120
ctctcctgca gggccagtca gagtgttagc aacagctact tagcctggta ccagcagaaa 180
cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggcccc tggcatccca 240
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 300
cctgaagatt ttgcagtgta ttactgtcag cagtatgatc actcagcagg gtggacgttc 360
ggccaaggga ccaaggtgga gatcaaacgt acggtggctg caccatctgt cttcatcttc 420
ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac 480
ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 540
tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc 600
ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga agtcacccat 660
cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 708
<210> 102
<211> 236
<212> PRT
<213> Homo sapiens
<400> 102
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Ala Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Asn Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Pro Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr
100 105 110
Asp His Ser Ala Gly Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 103
<211> 1680
<212> DNA
<213> Homo sapiens
<400> 103
atggggtcaa ccgccatcct tggcctcctc ctggctgttc tccaaggagt cgctagcgag 60
gttcagctgg tggagtctgg gggaggcttg gtacagcctg gggggtccct gagactctcc 120
tgtgcagcct ctggattcac cttcagtaga aatgctatgt tctgggttcg ccaggctcca 180
ggaaaaggtc tggagtgggt atcaggtatt ggtactggtg gtgccacaag ctatgcagac 240
tccgtgaagg gccgattcac catctccaga gacaatgcca agaactcctt gtatcttcaa 300
atgaacagcc tgagagccga ggacacggct gtgtattact gtgcaagagg gaggtactac 360
ttcccgtggt ggggccaggg aaccctggtc accgtctcct cagcctccac caagggccca 420
tcggtcttcc ccctggcgcc ctgctccagg agcacctccg agagcacagc ggccctgggc 480
tgcctggtca aggactactt ccccgaaccg gtgacggtgt cgtggaactc aggcgctctg 540
accagcggcg tgcacacctt cccggctgtc ctacagtcct caggactcta ctccctcagc 600
agcgtggtga ccgtgccctc cagcaacttc ggcacccaga cctacacctg caacgtagat 660
cacaagccca gcaacaccaa ggtggacaag acagttggtg agaggccagc tcagggaggg 720
agggtgtctg ctggaagcca ggctcagccc tcctgcctgg acgcaccccg gctgtgcagc 780
cccagcccag ggcagcaagg caggccccat ctgtctcctc acccggaggc ctctgcccgc 840
cccactcatg ctcagggaga gggtcttctg gctttttcca ccaggctcca ggcaggcaca 900
ggctgggtgc ccctacccca ggcccttcac acacaggggc aggtgcttgg ctcagacctg 960
ccaaaagcca tatccgggag gaccctgccc ctgaccgagc gcaaatgttg tgtcgagtgc 1020
ccaccgtgcc cagcaccacc tgtggcagga ccgtcagtct tcctcttccc cccaaaaccc 1080
aaggacaccc tcatgatctc ccggacccct gaggtcacgt gcgtggtggt ggacgtgagc 1140
cacgaagacc ccgaggtcca gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 1200
aagacaaagc cacgggagga gcagttcaac agcacgttcc gtgtggtcag cgtcctcacc 1260
gtcgtgcacc aggactggct gaacggcaag gagtacaagt gcaaggtctc caacaaaggc 1320
ctcccagccc ccatcgagaa aaccatctcc aaaaccaaag ggcagccccg agaaccacag 1380
gtgtacaccc tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc 1440
ctggtcaaag gcttctaccc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1500
gagaacaact acaagaccac acctcccatg ctggactccg acggctcctt cttcctctac 1560
agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1620
atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1680
<210> 104
<211> 460
<212> PRT
<213> Homo sapiens
<400> 104
Met Gly Ser Thr Ala Ile Leu Gly Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Val Ala Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Arg Asn Ala Met Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ser Gly Ile Gly Thr Gly Gly Ala Thr Ser Tyr Ala Asp
65 70 75 80
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser
85 90 95
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
100 105 110
Tyr Cys Ala Arg Gly Arg Tyr Tyr Phe Pro Trp Trp Gly Gln Gly Thr
115 120 125
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
130 135 140
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly
145 150 155 160
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
165 170 175
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
180 185 190
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
195 200 205
Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser
210 215 220
Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys
225 230 235 240
Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe
245 250 255
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
260 265 270
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe
275 280 285
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
290 295 300
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr
305 310 315 320
Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
325 330 335
Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
340 345 350
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
355 360 365
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
370 375 380
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
385 390 395 400
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser
405 410 415
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
420 425 430
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
435 440 445
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 105
<211> 702
<212> DNA
<213> Homo sapiens
<400> 105
atggaaaccc cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120
ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 180
cctggccagg ctcccaggct cctcatctat ggtgcatccc gcagggccac tggcatccca 240
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 300
cctgaagatt ttgcagtgta ttactgtcag cggtatggta gctcacacac ttttggccag 360
gggaccaagc tggagatcag ccgaactgtg gctgcaccat ctgtcttcat cttcccgcca 420
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 480
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 540
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 600
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 660
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 702
<210> 106
<211> 234
<212> PRT
<213> Homo sapiens
<400> 106
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr
100 105 110
Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 107
<211> 1401
<212> DNA
<213> Homo sapiens
<400> 107
atggggtcaa ccgccatcct cgccctcctc ctggctgttc tccaaggagt ctgtgccgag 60
gtgcagctgg tgcagtctgg agcagaggtg aaaaagcccg gggagtctct gaagatctcc 120
tgtaaggttt ctggatactt ctttaccacc tactggatcg gctgggtgcg ccagatgccc 180
gggaaaggcc tggagtatat ggggatcatc tatcctggtg actctgatac cagatacagc 240
ccgtccttcc aaggccaggt caccatctca gccgacaagt ccatcagcac cgcctacctg 300
cagtggagca gcctgaaggc ctcggacacc gccatgtatt actgtgcgag agggggtaac 360
tggaactgct ttgactactg gggccaggga accctggtca ccgtctcctc agcctccacc 420
aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 480
gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540
ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 600
tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 660
aacgtgaatc acaagcccag caacaccaag gtggacaaga gagttgagcc caaatcttgt 720
gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 780
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 840
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 900
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 960
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1020
tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1080
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 1140
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1200
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1260
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1320
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1380
ctctccctgt ctccgggtaa a 1401
<210> 108
<211> 467
<212> PRT
<213> Homo sapiens
<400> 108
Met Gly Ser Thr Ala Ile Leu Ala Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Val Cys Ala Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe
35 40 45
Thr Thr Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu
50 55 60
Glu Tyr Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser
65 70 75 80
Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser
85 90 95
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met
100 105 110
Tyr Tyr Cys Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 109
<211> 723
<212> DNA
<213> Homo sapiens
<400> 109
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcc 60
agatgtgatg ttgtgatgac tcagtctcca ctctccctgc ccgtcacccc tggagagccg 120
gcctccatct cctgcaggtc tagtcagagc ctcctgcata gtaatggata caactatttg 180
gattggtacc tgcagaagcc agggcagtct ccacagctcc tgatctattt gggttctaat 240
cgggcctccg gggtccctga caggttcagt ggcagtggat caggcacaga ttttacactg 300
aaaatcagca gggtggaggc tgaggatgtt ggggtttatt actgcatgca aggtacacac 360
tggcctctga cgttcggcca agggaccaag gtggagatca aacgaactgt ggctgcacca 420
tctgtcttca tcttcccgcc atctgatgag cagttgaaat ctggaactgc ctctgttgtg 480
tgcctgctga ataacttcta tcccagagag gccaaagtac agtggaaggt ggataacgcc 540
ctccaatcgg gtaactccca ggagagtgtc acagagcagg acagcaagga cagcacctac 600
agcctcagca gcaccctgac gctgagcaaa gcagactacg agaaacacaa agtctacgcc 660
tgcgaagtca cccatcaggg cctgagctcg cccgtcacaa agagcttcaa caggggagag 720
tgt 723
<210> 110
<211> 241
<212> PRT
<213> Homo sapiens
<400> 110
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Val Val Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu
50 55 60
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn
65 70 75 80
Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Met Gln Gly Thr His Trp Pro Leu Thr Phe Gly Gln Gly
115 120 125
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
Cys
<210> 111
<211> 1413
<212> DNA
<213> Homo sapiens
<400> 111
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcc 60
agatgtcagg tgcagctgca ggagtcgggc ccaggactgg tgaagccttc ggggaccctg 120
tccctcacct gcgctgtctc tggtggctcc atcagcagta gtaactggtg gagttgggtc 180
cgccagcccc cagggaaggg gctggagtgg attggggaaa tctatcatag tgggagcacc 240
aactacaacc cgtccctcaa gagtcgagtc accatatcag tagacaagtc caagaaccag 300
ttctccctga agctgagctc tgtgaccgcc gcggacacgg ccgtgtatta ctgtgcgaga 360
tggaccgggc gtactgatgc ttttgatatc tggggccaag ggacaatggt caccgtctct 420
agtgcctcca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 480
gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 540
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 600
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 660
acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 720
cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 780
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 840
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 900
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 960
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 1020
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1080
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggat 1140
gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1200
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1260
gtgctggact ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 1320
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1380
acgcagaaga gcctctccct gtctccgggt aaa 1413
<210> 112
<211> 471
<212> PRT
<213> Homo sapiens
<400> 112
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Pro Gly
20 25 30
Leu Val Lys Pro Ser Gly Thr Leu Ser Leu Thr Cys Ala Val Ser Gly
35 40 45
Gly Ser Ile Ser Ser Ser Asn Trp Trp Ser Trp Val Arg Gln Pro Pro
50 55 60
Gly Lys Gly Leu Glu Trp Ile Gly Glu Ile Tyr His Ser Gly Ser Thr
65 70 75 80
Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Lys
85 90 95
Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Trp Thr Gly Arg Thr Asp Ala Phe
115 120 125
Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
145 150 155 160
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
225 230 235 240
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
245 250 255
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
275 280 285
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
290 295 300
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
305 310 315 320
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
325 330 335
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
355 360 365
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
370 375 380
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
385 390 395 400
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
405 410 415
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
420 425 430
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 113
<211> 702
<212> DNA
<213> Homo sapiens
<400> 113
atggaagcgc cggcgcagct tctcttcctc ctgctactct ggctcccaga taccactgga 60
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctcctgggga aagagccacc 120
ctctcctgca gggccagtca gagtgttagc agcaacttag cctggttcca gcagaaacct 180
ggccaggctc ccaggcccct catctatgat gcatccacca gggccactgg tgtcccagcc 240
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctgcagtct 300
gaagattttg cagtttatta ctgtcagcag tatgataact ggccgctcac tttcggcgga 360
gggaccaagg tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 420
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 480
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 540
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 600
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 660
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 702
<210> 114
<211> 234
<212> PRT
<213> Homo sapiens
<400> 114
Met Glu Ala Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Asn Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro
50 55 60
Arg Pro Leu Ile Tyr Asp Ala Ser Thr Arg Ala Thr Gly Val Pro Ala
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp
100 105 110
Asn Trp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 115
<211> 1383
<212> DNA
<213> Homo sapiens
<400> 115
atggagtgga cctggagggt ccttttcttg gtggcagcag caacaggtgc ccactcccag 60
gttcagctgg tgcagtctgg agctgaggtg aagaagcctg gggcctcagt gaaggtctcc 120
tgcaaggctt ctggttacac ctttaccaga tatggtatca gctgggtgcg acaggcccct 180
ggacaagggc ttgagtggat gggatggatc agcacttaca gtggtaacac aaactatgca 240
cagaagctcc agggcagagt caccatgacc acagacacat ccacgagcac agcctacatg 300
gagctgagga gcctgagatc tgacgacacg gccgtgtatt actgtgcgag acggcagctt 360
tactttgact actggggcca gggaaccctg gtcaccgtct cctcagctag caccaagggc 420
ccatcggtct tccccctggc gccctgctcc aggagcacct ccgagagcac agcggccctg 480
ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgct 540
ctgaccagcg gcgtgcacac cttcccagct gtcctacagt cctcaggact ctactccctc 600
agcagcgtgg tgaccgtgcc ctccagcaac ttcggcaccc agacctacac ctgcaacgta 660
gatcacaagc ccagcaacac caaggtggac aagacagttg agcgcaaatg ttgtgtcgag 720
tgcccaccgt gcccagcacc acctgtggca ggaccgtcag tcttcctctt ccccccaaaa 780
cccaaggaca ccctcatgat ctcccggacc cctgaggtca cgtgcgtggt ggtggacgtg 840
agccacgaag accccgaggt ccagttcaac tggtacgtgg acggcgtgga ggtgcataat 900
gccaagacaa agccacggga ggagcagttc aacagcacgt tccgtgtggt cagcgtcctc 960
accgttgtgc accaggactg gctgaacggc aaggagtaca agtgcaaggt ctccaacaaa 1020
ggcctcccag cccccatcga gaaaaccatc tccaaaacca aagggcagcc ccgagaacca 1080
caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc 1140
tgcctggtca aaggcttcta ccccagcgac atcgccgtgg agtgggagag caatgggcag 1200
ccggagaaca actacaagac cacacctccc atgctggact ccgacggctc cttcttcctc 1260
tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1320
gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1380
aaa 1383
<210> 116
<211> 461
<212> PRT
<213> Homo sapiens
<400> 116
Met Glu Trp Thr Trp Arg Val Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Arg Tyr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Ser Thr Tyr Ser Gly Asn Thr Asn Tyr Ala
65 70 75 80
Gln Lys Leu Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Arg Gln Leu Tyr Phe Asp Tyr Trp Gly Gln Gly
115 120 125
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
130 135 140
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
145 150 155 160
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
165 170 175
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
180 185 190
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
195 200 205
Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
210 215 220
Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu
225 230 235 240
Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu
245 250 255
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
260 265 270
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln
275 280 285
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
290 295 300
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu
305 310 315 320
Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
325 330 335
Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
340 345 350
Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
355 360 365
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
370 375 380
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
385 390 395 400
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly
405 410 415
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
420 425 430
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
435 440 445
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 117
<211> 717
<212> DNA
<213> Homo sapiens
<400> 117
atgaggctcc ctgctcagct cctggggctg ctaatgctct ggatacctgg atccagtgca 60
gatattgtga tgacccagac tccactctct ctgtccgtca cccctggaca gccggcctcc 120
atctcctgca agtctggtca gagcctcctg catagtgatg gaaagaccta tttgtattgg 180
tacctgcaga agccaggcca gcctccacag ttcctgatct atgaagtttc caaccggttc 240
tctagagtgc cagataggtt cagtggcagc gggtcaggga cagatttcac actgagaatc 300
agccgggtgg aggctgagga tgttggaatt tattactgca tgcaaagtat acagcttccg 360
tggacgttcg gccaagggac ccaggtggaa atcaaacgaa ctgtggctgc accatctgtc 420
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 480
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 540
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 600
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 660
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 717
<210> 118
<211> 239
<212> PRT
<213> Homo sapiens
<400> 118
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Ile Pro
1 5 10 15
Gly Ser Ser Ala Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser
20 25 30
Val Thr Pro Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Gly Gln Ser
35 40 45
Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys
50 55 60
Pro Gly Gln Pro Pro Gln Phe Leu Ile Tyr Glu Val Ser Asn Arg Phe
65 70 75 80
Ser Arg Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
85 90 95
Thr Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr
100 105 110
Cys Met Gln Ser Ile Gln Leu Pro Trp Thr Phe Gly Gln Gly Thr Gln
115 120 125
Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
130 135 140
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
145 150 155 160
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
165 170 175
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
180 185 190
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
195 200 205
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
210 215 220
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 119
<211> 1377
<212> DNA
<213> Homo sapiens
<400> 119
atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60
gtgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120
tgtgcagcct ctggattcac cttcagtggc tatggcatgc actgggtccg ccaggctcca 180
ggcaaggggc tggagtgggt ggcagttata tcatatgatg gaaatgataa atactatgca 240
gactccgtga agggccgatt caccatctcc agagacaatg ccaagaacac gctgtatctg 300
caaatgaaca gcctgagagc tgaggacacg gctgtgtatt actgtgcgag agagctacgg 360
gtcctctggg gccagggaac cctggtcacc gtctctagtg cctccaccaa gggcccatcg 420
gtcttccccc tggcgccctg ctccaggagc acctccgaga gcacagcggc cctgggctgc 480
ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgctctgacc 540
agcggcgtgc acaccttccc agctgtccta cagtcctcag gactctactc cctcagcagc 600
gtggtgaccg tgccctccag caacttcggc acccagacct acacctgcaa cgtagatcac 660
aagcccagca acaccaaggt ggacaagaca gttgagcgca aatgttgtgt cgagtgccca 720
ccgtgcccag caccacctgt ggcaggaccg tcagtcttcc tcttcccccc aaaacccaag 780
gacaccctca tgatctcccg gacccctgag gtcacgtgcg tggtggtgga cgtgagccac 840
gaagaccccg aggtccagtt caactggtac gtggacggcg tggaggtgca taatgccaag 900
acaaagccac gggaggagca gttcaacagc acgttccgtg tggtcagcgt cctcaccgtt 960
gtgcaccagg actggctgaa cggcaaggag tacaagtgca aggtctccaa caaaggcctc 1020
ccagccccca tcgagaaaac catctccaaa accaaagggc agccccgaga accacaggtg 1080
tacaccctgc ccccatcccg ggaggagatg accaagaacc aggtcagcct gacctgcctg 1140
gtcaaaggct tctaccccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1200
aacaactaca agaccacacc tcccatgctg gactccgacg gctccttctt cctctacagc 1260
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1320
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 1377
<210> 120
<211> 459
<212> PRT
<213> Homo sapiens
<400> 120
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Gly Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Asn Asp Lys Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Leu Arg Val Leu Trp Gly Gln Gly Thr Leu
115 120 125
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
130 135 140
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
145 150 155 160
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
165 170 175
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
180 185 190
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
195 200 205
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
210 215 220
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
225 230 235 240
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
245 250 255
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
260 265 270
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
275 280 285
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
290 295 300
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
305 310 315 320
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
325 330 335
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
340 345 350
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
355 360 365
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
370 375 380
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
385 390 395 400
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
405 410 415
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
420 425 430
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
435 440 445
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 121
<211> 705
<212> DNA
<213> Homo sapiens
<400> 121
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcc 60
agatgtgaca tccagatgac ccagtctcca tcctccctgt ctgcatctgt aggtgaccgt 120
gtcaccatca cttgccgcgc aagtcaggat attagcagct atttaaattg gtatcagcag 180
aaaccaggga aagcccctaa gctcctgatc tattctactt cccgtttgaa tagtggggtc 240
ccatcacgct tcagtggcag tggctctggg acagatttca ctctcaccat cagcagtctg 300
caacctgaag attttgcaac ttactactgt caacaggata ttaaacaccc tacgttcggt 360
caaggcacca aggtggagat caaacgtacg gtggctgcac catctgtctt catcttcccg 420
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 705
<210> 122
<211> 235
<212> PRT
<213> Homo sapiens
<400> 122
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Ser Thr Ser Arg Leu Asn Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Asp Ile Lys His Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 123
<211> 1395
<212> DNA
<213> Homo sapiens
<400> 123
atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactccgag 60
gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg ggtcctcggt gaaggtctcc 120
tgcaaggctt ctggttttac cttcaccgac tatattatgc actgggtgcg tcaggcccct 180
ggtcaagggc ttgagtggat gggctatatc aacccttata atgatgacac cgaatacaac 240
gagaagttca agggccgtgt cacgattacc gcggacaaat ccacgagcac agcctacatg 300
gagctgagca gcctgcgctc tgaggacacg gccgtgtatt actgtgcgcg ttcgatttat 360
tactacgatg ccccgtttgc ttactggggc caagggactc tggtcaccgt ctctagtgcc 420
tccaccaagg gcccatcggt cttccccctg gcgccctgct ccaggagcac ctccgagagc 480
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540
aactcaggcg ctctgaccag cggcgtgcac accttcccag ctgtcctaca gtcctcagga 600
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca acttcggcac ccagacctac 660
acctgcaacg tagatcacaa gcccagcaac accaaggtgg acaagacagt tgagcgcaaa 720
tgttgtgtcg agtgcccacc gtgcccagca ccacctgtgg caggaccgtc agtcttcctc 780
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacgtgcgtg 840
gtggtggacg tgagccacga agaccccgag gtccagttca actggtacgt ggacggcgtg 900
gaggtgcata atgccaagac aaagccacgg gaggagcagt tcaacagcac gttccgtgtg 960
gtcagcgtcc tcaccgttgt gcaccaggac tggctgaacg gcaaggagta caagtgcaag 1020
gtctccaaca aaggcctccc agcccccatc gagaaaacca tctccaaaac caaagggcag 1080
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1140
gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtgggag 1200
agcaatgggc agccggagaa caactacaag accacacctc ccatgctgga ctccgacggc 1260
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1320
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1380
ctgtctccgg gtaaa 1395
<210> 124
<211> 465
<212> PRT
<213> Homo sapiens
<400> 124
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe
35 40 45
Thr Asp Tyr Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
210 215 220
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
225 230 235 240
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Lys
465
<210> 125
<211> 699
<212> DNA
<213> Homo sapiens
<400> 125
atggggtcaa ccgccatcct tggcctcctc ctggctgtcc tgcagggagg gcgcgcctcc 60
tatgtgctga ctcagccacc ctcggtgtca gtggccccag gacagacggc caggattacc 120
tgtgggggaa acaaccttgg aagtaaaagt gtgcactggt accagcagaa gccaggccag 180
gcccctgtgc tggtcgtcta tgatgatagc gaccggccct catggatccc tgagcgattc 240
tctggctcca actctgggaa cacggccacc ctgaccatca gcaggggcga agccggggat 300
gaggccgact attactgtca ggtgtgggat agtagtagtg atcatgtggt attcggcgga 360
gggaccaagc tgaccgtcct aggccaaccg aaagcggcgc cctcggtcac tctgttcccg 420
ccctcctctg aggagcttca agccaacaag gccacactgg tgtgtctcat aagtgacttc 480
tacccgggag ccgtgacagt ggcctggaag gcagatagca gccccgtcaa ggcgggagtg 540
gagaccacca caccctccaa acaaagcaac aacaagtacg cggccagcag ctatctgagc 600
ctgacgcctg agcagtggaa gtcccacaga agctacagct gccaggtcac gcatgaaggg 660
agcaccgtgg agaagacagt ggcccctaca gaatgttca 699
<210> 126
<211> 233
<212> PRT
<213> Homo sapiens
<400> 126
Met Gly Ser Thr Ala Ile Leu Gly Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Gly Arg Ala Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala
20 25 30
Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Leu Gly Ser
35 40 45
Lys Ser Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu
50 55 60
Val Val Tyr Asp Asp Ser Asp Arg Pro Ser Trp Ile Pro Glu Arg Phe
65 70 75 80
Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Gly
85 90 95
Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser
100 105 110
Ser Asp His Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
115 120 125
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
130 135 140
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
145 150 155 160
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
165 170 175
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
180 185 190
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
195 200 205
His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
210 215 220
Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230
<210> 127
<211> 1401
<212> DNA
<213> Homo sapiens
<400> 127
atggggtcaa ccgccatcct tggcctcctc ctggctgtcc tgcagggagg gcgcgcccag 60
atgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120
tgtgcagcgt ctggattcac cttcagaacc tatggcatgc actgggtccg ccaggctcca 180
ggcaagggac tggagtgggt ggcagttata tggtatgatg gaagtaataa acactatgca 240
gactccgtga agggccgatt caccatcacc agagacaatt ccaagaacac tctgaatctg 300
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agcccctcag 360
tgggagctag ttcatgaagc ttttgatatc tggggccaag ggacaatggt caccgtctct 420
tcagctagca ccaagggccc atcggtcttc cccctggcgc cctgctccag gagcacctcc 480
gagagcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 540
tcgtggaact caggcgctct gaccagcggc gtgcacacct tcccagctgt cctacagtcc 600
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcaactt cggcacccag 660
acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gacagttgag 720
cgcaaatgtt gtgtcgagtg cccaccgtgc ccagcaccac ctgtggcagg accgtcagtc 780
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcacg 840
tgcgtggtgg tggacgtgag ccacgaagac cccgaggtcc agttcaactg gtacgtggac 900
ggcgtggagg tgcataatgc caagacaaag ccacgggagg agcagttcaa cagcacgttc 960
cgtgtggtca gcgtcctcac cgttgtgcac caggactggc tgaacggcaa ggagtacaag 1020
tgcaaggtct ccaacaaagg cctcccagcc cccatcgaga aaaccatctc caaaaccaaa 1080
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1140
aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1200
tgggagagca atgggcagcc ggagaacaac tacaagacca cacctcccat gctggactcc 1260
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1320
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1380
ctctccctgt ctccgggtaa a 1401
<210> 128
<211> 467
<212> PRT
<213> Homo sapiens
<400> 128
Met Gly Ser Thr Ala Ile Leu Gly Leu Leu Leu Ala Val Leu Gln Gly
1 5 10 15
Gly Arg Ala Gln Met Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Arg Thr Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys His Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Thr Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Asn Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ala Pro Gln Trp Glu Leu Val His Glu Ala Phe
115 120 125
Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
145 150 155 160
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys
210 215 220
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu
225 230 235 240
Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 129
<211> 702
<212> DNA
<213> Homo sapiens
<400> 129
atgggtgtgc ctactcatct cctgggtttg ttgctgctct ggattacaca tgccatatgt 60
gatatccgga tgacacagtc tccagcttcc ctgtctgcat ctctgggaga aactgtcaac 120
atcgaatgtc tagcaagtga ggacatttac agtgatttag catggtatca gcagaagcca 180
gggaaatctc ctcagctcct gatctataat gcaaatagct tgcaaaatgg ggtcccttca 240
cggtttagtg gcagtggatc tggcacacag tattctctaa aaataaacag cctgcaatct 300
gaagatgtcg cgacttattt ctgtcaacaa tataacaatt atcctccgac gttcggtgga 360
ggcaccaagc tggaattgaa acgggctgat gctgcaccaa ctgtatctat cttcccacca 420
tccacggaac agttagcaac tggaggtgcc tcagtcgtgt gcctcatgaa caacttctat 480
cccagagaca tcagtgtcaa gtggaagatt gatggcactg aacgacgaga tggtgtcctg 540
gacagtgtta ctgatcagga cagcaaagac agcacgtaca gcatgagcag caccctctcg 600
ttgaccaagg ctgactatga aagtcataac ctctatacct gtgaggttgt tcataagaca 660
tcatcctcac ccgtcgtcaa gagcttcaac aggaatgagt gt 702
<210> 130
<211> 234
<212> PRT
<213> Homo sapiens
<400> 130
Met Gly Val Pro Thr His Leu Leu Gly Leu Leu Leu Leu Trp Ile Thr
1 5 10 15
His Ala Ile Cys Asp Ile Arg Met Thr Gln Ser Pro Ala Ser Leu Ser
20 25 30
Ala Ser Leu Gly Glu Thr Val Asn Ile Glu Cys Leu Ala Ser Glu Asp
35 40 45
Ile Tyr Ser Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro
50 55 60
Gln Leu Leu Ile Tyr Asn Ala Asn Ser Leu Gln Asn Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn
85 90 95
Ser Leu Gln Ser Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Tyr Asn
100 105 110
Asn Tyr Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Thr Glu Gln
130 135 140
Leu Ala Thr Gly Gly Ala Ser Val Val Cys Leu Met Asn Asn Phe Tyr
145 150 155 160
Pro Arg Asp Ile Ser Val Lys Trp Lys Ile Asp Gly Thr Glu Arg Arg
165 170 175
Asp Gly Val Leu Asp Ser Val Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Ser Leu Thr Lys Ala Asp Tyr Glu Ser
195 200 205
His Asn Leu Tyr Thr Cys Glu Val Val His Lys Thr Ser Ser Ser Pro
210 215 220
Val Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 131
<211> 1395
<212> DNA
<213> Homo sapiens
<400> 131
atggacatca ggctcagctt ggctttcctt gtccttttca taaaaggtgt ccagtgtgag 60
gtacagctgg tggagtctgg cggaggattg gtacagcctg caaactccct gaaactctcc 120
tgtgcagcct caggattcac tttcagtgac tatgccatgg cctgggtccg ccagtctcca 180
aagaagggtc tggagtgggt cgcaaccatt atttatgatg gtagtagcac ttactatcga 240
gactccgtga agggccgatt cactatctcc agagataatg caaaaagcac cctatacctg 300
caaatggaca gtctgaggtc tgaggacacg gccacttatt actgtgcaac aggtctgggt 360
atagctacgg actactttga ttactggggc caaggagtcc tggtcacagt ctcctcagct 420
gaaacaacag ccccatctgt ctatccactg gctcctggaa ctgctctcaa aagtaactcc 480
atggtgaccc tgggatgcct ggtcaagggc tatttccctg agccagtcac cgtgacctgg 540
aactctggag ccctgtccag cggtgtgcac accttcccag ctgtcctgca gtctgggctc 600
tacactctca ccagctcagt gactgtaccc tccagcacct ggcccagcca gaccgtcacc 660
tgcaacgtag cccacccggc cagcagcacc aaggtggaca agaaaattgt gcccagaaac 720
tgtggaggtg attgcaagcc ttgtatatgt acaggctcag aagtatcatc tgtcttcatc 780
ttccccccaa agcccaaaga tgtgctcacc atcactctga ctcctaaggt cacgtgtgtt 840
gtggtagaca ttagccagga cgatcccgag gtccatttca gctggtttgt agatgacgtg 900
gaagtccaca cagctcagac tcgaccacca gaggagcagt tcaacagcac tttccgctca 960
gtcagtgaac tccccatcct gcaccaggac tggctcaatg gcaggacgtt cagatgcaag 1020
gtcaccagtg cagctttccc atcccccatc gagaaaacca tctccaaacc cgaaggcaga 1080
acacaagttc cgcatgtata caccatgtca cctaccaagg aagagatgac ccagaatgaa 1140
gtcagtatca cctgcatggt aaaaggcttc tatcccccag acatttatgt ggagtggcag 1200
atgaacgggc agccacagga aaactacaag aacactccac ctacgatgga cacagatggg 1260
agttacttcc tctacagcaa gctcaatgtg aagaaggaaa aatggcagca gggaaacacg 1320
ttcacgtgtt ctgtgctgca tgaaggcctg cacaaccacc atactgagaa gagtctctcc 1380
cactctccgg gtaaa 1395
<210> 132
<211> 465
<212> PRT
<213> Homo sapiens
<400> 132
Met Asp Ile Arg Leu Ser Leu Ala Phe Leu Val Leu Phe Ile Lys Gly
1 5 10 15
Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Ala Asn Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Asp Tyr Ala Met Ala Trp Val Arg Gln Ser Pro Lys Lys Gly Leu
50 55 60
Glu Trp Val Ala Thr Ile Ile Tyr Asp Gly Ser Ser Thr Tyr Tyr Arg
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser
85 90 95
Thr Leu Tyr Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr
100 105 110
Tyr Tyr Cys Ala Thr Gly Leu Gly Ile Ala Thr Asp Tyr Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Val Leu Val Thr Val Ser Ser Ala Glu Thr Thr Ala
130 135 140
Pro Ser Val Tyr Pro Leu Ala Pro Gly Thr Ala Leu Lys Ser Asn Ser
145 150 155 160
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Thr Trp Asn Ser Gly Ala Leu Ser Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Gly Leu Tyr Thr Leu Thr Ser Ser Val Thr
195 200 205
Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala
210 215 220
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asn
225 230 235 240
Cys Gly Gly Asp Cys Lys Pro Cys Ile Cys Thr Gly Ser Glu Val Ser
245 250 255
Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr
260 265 270
Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Gln Asp Asp
275 280 285
Pro Glu Val His Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr
290 295 300
Ala Gln Thr Arg Pro Pro Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser
305 310 315 320
Val Ser Glu Leu Pro Ile Leu His Gln Asp Trp Leu Asn Gly Arg Thr
325 330 335
Phe Arg Cys Lys Val Thr Ser Ala Ala Phe Pro Ser Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Pro Glu Gly Arg Thr Gln Val Pro His Val Tyr Thr
355 360 365
Met Ser Pro Thr Lys Glu Glu Met Thr Gln Asn Glu Val Ser Ile Thr
370 375 380
Cys Met Val Lys Gly Phe Tyr Pro Pro Asp Ile Tyr Val Glu Trp Gln
385 390 395 400
Met Asn Gly Gln Pro Gln Glu Asn Tyr Lys Asn Thr Pro Pro Thr Met
405 410 415
Asp Thr Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Asn Val Lys Lys
420 425 430
Glu Lys Trp Gln Gln Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu
435 440 445
Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly
450 455 460
Lys
465
<210> 133
<211> 711
<212> DNA
<213> Homo sapiens
<400> 133
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcc 60
agatgtgagt ctgccctgac tcagcctgcc tccgtgtctg ggtctcctgg acagtcgatc 120
accatctcct gcactggaac cagcagtgac gttggtggtt ataactctgt ctcctggtac 180
caacagcacc caggcaaagc ccccaaactc atgatttatg aggtcagtaa tcggccctca 240
ggggtttcta atcgcttctc tggctccaag tctggcaaca cggcctccct gaccatctct 300
gggctccagg ctgaggacga ggctgattat tactgcaatt catatacaag caccagcatg 360
gtattcggcg gagggaccaa gctgaccgtc ctaggtcagc ccaaggctgc cccctcggtc 420
actctgttcc cgccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 480
ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 540
aaggcgggag tggagaccac cacaccctcc aaacaaagca acaacaagta cgcggccagc 600
agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag ctgccaggtc 660
acgcatgaag ggagcaccgt ggagaagaca gtggccccta cagaatgttc a 711
<210> 134
<211> 237
<212> PRT
<213> Homo sapiens
<400> 134
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Ser Ala Leu Thr Gln Pro Ala Ser Val
20 25 30
Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser
35 40 45
Ser Asp Val Gly Gly Tyr Asn Ser Val Ser Trp Tyr Gln Gln His Pro
50 55 60
Gly Lys Ala Pro Lys Leu Met Ile Tyr Glu Val Ser Asn Arg Pro Ser
65 70 75 80
Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser
85 90 95
Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
100 105 110
Asn Ser Tyr Thr Ser Thr Ser Met Val Phe Gly Gly Gly Thr Lys Leu
115 120 125
Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro
130 135 140
Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu
145 150 155 160
Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp
165 170 175
Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln
180 185 190
Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu
195 200 205
Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly
210 215 220
Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230 235
<210> 135
<211> 1380
<212> DNA
<213> Homo sapiens
<400> 135
atggactgga cctggaggat ccttttcttg gtggcagcag ccacaggtgt ccactccgag 60
gttcagctgg tgcagtctgg agctgaggtg aagaagcctg gggcctcagt gaaggtctcc 120
tgcaaggctt ctggttacac cttaaccagc tatggtatca gctgggtgcg acaggcccct 180
ggacaagggc ttgagtggat gggatgggtc agtttttata atggtaacac aaactatgca 240
cagaagctcc agggcagagg caccatgacc acagacccat ccacgagcac agcctacatg 300
gagctgagga gcctgagatc tgacgacacg gccgtgtatt actgtgcgag aggctacggt 360
atggacgtct ggggccaagg gaccacggtc accgtctcct ctgcctccac caagggccca 420
tcggtcttcc ccctggcgcc ctgctccagg agcacctccg agagcacagc ggccctgggc 480
tgcctggtca aggactactt ccccgaaccg gtgacggtgt cgtggaactc aggcgctctg 540
accagcggcg tgcacacctt cccagctgtc ctacagtcct caggactcta ctccctcagc 600
agcgtggtga ccgtgccctc cagcaacttc ggcacccaga cctacacctg caacgtagat 660
cacaagccca gcaacaccaa ggtggacaag acagttgagc gcaaatgttg tgtcgagtgc 720
ccaccgtgcc cagcaccacc tgtggcagga ccgtcagtct tcctcttccc cccaaaaccc 780
aaggacaccc tcatgatctc ccggacccct gaggtcacgt gcgtggtggt ggacgtgagc 840
cacgaagacc ccgaggtcca gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 900
aagacaaagc cacgggagga gcagttcaac agcacgttcc gtgtggtcag cgtcctcacc 960
gttgtgcacc aggactggct gaacggcaag gagtacaagt gcaaggtctc caacaaaggc 1020
ctcccagccc ccatcgagaa aaccatctcc aaaaccaaag ggcagccccg agaaccacag 1080
gtgtacaccc tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc 1140
ctggtcaaag gcttctaccc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1200
gagaacaact acaagaccac acctcccatg ctggactccg acggctcctt cttcctctac 1260
agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1320
atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1380
<210> 136
<211> 460
<212> PRT
<213> Homo sapiens
<400> 136
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Leu
35 40 45
Thr Ser Tyr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Val Ser Phe Tyr Asn Gly Asn Thr Asn Tyr Ala
65 70 75 80
Gln Lys Leu Gln Gly Arg Gly Thr Met Thr Thr Asp Pro Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gly Tyr Gly Met Asp Val Trp Gly Gln Gly Thr
115 120 125
Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
130 135 140
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly
145 150 155 160
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
165 170 175
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
180 185 190
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
195 200 205
Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser
210 215 220
Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys
225 230 235 240
Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe
245 250 255
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
260 265 270
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe
275 280 285
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
290 295 300
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr
305 310 315 320
Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
325 330 335
Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
340 345 350
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
355 360 365
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
370 375 380
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
385 390 395 400
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser
405 410 415
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
420 425 430
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
435 440 445
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 137
<211> 693
<212> DNA
<213> Homo sapiens
<400> 137
atggcatgga tccctctctt cctcggcgtc cttgcttact gcacaggatc cgtggcctcc 60
tatgaggtga ctcaggcacc ctcagtgtcc gtgtccccag gacagacagc cagcatcacc 120
tgctctggag ataaattggg ggataaatat gcttgttggt atcagcagaa gccaggccag 180
tcccctgtgc tggtcatcta tcaagatagc aagcggccct cagggatccc tgagcgattc 240
tctggctcca actctggaaa cacagccact ctgaccatca gcgggaccca ggctatggat 300
gaggctgact attactgtca ggcgtgggac agcagcactg cggtattcgg cggagggacc 360
aagctgaccg tcctaggtca gcccaaggct gccccctcgg tcactctgtt cccgccctcc 420
tctgaggagc ttcaagccaa caaggccaca ctggtgtgtc tcataagtga cttctacccg 480
ggagccgtga cagtggcctg gaaggcagat agcagccccg tcaaggcggg agtggagacc 540
accacaccct ccaaacaaag caacaacaag tacgcggcca gcagctatct gagcctgacg 600
cctgagcagt ggaagtccca cagaagctac agctgccagg tcacgcatga agggagcacc 660
gtggagaaga cagtggcccc tacagaatgt tca 693
<210> 138
<211> 231
<212> PRT
<213> Homo sapiens
<400> 138
Met Ala Trp Ile Pro Leu Phe Leu Gly Val Leu Ala Tyr Cys Thr Gly
1 5 10 15
Ser Val Ala Ser Tyr Glu Val Thr Gln Ala Pro Ser Val Ser Val Ser
20 25 30
Pro Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp
35 40 45
Lys Tyr Ala Cys Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu
50 55 60
Val Ile Tyr Gln Asp Ser Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe
65 70 75 80
Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr
85 90 95
Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Ser Ser
100 105 110
Thr Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro
115 120 125
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu
130 135 140
Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro
145 150 155 160
Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala
165 170 175
Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala
180 185 190
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg
195 200 205
Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr
210 215 220
Val Ala Pro Thr Glu Cys Ser
225 230
<210> 139
<211> 1401
<212> DNA
<213> Homo sapiens
<400> 139
atggactgga cctggagcat ccttttcttg gtggcagcag caacaggtgc ccactcccag 60
gttcagctgg tgcagtctgg agctgaggtg aagaagcctg gggcctcagt gaaggtctcc 120
tgcaaggctt ctggttacac ctttaccagt tatggtctca gctgggtgcg acaggcccct 180
ggacaagggc ttgagtggat gggatggatc atcccttaca atggtaacac aaactctgca 240
cagaaactcc agggcagagt caccatgacc acagacacat ccacgagcac agcctacatg 300
gagctgagga gcctgagatc tgacgacacg gccgtgtatt tctgtgcgag agacagggac 360
tacggtgtca attatgatgc ttttgatatc tggggccaag ggacaatggt caccgtctct 420
tcagcctcca ccaagggccc atcggtcttc cccctggcgc cctgctccag gagcacctcc 480
gagagcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 540
tcgtggaact caggcgctct gaccagcggc gtgcacacct tcccagctgt cctacagtcc 600
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcaactt cggcacccag 660
acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gacagttgag 720
cgcaaatgtt gtgtcgagtg cccaccgtgc ccagcaccac ctgtggcagg accgtcagtc 780
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcacg 840
tgcgtggtgg tggacgtgag ccacgaagac cccgaggtcc agttcaactg gtacgtggac 900
ggcgtggagg tgcataatgc caagacaaag ccacgggagg agcagttcaa cagcacgttc 960
cgtgtggtca gcgtcctcac cgttgtgcac caggactggc tgaacggcaa ggagtacaag 1020
tgcaaggtct ccaacaaagg cctcccagcc cccatcgaga aaaccatctc caaaaccaaa 1080
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1140
aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1200
tgggagagca atgggcagcc ggagaacaac tacaagacca cacctcccat gctggactcc 1260
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1320
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1380
ctctccctgt ctccgggtaa a 1401
<210> 140
<211> 467
<212> PRT
<213> Homo sapiens
<400> 140
Met Asp Trp Thr Trp Ser Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Ile Pro Tyr Asn Gly Asn Thr Asn Ser Ala
65 70 75 80
Gln Lys Leu Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Phe Cys Ala Arg Asp Arg Asp Tyr Gly Val Asn Tyr Asp Ala Phe
115 120 125
Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
145 150 155 160
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys
210 215 220
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu
225 230 235 240
Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 141
<211> 705
<212> DNA
<213> Homo sapiens
<400> 141
atggcctggg ctccactact tctcaccctc ctcgctcact gcacaggttc ttgggccaat 60
tttatgctga ctcagcccca ctctgtgtcg gagtctccgg ggaagacggt ggccatctcc 120
tgcacccgca acagtggcag cattgccagc aactctgtgc agtggtacca gcagcgcccg 180
ggcagttccc ccaccactgt gatctttgag gataaccaaa gaccctctgg ggtccctgat 240
cggttctctg gctccatcga cagctcctcc aactctgcct ccctcaccat ctctggtctg 300
aagactgagg acgaggctga ctactactgt cagtcttatg atagcaacaa ttgggtgttc 360
ggcggaggga ccaaactgac cgtcctaggt cagcccaagg ccaaccccac tgtcactctg 420
ttcccgccct cctctgagga gctccaagcc aacaaggcca cactagtgtg tctgatcagt 480
gacttctacc cgggagctgt gacagtggcc tggaaggcag atggcagccc cgtcaaggcg 540
ggagtggaga ccaccaaacc ctccaaacag agcaacaaca agtacgcggc cagcagctac 600
ctgagcctga cgcccgagca gtggaagtcc cacagaagct acagctgcca ggtcacgcat 660
gaagggagca ccgtggagaa gacagtggcc cctacagaat gttca 705
<210> 142
<211> 235
<212> PRT
<213> Homo sapiens
<400> 142
Met Ala Trp Ala Pro Leu Leu Leu Thr Leu Leu Ala His Cys Thr Gly
1 5 10 15
Ser Trp Ala Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser
20 25 30
Pro Gly Lys Thr Val Ala Ile Ser Cys Thr Arg Asn Ser Gly Ser Ile
35 40 45
Ala Ser Asn Ser Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ser Pro
50 55 60
Thr Thr Val Ile Phe Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr
85 90 95
Ile Ser Gly Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser
100 105 110
Tyr Asp Ser Asn Asn Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
115 120 125
Leu Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser
130 135 140
Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser
145 150 155 160
Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser
165 170 175
Pro Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn
180 185 190
Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp
195 200 205
Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr
210 215 220
Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230 235
<210> 143
<211> 1410
<212> DNA
<213> Homo sapiens
<400> 143
atggagtttg ggctgagctg ggttttcctc gttgctcttt taagaggtgt ccagtgtcag 60
gtgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 120
tgtgcagcgt ctggattcac cttcagtagc tatgtcatgc actgggtccg ccaggctcca 180
ggcaaggggc tggagtgggt ggctgttata tggtatgatg gaagtaataa atactatgca 240
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctg 300
caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agaggggtat 360
gactacggtg aagactacta ctactacggt atggacgtct ggggccaagg gaccacggtc 420
accgtctcta gtgcctccac caagggccca tcggtcttcc ccctggcgcc ctgctccagg 480
agcacctccg agagcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 540
gtgacggtgt cgtggaactc aggcgctctg accagcggcg tgcacacctt cccagctgtc 600
ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcaacttc 660
ggcacccaga cctacacctg caacgtagat cacaagccca gcaacaccaa ggtggacaag 720
acagttgagc gcaaatgttg tgtcgagtgc ccaccgtgcc cagcaccacc tgtggcagga 780
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 840
gaggtcacgt gcgtggtggt ggacgtgagc cacgaagacc ccgaggtcca gttcaactgg 900
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cacgggagga gcagttcaac 960
agcacgttcc gtgtggtcag cgtcctcacc gttgtgcacc aggactggct gaacggcaag 1020
gagtacaagt gcaaggtctc caacaaaggc ctcccagccc ccatcgagaa aaccatctcc 1080
aaaaccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1140
atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctaccc cagcgacatc 1200
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac acctcccatg 1260
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1320
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1380
cagaagagcc tctccctgtc tccgggtaaa 1410
<210> 144
<211> 470
<212> PRT
<213> Homo sapiens
<400> 144
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Gly Tyr Asp Tyr Gly Glu Asp Tyr Tyr Tyr
115 120 125
Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
130 135 140
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
145 150 155 160
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
165 170 175
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
180 185 190
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
195 200 205
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
210 215 220
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
225 230 235 240
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
245 250 255
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
305 310 315 320
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
<210> 145
<211> 708
<212> DNA
<213> Homo sapiens
<400> 145
atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60
agatgtgaca tccagatgac ccagtctcca tcctccctct ccgcatccgt aggcgaccgc 120
gtaaccataa catgtagagc atctcaagat atttccaact atttgaattg gtaccaacaa 180
aaacccggca aagcacctaa actcctcatt tactatacat caagactcct ctccggcgtt 240
ccatcacgat tctcaggctc cggctccggc acagatttca cactcactat ttcctccctc 300
caaccagaag attttgcaac ctattactgt caacaaggcg atacactccc atacacattc 360
ggcggcggca caaaagttga aattaaacgt acggtggctg caccatctgt cttcatcttc 420
ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac 480
ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 540
tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc 600
ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga agtcacccat 660
cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 708
<210> 146
<211> 236
<212> PRT
<213> Homo sapiens
<400> 146
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Leu Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Gly Asp Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 147
<211> 1404
<212> DNA
<213> Homo sapiens
<400> 147
atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactccgag 60
gtgcagctgg tgcagagcgg cgccgaggta aaaaaaccag gagcaagcgt taaagtttct 120
tgtaaagcaa gcggatatac atttacagat tacaacatgc attgggtaag acaagcgcca 180
ggacaaggat tggaatggat gggcgaaatt aaccctaata gtggaggagc aggctacaat 240
caaaaattca aagggagagt tacaatgaca acagacacaa gcacttcaac agcatatatg 300
gaactgcgat cacttagaag cgacgataca gctgtatact attgcgcacg acttgggtat 360
gatgatatat atgatgactg gtatttcgat gtttggggcc agggaacaac agttaccgtc 420
tctagtgcct ccaccaaggg cccatcggtc ttccccctgg cgccctgctc caggagcacc 480
tccgagagca cagcggccct gggctgcctg gtcaaggact acttccccga accggtgacg 540
gtgtcgtgga actcaggcgc tctgaccagc ggcgtgcaca ccttcccagc tgtcctacag 600
tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcaa cttcggcacc 660
cagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagacagtt 720
gagcgcaaat gttgtgtcga gtgcccaccg tgcccagcac cacctgtggc aggaccgtca 780
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 840
acgtgcgtgg tggtggacgt gagccacgaa gaccccgagg tccagttcaa ctggtacgtg 900
gacggcgtgg aggtgcataa tgccaagaca aagccacggg aggagcagtt caacagcacg 960
ttccgtgtgg tcagcgtcct caccgttgtg caccaggact ggctgaacgg caaggagtac 1020
aagtgcaagg tctccaacaa aggcctccca gcccccatcg agaaaaccat ctccaaaacc 1080
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga ggagatgacc 1140
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1200
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacacctcc catgctggac 1260
tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1320
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1380
agcctctccc tgtctccggg taaa 1404
<210> 148
<211> 468
<212> PRT
<213> Homo sapiens
<400> 148
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr
115 120 125
Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser
130 135 140
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr
145 150 155 160
Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
195 200 205
Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr
210 215 220
Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val
225 230 235 240
Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val
245 250 255
Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
260 265 270
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
275 280 285
His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
290 295 300
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
305 310 315 320
Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro
340 345 350
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln
355 360 365
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
370 375 380
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
385 390 395 400
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
405 410 415
Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
420 425 430
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
435 440 445
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
450 455 460
Ser Pro Gly Lys
465
<210> 149
<211> 720
<212> DNA
<213> Homo sapiens
<400> 149
atggtgttgc agacccaggt cttcatttct ctgttgctct ggatctctgg tgcctacggg 60
gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 120
atcaactgca agtccagcca gagtgtttta gacagctccg acaataagaa ctacttagct 180
tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctaaccgg 240
gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 300
atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtgat 360
ccattcactt tcggccctgg gaccaaagtg gatatcaaac gtacggtggc tgcaccatct 420
gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 480
ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 540
caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 600
ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 660
gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 720
<210> 150
<211> 240
<212> PRT
<213> Homo sapiens
<400> 150
Met Val Leu Gln Thr Gln Val Phe Ile Ser Leu Leu Leu Trp Ile Ser
1 5 10 15
Gly Ala Tyr Gly Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala
20 25 30
Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser
35 40 45
Val Leu Asp Ser Ser Asp Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln
50 55 60
Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Asn Arg
65 70 75 80
Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr
100 105 110
Tyr Cys Gln Gln Tyr Tyr Ser Asp Pro Phe Thr Phe Gly Pro Gly Thr
115 120 125
Lys Val Asp Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
130 135 140
Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys
145 150 155 160
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
165 170 175
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
180 185 190
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
195 200 205
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
210 215 220
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235 240
<210> 151
<211> 1395
<212> DNA
<213> Homo sapiens
<400> 151
atggactgga cctggagcat ccttttcttg gtggcagcac caacaggtgc ccactcccag 60
gttcagctgg tgcagtctgg agctgaggtg aagaagcctg gggcctcagt gaaggtctcc 120
tgcaaggctt ctggttacac ctttaccagc tatggtatca gctgggtgcg acaggcccct 180
ggacaagggc ttgagtggat gggatggatc agcgcttaca atggtaacac aaactatgca 240
cagaagctcc agggcagagt caccatgacc acagacacat ccacgagcac agcctacatg 300
gagctgagga gcctgagatc tgacgacacg gccgtgtatt actgtgcgag agagtcgtgg 360
ttcggggagg tattctttga ctactggggc cagggaaccc tggtcaccgt ctcctcagct 420
agcaccaagg gcccatcggt cttccccctg gcgccctgct ccaggagcac ctccgagagc 480
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540
aactcaggcg ctctgaccag cggcgtgcac accttcccag ctgtcctaca gtcctcagga 600
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca acttcggcac ccagacctac 660
acctgcaacg tagatcacaa gcccagcaac accaaggtgg acaagacagt tgagcgcaaa 720
tgttgtgtcg agtgcccacc gtgcccagca ccacctgtgg caggaccgtc agtcttcctc 780
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacgtgcgtg 840
gtggtggacg tgagccacga agaccccgag gtccagttca actggtacgt ggacggcgtg 900
gaggtgcata atgccaagac aaagccacgg gaggagcagt tcaacagcac gttccgtgtg 960
gtcagcgtcc tcaccgttgt gcaccaggac tggctgaacg gcaaggagta caagtgcaag 1020
gtctccaaca aaggcctccc agcccccatc gagaaaacca tctccaaaac caaagggcag 1080
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1140
gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtgggag 1200
agcaatgggc agccggagaa caactacaag accacacctc ccatgctgga ctccgacggc 1260
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1320
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1380
ctgtctccgg gtaaa 1395
<210> 152
<211> 465
<212> PRT
<213> Homo sapiens
<400> 152
Met Asp Trp Thr Trp Ser Ile Leu Phe Leu Val Ala Ala Pro Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala
65 70 75 80
Gln Lys Leu Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Ser Trp Phe Gly Glu Val Phe Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
210 215 220
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
225 230 235 240
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Lys
465
<210> 153
<211> 708
<212> DNA
<213> Homo sapiens
<400> 153
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60
cgctgtgaca tccagatgac ccagtctcca tcttccgtgt ctgcatctgt aggagacaga 120
gtcaccatca cttgtcgggc gagtcagggt attagcagct ggttagcctg gtatcaacag 180
aaaccaggga aagcccctaa gctcctgatc tatggtgcat ccaatttgga aagtggggtc 240
ccatcaaggt tcagcggcag tggatctggg acagatttca ctctcaccat cagcagcctg 300
cagcctgaag attttgcaaa ttactattgt caacaggcta acagtttccc gtggacgttc 360
ggccaaggga ccaaggtgga aatcaaacgt acggtggctg caccatctgt cttcatcttc 420
ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac 480
ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 540
tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc 600
ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga agtcacccat 660
cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 708
<210> 154
<211> 236
<212> PRT
<213> Homo sapiens
<400> 154
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Gly Ala Ser Asn Leu Glu Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Asn Tyr Tyr Cys Gln Gln
100 105 110
Ala Asn Ser Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 155
<211> 1398
<212> DNA
<213> Homo sapiens
<400> 155
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60
cgctgtcagg tccagctggt acagtctggg gctgaggtga agaagcctgg ggcctcagtg 120
aaggtctcct gcaaggtttc cggatacacc ctcagtgatt tatccatcca ctgggtgcga 180
caggctcctg gaaaagggct tgagtggatg ggaggttttg atcctcaaga tggtgaaaca 240
atctacgcac agaagttcca gggcagagtc accatgaccg aggacacatc tacagacaca 300
gcctacatgg agctgagcag cctgaaatct gaggacacgg ccgtgtatta ctgcgcaacg 360
gggagcagct cgtcctggtt cgacccctgg ggccagggaa ccctggtcac cgtctctagt 420
gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 480
agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540
tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 600
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 660
tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 720
aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 780
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 840
gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 900
gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 960
gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc 1020
aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 1080
cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1140
caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 1200
gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 1260
ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1320
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1380
tccctgtctc cgggtaaa 1398
<210> 156
<211> 466
<212> PRT
<213> Homo sapiens
<400> 156
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Gln Ser Gly Ala Glu
20 25 30
Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly
35 40 45
Tyr Thr Leu Ser Asp Leu Ser Ile His Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Met Gly Gly Phe Asp Pro Gln Asp Gly Glu Thr
65 70 75 80
Ile Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Glu Asp Thr
85 90 95
Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu Lys Ser Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Thr Gly Ser Ser Ser Ser Trp Phe Asp
115 120 125
Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu
145 150 155 160
Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn
210 215 220
Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg
225 230 235 240
Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Lys
465
<210> 157
<211> 702
<212> DNA
<213> Homo sapiens
<400> 157
atggagaccc ctgcccagct gctgttcctg ctgctgctgt ggctgcccga cacaaccggc 60
gaaatcgtca tgacacagag ccctgccaca ctgtccgtga gccctggaga gagggctacc 120
ctgagctgca gggcttccca gagcgtgagc agcaacctgg cctggtacca acagaagcct 180
ggccaggccc ctaggctgct gatctacggc gctgctacca gggccaccgg tattcctgcc 240
agggtgtccg gctccggatc cggcaccgag tttaccctga ccatcagcag cctgcagagc 300
gaggacttcg ccgtgtacta ctgtcagcaa tacaacaact ggcccctgac ctttggcggc 360
ggcaccaagg tggagatcaa gaggacagtg gccgccccca gcgtgttcat cttccctccc 420
agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gtctgctgaa caacttctac 480
cccagggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagtccgg caactcccag 540
gagtccgtga ccgagcagga ctccaaggac tccacctact ccctgtcctc caccctgacc 600
ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc 660
ctgtcctccc ctgtgaccaa gagcttcaac aggggcgagt gc 702
<210> 158
<211> 234
<212> PRT
<213> Homo sapiens
<400> 158
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
50 55 60
Arg Leu Leu Ile Tyr Gly Ala Ala Thr Arg Ala Thr Gly Ile Pro Ala
65 70 75 80
Arg Val Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn
100 105 110
Asn Trp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 159
<211> 1416
<212> DNA
<213> Homo sapiens
<400> 159
atggatatgc gggtccctgc tcagctgctg ggactgctgc tgctgtggct gaggggcgcc 60
aggtgtcagg tgcagctggt cgaaagcgga ggaggagtgg tgcagcccgg aaggtccctg 120
aggctgtcct gcgccgctag cggcttcacc ttttccaact acggcatgca ctgggtgagg 180
caagcccctg gagagggcct ggaatgggtg gctgctatct ggttcgacgc cagcgacaag 240
tactatgccg acgctgtgaa gggccggttc accatcagca gggacaacag caagaacacc 300
ctctacctgc agatgaacag cctccgggcc gaggacaccg ctgtctatta ctgtgccagg 360
gaccaggcca tcttcggagt ggtccccgat tactggggcc agggaaccct ggtgaccgtg 420
tcctccgctt ccacaaaggg acctagcgtg ttccctctgg cccctagcag caagtccaca 480
agcggaggaa cagccgccct gggctgtctc gtgaaggact attttcccga gcccgtgacc 540
gtgtcctgga actccggagc cctgacctcc ggcgtgcata cattccccgc tgtcctgcag 600
tccagcggcc tctactccct gtcctccgtg gtcaccgtgc ctagcagcag cctgggcacc 660
cagacataca tctgcaacgt caaccacaag ccttccaaca ccaaggtgga caagaaggtg 720
gagcccaagt cctgtgacaa gacccacacc tgtcctccct gtcctgctcc tgagctgctg 780
ggaggcccct ccgtcttcct gttccctccc aagcccaagg acaccctgat gatctccagg 840
acccctgaag tgacatgtgt ggtggtggat gtgagccacg aagatcccga ggtgaagttc 900
aactggtacg tggacggcgt ggaggtgcac aacgctaaaa caaagccctg cgaggagcag 960
tacggatcca cctacaggtg cgtgtccgtg ctcaccgtgc tccatcagga ctggctgaac 1020
ggaaaagagt acaagtgcaa agtcagcaat aaggccctgc ccgcccctat cgagaaaacc 1080
atcagcaagg ccaaaggcca gcccagggag cctcaggtgt ataccctgcc tccctccagg 1140
gaggagatga ccaagaacca ggtgagcctg acctgcctcg tgaagggctt ttatccctcc 1200
gacatcgctg tggagtggga gagcaatggc cagcctgaaa acaactacaa aaccaccccc 1260
cctgtgctgg atagcgacgg cagcttcttc ctctactcca agctgaccgt cgataagtcc 1320
cggtggcagc agggcaacgt gtttagctgc agcgtgatgc acgaagccct gcataaccac 1380
tacacccaga agagcctgag cctcagcccc ggaaag 1416
<210> 160
<211> 472
<212> PRT
<213> Homo sapiens
<400> 160
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Asn Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Glu Gly Leu Glu Trp Val Ala Ala Ile Trp Phe Asp Ala Ser Asp Lys
65 70 75 80
Tyr Tyr Ala Asp Ala Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gln Ala Ile Phe Gly Val Val
115 120 125
Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
130 135 140
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
145 150 155 160
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
195 200 205
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
210 215 220
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
225 230 235 240
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
245 250 255
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
260 265 270
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
275 280 285
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
290 295 300
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
305 310 315 320
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
325 330 335
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
340 345 350
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
355 360 365
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
370 375 380
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
385 390 395 400
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
405 410 415
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
420 425 430
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
435 440 445
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
450 455 460
Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 161
<211> 702
<212> DNA
<213> Homo sapiens
<400> 161
atggagaccc ctgcccagct gctgttcctg ctgctgctgt ggctgcccga cacaaccggc 60
gaaatcgtcc tgacacagag ccctgccaca ctgtccctga gccctggaga gagggctacc 120
ctgagctgca gggcttccca gagcgtgagc agcaacctgg cctggtacca acagaagcct 180
ggccaggccc ctaggctgct gatctacggc gctgctacca gggccaccgg tattcctgac 240
agggtgtccg gctccggatc cggcaccgag tttaccctga ccatcagccg cctggagccc 300
gaggacttcg ccgtgtacta ctgtcagcaa tacaacaact ggcccctgac ctttggcggc 360
ggcaccaagg tggagatcaa gaggacagtg gccgccccca gcgtgttcat cttccctccc 420
agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gtctgctgaa caacttctac 480
cccagggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagtccgg caactcccag 540
gagtccgtga ccgagcagga ctccaaggac tccacctact ccctgtcctc caccctgacc 600
ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc 660
ctgtcctccc ctgtgaccaa gagcttcaac aggggcgagt gc 702
<210> 162
<211> 234
<212> PRT
<213> Homo sapiens
<400> 162
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Ser Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
50 55 60
Arg Leu Leu Ile Tyr Gly Ala Ala Thr Arg Ala Thr Gly Ile Pro Asp
65 70 75 80
Arg Val Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
85 90 95
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn
100 105 110
Asn Trp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 163
<211> 1416
<212> DNA
<213> Homo sapiens
<400> 163
atggatatgc gggtccctgc tcagctgctg ggactgctgc tgctgtggct gaggggcgcc 60
aggtgtgagg tgcagctggt cgaaagcgga ggaggagtgg tgcagcccgg agggtccctg 120
aggctgtcct gcgccgctag cggcttcacc ttttccaact acggcatgca ctgggtgagg 180
caagcccctg gagagggcct ggaatgggtg gctgctatct ggttcgacgc cagcgacaag 240
tactatgccg acgctgtgaa gggccggttc accatcagca gggacaacgc caagaacacc 300
ctctacctgc agatgaacag cctccgggcc gaggacaccg ctgtctatta ctgtgccagg 360
gaccaggcca tcttcggagt ggtccccgat tactggggcc agggaaccct ggtgaccgtg 420
tcctccgctt ccacaaaggg acctagcgtg ttccctctgg cccctagcag caagtccaca 480
agcggaggaa cagccgccct gggctgtctc gtgaaggact attttcccga gcccgtgacc 540
gtgtcctgga actccggagc cctgacctcc ggcgtgcata cattccccgc tgtcctgcag 600
tccagcggcc tctactccct gtcctccgtg gtcaccgtgc ctagcagcag cctgggcacc 660
cagacataca tctgcaacgt caaccacaag ccttccaaca ccaaggtgga caagaaggtg 720
gagcccaagt cctgtgacaa gacccacacc tgtcctccct gtcctgctcc tgagctgctg 780
ggaggcccct ccgtcttcct gttccctccc aagcccaagg acaccctgat gatctccagg 840
acccctgaag tgacatgtgt ggtggtggat gtgagccacg aagatcccga ggtgaagttc 900
aactggtacg tggacggcgt ggaggtgcac aacgctaaaa caaagccctg cgaggagcag 960
tacggatcca cctacaggtg cgtgtccgtg ctcaccgtgc tccatcagga ctggctgaac 1020
ggaaaagagt acaagtgcaa agtcagcaat aaggccctgc ccgcccctat cgagaaaacc 1080
atcagcaagg ccaaaggcca gcccagggag cctcaggtgt ataccctgcc tccctccagg 1140
gaggagatga ccaagaacca ggtgagcctg acctgcctcg tgaagggctt ttatccctcc 1200
gacatcgctg tggagtggga gagcaatggc cagcctgaaa acaactacaa aaccaccccc 1260
cctgtgctgg atagcgacgg cagcttcttc ctctactcca agctgaccgt cgataagtcc 1320
cggtggcagc agggcaacgt gtttagctgc agcgtgatgc acgaagccct gcataaccac 1380
tacacccaga agagcctgag cctcagcccc ggaaag 1416
<210> 164
<211> 472
<212> PRT
<213> Homo sapiens
<400> 164
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Asn Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly
50 55 60
Glu Gly Leu Glu Trp Val Ala Ala Ile Trp Phe Asp Ala Ser Asp Lys
65 70 75 80
Tyr Tyr Ala Asp Ala Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gln Ala Ile Phe Gly Val Val
115 120 125
Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
130 135 140
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
145 150 155 160
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
195 200 205
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
210 215 220
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
225 230 235 240
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
245 250 255
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
260 265 270
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
275 280 285
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
290 295 300
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
305 310 315 320
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
325 330 335
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
340 345 350
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
355 360 365
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
370 375 380
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
385 390 395 400
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
405 410 415
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
420 425 430
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
435 440 445
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
450 455 460
Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 165
<211> 717
<212> DNA
<213> Homo sapiens
<400> 165
atgaggctcc ctgctcagct cctggggctg ctaatgctct gggtccctgg atccagtggg 60
gatattgtga tgacccagac tccactctcc tcacctgtca cccttggaca gccggcctcc 120
atctcctgca ggtctagtca aagcctcgta cacagtgatg gaaacaccta cttgaattgg 180
cttcagcaga ggccaggcca gcctccaaga ctcctaattt ataagatttc taaccggttc 240
tctggggtcc cagacagatt cactggcagt ggggcaggga cagatttcac actgaaaatc 300
agcagggtgg aagctgagga tgtcggggtt tatacctgca tgcaagttac acaatttcct 360
ctcaccttcg gccaagggac acgactggag attaaacgaa ctgtggctgc accatctgtc 420
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 480
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 540
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 600
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 660
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 717
<210> 166
<211> 239
<212> PRT
<213> Homo sapiens
<400> 166
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp Val Pro
1 5 10 15
Gly Ser Ser Gly Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser Pro
20 25 30
Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
35 40 45
Leu Val His Ser Asp Gly Asn Thr Tyr Leu Asn Trp Leu Gln Gln Arg
50 55 60
Pro Gly Gln Pro Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ala Gly Thr Asp Phe
85 90 95
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Thr
100 105 110
Cys Met Gln Val Thr Gln Phe Pro Leu Thr Phe Gly Gln Gly Thr Arg
115 120 125
Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
130 135 140
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
145 150 155 160
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
165 170 175
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
180 185 190
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
195 200 205
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
210 215 220
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 167
<211> 1410
<212> DNA
<213> Homo sapiens
<400> 167
atggacacac tttgctacac actcctgctg ctgaccaccc cttcctgggt cttgtcccag 60
gtcaccttga aggagtctgg tcctgtgctg ctgaaaccca cagagaccct cacgctgacc 120
tgcaccgtct ctgggttctc actcagcaat gctagaatgg gtgtgagctg gatccgtcag 180
cccccaggga aggccctgga gtggcttgca cacatttttt cgaatgacga aaaatcctac 240
atcacatctc tgaagagcag gctcaccatc tccaaggaca cctccaaaag ccaggtggtc 300
cttaccatga ccaacatgga ccctgtggac acagccacat attactgtgc acggataccc 360
ctacgatccc cgggtgcttt tgatatctgg ggccaaggga caatggtcac cgtctcttca 420
gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 480
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 600
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 660
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 720
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 780
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 840
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 900
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 960
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 1020
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1080
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1140
atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1200
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1260
ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 1320
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1380
cagaagagcc tctcactgtc tccgggtaaa 1410
<210> 168
<211> 470
<212> PRT
<213> Homo sapiens
<400> 168
Met Asp Thr Leu Cys Tyr Thr Leu Leu Leu Leu Thr Thr Pro Ser Trp
1 5 10 15
Val Leu Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Leu Lys
20 25 30
Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu
35 40 45
Ser Asn Ala Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys
50 55 60
Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr
65 70 75 80
Ile Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys
85 90 95
Ser Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala
100 105 110
Thr Tyr Tyr Cys Ala Arg Ile Pro Leu Arg Ser Pro Gly Ala Phe Asp
115 120 125
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
145 150 155 160
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
210 215 220
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro
225 230 235 240
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
<210> 169
<211> 705
<212> DNA
<213> Homo sapiens
<400> 169
atggaaaccc cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120
ctctcctgta gggccagtca gagtgttcgc ggcaggtact tagcctggta ccagcagaaa 180
cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 240
gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 300
cctgaagatt ttgcagtgtt ttactgtcag cagtatggta gttcacctcg gacgttcggc 360
caagggacca aggtggaaat caaacgaact gtggctgcac catctgtctt catcttcccg 420
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 705
<210> 170
<211> 235
<212> PRT
<213> Homo sapiens
<400> 170
Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15
Asp Thr Thr Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
20 25 30
Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
35 40 45
Val Arg Gly Arg Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Phe Tyr Cys Gln Gln Tyr
100 105 110
Gly Ser Ser Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 171
<211> 1401
<212> DNA
<213> Homo sapiens
<400> 171
atggagtttg ggctgagctg gctttttctt gtggctattt taaaaggtgt ccagtgtgag 60
gtgcagctgt tggagtctgg gggaggcttg gtacagcctg gggggtccct gagactctcc 120
tgtgcagcct ctggattcac ctttagcagc tatgccatga gctgggtccg ccaggctcca 180
gggaaggggc tggagtgggt ctcaggtatt actgggagtg gtggtagtac atactacgca 240
gactccgtga agggccggtt caccatctcc agagacaatt ccaagaacac gctgtatctg 300
caaatgaaca gcctgagagc cgaggacacg gccgtatatt actgtgcgaa agatccaggg 360
actacggtga ttatgagttg gttcgacccc tggggccagg gaaccctggt caccgtctcc 420
tcagcctcca ccaagggccc atcggtcttc cccctggcgc cctgctccag gagcacctcc 480
gagagcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 540
tcgtggaact caggcgctct gaccagcggc gtgcacacct tcccagctgt cctacagtcc 600
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcaactt cggcacccag 660
acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gacagttgag 720
cgcaaatgtt gtgtcgagtg cccaccgtgc ccagcaccac ctgtggcagg accgtcagtc 780
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcacg 840
tgcgtggtgg tggacgtgag ccacgaagac cccgaggtcc agttcaactg gtacgtggac 900
ggcgtggagg tgcataatgc caagacaaag ccacgggagg agcagttcaa cagcacgttc 960
cgtgtggtca gcgtcctcac cgttgtgcac caggactggc tgaacggcaa ggagtacaag 1020
tgcaaggtct ccaacaaagg cctcccagcc cccatcgaga aaaccatctc caaaaccaaa 1080
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1140
aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1200
tgggagagca atgggcagcc ggagaacaac tacaagacca cacctcccat gctggactcc 1260
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1320
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1380
ctctccctgt ctccgggtaa a 1401
<210> 172
<211> 467
<212> PRT
<213> Homo sapiens
<400> 172
Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ser Gly Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Lys Asp Pro Gly Thr Thr Val Ile Met Ser Trp Phe
115 120 125
Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
145 150 155 160
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys
210 215 220
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu
225 230 235 240
Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 173
<211> 714
<212> DNA
<213> Homo sapiens
<400> 173
atggtgttgc agacccaggt cttcatttct ctgttgctct ggatctctgg tgcctacggg 60
gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 120
atcaactgca gagccagtga aagtgttgat atttatggca atagttttat gcactggtac 180
cagcagaaac caggacagcc tcctaagctg ctcatttacc ttgcatccaa cctagaatct 240
ggggtccctg accgattcag tggcagcggg tctgggacag atttcactct caccatcagc 300
agcctgcagg ctgaagatgt ggcagtttat tactgtcagc aaaataatga ggatccgtac 360
acgttcggag gtgggaccaa ggtggaaata aaacgtacgg tggctgcacc atctgtcttc 420
atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 480
aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 540
ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 600
agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 660
acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgt 714
<210> 174
<211> 238
<212> PRT
<213> Homo sapiens
<400> 174
Met Val Leu Gln Thr Gln Val Phe Ile Ser Leu Leu Leu Trp Ile Ser
1 5 10 15
Gly Ala Tyr Gly Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala
20 25 30
Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Ile Tyr Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys
100 105 110
Gln Gln Asn Asn Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val
115 120 125
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
130 135 140
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
165 170 175
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
195 200 205
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
210 215 220
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 175
<211> 1398
<212> DNA
<213> Homo sapiens
<400> 175
atggactgga cctggagggt cttctgcttg ctggcagtgg ccccaggtgc ccactcccag 60
gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg gggcctcagt gaaggtctcc 120
tgcaaggctt ctggatacac cttcaccagt tacaatatgc actgggtgcg ccaggcccct 180
ggacaagggc ttgagtggat gggagttatt tattcaggaa atggtgatac ttcctacaat 240
cagaagttca aaggcagggt caccattacc gctgacaaat ccaccagcac agcctacatg 300
gagctgagca gcctgagatc tgaggacacg gccgtgtatt actgtgcgag agagagggat 360
actcgttttg gtaactgggg ccaagggact ctggtcaccg tctctagtgc ctccaccaag 420
ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 480
ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 540
gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 600
ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 660
gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 720
aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 780
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 840
gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 900
gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtaccagag cacgtaccgt 960
gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 1020
aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1080
cagccccgag aaccacaggt gtacaccctg cccccatccc gggatgagct gaccaagaac 1140
caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1200
gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1260
ggctccttct tcctctatag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1320
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1380
tccctgtctc cgggtaaa 1398
<210> 176
<211> 466
<212> PRT
<213> Homo sapiens
<400> 176
Met Asp Trp Thr Trp Arg Val Phe Cys Leu Leu Ala Val Ala Pro Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Val Ile Tyr Ser Gly Asn Gly Asp Thr Ser Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Arg Asp Thr Arg Phe Gly Asn Trp Gly Gln
115 120 125
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
130 135 140
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
145 150 155 160
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
165 170 175
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
180 185 190
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
195 200 205
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
210 215 220
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
225 230 235 240
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Ser Thr Tyr Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Lys
465
<210> 177
<211> 705
<212> DNA
<213> Homo sapiens
<400> 177
atggcctggg ctctgctgct cctcactctc ctcactcagg acacagggtc ctgggcccag 60
tctgtgctga ctcagtcacc ctcagcgtct gggacccccg ggcagagagt caccatctct 120
tgttctggaa gcagctccaa catcggcagt aattatgtat actggtacca gcagctccca 180
ggagcggccc ccaaactcct catccttagg aataatcagc ggccctcagg ggtccctgac 240
cgattctctg gctccaagtc tggcacctca gcctccctga ccatcagtgg gctccggtcc 300
gaggatgagg ctgactatta ttgtgcagca tgggatgaca gcctgagtgg ttgggtgttc 360
ggcggaggga ccaagctgac cgtcctaggt cagcccaagg ccaaccccac tgtcactctg 420
ttcccgccct cctctgagga gctccaagcc aacaaggcca cactagtgtg tctgatcagt 480
gacttctacc cgggagctgt gacagtggcc tggaaggcag atggcagccc cgtcaaggcg 540
ggagtggaga ccaccaaacc ctccaaacag agcaacaaca agtacgcggc cagcagctac 600
ctgagcctga cgcccgagca gtggaagtcc cacagaagct acagctgcca ggtcacgcat 660
gaagggagca ccgtggagaa gacagtggcc cctacagaat gttca 705
<210> 178
<211> 235
<212> PRT
<213> Homo sapiens
<400> 178
Met Ala Trp Ala Leu Leu Leu Leu Thr Leu Leu Thr Gln Asp Thr Gly
1 5 10 15
Ser Trp Ala Gln Ser Val Leu Thr Gln Ser Pro Ser Ala Ser Gly Thr
20 25 30
Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile
35 40 45
Gly Ser Asn Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro
50 55 60
Lys Leu Leu Ile Leu Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Thr Ile Ser
85 90 95
Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp
100 105 110
Asp Ser Leu Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
115 120 125
Leu Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser
130 135 140
Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser
145 150 155 160
Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser
165 170 175
Pro Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn
180 185 190
Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp
195 200 205
Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr
210 215 220
Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
225 230 235
<210> 179
<211> 1437
<212> DNA
<213> Homo sapiens
<400> 179
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60
cgctgtgagg tgcagctggt ggagtctggg ggaggcttgg taaagcctgg ggggtccctt 120
agactctcct gtgcagcctc tggattcact ttcagtaacg cctggatgag ctgggtccgc 180
caggctccag ggaaggggct ggagtgggtt ggccgtatta aaagcaaaac tgatggtggg 240
acaacagact acactgcacc cgtgaaaggc agattcacca tctcaagaga tgattcaaaa 300
aacacgctgt atctgcaaat gaatagcctg aaagccgagg acacagccgt gtattactgt 360
accacagatc ggaccgggta tagcatcagc tggtctagtt actactacta ctacggtatg 420
gacgtctggg gccaagggac cacggtcacc gtctctagtg cctccaccaa gggcccatcg 480
gtcttccccc tggcgccctg ctccaggagc acctccgaga gcacagcggc cctgggctgc 540
ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgctctgacc 600
agcggcgtgc acaccttccc agctgtccta cagtcctcag gactctactc cctcagcagc 660
gtggtgaccg tgccctccag caacttcggc acccagacct acacctgcaa cgtagatcac 720
aagcccagca acaccaaggt ggacaagaca gttgagcgca aatgttgtgt cgagtgccca 780
ccgtgcccag caccacctgt ggcaggaccg tcagtcttcc tcttcccccc aaaacccaag 840
gacaccctca tgatctcccg gacccctgag gtcacgtgcg tggtggtgga cgtgagccac 900
gaagaccccg aggtccagtt caactggtac gtggacggcg tggaggtgca taatgccaag 960
acaaagccac gggaggagca gttcaacagc acgttccgtg tggtcagcgt cctcaccgtt 1020
gtgcaccagg actggctgaa cggcaaggag tacaagtgca aggtctccaa caaaggcctc 1080
ccagccccca tcgagaaaac catctccaaa accaaagggc agccccgaga accacaggtg 1140
tacaccctgc ccccatcccg ggaggagatg accaagaacc aggtcagcct gacctgcctg 1200
gtcaaaggct tctaccccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1260
aacaactaca agaccacacc tcccatgctg gactccgacg gctccttctt cctctacagc 1320
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1380
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 1437
<210> 180
<211> 479
<212> PRT
<213> Homo sapiens
<400> 180
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Asn Ala Trp Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly
65 70 75 80
Thr Thr Asp Tyr Thr Ala Pro Val Lys Gly Arg Phe Thr Ile Ser Arg
85 90 95
Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Ala
100 105 110
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Thr Asp Arg Thr Gly Tyr Ser
115 120 125
Ile Ser Trp Ser Ser Tyr Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly
130 135 140
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
145 150 155 160
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
165 170 175
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
180 185 190
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
195 200 205
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
210 215 220
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
225 230 235 240
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
245 250 255
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
260 265 270
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
275 280 285
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
290 295 300
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
305 310 315 320
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
325 330 335
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
340 345 350
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
355 360 365
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
370 375 380
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
385 390 395 400
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
405 410 415
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
420 425 430
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
435 440 445
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
450 455 460
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 181
<211> 23
<212> PRT
<213> Homo sapiens
<400> 181
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys
20
<210> 182
<211> 15
<212> PRT
<213> Homo sapiens
<400> 182
Trp Tyr Arg Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
1 5 10 15
<210> 183
<211> 32
<212> PRT
<213> Homo sapiens
<400> 183
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys
20 25 30
<210> 184
<211> 10
<212> PRT
<213> Homo sapiens
<400> 184
Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
1 5 10
<210> 185
<211> 23
<212> PRT
<213> Homo sapiens
<400> 185
Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
1 5 10 15
Glu Lys Val Thr Ile Thr Cys
20
<210> 186
<211> 15
<212> PRT
<213> Homo sapiens
<400> 186
Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile Lys
1 5 10 15
<210> 187
<211> 32
<212> PRT
<213> Homo sapiens
<400> 187
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Asn Ser Leu Glu Ala Glu Asp Ala Ala Ala Tyr Tyr Cys
20 25 30
<210> 188
<211> 10
<212> PRT
<213> Homo sapiens
<400> 188
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 189
<211> 23
<212> PRT
<213> Homo sapiens
<400> 189
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys
20
<210> 190
<211> 15
<212> PRT
<213> Homo sapiens
<400> 190
Trp Leu Gln Gln Arg Pro Gly Gln Pro Pro Arg Leu Leu Ile Tyr
1 5 10 15
<210> 191
<211> 32
<212> PRT
<213> Homo sapiens
<400> 191
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ala Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Thr Cys
20 25 30
<210> 192
<211> 10
<212> PRT
<213> Homo sapiens
<400> 192
Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
1 5 10
<210> 193
<211> 23
<212> PRT
<213> Homo sapiens
<400> 193
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys
20
<210> 194
<211> 15
<212> PRT
<213> Homo sapiens
<400> 194
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
1 5 10 15
<210> 195
<211> 32
<212> PRT
<213> Homo sapiens
<400> 195
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Phe Tyr Cys
20 25 30
<210> 196
<211> 10
<212> PRT
<213> Homo sapiens
<400> 196
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 197
<211> 23
<212> PRT
<213> Homo sapiens
<400> 197
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Asp Arg Ala Thr Leu Ser Cys
20
<210> 198
<211> 32
<212> PRT
<213> Homo sapiens
<400> 198
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
20 25 30
<210> 199
<211> 15
<212> PRT
<213> Homo sapiens
<400> 199
Trp His Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
1 5 10 15
<210> 200
<211> 15
<212> PRT
<213> Homo sapiens
<400> 200
Trp His Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
1 5 10 15
<210> 201
<211> 32
<212> PRT
<213> Homo sapiens
<400> 201
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Val Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
20 25 30
<210> 202
<211> 15
<212> PRT
<213> Homo sapiens
<400> 202
Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
1 5 10 15
<210> 203
<211> 32
<212> PRT
<213> Homo sapiens
<400> 203
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Phe Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
20 25 30
<210> 204
<211> 10
<212> PRT
<213> Homo sapiens
<400> 204
Phe Gly Gln Gly Thr Thr Val Glu Ile Lys
1 5 10
<210> 205
<211> 23
<212> PRT
<213> Homo sapiens
<400> 205
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys
20
<210> 206
<211> 15
<212> PRT
<213> Homo sapiens
<400> 206
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 207
<211> 32
<212> PRT
<213> Homo sapiens
<400> 207
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25 30
<210> 208
<211> 23
<212> PRT
<213> Homo sapiens
<400> 208
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys
20
<210> 209
<211> 32
<212> PRT
<213> Homo sapiens
<400> 209
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Asn Tyr Tyr Cys
20 25 30
<210> 210
<211> 23
<212> PRT
<213> Homo sapiens
<400> 210
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys
20
<210> 211
<211> 15
<212> PRT
<213> Homo sapiens
<400> 211
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 212
<211> 32
<212> PRT
<213> Homo sapiens
<400> 212
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys
20 25 30
<210> 213
<211> 32
<212> PRT
<213> Homo sapiens
<400> 213
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys
20 25 30
<210> 214
<211> 10
<212> PRT
<213> Homo sapiens
<400> 214
Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
1 5 10
<210> 215
<211> 23
<212> PRT
<213> Homo sapiens
<400> 215
Asp Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys
20
<210> 216
<211> 32
<212> PRT
<213> Homo sapiens
<400> 216
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Val Tyr Tyr Cys
20 25 30
<210> 217
<211> 10
<212> PRT
<213> Homo sapiens
<400> 217
Phe Gly Gln Gly Thr Arg Val Glu Ile Lys
1 5 10
<210> 218
<211> 23
<212> PRT
<213> Homo sapiens
<400> 218
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Ser Cys
20
<210> 219
<211> 32
<212> PRT
<213> Homo sapiens
<400> 219
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
20 25 30
<210> 220
<211> 10
<212> PRT
<213> Homo sapiens
<400> 220
Phe Gly Gly Gly Thr Lys Val Gln Ile Lys
1 5 10
<210> 221
<211> 32
<212> PRT
<213> Homo sapiens
<400> 221
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys
20 25 30
<210> 222
<211> 15
<212> PRT
<213> Homo sapiens
<400> 222
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr
1 5 10 15
<210> 223
<211> 32
<212> PRT
<213> Homo sapiens
<400> 223
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Val Gln Pro Glu Asp Phe Val Thr Tyr Tyr Cys
20 25 30
<210> 224
<211> 23
<212> PRT
<213> Homo sapiens
<400> 224
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys
20
<210> 225
<211> 15
<212> PRT
<213> Homo sapiens
<400> 225
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr
1 5 10 15
<210> 226
<211> 32
<212> PRT
<213> Homo sapiens
<400> 226
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys
20 25 30
<210> 227
<211> 23
<212> PRT
<213> Homo sapiens
<400> 227
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys
20
<210> 228
<211> 32
<212> PRT
<213> Homo sapiens
<400> 228
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr His Leu Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys
20 25 30
<210> 229
<211> 15
<212> PRT
<213> Homo sapiens
<400> 229
Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile Tyr
1 5 10 15
<210> 230
<211> 10
<212> PRT
<213> Homo sapiens
<400> 230
Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser
1 5 10
<210> 231
<211> 10
<212> PRT
<213> Homo sapiens
<400> 231
Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 232
<211> 15
<212> PRT
<213> Homo sapiens
<400> 232
Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile Tyr
1 5 10 15
<210> 233
<211> 32
<212> PRT
<213> Homo sapiens
<400> 233
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys
20 25 30
<210> 234
<211> 32
<212> PRT
<213> Homo sapiens
<400> 234
Gly Ile Pro Ala Arg Val Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys
20 25 30
<210> 235
<211> 23
<212> PRT
<213> Homo sapiens
<400> 235
Asp Val Leu Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys
20
<210> 236
<211> 15
<212> PRT
<213> Homo sapiens
<400> 236
Trp Tyr Leu Gln Arg Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 237
<211> 10
<212> PRT
<213> Homo sapiens
<400> 237
Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 238
<211> 23
<212> PRT
<213> Homo sapiens
<400> 238
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys
20
<210> 239
<211> 32
<212> PRT
<213> Homo sapiens
<400> 239
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
20 25 30
<210> 240
<211> 23
<212> PRT
<213> Homo sapiens
<400> 240
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys
20
<210> 241
<211> 15
<212> PRT
<213> Homo sapiens
<400> 241
Trp Tyr Leu Gln Lys Pro Gly Gln Pro Pro Gln Phe Leu Ile Tyr
1 5 10 15
<210> 242
<211> 32
<212> PRT
<213> Homo sapiens
<400> 242
Arg Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys
20 25 30
<210> 243
<211> 10
<212> PRT
<213> Homo sapiens
<400> 243
Phe Gly Gln Gly Thr Gln Val Glu Ile Lys
1 5 10
<210> 244
<211> 32
<212> PRT
<213> Homo sapiens
<400> 244
Gly Ile Pro Asp Arg Val Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
1 5 10 15
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
20 25 30
<210> 245
<211> 15
<212> PRT
<213> Homo sapiens
<400> 245
Trp Tyr Gln Gln Lys Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 246
<211> 23
<212> PRT
<213> Homo sapiens
<400> 246
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys
20
<210> 247
<211> 22
<212> PRT
<213> Homo sapiens
<400> 247
Glu Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys
20
<210> 248
<211> 15
<212> PRT
<213> Homo sapiens
<400> 248
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr
1 5 10 15
<210> 249
<211> 32
<212> PRT
<213> Homo sapiens
<400> 249
Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser
1 5 10 15
Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 250
<211> 10
<212> PRT
<213> Homo sapiens
<400> 250
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
1 5 10
<210> 251
<211> 22
<212> PRT
<213> Homo sapiens
<400> 251
Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln
1 5 10 15
Thr Ala Arg Ile Thr Cys
20
<210> 252
<211> 15
<212> PRT
<213> Homo sapiens
<400> 252
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr
1 5 10 15
<210> 253
<211> 32
<212> PRT
<213> Homo sapiens
<400> 253
Trp Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr
1 5 10 15
Leu Thr Ile Ser Arg Gly Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 254
<211> 22
<212> PRT
<213> Homo sapiens
<400> 254
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Lys Val Thr Ile Ser Cys
20
<210> 255
<211> 15
<212> PRT
<213> Homo sapiens
<400> 255
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 256
<211> 32
<212> PRT
<213> Homo sapiens
<400> 256
Gly Ile Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Thr Thr
1 5 10 15
Leu Gly Ile Thr Gly Leu Gln Thr Gly Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 257
<211> 22
<212> PRT
<213> Homo sapiens
<400> 257
Gln Ser Val Leu Thr Gln Ser Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys
20
<210> 258
<211> 15
<212> PRT
<213> Homo sapiens
<400> 258
Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu Ile Leu
1 5 10 15
<210> 259
<211> 32
<212> PRT
<213> Homo sapiens
<400> 259
Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser
1 5 10 15
Leu Thr Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 260
<211> 22
<212> PRT
<213> Homo sapiens
<400> 260
Ser Tyr Glu Val Thr Gln Ala Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys
20
<210> 261
<211> 15
<212> PRT
<213> Homo sapiens
<400> 261
Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr
1 5 10 15
<210> 262
<211> 32
<212> PRT
<213> Homo sapiens
<400> 262
Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr
1 5 10 15
Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 263
<211> 22
<212> PRT
<213> Homo sapiens
<400> 263
Cys Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Thr Ile Thr Cys
20
<210> 264
<211> 15
<212> PRT
<213> Homo sapiens
<400> 264
Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Val Leu Val Ile Tyr
1 5 10 15
<210> 265
<211> 32
<212> PRT
<213> Homo sapiens
<400> 265
Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr
1 5 10 15
Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Phe Cys
20 25 30
<210> 266
<211> 22
<212> PRT
<213> Homo sapiens
<400> 266
Ser Ser Glu Leu Thr Gln Asp Pro Thr Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Lys Ile Thr Cys
20
<210> 267
<211> 15
<212> PRT
<213> Homo sapiens
<400> 267
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Phe Tyr
1 5 10 15
<210> 268
<211> 32
<212> PRT
<213> Homo sapiens
<400> 268
Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser
1 5 10 15
Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 269
<211> 10
<212> PRT
<213> Homo sapiens
<400> 269
Leu Gly Gly Gly Thr Lys Leu Thr Val Leu
1 5 10
<210> 270
<211> 22
<212> PRT
<213> Homo sapiens
<400> 270
Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys
1 5 10 15
Thr Val Ala Ile Ser Cys
20
<210> 271
<211> 15
<212> PRT
<213> Homo sapiens
<400> 271
Trp Tyr Gln Gln Arg Pro Gly Ser Ser Pro Thr Thr Val Ile Phe
1 5 10 15
<210> 272
<211> 34
<212> PRT
<213> Homo sapiens
<400> 272
Gly Val Pro Asp Arg Phe Ser Gly Ser Ile Asp Ser Ser Ser Asn Ser
1 5 10 15
Ala Ser Leu Thr Ile Ser Gly Leu Lys Thr Glu Asp Glu Ala Asp Tyr
20 25 30
Tyr Cys
<210> 273
<211> 30
<212> PRT
<213> Homo sapiens
<400> 273
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
20 25 30
<210> 274
<211> 14
<212> PRT
<213> Homo sapiens
<400> 274
Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 275
<211> 32
<212> PRT
<213> Homo sapiens
<400> 275
Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys
1 5 10 15
Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 276
<211> 11
<212> PRT
<213> Homo sapiens
<400> 276
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 277
<211> 30
<212> PRT
<213> Homo sapiens
<400> 277
Glu Val Gln Leu Met Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser
20 25 30
<210> 278
<211> 14
<212> PRT
<213> Homo sapiens
<400> 278
Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met Gly
1 5 10
<210> 279
<211> 32
<212> PRT
<213> Homo sapiens
<400> 279
Gln Val Thr Ile Ser Ala Asp Asn Ser Asn Ser Ala Thr Tyr Leu Gln
1 5 10 15
Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Phe Cys Ala Arg
20 25 30
<210> 280
<211> 30
<212> PRT
<213> Homo sapiens
<400> 280
Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Leu Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser
20 25 30
<210> 281
<211> 14
<212> PRT
<213> Homo sapiens
<400> 281
Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu Ala
1 5 10
<210> 282
<211> 32
<212> PRT
<213> Homo sapiens
<400> 282
Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Ser Gln Val Val Leu Thr
1 5 10 15
Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg
20 25 30
<210> 283
<211> 11
<212> PRT
<213> Homo sapiens
<400> 283
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
1 5 10
<210> 284
<211> 30
<212> PRT
<213> Homo sapiens
<400> 284
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Leu Thr
20 25 30
<210> 285
<211> 14
<212> PRT
<213> Homo sapiens
<400> 285
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 286
<211> 32
<212> PRT
<213> Homo sapiens
<400> 286
Arg Gly Thr Met Thr Thr Asp Pro Ser Thr Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 287
<211> 11
<212> PRT
<213> Homo sapiens
<400> 287
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 288
<211> 30
<212> PRT
<213> Homo sapiens
<400> 288
Gln Met Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg
20 25 30
<210> 289
<211> 14
<212> PRT
<213> Homo sapiens
<400> 289
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala
1 5 10
<210> 290
<211> 32
<212> PRT
<213> Homo sapiens
<400> 290
Arg Phe Thr Ile Thr Arg Asp Asn Ser Lys Asn Thr Leu Asn Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 291
<211> 30
<212> PRT
<213> Homo sapiens
<400> 291
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
20 25 30
<210> 292
<211> 14
<212> PRT
<213> Homo sapiens
<400> 292
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
1 5 10
<210> 293
<211> 32
<212> PRT
<213> Homo sapiens
<400> 293
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys
20 25 30
<210> 294
<211> 30
<212> PRT
<213> Homo sapiens
<400> 294
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr
20 25 30
<210> 295
<211> 32
<212> PRT
<213> Homo sapiens
<400> 295
Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 296
<211> 30
<212> PRT
<213> Homo sapiens
<400> 296
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Ser
20 25 30
<210> 297
<211> 14
<212> PRT
<213> Homo sapiens
<400> 297
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly
1 5 10
<210> 298
<211> 32
<212> PRT
<213> Homo sapiens
<400> 298
Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Thr
20 25 30
<210> 299
<211> 30
<212> PRT
<213> Homo sapiens
<400> 299
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 300
<211> 30
<212> PRT
<213> Homo sapiens
<400> 300
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ser Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 301
<211> 32
<212> PRT
<213> Homo sapiens
<400> 301
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 302
<211> 30
<212> PRT
<213> Homo sapiens
<400> 302
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
20 25 30
<210> 303
<211> 33
<212> PRT
<213> Homo sapiens
<400> 303
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
Gly
<210> 304
<211> 30
<212> PRT
<213> Homo sapiens
<400> 304
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
20 25 30
<210> 305
<211> 32
<212> PRT
<213> Homo sapiens
<400> 305
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 306
<211> 32
<212> PRT
<213> Homo sapiens
<400> 306
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 307
<211> 30
<212> PRT
<213> Homo sapiens
<400> 307
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 308
<211> 14
<212> PRT
<213> Homo sapiens
<400> 308
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 309
<211> 32
<212> PRT
<213> Homo sapiens
<400> 309
Lys Ala Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Phe Cys Ala Arg
20 25 30
<210> 310
<211> 32
<212> PRT
<213> Homo sapiens
<400> 310
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Arg Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 311
<211> 30
<212> PRT
<213> Homo sapiens
<400> 311
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser
20 25 30
<210> 312
<211> 14
<212> PRT
<213> Homo sapiens
<400> 312
Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 313
<211> 32
<212> PRT
<213> Homo sapiens
<400> 313
Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser Leu Lys
1 5 10 15
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 314
<211> 32
<212> PRT
<213> Homo sapiens
<400> 314
Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 315
<211> 32
<212> PRT
<213> Homo sapiens
<400> 315
Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ser Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 316
<211> 30
<212> PRT
<213> Homo sapiens
<400> 316
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
20 25 30
<210> 317
<211> 14
<212> PRT
<213> Homo sapiens
<400> 317
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly
1 5 10
<210> 318
<211> 32
<212> PRT
<213> Homo sapiens
<400> 318
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys Thr Thr
20 25 30
<210> 319
<211> 30
<212> PRT
<213> Homo sapiens
<400> 319
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
20 25 30
<210> 320
<211> 14
<212> PRT
<213> Homo sapiens
<400> 320
Trp Ile Arg Gln Leu Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 321
<211> 32
<212> PRT
<213> Homo sapiens
<400> 321
Arg Val Thr Ile Ser Val Asp Thr Ser Lys Lys Gln Phe Ser Leu Arg
1 5 10 15
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 322
<211> 30
<212> PRT
<213> Homo sapiens
<400> 322
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr
20 25 30
<210> 323
<211> 14
<212> PRT
<213> Homo sapiens
<400> 323
Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met Gly
1 5 10
<210> 324
<211> 32
<212> PRT
<213> Homo sapiens
<400> 324
Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln
1 5 10 15
Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg
20 25 30
<210> 325
<211> 32
<212> PRT
<213> Homo sapiens
<400> 325
Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys Ala Arg
20 25 30
<210> 326
<211> 30
<212> PRT
<213> Homo sapiens
<400> 326
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
20 25 30
<210> 327
<211> 30
<212> PRT
<213> Homo sapiens
<400> 327
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 328
<211> 32
<212> PRT
<213> Homo sapiens
<400> 328
Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 329
<211> 30
<212> PRT
<213> Homo sapiens
<400> 329
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe Thr
20 25 30
<210> 330
<211> 14
<212> PRT
<213> Homo sapiens
<400> 330
Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Leu Met Gly
1 5 10
<210> 331
<211> 32
<212> PRT
<213> Homo sapiens
<400> 331
Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln
1 5 10 15
Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Gly Ser
20 25 30
<210> 332
<211> 11
<212> PRT
<213> Homo sapiens
<400> 332
Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 333
<211> 30
<212> PRT
<213> Homo sapiens
<400> 333
Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Arg
20 25 30
<210> 334
<211> 32
<212> PRT
<213> Homo sapiens
<400> 334
Gln Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu Thr
1 5 10 15
Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg
20 25 30
<210> 335
<211> 30
<212> PRT
<213> Homo sapiens
<400> 335
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser
20 25 30
<210> 336
<211> 14
<212> PRT
<213> Homo sapiens
<400> 336
Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 337
<211> 32
<212> PRT
<213> Homo sapiens
<400> 337
Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe Ser Leu Lys
1 5 10 15
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr Cys Val Arg
20 25 30
<210> 338
<211> 32
<212> PRT
<213> Homo sapiens
<400> 338
Arg Phe Ile Ile Ser Arg Asp Lys Ser Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 339
<211> 32
<212> PRT
<213> Homo sapiens
<400> 339
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys Ala Arg
20 25 30
<210> 340
<211> 30
<212> PRT
<213> Homo sapiens
<400> 340
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser
20 25 30
<210> 341
<211> 32
<212> PRT
<213> Homo sapiens
<400> 341
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 342
<211> 14
<212> PRT
<213> Homo sapiens
<400> 342
Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Val Ala
1 5 10
<210> 343
<211> 30
<212> PRT
<213> Homo sapiens
<400> 343
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
20 25 30
<210> 344
<211> 30
<212> PRT
<213> Homo sapiens
<400> 344
Gln Val Gln Leu Val Gln Ser Gly Ala Ala Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 345
<211> 32
<212> PRT
<213> Homo sapiens
<400> 345
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Ser Met Glu
1 5 10 15
Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys Ala Arg
20 25 30
<210> 346
<211> 32
<212> PRT
<213> Homo sapiens
<400> 346
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Thr Glu
20 25 30
<210> 347
<211> 30
<212> PRT
<213> Homo sapiens
<400> 347
Gln Val Gln Leu Val Gln Ser Gly Thr Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Met Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 348
<211> 32
<212> PRT
<213> Homo sapiens
<400> 348
Arg Val Thr Met Thr Arg Asp Thr Ser Thr Asn Thr Val Tyr Met Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala Arg
20 25 30
<210> 349
<211> 32
<212> PRT
<213> Homo sapiens
<400> 349
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 350
<211> 441
<212> PRT
<213> Homo sapiens
<400> 350
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Leu Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Val Ser Phe Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Gly Thr Met Thr Thr Asp Pro Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly
180 185 190
Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys
210 215 220
Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
245 250 255
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
260 265 270
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
275 280 285
Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
305 310 315 320
Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
325 330 335
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
340 345 350
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
355 360 365
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
370 375 380
Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
385 390 395 400
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
405 410 415
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
420 425 430
Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 351
<211> 215
<212> PRT
<213> Homo sapiens
<400> 351
Glu Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Ser Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Tyr Thr Ser Thr
85 90 95
Ser Met Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro
100 105 110
Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu
115 120 125
Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro
130 135 140
Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala
145 150 155 160
Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala
165 170 175
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg
180 185 190
Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr
195 200 205
Val Ala Pro Thr Glu Cys Ser
210 215
<210> 352
<211> 441
<212> PRT
<213> Homo sapiens
<400> 352
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Leu Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Val Ser Phe Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Gly Thr Met Thr Arg Asp Pro Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly
180 185 190
Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys
210 215 220
Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
245 250 255
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
260 265 270
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
275 280 285
Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
305 310 315 320
Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
325 330 335
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
340 345 350
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
355 360 365
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
370 375 380
Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
385 390 395 400
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
405 410 415
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
420 425 430
Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 353
<211> 441
<212> PRT
<213> Homo sapiens
<400> 353
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Leu Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Val Ser Phe Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Gly Thr Met Thr Thr Asp Pro Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly
180 185 190
Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys
210 215 220
Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
245 250 255
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
260 265 270
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
275 280 285
Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
305 310 315 320
Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
325 330 335
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
340 345 350
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
355 360 365
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
370 375 380
Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
385 390 395 400
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
405 410 415
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
420 425 430
Lys Lys Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 354
<211> 441
<212> PRT
<213> Homo sapiens
<400> 354
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Leu Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Val Ser Phe Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Gly Thr Met Thr Arg Asp Pro Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly
180 185 190
Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys
210 215 220
Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
245 250 255
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
260 265 270
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
275 280 285
Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
305 310 315 320
Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
325 330 335
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
340 345 350
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
355 360 365
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
370 375 380
Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
385 390 395 400
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
405 410 415
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
420 425 430
Lys Lys Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 355
<211> 220
<212> PRT
<213> Homo sapiens
<400> 355
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asp Ser
20 25 30
Ser Asp Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Asn Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Asp Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 356
<211> 446
<212> PRT
<213> Homo sapiens
<400> 356
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Ser Trp Phe Gly Glu Val Phe Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val
210 215 220
Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val
290 295 300
Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 357
<211> 446
<212> PRT
<213> Homo sapiens
<400> 357
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Ser Trp Phe Gly Glu Val Phe Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val
210 215 220
Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val
290 295 300
Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 358
<211> 446
<212> PRT
<213> Homo sapiens
<400> 358
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Lys Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Ser Trp Phe Gly Glu Val Phe Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val
210 215 220
Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val
290 295 300
Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 359
<211> 450
<212> PRT
<213> Homo sapiens
<400> 359
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Trp Phe Asp Ala Ser Asp Lys Tyr Tyr Ala Asp Ala Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Ala Ile Phe Gly Val Val Pro Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg
290 295 300
Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 360
<211> 214
<212> PRT
<213> Homo sapiens
<400> 360
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ala Thr Arg Ala Thr Gly Ile Pro Ala Arg Val Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 361
<211> 450
<212> PRT
<213> Homo sapiens
<400> 361
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Trp Phe Asp Ala Ser Asp Lys Tyr Tyr Ala Asp Ala Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Ala Ile Phe Gly Val Val Pro Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg
290 295 300
Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 362
<211> 450
<212> PRT
<213> Homo sapiens
<400> 362
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Trp Phe Asp Ala Ser Asp Lys Tyr Tyr Ala Asp Ala Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Ala Ile Phe Gly Val Val Pro Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg
290 295 300
Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 363
<211> 214
<212> PRT
<213> Homo sapiens
<400> 363
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ala Thr Arg Ala Thr Gly Ile Pro Asp Arg Val Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 364
<211> 450
<212> PRT
<213> Homo sapiens
<400> 364
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Trp Phe Asp Ala Ser Asp Lys Tyr Tyr Ala Asp Ala Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Ala Ile Phe Gly Val Val Pro Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg
290 295 300
Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 365
<211> 214
<212> PRT
<213> Homo sapiens
<400> 365
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ala Thr Arg Ala Thr Gly Ile Pro Asp Arg Val Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 366
<211> 441
<212> PRT
<213> Homo sapiens
<400> 366
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Leu Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Val Ser Phe Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Gly Thr Met Thr Thr Asp Pro Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly
180 185 190
Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys
210 215 220
Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
245 250 255
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
260 265 270
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
275 280 285
Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
305 310 315 320
Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
325 330 335
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
340 345 350
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
355 360 365
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
370 375 380
Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
385 390 395 400
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
405 410 415
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
420 425 430
Lys Lys Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 367
<211> 214
<212> PRT
<213> Homo sapiens
<400> 367
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ala Thr Arg Ala Thr Gly Ile Pro Ala Arg Val Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 368
<211> 450
<212> PRT
<213> Homo sapiens
<400> 368
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Trp Phe Asp Ala Ser Asp Lys Tyr Tyr Ala Asp Ala Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Ala Ile Phe Gly Val Val Pro Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg
290 295 300
Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Lys Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 369
<211> 692
<212> PRT
<213> Homo sapiens
<400> 369
Met Gly Thr Val Ser Ser Arg Arg Ser Trp Trp Pro Leu Pro Leu Leu
1 5 10 15
Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gln Glu
20 25 30
Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg Ser Glu
35 40 45
Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala Thr Phe
50 55 60
His Arg Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr Val Val
65 70 75 80
Val Leu Lys Glu Glu Thr His Leu Ser Gln Ser Glu Arg Thr Ala Arg
85 90 95
Arg Leu Gln Ala Gln Ala Ala Arg Arg Gly Tyr Leu Thr Lys Ile Leu
100 105 110
His Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met Ser Gly
115 120 125
Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr Ile Glu
130 135 140
Glu Asp Ser Ser Val Phe Ala Gln Ser Ile Pro Trp Asn Leu Glu Arg
145 150 155 160
Ile Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gln Pro Pro Asp Gly
165 170 175
Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser Ile Gln Ser Asp
180 185 190
His Arg Glu Ile Glu Gly Arg Val Met Val Thr Asp Phe Glu Asn Val
195 200 205
Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gln Ala Ser Lys Cys Asp
210 215 220
Ser His Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp Ala Gly
225 230 235 240
Val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn Cys Gln
245 250 255
Gly Lys Gly Thr Val Ser Gly Thr Leu Ile Gly Leu Glu Phe Ile Arg
260 265 270
Lys Ser Gln Leu Val Gln Pro Val Gly Pro Leu Val Val Leu Leu Pro
275 280 285
Leu Ala Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala Cys Gln Arg Leu
290 295 300
Ala Arg Ala Gly Val Val Leu Val Thr Ala Ala Gly Asn Phe Arg Asp
305 310 315 320
Asp Ala Cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu Val Ile Thr Val
325 330 335
Gly Ala Thr Asn Ala Gln Asp Gln Pro Val Thr Leu Gly Thr Leu Gly
340 345 350
Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Glu Asp Ile
355 360 365
Ile Gly Ala Ser Ser Asp Cys Ser Thr Cys Phe Val Ser Gln Ser Gly
370 375 380
Thr Ser Gln Ala Ala Ala His Val Ala Gly Ile Ala Ala Met Met Leu
385 390 395 400
Ser Ala Glu Pro Glu Leu Thr Leu Ala Glu Leu Arg Gln Arg Leu Ile
405 410 415
His Phe Ser Ala Lys Asp Val Ile Asn Glu Ala Trp Phe Pro Glu Asp
420 425 430
Gln Arg Val Leu Thr Pro Asn Leu Val Ala Ala Leu Pro Pro Ser Thr
435 440 445
His Gly Ala Gly Trp Gln Leu Phe Cys Arg Thr Val Trp Ser Ala His
450 455 460
Ser Gly Pro Thr Arg Met Ala Thr Ala Ile Ala Arg Cys Ala Pro Asp
465 470 475 480
Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys Arg Arg
485 490 495
Gly Glu Arg Met Glu Ala Gln Gly Gly Lys Leu Val Cys Arg Ala His
500 505 510
Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala Ile Ala Arg Cys Cys Leu
515 520 525
Leu Pro Gln Ala Asn Cys Ser Val His Thr Ala Pro Pro Ala Glu Ala
530 535 540
Ser Met Gly Thr Arg Val His Cys His Gln Gln Gly His Val Leu Thr
545 550 555 560
Gly Cys Ser Ser His Trp Glu Val Glu Asp Leu Gly Thr His Lys Pro
565 570 575
Pro Val Leu Arg Pro Arg Gly Gln Pro Asn Gln Cys Val Gly His Arg
580 585 590
Glu Ala Ser Ile His Ala Ser Cys Cys His Ala Pro Gly Leu Glu Cys
595 600 605
Lys Val Lys Glu His Gly Ile Pro Ala Pro Gln Gly Gln Val Thr Val
610 615 620
Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly
625 630 635 640
Thr Ser His Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys Val Val
645 650 655
Arg Ser Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Glu Ala Val
660 665 670
Thr Ala Val Ala Ile Cys Cys Arg Ser Arg His Leu Ala Gln Ala Ser
675 680 685
Gln Glu Leu Gln
690
<210> 370
<211> 14
<212> PRT
<213> Homo sapiens
<400> 370
Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Ser Val Ser
1 5 10
<210> 371
<211> 7
<212> PRT
<213> Homo sapiens
<400> 371
Glu Val Ser Asn Arg Pro Ser
1 5
<210> 372
<211> 9
<212> PRT
<213> Homo sapiens
<400> 372
Asn Ser Tyr Thr Ser Thr Ser Met Val
1 5
<210> 373
<211> 10
<212> PRT
<213> Homo sapiens
<400> 373
Gly Tyr Thr Leu Thr Ser Tyr Gly Ile Ser
1 5 10
<210> 374
<211> 16
<212> PRT
<213> Homo sapiens
<400> 374
Trp Val Ser Phe Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu Gln
1 5 10 15
<210> 375
<211> 6
<212> PRT
<213> Homo sapiens
<400> 375
Gly Tyr Gly Met Asp Val
1 5
<210> 376
<211> 115
<212> PRT
<213> Homo sapiens
<400> 376
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Leu Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Val Ser Phe Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Gly Thr Met Thr Thr Asp Pro Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser
115
<210> 377
<211> 109
<212> PRT
<213> Homo sapiens
<400> 377
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Ser Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Tyr Thr Ser Thr
85 90 95
Ser Met Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 378
<211> 115
<212> PRT
<213> Homo sapiens
<400> 378
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Leu Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Val Ser Phe Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Gly Thr Met Thr Thr Asp Pro Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser
115
<210> 379
<211> 109
<212> PRT
<213> Homo sapiens
<400> 379
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Ser Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Tyr Thr Ser Thr
85 90 95
Ser Met Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 380
<211> 4
<212> PRT
<213> Homo sapiens
<400> 380
Lys Lys Lys Pro
1
<210> 381
<211> 4
<212> PRT
<213> Homo sapiens
<400> 381
Pro Gly Lys Pro
1
<210> 382
<211> 5
<212> PRT
<213> Homo sapiens
<400> 382
Pro Gly Lys Lys Pro
1 5
<210> 383
<211> 6
<212> PRT
<213> Homo sapiens
<400> 383
Pro Gly Lys Lys Lys Pro
1 5
Claims (12)
- 항원 결합 단백질의 서열에 하나 이상의 변형을 만드는 단계를 포함하는, 항원 결합 단백질의 점도를 감소시키는 방법으로서,
a) 항원 결합 단백질이 VH3|3-33 생식선 서브패밀리를 포함하는 경우, 상기 방법은 1X4, 17X5 및 85X6으로부터 선택되는 하나 이상의 치환을 포함하도록 VH3 서열을 변형시키는 단계로, 여기서 X4는 D 및 E로부터 선택되고, X5는 G, A, V, I, L 및 M. 및 W로부터 선택되며, X6은 G, A, V, I, L 및 M으로부터 선택되는, 단계를 포함하거나;
b) 항원 결합 단백질이 VK3|L16 생식선 서브패밀리를 포함하는 경우, 상기 방법은 4X10, 13X11, 76X12, 78F, 95X13, 97X14 및 98P로부터 선택되는 하나 이상의 치환을 포함하도록 VK3 서열을 변형시키는 단계로, 여기서 X10은 G, A, V, I, L 및 M으로부터 선택되고, X11은 G, A, V, I, L 및 M으로부터 선택되며, X12는 D 및 E로부터 선택되고, X13은 R, K 및 H로부터 선택되며, X14는 D 및 E로부터 선택되는, 단계를 포함하거나;
c) 항원 결합 단백질이 VK3|L6 생식선 서브패밀리를 포함하는 경우, 상기 방법은 76X12 및 95X13으로부터 선택되는 하나 이상의 치환을 포함하도록 VK3 서열을 변형시키는 단계를 포함하거나;
d) 항원 결합 단백질이 Fc 도메인을 포함하고 상기 방법은 253X15, 440X16 및 439X17로부터 선택되는 하나 이상의 치환을 포함하도록 Fc 도메인 서열을 변형시키는 단계로, 여기서 X15는 G, A, V, I, L 및 M으로부터 선택되고, X16은 R, K 및 H로부터 선택되며, X17은 D 및 E로부터 선택되고, Fc 도메인 서열은 440X16 및 439X17 중 하나만 포함하는, 단계를 포함하거나;
e) 항원 결합 단백질이 Fc 도메인을 포함하고 상기 방법은 X18X19를 포함하도록 Fc 도메인 서열의 C-말단을 변형시키는 단계로, 여기서 X18은 D 및 E로부터 또는 H, K 및 R로부터 선택되는 1 내지 4개의 아미노산을 포함하고, X19는 P, M, G, A, V, I, L, S, T, N, Q, F, Y 및 W로부터 선택되며, X18이 D 또는 E를 포함하는 경우 부재하고, X18이 이의 C-말단부에 K 또는 R을 포함하는 경우 존재하고, X18이 이의 C-말단부에 H를 포함하는 경우 존재하거나 부재하는, 단계를 포함하고,
여기서 하위단락 a), b), 및 c)의 아미노산은 Aho 넘버링 시스템에 따라 넘버링되고, 하위단락 d)의 아미노산은 Eu 넘버링 시스템에 따라 넘버링되는, 방법. - 제1항에 있어서, 항원 결합 단백질이, 치환된 것을 제외하고, 각각 서열번호: 166 및 168; 서열번호: 2 및 4; 서열번호: 178 및 180; 서열번호: 170 및 172; 서열번호: 6 및 8; 서열번호: 10 및 12; 서열번호: 14 및 16; 서열번호: 18 및 20; 서열번호: 22 및 24; 서열번호: 26 및 28; 서열번호: 30 및 32; 서열번호: 34 및 36; 서열번호: 38 및 40; 서열번호: 43 및 44; 서열번호: 46 및 48; 서열번호: 50 및 52; 서열번호: 54 및 56; 서열번호: 58 및 60; 서열번호: 62 및 64; 서열번호: 66 및 68; 서열번호: 70 및 72; 서열번호: 74 및 76; 서열번호: 78 및 80; 서열번호: 82 및 84; 서열번호: 86 및 88; 서열번호: 90 및 92; 서열번호: 94 및 96; 서열번호: 98 및 100; 서열번호: 102 및 104; 서열번호: 106 및 108; 서열번호: 110 및 112; 서열번호: 118 및 120; 서열번호: 122 및 124; 서열번호: 126 및 128; 서열번호: 130 및 132; 서열번호: 158 및 160; 서열번호: 142 및 144; 및 서열번호: 154 및 156으로부터 선택된 중쇄 및 경쇄 서열을 포함하는, 방법.
- 제1항에 있어서, 1E, 17G 및 85A로부터 선택되는 하나 이상의 치환을 포함하도록 VH3|3-33 생식선 서브패밀리를 포함하는 항원 결합 단백질의 VH3 서열을 변형시키는 단계를 포함하는, 방법.
- 제3항에 있어서, 항원 결합 단백질이, 치환된 것을 제외하고, 도 1b로부터의 항체 AQ, AM, AI 또는 AG의 중쇄 및 경쇄 아미노산 서열(각각 서열번호: 158 및 160; 서열번호: 142 및 144; 서열번호: 126 및 128; 또는 서열번호: 118 및 120)을 포함하는, 방법.
- 제1항에 있어서, 4L, 13L, 76D, 78F, 95R, 97E, 및 98P로부터 선택되는 하나 이상의 치환을 포함하도록 항원 결합 단백질의 VK3|L16 서열을 변형시키는 단계를 포함하는, 방법.
- 제5항에 있어서, 항원 결합 단백질이, 치환된 것을 제외하고, 도 1b로부터의 항체 AF 또는 AQ의 중쇄 및 경쇄 아미노산 서열(각각 서열번호: 114 및 116; 또는 서열번호: 158 및 160)을 포함하는, 방법.
- 제1항에 있어서, 76D 및 95R로부터 선택되는 하나 이상의 치환을 포함하도록 항원 결합 단백질의 VK3|L6 서열을 변형시키는 단계를 포함하는, 방법.
- 제7항에 있어서, 항원 결합 단백질이, 치환된 것을 제외하고, 도 1b로부터의 항체 AJ의 중쇄 및 경쇄 아미노산 서열(각각 서열번호: 130 및 132)을 포함하는, 방법.
- 제1항에 있어서, EU 넘버링 시스템에 따라 넘버링된 253A, 440K, 및 439E로부터 선택되는 하나 이상의 치환을 포함하도록 Fc 도메인 서열을 변형시키는 단계를 포함하는, 방법.
- 제9항에 있어서, 항원 결합 단백질이, 치환된 것을 제외하고, 도 1b로부터의 항체 BA, AH, 또는 AN의 중쇄 및 경쇄 아미노산 서열(각각 서열번호: 174 및 176; 서열번호: 122 및 124; 또는 서열번호: 146 및 148)을 포함하는, 방법.
- 제1항에 있어서, KP, KKP, KKKP(서열번호: 380), 및 E로부터 선택되는 아미노산 서열을 포함하도록 Fc 도메인의 C-말단을 변형시키는 단계를 포함하는, 방법.
- 제1항 내지 제11항 중 어느 한 항에 있어서, 항원 결합 단백질이 IgG 항체인, 방법.
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662401770P | 2016-09-29 | 2016-09-29 | |
| US62/401,770 | 2016-09-29 | ||
| US201662430773P | 2016-12-06 | 2016-12-06 | |
| US62/430,773 | 2016-12-06 | ||
| US201762546469P | 2017-08-16 | 2017-08-16 | |
| US62/546,469 | 2017-08-16 | ||
| PCT/US2017/053967 WO2018064307A2 (en) | 2016-09-29 | 2017-09-28 | Low-viscosity antigen binding proteins and methods of making them |
| KR1020197012239A KR102551269B1 (ko) | 2016-09-29 | 2017-09-28 | 저-점도 항원 결합 단백질 및 이의 제조 방법 |
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| KR1020197012239A Division KR102551269B1 (ko) | 2016-09-29 | 2017-09-28 | 저-점도 항원 결합 단백질 및 이의 제조 방법 |
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| KR20230107696A true KR20230107696A (ko) | 2023-07-17 |
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| KR1020237022133A KR20230107696A (ko) | 2016-09-29 | 2017-09-28 | 저-점도 항원 결합 단백질 및 이의 제조 방법 |
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| EP (1) | EP3519439A2 (ko) |
| JP (3) | JP2019532063A (ko) |
| KR (2) | KR102551269B1 (ko) |
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| JP6454547B2 (ja) * | 2011-07-06 | 2019-01-16 | ゲンマブ エー／エス | 抗体重鎖のｃ末端の修飾による補体依存性細胞傷害の調節 |
| JP6367836B2 (ja) | 2013-02-07 | 2018-08-01 | ザ ジェネラル ホスピタル コーポレイション | Ｔ制御性細胞の増殖または枯渇方法 |
| CA2954767A1 (en) * | 2014-07-14 | 2016-01-21 | Amgen Inc. | Crystalline antibody formulations |
| SG11201703152RA (en) | 2014-10-23 | 2017-05-30 | Amgen Inc | Reducing viscosity of pharmaceutical formulations |
| AU2017263833B2 (en) | 2016-05-13 | 2023-08-03 | The General Hospital Corporation | Antagonistic anti-tumor necrosis factor receptor superfamily antibodies |
| JP7377596B2 (ja) * | 2017-02-22 | 2023-11-10 | アムジエン・インコーポレーテツド | 低粘度、高濃度エボロクマブ製剤及びそれらの製造方法 |
| KR20190132215A (ko) | 2018-05-18 | 2019-11-27 | 서울반도체 주식회사 | 발광 다이오드, 발광 다이오드 모듈 및 그것을 갖는 표시 장치 |
| AU2019324134A1 (en) * | 2018-08-20 | 2021-04-15 | The General Hospital Corporation | Antagonistic anti-tumor necrosis factor receptor superfamily polypeptides |
| US20220177581A1 (en) * | 2019-03-11 | 2022-06-09 | Memorial Sloan Kettering Cancer Center | Cd22 antibodies and methods of using the same |
| GB2590642B (en) * | 2019-12-20 | 2024-02-14 | Kymab Ltd | Improved lambda antibodies |
| KR20220038356A (ko) * | 2019-06-26 | 2022-03-28 | 아뮤닉스 파마슈티컬스, 인크. | Egfr 항원 결합 단편 및 이를 포함하는 조성물 |
| CA3176090A1 (en) * | 2020-03-30 | 2021-10-07 | Crystal Bioscience Inc. | Anti-gipr antibody and methods of use thereof |
| CN113512116B (zh) * | 2020-04-10 | 2022-09-20 | 苏州普乐康医药科技有限公司 | 一种抗igf-1r抗体及其应用 |
| US20230340082A1 (en) * | 2020-07-10 | 2023-10-26 | The Wistar Institute Of Anatomy And Biology | Dna antibody constructs for use against rotavirus |
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| GB8308235D0 (en) | 1983-03-25 | 1983-05-05 | Celltech Ltd | Polypeptides |
| US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
| JPS6147500A (ja) | 1984-08-15 | 1986-03-07 | Res Dev Corp Of Japan | キメラモノクロ−ナル抗体及びその製造法 |
| EP0173494A3 (en) | 1984-08-27 | 1987-11-25 | The Board Of Trustees Of The Leland Stanford Junior University | Chimeric receptors by dna splicing and expression |
| GB8422238D0 (en) | 1984-09-03 | 1984-10-10 | Neuberger M S | Chimeric proteins |
| SG48759A1 (en) | 1990-01-12 | 2002-07-23 | Abgenix Inc | Generation of xenogenic antibodies |
| AR083495A1 (es) * | 2010-10-22 | 2013-02-27 | Esbatech Alcon Biomed Res Unit | Anticuerpos estables y solubles |
| CA2829628A1 (en) | 2011-03-11 | 2012-09-20 | Amgen Inc. | Method of correlated mutational analysis to improve therapeutic antibodies |
| JOP20200043A1 (ar) * | 2011-05-10 | 2017-06-16 | Amgen Inc | طرق معالجة أو منع الاضطرابات المختصة بالكوليسترول |
| WO2014009465A1 (en) | 2012-07-13 | 2014-01-16 | Roche Glycart Ag | Bispecific anti-vegf/anti-ang-2 antibodies and their use in the treatment of ocular vascular diseases |
| EP2992010B1 (en) | 2013-04-29 | 2021-03-24 | F.Hoffmann-La Roche Ag | Fc-receptor binding modified asymmetric antibodies and methods of use |
| EP3026061A1 (en) * | 2014-11-26 | 2016-06-01 | Novo Nordisk A/S | Site directed mutagenesis of trem-1 antibodies for decreasing viscosity. |
| JP6948330B2 (ja) | 2015-12-23 | 2021-10-13 | アムジエン・インコーポレーテツド | 胃抑制ペプチド受容体（ｇｉｐｒ）に対する結合タンパク質をｇｌｐ−１アゴニストと組み合わせて使用する、代謝障害の治療方法または寛解方法 |
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| EP3519439A2 (en) | 2019-08-07 |
| US20210371544A1 (en) | 2021-12-02 |
| WO2018064307A3 (en) | 2018-07-05 |
| IL265692B1 (en) | 2023-11-01 |
| AU2017336673A1 (en) | 2019-04-18 |
| US20190233543A1 (en) | 2019-08-01 |
| KR20190053271A (ko) | 2019-05-17 |
| IL265692A (en) | 2019-05-30 |
| WO2018064307A2 (en) | 2018-04-05 |
| WO2018064307A4 (en) | 2018-09-27 |
| US11059908B2 (en) | 2021-07-13 |
| US11993663B2 (en) | 2024-05-28 |
| CA3038909A1 (en) | 2018-04-05 |
| JP2019532063A (ja) | 2019-11-07 |
| CL2019000835A1 (es) | 2019-05-31 |
| ZA201902297B (en) | 2019-12-18 |
| KR102551269B1 (ko) | 2023-07-05 |
| MX2019003727A (es) | 2019-08-05 |
| IL265692B2 (en) | 2024-03-01 |
| CL2021003596A1 (es) | 2022-08-19 |
| CN110036031A (zh) | 2019-07-19 |
| MA46359A (fr) | 2019-08-07 |
| IL307684A (en) | 2023-12-01 |
| JP2023178409A (ja) | 2023-12-14 |
| SG10201912565QA (en) | 2020-02-27 |
| JP2022081654A (ja) | 2022-05-31 |
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