KR20120038494A - 개선된 항-혈청 알부민 결합 단일 가변 도메인 - Google Patents
개선된 항-혈청 알부민 결합 단일 가변 도메인 Download PDFInfo
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- KR20120038494A KR20120038494A KR1020127003939A KR20127003939A KR20120038494A KR 20120038494 A KR20120038494 A KR 20120038494A KR 1020127003939 A KR1020127003939 A KR 1020127003939A KR 20127003939 A KR20127003939 A KR 20127003939A KR 20120038494 A KR20120038494 A KR 20120038494A
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Classifications
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- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- A—HUMAN NECESSITIES
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/31—Fusion polypeptide fusions, other than Fc, for prolonged plasma life, e.g. albumin
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
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Abstract
본 발명은 개선된 항-혈청 알부민 이뮤노글로불린 단일 가변 도메인, 뿐만 아니라 상기 가변 도메인을 포함하는 리간드 및 약물 접합체, 조성물, 핵산, 벡터 및 숙주에 관한 것이다.
Description
본 발명은 개선된 항-혈청 알부민 이뮤노글로불린 단일 가변 도메인, 뿐만 아니라 상기 도메인을 포함하는 리간드 및 약물 접합체, 조성물, 핵산, 벡터 및 숙주에 관한 것이다.
WO04003019 및 WO2008/096158은 치료상 유용한 반감기를 갖는 항-혈청 알부민 (SA) 결합 모이어티, 예컨대 항-SA 이뮤노글로불린 단일 가변 도메인 (dAb)을 개시하고 있다. 이들 문헌은 단량체 항-SA dAb 뿐만 아니라 이러한 dAb를 포함하는 다중-특이적 리간드, 예를 들어 항-SA dAb, 및 표적 항원, 예컨대 TNFR1에 특이적으로 결합하는 dAb를 포함하는 리간드를 개시하고 있다. 하나 초과의 종으로부터 혈청 알부민에 특이적으로 결합하는 결합 모이어티, 예를 들어 인간/마우스 교차-반응성 항-SA dAb가 개시되어 있다.
WO05118642 및 WO2006/059106은 약물의 반감기를 증가시키기 위해 항-SA 결합 모이어티, 예컨대 항-SA 이뮤노글로불린 단일 가변 도메인을 약물에 접합시키거나 또는 결합시키는 개념을 개시하고 있다. 단백질, 펩티드 및 NCE (화학 물질) 약물이 개시되고 예시되어 있다. WO2006/059106은 인슐린분비자극제, 예를 들어 인크레틴 호르몬, 예컨대 글루카곤-유사 펩티드 (GLP)-1의 반감기를 증가시키는데 이러한 개념을 사용하는 것을 개시하고 있다.
또한, 문헌 [Holt et al., "Anti-Serum albumin domain antibodies for extending the half-lives of short lived drugs", Protein Engineering, Design & Selection, vol 21, no 5, pp283-288, 2008]을 참조한다.
혈청 알부민, 바람직하게는 인간 및 비-인간 종으로부터의 알부민에 특이적으로 결합하는 개선된 중쇄 가변 도메인 dAb를 제공하는 것이 바람직할 것이며, 이는 동물 질환 모델 뿐만 아니라 인간 치료 및/또는 진단에서 유용성을 제공할 것이다. 또한, 상대적으로 중등도- 및 고-친화도 항-SA 결합 모이어티 (dAb) 사이의 선택을 제공하는 것이 바람직할 것이다. 이러한 모이어티는 약물에 연결될 수 있으며, 항-SA 결합 모이어티는 고려되는 최종 적용에 따라 선택된다. 이는 약물이 항-SA 결합 모이어티의 선택에 따라 만성 또는 급성 적응증의 치료 및/또는 예방에 보다 적합하게 되도록 한다. 또한, 단량체성 또는 용액 중에서 실질적으로 단량체성인 항-SA dAb를 제공하는 것이 바람직할 것이다. 이는 특히 항-SA dAb가 세포-표면 수용체, 예컨대 TNFR1에 수용체에 길항할 목적으로 특이적으로 결합하는 결합 모이어티, 예를 들어 dAb에 연결되는 경우에 유리할 것이다. 항-SA dAb의 단량체 상태가 수용체 가교의 기회를 감소시키는데 유용한데, 이는 세포 표면 상에서 수용체 (예를 들어, TNFR1)에 결합하고 가교되어 수용체 효능작용 및 해로운 수용체 신호전달의 가능성을 증가시키는 다량체가 형성될 가능성이 보다 적기 때문이다. 또한, 상대적으로 높은 용융 온도를 갖는 항-SA dAb를 제공하는 것이 바람직할 것이다. 이는 안정한 제제, 예를 들어 저장 안정성 제제 및 우수한 저장 수명을 갖는 가변 도메인을 제공하는데 유용하다.
발명의 개요
본 발명의 측면은 이러한 문제를 해결한다.
따라서, 본 발명의 한 측면에서, 서열 97 내지 191 및 198 내지 203으로부터 선택된 아미노산 서열과 적어도 80％ 동일한 아미노산 서열을 포함하는 항-혈청 알부민 (SA) 이뮤노글로불린 단일 가변 도메인을 제공한다.
본 발명의 측면은 서열 97 내지 191 및 198 내지 203으로부터 선택된 아미노산 서열과 비교하여 최대 4개의 아미노산 변화를 갖는 아미노산 서열을 포함하는 항-혈청 알부민 (SA) 이뮤노글로불린 단일 가변 도메인을 제공한다.
본 발명의 측면은 서열 1 내지 96 및 192 내지 197로부터 선택된 서열과 적어도 80％ 동일한 뉴클레오티드 서열에 의해 코딩된 아미노산 서열을 포함하는 항-혈청 알부민 (SA) 이뮤노글로불린 단일 가변 도메인을 제공한다.
본 발명의 측면은 본 발명의 항-SA 가변 도메인 및 SA 이외의 표적 항원에 특이적으로 결합하는 결합 모이어티를 포함하는 다중특이적 리간드를 제공한다.
본 발명의 측면은 가변 도메인이 약물 (임의로는 NCE 약물)에 접합된 본 발명의 항-SA 단일 가변 도메인을 제공한다.
본 발명의 측면은 본 발명의 임의의 항-SA 가변 도메인에 융합되거나 접합된 (NCE (신규 화학 물질)의 경우) 폴리펩티드, 단백질, 펩티드 또는 NCE 약물을 포함하는, 융합 산물, 예를 들어 융합 단백질 또는 펩티드 또는 NCE 약물과의 융합체를 제공한다. 예를 들어, 가변 도메인은 서열 97 내지 103 및 198 내지 203 중 어느 하나의 아미노산 서열 (또는 서열 97 내지 103 및 198 내지 203 중 어느 하나의 아미노산 서열과 적어도 95, 96, 97, 98 또는 99％ 동일한 아미노산 서열)을 포함하거나 이것으로 이루어진다.
본 발명의 측면은 본 발명의 가변 도메인, 융합 단백질 또는 리간드 및 제약상 허용되는 희석제, 담체, 부형제 또는 비히클을 포함하는 조성물을 제공한다.
본 발명의 측면은 본 발명의 가변 도메인, 또는 다중특이적 리간드 또는 융합 단백질을 코딩하는 뉴클레오티드 서열을 포함하는 핵산을 제공한다.
본 발명의 측면은 서열 1 내지 96 및 192-197로부터 선택된 서열과 적어도 80％ 동일한 뉴클레오티드 서열을 포함하는 핵산을 제공한다.
본 발명의 측면은 본 발명의 핵산을 포함하는 벡터를 제공한다.
본 발명의 측면은 본 발명의 벡터를 포함하는 단리된 숙주 세포를 제공한다.
본 발명의 측면은 본 발명의 가변 도메인, 또는 다중특이적 리간드 또는 융합 단백질 중 적어도 하나의 용량을 환자에게 투여하는 것을 포함하는, 환자에서 질환 또는 장애를 치료 또는 예방하는 방법을 제공한다.
본 발명의 임의의 측면의 실시양태는 항-혈청 알부민 친화성이 우수한 항-혈청 알부민 단일 가변 도메인을 제공한다. 가변 도메인의 선택은 목적하는 치료 및/또는 예방 설정에 따라 반감기를 맞추도록 할 수 있다. 예를 들어, 한 실시양태에서, 가변 도메인이 만성 또는 지속성 질환, 상태, 독성 또는 다른 만성 적응증을 치료하고/거나 예방하는데 있어서 유용성을 찾는 제품에 포함되는데 유용하도록 혈청 알부민에 대한 가변 도메인의 친화도는 비교적 높다. 한 실시양태에서는, 가변 도메인이 급성 질환, 상태, 독성 또는 다른 급성 적응증을 치료하고/거나 예방하는데 있어서 유용성을 찾는 제품에 포함되는데 유용하도록 혈청 알부민에 대한 가변 도메인의 친화도는 비교적 높지 않다. 한 실시양태에서는, 가변 도메인이 급성 또는 만성 질환, 상태, 독성 또는 다른 급성 또는 만성 적응증을 치료하고/거나 예방하는데 있어서 유용성을 찾는 제품에 포함되는데 유용하도록 혈청 알부민에 대한 가변 도메인의 친화도는 비교적 중간 정도이다.
혈청 알부민에 대해 적절하게 높은 친화성 및 특이성을 갖는 분자가 목적하는 치료 효과를 나타내기에 충분히 오래 순환에 머물게 되는 것이 가능하다 (문헌 [Tomlinson, Nature Biotechnology 22, 521 - 522 (2004)]). 높은 친화도 항-SA 가변 도메인은 종의 혈청 알부민과 일치하는 혈청 순환에 머물 것이다 (WO2008096158). 순환되면, AlbudAb 가변 도메인에 융합된 임의의 치료제, 즉 NCE, 펩티드 또는 단백질은 결과적으로 그의 표적에서 보다 오래 작용할 수 있을 것이고, 보다 오래 지속되는 치료 효과를 나타낼 수 있을 것이다. 이는 자주 투여할 필요 없이 만성 또는 지속성 질환을 표적화 가능하게 할 것이다.
적당한 친화성 (그러나 SA에 대해 특이성)를 갖는 가변 도메인은 단지 짧은 시간 (예를 들어, 수 시간 또는 수일) 동안 혈청 순환에 머물러, 융합된 치료제에 의한 급성 질환과 관련된 치료 표적의 특이적 표적화를 허용할 것이다.
이러한 방식으로 적절한 알부민 결합 친화도 및/또는 혈청 반감기를 갖는 항-SA 가변 도메인을 선택함으로써 항-SA-함유 생성물을 치료 질환 영역에 맞추는 것이 가능하다.
발명의 상세한 설명
본 명세서에는, 실시양태들을 참고하여, 명확하고 정확한 명세서가 기재될 수 있도록 하는 방식으로 본 발명이 기재되어 있다. 실시양태들이 본 발명으로부터 벗어나지 않으면서 다양하게 조합 또는 분리될 수 있도록 의도되고, 그럴 수 있는 것으로 이해되어야 한다.
달리 정의되지 않는 한, 본원에 사용된 모든 전문 학술 용어는 (예를 들어, 세포 배양, 분자 유전학, 핵산 화학, 혼성화 기술 및 생화학에서) 당업자에 의해 통상적으로 이해되는 바와 동일한 의미를 갖는다. 표준 기술은 분자적, 유전자적 및 생화학적 방법 (일반적으로, 본원에 참고로 포함되는 문헌 [Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.] 및 [Ausubel et al., Short Protocols in Molecular Biology (1999) 4th Ed, John Wiley & Sons, Inc.] 참조) 및 화학적 방법에 사용된다.
본원에 사용된 용어 "종양 괴사 인자 수용체 1 (TNFR1)의 길항제" 또는 "항-TNFR1 길항제" 등은 TNFR1에 결합하고, TNFR1의 기능 (즉, 하나 이상)을 억제할 수 있는 작용제 (예를 들어, 분자, 화합물)를 지칭한다. 예를 들어, TNFR1의 길항제는 TNFR1에 대한 TNFα의 결합을 억제할 수 있고/거나 TNFR1을 통해 매개되는 신호 전달을 억제할 수 있다. 따라서, TNFR1-매개 과정 및 세포 반응 (예를 들어, 표준 L929 세포독성 검정에서의 TNFα-유도된 세포 사멸)은 TNFR1의 길항제에 의해 억제될 수 있다.
"환자"는 임의의 동물, 예를 들어 포유동물, 예를 들어 비-인간 영장류 (예컨대, 개코원숭이, 레서스 원숭이 또는 시노몰구스 원숭이), 마우스, 인간, 토끼, 래트, 개, 고양이 또는 돼지이다. 한 실시양태에서, 환자는 인간이다.
본원에 사용된 "펩티드"는 펩티드 결합을 통해 함께 연결된 약 2 내지 약 50개의 아미노산을 지칭한다.
본원에 사용된 "폴리펩티드"는 펩티드 결합에 의해 함께 연결된 적어도 약 50개의 아미노산을 지칭한다. 폴리펩티드는 일반적으로 3차 구조를 포함하고, 기능적 도메인으로 폴딩(folding)된다.
본원에 사용된 바와 같은 항체는 자연적으로 항체를 생산하는 임의의 종으로부터 유래되는지 또는 재조합 DNA 기술에 의해 제작되는지에 관계없이; 혈청, B-세포, 하이브리도마, 트랜스펙토마, 효모 또는 박테리아로부터 단리되는지에 관계없이, IgG, IgM, IgA, IgD 또는 IgE 또는 단편 (예컨대, Fab, F(ab')2, Fv, 디술피드 연결된 Fv, scFv, 폐쇄 입체형태 다중특이적 항체, 디술피드-연결된 scFv, 디아바디)을 지칭한다.
본원에 사용된 "항체 포맷"은 구조 상에 항원에 대한 결합 특이성을 부여하도록 하나 이상의 항체 가변 도메인이 혼입될 수 있는 임의의 적합한 폴리펩티드 구조를 지칭한다. 다양한 적합한 항체 포맷, 예컨대 키메라 항체, 인간화 항체, 인간 항체, 단일쇄 항체, 이중특이적 항체, 항체 중쇄, 항체 경쇄, 항체 중쇄 및/또는 경쇄의 동종이량체 및 이종이량체, 상기의 것들 중 임의의 것의 항원-결합 단편 (예를 들어, Fv 단편 (예를 들어, 단일쇄 Fv (scFv), 디술피드 결합 Fv), Fab 단편, Fab' 단편, F(ab')2 단편), 단일 항체 가변 도메인 (예를 들어, dAb, VH, VHH, VL), 및 상기의 것들 중 임의의 것의 변형된 버전 (예를 들어, 폴리에틸렌 글리콜 또는 다른 적합한 중합체의 공유 부착에 의해 변형된 것, 또는 인간화 VHH)이 당업계에 공지되어 있다.
어구 "이뮤노글로불린 단일 가변 도메인"은 독립적으로 상이한 V 영역 또는 도메인의 항원 또는 에피토프에 특이적으로 결합하는 항체 가변 도메인 (VH, VHH, VL)을 지칭한다. 이뮤노글로불린 단일 가변 도메인은 다른 영역 또는 도메인이 단일 이뮤노글로불린 가변 도메인에 의한 항원 결합을 필요로 하지 않는 경우 (즉, 이뮤노글로불린 단일 가변 도메인이 추가의 가변 도메인과 독립적으로 항원에 결합하는 경우) 다른 가변 영역 또는 가변 도메인과 (예를 들어, 동종- 또는 이종-다량체) 포맷으로 존재할 수 있다. "도메인 항체" 또는 "dAb"는 본원에 사용된 용어 "이뮤노글로불린 단일 가변 도메인"과 동일하다. "단일 이뮤노글로불린 가변 도메인"은 본원에 사용된 용어 "이뮤노글로불린 단일 가변 도메인"과 동일하다. "단일 항체 가변 도메인" 또는 "항체 단일 가변 도메인"은 본원에 사용된 용어 "이뮤노글로불린 단일 가변 도메인"과 동일하다. 이뮤노글로불린 단일 가변 도메인은 한 실시양태에서 인간 항체 가변 도메인이나, 또한 다른 종으로부터의 단일 항체 가변 도메인, 예컨대 설치류 (예를 들어, 그 전체 내용이 본원에 참고로 포함되는 WO 00/29004에 개시되어 있음), 너스 상어 및 낙타류 VHH dAb를 포함한다. 낙타류 VHH는 낙타, 라마, 알파카, 단봉낙타 및 과나코를 비롯한 종으로부터 유래된 이뮤노글로불린 단일 가변 도메인 폴리펩티드이고, 자연적으로 경쇄가 결여된 중쇄 항체를 생성한다. VHH는 인간화될 수 있다.
"도메인"은 단백질의 나머지 부분과 독립적인 3차 구조를 갖는 폴딩된 단백질 구조이다. 일반적으로, 도메인은 단백질의 개별적인 기능적 특성들을 담당하고, 다수의 경우에 단백질의 나머지 부분 및/또는 도메인의 기능 손실 없이 부가되거나 또는 제거되거나 또는 다른 단백질로 옮겨질 수 있다. "단일 항체 가변 도메인"은 항체 가변 도메인의 특징적인 서열을 포함하는 폴딩된 폴리펩티드 도메인이다. 따라서, 이는 완전한 항체 가변 도메인 및 변형된 가변 도메인, 예를 들어 하나 이상의 루프가 항체 가변 도메인의 특징이 아닌 서열로 교체된 도메인, 또는 말단절단되었거나 또는 N- 또는 C-말단 연장부를 포함하는 항체 가변 도메인 뿐만 아니라, 적어도 전장 도메인의 결합 활성 및 특이성을 유지하는 가변 도메인의 폴딩된 단편을 포함한다.
본 출원에서, 용어 "예방" 및 "예방하는"은 질환 또는 상태의 유도 이전에 보호성 조성물을 투여하는 것을 포함한다. "치료" 및 "치료하는"은 질환 또는 상태 증상이 나타난 후에 보호성 조성물을 투여하는 것을 포함한다. "저해" 또는 "저해하는"은 유도된 사건 후에, 그러나 질환 또는 상태의 임상적 출현 이전에 조성물을 투여하는 것을 지칭한다.
본원에 사용된 용어 "용량"은 모두 한 번에 (단위 용량), 또는 정해진 시간 간격에 걸쳐 2회 이상의 투여로 대상체에게 투여되는 리간드의 양을 지칭한다. 예를 들어, 용량은 1일 (24시간) (1일 용량), 2일, 1주, 2주, 3주 또는 1개월 이상의 과정에 걸쳐 (예를 들어, 단일 투여 또는 2회 이상의 투여에 의해) 대상체에게 투여되는 리간드 (예를 들어, 표적 항원에 결합하는 이뮤노글로불린 단일 가변 도메인을 포함하는 리간드)의 양을 지칭할 수 있다. 용량 사이의 간격은 임의의 목적하는 양의 시간일 수 있다. 용량을 언급할 때 용어 "제약상 유효한"은 목적하는 효과를 제공하기에 충분한 리간드, 도메인 또는 제약 활성제의 양을 의미한다. "효과적인" 양은 개체의 연령 및 일반적인 상태, 특정 약물 또는 제약 활성제 등에 따라 대상체마다 달라질 것이다. 따라서, 모든 환자에게 적용가능한 정확한 "효과적인" 양을 특정하는 것이 항상 가능하지는 않다. 그러나, 임의의 개별적인 경우에 적절한 "효과적인" 용량이 일상적인 실험을 이용하여 당업자에 의해 결정될 수 있다.
리간드 (예를 들어, 단일 가변 도메인, 융합 단백질 또는 다중-특이적 리간드) 반감기의 약동학 분석 및 결정을 위한 방법이 당업자에게 친숙할 것이다. 상세한 사항은 문헌 [Kenneth, A et al.: Chemical Stability of Pharmaceuticals: A Handbook for Pharmacists] 및 [Peters et al., Pharmacokinetc analysis: A Practical Approach (1996)]에서 찾아볼 수 있다. 또한, t 알파 및 t 베타 반감기 및 곡선하 면적 (AUC)과 같은 약동학 파라미터가 기재되어 있는 문헌 ["Pharmacokinetics", M Gibaldi & D Perron, published by Marcel Dekker, 2nd Rev. ex edition (1982)]을 참조한다. 임의로는, 본원에 인용된 모든 약동학 파라미터 및 값은 인간에서의 값으로 판독될 것이다. 임의로는, 본원에 인용된 모든 약동학 파라미터 및 값은 마우스 또는 래트 또는 시노몰구스 원숭이에서의 값으로 판독될 것이다.
반감기 (t½ 알파 및 t½ 베타) 및 AUC는 시간에 대한 리간드의 혈청 농도의 곡선으로부터 결정할 수 있다. 윈놀린(WinNonlin) 분석 패키지, 예를 들어 버전 5.1 (파르사이트 코포레이션 (Pharsight Corp., 미국 CA94040 마운틴 뷰)으로부터 이용가능함)을 사용하여, 예를 들어 곡선을 모델링할 수 있다. 2-구획 모델링이 사용되는 경우, 제1 단계 (알파 단계)에서 리간드는 주로 환자 내에 분포되고, 일부 제거되었다. 제2 단계 (베타 단계)는 리간드가 분포되어 있고, 리간드가 환자로부터 소거됨에 따라 혈청 농도가 감소되는 단계이다. t 알파 반감기는 제1 단계의 반감기이고, t 베타 반감기는 제2 단계의 반감기이다. 따라서, 한 실시양태에서, 본 발명의 문맥에서, 가변 도메인, 융합 단백질 또는 리간드는 15분 (또는 약 15분) 이상의 범위의 tα 반감기를 갖는다. 한 실시양태에서, 범위의 하한은 30분, 45분, 1시간, 2시간, 3시간, 4시간, 5시간, 6시간, 7시간, 10시간, 11시간 또는 12시간 (또는 약 30분, 45분, 1시간, 2시간, 3시간, 4시간, 5시간, 6시간, 7시간, 10시간, 11시간 또는 12시간)이다. 부가적으로 또는 다르게는, 본 발명에 따른 가변 도메인, 융합 단백질 또는 리간드는 12시간 (또는 약 12시간) 이하 (상한 포함)의 범위의 tα 반감기를 가질 것이다. 한 실시양태에서, 범위의 상한은 11, 10, 9, 8, 7, 6 또는 5시간 (또는 약 11, 10, 9, 8, 7, 6 또는 5시간)이다. 적합한 범위의 예는 1 내지 6시간, 2 내지 5시간 또는 3 내지 4시간 (또는 약 1 내지 6시간, 2 내지 5시간 또는 3 내지 4시간)이다.
한 실시양태에서, 본 발명은 2.5시간 (또는 약 2.5시간) 이상의 범위의 tβ 반감기를 갖는 본 발명에 따른 가변 도메인, 융합 단백질 또는 리간드를 제공한다. 한 실시양태에서, 범위의 하한은 3시간, 4시간, 5시간, 6시간, 7시간, 10시간, 11시간 또는 12시간 (또는 약 3시간, 4시간, 5시간, 6시간, 7시간, 10시간, 11시간 또는 12시간)이다. 부가적으로 또는 다르게는, tβ 반감기는 21 또는 25일 (또는 약 21 또는 25일) 이하 (상한 포함)이다. 한 실시양태에서, 범위의 상한은 12시간, 24시간, 2일, 3일, 5일, 10일, 15일, 19일, 20일, 21일 또는 22일 (또는 약 12시간, 24시간, 2일, 3일, 5일, 10일, 15일, 19일, 20일, 21일 또는 22일)이다. 예를 들어, 본 발명에 따른 가변 도메인, 융합 단백질 또는 리간드는 12 내지 60시간 (또는 약 12 내지 60시간) 범위의 tβ 반감기를 가질 것이다. 추가의 실시양태에서, 이는 12 내지 48시간 (또는 약 12 내지 48시간)의 범위일 것이다. 다른 추가의 실시양태에서, 이는 12 내지 26시간 (또는 약 12 내지 26시간)의 범위일 것이다.
2-구획 모델링을 사용하는 것에 대한 대안으로, 당업자는 최종 반감기를 결정하는데 사용될 수 있는 비-구획 모델링의 사용이 친숙할 것이다 (이와 관련하여, 본원에 사용된 용어 "최종 반감기"는 비-구획 모델링을 사용하여 결정된 최종 반감기를 의미함). 윈논린 분석 패키지, 예를 들어 버전 5.1 (파르사이트 코포레이션 (미국 CA94040 마운틴 뷰)으로부터 이용가능함)을 사용하여, 예를 들어 이 방식으로 곡선을 모델링할 수 있다. 이 경우에, 한 실시양태에서, 단일 가변 도메인, 융합 단백질 또는 리간드는 적어도 8시간, 10시간, 12시간, 15시간, 28시간, 20시간, 1일, 2일, 3일, 7일, 14일, 15일, 16일, 17일, 18일, 19일, 20일, 21일, 22일, 23일, 24일 또는 25일 (또는 적어도 약 8시간, 10시간, 12시간, 15시간, 28시간, 20시간, 1일, 2일, 3일, 7일, 14일, 15일, 16일, 17일, 18일, 19일, 20일, 21일, 22일, 23일, 24일 또는 25일)의 최종 반감기를 갖는다. 한 실시양태에서, 이 범위의 상한은 24시간, 48시간, 60시간 또는 72시간 또는 120시간 (또는 약 24시간, 48시간, 60시간 또는 72시간 또는 120시간)이다. 예를 들어, 최종 반감기는 예를 들어 인간에서 8시간 내지 60시간, 또는 8시간 내지 48시간 또는 12시간 내지 120시간 (또는 약 8시간 내지 60시간, 또는 8시간 내지 48시간 또는 12시간 내지 120시간)이다.
상기 기준에 대해 부가적으로 또는 다르게는, 본 발명에 따른 가변 도메인, 융합 단백질 또는 리간드는 1 mg.min/ml (또는 약 1 mg.min/ml) 이상의 범위의 AUC 값 (곡선하 면적)을 갖는다. 한 실시양태에서, 범위의 하한은 5, 10, 15, 20, 30, 100, 200 또는 300 mg.min/ml (또는 약 5, 10, 15, 20, 30, 100, 200 또는 300 mg.min/ml)이다. 부가적으로 또는 다르게는, 본 발명에 따른 가변 도메인, 융합 단백질 또는 리간드는 600 mg.min/ml (또는 약 600 mg.min/ml) 이하의 범위의 AUC를 갖는다. 한 실시양태에서, 범위의 상한은 500, 400, 300, 200, 150, 100, 75 또는 50 mg.min/ml (또는 약 500, 400, 300, 200, 150, 100, 75 또는 50 mg.min/ml)이다. 유리하게는, 가변 도메인, 융합 단백질 또는 리간드는 15 내지 150 mg.min/ml, 15 내지 100 mg.min/ml, 15 내지 75 mg.min/ml 및 15 내지 50 mg.min/ml로 이루어진 군으로부터 선택된 범위 (또는 약 상기 범위)의 AUC를 가질 것이다.
"표면 플라즈몬 공명": 경쟁 검정을 사용하여 특정 항원 또는 에피토프, 예컨대 인간 혈청 알부민이 본원에 기재된 혈청 알부민 결합 리간드, 예컨대 특정 dAb에 대한 결합에 대해 다른 항원 또는 에피토프, 예컨대 시노몰구스 혈청 알부민과 경쟁하는지 여부를 결정할 수 있다. 이와 유사하게, 경쟁 검정을 사용하여 제1 리간드, 예컨대 dAb가 표적 항원 또는 에피토프에 대한 결합에 대해 제2 리간드, 예컨대 dAb와 경쟁하는지 여부를 결정할 수 있다. 본원에 사용된 용어 "경쟁하다"는 2가지 이상의 분자 사이의 특이적 결합 상호작용을 임의의 정도로 방해할 수 있는 물질, 예컨대 분자, 화합물, 바람직하게는 단백질을 지칭한다. 어구 "경쟁적으로 억제하지 않는다"는 물질, 예컨대 분자, 화합물, 바람직하게는 단백질이 2가지 이상의 분자 사이의 특이적 결합 상호작용을 임의의 측정가능하거나 또는 유의한 정도로 방해하지 않는다는 것을 의미한다. 2가지 이상의 분자 사이의 특이적 결합 상호작용은 바람직하게는 단일 가변 도메인과 그의 동족 상대 또는 표적 사이의 특이적 결합 상호작용을 포함한다. 분자를 방해하거나 또는 이와 경쟁하는 것은 다른 단일 가변 도메인일 수 있거나 또는 이는 동족 상대 또는 표적과 구조적으로 및/또는 기능적으로 유사한 분자일 수 있다.
용어 "결합 모이어티"는 상이한 에피토프 또는 항원 결합 도메인과 독립적으로 항원 또는 에피토프에 특이적으로 결합하는 도메인을 지칭한다. 결합 모이어티는 도메인 항체 (dAb)일 수 있거나 또는 천연 리간드가 아닌 리간드에 결합하는 비-이뮤노글로불린 단백질 스캐폴드, 예를 들어 CTLA-4, 리포칼린, SpA, 애드넥틴, 아피바디, 아비머, GroEl, 트랜스페린, GroES 및 피브로넥틴으로 이루어진 군으로부터 선택된 스캐폴드의 유도체인 도메인일 수 있다 (본 발명의 경우, 모이어티는 혈청 알부민에 결합함). 단백질 스캐폴드 및 레퍼토리로부터 항원 또는 에피토프-특이적 결합 도메인을 선별하는 방법의 예를 개시하고 있는 WO2008/096158을 참조한다 (실시예 17 내지 25 참조). 이들 WO2008/096158의 특정 개시내용은 명백하게 본원에 기재된 바와 같이, 그리고 본 발명과 함께 사용하기 위해 본원에 참고로 포함되며, 이러한 개시내용의 임의의 부분이 본원의 하나 이상의 특허청구범위에 포함될 수 있는 것으로 고려된다.
한 실시양태에서, 본 발명의 가변 도메인은 하기 동역학 특성 중 하나 이상을 포함한다:-
(a) 가변 도메인은 표면 플라즈몬 공명에 의해 결정된, 0.1 (또는 약 0.1) 내지 10000 (또는 약 10000) nM, 임의로는 1 (또는 약 1) 내지 6000 (또는 약 6000) nM의 해리 상수 (KD)로 인간 SA에 특이적으로 결합하는 결합 부위를 포함하고/거나;
(b) 가변 도메인은 표면 플라즈몬 공명에 의해 결정된, 1.5 x 10-4 (또는 약 1.5 x 10-4) 내지 0.1 (또는 약 0.1) sec-1, 임의로는 3 x 10-4 (또는 약 3 x 10-4) 내지 0.1 (또는 약 0.1) sec-1의 오프-레이트 상수 (Kd)로 인간 SA에 특이적으로 결합하는 결합 부위를 포함하고/거나;
(c) 가변 도메인은 표면 플라즈몬 공명에 의해 결정된, 2 x 106 (또는 약 2 x 106) 내지 1 x 104 (또는 약 1 x 104) M-1sec-1, 임의로는 1 x 106 (또는 약 1 x 106) 내지 2 x 104 (또는 약 2 x 104) M-1sec-1의 온-레이트(on-rate) 상수 (Ka)로 인간 SA에 특이적으로 결합하는 결합 부위를 포함하고/거나;
(d) 가변 도메인은 표면 플라즈몬 공명에 의해 결정된, 0.1 (또는 약 0.1) 내지 10000 (또는 약 10000) nM, 임의로는 1 (또는 약 1) 내지 6000 (또는 약 6000) nM의 해리 상수 (KD)로 시노몰구스 원숭이 SA에 특이적으로 결합하는 결합 부위를 포함하고/거나;
(e) 가변 도메인은 표면 플라즈몬 공명에 의해 결정된, 1.5 x 10-4 (또는 약 1.5 x 10-4) 내지 0.1 (또는 약 0.1) sec-1, 임의로는 3 x 10-4 (또는 약 3 x 10-4) 내지 0.1 (또는 약 0.1) sec-1의 오프-레이트 상수 (Kd)로 시노몰구스 원숭이 SA에 특이적으로 결합하는 결합 부위를 포함하고/거나;
(f) 가변 도메인은 표면 플라즈몬 공명에 의해 결정된, 2 x 106 (또는 약 2 x 106) 내지 1 x 104 (또는 약 1 x 104) M-1sec-1, 임의로는 1 x 106 (또는 약 1 x 106) 내지 5 x 103 (또는 약 5 x 103) M-1sec-1의 온-레이트 상수 (Ka)로 시노몰구스 원숭이 SA에 특이적으로 결합하는 결합 부위를 포함하고/거나;
(g) 가변 도메인은 표면 플라즈몬 공명에 의해 결정된, 1 (또는 약 1) 내지 10000 (또는 약 10000) nM, 임의로는 20 (또는 약 20) 내지 6000 (또는 약 6000) nM의 해리 상수 (KD)로 래트 SA에 특이적으로 결합하는 결합 부위를 포함하고/거나;
(h) 가변 도메인은 표면 플라즈몬 공명에 의해 결정된, 2 x 10-3 (또는 약 2 x 10-3) 내지 0.15 (또는 약 0.15) sec-1, 임의로는 9 x 10-3 (또는 약 9 x 10-3) 내지 0.14 (또는 약 0.14) sec-1의 오프-레이트 상수 (Kd)로 래트 SA에 특이적으로 결합하는 결합 부위를 포함하고/거나;
(i) 가변 도메인은 표면 플라즈몬 공명에 의해 결정된, 2 x 106 (또는 약 2 x 106) 내지 1 x 104 (또는 약 1 x 104) M-1sec-1, 임의로는 1 x 106 (또는 약 1 x 106) 내지 3 x 104 (또는 약 3 x 104) M-1sec-1의 온-레이트 상수 (Ka)로 래트 SA에 특이적으로 결합하는 결합 부위를 포함하고/거나;
(j) 가변 도메인은 표면 플라즈몬 공명에 의해 결정된, 1 (또는 약 1) 내지 10000 (또는 약 10000) nM의 해리 상수 (KD)로 마우스 SA에 특이적으로 결합하는 결합 부위를 포함하고/거나;
(k) 가변 도메인은 표면 플라즈몬 공명에 의해 결정된, 2 x 10-3 (또는 약 2 x 10-3) 내지 0.15 (또는 약 0.15) sec-1의 오프-레이트 상수 (Kd)로 마우스 SA에 특이적으로 결합하는 결합 부위를 포함하고/거나;
(l) 가변 도메인은 표면 플라즈몬 공명에 의해 결정된, 2 x 106 (또는 약 2 x 106) 내지 1 x 104 (또는 약 1 x 104) M-1sec-1, 임의로는 2 x 106 (또는 약 2 x 106) 내지 1.5 x 104 (또는 약 1.5 x 104) M-1sec-1의 온-레이트 상수 (Ka)로 마우스 SA에 특이적으로 결합하는 결합 부위를 포함한다.
임의로, 가변 도메인은
I: (a) 및 (d)에 따른 KD, (b) 및 (e)에 따른 Kd, 및 (c) 및 (f)에 따른 Ka; 또는
II: (a) 및 (g)에 따른 KD, (b) 및 (h)에 따른 Kd, 및 (c) 및 (i)에 따른 Ka; 또는
III: (a) 및 (j)에 따른 KD, (b) 및 (k)에 따른 Kd, 및 (c) 및 (l)에 따른 Ka; 또는
IV: I 및 II에 따른 동역학; 또는
V: I 및 III에 따른 동역학; 또는
VI: I, II 및 III에 따른 동역학을 갖는다.
본 발명은 또한 본 발명의 임의의 상기 측면 또는 실시양태의 가변 도메인을 포함하는 리간드를 제공한다. 예를 들어, 리간드는 이중-특이적 리간드일 수 있다 (이중-특이적 리간드의 예에 대해 WO04003019 참조). 한 측면에서, 본 발명은 본 발명의 임의의 상기 측면 또는 실시양태의 항-SA 가변 도메인 및 SA가 아닌 표적 항원에 특이적으로 결합하는 결합 모이어티를 포함하는 다중특이적 리간드를 제공한다. 결합 모이어티는 표적에 특이적으로 결합하는 임의의 결합 모이어티일 수 있고, 예를 들어 모이어티는 항체, 항체 단편, scFv, Fab, dAb, 또는 비-이뮤노글로불린 단백질 스캐폴드를 포함하는 결합 모이어티이다. 이러한 잔기는 WO2008/096158에 상세히 기재되어 있다 (실시예 17 내지 25 참조, 개시내용은 본원에 참고로 포함됨). 비-이뮤노글로불린 스캐폴드의 예는 CTLA-4, 리포칼린, 스타필로코쿠스 단백질 A (spA), 아피바디™, 아비머™, 애드넥틴, GroEL 및 피브로넥틴이다.
한 실시양태에서, 링커는 항-표적 결합 모이어티와 항-SA 가변 도메인 사이에 제공되고, 이 링커는 아미노산 서열 AST, 임의로는 ASTSGPS를 포함한다. 다른 링커가 WO2007085814 (본원에 참고로 포함됨) 및 WO2008/096158 (135면, 12행 내지 140면, 14행의 내용 참조, 개시내용 및 링커의 모든 서열은 명백하게 본원에 기재된 바와 같이, 그리고 본 발명과 함께 사용하기 위해 본원에 참고로 포함되며, 이러한 개시내용의 임의의 부분이 본원의 하나 이상의 특허청구범위에 포함될 수 있는 것으로 고려됨)에 기재되어 있다.
다중특이적 리간드의 한 실시양태에서, 표적 항원은 자연 발생되거나 또는 합성될 수 있는 폴리펩티드, 단백질 또는 핵산일 수 있거나 또는 이들의 부분일 수 있다. 이와 관련하여, 본 발명의 리간드는 표적 항원에 결합하여, 길항제 또는 효능제 (예를 들어, EPO 수용체 효능제)로서 작용할 수 있다. 당업자는 선택이 광범위하고 다양하다는 것을 이해할 것이다. 이들은 예를 들어 인간 또는 동물 단백질, 시토카인, 시토카인 수용체 (여기서, 시토카인 수용체는 시토카인에 대한 수용체를 포함함), 효소, 효소에 대한 보조-인자 또는 DNA 결합 단백질일 수 있다. 적합한 시토카인 및 성장 인자는 ApoE, Apo-SAA, BDNF, 카디오트로핀-1, EGF, EGF 수용체, ENA-78, 에오탁신, 에오탁신-2, 엑소두스-2, EpoR, FGF-산성, FGF-염기성, 섬유모세포 성장 인자-10, FLT3 리간드, 프랙탈카인 (CX3C), GDNF, G-CSF, GM-CSF, GF-β1, 인슐린, IFN-γ, IGF-I, IGF-II, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8 (72 a.a.), IL-8 (77 a.a.), IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18 (IGIF), 인히빈 α, 인히빈 β, IP-10, 각질세포 성장 인자-2 (KGF-2), KGF, 렙틴, LIF, 림포탁틴, 뮐러 억제 물질, 단핵구 콜로니 억제 인자, 단핵구 유인 단백질, M-CSF, MDC (67 a.a.), MDC (69 a.a.), MCP-1 (MCAF), MCP-2, MCP-3, MCP-4, MDC (67 a.a.), MDC (69 a.a.), MIG, MIP-1α, MIP-1β, MIP-3α, MIP-3β, MIP-4, 골수 선조체 억제제 인자-1 (MPIF-1), NAP-2, 뉴르투린, 신경 성장 인자, β-NGF, NT-3, NT-4, 온코스타틴 M, PDGF-AA, PDGF-AB, PDGF-BB, PF-4, RANTES, SDF1α, SDF1β, SCF, SCGF, 줄기 세포 인자 (SCF), TARC, TGF-α, TGF-β, TGF-β2, TGF-β3, 종양 괴사 인자 (TNF), TNF-α, TNF-β, TNF 수용체 I, TNF 수용체 II, TNIL-1, TPO, VEGF, VEGF 수용체 1, VEGF 수용체 2, VEGF 수용체 3, GCP-2, GRO/MGSA, GRO-β, GRO-γ, HCC1, 1-309, HER 1, HER 2, HER 3 및 HER 4, CD4, 인간 케모카인 수용체 CXCR4 또는 CCR5, C형 간염 바이러스로부터의 비-구조적 단백질 유형 3 (NS3), TNF-알파, IgE, IFN-감마, MMP-12, CEA, 에이치. 필로리(H. pylori), TB, 인플루엔자, E형 간염, MMP-12, 특정 세포 상에서 과다발현되는 내재화 수용체, 예컨대 표피 성장 인자 수용체 (EGFR), 종양 세포 상의 ErBb2 수용체, 내재화 세포 수용체, LDL 수용체, FGF2 수용체, ErbB2 수용체, 트랜스페린 수용체, PDGF 수용체, VEGF 수용체, PsmAr, 세포외 기질 단백질, 엘라스틴, 피브로넥틴, 라미닌, α1-항트립신, 조직 인자 프로테아제 억제제, PDK1, GSK1, Bad, 카스파제-9, 포크헤드, 헬리코박터 필로리의 항원, 미코박테리움 투베르쿨로시스(Mycobacterium tuberculosis)의 항원 및 인플루엔자 바이러스의 항원을 포함하나, 바람직하게는 이에 제한되지는 않는다. 이 목록이 결코 전부는 아닌 것으로 이해될 것이다.
한 실시양태에서, 다중특이적 리간드는 본 발명의 항-SA dAb 가변 도메인 및 항-TNFR1 결합 모이어티, 예를 들어 항-TNFR1 dAb를 포함한다. 임의로는, 리간드는 수용체 가교의 기회를 감소시키기 위해 오직 하나의 항-TNFR1 결합 모이어티 (예를 들어, dAb)를 갖는다. 한 실시양태에서, 항-SA dAb는 서열 97 내지 103 및 198 내지 203 중 어느 하나의 아미노산 서열 (또는 서열 97 내지 103 및 198 내지 203 중 어느 하나의 아미노산 서열과 적어도 95, 96, 97, 98 또는 99％ 동일한 아미노산 서열)을 포함하거나 또는 이것으로 이루어진다.
한 실시양태에서, 항-TNFR1 결합 모이어티는 WO2008149148 (이 PCT 출원에 개시된 그의 아미노산 서열 및 그의 뉴클레오티드 서열은 명백하게 본원에 기재된 바와 같이, 그리고 본 발명과 함께 사용하기 위해 본원에 참고로 포함되며, 이러한 개시내용의 임의의 부분이 본원의 하나 이상의 특허청구범위에 포함될 수 있는 것으로 고려됨)에 개시된 DOM1h-131-206이다. 한 실시양태에서, 다중특이적 리간드는 DOM1h-131-206의 아미노산 서열 및 서열 97 내지 103 및 198 내지 203 중 어느 하나의 아미노산 서열 (또는 서열 97 내지 103 및 198 내지 203 중 어느 하나의 아미노산 서열과 적어도 95, 96, 97, 98 또는 99％ 동일한 아미노산 서열)을 포함하거나 또는 이것으로 이루어진다.
한 실시양태에서, 항-TNFR1 결합 모이어티 또는 dAb는 동시-계류 중인 출원 USSN 61/153,746 (그 개시내용은 본원에 참고로 포함됨)에 개시된 임의의 이러한 모이어티 또는 dAb이다. 한 실시양태에서, 항-TNFR1 결합 모이어티는 DOM1h-574-156, DOM1h-574-72, DOM1h-574-109, DOM1h-574-138, DOM1h-574-162 또는 DOM1h-574-180의 아미노산 서열 또는 본원에 개시된 임의의 항-TNFR1 dAb의 아미노산 서열과 적어도 95％ 동일한 아미노산 서열을 포함한다. 한 실시양태에서, 다중특이적 리간드는 DOM1h-574-156의 아미노산 서열 및 서열 97 내지 103 및 198 내지 203 중 어느 하나의 아미노산 서열 (또는 서열 97 내지 103 및 198 내지 203 중 어느 하나의 아미노산 서열과 적어도 95, 96, 97, 98 또는 99％ 동일한 아미노산 서열)을 포함하거나 또는 이것으로 이루어진다.
한 실시양태에서, 본 발명의 리간드는 하나 이상의 폴리펩티드에 직접 또는 간접적으로 융합된 본 발명의 가변 도메인을 포함하는 융합 단백질이다. 예를 들어, 융합 단백질은 WO2005/118642 (그 개시내용은 본원에 참고로 포함됨)에 개시된 "약물 융합체"일 수 있으며, 이는 본 발명의 가변 도메인 및 상기 PCT 출원에 정의된 폴리펩티드 약물을 포함한다.
본원에 사용된 "약물"은 개체에서 생물학적 표적 분자에 결합하고/거나 그의 기능을 변경시키는 것을 통해 유익한 치료 또는 진단 효과를 생성하기 위해 개체에게 투여될 수 있는 임의의 화합물 (예를 들어, 유기 소분자, 핵산, 폴리펩티드)을 지칭한다. 표적 분자는 개체의 게놈에 의해 코딩되는 내인성 표적 분자 (예를 들어, 개체의 게놈에 의해 코딩되는 효소, 수용체, 성장 인자, 시토카인) 또는 병원체의 게놈에 의해 코딩되는 외인성 표적 분자 (예를 들어, 바이러스, 박테리아, 진균, 선충류 또는 다른 병원체의 게놈에 의해 코딩되는 효소)일 수 있다. 본 발명의 항-SA dAb 가변 도메인을 포함하는 융합 단백질 및 접합체에 사용하기에 적합한 약물은 WO2005/118642 및 WO2006/059106에 개시되어 있다 (특정 약물에 대한 전체 목록을 비롯하여 이들의 전체 개시내용은 상기 목록이 명백하게 본원에 기재된 바와 같이 본원에 참고로 포함되며, 이같은 포함은 본원의 특허청구범위에 포함되도록 특정 약물을 개시하는 것으로 고려됨). 예를 들어, 약물은 글루카곤-유사 펩티드 1 (GLP-1) 또는 변이체, 인터페론 알파 2b 또는 변이체 또는 엑센딘-4 또는 변이체일 수 있다.
한 실시양태에서, 본 발명은 WO2005/118642 및 WO2006/059106에 정의되고 개시된 약물 접합체를 제공하고, 여기서 접합체는 본 발명의 가변 도메인을 포함한다. 한 예에서, 약물은 가변 도메인에 공유적으로 연결된다 (예를 들어, 가변 도메인 및 약물은 단일 폴리펩티드의 일부로 나타내어짐). 다르게는, 한 예에서, 약물은 가변 도메인에 비공유적으로 결합되거나 회합된다. 약물은 가변 도메인에 직접 또는 간접적으로 (예를 들어, 적합한 링커 및/또는 상보적 결합 상대 (예를 들어, 비오틴 및 아비딘)의 비공유 결합을 통해) 공유 또는 비공유 결합될 수 있다. 상보적 결합 상대가 사용되는 경우, 결합 상대 중 하나는 약물에 직접적으로 또는 적합한 링커 모이어티를 통해 공유 결합될 수 있고, 상보적 결합 상대는 가변 도메인에 직접적으로 또는 적합한 링커 모이어티를 통해 공유 결합될 수 있다. 약물이 폴리펩티드 또는 펩티드인 경우, 약물 조성물은 융합 단백질일 수 있고, 여기서 폴리펩티드 또는 펩티드, 약물 및 폴리펩티드 결합 모이어티는 연속적인 폴리펩티드 쇄의 불연속적인 부분 (모이어티)이다. 본원에 기재된 바와 같이, 폴리펩티드 결합 모이어티 및 폴리펩티드 약물 모이어티는 펩티드 결합을 통해 서로 직접 결합되거나 또는 적합한 아미노산, 또는 펩티드 또는 폴리펩티드 링커를 통해 연결될 수 있다.
혈청 알부민에 특이적으로 결합하는 본 발명의 하나의 단일 가변 도메인 (예를 들어 단량체) 또는 하나 초과의 단일 가변 도메인 (본원에 정의된 바와 같은 다량체, 융합 단백질, 접합체 및 이중 특이적 리간드)를 함유하는 리간드는 표지, 태그, 추가의 단일 가변 도메인, dAb, 항체, 및 항체 단편, 마커 및 약물 (바람직하게는 이에 제한되지는 않음)로부터 선택된 하나 이상의 물질을 추가로 포함할 수 있다. 이들 물질 중 하나 이상은 단일 가변 도메인 (이뮤노글로불린 또는 비-이뮤노글로불린 단일 가변 도메인)을 포함하는 리간드의 COOH 말단 또는 N 말단 또는 N 말단 및 COOH 말단 둘 모두에 위치할 수 있다. 이들 물질 중 하나 이상은 하나의 단일 가변 도메인 (단량체) 또는 하나 초과의 단일 가변 도메인 (본원에 정의된 바와 같은 다량체, 융합 단백질, 접합체 및 이중 특이적 리간드)을 함유하는 리간드의 혈청 알부민에 특이적으로 결합하는 단일 가변 도메인의 COOH 말단 또는 N 말단 또는 N 말단 및 COOH 말단 둘 모두에 위치할 수 있다. 이들 말단 중 하나 또는 둘 모두에 위치할 수 있는 태그의 비제한적 예는 HA, his 또는 myc 태그를 포함한다. 하나 이상의 태그, 표지 및 약물을 비롯한 물질은 상기 기재된 바와 같이 혈청 알부민에 직접 또는 링커를 통해 결합하는 하나의 단일 가변 도메인 (단량체) 또는 하나 초과의 단일 가변 도메인 (본원에 정의된 바와 같은 다량체, 융합 단백질, 접합체 및 이중 특이적 리간드)을 함유하는 리간드에 결합될 수 있다.
본 발명의 측면은 상기 기재된 임의의 가변 도메인에 융합되거나 또는 접합된 (NCE의 경우) 폴리펩티드 약물을 포함하는 융합 생성물, 예를 들어 펩티드와의 융합 단백질 또는 융합체, 또는 NCE (신규 화학 물질) 약물과의 접합체를 제공하며, 임의로는 여기서 가변 도메인은 서열 97 내지 103 및 198 내지 203 중 어느 하나의 아미노산 서열 (또는 서열 97 내지 103 및 198 내지 203 중 어느 하나의 아미노산 서열과 적어도 95, 96, 97, 98 또는 99％ 동일한 아미노산 서열)을 포함하거나 또는 이것으로 이루어진다.
본 발명은 본 발명의 임의의 측면의 가변 도메인, 융합 단백질, 접합체 또는 리간드 및 제약상 허용되는 희석제, 담체, 부형제 또는 비히클을 포함하는 조성물을 제공한다.
또한, 혈청 알부민에 특이적으로 결합하거나 또는 인간 혈청 알부민 및 적어도 하나의 비-인간 혈청 알부민 또는 이들의 기능적 활성 단편 둘 모두에 특이적으로 결합하는, 본원에 기재된 임의의 가변 도메인, 융합 단백질, 접합체 또는 리간드, 예를 들어 본 발명의 하나의 단일 가변 도메인 (예를 들어 단량체) 또는 하나 초과의 단일 가변 도메인 (예를 들어, 본원에 정의된 바와 같은 다량체, 융합 단백질, 접합체 및 이중 특이적 리간드)을 함유하는 리간드를 코딩하는 단리된 핵산이 본원에 포함된다. 또한, 벡터 및/또는 발현 벡터, 벡터를 포함하는 숙주 세포 (예를 들어 비-인간 숙주 세포 또는 인간 또는 인간 배아로부터 단리되지 않은 숙주 세포), 예를 들어 벡터로 형질전환된 식물 또는 동물 세포 및/또는 세포주, 혈청 알부민에 특이적으로 결합하는, 상기 벡터에 의해 코딩된 하나의 단일 가변 도메인 (단량체) 또는 하나 초과의 단일 가변 도메인 (예를 들어, 본원에 정의된 바와 같은 다량체, 융합 단백질, 접합체, 및 이중 특이적 리간드)을 함유하는 하나 이상의 가변 도메인, 융합 단백질 또는 리간드 또는 그의 단편(들)의 발현 및/또는 생성 방법 (일부 예에서는 숙주 세포를 배양하여 하나 이상의 가변 도메인, 융합 단백질 또는 리간드 또는 그의 단편을 발현시키고, 임의로는 숙주 세포 배양 배지로부터 혈청 알부민에 특이적으로 결합하는 하나의 단일 가변 도메인 (단량체) 또는 하나 초과의 단일 가변 도메인 (예를 들어, 본원에 정의된 바와 같은 다량체, 융합 단백질, 접합체, 및 이중 특이적 리간드)을 함유하는 리간드를 회수하는 방법을 포함함)이 본원에 포함된다. 또한, 본원에 기재된 리간드를 혈청 알부민 및/또는 비-인간 혈청 알부민(들)을 비롯한 혈청 알부민, 및/또는 혈청 알부민이 아닌 하나 이상의 표적과 접촉시키는 방법이 포함되며, 여기서 표적은 생물학적 활성 분자를 포함하고, 상기 열거된 동물 단백질, 시토카인을 포함하며, 접촉을 시험관내에서 수행할 뿐만 아니라 본원에 기재된 임의의 가변 도메인, 융합 단백질 또는 리간드를 생체내 및/또는 생체외에서 개별 숙주 동물 또는 세포에 투여하는 방법을 포함한다. 바람직하게는, 혈청 알부민 및/또는 비-인간 혈청 도메인(들)에 대해 지시된 단일 가변 도메인 (이뮤노글로불린 또는 비-이뮤노글로불린) 및 혈청 알부민이 아닌 하나 이상의 표적에 대해 지시된 하나 이상의 도메인을 포함하는, 본원에 기재된 리간드를 투여하는 것은 항-표적 리간드의 반감기 (T 베타 및/또는 최종 반감기 포함)를 증가시킬 것이다. 리간드 또는 그의 단편 (그의 기능적 단편 포함)을 함유하는 도메인, 융합 단백질 또는 단일 도메인을 코딩하는 핵산 분자가 본원에서 고려된다. 발현 벡터를 비롯하여 (바람직하게는 이에 제한되지는 않음), 핵산 분자를 코딩하는 벡터가 본원에서 고려되고, 하나 이상의 이들 발현 벡터를 함유하는 세포주 또는 유기체로부터의 숙주 세포가 고려된다. 또한, 임의의 상기 언급된 핵산, 벡터 및 숙주 세포를 비롯하여 (바람직하게는 이에 제한되지는 않음), 임의의 도메인, 융합 단백질 또는 리간드를 생성하는 방법이 고려된다.
본 발명의 측면은 본 발명에 따른 가변 도메인 또는 본 발명의 다중특이적 리간드 또는 본 발명의 융합 단백질을 코딩하는 뉴클레오티드 서열을 포함하는 핵산을 제공한다.
본 발명의 측면은 서열 1 내지 96 및 192-197 중 어느 하나로부터 선택된 뉴클레오티드 서열, 또는 상기 선택된 서열과 적어도 70, 75, 80, 85, 90, 95, 96, 97, 98 또는 99％ 동일한 뉴클레오티드 서열을 포함하는 핵산을 제공한다.
본 발명의 측면은 본 발명의 핵산을 포함하는 벡터를 제공한다. 본 발명의 측면은 벡터를 포함하는 단리된 숙주 세포를 제공한다.
라이브러리 벡터 시스템, 단일 가변 도메인의 조합, 이중 특이적 리간드의 특성화, 이중 특이적 리간드의 구조, 이중 특이적 리간드의 구축에 사용하기 위한 스캐폴드, 항-혈청 알부민 dAb 및 다중특이적 리간드 및 반감기-향상된 리간드의 사용, 및 항-혈청 알부민 dAb를 포함하는 조성물 및 제제의 상세한 내용에 대해 WO2008/096158을 참조한다. 이들 개시내용은 본 발명의 도메인, 리간드, 융합 단백질, 접합체, 핵산, 벡터, 숙주 및 조성물에 대한 것을 비롯하여, 본 발명과 함께 사용하기 위한 안내를 제공하기 위해 본원에 참고로 포함된다.
항-혈청 알부민 VH 단일 가변 도메인의 서열
모든 가변 도메인은 SPR에 의해 결정되는 바와 같이, 혈청 알부민의 적어도 하나의 종에 결합한다.
예증
실시예 1
생물물리학적 특성화:
2.5 L 진탕 플라스크에서의 일상적인 박테리아 발현 수준을 오넥스(Onex) 배지에서 30℃에서 48 시간 동안 250 rpm으로 배양한 후 결정하였다. 생물물리학적 특성은 SEC MALLS 및 DSC로 결정하였다.
SEC MALLS (크기 배제 크로마토그래피-다각도 레이저 광산란 검출법)는 용액에서 거대분자를 특성화하기 위한 비-침습적 기술이다. 간략하게, 단백질 (완충제 둘베코(Dulbecco)의 PBS 중 1 mg/mL의 농도)을 크기 배제 크로마토그래피 (칼럼: TSK3000; S200)에 의해 그의 유체역학적 특성에 따라 분리하였다. 분리 후에, 광을 산란시키는 단백질의 경향을 다각도 레이저 광산란 (MALLS) 검출기를 이용하여 측정하였다. 단백질이 검출기를 통과하는 동안 산란광의 강도를 각도의 함수로 측정하였다. 이 측정값을 굴절률 (RI) 검출기를 이용하여 결정된 단백질 농도와 함께 사용하여 적절한 방정식 (분석 소프트웨어 아스트라(Astra) v.5.3.4.12의 적분 부분)을 이용하여 몰 질량을 계산한다. 용리 피크의 중간 지점에서의 가장 높은 농도는 약 8-10 μM이었고, 이는 결과적으로 MALLS가 단백질의 용액중 상태를 결정할 시점의 농도이다.
DSC (시차 주사 열량법): 간략하게, 단백질을 180℃/시의 일정한 속도로 가열하고 (PBS 중 1 mg/mL), 열 변성과 관련된 검출가능한 열 변화를 측정하였다. 전이 중앙점 (appTm)을 결정하였으며, 이는 단백질의 50％가 그의 본래 입체형태로 있고 다른 50％가 변성된 온도로 기재하였다. 여기서, DSC는 검사된 대부분의 단백질이 다시 완전히 재폴딩되지 않는 겉보기 전이 중앙점 (appTm)을 결정하였다. Tm이 더 높을수록, 분자는 더 안정하였다. 사용된 소프트웨어 패키지는 오리진(Origin)R v7.0383이었다.
VH dAb의 특징을 이하의 표 1에 요약하였다. AlbudAb™ (즉, 항-혈청 알부민 dAb)의 교차 반응성을 표면 플라즈몬 공명 (SPR)을 이용하여 인간, 시노몰구스 원숭이 (cyno), 래트 및 마우스 혈청 알부민 (표의 "4AG")에 대해 결정하였다. 이 경우, 비아코어(Biacore)™를 사용하였다. SPR 및 CM5 칩에 공유적으로 커플링된 (아민 커플링) HSA (사내)의 정제된 개별 도메인을 이용하여 인간 혈청 알부민 (HSA)의 도메인 1, 2 및/또는 3 (D1,2,3)에 대한 에피토프 맵핑을 수행하였다. 발현은 2.5 L 칸막이형 유리 플라스크에서 오버나이트 익스프레스(OverNight Express)™ 중 500 mL의 부피로 30℃, 250 rpm에서 이루어졌다.
MALLS 결과: 단일 VH AlbudAb는 크기가 14 kDa이었다. MALLS에 의해 결정된 14 및 28 kDa 사이의 임의의 값은 다양한 정도의 자가-회합 또는 이량체 형성을 나타낸다 (즉 16 kDa은 시험한 조건하에서 우세하게 단량체성이고, 반면 22 kDa은 MALLS 조건하에서 이량체화되는 경향이 강함을 나타냄).
DSC 결과: DSC 실험에서의 단백질의 농도는 1 mg/mL로 MALLS와 비교하여 실제 반응 세포에서 보다 높다. 이와 같이 보다 높은 농도는 부분적으로, 표 1에서 관찰되는 바와 같이 일부 AlbudAb의 경우 두 개의 appTm의 존재로 설명될 수 있으며; 제1 Tm은 이량체 복합체의 해리를 구성하고, 제2 Tm은 폴딩되지 않은 실제 AlbudAb 단백질을 나타낸다.
DOM7h-112를 제외하고, 상기의 모든 선도 AlbudAb는 4종의 혈청 알부민 사이에서 완전히 교차 반응성이었다. 모든 확인된 AlbudAb는 HSA의 도메인2에 결합하였고, 비최적화된 조건하에서 진탕 플라스크에서 상당히 잘 발현되었다. 7 종의 AlbudAb 중 5종은 MALLS에 의해 단량체로 결정되었고, DOM7r-35는 MALLS 조건하에서 이량체화 경향이 상당한 것으로 나타났다. 단량체 상태는 이량체화 및 세포 표면 수용체와 같은 표적과 가교될 수 있는 생성물의 위험이 회피되기 때문에 유익하다.
DOM7r-36은 어느 정도의 응집체 형성을 나타내었다 (MALLS로 정량화시 10％ 미만). 7 종의 AlbudAb 중 5종의 경우, 2 appTm을 결정할 수 있었다. 이는 DSC 실험에서의 보다 높은 실험 농도 및 이와 같이 상승된 농도에서 dAb의 약간 상이한 용액중 상태로 인한 것이다 (상세 내용에 대해서는, 또한 상기의 설명을 참조한다).
실시예 2
래트에서의 혈청 반감기의 결정
AlbudAb를 pDOM5 벡터로 클로닝하였다. pDOM5 벡터는 단백질 발현이 LacZ 프로모터에 의해 구동되는 pUC119-기재 발현 벡터이다. GAS1 리더 서열 (WO 2005/093074 참조)은 이. 콜라이의 주변세포질 및 배양 상청액으로 단리된 가용성 dAb의 분비를 확실하게 한다. dAb를 이 벡터에 SalI/NotI 클로닝하여, dAb의 C-말단에 myc 태그를 부착하였다. 각각의 AlbudAb의 경우, 20 내지 50 mg의 양이 이. 콜라이에서 발현되었으며, 단백질 A 친화성 수지를 사용하여 박테리아 배양 상청액으로부터 정제하고, 100 mM 글리신 pH 2로 용출하였다. 단백질을 1 mg/ml 초과로 농축하고, 완충제를 PBS로 교체하고, 내독소를 Q 스핀 칼럼 (비바사이언스(Vivascience))을 사용하여 고갈시켰다. 래트 약동학 (PK) 분석을 위해, AlbudAb를 화합물 당 3마리의 래트를 사용하여 2.5 mg/kg으로 단일 i.v. 주사로 투여하였다. 혈청 샘플을 0.16, 1, 4, 12, 24, 48, 72, 96, 120, 168시간에 채취하였다. 혈청 수준 분석은 아래 기재하는 방법에 따라 항-myc 포획에 이어 항-VH 검출 ELISA에 의해 수행하였다.
결과를 표 2에 나타낸다. 모든 시험된 AlbudAb는 다양한 정도로 혈청 반감기 연장 능력을 나타내었고 (음성 대조군 HEL4 dAb는 래트에서 T1/2이 20분임); 이러한 경향은 또한 계산된 AUC (가장 긴 t1/2에 대한 가장 큰 값)에서도 관찰되었다. 가장 긴 혈청 반감기 (34.5시간)는 래트 혈청 알부민의 혈청 반감기의 근사치였다.
RSA에 대한 AlbudAb의 특이적 친화성을 결정할 필요가 있을 것이다.
MSD를 이용한 항-myc ELISA 방법
혈청 내의 AlbudAb 농도를 항-myc ELISA에 의해 측정하였다. 간략하게, 염소 항-myc 폴리클로날 항체 (1:500; 아브캄(Abcam), 카달로그 번호 ab9132)를 넌크(Nunc) 96-웰 맥시소르프(Maxisorp) 플레이트 상에 밤새 코팅하고, 5％ BSA/PBS + 1％ 트윈™으로 차단하였다. 혈청 샘플을 공지된 농도의 표준물과 함께 소정 범위의 희석액으로 첨가하였다. 이어서, MSD 술포-태그로 직접 표지된 토끼 폴리클로날 항-VH를 이용하여 결합된 myc-태그된 AlbudAb를 검출하였다. 각각의 dAb를 10％ 대조군 래트 혈청을 함유하는 검정 완충제 (1:1000; 사내 시약) 중에 희석하였다 (방법 DM222). MSD (메조스케일디스커버리(MesoScaleDiscovery); MesoScale.com)는 전기화학 자극 이후에 술포-태그의 전기화학발광 검출을 이용한다.
원래 ELISA 데이터로부터, 알려지지 않은 샘플의 농도를 희석 배율을 고려하는 표준 곡선에 대한 보간법에 의해 확립하였다. 각각의 시점으로부터의 평균 농도 결과를 반복된 값으로부터 결정하고, 윈논린 분석 패키지 (예를 들어, 버전 5.1 (파르사이트 코포레이션 (미국 CA94040 마운틴 뷰)으로부터 이용가능함)에 입력하였다. 데이터를 비-구획 모델을 사용하여 맞추고, 여기서 PK 파라미터는 최종 반감기를 제공하는 소프트웨어에 의해 평가하였다. 투여 정보 및 시점은 각각의 PK 프로파일의 최종 단계를 반영하도록 선택하였다.
실시예 3: 나이브 VH AlbudAb™의 친화도 성숙
친화도 성숙을 위해 나이브 선별로부터 단리된 12 종의 선도 VH AlbudAb를 취하였다. DOM7r-36, DOM7r-35, DOM7r-31, DOM7h-98, DOM7h-112, DOM7r-38 및 DOM7r-29의 개별적인 에러 유발 라이브러리 (EP)를 제작하는 한편, 다음과 같은 모 클론을 풀링하고, 단일 EP 라이브러리에서 합하고, 함께 스크리닝하였다: DOM7r-83, DOM7r-85, DOM7r-92, DOM7r-94 및 DOM7r-95. 모든 라이브러리는 2 x 109 CFU/mL 보다 더 컸다.
선별은 감소되는 항원 농도를 이용한 교차 선별에 의해 가용성 항원에 대해 4 라운드로 수행하였다 (비오틴-HSA; 비오틴-RSA; 2％ 마르벨(Marvel)로 차단): 라운드 1 1 μM (HSA 또는 RSA), 라운드 2 1 μM (RSA 또는 HSA), 이어서 라운드 2에서와 동일한 항원을 이용하여 각각 100 nM 및 10 nM로 2회의 추가 선별 라운드. R3 및 R4 결과물 둘 모두로부터 대략 3000개의 샘플을 상청액 비아코어에 의해 스크리닝하고, 클론을 그들의 오프-레이트에 따라서만 순위를 매겼다. 개선된 클론에 대해 8-점 희석 역학 친화도를 측정하였다 (이하의 데이터).
SEQUENCE LISTING
<110> Glaxo Group Limited
Edward COULSTOCK
Elena DE ANGELIS
Haiqun LIU
Oliver SCHON
<120> Improved anti-serum albumin binding
single variable domains
<130> IJF/DB63748 WO
<140> PCT/EP2010/060112
<141> 2010-07-14
<150> 61/226028
<151> 2009-07-16
<150> 61/307554
<151> 2010-02-24
<160> 203
<170> FastSEQ for Windows Version 4.0
<210> 1
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 1
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggg gggtatgtga tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcagct attaataggt ttggttcgtc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaggtagt 300
ttgcggcatt ttgactactg gggtcaggga accctggtca ccgtctcgag c 351
<210> 2
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 2
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggt aattatgcga tggcgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatcg attgatatgg ttggtattaa gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaggtttt 300
cgtatttttg actactgggg tcagggaacc ctggtcaccg tctcgagc 348
<210> 3
<211> 361
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 3
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttaag gattatgata tgacttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaatg atttcttcgt cgggtctttg gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaggtttt 300
aggctgtttc ctcggacttt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
g 361
<210> 4
<211> 372
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 4
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt caccttttcg ctgtatagga tggtgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaatg atttctcagt ttggtaatca gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagttagg 300
tcttgggatc agactggtgg tcgtcgtact tttgactact ggggtcaggg aaccctggtc 360
accgtctcga gc 372
<210> 5
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 5
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttaat cattatacga tggggtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcattg attcatccga gtggtacggt gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatggagt 300
tcgagggcgt ttgactactg gggtcaggga accctggtca ccgtctcgag c 351
<210> 6
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 6
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat aataatgcga tggggtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaact attagtgcga atggtaatgc gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagga cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagggttt 300
cgtcggtttg actactgggg tcagggaacc ctggtcaccg tctcgagc 348
<210> 7
<211> 355
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 7
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtacag cctccggatt cacctttagg cattatcgta tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatgg attcgtccgg atggtacgtt tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatcttat 300
atgggtgata ggtttgacta ctggggtcag ggaaccctgg tcaccgtctc gagcg 355
<210> 8
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 8
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgcgcag cctccggatt cacctttggt aattatccga tgacgtgggt ccgccaggct 120
ccagggaagg gtctggagtg ggtctcaact attagttatg gtggtcttgc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaatggcg 300
attaatggtg ttaggcctag gcggtttgac tactggggtc agggaaccct ggtcaccgtc 360
tcgagc 366
<210> 9
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 9
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttatg gcgtatcaga tggcttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaact attcatcaga cgggtttttc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggat accgcggtat attactgtgc gaaagtgcgt 300
tctatgcgtc cttataagtt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 10
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 10
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggt gataaggcaa tggggtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaacg attagtgctc ctggtaaccg tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaggtttt 300
cggaattttg actactgggg tcagggaacc ctggtcaccg tctcgagc 348
<210> 11
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 11
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat gggatgcgta tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcagct attgaggtga atggtcagca tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaatggct 300
catcctcagt cgggggtggc ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 12
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 12
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttacg cctgatgcta tggcgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatcg attggtgtga atggttctcc gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaggaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaatggct 300
catcctcagt cgggggtggc ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 13
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 13
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt caccttttat cagtcggata tgtcttgggt ccgccaggct 120
ccagggaaag gtctagagtg ggtctcatct atttcttctc agggtcgttc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaatggct 300
catcctcagt cgggggtggc ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 14
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 14
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtacag cctccggatt cacctttgcg gcgagggata tgagttgggt ccgccaggct 120
ccagggaagg gtctggagtg ggtctcaagt atttctgctc agggtgctca tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgacg attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggat accgcggtat attactgtgc gaaacctcgg 300
catcctcagg ggggggttac ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 15
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 15
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat aatggggata tggtttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaggg attgcgcata atggtcgtaa tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaaatttg 300
ggtcagggtt ttgactactg gggtcaggga accctggtca ccgtctcgag c 351
<210> 16
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 16
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
acctgtgcag cctccggatt caccttgaat ggtacgtcga tggggtgggt ccgccaggct 120
ccagggaagg atctagagtg ggtctcatct attatgcctg tgggttctca tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaatggct 300
catcctcagt cgggggtggc ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 17
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 17
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat catgcgccta tgaagtgggc ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatat attgggtcgg cgggtaatat gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagatgag 300
gggccgtttg actactgggg tcagggaacc ctggtcaccg tctcgagc 348
<210> 18
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 18
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtacag cctccggatt cacctttgat gggatggata tgagttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaagt atttctacga ctggtgggac tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacctcgg 300
catcctcagg ggggggttac ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 19
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 19
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgag gcggagacga tggcttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaact attcattcgg agggttctcg gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacctcgg 300
catcctcagg ggggggttac ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 20
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 20
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttagt actggggaga tggcttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatct attagttcga gtggtgctac gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacctcgg 300
catcctcagg ggggggttac ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 21
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 21
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttcct agtgctgata tggtttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcacgt atttcgcctg agggtaatca tacatactac 180
gcagactccg tgaagggtcg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggat accgcggtat attactgtgc ggaacggcct 300
ccttcggatt atgtttcttt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 22
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 22
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgcg aatgcgacta tgtcgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcagat attgatcagg tgggtcatgc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatattcg 300
tggcatccgg atctgtttga ctactggggt cagggaaccc tggtcaccgt ctcgagc 357
<210> 23
<211> 369
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 23
gaggtgcggc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttaag gattatggga tgaattgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcacgg attagtagga atggtactgt tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca actccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaattggct 300
gctccggttc gtcagaaggg gatggatttt gactactggg gtcagggaac cctggtcacc 360
gtctcgagc 369
<210> 24
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 24
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgag tggtataata tgtcgtgggt ccgccaggct 120
ccagggaagg atctggagtg ggtctcatcg atttctcatg atggttggaa tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagggatg 300
attggttttg actactgggg tcagggaacc ctggtcaccg tctcgagc 348
<210> 25
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 25
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat atttatacga tgcattgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaact attgttccgc agggtactcc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatctaag 300
cgtaggtttc ttaagaggtt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 26
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 26
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgct aggtatgata tgcagtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatcg attaagagta atggtatgaa gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagctagt 300
atgtggacgt ttgactactg gggtcaggga accctggtca ccgtctcgaa c 351
<210> 27
<211> 369
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 27
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttatg ttgtatcata tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcagct attaccgggg ggggttatcc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaactgggg 300
cttcggggtg tgctgtggcg gaggaggttt gactactggg gtcagggaac cctggtcacc 360
gtctcgagc 369
<210> 28
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 28
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggt gcttattcta tgatgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcacgg attagtagga atggtactgt tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaattagg 300
tggaatactg ctcaggtgcc tgtgtttgac tactggggtc agggaactct ggtcaccgtc 360
tcgagc 366
<210> 29
<211> 369
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 29
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggt ccgtattgga tggcttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaacg attacgcctt cgggtcgtgg gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggat accgcggtat attactgtgc gaaagggcgt 300
cctcgtgttg gtttgtggag gtcggggttt gactactggg gtcagggaac cctggtcacc 360
gtctcgagc 369
<210> 30
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 30
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggg cagtatgcta tgcagtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatct attaatatta ctggttctac tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcagatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaggtttt 300
aggtcttttg actactgggg tcagggaacc ctggtcaccg tctcgagc 348
<210> 31
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 31
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgct ggttatacga tgtcgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaacg atttcgggtt ttggttggac tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggat accgcggtat attactgtgc gaaaaggctg 300
gggatgcgtt ttgactactg gggtcaggga accctggtca ccgtctcgag c 351
<210> 33
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 33
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggt ccgtattcga tggggtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcattt attcattctg atggtcgtca tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaaagacg 300
ccttataggt ttgactactg gggtcaggga accctggtca ccgtctcgag c 351
<210> 34
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 34
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggg cagtatgcta tgcagtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatct attaatatta ctggttctac tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcagatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaggtttt 300
aggtcttttg actactgggg tcagggaacc ctggtcaccg tctcgagc 348
<210> 35
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 35
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttagg cggtatgcga tgtcttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaacg atttcgcctt atggtcctgt tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga atagcctgcg tgccgaggac accgcggtat attactgtgc gaaagcttat 300
tatggtgggt ttgactactg gggtcaggga accctggtca ccgtctcgag c 351
<210> 36
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 36
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat gcttatgcta tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaaag attgattctc ctggttggag gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatcggct 300
cggatgcgtt ctcggcattt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 37
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 37
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttaag gattatggga tgaattgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcacgg attagtagga atggtactgt tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaattagg 300
tggaatactg ctcaggtgcc tgtgtttgac tactggggtc agggaactct ggtcaccgtc 360
tcgagc 366
<210> 38
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 38
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcaa cctccggatt cacctttccg tcttatacga tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcacgt atttctcgta ctgggaatta tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggat accgcggtat attactgtgc gaaacctatg 300
tataataggg ggtcttcgta ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 39
<211> 369
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 39
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt caccttttcg cagtatcaga tgtcgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatcg atttcgccta cgggtattca gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaaggctt 300
attgggatgc cgtatgttga ggatactttt gactactggg gtcagggaac cctggtcacc 360
gtctcgagc 369
<210> 40
<211> 372
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 40
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttatg gagtatgaga tggagtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaggt attactaatt ctggttctgg gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca actccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gataatgcag 300
catcctcagg cgactggggg gagggttggg tttgactact ggggtcaggg aaccctggtc 360
accgtctcga gc 372
<210> 41
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 41
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttccg aggtatacta tgaagtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatcg attgatagga cgggtcgtaa gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggat accgcggtat attactgtgc gaaagagtcg 300
ttggtttcgt ttgactactg gggtcaggga accctggtca ccgtctcgag c 351
<210> 42
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 42
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggt ggttatacga tgccttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaact atttctcgtg atggtaatta tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagatatt 300
ggtatgggtt ttgactacgg ggggcgggga accctggtca ccgtctcgag c 351
<210> 43
<211> 369
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 43
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgag atttatgcga tgcattgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaacg attagttcgg gtggtaaggg gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatcgcgt 300
actatgtatt ttcgtgttag ggaggctttt gactactggg gtcagggaac cctggtcacc 360
gtctcgagc 369
<210> 44
<211> 372
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 44
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttcgt gcttatagga tgatgtgggt ccgccaggct 120
ccagggaagg gtctggagtg ggtctcatct attgatcctg atggtgcggt tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc ggaacatttt 300
gatcttgcga tgccgaatcc gaatgcgaag tttgactact ggggtcaggg aaccctggtc 360
accgtctcga gc 372
<210> 45
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 45
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgcctc 60
tcctgtgcag cctccggatt caccttttct cgttatcaga tgtcttgggt ccgccaggct 120
ccagggaagg gtctggagtg ggtctcatct attaagtcga atggttcttc gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacctagt 300
cggcagagtt ttcagtatcc gagttttgac tactggggtc agggaaccct ggtcaccgtc 360
tcgagc 366
<210> 46
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 46
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggg cgttataaga tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatct atttcgccta cgggttcgtc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaactggg 300
tatgttatgg ttgagcattt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 47
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 47
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttagt gattatccga tgaagtgggt ccgccaggct 120
ccagggaagg gtctggagtg ggtctcaact attaattctt cgggtacgat tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaccgttg 300
ttgccgtttg actactgggg tcagggaacc ctggtcaccg tctcgagc 348
<210> 48
<211> 369
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 48
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgct aggtatagga tgtgttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatgt attcgggatc cgggttttcc gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatgttcg 300
ccgtcttcta cgcagtgtac ggggcttttt gactactggg gtcagggaac cctggtcacc 360
gtctcgagc 369
<210> 49
<211> 372
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 49
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttagg ttttatggga tggcgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcactt attgatcctc ctggtggggc gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaatggag 300
aggcggcatc ttaagagtgg tcataagggg tttgactact ggggtcaggg aaccctggtc 360
accgtctcga gc 372
<210> 50
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 50
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttacg gagtatgata tgatgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatct attagtcata ggggtgagaa gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagataag 300
cgttatcggg ggtctcagca ttattttgac tactggggtc agggaaccct ggtcaccgtc 360
tcgagc 366
<210> 51
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 51
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttcgg agttatgata tgggttgggc ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaact attgggtcga atggtgctaa tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacttatg 300
ggtatgtttg actactgggg tcagggaacc ctggtcaccg tctcgagc 348
<210> 52
<211> 354
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 52
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgag cgttattcta tgaggtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaacg attggttcga cgggtaagtg gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagggcgt 300
gggttggttt cttttgacta ctggggtcag ggaaccctgg tcaccgtctc gagc 354
<210> 53
<211> 372
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 53
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttagg cgttattcga tgtcttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatct attgatcggt ctggtaggat gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatctcgg 300
ctgtcttcga cgggttctga gggtcataat tttgactact ggggtcaggg aaccctggtc 360
accgtctcga gc 372
<210> 54
<211> 372
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 54
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttaag tggtatccga tgaagtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaact attgcttatg atggtgttca gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaattgggt 300
ccgactagtc gtgtgtttgc tgctactgat tttgactact ggggtcaggg aaccctggtc 360
accgtctcga gc 372
<210> 55
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 55
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttccg aattatgcga tgaagtgggg ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaact attgatacga gtggtagtac tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacttact 300
catcctatgg cgccgcgtcc ggcttttgac tactggggtc agggaaccct ggtcaccgtc 360
tcgagc 366
<210> 56
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 56
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat cttacggaga tggagtgggt ccgccaggct 120
ccagggaagg gtctggagtg ggtctcatcg attgggcctt ggggtactcc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaatttcg 300
catcctcagg cgatgtatca tacgtttgac tactggggtc agggaaccct ggtcaccgtc 360
tcgagc 366
<210> 57
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 57
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgcg catcaggata tgacgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcagat attgatcatt cgggttcgta tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatggtgg 300
catccgcagg gggggacttt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 58
<211> 369
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 58
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggt tctaaggata tgtcgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaacg attggggcga atggtaaggc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc ggaagcgggt 300
catcctcagg cgccgtcttt taagagtttt gactactggg gtcagggaac cctggtcacc 360
gtctcgagc 369
<210> 59
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 59
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttctg aatgcggaga tgagttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaact attgatcggg atggtgctaa tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacttcct 300
ccgccgatgt cgccgaagaa gtttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 60
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 60
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgag agggagggta tgatgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtttcaact attgatcgta tgggtaggta tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaagggat 300
tcgcatccta tggggtttga ctaccggggt cagggaaccc tggtcaccgt ctcgagc 357
<210> 61
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 61
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccgggtt cacctttgag aatgagaaga tgagttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatcg attggtccta cgggtagtgg tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaactcct 300
catccgcagg tttctagttt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 62
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 62
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgag attgatcata tggggtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcagag attgcgcctt cgggtgatcg tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggat accgcggtat attactgtgc gaaagtgatt 300
tgtcagaatc agtgtctgtt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 63
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 63
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttagg gattctgaga tgtcgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcattt attacttctg atggtcggga tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacctagt 300
ctgcctcatg ttacggcttt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 64
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 64
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgag gatgagacga tgagttgggc ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatcg attggggatg ctggtatgcc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaggggag 300
ccgatttatg ttcatacgac tcattttgac tactggggtc agggaaccct ggtcaccgtc 360
tcgagc 366
<210> 65
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 65
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttccg catggtaaga tggggtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatgg attgctgggt ctggtgatat gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaattgggt 300
catcctcagc ggggttttga ctactggggt cagggaaccc tggtcaccgt ctcgagc 357
<210> 66
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 66
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggg acttctgata tgtcgtgggt ccgccaggcc 120
ccagggaagg gtctagagtg ggtctcaact attgattctg ggggtagttt tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacctcgg 300
catcctcagg ggggggttac ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 68
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 68
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgag catgttccta tggcttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcacgg attagtgagc agggtagtaa tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagtgcag 300
catcctatgt ctccgcatga gtttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 69
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 69
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgag cagggtatga tgtcgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatcg attaatcctg gtggtcagtt tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaggaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc ggaagatctg 300
gggccgggtt ttgactactg gggtcaggga accctggtca ccgtctcgag c 351
<210> 70
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 70
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgag cgttggccta tgtcttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaact attgataggt ctggtaatac tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggat accgcggtat attactgtgc gaaagttttg 300
catcctcagg cggggtctgc ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 71
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 71
gaggtgcagc tgttggagtc tgggggaggc tcggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggg ggtagtgata tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatat attgataatc agggttataa tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatataag 300
cttctgggtc cgtctactga gtttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 72
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 72
gaggtgcagc tgttggagtc agggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttagt agtgatgtta tgtcttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaagt attacgaggt cgggtatgca gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatatgcg 300
catcctcagt cggctgttga gtttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 73
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 73
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttcgt aatgagccga tgagttgggt gcgccaggct 120
ccagtgaagg gtctagagtg ggtctcaact atttcgcctg atggtagtgg gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacatggt 300
catcctcagg gggctcgttt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 74
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 74
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttttg aatagtgaga tgtcgtgggt ccgccaggct 120
ccagggaagg gtctggagtg ggtctcaact attgggtatg cgggtactcc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacctcgg 300
catcctcagg ggggggttac ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 75
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 75
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgct cgggggccta tgtcttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaact attacgaatg atggtacgtc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc ggaaccgcct 300
catagtggta ggcctatgtt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 76
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 76
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttcag cggactgcta tgtcttgggt ccgccaggct 120
ccagggaagg gtcttgagtg ggtctcatct attgaggctt cgggtcggta tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacagtcg 300
catcctcaga atggtcgttt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 77
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 77
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat gcgtcggaga tggcttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaagt attacggttt atggtgatag gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacctcgg 300
catcctcagg ggggggttac ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 78
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 78
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat gattcgcata tggcttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaagg atttcgaggg agggtaaggc gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc ggcaccgaat 300
gatcagtcgg cggcttttga ctactggggt cagggaaccc tggtcaccgt ctcgagc 357
<210> 79
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 79
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat atgagtgaga tgtcgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcagct attacttcgg atggtagttc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacctagt 300
ctgcctcatg ttacggcttt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 80
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 80
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgag aggtctacta tgcattgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcagag attgatgctc tgggtacgga tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatcgtct 300
gatcatcctc agaatagttt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 81
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 81
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgag cctcgtgaga tgtattgggc ccgccaggct 120
ccagggaagg gtctagagtg ggtcgcacgg attggttggg atggtcatac gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacagctg 300
ggtcagtttg actactgggg tcagggaacc ctggtcaccg tctcgagc 348
<210> 82
<211> 372
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 82
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat gcttatagta tgatgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaact attggtaggt ggggtgagat tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggat accgcggtat attactgtgc gaaacgtcgt 300
tatattgggc cttatatgct ttcgggtcgt tttgactact ggggtcaggg aaccctggtc 360
accgtctcga gc 372
<210> 83
<211> 372
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 83
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttatg cggtatccta tggtgtgggt ccgccaggct 120
ccagggaggg gtctagagtg ggtctcatct atttctcctg ctggttatgg tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaggtcat 300
gagattagtc ggttttctcg ttggtcttct tttgactact ggggtcaggg aaccctggtc 360
accgtctcga gc 372
<210> 84
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 84
gaggtgcagc tgttggagtc tggggggggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttcgg aagtatagga tgtcgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatct attgcgagga atggtcgttc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaactacg 300
tctgggtttg actactgggg tcagggaacc ctggtcaccg tctcgagc 348
<210> 85
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 85
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttaat aagaaggaga tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatct attgatgtga gtggtaatgt tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaaatggct 300
catcctcagt cgggggtggc ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 86
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 86
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttcgg atgtatgata tggcgtgggt ccgccaggct 120
ccagggaagg gtctaaagtg ggtctcaact attctgtctt ctggtaaggg tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaattggct 300
catcctcaga agggtagtat ttttgactac cggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 87
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 87
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttcat cagggtccta tggggtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatgg attcaggcta cgggtggtgc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagggatg 300
catcctcaga gtggtactct ttttgactac tggggtcagg gaaccctggt caccgtctcg 360
agc 363
<210> 88
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 88
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat gttgcggata tggattgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaggg atttcgtcgt cgggtggtta tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggat accgcggtat attactgtgc gaaaaatttg 300
ggtcagggtt ttgactactg gggtcaggga accctggtca ccgtctcgag c 351
<210> 89
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 89
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat acgagtagta tgttgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcagtt attcatcaga gtggtacgcc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatttccg 300
tttactcatg gtaagtttga ctactggggt cagggaaccc tggtcaccgt ctcgagc 357
<210> 90
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 90
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttaat aattatacga tggggtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcattg attcatacga gtggtacggt gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatggagt 300
tcgagggcgt ttgactactg gggtcaggga accctggtca ccgtctcgag c 351
<210> 91
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 91
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggg aattatagga tgacttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcaact atttctcctt tgggtacgta tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagggcgt 300
tggtcgattt ttgactactg gggtcaggga accctggtca ccgtctcgag c 351
<210> 92
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 92
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggt agttatccta tgggttgggt ccgccaggct 120
ccagggaagg gtctggagtg ggtctcatgg attcgtggga ggggtcttgc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatatttt 300
catggtaagt ttgactactg gggtcaggga accctggtca ccgtctcgag c 351
<210> 93
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 93
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttagt gcttatgtga tgggttgggt acgccaggct 120
ccagggaagg gtctagagtg ggtctcatcg attcggatgc cgggttatct gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaacgtact 300
cctttttttg actactgggg tcagggaacc ctggtcaccg tctcgagc 348
<210> 94
<211> 369
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 94
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgag cattattcga tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcagag attgatccgg atggtattat gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagcgccg 300
ggggttcttg agatgtggat tacgcatttt gactactggg gtcagggaac cctggtcacc 360
gtctcgagc 369
<210> 95
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 95
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttcgt cattatgtga tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcagct atttctgcgc atggtaatcg gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatcttat 300
agccttgctc tgactccttt tgactactgg ggtcagggaa ccctggtcac cgtctcgagc 360
<210> 96
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 96
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttact gtgtatgaga tgaagtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcagcg atttctgctg ggggtaagta tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaagagatt 300
cggcatcttg ataatgcggt tgagtttgac tactggggtc agggaaccct ggtcaccgtc 360
tcgagc 366
<210> 97
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 97
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 Gly Gly Tyr
20 25 30
Val Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Asn Arg Phe Gly Ser Ser Thr Tyr Tyr Ala Asp Ser 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 Lys Gly Ser Leu Arg His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 98
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 98
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 Gly Asn Tyr
20 25 30
Ala Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asp Met Val Gly Ile Lys Thr Tyr Tyr Ala Asp Ser 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 Lys Gly Phe Arg Ile Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 99
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 99
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 Lys Asp Tyr
20 25 30
Asp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Met Ile Ser Ser Ser Gly Leu Trp Thr Tyr Tyr Ala Asp Ser 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 Lys Gly Phe Arg Leu Phe Pro Arg Thr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 100
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 100
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 Leu Tyr
20 25 30
Arg Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Met Ile Ser Gln Phe Gly Asn Gln Thr Tyr Tyr Ala Asp Ser 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 Lys Val Arg Ser Trp Asp Gln Thr Gly Gly Arg Arg Thr Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 101
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 101
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 Asn His Tyr
20 25 30
Thr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile His Pro Ser Gly Thr Val Thr Tyr Tyr Ala Asp Ser 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 Lys Trp Ser Ser Arg Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 102
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 102
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 Asp Asn Asn
20 25 30
Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Ala Asn Gly Asn Ala Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp 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 Lys Gly Phe Arg Arg Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 103
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 103
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 Thr Ala Ser Gly Phe Thr Phe Arg His Tyr
20 25 30
Arg Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Trp Ile Arg Pro Asp Gly Thr Phe Thr Tyr Tyr Ala Asp Ser 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 Lys Ser Tyr Met Gly Asp Arg Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 104
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 104
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 Gly Asn Tyr
20 25 30
Pro Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Tyr Gly Gly Leu Ala Thr Tyr Tyr Ala Asp Ser 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 Lys Met Ala Ile Asn Gly Val Arg Pro Arg Arg Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 105
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 105
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 Met Ala Tyr
20 25 30
Gln Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile His Gln Thr Gly Phe Ser Thr Tyr Tyr Ala Asp Ser 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 Lys Val Arg Ser Met Arg Pro Tyr Lys Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 106
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 106
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 Gly Asp Lys
20 25 30
Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Ala Pro Gly Asn Arg Thr Tyr Tyr Ala Asp Ser 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 Lys Gly Phe Arg Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 107
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 107
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 Asp Gly Met
20 25 30
Arg Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Glu Val Asn Gly Gln His Thr Tyr Tyr Ala Asp Ser 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 Lys Met Ala His Pro Gln Ser Gly Val Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 108
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 108
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 Thr Pro Asp
20 25 30
Ala Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Gly Val Asn Gly Ser Pro Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg 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 Lys Met Ala His Pro Gln Ser Gly Val Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 109
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 109
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 Tyr Gln Ser
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Gln Gly Arg Ser Thr Tyr Tyr Ala Asp Ser 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 Lys Met Ala His Pro Gln Ser Gly Val Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 110
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 110
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 Thr Ala Ser Gly Phe Thr Phe Ala Ala Arg
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ala Gln Gly Ala His Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp 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 Lys Pro Arg His Pro Gln Gly Gly Val Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 111
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 111
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 Asp Asn Gly
20 25 30
Asp Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ala His Asn Gly Arg Asn Thr Tyr Tyr Ala Asp Ser 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 Lys Asn Leu Gly Gln Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 112
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 112
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Thr Cys Ala Ala Ser Gly Phe Thr Leu Asn Gly Thr
20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Asp Leu Glu Trp Val
35 40 45
Ser Ser Ile Met Pro Val Gly Ser His Thr Tyr Tyr Ala Asp Ser 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 Lys Met Ala His Pro Gln Ser Gly Val Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 113
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 113
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 Asp His Ala
20 25 30
Pro Met Lys Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Gly Ser Ala Gly Asn Met Thr Tyr Tyr Ala Asp Ser 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 Lys Asp Glu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 114
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 114
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 Thr Ala Ser Gly Phe Thr Phe Asp Gly Met
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Thr Thr Gly Gly Thr Thr Tyr Tyr Ala Asp Ser 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 Lys Pro Arg His Pro Gln Gly Gly Val Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 115
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 115
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 Glu Ala Glu
20 25 30
Thr Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile His Ser Glu Gly Ser Arg Thr Tyr Tyr Ala Asp Ser 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 Lys Pro Arg His Pro Gln Gly Gly Val Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 116
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 116
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 Thr Gly
20 25 30
Glu Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Gly Ala Thr Thr Tyr Tyr Ala Asp Ser 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 Lys Pro Arg His Pro Gln Gly Gly Val Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 117
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 117
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 Pro Ser Ala
20 25 30
Asp Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Arg Ile Ser Pro Glu Gly Asn His Thr Tyr Tyr Ala Asp Ser 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 Glu Arg Pro Pro Ser Asp Tyr Val Ser Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 118
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 118
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 Ala Asn Ala
20 25 30
Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Asp Gln Val Gly His Ala Thr Tyr Tyr Ala Asp Ser 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 Lys Tyr Ser Trp His Pro Asp Leu Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 119
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 119
Glu Val Arg 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 Lys Asp Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Arg Ile Ser Arg Asn Gly Thr Val Thr Tyr Tyr Ala Asp Ser 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 Lys Leu Ala Ala Pro Val Arg Gln Lys Gly Met Asp Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 120
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 120
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 Glu Trp Tyr
20 25 30
Asn Met Ser Trp Val Arg Gln Ala Pro Gly Lys Asp Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser His Asp Gly Trp Asn Thr Tyr Tyr Ala Asp Ser 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 Lys Gly Met Ile Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 121
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 121
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Ile Tyr Thr
20 25 30
Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
35 40 45
Thr Ile Val Pro Gln Gly Thr Pro Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Ser Lys Arg Arg Phe Leu Lys Arg Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 122
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 122
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 Ala Arg Tyr
20 25 30
Asp Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Lys Ser Asn Gly Met Lys Thr Tyr Tyr Ala Asp Ser 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 Lys Ala Ser Met Trp Thr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Asn
115
<210> 123
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 123
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 Met Leu Tyr
20 25 30
His Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Gly Gly Gly Tyr Pro Thr Tyr Tyr Ala Asp Ser 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 Lys Leu Gly Leu Arg Gly Val Leu Trp Arg Arg Arg Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 124
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 124
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 Gly Ala Tyr
20 25 30
Ser Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Arg Ile Ser Arg Asn Gly Thr Val Thr Tyr Tyr Ala Asp Ser 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 Lys Ile Arg Trp Asn Thr Ala Gln Val Pro Val Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 125
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 125
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 Gly Pro Tyr
20 25 30
Trp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Thr Pro Ser Gly Arg Gly Thr Tyr Tyr Ala Asp Ser 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 Lys Gly Arg Pro Arg Val Gly Leu Trp Arg Ser Gly Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 126
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 126
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 Gly Gln Tyr
20 25 30
Ala Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Ile Thr Gly Ser Thr Thr Tyr Tyr Ala Asp Ser 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 Lys Gly Phe Arg Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 127
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 127
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Gly Tyr Thr
20 25 30
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
35 40 45
Thr Ile Ser Gly Phe Gly Trp Thr Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Arg Leu Gly Met Arg Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 129
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 129
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 Gly Pro Tyr
20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Phe Ile His Ser Asp Gly Arg His Thr Tyr Tyr Ala Asp Ser 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 Lys Lys Thr Pro Tyr Arg Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 130
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 130
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 Gly Gln Tyr
20 25 30
Ala Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Ile Thr Gly Ser Thr Thr Tyr Tyr Ala Asp Ser 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 Lys Gly Phe Arg Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 131
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 131
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 Arg Arg Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Pro Tyr Gly Pro Val Thr Tyr Tyr Ala Asp Ser 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 Lys Ala Tyr Tyr Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 132
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 132
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 Asp Ala Tyr
20 25 30
Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Lys Ile Asp Ser Pro Gly Trp Arg Thr Tyr Tyr Ala Asp Ser 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 Lys Ser Ala Arg Met Arg Ser Arg His Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 133
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 133
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 Lys Asp Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Arg Ile Ser Arg Asn Gly Thr Val Thr Tyr Tyr Ala Asp Ser 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 Lys Ile Arg Trp Asn Thr Ala Gln Val Pro Val Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 134
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 134
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 Thr Ser Gly Phe Thr Phe Pro Ser Tyr
20 25 30
Thr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Arg Ile Ser Arg Thr Gly Asn Tyr Thr Tyr Tyr Ala Asp Ser 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 Lys Pro Met Tyr Asn Arg Gly Ser Ser Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 135
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 135
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 Gln Tyr
20 25 30
Gln Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Pro Thr Gly Ile Gln Thr Tyr Tyr Ala Asp Ser 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 Lys Arg Leu Ile Gly Met Pro Tyr Val Glu Asp Thr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 136
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 136
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 Met Glu Tyr
20 25 30
Glu Met Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Thr Asn Ser Gly Ser Gly Thr Tyr Tyr Ala Asp Ser 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 Ile Met Gln His Pro Gln Ala Thr Gly Gly Arg Val Gly Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 137
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 137
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 Pro Arg Tyr
20 25 30
Thr Met Lys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asp Arg Thr Gly Arg Lys Thr Tyr Tyr Ala Asp Ser 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 Lys Glu Ser Leu Val Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 138
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 138
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 Gly Gly Tyr
20 25 30
Thr Met Pro Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Arg Asp Gly Asn Tyr Thr Tyr Tyr Ala Asp Ser 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 Lys Asp Ile Gly Met Gly Phe Asp Tyr Gly Gly Arg Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 139
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 139
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 Glu Ile Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Ser Gly Gly Lys Gly Thr Tyr Tyr Ala Asp Ser 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 Lys Ser Arg Thr Met Tyr Phe Arg Val Arg Glu Ala Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 140
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 140
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 Arg Ala Tyr
20 25 30
Arg Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asp Pro Asp Gly Ala Val Thr Tyr Tyr Ala Asp Ser 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 Glu His Phe Asp Leu Ala Met Pro Asn Pro Asn Ala Lys Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 141
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 141
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 Arg Tyr
20 25 30
Gln Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Lys Ser Asn Gly Ser Ser Thr Tyr Tyr Ala Asp Ser 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 Lys Pro Ser Arg Gln Ser Phe Gln Tyr Pro Ser Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 142
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 142
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 Gly Arg Tyr
20 25 30
Lys Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Pro Thr Gly Ser Ser Thr Tyr Tyr Ala Asp Ser 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 Lys Thr Gly Tyr Val Met Val Glu His Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 143
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 143
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 Asp Tyr
20 25 30
Pro Met Lys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Ser Ser Gly Thr Ile Thr Tyr Tyr Ala Asp Ser 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 Lys Pro Leu Leu Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 144
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 144
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 Ala Arg Tyr
20 25 30
Arg Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Cys Ile Arg Asp Pro Gly Phe Pro Thr Tyr Tyr Ala Asp Ser 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 Lys Cys Ser Pro Ser Ser Thr Gln Cys Thr Gly Leu Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 145
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 145
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Phe Tyr Gly
20 25 30
Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
35 40 45
Leu Ile Asp Pro Pro Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Met Glu Arg Arg His Leu Lys Ser Gly His Lys Gly Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 146
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 146
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 Thr Glu Tyr
20 25 30
Asp Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser His Arg Gly Glu Lys Thr Tyr Tyr Ala Asp Ser 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 Lys Asp Lys Arg Tyr Arg Gly Ser Gln His Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 147
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 147
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr Asp
20 25 30
Met Gly Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
35 40 45
Thr Ile Gly Ser Asn Gly Ala Asn Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Leu Met Gly Met Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 148
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 148
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 Glu Arg Tyr
20 25 30
Ser Met Arg Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Gly Ser Thr Gly Lys Trp Thr Tyr Tyr Ala Asp Ser 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 Lys Gly Arg Gly Leu Val Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 149
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 149
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 Arg Arg Tyr
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asp Arg Ser Gly Arg Met Thr Tyr Tyr Ala Asp Ser 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 Lys Ser Arg Leu Ser Ser Thr Gly Ser Glu Gly His Asn Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 150
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 150
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Lys Trp Tyr Pro
20 25 30
Met Lys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
35 40 45
Thr Ile Ala Tyr Asp Gly Val Gln Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Leu Gly Pro Thr Ser Arg Val Phe Ala Ala Thr Asp Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 151
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 151
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 Pro Asn Tyr
20 25 30
Ala Met Lys Trp Gly Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asp Thr Ser Gly Ser Thr Thr Tyr Tyr Ala Asp Ser 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 Lys Leu Thr His Pro Met Ala Pro Arg Pro Ala Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 152
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 152
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 Asp Leu Thr
20 25 30
Glu Met Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Gly Pro Trp Gly Thr Pro Thr Tyr Tyr Ala Asp Ser 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 Lys Ile Ser His Pro Gln Ala Met Tyr His Thr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 153
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 153
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 Ala His Gln
20 25 30
Asp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Asp His Ser Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser 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 Lys Trp Trp His Pro Gln Gly Gly Thr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 154
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 154
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 Gly Ser Lys
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Gly Ala Asn Gly Lys Ala Thr Tyr Tyr Ala Asp Ser 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 Glu Ala Gly His Pro Gln Ala Pro Ser Phe Lys Ser Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 155
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 155
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 Leu Asn Ala
20 25 30
Glu Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asp Arg Asp Gly Ala Asn Thr Tyr Tyr Ala Asp Ser 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 Lys Leu Pro Pro Pro Met Ser Pro Lys Lys Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 156
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 156
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 Glu Arg Glu
20 25 30
Gly Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asp Arg Met Gly Arg Tyr Thr Tyr Tyr Ala Asp Ser 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 Lys Arg Asp Ser His Pro Met Gly Phe Asp Tyr Arg Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 157
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 157
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 Glu Asn Glu
20 25 30
Lys Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Gly Pro Thr Gly Ser Gly Thr Tyr Tyr Ala Asp Ser 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 Lys Thr Pro His Pro Gln Val Ser Ser Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 158
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 158
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 Glu Ile Asp
20 25 30
His Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Glu Ile Ala Pro Ser Gly Asp Arg Thr Tyr Tyr Ala Asp Ser 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 Lys Val Ile Cys Gln Asn Gln Cys Leu Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 159
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 159
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 Arg Asp Ser
20 25 30
Glu Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Phe Ile Thr Ser Asp Gly Arg Asp Thr Tyr Tyr Ala Asp Ser 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 Lys Pro Ser Leu Pro His Val Thr Ala Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 160
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 160
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 Glu Asp Glu
20 25 30
Thr Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Gly Asp Ala Gly Met Pro Thr Tyr Tyr Ala Asp Ser 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 Lys Gly Glu Pro Ile Tyr Val His Thr Thr His Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 161
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 161
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 Pro His Gly
20 25 30
Lys Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Trp Ile Ala Gly Ser Gly Asp Met Thr Tyr Tyr Ala Asp Ser 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 Lys Leu Gly His Pro Gln Arg Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 162
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 162
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 Gly Thr Ser
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asp Ser Gly Gly Ser Phe Thr Tyr Tyr Ala Asp Ser 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 Lys Pro Arg His Pro Gln Gly Gly Val Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 163
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 163
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 Glu His Val
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Arg Ile Ser Glu Gln Gly Ser Asn Thr Tyr Tyr Ala Asp Ser 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 Lys Val Gln His Pro Met Ser Phe Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 164
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 164
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 Glu Gln Gly
20 25 30
Met Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Pro Gly Gly Gln Phe Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg 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 Glu Asp Leu Gly Pro Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 165
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 165
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 Glu Arg Trp
20 25 30
Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asp Arg Ser Gly Asn Thr Thr Tyr Tyr Ala Asp Ser 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 Lys Val Leu His Pro Gln Ala Gly Ser Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 166
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 166
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Gly Ser
20 25 30
Asp Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Asp Asn Gln Gly Tyr Asn Thr Tyr Tyr Ala Asp Ser 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 Lys Tyr Lys Leu Leu Gly Pro Ser Thr Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 167
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 167
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 Ser Asp
20 25 30
Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Thr Arg Ser Gly Met Gln Thr Tyr Tyr Ala Asp Ser 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 Lys Tyr Ala His Pro Gln Ser Ala Val Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 168
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 168
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 Arg Asn Glu
20 25 30
Pro Met Ser Trp Val Arg Gln Ala Pro Val Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Pro Asp Gly Ser Gly Thr Tyr Tyr Ala Asp Ser 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 Lys His Gly His Pro Gln Gly Ala Arg Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 169
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 169
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 Leu Asn Ser
20 25 30
Glu Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Gly Tyr Ala Gly Thr Pro Thr Tyr Tyr Ala Asp Ser 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 Lys Pro Arg His Pro Gln Gly Gly Val Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 170
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 170
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 Arg Pro Met
20 25 30
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr
35 40 45
Ile Thr Asn Asp Gly Thr Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Glu
85 90 95
Pro Pro His Ser Gly Arg Pro Met Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 171
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 171
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 Gln Arg Thr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Glu Ala Ser Gly Arg Tyr Thr Tyr Tyr Ala Asp Ser 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 Lys Gln Ser His Pro Gln Asn Gly Arg Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 172
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 172
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 Asp Ala Ser
20 25 30
Glu Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Thr Val Tyr Gly Asp Arg Thr Tyr Tyr Ala Asp Ser 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 Lys Pro Arg His Pro Gln Gly Gly Val Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 173
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 173
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 Asp Asp Ser
20 25 30
His Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Arg Ile Ser Arg Glu Gly Lys Ala Thr Tyr Tyr Ala Asp Ser 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 Ala Pro Asn Asp Gln Ser Ala Ala Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 174
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 174
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 Asp Met Ser
20 25 30
Glu Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Ser Asp Gly Ser Ser Thr Tyr Tyr Ala Asp Ser 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 Lys Pro Ser Leu Pro His Val Thr Ala Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 175
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 175
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 Glu Arg Ser
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Glu Ile Asp Ala Leu Gly Thr Asp Thr Tyr Tyr Ala Asp Ser 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 Lys Ser Ser Asp His Pro Gln Asn Ser Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 176
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 176
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 Glu Pro Arg
20 25 30
Glu Met Tyr Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Gly Trp Asp Gly His Thr Thr Tyr Tyr Ala Asp Ser 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 Lys Gln Leu Gly Gln Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 177
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 177
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 Asp Ala Tyr
20 25 30
Ser Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Gly Arg Trp Gly Glu Ile Thr Tyr Tyr Ala Asp Ser 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 Lys Arg Arg Tyr Ile Gly Pro Tyr Met Leu Ser Gly Arg Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 178
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 178
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 Met Arg Tyr
20 25 30
Pro Met Val Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Pro Ala Gly Tyr Gly Thr Tyr Tyr Ala Asp Ser 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 Lys Gly His Glu Ile Ser Arg Phe Ser Arg Trp Ser Ser Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 179
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 179
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 Arg Lys Tyr
20 25 30
Arg Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ala Arg Asn Gly Arg Ser Thr Tyr Tyr Ala Asp Ser 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 Lys Thr Thr Ser Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 180
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 180
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 Asn Lys Lys
20 25 30
Glu Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asp Val Ser Gly Asn Val Thr Tyr Tyr Ala Asp Ser 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 Lys Met Ala His Pro Gln Ser Gly Val Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 181
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 181
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 Arg Met Tyr
20 25 30
Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Lys Trp Val
35 40 45
Ser Thr Ile Leu Ser Ser Gly Lys Gly Thr Tyr Tyr Ala Asp Ser 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 Lys Leu Ala His Pro Gln Lys Gly Ser Ile Phe Asp Tyr Arg Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 182
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 182
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 His Gln Gly
20 25 30
Pro Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Trp Ile Gln Ala Thr Gly Gly Ala Thr Tyr Tyr Ala Asp Ser 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 Lys Gly Met His Pro Gln Ser Gly Thr Leu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 183
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 183
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 Asp Val Ala
20 25 30
Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Ser Ser Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser 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 Lys Asn Leu Gly Gln Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 184
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 184
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 Asp Thr Ser
20 25 30
Ser Met Leu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile His Gln Ser Gly Thr Pro Thr Tyr Tyr Ala Asp Ser 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 Lys Phe Pro Phe Thr His Gly Lys Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 185
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 185
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 Asn Asn Tyr
20 25 30
Thr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile His Thr Ser Gly Thr Val Thr Tyr Tyr Ala Asp Ser 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 Lys Trp Ser Ser Arg Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 186
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 186
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 Gly Asn Tyr
20 25 30
Arg Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Pro Leu Gly Thr Tyr Thr Tyr Tyr Ala Asp Ser 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 Lys Gly Arg Trp Ser Ile Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 187
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 187
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 Gly Ser Tyr
20 25 30
Pro Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Trp Ile Arg Gly Arg Gly Leu Ala Thr Tyr Tyr Ala Asp Ser 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 Lys Tyr Phe His Gly Lys Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 188
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 188
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 Ala Tyr
20 25 30
Val Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Arg Met Pro Gly Tyr Leu Thr Tyr Tyr Ala Asp Ser 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 Lys Arg Thr Pro Phe Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 189
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 189
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 Glu His Tyr
20 25 30
Ser Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Glu Ile Asp Pro Asp Gly Ile Met Thr Tyr Tyr Ala Asp Ser 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 Lys Ala Pro Gly Val Leu Glu Met Trp Ile Thr His Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 190
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 190
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 Arg His Tyr
20 25 30
Val Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Ala His Gly Asn Arg Thr Tyr Tyr Ala Asp Ser 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 Lys Ser Tyr Ser Leu Ala Leu Thr Pro Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 191
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 191
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 Thr Val Tyr
20 25 30
Glu Met Lys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Ala Gly Gly Lys Tyr Thr Tyr Tyr Ala Asp Ser 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 Lys Glu Ile Arg His Leu Asp Asn Ala Val Glu Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 192
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 192
gaggtgcaac tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttaat cattatacga tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcattg attcatccga gtggtacggt gatatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatggagt 300
tcgagggcat ttgactactg gggtcaggga accctggtca ccgtctctag c 351
<210> 193
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 193
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttaat cattatacga tggggtgggt ccgccaggct 120
ccagggaagg gtcgagagtg ggtctcattg attcatccga gtggtacggt gacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatggagt 300
tcgagggcgt ttgactactg gggtcaggga accctggtca ccgtctcgag c 351
<210> 194
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 194
gaggtgcaac tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttaat cattatacga tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcattg attcatccga gtggtacggt gatatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gagatggagt 300
tcgagggcgt ttgactactg gggtcagggg accctggtca ccgtctcgag c 351
<210> 195
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 195
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttgat acgagtagta tgttgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcagtt attcatcaga gtggtacgcc tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatttccg 300
tctactcatg gtaagtttga ctactggggt cagggaaccc tggtcaccgt ctcgagc 357
<210> 196
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 196
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctccggatt cacctttggt aattatgcga tggcgtgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatcg attgatatgg ttggtattaa gacatactac 180
gcagactccg tgaagggccg gttcaccaat tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gagaggtttt 300
cgtatttttg actactgggg tcagggaacc ctggtcaccg tctcgagc 348
<210> 197
<211> 354
<212> DNA
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 197
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgcgtctc 60
tcctgtacag cctccggatt cacctttagg cattatcgta tgggttgggt ccgccaggct 120
ccagggaagg gtctagagtg ggtctcatgg attcgtccgg atggtacgtt tacatactac 180
gcagactccg tgaagggccg gttcaccatc tcccgcgaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgcg tgccgaggac accgcggtat attactgtgc gaaatcttat 300
atggctgata ggtttgacta ctggggtcag ggaaccctgg tcaccgtctc gagc 354
<210> 198
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 198
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 Asn His Tyr
20 25 30
Thr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile His Pro Ser Gly Thr Val Ile Tyr Tyr Ala Asp Ser 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 Lys Trp Ser Ser Arg Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 199
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 199
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 Asn His Tyr
20 25 30
Thr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val
35 40 45
Ser Leu Ile His Pro Ser Gly Thr Val Thr Tyr Tyr Ala Asp Ser 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 Lys Trp Ser Ser Arg Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 200
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 200
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 Asn His Tyr
20 25 30
Thr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile His Pro Ser Gly Thr Val Ile Tyr Tyr Ala Asp Ser 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 Trp Ser Ser Arg Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 201
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 201
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 Asp Thr Ser
20 25 30
Ser Met Leu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile His Gln Ser Gly Thr Pro Thr Tyr Tyr Ala Asp Ser 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 Lys Phe Pro Ser Thr His Gly Lys Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 202
<211> 114
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 202
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 Gly Asn Tyr
20 25 30
Ala Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asp Met Val Gly Ile Lys Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Asn 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
Arg Phe Arg Ile Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 203
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Derived from a Human germline sequence
<400> 203
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 Thr Ala Ser Gly Phe Thr Phe Arg His Tyr
20 25 30
Arg Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Trp Arg Pro Asp Gly Thr Phe Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Ser Tyr Met Ala Asp Arg Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
Claims (21)
- 서열 97 내지 191 및 198 내지 203으로부터 선택된 아미노산 서열과 80％ 이상 동일한 아미노산 서열을 포함하는 항-혈청 알부민 (SA) 이뮤노글로불린 단일 가변 도메인.
- 서열 97 내지 191 및 198 내지 203으로부터 선택된 아미노산 서열과 비교하여 최대 4개의 아미노산 변화를 갖는 아미노산 서열을 포함하는 항-혈청 알부민 (SA) 이뮤노글로불린 단일 가변 도메인.
- 서열 1 내지 96 및 192 내지 197로부터 선택된 서열과 80％ 이상 동일한 뉴클레오티드 서열에 의해 코딩된 아미노산 서열을 포함하는 항-혈청 알부민 (SA) 이뮤노글로불린 단일 가변 도메인.
- 제1항 내지 제3항 중 어느 한 항에 있어서, 서열 97 내지 103 및 198 내지 203 중 어느 하나의 아미노산 서열을 포함하는 가변 도메인.
- 제1항 내지 제4항 중 어느 한 항에 있어서, 표면 플라즈몬 공명에 의해 결정된 약 0.1 내지 약 10000 nM, 임의로는 약 1 내지 약 6000 nM의 해리 상수 (KD)로 인간 SA에 특이적으로 결합하는 결합 부위를 포함하는 가변 도메인.
- 제1항 내지 제5항 중 어느 한 항에 있어서, 표면 플라즈몬 공명에 의해 결정된 약 1.5 x 10-4 내지 약 0.1 sec-1, 임의로는 약 3 x 10-4 내지 약 0.1 sec-1의 오프-레이트(off-rate) 상수 (Kd)로 인간 SA에 특이적으로 결합하는 결합 부위를 포함하는 가변 도메인.
- 제1항 내지 제6항 중 어느 한 항에 있어서, 표면 플라즈몬 공명에 의해 결정된 약 2 x 106 내지 약 1 x 104 M-1sec-1, 임의로는 약 1 x 106 내지 약 2 x 104 M-1sec-1의 온-레이트(on-rate) 상수 (Ka)로 인간 SA에 특이적으로 결합하는 결합 부위를 포함하는 가변 도메인.
- 제1항 내지 제7항 중 어느 한 항에 있어서, 표면 플라즈몬 공명에 의해 결정된 약 0.1 내지 약 10000 nM, 임의로는 약 1 내지 약 6000 nM의 해리 상수 (KD)로 시노몰구스 원숭이 SA에 특이적으로 결합하는 결합 부위를 포함하는 가변 도메인.
- 제1항 내지 제8항 중 어느 한 항에 있어서, 표면 플라즈몬 공명에 의해 결정된 약 1.5 x 10-4 내지 약 0.1 sec-1, 임의로는 약 3 x 10-4 내지 약 0.1 sec-1의 오프-레이트 상수 (Kd)로 시노몰구스 원숭이 SA에 특이적으로 결합하는 결합 부위를 포함하는 가변 도메인.
- 제1항 내지 제9항 중 어느 한 항에 있어서, 표면 플라즈몬 공명에 의해 결정된 약 2 x 106 내지 약 1 x 104 M-1sec-1, 임의로는 약 1 x 106 내지 약 5 x 103 M-1sec-1의 온-레이트 상수 (Ka)로 시노몰구스 원숭이 SA에 특이적으로 결합하는 결합 부위를 포함하는 가변 도메인.
- 제1항 내지 제10항 중 어느 한 항에 있어서, DSC (시차 주사 열량법)에 의해 결정된 용융 온도 (Tm)가 55℃ 이상, 임의로는 55 ≤ Tm ≤ 75℃인 가변 도메인.
- 제1항 내지 제11항 중 어느 한 항에 있어서, SEC-MALLS (크기 배제 크로마토그래피-다각도 레이저 광산란 검출법)에 의해 결정된 바와 같이, 실질적으로 단량체인 가변 도메인.
- 제1항 내지 제12항 중 어느 한 항에 따른 항-SA 가변 도메인 및 SA 이외의 표적 항원에 특이적으로 결합하는 결합 모이어티를 포함하고, 임의로는 결합 모이어티가 TNFR1 길항제인 다중특이적 리간드.
- 제1항 내지 제12항 중 어느 한 항에 있어서, 약물 (임의로 NCE 약물)에 접합된 것으로, 임의로는 선택된 가변 도메인이 제4항에 따른 것인 항-SA 단일 가변 도메인.
- 제1항 내지 제12항 중 어느 한 항에 따른 가변 도메인에 융합된 폴리펩티드 또는 펩티드 약물을 포함하고, 임의로는 선택된 가변 도메인이 제4항에 따른 것인 융합 단백질.
- 제1항 내지 제15항 중 어느 한 항에 따른 가변 도메인, 융합 단백질 또는 리간드, 및 제약상 허용되는 희석제, 담체, 부형제 또는 비히클을 포함하는 조성물.
- 제1항 내지 제12항 및 제14항 중 어느 한 항에 따른 가변 도메인, 또는 제13항의 다중특이적 리간드 또는 제15항의 융합 단백질을 코딩하는 뉴클레오티드 서열을 포함하는 핵산.
- 서열 1 내지 96 및 192-197로부터 선택된 서열과 80％ 이상 동일한 뉴클레오티드 서열을 포함하는 핵산.
- 제17항 또는 제18항의 핵산을 포함하는 벡터.
- 제19항의 벡터를 포함하는 단리된 숙주 세포.
- 제1항 내지 제12항 및 제14항 중 어느 한 항에 따른 가변 도메인, 또는 제13항의 다중특이적 리간드 또는 제15항의 융합 단백질 중 하나 이상의 용량을 환자에게 투여하는 것을 포함하는, 환자에서 질환 또는 장애를 치료 또는 예방하는 방법.
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| JP (1) | JP2012532620A (ko) |
| KR (1) | KR20120038494A (ko) |
| CN (1) | CN102574914A (ko) |
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| KR20190104608A (ko) * | 2017-01-17 | 2019-09-10 | 아블린쓰 엔.브이. | 개선된 혈청 알부민 결합제 |
| KR20190104609A (ko) * | 2017-01-17 | 2019-09-10 | 아블린쓰 엔.브이. | 개선된 혈청 알부민 결합제 |
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2010
- 2010-07-14 IN IN640DEN2012 patent/IN2012DN00640A/en unknown
- 2010-07-14 AU AU2010272590A patent/AU2010272590B2/en not_active Ceased
- 2010-07-14 EP EP10734965A patent/EP2454285A2/en not_active Withdrawn
- 2010-07-14 EA EA201270174A patent/EA201270174A1/ru unknown
- 2010-07-14 US US13/384,316 patent/US8679496B2/en not_active Expired - Fee Related
- 2010-07-14 KR KR1020127003939A patent/KR20120038494A/ko not_active Application Discontinuation
- 2010-07-14 JP JP2012520016A patent/JP2012532620A/ja active Pending
- 2010-07-14 CN CN2010800414331A patent/CN102574914A/zh active Pending
- 2010-07-14 CA CA2768462A patent/CA2768462A1/en not_active Abandoned
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20190091524A (ko) * | 2016-12-07 | 2019-08-06 | 아블린쓰 엔.브이. | 개선된 혈청 알부민 결합성 면역글로불린 단일 가변 도메인 |
| KR20190104608A (ko) * | 2017-01-17 | 2019-09-10 | 아블린쓰 엔.브이. | 개선된 혈청 알부민 결합제 |
| KR20190104609A (ko) * | 2017-01-17 | 2019-09-10 | 아블린쓰 엔.브이. | 개선된 혈청 알부민 결합제 |
| US11897944B2 (en) | 2017-01-17 | 2024-02-13 | Ablynx N.V. | Immunoglobulin single variable domain (ISVD) capable of binding to serum albumin |
Also Published As
| Publication number | Publication date |
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| US20120114647A1 (en) | 2012-05-10 |
| BR112012001681A2 (pt) | 2019-09-24 |
| AU2010272590B2 (en) | 2013-10-10 |
| SG177601A1 (en) | 2012-02-28 |
| CA2768462A1 (en) | 2011-01-20 |
| EP2454285A2 (en) | 2012-05-23 |
| CN102574914A (zh) | 2012-07-11 |
| IL217520A0 (en) | 2012-02-29 |
| EA201270174A1 (ru) | 2012-07-30 |
| US8679496B2 (en) | 2014-03-25 |
| WO2011006915A2 (en) | 2011-01-20 |
| IN2012DN00640A (ko) | 2015-08-21 |
| JP2012532620A (ja) | 2012-12-20 |
| ZA201200276B (en) | 2012-09-26 |
| AU2010272590A1 (en) | 2012-02-02 |
| US20140140996A1 (en) | 2014-05-22 |
| WO2011006915A3 (en) | 2011-03-03 |
| MX2012000765A (es) | 2012-02-13 |
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