KR102006527B1 - 전립선-연관 항원의 발현을 위한 벡터 - Google Patents
전립선-연관 항원의 발현을 위한 벡터 Download PDFInfo
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Abstract
본 개시내용은 (a) 2, 3개, 또는 그 초과의 면역원성 PAA 폴리펩티드를 코딩하는 다중-항원 구축물을 포함하는 벡터; (b) 상기 벡터를 포함하는 조성물, (c) 전립선암에 대한 면역 반응을 유도하거나 또는 이를 치료하기 위한 상기 벡터 및 조성물의 사용에 관련된 방법을 제공한다.
Description
관련 출원에 대한 참조
본원은 그 전문이 본원에 참조로 포함된, 2013년 11월 1일 출원한 미국 특허 가출원 61/898,966을 기초로 한 우선권을 주장한다.
서열 목록에 대한 참조
본원은 전자 형태의 서열 목록과 함께 출원된다. 서열 목록은 2014년 10월 6일 생성되고 크기가 429 KB이고 명칭이 "PC72055A_FF_SEQ_LISTING_ST25.txt"인 .txt 형식의 파일로서 제출된다. .txt 파일에 포함된 서열 목록은 본원 명세서의 일부이고, 그 전부가 본원에 참고로 포함된다.
발명의 분야
본 발명은 일반적으로 면역치료, 구체적으로 신생물 질환의 치료 또는 예방을 위한 백신 및 방법에 관한 것이다.
전립선암은 전세계적으로 선진국에서 남성의 두 번째로 가장 흔히 진단되는 암이고 암 관련 사망의 제4의 주된 원인이다. 다양한 전립선-연관 항원 (PAA), 예컨대 전립선-특이적 항원 (PSA), 전립선-특이적 막 항원 (PSMA), 및 전립선 줄기 세포 항원 (PSCA)은 정상적인 대응물에 비해 전립선암 세포에 의해 과다발현되는 것으로 밝혀졌다. 이들 항원은 따라서 백신-기반 면역요법의 사용을 통해 항원을 발현하는 암에 대해 특이적 면역 반응을 유도하기 위한 가능한 표적을 나타낸다 (예를 들어, 문헌 [Marrari, A., M. lero, et al. (2007). "Vaccination therapy in prostate cancer." Cancer Immunol Immunother 56(4): 429-45] 참조).
PSCA는 123개 아미노산의 막 단백질이다. 천연 전장 인간 PSCA는 서열 21의 아미노산 1 및 4-125로 이루어진다 (각각 제2 및 제3 위치의 알라닌 및 세린 잔기 미포함). PSCA는 높은 조직 특이성을 갖고, 85% 초과의 전립선암 시료에서 발현되고, 그 발현 수준은 글리슨 점수 (Gleason score) 및 안드로겐 비의존성이 높을수록 증가한다. 이것은 전립선암 환자의 뼈 전이 중 80-100%에서 발현된다.
PSA는 전립선의 선방 및 관의 내부를 막처럼 감싸는 원주형 상피 세포에 의해서만 생산되는 칼리크레인-유사 세린 프로테아제이다. PSA mRNA는 불활성 261-아미노산 프리프로PSA 전구체로서 번역된다. 프리프로PSA는 프리-영역 (신호 폴리펩티드) 및 프로폴리펩티드를 구성하는 24개의 추가의 잔기를 갖는다. 프로폴리펩티드의 방출은 효소 활성을 보이는 237-아미노산의 성숙 세포외 형태를 생성한다. 천연 인간 PSA의 전장 서열은 서열 15의 아미노산 4-263으로 이루어진다. PSA는 장기 특이적이고, 그 결과, 양성 전립선 비대 (BPH) 조직, 원발 전립선암 조직, 및 전이성 전립선암 조직의 상피 세포에 의해 생산된다.
폴레이트 히드롤라제 1 (FOLH1)로도 알려진 PSMA는 750개의 아미노산으로 이루어진다. 전장 인간 PSMA의 아미노산 서열은 서열 1에 제시된다. PSMA는 세포질 도메인 (아미노산 1-19), 막횡단 도메인 (아미노산 20-43), 및 세포외 도메인 (아미노산 44-750)을 포함한다. PSMA는 정상 조직보다 전립선암 세포에서 1000배 더 높은 수준으로 발현되는 것으로 밝혀졌다. 이것은 다양한 다른 고형 종양, 예컨대 결장, 유방, 간, 방광, 췌장, 폐, 신장암 및 흑색종 및 육종의 신생혈관계에서 풍부하게 발현된다. 따라서, PSMA는 전립선암 세포에 특이적인 표적뿐만 아니라 다른 암에 대한 pan-암종 표적으로도 간주된다.
매우 많은 종양-연관 항원이 확인되었고 이들 중 많은 항원이 암의 치료 또는 예방을 위한 단백질-기반 또는 DNA-기반 백신으로 연구되었지만, 지금까지 대부분의 임상 시험은 치료 제품의 생산에 실패하였다. 암 백신 개발에서 하나의 과제는 암 항원이 대체로 자기-유래되고, 따라서 면역 시스템은 자기-단백질을 인식하지 않도록 자기-조절되기 때문에 면역원성이 낮다는 사실이다. 따라서, 암 백신의 면역원성 또는 치료 효과를 향상시키는 방법에 대한 필요성이 존재한다.
암 백신의 면역원성 또는 항-종양 효능을 향상시키기 위한 많은 방안이 연구되었다. 그러한 방안 중의 하나는 다양한 면역 조절제, 예컨대 TLR 효능제, TNFR 효능제, CTLA-4 억제제, 및 단백질 키나제 억제제의 사용을 수반한다.
Toll-유사 수용체 (TLR)는 조혈 및 비-조혈 세포에서 발현되는 타입 1 막 수용체이다. 적어도 11개의 멤버가 TLR 패밀리에서 확인되었다. 이들 수용체는 병원성 유기체에 의해 발현되는 병원체-관련 분자 패턴 (PAMP)을 인식하는 그들의 능력을 특징으로 한다. 선천 면역 시스템에서 이들 수용체는 뒤이은 후천 면역 반응의 극성에 대한 제어력을 발휘한다. TLR 중에서, TLR9가 면역 반응에서의 그의 기능에 대해 심도있게 조사되었다. TLR9 수용체의 자극은 염증유발성 시토카인의 생산 및 T 세포에 대한 공동-자극 분자의 제시를 증가시킴으로써 항원-제시 세포 (APC)를 프라이밍 (priming) 효능있는 TH1-우세 T-세포 반응을 향하도록 유도한다. TLR9에 대한 리간드인 CpG 올리고뉴클레오티드는 효능있는 면역자극 인자의 클래스로 밝혀졌다. CpG 요법은 마우스에서 매우 다양한 종양 모델에 대해 시험되었고, 종양 억제 또는 퇴행을 촉진하는 것으로 일관되게 밝혀졌다.
세포독성 T-림프구 항원 4 (CTLA-4)는 이뮤노글로불린 수퍼패밀리의 멤버이고, 헬퍼 T 세포의 표면 상에 발현된다. CTLA-4는 CD28 의존성 T 세포 활성화의 음성 조절인자이고, 적응 면역 반응에 대한 억제 검문소 (checkpoint)로서 작용한다. T-세포 공동자극 단백질 CD28과 유사하게, CTLA-4는 항원-제시 세포 상의 CD80 및 CD86에 결합한다. CTLA-4는 억제 신호를 T 세포로 전송하는 반면, CD28은 자극 신호를 전송한다. 인간 CTLA-4에 대한 인간 항체는 많은 질환 병태에서, 예컨대 바이러스 및 박테리아 감염의 치료 또는 예방 및 암의 치료를 위한 면역자극 조절제로서 설명되어 있다 (WO 01/14424 및 WO 00/37504). 다양한 전임상 연구는 모노클로날 항체에 의한 CTLA-4 차단이 면역원성 종양에 대한 숙주 면역 반응을 향상시키고, 심지어 확립된 종양을 거부할 수 있음을 보여주었다. 2가지 완전 인간 항-인간 CTLA-4 모노클로날 항체 (mAb)인 이필리무맙 (MDX-010) 및 트레멜리무맙 (CP-675206으로도 알려짐)이 다양한 종류의 고형 종양의 치료를 위한 임상 시험에서 조사되었다.
종양 괴사 인자 (TNF) 수퍼패밀리는 특이적 동족 (cognate) 세포 표면 수용체인 TNF 수용체 (TNFR) 수퍼패밀리에 결합하는 일군의 시토카인이다. 종양 괴사 인자 수퍼패밀리의 멤버는 리간드-매개 삼량체화를 통해 작용하고, 신호 전달 경로, 예컨대 아폽토시스 (apoptosis), NF-κB 경로, JNK 경로, 및 면역 및 염증 반응을 활성화하기 위해 몇몇의 세포내 어댑터의 동원을 유도한다. TNF 수퍼패밀리의 예는 CD40 리간드, OX40 리간드, 4-1BB 리간드, CD27, CD30 리간드 (CD153), TNF-알파, TNF-베타, RANK 리간드, LT-알파, LT-베타, GITR 리간드, 및 LIGHT를 포함한다. TNFR 수퍼패밀리는 예를 들어 CD40, OX40, 4-1BB, CD70 (CD27 리간드), CD30, TNFR2, RANK, LT-베타 R, HVEM, GITR, TROY, 및 RELT를 포함한다. TNF 멤버 중에서, 다양한 CD40 효능제 항체, 예컨대 완전 인간 효능제 CD40 모노클로날 항체 CP870893을 포함하는 CD40 효능제가 요법에 사용하기 위해 심도있게 연구되었다.
단백질 키나제는 단백질 내의 특정 잔기의 인산화를 촉매하는 효소의 패밀리이다. 많은 키나제 억제제가 항암 요법에 사용하기 위해 임상 조사에서 조사되었고, 이들은 예를 들어 MK0457, VX-680, ZD6474, MLN8054, AZD2171, SNS-032, PTK787/ZK222584, 소라페닙 (BAY43-9006), SU5416, SU6668 AMG706, 작티마 (ZD6474), MP-412, 다사티닙, CEP-701, (레스타우르티닙), XL647, XL999, 티케르브, (라파티닙), MLN518 (이전에 CT53518로 알려짐), PKC412, ST1571, AMN107, AEE 788, OSI-930, OSI-817, 수니티닙 말레이트 (수텐트 (Sutent); SU11248), 바탈라닙 (PTK787/ZK 222584), SNS-032, SNS-314 및 악시티닙 (AG-013736)을 포함한다. 게피티닙 및 에를로티닙은 2가지 경구 이용가능 EGFR-TKI이다.
발명의 개요
본 개시내용은 2 이상의 면역원성 PAA 폴리펩티드의 발현을 위한 침팬지 아데노바이러스 ChAd68 게놈 서열로부터 구축된 벡터에 관한 것이다. 벡터는 (1) C68 DNA 서열, (2) 2 이상의 면역원성 PAA 폴리펩티드의 발현을 위한 다중-항원 구축물, 및 (3) 항원 생성물 (즉, 면역원성 PAA 폴리펩티드)의 전사 및 번역을 제어하는 조절 서열을 포함한다. 벡터에 포함되는 C68 DNA 서열은 하나 이상의 바이러스 유전자의 기능적 결실에 의해 C68 게놈 서열로부터 유래되지만, 감염성 바이러스 입자의 생산을 위해 충분하다. 특정 실시양태에서, 벡터 내에 사용된 C68 DNA 서열은 E1 및 E3 영역의 기능적 결실만을 갖는 전체 C68 게놈이다.
벡터에 의해 운반되는 다중-항원 구축물은 면역원성 PSMA 폴리펩티드, 면역원성 PSA 폴리펩티드, 및 면역원성 PSCA 폴리펩티드로부터 선택된 2 이상의 면역원성 PAA 폴리펩티드를 코딩하는 뉴클레오티드 서열을 포함한다. 일부 실시양태에서, 벡터에 의해 운반되는 다중-항원 구축물은 (1) 적어도 하나의 면역원성 PSMA 폴리펩티드를 코딩하는 뉴클레오티드 서열, (2) 적어도 하나의 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열, 및 (3) 적어도 하나의 면역원성 PSCA 폴리펩티드를 코딩하는 뉴클레오티드 서열을 포함한다. 다중-항원 구축물은 또한 구축물에 의해 코딩되는 별개의 PAA 폴리펩티드의 발현을 가능하게 하는 분리자 (separator) 서열을 포함할 수 있다. 분리자 서열의 예는 2A 펩티드 서열 및 IRES를 포함한다. 일부 실시양태에서, 벡터는 다음 구조 중의 하나를 갖는 다중-항원 구축물을 포함한다:
(1) PSA-F2A-PSMA-mIRES-PSCA;
(2) PSA-F2A-PSMA-T2A-PSCA;
(3) PSA-T2A-PSCA-F2A-PSMA; 및
(4) PSCA-F2A-PSMA-mIRES-PSA.
일부 실시양태에서, 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열은 서열 58의 뉴클레오티드 1115-1825를 포함하거나 또는 서열 58의 뉴클레오티드 1106-1825를 포함하고, 면역원성 PSCA 폴리펩티드를 코딩하는 뉴클레오티드 서열은 서열 58의 뉴클레오티드 1892-2257을 포함하거나 또는 서열 58의 뉴클레오티드 1886-2257을 포함하고, 면역원성 PSMA 폴리펩티드를 코딩하는 뉴클레오티드 서열은 서열 58의 뉴클레오티드 2333-4543을 포함하거나 또는 서열 58의 뉴클레오티드 2324-4543을 포함한다. 일부 특정 실시양태에서, 다중-항원 구축물은 서열 33, 34, 35, 및 36으로 이루어진 군으로부터 선택되는 뉴클레오티드 서열을 포함한다. 특정 실시양태에서, 다중-항원 구축물은 서열 60의 폴리펩티드 서열을 코딩하는 뉴클레오티드 서열을 포함한다. 또 다른 특정 실시양태에서, 다중-항원 구축물은 서열 61의 뉴클레오티드 서열을 포함한다.
본 개시내용은 또한 벡터를 포함하는 조성물을 제공한다. 일부 실시양태에서, 조성물은 포유동물, 예컨대 마우스, 개, 원숭이, 또는 인간에서 PAA에 대한 면역 반응의 유도에 유용한 면역원성 조성물이다. 일부 실시양태에서, 조성물은 암의 발생에 대한 보호를 제공하기 위한 (예방제로서 사용된), 또는 PAA 과다발현과 연관된 장애, 예컨대 암, 특히 전립선암의 치료를 위한 (치료제로서 사용된), 포유동물, 예컨대 인간의 면역화에 유용한 백신 조성물이다.
본 개시내용은 또한 포유동물, 특히 인간에서 PAA에 대한 면역 반응의 유도를 위한 또는 암, 예컨대 전립선암의 치료를 위한 벡터 또는 조성물의 사용 방법에 관한 것이다. 일부 실시양태에서, 벡터 또는 백신 조성물을 포함하는 조성물은 벡터 또는 조성물의 면역원성 또는 효과를 향상시키는 하나 이상의 면역 조절제와 조합하여 포유동물, 특히 인간에게 투여된다. 일부 특정 실시양태에서, 방법은 적어도 하나의 면역-억제성-세포 억제제 및 적어도 하나의 면역-이펙터-세포 증강제와 조합한, 본 발명에서 제공되는 백신의 동시-투여를 수반한다.
도 1. PJV7563 벡터의 개략도.
도 2. 5개의 바이러스 2A 카세트의 아미노산 정렬. 생략된 글라이신-프롤린 결합은 별표로 표시한다.
도 3. 바람직한 EMCV IRES의 서열. 번역 개시 부위는 별표로 표시한다. 최소 IRES 요소는 EMCV L 단백질의 밑줄친 처음 5개의 코돈을 제외한다.
도 4. 피하 TUBO 종양 보유 BALB/neuT 마우스에서 암 백신 (백신)의 항-종양 효능에 대한 수니티닙 말레이트 (수텐트) 및 항-뮤린 CTLA-4 모노클로날 항체 (클론 9D9)의 효과를 평가하는 대표적인 연구로부터 마우스의 군의 카플란-마이어 (Kaplan-Meier) 생존 곡선을 보여주는 그래프.
도 5. 암 백신 (rHER2)에 의해 유도된 항원 특이적 T 세포 반응에 대한 CpG7909 및 항-CD40 항체 (바이옥셀 (Bioxcell) #BE0016-2)의 효과를 평가하는 IFNγ ELISPOT 결과를 보여주는 그래프.
도 6. 시토카인 양성 CD8 T 세포를 측정하는 세포내 시토카인 염색 검정을 사용하여 암 백신 (PMED)에 의해 유도된 면역 반응의 품질에 대한 CpG7909의 면역조절 활성을 평가하는 대표적인 연구의 결과를 보여주는 그래프 (*는 스튜던트 T-시험 (Student's T-test)에 의한 P<0.05를 나타낸다).
도 7. 시토카인 양성 CD4 T 세포 (도 7)를 측정하는 세포내 시토카인 염색 검정을 사용하여 암 백신 (PMED)에 의해 유도된 면역 반응의 품질에 대한 CpG7909의 면역조절 활성을 평가하는 대표적인 연구의 결과를 보여주는 그래프 (*는 스튜던트 T-시험에 의한 P<0.05를 나타낸다).
도 8. 시토카인 양성 CD8 T 세포를 측정하는 세포내 시토카인 염색 검정을 사용하여 암 백신 (PMED)에 의해 유도된 면역 반응의 품질에 대한 효능제 항-뮤린 CD40 모노클로날 항체의 면역조절 활성을 평가하는 대표적인 연구의 결과를 보여주는 그래프 (*는 스튜던트 T-시험에 의한 P<0.05를 나타낸다).
도 9. 시토카인 양성 CD4 T 세포를 측정하는 세포내 시토카인 염색 검정을 사용하여 암 백신 (PMED)에 의해 유도된 면역 반응의 품질에 대한 효능제 항-뮤린 CD40 모노클로날 항체의 면역조절 활성을 평가하는 대표적인 연구의 결과를 보여주는 그래프 (*는 스튜던트 T-시험에 의한 P<0.05를 나타낸다).
도 10. 자발적 유방 종양 보유 BALB/neuT 마우스에서 암 백신의 항-종양 효능에 대한 저용량 수니티닙 말레이트 (수텐트)의 효과를 평가하는 대표적인 연구로부터 마우스의 군의 카플란-마이어 생존 곡선을 보여주는 그래프.
도 11. AdC68-734 벡터의 게놈 구성을 보여주는 그래프. CMV Enh/pro = 인간 사이토메갈로바이러스 최조기 (immediate early) 인핸서 및 프로모터; tet op = 테트라사이클린 작동유전자; T2A = 토세아 아시그나(Thosea asigna) 바이러스 2A; F2A = 구제역 바이러스 2A; SV40 pA = 원숭이 바이러스 40 폴리아데닐화 신호; LITR = 좌측 역위 말단 반복체; RITR = 우측 역위 말단 반복체.
도 12. 유동 세포 분석에 의해 삼중 항원 발현 AdC68 벡터로 형질도입된 A549 세포의 표면 상의 PSMA 및 PSCA의 발현을 보여주는 점 그래프.
도 13. AdC68 벡터에 의해 감염된 A549의 용해물에 대한 웨스턴 블롯 (Western blot).
도 2. 5개의 바이러스 2A 카세트의 아미노산 정렬. 생략된 글라이신-프롤린 결합은 별표로 표시한다.
도 3. 바람직한 EMCV IRES의 서열. 번역 개시 부위는 별표로 표시한다. 최소 IRES 요소는 EMCV L 단백질의 밑줄친 처음 5개의 코돈을 제외한다.
도 4. 피하 TUBO 종양 보유 BALB/neuT 마우스에서 암 백신 (백신)의 항-종양 효능에 대한 수니티닙 말레이트 (수텐트) 및 항-뮤린 CTLA-4 모노클로날 항체 (클론 9D9)의 효과를 평가하는 대표적인 연구로부터 마우스의 군의 카플란-마이어 (Kaplan-Meier) 생존 곡선을 보여주는 그래프.
도 5. 암 백신 (rHER2)에 의해 유도된 항원 특이적 T 세포 반응에 대한 CpG7909 및 항-CD40 항체 (바이옥셀 (Bioxcell) #BE0016-2)의 효과를 평가하는 IFNγ ELISPOT 결과를 보여주는 그래프.
도 6. 시토카인 양성 CD8 T 세포를 측정하는 세포내 시토카인 염색 검정을 사용하여 암 백신 (PMED)에 의해 유도된 면역 반응의 품질에 대한 CpG7909의 면역조절 활성을 평가하는 대표적인 연구의 결과를 보여주는 그래프 (*는 스튜던트 T-시험 (Student's T-test)에 의한 P<0.05를 나타낸다).
도 7. 시토카인 양성 CD4 T 세포 (도 7)를 측정하는 세포내 시토카인 염색 검정을 사용하여 암 백신 (PMED)에 의해 유도된 면역 반응의 품질에 대한 CpG7909의 면역조절 활성을 평가하는 대표적인 연구의 결과를 보여주는 그래프 (*는 스튜던트 T-시험에 의한 P<0.05를 나타낸다).
도 8. 시토카인 양성 CD8 T 세포를 측정하는 세포내 시토카인 염색 검정을 사용하여 암 백신 (PMED)에 의해 유도된 면역 반응의 품질에 대한 효능제 항-뮤린 CD40 모노클로날 항체의 면역조절 활성을 평가하는 대표적인 연구의 결과를 보여주는 그래프 (*는 스튜던트 T-시험에 의한 P<0.05를 나타낸다).
도 9. 시토카인 양성 CD4 T 세포를 측정하는 세포내 시토카인 염색 검정을 사용하여 암 백신 (PMED)에 의해 유도된 면역 반응의 품질에 대한 효능제 항-뮤린 CD40 모노클로날 항체의 면역조절 활성을 평가하는 대표적인 연구의 결과를 보여주는 그래프 (*는 스튜던트 T-시험에 의한 P<0.05를 나타낸다).
도 10. 자발적 유방 종양 보유 BALB/neuT 마우스에서 암 백신의 항-종양 효능에 대한 저용량 수니티닙 말레이트 (수텐트)의 효과를 평가하는 대표적인 연구로부터 마우스의 군의 카플란-마이어 생존 곡선을 보여주는 그래프.
도 11. AdC68-734 벡터의 게놈 구성을 보여주는 그래프. CMV Enh/pro = 인간 사이토메갈로바이러스 최조기 (immediate early) 인핸서 및 프로모터; tet op = 테트라사이클린 작동유전자; T2A = 토세아 아시그나(Thosea asigna) 바이러스 2A; F2A = 구제역 바이러스 2A; SV40 pA = 원숭이 바이러스 40 폴리아데닐화 신호; LITR = 좌측 역위 말단 반복체; RITR = 우측 역위 말단 반복체.
도 12. 유동 세포 분석에 의해 삼중 항원 발현 AdC68 벡터로 형질도입된 A549 세포의 표면 상의 PSMA 및 PSCA의 발현을 보여주는 점 그래프.
도 13. AdC68 벡터에 의해 감염된 A549의 용해물에 대한 웨스턴 블롯 (Western blot).
A. 정의
용어 "아주반트 (adjuvant)"는 백신 면역원에 의해 유도되는 면역 반응을 향상시키거나, 가속화하거나 연장할 수 있는 물질을 의미한다.
용어 "효능제"는 또 다른 분자 또는 수용체의 활성을 촉진하는 (유도, 유발, 향상 또는 증가시키는) 물질을 의미한다. 용어 효능제는 수용체에 결합하는 물질 (예를 들어, 항체, 다른 종으로부터의 천연 리간드의 상동체) 및 그에 대해 결합하지 않으면서 수용체 기능을 촉진하는 물질 (예를 들어, 연관 단백질의 활성화에 의해)을 포함한다.
용어 "길항제" 또는 "억제제"는 또 다른 분자 또는 수용체의 생물학적 활성을 부분적으로 또는 완전히 차단, 억제 또는 중화하는 물질을 의미한다.
용어 "동시-투여"는 치료기간 동안 동일한 대상체에게 2 이상의 작용제의 투여를 의미한다. 2 이상의 작용제는 단일 제제 내에 포함될 수 있고, 따라서 동시에 투여될 수 있다. 별법으로, 2 이상의 작용제는 별개의 물리적 제제 내에 포함될 수 있고, 대상체에 별개로 순차적으로 또는 동시에 투여될 수 있다. 용어 "동시에 투여되는" 또는 "동시 투여"는 제1 작용제의 투여와 제2 작용제의 투여가 서로 시간상 중첩됨을 의미하고, 용어 "순차적으로 투여되는" 또는 "순차적 투여"는 제1 작용제의 투여와 제2 작용제의 투여가 서로 시간상 중첩되지 않음을 의미한다.
용어 "세포액형 (cytosolic)"은 특정 폴리펩티드를 코딩하는 뉴클레오티드 서열이 숙주 세포에 의해 발현된 후, 발현된 폴리펩티드가 숙주 세포 내에 보유됨을 의미한다.
용어 "축중성 (degenerate) 변이체"는 참조 뉴클레오티드 서열에 비해 염기의 치환이 존재하지만, 유전자 코드의 축중성 때문에 참조 뉴클레오티드 서열과 동일한 아미노산 서열을 코딩하는 뉴클레오티드 서열을 의미한다.
용어 "유효량"은 포유동물에서 목적하는 효과를 유도하기에 충분한, 포유동물에게 투여되는 양을 나타낸다.
용어 제시된 폴리펩티드의 "단편"은 제시된 폴리펩티드보다 짧고 제시된 폴리펩티드의 서열과 100% 동일성을 공유하는 폴리펩티드를 의미한다.
2 이상의 핵산 또는 폴리펩티드 서열의 측면에서 용어 "동일한" 또는 % "동일성"은 2 이상의 서열 또는 하위서열이 동일하거나, 또는 최대 대응도로 정렬되고 비교될 때, 특정 백분율의 아미노산 잔기 또는 뉴클레오티드를 갖는다는 것을 나타낸다.
용어 "면역-이펙터-세포 증강제" 또는 "IEC 증강제"는 포유동물의 하나 이상의 종류의 면역 이펙터 세포의 수, 품질, 또는 기능을 증가 또는 향상시킬 수 있는 물질을 나타낸다. 면역 이펙터 세포의 예는 세포용해성 CD8 T 세포, CD40 T 세포, NK 세포, 및 B 세포를 포함한다.
용어 "면역 조절제"는 포유동물의 선천, 체액성 또는 세포성 면역 시스템의 임의의 성분의 작용을 변경 (예를 들어, 억제, 감소, 증가, 향상 또는 자극)할 수 있는 물질을 나타낸다. 따라서, 용어 "면역 조절제"는 본원에서 규정되는 "면역-이펙터-세포 증강제", 본원에서 규정되는 "면역-억제성-세포 억제제", 및 포유동물의 면역 시스템의 다른 성분에 영향을 주는 물질을 포함한다.
용어 "면역 반응"은 선천 면역 반응 (예를 들어, Toll 수용체 신호전달 캐스케이드의 활성화), 세포 매개 면역 반응 (예를 들어, T 세포, 예컨대 면역 시스템의 항원-특이적 T 세포, 및 비-특이적 세포에 의해 매개되는 반응), 및 체액성 면역 반응 (예를 들어, B 세포에 의해 매개되는 반응, 예컨대 항체의 생성 및 혈장, 림프액, 및/또는 조직 유체 내로의 분비)을 포함하고 이로 제한되지 않는 숙주 척추동물의 면역 시스템에 의한 특정 물질 (예컨대, 항원 또는 면역원)의 임의의 검출가능한 반응을 의미한다. 면역 반응의 예는 Toll-유사 수용체 활성화, 림포카인 (예를 들어, 시토카인 (예를 들어, Th1, Th2 또는 Th17 타입 시토카인) 또는 케모카인) 발현 또는 분비, 대식세포 활성화, 수지상 세포 활성화, T 세포 (예를 들어, CD4+ 또는 CD8+ T 세포) 활성화, NK 세포 활성화, B 세포 활성화 (예를 들어, 항체 생성 및/또는 분비), 면역원 (예를 들어, 항원 (예를 들어, 면역원성 폴리폴리펩티드))의 MHC 분자에 대한 결합, 세포독성 T 림프구 ("CTL") 반응의 유도, B 세포 반응 (예를 들어, 항체 생산)의 유도, 및 면역 시스템의 세포 (예를 들어, T 세포 및 B 세포)의 팽창 (예를 들어, 세포 집단의 성장)의 변경 (예를 들어, 증가), 및 항원 제시 세포에 의한 항원의 처리 및 제시 증가를 포함한다. 용어 "면역 반응"은 또한 시험관 내에서 척추동물의 면역 시스템의 하나 이상의 성분에 의한 특정 물질 (예컨대 항원 또는 면역원)에 대한 임의의 검출가능한 반응을 포함한다.
용어 "면역원성"은 단독으로 또는 담체에 연결될 상태에서, 특정 항원에 대한 면역 반응을 야기, 유도, 자극 또는 유발하거나, 또는 기존재하는 면역 반응을 개선, 향상, 증가 또는 연장하는 물질의 능력을 나타낸다.
용어 "면역원성 PSA 폴리펩티드"는 인간 PSA 단백질에 대해 또는 인간 PSA 단백질을 발현하는 세포에 대해 면역원성인 폴리펩티드를 의미한다.
용어 "면역원성 PSCA 폴리펩티드"는 인간 PSCA 단백질에 대해 또는 인간 PSCA 단백질을 발현하는 세포에 대해 면역원성인 폴리펩티드를 의미한다.
용어 "면역원성 PSMA 폴리펩티드"는 인간 PSMA 단백질에 대해 또는 인간 PSMA 단백질을 발현하는 세포에 대해 면역원성인 폴리펩티드를 의미한다.
용어 "면역원성 PAA 폴리펩티드"는 본원에서 규정되는 "면역원성 PSA 폴리펩티드", "면역원성 PSCA 폴리펩티드" 또는 "면역원성 PSMA 폴리펩티드"를 의미한다.
용어 "면역-억제성-세포 억제제" 또는 "ISC 억제제"는 포유동물의 면역 억제성 세포의 수 또는 기능을 감소 또는 억제할 수 있는 물질을 나타낸다. 면역 억제성 세포의 예는 조절 T 세포 ("T reg"), 골수성-유래 억제 세포, 및 종양-연관 대식세포를 포함한다.
물질, 예컨대 치료제 또는 면역 조절제의 인간을 포함한 포유동물에 대한 투여의 측면에서 용어 "피내 투여", 또는 "피내 투여된"은 포유동물의 피부의 진피층 내로의 물질의 전달을 의미한다. 포유동물의 피부는 3개의 층 - 표피, 진피, 및 피하층으로 이루어진다. 표피는 피부의 비교적 얇고, 거친 외부층이다. 표피 내의 대부분의 세포는 각질세포이다. 피부의 다음 층인 진피는 피부의 탄력성과 강도를 부여하는 섬유상의 탄성 조직 (대부분 콜라겐, 엘라스틴, 및 피브릴린으로 이루어짐)의 두꺼운 층이다. 진피는 신경말단, 땀샘 및 지방 (피지) 분비선, 모낭, 및 혈관을 포함한다. 진피의 두께는 피부의 위치에 따라 상이하다. 인간에서, 진피는 눈꺼풀에서 약 0.3 mm이고, 등에서 약 3.0 mm이다. 피하층은 보다 큰 혈관 및 신경을 수용하는 지방 및 연결 조직으로 이루어진다. 이 층의 두께는 신체 전체게 걸쳐, 사람마다 상이하다. 용어 "피내 투여"는 진피층 내로의 물질의 전달을 의미한다. 이와 대조적으로, "피하 투여"는 피하층 내로의 물질의 투여를 의미하고, "국소 투여"는 피부의 표면 상의 물질의 투여를 의미한다.
용어 "국소 투여" 또는 "국소 투여된"은 각각 상기 본원에서 정의한 바와 같은 "외용 (topical) 투여", "피내 투여", 및 "피하 투여"를 포함한다. 상기 용어는 또한 "종양내 투여"를 포함하고, 이것은 종양 내 물질의 투여를 의미한다. 국소 투여는 전신 생체분포가 투여된 물질로 달성될 때까지의 시간 동안 투여 부위 주위에 높은 국소 농도를 허용하는 것이 의도되고, "전신 투여"는 투여된 물질이 혈액 내로 흡수되고 순환계를 통해 신체 전체에 걸친 장기 또는 조직으로 분배됨으로써 신속하게 전신 노출을 달성함이 의도된다.
용어 "포유동물"은 포유류 강의 임의의 동물 종을 의미한다. 포유동물의 예는 다음을 포함한다: 인간; 비-인간 영장류, 예컨대 원숭이; 실험실 동물, 예컨대 래트, 마우스, 기니 피그; 가축, 예컨대 고양이, 개, 토끼, 소, 양, 염소, 말, 및 돼지; 및 사로잡힌 야생 동물, 예컨대 사자, 호랑이, 코끼리 등.
용어 "막-결합된"은 특정 폴리펩티드를 코딩하는 뉴클레오티드 서열이 숙주 세포에 의해 발현된 후, 발현된 폴리펩티드가 세포의 막에 결합되거나, 부착되거나, 또는 다른 방식으로 회합됨을 의미한다.
용어 "신생물 질환"은 세포가 둘러싸는 정상 조직의 속도를 초과하고 이와 조화되지 않은, 비정상적으로 높고 비제어된 속도로 증식하는 병태를 의미한다. 이것은 대체로 "종양"으로 알려진 고형 병변 또는 덩어리를 야기한다. 이 용어는 양성 및 악성 신생물 질환을 포함한다. 본 개시내용에서 용어 "암"과 교환가능하게 사용되는 용어 "악성 신생물 질환"은 신체의 다른 위치로 전파되는 ("전이"로 알려진) 종양 세포의 능력을 특징으로 하는 신생물 질환을 의미한다. 용어 "양성 신생물 질환"은 종양 세포에 전이 능력이 결여된 신생물 질환을 의미한다.
용어 "작동가능하게 연결된"은 설명되는 성분들이 그의 의도된 방식으로 기능하도록 허용하는 관계로 존재하는 병렬 (juxtaposition)을 의미한다. 트랜스젠 (transgene)에 "작동가능하게 연결된" 제어 서열은 트랜스젠의 발현이 제어 서열에 적합한 조건 하에 달성되는 방삭으로 라이게이팅된다.
용어 "제약상 허용되는 부형제"는 활성 성분과 상용성이고 투여되는 대상체에서 유의한 나쁜 효과를 야기하지 않는, 면역원성 또는 백신 조성물 내의 활성 성분 (예를 들어, 항원, 항원-코딩 핵산, 면역 조절제, 또는 아주반트) 이외의 다른 물질을 나타낸다.
용어 "펩티드", "폴리펩티드", 및 "단백질"은 본원에서 교환가능하게 사용되고, 코딩 및 비-코딩되는 아미노산, 화학적으로, 또는 생화학적으로 변형된 또는 유도체화된 아미노산을 포함할 수 있는 임의의 길이의 아미노산의 중합체 형태, 및 변형된 폴리펩티드 백본을 갖는 폴리펩티드를 의미한다.
용어 "예방하는" 또는 "예방하다"는 (a) 장애 발생 방지 또는 (b) 장애의 발현 또는 장애의 증상 발현의 지연을 의미한다.
용어 "전립선-연관-항원" (또는 PAA)는 전립선 종양 세포에서 특이적으로 발현되거나 또는 동일한 조직 종류의 비-종양 세포보다 종양 세포에 의해 더 높은 빈도 또는 밀도로 발현되는 TAA (본원에서 규정되는)를 의미한다. PAA의 예는 PSA, PSCA, 및 PSMA를 포함한다.
폴리펩티드의 측면에서 용어 "분비된"은 폴리펩티드를 코딩하는 뉴클레오티드 서열이 숙주 세포에 의해 발현된 후, 발현된 폴리펩티드가 숙주 세포의 외부에 분비됨을 의미한다.
면역 조절제, 예컨대 단백질 키나제 억제제의 양을 설명하기 위해 사용될 때 용어 "준최적 (suboptimal) 용량"은 면역 조절제를 환자에게 단독 투여할 때 치료받는 질환에 대한 목적하는 치료 효과를 생성하기 위해 요구되는 최소량 미만의 면역 조절제의 용량을 나타낸다.
용어 "치료하는", "치료", 또는 "치료하다"는 장애의 제거, 장애의 중증도 감소, 또는 장애의 증상의 중증도 또는 발생 빈도의 감소를 의미한다.
용어 "종양-연관 항원" 또는 "TAA"는 종양 세포에서 특이적으로 발현되거나 또는 동일한 조직 종류의 비-종양 세포보다 종양 세포에 의해 더 높은 빈도 또는 밀도로 발현되는 항원을 의미한다. 종양-연관 항원은 정상적으로는 숙주에 의해 발현되지 않는 항원일 수 있거나; 정상적으로 숙주에 의해 발현되는 분자의 돌연변이된, 말단절단된 (truncated), 오류폴딩된 (misfolded), 또는 다른 비정상적인 표시일 수 있거나; 정상적으로 발현되지만 비정상적으로 높은 수준으로 발현되는 분자와 동일할 수 있거나; 또는 비정상적인 상황 또는 환경에서 발현될 수 있다. 종양-연관 항원은 예를 들어 단백질 또는 단백질 단편, 복합 탄수화물, 강글리오시드, 합텐, 핵산, 또는 이들 또는 다른 생물학적 분자의 임의의 조합물일 수 있다.
용어 "백신"은 특정 항원에 대한 면역 반응을 유도하기 위해 포유동물에 투여하기 위한 면역원성 조성물을 의미한다.
용어 "벡터"는 외래 핵산 분자를 수송하거나 전달할 수 있는 핵산 분자를 의미한다. 외래 핵산 분자는 "삽입" 또는 "트랜스젠"으로 언급된다. 벡터는 일반적으로 삽입체 및 벡터의 백본으로서 기능하는 보다 큰 서열로 이루어진다. 용어 "벡터"는 발현 벡터 및 전사 벡터를 모두 포함한다. 용어 "발현 벡터"는 표적 세포에서 삽입체를 발현할 수 있는 벡터를 의미한다. 이것은 일반적으로 삽입체의 발현을 유도하는 제어 서열, 예컨대 인핸서, 프로모터, 및 종결자 (terminator) 서열을 함유한다. 용어 "전사 벡터"는 전사될 수 있지만 번역되지는 않는 벡터를 의미한다. 전사 벡터는 그들의 삽입체를 증폭하기 위해 사용된다. 벡터의 구조 또는 기원을 기초로 하여, 벡터의 주요 유형은 플라스미드 벡터, 코스미드 벡터, 파지 벡터, 예컨대 람다 파지, 바이러스 벡터, 예컨대 아데노바이러스 (Ad) 벡터, 및 인공 염색체를 포함한다.
B. 다중-항원 구축물을 함유하는 벡터
한 측면에서, 본 개시내용은 2 이상의 면역원성 PAA 폴리펩티드의 발현을 위해 침팬지 아데노바이러스 ChAd68의 게놈으로부터 구축된 바이러스 벡터를 제공한다. 침팬지 아데노바이러스 ChAd68은 또한 문헌에서 원숭이 아데노바이러스 25, C68, Chad68, SAdV25, PanAd9, 또는 Pan9로서 언급된다. 편의성을 위해, 침팬지 아데노바이러스 ChAd68을 본 명세서에서 "C68"로서 언급할 수 있고, 침팬지 아데노바이러스 ChAd68의 게놈으로부터 구축된 바이러스 벡터를 "C68 벡터"로서 언급한다. C68의 전장 게놈 서열은 젠뱅크 (Genbank) (기탁 번호 AC_000011.1)로부터 이용가능하고, 서열 57에 제시한다. 추가로, C68의 전장 게놈 서열 및 아데노바이러스 유전자 E1a, E1b, E2a, E2b, E3, E4, I1, I2, L3, L4, 및 L5의 위치는 US 특허 6,083,716에도 제시되어 있다.
본 개시내용에서 제시되는 C68 벡터는 (1) C68 DNA 서열, (2) 2 이상의 면역원성 PAA 폴리펩티드의 발현을 위한 다중-항원 구축물을 포함한다. 벡터는 또한 항원 생성물의 전사 및 번역을 제어하는 비-천연 조절 서열을 포함할 수 있다. 비-천연 조절 서열은 C68 게놈의 일부가 아닌 서열을 의미한다. C68 DNA 서열, 다중-항원 구축물, 및 조절 서열은 서로 작동가능하게 연결된다.
C68 벡터는 복제-가능, 조건부 복제-가능, 또는 복제-결여 상태일 수 있다. 복제-가능 C68 벡터는 일반적인 숙주 세포, 즉, 일반적으로 아데노바이러스에 의해 감염될 수 있는 세포에서 복제할 수 있다. 복제-가능 바이러스 벡터는 숙주 세포에서 바이러스 복제를 억제하지 않는 아데노바이러스 게놈 내에, 야생형 아데노바이러스에 비해 하나 이상의 돌연변이 (예를 들어, 하나 이상의 결실, 삽입, 및/또는 치환)를 가질 수 있다. 조건부-복제능 C68 벡터는 미리 결정된 조건 하에 복제하도록 조작된 바이러스 벡터이다. 예를 들어, 복제-필수 유전자 기능, 예를 들어, 아데노바이러스 초기 영역에 의해 코딩되는 유전자 기능은 유도가능, 억제가능, 또는 조직-특이적 전사 제어 서열, 예를 들어, 프로모터에 작동가능하게 연결될 수 있다. 복제-결핍 C68 벡터는 벡터가 일반적인 숙주 세포, 특히 벡터에 의해 감염시킬 인간의 세포에서 복제하지 않도록, 예를 들어 하나 이상의 복제-필수 유전자 기능 또는 영역의 결핍의 결과로서 복제에 필요한 바이러스 게놈의 하나 이상의 유전자 기능 또는 영역의 보완을 필요로 하는 바이러스 벡터이다.
벡터는 면역원성 PAA 폴리펩티드의 클로닝 또는 발현을 위해, 또는 조성물, 예컨대 백신 내의 다중-항원 구축물을 숙주 세포에 또는 숙주 동물, 예컨대 인간에게 전달하기 위해 유용하다. 일부 특정 실시양태에서, 본 개시내용은 (i) 서열 58의 뉴클레오티드 서열을 포함하거나 이로 이루어지는 벡터; (ii) 서열 58의 뉴클레오티드 9 - 34811을 포함하거나 이로 이루어지는 벡터; 및 (iii) 서열 63의 뉴클레오티드 서열을 포함하거나 이로 이루어지는 벡터로 이루어진 군으로부터 선택되는 벡터를 제공한다.
본 개시내용에서 제시되는 C68 벡터는 또한 본원에서 구체적으로 설명되거나 예시되는 벡터의 기능적 변이체를 포함한다. "기능적 변이체"는 본원에서 구체적으로 설명되거나 예시되는 벡터 ("모 벡터")의 서열에 비해 돌연변이 (예를 들어, 부가, 결실, 또는 치환)를 포함하지만 모 벡터의 기능 또는 특성을 보유하는 벡터를 의미한다. 예를 들어, 기능적 변이체는 본 개시내용에서 예시되는 모 벡터에 대응하는 코돈-최적화 서열을 포함할 수 있다.
B1. C68 DNA 서열
용어 "C68 DNA 서열"은 C68 게놈 서열의 일부인 DNA 서열을 의미한다. 벡터에 포함되는 C68 DNA 서열은 하나 이상의 바이러스 유전자 또는 게놈 영역의 기능적 결실에 의해 C68 게놈 서열로부터 유래된다. 용어 "기능적 결실"은 바이러스의 충분한 양의 유전자 영역이 제거되거나, 예를 들어 돌연변이 또는 변형에 의해 달리 변경되어, 유전자 영역이 더 이상 유전자 발현의 기능적 생성물을 생산할 수 없거나 그의 정상적인 기능을 다른 방식으로 수행함을 의미한다. 전체 유전자 영역의 결실은 종종 복제-필수 유전자 기능의 붕괴를 필요로 하지 않는다. 그러나, C68 게놈 내의 충분한 공간을 하나 이상의 트랜스젠에 대해 제공하기 위해, 대부분의 하나 이상의 유전자 영역의 제거가 바람직할 수 있다. 유전 물질의 결실이 바람직하지만, 부가 또는 치환에 의한 유전 물질의 돌연변이도 유전자 기능의 붕괴를 위해 적절하다.
일부 실시양태에서, 벡터의 C68 DNA 서열은 아데노바이러스 최조기 유전자 E1a 및 지연된 초기 유전자 E1b의 전체, 또는 충분한 부분을 기능적으로 결실시킴으로써 C68 게놈 서열로부터 유래된다. 다른 실시양태에서, E1a 및 E1b의 기능적 결실 이외에, 기능적 결실은 또한 하나 이상의 다른 유전자, 예컨대 지연된 초기 유전자 E2a, 지연된 초기 유전자 E3, E4, 임의의 후기 유전자 L1 내지 L5, 중기 유전자 IX, 및 IVa2에도 이루어질 수 있다. 따라서, 본 발명의 벡터의 구축에 사용하기 위한 C68 DNA 서열은 E1 내의 결실만을 포함할 수 있다. 별법으로, 그의 생물학적 활성의 파괴를 위해 효과적인 전체 유전자 또는 그의 일부의 결실은 임의의 조합으로 사용될 수 있다. 예를 들어, 하나의 예시적인 벡터에서, C68 DNA 서열은 E1 유전자 및 E4 유전자의, 또는 E1, E2a 및 E3 유전자의, 또는 E1 및 E3 유전자의, 또는 E3의 결실의 존재 또는 부재 하에 E1, E2a 및 E4 유전자의 기능적 결실 등에 의해 C68 게놈 서열로부터 유래된다. 추가로, 상기 결실은 목적하는 결과를 달성하기 위해 다른 돌연변이, 예컨대 온도-감수성 돌연변이와 조합하여 사용될 수 있다. 특정 실시양태에서, C68 DNA 서열은 E1 및 E3 영역에만 기능적 결실이 존재하는 전체 C68 게놈이다.
일부 특정 실시양태에서, E1 유전자의 기능적 결실은 서열 57의 뉴클레오티드 577-3403의 결실에 의해 또는 서열 57의 뉴클레오티드 456-3012의 결실에 의해 수행되고, E3 유전자의 기능적 결실은 서열 57의 뉴클레오티드 27125-31831의 결실에 의해 또는 서열 57의 뉴클레오티드 27812-31330의 결실에 의해 수행된다. 다른 특정 실시양태에서, 벡터에 포함되는 C68 DNA 서열은 서열 57의 뉴클레오티드 3013 - 27811을 포함한다. 또다른 특정 실시양태에서, 벡터에 포함되는 C68 DNA 서열은 서열 57의 뉴클레오티드 3013 - 27811 및 31331 - 36519를 포함한다.
다중-항원 구축물은 아데노바이러스 게놈의 임의의 결실된 영역 내로 삽입될 수 있다. 다중-항원 구축물은 또한 존재하는 유전자 영역의 기능을 붕괴시키기 위해 이 유전자 영역 내로 삽입될 수 있다. 일부 실시양태에서, 다중-항원 구축물은 결실된 E1 유전자 대신에 삽입된다.
B2. 다중-항원 구축물
용어 "다중-항원 구축물"은 2가지 이상의 PAA 폴리펩티드를 코딩하는 핵산 분자 또는 서열을 나타낸다. 상기 분자 또는 서열은 또한 본원에서 "다중-항원 백신" 또는 "다중-항원 플라스미드"로 언급할 수 있다. 다중-항원 구축물은 2가지의 코딩 뉴클레오티드 서열을 보유할 수 있고, 여기서 각각의 코딩 뉴클레오티드 서열은 개별 면역원성 PAA 폴리펩티드를 발현한다. 상기 구축물을 본원에서 또한 "이중 (dual) 항원 구축물", "이중 항원 백신", 또는 "이중 항원 플라스미드"로서 칭한다. 다중-항원 구축물은 또한 3가지의 코딩 뉴클레오티드 서열을 보유할 수 있고, 여기서 각각의 코딩 뉴클레오티드 서열은 개별 면역원성 PAA 폴리펩티드를 발현한다. 그러한 구축물을 또한 본원에서 "삼중 항원 구축물", "삼중 항원 백신", 또는 "삼중 항원 플라스미드"로서 언급한다. 다중-항원 구축물에 의해 코딩되는 개별 PAA 폴리펩티드는 동일한 항원, 예컨대 PSMA, PSA, 또는 PSCA에 대해 면역원성일 수 있다. 예를 들어, 이중 항원 구축물은 둘 모두 PSMA에 대해 면역원성인 2가지의 상이한 PAA 항원을 발현할 수 있다. 다중-항원 구축물에 의해 코딩되는 개별 PAA 폴리펩티드는 상이한 항원에 대해 면역원성일 수 있고, 예를 들어, 이중 항원 구축물은 PSMA 및 PSA에 대해 면역원성인 2가지의 PAA 폴리펩티드를 발현할 수 있다. 다중-항원 구축물은 상이한 항원에 대해 면역원성인 2가지 이상의 개별 PAA 폴리펩티드를 코딩하는 것이 바람직하다.
일부 실시양태에서, 다중-항원 구축물은 다음 조합물 중 임의의 하나의 적어도 2가지의 면역원성 PAA 폴리펩티드를 코딩한다:
1) 면역원성 PSMA 폴리펩티드 및 면역원성 PSA 폴리펩티드;
2) 면역원성 PSMA 폴리펩티드 및 면역원성 PSCA 폴리펩티드; 및
3) 면역원성 PSA 폴리펩티드 및 면역원성 PSCA 폴리펩티드.
일부 특정 실시양태에서, 다중-항원 구축물은 적어도 하나의 면역원성 PSMA 폴리펩티드, 적어도 하나의 면역원성 PSA 폴리펩티드, 및 적어도 하나의 면역원성 PSCA 폴리펩티드를 코딩한다.
다중-항원 구축물에 의해 발현된 면역원성 PSMA 폴리펩티드는 세포액형, 분비형, 또는 막-결합형일 수 있지만, 바람직하게는 막-결합형이다. 일부 실시양태에서, 면역원성 PSMA 폴리펩티드는 다음으로 이루어진 군 중에서 선택된 아미노산 서열을 포함한다:
1) 서열 1의 아미노산 서열,
2) 서열 1의 아미노산 15-750;
3) 서열 3의 아미노산 서열;
4) 서열 5의 아미노산 서열;
5) 서열 7의 아미노산 서열;
6) 서열 3의 아미노산 4-739;
7) 서열 5의 아미노산 4-739;
8) 서열 7의 아미노산 4-739;
9) 서열 9의 아미노산 서열; 및
10) 서열 9의 아미노산 4-739.
다중-항원 구축물에 의해 발현된 면역원성 PSA 폴리펩티드는 세포액형, 분비형, 또는 막-결합형일 수 있지만, 바람직하게는 세포액형이다. 일부 실시양태에서, 면역원성 PSA 폴리펩티드는 다음으로 이루어진 군 중에서 선택된 아미노산 서열을 포함한다:
1) 서열 15의 아미노산 27-263;
2) 서열 17의 아미노산 서열;
3) 서열 17의 아미노산 4-240.
다중-항원 구축물에 의해 발현되는 면역원성 PSCA 폴리펩티드는 전장 인간 PSCA 단백질일 수 있다. 일부 실시양태에서, 면역원성 PSCA 폴리펩티드는 다음으로 이루어진 군 중에서 선택된 아미노산 서열을 포함한다:
1) 서열 21의 아미노산 서열;
2) 서열 21의 아미노산 2-125; 및
3) 서열 21의 아미노산 4-125.
일부 다른 실시양태에서, 다중-항원 구축물은 적어도 하나의 면역원성 PSA 폴리펩티드, 적어도 하나의 면역원성 PSCA 폴리펩티드 및 적어도 하나의 면역원성 PSMA 폴리펩티드를 코딩하고, 여기서 면역원성 PSA 폴리펩티드는 서열 17의 아미노산 서열 또는 서열 17의 아미노산 4-240을 포함하고, 면역원성 PSCA 폴리펩티드는 서열 21의 아미노산 서열 또는 서열 21의 아미노산 2-125를 포함하고, 면역원성 PSMA 폴리펩티드는 하기로 이루어진 군 중에서 선택된 아미노산 서열을 포함한다:
1) 서열 1의 아미노산 15-750;
2) 서열 9의 아미노산 4-739; 및
3) 서열 9의 아미노산 서열.
일부 특정 실시양태에서, 다중-항원 구축물은 서열 60 또는 64의 아미노산 서열을 코딩하는 뉴클레오티드 서열을 포함한다.
일부 특정 실시양태에서, 다중-항원 구축물은 (i) 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열, (ii) 면역원성 PSCA 폴리펩티드를 코딩하는 뉴클레오티드 서열, 및 (iii) 면역원성 PSMA 폴리펩티드를 코딩하는 뉴클레오티드 서열을 포함하고, 여기서
(1) 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열은 (i) 서열 18의 뉴클레오티드 서열; (ii) 서열 20의 뉴클레오티드 서열; (iii) 서열 18의 뉴클레오티드 10-720을 포함하는 뉴클레오티드 서열; (iv) 서열 58 또는 서열 63의 뉴클레오티드 1115-1825를 포함하는 뉴클레오티드 서열; (v) 서열 58 또는 서열 63의 뉴클레오티드 1106-1825를 포함하는 뉴클레오티드 서열; 및 (vi) 상기 (i) - (v)에 제시된 임의의 뉴클레오티드 서열의 축중성 변이체로 이루어진 군으로부터 선택되고;
(2) 면역원성 PSCA 폴리펩티드를 코딩하는 뉴클레오티드 서열은 (i) 서열 22의 뉴클레오티드 서열; (ii) 서열 22의 뉴클레오티드 10-375를 포함하는 뉴클레오티드 서열; (iii) 서열 58 또는 서열 63의 뉴클레오티드 1892-2257을 포함하는 뉴클레오티드 서열; (iv) 서열 58 또는 서열 63의 뉴클레오티드 1886-2257을 포함하는 뉴클레오티드 서열; 및 (v) 상기 (i) - (iv)에 제시된 임의의 뉴클레오티드 서열의 축중성 변이체로 이루어진 군으로부터 선택되고;
(3) 면역원성 PSMA 폴리펩티드를 코딩하는 뉴클레오티드 서열은 (i) 서열 2의 뉴클레오티드 43-2250을 포함하는 뉴클레오티드 서열; (ii) 서열 4의 뉴클레오티드 서열; (iii) 서열 6의 뉴클레오티드 서열; (iv) 서열 8의 뉴클레오티드 서열; (v) 서열 10의 뉴클레오티드 서열; (vi) 서열 4의 뉴클레오티드 10-2217을 포함하는 뉴클레오티드 서열; (vii) 서열 6의 뉴클레오티드 10-2217을 포함하는 뉴클레오티드 서열; (viii) 서열 8의 뉴클레오티드 10-2217을 포함하는 뉴클레오티드 서열; (ix) 서열 10의 뉴클레오티드 10-2217을 포함하는 뉴클레오티드 서열; (x) 서열 58 또는 서열 63의 뉴클레오티드 2333-4543을 포함하는 뉴클레오티드 서열; (xi) 서열 58 또는 서열 63의 뉴클레오티드 2324-4543을 포함하는 뉴클레오티드 서열; 및 (xii) 상기 (i) - (xi)에 제시된 임의의 뉴클레오티드 서열의 축중성 변이체로 이루어진 군으로부터 선택된다.
또 다른 특이적 실시양태에서, 다중-항원 구축물은 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열, 면역원성 PSCA 폴리펩티드를 코딩하는 뉴클레오티드 서열, 및 면역원성 PSMA 폴리펩티드를 코딩하는 뉴클레오티드 서열을 포함하고, 여기서, 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열은 서열 58 또는 서열 63의 뉴클레오티드 1106-1825를 포함하고; 면역원성 PSCA 폴리펩티드를 코딩하는 뉴클레오티드 서열은 서열 58 또는 서열 62의 뉴클레오티드 1886-2257을 포함하고; 면역원성 PSMA 폴리펩티드를 코딩하는 뉴클레오티드 서열은 서열 58 또는 서열 63의 뉴클레오티드 2324-4543을 포함한다.
벡터에 의해 운반되는 하나의 다중-항원 구축물로부터 별개의 면역원성 PAA 폴리펩티드의 발현을 가능하게 하기 위해, 개재하는 서열이 개별 면역원성 PAA 폴리펩티드 (즉, PSA, PSCA, 및 PSMA 폴리펩티드)를 코딩하는 서열들 사이에 포함된다. 이들 개재하는 서열은 하류 면역원성 PAA 폴리펩티드의 별개의 번역을 가능하게 한다. 상기 개재하는 서열은 본 명세서에서 "분리자 서열"로서 언급한다. 단일 벡터로부터 다수의 폴리펩티드의 동시-발현을 위해 사용될 수 있는 임의의 서열은 본 개시내용에서 제시되는 벡터에 분리자 서열로서 사용될 수 있다. 유용한 분리자 서열의 예는 내부 리보솜 유입 부위 (IRES) 및 2A 펩티드 서열을 포함한다.
절단 카세트 또는 CHYSEL (시스-작용 (cis-acting) 히드롤라제 요소)로도 언급되는 2A 펩티드 및 2A 펩티드-유사 서열은 약 20개 아미노산 길이이고, 고도로 보존된 카르복시 말단 D-V/I-EXNPGP 모티프를 갖는다 (도 2). 서열은 자연에서 희귀하고, 바이러스, 예컨대 구제역 바이러스 (FMDV), 말 비염 A 바이러스 (ERAV), 뇌심근염 바이러스 (EMCV), 돼지 테스코바이러스 (PTV), 및 토세아 아시그나 바이러스 (TAV)에서 가장 흔하게 발견된다 (Luke, G. A., P. de Felipe, et al. (2008). "Occurrence, function and evolutionary origins of '2A-like' sequences in virus genomes." J Gen Virol 89(Pt 4): 1036-1042). 2A-기반 다중-항원 발현 전략을 이용하여, 다수의 표적 항원을 코딩하는 유전자가 2A 서열에 의해 분리되어 단일 개방 해독 프레임 (open reading frame) 내에 함께 연결된다. 전체 개방 해독 프레임을 단일 프로모터 및 종결자를 갖는 벡터 내로 클로닝된다. 구축물을 숙주 세포로 전달 시에, 다수의 항원을 코딩하는 mRNA가 전사되고, 단일 폴리단백질로서 번역된다. 2A 서열의 번역 동안, 리보솜은 C-말단 글라이신 및 프롤린 사이의 결합을 건너뛴다. 리보솜 건너뜀은 하류 단백질로부터 상류를 방출하는 동시번역 자가촉매적 (cotranslational autocatalytic) "절단"처럼 작용한다. 다수의 폴리펩티드를 동시 발현하는 벡터에서 다양한 2A 펩티드 서열의 사용에 대한 일반적인 정보는 그 개시내용이 본원에 참조로 포함된 문헌 [Andrea L. Szymczak & Darrio AA Vignali: Development of 2A peptide-based strategies in the design of multicistronic vectors. Expert Opinion Biol. Ther. (2005)5(5) 627-638]에서 볼 수 있다. 2가지의 단백질 항원 사이에 2A 서열을 포함시키면, 상류 폴리펩티드의 C-말단 상에 ~20개 아미노산이, 및 하류 단백질의 N-말단에 1개의 아미노산 (프롤린)이 부가된다. 상기 방법의 적용시에, 도처에 존재하는 (ubiquitous) 프로테아제가 카세트를 상류 단백질로부터 절단하도록 프로테아제 절단 부위는 2A 카세트의 N 말단에 포함될 수 있다 (Fang, J., S. Yi, et al. (2007). "An antibody delivery system for regulated expression of therapeutic levels of monoclonal antibodies in vivo." Mol Ther 15(6): 1153-1159).
본 발명에서 사용될 수 있는 특이적 2A-펩티드 서열의 예는 문헌 [Andrea L. Szymczak & Darrio AA Vignali: Development of 2A peptide-based strategies in the design of multicistronic vectors. Expert Opinion Biol. Ther. (2005)5(5) 627-638]에 개시되어 있고, 표 1에 제공한다.
<표 1> 2A-펩티드 서열
내부 리보솜 유입 부위 (IRES)는 특정 RNA 분자의 5' 비번역 영역에서 발견되는 RNA 요소 (도 3)이다 (Bonnal, S., C. Boutonnet, et al. (2003). "IRESdb: the Internal Ribosome Entry Site database." Nucleic Acids Res 31 (1): 427-428). 이들은 하류 개방 해독 프레임의 번역을 용이하게 하기 위해 진핵 리보솜을 RNA로 유인한다. 정상적인 세포 7-메틸구아노신 캡(cap)-의존성 번역과 달리, IRES-매개 번역은 RNA 분자 내에서 먼 AUG 코돈에서 개시할 수 있다. 고효율 과정은 다중시스트론성 발현 벡터에서 사용하기 위해 이용될 수 있다 (Bochkov, Y. A. and A. C. Palmenberg (2006). "Translational efficiency of EMCV IRES in bicistronic vectors is dependent upon IRES sequence and gene location." Biotechniques 41(3): 283-284, 286, 288). 바람직한 EMCV IRES (pIRES)의 서열을 도 3 및 서열 59에 제공한다. 최소 EMCV IRES (mIRES)는 도 3에 제시된 바와 같이 EMCV L 단백질의 밑줄친 처음 5개의 코돈을 제외한다. 일반적으로, 2개의 트랜스젠은 2개의 별개의 개방 해독 프레임이 IRES에 의해 분리되는 바와 같이 프로모터와 전사 종결자 사이에서 벡터 내로 삽입된다. 구축물을 숙주 세포로 전달할 때, 두 트랜스젠을 모두 코딩하는 하나의 긴 전사체가 전사될 것이다. 제1 ORF는 전통적인 캡-의존성 방식으로 번역되고, IRES 상류의 중지 코돈 코돈에서 종결될 것이다. 제2 ORF는 IRES를 사용하여 캡-비의존성 방식으로 번역될 것이다. 상기 방식으로, 단일 발현 카세트를 갖는 벡터로부터 전사되는 단일 mRNA로부터 2가지의 독립적인 단백질이 생산될 수 있다. 일부 실시양태에서, 다중-항원 구축물은 서열 59의 뉴클레오티드 1-553을 포함하는 EMCV IRES를 포함한다.
일반적으로, 다중-항원 구축물 상의 2개의 면역원성 PAA 폴리펩티드-코딩 서열 사이에 단지 1개의 분리자 서열이 필요하다. 다중-항원 구축물 상의 분리자 서열, 및 PAA 폴리펩티드를 코딩하는 뉴클레오티드 서열의 순서를 식 (I)에 제시한다:
PAA1-SS1-PAA2-SS2-PAA3 (I)
여기서, (i) PAA1, PAA2, 및 PAA3이 상이한 PAA 폴리펩티드를 코딩할 경우, PAA1, PAA2, 및 PAA3은 각각 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열, 면역원성 PSCA 폴리펩티드를 코딩하는 뉴클레오티드 서열, 또는 면역원성 PSMA 폴리펩티드를 코딩하는 뉴클레오티드 서열이고, (ii) SS1 및 SS2는 분리자 서열이고, 동일하거나 상이할 수 있다.
일부 실시양태에서, 벡터는 식 (I)의 다중-항원 구축물을 포함하고, 여기서
(i) PAA1은 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열이고;
(ii) PAA2는 면역원성 PSCA 또는 PSMA 폴리펩티드를 코딩하는 뉴클레오티드 서열이고 (여기서, PAA2는 면역원성 PSCA를 코딩하는 뉴클레오티드 서열이고, PAA3은 면역원성 PSMA를 코딩하는 뉴클레오티드 서열이거나, 또는 그 반대이고);
(iii) SS1은 2A-펩티드 서열이고;
(iv) SS2는 2A-펩티드 서열 또는 IRES이다.
일부 특정 실시양태에서, 다중-항원 구축물은 다음으로 이루어진 군으로부터 선택되는 구조를 갖는다:
(1) PSA-F2A-PSMA-mIRES-PSCA;
(2) PSA-F2A-PSMA-T2A-PSCA;
(3) PSA-T2A-PSCA-F2A-PSMA; 및
(4) PSCA-F2A-PSMA-mIRES-PSA.
구체적인 실시양태에서, 벡터는 식 (I)의 구조를 갖는 다중-항원 구축물을 포함한다:
PAA1-SS1-PAA2-SS2-PAA3 (I)
여기서,
(i) PAA1은 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열이고, 서열 58의 뉴클레오티드 1115-1825를 포함하거나 또는 서열 58 또는 63의 1106-1825를 포함하고;
(ii) PAA2는 면역원성 PSCA 폴리펩티드를 코딩하는 뉴클레오티드 서열이고, 서열 58의 뉴클레오티드 1892-2257을 포함하거나 또는 서열 58 또는 63의 1886-2257을 포함하고;
(iii) PAA3은 면역원성 PSMA 폴리펩티드를 코딩하는 뉴클레오티드 서열이고, 서열 58의 뉴클레오티드 2333-4543을 포함하거나 또는 서열 58 또는 63의 2324-4543을 포함하고;
(iv) SS1은 T2A를 코딩하는 뉴클레오티드 서열이고;
(v) SS2는 F2A를 코딩하는 뉴클레오티드 서열이다.
다중-항원 구축물은 또한 면역원성 PAA 폴리펩티드 (즉, 면역원성 PSA, PSCA, 또는 PSMA 폴리펩티드)를 코딩하는 뉴클레오티드 서열과 하류 분리자 서열 사이에 링커 (linker) 서열을 포함할 수 있다. 그러한 링커 서열의 한 예는 글라이신-세린을 코딩하는 뉴클레오티드 서열이다.
일부 특정 실시양태에서, 다중-항원 구축물은 서열 60의 아미노산 서열을 코딩하거나 서열 61의 아미노산 서열을 코딩하는 뉴클레오티드 서열을 포함한다. 특정 실시양태에서, 다중-항원 구축물은 서열 61의 뉴클레오티드 서열, 서열 65의 뉴클레오티드 서열, 서열 66의 뉴클레오티드 서열, 및 임의의 상기 뉴클레오티드 서열의 축중성 변이체로 이루어진 군 중에서 선택된 뉴클레오티드 서열을 포함한다.
B3. 조절 서열
상기 설명된 분리자 서열 및 링커 서열 외에, 벡터는 코딩된 PAA 폴리펩티드의 효율적인 발현을 유도하는 다른 비-천연 조절 서열을 포함할 수 있다. 조절 서열의 예는 (1) 전사 개시, 종결, 프로모터, 및 인핸서 서열; (2) 효율적인 RNA 처리 신호, 예컨대 스플라이싱 (splicing) 및 폴리아데닐화 신호; (3) 세포질 mRNA를 안정화하는 서열; (4) 번역 효율을 향상시키는 서열 (즉, 코자크 (Kozak) 컨센서스 (consensus) 서열); (5) 단백질 안정성을 향상시키는 서열; 및 (6) 단백질 분비를 향상시키는 서열을 포함한다. 포유동물 세포 내에서 효율적인 발현을 유도하기 위해 본 개시내용에 의해 제시되는 벡터 내에 사용할 수 있는 프로모터 시스템의 예는 SV40 프로모터, 닭 B 액틴 프로모터, 인간 연장 (elongation) 인자 프로모터, 인간 사이토메갈로바이러스 (CMV) 프로모터, 원숭이 CMV 프로모터, 뮤린 CMV 프로모터, 위광견병 (psudorabies) 프로모터, 로우스 (Rous) 육종 바이러스 프로모터, 포스포글리세레이트 키나제 프로모터, 뮤린 백혈병 바이러스 LTR 프로모터, 조류 백혈증 바이러스 LTR 프로모터, 마우스 유방 종양 바이러스 LTR 프로모터, 몰로니 뮤린 백혈병 바이러스 LTR 프로모터, 플라스미노겐 활성제 억제제 프로모터, CYR61, 아데노바이러스 주요 후기 프로모터, 마우스 메탈로티오네인 프로모터, 마우스 포스포에놀-피루베이트 카르복시키나제 프로모터, 소 B-락토글로불린 프로모터, 소 프로락틴 프로모터, 유비퀴틴 C 프로모터, 및 단순 포진 바이러스 티미딘 키나제 프로모터를 포함한다. 전사 종결 신호의 예는 SV40 폴리아데닐화 (폴리A); 소 성장 호르몬 폴리A; 토끼 B 글로빈 폴리A; HSV 티미딘 키나제, 당단백질 B, 및 당단백질 D; HPV E 및 L, 및 합성 종결자를 포함한다.
일부 실시양태에서, C68 벡터는 임의로 CMV 인핸서, 및 SV40 폴리A와 함께 인간 사이토메갈로바이러스 (CMV) 프로모터를 포함한다.
C. 다중-항원 구축물을 운반하는 벡터를 포함하는 조성물 (벡터 조성물)
본 개시내용은 또한 본 개시내용에서 제시되는 벡터를 포함하는 조성물 (본원에서 "벡터 조성물")을 제공한다. 벡터 조성물은 시험관 내에서 또는 인간을 포함한 포유동물에서 생체 내에서 PAA 단백질에 대한 면역 반응의 유도에 유용하다. 벡터 조성물은 벡터를 단독으로 포함할 수 있거나, 또는 부형제를 추가로 포함할 수 있다.
일부 실시양태에서, 벡터 조성물은 본 개시내용에서 제시되는 벡터 및 제약상 허용되는 부형제를 포함하는 제약 조성물이다. 제약 조성물에 적합한 부형제는 관련 기술 분야에 알려져 있다. 부형제는 수성 용액, 비-수성 용액, 현탁액, 및 에멀젼을 포함할 수 있다. 비-수성 부형제의 예는 프로필렌 글리콜, 폴리에틸렌 글리콜, 식물성 오일, 예컨대 올리브 오일, 및 주사용 유기 에스테르, 예컨대 에틸 올레에이트를 포함한다. 수성 부형제의 예는 염수 및 완충된 매질을 포함하는 물, 알콜/수성 용액, 에멀젼 또는 현탁액을 포함한다. 적합한 부형제는 또한 벡터의 세포 흡수를 돕는 물질을 포함한다.
일부 실시양태에서, 제약 조성물은 비정상적인 세포 증식을 억제하고, 암의 발병에 대한 보호를 제공하거나 (예방제로서 사용된), 또는 PAA 과다발현과 연관된 암의 치료를 위해 (치료제로서 사용된), 또는 특정 인간 PAA, 예컨대 PSMA, PSA, 및 PSCA에 대한 면역 반응을 유도하기 위해 인간에 투여하기 위한 백신 조성물이다. 백신 조성물은 하나 이상의 아주반트를 추가로 포함할 수 있다. 백신 조성물 내에 포함될 수 있는 아주반트의 예는 아래에서 제공된다.
D. 벡터 및 벡터 조성물의 용도
다른 측면에서, 본 개시내용은 상기 논의된 벡터 또는 벡터를 포함하는 조성물의 사용 방법을 제공한다.
한 측면에서, 본 개시내용은 포유동물에게 유효량의 (1) 다중-항원 구축물을 함유하는 벡터, 또는 (2) 상기 벡터를 포함하는 조성물을 투여하는 것을 포함하는, 포유동물, 특히 인간에서 PAA에 대한 면역 반응의 유도 방법을 제공한다.
또 다른 측면에서, 본 개시내용은 인간에서 비정상적인 세포 증식을 억제하는 방법을 제공하고, 여기서 비정상적인 세포 증식은 PAA의 과다발현과 연관된다. 방법은 포유동물에게 유효량의 (1) 2 이상의 면역원성 PAA 폴리펩티드를 코딩하는 다중-항원 구축물을 함유하는 벡터, 또는 (2) 상기 벡터를 포함하는 조성물을 투여하는 것을 포함한다. 일부 실시양태에서, 방법은 인간에서 전립선의 비정상적인 세포 증식을 억제하기 위한 것이다. 특정 실시양태에서, 본 개시내용은 PSMA를 과다발현하는 전립선에서 비정상적인 세포 증식을 억제하는 방법을 제공한다. 일부 실시양태에서, 본 개시내용은 인간에게 유효량의 (1) 다중-항원 구축물을 함유하는 벡터, 또는 (2) 상기 벡터를 포함하는 조성물을 투여하는 것을 포함하는, 인간에서 전립선암의 치료 방법을 제공한다. 바람직한 실시양태에서, 다중-항원 구축물은 면역원성 PSMA 폴리펩티드, 면역원성 PSA 폴리펩티드, 및 면역원성 PSCA 폴리펩티드를 코딩하는 삼중 항원 구축물이다.
벡터 또는 벡터 조성물은 관련 기술 분야에 알려진 많은 방법에 의해 인간을 포함한 동물에게 투여될 수 있다. 적합한 방법의 예는 다음을 포함한다: (1) 근육내, 피내, 표피내, 정맥내, 동맥내, 피하, 또는 복강내 투여, (2) 경구 투여, 및 (3) 외용 적용 (예컨대 눈, 비내, 및 질내 적용). 핵산 백신 조성물의 피내 또는 표피내 투여의 한가지 특정 방법은 유전자 총 전달 기술, 예컨대 PowderMed에 의해 시판되는 입자 매개 표피 전달 (Particle Mediated Epidermal Delivery) (PMED™) 백신 전달 장치의 사용을 수반한다. 핵산 백신의 근육내 투여를 위한 또 다른 특정 방법은 주사 및 이후의 전기천공이다.
제시된 방법에서 투여되는 벡터 또는 벡터 조성물의 유효량은 통상의 기술자에 의해 쉽게 결정될 수 있고, 많은 인자에 따라 결정될 것이다. 암, 예컨대 전립선암의 치료 방법에서, 유효량 결정에서 고려될 수 있는 인자는 다음을 포함하고, 이로 제한되지 않는다: (1) 대상체의 면역 상태 및 건강을 포함하는, 치료되는 대상체, (2) 치료되는 암의 중증도 또는 병기, (3) 발현되는 특정 면역원성 PAA 폴리펩티드, (4) 요구되는 보호 또는 치료의 정도, (5) 투여 방법 및 스케줄, (6) 사용되는 제제, 및 (7) 다른 치료제 (예컨대 아주반트 또는 면역 조절제)의 동시-투여. 예를 들어, 벡터의 유효량은 핵산 백신 조성물이 수성 용액으로 제제화되고 피하 침 주사 또는 공기압 (pneumatic) 주사에 의해 투여될 때 2 ㎍/용량 - 10 mg/용량의 범위일 수 있는 반면, 핵산이 코팅된 금 비드로 제조되고 유전자 총 기술을 사용하여 전달될 때는 단지 16 ng/용량 - 16 ㎍/용량이 필요할 수 있다.
본 개시내용에서 제시되는 벡터 또는 백신 조성물을 포함하는 벡터 조성물은 하나 이상의 아주반트와 함께 사용될 수 있다. 적합한 아주반트의 예는 다음을 포함한다: (1) 수중유 에멀젼 제제 (다른 특이적 면역자극제, 예컨대 무라밀 폴리펩티드 또는 박테리아 세포벽 성분 함유 또는 비함유), 예컨대 MF59™ (5% 스쿠알렌, 0.5% 트윈 (Tween) 80, 및 0.5% 소르비탄 트리올레에이트 함유) 및 SAF (10% 스쿠알렌, 0.4% 트윈 80, 5% 플루로닉 (pluronic)-블록 중합체 L121, 및 thr-MDP 함유); (2) 사포닌 아주반트, 예컨대 QS21, 스티물론(STIMULON)™ (캠브리지 바이오사이언스 (Cambridge Bioscience), 미국 매사추세츠주 워세스터), 아비스코(Abisco)® (이스코노바 (Isconova), 스웨덴), 또는 이스코매트릭스(Iscomatrix)® (커먼웰쓰 시럼 래버러토리스 (Commonwealth Serum Laboratories), 호주); (3) 완전 프로인트 (Freund) 아주반트 (CFA) 및 불완전 프로인트 아주반트 (IFA); (4) CpG 모티프를 포함하는, 즉 적어도 하나의 CG 디뉴클레오티드 (여기서, 시토신이 메틸화되지 않음)를 함유하는 올리고뉴클레오티드 (예를 들어, 문헌 [Krieg, Vaccine (2000) 19:618-622]; [Krieg, Curr Opin Mol Ther (2001) 3:15-24]; WO 98/40100, WO 98/55495, WO 98/37919 및 WO 98/52581); 및 (5) 알루미늄 염 (예컨대 명반 (alum), 인산알루미늄, 수산화알루미늄)을 포함하는 금속 염; (12) 사포닌 및 수중유 에멀젼 (예를 들어 WO 99/11241)를 포함한다.
본 개시내용에서 제시되는 벡터 또는 벡터 조성물은 하나 이상의 면역 조절제와 함께 사용될 수 있다. 추가의 측면에서, 본 개시내용은 포유동물에게 (1) 유효량의 본 발명에서 제공되는 벡터, 벡터 조성물, 또는 백신; (2) 유효량의 적어도 하나의 면역-억제성-세포 억제제 (ISC 억제제); 및 (3) 유효량의 적어도 하나의 면역-이펙터-세포 증강제 (IEC 증강제)를 투여하는 것을 포함하는, 포유동물, 특히 인간에서 전립선암의 치료 방법을 제공한다. 상기 방법은 또한 본 개시내용에서 "백신-기반 면역치료 요법" (또는 "VBIR")로 언급된다.
IEC 증강제 및 ISC 억제제는 임의의 적합한 방법 및 (1) 전신 투여, 예컨대 정맥내, 근육내, 또는 경구 투여, 및 (2) 국소 투여, 예컨대 피내 및 피하 투여를 포함하는 경로에 의해 투여될 수 있다. 적절한 또는 적합한 경우, 국소 투여가 일반적으로 전신 투여보다 바람직하다. 임의의 IEC 증강제 및 ISC 억제제의 국소 투여는 약제의 국소 투여를 위해 적합한 포유동물의 신체의 임의의 위치에서 수행할 수 있지만; 이들 면역 조절제는 백신 배액 (draining) 림프절에 아주 근접하게 국소 투여되는 것이 보다 바람직하다.
단일 클래스의 IEC 증강제로부터의 2가지 이상의 특이적 IEC 증강제 (예를 들어, 2가지 CTLA-길항제)를 ISC 억제제와 조합하여 투여할 수 있다. 추가로, 2가지 이상의 상이한 클래스의 IEC 증강제로부터의 2가지 이상의 특이적 IEC 증강제 (예를 들어, 하나의 CTLA-4 길항제 및 하나의 TLR 효능제, 또는 하나의 CTLA-4 길항제 및 하나의 PD-1 길항제)가 함께 투여될 수 있다. 유사하게, 단일 클래스의 ISC 억제제로부터의 2가지 이상의 특이적 ISC 억제제 (예를 들어, 2가지 이상의 단백질 키나제 억제제)를 IEC 증강제와 조합하여 투여할 수 있다. 추가로, 2가지 이상의 상이한 클래스의 ISC 억제제로부터의 2가지 이상의 특이적 ISC 억제제 (예를 들어, 하나의 단백질 키나제 억제제 및 하나의 COX-2 억제제)가 함께 투여될 수 있다.
벡터 또는 벡터 조성물은 사용되는 임의의 또는 모든 면역 조절제 (즉, ISC 억제제 및 IEC 증강제)와 동시에 또는 순차적으로 투여될 수 있다. 유사하게, 2 이상의 면역 조절제가 사용될 때, 이들은 동시에 또는 서로 순차적으로 투여될 수 있다. 일부 실시양태에서, 벡터 또는 벡터 조성물은 한 면역 조절제에 대해 동시에 (예를 들어, 혼합물로) 투여되지만, 하나 이상의 추가의 면역 조절제에 대해서는 순차적으로 투여될 수 있다. 벡터 또는 벡터 조성물 및 면역 조절제의 동시-투여는 항원 및 면역 조절제가 동시에 투여되지 않는 경우에도, 백신 및 적어도 하나의 면역 조절제가 각각 투여 부위, 예컨대 백신 배액 림프절에 동시에 존재하도록 투여되는 경우를 포함할 수 있다. 백신 및 면역 조절제의 동시-투여는 또한 백신 또는 면역 조절제가 투여 부위로부터 청소되지만, 청소된 백신 또는 면역 조절제의 적어도 하나의 세포 효과가 적어도 하나 이상의 추가의 면역 조절제가 투여 부위에 투여될 때까지, 투여 부위, 예컨대 백신 배액 림프절에서 지속되는 경우를 포함할 수 있다. 핵산 백신이 CpG와 조합하여 투여되는 경우에, 백신 및 CpG는 단일 제제에 함유되고, 임의의 적합한 방법에 의해 함께 투여될 수 있다. 일부 실시양태에서, 공동-제제 (혼합물) 내의 핵산 백신 및 CpG는 전기천공과 조합하여 근육내 주사에 의해 투여된다.
임의의 ISC 억제제는 본 발명에서 제공되는 벡터 또는 벡터 조성물과 조합으로 사용될 수 있다. ISC 억제제의 클래스의 예는 PD-1/PD-L1 길항제, 단백질 키나제 억제제, 시클로옥시게나제-2 (COX-2) 억제제, 포스포디에스테라제 타입 5 (PDE5) 억제제, 및 DNA 가교결합제를 포함한다. PD-1/PD-L1 길항제의 예는 항-PD-1 및 PD-L1 모노클로날 항체를 포함한다. COX-2 억제제의 예는 셀레콕시브 및 로페콕시브를 포함한다. PDE5 억제제의 예는 아바나필, 로데나필, 미로데나필, 실데나필, 타다라필, 바데나필, 유데나필, 및 자프리나스트를 포함한다. DNA 가교결합제의 예는 시클로포스파미드를 포함한다. 특이적 단백질 키나제 억제제의 예는 아래에 상세히 설명한다.
용어 "단백질 키나제 억제제"는 단백질 키나제의 선택적 또는 비-선택적 억제제로서 작용하는 임의의 물질을 나타낸다. 용어 "단백질 키나제"는 아데노신 트리인산염의 말단 인산염의 단백질 기질 내의 티로신, 세린 또는 트레오닌 잔기로의 전달을 촉매하는 효소를 나타낸다. 단백질 키나제는 수용체 티로신 키나제 및 비-수용체 티로신 키나제를 포함한다. 수용체 티로신 키나제의 예는 EGFR (예를 들어, EGFR/HER1/ErbB1, HER2/Neu/ErbB2, HER3/ErbB3, HER4/ErbB4), INSR (인슐린 수용체), IGF-IR, IGF-II1R, IRR (인슐린 수용체-관련 수용체), PDGFR (예를 들어, PDGFRA, PDGFRB), c-KIT/SCFR, VEGFR-1/FLT-1, VEGFR-2/FLK-1/KDR, VEGFR-3/FLT-4, FLT-3/FLK-2, CSF-1R, FGFR 1-4, CCK4, TRK A-C, MET, RON, EPHA 1-8, EPHB 1-6, AXL, MER, TYRO3, TIE, TEK, RYK, DDR 1-2, RET, c-ROS, LTK (백혈구 티로신 키나제), ALK (역형성 림프종 키나제), ROR 1-2, MUSK, AATYK 1-3, 및 RTK 106을 포함한다. 비-수용체 티로신 키나제의 예는 BCR-ABL, Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, 및 LIMK를 포함한다. 본원에서 제공되는 백신-기반 면역치료 요법에서, 단백질 키나제 억제제는 최적하 용량으로 포유동물에게 투여된다. 용어 "최적하 용량"은 표적 신생물 질환에 대해 티로신 키나제 억제제를 단제요법으로 투여할 때 (즉, 단백질 키나제 억제제가 임의의 다른 치료제 없이 단독으로 투여되는 경우) 최소 유효 용량 미만의 용량을 나타낸다.
백신-기반 면역치료 요법에서 사용하기 위해 적합한 특이적 단백질 키나제 억제제의 예는 라파티닙, AZD 2171, ET18OCH 3, 인디루빈-3'-옥심, NSC-154020, PD 169316, 퀘르세틴, 로스코비틴, 트리시리빈, ZD1839, 5-로도투베르시딘, 아다포스틴, 알로이신, 알스테르파울론, 아미노게니스테인, API-2, 아피게닌, 아르크티게닌, ARRY-334543, 악시티닙, AY-22989, AZD 2171, 비스인돌릴말레이미드 IX, CCI-779, 켈레리트린, DMPQ, DRB, 에델포신, ENMD-981693, 엘브스타틴 유사체, 에를로티닙, 파수딜, 게피티닙 (ZD1839), H-7, H-8, H-89, HA-100, HA-1004, HA-1077, HA-1100, 히드록시파수딜, 켄파울론, KN-62, KY12420, LFM-A13, 루테올린, LY294002, LY-294002, 말로톡신, ML-9, MLN608, NSC-226080, NSC-231634, NSC-664704, NSC-680410, NU6102, 오로마우신, 옥신돌 I, PD 153035, PD 98059, 플로리진, 피세아타놀, 피크로포도필린, PKI, PP1, PP2, PTK787/ZK222584, PTK787/ZK-222584, 푸르바라놀 A, 라파뮨, 라파마이신, Ro 31-8220, 로트레린, SB202190, SB203580, 시롤리무스, SL327, SP600125, 스타우로스포린, STI-571, SU1498, SU4312, SU5416, 세막사닙, SU6656, SU6668, syk 억제제, TBB, TCN, 티르포스틴 AG 1024, 티르포스틴 AG 490, 티르포스틴 AG 825, 티르포스틴 AG 957, U0126, W-7, 워트만닌, Y-27632, 작티마, ZM 252868, 게피티닙, 수니티닙 말레이트, 에를로티닙, 라파티닙, 카넬티닙, 세막시닙, 바탈라닙, 소라페닙, 이마티닙, 다사티닙, 레플루노미드, 반데타닙, 및 닐로티닙을 포함한다.
일부 실시양태에서, 단백질 키나제 억제제는 하나 초과의 특이적 키나제에 대해 작용하는 억제제인 다중-키나제 억제제이다. 다중-키나제 억제제의 예는 이마티닙, 소라페닙, 라파티닙, BIRB-796, 및 AZD-1152, AMG706, 작티마, MP-412, 소라페닙, 다사티닙, 레스타우르티닙, XL647, XL999, 라파티닙, MLN518 (또한 CT53518로서 공지됨), PKC412, ST1571, AEE 788, OSI-930, OSI-817, 수니티닙 말레이트, 에를로티닙, 게피티닙, 악시티닙, 보수티닙, 템시롤리스무스 및 닐로티닙을 포함한다. 일부 특정 실시양태에서, 티로신 키나제 억제제는 수니티닙, 소라페닙, 또는 수니티닙 또는 소라페닙의 제약상 허용되는 염 또는 유도체 (예컨대 말레이트 또는 토실레이트)이다.
화이자 인크. (Pfizer Inc.)에서 상표명 수텐트로서 시판되는 수니티닙 말레이트는 화학적으로 N-[2-(디에틸아미노)에틸]-5-[(Z)-(5-플루오로-1,2-디히드로-2-옥소-3H-인돌-3-일리딘)메틸]-2,4-디메틸-1H-피롤-3-카르복스아미드를 갖는 부탄디온산, 히드록시-, (2S)-, 화합물 (1:1)로서 설명된다. 화합물, 그의 합성, 및 특정 다형체는 미국 특허 6,573,293, 미국 특허 공개 2003-0229229, 2003-0069298 및 2005-0059824, 및 문헌 [J. M. Manley, M. J. Kalman, B. G. Conway, C. C. Ball, J. L Havens and R. Vaidyanathan, "Early Amidation Approach to 3-[(4-amido)pyrrol-2-yl]-2-indolinones", J. Org. Chew. 68, 6447-6450 (2003)]에 기재되어 있다. 수니티닙 및 그의 L-말레이트 염의 제조는 PCT 공개 WO 2004/024127에 기재되어 있다. 수니티닙 말레이트는 제거가 힘든 (unresectable) 국소 진행성 또는 전이성 질환이 있는 환자에서 위장관 기질 종양, 진행성 신세포 암종, 및 진행성의 고도 분화된 췌장 신경내분비 종양의 치료를 위해 미국에서 승인받았다. 인간을 위한 위장관 기질 종양 (GIST) 및 진행성 신세포 암종 (RCC)에 대한 수니티닙 말레이트의 권장 용량은 50 mg 1일 1회 경구 복용으로 치료의 4주 스케줄에 이어 2주 휴약 (off)이다 (스케줄 4/2). 췌장 신경내분비 종양 (pNET)에 대한 수니티닙 말레이트의 권장 용량은 37.5 mg 1일 1회 경구 복용이다.
백신-기반 면역치료 요법에서, 수니티닙 말레이트는 단일 용량으로 또는 다수 용량으로 경구 투여될 수 있다. 대개, 수니티닙 말레이트는 2, 3, 4주 이상의 연속 매주 용량으로 전달된 후, 수니티닙 말레이트를 투여하지 않는 약 1 또는 2주 이상의 "휴약" 기간을 갖는다. 한 실시양태에서, 용량은 약 4주 동안 전달되고, 2주 휴약 기간을 갖는다. 또 다른 실시양태에서, 수니티닙 말레이트는 2주 동안 전달되고, 1주 휴약 기간을 갖는다. 그러나, 또한 전체 치료 기간 동안 "휴약" 기간 없이 전달될 수 있다. 백신-기반 면역치료 요법에서 인간에게 경구 투여되는 수니티닙 말레이트의 유효량은 대개 용량당 사람당 40 mg 미만이다. 예를 들어, 매일 사람당 37.5, 31.25, 25, 18.75, 12.5, 6.25 mg으로 경구 투여될 수 있다. 일부 실시양태에서, 수니티닙 말레이트는 용량당 사람당 1 - 25 mg의 범위로 경구 투여된다. 일부 다른 실시양태에서, 수니티닙 말레이트는 용량당 사람당 6.25, 12.5, 또는 18.75 mg의 범위로 경구 투여된다. 다른 투여 치료계획 및 변형이 예측가능하고, 의사의 지도를 통해 결정될 것이다.
상표명 넥사바 (NEXAVAR)로서 시판되는 소라페닙 토실레이트는 또한 다중-키나제 억제제이다. 그의 화학명은 4-(4-{3-[4-클로로-3-(트리플루오로메틸)페닐]유레이도}페녹시)-N-메틸피리딘-2-카르복스아미드이다. 이것은 원발 신장암 (진행성 신세포 암종) 및 진행성 원발 간암 (간세포 암종)의 치료를 위해 미국에서 승인받았다. 권장 1일 용량은 400 mg 1일 2회 경구 복용이다. 본원에서 제공되는 백신-기반 면역치료 요법에서, 경구 투여되는 소라페닙 토실레이트의 유효량은 대개 매일 사람당 400 mg 미만이다. 일부 실시양태에서, 경구 투여되는 소라페닙 토실레이트의 유효량은 매일 사람당 10 - 300 mg 범위이다. 일부 다른 실시양태에서, 경구 투여되는 소라페닙 토실레이트의 유효량은 매일 사람당 10 - 200 mg 범위, 예컨대 매일 사람당 10, 20, 60, 80, 100, 120, 140, 160, 180, 또는 200 mg이다.
상표명 인라이타(INLYTA)로 시판되는 악시티닙은 VEGF 수용체 1, 2, 및 3의 선택적 억제제이다. 그의 화학명은 (N-메틸-2-[3-((E)-2-피리딘-2-일-비닐)-1H-인다졸-6-일술파닐]-벤즈아미드이다. 이것은 이전의 한 가지 전신요법 치료에 실패한 후 진행성 신세포 암종의 치료를 위해 승인받았다. 개시 용량은 5 mg 1일 2회 경구 복용이다. 용량 조정은 개인의 안전성 및 내약성에 근거하여 이루어질 수 있다. 본원에서 제공되는 백신-기반 면역치료 요법에서, 경구 투여되는 악시티닙의 유효량은 대개 1일 2회 5 mg 미만이다. 일부 다른 실시양태에서, 경구 투여되는 악시티닙의 유효량은 1일 2회 1-5 mg이다. 일부 다른 실시양태에서, 경구 투여되는 악시티닙의 유효량은 1일 2회 1, 2, 3, 4, 또는 5 mg이다.
백신-기반 면역치료 요법에서, 임의의 IEC 증강제를 사용할 수 있다. 이들은 소분자 또는 큰 분자 (예컨대 단백질, 폴리펩티드, DNA, RNA, 및 항체)일 수 있다. 사용할 수 있는 IEC 증강제의 예는 TNFR 효능제, CTLA-4 길항제, TLR 효능제, 프로그래밍된 세포 사멸 단백질 1 (PD-1) 길항제 (예컨대 항-PD-1 항체 CT-011), 및 프로그래밍된 세포 사멸 단백질 1 리간드 1 (PD-L1) 길항제 (예컨대 BMS-936559), 림프구-활성화 유전자 3 (LAG3) 길항제, 및 T 세포 이뮤노글로불린- 및 뮤신-도메인-함유 분자-3 (TIM-3) 길항제를 포함한다. 특이적 TNFR 효능제, CTLA-4 길항제, 및 TLR 효능제의 예를 본원에서 아래에 상세히 제공한다.
TNFR
효능제
TNFR 효능제의 예는 OX40, 4-1BB (예컨대 BMS-663513), GITR (예컨대 TRX518), 및 CD40의 효능제를 포함한다. 특이적 CD40 효능제의 예를 본원에서 아래에 상세히 설명한다.
CD40 효능제는 세포 상의 CD40 수용체에 결합하는 물질이고 하나 이상의 CD40 또는 CD40L 연관 활성을 증가시킬 수 있다. 따라서, CD40 "효능제"는 CD40 "리간드"를 포괄한다.
CD40 효능제의 예는 CD40 효능제 항체, CD40 효능제 항체의 단편, CD40 리간드 (CD40L), 및 CD40L의 단편 및 유도체, 예컨대 올리고머체 (예를 들어, 2가, 삼량체성 CD40L), 그의 변이체를 함유하는 융합 단백질을 포함한다.
본 발명에서 사용하기 위한 CD40 리간드는 세포 상의 하나 이상의 CD40 수용체에 결합하고 활성화시킬 수 있는 임의의 펩티드, 폴리펩티드 또는 단백질, 또는 펩티드, 폴리펩티드 또는 단백질을 코딩하는 핵산을 포함한다. 적합한 CD40 리간드는 예를 들어, 미국 특허 6,482,411; 미국 특허 6,410,711; 미국 특허 6,391,637; 및 미국 특허 5,981,724에 기재되어 있고, 모든 상기 특허 및 출원과 여기에 개시된 CD40L 서열을 전체를 본원에 참조로 포함시킨다. 인간 CD40 리간드가 인간 치료법에서 사용하기 위해 바람직할 것이지만, 임의의 종으로부터의 CD40 리간드를 본 발명에서 사용할 수 있다. 다른 동물 종에서 사용하기 위해, 예컨대 수의과 실시양태에서, 치료받는 동물에 매칭시킨 CD40 리간드의 종이 바람직할 것이다. 특정 실시양태에서, CD40 리간드는 천연 형성 gp39 펩티드, 폴리펩티드 또는 단백질 올리고머뿐만 아니라 올리고머화 서열을 포함하는 gp39 펩티드, 폴리펩티드, 단백질 (및 코딩 핵산)을 포함한 gp39 펩티드 또는 단백질 올리고머이다. 이량체, 삼량체 및 사량체와 같은 올리고머가 본 발명의 특정 측면에서 바람직한 한편, 본 발명의 다른 측면에서, 올리고머 구조가 하나 이상의 CD40 수용체(들)에 결합하고 활성화시키는 능력을 보유하는 한 보다 큰 올리고머 구조가 사용을 위해 고려된다.
특정 다른 실시양태에서, CD40 효능제는 항-CD40 항체 또는 그의 항원-결합 단편이다. 항체는 인간, 인간화 또는 부분-인간 키메라 항-CD40 항체일 수 있다. 특이적 항-CD40 모노클로날 항체의 예는 G28-5, mAb89, EA-5 또는 S2C6 모노클로날 항체, 및 CP870893을 포함한다. 특정 실시양태에서, 항-CD40 효능제 항체는 CP870893 또는 다세투주맙 (SGN-40)이다.
CP-870,893은 항-종양 치료제로서 임상 조사된 완전 인간 효능제 CD40 모노클로날 항체 (mAb)이다. CP870,893의 구조 및 제조는 WO2003041070에 개시되어 있다 (여기서, 항체는 내부 확인된 "21.4.1"에 의해 확인된다). CP-870,893의 중쇄 및 경쇄의 아미노산 서열을 각각 서열 40 및 서열 41에 제시한다. 임상 시험에서, CP870,893은 일반적으로 주입당 0.05 - 0.25 mg/kg 범위의 용량으로 정맥내 주입에 의해 투여되었다. I상 임상 연구에서, CP-870893의 최대 허용 용량 (MTD)은 0.2 mg/kg인 것으로 추정되고, 용량-제한 독성은 등급 3 CRS 및 등급 3 두드러기를 포함하였다 (Jens Ruter et al.: Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors. [Cancer Biology & Therapy 10:10, 983-993; November 15, 2010]). 본원에서 제공되는 백신-기반 면역치료 요법에서, CP-870,893은 피내, 피하, 또는 외용 투여될 수 있다. 피내 투여되는 것이 바람직하다. 치료법에서 투여할 CP870893의 유효량은 일반적으로 0.2 mg/kg 미만, 대개 0.01 mg - 0.15 mg/kg, 또는 0.05 - 0.1 mg/kg 범위이다.
다세투주맙 (또한 SGN-40 또는 huS2C6로서도 알려짐; CAS 번호 88-486-59-9)은 무통성 림프종, 미만성 큰 B 세포 림프종 및 다발 골수종에 대한 임상 시험에서 조사되고 있는 또 다른 항-CD40 효능제 항체이다. 임상 시험에서, 다세투주맙은 2 mg/kg 내지 16 mg/kg 범위의 매주 용량으로 정맥내 투여되었다. 본원에서 제공되는 백신-기반 면역치료 요법에서, 다세투주맙은 피내, 피하, 또는 외용 투여될 수 있다. 피내 투여되는 것이 바람직하다. 백신-기반 면역치료 요법에서 투여될 다세투주맙의 유효량은 일반적으로 16 mg/kg 미만, 대개 0.2 mg - 14 mg/kg 또는 0.5 - 8 mg/kg, 또는 1 - 5 mg/kg 범위이다.
CTLA -4 억제제.
본원에서 제공되는 백신-기반 면역치료 요법에 사용하기 위해 적합한 항-CTLA-4 길항제는 비제한적으로 항-CTLA-4 항체 (예컨대 인간 항-CTLA-4 항체, 마우스 항-CTLA-4 항체, 포유동물 항-CTLA-4 항체, 인간화 항-CTLA-4 항체, 모노클로날 항-CTLA-4 항체, 폴리클로날 항-CTLA-4 항체, 키메라 항-CTLA-4 항체, 항-CTLA-4 도메인 항체), 항-CTLA-4 항체의 단편 (예컨대 단일쇄 항-CTLA-4 단편, 중쇄 항-CTLA-4 단편, 및 경쇄 항-CTLA-4 단편), 및 공동-자극 경로에 작용성인 CTLA-4의 억제제를 포함한다. 일부 실시양태에서, CTLA-4 억제제는 이필리무맙 또는 트레멜리무맙이다.
예르보이 (YERVOY)로서 시판되는 이필리무맙 (또한 MEX-010 또는 MDX-101로도 알려짐)은 인간 항-인간 CTLA-4 항체이다. 이필리무맙은 또한 그의 CAS 등록 No. 477202-00-9로 언급할 수 있고, 그 전문을 본원에 참조로 포함시킨 PCT 공개 WO01/14424에 항체 10DI로서 개시되어 있다. 이필리무맙을 포함하는 제약 조성물의 예는 PCT 공개 WO2007/67959에 제공되어 있다. 이필리무맙은 제거가 힘든 또는 전이성 흑색종의 치료에 대해 미국에서 승인받았다. 단제요법으로서 이필리무맙의 권장 용량은 총 4회 용량에 대해 3주마다 정맥내 투여되는 3 mg/kg이다. 본 발명에서 제공되는 방법에서, 이필리무맙은 국소, 특히 피내 또는 피하 투여된다. 국소 투여되는 이필리무맙의 유효량은 대개 사람당 5 - 200 mg/용량의 범위 내에 있다. 일부 실시양태에서, 이필리무맙의 유효량은 사람당 10 - 150 mg/용량의 범위 내에 있다. 일부 특정 실시양태에서, 이필리무맙의 유효량은 사람당 약 10, 25, 50, 75, 100, 125, 150, 175, 또는 200 mg/용량이다.
트레멜리무맙(또한 CP-675,206로서 공지됨)은 완전 인간 IgG2 모노클로날 항체이고, CAS 번호 745013-59-6를 갖는다. 트레멜리무맙은 모든 목적을 위해 그 전문을 본원에 참조로 포함된 미국 특허 6,682,736에 항체 11.2.1로 개시되어 있다. 트레멜리무맙의 중쇄 및 경쇄의 아미노산 서열을 각각 서열 42 및 43에 제시한다. 트레멜리무맙은 흑색종 및 유방암을 비롯한 다양한 종양의 치료를 위해 임상 시험에서 연구되고 있고; 여기서, 트레멜리무맙은 0.01 내지 15 mg/kg의 용량 범위에서 단일 용량으로서 또는 다수 용량으로서 4주 또는 12주마다 정맥내 투여된다. 본 발명에서 제공되는 치료법에서, 트레멜리무맙은 국소, 특히 피내 또는 피하 투여된다. 피내 또는 피하 투여되는 트레멜리무맙의 유효량은 대개 사람당 5 - 200 mg/용량의 범위이다. 일부 실시양태에서, 트레멜리무맙의 유효량은 사람당 10 - 150 mg/용량의 범위 내에 있다. 일부 특정 실시양태에서, 트레멜리무맙의 유효량은 사람당 약 10, 25, 37.5, 40, 50, 75, 100, 125, 150, 175, 또는 200 mg/용량이다.
Toll-유사 수용체 ( TLR ) 효능제.
용어 "toll-유사 수용체 효능제" 또는 "TLR 효능제"는 toll-유사 수용체 (TLR)의 효능제로서 작용하는 화합물을 나타낸다. 이것은 TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, 및 TLR11 또는 그의 조합물의 효능제를 포함한다. 달리 지시되지 않으면, TLR 효능제 화합물에 대한 언급은 임의의 이성질체 (예를 들어, 부분입체이성질체 또는 거울상이성질체), 염, 용매화물, 다형체 등을 비롯한 임의의 제약상 허용되는 형태의 화합물을 포함할 수 있다. 특히, 화합물이 광학 활성이면, 화합물에 대한 언급은 각각의 화합물의 거울상이성질체 및 거울상이성질체의 라세미체 혼합물을 포함할 수 있다. 또한, 화합물은 하나 이상의 특정 TLR의 효능제 (예를 들어, TLR7 효능제, TLR8 효능제, 또는 TLR7/8 효능제)로서 확인될 수 있다.
일부 실시양태에서, TLR 효능제는 TLR9 효능제, 특히 CpG 올리고뉴클레오티드 (또는 CpG.ODN)이다. CpG 올리고뉴클레오티드는 포스페이트 결합에 의해 연결된 시토신에 이어지는 구아닌을 함유하는 짧은 핵산 분자이고, 여기서 시토신의 피리미딘 고리는 메틸화되지 않는다. CpG 모티프는 중심 CpG의 (3' 및 5' 측면 상에) 측면에 있는 적어도 하나의 염기에 의해 둘러싸인, 메틸화되지 않은 중심 CpG를 포함하는 염기의 패턴이다. CpG 올리고뉴클레오티드는 D 및 K 올리고뉴클레오티드를 모두 포함한다. 전체 CpG 올리고뉴클레오티드는 메틸화되지 않을 수 있거나, 또는 일부가 메틸화되지 않을 수 있다. 본원에서 제공되는 방법에서 유용한 CpG 올리고뉴클레오티드의 예는 미국 특허 6194388, 6207646, 6214806, 628371, 6239116, 및 6339068에 개시된 것을 포함한다.
본원에서 제공되는 방법에서 유용한 특정 CpG 올리고뉴클레오티드의 예는 다음을 포함한다:
5'TCGTCGTTTTGTCGTTTTGTCGTT3' (CpG 7909);
5'TCGTCGTTTTTCGGTGCTTTT3' (CpG 24555); 및
5'TCGTCGTTTTTCGGTCGTTTT3' (CpG 10103).
CpG7909 (합성 24량체 단일 가닥 올리고뉴클레오티드)는 암의 치료를 위해 단제요법으로서 및 화학요법제와 조합으로, 및 암 및 감염성 질환에 대한 백신을 위한 아주반트로서 광범하게 조사되었다. CpG 7909의 단일 정맥내 용량은 1.05 mg/kg까지 임상 효과 및 유의한 독성 없이 잘 견뎌진 한편, 단일 용량 피하 CpG 7909는 근육통 및 구성적 효과의 용량 제한 독성을 가지면서 0.45 mg/kg의 최대 허용 용량 (MTD)을 가졌음이 보고되었다 (문헌 [Zent, Clive S, et al.: Phase I clinical trial of CpG 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia. Leukemia and Lymphoma, 53(2):211-217(7)(2012)] 참조). 본원에서 제공되는 치료법에서, CpG7909는 주사에 의해 근육 내로 또는 임의의 다른 적합한 방법에 의해 투여될 수 있다. 백신 배액 림프절에 근접하게, 특히 피내 또는 피하 투여에 의해 국소 투여되는 것이 바람직하다. 핵산 백신, 예컨대 DNA 백신과 함께 사용하기 위해, CpG는 바람직하게는 단일 제제 내에 백신과 함께 동시-조제되고, 전기천공과 연결된 근육내 주사에 의해 투여될 수 있다. 근육내, 피내, 또는 피하 투여에 의한 CpG7909의 유효량은 대개 10 ㎍/용량 - 10 mg/용량의 범위 내에 있다. 일부 실시양태에서, CpG7909의 유효량은 0.05 mg - 14 mg/용량의 범위 내에 있다. 일부 특정 실시양태에서, CpG7909의 유효량은 약 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1 mg/용량이다. CpG 24555 및 CpG 10103을 비롯한 다른 CpG 올리고뉴클레오티드가 유사한 방식 및 용량 수준으로 투여될 수 있다.
일부 특정 실시양태에서, 본 개시내용은 인간에게 (1) 유효량의 적어도 하나의 ISC 억제제, 및 (2) 유효량의 적어도 하나의 IEC 증강제를 투여하는 것을 포함하는, 인간에서 신생물 질환의 치료를 위한 백신의 면역원성 또는 치료 효과를 향상시키는 방법을 제공하고, 여기서 적어도 하나의 ISC 억제제는 소라페닙 토실레이트, 수니티닙 말레이트, 악시티닙, 에를로티닙, 게피티닙, 악시티닙, 보수티닙, 템시롤리스무스, 또는 닐로티닙으로부터 선택된 단백질 키나제 억제제이고, 적어도 하나의 IEC 증강제는 CTLA-4 억제제, TLR 효능제, 또는 CD40 효능제로부터 선택된다. 일부 바람직한 실시양태에서, 치료법은 인간에게 (1) 유효량의 적어도 하나의 ISC 억제제 및 (2) 유효량의 적어도 하나의 IEC 증강제를 투여하는 것을 포함하고, 여기서 적어도 하나의 ISC 억제제는 악시티닙, 소라페닙 토실레이트, 또는 수니티닙 말레이트로부터 선택된 단백질 키나제 억제제이고, 적어도 하나의 IEC 증강제는 이필리무맙 또는 트레멜리무맙로부터 선택된 CTLA-4 억제제이다. 일부 추가의 바람직한 실시양태에서, 치료법은 인간에게 (1) 유효량의 적어도 하나의 ISC 억제제, 및 (2) 유효량의 적어도 2가지 IEC 증강제를 투여하는 것을 포함하고, 여기서 적어도 하나의 ISC 억제제는 수니티닙 또는 악시티닙으로부터 선택된 단백질 키나제 억제제이고, 적어도 2가지 IEC 증강제는 트레멜리무맙, 및 CpG7909, CpG2455, 또는 CpG10103으로부터 선택된 TLR 효능제이다.
일부 다른 실시양태에서, 본 개시내용은 인간에게 (1) 인간 PAA에 대한 면역 반응을 유발할 수 있는 유효량의 백신, (2) 유효량의 적어도 하나의 ISC 억제제, 및 (3) 유효량의 적어도 하나의 IEC 증강제를 투여하는 것을 포함하는, 인간에서 전립선암의 치료 방법을 제공하고, 여기서 적어도 하나의 ISC 억제제는 소라페닙 토실레이트, 수니티닙 말레이트, 악시티닙, 에를로티닙, 게피티닙, 악시티닙, 보수티닙, 템시롤리스무스, 또는 닐로티닙으로부터 선택된 단백질 키나제 억제제이고, 적어도 하나의 IEC 증강제는 CTLA-4 억제제, TLR 효능제, 또는 CD40 효능제로부터 선택된다. 일부 바람직한 실시양태에서, 방법은 인간에게 (1) 인간 PAA에 대한 면역 반응을 유발할 수 있는 유효량의 백신, (2) 유효량의 적어도 하나의 ISC 억제제, 및 (3) 유효량의 적어도 하나의 IEC 증강제를 투여하는 것을 포함하고, 여기서 적어도 하나의 ISC 억제제는 소라페닙 토실레이트, 수니티닙 말레이트, 또는 악시티닙으로부터 선택된 단백질 키나제 억제제이고, 적어도 하나의 IEC 증강제는 이필리무맙 또는 트레멜리무맙으로부터 선택된 CTLA-4 억제제이다.
일부 추가의 특이적 실시양태에서, 방법은 인간에게 (1) 유효량의 적어도 하나의 ISC 억제제, 및 (2) 유효량의 적어도 2가지 IEC 증강제를 투여하는 것을 포함하고, 여기서 적어도 하나의 ISC 억제제는 수니티닙 또는 악시티닙으로부터 선택된 단백질 키나제 억제제이고, 적어도 2가지 IEC 증강제는 트레멜리무맙, 및 CpG7909, CpG2455, 또는 CpG10103으로부터 선택된 TLR 효능제이다.
추가의 치료제.
본원에서 제공되는 백신-기반 면역치료 요법은 추가의 치료제를 추가로 포함할 수 있다. 화학요법제 및 호르몬 치료제를 비롯한 매우 다양한 암 치료제가 사용될 수 있다. 용어 "화학요법제"는 암 세포의 사멸을 유발하거나, 암 세포의 성장, 분할, 수복, 및/또는 기능을 저해할 수 있는 화학적 또는 생물학적 물질을 나타낸다. 특정 화학요법제의 예는 아비라테론 아세테이트, 카바지탁셀, 데가렐릭스, 데노수맙, 도세탁셀, 엔잘루타미드, 류프롤라이드 아세테이트, 프레드니손, 시푸류셀-T, 및 염화라듐223을 포함한다. 용어 "호르몬 치료제"는 호르몬의 생산을 억제 또는 제거하거나, 또는 암 세포의 성장 및/또는 생존에 대한 호르몬의 효과를 억제 또는 중화시키는 화학적 또는 생물학적 물질을 나타낸다. 특정 호르몬 치료제의 예는 류프롤라이드, 고세렐린, 트립토렐린, 히스트렐린, 비칼루타미드, 플루타미드, 및 닐루타미드를 포함한다. 본원에서 제공되는 VBIR은 (1) 난소, 고환, 부신선 및 뇌하수체와 같은, 호르몬의 생산에 관여하는 장기 또는 분비샘의 전부 또는 일부를 제거하는 수술적 방법, 및 (2) 환자의 장기 또는 분비샘이 표적화된 호르몬의 생산을 억제 또는 제거하기 위해 충분한 양의 방사선에 노출되는 방사선 치료를 비롯한 다른 치료법과 조합으로 또한 사용될 수 있다.
E. 실시예
다음 실시예를 본 발명의 특정 실시양태를 예시하기 위해 제공한다. 이것은 본 발명의 범위를 어떠한 방식으로도 제한하는 것으로 해석되어서는 안 된다. 상기 논의 및 이들 실시예로부터, 통상의 기술자는 본 발명의 본질적인 특징을 확인할 수 있고, 및 그 취지와 범위를 벗어나지 않으면서, 다양한 용도 및 조건에 맞도록 본 발명의 다양한 변화 및 변형을 이룰 수 있다.
실시예 1. 인간 PSMA 단백질로부터 유래된 세포액형, 분비형, 및 막-결합형 형식의 항원
1A. 면역원성
PSMA
폴리펩티드의 설계
세포액형, 분비형, 및 변형된 형식의 면역원성 PSMA 폴리펩티드를 코딩하는 DNA 구축물을 천연 인간 PSMA 단백질 서열에 기반하여 구축하고, 항-종양 이펙터 면역 반응을 유도하는 능력에 대해 시험하였다. 각각의 인간 PSMA 항원 형식의 구조 및 제조를 다음과 같이 제공한다.
1A1. 인간 PSMA 세포액형 항원. 세포액형 형태의 면역원성 PSMA 폴리펩티드를 일단 발현된 후에 면역원성 폴리펩티드를 세포 내부에 보유하도록 설계하였다. 인간 PSMA의 세포질 도메인 (아미노산 1-19) 및 막횡단 도메인 (아미노산 20-43)을 제거하여, 서열 1의 인간 PSMA의 아미노산 44-750 (세포외 도메인 또는 ECD)로 이루어지는 세포액형 PSMA 폴리펩티드를 생성하였다. 발현을 향상시키기 위해 또는 클로닝을 용이하게 하기 위해 최적 코자크 서열 "MAS"를 폴리펩티드의 N-말단에 첨가할 수 있다.
1A2. 인간 PSMA 분비형 항원. 분비형 형태의 면역원성 PSMA 폴리펩티드를 일단 발현된 후에 폴리펩티드를 세포 외부로 분비하도록 설계하였다. 분비형 폴리펩티드는 서열 1의 인간 PSMA의 아미노산 44-750 (ECD), 아미노산 서열 ETDTLLLWVLLLWVPGSTGD을 갖는 Ig 카파 분비 요소, 및 일단 발현된 후에 PSMA 항원의 분비를 최대화하기 위해 N-말단에 2-아미노산 링커 (AA)로 이루어진다.
1A3. 인간 PSMA 막-결합형 항원. 면역원성 PSMA 막-결합형 폴리펩티드를 폴리펩티드를 세포 표면 상에 안정화시키도록 설계하였다. 인간 PSMA 단백질의 처음 14개 아미노산을 제거하고, 생성된 면역원성 폴리펩티드는 서열 1의 인간 PSMA 단백질의 아미노산 15-750으로 이루어진다. 서열 1의 천연 인간 PSMA 단백질의 아미노산 15-750으로 이루어지고 천연 인간 PSMA 단백질과 100% 서열 동일성을 공유하는 면역원성 폴리펩티드를 본원에서 "인간 PSMA 변형된", "hPSMA 변형된", 또는 "hPSMAmod" 항원으로 또한 칭한다. 인간 PSMA 변형된 항원 (서열 9)의 변이체인 다음 3가지 면역원성 PSMA 폴리펩티드 ("셔플링된 (shuffled) PSMA 변형된 항원"으로서 언급함)를 또한 생성하였다:
(1) 서열 3의 아미노산 서열을 갖는 셔플링된 PSMA 변형된 항원 1;
(2) 서열 5의 아미노산 서열을 갖는 셔플링된 PSMA 변형된 항원 2; 및
(3) 서열 7의 아미노산 서열을 갖는 셔플링된 PSMA 변형된 항원 3.
셔플링된 PSMA 변형된 항원 1, 2, 및 3을 코딩하는 뉴클레오티드 서열을 각각 서열 4, 6, 및 8에 제시한다.
1B.
PSMA
항원을 발현하기 위한 DNA 플라스미드의 제조
PSMA 세포액형, PSMA 분비형, 및 PSMA 변형된 항원을 코딩하는 DNA 구축물을 동물에서 생체내 시험을 위해 적합한 PJV7563 벡터 내로 개별적으로 클로닝하였다 (도 1). 설계 완전성 (integrity)을 확인하기 위해, PJV7563 벡터 내의 DNA의 양 가닥을 서열 결정하였다.
서열 확인된 클론으로부터 대규모 플라스미드 DNA 제제 (퀴아젠 (Qiagen)/CsCl)를 생산하였다. 플라스미드 DNA의 품질은 높은 260/280 비, 높은 수퍼코일드 (super coiled)/닉드 (nicked) DNA 비, 낮은 내독소 수준 (<10 U/mg DNA) 및 음성 생물부하 (bio burden)에 의해 확인하였다.
1C. 포유동물 세포 내에서
PSMA
구축물의 발현
PSMA 세포액형, 분비형, 및 변형된 항원의 발현을 FACS에 의해 결정하였다. 포유동물 293 세포를 다양한 면역원성 PSMA 폴리펩티드를 코딩하는 PJV7563 PMED 벡터로 형질감염시켰다. 3일 후에, 293 세포를 마우스 항-PSMA 항체에 이어 형광 접합된 (FITC) 래트 항-마우스 2차 항체로 염색하였다. 결과를 표 2에 제시한다. 데이타를 음성 대조군에 비해 평균 형광 강도 (MFI)로서 기록하였고, 이것은 인간 PSMA 변형된 항원이 세포 표면 상에 발현되는 것을 확인하였다.
<표 2> 세포 표면 상의 인간 PSMA 변형된 항원의 발현
실시예 2. 다양한 면역원성 PSA 폴리펩티드의 설계
3A. 면역원성 PSA 폴리펩티드의 구축
3가지 상이한 면역원성 PSMA 폴리펩티드 형태 (예를 들어, 세포액형, 막-결합형, 및 분비형 형태)에 대해 실시예 1에 설명된 것과 유사하게, 3가지 형태의 면역원성 PSA 폴리펩티드를 또한 인간 PSA 서열에 기반하여 설계하였다. 세포액형 형태의 면역원성 PSA 폴리펩티드 (이것은 천연 인간 PSA의 아미노산 25-261로 이루어짐)는 분비 신호 및 프로 (pro) 도메인 (아미노산 1-24)을 결실시킴으로써 구축하였다. 상기 세포액형 면역원성 PSA 폴리펩티드의 아미노산 서열을 서열 17에 제공한다. 분비형 형태의 PSA 폴리펩티드는 천연 전장 인간 PSA (아미노산 1-261)이다. 막-결합형 형태의 면역원성 PSA 폴리펩티드는 면역원성 PSA 폴리펩티드 세포액형 형태 (천연 인간 PSA의 아미노산 25-261)를 인간 PSMA 막횡단 도메인 (인간 PSMA의 아미노산 15-54)에 연결시킴으로써 구축하였다.
3B. 파스퇴르 및
HLA
A24 마우스에서 면역 반응
연구 설계. 8 내지 10주령 HLA A2 파스퇴르 마우스 또는 HLA A24 마우스를 실시예 1에 설명된 바와 같이 각각의 백신접종 사이에 2주 간격을 갖는 초회접종(prime)/추가접종(boost)/추가접종 요법으로, 실시예 3A에 제공된 PMED를 이용하여 다양한 PSA 항원을 발현하는 DNA로 면역화하였다. 항원 특이적 T 및 B 세포 반응을, 마지막 면역화의 7일 후에 인터페론-감마 (IFNγ) ELISPOT 검정 및 샌드위치 (sandwich) ELISA에서 측정하였다.
표 3에 제시된 ELISpot 데이타는 세포액형 및 막-결합형 형태의 면역원성 PSA 폴리펩티드가 모두 세포액형 PSA 항원을 발현하도록 아데노바이러스로 형질유도된 인간 종양 세포 (SKmel5-Ad-PSA)를 인식하지만 eGFP를 발현하도록 아데노바이러스로 형질유도된 세포 (SKmel5-Ad-eGFP)를 인식하지 않는 T 세포를 유도할 수 있음을 나타낸다. 이들 2가지 항원은 또한 PSA 단백질에 대한 반응을 야기하였다. PSA 분비형 항원은 SKmel5-Ad-PSA 또는 PSA 단백질에 대해 T 세포를 유도하지 못하였다. SFC>50을 양성으로 간주한다.
<표 3> PSA+ HLA A2.1+ SKmel5 인간 암세포에 대한 파스퇴르 마우스에서 PSA 항원에 의한 T 세포 반응의 유도
<표 4> 샌드위치 ELISA 검정에 의해 측정된 항-PSA 항체 반응의 유도
표 4의 데이타는 분비형 및 막-결합형 형태의 면역원성 PSA 폴리펩티드가 모두 항-PSA 항체 반응을 유도할 수 있음을 입증한다.
실시예 3. 다중-항원 백신 구축물의 구축
본 실시예에서, 상이한 전략을 이용하는 다중-항원 구축물을 포함하는 플라스미드의 구축을 설명한다. 이들 플라스미드는 pPJV7563과 동일한 일반적인 플라스미드 백본을 공유한다. 달리 특정되지 않으면, 다중-항원 구축물에 포함되는 유전자는 (1) 서열 9의 면역원성 PSMA 폴리펩티드, (2) 서열 21의 아미노산 2-125를 포함하는 면역원성 PSCA 폴리펩티드, 및 (3) 서열 17의 면역원성 PSA 폴리펩티드를 코딩한다.
실시예 3A. 이중 항원 구축물을 포함하는 플라스미드
3A1. 다중 프로모터를 이용하는 플라스미드의 구축
플라스미드 460 ( PSMA / PSCA 이중 프로모터). 부위-지정 돌연변이유발, PCR, 및 제한 단편 삽입의 기술을 이용하여 플라스미드 460을 구축하였다. 먼저, Kpn I 제한 부위를 제조자의 프로토콜 (퀵체인지 (Quickchange) 키트, 애질런트 테크놀로지스 (Agilent Technologies), 미국 캘리포니아주 산타클라라)에 따라 MD5 및 MD6 프라이머를 사용하는 부위-지정 돌연변이유발을 이용하여 플라스미드 5259 내에서 CMV 프로모터의 상류에 도입하였다. 두 번째로, 최소 CMV 프로모터, 인간 PSMA, 및 토끼 B 글로불린 전사 종결자로 이루어지는 발현 카세트를, Kpn I 제한 부위를 보유하는 프라이머 (MD7 및 MD8)을 이용하여 플라스미드 5166으로부터 PCR에 의해 증폭하였다. PCR 앰플리콘을 Kpn I로 소화시키고, 소 창자 알칼리성 포스파타제 (CIP)-처리한 플라스미드 5259의 새로 도입된 Kpn I 부위 내로 삽입하였다.
3A2. 2A 펩티드를 이용하는 이중 항원 구축물의 구축
플라스미드 451 ( PSMA - T2A - PSCA). 플라스미드 451은 중복 (overlapping) PCR 및 제한 단편 교환의 기술을 이용하여 구축하였다. 먼저, 인간 PSMA 아미노산 15-750을 코딩하는 유전자를, 프라이머 119 및 117을 사용하여 주형 (template)으로서 플라스미드 5166을 이용하여 PCR에 의해 증폭하였다. 전장 인간 PSCA를 코딩하는 유전자를, 프라이머 118 및 120을 사용하여 주형으로서 플라스미드 5259를 이용하여 PCR에 의해 증폭하였다. PCR은 PSMA의 3' 단부 및 PSCA의 5' 단부에서 중복 TAV 2A (T2A) 서열의 부가를 일으켰다. 앰플리콘들을 함께 혼합하고, 프라이머 119 및 120을 사용하여 PCR에 의해 증폭하였다. PSMA-T2A-PSCA 앰플리콘을 Nhe I 및 Bgl II로 소화시키고, 유사하게 소화시킨 플라스미드 5166 내로 삽입하였다. 높은 절단 효율을 촉진시키기 위해 글라이신-세린 링커를 PSMA 및 T2A 카세트 사이에 포함시켰다.
플라스미드 454 ( PSCA - F2A - PSMA). 플라스미드 454는 PCR 및 제한 단편 교환의 기술을 이용하여 생성하였다. 먼저, 전장 인간 PSCA를 코딩하는 유전자를, 프라이머 42 및 132를 사용하여 주형으로서 플라스미드 5259를 이용하여 PCR에 의해 증폭하였다. 앰플리콘을 BamH I로 소화시키고 유사하게 소화시킨, CIP-처리된 플라스미드 5300 내로 삽입하였다. 높은 절단 효율을 촉진시키기 위해 글라이신-세린 링커를 PSCA 및 FMDV 2A (F2A) 카세트 사이에 포함시켰다.
플라스미드 5300 (PSA- F2A - PSMA). 플라스미드 5300을 중복 PCR 및 제한 단편 교환의 기술을 이용하여 구축하였다. 먼저, PSA 아미노산 25-261을 코딩하는 유전자를, 프라이머 MD1 및 MD2를 사용하여 플라스미드 5297로부터 PCR에 의해 증폭하였다. 인간 PSMA 아미노산 15-750을 코딩하는 유전자를, 프라이머 MD3 및 MD4를 사용하여 플라스미드 5166으로부터 PCR에 의해 증폭하였다. PCR은 PSA의 3' 단부 및 PSMA의 5' 단부에서 겹치는 F2A 서열의 부가를 일으켰다. 앰플리콘들을 함께 혼합하고 PCR에 의해 연장시켰다. PSA-F2A-PSMA 앰플리콘을 Nhe I 및 Bgl II로 소화시키고, 유사하게 소화시킨 플라스미드 pPJV7563 내로 삽입하였다.
3A3. 내부 리보솜 유입 부위를 이용하는 이중 항원 구축물
플라스미드 449 ( PSMA - mIRES - PSCA). 플라스미드 449는 중복 PCR 및 제한 단편 교환의 기술을 이용하여 구축하였다. 먼저, 전장 인간 PSCA를 코딩하는 유전자를, 프라이머 124 및 123을 사용하여 플라스미드 5259로부터 PCR에 의해 증폭하였다. 최소 EMCV IRES를, 프라이머 101 및 125를 사용하여 pShuttle-IRES로부터 PCR에 의해 증폭하였다. 겹치는 앰플리콘들을 함께 혼합하고, 프라이머 101 및 123을 사용하여 PCR에 의해 증폭하였다. IRES-PSCA 앰플리콘을 Bgl II 및 BamH I로 소화시키고, Bgl II-소화시킨, CIP-처리된 플라스미드 5166 내로 삽입하였다. 자발적 돌연변이를 IRES 내에 고정하기 위해, Avr II 내지 Kpn I 서열을 함유하는 IRES를 pShuttle-IRES로부터 동등한 단편으로 교체하였다.
플라스미드 603 ( PSCA - pIRES - PSMA). 플라스미드 603은 PCR 및 무접합 클로닝 (seamless cloning)의 기술을 이용하여 구축하였다. 그의 3' 단부에서 바람직한 EMCV IRES에 부착된 전장 인간 PSCA를 코딩하는 유전자를, 프라이머 SD546 및 SD547를 사용하여 플라스미드 455로부터 PCR에 의해 증폭하였다. 인간 PSMA 아미노산 15-750을 코딩하는 유전자를, 프라이머 SD548 및 SD550을 이용하여 플라스미드 5166으로부터 PCR에 의해 증폭하였다. 2개의 겹치는 PCR 앰플리콘을 제조자의 지시 (인비트로겐 (Invitrogen), 미국 캘리포니아주 칼스바드)에 따라 무접합 클로닝에 의해 Nhe I 및 Bgl II-소화시킨 pPJV7563 내로 삽입하였다.
플라스미드 455 ( PSCA - mIRES - PSA). 플라스미드 455는 중복 PCR 및 제한 단편 교환의 기술을 이용하여 구축하였다. 먼저, 인간 PSA 아미노산 25-261을 코딩하는 유전자를, 프라이머 115 및 114를 사용하여 플라스미드 5297로부터 PCR에 의해 증폭하였다. 최소 EMCV IRES를, 프라이머 101 및 116을 사용하여 pShuttle-IRES로부터 PCR에 의해 증폭하였다. 겹치는 앰플리콘들을 함께 혼합하고, 프라이머 101 및 114를 사용하여 PCR에 의해 증폭하였다. IRES-PSA 앰플리콘을 Bgl II 및 BamH I로 소화시키고, Bgl II-소화시킨, CIP-처리된 플라스미드 5259 내로 삽입하였다. 자발적 돌연변이를 상기 클론 내에 고정하기 위해, Bgl II 내지 BstE II 서열을 신선한 중복 PCR 반응으로부터 동등한 단편으로 교체하였다.
실시예 3B. 삼중 항원 구축물을 포함하는 플라스미드
일반적 전략. PSA-F2A-PSMA, PSMA-mIRES-PSCA, PSMA-T2A-PSCA, PSA-T2A-PSCA, PSCA-F2A-PSMA, PSCA-pIRES-PSMA, 및 PSMA-mIRES-PSA를 비롯한 많은 이중 항원 플라스미드가 삼중 항원 플라스미드 벡터 내로 다양한 조합으로 포함시키기 위해 선택되었다. 모든 경우에, 플라스미드 벡터는 모 pPJV7563 플라스미드 백본에 기반하였다. 4가지 플라스미드 벡터 (플라스미드 456, 457, 458, 및 459)는 3가지 모든 항원의 발현을 유도하기 위해 토끼 B 글로불린 전사 종결자를 갖는 단일 전체 CMV 프로모터를 이용하였다. 2가지 다른 플라스미드 벡터 (플라스미드 846 및 850)는 3가지 항원의 발현을 유도시키기 위해 IRES 또는 2A와 조합으로 이중 프로모터 전략을 포함하였다. 다수의 2A 카세트를 갖는 플라스미드는, 플라스미드/벡터 증폭 동안 제1 및 제2 카세트 사이에 재조합의 가능성을 최소화하기 위해 상이한 카세트를 보유하도록 조작하였다. 항원 발현은 유동 세포 분석 (도 7a 및 7b) 및 웨스턴 블로팅 (도 8a 및 8b)에 의해 입증되었다.
플라스미드 456 (PSA- F2A - PSMA - mIRES - PSCA). 플라스미드 456은 제한 단편 교환에 의해 구축하였다. 플라스미드 5300을 Nhe I 및 Hpa I로 소화시키고, ~1.8 kb 삽입체를 유사하게 소화시킨 플라스미드 449 내로 라이게이팅하였다.
플라스미드 457 (PSA- F2A - PSMA - T2A - PSCA). 플라스미드 457은 제한 단편 교환에 의해 구축하였다. 플라스미드 5300을 Nhe I 및 Hpa I로 소화시키고, ~1.8 kb 삽입체를 유사하게 소화시킨 플라스미드 451 내로 라이게이팅하였다.
플라스미드 458 (PSA- T2A - PSCA - F2A - PSMA). 플라스미드 458은 PCR 및 제한 단편 교환의 기술을 이용하여 구축하였다. 인간 PSA 아미노산 25-261을 코딩하는 유전자를, 프라이머 119 및 139를 사용하여 플라스미드 5297로부터 PCR에 의해 증폭하여, 3' 단부에서 T2A 서열 및 Nhe I 제한 부위의 부가를 일으켰다. 앰플리콘을 Nhe I로 소화시키고, 유사하게 소화시킨 플라스미드 454 내로 삽입하였다.
플라스미드 459 ( PSCA - F2A - PSMA - mIRES - PSA). 플라스미드 459는 제한 단편 교환의해 구축하였다. 플라스미드 454를 Nhe I 및 Bgl II로 소화시키고, PSCA-F2A-PSMA 함유 삽입체를 유사하게 소화시킨 플라스미드 455 내로 라이게이팅시켰다.
플라스미드 846 ( CBA -PSA, CMV - PSCA - pIRES - PSMA). 플라스미드 846은 PCR 및 무접합 클로닝의 기술을 이용하여 구축하였다. 먼저, 1) 닭 베타 액틴 (CBA) 유전자로부터 프로모터 및 5' 비번역 영역, 2) 하이브리드 닭 베타 액틴/토끼 베타 글로빈 인트론, 3) 인간 PSA 아미노산 25-261을 코딩하는 유전자, 및 4) 소 성장 호르몬 종결자로 이루어진 발현 카세트를 합성하였다. 상기 PSA 발현 카세트를, 프라이머 3SalICBA 및 5SalIBGH를 사용하여 플라스미드 796으로부터 PCR에 의해 증폭하였다. 앰플리콘을 진아트 심리스 클로닝 앤드 어셈블리 (GeneArt Seamless Cloning and Assembly) 키트 (인비트로겐, 미국 캘리포니아주 칼스바드)를 사용하여 플라스미드 603의 SalI 부위 내로 클로닝하였다. 상기 플라스미드의 세포 내로 전달 시에, PSA 발현은 CBA 프로모터에서 유도될 것인 한편, PSCA 및 PSMA 발현은 CMV 프로모터에서 유도될 것이다.
플라스미드 850 ( CBA -PSA, CMV - PSCA - F2A - PSMA ). 플라스미드 850은 PCR 및 무접합 클로닝의 기술을 이용하여 구축하였다. 먼저, CBA 프로모터-유도된 PSA 발현 카세트를, 프라이머 3SalICBA 및 5SalIBGH를 사용하여 플라스미드 796으로부터 PCR에 의해 증폭하였다. 앰플리콘을 진아트 심리스 클로닝을 사용하여 플라스미드 454의 SalI 부위 내로 클로닝하였다. 상기 플라스미드의 세포 내로 전달 시에, PSA 발현은 CBA 프로모터에서 유도될 것인 한편, PSCA 및 PSMA 발현은 CMV 프로모터에서 유도될 것이다.
플라스미드 916 (PSA- T2A - PSCA - F2A - PSMA ). 플라스미드 916은 PCR 및 깁슨 (Gibson) 클로닝의 기술을 이용하여 구축하였다. 3가지 PAA 폴리펩티드를 코딩하는 유전자를 PCR에 의해 증폭하고, 깁슨 클로닝 기술에 의해 pPJV7563의 Nhe I/Bgl II 부위 내로 라이게이팅하였다. 플라스미드 916의 완전 뉴클레오티드 서열을 서열 62에 제시한다. 플라스미드 458 및 플라스미드 916은 3가지 면역원성 PAA 폴리펩티드를 포함하는 동일한 아미노산 서열을 코딩하고, 상기 아미노산 서열을 서열 60에 제시한다. 3가지 PAA 폴리펩티드를 포함하는 아미노산 서열을 코딩하는 플라스미드 916 내의 뉴클레오티드 서열은 코돈-최적화되고, 또한 서열 61에 제시된다.
<표 21> 다중-항원 플라스미드의 구축에 사용된 프라이머의 목록
실시예 3C. 삼중 항원 아데노바이러스 벡터
일반적 전략. DNA 플라스미드를 사용할 때와 같이, 바이러스 벡터는 다수의 전립선암 항원을 전달하도록 조작될 수 있다. 다중-항원 구축물 - 이중 프로모터, 2A 펩티드, 및 내부 내부 리보솜 유입 부위 - 에 대한 상기 설명된 3가지 다중-항원 발현 전략을 다양한 조합으로 포함시켜 삼중 항원 아데노바이러스 벡터를 생성하였다. 간단히 설명하면, 다중-항원 발현 카세트를, 2개의 카피의 테트라사이클린 작동유전자 서열 (TetO2)을 보유하도록 변형된 pShuttle-CMV 플라스미드 내로 클로닝하였다. 재조합 아데노바이러스 혈청형 5 벡터는 제조자의 프로토콜 (애질런트 테크놀로지스, 인크., 미국 캘리포니아주 산타클라라)에 따라 애드이지 벡터 시스템 (AdEasy Vector System)을 이용하여 생성하였다. 바이러스를 HEK293 세포 내에서 증폭하고, 표준 프로토콜에 따라 이중 염화세슘 밴딩 (banding)에 의해 정제하였다. 생체내 연구에 앞서, 바이러스 원액 (stock)을 바이러스 입자 농도, 감염 역가, 무균성, 내독소, 게놈 및 트랜스젠 완전성, 트랜스젠 동일성 및 발현에 대해 철저하게 특성화하였다.
아데노바이러스 -733 (PSA- F2A - PSMA - T2A - PSCA ). Ad-733은 플라스미드 457의 바이러스 동등물이다. 3가지 항원의 발현은 Tet 억제유전자 (repressor) 발현 HEK293 세포주 내에서 대규모 생산 동안 트랜스젠 발현을 억제하기 위한 테트라사이클린 작동유전자를 갖는 단일 CMV 프로모터에서 유도된다. 다중-항원 발현 전략은 2개의 상이한 2A 서열을 포함한다.
아데노바이러스 -734 (PSA- T2A - PSCA - F2A - PSMA ). Ad-734는 플라스미드 458의 바이러스 동등물이다. 3가지 항원의 발현은 Tet 억제유전자 발현 HEK293 세포주 내에서 대규모 생산 동안 트랜스젠 발현을 억제하기 위한 테트라사이클린 작동유전자를 갖는 단일 CMV 프로모터에서 유도된다. 다중-항원 발현 전략은 2개의 상이한 2A 서열을 포함한다.
아데노바이러스 -735 ( PSCA - F2A - PSMA - mIRES -PSA). Ad-735는 플라스미드 459의 바이러스 동등물이다. 3가지 항원의 발현은 Tet 억제유전자 발현 HEK293 세포주 내에서 대규모 생산 동안 트랜스젠 발현을 억제하기 위한 테트라사이클린 작동유전자를 갖는 단일 CMV 프로모터에서 유도된다. 다중-항원 발현 전략은 2A 서열 및 IRES를 포함한다.
아데노바이러스 -796 ( CBA -PSA, CMV - PSCA - pIRES - PSMA ). Ad-796은 플라스미드 846의 바이러스 동등물이다. PSA의 발현은 닭 베타 액틴 프로모터에서 유도되는 한편, PSCA 및 PSMA 발현은 CMV-TetO2 프로모터에서 유도된다. 다중-항원 발현 전략은 2개의 프로모터 및 IRES를 포함한다.
아데노바이러스 -809 ( CBA -PSA, CMV - PSCA - F2A - PSMA ). Ad-809는 플라스미드 850의 바이러스 동등물이다. PSA의 발현은 닭 베타 액틴 프로모터에서 유도되는 한편, PSCA 및 PSMA 발현은 CMV-TetO2 프로모터에서 유도된다. 다중-항원 발현 전략은 2개의 프로모터 및 2A 서열을 포함한다.
실시예 4. 수니티닙 및 항-CTLA-4 항체와의 조합물 내에서 백신의 항암 효능
수니티닙 및 항-CTLA-4 모노클로날 항체 (클론 9D9)와의 조합물 내에서 암 백신의 항-종양 효능을 피하 TUBO 종양 보유 BALB/neuT 마우스에서 조사하였다.
연구 절차. 간단히 설명하면, 각각의 군 당 10마리 마우스에게 종양 이식 후 제10일에 시작하여 제64일까지 비히클 또는 수니티닙 말레이트 20 mg/kg를 매일 경구 투여하였다. 아데노바이러스 벡터로서 항원을 코딩하지 않거나 (대조군 백신) 서열 54의 래트 Her-2 항원을 코딩하는 (암 백신) DNA 구축물을 사용한 백신접종을 제13일에 개시하고, 이어서, 후속적으로 DNA에 의한 각각의 항원 (HBV 항원 또는 rHer-2)의 2회의 매주 면역화, 2회의 격주 면역화, 및 7회의 매주 면역화를 수행하였다. 항-뮤린 CTLA-4 모노클로날 항체로 치료한 마우스의 군 (막힌 원 및 빈 삼각형)에게 PMED 주사 직후에 제20, 27, 41, 55, 62, 69, 76, 83, 90, 및 97일에 250 ㎍의 항체를 복강내 주사하였다.
결과. 도 4는 암 백신과 조합물로 수니티닙 및 항-뮤린 CTLA-4 모노클로날 항체 (클론 9D9)의 항-종양 효능을 평가하는 대표적인 연구로부터 마우스의 군의 카플란-마이어 생존 곡선을 보여준다. 대조군 백신 (빈 원), 항-뮤린 CTLA-4 모노클로날 항체 (빈 삼각형) 또는 암 백신 (막힌 삼각형)과 함께 수텐트로 치료한 마우스에서 생존 시간 증가가 관찰되었다. 항-뮤린 CTLA-4과 조합한 수텐트 및 암 백신으로 치료한 마우스 (막힌 원)에서 추가의 생존 증가가 관찰되었다. P 값은 로그 순위 검정 (log-rank test)에 의해 계산하였다.
실시예 5. 암 백신에 의해 유도된 면역 반응에 대한 CpG 또는 CD40 효능제의 효과
BALB
/c 마우스에서 면역원성 연구
암에 의해 유도된 항원 특이적 면역 반응의 규모 (magnitude) 및 품질에 대한 면역 조절제의 국소 투여의 효과를 BALB/c 마우스에서 조사하였고, 여기서 면역 반응은 IFNγ ELISPOT 검정 또는 세포내 시토카인 염색 검정을 이용하여 rHER2 특이적 T 세포 반응을 측정함으로써 평가하였다. 간단히 설명하면, 지시된 바와 같이 군 당 4 내지 6마리 암컷 BALB/c 마우스를 PMED 전달 시스템에 의해 rHER2 항원 서열 (서열 54)을 코딩하는 DNA 플라스미드 발현 구축물로 면역화하였다. PMED 작동 후 후속적으로 면역 조절제, CpG7909 (PF-03512676) 및 항-CD40 모노클로날 효능제 항체를 백신 배액 서혜 림프절에 근접하게 피내 주사에 의해 국소 투여하였다. 항원 특이적 T 세포 반응은 아래에 설명된 절차에 따라 IFNγ ELISPOT 또는 세포내 시토카인 염색 검정에 의해 측정하였다.
세포내
시토카인
염색 (ICS) 검정
rHer-2 특이적 다기능성 (다중-시토카인 양성) T 세포 면역 반응은 ICS 검정에 의해 개별 동물로부터 단리된 비장세포 또는 PBMC로부터 측정하였다. 대개 1e6개 비장세포를 브레펠딘 (Brefeldin A) 1 ㎍/ml 및 펩티드 자극제 (rHer-2 특이적 CD8 p66, rHer-2 특이적 CD4 p169 또는 비관련 HBV p87) 10 ㎍/ml과 함께 5hr 동안 37℃에서 5% CO2 인큐베이터 내에서 인큐베이팅하였다. 자극 후에, 비장세포를 세척하고, Fcγ 차단제 (항-마우스 CD16/CD32)로 10 min 동안 4℃에서 차단한 후, 라이브/데드 아쿠아 스테인 (Live/dead aqua stain), 항-마우스 CD3ePE-Cy7, 항-마우스 CD8a 퍼시픽 블루 (Pacific blue), 및 항-마우스 CD45R/B220 PerCP-Cy5.5로 20 min 동안 염색하였다. 세포를 세척하고, 4% 파라포름알데히드로 4℃에서 철야 고정하고, 비디 픽스/펌 (BD fix/perm) 용액으로 30 min 동안 RT에서 투과시키고, 항-마우스 IFNγ APC, 항-마우스 TNFα Alexa488 및 항-마우스 IL-2 PE와 함께 30 min 동안 RT에서 인큐베이팅하였다. 세포를 세척하고, 유동 세포 분석에 의한 분석을 위해 20,000개의 CD4 또는 CD8 T 세포를 획득하였다. 각각의 동물의 전체 비장마다 항원 특이적 단일, 이중 또는 삼중 시토카인 양성 T 세포의 총 수는 비관련 펩티드 HBV에 대한 rHer-2 특이적 반응을 백신 특이적 반응으로부터 공제함으로써 계산하고 비장으로부터 단리된 비장세포의 총수로 정규화한다.
IFNγ
ELISPOT
검정 결과
도 5는 지시된 바와 같은 면역 조절제가 제공될 때 rHER2 백신에 의해 유도된 항원 특이적 T 세포 반응의 규모를 평가하는 대표적인 연구로부터 마우스의 군으로부터 IFNγ ELISPOT 결과를 보여준다. 간단히 설명하면, 치료군 당 각각의 마우스 (n=4)를, PMED에 의해 rHER2 항원 서열 (서열 54)을 코딩하는 DNA 플라스미드 발현 구축물, 그 직후에 지시된 바와 같이 100 ㎍의 대조군 래트 IgG 모노클로날 항체 (바이옥셀 #BE0089: 대조군 mAb) 또는 50 ㎍ CpG7909 또는 100 ㎍의 항-CD40 모노클로날 항체 (바이옥셀 #BE0016-2: a-CD40 mAb)로 면역화하였다. 항원 특이적 면역 반응은 PMED 작동 7일 후에 대조군 또는 rHer-2 특이적 p66 펩티드와 10 ㎍/ml 농도로 혼합된 5e5 비장세포로부터 IFNγ ELISPOT 검정에 의해 측정하였다. 1e5 CD8 T 세포를 함유하는 비장세포로부터 총 IFNγ 분비 세포의 수는 개별 동물로부터 ELISPOT 결과로부터 계산하고, 비장세포 내의 CD8 T 세포의 % 및 각각의 군의 평균 및 평균의 표준 오차를 그래프로 그렸다. 도시된 바와 같이, CpG7909 및 항-CD40 모노클로날 항체는 모두 대조군 항체를 투여한 마우스에 비해 rHer-2 DNA에 의해 유도된 항원 특이적 면역 반응의 규모를 유의하게 향상시켰다.
세포내 시토카인 염색 (ICS) 검정 결과. 도 6 및 7은 세포내 시토카인 염색 검정에 의한 백신 유도된 면역 반응의 품질에 대한 CpG 7909의 면역조절 활성을 평가하는 대표적인 연구의 결과를 보여준다. 간단히 설명하면, 각각의 동물을 4주 간격으로 PMED에 의해 전달된 rHER2 항원 서열 (서열 54)을 코딩하는 DNA 플라스미드 발현 구축물로 2회 면역화하였다. 각각의 군 내의 마우스 (n=5)에게 PMED에 의한 두 DNA 면역화 직후에 우측 백신 배액 서혜 림프절에 근접하게 PBS (PMED 군) 또는 50 ㎍의 CpG 7909 (PMED+CpG 군)의 피내 주사를 투여하였다. PMED에 의한 마지막 면역화의 7일 후에, IFNγ, TNFα 및/또는 IL-2를 분비하는 항원 특이적 다기능성 CD8 또는 CD4 T 세포를 검출하기 위해 각각의 개별 마우스로부터 단리한 비장세포에 대해 ICS 검정을 수행하였다. PBS에 비해 CpG 7909의 국소 전달로 치료한 마우스로부터, rHer-2 특이적 다중-시토카인 양성 CD8 및 CD4 T 세포 반응의 유의한 증가가 검출되었다. PBS에 비해 CpG7909의 국소 전달을 투여한 동물에서, 단일 시토카인 양성 CD8 집단의 증가가 관찰되었다.
도 8 및 9는 세포내 시토카인 염색 검정에 의한 백신 유도된 면역 반응의 품질에 대한 효능제 항-CD40 모노클로날 항체의 면역조절 활성을 평가하는 대표적인 연구의 결과를 보여준다. 간단히 설명하면, 각각의 동물을 4주 간격으로 PMED에 의해 전달된 rHER2 항원 서열 (서열 54)을 코딩하는 DNA 플라스미드 발현 구축물로 2회 면역화하였다. 각각의 군 내의 마우스 (n=6)에게 우측 백신 배액 서혜 림프절에 근접하게 이소형 IgG 대조군 (IgG를 갖는 PMED) 또는 항-CD40 모노클로날 항체 (aCD40을 갖는 PMED)의 100 ㎍의 피내 주사를, 제1 면역화의 1일 후에 PMED에 의해 투여하였다. 마지막 PMED의 7일 후에, IFNγ, TNFα 및/또는 IL-2를 분비하는 rHer-2 특이적 다기능성 CD8 또는 CD4 T 세포를 검출하기 위해 각각의 개별 마우스로부터 단리한 비장세포에 대해 ICS 검정을 수행하였다. 이소형 IgG 대조군에 비해 항-CD40 모노클로날 항체의 국소 전달로 치료한 마우스로부터 rHer-2 특이적 삼중-시토카인 양성 CD8 및 CD4 T 세포 반응의 유의한 증가가 검출되었다. 국소 제공한 항-CD40 모노클로날 항체에 의한 rHer-2 특이적 단일 및 이중 시토카인 양성 CD4 T 세포의 유의한 증가가 또한 관찰되었다.
실시예 6. 저용량 수니티닙과 조합한 암 백신의 항암 효능
저용량 수니티닙과 조합한 항암 백신의 항-종양 효능을 자발적 유방 지방층 (mammary pad) 종양을 갖는 BALB/neuT 마우스에서 조사하였다.
동물 치료. 간단히 설명하면, 13-14주령 암컷 마우스에게 수니티닙 말레이트 (수텐트)를 5 mg/kg로 112일 동안 1일 2회 경구 투여하였다. 항원을 전달하지 않는 대조군 백신, 및 서열 54의 래트 Her-2 항원을 전달하는 암 백신 (rHer-2)을 초회접종으로서 제3일에 아데노바이러스 주사에 의해 제공한 후, 각각 HBV 항원 (대조군 백신) 또는 rHer-2 (암 백신)을 전달하는 DNA의 PMED를 7회 격주 투여하였다. 생존 종점은 10개의 모든 유방 지방층이 종양 양성으로 될 때 또는 임의의 유방 종양의 부피가 2000 mm3에 도달할 때 결정되었다.
결과. 결과를 도 10에 제시한다. 이전에 공개된 수텐트의 약동학적 프로파일 (Mendel, D., Laird, D., et al.: "In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship". Clinical Cancer Research, 203, 9:327-337)에 비해, 5 mg/kg로 1일 2회 투여한 마우스에서 수텐트의 CMax는 마우스 및 인간에서 효율적인 항종양 효능을 달성하기 위해 필요한 최소 혈액 수준보다 유의하게 더 낮은 것으로 예상된다. 데이타는 저용량 수텐트 단제요법으로 치료한 마우스의 생존의 신속하고 일시적인 개선을 보여준다. 그러나, 암 백신과 함께 제공될 때, 생존의 보다 지속적이고 유의한 개선이 관찰되었다 (로그 순위 검정에 의해 P<0.0001).
실시예 7. CpG의 국소 투여에 의한 백신-유도된 면역 반응의 향상
본 발명에서 제공된 인간 PSMA 핵산에 의해 유도된 면역 반응에 대한 CpG (PF-03512676)의 국소 투여의 면역 향상을 원숭이 연구에서 조사하였고, 여기서 면역 반응은 IFNγ ELISPOT 검정을 이용하여 PSMA 특이적 T 세포 반응을 측정함으로써 평가하였다.
동물 치료 및 샘플 수집. 6개의 군의 필리핀 원숭이 (chineses cynomolgus macaque) (각각의 시험군 당 6마리 (#1 내지 6))를 전기천공에 의해 전달된 인간 PSMA 변형된 항원 (서열 9의 폴리펩티드)를 코딩하는 플라스미드 DNA로 면역화하였다. 간단히 설명하면, 제0일에 모든 동물에게 5 mg의 플라스미드 DNA의 양측 근육내 주사에 이어 전기천공 (DNA EP)을 적용하였다. 후속적으로, 전기천공 직후에, 군 2에게 DNA 주사 부위에 근접하게 1 mg 명반과 혼합한 2 mg의 CpG의 양측 근육내 주사를 투여하였다. 군 3 및 4에게 각각 제0일 또는 제3일에 DNA 주사 부위에 근접하게 명반 없이 전달된 2 mg의 CpG의 양측 근육내 주사를 투여하였다. 군 5에게 제3일에 백신 배액 서혜 림프절에 근접하게 전달된 2 mg의 CpG의 양측 피내 주사를 투여하였다. 군 6에게 제0일에 근육 내로 동시-전기천공된 DNA 용액과 혼합한 200 ㎍의 CpG의 양측 주사를 투여하였다.
IFNγ ELISPOT 검정 절차. DNA 면역화의 15일 후에 각각의 동물로부터 말초 혈액 샘플을 수집하였다. 말초 혈액 단핵 세포 (PBMC)를 혈액 샘플로부터 단리하고, IFNγ ELISPOT 검정으로 분석하여 PSMA 특이적 T 세포 반응을 측정하였다. 간단히 설명하면, 개별 동물로부터 4e5 PBMC를 IFNγ ELISPOT 플레이트 내에서 각각 2 ㎍/ml로 PSMA 특이적 펩티드 또는 비특이적 대조군 펩티드의 풀 (pool) (인간 HER2 펩티드 풀)과 함께 웰마다 플레이팅하였다. 각각의 PSMA 특이적 펩티드 풀의 조성을 표 24A에 제공한다. 플레이트를 16 hr 동안 37℃ 및 5% CO2에서 인큐베이팅하고, 세척하고, 제조자의 지시에 따라 인큐베이션 후에 발색시켰다. IFNγ 스팟 형성 세포 (SFC: spot forming cell)의 수를 CTL 판독기에 의해 계수하였다. 각각의 조건을 이중으로 수행하였다.
결과. 표 6은 근육내 (군 2, 3, 4, 및 5) 또는 피내 주사 (군 6)에 의해 국소 제공된, CpG를 갖지 않는 (군 1) 또는 CpG를 갖는 (PF-03512676) 백신에 의해 유도된 IFNγ T 세포 반응을 평가하고 비교하는 대표적인 IFNγ ELISPOT 검정의 결과를 보여준다. 보고된 PSMA 특이적 반응은 비특이적 대조군 펩티드 (인간 HER2 펩티드 풀)에 대한 SFC의 평균 수를 PSMA 펩티드 풀에 대한 SFC의 평균 수로부터 공제함으로써 계산하고, 1e6 PBMC를 사용하여 관찰된 SFC에 대해 정규화하였다. ∧는 스팟의 수가 계수하기에 너무 많기 때문에 계수가 정확하지 않음을 지시한다. ND는 결정되지 않음을 지시한다.
6마리의 모든 동물 (군 1)에서 CpG (PF-03512676)의 부재 하에 다수의 PSMA 특이적 펩티드 풀에 대해 PSMA 특이적 IFNγ T 세포 반응을 검출하였다. 측정된 PSMA 펩티드에 대한 전체 반응은 DNA 전기천공의 3일 후에 근육내 (군 4: 3/6) 또는 피내 (군 5: 2/6) 주사에 의해 CpG (PF-03512676)를 추가로 투여한 몇몇 동물에서 보통으로 더 높았다. 그러나, CpG를 동일한 날에 전기천공 직후에 후속적으로 전달할 때 (군 2 및 3), 명반을 혼합하든 혼합하지 않든 간에 몇몇 동물은 높은 반응을 생성하지 못하였다 (군 2: 4/6 및 군 3: 3/6). 그러나, 10배 더 낮은 용량의 CpG를 근육 (군 6) 내로 DNA 용액과 함께 동시-전기천공했을 때 4/6 동물에서 보다 높은 순수한 반응이 검출되었고, 여기서 CpG를 투여하지 않은 동물 (군 1)에 비해 펩티드 풀 H1 및 R1에 대해 통계상 보다 높은 반응 (P<0.05)을 가졌다. 데이타는 저용량의 CpG가 근육 내로 동시-전기천공될 때 DNA 백신에 의해 유도된 IFNγ T 세포 반응을 효과적으로 향상시킬 수 있음을 보여준다.
<표 6> CpG를 갖지 않는 (군 1) 또는 CpG를 갖는 (군 2, 3, 4, 5 및 6) DNA 백신에 의해 유도된 PSMA 특이적 IFNγ T 세포 반응을 DNA 전기천공의 15일 후에 PBMC로부터 IFNγ ELISPOT 검정에 의해 측정한다.
실시예 8.
항-CTLA-4 항체의 국소 투여에 의한 백신-유도된 면역 반응의 향상
붉은털원숭이 (rhesus) PSMA 핵산에 의해 유도된 면역 반응에 대한 항-CTLA-4 모노클로날 항체 (CP-675,206)의 저용량 피하 투여의 효과를 원숭이 연구에서 조사하였고, 여기서, 면역 반응은 IFNγ ELISPOT 검정을 이용하여 PSMA 특이적 T 세포 반응을 측정함으로써 평가하였다. 연구에 사용된 붉은털원숭이 PSMA 핵산은 서열 56에 제시된 서열을 갖고, 서열 55의 면역원성 PSMA 폴리펩티드를 코딩한다.
동물 치료 및 샘플 수집. 5개의 군의 수컷 히말라야 원숭이 (Indian rhesus macaque) (각각의 시험군 당 7마리 (#1 내지 7))를 양측 근육내 주사 (2x 5e10 V.P.)에 의해 전달된 붉은털원숭이 PSMA 변형된 폴리펩티드를 코딩하는 아데노바이러스로 면역화하였다. 아데노바이러스 주사 직후에, 군 1에게 비히클을 투여하고, 군 2 내지 4에게 백신 배액 림프절에 근접하게 각각 2x 25 mg, 2x 16.7 mg 및 2x 8.4 mg의 용량으로 항-CTLA-4 항체 (CP-675,206)의 양측 피하 주사를 투여하였다.
면역화의 9일 후에, 각각의 동물로부터 말초 혈액 단핵 세포 (PBMC)를 단리하고, IFNγ ELISPOT 검정으로 분석하여 붉은털원숭이 PSMA 특이적 T 세포 반응을 측정하였다. 간단히 설명하면, 개별 동물로부터 4e5 PBMC를 IFNγ ELISPOT 플레이트 내에서 각각 2 ㎍/ml의 붉은털원숭이 PSMA 특이적 펩티드의 풀 (표 24A에 규정된 P1, P2, P3 또는 R1+R2) 또는 비특이적 대조군 펩티드 (인간 HER2 펩티드 풀)과 함께 웰마다 플레이팅하였다. 플레이트를 16 hr 동안 37℃ 및 5% CO2에서 인큐베이팅하고, 세척하고, 제조자의 지시에 따라 인큐베이션 후에 발색시켰다. IFNγ 스팟 형성 세포 (SFC)의 수를 CTL 판독기에 의해 계수하였다. 각각의 조건을 이중으로 수행하였다. 붉은털원숭이 PSMA 특이적 펩티드 풀의 배경 조정된 SFC로부터 이중실험의 평균을 1e6 PBMC에서의 반응에 대해 정규화하였다. 각각의 개별 동물로부터 펩티드 풀에 대한 개별 및 합계 반응을 표 29에 제시한다.
IFNγ ELISPOT 검정 절차. IFNγ에 특이적인 포획 항체 (비디 바이오사이언스 (BD Bioscience), #51-2525kc)를 미세플레이트 내에서 폴리비닐리덴 플루오라이드 (PVDF) 막 상에 4℃에서 철야 코팅하였다. 플레이트를 혈청/단백질로 차단하여, 항체에 대한 비특이적 결합을 방지하였다. 차단 후에, 이펙터 세포 (예컨대, 면역화한 마우스로부터 단리된 비장세포, 또는 히말라야 원숭이로부터 단리된 PBMC) 및 표적 (예컨대, 펩티드 라이브러리 (library)로부터 PSMA 펩티드, 항원 특이적 펩티드로 펄싱한 표적 세포, 또는 관련 항원을 발현하는 종양 세포)을 웰에 첨가하고, 37℃에서 5% CO2 인큐베이터 내에서 철야 인큐베이팅하였다. 이펙터 세포에 의해 분비된 시토카인은 PVDF 막의 표면 상에서 코팅 항체에 의해 포획되었다. 세포 및 배양 배지를 제거한 후에, 검출을 위해 100 ㎕의 비오티닐화 폴리클로날 항-인간 IFNγ 항체를 각각의 웰에 첨가하였다. 스트렙타비딘-양고추냉이 페록시다제 및 침전 기질, 3-아미노-9-에틸카르바졸 (AEC)을 제조자 (맙테크 (Mabtech))의 프로토콜에 따라 첨가하여 적색 스팟을 생성함으로써 스팟을 시각화하였다. 각각의 스팟은 단일 시토카인 생산 T 세포를 나타낸다.
결과. 표 7은 백신 배액 림프절에 근접하게 피하 주사에 의해 국소 제공된, 항-CTLA-4 모노클로날 항체 (CP-675,206)을 갖지 않는 (군 1) 또는 갖는 (군 2-4) 백신에 의해 유도된 T 세포 반응을 비교하는 대표적인 IFNγ ELISPOT 검정의 결과를 보여준다. 백신은 50 mg 용량의 항-CTLA-4 항체 (CP-675,206)의 국소 투여 (군 2, 어림값을 이용하여 스튜던트 T-시험에 의한 P=0.001)에 의해 유의하게 향상된 면역 반응 (군 1)을 생성하였다. 반응은 각각 33.4 mg (군 3: 어림값을 이용하여 스튜던트 T-시험에 의한 P=0.004) 및 16.7 mg (군 4: 스튜던트 T-시험에 의한 P=0.05)의 저용량의 항-CTLA-4 항체에 의해 또한 유의하게 향상되었다. 데이타는 피하 주사에 의해 전달된 저용량의 항-CTLA-4가 백신 유도된 면역 반응을 유의하게 향상시킬 수 있음을 제안한다.
<표 7> 항-CTLA-4 항체 (CP-675,206)의 피하 주사를 갖지 않는 (군 1) 또는 갖는 백신에 의해 유도된 IFNγ T 세포 반응. ∧는 많은 스팟 수 때문에 계수가 어림됨을 지시한다. TNTC는 계수하기에 너무 많음을 의미한다.
실시예 9. 저용량 수니티닙에 의한 골수 유래 면역억제 세포의 면역조절
다음 실시예는 비-종양 마우스 모델에서 생체 내에서 골수 유래 면역억제 세포 (MDSC)에 대한 저용량 수니티닙의 면역조절 효과를 설명하기 위해 제공된다.
연구 절차.
MDSC 농축 비장세포를 생성하기 위해, TUBO 세포 (1x106)를 5마리 BALB/neuT 마우스의 옆구리 내에 이식하고, 종양 부피가 1000-1500 mm3에 도달할 때까지 약 20-30일 동안 방치하였다. 이어서, 마우스를 희생시키고, 비장을 제거하고, MDSC 농축 비장세포를 회수하였다. 비장세포를 10분 동안 5 μΜ CFSE로 표지하고, PBS로 세척하고, 계수하였다. 표지된 세포를 후속적으로 PBS 용액 내에 5x107개 비장세포/ml로 재현탁하고, i.v. 꼬리 정맥 주사를 통해 나이브 (naive) BALB/c 수여체 마우스 내로 입양 전달하였다. 입양 전달 (adoptive transfer)의 3일 전에, 수여체 마우스에게 5 mg/kg, 10 mg/kg 및 20 mg/kg의 비히클 또는 수니티닙 말레이트 (수텐트)의 1일 2회 투여를 시작하였다. 입양 전달 이후, 수여체 마우스에게 추가의 2일 동안 비히클 또는 수니티닙의 1일 2회 투여를 계속하고, 그 후에 마우스를 희생시키고, 비장을 제거하고, 비장세포를 회수하고, 표현형 분석을 위해 처리하였다.
비장세포를 계수하고, FACS 염색 완충제 (PBS, 0.2% (w/v) 소 혈청 알부민, 및 0.02% (w/v) 소듐 아지드) 내에 5x106개 세포/ml로 재현탁하였다. 비장세포의 유동 세포측정 염색을 위해, 2.5x106개 세포를 먼저, Fc 수용체를 차단하고 비-특이적 결합을 최소화하기 위해 CD16/CD32에 대한 항체와 함께 10분 동안 4℃에서 인큐베이팅하였다. 이어서, 비장세포를 20분 동안 4℃에서 뮤린 세포 표면 마커에 대한 적절한 형광단 접합된 항체 (바이오레전드 (Biolegend))로 염색하였다. T 세포 (항-CD3 (퍼시픽 블루), 클론 17A2) 및 MDSC (항-GR-1 (APC), 클론 RB6-8C5 및 항-CD11b (PerCp Cy5.5), 클론 M1/70). 라이브/데드 스테인이 또한 포함되었다. 항체 인큐베이션 후에, 염색된 비장세포를 2 ml의 FACS 완충제로 세척하고, 원심분리에 의해 펠렛화하고, 0.2 ml의 FACS 완충제 내에 재현탁한 후에, 비디 CANTO II 유동 세포측정기 상에서 데이타 획득을 수행하였다. 입양 전달된 MDSC 생존에 대한 수니티닙 또는 비히클의 효과를 모니터링하기 위해, 본 발명자들은 라이브 단일항 게이트 (live, singlet gate)에서 CFSE+,CD3-,GR1+,CD11b+의 백분율을 계산하였다. 이어서, 본 발명자들은 어떠한 실제 세포수가 총 비장세포 계수의 백분율을 나타내는지 계산함으로써 비장 당 입양 전달된 MDSC의 수를 결정하였다. 데이타를 플로조 (FloJo) 및 그래프패드 (Graph pad) 소프트웨어에 의해 분석하였다.
결과. 표 27에 제시된 데이타는 비히클 또는 5 mg/kg, 10 mg/kg 및 20 mg/kg 수니티닙을 1일 2회 투여한 마우스로부터, 입양 전달 2일 후에 비장 (n=7/군) 당 회수된 입양 전달된 CSFE+,CD3-,GR1+,CD11b+ 세포의 평균 수를 나타낸다. 통계적 유의성은 수니티닙 투여군을 0 mg/kg (비히클) 군에 대해 비교하는, 던넷 (Dunnett)의 다중 비교 검정을 이용하여 일원 (one-way) ANOVA에 의해 결정하였다. 데이타는 생체 내에서 1일 2회 투여한 수니티닙이 5 mg/kg만큼 적게 투여할 때에조차 비히클 처리 대조군에 비해 회수된 수의 통계상 유의한 감소를 일으켜, MDSC에 대해 면역조절 효과를 가짐을 입증한다.
<표 8> 비장으로부터 회수된 CFSE+,CD3-,GR1+,CD11b+ MDSC의 평균 수
실시예 10. 삼중 항원 아데노바이러스 및 DNA 구축물의 면역원성
다음 실시예는 비-인간 영장류에서 3가지 모든 코딩된 항원에 대한 특이적 T 세포 반응을 일으키는, 본 발명에서 제공된 3가지 항원 PSMA, PSCA 및 PSA를 발현하는 삼중 항원 백신 구축물 (아데노바이러스 벡터 또는 DNA 플라스미드의 형태)의 능력을 설명하도록 제공된다.
생체내 연구 절차. 각각 본 발명에서 제공된 3가지 항원을 발현하는 5가지 아데노바이러스 벡터 (PSMA, PSCA 및 PSA; Ad-733, Ad-734, Ad-735, Ad-796 및 Ad-809)의 T 세포 면역원성을, 초회접종 9일 후에 각각 단지 단일 항원 (PSMA, PSA 또는 PSCA)을 발현하는 3가지 아데노바이러스 벡터의 혼합물과 비교하였다. 특이성을 입증하기 위해, 단일 항원을 발현하는 단일 아데노바이러스에 대한 반응 (군 1-3)을 평가하였다. 간단히 설명하면, 히말라야 원숭이 (군 1 및 3에 대해 n=6, 군 2에 대해 n=7, 군 4-9에 대해 n=8)에게 총 1e11 V.P.를 근육내 주사한 후, 동일한 날에 항-CTLA-4를 10 mg/kg로 피내 주사하였다. 주사 9일 후에, 각각의 동물로부터 말초 혈액 단핵 세포 (PBMC)를 단리하고, IFNγ ELISPOT 검정으로 분석하여 PSMA, PSA 및 PSCA 특이적 T 세포 반응을 측정하였다.
T 세포 반응이 축소되는 아데노바이러스 및 항-CTLA-4 주사의 13주 후에, 원숭이에게 DNA (군 1: PSMA, 플라스미드 5166; 군 2: PSA, 플라스미드 5297; 군 3: PSCA, 플라스미드 5259; 군 4: PSMA, PSA 및 PSCA의 혼합물, 플라스미드 5166, 5259 및 5297; 군 4: 플라스미드 457; 군 6: 플라스미드 458; 군 7: 플라스미드 459; 군 8: 플라스미드 796, 및 군 9: 플라스미드 809) 추가 백신접종을 전기천공에 의해 전달하였다. 요약하면, 각각의 동물에게 초회접종에 사용된 아데노바이러스 내에 코딩된 동일한 발현 카세트를 전달하는 본 발명에서 제공된 플라스미드 DNA 총 5 mg을 투여하였다. 추가 백신접종의 9일 후에, 말초 혈액 단핵 세포 (PBMC)를 각각의 동물로부터 단리하고, IFNγ ELISPOT 검정으로 분석하였다.
IFNγ ELISPOT 검정. 간단히 설명하면, 개별 동물로부터 4e5 PBMC를 IFNγ ELISPOT 플레이트 내에서 각각 2 ㎍/ml로 PSMA 특이적 펩티드 풀 P1, P2, P3 또는 H1 및 H2 (표 9A), PSA 특이적 풀 1 또는 2 (표 9B), PSCA 특이적 풀 (표 10) 또는 비특이적 대조군 펩티드 (인간 HER2 펩티드 풀)와 함께 웰 마다 플레이팅하였다. 플레이트를 16 hr 동안 37℃ 및 5% CO2에서 인큐베이팅하고, 세척하고, 제조자의 지시에 따라 인큐베이션 후에 발색시켰다. IFNγ 스팟 형성 세포 (SFC)의 수를 CTL 판독기에 의해 계수하였다. 각각의 조건을 이중으로 수행하였다. 항원 특이적 펩티드 풀의 배경 조정된 SFC로부터 이중실험의 평균을 1e6 PBMC에서 반응에 대해 정규화하였다. 표에서 항원 특이적 반응은 대응하는 항원 특이적 펩티드 또는 펩티드 풀에 대한 반응의 합계를 제시한다.
결과: 표 11은 IFNγ ELISPOT에 의한 히말라야 원숭이에서 각각 단일 항원을 발현하는 3가지 아데노바이러스의 혼합물에 비해, 각각 3가지 모든 항원을 발현하는 5가지 상이한 아데노바이러스의 T 세포 면역원성을 평가하는 연구를 나타낸다. 단지 Ad-PSMA 주사를 투여받은 대다수의 동물 (군 1)은 PSMA에 대한 특이적 반응을 유도하였지만, PSA 또는 PSCA에 대해서는 그렇지 않았다 (스튜던트 T-시험, P<0.03. PSCA에 대한 반응을 우선적으로 유도한 1마리 동물 (#4)은 통계 분석으로부터 제거하였다). 단지 Ad-PSA의 주사를 투여받은 동물 (군 2)은 PSA에 대한 특이적 반응을 유도하였지만, PSMA 또는 PSCA에 대해서는 그렇지 않았다 (스튜던트 T-시험, P<0.02). 단지 Ad-PSCA의 주사를 투여받은 동물 (군 3)은 PSCA에 대한 특이적 반응을 유도하였지만, PSMA 또는 PSA에 대해서는 그렇지 않았다 (스튜던트 T-시험, P<0.03). 5가지 모든 삼중-항원 발현 아데노바이러스 벡터 (군 5-9)는 3가지 모든 항원에 대해 IFNγ T 세포 반응을 유도하였고, 그 규모는 동물마다 다양하였다. 삼중 항원 발현 아데노바이러스에 의해 유도된 PSCA에 대한 반응의 규모는 개별 벡터의 혼합물 (군 4)과 유사하였다. 그러나, Ad-809 (군 9)에 의해 유도된 PSMA에 대한 반응 및 Ad-796 (군 8)에 의해 유도된 PSA에 대한 반응의 규모는 혼합물에 비해 각각 유의하게 우월하였다 (스튜던트 T-시험, P=0.04 및 P=0.02). 이들 결과는 삼중 항원을 발현하는 아데노바이러스를 사용하여 백신접종이 비-인간 영장류에서 개별 아데노바이러스의 혼합물을 사용한 백신접종에 비해 동등하거나 우월한 T 세포 면역 반응을 일으킬 수 있음을 나타낸다.
표 12는 IFNγ ELISPOT 결과가 항-CTLA-4와 조합으로 아데노바이러스 초회접종에 이어 대응하는 플라스미드 DNA의 전기천공 추가접종에 의해 전달된 본 발명에서 제공된 5가지 상이한 삼중 항원 발현 카세트의 면역원성을 평가하는 연구를 나타냄을 보여준다. 면역 반응을 항-CTLA-4의 아데노바이러스 초회접종 및 DNA 전기천공 추가접종 면역화에 의해 유사하게 전달된 단일 항원을 발현하는 3가지 구축물의 혼합물에 비교하였다.
단지 항-CTLA-4와 함께 Ad-PSMA에 이어 플라스미드-PSMA (군 1) 면역화를 투여받은 모든 동물은 PSMA에 대한 특이적 반응을 유도하였지만 PSA 또는 PSCA에 대해서는 그렇지 않았다. 유사하게, 단지 항-CTLA-4와 함께 Ad-PSA에 이어 플라스미드-PSA 면역화 (군 2)를 투여받은 모든 동물은 PSA에 대한 특이적 반응을 유도하였지만 PSMA 또는 PSCA에 대해서는 그렇지 않았고, 마지막으로, 단지 항-CTLA-4와 함께 Ad-PSCA에 이어 플라스미드-PSCA (군 3) 면역화를 투여받은 모든 동물은 PSCA에 대한 특이적 반응을 유도하였지만 PSMA 또는 PSA에 대해서는 그렇지 않았다 (스튜던트 T-시험, P<0.01).
삼중-항원 발현 벡터 (군 5-9) 또는 혼합물 (군 4)로 면역화한 모든 동물은 3가지 모든 항원에 대해 IFNγ T 세포 반응을 유도하였다. 검출된 PSCA 또는 PSA 특이적 IFNγ T 세포의 빈도는 각각 이들 모든 군 (군 4-9)에서 유사하였다. 그러나, 삼중 항원 발현 벡터 백신접종을 투여받은 구성체 군 7 및 9는 3가지 단일 항원 발현 구축물의 혼합물 (군 4)보다 PSMA에 대한 유의하게 더 높은 빈도의 반응을 생성하였다. 이들 결과는 하나의 카세트 내에 아데노바이러스 및 삼중 항원을 발현하는 DNA 백신이 비-인간 영장류에서 아데노바이러스 및 단일 항원을 발현하는 DNA의 혼합물에 비해 동등하거나 우월한 IFNγ T 세포 반응을 일으킬 수 있음을 나타낸다.
<표 9A> PSMA 펩티드 풀*
<표 9B> PSA 펩티드 풀: PSA 펩티드 라이브러리로부터 13개의 아미노산이 겹치는 15개의 아미노산 펩티드의 아미노산 위치 및 서열을 제시한다.
<표 10> PSCA 펩티드 풀: PSCA 펩티드 라이브러리로부터 13개의 아미노산이 겹치는 15개의 아미노산 펩티드의 아미노산 위치 및 서열을 제시한다.
<표 11> ELISPOT 검정에 의해 분석된 항-CTLA-4와 함께 아데노바이러스 초회접종 후 단일 항원 (군 1: Ad-PSMA; 군 2: Ad-PSA; 군 3: Ad-PSCA; 군 4: Ad-PSMA, Ad-PSA 및 Ad-PSCA의 혼합물) 또는 삼중 항원 발현 아데노바이러스 벡터 (군 4: Ad-733; 군 6: Ad-734; 군 7: Ad-735; 군 8: Ad-796, 및 군 9: Ad-809)에 의해 유도된 IFNγ T 세포 반응.
<표 12> ELISPOT 검정에 의해 분석된 항-CTLA-4와 함께 아데노바이러스 초회접종 및 DNA 전기천공 추가접종 면역화 후에, 단일 항원 (군 1: PSMA; 군 2: PSA; 군 3: PSCA; 군 4: PSMA, PSA 및 PSCA의 혼합물) 또는 삼중 항원 발현 벡터 (군 5-9)에 의해 유도된 IFNγ T 세포 반응.
실시예 11. C68 벡터의 구축
11A. 벡터 AdC68-734 구축
AdC68-734는 3가지 면역원성 PAA 폴리펩티드, 즉 면역원성 PSA 폴리펩티드, 면역원성 PSCA 폴리펩티드 및 면역원성 PSMA 폴리펩티드를 코딩하는 침팬지 아데노바이러스 C68에 기반한 복제 불능 아데노바이러스 벡터이다. 벡터 서열을 인 실리코 설계하였다. 먼저, 기준선 전장 C68 서열을 젠뱅크로부터 입수하였다 (정의: 원숭이 아데노바이러스 25, 완전 게놈; 기탁 번호 AC_000011.1). 문헌에 설명된 5개의 점 돌연변이를 서열 내로 도입하였다 (Roshorm, Y., M. G. Cottingham, et al. (2012). "T cells induced by recombinant chimpanzee adenovirus alone and in prime-boost regimens decrease chimeric EcoHIV/NDK challenge virus load." Eur J Immunol 42(12): 3243-3255). 다음, 2.6 kb의 바이러스 초기 전사 영역 1 (E1)을 결실시켜, 벡터를 복제 불능으로 만들고, 3.5 kb의 초기 전사 영역 3 (E3)을 제거하여 트랜스젠 발현 카세트를 위한 벡터 내에 공간을 생성하였다 (Tatsis, N., L. Tesema, et al. (2006). Chimpanze-origin adenovirus vectors as vaccine carriers. Gene Ther. 13: 421-429). 이어서, 고도로 효율적인 진핵 발현 카세트를 E1 영역 내로 도입하였다. 발현 카세트는 다음 성분들을 포함하였다: (A) 사이토메갈로 (CMV) 최조기 인핸서/프로모터, (B) Tet 작동유전자 (테트라사이클린 억제유전자에 대한 결합 부위), (C) 다음을 포함하는 다중-항원 구축물: (1) 인간 PSA의 아미노산 25 내지 261을 코딩하는 뉴클레오티드 서열, (2) 글라이신-세린 링커를 코딩하는 시스-작용 히드롤라제 요소 및 토세아 아시그나 바이러스 2A 펩티드 (T2A), (3) 인간 PSCA의 아미노산 2 내지 123을 코딩하는 뉴클레오티드 서열, (4) 글라이신-세린 링커를 코딩하는 시스-작용 히드롤라제 요소 및 구제역 바이러스 2A 펩티드 (F2A), 및 (5) 인간 PSMA의 아미노산 15 내지 750을 코딩하는 뉴클레오티드 서열; 및 (D) SV40 폴리A 전사 종결 신호. 마지막으로, PacI 제한 부위를 바이러스 게놈의 각각의 단부에 삽입하여, 모 Bacmid로부터 게놈을 방출을 용이하게 하였다. 바이러스 증식 동안 PacI 제한 부위로부터 뉴클레오티드는 제거되고, 따라서, 벡터 생성물 자체의 게놈 내에 포함되지 않는다. 전체 벡터 AdC68-734의 뉴클레오티드 서열 (PacI 제한 부위 포함)을 서열 58에 제시한다. 벡터 AdC68-734 내에 (및 플라스미드 458 내에) 포함된 다중-항원 구축물 (PSA-T2A-PSCA-F2A-PSMA)을 또한 서열 61에 제시한다. 서열 61의 다중-항원 구축물에 의해 코딩된 아미노산 서열을 서열 60에 제시한다. 벡터 AdC68-734의 성분들을 표 13에 제공한다.
<표 13> 벡터 AdC68-734의 성분들
인 실리코 설계 이후, 34,819개 염기쌍 서열을 시험관내 올리고 합성 및 이. 콜라이(E. coli) 및 효모 내에서 후속적인 재조합-매개 중간체 조립을 이용하는 다-단계 공정으로 생화학적으로 합성하였다. 바이러스 게놈을 증식을 위해 최종적으로 박테리아 인공 염색체 (pCC1BAC-LCyeast-TRP Trunc) 내로 삽입하였다. 바이러스 씨드 (seed) 원액을 생성하기 위해 사용된 최종 Bacmid 17.3.3.22 로트를 포함하여, 차세대 서열결정 (MiSeq 기술)을 생산 공정에서 다수 단계로 수행하였다. 바이러스 씨드 원액은 Bacmid 17.3.3.22를 PacI로 소화시켜 BAC 백본으로부터 AdC68-734 게놈을 방출시켜 생성하였다. 선형화된 핵산을 E1 보완 부착성 HEK293 세포주 내로 형질감염시키고, 가시적인 세포변성 효과 및 아데노바이러스 병소 형성시에, 세포로부터 바이러스를 방출시키기 위해 배양액을 다수 라운드의 동결/해동에 의해 수거하였다. 바이러스를 표준 기술에 의해 증폭하고 정제하였다. Bacmid 17.3.3.22의 유전적 구성을 도 11에 제공한다.
11B. 추가의 C68 벡터의 구축
추가의 삼중 항원 C68 벡터를 AdC68-734와 유사한 방식으로 구축하였다. 일부의 추가의 벡터는 벡터 AdC68-734의 것과 경미하게 상이한 C68 게놈 내의 기능적 결실을 포함하는 반면, 다른 벡터는 상이한 다중-항원 구축물을 포함한다. 이들 예 및 본 개시내용의 다른 설명을 기초로 하여, 통상의 기술자는 다양한 다중-항원 구축물을 발현하기 위해 추가의 벡터를 C68로부터 구축할 수 있을 것이고, 이들은 모두 본 발명의 범위 내에 포함된다.
(1) AdC68X-734 및 AdC68W-734
벡터 AdC68X-734는 서열 57의 C68 게놈의 뉴클레오티드 577-3403 (E1 영역) 및 27125-31831 (E2 영역)의 결실을 통한 C68 게놈의 E1 및 E3 영역의 기능적 결실에 의해 및 결실된 E1 영역 내의 서열 61의 삼중 항원 구축물 (PSA-T2A-PSCA-F2A-PSMA)의 삽입에 의해 C68로부터 구축하였다. AdC68W-734가 C68 NDA 서열 내에 하나 이상의 돌연변이를 함유하는 것을 제외하고는, 벡터 AdC68W-734는 벡터 벡터 AdC68-734와 동일하다.
(2) AdC68X-733 및 AdC68X-735
AdC68X-734 벡터에 포함된 삼중 항원-구축물을 각각 서열 65 및 66의 삼중 항원 구축물로 교체함으로써 벡터 AdC68X-733 및 AdC68X-735를 생성하였다. 벡터 AdC68X-733에 포함된 다중-항원 구축물 (즉, PSA-F2A-PSMA-T2A-PSCA)은 플라스미드 457에 포함된 것과 동일하고, 벡터 AdC68X-735에 포함된 다중-항원 구축물 (즉, PSCA-F2A-PSMA-mIRES-PSA)은 플라스미드 459 내의 것과 동일하다.
11C. 연구 생산성 특성
AdC68-734의 다양한 연구 등급 로트를 생산하고, 생산성에 대해 시험하였다. Bacmid를 PacI로 소화시켜 BAC 백본으로부터 벡터 게놈을 방출시키고, 선형화된 핵산을 E1 보완 부착성 HEK293 세포주 내로 형질감염시켰다. 광범한 세포변성 효과 및 아데노바이러스 병소가 가시화될 때, 세포로부터 바이러스를 방출시키기 위해 배양액을 다수 라운드의 동결/해동에 의해 수거하였다. 이들 계대배양 0 (P0) 배양액으로부터의 바이러스를 조직 배양 플라스크에서 적어도 하나의 추가의 계대배양으로 증폭한 후, 연구 규모 생산의 실행을 위한 씨드 원액 (로트당 ~0.5 내지 3e13 총 바이러스 입자)으로 사용하였다. 총 11회의 생산 실행을 실시하였다 (HEK293 현탁액 세포에서 5회 및 HEK293 부착성 세포에서 6회). 평균 비생산성은 초기 감염된 세포당 정제된 15,000 +/- 6,000개 바이러스 입자이었고, 바이러스 입자:감염 단위 비는 55이었다. 연구 규모 생산성을 표 14에 요약한다.
<표 14> 연구 규모 생산 로트의 비생산성 및 감염성
*생산에 사용된 후기 계대배양 HEK293 현탁액 세포
11D. 항원 발현
PSMA 및 PSCA의 표면 발현을 유동 세포 분석 (도 12)에 의해 측정하고, PSMA, PSCA 및 PSA의 총 세포 발현을 MOI=10,000에서 AdC68-벡터 감염된 A549 세포로부터 웨스턴 블롯 분석 (도 13)에 의해 측정하였다. 모의 (mock) 및 AdC68 감염된 세포를 감염의 2일 후에 유동 세포측정 분석을 위해 항-PSCA (플루오레세인 이소티오시아네이트-접합된 모노클로날 항체 1G8 [1:200]) 및 PSMA 항체 (알로피코시아닌-접합된 모노클로날 항체 J591 [1:200])로 염색하였다. PSCA 및 PSMA의 표면 발현은 상이한 삼중 항원-발현 AdC68 벡터로 다양한 수준으로 감염된 대다수의 세포로부터 검출되었다. PSCA 및 PSMA의 비교적 보다 높은 수준의 발현이 AdC68X-809 감염된 세포로부터 검출되었고, 보다 낮은 수준은 AdC68X-733 감염된 세포로부터 검출되었다. 감염 2일 후에, 약 1x105개의 감염된 세포로부터 총 세포 용해물을 소듐 도데실 술페이트 폴리아크릴아미드 겔의 각각의 레인 (lane) 상에 로딩하였다. 웨스턴 블롯 분석에 의해 PSA, PSMA, 및 PSCA에 특이적인 1차 항체를 사용하여 PSA, PSMA, 및 PSCA 단백질을 검출하기 위해 겔을 후속적으로 막에 옮겼다. 3개의 모든 항원의 발현이 감염된 세포 내에서 다양한 정도로 검출되었다. 비교적 유사한 수준의 PSMA 및 PSCA가 AdC68-734 및 AdC68X-735 감염된 용해물로부터 검출된 반면, AdC68X-735 용해물에 비해 보다 높은 수준의 PSA가 AdC68-734 용해물로부터 검출되었다.
11E. 면역원성
다양한 삼중 항원 AdC68 벡터에 의해 유도된 CD8 IFNγ 반응의 직접적인 (head-to head) 비교를 수행하였다. 각각의 군의 마우스 (군당 n=5)를 사두근에서 1e9 또는 1e10 VP로 AdC68-734, AdC68X-735, AdC68X-809, 또는 Ad5-734로 면역화하였다. 면역화 후 제13일에 각각의 동물로부터의 비장을 수집함으로써 마우스에서 IFNγ CD8+ T 세포 반응을 측정하였다. 비장세포를 단리하고, IFNγ ELISPOT 검정으로 분석하여 PSMA, PSCA, 및 PSA-특이적 T 세포 반응을 측정하였다. 간단히 설명하면, 면역화한 동물로부터의 2.5 내지 5x105개의 비장세포를 10 ㎍/ml에서 개별 인간 PSMA, PSCA, 또는 PSA-특이적 펩티드의 존재 하에 배양하였다. 15-mer 펩티드는 각각의 전립선 항원에 대한 CD8+ T 세포 에피토프를 함유하는 것으로 이전에 규정되었다. 배지 단독으로 배양된 비장세포를 대조군으로서 사용하였다. 각각의 조건을 삼중으로 수행하였다. 플레이트를 20h 동안 37℃ 및 5% CO2에서 인큐베이팅하고, 세척하고, 제조자의 지시에 따라 인큐베이션 후에 발색시켰다. IFNγ SFC의 수를 CTL 판독기에 의해 계수하였다. 결과는 배지 단독 배경 값을 뺀, 1x106개의 비장세포에 대해 정규화된 PSMA, PSCA, 및 PSA-특이적 SFC의 평균 수를 보여준다.
요약하면, 모든 삼중 항원 발현 AdC68 벡터는 규모는 상이하지만, 3가지 모든 항원에 대해 면역 반응을 유도하였다. 1e9 VP에서, AdC68 벡터에 의한 PSMA에 대한 반응은 Ad5와 유사하였다. 3가지 AdC68 벡터에 의한 PSCA에 대한 반응은 Ad5에 의해 유도된 반응에 비해 유사하거나 더 낮은 반면, PSA에 대한 반응은 시험한 모든 벡터에 비해 Ad68-735를 사용할 때 더 낮았다. 그러나, 1e10 VP에서, AdC68-809는 AdC68-734, AdC68-735 또는 Ad5에 비해 3가지 모든 항원에 대해 유사하거나 더 우수한 반응을 유도하였다. 결과를 표 15에 제공한다.
<표 15> IFNγ ELISPOT 검정에 의해 C57BL6 마우스에서 PSMA, PSA, 및 PSCA를 동시 발현하는 AdC68 벡터에 의한 IFNγ T 세포 면역원성
선택된 가공되지 않은 서열
서열 1. 전장 인간
PSMA의
아미노산 서열
서열 2. 서열 1의 전장 인간
PSMA를
코딩하는 뉴클레오티드 서열
서열
3. PSMA
셔플링된
항원 1의 아미노산 서열
서열 4. 서열 3의
PSMA
셔플링된
항원 1의 아미노산 서열을 코딩하는 뉴클레오티드 서열
서열
5. PSMA
셔플링된
항원 2의 아미노산 서열
서열 6. 서열 5의
PSMA
셔플링된
항원 2의 아미노산 서열을 코딩하는 뉴클레오티드 서열
서열 7.
PSMA
셔플링된
항원 3의 아미노산 서열
서열 8. 서열 7의
PSMA
셔플링된
항원 3의 아미노산 서열을 코딩하는 뉴클레오티드 서열
서열
9. 막
-결합형
PSMA
항원의 아미노산 서열
서열
10. 서열
9의 막-결합형
PSMA
항원의 아미노산 서열을 코딩하는 뉴클레오티드 서열
서열
11. 세포액형
PSMA
항원의 아미노산 서열
서열
12. 서열
11의 세포액형
PSMA
항원의 아미노산 서열을 코딩하는 뉴클레오티드 서열
서열
13. 분비형
PSMA
항원의 아미노산 서열
서열
14. 서열
13의 분비형
PSMA
항원의 아미노산 서열을 코딩하는 뉴클레오티드 서열
서열
15. 전장
인간 PSA의
아미노산 서열
서열
16. 서열
15의 전장 인간 PSA의 아미노산 서열을 코딩하는 뉴클레오티드 서열
서열 17. 세포액형 PSA 항원의 아미노산 서열
서열 18. 서열 17의 세포액형 PSA 항원의 아미노산 서열을 코딩하는 뉴클레오티드 서열
서열
19. 막
-결합형 PSA 항원의 아미노산 서열
서열
20. 서열
19의 막-결합형 PSA 항원의 아미노산 서열을 코딩하는 뉴클레오티드 서열
서열
21. 전장
인간
PSCA의
아미노산 서열
서열 22. 서열 21의 전장 인간
PSCA의
아미노산 서열을 코딩하는 뉴클레오티드 서열
서열 24. 플라스미드 5259의 뉴클레오티드 서열
서열 25. 플라스미드 5297의 뉴클레오티드 서열
서열 26. 플라스미드 460의 뉴클레오티드 서열
서열 27. 플라스미드 451의 뉴클레오티드 서열
서열 28. 플라스미드 454의 뉴클레오티드 서열
서열 29. 플라스미드 5300의 뉴클레오티드 서열
서열 30. 플라스미드 449의 뉴클레오티드 서열
서열 31. 플라스미드 603의 뉴클레오티드 서열
서열 32. 플라스미드 455의 뉴클레오티드 서열
서열 33. 플라스미드 456의 뉴클레오티드 서열
서열 34. 플라스미드 457의 뉴클레오티드 서열
서열 35. 플라스미드 458의 뉴클레오티드 서열
서열 36. 플라스미드 459의 뉴클레오티드 서열
서열 37. P셔틀 IRES의 뉴클레오티드 서열
서열 38. Her-2 항원의 아미노산 서열
서열 39. 서열 38의 Her-2 항원 아미노산 서열을 코딩하는 핵산 서열
서열 40. 항-CD40 항체 CP870,893의
중쇄의
아미노산 서열:
서열 41. 항-CD40 항체 CP870,893의
경쇄의
아미노산 서열:
서열 42. 항-
CTLA
-4 항체
트레멜리무맙의
중쇄의
아미노산 서열:
서열 43. 항-
CTLA
-4 항체
트레멜리무맙의
경쇄의
아미노산 서열:
서열 44.
CpG
7909의 뉴클레오티드 서열
서열 45.
CpG
24555의 뉴클레오티드 서열
서열 46.
CpG
10103의 뉴클레오티드 서열
서열
47. eGFP의
아미노산 서열
서열
48. HBV
코어 항원의 아미노산 서열
서열
49. HBV
표면 항원의 아미노산 서열
서열
50. 붉은털원숭이
PSMA
ECD
단백질의 아미노산 서열
서열
51. 래트
Her-2 p66 펩티드 (H-2d T 세포
에피토프
)의 아미노산 서열
서열
52. 래트
Her-2 p169 펩티드 (H-2d T 세포
에피토프
)의 아미노산 서열
서열
53. HBV
코어 항원 p87 펩티드의 아미노산 서열
서열
54. 래트
Her-2 항원 (
rHer
-
2)의
아미노산 서열
서열
55. 붉은털원숭이
PSMA
항원의 아미노산 서열
서열
56. 서열
55의 붉은털원숭이
PSMA
항원을 코딩하는 뉴클레오티드 서열
서열
57. 원숭이
아데노바이러스
25 (C68)의 완전 게놈
서열 58.
AdC68
-734 벡터의 완전 서열
서열 59: 바람직한
EMCV
IRES (
pIRES
)의 뉴클레오티드 서열
(최소 EMCV IRES (mIRES)에는 밑줄친 15개의 뉴클레오티드가 결여됨)
서열
60. 면역원성
PSA,
PSCA
, 및
PSMA
폴리펩티드 (플라스미드 916 및 벡터
AdC68
-734 및
AdC68W
-734에 의해 코딩됨)를 포함하는 아미노산 서열
서열 61. 서열 60의 아미노산 서열을 코딩하는 뉴클레오티드 서열
서열 62. 플라스미드 916의 뉴클레오티드 서열
서열
63. AdC68W
-734 벡터의 완전한 서열
서열 64. 면역원성 PSA,
PSMA
, 및
PSCA
폴리펩티드 (플라스미드 457 및 벡터 AdC68X-733에 의해 코딩됨)를 포함하는 아미노산 서열
서열 65. 서열 64의 아미노산 서열을 코딩하는 뉴클레오티드 서열
서열 66. 플라스미드 459 및 벡터
AdC68X
-735 내에 통합된 다중-항원 구축물 (PSCA-F2A-PSMA-mIRES-PSA)의 뉴클레오티드 서열
SEQUENCE LISTING
<110> PFIZER INC.
<120> VECTORS FOR EXPRESSION OF PROSTATE-ASSOCIATED ANTIGENS
<130> PC72055A
<150> US 61/898,966
<151> 2013-11-01
<160> 66
<170> PatentIn version 3.5
<210> 1
<211> 750
<212> PRT
<213> Homo sapiens
<400> 1
Met Trp Asn Leu Leu His Glu Thr Asp Ser Ala Val Ala Thr Ala Arg
1 5 10 15
Arg Pro Arg Trp Leu Cys Ala Gly Ala Leu Val Leu Ala Gly Gly Phe
20 25 30
Phe Leu Leu Gly Phe Leu Phe Gly Trp Phe Ile Lys Ser Ser Asn Glu
35 40 45
Ala Thr Asn Ile Thr Pro Lys His Asn Met Lys Ala Phe Leu Asp Glu
50 55 60
Leu Lys Ala Glu Asn Ile Lys Lys Phe Leu Tyr Asn Phe Thr Gln Ile
65 70 75 80
Pro His Leu Ala Gly Thr Glu Gln Asn Phe Gln Leu Ala Lys Gln Ile
85 90 95
Gln Ser Gln Trp Lys Glu Phe Gly Leu Asp Ser Val Glu Leu Ala His
100 105 110
Tyr Asp Val Leu Leu Ser Tyr Pro Asn Lys Thr His Pro Asn Tyr Ile
115 120 125
Ser Ile Ile Asn Glu Asp Gly Asn Glu Ile Phe Asn Thr Ser Leu Phe
130 135 140
Glu Pro Pro Pro Pro Gly Tyr Glu Asn Val Ser Asp Ile Val Pro Pro
145 150 155 160
Phe Ser Ala Phe Ser Pro Gln Gly Met Pro Glu Gly Asp Leu Val Tyr
165 170 175
Val Asn Tyr Ala Arg Thr Glu Asp Phe Phe Lys Leu Glu Arg Asp Met
180 185 190
Lys Ile Asn Cys Ser Gly Lys Ile Val Ile Ala Arg Tyr Gly Lys Val
195 200 205
Phe Arg Gly Asn Lys Val Lys Asn Ala Gln Leu Ala Gly Ala Lys Gly
210 215 220
Val Ile Leu Tyr Ser Asp Pro Ala Asp Tyr Phe Ala Pro Gly Val Lys
225 230 235 240
Ser Tyr Pro Asp Gly Trp Asn Leu Pro Gly Gly Gly Val Gln Arg Gly
245 250 255
Asn Ile Leu Asn Leu Asn Gly Ala Gly Asp Pro Leu Thr Pro Gly Tyr
260 265 270
Pro Ala Asn Glu Tyr Ala Tyr Arg Arg Gly Ile Ala Glu Ala Val Gly
275 280 285
Leu Pro Ser Ile Pro Val His Pro Ile Gly Tyr Tyr Asp Ala Gln Lys
290 295 300
Leu Leu Glu Lys Met Gly Gly Ser Ala Pro Pro Asp Ser Ser Trp Arg
305 310 315 320
Gly Ser Leu Lys Val Pro Tyr Asn Val Gly Pro Gly Phe Thr Gly Asn
325 330 335
Phe Ser Thr Gln Lys Val Lys Met His Ile His Ser Thr Asn Glu Val
340 345 350
Thr Arg Ile Tyr Asn Val Ile Gly Thr Leu Arg Gly Ala Val Glu Pro
355 360 365
Asp Arg Tyr Val Ile Leu Gly Gly His Arg Asp Ser Trp Val Phe Gly
370 375 380
Gly Ile Asp Pro Gln Ser Gly Ala Ala Val Val His Glu Ile Val Arg
385 390 395 400
Ser Phe Gly Thr Leu Lys Lys Glu Gly Trp Arg Pro Arg Arg Thr Ile
405 410 415
Leu Phe Ala Ser Trp Asp Ala Glu Glu Phe Gly Leu Leu Gly Ser Thr
420 425 430
Glu Trp Ala Glu Glu Asn Ser Arg Leu Leu Gln Glu Arg Gly Val Ala
435 440 445
Tyr Ile Asn Ala Asp Ser Ser Ile Glu Gly Asn Tyr Thr Leu Arg Val
450 455 460
Asp Cys Thr Pro Leu Met Tyr Ser Leu Val His Asn Leu Thr Lys Glu
465 470 475 480
Leu Lys Ser Pro Asp Glu Gly Phe Glu Gly Lys Ser Leu Tyr Glu Ser
485 490 495
Trp Thr Lys Lys Ser Pro Ser Pro Glu Phe Ser Gly Met Pro Arg Ile
500 505 510
Ser Lys Leu Gly Ser Gly Asn Asp Phe Glu Val Phe Phe Gln Arg Leu
515 520 525
Gly Ile Ala Ser Gly Arg Ala Arg Tyr Thr Lys Asn Trp Glu Thr Asn
530 535 540
Lys Phe Ser Gly Tyr Pro Leu Tyr His Ser Val Tyr Glu Thr Tyr Glu
545 550 555 560
Leu Val Glu Lys Phe Tyr Asp Pro Met Phe Lys Tyr His Leu Thr Val
565 570 575
Ala Gln Val Arg Gly Gly Met Val Phe Glu Leu Ala Asn Ser Ile Val
580 585 590
Leu Pro Phe Asp Cys Arg Asp Tyr Ala Val Val Leu Arg Lys Tyr Ala
595 600 605
Asp Lys Ile Tyr Ser Ile Ser Met Lys His Pro Gln Glu Met Lys Thr
610 615 620
Tyr Ser Val Ser Phe Asp Ser Leu Phe Ser Ala Val Lys Asn Phe Thr
625 630 635 640
Glu Ile Ala Ser Lys Phe Ser Glu Arg Leu Gln Asp Phe Asp Lys Ser
645 650 655
Asn Pro Ile Val Leu Arg Met Met Asn Asp Gln Leu Met Phe Leu Glu
660 665 670
Arg Ala Phe Ile Asp Pro Leu Gly Leu Pro Asp Arg Pro Phe Tyr Arg
675 680 685
His Val Ile Tyr Ala Pro Ser Ser His Asn Lys Tyr Ala Gly Glu Ser
690 695 700
Phe Pro Gly Ile Tyr Asp Ala Leu Phe Asp Ile Glu Ser Lys Val Asp
705 710 715 720
Pro Ser Lys Ala Trp Gly Glu Val Lys Arg Gln Ile Tyr Val Ala Ala
725 730 735
Phe Thr Val Gln Ala Ala Ala Glu Thr Leu Ser Glu Val Ala
740 745 750
<210> 2
<211> 2250
<212> DNA
<213> Homo sapiens
<400> 2
atgtggaatc tccttcacga aaccgactcg gctgtggcca ccgcgcgccg cccgcgctgg 60
ctgtgcgctg gggcgctggt gctggcgggt ggcttctttc tcctcggctt cctcttcggg 120
tggtttataa aatcctccaa tgaagctact aacattactc caaagcataa tatgaaagca 180
tttttggatg aattgaaagc tgagaacatc aagaagttct tatataattt tacacagata 240
ccacatttag caggaacaga acaaaacttt cagcttgcaa agcaaattca atcccagtgg 300
aaagaatttg gcctggattc tgttgagcta gcacattatg atgtcctgtt gtcctaccca 360
aataagactc atcccaacta catctcaata attaatgaag atggaaatga gattttcaac 420
acatcattat ttgaaccacc tcctccagga tatgaaaatg tttcggatat tgtaccacct 480
ttcagtgctt tctctcctca aggaatgcca gagggcgatc tagtgtatgt taactatgca 540
cgaactgaag acttctttaa attggaacgg gacatgaaaa tcaattgctc tgggaaaatt 600
gtaattgcca gatatgggaa agttttcaga ggaaataagg ttaaaaatgc ccagctggca 660
ggggccaaag gagtcattct ctactccgac cctgctgact actttgctcc tggggtgaag 720
tcctatccag atggttggaa tcttcctgga ggtggtgtcc agcgtggaaa tatcctaaat 780
ctgaatggtg caggagaccc tctcacacca ggttacccag caaatgaata tgcttatagg 840
cgtggaattg cagaggctgt tggtcttcca agtattcctg ttcatccaat tggatactat 900
gatgcacaga agctcctaga aaaaatgggt ggctcagcac caccagatag cagctggaga 960
ggaagtctca aagtgcccta caatgttgga cctggcttta ctggaaactt ttctacacaa 1020
aaagtcaaga tgcacatcca ctctaccaat gaagtgacaa gaatttacaa tgtgataggt 1080
actctcagag gagcagtgga accagacaga tatgtcattc tgggaggtca ccgggactca 1140
tgggtgtttg gtggtattga ccctcagagt ggagcagctg ttgttcatga aattgtgagg 1200
agctttggaa cactgaaaaa ggaagggtgg agacctagaa gaacaatttt gtttgcaagc 1260
tgggatgcag aagaatttgg tcttcttggt tctactgagt gggcagagga gaattcaaga 1320
ctccttcaag agcgtggcgt ggcttatatt aatgctgact catctataga aggaaactac 1380
actctgagag ttgattgtac accgctgatg tacagcttgg tacacaacct aacaaaagag 1440
ctgaaaagcc ctgatgaagg ctttgaaggc aaatctcttt atgaaagttg gactaaaaaa 1500
agtccttccc cagagttcag tggcatgccc aggataagca aattgggatc tggaaatgat 1560
tttgaggtgt tcttccaacg acttggaatt gcttcaggca gagcacggta tactaaaaat 1620
tgggaaacaa acaaattcag cggctatcca ctgtatcaca gtgtctatga aacatatgag 1680
ttggtggaaa agttttatga tccaatgttt aaatatcacc tcactgtggc ccaggttcga 1740
ggagggatgg tgtttgagct agccaattcc atagtgctcc cttttgattg tcgagattat 1800
gctgtagttt taagaaagta tgctgacaaa atctacagta tttctatgaa acatccacag 1860
gaaatgaaga catacagtgt atcatttgat tcactttttt ctgcagtaaa gaattttaca 1920
gaaattgctt ccaagttcag tgagagactc caggactttg acaaaagcaa cccaatagta 1980
ttaagaatga tgaatgatca actcatgttt ctggaaagag catttattga tccattaggg 2040
ttaccagaca ggccttttta taggcatgtc atctatgctc caagcagcca caacaagtat 2100
gcaggggagt cattcccagg aatttatgat gctctgtttg atattgaaag caaagtggac 2160
ccttccaagg cctggggaga agtgaagaga cagatttatg ttgcagcctt cacagtgcag 2220
gcagctgcag agactttgag tgaagtagcc 2250
<210> 3
<211> 739
<212> PRT
<213> Artificial
<220>
<223> synthetic construct
<400> 3
Met Ala Ser Ala Arg Arg Pro Arg Trp Leu Cys Ala Gly Ala Leu Val
1 5 10 15
Leu Ala Gly Gly Phe Phe Leu Leu Gly Phe Leu Phe Gly Trp Phe Ile
20 25 30
Lys Ser Ser Ser Glu Ala Thr Asn Ile Ser Pro Gln His Asn Val Lys
35 40 45
Ala Phe Leu Asp Glu Met Lys Ala Glu Asn Ile Lys Lys Phe Leu Tyr
50 55 60
Leu Phe Thr Gln Ile Pro His Leu Ala Gly Thr Glu Gln Asn Phe Gln
65 70 75 80
Leu Ala Lys Gln Ile Gln Ala Glu Trp Lys Glu Phe Gly Leu Asp Ser
85 90 95
Val Glu Leu Ala His Tyr Asp Val Leu Leu Ser Tyr Pro Asn Glu Thr
100 105 110
His Pro Asn Tyr Ile Ser Ile Ile Asp Glu Asp Gly Asn Glu Ile Phe
115 120 125
Asn Thr Ser Leu Phe Glu Pro Pro Pro Pro Gly Tyr Glu Asn Ile Ser
130 135 140
Asp Val Val Pro Pro Tyr Ser Ala Phe Ser Pro Gln Gly Met Pro Glu
145 150 155 160
Gly Asp Leu Val Tyr Val Asn Tyr Ala Arg Thr Glu Asp Phe Phe Lys
165 170 175
Leu Glu Arg Glu Leu Lys Ile Asn Cys Ser Gly Lys Ile Leu Ile Ala
180 185 190
Arg Tyr Gly Lys Val Phe Arg Gly Asn Lys Val Lys Asn Ala Gln Leu
195 200 205
Ala Gly Ala Lys Gly Ile Ile Leu Tyr Ser Asp Pro Ala Asp Tyr Phe
210 215 220
Ala Pro Gly Val Lys Ser Tyr Pro Asp Gly Trp Asn Leu Pro Gly Gly
225 230 235 240
Gly Val Gln Arg Gly Asn Val Leu Asn Leu Asn Gly Ala Gly Asp Pro
245 250 255
Leu Thr Pro Gly Tyr Pro Ala Asn Glu Tyr Ala Tyr Arg Arg Glu Leu
260 265 270
Ala Glu Ala Val Gly Leu Pro Ser Ile Pro Val His Pro Ile Gly Tyr
275 280 285
Tyr Asp Ala Gln Lys Leu Leu Glu Lys Met Gly Gly Ser Ala Pro Pro
290 295 300
Asp Ser Ser Trp Lys Gly Ser Leu Lys Val Pro Tyr Asn Val Gly Pro
305 310 315 320
Gly Phe Thr Gly Asn Phe Ser Thr Gln Lys Val Lys Met His Ile His
325 330 335
Ser Thr Asn Glu Val Thr Arg Ile Tyr Asn Val Ile Gly Thr Ile Arg
340 345 350
Gly Ala Val Glu Pro Asp Arg Tyr Val Ile Leu Gly Gly His Arg Asp
355 360 365
Ala Trp Val Phe Gly Gly Ile Asp Pro Gln Ser Gly Ala Ala Val Val
370 375 380
His Glu Ile Val Arg Ser Phe Gly Thr Leu Lys Lys Lys Gly Trp Arg
385 390 395 400
Pro Arg Arg Thr Ile Ile Phe Ala Ser Trp Asp Ala Glu Glu Phe Gly
405 410 415
Leu Leu Gly Ser Thr Glu Trp Ala Glu Glu Asn Ser Arg Leu Leu Gln
420 425 430
Glu Arg Gly Val Ala Tyr Ile Asn Ala Asp Ser Ser Ile Glu Gly Asn
435 440 445
Tyr Thr Leu Arg Val Asp Cys Thr Pro Leu Met Tyr Ser Leu Val Tyr
450 455 460
Asn Leu Thr Lys Glu Leu Gln Ser Pro Asp Glu Gly Phe Glu Gly Lys
465 470 475 480
Ser Leu Tyr Glu Ser Trp Thr Lys Lys Ser Pro Ser Pro Glu Phe Ser
485 490 495
Gly Val Pro Arg Ile Asn Lys Leu Gly Ser Gly Asn Asp Phe Glu Val
500 505 510
Phe Phe Gln Arg Leu Gly Ile Ala Ser Gly Arg Ala Arg Tyr Thr Lys
515 520 525
Asn Trp Lys Thr Asn Lys Phe Ser Gly Tyr Pro Leu Tyr His Ser Val
530 535 540
Tyr Glu Thr Tyr Glu Leu Val Glu Lys Phe Tyr Asp Pro Met Phe Lys
545 550 555 560
Tyr His Leu Thr Val Ala Gln Val Arg Gly Gly Leu Val Phe Glu Leu
565 570 575
Ala Asp Ser Ile Val Leu Pro Phe Asp Cys Gln Asp Tyr Ala Val Val
580 585 590
Leu Arg Lys Tyr Ala Asp Lys Ile Tyr Asn Leu Ala Met Lys His Pro
595 600 605
Glu Glu Leu Lys Thr Tyr Ser Val Ser Phe Asp Ser Leu Phe Ser Ala
610 615 620
Val Lys Asn Phe Thr Glu Ile Ala Ser Lys Phe Asn Gln Arg Leu Gln
625 630 635 640
Asp Phe Asp Lys Asn Asn Pro Leu Leu Val Arg Met Leu Asn Asp Gln
645 650 655
Leu Met Phe Leu Glu Arg Ala Phe Val Asp Pro Leu Gly Leu Pro Asp
660 665 670
Arg Pro Phe Tyr Arg His Val Ile Tyr Ala Pro Ser Ser His Asn Lys
675 680 685
Tyr Ala Gly Glu Ser Phe Pro Gly Ile Tyr Asp Ala Leu Phe Asp Ile
690 695 700
Glu Ser Lys Val Asp Pro Ser Lys Ala Trp Gly Glu Val Lys Arg Gln
705 710 715 720
Ile Tyr Val Ala Ala Phe Thr Val Gln Ala Ala Ala Glu Thr Leu Ser
725 730 735
Glu Val Ala
<210> 4
<211> 2217
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 4
atggctagcg ccagacggcc cagatggctg tgcgccggag ccctggtgct ggccggagga 60
ttcttcctgc tgggcttcct gttcggctgg ttcatcaaga gcagcagcga ggccaccaac 120
atcagccccc agcacaacgt gaaggccttt ctggacgaga tgaaggccga gaacatcaag 180
aagtttctgt acctgttcac ccagatcccc cacctggccg gcaccgagca gaacttccag 240
ctggccaagc agattcaggc tgagtggaaa gagttcggcc tggacagcgt ggagctggcc 300
cactacgacg tgctgctgtc ctaccccaac gagacacacc ccaactacat cagcatcatc 360
gacgaggacg gcaacgagat tttcaacacc agcctgttcg agccccctcc ccctggctac 420
gagaacatct ccgacgtggt gcccccctac agcgccttca gccctcaggg aatgcctgaa 480
ggcgacctgg tgtacgtgaa ctacgcccgg accgaggact tcttcaagct ggaacgggag 540
ctgaagatca actgcagcgg caagatcctg atcgccagat acggcaaggt gttccggggc 600
aacaaagtga agaacgcaca gctggctgga gccaagggca tcatcctgta cagcgacccc 660
gccgactact tcgcccctgg cgtgaagtcc taccctgacg gctggaacct gcctggcggc 720
ggagtgcagc ggggcaacgt gctgaacctg aacggagccg gcgaccctct gaccccaggc 780
taccccgcca acgagtacgc ctaccggcgg gagctggccg aagccgtggg cctgcccagc 840
atccccgtgc accccatcgg ctactacgac gcccagaaac tgctggaaaa gatgggcggc 900
agcgcccctc ccgacagcag ctggaagggc agcctgaagg tgccctacaa cgtgggccct 960
ggcttcaccg gcaacttcag cacccagaaa gtgaagatgc acatccacag caccaacgaa 1020
gtgacccgga tctacaacgt gatcggcacc atcagaggcg ccgtggagcc cgacagatac 1080
gtgatcctgg gcggccaccg ggacgcctgg gtgttcggcg gcatcgaccc ccagagcgga 1140
gccgccgtgg tgcacgagat cgtgcggagc ttcggcaccc tgaagaagaa gggctggcgg 1200
cccagacgga ccatcatctt cgccagctgg gacgccgagg aattcggact gctgggctct 1260
accgagtggg ccgaggaaaa cagcagactg ctgcaggaac ggggcgtcgc ctacatcaac 1320
gccgacagct ccatcgaggg caactacacc ctgcgggtgg actgcacccc cctgatgtac 1380
agcctggtgt acaacctgac caaagagctg cagagccccg acgagggctt cgagggcaag 1440
agcctgtacg agagctggac caagaagtcc cccagccccg agttcagcgg cgtgccccgg 1500
atcaacaagc tgggcagcgg caacgacttc gaggtgttct tccagaggct gggcattgcc 1560
agcggcagag cccggtacac caagaactgg aaaaccaaca agttctccgg ctaccccctg 1620
taccacagcg tgtacgagac atacgaactg gtggagaagt tctacgaccc catgttcaag 1680
taccacctga ccgtggccca ggtccgggga gggctggtgt tcgaactggc cgacagcatc 1740
gtgctgccct tcgactgcca ggactatgct gtggtgctgc ggaagtacgc cgacaaaatc 1800
tacaacctgg ccatgaagca ccccgaggaa ctgaaaacct acagcgtgtc cttcgacagc 1860
ctgttcagcg ccgtgaagaa cttcaccgag atcgccagca agttcaacca gcggctgcag 1920
gacttcgaca agaacaaccc cctgctggtc cggatgctga acgaccagct gatgttcctg 1980
gaacgggcct tcgtggaccc cctgggcctg cctgaccggc ccttctaccg gcacgtgatc 2040
tatgccccca gcagccacaa caagtacgct ggcgagagct tccccggcat ctacgatgcc 2100
ctgttcgaca tcgagagcaa ggtggacccc agcaaggcct ggggcgaagt gaagcggcag 2160
atatacgtgg ccgccttcac agtgcaggcc gctgccgaga cactgagcga ggtggcc 2217
<210> 5
<211> 739
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 5
Met Ala Ser Ala Arg Arg Pro Arg Trp Leu Cys Ala Gly Ala Leu Val
1 5 10 15
Leu Ala Gly Gly Phe Phe Leu Leu Gly Phe Leu Phe Gly Trp Phe Ile
20 25 30
Lys Ser Ser Ser Glu Ala Thr Asn Ile Thr Pro Gln His Asn Val Lys
35 40 45
Ala Phe Leu Asp Glu Leu Lys Ala Glu Asn Ile Lys Lys Phe Leu Tyr
50 55 60
Asn Phe Thr Gln Ile Pro His Leu Ala Gly Thr Glu Gln Asn Phe Glu
65 70 75 80
Leu Ala Lys Gln Ile Gln Ala Gln Trp Lys Glu Phe Gly Leu Asp Ser
85 90 95
Val Glu Leu Ser His Tyr Asp Val Leu Leu Ser Tyr Pro Asn Glu Thr
100 105 110
His Pro Asn Tyr Ile Ser Ile Ile Asp Glu Asp Gly Asn Glu Ile Phe
115 120 125
Asn Thr Ser Leu Phe Glu Pro Pro Pro Pro Gly Tyr Glu Asn Ile Ser
130 135 140
Asp Val Val Pro Pro Tyr Ser Ala Phe Ser Pro Gln Gly Met Pro Glu
145 150 155 160
Gly Asp Leu Val Tyr Val Asn Tyr Ala Arg Thr Glu Asp Phe Phe Lys
165 170 175
Leu Glu Arg Asp Met Lys Ile Asn Cys Ser Gly Lys Ile Leu Ile Ala
180 185 190
Arg Tyr Gly Lys Val Phe Arg Gly Asn Lys Val Lys Asn Ala Gln Leu
195 200 205
Ala Gly Ala Lys Gly Ile Ile Leu Tyr Ser Asp Pro Ala Asp Tyr Phe
210 215 220
Ala Pro Gly Val Lys Ser Tyr Pro Asp Gly Trp Asn Leu Pro Gly Gly
225 230 235 240
Gly Val Gln Arg Gly Asn Val Leu Asn Leu Asn Gly Ala Gly Asp Pro
245 250 255
Leu Thr Pro Gly Tyr Pro Ala Asn Glu Tyr Ala Tyr Arg Arg Gly Ile
260 265 270
Ala Glu Ala Val Gly Leu Pro Ser Ile Pro Val His Pro Ile Gly Tyr
275 280 285
Tyr Asp Ala Gln Lys Leu Leu Glu Lys Met Gly Gly Ala Ala Pro Pro
290 295 300
Asp Ser Ser Trp Lys Gly Ser Leu Gln Val Pro Tyr Asn Val Gly Pro
305 310 315 320
Gly Phe Thr Gly Asn Phe Ser Thr Gln Lys Val Lys Met His Ile His
325 330 335
Ser Thr Asn Glu Val Thr Arg Ile Tyr Asn Val Ile Gly Thr Leu Lys
340 345 350
Gly Ala Val Glu Pro Asp Arg Tyr Val Ile Leu Gly Gly His Arg Asp
355 360 365
Ala Trp Val Phe Gly Gly Ile Asp Pro Gln Ser Gly Ala Ala Val Val
370 375 380
His Glu Ile Val Arg Ser Phe Gly Thr Leu Lys Lys Lys Gly Trp Arg
385 390 395 400
Pro Arg Arg Thr Ile Leu Phe Ala Ser Trp Asp Ala Glu Glu Phe Gly
405 410 415
Leu Leu Gly Ser Thr Glu Trp Ala Glu Glu Asn Ser Arg Leu Leu Gln
420 425 430
Glu Arg Gly Val Ala Tyr Ile Asn Ala Asp Ser Ser Ile Glu Gly Asn
435 440 445
Tyr Thr Leu Arg Val Asp Cys Thr Pro Leu Met Tyr Ser Leu Val Tyr
450 455 460
Asn Leu Thr Lys Glu Leu Gln Ser Pro Asp Glu Gly Phe Glu Gly Lys
465 470 475 480
Ser Leu Phe Asp Ser Trp Thr Glu Lys Ser Pro Ser Pro Glu Phe Ser
485 490 495
Gly Leu Pro Arg Ile Ser Lys Leu Gly Ser Gly Asn Asp Phe Glu Val
500 505 510
Phe Phe Gln Arg Leu Gly Ile Ala Ser Gly Arg Ala Arg Tyr Thr Lys
515 520 525
Asp Trp Lys Thr Ser Lys Phe Ser Gly Tyr Pro Leu Tyr His Ser Val
530 535 540
Tyr Glu Thr Tyr Glu Leu Val Glu Lys Phe Tyr Asp Pro Met Phe Lys
545 550 555 560
Tyr His Leu Thr Val Ala Gln Val Arg Gly Gly Ile Val Phe Glu Leu
565 570 575
Ala Asn Ser Val Val Leu Pro Phe Asp Cys Gln Asp Tyr Ala Val Val
580 585 590
Leu Lys Lys Tyr Ala Asp Lys Ile Tyr Asn Ile Ser Met Lys His Pro
595 600 605
Gln Glu Met Lys Thr Tyr Ser Val Ser Phe Asp Ser Leu Phe Ser Ala
610 615 620
Val Lys Asn Phe Thr Glu Ile Ala Ser Lys Phe Asn Gln Arg Leu Gln
625 630 635 640
Asp Phe Asp Lys Asn Asn Pro Ile Leu Leu Arg Met Met Asn Asp Gln
645 650 655
Leu Met Phe Leu Glu Arg Ala Phe Ile Asp Pro Leu Gly Leu Pro Asp
660 665 670
Arg Pro Phe Tyr Arg His Val Ile Tyr Ala Pro Ser Ser His Asn Lys
675 680 685
Tyr Ala Gly Glu Ser Phe Pro Gly Ile Tyr Asp Ala Leu Phe Asp Ile
690 695 700
Glu Ser Lys Val Asp Pro Ser Lys Ala Trp Gly Glu Val Lys Arg Gln
705 710 715 720
Ile Tyr Val Ala Ala Phe Thr Val Gln Ala Ala Ala Glu Thr Leu Ser
725 730 735
Glu Val Ala
<210> 6
<211> 2217
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 6
atggctagcg ccagacggcc cagatggctg tgtgctggcg ccctggtgct ggctggcggc 60
tttttcctgc tgggcttcct gttcggctgg ttcatcaaga gcagcagcga ggccaccaac 120
atcacccccc agcacaacgt gaaggccttt ctggacgagc tgaaggccga gaatatcaag 180
aagttcctgt acaacttcac ccagatcccc cacctggccg gcaccgagca gaacttcgag 240
ctggccaagc agatccaggc ccagtggaaa gagttcggcc tggacagcgt ggaactgagc 300
cactacgacg tgctgctgag ctaccccaac gagacacacc ccaactacat cagcatcatc 360
gacgaggacg gcaacgagat tttcaacacc agcctgttcg agccccctcc acccggctac 420
gagaacatca gcgacgtggt gcccccctac agcgcattca gtccacaggg aatgcccgag 480
ggcgacctgg tgtacgtgaa ctacgcccgg accgaggact tcttcaagct ggaacgggac 540
atgaagatca actgcagcgg caagatcctg atcgccagat acggcaaggt gttccggggc 600
aacaaagtga agaacgccca gctggcaggc gccaagggca tcatcctgta cagcgacccc 660
gccgactact tcgcccctgg cgtgaagtcc taccccgacg gctggaacct gcctggcggc 720
ggagtgcaga ggggcaacgt gctgaacctg aacggcgctg gcgaccctct gacccctggc 780
taccccgcca acgagtacgc ctacagacgg ggaatcgccg aggccgtggg cctgcctagc 840
atccctgtgc accccatcgg ctactacgac gcccagaaac tgctggaaaa gatgggcgga 900
gccgcccctc ccgacagctc ttggaagggc agcctgcagg tcccctacaa cgtgggccct 960
ggcttcaccg gcaacttcag cacccagaaa gtgaagatgc acatccacag caccaacgaa 1020
gtgacccgga tctacaacgt gatcggcacc ctgaagggcg ccgtggaacc cgacagatac 1080
gtgatcctgg gcggccaccg ggacgcctgg gtgttcggag gcatcgaccc tcagagcggc 1140
gctgccgtgg tgcacgagat cgtgcggagc ttcggcacac tgaagaagaa gggctggcgg 1200
cccagacgga ccatcctgtt cgccagctgg gacgccgagg aattcggcct gctgggcagc 1260
accgagtggg ccgaggaaaa cagtcggctg ctgcaggaac ggggcgtcgc ctacatcaac 1320
gccgacagca gcatcgaggg caactacacc ctgcgggtgg actgcacccc cctgatgtac 1380
agcctggtgt acaacctgac caaagagctg cagagccccg acgagggctt cgagggcaag 1440
tccctgttcg actcctggac cgagaagtcc cccagccccg agttcagcgg cctgcccaga 1500
atcagcaagc tgggcagcgg caacgacttc gaggtgttct tccagcggct gggaatcgcc 1560
agcggcagag cccggtacac caaggactgg aaaaccagca agttctccgg ctaccccctg 1620
taccacagcg tgtacgagac atacgagctg gtggaaaagt tctacgaccc catgttcaag 1680
taccacctga ccgtggccca ggtccgaggc ggcatcgtgt tcgaactggc caacagcgtg 1740
gtgctgccat tcgattgtca ggactacgcc gtggtgctga agaagtacgc cgacaaaatc 1800
tacaacatca gcatgaagca cccccaggaa atgaaaacct acagcgtgtc cttcgacagc 1860
ctgttcagcg ccgtgaagaa tttcaccgag atcgcctcca agttcaacca gagactgcag 1920
gacttcgaca agaacaaccc catcctgctg cggatgatga acgaccagct gatgttcctg 1980
gaacgggcct tcatcgaccc cctgggcctg cccgaccggc ccttttaccg gcacgtgatc 2040
tatgccccca gcagccacaa caaatacgcc ggcgagagtt tccccggcat ctacgatgcc 2100
ctgttcgata tcgagagcaa ggtggacccc agcaaggcct ggggcgaagt gaagcggcag 2160
atttacgtgg ccgcattcac agtgcaggct gctgccgaga cactgagcga ggtggcc 2217
<210> 7
<211> 739
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 7
Met Ala Ser Ala Arg Arg Pro Arg Trp Leu Cys Ala Gly Ala Leu Val
1 5 10 15
Leu Ala Gly Gly Phe Phe Leu Leu Gly Phe Leu Phe Gly Trp Phe Ile
20 25 30
Lys Ser Ser Asn Glu Ala Thr Asn Ile Thr Pro Lys His Asn Met Lys
35 40 45
Ala Phe Leu Asp Glu Leu Lys Ala Glu Asn Ile Lys Lys Phe Leu Tyr
50 55 60
Asn Phe Thr Gln Ile Pro His Leu Ala Gly Thr Glu Gln Asn Phe Gln
65 70 75 80
Leu Ala Lys Gln Ile Gln Ser Gln Trp Lys Glu Phe Gly Leu Asp Ser
85 90 95
Val Glu Leu Ala His Tyr Asp Val Leu Leu Ser Tyr Pro Asn Lys Thr
100 105 110
His Pro Asn Tyr Ile Ser Ile Ile Asn Glu Asp Gly Asn Glu Ile Phe
115 120 125
Asn Thr Ser Leu Phe Glu Pro Pro Pro Pro Gly Tyr Glu Asn Val Ser
130 135 140
Asp Ile Val Pro Pro Phe Ser Ala Phe Ser Pro Gln Gly Met Pro Glu
145 150 155 160
Gly Asp Leu Val Tyr Val Asn Tyr Ala Arg Thr Glu Asp Phe Phe Lys
165 170 175
Leu Glu Arg Asp Met Lys Ile Asn Cys Ser Gly Lys Ile Val Ile Ala
180 185 190
Arg Tyr Gly Lys Val Phe Arg Gly Asn Lys Val Lys Asn Ala Gln Leu
195 200 205
Ala Gly Ala Lys Gly Val Ile Leu Tyr Ser Asp Pro Ala Asp Tyr Phe
210 215 220
Ala Pro Gly Val Lys Ser Tyr Pro Asp Gly Trp Asn Leu Pro Gly Gly
225 230 235 240
Gly Val Gln Arg Gly Asn Ile Leu Asn Leu Asn Gly Ala Gly Asp Pro
245 250 255
Leu Thr Pro Gly Tyr Pro Ala Asn Glu Tyr Ala Tyr Arg Arg Gly Ile
260 265 270
Ala Glu Ala Val Gly Leu Pro Ser Ile Pro Val His Pro Ile Gly Tyr
275 280 285
Tyr Asp Ala Gln Lys Leu Leu Glu Lys Met Gly Gly Ser Ala Pro Pro
290 295 300
Asp Ser Ser Trp Arg Gly Ser Leu Lys Val Pro Tyr Asn Val Gly Pro
305 310 315 320
Gly Phe Thr Gly Asn Phe Ser Ala Gln Lys Leu Lys Leu His Ile His
325 330 335
Ser Asn Thr Lys Val Thr Arg Ile Tyr Asn Val Ile Gly Thr Leu Arg
340 345 350
Gly Ala Val Glu Pro Asp Arg Tyr Val Ile Leu Gly Gly His Arg Asp
355 360 365
Ser Trp Val Phe Gly Gly Ile Asp Pro Gln Ser Gly Ala Ala Val Val
370 375 380
His Glu Ile Val Arg Thr Phe Gly Thr Leu Lys Lys Lys Gly Trp Arg
385 390 395 400
Pro Arg Arg Thr Ile Leu Phe Ala Ser Trp Asp Ala Glu Glu Phe Gly
405 410 415
Leu Leu Gly Ser Thr Glu Trp Ala Glu Glu Asn Ser Arg Leu Leu Gln
420 425 430
Glu Arg Gly Val Ala Tyr Ile Asn Ala Asp Ser Ser Ile Glu Gly Asn
435 440 445
Tyr Thr Leu Arg Val Asp Cys Thr Pro Leu Leu His Ser Leu Val Tyr
450 455 460
Asn Leu Thr Lys Glu Leu Lys Ser Pro Asp Glu Gly Phe Glu Gly Lys
465 470 475 480
Ser Leu Tyr Glu Ser Trp Thr Lys Lys Ser Pro Ser Pro Glu Leu Ser
485 490 495
Gly Leu Pro Arg Ile Ser Lys Leu Gly Ser Gly Asn Asp Phe Glu Val
500 505 510
Phe Phe Gln Arg Leu Gly Ile Ser Ser Gly Arg Ala Arg Tyr Thr Lys
515 520 525
Asp Trp Lys Thr Ser Lys Phe Ser Ser Tyr Pro Leu Tyr His Ser Ile
530 535 540
Tyr Glu Thr Tyr Glu Leu Val Val Lys Phe Tyr Asp Pro Met Phe Lys
545 550 555 560
Tyr His Leu Thr Val Ala Gln Val Arg Gly Gly Met Val Phe Glu Leu
565 570 575
Ala Asn Ser Ile Val Leu Pro Phe Asp Cys Arg Asp Tyr Ala Val Ala
580 585 590
Leu Lys Asn His Ala Glu Asn Leu Tyr Ser Ile Ser Met Lys His Pro
595 600 605
Gln Glu Met Lys Thr Tyr Ser Val Ser Phe Asp Ser Leu Phe Ser Ala
610 615 620
Val Lys Asn Phe Thr Glu Ile Ala Ser Lys Phe Ser Glu Arg Leu Gln
625 630 635 640
Asp Phe Asp Lys Ser Asn Pro Ile Val Leu Arg Met Met Asn Asp Gln
645 650 655
Leu Met Phe Leu Glu Arg Ala Phe Ile Asp Pro Leu Gly Leu Pro Asp
660 665 670
Arg Pro Phe Tyr Arg His Val Ile Tyr Ala Pro Ser Ser His Asn Lys
675 680 685
Tyr Ala Gly Glu Ser Phe Pro Gly Ile Tyr Asp Ala Leu Phe Asp Ile
690 695 700
Glu Ser Lys Val Asp Pro Ser Lys Ala Trp Gly Glu Val Lys Arg Gln
705 710 715 720
Ile Tyr Val Ala Ala Phe Thr Val Gln Ala Ala Ala Glu Thr Leu Ser
725 730 735
Glu Val Ala
<210> 8
<211> 2217
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 8
atggctagcg ccagacggcc cagatggctg tgtgctggcg ccctggtgct ggctggcggc 60
tttttcctgc tgggcttcct gttcggctgg ttcatcaaga gcagcaacga ggccaccaac 120
atcaccccca agcacaacat gaaggccttt ctggacgagc tgaaggccga gaatatcaag 180
aagttcctgt acaacttcac ccagatcccc cacctggccg gcaccgagca gaacttccag 240
ctggccaagc agatccagag ccagtggaaa gagttcggcc tggacagcgt ggaactggcc 300
cactacgacg tgctgctgag ctaccccaac aagacccacc ccaactacat cagcatcatc 360
aacgaggacg gcaacgagat tttcaacacc agcctgttcg agccccctcc acccggctac 420
gagaacgtgt ccgacatcgt gcccccattc agcgcattca gtccacaggg aatgcccgag 480
ggcgacctgg tgtacgtgaa ctacgcccgg accgaggact tcttcaagct ggaacgggac 540
atgaagatca actgcagcgg caagatcgtg atcgccagat acggcaaggt gttccggggc 600
aacaaagtga agaacgccca gctggcaggc gccaagggcg tgatcctgta tagcgacccc 660
gccgactact tcgcccctgg cgtgaagtcc taccccgacg gctggaacct gcctggcggc 720
ggagtgcagc ggggcaacat cctgaacctg aacggcgctg gcgaccccct gacccctggc 780
tatcccgcca acgagtacgc ctacagacgg ggaatcgccg aggccgtggg cctgcctagc 840
atccctgtgc accccatcgg ctactacgac gcccagaaac tgctggaaaa gatgggcggc 900
agcgcccctc ccgatagctc ttggagaggc agcctgaagg tgccctacaa cgtgggccct 960
ggcttcaccg gcaacttcag cgcccagaag ctgaagctgc acatccacag caacaccaaa 1020
gtgacccgga tctacaacgt gatcggcacc ctgagaggcg ccgtggaacc cgacagatac 1080
gtgatcctgg gcggccaccg ggacagctgg gtgttcggcg gcatcgaccc tcagtctggc 1140
gccgctgtgg tgcacgagat cgtgcggacc tttggcaccc tgaagaagaa gggctggcgg 1200
cccagacgga ccatcctgtt cgccagctgg gacgccgagg aattcggcct gctgggcagc 1260
accgagtggg ccgaggaaaa cagtcggctg ctgcaggaac ggggcgtcgc ctacatcaac 1320
gccgacagca gcatcgaggg caactacacc ctgcgggtgg actgcacccc cctgctgcac 1380
agcctggtgt acaacctgac caaagagctg aagtcccccg acgagggctt cgagggcaag 1440
agcctgtacg agagctggac caagaagtcc cccagccccg agctgagcgg cctgcccaga 1500
atcagcaagc tgggcagcgg caacgacttc gaggtgttct tccagcggct gggcatcagc 1560
agcggcagag cccggtacac caaggactgg aaaaccagca agttcagcag ctaccccctg 1620
taccacagca tctacgagac atacgagctg gtggtcaagt tctacgaccc catgttcaag 1680
taccacctga ccgtggccca ggtccgaggc ggcatggtgt tcgagctggc caacagcatc 1740
gtgctgccct tcgactgccg ggactacgcc gtggccctga agaaccacgc cgagaacctg 1800
tacagcatca gcatgaagca cccccaggaa atgaaaacct acagcgtgtc cttcgacagc 1860
ctgttcagcg ccgtgaagaa tttcaccgag atcgcctcca agttcagcga gcggctgcag 1920
gacttcgaca agagcaaccc catcgtgctg agaatgatga acgaccagct gatgttcctg 1980
gaacgggcct tcatcgaccc cctgggcctg cccgaccggc ccttttaccg gcacgtgatc 2040
tatgccccca gcagccacaa caaatacgcc ggcgagagtt tccccggcat ctacgatgcc 2100
ctgttcgaca tcgagagcaa ggtggacccc agcaaggcct ggggcgaagt gaagcggcag 2160
atttacgtgg ccgcattcac agtgcaggcc gctgccgaga cactgagcga ggtggcc 2217
<210> 9
<211> 739
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 9
Met Ala Ser Ala Arg Arg Pro Arg Trp Leu Cys Ala Gly Ala Leu Val
1 5 10 15
Leu Ala Gly Gly Phe Phe Leu Leu Gly Phe Leu Phe Gly Trp Phe Ile
20 25 30
Lys Ser Ser Asn Glu Ala Thr Asn Ile Thr Pro Lys His Asn Met Lys
35 40 45
Ala Phe Leu Asp Glu Leu Lys Ala Glu Asn Ile Lys Lys Phe Leu Tyr
50 55 60
Asn Phe Thr Gln Ile Pro His Leu Ala Gly Thr Glu Gln Asn Phe Gln
65 70 75 80
Leu Ala Lys Gln Ile Gln Ser Gln Trp Lys Glu Phe Gly Leu Asp Ser
85 90 95
Val Glu Leu Ala His Tyr Asp Val Leu Leu Ser Tyr Pro Asn Lys Thr
100 105 110
His Pro Asn Tyr Ile Ser Ile Ile Asn Glu Asp Gly Asn Glu Ile Phe
115 120 125
Asn Thr Ser Leu Phe Glu Pro Pro Pro Pro Gly Tyr Glu Asn Val Ser
130 135 140
Asp Ile Val Pro Pro Phe Ser Ala Phe Ser Pro Gln Gly Met Pro Glu
145 150 155 160
Gly Asp Leu Val Tyr Val Asn Tyr Ala Arg Thr Glu Asp Phe Phe Lys
165 170 175
Leu Glu Arg Asp Met Lys Ile Asn Cys Ser Gly Lys Ile Val Ile Ala
180 185 190
Arg Tyr Gly Lys Val Phe Arg Gly Asn Lys Val Lys Asn Ala Gln Leu
195 200 205
Ala Gly Ala Lys Gly Val Ile Leu Tyr Ser Asp Pro Ala Asp Tyr Phe
210 215 220
Ala Pro Gly Val Lys Ser Tyr Pro Asp Gly Trp Asn Leu Pro Gly Gly
225 230 235 240
Gly Val Gln Arg Gly Asn Ile Leu Asn Leu Asn Gly Ala Gly Asp Pro
245 250 255
Leu Thr Pro Gly Tyr Pro Ala Asn Glu Tyr Ala Tyr Arg Arg Gly Ile
260 265 270
Ala Glu Ala Val Gly Leu Pro Ser Ile Pro Val His Pro Ile Gly Tyr
275 280 285
Tyr Asp Ala Gln Lys Leu Leu Glu Lys Met Gly Gly Ser Ala Pro Pro
290 295 300
Asp Ser Ser Trp Arg Gly Ser Leu Lys Val Pro Tyr Asn Val Gly Pro
305 310 315 320
Gly Phe Thr Gly Asn Phe Ser Thr Gln Lys Val Lys Met His Ile His
325 330 335
Ser Thr Asn Glu Val Thr Arg Ile Tyr Asn Val Ile Gly Thr Leu Arg
340 345 350
Gly Ala Val Glu Pro Asp Arg Tyr Val Ile Leu Gly Gly His Arg Asp
355 360 365
Ser Trp Val Phe Gly Gly Ile Asp Pro Gln Ser Gly Ala Ala Val Val
370 375 380
His Glu Ile Val Arg Ser Phe Gly Thr Leu Lys Lys Glu Gly Trp Arg
385 390 395 400
Pro Arg Arg Thr Ile Leu Phe Ala Ser Trp Asp Ala Glu Glu Phe Gly
405 410 415
Leu Leu Gly Ser Thr Glu Trp Ala Glu Glu Asn Ser Arg Leu Leu Gln
420 425 430
Glu Arg Gly Val Ala Tyr Ile Asn Ala Asp Ser Ser Ile Glu Gly Asn
435 440 445
Tyr Thr Leu Arg Val Asp Cys Thr Pro Leu Met Tyr Ser Leu Val His
450 455 460
Asn Leu Thr Lys Glu Leu Lys Ser Pro Asp Glu Gly Phe Glu Gly Lys
465 470 475 480
Ser Leu Tyr Glu Ser Trp Thr Lys Lys Ser Pro Ser Pro Glu Phe Ser
485 490 495
Gly Met Pro Arg Ile Ser Lys Leu Gly Ser Gly Asn Asp Phe Glu Val
500 505 510
Phe Phe Gln Arg Leu Gly Ile Ala Ser Gly Arg Ala Arg Tyr Thr Lys
515 520 525
Asn Trp Glu Thr Asn Lys Phe Ser Gly Tyr Pro Leu Tyr His Ser Val
530 535 540
Tyr Glu Thr Tyr Glu Leu Val Glu Lys Phe Tyr Asp Pro Met Phe Lys
545 550 555 560
Tyr His Leu Thr Val Ala Gln Val Arg Gly Gly Met Val Phe Glu Leu
565 570 575
Ala Asn Ser Ile Val Leu Pro Phe Asp Cys Arg Asp Tyr Ala Val Val
580 585 590
Leu Arg Lys Tyr Ala Asp Lys Ile Tyr Ser Ile Ser Met Lys His Pro
595 600 605
Gln Glu Met Lys Thr Tyr Ser Val Ser Phe Asp Ser Leu Phe Ser Ala
610 615 620
Val Lys Asn Phe Thr Glu Ile Ala Ser Lys Phe Ser Glu Arg Leu Gln
625 630 635 640
Asp Phe Asp Lys Ser Asn Pro Ile Val Leu Arg Met Met Asn Asp Gln
645 650 655
Leu Met Phe Leu Glu Arg Ala Phe Ile Asp Pro Leu Gly Leu Pro Asp
660 665 670
Arg Pro Phe Tyr Arg His Val Ile Tyr Ala Pro Ser Ser His Asn Lys
675 680 685
Tyr Ala Gly Glu Ser Phe Pro Gly Ile Tyr Asp Ala Leu Phe Asp Ile
690 695 700
Glu Ser Lys Val Asp Pro Ser Lys Ala Trp Gly Glu Val Lys Arg Gln
705 710 715 720
Ile Tyr Val Ala Ala Phe Thr Val Gln Ala Ala Ala Glu Thr Leu Ser
725 730 735
Glu Val Ala
<210> 10
<211> 2217
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 10
atggctagcg cgcgccgccc gcgctggctg tgcgctgggg cgctggtgct ggcgggtggc 60
ttctttctcc tcggcttcct cttcgggtgg tttataaaat cctccaatga agctactaac 120
attactccaa agcataatat gaaagcattt ttggatgaat tgaaagctga gaacatcaag 180
aagttcttat ataattttac acagatacca catttagcag gaacagaaca aaactttcag 240
cttgcaaagc aaattcaatc ccagtggaaa gaatttggcc tggattctgt tgagctggca 300
cattatgatg tcctgttgtc ctacccaaat aagactcatc ccaactacat ctcaataatt 360
aatgaagatg gaaatgagat tttcaacaca tcattatttg aaccacctcc tccaggatat 420
gaaaatgttt cggatattgt accacctttc agtgctttct ctcctcaagg aatgccagag 480
ggcgatctag tgtatgttaa ctatgcacga actgaagact tctttaaatt ggaacgggac 540
atgaaaatca attgctctgg gaaaattgta attgccagat atgggaaagt tttcagagga 600
aataaggtta aaaatgccca gctggcaggg gccaaaggag tcattctcta ctccgaccct 660
gctgactact ttgctcctgg ggtgaagtcc tatccagatg gttggaatct tcctggaggt 720
ggtgtccagc gtggaaatat cctaaatctg aatggtgcag gagaccctct cacaccaggt 780
tacccagcaa atgaatatgc ttataggcgt ggaattgcag aggctgttgg tcttccaagt 840
attcctgttc atccaattgg atactatgat gcacagaagc tcctagaaaa aatgggtggc 900
tcagcaccac cagatagcag ctggagagga agtctcaaag tgccctacaa tgttggacct 960
ggctttactg gaaacttttc tacacaaaaa gtcaagatgc acatccactc taccaatgaa 1020
gtgacaagaa tttacaatgt gataggtact ctcagaggag cagtggaacc agacagatat 1080
gtcattctgg gaggtcaccg ggactcatgg gtgtttggtg gtattgaccc tcagagtgga 1140
gcagctgttg ttcatgaaat tgtgaggagc tttggaacac tgaaaaagga agggtggaga 1200
cctagaagaa caattttgtt tgcaagctgg gatgcagaag aatttggtct tcttggttct 1260
actgagtggg cagaggagaa ttcaagactc cttcaagagc gtggcgtggc ttatattaat 1320
gctgactcat ctatagaagg aaactacact ctgagagttg attgtacacc gctgatgtac 1380
agcttggtac acaacctaac aaaagagctg aaaagccctg atgaaggctt tgaaggcaaa 1440
tctctttatg aaagttggac taaaaaaagt ccttccccag agttcagtgg catgcccagg 1500
ataagcaaat tgggatctgg aaatgatttt gaggtgttct tccaacgact tggaattgct 1560
tcaggcagag cacggtatac taaaaattgg gaaacaaaca aattcagcgg ctatccactg 1620
tatcacagtg tctatgaaac atatgagttg gtggaaaagt tttatgatcc aatgtttaaa 1680
tatcacctca ctgtggccca ggttcgagga gggatggtgt ttgagctggc caattccata 1740
gtgctccctt ttgattgtcg agattatgct gtagttttaa gaaagtatgc tgacaaaatc 1800
tacagtattt ctatgaaaca tccacaggaa atgaagacat acagtgtatc atttgattca 1860
cttttttctg cagtaaagaa ttttacagaa attgcttcca agttcagtga gagactccag 1920
gactttgaca aaagcaaccc aatagtatta agaatgatga atgatcaact catgtttctg 1980
gaaagagcat ttattgatcc attagggtta ccagacaggc ctttttatag gcatgtcatc 2040
tatgctccaa gcagccacaa caagtatgca ggggagtcat tcccaggaat ttatgatgct 2100
ctgtttgata ttgaaagcaa agtggaccct tccaaggcct ggggagaagt gaagagacag 2160
atttatgttg cagccttcac agtgcaggca gctgcagaga ctttgagtga agtagcc 2217
<210> 11
<211> 710
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 11
Met Ala Ser Lys Ser Ser Asn Glu Ala Thr Asn Ile Thr Pro Lys His
1 5 10 15
Asn Met Lys Ala Phe Leu Asp Glu Leu Lys Ala Glu Asn Ile Lys Lys
20 25 30
Phe Leu Tyr Asn Phe Thr Gln Ile Pro His Leu Ala Gly Thr Glu Gln
35 40 45
Asn Phe Gln Leu Ala Lys Gln Ile Gln Ser Gln Trp Lys Glu Phe Gly
50 55 60
Leu Asp Ser Val Glu Leu Ala His Tyr Asp Val Leu Leu Ser Tyr Pro
65 70 75 80
Asn Lys Thr His Pro Asn Tyr Ile Ser Ile Ile Asn Glu Asp Gly Asn
85 90 95
Glu Ile Phe Asn Thr Ser Leu Phe Glu Pro Pro Pro Pro Gly Tyr Glu
100 105 110
Asn Val Ser Asp Ile Val Pro Pro Phe Ser Ala Phe Ser Pro Gln Gly
115 120 125
Met Pro Glu Gly Asp Leu Val Tyr Val Asn Tyr Ala Arg Thr Glu Asp
130 135 140
Phe Phe Lys Leu Glu Arg Asp Met Lys Ile Asn Cys Ser Gly Lys Ile
145 150 155 160
Val Ile Ala Arg Tyr Gly Lys Val Phe Arg Gly Asn Lys Val Lys Asn
165 170 175
Ala Gln Leu Ala Gly Ala Lys Gly Val Ile Leu Tyr Ser Asp Pro Ala
180 185 190
Asp Tyr Phe Ala Pro Gly Val Lys Ser Tyr Pro Asp Gly Trp Asn Leu
195 200 205
Pro Gly Gly Gly Val Gln Arg Gly Asn Ile Leu Asn Leu Asn Gly Ala
210 215 220
Gly Asp Pro Leu Thr Pro Gly Tyr Pro Ala Asn Glu Tyr Ala Tyr Arg
225 230 235 240
Arg Gly Ile Ala Glu Ala Val Gly Leu Pro Ser Ile Pro Val His Pro
245 250 255
Ile Gly Tyr Tyr Asp Ala Gln Lys Leu Leu Glu Lys Met Gly Gly Ser
260 265 270
Ala Pro Pro Asp Ser Ser Trp Arg Gly Ser Leu Lys Val Pro Tyr Asn
275 280 285
Val Gly Pro Gly Phe Thr Gly Asn Phe Ser Thr Gln Lys Val Lys Met
290 295 300
His Ile His Ser Thr Asn Glu Val Thr Arg Ile Tyr Asn Val Ile Gly
305 310 315 320
Thr Leu Arg Gly Ala Val Glu Pro Asp Arg Tyr Val Ile Leu Gly Gly
325 330 335
His Arg Asp Ser Trp Val Phe Gly Gly Ile Asp Pro Gln Ser Gly Ala
340 345 350
Ala Val Val His Glu Ile Val Arg Ser Phe Gly Thr Leu Lys Lys Glu
355 360 365
Gly Trp Arg Pro Arg Arg Thr Ile Leu Phe Ala Ser Trp Asp Ala Glu
370 375 380
Glu Phe Gly Leu Leu Gly Ser Thr Glu Trp Ala Glu Glu Asn Ser Arg
385 390 395 400
Leu Leu Gln Glu Arg Gly Val Ala Tyr Ile Asn Ala Asp Ser Ser Ile
405 410 415
Glu Gly Asn Tyr Thr Leu Arg Val Asp Cys Thr Pro Leu Met Tyr Ser
420 425 430
Leu Val His Asn Leu Thr Lys Glu Leu Lys Ser Pro Asp Glu Gly Phe
435 440 445
Glu Gly Lys Ser Leu Tyr Glu Ser Trp Thr Lys Lys Ser Pro Ser Pro
450 455 460
Glu Phe Ser Gly Met Pro Arg Ile Ser Lys Leu Gly Ser Gly Asn Asp
465 470 475 480
Phe Glu Val Phe Phe Gln Arg Leu Gly Ile Ala Ser Gly Arg Ala Arg
485 490 495
Tyr Thr Lys Asn Trp Glu Thr Asn Lys Phe Ser Gly Tyr Pro Leu Tyr
500 505 510
His Ser Val Tyr Glu Thr Tyr Glu Leu Val Glu Lys Phe Tyr Asp Pro
515 520 525
Met Phe Lys Tyr His Leu Thr Val Ala Gln Val Arg Gly Gly Met Val
530 535 540
Phe Glu Leu Ala Asn Ser Ile Val Leu Pro Phe Asp Cys Arg Asp Tyr
545 550 555 560
Ala Val Val Leu Arg Lys Tyr Ala Asp Lys Ile Tyr Ser Ile Ser Met
565 570 575
Lys His Pro Gln Glu Met Lys Thr Tyr Ser Val Ser Phe Asp Ser Leu
580 585 590
Phe Ser Ala Val Lys Asn Phe Thr Glu Ile Ala Ser Lys Phe Ser Glu
595 600 605
Arg Leu Gln Asp Phe Asp Lys Ser Asn Pro Ile Val Leu Arg Met Met
610 615 620
Asn Asp Gln Leu Met Phe Leu Glu Arg Ala Phe Ile Asp Pro Leu Gly
625 630 635 640
Leu Pro Asp Arg Pro Phe Tyr Arg His Val Ile Tyr Ala Pro Ser Ser
645 650 655
His Asn Lys Tyr Ala Gly Glu Ser Phe Pro Gly Ile Tyr Asp Ala Leu
660 665 670
Phe Asp Ile Glu Ser Lys Val Asp Pro Ser Lys Ala Trp Gly Glu Val
675 680 685
Lys Arg Gln Ile Tyr Val Ala Ala Phe Thr Val Gln Ala Ala Ala Glu
690 695 700
Thr Leu Ser Glu Val Ala
705 710
<210> 12
<211> 2130
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 12
atggctagca aatcctccaa tgaagctact aacattactc caaagcataa tatgaaagca 60
tttttggatg aattgaaagc tgagaacatc aagaagttct tatataattt tacacagata 120
ccacatttag caggaacaga acaaaacttt cagcttgcaa agcaaattca atcccagtgg 180
aaagaatttg gcctggattc tgttgagctg gcacattatg atgtcctgtt gtcctaccca 240
aataagactc atcccaacta catctcaata attaatgaag atggaaatga gattttcaac 300
acatcattat ttgaaccacc tcctccagga tatgaaaatg tttcggatat tgtaccacct 360
ttcagtgctt tctctcctca aggaatgcca gagggcgatc tagtgtatgt taactatgca 420
cgaactgaag acttctttaa attggaacgg gacatgaaaa tcaattgctc tgggaaaatt 480
gtaattgcca gatatgggaa agttttcaga ggaaataagg ttaaaaatgc ccagctggca 540
ggggccaaag gagtcattct ctactccgac cctgctgact actttgctcc tggggtgaag 600
tcctatccag atggttggaa tcttcctgga ggtggtgtcc agcgtggaaa tatcctaaat 660
ctgaatggtg caggagaccc tctcacacca ggttacccag caaatgaata tgcttatagg 720
cgtggaattg cagaggctgt tggtcttcca agtattcctg ttcatccaat tggatactat 780
gatgcacaga agctcctaga aaaaatgggt ggctcagcac caccagatag cagctggaga 840
ggaagtctca aagtgcccta caatgttgga cctggcttta ctggaaactt ttctacacaa 900
aaagtcaaga tgcacatcca ctctaccaat gaagtgacaa gaatttacaa tgtgataggt 960
actctcagag gagcagtgga accagacaga tatgtcattc tgggaggtca ccgggactca 1020
tgggtgtttg gtggtattga ccctcagagt ggagcagctg ttgttcatga aattgtgagg 1080
agctttggaa cactgaaaaa ggaagggtgg agacctagaa gaacaatttt gtttgcaagc 1140
tgggatgcag aagaatttgg tcttcttggt tctactgagt gggcagagga gaattcaaga 1200
ctccttcaag agcgtggcgt ggcttatatt aatgctgact catctataga aggaaactac 1260
actctgagag ttgattgtac accgctgatg tacagcttgg tacacaacct aacaaaagag 1320
ctgaaaagcc ctgatgaagg ctttgaaggc aaatctcttt atgaaagttg gactaaaaaa 1380
agtccttccc cagagttcag tggcatgccc aggataagca aattgggatc tggaaatgat 1440
tttgaggtgt tcttccaacg acttggaatt gcttcaggca gagcacggta tactaaaaat 1500
tgggaaacaa acaaattcag cggctatcca ctgtatcaca gtgtctatga aacatatgag 1560
ttggtggaaa agttttatga tccaatgttt aaatatcacc tcactgtggc ccaggttcga 1620
ggagggatgg tgtttgagct ggccaattcc atagtgctcc cttttgattg tcgagattat 1680
gctgtagttt taagaaagta tgctgacaaa atctacagta tttctatgaa acatccacag 1740
gaaatgaaga catacagtgt atcatttgat tcactttttt ctgcagtaaa gaattttaca 1800
gaaattgctt ccaagttcag tgagagactc caggactttg acaaaagcaa cccaatagta 1860
ttaagaatga tgaatgatca actcatgttt ctggaaagag catttattga tccattaggg 1920
ttaccagaca ggccttttta taggcatgtc atctatgctc caagcagcca caacaagtat 1980
gcaggggagt cattcccagg aatttatgat gctctgtttg atattgaaag caaagtggac 2040
ccttccaagg cctggggaga agtgaagaga cagatttatg ttgcagcctt cacagtgcag 2100
gcagctgcag agactttgag tgaagtagcc 2130
<210> 13
<211> 732
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 13
Met Ala Ser Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp
1 5 10 15
Val Pro Gly Ser Thr Gly Asp Ala Ala Lys Ser Ser Asn Glu Ala Thr
20 25 30
Asn Ile Thr Pro Lys His Asn Met Lys Ala Phe Leu Asp Glu Leu Lys
35 40 45
Ala Glu Asn Ile Lys Lys Phe Leu Tyr Asn Phe Thr Gln Ile Pro His
50 55 60
Leu Ala Gly Thr Glu Gln Asn Phe Gln Leu Ala Lys Gln Ile Gln Ser
65 70 75 80
Gln Trp Lys Glu Phe Gly Leu Asp Ser Val Glu Leu Ala His Tyr Asp
85 90 95
Val Leu Leu Ser Tyr Pro Asn Lys Thr His Pro Asn Tyr Ile Ser Ile
100 105 110
Ile Asn Glu Asp Gly Asn Glu Ile Phe Asn Thr Ser Leu Phe Glu Pro
115 120 125
Pro Pro Pro Gly Tyr Glu Asn Val Ser Asp Ile Val Pro Pro Phe Ser
130 135 140
Ala Phe Ser Pro Gln Gly Met Pro Glu Gly Asp Leu Val Tyr Val Asn
145 150 155 160
Tyr Ala Arg Thr Glu Asp Phe Phe Lys Leu Glu Arg Asp Met Lys Ile
165 170 175
Asn Cys Ser Gly Lys Ile Val Ile Ala Arg Tyr Gly Lys Val Phe Arg
180 185 190
Gly Asn Lys Val Lys Asn Ala Gln Leu Ala Gly Ala Lys Gly Val Ile
195 200 205
Leu Tyr Ser Asp Pro Ala Asp Tyr Phe Ala Pro Gly Val Lys Ser Tyr
210 215 220
Pro Asp Gly Trp Asn Leu Pro Gly Gly Gly Val Gln Arg Gly Asn Ile
225 230 235 240
Leu Asn Leu Asn Gly Ala Gly Asp Pro Leu Thr Pro Gly Tyr Pro Ala
245 250 255
Asn Glu Tyr Ala Tyr Arg Arg Gly Ile Ala Glu Ala Val Gly Leu Pro
260 265 270
Ser Ile Pro Val His Pro Ile Gly Tyr Tyr Asp Ala Gln Lys Leu Leu
275 280 285
Glu Lys Met Gly Gly Ser Ala Pro Pro Asp Ser Ser Trp Arg Gly Ser
290 295 300
Leu Lys Val Pro Tyr Asn Val Gly Pro Gly Phe Thr Gly Asn Phe Ser
305 310 315 320
Thr Gln Lys Val Lys Met His Ile His Ser Thr Asn Glu Val Thr Arg
325 330 335
Ile Tyr Asn Val Ile Gly Thr Leu Arg Gly Ala Val Glu Pro Asp Arg
340 345 350
Tyr Val Ile Leu Gly Gly His Arg Asp Ser Trp Val Phe Gly Gly Ile
355 360 365
Asp Pro Gln Ser Gly Ala Ala Val Val His Glu Ile Val Arg Ser Phe
370 375 380
Gly Thr Leu Lys Lys Glu Gly Trp Arg Pro Arg Arg Thr Ile Leu Phe
385 390 395 400
Ala Ser Trp Asp Ala Glu Glu Phe Gly Leu Leu Gly Ser Thr Glu Trp
405 410 415
Ala Glu Glu Asn Ser Arg Leu Leu Gln Glu Arg Gly Val Ala Tyr Ile
420 425 430
Asn Ala Asp Ser Ser Ile Glu Gly Asn Tyr Thr Leu Arg Val Asp Cys
435 440 445
Thr Pro Leu Met Tyr Ser Leu Val His Asn Leu Thr Lys Glu Leu Lys
450 455 460
Ser Pro Asp Glu Gly Phe Glu Gly Lys Ser Leu Tyr Glu Ser Trp Thr
465 470 475 480
Lys Lys Ser Pro Ser Pro Glu Phe Ser Gly Met Pro Arg Ile Ser Lys
485 490 495
Leu Gly Ser Gly Asn Asp Phe Glu Val Phe Phe Gln Arg Leu Gly Ile
500 505 510
Ala Ser Gly Arg Ala Arg Tyr Thr Lys Asn Trp Glu Thr Asn Lys Phe
515 520 525
Ser Gly Tyr Pro Leu Tyr His Ser Val Tyr Glu Thr Tyr Glu Leu Val
530 535 540
Glu Lys Phe Tyr Asp Pro Met Phe Lys Tyr His Leu Thr Val Ala Gln
545 550 555 560
Val Arg Gly Gly Met Val Phe Glu Leu Ala Asn Ser Ile Val Leu Pro
565 570 575
Phe Asp Cys Arg Asp Tyr Ala Val Val Leu Arg Lys Tyr Ala Asp Lys
580 585 590
Ile Tyr Ser Ile Ser Met Lys His Pro Gln Glu Met Lys Thr Tyr Ser
595 600 605
Val Ser Phe Asp Ser Leu Phe Ser Ala Val Lys Asn Phe Thr Glu Ile
610 615 620
Ala Ser Lys Phe Ser Glu Arg Leu Gln Asp Phe Asp Lys Ser Asn Pro
625 630 635 640
Ile Val Leu Arg Met Met Asn Asp Gln Leu Met Phe Leu Glu Arg Ala
645 650 655
Phe Ile Asp Pro Leu Gly Leu Pro Asp Arg Pro Phe Tyr Arg His Val
660 665 670
Ile Tyr Ala Pro Ser Ser His Asn Lys Tyr Ala Gly Glu Ser Phe Pro
675 680 685
Gly Ile Tyr Asp Ala Leu Phe Asp Ile Glu Ser Lys Val Asp Pro Ser
690 695 700
Lys Ala Trp Gly Glu Val Lys Arg Gln Ile Tyr Val Ala Ala Phe Thr
705 710 715 720
Val Gln Ala Ala Ala Glu Thr Leu Ser Glu Val Ala
725 730
<210> 14
<211> 2196
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 14
atggctagcg aaaccgacac tttgttgttg tgggtgcttt tgctttgggt acccggatct 60
actggtgatg ctgctaaatc ctccaatgaa gctactaaca ttactccaaa gcataatatg 120
aaagcatttt tggatgaatt gaaagctgag aacatcaaga agttcttata taattttaca 180
cagataccac atttagcagg aacagaacaa aactttcagc ttgcaaagca aattcaatcc 240
cagtggaaag aatttggcct ggattctgtt gagctagcac attatgatgt cctgttgtcc 300
tacccaaata agactcatcc caactacatc tcaataatta atgaagatgg aaatgagatt 360
ttcaacacat cattatttga accacctcct ccaggatatg aaaatgtttc ggatattgta 420
ccacctttca gtgctttctc tcctcaagga atgccagagg gcgatctagt gtatgttaac 480
tatgcacgaa ctgaagactt ctttaaattg gaacgggaca tgaaaatcaa ttgctctggg 540
aaaattgtaa ttgccagata tgggaaagtt ttcagaggaa ataaggttaa aaatgcccag 600
ctggcagggg ccaaaggagt cattctctac tccgaccctg ctgactactt tgctcctggg 660
gtgaagtcct atccagatgg ttggaatctt cctggaggtg gtgtccagcg tggaaatatc 720
ctaaatctga atggtgcagg agaccctctc acaccaggtt acccagcaaa tgaatatgct 780
tataggcgtg gaattgcaga ggctgttggt cttccaagta ttcctgttca tccaattgga 840
tactatgatg cacagaagct cctagaaaaa atgggtggct cagcaccacc agatagcagc 900
tggagaggaa gtctcaaagt gccctacaat gttggacctg gctttactgg aaacttttct 960
acacaaaaag tcaagatgca catccactct accaatgaag tgacaagaat ttacaatgtg 1020
ataggtactc tcagaggagc agtggaacca gacagatatg tcattctggg aggtcaccgg 1080
gactcatggg tgtttggtgg tattgaccct cagagtggag cagctgttgt tcatgaaatt 1140
gtgaggagct ttggaacact gaaaaaggaa gggtggagac ctagaagaac aattttgttt 1200
gcaagctggg atgcagaaga atttggtctt cttggttcta ctgagtgggc agaggagaat 1260
tcaagactcc ttcaagagcg tggcgtggct tatattaatg ctgactcatc tatagaagga 1320
aactacactc tgagagttga ttgtacaccg ctgatgtaca gcttggtaca caacctaaca 1380
aaagagctga aaagccctga tgaaggcttt gaaggcaaat ctctttatga aagttggact 1440
aaaaaaagtc cttccccaga gttcagtggc atgcccagga taagcaaatt gggatctgga 1500
aatgattttg aggtgttctt ccaacgactt ggaattgctt caggcagagc acggtatact 1560
aaaaattggg aaacaaacaa attcagcggc tatccactgt atcacagtgt ctatgaaaca 1620
tatgagttgg tggaaaagtt ttatgatcca atgtttaaat atcacctcac tgtggcccag 1680
gttcgaggag ggatggtgtt tgagctagcc aattccatag tgctcccttt tgattgtcga 1740
gattatgctg tagttttaag aaagtatgct gacaaaatct acagtatttc tatgaaacat 1800
ccacaggaaa tgaagacata cagtgtatca tttgattcac ttttttctgc agtaaagaat 1860
tttacagaaa ttgcttccaa gttcagtgag agactccagg actttgacaa aagcaaccca 1920
atagtattaa gaatgatgaa tgatcaactc atgtttctgg aaagagcatt tattgatcca 1980
ttagggttac cagacaggcc tttttatagg catgtcatct atgctccaag cagccacaac 2040
aagtatgcag gggagtcatt cccaggaatt tatgatgctc tgtttgatat tgaaagcaaa 2100
gtggaccctt ccaaggcctg gggagaagtg aagagacaga tttatgttgc agccttcaca 2160
gtgcaggcag ctgcagagac tttgagtgaa gtagcc 2196
<210> 15
<211> 263
<212> PRT
<213> Homo sapiens
<400> 15
Met Ala Ser Trp Val Pro Val Val Phe Leu Thr Leu Ser Val Thr Trp
1 5 10 15
Ile Gly Ala Ala Pro Leu Ile Leu Ser Arg Ile Val Gly Gly Trp Glu
20 25 30
Cys Glu Lys His Ser Gln Pro Trp Gln Val Leu Val Ala Ser Arg Gly
35 40 45
Arg Ala Val Cys Gly Gly Val Leu Val His Pro Gln Trp Val Leu Thr
50 55 60
Ala Ala His Cys Ile Arg Asn Lys Ser Val Ile Leu Leu Gly Arg His
65 70 75 80
Ser Leu Phe His Pro Glu Asp Thr Gly Gln Val Phe Gln Val Ser His
85 90 95
Ser Phe Pro His Pro Leu Tyr Asp Met Ser Leu Leu Lys Asn Arg Phe
100 105 110
Leu Arg Pro Gly Asp Asp Ser Ser His Asp Leu Met Leu Leu Arg Leu
115 120 125
Ser Glu Pro Ala Glu Leu Thr Asp Ala Val Lys Val Met Asp Leu Pro
130 135 140
Thr Gln Glu Pro Ala Leu Gly Thr Thr Cys Tyr Ala Ser Gly Trp Gly
145 150 155 160
Ser Ile Glu Pro Glu Glu Phe Leu Thr Pro Lys Lys Leu Gln Cys Val
165 170 175
Asp Leu His Val Ile Ser Asn Asp Val Cys Ala Gln Val His Pro Gln
180 185 190
Lys Val Thr Lys Phe Met Leu Cys Ala Gly Arg Trp Thr Gly Gly Lys
195 200 205
Ser Thr Cys Ser Gly Asp Ser Gly Gly Pro Leu Val Cys Asn Gly Val
210 215 220
Leu Gln Gly Ile Thr Ser Trp Gly Ser Glu Pro Cys Ala Leu Pro Glu
225 230 235 240
Arg Pro Ser Leu Tyr Thr Lys Val Val His Tyr Arg Lys Trp Ile Lys
245 250 255
Asp Thr Ile Val Ala Asn Pro
260
<210> 16
<211> 789
<212> DNA
<213> Homo sapiens
<400> 16
atggctagct gggtcccggt tgtcttcctc accctgtccg tgacgtggat tggcgctgcg 60
cccctcatcc tgtctcggat tgtgggaggc tgggagtgcg agaagcattc ccaaccctgg 120
caggtgcttg tggcctctcg tggcagggca gtctgcggcg gtgttctggt gcacccccag 180
tgggtcctca cagctgccca ctgcatcagg aacaaaagcg tgatcttgct gggtcggcac 240
agcttgtttc atcctgaaga cacaggccag gtatttcagg tcagccacag cttcccacac 300
ccgctctacg atatgagcct cctgaagaat cgattcctca ggccaggtga tgactccagc 360
cacgacctca tgctgctccg cctgtcagag cctgccgagc tcacggatgc tgtgaaggtc 420
atggacctgc ccacccagga gccagcactg gggaccacct gctacgcctc aggctggggc 480
agcattgaac cagaggagtt cttgacccca aagaaacttc agtgtgtgga cctccatgtt 540
atttccaatg acgtgtgtgc gcaagttcac cctcagaagg tgaccaagtt catgctgtgt 600
gctggacgct ggacaggggg caaaagcacc tgctcgggtg attctggggg cccacttgtc 660
tgtaatggtg tgcttcaagg tatcacgtca tggggcagtg aaccatgtgc cctgcccgaa 720
aggccttccc tgtacaccaa ggtggtgcat taccggaagt ggatcaagga caccatcgtg 780
gccaacccc 789
<210> 17
<211> 240
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 17
Met Ala Ser Ile Val Gly Gly Trp Glu Cys Glu Lys His Ser Gln Pro
1 5 10 15
Trp Gln Val Leu Val Ala Ser Arg Gly Arg Ala Val Cys Gly Gly Val
20 25 30
Leu Val His Pro Gln Trp Val Leu Thr Ala Ala His Cys Ile Arg Asn
35 40 45
Lys Ser Val Ile Leu Leu Gly Arg His Ser Leu Phe His Pro Glu Asp
50 55 60
Thr Gly Gln Val Phe Gln Val Ser His Ser Phe Pro His Pro Leu Tyr
65 70 75 80
Asp Met Ser Leu Leu Lys Asn Arg Phe Leu Arg Pro Gly Asp Asp Ser
85 90 95
Ser His Asp Leu Met Leu Leu Arg Leu Ser Glu Pro Ala Glu Leu Thr
100 105 110
Asp Ala Val Lys Val Met Asp Leu Pro Thr Gln Glu Pro Ala Leu Gly
115 120 125
Thr Thr Cys Tyr Ala Ser Gly Trp Gly Ser Ile Glu Pro Glu Glu Phe
130 135 140
Leu Thr Pro Lys Lys Leu Gln Cys Val Asp Leu His Val Ile Ser Asn
145 150 155 160
Asp Val Cys Ala Gln Val His Pro Gln Lys Val Thr Lys Phe Met Leu
165 170 175
Cys Ala Gly Arg Trp Thr Gly Gly Lys Ser Thr Cys Ser Gly Asp Ser
180 185 190
Gly Gly Pro Leu Val Cys Asn Gly Val Leu Gln Gly Ile Thr Ser Trp
195 200 205
Gly Ser Glu Pro Cys Ala Leu Pro Glu Arg Pro Ser Leu Tyr Thr Lys
210 215 220
Val Val His Tyr Arg Lys Trp Ile Lys Asp Thr Ile Val Ala Asn Pro
225 230 235 240
<210> 18
<211> 720
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 18
atggctagca ttgtgggagg ctgggagtgc gagaagcatt cccaaccctg gcaggtgctt 60
gtggcctctc gtggcagggc agtctgcggc ggtgttctgg tgcaccccca gtgggtcctc 120
acagctgccc actgcatcag gaacaaaagc gtgatcttgc tgggtcggca cagcttgttt 180
catcctgaag acacaggcca ggtatttcag gtcagccaca gcttcccaca cccgctctac 240
gatatgagcc tcctgaagaa tcgattcctc aggccaggtg atgactccag ccacgacctc 300
atgctgctcc gcctgtcaga gcctgccgag ctcacggatg ctgtgaaggt catggacctg 360
cccacccagg agccagcact ggggaccacc tgctacgcct caggctgggg cagcattgaa 420
ccagaggagt tcttgacccc aaagaaactt cagtgtgtgg acctccatgt tatttccaat 480
gacgtgtgtg cgcaagttca ccctcagaag gtgaccaagt tcatgctgtg tgctggacgc 540
tggacagggg gcaaaagcac ctgctcgggt gattctgggg gcccacttgt ctgtaatggt 600
gtgcttcaag gtatcacgtc atggggcagt gaaccatgtg ccctgcccga aaggccttcc 660
ctgtacacca aggtggtgca ttaccggaag tggatcaagg acaccatcgt ggccaacccc 720
<210> 19
<211> 281
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 19
Met Ala Ser Ala Arg Arg Pro Arg Trp Leu Cys Ala Gly Ala Leu Val
1 5 10 15
Leu Ala Gly Gly Phe Phe Leu Leu Gly Phe Leu Phe Gly Trp Phe Ile
20 25 30
Lys Ser Ser Asn Glu Ala Thr Asn Ile Thr Pro Gly Ile Val Gly Gly
35 40 45
Trp Glu Cys Glu Lys His Ser Gln Pro Trp Gln Val Leu Val Ala Ser
50 55 60
Arg Gly Arg Ala Val Cys Gly Gly Val Leu Val His Pro Gln Trp Val
65 70 75 80
Leu Thr Ala Ala His Cys Ile Arg Asn Lys Ser Val Ile Leu Leu Gly
85 90 95
Arg His Ser Leu Phe His Pro Glu Asp Thr Gly Gln Val Phe Gln Val
100 105 110
Ser His Ser Phe Pro His Pro Leu Tyr Asp Met Ser Leu Leu Lys Asn
115 120 125
Arg Phe Leu Arg Pro Gly Asp Asp Ser Ser His Asp Leu Met Leu Leu
130 135 140
Arg Leu Ser Glu Pro Ala Glu Leu Thr Asp Ala Val Lys Val Met Asp
145 150 155 160
Leu Pro Thr Gln Glu Pro Ala Leu Gly Thr Thr Cys Tyr Ala Ser Gly
165 170 175
Trp Gly Ser Ile Glu Pro Glu Glu Phe Leu Thr Pro Lys Lys Leu Gln
180 185 190
Cys Val Asp Leu His Val Ile Ser Asn Asp Val Cys Ala Gln Val His
195 200 205
Pro Gln Lys Val Thr Lys Phe Met Leu Cys Ala Gly Arg Trp Thr Gly
210 215 220
Gly Lys Ser Thr Cys Ser Gly Asp Ser Gly Gly Pro Leu Val Cys Asn
225 230 235 240
Gly Val Leu Gln Gly Ile Thr Ser Trp Gly Ser Glu Pro Cys Ala Leu
245 250 255
Pro Glu Arg Pro Ser Leu Tyr Thr Lys Val Val His Tyr Arg Lys Trp
260 265 270
Ile Lys Asp Thr Ile Val Ala Asn Pro
275 280
<210> 20
<211> 846
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 20
atggctagcg cgcgccgccc gcgctggctg tgcgctgggg cgctggtgct ggcgggtggc 60
ttctttctcc tcggcttcct cttcgggtgg tttataaaat cctccaatga agctactaac 120
attactccag gaattgtggg aggctgggag tgcgagaagc attcccaacc ctggcaggtg 180
cttgtggcct ctcgtggcag ggcagtctgc ggcggtgttc tggtgcaccc ccagtgggtc 240
ctcacagctg cccactgcat caggaacaaa agcgtgatct tgctgggtcg gcacagcttg 300
tttcatcctg aagacacagg ccaggtattt caggtcagcc acagcttccc acacccgctc 360
tacgatatga gcctcctgaa gaatcgattc ctcaggccag gtgatgactc cagccacgac 420
ctcatgctgc tccgcctgtc agagcctgcc gagctcacgg atgctgtgaa ggtcatggac 480
ctgcccaccc aggagccagc actggggacc acctgctacg cctcaggctg gggcagcatt 540
gaaccagagg agttcttgac cccaaagaaa cttcagtgtg tggacctcca tgttatttcc 600
aatgacgtgt gtgcgcaagt tcaccctcag aaggtgacca agttcatgct gtgtgctgga 660
cgctggacag ggggcaaaag cacctgctcg ggtgattctg ggggcccact tgtctgtaat 720
ggtgtgcttc aaggtatcac gtcatggggc agtgaaccat gtgccctgcc cgaaaggcct 780
tccctgtaca ccaaggtggt gcattaccgg aagtggatca aggacaccat cgtggccaac 840
ccctga 846
<210> 21
<211> 125
<212> PRT
<213> Homo sapiens
<400> 21
Met Ala Ser Lys Ala Val Leu Leu Ala Leu Leu Met Ala Gly Leu Ala
1 5 10 15
Leu Gln Pro Gly Thr Ala Leu Leu Cys Tyr Ser Cys Lys Ala Gln Val
20 25 30
Ser Asn Glu Asp Cys Leu Gln Val Glu Asn Cys Thr Gln Leu Gly Glu
35 40 45
Gln Cys Trp Thr Ala Arg Ile Arg Ala Val Gly Leu Leu Thr Val Ile
50 55 60
Ser Lys Gly Cys Ser Leu Asn Cys Val Asp Asp Ser Gln Asp Tyr Tyr
65 70 75 80
Val Gly Lys Lys Asn Ile Thr Cys Cys Asp Thr Asp Leu Cys Asn Ala
85 90 95
Ser Gly Ala His Ala Leu Gln Pro Ala Ala Ala Ile Leu Ala Leu Leu
100 105 110
Pro Ala Leu Gly Leu Leu Leu Trp Gly Pro Gly Gln Leu
115 120 125
<210> 22
<211> 375
<212> DNA
<213> Homo sapiens
<400> 22
atggctagca aggctgtgct gcttgccctg ttgatggcag gcttggccct gcagccaggc 60
actgccctgc tgtgctactc ctgcaaagcc caggtgagca acgaggactg cctgcaggtg 120
gagaactgca cccagctggg ggagcagtgc tggaccgcgc gcatccgcgc agttggcctc 180
ctgaccgtca tcagcaaagg ctgcagcttg aactgcgtgg atgactcaca ggactactac 240
gtgggcaaga agaacatcac gtgctgtgac accgacttgt gcaacgccag cggggcccat 300
gccctgcagc cggctgccgc catccttgcg ctgctccctg cactcggcct gctgctctgg 360
ggacccggcc agcta 375
<210> 23
<211> 5964
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 23
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcgcgcgcc gcccgcgctg gctgtgcgct ggggcgctgg tgctggcggg 2040
tggcttcttt ctcctcggct tcctcttcgg gtggtttata aaatcctcca atgaagctac 2100
taacattact ccaaagcata atatgaaagc atttttggat gaattgaaag ctgagaacat 2160
caagaagttc ttatataatt ttacacagat accacattta gcaggaacag aacaaaactt 2220
tcagcttgca aagcaaattc aatcccagtg gaaagaattt ggcctggatt ctgttgagct 2280
ggcacattat gatgtcctgt tgtcctaccc aaataagact catcccaact acatctcaat 2340
aattaatgaa gatggaaatg agattttcaa cacatcatta tttgaaccac ctcctccagg 2400
atatgaaaat gtttcggata ttgtaccacc tttcagtgct ttctctcctc aaggaatgcc 2460
agagggcgat ctagtgtatg ttaactatgc acgaactgaa gacttcttta aattggaacg 2520
ggacatgaaa atcaattgct ctgggaaaat tgtaattgcc agatatggga aagttttcag 2580
aggaaataag gttaaaaatg cccagctggc aggggccaaa ggagtcattc tctactccga 2640
ccctgctgac tactttgctc ctggggtgaa gtcctatcca gatggttgga atcttcctgg 2700
aggtggtgtc cagcgtggaa atatcctaaa tctgaatggt gcaggagacc ctctcacacc 2760
aggttaccca gcaaatgaat atgcttatag gcgtggaatt gcagaggctg ttggtcttcc 2820
aagtattcct gttcatccaa ttggatacta tgatgcacag aagctcctag aaaaaatggg 2880
tggctcagca ccaccagata gcagctggag aggaagtctc aaagtgccct acaatgttgg 2940
acctggcttt actggaaact tttctacaca aaaagtcaag atgcacatcc actctaccaa 3000
tgaagtgaca agaatttaca atgtgatagg tactctcaga ggagcagtgg aaccagacag 3060
atatgtcatt ctgggaggtc accgggactc atgggtgttt ggtggtattg accctcagag 3120
tggagcagct gttgttcatg aaattgtgag gagctttgga acactgaaaa aggaagggtg 3180
gagacctaga agaacaattt tgtttgcaag ctgggatgca gaagaatttg gtcttcttgg 3240
ttctactgag tgggcagagg agaattcaag actccttcaa gagcgtggcg tggcttatat 3300
taatgctgac tcatctatag aaggaaacta cactctgaga gttgattgta caccgctgat 3360
gtacagcttg gtacacaacc taacaaaaga gctgaaaagc cctgatgaag gctttgaagg 3420
caaatctctt tatgaaagtt ggactaaaaa aagtccttcc ccagagttca gtggcatgcc 3480
caggataagc aaattgggat ctggaaatga ttttgaggtg ttcttccaac gacttggaat 3540
tgcttcaggc agagcacggt atactaaaaa ttgggaaaca aacaaattca gcggctatcc 3600
actgtatcac agtgtctatg aaacatatga gttggtggaa aagttttatg atccaatgtt 3660
taaatatcac ctcactgtgg cccaggttcg aggagggatg gtgtttgagc tggccaattc 3720
catagtgctc ccttttgatt gtcgagatta tgctgtagtt ttaagaaagt atgctgacaa 3780
aatctacagt atttctatga aacatccaca ggaaatgaag acatacagtg tatcatttga 3840
ttcacttttt tctgcagtaa agaattttac agaaattgct tccaagttca gtgagagact 3900
ccaggacttt gacaaaagca acccaatagt attaagaatg atgaatgatc aactcatgtt 3960
tctggaaaga gcatttattg atccattagg gttaccagac aggccttttt ataggcatgt 4020
catctatgct ccaagcagcc acaacaagta tgcaggggag tcattcccag gaatttatga 4080
tgctctgttt gatattgaaa gcaaagtgga cccttccaag gcctggggag aagtgaagag 4140
acagatttat gttgcagcct tcacagtgca ggcagctgca gagactttga gtgaagtagc 4200
ctaaagatct gggccctaac aaaacaaaaa gatggggtta ttccctaaac ttcatgggtt 4260
acgtaattgg aagttggggg acattgccac aagatcatat tgtacaaaag atcaaacact 4320
gttttagaaa acttcctgta aacaggccta ttgattggaa agtatgtcaa aggattgtgg 4380
gtcttttggg ctttgctgct ccatttacac aatgtggata tcctgcctta atgcctttgt 4440
atgcatgtat acaagctaaa caggctttca ctttctcgcc aacttacaag gcctttctaa 4500
gtaaacagta catgaacctt taccccgttg ctcggcaacg gcctggtctg tgccaagtgt 4560
ttgctgacgc aacccccact ggctggggct tggccatagg ccatcagcgc atgcgtggaa 4620
cctttgtggc tcctctgccg atccatactg cggaactcct agccgcttgt tttgctcgca 4680
gccggtctgg agcaaagctc ataggaactg acaattctgt cgtcctctcg cggaaatata 4740
catcgtttcg atctacgtat gatctttttc cctctgccaa aaattatggg gacatcatga 4800
agccccttga gcatctgact tctggctaat aaaggaaatt tattttcatt gcaatagtgt 4860
gttggaattt tttgtgtctc tcactcggaa ggaattctgc attaatgaat cggccaacgc 4920
gcggggagag gcggtttgcg tattgggcgc tcttccgctt cctcgctcac tgactcgctg 4980
cgctcggtcg ttcggctgcg gcgagcggta tcagctcact caaaggcggt aatacggtta 5040
tccacagaat caggggataa cgcaggaaag aacatgtgag caaaaggcca gcaaaaggcc 5100
aggaaccgta aaaaggccgc gttgctggcg tttttccata ggctccgccc ccctgacgag 5160
catcacaaaa atcgacgctc aagtcagagg tggcgaaacc cgacaggact ataaagatac 5220
caggcgtttc cccctggaag ctccctcgtg cgctctcctg ttccgaccct gccgcttacc 5280
ggatacctgt ccgcctttct cccttcggga agcgtggcgc tttctcatag ctcacgctgt 5340
aggtatctca gttcggtgta ggtcgttcgc tccaagctgg gctgtgtgca cgaacccccc 5400
gttcagcccg accgctgcgc cttatccggt aactatcgtc ttgagtccaa cccggtaaga 5460
cacgacttat cgccactggc agcagccact ggtaacagga ttagcagagc gaggtatgta 5520
ggcggtgcta cagagttctt gaagtggtgg cctaactacg gctacactag aagaacagta 5580
tttggtatct gcgctctgct gaagccagtt accttcggaa aaagagttgg tagctcttga 5640
tccggcaaac aaaccaccgc tggtagcggt ggtttttttg tttgcaagca gcagattacg 5700
cgcagaaaaa aaggatctca agaagatcct ttgatctttt ctacggggtc tgacgctcag 5760
tggaacgaaa actcacgtta agggattttg gtcatgagat tatcaaaaag gatcttcacc 5820
tagatccttt taaattaaaa atgaagtttt aaatcaatct aaagtatata tgagtaaact 5880
tggtctgaca gttaccaatg cttaatcagt gaggcaccta tctcagcgat ctgtctattt 5940
cgttcatcca tagttgcctg actc 5964
<210> 24
<211> 4122
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 24
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcaaggctg tgctgcttgc cctgttgatg gcaggcttgg ccctgcagcc 2040
aggcactgcc ctgctgtgct actcctgcaa agcccaggtg agcaacgagg actgcctgca 2100
ggtggagaac tgcacccagc tgggggagca gtgctggacc gcgcgcatcc gcgcagttgg 2160
cctcctgacc gtcatcagca aaggctgcag cttgaactgc gtggatgact cacaggacta 2220
ctacgtgggc aagaagaaca tcacgtgctg tgacaccgac ttgtgcaacg ccagcggggc 2280
ccatgccctg cagccggctg ccgccatcct tgcgctgctc cctgcactcg gcctgctgct 2340
ctggggaccc ggccagctat agagatctgg gccctaacaa aacaaaaaga tggggttatt 2400
ccctaaactt catgggttac gtaattggaa gttgggggac attgccacaa gatcatattg 2460
tacaaaagat caaacactgt tttagaaaac ttcctgtaaa caggcctatt gattggaaag 2520
tatgtcaaag gattgtgggt cttttgggct ttgctgctcc atttacacaa tgtggatatc 2580
ctgccttaat gcctttgtat gcatgtatac aagctaaaca ggctttcact ttctcgccaa 2640
cttacaaggc ctttctaagt aaacagtaca tgaaccttta ccccgttgct cggcaacggc 2700
ctggtctgtg ccaagtgttt gctgacgcaa cccccactgg ctggggcttg gccataggcc 2760
atcagcgcat gcgtggaacc tttgtggctc ctctgccgat ccatactgcg gaactcctag 2820
ccgcttgttt tgctcgcagc cggtctggag caaagctcat aggaactgac aattctgtcg 2880
tcctctcgcg gaaatataca tcgtttcgat ctacgtatga tctttttccc tctgccaaaa 2940
attatgggga catcatgaag ccccttgagc atctgacttc tggctaataa aggaaattta 3000
ttttcattgc aatagtgtgt tggaattttt tgtgtctctc actcggaagg aattctgcat 3060
taatgaatcg gccaacgcgc ggggagaggc ggtttgcgta ttgggcgctc ttccgcttcc 3120
tcgctcactg actcgctgcg ctcggtcgtt cggctgcggc gagcggtatc agctcactca 3180
aaggcggtaa tacggttatc cacagaatca ggggataacg caggaaagaa catgtgagca 3240
aaaggccagc aaaaggccag gaaccgtaaa aaggccgcgt tgctggcgtt tttccatagg 3300
ctccgccccc ctgacgagca tcacaaaaat cgacgctcaa gtcagaggtg gcgaaacccg 3360
acaggactat aaagatacca ggcgtttccc cctggaagct ccctcgtgcg ctctcctgtt 3420
ccgaccctgc cgcttaccgg atacctgtcc gcctttctcc cttcgggaag cgtggcgctt 3480
tctcatagct cacgctgtag gtatctcagt tcggtgtagg tcgttcgctc caagctgggc 3540
tgtgtgcacg aaccccccgt tcagcccgac cgctgcgcct tatccggtaa ctatcgtctt 3600
gagtccaacc cggtaagaca cgacttatcg ccactggcag cagccactgg taacaggatt 3660
agcagagcga ggtatgtagg cggtgctaca gagttcttga agtggtggcc taactacggc 3720
tacactagaa gaacagtatt tggtatctgc gctctgctga agccagttac cttcggaaaa 3780
agagttggta gctcttgatc cggcaaacaa accaccgctg gtagcggtgg tttttttgtt 3840
tgcaagcagc agattacgcg cagaaaaaaa ggatctcaag aagatccttt gatcttttct 3900
acggggtctg acgctcagtg gaacgaaaac tcacgttaag ggattttggt catgagatta 3960
tcaaaaagga tcttcaccta gatcctttta aattaaaaat gaagttttaa atcaatctaa 4020
agtatatatg agtaaacttg gtctgacagt taccaatgct taatcagtga ggcacctatc 4080
tcagcgatct gtctatttcg ttcatccata gttgcctgac tc 4122
<210> 25
<211> 4467
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 25
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcattgtgg gaggctggga gtgcgagaag cattcccaac cctggcaggt 2040
gcttgtggcc tctcgtggca gggcagtctg cggcggtgtt ctggtgcacc cccagtgggt 2100
cctcacagct gcccactgca tcaggaacaa aagcgtgatc ttgctgggtc ggcacagctt 2160
gtttcatcct gaagacacag gccaggtatt tcaggtcagc cacagcttcc cacacccgct 2220
ctacgatatg agcctcctga agaatcgatt cctcaggcca ggtgatgact ccagccacga 2280
cctcatgctg ctccgcctgt cagagcctgc cgagctcacg gatgctgtga aggtcatgga 2340
cctgcccacc caggagccag cactggggac cacctgctac gcctcaggct ggggcagcat 2400
tgaaccagag gagttcttga ccccaaagaa acttcagtgt gtggacctcc atgttatttc 2460
caatgacgtg tgtgcgcaag ttcaccctca gaaggtgacc aagttcatgc tgtgtgctgg 2520
acgctggaca gggggcaaaa gcacctgctc gggtgattct gggggcccac ttgtctgtaa 2580
tggtgtgctt caaggtatca cgtcatgggg cagtgaacca tgtgccctgc ccgaaaggcc 2640
ttccctgtac accaaggtgg tgcattaccg gaagtggatc aaggacacca tcgtggccaa 2700
cccctgaaga tctgggccct aacaaaacaa aaagatgggg ttattcccta aacttcatgg 2760
gttacgtaat tggaagttgg gggacattgc cacaagatca tattgtacaa aagatcaaac 2820
actgttttag aaaacttcct gtaaacaggc ctattgattg gaaagtatgt caaaggattg 2880
tgggtctttt gggctttgct gctccattta cacaatgtgg atatcctgcc ttaatgcctt 2940
tgtatgcatg tatacaagct aaacaggctt tcactttctc gccaacttac aaggcctttc 3000
taagtaaaca gtacatgaac ctttaccccg ttgctcggca acggcctggt ctgtgccaag 3060
tgtttgctga cgcaaccccc actggctggg gcttggccat aggccatcag cgcatgcgtg 3120
gaacctttgt ggctcctctg ccgatccata ctgcggaact cctagccgct tgttttgctc 3180
gcagccggtc tggagcaaag ctcataggaa ctgacaattc tgtcgtcctc tcgcggaaat 3240
atacatcgtt tcgatctacg tatgatcttt ttccctctgc caaaaattat ggggacatca 3300
tgaagcccct tgagcatctg acttctggct aataaaggaa atttattttc attgcaatag 3360
tgtgttggaa ttttttgtgt ctctcactcg gaaggaattc tgcattaatg aatcggccaa 3420
cgcgcgggga gaggcggttt gcgtattggg cgctcttccg cttcctcgct cactgactcg 3480
ctgcgctcgg tcgttcggct gcggcgagcg gtatcagctc actcaaaggc ggtaatacgg 3540
ttatccacag aatcagggga taacgcagga aagaacatgt gagcaaaagg ccagcaaaag 3600
gccaggaacc gtaaaaaggc cgcgttgctg gcgtttttcc ataggctccg cccccctgac 3660
gagcatcaca aaaatcgacg ctcaagtcag aggtggcgaa acccgacagg actataaaga 3720
taccaggcgt ttccccctgg aagctccctc gtgcgctctc ctgttccgac cctgccgctt 3780
accggatacc tgtccgcctt tctcccttcg ggaagcgtgg cgctttctca tagctcacgc 3840
tgtaggtatc tcagttcggt gtaggtcgtt cgctccaagc tgggctgtgt gcacgaaccc 3900
cccgttcagc ccgaccgctg cgccttatcc ggtaactatc gtcttgagtc caacccggta 3960
agacacgact tatcgccact ggcagcagcc actggtaaca ggattagcag agcgaggtat 4020
gtaggcggtg ctacagagtt cttgaagtgg tggcctaact acggctacac tagaagaaca 4080
gtatttggta tctgcgctct gctgaagcca gttaccttcg gaaaaagagt tggtagctct 4140
tgatccggca aacaaaccac cgctggtagc ggtggttttt ttgtttgcaa gcagcagatt 4200
acgcgcagaa aaaaaggatc tcaagaagat cctttgatct tttctacggg gtctgacgct 4260
cagtggaacg aaaactcacg ttaagggatt ttggtcatga gattatcaaa aaggatcttc 4320
acctagatcc ttttaaatta aaaatgaagt tttaaatcaa tctaaagtat atatgagtaa 4380
acttggtctg acagttacca atgcttaatc agtgaggcac ctatctcagc gatctgtcta 4440
tttcgttcat ccatagttgc ctgactc 4467
<210> 26
<211> 7563
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 26
gaattctgca ttaatgaatc ggccaacgcg cggggagagg cggtttgcgt attgggcgct 60
cttccgcttc ctcgctcact gactcgctgc gctcggtcgt tcggctgcgg cgagcggtat 120
cagctcactc aaaggcggta atacggttat ccacagaatc aggggataac gcaggaaaga 180
acatgtgagc aaaaggccag caaaaggcca ggaaccgtaa aaaggccgcg ttgctggcgt 240
ttttccatag gctccgcccc cctgacgagc atcacaaaaa tcgacgctca agtcagaggt 300
ggcgaaaccc gacaggacta taaagatacc aggcgtttcc ccctggaagc tccctcgtgc 360
gctctcctgt tccgaccctg ccgcttaccg gatacctgtc cgcctttctc ccttcgggaa 420
gcgtggcgct ttctcatagc tcacgctgta ggtatctcag ttcggtgtag gtcgttcgct 480
ccaagctggg ctgtgtgcac gaaccccccg ttcagcccga ccgctgcgcc ttatccggta 540
actatcgtct tgagtccaac ccggtaagac acgacttatc gccactggca gcagccactg 600
gtaacaggat tagcagagcg aggtatgtag gcggtgctac agagttcttg aagtggtggc 660
ctaactacgg ctacactaga agaacagtat ttggtatctg cgctctgctg aagccagtta 720
ccttcggaaa aagagttggt agctcttgat ccggcaaaca aaccaccgct ggtagcggtg 780
gtttttttgt ttgcaagcag cagattacgc gcagaaaaaa aggatctcaa gaagatcctt 840
tgatcttttc tacggggtct gacgctcagt ggaacgaaaa ctcacgttaa gggattttgg 900
tcatgagatt atcaaaaagg atcttcacct agatcctttt aaattaaaaa tgaagtttta 960
aatcaatcta aagtatatat gagtaaactt ggtctgacag ttaccaatgc ttaatcagtg 1020
aggcacctat ctcagcgatc tgtctatttc gttcatccat agttgcctga ctcggcgtaa 1080
tgctctgcca gtgttacaac caattaacca attctgatta gaaaaactca tcgagcatca 1140
aatgaaactg caatttattc atatcaggat tatcaatacc atatttttga aaaagccgtt 1200
tctgtaatga aggagaaaac tcaccgaggc agttccatag gatggcaaga tcctggtatc 1260
ggtctgcgat tccgactcgt ccaacatcaa tacaacctat taatttcccc tcgtcaaaaa 1320
taaggttatc aagtgagaaa tcaccatgag tgacgactga atccggtgag aatggcaaaa 1380
gcttatgcat ttctttccag acttgttcaa caggccagcc attacgctcg tcatcaaaat 1440
cactcgcatc aaccaaaccg ttattcattc gtgattgcgc ctgagcgaga cgaaatacgc 1500
gatcgctgtt aaaaggacaa ttacaaacag gaatcaaatg caaccggcgc aggaacactg 1560
ccagcgcatc aacaatattt tcacctgaat caggatattc ttctaatacc tggaatgctg 1620
ttttcccggg gatcgcagtg gtgagtaacc atgcatcatc aggagtacgg ataaaatgct 1680
tgatggtcgg aagaggcata aattccgtca gccagtttag tctgaccatc tcatctgtaa 1740
catcattggc aacgctacct ttgccatgtt tcagaaacaa ctctggcgca tcgggcttcc 1800
catacaatcg atagattgtc gcacctgatt gcccgacatt atcgcgagcc catttatacc 1860
catataaatc agcatccatg ttggaattta atcgcggcct cgagcaagac gtttcccgtt 1920
gaatatggct cataacaccc cttgtattac tgtttatgta agcagacagg gtaccaatct 1980
tccgagtgag agacacaaaa aattccaaca cactattgca atgaaaataa atttccttta 2040
ttagccagaa gtcagatgct caaggggctt catgatgtcc ccataatttt tggcagaggg 2100
aaaaagatca tacgtagatc gaaacgatgt atatttccgc gagaggacga cagaattgtc 2160
agttcctatg agctttgctc cagaccggct gcgagcaaaa caagcggcta ggagttccgc 2220
agtatggatc ggcagaggag ccacaaaggt tccacgcatg cgctgatggc ctatggccaa 2280
gccccagcca gtgggggttg cgtcagcaaa cacttggcac agaccaggcc gttgccgagc 2340
aacggggtaa aggttcatgt actgtttact tagaaaggcc ttgtaagttg gcgagaaagt 2400
gaaagcctgt ttagcttgta tacatgcata caaaggcatt aaggcaggat atccacattg 2460
tgtaaatgga gcagcaaagc ccaaaagacc cacaatcctt tgacatactt tccaatcaat 2520
aggcctgttt acaggaagtt ttctaaaaca gtgtttgatc ttttgtacaa tatgatcttg 2580
tggcaatgtc ccccaacttc caattacgta acccatgaag tttagggaat aaccccatct 2640
ttttgttttg ttagggccca gatctttagg ctacttcact caaagtctct gcagctgcct 2700
gcactgtgaa ggctgcaaca taaatctgtc tcttcacttc tccccaggcc ttggaagggt 2760
ccactttgct ttcaatatca aacagagcat cataaattcc tgggaatgac tcccctgcat 2820
acttgttgtg gctgcttgga gcatagatga catgcctata aaaaggcctg tctggtaacc 2880
ctaatggatc aataaatgct ctttccagaa acatgagttg atcattcatc attcttaata 2940
ctattgggtt gcttttgtca aagtcctgga gtctctcact gaacttggaa gcaatttctg 3000
taaaattctt tactgcagaa aaaagtgaat caaatgatac actgtatgtc ttcatttcct 3060
gtggatgttt catagaaata ctgtagattt tgtcagcata ctttcttaaa actacagcat 3120
aatctcgaca atcaaaaggg agcactatgg aattggccag ctcaaacacc atccctcctc 3180
gaacctgggc cacagtgagg tgatatttaa acattggatc ataaaacttt tccaccaact 3240
catatgtttc atagacactg tgatacagtg gatagccgct gaatttgttt gtttcccaat 3300
ttttagtata ccgtgctctg cctgaagcaa ttccaagtcg ttggaagaac acctcaaaat 3360
catttccaga tcccaatttg cttatcctgg gcatgccact gaactctggg gaaggacttt 3420
ttttagtcca actttcataa agagatttgc cttcaaagcc ttcatcaggg cttttcagct 3480
cttttgttag gttgtgtacc aagctgtaca tcagcggtgt acaatcaact ctcagagtgt 3540
agtttccttc tatagatgag tcagcattaa tataagccac gccacgctct tgaaggagtc 3600
ttgaattctc ctctgcccac tcagtagaac caagaagacc aaattcttct gcatcccagc 3660
ttgcaaacaa aattgttctt ctaggtctcc acccttcctt tttcagtgtt ccaaagctcc 3720
tcacaatttc atgaacaaca gctgctccac tctgagggtc aataccacca aacacccatg 3780
agtcccggtg acctcccaga atgacatatc tgtctggttc cactgctcct ctgagagtac 3840
ctatcacatt gtaaattctt gtcacttcat tggtagagtg gatgtgcatc ttgacttttt 3900
gtgtagaaaa gtttccagta aagccaggtc caacattgta gggcactttg agacttcctc 3960
tccagctgct atctggtggt gctgagccac ccattttttc taggagcttc tgtgcatcat 4020
agtatccaat tggatgaaca ggaatacttg gaagaccaac agcctctgca attccacgcc 4080
tataagcata ttcatttgct gggtaacctg gtgtgagagg gtctcctgca ccattcagat 4140
ttaggatatt tccacgctgg acaccacctc caggaagatt ccaaccatct ggataggact 4200
tcaccccagg agcaaagtag tcagcagggt cggagtagag aatgactcct ttggcccctg 4260
ccagctgggc atttttaacc ttatttcctc tgaaaacttt cccatatctg gcaattacaa 4320
ttttcccaga gcaattgatt ttcatgtccc gttccaattt aaagaagtct tcagttcgtg 4380
catagttaac atacactaga tcgccctctg gcattccttg aggagagaaa gcactgaaag 4440
gtggtacaat atccgaaaca ttttcatatc ctggaggagg tggttcaaat aatgatgtgt 4500
tgaaaatctc atttccatct tcattaatta ttgagatgta gttgggatga gtcttatttg 4560
ggtaggacaa caggacatca taatgtgcca gctcaacaga atccaggcca aattctttcc 4620
actgggattg aatttgcttt gcaagctgaa agttttgttc tgttcctgct aaatgtggta 4680
tctgtgtaaa attatataag aacttcttga tgttctcagc tttcaattca tccaaaaatg 4740
ctttcatatt atgctttgga gtaatgttag tagcttcatt ggaggatttt ataaaccacc 4800
cgaagaggaa gccgaggaga aagaagccac ccgccagcac cagcgcccca gcgcacagcc 4860
agcgcgggcg gcgcgcgcta gccatgttcg tcacagggtc cccagtcctc gcggagattg 4920
acgagatgtg agaggcaata ttcggagcag ggtttactgt tcctgaactg gagccaccag 4980
caggaaaata cagacccctg actctgggat cctgacctgg aagatagtca gggttgaggc 5040
aagcaaaagg tacatgtaag agaagagccc acagcgtccc tcaaatccct ggagtcttga 5100
ctggggaagc caggcccacc ctggagagta catacctgct tgctgagatc cggacggtga 5160
gtcactcttg gcacggggaa tccgcgttcc aatgcaccgt tcccggccgc ggaggctgga 5220
tcggtcccgg tgtcttctat ggaggtcaaa acagcgtgga tggcgtctcc aggcgatctg 5280
acggttcact aaacgagctc tgcttatata gacctcccac cgtacacgcc taccgcccat 5340
ttgcgtcaac ggggcggggt tattacgaca ttttggaaag tcccgttgat tttggtgctc 5400
gacctgcagg gtaccaatat tggctattgg ccattgcata cgttgtatct atatcataat 5460
atgtacattt atattggctc atgtccaata tgaccgccat gttgacattg attattgact 5520
agttattaat agtaatcaat tacggggtca ttagttcata gcccatatat ggagttccgc 5580
gttacataac ttacggtaaa tggcccgcct ggctgaccgc ccaacgaccc ccgcccattg 5640
acgtcaataa tgacgtatgt tcccatagta acgccaatag ggactttcca ttgacgtcaa 5700
tgggtggagt atttacggta aactgcccac ttggcagtac atcaagtgta tcatatgcca 5760
agtccgcccc ctattgacgt caatgacggt aaatggcccg cctggcatta tgcccagtac 5820
atgaccttac gggactttcc tacttggcag tacatctacg tattagtcat cgctattacc 5880
atggtgatgc ggttttggca gtacaccaat gggcgtggat agcggtttga ctcacgggga 5940
tttccaagtc tccaccccat tgacgtcaat gggagtttgt tttggcacca aaatcaacgg 6000
gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc aaatgggcgg taggcgtgta 6060
cggtgggagg tctatataag cagagctcgt ttagtgaacc gtcagatcgc ctggagacgc 6120
catccacgct gttttgacct ccatagaaga caccgggacc gatccagcct ccgcggccgg 6180
gaacggtgca ttggaacgcg gattccccgt gccaagagtg actcaccgtc cggatctcag 6240
caagcaggta tgtactctcc agggtgggcc tggcttcccc agtcaagact ccagggattt 6300
gagggacgct gtgggctctt ctcttacatg taccttttgc ttgcctcaac cctgactatc 6360
ttccaggtca ggatcccaga gtcaggggtc tgtattttcc tgctggtggc tccagttcag 6420
gaacagtaaa ccctgctccg aatattgcct ctcacatctc gtcaatctcc gcgaggactg 6480
gggaccctgt gacgaacatg gctagcaagg ctgtgctgct tgccctgttg atggcaggct 6540
tggccctgca gccaggcact gccctgctgt gctactcctg caaagcccag gtgagcaacg 6600
aggactgcct gcaggtggag aactgcaccc agctggggga gcagtgctgg accgcgcgca 6660
tccgcgcagt tggcctcctg accgtcatca gcaaaggctg cagcttgaac tgcgtggatg 6720
actcacagga ctactacgtg ggcaagaaga acatcacgtg ctgtgacacc gacttgtgca 6780
acgccagcgg ggcccatgcc ctgcagccgg ctgccgccat ccttgcgctg ctccctgcac 6840
tcggcctgct gctctgggga cccggccagc tatagagatc tgggccctaa caaaacaaaa 6900
agatggggtt attccctaaa cttcatgggt tacgtaattg gaagttgggg gacattgcca 6960
caagatcata ttgtacaaaa gatcaaacac tgttttagaa aacttcctgt aaacaggcct 7020
attgattgga aagtatgtca aaggattgtg ggtcttttgg gctttgctgc tccatttaca 7080
caatgtggat atcctgcctt aatgcctttg tatgcatgta tacaagctaa acaggctttc 7140
actttctcgc caacttacaa ggcctttcta agtaaacagt acatgaacct ttaccccgtt 7200
gctcggcaac ggcctggtct gtgccaagtg tttgctgacg caacccccac tggctggggc 7260
ttggccatag gccatcagcg catgcgtgga acctttgtgg ctcctctgcc gatccatact 7320
gcggaactcc tagccgcttg ttttgctcgc agccggtctg gagcaaagct cataggaact 7380
gacaattctg tcgtcctctc gcggaaatat acatcgtttc gatctacgta tgatcttttt 7440
ccctctgcca aaaattatgg ggacatcatg aagccccttg agcatctgac ttctggctaa 7500
taaaggaaat ttattttcat tgcaatagtg tgttggaatt ttttgtgtct ctcactcgga 7560
agc 7563
<210> 27
<211> 6396
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 27
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcgcgcgcc gcccgcgctg gctgtgcgct ggggcgctgg tgctggcggg 2040
tggcttcttt ctcctcggct tcctcttcgg gtggtttata aaatcctcca atgaagctac 2100
taacattact ccaaagcata atatgaaagc atttttggat gaattgaaag ctgagaacat 2160
caagaagttc ttatataatt ttacacagat accacattta gcaggaacag aacaaaactt 2220
tcagcttgca aagcaaattc aatcccagtg gaaagaattt ggcctggatt ctgttgagct 2280
ggcacattat gatgtcctgt tgtcctaccc aaataagact catcccaact acatctcaat 2340
aattaatgaa gatggaaatg agattttcaa cacatcatta tttgaaccac ctcctccagg 2400
atatgaaaat gtttcggata ttgtaccacc tttcagtgct ttctctcctc aaggaatgcc 2460
agagggcgat ctagtgtatg ttaactatgc acgaactgaa gacttcttta aattggaacg 2520
ggacatgaaa atcaattgct ctgggaaaat tgtaattgcc agatatggga aagttttcag 2580
aggaaataag gttaaaaatg cccagctggc aggggccaaa ggagtcattc tctactccga 2640
ccctgctgac tactttgctc ctggggtgaa gtcctatcca gatggttgga atcttcctgg 2700
aggtggtgtc cagcgtggaa atatcctaaa tctgaatggt gcaggagacc ctctcacacc 2760
aggttaccca gcaaatgaat atgcttatag gcgtggaatt gcagaggctg ttggtcttcc 2820
aagtattcct gttcatccaa ttggatacta tgatgcacag aagctcctag aaaaaatggg 2880
tggctcagca ccaccagata gcagctggag aggaagtctc aaagtgccct acaatgttgg 2940
acctggcttt actggaaact tttctacaca aaaagtcaag atgcacatcc actctaccaa 3000
tgaagtgaca agaatttaca atgtgatagg tactctcaga ggagcagtgg aaccagacag 3060
atatgtcatt ctgggaggtc accgggactc atgggtgttt ggtggtattg accctcagag 3120
tggagcagct gttgttcatg aaattgtgag gagctttgga acactgaaaa aggaagggtg 3180
gagacctaga agaacaattt tgtttgcaag ctgggatgca gaagaatttg gtcttcttgg 3240
ttctactgag tgggcagagg agaattcaag actccttcaa gagcgtggcg tggcttatat 3300
taatgctgac tcatctatag aaggaaacta cactctgaga gttgattgta caccgctgat 3360
gtacagcttg gtacacaacc taacaaaaga gctgaaaagc cctgatgaag gctttgaagg 3420
caaatctctt tatgaaagtt ggactaaaaa aagtccttcc ccagagttca gtggcatgcc 3480
caggataagc aaattgggat ctggaaatga ttttgaggtg ttcttccaac gacttggaat 3540
tgcttcaggc agagcacggt atactaaaaa ttgggaaaca aacaaattca gcggctatcc 3600
actgtatcac agtgtctatg aaacatatga gttggtggaa aagttttatg atccaatgtt 3660
taaatatcac ctcactgtgg cccaggttcg aggagggatg gtgtttgagc tggccaattc 3720
catagtgctc ccttttgatt gtcgagatta tgctgtagtt ttaagaaagt atgctgacaa 3780
aatctacagt atttctatga aacatccaca ggaaatgaag acatacagtg tatcatttga 3840
ttcacttttt tctgcagtaa agaattttac agaaattgct tccaagttca gtgagagact 3900
ccaggacttt gacaaaagca acccaatagt attaagaatg atgaatgatc aactcatgtt 3960
tctggaaaga gcatttattg atccattagg gttaccagac aggccttttt ataggcatgt 4020
catctatgct ccaagcagcc acaacaagta tgcaggggag tcattcccag gaatttatga 4080
tgctctgttt gatattgaaa gcaaagtgga cccttccaag gcctggggag aagtgaagag 4140
acagatttat gttgcagcct tcacagtgca ggcagctgca gagactttga gtgaagtagc 4200
cggatccgaa ggtaggggtt cattattgac ctgtggagat gtcgaagaaa acccaggacc 4260
cgcaagcaag gctgtgctgc ttgccctgtt gatggcaggc ttggccctgc agccaggcac 4320
tgccctgctg tgctactcct gcaaagccca ggtgagcaac gaggactgcc tgcaggtgga 4380
gaactgcacc cagctggggg agcagtgctg gaccgcgcgc atccgcgcag ttggcctcct 4440
gaccgtcatc agcaaaggct gcagcttgaa ctgcgtggat gactcacagg actactacgt 4500
gggcaagaag aacatcacgt gctgtgacac cgacttgtgc aacgccagcg gggcccatgc 4560
cctgcagccg gctgccgcca tccttgcgct gctccctgca ctcggcctgc tgctctgggg 4620
acccggccag ctatagagat ctgggcccta acaaaacaaa aagatggggt tattccctaa 4680
acttcatggg ttacgtaatt ggaagttggg ggacattgcc acaagatcat attgtacaaa 4740
agatcaaaca ctgttttaga aaacttcctg taaacaggcc tattgattgg aaagtatgtc 4800
aaaggattgt gggtcttttg ggctttgctg ctccatttac acaatgtgga tatcctgcct 4860
taatgccttt gtatgcatgt atacaagcta aacaggcttt cactttctcg ccaacttaca 4920
aggcctttct aagtaaacag tacatgaacc tttaccccgt tgctcggcaa cggcctggtc 4980
tgtgccaagt gtttgctgac gcaaccccca ctggctgggg cttggccata ggccatcagc 5040
gcatgcgtgg aacctttgtg gctcctctgc cgatccatac tgcggaactc ctagccgctt 5100
gttttgctcg cagccggtct ggagcaaagc tcataggaac tgacaattct gtcgtcctct 5160
cgcggaaata tacatcgttt cgatctacgt atgatctttt tccctctgcc aaaaattatg 5220
gggacatcat gaagcccctt gagcatctga cttctggcta ataaaggaaa tttattttca 5280
ttgcaatagt gtgttggaat tttttgtgtc tctcactcgg aaggaattct gcattaatga 5340
atcggccaac gcgcggggag aggcggtttg cgtattgggc gctcttccgc ttcctcgctc 5400
actgactcgc tgcgctcggt cgttcggctg cggcgagcgg tatcagctca ctcaaaggcg 5460
gtaatacggt tatccacaga atcaggggat aacgcaggaa agaacatgtg agcaaaaggc 5520
cagcaaaagg ccaggaaccg taaaaaggcc gcgttgctgg cgtttttcca taggctccgc 5580
ccccctgacg agcatcacaa aaatcgacgc tcaagtcaga ggtggcgaaa cccgacagga 5640
ctataaagat accaggcgtt tccccctgga agctccctcg tgcgctctcc tgttccgacc 5700
ctgccgctta ccggatacct gtccgccttt ctcccttcgg gaagcgtggc gctttctcat 5760
agctcacgct gtaggtatct cagttcggtg taggtcgttc gctccaagct gggctgtgtg 5820
cacgaacccc ccgttcagcc cgaccgctgc gccttatccg gtaactatcg tcttgagtcc 5880
aacccggtaa gacacgactt atcgccactg gcagcagcca ctggtaacag gattagcaga 5940
gcgaggtatg taggcggtgc tacagagttc ttgaagtggt ggcctaacta cggctacact 6000
agaagaacag tatttggtat ctgcgctctg ctgaagccag ttaccttcgg aaaaagagtt 6060
ggtagctctt gatccggcaa acaaaccacc gctggtagcg gtggtttttt tgtttgcaag 6120
cagcagatta cgcgcagaaa aaaaggatct caagaagatc ctttgatctt ttctacgggg 6180
tctgacgctc agtggaacga aaactcacgt taagggattt tggtcatgag attatcaaaa 6240
aggatcttca cctagatcct tttaaattaa aaatgaagtt ttaaatcaat ctaaagtata 6300
tatgagtaaa cttggtctga cagttaccaa tgcttaatca gtgaggcacc tatctcagcg 6360
atctgtctat ttcgttcatc catagttgcc tgactc 6396
<210> 28
<211> 6405
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 28
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcaaggctg tgctgcttgc cctgttgatg gcaggcttgg ccctgcagcc 2040
aggcactgcc ctgctgtgct actcctgcaa agcccaggtg agcaacgagg actgcctgca 2100
ggtggagaac tgcacccagc tgggggagca gtgctggacc gcgcgcatcc gcgcagttgg 2160
cctcctgacc gtcatcagca aaggctgcag cttgaactgc gtggatgact cacaggacta 2220
ctacgtgggc aagaagaaca tcacgtgctg tgacaccgac ttgtgcaacg ccagcggggc 2280
ccatgccctg cagccggctg ccgccatcct tgcgctgctc cctgcactcg gcctgctgct 2340
ctggggaccc ggccagctag gatcccagac cctgaacttt gatctgctga aactggcagg 2400
cgatgtggaa agcaacccag gcccaatggc aagcgcgcgc cgcccgcgct ggctgtgcgc 2460
tggggcgctg gtgctggcgg gtggcttctt tctcctcggc ttcctcttcg ggtggtttat 2520
aaaatcctcc aatgaagcta ctaacattac tccaaagcat aatatgaaag catttttgga 2580
tgaattgaaa gctgagaaca tcaagaagtt cttatataat tttacacaga taccacattt 2640
agcaggaaca gaacaaaact ttcagcttgc aaagcaaatt caatcccagt ggaaagaatt 2700
tggcctggat tctgttgagc tggcacatta tgatgtcctg ttgtcctacc caaataagac 2760
tcatcccaac tacatctcaa taattaatga agatggaaat gagattttca acacatcatt 2820
atttgaacca cctcctccag gatatgaaaa tgtttcggat attgtaccac ctttcagtgc 2880
tttctctcct caaggaatgc cagagggcga tctagtgtat gttaactatg cacgaactga 2940
agacttcttt aaattggaac gggacatgaa aatcaattgc tctgggaaaa ttgtaattgc 3000
cagatatggg aaagttttca gaggaaataa ggttaaaaat gcccagctgg caggggccaa 3060
aggagtcatt ctctactccg accctgctga ctactttgct cctggggtga agtcctatcc 3120
agatggttgg aatcttcctg gaggtggtgt ccagcgtgga aatatcctaa atctgaatgg 3180
tgcaggagac cctctcacac caggttaccc agcaaatgaa tatgcttata ggcgtggaat 3240
tgcagaggct gttggtcttc caagtattcc tgttcatcca attggatact atgatgcaca 3300
gaagctccta gaaaaaatgg gtggctcagc accaccagat agcagctgga gaggaagtct 3360
caaagtgccc tacaatgttg gacctggctt tactggaaac ttttctacac aaaaagtcaa 3420
gatgcacatc cactctacca atgaagtgac aagaatttac aatgtgatag gtactctcag 3480
aggagcagtg gaaccagaca gatatgtcat tctgggaggt caccgggact catgggtgtt 3540
tggtggtatt gaccctcaga gtggagcagc tgttgttcat gaaattgtga ggagctttgg 3600
aacactgaaa aaggaagggt ggagacctag aagaacaatt ttgtttgcaa gctgggatgc 3660
agaagaattt ggtcttcttg gttctactga gtgggcagag gagaattcaa gactccttca 3720
agagcgtggc gtggcttata ttaatgctga ctcatctata gaaggaaact acactctgag 3780
agttgattgt acaccgctga tgtacagctt ggtacacaac ctaacaaaag agctgaaaag 3840
ccctgatgaa ggctttgaag gcaaatctct ttatgaaagt tggactaaaa aaagtccttc 3900
cccagagttc agtggcatgc ccaggataag caaattggga tctggaaatg attttgaggt 3960
gttcttccaa cgacttggaa ttgcttcagg cagagcacgg tatactaaaa attgggaaac 4020
aaacaaattc agcggctatc cactgtatca cagtgtctat gaaacatatg agttggtgga 4080
aaagttttat gatccaatgt ttaaatatca cctcactgtg gcccaggttc gaggagggat 4140
ggtgtttgag ctggccaatt ccatagtgct cccttttgat tgtcgagatt atgctgtagt 4200
tttaagaaag tatgctgaca aaatctacag tatttctatg aaacatccac aggaaatgaa 4260
gacatacagt gtatcatttg attcactttt ttctgcagta aagaatttta cagaaattgc 4320
ttccaagttc agtgagagac tccaggactt tgacaaaagc aacccaatag tattaagaat 4380
gatgaatgat caactcatgt ttctggaaag agcatttatt gatccattag ggttaccaga 4440
caggcctttt tataggcatg tcatctatgc tccaagcagc cacaacaagt atgcagggga 4500
gtcattccca ggaatttatg atgctctgtt tgatattgaa agcaaagtgg acccttccaa 4560
ggcctgggga gaagtgaaga gacagattta tgttgcagcc ttcacagtgc aggcagctgc 4620
agagactttg agtgaagtag cctaaagatc tgggccctaa caaaacaaaa agatggggtt 4680
attccctaaa cttcatgggt tacgtaattg gaagttgggg gacattgcca caagatcata 4740
ttgtacaaaa gatcaaacac tgttttagaa aacttcctgt aaacaggcct attgattgga 4800
aagtatgtca aaggattgtg ggtcttttgg gctttgctgc tccatttaca caatgtggat 4860
atcctgcctt aatgcctttg tatgcatgta tacaagctaa acaggctttc actttctcgc 4920
caacttacaa ggcctttcta agtaaacagt acatgaacct ttaccccgtt gctcggcaac 4980
ggcctggtct gtgccaagtg tttgctgacg caacccccac tggctggggc ttggccatag 5040
gccatcagcg catgcgtgga acctttgtgg ctcctctgcc gatccatact gcggaactcc 5100
tagccgcttg ttttgctcgc agccggtctg gagcaaagct cataggaact gacaattctg 5160
tcgtcctctc gcggaaatat acatcgtttc gatctacgta tgatcttttt ccctctgcca 5220
aaaattatgg ggacatcatg aagccccttg agcatctgac ttctggctaa taaaggaaat 5280
ttattttcat tgcaatagtg tgttggaatt ttttgtgtct ctcactcgga aggaattctg 5340
cattaatgaa tcggccaacg cgcggggaga ggcggtttgc gtattgggcg ctcttccgct 5400
tcctcgctca ctgactcgct gcgctcggtc gttcggctgc ggcgagcggt atcagctcac 5460
tcaaaggcgg taatacggtt atccacagaa tcaggggata acgcaggaaa gaacatgtga 5520
gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg cgttgctggc gtttttccat 5580
aggctccgcc cccctgacga gcatcacaaa aatcgacgct caagtcagag gtggcgaaac 5640
ccgacaggac tataaagata ccaggcgttt ccccctggaa gctccctcgt gcgctctcct 5700
gttccgaccc tgccgcttac cggatacctg tccgcctttc tcccttcggg aagcgtggcg 5760
ctttctcata gctcacgctg taggtatctc agttcggtgt aggtcgttcg ctccaagctg 5820
ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg ccttatccgg taactatcgt 5880
cttgagtcca acccggtaag acacgactta tcgccactgg cagcagccac tggtaacagg 5940
attagcagag cgaggtatgt aggcggtgct acagagttct tgaagtggtg gcctaactac 6000
ggctacacta gaagaacagt atttggtatc tgcgctctgc tgaagccagt taccttcgga 6060
aaaagagttg gtagctcttg atccggcaaa caaaccaccg ctggtagcgg tggttttttt 6120
gtttgcaagc agcagattac gcgcagaaaa aaaggatctc aagaagatcc tttgatcttt 6180
tctacggggt ctgacgctca gtggaacgaa aactcacgtt aagggatttt ggtcatgaga 6240
ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa aatgaagttt taaatcaatc 6300
taaagtatat atgagtaaac ttggtctgac agttaccaat gcttaatcag tgaggcacct 6360
atctcagcga tctgtctatt tcgttcatcc atagttgcct gactc 6405
<210> 29
<211> 6750
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 29
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcattgtgg gaggctggga gtgcgagaag cattcccaac cctggcaggt 2040
gcttgtggcc tctcgtggca gggcagtctg cggcggtgtt ctggtgcacc cccagtgggt 2100
cctcacagct gcccactgca tcaggaacaa aagcgtgatc ttgctgggtc ggcacagctt 2160
gtttcatcct gaagacacag gccaggtatt tcaggtcagc cacagcttcc cacacccgct 2220
ctacgatatg agcctcctga agaatcgatt cctcaggcca ggtgatgact ccagccacga 2280
cctcatgctg ctccgcctgt cagagcctgc cgagctcacg gatgctgtga aggtcatgga 2340
cctgcccacc caggagccag cactggggac cacctgctac gcctcaggct ggggcagcat 2400
tgaaccagag gagttcttga ccccaaagaa acttcagtgt gtggacctcc atgttatttc 2460
caatgacgtg tgtgcgcaag ttcaccctca gaaggtgacc aagttcatgc tgtgtgctgg 2520
acgctggaca gggggcaaaa gcacctgctc gggtgattct gggggcccac ttgtctgtaa 2580
tggtgtgctt caaggtatca cgtcatgggg cagtgaacca tgtgccctgc ccgaaaggcc 2640
ttccctgtac accaaggtgg tgcattaccg gaagtggatc aaggacacca tcgtggccaa 2700
ccccggatcc cagaccctga actttgatct gctgaaactg gcaggcgatg tggaaagcaa 2760
cccaggccca atggcaagcg cgcgccgccc gcgctggctg tgcgctgggg cgctggtgct 2820
ggcgggtggc ttctttctcc tcggcttcct cttcgggtgg tttataaaat cctccaatga 2880
agctactaac attactccaa agcataatat gaaagcattt ttggatgaat tgaaagctga 2940
gaacatcaag aagttcttat ataattttac acagatacca catttagcag gaacagaaca 3000
aaactttcag cttgcaaagc aaattcaatc ccagtggaaa gaatttggcc tggattctgt 3060
tgagctggca cattatgatg tcctgttgtc ctacccaaat aagactcatc ccaactacat 3120
ctcaataatt aatgaagatg gaaatgagat tttcaacaca tcattatttg aaccacctcc 3180
tccaggatat gaaaatgttt cggatattgt accacctttc agtgctttct ctcctcaagg 3240
aatgccagag ggcgatctag tgtatgttaa ctatgcacga actgaagact tctttaaatt 3300
ggaacgggac atgaaaatca attgctctgg gaaaattgta attgccagat atgggaaagt 3360
tttcagagga aataaggtta aaaatgccca gctggcaggg gccaaaggag tcattctcta 3420
ctccgaccct gctgactact ttgctcctgg ggtgaagtcc tatccagatg gttggaatct 3480
tcctggaggt ggtgtccagc gtggaaatat cctaaatctg aatggtgcag gagaccctct 3540
cacaccaggt tacccagcaa atgaatatgc ttataggcgt ggaattgcag aggctgttgg 3600
tcttccaagt attcctgttc atccaattgg atactatgat gcacagaagc tcctagaaaa 3660
aatgggtggc tcagcaccac cagatagcag ctggagagga agtctcaaag tgccctacaa 3720
tgttggacct ggctttactg gaaacttttc tacacaaaaa gtcaagatgc acatccactc 3780
taccaatgaa gtgacaagaa tttacaatgt gataggtact ctcagaggag cagtggaacc 3840
agacagatat gtcattctgg gaggtcaccg ggactcatgg gtgtttggtg gtattgaccc 3900
tcagagtgga gcagctgttg ttcatgaaat tgtgaggagc tttggaacac tgaaaaagga 3960
agggtggaga cctagaagaa caattttgtt tgcaagctgg gatgcagaag aatttggtct 4020
tcttggttct actgagtggg cagaggagaa ttcaagactc cttcaagagc gtggcgtggc 4080
ttatattaat gctgactcat ctatagaagg aaactacact ctgagagttg attgtacacc 4140
gctgatgtac agcttggtac acaacctaac aaaagagctg aaaagccctg atgaaggctt 4200
tgaaggcaaa tctctttatg aaagttggac taaaaaaagt ccttccccag agttcagtgg 4260
catgcccagg ataagcaaat tgggatctgg aaatgatttt gaggtgttct tccaacgact 4320
tggaattgct tcaggcagag cacggtatac taaaaattgg gaaacaaaca aattcagcgg 4380
ctatccactg tatcacagtg tctatgaaac atatgagttg gtggaaaagt tttatgatcc 4440
aatgtttaaa tatcacctca ctgtggccca ggttcgagga gggatggtgt ttgagctggc 4500
caattccata gtgctccctt ttgattgtcg agattatgct gtagttttaa gaaagtatgc 4560
tgacaaaatc tacagtattt ctatgaaaca tccacaggaa atgaagacat acagtgtatc 4620
atttgattca cttttttctg cagtaaagaa ttttacagaa attgcttcca agttcagtga 4680
gagactccag gactttgaca aaagcaaccc aatagtatta agaatgatga atgatcaact 4740
catgtttctg gaaagagcat ttattgatcc attagggtta ccagacaggc ctttttatag 4800
gcatgtcatc tatgctccaa gcagccacaa caagtatgca ggggagtcat tcccaggaat 4860
ttatgatgct ctgtttgata ttgaaagcaa agtggaccct tccaaggcct ggggagaagt 4920
gaagagacag atttatgttg cagccttcac agtgcaggca gctgcagaga ctttgagtga 4980
agtagcctaa agatctgggc cctaacaaaa caaaaagatg gggttattcc ctaaacttca 5040
tgggttacgt aattggaagt tgggggacat tgccacaaga tcatattgta caaaagatca 5100
aacactgttt tagaaaactt cctgtaaaca ggcctattga ttggaaagta tgtcaaagga 5160
ttgtgggtct tttgggcttt gctgctccat ttacacaatg tggatatcct gccttaatgc 5220
ctttgtatgc atgtatacaa gctaaacagg ctttcacttt ctcgccaact tacaaggcct 5280
ttctaagtaa acagtacatg aacctttacc ccgttgctcg gcaacggcct ggtctgtgcc 5340
aagtgtttgc tgacgcaacc cccactggct ggggcttggc cataggccat cagcgcatgc 5400
gtggaacctt tgtggctcct ctgccgatcc atactgcgga actcctagcc gcttgttttg 5460
ctcgcagccg gtctggagca aagctcatag gaactgacaa ttctgtcgtc ctctcgcgga 5520
aatatacatc gtttcgatct acgtatgatc tttttccctc tgccaaaaat tatggggaca 5580
tcatgaagcc ccttgagcat ctgacttctg gctaataaag gaaatttatt ttcattgcaa 5640
tagtgtgttg gaattttttg tgtctctcac tcggaaggaa ttctgcatta atgaatcggc 5700
caacgcgcgg ggagaggcgg tttgcgtatt gggcgctctt ccgcttcctc gctcactgac 5760
tcgctgcgct cggtcgttcg gctgcggcga gcggtatcag ctcactcaaa ggcggtaata 5820
cggttatcca cagaatcagg ggataacgca ggaaagaaca tgtgagcaaa aggccagcaa 5880
aaggccagga accgtaaaaa ggccgcgttg ctggcgtttt tccataggct ccgcccccct 5940
gacgagcatc acaaaaatcg acgctcaagt cagaggtggc gaaacccgac aggactataa 6000
agataccagg cgtttccccc tggaagctcc ctcgtgcgct ctcctgttcc gaccctgccg 6060
cttaccggat acctgtccgc ctttctccct tcgggaagcg tggcgctttc tcatagctca 6120
cgctgtaggt atctcagttc ggtgtaggtc gttcgctcca agctgggctg tgtgcacgaa 6180
ccccccgttc agcccgaccg ctgcgcctta tccggtaact atcgtcttga gtccaacccg 6240
gtaagacacg acttatcgcc actggcagca gccactggta acaggattag cagagcgagg 6300
tatgtaggcg gtgctacaga gttcttgaag tggtggccta actacggcta cactagaaga 6360
acagtatttg gtatctgcgc tctgctgaag ccagttacct tcggaaaaag agttggtagc 6420
tcttgatccg gcaaacaaac caccgctggt agcggtggtt tttttgtttg caagcagcag 6480
attacgcgca gaaaaaaagg atctcaagaa gatcctttga tcttttctac ggggtctgac 6540
gctcagtgga acgaaaactc acgttaaggg attttggtca tgagattatc aaaaaggatc 6600
ttcacctaga tccttttaaa ttaaaaatga agttttaaat caatctaaag tatatatgag 6660
taaacttggt ctgacagtta ccaatgctta atcagtgagg cacctatctc agcgatctgt 6720
ctatttcgtt catccatagt tgcctgactc 6750
<210> 30
<211> 6908
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 30
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcgcgcgcc gcccgcgctg gctgtgcgct ggggcgctgg tgctggcggg 2040
tggcttcttt ctcctcggct tcctcttcgg gtggtttata aaatcctcca atgaagctac 2100
taacattact ccaaagcata atatgaaagc atttttggat gaattgaaag ctgagaacat 2160
caagaagttc ttatataatt ttacacagat accacattta gcaggaacag aacaaaactt 2220
tcagcttgca aagcaaattc aatcccagtg gaaagaattt ggcctggatt ctgttgagct 2280
ggcacattat gatgtcctgt tgtcctaccc aaataagact catcccaact acatctcaat 2340
aattaatgaa gatggaaatg agattttcaa cacatcatta tttgaaccac ctcctccagg 2400
atatgaaaat gtttcggata ttgtaccacc tttcagtgct ttctctcctc aaggaatgcc 2460
agagggcgat ctagtgtatg ttaactatgc acgaactgaa gacttcttta aattggaacg 2520
ggacatgaaa atcaattgct ctgggaaaat tgtaattgcc agatatggga aagttttcag 2580
aggaaataag gttaaaaatg cccagctggc aggggccaaa ggagtcattc tctactccga 2640
ccctgctgac tactttgctc ctggggtgaa gtcctatcca gatggttgga atcttcctgg 2700
aggtggtgtc cagcgtggaa atatcctaaa tctgaatggt gcaggagacc ctctcacacc 2760
aggttaccca gcaaatgaat atgcttatag gcgtggaatt gcagaggctg ttggtcttcc 2820
aagtattcct gttcatccaa ttggatacta tgatgcacag aagctcctag aaaaaatggg 2880
tggctcagca ccaccagata gcagctggag aggaagtctc aaagtgccct acaatgttgg 2940
acctggcttt actggaaact tttctacaca aaaagtcaag atgcacatcc actctaccaa 3000
tgaagtgaca agaatttaca atgtgatagg tactctcaga ggagcagtgg aaccagacag 3060
atatgtcatt ctgggaggtc accgggactc atgggtgttt ggtggtattg accctcagag 3120
tggagcagct gttgttcatg aaattgtgag gagctttgga acactgaaaa aggaagggtg 3180
gagacctaga agaacaattt tgtttgcaag ctgggatgca gaagaatttg gtcttcttgg 3240
ttctactgag tgggcagagg agaattcaag actccttcaa gagcgtggcg tggcttatat 3300
taatgctgac tcatctatag aaggaaacta cactctgaga gttgattgta caccgctgat 3360
gtacagcttg gtacacaacc taacaaaaga gctgaaaagc cctgatgaag gctttgaagg 3420
caaatctctt tatgaaagtt ggactaaaaa aagtccttcc ccagagttca gtggcatgcc 3480
caggataagc aaattgggat ctggaaatga ttttgaggtg ttcttccaac gacttggaat 3540
tgcttcaggc agagcacggt atactaaaaa ttgggaaaca aacaaattca gcggctatcc 3600
actgtatcac agtgtctatg aaacatatga gttggtggaa aagttttatg atccaatgtt 3660
taaatatcac ctcactgtgg cccaggttcg aggagggatg gtgtttgagc tggccaattc 3720
catagtgctc ccttttgatt gtcgagatta tgctgtagtt ttaagaaagt atgctgacaa 3780
aatctacagt atttctatga aacatccaca ggaaatgaag acatacagtg tatcatttga 3840
ttcacttttt tctgcagtaa agaattttac agaaattgct tccaagttca gtgagagact 3900
ccaggacttt gacaaaagca acccaatagt attaagaatg atgaatgatc aactcatgtt 3960
tctggaaaga gcatttattg atccattagg gttaccagac aggccttttt ataggcatgt 4020
catctatgct ccaagcagcc acaacaagta tgcaggggag tcattcccag gaatttatga 4080
tgctctgttt gatattgaaa gcaaagtgga cccttccaag gcctggggag aagtgaagag 4140
acagatttat gttgcagcct tcacagtgca ggcagctgca gagactttga gtgaagtagc 4200
ctaaagatct gaccccctaa cgttactggc cgaagccgct tggaataagg ccggtgtgcg 4260
tttgtctata tgttattttc caccatattg ccgtcttttg gcaatgtgag ggcccggaaa 4320
cctggccctg tcttcttgac gagcattcct aggggtcttt cccctctcgc caaaggaatg 4380
caaggtctgt tgaatgtcgt gaaggaagca gttcctctgg aagcttcttg aagacaaaca 4440
acgtctgtag cgaccctttg caggcagcgg aaccccccac ctggcgacag gtgcctctgc 4500
ggccaaaagc cacgtgtata agatacacct gcaaaggcgg cacaacccca gtgccacgtt 4560
gtgagttgga tagttgtgga aagagtcaaa tggctctcct caagcgtatt caacaagggg 4620
ctgaaggatg cccagaaggt accccattgt atgggatctg atctggggcc tcggtgcaca 4680
tgctttacat gtgtttagtc gaggttaaaa aacgtctagg ccccccgaac cacggggacg 4740
tggttttcct ttgaaaaaca cgatgataat atggccagca aggctgtgct gcttgccctg 4800
ttgatggcag gcttggccct gcagccaggc actgccctgc tgtgctactc ctgcaaagcc 4860
caggtgagca acgaggactg cctgcaggtg gagaactgca cccagctggg ggagcagtgc 4920
tggaccgcgc gcatccgcgc agttggcctc ctgaccgtca tcagcaaagg ctgcagcttg 4980
aactgcgtgg atgactcaca ggactactac gtgggcaaga agaacatcac gtgctgtgac 5040
accgacttgt gcaacgccag cggggcccat gccctgcagc cggctgccgc catccttgcg 5100
ctgctccctg cactcggcct gctgctctgg ggacccggcc agctataggg atctgggccc 5160
taacaaaaca aaaagatggg gttattccct aaacttcatg ggttacgtaa ttggaagttg 5220
ggggacattg ccacaagatc atattgtaca aaagatcaaa cactgtttta gaaaacttcc 5280
tgtaaacagg cctattgatt ggaaagtatg tcaaaggatt gtgggtcttt tgggctttgc 5340
tgctccattt acacaatgtg gatatcctgc cttaatgcct ttgtatgcat gtatacaagc 5400
taaacaggct ttcactttct cgccaactta caaggccttt ctaagtaaac agtacatgaa 5460
cctttacccc gttgctcggc aacggcctgg tctgtgccaa gtgtttgctg acgcaacccc 5520
cactggctgg ggcttggcca taggccatca gcgcatgcgt ggaacctttg tggctcctct 5580
gccgatccat actgcggaac tcctagccgc ttgttttgct cgcagccggt ctggagcaaa 5640
gctcatagga actgacaatt ctgtcgtcct ctcgcggaaa tatacatcgt ttcgatctac 5700
gtatgatctt tttccctctg ccaaaaatta tggggacatc atgaagcccc ttgagcatct 5760
gacttctggc taataaagga aatttatttt cattgcaata gtgtgttgga attttttgtg 5820
tctctcactc ggaaggaatt ctgcattaat gaatcggcca acgcgcgggg agaggcggtt 5880
tgcgtattgg gcgctcttcc gcttcctcgc tcactgactc gctgcgctcg gtcgttcggc 5940
tgcggcgagc ggtatcagct cactcaaagg cggtaatacg gttatccaca gaatcagggg 6000
ataacgcagg aaagaacatg tgagcaaaag gccagcaaaa ggccaggaac cgtaaaaagg 6060
ccgcgttgct ggcgtttttc cataggctcc gcccccctga cgagcatcac aaaaatcgac 6120
gctcaagtca gaggtggcga aacccgacag gactataaag ataccaggcg tttccccctg 6180
gaagctccct cgtgcgctct cctgttccga ccctgccgct taccggatac ctgtccgcct 6240
ttctcccttc gggaagcgtg gcgctttctc atagctcacg ctgtaggtat ctcagttcgg 6300
tgtaggtcgt tcgctccaag ctgggctgtg tgcacgaacc ccccgttcag cccgaccgct 6360
gcgccttatc cggtaactat cgtcttgagt ccaacccggt aagacacgac ttatcgccac 6420
tggcagcagc cactggtaac aggattagca gagcgaggta tgtaggcggt gctacagagt 6480
tcttgaagtg gtggcctaac tacggctaca ctagaagaac agtatttggt atctgcgctc 6540
tgctgaagcc agttaccttc ggaaaaagag ttggtagctc ttgatccggc aaacaaacca 6600
ccgctggtag cggtggtttt tttgtttgca agcagcagat tacgcgcaga aaaaaaggat 6660
ctcaagaaga tcctttgatc ttttctacgg ggtctgacgc tcagtggaac gaaaactcac 6720
gttaagggat tttggtcatg agattatcaa aaaggatctt cacctagatc cttttaaatt 6780
aaaaatgaag ttttaaatca atctaaagta tatatgagta aacttggtct gacagttacc 6840
aatgcttaat cagtgaggca cctatctcag cgatctgtct atttcgttca tccatagttg 6900
cctgactc 6908
<210> 31
<211> 6914
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 31
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcaaggctg tgctgcttgc cctgttgatg gcaggcttgg ccctgcagcc 2040
aggcactgcc ctgctgtgct actcctgcaa agcccaggtg agcaacgagg actgcctgca 2100
ggtggagaac tgcacccagc tgggggagca gtgctggacc gcgcgcatcc gcgcagttgg 2160
cctcctgacc gtcatcagca aaggctgcag cttgaactgc gtggatgact cacaggacta 2220
ctacgtgggc aagaagaaca tcacgtgctg tgacaccgac ttgtgcaacg ccagcggggc 2280
ccatgccctg cagccggctg ccgccatcct tgcgctgctc cctgcactcg gcctgctgct 2340
ctggggaccc ggccagctat agagatctga ccccctaacg ttactggccg aagccgcttg 2400
gaataaggcc ggtgtgcgtt tgtctatatg ttattttcca ccatattgcc gtcttttggc 2460
aatgtgaggg cccggaaacc tggccctgtc ttcttgacga gcattcctag gggtctttcc 2520
cctctcgcca aaggaatgca aggtctgttg aatgtcgtga aggaagcagt tcctctggaa 2580
gcttcttgaa gacaaacaac gtctgtagcg accctttgca ggcagcggaa ccccccacct 2640
ggcgacaggt gcctctgcgg ccaaaagcca cgtgtataag atacacctgc aaaggcggca 2700
caaccccagt gccacgttgt gagttggata gttgtggaaa gagtcaaatg gctctcctca 2760
agcgtattca acaaggggct gaaggatgcc cagaaggtac cccattgtat gggatctgat 2820
ctggggcctc ggtgcacatg ctttacatgt gtttagtcga ggttaaaaaa cgtctaggcc 2880
ccccgaacca cggggacgtg gttttccttt gaaaaacacg atgataatat ggccacaacc 2940
atggcgcgcc gcccgcgctg gctgtgcgct ggggcgctgg tgctggcggg tggcttcttt 3000
ctcctcggct tcctcttcgg gtggtttata aaatcctcca atgaagctac taacattact 3060
ccaaagcata atatgaaagc atttttggat gaattgaaag ctgagaacat caagaagttc 3120
ttatataatt ttacacagat accacattta gcaggaacag aacaaaactt tcagcttgca 3180
aagcaaattc aatcccagtg gaaagaattt ggcctggatt ctgttgagct ggcacattat 3240
gatgtcctgt tgtcctaccc aaataagact catcccaact acatctcaat aattaatgaa 3300
gatggaaatg agattttcaa cacatcatta tttgaaccac ctcctccagg atatgaaaat 3360
gtttcggata ttgtaccacc tttcagtgct ttctctcctc aaggaatgcc agagggcgat 3420
ctagtgtatg ttaactatgc acgaactgaa gacttcttta aattggaacg ggacatgaaa 3480
atcaattgct ctgggaaaat tgtaattgcc agatatggga aagttttcag aggaaataag 3540
gttaaaaatg cccagctggc aggggccaaa ggagtcattc tctactccga ccctgctgac 3600
tactttgctc ctggggtgaa gtcctatcca gatggttgga atcttcctgg aggtggtgtc 3660
cagcgtggaa atatcctaaa tctgaatggt gcaggagacc ctctcacacc aggttaccca 3720
gcaaatgaat atgcttatag gcgtggaatt gcagaggctg ttggtcttcc aagtattcct 3780
gttcatccaa ttggatacta tgatgcacag aagctcctag aaaaaatggg tggctcagca 3840
ccaccagata gcagctggag aggaagtctc aaagtgccct acaatgttgg acctggcttt 3900
actggaaact tttctacaca aaaagtcaag atgcacatcc actctaccaa tgaagtgaca 3960
agaatttaca atgtgatagg tactctcaga ggagcagtgg aaccagacag atatgtcatt 4020
ctgggaggtc accgggactc atgggtgttt ggtggtattg accctcagag tggagcagct 4080
gttgttcatg aaattgtgag gagctttgga acactgaaaa aggaagggtg gagacctaga 4140
agaacaattt tgtttgcaag ctgggatgca gaagaatttg gtcttcttgg ttctactgag 4200
tgggcagagg agaattcaag actccttcaa gagcgtggcg tggcttatat taatgctgac 4260
tcatctatag aaggaaacta cactctgaga gttgattgta caccgctgat gtacagcttg 4320
gtacacaacc taacaaaaga gctgaaaagc cctgatgaag gctttgaagg caaatctctt 4380
tatgaaagtt ggactaaaaa aagtccttcc ccagagttca gtggcatgcc caggataagc 4440
aaattgggat ctggaaatga ttttgaggtg ttcttccaac gacttggaat tgcttcaggc 4500
agagcacggt atactaaaaa ttgggaaaca aacaaattca gcggctatcc actgtatcac 4560
agtgtctatg aaacatatga gttggtggaa aagttttatg atccaatgtt taaatatcac 4620
ctcactgtgg cccaggttcg aggagggatg gtgtttgagc tggccaattc catagtgctc 4680
ccttttgatt gtcgagatta tgctgtagtt ttaagaaagt atgctgacaa aatctacagt 4740
atttctatga aacatccaca ggaaatgaag acatacagtg tatcatttga ttcacttttt 4800
tctgcagtaa agaattttac agaaattgct tccaagttca gtgagagact ccaggacttt 4860
gacaaaagca acccaatagt attaagaatg atgaatgatc aactcatgtt tctggaaaga 4920
gcatttattg atccattagg gttaccagac aggccttttt ataggcatgt catctatgct 4980
ccaagcagcc acaacaagta tgcaggggag tcattcccag gaatttatga tgctctgttt 5040
gatattgaaa gcaaagtgga cccttccaag gcctggggag aagtgaagag acagatttat 5100
gttgcagcct tcacagtgca ggcagctgca gagactttga gtgaagtagc ctaaagatct 5160
gggccctaac aaaacaaaaa gatggggtta ttccctaaac ttcatgggtt acgtaattgg 5220
aagttggggg acattgccac aagatcatat tgtacaaaag atcaaacact gttttagaaa 5280
acttcctgta aacaggccta ttgattggaa agtatgtcaa aggattgtgg gtcttttggg 5340
ctttgctgct ccatttacac aatgtggata tcctgcctta atgcctttgt atgcatgtat 5400
acaagctaaa caggctttca ctttctcgcc aacttacaag gcctttctaa gtaaacagta 5460
catgaacctt taccccgttg ctcggcaacg gcctggtctg tgccaagtgt ttgctgacgc 5520
aacccccact ggctggggct tggccatagg ccatcagcgc atgcgtggaa cctttgtggc 5580
tcctctgccg atccatactg cggaactcct agccgcttgt tttgctcgca gccggtctgg 5640
agcaaagctc ataggaactg acaattctgt cgtcctctcg cggaaatata catcgtttcg 5700
atctacgtat gatctttttc cctctgccaa aaattatggg gacatcatga agccccttga 5760
gcatctgact tctggctaat aaaggaaatt tattttcatt gcaatagtgt gttggaattt 5820
tttgtgtctc tcactcggaa ggaattctgc attaatgaat cggccaacgc gcggggagag 5880
gcggtttgcg tattgggcgc tcttccgctt cctcgctcac tgactcgctg cgctcggtcg 5940
ttcggctgcg gcgagcggta tcagctcact caaaggcggt aatacggtta tccacagaat 6000
caggggataa cgcaggaaag aacatgtgag caaaaggcca gcaaaaggcc aggaaccgta 6060
aaaaggccgc gttgctggcg tttttccata ggctccgccc ccctgacgag catcacaaaa 6120
atcgacgctc aagtcagagg tggcgaaacc cgacaggact ataaagatac caggcgtttc 6180
cccctggaag ctccctcgtg cgctctcctg ttccgaccct gccgcttacc ggatacctgt 6240
ccgcctttct cccttcggga agcgtggcgc tttctcatag ctcacgctgt aggtatctca 6300
gttcggtgta ggtcgttcgc tccaagctgg gctgtgtgca cgaacccccc gttcagcccg 6360
accgctgcgc cttatccggt aactatcgtc ttgagtccaa cccggtaaga cacgacttat 6420
cgccactggc agcagccact ggtaacagga ttagcagagc gaggtatgta ggcggtgcta 6480
cagagttctt gaagtggtgg cctaactacg gctacactag aagaacagta tttggtatct 6540
gcgctctgct gaagccagtt accttcggaa aaagagttgg tagctcttga tccggcaaac 6600
aaaccaccgc tggtagcggt ggtttttttg tttgcaagca gcagattacg cgcagaaaaa 6660
aaggatctca agaagatcct ttgatctttt ctacggggtc tgacgctcag tggaacgaaa 6720
actcacgtta agggattttg gtcatgagat tatcaaaaag gatcttcacc tagatccttt 6780
taaattaaaa atgaagtttt aaatcaatct aaagtatata tgagtaaact tggtctgaca 6840
gttaccaatg cttaatcagt gaggcaccta tctcagcgat ctgtctattt cgttcatcca 6900
tagttgcctg actc 6914
<210> 32
<211> 5411
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 32
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcaaggctg tgctgcttgc cctgttgatg gcaggcttgg ccctgcagcc 2040
aggcactgcc ctgctgtgct actcctgcaa agcccaggtg agcaacgagg actgcctgca 2100
ggtggagaac tgcacccagc tgggggagca gtgctggacc gcgcgcatcc gcgcagttgg 2160
cctcctgacc gtcatcagca aaggctgcag cttgaactgc gtggatgact cacaggacta 2220
ctacgtgggc aagaagaaca tcacgtgctg tgacaccgac ttgtgcaacg ccagcggggc 2280
ccatgccctg cagccggctg ccgccatcct tgcgctgctc cctgcactcg gcctgctgct 2340
ctggggaccc ggccagctat agagatctga ccccctaacg ttactggccg aagccgcttg 2400
gaataaggcc ggtgtgcgtt tgtctatatg ttattttcca ccatattgcc gtcttttggc 2460
aatgtgaggg cccggaaacc tggccctgtc ttcttgacga gcattcctag gggtctttcc 2520
cctctcgcca aaggaatgca aggtctgttg aatgtcgtga aggaagcagt tcctctggaa 2580
gcttcttgaa gacaaacaac gtctgtagcg accctttgca ggcagcggaa ccccccacct 2640
ggcgacaggt gcctctgcgg ccaaaagcca cgtgtataag atacacctgc aaaggcggca 2700
caaccccagt gccacgttgt gagttggata gttgtggaaa gagtcaaatg gctctcctca 2760
agcgtattca acaaggggct gaaggatgcc cagaaggtac cccattgtat gggatctgat 2820
ctggggcctc ggtgcacatg ctttacatgt gtttagtcga ggttaaaaaa cgtctaggcc 2880
ccccgaacca cggggacgtg gttttccttt gaaaaacacg atgataatat ggccagcatt 2940
gtgggaggct gggagtgcga gaagcattcc caaccctggc aggtgcttgt ggcctctcgt 3000
ggcagggcag tctgcggcgg tgttctggtg cacccccagt gggtcctcac agctgcccac 3060
tgcatcagga acaaaagcgt gatcttgctg ggtcggcaca gcttgtttca tcctgaagac 3120
acaggccagg tatttcaggt cagccacagc ttcccacacc cgctctacga tatgagcctc 3180
ctgaagaatc gattcctcag gccaggtgat gactccagcc acgacctcat gctgctccgc 3240
ctgtcagagc ctgccgagct cacggatgct gtgaaggtca tggacctgcc cacccaggag 3300
ccagcactgg ggaccacctg ctacgcctca ggctggggca gcattgaacc agaggagttc 3360
ttgaccccaa agaaacttca gtgtgtggac ctccatgtta tttccaatga cgtgtgtgcg 3420
caagttcacc ctcagaaggt gaccaagttc atgctgtgtg ctggacgctg gacagggggc 3480
aaaagcacct gctcgggtga ttctgggggc ccacttgtct gtaatggtgt gcttcaaggt 3540
atcacgtcat ggggcagtga accatgtgcc ctgcccgaaa ggccttccct gtacaccaag 3600
gtggtgcatt accggaagtg gatcaaggac accatcgtgg ccaacccctg aggatctggg 3660
ccctaacaaa acaaaaagat ggggttattc cctaaacttc atgggttacg taattggaag 3720
ttgggggaca ttgccacaag atcatattgt acaaaagatc aaacactgtt ttagaaaact 3780
tcctgtaaac aggcctattg attggaaagt atgtcaaagg attgtgggtc ttttgggctt 3840
tgctgctcca tttacacaat gtggatatcc tgccttaatg cctttgtatg catgtataca 3900
agctaaacag gctttcactt tctcgccaac ttacaaggcc tttctaagta aacagtacat 3960
gaacctttac cccgttgctc ggcaacggcc tggtctgtgc caagtgtttg ctgacgcaac 4020
ccccactggc tggggcttgg ccataggcca tcagcgcatg cgtggaacct ttgtggctcc 4080
tctgccgatc catactgcgg aactcctagc cgcttgtttt gctcgcagcc ggtctggagc 4140
aaagctcata ggaactgaca attctgtcgt cctctcgcgg aaatatacat cgtttcgatc 4200
tacgtatgat ctttttccct ctgccaaaaa ttatggggac atcatgaagc cccttgagca 4260
tctgacttct ggctaataaa ggaaatttat tttcattgca atagtgtgtt ggaatttttt 4320
gtgtctctca ctcggaagga attctgcatt aatgaatcgg ccaacgcgcg gggagaggcg 4380
gtttgcgtat tgggcgctct tccgcttcct cgctcactga ctcgctgcgc tcggtcgttc 4440
ggctgcggcg agcggtatca gctcactcaa aggcggtaat acggttatcc acagaatcag 4500
gggataacgc aggaaagaac atgtgagcaa aaggccagca aaaggccagg aaccgtaaaa 4560
aggccgcgtt gctggcgttt ttccataggc tccgcccccc tgacgagcat cacaaaaatc 4620
gacgctcaag tcagaggtgg cgaaacccga caggactata aagataccag gcgtttcccc 4680
ctggaagctc cctcgtgcgc tctcctgttc cgaccctgcc gcttaccgga tacctgtccg 4740
cctttctccc ttcgggaagc gtggcgcttt ctcatagctc acgctgtagg tatctcagtt 4800
cggtgtaggt cgttcgctcc aagctgggct gtgtgcacga accccccgtt cagcccgacc 4860
gctgcgcctt atccggtaac tatcgtcttg agtccaaccc ggtaagacac gacttatcgc 4920
cactggcagc agccactggt aacaggatta gcagagcgag gtatgtaggc ggtgctacag 4980
agttcttgaa gtggtggcct aactacggct acactagaag aacagtattt ggtatctgcg 5040
ctctgctgaa gccagttacc ttcggaaaaa gagttggtag ctcttgatcc ggcaaacaaa 5100
ccaccgctgg tagcggtggt ttttttgttt gcaagcagca gattacgcgc agaaaaaaag 5160
gatctcaaga agatcctttg atcttttcta cggggtctga cgctcagtgg aacgaaaact 5220
cacgttaagg gattttggtc atgagattat caaaaaggat cttcacctag atccttttaa 5280
attaaaaatg aagttttaaa tcaatctaaa gtatatatga gtaaacttgg tctgacagtt 5340
accaatgctt aatcagtgag gcacctatct cagcgatctg tctatttcgt tcatccatag 5400
ttgcctgact c 5411
<210> 33
<211> 7694
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 33
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcattgtgg gaggctggga gtgcgagaag cattcccaac cctggcaggt 2040
gcttgtggcc tctcgtggca gggcagtctg cggcggtgtt ctggtgcacc cccagtgggt 2100
cctcacagct gcccactgca tcaggaacaa aagcgtgatc ttgctgggtc ggcacagctt 2160
gtttcatcct gaagacacag gccaggtatt tcaggtcagc cacagcttcc cacacccgct 2220
ctacgatatg agcctcctga agaatcgatt cctcaggcca ggtgatgact ccagccacga 2280
cctcatgctg ctccgcctgt cagagcctgc cgagctcacg gatgctgtga aggtcatgga 2340
cctgcccacc caggagccag cactggggac cacctgctac gcctcaggct ggggcagcat 2400
tgaaccagag gagttcttga ccccaaagaa acttcagtgt gtggacctcc atgttatttc 2460
caatgacgtg tgtgcgcaag ttcaccctca gaaggtgacc aagttcatgc tgtgtgctgg 2520
acgctggaca gggggcaaaa gcacctgctc gggtgattct gggggcccac ttgtctgtaa 2580
tggtgtgctt caaggtatca cgtcatgggg cagtgaacca tgtgccctgc ccgaaaggcc 2640
ttccctgtac accaaggtgg tgcattaccg gaagtggatc aaggacacca tcgtggccaa 2700
ccccggatcc cagaccctga actttgatct gctgaaactg gcaggcgatg tggaaagcaa 2760
cccaggccca atggcaagcg cgcgccgccc gcgctggctg tgcgctgggg cgctggtgct 2820
ggcgggtggc ttctttctcc tcggcttcct cttcgggtgg tttataaaat cctccaatga 2880
agctactaac attactccaa agcataatat gaaagcattt ttggatgaat tgaaagctga 2940
gaacatcaag aagttcttat ataattttac acagatacca catttagcag gaacagaaca 3000
aaactttcag cttgcaaagc aaattcaatc ccagtggaaa gaatttggcc tggattctgt 3060
tgagctggca cattatgatg tcctgttgtc ctacccaaat aagactcatc ccaactacat 3120
ctcaataatt aatgaagatg gaaatgagat tttcaacaca tcattatttg aaccacctcc 3180
tccaggatat gaaaatgttt cggatattgt accacctttc agtgctttct ctcctcaagg 3240
aatgccagag ggcgatctag tgtatgttaa ctatgcacga actgaagact tctttaaatt 3300
ggaacgggac atgaaaatca attgctctgg gaaaattgta attgccagat atgggaaagt 3360
tttcagagga aataaggtta aaaatgccca gctggcaggg gccaaaggag tcattctcta 3420
ctccgaccct gctgactact ttgctcctgg ggtgaagtcc tatccagatg gttggaatct 3480
tcctggaggt ggtgtccagc gtggaaatat cctaaatctg aatggtgcag gagaccctct 3540
cacaccaggt tacccagcaa atgaatatgc ttataggcgt ggaattgcag aggctgttgg 3600
tcttccaagt attcctgttc atccaattgg atactatgat gcacagaagc tcctagaaaa 3660
aatgggtggc tcagcaccac cagatagcag ctggagagga agtctcaaag tgccctacaa 3720
tgttggacct ggctttactg gaaacttttc tacacaaaaa gtcaagatgc acatccactc 3780
taccaatgaa gtgacaagaa tttacaatgt gataggtact ctcagaggag cagtggaacc 3840
agacagatat gtcattctgg gaggtcaccg ggactcatgg gtgtttggtg gtattgaccc 3900
tcagagtgga gcagctgttg ttcatgaaat tgtgaggagc tttggaacac tgaaaaagga 3960
agggtggaga cctagaagaa caattttgtt tgcaagctgg gatgcagaag aatttggtct 4020
tcttggttct actgagtggg cagaggagaa ttcaagactc cttcaagagc gtggcgtggc 4080
ttatattaat gctgactcat ctatagaagg aaactacact ctgagagttg attgtacacc 4140
gctgatgtac agcttggtac acaacctaac aaaagagctg aaaagccctg atgaaggctt 4200
tgaaggcaaa tctctttatg aaagttggac taaaaaaagt ccttccccag agttcagtgg 4260
catgcccagg ataagcaaat tgggatctgg aaatgatttt gaggtgttct tccaacgact 4320
tggaattgct tcaggcagag cacggtatac taaaaattgg gaaacaaaca aattcagcgg 4380
ctatccactg tatcacagtg tctatgaaac atatgagttg gtggaaaagt tttatgatcc 4440
aatgtttaaa tatcacctca ctgtggccca ggttcgagga gggatggtgt ttgagctggc 4500
caattccata gtgctccctt ttgattgtcg agattatgct gtagttttaa gaaagtatgc 4560
tgacaaaatc tacagtattt ctatgaaaca tccacaggaa atgaagacat acagtgtatc 4620
atttgattca cttttttctg cagtaaagaa ttttacagaa attgcttcca agttcagtga 4680
gagactccag gactttgaca aaagcaaccc aatagtatta agaatgatga atgatcaact 4740
catgtttctg gaaagagcat ttattgatcc attagggtta ccagacaggc ctttttatag 4800
gcatgtcatc tatgctccaa gcagccacaa caagtatgca ggggagtcat tcccaggaat 4860
ttatgatgct ctgtttgata ttgaaagcaa agtggaccct tccaaggcct ggggagaagt 4920
gaagagacag atttatgttg cagccttcac agtgcaggca gctgcagaga ctttgagtga 4980
agtagcctaa agatctgacc ccctaacgtt actggccgaa gccgcttgga ataaggccgg 5040
tgtgcgtttg tctatatgtt attttccacc atattgccgt cttttggcaa tgtgagggcc 5100
cggaaacctg gccctgtctt cttgacgagc attcctaggg gtctttcccc tctcgccaaa 5160
ggaatgcaag gtctgttgaa tgtcgtgaag gaagcagttc ctctggaagc ttcttgaaga 5220
caaacaacgt ctgtagcgac cctttgcagg cagcggaacc ccccacctgg cgacaggtgc 5280
ctctgcggcc aaaagccacg tgtataagat acacctgcaa aggcggcaca accccagtgc 5340
cacgttgtga gttggatagt tgtggaaaga gtcaaatggc tctcctcaag cgtattcaac 5400
aaggggctga aggatgccca gaaggtaccc cattgtatgg gatctgatct ggggcctcgg 5460
tgcacatgct ttacatgtgt ttagtcgagg ttaaaaaacg tctaggcccc ccgaaccacg 5520
gggacgtggt tttcctttga aaaacacgat gataatatgg ccagcaaggc tgtgctgctt 5580
gccctgttga tggcaggctt ggccctgcag ccaggcactg ccctgctgtg ctactcctgc 5640
aaagcccagg tgagcaacga ggactgcctg caggtggaga actgcaccca gctgggggag 5700
cagtgctgga ccgcgcgcat ccgcgcagtt ggcctcctga ccgtcatcag caaaggctgc 5760
agcttgaact gcgtggatga ctcacaggac tactacgtgg gcaagaagaa catcacgtgc 5820
tgtgacaccg acttgtgcaa cgccagcggg gcccatgccc tgcagccggc tgccgccatc 5880
cttgcgctgc tccctgcact cggcctgctg ctctggggac ccggccagct atagggatct 5940
gggccctaac aaaacaaaaa gatggggtta ttccctaaac ttcatgggtt acgtaattgg 6000
aagttggggg acattgccac aagatcatat tgtacaaaag atcaaacact gttttagaaa 6060
acttcctgta aacaggccta ttgattggaa agtatgtcaa aggattgtgg gtcttttggg 6120
ctttgctgct ccatttacac aatgtggata tcctgcctta atgcctttgt atgcatgtat 6180
acaagctaaa caggctttca ctttctcgcc aacttacaag gcctttctaa gtaaacagta 6240
catgaacctt taccccgttg ctcggcaacg gcctggtctg tgccaagtgt ttgctgacgc 6300
aacccccact ggctggggct tggccatagg ccatcagcgc atgcgtggaa cctttgtggc 6360
tcctctgccg atccatactg cggaactcct agccgcttgt tttgctcgca gccggtctgg 6420
agcaaagctc ataggaactg acaattctgt cgtcctctcg cggaaatata catcgtttcg 6480
atctacgtat gatctttttc cctctgccaa aaattatggg gacatcatga agccccttga 6540
gcatctgact tctggctaat aaaggaaatt tattttcatt gcaatagtgt gttggaattt 6600
tttgtgtctc tcactcggaa ggaattctgc attaatgaat cggccaacgc gcggggagag 6660
gcggtttgcg tattgggcgc tcttccgctt cctcgctcac tgactcgctg cgctcggtcg 6720
ttcggctgcg gcgagcggta tcagctcact caaaggcggt aatacggtta tccacagaat 6780
caggggataa cgcaggaaag aacatgtgag caaaaggcca gcaaaaggcc aggaaccgta 6840
aaaaggccgc gttgctggcg tttttccata ggctccgccc ccctgacgag catcacaaaa 6900
atcgacgctc aagtcagagg tggcgaaacc cgacaggact ataaagatac caggcgtttc 6960
cccctggaag ctccctcgtg cgctctcctg ttccgaccct gccgcttacc ggatacctgt 7020
ccgcctttct cccttcggga agcgtggcgc tttctcatag ctcacgctgt aggtatctca 7080
gttcggtgta ggtcgttcgc tccaagctgg gctgtgtgca cgaacccccc gttcagcccg 7140
accgctgcgc cttatccggt aactatcgtc ttgagtccaa cccggtaaga cacgacttat 7200
cgccactggc agcagccact ggtaacagga ttagcagagc gaggtatgta ggcggtgcta 7260
cagagttctt gaagtggtgg cctaactacg gctacactag aagaacagta tttggtatct 7320
gcgctctgct gaagccagtt accttcggaa aaagagttgg tagctcttga tccggcaaac 7380
aaaccaccgc tggtagcggt ggtttttttg tttgcaagca gcagattacg cgcagaaaaa 7440
aaggatctca agaagatcct ttgatctttt ctacggggtc tgacgctcag tggaacgaaa 7500
actcacgtta agggattttg gtcatgagat tatcaaaaag gatcttcacc tagatccttt 7560
taaattaaaa atgaagtttt aaatcaatct aaagtatata tgagtaaact tggtctgaca 7620
gttaccaatg cttaatcagt gaggcaccta tctcagcgat ctgtctattt cgttcatcca 7680
tagttgcctg actc 7694
<210> 34
<211> 7182
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 34
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcattgtgg gaggctggga gtgcgagaag cattcccaac cctggcaggt 2040
gcttgtggcc tctcgtggca gggcagtctg cggcggtgtt ctggtgcacc cccagtgggt 2100
cctcacagct gcccactgca tcaggaacaa aagcgtgatc ttgctgggtc ggcacagctt 2160
gtttcatcct gaagacacag gccaggtatt tcaggtcagc cacagcttcc cacacccgct 2220
ctacgatatg agcctcctga agaatcgatt cctcaggcca ggtgatgact ccagccacga 2280
cctcatgctg ctccgcctgt cagagcctgc cgagctcacg gatgctgtga aggtcatgga 2340
cctgcccacc caggagccag cactggggac cacctgctac gcctcaggct ggggcagcat 2400
tgaaccagag gagttcttga ccccaaagaa acttcagtgt gtggacctcc atgttatttc 2460
caatgacgtg tgtgcgcaag ttcaccctca gaaggtgacc aagttcatgc tgtgtgctgg 2520
acgctggaca gggggcaaaa gcacctgctc gggtgattct gggggcccac ttgtctgtaa 2580
tggtgtgctt caaggtatca cgtcatgggg cagtgaacca tgtgccctgc ccgaaaggcc 2640
ttccctgtac accaaggtgg tgcattaccg gaagtggatc aaggacacca tcgtggccaa 2700
ccccggatcc cagaccctga actttgatct gctgaaactg gcaggcgatg tggaaagcaa 2760
cccaggccca atggcaagcg cgcgccgccc gcgctggctg tgcgctgggg cgctggtgct 2820
ggcgggtggc ttctttctcc tcggcttcct cttcgggtgg tttataaaat cctccaatga 2880
agctactaac attactccaa agcataatat gaaagcattt ttggatgaat tgaaagctga 2940
gaacatcaag aagttcttat ataattttac acagatacca catttagcag gaacagaaca 3000
aaactttcag cttgcaaagc aaattcaatc ccagtggaaa gaatttggcc tggattctgt 3060
tgagctggca cattatgatg tcctgttgtc ctacccaaat aagactcatc ccaactacat 3120
ctcaataatt aatgaagatg gaaatgagat tttcaacaca tcattatttg aaccacctcc 3180
tccaggatat gaaaatgttt cggatattgt accacctttc agtgctttct ctcctcaagg 3240
aatgccagag ggcgatctag tgtatgttaa ctatgcacga actgaagact tctttaaatt 3300
ggaacgggac atgaaaatca attgctctgg gaaaattgta attgccagat atgggaaagt 3360
tttcagagga aataaggtta aaaatgccca gctggcaggg gccaaaggag tcattctcta 3420
ctccgaccct gctgactact ttgctcctgg ggtgaagtcc tatccagatg gttggaatct 3480
tcctggaggt ggtgtccagc gtggaaatat cctaaatctg aatggtgcag gagaccctct 3540
cacaccaggt tacccagcaa atgaatatgc ttataggcgt ggaattgcag aggctgttgg 3600
tcttccaagt attcctgttc atccaattgg atactatgat gcacagaagc tcctagaaaa 3660
aatgggtggc tcagcaccac cagatagcag ctggagagga agtctcaaag tgccctacaa 3720
tgttggacct ggctttactg gaaacttttc tacacaaaaa gtcaagatgc acatccactc 3780
taccaatgaa gtgacaagaa tttacaatgt gataggtact ctcagaggag cagtggaacc 3840
agacagatat gtcattctgg gaggtcaccg ggactcatgg gtgtttggtg gtattgaccc 3900
tcagagtgga gcagctgttg ttcatgaaat tgtgaggagc tttggaacac tgaaaaagga 3960
agggtggaga cctagaagaa caattttgtt tgcaagctgg gatgcagaag aatttggtct 4020
tcttggttct actgagtggg cagaggagaa ttcaagactc cttcaagagc gtggcgtggc 4080
ttatattaat gctgactcat ctatagaagg aaactacact ctgagagttg attgtacacc 4140
gctgatgtac agcttggtac acaacctaac aaaagagctg aaaagccctg atgaaggctt 4200
tgaaggcaaa tctctttatg aaagttggac taaaaaaagt ccttccccag agttcagtgg 4260
catgcccagg ataagcaaat tgggatctgg aaatgatttt gaggtgttct tccaacgact 4320
tggaattgct tcaggcagag cacggtatac taaaaattgg gaaacaaaca aattcagcgg 4380
ctatccactg tatcacagtg tctatgaaac atatgagttg gtggaaaagt tttatgatcc 4440
aatgtttaaa tatcacctca ctgtggccca ggttcgagga gggatggtgt ttgagctggc 4500
caattccata gtgctccctt ttgattgtcg agattatgct gtagttttaa gaaagtatgc 4560
tgacaaaatc tacagtattt ctatgaaaca tccacaggaa atgaagacat acagtgtatc 4620
atttgattca cttttttctg cagtaaagaa ttttacagaa attgcttcca agttcagtga 4680
gagactccag gactttgaca aaagcaaccc aatagtatta agaatgatga atgatcaact 4740
catgtttctg gaaagagcat ttattgatcc attagggtta ccagacaggc ctttttatag 4800
gcatgtcatc tatgctccaa gcagccacaa caagtatgca ggggagtcat tcccaggaat 4860
ttatgatgct ctgtttgata ttgaaagcaa agtggaccct tccaaggcct ggggagaagt 4920
gaagagacag atttatgttg cagccttcac agtgcaggca gctgcagaga ctttgagtga 4980
agtagccgga tccgaaggta ggggttcatt attgacctgt ggagatgtcg aagaaaaccc 5040
aggacccgca agcaaggctg tgctgcttgc cctgttgatg gcaggcttgg ccctgcagcc 5100
aggcactgcc ctgctgtgct actcctgcaa agcccaggtg agcaacgagg actgcctgca 5160
ggtggagaac tgcacccagc tgggggagca gtgctggacc gcgcgcatcc gcgcagttgg 5220
cctcctgacc gtcatcagca aaggctgcag cttgaactgc gtggatgact cacaggacta 5280
ctacgtgggc aagaagaaca tcacgtgctg tgacaccgac ttgtgcaacg ccagcggggc 5340
ccatgccctg cagccggctg ccgccatcct tgcgctgctc cctgcactcg gcctgctgct 5400
ctggggaccc ggccagctat agagatctgg gccctaacaa aacaaaaaga tggggttatt 5460
ccctaaactt catgggttac gtaattggaa gttgggggac attgccacaa gatcatattg 5520
tacaaaagat caaacactgt tttagaaaac ttcctgtaaa caggcctatt gattggaaag 5580
tatgtcaaag gattgtgggt cttttgggct ttgctgctcc atttacacaa tgtggatatc 5640
ctgccttaat gcctttgtat gcatgtatac aagctaaaca ggctttcact ttctcgccaa 5700
cttacaaggc ctttctaagt aaacagtaca tgaaccttta ccccgttgct cggcaacggc 5760
ctggtctgtg ccaagtgttt gctgacgcaa cccccactgg ctggggcttg gccataggcc 5820
atcagcgcat gcgtggaacc tttgtggctc ctctgccgat ccatactgcg gaactcctag 5880
ccgcttgttt tgctcgcagc cggtctggag caaagctcat aggaactgac aattctgtcg 5940
tcctctcgcg gaaatataca tcgtttcgat ctacgtatga tctttttccc tctgccaaaa 6000
attatgggga catcatgaag ccccttgagc atctgacttc tggctaataa aggaaattta 6060
ttttcattgc aatagtgtgt tggaattttt tgtgtctctc actcggaagg aattctgcat 6120
taatgaatcg gccaacgcgc ggggagaggc ggtttgcgta ttgggcgctc ttccgcttcc 6180
tcgctcactg actcgctgcg ctcggtcgtt cggctgcggc gagcggtatc agctcactca 6240
aaggcggtaa tacggttatc cacagaatca ggggataacg caggaaagaa catgtgagca 6300
aaaggccagc aaaaggccag gaaccgtaaa aaggccgcgt tgctggcgtt tttccatagg 6360
ctccgccccc ctgacgagca tcacaaaaat cgacgctcaa gtcagaggtg gcgaaacccg 6420
acaggactat aaagatacca ggcgtttccc cctggaagct ccctcgtgcg ctctcctgtt 6480
ccgaccctgc cgcttaccgg atacctgtcc gcctttctcc cttcgggaag cgtggcgctt 6540
tctcatagct cacgctgtag gtatctcagt tcggtgtagg tcgttcgctc caagctgggc 6600
tgtgtgcacg aaccccccgt tcagcccgac cgctgcgcct tatccggtaa ctatcgtctt 6660
gagtccaacc cggtaagaca cgacttatcg ccactggcag cagccactgg taacaggatt 6720
agcagagcga ggtatgtagg cggtgctaca gagttcttga agtggtggcc taactacggc 6780
tacactagaa gaacagtatt tggtatctgc gctctgctga agccagttac cttcggaaaa 6840
agagttggta gctcttgatc cggcaaacaa accaccgctg gtagcggtgg tttttttgtt 6900
tgcaagcagc agattacgcg cagaaaaaaa ggatctcaag aagatccttt gatcttttct 6960
acggggtctg acgctcagtg gaacgaaaac tcacgttaag ggattttggt catgagatta 7020
tcaaaaagga tcttcaccta gatcctttta aattaaaaat gaagttttaa atcaatctaa 7080
agtatatatg agtaaacttg gtctgacagt taccaatgct taatcagtga ggcacctatc 7140
tcagcgatct gtctatttcg ttcatccata gttgcctgac tc 7182
<210> 35
<211> 7182
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 35
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcattgtgg gaggctggga gtgcgagaag cattcccaac cctggcaggt 2040
gcttgtggcc tctcgtggca gggcagtctg cggcggtgtt ctggtgcacc cccagtgggt 2100
cctcacagct gcccactgca tcaggaacaa aagcgtgatc ttgctgggtc ggcacagctt 2160
gtttcatcct gaagacacag gccaggtatt tcaggtcagc cacagcttcc cacacccgct 2220
ctacgatatg agcctcctga agaatcgatt cctcaggcca ggtgatgact ccagccacga 2280
cctcatgctg ctccgcctgt cagagcctgc cgagctcacg gatgctgtga aggtcatgga 2340
cctgcccacc caggagccag cactggggac cacctgctac gcctcaggct ggggcagcat 2400
tgaaccagag gagttcttga ccccaaagaa acttcagtgt gtggacctcc atgttatttc 2460
caatgacgtg tgtgcgcaag ttcaccctca gaaggtgacc aagttcatgc tgtgtgctgg 2520
acgctggaca gggggcaaaa gcacctgctc gggtgattct gggggcccac ttgtctgtaa 2580
tggtgtgctt caaggtatca cgtcatgggg cagtgaacca tgtgccctgc ccgaaaggcc 2640
ttccctgtac accaaggtgg tgcattaccg gaagtggatc aaggacacca tcgtggccaa 2700
ccccggatcc gaaggtaggg gttcattatt gacctgtgga gatgtcgaag aaaacccagg 2760
acccgctagc aaggctgtgc tgcttgccct gttgatggca ggcttggccc tgcagccagg 2820
cactgccctg ctgtgctact cctgcaaagc ccaggtgagc aacgaggact gcctgcaggt 2880
ggagaactgc acccagctgg gggagcagtg ctggaccgcg cgcatccgcg cagttggcct 2940
cctgaccgtc atcagcaaag gctgcagctt gaactgcgtg gatgactcac aggactacta 3000
cgtgggcaag aagaacatca cgtgctgtga caccgacttg tgcaacgcca gcggggccca 3060
tgccctgcag ccggctgccg ccatccttgc gctgctccct gcactcggcc tgctgctctg 3120
gggacccggc cagctaggat cccagaccct gaactttgat ctgctgaaac tggcaggcga 3180
tgtggaaagc aacccaggcc caatggcaag cgcgcgccgc ccgcgctggc tgtgcgctgg 3240
ggcgctggtg ctggcgggtg gcttctttct cctcggcttc ctcttcgggt ggtttataaa 3300
atcctccaat gaagctacta acattactcc aaagcataat atgaaagcat ttttggatga 3360
attgaaagct gagaacatca agaagttctt atataatttt acacagatac cacatttagc 3420
aggaacagaa caaaactttc agcttgcaaa gcaaattcaa tcccagtgga aagaatttgg 3480
cctggattct gttgagctgg cacattatga tgtcctgttg tcctacccaa ataagactca 3540
tcccaactac atctcaataa ttaatgaaga tggaaatgag attttcaaca catcattatt 3600
tgaaccacct cctccaggat atgaaaatgt ttcggatatt gtaccacctt tcagtgcttt 3660
ctctcctcaa ggaatgccag agggcgatct agtgtatgtt aactatgcac gaactgaaga 3720
cttctttaaa ttggaacggg acatgaaaat caattgctct gggaaaattg taattgccag 3780
atatgggaaa gttttcagag gaaataaggt taaaaatgcc cagctggcag gggccaaagg 3840
agtcattctc tactccgacc ctgctgacta ctttgctcct ggggtgaagt cctatccaga 3900
tggttggaat cttcctggag gtggtgtcca gcgtggaaat atcctaaatc tgaatggtgc 3960
aggagaccct ctcacaccag gttacccagc aaatgaatat gcttataggc gtggaattgc 4020
agaggctgtt ggtcttccaa gtattcctgt tcatccaatt ggatactatg atgcacagaa 4080
gctcctagaa aaaatgggtg gctcagcacc accagatagc agctggagag gaagtctcaa 4140
agtgccctac aatgttggac ctggctttac tggaaacttt tctacacaaa aagtcaagat 4200
gcacatccac tctaccaatg aagtgacaag aatttacaat gtgataggta ctctcagagg 4260
agcagtggaa ccagacagat atgtcattct gggaggtcac cgggactcat gggtgtttgg 4320
tggtattgac cctcagagtg gagcagctgt tgttcatgaa attgtgagga gctttggaac 4380
actgaaaaag gaagggtgga gacctagaag aacaattttg tttgcaagct gggatgcaga 4440
agaatttggt cttcttggtt ctactgagtg ggcagaggag aattcaagac tccttcaaga 4500
gcgtggcgtg gcttatatta atgctgactc atctatagaa ggaaactaca ctctgagagt 4560
tgattgtaca ccgctgatgt acagcttggt acacaaccta acaaaagagc tgaaaagccc 4620
tgatgaaggc tttgaaggca aatctcttta tgaaagttgg actaaaaaaa gtccttcccc 4680
agagttcagt ggcatgccca ggataagcaa attgggatct ggaaatgatt ttgaggtgtt 4740
cttccaacga cttggaattg cttcaggcag agcacggtat actaaaaatt gggaaacaaa 4800
caaattcagc ggctatccac tgtatcacag tgtctatgaa acatatgagt tggtggaaaa 4860
gttttatgat ccaatgttta aatatcacct cactgtggcc caggttcgag gagggatggt 4920
gtttgagctg gccaattcca tagtgctccc ttttgattgt cgagattatg ctgtagtttt 4980
aagaaagtat gctgacaaaa tctacagtat ttctatgaaa catccacagg aaatgaagac 5040
atacagtgta tcatttgatt cacttttttc tgcagtaaag aattttacag aaattgcttc 5100
caagttcagt gagagactcc aggactttga caaaagcaac ccaatagtat taagaatgat 5160
gaatgatcaa ctcatgtttc tggaaagagc atttattgat ccattagggt taccagacag 5220
gcctttttat aggcatgtca tctatgctcc aagcagccac aacaagtatg caggggagtc 5280
attcccagga atttatgatg ctctgtttga tattgaaagc aaagtggacc cttccaaggc 5340
ctggggagaa gtgaagagac agatttatgt tgcagccttc acagtgcagg cagctgcaga 5400
gactttgagt gaagtagcct aaagatctgg gccctaacaa aacaaaaaga tggggttatt 5460
ccctaaactt catgggttac gtaattggaa gttgggggac attgccacaa gatcatattg 5520
tacaaaagat caaacactgt tttagaaaac ttcctgtaaa caggcctatt gattggaaag 5580
tatgtcaaag gattgtgggt cttttgggct ttgctgctcc atttacacaa tgtggatatc 5640
ctgccttaat gcctttgtat gcatgtatac aagctaaaca ggctttcact ttctcgccaa 5700
cttacaaggc ctttctaagt aaacagtaca tgaaccttta ccccgttgct cggcaacggc 5760
ctggtctgtg ccaagtgttt gctgacgcaa cccccactgg ctggggcttg gccataggcc 5820
atcagcgcat gcgtggaacc tttgtggctc ctctgccgat ccatactgcg gaactcctag 5880
ccgcttgttt tgctcgcagc cggtctggag caaagctcat aggaactgac aattctgtcg 5940
tcctctcgcg gaaatataca tcgtttcgat ctacgtatga tctttttccc tctgccaaaa 6000
attatgggga catcatgaag ccccttgagc atctgacttc tggctaataa aggaaattta 6060
ttttcattgc aatagtgtgt tggaattttt tgtgtctctc actcggaagg aattctgcat 6120
taatgaatcg gccaacgcgc ggggagaggc ggtttgcgta ttgggcgctc ttccgcttcc 6180
tcgctcactg actcgctgcg ctcggtcgtt cggctgcggc gagcggtatc agctcactca 6240
aaggcggtaa tacggttatc cacagaatca ggggataacg caggaaagaa catgtgagca 6300
aaaggccagc aaaaggccag gaaccgtaaa aaggccgcgt tgctggcgtt tttccatagg 6360
ctccgccccc ctgacgagca tcacaaaaat cgacgctcaa gtcagaggtg gcgaaacccg 6420
acaggactat aaagatacca ggcgtttccc cctggaagct ccctcgtgcg ctctcctgtt 6480
ccgaccctgc cgcttaccgg atacctgtcc gcctttctcc cttcgggaag cgtggcgctt 6540
tctcatagct cacgctgtag gtatctcagt tcggtgtagg tcgttcgctc caagctgggc 6600
tgtgtgcacg aaccccccgt tcagcccgac cgctgcgcct tatccggtaa ctatcgtctt 6660
gagtccaacc cggtaagaca cgacttatcg ccactggcag cagccactgg taacaggatt 6720
agcagagcga ggtatgtagg cggtgctaca gagttcttga agtggtggcc taactacggc 6780
tacactagaa gaacagtatt tggtatctgc gctctgctga agccagttac cttcggaaaa 6840
agagttggta gctcttgatc cggcaaacaa accaccgctg gtagcggtgg tttttttgtt 6900
tgcaagcagc agattacgcg cagaaaaaaa ggatctcaag aagatccttt gatcttttct 6960
acggggtctg acgctcagtg gaacgaaaac tcacgttaag ggattttggt catgagatta 7020
tcaaaaagga tcttcaccta gatcctttta aattaaaaat gaagttttaa atcaatctaa 7080
agtatatatg agtaaacttg gtctgacagt taccaatgct taatcagtga ggcacctatc 7140
tcagcgatct gtctatttcg ttcatccata gttgcctgac tc 7182
<210> 36
<211> 7694
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 36
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcaaggctg tgctgcttgc cctgttgatg gcaggcttgg ccctgcagcc 2040
aggcactgcc ctgctgtgct actcctgcaa agcccaggtg agcaacgagg actgcctgca 2100
ggtggagaac tgcacccagc tgggggagca gtgctggacc gcgcgcatcc gcgcagttgg 2160
cctcctgacc gtcatcagca aaggctgcag cttgaactgc gtggatgact cacaggacta 2220
ctacgtgggc aagaagaaca tcacgtgctg tgacaccgac ttgtgcaacg ccagcggggc 2280
ccatgccctg cagccggctg ccgccatcct tgcgctgctc cctgcactcg gcctgctgct 2340
ctggggaccc ggccagctag gatcccagac cctgaacttt gatctgctga aactggcagg 2400
cgatgtggaa agcaacccag gcccaatggc aagcgcgcgc cgcccgcgct ggctgtgcgc 2460
tggggcgctg gtgctggcgg gtggcttctt tctcctcggc ttcctcttcg ggtggtttat 2520
aaaatcctcc aatgaagcta ctaacattac tccaaagcat aatatgaaag catttttgga 2580
tgaattgaaa gctgagaaca tcaagaagtt cttatataat tttacacaga taccacattt 2640
agcaggaaca gaacaaaact ttcagcttgc aaagcaaatt caatcccagt ggaaagaatt 2700
tggcctggat tctgttgagc tggcacatta tgatgtcctg ttgtcctacc caaataagac 2760
tcatcccaac tacatctcaa taattaatga agatggaaat gagattttca acacatcatt 2820
atttgaacca cctcctccag gatatgaaaa tgtttcggat attgtaccac ctttcagtgc 2880
tttctctcct caaggaatgc cagagggcga tctagtgtat gttaactatg cacgaactga 2940
agacttcttt aaattggaac gggacatgaa aatcaattgc tctgggaaaa ttgtaattgc 3000
cagatatggg aaagttttca gaggaaataa ggttaaaaat gcccagctgg caggggccaa 3060
aggagtcatt ctctactccg accctgctga ctactttgct cctggggtga agtcctatcc 3120
agatggttgg aatcttcctg gaggtggtgt ccagcgtgga aatatcctaa atctgaatgg 3180
tgcaggagac cctctcacac caggttaccc agcaaatgaa tatgcttata ggcgtggaat 3240
tgcagaggct gttggtcttc caagtattcc tgttcatcca attggatact atgatgcaca 3300
gaagctccta gaaaaaatgg gtggctcagc accaccagat agcagctgga gaggaagtct 3360
caaagtgccc tacaatgttg gacctggctt tactggaaac ttttctacac aaaaagtcaa 3420
gatgcacatc cactctacca atgaagtgac aagaatttac aatgtgatag gtactctcag 3480
aggagcagtg gaaccagaca gatatgtcat tctgggaggt caccgggact catgggtgtt 3540
tggtggtatt gaccctcaga gtggagcagc tgttgttcat gaaattgtga ggagctttgg 3600
aacactgaaa aaggaagggt ggagacctag aagaacaatt ttgtttgcaa gctgggatgc 3660
agaagaattt ggtcttcttg gttctactga gtgggcagag gagaattcaa gactccttca 3720
agagcgtggc gtggcttata ttaatgctga ctcatctata gaaggaaact acactctgag 3780
agttgattgt acaccgctga tgtacagctt ggtacacaac ctaacaaaag agctgaaaag 3840
ccctgatgaa ggctttgaag gcaaatctct ttatgaaagt tggactaaaa aaagtccttc 3900
cccagagttc agtggcatgc ccaggataag caaattggga tctggaaatg attttgaggt 3960
gttcttccaa cgacttggaa ttgcttcagg cagagcacgg tatactaaaa attgggaaac 4020
aaacaaattc agcggctatc cactgtatca cagtgtctat gaaacatatg agttggtgga 4080
aaagttttat gatccaatgt ttaaatatca cctcactgtg gcccaggttc gaggagggat 4140
ggtgtttgag ctggccaatt ccatagtgct cccttttgat tgtcgagatt atgctgtagt 4200
tttaagaaag tatgctgaca aaatctacag tatttctatg aaacatccac aggaaatgaa 4260
gacatacagt gtatcatttg attcactttt ttctgcagta aagaatttta cagaaattgc 4320
ttccaagttc agtgagagac tccaggactt tgacaaaagc aacccaatag tattaagaat 4380
gatgaatgat caactcatgt ttctggaaag agcatttatt gatccattag ggttaccaga 4440
caggcctttt tataggcatg tcatctatgc tccaagcagc cacaacaagt atgcagggga 4500
gtcattccca ggaatttatg atgctctgtt tgatattgaa agcaaagtgg acccttccaa 4560
ggcctgggga gaagtgaaga gacagattta tgttgcagcc ttcacagtgc aggcagctgc 4620
agagactttg agtgaagtag cctaaagatc tgacccccta acgttactgg ccgaagccgc 4680
ttggaataag gccggtgtgc gtttgtctat atgttatttt ccaccatatt gccgtctttt 4740
ggcaatgtga gggcccggaa acctggccct gtcttcttga cgagcattcc taggggtctt 4800
tcccctctcg ccaaaggaat gcaaggtctg ttgaatgtcg tgaaggaagc agttcctctg 4860
gaagcttctt gaagacaaac aacgtctgta gcgacccttt gcaggcagcg gaacccccca 4920
cctggcgaca ggtgcctctg cggccaaaag ccacgtgtat aagatacacc tgcaaaggcg 4980
gcacaacccc agtgccacgt tgtgagttgg atagttgtgg aaagagtcaa atggctctcc 5040
tcaagcgtat tcaacaaggg gctgaaggat gcccagaagg taccccattg tatgggatct 5100
gatctggggc ctcggtgcac atgctttaca tgtgtttagt cgaggttaaa aaacgtctag 5160
gccccccgaa ccacggggac gtggttttcc tttgaaaaac acgatgataa tatggccagc 5220
attgtgggag gctgggagtg cgagaagcat tcccaaccct ggcaggtgct tgtggcctct 5280
cgtggcaggg cagtctgcgg cggtgttctg gtgcaccccc agtgggtcct cacagctgcc 5340
cactgcatca ggaacaaaag cgtgatcttg ctgggtcggc acagcttgtt tcatcctgaa 5400
gacacaggcc aggtatttca ggtcagccac agcttcccac acccgctcta cgatatgagc 5460
ctcctgaaga atcgattcct caggccaggt gatgactcca gccacgacct catgctgctc 5520
cgcctgtcag agcctgccga gctcacggat gctgtgaagg tcatggacct gcccacccag 5580
gagccagcac tggggaccac ctgctacgcc tcaggctggg gcagcattga accagaggag 5640
ttcttgaccc caaagaaact tcagtgtgtg gacctccatg ttatttccaa tgacgtgtgt 5700
gcgcaagttc accctcagaa ggtgaccaag ttcatgctgt gtgctggacg ctggacaggg 5760
ggcaaaagca cctgctcggg tgattctggg ggcccacttg tctgtaatgg tgtgcttcaa 5820
ggtatcacgt catggggcag tgaaccatgt gccctgcccg aaaggccttc cctgtacacc 5880
aaggtggtgc attaccggaa gtggatcaag gacaccatcg tggccaaccc ctgaggatct 5940
gggccctaac aaaacaaaaa gatggggtta ttccctaaac ttcatgggtt acgtaattgg 6000
aagttggggg acattgccac aagatcatat tgtacaaaag atcaaacact gttttagaaa 6060
acttcctgta aacaggccta ttgattggaa agtatgtcaa aggattgtgg gtcttttggg 6120
ctttgctgct ccatttacac aatgtggata tcctgcctta atgcctttgt atgcatgtat 6180
acaagctaaa caggctttca ctttctcgcc aacttacaag gcctttctaa gtaaacagta 6240
catgaacctt taccccgttg ctcggcaacg gcctggtctg tgccaagtgt ttgctgacgc 6300
aacccccact ggctggggct tggccatagg ccatcagcgc atgcgtggaa cctttgtggc 6360
tcctctgccg atccatactg cggaactcct agccgcttgt tttgctcgca gccggtctgg 6420
agcaaagctc ataggaactg acaattctgt cgtcctctcg cggaaatata catcgtttcg 6480
atctacgtat gatctttttc cctctgccaa aaattatggg gacatcatga agccccttga 6540
gcatctgact tctggctaat aaaggaaatt tattttcatt gcaatagtgt gttggaattt 6600
tttgtgtctc tcactcggaa ggaattctgc attaatgaat cggccaacgc gcggggagag 6660
gcggtttgcg tattgggcgc tcttccgctt cctcgctcac tgactcgctg cgctcggtcg 6720
ttcggctgcg gcgagcggta tcagctcact caaaggcggt aatacggtta tccacagaat 6780
caggggataa cgcaggaaag aacatgtgag caaaaggcca gcaaaaggcc aggaaccgta 6840
aaaaggccgc gttgctggcg tttttccata ggctccgccc ccctgacgag catcacaaaa 6900
atcgacgctc aagtcagagg tggcgaaacc cgacaggact ataaagatac caggcgtttc 6960
cccctggaag ctccctcgtg cgctctcctg ttccgaccct gccgcttacc ggatacctgt 7020
ccgcctttct cccttcggga agcgtggcgc tttctcatag ctcacgctgt aggtatctca 7080
gttcggtgta ggtcgttcgc tccaagctgg gctgtgtgca cgaacccccc gttcagcccg 7140
accgctgcgc cttatccggt aactatcgtc ttgagtccaa cccggtaaga cacgacttat 7200
cgccactggc agcagccact ggtaacagga ttagcagagc gaggtatgta ggcggtgcta 7260
cagagttctt gaagtggtgg cctaactacg gctacactag aagaacagta tttggtatct 7320
gcgctctgct gaagccagtt accttcggaa aaagagttgg tagctcttga tccggcaaac 7380
aaaccaccgc tggtagcggt ggtttttttg tttgcaagca gcagattacg cgcagaaaaa 7440
aaggatctca agaagatcct ttgatctttt ctacggggtc tgacgctcag tggaacgaaa 7500
actcacgtta agggattttg gtcatgagat tatcaaaaag gatcttcacc tagatccttt 7560
taaattaaaa atgaagtttt aaatcaatct aaagtatata tgagtaaact tggtctgaca 7620
gttaccaatg cttaatcagt gaggcaccta tctcagcgat ctgtctattt cgttcatcca 7680
tagttgcctg actc 7694
<210> 37
<211> 8461
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 37
catcatcaat aatatacctt attttggatt gaagccaata tgataatgag ggggtggagt 60
ttgtgacgtg gcgcggggcg tgggaacggg gcgggtgacg tagtagtgtg gcggaagtgt 120
gatgttgcaa gtgtggcgga acacatgtaa gcgacggatg tggcaaaagt gacgtttttg 180
gtgtgcgccg gtgtacacag gaagtgacaa ttttcgcgcg gttttaggcg gatgttgtag 240
taaatttggg cgtaaccgag taagatttgg ccattttcgc gggaaaactg aataagagga 300
agtgaaatct gaataatttt gtgttactca tagcgcgtaa tactgtaata gtaatcaatt 360
acggggtcat tagttcatag cccatatatg gagttccgcg ttacataact tacggtaaat 420
ggcccgcctg gctgaccgcc caacgacccc cgcccattga cgtcaataat gacgtatgtt 480
cccatagtaa cgccaatagg gactttccat tgacgtcaat gggtggagta tttacggtaa 540
actgcccact tggcagtaca tcaagtgtat catatgccaa gtacgccccc tattgacgtc 600
aatgacggta aatggcccgc ctggcattat gcccagtaca tgaccttatg ggactttcct 660
acttggcagt acatctacgt attagtcatc gctattacca tggtgatgcg gttttggcag 720
tacatcaatg ggcgtggata gcggtttgac tcacggggat ttccaagtct ccaccccatt 780
gacgtcaatg ggagtttgtt ttggcaccaa aatcaacggg actttccaaa atgtcgtaac 840
aactccgccc cattgacgca aatgggcggt aggcgtgtac ggtgggaggt ctatataagc 900
agagctggtt tagtgaaccg tcagatccgc tagagatcca ccatggctag cggtgccccg 960
acgttgcccc ctgcctggca gccctttctc aaggaccacc gcatctctac attcaagaac 1020
tggcccttct tggagggctg cgcctgcgcc ccggagcgga tggccgaggc tggcttcatc 1080
cactgcccca ctgagaacga gccagacttg gcccagtgtt tcttctgctt caaggagctg 1140
gaaggctggg agccagatga cgaccccata gaggaacata aaaagcattc gtccggttgc 1200
gctttccttt ctgtcaagaa gcagtttgaa gaattaaccc ttggtgaatt tttgaaactg 1260
gacagagaaa gagccaagaa caaaattgca aaggaaacca acaataagaa gaaagaattt 1320
gaggaaactg cggagaaagt gcgccgtgcc atcgagcagc tggctgccat ggattagaga 1380
tctgaccccc taacgttact ggccgaagcc gcttggaata aggccggtgt gcgtttgtct 1440
atatgttatt ttccaccata ttgccgtctt ttggcaatgt gagggcccgg aaacctggcc 1500
ctgtcttctt gacgagcatt cctaggggtc tttcccctct cgccaaagga atgcaaggtc 1560
tgttgaatgt cgtgaaggaa gcagttcctc tggaagcttc ttgaagacaa acaacgtctg 1620
tagcgaccct ttgcaggcag cggaaccccc cacctggcga caggtgcctc tgcggccaaa 1680
agccacgtgt ataagataca cctgcaaagg cggcacaacc ccagtgccac gttgtgagtt 1740
ggatagttgt ggaaagagtc aaatggctct cctcaagcgt attcaacaag gggctgaagg 1800
atgcccagaa ggtaccccat tgtatgggat ctgatctggg gcctcggtgc acatgcttta 1860
catgtgttta gtcgaggtta aaaaacgtct aggccccccg aaccacgggg acgtggtttt 1920
cctttgaaaa acacgataat atggcggccg ctcgagccta agcttctaga taagatatcc 1980
gatccaccgg atctagataa ctgatcataa tcagccatac cacatttgta gaggttttac 2040
ttgctttaaa aaacctccca cacctccccc tgaacctgaa acataaaatg aatgcaattg 2100
ttgttgttaa cttgtttatt gcagcttata atggttacaa ataaagcaat agcatcacaa 2160
atttcacaaa taaagcattt ttttcactgc attctagttg tggtttgtcc aaactcatca 2220
atgtatctta acgcggatct gggcgtggtt aagggtggga aagaatatat aaggtggggg 2280
tcttatgtag ttttgtatct gttttgcagc agccgccgcc gccatgagca ccaactcgtt 2340
tgatggaagc attgtgagct catatttgac aacgcgcatg cccccatggg ccggggtgcg 2400
tcagaatgtg atgggctcca gcattgatgg tcgccccgtc ctgcccgcaa actctactac 2460
cttgacctac gagaccgtgt ctggaacgcc gttggagact gcagcctccg ccgccgcttc 2520
agccgctgca gccaccgccc gcgggattgt gactgacttt gctttcctga gcccgcttgc 2580
aagcagtgca gcttcccgtt catccgcccg cgatgacaag ttgacggctc ttttggcaca 2640
attggattct ttgacccggg aacttaatgt cgtttctcag cagctgttgg atctgcgcca 2700
gcaggtttct gccctgaagg cttcctcccc tcccaatgcg gtttaaaaca taaataaaaa 2760
accagactct gtttggattt ggatcaagca agtgtcttgc tgtctttatt taggggtttt 2820
gcgcgcgcgg taggcccggg accagcggtc tcggtcgttg agggtcctgt gtattttttc 2880
caggacgtgg taaaggtgac tctggatgtt cagatacatg ggcataagcc cgtctctggg 2940
gtggaggtag caccactgca gagcttcatg ctgcggggtg gtgttgtaga tgatccagtc 3000
gtagcaggag cgctgggcgt ggtgcctaaa aatgtctttc agtagcaagc tgattgccag 3060
gggcaggccc ttggtgtaag tgtttacaaa gcggttaagc tgggatgggt gcatacgtgg 3120
ggatatgaga tgcatcttgg actgtatttt taggttggct atgttcccag ccatatccct 3180
ccggggattc atgttgtgca gaaccaccag cacagtgtat ccggtgcact tgggaaattt 3240
gtcatgtagc ttagaaggaa atgcgtggaa gaacttggag acgcccttgt gacctccaag 3300
attttccatg cattcgtcca taatgatggc aatgggccca cgggcggcgg cctgggcgaa 3360
gatatttctg ggatcactaa cgtcatagtt gtgttccagg atgagatcgt cataggccat 3420
ttttacaaag cgcgggcgga gggtgccaga ctgcggtata atggttccat ccggcccagg 3480
ggcgtagtta ccctcacaga tttgcatttc ccacgctttg agttcagatg gggggatcat 3540
gtctacctgc ggggcgatga agaaaacggt ttccggggta ggggagatca gctgggaaga 3600
aagcaggttc ctgagcagct gcgacttacc gcagccggtg ggcccgtaaa tcacacctat 3660
taccggctgc aactggtagt taagagagct gcagctgccg tcatccctga gcaggggggc 3720
cacttcgtta agcatgtccc tgactcgcat gttttccctg accaaatccg ccagaaggcg 3780
ctcgccgccc agcgatagca gttcttgcaa ggaagcaaag tttttcaacg gtttgagacc 3840
gtccgccgta ggcatgcttt tgagcgtttg accaagcagt tccaggcggt cccacagctc 3900
ggtcacctgc tctacggcat ctcgatccag catatctcct cgtttcgcgg gttggggcgg 3960
ctttcgctgt acggcagtag tcggtgctcg tccagacggg ccagggtcat gtctttccac 4020
gggcgcaggg tcctcgtcag cgtagtctgg gtcacggtga aggggtgcgc tccgggctgc 4080
gcgctggcca gggtgcgctt gaggctggtc ctgctggtgc tgaagcgctg ccggtcttcg 4140
ccctgcgcgt cggccaggta gcatttgacc atggtgtcat agtccagccc ctccgcggcg 4200
tggcccttgg cgcgcagctt gcccttggag gaggcgccgc acgaggggca gtgcagactt 4260
ttgagggcgt agagcttggg cgcgagaaat accgattccg gggagtaggc atccgcgccg 4320
caggccccgc agacggtctc gcattccacg agccaggtga gctctggccg ttcggggtca 4380
aaaaccaggt ttcccccatg ctttttgatg cgtttcttac ctctggtttc catgagccgg 4440
tgtccacgct cggtgacgaa aaggctgtcc gtgtccccgt atacagactt gagagggagt 4500
ttaaacgaat tcaatagctt gttgcatggg cggcgatata aaatgcaagg tgctgctcaa 4560
aaaatcaggc aaagcctcgc gcaaaaaaga aagcacatcg tagtcatgct catgcagata 4620
aaggcaggta agctccggaa ccaccacaga aaaagacacc atttttctct caaacatgtc 4680
tgcgggtttc tgcataaaca caaaataaaa taacaaaaaa acatttaaac attagaagcc 4740
tgtcttacaa caggaaaaac aacccttata agcataagac ggactacggc catgccggcg 4800
tgaccgtaaa aaaactggtc accgtgatta aaaagcacca ccgacagctc ctcggtcatg 4860
tccggagtca taatgtaaga ctcggtaaac acatcaggtt gattcacatc ggtcagtgct 4920
aaaaagcgac cgaaatagcc cgggggaata catacccgca ggcgtagaga caacattaca 4980
gcccccatag gaggtataac aaaattaata ggagagaaaa acacataaac acctgaaaaa 5040
ccctcctgcc taggcaaaat agcaccctcc cgctccagaa caacatacag cgcttccaca 5100
gcggcagcca taacagtcag ccttaccagt aaaaaagaaa acctattaaa aaaacaccac 5160
tcgacacggc accagctcaa tcagtcacag tgtaaaaaag ggccaagtgc agagcgagta 5220
tatataggac taaaaaatga cgtaacggtt aaagtccaca aaaaacaccc agaaaaccgc 5280
acgcgaacct acgcccagaa acgaaagcca aaaaacccac aacttcctca aatcgtcact 5340
tccgttttcc cacgttacgt cacttcccat tttaagaaaa ctacaattcc caacacatac 5400
aagttactcc gccctaaaac ctacgtcacc cgccccgttc ccacgccccg cgccacgtca 5460
caaactccac cccctcatta tcatattggc ttcaatccaa aataaggtat attattgatg 5520
atgttaatta acatgcatgg atccatatgc ggtgtgaaat accgcacaga tgcgtaagga 5580
gaaaataccg catcaggcgc tcttccgctt cctcgctcac tgactcgctg cgctcggtcg 5640
ttcggctgcg gcgagcggta tcagctcact caaaggcggt aatacggtta tccacagaat 5700
caggggataa cgcaggaaag aacatgtgag caaaaggcca gcaaaaggcc aggaaccgta 5760
aaaaggccgc gttgctggcg tttttccata ggctccgccc ccctgacgag catcacaaaa 5820
atcgacgctc aagtcagagg tggcgaaacc cgacaggact ataaagatac caggcgtttc 5880
cccctggaag ctccctcgtg cgctctcctg ttccgaccct gccgcttacc ggatacctgt 5940
ccgcctttct cccttcggga agcgtggcgc tttctcatag ctcacgctgt aggtatctca 6000
gttcggtgta ggtcgttcgc tccaagctgg gctgtgtgca cgaacccccc gttcagcccg 6060
accgctgcgc cttatccggt aactatcgtc ttgagtccaa cccggtaaga cacgacttat 6120
cgccactggc agcagccact ggtaacagga ttagcagagc gaggtatgta ggcggtgcta 6180
cagagttctt gaagtggtgg cctaactacg gctacactag aaggacagta tttggtatct 6240
gcgctctgct gaagccagtt accttcggaa aaagagttgg tagctcttga tccggcaaac 6300
aaaccaccgc tggtagcggt ggtttttttg tttgcaagca gcagattacg cgcagaaaaa 6360
aaggatctca agaagatcct ttgatctttt ctacggggtc tgacgctcag tggaacgaaa 6420
actcacgtta agggattttg gtcatgagat tatcaaaaag gatcttcacc tagatccttt 6480
taaattaaaa atgaagtttt aaatcaatct aaagtatata tgagtaaact tggtctgaca 6540
gttaccaatg cttaatcagt gaggcaccta tctcagcgat ctgtctattt cgttcatcca 6600
tagttgcctg actccccgtc gtgtagataa ctacgatacg ggagggctta ccatctggcc 6660
ccagtgctgc aatgataccg cgagacccac gctcaccggc tccagattta tcagcaataa 6720
accagccagc cggaagggcc gagcgcagaa gtggtcctgc aactttatcc gcctccatcc 6780
agtctattaa ttgttgccgg gaagctagag taagtagttc gccagttaat agtttgcgca 6840
acgttgttgc cattgctgca gccatgagat tatcaaaaag gatcttcacc tagatccttt 6900
tcacgtagaa agccagtccg cagaaacggt gctgaccccg gatgaatgtc agctactggg 6960
ctatctggac aagggaaaac gcaagcgcaa agagaaagca ggtagcttgc agtgggctta 7020
catggcgata gctagactgg gcggttttat ggacagcaag cgaaccggaa ttgccagctg 7080
gggcgccctc tggtaaggtt gggaagccct gcaaagtaaa ctggatggct ttcttgccgc 7140
caaggatctg atggcgcagg ggatcaagct ctgatcaaga gacaggatga ggatcgtttc 7200
gcatgattga acaagatgga ttgcacgcag gttctccggc cgcttgggtg gagaggctat 7260
tcggctatga ctgggcacaa cagacaatcg gctgctctga tgccgccgtg ttccggctgt 7320
cagcgcaggg gcgcccggtt ctttttgtca agaccgacct gtccggtgcc ctgaatgaac 7380
tgcaagacga ggcagcgcgg ctatcgtggc tggccacgac gggcgttcct tgcgcagctg 7440
tgctcgacgt tgtcactgaa gcgggaaggg actggctgct attgggcgaa gtgccggggc 7500
aggatctcct gtcatctcac cttgctcctg ccgagaaagt atccatcatg gctgatgcaa 7560
tgcggcggct gcatacgctt gatccggcta cctgcccatt cgaccaccaa gcgaaacatc 7620
gcatcgagcg agcacgtact cggatggaag ccggtcttgt cgatcaggat gatctggacg 7680
aagagcatca ggggctcgcg ccagccgaac tgttcgccag gctcaaggcg agcatgcccg 7740
acggcgagga tctcgtcgtg acccatggcg atgcctgctt gccgaatatc atggtggaaa 7800
atggccgctt ttctggattc atcgactgtg gccggctggg tgtggcggac cgctatcagg 7860
acatagcgtt ggctacccgt gatattgctg aagagcttgg cggcgaatgg gctgaccgct 7920
tcctcgtgct ttacggtatc gccgctcccg attcgcagcg catcgccttc tatcgccttc 7980
ttgacgagtt cttctgaatt ttgttaaaat ttttgttaaa tcagctcatt ttttaaccaa 8040
taggccgaaa tcggcaccat cccttataaa tcaaaagaat agaccgagat agggttgagt 8100
gttgttccag tttggaacaa gagtccacta ttaaagaacg tggactccaa cgtcaaaggg 8160
cgaaaaaccg tctatcaggg cgatggccca ctacgtgaac catcacccta atcaagtttt 8220
ttgtggtcga ggtgccgtaa agcactaaat cggaacccta aagggagccc ccgatttaga 8280
gcttgacggg gaaagccggc gaacgtggcg agaaaggaag ggaagaaagc gaaaggagcg 8340
ggcgctaggg cgctggcaag tgtagcggtc acgctgcgcg taaccaccac acccgcgcgc 8400
ttaatgcgcc gctacagggc gcgtccattc gccattcagg atcgaattaa ttcttaatta 8460
a 8461
<210> 38
<211> 956
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 38
Met Ala Ser Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala
1 5 10 15
Leu Leu Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp
20 25 30
Met Lys Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu
35 40 45
Arg His Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu
50 55 60
Thr Tyr Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln
65 70 75 80
Glu Val Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val
85 90 95
Pro Leu Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp
100 105 110
Asn Tyr Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asp Ser Val
115 120 125
Ala Pro Ala Ala Gly Ala Thr Pro Gly Gly Leu Gln Glu Leu Gln Leu
130 135 140
Arg Ser Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Arg Arg Ser
145 150 155 160
Pro Gln Leu Cys His Gln Asp Thr Val Leu Trp Glu Asp Val Phe Arg
165 170 175
Lys Asn Asn Gln Leu Ala Leu Val Leu Met Asp Thr Asn Arg Ser Arg
180 185 190
Ala Cys His Pro Cys Ala Pro Met Cys Lys Ala Asn His Cys Trp Gly
195 200 205
Glu Ser Ser Gln Asp Cys Gln Thr Leu Thr Arg Thr Ile Cys Thr Ser
210 215 220
Ala Cys Ala Arg Cys Lys Ala Pro Leu Pro Thr Asp Cys Cys His Glu
225 230 235 240
Gln Cys Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala
245 250 255
Cys Leu His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala
260 265 270
Leu Val Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu
275 280 285
Gly Arg Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn
290 295 300
Tyr Leu Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His
305 310 315 320
Asn Gln Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys
325 330 335
Ser Lys Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu
340 345 350
Arg Glu Ala Arg Ala Ile Thr Ser Ala Asn Val Gln Asp Phe Val Gly
355 360 365
Cys Lys Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp
370 375 380
Gly Asp Pro Ala Ser Gly Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln
385 390 395 400
Val Phe Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala
405 410 415
Trp Pro Asp Ser Phe Pro Asn Leu Ser Val Phe Gln Asn Leu Arg Val
420 425 430
Ile Arg Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln
435 440 445
Gly Leu Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Gln Glu Leu Gly
450 455 460
Ser Gly Leu Ala Leu Val His Arg Asn Ala Arg Leu Cys Phe Val His
465 470 475 480
Thr Val Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu
485 490 495
His Ser Gly Asn Arg Pro Glu Glu Asp Cys Val Gly Glu Gly Phe Val
500 505 510
Cys Tyr Ser Leu Cys Ala His Gly His Cys Trp Gly Pro Gly Pro Thr
515 520 525
Gln Cys Val Asn Cys Ser His Phe Leu Arg Gly Gln Glu Cys Val Glu
530 535 540
Glu Cys Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg
545 550 555 560
His Cys Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val
565 570 575
Thr Cys Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr
580 585 590
Lys Asp Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro
595 600 605
Asp Leu Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala
610 615 620
Cys Gln Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp
625 630 635 640
Asp Lys Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile
645 650 655
Ile Ser Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val
660 665 670
Phe Gly Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr
675 680 685
Met Arg Arg Asn Glu Asp Leu Gly Pro Ser Ser Pro Met Asp Ser Thr
690 695 700
Phe Tyr Arg Ser Leu Leu Glu Asp Glu Asp Met Gly Glu Leu Val Asp
705 710 715 720
Ala Glu Glu Tyr Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro
725 730 735
Thr Pro Gly Thr Gly Ser Thr Ala His Arg Arg His Arg Ser Ser Ser
740 745 750
Ala Arg Asn Gly Gly Gly Asp Leu Thr Leu Gly Met Glu Pro Ser Gly
755 760 765
Glu Gly Pro Pro Arg Ser Pro Arg Ala Pro Ser Glu Gly Thr Gly Ser
770 775 780
Asp Val Phe Asp Gly Asp Leu Ala Val Gly Val Thr Lys Gly Leu Gln
785 790 795 800
Ser Leu Ser Pro Gln Asp Leu Ser Pro Leu Gln Arg Tyr Ser Glu Asp
805 810 815
Pro Thr Leu Pro Leu Pro Ser Glu Thr Asp Gly Lys Val Ala Pro Leu
820 825 830
Ser Cys Ser Pro Gln Pro Glu Phe Val Asn Gln Ser Asp Val Gln Pro
835 840 845
Lys Ser Pro Leu Thr Pro Glu Gly Pro Pro Ser Pro Ala Arg Pro Thr
850 855 860
Gly Ala Thr Leu Glu Arg Ala Lys Thr Leu Ser Pro Gly Lys Asn Gly
865 870 875 880
Val Val Lys Asp Val Phe Thr Phe Gly Gly Ala Val Glu Asn Pro Glu
885 890 895
Phe Leu Ala Pro Arg Glu Gly Thr Ala Ser Pro Pro His Pro Ser Pro
900 905 910
Ala Phe Ser Pro Ala Phe Asp Asn Leu Phe Phe Trp Asp Gln Asn Ser
915 920 925
Ser Glu Gln Gly Pro Pro Pro Ser Asn Phe Glu Gly Thr Pro Thr Ala
930 935 940
Glu Asn Pro Glu Phe Leu Gly Leu Asp Val Pro Val
945 950 955
<210> 39
<211> 2871
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 39
atggctagcg agctggccgc cctgtgtaga tggggactgc tgctggctct gctgcctcct 60
ggagccgctt ctacacaggt ctgcaccggc accgacatga agctgagact gcccgccagc 120
cccgagacac acctggacat gctgcggcac ctgtaccagg gctgccaggt ggtccagggg 180
aatctggaac tgacctacct gcccaccaac gccagcctga gcttcctgca ggacatccag 240
gaagtgcagg gctacgtcct gatcgcccac aaccaggtcc gccaggtgcc cctgcagcgg 300
ctgagaatcg tgcggggcac ccagctgttc gaggacaact acgccctggc cgtgctggac 360
aacggcgacc ctctggatag cgtggcccct gctgctgggg ctacacctgg cggactgcag 420
gaactgcagc tgcggagcct gaccgagatc ctgaagggcg gcgtgctgat caggcggagc 480
cctcagctgt gccaccagga caccgtgctg tgggaggacg tgttccggaa gaacaaccag 540
ctggccctcg tgctgatgga caccaacaga agccgggcct gccacccctg cgcccccatg 600
tgcaaggcca atcactgctg gggagagagc agccaggact gccagaccct gacccggacc 660
atctgcacca gcgcctgcgc cagatgcaag gcccccctgc ctaccgactg ctgccacgaa 720
cagtgcgccg ctggctgcac cggccccaag cacagcgatt gcctggcctg cctgcacttc 780
aaccacagcg gcatctgcga gctgcactgc cctgccctgg tgacatacaa caccgacacc 840
ttcgagagca tgcccaaccc cgagggccgg tacaccttcg gcgccagctg tgtgaccgcc 900
tgcccctaca actacctgag caccgacgtg ggcagctgca ccctggtgtg ccccctgcac 960
aaccaggaag tgaccgccga ggacggcacc cagagatgcg agaagtgcag caagccttgc 1020
gccagagtgt gctacggcct gggcatggaa cacctgagag aggccagagc catcaccagc 1080
gccaacgtgc aggacttcgt gggctgcaag aagattttcg gctccctggc cttcctgccc 1140
gagagcttcg acggcgatcc tgcctctggc accgcccctc tgcagcctga gcagctgcag 1200
gtcttcgaga cactggaaga gatcaccggc tacctgtaca tcagcgcctg gcccgacagc 1260
ttccccaacc tgagcgtgtt ccagaacctg agagtgatcc ggggcagaat cctgcacaac 1320
ggcgcctaca gcctgaccct gcagggcctg ggaatcagct ggctgggcct gcggagcctg 1380
caggaactgg gatctggcct ggctctggtg caccggaacg cccggctgtg cttcgtgcac 1440
accgtgccct gggaccagct gttcagaaac ccccaccagg ctctgctgca cagcggcaac 1500
cggcccgaag aggattgcgt gggcgagggc ttcgtgtgct actccctgtg cgcccacggc 1560
cactgttggg gacctggccc tacccagtgc gtgaactgca gccacttcct gcggggccaa 1620
gaatgcgtgg aagagtgccg ggtgctgcag ggactgcccc gggaatacgt gaacgccaga 1680
cactgcctgc cttgccaccc cgagtgccag ccccagaatg gcagcgtgac ctgcttcgga 1740
cccgaggccg atcagtgtgt ggcctgcgcc cactacaagg accccccatt ctgcgtggcc 1800
agatgcccca gcggcgtgaa gcccgacctg agctacatgc ccatctggaa gttccccgac 1860
gaggaaggcg cctgccagcc ttgccccatc aactgcaccc acagctgcgt ggacctggac 1920
gacaagggct gccctgccga gcagagagcc agccccctga ccagcatcat cagcgccgtg 1980
gtgggaatcc tgctggtggt ggtgctgggc gtggtgttcg gcatcctgat caagcggcgg 2040
cagcagaaga tccggaagta caccatgcgg cggaacgagg acctgggccc ctctagcccc 2100
atggacagca ccttctaccg gtccctgctg gaagatgagg acatgggcga gctggtggac 2160
gccgaggaat acctggtgcc tcagcagggc ttcttctgcc ccgaccctac ccctggcacc 2220
ggctctaccg cccacagacg gcacagaagc agcagcgcca gaaacggcgg aggcgacctg 2280
accctgggaa tggaacctag cggcgaggga cctcccagaa gccctagagc ccctagcgag 2340
ggcaccggca gcgacgtgtt cgatggcgat ctggccgtgg gcgtgaccaa gggactgcag 2400
agcctgagcc cccaggacct gtcccccctg cagagataca gcgaggaccc caccctgccc 2460
ctgcccagcg agacagatgg caaggtggcc cccctgagct gcagccctca gcccgagttc 2520
gtgaaccaga gcgacgtgca gcccaagtcc cccctgacac ccgagggacc tccaagccct 2580
gccagaccta ccggcgccac cctggaaaga gccaagaccc tgagccccgg caagaacggc 2640
gtggtgaaag acgtgttcac cttcggaggc gccgtggaaa accccgagtt cctggccccc 2700
agagagggca cagccagccc tccacacccc agcccagcct tctcccccgc cttcgacaac 2760
ctgttcttct gggaccagaa cagcagcgag cagggcccac cccccagcaa tttcgagggc 2820
acccccaccg ccgagaatcc tgagttcctg ggcctggacg tgcccgtgtg a 2871
<210> 40
<211> 471
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 40
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Asn Pro Asp Ser Gly Gly Thr Asn Tyr Ala
65 70 75 80
Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
85 90 95
Thr Ala Tyr Met Glu Leu Asn Arg Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Asp Gln Pro Leu Gly Tyr Cys Thr Asn Gly Val
115 120 125
Cys Ser Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
130 135 140
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
145 150 155 160
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
165 170 175
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
180 185 190
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
195 200 205
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln
210 215 220
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
225 230 235 240
Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala
245 250 255
Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
275 280 285
Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
290 295 300
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
305 310 315 320
Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
325 330 335
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg
355 360 365
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
370 375 380
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
385 390 395 400
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
405 410 415
Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
420 425 430
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 41
<211> 234
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 41
Met Arg Leu Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Phe Pro
1 5 10 15
Gly Ser Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
35 40 45
Ile Tyr Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
50 55 60
Asn Leu Leu Ile Tyr Thr Ala Ser Thr Leu Gln Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn
100 105 110
Ile Phe Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 42
<211> 451
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 42
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys 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 Asp Pro Arg Gly Ala Thr Leu Tyr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr
115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
130 135 140
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
180 185 190
Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys
195 200 205
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu
210 215 220
Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
290 295 300
Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 43
<211> 214
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 43
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 44
<211> 24
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 44
tcgtcgtttt gtcgttttgt cgtt 24
<210> 45
<211> 21
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 45
tcgtcgtttt tcggtgcttt t 21
<210> 46
<211> 21
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 46
tcgtcgtttt tcggtcgttt t 21
<210> 47
<211> 239
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 47
Met Val Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu
1 5 10 15
Val Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly
20 25 30
Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile
35 40 45
Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr
50 55 60
Leu Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His Met Lys
65 70 75 80
Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln Glu
85 90 95
Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu
100 105 110
Val Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly
115 120 125
Ile Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr
130 135 140
Asn Tyr Asn Ser His Asn Val Tyr Ile Met Ala Asp Lys Gln Lys Asn
145 150 155 160
Gly Ile Lys Val Asn Phe Lys Ile Arg His Asn Ile Glu Asp Gly Ser
165 170 175
Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly Asp Gly
180 185 190
Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser Ala Leu
195 200 205
Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu Glu Phe
210 215 220
Val Thr Ala Ala Gly Ile Thr Leu Gly Met Asp Glu Leu Tyr Lys
225 230 235
<210> 48
<211> 185
<212> PRT
<213> Orthohepadnavirus hepatitis B virus
<400> 48
Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu
1 5 10 15
Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp
20 25 30
Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45
Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60
Leu Met Thr Leu Ala Thr Trp Val Gly Asn Asn Leu Glu Asp Pro Ala
65 70 75 80
Ser Arg Asp Leu Val Val Asn Tyr Val Asn Thr Asn Met Gly Leu Lys
85 90 95
Ile Arg Gln Leu Leu Trp Phe His Ile Ser Cys Leu Thr Phe Gly Arg
100 105 110
Glu Thr Val Leu Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125
Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro
130 135 140
Glu Thr Thr Val Val Arg Arg Arg Gly Arg Gly Arg Ser Pro Arg Arg
145 150 155 160
Arg Thr Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg
165 170 175
Arg Ser Gln Ser Arg Glu Ser Gln Cys
180 185
<210> 49
<211> 226
<212> PRT
<213> Orthohepadnavirus hepatitis B virus
<400> 49
Met Glu Asn Ile Thr Ser Gly Phe Leu Gly Pro Leu Leu Val Leu Gln
1 5 10 15
Ala Gly Phe Phe Leu Leu Thr Arg Ile Leu Thr Ile Pro Gln Ser Leu
20 25 30
Asp Ser Trp Trp Thr Ser Leu Asn Phe Leu Gly Gly Ser Pro Val Cys
35 40 45
Leu Gly Gln Asn Ser Gln Ser Pro Thr Ser Asn His Ser Pro Thr Ser
50 55 60
Cys Pro Pro Ile Cys Pro Gly Tyr Arg Trp Met Cys Leu Arg Arg Phe
65 70 75 80
Ile Ile Phe Leu Phe Ile Leu Leu Leu Cys Leu Ile Phe Leu Leu Val
85 90 95
Leu Leu Asp Tyr Gln Gly Met Leu Pro Val Cys Pro Leu Ile Pro Gly
100 105 110
Ser Thr Thr Thr Ser Thr Gly Pro Cys Lys Thr Cys Thr Thr Pro Ala
115 120 125
Gln Gly Asn Ser Met Phe Pro Ser Cys Cys Cys Thr Lys Pro Thr Asp
130 135 140
Gly Asn Cys Thr Cys Ile Pro Ile Pro Ser Ser Trp Ala Phe Ala Lys
145 150 155 160
Tyr Leu Trp Glu Trp Ala Ser Val Arg Phe Ser Trp Leu Ser Leu Leu
165 170 175
Val Pro Phe Val Gln Trp Phe Val Gly Leu Ser Pro Thr Val Trp Leu
180 185 190
Ser Ala Ile Trp Met Met Trp Tyr Trp Gly Pro Ser Leu Tyr Ser Ile
195 200 205
Val Ser Pro Phe Ile Pro Leu Leu Pro Ile Phe Phe Cys Leu Trp Val
210 215 220
Tyr Ile
225
<210> 50
<211> 737
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 50
Met Ala Ser Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp
1 5 10 15
Val Pro Gly Ser Thr Gly Asp Ala Ala His His His His His His Lys
20 25 30
Ser Ser Ser Glu Ala Thr Asn Ile Thr Pro Lys His Asn Met Lys Ala
35 40 45
Phe Leu Asp Glu Leu Lys Ala Glu Asn Ile Lys Lys Phe Leu His Asn
50 55 60
Phe Thr Gln Ile Pro His Leu Ala Gly Thr Glu Gln Asn Phe Gln Leu
65 70 75 80
Ala Lys Gln Ile Gln Ser Gln Trp Lys Glu Phe Gly Leu Asp Ser Val
85 90 95
Glu Leu Thr His Tyr Asp Val Leu Leu Ser Tyr Pro Asn Lys Thr His
100 105 110
Pro Asn Tyr Ile Ser Ile Ile Asn Glu Asp Gly Asn Glu Ile Phe Asn
115 120 125
Thr Ser Leu Phe Glu Pro Pro Pro Ala Gly Tyr Glu Asn Val Ser Asp
130 135 140
Ile Val Pro Pro Phe Ser Ala Phe Ser Pro Gln Gly Met Pro Glu Gly
145 150 155 160
Asp Leu Val Tyr Val Asn Tyr Ala Arg Thr Glu Asp Phe Phe Lys Leu
165 170 175
Glu Arg Asp Met Lys Ile Asn Cys Ser Gly Lys Ile Val Ile Ala Arg
180 185 190
Tyr Gly Lys Val Phe Arg Gly Asn Lys Val Lys Asn Ala Gln Leu Ala
195 200 205
Gly Ala Thr Gly Val Ile Leu Tyr Ser Asp Pro Ala Asp Tyr Phe Ala
210 215 220
Pro Gly Val Lys Ser Tyr Pro Asp Gly Trp Asn Leu Pro Gly Gly Gly
225 230 235 240
Val Gln Arg Gly Asn Ile Leu Asn Leu Asn Gly Ala Gly Asp Pro Leu
245 250 255
Thr Pro Gly Tyr Pro Ala Asn Glu Tyr Ala Tyr Arg Arg Gly Ile Ala
260 265 270
Glu Ala Val Gly Leu Pro Ser Ile Pro Val His Pro Ile Gly Tyr Tyr
275 280 285
Asp Ala Gln Lys Leu Leu Glu Lys Met Gly Gly Ser Ala Ser Pro Asp
290 295 300
Ser Ser Trp Arg Gly Ser Leu Lys Val Pro Tyr Asn Val Gly Pro Gly
305 310 315 320
Phe Thr Gly Asn Phe Ser Thr Gln Lys Val Lys Met His Ile His Ser
325 330 335
Thr Ser Glu Val Thr Arg Ile Tyr Asn Val Ile Gly Thr Leu Arg Gly
340 345 350
Ala Val Glu Pro Asp Arg Tyr Val Ile Leu Gly Gly His Arg Asp Ser
355 360 365
Trp Val Phe Gly Gly Ile Asp Pro Gln Ser Gly Ala Ala Val Val His
370 375 380
Glu Ile Val Arg Ser Phe Gly Thr Leu Lys Lys Glu Gly Trp Arg Pro
385 390 395 400
Arg Arg Thr Ile Leu Phe Ala Ser Trp Asp Ala Glu Glu Phe Gly Leu
405 410 415
Leu Gly Ser Thr Glu Trp Ala Glu Glu Asn Ser Arg Leu Leu Gln Glu
420 425 430
Arg Gly Val Ala Tyr Ile Asn Ala Asp Ser Ser Ile Glu Gly Asn Tyr
435 440 445
Thr Leu Arg Val Asp Cys Thr Pro Leu Met Tyr Ser Leu Val Tyr Asn
450 455 460
Leu Thr Lys Glu Leu Glu Ser Pro Asp Glu Gly Phe Glu Gly Lys Ser
465 470 475 480
Leu Tyr Glu Ser Trp Thr Lys Ser Pro Ser Pro Glu Phe Ser Gly Met
485 490 495
Pro Arg Ile Ser Lys Leu Gly Ser Gly Asn Asp Phe Glu Val Phe Phe
500 505 510
Gln Arg Leu Gly Ile Ala Ser Gly Arg Ala Arg Tyr Thr Lys Asn Trp
515 520 525
Glu Thr Asn Lys Phe Ser Ser Tyr Pro Leu Tyr His Ser Val Tyr Glu
530 535 540
Thr Tyr Glu Leu Val Glu Lys Phe Tyr Asp Pro Met Phe Lys Tyr His
545 550 555 560
Leu Thr Val Ala Gln Val Arg Gly Gly Met Val Phe Glu Leu Ala Asn
565 570 575
Ser Val Val Leu Pro Phe Asp Cys Arg Asp Tyr Ala Val Val Leu Arg
580 585 590
Lys Tyr Ala Asp Lys Ile Tyr Asn Ile Ser Met Lys His Pro Gln Glu
595 600 605
Met Lys Thr Tyr Ser Val Ser Phe Asp Ser Leu Phe Ser Ala Val Lys
610 615 620
Asn Phe Thr Glu Ile Ala Ser Lys Phe Ser Glu Arg Leu Arg Asp Phe
625 630 635 640
Asp Lys Ser Asn Pro Ile Leu Leu Arg Met Met Asn Asp Gln Leu Met
645 650 655
Phe Leu Glu Arg Ala Phe Ile Asp Pro Leu Gly Leu Pro Asp Arg Pro
660 665 670
Phe Tyr Arg His Val Ile Tyr Ala Pro Ser Ser His Asn Lys Tyr Ala
675 680 685
Gly Glu Ser Phe Pro Gly Ile Tyr Asp Ala Leu Phe Asp Ile Glu Ser
690 695 700
Lys Val Asp Pro Ser Gln Ala Trp Gly Glu Val Lys Arg Gln Ile Ser
705 710 715 720
Ile Ala Thr Phe Thr Val Gln Ala Ala Ala Glu Thr Leu Ser Glu Val
725 730 735
Ala
<210> 51
<211> 9
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 51
Thr Tyr Val Pro Ala Asn Ala Ser Leu
1 5
<210> 52
<211> 15
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 52
Asp Met Val Leu Trp Lys Asp Val Phe Arg Lys Asn Asn Gln Leu
1 5 10 15
<210> 53
<211> 9
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 53
Ser Tyr Val Asn Thr Asn Met Gly Leu
1 5
<210> 54
<211> 957
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 54
Met Ala Ser Glu Leu Ala Ala Trp Cys Arg Trp Gly Phe Leu Leu Ala
1 5 10 15
Leu Leu Pro Pro Gly Ile Ala Gly Thr Gln Val Cys Thr Gly Thr Asp
20 25 30
Met Lys Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu
35 40 45
Arg His Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu
50 55 60
Thr Tyr Val Pro Ala Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln
65 70 75 80
Glu Val Gln Gly Tyr Met Leu Ile Ala His Asn Gln Val Lys Arg Val
85 90 95
Pro Leu Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp
100 105 110
Lys Tyr Ala Leu Ala Val Leu Asp Asn Arg Asp Pro Gln Asp Asn Val
115 120 125
Ala Ala Ser Thr Pro Gly Arg Thr Pro Glu Gly Leu Arg Glu Leu Gln
130 135 140
Leu Arg Ser Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Arg Gly
145 150 155 160
Asn Pro Gln Leu Cys Tyr Gln Asp Met Val Leu Trp Lys Asp Val Phe
165 170 175
Arg Lys Asn Asn Gln Leu Ala Pro Val Asp Ile Asp Thr Asn Arg Ser
180 185 190
Arg Ala Cys Pro Pro Cys Ala Pro Ala Cys Lys Asp Asn His Cys Trp
195 200 205
Gly Glu Ser Pro Glu Asp Cys Gln Ile Leu Thr Gly Thr Ile Cys Thr
210 215 220
Ser Gly Cys Ala Arg Cys Lys Gly Arg Leu Pro Thr Asp Cys Cys His
225 230 235 240
Glu Gln Cys Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu
245 250 255
Ala Cys Leu His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro
260 265 270
Ala Leu Val Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met His Asn Pro
275 280 285
Glu Gly Arg Tyr Thr Phe Gly Ala Ser Cys Val Thr Thr Cys Pro Tyr
290 295 300
Asn Tyr Leu Ser Thr Glu Val Gly Ser Cys Thr Leu Val Cys Pro Pro
305 310 315 320
Asn Asn Gln Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys
325 330 335
Cys Ser Lys Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His
340 345 350
Leu Arg Gly Ala Arg Ala Ile Thr Ser Asp Asn Val Gln Glu Phe Asp
355 360 365
Gly Cys Lys Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe
370 375 380
Asp Gly Asp Pro Ser Ser Gly Ile Ala Pro Leu Arg Pro Glu Gln Leu
385 390 395 400
Gln Val Phe Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser
405 410 415
Ala Trp Pro Asp Ser Leu Arg Asp Leu Ser Val Phe Gln Asn Leu Arg
420 425 430
Ile Ile Arg Gly Arg Ile Leu His Asp Gly Ala Tyr Ser Leu Thr Leu
435 440 445
Gln Gly Leu Gly Ile His Ser Leu Gly Leu Arg Ser Leu Arg Glu Leu
450 455 460
Gly Ser Gly Leu Ala Leu Ile His Arg Asn Ala His Leu Cys Phe Val
465 470 475 480
His Thr Val Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu
485 490 495
Leu His Ser Gly Asn Arg Pro Glu Glu Asp Cys Gly Leu Glu Gly Leu
500 505 510
Val Cys Asn Ser Leu Cys Ala His Gly His Cys Trp Gly Pro Gly Pro
515 520 525
Thr Gln Cys Val Asn Cys Ser His Phe Leu Arg Gly Gln Glu Cys Val
530 535 540
Glu Glu Cys Arg Val Trp Lys Gly Leu Pro Arg Glu Tyr Val Ser Asp
545 550 555 560
Lys Arg Cys Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Ser Ser
565 570 575
Glu Thr Cys Phe Gly Ser Glu Ala Asp Gln Cys Ala Ala Cys Ala His
580 585 590
Tyr Lys Asp Ser Ser Ser Cys Val Ala Arg Cys Pro Ser Gly Val Lys
595 600 605
Pro Asp Leu Ser Tyr Met Pro Ile Trp Lys Tyr Pro Asp Glu Glu Gly
610 615 620
Ile Cys Gln Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu
625 630 635 640
Asp Glu Arg Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Val Thr Phe
645 650 655
Ile Ile Ala Thr Val Val Gly Val Leu Leu Phe Leu Ile Leu Val Val
660 665 670
Val Val Gly Ile Leu Ile Lys Arg Arg Arg Gln Lys Ile Arg Lys Tyr
675 680 685
Thr Met Arg Arg Asn Glu Asp Leu Gly Pro Ser Ser Pro Met Asp Ser
690 695 700
Thr Phe Tyr Arg Ser Leu Leu Glu Asp Asp Asp Met Gly Asp Leu Val
705 710 715 720
Asp Ala Glu Glu Tyr Leu Val Pro Gln Gln Gly Phe Phe Ser Pro Asp
725 730 735
Pro Thr Pro Gly Thr Gly Ser Thr Ala His Arg Arg His Arg Ser Ser
740 745 750
Ser Thr Arg Ser Gly Gly Gly Glu Leu Thr Leu Gly Leu Glu Pro Ser
755 760 765
Glu Glu Gly Pro Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly
770 775 780
Ser Asp Val Phe Asp Gly Asp Leu Ala Met Gly Val Thr Lys Gly Leu
785 790 795 800
Gln Ser Leu Ser Pro His Asp Leu Ser Pro Leu Gln Arg Tyr Ser Glu
805 810 815
Asp Pro Thr Leu Pro Leu Pro Pro Glu Thr Asp Gly Tyr Val Ala Pro
820 825 830
Leu Ala Cys Ser Pro Gln Pro Glu Phe Val Asn Gln Ser Glu Val Gln
835 840 845
Pro Gln Pro Pro Leu Thr Pro Glu Gly Pro Leu Pro Pro Val Arg Pro
850 855 860
Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu Ser Pro Gly Lys Asn
865 870 875 880
Gly Val Val Lys Asp Val Phe Ala Phe Gly Gly Ala Val Glu Asn Pro
885 890 895
Glu Phe Leu Val Pro Arg Glu Gly Thr Ala Ser Pro Pro His Pro Ser
900 905 910
Pro Ala Phe Ser Pro Ala Phe Asp Asn Leu Phe Phe Trp Asp Gln Asn
915 920 925
Ser Ser Glu Gln Gly Pro Pro Pro Ser Asn Phe Glu Gly Thr Pro Thr
930 935 940
Ala Glu Asn Pro Glu Phe Leu Gly Leu Asp Val Pro Val
945 950 955
<210> 55
<211> 739
<212> PRT
<213> Artificial
<220>
<223> Synthetic Construct
<400> 55
Met Ala Ser Ala Arg Arg Pro Arg Trp Leu Cys Ala Gly Ala Leu Val
1 5 10 15
Leu Ala Gly Gly Phe Phe Leu Leu Gly Phe Leu Phe Gly Trp Phe Ile
20 25 30
Lys Ser Ser Ser Glu Ala Thr Asn Ile Thr Pro Lys His Asn Met Lys
35 40 45
Ala Phe Leu Asp Glu Leu Lys Ala Glu Asn Ile Lys Lys Phe Leu His
50 55 60
Asn Phe Thr Gln Ile Pro His Leu Ala Gly Thr Glu Gln Asn Phe Gln
65 70 75 80
Leu Ala Lys Gln Ile Gln Ser Gln Trp Lys Glu Phe Gly Leu Asp Ser
85 90 95
Val Glu Leu Thr His Tyr Asp Val Leu Leu Ser Tyr Pro Asn Lys Thr
100 105 110
His Pro Asn Tyr Ile Ser Ile Ile Asn Glu Asp Gly Asn Glu Ile Phe
115 120 125
Asn Thr Ser Leu Phe Glu Pro Pro Pro Ala Gly Tyr Glu Asn Val Ser
130 135 140
Asp Ile Val Pro Pro Phe Ser Ala Phe Ser Pro Gln Gly Met Pro Glu
145 150 155 160
Gly Asp Leu Val Tyr Val Asn Tyr Ala Arg Thr Glu Asp Phe Phe Lys
165 170 175
Leu Glu Arg Asp Met Lys Ile Asn Cys Ser Gly Lys Ile Val Ile Ala
180 185 190
Arg Tyr Gly Lys Val Phe Arg Gly Asn Lys Val Lys Asn Ala Gln Leu
195 200 205
Ala Gly Ala Thr Gly Val Ile Leu Tyr Ser Asp Pro Ala Asp Tyr Phe
210 215 220
Ala Pro Gly Val Lys Ser Tyr Pro Asp Gly Trp Asn Leu Pro Gly Gly
225 230 235 240
Gly Val Gln Arg Gly Asn Ile Leu Asn Leu Asn Gly Ala Gly Asp Pro
245 250 255
Leu Thr Pro Gly Tyr Pro Ala Asn Glu Tyr Ala Tyr Arg Arg Gly Ile
260 265 270
Ala Glu Ala Val Gly Leu Pro Ser Ile Pro Val His Pro Ile Gly Tyr
275 280 285
Tyr Asp Ala Gln Lys Leu Leu Glu Lys Met Gly Gly Ser Ala Ser Pro
290 295 300
Asp Ser Ser Trp Arg Gly Ser Leu Lys Val Pro Tyr Asn Val Gly Pro
305 310 315 320
Gly Phe Thr Gly Asn Phe Ser Thr Gln Lys Val Lys Met His Ile His
325 330 335
Ser Thr Ser Glu Val Thr Arg Ile Tyr Asn Val Ile Gly Thr Leu Arg
340 345 350
Gly Ala Val Glu Pro Asp Arg Tyr Val Ile Leu Gly Gly His Arg Asp
355 360 365
Ser Trp Val Phe Gly Gly Ile Asp Pro Gln Ser Gly Ala Ala Val Val
370 375 380
His Glu Ile Val Arg Ser Phe Gly Thr Leu Lys Lys Glu Gly Trp Arg
385 390 395 400
Pro Arg Arg Thr Ile Leu Phe Ala Ser Trp Asp Ala Glu Glu Phe Gly
405 410 415
Leu Leu Gly Ser Thr Glu Trp Ala Glu Glu Asn Ser Arg Leu Leu Gln
420 425 430
Glu Arg Gly Val Ala Tyr Ile Asn Ala Asp Ser Ser Ile Glu Gly Asn
435 440 445
Tyr Thr Leu Arg Val Asp Cys Thr Pro Leu Met Tyr Ser Leu Val Tyr
450 455 460
Asn Leu Thr Lys Glu Leu Glu Ser Pro Asp Glu Gly Phe Glu Gly Lys
465 470 475 480
Ser Leu Tyr Glu Ser Trp Thr Lys Lys Ser Pro Ser Pro Glu Phe Ser
485 490 495
Gly Met Pro Arg Ile Ser Lys Leu Gly Ser Gly Asn Asp Phe Glu Val
500 505 510
Phe Phe Gln Arg Leu Gly Ile Ala Ser Gly Arg Ala Arg Tyr Thr Lys
515 520 525
Asn Trp Glu Thr Asn Lys Phe Ser Ser Tyr Pro Leu Tyr His Ser Val
530 535 540
Tyr Glu Thr Tyr Glu Leu Val Glu Lys Phe Tyr Asp Pro Met Phe Lys
545 550 555 560
Tyr His Leu Thr Val Ala Gln Val Arg Gly Gly Met Val Phe Glu Leu
565 570 575
Ala Asn Ser Val Val Leu Pro Phe Asp Cys Arg Asp Tyr Ala Val Val
580 585 590
Leu Arg Lys Tyr Ala Asp Lys Ile Tyr Asn Ile Ser Met Lys His Pro
595 600 605
Gln Glu Met Lys Thr Tyr Ser Val Ser Phe Asp Ser Leu Phe Ser Ala
610 615 620
Val Lys Asn Phe Thr Glu Ile Ala Ser Lys Phe Ser Glu Arg Leu Arg
625 630 635 640
Asp Phe Asp Lys Ser Asn Pro Ile Leu Leu Arg Met Met Asn Asp Gln
645 650 655
Leu Met Phe Leu Glu Arg Ala Phe Ile Asp Pro Leu Gly Leu Pro Asp
660 665 670
Arg Pro Phe Tyr Arg His Val Ile Tyr Ala Pro Ser Ser His Asn Lys
675 680 685
Tyr Ala Gly Glu Ser Phe Pro Gly Ile Tyr Asp Ala Leu Phe Asp Ile
690 695 700
Glu Ser Lys Val Asp Pro Ser Gln Ala Trp Gly Glu Val Lys Arg Gln
705 710 715 720
Ile Ser Ile Ala Thr Phe Thr Val Gln Ala Ala Ala Glu Thr Leu Ser
725 730 735
Glu Val Ala
<210> 56
<211> 2217
<212> DNA
<213> Artificial
<220>
<223> Synthetic Construct
<400> 56
atggctagcg ctagaaggcc cagatggctg tgcgctggcg ccctggtgct ggctggcgga 60
ttcttcctgc tgggcttcct gttcggctgg ttcatcaagt cctccagcga ggccaccaac 120
atcaccccca agcacaacat gaaggccttt ctggacgagc tgaaggccga gaatatcaag 180
aagttcctgc acaacttcac ccagatcccc cacctggccg gcaccgagca gaacttccag 240
ctggccaagc agatccagtc ccagtggaaa gagttcggcc tggactccgt ggaactgacc 300
cactacgacg tgctgctgtc ctaccccaac aagacccacc ccaactacat ctccatcatc 360
aacgaggacg gcaacgaaat cttcaacacc tccctgttcg agcccccacc agccggctac 420
gagaacgtgt ccgacatcgt gcccccattc tccgcattca gtccacaagg catgcccgag 480
ggcgacctgg tgtacgtgaa ctacgccagg accgaggact tcttcaagct ggaaagggac 540
atgaagatca actgctccgg caagatcgtg atcgccagat acggcaaggt gttcaggggc 600
aacaaagtga agaacgctca gctggctggg gccaccggcg tgatcctgta ctctgacccc 660
gccgactact tcgccccagg cgtgaagtcc taccccgacg gctggaacct gccaggtggc 720
ggagtgcaga ggggcaacat cctgaacctg aacggcgctg gcgaccccct gaccccagga 780
taccccgcca acgagtacgc ctacagaaga ggaatcgccg aggccgtggg cctgccctct 840
atcccagtgc accccatcgg ctactacgac gcccagaaac tgctggaaaa gatgggcggc 900
tccgcctccc ccgactcctc ttggagaggc tccctgaagg tgccctacaa cgtgggccca 960
ggcttcaccg gcaacttctc cacccagaaa gtgaagatgc acatccactc cacctccgaa 1020
gtgaccagga tctacaacgt gatcggcacc ctgagaggcg ccgtggaacc cgacagatac 1080
gtgatcctgg gcggccacag ggacagctgg gtgttcggcg gcatcgaccc acagtctggc 1140
gccgctgtgg tgcacgagat cgtgcggtcc ttcggaaccc tgaagaaaga gggatggcgc 1200
cccagaagga caatcctgtt cgcctcctgg gacgccgagg aattcggcct gctgggatcc 1260
accgagtggg ccgaggaaaa ctccaggctg ctgcaggaaa ggggcgtcgc ctacatcaac 1320
gccgactcct ccatcgaggg caactacacc ctgagggtgg actgcacccc cctgatgtac 1380
tccctggtgt acaacctgac caaagagctg gaatcccccg acgagggctt cgagggcaag 1440
tccctgtacg agtcctggac caagaagtcc ccatcccccg agttctccgg catgcccagg 1500
atctccaagc tgggctccgg caacgacttc gaggtgttct tccagaggct gggaatcgcc 1560
tccggcaggg ccagatacac caagaactgg gagacaaaca agttctcctc ctaccccctg 1620
taccactccg tgtacgaaac ctacgagctg gtggaaaagt tctacgaccc catgttcaag 1680
taccacctga ccgtggccca ggtccgcgga ggcatggtgt tcgagctggc caactccgtg 1740
gtgctgccct tcgactgcag agactatgct gtggtgctga ggaagtacgc cgacaaaatc 1800
tacaacatct ccatgaagca cccccaggaa atgaagacct actccgtgtc cttcgactcc 1860
ctgttctccg ccgtgaagaa tttcaccgag atcgcctcca agttctccga gaggctgagg 1920
gacttcgaca agtccaaccc catcctgctg aggatgatga acgaccagct gatgttcctg 1980
gaaagggcct tcatcgaccc cctgggcctg ccagacaggc ccttctacag gcacgtgatc 2040
tacgccccat cctcccacaa caaatacgcc ggcgagtcct tccccggcat ctacgatgcc 2100
ctgttcgaca tcgagtccaa ggtggacccc tcccaggctt ggggcgaagt gaagaggcag 2160
atcagtatcg ccacattcac agtgcaggcc gctgccgaaa ccctgtccga ggtggcc 2217
<210> 57
<211> 36519
<212> DNA
<213> Simian adenovirus type 25
<400> 57
ccatcttcaa taatatacct caaacttttt gtgcgcgtta atatgcaaat gaggcgtttg 60
aatttgggga ggaagggcgg tgattggtcg agggatgagc gaccgttagg ggcggggcga 120
gtgacgtttt gatgacgtgg ttgcgaggag gagccagttt gcaagttctc gtgggaaaag 180
tgacgtcaaa cgaggtgtgg tttgaacacg gaaatactca attttcccgc gctctctgac 240
aggaaatgag gtgtttctgg gcggatgcaa gtgaaaacgg gccattttcg cgcgaaaact 300
gaatgaggaa gtgaaaatct gagtaatttc gcgtttatgg cagggaggag tatttgccga 360
gggccgagta gactttgacc gattacgtgg gggtttcgat taccgtgttt ttcacctaaa 420
tttccgcgta cggtgtcaaa gtccggtgtt tttacgtagg tgtcagctga tcgccagggt 480
atttaaacct gcgctctcca gtcaagaggc cactcttgag tgccagcgag aagagttttc 540
tcctccgcgc cgcgagtcag atctacactt tgaaagatga ggcacctgag agacctgccc 600
gatgagaaaa tcatcatcgc ttccgggaac gagattctgg aactggtggt aaatgccatg 660
atgggcgacg accctccgga gccccccacc ccatttgaga caccttcgct gcacgatttg 720
tatgatctgg aggtggatgt gcccgaggac gatcccaatg aggaggcggt aaatgatttt 780
tttagcgatg ccgcgctgct agctgccgag gaggcttcga gctctagctc agacagcgac 840
tcttcactgc atacccctag acccggcaga ggtgagaaaa agatccccga gcttaaaggg 900
gaagagatgg acttgcgctg ctatgaggaa tgcttgcccc cgagcgatga tgaggacgag 960
caggcgatcc agaacgcagc gagccaggga gtgcaagccg ccagcgagag ctttgcgctg 1020
gactgcccgc ctctgcccgg acacggctgt aagtcttgtg aatttcatcg catgaatact 1080
ggagataaag ctgtgttgtg tgcactttgc tatatgagag cttacaacca ttgtgtttac 1140
agtaagtgtg attaagttga actttagagg gaggcagaga gcagggtgac tgggcgatga 1200
ctggtttatt tatgtatata tgttctttat ataggtcccg tctctgacgc agatgatgag 1260
acccccacta caaagtccac ttcgtcaccc ccagaaattg gcacatctcc acctgagaat 1320
attgttagac cagttcctgt tagagccact gggaggagag cagctgtgga atgtttggat 1380
gacttgctac agggtggggt tgaacctttg gacttgtgta cccggaaacg ccccaggcac 1440
taagtgccac acatgtgtgt ttacttgagg tgatgtcagt atttataggg tgtggagtgc 1500
aataaaaaat gtgttgactt taagtgcgtg gtttatgact caggggtggg gactgtgagt 1560
atataagcag gtgcagacct gtgtggttag ctcagagcgg catggagatt tggacggtct 1620
tggaagactt tcacaagact agacagctgc tagagaacgc ctcgaacgga gtctcttacc 1680
tgtggagatt ctgcttcggt ggcgacctag ctaggctagt ctacagggcc aaacaggatt 1740
atagtgaaca atttgaggtt attttgagag agtgttctgg tctttttgac gctcttaact 1800
tgggccatca gtctcacttt aaccagagga tttcgagagc ccttgatttt actactcctg 1860
gcagaaccac tgcagcagta gccttttttg cttttattct tgacaaatgg agtcaagaaa 1920
cccatttcag cagggattac cagctggatt tcttagcagt agctttgtgg agaacatgga 1980
agtgccagcg cctgaatgca atctccggct acttgccggt acagccgcta gacactctga 2040
ggatcctgaa tctccaggag agtcccaggg cacgccaacg tcgccagcag cagcagcagg 2100
aggaggatca agaagagaac ccgagagccg gcctggaccc tccggcggag gaggaggagt 2160
agctgacctg tttcctgaac tgcgccgggt gctgactagg tcttcgagtg gtcgggagag 2220
ggggattaag cgggagaggc atgatgagac taatcacaga actgaactga ctgtgggtct 2280
gatgagtcgc aagcgcccag aaacagtgtg gtggcatgag gtgcagtcga ctggcacaga 2340
tgaggtgtcg gtgatgcatg agaggttttc tctagaacaa gtcaagactt gttggttaga 2400
gcctgaggat gattgggagg tagccatcag gaattatgcc aagctggctc tgaggccaga 2460
caagaagtac aagattacta agctgataaa tatcagaaat gcctgctaca tctcagggaa 2520
tggggctgaa gtggagatct gtctccagga aagggtggct ttcagatgct gcatgatgaa 2580
tatgtacccg ggagtggtgg gcatggatgg ggttaccttt atgaacatga ggttcagggg 2640
agatgggtat aatggcacgg tctttatggc caataccaag ctgacagtcc atggctgctc 2700
cttctttggg tttaataaca cctgcatcga ggcctggggt caggtcggtg tgaggggctg 2760
cagtttttca gccaactgga tgggggtcgt gggcaggacc aagagtatgc tgtccgtgaa 2820
gaaatgcttg tttgagaggt gccacctggg ggtgatgagc gagggcgaag ccagaatccg 2880
ccactgcgcc tctaccgaga cgggctgctt tgtgctgtgc aagggcaatg ctaagatcaa 2940
gcataatatg atctgtggag cctcggacga gcgcggctac cagatgctga cctgcgccgg 3000
cgggaacagc catatgctgg ccaccgtaca tgtggcttcc catgctcgca agccctggcc 3060
cgagttcgag cacaatgtca tgaccaggtg caatatgcat ctggggtccc gccgaggcat 3120
gttcatgccc taccagtgca acctgaatta tgtgaaggtg ctgctggagc ccgatgccat 3180
gtccagagtg agcctgacgg gggtgtttga catgaatgtg gaggtgtgga agattctgag 3240
atatgatgaa tccaagacca ggtgccgagc ctgcgagtgc ggagggaagc atgccaggtt 3300
ccagcccgtg tgtgtggatg tgacggagga cctgcgaccc gatcatttgg tgttgccctg 3360
caccgggacg gagttcggtt ccagcgggga agaatctgac tagagtgagt agtgttctgg 3420
ggcgggggag gacctgcatg agggccagaa taactgaaat ctgtgctttt ctgtgtgttg 3480
cagcagcatg agcggaagcg gctcctttga gggaggggta ttcagccctt atctgacggg 3540
gcgtctcccc tcctgggcgg gagtgcgtca gaatgtgatg ggatccacgg tggacggccg 3600
gcccgtgcag cccgcgaact cttcaaccct gacctatgca accctgagct cttcgtcgtt 3660
ggacgcagct gccgccgcag ctgctgcatc tgccgccagc gccgtgcgcg gaatggccat 3720
gggcgccggc tactacggca ctctggtggc caactcgagt tccaccaata atcccgccag 3780
cctgaacgag gagaagctgt tgctgctgat ggcccagctc gaggccttga cccagcgcct 3840
gggcgagctg acccagcagg tggctcagct gcaggagcag acgcgggccg cggttgccac 3900
ggtgaaatcc aaataaaaaa tgaatcaata aataaacgga gacggttgtt gattttaaca 3960
cagagtctga atctttattt gatttttcgc gcgcggtagg ccctggacca ccggtctcga 4020
tcattgagca cccggtggat cttttccagg acccggtaga ggtgggcttg gatgttgagg 4080
tacatgggca tgagcccgtc ccgggggtgg aggtagctcc attgcagggc ctcgtgctcg 4140
ggggtggtgt tgtaaatcac ccagtcatag caggggcgca gggcatggtg ttgcacaata 4200
tctttgagga ggagactgat ggccacgggc agccctttgg tgtaggtgtt tacaaatctg 4260
ttgagctggg agggatgcat gcggggggag atgaggtgca tcttggcctg gatcttgaga 4320
ttggcgatgt taccgcccag atcccgcctg gggttcatgt tgtgcaggac caccagcacg 4380
gtgtatccgg tgcacttggg gaatttatca tgcaacttgg aagggaaggc gtgaaagaat 4440
ttggcgacgc ctttgtgccc gcccaggttt tccatgcact catccatgat gatggcgatg 4500
ggcccgtggg cggcggcctg ggcaaagacg tttcgggggt cggacacatc atagttgtgg 4560
tcctgggtga ggtcatcata ggccatttta atgaatttgg ggcggagggt gccggactgg 4620
gggacaaagg taccctcgat cccgggggcg tagttcccct cacagatctg catctcccag 4680
gctttgagct cggagggggg gatcatgtcc acctgcgggg cgataaagaa cacggtttcc 4740
ggggcggggg agatgagctg ggccgaaagc aagttccgga gcagctggga cttgccgcag 4800
ccggtggggc cgtagatgac cccgatgacc ggctgcaggt ggtagttgag ggagagacag 4860
ctgccgtcct cccggaggag gggggccacc tcgttcatca tctcgcgcac gtgcatgttc 4920
tcgcgcacca gttccgccag gaggcgctct ccccccaggg ataggagctc ctggagcgag 4980
gcgaagtttt tcagcggctt gagtccgtcg gccatgggca ttttggagag ggtttgttgc 5040
aagagttcca ggcggtccca gagctcggtg atgtgctcta cggcatctcg atccagcaga 5100
cctcctcgtt tcgcgggttg ggacggctgc gggagtaggg caccagacga tgggcgtcca 5160
gcgcagccag ggtccggtcc ttccagggtc gcagcgtccg cgtcagggtg gtctccgtca 5220
cggtgaaggg gtgcgcgccg ggctgggcgc ttgcgagggt gcgcttcagg ctcatccggc 5280
tggtcgaaaa ccgctcccga tcggcgccct gcgcgtcggc caggtagcaa ttgaccatga 5340
gttcgtagtt gagcgcctcg gccgcgtggc ctttggcgcg gagcttacct ttggaagtct 5400
gcccgcaggc gggacagagg agggacttga gggcgtagag cttgggggcg aggaagacgg 5460
actcgggggc gtaggcgtcc gcgccgcagt gggcgcagac ggtctcgcac tccacgagcc 5520
aggtgaggtc gggctggtcg gggtcaaaaa ccagtttccc gccgttcttt ttgatgcgtt 5580
tcttaccttt ggtctccatg agctcgtgtc cccgctgggt gacaaagagg ctgtccgtgt 5640
ccccgtagac cgactttatg ggccggtcct cgagcggtgt gccgcggtcc tcctcgtaga 5700
ggaaccccgc ccactccgag acgaaagccc gggtccaggc cagcacgaag gaggccacgt 5760
gggacgggta gcggtcgttg tccaccagcg ggtccacctt ttccagggta tgcaaacaca 5820
tgtccccctc gtccacatcc aggaaggtga ttggcttgta agtgtaggcc acgtgaccgg 5880
gggtcccggc cgggggggta taaaagggtg cgggtccctg ctcgtcctca ctgtcttccg 5940
gatcgctgtc caggagcgcc agctgttggg gtaggtattc cctctcgaag gcgggcatga 6000
cctcggcact caggttgtca gtttctagaa acgaggagga tttgatattg acggtgccgg 6060
cggagatgcc tttcaagagc ccctcgtcca tctggtcaga aaagacgatc tttttgttgt 6120
cgagcttggt ggcgaaggag ccgtagaggg cgttggagag gagcttggcg atggagcgca 6180
tggtctggtt tttttccttg tcggcgcgct ccttggcggc gatgttgagc tgcacgtact 6240
cgcgcgccac gcacttccat tcggggaaga cggtggtcag ctcgtcgggc acgattctga 6300
cctgccagcc ccgattatgc agggtgatga ggtccacact ggtggccacc tcgccgcgca 6360
ggggctcatt agtccagcag aggcgtccgc ccttgcgcga gcagaagggg ggcagggggt 6420
ccagcatgac ctcgtcgggg gggtcggcat cgatggtgaa gatgccgggc aggaggtcgg 6480
ggtcaaagta gctgatggaa gtggccagat cgtccagggc agcttgccat tcgcgcacgg 6540
ccagcgcgcg ctcgtaggga ctgaggggcg tgccccaggg catgggatgg gtaagcgcgg 6600
aggcgtacat gccgcagatg tcgtagacgt agaggggctc ctcgaggatg ccgatgtagg 6660
tggggtagca gcgccccccg cggatgctgg cgcgcacgta gtcatacagc tcgtgcgagg 6720
gggcgaggag ccccgggccc aggttggtgc gactgggctt ttcggcgcgg tagacgatct 6780
ggcggaaaat ggcatgcgag ttggaggaga tggtgggcct ttggaagatg ttgaagtggg 6840
cgtggggcag tccgaccgag tcgcggatga agtgggcgta ggagtcttgc agcttggcga 6900
cgagctcggc ggtgactagg acgtccagag cgcagtagtc gagggtctcc tggatgatgt 6960
catacttgag ctgtcccttt tgtttccaca gctcgcggtt gagaaggaac tcttcgcggt 7020
ccttccagta ctcttcgagg gggaacccgt cctgatctgc acggtaagag cctagcatgt 7080
agaactggtt gacggccttg taggcgcagc agcccttctc cacggggagg gcgtaggcct 7140
gggcggcctt gcgcagggag gtgtgcgtga gggcgaaagt gtccctgacc atgaccttga 7200
ggaactggtg cttgaagtcg atatcgtcgc agcccccctg ctcccagagc tggaagtccg 7260
tgcgcttctt gtaggcgggg ttgggcaaag cgaaagtaac atcgttgaag aggatcttgc 7320
ccgcgcgggg cataaagttg cgagtgatgc ggaaaggttg gggcacctcg gcccggttgt 7380
tgatgacctg ggcggcgagc acgatctcgt cgaagccgtt gatgttgtgg cccacgatgt 7440
agagttccac gaatcgcgga cggcccttga cgtggggcag tttcttgagc tcctcgtagg 7500
tgagctcgtc ggggtcgctg agcccgtgct gctcgagcgc ccagtcggcg agatgggggt 7560
tggcgcggag gaaggaagtc cagagatcca cggccagggc ggtttgcaga cggtcccggt 7620
actgacggaa ctgctgcccg acggccattt tttcgggggt gacgcagtag aaggtgcggg 7680
ggtccccgtg ccagcgatcc catttgagct ggagggcgag atcgagggcg agctcgacga 7740
gccggtcgtc cccggagagt ttcatgacca gcatgaaggg gacgagctgc ttgccgaagg 7800
accccatcca ggtgtaggtt tccacatcgt aggtgaggaa gagcctttcg gtgcgaggat 7860
gcgagccgat ggggaagaac tggatctcct gccaccaatt ggaggaatgg ctgttgatgt 7920
gatggaagta gaaatgccga cggcgcgccg aacactcgtg cttgtgttta tacaagcggc 7980
cacagtgctc gcaacgctgc acgggatgca cgtgctgcac gagctgtacc tgagttcctt 8040
tgacgaggaa tttcagtggg aagtggagtc gtggcgcctg catctcgtgc tgtactacgt 8100
cgtggtggtc ggcctggccc tcttctgcct cgatggtggt catgctgacg agcccgcgcg 8160
ggaggcaggt ccagacctcg gcgcgagcgg gtcggagagc gaggacgagg gcgcgcaggc 8220
cggagctgtc cagggtcctg agacgctgcg gagtcaggtc agtgggcagc ggcggcgcgc 8280
ggttgacttg caggagtttt tccagggcgc gcgggaggtc cagatggtac ttgatctcca 8340
ccgcgccatt ggtggcgacg tcgatggctt gcagggtccc gtgcccctgg ggtgtgacca 8400
ccgtcccccg tttcttcttg ggcggctggg gcgacggggg cggtgcctct tccatggtta 8460
gaagcggcgg cgaggacgcg cgccgggcgg caggggcggc tcggggcccg gaggcagggg 8520
cggcaggggc acgtcggcgc cgcgcgcggg taggttctgg tactgcgccc ggagaagact 8580
ggcgtgagcg acgacgcgac ggttgacgtc ctggatctga cgcctctggg tgaaggccac 8640
gggacccgtg agtttgaacc tgaaagagag ttcgacagaa tcaatctcgg tatcgttgac 8700
ggcggcctgc cgcaggatct cttgcacgtc gcccgagttg tcctggtagg cgatctcggt 8760
catgaactgc tcgatctcct cctcttgaag gtctccgcgg ccggcgcgct ccacggtggc 8820
cgcgaggtcg ttggagatgc ggcccatgag ctgcgagaag gcgttcatgc ccgcctcgtt 8880
ccagacgcgg ctgtagacca cgacgccctc gggatcgccg gcgcgcatga ccacctgggc 8940
gaggttgagc tccacgtggc gcgtgaagac cgcgtagttg cagaggcgct ggtagaggta 9000
gttgagcgtg gtggcgatgt gctcggtgac gaagaaatac atgatccagc ggcggagcgg 9060
catctcgctg acgtcgccca gcgcctccaa acgttccatg gcctcgtaaa agtccacggc 9120
gaagttgaaa aactgggagt tgcgcgccga gacggtcaac tcctcctcca gaagacggat 9180
gagctcggcg atggtggcgc gcacctcgcg ctcgaaggcc cccgggagtt cctccacttc 9240
ctcttcttcc tcctccacta acatctcttc tacttcctcc tcaggcggca gtggtggcgg 9300
gggagggggc ctgcgtcgcc ggcggcgcac gggcagacgg tcgatgaagc gctcgatggt 9360
ctcgccgcgc cggcgtcgca tggtctcggt gacggcgcgc ccgtcctcgc ggggccgcag 9420
cgtgaagacg ccgccgcgca tctccaggtg gccggggggg tccccgttgg gcagggagag 9480
ggcgctgacg atgcatctta tcaattgccc cgtagggact ccgcgcaagg acctgagcgt 9540
ctcgagatcc acgggatctg aaaaccgctg aacgaaggct tcgagccagt cgcagtcgca 9600
aggtaggctg agcacggttt cttctggcgg gtcatgttgg ttgggagcgg ggcgggcgat 9660
gctgctggtg atgaagttga aataggcggt tctgagacgg cggatggtgg cgaggagcac 9720
caggtctttg ggcccggctt gctggatgcg cagacggtcg gccatgcccc aggcgtggtc 9780
ctgacacctg gccaggtcct tgtagtagtc ctgcatgagc cgctccacgg gcacctcctc 9840
ctcgcccgcg cggccgtgca tgcgcgtgag cccgaagccg cgctggggct ggacgagcgc 9900
caggtcggcg acgacgcgct cggcgaggat ggcttgctgg atctgggtga gggtggtctg 9960
gaagtcatca aagtcgacga agcggtggta ggctccggtg ttgatggtgt aggagcagtt 10020
ggccatgacg gaccagttga cggtctggtg gcccggacgc acgagctcgt ggtacttgag 10080
gcgcgagtag gcgcgcgtgt cgaagatgta gtcgttgcag gtgcgcacca ggtactggta 10140
gccgatgagg aagtgcggcg gcggctggcg gtagagcggc catcgctcgg tggcgggggc 10200
gccgggcgcg aggtcctcga gcatggtgcg gtggtagccg tagatgtacc tggacatcca 10260
ggtgatgccg gcggcggtgg tggaggcgcg cgggaactcg cggacgcggt tccagatgtt 10320
gcgcagcggc aggaagtagt tcatggtggg cacggtctgg cccgtgaggc gcgcgcagtc 10380
gtggatgctc tatacgggca aaaacgaaag cggtcagcgg ctcgactccg tggcctggag 10440
gctaagcgaa cgggttgggc tgcgcgtgta ccccggttcg aatctcgaat caggctggag 10500
ccgcagctaa cgtggtattg gcactcccgt ctcgacccaa gcctgcacca accctccagg 10560
atacggaggc gggtcgtttt gcaacttttt tttggaggcc ggatgagact agtaagcgcg 10620
gaaagcggcc gaccgcgatg gctcgctgcc gtagtctgga gaagaatcgc cagggttgcg 10680
ttgcggtgtg ccccggttcg aggccggccg gattccgcgg ctaacgaggg cgtggctgcc 10740
ccgtcgtttc caagacccca tagccagccg acttctccag ttacggagcg agcccctctt 10800
ttgttttgtt tgtttttgcc agatgcatcc cgtactgcgg cagatgcgcc cccaccaccc 10860
tccaccgcaa caacagcccc ctccacagcc ggcgcttctg cccccgcccc agcagcaact 10920
tccagccacg accgccgcgg ccgccgtgag cggggctgga cagagttatg atcaccagct 10980
ggccttggaa gagggcgagg ggctggcgcg cctgggggcg tcgtcgccgg agcggcaccc 11040
gcgcgtgcag atgaaaaggg acgctcgcga ggcctacgtg cccaagcaga acctgttcag 11100
agacaggagc ggcgaggagc ccgaggagat gcgcgcggcc cggttccacg cggggcggga 11160
gctgcggcgc ggcctggacc gaaagagggt gctgagggac gaggatttcg aggcggacga 11220
gctgacgggg atcagccccg cgcgcgcgca cgtggccgcg gccaacctgg tcacggcgta 11280
cgagcagacc gtgaaggagg agagcaactt ccaaaaatcc ttcaacaacc acgtgcgcac 11340
cctgatcgcg cgcgaggagg tgaccctggg cctgatgcac ctgtgggacc tgctggaggc 11400
catcgtgcag aaccccacca gcaagccgct gacggcgcag ctgttcctgg tggtgcagca 11460
tagtcgggac aacgaagcgt tcagggaggc gctgctgaat atcaccgagc ccgagggccg 11520
ctggctcctg gacctggtga acattctgca gagcatcgtg gtgcaggagc gcgggctgcc 11580
gctgtccgag aagctggcgg ccatcaactt ctcggtgctg agtttgggca agtactacgc 11640
taggaagatc tacaagaccc cgtacgtgcc catagacaag gaggtgaaga tcgacgggtt 11700
ttacatgcgc atgaccctga aagtgctgac cctgagcgac gatctggggg tgtaccgcaa 11760
cgacaggatg caccgtgcgg tgagcgccag caggcggcgc gagctgagcg accaggagct 11820
gatgcatagt ctgcagcggg ccctgaccgg ggccgggacc gagggggaga gctactttga 11880
catgggcgcg gacctgcact ggcagcccag ccgccgggcc ttggaggcgg cggcaggacc 11940
ctacgtagaa gaggtggacg atgaggtgga cgaggagggc gagtacctgg aagactgatg 12000
gcgcgaccgt atttttgcta gatgcaacaa caacagccac ctcctgatcc cgcgatgcgg 12060
gcggcgctgc agagccagcc gtccggcatt aactcctcgg acgattggac ccaggccatg 12120
caacgcatca tggcgctgac gacccgcaac cccgaagcct ttagacagca gccccaggcc 12180
aaccggctct cggccatcct ggaggccgtg gtgccctcgc gctccaaccc cacgcacgag 12240
aaggtcctgg ccatcgtgaa cgcgctggtg gagaacaagg ccatccgcgg cgacgaggcc 12300
ggcctggtgt acaacgcgct gctggagcgc gtggcccgct acaacagcac caacgtgcag 12360
accaacctgg accgcatggt gaccgacgtg cgcgaggccg tggcccagcg cgagcggttc 12420
caccgcgagt ccaacctggg atccatggtg gcgctgaacg ccttcctcag cacccagccc 12480
gccaacgtgc cccggggcca ggaggactac accaacttca tcagcgccct gcgcctgatg 12540
gtgaccgagg tgccccagag cgaggtgtac cagtccgggc cggactactt cttccagacc 12600
agtcgccagg gcttgcagac cgtgaacctg agccaggctt tcaagaactt gcagggcctg 12660
tggggcgtgc aggccccggt cggggaccgc gcgacggtgt cgagcctgct gacgccgaac 12720
tcgcgcctgc tgctgctgct ggtggccccc ttcacggaca gcggcagcat caaccgcaac 12780
tcgtacctgg gctacctgat taacctgtac cgcgaggcca tcggccaggc gcacgtggac 12840
gagcagacct accaggagat cacccacgtg agccgcgccc tgggccagga cgacccgggc 12900
aacctggaag ccaccctgaa ctttttgctg accaaccggt cgcagaagat cccgccccag 12960
tacgcgctca gcaccgagga ggagcgcatc ctgcgttacg tgcagcagag cgtgggcctg 13020
ttcctgatgc aggagggggc cacccccagc gccgcgctcg acatgaccgc gcgcaacatg 13080
gagcccagca tgtacgccag caaccgcccg ttcatcaata aactgatgga ctacttgcat 13140
cgggcggccg ccatgaactc tgactatttc accaacgcca tcctgaatcc ccactggctc 13200
ccgccgccgg ggttctacac gggcgagtac gacatgcccg accccaatga cgggttcctg 13260
tgggacgatg tggacagcag cgtgttctcc ccccgaccgg gtgctaacga gcgccccttg 13320
tggaagaagg aaggcagcga ccgacgcccg tcctcggcgc tgtccggccg cgagggtgct 13380
gccgcggcgg tgcccgaggc cgccagtcct ttcccgagct tgcccttctc gctgaacagt 13440
atccgcagca gcgagctggg caggatcacg cgcccgcgct tgctgggcga agaggagtac 13500
ttgaatgact cgctgttgag acccgagcgg gagaagaact tccccaataa cgggatagaa 13560
agcctggtgg acaagatgag ccgctggaag acgtatgcgc aggagcacag ggacgatccc 13620
cgggcgtcgc agggggccac gagccggggc agcgccgccc gtaaacgccg gtggcacgac 13680
aggcagcggg gacagatgtg ggacgatgag gactccgccg acgacagcag cgtgttggac 13740
ttgggtggga gtggtaaccc gttcgctcac ctgcgccccc gtatcgggcg catgatgtaa 13800
gagaaaccga aaataaatga tactcaccaa ggccatggcg accagcgtgc gttcgtttct 13860
tctctgttgt tgttgtatct agtatgatga ggcgtgcgta cccggagggt cctcctccct 13920
cgtacgagag cgtgatgcag caggcgatgg cggcggcggc gatgcagccc ccgctggagg 13980
ctccttacgt gcccccgcgg tacctggcgc ctacggaggg gcggaacagc attcgttact 14040
cggagctggc acccttgtac gataccaccc ggttgtacct ggtggacaac aagtcggcgg 14100
acatcgcctc gctgaactac cagaacgacc acagcaactt cctgaccacc gtggtgcaga 14160
acaatgactt cacccccacg gaggccagca cccagaccat caactttgac gagcgctcgc 14220
ggtggggcgg ccagctgaaa accatcatgc acaccaacat gcccaacgtg aacgagttca 14280
tgtacagcaa caagttcaag gcgcgggtga tggtctcccg caagaccccc aatggggtga 14340
cagtgacaga ggattatgat ggtagtcagg atgagctgaa gtatgaatgg gtggaatttg 14400
agctgcccga aggcaacttc tcggtgacca tgaccatcga cctgatgaac aacgccatca 14460
tcgacaatta cttggcggtg gggcggcaga acggggtgct ggagagcgac atcggcgtga 14520
agttcgacac taggaacttc aggctgggct gggaccccgt gaccgagctg gtcatgcccg 14580
gggtgtacac caacgaggct ttccatcccg atattgtctt gctgcccggc tgcggggtgg 14640
acttcaccga gagccgcctc agcaacctgc tgggcattcg caagaggcag cccttccagg 14700
aaggcttcca gatcatgtac gaggatctgg aggggggcaa catccccgcg ctcctggatg 14760
tcgacgccta tgagaaaagc aaggaggatg cagcagctga agcaactgca gccgtagcta 14820
ccgcctctac cgaggtcagg ggcgataatt ttgcaagcgc cgcagcagtg gcagcggccg 14880
aggcggctga aaccgaaagt aagatagtca ttcagccggt ggagaaggat agcaagaaca 14940
ggagctacaa cgtactaccg gacaagataa acaccgccta ccgcagctgg tacctagcct 15000
acaactatgg cgaccccgag aagggcgtgc gctcctggac gctgctcacc acctcggacg 15060
tcacctgcgg cgtggagcaa gtctactggt cgctgcccga catgatgcaa gacccggtca 15120
ccttccgctc cacgcgtcaa gttagcaact acccggtggt gggcgccgag ctcctgcccg 15180
tctactccaa gagcttcttc aacgagcagg ccgtctactc gcagcagctg cgcgccttca 15240
cctcgcttac gcacgtcttc aaccgcttcc ccgagaacca gatcctcgtc cgcccgcccg 15300
cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15360
cgctgcgcag cagtatccgg ggagtccagc gcgtgaccgt tactgacgcc agacgccgca 15420
cctgccccta cgtctacaag gccctgggca tagtcgcgcc gcgcgtcctc tcgagccgca 15480
ccttctaaat gtccattctc atctcgccca gtaataacac cggttggggc ctgcgcgcgc 15540
ccagcaagat gtacggaggc gctcgccaac gctccacgca acaccccgtg cgcgtgcgcg 15600
ggcacttccg cgctccctgg ggcgccctca agggccgcgt gcggtcgcgc accaccgtcg 15660
acgacgtgat cgaccaggtg gtggccgacg cgcgcaacta cacccccgcc gccgcgcccg 15720
tctccaccgt ggacgccgtc atcgacagcg tggtggcgga cgcgcgccgg tacgcccgcg 15780
ccaagagccg gcggcggcgc atcgcccggc ggcaccggag cacccccgcc atgcgcgcgg 15840
cgcgagcctt gctgcgcagg gccaggcgca cgggacgcag ggccatgctc agggcggcca 15900
gacgcgcggc ttcaggcgcc agcgccggca ggacccggag acgcgcggcc acggcggcgg 15960
cagcggccat cgccagcatg tcccgcccgc ggcgagggaa cgtgtactgg gtgcgcgacg 16020
ccgccaccgg tgtgcgcgtg cccgtgcgca cccgcccccc tcgcacttga agatgttcac 16080
ttcgcgatgt tgatgtgtcc cagcggcgag gaggatgtcc aagcgcaaat tcaaggaaga 16140
gatgctccag gtcatcgcgc ctgagatcta cggccctgcg gtggtgaagg aggaaagaaa 16200
gccccgcaaa atcaagcggg tcaaaaagga caaaaaggaa gaagaaagtg atgtggacgg 16260
attggtggag tttgtgcgcg agttcgcccc ccggcggcgc gtgcagtggc gcgggcggaa 16320
ggtgcaaccg gtgctgagac ccggcaccac cgtggtcttc acgcccggcg agcgctccgg 16380
caccgcttcc aagcgctcct acgacgaggt gtacggggat gatgatattc tggagcaggc 16440
ggccgagcgc ctgggcgagt ttgcttacgg caagcgcagc cgttccgcac cgaaggaaga 16500
ggcggtgtcc atcccgctgg accacggcaa ccccacgccg agcctcaagc ccgtgacctt 16560
gcagcaggtg ctgccgaccg cggcgccgcg ccgggggttc aagcgcgagg gcgaggatct 16620
gtaccccacc atgcagctga tggtgcccaa gcgccagaag ctggaagacg tgctggagac 16680
catgaaggtg gacccggacg tgcagcccga ggtcaaggtg cggcccatca agcaggtggc 16740
cccgggcctg ggcgtgcaga ccgtggacat caagattccc acggagccca tggaaacgca 16800
gaccgagccc atgatcaagc ccagcaccag caccatggag gtgcagacgg atccctggat 16860
gccatcggct cctagtcgaa gaccccggcg caagtacggc gcggccagcc tgctgatgcc 16920
caactacgcg ctgcatcctt ccatcatccc cacgccgggc taccgcggca cgcgcttcta 16980
ccgcggtcat accagcagcc gccgccgcaa gaccaccact cgccgccgcc gtcgccgcac 17040
cgccgctgca accacccctg ccgccctggt gcggagagtg taccgccgcg gccgcgcacc 17100
tctgaccctg ccgcgcgcgc gctaccaccc gagcatcgcc atttaaactt tcgccagctt 17160
tgcagatcaa tggccctcac atgccgcctt cgcgttccca ttacgggcta ccgaggaaga 17220
aaaccgcgcc gtagaaggct ggcggggaac gggatgcgtc gccaccacca ccggcggcgg 17280
cgcgccatca gcaagcggtt ggggggaggc ttcctgcccg cgctgatccc catcatcgcc 17340
gcggcgatcg gggcgatccc cggcattgct tccgtggcgg tgcaggcctc tcagcgccac 17400
tgagacacac ttggaaacat cttgtaataa acccatggac tctgacgctc ctggtcctgt 17460
gatgtgtttt cgtagacaga tggaagacat caatttttcg tccctggctc cgcgacacgg 17520
cacgcggccg ttcatgggca cctggagcga catcggcacc agccaactga acgggggcgc 17580
cttcaattgg agcagtctct ggagcgggct taagaatttc gggtccacgc ttaaaaccta 17640
tggcagcaag gcgtggaaca gcaccacagg gcaggcgctg agggataagc tgaaagagca 17700
gaacttccag cagaaggtgg tcgatgggct cgcctcgggc atcaacgggg tggtggacct 17760
ggccaaccag gccgtgcagc ggcagatcaa cagccgcctg gacccggtgc cgcccgccgg 17820
ctccgtggag atgccgcagg tggaggagga gctgcctccc ctggacaagc ggggcgagaa 17880
gcgaccccgc cccgatgcgg aggagacgct gctgacgcac acggacgagc cgcccccgta 17940
cgaggaggcg gtgaaactgg gtctgcccac cacgcggccc atcgcgcccc tggccaccgg 18000
ggtgctgaaa cccgaaaagc ccgcgaccct ggacttgcct cctccccagc cttcccgccc 18060
ctctacagtg gctaagcccc tgccgccggt ggccgtggcc cgcgcgcgac ccgggggcac 18120
cgcccgccct catgcgaact ggcagagcac tctgaacagc atcgtgggtc tgggagtgca 18180
gagtgtgaag cgccgccgct gctattaaac ctaccgtagc gcttaacttg cttgtctgtg 18240
tgtgtatgta ttatgtcgcc gccgccgctg tccaccagaa ggaggagtga agaggcgcgt 18300
cgccgagttg caagatggcc accccatcga tgctgcccca gtgggcgtac atgcacatcg 18360
ccggacagga cgcttcggag tacctgagtc cgggtctggt gcagtttgcc cgcgccacag 18420
acacctactt cagtctgggg aacaagttta ggaaccccac ggtggcgccc acgcacgatg 18480
tgaccaccga ccgcagccag cggctgacgc tgcgcttcgt gcccgtggac cgcgaggaca 18540
acacctactc gtacaaagtg cgctacacgc tggccgtggg cgacaaccgc gtgctggaca 18600
tggccagcac ctactttgac atccgcggcg tgctggatcg gggccctagc ttcaaaccct 18660
actccggcac cgcctacaac agtctggccc ccaagggagc acccaacact tgtcagtgga 18720
catataaagc cgatggtgaa actgccacag aaaaaaccta tacatatgga aatgcacccg 18780
tgcagggcat taacatcaca aaagatggta ttcaacttgg aactgacacc gatgatcagc 18840
caatctacgc agataaaacc tatcagcctg aacctcaagt gggtgatgct gaatggcatg 18900
acatcactgg tactgatgaa aagtatggag gcagagctct taagcctgat accaaaatga 18960
agccttgtta tggttctttt gccaagccta ctaataaaga aggaggtcag gcaaatgtga 19020
aaacaggaac aggcactact aaagaatatg acatagacat ggctttcttt gacaacagaa 19080
gtgcggctgc tgctggccta gctccagaaa ttgttttgta tactgaaaat gtggatttgg 19140
aaactccaga tacccatatt gtatacaaag caggcacaga tgacagcagc tcttctatta 19200
atttgggtca gcaagccatg cccaacagac ctaactacat tggtttcaga gacaacttta 19260
tcgggctcat gtactacaac agcactggca atatgggggt gctggccggt caggcttctc 19320
agctgaatgc tgtggttgac ttgcaagaca gaaacaccga gctgtcctac cagctcttgc 19380
ttgactctct gggtgacaga acccggtatt tcagtatgtg gaatcaggcg gtggacagct 19440
atgatcctga tgtgcgcatt attgaaaatc atggtgtgga ggatgaactt cccaactatt 19500
gtttccctct ggatgctgtt ggcagaacag atacttatca gggaattaag gctaatggaa 19560
ctgatcaaac cacatggacc aaagatgaca gtgtcaatga tgctaatgag ataggcaagg 19620
gtaatccatt cgccatggaa atcaacatcc aagccaacct gtggaggaac ttcctctacg 19680
ccaacgtggc cctgtacctg cccgactctt acaagtacac gccggccaat gttaccctgc 19740
ccaccaacac caacacctac gattacatga acggccgggt ggtggcgccc tcgctggtgg 19800
actcctacat caacatcggg gcgcgctggt cgctggatcc catggacaac gtgaacccct 19860
tcaaccacca ccgcaatgcg gggctgcgct accgctccat gctcctgggc aacgggcgct 19920
acgtgccctt ccacatccag gtgccccaga aatttttcgc catcaagagc ctcctgctcc 19980
tgcccgggtc ctacacctac gagtggaact tccgcaagga cgtcaacatg atcctgcaga 20040
gctccctcgg caacgacctg cgcacggacg gggcctccat ctccttcacc agcatcaacc 20100
tctacgccac cttcttcccc atggcgcaca acacggcctc cacgctcgag gccatgctgc 20160
gcaacgacac caacgaccag tccttcaacg actacctctc ggcggccaac atgctctacc 20220
ccatcccggc caacgccacc aacgtgccca tctccatccc ctcgcgcaac tgggccgcct 20280
tccgcggctg gtccttcacg cgtctcaaga ccaaggagac gccctcgctg ggctccgggt 20340
tcgaccccta cttcgtctac tcgggctcca tcccctacct cgacggcacc ttctacctca 20400
accacacctt caagaaggtc tccatcacct tcgactcctc cgtcagctgg cccggcaacg 20460
accggctcct gacgcccaac gagttcgaaa tcaagcgcac cgtcgacggc gagggctaca 20520
acgtggccca gtgcaacatg accaaggact ggttcctggt ccagatgctg gcccactaca 20580
acatcggcta ccagggcttc tacgtgcccg agggctacaa ggaccgcatg tactccttct 20640
tccgcaactt ccagcccatg agccgccagg tggtggacga ggtcaactac aaggactacc 20700
aggccgtcac cctggcctac cagcacaaca actcgggctt cgtcggctac ctcgcgccca 20760
ccatgcgcca gggccagccc taccccgcca actaccccta cccgctcatc ggcaagagcg 20820
ccgtcaccag cgtcacccag aaaaagttcc tctgcgacag ggtcatgtgg cgcatcccct 20880
tctccagcaa cttcatgtcc atgggcgcgc tcaccgacct cggccagaac atgctctatg 20940
ccaactccgc ccacgcgcta gacatgaatt tcgaagtcga ccccatggat gagtccaccc 21000
ttctctatgt tgtcttcgaa gtcttcgacg tcgtccgagt gcaccagccc caccgcggcg 21060
tcatcgaggc cgtctacctg cgcaccccct tctcggccgg taacgccacc acctaagctc 21120
ttgcttcttg caagccatgg ccgcgggctc cggcgagcag gagctcaggg ccatcatccg 21180
cgacctgggc tgcgggccct acttcctggg caccttcgat aagcgcttcc cgggattcat 21240
ggccccgcac aagctggcct gcgccatcgt caacacggcc ggccgcgaga ccgggggcga 21300
gcactggctg gccttcgcct ggaacccgcg ctcgaacacc tgctacctct tcgacccctt 21360
cgggttctcg gacgagcgcc tcaagcagat ctaccagttc gagtacgagg gcctgctgcg 21420
ccgcagcgcc ctggccaccg aggaccgctg cgtcaccctg gaaaagtcca cccagaccgt 21480
gcagggtccg cgctcggccg cctgcgggct cttctgctgc atgttcctgc acgccttcgt 21540
gcactggccc gaccgcccca tggacaagaa ccccaccatg aacttgctga cgggggtgcc 21600
caacggcatg ctccagtcgc cccaggtgga acccaccctg cgccgcaacc aggaggcgct 21660
ctaccgcttc ctcaactccc actccgccta ctttcgctcc caccgcgcgc gcatcgagaa 21720
ggccaccgcc ttcgaccgca tgaatcaaga catgtaaacc gtgtgtgtat gttaaatgtc 21780
tttaataaac agcactttca tgttacacat gcatctgaga tgatttattt agaaatcgaa 21840
agggttctgc cgggtctcgg catggcccgc gggcagggac acgttgcgga actggtactt 21900
ggccagccac ttgaactcgg ggatcagcag tttgggcagc ggggtgtcgg ggaaggagtc 21960
ggtccacagc ttccgcgtca gttgcagggc gcccagcagg tcgggcgcgg agatcttgaa 22020
atcgcagttg ggacccgcgt tctgcgcgcg ggagttgcgg tacacggggt tgcagcactg 22080
gaacaccatc agggccgggt gcttcacgct cgccagcacc gtcgcgtcgg tgatgctctc 22140
cacgtcgagg tcctcggcgt tggccatccc gaagggggtc atcttgcagg tctgccttcc 22200
catggtgggc acgcacccgg gcttgtggtt gcaatcgcag tgcaggggga tcagcatcat 22260
ctgggcctgg tcggcgttca tccccgggta catggccttc atgaaagcct ccaattgcct 22320
gaacgcctgc tgggccttgg ctccctcggt gaagaagacc ccgcaggact tgctagagaa 22380
ctggttggtg gcgcacccgg cgtcgtgcac gcagcagcgc gcgtcgttgt tggccagctg 22440
caccacgctg cgcccccagc ggttctgggt gatcttggcc cggtcggggt tctccttcag 22500
cgcgcgctgc ccgttctcgc tcgccacatc catctcgatc atgtgctcct tctggatcat 22560
ggtggtcccg tgcaggcacc gcagcttgcc ctcggcctcg gtgcacccgt gcagccacag 22620
cgcgcacccg gtgcactccc agttcttgtg ggcgatctgg gaatgcgcgt gcacgaagcc 22680
ctgcaggaag cggcccatca tggtggtcag ggtcttgttg ctagtgaagg tcagcggaat 22740
gccgcggtgc tcctcgttga tgtacaggtg gcagatgcgg cggtacacct cgccctgctc 22800
gggcatcagc tggaagttgg ctttcaggtc ggtctccacg cggtagcggt ccatcagcat 22860
agtcatgatt tccataccct tctcccaggc cgagacgatg ggcaggctca tagggttctt 22920
caccatcatc ttagcgctag cagccgcggc cagggggtcg ctctcgtcca gggtctcaaa 22980
gctccgcttg ccgtccttct cggtgatccg caccgggggg tagctgaagc ccacggccgc 23040
cagctcctcc tcggcctgtc tttcgtcctc gctgtcctgg ctgacgtcct gcaggaccac 23100
atgcttggtc ttgcggggtt tcttcttggg cggcagcggc ggcggagatg ttggagatgg 23160
cgagggggag cgcgagttct cgctcaccac tactatctct tcctcttctt ggtccgaggc 23220
cacgcggcgg taggtatgtc tcttcggggg cagaggcgga ggcgacgggc tctcgccgcc 23280
gcgacttggc ggatggctgg cagagcccct tccgcgttcg ggggtgcgct cccggcggcg 23340
ctctgactga cttcctccgc ggccggccat tgtgttctcc tagggaggaa caacaagcat 23400
ggagactcag ccatcgccaa cctcgccatc tgcccccacc gccgacgaga agcagcagca 23460
gcagaatgaa agcttaaccg ccccgccgcc cagccccgcc acctccgacg cggccgtccc 23520
agacatgcaa gagatggagg aatccatcga gattgacctg ggctatgtga cgcccgcgga 23580
gcacgaggag gagctggcag tgcgcttttc acaagaagag atacaccaag aacagccaga 23640
gcaggaagca gagaatgagc agagtcaggc tgggctcgag catgacggcg actacctcca 23700
cctgagcggg ggggaggacg cgctcatcaa gcatctggcc cggcaggcca ccatcgtcaa 23760
ggatgcgctg ctcgaccgca ccgaggtgcc cctcagcgtg gaggagctca gccgcgccta 23820
cgagttgaac ctcttctcgc cgcgcgtgcc ccccaagcgc cagcccaatg gcacctgcga 23880
gcccaacccg cgcctcaact tctacccggt cttcgcggtg cccgaggccc tggccaccta 23940
ccacatcttt ttcaagaacc aaaagatccc cgtctcctgc cgcgccaacc gcacccgcgc 24000
cgacgccctt ttcaacctgg gtcccggcgc ccgcctacct gatatcgcct ccttggaaga 24060
ggttcccaag atcttcgagg gtctgggcag cgacgagact cgggccgcga acgctctgca 24120
aggagaagga ggagagcatg agcaccacag cgccctggtc gagttggaag gcgacaacgc 24180
gcggctggcg gtgctcaaac gcacggtcga gctgacccat ttcgcctacc cggctctgaa 24240
cctgcccccc aaagtcatga gcgcggtcat ggaccaggtg ctcatcaagc gcgcgtcgcc 24300
catctccgag gacgagggca tgcaagactc cgaggagggc aagcccgtgg tcagcgacga 24360
gcagctggcc cggtggctgg gtcctaatgc tagtccccag agtttggaag agcggcgcaa 24420
actcatgatg gccgtggtcc tggtgaccgt ggagctggag tgcctgcgcc gcttcttcgc 24480
cgacgcggag accctgcgca aggtcgagga gaacctgcac tacctcttca ggcacgggtt 24540
cgtgcgccag gcctgcaaga tctccaacgt ggagctgacc aacctggtct cctacatggg 24600
catcttgcac gagaaccgcc tggggcagaa cgtgctgcac accaccctgc gcggggaggc 24660
ccggcgcgac tacatccgcg actgcgtcta cctctacctc tgccacacct ggcagacggg 24720
catgggcgtg tggcagcagt gtctggagga gcagaacctg aaagagctct gcaagctcct 24780
gcagaagaac ctcaagggtc tgtggaccgg gttcgacgag cgcaccaccg cctcggacct 24840
ggccgacctc attttccccg agcgcctcag gctgacgctg cgcaacggcc tgcccgactt 24900
tatgagccaa agcatgttgc aaaactttcg ctctttcatc ctcgaacgct ccggaatcct 24960
gcccgccacc tgctccgcgc tgccctcgga cttcgtgccg ctgaccttcc gcgagtgccc 25020
cccgccgctg tggagccact gctacctgct gcgcctggcc aactacctgg cctaccactc 25080
ggacgtgatc gaggacgtca gcggcgaggg cctgctcgag tgccactgcc gctgcaacct 25140
ctgcacgccg caccgctccc tggcctgcaa cccccagctg ctgagcgaga cccagatcat 25200
cggcaccttc gagttgcaag ggcccagcga aggcgagggt tcagccgcca aggggggtct 25260
gaaactcacc ccggggctgt ggacctcggc ctacttgcgc aagttcgtgc ccgaggacta 25320
ccatcccttc gagatcaggt tctacgagga ccaatcccat ccgcccaagg ccgagctgtc 25380
ggcctgcgtc atcacccagg gggcgatcct ggcccaattg caagccatcc agaaatcccg 25440
ccaagaattc ttgctgaaaa agggccgcgg ggtctacctc gacccccaga ccggtgagga 25500
gctcaacccc ggcttccccc aggatgcccc gaggaaacaa gaagctgaaa gtggagctgc 25560
cgcccgtgga ggatttggag gaagactggg agaacagcag tcaggcagag gaggaggaga 25620
tggaggaaga ctgggacagc actcaggcag aggaggacag cctgcaagac agtctggagg 25680
aagacgagga ggaggcagag gaggaggtgg aagaagcagc cgccgccaga ccgtcgtcct 25740
cggcggggga gaaagcaagc agcacggata ccatctccgc tccgggtcgg ggtcccgctc 25800
gaccacacag tagatgggac gagaccggac gattcccgaa ccccaccacc cagaccggta 25860
agaaggagcg gcagggatac aagtcctggc gggggcacaa aaacgccatc gtctcctgct 25920
tgcaggcctg cgggggcaac atctccttca cccggcgcta cctgctcttc caccgcgggg 25980
tgaactttcc ccgcaacatc ttgcattact accgtcacct ccacagcccc tactacttcc 26040
aagaagaggc agcagcagca gaaaaagacc agcagaaaac cagcagctag aaaatccaca 26100
gcggcggcag caggtggact gaggatcgcg gcgaacgagc cggcgcaaac ccgggagctg 26160
aggaaccgga tctttcccac cctctatgcc atcttccagc agagtcgggg gcaggagcag 26220
gaactgaaag tcaagaaccg ttctctgcgc tcgctcaccc gcagttgtct gtatcacaag 26280
agcgaagacc aacttcagcg cactctcgag gacgccgagg ctctcttcaa caagtactgc 26340
gcgctcactc ttaaagagta gcccgcgccc gcccagtcgc agaaaaaggc gggaattacg 26400
tcacctgtgc ccttcgccct agccgcctcc acccatcatc atgagcaaag agattcccac 26460
gccttacatg tggagctacc agccccagat gggcctggcc gccggtgccg cccaggacta 26520
ctccacccgc atgaattggc tcagcgccgg gcccgcgatg atctcacggg tgaatgacat 26580
ccgcgcccac cgaaaccaga tactcctaga acagtcagcg ctcaccgcca cgccccgcaa 26640
tcacctcaat ccgcgtaatt ggcccgccgc cctggtgtac caggaaattc cccagcccac 26700
gaccgtacta cttccgcgag acgcccaggc cgaagtccag ctgactaact caggtgtcca 26760
gctggcgggc ggcgccaccc tgtgtcgtca ccgccccgct cagggtataa agcggctggt 26820
gatccggggc agaggcacac agctcaacga cgaggtggtg agctcttcgc tgggtctgcg 26880
acctgacgga gtcttccaac tcgccggatc ggggagatct tccttcacgc ctcgtcaggc 26940
cgtcctgact ttggagagtt cgtcctcgca gccccgctcg ggtggcatcg gcactctcca 27000
gttcgtggag gagttcactc cctcggtcta cttcaacccc ttctccggct cccccggcca 27060
ctacccggac gagttcatcc cgaacttcga cgccatcagc gagtcggtgg acggctacga 27120
ttgaatgtcc catggtggcg cagctgacct agctcggctt cgacacctgg accactgccg 27180
ccgcttccgc tgcttcgctc gggatctcgc cgagtttgcc tactttgagc tgcccgagga 27240
gcaccctcag ggcccggccc acggagtgcg gatcgtcgtc gaagggggcc tcgactccca 27300
cctgcttcgg atcttcagcc agcgtccgat cctggtcgag cgcgagcaag gacagaccct 27360
tctgactctg tactgcatct gcaaccaccc cggcctgcat gaaagtcttt gttgtctgct 27420
gtgtactgag tataataaaa gctgagatca gcgactactc cggacttccg tgtgttcctg 27480
aatccatcaa ccagtctttg ttcttcaccg ggaacgagac cgagctccag ctccagtgta 27540
agccccacaa gaagtacctc acctggctgt tccagggctc cccgatcgcc gttgtcaacc 27600
actgcgacaa cgacggagtc ctgctgagcg gccctgccaa ccttactttt tccacccgca 27660
gaagcaagct ccagctcttc caacccttcc tccccgggac ctatcagtgc gtctcgggac 27720
cctgccatca caccttccac ctgatcccga ataccacagc gtcgctcccc gctactaaca 27780
accaaactaa cctccaccaa cgccaccgtc gcgacctttc tgaatctaat actaccaccc 27840
acaccggagg tgagctccga ggtcaaccaa cctctgggat ttactacggc ccctgggagg 27900
tggttgggtt aatagcgcta ggcctagttg cgggtgggct tttggttctc tgctacctat 27960
acctcccttg ctgttcgtac ttagtggtgc tgtgttgctg gtttaagaaa tggggaagat 28020
caccctagtg agctgcggtg cgctggtggc ggtgttgctt tcgattgtgg gactgggcgg 28080
tgcggctgta gtgaaggaga aggccgatcc ctgcttgcat ttcaatccca acaaatgcca 28140
gctgagtttt cagcccgatg gcaatcggtg cgcggtactg atcaagtgcg gatgggaatg 28200
cgagaacgtg agaatcgagt acaataacaa gactcggaac aatactctcg cgtccgtgtg 28260
gcagcccggg gaccccgagt ggtacaccgt ctctgtcccc ggtgctgacg gctccccgcg 28320
caccgtgaat aatactttca tttttgcgca catgtgcgac acggtcatgt ggatgagcaa 28380
gcagtacgat atgtggcccc ccacgaagga gaacatcgtg gtcttctcca tcgcttacag 28440
cctgtgcacg gcgctaatca ccgctatcgt gtgcctgagc attcacatgc tcatcgctat 28500
tcgccccaga aataatgccg aaaaagaaaa acagccataa cgtttttttt cacacctttt 28560
tcagaccatg gcctctgtta aatttttgct tttatttgcc agtctcattg ccgtcattca 28620
tggaatgagt aatgagaaaa ttactattta cactggcact aatcacacat tgaaaggtcc 28680
agaaaaagcc acagaagttt catggtattg ttattttaat gaatcagatg tatctactga 28740
actctgtgga aacaataaca aaaaaaatga gagcattact ctcatcaagt ttcaatgtgg 28800
atctgactta accctaatta acatcactag agactatgta ggtatgtatt atggaactac 28860
agcaggcatt tcggacatgg aattttatca agtttctgtg tctgaaccca ccacgcctag 28920
aatgaccaca accacaaaaa ctacacctgt taccactatg cagctcacta ccaataacat 28980
ttttgccatg cgtcaaatgg tcaacaatag cactcaaccc accccaccca gtgaggaaat 29040
tcccaaatcc atgattggca ttattgttgc tgtagtggtg tgcatgttga tcatcgcctt 29100
gtgcatggtg tactatgcct tctgctacag aaagcacaga ctgaacgaca agctggaaca 29160
cttactaagt gttgaatttt aattttttag aaccatgaag atcctaggcc ttttaatttt 29220
ttctatcatt acctctgctc tatgcaattc tgacaatgag gacgttactg tcgttgtcgg 29280
atcaaattat acactgaaag gtccagcgaa gggtatgctt tcgtggtatt gctattttgg 29340
atctgacact acagaaactg aattatgcaa tcttaagaat ggcaaaattc aaaattctaa 29400
aattaacaat tatatatgca atggtactga tctgatactc ctcaatatca cgaaatcata 29460
tgctggcagt tacacctgcc ctggagatga tgctgacagt atgatttttt acaaagtaac 29520
tgttgttgat cccactactc cacctccacc caccacaact actcacacca cacacacaga 29580
tcaaaccgca gcagaggagg cagcaaagtt agccttgcag gtccaagaca gttcatttgt 29640
tggcattacc cctacacctg atcagcggtg tccggggctg ctagtcagcg gcattgtcgg 29700
tgtgctttcg ggattagcag tcataatcat ctgcatgttc atttttgctt gctgctatag 29760
aaggctttac cgacaaaaat cagacccact gctgaacctc tatgtttaat tttttccaga 29820
gtcatgaagg cagttagcgc tctagttttt tgttctttga ttggcattgt tttttgcaat 29880
cctattccta aagttagctt tattaaagat gtgaatgtta ctgagggggg caatgtgaca 29940
ctggtaggtg tagagggtgc tgaaaacacc acctggacaa aataccacct caatgggtgg 30000
aaagatattt gcaattggag tgtattagtt tatacatgtg agggagttaa tcttaccatt 30060
gtcaatgcca cctcagctca aaatggtaga attcaaggac aaagtgtcag tgtatctaat 30120
gggtatttta cccaacatac ttttatctat gacgttaaag tcataccact gcctacgcct 30180
agcccaccta gcactaccac acagacaacc cacactacac agacaaccac atacagtaca 30240
ttaaatcagc ctaccaccac tacagcagca gaggttgcca gctcgtctgg ggtccgagtg 30300
gcatttttga tgtgggcccc atctagcagt cccactgcta gtaccaatga gcagactact 30360
gaatttttgt ccactgtcga gagccacacc acagctacct ccagtgcctt ctctagcacc 30420
gccaatctct cctcgctttc ctctacacca atcagtcccg ctactactcc tagccccgct 30480
cctcttccca ctcccctgaa gcaaacagac ggcggcatgc aatggcagat caccctgctc 30540
attgtgatcg ggttggtcat cctggccgtg ttgctctact acatcttctg ccgccgcatt 30600
cccaacgcgc accgcaagcc ggtctacaag cccatcattg tcgggcagcc ggagccgctt 30660
caggtggaag ggggtctaag gaatcttctc ttctctttta cagtatggtg attgaactat 30720
gattcctaga caattcttga tcactattct tatctgcctc ctccaagtct gtgccaccct 30780
cgctctggtg gccaacgcca gtccagactg tattgggccc ttcgcctcct acgtgctctt 30840
tgccttcacc acctgcatct gctgctgtag catagtctgc ctgcttatca ccttcttcca 30900
gttcattgac tggatctttg tgcgcatcgc ctacctgcgc caccaccccc agtaccgcga 30960
ccagcgagtg gcgcggctgc tcaggctcct ctgataagca tgcgggctct gctacttctc 31020
gcgcttctgc tgttagtgct cccccgtccc gtcgaccccc ggtcccccac ccagtccccc 31080
gaggaggtcc gcaaatgcaa attccaagaa ccctggaaat tcctcaaatg ctaccgccaa 31140
aaatcagaca tgcatcccag ctggatcatg atcattggga tcgtgaacat tctggcctgc 31200
accctcatct cctttgtgat ttacccctgc tttgactttg gttggaactc gccagaggcg 31260
ctctatctcc cgcctgaacc tgacacacca ccacagcaac ctcaggcaca cgcactacca 31320
ccactacagc ctaggccaca atacatgccc atattagact atgaggccga gccacagcga 31380
cccatgctcc ccgctattag ttacttcaat ctaaccggcg gagatgactg acccactggc 31440
caacaacaac gtcaacgacc ttctcctgga catggacggc cgcgcctcgg agcagcgact 31500
cgcccaactt cgcattcgcc agcagcagga gagagccgtc aaggagctgc aggatgcggt 31560
ggccatccac cagtgcaaga gaggcatctt ctgcctggtg aaacaggcca agatctccta 31620
cgaggtcact ccaaacgacc atcgcctctc ctacgagctc ctgcagcagc gccagaagtt 31680
cacctgcctg gtcggagtca accccatcgt catcacccag cagtctggcg ataccaaggg 31740
gtgcatccac tgctcctgcg actcccccga ctgcgtccac actctgatca agaccctctg 31800
cggcctccgc gacctcctcc ccatgaacta atcaccccct tatccagtga aataaagatc 31860
atattgatga tgattttaca gaaataaaaa ataatcattt gatttgaaat aaagatacaa 31920
tcatattgat gatttgagtt taacaaaaaa ataaagaatc acttacttga aatctgatac 31980
caggtctctg tccatgtttt ctgccaacac cacttcactc ccctcttccc agctctggta 32040
ctgcaggccc cggcgggctg caaacttcct ccacacgctg aaggggatgt caaattcctc 32100
ctgtccctca atcttcattt tatcttctat cagatgtcca aaaagcgcgt ccgggtggat 32160
gatgacttcg accccgtcta cccctacgat gcagacaacg caccgaccgt gcccttcatc 32220
aaccccccct tcgtctcttc agatggattc caagagaagc ccctgggggt gttgtccctg 32280
cgactggccg accccgtcac caccaagaac ggggaaatca ccctcaagct gggagagggg 32340
gtggacctcg attcctcggg aaaactcatc tccaacacgg ccaccaaggc cgccgcccct 32400
ctcagttttt ccaacaacac catttccctt aacatggatc acccctttta cactaaagat 32460
ggaaaattat ccttacaagt ttctccacca ttaaatatac tgagaacaag cattctaaac 32520
acactagctt taggttttgg atcaggttta ggactccgtg gctctgcctt ggcagtacag 32580
ttagtctctc cacttacatt tgatactgat ggaaacataa agcttacctt agacagaggt 32640
ttgcatgtta caacaggaga tgcaattgaa agcaacataa gctgggctaa aggtttaaaa 32700
tttgaagatg gagccatagc aaccaacatt ggaaatgggt tagagtttgg aagcagtagt 32760
acagaaacag gtgttgatga tgcttaccca atccaagtta aacttggatc tggccttagc 32820
tttgacagta caggagccat aatggctggt aacaaagaag acgataaact cactttgtgg 32880
acaacacctg atccatcacc aaactgtcaa atactcgcag aaaatgatgc aaaactaaca 32940
ctttgcttga ctaaatgtgg tagtcaaata ctggccactg tgtcagtctt agttgtagga 33000
agtggaaacc taaaccccat tactggcacc gtaagcagtg ctcaggtgtt tctacgtttt 33060
gatgcaaacg gtgttctttt aacagaacat tctacactaa aaaaatactg ggggtatagg 33120
cagggagata gcatagatgg cactccatat accaatgctg taggattcat gcccaattta 33180
aaagcttatc caaagtcaca aagttctact actaaaaata atatagtagg gcaagtatac 33240
atgaatggag atgtttcaaa acctatgctt ctcactataa ccctcaatgg tactgatgac 33300
agcaacagta catattcaat gtcattttca tacacctgga ctaatggaag ctatgttgga 33360
gcaacatttg gggctaactc ttataccttc tcatacatcg cccaagaatg aacactgtat 33420
cccaccctgc atgccaaccc ttcccacccc actctgtgga acaaactctg aaacacaaaa 33480
taaaataaag ttcaagtgtt ttattgattc aacagtttta caggattcga gcagttattt 33540
ttcctccacc ctcccaggac atggaataca ccaccctctc cccccgcaca gccttgaaca 33600
tctgaatgcc attggtgatg gacatgcttt tggtctccac gttccacaca gtttcagagc 33660
gagccagtct cgggtcggtc agggagatga aaccctccgg gcactcccgc atctgcacct 33720
cacagctcaa cagctgagga ttgtcctcgg tggtcgggat cacggttatc tggaagaagc 33780
agaagagcgg cggtgggaat catagtccgc gaacgggatc ggccggtggt gtcgcatcag 33840
gccccgcagc agtcgctgcc gccgccgctc cgtcaagctg ctgctcaggg ggtccgggtc 33900
cagggactcc ctcagcatga tgcccacggc cctcagcatc agtcgtctgg tgcggcgggc 33960
gcagcagcgc atgcggatct cgctcaggtc gctgcagtac gtgcaacaca gaaccaccag 34020
gttgttcaac agtccatagt tcaacacgct ccagccgaaa ctcatcgcgg gaaggatgct 34080
acccacgtgg ccgtcgtacc agatcctcag gtaaatcaag tggtgccccc tccagaacac 34140
gctgcccacg tacatgatct ccttgggcat gtggcggttc accacctccc ggtaccacat 34200
caccctctgg ttgaacatgc agccccggat gatcctgcgg aaccacaggg ccagcaccgc 34260
cccgcccgcc atgcagcgaa gagaccccgg gtcccggcaa tggcaatgga ggacccaccg 34320
ctcgtacccg tggatcatct gggagctgaa caagtctatg ttggcacagc acaggcatat 34380
gctcatgcat ctcttcagca ctctcaactc ctcgggggtc aaaaccatat cccagggcac 34440
ggggaactct tgcaggacag cgaaccccgc agaacagggc aatcctcgca cagaacttac 34500
attgtgcatg gacagggtat cgcaatcagg cagcaccggg tgatcctcca ccagagaagc 34560
gcgggtctcg gtctcctcac agcgtggtaa gggggccggc cgatacgggt gatggcggga 34620
cgcggctgat cgtgttcgcg accgtgtcat gatgcagttg ctttcggaca ttttcgtact 34680
tgctgtagca gaacctggtc cgggcgctgc acaccgatcg ccggcggcgg tctcggcgct 34740
tggaacgctc ggtgttgaaa ttgtaaaaca gccactctct cagaccgtgc agcagatcta 34800
gggcctcagg agtgatgaag atcccatcat gcctgatggc tctgatcaca tcgaccaccg 34860
tggaatgggc cagacccagc cagatgatgc aattttgttg ggtttcggtg acggcggggg 34920
agggaagaac aggaagaacc atgattaact tttaatccaa acggtctcgg agtacttcaa 34980
aatgaagatc gcggagatgg cacctctcgc ccccgctgtg ttggtggaaa ataacagcca 35040
ggtcaaaggt gatacggttc tcgagatgtt ccacggtggc ttccagcaaa gcctccacgc 35100
gcacatccag aaacaagaca atagcgaaag cgggagggtt ctctaattcc tcaatcatca 35160
tgttacactc ctgcaccatc cccagataat tttcattttt ccagccttga atgattcgaa 35220
ctagttcgtg aggtaaatcc aagccagcca tgataaagag ctcgcgcaga gcgccctcca 35280
ccggcattct taagcacacc ctcataattc caagatattc tgctcctggt tcacctgcag 35340
cagattgaca agcggaatat caaaatctct gccgcgatcc ctgagctcct ccctcagcaa 35400
taactgtaag tactctttca tatcctctcc gaaattttta gccataggac caccaggaat 35460
aagattaggg caagccacag tacagataaa ccgaagtcct ccccagtgag cattgccaaa 35520
tgcaagactg ctataagcat gctggctaga cccggtgata tcttccagat aactggacag 35580
aaaatcgccc aggcaatttt taagaaaatc aacaaaagaa aaatcctcca ggtggacgtt 35640
tagagcctcg ggaacaacga tgaagtaaat gcaagcggtg cgttccagca tggttagtta 35700
gctgatctgt agaaaaaaca aaaatgaaca ttaaaccatg ctagcctggc gaacaggtgg 35760
gtaaatcgtt ctctccagca ccaggcaggc cacggggtct ccggcgcgac cctcgtaaaa 35820
attgtcgcta tgattgaaaa ccatcacaga gagacgttcc cggtggccgg cgtgaatgat 35880
tcgacaagat gaatacaccc ccggaacatt ggcgtccgcg agtgaaaaaa agcgcccgag 35940
gaagcaataa ggcactacaa tgctcagtct caagtccagc aaagcgatgc catgcggatg 36000
aagcacaaaa ttctcaggtg cgtacaaaat gtaattactc ccctcctgca caggcagcaa 36060
agcccccgat ccctccaggt acacatacaa agcctcagcg tccatagctt accgagcagc 36120
agcacacaac aggcgcaaga gtcagagaaa ggctgagctc taacctgtcc acccgctctc 36180
tgctcaatat atagcccaga tctacactga cgtaaaggcc aaagtctaaa aatacccgcc 36240
aaataatcac acacgcccag cacacgccca gaaaccggtg acacactcaa aaaaatacgc 36300
gcacttcctc aaacgcccaa aactgccgtc atttccgggt tcccacgcta cgtcatcaaa 36360
acacgacttt caaattccgt cgaccgttaa aaacgtcacc cgccccgccc ctaacggtcg 36420
cccgtctctc agccaatcag cgccccgcat ccccaaattc aaacacctca tttgcatatt 36480
aacgcgcaca aaaagtttga ggtatattat tgatgatgg 36519
<210> 58
<211> 34819
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 58
ttaattaacc atcttcaata atatacctca aactttttgt gcgcgttaat atgcaaatga 60
ggcgtttgaa tttggggagg aagggcggtg attggtcgag ggatgagcga ccgttagggg 120
cggggcgagt gacgttttga tgacgtggtt gcgaggagga gccagtttgc aagttctcgt 180
gggaaaagtg acgtcaaacg aggtgtggtt tgaacacgga aatactcaat tttcccgcgc 240
tctctgacag gaaatgaggt gtttctgggc ggatgcaagt gaaaacgggc cattttcgcg 300
cgaaaactga atgaggaagt gaaaatctga gtaatttcgc gtttatggca gggaggagta 360
tttgccgagg gccgagtaga ctttgaccga ttacgtgggg gtttcgatta ccgtgttttt 420
cacctaaatt tccgcgtacg gtgtcaaagt ccggtgtttt tactactgta atagtaatca 480
attacggggt cattagttca tagcccatat atggagttcc gcgttacata acttacggta 540
aatggcccgc ctggctgacc gcccaacgac ccccgcccat tgacgtcaat aatgacgtat 600
gttcccatag taacgccaat agggactttc cattgacgtc aatgggtgga gtatttacgg 660
taaactgccc acttggcagt acatcaagtg tatcatatgc caagtacgcc ccctattgac 720
gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt acatgacctt atgggacttt 780
cctacttggc agtacatcta cgtattagtc atcgctatta ccatggtgat gcggttttgg 840
cagtacatca atgggcgtgg atagcggttt gactcacggg gatttccaag tctccacccc 900
attgacgtca atgggagttt gttttggcac caaaatcaac gggactttcc aaaatgtcgt 960
aacaactccg ccccattgac gcaaatgggc ggtaggcgtg tacggtggga ggtctatata 1020
agcagagctg tccctatcag tgatagagat ctccctatca gtgatagaga gtttagtgaa 1080
ccgtcagatc cgctagggta ccaacatggc tagcatcgtc ggagggtggg agtgcgaaaa 1140
gcactcacag ccatggcagg tcctggtcgc ctcgcgcgga cgcgccgtgt gtggaggtgt 1200
gctggtccac ccgcagtggg tgttgactgc ggcccattgc atcagaaata agtccgtgat 1260
cctcttgggg agacattccc tgtttcaccc cgaagatact ggacaggtgt tccaagtgag 1320
ccactccttc ccgcatccac tgtacgacat gagcctgctg aagaaccgct ttctgcggcc 1380
aggggacgac tcatcacacg atttgatgct gcttcggctc tcggaaccgg ccgagctcac 1440
cgacgcagtg aaggtcatgg acctccctac gcaagagcct gctctcggta ccacttgtta 1500
cgcatcggga tggggctcca tcgagccgga agaattcctg accccgaaaa agctgcagtg 1560
cgtggatctg cacgtgattt cgaatgacgt gtgcgcgcaa gtgcatccac aaaaggtcac 1620
taagttcatg ctgtgcgccg gaaggtggac cggcggaaaa tcgacctgtt ccggcgacag 1680
cggaggccca ctcgtgtgca acggtgtgct gcagggcatc actagctggg gatcagaacc 1740
gtgcgcgctt ccggagcggc cctcgctcta cacgaaggtg gtgcactacc gcaaatggat 1800
taaagatacc atcgtcgcaa accctggatc cgaaggtagg ggttcattat tgacctgtgg 1860
agatgtcgaa gaaaacccag gacccgctag caaagcagtg ctgctggcgc tcctgatggc 1920
tggactcgcg ctgcagcctg gaaccgccct gctctgttac tcgtgcaagg cccaagtctc 1980
gaatgaggac tgtttgcaag tggaaaactg cacccagctc ggagaacaat gctggactgc 2040
acggatccgc gctgtcggcc tgctgaccgt gatctccaaa gggtgctcat tgaactgcgt 2100
ggacgatagc caggactact acgtgggaaa gaagaatatc acttgttgcg acacggatct 2160
ttgcaacgcg tccggagcgc acgccctgca gccagcagcc gccattctgg ccctgcttcc 2220
ggccctgggg ttgctgctct ggggtccggg ccagctcgga tcccagaccc tgaactttga 2280
tctgctgaaa ctggcaggcg atgtggaaag caacccaggc ccaatggcta gcgctcgcag 2340
accgcggtgg ctgtgtgcag gggcgctcgt cctggcgggt ggcttctttt tgctcggctt 2400
tcttttcgga tggttcatca aatcgtcaaa cgaagctacc aatatcaccc cgaagcacaa 2460
catgaaggcc tttctggatg agctgaaggc tgagaacatt aagaagttcc tctacaactt 2520
cacccagatc ccacatttgg cgggcactga gcagaacttt cagttggcta agcagatcca 2580
gagccagtgg aaggaattcg gcctggactc cgtcgagctg gcgcattacg atgtgctgct 2640
gagctaccct aataagactc atccgaacta tatctcgatt atcaatgagg acggaaacga 2700
aatctttaac acgtccctct tcgagccgcc accgcctgga tacgagaacg tgtcagatat 2760
cgtgcctccg ttctcggcct tctcgcccca gggaatgccc gaaggggacc tggtgtacgt 2820
gaactacgca aggaccgagg acttcttcaa gttggagcgg gatatgaaga tcaattgcag 2880
cggaaagatc gtcatcgccc gctacggcaa agtgttccgc ggcaacaagg tgaagaatgc 2940
acagttggca ggcgccaagg gcgtcatcct ctactcggat cctgccgact acttcgctcc 3000
tggcgtgaaa tcctaccctg atggttggaa tctgccagga ggaggggtgc agaggggaaa 3060
tatcctgaac ctgaacggtg ccggtgaccc acttactccg ggttacccgg ccaacgaata 3120
cgcgtacagg cggggtatcg cggaagccgt cggactgccg tccatcccgg tccatccgat 3180
tggttactac gacgcccaga agctcctcga aaagatggga ggcagcgccc ctccggactc 3240
gtcatggaga ggctcgctga aggtgccata caacgtggga cccggattca ctggaaattt 3300
cagcactcaa aaagtgaaga tgcacattca ctccactaac gaagtcacca ggatctacaa 3360
cgtcatcgga accctccggg gagcggtgga accggaccgc tacgtgatcc tcggtggaca 3420
ccgggatagc tgggtgttcg gaggaatcga tcctcaatcg ggcgcagccg tcgtccatga 3480
aatcgtcagg tcctttggta ctcttaagaa ggagggctgg cgccctagac gcactattct 3540
gttcgcctcg tgggatgccg aagaatttgg tctgctcggc agcaccgaat gggctgagga 3600
aaactcccgc ctgctccaag aacgcggagt ggcgtacatc aatgccgact catccatcga 3660
aggaaactac acgctgcggg tggactgcac tccactgatg tactcgctcg tgcacaacct 3720
gaccaaagaa ctcaaatccc cagacgaagg attcgaggga aaatcgctgt acgagtcgtg 3780
gaccaagaag agcccatccc cggagttcag cgggatgccg cggatctcaa agctcggatc 3840
aggaaatgat ttcgaagtgt tctttcagag gctgggaatt gcgtcgggaa gggctcggta 3900
cacgaaaaac tgggaaacta acaagttctc gggatacccg ctgtaccact cggtgtatga 3960
aacttacgaa ctggtggaga aattctacga tcctatgttt aagtaccacc tgactgtggc 4020
ccaagtgaga ggcggaatgg tgttcgagtt ggccaattca attgtgctgc cattcgattg 4080
ccgcgactac gccgtggtgc tgagaaagta cgcagacaaa atctactcaa tcagcatgaa 4140
gcacccacaa gagatgaaaa cctactcagt ctccttcgac tccctcttct ccgcggtgaa 4200
gaacttcacc gagatcgcga gcaaattctc ggagcgcctt caagattttg acaaatccaa 4260
tccgatcgtc ctccgcatga tgaatgacca gctcatgttt ctcgaacggg ccttcatcga 4320
tccactggga cttccggacc ggccgtttta ccgccacgtg atctacgcgc cctcgtcgca 4380
taacaagtat gctggagaga gcttcccggg tatctacgac gcattgttcg acattgagtc 4440
caaggtggat ccgtccaaag cctggggtga agtgaagcgc caaatctacg tggcggcctt 4500
taccgtccag gcggcagcag aaaccttgag cgaggtggct tgactcgagc ctaagcttct 4560
agataagata tccgatccac cggatctaga taactgatca taatcagcca taccacattt 4620
gtagaggttt tacttgcttt aaaaaacctc ccacacctcc ccctgaacct gaaacataaa 4680
atgaatgcaa ttgttgttgt taacttgttt attgcagctt ataatggtta caaataaagc 4740
aatagcatca caaatttcac aaataaagca tttttttcac tgcattctag ttgtggtttg 4800
tccaaactca tcaatgtatc ttatatgctg gccaccgtac atgtggcttc ccatgctcgc 4860
aagccctggc ccgagttcga gcacaatgtc atgaccaggt gcaatatgca tctggggtcc 4920
cgccgaggca tgttcatgcc ctaccagtgc aacctgaatt atgtgaaggt gctgctggag 4980
cccgatgcca tgtccagagt gagcctgacg ggggtgtttg acatgaatgt ggaggtgtgg 5040
aagattctga gatatgatga atccaagacc aggtgccgag cctgcgagtg cggagggaag 5100
catgccaggt tccagcccgt gtgtgtggat gtgacggagg acctgcgacc cgatcatttg 5160
gtgttgccct gcaccgggac ggagttcggt tccagcgggg aagaatctga ctagagtgag 5220
tagtgttctg gggcggggga ggacctgcat gagggccaga ataactgaaa tctgtgcttt 5280
tctgtgtgtt gcagcagcat gagcggaagc ggctcctttg agggaggggt attcagccct 5340
tatctgacgg ggcgtctccc ctcctgggcg ggagtgcgtc agaatgtgat gggatccacg 5400
gtggacggcc ggcccgtgca gcccgcgaac tcttcaaccc tgacctatgc aaccctgagc 5460
tcttcgtcgt tggacgcagc tgccgccgca gctgctgcat ctgccgccag cgccgtgcgc 5520
ggaatggcca tgggcgccgg ctactacggc actctggtgg ccaactcgag ttccaccaat 5580
aatcccgcca gcctgaacga ggagaagctg ttgctgctga tggcccagct cgaggccttg 5640
acccagcgcc tgggcgagct gacccagcag gtggctcagc tgcaggagca gacgcgggcc 5700
gcggttgcca cggtgaaatc caaataaaaa atgaatcaat aaataaacgg agacggttgt 5760
tgattttaac acagagtctg aatctttatt tgatttttcg cgcgcggtag gccctggacc 5820
accggtctcg atcattgagc acccggtgga tcttttccag gacccggtag aggtgggctt 5880
ggatgttgag gtacatgggc atgagcccgt cccgggggtg gaggtagctc cattgcaggg 5940
cctcgtgctc gggggtggtg ttgtaaatca cccagtcata gcaggggcgc agggcatggt 6000
gttgcacaat atctttgagg aggagactga tggccacggg cagccctttg gtgtaggtgt 6060
ttacaaatct gttgagctgg gagggatgca tgcgggggga gatgaggtgc atcttggcct 6120
ggatcttgag attggcgatg ttaccgccca gatcccgcct ggggttcatg ttgtgcagga 6180
ccaccagcac ggtgtatccg gtgcacttgg ggaatttatc atgcaacttg gaagggaagg 6240
cgtgaaagaa tttggcgacg cctttgtgcc cgcccaggtt ttccatgcac tcatccatga 6300
tgatggcgat gggcccgtgg gcggcggcct gggcaaagac gtttcggggg tcggacacat 6360
catagttgtg gtcctgggtg aggtcatcat aggccatttt aatgaatttg gggcggaggg 6420
tgccggactg ggggacaaag gtaccctcga tcccgggggc gtagttcccc tcacagatct 6480
gcatctccca ggctttgagc tcggaggggg ggatcatgtc cacctgcggg gcgataaaga 6540
acacggtttc cggggcgggg gagatgagct gggccgaaag caagttccgg agcagctggg 6600
acttgccgca gccggtgggg ccgtagatga ccccgatgac cggctgcagg tggtagttga 6660
gggagagaca gctgccgtcc tcccggagga ggggggccac ctcgttcatc atctcgcgca 6720
cgtgcatgtt ctcgcgcacc agttccgcca ggaggcgctc tccccccagg gataggagct 6780
cctggagcga ggcgaagttt ttcagcggct tgagtccgtc ggccatgggc attttggaga 6840
gggtttgttg caagagttcc aggcggtccc agagctcggt gatgtgctct acggcatctc 6900
gatccagcag acctcctcgt ttcgcgggtt gggacggctg cgggagtagg gcaccagacg 6960
atgggcgtcc agcgcagcca gggtccggtc cttccagggt cgcagcgtcc gcgtcagggt 7020
ggtctccgtc acggtgaagg ggtgcgcgcc gggctgggcg cttgcgaggg tgcgcttcag 7080
gctcatccgg ctggtcgaaa accgctcccg atcggcgccc tgcgcgtcgg ccaggtagca 7140
attgaccatg agttcgtagt tgagcgcctc ggccgcgtgg cctttggcgc ggagcttacc 7200
tttggaagtc tgcccgcagg cgggacagag gagggacttg agggcgtaga gcttgggggc 7260
gaggaagacg gactcggggg cgtaggcgtc cgcgccgcag tgggcgcaga cggtctcgca 7320
ctccacgagc caggtgaggt cgggctggtc ggggtcaaaa accagtttcc cgccgttctt 7380
tttgatgcgt ttcttacctt tggtctccat gagctcgtgt ccccgctggg tgacaaagag 7440
gctgtccgtg tccccgtaga ccgactttat gggccggtcc tcgagcggtg tgccgcggtc 7500
ctcctcgtag aggaaccccg cccactccga gacgaaagcc cgggtccagg ccagcacgaa 7560
ggaggccacg tgggacgggt agcggtcgtt gtccaccagc gggtccacct tttccagggt 7620
atgcaaacac atgtccccct cgtccacatc caggaaggtg attggcttgt aagtgtaggc 7680
cacgtgaccg ggggtcccgg ccgggggggt ataaaagggt gcgggtccct gctcgtcctc 7740
actgtcttcc ggatcgctgt ccaggagcgc cagctgttgg ggtaggtatt ccctctcgaa 7800
ggcgggcatg acctcggcac tcaggttgtc agtttctaga aacgaggagg atttgatatt 7860
gacggtgccg gcggagatgc ctttcaagag cccctcgtcc atctggtcag aaaagacgat 7920
ctttttgttg tcgagcttgg tggcgaagga gccgtagagg gcgttggaga ggagcttggc 7980
gatggagcgc atggtctggt ttttttcctt gtcggcgcgc tccttggcgg cgatgttgag 8040
ctgcacgtac tcgcgcgcca cgcacttcca ttcggggaag acggtggtca gctcgtcggg 8100
cacgattctg acctgccagc cccgattatg cagggtgatg aggtccacac tggtggccac 8160
ctcgccgcgc aggggctcat tagtccagca gaggcgtccg cccttgcgcg agcagaaggg 8220
gggcaggggg tccagcatga cctcgtcggg ggggtcggca tcgatggtga agatgccggg 8280
caggaggtcg gggtcaaagt agctgatgga agtggccaga tcgtccaggg cagcttgcca 8340
ttcgcgcacg gccagcgcgc gctcgtaggg actgaggggc gtgccccagg gcatgggatg 8400
ggtaagcgcg gaggcgtaca tgccgcagat gtcgtagacg tagaggggct cctcgaggat 8460
gccgatgtag gtggggtagc agcgcccccc gcggatgctg gcgcgcacgt agtcatacag 8520
ctcgtgcgag ggggcgagga gccccgggcc caggttggtg cgactgggct tttcggcgcg 8580
gtagacgatc tggcggaaaa tggcatgcga gttggaggag atggtgggcc tttggaagat 8640
gttgaagtgg gcgtggggca gtccgaccga gtcgcggatg aagtgggcgt aggagtcttg 8700
cagcttggcg acgagctcgg cggtgactag gacgtccaga gcgcagtagt cgagggtctc 8760
ctggatgatg tcatacttga gctgtccctt ttgtttccac agctcgcggt tgagaaggaa 8820
ctcttcgcgg tccttccagt actcttcgag ggggaacccg tcctgatctg cacggtaaga 8880
gcctagcatg tagaactggt tgacggcctt gtaggcgcag cagcccttct ccacggggag 8940
ggcgtaggcc tgggcggcct tgcgcaggga ggtgtgcgtg agggcgaaag tgtccctgac 9000
catgaccttg aggaactggt gcttgaagtc gatatcgtcg cagcccccct gctcccagag 9060
ctggaagtcc gtgcgcttct tgtaggcggg gttgggcaaa gcgaaagtaa catcgttgaa 9120
gaggatcttg cccgcgcggg gcataaagtt gcgagtgatg cggaaaggtt ggggcacctc 9180
ggcccggttg ttgatgacct gggcggcgag cacgatctcg tcgaagccgt tgatgttgtg 9240
gcccacgatg tagagttcca cgaatcgcgg acggcccttg acgtggggca gtttcttgag 9300
ctcctcgtag gtgagctcgt cggggtcgct gagcccgtgc tgctcgagcg cccagtcggc 9360
gagatggggg ttggcgcgga ggaaggaagt ccagagatcc acggccaggg cggtttgcag 9420
acggtcccgg tactgacgga actgctgccc gacggccatt ttttcggggg tgacgcagta 9480
gaaggtgcgg gggtccccgt gccagcgatc ccatttgagc tggagggcga gatcgagggc 9540
gagctcgacg agccggtcgt ccccggagag tttcatgacc agcatgaagg ggacgagctg 9600
cttgccgaag gaccccatcc aggtgtaggt ttccacatcg taggtgagga agagcctttc 9660
ggtgcgagga tgcgagccga tggggaagaa ctggatctcc tgccaccaat tggaggaatg 9720
gctgttgatg tgatggaagt agaaatgccg acggcgcgcc gaacactcgt gcttgtgttt 9780
atacaagcgg ccacagtgct cgcaacgctg cacgggatgc acgtgctgca cgagctgtac 9840
ctgagttcct ttgacgagga atttcagtgg gaagtggagt cgtggcgcct gcatctcgtg 9900
ctgtactacg tcgtggtggt cggcctggcc ctcttctgcc tcgatggtgg tcatgctgac 9960
gagcccgcgc gggaggcagg tccagacctc ggcgcgagcg ggtcggagag cgaggacgag 10020
ggcgcgcagg ccggagctgt ccagggtcct gagacgctgc ggagtcaggt cagtgggcag 10080
cggcggcgcg cggttgactt gcaggagttt ttccagggcg cgcgggaggt ccagatggta 10140
cttgatctcc accgcgccat tggtggcgac gtcgatggct tgcagggtcc cgtgcccctg 10200
gggtgtgacc accgtccccc gtttcttctt gggcggctgg ggcgacgggg gcggtgcctc 10260
ttccatggtt agaagcggcg gcgaggacgc gcgccgggcg gcaggggcgg ctcggggccc 10320
ggaggcaggg gcggcagggg cacgtcggcg ccgcgcgcgg gtaggttctg gtactgcgcc 10380
cggagaagac tggcgtgagc gacgacgcga cggttgacgt cctggatctg acgcctctgg 10440
gtgaaggcca cgggacccgt gagtttgaac ctgaaagaga gttcgacaga atcaatctcg 10500
gtatcgttga cggcggcctg ccgcaggatc tcttgcacgt cgcccgagtt gtcctggtag 10560
gcgatctcgg tcatgaactg ctcgatctcc tcctcttgaa ggtctccgcg gccggcgcgc 10620
tccacggtgg ccgcgaggtc gttggagatg cggcccatga gctgcgagaa ggcgttcatg 10680
cccgcctcgt tccagacgcg gctgtagacc acgacgccct cgggatcgcg ggcgcgcatg 10740
accacctggg cgaggttgag ctccacgtgg cgcgtgaaga ccgcgtagtt gcagaggcgc 10800
tggtagaggt agttgagcgt ggtggcgatg tgctcggtga cgaagaaata catgatccag 10860
cggcggagcg gcatctcgct gacgtcgccc agcgcctcca aacgttccat ggcctcgtaa 10920
aagtccacgg cgaagttgaa aaactgggag ttgcgcgccg agacggtcaa ctcctcctcc 10980
agaagacgga tgagctcggc gatggtggcg cgcacctcgc gctcgaaggc ccccgggagt 11040
tcctccactt cctcttcttc ctcctccact aacatctctt ctacttcctc ctcaggcggc 11100
agtggtggcg ggggaggggg cctgcgtcgc cggcggcgca cgggcagacg gtcgatgaag 11160
cgctcgatgg tctcgccgcg ccggcgtcgc atggtctcgg tgacggcgcg cccgtcctcg 11220
cggggccgca gcgtgaagac gccgccgcgc atctccaggt ggccgggggg gtccccgttg 11280
ggcagggaga gggcgctgac gatgcatctt atcaattgcc ccgtagggac tccgcgcaag 11340
gacctgagcg tctcgagatc cacgggatct gaaaaccgct gaacgaaggc ttcgagccag 11400
tcgcagtcgc aaggtaggct gagcacggtt tcttctggcg ggtcatgttg gttgggagcg 11460
gggcgggcga tgctgctggt gatgaagttg aaataggcgg ttctgagacg gcggatggtg 11520
gcgaggagca ccaggtcttt gggcccggct tgctggatgc gcagacggtc ggccatgccc 11580
caggcgtggt cctgacacct ggccaggtcc ttgtagtagt cctgcatgag ccgctccacg 11640
ggcacctcct cctcgcccgc gcggccgtgc atgcgcgtga gcccgaagcc gcgctggggc 11700
tggacgagcg ccaggtcggc gacgacgcgc tcggcgagga tggcttgctg gatctgggtg 11760
agggtggtct ggaagtcatc aaagtcgacg aagcggtggt aggctccggt gttgatggtg 11820
taggagcagt tggccatgac ggaccagttg acggtctggt ggcccggacg cacgagctcg 11880
tggtacttga ggcgcgagta ggcgcgcgtg tcgaagatgt agtcgttgca ggtgcgcacc 11940
aggtactggt agccgatgag gaagtgcggc ggcggctggc ggtagagcgg ccatcgctcg 12000
gtggcggggg cgccgggcgc gaggtcctcg agcatggtgc ggtggtagcc gtagatgtac 12060
ctggacatcc aggtgatgcc ggcggcggtg gtggaggcgc gcgggaactc gcggacgcgg 12120
ttccagatgt tgcgcagcgg caggaagtag ttcatggtgg gcacggtctg gcccgtgagg 12180
cgcgcgcagt cgtggatgct ctatacgggc aaaaacgaaa gcggtcagcg gctcgactcc 12240
gtggcctgga ggctaagcga acgggttggg ctgcgcgtgt accccggttc gaatctcgaa 12300
tcaggctgga gccgcagcta acgtggtatt ggcactcccg tctcgaccca agcctgcacc 12360
aaccctccag gatacggagg cgggtcgttt tgcaactttt ttttggaggc cggatgagac 12420
tagtaagcgc ggaaagcggc cgaccgcgat ggctcgctgc cgtagtctgg agaagaatcg 12480
ccagggttgc gttgcggtgt gccccggttc gaggccggcc ggattccgcg gctaacgagg 12540
gcgtggctgc cccgtcgttt ccaagacccc atagccagcc gacttctcca gttacggagc 12600
gagcccctct tttgttttgt ttgtttttgc cagatgcatc ccgtactgcg gcagatgcgc 12660
ccccaccacc ctccaccgca acaacagccc cctccacagc cggcgcttct gcccccgccc 12720
cagcagcaac ttccagccac gaccgccgcg gccgccgtga gcggggctgg acagagttat 12780
gatcaccagc tggccttgga agagggcgag gggctggcgc gcctgggggc gtcgtcgccg 12840
gagcggcacc cgcgcgtgca gatgaaaagg gacgctcgcg aggcctacgt gcccaagcag 12900
aacctgttca gagacaggag cggcgaggag cccgaggaga tgcgcgcggc ccggttccac 12960
gcggggcggg agctgcggcg cggcctggac cgaaagaggg tgctgaggga cgaggatttc 13020
gaggcggacg agctgacggg gatcagcccc gcgcgcgcgc acgtggccgc ggccaacctg 13080
gtcacggcgt acgagcagac cgtgaaggag gagagcaact tccaaaaatc cttcaacaac 13140
cacgtgcgca ccctgatcgc gcgcgaggag gtgaccctgg gcctgatgca cctgtgggac 13200
ctgctggagg ccatcgtgca gaaccccacc agcaagccgc tgacggcgca gctgttcctg 13260
gtggtgcagc atagtcggga caacgaagcg ttcagggagg cgctgctgaa tatcaccgag 13320
cccgagggcc gctggctcct ggacctggtg aacattctgc agagcatcgt ggtgcaggag 13380
cgcgggctgc cgctgtccga gaagctggcg gccatcaact tctcggtgct gagtttgggc 13440
aagtactacg ctaggaagat ctacaagacc ccgtacgtgc ccatagacaa ggaggtgaag 13500
atcgacgggt tttacatgcg catgaccctg aaagtgctga ccctgagcga cgatctgggg 13560
gtgtaccgca acgacaggat gcaccgtgcg gtgagcgcca gcaggcggcg cgagctgagc 13620
gaccaggagc tgatgcatag tctgcagcgg gccctgaccg gggccgggac cgagggggag 13680
agctactttg acatgggcgc ggacctgcac tggcagccca gccgccgggc cttggaggcg 13740
gcggcaggac cctacgtaga agaggtggac gatgaggtgg acgaggaggg cgagtacctg 13800
gaagactgat ggcgcgaccg tatttttgct agatgcaaca acaacagcca cctcctgatc 13860
ccgcgatgcg ggcggcgctg cagagccagc cgtccggcat taactcctcg gacgattgga 13920
cccaggccat gcaacgcatc atggcgctga cgacccgcaa ccccgaagcc tttagacagc 13980
agccccaggc caaccggctc tcggccatcc tggaggccgt ggtgccctcg cgctccaacc 14040
ccacgcacga gaaggtcctg gccatcgtga acgcgctggt ggagaacaag gccatccgcg 14100
gcgacgaggc cggcctggtg tacaacgcgc tgctggagcg cgtggcccgc tacaacagca 14160
ccaacgtgca gaccaacctg gaccgcatgg tgaccgacgt gcgcgaggcc gtggcccagc 14220
gcgagcggtt ccaccgcgag tccaacctgg gatccatggt ggcgctgaac gccttcctca 14280
gcacccagcc cgccaacgtg ccccggggcc aggaggacta caccaacttc atcagcgccc 14340
tgcgcctgat ggtgaccgag gtgccccaga gcgaggtgta ccagtccggg ccggactact 14400
tcttccagac cagtcgccag ggcttgcaga ccgtgaacct gagccaggct ttcaagaact 14460
tgcagggcct gtggggcgtg caggccccgg tcggggaccg cgcgacggtg tcgagcctgc 14520
tgacgccgaa ctcgcgcctg ctgctgctgc tggtggcccc cttcacggac agcggcagca 14580
tcaaccgcaa ctcgtacctg ggctacctga ttaacctgta ccgcgaggcc atcggccagg 14640
cgcacgtgga cgagcagacc taccaggaga tcacccacgt gagccgcgcc ctgggccagg 14700
acgacccggg caacctggaa gccaccctga actttttgct gaccaaccgg tcgcagaaga 14760
tcccgcccca gtacgcgctc agcaccgagg aggagcgcat cctgcgttac gtgcagcaga 14820
gcgtgggcct gttcctgatg caggaggggg ccacccccag cgccgcgctc gacatgaccg 14880
cgcgcaacat ggagcccagc atgtacgcca gcaaccgccc gttcatcaat aaactgatgg 14940
actacttgca tcgggcggcc gccatgaact ctgactattt caccaacgcc atcctgaatc 15000
cccactggct cccgccgccg gggttctaca cgggcgagta cgacatgccc gaccccaatg 15060
acgggttcct gtgggacgat gtggacagca gcgtgttctc cccccgaccg ggtgctaacg 15120
agcgcccctt gtggaagaag gaaggcagcg accgacgccc gtcctcggcg ctgtccggcc 15180
gcgagggtgc tgccgcggcg gtgcccgagg ccgccagtcc tttcccgagc ttgcccttct 15240
cgctgaacag tatccgcagc agcgagctgg gcaggatcac gcgcccgcgc ttgctgggcg 15300
aagaggagta cttgaatgac tcgctgttga gacccgagcg ggagaagaac ttccccaata 15360
acgggataga aagcctggtg gacaagatga gccgctggaa gacgtatgcg caggagcaca 15420
gggacgatcc ccgggcgtcg cagggggcca cgagccgggg cagcgccgcc cgtaaacgcc 15480
ggtggcacga caggcagcgg ggacagatgt gggacgatga ggactccgcc gacgacagca 15540
gcgtgttgga cttgggtggg agtggtaacc cgttcgctca cctgcgcccc cgtatcgggc 15600
gcatgatgta agagaaaccg aaaataaatg atactcacca aggccatggc gaccagcgtg 15660
cgttcgtttc ttctctgttg ttgttgtatc tagtatgatg aggcgtgcgt acccggaggg 15720
tcctcctccc tcgtacgaga gcgtgatgca gcaggcgatg gcggcggcgg cgatgcagcc 15780
cccgctggag gctccttacg tgcccccgcg gtacctggcg cctacggagg ggcggaacag 15840
cattcgttac tcggagctgg cacccttgta cgataccacc cggttgtacc tggtggacaa 15900
caagtcggcg gacatcgcct cgctgaacta ccagaacgac cacagcaact tcctgaccac 15960
cgtggtgcag aacaatgact tcacccccac ggaggccagc acccagacca tcaactttga 16020
cgagcgctcg cggtggggcg gccagctgaa aaccatcatg cacaccaaca tgcccaacgt 16080
gaacgagttc atgtacagca acaagttcaa ggcgcgggtg atggtctccc gcaagacccc 16140
caatggggtg acagtgacag aggattatga tggtagtcag gatgagctga agtatgaatg 16200
ggtggaattt gagctgcccg aaggcaactt ctcggtgacc atgaccatcg acctgatgaa 16260
caacgccatc atcgacaatt acttggcggt ggggcggcag aacggggtgc tggagagcga 16320
catcggcgtg aagttcgaca ctaggaactt caggctgggc tgggaccccg tgaccgagct 16380
ggtcatgccc ggggtgtaca ccaacgaggc tttccatccc gatattgtct tgctgcccgg 16440
ctgcggggtg gacttcaccg agagccgcct cagcaacctg ctgggcattc gcaagaggca 16500
gcccttccag gaaggcttcc agatcatgta cgaggatctg gaggggggca acatccccgc 16560
gctcctggat gtcgacgcct atgagaaaag caaggaggat gcagcagctg aagcaactgc 16620
agccgtagct accgcctcta ccgaggtcag gggcgataat tttgcaagcg ccgcagcagt 16680
ggcagcggcc gaggcggctg aaaccgaaag taagatagtc attcagccgg tggagaagga 16740
tagcaagaac aggagctaca acgtactacc ggacaagata aacaccgcct accgcagctg 16800
gtacctagcc tacaactatg gcgaccccga gaagggcgtg cgctcctgga cgctgctcac 16860
cacctcggac gtcacctgcg gcgtggagca agtctactgg tcgctgcccg acatgatgca 16920
agacccggtc accttccgct ccacgcgtca agttagcaac tacccggtgg tgggcgccga 16980
gctcctgccc gtctactcca agagcttctt caacgagcag gccgtctact cgcagcagct 17040
gcgcgccttc acctcgctta cgcacgtctt caaccgcttc cccgagaacc agatcctcgt 17100
ccgcccgccc gcgcccacca ttaccaccgt cagtgaaaac gttcctgctc tcacagatca 17160
cgggaccctg ccgctgcgca gcagtatccg gggagtccag cgcgtgaccg ttactgacgc 17220
cagacgccgc acctgcccct acgtctacaa ggccctgggc atagtcgcgc cgcgcgtcct 17280
ctcgagccgc accttctaaa tgtccattct catctcgccc agtaataaca ccggttgggg 17340
cctgcgcgcg cccagcaaga tgtacggagg cgctcgccaa cgctccacgc aacaccccgt 17400
gcgcgtgcgc gggcacttcc gcgctccctg gggcgccctc aagggccgcg tgcggtcgcg 17460
caccaccgtc gacgacgtga tcgaccaggt ggtggccgac gcgcgcaact acacccccgc 17520
cgccgcgccc gtctccaccg tggacgccgt catcgacagc gtggtggccg acgcgcgccg 17580
gtacgcccgc gccaagagcc ggcggcggcg catcgcccgg cggcaccgga gcacccccgc 17640
catgcgcgcg gcgcgagcct tgctgcgcag ggccaggcgc acgggacgca gggccatgct 17700
cagggcggcc agacgcgcgg cttcaggcgc cagcgccggc aggacccgga gacgcgcggc 17760
cacggcggcg gcagcggcca tcgccagcat gtcccgcccg cggcgaggga acgtgtactg 17820
ggtgcgcgac gccgccaccg gtgtgcgcgt gcccgtgcgc acccgccccc ctcgcacttg 17880
aagatgttca cttcgcgatg ttgatgtgtc ccagcggcga ggaggatgtc caagcgcaaa 17940
ttcaaggaag agatgctcca ggtcatcgcg cctgagatct acggccctgc ggtggtgaag 18000
gaggaaagaa agccccgcaa aatcaagcgg gtcaaaaagg acaaaaagga agaagaaagt 18060
gatgtggacg gattggtgga gtttgtgcgc gagttcgccc cccggcggcg cgtgcagtgg 18120
cgcgggcgga aggtgcaacc ggtgctgaga cccggcacca ccgtggtctt cacgcccggc 18180
gagcgctccg gcaccgcttc caagcgctcc tacgacgagg tgtacgggga tgatgatatt 18240
ctggagcagg cggccgagcg cctgggcgag tttgcttacg gcaagcgcag ccgttccgca 18300
ccgaaggaag aggcggtgtc catcccgctg gaccacggca accccacgcc gagcctcaag 18360
cccgtgacct tgcagcaggt gctgccgacc gcggcgccgc gccgggggtt caagcgcgag 18420
ggcgaggatc tgtaccccac catgcagctg atggtgccca agcgccagaa gctggaagac 18480
gtgctggaga ccatgaaggt ggacccggac gtgcagcccg aggtcaaggt gcggcccatc 18540
aagcaggtgg ccccgggcct gggcgtgcag accgtggaca tcaagattcc cacggagccc 18600
atggaaacgc agaccgagcc catgatcaag cccagcacca gcaccatgga ggtgcagacg 18660
gatccctgga tgccatcggc tcctagtcga agaccccggc gcaagtacgg cgcggccagc 18720
ctgctgatgc ccaactacgc gctgcatcct tccatcatcc ccacgccggg ctaccgcggc 18780
acgcgcttct accgcggtca taccagcagc cgccgccgca agaccaccac tcgccgccgc 18840
cgtcgccgca ccgccgctgc aaccacccct gccgccctgg tgcggagagt gtaccgccgc 18900
ggccgcgcac ctctgaccct gccgcgcgcg cgctaccacc cgagcatcgc catttaaact 18960
ttcgcctgct ttgcagatca atggccctca catgccgcct tcgcgttccc attacgggct 19020
accgaggaag aaaaccgcgc cgtagaaggc tggcggggaa cgggatgcgt cgccaccacc 19080
accggcggcg gcgcgccatc agcaagcggt tggggggagg cttcctgccc gcgctgatcc 19140
ccatcatcgc cgcggcgatc ggggcgatcc ccggcattgc ttccgtggcg gtgcaggcct 19200
ctcagcgcca ctgagacaca cttggaaaca tcttgtaata aaccaatgga ctctgacgct 19260
cctggtcctg tgatgtgttt tcgtagacag atggaagaca tcaatttttc gtccctggct 19320
ccgcgacacg gcacgcggcc gttcatgggc acctggagcg acatcggcac cagccaactg 19380
aacgggggcg ccttcaattg gagcagtctc tggagcgggc ttaagaattt cgggtccacg 19440
cttaaaacct atggcagcaa ggcgtggaac agcaccacag ggcaggcgct gagggataag 19500
ctgaaagagc agaacttcca gcagaaggtg gtcgatgggc tcgcctcggg catcaacggg 19560
gtggtggacc tggccaacca ggccgtgcag cggcagatca acagccgcct ggacccggtg 19620
ccgcccgccg gctccgtgga gatgccgcag gtggaggagg agctgcctcc cctggacaag 19680
cggggcgaga agcgaccccg ccccgatgcg gaggagacgc tgctgacgca cacggacgag 19740
ccgcccccgt acgaggaggc ggtgaaactg ggtctgccca ccacgcggcc catcgcgccc 19800
ctggccaccg gggtgctgaa acccgaaaag cccgcgaccc tggacttgcc tcctccccag 19860
ccttcccgcc cctctacagt ggctaagccc ctgccgccgg tggccgtggc ccgcgcgcga 19920
cccgggggca ccgcccgccc tcatgcgaac tggcagagca ctctgaacag catcgtgggt 19980
ctgggagtgc agagtgtgaa gcgccgccgc tgctattaaa cctaccgtag cgcttaactt 20040
gcttgtctgt gtgtgtatgt attatgtcgc cgccgccgct gtccaccaga aggaggagtg 20100
aagaggcgcg tcgccgagtt gcaagatggc caccccatcg atgctgcccc agtgggcgta 20160
catgcacatc gccggacagg acgcttcgga gtacctgagt ccgggtctgg tgcagtttgc 20220
ccgcgccaca gacacctact tcagtctggg gaacaagttt aggaacccca cggtggcgcc 20280
cacgcacgat gtgaccaccg accgcagcca gcggctgacg ctgcgcttcg tgcccgtgga 20340
ccgcgaggac aacacctact cgtacaaagt gcgctacacg ctggccgtgg gcgacaaccg 20400
cgtgctggac atggccagca cctactttga catccgcggc gtgctggatc ggggccctag 20460
cttcaaaccc tactccggca ccgcctacaa cagtctggcc cccaagggag cacccaacac 20520
ttgtcagtgg acatataaag ccgatggtga aactgccaca gaaaaaacct atacatatgg 20580
aaatgcaccc gtgcagggca ttaacatcac aaaagatggt attcaacttg gaactgacac 20640
cgatgatcag ccaatctacg cagataaaac ctatcagcct gaacctcaag tgggtgatgc 20700
tgaatggcat gacatcactg gtactgatga aaagtatgga ggcagagctc ttaagcctga 20760
taccaaaatg aagccttgtt atggttcttt tgccaagcct actaataaag aaggaggtca 20820
ggcaaatgtg aaaacaggaa caggcactac taaagaatat gacatagaca tggctttctt 20880
tgacaacaga agtgcggctg ctgctggcct agctccagaa attgttttgt atactgaaaa 20940
tgtggatttg gaaactccag atacccatat tgtatacaaa gcaggcacag atgacagcag 21000
ctcttctatt aatttgggtc agcaagccat gcccaacaga cctaactaca ttggtttcag 21060
agacaacttt atcgggctca tgtactacaa cagcactggc aatatggggg tgctggccgg 21120
tcaggcttct cagctgaatg ctgtggttga cttgcaagac agaaacaccg agctgtccta 21180
ccagctcttg cttgactctc tgggtgacag aacccggtat ttcagtatgt ggaatcaggc 21240
ggtggacagc tatgatcctg atgtgcgcat tattgaaaat catggtgtgg aggatgaact 21300
tcccaactat tgtttccctc tggatgctgt tggcagaaca gatacttatc agggaattaa 21360
ggctaatgga actgatcaaa ccacatggac caaagatgac agtgtcaatg atgctaatga 21420
gataggcaag ggtaatccat tcgccatgga aatcaacatc caagccaacc tgtggaggaa 21480
cttcctctac gccaacgtgg ccctgtacct gcccgactct tacaagtaca cgccggccaa 21540
tgttaccctg cccaccaaca ccaacaccta cgattacatg aacggccggg tggtggcgcc 21600
ctcgctggtg gactcctaca tcaacatcgg ggcgcgctgg tcgctggatc ccatggacaa 21660
cgtgaacccc ttcaaccacc accgcaatgc ggggctgcgc taccgctcca tgctcctggg 21720
caacgggcgc tacgtgccct tccacatcca ggtgccccag aaatttttcg ccatcaagag 21780
cctcctgctc ctgcccgggt cctacaccta cgagtggaac ttccgcaagg acgtcaacat 21840
gatcctgcag agctccctcg gcaacgacct gcgcacggac ggggcctcca tctccttcac 21900
cagcatcaac ctctacgcca ccttcttccc catggcgcac aacacggcct ccacgctcga 21960
ggccatgctg cgcaacgaca ccaacgacca gtccttcaac gactacctct cggcggccaa 22020
catgctctac cccatcccgg ccaacgccac caacgtgccc atctccatcc cctcgcgcaa 22080
ctgggccgcc ttccgcggct ggtccttcac gcgtctcaag accaaggaga cgccctcgct 22140
gggctccggg ttcgacccct acttcgtcta ctcgggctcc atcccctacc tcgacggcac 22200
cttctacctc aaccacacct tcaagaaggt ctccatcacc ttcgactcct ccgtcagctg 22260
gcccggcaac gaccggctcc tgacgcccaa cgagttcgaa atcaagcgca ccgtcgacgg 22320
cgagggctac aacgtggccc agtgcaacat gaccaaggac tggttcctgg tccagatgct 22380
ggcccactac aacatcggct accagggctt ctacgtgccc gagggctaca aggaccgcat 22440
gtactccttc ttccgcaact tccagcccat gagccgccag gtggtggacg aggtcaacta 22500
caaggactac caggccgtca ccctggccta ccagcacaac aactcgggct tcgtcggcta 22560
cctcgcgccc accatgcgcc agggccagcc ctaccccgcc aactacccct acccgctcat 22620
cggcaagagc gccgtcacca gcgtcaccca gaaaaagttc ctctgcgaca gggtcatgtg 22680
gcgcatcccc ttctccagca acttcatgtc catgggcgcg ctcaccgacc tcggccagaa 22740
catgctctat gccaactccg cccacgcgct agacatgaat ttcgaagtcg accccatgga 22800
tgagtccacc cttctctatg ttgtcttcga agtcttcgac gtcgtccgag tgcaccagcc 22860
ccaccgcggc gtcatcgagg ccgtctacct gcgcaccccc ttctcggccg gtaacgccac 22920
cacctaagct cttgcttctt gcaagccatg gccgcgggct ccggcgagca ggagctcagg 22980
gccatcatcc gcgacctggg ctgcgggccc tacttcctgg gcaccttcga taagcgcttc 23040
ccgggattca tggccccgca caagctggcc tgcgccatcg tcaacacggc cggccgcgag 23100
accgggggcg agcactggct ggccttcgcc tggaacccgc gctcgaacac ctgctacctc 23160
ttcgacccct tcgggttctc ggacgagcgc ctcaagcaga tctaccagtt cgagtacgag 23220
ggcctgctgc gccgcagcgc cctggccacc gaggaccgct gcgtcaccct ggaaaagtcc 23280
acccagaccg tgcagggtcc gcgctcggcc gcctgcgggc tcttctgctg catgttcctg 23340
cacgccttcg tgcactggcc cgaccgcccc atggacaaga accccaccat gaacttgctg 23400
acgggggtgc ccaacggcat gctccagtcg ccccaggtgg aacccaccct gcgccgcaac 23460
caggaggcgc tctaccgctt cctcaactcc cactccgcct actttcgctc ccaccgcgcg 23520
cgcatcgaga aggccaccgc cttcgaccgc atgaatcaag acatgtaaac cgtgtgtgta 23580
tgttaaatgt ctttaataaa cagcactttc atgttacaca tgcatctgag atgatttatt 23640
tagaaatcga aagggttctg ccgggtctcg gcatggcccg cgggcaggga cacgttgcgg 23700
aactggtact tggccagcca cttgaactcg gggatcagca gtttgggcag cggggtgtcg 23760
gggaaggagt cggtccacag cttccgcgtc agttgcaggg cgcccagcag gtcgggcgcg 23820
gagatcttga aatcgcagtt gggacccgcg ttctgcgcgc gggagttgcg gtacacgggg 23880
ttgcagcact ggaacaccat cagggccggg tgcttcacgc tcgccagcac cgtcgcgtcg 23940
gtgatgctct ccacgtcgag gtcctcggcg ttggccatcc cgaagggggt catcttgcag 24000
gtctgccttc ccatggtggg cacgcacccg ggcttgtggt tgcaatcgca gtgcaggggg 24060
atcagcatca tctgggcctg gtcggcgttc atccccgggt acatggcctt catgaaagcc 24120
tccaattgcc tgaacgcctg ctgggccttg gctccctcgg tgaagaagac cccgcaggac 24180
ttgctagaga actggttggt ggcgcacccg gcgtcgtgca cgcagcagcg cgcgtcgttg 24240
ttggccagct gcaccacgct gcgcccccag cggttctggg tgatcttggc ccggtcgggg 24300
ttctccttca gcgcgcgctg cccgttctcg ctcgccacat ccatctcgat catgtgctcc 24360
ttctggatca tggtggtccc gtgcaggcac cgcagcttgc cctcggcctc ggtgcacccg 24420
tgcagccaca gcgcgcaccc ggtgcactcc cagttcttgt gggcgatctg ggaatgcgcg 24480
tgcacgaagc cctgcaggaa gcggcccatc atggtggtca gggtcttgtt gctagtgaag 24540
gtcagcggaa tgccgcggtg ctcctcgttg atgtacaggt ggcagatgcg gcggtacacc 24600
tcgccctgct cgggcatcag ctggaagttg gctttcaggt cggtctccac gcggtagcgg 24660
tccatcagca tagtcatgat ttccataccc ttctcccagg ccgagacgat gggcaggctc 24720
atagggttct tcaccatcat cttagcgcta gcagccgcgg ccagggggtc gctctcgtcc 24780
agggtctcaa agctccgctt gccgtccttc tcggtgatcc gcaccggggg gtagctgaag 24840
cccacggccg ccagctcctc ctcggcctgt ctttcgtcct cgctgtcctg gctgacgtcc 24900
tgcaggacca catgcttggt cttgcggggt ttcttcttgg gcggcagcgg cggcggagat 24960
gttggagatg gcgaggggga gcgcgagttc tcgctcacca ctactatctc ttcctcttct 25020
tggtccgagg ccacgcggcg gtaggtatgt ctcttcgggg gcagaggcgg aggcgacggg 25080
ctctcgccgc cgcgacttgg cggatggctg gcagagcccc ttccgcgttc gggggtgcgc 25140
tcccggcggc gctctgactg acttcctccg cggccggcca ttgtgttctc ctagggagga 25200
acaacaagca tggagactca gccatcgcca acctcgccat ctgcccccac cgccgacgag 25260
aagcagcagc agcagaatga aagcttaacc gccccgccgc ccagccccgc cacctccgac 25320
gcggccgtcc cagacatgca agagatggag gaatccatcg agattgacct gggctatgtg 25380
acgcccgcgg agcacgagga ggagctggca gtgcgctttt cacaagaaga gatacaccaa 25440
gaacagccag agcaggaagc agagaatgag cagagtcagg ctgggctcga gcatgacggc 25500
gactacctcc acctgagcgg gggggaggac gcgctcatca agcatctggc ccggcaggcc 25560
accatcgtca aggatgcgct gctcgaccgc accgaggtgc ccctcagcgt ggaggagctc 25620
agccgcgcct acgagttgaa cctcttctcg ccgcgcgtgc cccccaagcg ccagcccaat 25680
ggcacctgcg agcccaaccc gcgcctcaac ttctacccgg tcttcgcggt gcccgaggcc 25740
ctggccacct accacatctt tttcaagaac caaaagatcc ccgtctcctg ccgcgccaac 25800
cgcacccgcg ccgacgccct tttcaacctg ggtcccggcg cccgcctacc tgatatcgcc 25860
tccttggaag aggttcccaa gatcttcgag ggtctgggca gcgacgagac tcgggccgcg 25920
aacgctctgc aaggagaagg aggagagcat gagcaccaca gcgccctggt cgagttggaa 25980
ggcgacaacg cgcggctggc ggtgctcaaa cgcacggtcg agctgaccca tttcgcctac 26040
ccggctctga acctgccccc caaagtcatg agcgcggtca tggaccaggt gctcatcaag 26100
cgcgcgtcgc ccatctccga ggacgagggc atgcaagact ccgaggaggg caagcccgtg 26160
gtcagcgacg agcagctggc ccggtggctg ggtcctaatg ctagtcccca gagtttggaa 26220
gagcggcgca aactcatgat ggccgtggtc ctggtgaccg tggagctgga gtgcctgcgc 26280
cgcttcttcg ccgacgcgga gaccctgcgc aaggtcgagg agaacctgca ctacctcttc 26340
aggcacgggt tcgtgcgcca ggcctgcaag atctccaacg tggagctgac caacctggtc 26400
tcctacatgg gcatcttgca cgagaaccgc ctggggcaga acgtgctgca caccaccctg 26460
cgcggggagg cccggcgcga ctacatccgc gactgcgtct acctctacct ctgccacacc 26520
tggcagacgg gcatgggcgt gtggcagcag tgtctggagg agcagaacct gaaagagctc 26580
tgcaagctcc tgcagaagaa cctcaagggt ctgtggaccg ggttcgacga gcgcaccacc 26640
gcctcggacc tggccgacct cattttcccc gagcgcctca ggctgacgct gcgcaacggc 26700
ctgcccgact ttatgagcca aagcatgttg caaaactttc gctctttcat cctcgaacgc 26760
tccggaatcc tgcccgccac ctgctccgcg ctgccctcgg acttcgtgcc gctgaccttc 26820
cgcgagtgcc ccccgccgct gtggagccac tgctacctgc tgcgcctggc caactacctg 26880
gcctaccact cggacgtgat cgaggacgtc agcggcgagg gcctgctcga gtgccactgc 26940
cgctgcaacc tctgcacgcc gcaccgctcc ctggcctgca acccccagct gctgagcgag 27000
acccagatca tcggcacctt cgagttgcaa gggcccagcg aaggcgaggg ttcagccgcc 27060
aaggggggtc tgaaactcac cccggggctg tggacctcgg cctacttgcg caagttcgtg 27120
cccgaggact accatccctt cgagatcagg ttctacgagg accaatccca tccgcccaag 27180
gccgagctgt cggcctgcgt catcacccag ggggcgatcc tggcccaatt gcaagccatc 27240
cagaaatccc gccaagaatt cttgctgaaa aagggccgcg gggtctacct cgacccccag 27300
accggtgagg agctcaaccc cggcttcccc caggatgccc cgaggaaaca agaagctgaa 27360
agtggagctg ccgcccgtgg aggatttgga ggaagactgg gagaacagca gtcaggcaga 27420
ggaggaggag atggaggaag actgggacag cactcaggca gaggaggaca gcctgcaaga 27480
cagtctggag gaagacgagg aggaggcaga ggaggaggtg gaagaagcag ccgccgccag 27540
accgtcgtcc tcggcggggg agaaagcaag cagcacggat accatctccg ctccgggtcg 27600
gggtcccgct cgaccacaca gtagatggga cgagaccgga cgattcccga accccaccac 27660
ccagaccggt aagaaggagc ggcagggata caagtcctgg cgggggcaca aaaacgccat 27720
cgtctcctgc ttgcaggcct gcgggggcaa catctccttc acccggcgct acctgctctt 27780
ccaccgcggg gtgaactttc cccgcaacat cttgcattac taccgtcacc tccacagccc 27840
ctactacttc caagaagagg cagcagcagc agaaaaagac cagcagaaaa ccagcagcta 27900
gaaaatccac agcggcggca gcaggtggac tgaggatcgc ggcgaacgag ccggcgcaaa 27960
cccgggagct gaggaaccgg atctttccca ccctctatgc catcttccag cagagtcggg 28020
ggcaggagca ggaactgaaa gtcaagaacc gttctctgcg ctcgctcacc cgcagttgtc 28080
tgtatcacaa gagcgaagac caacttcagc gcactctcga ggacgccgag gctctcttca 28140
acaagtactg cgcgctcact cttaaagagt agcccgcgcc cgcccagtcg cagaaaaagg 28200
cgggaattac gtcacctgtg cccttcgccc tagccgcctc cacccatcat catgagcaaa 28260
gagattccca cgccttacat gtggagctac cagccccaga tgggcctggc cgccggtgcc 28320
gcccaggact actccacccg catgaattgg ctcagcgccg ggcccgcgat gatctcacgg 28380
gtgaatgaca tccgcgccca ccgaaaccag atactcctag aacagtcagc gctcaccgcc 28440
acgccccgca atcacctcaa tccgcgtaat tggcccgccg ccctggtgta ccaggaaatt 28500
ccccagccca cgaccgtact acttccgcga gacgcccagg ccgaagtcca gctgactaac 28560
tcaggtgtcc agctggcggg cggcgccacc ctgtgtcgtc accgccccgc tcagggtata 28620
aagcggctgg tgatccgggg cagaggcaca cagctcaacg acgaggtggt gagctcttcg 28680
ctgggtctgc gacctgacgg agtcttccaa ctcgccggat cggggagatc ttccttcacg 28740
cctcgtcagg ccgtcctgac tttggagagt tcgtcctcgc agccccgctc gggtggcatc 28800
ggcactctcc agttcgtgga ggagttcact ccctcggtct acttcaaccc cttctccggc 28860
tcccccggcc actacccgga cgagttcatc ccgaacttcg acgccatcag cgagtcggtg 28920
gacggctacg attgaatgtc ccatggtggc gcagctgacc tagctcggct tcgacacctg 28980
gaccactgcc gccgcttccg ctgcttcgct cgggatctcg ccgagtttgc ctactttgag 29040
ctgcccgagg agcaccctca gggcccggcc cacggagtgc ggatcgtcgt cgaagggggc 29100
ctcgactccc acctgcttcg gatcttcagc cagcgtccga tcctggtcga gcgcgagcaa 29160
ggacagaccc ttctgactct gtactgcatc tgcaaccacc ccggcctgca tgaaagtctt 29220
tgttgtctgc tgtgtactga gtataataaa agctgagatc agcgactact ccggacttcc 29280
gtgtgttcct gaatccatca accagtcttt gttcttcacc gggaacgaga ccgagctcca 29340
gctccagtgt aagccccaca agaagtacct cacctggctg ttccagggct ccccgatcgc 29400
cgttgtcaac cactgcgaca acgacggagt cctgctgagc ggccctgcca accttacttt 29460
ttccacccgc agaagcaagc tccagctctt ccaacccttc ctccccggga cctatcagtg 29520
cgtctcggga ccctgccatc acaccttcca cctgatcccg aataccacag cgtcgctccc 29580
cgctactaac aaccaaacta acctccacca acgccaccgt cgctaggcca caatacatgc 29640
ccatattaga ctatgaggcc gagccacagc gacccatgct ccccgctatt agttacttca 29700
atctaaccgg cggagatgac tgacccactg gccaacaaca acgtcaacga ccttctcctg 29760
gacatggacg gccgcgcctc ggagcagcga ctcgcccaac ttcgcattcg ccagcagcag 29820
gagagagccg tcaaggagct gcaggatgcg gtggccatcc accagtgcaa gagaggcatc 29880
ttctgcctgg tgaaacaggc caagatctcc tacgaggtca ctccaaacga ccatcgcctc 29940
tcctacgagc tcctgcagca gcgccagaag ttcacctgcc tggtcggagt caaccccatc 30000
gtcatcaccc agcagtctgg cgataccaag gggtgcatcc actgctcctg cgactccccc 30060
gactgcgtcc acactctgat caagaccctc tgcggcctcc gcgacctcct ccccatgaac 30120
taatcacccc cttatccagt gaaataaaga tcatattgat gatgatttta cagaaataaa 30180
aaataatcat ttgatttgaa ataaagatac aatcatattg atgatttgag tttaacaaaa 30240
aaataaagaa tcacttactt gaaatctgat accaggtctc tgtccatgtt ttctgccaac 30300
accacttcac tcccctcttc ccagctctgg tactgcaggc cccggcgggc tgcaaacttc 30360
ctccacacgc tgaaggggat gtcaaattcc tcctgtccct caatcttcat tttatcttct 30420
atcagatgtc caaaaagcgc gtccgggtgg atgatgactt cgaccccgtc tacccctacg 30480
atgcagacaa cgcaccgacc gtgcccttca tcaacccccc cttcgtctct tcagatggat 30540
tccaagagaa gcccctgggg gtgttgtccc tgcgactggc cgaccccgtc accaccaaga 30600
acggggaaat caccctcaag ctgggagagg gggtggacct cgattcctcg ggaaaactca 30660
tctccaacac ggccaccaag gccgccgccc ctctcagttt ttccaacaac accatttccc 30720
ttaacatgga tcaccccttt tacactaaag atggaaaatt atccttacaa gtttctccac 30780
cattaaatat actgagaaca agcattctaa acacactagc tttaggtttt ggatcaggtt 30840
taggactccg tggctctgcc ttggcagtac agttagtctc tccacttaca tttgatactg 30900
atggaaacat aaagcttacc ttagacagag gtttgcatgt tacaacagga gatgcaattg 30960
aaagcaacat aagctgggct aaaggtttaa aatttgaaga tggagccata gcaaccaaca 31020
ttggaaatgg gttagagttt ggaagcagta gtacagaaac aggtgttgat gatgcttacc 31080
caatccaagt taaacttgga tctggcctta gctttgacag tacaggagcc ataatggctg 31140
gtaacaaaga agacgataaa ctcactttgt ggacaacacc tgatccatca ccaaactgtc 31200
aaatactcgc agaaaatgat gcaaaactaa cactttgctt gactaaatgt ggtagtcaaa 31260
tactggccac tgtgtcagtc ttagttgtag gaagtggaaa cctaaacccc attactggca 31320
ccgtaagcag tgctcaggtg tttctacgtt ttgatgcaaa cggtgttctt ttaacagaac 31380
attctacact aaaaaaatac tgggggtata ggcagggaga tagcatagat ggcactccat 31440
ataccaatgc tgtaggattc atgcccaatt taaaagctta tccaaagtca caaagttcta 31500
ctactaaaaa taatatagta gggcaagtat acatgaatgg agatgtttca aaacctatgc 31560
ttctcactat aaccctcaat ggtactgatg acagcaacag tacatattca atgtcatttt 31620
catacacctg gactaatgga agctatgttg gagcaacatt tggggctaac tcttatacct 31680
tctcatacat cgcccaagaa tgaacactgt atcccaccct gcatgccaac ccttcccacc 31740
ccactctgtg gaacaaactc tgaaacacaa aataaaataa agttcaagtg ttttattgat 31800
tcaacagttt tacaggattc gagcagttat ttttcctcca ccctcccagg acatggaata 31860
caccaccctc tccccccgca cagccttgaa catctgaatg ccattggtga tggacatgct 31920
tttggtctcc acgttccaca cagtttcaga gcgagccagt ctcgggtcgg tcagggagat 31980
gaaaccctcc gggcactccc gcatctgcac ctcacagctc aacagctgag gattgtcctc 32040
ggtggtcggg atcacggtta tctggaagaa gcagaagagc ggcggtggga atcatagtcc 32100
gcgaacggga tcggccggtg gtgtcgcatc aggccccgca gcagtcgctg ccgccgccgc 32160
tccgtcaagc tgctgctcag ggggtccggg tccagggact ccctcagcat gatgcccacg 32220
gccctcagca tcagtcgtct ggtgcggcgg gcgcagcagc gcatgcggat ctcgctcagg 32280
tcgctgcagt acgtgcaaca cagaaccacc aggttgttca acagtccata gttcaacacg 32340
ctccagccga aactcatcgc gggaaggatg ctacccacgt ggccgtcgta ccagatcctc 32400
aggtaaatca agtggtgccc cctccagaac acgctgccca cgtacatgat ctccttgggc 32460
atgtggcggt tcaccacctc ccggtaccac atcaccctct ggttgaacat gcagccccgg 32520
atgatcctgc ggaaccacag ggccagcacc gccccgcccg ccatgcagcg aagagacccc 32580
gggtcccggc aatggcaatg gaggacccac cgctcgtacc cgtggatcat ctgggagctg 32640
aacaagtcta tgttggcaca gcacaggcat atgctcatgc atctcttcag cactctcaac 32700
tcctcggggg tcaaaaccat atcccagggc acggggaact cttgcaggac agcgaacccc 32760
gcagaacagg gcaatcctcg cacagaactt acattgtgca tggacagggt atcgcaatca 32820
ggcagcaccg ggtgatcctc caccagagaa gcgcgggtct cggtctcctc acagcgtggt 32880
aagggggccg gccgatacgg gtgatggcgg gacgcggctg atcgtgttcg cgaccgtgtc 32940
atgatgcagt tgctttcgga cattttcgta cttgctgtag cagaacctgg tccgggcgct 33000
gcacaccgat cgccggcggc ggtctcggcg cttggaacgc tcggtgttga aattgtaaaa 33060
cagccactct ctcagaccgt gcagcagatc tagggcctca ggagtgatga agatcccatc 33120
atgcctgatg gctctgatca catcgaccac cgtggaatgg gccagaccca gccagatgat 33180
gcaattttgt tgggtttcgg tgacggcggg ggagggaaga acaggaagaa ccatgattaa 33240
cttttaatcc aaacggtctc ggagtacttc aaaatgaaga tcgcggagat ggcacctctc 33300
gcccccgctg tgttggtgga aaataacagc caggtcaaag gtgatacggt tctcgagatg 33360
ttccacggtg gcttccagca aagcctccac gcgcacatcc agaaacaaga caatagcgaa 33420
agcgggaggg ttctctaatt cctcaatcat catgttacac tcctgcacca tccccagata 33480
attttcattt ttccagcctt gaatgattcg aactagttcc tgaggtaaat ccaagccagc 33540
catgataaag agctcgcgca gagcgccctc caccggcatt cttaagcaca ccctcataat 33600
tccaagatat tctgctcctg gttcacctgc agcagattga caagcggaat atcaaaatct 33660
ctgccgcgat ccctgagctc ctccctcagc aataactgta agtactcttt catatcctct 33720
ccgaaatttt tagccatagg accaccagga ataagattag ggcaagccac agtacagata 33780
aaccgaagtc ctccccagtg agcattgcca aatgcaagac tgctataagc atgctggcta 33840
gacccggtga tatcttccag ataactggac agaaaatcgc ccaggcaatt tttaagaaaa 33900
tcaacaaaag aaaaatcctc caggtggacg tttagagcct cgggaacaac gatgaagtaa 33960
atgcaagcgg tgcgttccag catggttagt tagctgatct gtagaaaaaa caaaaatgaa 34020
cattaaacca tgctagcctg gcgaacaggt gggtaaatcg ttctctccag caccaggcag 34080
gccacggggt ctccggcgcg accctcgtaa aaattgtcgc tatgattgaa aaccatcaca 34140
gagagacgtt cccggtggcc ggcgtgaatg attcgacaag atgaatacac ccccggaaca 34200
ttggcgtccg cgagtgaaaa aaagcgcccg aggaagcaat aaggcactac aatgctcagt 34260
ctcaagtcca gcaaagcgat gccatgcgga tgaagcacaa aattctcagg tgcgtacaaa 34320
atgtaattac tcccctcctg cacaggcagc aaagcccccg atccctccag gtacacatac 34380
aaagcctcag cgtccatagc ttaccgagca gcagcacaca acaggcgcaa gagtcagaga 34440
aaggctgagc tctaacctgt ccacccgctc tctgctcaat atatagccca gatctacact 34500
gacgtaaagg ccaaagtcta aaaatacccg ccaaataatc acacacgccc agcacacgcc 34560
cagaaaccgg tgacacactc aaaaaaatac gcgcacttcc tcaaacgccc aaaactgccg 34620
tcatttccgg gttcccacgc tacgtcatca aaacacgact ttcaaattcc gtcgaccgtt 34680
aaaaacgtca cccgccccgc ccctaacggt cgcccgtctc tcagccaatc agcgccccgc 34740
atccccaaat tcaaacacct catttgcata ttaacgcgca caaaaagttt gaggtatatt 34800
attgatgatg gttaattaa 34819
<210> 59
<211> 568
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 59
taacgttact ggccgaagcc gcttggaata aggccggtgt gcgtttgtct atatgttatt 60
ttccaccata ttgccgtctt ttggcaatgt gagggcccgg aaacctggcc ctgtcttctt 120
gacgagcatt cctaggggtc tttcccctct cgccaaagga atgcaaggtc tgttgaatgt 180
cgtgaaggaa gcagttcctc tggaagcttc ttgaagacaa acaacgtctg tagcgaccct 240
ttgcaggcag cggaaccccc cacctggcga caggtgcctc tgcggccaaa agccacgtgt 300
ataagataca cctgcaaagg cggcacaacc ccagtgccac gttgtgagtt ggatagttgt 360
ggaaagagtc aaatggctct cctcaagcgt attcaacaag gggctgaagg atgcccagaa 420
ggtaccccat tgtatgggat ctgatctggg gcctcggtgc acatgcttta catgtgttta 480
gtcgaggtta aaaaacgtct aggccccccg aaccacgggg acgtggtttt cctttgaaaa 540
acacgatgat aatatggcca caaccatg 568
<210> 60
<211> 1145
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic construct
<400> 60
Met Ala Ser Ile Val Gly Gly Trp Glu Cys Glu Lys His Ser Gln Pro
1 5 10 15
Trp Gln Val Leu Val Ala Ser Arg Gly Arg Ala Val Cys Gly Gly Val
20 25 30
Leu Val His Pro Gln Trp Val Leu Thr Ala Ala His Cys Ile Arg Asn
35 40 45
Lys Ser Val Ile Leu Leu Gly Arg His Ser Leu Phe His Pro Glu Asp
50 55 60
Thr Gly Gln Val Phe Gln Val Ser His Ser Phe Pro His Pro Leu Tyr
65 70 75 80
Asp Met Ser Leu Leu Lys Asn Arg Phe Leu Arg Pro Gly Asp Asp Ser
85 90 95
Ser His Asp Leu Met Leu Leu Arg Leu Ser Glu Pro Ala Glu Leu Thr
100 105 110
Asp Ala Val Lys Val Met Asp Leu Pro Thr Gln Glu Pro Ala Leu Gly
115 120 125
Thr Thr Cys Tyr Ala Ser Gly Trp Gly Ser Ile Glu Pro Glu Glu Phe
130 135 140
Leu Thr Pro Lys Lys Leu Gln Cys Val Asp Leu His Val Ile Ser Asn
145 150 155 160
Asp Val Cys Ala Gln Val His Pro Gln Lys Val Thr Lys Phe Met Leu
165 170 175
Cys Ala Gly Arg Trp Thr Gly Gly Lys Ser Thr Cys Ser Gly Asp Ser
180 185 190
Gly Gly Pro Leu Val Cys Asn Gly Val Leu Gln Gly Ile Thr Ser Trp
195 200 205
Gly Ser Glu Pro Cys Ala Leu Pro Glu Arg Pro Ser Leu Tyr Thr Lys
210 215 220
Val Val His Tyr Arg Lys Trp Ile Lys Asp Thr Ile Val Ala Asn Pro
225 230 235 240
Gly Ser Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu
245 250 255
Asn Pro Gly Pro Ala Ser Lys Ala Val Leu Leu Ala Leu Leu Met Ala
260 265 270
Gly Leu Ala Leu Gln Pro Gly Thr Ala Leu Leu Cys Tyr Ser Cys Lys
275 280 285
Ala Gln Val Ser Asn Glu Asp Cys Leu Gln Val Glu Asn Cys Thr Gln
290 295 300
Leu Gly Glu Gln Cys Trp Thr Ala Arg Ile Arg Ala Val Gly Leu Leu
305 310 315 320
Thr Val Ile Ser Lys Gly Cys Ser Leu Asn Cys Val Asp Asp Ser Gln
325 330 335
Asp Tyr Tyr Val Gly Lys Lys Asn Ile Thr Cys Cys Asp Thr Asp Leu
340 345 350
Cys Asn Ala Ser Gly Ala His Ala Leu Gln Pro Ala Ala Ala Ile Leu
355 360 365
Ala Leu Leu Pro Ala Leu Gly Leu Leu Leu Trp Gly Pro Gly Gln Leu
370 375 380
Gly Ser Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val
385 390 395 400
Glu Ser Asn Pro Gly Pro Met Ala Ser Ala Arg Arg Pro Arg Trp Leu
405 410 415
Cys Ala Gly Ala Leu Val Leu Ala Gly Gly Phe Phe Leu Leu Gly Phe
420 425 430
Leu Phe Gly Trp Phe Ile Lys Ser Ser Asn Glu Ala Thr Asn Ile Thr
435 440 445
Pro Lys His Asn Met Lys Ala Phe Leu Asp Glu Leu Lys Ala Glu Asn
450 455 460
Ile Lys Lys Phe Leu Tyr Asn Phe Thr Gln Ile Pro His Leu Ala Gly
465 470 475 480
Thr Glu Gln Asn Phe Gln Leu Ala Lys Gln Ile Gln Ser Gln Trp Lys
485 490 495
Glu Phe Gly Leu Asp Ser Val Glu Leu Ala His Tyr Asp Val Leu Leu
500 505 510
Ser Tyr Pro Asn Lys Thr His Pro Asn Tyr Ile Ser Ile Ile Asn Glu
515 520 525
Asp Gly Asn Glu Ile Phe Asn Thr Ser Leu Phe Glu Pro Pro Pro Pro
530 535 540
Gly Tyr Glu Asn Val Ser Asp Ile Val Pro Pro Phe Ser Ala Phe Ser
545 550 555 560
Pro Gln Gly Met Pro Glu Gly Asp Leu Val Tyr Val Asn Tyr Ala Arg
565 570 575
Thr Glu Asp Phe Phe Lys Leu Glu Arg Asp Met Lys Ile Asn Cys Ser
580 585 590
Gly Lys Ile Val Ile Ala Arg Tyr Gly Lys Val Phe Arg Gly Asn Lys
595 600 605
Val Lys Asn Ala Gln Leu Ala Gly Ala Lys Gly Val Ile Leu Tyr Ser
610 615 620
Asp Pro Ala Asp Tyr Phe Ala Pro Gly Val Lys Ser Tyr Pro Asp Gly
625 630 635 640
Trp Asn Leu Pro Gly Gly Gly Val Gln Arg Gly Asn Ile Leu Asn Leu
645 650 655
Asn Gly Ala Gly Asp Pro Leu Thr Pro Gly Tyr Pro Ala Asn Glu Tyr
660 665 670
Ala Tyr Arg Arg Gly Ile Ala Glu Ala Val Gly Leu Pro Ser Ile Pro
675 680 685
Val His Pro Ile Gly Tyr Tyr Asp Ala Gln Lys Leu Leu Glu Lys Met
690 695 700
Gly Gly Ser Ala Pro Pro Asp Ser Ser Trp Arg Gly Ser Leu Lys Val
705 710 715 720
Pro Tyr Asn Val Gly Pro Gly Phe Thr Gly Asn Phe Ser Thr Gln Lys
725 730 735
Val Lys Met His Ile His Ser Thr Asn Glu Val Thr Arg Ile Tyr Asn
740 745 750
Val Ile Gly Thr Leu Arg Gly Ala Val Glu Pro Asp Arg Tyr Val Ile
755 760 765
Leu Gly Gly His Arg Asp Ser Trp Val Phe Gly Gly Ile Asp Pro Gln
770 775 780
Ser Gly Ala Ala Val Val His Glu Ile Val Arg Ser Phe Gly Thr Leu
785 790 795 800
Lys Lys Glu Gly Trp Arg Pro Arg Arg Thr Ile Leu Phe Ala Ser Trp
805 810 815
Asp Ala Glu Glu Phe Gly Leu Leu Gly Ser Thr Glu Trp Ala Glu Glu
820 825 830
Asn Ser Arg Leu Leu Gln Glu Arg Gly Val Ala Tyr Ile Asn Ala Asp
835 840 845
Ser Ser Ile Glu Gly Asn Tyr Thr Leu Arg Val Asp Cys Thr Pro Leu
850 855 860
Met Tyr Ser Leu Val His Asn Leu Thr Lys Glu Leu Lys Ser Pro Asp
865 870 875 880
Glu Gly Phe Glu Gly Lys Ser Leu Tyr Glu Ser Trp Thr Lys Lys Ser
885 890 895
Pro Ser Pro Glu Phe Ser Gly Met Pro Arg Ile Ser Lys Leu Gly Ser
900 905 910
Gly Asn Asp Phe Glu Val Phe Phe Gln Arg Leu Gly Ile Ala Ser Gly
915 920 925
Arg Ala Arg Tyr Thr Lys Asn Trp Glu Thr Asn Lys Phe Ser Gly Tyr
930 935 940
Pro Leu Tyr His Ser Val Tyr Glu Thr Tyr Glu Leu Val Glu Lys Phe
945 950 955 960
Tyr Asp Pro Met Phe Lys Tyr His Leu Thr Val Ala Gln Val Arg Gly
965 970 975
Gly Met Val Phe Glu Leu Ala Asn Ser Ile Val Leu Pro Phe Asp Cys
980 985 990
Arg Asp Tyr Ala Val Val Leu Arg Lys Tyr Ala Asp Lys Ile Tyr Ser
995 1000 1005
Ile Ser Met Lys His Pro Gln Glu Met Lys Thr Tyr Ser Val Ser
1010 1015 1020
Phe Asp Ser Leu Phe Ser Ala Val Lys Asn Phe Thr Glu Ile Ala
1025 1030 1035
Ser Lys Phe Ser Glu Arg Leu Gln Asp Phe Asp Lys Ser Asn Pro
1040 1045 1050
Ile Val Leu Arg Met Met Asn Asp Gln Leu Met Phe Leu Glu Arg
1055 1060 1065
Ala Phe Ile Asp Pro Leu Gly Leu Pro Asp Arg Pro Phe Tyr Arg
1070 1075 1080
His Val Ile Tyr Ala Pro Ser Ser His Asn Lys Tyr Ala Gly Glu
1085 1090 1095
Ser Phe Pro Gly Ile Tyr Asp Ala Leu Phe Asp Ile Glu Ser Lys
1100 1105 1110
Val Asp Pro Ser Lys Ala Trp Gly Glu Val Lys Arg Gln Ile Tyr
1115 1120 1125
Val Ala Ala Phe Thr Val Gln Ala Ala Ala Glu Thr Leu Ser Glu
1130 1135 1140
Val Ala
1145
<210> 61
<211> 3435
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic construct
<400> 61
atggctagca tcgtcggagg gtgggagtgc gaaaagcact cacagccatg gcaggtcctg 60
gtcgcctcgc gcggacgcgc cgtgtgtgga ggtgtgctgg tccacccgca gtgggtgttg 120
actgcggccc attgcatcag aaataagtcc gtgatcctct tggggagaca ttccctgttt 180
caccccgaag atactggaca ggtgttccaa gtgagccact ccttcccgca tccactgtac 240
gacatgagcc tgctgaagaa ccgctttctg cggccagggg acgactcatc acacgatttg 300
atgctgcttc ggctctcgga accggccgag ctcaccgacg cagtgaaggt catggacctc 360
cctacgcaag agcctgctct cggtaccact tgttacgcat cgggatgggg ctccatcgag 420
ccggaagaat tcctgacccc gaaaaagctg cagtgcgtgg atctgcacgt gatttcgaat 480
gacgtgtgcg cgcaagtgca tccacaaaag gtcactaagt tcatgctgtg cgccggaagg 540
tggaccggcg gaaaatcgac ctgttccggc gacagcggag gcccactcgt gtgcaacggt 600
gtgctgcagg gcatcactag ctggggatca gaaccgtgcg cgcttccgga gcggccctcg 660
ctctacacga aggtggtgca ctaccgcaaa tggattaaag ataccatcgt cgcaaaccct 720
ggatccgaag gtaggggttc attattgacc tgtggagatg tcgaagaaaa cccaggaccc 780
gctagcaaag cagtgctgct ggcgctcctg atggctggac tcgcgctgca gcctggaacc 840
gccctgctct gttactcgtg caaggcccaa gtctcgaatg aggactgttt gcaagtggaa 900
aactgcaccc agctcggaga acaatgctgg actgcacgga tccgcgctgt cggcctgctg 960
accgtgatct ccaaagggtg ctcattgaac tgcgtggacg atagccagga ctactacgtg 1020
ggaaagaaga atatcacttg ttgcgacacg gatctttgca acgcgtccgg agcgcacgcc 1080
ctgcagccag cagccgccat tctggccctg cttccggccc tggggttgct gctctggggt 1140
ccgggccagc tcggatccca gaccctgaac tttgatctgc tgaaactggc aggcgatgtg 1200
gaaagcaacc caggcccaat ggctagcgct cgcagaccgc ggtggctgtg tgcaggggcg 1260
ctcgtcctgg cgggtggctt ctttttgctc ggctttcttt tcggatggtt catcaaatcg 1320
tcaaacgaag ctaccaatat caccccgaag cacaacatga aggcctttct ggatgagctg 1380
aaggctgaga acattaagaa gttcctctac aacttcaccc agatcccaca tttggcgggc 1440
actgagcaga actttcagtt ggctaagcag atccagagcc agtggaagga attcggcctg 1500
gactccgtcg agctggcgca ttacgatgtg ctgctgagct accctaataa gactcatccg 1560
aactatatct cgattatcaa tgaggacgga aacgaaatct ttaacacgtc cctcttcgag 1620
ccgccaccgc ctggatacga gaacgtgtca gatatcgtgc ctccgttctc ggccttctcg 1680
ccccagggaa tgcccgaagg ggacctggtg tacgtgaact acgcaaggac cgaggacttc 1740
ttcaagttgg agcgggatat gaagatcaat tgcagcggaa agatcgtcat cgcccgctac 1800
ggcaaagtgt tccgcggcaa caaggtgaag aatgcacagt tggcaggcgc caagggcgtc 1860
atcctctact cggatcctgc cgactacttc gctcctggcg tgaaatccta ccctgatggt 1920
tggaatctgc caggaggagg ggtgcagagg ggaaatatcc tgaacctgaa cggtgccggt 1980
gacccactta ctccgggtta cccggccaac gaatacgcgt acaggcgggg tatcgcggaa 2040
gccgtcggac tgccgtccat cccggtccat ccgattggtt actacgacgc ccagaagctc 2100
ctcgaaaaga tgggaggcag cgcccctccg gactcgtcat ggagaggctc gctgaaggtg 2160
ccatacaacg tgggacccgg attcactgga aatttcagca ctcaaaaagt gaagatgcac 2220
attcactcca ctaacgaagt caccaggatc tacaacgtca tcggaaccct ccggggagcg 2280
gtggaaccgg accgctacgt gatcctcggt ggacaccggg atagctgggt gttcggagga 2340
atcgatcctc aatcgggcgc agccgtcgtc catgaaatcg tcaggtcctt tggtactctt 2400
aagaaggagg gctggcgccc tagacgcact attctgttcg cctcgtggga tgccgaagaa 2460
tttggtctgc tcggcagcac cgaatgggct gaggaaaact cccgcctgct ccaagaacgc 2520
ggagtggcgt acatcaatgc cgactcatcc atcgaaggaa actacacgct gcgggtggac 2580
tgcactccac tgatgtactc gctcgtgcac aacctgacca aagaactcaa atccccagac 2640
gaaggattcg agggaaaatc gctgtacgag tcgtggacca agaagagccc atccccggag 2700
ttcagcggga tgccgcggat ctcaaagctc ggatcaggaa atgatttcga agtgttcttt 2760
cagaggctgg gaattgcgtc gggaagggct cggtacacga aaaactggga aactaacaag 2820
ttctcgggat acccgctgta ccactcggtg tatgaaactt acgaactggt ggagaaattc 2880
tacgatccta tgtttaagta ccacctgact gtggcccaag tgagaggcgg aatggtgttc 2940
gagttggcca attcaattgt gctgccattc gattgccgcg actacgccgt ggtgctgaga 3000
aagtacgcag acaaaatcta ctcaatcagc atgaagcacc cacaagagat gaaaacctac 3060
tcagtctcct tcgactccct cttctccgcg gtgaagaact tcaccgagat cgcgagcaaa 3120
ttctcggagc gccttcaaga ttttgacaaa tccaatccga tcgtcctccg catgatgaat 3180
gaccagctca tgtttctcga acgggccttc atcgatccac tgggacttcc ggaccggccg 3240
ttttaccgcc acgtgatcta cgcgccctcg tcgcataaca agtatgctgg agagagcttc 3300
ccgggtatct acgacgcatt gttcgacatt gagtccaagg tggatccgtc caaagcctgg 3360
ggtgaagtga agcgccaaat ctacgtggcg gcctttaccg tccaggcggc agcagaaacc 3420
ttgagcgagg tggct 3435
<210> 62
<211> 7182
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic construct
<400> 62
ggcgtaatgc tctgccagtg ttacaaccaa ttaaccaatt ctgattagaa aaactcatcg 60
agcatcaaat gaaactgcaa tttattcata tcaggattat caataccata tttttgaaaa 120
agccgtttct gtaatgaagg agaaaactca ccgaggcagt tccataggat ggcaagatcc 180
tggtatcggt ctgcgattcc gactcgtcca acatcaatac aacctattaa tttcccctcg 240
tcaaaaataa ggttatcaag tgagaaatca ccatgagtga cgactgaatc cggtgagaat 300
ggcaaaagct tatgcatttc tttccagact tgttcaacag gccagccatt acgctcgtca 360
tcaaaatcac tcgcatcaac caaaccgtta ttcattcgtg attgcgcctg agcgagacga 420
aatacgcgat cgctgttaaa aggacaatta caaacaggaa tcaaatgcaa ccggcgcagg 480
aacactgcca gcgcatcaac aatattttca cctgaatcag gatattcttc taatacctgg 540
aatgctgttt tcccggggat cgcagtggtg agtaaccatg catcatcagg agtacggata 600
aaatgcttga tggtcggaag aggcataaat tccgtcagcc agtttagtct gaccatctca 660
tctgtaacat cattggcaac gctacctttg ccatgtttca gaaacaactc tggcgcatcg 720
ggcttcccat acaatcgata gattgtcgca cctgattgcc cgacattatc gcgagcccat 780
ttatacccat ataaatcagc atccatgttg gaatttaatc gcggcctcga gcaagacgtt 840
tcccgttgaa tatggctcat aacacccctt gtattactgt ttatgtaagc agacaggtcg 900
acaatattgg ctattggcca ttgcatacgt tgtatctata tcataatatg tacatttata 960
ttggctcatg tccaatatga ccgccatgtt gacattgatt attgactagt tattaatagt 1020
aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 1080
cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 1140
cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 1200
tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt ccgcccccta 1260
ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttacggg 1320
actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg gtgatgcggt 1380
tttggcagta caccaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 1440
accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 1500
gtcgtaataa ccccgccccg ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 1560
atataagcag agctcgttta gtgaaccgtc agatcgcctg gagacgccat ccacgctgtt 1620
ttgacctcca tagaagacac cgggaccgat ccagcctccg cggccgggaa cggtgcattg 1680
gaacgcggat tccccgtgcc aagagtgact caccgtccgg atctcagcaa gcaggtatgt 1740
actctccagg gtgggcctgg cttccccagt caagactcca gggatttgag ggacgctgtg 1800
ggctcttctc ttacatgtac cttttgcttg cctcaaccct gactatcttc caggtcagga 1860
tcccagagtc aggggtctgt attttcctgc tggtggctcc agttcaggaa cagtaaaccc 1920
tgctccgaat attgcctctc acatctcgtc aatctccgcg aggactgggg accctgtgac 1980
gaacatggct agcatcgtcg gagggtggga gtgcgaaaag cactcacagc catggcaggt 2040
cctggtcgcc tcgcgcggac gcgccgtgtg tggaggtgtg ctggtccacc cgcagtgggt 2100
gttgactgcg gcccattgca tcagaaataa gtccgtgatc ctcttgggga gacattccct 2160
gtttcacccc gaagatactg gacaggtgtt ccaagtgagc cactccttcc cgcatccact 2220
gtacgacatg agcctgctga agaaccgctt tctgcggcca ggggacgact catcacacga 2280
tttgatgctg cttcggctct cggaaccggc cgagctcacc gacgcagtga aggtcatgga 2340
cctccctacg caagagcctg ctctcggtac cacttgttac gcatcgggat ggggctccat 2400
cgagccggaa gaattcctga ccccgaaaaa gctgcagtgc gtggatctgc acgtgatttc 2460
gaatgacgtg tgcgcgcaag tgcatccaca aaaggtcact aagttcatgc tgtgcgccgg 2520
aaggtggacc ggcggaaaat cgacctgttc cggcgacagc ggaggcccac tcgtgtgcaa 2580
cggtgtgctg cagggcatca ctagctgggg atcagaaccg tgcgcgcttc cggagcggcc 2640
ctcgctctac acgaaggtgg tgcactaccg caaatggatt aaagatacca tcgtcgcaaa 2700
ccctggatcc gaaggtaggg gttcattatt gacctgtgga gatgtcgaag aaaacccagg 2760
acccgctagc aaagcagtgc tgctggcgct cctgatggct ggactcgcgc tgcagcctgg 2820
aaccgccctg ctctgttact cgtgcaaggc ccaagtctcg aatgaggact gtttgcaagt 2880
ggaaaactgc acccagctcg gagaacaatg ctggactgca cggatccgcg ctgtcggcct 2940
gctgaccgtg atctccaaag ggtgctcatt gaactgcgtg gacgatagcc aggactacta 3000
cgtgggaaag aagaatatca cttgttgcga cacggatctt tgcaacgcgt ccggagcgca 3060
cgccctgcag ccagcagccg ccattctggc cctgcttccg gccctggggt tgctgctctg 3120
gggtccgggc cagctcggat cccagaccct gaactttgat ctgctgaaac tggcaggcga 3180
tgtggaaagc aacccaggcc caatggctag cgctcgcaga ccgcggtggc tgtgtgcagg 3240
ggcgctcgtc ctggcgggtg gcttcttttt gctcggcttt cttttcggat ggttcatcaa 3300
atcgtcaaac gaagctacca atatcacccc gaagcacaac atgaaggcct ttctggatga 3360
gctgaaggct gagaacatta agaagttcct ctacaacttc acccagatcc cacatttggc 3420
gggcactgag cagaactttc agttggctaa gcagatccag agccagtgga aggaattcgg 3480
cctggactcc gtcgagctgg cgcattacga tgtgctgctg agctacccta ataagactca 3540
tccgaactat atctcgatta tcaatgagga cggaaacgaa atctttaaca cgtccctctt 3600
cgagccgcca ccgcctggat acgagaacgt gtcagatatc gtgcctccgt tctcggcctt 3660
ctcgccccag ggaatgcccg aaggggacct ggtgtacgtg aactacgcaa ggaccgagga 3720
cttcttcaag ttggagcggg atatgaagat caattgcagc ggaaagatcg tcatcgcccg 3780
ctacggcaaa gtgttccgcg gcaacaaggt gaagaatgca cagttggcag gcgccaaggg 3840
cgtcatcctc tactcggatc ctgccgacta cttcgctcct ggcgtgaaat cctaccctga 3900
tggttggaat ctgccaggag gaggggtgca gaggggaaat atcctgaacc tgaacggtgc 3960
cggtgaccca cttactccgg gttacccggc caacgaatac gcgtacaggc ggggtatcgc 4020
ggaagccgtc ggactgccgt ccatcccggt ccatccgatt ggttactacg acgcccagaa 4080
gctcctcgaa aagatgggag gcagcgcccc tccggactcg tcatggagag gctcgctgaa 4140
ggtgccatac aacgtgggac ccggattcac tggaaatttc agcactcaaa aagtgaagat 4200
gcacattcac tccactaacg aagtcaccag gatctacaac gtcatcggaa ccctccgggg 4260
agcggtggaa ccggaccgct acgtgatcct cggtggacac cgggatagct gggtgttcgg 4320
aggaatcgat cctcaatcgg gcgcagccgt cgtccatgaa atcgtcaggt cctttggtac 4380
tcttaagaag gagggctggc gccctagacg cactattctg ttcgcctcgt gggatgccga 4440
agaatttggt ctgctcggca gcaccgaatg ggctgaggaa aactcccgcc tgctccaaga 4500
acgcggagtg gcgtacatca atgccgactc atccatcgaa ggaaactaca cgctgcgggt 4560
ggactgcact ccactgatgt actcgctcgt gcacaacctg accaaagaac tcaaatcccc 4620
agacgaagga ttcgagggaa aatcgctgta cgagtcgtgg accaagaaga gcccatcccc 4680
ggagttcagc gggatgccgc ggatctcaaa gctcggatca ggaaatgatt tcgaagtgtt 4740
ctttcagagg ctgggaattg cgtcgggaag ggctcggtac acgaaaaact gggaaactaa 4800
caagttctcg ggatacccgc tgtaccactc ggtgtatgaa acttacgaac tggtggagaa 4860
attctacgat cctatgttta agtaccacct gactgtggcc caagtgagag gcggaatggt 4920
gttcgagttg gccaattcaa ttgtgctgcc attcgattgc cgcgactacg ccgtggtgct 4980
gagaaagtac gcagacaaaa tctactcaat cagcatgaag cacccacaag agatgaaaac 5040
ctactcagtc tccttcgact ccctcttctc cgcggtgaag aacttcaccg agatcgcgag 5100
caaattctcg gagcgccttc aagattttga caaatccaat ccgatcgtcc tccgcatgat 5160
gaatgaccag ctcatgtttc tcgaacgggc cttcatcgat ccactgggac ttccggaccg 5220
gccgttttac cgccacgtga tctacgcgcc ctcgtcgcat aacaagtatg ctggagagag 5280
cttcccgggt atctacgacg cattgttcga cattgagtcc aaggtggatc cgtccaaagc 5340
ctggggtgaa gtgaagcgcc aaatctacgt ggcggccttt accgtccagg cggcagcaga 5400
aaccttgagc gaggtggctt aaagatctgg gccctaacaa aacaaaaaga tggggttatt 5460
ccctaaactt catgggttac gtaattggaa gttgggggac attgccacaa gatcatattg 5520
tacaaaagat caaacactgt tttagaaaac ttcctgtaaa caggcctatt gattggaaag 5580
tatgtcaaag gattgtgggt cttttgggct ttgctgctcc atttacacaa tgtggatatc 5640
ctgccttaat gcctttgtat gcatgtatac aagctaaaca ggctttcact ttctcgccaa 5700
cttacaaggc ctttctaagt aaacagtaca tgaaccttta ccccgttgct cggcaacggc 5760
ctggtctgtg ccaagtgttt gctgacgcaa cccccactgg ctggggcttg gccataggcc 5820
atcagcgcat gcgtggaacc tttgtggctc ctctgccgat ccatactgcg gaactcctag 5880
ccgcttgttt tgctcgcagc cggtctggag caaagctcat aggaactgac aattctgtcg 5940
tcctctcgcg gaaatataca tcgtttcgat ctacgtatga tctttttccc tctgccaaaa 6000
attatgggga catcatgaag ccccttgagc atctgacttc tggctaataa aggaaattta 6060
ttttcattgc aatagtgtgt tggaattttt tgtgtctctc actcggaagg aattctgcat 6120
taatgaatcg gccaacgcgc ggggagaggc ggtttgcgta ttgggcgctc ttccgcttcc 6180
tcgctcactg actcgctgcg ctcggtcgtt cggctgcggc gagcggtatc agctcactca 6240
aaggcggtaa tacggttatc cacagaatca ggggataacg caggaaagaa catgtgagca 6300
aaaggccagc aaaaggccag gaaccgtaaa aaggccgcgt tgctggcgtt tttccatagg 6360
ctccgccccc ctgacgagca tcacaaaaat cgacgctcaa gtcagaggtg gcgaaacccg 6420
acaggactat aaagatacca ggcgtttccc cctggaagct ccctcgtgcg ctctcctgtt 6480
ccgaccctgc cgcttaccgg atacctgtcc gcctttctcc cttcgggaag cgtggcgctt 6540
tctcatagct cacgctgtag gtatctcagt tcggtgtagg tcgttcgctc caagctgggc 6600
tgtgtgcacg aaccccccgt tcagcccgac cgctgcgcct tatccggtaa ctatcgtctt 6660
gagtccaacc cggtaagaca cgacttatcg ccactggcag cagccactgg taacaggatt 6720
agcagagcga ggtatgtagg cggtgctaca gagttcttga agtggtggcc taactacggc 6780
tacactagaa gaacagtatt tggtatctgc gctctgctga agccagttac cttcggaaaa 6840
agagttggta gctcttgatc cggcaaacaa accaccgctg gtagcggtgg tttttttgtt 6900
tgcaagcagc agattacgcg cagaaaaaaa ggatctcaag aagatccttt gatcttttct 6960
acggggtctg acgctcagtg gaacgaaaac tcacgttaag ggattttggt catgagatta 7020
tcaaaaagga tcttcaccta gatcctttta aattaaaaat gaagttttaa atcaatctaa 7080
agtatatatg agtaaacttg gtctgacagt taccaatgct taatcagtga ggcacctatc 7140
tcagcgatct gtctatttcg ttcatccata gttgcctgac tc 7182
<210> 63
<211> 34803
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic organism
<400> 63
ccatcttcaa taatatacct caaacttttt gtgcgcgtta atatgcaaat gaggcgtttg 60
aatttgggga ggaagggcgg tgattggtcg agggatgagc gaccgttagg ggcggggcga 120
gtgacgtttt gatgacgtgg ttgcgaggag gagccagttt gcaagttctc gtgggaaaag 180
tgacgtcaaa cgaggtgtgg tttgaacacg gaaatactca attttcccgc gctctctgac 240
aggaaatgag gtgtttctgg gcggatgcaa gtgaaaacgg gccattttcg cgcgaaaact 300
gaatgaggaa gtgaaaatct gagtaatttc gcgtttatgg cagggaggag tatttgccga 360
gggccgagta gactttgacc gattacgtgg gggtttcgat taccgtgttt ttcacctaaa 420
tttccgcgta cggtgtcaaa gtccggtgtt tttactactg taatagtaat caattacggg 480
gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc 540
gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat 600
agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc 660
ccacttggca gtacatcaag tgtatcatat gccaagtacg ccccctattg acgtcaatga 720
cggtaaatgg cccgcctggc attatgccca gtacatgacc ttatgggact ttcctacttg 780
gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacat 840
caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt 900
caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaacaactc 960
cgccccattg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata taagcagagc 1020
tgtccctatc agtgatagag atctccctat cagtgataga gagtttagtg aaccgtcaga 1080
tccgctaggg taccaacatg gctagcatcg tcggagggtg ggagtgcgaa aagcactcac 1140
agccatggca ggtcctggtc gcctcgcgcg gacgcgccgt gtgtggaggt gtgctggtcc 1200
acccgcagtg ggtgttgact gcggcccatt gcatcagaaa taagtccgtg atcctcttgg 1260
ggagacattc cctgtttcac cccgaagata ctggacaggt gttccaagtg agccactcct 1320
tcccgcatcc actgtacgac atgagcctgc tgaagaaccg ctttctgcgg ccaggggacg 1380
actcatcaca cgatttgatg ctgcttcggc tctcggaacc ggccgagctc accgacgcag 1440
tgaaggtcat ggacctccct acgcaagagc ctgctctcgg taccacttgt tacgcatcgg 1500
gatggggctc catcgagccg gaagaattcc tgaccccgaa aaagctgcag tgcgtggatc 1560
tgcacgtgat ttcgaatgac gtgtgcgcgc aagtgcatcc acaaaaggtc actaagttca 1620
tgctgtgcgc cggaaggtgg accggcggaa aatcgacctg ttccggcgac agcggaggcc 1680
cactcgtgtg caacggtgtg ctgcagggca tcactagctg gggatcagaa ccgtgcgcgc 1740
ttccggagcg gccctcgctc tacacgaagg tggtgcacta ccgcaaatgg attaaagata 1800
ccatcgtcgc aaaccctgga tccgaaggta ggggttcatt attgacctgt ggagatgtcg 1860
aagaaaaccc aggacccgct agcaaagcag tgctgctggc gctcctgatg gctggactcg 1920
cgctgcagcc tggaaccgcc ctgctctgtt actcgtgcaa ggcccaagtc tcgaatgagg 1980
actgtttgca agtggaaaac tgcacccagc tcggagaaca atgctggact gcacggatcc 2040
gcgctgtcgg cctgctgacc gtgatctcca aagggtgctc attgaactgc gtggacgata 2100
gccaggacta ctacgtggga aagaagaata tcacttgttg cgacacggat ctttgcaacg 2160
cgtccggagc gcacgccctg cagccagcag ccgccattct ggccctgctt ccggccctgg 2220
ggttgctgct ctggggtccg ggccagctcg gatcccagac cctgaacttt gatctgctga 2280
aactggcagg cgatgtggaa agcaacccag gcccaatggc tagcgctcgc agaccgcggt 2340
ggctgtgtgc aggggcgctc gtcctggcgg gtggcttctt tttgctcggc tttcttttcg 2400
gatggttcat caaatcgtca aacgaagcta ccaatatcac cccgaagcac aacatgaagg 2460
cctttctgga tgagctgaag gctgagaaca ttaagaagtt cctctacaac ttcacccaga 2520
tcccacattt ggcgggcact gagcagaact ttcagttggc taagcagatc cagagccagt 2580
ggaaggaatt cggcctggac tccgtcgagc tggcgcatta cgatgtgctg ctgagctacc 2640
ctaataagac tcatccgaac tatatctcga ttatcaatga ggacggaaac gaaatcttta 2700
acacgtccct cttcgagccg ccaccgcctg gatacgagaa cgtgtcagat atcgtgcctc 2760
cgttctcggc cttctcgccc cagggaatgc ccgaagggga cctggtgtac gtgaactacg 2820
caaggaccga ggacttcttc aagttggagc gggatatgaa gatcaattgc agcggaaaga 2880
tcgtcatcgc ccgctacggc aaagtgttcc gcggcaacaa ggtgaagaat gcacagttgg 2940
caggcgccaa gggcgtcatc ctctactcgg atcctgccga ctacttcgct cctggcgtga 3000
aatcctaccc tgatggttgg aatctgccag gaggaggggt gcagagggga aatatcctga 3060
acctgaacgg tgccggtgac ccacttactc cgggttaccc ggccaacgaa tacgcgtaca 3120
ggcggggtat cgcggaagcc gtcggactgc cgtccatccc ggtccatccg attggttact 3180
acgacgccca gaagctcctc gaaaagatgg gaggcagcgc ccctccggac tcgtcatgga 3240
gaggctcgct gaaggtgcca tacaacgtgg gacccggatt cactggaaat ttcagcactc 3300
aaaaagtgaa gatgcacatt cactccacta acgaagtcac caggatctac aacgtcatcg 3360
gaaccctccg gggagcggtg gaaccggacc gctacgtgat cctcggtgga caccgggata 3420
gctgggtgtt cggaggaatc gatcctcaat cgggcgcagc cgtcgtccat gaaatcgtca 3480
ggtcctttgg tactcttaag aaggagggct ggcgccctag acgcactatt ctgttcgcct 3540
cgtgggatgc cgaagaattt ggtctgctcg gcagcaccga atgggctgag gaaaactccc 3600
gcctgctcca agaacgcgga gtggcgtaca tcaatgccga ctcatccatc gaaggaaact 3660
acacgctgcg ggtggactgc actccactga tgtactcgct cgtgcacaac ctgaccaaag 3720
aactcaaatc cccagacgaa ggattcgagg gaaaatcgct gtacgagtcg tggaccaaga 3780
agagcccatc cccggagttc agcgggatgc cgcggatctc aaagctcgga tcaggaaatg 3840
atttcgaagt gttctttcag aggctgggaa ttgcgtcggg aagggctcgg tacacgaaaa 3900
actgggaaac taacaagttc tcgggatacc cgctgtacca ctcggtgtat gaaacttacg 3960
aactggtgga gaaattctac gatcctatgt ttaagtacca cctgactgtg gcccaagtga 4020
gaggcggaat ggtgttcgag ttggccaatt caattgtgct gccattcgat tgccgcgact 4080
acgccgtggt gctgagaaag tacgcagaca aaatctactc aatcagcatg aagcacccac 4140
aagagatgaa aacctactca gtctccttcg actccctctt ctccgcggtg aagaacttca 4200
ccgagatcgc gagcaaattc tcggagcgcc ttcaagattt tgacaaatcc aatccgatcg 4260
tcctccgcat gatgaatgac cagctcatgt ttctcgaacg ggccttcatc gatccactgg 4320
gacttccgga ccggccgttt taccgccacg tgatctacgc gccctcgtcg cataacaagt 4380
atgctggaga gagcttcccg ggtatctacg acgcattgtt cgacattgag tccaaggtgg 4440
atccgtccaa agcctggggt gaagtgaagc gccaaatcta cgtggcggcc tttaccgtcc 4500
aggcggcagc agaaaccttg agcgaggtgg cttgactcga gcctaagctt ctagataaga 4560
tatccgatcc accggatcta gataactgat cataatcagc cataccacat ttgtagaggt 4620
tttacttgct ttaaaaaacc tcccacacct ccccctgaac ctgaaacata aaatgaatgc 4680
aattgttgtt gttaacttgt ttattgcagc ttataatggt tacaaataaa gcaatagcat 4740
cacaaatttc acaaataaag catttttttc actgcattct agttgtggtt tgtccaaact 4800
catcaatgta tcttatatgc tggccaccgt acatgtggct tcccatgctc gcaagccctg 4860
gcccgagttc gagcacaatg tcatgaccag gtgcaatatg catctggggt cccgccgagg 4920
catgttcatg ccctaccagt gcaacctgaa ttatgtgaag gtgctgctgg agcccgatgc 4980
catgtccaga gtgagcctga cgggggtgtt tgacatgaat gtggaggtgt ggaagattct 5040
gagatatgat gaatccaaga ccaggtgccg agcctgcgag tgcggaggga agcatgccag 5100
gttccagccc gtgtgtgtgg atgtgacgga ggacctgcga cccgatcatt tggtgttgcc 5160
ctgcaccggg acggagttcg gttccagcgg ggaagaatct gactagagtg agtagtgttc 5220
tggggcgggg gaggacctgc atgagggcca gaataactga aatctgtgct tttctgtgtg 5280
ttgcagcagc atgagcggaa gcggctcctt tgagggaggg gtattcagcc cttatctgac 5340
ggggcgtctc ccctcctggg cgggagtgcg tcagaatgtg atgggatcca cggtggacgg 5400
ccggcccgtg cagcccgcga actcttcaac cctgacctat gcaaccctga gctcttcgtc 5460
gttggacgca gctgccgccg cagctgctgc atctgccgcc agcgccgtgc gcggaatggc 5520
catgggcgcc ggctactacg gcactctggt ggccaactcg agttccacca ataatcccgc 5580
cagcctgaac gaggagaagc tgttgctgct gatggcccag ctcgaggcct tgacccagcg 5640
cctgggcgag ctgacccagc aggtggctca gctgcaggag cagacgcggg ccgcggttgc 5700
cacggtgaaa tccaaataaa aaatgaatca ataaataaac ggagacggtt gttgatttta 5760
acacagagtc tgaatcttta tttgattttt cgcgcgcggt aggccctgga ccaccggtct 5820
cgatcattga gcacccggtg gatcttttcc aggacccggt agaggtgggc ttggatgttg 5880
aggtacatgg gcatgagccc gtcccggggg tggaggtagc tccattgcag ggcctcgtgc 5940
tcgggggtgg tgttgtaaat cacccagtca tagcaggggc gcagggcatg gtgttgcaca 6000
atatctttga ggaggagact gatggccacg ggcagccctt tggtgtaggt gtttacaaat 6060
ctgttgagct gggagggatg catgcggggg gagatgaggt gcatcttggc ctggatcttg 6120
agattggcga tgttaccgcc cagatcccgc ctggggttca tgttgtgcag gaccaccagc 6180
acggtgtatc cggtgcactt ggggaattta tcatgcaact tggaagggaa ggcgtgaaag 6240
aatttggcga cgcctttgtg cccgcccagg ttttccatgc actcatccat gatgatggcg 6300
atgggcccgt gggcggcggc ctgggcaaag acgtttcggg ggtcggacac atcatagttg 6360
tggtcctggg tgaggtcatc ataggccatt ttaatgaatt tggggcggag ggtgccggac 6420
tgggggacaa aggtaccctc gatcccgggg gcgtagttcc cctcacagat ctgcatctcc 6480
caggctttga gctcggaggg ggggatcatg tccacctgcg gggcgataaa gaacacggtt 6540
tccggggcgg gggagatgag ctgggccgaa agcaagttcc ggagcagctg ggacttgccg 6600
cagccggtgg ggccgtagat gaccccgatg accggctgca ggtggtagtt gagggagaga 6660
cagctgccgt cctcccggag gaggggggcc acctcgttca tcatctcgcg cacgtgcatg 6720
ttctcgcgca ccagttccgc caggaggcgc tctcccccca gggataggag ctcctggagc 6780
gaggcgaagt ttttcagcgg cttgagtccg tcggccatgg gcattttgga gagggtttgt 6840
tgcaagagtt ccaggcggtc ccagagctcg gtgatgtgct ctacggcatc tcgatccagc 6900
agacctcctc gtttcgcggg ttgggacggc tgcgggagta gggcaccaga cgatgggcgt 6960
ccagcgcagc cagggtccgg tccttccagg gtcgcagcgt ccgcgtcagg gtggtctccg 7020
tcacggtgaa ggggtgcgcg ccgggctggg cgcttgcgag ggtgcgcttc aggctcatcc 7080
ggctggtcga aaaccgctcc cgatcggcgc cctgcgcgtc ggccaggtag caattgacca 7140
tgagttcgta gttgagcgcc tcggccgcgt ggcctttggc gcggagctta cctttggaag 7200
tctgcccgca ggcgggacag aggagggact tgagggcgta gagcttgggg gcgaggaaga 7260
cggactcggg ggcgtaggcg tccgcgccgc agtgggcgca gacggtctcg cactccacga 7320
gccaggtgag gtcgggctgg tcggggtcaa aaaccagttt cccgccgttc tttttgatgc 7380
gtttcttacc tttggtctcc atgagctcgt gtccccgctg ggtgacaaag aggctgtccg 7440
tgtccccgta gaccgacttt atgggccggt cctcgagcgg tgtgccgcgg tcctcctcgt 7500
agaggaaccc cgcccactcc gagacgaaag cccgggtcca ggccagcacg aaggaggcca 7560
cgtgggacgg gtagcggtcg ttgtccacca gcgggtccac cttttccagg gtatgcaaac 7620
acatgtcccc ctcgtccaca tccaggaagg tgattggctt gtaagtgtag gccacgtgac 7680
cgggggtccc ggccgggggg gtataaaagg gtgcgggtcc ctgctcgtcc tcactgtctt 7740
ccggatcgct gtccaggagc gccagctgtt ggggtaggta ttccctctcg aaggcgggca 7800
tgacctcggc actcaggttg tcagtttcta gaaacgagga ggatttgata ttgacggtgc 7860
cggcggagat gcctttcaag agcccctcgt ccatctggtc agaaaagacg atctttttgt 7920
tgtcgagctt ggtggcgaag gagccgtaga gggcgttgga gaggagcttg gcgatggagc 7980
gcatggtctg gtttttttcc ttgtcggcgc gctccttggc ggcgatgttg agctgcacgt 8040
actcgcgcgc cacgcacttc cattcgggga agacggtggt cagctcgtcg ggcacgattc 8100
tgacctgcca gccccgatta tgcagggtga tgaggtccac actggtggcc acctcgccgc 8160
gcaggggctc attagtccag cagaggcgtc cgcccttgcg cgagcagaag gggggcaggg 8220
ggtccagcat gacctcgtcg ggggggtcgg catcgatggt gaagatgccg ggcaggaggt 8280
cggggtcaaa gtagctgatg gaagtggcca gatcgtccag ggcagcttgc cattcgcgca 8340
cggccagcgc gcgctcgtag ggactgaggg gcgtgcccca gggcatggga tgggtaagcg 8400
cggaggcgta catgccgcag atgtcgtaga cgtagagggg ctcctcgagg atgccgatgt 8460
aggtggggta gcagcgcccc ccgcggatgc tggcgcgcac gtagtcatac agctcgtgcg 8520
agggggcgag gagccccggg cccaggttgg tgcgactggg cttttcggcg cggtagacga 8580
tctggcggaa aatggcatgc gagttggagg agatggtggg cctttggaag atgttgaagt 8640
gggcgtgggg cagtccgacc gagtcgcgga tgaagtgggc gtaggagtct tgcagcttgg 8700
cgacgagctc ggcggtgact aggacgtcca gagcgcagta gtcgagggtc tcctggatga 8760
tgtcatactt gagctgtccc ttttgtttcc acagctcgcg gttgagaagg aactcttcgc 8820
ggtccttcca gtactcttcg agggggaacc cgtcctgatc tgcacggtaa gagcctagca 8880
tgtagaactg gttgacggcc ttgtaggcgc agcagccctt ctccacgggg agggcgtagg 8940
cctgggcggc cttgcgcagg gaggtgtgcg tgagggcgaa agtgtccctg accatgacct 9000
tgaggaactg gtgcttgaag tcgatatcgt cgcagccccc ctgctcccag agctggaagt 9060
ccgtgcgctt cttgtaggcg gggttgggca aagcgaaagt aacatcgttg aagaggatct 9120
tgcccgcgcg gggcataaag ttgcgagtga tgcggaaagg ttggggcacc tcggcccggt 9180
tgttgatgac ctgggcggcg agcacgatct cgtcgaagcc gttgatgttg tggcccacga 9240
tgtagagttc cacgaatcgc ggacggccct tgacgtgggg cagtttcttg agctcctcgt 9300
aggtgagctc gtcggggtcg ctgagcccgt gctgctcgag cgcccagtcg gcgagatggg 9360
ggttggcgcg gaggaaggaa gtccagagat ccacggccag ggcggtttgc agacggtccc 9420
ggtactgacg gaactgctgc ccgacggcca ttttttcggg ggtgacgcag tagaaggtgc 9480
gggggtcccc gtgccagcga tcccatttga gctggagggc gagatcgagg gcgagctcga 9540
cgagccggtc gtccccggag agtttcatga ccagcatgaa ggggacgagc tgcttgccga 9600
aggaccccat ccaggtgtag gtttccacat cgtaggtgag gaagagcctt tcggtgcgag 9660
gatgcgagcc gatggggaag aactggatct cctgccacca attggaggaa tggctgttga 9720
tgtgatggaa gtagaaatgc cgacggcgcg ccgaacactc gtgcttgtgt ttatacaagc 9780
ggccacagtg ctcgcaacgc tgcacgggat gcacgtgctg cacgagctgt acctgagttc 9840
ctttgacgag gaatttcagt gggaagtgga gtcgtggcgc ctgcatctcg tgctgtacta 9900
cgtcgtggtg gtcggcctgg ccctcttctg cctcgatggt ggtcatgctg acgagcccgc 9960
gcgggaggca ggtccagacc tcggcgcgag cgggtcggag agcgaggacg agggcgcgca 10020
ggccggagct gtccagggtc ctgagacgct gcggagtcag gtcagtgggc agcggcggcg 10080
cgcggttgac ttgcaggagt ttttccaggg cgcgcgggag gtccagatgg tacttgatct 10140
ccaccgcgcc attggtggcg acgtcgatgg cttgcagggt cccgtgcccc tggggtgtga 10200
ccaccgtccc ccgtttcttc ttgggcggct ggggcgacgg gggcggtgcc tcttccatgg 10260
ttagaagcgg cggcgaggac gcgcgccggg cggcaggggc ggctcggggc ccggaggcag 10320
gggcggcagg ggcacgtcgg cgccgcgcgc gggtaggttc tggtactgcg cccggagaag 10380
actggcgtga gcgacgacgc gacggttgac gtcctggatc tgacgcctct gggtgaaggc 10440
cacgggaccc gtgagtttga acctgaaaga gagttcgaca gaatcaatct cggtatcgtt 10500
gacggcggcc tgccgcagga tctcttgcac gtcgcccgag ttgtcctggt aggcgatctc 10560
ggtcatgaac tgctcgatct cctcctcttg aaggtctccg cggccggcgc gctccacggt 10620
ggccgcgagg tcgttggaga tgcggcccat gagctgcgag aaggcgttca tgcccgcctc 10680
gttccagacg cggctgtaga ccacgacgcc ctcgggatcg cgggcgcgca tgaccacctg 10740
ggcgaggttg agctccacgt ggcgcgtgaa gaccgcgtag ttgcagaggc gctggtagag 10800
gtagttgagc gtggtggcga tgtgctcggt gacgaagaaa tacatgatcc agcggcggag 10860
cggcatctcg ctgacgtcgc ccagcgcctc caaacgttcc atggcctcgt aaaagtccac 10920
ggcgaagttg aaaaactggg agttgcgcgc cgagacggtc aactcctcct ccagaagacg 10980
gatgagctcg gcgatggtgg cgcgcacctc gcgctcgaag gcccccggga gttcctccac 11040
ttcctcttct tcctcctcca ctaacatctc ttctacttcc tcctcaggcg gcagtggtgg 11100
cgggggaggg ggcctgcgtc gccggcggcg cacgggcaga cggtcgatga agcgctcgat 11160
ggtctcgccg cgccggcgtc gcatggtctc ggtgacggcg cgcccgtcct cgcggggccg 11220
cagcgtgaag acgccgccgc gcatctccag gtggccgggg gggtccccgt tgggcaggga 11280
gagggcgctg acgatgcatc ttatcaattg ccccgtaggg actccgcgca aggacctgag 11340
cgtctcgaga tccacgggat ctgaaaaccg ctgaacgaag gcttcgagcc agtcgcagtc 11400
gcaaggtagg ctgagcacgg tttcttctgg cgggtcatgt tggttgggag cggggcgggc 11460
gatgctgctg gtgatgaagt tgaaataggc ggttctgaga cggcggatgg tggcgaggag 11520
caccaggtct ttgggcccgg cttgctggat gcgcagacgg tcggccatgc cccaggcgtg 11580
gtcctgacac ctggccaggt ccttgtagta gtcctgcatg agccgctcca cgggcacctc 11640
ctcctcgccc gcgcggccgt gcatgcgcgt gagcccgaag ccgcgctggg gctggacgag 11700
cgccaggtcg gcgacgacgc gctcggcgag gatggcttgc tggatctggg tgagggtggt 11760
ctggaagtca tcaaagtcga cgaagcggtg gtaggctccg gtgttgatgg tgtaggagca 11820
gttggccatg acggaccagt tgacggtctg gtggcccgga cgcacgagct cgtggtactt 11880
gaggcgcgag taggcgcgcg tgtcgaagat gtagtcgttg caggtgcgca ccaggtactg 11940
gtagccgatg aggaagtgcg gcggcggctg gcggtagagc ggccatcgct cggtggcggg 12000
ggcgccgggc gcgaggtcct cgagcatggt gcggtggtag ccgtagatgt acctggacat 12060
ccaggtgatg ccggcggcgg tggtggaggc gcgcgggaac tcgcggacgc ggttccagat 12120
gttgcgcagc ggcaggaagt agttcatggt gggcacggtc tggcccgtga ggcgcgcgca 12180
gtcgtggatg ctctatacgg gcaaaaacga aagcggtcag cggctcgact ccgtggcctg 12240
gaggctaagc gaacgggttg ggctgcgcgt gtaccccggt tcgaatctcg aatcaggctg 12300
gagccgcagc taacgtggta ttggcactcc cgtctcgacc caagcctgca ccaaccctcc 12360
aggatacgga ggcgggtcgt tttgcaactt ttttttggag gccggatgag actagtaagc 12420
gcggaaagcg gccgaccgcg atggctcgct gccgtagtct ggagaagaat cgccagggtt 12480
gcgttgcggt gtgccccggt tcgaggccgg ccggattccg cggctaacga gggcgtggct 12540
gccccgtcgt ttccaagacc ccatagccag ccgacttctc cagttacgga gcgagcccct 12600
cttttgtttt gtttgttttt gccagatgca tcccgtactg cggcagatgc gcccccacca 12660
ccctccaccg caacaacagc cccctccaca gccggcgctt ctgcccccgc cccagcagca 12720
acttccagcc acgaccgccg cggccgccgt gagcggggct ggacagagtt atgatcacca 12780
gctggccttg gaagagggcg aggggctggc gcgcctgggg gcgtcgtcgc cggagcggca 12840
cccgcgcgtg cagatgaaaa gggacgctcg cgaggcctac gtgcccaagc agaacctgtt 12900
cagagacagg agcggcgagg agcccgagga gatgcgcgcg gcccggttcc acgcggggcg 12960
ggagctgcgg cgcggcctgg accgaaagag ggtgctgagg gacgaggatt tcgaggcgga 13020
cgagctgacg gggatcagcc ccgcgcgcgc gcacgtggcc gcggccaacc tggtcacggc 13080
gtacgagcag accgtgaagg aggagagcaa cttccaaaaa tccttcaaca accacgtgcg 13140
caccctgatc gcgcgcgagg aggtgaccct gggcctgatg cacctgtggg acctgctgga 13200
ggccatcgtg cagaacccca ccagcaagcc gctgacggcg cagctgttcc tggtggtgca 13260
gcatagtcgg gacaacgaag cgttcaggga ggcgctgctg aatatcaccg agcccgaggg 13320
ccgctggctc ctggacctgg tgaacattct gcagagcatc gtggtgcagg agcgcgggct 13380
gccgctgtcc gagaagctgg cggccatcaa cttctcggtg ctgagtttgg gcaagtacta 13440
cgctaggaag atctacaaga ccccgtacgt gcccatagac aaggaggtga agatcgacgg 13500
gttttacatg cgcatgaccc tgaaagtgct gaccctgagc gacgatctgg gggtgtaccg 13560
caacgacagg atgcaccgtg cggtgagcgc cagcaggcgg cgcgagctga gcgaccagga 13620
gctgatgcat agtctgcagc gggccctgac cggggccggg accgaggggg agagctactt 13680
tgacatgggc gcggacctgc actggcagcc cagccgccgg gccttggagg cggcggcagg 13740
accctacgta gaagaggtgg acgatgaggt ggacgaggag ggcgagtacc tggaagactg 13800
atggcgcgac cgtatttttg ctagatgcaa caacaacagc cacctcctga tcccgcgatg 13860
cgggcggcgc tgcagagcca gccgtccggc attaactcct cggacgattg gacccaggcc 13920
atgcaacgca tcatggcgct gacgacccgc aaccccgaag cctttagaca gcagccccag 13980
gccaaccggc tctcggccat cctggaggcc gtggtgccct cgcgctccaa ccccacgcac 14040
gagaaggtcc tggccatcgt gaacgcgctg gtggagaaca aggccatccg cggcgacgag 14100
gccggcctgg tgtacaacgc gctgctggag cgcgtggccc gctacaacag caccaacgtg 14160
cagaccaacc tggaccgcat ggtgaccgac gtgcgcgagg ccgtggccca gcgcgagcgg 14220
ttccaccgcg agtccaacct gggatccatg gtggcgctga acgccttcct cagcacccag 14280
cccgccaacg tgccccgggg ccaggaggac tacaccaact tcatcagcgc cctgcgcctg 14340
atggtgaccg aggtgcccca gagcgaggtg taccagtccg ggccggacta cttcttccag 14400
accagtcgcc agggcttgca gaccgtgaac ctgagccagg ctttcaagaa cttgcagggc 14460
ctgtggggcg tgcaggcccc ggtcggggac cgcgcgacgg tgtcgagcct gctgacgccg 14520
aactcgcgcc tgctgctgct gctggtggcc cccttcacgg acagcggcag catcaaccgc 14580
aactcgtacc tgggctacct gattaacctg taccgcgagg ccatcggcca ggcgcacgtg 14640
gacgagcaga cctaccagga gatcacccac gtgagccgcg ccctgggcca ggacgacccg 14700
ggcaacctgg aagccaccct gaactttttg ctgaccaacc ggtcgcagaa gatcccgccc 14760
cagtacgcgc tcagcaccga ggaggagcgc atcctgcgtt acgtgcagca gagcgtgggc 14820
ctgttcctga tgcaggaggg ggccaccccc agcgccgcgc tcgacatgac cgcgcgcaac 14880
atggagccca gcatgtacgc cagcaaccgc ccgttcatca ataaactgat ggactacttg 14940
catcgggcgg ccgccatgaa ctctgactat ttcaccaacg ccatcctgaa tccccactgg 15000
ctcccgccgc cggggttcta cacgggcgag tacgacatgc ccgaccccaa tgacgggttc 15060
ctgtgggacg atgtggacag cagcgtgttc tccccccgac cgggtgctaa cgagcgcccc 15120
ttgtggaaga aggaaggcag cgaccgacgc ccgtcctcgg cgctgtccgg ccgcgagggt 15180
gctgccgcgg cggtgcccga ggccgccagt cctttcccga gcttgccctt ctcgctgaac 15240
agtatccgca gcagcgagct gggcaggatc acgcgcccgc gcttgctggg cgaagaggag 15300
tacttgaatg actcgctgtt gagacccgag cgggagaaga acttccccaa taacgggata 15360
gaaagcctgg tggacaagat gagccgctgg aagacgtatg cgcaggagca cagggacgat 15420
ccccgggcgt cgcagggggc cacgagccgg ggcagcgccg cccgtaaacg ccggtggcac 15480
gacaggcagc ggggacagat gtgggacgat gaggactccg ccgacgacag cagcgtgttg 15540
gacttgggtg ggagtggtaa cccgttcgct cacctgcgcc cccgtatcgg gcgcatgatg 15600
taagagaaac cgaaaataaa tgatactcac caaggccatg gcgaccagcg tgcgttcgtt 15660
tcttctctgt tgttgttgta tctagtatga tgaggcgtgc gtacccggag ggtcctcctc 15720
cctcgtacga gagcgtgatg cagcaggcga tggcggcggc ggcgatgcag cccccgctgg 15780
aggctcctta cgtgcccccg cggtacctgg cgcctacgga ggggcggaac agcattcgtt 15840
actcggagct ggcacccttg tacgatacca cccggttgta cctggtggac aacaagtcgg 15900
cggacatcgc ctcgctgaac taccagaacg accacagcaa cttcctgacc accgtggtgc 15960
agaacaatga cttcaccccc acggaggcca gcacccagac catcaacttt gacgagcgct 16020
cgcggtgggg cggccagctg aaaaccatca tgcacaccaa catgcccaac gtgaacgagt 16080
tcatgtacag caacaagttc aaggcgcggg tgatggtctc ccgcaagacc cccaatgggg 16140
tgacagtgac agaggattat gatggtagtc aggatgagct gaagtatgaa tgggtggaat 16200
ttgagctgcc cgaaggcaac ttctcggtga ccatgaccat cgacctgatg aacaacgcca 16260
tcatcgacaa ttacttggcg gtggggcggc agaacggggt gctggagagc gacatcggcg 16320
tgaagttcga cactaggaac ttcaggctgg gctgggaccc cgtgaccgag ctggtcatgc 16380
ccggggtgta caccaacgag gctttccatc ccgatattgt cttgctgccc ggctgcgggg 16440
tggacttcac cgagagccgc ctcagcaacc tgctgggcat tcgcaagagg cagcccttcc 16500
aggaaggctt ccagatcatg tacgaggatc tggagggggg caacatcccc gcgctcctgg 16560
atgtcgacgc ctatgagaaa agcaaggagg atgcagcagc tgaagcaact gcagccgtag 16620
ctaccgcctc taccgaggtc aggggcgata attttgcaag cgccgcagca gtggcagcgg 16680
ccgaggcggc tgaaaccgaa agtaagatag tcattcagcc ggtggagaag gatagcaaga 16740
acaggagcta caacgtacta ccggacaaga taaacaccgc ctaccgcagc tggtacctag 16800
cctacaacta tggcgacccc gagaagggcg tgcgctcctg gacgctgctc accacctcgg 16860
acgtcacctg cggcgtggag caagtctact ggtcgctgcc cgacatgatg caagacccgg 16920
tcaccttccg ctccacgcgt caagttagca actacccggt ggtgggcgcc gagctcctgc 16980
ccgtctactc caagagcttc ttcaacgagc aggccgtcta ctcgcagcag ctgcgcgcct 17040
tcacctcgct tacgcacgtc ttcaaccgct tccccgagaa ccagatcctc gtccgcccgc 17100
ccgcgcccac cattaccacc gtcagtgaaa acgttcctgc tctcacagat cacgggaccc 17160
tgccgctgcg cagcagtatc cggggagtcc agcgcgtgac cgttactgac gccagacgcc 17220
gcacctgccc ctacgtctac aaggccctgg gcatagtcgc gccgcgcgtc ctctcgagcc 17280
gcaccttcta aatgtccatt ctcatctcgc ccagtaataa caccggttgg ggcctgcgcg 17340
cgcccagcaa gatgtacgga ggcgctcgcc aacgctccac gcaacacccc gtgcgcgtgc 17400
gcgggcactt ccgcgctccc tggggcgccc tcaagggccg cgtgcggtcg cgcaccaccg 17460
tcgacgacgt gatcgaccag gtggtggccg acgcgcgcaa ctacaccccc gccgccgcgc 17520
ccgtctccac cgtggacgcc gtcatcgaca gcgtggtggc cgacgcgcgc cggtacgccc 17580
gcgccaagag ccggcggcgg cgcatcgccc ggcggcaccg gagcaccccc gccatgcgcg 17640
cggcgcgagc cttgctgcgc agggccaggc gcacgggacg cagggccatg ctcagggcgg 17700
ccagacgcgc ggcttcaggc gccagcgccg gcaggacccg gagacgcgcg gccacggcgg 17760
cggcagcggc catcgccagc atgtcccgcc cgcggcgagg gaacgtgtac tgggtgcgcg 17820
acgccgccac cggtgtgcgc gtgcccgtgc gcacccgccc ccctcgcact tgaagatgtt 17880
cacttcgcga tgttgatgtg tcccagcggc gaggaggatg tccaagcgca aattcaagga 17940
agagatgctc caggtcatcg cgcctgagat ctacggccct gcggtggtga aggaggaaag 18000
aaagccccgc aaaatcaagc gggtcaaaaa ggacaaaaag gaagaagaaa gtgatgtgga 18060
cggattggtg gagtttgtgc gcgagttcgc cccccggcgg cgcgtgcagt ggcgcgggcg 18120
gaaggtgcaa ccggtgctga gacccggcac caccgtggtc ttcacgcccg gcgagcgctc 18180
cggcaccgct tccaagcgct cctacgacga ggtgtacggg gatgatgata ttctggagca 18240
ggcggccgag cgcctgggcg agtttgctta cggcaagcgc agccgttccg caccgaagga 18300
agaggcggtg tccatcccgc tggaccacgg caaccccacg ccgagcctca agcccgtgac 18360
cttgcagcag gtgctgccga ccgcggcgcc gcgccggggg ttcaagcgcg agggcgagga 18420
tctgtacccc accatgcagc tgatggtgcc caagcgccag aagctggaag acgtgctgga 18480
gaccatgaag gtggacccgg acgtgcagcc cgaggtcaag gtgcggccca tcaagcaggt 18540
ggccccgggc ctgggcgtgc agaccgtgga catcaagatt cccacggagc ccatggaaac 18600
gcagaccgag cccatgatca agcccagcac cagcaccatg gaggtgcaga cggatccctg 18660
gatgccatcg gctcctagtc gaagaccccg gcgcaagtac ggcgcggcca gcctgctgat 18720
gcccaactac gcgctgcatc cttccatcat ccccacgccg ggctaccgcg gcacgcgctt 18780
ctaccgcggt cataccagca gccgccgccg caagaccacc actcgccgcc gccgtcgccg 18840
caccgccgct gcaaccaccc ctgccgccct ggtgcggaga gtgtaccgcc gcggccgcgc 18900
acctctgacc ctgccgcgcg cgcgctacca cccgagcatc gccatttaaa ctttcgcctg 18960
ctttgcagat caatggccct cacatgccgc cttcgcgttc ccattacggg ctaccgagga 19020
agaaaaccgc gccgtagaag gctggcgggg aacgggatgc gtcgccacca ccaccggcgg 19080
cggcgcgcca tcagcaagcg gttgggggga ggcttcctgc ccgcgctgat ccccatcatc 19140
gccgcggcga tcggggcgat ccccggcatt gcttccgtgg cggtgcaggc ctctcagcgc 19200
cactgagaca cacttggaaa catcttgtaa taaaccaatg gactctgacg ctcctggtcc 19260
tgtgatgtgt tttcgtagac agatggaaga catcaatttt tcgtccctgg ctccgcgaca 19320
cggcacgcgg ccgttcatgg gcacctggag cgacatcggc accagccaac tgaacggggg 19380
cgccttcaat tggagcagtc tctggagcgg gcttaagaat ttcgggtcca cgcttaaaac 19440
ctatggcagc aaggcgtgga acagcaccac agggcaggcg ctgagggata agctgaaaga 19500
gcagaacttc cagcagaagg tggtcgatgg gctcgcctcg ggcatcaacg gggtggtgga 19560
cctggccaac caggccgtgc agcggcagat caacagccgc ctggacccgg tgccgcccgc 19620
cggctccgtg gagatgccgc aggtggagga ggagctgcct cccctggaca agcggggcga 19680
gaagcgaccc cgccccgatg cggaggagac gctgctgacg cacacggacg agccgccccc 19740
gtacgaggag gcggtgaaac tgggtctgcc caccacgcgg cccatcgcgc ccctggccac 19800
cggggtgctg aaacccgaaa agcccgcgac cctggacttg cctcctcccc agccttcccg 19860
cccctctaca gtggctaagc ccctgccgcc ggtggccgtg gcccgcgcgc gacccggggg 19920
caccgcccgc cctcatgcga actggcagag cactctgaac agcatcgtgg gtctgggagt 19980
gcagagtgtg aagcgccgcc gctgctatta aacctaccgt agcgcttaac ttgcttgtct 20040
gtgtgtgtat gtattatgtc gccgccgccg ctgtccacca gaaggaggag tgaagaggcg 20100
cgtcgccgag ttgcaagatg gccaccccat cgatgctgcc ccagtgggcg tacatgcaca 20160
tcgccggaca ggacgcttcg gagtacctga gtccgggtct ggtgcagttt gcccgcgcca 20220
cagacaccta cttcagtctg gggaacaagt ttaggaaccc cacggtggcg cccacgcacg 20280
atgtgaccac cgaccgcagc cagcggctga cgctgcgctt cgtgcccgtg gaccgcgagg 20340
acaacaccta ctcgtacaaa gtgcgctaca cgctggccgt gggcgacaac cgcgtgctgg 20400
acatggccag cacctacttt gacatccgcg gcgtgctgga tcggggccct agcttcaaac 20460
cctactccgg caccgcctac aacagtctgg cccccaaggg agcacccaac acttgtcagt 20520
ggacatataa agccgatggt gaaactgcca cagaaaaaac ctatacatat ggaaatgcac 20580
ccgtgcaggg cattaacatc acaaaagatg gtattcaact tggaactgac accgatgatc 20640
agccaatcta cgcagataaa acctatcagc ctgaacctca agtgggtgat gctgaatggc 20700
atgacatcac tggtactgat gaaaagtatg gaggcagagc tcttaagcct gataccaaaa 20760
tgaagccttg ttatggttct tttgccaagc ctactaataa agaaggaggt caggcaaatg 20820
tgaaaacagg aacaggcact actaaagaat atgacataga catggctttc tttgacaaca 20880
gaagtgcggc tgctgctggc ctagctccag aaattgtttt gtatactgaa aatgtggatt 20940
tggaaactcc agatacccat attgtataca aagcaggcac agatgacagc agctcttcta 21000
ttaatttggg tcagcaagcc atgcccaaca gacctaacta cattggtttc agagacaact 21060
ttatcgggct catgtactac aacagcactg gcaatatggg ggtgctggcc ggtcaggctt 21120
ctcagctgaa tgctgtggtt gacttgcaag acagaaacac cgagctgtcc taccagctct 21180
tgcttgactc tctgggtgac agaacccggt atttcagtat gtggaatcag gcggtggaca 21240
gctatgatcc tgatgtgcgc attattgaaa atcatggtgt ggaggatgaa cttcccaact 21300
attgtttccc tctggatgct gttggcagaa cagatactta tcagggaatt aaggctaatg 21360
gaactgatca aaccacatgg accaaagatg acagtgtcaa tgatgctaat gagataggca 21420
agggtaatcc attcgccatg gaaatcaaca tccaagccaa cctgtggagg aacttcctct 21480
acgccaacgt ggccctgtac ctgcccgact cttacaagta cacgccggcc aatgttaccc 21540
tgcccaccaa caccaacacc tacgattaca tgaacggccg ggtggtggcg ccctcgctgg 21600
tggactccta catcaacatc ggggcgcgct ggtcgctgga tcccatggac aacgtgaacc 21660
ccttcaacca ccaccgcaat gcggggctgc gctaccgctc catgctcctg ggcaacgggc 21720
gctacgtgcc cttccacatc caggtgcccc agaaattttt cgccatcaag agcctcctgc 21780
tcctgcccgg gtcctacacc tacgagtgga acttccgcaa ggacgtcaac atgatcctgc 21840
agagctccct cggcaacgac ctgcgcacgg acggggcctc catctccttc accagcatca 21900
acctctacgc caccttcttc cccatggcgc acaacacggc ctccacgctc gaggccatgc 21960
tgcgcaacga caccaacgac cagtccttca acgactacct ctcggcggcc aacatgctct 22020
accccatccc ggccaacgcc accaacgtgc ccatctccat cccctcgcgc aactgggccg 22080
ccttccgcgg ctggtccttc acgcgtctca agaccaagga gacgccctcg ctgggctccg 22140
ggttcgaccc ctacttcgtc tactcgggct ccatccccta cctcgacggc accttctacc 22200
tcaaccacac cttcaagaag gtctccatca ccttcgactc ctccgtcagc tggcccggca 22260
acgaccggct cctgacgccc aacgagttcg aaatcaagcg caccgtcgac ggcgagggct 22320
acaacgtggc ccagtgcaac atgaccaagg actggttcct ggtccagatg ctggcccact 22380
acaacatcgg ctaccagggc ttctacgtgc ccgagggcta caaggaccgc atgtactcct 22440
tcttccgcaa cttccagccc atgagccgcc aggtggtgga cgaggtcaac tacaaggact 22500
accaggccgt caccctggcc taccagcaca acaactcggg cttcgtcggc tacctcgcgc 22560
ccaccatgcg ccagggccag ccctaccccg ccaactaccc ctacccgctc atcggcaaga 22620
gcgccgtcac cagcgtcacc cagaaaaagt tcctctgcga cagggtcatg tggcgcatcc 22680
ccttctccag caacttcatg tccatgggcg cgctcaccga cctcggccag aacatgctct 22740
atgccaactc cgcccacgcg ctagacatga atttcgaagt cgaccccatg gatgagtcca 22800
cccttctcta tgttgtcttc gaagtcttcg acgtcgtccg agtgcaccag ccccaccgcg 22860
gcgtcatcga ggccgtctac ctgcgcaccc ccttctcggc cggtaacgcc accacctaag 22920
ctcttgcttc ttgcaagcca tggccgcggg ctccggcgag caggagctca gggccatcat 22980
ccgcgacctg ggctgcgggc cctacttcct gggcaccttc gataagcgct tcccgggatt 23040
catggccccg cacaagctgg cctgcgccat cgtcaacacg gccggccgcg agaccggggg 23100
cgagcactgg ctggccttcg cctggaaccc gcgctcgaac acctgctacc tcttcgaccc 23160
cttcgggttc tcggacgagc gcctcaagca gatctaccag ttcgagtacg agggcctgct 23220
gcgccgcagc gccctggcca ccgaggaccg ctgcgtcacc ctggaaaagt ccacccagac 23280
cgtgcagggt ccgcgctcgg ccgcctgcgg gctcttctgc tgcatgttcc tgcacgcctt 23340
cgtgcactgg cccgaccgcc ccatggacaa gaaccccacc atgaacttgc tgacgggggt 23400
gcccaacggc atgctccagt cgccccaggt ggaacccacc ctgcgccgca accaggaggc 23460
gctctaccgc ttcctcaact cccactccgc ctactttcgc tcccaccgcg cgcgcatcga 23520
gaaggccacc gccttcgacc gcatgaatca agacatgtaa accgtgtgtg tatgttaaat 23580
gtctttaata aacagcactt tcatgttaca catgcatctg agatgattta tttagaaatc 23640
gaaagggttc tgccgggtct cggcatggcc cgcgggcagg gacacgttgc ggaactggta 23700
cttggccagc cacttgaact cggggatcag cagtttgggc agcggggtgt cggggaagga 23760
gtcggtccac agcttccgcg tcagttgcag ggcgcccagc aggtcgggcg cggagatctt 23820
gaaatcgcag ttgggacccg cgttctgcgc gcgggagttg cggtacacgg ggttgcagca 23880
ctggaacacc atcagggccg ggtgcttcac gctcgccagc accgtcgcgt cggtgatgct 23940
ctccacgtcg aggtcctcgg cgttggccat cccgaagggg gtcatcttgc aggtctgcct 24000
tcccatggtg ggcacgcacc cgggcttgtg gttgcaatcg cagtgcaggg ggatcagcat 24060
catctgggcc tggtcggcgt tcatccccgg gtacatggcc ttcatgaaag cctccaattg 24120
cctgaacgcc tgctgggcct tggctccctc ggtgaagaag accccgcagg acttgctaga 24180
gaactggttg gtggcgcacc cggcgtcgtg cacgcagcag cgcgcgtcgt tgttggccag 24240
ctgcaccacg ctgcgccccc agcggttctg ggtgatcttg gcccggtcgg ggttctcctt 24300
cagcgcgcgc tgcccgttct cgctcgccac atccatctcg atcatgtgct ccttctggat 24360
catggtggtc ccgtgcaggc accgcagctt gccctcggcc tcggtgcacc cgtgcagcca 24420
cagcgcgcac ccggtgcact cccagttctt gtgggcgatc tgggaatgcg cgtgcacgaa 24480
gccctgcagg aagcggccca tcatggtggt cagggtcttg ttgctagtga aggtcagcgg 24540
aatgccgcgg tgctcctcgt tgatgtacag gtggcagatg cggcggtaca cctcgccctg 24600
ctcgggcatc agctggaagt tggctttcag gtcggtctcc acgcggtagc ggtccatcag 24660
catagtcatg atttccatac ccttctccca ggccgagacg atgggcaggc tcatagggtt 24720
cttcaccatc atcttagcgc tagcagccgc ggccaggggg tcgctctcgt ccagggtctc 24780
aaagctccgc ttgccgtcct tctcggtgat ccgcaccggg gggtagctga agcccacggc 24840
cgccagctcc tcctcggcct gtctttcgtc ctcgctgtcc tggctgacgt cctgcaggac 24900
cacatgcttg gtcttgcggg gtttcttctt gggcggcagc ggcggcggag atgttggaga 24960
tggcgagggg gagcgcgagt tctcgctcac cactactatc tcttcctctt cttggtccga 25020
ggccacgcgg cggtaggtat gtctcttcgg gggcagaggc ggaggcgacg ggctctcgcc 25080
gccgcgactt ggcggatggc tggcagagcc ccttccgcgt tcgggggtgc gctcccggcg 25140
gcgctctgac tgacttcctc cgcggccggc cattgtgttc tcctagggag gaacaacaag 25200
catggagact cagccatcgc caacctcgcc atctgccccc accgccgacg agaagcagca 25260
gcagcagaat gaaagcttaa ccgccccgcc gcccagcccc gccacctccg acgcggccgt 25320
cccagacatg caagagatgg aggaatccat cgagattgac ctgggctatg tgacgcccgc 25380
ggagcacgag gaggagctgg cagtgcgctt ttcacaagaa gagatacacc aagaacagcc 25440
agagcaggaa gcagagaatg agcagagtca ggctgggctc gagcatgacg gcgactacct 25500
ccacctgagc gggggggagg acgcgctcat caagcatctg gcccggcagg ccaccatcgt 25560
caaggatgcg ctgctcgacc gcaccgaggt gcccctcagc gtggaggagc tcagccgcgc 25620
ctacgagttg aacctcttct cgccgcgcgt gccccccaag cgccagccca atggcacctg 25680
cgagcccaac ccgcgcctca acttctaccc ggtcttcgcg gtgcccgagg ccctggccac 25740
ctaccacatc tttttcaaga accaaaagat ccccgtctcc tgccgcgcca accgcacccg 25800
cgccgacgcc cttttcaacc tgggtcccgg cgcccgccta cctgatatcg cctccttgga 25860
agaggttccc aagatcttcg agggtctggg cagcgacgag actcgggccg cgaacgctct 25920
gcaaggagaa ggaggagagc atgagcacca cagcgccctg gtcgagttgg aaggcgacaa 25980
cgcgcggctg gcggtgctca aacgcacggt cgagctgacc catttcgcct acccggctct 26040
gaacctgccc cccaaagtca tgagcgcggt catggaccag gtgctcatca agcgcgcgtc 26100
gcccatctcc gaggacgagg gcatgcaaga ctccgaggag ggcaagcccg tggtcagcga 26160
cgagcagctg gcccggtggc tgggtcctaa tgctagtccc cagagtttgg aagagcggcg 26220
caaactcatg atggccgtgg tcctggtgac cgtggagctg gagtgcctgc gccgcttctt 26280
cgccgacgcg gagaccctgc gcaaggtcga ggagaacctg cactacctct tcaggcacgg 26340
gttcgtgcgc caggcctgca agatctccaa cgtggagctg accaacctgg tctcctacat 26400
gggcatcttg cacgagaacc gcctggggca gaacgtgctg cacaccaccc tgcgcgggga 26460
ggcccggcgc gactacatcc gcgactgcgt ctacctctac ctctgccaca cctggcagac 26520
gggcatgggc gtgtggcagc agtgtctgga ggagcagaac ctgaaagagc tctgcaagct 26580
cctgcagaag aacctcaagg gtctgtggac cgggttcgac gagcgcacca ccgcctcgga 26640
cctggccgac ctcattttcc ccgagcgcct caggctgacg ctgcgcaacg gcctgcccga 26700
ctttatgagc caaagcatgt tgcaaaactt tcgctctttc atcctcgaac gctccggaat 26760
cctgcccgcc acctgctccg cgctgccctc ggacttcgtg ccgctgacct tccgcgagtg 26820
ccccccgccg ctgtggagcc actgctacct gctgcgcctg gccaactacc tggcctacca 26880
ctcggacgtg atcgaggacg tcagcggcga gggcctgctc gagtgccact gccgctgcaa 26940
cctctgcacg ccgcaccgct ccctggcctg caacccccag ctgctgagcg agacccagat 27000
catcggcacc ttcgagttgc aagggcccag cgaaggcgag ggttcagccg ccaagggggg 27060
tctgaaactc accccggggc tgtggacctc ggcctacttg cgcaagttcg tgcccgagga 27120
ctaccatccc ttcgagatca ggttctacga ggaccaatcc catccgccca aggccgagct 27180
gtcggcctgc gtcatcaccc agggggcgat cctggcccaa ttgcaagcca tccagaaatc 27240
ccgccaagaa ttcttgctga aaaagggccg cggggtctac ctcgaccccc agaccggtga 27300
ggagctcaac cccggcttcc cccaggatgc cccgaggaaa caagaagctg aaagtggagc 27360
tgccgcccgt ggaggatttg gaggaagact gggagaacag cagtcaggca gaggaggagg 27420
agatggagga agactgggac agcactcagg cagaggagga cagcctgcaa gacagtctgg 27480
aggaagacga ggaggaggca gaggaggagg tggaagaagc agccgccgcc agaccgtcgt 27540
cctcggcggg ggagaaagca agcagcacgg ataccatctc cgctccgggt cggggtcccg 27600
ctcgaccaca cagtagatgg gacgagaccg gacgattccc gaaccccacc acccagaccg 27660
gtaagaagga gcggcaggga tacaagtcct ggcgggggca caaaaacgcc atcgtctcct 27720
gcttgcaggc ctgcgggggc aacatctcct tcacccggcg ctacctgctc ttccaccgcg 27780
gggtgaactt tccccgcaac atcttgcatt actaccgtca cctccacagc ccctactact 27840
tccaagaaga ggcagcagca gcagaaaaag accagcagaa aaccagcagc tagaaaatcc 27900
acagcggcgg cagcaggtgg actgaggatc gcggcgaacg agccggcgca aacccgggag 27960
ctgaggaacc ggatctttcc caccctctat gccatcttcc agcagagtcg ggggcaggag 28020
caggaactga aagtcaagaa ccgttctctg cgctcgctca cccgcagttg tctgtatcac 28080
aagagcgaag accaacttca gcgcactctc gaggacgccg aggctctctt caacaagtac 28140
tgcgcgctca ctcttaaaga gtagcccgcg cccgcccagt cgcagaaaaa ggcgggaatt 28200
acgtcacctg tgcccttcgc cctagccgcc tccacccatc atcatgagca aagagattcc 28260
cacgccttac atgtggagct accagcccca gatgggcctg gccgccggtg ccgcccagga 28320
ctactccacc cgcatgaatt ggctcagcgc cgggcccgcg atgatctcac gggtgaatga 28380
catccgcgcc caccgaaacc agatactcct agaacagtca gcgctcaccg ccacgccccg 28440
caatcacctc aatccgcgta attggcccgc cgccctggtg taccaggaaa ttccccagcc 28500
cacgaccgta ctacttccgc gagacgccca ggccgaagtc cagctgacta actcaggtgt 28560
ccagctggcg ggcggcgcca ccctgtgtcg tcaccgcccc gctcagggta taaagcggct 28620
ggtgatccgg ggcagaggca cacagctcaa cgacgaggtg gtgagctctt cgctgggtct 28680
gcgacctgac ggagtcttcc aactcgccgg atcggggaga tcttccttca cgcctcgtca 28740
ggccgtcctg actttggaga gttcgtcctc gcagccccgc tcgggtggca tcggcactct 28800
ccagttcgtg gaggagttca ctccctcggt ctacttcaac cccttctccg gctcccccgg 28860
ccactacccg gacgagttca tcccgaactt cgacgccatc agcgagtcgg tggacggcta 28920
cgattgaatg tcccatggtg gcgcagctga cctagctcgg cttcgacacc tggaccactg 28980
ccgccgcttc cgctgcttcg ctcgggatct cgccgagttt gcctactttg agctgcccga 29040
ggagcaccct cagggcccgg cccacggagt gcggatcgtc gtcgaagggg gcctcgactc 29100
ccacctgctt cggatcttca gccagcgtcc gatcctggtc gagcgcgagc aaggacagac 29160
ccttctgact ctgtactgca tctgcaacca ccccggcctg catgaaagtc tttgttgtct 29220
gctgtgtact gagtataata aaagctgaga tcagcgacta ctccggactt ccgtgtgttc 29280
ctgaatccat caaccagtct ttgttcttca ccgggaacga gaccgagctc cagctccagt 29340
gtaagcccca caagaagtac ctcacctggc tgttccaggg ctccccgatc gccgttgtca 29400
accactgcga caacgacgga gtcctgctga gcggccctgc caaccttact ttttccaccc 29460
gcagaagcaa gctccagctc ttccaaccct tcctccccgg gacctatcag tgcgtctcgg 29520
gaccctgcca tcacaccttc cacctgatcc cgaataccac agcgtcgctc cccgctacta 29580
acaaccaaac taacctccac caacgccacc gtcgctaggc cacaatacat gcccatatta 29640
gactatgagg ccgagccaca gcgacccatg ctccccgcta ttagttactt caatctaacc 29700
ggcggagatg actgacccac tggccaacaa caacgtcaac gaccttctcc tggacatgga 29760
cggccgcgcc tcggagcagc gactcgccca acttcgcatt cgccagcagc aggagagagc 29820
cgtcaaggag ctgcaggatg cggtggccat ccaccagtgc aagagaggca tcttctgcct 29880
ggtgaaacag gccaagatct cctacgaggt cactccaaac gaccatcgcc tctcctacga 29940
gctcctgcag cagcgccaga agttcacctg cctggtcgga gtcaacccca tcgtcatcac 30000
ccagcagtct ggcgatacca aggggtgcat ccactgctcc tgcgactccc ccgactgcgt 30060
ccacactctg atcaagaccc tctgcggcct ccgcgacctc ctccccatga actaatcacc 30120
cccttatcca gtgaaataaa gatcatattg atgatgattt tacagaaata aaaaataatc 30180
atttgatttg aaataaagat acaatcatat tgatgatttg agtttaacaa aaaaataaag 30240
aatcacttac ttgaaatctg ataccaggtc tctgtccatg ttttctgcca acaccacttc 30300
actcccctct tcccagctct ggtactgcag gccccggcgg gctgcaaact tcctccacac 30360
gctgaagggg atgtcaaatt cctcctgtcc ctcaatcttc attttatctt ctatcagatg 30420
tccaaaaagc gcgtccgggt ggatgatgac ttcgaccccg tctaccccta cgatgcagac 30480
aacgcaccga ccgtgccctt catcaacccc cccttcgtct cttcagatgg attccaagag 30540
aagcccctgg gggtgttgtc cctgcgactg gccgaccccg tcaccaccaa gaacggggaa 30600
atcaccctca agctgggaga gggggtggac ctcgattcct cgggaaaact catctccaac 30660
acggccacca aggccgccgc ccctctcagt ttttccaaca acaccatttc ccttaacatg 30720
gatcacccct tttacactaa agatggaaaa ttatccttac aagtttctcc accattaaat 30780
atactgagaa caagcattct aaacacacta gctttaggtt ttggatcagg tttaggactc 30840
cgtggctctg ccttggcagt acagttagtc tctccactta catttgatac tgatggaaac 30900
ataaagctta ccttagacag aggtttgcat gttacaacag gagatgcaat tgaaagcaac 30960
ataagctggg ctaaaggttt aaaatttgaa gatggagcca tagcaaccaa cattggaaat 31020
gggttagagt ttggaagcag tagtacagaa acaggtgttg atgatgctta cccaatccaa 31080
gttaaacttg gatctggcct tagctttgac agtacaggag ccataatggc tggtaacaaa 31140
gaagacgata aactcacttt gtggacaaca cctgatccat caccaaactg tcaaatactc 31200
gcagaaaatg atgcaaaact aacactttgc ttgactaaat gtggtagtca aatactggcc 31260
actgtgtcag tcttagttgt aggaagtgga aacctaaacc ccattactgg caccgtaagc 31320
agtgctcagg tgtttctacg ttttgatgca aacggtgttc ttttaacaga acattctaca 31380
ctaaaaaaat actgggggta taggcaggga gatagcatag atggcactcc atataccaat 31440
gctgtaggat tcatgcccaa tttaaaagct tatccaaagt cacaaagttc tactactaaa 31500
aataatatag tagggcaagt atacatgaat ggagatgttt caaaacctat gcttctcact 31560
ataaccctca atggtactga tgacagcaac agtacatatt caatgtcatt ttcatacacc 31620
tggactaatg gaagctatgt tggagcaaca tttggggcta actcttatac cttctcatac 31680
atcgcccaag aatgaacact gtatcccacc ctgcatgcca acccttccca ccccactctg 31740
tggaacaaac tctgaaacac aaaataaaat aaagttcaag tgttttattg attcaacagt 31800
tttacaggat tcgagcagtt atttttcctc caccctccca ggacatggaa tacaccaccc 31860
tctccccccg cacagccttg aacatctgaa tgccattggt gatggacatg cttttggtct 31920
ccacgttcca cacagtttca gagcgagcca gtctcgggtc ggtcagggag atgaaaccct 31980
ccgggcactc ccgcatctgc acctcacagc tcaacagctg aggattgtcc tcggtggtcg 32040
ggatcacggt tatctggaag aagcagaaga gcggcggtgg gaatcatagt ccgcgaacgg 32100
gatcggccgg tggtgtcgca tcaggccccg cagcagtcgc tgccgccgcc gctccgtcaa 32160
gctgctgctc agggggtccg ggtccaggga ctccctcagc atgatgccca cggccctcag 32220
catcagtcgt ctggtgcggc gggcgcagca gcgcatgcgg atctcgctca ggtcgctgca 32280
gtacgtgcaa cacagaacca ccaggttgtt caacagtcca tagttcaaca cgctccagcc 32340
gaaactcatc gcgggaagga tgctacccac gtggccgtcg taccagatcc tcaggtaaat 32400
caagtggtgc cccctccaga acacgctgcc cacgtacatg atctccttgg gcatgtggcg 32460
gttcaccacc tcccggtacc acatcaccct ctggttgaac atgcagcccc ggatgatcct 32520
gcggaaccac agggccagca ccgccccgcc cgccatgcag cgaagagacc ccgggtcccg 32580
gcaatggcaa tggaggaccc accgctcgta cccgtggatc atctgggagc tgaacaagtc 32640
tatgttggca cagcacaggc atatgctcat gcatctcttc agcactctca actcctcggg 32700
ggtcaaaacc atatcccagg gcacggggaa ctcttgcagg acagcgaacc ccgcagaaca 32760
gggcaatcct cgcacagaac ttacattgtg catggacagg gtatcgcaat caggcagcac 32820
cgggtgatcc tccaccagag aagcgcgggt ctcggtctcc tcacagcgtg gtaagggggc 32880
cggccgatac gggtgatggc gggacgcggc tgatcgtgtt cgcgaccgtg tcatgatgca 32940
gttgctttcg gacattttcg tacttgctgt agcagaacct ggtccgggcg ctgcacaccg 33000
atcgccggcg gcggtctcgg cgcttggaac gctcggtgtt gaaattgtaa aacagccact 33060
ctctcagacc gtgcagcaga tctagggcct caggagtgat gaagatccca tcatgcctga 33120
tggctctgat cacatcgacc accgtggaat gggccagacc cagccagatg atgcaatttt 33180
gttgggtttc ggtgacggcg ggggagggaa gaacaggaag aaccatgatt aacttttaat 33240
ccaaacggtc tcggagtact tcaaaatgaa gatcgcggag atggcacctc tcgcccccgc 33300
tgtgttggtg gaaaataaca gccaggtcaa aggtgatacg gttctcgaga tgttccacgg 33360
tggcttccag caaagcctcc acgcgcacat ccagaaacaa gacaatagcg aaagcgggag 33420
ggttctctaa ttcctcaatc atcatgttac actcctgcac catccccaga taattttcat 33480
ttttccagcc ttgaatgatt cgaactagtt cctgaggtaa atccaagcca gccatgataa 33540
agagctcgcg cagagcgccc tccaccggca ttcttaagca caccctcata attccaagat 33600
attctgctcc tggttcacct gcagcagatt gacaagcgga atatcaaaat ctctgccgcg 33660
atccctgagc tcctccctca gcaataactg taagtactct ttcatatcct ctccgaaatt 33720
tttagccata ggaccaccag gaataagatt agggcaagcc acagtacaga taaaccgaag 33780
tcctccccag tgagcattgc caaatgcaag actgctataa gcatgctggc tagacccggt 33840
gatatcttcc agataactgg acagaaaatc gcccaggcaa tttttaagaa aatcaacaaa 33900
agaaaaatcc tccaggtgga cgtttagagc ctcgggaaca acgatgaagt aaatgcaagc 33960
ggtgcgttcc agcatggtta gttagctgat ctgtagaaaa aacaaaaatg aacattaaac 34020
catgctagcc tggcgaacag gtgggtaaat cgttctctcc agcaccaggc aggccacggg 34080
gtctccggcg cgaccctcgt aaaaattgtc gctatgattg aaaaccatca cagagagacg 34140
ttcccggtgg ccggcgtgaa tgattcgaca agatgaatac acccccggaa cattggcgtc 34200
cgcgagtgaa aaaaagcgcc cgaggaagca ataaggcact acaatgctca gtctcaagtc 34260
cagcaaagcg atgccatgcg gatgaagcac aaaattctca ggtgcgtaca aaatgtaatt 34320
actcccctcc tgcacaggca gcaaagcccc cgatccctcc aggtacacat acaaagcctc 34380
agcgtccata gcttaccgag cagcagcaca caacaggcgc aagagtcaga gaaaggctga 34440
gctctaacct gtccacccgc tctctgctca atatatagcc cagatctaca ctgacgtaaa 34500
ggccaaagtc taaaaatacc cgccaaataa tcacacacgc ccagcacacg cccagaaacc 34560
ggtgacacac tcaaaaaaat acgcgcactt cctcaaacgc ccaaaactgc cgtcatttcc 34620
gggttcccac gctacgtcat caaaacacga ctttcaaatt ccgtcgaccg ttaaaaacgt 34680
cacccgcccc gcccctaacg gtcgcccgtc tctcagccaa tcagcgcccc gcatccccaa 34740
attcaaacgc ctcatttgca tattaacgcg cacaaaaagt ttgaggtata ttattgatga 34800
tgg 34803
<210> 64
<211> 1145
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 64
Met Ala Ser Ile Val Gly Gly Trp Glu Cys Glu Lys His Ser Gln Pro
1 5 10 15
Trp Gln Val Leu Val Ala Ser Arg Gly Arg Ala Val Cys Gly Gly Val
20 25 30
Leu Val His Pro Gln Trp Val Leu Thr Ala Ala His Cys Ile Arg Asn
35 40 45
Lys Ser Val Ile Leu Leu Gly Arg His Ser Leu Phe His Pro Glu Asp
50 55 60
Thr Gly Gln Val Phe Gln Val Ser His Ser Phe Pro His Pro Leu Tyr
65 70 75 80
Asp Met Ser Leu Leu Lys Asn Arg Phe Leu Arg Pro Gly Asp Asp Ser
85 90 95
Ser His Asp Leu Met Leu Leu Arg Leu Ser Glu Pro Ala Glu Leu Thr
100 105 110
Asp Ala Val Lys Val Met Asp Leu Pro Thr Gln Glu Pro Ala Leu Gly
115 120 125
Thr Thr Cys Tyr Ala Ser Gly Trp Gly Ser Ile Glu Pro Glu Glu Phe
130 135 140
Leu Thr Pro Lys Lys Leu Gln Cys Val Asp Leu His Val Ile Ser Asn
145 150 155 160
Asp Val Cys Ala Gln Val His Pro Gln Lys Val Thr Lys Phe Met Leu
165 170 175
Cys Ala Gly Arg Trp Thr Gly Gly Lys Ser Thr Cys Ser Gly Asp Ser
180 185 190
Gly Gly Pro Leu Val Cys Asn Gly Val Leu Gln Gly Ile Thr Ser Trp
195 200 205
Gly Ser Glu Pro Cys Ala Leu Pro Glu Arg Pro Ser Leu Tyr Thr Lys
210 215 220
Val Val His Tyr Arg Lys Trp Ile Lys Asp Thr Ile Val Ala Asn Pro
225 230 235 240
Gly Ser Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val
245 250 255
Glu Ser Asn Pro Gly Pro Met Ala Ser Ala Arg Arg Pro Arg Trp Leu
260 265 270
Cys Ala Gly Ala Leu Val Leu Ala Gly Gly Phe Phe Leu Leu Gly Phe
275 280 285
Leu Phe Gly Trp Phe Ile Lys Ser Ser Asn Glu Ala Thr Asn Ile Thr
290 295 300
Pro Lys His Asn Met Lys Ala Phe Leu Asp Glu Leu Lys Ala Glu Asn
305 310 315 320
Ile Lys Lys Phe Leu Tyr Asn Phe Thr Gln Ile Pro His Leu Ala Gly
325 330 335
Thr Glu Gln Asn Phe Gln Leu Ala Lys Gln Ile Gln Ser Gln Trp Lys
340 345 350
Glu Phe Gly Leu Asp Ser Val Glu Leu Ala His Tyr Asp Val Leu Leu
355 360 365
Ser Tyr Pro Asn Lys Thr His Pro Asn Tyr Ile Ser Ile Ile Asn Glu
370 375 380
Asp Gly Asn Glu Ile Phe Asn Thr Ser Leu Phe Glu Pro Pro Pro Pro
385 390 395 400
Gly Tyr Glu Asn Val Ser Asp Ile Val Pro Pro Phe Ser Ala Phe Ser
405 410 415
Pro Gln Gly Met Pro Glu Gly Asp Leu Val Tyr Val Asn Tyr Ala Arg
420 425 430
Thr Glu Asp Phe Phe Lys Leu Glu Arg Asp Met Lys Ile Asn Cys Ser
435 440 445
Gly Lys Ile Val Ile Ala Arg Tyr Gly Lys Val Phe Arg Gly Asn Lys
450 455 460
Val Lys Asn Ala Gln Leu Ala Gly Ala Lys Gly Val Ile Leu Tyr Ser
465 470 475 480
Asp Pro Ala Asp Tyr Phe Ala Pro Gly Val Lys Ser Tyr Pro Asp Gly
485 490 495
Trp Asn Leu Pro Gly Gly Gly Val Gln Arg Gly Asn Ile Leu Asn Leu
500 505 510
Asn Gly Ala Gly Asp Pro Leu Thr Pro Gly Tyr Pro Ala Asn Glu Tyr
515 520 525
Ala Tyr Arg Arg Gly Ile Ala Glu Ala Val Gly Leu Pro Ser Ile Pro
530 535 540
Val His Pro Ile Gly Tyr Tyr Asp Ala Gln Lys Leu Leu Glu Lys Met
545 550 555 560
Gly Gly Ser Ala Pro Pro Asp Ser Ser Trp Arg Gly Ser Leu Lys Val
565 570 575
Pro Tyr Asn Val Gly Pro Gly Phe Thr Gly Asn Phe Ser Thr Gln Lys
580 585 590
Val Lys Met His Ile His Ser Thr Asn Glu Val Thr Arg Ile Tyr Asn
595 600 605
Val Ile Gly Thr Leu Arg Gly Ala Val Glu Pro Asp Arg Tyr Val Ile
610 615 620
Leu Gly Gly His Arg Asp Ser Trp Val Phe Gly Gly Ile Asp Pro Gln
625 630 635 640
Ser Gly Ala Ala Val Val His Glu Ile Val Arg Ser Phe Gly Thr Leu
645 650 655
Lys Lys Glu Gly Trp Arg Pro Arg Arg Thr Ile Leu Phe Ala Ser Trp
660 665 670
Asp Ala Glu Glu Phe Gly Leu Leu Gly Ser Thr Glu Trp Ala Glu Glu
675 680 685
Asn Ser Arg Leu Leu Gln Glu Arg Gly Val Ala Tyr Ile Asn Ala Asp
690 695 700
Ser Ser Ile Glu Gly Asn Tyr Thr Leu Arg Val Asp Cys Thr Pro Leu
705 710 715 720
Met Tyr Ser Leu Val His Asn Leu Thr Lys Glu Leu Lys Ser Pro Asp
725 730 735
Glu Gly Phe Glu Gly Lys Ser Leu Tyr Glu Ser Trp Thr Lys Lys Ser
740 745 750
Pro Ser Pro Glu Phe Ser Gly Met Pro Arg Ile Ser Lys Leu Gly Ser
755 760 765
Gly Asn Asp Phe Glu Val Phe Phe Gln Arg Leu Gly Ile Ala Ser Gly
770 775 780
Arg Ala Arg Tyr Thr Lys Asn Trp Glu Thr Asn Lys Phe Ser Gly Tyr
785 790 795 800
Pro Leu Tyr His Ser Val Tyr Glu Thr Tyr Glu Leu Val Glu Lys Phe
805 810 815
Tyr Asp Pro Met Phe Lys Tyr His Leu Thr Val Ala Gln Val Arg Gly
820 825 830
Gly Met Val Phe Glu Leu Ala Asn Ser Ile Val Leu Pro Phe Asp Cys
835 840 845
Arg Asp Tyr Ala Val Val Leu Arg Lys Tyr Ala Asp Lys Ile Tyr Ser
850 855 860
Ile Ser Met Lys His Pro Gln Glu Met Lys Thr Tyr Ser Val Ser Phe
865 870 875 880
Asp Ser Leu Phe Ser Ala Val Lys Asn Phe Thr Glu Ile Ala Ser Lys
885 890 895
Phe Ser Glu Arg Leu Gln Asp Phe Asp Lys Ser Asn Pro Ile Val Leu
900 905 910
Arg Met Met Asn Asp Gln Leu Met Phe Leu Glu Arg Ala Phe Ile Asp
915 920 925
Pro Leu Gly Leu Pro Asp Arg Pro Phe Tyr Arg His Val Ile Tyr Ala
930 935 940
Pro Ser Ser His Asn Lys Tyr Ala Gly Glu Ser Phe Pro Gly Ile Tyr
945 950 955 960
Asp Ala Leu Phe Asp Ile Glu Ser Lys Val Asp Pro Ser Lys Ala Trp
965 970 975
Gly Glu Val Lys Arg Gln Ile Tyr Val Ala Ala Phe Thr Val Gln Ala
980 985 990
Ala Ala Glu Thr Leu Ser Glu Val Ala Gly Ser Glu Gly Arg Gly Ser
995 1000 1005
Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Ala Ser
1010 1015 1020
Lys Ala Val Leu Leu Ala Leu Leu Met Ala Gly Leu Ala Leu Gln
1025 1030 1035
Pro Gly Thr Ala Leu Leu Cys Tyr Ser Cys Lys Ala Gln Val Ser
1040 1045 1050
Asn Glu Asp Cys Leu Gln Val Glu Asn Cys Thr Gln Leu Gly Glu
1055 1060 1065
Gln Cys Trp Thr Ala Arg Ile Arg Ala Val Gly Leu Leu Thr Val
1070 1075 1080
Ile Ser Lys Gly Cys Ser Leu Asn Cys Val Asp Asp Ser Gln Asp
1085 1090 1095
Tyr Tyr Val Gly Lys Lys Asn Ile Thr Cys Cys Asp Thr Asp Leu
1100 1105 1110
Cys Asn Ala Ser Gly Ala His Ala Leu Gln Pro Ala Ala Ala Ile
1115 1120 1125
Leu Ala Leu Leu Pro Ala Leu Gly Leu Leu Leu Trp Gly Pro Gly
1130 1135 1140
Gln Leu
1145
<210> 65
<211> 246
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 65
atggctagca tcgtcggagg gtgggagtgc gaaaagcact cacagccatg gcaggtcctg 60
gtcgcctcgc gcggacgcgc cgtgtgtgga ggtgtgctgg tccacccgca gtgggtgttg 120
actgcggccc attgcatcag aaataagtcc gtgatcctct tggggagaca ttccctgttt 180
caccccgaag atactggaca ggtgttccaa gtgagccact ccttcccgca tccactgtac 240
gacatg 246
<210> 66
<211> 245
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 66
atggctagca aagcagtgct gctggcgctc ctgatggctg gactcgcgct gcagcctgga 60
accgccctgc tctgttactc gtgcaaggcc caagtctcga atgaggactg tttgcaagtg 120
gaaaactgca cccagctcgg agaacaatgc tggactgcac ggatccgcgc tgtcggcctg 180
ctgaccgtga tctccaaagg gtgctcattg aactgcgtgg acgatagcca ggactactac 240
gtggg 245
Claims (24)
- (a) C68 뉴클레오티드 서열; 및
(b) 면역원성 PSA 폴리펩티드를 코딩하는 적어도 하나의 뉴클레오티드 서열, 면역원성 PSCA 폴리펩티드를 코딩하는 적어도 하나의 뉴클레오티드 서열, 및 면역원성 PSMA 폴리펩티드를 코딩하는 적어도 하나의 뉴클레오티드 서열을 포함하는 다중-항원 구축물을 포함하고,
여기서 면역원성 PSA 폴리펩티드는 서열 15의 아미노산 27-263 또는 서열 17의 아미노산 4-240을 포함하는 다중-항원 구축물을 포함하는 것이고,
면역원성 PSMA 폴리펩티드가
1) 서열 1의 아미노산 15-750을 포함하는 폴리펩티드;
2) 서열 3의 아미노산 서열을 포함하는 폴리펩티드;
3) 서열 5의 아미노산 서열을 포함하는 폴리펩티드;
4) 서열 7의 아미노산 서열을 포함하는 폴리펩티드;
5) 서열 9의 아미노산 4-739를 포함하는 폴리펩티드;
6) 서열 3의 아미노산 4-739를 포함하는 폴리펩티드;
7) 서열 5의 아미노산 4-739를 포함하는 폴리펩티드;
8) 서열 7의 아미노산 4-739를 포함하는 폴리펩티드; 및
9) 서열 9의 아미노산 서열을 포함하는 폴리펩티드
로 이루어진 군으로부터 선택되는 것인,
C68 벡터. - 제1항에 있어서, C68 뉴클레오티드 서열이 E1A, E1B, E2A, E2B, E3, E4, L1, L2, L3, L4 및 L5 유전자로 이루어진 군으로부터 선택되는 적어도 하나의 유전자가 결여된 서열 57의 서열이고, 면역원성 PSCA 폴리펩티드가 서열 21의 아미노산 서열 또는 서열 21의 아미노산 4-125를 포함하는 것이고, 면역원성 PSMA 폴리펩티드가 서열 1의 아미노산 15-750을 포함하는 것인 C68 벡터.
- 제1항에 있어서, C68 뉴클레오티드 서열이 E1A, E1B, 및 E3의 유전자가 결여된 서열 57의 서열이고, 다중-항원 구축물이 2개의 상이한 면역원성 폴리펩티드를 코딩하는 2개의 뉴클레오티드 서열 사이에 분리자 서열을 추가로 포함하고 하기 식 (I)의 구조를 갖는 것인 C68 벡터.
PAA1-SS1-PAA2-SS2-PAA3 (I)
식 (I)에서,
(i) PAA1, PAA2, 및 PAA3이 상이한 PAA 폴리펩티드를 코딩할 경우, PAA1, PAA2, 및 PAA3은 각각 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열, 면역원성 PSCA 폴리펩티드를 코딩하는 뉴클레오티드 서열, 또는 면역원성 PSMA 폴리펩티드를 코딩하는 뉴클레오티드 서열이고,
(ii) SS1 및 SS2는 분리자 서열이며, 동일하거나 상이할 수 있다. - 제3항에 있어서, 분리자 서열이 2A 펩티드 서열 및 IRES로부터 선택되는 것인 C68 벡터.
- 제4항에 있어서, 2A 펩티드 서열이 FMDV, ERAV, PTV1, EMC-B, EMCV, TME-GD7, ERBV, TaV, DrosC, CrPV, ABPV, IFV, 돼지 로타바이러스, 인간 로타바이러스, 티. 브루세이(T. brucei) TSR1, 및 티. 크루지(T. cruzi) AP 엔도뉴클레아제의 2A-펩티드 서열로 이루어진 군으로부터 선택되고; IRES가 EMCV IRES인 C68 벡터.
- 제5항에 있어서, 식 (I)에서 PAA1이 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열, 또는 면역원성 PSCA 폴리펩티드를 코딩하는 뉴클레오티드 서열인 C68 벡터.
- 제6항에 있어서,
(i) PAA1이 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열이고;
(ii) PAA2가 면역원성 PSCA 또는 PSMA 폴리펩티드를 코딩하는 뉴클레오티드 서열이고;
(iii) SS1이 2A-펩티드 서열이고;
(iv) SS2가 2A-펩티드 서열 또는 EMCV IRES인 C68 벡터. - 제7항에 있어서, 2A-펩티드 서열이 FMDV 2A-펩티드 서열 또는 TAV 2A-펩티드 서열인 C68 벡터.
- 제1항에 있어서,
(1) 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열이 (i) 서열 18의 뉴클레오티드 서열; (ii) 서열 20의 뉴클레오티드 서열; (iii) 서열 18의 뉴클레오티드 10-720을 포함하는 뉴클레오티드 서열; (iv) 서열 58의 뉴클레오티드 1115-1825를 포함하는 뉴클레오티드 서열; 및 (v) 서열 58의 뉴클레오티드 1106-1825를 포함하는 뉴클레오티드 서열로 이루어진 군으로부터 선택되고;
(2) 면역원성 PSCA 폴리펩티드를 코딩하는 뉴클레오티드 서열이 (i) 서열 22의 뉴클레오티드 서열; (ii) 서열 58의 뉴클레오티드 1892-2257을 포함하는 뉴클레오티드 서열; 및 (iii) 서열 58의 뉴클레오티드 1886-2257을 포함하는 뉴클레오티드 서열로 이루어진 군으로부터 선택되고;
(3) 면역원성 PSMA 폴리펩티드를 코딩하는 뉴클레오티드 서열이 (i) 서열 2의 뉴클레오티드 43-2250을 포함하는 뉴클레오티드 서열; (ii) 서열 4의 뉴클레오티드 서열; (iii) 서열 6의 뉴클레오티드 서열; (iv) 서열 8의 뉴클레오티드 서열; (v) 서열 10의 뉴클레오티드 서열; (vi) 서열 4의 뉴클레오티드 10-2217을 포함하는 뉴클레오티드 서열; (vii) 서열 6의 뉴클레오티드 10-2217을 포함하는 뉴클레오티드 서열; (viii) 서열 8의 뉴클레오티드 10-2217을 포함하는 뉴클레오티드 서열; (ix) 서열 10의 뉴클레오티드 10-2217을 포함하는 뉴클레오티드 서열; (x) 서열 58의 뉴클레오티드 2333-4543을 포함하는 뉴클레오티드 서열; 및 (xi) 서열 58의 뉴클레오티드 2324-4543을 포함하는 뉴클레오티드 서열로 이루어진 군으로부터 선택되는 것인 C68 벡터. - 제3항에 있어서, 식 (I)에서
(1) PAA1이 면역원성 PSA 폴리펩티드를 코딩하는 뉴클레오티드 서열이고, 서열 58의 뉴클레오티드 1115-1825를 포함하거나 서열 58의 1106-1825를 포함하고;
(2) PAA2가 면역원성 PSCA 폴리펩티드를 코딩하는 뉴클레오티드 서열이고, 서열 58의 뉴클레오티드 1892-2257을 포함하거나 서열 58의 1886-2257을 포함하고;
(3) PAA3이 면역원성 PSMA 폴리펩티드를 코딩하는 뉴클레오티드 서열이고, 서열 58의 뉴클레오티드 2333-4543을 포함하거나 서열 58의 2324-4543을 포함하고;
(4) SS1이 T2A를 코딩하는 뉴클레오티드 서열이고;
(5) SS2가 F2A를 코딩하는 뉴클레오티드 서열인 C68 벡터. - 제1항에 있어서, 다중-항원 구축물이 서열 60 또는 서열 64의 아미노산 서열을 코딩하는 뉴클레오티드 서열을 포함하는 것인 C68 벡터.
- 제1항에 있어서, 다중-항원 구축물이 서열 61, 서열 65, 또는 서열 66의 뉴클레오티드 서열, 또는 서열 61, 서열 65, 또는 서열 66의 뉴클레오티드 서열의 축중성 변이체를 포함하는 것인 C68 벡터.
- 제11항에 있어서, CMV 프로모터를 추가로 포함하는 C68 벡터.
- 제1항에 있어서, 서열 58의 뉴클레오티드 서열, 서열 58의 뉴클레오티드 9-34811, 또는 서열 63의 뉴클레오티드 서열을 포함하는 C68 벡터.
- 제1항 내지 제14항 중 어느 한 항에 따른 C68 벡터를 포함하고, 인간에서 전립선암의 치료를 위한 조성물.
- 제1항 내지 제14항 중 어느 한 항에 따른 C68 벡터를 포함하는 세포.
- 제1항 내지 제14항 중 어느 한 항에 따른 벡터 및 제약상 허용되는 부형제를 포함하고, 인간에서 전립선암의 치료를 위한 제약 조성물.
- 삭제
- 제17항에 있어서, 유효량의 면역 조절제를 추가로 포함하는 제약 조성물.
- 제17항에 있어서, (a) 유효량의 적어도 하나의 면역억제성-세포 억제제 및 (b) 유효량의 적어도 하나의 면역이펙터-세포 증강제를 추가로 포함하는 제약 조성물.
- 제20항에 있어서, 면역억제성-세포 억제제가 단백질 키나제 억제제, COX-2 억제제, 및 PDE5 억제제로 이루어진 군으로부터 선택되고, 면역이펙터-세포 증강제가 CTLA-4 억제제, CD40 효능제, TLR 효능제, 4-1BB 효능제, OX40 효능제, GITR 효능제, PD-1 길항제, 및 PD-L1 길항제로 이루어진 군으로부터 선택되는 것인 제약 조성물.
- 제21항에 있어서,
(1) 단백질 키나제 억제제가 이마티닙, 소라페닙, 라파티닙, 작티마, MP-412, 다사티닙, 레스타우르티닙, 수니티닙 말레이트, 악시티닙, 에를로티닙, 게피티닙, 보수티닙, 템시롤리스무스, 및 닐로티닙으로 이루어진 군으로부터 선택되고;
(2) CTLA-4 억제제가 이필리무맙 및 트레멜리무맙으로 이루어진 군으로부터 선택되고;
(3) CD40 효능제가 G28-5, mAb89, EA-5, S2C6, CP870893, 및 다세투주맙으로 이루어진 군으로부터 선택되는 항-CD40 항체이고;
(4) TLR 효능제가 CpG24555, CpG10103, CpG7909, 및 CpG1018로 이루어진 군으로부터 선택되는 CpG 올리고뉴클레오티드인 제약 조성물. - 제22항에 있어서, 면역억제성-세포 억제제가 소라페닙, 다사티닙, 이마티닙, 악시티닙, 및 수니티닙 말레이트로 이루어진 군으로부터 선택되는 단백질 키나제 억제제이고, 면역이펙터-세포 증강제가 트레멜리무맙인 제약 조성물.
- 제22항에 있어서, 면역억제성-세포 억제제가 소라페닙, 다사티닙, 이마티닙, 악시티닙, 및 수니티닙 말레이트로 이루어진 군으로부터 선택되는 단백질 키나제 억제제이고, 면역이펙터-세포 증강제가 CpG24555, CpG10103, CpG7909, 및 CpG1018로 이루어진 군으로부터 선택되는 CpG 올리고뉴클레오티드인 제약 조성물.
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Cancer Immunol Immunother. 55(12):1524-33 (2006.12.)* |
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