KR20220109444A - 자궁경부암 치료방법 - Google Patents
자궁경부암 치료방법 Download PDFInfo
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- KR20220109444A KR20220109444A KR1020227022552A KR20227022552A KR20220109444A KR 20220109444 A KR20220109444 A KR 20220109444A KR 1020227022552 A KR1020227022552 A KR 1020227022552A KR 20227022552 A KR20227022552 A KR 20227022552A KR 20220109444 A KR20220109444 A KR 20220109444A
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- South Korea
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- leu
- arg
- glu
- cys
- asp
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Abstract
인유두종바이러스(HPV) 감염에 의해 발생하는 자궁경부암 치료제가 개시된다. 인유두종바이러스(HPV) 백신 및 체크포인트 억제제를 포함하는 인유두종바이러스(HPV)에 의해 유발된 암의 예방 또는 치료용 약학적 조성물이 개시된다.
Description
본 발명은 인유두종바이러스(HPV)에 의해 유발된 암의 예방 또는 치료, 인유두종바이러스(HPV) 감염으로 인한 자궁경부암 치료를 위한 (a) 인유두종바이러스(HPV) 백신; 및 (b) 체크포인트 억제제를 포함하는 약학적 조성물에 관한 것이다.
지속적인 바이러스 감염은 종종 바이러스 특이적 CD8 T 세포의 기능적 비활성화를 유도하여 증식, 면역 자극 사이토카인 생성 및 바이러스 감염 세포 용해 능력을 손상시킨다. 자궁경부암은 전 세계 여성 암 사망의 주요 원인 중 하나이며, 약 75%의 사례가 가장 흔한 고위험 인유두종바이러스(HPV) 유형인 HPV16 및 HPV18의 지속적인 감염으로 인해 발생한다. HPV의 지속성은 일반적으로 입증가능한 (demonstrable) HPV 특이적 T 세포 면역의 결핍과 관련이 있으며, 전암성(premalignant) 및 악성 환자에서 발견되는 바이러스 특이적 T 세포는 일반적으로 기능 장애를 가지거나 때로는 심지어 억제되어 있는 것으로 보고된다. 이러한 발견은 바이러스 특이적 T 세포의 기능적 손상이 HPV 유발 자궁경부암의 발생과 연관될 수 있음을 시사한다.
자궁경부암은 고위험 HPV 감염, 바이러스 지속성, 클론 확장 및 지속적으로 감염된 세포의 전암성 병변으로의 분화 및 이들의 침습성 암으로의 점진적인 변형 과정을 통해 발생한다.
세계보건기구(WHO)에 따르면 자궁경부암은 2018년에 약 570,000명의 새로운 사례가 발생하는 것으로 추정되는, 여성에게 네 번째로 흔한 암이며, 이는 전체 여성 암 사망의 7.5%를 나타낸다. 전암성 경부 상피내 종양 2 및 3(cervical intraepithelial neoplasia 2 및 3 (CIN2 및 3)), 특히 HPV16에 대해 양성인 종양은 침습성 암으로 발전할 확률이 약 30%인 고등급 병변으로 간주된다. 따라서, 지속적인 HPV 감염의 심각한 합병증을 예방하고 HPV 관련 신생물을 근절할 수 있는 효과적인 치료 백신이 시급히 요구되고 있다.
HPV E6 및 E7 단백질은 각각 종양 억제 단백질, p53 및 망막모세포종(pRb)에 결합하고 분해를 촉진함으로써 바이러스 종양단백질로 작용한다. 이 바이러스성 종양단백질은 종양 형성을 유도할 뿐만 아니라 HPV에 감염된 전암성 및 악성 세포에서 본질적으로 발현되므로 CIN2/3 및 자궁경부암에 대한 치료 백신을 위한 이상적인 표적 세트이다. 자궁경부 병변의 퇴행은 체액성 면역 반응이 아닌 세포성 면역 반응의 존재와 연관되기 때문에 강력한 E6/E7-특이적 T-세포 면역을 선택적으로 유도할 수 있는 치료 백신이 매우 바람직하다.
HPV에 의해 발생하는 자궁경부암의 효과적인 예방/치료를 제공하기 위한 지속적인 노력의 하나로 다음 중에서 선택된 3개 이상의 아미노산 서열을 포함하는 융합 단백질이 제공된다: (1) HPV16의 E6 단백질의 N-말단 부분, (2) HPV16의 E6 단백질의 C-말단 부분, (3) HPV16의 E7 단백질의 N-말단 부분, (4) HPV16의 E7 단백질의 C-말단 부분, (5) HPV18의 E6 단백질의 N-말단 부분, (6) HPV18의 E6 단백질의 C-말단 부분, (7) HPV18의 E7 단백질의 N-말단 부분, 및 (8) HPV18의 E7 단백질의 C-말단 부분, 여기서 상기 융합 단백질은 p53에 결합하지 않거나 HPV16 또는 HPV18의 E6 단백질과 이량체를 형성하지 않으며, 여기서 상기 융합 단백질은 pRb에 결합하지 않거나 HPV16 또는 HPV18의 E7 단백질과 이량체를 형성하지 않는다. 이는 동시 계류 중인 출원 번호 15/503,997에 기술되어 있으며, 동시 계류 중인 출원 번호 15/503,997의 전체 내용은 본 명세서에 참고로 포함된다.
HPV 유형 16 및 18 유래의 E6 및 E7의 3차원 구조를 변형시키는 융합 폴리펩타이드와 면역 증강 펩타이드를 포함하는 융합 단백질, 및 이를 코딩하는 폴리뉴클레오타이드는 동시 계류 중인 미국 출원 번호 13/816,716에 개시되어 있다. 동시 계류 중인 미국 출원 번호 13/816,716의 예시적인 일 구현예에 따른 융합 단백질이 HPV 유형 16 및 18에서 유래된 E6 및 E7의 3D 구조를 변형시키기 위해 재조합된 융합 폴리펩타이드를 포함할 수 있다. 보다 구체적으로, 상기 융합 폴리펩타이드는 상기 HPV 유형 16 유래의 E6 단백질의 1번째 내지 85번째 아미노산, E7 단백질의 1번째 내지 65번째 아미노산, E6 단백질의 71번째 내지 158번째 아미노산 및 E7 단백질의 51번째 내지 98번째 아미노산, HPV 유형 18 유래의 E6 단백질의 1번째 내지 85번째 아미노산, E7 단백질의 1번째 내지 65번째 아미노산, E6 단백질의 71번째 내지 158번째 아미노산, 및 E7 단백질의 51번째 내지 105번째 아미노산이 순서대로 결합되어 있는 융합 폴리펩타이드이다. 동시 계류 중인 미국 출원 번호 13/816,716은 융합 폴리펩타이드 및 면역 증강 펩타이드를 코딩하는 핵산 분자에 관한 것이다. 예시적인 면역 증강 펩타이드는 CD40 리간드, Flt3 리간드, 플라젤린(flagellin) 및/또는 OX40을 포함한다. 융합 단백질, 최적화된 신호 서열(예를 들어, tPa), 및 면역 증강 펩타이드(예를 들어, Flt3 리간드)를 코딩하는 폴리뉴클레오타이드의 구현예는 동시 계류 중인 출원 번호 13/816,716의 실시예 1을 참조하여 제조될 수 있다. 공동 계류 중인 미국 출원 번호 13/816,716의 전체 내용은 본 명세서에 참고로 포함된다.
신체 자체의 면역계를 강화시켜 신체가 암세포에 대한 면역반응을 증폭시킬 수 있도록 하는 면역요법은 면역 체계가 암세포를 찾아 공격할 수 있도록 작동 방식을 높이거나(boost) 변경할 수 있다.
암 치료를 위한 체크포인트 억제제 항체에 대한 연구는 이전에 암 치료에 내성이 있는 것으로 생각되었던 암에서 전례 없는 반응율을 생성하였다. CTLA-4, PD-1 및 PD-L1에 대한 길항 체크포인트 블로킹 항체를 사용한 요법은 암 및 기타 질환에 대한 면역 요법의 가장 유망한 새로운 방법 중 하나이다. 대부분의 항암제와 달리 체크포인트 억제제는 종양 세포를 직접 표적으로 삼지 않으며, 오히려 면역계의 내인성 항종양 활성을 강화시키기 위해 림프구 수용체 또는 이들의 리간드를 표적으로 한다. 면역 체크포인트 항체는 주로 질병에 걸린 세포, 조직 또는 병원체에 대한 면역 반응을 조절함으로써 작용하기 때문에 항체-약물 접합체의 항종양 효과를 강화시키기 위해 항체-약물 접합체와 같은 다른 치료 양식과 조합하여 사용될 수 있다.
Programmed cell death protein 1 (PD-1, CD279로도 알려짐)은 B 세포 및 NK 세포에서 발현되는 면역글로불린 슈퍼패밀리의 세포 표면 막 단백질을 암호화한다. 항-PD1 항체는 흑색종, 비소세포폐암, 방광암, 전립선암, 결장직장암, 두경부암, 삼중음성 유방암, 백혈병, 림프종 및 신장세포암의 치료에 사용되어 왔다. 예시적인 항-PD1 항체는 펨브롤리주맙(KEYTRUDA®, MERCK), 니볼루맙(BMS-936558, BRISTOL-MYERS SQUIBB), 세미플리맙(LIBTAYO®) 및 피딜리주맙(CT-011, CURETECH LTD.)을 포함한다.
Programmed cell death 1 ligand 1 (PD-L1, CD274로도 알려짐)은 활성화된 T 세포, B 세포, 골수 세포 및 대식세포에서 발견되는 PD-1에 대한 리간드이다. PD-1과 PD-L1의 복합체는 CD8+ T 세포의 증식을 억제하고 면역 반응을 감소시킨다. 항PD-L1 항체는 비소세포폐암, 흑색종, 결장직장암, 신장세포암, 췌장암, 위암, 난소암, 유방암 및 혈액암의 치료에 사용되어 왔다. 예시적인 항-PD-L1 항체는 MDX-1105(MEDAREX), 두르발루맙(MEDI4736, MEDIMMUNE), 아벨루맙(BAVENCIO®), 아테졸리주맙(TECENTRIQ®, MPDL3280A, GENENTECH) 및 BMS-936559(BRISTOL-MYERS SQUIBB)를 포함한다.
Cytotoxic T-lymphocyte antigen 4 (CTLA-4, CD152로도 알려짐)는 또한 T-세포에서만 독점적으로 발현되는 면역글로불린 슈퍼패밀리의 구성원이다. CTLA-4는 T 세포 활성화를 억제하는 작용을 하며 보조 T 세포 활성을 억제하고 조절 T 세포 면역억제 활성을 강화시키는 것으로 보고되어 있다. 예시적인 항-CTLA4 항체는 이필리무맙(Bristol-Myers Squibb) 및 트레멜리무맙(PFIZER)을 포함한다.
펨브롤리주맙(KEYTRUDA®, Merck and Co. Inc.)은 FDA 승인 테스트에 의해 결정된 바와 같이 종양에서 PD-L1(CPS≥1)을 발현하는 화학요법 중 또는 후에 질병 진행이 있는 재발성 또는 전이성 자궁경부암 환자에 대하여 최근 승인되었다. 주요 효능 결과는 BICR(blinded independent central review)에 의해 평가된 RECIST 1.1에 따른 객관적 반응율 (objective response rate, ORR) 및 반응 기간이었다. 평균 11.7개월의 추적 기간 동안 77명의 환자에서 ORR은 14.3% (95% CI: 7.4, 24.1) 이었으며, 완전 관해는 2.6%, 부분 관해는 11.7% 이었다. 독립적인 리뷰에 따른 반응이 있는 11명의 환자를 기반으로 한 예상 반응 기간 평균에는 도달하지 않았다(범위 4.1, 18.6개월 이상). 91%는 6개월 이상의 반응 기간을 가졌다. 종양에 PD-L1 발현이 없는 환자(CPS 1)에서는 반응이 관찰되지 않았다. 임상시험(KEYNOTE-158)에 등록된 자궁경부암 환자의 최소 10%에서 가장 흔한 이상반응은 피로, 통증, 발열, 말초부종, 근골격계 통증, 설사/대장염, 복통, 구역, 구토, 변비, 식욕감퇴, 출혈, 요로감염(UTI), 감염, 발진, 갑상선기능저하증, 두통, 호흡곤란이었다. 펨브롤리주맙은 환자의 8%에서 이상반응으로 인해 중단되었다. 환자의 39%에서 심각한 이상반응이 발생하였다. 보고된 가장 빈번한 중대한 이상반응은 빈혈(7%), 누공(4.1%), 출혈(4.1%), 감염(요로감염 제외)(4.1%)이었다.
그러나, 자궁경부암 환자의 약 70%는 HPV 16 및/또는 18 감염 및/또는 PD-L1 음성이며, 이의 효과적인 치료 및/또는 강화된 치료가 여전히 필요한 실정이다.
본 개시의 일 관점은 HPV 백신 요법 및 항-PD1 체크포인트 억제 항체 요법의 공통된 기간에 걸친 (over a common time period) 병용 투여를 포함하며, 광범위한 실험 후, 항-PD1 체크포인트 억제 항체 치료와 비교하여 상기 병용 투여는 자궁경부암, 특히 진행성, 전이성, 재발성 자궁경부암의 성장 억제 효과가 증가하는 것으로 나타났다. 본 병용 요법은 HPV 백신 단독 또는 항-PD1 체크포인트 억제 항체 단독요법보다 PD-1 양성 환자, HPV-16 양성 및/또는 HPV-17 양성 환자에서 치료 효능의 강화를 나타낸다. 놀랍게도 본 병용 요법은 항-PD1 항체 단독 요법에서 전혀 반응하지 않는 PD-1 음성 환자에서 치료 효능을 추가로 보여준다.
본 개시의 목적은 인유두종바이러스(HPV)에 의해 유발된 암의 예방 또는 치료를 위한 인유두종바이러스(HPV) 백신 및 체크포인트 억제제를 포함하는 약학적 조성물에 관한 것이다.
본 개시의 또 다른 목적은 인유두종바이러스(HPV)에 의해 유발된 암의 예방 또는 치료를 위한 약물의 제조에 있어서 유두종바이러스(HPV) 백신 및 체크포인트 억제제를 포함하는 약제학적 조성물의 용도를 포함한다.
본 개시의 또 다른 목적은, 공통된 기간 동안 단독 요법으로 사용될 때 HPV 백신 또는 체크포인트 억제제 단독보다 더 큰 치료 효과를 생성하기 위하여, 대상체에게 HPV 백신 및 체크포인트 억제제를 투여하는 단계를 포함하는, 이를 필요로하는 대상체의 인유두종바이러스(HPV)에 의해 유발된 암을 치료하는 방법을 포함한다.
본 개시는 자궁경부암을 가지는 대상체에 본원에 기재된 융합 단백질 또는 DNA 백신 및 면역조절제 화합물을 동시에 또는 순차적으로 투여하는 단계를 포함하는, 자궁경부암의 병용 요법에 관한 것이다. 일 양태에서, 상기 자궁경부암은 HPV 감염에 의해 유발된다.
본 개시는 자궁경부암을 치료하거나 치료를 강화시키고자 이를 필요로 하는 대상체에게 유효량의 HPV 백신 및 체크포인트 억제제를 병용 투여하는 단계를 포함하는 암의 병용 요법에 관한 것이다. 일 양태에서, 상기 자궁경부암은 HPV 감염에 의해 유발된다.
본 개시는 이를 필요로 하는 대상체에서 자궁경부암을 치료하거나 치료를 강화시키는 방법에 있어서, HPV 백신 및 체크포인트 억제제의 병용 용도에 관한 것으로, 상기 방법은 유효량의 HPV 백신 및 유효량의 체크포인트 억제제를 자궁경부암을 치료하거나 치료의 향상을 필요로 하는 개체에게 투여하는 단계를 포함한다. 일 양태에서, 상기 자궁경부암은 HPV 감염에 의해 유발된다. 일 양태에서, 상기 개체는 PD-L1 양성 또는 음성이다. 또 다른 양태에서, 상기 개체는 PD-L1 음성이다. 또 다른 양태에서, 상기 개체는 PD-L1 양성이고 HPV 16에 감염되어 있다. 일 양태에서, 상기 자궁경부암은 진행성, 재발성 또는 전이성 자궁경부암이다. 일 양태에서, 상기 자궁경부암은 편평 세포 암종 또는 선암종이다. 일 양태에서, 상기 개체는 PL-L1 양성이고 HPV 16에 감염되어 있으며, 편평 세포 암종을 앓고 있다.
본 개시는 자궁경부암을 치료하거나 치료를 강화시키기 위한 병용 요법 조성물에 관한 것으로, 상기 병용 요법 조성물은 유효량의 HPV 백신 및 유효량의 체크포인트 억제제를 포함하고, 상기 HPV 백신 및 체크포인트 억제제는 이를 필요로 하는 개체에게 동시에, 개별적으로, 또는 순차적으로 투여되는, 병용 요법 조성물에 관한 것이다. 일 양태에서, 상기 자궁경부암은 HPV 감염에 의해 유발된다. 일 양태에서, 상기 개체는 PD-L1 양성 또는 음성이다. 또 다른 양태에서, 상기 개체는 PD-L1 음성이다. 또 다른 양태에서, 상기 개체는 PD-L1 양성이고 HPV 16에 감염되어 있다. 일 양태에서, 상기 자궁경부암은 진행성, 재발성 또는 전이성 자궁경부암이다. 일 양태에서, 상기 자궁경부암은 편평 세포 암종 또는 선암종이다. 일 양태에서, 상기 개체는 PL-L1 양성이고 HPV 16에 감염되어 있으며, 편평 세포 암종을 앓고 있다.
본 개시는 자궁경부암을 치료하거나 치료를 강화시키기 위한 병용 요법 조성물에 관한 것으로, 상기 병용 요법 조성물은 본질적으로 유효량의 HPV 백신 및 유효량의 체크포인트 억제제로 구성되고, 상기 HPV 백신 및 체크포인트 억제제는 이를 필요로 하는 개체에게 동시에, 개별적으로, 또는 순차적으로 투여되는, 병용 요법 조성물에 관한 것이다. 일 양태에서, 상기 자궁경부암은 HPV 감염에 의해 유발된다. 일 양태에서, 상기 개체는 PD-L1 양성 또는 음성이다. 또 다른 양태에서, 상기 개체는 PD-L1 음성이다. 또 다른 양태에서, 상기 개체는 PD-L1 양성이고 HPV 16에 감염되어 있다. 일 양태에서, 상기 자궁경부암은 진행성, 재발성 또는 전이성 자궁경부암이다. 일 양태에서, 상기 자궁경부암은 편평 세포 암종 또는 선암종이다. 일 양태에서, 상기 개체는 PL-L1 양성이고 HPV 16에 감염되어 있으며, 편평 세포 암종을 앓고 있다.
본 개시는 인유두종바이러스(HPV)에 의해 유발된 암을 예방 또는 치료하기 위한 (a) 인유두종바이러스(HPV) 백신; 및 (b) 체크포인트 억제제를 포함하는 약학적 조성물에 관한 것으로, 여기서 (a) HPV 백신 요법 성분은 HPV 백신의 추가 부스트를 포함하여 대상체에게 투여되도록 적응되고, (b) 체크포인트 억제제 요법 성분은 체크포인트 억제제 요법의 추가 부스트를 포함하여 대상체에게 투여되도록 적응되어 있으며, 상기 성분 (a) 및 (b) 각각의 치료적 유효량에서 상기 병용 투여는 성분 (a) 또는 (b) 단독 투여에 의한 개체의 면역 반응 증가 이상으로 HPV에 의해 유발된 암을 치료하기 위해 대상체의 면역 반응을 증가시키는 능력을 가진다. 일 양태에서, 상기 대상체는 PD-L1 양성 또는 음성이다. 또 다른 양태에서, 상기 개체는 PD-L1 음성이다. 또 다른 양태에서, 상기 개체는 PD-L1 양성이고 HPV 16에 감염되어 있다. 일 양태에서, 상기 자궁경부암은 진행성, 재발성 또는 전이성 자궁경부암이다. 일 양태에서, 상기 자궁경부암은 편평 세포 암종 또는 선암종이다. 일 양태에서, 상기 개체는 PL-L1 양성이고 HPV 16에 감염되어 있으며, 편평 세포 암종을 앓고 있다.
본 개시는 본질적으로 (a) HPV 백신의 추가 부스트를 포함하여 대상체에게 투여되도록 적응된 HPV 백신 요법 성분, 및 (b) 체크포인트 억제제 요법의 추가 부스트를 포함하여 대상체에게 투여되도록 적응된 체크포인트 억제제 요법 성분으로 구성된 인유두종바이러스(HPV)에 의해 유발된 암을 이를 필요로하는 대상체에서 치료하기 위한 약학적 조성물에 관한 것으로, 상기 성분 (a) 및 (b) 각각의 치료적 유효량에서 상기 병용 투여는 성분 (a) 또는 (b) 단독 투여에 의한 개체의 면역 반응 증가 이상으로 HPV에 의해 유발된 암을 치료하기 위해 대상체의 면역 반응을 증가시키는 능력을 가진다. 일 양태에서, 상기 대상체는 PD-L1 양성 또는 음성이다. 또 다른 양태에서, 상기 개체는 PD-L1 음성이다. 또 다른 양태에서, 상기 개체는 PD-L1 양성이고 HPV 16에 감염되어 있다. 일 양태에서, 상기 자궁경부암은 진행성, 재발성 또는 전이성 자궁경부암이다. 일 양태에서, 상기 자궁경부암은 편평 세포 암종 또는 선암종이다. 일 양태에서, 상기 개체는 PL-L1 양성이고 HPV 16에 감염되어 있으며, 편평 세포 암종을 앓고 있다.
본 개시는 추가로, 2개의 개별 치료 성분을 포함하는 인유두종바이러스(HPV)-암 환자를 치료하기 위한 약학적 조성물에 관한 것으로, 상기 약학적 조성물은 (a) 두 번째 용량 수준(second dose level)으로 투여되도록 서열번호 9의 폴리뉴클레오타이드를 포함하는 HPV 백신 치료 성분 중 다수의 것을 포함하고, (b) 하나의 용량 수준(one dose level)으로 투여되도록 체크포인트 억제제 치료 성분의 다수의 것을 포함하며, 단일 요법으로 단독으로 투여되는 성분 (a) 및 (b) 각각에 대해 강화된 면역 반응의 이점을 제공하기 위하여 체크포인트 억제제 요법 성분 (b)의 효능을 증가시켜 환자의 면역 반응을 증가시키고자, HPV 백신 치료 성분 (a)은 체크포인트 억제제 치료 성분 (b)와 병용 투여되고, 여기서 성분 (a) 및 (b) 각각은 첫번째 및 두번째 용량 수준(first and second dose level)에서 유효량으로 각각 구성된다.
본 개시는 인유두종바이러스(HPV)에 의해 유발된 암의 예방 또는 치료를 위한 약물의 제조를 위한 (a) 인유두종바이러스(HPV) 백신; 및 (b) 체크포인트 억제제를 포함하는 약학적 조성물의 용도에 관한 것이다
본 개시는 인유두종바이러스(HPV)에 의해 유발된 암을 치료하는 방법에 있어서 약학적 조합(pharmaceutical combination)의 용도에 관한 것으로, 단독 요법으로 사용될 때 HPV 백신 또는 체크포인트 억제제 단독보다 더 큰 치료 효과를 생성하기 위하여, 상기 방법은 HPV 백신 및 체크포인트 억제제를 공통된 기간에 걸쳐 (over a common period of time) 이를 필요로 하는 대상체에게 투여하는 단계를 포함한다.
전술한 방법, 병용 요법, 용도, 조성물 및 약학적 조성물의 일 관점에서, 상기 HPV 백신은 DNA 백신일 수 있다. 일 양태에서 상기 체크포인트 억제제는 모노클로날 항체일 수 있다. 모노클로날 항체의 예시적인 양태는 항-PD1 항체, 항-PD-L1 항체, 또는 항-PD1/PD-L1 항체, 또는 이들의 조합일 수 있다. 일 양태에서 상기 체크포인트 억제제는 펨브롤리주맙일 수 있다. 일 양태에서, 상기 HPV 백신은 서열번호 15의 폴리뉴클레오타이드 또는 서열번호 15와 약 85% 이상, 약 86% 이상, 약 87% 이상, 약 88% 이상, 약 89% 이상, 약 90% 이상, 약 91% 이상, 약 92% 이상, 약 93 % 이상, 약 94% 이상, 약 95% 이상, 약 96% 이상, 약 97% 이상, 약 98% 이상, 약 99% 이상, 또는 약 100%의 서열 동일성을 가지는 변이체를 포함하는 DNA 백신일 수 있다.
전술한 방법, 병용 요법, 용도, 조성물 및 약학적 조성물의 일 관점에서, 상기 대상체, 개체 또는 환자는 진행성, 수술 불가 또는 전이성 자궁경부암을 가질 수 있다. 상기 암은 재발성일 수 있다. 일 양태에서, 상기 암은 편평 세포 암종 또는 선암종이다. 일 양태에서, 상기 암은 편평 세포 암종이다.
전술한 방법, 병용 요법, 용도, 조성물 및 약학적 조성물의 일 관점에서, 상기 대상체, 개체 또는 환자는 HPV 16 및/또는 HPV 18-양성이다. 또 다른 양태에서, 상기 개체는 PD-L1 양성이고 HPV 16에 감염되어 있다. 일 양태에서, 상기 개체는 PL-L1 양성이고 HPV 16에 감염되어 있으며, 편평 세포 암종을 앓고 있을 수 있다.
전술한 방법, 병용 요법, 용도, 조성물 및 약학적 조성물의 일 관점에서, 상기 대상체, 개체 또는 환자는 항암 치료를 받았거나 치료를 받고 있을 수 있다. 상기 항암 치료는 공지된 치료방법 중 하나일 수 있다. 일 양태에서, 상기 대상체, 개체 또는 환자는 적어도 하나의 화학요법을 받았거나 받고 있을 수 있다.
전술한 방법, 병용 요법, 용도, 조성물 및 약학적 조성물의 일 관점에서, 상기 대상체, 개체 또는 환자는 PD-L1-양성 또는 PD-1L 음성일 수 있다. 또 다른 양태에서, 상기 대상체, 개체 또는 환자는 HPV 16 양성일 수 있다. 또 다른 양태에서, 상기 대상체는 PD-L1-양성 및 HPV 16 양성일 수 있고, 상기 자궁경부암은 편평 세포 암종이다.
전술한 방법, 병용 요법, 용도, 조성물 및 약학적 조성물의 일 관점에서, 상기 HPV 백신은 GX-188 또는 GX-188 변이체일 수 있다. GX-188E는 tPA 및 Flt3L에 커플링된 HPV 16 및 18의 E6/E7 융합 단백질(서열번호 9)을 암호화하는 서열을 포함하는 서열번호 15의 서열을 포함하는 데옥시리보핵산 컨스트럭트이다(도 1 참조). 일 양태에서, 약 2 mg의 GX-188E가 1, 2, 4, 7, 13, 19주에 근육내 투여될 수 있고, 46주에 임의 용량이 투여될 수 있다.
전술한 방법, 병용 요법, 용도, 조성물 및 약학적 조성물의 일 관점에서, 상기 체크포인트 억제제는 펨브롤리주맙일 수 있고 상기 체크포인트 억제제의 용량은 3주마다 약 200 mg일 수 있다. 일 양태에서, 상기 펨브롤리주맙은 정맥내 투여될 수 있다.
일 양태에 따르면, 적어도 13주의 공통 기간 (common time period) 내에 대상체에 투여하기 위한 2개의 개별 치료법을 조합함으로써 대상체에서 HPV에 의해 유발된 암을 치료하는 방법이 개시되고, 상기 방법은 HPV 백신 요법 및 체크포인트 억제제 항체 요법을 포함하며, 체크포인트 억제제 항체는 첫 번째 고정 용량으로 여러 번 투여되고 백신은 두 번째 고정 용량으로 여러 번 투여되며, HPV 백신의 최초 투여 및 체크포인트 억제제의 최초 투여는 적어도 13주의 기간 중 한 날에 진행되고, HPV 백신의 후속 투여 및 체크포인트 억제제의 후속 투여는 상기 공통 기간 내에 발생한다.
병용 요법의 일 관점에서, 상기 체크포인트 억제제의 제1 고정 용량은 50 mg 내지 500 mg이고, HPV 백신의 제2 고정 용량은 0.5 mg 내지 5 mg이다. 상기 방법에 따르면, HPV 백신은 근육주사로, 체크포인트 억제제는 정맥 주사로 투여된다. 일 양태에서, 상기 체크포인트 억제제는 항-PD1 항체 또는 항-PD-L1 항체이고, 상기 HPV 백신은 서열번호 15의 핵산 컨스트럭트(construct) 또는 서열번호 15와 85% 이상의 서열 동일성을 가지는 기능적 변이체를 포함한다. 또 다른 양태로서, 상기 HPV-유도된 암은 전이성, 재발성 또는 진행성 자궁경부암이고 상기 대상체는 항암 치료를 받았거나 받고 있으며; 상기 HPV는 HPV 16, HPV 18, 또는 이들의 조합이고; 상기 대상체는 PD-L1 양성 또는 PD-L1 음성이다. 또 다른 양태에서, 상기 개체는 PD-L1 양성이고 HPV 16에 감염되어 있다. 또 다른 양태에서, 상기 개체는 PD-L1 양성이고 HPV 16에 감염되어 있으며, 편평 세포 암종을 앓고 있을 수 있다.
도 1은 GX-188을 운반하는 벡터 구조의 개략도이다.
도 2a는 C57BL/6 마우스를 이용한 자궁경부암 동물 모델에서 테스트 약물 투여 일정 및 항종양 효과 평가를 나타낸 것이다. D0, D7, D14, D21, D28, D35, D42 및 D49는 시작일(D0)부터의 일 수를 나타낸다. 테스트 약물에는 항-mPD1 단일클론항체(mAb), GX-188E, GX-188E + 항-mPD1 단일클론항체가 포함된다. HPV type 16의 E7을 발현하도록 형질전환된 C57BL/6 마우스 폐 상피세포의 세포주인 TC-1/Luc가 실험 1에 설명된 바와 같이 C57BL/6 마우스에서 종양을 유도하는 데 사용되었다.
도 2b 내지 2e는 대조군(도 2b), 항-mPD1 mAb 단독(도 2c), GX-188E 단독(도 2d), 및 항-mPD1 mAb + GX-188E의 조합(도 2e)에 의한 항종양 효능을 나타낸다. GX-188E 단독투여군은 종양세포의 성장지연으로 인한 평균생존기간의 뚜렷한 증가를 보였으나 최종생존율은 17%(1/6)였다. GX-188E + 항-mPD-1 mAb 조합 그룹은 종양 세포 성장의 지연 및 생존 기간에서 뚜렷한 증가를 보일 뿐만 아니라, 생존율도 50%(3/6)로 증가하였다.
도 3은 환자 등록 적격성(patient enrolment eligibility)과 1차 목표 및 2차 목표를 보여준다. 54명의 환자가 등록되었고 15명의 환자가 치료를 받았다. 안전성 분석을 위해 GX-188E 또는 항-mPD1 mAb(펨브롤리주맙) 중 하나를 적어도 하나의 용량으로 투여받은 54명의 환자가 포함되었다. 효능 분석을 위해 적어도 45일의 치료를 받은 48명의 환자가 프로토콜에 따라 GX-188E에 대한 반응성을 평가할 수 있는 것으로 간주되었다. 이 중간 분석은 적어도 하나의 기준선 이후 종양 평가 데이터 (post baseline tumor assessment data)를 얻은 후에 수행되었다.
도 4는 항-PD1 mAb(펨브롤리주맙) 단일요법과 비교하여 GX-188E + 항-PD1 mAb(펨브롤리주맙)의 병용 요법의 기준선 특성(baseline characteristics)을 보여준다.
도 5는 GX-188E + 항-PD1 mAb(펨프롤리주맙) 병용 요법의 안전성 프로파일을 나타내며, 임의의 등급(31.5%) 및 등급 3-4(5.6%)는 Keynote-158 단일요법을 사용하는 항-PD1 mAb(펨브롤리주맙) 단일요법의 임의의 등급(65.3%) 및 등급 3-4(12.2%)와 필적할 만하다. 3등급 치료 관련 유해 사례(TRAE)를 경험한 3명의 환자 중 1명은 또한 4등급이었다. 테스트 약물 관련 사망은 발생하지 않았다. 전반적으로, 항-PD1 mAb(펨브롤리주맙)와 조합된 GX-188E는 안전하고 내약성이 있었다.
도 6a 및 6b는 RECIST에 의해 평가된 최적의 전반적 반응율(BORR, best overall response rate)을 보여준다. 6개의 완전 관해(CR, complete response)이 확인되었으며 모든 CR 사례는 PD-L1 양성, HPV 16+ 및 편평 세포 암종 환자에서 관찰되었다. PD-L1 음성, HPV 18+ 또는 선암종 환자에서 임상 반응이 관찰되었다.
도 7은 종양 부담(tumor burden)의 기준선으로부터 표적 병변(target lesion)의 종단적 변화(longitudinal change)를 보여준다. 현재, 평균 추적관찰 기간은 6.1개월(범위, 1.7 - 24.2개월)이었다. CR: 완전 관해; PR: 부분 관해; SD: 안정 병변; PD: 진행 병변.
도 8은 최적의 전반적 반응이 CR 및 PR(N=16)이고 16개 반응 중 8개가 진행 중인 환자의 반응 기간을 보여준다. 무진행생존기간(PFS) 평균은 2.7개월(범위; 1.3 - 24.2)이었고 전체생존기간(OS) 평균은 도달하지 못하였다.
도 9a-9d는 CR 환자(도 9a 및 9b) 및 PR 환자(도 9c 및 9d)에서 기준선 및 10주 및 19주에 펨브롤리주맙 치료와 GX-188E 후의 표적 병변의 T 스캔을 보여준다. 도 9a은 이전에 두 차례 화학 요법을 받은 HPV 16, PD-L1 양성, 편평 세포 암종을 가진 63세 자궁경부암 환자에 관한 것으로, 오른쪽 폐문 림프절(hilar lymph node) 전이가 있었다. 축방향 폐 CT에서 전이성 림프절 병증(화살표)이 나타났다. 도 9b는 병용 요법 후 2개의 종양 마커(CEA 및 TA4)의 수준을 나타내고; 점선은 종양 마커의 정상 수준에 대한 컷오프 기준을 나타낸다. 도 9c는 이전에 두 차례 화학 요법을 받은 HPV 18, PD-L1 양성, 선암종을 가진 41세 자궁경부암 환자에 관한 것으로, 골반 CT에서 골반강에 난자, 저밀도 전이성 덩어리 (ova, low-density metastatic mass)(화살표)이 나타났다. 도 9d는 병용 요법 후 2개의 종양 마커(CEA 및 TA4)의 수준을 나타내고; 점선은 종양 마커의 정상 수준에 대한 컷오프 기준을 나타낸다.
도 10은 기준선으로부터 표적 병변 크기의 합(sum of target lesion size)의 최대 변화를 나타내는 그래프이다. 표적 병변의 기준선으로부터의 최대 변화는 하나 이상의 평가 가능한 기준선 이후 이미지 (post-baseline images)가 있는 환자 (n=45)에서 RECIST v1.1에 의해 평가되었다. 각 막대는 한 명의 환자를 나타내고 점선은 PD(+20%) 또는 PR(-30%)에 대한 RECIST v1.1 기준을 나타낸다. 48명의 환자 중 3명의 환자(환자 ID 1607, 1608, 1802)는 표적 병변이 맹검 독립 중앙 검토(BICR, blinded independent central review)에 의해 평가할 수 없는 것으로 평가되었기 때문에 이 그래프에 포함되지 않았다.
도 2a는 C57BL/6 마우스를 이용한 자궁경부암 동물 모델에서 테스트 약물 투여 일정 및 항종양 효과 평가를 나타낸 것이다. D0, D7, D14, D21, D28, D35, D42 및 D49는 시작일(D0)부터의 일 수를 나타낸다. 테스트 약물에는 항-mPD1 단일클론항체(mAb), GX-188E, GX-188E + 항-mPD1 단일클론항체가 포함된다. HPV type 16의 E7을 발현하도록 형질전환된 C57BL/6 마우스 폐 상피세포의 세포주인 TC-1/Luc가 실험 1에 설명된 바와 같이 C57BL/6 마우스에서 종양을 유도하는 데 사용되었다.
도 2b 내지 2e는 대조군(도 2b), 항-mPD1 mAb 단독(도 2c), GX-188E 단독(도 2d), 및 항-mPD1 mAb + GX-188E의 조합(도 2e)에 의한 항종양 효능을 나타낸다. GX-188E 단독투여군은 종양세포의 성장지연으로 인한 평균생존기간의 뚜렷한 증가를 보였으나 최종생존율은 17%(1/6)였다. GX-188E + 항-mPD-1 mAb 조합 그룹은 종양 세포 성장의 지연 및 생존 기간에서 뚜렷한 증가를 보일 뿐만 아니라, 생존율도 50%(3/6)로 증가하였다.
도 3은 환자 등록 적격성(patient enrolment eligibility)과 1차 목표 및 2차 목표를 보여준다. 54명의 환자가 등록되었고 15명의 환자가 치료를 받았다. 안전성 분석을 위해 GX-188E 또는 항-mPD1 mAb(펨브롤리주맙) 중 하나를 적어도 하나의 용량으로 투여받은 54명의 환자가 포함되었다. 효능 분석을 위해 적어도 45일의 치료를 받은 48명의 환자가 프로토콜에 따라 GX-188E에 대한 반응성을 평가할 수 있는 것으로 간주되었다. 이 중간 분석은 적어도 하나의 기준선 이후 종양 평가 데이터 (post baseline tumor assessment data)를 얻은 후에 수행되었다.
도 4는 항-PD1 mAb(펨브롤리주맙) 단일요법과 비교하여 GX-188E + 항-PD1 mAb(펨브롤리주맙)의 병용 요법의 기준선 특성(baseline characteristics)을 보여준다.
도 5는 GX-188E + 항-PD1 mAb(펨프롤리주맙) 병용 요법의 안전성 프로파일을 나타내며, 임의의 등급(31.5%) 및 등급 3-4(5.6%)는 Keynote-158 단일요법을 사용하는 항-PD1 mAb(펨브롤리주맙) 단일요법의 임의의 등급(65.3%) 및 등급 3-4(12.2%)와 필적할 만하다. 3등급 치료 관련 유해 사례(TRAE)를 경험한 3명의 환자 중 1명은 또한 4등급이었다. 테스트 약물 관련 사망은 발생하지 않았다. 전반적으로, 항-PD1 mAb(펨브롤리주맙)와 조합된 GX-188E는 안전하고 내약성이 있었다.
도 6a 및 6b는 RECIST에 의해 평가된 최적의 전반적 반응율(BORR, best overall response rate)을 보여준다. 6개의 완전 관해(CR, complete response)이 확인되었으며 모든 CR 사례는 PD-L1 양성, HPV 16+ 및 편평 세포 암종 환자에서 관찰되었다. PD-L1 음성, HPV 18+ 또는 선암종 환자에서 임상 반응이 관찰되었다.
도 7은 종양 부담(tumor burden)의 기준선으로부터 표적 병변(target lesion)의 종단적 변화(longitudinal change)를 보여준다. 현재, 평균 추적관찰 기간은 6.1개월(범위, 1.7 - 24.2개월)이었다. CR: 완전 관해; PR: 부분 관해; SD: 안정 병변; PD: 진행 병변.
도 8은 최적의 전반적 반응이 CR 및 PR(N=16)이고 16개 반응 중 8개가 진행 중인 환자의 반응 기간을 보여준다. 무진행생존기간(PFS) 평균은 2.7개월(범위; 1.3 - 24.2)이었고 전체생존기간(OS) 평균은 도달하지 못하였다.
도 9a-9d는 CR 환자(도 9a 및 9b) 및 PR 환자(도 9c 및 9d)에서 기준선 및 10주 및 19주에 펨브롤리주맙 치료와 GX-188E 후의 표적 병변의 T 스캔을 보여준다. 도 9a은 이전에 두 차례 화학 요법을 받은 HPV 16, PD-L1 양성, 편평 세포 암종을 가진 63세 자궁경부암 환자에 관한 것으로, 오른쪽 폐문 림프절(hilar lymph node) 전이가 있었다. 축방향 폐 CT에서 전이성 림프절 병증(화살표)이 나타났다. 도 9b는 병용 요법 후 2개의 종양 마커(CEA 및 TA4)의 수준을 나타내고; 점선은 종양 마커의 정상 수준에 대한 컷오프 기준을 나타낸다. 도 9c는 이전에 두 차례 화학 요법을 받은 HPV 18, PD-L1 양성, 선암종을 가진 41세 자궁경부암 환자에 관한 것으로, 골반 CT에서 골반강에 난자, 저밀도 전이성 덩어리 (ova, low-density metastatic mass)(화살표)이 나타났다. 도 9d는 병용 요법 후 2개의 종양 마커(CEA 및 TA4)의 수준을 나타내고; 점선은 종양 마커의 정상 수준에 대한 컷오프 기준을 나타낸다.
도 10은 기준선으로부터 표적 병변 크기의 합(sum of target lesion size)의 최대 변화를 나타내는 그래프이다. 표적 병변의 기준선으로부터의 최대 변화는 하나 이상의 평가 가능한 기준선 이후 이미지 (post-baseline images)가 있는 환자 (n=45)에서 RECIST v1.1에 의해 평가되었다. 각 막대는 한 명의 환자를 나타내고 점선은 PD(+20%) 또는 PR(-30%)에 대한 RECIST v1.1 기준을 나타낸다. 48명의 환자 중 3명의 환자(환자 ID 1607, 1608, 1802)는 표적 병변이 맹검 독립 중앙 검토(BICR, blinded independent central review)에 의해 평가할 수 없는 것으로 평가되었기 때문에 이 그래프에 포함되지 않았다.
용어 정의
달리 명시되지 않거나 문맥으로부터 암시되지 않는 한, 하기 용어 및 문구에는 아래 제공된 의미가 포함된다. 달리 명시적으로 언급되지 않거나 문맥상 명백하지 않는 한, 하기 용어 및 문구는 해당 용어 또는 문구와 관련된 기술 분야에서 획득한 의미를 배제하지 않는다. 상기 정의는 특정 양태를 기술하는데 도움을 주기 위해 제공되며, 본원에 제공된 관점의 범위가 청구범위에 의해서만 제한되기 때문에, 본원에 제공된 관점을 제한하도록 의도되지 않는다. 달리 정의되지 않는 한, 본원에 사용된 모든 기술 및 과학 용어는 본원이 제공하는 관점이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 갖는다.
본 명세서에서 사용된 용어 "GX-188 변이체(variant)", "GX-188 유사체(analogue)", "GX-188 변이체 컨스트럭트", "GX-188 유사체 컨스트럭트" 또는 임의의 유사한 용어는, 상기 컨스트럭트를 적어도 하나의 용량으로 투여 후, 상기 컨스트럭트가 GX-188 투여 후 유도되는 세포성 면역 반응과 유사한 생체 내 세포성 면역 반응을 유도한다는 것을 나타낸다 (도 1 또는 서열번호 9). 상기 변이체 컨스트럭트가 GX-188에 의해 유도된 세포성 면역 반응과 동일하거나 더 높은 세포성 면역 반응을 유도할 수 있다면, 상기 세포성 면역 반응은 유사한 것일 수 있다. 다른 양태에서, 상기 변이체 컨스트럭트가 GX-188에 의해 유도된 면역 반응보다 적어도 약 0.9배(예를 들어, 90%), 약 0.8배, 약 0.7배, 약 0.6배, 약 0.5배, 또는 약 0.4배 더 높은 세포성 면역 반응을 유도하는 경우, 상기 세포성 면역 반응은 유사한 것일 수 있다. 일 양태에서, 상기 세포성 면역 반응은 CD8 T 세포 반응, CD4 T 세포 반응, 사이토카인 분비, 또는 이들의 임의의 조합이다. 또 다른 양태에서, 상기 세포성 면역 반응은 증가된 수의 다작용성(poly-functional) T 세포를 포함한다. 특정 양태에서, 상기 다작용성 T 세포는 유세포 분석에 의해 측정할 때 IFN-γIL-2, TNF-α, MIP-β CD107a/b, 및 이들의 임의의 조합으로부터 선택되는 적어도 3개, 적어도 4개, 또는 적어도 5개의 마커를 전시(exhibit)한다. 상기 GX-188 변이체의 예는 GX-188E(서열번호 15)일 수 있다.
본 명세서에 사용된 바와 같이, 용어 "GX-188E"는 서열번호 15의 뉴클레오타이드 서열을 가지는 핵산 컨스트럭트 또는 서열번호 15와 적어도 약 80% 이상, 약 81% 이상, 약 82% 이상, 약 84% 이상, 약 85% 이상, 약 86% 이상, 약 87% 이상, 약 88% 이상, 약 89% 이상, 약 90% 이상, 약 91% 이상, 약 92% 이상, 약 93% 이상, 약 94% 이상, 약 95% 이상, 약 96% 이상, 약 97 % 이상, 약 98% 이상, 약 99% 이상, 또는 약 100%의 서열 동일성을 가지는 그의 변이체이다.
2개의 폴리펩타이드 사이의 "서열 동일성(sequence identity)"이라는 용어는 한 폴리펩타이드의 아미노산 서열을 두 번째 폴리펩타이드의 서열과 비교함으로써 결정된다. 본원에서 논의될 때, 특정 폴리펩타이드가 또 다른 폴리펩타이드와 적어도 약 50%, 약 60%, 약 70%, 약 75%, 약 80%, 약 85%, 약 86%, 약 87%, 약 88%, 약 89%, 약 90%, 약 91%, 약 92%, 약 93%, 약 94%, 약 95%, 약 96%, 약 97%, 약 98%, 약 99%, 또는 100% 동일하다는 것은, 이에 제한되지는 않으나, BESTFIT 프로그램(Wisconsin Sequence Analysis Package, Unix용 버전 8, Genetics Computer Group, University Research Park, 575 Science Drive, Madison, Wis. 53711)과 같은 당업계에 알려진 방법 및 컴퓨터 프로그램/소프트웨어를 사용하여 결정할 수 있다. BESTFIT는 두 서열 간의 상동성의 최상의 세그먼트를 찾고자, Smith and Waterman, Advances in Applied Mathematics 2:482-489(1981)의 로컬 상동성 알고리즘을 사용한다. 특정 서열이 예를 들어, 본 발명에 따른 참조 서열과 95% 동일한지 여부를 결정하기 위해 BESTFIT 또는 임의의 다른 서열 정렬 프로그램을 사용할 때, 물론 매개변수는 동일성 백분율이 참조 폴리펩타이드 서열의 전체 길이에 대해 계산되고 참조 서열에 있는 아미노산의 총 수의 최대 5%의 상동성의 갭이 허용되도록 설정된다.
"약"이라는 용어는 대략적으로(approximately), 거의(roughly), 가량(around), 또는 ~의 영영에서(in the regions of)를 의미하는 데 사용된다. "약"이라는 용어가 수치 범위와 함께 사용되는 경우 명시된 수치 값의 위아래 경계를 확장하여 해당 범위를 수정한다. 일반적으로, 용어 "약"은 명시된 값을 위 또는 아래의 수치 값으로 10%의 변동에 의해 위 또는 아래(더 높거나 더 낮음)로 수정하는 데 사용된다.
"유의한(significant)" 또는 "유의하게(significantly)"라는 용어는 통계적 유의성을 나타내며 일반적으로 2 표준편차 (2SD) 이상의 차이를 의미한다.
본 명세서에 사용된 용어 "포함하는(comprising)" 또는 "포함한다(comprises")"는 조성물, 방법 및 이의 각각의 성분(들)과 관련하여 사용되며, 상기 방법이나 조성물에 필수적이지만, 필수 여부에 관계없이, 불특정 요소를 포함할 가능성이 있다.
"~로 구성되는(consisting of)"이라는 용어는 해당 양태의 설명에서 언급하지 않는 임의의 요소를 배제한 본 명세서에 기재된 바와 같은 조성물, 방법, 및 이들의 각각의 성분을 지칭한다.
본 명세서에 사용된 용어 "본질적으로 ~로 구성되는(consisting essentially of)"은 주어진 양태에 필요한 요소들을 지칭한다. 이 용어는 해당 양태의 기본이고 신규하거나 기능적 특성(들)에 실질적으로 영향을 미치지 않는 요소의 존재를 허용한다.
단수 용어 "a", "an" 및 "the"는 문맥이 달리 명백하게 나타내지 않는 한 복수의 지시 대상을 포함한다. 유사하게, "또는" 이라는 단어는 문맥이 명백하게 달리 나타내지 않는 한 "및"을 포함하도록 의도된다. 본 명세서에 기재된 것과 유사하거나 등가인 방법 및 재료가 본 개시의 실시 또는 시험에 사용될 수 있지만, 적합한 방법 및 재료가 하기에 기재되어 있다. 약어, 라틴어 exempli gratia에서 파생된 "예컨대(e.g.)"는 비제한적인 예를 나타내기 위하여 본원에서 사용된다. 따라서 약어 "예컨대"는 "예를 들어(for example)"라는 용어와 동의어이다.
일 양태에서, "면역조절 화합물(immunomodulatory compound)"은 인터페론과 같은 사이토카인, PD-1/PD-L1 경로 억제제(PD-1/PD-L1 억제제), 항-CTLA4 항체와 같은 모노클로날 항체, 시클로포스파미드, 탈리도마이드, 레바미솔, 레날리도마이드, 또는 이들의 조합을 포함하지만 이에 제한되지 않는다. 일 양태에서, 상기 면역조절 화합물은 항-PD1 항체, 항-PD-L1 항체, 항-CTLA4 항체, 항-PD1 항체와 항-CTLA4 항체의 조합, 항-PD-L1 항체와 항-CTLA 항체의 조합이다. "PD-1/PD-L1 경로 억제제"라는 용어는 PD-1에 대한 PD-L1의 결합을 억제하거나 차단하는 화합물로, 항-PD-1 항체, 항-PD-L1 항체, 및 항-PD-1/PD-L1 항체를 포함할 수 있다.
상기 면역조절 화합물은 항-PD1 항체 또는 항-PD-L1 항체, 예를 들어 펨브롤리주맙 또는 MDX-1106(Merck), 니볼루맙, 세미플리맙, 아테졸리주맙, 아벨루맙, 더발루맙, THALOMID®(탈리도마이드), 사이클로포스파미드, 레바미솔, 레날리도마이드, CC-404(포말리도마이드), CC-11006(Celgene) 및 CC-10015(Celgene), 및 WO2007028047, WO2002059106, 및 WO2002094180 중 어느 하나에 기재된 면역조절 화합물로부터 선택될 수 있다. 상기 면역조절 화합물은 항-PD1 항체일 수 있다. 일 양태에서, 상기 항-PD1 항체는 펨브롤리주맙이다.
"암(cancer)" 및 "암성(cancerous)"이라는 용어는 세포 집단이 조절되지 않은 세포 성장을 특징으로 하는 포유동물의 생리학적 상태를 지칭하거나 설명한다. 암의 예에는 암종, 림프종, 모세포종, 육종 및 백혈병이 포함되지만 이에 제한되지는 않는다. 이러한 암의 보다 구체적인 예는 편평세포암, 소세포폐암, 비소세포폐암, 폐선암, 폐암, 복막암, 간세포암, 위장관암, 췌장암, 교모세포종, 자궁경부암, 난소암, 간암, 방광암, 간암, 유방암, 결장암, 결장직장암, 자궁내막암 또는 자궁암, 침샘암, 신장암, 간암, 전립선암, 외음부암, 갑상선암, 간암 및 각종 두경부암을 포함한다.
"종양(tumor)" 및 "신생물(neoplasm")"이라는 용어는 양성(비암성) 또는 전암성 병변을 포함하여 악성(암성)의, 과도한 세포 성장 또는 증식으로 인한 조직 덩어리를 의미한다. 종양은 자궁경부 종양일 수 있다. 특정 양태에서, 상기 자궁경부 종양은 양성 종양 또는 악성 종양이다. 특정 양태에서, 상기 자궁경부 종양은 편평 세포 암종(SCC), 선암종, 선편평 암종, 소세포 암종, 신경내분비 종양(NET), 유리상 세포 암종, 융모선 선암종(VGA), 비암종 악성종양, 흑색종, 림프종 또는 자궁 경부 상피내 종양(CIN)이다. 일부 양태에서, 상기 자궁경부 종양은 CIN1, CIN2, CIN3, 또는 자궁경부암이다.
용어 "암 세포", "종양 세포" 및 문법적 등가물은 종양 세포 집단의 대부분을 구성하는 비종양형성 세포(non-tumorigenic cells) 및 종양 형성 줄기 세포(암 줄기 세포)를 포함하는, 종양 또는 전암성 병변에서 유래된 세포의 총 집단을 지칭한다.
본원에 개시된 바와 같은 융합 단백질을 코딩하는 폴리뉴클레오타이드의 "유효량(effective amount)"은 구체적으로 언급된 목적을 수행하기에 충분한 양이다. "유효량"은 명시된 목적과 관련하여 경험적으로 그리고 일상적인 방식으로 결정될 수 있다.
본원에 사용된 "치료적 유효량(therapeutically effective amount)""은 필요한 투여량 및 기간 동안 원하는 치료 결과를 달성하기 위하여 효과적인 양을 의미한다. 치료 결과는 예를 들어, 증상의 감소, 연장된 생존, 종양의 크기 및/또는 부피의 감소, 종양의 성장 억제 등일 수 있다. 치료 결과가 "치유(cure)"일 필요는 없다.
"치료하는(treating)" 또는 "치료(treatment)" 또는 "치료하기 위하여(to treat)" 또는 "경감시키는(alleviating)" 또는 "경감시키기 위한(to alleviate")"과 같은 용어는 진단된 병리학적 상태(pathologic condition) 또는 장애(disorder)의 치유, 속도의 감소, 증상 완화, 진행 정지, 종양 조직의 크기 또는 부피 감소 및/또는 종양 성장을 정지시키는 치료적 조치를 지칭한다. 따라서, 치료를 필요로 하는 대상체는 장애를 이미 가지고 있는 것으로 진단되거나 의심되는 대상체를 포함한다.
"대상체(subject)" 또는 "개체(individual)" 또는 "동물(animal)" 또는 "환자(patient)" 또는 "포유동물(mammal)"은 진단, 예후 또는 치료가 필요한 임의의 대상체, 특히 포유동물 대상체를 의미한다. 포유동물 대상체는 인간, 가축, 농장 동물, 동물원 동물, 스포츠 동물, 개, 고양이, 기니피그, 토끼, 쥐, 생쥐, 말, 소, 젖소와 같은 애완 동물; 유인원, 원숭이, 오랑우탄 및 침팬지와 같은 영장류; 개 및 늑대와 같은 개과; 고양이, 사자 및 호랑이와 같은 고양이과; 말, 당나귀, 얼룩말과 같은 말과; 곰, 소, 돼지 및 양과 같은 식용 동물; 사슴 및 기린과 같은 유제류; 마우스, 래트, 햄스터 및 기니피그와 같은 설치류; 등을 포함하나, 이에 제한되지는 않는다. 특정 양태에서, 상기 포유동물은 인간 대상체이다.
"병용 치료/요법(combination treatment/therapy)", "병용 치료(combined treatment)", "병용의(combinatorial)" 또는 "병용으로(in combination)"라는 용어는 규정된 기간 내에서 동시에 및/또는 다른 시간에 적어도 상기 2개의 별개의 치료제를 사용하는 적어도 백신 및 체크포인트 억제제에 의한 치료를 의미한다.
"체크포인트 억제제(checkpoint inhibitor)" 및/또는 "항체(antibody)"라는 용어는 투여 방법에 관계없이 면역 체계가 신체의 T 세포를 사용하여 암을 공격하는 것을 부분적으로 또는 전체적으로 방지할 수 있는 신체의 체크포인트를 차단 해제하기 위하여, 개체(또는 동물)에게 투여하기 위하여 상업화 및/또는 판매되는지 여부를 불문하고 설계된 상업적 약물 및/또는 비상업적 약물 중 하나 이상을 의미한다.
용어 "PD-1"은 체크포인트 억제제 항체의 한 예를 의미한다.
용어 "기준선(baseline)"은 실험 1일차의 종양 부피(TV)를 의미한다.
용어 "벡터(vector)"는 전사 단위를 포함 ("발현 벡터"로도 알려짐)하는 용어이며, 본원에서 사용되는 바와 같이 생체 내 투여 시 표적 세포에 들어가 암호화된 단백질을 발현할 수 있는 바이러스 및/또는 비-바이러스 발현 벡터를 의미한다. 생체내 전달 및 외인성 단백질의 발현에 적합한 바이러스 벡터는 잘 알려져 있으며, 아데노바이러스 벡터, 아데노-연관 바이러스 벡터, 레트로바이러스 벡터, 백시니아 벡터, 수두 벡터, 단순 포진 바이러스 벡터 등을 포함한다. 바이러스 벡터는 바람직하게는 정상 세포에서 복제 결함이 있게 제조된다. 예를 들어, 미국 특허 6,669,942; 6,566,128; 6,794,188; 6,110,744 및 5,133,029를 참조하라. 상기 벡터는 정맥내, 동맥내, 근육내, 피하 등과 같은 비경구적으로 투여될 수 있다. 투여는 또한 경구, 비강, 직장, 경피 또는 에어로졸 흡입일 수 있다. 상기 벡터는 볼루스(bolus)로 투여하거나 천천히 주입할 수 있다. 본 출원에서의 벡터는 바람직하게는 피하 투여된다.
조성물 및 치료 (COMPOSITION AND TREATMENT)
GX-188의 조성물은 주사에 의해, 비경구로, 예를 들어, 진피하(subcutaneously), 진피내(intracutaneously), 피내(intradermally), 피하(subdermally) 또는 근육내(intramuscularly) 투여될 수 있다. 본원에 사용된 용어 "GX-188 조성물(GX-188 composition)", "GX-188의 조성물(composition of GX-188)", "GX-188 제형(GX-188 formulation)" 및 "GX-188-함유 제형(GX-188-containing formulation)"은 서열번호 9 또는 서열번호 15를 포함하는 폴리뉴클레오타이드 또는 서열번호 9 또는 서열번호 15와 약 85% 이상, 약 86% 이상, 약 87% 이상, 약 88% 이상, 약 89% 이상, 약 89% 이상, 약 90% 이상, 약 91% 또는 약 92% 이상, 약 93% 이상, 약 94% 이상, 약 95% 이상, 약 96% 이상, 약 97% 이상, 약 98% 이상, 또는 약 99% 이상의 서열 동일성을 가지는 이의 변이체를 포함하는 조성물 또는 제형을 의미한다.
다른 투여 방식에 적합한 추가 제형은 좌약 및 일부 경우에 경구, 비강, 협측, 설하, 복강내, 질내, 항문, 경막외, 척추 및 두개내 제형을 포함한다. 좌약의 경우, 전통적인 결합제 및 담체는 예를 들어 폴리알칼렌 글리콜(polyalkalene glycol) 또는 트리글리세리드(triglyceride)를 포함할 수 있고; 이러한 좌약은 0.5% 내지 10%(w/w), 바람직하게는 1% 내지 2%(w/w) 범위의 활성 성분을 함유하는 혼합물로부터 형성될 수 있다. 경구 제형은 예를 들어 약학적 등급의 만니톨, 락토스, 전분, 마그네슘 스테아레이트, 나트륨 사카린, 셀룰로스, 탄산마그네슘 등과 같은 일반적으로 사용되는 부형제를 포함한다. 이들 조성물은 용액, 현탁액, 정제, 환제, 캡슐, 지속 방출 제형 또는 분말의 형태를 취하고 10% 내지 95%(w/w), 바람직하게는 25% 내지 70%(w/w)의 활성 성분을 함유할 수 있다.
GX-188-함유 제형은 투약 제형(dosage formulation)과 양립할 수 있는 방식으로, 그리고 치료적으로 유효하고 면역원성이 있는 양으로 투여될 수 있다. 투여되는 양은 예를 들어 면역 반응을 일으키는 개체의 면역계 능력 및 요구되는 면역 정도를 포함하여 치료될 대상에 의존한다. 적합한 투여량 범위는 백신 접종당 대략 수백 마이크로그램의 활성 성분이며, 바람직한 범위는 약 1㎍ 내지 20mg, 예컨대 약 5㎍ 내지 10mg의 범위이다. 일 양태에서, 상기 용량은 약 0.5㎍ 내지 1000㎍, 1㎍ 내지 1000㎍, 또는 1㎍ 내지 500㎍ 범위, 특히 약 10㎍ 내지 100㎍ 범위일 수 있다. 또 다른 관점에서, 상기 투여량은 0.1 mg 내지 20 mg 범위일 수 있다. 또 다른 관점에서, 상기 투여량은 0.5 mg 내지 10 mg의 범위일 수 있다. 또 다른 관점에서, 상기 투여량은 1 mg 내지 5 mg의 범위일 수 있다. 또 다른 관점에서, 상기 투여량은 0.5 mg 내지 20mg, 1 mg 내지 20 mg, 0.5 mg 내지 5 mg, 1.5 mg 내지 10 mg, 2 mg 내지 5 mg, 2.5 mg 내지 5 mg, 3 mg 내지 5 mg, 또는 2 mg 내지 10 mg 범위일 수 있다. 또 다른 양태에서, 상기 GX-188의 투여량은 약 0.5 mg, 약 0.6 mg, 약 0.7 mg, 약 0.8 mg, 약 0.9 mg, 약 1 mg, 약 1.1 mg, 약 1.2 mg, 약 1.3 mg, 약 1.3 mg, 약 1.4 mg, 약 1.5 mg, 약 1.6 mg, 약 1.7 mg, 약 1.8 mg, 약 1.9 mg, 약 2 mg, 약 2.1 mg, 약 1.2 mg, 약 1.3 mg, 약 1.4 mg, 약 1.5 mg, 약 1.6 mg, 약 1.7 mg, 약 1.8 mg, 약 1.9 mg, 약 2 mg, 약 2.1 mg, 약 2.2 mg, 약 2.3 mg, 약 2.4 mg, 약 2.5 mg, 약 2.6 mg, 약 2.7 mg, 약 2.8 mg, 약 2.9 mg, 약 3 mg, 약 3.1 mg, 약 3.2 mg, 약 3.3 mg, 약 3.4 mg, 약 3.5 mg, 약 3.6 mg, 약 3.7 mg, 약 3.8 mg, 약 3.9 mg, 약 4 mg, 약 4.1 mg, 약 4.2 mg, 약 4.3 mg, 약 4.4 mg, 약 4.5 mg, 약 4.6 mg, 약 4.7 mg, 약 4.8 mg, 약 4.9 mg, 또는 약 5 mg으로 대략 매주, 격주에 한 번, 3주마다 한 번, 4주마다 한 번 투여될 수 있다. 상기 GX-188 제형은 5일, 10일, 15일, 20일, 30일 또는 40일의 간격으로 투여될 수 있다.
일 관점에 따르면, 초기 투여 및 부스터 주사에 대한 적합한 요법은 가변적이나, 초기 투여 후 후속 접종 또는 기타 투여로 대표된다. 예를 들어, 일 양태에서, GX-188은 1주차, 2주차, 4주차, 7주차, 13주차 및 19주차에 약 2 mg의 고정 용량으로 투여될 수 있고, 선택적으로 46주차에 추가로 투여될 수 있다. 상기 투여는 근육내 경로를 통해 이루어질 수 있다. 또 다른 양태에서, GX-188은 1주차, 2주차, 4주차, 8주차, 14주차 및 20주차에 약 2 mg의 고정 용량으로 투여될 수 있고, 선택적으로 46주차에 추가로 투여될 수 있다. 다른 양태에서, 상기 투여량은 각 투여마다 다를 수 있다.
상기 면역조절제는 별도의 제형으로 투여될 수 있다. 일 양태에서, 항-PD1 항체는 GX-188 투여와 동시에 또는 상이한 시간에 정맥내 투여될 수 있다. 상기 항-PD1 항체는 약 1 mg 내지 1000 mg의 용량으로 투여될 수 있다. 일 양태에서, 상기 항-PD1 항체의 용량은 약 10 mg 내지 500 mg, 약 50 mg 내지 500 mg, 약 100 mg 내지 500 mg, 100 mg 내지 300 mg, 약 150 mg 내지 300 mg, 약 180 mg 내지 250 mg, 약 190 mg 내지 250 mg, 약 185 mg 내지 225 mg, 약 185 mg 내지 220 mg, 약 195 mg 내지 250 mg, 약 195 mg 내지 225 mg, 약 190 mg 내지 230 mg, 약 200 mg 내지 400 mg, 약 200 mg 내지 300 mg, 약 250 mg 내지 300 mg, 약 280 mg 내지 350 mg, 약 300 mg 내지 500 mg, 약 300 mg 내지 400 mg, 약 300 mg 내지 1000 mg, 약 300 mg 내지 900 mg, 약 300 mg 내지 800 mg, 약 300 mg 내지 700 mg, 또는 약 300 mg 내지 600mg의 범위일 수 있다. 상기 항-PD1 항체는 일주일에 한 번, 일주일에 두 번, 일주일에 세 번, 일주일에 네 번, 매주, 10일마다, 격주에 한 번, 20일마다, 3주마다, 4주마다, 한 달에 한 번, 격월에 한 번, 또는 3개월에 한 번 등과 같은 간격으로 투여될 수 있다. 일 양태에서, 항-PD1 항체는 펨브롤리주맙이고, GX-188의 첫 번째 투여 전, 동시에 또는 후에 시작하여 주 3회 200 mg의 용량으로 5주, 6주, 7주, 8주, 9주, 10주, 11주, 12주, 13주, 14주, 15주, 16주, 17주, 18주, 19주, 20 주, 21주, 22주, 23주, 24주, 25주 또는 그 이상 기간 동안 정맥내 투여될 수 있다. 상기 기간은 1개월, 2개월, 3개월, 4개월, 5개월, 6개월, 7개월 또는 그 이상과 같은 달력 개월로 측정될 수 있다. 또는, 상기 치료 요법에는 예를 들어, 약 200 mg의 고정 투여량으로, 10회분, 11회분, 12회분, 13회분, 14회분, 15회분, 16회분, 17회분, 18회분, 19회분, 20회분, 21회분, 22회분, 23회분, 24회분, 25회분, 26회분, 27회분, 28회분, 29회분, 30회분, 31회분, 32회분, 33회분, 34회분, 35회분 또는 그 이상과 같은 투여 횟수가 포함될 수 있다.
서열번호 10의 서열을 포함하는 융합 단백질 또는 이의 기능적 변이체는 중성 또는 염 형태로서 백신으로 제형화될 수 있다. 약학적으로 허용되는 염에는 산부가염 (acid addition salts)(펩타이드의 유리 아미노기로 형성됨)을 포함하며, 이는 예를 들어 염산 또는 인산과 같은 무기산, 또는 아세트산, 옥살산, 타르타르산, 만델산 등과 같은 유기산으로 형성된다. 자유 카르복실기로 형성된 염은 또한 예를 들어, 나트륨, 칼륨, 암모늄, 칼슘 또는 수산화 제2철과 같은 무기 염기 및 이소프로필아민, 트리메틸아민, 2-에틸아미노 에탄올, 히스티딘, 프로카인 등과 같은 유기 염기로부터 유도될 수 있다. 서열번호 10의 서열을 포함하는 융합 단백질의 기능적 변이체는 서열번호 10과 약 85% 이상, 약 86% 이상, 약 87% 이상, 약 88% 이상, 약 89% 이상, 약 89% 이상, 약 90% 이상, 약 91% 이상, 약 92 % 이상, 약 93% 이상, 약 94% 이상, 약 95% 이상, 약 96% 이상, 약 97% 이상, 약 98% 이상, 또는 약 99% 이상의 서열 동일성의 폴리펩타이드일 수 있다.
일 양태에 따르면, 진행성, 수술 불가능 또는 전이성 자궁경부암 환자에게 GX-188 및 항-PD1 항체 투여하면, 종양의 크기 및/또는 부피 감소와 같은 현저한 치료 효과와 T 세포 반응, PD-L1, CEA 및/또는 TA4 수준에 의해 측정된 개선된 항암 면역 반응을 보여준다. 예를 들어, GX-188 변이체와 항-PD1 항체의 투여는 HPV 특이적 T 세포 반응을 효과적으로 유도하였다. 펨브롤리주맙 단독요법은 PD-1 음성 환자에게 효과가 없는 반면, GX-188과 펨브롤리주맙 병용 요법은 PD1 음성인 자궁경부암 환자의 치료 또는 치료 강화에 효과적이다.
실시예
이하, 실시예를 통하여 본 발명을 더욱 상세하게 설명한다. 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 범위가 이들 실시예에 의해 한정되는 것은 아님은 당업자에게 자명할 것이다.
실시예 1. 전임상 연구
자궁경부암에 대한 GX-188E 및 항-PD1 항체 병용 요법의 항종양 효능을 동물 모델에서 평가하였다. HPV 유형 16 E7을 발현하도록 형질전환된 C57BL/6 마우스 폐 상피세포의 세포주인 TC-1 세포를 GX-188E 효능 평가를 위한 동물 모델 생산을 위한 세포주로 선택하였다.
C57BL/6 마우스에 1 Х105 TC-1 종양 세포(제공: 이재태 교수, 경북대학교 병원)를 피하 이식하여 종양을 형성한 후, 마우스에 4 μg의 GX-188E 또는 제형 완충제(PBS)를 1주, 2주 및 4주에 전기천공법(OrbijectorTM, Elimtek Co., Ltd)을 통해 근육내 투여하였다. 병용 요법 및 항-마우스 PD-1 항체 (항-mPD-1 mAb) 단독군의 경우, 250㎍ 항-mPD1 항체(BioXcell, 클론 RMP1-14)를 TC-1 세포 이식 후 2 주 후에 시작하여 1주 간격으로 5회 복강내 투여하였다. 종양 세포 공격(callenge) 후 종양 크기를 측정하고 주 2회 생존율을 확인하였다(도 2a).
대조군(PBS) 그룹의 모든 동물이 사망하여 사용된 종양 공격 조건이 적절함을 확인하였다. 항-mPD-1 항체만 투여한 경우 일부 동물은 약한 효과, 즉, 대조군에 비해 종양세포 성장 지연을 보여주었다. 그러나 모든 동물이 결국 사망하여, 항-mPD-1 항체는 생존율에서는 변화를 유도하지 못했다. GX-188E만 투여한 경우, 종양세포의 성장 지연으로 인한 평균 생존기간의 뚜렷한 증가가 있었고 최종생존율은 17%(1/6)였다. 반면, GX-188E와 항-mPD-1 항체를 병용 투여한 경우 종양세포의 성장지연과 생존기간이 현저히 증가하고, 생존율도 50%까지 증가하였다 (3/6). (도 2b-2e).
이러한 발견에 기초하여, 본 발명자들은 GX-188E에 의해 유도된 항원 특이적 세포 면역 반응이 이미 형성된 종양 세포를 효과적으로 제거할 수 있고, 이는 종양 세포 성장을 지연시키고 생존 기간을 증가시킬 수 있음을 확인하였다. 또한, 면역조절 화합물과 GX-188E 치료백신을 병용 투여한 그룹은 GX-188E 단독 그룹과 유사한 수준의 지연된 종양 세포 성장 및 연장된 생존을 보였고, 이는 또한 장기적 관점에서 생존율의 증가로 이어졌다.
주어진 체크포인트 억제제의 작용 기전을 근거로 유추해보면, 본 연구의 결과는 항-PD1 항체가 T 세포의 항종양 활성을 연장시킨다는 이전 연구의 결과와 유사하였다. 따라서 본 연구 결과는 체크포인트 억제제가 GX-188E를 포함하는 HPV 표적 면역치료 백신의 효능을 향상시키기 위한 적절한 시너지 파트너임을 시사한다.
이번 연구의 결과는 항-PD1 항체와 면역치료 백신 GX-188E의 병용이 GX-188E의 효능을 강화시키는 것을 보여주었으며, 이는 체크포인트 억제제가 면역치료 백신과의 병용 요법에 사용하기에 적합한 후보가 될 수 있음을 시사한다.
실시예 2. 임상 연구
GX-188E(서열번호 15)는 HPV 16/18 E6/E7을 암호화하는 HPV 치료용 DNA 백신이다. 12명의 전암 환자가 GX-188E로 면역화 되고(immunized), 1상 환자 9명 중 7명, 2상 환자 52명 중 35명이 백신 접종 후 36주 이내에 자궁경부 병변의 퇴행을 나타냈다. 임상적 이점은 GX-188E 백신접종에 의한 HPV 특이적 IFN-γ반응의 향상과 관련이 있었다. 전암 환자의 임상적 개념 증명을 감안할 때, 본 발명자들은 자궁경부암 환자에서 GX-188E 백신 접종이 HPV 특이적 T 세포의 빈도를 증가시켜 체크포인트 억제제에 대한 임상 반응자의 비율을 증가시킨 것이라고 추측하였다.
II상 임상 시험에서, 본 발명자들은 1차 또는 그 이후의 화학요법에 실패한 HPV 16 및/또는 18-양성 재발성/진행성 자궁경부암 환자를 대상으로 펨브롤리주맙과 조합된 GX-188E의 안전성 및 효능을 평가하였다.
A. 연구 설계 및 참가자
본 연구는 사전, 개방형 레이블, 2상 연구(prospective, open-label, phase II study)였다. 본 프로토콜은 각 연구 사이트의 기관 검토 위원회 또는 윤리 위원회의 승인을 받았으며 각 환자로부터 서면 동의서를 받았다. 본 연구는 헬싱키 선언 및 모든 관련 법률에 따라 수행되었다.
54명의 환자가 등록되었고 연구 조합(investigational combination)으로 치료되었다. 포함 기준에는 사전 동의서에 서명한 18세 이상의 여성 환자; Eastern Cooperative Oncology Group 수행 상태가 0-1이고 조직학적으로 재발성/진행성 HPV 양성(HPV 16 및/또는 HPV 18) 자궁경부암이 확인된 사람들; 재발성/진행성 암에 대해 이용 가능한 치료법으로 치료 후 질병 진행이 있었던 사람들이 포함되었다. 활동성 중추신경계 전이(active central nervous system metastases) 또는 활동성 자가면역 질환, 동종 고형 장기 또는 골수 이식의 이력(allogeneic solid organ or bone marrow transplant)이 있거나 면역결핍 진단을 받은 환자는 연구에서 제외되었다. 모든 환자는 스크리닝/기준선에서 분자 및 조직학적 분석을 위해 기록 보관 또는 새로운 생검 샘플(archival or fresh biopsy sample)을 제출하였다. IFN-γELISpot 분석을 위해 스크리닝 시 및 1, 4, 7, 10, 16, 22 및 49주에 환자로부터 말초 혈액 샘플을 채취하였다.
B. 절차
GX-188E는 삼각근 또는 외측근 (deltoid or lateralis muscles)에 2mg을 근육내 투여하고, 1주, 2주, 4주, 7주, 13주, 19주에 동시 국소 전기천공법(TriGrid Delivery System, Ichor Medical Systems, Inc.)을 즉시 시행하고, 46주차에 1회의 선택적 투여를 진행하였다. 펨브롤리주맙은 표준 임상 및 기관 관행에 따라 모든 절차 및 평가가 완료된 후 각 3주 치료 주기의 1일째에 정맥내 주입을 사용하여 투여되었다.
GX-188E에 의해 유도된 세포 면역 반응을 조사하기 위하여 HPV 16/18 E6/E7 특이적 T 세포 반응을 '연구 설계 및 참가자(Study design and participants)'에 표시된 시간에 분석하였다. IFN-γ ELISpot 분석(BD Bioscience, CA, USA)을 위해 냉동보존 및 해동된 말초혈액 단핵세포(PBMC)를 적응시키고 Kim TJ, Jin H-T, Hur S-Y, et al. Clearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients. Nature communications 2014; 5(1): 1-14.에서 이전에 설명한 대로 추가 처리하였다. HPV E6/E7에 대한 T 세포 반응은 신호를 기준선 수준과 비교하여 측정되었으며 백신 접종 후 반응이 기준선보다 5배 더 높을 때 양성으로 간주되었다.
C. 결과
환자는 약 9주마다 반응에 대해 방사선학적으로 평가 (RECIST v1·1 및 iRECIST 모두에 의해) 되었다. 임상시험 제품(investigational product)의 안전성은 환자의 기저질환, 이상반응, 활력징후 등을 고려한 검사실 검사 및 신체검사 결과를 기록, 보고, 분석하여 평가하였다. 약물 독성과 같은 환자가 경험한 이상반응(AE)을 종합적으로 평가하였다. 연구자들은 국립 암 연구소(National Cancer Institute)의 유해 사례에 대한 공통 용어 기준(CTCAE v4·03)을 기반으로 AE의 심각성을 평가하였다.
D. 통계 분석
시험용 치료(investigational treatment)의 최소 1회 용량을 받은 모든 환자는 안전성 모집단에 포함되었고 안전성 프로파일에 대해 분석되었다. AE는 MedDRA 유해 사례 사전에 따라 코딩되었다. 결과는 빈도, 영향을 받은 장기 시스템 및 연구 치료와의 관계를 조사하기 위해 표로 작성되었다. 최적의 전반적 반응률(Best overall response rate)을 포함한 효능 결과는 기술 통계(descriptive statistics)를 사용하여 분석되었다. 객관적인 반응은 RECIST v1·1 및 Response Evaluation Criteria in Solid Tumors for Immunotherapeutics (iRECIST)에 따라 평가되었다. 객관적 반응(objective response, PR 또는 CR), 안정 병변(stable disease, SD) 및 질행 병변(disease progression, PD)의 모든 결정에 대해 확증 스캔(confirmatory scans)을 획득하였다.
E. 결과
54명의 환자가 등록되었고 48명의 환자가 안전성에 대해 평가되었다(도 3). 45일의 치료를 받지 않은 3명의 환자는 프로토콜에 따라 GX-188E 백신 접종에 대한 반응 평가에 부적격한 것으로 간주되었다. 따라서, 치료 효능에 대해 48명의 환자가 평가되었다. GX-188E와 펨브롤리주맙 병용 요법을 받은 환자의 기준선 특성은 도 4에 나타나 있으며, 이는 조직학 및 HPV 유형을 제외하고 이전에 보고된 펨브롤리주맙 단일 요법으로 치료된 것들과 유사하였다.
54명의 환자가 치료 및 안전성 평가를 받았으며, 그 결과 임의의 등급의 31.5% TRAE(치료 관련 유해 사례) 및 5.6%의 3-4 등급 TRAE를 나타내었다(도 5). 전신 기관 분류(systemic organ class)에 따라 가장 흔한 TRAE는 위장 장애(9.3%)와 피부 및 피하 조직 장애(7.4%)였다. 3명의 환자(5.6%)가 3등급 TRAE를 경험했으며, 그 중 1명은 ALT(알라닌 아미노트랜스퍼라제) 수준의 4등급 상승과 관련된 3등급 AST(아스파테이트 아미노트랜스퍼라제) 수준 상승을 보였다. 이 환자는 면역 관련 부작용(irAE)으로 평가된 TRAE 때문에 치료를 중단하였다. 전반적으로, 항 PD1 항체(펨브롤리주맙) 투여와 함께 GX-188E 백신 접종은 안전하고 내약성이 있는 것으로 간주되었다. 도 6a 및 6b는 연구 장소에서 방사선 전문의에 의해 평가된 항종양 반응의 요약을 보여준다.
도 5 내지 도 6a 및 6b에서 약어는 다음 의미를 나타낸다:
TRAE: Treatment related Adverse Event (치료 관련 이상반응);
BOR: Best Overall Response (최적의 전반적 반응);
DOR: Duration of Response (반응 기간);
CR: Complete Response (완전 관해);
PR: Partial Response (부분 관해);
SD: Stable Disease (안정 병변);
PD: Progressive Disease (진행 병변);
NE: Non evaluable (평가 불가능);
DCR: Disease Control Rate (질병 조절율);
PD-L1: programmed death-ligand 1 (프로그램된 사멸 리간드 1);
SCC: Squamous Cell Carcinoma (편평 세포 암종); 및
AC: Adenocarcinoma (선암종).
도 6a에 도시된 바와 같이, BORR은 33.3%(16/48)이고 DCR은 50%(24/48)였다. BORR을 보이는 16명의 환자 중 6명의 환자가 CR을 보이는 것으로 확인되었으며, 이는 모두 지속성이고 진행 중이며, 반응 지속 기간은 컷오프 시점에서 1.3개월에서 24.2개월 사이였다; 모든 CR 환자는 PD-L1 양성이었고 HPV 16 및 편평 세포 암종을 가졌다. HPV 16 및/또는 18 양성 환자 모두에서 반응이 관찰되었지만 HPV 16 양성 환자는 더 호의적인 반응을 보였다(35.3% 대 28.6%). 예상 외로 반응은 PD-L1 양성 종양 뿐만 아니라 PD-L1 음성 종양에서도 관찰되었다: 각각 PD-L1 양성 종양이 있는 환자의 BORR 및 DCR은 41.7%(15/36) 및 61.1%(22/36), PD-L1-음성 종양에서는 8.3%(1/12) 및 16.7%(2/12).
도 7 및 도 8에 도시된 바와 같이, 10주차에 종양 감소를 보인 환자는 시간이 지남에 따라 반응이 개선되는 경향이 있었다. 평균 추적관찰 기간은 6.1개월(범위, 컷오프 날짜 기준 1.7~24.2개월)이며, 이 기간까지 24명의 환자(50.0%)에서 진행 병변(PD)이 발생하였다.
63세 환자의 종양 이미지를 도 9a에 나타내었다. 상기 환자는 HPV 16 및 PD-L1 양성 편평세포암을 가지고, 이전에 두 가지 화학요법을 받았으며, 림프절 전이가 있었다. 치료 후 상기 환자는 CR을 나타내었고 종양 마커 TA4가 정상 수준으로의 상당한 감소를 보였다. 도 9c는 이전에 두 가지 화학 요법을 받았고 골반 종괴와 림프절 전이가 있었던 HPV 18 및 PD-L1 양성 선암종을 가진 41세 환자의 종양 이미지를 보여준다. 치료 후 환자는 시간이 지남에 따라 PR과 다른 종양 표지자 CEA의 상당한 감소를 보였다. 도 9b 및 9d는 병용 치료 후 2개의 종양 마커(CEA 및 TA4)의 수준을 나타내고; 점선은 종양 마커의 정상 수준에 대한 컷오프 기준을 나타낸다.
도 10에는, 표적 병변 크기의 기준선(도 7에 도시됨)으로부터의 최대 변화가 PD-L1 발현 상태를 갖는 waterfall plot에 요약되어 있다. PD-L1 양성 환자는 PD-L1 음성 환자보다 BORR 관점에서 GX-188E와 펨브롤리주맙의 병용 요법에 더 나은 반응을 보였다(15/36 대 1/12)(도 6a).
중요하게는, 펨브롤리주맙 단독 연구에서는 PD-L1 음성 환자에서 반응이 관찰되지 않은 반면, 한 명의 PD-L1 음성 환자에서 30% 이상의 표적 크기 감소가 관찰되었다. 항원 특이적 T 세포 반응과 관련하여, IFN-γELISpot 분석의 결과는 기준선(표시되지 않음)으로부터 배수 변화로 표시되었다. 반응 평가 가능 환자 23명 중 18명(78.3%)은 DNA 백신 유도 T 세포 반응을 보인 바, 이는 GX-188E와 펨브롤리주맙의 조합은 사전 치료를 많이 받은 암 환자에서도 HPV E6/E7 특이적 T 세포 반응을 효과적으로 유도했음을 나타낸다.
A. 논의
임상 연구 결과에 따르면 펨브롤리주맙과 조합된 HPV 백신은 재발성/진행성, 수술 불가능 또는 전이성 자궁경부암 환자에서 효과적인 항종양 반응을 유도하였다. 그 임상적 이점은 유망하였다(전체 환자에서 33.3% BORR, PD-L1 양성 환자에서 41.7%). 우리가 아는 한, 이는 재발성/진행성 자궁경부암 환자에 대한 암 백신과 체크포인트 억제제와의 병용 요법에 대한 첫 번째 보고서이다. 일단 종양 항원 특이적 T 세포가 암 백신에 의해 유도되면 종양 조직으로 이동 및 침투하여 cold tumor를 hot tumor로 전환한다. 종양 침윤 림프구(TIL)는 IFN-γ를 분비하여 면역 공격에 대한 적응 저항 기전으로서 종양 세포로부터 PD-L1의 발현을 유도한다. 체크포인트 억제제는 소진된 TIL의 종양 세포 용해 기능을 활성화하여 항종양 반응을 유도하므로, 종양 특이적 TIL의 존재는 체크포인트 억제제에 대한 항종양 반응의 전제 조건이다. TIL의 부재 및 PD-L1 음성과 체크포인트 억제제에 대한 상대적으로 열악한 임상 반응의 상관관계에 의해 입증된 바와 같이, PD-L1 음성을 가지는 비면역원성 cold tumor는 TIL 및 PD-L1 발현을 증가시키기 위한 추가 전략이 필요하다고 제안된다.
암 백신은 종양 특이적 T 세포 반응을 유도하는 가장 효율적인 방법으로 간주된다. GX-188E 백신 접종은 HPV 전암 환자에서 Ag 특이적 T 세포 반응을 효과적으로 유도하였다. GX188E 백신 접종은 TIL의 빈도를 증가시킨 다음 종양에서 PD-L1 발현을 증가시킬 가능성이 있다. 이것이 GX188E 백신 접종이 항-PD1 항체와 함께 임상 효능을 어떻게 향상시켰는지에 대한 가능한 설명이다.
HPV 16 감염, PD-L1 양성, 편평 세포 암종에 비해 HPV 18 감염, PD-L1 음성, 선암종을 동반한 재발성/진행성 자궁경부암은 임상 반응이 좋지 않은 경향이 있다는 결과가 나타났다.
요약하면, 과도하게 사전 치료된 재발성/진행성 자궁경부암 환자에서 GX-188E와 체크포인트 억제제(펨브롤리주맙을 포함한 PD-1/PD-L1 경로 억제제)와의 병용 치료는 안전하고 내약성이 있었으며, 이전에 보고된 펨브롤리주맙 단독 요법과 유사한 안전성 프로파일을 보여준다. 이 결과는 GX-188E 백신이 많은 사전 치료를 받은 자궁경부암 환자에서 HPV 특이적 T 세포 반응을 효과적으로 유도하면서 유의한 부작용을 추가하지 않았음을 나타낸다. 본 병용 요법은 PD-L1 양성 환자에서 약 41.7%, HPV 16 양성 환자에서 35.3%, 편평 세포 암종 환자에서 33.3%의 높은 반응율을 보였다. 그리고 펨브롤리주맙 단독요법이 효과가 없는 것과 대조적으로, 본 병용 요법은 PD-L1 음성 환자에서 효과적이었다. 또한, 본 조합 치료는 HPV 18 및 선암종에서도 임상 반응을 입증했다.
따라서 GX-188E와 항-PD1 항체를 병용하는 본 병용 요법은 현재 이용 가능한 표준 요법에 실패한 HPV 16-/18-양성 재발성 또는 진행성 자궁경부암 환자의 치료에 안전하고 효과적이며, 자궁경부암 뿐만 아니라 인두암, 항문암과 같은 HPV 16/18 관련 암에 대한 새로운 표준 치료법이 될 가능성이 있다.
<110> GENEXINE, INC.
<120> Methods of Treating Cervical Cancer
<130> 1071126KR
<150> US 63/015,076
<151> 2020-04-24
<160> 116
<170> PatentIn version 3.5
<210> 1
<211> 477
<212> DNA
<213> Artificial Sequence
<220>
<223> E6 nucleotide sequence
<400> 1
atgcaccaaa agagaactgc aatgtttcag gacccacagg agcgacccag aaagttacca 60
catttatgca cagagctgca aacaactata catgatataa tattagaatg tgtgtactgc 120
aagcaacagt tactgcgacg tgaggtatat gactttgctt ttcgggattt atgcatagta 180
tatagagatg ggaatccata tgcagtgtgt gataaatgtt taaagtttta ttctaaaatt 240
agtgagtata gatattattg ttatagtgtg tatggaacaa cattagaaca gcaatacaac 300
aaaccgttgt gtgatttgtt aattaggtgt attaactgtc aaaagccact gtgtcctgaa 360
gaaaagcaaa gacatctgga caaaaagcaa agattccata atataagggg tcggtggacc 420
ggtcgatgta tgtcttgttg cagatcatca agaacacgta gagaaaccca gctgtaa 477
<210> 2
<211> 158
<212> PRT
<213> Artificial Sequence
<220>
<223> E6 protein
<400> 2
Met His Gln Lys Arg Thr Ala Met Phe Gln Asp Pro Gln Glu Arg Pro
1 5 10 15
Arg Lys Leu Pro His Leu Cys Thr Glu Leu Gln Thr Thr Ile His Asp
20 25 30
Ile Ile Leu Glu Cys Val Tyr Cys Lys Gln Gln Leu Leu Arg Arg Glu
35 40 45
Val Tyr Asp Phe Ala Phe Arg Asp Leu Cys Ile Val Tyr Arg Asp Gly
50 55 60
Asn Pro Tyr Ala Val Cys Asp Lys Cys Leu Lys Phe Tyr Ser Lys Ile
65 70 75 80
Ser Glu Tyr Arg Tyr Tyr Cys Tyr Ser Val Tyr Gly Thr Thr Leu Glu
85 90 95
Gln Gln Tyr Asn Lys Pro Leu Cys Asp Leu Leu Ile Arg Cys Ile Asn
100 105 110
Cys Gln Lys Pro Leu Cys Pro Glu Glu Lys Gln Arg His Leu Asp Lys
115 120 125
Lys Gln Arg Phe His Asn Ile Arg Gly Arg Trp Thr Gly Arg Cys Met
130 135 140
Ser Cys Cys Arg Ser Ser Arg Thr Arg Arg Glu Thr Gln Leu
145 150 155
<210> 3
<211> 477
<212> DNA
<213> Artificial Sequence
<220>
<223> E6 nucleotide sequence
<400> 3
atggcgcgct ttgaggatcc aacacggcga ccctacaagc tacctgatct gtgcacggaa 60
ctgaacactt cactgcaaga catagaaata acctgtgtat attgcaagac agtattggaa 120
cttacagagg tatttgaatt tgcattcaaa gatttatttg tagtgtatag agacagtata 180
ccgcatgctg catgccataa atgtatagat ttctattcta gaattagaga attaagatat 240
tattcagact ctgtgtatgg agacacatta gaaaaactaa ctaacactgg gttatacaat 300
ttattaataa ggtgcctgcg gtgccagaaa ccgttgaatc cagcagaaaa acttagacac 360
cttaatgaaa aacgacgatt ccacaaaata gctgggcact atagaggcca gtgccattcg 420
tgctgcaacc gagcacgaca ggagagactc caacgacgca gagaaacaca agtataa 477
<210> 4
<211> 158
<212> PRT
<213> Artificial Sequence
<220>
<223> E6 protein
<400> 4
Met Ala Arg Phe Glu Asp Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp
1 5 10 15
Leu Cys Thr Glu Leu Asn Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys
20 25 30
Val Tyr Cys Lys Thr Val Leu Glu Leu Thr Glu Val Phe Glu Phe Ala
35 40 45
Phe Lys Asp Leu Phe Val Val Tyr Arg Asp Ser Ile Pro His Ala Ala
50 55 60
Cys His Lys Cys Ile Asp Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr
65 70 75 80
Tyr Ser Asp Ser Val Tyr Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr
85 90 95
Gly Leu Tyr Asn Leu Leu Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu
100 105 110
Asn Pro Ala Glu Lys Leu Arg His Leu Asn Glu Lys Arg Arg Phe His
115 120 125
Lys Ile Ala Gly His Tyr Arg Gly Gln Cys His Ser Cys Cys Asn Arg
130 135 140
Ala Arg Gln Glu Arg Leu Gln Arg Arg Arg Glu Thr Gln Val
145 150 155
<210> 5
<211> 297
<212> DNA
<213> Artificial Sequence
<220>
<223> E7 nucleotide sequence
<400> 5
atgcatggag atacacctac attgcatgaa tatatgttag atttgcaacc agagacaact 60
gatctctact gttatgagca attaaatgac agctcagagg aggaggatga aatagatggt 120
ccagctggac aagcagaacc ggacagagcc cattacaata ttgtaacctt ttgttgcaag 180
tgtgactcta cgcttcggtt gtgcgtacaa agcacacacg tagacattcg tactttggaa 240
gacctgttaa tgggcacact aggaattgtg tgccccatct gttctcagaa accataa 297
<210> 6
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> E7 protein
<400> 6
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln
85 90 95
Lys Pro
<210> 7
<211> 318
<212> DNA
<213> Artificial Sequence
<220>
<223> E7 nucleotide sequence
<400> 7
atgtatggac ctaaggcaac attgcaagac attgtattgc atttagagcc tcaaaatgaa 60
attccggttg accttctatg tcacgagcaa ttaagcgact cagaggaaga aaacgatgaa 120
atagatggag ttaatcatca acatttacca gcccgacgag ccgaaccaca acgtcacaca 180
atgttgtgta tgtgttgtaa gtgtgaagcc agaattgagc tagtagtaga aagctcagca 240
gacgaccttc gagcattcca gcagctgttt ctgagcaccc tgtcctttgt gtgtccgtgg 300
tgtgcatccc agcagtaa 318
<210> 8
<211> 105
<212> PRT
<213> Artificial Sequence
<220>
<223> E7 protein
<400> 8
Met Tyr Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu His Leu Glu
1 5 10 15
Pro Gln Asn Glu Ile Pro Val Asp Leu Leu Cys His Glu Gln Leu Ser
20 25 30
Asp Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln His
35 40 45
Leu Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys Met
50 55 60
Cys Cys Lys Cys Glu Ala Arg Ile Glu Leu Val Val Glu Ser Ser Ala
65 70 75 80
Asp Asp Leu Arg Ala Phe Gln Gln Leu Phe Leu Ser Thr Leu Ser Phe
85 90 95
Val Cys Pro Trp Cys Ala Ser Gln Gln
100 105
<210> 9
<211> 1737
<212> DNA
<213> Artificial Sequence
<220>
<223> codon optimized sequence of GX-188 without FLT3L and signal
peptide
<400> 9
atgcaccaga agagaaccgc catgttccag gaccctcagg agagacctag gaagctgcct 60
cacctgtgta cagagctcca gacaaccatc cacgacatca tcctggagtg cgtgtactgt 120
aagcagcagc tgctgagaag agaggtgtac gacttcgcct tcagagacct gtgcatcgtg 180
tacagagacg gcaaccctta cgccgtgtgc gataagtgtc tgaagttcta ttccaaaatc 240
tccgaatata ggtacatgca cggcgacacc cctaccctgc acgagtacat gctggacctc 300
cagcctgaga ccacagacct gtactgctac gagcagctga acgacagctc tgaggaagag 360
gacgagattg acggacctgc tggccaggcc gagcctgaca gagcccacta caatatcgtg 420
acattctgtt gcaaatgcga ctccacactg gacaagtgcc tgaagttcta cagcaagatc 480
tctgagtaca gatactactg ctactctgtg tacggcacca cactggagca gcagtacaac 540
aagcctctgt gcgacctcct gatccgctgc atcaactgcc agaagcctct gtgccctgag 600
gagaagcaga gacacctgga caagaagcag cggttccaca acatcagagg cagatggacc 660
ggcaggtgca tgtcctgctg tagatcctcc agaaccagac gggagaccca gctgcactac 720
aacatcgtga ccttctgctg caagtgcgac tctaccctga gactgtgcgt gcagtctacc 780
cacgtggaca tcagaaccct ggaggacctg ctgatgggca ccctgggcat cgtgtgccct 840
atctgctctc agaagcctat ggccaggttc gaggacccta ccagaagacc ctacaagctg 900
cctgacctgt gcaccgagct gaacacctct ctgcaagaca tcgagatcac ctgcgtgtac 960
tgcaagaccg tgctggagct gaccgaggtg ttcgagttcg ccttcaagga cctgttcgtg 1020
gtgtacagag acagcatccc tcacgctgcc tgccacaagt gcatcgactt ctattccagg 1080
atcagggagc tgcgctatta ctccgactct gtgatgtacg gccccaaggc caccctccag 1140
gacatcgtgc tgcacctgga gcctcagaac gagatccccg tggacctgct gtgccacgag 1200
cagctgtctg actctgaaga ggagaacgac gagatcgacg gcgtgaacca ccagcacctg 1260
cctgccagga gagctgaacc ccagcggcat accatgctgt gtatgtgctt ctactctagg 1320
atcagagagc tgaggtacta ctctgactct gtgtacggcg acaccctgga gaagctgacc 1380
aacaccggcc tgtacaacct gctgatccgg tgcctgaggt gccagaagcc tctgaaccct 1440
gccgagaagc tgagacacct gaacgagaag agaagattcc acaagatcgc tggccactac 1500
agaggccagt gccactcttg ctgcaacaga gccagacagg agagactcca gcggagaagg 1560
gagacccagg tggccagaag agccgagcct cagagacaca ccatgctgtg catgtgctgc 1620
aagtgcgagg ccagaatcga gctggtggtg gagagctctg ccgacgacct gagagccttc 1680
cagcagctgt tcctgtctac cctgagcttc gtgtgccctt ggtgcgcctc tcagcag 1737
<210> 10
<211> 579
<212> PRT
<213> Artificial Sequence
<220>
<223> amino acid sequence of GX-188 without FLT3L and signal peptide
<400> 10
Met His Gln Lys Arg Thr Ala Met Phe Gln Asp Pro Gln Glu Arg Pro
1 5 10 15
Arg Lys Leu Pro His Leu Cys Thr Glu Leu Gln Thr Thr Ile His Asp
20 25 30
Ile Ile Leu Glu Cys Val Tyr Cys Lys Gln Gln Leu Leu Arg Arg Glu
35 40 45
Val Tyr Asp Phe Ala Phe Arg Asp Leu Cys Ile Val Tyr Arg Asp Gly
50 55 60
Asn Pro Tyr Ala Val Cys Asp Lys Cys Leu Lys Phe Tyr Ser Lys Ile
65 70 75 80
Ser Glu Tyr Arg Tyr Met His Gly Asp Thr Pro Thr Leu His Glu Tyr
85 90 95
Met Leu Asp Leu Gln Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln
100 105 110
Leu Asn Asp Ser Ser Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly
115 120 125
Gln Ala Glu Pro Asp Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys
130 135 140
Lys Cys Asp Ser Thr Leu Asp Lys Cys Leu Lys Phe Tyr Ser Lys Ile
145 150 155 160
Ser Glu Tyr Arg Tyr Tyr Cys Tyr Ser Val Tyr Gly Thr Thr Leu Glu
165 170 175
Gln Gln Tyr Asn Lys Pro Leu Cys Asp Leu Leu Ile Arg Cys Ile Asn
180 185 190
Cys Gln Lys Pro Leu Cys Pro Glu Glu Lys Gln Arg His Leu Asp Lys
195 200 205
Lys Gln Arg Phe His Asn Ile Arg Gly Arg Trp Thr Gly Arg Cys Met
210 215 220
Ser Cys Cys Arg Ser Ser Arg Thr Arg Arg Glu Thr Gln Leu His Tyr
225 230 235 240
Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr Leu Arg Leu Cys
245 250 255
Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu Asp Leu Leu Met
260 265 270
Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln Lys Pro Met Ala
275 280 285
Arg Phe Glu Asp Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp Leu Cys
290 295 300
Thr Glu Leu Asn Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys Val Tyr
305 310 315 320
Cys Lys Thr Val Leu Glu Leu Thr Glu Val Phe Glu Phe Ala Phe Lys
325 330 335
Asp Leu Phe Val Val Tyr Arg Asp Ser Ile Pro His Ala Ala Cys His
340 345 350
Lys Cys Ile Asp Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser
355 360 365
Asp Ser Val Met Tyr Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu
370 375 380
His Leu Glu Pro Gln Asn Glu Ile Pro Val Asp Leu Leu Cys His Glu
385 390 395 400
Gln Leu Ser Asp Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn
405 410 415
His Gln His Leu Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met
420 425 430
Leu Cys Met Cys Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser
435 440 445
Asp Ser Val Tyr Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr Gly Leu
450 455 460
Tyr Asn Leu Leu Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu Asn Pro
465 470 475 480
Ala Glu Lys Leu Arg His Leu Asn Glu Lys Arg Arg Phe His Lys Ile
485 490 495
Ala Gly His Tyr Arg Gly Gln Cys His Ser Cys Cys Asn Arg Ala Arg
500 505 510
Gln Glu Arg Leu Gln Arg Arg Arg Glu Thr Gln Val Ala Arg Arg Ala
515 520 525
Glu Pro Gln Arg His Thr Met Leu Cys Met Cys Cys Lys Cys Glu Ala
530 535 540
Arg Ile Glu Leu Val Val Glu Ser Ser Ala Asp Asp Leu Arg Ala Phe
545 550 555 560
Gln Gln Leu Phe Leu Ser Thr Leu Ser Phe Val Cys Pro Trp Cys Ala
565 570 575
Ser Gln Gln
<210> 11
<211> 489
<212> DNA
<213> Artificial Sequence
<220>
<223> Nucleotide sequence of FLT3L (fms-like tyrosine kinase-3 ligand)
<400> 11
atcacccagg actgctcctt ccaacacagc cccatctcct ccgacttcgc tgtcaaaatc 60
cgtgagctgt ctgactacct gcttcaagat tacccagtca ccgtggcctc caacctgcag 120
gacgaggagc tctgcggggg cctctggcgg ctggtcctgg cacagcgctg gatggagcgg 180
ctcaagactg tcgctgggtc caagatgcaa ggcttgctgg agcgcgtgaa cacggagata 240
cactttgtca ccaaatgtgc ctttcagccc ccccccagct gtcttcgctt cgtccagacc 300
aacatctccc gcctcctgca ggagacctcc gagcagctgg tggcgctgaa gccctggatc 360
actcgccaga acttctcccg gtgcctggag ctgcagtgtc agcccgactc ctcaaccctg 420
ccacccccat ggagtccccg gcccctggag gccacagccc cgacagcccc gggcggcggc 480
agcggcgat 489
<210> 12
<211> 163
<212> PRT
<213> Artificial Sequence
<220>
<223> Amino acid sequence of FLT3L (fms-like tyrosine kinase-3 ligand)
<400> 12
Ile Thr Gln Asp Cys Ser Phe Gln His Ser Pro Ile Ser Ser Asp Phe
1 5 10 15
Ala Val Lys Ile Arg Glu Leu Ser Asp Tyr Leu Leu Gln Asp Tyr Pro
20 25 30
Val Thr Val Ala Ser Asn Leu Gln Asp Glu Glu Leu Cys Gly Gly Leu
35 40 45
Trp Arg Leu Val Leu Ala Gln Arg Trp Met Glu Arg Leu Lys Thr Val
50 55 60
Ala Gly Ser Lys Met Gln Gly Leu Leu Glu Arg Val Asn Thr Glu Ile
65 70 75 80
His Phe Val Thr Lys Cys Ala Phe Gln Pro Pro Pro Ser Cys Leu Arg
85 90 95
Phe Val Gln Thr Asn Ile Ser Arg Leu Leu Gln Glu Thr Ser Glu Gln
100 105 110
Leu Val Ala Leu Lys Pro Trp Ile Thr Arg Gln Asn Phe Ser Arg Cys
115 120 125
Leu Glu Leu Gln Cys Gln Pro Asp Ser Ser Thr Leu Pro Pro Pro Trp
130 135 140
Ser Pro Arg Pro Leu Glu Ala Thr Ala Pro Thr Ala Pro Gly Gly Gly
145 150 155 160
Ser Gly Asp
<210> 13
<211> 69
<212> DNA
<213> Artificial Sequence
<220>
<223> Signal peptide of tPA
<400> 13
atggatgcta tgaaacgggg cctgtgctgc gtgctgctcc tgtgcggcgc tgtgtttgtg 60
agccctagc 69
<210> 14
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> Signal peptide of tPA
<400> 14
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser
20
<210> 15
<211> 6085
<212> DNA
<213> Artificial Sequence
<220>
<223> GX-188E
<400> 15
acgcgttgac attgattatt gactagttat taatagtaat caattacggg gtcattagtt 60
catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc gcctggctga 120
ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat agtaacgcca 180
atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc ccacttggca 240
gtacatcaag tgtatcatat gccaagtacg ccccctattg acgtcaatga cggtaaatgg 300
cccgcctggc attatgccca gtacatgacc ttatgggact ttcctacttg gcagtacatc 360
tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacat caatgggcgt 420
ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt caatgggagt 480
ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaacaactc cgccccattg 540
acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata taagcagagc tctctggcta 600
actagagaac ccactgctta ctggcttatc gaaattaata cgactcacta tagggagacc 660
caagctggct agcgtgagtt tggggaccct tgattgttct ttctttttcg ctattgtaaa 720
attcatgtta tatggagggg gcaaagtttt cagggtgttg tttagaacgg gaagatgtcc 780
cttgtatcac catggaccct catgataatt ttgtttcttt cactttctac tctgttgaca 840
accattgtct cctcttattt tcttttcatt ttctgtaact ttttcgttaa actttagctt 900
gcatttgtaa cgaattttta aattcacttt tgtttatttg tcagattgta agtactttct 960
ctaatcactt ttttttcaag gcaatcaggg tatattatat tgtacttcag cacagtttta 1020
gagaacaatt gttataatta aatgataagg tagaatattt ctgcatataa attctggctg 1080
gcgtggaaat attcttattg gtagaaacaa ctacatcctg gtcatcatcc tgcctttctc 1140
tttatggtta caatgatata cactgtttga gatgaggata aaatactctg agtccaaacc 1200
gggcccctct gctaaccatg ttcatgcctt cttctttttc ctacagctcc tgggcaacgt 1260
gctggttatt gtgctgtctc atcattttgg caaagaattg taatacgact cactataggg 1320
cgaattgaag cttggtaccg ccaccatgga tgctatgaaa cggggcctgt gctgcgtgct 1380
gctcctgtgc ggcgctgtgt ttgtgagccc tagcatcacc caggactgct ccttccaaca 1440
cagccccatc tcctccgact tcgctgtcaa aatccgtgag ctgtctgact acctgcttca 1500
agattaccca gtcaccgtgg cctccaacct gcaggacgag gagctctgcg ggggcctctg 1560
gcggctggtc ctggcacagc gctggatgga gcggctcaag actgtcgctg ggtccaagat 1620
gcaaggcttg ctggagcgcg tgaacacgga gatacacttt gtcaccaaat gtgcctttca 1680
gccccccccc agctgtcttc gcttcgtcca gaccaacatc tcccgcctcc tgcaggagac 1740
ctccgagcag ctggtggcgc tgaagccctg gatcactcgc cagaacttct cccggtgcct 1800
ggagctgcag tgtcagcccg actcctcaac cctgccaccc ccatggagtc cccggcccct 1860
ggaggccaca gccccgacag ccccgggcgg cggcagcggc gatgctagca tgcaccagaa 1920
gagaaccgcc atgttccagg accctcagga gagacctagg aagctgcctc acctgtgtac 1980
agagctccag acaaccatcc acgacatcat cctggagtgc gtgtactgta agcagcagct 2040
gctgagaaga gaggtgtacg acttcgcctt cagagacctg tgcatcgtgt acagagacgg 2100
caacccttac gccgtgtgcg ataagtgtct gaagttctat tccaaaatct ccgaatatag 2160
gtacatgcac ggcgacaccc ctaccctgca cgagtacatg ctggacctcc agcctgagac 2220
cacagacctg tactgctacg agcagctgaa cgacagctct gaggaagagg acgagattga 2280
cggacctgct ggccaggccg agcctgacag agcccactac aatatcgtga cattctgttg 2340
caaatgcgac tccacactgg acaagtgcct gaagttctac agcaagatct ctgagtacag 2400
atactactgc tactctgtgt acggcaccac actggagcag cagtacaaca agcctctgtg 2460
cgacctcctg atccgctgca tcaactgcca gaagcctctg tgccctgagg agaagcagag 2520
acacctggac aagaagcagc ggttccacaa catcagaggc agatggaccg gcaggtgcat 2580
gtcctgctgt agatcctcca gaaccagacg ggagacccag ctgcactaca acatcgtgac 2640
cttctgctgc aagtgcgact ctaccctgag actgtgcgtg cagtctaccc acgtggacat 2700
cagaaccctg gaggacctgc tgatgggcac cctgggcatc gtgtgcccta tctgctctca 2760
gaagcctatg gccaggttcg aggaccctac cagaagaccc tacaagctgc ctgacctgtg 2820
caccgagctg aacacctctc tgcaagacat cgagatcacc tgcgtgtact gcaagaccgt 2880
gctggagctg accgaggtgt tcgagttcgc cttcaaggac ctgttcgtgg tgtacagaga 2940
cagcatccct cacgctgcct gccacaagtg catcgacttc tattccagga tcagggagct 3000
gcgctattac tccgactctg tgatgtacgg ccccaaggcc accctccagg acatcgtgct 3060
gcacctggag cctcagaacg agatccccgt ggacctgctg tgccacgagc agctgtctga 3120
ctctgaagag gagaacgacg agatcgacgg cgtgaaccac cagcacctgc ctgccaggag 3180
agctgaaccc cagcggcata ccatgctgtg tatgtgcttc tactctagga tcagagagct 3240
gaggtactac tctgactctg tgtacggcga caccctggag aagctgacca acaccggcct 3300
gtacaacctg ctgatccggt gcctgaggtg ccagaagcct ctgaaccctg ccgagaagct 3360
gagacacctg aacgagaaga gaagattcca caagatcgct ggccactaca gaggccagtg 3420
ccactcttgc tgcaacagag ccagacagga gagactccag cggagaaggg agacccaggt 3480
ggccagaaga gccgagcctc agagacacac catgctgtgc atgtgctgca agtgcgaggc 3540
cagaatcgag ctggtggtgg agagctctgc cgacgacctg agagccttcc agcagctgtt 3600
cctgtctacc ctgagcttcg tgtgcccttg gtgcgcctct cagcagtaat ctagagtcgg 3660
ggcggccggc cgcttcgagc agacatgata agatacattg atgagtttgg acaaaccaca 3720
actagaatgc agtgaaaaaa atgctttatt tgtgaaattt gtgatgctat tgctttattt 3780
gtaaccatta taagctgcaa taaacaagtt aacaacaaca attgcattca ttttatgttt 3840
caggttcagg gggaggtgtg ggaggttttt taaagcaagt aaaacctcta caaatgtggt 3900
aaaatcgata aggatctgaa cgatggagcg gagaatgggc ggaactgggc ggagttaggg 3960
gcgggatggg cggagttagg ggcgggacta tggttgctga ctaattgaga tgcatgcttt 4020
gcatacttct gcctgctggg gagcctgggg actttccaca cctggttgct gactaattga 4080
gatgcatgct ttgcatactt ctgcctgctg gggagcctgg ggactttcca caccctaact 4140
gacacacatt ccacagcgga tccgtcgact tcagaagaac tcgtcaagaa ggcgatagaa 4200
ggcgatgcgc cgcgaatcgg gagcggcgat accgtagagc acgaggaagc ggtcagccca 4260
ttcgccgcca agctcttcag caatatcacg ggtagccaac gctatgtcct gatagcggtc 4320
cgccacaccc agccggccac agtcgatgaa tccagaaaag cggccatttt ccaccatgat 4380
attcggcaag caggcatcgc catgggtcac gacgagatcc tcgccgtcgg gcatgctcgc 4440
cttgagcctg gcgaacagtt cggctggcgc gagcccctga tgctcttcgt ccagatcatc 4500
ctgatcgaca agaccggctt ccatccgagt acgtgctcgc tcgatgcgat gtttcgcttg 4560
gtggtcgaat gggcaggtag ccggatcaag cgtatgcagc cgccgcattg catcagccat 4620
gatggatact ttctcggcag gagcaaggtg agatgacagg agatcctgcc ccggcacttc 4680
gcccaatagc agccagtccc ttcccgcttc agtgacaacg tcgagcacag ctgcgcaagg 4740
aacgcccgtc gtggccagcc acgatagccg cgctgcctcg tcttgcagtt cattcagggc 4800
accggacagg tcggtcttga caaaaagaac cgggcgcccc tgcgctgaca gccggaacac 4860
ggcggcatca gagcagccga ttgtctgttg tgcccagtca tagccgaata gcctctccac 4920
ccaagcggcc ggagaacctg cgtgcaatcc atcttgttca atcatgcgaa acgatcctca 4980
tcctgtctct tgatcagatc ttgatcccct gcgccatcag atccttggcg gcaagaaagc 5040
catccagttt actttgcagg gcttcccaac cttaccagag ggcgccccag ctggcaattc 5100
cggttcgctt gctgtccata aaaccgccca gtctagctat cgccatgtaa gcccactgca 5160
agctacctgc tttctctttg cgcttgcgtt ttcccttgtc cagatagccc agtagctgac 5220
attcatccgg ggtcagcacc gtttctgcgg actggctttc tacgtgaaaa ggatctaggt 5280
gaagatcctt tttgataatc tcatgaccaa aatcccttaa cgtgagtttt cgttccactg 5340
agcgtcagac cccgtagaaa agatcaaagg atcttcttga gatccttttt ttctgcgcgt 5400
aatctgctgc ttgcaaacaa aaaaaccacc gctaccagcg gtggtttgtt tgccggatca 5460
agagctacca actctttttc cgaaggtaac tggcttcagc agagcgcaga taccaaatac 5520
tgttcttcta gtgtagccgt agttaggcca ccacttcaag aactctgtag caccgcctac 5580
atacctcgct ctgctaatcc tgttaccagt ggctgctgcc agtggcgata agtcgtgtct 5640
taccgggttg gactcaagac gatagttacc ggataaggcg cagcggtcgg gctgaacggg 5700
gggttcgtgc acacagccca gcttggagcg aacgacctac accgaactga gatacctaca 5760
gcgtgagcta tgagaaagcg ccacgcttcc cgaagggaga aaggcggaca ggtatccggt 5820
aagcggcagg gtcggaacag gagagcgcac gagggagctt ccagggggaa acgcccggta 5880
tctttatagt cctgtcgggt ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc 5940
gtcagggggg cggagcctat ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc 6000
cttttgctgg ccttttgctc acatgttcgg gcccaatcga cccgggcgac ggccagtgaa 6060
ttgtaccgat gtacgggcca gatat 6085
<210> 16
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> alpha-1 helix of E7 protein of HPV16 (position 73-84)
<400> 16
His Val Asp Ile Arg Thr Leu Glu Asp Leu Leu Met
1 5 10
<210> 17
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> beta-2 sheet of E7 protein of HPV16 (position 64-71)
<400> 17
Thr Leu Arg Leu Cys Val Gln Ser
1 5
<210> 18
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> beta-1 sheet of E7 protein of HPV16 (position 48-58)
<400> 18
Asp Arg Ala His Tyr Asn Ile Val Thr Phe Cys
1 5 10
<210> 19
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91670.1 E6 Variant
<400> 19
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 20
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91673.1 E6 Variant
<400> 20
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 21
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91669.1 E6 Variant
<400> 21
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Lys Asn Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 22
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91674.1 E6 Variant
<400> 22
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 23
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91680.1 E6 Variant
<400> 23
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 24
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91681.1
<400> 24
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 25
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91668.1 E6 Variant
<400> 25
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 26
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91658.1 E6 Variant
<400> 26
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 27
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91662.1 E6 Variant
<400> 27
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Glu Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 28
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91667.1 E6 Variant
<400> 28
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Glu Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 29
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91676.1 E6 Variant
<400> 29
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Glu Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 30
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91671.1 E6 Variant
<400> 30
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Glu Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 31
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91656.1 E6 Variant
<400> 31
Met Phe Gln Asp Pro Gln Glu Arg Pro Gly Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 32
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91682.1 E6 Variant
<400> 32
Met Phe Gln Asp Pro Gln Glu Arg Pro Gly Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 33
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91657.1 E6 Variant
<400> 33
Met Phe Gln Asp Pro Gln Glu Arg Pro Gly Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 34
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91660.1 E6 Variant
<400> 34
Met Phe Gln Asp Pro Gln Glu Arg Pro Gly Lys Leu Pro Gln Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg His Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 35
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91677.1 E6 Variant
<400> 35
Met Phe Gln Asp Pro Gln Glu Arg Pro Thr Lys Leu Pro Asp Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 36
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91678.1 E6 Variant
<400> 36
Met Phe Gln Asp Pro Gln Glu Arg Pro Thr Lys Leu Pro Asp Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 37
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91672.1 E6 Variant
<400> 37
Met Phe Gln Asp Pro Gln Glu Arg Pro Thr Lys Leu Pro Asp Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 38
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91661.1 E6 Variant
<400> 38
Met Phe Gln Asp Pro Gln Glu Arg Pro Thr Lys Leu Pro Asp Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 39
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91664.1 E6 Variant
<400> 39
Met Phe Gln Asp Pro Gln Glu Arg Pro Ile Lys Leu Pro Asp Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 40
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91675.1 E6 Variant
<400> 40
Met Phe Gln Asp Pro Gln Glu Arg Pro Ile Lys Leu Pro Asp Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 41
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91665.1 E6 Variant
<400> 41
Met Phe Gln Asp Pro Gln Glu Arg Pro Ile Lys Leu Pro Asp Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys
65 70 75 80
Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 42
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91663.1 E6 Variant
<400> 42
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro His Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 43
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91659.1 E6 Variant
<400> 43
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro His Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 44
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91654.1 E6 Variant
<400> 44
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro His Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 45
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91666.1 E6 Variant
<400> 45
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro His Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 46
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91679.1 E6 Variant
<400> 46
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro His Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 47
<211> 151
<212> PRT
<213> Artificial Sequence
<220>
<223> AAA91655.1 E6 Variant
<400> 47
Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro His Leu Cys
1 5 10 15
Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr
20 25 30
Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg
35 40 45
Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp
50 55 60
Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys
65 70 75 80
Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu
85 90 95
Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro
100 105 110
Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile
115 120 125
Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg
130 135 140
Thr Arg Arg Glu Thr Gln Leu
145 150
<210> 48
<211> 147
<212> PRT
<213> Artificial Sequence
<220>
<223> AHZ96678.1 E6 Variant
<400> 48
Met Ala Arg Phe Glu Asp Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp
1 5 10 15
Leu Cys Thr Glu Leu Asn Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys
20 25 30
Val Tyr Cys Lys Thr Val Leu Glu Leu Thr Glu Val Phe Glu Phe Ala
35 40 45
Phe Lys Asp Leu Phe Val Val Tyr Arg Asp Ser Ile Pro His Ala Ala
50 55 60
Cys His Lys Cys Ile Asp Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr
65 70 75 80
Tyr Ser Asp Ser Val Tyr Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr
85 90 95
Gly Leu Tyr Asn Leu Leu Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu
100 105 110
Asn Pro Ala Glu Lys Leu Arg His Leu Asn Glu Lys Arg Arg Phe His
115 120 125
Lys Ile Ala Gly His Tyr Arg Gly Gln Cys His Ser Cys Cys Asn Arg
130 135 140
Ala Arg Gln
145
<210> 49
<211> 158
<212> PRT
<213> Artificial Sequence
<220>
<223> ABP99784.1 E6 Variant
<400> 49
Met Ala Arg Phe Glu Asp Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp
1 5 10 15
Leu Cys Thr Glu Leu Asn Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys
20 25 30
Val Tyr Cys Lys Thr Val Leu Glu Leu Thr Glu Val Phe Glu Phe Ala
35 40 45
Phe Lys Asp Leu Phe Val Val Tyr Arg Asp Ser Ile Pro His Ala Ala
50 55 60
Cys His Lys Cys Ile Asp Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr
65 70 75 80
Tyr Ser Asp Ser Val Tyr Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr
85 90 95
Gly Leu Tyr Asn Leu Leu Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu
100 105 110
Asn Pro Ala Glu Lys Leu Arg His Leu Asn Glu Lys Arg Arg Phe His
115 120 125
Lys Ile Ala Gly His Tyr Arg Gly Gln Cys His Ser Cys Cys Asn Arg
130 135 140
Ala Arg Gln Glu Arg Leu Gln Arg Arg Arg Glu Thr Gln Val
145 150 155
<210> 50
<211> 158
<212> PRT
<213> Artificial Sequence
<220>
<223> CAB53096.1 E6 Variant
<400> 50
Met Ala Arg Phe Glu Asp Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp
1 5 10 15
Leu Cys Thr Glu Leu Asn Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys
20 25 30
Val Tyr Cys Lys Thr Val Leu Glu Leu Thr Glu Val Phe Glu Phe Ala
35 40 45
Phe Lys Asp Leu Phe Val Val Tyr Arg Asp Ser Ile Pro His Ala Ala
50 55 60
Cys His Lys Cys Ile Asp Phe Tyr Ser Arg Ile Arg Glu Leu Arg His
65 70 75 80
Tyr Ser Asp Ser Val Tyr Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr
85 90 95
Gly Leu Tyr Asn Leu Leu Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu
100 105 110
Asn Pro Ala Glu Lys Leu Arg His Leu Asn Glu Lys Arg Arg Phe His
115 120 125
Lys Ile Ala Gly His Tyr Arg Gly Gln Cys His Ser Cys Cys Asn Arg
130 135 140
Ala Arg Gln Glu Arg Leu Gln Arg Arg Arg Glu Thr Gln Val
145 150 155
<210> 51
<211> 158
<212> PRT
<213> Artificial Sequence
<220>
<223> AGU90327.1 E6 Variant
<400> 51
Met Ala Arg Phe Glu Asp Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp
1 5 10 15
Leu Cys Thr Glu Leu Asn Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys
20 25 30
Val Tyr Cys Lys Thr Val Leu Glu Leu Thr Glu Val Phe Glu Phe Ala
35 40 45
Phe Lys Asp Leu Phe Val Val Tyr Arg Asp Ser Ile Pro His Ala Ala
50 55 60
Cys His Lys Cys Ile Asp Phe Tyr Ser Arg Ile Arg Glu Leu Arg His
65 70 75 80
Tyr Ser Asp Ser Val Tyr Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr
85 90 95
Gly Leu Tyr Asn Leu Leu Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu
100 105 110
Asn Pro Ala Glu Lys Leu Arg His Leu Asn Glu Lys Arg Arg Phe His
115 120 125
Lys Ile Ala Gly His Tyr Arg Gly Gln Cys His Ser Cys Cys Asn Gln
130 135 140
Ala Arg Gln Glu Arg Leu Gln Arg Arg Arg Glu Thr Gln Val
145 150 155
<210> 52
<211> 158
<212> PRT
<213> Artificial Sequence
<220>
<223> ADC35660.1 E6 Variant
<400> 52
Met Ala Arg Phe Glu Asp Pro Thr Arg Arg Pro Tyr Lys Val Pro Asp
1 5 10 15
Leu Cys Thr Glu Leu Asn Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys
20 25 30
Val Tyr Cys Lys Thr Val Leu Glu Leu Thr Glu Val Phe Glu Phe Ala
35 40 45
Phe Lys Asp Leu Phe Val Val Tyr Arg Asp Ser Ile Pro His Ala Ala
50 55 60
Cys His Lys Cys Ile Asp Phe Tyr Ser Arg Ile Arg Glu Leu Arg His
65 70 75 80
Tyr Ser Asp Ser Val Tyr Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr
85 90 95
Gly Leu Tyr Asn Leu Leu Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu
100 105 110
Asn Pro Ala Glu Lys Leu Arg His Leu Asn Glu Lys Arg Arg Phe His
115 120 125
Asn Ile Ala Gly His Tyr Arg Gly Gln Cys His Ser Cys Cys Asn Arg
130 135 140
Ala Arg Gln Glu Arg Leu Gln Arg Arg Arg Glu Thr Gln Val
145 150 155
<210> 53
<211> 158
<212> PRT
<213> Artificial Sequence
<220>
<223> AHZ96677.1 E6 Variant
<400> 53
Met Ala Arg Phe Glu Asp Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp
1 5 10 15
Leu Cys Thr Glu Leu Asn Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys
20 25 30
Val Tyr Cys Lys Thr Val Leu Glu Leu Thr Glu Val Phe Glu Phe Ala
35 40 45
Phe Lys Asp Leu Phe Val Val Tyr Arg Asp Ser Ile Pro His Ala Ala
50 55 60
Cys His Lys Cys Ile Asp Phe Tyr Ser Arg Ile Arg Glu Leu Arg His
65 70 75 80
Tyr Ser Asp Ser Val Tyr Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr
85 90 95
Gly Leu Tyr Asn Leu Leu Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu
100 105 110
Asn Pro Ala Glu Lys Leu Arg His Leu Asn Glu Lys Arg Arg Phe His
115 120 125
Asn Ile Ala Gly His Tyr Arg Gly Gln Cys His Ser Cys Cys Asn Arg
130 135 140
Ala Arg Gln Glu Arg Leu Gln Arg His Arg Glu Thr Gln Val
145 150 155
<210> 54
<211> 158
<212> PRT
<213> Artificial Sequence
<220>
<223> ABP99736.1 E6 Variant
<400> 54
Met Ala Arg Phe Glu Asp Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp
1 5 10 15
Leu Cys Thr Glu Leu Asn Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys
20 25 30
Val Tyr Cys Lys Thr Val Leu Glu Leu Thr Gly Val Phe Glu Phe Ala
35 40 45
Phe Lys Asp Leu Phe Val Val Tyr Arg Asp Ser Ile Pro His Ala Ala
50 55 60
Cys His Lys Cys Ile Asp Phe Tyr Ser Arg Ile Arg Glu Leu Arg His
65 70 75 80
Tyr Ser Asp Ser Val Tyr Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr
85 90 95
Gly Leu Tyr Asn Leu Leu Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu
100 105 110
Asn Pro Ala Glu Lys Leu Arg His Leu Asn Glu Lys Arg Arg Phe His
115 120 125
Asn Ile Ala Gly His Tyr Arg Gly Gln Cys His Ser Cys Cys Asn Arg
130 135 140
Ala Arg Gln Glu Arg Leu Gln Arg Arg Arg Glu Thr Gln Val
145 150 155
<210> 55
<211> 158
<212> PRT
<213> Artificial Sequence
<220>
<223> ABP99704.1 E6 Variant
<400> 55
Met Ala Arg Phe Glu Asp Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp
1 5 10 15
Leu Cys Thr Glu Leu Asn Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys
20 25 30
Val Tyr Cys Lys Thr Val Leu Glu Leu Thr Glu Val Phe Glu Phe Ala
35 40 45
Phe Lys Asp Leu Phe Val Val Tyr Arg Asp Ser Ile Pro His Ala Ala
50 55 60
Cys His Lys Cys Ile Asp Phe Tyr Ser Arg Ile Arg Glu Leu Arg His
65 70 75 80
Tyr Ser Asp Ser Val Tyr Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr
85 90 95
Gly Leu Tyr Asn Leu Leu Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu
100 105 110
Asn Pro Ala Glu Lys Leu Arg His Leu Asn Glu Lys Arg Arg Phe His
115 120 125
Asn Ile Ala Gly Arg Tyr Arg Gly Gln Cys His Ser Cys Cys Asn Arg
130 135 140
Ala Arg Gln Glu Arg Leu Gln Arg Arg Arg Glu Thr Gln Val
145 150 155
<210> 56
<211> 90
<212> PRT
<213> Artificial Sequence
<220>
<223> ABL96587.1 E7 Variant
<400> 56
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Ser Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Arg Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val
85 90
<210> 57
<211> 90
<212> PRT
<213> Artificial Sequence
<220>
<223> ABL96591.1 E7 Variant
<400> 57
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Ser Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Cys Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val
85 90
<210> 58
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19726.1 E7 Variant
<400> 58
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Val Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 59
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19722.1 E7 Variant
<400> 59
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Val Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 60
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19752.1 E7 Variant
<400> 60
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Thr Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 61
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19732.1 E7 Variant
<400> 61
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Lys Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Val Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 62
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19762.1 E7 Variant
<400> 62
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Arg Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 63
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19668.1 E7 Variant
<400> 63
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Ser Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Met Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 64
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19664.1 E7 Variant
<400> 64
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Ser Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Ser Thr Leu Gly Ile Val Cys Pro
85 90
<210> 65
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19766.1 E7 Variant
<400> 65
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Asn Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Phe Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 66
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19756.1 E7 Variant
<400> 66
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Lys Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Ile Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 67
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19680.1 E7 Variant
<400> 67
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Lys Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Thr Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 68
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19772.1 E7 Variant
<400> 68
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Asp Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Asp Thr Leu Gly Ile Val Cys Pro
85 90
<210> 69
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19696.1 E7 Variant
<400> 69
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Lys Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Lys Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 70
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19690.1 E7 Variant
<400> 70
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Val Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Gly Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 71
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19712.1 E7 Variant
<400> 71
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Lys Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu His Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Ile Thr Phe Cys Cys Arg Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 72
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AGO04504.1 E7 Variant
<400> 72
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Gly Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Met Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Ala Leu Gly Ile Val Cys Pro
85 90
<210> 73
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19770.1 E7 Variant
<400> 73
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Tyr Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Gln Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Ala Leu Gly Ile Val Cys Pro
85 90
<210> 74
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19520.2 E7 Variant
<400> 74
Met His Gly Asp Thr Pro Thr Leu His Lys Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Tyr Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Ser Thr Leu Gly Ile Val Cys Pro
85 90
<210> 75
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19708.1 E7 Variant
<400> 75
Met His Gly Asp Thr Pro Lys Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Gln Ala Gly Gln Ala Lys Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Gly Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 76
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19674.1 E7 Variant
<400> 76
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Asn Ser
20 25 30
Glu Glu Asp His Glu Ile Asp Gly Pro Asp Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 77
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AGO04498.1 E7 Variant
<400> 77
Met His Gly Asp Thr Ser Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Asn Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr Leu Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Met Leu Met Gly Thr Leu Gly Ile Val Ser Pro
85 90
<210> 78
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AGO04496.1 E7 Variant
<400> 78
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Val Leu Gly Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Val
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Phe Cys Val Gln Ser Thr Arg Leu Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 79
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19684.1 E7 Variant
<400> 79
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Lys Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu His Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Cys Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Lys Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Ile Leu Gly Ile Val Cys Pro
85 90
<210> 80
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19678.1 E7 Variant
<400> 80
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Lys Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Cys Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Thr Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Thr Ile Val Thr Phe Cys Cys Met Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 81
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19698.1 E7 Variant
<400> 81
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Lys Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn His Ser Ser
20 25 30
Glu Gly Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Pro Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Asp Thr Leu Gly Ile Val Cys Pro
85 90
<210> 82
<211> 92
<212> PRT
<213> Artificial Sequence
<220>
<223> AFJ19746.1 E7 Variant
<400> 82
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Lys Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Asp Glu Gln Leu Asn His Ser Ser
20 25 30
Glu Gly Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Pro Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro
85 90
<210> 83
<211> 93
<212> PRT
<213> Artificial Sequence
<220>
<223> AAF13395.1 E7 Variant
<400> 83
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Phe Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile
85 90
<210> 84
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> AFU06654.1 E7 Variant
<400> 84
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser
85 90 95
<210> 85
<211> 95
<212> PRT
<213> Artificial Sequence
<220>
<223> AFU06650.1 E7 Variant
<400> 85
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Phe Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser
85 90 95
<210> 86
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> AAB70738.1 E7 Variant
<400> 86
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Phe Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln
85 90 95
Lys Pro
<210> 87
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> ACN22555.1 E7 Variant
<400> 87
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Val Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln
85 90 95
Lys Pro
<210> 88
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> ABK32510.1 E7 Variant
<400> 88
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Ser Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln
85 90 95
Lys Pro
<210> 89
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> ABC54573.1 E7 Variant
<400> 89
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Ala Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln
85 90 95
Lys Pro
<210> 90
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> ACN22554.1 E7 Variant
<400> 90
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Arg Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln
85 90 95
Lys Pro
<210> 91
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> ABK32511.1 E7 Variant
<400> 91
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Lys Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Ser Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln
85 90 95
Lys Pro
<210> 92
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> ACQ90216.1 E7 Variant
<400> 92
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Arg Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln
85 90 95
Lys Pro
<210> 93
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> ADY75576.1 E7 Variant
<400> 93
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Asn Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Phe Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln
85 90 95
Lys Pro
<210> 94
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> AAM03025.1 E7 Variant
<400> 94
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Cys Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln
85 90 95
Lys Pro
<210> 95
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> AAL96634.1 E7 Variant
<400> 95
Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln
1 5 10 15
Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Ser Asp Ser Ser
20 25 30
Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp
35 40 45
Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr
50 55 60
Leu Trp Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu
65 70 75 80
Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln
85 90 95
Lys Pro
<210> 96
<211> 105
<212> PRT
<213> Artificial Sequence
<220>
<223> ABP99785.1 E7 Variant
<400> 96
Met Tyr Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu His Leu Glu
1 5 10 15
Pro Gln Asn Glu Ile Pro Val Asp Leu Leu Cys His Glu Gln Leu Ser
20 25 30
Asp Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln His
35 40 45
Leu Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys Met
50 55 60
Cys Cys Lys Cys Glu Ala Arg Ile Glu Leu Val Val Glu Ser Ser Ala
65 70 75 80
Asp Asp Leu Arg Ala Phe Gln Gln Leu Phe Leu Ser Thr Leu Ser Phe
85 90 95
Val Cys Pro Trp Cys Ala Ser Gln Gln
100 105
<210> 97
<211> 105
<212> PRT
<213> Artificial Sequence
<220>
<223> AGU90416.1 E7 Variant
<400> 97
Met Tyr Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu His Leu Glu
1 5 10 15
Pro Gln Asn Glu Ile Pro Val Asp Leu Leu Cys His Glu Gln Leu Ser
20 25 30
Asp Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln His
35 40 45
Leu Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys Met
50 55 60
Cys Cys Lys Cys Glu Ala Arg Ile Glu Leu Val Val Glu Ser Ser Ala
65 70 75 80
Asp Asp Leu Arg Ala Phe Gln Gln Leu Phe Leu Asn Thr Leu Ser Phe
85 90 95
Val Cys Pro Trp Cys Ala Ser Gln Gln
100 105
<210> 98
<211> 105
<212> PRT
<213> Artificial Sequence
<220>
<223> AGU90384.1 E7 Variant
<400> 98
Met Tyr Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu His Leu Glu
1 5 10 15
Pro Gln Asn Asp Ile Pro Val Asp Leu Leu Cys His Glu Gln Leu Ser
20 25 30
Asp Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln His
35 40 45
Leu Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys Met
50 55 60
Cys Cys Lys Cys Glu Ala Arg Ile Glu Leu Val Val Glu Ser Ser Ala
65 70 75 80
Asp Asp Leu Arg Ala Phe Gln Gln Leu Phe Leu Ser Thr Leu Ser Phe
85 90 95
Val Cys Pro Trp Cys Ala Ser Gln Gln
100 105
<210> 99
<211> 105
<212> PRT
<213> Artificial Sequence
<220>
<223> CAB53097.1 E7 Variant
<400> 99
Met His Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu His Leu Glu
1 5 10 15
Pro Gln Asn Glu Ile Pro Val Asp Leu Leu Cys His Glu Gln Leu Ser
20 25 30
Asp Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln His
35 40 45
Leu Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys Met
50 55 60
Cys Cys Lys Cys Glu Ala Arg Ile Glu Leu Val Val Glu Ser Ser Ala
65 70 75 80
Asp Asp Leu Arg Ala Phe Gln Gln Leu Phe Leu Lys Thr Leu Ser Phe
85 90 95
Val Cys Pro Trp Cys Ala Ser Gln Gln
100 105
<210> 100
<211> 105
<212> PRT
<213> Artificial Sequence
<220>
<223> P06788.2 E7 Variant
<400> 100
Met His Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu His Leu Glu
1 5 10 15
Pro Gln Asn Glu Ile Pro Val Asp Leu Leu Cys His Glu Gln Leu Ser
20 25 30
Asp Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln His
35 40 45
Leu Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys Met
50 55 60
Cys Cys Lys Cys Glu Ala Arg Ile Lys Leu Val Val Glu Ser Ser Ala
65 70 75 80
Asp Asp Leu Arg Ala Phe Gln Gln Leu Phe Leu Asn Thr Leu Ser Phe
85 90 95
Val Cys Pro Trp Cys Ala Ser Gln Gln
100 105
<210> 101
<211> 105
<212> PRT
<213> Artificial Sequence
<220>
<223> CAB53098.1 E7 Variant
<400> 101
Met His Gly Pro Lys Ala Thr Leu Gln Asn Ile Val Leu His Leu Glu
1 5 10 15
Pro Gln Asn Glu Ile Pro Val Asp Leu Leu Cys His Glu Gln Leu Ser
20 25 30
Asp Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln His
35 40 45
Leu Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys Met
50 55 60
Cys Cys Lys Cys Glu Ala Arg Ile Glu Leu Val Val Glu Ser Ser Ala
65 70 75 80
Asp Asp Leu Arg Ala Phe Gln Gln Leu Phe Leu Lys Thr Leu Ser Phe
85 90 95
Val Cys Pro Trp Cys Ala Ser Gln Gln
100 105
<210> 102
<211> 105
<212> PRT
<213> Artificial Sequence
<220>
<223> CAB53099.1 E7 Variant
<400> 102
Met His Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu His Leu Glu
1 5 10 15
Pro Gln Asn Glu Ile Pro Val Gly Leu Leu Cys His Glu Gln Leu Ser
20 25 30
Asp Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln His
35 40 45
Leu Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys Met
50 55 60
Cys Cys Lys Cys Glu Ala Arg Ile Glu Leu Val Val Glu Ser Ser Ala
65 70 75 80
Asp Asp Leu Arg Ala Phe Gln Gln Leu Phe Leu Lys Thr Leu Ser Phe
85 90 95
Val Cys Pro Trp Cys Ala Ser Gln Gln
100 105
<210> 103
<211> 145
<212> PRT
<213> Artificial Sequence
<220>
<223> AGM34425.1 E6 Variant
<400> 103
Leu Pro Asp Leu Cys Thr Glu Leu Asn Thr Ser Leu Gln Asp Ile Glu
1 5 10 15
Ile Thr Cys Val Tyr Cys Lys Thr Val Leu Glu Leu Thr Glu Val Phe
20 25 30
Glu Phe Ala Phe Lys Asp Leu Phe Val Val Tyr Arg Asp Ser Ile Pro
35 40 45
His Ala Ala Cys His Lys Cys Ile Asp Phe Tyr Ser Arg Ile Arg Glu
50 55 60
Leu Arg Tyr Tyr Ser Asp Ser Val Tyr Gly Asp Thr Leu Glu Lys Leu
65 70 75 80
Thr Asn Thr Gly Leu Tyr Asn Leu Leu Ile Arg Cys Leu Arg Cys Gln
85 90 95
Lys Pro Leu Asn Pro Ala Glu Lys Leu Arg His Leu Asn Glu Lys Arg
100 105 110
Arg Phe His Lys Ile Ala Gly His Tyr Arg Gly Gln Cys His Ser Cys
115 120 125
Cys Asn Arg Ala Arg Gln Glu Arg Leu Gln Arg Arg Arg Glu Thr Gln
130 135 140
Val
145
<210> 104
<211> 145
<212> PRT
<213> Artificial Sequence
<220>
<223> AGM34424.1 E6 Variant
<400> 104
Leu Pro Asp Leu Cys Thr Glu Leu Asn Thr Ser Leu Gln Asp Ile Glu
1 5 10 15
Ile Thr Cys Val Tyr Cys Lys Thr Val Leu Glu Leu Thr Glu Val Phe
20 25 30
Glu Phe Ala Phe Lys Asp Leu Phe Val Val Tyr Arg Asp Ser Ile Pro
35 40 45
His Ala Ala Cys His Lys Cys Ile Asp Phe Tyr Ser Arg Ile Arg Glu
50 55 60
Leu Arg His Tyr Ser Asp Ser Val Tyr Gly Asp Thr Leu Glu Lys Leu
65 70 75 80
Thr Asn Thr Gly Leu Tyr Asn Leu Leu Ile Arg Cys Leu Arg Cys Gln
85 90 95
Lys Pro Leu Asn Pro Ala Glu Lys Leu Arg His Leu Asn Glu Lys Arg
100 105 110
Arg Phe His Asn Ile Ala Gly His Tyr Arg Gly Gln Cys His Ser Cys
115 120 125
Cys Asn Arg Ala Arg Gln Glu Arg Leu Gln Arg Arg Arg Glu Thr Gln
130 135 140
Val
145
<210> 105
<211> 6085
<212> DNA
<213> Artificial Sequence
<220>
<223> C-1 mutant
<220>
<221> misc_feature
<222> (1368)..(1433)
<223> encodes tPA
<220>
<221> misc_feature
<222> (1434)..(1925)
<223> encodes FLT3L
<220>
<221> misc_feature
<222> (1932)..(2186)
<223> 16E6N (H21Q)
<220>
<221> misc_feature
<222> (1932)..(2789)
<223> 16E6/E7
<220>
<221> misc_feature
<222> (2187)..(2381)
<223> 16E7N
<220>
<221> misc_feature
<222> (2382)..(2645)
<223> 16E6C (Y85H, V90L)
<220>
<221> misc_feature
<222> (2646)..(2789)
<223> 16E7C
<220>
<221> misc_feature
<222> (2790)..(3671)
<223> 18E6/E7
<400> 105
taccgatgta cgggccagat atacgcgttg acattgatta ttgactagtt attaatagta 60
atcaattacg gggtcattag ttcatagccc atatatggag ttccgcgtta cataacttac 120
ggtaaatggc ccgcctggct gaccgcccaa cgacccccgc ccattgacgt caataatgac 180
gtatgttccc atagtaacgc caatagggac tttccattga cgtcaatggg tggagtattt 240
acggtaaact gcccacttgg cagtacatca agtgtatcat atgccaagta cgccccctat 300
tgacgtcaat gacggtaaat ggcccgcctg gcattatgcc cagtacatga ccttatggga 360
ctttcctact tggcagtaca tctacgtatt agtcatcgct attaccatgg tgatgcggtt 420
ttggcagtac atcaatgggc gtggatagcg gtttgactca cggggatttc caagtctcca 480
ccccattgac gtcaatggga gtttgttttg gcaccaaaat caacgggact ttccaaaatg 540
tcgtaacaac tccgccccat tgacgcaaat gggcggtagg cgtgtacggt gggaggtcta 600
tataagcaga gctctctggc taactagaga acccactgct tactggctta tcgaaattaa 660
tacgactcac tatagggaga cccaagctgg ctagcgtgag tttggggacc cttgattgtt 720
ctttcttttt cgctattgta aaattcatgt tatatggagg gggcaaagtt ttcagggtgt 780
tgtttagaac gggaagatgt cccttgtatc accatggacc ctcatgataa ttttgtttct 840
ttcactttct actctgttga caaccattgt ctcctcttat tttcttttca ttttctgtaa 900
ctttttcgtt aaactttagc ttgcatttgt aacgaatttt taaattcact tttgtttatt 960
tgtcagattg taagtacttt ctctaatcac ttttttttca aggcaatcag ggtatattat 1020
attgtacttc agcacagttt tagagaacaa ttgttataat taaatgataa ggtagaatat 1080
ttctgcatat aaattctggc tggcgtggaa atattcttat tggtagaaac aactacatcc 1140
tggtcatcat cctgcctttc tctttatggt tacaatgata tacactgttt gagatgagga 1200
taaaatactc tgagtccaaa ccgggcccct ctgctaacca tgttcatgcc ttcttctttt 1260
tcctacagct cctgggcaac gtgctggtta ttgtgctgtc tcatcatttt ggcaaagaat 1320
tgtaatacga ctcactatag ggcgaattga agcttggtac cgccaccatg gatgctatga 1380
aacggggcct gtgctgcgtg ctgctcctgt gcggcgctgt gtttgtgagc cctagcatca 1440
cccaggactg ctccttccaa cacagcccca tctcctccga cttcgctgtc aaaatccgtg 1500
agctgtctga ctacctgctt caagattacc cagtcaccgt ggcctccaac ctgcaggacg 1560
aggagctctg cgggggcctc tggcggctgg tcctggcaca gcgctggatg gagcggctca 1620
agactgtcgc tgggtccaag atgcaaggct tgctggagcg cgtgaacacg gagatacact 1680
ttgtcaccaa atgtgccttt cagccccccc ccagctgtct tcgcttcgtc cagaccaaca 1740
tctcccgcct cctgcaggag acctccgagc agctggtggc gctgaagccc tggatcactc 1800
gccagaactt ctcccggtgc ctggagctgc agtgtcagcc cgactcctca accctgccac 1860
ccccatggag tccccggccc ctggaggcca cagccccgac agccccgggc ggcggcagcg 1920
gcgatgctag catgcaccag aagagaaccg ccatgttcca ggaccctcag gagagaccta 1980
ggaagctgcc tcagctgtgt acagagctcc agacaaccat ccacgacatc atcctggagt 2040
gcgtgtactg taagcagcag ctgctgagaa gagaggtgta cgacttcgcc ttcagagacc 2100
tgtgcatcgt gtacagagac ggcaaccctt acgccgtgtg cgataagtgt ctgaagttct 2160
attccaaaat ctccgaatat aggtacatgc acggcgacac ccctaccctg cacgagtaca 2220
tgctggacct ccagcctgag accacagacc tgtactgcta cgagcagctg aacgacagct 2280
ctgaggaaga ggacgagatt gacggacctg ctggccaggc cgagcctgac agagcccact 2340
acaatatcgt gacattctgt tgcaaatgcg actccacact ggacaagtgc ctgaagttct 2400
acagcaagat ctctgagtac agacactact gctactctct gtacggcacc acactggagc 2460
agcagtacaa caagcctctg tgcgacctcc tgatccgctg catcaactgc cagaagcctc 2520
tgtgccctga ggagaagcag agacacctgg acaagaagca gcggttccac aacatcagag 2580
gcagatggac cggcaggtgc atgtcctgct gtagatcctc cagaaccaga cgggagaccc 2640
agctgcacta caacatcgtg accttctgct gcaagtgcga ctctaccctg agactgtgcg 2700
tgcagtctac ccacgtggac atcagaaccc tggaggacct gctgatgggc accctgggca 2760
tcgtgtgccc tatctgctct cagaagccta tggccaggtt cgaggaccct accagaagac 2820
cctacaagct gcctgacctg tgcaccgagc tgaacacctc tctgcaagac atcgagatca 2880
cctgcgtgta ctgcaagacc gtgctggagc tgaccgaggt gttcgagttc gccttcaagg 2940
acctgttcgt ggtgtacaga gacagcatcc ctcacgctgc ctgccacaag tgcatcgact 3000
tctattccag gatcagggag ctgcgctatt actccgactc tgtgatgtac ggccccaagg 3060
ccaccctcca ggacatcgtg ctgcacctgg agcctcagaa cgagatcccc gtggacctgc 3120
tgtgccacga gcagctgtct gactctgaag aggagaacga cgagatcgac ggcgtgaacc 3180
accagcacct gcctgccagg agagctgaac cccagcggca taccatgctg tgtatgtgct 3240
tctactctag gatcagagag ctgaggtact actctgactc tgtgtacggc gacaccctgg 3300
agaagctgac caacaccggc ctgtacaacc tgctgatccg gtgcctgagg tgccagaagc 3360
ctctgaaccc tgccgagaag ctgagacacc tgaacgagaa gagaagattc cacaagatcg 3420
ctggccacta cagaggccag tgccactctt gctgcaacag agccagacag gagagactcc 3480
agcggagaag ggagacccag gtggccagaa gagccgagcc tcagagacac accatgctgt 3540
gcatgtgctg caagtgcgag gccagaatcg agctggtggt ggagagctct gccgacgacc 3600
tgagagcctt ccagcagctg ttcctgtcta ccctgagctt cgtgtgccct tggtgcgcct 3660
ctcagcagta atctagagtc ggggcggccg gccgcttcga gcagacatga taagatacat 3720
tgatgagttt ggacaaacca caactagaat gcagtgaaaa aaatgcttta tttgtgaaat 3780
ttgtgatgct attgctttat ttgtaaccat tataagctgc aataaacaag ttaacaacaa 3840
caattgcatt cattttatgt ttcaggttca gggggaggtg tgggaggttt tttaaagcaa 3900
gtaaaacctc tacaaatgtg gtaaaatcga taaggatctg aacgatggag cggagaatgg 3960
gcggaactgg gcggagttag gggcgggatg ggcggagtta ggggcgggac tatggttgct 4020
gactaattga gatgcatgct ttgcatactt ctgcctgctg gggagcctgg ggactttcca 4080
cacctggttg ctgactaatt gagatgcatg ctttgcatac ttctgcctgc tggggagcct 4140
ggggactttc cacaccctaa ctgacacaca ttccacagcg gatccgtcga cttcagaaga 4200
actcgtcaag aaggcgatag aaggcgatgc gccgcgaatc gggagcggcg ataccgtaga 4260
gcacgaggaa gcggtcagcc cattcgccgc caagctcttc agcaatatca cgggtagcca 4320
acgctatgtc ctgatagcgg tccgccacac ccagccggcc acagtcgatg aatccagaaa 4380
agcggccatt ttccaccatg atattcggca agcaggcatc gccatgggtc acgacgagat 4440
cctcgccgtc gggcatgctc gccttgagcc tggcgaacag ttcggctggc gcgagcccct 4500
gatgctcttc gtccagatca tcctgatcga caagaccggc ttccatccga gtacgtgctc 4560
gctcgatgcg atgtttcgct tggtggtcga atgggcaggt agccggatca agcgtatgca 4620
gccgccgcat tgcatcagcc atgatggata ctttctcggc aggagcaagg tgagatgaca 4680
ggagatcctg ccccggcact tcgcccaata gcagccagtc ccttcccgct tcagtgacaa 4740
cgtcgagcac agctgcgcaa ggaacgcccg tcgtggccag ccacgatagc cgcgctgcct 4800
cgtcttgcag ttcattcagg gcaccggaca ggtcggtctt gacaaaaaga accgggcgcc 4860
cctgcgctga cagccggaac acggcggcat cagagcagcc gattgtctgt tgtgcccagt 4920
catagccgaa tagcctctcc acccaagcgg ccggagaacc tgcgtgcaat ccatcttgtt 4980
caatcatgcg aaacgatcct catcctgtct cttgatcaga tcttgatccc ctgcgccatc 5040
agatccttgg cggcaagaaa gccatccagt ttactttgca gggcttccca accttaccag 5100
agggcgcccc agctggcaat tccggttcgc ttgctgtcca taaaaccgcc cagtctagct 5160
atcgccatgt aagcccactg caagctacct gctttctctt tgcgcttgcg ttttcccttg 5220
tccagatagc ccagtagctg acattcatcc ggggtcagca ccgtttctgc ggactggctt 5280
tctacgtgaa aaggatctag gtgaagatcc tttttgataa tctcatgacc aaaatccctt 5340
aacgtgagtt ttcgttccac tgagcgtcag accccgtaga aaagatcaaa ggatcttctt 5400
gagatccttt ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca ccgctaccag 5460
cggtggtttg tttgccggat caagagctac caactctttt tccgaaggta actggcttca 5520
gcagagcgca gataccaaat actgttcttc tagtgtagcc gtagttaggc caccacttca 5580
agaactctgt agcaccgcct acatacctcg ctctgctaat cctgttacca gtggctgctg 5640
ccagtggcga taagtcgtgt cttaccgggt tggactcaag acgatagtta ccggataagg 5700
cgcagcggtc gggctgaacg gggggttcgt gcacacagcc cagcttggag cgaacgacct 5760
acaccgaact gagataccta cagcgtgagc tatgagaaag cgccacgctt cccgaaggga 5820
gaaaggcgga caggtatccg gtaagcggca gggtcggaac aggagagcgc acgagggagc 5880
ttccaggggg aaacgcccgg tatctttata gtcctgtcgg gtttcgccac ctctgacttg 5940
agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac gccagcaacg 6000
cggccttttt acggttcctg gccttttgct ggccttttgc tcacatgttc gggcccaatc 6060
gacccgggcg acggccagtg aattg 6085
<210> 106
<211> 767
<212> PRT
<213> Artificial Sequence
<220>
<223> C-1
<400> 106
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser Ile Thr Gln Asp Cys Ser Phe Gln His
20 25 30
Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu Ser Asp
35 40 45
Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu Gln Asp
50 55 60
Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln Arg Trp
65 70 75 80
Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly Leu Leu
85 90 95
Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala Phe Gln
100 105 110
Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser Arg Leu
115 120 125
Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp Ile Thr
130 135 140
Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro Asp Ser
145 150 155 160
Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala Thr Ala
165 170 175
Pro Thr Ala Pro Gly Gly Gly Ser Gly Asp Ala Ser Met His Gln Lys
180 185 190
Arg Thr Ala Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro
195 200 205
Gln Leu Cys Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu
210 215 220
Cys Val Tyr Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe
225 230 235 240
Ala Phe Arg Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala
245 250 255
Val Cys Asp Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg
260 265 270
Tyr Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu
275 280 285
Gln Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser
290 295 300
Ser Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro
305 310 315 320
Asp Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser
325 330 335
Thr Leu Asp Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg
340 345 350
His Tyr Cys Tyr Ser Leu Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn
355 360 365
Lys Pro Leu Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro
370 375 380
Leu Cys Pro Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe
385 390 395 400
His Asn Ile Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg
405 410 415
Ser Ser Arg Thr Arg Arg Glu Thr Gln Leu His Tyr Asn Ile Val Thr
420 425 430
Phe Cys Cys Lys Cys Asp Ser Thr Leu Arg Leu Cys Val Gln Ser Thr
435 440 445
His Val Asp Ile Arg Thr Leu Glu Asp Leu Leu Met Gly Thr Leu Gly
450 455 460
Ile Val Cys Pro Ile Cys Ser Gln Lys Pro Met Ala Arg Phe Glu Asp
465 470 475 480
Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp Leu Cys Thr Glu Leu Asn
485 490 495
Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys Val Tyr Cys Lys Thr Val
500 505 510
Leu Glu Leu Thr Glu Val Phe Glu Phe Ala Phe Lys Asp Leu Phe Val
515 520 525
Val Tyr Arg Asp Ser Ile Pro His Ala Ala Cys His Lys Cys Ile Asp
530 535 540
Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser Asp Ser Val Met
545 550 555 560
Tyr Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu His Leu Glu Pro
565 570 575
Gln Asn Glu Ile Pro Val Asp Leu Leu Cys His Glu Gln Leu Ser Asp
580 585 590
Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln His Leu
595 600 605
Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys Met Cys
610 615 620
Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser Asp Ser Val Tyr
625 630 635 640
Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr Gly Leu Tyr Asn Leu Leu
645 650 655
Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu Asn Pro Ala Glu Lys Leu
660 665 670
Arg His Leu Asn Glu Lys Arg Arg Phe His Lys Ile Ala Gly His Tyr
675 680 685
Arg Gly Gln Cys His Ser Cys Cys Asn Arg Ala Arg Gln Glu Arg Leu
690 695 700
Gln Arg Arg Arg Glu Thr Gln Val Ala Arg Arg Ala Glu Pro Gln Arg
705 710 715 720
His Thr Met Leu Cys Met Cys Cys Lys Cys Glu Ala Arg Ile Glu Leu
725 730 735
Val Val Glu Ser Ser Ala Asp Asp Leu Arg Ala Phe Gln Gln Leu Phe
740 745 750
Leu Ser Thr Leu Ser Phe Val Cys Pro Trp Cys Ala Ser Gln Gln
755 760 765
<210> 107
<211> 6085
<212> DNA
<213> Artificial Sequence
<220>
<223> C-2 mutant
<220>
<221> misc_feature
<222> (1368)..(1433)
<223> encodes tPA
<220>
<221> misc_feature
<222> (1434)..(1925)
<223> encodes FLT3L
<220>
<221> misc_feature
<222> (1932)..(2186)
<223> 16E6N
<220>
<221> misc_feature
<222> (1932)..(2789)
<223> 16E6/E7
<220>
<221> misc_feature
<222> (2187)..(2381)
<223> 16E7N (M12K, N29S)
<220>
<221> misc_feature
<222> (2382)..(2645)
<223> 16E6C
<220>
<221> misc_feature
<222> (2646)..(2789)
<223> 16E7C (R77S, G85S)
<220>
<221> misc_feature
<222> (2790)..(3671)
<223> 18E6/E7
<400> 107
taccgatgta cgggccagat atacgcgttg acattgatta ttgactagtt attaatagta 60
atcaattacg gggtcattag ttcatagccc atatatggag ttccgcgtta cataacttac 120
ggtaaatggc ccgcctggct gaccgcccaa cgacccccgc ccattgacgt caataatgac 180
gtatgttccc atagtaacgc caatagggac tttccattga cgtcaatggg tggagtattt 240
acggtaaact gcccacttgg cagtacatca agtgtatcat atgccaagta cgccccctat 300
tgacgtcaat gacggtaaat ggcccgcctg gcattatgcc cagtacatga ccttatggga 360
ctttcctact tggcagtaca tctacgtatt agtcatcgct attaccatgg tgatgcggtt 420
ttggcagtac atcaatgggc gtggatagcg gtttgactca cggggatttc caagtctcca 480
ccccattgac gtcaatggga gtttgttttg gcaccaaaat caacgggact ttccaaaatg 540
tcgtaacaac tccgccccat tgacgcaaat gggcggtagg cgtgtacggt gggaggtcta 600
tataagcaga gctctctggc taactagaga acccactgct tactggctta tcgaaattaa 660
tacgactcac tatagggaga cccaagctgg ctagcgtgag tttggggacc cttgattgtt 720
ctttcttttt cgctattgta aaattcatgt tatatggagg gggcaaagtt ttcagggtgt 780
tgtttagaac gggaagatgt cccttgtatc accatggacc ctcatgataa ttttgtttct 840
ttcactttct actctgttga caaccattgt ctcctcttat tttcttttca ttttctgtaa 900
ctttttcgtt aaactttagc ttgcatttgt aacgaatttt taaattcact tttgtttatt 960
tgtcagattg taagtacttt ctctaatcac ttttttttca aggcaatcag ggtatattat 1020
attgtacttc agcacagttt tagagaacaa ttgttataat taaatgataa ggtagaatat 1080
ttctgcatat aaattctggc tggcgtggaa atattcttat tggtagaaac aactacatcc 1140
tggtcatcat cctgcctttc tctttatggt tacaatgata tacactgttt gagatgagga 1200
taaaatactc tgagtccaaa ccgggcccct ctgctaacca tgttcatgcc ttcttctttt 1260
tcctacagct cctgggcaac gtgctggtta ttgtgctgtc tcatcatttt ggcaaagaat 1320
tgtaatacga ctcactatag ggcgaattga agcttggtac cgccaccatg gatgctatga 1380
aacggggcct gtgctgcgtg ctgctcctgt gcggcgctgt gtttgtgagc cctagcatca 1440
cccaggactg ctccttccaa cacagcccca tctcctccga cttcgctgtc aaaatccgtg 1500
agctgtctga ctacctgctt caagattacc cagtcaccgt ggcctccaac ctgcaggacg 1560
aggagctctg cgggggcctc tggcggctgg tcctggcaca gcgctggatg gagcggctca 1620
agactgtcgc tgggtccaag atgcaaggct tgctggagcg cgtgaacacg gagatacact 1680
ttgtcaccaa atgtgccttt cagccccccc ccagctgtct tcgcttcgtc cagaccaaca 1740
tctcccgcct cctgcaggag acctccgagc agctggtggc gctgaagccc tggatcactc 1800
gccagaactt ctcccggtgc ctggagctgc agtgtcagcc cgactcctca accctgccac 1860
ccccatggag tccccggccc ctggaggcca cagccccgac agccccgggc ggcggcagcg 1920
gcgatgctag catgcaccag aagagaaccg ccatgttcca ggaccctcag gagagaccta 1980
ggaagctgcc tcacctgtgt acagagctcc agacaaccat ccacgacatc atcctggagt 2040
gcgtgtactg taagcagcag ctgctgagaa gagaggtgta cgacttcgcc ttcagagacc 2100
tgtgcatcgt gtacagagac ggcaaccctt acgccgtgtg cgataagtgt ctgaagttct 2160
attccaaaat ctccgaatat aggtacatgc acggcgacac ccctaccctg cacgagtaca 2220
agctggacct ccagcctgag accacagacc tgtactgcta cgagcagctg tctgacagct 2280
ctgaggaaga ggacgagatt gacggacctg ctggccaggc cgagcctgac agagcccact 2340
acaatatcgt gacattctgt tgcaaatgcg actccacact ggacaagtgc ctgaagttct 2400
acagcaagat ctctgagtac agatactact gctactctgt gtacggcacc acactggagc 2460
agcagtacaa caagcctctg tgcgacctcc tgatccgctg catcaactgc cagaagcctc 2520
tgtgccctga ggagaagcag agacacctgg acaagaagca gcggttccac aacatcagag 2580
gcagatggac cggcaggtgc atgtcctgct gtagatcctc cagaaccaga cgggagaccc 2640
agctgcacta caacatcgtg accttctgct gcaagtgcga ctctaccctg agactgtgcg 2700
tgcagtctac ccacgtggac atcctcaccc tggaggacct gctgatgctc accctgggca 2760
tcgtgtgccc tatctgctct cagaagccta tggccaggtt cgaggaccct accagaagac 2820
cctacaagct gcctgacctg tgcaccgagc tgaacacctc tctgcaagac atcgagatca 2880
cctgcgtgta ctgcaagacc gtgctggagc tgaccgaggt gttcgagttc gccttcaagg 2940
acctgttcgt ggtgtacaga gacagcatcc ctcacgctgc ctgccacaag tgcatcgact 3000
tctattccag gatcagggag ctgcgctatt actccgactc tgtgatgtac ggccccaagg 3060
ccaccctcca ggacatcgtg ctgcacctgg agcctcagaa cgagatcccc gtggacctgc 3120
tgtgccacga gcagctgtct gactctgaag aggagaacga cgagatcgac ggcgtgaacc 3180
accagcacct gcctgccagg agagctgaac cccagcggca taccatgctg tgtatgtgct 3240
tctactctag gatcagagag ctgaggtact actctgactc tgtgtacggc gacaccctgg 3300
agaagctgac caacaccggc ctgtacaacc tgctgatccg gtgcctgagg tgccagaagc 3360
ctctgaaccc tgccgagaag ctgagacacc tgaacgagaa gagaagattc cacaagatcg 3420
ctggccacta cagaggccag tgccactctt gctgcaacag agccagacag gagagactcc 3480
agcggagaag ggagacccag gtggccagaa gagccgagcc tcagagacac accatgctgt 3540
gcatgtgctg caagtgcgag gccagaatcg agctggtggt ggagagctct gccgacgacc 3600
tgagagcctt ccagcagctg ttcctgtcta ccctgagctt cgtgtgccct tggtgcgcct 3660
ctcagcagta atctagagtc ggggcggccg gccgcttcga gcagacatga taagatacat 3720
tgatgagttt ggacaaacca caactagaat gcagtgaaaa aaatgcttta tttgtgaaat 3780
ttgtgatgct attgctttat ttgtaaccat tataagctgc aataaacaag ttaacaacaa 3840
caattgcatt cattttatgt ttcaggttca gggggaggtg tgggaggttt tttaaagcaa 3900
gtaaaacctc tacaaatgtg gtaaaatcga taaggatctg aacgatggag cggagaatgg 3960
gcggaactgg gcggagttag gggcgggatg ggcggagtta ggggcgggac tatggttgct 4020
gactaattga gatgcatgct ttgcatactt ctgcctgctg gggagcctgg ggactttcca 4080
cacctggttg ctgactaatt gagatgcatg ctttgcatac ttctgcctgc tggggagcct 4140
ggggactttc cacaccctaa ctgacacaca ttccacagcg gatccgtcga cttcagaaga 4200
actcgtcaag aaggcgatag aaggcgatgc gccgcgaatc gggagcggcg ataccgtaga 4260
gcacgaggaa gcggtcagcc cattcgccgc caagctcttc agcaatatca cgggtagcca 4320
acgctatgtc ctgatagcgg tccgccacac ccagccggcc acagtcgatg aatccagaaa 4380
agcggccatt ttccaccatg atattcggca agcaggcatc gccatgggtc acgacgagat 4440
cctcgccgtc gggcatgctc gccttgagcc tggcgaacag ttcggctggc gcgagcccct 4500
gatgctcttc gtccagatca tcctgatcga caagaccggc ttccatccga gtacgtgctc 4560
gctcgatgcg atgtttcgct tggtggtcga atgggcaggt agccggatca agcgtatgca 4620
gccgccgcat tgcatcagcc atgatggata ctttctcggc aggagcaagg tgagatgaca 4680
ggagatcctg ccccggcact tcgcccaata gcagccagtc ccttcccgct tcagtgacaa 4740
cgtcgagcac agctgcgcaa ggaacgcccg tcgtggccag ccacgatagc cgcgctgcct 4800
cgtcttgcag ttcattcagg gcaccggaca ggtcggtctt gacaaaaaga accgggcgcc 4860
cctgcgctga cagccggaac acggcggcat cagagcagcc gattgtctgt tgtgcccagt 4920
catagccgaa tagcctctcc acccaagcgg ccggagaacc tgcgtgcaat ccatcttgtt 4980
caatcatgcg aaacgatcct catcctgtct cttgatcaga tcttgatccc ctgcgccatc 5040
agatccttgg cggcaagaaa gccatccagt ttactttgca gggcttccca accttaccag 5100
agggcgcccc agctggcaat tccggttcgc ttgctgtcca taaaaccgcc cagtctagct 5160
atcgccatgt aagcccactg caagctacct gctttctctt tgcgcttgcg ttttcccttg 5220
tccagatagc ccagtagctg acattcatcc ggggtcagca ccgtttctgc ggactggctt 5280
tctacgtgaa aaggatctag gtgaagatcc tttttgataa tctcatgacc aaaatccctt 5340
aacgtgagtt ttcgttccac tgagcgtcag accccgtaga aaagatcaaa ggatcttctt 5400
gagatccttt ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca ccgctaccag 5460
cggtggtttg tttgccggat caagagctac caactctttt tccgaaggta actggcttca 5520
gcagagcgca gataccaaat actgttcttc tagtgtagcc gtagttaggc caccacttca 5580
agaactctgt agcaccgcct acatacctcg ctctgctaat cctgttacca gtggctgctg 5640
ccagtggcga taagtcgtgt cttaccgggt tggactcaag acgatagtta ccggataagg 5700
cgcagcggtc gggctgaacg gggggttcgt gcacacagcc cagcttggag cgaacgacct 5760
acaccgaact gagataccta cagcgtgagc tatgagaaag cgccacgctt cccgaaggga 5820
gaaaggcgga caggtatccg gtaagcggca gggtcggaac aggagagcgc acgagggagc 5880
ttccaggggg aaacgcccgg tatctttata gtcctgtcgg gtttcgccac ctctgacttg 5940
agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac gccagcaacg 6000
cggccttttt acggttcctg gccttttgct ggccttttgc tcacatgttc gggcccaatc 6060
gacccgggcg acggccagtg aattg 6085
<210> 108
<211> 767
<212> PRT
<213> Artificial Sequence
<220>
<223> C-2
<400> 108
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser Ile Thr Gln Asp Cys Ser Phe Gln His
20 25 30
Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu Ser Asp
35 40 45
Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu Gln Asp
50 55 60
Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln Arg Trp
65 70 75 80
Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly Leu Leu
85 90 95
Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala Phe Gln
100 105 110
Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser Arg Leu
115 120 125
Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp Ile Thr
130 135 140
Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro Asp Ser
145 150 155 160
Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala Thr Ala
165 170 175
Pro Thr Ala Pro Gly Gly Gly Ser Gly Asp Ala Ser Met His Gln Lys
180 185 190
Arg Thr Ala Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro
195 200 205
His Leu Cys Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu
210 215 220
Cys Val Tyr Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe
225 230 235 240
Ala Phe Arg Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala
245 250 255
Val Cys Asp Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg
260 265 270
Tyr Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Lys Leu Asp Leu
275 280 285
Gln Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Ser Asp Ser
290 295 300
Ser Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro
305 310 315 320
Asp Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser
325 330 335
Thr Leu Asp Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg
340 345 350
Tyr Tyr Cys Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn
355 360 365
Lys Pro Leu Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro
370 375 380
Leu Cys Pro Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe
385 390 395 400
His Asn Ile Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg
405 410 415
Ser Ser Arg Thr Arg Arg Glu Thr Gln Leu His Tyr Asn Ile Val Thr
420 425 430
Phe Cys Cys Lys Cys Asp Ser Thr Leu Arg Leu Cys Val Gln Ser Thr
435 440 445
His Val Asp Ile Leu Thr Leu Glu Asp Leu Leu Met Leu Thr Leu Gly
450 455 460
Ile Val Cys Pro Ile Cys Ser Gln Lys Pro Met Ala Arg Phe Glu Asp
465 470 475 480
Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp Leu Cys Thr Glu Leu Asn
485 490 495
Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys Val Tyr Cys Lys Thr Val
500 505 510
Leu Glu Leu Thr Glu Val Phe Glu Phe Ala Phe Lys Asp Leu Phe Val
515 520 525
Val Tyr Arg Asp Ser Ile Pro His Ala Ala Cys His Lys Cys Ile Asp
530 535 540
Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser Asp Ser Val Met
545 550 555 560
Tyr Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu His Leu Glu Pro
565 570 575
Gln Asn Glu Ile Pro Val Asp Leu Leu Cys His Glu Gln Leu Ser Asp
580 585 590
Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln His Leu
595 600 605
Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys Met Cys
610 615 620
Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser Asp Ser Val Tyr
625 630 635 640
Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr Gly Leu Tyr Asn Leu Leu
645 650 655
Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu Asn Pro Ala Glu Lys Leu
660 665 670
Arg His Leu Asn Glu Lys Arg Arg Phe His Lys Ile Ala Gly His Tyr
675 680 685
Arg Gly Gln Cys His Ser Cys Cys Asn Arg Ala Arg Gln Glu Arg Leu
690 695 700
Gln Arg Arg Arg Glu Thr Gln Val Ala Arg Arg Ala Glu Pro Gln Arg
705 710 715 720
His Thr Met Leu Cys Met Cys Cys Lys Cys Glu Ala Arg Ile Glu Leu
725 730 735
Val Val Glu Ser Ser Ala Asp Asp Leu Arg Ala Phe Gln Gln Leu Phe
740 745 750
Leu Ser Thr Leu Ser Phe Val Cys Pro Trp Cys Ala Ser Gln Gln
755 760 765
<210> 109
<211> 5995
<212> DNA
<213> Artificial Sequence
<220>
<223> D-1 (overlapping-1)
<220>
<221> misc_feature
<222> (1368)..(1433)
<223> encodes tPA
<220>
<221> misc_feature
<222> (1434)..(1925)
<223> encodes FLT3L
<220>
<221> misc_feature
<222> (1932)..(2165)
<223> 16E6N (1-78aa)
<220>
<221> misc_feature
<222> (2166)..(2339)
<223> 16E7N (1-58aa)
<220>
<221> misc_feature
<222> (2340)..(2579)
<223> 16E6C (79-158aa)
<220>
<221> misc_feature
<222> (2580)..(2699)
<223> 16E7C (59-98aa)
<220>
<221> misc_feature
<222> (2700)..(3581)
<223> 18E6/E7
<400> 109
taccgatgta cgggccagat atacgcgttg acattgatta ttgactagtt attaatagta 60
atcaattacg gggtcattag ttcatagccc atatatggag ttccgcgtta cataacttac 120
ggtaaatggc ccgcctggct gaccgcccaa cgacccccgc ccattgacgt caataatgac 180
gtatgttccc atagtaacgc caatagggac tttccattga cgtcaatggg tggagtattt 240
acggtaaact gcccacttgg cagtacatca agtgtatcat atgccaagta cgccccctat 300
tgacgtcaat gacggtaaat ggcccgcctg gcattatgcc cagtacatga ccttatggga 360
ctttcctact tggcagtaca tctacgtatt agtcatcgct attaccatgg tgatgcggtt 420
ttggcagtac atcaatgggc gtggatagcg gtttgactca cggggatttc caagtctcca 480
ccccattgac gtcaatggga gtttgttttg gcaccaaaat caacgggact ttccaaaatg 540
tcgtaacaac tccgccccat tgacgcaaat gggcggtagg cgtgtacggt gggaggtcta 600
tataagcaga gctctctggc taactagaga acccactgct tactggctta tcgaaattaa 660
tacgactcac tatagggaga cccaagctgg ctagcgtgag tttggggacc cttgattgtt 720
ctttcttttt cgctattgta aaattcatgt tatatggagg gggcaaagtt ttcagggtgt 780
tgtttagaac gggaagatgt cccttgtatc accatggacc ctcatgataa ttttgtttct 840
ttcactttct actctgttga caaccattgt ctcctcttat tttcttttca ttttctgtaa 900
ctttttcgtt aaactttagc ttgcatttgt aacgaatttt taaattcact tttgtttatt 960
tgtcagattg taagtacttt ctctaatcac ttttttttca aggcaatcag ggtatattat 1020
attgtacttc agcacagttt tagagaacaa ttgttataat taaatgataa ggtagaatat 1080
ttctgcatat aaattctggc tggcgtggaa atattcttat tggtagaaac aactacatcc 1140
tggtcatcat cctgcctttc tctttatggt tacaatgata tacactgttt gagatgagga 1200
taaaatactc tgagtccaaa ccgggcccct ctgctaacca tgttcatgcc ttcttctttt 1260
tcctacagct cctgggcaac gtgctggtta ttgtgctgtc tcatcatttt ggcaaagaat 1320
tgtaatacga ctcactatag ggcgaattga agcttggtac cgccaccatg gatgctatga 1380
aacggggcct gtgctgcgtg ctgctcctgt gcggcgctgt gtttgtgagc cctagcatca 1440
cccaggactg ctccttccaa cacagcccca tctcctccga cttcgctgtc aaaatccgtg 1500
agctgtctga ctacctgctt caagattacc cagtcaccgt ggcctccaac ctgcaggacg 1560
aggagctctg cgggggcctc tggcggctgg tcctggcaca gcgctggatg gagcggctca 1620
agactgtcgc tgggtccaag atgcaaggct tgctggagcg cgtgaacacg gagatacact 1680
ttgtcaccaa atgtgccttt cagccccccc ccagctgtct tcgcttcgtc cagaccaaca 1740
tctcccgcct cctgcaggag acctccgagc agctggtggc gctgaagccc tggatcactc 1800
gccagaactt ctcccggtgc ctggagctgc agtgtcagcc cgactcctca accctgccac 1860
ccccatggag tccccggccc ctggaggcca cagccccgac agccccgggc ggcggcagcg 1920
gcgatgctag catgcaccag aagagaaccg ccatgttcca ggaccctcag gagagaccta 1980
ggaagctgcc tcacctgtgt acagagctcc agacaaccat ccacgacatc atcctggagt 2040
gcgtgtactg taagcagcag ctgctgagaa gagaggtgta cgacttcgcc ttcagagacc 2100
tgtgcatcgt gtacagagac ggcaaccctt acgccgtgtg cgataagtgt ctgaagttct 2160
attccatgca cggcgacacc cctaccctgc acgagtacat gctggacctc cagcctgaga 2220
ccacagacct gtactgctac gagcagctga acgacagctc tgaggaagag gacgagattg 2280
acggacctgc tggccaggcc gagcctgaca gagcccacta caatatcgtg acattctgta 2340
agatctctga gtacagatac tactgctact ctgtgtacgg caccacactg gagcagcagt 2400
acaacaagcc tctgtgcgac ctcctgatcc gctgcatcaa ctgccagaag cctctgtgcc 2460
ctgaggagaa gcagagacac ctggacaaga agcagcggtt ccacaacatc agaggcagat 2520
ggaccggcag gtgcatgtcc tgctgtagat cctccagaac cagacgggag acccagctgt 2580
gcaagtgcga ctctaccctg agactgtgcg tgcagtctac ccacgtggac atcagaaccc 2640
tggaggacct gctgatgggc accctgggca tcgtgtgccc tatctgctct cagaagccta 2700
tggccaggtt cgaggaccct accagaagac cctacaagct gcctgacctg tgcaccgagc 2760
tgaacacctc tctgcaagac atcgagatca cctgcgtgta ctgcaagacc gtgctggagc 2820
tgaccgaggt gttcgagttc gccttcaagg acctgttcgt ggtgtacaga gacagcatcc 2880
ctcacgctgc ctgccacaag tgcatcgact tctattccag gatcagggag ctgcgctatt 2940
actccgactc tgtgatgtac ggccccaagg ccaccctcca ggacatcgtg ctgcacctgg 3000
agcctcagaa cgagatcccc gtggacctgc tgtgccacga gcagctgtct gactctgaag 3060
aggagaacga cgagatcgac ggcgtgaacc accagcacct gcctgccagg agagctgaac 3120
cccagcggca taccatgctg tgtatgtgct tctactctag gatcagagag ctgaggtact 3180
actctgactc tgtgtacggc gacaccctgg agaagctgac caacaccggc ctgtacaacc 3240
tgctgatccg gtgcctgagg tgccagaagc ctctgaaccc tgccgagaag ctgagacacc 3300
tgaacgagaa gagaagattc cacaagatcg ctggccacta cagaggccag tgccactctt 3360
gctgcaacag agccagacag gagagactcc agcggagaag ggagacccag gtggccagaa 3420
gagccgagcc tcagagacac accatgctgt gcatgtgctg caagtgcgag gccagaatcg 3480
agctggtggt ggagagctct gccgacgacc tgagagcctt ccagcagctg ttcctgtcta 3540
ccctgagctt cgtgtgccct tggtgcgcct ctcagcagta atctagagtc ggggcggccg 3600
gccgcttcga gcagacatga taagatacat tgatgagttt ggacaaacca caactagaat 3660
gcagtgaaaa aaatgcttta tttgtgaaat ttgtgatgct attgctttat ttgtaaccat 3720
tataagctgc aataaacaag ttaacaacaa caattgcatt cattttatgt ttcaggttca 3780
gggggaggtg tgggaggttt tttaaagcaa gtaaaacctc tacaaatgtg gtaaaatcga 3840
taaggatctg aacgatggag cggagaatgg gcggaactgg gcggagttag gggcgggatg 3900
ggcggagtta ggggcgggac tatggttgct gactaattga gatgcatgct ttgcatactt 3960
ctgcctgctg gggagcctgg ggactttcca cacctggttg ctgactaatt gagatgcatg 4020
ctttgcatac ttctgcctgc tggggagcct ggggactttc cacaccctaa ctgacacaca 4080
ttccacagcg gatccgtcga cttcagaaga actcgtcaag aaggcgatag aaggcgatgc 4140
gccgcgaatc gggagcggcg ataccgtaga gcacgaggaa gcggtcagcc cattcgccgc 4200
caagctcttc agcaatatca cgggtagcca acgctatgtc ctgatagcgg tccgccacac 4260
ccagccggcc acagtcgatg aatccagaaa agcggccatt ttccaccatg atattcggca 4320
agcaggcatc gccatgggtc acgacgagat cctcgccgtc gggcatgctc gccttgagcc 4380
tggcgaacag ttcggctggc gcgagcccct gatgctcttc gtccagatca tcctgatcga 4440
caagaccggc ttccatccga gtacgtgctc gctcgatgcg atgtttcgct tggtggtcga 4500
atgggcaggt agccggatca agcgtatgca gccgccgcat tgcatcagcc atgatggata 4560
ctttctcggc aggagcaagg tgagatgaca ggagatcctg ccccggcact tcgcccaata 4620
gcagccagtc ccttcccgct tcagtgacaa cgtcgagcac agctgcgcaa ggaacgcccg 4680
tcgtggccag ccacgatagc cgcgctgcct cgtcttgcag ttcattcagg gcaccggaca 4740
ggtcggtctt gacaaaaaga accgggcgcc cctgcgctga cagccggaac acggcggcat 4800
cagagcagcc gattgtctgt tgtgcccagt catagccgaa tagcctctcc acccaagcgg 4860
ccggagaacc tgcgtgcaat ccatcttgtt caatcatgcg aaacgatcct catcctgtct 4920
cttgatcaga tcttgatccc ctgcgccatc agatccttgg cggcaagaaa gccatccagt 4980
ttactttgca gggcttccca accttaccag agggcgcccc agctggcaat tccggttcgc 5040
ttgctgtcca taaaaccgcc cagtctagct atcgccatgt aagcccactg caagctacct 5100
gctttctctt tgcgcttgcg ttttcccttg tccagatagc ccagtagctg acattcatcc 5160
ggggtcagca ccgtttctgc ggactggctt tctacgtgaa aaggatctag gtgaagatcc 5220
tttttgataa tctcatgacc aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag 5280
accccgtaga aaagatcaaa ggatcttctt gagatccttt ttttctgcgc gtaatctgct 5340
gcttgcaaac aaaaaaacca ccgctaccag cggtggtttg tttgccggat caagagctac 5400
caactctttt tccgaaggta actggcttca gcagagcgca gataccaaat actgttcttc 5460
tagtgtagcc gtagttaggc caccacttca agaactctgt agcaccgcct acatacctcg 5520
ctctgctaat cctgttacca gtggctgctg ccagtggcga taagtcgtgt cttaccgggt 5580
tggactcaag acgatagtta ccggataagg cgcagcggtc gggctgaacg gggggttcgt 5640
gcacacagcc cagcttggag cgaacgacct acaccgaact gagataccta cagcgtgagc 5700
tatgagaaag cgccacgctt cccgaaggga gaaaggcgga caggtatccg gtaagcggca 5760
gggtcggaac aggagagcgc acgagggagc ttccaggggg aaacgcccgg tatctttata 5820
gtcctgtcgg gtttcgccac ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg 5880
ggcggagcct atggaaaaac gccagcaacg cggccttttt acggttcctg gccttttgct 5940
ggccttttgc tcacatgttc gggcccaatc gacccgggcg acggccagtg aattg 5995
<210> 110
<211> 737
<212> PRT
<213> Artificial Sequence
<220>
<223> D-1
<400> 110
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser Ile Thr Gln Asp Cys Ser Phe Gln His
20 25 30
Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu Ser Asp
35 40 45
Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu Gln Asp
50 55 60
Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln Arg Trp
65 70 75 80
Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly Leu Leu
85 90 95
Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala Phe Gln
100 105 110
Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser Arg Leu
115 120 125
Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp Ile Thr
130 135 140
Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro Asp Ser
145 150 155 160
Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala Thr Ala
165 170 175
Pro Thr Ala Pro Gly Gly Gly Ser Gly Asp Ala Ser Met His Gln Lys
180 185 190
Arg Thr Ala Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro
195 200 205
His Leu Cys Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu
210 215 220
Cys Val Tyr Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe
225 230 235 240
Ala Phe Arg Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala
245 250 255
Val Cys Asp Lys Cys Leu Lys Phe Tyr Ser Met His Gly Asp Thr Pro
260 265 270
Thr Leu His Glu Tyr Met Leu Asp Leu Gln Pro Glu Thr Thr Asp Leu
275 280 285
Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser Glu Glu Glu Asp Glu Ile
290 295 300
Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp Arg Ala His Tyr Asn Ile
305 310 315 320
Val Thr Phe Cys Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys Tyr Ser Val
325 330 335
Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu Cys Asp Leu
340 345 350
Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro Glu Glu Lys
355 360 365
Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile Arg Gly Arg
370 375 380
Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg Thr Arg Arg
385 390 395 400
Glu Thr Gln Leu Cys Lys Cys Asp Ser Thr Leu Arg Leu Cys Val Gln
405 410 415
Ser Thr His Val Asp Ile Arg Thr Leu Glu Asp Leu Leu Met Gly Thr
420 425 430
Leu Gly Ile Val Cys Pro Ile Cys Ser Gln Lys Pro Met Ala Arg Phe
435 440 445
Glu Asp Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp Leu Cys Thr Glu
450 455 460
Leu Asn Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys Val Tyr Cys Lys
465 470 475 480
Thr Val Leu Glu Leu Thr Glu Val Phe Glu Phe Ala Phe Lys Asp Leu
485 490 495
Phe Val Val Tyr Arg Asp Ser Ile Pro His Ala Ala Cys His Lys Cys
500 505 510
Ile Asp Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser Asp Ser
515 520 525
Val Met Tyr Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu His Leu
530 535 540
Glu Pro Gln Asn Glu Ile Pro Val Asp Leu Leu Cys His Glu Gln Leu
545 550 555 560
Ser Asp Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln
565 570 575
His Leu Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys
580 585 590
Met Cys Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser Asp Ser
595 600 605
Val Tyr Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr Gly Leu Tyr Asn
610 615 620
Leu Leu Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu Asn Pro Ala Glu
625 630 635 640
Lys Leu Arg His Leu Asn Glu Lys Arg Arg Phe His Lys Ile Ala Gly
645 650 655
His Tyr Arg Gly Gln Cys His Ser Cys Cys Asn Arg Ala Arg Gln Glu
660 665 670
Arg Leu Gln Arg Arg Arg Glu Thr Gln Val Ala Arg Arg Ala Glu Pro
675 680 685
Gln Arg His Thr Met Leu Cys Met Cys Cys Lys Cys Glu Ala Arg Ile
690 695 700
Glu Leu Val Val Glu Ser Ser Ala Asp Asp Leu Arg Ala Phe Gln Gln
705 710 715 720
Leu Phe Leu Ser Thr Leu Ser Phe Val Cys Pro Trp Cys Ala Ser Gln
725 730 735
Gln
<210> 111
<211> 6379
<212> DNA
<213> Artificial Sequence
<220>
<223> D-2 (overlapping-2)
<220>
<221> misc_feature
<222> (1368)..(1433)
<223> encodes tPA
<220>
<221> misc_feature
<222> (1434)..(1925)
<223> encodes FLT3L
<220>
<221> misc_feature
<222> (1932)..(2321)
<223> 16E6N (1-130aa)
<220>
<221> misc_feature
<222> (1932)..(3083)
<223> 16E6/E7
<220>
<221> misc_feature
<222> (2322)..(2576)
<223> 16E7N (1-85aa)
<220>
<221> misc_feature
<222> (2577)..(2918)
<223> 16E6C (45-158aa)
<220>
<221> misc_feature
<222> (2919)..(3083)
<223> 16E7C (44-98aa)
<220>
<221> misc_feature
<222> (3084)..(3965)
<223> 18E6/E7
<400> 111
taccgatgta cgggccagat atacgcgttg acattgatta ttgactagtt attaatagta 60
atcaattacg gggtcattag ttcatagccc atatatggag ttccgcgtta cataacttac 120
ggtaaatggc ccgcctggct gaccgcccaa cgacccccgc ccattgacgt caataatgac 180
gtatgttccc atagtaacgc caatagggac tttccattga cgtcaatggg tggagtattt 240
acggtaaact gcccacttgg cagtacatca agtgtatcat atgccaagta cgccccctat 300
tgacgtcaat gacggtaaat ggcccgcctg gcattatgcc cagtacatga ccttatggga 360
ctttcctact tggcagtaca tctacgtatt agtcatcgct attaccatgg tgatgcggtt 420
ttggcagtac atcaatgggc gtggatagcg gtttgactca cggggatttc caagtctcca 480
ccccattgac gtcaatggga gtttgttttg gcaccaaaat caacgggact ttccaaaatg 540
tcgtaacaac tccgccccat tgacgcaaat gggcggtagg cgtgtacggt gggaggtcta 600
tataagcaga gctctctggc taactagaga acccactgct tactggctta tcgaaattaa 660
tacgactcac tatagggaga cccaagctgg ctagcgtgag tttggggacc cttgattgtt 720
ctttcttttt cgctattgta aaattcatgt tatatggagg gggcaaagtt ttcagggtgt 780
tgtttagaac gggaagatgt cccttgtatc accatggacc ctcatgataa ttttgtttct 840
ttcactttct actctgttga caaccattgt ctcctcttat tttcttttca ttttctgtaa 900
ctttttcgtt aaactttagc ttgcatttgt aacgaatttt taaattcact tttgtttatt 960
tgtcagattg taagtacttt ctctaatcac ttttttttca aggcaatcag ggtatattat 1020
attgtacttc agcacagttt tagagaacaa ttgttataat taaatgataa ggtagaatat 1080
ttctgcatat aaattctggc tggcgtggaa atattcttat tggtagaaac aactacatcc 1140
tggtcatcat cctgcctttc tctttatggt tacaatgata tacactgttt gagatgagga 1200
taaaatactc tgagtccaaa ccgggcccct ctgctaacca tgttcatgcc ttcttctttt 1260
tcctacagct cctgggcaac gtgctggtta ttgtgctgtc tcatcatttt ggcaaagaat 1320
tgtaatacga ctcactatag ggcgaattga agcttggtac cgccaccatg gatgctatga 1380
aacggggcct gtgctgcgtg ctgctcctgt gcggcgctgt gtttgtgagc cctagcatca 1440
cccaggactg ctccttccaa cacagcccca tctcctccga cttcgctgtc aaaatccgtg 1500
agctgtctga ctacctgctt caagattacc cagtcaccgt ggcctccaac ctgcaggacg 1560
aggagctctg cgggggcctc tggcggctgg tcctggcaca gcgctggatg gagcggctca 1620
agactgtcgc tgggtccaag atgcaaggct tgctggagcg cgtgaacacg gagatacact 1680
ttgtcaccaa atgtgccttt cagccccccc ccagctgtct tcgcttcgtc cagaccaaca 1740
tctcccgcct cctgcaggag acctccgagc agctggtggc gctgaagccc tggatcactc 1800
gccagaactt ctcccggtgc ctggagctgc agtgtcagcc cgactcctca accctgccac 1860
ccccatggag tccccggccc ctggaggcca cagccccgac agccccgggc ggcggcagcg 1920
gcgatgctag catgcaccag aagagaaccg ccatgttcca ggaccctcag gagagaccta 1980
ggaagctgcc tcacctgtgt acagagctcc agacaaccat ccacgacatc atcctggagt 2040
gcgtgtactg taagcagcag ctgctgagaa gagaggtgta cgacttcgcc ttcagagacc 2100
tgtgcatcgt gtacagagac ggcaaccctt acgccgtgtg cgataagtgt ctgaagttct 2160
attccaagat ctctgagtac agatactact gctactctgt gtacggcacc acactggagc 2220
agcagtacaa caagcctctg tgcgacctcc tgatccgctg catcaactgc cagaagcctc 2280
tgtgccctga ggagaagcag agacacctgg acaagaagca gatgcacggc gacaccccta 2340
ccctgcacga gtacatgctg gacctccagc ctgagaccac agacctgtac tgctacgagc 2400
agctgaacga cagctctgag gaagaggacg agattgacgg acctgctggc caggccgagc 2460
ctgacagagc ccactacaat atcgtgacat tctgttgcaa gtgcgactct accctgagac 2520
tgtgcgtgca gtctacccac gtggacatca gaaccctgga ggacctgctg atgggcctga 2580
gaagagaggt gtacgacttc gccttcagag acctgtgcat cgtgtacaga gacggcaacc 2640
cttacgccgt gtgcgataag tgtctgaagt tctattccaa gatctctgag tacagatact 2700
actgctactc tgtgtacggc accacactgg agcagcagta caacaagcct ctgtgcgacc 2760
tcctgatccg ctgcatcaac tgccagaagc ctctgtgccc tgaggagaag cagagacacc 2820
tggacaagaa gcagcggttc cacaacatca gaggcagatg gaccggcagg tgcatgtcct 2880
gctgtagatc ctccagaacc agacgggaga cccagctgca ggccgagcct gacagagccc 2940
actacaatat cgtgacattc tgttgcaagt gcgactctac cctgagactg tgcgtgcagt 3000
ctacccacgt ggacatcaga accctggagg acctgctgat gggcaccctg ggcatcgtgt 3060
gccctatctg ctctcagaag cctatggcca ggttcgagga ccctaccaga agaccctaca 3120
agctgcctga cctgtgcacc gagctgaaca cctctctgca agacatcgag atcacctgcg 3180
tgtactgcaa gaccgtgctg gagctgaccg aggtgttcga gttcgccttc aaggacctgt 3240
tcgtggtgta cagagacagc atccctcacg ctgcctgcca caagtgcatc gacttctatt 3300
ccaggatcag ggagctgcgc tattactccg actctgtgat gtacggcccc aaggccaccc 3360
tccaggacat cgtgctgcac ctggagcctc agaacgagat ccccgtggac ctgctgtgcc 3420
acgagcagct gtctgactct gaagaggaga acgacgagat cgacggcgtg aaccaccagc 3480
acctgcctgc caggagagct gaaccccagc ggcataccat gctgtgtatg tgcttctact 3540
ctaggatcag agagctgagg tactactctg actctgtgta cggcgacacc ctggagaagc 3600
tgaccaacac cggcctgtac aacctgctga tccggtgcct gaggtgccag aagcctctga 3660
accctgccga gaagctgaga cacctgaacg agaagagaag attccacaag atcgctggcc 3720
actacagagg ccagtgccac tcttgctgca acagagccag acaggagaga ctccagcgga 3780
gaagggagac ccaggtggcc agaagagccg agcctcagag acacaccatg ctgtgcatgt 3840
gctgcaagtg cgaggccaga atcgagctgg tggtggagag ctctgccgac gacctgagag 3900
ccttccagca gctgttcctg tctaccctga gcttcgtgtg cccttggtgc gcctctcagc 3960
agtaatctag agtcggggcg gccggccgct tcgagcagac atgataagat acattgatga 4020
gtttggacaa accacaacta gaatgcagtg aaaaaaatgc tttatttgtg aaatttgtga 4080
tgctattgct ttatttgtaa ccattataag ctgcaataaa caagttaaca acaacaattg 4140
cattcatttt atgtttcagg ttcaggggga ggtgtgggag gttttttaaa gcaagtaaaa 4200
cctctacaaa tgtggtaaaa tcgataagga tctgaacgat ggagcggaga atgggcggaa 4260
ctgggcggag ttaggggcgg gatgggcgga gttaggggcg ggactatggt tgctgactaa 4320
ttgagatgca tgctttgcat acttctgcct gctggggagc ctggggactt tccacacctg 4380
gttgctgact aattgagatg catgctttgc atacttctgc ctgctgggga gcctggggac 4440
tttccacacc ctaactgaca cacattccac agcggatccg tcgacttcag aagaactcgt 4500
caagaaggcg atagaaggcg atgcgccgcg aatcgggagc ggcgataccg tagagcacga 4560
ggaagcggtc agcccattcg ccgccaagct cttcagcaat atcacgggta gccaacgcta 4620
tgtcctgata gcggtccgcc acacccagcc ggccacagtc gatgaatcca gaaaagcggc 4680
cattttccac catgatattc ggcaagcagg catcgccatg ggtcacgacg agatcctcgc 4740
cgtcgggcat gctcgccttg agcctggcga acagttcggc tggcgcgagc ccctgatgct 4800
cttcgtccag atcatcctga tcgacaagac cggcttccat ccgagtacgt gctcgctcga 4860
tgcgatgttt cgcttggtgg tcgaatgggc aggtagccgg atcaagcgta tgcagccgcc 4920
gcattgcatc agccatgatg gatactttct cggcaggagc aaggtgagat gacaggagat 4980
cctgccccgg cacttcgccc aatagcagcc agtcccttcc cgcttcagtg acaacgtcga 5040
gcacagctgc gcaaggaacg cccgtcgtgg ccagccacga tagccgcgct gcctcgtctt 5100
gcagttcatt cagggcaccg gacaggtcgg tcttgacaaa aagaaccggg cgcccctgcg 5160
ctgacagccg gaacacggcg gcatcagagc agccgattgt ctgttgtgcc cagtcatagc 5220
cgaatagcct ctccacccaa gcggccggag aacctgcgtg caatccatct tgttcaatca 5280
tgcgaaacga tcctcatcct gtctcttgat cagatcttga tcccctgcgc catcagatcc 5340
ttggcggcaa gaaagccatc cagtttactt tgcagggctt cccaacctta ccagagggcg 5400
ccccagctgg caattccggt tcgcttgctg tccataaaac cgcccagtct agctatcgcc 5460
atgtaagccc actgcaagct acctgctttc tctttgcgct tgcgttttcc cttgtccaga 5520
tagcccagta gctgacattc atccggggtc agcaccgttt ctgcggactg gctttctacg 5580
tgaaaaggat ctaggtgaag atcctttttg ataatctcat gaccaaaatc ccttaacgtg 5640
agttttcgtt ccactgagcg tcagaccccg tagaaaagat caaaggatct tcttgagatc 5700
ctttttttct gcgcgtaatc tgctgcttgc aaacaaaaaa accaccgcta ccagcggtgg 5760
tttgtttgcc ggatcaagag ctaccaactc tttttccgaa ggtaactggc ttcagcagag 5820
cgcagatacc aaatactgtt cttctagtgt agccgtagtt aggccaccac ttcaagaact 5880
ctgtagcacc gcctacatac ctcgctctgc taatcctgtt accagtggct gctgccagtg 5940
gcgataagtc gtgtcttacc gggttggact caagacgata gttaccggat aaggcgcagc 6000
ggtcgggctg aacggggggt tcgtgcacac agcccagctt ggagcgaacg acctacaccg 6060
aactgagata cctacagcgt gagctatgag aaagcgccac gcttcccgaa gggagaaagg 6120
cggacaggta tccggtaagc ggcagggtcg gaacaggaga gcgcacgagg gagcttccag 6180
ggggaaacgc ccggtatctt tatagtcctg tcgggtttcg ccacctctga cttgagcgtc 6240
gatttttgtg atgctcgtca ggggggcgga gcctatggaa aaacgccagc aacgcggcct 6300
ttttacggtt cctggccttt tgctggcctt ttgctcacat gttcgggccc aatcgacccg 6360
ggcgacggcc agtgaattg 6379
<210> 112
<211> 865
<212> PRT
<213> Artificial Sequence
<220>
<223> D-2
<400> 112
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser Ile Thr Gln Asp Cys Ser Phe Gln His
20 25 30
Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu Ser Asp
35 40 45
Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu Gln Asp
50 55 60
Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln Arg Trp
65 70 75 80
Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly Leu Leu
85 90 95
Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala Phe Gln
100 105 110
Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser Arg Leu
115 120 125
Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp Ile Thr
130 135 140
Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro Asp Ser
145 150 155 160
Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala Thr Ala
165 170 175
Pro Thr Ala Pro Gly Gly Gly Ser Gly Asp Ala Ser Met His Gln Lys
180 185 190
Arg Thr Ala Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro
195 200 205
His Leu Cys Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu
210 215 220
Cys Val Tyr Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe
225 230 235 240
Ala Phe Arg Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala
245 250 255
Val Cys Asp Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg
260 265 270
Tyr Tyr Cys Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn
275 280 285
Lys Pro Leu Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro
290 295 300
Leu Cys Pro Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Met His
305 310 315 320
Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu Gln Pro Glu
325 330 335
Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser Ser Glu Glu
340 345 350
Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro Asp Arg Ala
355 360 365
His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr Leu Arg
370 375 380
Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu Asp Leu
385 390 395 400
Leu Met Gly Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg Asp Leu
405 410 415
Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp Lys Cys
420 425 430
Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys Tyr Ser
435 440 445
Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu Cys Asp
450 455 460
Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro Glu Glu
465 470 475 480
Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile Arg Gly
485 490 495
Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg Thr Arg
500 505 510
Arg Glu Thr Gln Leu Gln Ala Glu Pro Asp Arg Ala His Tyr Asn Ile
515 520 525
Val Thr Phe Cys Cys Lys Cys Asp Ser Thr Leu Arg Leu Cys Val Gln
530 535 540
Ser Thr His Val Asp Ile Arg Thr Leu Glu Asp Leu Leu Met Gly Thr
545 550 555 560
Leu Gly Ile Val Cys Pro Ile Cys Ser Gln Lys Pro Met Ala Arg Phe
565 570 575
Glu Asp Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp Leu Cys Thr Glu
580 585 590
Leu Asn Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys Val Tyr Cys Lys
595 600 605
Thr Val Leu Glu Leu Thr Glu Val Phe Glu Phe Ala Phe Lys Asp Leu
610 615 620
Phe Val Val Tyr Arg Asp Ser Ile Pro His Ala Ala Cys His Lys Cys
625 630 635 640
Ile Asp Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser Asp Ser
645 650 655
Val Met Tyr Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu His Leu
660 665 670
Glu Pro Gln Asn Glu Ile Pro Val Asp Leu Leu Cys His Glu Gln Leu
675 680 685
Ser Asp Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln
690 695 700
His Leu Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys
705 710 715 720
Met Cys Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser Asp Ser
725 730 735
Val Tyr Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr Gly Leu Tyr Asn
740 745 750
Leu Leu Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu Asn Pro Ala Glu
755 760 765
Lys Leu Arg His Leu Asn Glu Lys Arg Arg Phe His Lys Ile Ala Gly
770 775 780
His Tyr Arg Gly Gln Cys His Ser Cys Cys Asn Arg Ala Arg Gln Glu
785 790 795 800
Arg Leu Gln Arg Arg Arg Glu Thr Gln Val Ala Arg Arg Ala Glu Pro
805 810 815
Gln Arg His Thr Met Leu Cys Met Cys Cys Lys Cys Glu Ala Arg Ile
820 825 830
Glu Leu Val Val Glu Ser Ser Ala Asp Asp Leu Arg Ala Phe Gln Gln
835 840 845
Leu Phe Leu Ser Thr Leu Ser Phe Val Cys Pro Trp Cys Ala Ser Gln
850 855 860
Gln
865
<210> 113
<211> 6085
<212> DNA
<213> Artificial Sequence
<220>
<223> E-1 (Order-1)
<220>
<221> misc_feature
<222> (1368)..(1433)
<223> encodes tPA
<220>
<221> misc_feature
<222> (1434)..(1925)
<223> encodes FLT3L
<220>
<221> misc_feature
<222> (1932)..(2186)
<223> 16E6N
<220>
<221> misc_feature
<222> (1932)..(2789)
<223> 16E6/E7
<220>
<221> misc_feature
<222> (2187)..(2330)
<223> 16E7C
<220>
<221> misc_feature
<222> (2331)..(2525)
<223> 16E7N
<220>
<221> misc_feature
<222> (2526)..(2789)
<223> 16E6C
<220>
<221> misc_feature
<222> (2790)..(3671)
<223> 18E6/E7
<400> 113
taccgatgta cgggccagat atacgcgttg acattgatta ttgactagtt attaatagta 60
atcaattacg gggtcattag ttcatagccc atatatggag ttccgcgtta cataacttac 120
ggtaaatggc ccgcctggct gaccgcccaa cgacccccgc ccattgacgt caataatgac 180
gtatgttccc atagtaacgc caatagggac tttccattga cgtcaatggg tggagtattt 240
acggtaaact gcccacttgg cagtacatca agtgtatcat atgccaagta cgccccctat 300
tgacgtcaat gacggtaaat ggcccgcctg gcattatgcc cagtacatga ccttatggga 360
ctttcctact tggcagtaca tctacgtatt agtcatcgct attaccatgg tgatgcggtt 420
ttggcagtac atcaatgggc gtggatagcg gtttgactca cggggatttc caagtctcca 480
ccccattgac gtcaatggga gtttgttttg gcaccaaaat caacgggact ttccaaaatg 540
tcgtaacaac tccgccccat tgacgcaaat gggcggtagg cgtgtacggt gggaggtcta 600
tataagcaga gctctctggc taactagaga acccactgct tactggctta tcgaaattaa 660
tacgactcac tatagggaga cccaagctgg ctagcgtgag tttggggacc cttgattgtt 720
ctttcttttt cgctattgta aaattcatgt tatatggagg gggcaaagtt ttcagggtgt 780
tgtttagaac gggaagatgt cccttgtatc accatggacc ctcatgataa ttttgtttct 840
ttcactttct actctgttga caaccattgt ctcctcttat tttcttttca ttttctgtaa 900
ctttttcgtt aaactttagc ttgcatttgt aacgaatttt taaattcact tttgtttatt 960
tgtcagattg taagtacttt ctctaatcac ttttttttca aggcaatcag ggtatattat 1020
attgtacttc agcacagttt tagagaacaa ttgttataat taaatgataa ggtagaatat 1080
ttctgcatat aaattctggc tggcgtggaa atattcttat tggtagaaac aactacatcc 1140
tggtcatcat cctgcctttc tctttatggt tacaatgata tacactgttt gagatgagga 1200
taaaatactc tgagtccaaa ccgggcccct ctgctaacca tgttcatgcc ttcttctttt 1260
tcctacagct cctgggcaac gtgctggtta ttgtgctgtc tcatcatttt ggcaaagaat 1320
tgtaatacga ctcactatag ggcgaattga agcttggtac cgccaccatg gatgctatga 1380
aacggggcct gtgctgcgtg ctgctcctgt gcggcgctgt gtttgtgagc cctagcatca 1440
cccaggactg ctccttccaa cacagcccca tctcctccga cttcgctgtc aaaatccgtg 1500
agctgtctga ctacctgctt caagattacc cagtcaccgt ggcctccaac ctgcaggacg 1560
aggagctctg cgggggcctc tggcggctgg tcctggcaca gcgctggatg gagcggctca 1620
agactgtcgc tgggtccaag atgcaaggct tgctggagcg cgtgaacacg gagatacact 1680
ttgtcaccaa atgtgccttt cagccccccc ccagctgtct tcgcttcgtc cagaccaaca 1740
tctcccgcct cctgcaggag acctccgagc agctggtggc gctgaagccc tggatcactc 1800
gccagaactt ctcccggtgc ctggagctgc agtgtcagcc cgactcctca accctgccac 1860
ccccatggag tccccggccc ctggaggcca cagccccgac agccccgggc ggcggcagcg 1920
gcgatgctag catgcaccag aagagaaccg ccatgttcca ggaccctcag gagagaccta 1980
ggaagctgcc tcacctgtgt acagagctcc agacaaccat ccacgacatc atcctggagt 2040
gcgtgtactg taagcagcag ctgctgagaa gagaggtgta cgacttcgcc ttcagagacc 2100
tgtgcatcgt gtacagagac ggcaaccctt acgccgtgtg cgataagtgt ctgaagttct 2160
attccaaaat ctccgaatat aggtaccact acaacatcgt gaccttctgc tgcaagtgcg 2220
actctaccct gagactgtgc gtgcagtcta cccacgtgga catcagaacc ctggaggacc 2280
tgctgatggg caccctgggc atcgtgtgcc ctatctgctc tcagaagcct atgcacggcg 2340
acacccctac cctgcacgag tacatgctgg acctccagcc tgagaccaca gacctgtact 2400
gctacgagca gctgaacgac agctctgagg aagaggacga gattgacgga cctgctggcc 2460
aggccgagcc tgacagagcc cactacaata tcgtgacatt ctgttgcaaa tgcgactcca 2520
cactggacaa gtgcctgaag ttctacagca agatctctga gtacagatac tactgctact 2580
ctgtgtacgg caccacactg gagcagcagt acaacaagcc tctgtgcgac ctcctgatcc 2640
gctgcatcaa ctgccagaag cctctgtgcc ctgaggagaa gcagagacac ctggacaaga 2700
agcagcggtt ccacaacatc agaggcagat ggaccggcag gtgcatgtcc tgctgtagat 2760
cctccagaac cagacgggag acccagctga tggccaggtt cgaggaccct accagaagac 2820
cctacaagct gcctgacctg tgcaccgagc tgaacacctc tctgcaagac atcgagatca 2880
cctgcgtgta ctgcaagacc gtgctggagc tgaccgaggt gttcgagttc gccttcaagg 2940
acctgttcgt ggtgtacaga gacagcatcc ctcacgctgc ctgccacaag tgcatcgact 3000
tctattccag gatcagggag ctgcgctatt actccgactc tgtgatgtac ggccccaagg 3060
ccaccctcca ggacatcgtg ctgcacctgg agcctcagaa cgagatcccc gtggacctgc 3120
tgtgccacga gcagctgtct gactctgaag aggagaacga cgagatcgac ggcgtgaacc 3180
accagcacct gcctgccagg agagctgaac cccagcggca taccatgctg tgtatgtgct 3240
tctactctag gatcagagag ctgaggtact actctgactc tgtgtacggc gacaccctgg 3300
agaagctgac caacaccggc ctgtacaacc tgctgatccg gtgcctgagg tgccagaagc 3360
ctctgaaccc tgccgagaag ctgagacacc tgaacgagaa gagaagattc cacaagatcg 3420
ctggccacta cagaggccag tgccactctt gctgcaacag agccagacag gagagactcc 3480
agcggagaag ggagacccag gtggccagaa gagccgagcc tcagagacac accatgctgt 3540
gcatgtgctg caagtgcgag gccagaatcg agctggtggt ggagagctct gccgacgacc 3600
tgagagcctt ccagcagctg ttcctgtcta ccctgagctt cgtgtgccct tggtgcgcct 3660
ctcagcagta atctagagtc ggggcggccg gccgcttcga gcagacatga taagatacat 3720
tgatgagttt ggacaaacca caactagaat gcagtgaaaa aaatgcttta tttgtgaaat 3780
ttgtgatgct attgctttat ttgtaaccat tataagctgc aataaacaag ttaacaacaa 3840
caattgcatt cattttatgt ttcaggttca gggggaggtg tgggaggttt tttaaagcaa 3900
gtaaaacctc tacaaatgtg gtaaaatcga taaggatctg aacgatggag cggagaatgg 3960
gcggaactgg gcggagttag gggcgggatg ggcggagtta ggggcgggac tatggttgct 4020
gactaattga gatgcatgct ttgcatactt ctgcctgctg gggagcctgg ggactttcca 4080
cacctggttg ctgactaatt gagatgcatg ctttgcatac ttctgcctgc tggggagcct 4140
ggggactttc cacaccctaa ctgacacaca ttccacagcg gatccgtcga cttcagaaga 4200
actcgtcaag aaggcgatag aaggcgatgc gccgcgaatc gggagcggcg ataccgtaga 4260
gcacgaggaa gcggtcagcc cattcgccgc caagctcttc agcaatatca cgggtagcca 4320
acgctatgtc ctgatagcgg tccgccacac ccagccggcc acagtcgatg aatccagaaa 4380
agcggccatt ttccaccatg atattcggca agcaggcatc gccatgggtc acgacgagat 4440
cctcgccgtc gggcatgctc gccttgagcc tggcgaacag ttcggctggc gcgagcccct 4500
gatgctcttc gtccagatca tcctgatcga caagaccggc ttccatccga gtacgtgctc 4560
gctcgatgcg atgtttcgct tggtggtcga atgggcaggt agccggatca agcgtatgca 4620
gccgccgcat tgcatcagcc atgatggata ctttctcggc aggagcaagg tgagatgaca 4680
ggagatcctg ccccggcact tcgcccaata gcagccagtc ccttcccgct tcagtgacaa 4740
cgtcgagcac agctgcgcaa ggaacgcccg tcgtggccag ccacgatagc cgcgctgcct 4800
cgtcttgcag ttcattcagg gcaccggaca ggtcggtctt gacaaaaaga accgggcgcc 4860
cctgcgctga cagccggaac acggcggcat cagagcagcc gattgtctgt tgtgcccagt 4920
catagccgaa tagcctctcc acccaagcgg ccggagaacc tgcgtgcaat ccatcttgtt 4980
caatcatgcg aaacgatcct catcctgtct cttgatcaga tcttgatccc ctgcgccatc 5040
agatccttgg cggcaagaaa gccatccagt ttactttgca gggcttccca accttaccag 5100
agggcgcccc agctggcaat tccggttcgc ttgctgtcca taaaaccgcc cagtctagct 5160
atcgccatgt aagcccactg caagctacct gctttctctt tgcgcttgcg ttttcccttg 5220
tccagatagc ccagtagctg acattcatcc ggggtcagca ccgtttctgc ggactggctt 5280
tctacgtgaa aaggatctag gtgaagatcc tttttgataa tctcatgacc aaaatccctt 5340
aacgtgagtt ttcgttccac tgagcgtcag accccgtaga aaagatcaaa ggatcttctt 5400
gagatccttt ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca ccgctaccag 5460
cggtggtttg tttgccggat caagagctac caactctttt tccgaaggta actggcttca 5520
gcagagcgca gataccaaat actgttcttc tagtgtagcc gtagttaggc caccacttca 5580
agaactctgt agcaccgcct acatacctcg ctctgctaat cctgttacca gtggctgctg 5640
ccagtggcga taagtcgtgt cttaccgggt tggactcaag acgatagtta ccggataagg 5700
cgcagcggtc gggctgaacg gggggttcgt gcacacagcc cagcttggag cgaacgacct 5760
acaccgaact gagataccta cagcgtgagc tatgagaaag cgccacgctt cccgaaggga 5820
gaaaggcgga caggtatccg gtaagcggca gggtcggaac aggagagcgc acgagggagc 5880
ttccaggggg aaacgcccgg tatctttata gtcctgtcgg gtttcgccac ctctgacttg 5940
agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac gccagcaacg 6000
cggccttttt acggttcctg gccttttgct ggccttttgc tcacatgttc gggcccaatc 6060
gacccgggcg acggccagtg aattg 6085
<210> 114
<211> 767
<212> PRT
<213> Artificial Sequence
<220>
<223> E-1
<400> 114
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser Ile Thr Gln Asp Cys Ser Phe Gln His
20 25 30
Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu Ser Asp
35 40 45
Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu Gln Asp
50 55 60
Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln Arg Trp
65 70 75 80
Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly Leu Leu
85 90 95
Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala Phe Gln
100 105 110
Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser Arg Leu
115 120 125
Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp Ile Thr
130 135 140
Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro Asp Ser
145 150 155 160
Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala Thr Ala
165 170 175
Pro Thr Ala Pro Gly Gly Gly Ser Gly Asp Ala Ser Met His Gln Lys
180 185 190
Arg Thr Ala Met Phe Gln Asp Pro Gln Glu Arg Pro Arg Lys Leu Pro
195 200 205
His Leu Cys Thr Glu Leu Gln Thr Thr Ile His Asp Ile Ile Leu Glu
210 215 220
Cys Val Tyr Cys Lys Gln Gln Leu Leu Arg Arg Glu Val Tyr Asp Phe
225 230 235 240
Ala Phe Arg Asp Leu Cys Ile Val Tyr Arg Asp Gly Asn Pro Tyr Ala
245 250 255
Val Cys Asp Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg
260 265 270
Tyr His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser Thr Leu
275 280 285
Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr Leu Glu Asp
290 295 300
Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys Ser Gln Lys
305 310 315 320
Pro Met His Gly Asp Thr Pro Thr Leu His Glu Tyr Met Leu Asp Leu
325 330 335
Gln Pro Glu Thr Thr Asp Leu Tyr Cys Tyr Glu Gln Leu Asn Asp Ser
340 345 350
Ser Glu Glu Glu Asp Glu Ile Asp Gly Pro Ala Gly Gln Ala Glu Pro
355 360 365
Asp Arg Ala His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp Ser
370 375 380
Thr Leu Asp Lys Cys Leu Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg
385 390 395 400
Tyr Tyr Cys Tyr Ser Val Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn
405 410 415
Lys Pro Leu Cys Asp Leu Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro
420 425 430
Leu Cys Pro Glu Glu Lys Gln Arg His Leu Asp Lys Lys Gln Arg Phe
435 440 445
His Asn Ile Arg Gly Arg Trp Thr Gly Arg Cys Met Ser Cys Cys Arg
450 455 460
Ser Ser Arg Thr Arg Arg Glu Thr Gln Leu Met Ala Arg Phe Glu Asp
465 470 475 480
Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp Leu Cys Thr Glu Leu Asn
485 490 495
Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys Val Tyr Cys Lys Thr Val
500 505 510
Leu Glu Leu Thr Glu Val Phe Glu Phe Ala Phe Lys Asp Leu Phe Val
515 520 525
Val Tyr Arg Asp Ser Ile Pro His Ala Ala Cys His Lys Cys Ile Asp
530 535 540
Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser Asp Ser Val Met
545 550 555 560
Tyr Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu His Leu Glu Pro
565 570 575
Gln Asn Glu Ile Pro Val Asp Leu Leu Cys His Glu Gln Leu Ser Asp
580 585 590
Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln His Leu
595 600 605
Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys Met Cys
610 615 620
Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser Asp Ser Val Tyr
625 630 635 640
Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr Gly Leu Tyr Asn Leu Leu
645 650 655
Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu Asn Pro Ala Glu Lys Leu
660 665 670
Arg His Leu Asn Glu Lys Arg Arg Phe His Lys Ile Ala Gly His Tyr
675 680 685
Arg Gly Gln Cys His Ser Cys Cys Asn Arg Ala Arg Gln Glu Arg Leu
690 695 700
Gln Arg Arg Arg Glu Thr Gln Val Ala Arg Arg Ala Glu Pro Gln Arg
705 710 715 720
His Thr Met Leu Cys Met Cys Cys Lys Cys Glu Ala Arg Ile Glu Leu
725 730 735
Val Val Glu Ser Ser Ala Asp Asp Leu Arg Ala Phe Gln Gln Leu Phe
740 745 750
Leu Ser Thr Leu Ser Phe Val Cys Pro Trp Cys Ala Ser Gln Gln
755 760 765
<210> 115
<211> 6085
<212> DNA
<213> Artificial Sequence
<220>
<223> E-2 (Order-2)
<220>
<221> misc_feature
<222> (1368)..(1433)
<223> encodes tPA
<220>
<221> misc_feature
<222> (1434)..(1925)
<223> encodes FLT3L
<220>
<221> misc_feature
<222> (1932)..(2195)
<223> 16E6C
<220>
<221> misc_feature
<222> (1932)..(2789)
<223> 16E6/E7
<220>
<221> misc_feature
<222> (2196)..(2339)
<223> 16E7C
<220>
<221> misc_feature
<222> (2340)..(2594)
<223> 16E6N
<220>
<221> misc_feature
<222> (2595)..(2789)
<223> 16E7N
<220>
<221> misc_feature
<222> (2790)..(3671)
<223> 18E6/E7
<400> 115
taccgatgta cgggccagat atacgcgttg acattgatta ttgactagtt attaatagta 60
atcaattacg gggtcattag ttcatagccc atatatggag ttccgcgtta cataacttac 120
ggtaaatggc ccgcctggct gaccgcccaa cgacccccgc ccattgacgt caataatgac 180
gtatgttccc atagtaacgc caatagggac tttccattga cgtcaatggg tggagtattt 240
acggtaaact gcccacttgg cagtacatca agtgtatcat atgccaagta cgccccctat 300
tgacgtcaat gacggtaaat ggcccgcctg gcattatgcc cagtacatga ccttatggga 360
ctttcctact tggcagtaca tctacgtatt agtcatcgct attaccatgg tgatgcggtt 420
ttggcagtac atcaatgggc gtggatagcg gtttgactca cggggatttc caagtctcca 480
ccccattgac gtcaatggga gtttgttttg gcaccaaaat caacgggact ttccaaaatg 540
tcgtaacaac tccgccccat tgacgcaaat gggcggtagg cgtgtacggt gggaggtcta 600
tataagcaga gctctctggc taactagaga acccactgct tactggctta tcgaaattaa 660
tacgactcac tatagggaga cccaagctgg ctagcgtgag tttggggacc cttgattgtt 720
ctttcttttt cgctattgta aaattcatgt tatatggagg gggcaaagtt ttcagggtgt 780
tgtttagaac gggaagatgt cccttgtatc accatggacc ctcatgataa ttttgtttct 840
ttcactttct actctgttga caaccattgt ctcctcttat tttcttttca ttttctgtaa 900
ctttttcgtt aaactttagc ttgcatttgt aacgaatttt taaattcact tttgtttatt 960
tgtcagattg taagtacttt ctctaatcac ttttttttca aggcaatcag ggtatattat 1020
attgtacttc agcacagttt tagagaacaa ttgttataat taaatgataa ggtagaatat 1080
ttctgcatat aaattctggc tggcgtggaa atattcttat tggtagaaac aactacatcc 1140
tggtcatcat cctgcctttc tctttatggt tacaatgata tacactgttt gagatgagga 1200
taaaatactc tgagtccaaa ccgggcccct ctgctaacca tgttcatgcc ttcttctttt 1260
tcctacagct cctgggcaac gtgctggtta ttgtgctgtc tcatcatttt ggcaaagaat 1320
tgtaatacga ctcactatag ggcgaattga agcttggtac cgccaccatg gatgctatga 1380
aacggggcct gtgctgcgtg ctgctcctgt gcggcgctgt gtttgtgagc cctagcatca 1440
cccaggactg ctccttccaa cacagcccca tctcctccga cttcgctgtc aaaatccgtg 1500
agctgtctga ctacctgctt caagattacc cagtcaccgt ggcctccaac ctgcaggacg 1560
aggagctctg cgggggcctc tggcggctgg tcctggcaca gcgctggatg gagcggctca 1620
agactgtcgc tgggtccaag atgcaaggct tgctggagcg cgtgaacacg gagatacact 1680
ttgtcaccaa atgtgccttt cagccccccc ccagctgtct tcgcttcgtc cagaccaaca 1740
tctcccgcct cctgcaggag acctccgagc agctggtggc gctgaagccc tggatcactc 1800
gccagaactt ctcccggtgc ctggagctgc agtgtcagcc cgactcctca accctgccac 1860
ccccatggag tccccggccc ctggaggcca cagccccgac agccccgggc ggcggcagcg 1920
gcgatgctag cgacaagtgc ctgaagttct acagcaagat ctctgagtac agatactact 1980
gctactctgt gtacggcacc acactggagc agcagtacaa caagcctctg tgcgacctcc 2040
tgatccgctg catcaactgc cagaagcctc tgtgccctga ggagaagcag agacacctgg 2100
acaagaagca gcggttccac aacatcagag gcagatggac cggcaggtgc atgtcctgct 2160
gtagatcctc cagaaccaga cgggagaccc agctgcacta caacatcgtg accttctgct 2220
gcaagtgcga ctctaccctg agactgtgcg tgcagtctac ccacgtggac atcagaaccc 2280
tggaggacct gctgatgggc accctgggca tcgtgtgccc tatctgctct cagaagccta 2340
tgcaccagaa gagaaccgcc atgttccagg accctcagga gagacctagg aagctgcctc 2400
acctgtgtac agagctccag acaaccatcc acgacatcat cctggagtgc gtgtactgta 2460
agcagcagct gctgagaaga gaggtgtacg acttcgcctt cagagacctg tgcatcgtgt 2520
acagagacgg caacccttac gccgtgtgcg ataagtgtct gaagttctat tccaaaatct 2580
ccgaatatag gtacatgcac ggcgacaccc ctaccctgca cgagtacatg ctggacctcc 2640
agcctgagac cacagacctg tactgctacg agcagctgaa cgacagctct gaggaagagg 2700
acgagattga cggacctgct ggccaggccg agcctgacag agcccactac aatatcgtga 2760
cattctgttg caaatgcgac tccacactga tggccaggtt cgaggaccct accagaagac 2820
cctacaagct gcctgacctg tgcaccgagc tgaacacctc tctgcaagac atcgagatca 2880
cctgcgtgta ctgcaagacc gtgctggagc tgaccgaggt gttcgagttc gccttcaagg 2940
acctgttcgt ggtgtacaga gacagcatcc ctcacgctgc ctgccacaag tgcatcgact 3000
tctattccag gatcagggag ctgcgctatt actccgactc tgtgatgtac ggccccaagg 3060
ccaccctcca ggacatcgtg ctgcacctgg agcctcagaa cgagatcccc gtggacctgc 3120
tgtgccacga gcagctgtct gactctgaag aggagaacga cgagatcgac ggcgtgaacc 3180
accagcacct gcctgccagg agagctgaac cccagcggca taccatgctg tgtatgtgct 3240
tctactctag gatcagagag ctgaggtact actctgactc tgtgtacggc gacaccctgg 3300
agaagctgac caacaccggc ctgtacaacc tgctgatccg gtgcctgagg tgccagaagc 3360
ctctgaaccc tgccgagaag ctgagacacc tgaacgagaa gagaagattc cacaagatcg 3420
ctggccacta cagaggccag tgccactctt gctgcaacag agccagacag gagagactcc 3480
agcggagaag ggagacccag gtggccagaa gagccgagcc tcagagacac accatgctgt 3540
gcatgtgctg caagtgcgag gccagaatcg agctggtggt ggagagctct gccgacgacc 3600
tgagagcctt ccagcagctg ttcctgtcta ccctgagctt cgtgtgccct tggtgcgcct 3660
ctcagcagta atctagagtc ggggcggccg gccgcttcga gcagacatga taagatacat 3720
tgatgagttt ggacaaacca caactagaat gcagtgaaaa aaatgcttta tttgtgaaat 3780
ttgtgatgct attgctttat ttgtaaccat tataagctgc aataaacaag ttaacaacaa 3840
caattgcatt cattttatgt ttcaggttca gggggaggtg tgggaggttt tttaaagcaa 3900
gtaaaacctc tacaaatgtg gtaaaatcga taaggatctg aacgatggag cggagaatgg 3960
gcggaactgg gcggagttag gggcgggatg ggcggagtta ggggcgggac tatggttgct 4020
gactaattga gatgcatgct ttgcatactt ctgcctgctg gggagcctgg ggactttcca 4080
cacctggttg ctgactaatt gagatgcatg ctttgcatac ttctgcctgc tggggagcct 4140
ggggactttc cacaccctaa ctgacacaca ttccacagcg gatccgtcga cttcagaaga 4200
actcgtcaag aaggcgatag aaggcgatgc gccgcgaatc gggagcggcg ataccgtaga 4260
gcacgaggaa gcggtcagcc cattcgccgc caagctcttc agcaatatca cgggtagcca 4320
acgctatgtc ctgatagcgg tccgccacac ccagccggcc acagtcgatg aatccagaaa 4380
agcggccatt ttccaccatg atattcggca agcaggcatc gccatgggtc acgacgagat 4440
cctcgccgtc gggcatgctc gccttgagcc tggcgaacag ttcggctggc gcgagcccct 4500
gatgctcttc gtccagatca tcctgatcga caagaccggc ttccatccga gtacgtgctc 4560
gctcgatgcg atgtttcgct tggtggtcga atgggcaggt agccggatca agcgtatgca 4620
gccgccgcat tgcatcagcc atgatggata ctttctcggc aggagcaagg tgagatgaca 4680
ggagatcctg ccccggcact tcgcccaata gcagccagtc ccttcccgct tcagtgacaa 4740
cgtcgagcac agctgcgcaa ggaacgcccg tcgtggccag ccacgatagc cgcgctgcct 4800
cgtcttgcag ttcattcagg gcaccggaca ggtcggtctt gacaaaaaga accgggcgcc 4860
cctgcgctga cagccggaac acggcggcat cagagcagcc gattgtctgt tgtgcccagt 4920
catagccgaa tagcctctcc acccaagcgg ccggagaacc tgcgtgcaat ccatcttgtt 4980
caatcatgcg aaacgatcct catcctgtct cttgatcaga tcttgatccc ctgcgccatc 5040
agatccttgg cggcaagaaa gccatccagt ttactttgca gggcttccca accttaccag 5100
agggcgcccc agctggcaat tccggttcgc ttgctgtcca taaaaccgcc cagtctagct 5160
atcgccatgt aagcccactg caagctacct gctttctctt tgcgcttgcg ttttcccttg 5220
tccagatagc ccagtagctg acattcatcc ggggtcagca ccgtttctgc ggactggctt 5280
tctacgtgaa aaggatctag gtgaagatcc tttttgataa tctcatgacc aaaatccctt 5340
aacgtgagtt ttcgttccac tgagcgtcag accccgtaga aaagatcaaa ggatcttctt 5400
gagatccttt ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca ccgctaccag 5460
cggtggtttg tttgccggat caagagctac caactctttt tccgaaggta actggcttca 5520
gcagagcgca gataccaaat actgttcttc tagtgtagcc gtagttaggc caccacttca 5580
agaactctgt agcaccgcct acatacctcg ctctgctaat cctgttacca gtggctgctg 5640
ccagtggcga taagtcgtgt cttaccgggt tggactcaag acgatagtta ccggataagg 5700
cgcagcggtc gggctgaacg gggggttcgt gcacacagcc cagcttggag cgaacgacct 5760
acaccgaact gagataccta cagcgtgagc tatgagaaag cgccacgctt cccgaaggga 5820
gaaaggcgga caggtatccg gtaagcggca gggtcggaac aggagagcgc acgagggagc 5880
ttccaggggg aaacgcccgg tatctttata gtcctgtcgg gtttcgccac ctctgacttg 5940
agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac gccagcaacg 6000
cggccttttt acggttcctg gccttttgct ggccttttgc tcacatgttc gggcccaatc 6060
gacccgggcg acggccagtg aattg 6085
<210> 116
<211> 767
<212> PRT
<213> Artificial Sequence
<220>
<223> E-2
<400> 116
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser Ile Thr Gln Asp Cys Ser Phe Gln His
20 25 30
Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu Ser Asp
35 40 45
Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu Gln Asp
50 55 60
Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln Arg Trp
65 70 75 80
Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly Leu Leu
85 90 95
Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala Phe Gln
100 105 110
Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser Arg Leu
115 120 125
Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp Ile Thr
130 135 140
Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro Asp Ser
145 150 155 160
Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala Thr Ala
165 170 175
Pro Thr Ala Pro Gly Gly Gly Ser Gly Asp Ala Ser Asp Lys Cys Leu
180 185 190
Lys Phe Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Tyr Cys Tyr Ser Val
195 200 205
Tyr Gly Thr Thr Leu Glu Gln Gln Tyr Asn Lys Pro Leu Cys Asp Leu
210 215 220
Leu Ile Arg Cys Ile Asn Cys Gln Lys Pro Leu Cys Pro Glu Glu Lys
225 230 235 240
Gln Arg His Leu Asp Lys Lys Gln Arg Phe His Asn Ile Arg Gly Arg
245 250 255
Trp Thr Gly Arg Cys Met Ser Cys Cys Arg Ser Ser Arg Thr Arg Arg
260 265 270
Glu Thr Gln Leu His Tyr Asn Ile Val Thr Phe Cys Cys Lys Cys Asp
275 280 285
Ser Thr Leu Arg Leu Cys Val Gln Ser Thr His Val Asp Ile Arg Thr
290 295 300
Leu Glu Asp Leu Leu Met Gly Thr Leu Gly Ile Val Cys Pro Ile Cys
305 310 315 320
Ser Gln Lys Pro Met His Gln Lys Arg Thr Ala Met Phe Gln Asp Pro
325 330 335
Gln Glu Arg Pro Arg Lys Leu Pro His Leu Cys Thr Glu Leu Gln Thr
340 345 350
Thr Ile His Asp Ile Ile Leu Glu Cys Val Tyr Cys Lys Gln Gln Leu
355 360 365
Leu Arg Arg Glu Val Tyr Asp Phe Ala Phe Arg Asp Leu Cys Ile Val
370 375 380
Tyr Arg Asp Gly Asn Pro Tyr Ala Val Cys Asp Lys Cys Leu Lys Phe
385 390 395 400
Tyr Ser Lys Ile Ser Glu Tyr Arg Tyr Met His Gly Asp Thr Pro Thr
405 410 415
Leu His Glu Tyr Met Leu Asp Leu Gln Pro Glu Thr Thr Asp Leu Tyr
420 425 430
Cys Tyr Glu Gln Leu Asn Asp Ser Ser Glu Glu Glu Asp Glu Ile Asp
435 440 445
Gly Pro Ala Gly Gln Ala Glu Pro Asp Arg Ala His Tyr Asn Ile Val
450 455 460
Thr Phe Cys Cys Lys Cys Asp Ser Thr Leu Met Ala Arg Phe Glu Asp
465 470 475 480
Pro Thr Arg Arg Pro Tyr Lys Leu Pro Asp Leu Cys Thr Glu Leu Asn
485 490 495
Thr Ser Leu Gln Asp Ile Glu Ile Thr Cys Val Tyr Cys Lys Thr Val
500 505 510
Leu Glu Leu Thr Glu Val Phe Glu Phe Ala Phe Lys Asp Leu Phe Val
515 520 525
Val Tyr Arg Asp Ser Ile Pro His Ala Ala Cys His Lys Cys Ile Asp
530 535 540
Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser Asp Ser Val Met
545 550 555 560
Tyr Gly Pro Lys Ala Thr Leu Gln Asp Ile Val Leu His Leu Glu Pro
565 570 575
Gln Asn Glu Ile Pro Val Asp Leu Leu Cys His Glu Gln Leu Ser Asp
580 585 590
Ser Glu Glu Glu Asn Asp Glu Ile Asp Gly Val Asn His Gln His Leu
595 600 605
Pro Ala Arg Arg Ala Glu Pro Gln Arg His Thr Met Leu Cys Met Cys
610 615 620
Phe Tyr Ser Arg Ile Arg Glu Leu Arg Tyr Tyr Ser Asp Ser Val Tyr
625 630 635 640
Gly Asp Thr Leu Glu Lys Leu Thr Asn Thr Gly Leu Tyr Asn Leu Leu
645 650 655
Ile Arg Cys Leu Arg Cys Gln Lys Pro Leu Asn Pro Ala Glu Lys Leu
660 665 670
Arg His Leu Asn Glu Lys Arg Arg Phe His Lys Ile Ala Gly His Tyr
675 680 685
Arg Gly Gln Cys His Ser Cys Cys Asn Arg Ala Arg Gln Glu Arg Leu
690 695 700
Gln Arg Arg Arg Glu Thr Gln Val Ala Arg Arg Ala Glu Pro Gln Arg
705 710 715 720
His Thr Met Leu Cys Met Cys Cys Lys Cys Glu Ala Arg Ile Glu Leu
725 730 735
Val Val Glu Ser Ser Ala Asp Asp Leu Arg Ala Phe Gln Gln Leu Phe
740 745 750
Leu Ser Thr Leu Ser Phe Val Cys Pro Trp Cys Ala Ser Gln Gln
755 760 765
Claims (21)
- 인유두종바이러스(HPV) 백신 및 체크포인트 억제제를 포함하는 인유두종바이러스(HPV)에 의해 유발된 암 예방 또는 치료용 약학적 조성물.
- 제1항에 있어서, 상기 HPV 백신은 서열번호 15의 폴리뉴클레오타이드 또는 서열번호 15와 85% 이상의 서열 동일성을 갖는 기능적 변이체를 포함하는 HPV 백신을 포함하는, 약학적 조성물.
- 제2항에 있어서, 상기 HPV 백신의 용량은 0.5 mg 내지 5 mg인, 약학적 조성물.
- 제2항에 있어서, 상기 HPV 백신은 근육주사용인, 약학적 조성물.
- 제1항에 있어서, 상기 체크포인트 억제제는 programmed death (PD)-1/PD-L1 억제제인, 약학적 조성물.
- 제1항에 있어서, 상기 체크포인트 억제제는 항-PD-1 항체 또는 항-PD-L1 항체인, 약학적 조성물.
- 제1항에 있어서, 상기 체크포인트 억제제는 펨브롤리주맙(pembrolizumab), 니볼루맙(nivolumab), 아테졸리주맙(atezolizumab), 아벨루맙(avelumab), 더발루맙(durvalumab), 세미플리맙(cemiplimab) 및 이들의 조합으로 구성된 군에서 선택되는, 약학적 조성물.
- 제5항에 있어서, 상기 체크포인트 억제제의 용량은 50 mg 내지 500 mg인, 약학적 조성물.
- 제5항에 있어서, 상기 체크포인트 억제제는 정맥 주사용인, 약학적 조성물.
- 제1항에 있어서, 상기 HPV 백신 및 상기 체크포인트 억제제는 수 회 (multiple times) 투여되는, 약학적 조성물.
- 제1항에 있어서, 상기 HPV 백신 및 상기 체크포인트 억제제는 동시에(simultaneously), 별도로(separately), 또는 순차적으로(sequentially) 투여되는, 약학적 조성물.
- 제1항에 있어서, 상기 HPV 백신은 1주, 2주, 4주, 7주, 13주 및 19주에 투여되고, 추가로 선택적으로 46주에 투여되는, 약학적 조성물.
- 제1항에 있어서, 상기 체크포인트 억제제는 3주 간격으로 투여되는, 약학적 조성물.
- 제1항에 있어서, 상기 HPV에 의해 유발된 암은 자궁경부암인, 약학적 조성물.
- 제14항에 있어서, 상기 자궁경부암은 편평 세포 암종(squamous cell carcinoma) 또는 선암종(adenocarcinoma)인, 약학적 조성물.
- 제1항에 있어서, 상기 HPV에 의해 유발된 암은 전이성(metastatic), 재발성(recurrent) 또는 진행성(advanced) 암이고, 상기 대상체는 항암 치료를 받았거나 받고 있는 대상체인, 약학적 조성물.
- 제1항에 있어서, 상기 HPV는 HPV 16, HPV 18, 또는 이들의 조합인 약학적 조성물.
- 제1항에 있어서, 상기 HPV에 의해 유발된 암의 예방 또는 치료의 대상체는 PD-L1 양성 또는 PD-L1 음성인, 약학적 조성물.
- 제1항에 있어서, 상기 HPV는 HPV 16이고; 상기 HPV에 의해 유발된 암의 예방 또는 치료의 대상체는 PD-L1 양성인, 약학적 조성물.
- 제1항에 있어서, 상기 HPV에 의해 유발된 암은 편평 세포 암종인 자궁경부암; HPV는 HPV 16; 및/또는 상기 HPV에 의해 유발된 암을 예방 또는 치료하기 위한 대상체는 PD-L1 양성인, 약학적 조성물.
- 인유두종바이러스(HPV)에 의해 유발된 암의 예방 또는 치료를 위한 약물의 제조에 있어서 (a) 인유두종바이러스(HPV) 백신 및 (b) 체크포인트 억제제를 포함하는 약학적 조성물의 용도.
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WO2023196884A1 (en) | 2022-04-06 | 2023-10-12 | Juno Therapeutics, Inc. | Detection assay for human papillomavirus (hpv) type 16 (hpv-16) |
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WO2021215896A1 (en) | 2021-10-28 |
BR112022021284A2 (pt) | 2022-12-06 |
KR20240029786A (ko) | 2024-03-06 |
US20210330779A1 (en) | 2021-10-28 |
PE20231054A1 (es) | 2023-07-11 |
EP4138900A4 (en) | 2024-05-15 |
CN115551547A (zh) | 2022-12-30 |
IL297502A (en) | 2022-12-01 |
AU2021261676A1 (en) | 2022-11-24 |
MX2022013063A (es) | 2022-12-08 |
ZA202211410B (en) | 2024-02-28 |
JP7460094B2 (ja) | 2024-04-02 |
US11883479B2 (en) | 2024-01-30 |
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