KR20160016725A - 암 세포에 과발현되는 IL13Rα2에 특이적으로 결합하는 키메라 항원 수용체로 변형된 T 세포 - Google Patents
암 세포에 과발현되는 IL13Rα2에 특이적으로 결합하는 키메라 항원 수용체로 변형된 T 세포 Download PDFInfo
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- KR20160016725A KR20160016725A KR1020150110784A KR20150110784A KR20160016725A KR 20160016725 A KR20160016725 A KR 20160016725A KR 1020150110784 A KR1020150110784 A KR 1020150110784A KR 20150110784 A KR20150110784 A KR 20150110784A KR 20160016725 A KR20160016725 A KR 20160016725A
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Abstract
키메라 항원 수용체(CAR)를 암호화하는 핵산 서열에 있어서, 상기 CAR은 암세포 항원을 인식하는 리간드를 포함하는 세포 외부 표적 도메인; 세포 내부 신호 전달 도메인; 및 상기 세포 외부 표적 도메인과 상기 세포 내부 신호 전달 도메인을 연결하는 중간 도메인으로 구성되고, 상기 세포 외부 표적 도메인을 암호화하는 핵산서열은 서열번호 No.1 내지 No. 4으로부터 선택되는 것을 특징으로 하는 핵산 서열이 제공된다.
Description
본 발명은 암 세포에 과발현되는 IL13α2에 특이적으로 결합하는 키메라 항원 수용체로 변형된 T 세포에 관한 것이다. 보다 구체적으로는, 교모세포종에 과발현되는 IL13α2에 특이적으로 결합할 수 있는 키메라 항원 수용체를 암호화하는 핵산 서열을 이용하여 T 세포를 형질전환시킴으로써 CAR-T 세포를 제작하고, 이를 이용해서 암세포를 사멸함으로써 암을 치료하는 방법에 관한 것이다. 본 특허출원은 미국 가출원 62/033,305호(출원일 2014.8.5.) 및 62/034,385호(출원일 2014.8.7.)에 대한 우선권을 주장하며, 여기에 기재된 전체내용이 본원발명의 일부를 구성한다.
키메라 항원 수용체를 발현하는 T 세포(CAR-T cell)는, 암세포의 표면에 특이적으로 발현되는 암세포 표면 항원을 인식하는 수용체를 코딩하는 유전자를 T 세포에 도입하여 암세포를 사멸시킬 수 있도록 유전자가 재조합된 T 세포를 의미한다. 키메라 항원 수용체(chimeric antigen receptor, CAR) 단백질은 암세포 표면 항원을 인지하는 세포 외 표적 결합 영역(extracellular target binding domain)과 활성화 신호를 보내는 세포 내 신호 전달 도메인(intracellular signaling domain)으로 구성된 물질을 T 세포에 형질도입 함으로써 만들어진다 (Gianpietro Dotti 등, Immunol Rev, 2014, 257(1):107-126; David M. Barrett 등, Annu Rev Med, 2014, 65:333-347; 및 Marcela V. Maus 등, Blood, 2014, 123:2625-2635).
CAR-T세포를 이용해서 암을 치료하는 방법과 관련하여, 3명의 말기 만성림프성백혈병(CCL, chronic lymphoid leukemia) 환자에게 CD19를 인지할 수 있도록 변형된 세포독성T세포(Cytotoxic T cell)을 주사했더니, 그 중 2명에서 백혈병이 완전히 치료되었고, 그 상태가 10개월 정도 지속되었다는 보고가 있고, (N. Engl J Med 2011;365:725-733 August 25, 2011, Sic. Transl. Med 2011 Aug 10;3(95):95ra73) 여기에서 사용된 CAR-T는 2세대에 해당되는 것으로서 세포질부분(cytosolic part)에 4-1BB와 CD3-zeta 부분을 넣어서 증식신호를 발생하게 만든 것이다. 위의 항체 scFv는 백혈병 암세포의 표면에서 발견되는 CD19를 항원으로 인식한다.
또한, 급성 백혈병 환자에게 CTL019를 투여하여 치료하였더니, 환자 30명중 27명이 완전 관해를 경험하였고, 전체 환자의 67%가 2년동안 완전관해, 78%가 2년간 생존하였다는 보고가 있으며, 대상 환자가 재발성 혹은 불응성환자였음을 고려한다면, 이는 매우 놀라운 것이다.(N Engl J Med 2014; 371:1507-1517, October 16, 2014)
현재, 다양한 CAR-T세포를 이용한 치료법에 대하여 lymphoma, myeloma 등 다양한 혈액암을 대상으로 임상시험이 진행중에 있으며 조만간 FDA에 NDA허가를 신청할 수 있을 것으로 예상되며, 따라서, 치료제로서의 CAR-T가 시장에 등장할 것으로 예상된다.
CAR-T 세포를 이용한 암치료는 자가 유래 방식이어서 대량생산되는 제품은 아니지만, 환자 맞춤형으로서 그 치료효과가 기존의 항암제와 비교할 수 없을 정도로 높다.
한편, 교모세포종(Gliobastoma, GBM) 또는 다형성아교모세포종(glioblastoma multiforme)는 뇌종양의 약 12~15%를 차지하는 가장 일반적인 뇌종양 중 하나로서, 일반적인 악성 뇌암에 해당한다. 대장암이나 폐암에 비해서 상대적으로 드문 편이므로 그 치료법에 대한 연구가 활발하지 않은 편이다. 교모세포종의 세포는 성상세포(astrocyte)와 유사한데, 성상세포는 신경 세포를 유지하고 신경에 영양을 주고, 뇌 조직의 손상에 대한 방어 반응을 담당하고 있다. 교모세포종의 발생과 악성화에는 줄기 세포 또는 미성숙한 성상 세포의 유전자 이상이 관여하고 있다고 생각되어지고 있다.
교모세포종의 치료는, 수술, 방사선 치료 및 화학항암요법제가 사용된다. 화학항암요법제로서는, 테모졸로미드, 로무스틴 및 카르무스틴등을 사용하고 있고, 최근에는 종양 백신 치료 및 분자 표적 치료등의 임상시험이 진행되고 있다. 그러나, 여전히 교모세포종 치료에 대해서 유용한 치료제는 없는 실정이다.
Immunol Rev, 2014, 257(1):107-126
N Engl J Med 2014; 371:1507-1517, October 16, 2014
Science Translational Medicine 18 Feb 2015: Vol. 7, Issue 275, pp. 275ra22
본 발명은 교모세포종 치료를 위한 CAR-T 세포를 제공하는 것을 해결과제로 한다. 나아가, 교모세포종 치료를 위하여, 암세포의 표면에 특이적으로 발현하는 항원을 인식하는 키메라 수용체 단백질 및 이를 코딩하는 유전자를 제공하는 것을 해결과제로 한다.
상기 해결과제를 해결하기 위한 수단으로서, 본 발명에서는,
키메라 항원 수용체(CAR)를 암호화하는 핵산 서열에 있어서, 상기 CAR은 암세포 항원을 인식하는 리간드를 포함하는 세포 외부 표적 도메인, 세포 내부 신호 전달 도메인 및 상기 세포 외부 표적 도메인과 상기 세포 내부 신호 전달 도메인을 연결하는 중간 도메인으로 구성되고, 상기 세포 외부 표적 도메인은 서열번호 17, 19, 21, 23 및 25중에서 선택된 어느 하나를 포함하는 것을 특징으로 하는 핵산 서열이 제공된다.
본 발명의 CAR-T 세포는 교모세포종 치료효과를 갖는다.
도 1과 2는, 본 발명에서 사용된 IL13Rα2에 특이적으로 결합할 수 있는 키메라 항원 수용체(chimeric antigen receptor, CAR)유전자 전달 벡터인 레트로바이러스 벡터 및 이식 유전자를 개략적으로 보여주는 일련의 이미지이다. 도 1은 본 발명에서 사용된 이식 유전자 구조체의 구조를 설명하고 있다. 본 도면에서 나타내는 구조체에서 IL13은 인간으로부터 유래한 IL13을, H는 인간 CDα8 힌지(hinge) 영역을, TM은 막 통과 도메인을, 28은 CD28 활성 신호 전달 도메인(coactivation signaling domain)을, TNSRSF9은 tumor necrosis factor superfamily member9 활성 신호 전달 도메인(coactivation signaling domain)을, CD3ζ는 CD3 제타 살해(killing) 신호 도매인을 나타낸다.
도 2는 IL13 pMEG-Map 레트로바이러스성 벡터의 제한효소 지도(restriction map)을 나타낸다.
도 3은, IL13Rα2에 특이적으로 결합할 수 있는 CAR를 이용하여 형질전환 된 anti-IL13Rα2 CAR-T 세포를 유세포 분석기를 사용해서 분석한 결과를 나타내는 도면이다. 각 형질전환 된 anti-IL13Rα2 CAR-T 세포의 CAR 발현 정도는 각 히스토그램 위에 제공하였다.
도 4는, 실시예 1, 2 및 3에서 설명된 각각의 IL13α2에 특이적인 CAR가 형질도입 된 T 세포가 표적 암세포에 미치는 세포독성(cytotoxicity) 활성을 나타내는 도면이다. 각각의 IL13α2에 특이적인 CAR가 20% 형질도입 된 T 세포를, 표적 세포인 IL13Rα2가 과발현되는 교모세포종 U251 세포(IL13α1+ IL13α2+) 및 primary normal cell control인 HUVEC 세포(IL13α1+ IL13α2-)와 각각 5:1의 비율로 배양하여 4시간 세포독성 활성을 측정하였다.
도 5는, IL13α2 특이적인 CAR가 형질도입 된 T 세포의 사이토카인 IFN-γ의 생산량을 나타내는 도면이다. 각각의 IL13α2 특이적인 CAR가 20% 형질도입 된 T 세포를 표적 세포인 IL13Rα2가 과발현되는 교모세포종 U251 세포(IL13α1+ IL13α2+), primary normal cell control HUVEC 세포(IL13α1+ IL13α2-), 및 THP-1 세포(IL13α1+ IL13α2-)와 각각 2:1의 비율로 배양하여 24시간 사이토카인 IFN-γ의 생산량을 측정하였다. anti-IL13Rα2 CAR-T 세포들의 교모세포종(GBM)에 과발현되는 IL13Rα2에 특이적인지를 체크하기 위해 THP-1 세포(IL13α1+ IL13α2-)를 사용하였다.
도 6는, IL13α2 특이적인 CAR가 형질도입 된 T 세포의 사이토카인 IL-2의 생산량을 나타내는 도면이다. IL13α2 특이적인 CAR가 20% 형질도입 된 T 세포를 표적 세포인 IL13Rα2가 과발현되는 교모세포종 U251 세포(IL13α1+ IL13α2+), primary normal cell control HUVEC 세포(IL13α1+ IL13α2-)와 각각 2:1의 비율로 24시간 배양하여 사이토카인 IL-2의 생산량을 측정하였다.
도 7 내지 38은, anti-IL13Rα2 CAR 단백질들의 생산에 관련된 핵산서열들 및 단백질서열들을 나타낸다. 도 7 내지 38과 본원 명세서에 첨부한 서열번호의 상관관계는 다음과 같으며, 각 도면에서 있어서 상단에 표시된 것은 DNA 서열이며, 하단에 표시된 것은 위 DNA에 의해서 발현되는 단백질 서열이다. 도 31 내지 도 38의 경우, 상단에 2개의 DNA 서열이 표시되어 있으며, 하단에 위 각각의 DNA가 발현되어 나타나는 단백질 서열이 표시된다.
[표 1]
도 2는 IL13 pMEG-Map 레트로바이러스성 벡터의 제한효소 지도(restriction map)을 나타낸다.
도 3은, IL13Rα2에 특이적으로 결합할 수 있는 CAR를 이용하여 형질전환 된 anti-IL13Rα2 CAR-T 세포를 유세포 분석기를 사용해서 분석한 결과를 나타내는 도면이다. 각 형질전환 된 anti-IL13Rα2 CAR-T 세포의 CAR 발현 정도는 각 히스토그램 위에 제공하였다.
도 4는, 실시예 1, 2 및 3에서 설명된 각각의 IL13α2에 특이적인 CAR가 형질도입 된 T 세포가 표적 암세포에 미치는 세포독성(cytotoxicity) 활성을 나타내는 도면이다. 각각의 IL13α2에 특이적인 CAR가 20% 형질도입 된 T 세포를, 표적 세포인 IL13Rα2가 과발현되는 교모세포종 U251 세포(IL13α1+ IL13α2+) 및 primary normal cell control인 HUVEC 세포(IL13α1+ IL13α2-)와 각각 5:1의 비율로 배양하여 4시간 세포독성 활성을 측정하였다.
도 5는, IL13α2 특이적인 CAR가 형질도입 된 T 세포의 사이토카인 IFN-γ의 생산량을 나타내는 도면이다. 각각의 IL13α2 특이적인 CAR가 20% 형질도입 된 T 세포를 표적 세포인 IL13Rα2가 과발현되는 교모세포종 U251 세포(IL13α1+ IL13α2+), primary normal cell control HUVEC 세포(IL13α1+ IL13α2-), 및 THP-1 세포(IL13α1+ IL13α2-)와 각각 2:1의 비율로 배양하여 24시간 사이토카인 IFN-γ의 생산량을 측정하였다. anti-IL13Rα2 CAR-T 세포들의 교모세포종(GBM)에 과발현되는 IL13Rα2에 특이적인지를 체크하기 위해 THP-1 세포(IL13α1+ IL13α2-)를 사용하였다.
도 6는, IL13α2 특이적인 CAR가 형질도입 된 T 세포의 사이토카인 IL-2의 생산량을 나타내는 도면이다. IL13α2 특이적인 CAR가 20% 형질도입 된 T 세포를 표적 세포인 IL13Rα2가 과발현되는 교모세포종 U251 세포(IL13α1+ IL13α2+), primary normal cell control HUVEC 세포(IL13α1+ IL13α2-)와 각각 2:1의 비율로 24시간 배양하여 사이토카인 IL-2의 생산량을 측정하였다.
도 7 내지 38은, anti-IL13Rα2 CAR 단백질들의 생산에 관련된 핵산서열들 및 단백질서열들을 나타낸다. 도 7 내지 38과 본원 명세서에 첨부한 서열번호의 상관관계는 다음과 같으며, 각 도면에서 있어서 상단에 표시된 것은 DNA 서열이며, 하단에 표시된 것은 위 DNA에 의해서 발현되는 단백질 서열이다. 도 31 내지 도 38의 경우, 상단에 2개의 DNA 서열이 표시되어 있으며, 하단에 위 각각의 DNA가 발현되어 나타나는 단백질 서열이 표시된다.
[표 1]
본 발명은 인간을 포함한 포유동물에서 암세포에 대한 T 세포 매개 면역 반응을 자극하기 위한 방법에 있어서, 상기 방법은 CAR를 발현하기 위해 유전적으로 변경된 유효량의 세포를 포유동물에 투여하는 단계를 포함한다. 상기 CAR는 암세포 항원을 인식하는 리간드를 포함하는 세포 외부 표적 도메인, 세포 내부 신호 전달 도메인 및 상기 세포 외부 표적 도메인과 상기 세포 내부 신호 전달 도메인을 연결하는 중간 도메인, 및 세포 내부 신호 전달 도메인으로 구성되고, 상기 세포 외부 표적 도메인은 암세포를 특이적으로 인식하게 된다.
또한, 본 발명은 암세포 표면에 발현되는 종양 항원과 연관된 질병을 앓고 있는 포유동물을 치료하는 방법에 있어서, CAR를 발현하기 위해 유전적으로 변형된 유효량의 세포를 포유동물에 투여하는 단계를 포함하되, 상기 CAR는 암세포 항원을 인식하는 리간드를 포함하는 세포 외부 표적 도메인, 세포 내부 신호 전달 도메인 및 상기 세포 외부 표적 도메인과 상기 세포 내부 신호 전달 도메인을 연결하는 중간 도메인, 및 세포 내부 신호 전달 도메인으로 구성되고, 상기 세포 외부 표적 도메인은 암세포를 특이적으로 인식하게 된다.
본 발명의 하나의 실시태양에 있어서, 상기 세포는 자가성 T 세포일 수 있다.
하나의 실시태양에 있어서, 상기 종양 항원은 IL13Rα2 일 수 있다.
하나의 실시태양에 있어서, 본 발명에 의해서 치료되는 암은 교모세포종일 수 있다.
본 발명은 혈액학적 악성 종양 및 고형 종양을 포함하지만, 이에 한정되지 않는 암을 치료하기 위한 조성물 및 방법에 관한 것이다. 본 발명은 키메릭 항원 수용체(CAR)를 발현하기 위해서 형질 도입된 T 세포에 관한 것이다. CAR는 특이적 항종양 세포성 면역 활성을 나타내는 키메라 단백질을 생성하기 위해 T 세포 수용체 활성화 세포 내 도메인과 목적하는 항원에 대한 항체 기반 특이성을 조합하는 분자이다.
본 발명에서는 CAR를 발현하는 T 세포를 CAR-T세포라 지칭한다. CAR-T 세포는 그 표면상에 암세포에서 특이적으로 발현하는 항원과 결합하는 도메인을 안정하게 발현한다.
본 발명에서는, 교모세포종(GBM)에 과발현되는 IL13Rα2에 특이적으로 결합할 수 있는 키메라 항원 수용체(chimeric antigen receptor, CAR)들을 개발하여, 형질 도입을 통해 유전적으로 변형된 CAR-T 세포들을 제작하였다. 제작된 CAR-T 세포는 관련 암종을 사멸시키는 결과를 보였다. 본 발명의 키메라 항원 수용체(chimeric antigen receptor, CAR)는 세포 외부 표적 결합 도메인(extracellular target binding domain), 세포 내부 신호 전달 도메인(intracellular signaling domain) 및 중간 도메인으로 구성된다.
세포 외부 표적 결합 도메인은 유전적으로 변형된 CAR-T 세포가 특정 표면 암 항원인 IL13Rα2를 인지하는 리간드로 제작되었고, DNA 서열 17, 19, 21, 23, 25 및 이들에 의해서 발현되는 아미노산서열 18, 20, 22, 24 및 26으로 특징지워진다. 본 발명자는 IL13Rα2를 인지하는 리간드로서, IL13의 2가지 아미노산 치환(Glu-11, Arg-107)만으로 IL13α2에 대한 특이적인 결합활성을 보임을 확인하였고, 인간 IL13(P35225.1)(서열 19/20 및 서열 21/22), 인간 CD3(P20963-1)(서열 13/14), 인간 CD8α(P01732)(서열 7/8), TNFRSF9(Q07011)(서열 15/16), 인간 카파 경쇄 신호 서열(HuVHCAMP)(서열 1/2)을 이용하여, codon-optimized synthetic DNA들로 구성된 IL13Rα2에 대한 결합력이 높은 돌연변이 anti-IL13Rα2 CAR(서열 27 내지 106)들을 제작하였다. 또한, 돌연변이 되지 않은 wild-type 인간 IL13(서열 17/18) 성숙 단백질 서열을 사용할 수도 있다. 나아가, 인간 IL13에 대한 돌연변이 IL13.E11K.R107K보다 높은 항원 친화력(affinity)를 부여하기 위해 돌연변이 IL13.E11K.R64D.S67D.R107K(서열 25/26) 및 IL13.E11Y.R64D.S67D.K103R(서열 23/24)를 사용할 수 있다.
세포 내부 신호 전달 도메인은, T 세포가 가지고 있는 기능, 예를 들면, 세포 용해성 활성 또는 헬퍼(helper) 활성을 활성화시키는 역할을 한다. 본 발명의 CAR에 사용하기 위한 세포 내부 신호전달 도메인의 바람직한 예로는 항원 수용체 관여(engagement) 이후에 신호 형질 도입을 개시하도록 협조적으로 작용하는 T 세포 수용체(TCR) 및 보조 수용체의 세포질 서열뿐만 아니라, 이들 서열의 임의의 유도체 또는 변이체, 및 동일한 기능적 능력을 갖는 임의의 합성 서열을 들 수 있다. TCR이 단독으로는 생성된 신호가 T 세포의 완전한 활성화에 불충분하고, 이차신호가 또한 요구된다는 것이 공지되어 있다. 따라서 T 세포 활성화는 신호전달 서열에 의해 매개되는 것으로 언급될 수 있으며, TCR을 통한 항원 의존성 일차 활성화를 개시하는 신호전달 서열(일차 세포질 신호전달 서열) 및 이차 신호를 제공하기 위해 항원 의존성 방식으로 작용하는 신호전달 서열(이차 세포질 신호전달 서열)이 있을 수 있다.
본 발명에서 사용되는 세포 내부 신호전달 도메인으로서는, TNFRSF9의 보조 자극 신호 도메인(서열 15/16), CD3 제타(서열 13/14), 변형되거나 변형되지 않은 CD28의 신호전달 도메인(서열 9/10 및 11/12)으로 이루어지는 군으로부터 선택되는 것이 특히 바람직하다.
본 발명의 CAR의 세포 내부 신호전달 도메인의 서열은 무작위 또는 구체화된 순서로 서로 연결될 수 있다
하나의 실시형태에서, 상기 세포 내부 신호전달 도메인은 TNFRSF9 및 CD28의 신호전달 도메인을 포함하도록 설계되었다. 다른 실시형태에서, 상기 세포 내부 신호전달 도메인은 CD28을 포함하도록 설계되었다. 또 다른 실시형태에서, 상기 세포 내부 신호전달 도메인은 CD3 제타를 포함하도록 설계되었다.
중간 도메인은 세포 외부 표적 결합 도메인(extracellular target binding domain)과 세포 내부 신호 전달 도메인을 연결하는 역할을 한다. 중간 도메인은 T 세포막에서 CAR 분자의 지지대 역할을 하는 막투과 부분(transmembrane portion)과 T 세포막으로부터 세포 외부 표적 결합 도메인(extracellular target binding domain)을 확장하기 위한 힌지 부분(hinge portion)으로 구성되어 있다. 막투과 부분은 CD3 또는 CD8 막투과 영역(transmembrane region)에서 유래되었으며, 힌지부분은 CD8 힌지영역(hinge region)에서 유래되었다. (서열 3/4 및 5/6)
본 발명은 T 세포에 anti-IL13Rα2 CAR 단백질의 생산에 관련된 핵산서열들, 단백질서열들, 벡터, 세포들 및 IL13Rα2와 관련된 종양을 치료하는 방법들을 포함한다.
하나의 실시형태에서, 본 발명의 CAR는 kozak consensus ribosome-binding sequence, 인간 카파 경쇄 신호 서열(HuVHCAMP, 서열 1/2) , 인간 IL13.E11K.R107K 성숙 단백질 서열(human IL13.E11K.R107K mature peptide sequence, 서열 19/20), 인간 CD8α의 힌지 영역(hinge region of human CD8α), 인간 CD8 또는 CD3 막 횡단(human CD8(서열 7/8) or CD3(서열 5/6) transmembrane), 세포질 TNFRSF9의 보조 자극 신호 도메인(cytoplasmic TNFRSF9 costimulatory signaling domain, 서열 15/16)), 세포질 TCRzeta 서열과 XhoI/NotI 절단 부분(restriction site)을 포함한다. 다른 하나의 실시형태에서, kozak consensus ribosome-binding sequence, 인간 카파 경쇄 신호 서열(HuVHCAMP, 서열 1/2)), wild-type 인간 IL13 성숙 단백질 서열(wild-type human IL13 mature peptide sequence, 서열 17/18)), 인간 CD8α의 힌지 영역(hinge region of human CD8α), 인간 CD3 막 횡단(human CD3 transmembrane, 서열 5/6)), 세포질 CD28의 보조 자극 신호 도메인(cytoplasmic CD28 costimulatory signaling domain, 서열 9/10 및 11/12), 세포질 TCRzeta 서열과 XhoI/NotI절단 부분(restriction site)을 포함할 수 있다. 다른 실시형태에서, kozak consensus ribosome-binding sequence, 인간 카파 경쇄 신호 서열(HuVHCAMP, 서열 1/2), 인간 IL13.E11K.R107K 성숙 단백질 서열(human IL13.E11K.R107K mature peptide sequence, 서열 19/20), 인간 CD8α의 힌지 영역(hinge region of human CD8α ), 인간 CD3 또는 CD8 막 횡단(human CD3 or CD8 transmembrane, 서열 5/6 또는 7/8), 변형된 세포질 CD28의 보조 자극 신호 도메인(cytoplasmic CD28 costimulatory signaling domain, 서열 11/12), 세포질 TNFRSF9의 보조 자극 신호 도메인(cytoplasmic TNFRSF9 costimulatory signaling domain, 서열 15/16), 세포질 TCRzeta 서열과 XhoI/NotI 절단 부분(restriction site)을 포함할 수 있다. 또 다른 실시형태에서, kozak consensus ribosome-binding sequence, 인간 카파 경쇄 신호 서열(HuVHCAMP, 서열 1/2), 인간 IL13.E11K.R64D.S67D.R107K(서열 25/26) 또는 IL13.E11Y.R64D.S67D.K103R(서열 23/24) 성숙 단백질 서열(human IL13.E11K.R64D.S67D.R107K 또는 IL13.E11Y.R64D.S67D.K103R mature peptide sequence), 인간 CD8α의 힌지 영역(hinge region of human CD8α), 인간 CD3 또는 CD8 막 횡단(human CD3 or CD8 transmembrane, 서열 5/6 또는 서열 7/8), 변형된 세포질 CD28의 보조 자극 신호 도메인(cytoplasmic CD28 costimulatory signaling domain, 서열 9/10), 세포질 TNFRSF9의 보조 자극 신호 도메인(cytoplasmic TNFRSF9 costimulatory signaling domain, 서열 15/16), 세포질 TCRzeta 서열과 XhoI/NotI 절단 부분(restriction site)을 포함할 수 있다.
목적하는 분자를 코딩하는 핵산 서열은 당해 기술분야에 공지된 재조합 방법을 이용하여 수득될 수 있으며, 예를 들어 표준 기법을 이용하여 상기 유전자를 발현하는 세포로부터 라이브러리를 스크리닝하거나, 상기 동일한 유전자를 포함하도록 공지된 벡터로부터 유전자를 유도하거나, 상기 동일한 유전자를 포함하는 세포 및 조직으로부터 직접 단리함으로써 수득될 수 있다. 대안적으로는, 상기 관심이 있는 유전자는 클로닝이 아닌 합성에 의해 생성될 수 있다. 본 발명은 또한 본 발명의 DNA가 삽입되어 있는 벡터를 제공한다. 렌티바이러스와 같은 레트로바이러스에서 유래한 벡터는 이들이 이식 유전자의 장기간 안정한 통합 및 딸세포에서의 상기 유전자의 증식을 허용하기 때문에 장기간 유전자 전달을 달성하기에 적합한 도구이다. 간단하게 요약하면, CAR을 암호화하는 천연 또는 합성 핵산의 발현은 전형적으로 CAR 폴리펩티드 또는 이의 일부를 암호화하는 핵산을 프로모터에 작동 가능하게 연결하고 상기 구조체를 발현 벡터에 도입함으로써 달성된다. 상기 벡터는 복제 및 통합 진핵생물용으로 적합할 수 있다. 전형적인 클로닝 벡터는 전사 및 번역 종결 종결인자, 개시 서열, 및 목적하는 핵산 서열의 발현의 조절에 유용한 프로모터를 포함한다. 상기 핵산은 다수 유형의 벡터 내로 클로닝될 수 있다. 예를 들어, 상기 핵산은 플라스미드, 파지미드(phagemid), 파지 유도체, 동물 바이러스 및 코스미드를 포함하지만 이에 제한되지 않는 벡터 내로 클로닝될 수 있다. 특히 관심이 있는 벡터로는 발현 벡터, 복제 벡터, 탐침 생성 벡터 및 시퀀싱 벡터를 들 수 있다. 또한 상기 발현 벡터는 바이러스성 벡터의 형태인 세포에 제공될 수 있다. 바이러스성 벡터 기술은 당해 기술분야에 널리 공지되어 있으며, 예를 들어 샘브룩(Sambrook) 등(2001, MolecularCloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York)에 개시되어 있으며, 기타 바이러스학 및 분자생물학 설명서에 개시되어 있다. 벡터로서 유용한 바이러스로는 레트로바이러스, 아데노바이러스, 아데노 연관 바이러스, 포진 바이러스 및 렌티바이러스를 들 수 있지만, 이에 제한되지 않는다. 일반적으로, 적합한 벡터는 적어도 하나의 유기체에서 기능적인 복제 기원, 프로모터 서열, 편리한 제한 엔도뉴클레아제 부위 및 하나 이상의 선택 가능한 마커를 포함한다(예를 들어, 국제 공개공보 제 WO 01/96584 호; 제 WO 01/29058 호; 및 미국 특허 제 6,326,193 호). 다수의 바이러스 기반 시스템은 포유동물 세포 내로의 유전자 전달을 위해 개발되었다. 예를 들어, 레트로바이러스는 유전자 전달 시스템을 위한 편리한 플랫폼(platform)을 제공한다. 선택된 유전자는 벡터 내로 삽입되고, 당해 기술분야에 공지된 기법을 이용하여 레트로바이러스성 입자에 패키징(packaging)된다. 이어 재조합 바이러스는 단리되어, 생체 내 및 생체 외 중 하나에서 개체의 세포로 전달될 수 있다. 다수의 레트로바이러스성 시스템이 당해 기술분야에 공지되어 있다. 몇몇 실시형태에서, 아데노바이러스 벡터가 사용된다. 다수의 아데노바이러스 벡터가 당해 기술분야에 공지되어 있다. 하나의 실시형태에서, 렌티바이러스 벡터가 사용된다.
세포 내로 유전자를 도입하고 발현하는 방법은 당해 기술분야에 공지되어 있다. 발현 벡터의 배경에서, 상기 벡터는 당해 기술분야에 공지된 임의의 방법에 의해 숙주 세포, 예를 들어, 포유동물 세포, 박테리아성 세포, 효모 세포 또는 곤충 세포 내로 신속하게 도입될 수 있다. 예를 들어, 발현 벡터는 물리적, 화학적 또는 생물학적 수단에 의해 숙주 세포에 전달될 수 있다.
포유동물에서 표적 항원을 갖는 암세포에 대한 T 세포 매개 면역 반응을 자극하기 위한 방법을 제공하며, 상기 방법은 CAR을 발현하는 T 세포를 포유동물에 투여하는 단계를 포함한다. 하나의 실시형태에서, 본 발명은 세포성 요법의 유형을 포함하며, 이때 T 세포는 CAR을 발현하기 위해 유전적으로 변형되어 있으며, 상기 CAR T 세포는 이의 치료가 필요한 환자에게 주입된다. 주입된 세포는 환자에서 종양 세포를 사멸할 수 있다. 항체 요법과는 달리, CAR T 세포는 생체 내에서 복제하여, 지속된 종양 제어를 야기할 수 있는 장기간 존속을 초래할 수 있다.
하나의 실시형태에서, 본 발명의 CAR T 세포는 강력한 생체 내 T 세포 증식을 경험할 수 있으며, 증가된 양의 시간 동안 존속할 수 있다. 다른 실시형태에서, 본 발명의 CAR T 세포는 임의의 부가적인 종양 형성 또는 성장을 억제하도록 반응성화될 수 있는 특정 메모리 T 세포로 발달한다. 예를 들어, 본 발명의 CAR T세포는 강력한 생체 내 T 세포 확장을 경험할 수 있고, 혈액 및 골수에서 증가된 양의 시간 동안 높은 수준으로 존속할 수 있으며, 특정 메모리 T 세포를 형성할 수 있다.
본 발명은 구조체의 성분 각각에 대한 다수의 임의의 변이체를 포함하는 것으로 이해되어야 한다.
치료될 수 있는 암은 교모세포종뿐만 아니라, 비-고형 종양(예를 들어, 혈액학적 종양, 예를 들어 백혈병 및 림프종)을 포함할 수 있거나, 고형 종양을 포함할 수 있다.
본 발명의 CAR 변형 T 세포는 단독으로 투여되거나, 희석제 및/또는 IL-2 또는 기타 사이토카인과 같은 기타 성분, 또는 세포 개체군과 함께 약학 조성물로서 투여될 수 있다. 간단하게는, 본 발명의 약학 조성물은 하나 이상의 약학적으로 또는 생리학적으로 허용 가능한 담체, 희석제 또는 부형제와 함께 본원에서 개시된 바와 같은 표적 세포 개체군을 포함할 수 있다. 이 같은 조성물은 중성 완충 식염수, 인산 완충 식염수 등과 같은 완충액; 글루코오스, 만노오스, 수크로오스 또는 덱스트란 등과 같은 탄수화물; 만니톨; 단백질; 폴리펩티드 또는 글리신과 같은 아미노산; 항산화제; EDTA 또는 글루타티온과 같은 킬레이트제; 보조제(예를 들어, 수산화알루미늄); 및 보존제를 포함할 수 있다. 본 발명의 조성물은 정맥 내 투여를 위해 제형화하는 것이 바람직하다.
본 발명의 약학 조성물은 치료(예방)될 질병에 적절한 방식으로 투여될 수 있다. 적절한 투여량이 임상 시험에 의해 결정될지라도 투여량 및 투여 빈도는 환자의 조건, 환자 질병의 유형 및 중증도와 같은 인자에 의해 결정될 것이다.
개별 조성물의 투여는 에어로졸 흡입, 주사, 섭취, 수혈, 주입 또는 이식을 포함한 임의의 편리한 방식으로 수행될 수 있다. 본원에서 개시된 조성물은 환자에 피하, 피내, 종양 내, 결절 내, 수질 내, 근육 내 투여될 수 있거나, 정맥 내(i.v.) 주사에 의해 투여되거나, 또는 복막 내 투여될 수 있다. 하나의 실시형태에서, 본 발명의 T 세포 조성물은 피내 또는 피하 주사에 의해 환자에 투여된다. 다른 실시형태에서, 본 발명의 T 세포 조성물은 바람직하게는 정맥 내 주사에 의해 투여된다. 상기 T 세포의 조성물은 종양, 림프절 또는 감염 부위 내로 직접 주사될 수 있다.
환자에 투여될 상기 치료 투여량은 치료되는 조건의 정확한 특성, 및 치료받을 수취인에 따라 다를 것이다. 인간 투여를 위한 투여량의 스케일링(scaling)은 당해 기술분야에서 허용된 관행에 따라 수행될 수 있다.
이하, 실시예를 통해서 본 발명을 구체화한다. 다만, 하기 실시예는 본 발명의 기술적 범위를 어떤 의미에서든지 제한하는 것은 아님을 유의해야 한다.
실시예 1: IL13α2 특이적인 2세대 키메라 항원 수용체(IL13.E11K.R107K.TNFRSF9.CD3ζ)를 갖는 발현 벡터의 구축
본 발명자는 IL13의 2가지 아미노산 치환(Glu-11, Arg-107)만으로도 IL13α2에 대한 특이적인 결합활성을 확인하였다. 이러한 결과들을 활용하여, 인간 IL13(P35225.1), 인간 CD3(P20963-1), 인간 CD8α(P01732), TNFRSF9(Q07011), 인간 카파 경쇄 신호 서열(HuVHCAMP)을 scientific literature, publicly available databases를 이용하여, codon-optimized synthetic DNA들로 구성된 IL13Rα2에 대한 결합력이 높은 돌연변이 anti-IL13Rα2 CAR들을 제작하였다(도 1과 7). 완성 된 구조체는 kozak consensus ribosome-binding sequence, 인간 카파 경쇄 신호 서열(HuVHCAMP), 인간 IL13.E11K.R107K 성숙 단백질 서열(human IL13.E11K.R107K mature peptide sequence), 인간 CD8α의 힌지 영역(hinge region of human CD8α), 인간 CD8 또는 CD3 막 횡단(human CD8 or CD3 transmembrane), 세포질 TNFRSF9의 보조 자극 신호 도메인(cytoplasmic TNFRSF9 costimulatory signaling domain), 세포질 TCRzeta 서열과 XhoI/NotI 절단 부분(restriction site)을 포함한다. 최종적으로 제작된 CAR 유전자 단편을 XhoI/NotI으로 절단된 MFG 레트로 바이러스 발현 벡터에 접합시켰다(Emtage PC 등, Clin Cancer Res, 2008, 14:8112-8122)(도 2).
본 실시예에서 키메라 항원 수용체(IL13.E11K.R107K.TNFRSF9.CD3ζ)의 활성을 비교하기 위해 wild-type 인간 IL13을 포함한 2세대 키메라 항원 수용체를 추가적으로 제작하였다. 해당 구조체는 kozak consensus ribosome-binding sequence, 인간 카파 경쇄 신호 서열(HuVHCAMP), wild-type 인간 IL13 성숙 단백질 서열(wild-type human IL13 mature peptide sequence), 인간 CD8α의 힌지 영역(hinge region of human CD8α), 인간 CD3 막 횡단(human CD3 transmembrane), 세포질 CD28의 보조 자극 신호 도메인(cytoplasmic CD28 costimulatory signaling domain), 세포질 TCRzeta 서열과 XhoI/NotI절단 부분(restriction site)을 포함한다.
실시예 2: IL13α2 특이적인 3세대 키메라 항원 수용체(IL13.E11K.R107K.CD28.TNFRSF9.CD3ζ)를 갖는 발현 벡터의 구축
실시예 1에서 제작된 IL13Rα2에 대한 결합력이 높은 돌연변이 IL13.E11K.R107K를 사용하여, T 세포 활성화를 위한 세포질 신호 도메인(cytoplasmic costimulatory signaling domain) 2가지(CD28, TNFRSF9)를 포함하는 제3세대 키메라 항원 수용체(chimeric antigen receptor, CAR)를 제작하였다. 인간 IL13(P35225.1), 인간 CD3(P20963-1), 인간 CD8α(P01732), 인간 CD28(P10747) 인간 TNFRSF9(Q07011), 인간 카파 경쇄 신호 서열(HuVHCAMP)을 scientific literature, publicly available databases를 이용하여, codon-optimized synthetic DNA로 구성된 3세대 키메라 항원 수용체(IL13.E11K.R107K.CD28.TNFRSF9.CD3ζ)를 제작하였다(도 1과 7).
본 발명에서 사용된 CD28 신호 세포질 도메인(human cytoplasmic CD28 costimulatory signaling domain)은 CAR단백질의 용해도를 높여 키메라 항원 수용체의 발현을 증가시키기 위한 돌연변이 염기 서열들을 포함한다(도 1).
완성 된 구조체는 kozak consensus ribosome-binding sequence, 인간 카파 경쇄 신호 서열(HuVHCAMP), 인간 IL13.E11K.R107K 성숙 단백질 서열(human IL13.E11K.R107K mature peptide sequence), 인간 CD8α의 힌지 영역(hinge region of human CD8α), 인간 CD3 또는 CD8 막 횡단(human CD3 or CD8 transmembrane), 변형된 세포질 CD28의 보조 자극 신호 도메인(cytoplasmic CD28 costimulatory signaling domain), 세포질 TNFRSF9의 보조 자극 신호 도메인(cytoplasmic TNFRSF9 costimulatory signaling domain), 세포질 TCRzeta 서열과 XhoI/NotI 절단 부분(restriction site)을 포함한다. 최종적으로 제작된 CAR 유전자 단편을 XhoI-NotI으로 절단된 MFG 레트로 바이러스 발현 벡터에 접합시켰다(도 2).
실시예 3: IL13α2 특이적인 3세대 novel 키메라 항원 수용체(IL13.E11K.R64D.S67D.R107K.CD28. TNFRSF9.CD3ζ)를 갖는 발현 벡터의 구축
실시예 1과 2에서 사용된 인간 IL13에 대한 돌연변이 IL13.E11K.R107K보다 높은 항원 친화력(affinity)를 부여하기 위해 돌연변이 IL13.E11K.R64D.S67D.R107K및 IL13.E11Y.R64D.S67D.K103R 를 제작하였으며, T 세포 활성화를 위한 세포질 신호 도메인(cytoplasmic costimulatory signaling domain) 2가지(CD28, TNFRSF9)를 포함하는 novel 제3세대 키메라 항원 수용체(chimeric antigen receptor, CAR)를 제작하였다.
인간 IL13(P35225.1), 인간 CD3(P20963-1), 인간 CD8α(P01732), 인간 CD28(P10747) 인간 TNFRSF9(Q07011), 인간 카파 경쇄 신호 서열(HuVHCAMP)을 scientific literature, publicly available databases를 이용하여, codon-optimized synthetic DNA로 구성된 novel 3세대 키메라 항원 수용체(IL13.E11K.R64D.S67D.R107K.CD28.TNFRSF9.CD3ζ 및 IL13.E11Y.R64D.S67D.K103R.CD28. TNFRSF9.CD3ζ)를 제작하였다(도 1과 7).
완성된 구조체는 kozak consensus ribosome-binding sequence, 인간 카파 경쇄 신호 서열(HuVHCAMP), 인간 IL13.E11K.R64D.S67D.R107K 또는 IL13.E11Y.R64D.S67D.K103R 성숙 단백질 서열(human IL13.E11K.R64D.S67D.R107K 또는 IL13.E11Y.R64D.S67D.K103R mature peptide sequence), 인간 CD8α의 힌지 영역(hinge region of human CD8α), 인간 CD3 또는 CD8 막 횡단(human CD3 or CD8 transmembrane), 변형된 세포질 CD28의 보조 자극 신호 도메인(cytoplasmic CD28 costimulatory signaling domain), 세포질 TNFRSF9의 보조 자극 신호 도메인(cytoplasmic TNFRSF9 costimulatory signaling domain), 세포질 TCRzeta 서열과 XhoI/NotI 절단 부분(restriction site)을 포함한다. 최종적으로 제작된 CAR 유전자 단편을 XhoI/NotI로 절단된 MFG 레트로 바이러스 발현 벡터에 접합시켰다(도 2).
실시예 4: IL13α2 특이적인 키메라 항원 수용체로 형질 변형된 T 세포의 제조
레트로 바이러스를 생산하기 위해, 실시예 1, 2 및 3에서 제작된 레트로바이러스 발현 벡터 각 5μg와 lipofectamine 2000(Invitrogen)을 이용하여, Phoenix™ retrovirus producer lines인 Phoenix™-Eco와 Phoenix™-Ampho로 형질주입(transfection)시켰다. 형질주입 후 48시간 후에 상층액을 수거하여 레트로 바이러스 생산 세포주인 PG-13에 형질 도입(transduction)하는데 사용 하였다. IL-13 단일클론 항체 (Becton Dickinson)를 이용하여 형질도입된 PG-13세포를 유세포 분석기(Flow cytometry analysis)를 사용, 형질 도입정도를 분석하였다. 형질도입된 PG-13세포의 상층 액은 레트로 바이러스를 포함하며 T 세포의 유전 적 변형을 위해 수거 하였다. 말초 혈액 단핵 세포(peripheral blood mononuclear cells, PBMC)는 건강한 공여자로부터 얻은 전혈(whole blood)에 Histopaque 1077(sigma)를 넣고 원심분리를 사용하여 분리되었다. Human IL-2(Chiron) 100units/mL 조건으로 있는 상태에서 anti-CD3 단일클론 항체인 OKT3(Ortho Biotech) 100ng/mL을 첨가하여 배양함으로써 분리된 PBMC에 포함되어 있는 T 세포 분획을 활성화시켰다(BL Levine, Cancer Gene Therapy, 2015, 22:79-84). 배양 3-5 후에, 세포의 대부분은 T cell이었으며 일부 자연 살해 세포(natural killer cell)가 0~2% 비율로 포함되어 있었다. 활성화 단계 2일 후, T 세포에 spin infection 방식으로 retroviral 상층액을 사용하여 2일에 걸쳐 4회 형질도입을 진행하였고, IL-2를 100IU/mL로 유지하였다. 이러한 방식으로 변형된 T 세포는 7~15일 동안 IL-2 100IU/mL 농도 조건 하에서 배양을 진행하여 분석 실험에 적용하였다.
실험 예 1: 키메라 항원 수용체로 형질 변형된 T 세포표면의 CAR 발현률 체크
실험방법 (flow cytometric analysis)
유세포 분석(>30,000 events)를 위해 BD LSRII 장비(Becton Dickinson)와 BD FACSDiva 소프트웨어(Becton Dickinson)을 사용하였다. 구체적으로는 항체를 첨가하기 전 세포를 2% bovine serum albumin을 함유한 PBS에 1회 세척을 진행하였다. 세척 후에 빛이 차단된 상태에서 4℃에서 30 분간 반응한 후, 세포를 1회 세정하고, 0.5% paraformaldehyde/FACS 완충액에 고정하였다. 형질 도입 된 T 세포 표면 CAR의 발현률을 체크하기 위해 PE-conjugated antihuman IL-13 단일클론 항체를 사용하였다. 또한 IL13Rα2 및 L13Rα1의 세포 표면 발현을 확인하기 위해, anti-human IL13Rα2 항체(R&D systems), donkey anti-goat IgG phycoerythrin secondary antibody(R&D systems), 및 anti-human IL13Rα1 phycoerythrin(R&D systems)을 사용하였으며, 대조군으로 isotype antibody를 포함시켰다.
실험결과
실시예 1, 2 및 3에서 제작한 IL13Rα2 특이적인 CAR(IL13.E11K.R107K.TNFRSF9.CD3ζ, IL13.E11K.R107K.CD28.TNFRSF9.CD3ζ, IL13.E11K.R64D.S67D.R107K.CD28.TNFRSF9.CD3ζ)가 T 세포 표면에서 발현되는지 확인하기 위해 실시예 4에 따라 T 세포 배양을 7-14일 동안 진행한 후 실험방법에 따라 유세포 분석(flow cytometric analysis)를 진행하였다. 분석 결과, 살아있는 T 세포의 표면에 발현된 키메라 항원 수용체의 발현률은 32.9% ~ 54.7%로 나타났다(도 3). 배양을 유지할 경우, 추가적인 T 세포 활성화나 형질도입이 없이도 IL13Rα2 특이적 키메라 항원 수용체의 발현은 4주까지 안정적으로 유지되었다.
실험예 2: IL13α2가 과발현되는 교모세포종에 대한 세포독성 체크
실험방법
IL13Rα2 특이적인 CAR-T 세포 effector(IL13Rα2-specific CAR+ T cell effector)의 세포 용해 활성을 측정하기 위해 CytoTox-GloTM(Promega) 사용하여 세포독성 분석(cytotoxicity assay)을 진행하였다. 구체적으로는 Effector 세포는 OKT3로 세포 활성화 후 10~14일 후에 사용하였으며, 표적 세포가 있는 96 well plate에 5:1(effector:target)의 비율로 effector 세포를 넣고 37℃에서 4시간 동안 반응하는 조건을 3반복 실험으로 구성하여 진행하였다. 분석 실험에 사용된 96 well plate에는 well 당 10,000개의 표적 세포가 첨가되었으며, 사용된 표적 세포는 IL13Rα2를 과발현하는 glioblastoma 세포주인 U251(또는 U87)과 control cell로 primary normal HUVEC을 사용하여다. 각 IL13Rα2에 특이적인 CAR-T 세포 effector의 형질 도입 fraction 비율이 최종 20%가 되도록 형질도입이 되지 않은 상태로 활성화된 T 세포(untransduced activated T cell)로 조정하였다.
실험결과
본 발명을 통해 제작된 IL13Rα2 특이적인 CAR(IL13.E11K.R107K.TNFRSF9.CD3ζ, IL13.E11K.R107K.CD28.TNFRSF9.CD3ζ, IL13.E11K.R64D.S67D.R107K.CD28.TNFRSF9.CD3ζ) T 세포에 의해 IL13Rα2가 과발현되는 표적 암세포(U251)을 효과적으로 사멸시키는지 분석하였다. 실험방법은 앞서 언급한 표적 암세포(U251)과 정상세포(HUVEC)을 각각의 활성화된 CAR-T 세포와 함께 배양하여 세포의 사멸 정도를 비교 분석하는 방법을 사용하였다. 도 4에 나타낸 바와 같이, 모든 경우에서 IL13Rα2에 특이적인 CAR가 발현된 경우 형질도입이 되지 않은 활성화된 T 세포와 비교하여 높은 수준으로 교모세포 종 U251 세포의 사멸을 유도하는 결과를 나타내었다. 구체적으로 본 발명의 실시예 1에서 제작한 IL13.E11K.R107K.TNFRSF9.CD3ζ CAR를 발현하는 T 세포(37% cytotoxicity)의 경우 형질도입이 안된 상태로 활성화된 T 세포(7% cytotoxicity)와 비교하여 약 5배 수준의 높은 표적 암세포(U251) 사멸 능력을 보였으며, 돌연변이가 되지 않은 IL13 2세대 CAR T 세포(32% cytotoxicity)와 비교하여 유의한 수준에서 표적 세포에 대한 사멸 능력이 증가되는 것을 확인하였다. 이는 키메라 항원 수용체에 사용된 변형된 IL13이 표적 암세포(U251)에서 발현되는 IL13Rα2 항원에 대해 보다 높은 친화력을 나타내어 효능이 증가된 것임을 보여준다. 본 발명의 실시예 2와 3에서 제작한 제3세대 CAR인 IL13.E11K.R107K.CD28.TNFRSF9.CD3ζ CAR T 세포(53% cytotoxicity)와 novel IL13.E11K.R64D.S67D.R107K.CD28.TNFRSF9.CD3ζ CAR T 세포(58% cytotoxicity)는 IL13 2세대 CAR를 발현하는 T 세포(32% cytotoxicity)와 비교하여 표적 암세포(U251)에 대한 사멸 능력이 약 60% 이상 증가하는 결과를 나타내었다. 상기 결과는 신호 전달 도메인을 추가한 3세대 키메라 항원 수용체를 가지는 T 세포가 2세대 키메라 항원 수용체를 가지는 T 세포보다 높은 암세포 활성을 갖기 때문이라고 판단할 수 있다.
표적 세포에 대한 비교 대상으로 HUVEC 세포를 사용한 실험 결과에서는 IL13Rα2에 특이적인 CAR-T 세포(6~9% cytotoxicity)와 형질도입이 되지 않은 상태로 활성화된 T 세포(5% cytotoxicity)와 비교하여 큰 차이가 없음을 확인하였다(도 4). 이는 IL13Rα1가 발현되고 IL13Rα2는 발현되지 않는 HUVEC 세포의 특성으로 인하여 실험에 사용된 키메라 항원 수용체가 IL13Rα2에만 결합한다는 것을 보여준다. 본 실험 예를 통해 IL13Rα2 특이적인 키메라 항원 수용체 T 세포가 정상세포(HUVEC)에는 독성을 나타내지 않으며, IL13Rα2를 발현하는 표적 암세포(U251)를 현저하게 사멸시킬 수 있음을 증명하였다.
실험예 3: IL13α2 특이적 키메라 항원 수용체로 형질 변형된 T 세포의 사이토카인(IFN-γ, IL-2) 생성 체크
실험방법
96 well tissue culture plate에 well당 배양 배지를 200ul씩 넣고 irradiated(7,000rads) 표적 세포(1×105)를 첨가하였다. 준비된 96 well tissue culture plate에 형질도입이 되지 않은 상태로 활성화된 T 세포(untransduced activated T cell)와 각 IL13Rα2에 특이적인 CAR-T 세포 effector(2×105)를 넣고 2반복(duplicate) 실험으로 구성하여 동시 배양하였다. 배양 24시간 후, 배양 상층액을 사용하여 분석기 제조사의 지침에 따라 ELISA 분석기(R&D systems)로 IFN-γ 및 IL-2 분석 실험을 진행하였다.
실험결과
일반적으로 활성화 된 T 세포는 자신의 성장 및 활성에 도움이 되는 사이토카인(cytokine)을 생성하며, 그 중 IL-2는 T 세포의 생존과 증식에 필수 성장 인자이다. 또한 IL-2와 IFN-γ의 분비는 다양한 종양을 사멸시키는 면역 기능을 활성화한다. 본 실험 예를 통해 IL13Rα2 특이적인 CAR를 발현하는 T 세포가 IL-2 및 IFN-γ 생성을 증가시킴으로써 세포 팽창(expansion) 및 활성이 증가되는지 확인하였다. 실험 방법에 따라 IL13Rα2 특이적인 CAR T 세포를 표적 세포(HUVEC 세포, U251 세포 또는 THP-1 세포)와 동시 배양한 후 ELISA 분석을 통해 IL-2 및 IFN-γ를 정량하였다.
도 5는 제작된 키메라 항원 수용체에 따라 IL13Ra2 항원 결합 시 증가된 IFN-γ를 나타낸다. 사용된 표적세포에 따라 IFN-γ의 생성 양상이 다름을 알 수 있다. 표적 암세포인 U251을 사용한 경우, 키메라 항원 수용체가 형질도입 되지 않은 T 세포는 IFN-γ를 거의 생성하지 못하며, 실시예 1, 2 및 3에서 제작된 CAR(IL13.E11K.R107K.TNFRSF9.CD3ζ, IL13.E11K.R107K.CD28.TNFRSF9.CD3ζ, IL13.E11K.R64D.S67D.R107K.CD28.TNFRSF9.CD3ζ) 순서에 비례하여 IFN-γ 분비량(3800, 4400, 5800pg/ml/2x105 T cells) 이 크게 증가하는 결과를 보여 주었다. 2세대 IL13 CAR가 발현된 T 세포(1500pg/ml/2x105 T cells)와 비교하면, 각 CAR의 종류에 따라 IFN-γ 분비량이 약 2~4배 증가한 것으로 본 발명에서 제작한 키메라 항원 수용체가 T 세포 활성 측면에서 크게 개선되었음을 나타낸다. 비교 대상으로 사용된 HUVEC 세포의 경우, 모든 조건에서 IFN-γ의 분비가 이루어지지 않음을 확인하였다. 또한 THP-1 세포의 경우 키메라 항원 수용체가 형질 도입되지 않은 T 세포만을 사용해도 약 3100pg/ml/2x105 T cells 수준의 IFN-γ를 분비하며, 실시예 1, 2 및 3에서 제작한 CAR(IL13.E11K.R107K.TNFRSF9.CD3ζ, IL13.E11K.R107K.CD28.TNFRSF9.CD3ζ, IL13.E11K.R64D.S67D.R107K.CD28.TNFRSF9.CD3ζ) 순서에 따라 점차적으로 감소하는 것을 확인하였다.
도 6은 IL13α2 특이적 키메라 항원 수용체로 형질 변형된 T 세포의 IL-2 분비량을 분석한 결과이다. 비교군인 HUVEC 세포를 사용한 경우 모든 조건에서 IL-2가 분비되지 않거나 매우 낮은 수준을 보여주었다. 이와 대조적으로 표적 암세포(U251)를 사용한 경우, 키메라 항원 수용체가 형질도입 되지 않은 T 세포는 IL-2가 검출되지 않은 반면 실시예 1, 2 및 3에서 제작된 CAR(IL13.E11K.R107K.TNFRSF9.CD3ζ, IL13.E11K.R107K.CD28.TNFRSF9.CD3ζ, IL13.E11K.R64D.S67D.R107K.CD28.TNFRSF9.CD3ζ) 순서에 따라 단계적으로 IL-2 생성량(400, 600, 800pg/ml/2x105 T cells)이 증가하는 결과를 확인하였다.
본 실험 예를 통해 실시예 1, 2 및 3에서 제작된 IL13α2 특이적 키메라 항원 수용체를 발현하는 T 세포가 표적 암세포에만 선택적으로 결합하여 T 세포 확장 및 암세포 사멸에 필요한 활성이 크게 증가되며, 정상세포에는 결합하지 않음을 검증하였다.
<110> YOOYOUNG PHARM.co., Ltd.
<120> CHIMERIC ANTIGEN RECEPTOR-MODIFIED T CELLS TARGETING IL13Ra2 ON
TUMORS
<130> KR15P0801
<150> US 62/033305
<151> 2014-08-05
<150> US 62/034385
<151> 2014-08-07
<160> 106
<170> KopatentIn 2.0
<210> 1
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<220>
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<210> 2
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<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 2
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210> 3
<211> 216
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 3
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gggctggact tcgcccaatt gctctgctac ctgctggatg gaatcctctt catctatggt 180
gtcattctca ctgccttgtt cctgagagtg gttaac 216
<210> 4
<211> 72
<212> PRT
<213> Artificial Sequence
<220>
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<400> 4
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
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Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
20 25 30
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Gln Leu Leu
35 40 45
Cys Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr
50 55 60
Ala Leu Phe Leu Arg Val Val Asn
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<210> 5
<211> 216
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 5
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gggctggact tcgcccaatt gctcgcctac ctgctggatg gaatcctctt catctatggt 180
gtcattctca ctgccttgtt cctgagagtg gttaac 216
<210> 6
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<212> PRT
<213> Artificial Sequence
<220>
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<400> 6
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
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Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Ala Arg Pro Ala
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Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Gln Leu Leu
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Ala Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr
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Ala Leu Phe Leu Arg Val Val Asn
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<210> 7
<211> 204
<212> DNA
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ggactggatt tcgcctgcga catctacatc tgggcccctc tggccggcac atgtggcgtg 180
ctgctgctga gcctcgtgat cacc 204
<210> 8
<211> 68
<212> PRT
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<400> 8
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
1 5 10 15
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
20 25 30
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
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Leu Val Ile Thr
65
<210> 9
<211> 138
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ttctgggtga ggagtaagag gagcaggctc ctgcacagtg actacatgaa catgactccc 60
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gcctatcgct ccacgcgt 138
<210> 10
<211> 46
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 10
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
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Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
20 25 30
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Thr Arg
35 40 45
<210> 11
<211> 123
<212> DNA
<213> Artificial Sequence
<220>
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<400> 11
agaagcaagc ggagcagagg cggccacagc gactacatga acatgacccc cagacggcct 60
ggccccaccc ggaaacacta tcagccttac gcccctccca gagacttcgc cgcctacaga 120
tcc 123
<210> 12
<211> 41
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 12
Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 13
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 13
aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 60
gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 120
cctgagatgg ggggaaagcc gcagagaagg aagaaccctc aggaaggcct gtacaatgaa 180
ctgcagaaag ataagatggc ggaggcctac agtgagattg ggatgaaagg cgagcgccgg 240
aggggcaagg ggcacgatgg cctttaccag ggtctcagta cagccaccaa ggacacctac 300
gacgcccttc acatgcaggc cctgccccct cgctaa 336
<210> 14
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 14
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
1 5 10 15
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
20 25 30
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln
35 40 45
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
50 55 60
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
65 70 75 80
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
85 90 95
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 15
<211> 132
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 15
aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 60
actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120
gaactgacgc gt 132
<210> 16
<211> 44
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 16
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Thr Arg
35 40
<210> 17
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 17
ggccctgtgc ctccctctac agccctcagg gagctcattg aggagctggt caacatcacc 60
cagaaccaga aggctccgct ctgcaatggc agcatggtat ggagcatcaa cctgacagct 120
ggcatgtact gtgcagccct ggaatccctg atcaacgtgt caggctgcag tgccatcgag 180
aagacccaga ggatgctgag cggattctgc ccgcacaagg tctcagctgg gcagttttcc 240
agcttgcatg tccgagacac caaaatcgag gtggcccagt ttgtaaagga cctgctctta 300
catttaaaga aactttttcg cgagggacag ttcaacggtg gcggacctag g 351
<210> 18
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 18
Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Glu Leu Ile Glu Glu Leu
1 5 10 15
Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn Gly Ser Met
20 25 30
Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala Ala Leu Glu
35 40 45
Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys Thr Gln Arg
50 55 60
Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly Gln Phe Ser
65 70 75 80
Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln Phe Val Lys
85 90 95
Asp Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly Gln Phe Asn
100 105 110
Gly Gly Gly Pro Arg
115
<210> 19
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 19
ggccctgtgc ctccctctac agccctcagg aagctcattg aggagctggt caacatcacc 60
cagaaccaga aggctccgct ctgcaatggc agcatggtat ggagcatcaa cctgacagct 120
ggcatgtact gtgcagccct ggaatccctg atcaacgtgt caggctgcag tgccatcgag 180
aagacccaga ggatgctgag cggattctgc ccgcacaagg tctcagctgg gcagttttcc 240
agcttgcatg tccgagacac caaaatcgag gtggcccagt ttgtaaagga cctgctctta 300
catttaaaga aactttttaa agagggacag ttcaacggtg gcggacctag g 351
<210> 20
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 20
Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile Glu Glu Leu
1 5 10 15
Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn Gly Ser Met
20 25 30
Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala Ala Leu Glu
35 40 45
Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys Thr Gln Arg
50 55 60
Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly Gln Phe Ser
65 70 75 80
Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln Phe Val Lys
85 90 95
Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly Gln Phe Asn
100 105 110
Gly Gly Gly Pro Arg
115
<210> 21
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 21
ggccctgtgc ctccctctac agccctcagg tatctcattg aggagctggt caacatcacc 60
cagaaccaga aggctccgct ctgcaatggc agcatggtat ggagcatcaa cctgacagct 120
ggcatgtact gtgcagccct ggaatccctg atcaacgtgt caggctgcag tgccatcgag 180
aagacccaga ggatgctgag cggattctgc ccgcacaagg tctcagctgg gcagttttcc 240
agcttgcatg tccgagacac caaaatcgag gtggcccagt ttgtaaagga cctgctctta 300
catttaaaga aactttttaa agagggacag ttcaacggtg gcggacctag g 351
<210> 22
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 22
Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile Glu Glu Leu
1 5 10 15
Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn Gly Ser Met
20 25 30
Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala Ala Leu Glu
35 40 45
Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys Thr Gln Arg
50 55 60
Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly Gln Phe Ser
65 70 75 80
Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln Phe Val Lys
85 90 95
Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly Gln Phe Asn
100 105 110
Gly Gly Gly Pro Arg
115
<210> 23
<211> 345
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 23
ggacctgtgc ctccaagcac cgccctgaga tacctgatcg aggaactcgt gaacatcacc 60
cagaaccaga aagcccccct gtgcaacggc agcatggtgt ggtccatcaa cctgaccgcc 120
ggcatgtact gtgccgccct ggaaagcctg atcaacgtgt ccggctgcag cgccatcgag 180
aaaacccagg atatgctgga cggcttctgc ccccacaagg tgtccgccgg acagttcagc 240
tctctgcacg tgcgggacac caagatcgag gtggcccagt tcgtgaagga cctgctgctg 300
cacctgagaa agctgttcag agagggccag ttcaacggcg gaggc 345
<210> 24
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 24
Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile Glu Glu Leu
1 5 10 15
Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn Gly Ser Met
20 25 30
Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala Ala Leu Glu
35 40 45
Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys Thr Gln Asp
50 55 60
Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly Gln Phe Ser
65 70 75 80
Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln Phe Val Lys
85 90 95
Asp Leu Leu Leu His Leu Arg Lys Leu Phe Arg Glu Gly Gln Phe Asn
100 105 110
Gly Gly Gly
115
<210> 25
<211> 351
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 25
ggacctgtgc ctccaagcac cgccctgaga aagctgatcg aggaactcgt gaacatcacc 60
cagaaccaga aagcccccct gtgcaacggc agcatggtgt ggtccatcaa cctgaccgcc 120
ggcatgtact gtgccgccct ggaaagcctg atcaacgtgt ccggctgcag cgccatcgag 180
aaaacccagg atatgctgga cggcttctgc ccccacaagg tgtccgccgg acagttcagc 240
tctctgcacg tgcgggacac caagatcgag gtggcccagt tcgtgaagga cctgctgctg 300
cacctgaaga agctgttcaa agagggccag ttcaacggcg gaggccctag g 351
<210> 26
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 26
Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile Glu Glu Leu
1 5 10 15
Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn Gly Ser Met
20 25 30
Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala Ala Leu Glu
35 40 45
Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys Thr Gln Asp
50 55 60
Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly Gln Phe Ser
65 70 75 80
Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln Phe Val Lys
85 90 95
Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly Gln Phe Asn
100 105 110
Gly Gly Gly Pro Arg
115
<210> 27
<211> 1098
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 27
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcagggag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccacgc gtaagttcag caggagcgca 780
gacgcccccg cgtaccagca gggccagaac cagctctata acgagctcaa tctaggacga 840
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 900
ccgcagagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 960
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1020
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1080
gccctgcccc ctcgctaa 1098
<210> 28
<211> 365
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 28
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Glu Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Thr Arg Lys Phe
245 250 255
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
260 265 270
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
275 280 285
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
290 295 300
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
305 310 315 320
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
325 330 335
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
340 345 350
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
355 360 365
<210> 29
<211> 1098
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 29
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcagggag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccacgc gtaagttcag caggagcgca 780
gacgcccccg cgtaccagca gggccagaac cagctctata acgagctcaa tctaggacga 840
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 900
ccgcagagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 960
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1020
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1080
gccctgcccc ctcgctaa 1098
<210> 30
<211> 365
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 30
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Glu Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Thr Arg Lys Phe
245 250 255
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
260 265 270
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
275 280 285
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
290 295 300
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
305 310 315 320
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
325 330 335
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
340 345 350
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
355 360 365
<210> 31
<211> 1080
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 31
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcagggag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcctacaaca 420
acccctgccc ctagacctcc caccccagcc cctacaattg ccagccagcc tctgagcctg 480
aggcccgagg cttgtagacc agctgctggc ggagccgtgc acaccagagg actggatttc 540
gcctgcgaca tctacatctg ggcccctctg gccggcacat gtggcgtgct gctgctgagc 600
ctcgtgatca ccaagcgggg cagaaagaag ctgctgtaca tcttcaagca gcccttcatg 660
cggcccgtgc agaccaccca ggaagaggac ggctgctcct gcagattccc cgaggaagaa 720
gaaggcggct gcgagctgag agtgaagttc agcagaagcg ccgacgcccc tgcctatcag 780
cagggccaga atcagctgta caacgagctg aacctgggca gacgggaaga gtacgacgtg 840
ctggacaagc ggagaggcag ggaccctgag atgggcggaa agccccagcg gagaaagaac 900
ccccaggaag gcctgtataa cgaactgcag aaagacaaga tggccgaggc ctacagcgag 960
atcggaatga agggcgagcg gagaaggggc aagggccacg atggactgta ccagggcctg 1020
agcaccgcca ccaaggacac ctatgacgcc ctgcacatgc aggccctgcc ccccagataa 1080
1080
<210> 32
<211> 359
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 32
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Glu Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Lys Arg Gly Arg
195 200 205
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
210 215 220
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
225 230 235 240
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
245 250 255
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
260 265 270
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
275 280 285
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
290 295 300
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
305 310 315 320
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
325 330 335
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
340 345 350
Met Gln Ala Leu Pro Pro Arg
355
<210> 33
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 33
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcagggag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 34
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 34
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Glu Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 35
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 35
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcagggag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 36
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 36
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Glu Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 37
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 37
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcagggag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gggcggccac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 38
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 38
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Glu Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 39
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 39
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcagggag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gggcggccac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 40
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 40
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Glu Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 41
<211> 1203
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 41
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcagggag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcctacaaca 420
acccctgccc ctagacctcc caccccagcc cctacaattg ccagccagcc tctgagcctg 480
aggcccgagg cttgtagacc agctgctggc ggagccgtgc acaccagagg actggatttc 540
gcctgcgaca tctacatctg ggcccctctg gccggcacat gtggcgtgct gctgctgagc 600
ctcgtgatca ccagaagcaa gcggagcaga ggcggccaca gcgactacat gaacatgacc 660
cccagacggc ctggccccac ccggaaacac tatcagcctt acgcccctcc cagagacttc 720
gccgcctaca gatccaagcg gggcagaaag aagctgctgt acatcttcaa gcagcccttc 780
atgcggcccg tgcagaccac ccaggaagag gacggctgct cctgcagatt ccccgaggaa 840
gaagaaggcg gctgcgagct gagagtgaag ttcagcagaa gcgccgacgc ccctgcctat 900
cagcagggcc agaatcagct gtacaacgag ctgaacctgg gcagacggga agagtacgac 960
gtgctggaca agcggagagg cagggaccct gagatgggcg gaaagcccca gcggagaaag 1020
aacccccagg aaggcctgta taacgaactg cagaaagaca agatggccga ggcctacagc 1080
gagatcggaa tgaagggcga gcggagaagg ggcaagggcc acgatggact gtaccagggc 1140
ctgagcaccg ccaccaagga cacctatgac gccctgcaca tgcaggccct gccccccaga 1200
taa 1203
<210> 42
<211> 400
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 42
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Glu Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Arg Ser Lys Arg
195 200 205
Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro
210 215 220
Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe
225 230 235 240
Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
245 250 255
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
260 265 270
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
275 280 285
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
290 295 300
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
305 310 315 320
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
325 330 335
Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
340 345 350
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
355 360 365
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
370 375 380
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
385 390 395 400
<210> 43
<211> 1098
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 43
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggaag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccacgc gtaagttcag caggagcgca 780
gacgcccccg cgtaccagca gggccagaac cagctctata acgagctcaa tctaggacga 840
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 900
ccgcagagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 960
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1020
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1080
gccctgcccc ctcgctaa 1098
<210> 44
<211> 365
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 44
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Thr Arg Lys Phe
245 250 255
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
260 265 270
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
275 280 285
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
290 295 300
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
305 310 315 320
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
325 330 335
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
340 345 350
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
355 360 365
<210> 45
<211> 1098
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 45
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggaag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccacgc gtaagttcag caggagcgca 780
gacgcccccg cgtaccagca gggccagaac cagctctata acgagctcaa tctaggacga 840
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 900
ccgcagagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 960
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1020
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1080
gccctgcccc ctcgctaa 1098
<210> 46
<211> 365
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 46
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Thr Arg Lys Phe
245 250 255
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
260 265 270
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
275 280 285
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
290 295 300
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
305 310 315 320
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
325 330 335
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
340 345 350
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
355 360 365
<210> 47
<211> 1080
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 47
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggaag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggcggag gccctaggaa gcctacaaca 420
acccctgccc ctagacctcc caccccagcc cctacaattg ccagccagcc tctgagcctg 480
aggcccgagg cttgtagacc agctgctggc ggagccgtgc acaccagagg actggatttc 540
gcctgcgaca tctacatctg ggcccctctg gccggcacat gtggcgtgct gctgctgagc 600
ctcgtgatca ccaagcgggg cagaaagaag ctgctgtaca tcttcaagca gcccttcatg 660
cggcccgtgc agaccaccca ggaagaggac ggctgctcct gcagattccc cgaggaagaa 720
gaaggcggct gcgagctgag agtgaagttc agcagaagcg ccgacgcccc tgcctatcag 780
cagggccaga atcagctgta caacgagctg aacctgggca gacgggaaga gtacgacgtg 840
ctggacaagc ggagaggcag ggaccctgag atgggcggaa agccccagcg gagaaagaac 900
ccccaggaag gcctgtataa cgaactgcag aaagacaaga tggccgaggc ctacagcgag 960
atcggaatga agggcgagcg gagaaggggc aagggccacg atggactgta ccagggcctg 1020
agcaccgcca ccaaggacac ctatgacgcc ctgcacatgc aggccctgcc ccccagataa 1080
1080
<210> 48
<211> 359
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 48
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Lys Arg Gly Arg
195 200 205
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
210 215 220
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
225 230 235 240
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
245 250 255
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
260 265 270
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
275 280 285
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
290 295 300
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
305 310 315 320
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
325 330 335
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
340 345 350
Met Gln Ala Leu Pro Pro Arg
355
<210> 49
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 49
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggaag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 50
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 50
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 51
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 51
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggaag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 52
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 52
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 53
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 53
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggaag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gggcggccac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 54
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 54
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 55
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 55
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggaag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gggcggccac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 56
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 56
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 57
<211> 1203
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 57
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggaag ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggcggag gccctaggaa gcctacaaca 420
acccctgccc ctagacctcc caccccagcc cctacaattg ccagccagcc tctgagcctg 480
aggcccgagg cttgtagacc agctgctggc ggagccgtgc acaccagagg actggatttc 540
gcctgcgaca tctacatctg ggcccctctg gccggcacat gtggcgtgct gctgctgagc 600
ctcgtgatca ccagaagcaa gcggagcaga ggcggccaca gcgactacat gaacatgacc 660
cccagacggc ctggccccac ccggaaacac tatcagcctt acgcccctcc cagagacttc 720
gccgcctaca gatccaagcg gggcagaaag aagctgctgt acatcttcaa gcagcccttc 780
atgcggcccg tgcagaccac ccaggaagag gacggctgct cctgcagatt ccccgaggaa 840
gaagaaggcg gctgcgagct gagagtgaag ttcagcagaa gcgccgacgc ccctgcctat 900
cagcagggcc agaatcagct gtacaacgag ctgaacctgg gcagacggga agagtacgac 960
gtgctggaca agcggagagg cagggaccct gagatgggcg gaaagcccca gcggagaaag 1020
aacccccagg aaggcctgta taacgaactg cagaaagaca agatggccga ggcctacagc 1080
gagatcggaa tgaagggcga gcggagaagg ggcaagggcc acgatggact gtaccagggc 1140
ctgagcaccg ccaccaagga cacctatgac gccctgcaca tgcaggccct gccccccaga 1200
taa 1203
<210> 58
<211> 400
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 58
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Arg Ser Lys Arg
195 200 205
Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro
210 215 220
Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe
225 230 235 240
Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
245 250 255
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
260 265 270
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
275 280 285
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
290 295 300
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
305 310 315 320
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
325 330 335
Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
340 345 350
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
355 360 365
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
370 375 380
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
385 390 395 400
<210> 59
<211> 1098
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 59
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccacgc gtaagttcag caggagcgca 780
gacgcccccg cgtaccagca gggccagaac cagctctata acgagctcaa tctaggacga 840
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 900
ccgcagagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 960
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1020
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1080
gccctgcccc ctcgctaa 1098
<210> 60
<211> 365
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 60
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Thr Arg Lys Phe
245 250 255
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
260 265 270
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
275 280 285
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
290 295 300
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
305 310 315 320
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
325 330 335
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
340 345 350
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
355 360 365
<210> 61
<211> 1098
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 61
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccacgc gtaagttcag caggagcgca 780
gacgcccccg cgtaccagca gggccagaac cagctctata acgagctcaa tctaggacga 840
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 900
ccgcagagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 960
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1020
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1080
gccctgcccc ctcgctaa 1098
<210> 62
<211> 365
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 62
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Thr Arg Lys Phe
245 250 255
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
260 265 270
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
275 280 285
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
290 295 300
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
305 310 315 320
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
325 330 335
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
340 345 350
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
355 360 365
<210> 63
<211> 1080
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 63
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcctacaaca 420
acccctgccc ctagacctcc caccccagcc cctacaattg ccagccagcc tctgagcctg 480
aggcccgagg cttgtagacc agctgctggc ggagccgtgc acaccagagg actggatttc 540
gcctgcgaca tctacatctg ggcccctctg gccggcacat gtggcgtgct gctgctgagc 600
ctcgtgatca ccaagcgggg cagaaagaag ctgctgtaca tcttcaagca gcccttcatg 660
cggcccgtgc agaccaccca ggaagaggac ggctgctcct gcagattccc cgaggaagaa 720
gaaggcggct gcgagctgag agtgaagttc agcagaagcg ccgacgcccc tgcctatcag 780
cagggccaga atcagctgta caacgagctg aacctgggca gacgggaaga gtacgacgtg 840
ctggacaagc ggagaggcag ggaccctgag atgggcggaa agccccagcg gagaaagaac 900
ccccaggaag gcctgtataa cgaactgcag aaagacaaga tggccgaggc ctacagcgag 960
atcggaatga agggcgagcg gagaaggggc aagggccacg atggactgta ccagggcctg 1020
agcaccgcca ccaaggacac ctatgacgcc ctgcacatgc aggccctgcc ccccagataa 1080
1080
<210> 64
<211> 359
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 64
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Lys Arg Gly Arg
195 200 205
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
210 215 220
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
225 230 235 240
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
245 250 255
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
260 265 270
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
275 280 285
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
290 295 300
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
305 310 315 320
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
325 330 335
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
340 345 350
Met Gln Ala Leu Pro Pro Arg
355
<210> 65
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 65
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 66
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 66
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 67
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 67
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 68
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 68
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 69
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 69
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gggcggccac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 70
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 70
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 71
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 71
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gggcggccac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 72
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 72
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 73
<211> 1203
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 73
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccagagga tgctgagcgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaagaaac tttttaaaga gggacagttc aacggtggcg gacctaggaa gcctacaaca 420
acccctgccc ctagacctcc caccccagcc cctacaattg ccagccagcc tctgagcctg 480
aggcccgagg cttgtagacc agctgctggc ggagccgtgc acaccagagg actggatttc 540
gcctgcgaca tctacatctg ggcccctctg gccggcacat gtggcgtgct gctgctgagc 600
ctcgtgatca ccagaagcaa gcggagcaga ggcggccaca gcgactacat gaacatgacc 660
cccagacggc ctggccccac ccggaaacac tatcagcctt acgcccctcc cagagacttc 720
gccgcctaca gatccaagcg gggcagaaag aagctgctgt acatcttcaa gcagcccttc 780
atgcggcccg tgcagaccac ccaggaagag gacggctgct cctgcagatt ccccgaggaa 840
gaagaaggcg gctgcgagct gagagtgaag ttcagcagaa gcgccgacgc ccctgcctat 900
cagcagggcc agaatcagct gtacaacgag ctgaacctgg gcagacggga agagtacgac 960
gtgctggaca agcggagagg cagggaccct gagatgggcg gaaagcccca gcggagaaag 1020
aacccccagg aaggcctgta taacgaactg cagaaagaca agatggccga ggcctacagc 1080
gagatcggaa tgaagggcga gcggagaagg ggcaagggcc acgatggact gtaccagggc 1140
ctgagcaccg ccaccaagga cacctatgac gccctgcaca tgcaggccct gccccccaga 1200
taa 1203
<210> 74
<211> 400
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 74
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Arg Met Leu Ser Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Arg Ser Lys Arg
195 200 205
Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro
210 215 220
Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe
225 230 235 240
Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
245 250 255
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
260 265 270
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
275 280 285
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
290 295 300
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
305 310 315 320
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
325 330 335
Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
340 345 350
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
355 360 365
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
370 375 380
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
385 390 395 400
<210> 75
<211> 1098
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 75
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccaggata tgctggacgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaggaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccacgc gtaagttcag caggagcgca 780
gacgcccccg cgtaccagca gggccagaac cagctctata acgagctcaa tctaggacga 840
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 900
ccgcagagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 960
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1020
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1080
gccctgcccc ctcgctaa 1098
<210> 76
<211> 1098
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 76
atgggctggt cctgcatcat cctgtttctg gtggccacag ccaccggcgt gcactctgga 60
cctgtgcctc caagcaccgc cctgagaaag ctgatcgagg aactcgtgaa catcacccag 120
aaccagaaag cccccctgtg caacggcagc atggtgtggt ccatcaacct gaccgccggc 180
atgtactgtg ccgccctgga aagcctgatc aacgtgtccg gctgcagcgc catcgagaaa 240
acccaggata tgctggacgg cttctgcccc cacaaggtgt ccgccggaca gttcagctct 300
ctgcacgtgc gggacaccaa gatcgaggtg gcccagttcg tgaaggacct gctgctgcac 360
ctgaagaagc tgttcaaaga gggccagttc aacggcggag gccctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccacgc gtaagttcag caggagcgca 780
gacgcccccg cgtaccagca gggccagaac cagctctata acgagctcaa tctaggacga 840
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 900
ccgcagagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 960
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1020
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1080
gccctgcccc ctcgctaa 1098
<210> 77
<211> 365
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 77
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Arg Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Thr Arg Lys Phe
245 250 255
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
260 265 270
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
275 280 285
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
290 295 300
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
305 310 315 320
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
325 330 335
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
340 345 350
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
355 360 365
<210> 78
<211> 365
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 78
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Thr Arg Lys Phe
245 250 255
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
260 265 270
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
275 280 285
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
290 295 300
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
305 310 315 320
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
325 330 335
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
340 345 350
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
355 360 365
<210> 79
<211> 1098
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 79
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccaggata tgctggacgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaggaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccacgc gtaagttcag caggagcgca 780
gacgcccccg cgtaccagca gggccagaac cagctctata acgagctcaa tctaggacga 840
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 900
ccgcagagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 960
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1020
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1080
gccctgcccc ctcgctaa 1098
<210> 80
<211> 1098
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 80
atgggctggt cctgcatcat cctgtttctg gtggccacag ccaccggcgt gcactctgga 60
cctgtgcctc caagcaccgc cctgagaaag ctgatcgagg aactcgtgaa catcacccag 120
aaccagaaag cccccctgtg caacggcagc atggtgtggt ccatcaacct gaccgccggc 180
atgtactgtg ccgccctgga aagcctgatc aacgtgtccg gctgcagcgc catcgagaaa 240
acccaggata tgctggacgg cttctgcccc cacaaggtgt ccgccggaca gttcagctct 300
ctgcacgtgc gggacaccaa gatcgaggtg gcccagttcg tgaaggacct gctgctgcac 360
ctgaagaagc tgttcaaaga gggccagttc aacggcggag gccctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccacgc gtaagttcag caggagcgca 780
gacgcccccg cgtaccagca gggccagaac cagctctata acgagctcaa tctaggacga 840
agagaggagt acgatgtttt ggacaagaga cgtggccggg accctgagat ggggggaaag 900
ccgcagagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 960
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1020
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1080
gccctgcccc ctcgctaa 1098
<210> 81
<211> 365
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 81
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Arg Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Thr Arg Lys Phe
245 250 255
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
260 265 270
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
275 280 285
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
290 295 300
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
305 310 315 320
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
325 330 335
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
340 345 350
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
355 360 365
<210> 82
<211> 365
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 82
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Thr Arg Lys Phe
245 250 255
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
260 265 270
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
275 280 285
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
290 295 300
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
305 310 315 320
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
325 330 335
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
340 345 350
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
355 360 365
<210> 83
<211> 1080
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 83
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccaggata tgctggacgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaggaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcctacaaca 420
acccctgccc ctagacctcc caccccagcc cctacaattg ccagccagcc tctgagcctg 480
aggcccgagg cttgtagacc agctgctggc ggagccgtgc acaccagagg actggatttc 540
gcctgcgaca tctacatctg ggcccctctg gccggcacat gtggcgtgct gctgctgagc 600
ctcgtgatca ccaagcgggg cagaaagaag ctgctgtaca tcttcaagca gcccttcatg 660
cggcccgtgc agaccaccca ggaagaggac ggctgctcct gcagattccc cgaggaagaa 720
gaaggcggct gcgagctgag agtgaagttc agcagaagcg ccgacgcccc tgcctatcag 780
cagggccaga atcagctgta caacgagctg aacctgggca gacgggaaga gtacgacgtg 840
ctggacaagc ggagaggcag ggaccctgag atgggcggaa agccccagcg gagaaagaac 900
ccccaggaag gcctgtataa cgaactgcag aaagacaaga tggccgaggc ctacagcgag 960
atcggaatga agggcgagcg gagaaggggc aagggccacg atggactgta ccagggcctg 1020
agcaccgcca ccaaggacac ctatgacgcc ctgcacatgc aggccctgcc ccccagataa 1080
1080
<210> 84
<211> 1080
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 84
atgggctggt cctgcatcat cctgtttctg gtggccacag ccaccggcgt gcactctgga 60
cctgtgcctc caagcaccgc cctgagaaag ctgatcgagg aactcgtgaa catcacccag 120
aaccagaaag cccccctgtg caacggcagc atggtgtggt ccatcaacct gaccgccggc 180
atgtactgtg ccgccctgga aagcctgatc aacgtgtccg gctgcagcgc catcgagaaa 240
acccaggata tgctggacgg cttctgcccc cacaaggtgt ccgccggaca gttcagctct 300
ctgcacgtgc gggacaccaa gatcgaggtg gcccagttcg tgaaggacct gctgctgcac 360
ctgaagaagc tgttcaaaga gggccagttc aacggcggag gccctaggaa gcctacaaca 420
acccctgccc ctagacctcc caccccagcc cctacaattg ccagccagcc tctgagcctg 480
aggcccgagg cttgtagacc agctgctggc ggagccgtgc acaccagagg actggatttc 540
gcctgcgaca tctacatctg ggcccctctg gccggcacat gtggcgtgct gctgctgagc 600
ctcgtgatca ccaagcgggg cagaaagaag ctgctgtaca tcttcaagca gcccttcatg 660
cggcccgtgc agaccaccca ggaagaggac ggctgctcct gcagattccc cgaggaagaa 720
gaaggcggct gcgagctgag agtgaagttc agcagaagcg ccgacgcccc tgcctatcag 780
cagggccaga atcagctgta caacgagctg aacctgggca gacgggaaga gtacgacgtg 840
ctggacaagc ggagaggcag ggaccctgag atgggcggaa agccccagcg gagaaagaac 900
ccccaggaag gcctgtataa cgaactgcag aaagacaaga tggccgaggc ctacagcgag 960
atcggaatga agggcgagcg gagaaggggc aagggccacg atggactgta ccagggcctg 1020
agcaccgcca ccaaggacac ctatgacgcc ctgcacatgc aggccctgcc ccccagataa 1080
1080
<210> 85
<211> 359
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 85
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Arg Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Lys Arg Gly Arg
195 200 205
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
210 215 220
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
225 230 235 240
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
245 250 255
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
260 265 270
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
275 280 285
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
290 295 300
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
305 310 315 320
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
325 330 335
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
340 345 350
Met Gln Ala Leu Pro Pro Arg
355
<210> 86
<211> 359
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 86
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Lys Arg Gly Arg
195 200 205
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
210 215 220
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
225 230 235 240
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
245 250 255
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
260 265 270
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
275 280 285
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
290 295 300
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
305 310 315 320
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
325 330 335
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
340 345 350
Met Gln Ala Leu Pro Pro Arg
355
<210> 87
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 87
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccaggata tgctggacgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaggaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 88
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 88
atgggctggt cctgcatcat cctgtttctg gtggccacag ccaccggcgt gcactctgga 60
cctgtgcctc caagcaccgc cctgagaaag ctgatcgagg aactcgtgaa catcacccag 120
aaccagaaag cccccctgtg caacggcagc atggtgtggt ccatcaacct gaccgccggc 180
atgtactgtg ccgccctgga aagcctgatc aacgtgtccg gctgcagcgc catcgagaaa 240
acccaggata tgctggacgg cttctgcccc cacaaggtgt ccgccggaca gttcagctct 300
ctgcacgtgc gggacaccaa gatcgaggtg gcccagttcg tgaaggacct gctgctgcac 360
ctgaagaagc tgttcaaaga gggccagttc aacggcggag gccctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 89
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 89
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Arg Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 90
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 90
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 91
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 91
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccaggata tgctggacgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaggaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 92
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 92
atgggctggt cctgcatcat cctgtttctg gtggccacag ccaccggcgt gcactctgga 60
cctgtgcctc caagcaccgc cctgagaaag ctgatcgagg aactcgtgaa catcacccag 120
aaccagaaag cccccctgtg caacggcagc atggtgtggt ccatcaacct gaccgccggc 180
atgtactgtg ccgccctgga aagcctgatc aacgtgtccg gctgcagcgc catcgagaaa 240
acccaggata tgctggacgg cttctgcccc cacaaggtgt ccgccggaca gttcagctct 300
ctgcacgtgc gggacaccaa gatcgaggtg gcccagttcg tgaaggacct gctgctgcac 360
ctgaagaagc tgttcaaaga gggccagttc aacggcggag gccctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gctcctgcac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 93
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 93
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Arg Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 94
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 94
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 95
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 95
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccaggata tgctggacgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaggaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gggcggccac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 96
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 96
atgggctggt cctgcatcat cctgtttctg gtggccacag ccaccggcgt gcactctgga 60
cctgtgcctc caagcaccgc cctgagaaag ctgatcgagg aactcgtgaa catcacccag 120
aaccagaaag cccccctgtg caacggcagc atggtgtggt ccatcaacct gaccgccggc 180
atgtactgtg ccgccctgga aagcctgatc aacgtgtccg gctgcagcgc catcgagaaa 240
acccaggata tgctggacgg cttctgcccc cacaaggtgt ccgccggaca gttcagctct 300
ctgcacgtgc gggacaccaa gatcgaggtg gcccagttcg tgaaggacct gctgctgcac 360
ctgaagaagc tgttcaaaga gggccagttc aacggcggag gccctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tctgctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gggcggccac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 97
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 97
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Arg Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 98
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 98
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Cys Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 99
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 99
atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactccggc 60
cctgtgcctc cctctacagc cctcaggtat ctcattgagg agctggtcaa catcacccag 120
aaccagaagg ctccgctctg caatggcagc atggtatgga gcatcaacct gacagctggc 180
atgtactgtg cagccctgga atccctgatc aacgtgtcag gctgcagtgc catcgagaag 240
acccaggata tgctggacgg attctgcccg cacaaggtct cagctgggca gttttccagc 300
ttgcatgtcc gagacaccaa aatcgaggtg gcccagtttg taaaggacct gctcttacat 360
ttaaggaaac tttttcgcga gggacagttc aacggtggcg gacctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gggcggccac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 100
<211> 1224
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 100
atgggctggt cctgcatcat cctgtttctg gtggccacag ccaccggcgt gcactctgga 60
cctgtgcctc caagcaccgc cctgagaaag ctgatcgagg aactcgtgaa catcacccag 120
aaccagaaag cccccctgtg caacggcagc atggtgtggt ccatcaacct gaccgccggc 180
atgtactgtg ccgccctgga aagcctgatc aacgtgtccg gctgcagcgc catcgagaaa 240
acccaggata tgctggacgg cttctgcccc cacaaggtgt ccgccggaca gttcagctct 300
ctgcacgtgc gggacaccaa gatcgaggtg gcccagttcg tgaaggacct gctgctgcac 360
ctgaagaagc tgttcaaaga gggccagttc aacggcggag gccctaggaa gcccaccacg 420
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 480
cgcccagagg cggcccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 540
gcccaattgc tcgcctacct gctggatgga atcctcttca tctatggtgt cattctcact 600
gccttgttcc tgagagtggt taacttctgg gtgaggagta agaggagcag gggcggccac 660
agtgactaca tgaacatgac tccccgccgc cccgggccca cccgcaagca ttaccagccc 720
tatgccccac cacgcgactt cgcagcctat cgctccaaac ggggcagaaa gaaactcctg 780
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 840
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgacgcgtaa gttcagcagg 900
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 960
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1020
ggaaagccgc agagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1080
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1140
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1200
atgcaggccc tgccccctcg ctaa 1224
<210> 101
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 101
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Arg Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 102
<211> 407
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 102
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Ala Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Gln Leu Leu Ala Tyr Leu Leu Asp Gly Ile Leu
180 185 190
Phe Ile Tyr Gly Val Ile Leu Thr Ala Leu Phe Leu Arg Val Val Asn
195 200 205
Phe Trp Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met
210 215 220
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
225 230 235 240
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg
245 250 255
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
260 265 270
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
275 280 285
Glu Gly Gly Cys Glu Leu Thr Arg Lys Phe Ser Arg Ser Ala Asp Ala
290 295 300
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
305 310 315 320
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
325 330 335
Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly
340 345 350
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
355 360 365
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
370 375 380
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
385 390 395 400
Met Gln Ala Leu Pro Pro Arg
405
<210> 103
<211> 1197
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 103
atgggctggt cctgcatcat cctgtttctg gtggccacag ccaccggcgt gcactctgga 60
cctgtgcctc caagcaccgc cctgagatac ctgatcgagg aactcgtgaa catcacccag 120
aaccagaaag cccccctgtg caacggcagc atggtgtggt ccatcaacct gaccgccggc 180
atgtactgtg ccgccctgga aagcctgatc aacgtgtccg gctgcagcgc catcgagaaa 240
acccaggata tgctggacgg cttctgcccc cacaaggtgt ccgccggaca gttcagctct 300
ctgcacgtgc gggacaccaa gatcgaggtg gcccagttcg tgaaggacct gctgctgcac 360
ctgagaaagc tgttcagaga gggccagttc aacggcggag gcaagcctac aacaacccct 420
gcccctagac ctcccacccc agcccctaca attgccagcc agcctctgag cctgaggccc 480
gaggcttgta gaccagctgc tggcggagcc gtgcacacca gaggactgga tttcgcctgc 540
gacatctaca tctgggcccc tctggccggc acatgtggcg tgctgctgct gagcctcgtg 600
atcaccagaa gcaagcggag cagaggcggc cacagcgact acatgaacat gacccccaga 660
cggcctggcc ccacccggaa acactatcag ccttacgccc ctcccagaga cttcgccgcc 720
tacagatcca agcggggcag aaagaagctg ctgtacatct tcaagcagcc cttcatgcgg 780
cccgtgcaga ccacccagga agaggacggc tgctcctgca gattccccga ggaagaagaa 840
ggcggctgcg agctgagagt gaagttcagc agaagcgccg acgcccctgc ctatcagcag 900
ggccagaatc agctgtacaa cgagctgaac ctgggcagac gggaagagta cgacgtgctg 960
gacaagcgga gaggcaggga ccctgagatg ggcggaaagc cccagcggag aaagaacccc 1020
caggaaggcc tgtataacga actgcagaaa gacaagatgg ccgaggccta cagcgagatc 1080
ggaatgaagg gcgagcggag aaggggcaag ggccacgatg gactgtacca gggcctgagc 1140
accgccacca aggacaccta tgacgccctg cacatgcagg ccctgccccc cagataa 1197
<210> 104
<211> 1203
<212> DNA
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 104
atgggctggt cctgcatcat cctgtttctg gtggccacag ccaccggcgt gcactctgga 60
cctgtgcctc caagcaccgc cctgagaaag ctgatcgagg aactcgtgaa catcacccag 120
aaccagaaag cccccctgtg caacggcagc atggtgtggt ccatcaacct gaccgccggc 180
atgtactgtg ccgccctgga aagcctgatc aacgtgtccg gctgcagcgc catcgagaaa 240
acccaggata tgctggacgg cttctgcccc cacaaggtgt ccgccggaca gttcagctct 300
ctgcacgtgc gggacaccaa gatcgaggtg gcccagttcg tgaaggacct gctgctgcac 360
ctgaagaagc tgttcaaaga gggccagttc aacggcggag gccctaggaa gcctacaaca 420
acccctgccc ctagacctcc caccccagcc cctacaattg ccagccagcc tctgagcctg 480
aggcccgagg cttgtagacc agctgctggc ggagccgtgc acaccagagg actggatttc 540
gcctgcgaca tctacatctg ggcccctctg gccggcacat gtggcgtgct gctgctgagc 600
ctcgtgatca ccagaagcaa gcggagcaga ggcggccaca gcgactacat gaacatgacc 660
cccagacggc ctggccccac ccggaaacac tatcagcctt acgcccctcc cagagacttc 720
gccgcctaca gatccaagcg gggcagaaag aagctgctgt acatcttcaa gcagcccttc 780
atgcggcccg tgcagaccac ccaggaagag gacggctgct cctgcagatt ccccgaggaa 840
gaagaaggcg gctgcgagct gagagtgaag ttcagcagaa gcgccgacgc ccctgcctat 900
cagcagggcc agaatcagct gtacaacgag ctgaacctgg gcagacggga agagtacgac 960
gtgctggaca agcggagagg cagggaccct gagatgggcg gaaagcccca gcggagaaag 1020
aacccccagg aaggcctgta taacgaactg cagaaagaca agatggccga ggcctacagc 1080
gagatcggaa tgaagggcga gcggagaagg ggcaagggcc acgatggact gtaccagggc 1140
ctgagcaccg ccaccaagga cacctatgac gccctgcaca tgcaggccct gccccccaga 1200
taa 1203
<210> 105
<211> 398
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 105
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Tyr Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Arg Lys Leu Phe Arg Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro
130 135 140
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
145 150 155 160
Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
165 170 175
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
180 185 190
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Arg Ser Lys Arg Ser Arg
195 200 205
Gly Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro
210 215 220
Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala
225 230 235 240
Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln
245 250 255
Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser
260 265 270
Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys
275 280 285
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
290 295 300
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
305 310 315 320
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg
325 330 335
Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
340 345 350
Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
355 360 365
Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
370 375 380
Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
385 390 395
<210> 106
<211> 400
<212> PRT
<213> Artificial Sequence
<220>
<223> chemically synthesized
<400> 106
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gly Pro Val Pro Pro Ser Thr Ala Leu Arg Lys Leu Ile
20 25 30
Glu Glu Leu Val Asn Ile Thr Gln Asn Gln Lys Ala Pro Leu Cys Asn
35 40 45
Gly Ser Met Val Trp Ser Ile Asn Leu Thr Ala Gly Met Tyr Cys Ala
50 55 60
Ala Leu Glu Ser Leu Ile Asn Val Ser Gly Cys Ser Ala Ile Glu Lys
65 70 75 80
Thr Gln Asp Met Leu Asp Gly Phe Cys Pro His Lys Val Ser Ala Gly
85 90 95
Gln Phe Ser Ser Leu His Val Arg Asp Thr Lys Ile Glu Val Ala Gln
100 105 110
Phe Val Lys Asp Leu Leu Leu His Leu Lys Lys Leu Phe Lys Glu Gly
115 120 125
Gln Phe Asn Gly Gly Gly Pro Arg Lys Pro Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Arg Ser Lys Arg
195 200 205
Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro
210 215 220
Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe
225 230 235 240
Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
245 250 255
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
260 265 270
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
275 280 285
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
290 295 300
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
305 310 315 320
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
325 330 335
Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
340 345 350
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
355 360 365
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
370 375 380
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
385 390 395 400
Claims (11)
- 키메라 항원 수용체(CAR)를 암호화하는 핵산 서열에 있어서, 상기 CAR은 암세포 항원을 인식하는 리간드를 포함하는 세포 외부 표적 도메인; 세포 내부 신호 전달 도메인; 및 상기 세포 외부 표적 도메인과 상기 세포 내부 신호 전달 도메인을 연결하는 중간 도메인으로 구성되고,
상기 세포 외부 표적 도메인을 암호화하는 핵산서열은 서열번호 No. 17, 19, 21, 23 및 25로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 핵산 서열. - 제 1항에 있어서, 상기 세포 내부 신호 전달 도메인을 암호화하는 핵산 서열은 서열번호 No. 9, 11, 13, 15로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 핵산 서열.
- 제 1항에 있어서, 상기 중간 도메인을 암호화하는 핵산서열은 서열번호 No. 3, 5 및 7로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 핵산 서열.
- 제 1항 또는 제 3항에 있어서, 키메라 항원 수용체를 암호화하는 전체 핵산 서열은 서열번호 No. 27 내지 106으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 핵산 서열.
- 키메라 항원 수용체(CAR)에 있어서, 상기 CAR은 암세포 항원을 인식하는 리간드를 포함하는 세포 외부 표적 도메인, 세포 내부 신호 전달 도메인 및 상기 세포 외부 표적 도메인과 상기 세포 내부 신호 전달 도메인을 연결하는 중간 도메인으로 구성되고, 상기 세포 외부 표적 도메인은 서열번호 No. 18, 20, 22, 24 및 26으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 키메라 항원 수용체.
- 제 5항에 있어서, 상기 세포 내부 신호 전달 도메인은 서열번호 No. 10, 12, 14 및 16으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 키메라 항원 수용체.
- 제 5항에 있어서, 상기 중간 도메인은 서열번호 No. 4, 6 및 8로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 키메라 항원 수용체.
- 제 5항 또는 제 7항에 있어서, 키메라 항원 수용체는 서열번호 No. 27 내지 No. 106으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 키메라 항원 수용체.
- 제 1항에 있어서, 상기 암세포는 교모세포종인 것을 특징으로 하는 핵산서열.
- 제 5항에 있어서, 상기 암세포는 교모세포종인 것을 특징으로 하는 키메라 항원 수용체.
- 제 1항 내지 제 3항 중 어느 한 항에 규정된 핵산 서열을 포함하는 벡터
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201462033305P | 2014-08-05 | 2014-08-05 | |
| US62/033,305 | 2014-08-05 | ||
| US201462034385P | 2014-08-07 | 2014-08-07 | |
| US62/034,385 | 2014-08-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20160016725A true KR20160016725A (ko) | 2016-02-15 |
Family
ID=55357289
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020150110784A Withdrawn KR20160016725A (ko) | 2014-08-05 | 2015-08-05 | 암 세포에 과발현되는 IL13Rα2에 특이적으로 결합하는 키메라 항원 수용체로 변형된 T 세포 |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR20160016725A (ko) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20200107016A (ko) | 2019-03-05 | 2020-09-16 | 주식회사 온코인사이트 | 항-fitc 키메릭 항원 수용체를 발현하는 대식세포 및 이의 용도 |
| RU2745319C2 (ru) * | 2016-03-16 | 2021-03-23 | Нексиммьюн, Инк. | Получение антигенспецифических t-клеток |
| WO2021107726A1 (ko) | 2019-11-28 | 2021-06-03 | 주식회사 센트릭스바이오 | Cd300c 항원 또는 그의 수용체에 특이적으로 결합하는 키메라 항원 수용체 |
| KR20210066743A (ko) | 2019-11-28 | 2021-06-07 | 주식회사 센트릭스바이오 | CD300c 항원 또는 그의 수용체에 특이적으로 결합하는 키메라 항원 수용체 |
| WO2021183960A1 (en) * | 2020-03-12 | 2021-09-16 | City Of Hope | TARGETED CHIMERIC ANTIGEN RECEPTOR MODIFIED T CELLS FOR TREATMENT OF IL13RαA2 POSITIVE MALIGNANCIES |
| US20220010023A1 (en) * | 2016-06-06 | 2022-01-13 | City Of Hope | Baff-r targeted chimeric antigen receptor-modified t-cells and uses thereof |
| JP2022120137A (ja) * | 2016-10-07 | 2022-08-17 | エンテローム エスエー | 癌治療のための免疫原性化合物 |
| WO2022250433A1 (ko) | 2021-05-24 | 2022-12-01 | 주식회사 센트릭스바이오 | Cd300c 항원 또는 그의 수용체에 특이적으로 결합하는 키메라 항원 수용체 |
| KR20240005850A (ko) | 2021-05-24 | 2024-01-12 | 주식회사 센트릭스바이오 | Cd300c 항원 또는 그의 수용체에 특이적으로 결합하는키메라 항원 수용체 |
-
2015
- 2015-08-05 KR KR1020150110784A patent/KR20160016725A/ko not_active Withdrawn
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2745319C2 (ru) * | 2016-03-16 | 2021-03-23 | Нексиммьюн, Инк. | Получение антигенспецифических t-клеток |
| US20220010023A1 (en) * | 2016-06-06 | 2022-01-13 | City Of Hope | Baff-r targeted chimeric antigen receptor-modified t-cells and uses thereof |
| US12215162B2 (en) * | 2016-06-06 | 2025-02-04 | City Of Hope | BAFF-R targeted chimeric antigen receptor-modified T-cells and uses thereof |
| JP2022120137A (ja) * | 2016-10-07 | 2022-08-17 | エンテローム エスエー | 癌治療のための免疫原性化合物 |
| KR20200107016A (ko) | 2019-03-05 | 2020-09-16 | 주식회사 온코인사이트 | 항-fitc 키메릭 항원 수용체를 발현하는 대식세포 및 이의 용도 |
| WO2021107726A1 (ko) | 2019-11-28 | 2021-06-03 | 주식회사 센트릭스바이오 | Cd300c 항원 또는 그의 수용체에 특이적으로 결합하는 키메라 항원 수용체 |
| KR20210066743A (ko) | 2019-11-28 | 2021-06-07 | 주식회사 센트릭스바이오 | CD300c 항원 또는 그의 수용체에 특이적으로 결합하는 키메라 항원 수용체 |
| WO2021183960A1 (en) * | 2020-03-12 | 2021-09-16 | City Of Hope | TARGETED CHIMERIC ANTIGEN RECEPTOR MODIFIED T CELLS FOR TREATMENT OF IL13RαA2 POSITIVE MALIGNANCIES |
| WO2022250433A1 (ko) | 2021-05-24 | 2022-12-01 | 주식회사 센트릭스바이오 | Cd300c 항원 또는 그의 수용체에 특이적으로 결합하는 키메라 항원 수용체 |
| KR20240005850A (ko) | 2021-05-24 | 2024-01-12 | 주식회사 센트릭스바이오 | Cd300c 항원 또는 그의 수용체에 특이적으로 결합하는키메라 항원 수용체 |
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