KR20210017449A - 신규한 융합 단백질 및 이의 용도 - Google Patents

신규한 융합 단백질 및 이의 용도 Download PDF

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KR20210017449A
KR20210017449A KR1020190096731A KR20190096731A KR20210017449A KR 20210017449 A KR20210017449 A KR 20210017449A KR 1020190096731 A KR1020190096731 A KR 1020190096731A KR 20190096731 A KR20190096731 A KR 20190096731A KR 20210017449 A KR20210017449 A KR 20210017449A
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김정호
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Abstract

본 발명은 Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질의 세포 외 도메인(extracellular domain) 및 면역글로불린(immunoglobulin) Fc 영역을 포함하는 융합 단백질에 관한 것이다.

Description

신규한 융합 단백질 및 이의 용도{A NEW FUSION PROTEIN AND USE OF TEREOF}
본 발명은 Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질의 세포 외 도메인(extracellular domain)과 면역글로불린(immunoglobulin) Fc 영역을 포함하는 신규한 융합 단백질과, 이의 용도에 관한 것이다.
면역글로불린(immunoglobulin)은 4개의 폴리펩타이드 쇄, 즉 쇄간 디술피드 결합을 통해 회합된 2개의 중쇄 및 2개의 경쇄를 포함한다. 각각의 경쇄는 2개의 도메인, 즉 가변 경쇄 도메인 (VL) 및 불변 경쇄 도메인 (CL)을 갖고, 각각의 중쇄는 2개의 영역, 즉 가변 중쇄 영역 (VH) 및 불변 중쇄 영역 (CH)을 갖는다. 불변 중쇄 영역 (CH)은 숫자에 의해 지정된 불변 중쇄 영역 (예를 들어, CH1, CH2, CH3 등)으로 이루어진다 (예를 들어, US 6,086,875 (블룸버그 알. 에스.(Blumberg R. S.) 등), US 5,624,821 (윈터 (Winter G. P.) 등) 및 US 5,116,964 (카폰 디. 제이.(Capon D. J.) 및 라스키 엘. 에이.(Lasky L. A.)) 참조). 면역글로불린은 그의 생물학적 특성, 유기체 내의 위치 및 상이한 항원을 처리하는 능력에 기초하여 상이한 이소형(즉, IgG, IgM, IgA, IgD 및 IgE)으로 분류된다. 이뮤노글로불린 이소형에 따라, 불변 중쇄 영역 (CH)은 3개 또는 4개의 CH 도메인을 가질 수 있다. 또한, 일부 이소형 (IgA, IgD 및 IgG)에서, 중쇄는 분자에 유연성을 부가하는 힌지 영역을 포함한다 (Janeway et al. 2001, Immunobiology, Garland Publishing, N.Y., N.Y.).
인간에는 4개의 IgG 하위클래스 (IgG1, 2, 3, 4)가 있고, 이들은 혈청에 풍부한 순서에 따라 명명된다 (IgG1이 가장 풍부하다). IgG 이소형은 2개의 경쇄 및 2개의 중쇄로 이루어지고, 각각의 중쇄는 3개의 불변 중쇄 도메인 (CH1, CH2, CH3)을 포함한다. IgG의 2개의 중쇄는 서로에 대해 및 경쇄에 각각 디술피드 결합 (-S-S-)에 의해 연결되어 있다. IgG의 항원 결합 부위는 가변 경쇄 (VL) 및 가변 중쇄 (VH) 도메인뿐만 아니라 불변 경쇄 (CL) 및 불변 중쇄 (CH1) 도메인을 포함하는 단편 항원 결합 영역 (Fab 영역)에 위치한다. IgG의 단편 결정화가능 영역 (Fc 영역)은 신생아 Fc 수용체 (FcRn)를 포함하는 특정 세포의 표면에서 발견되는 Fc 수용체에 결합하는 CH2 및 CH3 도메인을 함유하는 중쇄의 일부이다. IgG의 중쇄는 또한 Fab 영역을 Fc 영역으로부터 분리하고 2개의 중쇄를 디술피드 결합을 통해 함께 연결할 때 참여하는, CH1과 CH2 사이의 힌지 영역 (힌지)을 갖는다. 힌지 영역의 구조는 4개의 IgG 하위클래스 각각의 특유한 생물학적 특성에 기여한다.
IgG는 쉽게 조직을 관류할 수 있도록 허용하는 크기가 작은 단량체로 분비된다. 이것은 자궁 내의 태아를 보호하기 위해 인간 태반을 통과하는 것을 촉진하는 수용체 (신생아 Fc 수용체 (FcRn))를 갖는 유일한 이소형이다. 태반을 통해 흡수된 IgG는 그 자체 면역계가 발달하기 전에 체액성 면역을 신생아에게 제공한다.
IgG 신생아 Fc 수용체 (FcRn) 결합 부위는 항체의 Fc 영역에 위치한다. FcRn은 일반적으로 인간의 태반 및 상피 세포에서 발현되고, IgG의 분해를 막는 세포내이입 샐비지 경로에 참여한다. 이 샐비지 경로는 산성 pH에서 FcRn에 대한 IgG의 높은 pH 의존성 결합 친화도에 의해 매개된다. 산성 pH에서 FcRn에 대한 IgG의 높은 친화도는 산성 엔도솜 내로의 흡수 후에 내재화된 IgG의 FcRn에 대한 결합을 유발하는 것으로 생각된다 ([Goebl NA, et al., 2008]; [Junghans RP, et al., 1996]). 대부분의 가용성 단백질은 내재화 후에 리소솜으로 향하지만, 내재화된 FcRn-결합 IgG는 형질 막으로 되돌아가고, 기본 분해 경로로부터 효과적으로 구출된다. 세포 외 공간의 중성 pH에 노출시, IgG는 FcRn으로부터 해리되어 순환계로 되돌아갈 수 있다. 따라서, 항체의 연장된 혈청 반감기 특성은 Fc 단편에서 유지된다.
상기 샐비지 경로는 비변형된 단백질 약물에 비해 혈액 순환에서 반감기가 연장된 차세대 단백질 약물의 개발을 위한 하나의 메커니즘을 제공한다. 특히, 비변형된 단백질 약물은 순환 반감기가 짧고, 따라서 필요한 장기간의 치료 기간에 걸쳐 빈번한 투여가 필요하다. PEG화 융합 단백질 기술 (미국 식품의약국 (Food and Drug Administration), [Osborn BL, et al., 2002])을 포함한 많은 방법에 의해 단백질 약물의 반감기를 연장하기 위한 광범위한 노력이 이루어졌지만, 이러한 노력의 결과는 이상적이지 않았다.
본 발명의 일 목적은 다양한 링커를 포함하는 Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질의 세포 외 도메인(extracellular domain)과 면역글로불린(immunoglobulin) Fc 영역을 포함하는 신규한 융합 단백질을 제공하는 것이다.
본 발명의 다른 목적은 본 발명에 따른 상기 융합 단백질을 코딩하는 핵산 분자에 관한 것이다.
본 발명의 또 다른 목적은 본 발명에 따른 상기 핵산 분자가 삽입된 발현 벡터를 제공하는 것이다.
본 발명의 또 다른 목적은 본 발명에 따른 상기 발현 벡터가 형질 감염된 숙주 세포주를 제공하는 것이다.
본 발명의 또 다른 목적은 본 발명에 따른 융합 단백질을 유효성분으로 포함하는 암의 예방, 개선 또는 치료용 조성물을 제공하는 것이다.
본 발명의 또 다른 목적은 본 발명에 따른 융합 단백질을 유효성분으로 포함하는 면역 관련 질환의 예방, 개선 또는 치료용 조성물을 제공하는 것이다.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.
본 발명의 일 구현 예에 따르면, Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질의 세포 외 도메인(extracellular domain) 및 면역글로불린(immunoglobulin) Fc 영역을 포함하는 융합 단백질에 관한 것이다.
본 발명에서, 상기 "Lrig-1 단백질"은 조절 T 세포의 표면에 존재하는 1091개의 아미노산으로 이루어진 막관통 단백질로서, 세포 외 혹은 루멘 쪽의 루신 반복 서열(leucine-rich repeat(LRR))과 세개의 면역체 유사 도메인(immunoglobulin-like domains), 세포막 관통 서열 및 세포질 꼬리부분으로 구성되어 있다. LRIG 유전자 패밀리는 LRIG1, LRIG2와 LRIG3이 존재하며, 이들 간의 아미노산들은 매우 보전적으로 구성되어 있다.
본 발명의 일 예시에서 상기 Lrig-1 단백질의 세포 외 도메인은 인간, 원숭이 등의 영장류, 마우스, 래트 등의 설치류, 등을 포함하는 포유류로부터 유래된 Lrig-1 단백질의 세포 외 도메인일 수 있다.
본 발명의 일 예시에서 상기 Lrig-1 단백질의 세포 외 도메인은 인간 유래 Lrig-1 단백질의 35번째 내지 794번째 아미노산 서열에 해당하는 서열번호 1로 표시될 수 있고, 이는 서열번호 2로 표시되는 핵산 서열에 의해 코딩될 수 있으나, 이에 제한되는 것은 아니다(표 1 참조).
Figure pat00001
Figure pat00002
본 발명의 다른 예시에서 상기 Lrig-1 단백질의 세포 외 도메인은 마우스 유래 Lrig-1 단백질의 35번째 내지 794번째 아미노산 서열에 해당하는 서열번호 3으로 표시될 수 있고, 이는 서열번호 4로 표시되는 핵산 서열에 의해 코딩될 수 있으나, 이에 제한되는 것은 아니다(표 2 참조).
Figure pat00003
Figure pat00004
본 발명에서, "면역글로불린 Fc 영역"은, 면역글로불린의 중쇄와 경쇄 가변영역을 제외한, 중쇄 불변영역 2(CH2) 및/또는 중쇄 불변영역 3(CH3) 부분을 포함하는 부위를 의미한다. 상기 면역글로불린 Fc 영역은 본 발명의 단백질 결합체의 모이어티를 이루는 일 구성일 수 있다.
본 발명에서 상기 면역글로불린 Fc 영역은 중쇄 불변영역에 힌지(hinge) 부분을 포함함으로써 최종 제조될 융합 단백질의 구조적 유연성(flexibility)에 영향을 줄 수 있고, 융합 단백질의 생산성 및 안정성을 보다 높일 수 있으나, 이에 제한되는 것은 아니다.
또한 본 발명의 면역글로불린 Fc 영역은 천연형과 실질적으로 동등하거나 향상된 효과를 갖는 한, 면역 글로불린의 중쇄와 경쇄 가변영역만을 제외하고, 일부 또는 전체 중쇄 불변영역 1(CH1) 및/또는 경쇄 불변영역 1(CL1)을 포함하는 확장된 Fc영역일 수 있다. 또한, CH2 및/또는 CH3에 해당하는 상당히 긴 일부 아미노산 서열이 제거된 영역일 수도 있다.
예컨대, 본 발명에서 상기 면역글로불린 Fc 영역은 1) CH1 도메인, CH2 도메인, CH3 도메인 및 CH4 도메인, 2) CH1 도메인 및 CH2 도메인, 3) CH1 도메인 및 CH3 도메인, 4) CH2 도메인 및 CH3 도메인, 5) CH1 도메인, CH2 도메인, CH3 도메인 및 CH4 도메인 중 1개 또는 2개의 이상의 도메인과 면역글로불린 힌지 영역(또는 힌지 영역의 일부)와의 조합, 6) 중쇄 불변 영역 각 도메인과 경쇄 불변영역의 이량체일 수 있다. 그러나, 이에 제한되는 것은 아니다.
또한, 본 발명에서 면역글로불린 Fc 영역은 천연형 아미노산 서열뿐만 아니라 이의 서열 유도체를 포함한다. 아미노산 서열 유도체란 천연 아미노산 서열 중의 하나 이상의 아미노산 잔기가 결실, 삽입, 비보전적 또는 보전적 치환 또는 이들의 조합에 의하여 상이한 서열을 가지는 것을 의미한다.
예를 들면, IgG Fc의 경우 결합에 중요하다고 알려진 214 내지 238, 297 내지 299, 318 내지 322 또는 327 내지 331번째 아미노산 잔기들이 변형을 위해 적당한 부위로서 이용될 수 있다.
또한, 이황화 결합을 형성할 수 있는 부위가 제거되거나, 천연형 Fc에서 N-말단의 몇몇 아미노산이 제거되거나 또는 천연형 Fc의 N-말단에 메티오닌 잔기가 부가될 수도 있는 등 다양한 종류의 유도체가 가능하다. 또한, 이펙터 기능을 없애기 위해 보체결합부위, 예로 C1q 결합부위가 제거될 수도 있고, ADCC (antibody dependent cell mediated cytotoxicity) 부위가 제거될 수도 있다. 이러한 면역글로불린 Fc 영역의 서열 유도체(Fc 유도체)를 제조하는 기술은 국제공개특허 제WO 97/34631호, 국제공개특허 제WO96/32478호 등에 개시되어 있다.
본 발명에서 분자의 활성을 전체적으로 변경시키지 않는 단백질 및 펩타이드에서의 아미노산 교환은 당해 분야에 공지되어 있다(H.Neurath, R.L.Hill, The Proteins, Academic Press, New York, 1979). 가장 통상적으로 일어나는 교환은 아미노산 잔기 Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr, Ser/Asn, Ala/Val, Ser/Gly, Thy/Phe, Ala/Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Ala/Glu, Asp/Gly 간의 교환이다. 경우에 따라서는 인산화(phosphorylation), 황화(sulfation), 아크릴화(acrylation), 당화(glycosylation), 메틸화(methylation), 파네실화(farnesylation), 아세틸화(acetylation) 및 아미드화(amidation) 등으로 수식(modification)될 수도 있다.
본 발명에서 상기 기술한 Fc 유도체는 본 발명의 Fc 영역과 동등한 생물학적 활성을 나타내며 Fc 영역의 열, pH 등에 대한 구조적 안정성이 증대되도록 개선시킨 것일 수 있다.
또한, 본 발명에서 상기 Fc 영역은 인간, 소, 염소, 돼지, 마우스, 래빗, 햄스터, 랫트 또는 기니아 픽 등의 동물의 생체 내에서 분리한 천연형으로부터 얻어질 수도 있고, 형질 전환된 동물세포 또는 미생물로부터 얻어진 재조합형 또는 이의 유도체일 수 있다. 여기서, 천연형으로부터 획득하는 방법은 전체 면역글로불린을 인간 또는 동물의 생체로부터 분리한 후, 단백질 분해효소를 처리하여 획득하는 방법일 수 있다. 파파인으로 처리할 경우에는 Fab 및 Fc로 절단되고, 펩신으로 처리할 경우에는 pF'c 및 F(ab)2로 절단된다. 크기 배제 크로마토그래피(size-exclusion chromatography) 등을 이용하여 Fc 또는 pF'c를 분리할 수 있다. 더 구체적인 실시 형태에서는 인간 또는 마우스 유래의 Fc 영역을 미생물로부터 수득한 재조합형 면역글로불린 Fc 영역이다.
또한, 본 발명에서 면역글로불린 Fc 영역은 천연형 당쇄, 천연형에 비해 증가된 당쇄, 천연형에 비해 감소한 당쇄 또는 당쇄가 제거된 형태일 수 있다. 이러한 면역글로불린 Fc 당쇄의 증감 또는 제거에는 화학적 방법, 효소학적 방법 및 미생물을 이용한 유전 공학적 방법과 같은 통상적인 방법이 이용될 수 있다. 여기서, Fc에서 당쇄가 제거된 면역글로불린 Fc 영역은 보체(c1q)와의 결합력이 현저히 저하되고, 항체-의존성 세포독성 또는 보체-의존성 세포 독성이 감소 또는 제거되므로, 생체 내에서 불필요한 면역 반응을 유발하지 않는다. 이런 점에서 약물의 캐리어로서의 본래의 목적에 보다 부합하는 형태는 당쇄가 제거되거나 비당쇄화된 면역글로불린 Fc 영역이라 할 것이다.
본 발명에서 "당쇄의 제거(Deglycosylation)"는 효소로 당을 제거한 Fc 영역을 말하며, 비당쇄화(Aglycosylation)는 원핵동물, 더 구체적인 실시 형태에서는 대장균에서 생산하여 당쇄화되지 않은 Fc 영역을 의미한다.
한편, 면역글로불린 Fc 영역은 인간 또는 소, 염소, 돼지, 마우스, 래빗, 햄스터, 랫트, 기니아 픽 등의 동물 유래일 수 있으며, 바람직한 일 예시로 인간 또는 마우스 유래일 수 있다.
또한, 본 발명의 면역글로불린 Fc 영역은 IgG, IgA, IgD, IgE, IgM 유래 Fc 영역, 중쇄 불변영역 2(CH2), 중쇄 불변영역 3(CH3), 힌지(hinge), 이의 단편, 또는 이들의 조합(combination), 또는 이들의 조합을 포함하는 하이브리드 Fc(hybrid Fc)일 수 있다.
한편, 본 발명에서 "조합(combination)"이란 이량체 또는 다량체를 형성할 때, 동일 기원 단쇄 면역글로불린 Fc 영역, 중쇄 불변영역 2(CH2) 또는 중쇄 불변영역 3(CH3)을 코딩하는 폴리펩타이드가 상이한 기원의 단쇄 폴리펩타이드와 결합을 형성하는 것을 의미한다. 즉, IgG, IgA, IgM, IgD 또는 IgE 유래의 Fc 영역, 중쇄 불변영역 2(CH2) 또는 중쇄 불변영역 3(CH3)으로부터 선택된 2개 이상의 단편으로부터 이량체 또는 다량체의 제조가 가능하다.
본 발명에서 상기 "하이브리드 Fc"는 인간 IgG 서브클래스의 조합 또는 인간 IgD 및 IgG의 조합으로부터 유도될 수 있다. 하나의 실시예에서, 상기 하이브리드 Fc는 예를 들어, IgD 힌지 영역 및 CH2 N-말단 영역 + IgG4 CH2 및 CH3 영역을 포함할 수 있으며, 예를 들어, 한국등록특허 제0897938호에 개시된 하이브리드 Fc 형태를 동일하게 차용하여 사용할 수 있고, 본 명세서에 참조로서 도입된다. 본 발명에서 상기 하이브리드 Fc는 생물학적 활성 분자, 폴리펩타이드 등에 결합하는 경우, 생물학적 활성 분자의 혈청 반감기를 증가시킬 뿐만 아니라 Fc-폴리펩타이드 융합 단백질을 코딩하는 뉴클레오티드가 발현될 때 폴리펩타이드의 발현 수준을 높이는 효과가 있다.
본 발명에서 일 예시로 상기 면역글로불린 Fc 영역은 IgG, IgA, IgM, IgD 또는 IgE 유래의 Fc 영역이거나, 혹은 상기 IgG, IgA, IgM, IgD 또는 IgE 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함할 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 일 예시로 상기 면역글로불린 Fc 영역은 인간 혈액에 가장 풍부한 IgG 또는 IgM 유래 Fc 영역이거나, 혹은 상기 IgG 또는 IgM 유래 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함할 수 있고, 다른 예시로 리간드 결합 단백질의 반감기를 향상시키는 것으로 공지된 IgG 유래 Fc 영역이거나, 혹은 상기 IgG 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함할 수 있고, 또 다른 예시로 IgG1, IgG2, IgG3 또는 IgG4 유래 Fc 영역이거나, 혹은 상기 IgG1, IgG2, IgG3 또는 IgG4 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함할 수 있으며, 또 다른 예시로 IgG1 또는 IgG2 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함할 수 있다.
본 발명에서 바람직한 예시로서 상기 면역글로불린 Fc 영역은 서열번호 5로 표시되는 인간 IgG1 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함하거나, 서열번호 6으로 표시되는 마우스 IgG2 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함할 수 있으나, 이에 제한되는 것은 아니다(하기 표 3 참조).
Figure pat00005
본 발명의 일 예시로, 상기 면역글로불린 Fc 영역은 IgG, IgA, IgM, IgD, IgE, 또는 아바타셉트(Abatacept) 유래의 힌지 영역을 포함할 수 있고, 또 다른 예시로 IgG, IgD 또는 아바타셉트(Abatacept) 유래의 힌지 영역을 포함할 수 있으며, 혹은 IgG1, IgG2, IgG3, IgG4, IgD 또는 아바타셉트(Abatacept) 유래의 힌지 영역을 포함할 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 바람직한 예시로서 상기 면역글로불린 Fc 영역은 서열번호 7로 표시되는 인간 IgG1 유래의 힌지 영역; 서열번호 8로 표시되는 마우스 IgG2 유래의 힌지 영역; 서열번호 9로 표시되는 인간 IgD 유래의 힌지 영역; 및 서열번호 10으로 표시되는 아바타셉트(Abatacept)의 힌지 영역; 으로 이루어진 군에서 선택된 1종 이상을 포함함으로써(하기 표 4 참조) 최종 제조될 융합 단백질의 구조적 유연성(flexibility)을 높이고, 융합 단백질의 생산성 및 안정성을 현저히 향상시킬 수 있으나, 이에 제한되는 것은 아니다.
Figure pat00006
본 발명에서 상기 Lrig-1 단백질의 세포 외 도메인과 Fc 영역이 링커를 통해 연결되는 경우, 상기 링커는 Fc 단편의 N-말단, C-말단 또는 유리기 (free radical)에 연결될 수 있고, Lrig-1 단백질의 세포 외 도메인의 N-말단, C-말단 또는 유리기에 연결될 수 있다. 링커가 펩타이드 링커인 경우, 연결은 임의의 부위에서 일어날 수 있다. 예를 들면, 상기 링커는 상기 Lrig-1 단백질의 세포 외 도메인의 C-말단 및 상기 면역글로불린의 Fc 영역의 N-말단에 연결될 수 있고, 혹은 상기 면역글로불린의 Fc 영역의 C-말단 및 상기 Lrig-1 단백질의 세포 외 도메인의 N-말단에 연결될 수 있다.
본 발명에서 상기 "링커(linker)"는 융합 단백질 내 Lrig-1 단백질의 세포 외 도메인과 면역글로불린 Fc 영역 사이의 간섭 효과를 줄여 타겟 세포에서 상기 Lrig-1 단백질의 세포 외 도메인의 목적하는 활성을 높이는데 기여한다.
본 발명에서 상기 링커는 절단 가능한 링커일 수 있고, 바람직하게는 화학적; 바이러스 또는 효소에 의해 절단 가능한 링커일 수 있다. 또한, 본 발명에서 상기 링커는 목적하는 질환의 조직 또는 세포 내에서 과발현되는 효소에 의해 절단될 수 있는 서열을 포함할 수 있다. 상기와 같이 과발현되는 효소에 의해 절단될 수 있는 경우에는 Fc 영역으로 인하여 폴리펩타이드의 활성이 저하되는 것을 효과적으로 방지할 수 있다.
본 발명에서 상기 절단 가능한 링커는 효소 또는 바이러스에 인식 또는 절단되는 펩타이드 또는 비 펩타이드 링커일 수 있고, 예를 들면, 인터루킨-1b(interleukin-1beta)의 프로폼(proform); 카스파제(caspase); ADAMs(A disintegrin and metalloproteinases), ADAMTSs(a disintegrin and metalloproteinase with thrombospondin motifs) HIV-1 프로테아제(HIV-1 proteaste); 미리스토일화 신호 서열과 융합된 TEV 프로테아제(Tobacco Etch Virus protease); 프리시션 프로테아제(preScission protease); TEV 프로테아제(tobacco etch virus protease); HCV 프로테아제; RecA; TEV(Tobacco Etch Virus) 또는 기질단백질 분해효소 (matrix metalloproteinases, MMPs)에 의해 인식 또는 절단되는 펩타이드 링커일 수 있다. 본 발명의 상기 효소 또는 바이러스에 의해 인식 또는 절단되는 펩타이드 링커는 그 효소 또는 바이러스가 인지 또는 결합할 수 있는 효율을 높이기 위해 인식 또는 절단되는 펩타이드 링커의 아미노산 염기 서열을 기준으로 업 스트림(upstream) 또는 다운 스트림(downstream)에 일반적인 아미노산 서열을 추가로 포함할 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 효소에 의해 인식 또는 절단되는 비 펩타이드 링커는 리소좀성 효소 베타글루쿠로니다제에 의해 절단되도록 하는 그룹을 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다((Jeffrey 등 (3006) Bioconjug. Chem. 17 (3) : 831-840 참조).
본 발명의 일 예시로서 상기 링커는 1 내지 100개의 아미노산을 갖는 것이 바람직하나, 이에 제한되지는 않으며, Lrig-1 단백질의 세포 외 도메인과 면역글로불린 Fc 영역을 분리시킬 수 있는 어떠한 펩타이드라도 가능하다. 상기 링커를 구성하는 아미노산 서열에는 특별한 제한은 없으나, 글라이신(G) 및 세린(S)을 포함하거나, 이들을 반복적으로 또는 무작위적 패턴으로 포함하는 것이 바람직하다. 그러한 예로서, 상기 링커는 서열번호 11로 표시되는 펩타이드 링커; 및 서열번호 12로 표시되는 펩타이드 링커; 중 적어도 하나를 포함할 수 있고(하기 표 5 참조), 혹은 하기 식 1 내지 4로 표시되는 아미노산 서열로 이루어지는 펩타이드 링커로 구성된 군으로부터 선택되는 적어도 하나일 수 있다:
[식 1]
(G)n
[식 2]
(GGGGS)m
[식 3]
(EAAAK)p
[식 4]
(XP)q
상기 식 1 내지 4에서,
n, m 및 p는 각각 독립적으로 1 이상의 정수이고;
q는 5 내지 40의 정수이며;
X는 A(Ala), C(Cys), D(Asp), E(Glu), F(Phe), G(Gly), H(His), I(Ile), K(Lys), L(Leu), M(Met), N(Asn), O(Pyl), P(Pro), Q(Gln), R(Arg), S(Ser), T(Thr), U(Sec), V(Val), W(Trp) 및 Y(Tyr)로 구성된 군으로부터 선택되는 어느 하나의 아미노산이다.
본 발명에서 상기 식 1 내지 식 3의 상기 n, m 및 q는 1 이상의 정수, 바람직하게는 1 내지 20의 정수일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 식 4의 상기 X는 A(Ala)일 수 있으나, 이에 제한되는 것은 아니다.
또한, 본 발명에서 일 예시로서 상기 링커는 서열번호 95로 표시되는 펩타이드 링커(A(EAAAK)4ALEA(EAAAK)4A); 서열번호 96으로 표시되는 펩타이드 링커(PAPAP); 서열번호 97로 표시되는 펩타이드 링커(AEAAAKEAAAKA); 서열번호 98로 표시되는 펩타이드 링커(IEGRMD); 및 서열번호 99로 표시되는 펩타이드 링커(DIEGRMD)로 구성된 군으로부터 선택되는 적어도 하나를 포함할 수 있으나, 이에 제한되는 것은 아니다.
또한, 본 발명에서 상기 링커의 일 실시예로, (GGGS GGGGS GGGS)a, (GGSG)b, (GSAT)c, (SEG)d 및 (GGS)e 아미노산 서열로 구성된 군으로부터 선택되는 적어도 하나를 포함할 수 있으나, 이에 제한되는 것은 아니다. 여기서, 상기 a 내지 e는 각각 독립적으로 1 이상의 정수, 바람직하게는 1 내지 50의 정수일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 “E”는 글루탐산(Glu)이고, 상기 “S”는 세린(Ser)이고, 상기 “A”는 알라닌(Ala)이며, 상기 “K”는 리신(Lys)이고, 상기 “P”는 프롤린(Pro)이며, 상기 “I”는 아이소류신(Ile)이고, 상기 “G”는 글라이신(Gly)이며, 상기 “R”은 아르기닌(Arg)이고, 상기 “M”은 메티오닌(Met)이며, 상기 "T"는 트레오닌(Thr)이고, 상기 “D”는 아스파트산(Asp)을 의미한다.
본 발명에서 상기 융합 단백질이 상기 펩타이드 링커를 더 포함하는 경우 세포 내 활성 물질의 안정성을 높이고, 생산성을 보다 향상시킬 수 있다.
Figure pat00007
또한, 본 발명에서 상기 링커의 일 예시로, 혈액 내에 가장 많이 존재하는 인간 알부민의 282번 내지 314번째 부분에 위치한 33개의 아미노산으로 이루어진 펩타이드 링커, 보다 바람직하게는 292번 내지 304번째 부분에 위치한 13개의 아미노산으로 이루어진 펩타이드 링커일 수 있으며, 이러한 부분은 3차원적인 구조상 대부분 외부에 노출된 부분으로서 체내에서 면역반응을 유도할 가능성이 최소화된 부분이다. 단, 이에 제한되는 것은 아니다.
또한, 본 발명에서 상기 링커 및 Fc 영역이 별개로 발현된 후에 서로 결합될 때, 링커는 당업계에 알려진 가교제일 수 있다. 상기 가교제는, 예를 들어, 1,1-비스(디아조아세틸)-2-페닐에탄 (1,1-bis(diazoacetyl)-2-phenylethane), 글루타르알데하이드 (glutaraldehyde), 4-아지도살리실릭산 (4-azidosalicylic acid)과 같은 N-하이드로옥시석신이미드 에스테르 (N-hydroxysuccinimide ester), 3,3'-디사이오비스(석신이미딜프로피오네이트) (3,3'-dithiobis(succinimidylpropionate))와 같은 디석신이미딜에스테르 (disuccinimidyl esters)를 포함하는 이미도에스테르 (imidoesters), 및 비스-N-말레이미도-1,8-옥테인과 같은 이중 기능적 말레이미드 (bifunctional maleimides)일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 화학적으로 절단 가능한 링커는 미국 특허 제 4,618,492 호, 제 4,542,225 호 및 제 4,625,014 호 참조하여 다양한 화학적으로 절단 가능한 링커(예를 들면, 산 - 불안정성 링커, 다이 설파이드 링커 등)를 사용할 수 있으나, 이제 제한되는 것은 아니다.
본 발명에서 상기 산-불안정성 링커의 경우에는 혈액 내 pH에서는 매우 안정하지만 리소좀과 같은 낮은 pH의 환경에서는 불안정하여 분해될 수 있고, 예를 들면, 히드라존, 아세탈, cis-아코니테이트 유사 아미드밀 실릴 에테르 등일 수 있으나, 이에 제한되는 것은 아니다(Perez et al. (2013) Drug Discov Today, 1-13 참조). 또한, 상기 다이설파이드 링커의 경우에는 세포 환원성 환경에서 절단 가능하도록 제작된 것으로서 리소좀에서 특이적으로 절단될 수 있다(Saito et al. (2013) Adv. Drug Deliv. 55 (2):199-215 참조).
본 발명에서 제공하는 융합 단백질의 일 예시는 상기 서열번호 1로 표시되는 Lrig-1 단백질의 세포 외 도메인; 서열번호 7 내지 10 중 어느 하나로 표시되는 힌지 영역; 서열번호 5로 표시되는 인간 IgG1 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함하는 융합 단백질일 수 있다(하기 표 6 참조). 하기 표 6의 서열번호 13 내지 16으로 표시되는 융합 단백질은 하기 표 7의 서열번호 17 내지 20으로 표시되는 핵산 서열에 의해 코딩될 수 있다(하기 표 7 참조).
Figure pat00008
Figure pat00009
Figure pat00010
Figure pat00011
Figure pat00012
Figure pat00013
Figure pat00014
Figure pat00015
Figure pat00016
Figure pat00017
본 발명에서 제공하는 융합 단백질의 일 예시는 상기 서열번호 3로 표시되는 Lrig-1 단백질의 세포 외 도메인; 서열번호 7 내지 10 중 어느 하나로 표시되는 힌지 영역; 서열번호 5로 표시되는 인간 IgG1 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함하는 융합 단백질일 수 있다(하기 표 8 참조). 하기 표 8의 서열번호 21 내지 24로 표시되는 융합 단백질은 각각 하기 표 9의 서열번호 25 내지 28으로 표시되는 핵산 서열에 의해 코딩될 수 있다(하기 표 9 참조).
Figure pat00018
Figure pat00019
Figure pat00020
Figure pat00021
Figure pat00022
Figure pat00023
Figure pat00024
Figure pat00025
Figure pat00026
Figure pat00027
본 발명에서 제공하는 융합 단백질의 다른 일 예시는 상기 서열번호 3으로 표시되는 Lrig-1 단백질의 세포 외 도메인; 서열번호 7 내지 10 중 어느 하나로 표시되는 힌지 영역; 서열번호 6으로 표시되는 마우스 IgG2 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함하는 융합 단백질일 수 있다(하기 표 10 참조). 하기 표 10의 서열번호 29 내지 32로 표시되는 융합 단백질은 각각 하기 표 11의 서열번호 33 내지 36으로 표시되는 핵산 서열에 의해 코딩될 수 있다(하기 표 11 참조).
Figure pat00028
Figure pat00029
Figure pat00030
Figure pat00031
Figure pat00032
Figure pat00033
Figure pat00034
Figure pat00035
Figure pat00036
Figure pat00037
본 발명에서 제공하는 융합 단백질의 또 다른 일 예시는 상기 서열번호 1로 표시되는 Lrig-1 단백질의 세포 외 도메인; 서열번호 11로 표시되는 링커; 서열번호 7 내지 10 중 어느 하나로 표시되는 힌지 영역; 서열번호 5로 표시되는 인간 IgG1 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함하는 융합 단백질일 수 있다(하기 표 12 참조). 하기 표 12의 서열번호 37 내지 40으로 표시되는 융합 단백질은 각각 하기 표 13의 서열번호 41 내지 44로 표시되는 핵산 서열에 의해 코딩될 수 있다(하기 표 13 참조).
Figure pat00038
Figure pat00039
Figure pat00040
Figure pat00041
Figure pat00042
Figure pat00043
Figure pat00044
Figure pat00045
Figure pat00046
Figure pat00047
Figure pat00048
본 발명에서 제공하는 융합 단백질의 또 다른 일 예시는 상기 서열번호 3으로 표시되는 Lrig-1 단백질의 세포 외 도메인; 서열번호 11로 표시되는 링커; 서열번호 7 내지 10 중 어느 하나로 표시되는 힌지 영역; 서열번호 5로 표시되는 인간 IgG1 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함하는 융합 단백질일 수 있다(하기 표 14 참조). 하기 표 14의 서열번호 45 내지 48로 표시되는 융합 단백질은 각각 하기 표 15의 서열번호 49 내지 52로 표시되는 핵산 서열에 의해 코딩될 수 있다(하기 표 15 참조).
Figure pat00049
Figure pat00050
Figure pat00051
Figure pat00052
Figure pat00053
Figure pat00054
Figure pat00055
Figure pat00056
Figure pat00057
Figure pat00058
Figure pat00059
Figure pat00060
본 발명에서 제공하는 융합 단백질의 또 다른 일 예시는 상기 서열번호 3으로 표시되는 Lrig-1 단백질의 세포 외 도메인; 서열번호 11로 표시되는 링커; 서열번호 7 내지 10 중 어느 하나로 표시되는 힌지 영역; 서열번호 6로 표시되는 마우스 IgG2 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함하는 융합 단백질일 수 있다(하기 표 16 참조). 하기 표 16의 서열번호 53 내지 56으로 표시되는 융합 단백질은 각각 하기 표 17의 서열번호 57 내지 60으로 표시되는 핵산 서열에 의해 코딩될 수 있다(하기 표 17 참조).
Figure pat00061
Figure pat00062
Figure pat00063
Figure pat00064
Figure pat00065
Figure pat00066
Figure pat00067
Figure pat00068
Figure pat00069
Figure pat00070
Figure pat00071
Figure pat00072
본 발명에서 제공하는 융합 단백질의 또 다른 일 예시는 상기 서열번호 1로 표시되는 Lrig-1 단백질의 세포 외 도메인; 서열번호 12로 표시되는 링커; 서열번호 11로 표시되는 링커; 서열번호 7 내지 10 중 어느 하나로 표시되는 힌지 영역; 서열번호 5로 표시되는 인간 IgG1 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함하는 융합 단백질일 수 있다(하기 표 18 참조). 하기 표 18의 서열번호 61 내지 64로 표시되는 융합 단백질은 하기 표 19의 서열번호 65 내지 68로 표시되는 핵산 서열에 의해 코딩될 수 있다(하기 표 19 참조).
Figure pat00073
Figure pat00074
Figure pat00075
Figure pat00076
Figure pat00077
Figure pat00078
Figure pat00079
Figure pat00080
Figure pat00081
Figure pat00082
Figure pat00083
Figure pat00084
본 발명에서 제공하는 융합 단백질의 또 다른 일 예시는 상기 서열번호 3으로 표시되는 Lrig-1 단백질의 세포 외 도메인; 서열번호 12로 표시되는 링커; 서열번호 11로 표시되는 링커; 서열번호 7 내지 10 중 어느 하나로 표시되는 힌지 영역; 서열번호 5로 표시되는 인간 IgG1 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함하는 융합 단백질일 수 있다(하기 표 20 참조). 하기 표 20의 서열번호 69 내지 72로 표시되는 융합 단백질은 각각 하기 표 21의 서열번호 73 내지 76으로 표시되는 핵산 서열에 의해 코딩될 수 있다(하기 표 21 참조).
Figure pat00085
Figure pat00086
Figure pat00087
Figure pat00088
Figure pat00089
Figure pat00090
Figure pat00091
Figure pat00092
Figure pat00093
Figure pat00094
Figure pat00095
Figure pat00096
본 발명에서 제공하는 융합 단백질의 또 다른 일 예시는 상기 서열번호 3으로 표시되는 Lrig-1 단백질의 세포 외 도메인; 서열번호 12로 표시되는 링커; 서열번호 11로 표시되는 링커; 서열번호 7 내지 10 중 어느 하나로 표시되는 힌지 영역; 서열번호 6으로 표시되는 마우스 IgG2 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3)을 포함하는 융합 단백질일 수 있다(하기 표 22 참조). 하기 표 22의 서열번호 77 내지 80로 표시되는 융합 단백질은 하기 표 23의 서열번호 81 내지 84로 표시되는 핵산 서열에 의해 코딩될 수 있다(하기 표 23 참조).
Figure pat00097
Figure pat00098
Figure pat00099
Figure pat00100
Figure pat00101
Figure pat00102
Figure pat00103
Figure pat00104
Figure pat00105
Figure pat00106
Figure pat00107
Figure pat00108
본 발명에서 제공하는 상기의 융합 단백질은 이펙터 T 세포(effector T cell)에 존재하는 Lrig-1 단백질에 대한 리간드와 상호 작용하여, Lrig-1 단백질을 표면에 포함하고 있는 조절 T 세포(regulatory T cell, Treg cell)와 이펙터 T 세포간의 상호 작용을 저해함에 따라 조절 T 세포의 활성을 억제하고 이펙터 T 세포의 활성은 유지 혹은 상승시켜 암 세포 중에서도 특히 고형암 세포의 성장을 효과적으로 억제할 수 있다.
본 발명의 다른 구현 예에 따르면, 본 발명에서 제공하는 상기 융합 단백질을 코딩하는 핵산 분자를 제공한다.
본 발명의 핵산 분자는 본 발명에서 제공하는 융합 단백질의 아미노산 서열을 당업자에게 알려진 바와 같이 폴리뉴클레오티드 서열로 번역된 핵산 분자 모두를 포함한다. 그러므로 ORF(open reading frame)에 의한 다양한 폴리뉴클레오티드 서열이 제조될 수 있으며 이 또한 모두 본 발명의 핵산 분자에 포함된다.
본 발명의 바람직한 일 예시로, 상기 핵산 분자는 서열번호 17 내지 20, 25 내지 28, 33 내지 36, 41 내지 44, 49 내지 52, 57 내지 60, 65 내지 68, 73 내지 76 및 81 내지 84 중 어느 하나로 표시될 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 상기 단리된 핵산 분자가 삽입된 발현 벡터를 제공한다.
본 발명에서 상기 "벡터"는 어떤 핵산 분자가 연결된 또 다른 핵산을 수송할 수 있는 상기 핵산 분자이다. 벡터의 한 가지 유형은, 추가적인 DNA 세그멘트가 결찰될 수 있는 원형 이중가닥 DNA를 가리키는 "플라스미드"이다. 또 다른 유형의 벡터는 파지 벡터이다. 또 다른 유형의 벡터는 바이러스성 벡터로, 추가적인 DNA 세그멘트가 바이러스 게놈에 결찰될 수 있다. 어떤 벡터들은 그들이 유입된 숙주세포에서 자율적인 복제를 할 수 있다(예컨대, 박테리아성 벡터는 박테리아성 복제 기원을 갖는 에피솜 포유류 벡터). 기타 벡터(예컨대, 비-에피솜 포유류 벡터)는 숙주세포에 유입되면서 숙주세포의 게놈에 통합될 수 있고, 그럼으로써, 숙주 게놈과 함께 복제된다. 뿐만 아니라, 어떤 벡터는 이들이 작동차원에서 연결된 유전자의 발현을 지시할 수 있다. 이와 같은 벡터는 본원에서 "재조합 발현 벡터" 또는 단순히 "발현 벡터"라 명명된다. 일반적으로 재조합 DNA 기법에서 유용한 발현 벡터는 종종 플라스미드의 형태로 존재한다. 본 명세서에서, "플라스미드"와 "벡터"는, 플라스미드가 벡터 중 가장 통상적으로 사용되는 형태이기 때문에, 상호 교환하여 사용될 수 있다.
본 발명에서 상기 발현 벡터의 구체적인 예시로는 상업적으로 널리 사용되는 pCDNA 벡터, F, R1, RP1, Col, pBR322, ToL, Ti 벡터; 코스미드; 람다, 람도이드(lambdoid), M13, Mu, p1 P22, Qμ, T-even, T2, T3, T7 등의 파아지; 식물 바이러스로 이루어진 군으로부터 선택될 수 있으나, 이에 제한되는 것은 아니며, 당업자에게 발현 벡터로 알려진 모든 발현 벡터는 본 발명에 사용 가능하고, 발현 벡터를 선택할 때에는 목적으로 하는 숙주 세포의 성질에 따른다. 숙주세포로의 벡터 도입 시 인산칼슘 트랜스펙션, 바이러스 감염, DEAE-덱스트란 조절 트랜스펙션, 리포펙타민 트랜스펙션 또는 전기천공법에 의해 수행될 수 있으나 이에 한정되는 것은 아니며 당업자는 사용하는 발현 벡터 및 숙주 세포에 알맞은 도입 방법을 선택하여 이용할 수 있다. 바람직하게 벡터는 하나 이상의 선별 마커를 함유하나 이에 한정되지 않으며, 선별 마커를 포함하지 않은 벡터를 이용하여 생산물 생산 여부에 따라 선별이 가능하다. 선별 마커의 선택은 목적하는 숙주 세포에 의해 선별되며, 이는 이미 당업자에게 알려진 방법을 이용하므로 본 발명은 이에 제한을 두지 않는다.
본 발명의 핵산 분자를 정제를 용이하게 하기 위하여 태그 서열을 발현 벡터 상에 삽입하여 융합시킬 수 있다. 상기 태그로는 헥사-히스티딘 태그, 헤마글루티닌 태그, myc 태그 또는 flag 태그를 포함하나 이에 한정되는 것은 아니며 당업자에게 알려진 정제를 용이하게 하는 태그는 모두 본 발명에서 이용 가능하다.
본 발명의 또 다른 구현 예에 다르면, 본 발명에서 제공하는 상기 발현 벡터가 형질 감염된 숙주 세포주를 제공한다.
본 발명에서 상기 "숙주 세포"에는 폴리펩타이드 삽입물의 편입을 위한 벡터(들)의 수령자(recipient)일 수 있거나 또는 수령자였던 개별적인 세포 또는 세포배양물이 포함된다. 숙주 세포에는 단일 숙주 세포의 자손이 포함되고, 상기 자손은 자연적인, 우발적인 또는 고의의 돌연변이 때문에 반드시 원래 모세포와 완전히 동일(형태학상 또는 게놈 DNA 보완체에서)하지 않을 수 있다. 숙주 세포에는 본원의 폴리펩타이드(들)로 체내에서 형질주입된 세포가 포함된다.
본 발명에 있어서, 상기 숙주 세포로는 포유동물, 식물, 곤충, 균류 또는 세포성 기원의 세포를 포함할 수 있고, 예를 들면 대장균, 스트렙토미세스, 살모넬라 티피뮤리움 등의 박테리아 세포; 효모 세포, 피치아 파스 토리스 등의 균류세포; 드로조필라, 스포도프테라 Sf9 세포 등의 곤충 세포; CHO(중국 햄스터 난소 세포, Chinese hamster ovary cells), SP2/0(생쥐 골수종), 인간 림프아구(Human lymphoblastoid), COS, NSO(생쥐 골 수종), 293T, 보우 멜라노마 세포, HT-1080, BHK(베이비 햄스터 신장세포, Baby Hamster Kidney cells), HEK(인간 배아신장 세포, Human Embryonic Kidney cells) 또는 PERC.6(인간 망막 세포)의 동물 세포; 또는 식물 세포일 수 있으나, 이에 제한되는 것은 아니며, 당업자에게 알려진 숙주 세포주로 사용 가능한 세포는 모두 이용 가능하다.
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 융합 단백질을 유효 성분으로 포함하는 암 또는 면역 관련 질환의 예방, 개선 또는 치료용 조성물을 제공한다.
본 발명의 상기 조성물은 약학 조성물; 식품 조성물; 또는 화장료 조성물로 사용될 수 있다.
본 발명에서 상기 "암" 포유류에서 전형적으로 조절되지 않는 세포 성장으로 특징 지어진 생리적 상태를 나타내거나 가리킨다. 본 발명에서 예방, 개선 또는 치료의 대상이 되는 암은 고형 장기(solid organ)에서 비정상적으로 세포가 성장하여 발생한 덩어리로 이루어진 고형암(solid tumor)일 수 있고, 고형 장기의 부위에 따라 위암, 간암, 교세포종, 난소암, 대장암, 두경부암, 방광암, 신장세포암, 유방암, 전이암, 전립선암, 췌장암, 흑색종 또는 폐암 등일 수 있으며, 바람직하게는 흑색종 또는 대장암일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 "면역 관련 질환"은 다양한 면역 세포, 예를 들면 이펙터 T 세포(effector T cell) 또는 독성 T 세포(cytotoxic T cell) 및 염증 세포들의 과도화된 활성화 및/또는 증식에 의하여 유도되는 질환으로서, 자가면역질환; 이식편대숙주 질환; 장기이식거부반응; 천식; 아토피; 또는 급성 또는 만성의 염증 질환 등일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 "자가면역질환"은 류마티스성 관절염, 제1형 당뇨, 전신성 경피증, 전신 홍반성 낭창, 전신홍반루프스, 아토피 피부염, 건선, 원형탈모증, 천식, 크론씨병, 베체시병, 쇼그렌 증후군, 길리아-바레 증후군, 만성 갑상선염, 다발성 경화증, 다발성 근염, 강직성 척추염, 섬유조직염 및 결절성 다발성 동맥염으로 구성된 군으로부터 선택되는 적어도 하나인 것일 수 있으나, 이에 제한되는 것은 아니다.
또한, 본 발명에서 상기 "자가면역질환"은 활성화된 T 세포가 신경을 구성하는 세포에 침투하여 염증을 유발하거나, 세포의 사멸을 유도하는 과정을 통해 발생된 것일 수 있고, 예를 들면 신경 퇴행성 질환 또는 신경 염증성 질환일 수 있다(Neuromolecular Med. 2005; 7 (3) : 255-64. 참고).
본 발명에서 상기 신경 퇴행성 질환 또는 신경 염증성 질환은 뇌졸중, 치매, 알츠하이머병(Alzheimer's disease), 파킨슨병(Parkinson's disease), 헌팅턴병(Huntington's disease), 니만-피크병(Niemann-Pick disease), 프리온병(prion disease), 크로이펠츠-야콥병(Creutzfeldt-Jakob disease), 전두측두치매, 루이치매, 근위축성 측삭경화증(AlzAmyotrophic lateral sclerosis), 부신생물증후군(Paraneoplastic syndrome), 피질기저퇴행증, 다계통위축병, 진행성핵상마비, 신경계 자가면역질환, 척수 소뇌 실조(spinocerebellar ataxia), 염증성 및 신경병증성 통증, 뇌혈관 질환, 척수 손상(spinal cord injury) 및 타우병증(tauopathy)으로 이루어진 군에서 선택될 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 면역관련질환, 예를 들면 자가면역질환의 경우, 건강한 대조군과 비교하여 질환이 유발된 환자에서 자가면역성 T 세포(예를 들면, 효과 T 세포 또는 독성 T 세포 등)가 높은 수준의 빈도로 존재하거나, 그 활성이 현저하게 증가되어 있음으로써, 과도한 면역반응을 유도하거나 특정 기관의 세포를 파괴함으로써 유도되는 것일 수 있다(Clinical & Experimental Immunology, 180: 353-360., Immunity, Vol. 17, 1-6, July, 2002., Ann Rheum Dis 2004;63(Suppl II): ⅱ 96 -ⅱ 101., Immunol Res. 2013 December ; 57(0): 12-22. 참고).
본 발명에서 상기 면역 관련 질환은 T 세포(예를 들면, 이펙터 T 세포 또는 독성 T 세포), 바람직하게는 자가반응성 T 세포의 활성화 및/또는 증식에 필수적인 세포 내 신호 전달 경로를 방해함으로써 예방, 개선 또는 치료될 수 있다(Ann Rheum Dis 2004;63(Suppl II): ⅱ 96 - ⅱ 101. 참고). 구체적으로, 본 발명에 따른 상기 융합 단백질은 이펙터 T 세포에 동시억제 시그널(co-inhibitory signal)을 유도하여 이펙터 T 세포의 증식 억제 및 활성화를 조절할 수 있다. 따라서, T 세포(예를 들면, 이펙터 T 세포 또는 독성 T 세포)의 과도한 활성화 및/또는 증식으로 인해 발생될 수 있는 다양한 면역 관련 질환을 효과적으로 예방, 개선 또는 치료할 수 있다.
한편, 본 발명에서, "예방"은 본 발명의 약학 조성물을 이용하여 질환의 증상을 차단하거나, 그 증상을 억제 또는 지연시키는 모든 행위라면 제한없이 포함할 수 있다.
또한, 본 발명에서, "치료"는 본 발명의 약학 조성물을 이용하여 질환의 증상이 호전되거나 이롭게 되는 모든 행위라면 제한없이 포함할 수 있다.
본 발명에서 상기 약학 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다.
본 발명에서 상기 약학 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사 용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 약학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 약학 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형화할 수 있다.
한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항 응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.
본 발명에 상기 약학 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다.
본 발명에서 상기 "비경구"란, 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.
본 발명의 상기 약학 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여 시간, 투여 경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약무 형태, 투여 경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50mg/kg 또는 0.001 내지 50mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 의약 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형화될 수 있다.
본 발명에서 상기 식품 조성물은 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다.
본 발명에서 상기 유효성분이 식품 조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 50%의 비율로 첨가할 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 식품 조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 포함하는 것 외에 특별한 제한점은 없으며, 통상의 음료와 같이 다양한 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 구체적으로, 천연 탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등) 등일 수 있다.
본 발명에서 상기 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 더 포함할 수 있다.
본 발명에서 상기 성분은 독립적 또는 조합하여 사용할 수 있다. 상기 첨가제의 비율은 본 발명의 핵심적인 요소에 해당하지 아니하지만, 본 발명의 식품 조성물 100 중량부 당 0.1 내지 약 50 중량부의 범위에서 선택될 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 화장료 조성물은 화장수, 영양로션, 영양에센스, 마사지 크림, 미용목욕물첨가제, 바디로션, 바디밀크, 배스오일, 베이비오일, 베이비파우더, 샤워겔, 샤워크림, 선스크린로션, 선스크린크림, 선탠크림, 스킨로션, 스킨크림, 자외선차단용 화장품, 클렌징밀크, 탈모제화장용, 페이스 및 바디로션, 페이스 및 바디크림, 피부미백크림, 핸드로션, 헤어로션, 화장용 크림, 쟈스민오일, 목욕비누, 물비누, 미용비누, 샴푸, 손세정제(핸드클리너), 약용비누비의료용, 크림비누, 페이셜 워시, 전신 세정제, 두피 세정제, 헤어린스, 화장비누, 치아 미백용 겔, 치약 등의 형태로 제조될 수 있다. 본 발명의 조성물은 화장료 조성물의 제조에 통상적으로 사용하는 용매나, 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다.
본 발명에서 상기 화장료 조성물 내에 더 추가될 수 있는 용매의 종류는 특별히 한정하지 않으나, 예를 들어, 물, 식염수, DMSO 또는 이들의 조합을 사용할 수 있다. 또한, 담체, 부형제 또는 희석제로는 정제수, 오일, 왁스, 지방산, 지방산 알콜, 지방산 에스테르, 계면활성제, 흡습제(humectant), 증점제, 항산화제, 점도 안정화제, 킬레이팅제, 완충제, 저급 알콜 등이 포함되지만, 이에 제한되는 것은 아니다. 또한, 필요에 따라 미백제, 보습제, 비타민, 자외선 차단제, 향수, 염료, 항생제, 항박테리아제, 항진균제를 포함할 수 있다.
본 발명에서 상기 오일로서는 수소화 식물성유, 피마자유, 면실유, 올리브유, 야자인유, 호호바유, 아보카도유가 이용될 수 있으며, 왁스로는 밀랍, 경랍, 카르나우바, 칸델릴라, 몬탄, 세레신, 액체 파라핀, 라놀린이 이용될 수 있다.
본 발명에서 상기 지방산으로는 스테아르산, 리놀레산, 리놀렌산, 올레산이 이용될 수 있고, 지방산 알콜로는 세틸 알콜, 옥틸 도데칸올, 올레일 알콜, 판텐올, 라놀린 알콜, 스테아릴 알콜, 헥사데칸올이 이용될 수 있으며 지방산 에스테르로는 이소프로필 미리스테이트, 이소프로필 팔미테이트, 부틸 스테아레이트가 이용될 수 있다. 계면 활성제로는 당업계에 알려진 양이온 계면활성제, 음이온 계면활성제 및 비 이온성 계면활성제가 사용가능하며 가능한 한 천연물 유래의 계면활성제가 바람직하다. 그 외에도 화장품 분야에서 널리 알려진 흡습제, 증점제, 항산화제 등을 포함할 수 있으며, 이들의 종류와 양은 당업계에 공지된 바에 따른다.
본 발명의 또 다른 구현 예에 따르면, 본 발명에 따른 융합 단백질 또는 이를 포함하는 조성물을 개체에 투여하는 단계를 포함하는 암의 예방 또는 치료 방법에 관한 것이다.
본 발명의 융합 단백질은 이펙터 T 세포(effector T cell)에 존재하는 Lrig-1 단백질에 대한 리간드와 상호 작용하여, Lrig-1 단백질을 표면에 포함하고 있는 조절 T 세포(Treg cell)와 이펙터 T 세포간의 상호 작용을 저해함에 따라 조절 T 세포의 활성을 억제하고 이펙터 T 세포의 활성은 유지 혹은 상승시켜 암 세포 중에서도 특히 고형암 세포의 성장을 효과적으로 억제할 수 있다.
본 발명에서 상기 "개체"는 암의 발병이 의심되는 개체로서, 상기 암 발병의 의심 개체는 해당 질환이 발병하였거나 발병할 수 있는 인간을 포함한 쥐, 가축 등을 포함하는 포유동물을 의미하나, 본 발명의 융합 단백질 또는 이를 포함하는 상기 조성물로 치료 가능한 개체는 제한 없이 포함된다.
본 발명의 방법은 융합 단백질 또는 이를 포함하는 조성물을 약학적 유효량으로 투여하는 것을 포함할 수 있다. 적합한 총 1일 사용량은 올바른 의학적 판단범위 내에서 처치의에 의해 결정될 수 있으며, 1회 또는 수회로 나누어 투여할 수 있다. 그러나 본 발명의 목적상, 특정 환자에 대한 구체적인 치료적 유효량은 달성하고자 하는 반응의 종류와 정도, 경우에 따라 다른 제제가 사용되는지의 여부를 비롯한 구체적 조성물, 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 구체적 조성물과 함께 사용되거나 동시 사용되는 약물을 비롯한 다양한 인자와 의약 분야에 잘 알려진 유사 인자에 따라 다르게 적용하는 것이 바람직하다.
한편, 이에 제한되지 않으나, 상기 암의 예방 또는 치료 방법은 하나 이상의 암 질환에 대한 치료적 활성을 가지는 화합물 또는 물질을 투여하는 것을 더 포함하는 병용 요법일 수 있다.
본 발명에서 상기 "병용"은 동시, 개별 또는 순차 투여를 나타내는 것으로 이해되어야 한다. 상기 투여가 순차 또는 개별적인 경우, 2차 성분 투여의 간격은 상기 병용의 이로운 효과를 잃지 않도록 하는 것이어야 한다.
본 발명에서 상기 융합 단백질의 투여 용량은 환자 체중 1 kg당 약 0.0001 μg 내지 500 mg일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 제공하는 융합 단백질은 이펙터 T 세포(effector T cell)에 존재하는 Lrig-1 단백질에 대한 리간드와 상호 작용하여, Lrig-1 단백질을 표면에 포함하고 있는 조절 T 세포(Treg cell)와 이펙터 T 세포간의 상호 작용을 저해함에 따라 조절 T 세포의 활성을 억제하고 이펙터 T 세포의 활성은 유지 혹은 상승시켜 암 세포 중에서도 특히 고형암 세포의 성장을 효과적으로 억제할 수 있다.
도 1은 본 발명의 일 실시예에 따른 Lrig-1 단백질의 구조를 나타낸 것이다.
도 2는 본 발명의 일 실시예에 따른 Lrig-1 단백질의 구조를 나타낸 것이다.
도 3은 본 발명의 일 실시예에 따른 Lrig-1 단백질의 항원 결정기(epitope)를 예측한 결과를 나타낸 것이다.
도 4는 본 발명의 일 실시예에 따른 Lrig-1 단백질의 항원 결정기(epitope)를 예측한 결과를 나타낸 것이다.
도 5는 본 발명의 일 실시예에 따른 Lrig-1 mRNA의 발현 정도를 나타낸 것이다.
도 6은 본 발명의 일 실시예에 따른 Lrig-1 mRNA의 발현 정도를 나타낸 것이다.
도 7은 본 발명의 일 실시예에 따른 Lrig-1 mRNA의 발현 정도를 나타낸 것이다.
도 8은 본 발명의 일 실시예에 따른 Lrig-1, Lrig-2 및 Lrig-3 mRNA의 발현 정도를 나타낸 것이다.
도 9는 본 발명의 일 실시예에 따른 조절 T 세포와 비-조절 T 세포 내 Lrig-1 단백질의 발현량 비교 결과를 나타낸 것이다.
도 10은 본 발명의 일 실시예에 따른 조절 T 세포의 표면에 Lrig-1 단백질의 발현을 나타낸 것이다.
도 11은 본 발명의 일 실시예에 따른 융합 단백질의 이펙터 T 세포에 대한 조절 T 세포의 억제능을 저해하는 효과를 나타낸 것이다.
도 12는 본 발명의 일 실시예에 따른 융합 단백질에 의해 인식되는 리간드가 존재하는 T 세포 서브세트(subset)를 나타낸 것이다.
도 13은 본 발명의 일 실시예에 따른 융합 단백질을 이용한 암 치료 실험의 설계도를 나타낸 것이다.
도 14은 본 발명의 일 실시예에 따른 융합 단백질을 이용한 암 치료 효과를 분석한 결과를 나타낸 것이다.
도 15는 본 발명의 일 실시예에 따른 융합 단백질을 이용한 암 치료 효과를 분석한 결과를 나타낸 것이다.
도 16 및 도 17은 본 발명의 일 실시예에 따른 융합 단백질의 활성화된 T 세포에서 본 발명에 따른 융합 단백질에 의한 증식 억제 효과를 확인한 결과를 나타낸 것이다.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.
실시예
[ 준비예 1] T 세포 아형 세포 배양
조절 T 세포(Treg)에서만 Lrig-1 단백질이 발현되는지 확인하기 위하여, T 세포의 아형(subset)인 Th0, Th1, Th2, Th17 및 iTreg을 준비하였다. 상기 iTreg은 자연적으로 분리한 nTreg과는 달리 하기 조성을 포함하는 배지에서 분화를 인공적으로 유도한 세포를 의미한다.
T 세포의 아형은 우선, 쥐의 비장으로부터 얻은 나이브(naive) T 세포를 분리한 뒤, 우태아혈청(FBS; hyclone, logan, UT) 10%를 포함하는 RPMI1640(Invitrogen Gibco, Grand Island, NY) 영양배지에 하기 표 24의 성분을 각각 더 포함하도록 하여, 37℃, 5 % CO2 배양기 내에서 72시간 배양을 통해 각각의 세포로 분화 유도하였다.
Figure pat00109
[실시예 1] Lrig-1 구조 분석
조절 T 세포의 표면 단백질인 Lrig-1 단백질의 세포 외 도메인을 포함하는 융합 단백질을 제작하기 위하여 Lrig-1 단백질의 세포 외 도메인의 3차원 입체 구조를 예측하였다.
우선, 항원 결정기(Epitope) 염기서열 예측을 위해 Lrig-1 단백질의 세포 외 도메인(Extracellular domain; ECD)의 구조를 확인하기 위하여 Uniprot(http://www.uniprot.org)과 RCSB Protein Data Bank (http://www.rcsb.org/pdb) 툴을 이용하여 3차원 입체 구조를 예측한 뒤, 그 결과를 도 1 및 2에 나타내었다.
도 1에서 보는 바와 같이, Lrig-1 단백질의 세포 외 도메인 중 Lrig-LRR 도메인(아미노산 서열 41 ~ 494번) 내에는 LRR1 내지 LRR15의 총 15개의 류신 리치 부위(Leucine rich region)가 존재하였다. 상기 LRR 도메인 각각은 23 내지 27개의 아미노산으로 구성되고, 류신은 3 내지 5개가 존재하였다.
또한, 도 2에서 보는 바와 같이, Lrig-1 단백질의 세포외 도메인 중 Lrig-1 단백질의 아미노산 서열 494 내지 781번에는 면역글로불린 유사 도메인(Immunoglobulin-like domain)이 3개 존재하였다.
[실시예 2] Lrig-1 항원 결정기(epitope) 아미노산 서열 예측
상기 염기서열의 예측은 Lrig-1 단백질의 구조를 기반으로 하는 항원 결정기 예측 소프트웨어(epitope prediction software)인 Ellipro 서버(http://tools.iedb.org/ellipro/)를 이용하였다. 상기 Ellipro 검색 엔진은 현존하는 항원 결정기를 예측하는 알고리즘 중에서 가장 신뢰도가 높다고 알려진 검색엔진에 해당하여 이를 이용하였다.
항원 결정기 예측 소프트웨어에 상기 실시예 1에서 분석된 세포외 도메인을 입력한 뒤, 예측된 항원 결정기의 예측된 연속 또는 불연속 아미노산 서열을 도 3 및 4에 나타내었다.
도 3 및 4에서 보는 바와 같이, 연속된 항원 결정기 아미노산 서열은 총 22개가 예측되었고, 불연속된 항원 결정기 아미노산 서열은 총 8개가 예측되었다.
[실시예 3] Lrig-1 mRNA의 조절 T 세포에서의 특이적 발현 확인
Lrig-1 단백질이 조절 T 세포에 특이적인 바이오마커(biomarker)로 작용할 수 있는지 검증하였다.
상기 검증을 위하여, 쥐의 비장으로부터 CD4 비드를 통해 자석 활성 세포 분류기(magnet-activated cell sorting; MACS)를 이용하여 CD4+ T 세포를 분리하였다. 이후, CD25 항체를 이용하여 형광 활성 세포 분류기(FACS)를 이용해 조절 T (CD4+CD25+ T) 세포 및 비 조절 T (CD4+CD25- T) 세포를 분리하였다. 각각의 세포 및 상기 준비예 1에서 분화된 세포는 트리졸(Trizol)을 이용하여 전체 mRNA를 추출한 뒤, 게노믹 RNA는 gDNA 추출 키트(Qiagen)를 이용하여 업체에서 제공한 프로토콜에 의해 gDNA를 제거하였다. gDNA가 제거된 mRNA는 BDsprint cDNA 합성 키트 (Clonetech)를 통해 cDNA로 합성하였다.
상기 cDNA에서 Lrig-1 mRNA의 발현량을 정량적으로 확인하기 위하여 실시간 중합효소연쇄반응(real time PCR)을 수행하였다.
상기 실시간 중합효소연쇄반응은 SYBR Green (Molecular Probes)을 이용하여 업체에서 제공한 프로토콜에 의해 95℃에서 3분, 61℃에서 15초, 72℃에서 30초씩 40 사이클의 조건으로, 하기 표 25의 프라이머를 이용하여 수행하였고, 상대적인 유전자 발현량은 ΔCT 방법을 이용하여 계산하였으며, HPRT를 이용하여 일반화(normalization) 하여, 그 결과를 도 5 내지 8에 나타내었다.
Figure pat00110
도 5에서 보는 바와 같이, 비-조절 T 세포(CD4+CD25- T cell)에 비하여 조절 T 세포(CD4+CD25+ T cell)에서 Lrig-1의 발현이 18.1배 높은 것을 알 수 있다. 이는, 기존에 알려져 있는 조절 T 세포의 마커인 Lag3 및 Ikzf4와 비교하였을 때 약 10배 정도 발현양이 높은 수준이었다.
또한, 도 6 및 7에서 보는 바와 같이, 다른 종류의 면역 세포에 비하여 조절 T 세포, 특히 유도된 조절 T 세포(iTreg)에 비해 자연적으로 분리한 조절 T 세포(nTreg)에서 Lrig-1 mRNA의 발현이 현저하게 높았다.
또한, 도 8에서 보는 바와 같이, Lrig 패밀리에 해당하는 Lrig-1, Lrig-2 및 Lrig-3 중에서 Lrig-1의 발현이 가장 높았다.
상기 결과를 통해 본 발명에 따른 Lrig-1 단백질은 조절 T 세포, 특히 자연적으로 존재하는 조절 T 세포에서 특이적으로 발현하는 것을 알 수 있다.
[실시예 4] Lrig-1 단백질의 조절 T 세포에서의 특이적 발현 확인
Lrig-1 mRNA로부터 발현된 Lrig-1 단백질이 조절 T 세포에서만 특이적으로 발현되는지 확인하였다.
조절 T 세포 특이적인 전사 인자인 FOXP3 프로모터에 RFP(Red fluorescence protein)이 결합된 FOXP3-RFP 주입(Knock-in) 쥐를 이용하여, 상기 쥐의 비장으로부터 CD4 비드로 자석 활성 세포 분류기(magnet-activated cell sorting; MACS)를 이용하여 CD4+ T 세포를 분리하였다. 이후, RFP 단백질을 이용하여, 형광 활성 세포 분류기(FACS)를 통해 조절 T 세포(CD4+RFP+ T cell) 및 비-조절 T 세포(CD4+RFP- T cell)를 분리하여 얻었다. 각각의 상기 세포는 구입한 Lrig-1 항체 및 음성 대조군은 아이소타입(isotype)을 통해 염색하여 형광 활성 세포 분류기로 Lrig-1 단백질의 발현량을 측정하여, 그 결과를 도 9에 나타내었다.
도 9에서 보는 바와 같이, 점선으로 표시되는 비-조절 T 세포의 경우 음성 대조군과 거의 동일한 Lrig-1 단백질의 발현 수준을 보였지만, 조절 T 세포의 경우 Lrig-1 단백질의 발현 수준이 높은 세포가 다수 존재하였다.
상기 결과를 통해 본 발명에 따른 Lrig-1 단백질은 조절 T 세포에서 특이적으로 발현하는 것을 알 수 있다.
[실시예 5] 조절 T 세포 표면에서의 Lrig-1 단백질 특이적 발현 확인
Lrig-1 단백질이 세포 치료의 타겟이 되기 위해서는 조절 T 세포의 표면에서 발현되어야 더욱 효과적으로 타겟 치료를 할 수 있으므로, Lrig-1 단백질이 표면에서의 발현 여부를 확인하였다.
상기 준비예 1의 각각의 분화된 T 세포 아형을 항-CD4-APC 및 항 Lrig-1-PE 항체로 염색하고, 형광 이용 세포 분류기(Fluorescence-Activated Cell Sorter; FACS)를 이용하여 각각의 세포 표면에서 Lrig-1 단백질의 발현량을 측정하여, 그 결과를 도 10에 나타내었다.
도 10에서 보는 바와 같이, 활성화된 T 세포(activated T cell), Th1 세포, Th2 세포, Th17 세포 및 나이브(Naive) T 세포에서는 Lrig-1의 발현이 0.77 내지 15.3의 양으로 발현되는 반면, 분화가 유도된 T 세포(iTreg)에서는 83.9로 높게 발현되었다.
상기 결과를 통해 본 발명에 따른 Lrig-1 단백질은 조절 T 세포(Treg) 세포에서 특이적으로 발현될 뿐만 아니라, 특히 상기 조절 T 세포의 표면에서 더욱 높게 발현되는 것을 알 수 있다.
[제조예] 융합 단백질의 제작
1. 발현 벡터의 제작
본 발명에 따른 융합 단백질을 제조하기 위하여, 하기 표 26의 각각의 융합 단백질을 코딩하는 각 핵산 서열을 합성하였다. 핵산 서열의 5' 말단과 3' 말단에 각각 NheI과 EcoRI 제한효소 서열을 첨가하였고, 5' 말단의 제한효소 서열 뒤에 코작 서열(Kozak's sequence)(GCCACC)과, 단백질 번역을 위한 시작 코돈과 발현된 단백질을 세포 밖으로 분비하게 하는 마우스 IgG 카파 경쇄 시그널 펩타이드(Mouse kappa light chain signal peptide)(ATGGAAACCGATACTCTGCTGCTGTGGGTGCTGCTGCTGTGGGTGCCAGGCTCTACCGGG)를 삽입하였다. 이후 하기 표 26의 각각의 융합 단백질을 코딩하는 핵산 서열로, 인간 유래 Lrig-1 단백질의 세포 외 도메인; 선택적으로 링커; 힌지 영역; 인간 IgG1 유래의 중쇄 불변영역 2(CH2) 및 중쇄 불변영역 3(CH3);을 코딩화하는 핵산 서열 뒤에는 종결 코돈을 삽입하였다. NheI 과 EcoRI 두 제한효소 서열을 이용하여 본 발명의 융합 단백질을 코딩하는 핵산 서열을 pcDNA3.1(+) 발현 벡터에 클로닝하였다.
Figure pat00111
2. 융합 단백질의 정제
293F 세포에 폴리에틸렌이민(Polyethylenimine)을 이용하여 상기 1.에서 제작한 발현 벡터를 형질 전환시킨 뒤 37 ℃ 및 8% CO2 조건 하에서 6일 동안 배양하였다. 배양 상청액을 여과한 뒤 단백질 A 레진(Protein A resin)에 흘려준 후 1X PBS 로 세척하였다. pH 3.5의 0.1M 글리신(glycine) 용액을 이용하여 용출한 뒤 얻어진 용액에 pH 9.0의 1M TRIS 용액을 첨가하여 pH 중화하였다. 이후 용액을 투석하여 PBS 용액 상태로 만든 후 농축하여 사용하였다.
[ 실시예 6] 본 발명에 따른 융합 단백질에 의한, 조절 T 세포의 이펙터 T 세포에 대한 억제능(suppression activity) 저해 효과
상기 제조예 5에서 제작된 본 발명에 따른 서열번호 21로 표시되는 융합 단백질(서열번호 25로 표시되는 핵산 서열을 이용한 제작)이 Lrig-1 단백질에 대한 리간드(ligand)와 결합하여, 상기 리간드와 조절 T 세포 사이의 상호 작용을 저해함에 따라 최종적으로 조절 T 세포의 이펙터 T 세포에 대한 증식 억제능을 감소시키는지 확인하기 위하여 하기의 실험을 수행하였다. 구체적으로는, 조절 T 세포와 이펙터 T 세포를 공동 배양(coculture)하는 조건에서 상기 제조예 5의 융합 단백질을 첨가하여, 조절 T 세포의 이펙터 T 세포에 대한 증식 억제능의 변화를 확인하였다. 그 결과는 도 11에 나타내었다.
도 11에서 보는 바와 같이, 본 발명에 따른 융합 단백질을 처리하자 이펙터 T 세포에 대한 조절 T 세포의 증식 억제능이 저하된 것을 확인할 수 있었다.
이를 통하여 본 발명에 따른 융합 단백질은 Lrig-1 단백질에 대한 리간드와 상호 작용하여, Lrig-1 단백질을 표면에 포함하고 있는 조절 T 세포와 상기 리간드 사이의 상호 작용을 저해함에 따라 조절 T 세포의 활성을 억제하고 이펙터 T 세포의 활성은 유지 혹은 상승시키는 것을 알 수 있었다.
[ 실시예 7] 본 발명에 따른 융합 단백질에 의해 인식되는 Lrig -1 단백질의 리간드 분포 확인
상기 실시예 6에서 보는 바와 같이, 상기 제조예 5에서 제작된 본 발명에 따른 서열번호 21로 표시되는 융합 단백질(서열번호 25로 표시되는 핵산 서열을 이용한 제작)은 Lrig-1 단백질의 리간드를 인식할 수 있는 것을 알 수 있으므로, 상기 Lrig-1 단백질의 리간드가 존재하는 면역 세포들을 발굴하기 위하여, 조절 T 세포의 타겟으로 생각되는 나이브 T 세포(naive T cell)로부터, 활성화된 T 세포, Th1 세포, Th2 세포 또는 Th17 세포로 분화를 유도시킨 뒤 이들 세포를 상기 제조예 5의 융합 단백질(1차 항체) 및 항-인간-PE 항체(2차 항체)로 염색(staining) 하였다. 형광 이용 세포 분류기(Fluorescence-Activated Cell Sorter; FACS)를 이용하여 각각의 세포 표면에서 상기 융합 단백질의 발현량을 측정하여, 그 결과를 도 12에 나타내었다.
도 12에서 보는 바와 같이, 본 발명에 따른 융합 단백질은 나이브 T 세포의 표면에 있는 항원(antigen)은 거의 염색시키지 않았고(0.71%), 활성화된 T 세포, Th1 세포, Th2 세포 및 Th17 세포의 표면에 있는 항원은 96% 이상을 염색시켰다.
이를 통하여 Lrig-1 단백질의 리간드는 T 세포 리셉터(receptor)의 자극에 의하여 유도되는 표면 단백질인 것을 알 수 있었다.
[실시예 8] 본 발명에 따른 융합 단백질의 암 치료 효과
상기 제조예 5에서 제작된 본 발명에 따른 서열번호 21로 표시되는 융합 단백질(서열번호 25로 표시되는 핵산 서열을 이용한 제작)의 고형암에 대한 치료 효과를 확인하기 위하여, 도 13에서 보는 바와 같이, B16F10 흑색종 세포(melanoma cell)를 마우스 등에 3X105 세포의 양으로 피하 주사(subcutaneous injection)한 뒤, 4일, 8일, 12일 째에 상기 제조예 5의 융합 단백질을 200 ug의 양으로 복강 내 주사하였다. 상기 멜라노마 세포 이식 후 시간의 경과에 따른 종양의 부피 변화를 측정하여 그 결과를 도 14에 나타내었다.
도 14에서 보는 바와 같이, 본 발명에 따른 융합 단백질을 처리한 경우 아무런 처리하지 않은 음성 대조군에 비하여 흑색종 종양의 크기가 현저히 감소한 것을 확인할 수 있었다.
[실시예 9] 본 발명에 따른 융합 단백질의 암 치료 효과
상기 제조예 34에서 제작된 본 발명에 따른 서열번호 78로 표시되는 융합 단백질(서열번호 82로 표시되는 핵산 서열을 이용한 제작)의 고형암에 대한 치료 효과를 확인하기 위하여, CT-26 대장암 세포를 마우스 등에 3X105 세포의 양으로 피하 주사(subcutaneous injection)한 뒤, 4일, 8일, 12일 째에 상기 제조예 34의 융합 단백질을 200 ug의 양으로 복강 내 주사하였다. 상기 대장암 세포 이식 후 시간의 경과에 따른 종양의 부피 변화를 측정하여 그 결과를 도 15에 나타내었다.
도 15에서 보는 바와 같이, 본 발명에 따른 융합 단백질을 처리한 경우 아무런 처리하지 않은 음성 대조군에 비하여 대장암 종양의 크기가 현저히 감소한 것을 확인할 수 있었다.
이를 통하여, 본 발명에 따른 Lrig-1 단백질의 세포 외 도메인 및 면역글로불린 Fc 영역을 포함하는 융합 단백질은 조절 T 세포와 이펙터 T 세포간의 상호 작용을 저해함에 따라 조절 T 세포의 활성을 억제하고 이펙터 T 세포의 활성은 유지 혹은 상승시켜 암 세포 중에서도 특히 고형암 세포의 성장을 효과적으로 억제할 수 있는 것을 알 수 있다.
[실시예 10] 본 발명에 따른 융합 단백질의 면역 관련 질환의 치료 효과
8주령 C57BL/6 마우스의 비장으로부터 나이브 T 세포인 CD4+ CD62L+ T 세포를 분리한 다음, 플레이트(plate)에 고정화(immobilized)된 항-CD3/항-CD28 mAb를 이용하여 상기 나이브 T 세포를 활성화시킨 후, 상기 활성화된 T 세포를 96웰 플레이트에 분주하였다. 그런 다음, 상기 96웰 플레이트에 1 ㎍/ml의 항-CD3 mAb와, 1 ㎍/ml, 5 ㎍/ml 또는 10 ㎍/ml의 농도에 해당하는 제조예 5의 융합 단백질을 처리한 뒤, CSFE를 이용하여 염색한 뒤 FACS로 관찰하는 방식으로 세포의 증식 정도를 분석하여, 그 결과를 도 16 및 도 17에 나타내었다. 이때 대조군으로는 제조예 5의 융합 단백질을 대신하여 항-FLAG 항체를 사용하였다.
도 16 및 도 17에서 보는 바와 같이, 대조군(control) 및 CD3 단독으로 처리된 경우에는 활성화된 T 세포의 증식 억제 정도가 최대 7.87% 또는 9.82%에 해당한 반면, Lrig-1-IgG(mL1-hFc)를 처리한 경우에는 5㎍/ml의 농도에서는 18.17%, 10㎍/ml의 농도에서는 47.60%의 활성화된 T 세포 증식이 억제되는 것을 확인하였다(도 16 및 도 17).
이를 통하여, 본 발명에 따른 융합 단백질이 처리되었을 때, 활성화된 T 세포에 공동 억제 신호(co-inhibitory signal)가 발생되어 T 세포의 활성화가 현저히 저해될 수 있고, 이를 통해 활성화된 T 세포에 의해 발생되는 면역 관련 질환의 예방, 개선 또는 치료에 매우 효과적으로 적용될 수 있다.
이상에서 본 발명에 대하여 상세하게 설명하였지만 본 발명의 권리범위는 이에 한정되는 것은 아니고, 청구범위에 기재된 본 발명의 기술적 사상을 벗어나지 않는 범위 내에서 다양한 수정 및 변형이 가능하다는 것은 당 기술분야의 통상의 지식을 가진 자에게는 자명할 것이다.
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Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile 180 185 190 Glu Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu 195 200 205 Gln Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu 210 215 220 Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val 225 230 235 240 Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu 245 250 255 Ser Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys 260 265 270 Gln Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu 275 280 285 Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu 290 295 300 Ser His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu 305 310 315 320 Arg Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr 325 330 335 Ile Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys 340 345 350 Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe 355 360 365 Ser Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile 370 375 380 Arg Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu 385 390 395 400 Leu His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp 405 410 415 Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala 420 425 430 Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val 435 440 445 Pro Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile 450 455 460 Thr Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe 465 470 475 480 Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp 485 490 495 Lys Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val 500 505 510 His Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu 515 520 525 His Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val 530 535 540 Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr 545 550 555 560 Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile 565 570 575 Arg Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro 580 585 590 Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala 595 600 605 Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe 610 615 620 Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala 625 630 635 640 Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu 645 650 655 Glu Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val 660 665 670 Gly Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro 675 680 685 Arg Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg 690 695 700 His His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val 705 710 715 720 Ala Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly 725 730 735 Thr Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys 740 745 750 Arg Lys Asp Gly Thr Thr Val Gly Ile Phe 755 760 <210> 2 <211> 2286 <212> DNA <213> Homo sapiens <400> 2 gctgggcctc gggctccttg tgctgccgcc tgcacatgtg caggcgattc cctggactgc 60 ggcggcagag gcctggccgc cctgcctggc gatctgccat cctggacccg gagcctgaac 120 ctgagctaca acaagctgag cgagatcgat cccgccggct ttgaggacct gcctaacctg 180 caggaggtgt atctgaacaa taacgagctg accgcggtac catccctggg cgctgcttca 240 tcacatgtcg tctctctctt tctgcagcac aacaagattc gcagcgtgga ggggagccag 300 ctgaaggcct acctttcctt agaagtgtta gatctgagtt tgaacaacat cacggaagtg 360 cggaacacct gctttccaca cggaccgcct ataaaggagc tcaacctggc aggcaatcgg 420 attggcaccc tggagttggg agcatttgat ggtctgtcac ggtcgctgct aactcttcgc 480 ctgagcaaaa acaggatcac ccagcttcct gtaagagcat tcaagctacc caggctgaca 540 caactggacc tcaatcggaa caggattcgg ctgatagagg gcctcacctt ccaggggctc 600 aacagcttgg aggtgctgaa gcttcagcga aacaacatca gcaaactgac agatggggcc 660 ttctggggac tgtccaagat gcatgtgctg cacctggagt acaacagcct ggtagaagtg 720 aacagcggct cgctctacgg cctcacggcc ctgcatcagc tccacctcag caacaattcc 780 atcgctcgca ttcaccgcaa gggctggagc ttctgccaga agctgcatga gttggtcctg 840 tccttcaaca acctgacacg gctggacgag gagagcctgg ccgagctgag cagcctgagt 900 gtcctgcgtc tcagccacaa ttccatcagc cacattgcgg agggtgcctt caagggactc 960 aggagcctgc gagtcttgga tctggaccat aacgagattt cgggcacaat agaggacacg 1020 agcggcgcct tctcagggct cgacagcctc agcaagctga ctctgtttgg aaacaagatc 1080 aagtctgtgg ctaagagagc attctcgggg ctggaaggcc tggagcacct gaaccttgga 1140 gggaatgcga tcagatctgt ccagtttgat gcctttgtga agatgaagaa tcttaaagag 1200 ctccatatca gcagcgacag cttcctgtgt gactgccagc tgaagtggct gcccccgtgg 1260 ctaattggca ggatgctgca ggcctttgtg acagccacct gtgcccaccc agaatcactg 1320 aagggtcaga gcattttctc tgtgccacca gagagtttcg tgtgcgatga cttcctgaag 1380 ccacagatca tcacccagcc agaaaccacc atggctatgg tgggcaagga catccggttt 1440 acatgctcag cagccagcag cagcagctcc cccatgacct ttgcctggaa gaaagacaat 1500 gaagtcctga ccaatgcaga catggagaac tttgtccacg tccacgcgca ggacggggaa 1560 gtgatggagt acaccaccat cctgcacctc cgtcaggtca ctttcgggca cgagggccgc 1620 taccaatgtg tcatcaccaa ccactttggc tccacctatt cacataaggc caggctcacc 1680 gtgaatgtgt tgccatcatt caccaaaacg ccccacgaca taaccatccg gaccaccacc 1740 gtggcccgcc tcgaatgtgc tgccacaggt cacccaaacc ctcagattgc ctggcagaag 1800 gatggaggca cggatttccc cgctgcccgt gagcgacgca tgcatgtcat gccggatgac 1860 gacgtgtttt tcatcactga tgtgaaaata gatgacgcag gggtttacag ctgtactgct 1920 cagaactcag ccggttctat ttcagctaat gccaccctga ctgtcctaga gaccccatcc 1980 ttggtggtcc ccttggaaga ccgtgtggta tctgtgggag aaacagtggc cctccaatgc 2040 aaagccacgg ggaaccctcc gccccgcatc acctggttca agggggaccg cccgctgagc 2100 ctcactgagc ggcaccacct gacccctgac aaccagctcc tggtggttca gaacgtggtg 2160 gcagaggatg cgggccgata tacctgtgag atgtccaaca ccctgggcac ggagcgagct 2220 cacagccagc tgagcgtcct gcccgcagca ggctgcagga aggatgggac cacggtaggc 2280 atcttc 2286 <210> 3 <211> 760 <212> PRT <213> Mus musculus <400> 3 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr 755 760 <210> 4 <211> 2280 <212> DNA <213> Mus musculus <400> 4 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 2280 <210> 5 <211> 206 <212> PRT <213> Homo sapiens <400> 5 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 1 5 10 15 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 20 25 30 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 35 40 45 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 50 55 60 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 65 70 75 80 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 85 90 95 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 100 105 110 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 115 120 125 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 130 135 140 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 145 150 155 160 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 165 170 175 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 180 185 190 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 195 200 205 <210> 6 <211> 206 <212> PRT <213> Mus musculus <400> 6 Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro 1 5 10 15 Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val 20 25 30 Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr 35 40 45 Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala 50 55 60 Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys 65 70 75 80 Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser 85 90 95 Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro 100 105 110 Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val 115 120 125 Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly 130 135 140 Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp 145 150 155 160 Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp 165 170 175 Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His 180 185 190 Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 195 200 205 <210> 7 <211> 26 <212> PRT <213> Homo sapiens <400> 7 Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Cys Pro Ala 1 5 10 15 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 20 25 <210> 8 <211> 27 <212> PRT <213> Mus musculus <400> 8 Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 1 5 10 15 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe 20 25 <210> 9 <211> 39 <212> PRT <213> Homo sapiens <400> 9 Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys 1 5 10 15 Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His 20 25 30 Thr Gln Pro Leu Gly Val Phe 35 <210> 10 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> Abatacept hinge <400> 10 Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala 1 5 10 15 Pro Glu Leu Leu Gly Gly Ser Ser Val Phe 20 25 <210> 11 <211> 2 <212> PRT <213> Artificial Sequence <220> <223> peptide linker <400> 11 Gly Ser 111 <210> 12 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> peptide linker <400> 12 Gly Gly Gly 1 <210> 13 <211> 994 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 13 Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp 1 5 10 15 Ser Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu 20 25 30 Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu 35 40 45 Ile Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr 50 55 60 Leu Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser 65 70 75 80 Ser His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val 85 90 95 Glu Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu 100 105 110 Ser Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly 115 120 125 Pro Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu 130 135 140 Glu Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg 145 150 155 160 Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu 165 170 175 Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile 180 185 190 Glu Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu 195 200 205 Gln Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu 210 215 220 Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val 225 230 235 240 Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu 245 250 255 Ser Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys 260 265 270 Gln Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu 275 280 285 Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu 290 295 300 Ser His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu 305 310 315 320 Arg Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr 325 330 335 Ile Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys 340 345 350 Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe 355 360 365 Ser Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile 370 375 380 Arg Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu 385 390 395 400 Leu His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp 405 410 415 Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala 420 425 430 Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val 435 440 445 Pro Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile 450 455 460 Thr Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe 465 470 475 480 Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp 485 490 495 Lys Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val 500 505 510 His Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu 515 520 525 His Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val 530 535 540 Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr 545 550 555 560 Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile 565 570 575 Arg Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro 580 585 590 Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala 595 600 605 Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe 610 615 620 Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala 625 630 635 640 Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu 645 650 655 Glu Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val 660 665 670 Gly Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro 675 680 685 Arg Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg 690 695 700 His His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val 705 710 715 720 Ala Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly 725 730 735 Thr Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys 740 745 750 Arg Lys Asp Gly Thr Thr Val Gly Ile Phe Glu Pro Lys Ser Ser Asp 755 760 765 Lys Thr His Thr Ser Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 770 775 780 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 785 790 795 800 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 805 810 815 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 820 825 830 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 835 840 845 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 850 855 860 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 865 870 875 880 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 885 890 895 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 900 905 910 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 915 920 925 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 930 935 940 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 945 950 955 960 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 965 970 975 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 980 985 990 Gly Lys <210> 14 <211> 995 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 14 Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp 1 5 10 15 Ser Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu 20 25 30 Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu 35 40 45 Ile Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr 50 55 60 Leu Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser 65 70 75 80 Ser His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val 85 90 95 Glu Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu 100 105 110 Ser Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly 115 120 125 Pro Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu 130 135 140 Glu Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg 145 150 155 160 Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu 165 170 175 Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile 180 185 190 Glu Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu 195 200 205 Gln Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu 210 215 220 Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val 225 230 235 240 Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu 245 250 255 Ser Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys 260 265 270 Gln Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu 275 280 285 Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu 290 295 300 Ser His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu 305 310 315 320 Arg Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr 325 330 335 Ile Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys 340 345 350 Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe 355 360 365 Ser Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile 370 375 380 Arg Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu 385 390 395 400 Leu His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp 405 410 415 Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala 420 425 430 Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val 435 440 445 Pro Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile 450 455 460 Thr Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe 465 470 475 480 Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp 485 490 495 Lys Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val 500 505 510 His Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu 515 520 525 His Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val 530 535 540 Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr 545 550 555 560 Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile 565 570 575 Arg Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro 580 585 590 Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala 595 600 605 Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe 610 615 620 Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala 625 630 635 640 Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu 645 650 655 Glu Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val 660 665 670 Gly Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro 675 680 685 Arg Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg 690 695 700 His His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val 705 710 715 720 Ala Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly 725 730 735 Thr Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys 740 745 750 Arg Lys Asp Gly Thr Thr Val Gly Ile Phe Glu Pro Arg Gly Pro Thr 755 760 765 Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly 770 775 780 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 785 790 795 800 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 805 810 815 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 820 825 830 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 835 840 845 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 850 855 860 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 865 870 875 880 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 885 890 895 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 900 905 910 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 915 920 925 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 930 935 940 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 945 950 955 960 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 965 970 975 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 980 985 990 Pro Gly Lys 995 <210> 15 <211> 1007 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 15 Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp 1 5 10 15 Ser Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu 20 25 30 Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu 35 40 45 Ile Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr 50 55 60 Leu Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser 65 70 75 80 Ser His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val 85 90 95 Glu Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu 100 105 110 Ser Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly 115 120 125 Pro Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu 130 135 140 Glu Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg 145 150 155 160 Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu 165 170 175 Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile 180 185 190 Glu Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu 195 200 205 Gln Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu 210 215 220 Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val 225 230 235 240 Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu 245 250 255 Ser Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys 260 265 270 Gln Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu 275 280 285 Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu 290 295 300 Ser His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu 305 310 315 320 Arg Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr 325 330 335 Ile Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys 340 345 350 Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe 355 360 365 Ser Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile 370 375 380 Arg Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu 385 390 395 400 Leu His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp 405 410 415 Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala 420 425 430 Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val 435 440 445 Pro Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile 450 455 460 Thr Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe 465 470 475 480 Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp 485 490 495 Lys Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val 500 505 510 His Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu 515 520 525 His Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val 530 535 540 Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr 545 550 555 560 Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile 565 570 575 Arg Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro 580 585 590 Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala 595 600 605 Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe 610 615 620 Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala 625 630 635 640 Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu 645 650 655 Glu Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val 660 665 670 Gly Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro 675 680 685 Arg Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg 690 695 700 His His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val 705 710 715 720 Ala Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly 725 730 735 Thr Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys 740 745 750 Arg Lys Asp Gly Thr Thr Val Gly Ile Phe Arg Asn Thr Gly Arg Gly 755 760 765 Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg 770 775 780 Glu Thr Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro Leu Gly Val 785 790 795 800 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 805 810 815 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 820 825 830 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 835 840 845 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 850 855 860 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 865 870 875 880 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 885 890 895 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 900 905 910 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 915 920 925 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 930 935 940 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 945 950 955 960 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 965 970 975 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 980 985 990 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 995 1000 1005 <210> 16 <211> 994 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 16 Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp 1 5 10 15 Ser Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu 20 25 30 Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu 35 40 45 Ile Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr 50 55 60 Leu Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser 65 70 75 80 Ser His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val 85 90 95 Glu Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu 100 105 110 Ser Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly 115 120 125 Pro Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu 130 135 140 Glu Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg 145 150 155 160 Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu 165 170 175 Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile 180 185 190 Glu Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu 195 200 205 Gln Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu 210 215 220 Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val 225 230 235 240 Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu 245 250 255 Ser Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys 260 265 270 Gln Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu 275 280 285 Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu 290 295 300 Ser His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu 305 310 315 320 Arg Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr 325 330 335 Ile Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys 340 345 350 Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe 355 360 365 Ser Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile 370 375 380 Arg Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu 385 390 395 400 Leu His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp 405 410 415 Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala 420 425 430 Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val 435 440 445 Pro Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile 450 455 460 Thr Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe 465 470 475 480 Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp 485 490 495 Lys Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val 500 505 510 His Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu 515 520 525 His Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val 530 535 540 Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr 545 550 555 560 Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile 565 570 575 Arg Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro 580 585 590 Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala 595 600 605 Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe 610 615 620 Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala 625 630 635 640 Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu 645 650 655 Glu Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val 660 665 670 Gly Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro 675 680 685 Arg Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg 690 695 700 His His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val 705 710 715 720 Ala Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly 725 730 735 Thr Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys 740 745 750 Arg Lys Asp Gly Thr Thr Val Gly Ile Phe Glu Pro Lys Ser Ser Asp 755 760 765 Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu Leu Gly Gly 770 775 780 Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 785 790 795 800 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 805 810 815 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 820 825 830 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 835 840 845 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 850 855 860 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 865 870 875 880 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 885 890 895 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 900 905 910 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 915 920 925 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 930 935 940 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 945 950 955 960 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 965 970 975 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 980 985 990 Gly Lys <210> 17 <211> 2982 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 17 gctgggcctc gggctccttg tgctgccgcc tgcacatgtg caggcgattc cctggactgc 60 ggcggcagag gcctggccgc cctgcctggc gatctgccat cctggacccg gagcctgaac 120 ctgagctaca acaagctgag cgagatcgat cccgccggct ttgaggacct gcctaacctg 180 caggaggtgt atctgaacaa taacgagctg accgcggtac catccctggg cgctgcttca 240 tcacatgtcg tctctctctt tctgcagcac aacaagattc gcagcgtgga ggggagccag 300 ctgaaggcct acctttcctt agaagtgtta gatctgagtt tgaacaacat cacggaagtg 360 cggaacacct gctttccaca cggaccgcct ataaaggagc tcaacctggc aggcaatcgg 420 attggcaccc tggagttggg agcatttgat ggtctgtcac ggtcgctgct aactcttcgc 480 ctgagcaaaa acaggatcac ccagcttcct gtaagagcat tcaagctacc caggctgaca 540 caactggacc tcaatcggaa caggattcgg ctgatagagg gcctcacctt ccaggggctc 600 aacagcttgg aggtgctgaa gcttcagcga aacaacatca gcaaactgac agatggggcc 660 ttctggggac tgtccaagat gcatgtgctg cacctggagt acaacagcct ggtagaagtg 720 aacagcggct cgctctacgg cctcacggcc ctgcatcagc tccacctcag caacaattcc 780 atcgctcgca ttcaccgcaa gggctggagc ttctgccaga agctgcatga gttggtcctg 840 tccttcaaca acctgacacg gctggacgag gagagcctgg ccgagctgag cagcctgagt 900 gtcctgcgtc tcagccacaa ttccatcagc cacattgcgg agggtgcctt caagggactc 960 aggagcctgc gagtcttgga tctggaccat aacgagattt cgggcacaat agaggacacg 1020 agcggcgcct tctcagggct cgacagcctc agcaagctga ctctgtttgg aaacaagatc 1080 aagtctgtgg ctaagagagc attctcgggg ctggaaggcc tggagcacct gaaccttgga 1140 gggaatgcga tcagatctgt ccagtttgat gcctttgtga agatgaagaa tcttaaagag 1200 ctccatatca gcagcgacag cttcctgtgt gactgccagc tgaagtggct gcccccgtgg 1260 ctaattggca ggatgctgca ggcctttgtg acagccacct gtgcccaccc agaatcactg 1320 aagggtcaga gcattttctc tgtgccacca gagagtttcg tgtgcgatga cttcctgaag 1380 ccacagatca tcacccagcc agaaaccacc atggctatgg tgggcaagga catccggttt 1440 acatgctcag cagccagcag cagcagctcc cccatgacct ttgcctggaa gaaagacaat 1500 gaagtcctga ccaatgcaga catggagaac tttgtccacg tccacgcgca ggacggggaa 1560 gtgatggagt acaccaccat cctgcacctc cgtcaggtca ctttcgggca cgagggccgc 1620 taccaatgtg tcatcaccaa ccactttggc tccacctatt cacataaggc caggctcacc 1680 gtgaatgtgt tgccatcatt caccaaaacg ccccacgaca taaccatccg gaccaccacc 1740 gtggcccgcc tcgaatgtgc tgccacaggt cacccaaacc ctcagattgc ctggcagaag 1800 gatggaggca cggatttccc cgctgcccgt gagcgacgca tgcatgtcat gccggatgac 1860 gacgtgtttt tcatcactga tgtgaaaata gatgacgcag gggtttacag ctgtactgct 1920 cagaactcag ccggttctat ttcagctaat gccaccctga ctgtcctaga gaccccatcc 1980 ttggtggtcc ccttggaaga ccgtgtggta tctgtgggag aaacagtggc cctccaatgc 2040 aaagccacgg ggaaccctcc gccccgcatc acctggttca agggggaccg cccgctgagc 2100 ctcactgagc ggcaccacct gacccctgac aaccagctcc tggtggttca gaacgtggtg 2160 gcagaggatg cgggccgata tacctgtgag atgtccaaca ccctgggcac ggagcgagct 2220 cacagccagc tgagcgtcct gcccgcagca ggctgcagga aggatgggac cacggtaggc 2280 atcttcgagc caaagtcctc tgataagaca cacacctctc caccatgccc agcaccagag 2340 ctgctgggag gaccaagcgt gttcctgttt cctccaaagc ccaaggacac actgatgatc 2400 tccaggacac cagaggtgac ctgcgtggtg gtggacgtga gccacgagga ccccgaggtg 2460 aagttcaact ggtacgtgga tggcgtggag gtgcacaatg ccaagaccaa gcccagagag 2520 gagcagtaca actctaccta tagggtggtg agcgtgctga cagtgctgca ccaggactgg 2580 ctgaacggca aggagtataa gtgcaaggtg agcaataagg ccctgcctgc cccaatcgag 2640 aagacaatct ccaaggccaa gggccagcca agagagcccc aggtgtacac cctgccccct 2700 agcagggatg agctgacaaa gaaccaggtg tccctgacct gtctggtgaa gggcttttat 2760 ccctccgaca tcgccgtgga gtgggagtct aatggccagc ctgagaataa ctacaagaca 2820 accccacccg tgctggattc tgacggcagc ttctttctgt attctaagct gaccgtggac 2880 aagagcaggt ggcagcaggg caacgtgttc agctgctccg tgatgcacga agcactgcac 2940 aatcactaca cccagaaatc actgtcactg agccctggca aa 2982 <210> 18 <211> 2985 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 18 gctgggcctc gggctccttg tgctgccgcc tgcacatgtg caggcgattc cctggactgc 60 ggcggcagag gcctggccgc cctgcctggc gatctgccat cctggacccg gagcctgaac 120 ctgagctaca acaagctgag cgagatcgat cccgccggct ttgaggacct gcctaacctg 180 caggaggtgt atctgaacaa taacgagctg accgcggtac catccctggg cgctgcttca 240 tcacatgtcg tctctctctt tctgcagcac aacaagattc gcagcgtgga ggggagccag 300 ctgaaggcct acctttcctt agaagtgtta gatctgagtt tgaacaacat cacggaagtg 360 cggaacacct gctttccaca cggaccgcct ataaaggagc tcaacctggc aggcaatcgg 420 attggcaccc tggagttggg agcatttgat ggtctgtcac ggtcgctgct aactcttcgc 480 ctgagcaaaa acaggatcac ccagcttcct gtaagagcat tcaagctacc caggctgaca 540 caactggacc tcaatcggaa caggattcgg ctgatagagg gcctcacctt ccaggggctc 600 aacagcttgg aggtgctgaa gcttcagcga aacaacatca gcaaactgac agatggggcc 660 ttctggggac tgtccaagat gcatgtgctg cacctggagt acaacagcct ggtagaagtg 720 aacagcggct cgctctacgg cctcacggcc ctgcatcagc tccacctcag caacaattcc 780 atcgctcgca ttcaccgcaa gggctggagc ttctgccaga agctgcatga gttggtcctg 840 tccttcaaca acctgacacg gctggacgag gagagcctgg ccgagctgag cagcctgagt 900 gtcctgcgtc tcagccacaa ttccatcagc cacattgcgg agggtgcctt caagggactc 960 aggagcctgc gagtcttgga tctggaccat aacgagattt cgggcacaat agaggacacg 1020 agcggcgcct tctcagggct cgacagcctc agcaagctga ctctgtttgg aaacaagatc 1080 aagtctgtgg ctaagagagc attctcgggg ctggaaggcc tggagcacct gaaccttgga 1140 gggaatgcga tcagatctgt ccagtttgat gcctttgtga agatgaagaa tcttaaagag 1200 ctccatatca gcagcgacag cttcctgtgt gactgccagc tgaagtggct gcccccgtgg 1260 ctaattggca ggatgctgca ggcctttgtg acagccacct gtgcccaccc agaatcactg 1320 aagggtcaga gcattttctc tgtgccacca gagagtttcg tgtgcgatga cttcctgaag 1380 ccacagatca tcacccagcc agaaaccacc atggctatgg tgggcaagga catccggttt 1440 acatgctcag cagccagcag cagcagctcc cccatgacct ttgcctggaa gaaagacaat 1500 gaagtcctga ccaatgcaga catggagaac tttgtccacg tccacgcgca ggacggggaa 1560 gtgatggagt acaccaccat cctgcacctc cgtcaggtca ctttcgggca cgagggccgc 1620 taccaatgtg tcatcaccaa ccactttggc tccacctatt cacataaggc caggctcacc 1680 gtgaatgtgt tgccatcatt caccaaaacg ccccacgaca taaccatccg gaccaccacc 1740 gtggcccgcc tcgaatgtgc tgccacaggt cacccaaacc ctcagattgc ctggcagaag 1800 gatggaggca cggatttccc cgctgcccgt gagcgacgca tgcatgtcat gccggatgac 1860 gacgtgtttt tcatcactga tgtgaaaata gatgacgcag gggtttacag ctgtactgct 1920 cagaactcag ccggttctat ttcagctaat gccaccctga ctgtcctaga gaccccatcc 1980 ttggtggtcc ccttggaaga ccgtgtggta tctgtgggag aaacagtggc cctccaatgc 2040 aaagccacgg ggaaccctcc gccccgcatc acctggttca agggggaccg cccgctgagc 2100 ctcactgagc ggcaccacct gacccctgac aaccagctcc tggtggttca gaacgtggtg 2160 gcagaggatg cgggccgata tacctgtgag atgtccaaca ccctgggcac ggagcgagct 2220 cacagccagc tgagcgtcct gcccgcagca ggctgcagga aggatgggac cacggtaggc 2280 atcttcgagc ctcggggccc taccatcaag ccctgccccc cttgcaagtg ccctgcccct 2340 aatctgctgg gcggaccctc cgtgttcctg tttcctccaa agcccaagga cacactgatg 2400 atctccagga caccagaggt gacctgcgtg gtggtggacg tgagccacga ggaccccgag 2460 gtgaagttca actggtacgt ggatggcgtg gaggtgcaca atgccaagac caagcccaga 2520 gaggagcagt acaactctac ctatagggtg gtgagcgtgc tgacagtgct gcaccaggac 2580 tggctgaacg gcaaggagta taagtgcaag gtgagcaata aggccctgcc tgccccaatc 2640 gagaagacaa tctccaaggc caagggccag ccaagagagc cccaggtgta caccctgccc 2700 cctagcaggg atgagctgac aaagaaccag gtgtccctga cctgtctggt gaagggcttt 2760 tatccctccg acatcgccgt ggagtgggag tctaatggcc agcctgagaa taactacaag 2820 acaaccccac ccgtgctgga ttctgacggc agcttctttc tgtattctaa gctgaccgtg 2880 gacaagagca ggtggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaagcactg 2940 cacaatcact acacccagaa atcactgtca ctgagccctg gcaaa 2985 <210> 19 <211> 3021 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 19 gctgggcctc gggctccttg tgctgccgcc tgcacatgtg caggcgattc cctggactgc 60 ggcggcagag gcctggccgc cctgcctggc gatctgccat cctggacccg gagcctgaac 120 ctgagctaca acaagctgag cgagatcgat cccgccggct ttgaggacct gcctaacctg 180 caggaggtgt atctgaacaa taacgagctg accgcggtac catccctggg cgctgcttca 240 tcacatgtcg tctctctctt tctgcagcac aacaagattc gcagcgtgga ggggagccag 300 ctgaaggcct acctttcctt agaagtgtta gatctgagtt tgaacaacat cacggaagtg 360 cggaacacct gctttccaca cggaccgcct ataaaggagc tcaacctggc aggcaatcgg 420 attggcaccc tggagttggg agcatttgat ggtctgtcac ggtcgctgct aactcttcgc 480 ctgagcaaaa acaggatcac ccagcttcct gtaagagcat tcaagctacc caggctgaca 540 caactggacc tcaatcggaa caggattcgg ctgatagagg gcctcacctt ccaggggctc 600 aacagcttgg aggtgctgaa gcttcagcga aacaacatca gcaaactgac agatggggcc 660 ttctggggac tgtccaagat gcatgtgctg cacctggagt acaacagcct ggtagaagtg 720 aacagcggct cgctctacgg cctcacggcc ctgcatcagc tccacctcag caacaattcc 780 atcgctcgca ttcaccgcaa gggctggagc ttctgccaga agctgcatga gttggtcctg 840 tccttcaaca acctgacacg gctggacgag gagagcctgg ccgagctgag cagcctgagt 900 gtcctgcgtc tcagccacaa ttccatcagc cacattgcgg agggtgcctt caagggactc 960 aggagcctgc gagtcttgga tctggaccat aacgagattt cgggcacaat agaggacacg 1020 agcggcgcct tctcagggct cgacagcctc agcaagctga ctctgtttgg aaacaagatc 1080 aagtctgtgg ctaagagagc attctcgggg ctggaaggcc tggagcacct gaaccttgga 1140 gggaatgcga tcagatctgt ccagtttgat gcctttgtga agatgaagaa tcttaaagag 1200 ctccatatca gcagcgacag cttcctgtgt gactgccagc tgaagtggct gcccccgtgg 1260 ctaattggca ggatgctgca ggcctttgtg acagccacct gtgcccaccc agaatcactg 1320 aagggtcaga gcattttctc tgtgccacca gagagtttcg tgtgcgatga cttcctgaag 1380 ccacagatca tcacccagcc agaaaccacc atggctatgg tgggcaagga catccggttt 1440 acatgctcag cagccagcag cagcagctcc cccatgacct ttgcctggaa gaaagacaat 1500 gaagtcctga ccaatgcaga catggagaac tttgtccacg tccacgcgca ggacggggaa 1560 gtgatggagt acaccaccat cctgcacctc cgtcaggtca ctttcgggca cgagggccgc 1620 taccaatgtg tcatcaccaa ccactttggc tccacctatt cacataaggc caggctcacc 1680 gtgaatgtgt tgccatcatt caccaaaacg ccccacgaca taaccatccg gaccaccacc 1740 gtggcccgcc tcgaatgtgc tgccacaggt cacccaaacc ctcagattgc ctggcagaag 1800 gatggaggca cggatttccc cgctgcccgt gagcgacgca tgcatgtcat gccggatgac 1860 gacgtgtttt tcatcactga tgtgaaaata gatgacgcag gggtttacag ctgtactgct 1920 cagaactcag ccggttctat ttcagctaat gccaccctga ctgtcctaga gaccccatcc 1980 ttggtggtcc ccttggaaga ccgtgtggta tctgtgggag aaacagtggc cctccaatgc 2040 aaagccacgg ggaaccctcc gccccgcatc acctggttca agggggaccg cccgctgagc 2100 ctcactgagc ggcaccacct gacccctgac aaccagctcc tggtggttca gaacgtggtg 2160 gcagaggatg cgggccgata tacctgtgag atgtccaaca ccctgggcac ggagcgagct 2220 cacagccagc tgagcgtcct gcccgcagca ggctgcagga aggatgggac cacggtaggc 2280 atcttccgca acaccggccg cggcggcgag gagaagaaga aggagaagga gaaggaggag 2340 caggaggagc gcgagaccaa gacccccgag tgccccagcc acacccagcc cctgggcgtg 2400 ttcctgtttc ctccaaagcc caaggacaca ctgatgatct ccaggacacc agaggtgacc 2460 tgcgtggtgg tggacgtgag ccacgaggac cccgaggtga agttcaactg gtacgtggat 2520 ggcgtggagg tgcacaatgc caagaccaag cccagagagg agcagtacaa ctctacctat 2580 agggtggtga gcgtgctgac agtgctgcac caggactggc tgaacggcaa ggagtataag 2640 tgcaaggtga gcaataaggc cctgcctgcc ccaatcgaga agacaatctc caaggccaag 2700 ggccagccaa gagagcccca ggtgtacacc ctgcccccta gcagggatga gctgacaaag 2760 aaccaggtgt ccctgacctg tctggtgaag ggcttttatc cctccgacat cgccgtggag 2820 tgggagtcta atggccagcc tgagaataac tacaagacaa ccccacccgt gctggattct 2880 gacggcagct tctttctgta ttctaagctg accgtggaca agagcaggtg gcagcagggc 2940 aacgtgttca gctgctccgt gatgcacgaa gcactgcaca atcactacac ccagaaatca 3000 ctgtcactga gccctggcaa a 3021 <210> 20 <211> 2982 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 20 gctgggcctc gggctccttg tgctgccgcc tgcacatgtg caggcgattc cctggactgc 60 ggcggcagag gcctggccgc cctgcctggc gatctgccat cctggacccg gagcctgaac 120 ctgagctaca acaagctgag cgagatcgat cccgccggct ttgaggacct gcctaacctg 180 caggaggtgt atctgaacaa taacgagctg accgcggtac catccctggg cgctgcttca 240 tcacatgtcg tctctctctt tctgcagcac aacaagattc gcagcgtgga ggggagccag 300 ctgaaggcct acctttcctt agaagtgtta gatctgagtt tgaacaacat cacggaagtg 360 cggaacacct gctttccaca cggaccgcct ataaaggagc tcaacctggc aggcaatcgg 420 attggcaccc tggagttggg agcatttgat ggtctgtcac ggtcgctgct aactcttcgc 480 ctgagcaaaa acaggatcac ccagcttcct gtaagagcat tcaagctacc caggctgaca 540 caactggacc tcaatcggaa caggattcgg ctgatagagg gcctcacctt ccaggggctc 600 aacagcttgg aggtgctgaa gcttcagcga aacaacatca gcaaactgac agatggggcc 660 ttctggggac tgtccaagat gcatgtgctg cacctggagt acaacagcct ggtagaagtg 720 aacagcggct cgctctacgg cctcacggcc ctgcatcagc tccacctcag caacaattcc 780 atcgctcgca ttcaccgcaa gggctggagc ttctgccaga agctgcatga gttggtcctg 840 tccttcaaca acctgacacg gctggacgag gagagcctgg ccgagctgag cagcctgagt 900 gtcctgcgtc tcagccacaa ttccatcagc cacattgcgg agggtgcctt caagggactc 960 aggagcctgc gagtcttgga tctggaccat aacgagattt cgggcacaat agaggacacg 1020 agcggcgcct tctcagggct cgacagcctc agcaagctga ctctgtttgg aaacaagatc 1080 aagtctgtgg ctaagagagc attctcgggg ctggaaggcc tggagcacct gaaccttgga 1140 gggaatgcga tcagatctgt ccagtttgat gcctttgtga agatgaagaa tcttaaagag 1200 ctccatatca gcagcgacag cttcctgtgt gactgccagc tgaagtggct gcccccgtgg 1260 ctaattggca ggatgctgca ggcctttgtg acagccacct gtgcccaccc agaatcactg 1320 aagggtcaga gcattttctc tgtgccacca gagagtttcg tgtgcgatga cttcctgaag 1380 ccacagatca tcacccagcc agaaaccacc atggctatgg tgggcaagga catccggttt 1440 acatgctcag cagccagcag cagcagctcc cccatgacct ttgcctggaa gaaagacaat 1500 gaagtcctga ccaatgcaga catggagaac tttgtccacg tccacgcgca ggacggggaa 1560 gtgatggagt acaccaccat cctgcacctc cgtcaggtca ctttcgggca cgagggccgc 1620 taccaatgtg tcatcaccaa ccactttggc tccacctatt cacataaggc caggctcacc 1680 gtgaatgtgt tgccatcatt caccaaaacg ccccacgaca taaccatccg gaccaccacc 1740 gtggcccgcc tcgaatgtgc tgccacaggt cacccaaacc ctcagattgc ctggcagaag 1800 gatggaggca cggatttccc cgctgcccgt gagcgacgca tgcatgtcat gccggatgac 1860 gacgtgtttt tcatcactga tgtgaaaata gatgacgcag gggtttacag ctgtactgct 1920 cagaactcag ccggttctat ttcagctaat gccaccctga ctgtcctaga gaccccatcc 1980 ttggtggtcc ccttggaaga ccgtgtggta tctgtgggag aaacagtggc cctccaatgc 2040 aaagccacgg ggaaccctcc gccccgcatc acctggttca agggggaccg cccgctgagc 2100 ctcactgagc ggcaccacct gacccctgac aaccagctcc tggtggttca gaacgtggtg 2160 gcagaggatg cgggccgata tacctgtgag atgtccaaca ccctgggcac ggagcgagct 2220 cacagccagc tgagcgtcct gcccgcagca ggctgcagga aggatgggac cacggtaggc 2280 atcttcgaac cgaaatcttc tgacaaaacc cacacctctc cgccgtctcc ggctccggaa 2340 ctgctgggtg gttcttctgt tttcctgttt cctccaaagc ccaaggacac actgatgatc 2400 tccaggacac cagaggtgac ctgcgtggtg gtggacgtga gccacgagga ccccgaggtg 2460 aagttcaact ggtacgtgga tggcgtggag gtgcacaatg ccaagaccaa gcccagagag 2520 gagcagtaca actctaccta tagggtggtg agcgtgctga cagtgctgca ccaggactgg 2580 ctgaacggca aggagtataa gtgcaaggtg agcaataagg ccctgcctgc cccaatcgag 2640 aagacaatct ccaaggccaa gggccagcca agagagcccc aggtgtacac cctgccccct 2700 agcagggatg agctgacaaa gaaccaggtg tccctgacct gtctggtgaa gggcttttat 2760 ccctccgaca tcgccgtgga gtgggagtct aatggccagc ctgagaataa ctacaagaca 2820 accccacccg tgctggattc tgacggcagc ttctttctgt attctaagct gaccgtggac 2880 aagagcaggt ggcagcaggg caacgtgttc agctgctccg tgatgcacga agcactgcac 2940 aatcactaca cccagaaatc actgtcactg agccctggca aa 2982 <210> 21 <211> 992 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 21 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Glu Pro Lys Ser Ser Asp Lys Thr 755 760 765 His Thr Ser Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 770 775 780 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 785 790 795 800 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 805 810 815 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 820 825 830 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 835 840 845 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 850 855 860 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 865 870 875 880 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 885 890 895 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 900 905 910 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 915 920 925 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 930 935 940 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 945 950 955 960 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 965 970 975 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 980 985 990 <210> 22 <211> 993 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 22 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Glu Pro Arg Gly Pro Thr Ile Lys 755 760 765 Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro 770 775 780 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 785 790 795 800 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 805 810 815 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 820 825 830 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 835 840 845 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 850 855 860 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 865 870 875 880 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 885 890 895 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 900 905 910 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 915 920 925 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 930 935 940 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 945 950 955 960 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 965 970 975 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 980 985 990 Lys <210> 23 <211> 1005 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 23 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu 755 760 765 Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr 770 775 780 Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu 785 790 795 800 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 805 810 815 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 820 825 830 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 835 840 845 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 850 855 860 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 865 870 875 880 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 885 890 895 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 900 905 910 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 915 920 925 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 930 935 940 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 945 950 955 960 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 965 970 975 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 980 985 990 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 995 1000 1005 <210> 24 <211> 992 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 24 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Glu Pro Lys Ser Ser Asp Lys Thr 755 760 765 His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu Leu Gly Gly Ser Ser 770 775 780 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 785 790 795 800 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 805 810 815 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 820 825 830 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 835 840 845 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 850 855 860 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 865 870 875 880 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 885 890 895 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 900 905 910 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 915 920 925 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 930 935 940 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 945 950 955 960 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 965 970 975 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 980 985 990 <210> 25 <211> 2976 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 25 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 gagccaaagt cctctgataa gacacacacc tctccaccat gcccagcacc agagctgctg 2340 ggaggaccaa gcgtgttcct gtttcctcca aagcccaagg acacactgat gatctccagg 2400 acaccagagg tgacctgcgt ggtggtggac gtgagccacg aggaccccga ggtgaagttc 2460 aactggtacg tggatggcgt ggaggtgcac aatgccaaga ccaagcccag agaggagcag 2520 tacaactcta cctatagggt ggtgagcgtg ctgacagtgc tgcaccagga ctggctgaac 2580 ggcaaggagt ataagtgcaa ggtgagcaat aaggccctgc ctgccccaat cgagaagaca 2640 atctccaagg ccaagggcca gccaagagag ccccaggtgt acaccctgcc ccctagcagg 2700 gatgagctga caaagaacca ggtgtccctg acctgtctgg tgaagggctt ttatccctcc 2760 gacatcgccg tggagtggga gtctaatggc cagcctgaga ataactacaa gacaacccca 2820 cccgtgctgg attctgacgg cagcttcttt ctgtattcta agctgaccgt ggacaagagc 2880 aggtggcagc agggcaacgt gttcagctgc tccgtgatgc acgaagcact gcacaatcac 2940 tacacccaga aatcactgtc actgagccct ggcaaa 2976 <210> 26 <211> 2979 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 26 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 gagcctcggg gccctaccat caagccctgc cccccttgca agtgccctgc ccctaatctg 2340 ctgggcggac cctccgtgtt cctgtttcct ccaaagccca aggacacact gatgatctcc 2400 aggacaccag aggtgacctg cgtggtggtg gacgtgagcc acgaggaccc cgaggtgaag 2460 ttcaactggt acgtggatgg cgtggaggtg cacaatgcca agaccaagcc cagagaggag 2520 cagtacaact ctacctatag ggtggtgagc gtgctgacag tgctgcacca ggactggctg 2580 aacggcaagg agtataagtg caaggtgagc aataaggccc tgcctgcccc aatcgagaag 2640 acaatctcca aggccaaggg ccagccaaga gagccccagg tgtacaccct gccccctagc 2700 agggatgagc tgacaaagaa ccaggtgtcc ctgacctgtc tggtgaaggg cttttatccc 2760 tccgacatcg ccgtggagtg ggagtctaat ggccagcctg agaataacta caagacaacc 2820 ccacccgtgc tggattctga cggcagcttc tttctgtatt ctaagctgac cgtggacaag 2880 agcaggtggc agcagggcaa cgtgttcagc tgctccgtga tgcacgaagc actgcacaat 2940 cactacaccc agaaatcact gtcactgagc cctggcaaa 2979 <210> 27 <211> 3015 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 27 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 cgcaacaccg gccgcggcgg cgaggagaag aagaaggaga aggagaagga ggagcaggag 2340 gagcgcgaga ccaagacccc cgagtgcccc agccacaccc agcccctggg cgtgttcctg 2400 tttcctccaa agcccaagga cacactgatg atctccagga caccagaggt gacctgcgtg 2460 gtggtggacg tgagccacga ggaccccgag gtgaagttca actggtacgt ggatggcgtg 2520 gaggtgcaca atgccaagac caagcccaga gaggagcagt acaactctac ctatagggtg 2580 gtgagcgtgc tgacagtgct gcaccaggac tggctgaacg gcaaggagta taagtgcaag 2640 gtgagcaata aggccctgcc tgccccaatc gagaagacaa tctccaaggc caagggccag 2700 ccaagagagc cccaggtgta caccctgccc cctagcaggg atgagctgac aaagaaccag 2760 gtgtccctga cctgtctggt gaagggcttt tatccctccg acatcgccgt ggagtgggag 2820 tctaatggcc agcctgagaa taactacaag acaaccccac ccgtgctgga ttctgacggc 2880 agcttctttc tgtattctaa gctgaccgtg gacaagagca ggtggcagca gggcaacgtg 2940 ttcagctgct ccgtgatgca cgaagcactg cacaatcact acacccagaa atcactgtca 3000 ctgagccctg gcaaa 3015 <210> 28 <211> 2976 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 28 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 gaaccgaaat cttctgacaa aacccacacc tctccgccgt ctccggctcc ggaactgctg 2340 ggtggttctt ctgttttcct gtttcctcca aagcccaagg acacactgat gatctccagg 2400 acaccagagg tgacctgcgt ggtggtggac gtgagccacg aggaccccga ggtgaagttc 2460 aactggtacg tggatggcgt ggaggtgcac aatgccaaga ccaagcccag agaggagcag 2520 tacaactcta cctatagggt ggtgagcgtg ctgacagtgc tgcaccagga ctggctgaac 2580 ggcaaggagt ataagtgcaa ggtgagcaat aaggccctgc ctgccccaat cgagaagaca 2640 atctccaagg ccaagggcca gccaagagag ccccaggtgt acaccctgcc ccctagcagg 2700 gatgagctga caaagaacca ggtgtccctg acctgtctgg tgaagggctt ttatccctcc 2760 gacatcgccg tggagtggga gtctaatggc cagcctgaga ataactacaa gacaacccca 2820 cccgtgctgg attctgacgg cagcttcttt ctgtattcta agctgaccgt ggacaagagc 2880 aggtggcagc agggcaacgt gttcagctgc tccgtgatgc acgaagcact gcacaatcac 2940 tacacccaga aatcactgtc actgagccct ggcaaa 2976 <210> 29 <211> 992 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 29 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Glu Pro Lys Ser Ser Asp Lys Thr 755 760 765 His Thr Ser Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 770 775 780 Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu 785 790 795 800 Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro 805 810 815 Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala 820 825 830 Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val 835 840 845 Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe 850 855 860 Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr 865 870 875 880 Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu 885 890 895 Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys 900 905 910 Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn 915 920 925 Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp 930 935 940 Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys 945 950 955 960 Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly 965 970 975 Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 980 985 990 <210> 30 <211> 993 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 30 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Glu Pro Arg Gly Pro Thr Ile Lys 755 760 765 Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro 770 775 780 Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser 785 790 795 800 Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp 805 810 815 Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr 820 825 830 Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val 835 840 845 Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu 850 855 860 Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg 865 870 875 880 Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val 885 890 895 Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr 900 905 910 Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr 915 920 925 Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu 930 935 940 Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys 945 950 955 960 Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu 965 970 975 Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly 980 985 990 Lys <210> 31 <211> 1005 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 31 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu 755 760 765 Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr 770 775 780 Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Ile 785 790 795 800 Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile 805 810 815 Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln 820 825 830 Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln 835 840 845 Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu 850 855 860 Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys 865 870 875 880 Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys 885 890 895 Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro 900 905 910 Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr 915 920 925 Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys 930 935 940 Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly 945 950 955 960 Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val 965 970 975 Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn 980 985 990 His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 995 1000 1005 <210> 32 <211> 992 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 32 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Glu Pro Lys Ser Ser Asp Lys Thr 755 760 765 His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu Leu Gly Gly Ser Ser 770 775 780 Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu 785 790 795 800 Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro 805 810 815 Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala 820 825 830 Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val 835 840 845 Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe 850 855 860 Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr 865 870 875 880 Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu 885 890 895 Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys 900 905 910 Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn 915 920 925 Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp 930 935 940 Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys 945 950 955 960 Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly 965 970 975 Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 980 985 990 <210> 33 <211> 2976 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 33 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 gagccaaagt cctctgataa gacacacacc tctccaccat gcccagcacc agagctgctg 2340 ggaggaccaa gcgtgttcat cttcccaccc aagatcaagg acgtgctgat gatctccctg 2400 tcccccatcg tgacctgcgt ggtggtggac gtgtccgagg acgaccccga cgtgcagatc 2460 agttggttcg tgaacaacgt ggaagtgcac accgcccaga cccagaccca cagagaggac 2520 tacaactcca ccctgcgggt ggtgtccgcc ctgcccatcc agcaccagga ctggatgtcc 2580 ggcaaagaat tcaagtgcaa agtgaacaac aaggacctgc ctgcccccat cgagcggacc 2640 atctccaagc ccaagggctc cgtgcgggct ccccaggtgt acgtgctgcc ccctccagag 2700 gaagagatga ccaagaagca ggtcacactg acctgcatgg tcaccgactt catgcccgag 2760 gacatctacg tggaatggac caacaatggc aagaccgagc tgaactacaa gaacaccgag 2820 cctgtgctgg actccgacgg ctcctacttc atgtactcca agctgcgggt ggaaaagaag 2880 aactgggtcg agcggaactc ctactcctgc tccgtggtgc acgagggcct gcacaaccac 2940 cacaccacca agtccttctc ccggaccccc ggcaaa 2976 <210> 34 <211> 2979 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 34 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 gagcctcggg gccctaccat caagccctgc cccccttgca agtgccctgc ccctaatctg 2340 ctgggcggac cctccgtgtt catcttccca cccaagatca aggacgtgct gatgatctcc 2400 ctgtccccca tcgtgacctg cgtggtggtg gacgtgtccg aggacgaccc cgacgtgcag 2460 atcagttggt tcgtgaacaa cgtggaagtg cacaccgccc agacccagac ccacagagag 2520 gactacaact ccaccctgcg ggtggtgtcc gccctgccca tccagcacca ggactggatg 2580 tccggcaaag aattcaagtg caaagtgaac aacaaggacc tgcctgcccc catcgagcgg 2640 accatctcca agcccaaggg ctccgtgcgg gctccccagg tgtacgtgct gccccctcca 2700 gaggaagaga tgaccaagaa gcaggtcaca ctgacctgca tggtcaccga cttcatgccc 2760 gaggacatct acgtggaatg gaccaacaat ggcaagaccg agctgaacta caagaacacc 2820 gagcctgtgc tggactccga cggctcctac ttcatgtact ccaagctgcg ggtggaaaag 2880 aagaactggg tcgagcggaa ctcctactcc tgctccgtgg tgcacgaggg cctgcacaac 2940 caccacacca ccaagtcctt ctcccggacc cccggcaaa 2979 <210> 35 <211> 3015 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 35 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 cgcaacaccg gccgcggcgg cgaggagaag aagaaggaga aggagaagga ggagcaggag 2340 gagcgcgaga ccaagacccc cgagtgcccc agccacaccc agcccctggg cgtgttcatc 2400 ttcccaccca agatcaagga cgtgctgatg atctccctgt cccccatcgt gacctgcgtg 2460 gtggtggacg tgtccgagga cgaccccgac gtgcagatca gttggttcgt gaacaacgtg 2520 gaagtgcaca ccgcccagac ccagacccac agagaggact acaactccac cctgcgggtg 2580 gtgtccgccc tgcccatcca gcaccaggac tggatgtccg gcaaagaatt caagtgcaaa 2640 gtgaacaaca aggacctgcc tgcccccatc gagcggacca tctccaagcc caagggctcc 2700 gtgcgggctc cccaggtgta cgtgctgccc cctccagagg aagagatgac caagaagcag 2760 gtcacactga cctgcatggt caccgacttc atgcccgagg acatctacgt ggaatggacc 2820 aacaatggca agaccgagct gaactacaag aacaccgagc ctgtgctgga ctccgacggc 2880 tcctacttca tgtactccaa gctgcgggtg gaaaagaaga actgggtcga gcggaactcc 2940 tactcctgct ccgtggtgca cgagggcctg cacaaccacc acaccaccaa gtccttctcc 3000 cggacccccg gcaaa 3015 <210> 36 <211> 2976 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 36 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 gaaccgaaat cttctgacaa aacccacacc tctccgccgt ctccggctcc ggaactgctg 2340 ggtggttctt ctgttttcat cttcccaccc aagatcaagg acgtgctgat gatctccctg 2400 tcccccatcg tgacctgcgt ggtggtggac gtgtccgagg acgaccccga cgtgcagatc 2460 agttggttcg tgaacaacgt ggaagtgcac accgcccaga cccagaccca cagagaggac 2520 tacaactcca ccctgcgggt ggtgtccgcc ctgcccatcc agcaccagga ctggatgtcc 2580 ggcaaagaat tcaagtgcaa agtgaacaac aaggacctgc ctgcccccat cgagcggacc 2640 atctccaagc ccaagggctc cgtgcgggct ccccaggtgt acgtgctgcc ccctccagag 2700 gaagagatga ccaagaagca ggtcacactg acctgcatgg tcaccgactt catgcccgag 2760 gacatctacg tggaatggac caacaatggc aagaccgagc tgaactacaa gaacaccgag 2820 cctgtgctgg actccgacgg ctcctacttc atgtactcca agctgcgggt ggaaaagaag 2880 aactgggtcg agcggaactc ctactcctgc tccgtggtgc acgagggcct gcacaaccac 2940 cacaccacca agtccttctc ccggaccccc ggcaaa 2976 <210> 37 <211> 996 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 37 Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp 1 5 10 15 Ser Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu 20 25 30 Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu 35 40 45 Ile Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr 50 55 60 Leu Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser 65 70 75 80 Ser His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val 85 90 95 Glu Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu 100 105 110 Ser Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly 115 120 125 Pro Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu 130 135 140 Glu Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg 145 150 155 160 Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu 165 170 175 Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile 180 185 190 Glu Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu 195 200 205 Gln Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu 210 215 220 Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val 225 230 235 240 Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu 245 250 255 Ser Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys 260 265 270 Gln Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu 275 280 285 Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu 290 295 300 Ser His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu 305 310 315 320 Arg Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr 325 330 335 Ile Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys 340 345 350 Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe 355 360 365 Ser Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile 370 375 380 Arg Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu 385 390 395 400 Leu His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp 405 410 415 Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala 420 425 430 Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val 435 440 445 Pro Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile 450 455 460 Thr Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe 465 470 475 480 Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp 485 490 495 Lys Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val 500 505 510 His Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu 515 520 525 His Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val 530 535 540 Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr 545 550 555 560 Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile 565 570 575 Arg Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro 580 585 590 Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala 595 600 605 Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe 610 615 620 Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala 625 630 635 640 Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu 645 650 655 Glu Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val 660 665 670 Gly Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro 675 680 685 Arg Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg 690 695 700 His His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val 705 710 715 720 Ala Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly 725 730 735 Thr Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys 740 745 750 Arg Lys Asp Gly Thr Thr Val Gly Ile Phe Gly Ser Glu Pro Lys Ser 755 760 765 Ser Asp Lys Thr His Thr Ser Pro Pro Cys Pro Ala Pro Glu Leu Leu 770 775 780 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 785 790 795 800 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 805 810 815 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 820 825 830 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 835 840 845 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 850 855 860 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 865 870 875 880 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 885 890 895 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 900 905 910 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 915 920 925 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 930 935 940 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 945 950 955 960 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 965 970 975 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 980 985 990 Ser Pro Gly Lys 995 <210> 38 <211> 997 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 38 Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp 1 5 10 15 Ser Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu 20 25 30 Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu 35 40 45 Ile Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr 50 55 60 Leu Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser 65 70 75 80 Ser His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val 85 90 95 Glu Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu 100 105 110 Ser Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly 115 120 125 Pro Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu 130 135 140 Glu Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg 145 150 155 160 Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu 165 170 175 Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile 180 185 190 Glu Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu 195 200 205 Gln Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu 210 215 220 Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val 225 230 235 240 Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu 245 250 255 Ser Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys 260 265 270 Gln Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu 275 280 285 Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu 290 295 300 Ser His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu 305 310 315 320 Arg Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr 325 330 335 Ile Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys 340 345 350 Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe 355 360 365 Ser Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile 370 375 380 Arg Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu 385 390 395 400 Leu His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp 405 410 415 Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala 420 425 430 Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val 435 440 445 Pro Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile 450 455 460 Thr Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe 465 470 475 480 Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp 485 490 495 Lys Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val 500 505 510 His Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu 515 520 525 His Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val 530 535 540 Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr 545 550 555 560 Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile 565 570 575 Arg Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro 580 585 590 Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala 595 600 605 Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe 610 615 620 Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala 625 630 635 640 Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu 645 650 655 Glu Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val 660 665 670 Gly Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro 675 680 685 Arg Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg 690 695 700 His His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val 705 710 715 720 Ala Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly 725 730 735 Thr Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys 740 745 750 Arg Lys Asp Gly Thr Thr Val Gly Ile Phe Gly Ser Glu Pro Arg Gly 755 760 765 Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu 770 775 780 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 785 790 795 800 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 805 810 815 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 820 825 830 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 835 840 845 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 850 855 860 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 865 870 875 880 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 885 890 895 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 900 905 910 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 915 920 925 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 930 935 940 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 945 950 955 960 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 965 970 975 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 980 985 990 Leu Ser Pro Gly Lys 995 <210> 39 <211> 1009 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 39 Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp 1 5 10 15 Ser Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu 20 25 30 Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu 35 40 45 Ile Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr 50 55 60 Leu Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser 65 70 75 80 Ser His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val 85 90 95 Glu Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu 100 105 110 Ser Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly 115 120 125 Pro Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu 130 135 140 Glu Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg 145 150 155 160 Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu 165 170 175 Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile 180 185 190 Glu Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu 195 200 205 Gln Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu 210 215 220 Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val 225 230 235 240 Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu 245 250 255 Ser Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys 260 265 270 Gln Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu 275 280 285 Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu 290 295 300 Ser His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu 305 310 315 320 Arg Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr 325 330 335 Ile Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys 340 345 350 Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe 355 360 365 Ser Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile 370 375 380 Arg Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu 385 390 395 400 Leu His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp 405 410 415 Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala 420 425 430 Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val 435 440 445 Pro Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile 450 455 460 Thr Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe 465 470 475 480 Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp 485 490 495 Lys Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val 500 505 510 His Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu 515 520 525 His Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val 530 535 540 Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr 545 550 555 560 Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile 565 570 575 Arg Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro 580 585 590 Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala 595 600 605 Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe 610 615 620 Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala 625 630 635 640 Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu 645 650 655 Glu Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val 660 665 670 Gly Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro 675 680 685 Arg Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg 690 695 700 His His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val 705 710 715 720 Ala Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly 725 730 735 Thr Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys 740 745 750 Arg Lys Asp Gly Thr Thr Val Gly Ile Phe Gly Ser Arg Asn Thr Gly 755 760 765 Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu 770 775 780 Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro Leu 785 790 795 800 Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 805 810 815 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 820 825 830 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 835 840 845 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 850 855 860 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 865 870 875 880 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 885 890 895 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 900 905 910 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 915 920 925 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 930 935 940 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 945 950 955 960 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 965 970 975 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 980 985 990 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 995 1000 1005 Lys <210> 40 <211> 996 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 40 Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp 1 5 10 15 Ser Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu 20 25 30 Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu 35 40 45 Ile Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr 50 55 60 Leu Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser 65 70 75 80 Ser His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val 85 90 95 Glu Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu 100 105 110 Ser Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly 115 120 125 Pro Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu 130 135 140 Glu Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg 145 150 155 160 Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu 165 170 175 Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile 180 185 190 Glu Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu 195 200 205 Gln Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu 210 215 220 Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val 225 230 235 240 Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu 245 250 255 Ser Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys 260 265 270 Gln Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu 275 280 285 Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu 290 295 300 Ser His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu 305 310 315 320 Arg Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr 325 330 335 Ile Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys 340 345 350 Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe 355 360 365 Ser Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile 370 375 380 Arg Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu 385 390 395 400 Leu His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp 405 410 415 Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala 420 425 430 Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val 435 440 445 Pro Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile 450 455 460 Thr Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe 465 470 475 480 Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp 485 490 495 Lys Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val 500 505 510 His Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu 515 520 525 His Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val 530 535 540 Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr 545 550 555 560 Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile 565 570 575 Arg Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro 580 585 590 Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala 595 600 605 Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe 610 615 620 Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala 625 630 635 640 Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu 645 650 655 Glu Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val 660 665 670 Gly Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro 675 680 685 Arg Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg 690 695 700 His His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val 705 710 715 720 Ala Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly 725 730 735 Thr Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys 740 745 750 Arg Lys Asp Gly Thr Thr Val Gly Ile Phe Gly Ser Glu Pro Lys Ser 755 760 765 Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu Leu 770 775 780 Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 785 790 795 800 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 805 810 815 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 820 825 830 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 835 840 845 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 850 855 860 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 865 870 875 880 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 885 890 895 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 900 905 910 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 915 920 925 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 930 935 940 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 945 950 955 960 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 965 970 975 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 980 985 990 Ser Pro Gly Lys 995 <210> 41 <211> 2988 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 41 gctgggcctc gggctccttg tgctgccgcc tgcacatgtg caggcgattc cctggactgc 60 ggcggcagag gcctggccgc cctgcctggc gatctgccat cctggacccg gagcctgaac 120 ctgagctaca acaagctgag cgagatcgat cccgccggct ttgaggacct gcctaacctg 180 caggaggtgt atctgaacaa taacgagctg accgcggtac catccctggg cgctgcttca 240 tcacatgtcg tctctctctt tctgcagcac aacaagattc gcagcgtgga ggggagccag 300 ctgaaggcct acctttcctt agaagtgtta gatctgagtt tgaacaacat cacggaagtg 360 cggaacacct gctttccaca cggaccgcct ataaaggagc tcaacctggc aggcaatcgg 420 attggcaccc tggagttggg agcatttgat ggtctgtcac ggtcgctgct aactcttcgc 480 ctgagcaaaa acaggatcac ccagcttcct gtaagagcat tcaagctacc caggctgaca 540 caactggacc tcaatcggaa caggattcgg ctgatagagg gcctcacctt ccaggggctc 600 aacagcttgg aggtgctgaa gcttcagcga aacaacatca gcaaactgac agatggggcc 660 ttctggggac tgtccaagat gcatgtgctg cacctggagt acaacagcct ggtagaagtg 720 aacagcggct cgctctacgg cctcacggcc ctgcatcagc tccacctcag caacaattcc 780 atcgctcgca ttcaccgcaa gggctggagc ttctgccaga agctgcatga gttggtcctg 840 tccttcaaca acctgacacg gctggacgag gagagcctgg ccgagctgag cagcctgagt 900 gtcctgcgtc tcagccacaa ttccatcagc cacattgcgg agggtgcctt caagggactc 960 aggagcctgc gagtcttgga tctggaccat aacgagattt cgggcacaat agaggacacg 1020 agcggcgcct tctcagggct cgacagcctc agcaagctga ctctgtttgg aaacaagatc 1080 aagtctgtgg ctaagagagc attctcgggg ctggaaggcc tggagcacct gaaccttgga 1140 gggaatgcga tcagatctgt ccagtttgat gcctttgtga agatgaagaa tcttaaagag 1200 ctccatatca gcagcgacag cttcctgtgt gactgccagc tgaagtggct gcccccgtgg 1260 ctaattggca ggatgctgca ggcctttgtg acagccacct gtgcccaccc agaatcactg 1320 aagggtcaga gcattttctc tgtgccacca gagagtttcg tgtgcgatga cttcctgaag 1380 ccacagatca tcacccagcc agaaaccacc atggctatgg tgggcaagga catccggttt 1440 acatgctcag cagccagcag cagcagctcc cccatgacct ttgcctggaa gaaagacaat 1500 gaagtcctga ccaatgcaga catggagaac tttgtccacg tccacgcgca ggacggggaa 1560 gtgatggagt acaccaccat cctgcacctc cgtcaggtca ctttcgggca cgagggccgc 1620 taccaatgtg tcatcaccaa ccactttggc tccacctatt cacataaggc caggctcacc 1680 gtgaatgtgt tgccatcatt caccaaaacg ccccacgaca taaccatccg gaccaccacc 1740 gtggcccgcc tcgaatgtgc tgccacaggt cacccaaacc ctcagattgc ctggcagaag 1800 gatggaggca cggatttccc cgctgcccgt gagcgacgca tgcatgtcat gccggatgac 1860 gacgtgtttt tcatcactga tgtgaaaata gatgacgcag gggtttacag ctgtactgct 1920 cagaactcag ccggttctat ttcagctaat gccaccctga ctgtcctaga gaccccatcc 1980 ttggtggtcc ccttggaaga ccgtgtggta tctgtgggag aaacagtggc cctccaatgc 2040 aaagccacgg ggaaccctcc gccccgcatc acctggttca agggggaccg cccgctgagc 2100 ctcactgagc ggcaccacct gacccctgac aaccagctcc tggtggttca gaacgtggtg 2160 gcagaggatg cgggccgata tacctgtgag atgtccaaca ccctgggcac ggagcgagct 2220 cacagccagc tgagcgtcct gcccgcagca ggctgcagga aggatgggac cacggtaggc 2280 atcttcggat ccgagccaaa gtcctctgat aagacacaca cctctccacc atgcccagca 2340 ccagagctgc tgggaggacc aagcgtgttc ctgtttcctc caaagcccaa ggacacactg 2400 atgatctcca ggacaccaga ggtgacctgc gtggtggtgg acgtgagcca cgaggacccc 2460 gaggtgaagt tcaactggta cgtggatggc gtggaggtgc acaatgccaa gaccaagccc 2520 agagaggagc agtacaactc tacctatagg gtggtgagcg tgctgacagt gctgcaccag 2580 gactggctga acggcaagga gtataagtgc aaggtgagca ataaggccct gcctgcccca 2640 atcgagaaga caatctccaa ggccaagggc cagccaagag agccccaggt gtacaccctg 2700 ccccctagca gggatgagct gacaaagaac caggtgtccc tgacctgtct ggtgaagggc 2760 ttttatccct ccgacatcgc cgtggagtgg gagtctaatg gccagcctga gaataactac 2820 aagacaaccc cacccgtgct ggattctgac ggcagcttct ttctgtattc taagctgacc 2880 gtggacaaga gcaggtggca gcagggcaac gtgttcagct gctccgtgat gcacgaagca 2940 ctgcacaatc actacaccca gaaatcactg tcactgagcc ctggcaaa 2988 <210> 42 <211> 2991 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 42 gctgggcctc gggctccttg tgctgccgcc tgcacatgtg caggcgattc cctggactgc 60 ggcggcagag gcctggccgc cctgcctggc gatctgccat cctggacccg gagcctgaac 120 ctgagctaca acaagctgag cgagatcgat cccgccggct ttgaggacct gcctaacctg 180 caggaggtgt atctgaacaa taacgagctg accgcggtac catccctggg cgctgcttca 240 tcacatgtcg tctctctctt tctgcagcac aacaagattc gcagcgtgga ggggagccag 300 ctgaaggcct acctttcctt agaagtgtta gatctgagtt tgaacaacat cacggaagtg 360 cggaacacct gctttccaca cggaccgcct ataaaggagc tcaacctggc aggcaatcgg 420 attggcaccc tggagttggg agcatttgat ggtctgtcac ggtcgctgct aactcttcgc 480 ctgagcaaaa acaggatcac ccagcttcct gtaagagcat tcaagctacc caggctgaca 540 caactggacc tcaatcggaa caggattcgg ctgatagagg gcctcacctt ccaggggctc 600 aacagcttgg aggtgctgaa gcttcagcga aacaacatca gcaaactgac agatggggcc 660 ttctggggac tgtccaagat gcatgtgctg cacctggagt acaacagcct ggtagaagtg 720 aacagcggct cgctctacgg cctcacggcc ctgcatcagc tccacctcag caacaattcc 780 atcgctcgca ttcaccgcaa gggctggagc ttctgccaga agctgcatga gttggtcctg 840 tccttcaaca acctgacacg gctggacgag gagagcctgg ccgagctgag cagcctgagt 900 gtcctgcgtc tcagccacaa ttccatcagc cacattgcgg agggtgcctt caagggactc 960 aggagcctgc gagtcttgga tctggaccat aacgagattt cgggcacaat agaggacacg 1020 agcggcgcct tctcagggct cgacagcctc agcaagctga ctctgtttgg aaacaagatc 1080 aagtctgtgg ctaagagagc attctcgggg ctggaaggcc tggagcacct gaaccttgga 1140 gggaatgcga tcagatctgt ccagtttgat gcctttgtga agatgaagaa tcttaaagag 1200 ctccatatca gcagcgacag cttcctgtgt gactgccagc tgaagtggct gcccccgtgg 1260 ctaattggca ggatgctgca ggcctttgtg acagccacct gtgcccaccc agaatcactg 1320 aagggtcaga gcattttctc tgtgccacca gagagtttcg tgtgcgatga cttcctgaag 1380 ccacagatca tcacccagcc agaaaccacc atggctatgg tgggcaagga catccggttt 1440 acatgctcag cagccagcag cagcagctcc cccatgacct ttgcctggaa gaaagacaat 1500 gaagtcctga ccaatgcaga catggagaac tttgtccacg tccacgcgca ggacggggaa 1560 gtgatggagt acaccaccat cctgcacctc cgtcaggtca ctttcgggca cgagggccgc 1620 taccaatgtg tcatcaccaa ccactttggc tccacctatt cacataaggc caggctcacc 1680 gtgaatgtgt tgccatcatt caccaaaacg ccccacgaca taaccatccg gaccaccacc 1740 gtggcccgcc tcgaatgtgc tgccacaggt cacccaaacc ctcagattgc ctggcagaag 1800 gatggaggca cggatttccc cgctgcccgt gagcgacgca tgcatgtcat gccggatgac 1860 gacgtgtttt tcatcactga tgtgaaaata gatgacgcag gggtttacag ctgtactgct 1920 cagaactcag ccggttctat ttcagctaat gccaccctga ctgtcctaga gaccccatcc 1980 ttggtggtcc ccttggaaga ccgtgtggta tctgtgggag aaacagtggc cctccaatgc 2040 aaagccacgg ggaaccctcc gccccgcatc acctggttca agggggaccg cccgctgagc 2100 ctcactgagc ggcaccacct gacccctgac aaccagctcc tggtggttca gaacgtggtg 2160 gcagaggatg cgggccgata tacctgtgag atgtccaaca ccctgggcac ggagcgagct 2220 cacagccagc tgagcgtcct gcccgcagca ggctgcagga aggatgggac cacggtaggc 2280 atcttcggat ccgagcctcg gggccctacc atcaagccct gccccccttg caagtgccct 2340 gcccctaatc tgctgggcgg accctccgtg ttcctgtttc ctccaaagcc caaggacaca 2400 ctgatgatct ccaggacacc agaggtgacc tgcgtggtgg tggacgtgag ccacgaggac 2460 cccgaggtga agttcaactg gtacgtggat ggcgtggagg tgcacaatgc caagaccaag 2520 cccagagagg agcagtacaa ctctacctat agggtggtga gcgtgctgac agtgctgcac 2580 caggactggc tgaacggcaa ggagtataag tgcaaggtga gcaataaggc cctgcctgcc 2640 ccaatcgaga agacaatctc caaggccaag ggccagccaa gagagcccca ggtgtacacc 2700 ctgcccccta gcagggatga gctgacaaag aaccaggtgt ccctgacctg tctggtgaag 2760 ggcttttatc cctccgacat cgccgtggag tgggagtcta atggccagcc tgagaataac 2820 tacaagacaa ccccacccgt gctggattct gacggcagct tctttctgta ttctaagctg 2880 accgtggaca agagcaggtg gcagcagggc aacgtgttca gctgctccgt gatgcacgaa 2940 gcactgcaca atcactacac ccagaaatca ctgtcactga gccctggcaa a 2991 <210> 43 <211> 3027 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 43 gctgggcctc gggctccttg tgctgccgcc tgcacatgtg caggcgattc cctggactgc 60 ggcggcagag gcctggccgc cctgcctggc gatctgccat cctggacccg gagcctgaac 120 ctgagctaca acaagctgag cgagatcgat cccgccggct ttgaggacct gcctaacctg 180 caggaggtgt atctgaacaa taacgagctg accgcggtac catccctggg cgctgcttca 240 tcacatgtcg tctctctctt tctgcagcac aacaagattc gcagcgtgga ggggagccag 300 ctgaaggcct acctttcctt agaagtgtta gatctgagtt tgaacaacat cacggaagtg 360 cggaacacct gctttccaca cggaccgcct ataaaggagc tcaacctggc aggcaatcgg 420 attggcaccc tggagttggg agcatttgat ggtctgtcac ggtcgctgct aactcttcgc 480 ctgagcaaaa acaggatcac ccagcttcct gtaagagcat tcaagctacc caggctgaca 540 caactggacc tcaatcggaa caggattcgg ctgatagagg gcctcacctt ccaggggctc 600 aacagcttgg aggtgctgaa gcttcagcga aacaacatca gcaaactgac agatggggcc 660 ttctggggac tgtccaagat gcatgtgctg cacctggagt acaacagcct ggtagaagtg 720 aacagcggct cgctctacgg cctcacggcc ctgcatcagc tccacctcag caacaattcc 780 atcgctcgca ttcaccgcaa gggctggagc ttctgccaga agctgcatga gttggtcctg 840 tccttcaaca acctgacacg gctggacgag gagagcctgg ccgagctgag cagcctgagt 900 gtcctgcgtc tcagccacaa ttccatcagc cacattgcgg agggtgcctt caagggactc 960 aggagcctgc gagtcttgga tctggaccat aacgagattt cgggcacaat agaggacacg 1020 agcggcgcct tctcagggct cgacagcctc agcaagctga ctctgtttgg aaacaagatc 1080 aagtctgtgg ctaagagagc attctcgggg ctggaaggcc tggagcacct gaaccttgga 1140 gggaatgcga tcagatctgt ccagtttgat gcctttgtga agatgaagaa tcttaaagag 1200 ctccatatca gcagcgacag cttcctgtgt gactgccagc tgaagtggct gcccccgtgg 1260 ctaattggca ggatgctgca ggcctttgtg acagccacct gtgcccaccc agaatcactg 1320 aagggtcaga gcattttctc tgtgccacca gagagtttcg tgtgcgatga cttcctgaag 1380 ccacagatca tcacccagcc agaaaccacc atggctatgg tgggcaagga catccggttt 1440 acatgctcag cagccagcag cagcagctcc cccatgacct ttgcctggaa gaaagacaat 1500 gaagtcctga ccaatgcaga catggagaac tttgtccacg tccacgcgca ggacggggaa 1560 gtgatggagt acaccaccat cctgcacctc cgtcaggtca ctttcgggca cgagggccgc 1620 taccaatgtg tcatcaccaa ccactttggc tccacctatt cacataaggc caggctcacc 1680 gtgaatgtgt tgccatcatt caccaaaacg ccccacgaca taaccatccg gaccaccacc 1740 gtggcccgcc tcgaatgtgc tgccacaggt cacccaaacc ctcagattgc ctggcagaag 1800 gatggaggca cggatttccc cgctgcccgt gagcgacgca tgcatgtcat gccggatgac 1860 gacgtgtttt tcatcactga tgtgaaaata gatgacgcag gggtttacag ctgtactgct 1920 cagaactcag ccggttctat ttcagctaat gccaccctga ctgtcctaga gaccccatcc 1980 ttggtggtcc ccttggaaga ccgtgtggta tctgtgggag aaacagtggc cctccaatgc 2040 aaagccacgg ggaaccctcc gccccgcatc acctggttca agggggaccg cccgctgagc 2100 ctcactgagc ggcaccacct gacccctgac aaccagctcc tggtggttca gaacgtggtg 2160 gcagaggatg cgggccgata tacctgtgag atgtccaaca ccctgggcac ggagcgagct 2220 cacagccagc tgagcgtcct gcccgcagca ggctgcagga aggatgggac cacggtaggc 2280 atcttcggat cccgcaacac cggccgcggc ggcgaggaga agaagaagga gaaggagaag 2340 gaggagcagg aggagcgcga gaccaagacc cccgagtgcc ccagccacac ccagcccctg 2400 ggcgtgttcc tgtttcctcc aaagcccaag gacacactga tgatctccag gacaccagag 2460 gtgacctgcg tggtggtgga cgtgagccac gaggaccccg aggtgaagtt caactggtac 2520 gtggatggcg tggaggtgca caatgccaag accaagccca gagaggagca gtacaactct 2580 acctataggg tggtgagcgt gctgacagtg ctgcaccagg actggctgaa cggcaaggag 2640 tataagtgca aggtgagcaa taaggccctg cctgccccaa tcgagaagac aatctccaag 2700 gccaagggcc agccaagaga gccccaggtg tacaccctgc cccctagcag ggatgagctg 2760 acaaagaacc aggtgtccct gacctgtctg gtgaagggct tttatccctc cgacatcgcc 2820 gtggagtggg agtctaatgg ccagcctgag aataactaca agacaacccc acccgtgctg 2880 gattctgacg gcagcttctt tctgtattct aagctgaccg tggacaagag caggtggcag 2940 cagggcaacg tgttcagctg ctccgtgatg cacgaagcac tgcacaatca ctacacccag 3000 aaatcactgt cactgagccc tggcaaa 3027 <210> 44 <211> 2988 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 44 gctgggcctc gggctccttg tgctgccgcc tgcacatgtg caggcgattc cctggactgc 60 ggcggcagag gcctggccgc cctgcctggc gatctgccat cctggacccg gagcctgaac 120 ctgagctaca acaagctgag cgagatcgat cccgccggct ttgaggacct gcctaacctg 180 caggaggtgt atctgaacaa taacgagctg accgcggtac catccctggg cgctgcttca 240 tcacatgtcg tctctctctt tctgcagcac aacaagattc gcagcgtgga ggggagccag 300 ctgaaggcct acctttcctt agaagtgtta gatctgagtt tgaacaacat cacggaagtg 360 cggaacacct gctttccaca cggaccgcct ataaaggagc tcaacctggc aggcaatcgg 420 attggcaccc tggagttggg agcatttgat ggtctgtcac ggtcgctgct aactcttcgc 480 ctgagcaaaa acaggatcac ccagcttcct gtaagagcat tcaagctacc caggctgaca 540 caactggacc tcaatcggaa caggattcgg ctgatagagg gcctcacctt ccaggggctc 600 aacagcttgg aggtgctgaa gcttcagcga aacaacatca gcaaactgac agatggggcc 660 ttctggggac tgtccaagat gcatgtgctg cacctggagt acaacagcct ggtagaagtg 720 aacagcggct cgctctacgg cctcacggcc ctgcatcagc tccacctcag caacaattcc 780 atcgctcgca ttcaccgcaa gggctggagc ttctgccaga agctgcatga gttggtcctg 840 tccttcaaca acctgacacg gctggacgag gagagcctgg ccgagctgag cagcctgagt 900 gtcctgcgtc tcagccacaa ttccatcagc cacattgcgg agggtgcctt caagggactc 960 aggagcctgc gagtcttgga tctggaccat aacgagattt cgggcacaat agaggacacg 1020 agcggcgcct tctcagggct cgacagcctc agcaagctga ctctgtttgg aaacaagatc 1080 aagtctgtgg ctaagagagc attctcgggg ctggaaggcc tggagcacct gaaccttgga 1140 gggaatgcga tcagatctgt ccagtttgat gcctttgtga agatgaagaa tcttaaagag 1200 ctccatatca gcagcgacag cttcctgtgt gactgccagc tgaagtggct gcccccgtgg 1260 ctaattggca ggatgctgca ggcctttgtg acagccacct gtgcccaccc agaatcactg 1320 aagggtcaga gcattttctc tgtgccacca gagagtttcg tgtgcgatga cttcctgaag 1380 ccacagatca tcacccagcc agaaaccacc atggctatgg tgggcaagga catccggttt 1440 acatgctcag cagccagcag cagcagctcc cccatgacct ttgcctggaa gaaagacaat 1500 gaagtcctga ccaatgcaga catggagaac tttgtccacg tccacgcgca ggacggggaa 1560 gtgatggagt acaccaccat cctgcacctc cgtcaggtca ctttcgggca cgagggccgc 1620 taccaatgtg tcatcaccaa ccactttggc tccacctatt cacataaggc caggctcacc 1680 gtgaatgtgt tgccatcatt caccaaaacg ccccacgaca taaccatccg gaccaccacc 1740 gtggcccgcc tcgaatgtgc tgccacaggt cacccaaacc ctcagattgc ctggcagaag 1800 gatggaggca cggatttccc cgctgcccgt gagcgacgca tgcatgtcat gccggatgac 1860 gacgtgtttt tcatcactga tgtgaaaata gatgacgcag gggtttacag ctgtactgct 1920 cagaactcag ccggttctat ttcagctaat gccaccctga ctgtcctaga gaccccatcc 1980 ttggtggtcc ccttggaaga ccgtgtggta tctgtgggag aaacagtggc cctccaatgc 2040 aaagccacgg ggaaccctcc gccccgcatc acctggttca agggggaccg cccgctgagc 2100 ctcactgagc ggcaccacct gacccctgac aaccagctcc tggtggttca gaacgtggtg 2160 gcagaggatg cgggccgata tacctgtgag atgtccaaca ccctgggcac ggagcgagct 2220 cacagccagc tgagcgtcct gcccgcagca ggctgcagga aggatgggac cacggtaggc 2280 atcttcggat ccgaaccgaa atcttctgac aaaacccaca cctctccgcc gtctccggct 2340 ccggaactgc tgggtggttc ttctgttttc ctgtttcctc caaagcccaa ggacacactg 2400 atgatctcca ggacaccaga ggtgacctgc gtggtggtgg acgtgagcca cgaggacccc 2460 gaggtgaagt tcaactggta cgtggatggc gtggaggtgc acaatgccaa gaccaagccc 2520 agagaggagc agtacaactc tacctatagg gtggtgagcg tgctgacagt gctgcaccag 2580 gactggctga acggcaagga gtataagtgc aaggtgagca ataaggccct gcctgcccca 2640 atcgagaaga caatctccaa ggccaagggc cagccaagag agccccaggt gtacaccctg 2700 ccccctagca gggatgagct gacaaagaac caggtgtccc tgacctgtct ggtgaagggc 2760 ttttatccct ccgacatcgc cgtggagtgg gagtctaatg gccagcctga gaataactac 2820 aagacaaccc cacccgtgct ggattctgac ggcagcttct ttctgtattc taagctgacc 2880 gtggacaaga gcaggtggca gcagggcaac gtgttcagct gctccgtgat gcacgaagca 2940 ctgcacaatc actacaccca gaaatcactg tcactgagcc ctggcaaa 2988 <210> 45 <211> 994 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 45 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Ser Glu Pro Lys Ser Ser Asp 755 760 765 Lys Thr His Thr Ser Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 770 775 780 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 785 790 795 800 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 805 810 815 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 820 825 830 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 835 840 845 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 850 855 860 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 865 870 875 880 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 885 890 895 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 900 905 910 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 915 920 925 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 930 935 940 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 945 950 955 960 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 965 970 975 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 980 985 990 Gly Lys <210> 46 <211> 995 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 46 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Ser Glu Pro Arg Gly Pro Thr 755 760 765 Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly 770 775 780 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 785 790 795 800 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 805 810 815 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 820 825 830 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 835 840 845 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 850 855 860 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 865 870 875 880 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 885 890 895 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 900 905 910 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 915 920 925 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 930 935 940 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 945 950 955 960 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 965 970 975 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 980 985 990 Pro Gly Lys 995 <210> 47 <211> 1007 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 47 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Ser Arg Asn Thr Gly Arg Gly 755 760 765 Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg 770 775 780 Glu Thr Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro Leu Gly Val 785 790 795 800 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 805 810 815 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 820 825 830 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 835 840 845 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 850 855 860 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 865 870 875 880 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 885 890 895 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 900 905 910 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 915 920 925 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 930 935 940 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 945 950 955 960 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 965 970 975 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 980 985 990 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 995 1000 1005 <210> 48 <211> 994 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 48 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Ser Glu Pro Lys Ser Ser Asp 755 760 765 Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu Leu Gly Gly 770 775 780 Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 785 790 795 800 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 805 810 815 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 820 825 830 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 835 840 845 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 850 855 860 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 865 870 875 880 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 885 890 895 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 900 905 910 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 915 920 925 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 930 935 940 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 945 950 955 960 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 965 970 975 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 980 985 990 Gly Lys <210> 49 <211> 2982 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 49 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggatccgagc caaagtcctc tgataagaca cacacctctc caccatgccc agcaccagag 2340 ctgctgggag gaccaagcgt gttcctgttt cctccaaagc ccaaggacac actgatgatc 2400 tccaggacac cagaggtgac ctgcgtggtg gtggacgtga gccacgagga ccccgaggtg 2460 aagttcaact ggtacgtgga tggcgtggag gtgcacaatg ccaagaccaa gcccagagag 2520 gagcagtaca actctaccta tagggtggtg agcgtgctga cagtgctgca ccaggactgg 2580 ctgaacggca aggagtataa gtgcaaggtg agcaataagg ccctgcctgc cccaatcgag 2640 aagacaatct ccaaggccaa gggccagcca agagagcccc aggtgtacac cctgccccct 2700 agcagggatg agctgacaaa gaaccaggtg tccctgacct gtctggtgaa gggcttttat 2760 ccctccgaca tcgccgtgga gtgggagtct aatggccagc ctgagaataa ctacaagaca 2820 accccacccg tgctggattc tgacggcagc ttctttctgt attctaagct gaccgtggac 2880 aagagcaggt ggcagcaggg caacgtgttc agctgctccg tgatgcacga agcactgcac 2940 aatcactaca cccagaaatc actgtcactg agccctggca aa 2982 <210> 50 <211> 2985 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 50 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggatccgagc ctcggggccc taccatcaag ccctgccccc cttgcaagtg ccctgcccct 2340 aatctgctgg gcggaccctc cgtgttcctg tttcctccaa agcccaagga cacactgatg 2400 atctccagga caccagaggt gacctgcgtg gtggtggacg tgagccacga ggaccccgag 2460 gtgaagttca actggtacgt ggatggcgtg gaggtgcaca atgccaagac caagcccaga 2520 gaggagcagt acaactctac ctatagggtg gtgagcgtgc tgacagtgct gcaccaggac 2580 tggctgaacg gcaaggagta taagtgcaag gtgagcaata aggccctgcc tgccccaatc 2640 gagaagacaa tctccaaggc caagggccag ccaagagagc cccaggtgta caccctgccc 2700 cctagcaggg atgagctgac aaagaaccag gtgtccctga cctgtctggt gaagggcttt 2760 tatccctccg acatcgccgt ggagtgggag tctaatggcc agcctgagaa taactacaag 2820 acaaccccac ccgtgctgga ttctgacggc agcttctttc tgtattctaa gctgaccgtg 2880 gacaagagca ggtggcagca gggcaacgtg ttcagctgct ccgtgatgca cgaagcactg 2940 cacaatcact acacccagaa atcactgtca ctgagccctg gcaaa 2985 <210> 51 <211> 3021 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 51 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggatcccgca acaccggccg cggcggcgag gagaagaaga aggagaagga gaaggaggag 2340 caggaggagc gcgagaccaa gacccccgag tgccccagcc acacccagcc cctgggcgtg 2400 ttcctgtttc ctccaaagcc caaggacaca ctgatgatct ccaggacacc agaggtgacc 2460 tgcgtggtgg tggacgtgag ccacgaggac cccgaggtga agttcaactg gtacgtggat 2520 ggcgtggagg tgcacaatgc caagaccaag cccagagagg agcagtacaa ctctacctat 2580 agggtggtga gcgtgctgac agtgctgcac caggactggc tgaacggcaa ggagtataag 2640 tgcaaggtga gcaataaggc cctgcctgcc ccaatcgaga agacaatctc caaggccaag 2700 ggccagccaa gagagcccca ggtgtacacc ctgcccccta gcagggatga gctgacaaag 2760 aaccaggtgt ccctgacctg tctggtgaag ggcttttatc cctccgacat cgccgtggag 2820 tgggagtcta atggccagcc tgagaataac tacaagacaa ccccacccgt gctggattct 2880 gacggcagct tctttctgta ttctaagctg accgtggaca agagcaggtg gcagcagggc 2940 aacgtgttca gctgctccgt gatgcacgaa gcactgcaca atcactacac ccagaaatca 3000 ctgtcactga gccctggcaa a 3021 <210> 52 <211> 2982 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 52 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggatccgaac cgaaatcttc tgacaaaacc cacacctctc cgccgtctcc ggctccggaa 2340 ctgctgggtg gttcttctgt tttcctgttt cctccaaagc ccaaggacac actgatgatc 2400 tccaggacac cagaggtgac ctgcgtggtg gtggacgtga gccacgagga ccccgaggtg 2460 aagttcaact ggtacgtgga tggcgtggag gtgcacaatg ccaagaccaa gcccagagag 2520 gagcagtaca actctaccta tagggtggtg agcgtgctga cagtgctgca ccaggactgg 2580 ctgaacggca aggagtataa gtgcaaggtg agcaataagg ccctgcctgc cccaatcgag 2640 aagacaatct ccaaggccaa gggccagcca agagagcccc aggtgtacac cctgccccct 2700 agcagggatg agctgacaaa gaaccaggtg tccctgacct gtctggtgaa gggcttttat 2760 ccctccgaca tcgccgtgga gtgggagtct aatggccagc ctgagaataa ctacaagaca 2820 accccacccg tgctggattc tgacggcagc ttctttctgt attctaagct gaccgtggac 2880 aagagcaggt ggcagcaggg caacgtgttc agctgctccg tgatgcacga agcactgcac 2940 aatcactaca cccagaaatc actgtcactg agccctggca aa 2982 <210> 53 <211> 994 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 53 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Ser Glu Pro Lys Ser Ser Asp 755 760 765 Lys Thr His Thr Ser Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 770 775 780 Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile 785 790 795 800 Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp 805 810 815 Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His 820 825 830 Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg 835 840 845 Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys 850 855 860 Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu 865 870 875 880 Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr 885 890 895 Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu 900 905 910 Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp 915 920 925 Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val 930 935 940 Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu 945 950 955 960 Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His 965 970 975 Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro 980 985 990 Gly Lys <210> 54 <211> 995 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 54 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Ser Glu Pro Arg Gly Pro Thr 755 760 765 Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly 770 775 780 Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met 785 790 795 800 Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu 805 810 815 Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val 820 825 830 His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu 835 840 845 Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly 850 855 860 Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile 865 870 875 880 Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val 885 890 895 Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr 900 905 910 Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu 915 920 925 Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro 930 935 940 Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val 945 950 955 960 Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val 965 970 975 His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr 980 985 990 Pro Gly Lys 995 <210> 55 <211> 1007 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 55 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Ser Arg Asn Thr Gly Arg Gly 755 760 765 Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg 770 775 780 Glu Thr Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro Leu Gly Val 785 790 795 800 Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 805 810 815 Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 820 825 830 Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 835 840 845 Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser 850 855 860 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys 865 870 875 880 Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 885 890 895 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 900 905 910 Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met 915 920 925 Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 930 935 940 Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 945 950 955 960 Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 965 970 975 Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 980 985 990 His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 995 1000 1005 <210> 56 <211> 994 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 56 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Ser Glu Pro Lys Ser Ser Asp 755 760 765 Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu Leu Gly Gly 770 775 780 Ser Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile 785 790 795 800 Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp 805 810 815 Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His 820 825 830 Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg 835 840 845 Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys 850 855 860 Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu 865 870 875 880 Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr 885 890 895 Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu 900 905 910 Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp 915 920 925 Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val 930 935 940 Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu 945 950 955 960 Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His 965 970 975 Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro 980 985 990 Gly Lys <210> 57 <211> 2982 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 57 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggatccgagc caaagtcctc tgataagaca cacacctctc caccatgccc agcaccagag 2340 ctgctgggag gaccaagcgt gttcatcttc ccacccaaga tcaaggacgt gctgatgatc 2400 tccctgtccc ccatcgtgac ctgcgtggtg gtggacgtgt ccgaggacga ccccgacgtg 2460 cagatcagtt ggttcgtgaa caacgtggaa gtgcacaccg cccagaccca gacccacaga 2520 gaggactaca actccaccct gcgggtggtg tccgccctgc ccatccagca ccaggactgg 2580 atgtccggca aagaattcaa gtgcaaagtg aacaacaagg acctgcctgc ccccatcgag 2640 cggaccatct ccaagcccaa gggctccgtg cgggctcccc aggtgtacgt gctgccccct 2700 ccagaggaag agatgaccaa gaagcaggtc acactgacct gcatggtcac cgacttcatg 2760 cccgaggaca tctacgtgga atggaccaac aatggcaaga ccgagctgaa ctacaagaac 2820 accgagcctg tgctggactc cgacggctcc tacttcatgt actccaagct gcgggtggaa 2880 aagaagaact gggtcgagcg gaactcctac tcctgctccg tggtgcacga gggcctgcac 2940 aaccaccaca ccaccaagtc cttctcccgg acccccggca aa 2982 <210> 58 <211> 2985 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 58 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggatccgagc ctcggggccc taccatcaag ccctgccccc cttgcaagtg ccctgcccct 2340 aatctgctgg gcggaccctc cgtgttcatc ttcccaccca agatcaagga cgtgctgatg 2400 atctccctgt cccccatcgt gacctgcgtg gtggtggacg tgtccgagga cgaccccgac 2460 gtgcagatca gttggttcgt gaacaacgtg gaagtgcaca ccgcccagac ccagacccac 2520 agagaggact acaactccac cctgcgggtg gtgtccgccc tgcccatcca gcaccaggac 2580 tggatgtccg gcaaagaatt caagtgcaaa gtgaacaaca aggacctgcc tgcccccatc 2640 gagcggacca tctccaagcc caagggctcc gtgcgggctc cccaggtgta cgtgctgccc 2700 cctccagagg aagagatgac caagaagcag gtcacactga cctgcatggt caccgacttc 2760 atgcccgagg acatctacgt ggaatggacc aacaatggca agaccgagct gaactacaag 2820 aacaccgagc ctgtgctgga ctccgacggc tcctacttca tgtactccaa gctgcgggtg 2880 gaaaagaaga actgggtcga gcggaactcc tactcctgct ccgtggtgca cgagggcctg 2940 cacaaccacc acaccaccaa gtccttctcc cggacccccg gcaaa 2985 <210> 59 <211> 3021 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 59 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggatcccgca acaccggccg cggcggcgag gagaagaaga aggagaagga gaaggaggag 2340 caggaggagc gcgagaccaa gacccccgag tgccccagcc acacccagcc cctgggcgtg 2400 ttcatcttcc cacccaagat caaggacgtg ctgatgatct ccctgtcccc catcgtgacc 2460 tgcgtggtgg tggacgtgtc cgaggacgac cccgacgtgc agatcagttg gttcgtgaac 2520 aacgtggaag tgcacaccgc ccagacccag acccacagag aggactacaa ctccaccctg 2580 cgggtggtgt ccgccctgcc catccagcac caggactgga tgtccggcaa agaattcaag 2640 tgcaaagtga acaacaagga cctgcctgcc cccatcgagc ggaccatctc caagcccaag 2700 ggctccgtgc gggctcccca ggtgtacgtg ctgccccctc cagaggaaga gatgaccaag 2760 aagcaggtca cactgacctg catggtcacc gacttcatgc ccgaggacat ctacgtggaa 2820 tggaccaaca atggcaagac cgagctgaac tacaagaaca ccgagcctgt gctggactcc 2880 gacggctcct acttcatgta ctccaagctg cgggtggaaa agaagaactg ggtcgagcgg 2940 aactcctact cctgctccgt ggtgcacgag ggcctgcaca accaccacac caccaagtcc 3000 ttctcccgga cccccggcaa a 3021 <210> 60 <211> 2982 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 60 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggatccgaac cgaaatcttc tgacaaaacc cacacctctc cgccgtctcc ggctccggaa 2340 ctgctgggtg gttcttctgt tttcatcttc ccacccaaga tcaaggacgt gctgatgatc 2400 tccctgtccc ccatcgtgac ctgcgtggtg gtggacgtgt ccgaggacga ccccgacgtg 2460 cagatcagtt ggttcgtgaa caacgtggaa gtgcacaccg cccagaccca gacccacaga 2520 gaggactaca actccaccct gcgggtggtg tccgccctgc ccatccagca ccaggactgg 2580 atgtccggca aagaattcaa gtgcaaagtg aacaacaagg acctgcctgc ccccatcgag 2640 cggaccatct ccaagcccaa gggctccgtg cgggctcccc aggtgtacgt gctgccccct 2700 ccagaggaag agatgaccaa gaagcaggtc acactgacct gcatggtcac cgacttcatg 2760 cccgaggaca tctacgtgga atggaccaac aatggcaaga ccgagctgaa ctacaagaac 2820 accgagcctg tgctggactc cgacggctcc tacttcatgt actccaagct gcgggtggaa 2880 aagaagaact gggtcgagcg gaactcctac tcctgctccg tggtgcacga gggcctgcac 2940 aaccaccaca ccaccaagtc cttctcccgg acccccggca aa 2982 <210> 61 <211> 999 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 61 Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp 1 5 10 15 Ser Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu 20 25 30 Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu 35 40 45 Ile Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr 50 55 60 Leu Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser 65 70 75 80 Ser His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val 85 90 95 Glu Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu 100 105 110 Ser Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly 115 120 125 Pro Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu 130 135 140 Glu Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg 145 150 155 160 Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu 165 170 175 Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile 180 185 190 Glu Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu 195 200 205 Gln Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu 210 215 220 Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val 225 230 235 240 Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu 245 250 255 Ser Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys 260 265 270 Gln Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu 275 280 285 Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu 290 295 300 Ser His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu 305 310 315 320 Arg Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr 325 330 335 Ile Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys 340 345 350 Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe 355 360 365 Ser Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile 370 375 380 Arg Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu 385 390 395 400 Leu His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp 405 410 415 Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala 420 425 430 Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val 435 440 445 Pro Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile 450 455 460 Thr Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe 465 470 475 480 Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp 485 490 495 Lys Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val 500 505 510 His Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu 515 520 525 His Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val 530 535 540 Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr 545 550 555 560 Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile 565 570 575 Arg Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro 580 585 590 Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala 595 600 605 Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe 610 615 620 Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala 625 630 635 640 Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu 645 650 655 Glu Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val 660 665 670 Gly Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro 675 680 685 Arg Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg 690 695 700 His His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val 705 710 715 720 Ala Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly 725 730 735 Thr Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys 740 745 750 Arg Lys Asp Gly Thr Thr Val Gly Ile Phe Gly Gly Gly Gly Ser Glu 755 760 765 Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Cys Pro Ala Pro 770 775 780 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 785 790 795 800 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 805 810 815 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 820 825 830 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 835 840 845 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 850 855 860 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 865 870 875 880 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 885 890 895 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 900 905 910 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 915 920 925 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 930 935 940 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 945 950 955 960 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 965 970 975 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 980 985 990 Leu Ser Leu Ser Pro Gly Lys 995 <210> 62 <211> 1000 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 62 Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp 1 5 10 15 Ser Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu 20 25 30 Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu 35 40 45 Ile Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr 50 55 60 Leu Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser 65 70 75 80 Ser His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val 85 90 95 Glu Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu 100 105 110 Ser Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly 115 120 125 Pro Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu 130 135 140 Glu Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg 145 150 155 160 Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu 165 170 175 Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile 180 185 190 Glu Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu 195 200 205 Gln Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu 210 215 220 Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val 225 230 235 240 Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu 245 250 255 Ser Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys 260 265 270 Gln Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu 275 280 285 Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu 290 295 300 Ser His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu 305 310 315 320 Arg Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr 325 330 335 Ile Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys 340 345 350 Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe 355 360 365 Ser Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile 370 375 380 Arg Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu 385 390 395 400 Leu His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp 405 410 415 Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala 420 425 430 Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val 435 440 445 Pro Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile 450 455 460 Thr Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe 465 470 475 480 Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp 485 490 495 Lys Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val 500 505 510 His Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu 515 520 525 His Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val 530 535 540 Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr 545 550 555 560 Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile 565 570 575 Arg Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro 580 585 590 Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala 595 600 605 Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe 610 615 620 Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala 625 630 635 640 Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu 645 650 655 Glu Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val 660 665 670 Gly Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro 675 680 685 Arg Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg 690 695 700 His His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val 705 710 715 720 Ala Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly 725 730 735 Thr Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys 740 745 750 Arg Lys Asp Gly Thr Thr Val Gly Ile Phe Gly Gly Gly Gly Ser Glu 755 760 765 Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala 770 775 780 Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 785 790 795 800 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 805 810 815 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 820 825 830 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 835 840 845 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 850 855 860 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 865 870 875 880 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 885 890 895 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 900 905 910 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 915 920 925 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 930 935 940 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 945 950 955 960 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 965 970 975 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 980 985 990 Ser Leu Ser Leu Ser Pro Gly Lys 995 1000 <210> 63 <211> 1012 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 63 Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp 1 5 10 15 Ser Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu 20 25 30 Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu 35 40 45 Ile Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr 50 55 60 Leu Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser 65 70 75 80 Ser His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val 85 90 95 Glu Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu 100 105 110 Ser Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly 115 120 125 Pro Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu 130 135 140 Glu Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg 145 150 155 160 Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu 165 170 175 Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile 180 185 190 Glu Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu 195 200 205 Gln Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu 210 215 220 Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val 225 230 235 240 Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu 245 250 255 Ser Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys 260 265 270 Gln Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu 275 280 285 Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu 290 295 300 Ser His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu 305 310 315 320 Arg Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr 325 330 335 Ile Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys 340 345 350 Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe 355 360 365 Ser Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile 370 375 380 Arg Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu 385 390 395 400 Leu His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp 405 410 415 Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala 420 425 430 Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val 435 440 445 Pro Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile 450 455 460 Thr Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe 465 470 475 480 Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp 485 490 495 Lys Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val 500 505 510 His Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu 515 520 525 His Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val 530 535 540 Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr 545 550 555 560 Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile 565 570 575 Arg Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro 580 585 590 Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala 595 600 605 Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe 610 615 620 Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala 625 630 635 640 Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu 645 650 655 Glu Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val 660 665 670 Gly Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro 675 680 685 Arg Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg 690 695 700 His His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val 705 710 715 720 Ala Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly 725 730 735 Thr Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys 740 745 750 Arg Lys Asp Gly Thr Thr Val Gly Ile Phe Gly Gly Gly Gly Ser Arg 755 760 765 Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu 770 775 780 Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His Thr 785 790 795 800 Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 805 810 815 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 820 825 830 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 835 840 845 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 850 855 860 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 865 870 875 880 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 885 890 895 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 900 905 910 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 915 920 925 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 930 935 940 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 945 950 955 960 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 965 970 975 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 980 985 990 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 995 1000 1005 Ser Pro Gly Lys 1010 <210> 64 <211> 999 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 64 Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp 1 5 10 15 Ser Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu 20 25 30 Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu 35 40 45 Ile Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr 50 55 60 Leu Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser 65 70 75 80 Ser His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val 85 90 95 Glu Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu 100 105 110 Ser Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly 115 120 125 Pro Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu 130 135 140 Glu Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg 145 150 155 160 Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu 165 170 175 Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile 180 185 190 Glu Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu 195 200 205 Gln Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu 210 215 220 Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val 225 230 235 240 Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu 245 250 255 Ser Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys 260 265 270 Gln Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu 275 280 285 Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu 290 295 300 Ser His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu 305 310 315 320 Arg Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr 325 330 335 Ile Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys 340 345 350 Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe 355 360 365 Ser Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile 370 375 380 Arg Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu 385 390 395 400 Leu His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp 405 410 415 Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala 420 425 430 Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val 435 440 445 Pro Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile 450 455 460 Thr Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe 465 470 475 480 Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp 485 490 495 Lys Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val 500 505 510 His Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu 515 520 525 His Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val 530 535 540 Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr 545 550 555 560 Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile 565 570 575 Arg Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro 580 585 590 Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala 595 600 605 Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe 610 615 620 Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala 625 630 635 640 Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu 645 650 655 Glu Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val 660 665 670 Gly Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro 675 680 685 Arg Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg 690 695 700 His His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val 705 710 715 720 Ala Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly 725 730 735 Thr Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys 740 745 750 Arg Lys Asp Gly Thr Thr Val Gly Ile Phe Gly Gly Gly Gly Ser Glu 755 760 765 Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro 770 775 780 Glu Leu Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 785 790 795 800 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 805 810 815 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 820 825 830 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 835 840 845 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 850 855 860 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 865 870 875 880 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 885 890 895 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 900 905 910 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 915 920 925 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 930 935 940 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 945 950 955 960 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 965 970 975 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 980 985 990 Leu Ser Leu Ser Pro Gly Lys 995 <210> 65 <211> 2997 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 65 gctgggcctc gggctccttg tgctgccgcc tgcacatgtg caggcgattc cctggactgc 60 ggcggcagag gcctggccgc cctgcctggc gatctgccat cctggacccg gagcctgaac 120 ctgagctaca acaagctgag cgagatcgat cccgccggct ttgaggacct gcctaacctg 180 caggaggtgt atctgaacaa taacgagctg accgcggtac catccctggg cgctgcttca 240 tcacatgtcg tctctctctt tctgcagcac aacaagattc gcagcgtgga ggggagccag 300 ctgaaggcct acctttcctt agaagtgtta gatctgagtt tgaacaacat cacggaagtg 360 cggaacacct gctttccaca cggaccgcct ataaaggagc tcaacctggc aggcaatcgg 420 attggcaccc tggagttggg agcatttgat ggtctgtcac ggtcgctgct aactcttcgc 480 ctgagcaaaa acaggatcac ccagcttcct gtaagagcat tcaagctacc caggctgaca 540 caactggacc tcaatcggaa caggattcgg ctgatagagg gcctcacctt ccaggggctc 600 aacagcttgg aggtgctgaa gcttcagcga aacaacatca gcaaactgac agatggggcc 660 ttctggggac tgtccaagat gcatgtgctg cacctggagt acaacagcct ggtagaagtg 720 aacagcggct cgctctacgg cctcacggcc ctgcatcagc tccacctcag caacaattcc 780 atcgctcgca ttcaccgcaa gggctggagc ttctgccaga agctgcatga gttggtcctg 840 tccttcaaca acctgacacg gctggacgag gagagcctgg ccgagctgag cagcctgagt 900 gtcctgcgtc tcagccacaa ttccatcagc cacattgcgg agggtgcctt caagggactc 960 aggagcctgc gagtcttgga tctggaccat aacgagattt cgggcacaat agaggacacg 1020 agcggcgcct tctcagggct cgacagcctc agcaagctga ctctgtttgg aaacaagatc 1080 aagtctgtgg ctaagagagc attctcgggg ctggaaggcc tggagcacct gaaccttgga 1140 gggaatgcga tcagatctgt ccagtttgat gcctttgtga agatgaagaa tcttaaagag 1200 ctccatatca gcagcgacag cttcctgtgt gactgccagc tgaagtggct gcccccgtgg 1260 ctaattggca ggatgctgca ggcctttgtg acagccacct gtgcccaccc agaatcactg 1320 aagggtcaga gcattttctc tgtgccacca gagagtttcg tgtgcgatga cttcctgaag 1380 ccacagatca tcacccagcc agaaaccacc atggctatgg tgggcaagga catccggttt 1440 acatgctcag cagccagcag cagcagctcc cccatgacct ttgcctggaa gaaagacaat 1500 gaagtcctga ccaatgcaga catggagaac tttgtccacg tccacgcgca ggacggggaa 1560 gtgatggagt acaccaccat cctgcacctc cgtcaggtca ctttcgggca cgagggccgc 1620 taccaatgtg tcatcaccaa ccactttggc tccacctatt cacataaggc caggctcacc 1680 gtgaatgtgt tgccatcatt caccaaaacg ccccacgaca taaccatccg gaccaccacc 1740 gtggcccgcc tcgaatgtgc tgccacaggt cacccaaacc ctcagattgc ctggcagaag 1800 gatggaggca cggatttccc cgctgcccgt gagcgacgca tgcatgtcat gccggatgac 1860 gacgtgtttt tcatcactga tgtgaaaata gatgacgcag gggtttacag ctgtactgct 1920 cagaactcag ccggttctat ttcagctaat gccaccctga ctgtcctaga gaccccatcc 1980 ttggtggtcc ccttggaaga ccgtgtggta tctgtgggag aaacagtggc cctccaatgc 2040 aaagccacgg ggaaccctcc gccccgcatc acctggttca agggggaccg cccgctgagc 2100 ctcactgagc ggcaccacct gacccctgac aaccagctcc tggtggttca gaacgtggtg 2160 gcagaggatg cgggccgata tacctgtgag atgtccaaca ccctgggcac ggagcgagct 2220 cacagccagc tgagcgtcct gcccgcagca ggctgcagga aggatgggac cacggtaggc 2280 atcttcggcg gtggcggatc cgagccaaag tcctctgata agacacacac ctctccacca 2340 tgcccagcac cagagctgct gggaggacca agcgtgttcc tgtttcctcc aaagcccaag 2400 gacacactga tgatctccag gacaccagag gtgacctgcg tggtggtgga cgtgagccac 2460 gaggaccccg aggtgaagtt caactggtac gtggatggcg tggaggtgca caatgccaag 2520 accaagccca gagaggagca gtacaactct acctataggg tggtgagcgt gctgacagtg 2580 ctgcaccagg actggctgaa cggcaaggag tataagtgca aggtgagcaa taaggccctg 2640 cctgccccaa tcgagaagac aatctccaag gccaagggcc agccaagaga gccccaggtg 2700 tacaccctgc cccctagcag ggatgagctg acaaagaacc aggtgtccct gacctgtctg 2760 gtgaagggct tttatccctc cgacatcgcc gtggagtggg agtctaatgg ccagcctgag 2820 aataactaca agacaacccc acccgtgctg gattctgacg gcagcttctt tctgtattct 2880 aagctgaccg tggacaagag caggtggcag cagggcaacg tgttcagctg ctccgtgatg 2940 cacgaagcac tgcacaatca ctacacccag aaatcactgt cactgagccc tggcaaa 2997 <210> 66 <211> 3000 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 66 gctgggcctc gggctccttg tgctgccgcc tgcacatgtg caggcgattc cctggactgc 60 ggcggcagag gcctggccgc cctgcctggc gatctgccat cctggacccg gagcctgaac 120 ctgagctaca acaagctgag cgagatcgat cccgccggct ttgaggacct gcctaacctg 180 caggaggtgt atctgaacaa taacgagctg accgcggtac catccctggg cgctgcttca 240 tcacatgtcg tctctctctt tctgcagcac aacaagattc gcagcgtgga ggggagccag 300 ctgaaggcct acctttcctt agaagtgtta gatctgagtt tgaacaacat cacggaagtg 360 cggaacacct gctttccaca cggaccgcct ataaaggagc tcaacctggc aggcaatcgg 420 attggcaccc tggagttggg agcatttgat ggtctgtcac ggtcgctgct aactcttcgc 480 ctgagcaaaa acaggatcac ccagcttcct gtaagagcat tcaagctacc caggctgaca 540 caactggacc tcaatcggaa caggattcgg ctgatagagg gcctcacctt ccaggggctc 600 aacagcttgg aggtgctgaa gcttcagcga aacaacatca gcaaactgac agatggggcc 660 ttctggggac tgtccaagat gcatgtgctg cacctggagt acaacagcct ggtagaagtg 720 aacagcggct cgctctacgg cctcacggcc ctgcatcagc tccacctcag caacaattcc 780 atcgctcgca ttcaccgcaa gggctggagc ttctgccaga agctgcatga gttggtcctg 840 tccttcaaca acctgacacg gctggacgag gagagcctgg ccgagctgag cagcctgagt 900 gtcctgcgtc tcagccacaa ttccatcagc cacattgcgg agggtgcctt caagggactc 960 aggagcctgc gagtcttgga tctggaccat aacgagattt cgggcacaat agaggacacg 1020 agcggcgcct tctcagggct cgacagcctc agcaagctga ctctgtttgg aaacaagatc 1080 aagtctgtgg ctaagagagc attctcgggg ctggaaggcc tggagcacct gaaccttgga 1140 gggaatgcga tcagatctgt ccagtttgat gcctttgtga agatgaagaa tcttaaagag 1200 ctccatatca gcagcgacag cttcctgtgt gactgccagc tgaagtggct gcccccgtgg 1260 ctaattggca ggatgctgca ggcctttgtg acagccacct gtgcccaccc agaatcactg 1320 aagggtcaga gcattttctc tgtgccacca gagagtttcg tgtgcgatga cttcctgaag 1380 ccacagatca tcacccagcc agaaaccacc atggctatgg tgggcaagga catccggttt 1440 acatgctcag cagccagcag cagcagctcc cccatgacct ttgcctggaa gaaagacaat 1500 gaagtcctga ccaatgcaga catggagaac tttgtccacg tccacgcgca ggacggggaa 1560 gtgatggagt acaccaccat cctgcacctc cgtcaggtca ctttcgggca cgagggccgc 1620 taccaatgtg tcatcaccaa ccactttggc tccacctatt cacataaggc caggctcacc 1680 gtgaatgtgt tgccatcatt caccaaaacg ccccacgaca taaccatccg gaccaccacc 1740 gtggcccgcc tcgaatgtgc tgccacaggt cacccaaacc ctcagattgc ctggcagaag 1800 gatggaggca cggatttccc cgctgcccgt gagcgacgca tgcatgtcat gccggatgac 1860 gacgtgtttt tcatcactga tgtgaaaata gatgacgcag gggtttacag ctgtactgct 1920 cagaactcag ccggttctat ttcagctaat gccaccctga ctgtcctaga gaccccatcc 1980 ttggtggtcc ccttggaaga ccgtgtggta tctgtgggag aaacagtggc cctccaatgc 2040 aaagccacgg ggaaccctcc gccccgcatc acctggttca agggggaccg cccgctgagc 2100 ctcactgagc ggcaccacct gacccctgac aaccagctcc tggtggttca gaacgtggtg 2160 gcagaggatg cgggccgata tacctgtgag atgtccaaca ccctgggcac ggagcgagct 2220 cacagccagc tgagcgtcct gcccgcagca ggctgcagga aggatgggac cacggtaggc 2280 atcttcggcg gtggcggatc cgagcctcgg ggccctacca tcaagccctg ccccccttgc 2340 aagtgccctg cccctaatct gctgggcgga ccctccgtgt tcctgtttcc tccaaagccc 2400 aaggacacac tgatgatctc caggacacca gaggtgacct gcgtggtggt ggacgtgagc 2460 cacgaggacc ccgaggtgaa gttcaactgg tacgtggatg gcgtggaggt gcacaatgcc 2520 aagaccaagc ccagagagga gcagtacaac tctacctata gggtggtgag cgtgctgaca 2580 gtgctgcacc aggactggct gaacggcaag gagtataagt gcaaggtgag caataaggcc 2640 ctgcctgccc caatcgagaa gacaatctcc aaggccaagg gccagccaag agagccccag 2700 gtgtacaccc tgccccctag cagggatgag ctgacaaaga accaggtgtc cctgacctgt 2760 ctggtgaagg gcttttatcc ctccgacatc gccgtggagt gggagtctaa tggccagcct 2820 gagaataact acaagacaac cccacccgtg ctggattctg acggcagctt ctttctgtat 2880 tctaagctga ccgtggacaa gagcaggtgg cagcagggca acgtgttcag ctgctccgtg 2940 atgcacgaag cactgcacaa tcactacacc cagaaatcac tgtcactgag ccctggcaaa 3000 3000 <210> 67 <211> 3036 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 67 gctgggcctc gggctccttg tgctgccgcc tgcacatgtg caggcgattc cctggactgc 60 ggcggcagag gcctggccgc cctgcctggc gatctgccat cctggacccg gagcctgaac 120 ctgagctaca acaagctgag cgagatcgat cccgccggct ttgaggacct gcctaacctg 180 caggaggtgt atctgaacaa taacgagctg accgcggtac catccctggg cgctgcttca 240 tcacatgtcg tctctctctt tctgcagcac aacaagattc gcagcgtgga ggggagccag 300 ctgaaggcct acctttcctt agaagtgtta gatctgagtt tgaacaacat cacggaagtg 360 cggaacacct gctttccaca cggaccgcct ataaaggagc tcaacctggc aggcaatcgg 420 attggcaccc tggagttggg agcatttgat ggtctgtcac ggtcgctgct aactcttcgc 480 ctgagcaaaa acaggatcac ccagcttcct gtaagagcat tcaagctacc caggctgaca 540 caactggacc tcaatcggaa caggattcgg ctgatagagg gcctcacctt ccaggggctc 600 aacagcttgg aggtgctgaa gcttcagcga aacaacatca gcaaactgac agatggggcc 660 ttctggggac tgtccaagat gcatgtgctg cacctggagt acaacagcct ggtagaagtg 720 aacagcggct cgctctacgg cctcacggcc ctgcatcagc tccacctcag caacaattcc 780 atcgctcgca ttcaccgcaa gggctggagc ttctgccaga agctgcatga gttggtcctg 840 tccttcaaca acctgacacg gctggacgag gagagcctgg ccgagctgag cagcctgagt 900 gtcctgcgtc tcagccacaa ttccatcagc cacattgcgg agggtgcctt caagggactc 960 aggagcctgc gagtcttgga tctggaccat aacgagattt cgggcacaat agaggacacg 1020 agcggcgcct tctcagggct cgacagcctc agcaagctga ctctgtttgg aaacaagatc 1080 aagtctgtgg ctaagagagc attctcgggg ctggaaggcc tggagcacct gaaccttgga 1140 gggaatgcga tcagatctgt ccagtttgat gcctttgtga agatgaagaa tcttaaagag 1200 ctccatatca gcagcgacag cttcctgtgt gactgccagc tgaagtggct gcccccgtgg 1260 ctaattggca ggatgctgca ggcctttgtg acagccacct gtgcccaccc agaatcactg 1320 aagggtcaga gcattttctc tgtgccacca gagagtttcg tgtgcgatga cttcctgaag 1380 ccacagatca tcacccagcc agaaaccacc atggctatgg tgggcaagga catccggttt 1440 acatgctcag cagccagcag cagcagctcc cccatgacct ttgcctggaa gaaagacaat 1500 gaagtcctga ccaatgcaga catggagaac tttgtccacg tccacgcgca ggacggggaa 1560 gtgatggagt acaccaccat cctgcacctc cgtcaggtca ctttcgggca cgagggccgc 1620 taccaatgtg tcatcaccaa ccactttggc tccacctatt cacataaggc caggctcacc 1680 gtgaatgtgt tgccatcatt caccaaaacg ccccacgaca taaccatccg gaccaccacc 1740 gtggcccgcc tcgaatgtgc tgccacaggt cacccaaacc ctcagattgc ctggcagaag 1800 gatggaggca cggatttccc cgctgcccgt gagcgacgca tgcatgtcat gccggatgac 1860 gacgtgtttt tcatcactga tgtgaaaata gatgacgcag gggtttacag ctgtactgct 1920 cagaactcag ccggttctat ttcagctaat gccaccctga ctgtcctaga gaccccatcc 1980 ttggtggtcc ccttggaaga ccgtgtggta tctgtgggag aaacagtggc cctccaatgc 2040 aaagccacgg ggaaccctcc gccccgcatc acctggttca agggggaccg cccgctgagc 2100 ctcactgagc ggcaccacct gacccctgac aaccagctcc tggtggttca gaacgtggtg 2160 gcagaggatg cgggccgata tacctgtgag atgtccaaca ccctgggcac ggagcgagct 2220 cacagccagc tgagcgtcct gcccgcagca ggctgcagga aggatgggac cacggtaggc 2280 atcttcggcg gtggcggatc ccgcaacacc ggccgcggcg gcgaggagaa gaagaaggag 2340 aaggagaagg aggagcagga ggagcgcgag accaagaccc ccgagtgccc cagccacacc 2400 cagcccctgg gcgtgttcct gtttcctcca aagcccaagg acacactgat gatctccagg 2460 acaccagagg tgacctgcgt ggtggtggac gtgagccacg aggaccccga ggtgaagttc 2520 aactggtacg tggatggcgt ggaggtgcac aatgccaaga ccaagcccag agaggagcag 2580 tacaactcta cctatagggt ggtgagcgtg ctgacagtgc tgcaccagga ctggctgaac 2640 ggcaaggagt ataagtgcaa ggtgagcaat aaggccctgc ctgccccaat cgagaagaca 2700 atctccaagg ccaagggcca gccaagagag ccccaggtgt acaccctgcc ccctagcagg 2760 gatgagctga caaagaacca ggtgtccctg acctgtctgg tgaagggctt ttatccctcc 2820 gacatcgccg tggagtggga gtctaatggc cagcctgaga ataactacaa gacaacccca 2880 cccgtgctgg attctgacgg cagcttcttt ctgtattcta agctgaccgt ggacaagagc 2940 aggtggcagc agggcaacgt gttcagctgc tccgtgatgc acgaagcact gcacaatcac 3000 tacacccaga aatcactgtc actgagccct ggcaaa 3036 <210> 68 <211> 2997 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 68 gctgggcctc gggctccttg tgctgccgcc tgcacatgtg caggcgattc cctggactgc 60 ggcggcagag gcctggccgc cctgcctggc gatctgccat cctggacccg gagcctgaac 120 ctgagctaca acaagctgag cgagatcgat cccgccggct ttgaggacct gcctaacctg 180 caggaggtgt atctgaacaa taacgagctg accgcggtac catccctggg cgctgcttca 240 tcacatgtcg tctctctctt tctgcagcac aacaagattc gcagcgtgga ggggagccag 300 ctgaaggcct acctttcctt agaagtgtta gatctgagtt tgaacaacat cacggaagtg 360 cggaacacct gctttccaca cggaccgcct ataaaggagc tcaacctggc aggcaatcgg 420 attggcaccc tggagttggg agcatttgat ggtctgtcac ggtcgctgct aactcttcgc 480 ctgagcaaaa acaggatcac ccagcttcct gtaagagcat tcaagctacc caggctgaca 540 caactggacc tcaatcggaa caggattcgg ctgatagagg gcctcacctt ccaggggctc 600 aacagcttgg aggtgctgaa gcttcagcga aacaacatca gcaaactgac agatggggcc 660 ttctggggac tgtccaagat gcatgtgctg cacctggagt acaacagcct ggtagaagtg 720 aacagcggct cgctctacgg cctcacggcc ctgcatcagc tccacctcag caacaattcc 780 atcgctcgca ttcaccgcaa gggctggagc ttctgccaga agctgcatga gttggtcctg 840 tccttcaaca acctgacacg gctggacgag gagagcctgg ccgagctgag cagcctgagt 900 gtcctgcgtc tcagccacaa ttccatcagc cacattgcgg agggtgcctt caagggactc 960 aggagcctgc gagtcttgga tctggaccat aacgagattt cgggcacaat agaggacacg 1020 agcggcgcct tctcagggct cgacagcctc agcaagctga ctctgtttgg aaacaagatc 1080 aagtctgtgg ctaagagagc attctcgggg ctggaaggcc tggagcacct gaaccttgga 1140 gggaatgcga tcagatctgt ccagtttgat gcctttgtga agatgaagaa tcttaaagag 1200 ctccatatca gcagcgacag cttcctgtgt gactgccagc tgaagtggct gcccccgtgg 1260 ctaattggca ggatgctgca ggcctttgtg acagccacct gtgcccaccc agaatcactg 1320 aagggtcaga gcattttctc tgtgccacca gagagtttcg tgtgcgatga cttcctgaag 1380 ccacagatca tcacccagcc agaaaccacc atggctatgg tgggcaagga catccggttt 1440 acatgctcag cagccagcag cagcagctcc cccatgacct ttgcctggaa gaaagacaat 1500 gaagtcctga ccaatgcaga catggagaac tttgtccacg tccacgcgca ggacggggaa 1560 gtgatggagt acaccaccat cctgcacctc cgtcaggtca ctttcgggca cgagggccgc 1620 taccaatgtg tcatcaccaa ccactttggc tccacctatt cacataaggc caggctcacc 1680 gtgaatgtgt tgccatcatt caccaaaacg ccccacgaca taaccatccg gaccaccacc 1740 gtggcccgcc tcgaatgtgc tgccacaggt cacccaaacc ctcagattgc ctggcagaag 1800 gatggaggca cggatttccc cgctgcccgt gagcgacgca tgcatgtcat gccggatgac 1860 gacgtgtttt tcatcactga tgtgaaaata gatgacgcag gggtttacag ctgtactgct 1920 cagaactcag ccggttctat ttcagctaat gccaccctga ctgtcctaga gaccccatcc 1980 ttggtggtcc ccttggaaga ccgtgtggta tctgtgggag aaacagtggc cctccaatgc 2040 aaagccacgg ggaaccctcc gccccgcatc acctggttca agggggaccg cccgctgagc 2100 ctcactgagc ggcaccacct gacccctgac aaccagctcc tggtggttca gaacgtggtg 2160 gcagaggatg cgggccgata tacctgtgag atgtccaaca ccctgggcac ggagcgagct 2220 cacagccagc tgagcgtcct gcccgcagca ggctgcagga aggatgggac cacggtaggc 2280 atcttcggcg gtggcggatc cgaaccgaaa tcttctgaca aaacccacac ctctccgccg 2340 tctccggctc cggaactgct gggtggttct tctgttttcc tgtttcctcc aaagcccaag 2400 gacacactga tgatctccag gacaccagag gtgacctgcg tggtggtgga cgtgagccac 2460 gaggaccccg aggtgaagtt caactggtac gtggatggcg tggaggtgca caatgccaag 2520 accaagccca gagaggagca gtacaactct acctataggg tggtgagcgt gctgacagtg 2580 ctgcaccagg actggctgaa cggcaaggag tataagtgca aggtgagcaa taaggccctg 2640 cctgccccaa tcgagaagac aatctccaag gccaagggcc agccaagaga gccccaggtg 2700 tacaccctgc cccctagcag ggatgagctg acaaagaacc aggtgtccct gacctgtctg 2760 gtgaagggct tttatccctc cgacatcgcc gtggagtggg agtctaatgg ccagcctgag 2820 aataactaca agacaacccc acccgtgctg gattctgacg gcagcttctt tctgtattct 2880 aagctgaccg tggacaagag caggtggcag cagggcaacg tgttcagctg ctccgtgatg 2940 cacgaagcac tgcacaatca ctacacccag aaatcactgt cactgagccc tggcaaa 2997 <210> 69 <211> 997 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 69 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Gly Gly Gly Ser Glu Pro Lys 755 760 765 Ser Ser Asp Lys Thr His Thr Ser Pro Pro Cys Pro Ala Pro Glu Leu 770 775 780 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 785 790 795 800 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 805 810 815 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 820 825 830 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 835 840 845 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 850 855 860 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 865 870 875 880 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 885 890 895 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 900 905 910 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 915 920 925 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 930 935 940 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 945 950 955 960 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 965 970 975 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 980 985 990 Leu Ser Pro Gly Lys 995 <210> 70 <211> 998 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 70 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Gly Gly Gly Ser Glu Pro Arg 755 760 765 Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn 770 775 780 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 785 790 795 800 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 805 810 815 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 820 825 830 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 835 840 845 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 850 855 860 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 865 870 875 880 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 885 890 895 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 900 905 910 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 915 920 925 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 930 935 940 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 945 950 955 960 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 965 970 975 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 980 985 990 Ser Leu Ser Pro Gly Lys 995 <210> 71 <211> 1010 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 71 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Gly Gly Gly Ser Arg Asn Thr 755 760 765 Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln 770 775 780 Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro 785 790 795 800 Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 805 810 815 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 820 825 830 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 835 840 845 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 850 855 860 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 865 870 875 880 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 885 890 895 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 900 905 910 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 915 920 925 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 930 935 940 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 945 950 955 960 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 965 970 975 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 980 985 990 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 995 1000 1005 Gly Lys 1010 <210> 72 <211> 997 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 72 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Gly Gly Gly Ser Glu Pro Lys 755 760 765 Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu 770 775 780 Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 785 790 795 800 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 805 810 815 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 820 825 830 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 835 840 845 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 850 855 860 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 865 870 875 880 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 885 890 895 Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 900 905 910 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 915 920 925 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 930 935 940 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 945 950 955 960 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 965 970 975 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 980 985 990 Leu Ser Pro Gly Lys 995 <210> 73 <211> 2991 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 73 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggcggtggcg gatccgagcc aaagtcctct gataagacac acacctctcc accatgccca 2340 gcaccagagc tgctgggagg accaagcgtg ttcctgtttc ctccaaagcc caaggacaca 2400 ctgatgatct ccaggacacc agaggtgacc tgcgtggtgg tggacgtgag ccacgaggac 2460 cccgaggtga agttcaactg gtacgtggat ggcgtggagg tgcacaatgc caagaccaag 2520 cccagagagg agcagtacaa ctctacctat agggtggtga gcgtgctgac agtgctgcac 2580 caggactggc tgaacggcaa ggagtataag tgcaaggtga gcaataaggc cctgcctgcc 2640 ccaatcgaga agacaatctc caaggccaag ggccagccaa gagagcccca ggtgtacacc 2700 ctgcccccta gcagggatga gctgacaaag aaccaggtgt ccctgacctg tctggtgaag 2760 ggcttttatc cctccgacat cgccgtggag tgggagtcta atggccagcc tgagaataac 2820 tacaagacaa ccccacccgt gctggattct gacggcagct tctttctgta ttctaagctg 2880 accgtggaca agagcaggtg gcagcagggc aacgtgttca gctgctccgt gatgcacgaa 2940 gcactgcaca atcactacac ccagaaatca ctgtcactga gccctggcaa a 2991 <210> 74 <211> 2994 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 74 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggcggtggcg gatccgagcc tcggggccct accatcaagc cctgcccccc ttgcaagtgc 2340 cctgccccta atctgctggg cggaccctcc gtgttcctgt ttcctccaaa gcccaaggac 2400 acactgatga tctccaggac accagaggtg acctgcgtgg tggtggacgt gagccacgag 2460 gaccccgagg tgaagttcaa ctggtacgtg gatggcgtgg aggtgcacaa tgccaagacc 2520 aagcccagag aggagcagta caactctacc tatagggtgg tgagcgtgct gacagtgctg 2580 caccaggact ggctgaacgg caaggagtat aagtgcaagg tgagcaataa ggccctgcct 2640 gccccaatcg agaagacaat ctccaaggcc aagggccagc caagagagcc ccaggtgtac 2700 accctgcccc ctagcaggga tgagctgaca aagaaccagg tgtccctgac ctgtctggtg 2760 aagggctttt atccctccga catcgccgtg gagtgggagt ctaatggcca gcctgagaat 2820 aactacaaga caaccccacc cgtgctggat tctgacggca gcttctttct gtattctaag 2880 ctgaccgtgg acaagagcag gtggcagcag ggcaacgtgt tcagctgctc cgtgatgcac 2940 gaagcactgc acaatcacta cacccagaaa tcactgtcac tgagccctgg caaa 2994 <210> 75 <211> 3030 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 75 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggcggtggcg gatcccgcaa caccggccgc ggcggcgagg agaagaagaa ggagaaggag 2340 aaggaggagc aggaggagcg cgagaccaag acccccgagt gccccagcca cacccagccc 2400 ctgggcgtgt tcctgtttcc tccaaagccc aaggacacac tgatgatctc caggacacca 2460 gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc ccgaggtgaa gttcaactgg 2520 tacgtggatg gcgtggaggt gcacaatgcc aagaccaagc ccagagagga gcagtacaac 2580 tctacctata gggtggtgag cgtgctgaca gtgctgcacc aggactggct gaacggcaag 2640 gagtataagt gcaaggtgag caataaggcc ctgcctgccc caatcgagaa gacaatctcc 2700 aaggccaagg gccagccaag agagccccag gtgtacaccc tgccccctag cagggatgag 2760 ctgacaaaga accaggtgtc cctgacctgt ctggtgaagg gcttttatcc ctccgacatc 2820 gccgtggagt gggagtctaa tggccagcct gagaataact acaagacaac cccacccgtg 2880 ctggattctg acggcagctt ctttctgtat tctaagctga ccgtggacaa gagcaggtgg 2940 cagcagggca acgtgttcag ctgctccgtg atgcacgaag cactgcacaa tcactacacc 3000 cagaaatcac tgtcactgag ccctggcaaa 3030 <210> 76 <211> 2991 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 76 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggcggtggcg gatccgaacc gaaatcttct gacaaaaccc acacctctcc gccgtctccg 2340 gctccggaac tgctgggtgg ttcttctgtt ttcctgtttc ctccaaagcc caaggacaca 2400 ctgatgatct ccaggacacc agaggtgacc tgcgtggtgg tggacgtgag ccacgaggac 2460 cccgaggtga agttcaactg gtacgtggat ggcgtggagg tgcacaatgc caagaccaag 2520 cccagagagg agcagtacaa ctctacctat agggtggtga gcgtgctgac agtgctgcac 2580 caggactggc tgaacggcaa ggagtataag tgcaaggtga gcaataaggc cctgcctgcc 2640 ccaatcgaga agacaatctc caaggccaag ggccagccaa gagagcccca ggtgtacacc 2700 ctgcccccta gcagggatga gctgacaaag aaccaggtgt ccctgacctg tctggtgaag 2760 ggcttttatc cctccgacat cgccgtggag tgggagtcta atggccagcc tgagaataac 2820 tacaagacaa ccccacccgt gctggattct gacggcagct tctttctgta ttctaagctg 2880 accgtggaca agagcaggtg gcagcagggc aacgtgttca gctgctccgt gatgcacgaa 2940 gcactgcaca atcactacac ccagaaatca ctgtcactga gccctggcaa a 2991 <210> 77 <211> 997 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 77 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Gly Gly Gly Ser Glu Pro Lys 755 760 765 Ser Ser Asp Lys Thr His Thr Ser Pro Pro Cys Pro Ala Pro Glu Leu 770 775 780 Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val 785 790 795 800 Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val 805 810 815 Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val 820 825 830 Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser 835 840 845 Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met 850 855 860 Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala 865 870 875 880 Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro 885 890 895 Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln 900 905 910 Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr 915 920 925 Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr 930 935 940 Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu 945 950 955 960 Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser 965 970 975 Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser 980 985 990 Arg Thr Pro Gly Lys 995 <210> 78 <211> 998 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 78 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Gly Gly Gly Ser Glu Pro Arg 755 760 765 Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn 770 775 780 Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp 785 790 795 800 Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp 805 810 815 Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn 820 825 830 Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn 835 840 845 Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp 850 855 860 Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro 865 870 875 880 Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala 885 890 895 Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys 900 905 910 Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile 915 920 925 Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn 930 935 940 Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys 945 950 955 960 Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys 965 970 975 Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe 980 985 990 Ser Arg Thr Pro Gly Lys 995 <210> 79 <211> 1010 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 79 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Gly Gly Gly Ser Arg Asn Thr 755 760 765 Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu Glu Gln 770 775 780 Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro 785 790 795 800 Leu Gly Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile 805 810 815 Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp 820 825 830 Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His 835 840 845 Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg 850 855 860 Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys 865 870 875 880 Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu 885 890 895 Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr 900 905 910 Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu 915 920 925 Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp 930 935 940 Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val 945 950 955 960 Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu 965 970 975 Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His 980 985 990 Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro 995 1000 1005 Gly Lys 1010 <210> 80 <211> 997 <212> PRT <213> Artificial Sequence <220> <223> fusion protein <400> 80 Ala Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala 1 5 10 15 Gly Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg 20 25 30 Asp Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu 35 40 45 Ser Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu 50 55 60 Val Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala 65 70 75 80 Ala Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu 85 90 95 Ser Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu 100 105 110 Asp Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro 115 120 125 Asn Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser 130 135 140 Ile Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr 145 150 155 160 Leu Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe 165 170 175 Lys Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg 180 185 190 Leu Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu 195 200 205 Arg Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp 210 215 220 Gly Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val 225 230 235 240 Glu Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu 245 250 255 His Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser 260 265 270 Phe Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr 275 280 285 Arg Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu 290 295 300 Arg Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys 305 310 315 320 Gly Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser 325 330 335 Gly Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu 340 345 350 Ser Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg 355 360 365 Ala Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn 370 375 380 Ala Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu 385 390 395 400 Lys Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu 405 410 415 Lys Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val 420 425 430 Thr Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe 435 440 445 Ser Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln 450 455 460 Ile Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile 465 470 475 480 Arg Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe 485 490 495 Ala Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn 500 505 510 Phe Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr 515 520 525 Ile Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln 530 535 540 Cys Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg 545 550 555 560 Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile 565 570 575 Ala Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly 580 585 590 His Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe 595 600 605 Pro Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val 610 615 620 Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys 625 630 635 640 Thr Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr 645 650 655 Val Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val 660 665 670 Thr Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro 675 680 685 Thr Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr 690 695 700 Glu Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn 705 710 715 720 Val Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro 725 730 735 Leu Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro 740 745 750 Gly Cys Arg Lys Asp Gly Thr Thr Gly Gly Gly Gly Ser Glu Pro Lys 755 760 765 Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu 770 775 780 Leu Gly Gly Ser Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val 785 790 795 800 Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val 805 810 815 Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val 820 825 830 Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser 835 840 845 Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met 850 855 860 Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala 865 870 875 880 Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro 885 890 895 Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln 900 905 910 Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr 915 920 925 Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr 930 935 940 Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu 945 950 955 960 Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser 965 970 975 Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser 980 985 990 Arg Thr Pro Gly Lys 995 <210> 81 <211> 2991 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 81 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggcggtggcg gatccgagcc aaagtcctct gataagacac acacctctcc accatgccca 2340 gcaccagagc tgctgggagg accaagcgtg ttcatcttcc cacccaagat caaggacgtg 2400 ctgatgatct ccctgtcccc catcgtgacc tgcgtggtgg tggacgtgtc cgaggacgac 2460 cccgacgtgc agatcagttg gttcgtgaac aacgtggaag tgcacaccgc ccagacccag 2520 acccacagag aggactacaa ctccaccctg cgggtggtgt ccgccctgcc catccagcac 2580 caggactgga tgtccggcaa agaattcaag tgcaaagtga acaacaagga cctgcctgcc 2640 cccatcgagc ggaccatctc caagcccaag ggctccgtgc gggctcccca ggtgtacgtg 2700 ctgccccctc cagaggaaga gatgaccaag aagcaggtca cactgacctg catggtcacc 2760 gacttcatgc ccgaggacat ctacgtggaa tggaccaaca atggcaagac cgagctgaac 2820 tacaagaaca ccgagcctgt gctggactcc gacggctcct acttcatgta ctccaagctg 2880 cgggtggaaa agaagaactg ggtcgagcgg aactcctact cctgctccgt ggtgcacgag 2940 ggcctgcaca accaccacac caccaagtcc ttctcccgga cccccggcaa a 2991 <210> 82 <211> 2994 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 82 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggcggtggcg gatccgagcc tcggggccct accatcaagc cctgcccccc ttgcaagtgc 2340 cctgccccta atctgctggg cggaccctcc gtgttcatct tcccacccaa gatcaaggac 2400 gtgctgatga tctccctgtc ccccatcgtg acctgcgtgg tggtggacgt gtccgaggac 2460 gaccccgacg tgcagatcag ttggttcgtg aacaacgtgg aagtgcacac cgcccagacc 2520 cagacccaca gagaggacta caactccacc ctgcgggtgg tgtccgccct gcccatccag 2580 caccaggact ggatgtccgg caaagaattc aagtgcaaag tgaacaacaa ggacctgcct 2640 gcccccatcg agcggaccat ctccaagccc aagggctccg tgcgggctcc ccaggtgtac 2700 gtgctgcccc ctccagagga agagatgacc aagaagcagg tcacactgac ctgcatggtc 2760 accgacttca tgcccgagga catctacgtg gaatggacca acaatggcaa gaccgagctg 2820 aactacaaga acaccgagcc tgtgctggac tccgacggct cctacttcat gtactccaag 2880 ctgcgggtgg aaaagaagaa ctgggtcgag cggaactcct actcctgctc cgtggtgcac 2940 gagggcctgc acaaccacca caccaccaag tccttctccc ggacccccgg caaa 2994 <210> 83 <211> 3030 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 83 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggcggtggcg gatcccgcaa caccggccgc ggcggcgagg agaagaagaa ggagaaggag 2340 aaggaggagc aggaggagcg cgagaccaag acccccgagt gccccagcca cacccagccc 2400 ctgggcgtgt tcatcttccc acccaagatc aaggacgtgc tgatgatctc cctgtccccc 2460 atcgtgacct gcgtggtggt ggacgtgtcc gaggacgacc ccgacgtgca gatcagttgg 2520 ttcgtgaaca acgtggaagt gcacaccgcc cagacccaga cccacagaga ggactacaac 2580 tccaccctgc gggtggtgtc cgccctgccc atccagcacc aggactggat gtccggcaaa 2640 gaattcaagt gcaaagtgaa caacaaggac ctgcctgccc ccatcgagcg gaccatctcc 2700 aagcccaagg gctccgtgcg ggctccccag gtgtacgtgc tgccccctcc agaggaagag 2760 atgaccaaga agcaggtcac actgacctgc atggtcaccg acttcatgcc cgaggacatc 2820 tacgtggaat ggaccaacaa tggcaagacc gagctgaact acaagaacac cgagcctgtg 2880 ctggactccg acggctccta cttcatgtac tccaagctgc gggtggaaaa gaagaactgg 2940 gtcgagcgga actcctactc ctgctccgtg gtgcacgagg gcctgcacaa ccaccacacc 3000 accaagtcct tctcccggac ccccggcaaa 3030 <210> 84 <211> 2991 <212> DNA <213> Artificial Sequence <220> <223> fusion protein <400> 84 gctcaggctg gacctagggc tccttgcgct gccgcctgca cctgtgcagg cgattctctg 60 gactgcagcg gccggggcct ggccacactg cccagggacc tgccttcctg gaccagatct 120 ctgaacctga gctacaatcg gctgtccgag atcgattctg ccgcctttga ggacctgaca 180 aatctgcagg aggtgtatct gaacagcaat gagctgaccg caatcccctc cctgggagca 240 gcctctatcg gcgtggtgag cctgttcctg cagcacaaca agatcctgag cgtggatggc 300 tcccagctga agagctacct gtctctggag gtgctggacc tgagctccaa caatatcacc 360 gagatcagat ctagctgttt tcctaatggc ctgcggatca gagagctgaa cctggcctct 420 aatcggatca gcatcctgga gtccggcgcc ttcgatggcc tgagcagatc cctgctgaca 480 ctgcgcctgt ccaagaaccg gatcacccag ctgcccgtga aggcctttaa gctgcctagg 540 ctgacacagc tggacctgaa ccggaataga atcaggctga tcgagggcct gaccttccag 600 ggcctggata gcctggaggt gctgcgcctg cagcggaaca atatctcccg cctgacagac 660 ggagcatttt ggggcctgtc taagatgcac gtgctgcacc tggagtacaa tagcctggtg 720 gaggtgaact ctggcagcct gtatggcctg accgccctgc accagctgca cctgtccaac 780 aatagcatca gcagaatcca gagggatggc tggtccttct gccagaagct gcacgagctg 840 atcctgtctt ttaacaatct gaccaggctg gacgaggaga gcctggcaga gctgtcctct 900 ctgtccatcc tgcgcctgtc tcacaatgcc atcagccaca tcgccgaggg cgcctttaag 960 ggcctgaaga gcctgagggt gctggatctg gaccacaacg agatctctgg caccatcgag 1020 gatacaagcg gcgccttcac aggcctggac aatctgtcca agctgaccct gtttggcaac 1080 aagatcaagt ctgtggccaa gcgggccttc tctggcctgg agagcctgga gcacctgaac 1140 ctgggcgaga atgccatcag atccgtgcag ttcgatgcct ttgccaagat gaagaatctg 1200 aaggagctgt acatcagctc cgagagcttc ctgtgcgact gtcagctgaa gtggctgcca 1260 ccttggctga tgggaaggat gctgcaggcc tttgtgaccg ccacatgcgc ccacccagag 1320 agcctgaagg gccagagcat cttctccgtg ctgcccgata gcttcgtgtg cgacgatttt 1380 cctaagccac agatcatcac ccagccagag acaacaatgg ccgtggtggg caaggacatc 1440 cggtttacat gttccgccgc ctctagctcc tctagcccca tgaccttcgc ctggaagaag 1500 gataacgagg tgctggccaa tgccgacatg gagaacttcg cccacgtgag agcccaggat 1560 ggcgaagtga tggagtatac cacaatcctg cacctgcggc acgtgacctt tggccacgag 1620 ggcagatacc agtgcatcat cacaaatcac ttcggctcta cctatagcca caaggccagg 1680 ctgacagtga acgtgctgcc tagctttacc aagatcccac acgacatcgc catcagaaca 1740 ggcaccacag caaggctgga gtgtgcagca accggacacc caaaccctca gatcgcatgg 1800 cagaaggatg gaggcacaga cttccctgca gcccgcgaga ggagaatgca cgtgatgcca 1860 gacgatgacg tgttctttat cacagatgtg aagatcgatg acatgggcgt gtactcctgc 1920 accgcacaga acagcgccgg cagcgtgtcc gccaacgcca ccctgaccgt gctggagaca 1980 ccatccctgg ccgtgcccct ggaggacagg gtggtgaccg tgggcgagac agtggccttt 2040 cagtgtaagg ccaccggctc tccaacacca aggatcacct ggctgaaggg cggcaggccc 2100 ctgagcctga cagagcgcca ccacttcacc cctggcaatc agctgctggt ggtgcagaac 2160 gtgatgatcg atgacgccgg caggtataca tgcgagatga gcaatcctct gggcaccgag 2220 agggcacact cccagctgtc tatcctgcct accccaggct gccggaagga tggcaccaca 2280 ggcggtggcg gatccgaacc gaaatcttct gacaaaaccc acacctctcc gccgtctccg 2340 gctccggaac tgctgggtgg ttcttctgtt ttcatcttcc cacccaagat caaggacgtg 2400 ctgatgatct ccctgtcccc catcgtgacc tgcgtggtgg tggacgtgtc cgaggacgac 2460 cccgacgtgc agatcagttg gttcgtgaac aacgtggaag tgcacaccgc ccagacccag 2520 acccacagag aggactacaa ctccaccctg cgggtggtgt ccgccctgcc catccagcac 2580 caggactgga tgtccggcaa agaattcaag tgcaaagtga acaacaagga cctgcctgcc 2640 cccatcgagc ggaccatctc caagcccaag ggctccgtgc gggctcccca ggtgtacgtg 2700 ctgccccctc cagaggaaga gatgaccaag aagcaggtca cactgacctg catggtcacc 2760 gacttcatgc ccgaggacat ctacgtggaa tggaccaaca atggcaagac cgagctgaac 2820 tacaagaaca ccgagcctgt gctggactcc gacggctcct acttcatgta ctccaagctg 2880 cgggtggaaa agaagaactg ggtcgagcgg aactcctact cctgctccgt ggtgcacgag 2940 ggcctgcaca accaccacac caccaagtcc ttctcccgga cccccggcaa a 2991 <210> 85 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Lrig-1 forward primer <400> 85 gacggaattc agtgaggaga acct 24 <210> 86 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Lrig-1 reverse primer <400> 86 caactggtag tggcagcttg tagg 24 <210> 87 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Lrig-2 forward primer <400> 87 tcacaaggaa cattgtctga acca 24 <210> 88 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Lrig-2 reverse primer <400> 88 gcctgatcta acacatcctc ctca 24 <210> 89 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Lrig-3 forward primer <400> 89 cagcaccttg agctgaacag aaac 24 <210> 90 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Lrig-3 reverse primer <400> 90 ccagcctttg gtaatctcgg ttag 24 <210> 91 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> foxp3 forward primer <400> 91 ctttcaccta tcccaccctt atcc 24 <210> 92 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> foxp3 reverse primer <400> 92 attcatctac ggtccacact gctc 24 <210> 93 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ACTG1 forward primer <400> 93 ggcgtcatgg tgggcatggg 20 <210> 94 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ACTG1 reverse primer <400> 94 atggcgtggg gaagggcgta 20 <210> 95 <211> 46 <212> PRT <213> Artificial Sequence <220> <223> peptide linker <400> 95 Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys 1 5 10 15 Glu Ala Ala Ala Lys Ala Leu Glu Ala Glu Ala Ala Ala Lys Glu Ala 20 25 30 Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala 35 40 45 <210> 96 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> peptide linker <400> 96 Pro Ala Pro Ala Pro 1 5 <210> 97 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> peptide linker <400> 97 Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala 1 5 10 <210> 98 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> peptide linker <400> 98 Ile Glu Gly Arg Met Asp 1 5 <210> 99 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> peptide linker <400> 99 Asp Ile Glu Gly Arg Met Asp 1 5

Claims (23)

  1. Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질의 세포 외 도메인(extracellular domain) 및 면역글로불린(immunoglobulin) Fc 영역을 포함하는 융합 단백질.
  2. 제1항에 있어서,
    상기 Lrig-1 단백질의 세포 외 도메인은 서열번호 1 또는 3으로 표시되는, 융합 단백질.
  3. 제1항에 있어서,
    상기 면역글로불린 Fc 영역은 CH1, CH2, CH3 및 CH4 도메인으로 이루어진 그룹으로부터 선택된 1개 내지 4개 도메인을 포함하는, 융합 단백질.
  4. 제1항에 있어서,
    상기 면역글로불린 Fc 영역은 IgG, IgA, IgD, IgE 또는 IgM 유래 Fc 영역, 중쇄 불변영역 2(CH2), 중쇄 불변영역 3(CH3), 힌지(hinge), 이의 단편, 이들의 조합(combination), 또는 이들의 조합을 포함하는 하이브리드 Fc(hybrid Fc)인, 융합 단백질.
  5. 제1항에 있어서,
    상기 면역글로불린 Fc 영역은 IgG, IgA, IgD, IgE 또는 IgM 유래의 CH2 및 CH3 도메인을 포함하는, 융합 단백질
  6. 제1항에 있어서,
    상기 면역글로불린 Fc 영역은 IgG1, IgG2, IgG3 또는 IgG4 유래의 CH2 및 CH3 도메인을 포함하는, 융합 단백질.
  7. 제1항에 있어서,
    상기 면역글로불린 Fc 영역은 힌지(hinge) 영역을 포함하는, 융합 단백질.
  8. 제7항에 있어서,
    상기 면역글로불린 Fc 영역은 IgG, IgA, IgM, IgD, IgE, 또는 아바타셉트(Abatacept) 유래의 힌지 영역을 포함하는, 융합 단백질.
  9. 제7항에 있어서,
    상기 힌지(hinge) 영역은 IgG1, IgG2, IgG3, IgG4, IgD 또는 아바타셉트(Abatacept) 유래의 힌지 영역을 포함하는, 융합 단백질.
  10. 제1항에 있어서,
    상기 면역글로불린 Fc 영역은 서열번호 5 또는 6으로 표시되는 CH2 및 CH3을 포함하는, 융합 단백질.
  11. 제1항에 있어서,
    상기 면역글로불린 Fc 영역은 서열번호 7 내지 10 중 어느 하나로 표시되는 힌지 영역을 포함하는, 융합 단백질.
  12. 제1항에 있어서,
    상기 Lrig-1 단백질의 세포 외 도메인은 상기 면역글로불린 Fc 영역의 N-말단 또는 C-말단에 직접 연결되는, 융합 단백질.
  13. 제1항에 있어서,
    상기 Lrig-1 단백질의 세포 외 도메인은 링커를 통하여 상기 면역글로불린 Fc 영역의 N-말단 또는 C-말단에 연결되는, 융합 단백질.
  14. 제13항에 있어서,
    상기 링커는 서열번호 11로 표시되는 펩타이드 링커; 및 서열번호 12로 표시되는 펩타이드 링커; 중 적어도 하나인, 융합 단백질.
  15. 제13항에 있어서,
    상기 링커는 하기 식 1 내지 4로 표시되는 아미노산 서열로 이루어지는 펩타이드 링커로 구성된 군으로부터 선택되는 적어도 하나인, 융합 단백질:
    [식 1]
    (G)n
    [식 2]
    (GGGGS)m
    [식 3]
    (EAAAK)p
    [식 4]
    (XP)q
    n, m 및 p는 각각 독립적으로 1 이상의 정수이고;
    q는 5 내지 40의 정수이며;
    X는 A(Ala), C(Cys), D(Asp), E(Glu), F(Phe), G(Gly), H(His), I(Ile), K(Lys), L(Leu), M(Met), N(Asn), O(Pyl), P(Pro), Q(Gln), R(Arg), S(Ser), T(Thr), U(Sec), V(Val), W(Trp) 및 Y(Tyr)로 구성된 군으로부터 선택되는 어느 하나의 아미노산이다.
  16. 제 13항에 있어서,
    상기 링커는 서열번호 95 내지 99로 표시되는 펩타이드 링커로 구성된 군으로부터 선택되는 적어도 하나인 것인, 융합 단백질.
  17. 제1항 내지 제16항 중 어느 한 항의 융합 단백질을 코딩하는 핵산 분자.
  18. 제17항의 핵산 분자가 삽입된 발현 벡터.
  19. 제18항의 발현 벡터가 형질 감염된 숙주 세포주.
  20. 제1항 내지 제16항 중 어느 한 항의 융합 단백질을 유효 성분으로 포함하는 암의 예방 또는 치료용 약학 조성물.
  21. 제20항에 있어서,
    상기 암은 고형암인, 약학 조성물.
  22. 제21항에 있어서,
    상기 암은 위암, 간암, 교세포종, 난소암, 대장암, 두경부암, 방광암, 신장세포암, 유방암, 전이암, 전립선암, 췌장암, 흑색종 또는 폐암인, 약학 조성물.
  23. 제1항 내지 제16항 중 어느 한 항의 융합 단백질을 유효 성분으로 포함하는 면역 관련 질환의 예방 또는 치료용 약학 조성물.
KR1020190096731A 2019-08-08 2019-08-08 신규한 융합 단백질 및 이의 용도 KR20210017449A (ko)

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