KR101238795B1 - 동결건조 항원 조성물 - Google Patents
동결건조 항원 조성물 Download PDFInfo
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- KR101238795B1 KR101238795B1 KR1020097025005A KR20097025005A KR101238795B1 KR 101238795 B1 KR101238795 B1 KR 101238795B1 KR 1020097025005 A KR1020097025005 A KR 1020097025005A KR 20097025005 A KR20097025005 A KR 20097025005A KR 101238795 B1 KR101238795 B1 KR 101238795B1
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Abstract
본 발명은 항원-톨-유사 수용체(Toll-like receptor, TLR) 9 효능제를 포함하는 동결건조 조성물을 제공한다. 본 발명의 조성물은 리포좀, 미네랄 염, 에멀젼, 폴리머 및 ISCOM으로 이루어진 미립자화된 담체의 그룹에서 선택된 담체로 백신접종용 면역원성 조성물로 재구성될 수 있다. 본 발명의 동결건조 조성물로부터 면역원성 조성물을 제조하는 방법 및 예방접종(immunisation)에서의 상기 조성물의 용도가 또한 본 발명에서 제공된다.
Description
기술 분야
본 발명은 개선된 항원성 조성물과 면역원성 조성물을 제조하기 위해 상기 항원성 조성물을 사용하는 방법과 관련이 있다. 특히, 본 발명은 항원과 톨-유사 수용체(TLR, Toll-like receptor) 9 효능제를 포함하는 동결건조 조성물과 관련이 있다. 그러한 조성물은 리포좀, 미네랄 염, 에멀젼, 폴리머 및 ISCOM으로 이루어진 미립자 담체의 군에서 선택된 담체를 사용하여 백신접종(vaccination)에 사용하기 위한 면역원성 조성물로 재구성될 수 있다. 본 발명의 동결건조 조성물로부터 면역원성 조성물을 제조하는 방법 및 예방접종(immunisation)에 있어서 상기 동일한 조성물의 용도가 또한 본 발명의 일부를 이룬다.
발명의 배경
애주번트는 때때로 임의의 주어진 항원에 대해 야기되는 면역 반응을 개선시키는데 사용된다. 그러나, 백신 또는 면역원성 조성물내로 애주번트를 포함시키는 것은 성분 제조의 복잡성을 비롯한 백신 조정물의 분배 및 제형의 복잡성을 증가시킨다. 애주번트 성분들 각각의 제조를 비롯한 상기 항원 성분은 포뮬레이터에 의해 고려되어야만 한다. 이것은 특히, 예를 들어, 용액중의 애주번트 성분의 pH가 해당 항원을 위한 최적 pH와 매우 상이할 수 있고, 이러한 차이는, 예를 들어, 성분의 침전 또는 성분의 요망되는 특성의 손실을 막기 위해 주의하여 조절되고 관리될 필요가 있기 때문에 진실이다. 주사용수 중의 항원의 pH는, 예를 들어, 약 pH 7이거나 이보다 조금 더 높을 수 있고, 애주번트가 첨가되는 경우, 상기 pH는 pH 6.3 정도로 낮아질 수 있다. 항원은, 예를 들어, 이러한 pH에서 장기간 저장되는 경우 안정하지 않을 수 있다.
이후 성분은 가능한 안정한 형태로 제형화 및 분배되어야 하는데, 그 이유는 인간용 약제학 제품은 잘 특성결정되고, 안정하며, 안전해야만 그 이후에 시판용으로 승인될 수 있기 때문이다. 이러한 이유로 최종 제형이 적절한 기준을 충족하는지를 보장하기 위해 해당 최종 제형에 대해 장기간의 안정성 연구가 수행되어야 한다. 그러한 장기간의 연구에서 얻어진 정보는 해당 제품이 인간용으로 적합하다는 것을 드러내기 위해 FDA(연방 의약청 - USA에서 의약 승인을 담당하는 기관)와 같은 규제 당국에 대한 의견개진을 뒷받침하는데 사용된다.
동결건조(Freeze-drying 또는 lyophilisation)는 일반적으로 백신으로 사용되는 항원과 같은 약제학적 물질을 포함하는 물질의 안정성을 증가시키고 그에 따라 상기 물질의 저장수명을 증가시키기 위해 이용된다.
종종 동결건조된 항원 조성물은 환자에게 투여하기 직전에 희석제(예를 들어, 주사용수[WFI] 또는 일부 경우에 있어서 액체 애주번트 제형)를 사용하여 재구성하기 위해 헬쓰 케어 전문가에게 제공된다. 이러한 방식에서, 최종 백신의 다양한 성분들이 근접하여 유지되는 기간이 최소화된다.
리오 케이크(lyo cakes)(동결건조로부터의 건조 생성물)를 형성하도록 항원을 동결건조시킬 때, 많은 인자들이 고려되어야 한다. 예를 들어, 항원의 항원성/면역원성은 동결건조된 형태에서 유지되어야 한다. 항원은 동결건조된 형태에서도 응집되거나 파괴되어서는 않된다. 리오 케이크는 잘 형성되어야 하며 붕괴되어서는 않된다. 마지막으로, 항원은 물론 재구성시 급속하게 용해되는 형태로 존재하여야 한다. 재구성용 용액이 단순히 WFI가 아닌 경우, 예를 들어, 항원이 액체 애주번트로 재구성되는 경우, 재구성된 생성물의 특성에 대한 용액의 성분의 영향이 고려될 필요가 있다.
언급된 것과 같이, 애주번트는 백신의 항원 성분에 대한 면역 반응을 개선시키기 위해 수년동안 사용되어 왔다. 특히 효능있는 애주번트 조합물은 3탈아실화된-모노포스포릴 리피드 A(3D-MPL)과 사포닌, 특히 QS21(퀼라자 사포나리아 모나라(Quillaja saponaria Monara)의 나무껍질로부터 추출된 사포닌의 정제된 분획)을 포함하는 조합물이다. 이 조합물은, 예를 들어, 수중유 에멀젼, 리포좀 제형 또는 기타의 것으로 제공될 수 있다.
항원, 예를 들어, 말라리아 항원, 예컨대, RTS,S를 이용한 이전의 임상 시도에서, 동결건조된 항원이 제공되며 액체 애주번트, 예를 들어, 항원 재구성을 위한 MPL과 QS21의 수중유 제형 또는 MPL과 QS21의 리포좀 제형의 별개 바이얼이 또한 제공된다. 개별 성분들이 투여되기 직전에 최종 백신 조성물을 형성하도록 조합된다.
비메틸화된 CpG 디뉴클레오티드("CpG")를 함유하는 특별한 면역자극성 올리고뉴클레오티드는 TLR9 리간드이고 전신 및 점막 경로 둘 모두로 투여될 때 애주번팅되는 것으로 확인되었다(WO 96/02555, EP 468520, Davis et al., J. Immunol, 1998, 160(2):870-876; McCluskie and Davis, J. Immunol., 1998, 161(9):4463-6). CpG는 DNA내에 존재하는 시토신-구아노신 디뉴클레오티드 모티프의 축약어이다. 역사적으로, BCG의 DNA 분획은 항-종양 효과를 나타낼 수 있음이 관찰되었다. 추가 연구에서, BCG 유전자 서열로부터 유래된 합성 올리고뉴클레오티드는 면역자극 효과(시험관내 및 생체내 둘 모두에서)를 유도할 수 있는 것으로 드러났다. 이러한 연구에서 연구자들은 중심 CG 모티프를 포함하는, 특별한 팔린드로믹(palindromic) 서열이 이러한 활성을 지니는 것으로 결론내렸다. 면역자극에서 CG 모티프의 중심적인 역할은 그후 크레이그의 간행물[Krieg, Nature 374, p546 1995]에서 밝혀졌다. 상세한 분석은 CG 모티프가 특정 서열 목록으로 존재하여야 하며, 그러한 서열이 박테리아 DNA에서는 흔하나 척추동물 DNA에서는 희귀하다는 것을 밝혀내었다. 면역자극 서열은 흔히 다음과 같다: 퓨린, 퓨린, C, G, 피리미딘, 피리미딘; 디뉴클레오티드 CG 모티프는 메틸화되지 않으나, 다른 비메틸화된 CpG 서열은 면역자극성인 것으로 공지되어 있으며 본 발명에서 사용될 수 있다.
또한 면역자극성 올리고뉴클레오티드는 구아노신이 7-데아자구아노신 모티프로 돌연변이된 경우 면역학적 활성을 유지할 수 있는 것으로 밝혀졌다(WO 03057822).
이러한 면역자극성 올리고뉴클레오티드는 용액에서 산성 pH, 예를 들어, pH 7 미만, 예컨대, 6.3, 6.1 또는 그 미만의 pH를 지니는 것으로 생각된다. 이러한 pH는 이들이 액체 백신 제형내에 포함되기 어렵게 만드는데, 그 이유는 이들이 제형내의 다른 성분과 비유사하기 때문이다. 논의한 바와 같이, 이것은 침전 및/또는 장기간의 안정성 문제를 야기시킬 수 있다.
이러한 면역자극성 올리고뉴클레오티드는, 특히 기존의 애주번트 조합물, 예컨대, 3D-MPL과 QS21과 함께 조합되어 사용될 때, 매우 효과적인 애주번트가 될 가능성이 있는 것으로 생각된다. 그러한 애주번트는 현재까지 효과적인 백신을 제공하기 어려웠던 질병(예컨대, HIV, 암 및 어쩌면 말라리아)에 사용될 것임이 예상된다.
애주번트가 백신내에 포함될 수 있는 다수의 상이한 방식들이 존재하나, 이들 애주번트는 그들 자체의 안정성 또는 항원 조성물의 안정성에 영향을 주지 않는 방식으로 포함되어야 하며 또한 백신을 재구성하는 헬쓰 케어 전문가에게 과도한 부담을 지우지 아니할 방식으로 포함되어야 한다. 이것을 달성하기 위한 가장 단순한 방식은 추가 성분을 추가 바이얼내로 넣어 이들 성분이 재구성 바로 직전까지 따로 유지되게 하여, 그로 인해 성분들이 서로에게 영향을 미치게 될 시간을 최소화시키는 것이다. 이것은 항원과 면역자극성 올리고뉴클레오티드가 각각 별개의 바이얼로 제공될 것임을 의미한다. 이후, 추가의 애주번트 성분, 예컨대, MPL과 QS21이 사용되는 경우, 이들은 제 3의 바이얼내의 액체 혼합물로서 제공될 수 있다. 그러나, 증가된 수의 바이얼내의 증가된 수의 성분들은 비용, 폐기물의 증가를 초래하며, 중요하게는 구성 진행시 실수할 가능성을 증가시킨다.
발명의 요약
본 발명의 발명자들은 TLR9 리간드, 예컨대, CpG 면역자극성 올리고뉴클레오티드가 애주번트로서 면역원성 조성물의 일부분이 될 때, 상기 TLR9 리간드가 항원과 함께 동결건조되어 하나의 리오 케이크로 항원과 TLR9 리간드 애주번트를 함께 함유하는 단일 바이얼이 제공됨을 발견하였다.
따라서 본 발명은 항원과 TLR9 효능제를 포함하는 동결건조 조성물을 제공한다. 상기 TLR9 효능제는, 일 구체예에서, 면역자극성 올리고뉴클레오티드, 가능하게는, CpG 함유올리고뉴클레오티드이다. 한 양상에서, 상기 CpG 함유올리고뉴클레오티드는 퓨린, 퓨린, C,G, 피리미딘, 피리미딘 서열을 포함한다. 또 다른 양상에서, 상기 면역자극성 올리고뉴클레오티드는 서열번호 1; 서열번호 2; 서열번호 3; 서열번호 4; 및 서열번호 5로 이루어진 군에서 선택된다.
이론으로 국한되는 것을 바라지 아니하면서, 항원과 TLR9 효능제를 함께 제공하는 것은 MPL과 QS21의 액체 제형에 TLR9의 단순 첨가 보다 더 안정한 성분을 제공하는 것으로 생각된다.
본 발명은 항원과 TLR9 효능제가 WFI로 재구성되는 경우, 단지 하나의 바이얼에 당해 바이얼내의 동결건조된 제형을 제공할 수 있다는 이점을 제공한다. 더욱이, 항원과 TRL9 효능제가 액체 제형, 예컨대, 액체 애주번트 제형으로 재구성되는 경우, (3개 보다는) 2개의 바이얼로 성분들을 제공할 수 있다는 이점이 있다. 이것은 차례로 비용적 이점을 가지며, 동시에 일단 재구성되면 백신용으로 적합한 제품을 제공한다.
더욱이, 본 발명자들은 재구성 버퍼내에서 전반적인 양 전하를 띠지 않게 될 CpG와 항원의 동시-동결건조(co-lyophilisation)가 주사용수 또는 액체 애주번트로의 재구성에 있어서 항원의 용해도를 증가시킬 수 있음을 발견하였다. 따라서, 본 발명은 또한 TLR9 효능제, 바람직하게는 면역자극성 올리고뉴클레오티드 및, 더 바람직하게는, CpG 올리고뉴클레오티드와 항원을 동시-동결건조시키는 단계를 포함하는, 재구성시 동결건조된 항원의 용해도를 증가시키는 방법을 제공하는데, 여기서 상기 항원은 재구성 버퍼내에서 순 양 전하를 띠지 아니할 것이다. 본 발명은 또한 재구성시 동결건조된 양으로 비하전된 항원의 용해도를 증가시키기 위해 TLR9 효능제, 바람직하게는 면역자극성 올리고뉴클레오티드 및, 더 바람직하게는, CpG 올리고뉴클레오티드의 용도를 제공한다. "양으로 비하전된(non-positively charged)"은 단백질의 전체 전하가 양성이 아님을 의미한다. 단백질은 양 전하 및 음 전하 둘 모두를 함유할 수 있고, 단백질의 전체 전하는 중성 또는 음성이다.
본 발명은 또한 본원에 기재된 동결건조 조성물과 적당한 담체를 재구성하는 단계를 포함하는 면역원성 조성물을 제조하는 방법을 제공한다. 한 구체예에서, 상기 담체는 리포좀 용액 또는 수중유 에멀젼이다. 상기 담체는 선택적으로 하나 이상의 면역자극제를 함유할 수 있는데, 상기 면역자극제는 TLR4 효능제, TLR4 길항제, 사포닌, TLR7 효능제, TLR8 효능제, TLR9 효능제로 이루어진 군에서 선택될 수 있다. 한 구체예에서, 상기 담체는 2개 이상의 면역자극제를 함유하며 한 양상에서 이들은 3-탈아실화된 MPL과 QS21일 수 있다.
본 발명은 또한 하나 이상의 원하는 항원, TLR9 리간드 및 적합한 부형제를 조합하는 단계 및 그 결과 얻어진 혼합물을 동결 건조시키는 단계를 포함하는 본 발명의 동결건조 조성물을 제조하는 방법을 제공한다.
발명의 상세한 설명
본 발명자들은 TLR9 리간드, 예컨대, CpG 올리고뉴클레오티드가 관심있는 항원의 항원성 또는 안정성에 영향을 주지 않으면서 상기 항원과 동결건조될 수 있다는 것을 발견하였다. TLR9 리간드는 TLR9 수용체와 상호작용할 수 있는 화합물을 의미한다.
초파리(Drosophila)에서 제일 처음 발견된, 톨-유사 수용체(TLR) 패밀리의 일원들은, 패턴 인식 수용체인 것으로 드러났으며, 각각의 일원은 침입 미생물(microbes)을 제한/박멸하기 위해 상이한 미생물 성분을 인지하고 이에 반응한다. TLR에 병원균-연관 분자 패턴(pathogen-associated molecular patterns, PAMP)의 결합은 반응성 산소 및 질소 중간생성물의 생산, 향-염증성(pro-inflammatory) 사이토카인 네트워크의 개시, 및 후천성 면역력에 급속한 선천적 반응을 연결하는 동시자극성 분자의 상향조절을 유도한다. 많은 TLR 리간드가 애주번트로서 유용한 것으로 공지되어 있다. TLR9은 올리고뉴클레오티드 효능제와 반응하는 것으로 드러났다. 따라서, 본 발명의 TLR9 리간드는 면역자극성 올리고뉴클레오티드이다. 본 발명의 한 구체예에서, 그러한 TLR9 리간드는 CpG 모티프를 함유한다. 대안적인 면역자극성 올리고뉴클레오티드는 뉴클레오티드에 대한 변형을 포함할 수 있다. 예를 들어, WO0226757호 및 WO03057822호는 CpG 함유면역자극성 올리고뉴클레오티드의 C 및 G에 대한 변형을 개시하고 있다.
한 구체예에서, TLR9 리간드는 CpG 올리고뉴클레오티드이다. 이 구체예의 한 양상에서, CpG 올리고뉴클레오티드는 3개 이상, 가능하게는, 6개 이상의 뉴클레오티드에 의해 이격된(seperated) 2개 이상의 디뉴클레오티드 CpG 모티프를 함유한다. 본 발명의 올리고뉴클레오티드는 전형적으로 데옥시뉴클레오티드이다. 한 구체예에서, 혼재된 뉴클레오티드간(internucleotide) 연결을 지니는 올리고뉴클레오티드를 포함하여, 포스포디에스터 및 다른 뉴클레오티드간 결합이 또한 사용될 수 있지만, 올리고뉴클레오티드내의 뉴클레오티드간 결합은 포스포디티오에이트, 또는 가능하게는 포스포로티오에이트 결합이다. 포스포로티오에이트 올리고뉴클레오티드 또는 포스포로디티오에이트를 생산하기 위한 방법은 미국 특허 제5,666,153호, 미국 특허 제5,278,302호 및 WO95/26204호에 기재되어 있다. 상이한 뉴클레오티드간 연결을 포함하는 올리고뉴클레오티드는, 예를 들어, 혼재된 포스포로티오에티트 포스포디에스테르가 고려된다. 올리고뉴클레오티드를 안정화시키는 다른 뉴클레오티드간 결합이 사용될 수 있다.
CpG 올리고뉴클레오티드의 일예는 하기 서열을 지닌다. 한 구체예에서, 이들 서열은 포스포로티오에이트 변형 뉴클레오티드간 결합을 함유한다.
OLIGO 1(서열번호 1): TCC ATG ACG TTC CTG ACG TT (CpG 1826)
OLIGO 2(서열번호 2): TCT CCC AGC GTG CGC CAT (CpG 1758)
OLIGO 3(서열번호 3): ACC GAT GAC GTC GCC GGT GAC GGC ACC ACG
OLIGO 4(서열번호 4): TCG TCG TTT TGT CGT TTT GTC GTT (CpG 2006)
OLIGO 5(서열번호 5): TCC ATG ACG TTC CTG ATG CT (CpG 1668)
대안적인 CpG 올리고뉴클레오티드는 상기 서열에 대해 중요치 않은 결실 또는 부가를 지니는 상기 서열을 포함할 수 있다.
본 발명에서 사용된 CpG 올리고뉴클레오티드는 당업계의 공지된 임의의 방법으로 합성될 수 있다(예를 들어, EP 468520호). 편의상, 그러한 올리고뉴클레오티드는 자동화된 합성기를 사용하여 합성될 수 있다.
본 명세서의 본문에서, 용어 "항원"은 특이 면역 반응을 야기시키기 위해 적합하며, 백신 또는 면역원성 조성물내로 포함(inclusion)되는데 적합한 면역원성 성분, 예를 들어, 백신 또는 면역원성 조성물, 예를 들어, HIV-1 백신, 암 백신, 말라리아 백신, TB 백신 또는 이와 유사한 것내로 포함되는데 적합한 항원을 지칭하기 위해 의도적으로 사용된다.
한 구체예에서, 항원은 9.6 이하의 등전점을 지닌다. 한 구체예에서, 항원은 9 이하의 등전점을 지닌다. 한 구체예에서, 항원은 8.5 이하의 등전점을 지닌다. 한 구체예에서, 항원은 8.0 이하의 등전점을 지닌다. 한 구체예에서, 항원은 7.5 이하의 등전점을 지닌다. 한 구체예에서, 항원은 7 내지 8의 범위 이내에서 등전점을 지닌다.
버퍼 중에서 재구성될 때, 단백질의 순 전하는 단백질의 양 전하의 수 대 음 전하의 수에 좌우되며, 이 전하는 물론 당해 단백질의 순 전하가 중성이 되는 재구성 버퍼 등전점의 pH에 따라서 달라질 것이다. 재구성 버퍼의 pH가 항원의 등전점 미만이면, 단백질은 순 양 전하를 띠게 되는 경향이 있다. 재구성 버퍼의 pH가 항원의 등전점을 초과하면, 단백질은 순 음 전하를 띠게 되는 경향이 있다. 본 발명은, 의도된 재구성 버퍼에서, 단백질이 순 음 전하를 띠게 될 그러한 등전점을 갖는 항원을 동결건조 및 재구성할 때 특히 유용하다. 그러한 환경(실시예 3 참조)에서, 동결건조 조성물내의 CpG의 존재는 재구성 버퍼에서 항원의 용해도를 향상시킬 수 있다.
한 구체예에서, 동결건조된 항원과 TLR9 효능제는, 예를 들어, 한 바이얼내의, 1회 용량으로 제공된다.
한 구체예에서, 동결건조된 항원은, 재구성시, 10 내지 250 μg의 범위의 항원 농도로 제공되도록 소정 양으로 존재한다.
한 구체예에서, TRL9 효능제는, 재구성시, 10 내지 1000 μg의 범위의 농도(예컨대, 500μg)로 제공되도록 소정 양으로 존재한다.
본 발명의 한 구체예에서, 동결건조 조성물에서 TLR9 리간드와 조합된 항원은 항-종양 항원일 수 있다. 따라서, 본 발명의 동결건조된 항원 조성물을 사용하여 제조된 면역원성 조성물은 암의 면역요법 치료에 유용하다. 예를 들어, 동결건조 조성물은 본원에 기재된 것과 같은 암 항원, 종양 항원 또는 종양 거부 항원, 예컨대, 다른 것들 중에서 전립선 암, 유방암, 결장직장암, 폐암, 신장암, 난소암, 간암 및 두경부암에서 발현되는 그러한 단백질로 제조될 수 있다.
본 발명에 사용될 수 있는 고환암 항원은 항원 MAGE-A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 및 A12의 MAGE A 패밀리(또한 MAGE-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12로도 공지되어 있음); MAGE B1, B2, B3 및 B4의 MAGE B 항원; MAGE-C1와 MAGE-C2의 MAGE C 항원; LAGE 1 항원, LAGE 2 항원(NY-ESO-1으로도 공지되어 있음); 및 GAGE 항원을 포함한다.
전립선 특이 항원이 또한 본 발명에 사용될 수 있다. 융합될 수 있는 전립선 특이 항원의 일예는 전립선의 6-막관통 상피 항원(STEAP), 전립선 특이 항원(PSA), 전립선 포스파타아제(prostatic acid phosphatase, PAP), 전립선 줄기 세포 항원(prostate stem cell antigen, PSCA), 전립선-특이 막 항원(PSMA) 또는 프로스타제로 공지된 항원(P703P로도 공지됨)을 포함한다.
한 구체예에서, 전립선 항원은 P501S 또는 이의 단편이다. P501S(또한 프로스테인(prostein)으로 지칭됨)은 553개 아미노산 단백질이다. 20개 이상, 50개 이상, 또는 100개 이상의 연속된 아미노산을 포함하는 P501S의 면역원성 단편 및 일부분, 또는 20-50개 사이 또는 50-100개 사이의 연속된 아미노산을 포함하는 단편은, 본 발명의 종양 연관 항원 또는 유도체로 사용될 수 있다. 한 구체예에서, 종양 연관 항원 또는 유도체는 PS108 항원(WO98/50567호에 개시됨) 또는 전립선 암-연관 단백질(WO99/67384호)이다. 일부 구체예에서, 단편은 전장길이 P501S 단백질의 아미노산 51-553, 34-553 또는 55-553이다. 이들은 효모 시스템내에서 발현될 수 있는데, 예를 들어, 그러한 폴리펩티드를 엔코딩하는 DNA 서열은 효모 시스템내에서 발현될 수 있다.
한 구체예에서, 항원은 윌름(Wilm) 종양 유전자에 의해 발현된 WT-1, 또는 약 또는 대략 아미노산 1-249를 포함하는 이의 N-말단 단편 WT-1F을 포함하거나 이로 이루어질 수 있다. WT1은 처음에 소아성 신장암, 윌름 종양에서 과발현되는 것으로 밝혀진 단백질이다. 사용될 수 있는 항원은 항원으로써 거의 전장 길이의 단백질을 포함한다. 한 구체예에서, 항원은 WT1-A10 단백질을 포함하거나 이로 이루어질 수 있는데, 상기 단백질은 12머(mer) 절단된(truncated) tat 서열 및 WT1 서열의 아미노산 번호 2 - 281로 이루어진 292개 AA의 재조합 융합 단백질이다.
본 발명의 한 구체예에서, 종양 연관 항원 또는 유도체는 유방암 항원, 예를 들어, Her-2/neu, 맘마글로빈(mammaglobin) 또는 B305D 항원이다.
본 발명에서 사용하기 위한 Her-2/neu 항원은 전체 세포외 도메인(ECD; 예를 들어, Her-2/neu의 아미노산 서열의 대략 아미노산 1-645를 포함하는 서열) 또는 이의 단편을 포함할 수 있다. 대안적으로 또는 추가적으로 작제물은 전체 세포내(intracellular) 도메인의 적어도 면역원성 일부분(예를 들어, Her-2/neu 서열의 대략 C 말단 580개 아미노산)을 포함할 수 있다.
본 발명의 종양 연관 항원 유도체로서 사용될 수 있는 한 작제물은 ECD와 Her-2/neu의 인산화 도메인(phosphorylation domain, PD)의 융합 단백질(ECD-PD)이다. 사용될 수 있는 추가 작제물은 ECD와 Her-2/neu의 인산화 도메인의 단편의 융합 단백질(ECD-ΔPD)이다. 기재된 것과 같은 Her-2/neu 융합 단백질과 작제물은 인간, 래트, 마우스 또는 시미안/원숭이 Her-2/neu에서 유래될 수 있다. Her-2/neu의 대표적인 서열 및 작제물은 WO00/44899호에 기재되어 있다.
PRAME(DAGE로도 공지됨)은 본 발명의 종양 연관 항원으로서 사용될 수 있는 또 다른 항원이다. PRAME 항원을 포함하는 본 명세서에 기재된 것과 같은 융합 단백질이 또한 사용될 수 있다. 특히, 본 명세서에 기재된 것과 같은 PRAME 항원과 본 명세서에 기재된 것과 같은 단백질 D 융합 파트너 단백질 또는 유도체의 융합체가 본 발명에 사용되는 것이 고려된다.
PRAME 항원은 흑색종 및 폐암, 신장암 및 두경부암을 포함하는 매우 다양한 종양에서 발현된다는 것이 몇몇 그룹에 의해 밝혀졌다. 흥미롭게도, 상기 항원은 또한 급성 림프구성 백혈병 및 급성 골수성 백혈병과 같은 40-60% 백혈병에서 발현되는 것으로 보인다. 예를 들어, 다음 문헌을 참조하라: Exp Hematol. 2000 Dec;28(12):1413-22. 환자에서, PRAME의 과발현은 상기 단백질을 과발현시키지 않는 환자들에 비하여 더 높은 생존율 및 더 낮은 재발율과 연관되어 있는 것으로 관찰되었다.
항원 및 이의 제조는 미국 특허 제5,830,753호에 기재되어 있다. PRAME은 하기 수탁번호하에서 주석있는 인간 유전자 데이터베이스(Annotated Human Gene Database) H-Inv DB에서 확인된다.
한 양상에서, 본 발명의 항원은 PRAME 항원 또는 이의 면역원성 단편을 포함하거나 이로 이루어질 수 있다. 일반적으로, PRAME 단백질은 509개의 아미노산을 가지며, 한 구체예에서, PRAME의 509개 아미노산 모두가 항원에 포함될 수 있다.
결장직장 항원이 또한 본 발명의 종양 연관 항원으로서 사용될 수 있다. 사용될 수 있는 결장직장 항원의 일예는 하기한 것들을 포함한다: C1585P(MMP 11) 및 C1491(E1A 인핸서 결합 단백질), CASB618(WO00/53748호에 기재된 것과 같음); CASB7439(WO01/62778호에 기재된 것과 같음); 및 C1584(Cripto).
본 발명의 내용상 유용한 다른 종양 연관 항원은 하기한 것을 포함한다: Plu-1(J. Biol. Chem 274 (22) 15633-15645, 1999), HASH-1, HASH-2, Cripto(Salomon et al Bioessays 199, 2161-70, 미국 특허 제5,654,140호), Criptin(미국 특허 제5,981,215호). 추가적으로, 암 치료법에 있어서 백신용으로 특히 적절한 항원은 또한 티로시나제와 수비빈(survivin)을 포함한다.
Muc1과 같은 뮤신 유래 펩티드가 고려된다(예를 들어, 미국 특허 제5,744,144호, 미국 특허 제5,827,666호, WO 8805054호, 미국 특허 제4,963,484호 참조바람). Muc1 펩티드의 하나 이상의 반복 단위, 바람직하게는, 2개 이상의 그러한 반복 단위를 포함하며 SM3 항체에 의해 인지되는 Muc1 유래 펩티드가 특별히 고려된다(미국 특허 제6,054,438호). 다른 뮤신 유래 펩티드는 Muc5로부터의 펩티드를 포함한다.
다른 종양-특이적 항원이 본 발명의 동결건조된 조성물에 사용되기에 적합하며, 종양-특이적 강글리오시드, 예컨대, GM2 및 GM3 또는 담체 단백질과의 이의 컨주게이트를 포함하나, 이로만 국한되는 것은 아니며; 상기 항원은, 다수의 암의 치료에 유용하거나, 면역거세(immunocastration)에 유용한, 전장 길이 고나도트로핀(Gonadotrophin) 호르몬 방출 호르몬(GnRH, WO 95/20600)과 같은 자가 펩티드 호르몬(짧은 10개 아미노산 길이의 펩티드)일 수 있다.
본 발명은 또한 본 발명의 양상들에서의 동일한 것을 포함하는 상기 항원, 면역원성 유도체 및 면역원성 단편 및 융합 단백질의 용도까지 확장된다.
유도체, 단편 및 융합 단백질
본 발명의 종양 연관 항원은 천연적으로 생성되는 항원이라기 보다는 상기 항원의 유도체 또는 단편의 형태로 사용될 수 있다.
본원에 사용된, 용어 "유도체"는 이의 천연적으로 생성된 형태와 대비하여 변형된 항원을 의미한다. 유도체는 돌연변이, 예를 들어, 점 돌연변이를 포함할 수 있다. 한 예로, 유도체는, 예를 들어, 원핵생물 시스템에서의 발현을 개선시킴으로써 또는 바람직하지 않은 활성, 예를 들어, 효소 활성을 제거함으로써, 단백질의 특성을 변화시킬 수 있다. 본 발명의 유도체는 천연 항원과 충분히 유사하여 당해 항원 특성을 보유하며 상기 천연 항원에 대하여 면역 반응을 일으킬 수 있다. 당해 유도체가 그러한 면역 반응을 일으킬지 여부는 적절한 면역학적 검정법, 예컨대, ELISA 또는 유세포분석에 의해 측정될 수 있다.
본 발명의 한 구체예에서, 본 발명의 종양 연관 항원의 유도체는 이종성 융합 파트너 단백질에 연결된 종양 연관 항원을 포함하는 융합 단백질이다. 종양 연관 항원과 관련하여 "이종성"은 천연에서 종양 연관 항원에 연결되지 아니할 단백질 또는 폴리펩티드 서열이, 인간의 의도적 개입에 의해 종양 연관 항원에 연결됨을 의미하기 위해 의도적으로 사용된다.
항원 및 이종성 융합 파트너 단백질은 화학적으로 컨주게이션될 수 있거나 재조합 융합 단백질로 발현될 수 있다. 한 구체예에서, 본 발명의 융합 단백질은 비융합된 단백질과 비교하여 당해 융합 단백질의 생산 수준이 발현 시스템에서 증가될 수 있다. 따라서, 융합 파트너 단백질은 T 헬퍼 에피토프, 예를 들어, 인간에 의해 인지되는 T 헬퍼 에피토프 제공을 보조할 수 있다(즉, 융합 파트너 단백질은 면역학적 융합 파트너로서 역할함). 융합 파트너는 천연 재조합 단백질 보다 더 높은 수율로 당해 단백질이 발현되도록 보조할 수 있다(즉, 융합 파트너 단백질은 발현 인핸서로서 역할함). 한 구체예에서, 융합 파트너 단백질은 면역학적 융합 파트너와 발현 증강 파트너 둘 모두로 역할할 수 있다.
융합 파트너 단백질은, 예를 들어, 단백질 D 단백질로부터 유래된다. 단백질 D는 리포단백질(그램 음성 박테리아 헤모필루스 인플루엔자(Haemophilus influenzae)의 표면에 노출된 42 kDa 면역글로불린 D 결합 단백질)이다. 이 단백질은, 박테리아 리포단백질에 관한 컨센서스 서열을 함유하는, 18개 아미노산 잔기의 신호 서열을 지니는 전구체로서 합성된다(WO 91/18926호 참조). 천연 전구체 단백질 D 단백질은 분비되는 동안 가공되며 신호 서열은 절단된다. 가공된 단백질 D의 Cys(전구제 분자에서 위치 19)는 가공된 단백질의 N 말단 잔기가 되며 에스테르-연결된 지방산 및 아미드-연결된 지방산 둘 모두의 공유결합성 부착에 의해 동시적으로(concomitantly) 변형된다. 이후 아미노-말단 시스테인 잔기에 연결된 지방산은 막 앵커(anchor)로서 역할한다.
한 구체예에서, 본 발명에 사용하기 위한 종양 연관 항원 유도체는 융합 파트너 단백질로서 단백질 D 또는 이의 유도체를 포함할 수 있다.
본원에 기재된 단백질 D 또는 이의 유도체는, 예를 들어, 가공된 단백질 D의 처음(first) 또는 N-말단의 1/3 또는 가공된 단백질 D의 처음 또는 N-말단의 대략 또는 약 1/3을 포함할 수 있다. 한 구체예에서, 단백질 D 또는 이의 유도체는 가공된 단백질 D의 N-말단의 처음 또는 100 내지 115개 아미노산; 또는 가공된 단백질 D의 처음 또는 N-말단의 109개 아미노산을 포함할 수 있다. 한 구체예에서, 천연의 가공된 단백질 D 아미노산 2-Lys과 2-Leu은 아미노산 2-Asp와 3-Pro로 치환될 수 있다.
한 구체예에서, 단백질 D 또는 이의 유도체는 전구체 단백질 D의 18 또는 19개 아미노산 신호 서열을 추가로 포함할 수 있다. 한 구체예에서, 단백질 D에서 유래된 융합 파트너 단백질은 전구체 단백질 D의 아미노산 20 내지 127을 포함하거나 이로 이루어진다. 본 발명의 한 구체예에서, 전구체 단백질 D 융합 파트너 단백질의 2개의 아미노산 21-Lys 및 22-Leu는 아미노산 21-Asp 및 22-Pro로 치환될 수 있다.
본원에 기재된 것과 같은 단백질 D 융합 파트너 단백질은 야생형 전구체 또는 가공된 단백질 D 서열와 비교하여 아미노산 서열내에 결실, 치환 또는 삽입을 추가적으로 또는 달리 함유할 수 있다. 한 구체예에서, 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 그 이상의 아미노산이 삽입, 치환 또는 결실될 수 있다. 아미노산은 본원에 정의된 것과 같은 보존적 치환으로 치환되거나 다른 아미노산이 사용될 수 있다.
한 구체예에서, 융합 파트너 단백질은 서열번호 1로 제시된 것과 같은 단백질 D 서열을 포함하거나 이로 이루어질 수 있다. 한 구체예에서, 융합 파트너 단백질은 도 1에 밑줄처진 아미노산, 즉 서열번호 12의 아미노산 잔기 20 내지 127을 포함하거나 이로 이루어질 수 있다. 한 구체예에서, 본 발명에 사용하기 위한 항원은 단백질-D-MAGE-3일 수 있는데, 상기 MAGE-3 항원은 MAGE-3의 아미노산 3 내지 314로 이루어지며 단백질 D 융합 파트너 단백질은 도 1에 제시된 아미노산 서열로 이루어진다.
본 발명의 또 다른 구체예에서, 융합 파트너 단백질은 하기한 것과 같은 NS1 또는 LytA 또는 이의 유도체 중에서 선택될 수 있다.
NS1은 인플루엔자 바이러스로부터의 비구조 단백질이다. 한 구체예에서, 본 발명의 종양 연관 항원 유도체는 융합 파트너 단백질로서 NS1 또는 이의 유도체를 포함할 수 있다. NS1 또는 이의 유도체는 N 말단의 1 내지 81개 아미노산을 포함할 수 있다.
LytA는 스트렙토코쿠스 뉴모니애(Streptococcus pneumoniae)로부터 유래된다. LytA 단백질의 C-말단 도메인은 콜인 또는 DEAE와 같은 일부 콜린 유사체에 대한 친화력에 관여한다. 한 구체예에서, 본 발명의 종양 연관 항원 유도체는 융합 파트너 단백질로서 LytA 또는 이의 유도체를 포함할 수 있다. LytA 또는 이의 유도체는 잔기 178에서 시작되는 C 말단부에서 발견되는 LytA 분자의 반복부를 포함할 수 있다. 한 구체예에서, LytA 또는 이의 유도체는 C-LytA의 잔기 188-305를 포함한다.
본 발명에 사용하기 위한 면역원성 폴리펩티드는 전형적으로, 예를 들어, 이종 숙주, 예컨대, 박테리아 숙주, 효모 또는 배양된 포유동물 세포에서의 발현에 의해 생산된 재조합 단백질일 것이다.
용어 "종양 연관 항원 유도체"는 종양 연관 항원에서 천연적으로 생성되는 서열을 부분적으로 또는 전체적으로 함유하거나 상기 서열에 대해 고도의 서열 동일성(예를 들어, 10개 이상, 예를 들어, 20개 이상의 아미노산의 스트레치에 걸쳐 95% 이상의 동일성)을 지니는 폴리펩티드를 의미한다. 또한 유도체는 보존적 치환을 지니는 서열을 포함한다. 보존적 치환은 잘 알려져 있고 일반적으로 서열 정렬 컴퓨터 프로그램에서 디폴트 스코어링 행렬로 설정된다.
일반적인 관점에서, 하기 그룹내의 치환은 보존적 치환이나, 하기 그룹 간의 치환은 비보존적 치환으로 고려된다. 그룹은 다음과 같다:
i) 아스파테이트/아스파라진/글루타메이트/글루타민
ii) 세린/트레오닌
iii) 리신/아르기닌
iv) 페닐알라닌/티로신/트립토판
v) 루신/이소루신/발린/메티오닌
vi) 글리신/알라닌.
본 발명의 유도체는 또한 알데히드(예컨대, 포름알데히드 또는 글루타르알데히드)로의 처리, 카르복시메틸화, 카르복시아미드화, 아세틸화 및 기타 통상적인 화학적 처리와 같이 화학적으로 처리된 서열을 포함할 수 있다. 유도체화된 유리 티올 잔기를 지니는 본 발명의 작제물은 또한 본 발명에 사용될 수 있다. 특히, 카르복시아미드화되거나 카르복시메틸화된 티올 유도체가 사용될 수 있다.
본 발명의 한 구체예에서, 종양 연관 항원 유도체는 유도체화된 유리 티올 잔기를 지니는 본원에 기재된 것과 같은 MAGE 항원일 수 있다. 상기 유도체화된 유리 티올 잔기는 카르복시아미드화 또는 카르복시메틸화된 유도체일 수 있다.
본 발명의 종양 연관 항원 유도체는 달리 하나 이상의 종양 연관 항원을 포함하는 작제물을 포함할 수 있다. 본 발명의 한 구체예에서, 상기 종양 연관 항원 유도체는 2개 이상의 종양 연관 항원을 포함할 수 있다.
본원에 사용된 용어 "단편"은 하나 이상의 에피토프, 예를 들어, CTL 에피토프, 전형적으로 8개 이상의 아미노산의 펩티드를 포함하는 종양 연관 항원의 단편 또는 상기 항원의 유도체를 의미한다. 예를 들어, 8-10개의 아미노산 또는 최대 길이가 20개, 50개, 60개, 70개, 100개, 150개 또는 200개인 아미노산이 상기 단편의 항원성이 입증되는한, 즉 주요 에피토프(예를 들어, CTL 에피토프)가 상기 단편에 의해 보유되며 상기 단편이 천연적으로 생성되는 종양 연관 항원과 교차-반응하는 면역 반응을 유도할 수 있는한, 본 발명의 영역내에 속하는 것으로 간주된다. 대표적인 단편은 길이에 있어서 8-10개, 10-20개, 20-50개, 50-60개, 60-70개, 70-100개, 100-150개, 150-200개 아미노산 잔기(상기 범위내의 임의의 값을 포함함)일 수 있다.
본 발명의 한 구체예에서, Her-2/neu 항원 및 CpG 올리고뉴클레오티드를 포함하는 동결건조 조성물은 3D-MPL과 QS21을 함유하는 리포좀 또는 수중유 에멀젼 담체로 재구성된다. 그러한 재구성된 제형은 체액성 및 세포성 매개 반응 둘 모두를 일으킨다.
본 발명의 동결건조 조성물은 종양-보조 메카니즘(예를 들어, 혈관신생, 종양 침습)과 연관된 항원, 예를 들어, 타이(tie) 2, VEGF를 포함할 수 있다.
본 발명의 또 다른 양상에서, 본 발명의 동결건조 조성물 내의 항원은 HIV 유래 항원, 특히 HIV-1 유래 항원 중에서 선택된 항원이다. 하기 단락은 HIV-1에서 유래될 수 있는 항원을 기술한다.
HIV Tat 및 Nef 단백질은 초기 단백질인데, 즉, 이들은 감염 초기에 구조 단백질의 부재시에 발현된다.
Nef 유전자는 몇몇 활성을 소유하는 것으로 드러난 초기 부속 HIV 단백질을 엔코딩한다. 예를 들어, Nef 단백질은 세포 표면으로부터의, HIV 수용체인, CD4의 제거를 초래하는 것으로 알려져 있는데, 이러한 기능의 생물학적 중요성은 논란거리가 되고 있다. 추가적으로, Nef는 신호전달 경로의 T 세포와 상호작용하며 활성 상태로 유도하며, 차례로 더 효율적인 유전자 발현을 촉진할 수 있다. 일부 HIV 동정체(isolates)는 상기 영역내에 돌연변이 또는 결실을 지니는데, 이것은 이들 동정체가 기능성 단백질을 엔코딩하지 못하게 하며 이들의 복제 및 생체내 병인에 있어서 극심하게 저하된다.
Gag 유전자는 전장길이 RNA로부터 번역되어 3-5개 캡시드 단백질로 연이어 절단되는 전구체 폴리펩티드를 양산한다: 매트릭스 단백질 p17, 캡시드 단백질 p24 및 핵산 결합 단백질(Fundamental Virology, Fields BN, Knipe DM and Howley M 1996 2. Fields Virology vol 2 1996).
Gag 유전자는 55-킬로달톤(Kd) Gag 전구체 단백질(p55로도 불리움)을 생성시키는데, 상기 단백질은 스플라이싱되지 않은 바이러스 mRNA로부터 발현된다. 번역 진행시, p55의 N 말단은 미리스토일화되는데, 이것은 세포막의 세포질면(cytoplasmic aspect)과 이것의 결합을 촉발시킨다. 막-결합 Gag 폴리펩티드는 감염된 세포의 표면으로부터의 바이러스 입자의 발아를 촉발시키는 다른 바이러스 단백질 및 세포 단백질과 함께 2개의 바이러스 게노믹 RNA 복제본을 모집한다. 발아후, p55는 바이러스의 성숙 과정이 진행되는 동안 바이러스에 의해 엔코딩된 프로테아제(Pol 유전자의 산물)에 의해 MA(매트릭스 [p17]), CA(캡시드 [p24]), NC(뉴클레오캡시드 [p9]), 및 p6로 지정된 4개의 더 작은 단백질로 절단된다.
3개의 주요 Gag 단백질(p17, p24 및 p9) 이외에, 모든 Gag 전구체는 수개의 다른 영역을 함유하는데, 이들 영역은 절단되고 다양한 크기의 펩티드로서 비리온내에 유지된다. 이들 단백질은 서로 다른 역할을 갖는데, 예를 들어, p2 단백질은 프로테아제의 활성을 조절하는데 있어서 소정 역할을 하며 단백질가수분해 가공의 정확한 시기결정에 기여한다.
MA 폴리펩티드는 p55의 N-말단의, 미리스토일화된 말단부로부터 유래된다. 대부분의 MA 분자는 바이러스 입자를 안정화시키는, 비리온 지질 이중층의 내부 표면에 부착되어 유지된다. MA의 서브세트는 비리온의 더 깊은 층 내부에서 모집되는데, 상기 층에서 MA는 바이러스 DNA를 핵으로 에스코트하는 복합체의 일부분이 된다. 이들 MA 분자는 바이러스 게놈의 핵 운송을 촉진하는데, 이는 MA의 친핵성(karyophilic) 신호가 세포내 핵 유입 기구에 의해 인지되기 때문이다. 이러한 현상은 HIV가 비분열 세포에 감염되게 하며, 이것은 레트로바이러스의 특이한 특성이다.
p24(CA) 단백질은 바이러스 입자의 원추형 코어를 형성한다. 시클로필린(Cyclophilin) A는 이의 HIV 입자내로의 통합에 앞서 p55의 p24 영역과 상호작용하는 것으로 밝혀졌다. Gag와 시클로필린 A 간의 상호작용은 필수적인데, 이는 시클로스포린에 의한 이러한 상호작용의 붕괴가 바이러스 복제를 억제시키기 때문이다.
Gag의 NC 영역은 소위 HIV의 패키징 신호를 특이적으로 인지하는 것에 관여한다. 상기 패키징 신호는 바이러스 RNA의 5' 말단부 근처에 위치한 4개의 스템 루프 구조로 이루어져 있고, 이종성 RNA를 HIV-1 비리온내로의 통합을 매개하는데 충분하다. NC는 2개의 징크-핑거 모티프에 의해 매개되는 상호작용을 통해 상기 패키징 신호에 결합한다. NC는 또한 역 전사를 촉진한다.
p6 폴리펩티드 영역은, 조립중인 비리온내로의 Vpr의 통합에 선행하여, p55 Gag와 보조 단백질 Vpr 간의 상호작용을 매개한다. p6 영역은 또한 감염된 세포로부터의 발아중인 비리온의 효율적인 방출에 요구되는 소위 후기 도메인을 함유한다.
Pol 유전자는 초기 감염시의 비리온에 의해 요구되는 활성을 지니는 3가지 단백질, 역 전사효소 RT, 프로테아제, 및 바이러스 DNA의 세포내 DNA로의 통합을 위해 요구되는 인테그라제 단백질을 엔코딩한다. Pol의 일차 산물은 비리온 프로테아제에 의해 절단되어 DNA 합성에 필요한 활성을 내포하는 아미노 말단 RT 펩티드(RNA 및 DNA 유도성 DNA 폴리머라제, 리보뉴클레아제 H) 및 카르복시 말단 인테그라제 단백질을 생성시킨다. HIV RT는 전장 길이 RT(p66)와 카르복시 말단 RNase H 도메인이 결여된 절단 생성물(p51)의 이종이합체이다.
RT는 레트로바이러스 게놈에 의해 엔코딩된 가장 보존된 단백질 중 하나이다. RT의 2가지 주요 활성은 DNA Pol과 리보뉴클레아제 H 활성이다. RT의 DNA Pol 활성은 상호교체될 수 있게 주형으로써 RNA와 DNA를 사용하며 또한 공지된 모든 DNA 폴리머라제는 새로이(de novo) DNA 합성을 개시시킬 수 없으나, 프라이머(RNA)로서 역할하는 앞서-존재하는 분자를 필요로 한다.
모든 RT 단백질에서 타고난 RNase H 활성은 DNA 합성이 진행됨에 따라 제거되는 RNA 게놈의 복제 초기에 필수적인 역할을 한다. 상기 RNase H는 모든 RNA-DNA 하이브리드 분자로부터 상기 RNA를 선택적으로 분해한다. 구조적으로 폴리머라제와 리보 H는 Pol의 아미노산 2/3를 포함하면서 상기 Pol 내에서 별개의, 비중첩 도메인을 점유한다.
p66 촉매 서브유닛은 5개의 독특한 서브도메인으로 폴딩된다. 이들의 아미노 말단 23은 RT 활성을 지니는 부분을 갖는다. 이들의 카르복시 말단은 RNase H 도메인이다.
숙주 세포에 감염후, 레트로바이러스 RNA 게놈은 감염중인 입자내에 존재하는 역 전사효소에 의해 선형 이중 가닥 DNA내로 복제된다. 인테그라제(문헌[Skalka AM '99 Adv in Virus Res 52 271-273]에서 검토됨)는 바이러스 DNA의 말단부를 인지하고, 이들을 다듬고, 바이러스 DNA를 동반한체 숙주 염색체 부위로 이동하여 통합을 촉매한다. 숙수 DNA내의 많은 부위들이 통합을 위한 표적이 될 수 있다. 인테그라제가 시험관내에서 충분히 통합을 촉매하지만, 이 단백질이 생체내에서 바이러스 DNA와 결합된 유일한 단백질은 아니다 - 거대 단백질-감염된 세포로부터 동정된 바이러스 DNA 복합체는 사전 통합 복합체로 표기되었다. 상기 복합체는 자손 바이러스 게놈에 의해 숙주 세포 유전자의 획득을 촉진한다.
인테그라제는 3개의 독특한 도메인, N 말단 도메인, 촉매 코어 및 C 말단 도메인으로 이루어진다. 상기 촉매 코어 도메인은 폴리뉴클레오티드 전이의 화학을 위한 모든 필요조건들을 내포한다.
따라서, 본 발명에 사용하기 위한 HIV-1 유래 항원은, 예를 들어, Gag(예를 들어, 전장길이 Gag), p17(Gag의 일부분), p24(Gag의 또 다른 일부분), p41, p40, Pol(예를 들어, 전장길이 Pol), RT(Pol의 일부분), p51(RT의 일부분), 인테그라제(Pol의 일부분), 프로테아제(Pol의 일부분), Env, gp120, gp140 또는 gp160, gp41, Nef, Vif, Vpr, Vpu, Rev, Tat 및 이의 면역원성 유도체 및 이의 면역원성 단편 중에서 선택될 수 있으며, 특히 p17, p24, RT 및 인테그라제를 포함하는 Env, Gag, Nef 및 Pol 및 이의 면역원성 유도체 및 이의 면역원성 단편 중에서 선택될 수 있다. HIV 백신은 폴리펩티드 및/또는 다수의 상이한 HIV 항원, 예를 들어, 상기 목록에서 선택될 수 있는 2 또는 3 또는 4개 이상의 HIV 항원에 상응하는 폴리펩티드를 엔코딩하는 폴리뉴클레오티드를 포함할 수 있다. 몇몇 상이한 항원은, 예를 들어, 단일한 융합 단백질내에 포함될 수 있다. 각각이 HIV 항원 또는 하나 이상의 항원의 융합체인 하나 이상의 제 1 면역원성 폴리펩티드 및/또는 하나 이상의 제 2 면역원성 폴리펩티드가 사용될 수 있다. 예를 들어, 항원은, RT 또는 이의 면역원성 유도체 또는 면역원성 단편에 융합되거나, Nef 또는 이의 면역원성 유도체 또는 면역원성 단편에 융합된, Gag 또는 이의 면역원성 유도체 또는 면역원성 단편을 포함할 수 있는데, 여기서 융합 단백질의 Gag 부분은 폴리펩티드의 5' 말단부에 존재한다.
본 발명에 따른 용도의 Gag 서열은 Gag p6 폴리펩티드 엔코딩 서열을 배제할 수 있다. 본 ㅂ라명에 사용하기 위한 Gag 서열의 특별한 일예는 p17 및/또는 p24 엔코딩 서열을 포함한다.
RT 서열은 임의의 역 전사효소 호라성을 실질적으로 불활성화시키는 돌연변이를 함유할 수 있다(WO03/025003호 참조).
RT 유전자는 HIV 게놈내의 더 거대한 pol 유전자의 성분이다. 본 발명에 따라 사용되는 RT 서열은 Pol, 또는 적어도 RT에 상응하는 Pol의 단편의 맥락(context) 중에 존재할 수 있는 것으로 이해될 것이다.
Pol의 그러한 단편은 Pol의 주요 CTL 에피토프를 보유한다. 한 특이적 일예에서, RT는 RT의 p51 또는 p66 단편을 그대로 포함한다.
본 발명에 따른 융합 단백질 또는 조성물의 RT 성분은 원핵생물 발현 시스템내의 내부 개시 부위(internal initiation site)로서 역할하는 부위를 제거하기 위한 돌연변이를 임의로 포함한다.
임의로 본 발명에 사용하기 위한 Nef 서열은 N 말단 영역을 엔코딩하는 서열의 제거, 즉 30 내지 85개 아미노산, 예를 들어, 60 내지 85개 아미노산, 특히, N 말단 65개 아미노산의 제거를 위해 절단된다(후자의 제거는 본원에서 trNef로 지칭된다). 대안적으로 또는 추가적으로 Nef는 미리스틸화 부위를 제거하기 위해 변형될 수 있다. 예를 들어, Gly 2 미리스틸화 부위는 결실 또는 치환에 의해 제거될 수 있다. 대안적으로 또는 추가적으로 Nef는 하나 또는 두 루신의 결실 또는 치환에 의해 Leu 174 및 Leu 175의 디루신 모티프를 변경시키기 위해 변형될 수 있다. CD4 하향조절에서 디루신 모티프의 중요성은, 예를 들어, 문헌[Bresnahan P.A. et al (1998) Current Biology, 8(22): 1235-8]에 기재되어 있다.
Env 항원은 (gp120과 gp41 사이의 절단 부위 모티프를 파괴하기 위해 적합한 돌연변이를 지니거나 지니지 아니하면서) gp160으로서 이의 전장길이로 존재하거나 gp140으로서 또는 이 보다 더 짧게 절단될 수 있다. Env 항원은 또한 gp120과 gp41로서 이의 천연적으로 생성되는 가공 형태로 존재할 수 있다. 이러한 gp160의 2개의 유도체는 개별적으로 또는 조합물로써 함께 사용될 수 있다. 앞서 언급한 Env 항원은 결실(특히 가변 루프의 결실) 및 절단을 추가로 나타낼 수 있다. Env의 단편이 또한 사용될 수 있다.
대표적인 gp120 서열은 서열번호 6으로 제시된다. 대표적인 gp140 서열은 서열번호 7로 제시된다.
본 발명에 따른 동결건조 조성물에 사용하기 위한 면역원성 폴리펩티드는 Gag, Pol, Env 및 Nef를 포함할 수 있는데, 여기서 이들 천연 항원의 CTL 에피토프의 75% 이상, 또는 90% 이상 또는 95% 이상이 존재한다.
위에 정의된 것과 같은 p17/p24 Gag, p66 RT, 및 절단된 Nef를 포함하는 면역원성 폴리펩티드를 포함하는 동결건조 조성물에서, 천연 Gag, Pol 및 Nef 항원의 CTL 에피토프의 96%가 적당하게 존재한다.
본 발명의 한 구체예는 TLR9 리간드와 Gag, RT, Nef의 순서로 p17, p24 Gag, p66 RT, (말단 아미노산 1-85("trNef")를 엔코딩하는 뉴클레오티드가 결여된) 절단된 Nef를 함유하는 면역원성 폴리펩티드를 포함하는 동결건조 조성물을 제공한다.
본 발명에 따른 동결건조 조성물에 사용하기 위한 특이 폴리뉴클레오티드 작제물 및 상응하는 폴리펩티드 항원은 하기한 것들을 포함한다:
1. p17, p24(코돈 최적화됨) Gag - p66 RT(코돈 최적화됨) - 절단된 Nef;
2. 절단된 Nef - p66 RT(코돈 최적화됨) - p17, p24(코돈 최적화됨) Gag;
3. 절단된 Nef - p17, p24(코돈 최적화됨) Gag - p66 RT(코돈 최적화됨);
4. p66 RT(코돈 최적화됨) - p17, p24(코돈 최적화됨) Gag - 절단된 Nef;
5. p66 RT(코돈 최적화됨) - 절단된 Nef - p17, p24(코돈 최적화됨) Gag;
6. p17, p24(코돈 최적화됨) Gag - 절단된 Nef - p66 RT(코돈 최적화됨).
대표적인 융합체는 Gag, RT 및 Nef의 융합체인데, 특히 Gag-RT-Nef 순서로 융합된 융합체이다(예를 들어, 서열번호 8 또는 서열번호 9을 참조하라). 또 다른 대표적인 융합체는 p17, p24, RT 및 Nef의 융합체인데, 특히 p24-RT-Nef-p17 순서로 융합된 융합체이다. 이 융합체는 F4로 불리우며 WO2006/013106호에 기재되어 있다. F4는 본 발명의 동결건조 조성물에서 발견될 수 있는 HIV 항원의 바람직한 일예이다. F4의 뉴클레오티드 서열은 서열번호 10으로 주어지며, 여기서 p24 서열은 굵은 글씨로 표기되어 있으며, Nef 서열은 밑줄이 쳐저 있고, 박스는 유전자 작제에 의해 도입된 뉴클레오티드이다. F4의 아미노산 서열은 서열번호 11로 주어지며, 여기서:
P24 서열: 아미노산 1-232(굵은 글씨체)
RT 서열: 아미노산 235-795
Nef 서열: 아미노산 798-1002
P17 서열: 아미노산 1005-1136
박스: 유전자 작제에 의해 도입된 아미노산
K(리신): 트립토판(W) 대신. 효소 활성을 제거하기 위해 도입된 돌연변이.
또 다른 구체예에서, 동결건조 조성물은 Gag, RT, 인테그라제 및 Nef를 함유하는데, 특히 Gag-RT-인테그라제-Nef 순서로 함유한다(예를 들어, 서열번호 11을 참조하라).
다른 구체예에서, HIV 항원은 Nef 또는 이의 면역원성 유도체 또는 면역원성 단편, 및 p17 Gag 및/또는 p24 Gag 또는 이의 면역원성 유도체 또는 면역원성 단편을 포함하는 융합 폴리펩티드일 수 있는데, 여기서 p17 및 p24 둘 모두가 존재하는 경우, 이들 사이에 하나 이상의 HIV 항원 또는 면역원성 단편이 존재한다.
예를 들어, Nef는 전장길이 Nef인 것이 적합하다.
예를 들어, p17 Gag 및 p24 Gag는 각각 전장길이 p17 및 p24인 것이 적합하다.
한 구체예에서, 동결건조 조성물은 p17 및 p24 Gag 둘 모두 또는 이의 면역원성 단편을 포함하는 면역원성 폴리펩티드를 함유한다. 그러한 작제물에서, p24 Gag 성분 및 p17 Gag 성분은 하나 이상의 추가 HIV 항원 또는 면역원성 단편, 예컨대, Nef 및/또는 RT 또는 이의 면역원성 유도체 또는 이의 면역원성 단편에 의해 분리된다. 더 상세한 내용은 WO2006/013106호를 참조하라.
p24 및 RT를 포함하는 융합 단백질에서, p24가 작제물내에서 RT에 앞서 존재하는 것이 바람직할 수 있는데, 그 이유는 항원이 E. coli에서 단독으로 발현되는 경우, RT의 발현에 비해 p24의 발현이 더 나은 것으로 관찰되기 때문이다.
본 발명에 따른 동결건조 조성물에서 사용하기 위한 몇몇 작제물은 하기한 것들을 포함한다:
1. p24 - RT - Nef - p17
2. p24 - RT* - Nef - p17
3. p24 - p51 RT - - Nef - p17
4. p24 - p51 RT* - Nef - p17
5. p17 - p51 RT - - Nef
6. p17 - p51 RT* - Nef
7. Nef - p17
8. Nef - 링커와 함께 p17
9. p17 - Nef
10. p17 - 링커와 함께 Nef
*는 리신에 대한 RT 메티오닌592 돌연변이를 나타낸다.
또 다른 양상에서, 본 발명은 4개 이상의 HIV 항원 또는 면역원성 단편을 포함하는 HIV 항원의 융합 단백질을 함유하는 동결건조된 조성물을 제공하는데, 여기서 상기 4개의 항원 또는 단편은 Nef, Pol 및 Gag로부터 유래된다. 바람직하게는, Gag는 융합체에서 하나 이상의 다른 항원에 의해 이격된 2개의 별개 성분으로 존재한다. 바람직하게는, Nef는 전장길이 Nef이다. 바람직하게는, Pol은 p66 또는 p51 RT이다. 바람직하게는, Gag는 p17 및 p24 Gag이다. 본 발명의 이 양상에서 융합체의 항원 성분들의 다른 바람직한 특색 및 특성은 본 명세서에 기재되어 있다.
본 발명의 이 양상의 바람직한 구체예는 이미 앞서 나열한 것과 같은 4개의 성분들의 융합체이다:
1. p24 - RT - Nef - p17
2. p24 - RT* - Nef - p17
3. p24 - p51RT - Nef - p17
4. p24 - p51RT* - Nef - p17
본 발명의 동결건조된 조성물내에 사용된 면역원성 폴리펩티드는 특정 항원, 예컨대, Gag, RT 및 Nef에 상응하는 서열들 사이에 존재하는 링커 서열을 지닐 수 있다. 그러한 링커 서열의 길이는, 예를 들어, 최대 20개 아미노산일 수 있다. 특별한 일예에서, 링커는 1 내지 10개 아미노산, 또는 1 내지 6개 아미노산, 예를 들어, 4-6개 아미노산일 수 있다.
그러한 적합한 HIV 항원에 대한 추가 설명은 WO03/025003호에서 찾아볼 수 있다.
본 발명에 사용하기 위한 HIV 항원은 임의의 HIV 클레이드(clade), 예를 들어, 클레이드 A, 클레이드 B 또는 클레이드 C 중에서 유래될 수 있다. 예를 들어, HIV 항원은 클레이드 A 또는 B, 특히 B에서 유래될 수 있다.
본 발명의 한 특정 구체예에서, 동결건조된 조성물은 하나 이상의 면역원성 폴리펩티드를 함유한다. 이 구체예의 한 양상에서, 제 1 면역원성 폴리펩티드는 Gag 및/또는 Pol 및/또는 Nef 또는 상기한 것들 중 임의의 것의 단편 또는 유도체를 포함하는 폴리펩티드(예를 들어, p24-RT-Nef-p17)이다. 본 발명의 이 구체예의 한 특정 양상에서, 제 2 면역원성 폴리펩티드는 Gag 및/또는 Pol 및/또는 Nef 또는 상기한 것들 중 임의의 것의 단편 또는 유도체를 포함하는 폴리펩티드(예를 들어, Gag-RT-Nef 또는 Gag-RT-인테그라제-Nef)이다.
따라서, 한 특정 구체예에서, Gag 및/또는 Pol 및/또는 Nef 또는 상기한 것들 중 임의의 것의 단편 또는 유도체를 포함하는 폴리펩티드(예를 들어, p24-RT-Nef-p17)는 제 1 면역원성 폴리펩티드이고, Gag 및/또는 Pol 및/또는 Nef 또는 상기한 것들 중 임의의 것의 단편 또는 유도체를 포함하는 폴리펩티드(예를 들어, Gag-RT-Nef 또는 Gag-RT-인테그라제-Nef)는 제 2 면역원성 폴리펩티드이다.
본 발명의 또 다른 특정 구체예에서, 제 1 면역원성 폴리펩티드는 Env 또는 이의 단편 또는 유도체(예를 들어, gp120, gp140 또는 gp160)(특히 gp120)이다. 본 발명의 한 특정 구체예에서, 제 2 면역원성 폴리펩티드는 Gag 및/또는 Pol 및/또는 Nef 또는 상기한 것들 중 임의의 것의 단편 또는 유도체를 포함하는 폴리펩티드(예를 들어, p24-RT-Nef-p17)이다.
따라서, 한 특정 구체예에서, Env 또는 이의 단편 또는 유도체, 예를 들어, gp120, gp140 또는 gp160(특히 gp120)은 제 1 면역원성 폴리펩티드이고, Gag 및/또는 Pol 및/또는 Nef 또는 상기한 것들 중 임의의 것의 단편 또는 유도체를 포함하는 폴리펩티드(예를 들어, p24- RT-Nef-p17)는 제 2 면역원성 폴리펩티드이다.
본 발명의 또 다른 특정 구체예에서, 제 1 면역원성 폴리펩티드는 Gag 및/또는 Pol 및/또는 Nef 또는 상기한 것들 중 임의의 것의 단편 또는 유도체를 포함하는 폴리펩티드(예를 들어, p24-RT-Nef-p17)이다. 본 발명의 한 특정 구체예에서, 제 2 면역원성 폴리펩티드는 Env 또는 이의 단편 또는 유도체, 예를 들어, gp120, gp140 또는 gp160(특히, gp120)이다.
따라서, 한 특정 구체예에서, Gag 및/또는 Pol 및/또는 Nef 또는 상기한 것들 중 임의의 것의 단편 또는 유도체를 포함하는 폴리펩티드(예를 들어, p24-RT-Nef-p17)는 제 1 면역원성 폴리펩티드이고, Env 또는 이의 단편 또는 유도체, 예를 들어, gp120, gp140 또는 gp160(특히, gp120)이 제 2 면역원성 폴리펩티드이다.
동결건조 조성물은 하나의 항원을 함유하거나, 하나 이상의 항원을 함유할 수 있다.
본 발명의 한 양상에서, TLR9 리간드가 양으로 비하전된 항원의 용해도를 개선시키기 위해 사용된다. 본 발명자들은, 특히, 음으로 하전된 항원으로, Cpg의 동시-동결건조는 재구성시 이들의 용해도를 개선시킬 수 있음을 발견하였다. TLR9 리간드가 면역자극성 올리고뉴클레오티드인 경우, 항원은 순 음 전하를 지니는 분자일 것이다. 이 리간드가 순 양 전하를 지니는 항원과 함께 동시-동결건조되는 경우, 상기 TLR9 리간드가 동결건조 조성물의 재구성시 상기 항원과 상호작용하게 될 것이고, 추정컨대, 상기 항원의 침전을 야기시킬 가능성이 존재한다. 이것은 바람직하지 아니하며, 예를 들어, L-아르기닌과 같은, 그러한 상황에서 용해도를 증가시키는 것으로 공지된 부형제를 상기 동결건조용 조성물에 포함시킴으로써 당업계의 통상의 기술자에 의해 회피될 수 있다.
TLR9 리간드 및 하나 이상의 항원은 동결건조될 최종 벌크 제형을 형성하기 위해 적합한 부형제와 조합된다. 최적으로, 부형제는 동결건조의 초기 단계가 진행되는 동안 변성으로부터 단백질을 보호하기 위한 동결방지제, 건조가 진행되는 동안 단백질 불활성화를 막기위한 동결건조보호제(lyoprotectant)를 함유할 것이다. 2개의 상이한 분자가 사용될 수 있거나, 디사카라이드와 같은, 양쪽 특성을 지니는 1개의 분자가 사용될 수 있다. 임의로, 만니톨 또는 글리신과 같은 결정성 팽화제(bulking agent)가 또한 첨가될 수 있다. 폴리소르베이트 또는 트윈(Tween?)과 같은 비이온성 계면활성제가 또한 단백질의 응집을 막는 것을 돕기 위해 첨가될 수 있다. 부형제는 또한 최종 벌크의 pH를 변화시키기 위해 버퍼 염을 포함할 수 있다.
적합한 부형제는 하기한 것들을 포함한다: 당, 예컨대, 수크로즈, 트레할로즈, 라피노즈 및 말토덱스트린, 예컨대, 말토트리오즈, 말토테트라오즈, 말토펜타오즈 또는 말토헥사오즈; 폴리올, 예컨대, 만니톨 또는 소르비톨; 폴리머, 예컨대, 덱스트란, 폴리에틸렌 글리콜(PEG), 또는 폴리비닐피롤리돈(PVP); 아미노산, 예컨대, 글리신, 알라닌 또는 아르기닌.
부형제는 또한 조합되어 2개 이상, 예를 들어, 3개 또는 4개의 부형제와 함께 사용될 수 있다. 가능한 조합물은 당과 덱스트란, 예를 들어, 수크로즈와 덱스트란 또는 트레할로즈와 덱스트란; 당과 PEG, 예를 들어, PEG8000와 사카라이드; 당과 PVP, 예를 들어, 수크로즈와 PVP; 당과 아미노산, 예를 들어, 글리신과 수크로즈; 2개의 당, 예를 들어, 수크로즈와 글루코즈 또는 수크로즈와 라피노즈; 수크로즈와 폴리올, 예를 들어, 수크로즈와 소르비톨 또는 수크로즈와 만니톨; 폴리올과 아미노산, 예컨대, 만니톨과 글리신을 포함한다.
계면활성제, 예컨대, 폴리소르베이트 또는 트윈(Tween?)이 부형제의 임의의 조합에 첨가될 수 있다.
백신접종을 위해 사용될 수 있는 면역원성 조성물을 만들기 위해, 항원과 TLR9 리간드를 함유하는 동결건조 조성물이 약제학적으로 허용되는 희석제로 재구성된다. 그러한 희석제가 미립자화된 희석제, 예를 들어, 금속 염 입자의 용액, 또는 리포좀, 또는 수중유 에멀젼이어야 만 본 발명의 바람직한 양상이 된다.
한 구체예에서, 희석제는 추가로 면역자극제를 함유한다. 이것은 최종 재구성된 면역원성 조성물이 동결건조 조성물내에서 발견되는 TLR9 리간드 이외에 다른 면역자극제를 함유할 것임을 의미한다.
단독으로 또는 조합되어 애주번팅되는 것으로 알려진 다수의 공지된 면역자극제가 존재한다. 선천적 또는 자연적 면역 시스템은 이전의 노출에 대한 요구 없이 광범위한 병원균을 인지한다. 선천적 면역력에 관여하는 주요 세포, 단핵구/대식세포 및 호중구는 미생물 병원체를 대식하고(phagocytose) 선천적, 염증성, 및 특이적 면역 반응을 촉발시킨다.
리포폴리사카라이드(LPS)는 그램-음성 박테리아의 외막의 외부 소엽(external leaflet)의 주요 표면 분자이며, 상기 소입내에서 주로 생성된다. LPS는 TLR4 리간드인 것으로 드러났다. LPS는 혈청 보체 및 대식 세포에 의한 박테리아의 파괴를 방해하며, 콜로니화를 위한 부착에 관여한다. LPS는 대략 10,000 달톤 크기의 구조적으로 관련된 복합체 분자의 집단이며 하기 3개의 공유적으로 연결된 영역으로 이루어진다:
(i) 외부 영역에 O-특이적 폴리사카라이드 쇄(O-항원)
(ii) 코어 올리고사카라이드 중심 영역
(iii) 지질 A - 소수성 앵커로서 역할하는 가장 깊은 영역이며, 이것은 긴 지방산 쇄를 나르는 글루코사민 디사카라이드 유닛을 포함한다.
LPS의 생물학적 활성, 예컨대, 치명적 독성, 발열성(pyrogenicity) 및 애주번트성(adjuvanticity)이 지질 A 모이어티와 관련이 있는 것으로 드러났으며, 반대로, 면역원성은 O-특이적 폴리사카라이드 성분(O-항원)과 연관되어 있다. LPS와 지질 A 둘 모두가 이들의 강한 애주번트 효과로 유명하나, 이들 분자의 높은 독성은 백신 제형에서의 이들의 사용을 방해하였다. 따라서, 이들의 애주번트성을 유지하면서 LPS 또는 지질 A의 독성을 감소시키기 위한 상당한 노력이 행해졌다.
살모넬라 미네소타(Salmonella minnesota) 돌연변이체 R595가 1966년에 모 (부드러운) 균주의 배양물에서 동정되었다(Luderitz et al. 1966 Ann. N. Y. Acad. ScL 133:349-374). 선별된 콜로니는 파지 패널에 의한 용해에 대한 이들의 민감도에 관해 스크리닝되었으며, 좁은 범위의 민감도를 나타낸 콜로니만(단지 1 또는 2개의 파지에 민감한 콜로니) 추가 연구를 위해 선별되었다. 이러한 노력은 LPS 생합성에 결함이 있는 매우 거친 돌연변이 균주의 동정을 가져왔고 이 균주는 S. 미네소타 R595로 명명되었다.
다른 LPS와 비교하여, 돌연변이체 S. 미네소타 R595에 의해 생산된 LPS는 비교적 단순한 구조를 갖는다.
(i) 이들은 O-특이적 영역을 함유한다 - 야생형 부드러운 표현형에서 돌연변이체 거친 표현형으로의 전환에 관여하며 병원성의 손실을 초래하는 특성.
(ii) 코어 영역이 매우 짧다 - 이러한 특성은 다양한 화학물질에 대한 균주의 민감도를 증가시킨다.
(iii) 지질 A 모이어티는 최대 7개 지방산으로 고도로 아실화된다.
그램-음성 박테리아의 매우 거친 돌연변이체 균주에서 추출된 LPS의 산 가수분해에 의해 획득될 수 있는, 4'-모노포스포릴 리피드 A(MPL)는 LPS의 애주번트 특성을 보유하면서, 독성이 닭 배아 란에 치사 용량으로 측정시) 1000배 이상 감소되는 것으로 드러났다(Johnson et al. 1987 Rev. Infect. Dis. 9 Suppl:S512-S516). LPS는 전형적으로 대략 30분의 기간 동안 적절한 강도의 미네랄 산 용액(예를 들어, 0.1M HCl)에서 환류된다. 이러한 과정은 결과적으로 1번 위체에 탈인산화, 및 6' 위치에 탈탄화수소화(decarbohydration)를 초래하여, MPL을 생성시킨다.
MPL의 유순한 알카리 가수분해로 획득될 수 있는, 3-O-탈아실화된 모노포스포릴 리피드 A(3D-MPL)은 더 감소된 독성을 지니면서 다시 애주번트성을 유지한다(미국 특허 제 4,912,094호(Ribi Immunochemicals) 참조). 알칼리 가수분해는, 약 염기 용액, 예컨대, pH 10.5에서 0.5M 소디움 카르보네이트로의 포화에 의해, 전형적으로 유기 용애, 예컨대, 클로로포름/메탄올의 혼합물에서 수행된다.
3D-MPL의 제조에 관한 추가 정보는, 예를 들어, 미국 특허 제4,912,094호 및 WO02/078637호(Corixa Corporation)에서 가용하다.
TLR 리간드가 아닌 일부 분자들은 애주번트 활성을 지니는 것으로 드러났다. 퀼라자(Quillaja) 사포닌은 퀼라자 사포나리아(Quillaja saponaria) 나무의 줄기에서 추출된 트리테르펜 글리코시드의 혼합물이다. 미정제 사포닌은 수의 애주번트로서 폭넓게 사용되어 왔다. 퀼-A는 퀼라자 사포닌 물질의 부분 정제된 수성 추출물이다. QS21은 퀼 A의 Hplc 정제된 무독성 분획이고, 이의 생산 방법은 (QA21로) 미국 특허 제 5,057,540호에 개시되어 있다.
본 발명의 한 양상에서, 희석제는 하나의 추가 면역자극제를 함유한다. 본 발명의 또 다른 양상에서, 희석제는 하나 이상의 추가 면역자극제를 함유한다. 그러한 면역자극제는 TLR4 리간드, 사포닌, TLR7 리간드, TLR8 리간드 또는 TLR9 리간드일 수 있다. 본 발명의 한 구체예에서, 상기 추가 면역자극제는 TLR4 리간드, 예컨대, 본원에 기재된 3D-MPL이다. 본 발명의 추가 구체예에서, 상기 추가 면역자극제는 본원에 기재된 QS21이다. 본 발명의 아직 추가 구체예에서, 희석제는 QS21과 3D-MPL을 함유한다. 이 구체예의 한 양상에서, 상기 희석제는 QS21과 3D-MPL을 함유하는 수중유 에멀젼이다. 이 구체예의 또 다른 양상에서, 상기 희석제는 QS21과 3D-MPL을 함유하는 리포좀 용액이다.
본 발명은 이제 하기 비제한적 실시예를 참고하는 방식으로 더 상세히 기재될 것이다.
실시예
실시예 1: 항원으로서 CpG 올리고뉴클레오티드 및 CPC-P501S의 동결 건조
사용된 항원은 CPC-P501S이었다. 이 항원은 도 1에 개략적으로 도시되어 있고, TM2 내지 TM12를 도시한 부분은 P501S 항원을 나타낸다; 좌변(left hand side) 상의 난형(oval shapes)은 CPC 융합 파트너를 나타내고 His 테일이 우변에 도시되어 있다.
S. 세레비시애에서 확인된 His 태그를 지니는 항원을 생산하고 난 다음 트리스(5mM, pH 7.5)와 트윈8O(0.3%) 버퍼를 사용하여 700 μg/ml의 농도로 만들었다.
최종 벌크를 제조하기 위해, 수크로즈(35%)를 주사용수에 첨가하여 6.3%의 최종 농도에 도달시켰다. 이후 트리스(1M, pH 8.8)를 첨가하고, 뒤이어 트윈80(25%)을 첨가하여 최종 농도의 0.2%에 도달시켰다. 이 혼합물을 실온에서 5분간 자석을 이용하여 교반시켰다. CPC-P501S를 첨가하고 혼합물을 실온에서 4분 동안 자석을 이용하여 교반시켰다. 이후 서열번호 4의 CpG 올리고를 첨가하고, 그 결과 얻어진 혼합물을 실온에서 15분간 자석을 이용하여 교반시켜 최종 벌크를 수득하였다. 조성은 다음과 같이 분석되었다:
0.5ml의 조성물을 유리 바이얼에 채우고, 상기 조성물을 도 2에 도시된 것과 같은 동결건조 순환주기를 겪게 하였다.
상기 조성물의 3개 바이얼에 대해, 37℃에서 TO, 1주, 2주, 3주, 및 4주에 육안 검사 및 직경 측정으로 케이크 특성결정을 실시하였다(도 3 참조). 열중량분석(TG) 또는 칼 피셔(KF)를 사용하여 상기한 동일 시점 및 온도에서 잔류 수분 함량(Residual humidity content)을 측정하였다. 하기에서 확인할 수 있는 바와 같이, 케이크는 최대 2주 동안 안정하였다.
동결건조된 케이크
KF: 칼 피셔 방법
TG: 열중량분석 방법
nd: 미실시
OK: 응집 및 파쇄 없음
품질규격(Specs): 3% (열중량)
(안정도 분석을 빠르게 하기 위해) 37℃에 저장된 최종 용기내의 습도를 분석 시간 동안 증가시킨다. 37℃에서 1달 경과후, 케이크는 1.3% H2O를 함유하며 오그라 든다. 이 실험에서, 습도의 증가는 흡습성 분말이 대기로부터 물을 흡수한다는 사실에 기인한다. 스토퍼를 새로운 형태의 스토퍼로 교체하는 것은 이러한 오그라듦을 막는데 도움이 될 수 있다.
이후 케이크를 주사용수 또는 하기 담체 액체로 재구성하였다: 애주번트 시스템 A(WO2005/112991호에 제시된 것과 같이 제조된 리포좀 애주번트), 애주번트 시스템 E(WO2005/112991호에 제시된 것과 같이 제조된 수중유 에멀젼 애주번트) 또 는 애주번트 시스템 F(WO2005/112991호에 제시된 것과 같이 제조된 수중유 에멀젼 애주번트).
단백질 응집 또는 파쇄는 수사용수, 애주번트 시스템 E 또는 애주번트 시스템 F에서 관찰되지 않았다. 일부 응집 및 파쇄가 애주번트 시스템 A에서 관찰되었다. 이것은 pH가 CPC-P501S의 등전점 미만으로 감소되었기 때문인 것으로 결론내려졌다. 트리스 부형제의 농도를 5OmM로 증가시키는 것이 이러한 문제를 해결하였으며 이후 응집은 애주번트 시스템 A에서 관찰되지 않았다. 또한 리오 케이크(즉, 항원과 CpG 올리고뉴클레오티드의 동시-동결건조물)내의 CpG의 존재가 애주번트 시스템 A로의 재구성시 상기 항원의 응집을 막는데 도움이 되었음이 확인되었다. 애주번트 시스템 A를 사용한 CpG가 있거나 없는 리오 케이크의 재구성의 비교는 동결건조후 응집이 감소되었음을 보여주었다(데이타 미제시).
애주번트 시스템 A내의 리포좀의 크기에 대한 부형제의 영향을 또한 연구하였고, 애주번트 시스템 A 단독의 바이얼에서 확인된 리포좀과 항원, CpG, 트리스 및 트윈을 함유한 리오-케이크의 재구성후 애주번트 시스템 A의 바이얼에서 확인된 리포좀 간의 크기에서의 차이는 없음을 발견하였다. 따라서, 본 발명자들은 리오-케이크의 성분은 애주번트 시스템에 영향을 미치지 않는다는 결론을 내릴 수 있다(도 4).
마지막으로, 제형의 항원성을 연구하였고, 림프구증식 및 세포내 사이토카인(IFNγ) 생산의 측면에서, 액체 대 CPC-P501S의 제형 간의 차이가 없음이 확인되었다(데이타 미제시). 따라서, 본 발명자들은 항원의 면역원성이 CpG와 동시-동결 건조에 의해 영향받지 않는다는 결론을 내릴 수 있다.
실시예 2: CpG 올리고뉴클레오티드와 항원으로 Mage-3의 동결 건조
사용된 항원은 MAGE-3에 연결된 단백질 D 단백질의 일부분이었고, MAGE-3는 차례로 PD-Mage3-His 정제를 용이하게 하기 위해 His 테일에 연결되었다(도 5: 서열번호 13 참조).
정제된 벌크 항원을 E. coli에서 His 태그와 함께 생산하였고, 이후 대략 0.2% v/v(이론적으로), pH 7.5에서 NaH2PO4·2H2O/K2HPO4· 2H2O(2 mM)와 트윈80의 버퍼를 사용하여 750 μg/ml의 농도로 제조하였다.
최종 벌크를 제조하기 위해, 수크로즈(30%)를 주사용수에 첨가하여 최종 농도의 3.15%를 얻었다. 이후 항원 버퍼내에서 확인된 인산염을 고려하여 NaH2PO4·2H2O/K2HPO4· 2H2O(10O mM, pH 7.5)를 첨가하여 5 mM의 최종 PO4 농도를 얻었다. 또한 항원 버퍼내에서 확인된 트윈을 고려하여, 트윈80(3%)을 첨가하여 0.15%의 최종 농도를 얻었다. 이 혼합물을 실온에서 5 내지 15분 동안 자석을 이용하여 교반하였다. PD-Mage3-His를 첨가하고(750μg/ml) 이 혼합물을 실온에서 5-15분 동안 자석을 이용하여 교반하였다. 그런 다음 서열번호 4의 CpG 올리고를 첨가하고, 그 결과 얻어진 혼합물을 실온에서 15분 동안(+/- 5분) 자기적으로 교반하여 최종 벌크를 얻었다. pH를 0.05M 또는 0.5M NaOH, 또는 0.03M 또는 0.3M HCl을 사용하여 pH 7.5 +/- 0.1로 조정하였다.
조성은 다음과 같이 분석되었다:
이 조성물의 0.5ml를 유리 바이얼에 충진시키고, 이 바이얼이 도 6에 도시된 것과 같이 동결건조 순환주기를 겪게 하였다.
케이크 조성에 대한 부형제 및 동결 건조 순환주기의 영향을 37℃에서 7 내지 9일 동안 저장한 후 분석하였다.
케이크 모습 및 잔류 습도
케이크는 7일째에 임의의 붕괴를 나타내지 않으며 8일에 걸친 스크레스하에서 안정성 변화를 나타내지 않는다는 것을 알 수 있다.
37℃에서 7 내지 9일 동안 저장된 케이크의 잔류 습도는 품질규격(specification)의 3% 미만으로 유지된다.
37℃에서 7 내지 9일 동안의 저장후 직경의 발달(evolution)은 없었다.
이후, 케이크를 애주번트 시스템 A(WO2005/112991호에 제시된 것과 같이 제 조된 리포좀 애주번트)로 재구성하였다. 단백질 응집 또는 파괴는 관찰되지 않았고, 그로 인해 재구성될 때 항원의 활성에 영향을 미치지 않으면서 항원이 CpG와 함께 동시-동결건조될 수 있다는 것이 확증되었다.
제형의 항원성을 연구하였다. 애주번트 시스템 A로 재구성후, 24시간 경과후, 시간에 따라 항원성이 감소되었다. 이것은 재구성후 확인된 산성 pH(6.2+/-0.1)에 기인된 것으로 생각되었다. 이러한 생각은 항원성의 감소가 pH를 증가시킴으로써 줄어들 수 있다는 것이 확인되었을 때 확증되었다. 그러나, 시간 경과에 따른 항원성에서의 약간의 감소는 여전히 존재하였다. 따라서, 이러한 감소가 생체내 효능 시험에서 영향을 미치는지 여부를 알아 보기 위해 제형을 시험하였다. 인간 용량의 3/10회, 1/10회 및 1/30회(th) 희석액을 마우스 그룹에 투여하였다(도 7에 도시된 바와 같이 그룹당 10마리의 마우스로 구성됨). 마우스를 28일째에 채혈하였다.
O시(T0), 4시 및 24시가 애주번트 시스템 A로 케이크를 재구성한 후 시험한 시간이다. 도 7에서 알 수 있는 바와 같이, 효능에는 영향이 없었다.
실시예 3: 재구성후 항원 용해도에 대한 CpG의 영향
1. WT1은 소아 신장암인, 윌름 종양에서 과발현되어 최초로 확인된 단백질이다. 본 케이스에 사용된 후보 항원은 항원으로써 거의 전장길이의 단백질이 사용된다. WT1-A10 단백질은 12머(mer) 절단된 tat 서열(선도 서열) 및 WT1 서열의 아미노산 번호 2-281로 구성된 E. coli에서 발현된 292개 AA의 재조합 융합 단백질이 다. 단독의 동결건조후, 이 항원은 애주번트 시스템 A의 pH(6.1)에 가까운 이의 등전점(5.85 내지 7.5) 및 애주번트 시스템 A내의 소디움 클로라이드의 존재로인해 애주번트 시스템 A로의 재구성시 침전된다.
WT1-A1의 2가지 제형을 제조하였다. 재구성된 용량은 400 μg/ml의 WT 1-A10 항원, 10% 수크로즈, 10O mM 트리스, 및 0.2% 트윈80 ± 840 μg/ml CpG을 함유하였다.
두 제형을 500μl의 애주번트 시스템 A로 재구성하였다. 그 결과 얻어진 액체를 원심분리하고 비원심분리된 액체(NC), 상청액(SN) 및 펠렛(P)에 대해 웨스턴 블랏을 실행하였다. 결과는 도 8에 제시되어 있다.
도 8에서 알 수 있는 것과 같이, CpG 존재시, 재구성후 항원의 용해도는 개선되는데, 이것은 침전물 펠렛내의 항원의 결여에 의해 입증되는 바와 같다. 침전된 항원은 재구성된 동결건조 조성물의 펠렛내에서 발견할 수 있는데, 여기서 리오 케이크는 CpG를 함유하지 아니하였다. 이것은, 양으로 비하전된 항원의 경우, CpG의 동시-동결건조가 재구성시 항원의 용해도를 개선시킨다는 것을 입증한다.
2. 프레임(PRAME)
PRAME의 2가지 제형을 제조하였다. 재구성된 용량은 1000μg/ml의 PRAME 항원, 3.15% 수크로즈, 5 mM 보레에트(Borate), 15O nM 소디움 클로라이드 ± 840 μg/ml CpG를 함유하였다. 두 제형을 500μl의 애주번트 시스템 A로 재구성하였다. 그 결과 얻어진 액체를 원심분리하고 비원심분리된 액체(NC), 상청액(SN) 및 펠렛(P)에 대해 웨스턴 블랏을 실행하였다. 결과는 도 9에 제시되어 있다(여기서, NC = 비원심분리된 액체, SN = 상청액 및 P = 펠렛)
도 9에서 알 수 있는 것과 같이, CpG 존재시, 재구성후 항원의 용해도는 개선되는데, 이것은 침전물 펠렛내의 항원의 결여에 의해 입증되는 바와 같다. 침전된 항원은 재구성된 동결건조 조성물의 펠렛내에서 발견할 수 있는데, 여기서 리오 케이크는 CpG를 함유하지 아니하였다. 이것은, 양으로 비하전된 항원의 경우, CpG의 동시-동결건조가 재구성시 항원의 용해도를 개선시킨다는 것을 추가로 입증한다.
SEQUENCE LISTING
<110> Lemoine, Dominique
<120> Lyophilised Antigen Composition
<130> VB62731
<150> PCT/EP2007/055037
<151> 05-24-2007
<150> 0723044.4
<151> 11-23-2007
<150> 0723900.7
<151> 12-06-2007
<160> 12
<170> FastSEQ for Windows Version 4.0
<210> 1
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesised oligoe
<400> 1
tccatgacgt tcctgacgtt 20
<210> 2
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesised oligoe
<400> 2
tctcccagcg tgcgccat 18
<210> 3
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesised oligoe
<400> 3
accgatgacg tcgccggtga cggcaccacg 30
<210> 4
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesised oligoe
<400> 4
tcgtcgtttt gtcgttttgt cgtt 24
<210> 5
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthesised oligoe
<400> 5
tccatgacgt tcctgatgct 20
<210> 6
<211> 514
<212> PRT
<213> Artificial Sequence
<220>
<223> fusion protein
<400> 6
Met Lys Val Lys Glu Thr Arg Lys Asn Tyr Gln His Leu Trp Arg Trp
1 5 10 15
Gly Thr Met Leu Leu Gly Met Leu Met Ile Cys Ser Ala Ala Glu Gln
20 25 30
Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala Thr
35 40 45
Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val
50 55 60
His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro
65 70 75 80
Gln Glu Val Val Leu Gly Asn Val Thr Glu Tyr Phe Asn Met Trp Lys
85 90 95
Asn Asn Met Val Asp Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp
100 105 110
Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
115 120 125
Asp Cys Asp Asp Val Asn Thr Thr Asn Ser Thr Thr Thr Thr Ser Asn
130 135 140
Gly Trp Thr Gly Glu Ile Arg Lys Gly Glu Ile Lys Asn Cys Ser Phe
145 150 155 160
Asn Ile Thr Thr Ser Ile Arg Asp Lys Val Gln Lys Glu Tyr Ala Leu
165 170 175
Phe Tyr Asn Leu Asp Val Val Pro Ile Asp Asp Asp Asn Ala Thr Thr
180 185 190
Lys Asn Lys Thr Thr Arg Asn Phe Arg Leu Ile His Cys Asn Ser Ser
195 200 205
Val Met Thr Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile
210 215 220
His Tyr Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asn Lys
225 230 235 240
Thr Phe Asp Gly Lys Gly Leu Cys Thr Asn Val Ser Thr Val Gln Cys
245 250 255
Thr His Gly Ile Arg Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly
260 265 270
Ser Leu Ala Glu Glu Glu Val Val Ile Arg Ser Asp Asn Phe Met Asp
275 280 285
Asn Thr Lys Thr Ile Ile Val Gln Leu Asn Glu Ser Val Ala Ile Asn
290 295 300
Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Gly Ile His Ile Gly Pro
305 310 315 320
Gly Arg Ala Phe Tyr Ala Ala Arg Lys Ile Ile Gly Asp Ile Arg Gln
325 330 335
Ala His Cys Asn Leu Ser Arg Ala Gln Trp Asn Asn Thr Leu Lys Gln
340 345 350
Ile Val Ile Lys Leu Arg Glu His Phe Gly Asn Lys Thr Ile Lys Phe
355 360 365
Asn Gln Ser Ser Gly Gly Asp Pro Glu Ile Val Arg His Ser Phe Asn
370 375 380
Cys Gly Gly Glu Phe Phe Tyr Cys Asp Thr Thr Gln Leu Phe Asn Ser
385 390 395 400
Thr Trp Asn Gly Thr Glu Gly Asn Asn Thr Glu Gly Asn Ser Thr Ile
405 410 415
Thr Leu Pro Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val
420 425 430
Gly Lys Ala Met Tyr Ala Pro Pro Ile Gly Gly Gln Ile Arg Cys Ser
435 440 445
Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Thr Glu Gly
450 455 460
Asn Gly Thr Glu Asn Glu Thr Glu Ile Phe Arg Pro Gly Gly Gly Asp
465 470 475 480
Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys
485 490 495
Val Glu Pro Leu Gly Val Ala Pro Thr Arg Ala Lys Arg Arg Val Val
500 505 510
Gln Arg
<210> 7
<211> 674
<212> PRT
<213> Artificial Sequence
<220>
<223> fusion protein
<400> 7
Met Arg Val Met Glu Ile Gln Arg Asn Cys Gln His Leu Leu Arg Trp
1 5 10 15
Gly Ile Met Ile Leu Gly Met Ile Ile Ile Cys Ser Thr Ala Asp Asn
20 25 30
Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Arg Asp Ala Glu
35 40 45
Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Ser Thr Glu Lys
50 55 60
His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro
65 70 75 80
Gln Glu Ile Pro Leu Asp Asn Val Thr Glu Glu Phe Asn Met Trp Lys
85 90 95
Asn Asn Met Val Asp Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp
100 105 110
Gln Ser Leu Lys Pro Cys Val Gln Leu Thr Pro Leu Cys Val Thr Leu
115 120 125
Asn Cys Ser Asn Ala Arg Val Asn Ala Thr Phe Asn Ser Thr Glu Asp
130 135 140
Arg Glu Gly Met Lys Asn Cys Ser Phe Asn Met Thr Thr Glu Leu Arg
145 150 155 160
Asp Lys Lys Gln Gln Val Tyr Ser Leu Phe Tyr Arg Leu Asp Ile Glu
165 170 175
Lys Ile Asn Ser Ser Asn Asn Asn Ser Glu Tyr Arg Leu Val Asn Cys
180 185 190
Asn Thr Ser Ala Ile Thr Gln Ala Cys Pro Lys Val Thr Phe Glu Pro
195 200 205
Ile Pro Ile His Tyr Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys
210 215 220
Asn Asp Thr Glu Phe Asn Gly Thr Gly Pro Cys Lys Asn Val Ser Thr
225 230 235 240
Val Gln Cys Thr His Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu
245 250 255
Leu Asn Gly Ser Leu Ala Glu Arg Glu Val Arg Ile Arg Ser Glu Asn
260 265 270
Ile Ala Asn Asn Ala Lys Asn Ile Ile Val Gln Phe Ala Ser Pro Val
275 280 285
Lys Ile Asn Cys Ile Arg Pro Asn Asn Asn Thr Arg Lys Ser Tyr Arg
290 295 300
Ile Gly Pro Gly Gln Thr Phe Tyr Ala Thr Asp Ile Val Gly Asp Ile
305 310 315 320
Arg Gln Ala His Cys Asn Val Ser Arg Thr Asp Trp Asn Asn Thr Leu
325 330 335
Arg Leu Val Ala Asn Gln Leu Arg Lys Tyr Phe Ser Asn Lys Thr Ile
340 345 350
Ile Phe Thr Asn Ser Ser Gly Gly Asp Leu Glu Ile Thr Thr His Ser
355 360 365
Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Ser Gly Leu Phe
370 375 380
Asn Ser Thr Trp Thr Thr Asn Asn Met Gln Glu Ser Asn Asp Thr Ser
385 390 395 400
Asn Gly Thr Ile Thr Leu Pro Cys Arg Ile Lys Gln Ile Ile Arg Met
405 410 415
Trp Gln Arg Val Gly Gln Ala Met Tyr Ala Pro Pro Ile Glu Gly Val
420 425 430
Ile Arg Cys Glu Ser Asn Ile Thr Gly Leu Ile Leu Thr Arg Asp Gly
435 440 445
Gly Asn Asn Asn Ser Ala Asn Glu Thr Phe Arg Pro Gly Gly Gly Asp
450 455 460
Ile Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys
465 470 475 480
Ile Glu Pro Leu Gly Val Ala Pro Thr Arg Ala Lys Arg Arg Val Val
485 490 495
Glu Arg Glu Lys Arg Ala Val Gly Ile Gly Ala Val Phe Leu Gly Phe
500 505 510
Leu Gly Ala Ala Gly Ser Thr Met Gly Ala Ala Ser Ile Thr Leu Thr
515 520 525
Val Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Ser Asn
530 535 540
Leu Leu Arg Ala Ile Glu Ala Gln Gln Gln Leu Leu Lys Leu Thr Val
545 550 555 560
Trp Gly Ile Lys Gln Leu Gln Ala Arg Val Leu Ala Val Glu Arg Tyr
565 570 575
Leu Arg Asp Gln Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu
580 585 590
Ile Cys Thr Thr Asn Val Pro Trp Asn Ser Ser Trp Ser Asn Lys Ser
595 600 605
Tyr Asp Asp Ile Trp Gln Asn Met Thr Trp Leu Gln Trp Asp Lys Glu
610 615 620
Ile Ser Asn Tyr Thr Asp Ile Ile Tyr Ser Leu Ile Glu Glu Ser Gln
625 630 635 640
Asn Gln Gln Glu Lys Asn Glu Gln Asp Leu Leu Ala Leu Asp Lys Trp
645 650 655
Ala Asn Leu Trp Asn Trp Phe Asp Ile Ser Lys Trp Leu Trp Tyr Ile
660 665 670
Arg Ser
<210> 8
<211> 1067
<212> PRT
<213> Artificial Sequence
<220>
<223> fusion protein
<400> 8
Met Gly Ala Arg Ala Ser Val Leu Ser Gly Gly Glu Leu Asp Arg Trp
1 5 10 15
Glu Lys Ile Arg Leu Arg Pro Gly Gly Lys Lys Lys Tyr Lys Leu Lys
20 25 30
His Ile Val Trp Ala Ser Arg Glu Leu Glu Arg Phe Ala Val Asn Pro
35 40 45
Gly Leu Leu Glu Thr Ser Glu Gly Cys Arg Gln Ile Leu Gly Gln Leu
50 55 60
Gln Pro Ser Leu Gln Thr Gly Ser Glu Glu Leu Arg Ser Leu Tyr Asn
65 70 75 80
Thr Val Ala Thr Leu Tyr Cys Val His Gln Arg Ile Glu Ile Lys Asp
85 90 95
Thr Lys Glu Ala Leu Asp Lys Ile Glu Glu Glu Gln Asn Lys Ser Lys
100 105 110
Lys Lys Ala Gln Gln Ala Ala Ala Asp Thr Gly His Ser Asn Gln Val
115 120 125
Ser Gln Asn Tyr Pro Ile Val Gln Asn Ile Gln Gly Gln Met Val His
130 135 140
Gln Ala Ile Ser Pro Arg Thr Leu Asn Ala Trp Val Lys Val Val Glu
145 150 155 160
Glu Lys Ala Phe Ser Pro Glu Val Ile Pro Met Phe Ser Ala Leu Ser
165 170 175
Glu Gly Ala Thr Pro Gln Asp Leu Asn Thr Met Leu Asn Thr Val Gly
180 185 190
Gly His Gln Ala Ala Met Gln Met Leu Lys Glu Thr Ile Asn Glu Glu
195 200 205
Ala Ala Glu Trp Asp Arg Val His Pro Val His Ala Gly Pro Ile Ala
210 215 220
Pro Gly Gln Met Arg Glu Pro Arg Gly Ser Asp Ile Ala Gly Thr Thr
225 230 235 240
Ser Thr Leu Gln Glu Gln Ile Gly Trp Met Thr Asn Asn Pro Pro Ile
245 250 255
Pro Val Gly Glu Ile Tyr Lys Arg Trp Ile Ile Leu Gly Leu Asn Lys
260 265 270
Ile Val Arg Met Tyr Ser Pro Thr Ser Ile Leu Asp Ile Arg Gln Gly
275 280 285
Pro Lys Glu Pro Phe Arg Asp Tyr Val Asp Arg Phe Tyr Lys Thr Leu
290 295 300
Arg Ala Glu Gln Ala Ser Gln Glu Val Lys Asn Trp Met Thr Glu Thr
305 310 315 320
Leu Leu Val Gln Asn Ala Asn Pro Asp Cys Lys Thr Ile Leu Lys Ala
325 330 335
Leu Gly Pro Ala Ala Thr Leu Glu Glu Met Met Thr Ala Cys Gln Gly
340 345 350
Val Gly Gly Pro Gly His Lys Ala Arg Val Leu Met Gly Pro Ile Ser
355 360 365
Pro Ile Glu Thr Val Pro Val Lys Leu Lys Pro Gly Met Asp Gly Pro
370 375 380
Lys Val Lys Gln Trp Pro Leu Thr Glu Glu Lys Ile Lys Ala Leu Val
385 390 395 400
Glu Ile Cys Thr Glu Met Glu Lys Glu Gly Lys Ile Ser Lys Ile Gly
405 410 415
Pro Glu Asn Pro Tyr Asn Thr Pro Val Phe Ala Ile Lys Lys Lys Asp
420 425 430
Ser Thr Lys Trp Arg Lys Leu Val Asp Phe Arg Glu Leu Asn Lys Arg
435 440 445
Thr Gln Asp Phe Trp Glu Val Gln Leu Gly Ile Pro His Pro Ala Gly
450 455 460
Leu Lys Lys Lys Lys Ser Val Thr Val Leu Asp Val Gly Asp Ala Tyr
465 470 475 480
Phe Ser Val Pro Leu Asp Glu Asp Phe Arg Lys Tyr Thr Ala Phe Thr
485 490 495
Ile Pro Ser Ile Asn Asn Glu Thr Pro Gly Ile Arg Tyr Gln Tyr Asn
500 505 510
Val Leu Pro Gln Gly Trp Lys Gly Ser Pro Ala Ile Phe Gln Ser Ser
515 520 525
Met Thr Lys Ile Leu Glu Pro Phe Arg Lys Gln Asn Pro Asp Ile Val
530 535 540
Ile Tyr Gln Tyr Met Asp Asp Leu Tyr Val Gly Ser Asp Leu Glu Ile
545 550 555 560
Gly Gln His Arg Thr Lys Ile Glu Glu Leu Arg Gln His Leu Leu Arg
565 570 575
Trp Gly Leu Thr Thr Pro Asp Lys Lys His Gln Lys Glu Pro Pro Phe
580 585 590
Leu Lys Met Gly Tyr Glu Leu His Pro Asp Lys Trp Thr Val Gln Pro
595 600 605
Ile Val Leu Pro Glu Lys Asp Ser Trp Thr Val Asn Asp Ile Gln Lys
610 615 620
Leu Val Gly Lys Leu Asn Trp Ala Ser Gln Ile Tyr Pro Gly Ile Lys
625 630 635 640
Val Arg Gln Leu Cys Lys Leu Leu Arg Gly Thr Lys Ala Leu Thr Glu
645 650 655
Val Ile Pro Leu Thr Glu Glu Ala Glu Leu Glu Leu Ala Glu Asn Arg
660 665 670
Glu Ile Leu Lys Glu Pro Val His Gly Val Tyr Tyr Asp Pro Ser Lys
675 680 685
Asp Leu Ile Ala Glu Ile Gln Lys Gln Gly Gln Gly Gln Trp Thr Tyr
690 695 700
Gln Ile Tyr Gln Glu Pro Phe Lys Asn Leu Lys Thr Gly Lys Tyr Ala
705 710 715 720
Arg Met Arg Gly Ala His Thr Asn Asp Val Lys Gln Leu Thr Glu Ala
725 730 735
Val Gln Lys Ile Thr Thr Glu Ser Ile Val Ile Trp Gly Lys Thr Pro
740 745 750
Lys Phe Lys Leu Pro Ile Gln Lys Glu Thr Trp Glu Thr Trp Trp Thr
755 760 765
Glu Tyr Trp Gln Ala Thr Trp Ile Pro Glu Trp Glu Phe Val Asn Thr
770 775 780
Pro Pro Leu Val Lys Leu Trp Tyr Gln Leu Glu Lys Glu Pro Ile Val
785 790 795 800
Gly Ala Glu Thr Phe Tyr Val Asp Gly Ala Ala Asn Arg Glu Thr Lys
805 810 815
Leu Gly Lys Ala Gly Tyr Val Thr Asn Arg Gly Arg Gln Lys Val Val
820 825 830
Thr Leu Thr Asp Thr Thr Asn Gln Lys Thr Glu Leu Gln Ala Ile Tyr
835 840 845
Leu Ala Leu Gln Asp Ser Gly Leu Glu Val Asn Ile Val Thr Asp Ser
850 855 860
Gln Tyr Ala Leu Gly Ile Ile Gln Ala Gln Pro Asp Gln Ser Glu Ser
865 870 875 880
Glu Leu Val Asn Gln Ile Ile Glu Gln Leu Ile Lys Lys Glu Lys Val
885 890 895
Tyr Leu Ala Trp Val Pro Ala His Lys Gly Ile Gly Gly Asn Glu Gln
900 905 910
Val Asp Lys Leu Val Ser Ala Gly Ile Arg Lys Val Leu Met Val Gly
915 920 925
Phe Pro Val Thr Pro Gln Val Pro Leu Arg Pro Met Thr Tyr Lys Ala
930 935 940
Ala Val Asp Leu Ser His Phe Leu Lys Glu Lys Gly Gly Leu Glu Gly
945 950 955 960
Leu Ile His Ser Gln Arg Arg Gln Asp Ile Leu Asp Leu Trp Ile Tyr
965 970 975
His Thr Gln Gly Tyr Phe Pro Asp Trp Gln Asn Tyr Thr Pro Gly Pro
980 985 990
Gly Val Arg Tyr Pro Leu Thr Phe Gly Trp Cys Tyr Lys Leu Val Pro
995 1000 1005
Val Glu Pro Asp Lys Val Glu Glu Ala Asn Lys Gly Glu Asn Thr Ser
1010 1015 1020
Leu Leu His Pro Val Ser Leu His Gly Met Asp Asp Pro Glu Arg Glu
1025 1030 1035 1040
Val Leu Glu Trp Arg Phe Asp Ser Arg Leu Ala Phe His His Val Ala
1045 1050 1055
Arg Glu Leu His Pro Glu Tyr Phe Lys Asn Cys
1060 1065
<210> 9
<211> 3411
<212> DNA
<213> Artificial Sequence
<220>
<223> nucleic acid encoding fusion protein
<400> 9
atggttatcg tgcagaacat ccaggggcaa atggtacatc aggccatatc acctagaact 60
ttaaatgcat gggtaaaagt agtagaagag aaggctttca gcccagaagt aatacccatg 120
ttttcagcat tatcagaagg agccacccca caagatttaa acaccatgct aaacacagtg 180
gggggacatc aagcagccat gcaaatgtta aaagagacca tcaatgagga agctgcagaa 240
tgggatagag tacatccagt gcatgcaggg cctattgcac caggccagat gagagaacca 300
aggggaagtg acatagcagg aactactagt acccttcagg aacaaatagg atggatgaca 360
aataatccac ctatcccagt aggagaaatt tataaaagat ggataatcct gggattaaat 420
aaaatagtaa gaatgtatag ccctaccagc attctggaca taagacaagg accaaaagaa 480
ccttttagag actatgtaga ccggttctat aaaactctaa gagccgagca agcttcacag 540
gaggtaaaaa attggatgac agaaaccttg ttggtccaaa atgcgaaccc agattgtaag 600
actattttaa aagcattggg accagcggct acactagaag aaatgatgac agcatgtcag 660
ggagtaggag gacccggcca taaggcaaga gttttgcata tgggccccat tagccctatt 720
gagactgtgt cagtaaaatt aaagccagga atggatggcc caaaagttaa acaatggcca 780
ttgacagaag aaaaaataaa agcattagta gaaatttgta cagagatgga aaaggaaggg 840
aaaatttcaa aaattgggcc tgaaaatcca tacaatactc cagtatttgc cataaagaaa 900
aaagacagta ctaaatggag aaaattagta gatttcagag aacttaataa gagaactcaa 960
gacttctggg aagttcaatt aggaatacca catcccgcag ggttaaaaaa gaaaaaatca 1020
gtaacagtac tggatgtggg tgatgcatat ttttcagttc ccttagatga agacttcagg 1080
aaatatactg catttaccat acctagtata aacaatgaga caccagggat tagatatcag 1140
tacaatgtgc ttccacaggg atggaaagga tcaccagcaa tattccaaag tagcatgaca 1200
aaaatcttag agccttttag aaaacaaaat ccagacatag ttatctatca atacatggat 1260
gatttgtatg taggatctga cttagaaata gggcagcata gaacaaaaat agaggagctg 1320
agacaacatc tgttgaggtg gggacttacc acaccagaca aaaaacatca gaaagaacct 1380
ccattcctta aaatgggtta tgaactccat cctgataaat ggacagtaca gcctatagtg 1440
ctgccagaaa aagacagctg gactgtcaat gacatacaga agttagtggg gaaattgaat 1500
tgggcaagtc agatttaccc agggattaaa gtaaggcaat tatgtaaact ccttagagga 1560
accaaagcac taacagaagt aataccacta acagaagaag cagagctaga actggcagaa 1620
aacagagaga ttctaaaaga accagtacat ggagtgtatt atgacccatc aaaagactta 1680
atagcagaaa tacagaagca ggggcaaggc caatggacat atcaaattta tcaagagcca 1740
tttaaaaatc tgaaaacagg aaaatatgca agaatgaggg gtgcccacac taatgatgta 1800
aaacaattaa cagaggcagt gcaaaaaata accacagaaa gcatagtaat atggggaaag 1860
actcctaaat ttaaactgcc catacaaaag gaaacatggg aaacatggtg gacagagtat 1920
tggcaagcca cctggattcc tgagtgggag tttgttaata cccctccttt agtgaaatta 1980
tggtaccagt tagagaaaga acccatagta ggagcagaaa ccttctatgt agatggggca 2040
gctaacaggg agactaaatt aggaaaagca ggatatgtta ctaatagagg aagacaaaaa 2100
gttgtcaccc taactgacac aacaaatcag aagactgagt tacaagcaat ttatctagct 2160
ttgcaggatt cgggattaga agtaaacata gtaacagact cacaatatgc attaggaatc 2220
attcaagcac aaccagatca aagtgaatca gagttagtca atcaaataat agagcagtta 2280
ataaaaaagg aaaaggtcta tctggcatgg gtaccagcac acaaaggaat tggaggaaat 2340
gaacaagtag ataaattagt cagtgctgga atcaggaaag tgctagctat gggtggcaag 2400
tggtcaaaaa gtagtgtggt tggatggcct actgtaaggg aaagaatgag acgagctgag 2460
ccagcagcag atggggtggg agcagcatct cgagacctgg aaaaacatgg agcaatcaca 2520
agtagcaata cagcagctac caatgctgct tgtgcctggc tagaagcaca agaggaggag 2580
gaggtgggtt ttccagtcac acctcaggta cctttaagac caatgactta caaggcagct 2640
gtagatctta gccacttttt aaaagaaaag gggggactgg aagggctaat tcactcccaa 2700
cgaagacaag atatccttga tctgtggatc taccacacac aaggctactt ccctgattgg 2760
cagaactaca caccagggcc aggggtcaga tatccactga cctttggatg gtgctacaag 2820
ctagtaccag ttgagccaga taaggtagaa gaggccaata aaggagagaa caccagcttg 2880
ttacaccctg tgagcctgca tggaatggat gaccctgaga gagaagtgtt agagtggagg 2940
tttgacagcc gcctagcatt tcatcacgtg gcccgagagc tgcatccgga gtacttcaag 3000
aactgcaggc ctatgggtgc gagagcgtca gtattaagcg ggggagaatt agatcgatgg 3060
gaaaaaattc ggttaaggcc agggggaaag aaaaaatata aattaaaaca tatagtatgg 3120
gcaagcaggg agctagaacg attcgcagtt aatcctggcc tgttagaaac atcagaaggc 3180
tgtagacaaa tactgggaca gctacaacca tcccttcaga caggatcaga agaacttaga 3240
tcattatata atacagtagc aaccctctat tgtgtgcatc aaaggataga gataaaagac 3300
accaaggaag ctttagacaa gatagaggaa gagcaaaaca aaagtaagaa aaaagcacag 3360
caagcagcag ctgacacagg acacagcaat caggtcagcc aaaattacta a 3411
<210> 10
<211> 1136
<212> PRT
<213> Artificial Sequence
<220>
<223> fusion protein
<400> 10
Met Val Ile Val Gln Asn Ile Gln Gly Gln Met Val His Gln Ala Ile
1 5 10 15
Ser Pro Arg Thr Leu Asn Ala Trp Val Lys Val Val Glu Glu Lys Ala
20 25 30
Phe Ser Pro Glu Val Ile Pro Met Phe Ser Ala Leu Ser Glu Gly Ala
35 40 45
Thr Pro Gln Asp Leu Asn Thr Met Leu Asn Thr Val Gly Gly His Gln
50 55 60
Ala Ala Met Gln Met Leu Lys Glu Thr Ile Asn Glu Glu Ala Ala Glu
65 70 75 80
Trp Asp Arg Val His Pro Val His Ala Gly Pro Ile Ala Pro Gly Gln
85 90 95
Met Arg Glu Pro Arg Gly Ser Asp Ile Ala Gly Thr Thr Ser Thr Leu
100 105 110
Gln Glu Gln Ile Gly Trp Met Thr Asn Asn Pro Pro Ile Pro Val Gly
115 120 125
Glu Ile Tyr Lys Arg Trp Ile Ile Leu Gly Leu Asn Lys Ile Val Arg
130 135 140
Met Tyr Ser Pro Thr Ser Ile Leu Asp Ile Arg Gln Gly Pro Lys Glu
145 150 155 160
Pro Phe Arg Asp Tyr Val Asp Arg Phe Tyr Lys Thr Leu Arg Ala Glu
165 170 175
Gln Ala Ser Gln Glu Val Lys Asn Trp Met Thr Glu Thr Leu Leu Val
180 185 190
Gln Asn Ala Asn Pro Asp Cys Lys Thr Ile Leu Lys Ala Leu Gly Pro
195 200 205
Ala Ala Thr Leu Glu Glu Met Met Thr Ala Cys Gln Gly Val Gly Gly
210 215 220
Pro Gly His Lys Ala Arg Val Leu His Met Gly Pro Ile Ser Pro Ile
225 230 235 240
Glu Thr Val Ser Val Lys Leu Lys Pro Gly Met Asp Gly Pro Lys Val
245 250 255
Lys Gln Trp Pro Leu Thr Glu Glu Lys Ile Lys Ala Leu Val Glu Ile
260 265 270
Cys Thr Glu Met Glu Lys Glu Gly Lys Ile Ser Lys Ile Gly Pro Glu
275 280 285
Asn Pro Tyr Asn Thr Pro Val Phe Ala Ile Lys Lys Lys Asp Ser Thr
290 295 300
Lys Trp Arg Lys Leu Val Asp Phe Arg Glu Leu Asn Lys Arg Thr Gln
305 310 315 320
Asp Phe Trp Glu Val Gln Leu Gly Ile Pro His Pro Ala Gly Leu Lys
325 330 335
Lys Lys Lys Ser Val Thr Val Leu Asp Val Gly Asp Ala Tyr Phe Ser
340 345 350
Val Pro Leu Asp Glu Asp Phe Arg Lys Tyr Thr Ala Phe Thr Ile Pro
355 360 365
Ser Ile Asn Asn Glu Thr Pro Gly Ile Arg Tyr Gln Tyr Asn Val Leu
370 375 380
Pro Gln Gly Trp Lys Gly Ser Pro Ala Ile Phe Gln Ser Ser Met Thr
385 390 395 400
Lys Ile Leu Glu Pro Phe Arg Lys Gln Asn Pro Asp Ile Val Ile Tyr
405 410 415
Gln Tyr Met Asp Asp Leu Tyr Val Gly Ser Asp Leu Glu Ile Gly Gln
420 425 430
His Arg Thr Lys Ile Glu Glu Leu Arg Gln His Leu Leu Arg Trp Gly
435 440 445
Leu Thr Thr Pro Asp Lys Lys His Gln Lys Glu Pro Pro Phe Leu Lys
450 455 460
Met Gly Tyr Glu Leu His Pro Asp Lys Trp Thr Val Gln Pro Ile Val
465 470 475 480
Leu Pro Glu Lys Asp Ser Trp Thr Val Asn Asp Ile Gln Lys Leu Val
485 490 495
Gly Lys Leu Asn Trp Ala Ser Gln Ile Tyr Pro Gly Ile Lys Val Arg
500 505 510
Gln Leu Cys Lys Leu Leu Arg Gly Thr Lys Ala Leu Thr Glu Val Ile
515 520 525
Pro Leu Thr Glu Glu Ala Glu Leu Glu Leu Ala Glu Asn Arg Glu Ile
530 535 540
Leu Lys Glu Pro Val His Gly Val Tyr Tyr Asp Pro Ser Lys Asp Leu
545 550 555 560
Ile Ala Glu Ile Gln Lys Gln Gly Gln Gly Gln Trp Thr Tyr Gln Ile
565 570 575
Tyr Gln Glu Pro Phe Lys Asn Leu Lys Thr Gly Lys Tyr Ala Arg Met
580 585 590
Arg Gly Ala His Thr Asn Asp Val Lys Gln Leu Thr Glu Ala Val Gln
595 600 605
Lys Ile Thr Thr Glu Ser Ile Val Ile Trp Gly Lys Thr Pro Lys Phe
610 615 620
Lys Leu Pro Ile Gln Lys Glu Thr Trp Glu Thr Trp Trp Thr Glu Tyr
625 630 635 640
Trp Gln Ala Thr Trp Ile Pro Glu Trp Glu Phe Val Asn Thr Pro Pro
645 650 655
Leu Val Lys Leu Trp Tyr Gln Leu Glu Lys Glu Pro Ile Val Gly Ala
660 665 670
Glu Thr Phe Tyr Val Asp Gly Ala Ala Asn Arg Glu Thr Lys Leu Gly
675 680 685
Lys Ala Gly Tyr Val Thr Asn Arg Gly Arg Gln Lys Val Val Thr Leu
690 695 700
Thr Asp Thr Thr Asn Gln Lys Thr Glu Leu Gln Ala Ile Tyr Leu Ala
705 710 715 720
Leu Gln Asp Ser Gly Leu Glu Val Asn Ile Val Thr Asp Ser Gln Tyr
725 730 735
Ala Leu Gly Ile Ile Gln Ala Gln Pro Asp Gln Ser Glu Ser Glu Leu
740 745 750
Val Asn Gln Ile Ile Glu Gln Leu Ile Lys Lys Glu Lys Val Tyr Leu
755 760 765
Ala Trp Val Pro Ala His Lys Gly Ile Gly Gly Asn Glu Gln Val Asp
770 775 780
Lys Leu Val Ser Ala Gly Ile Arg Lys Val Leu Ala Met Gly Gly Lys
785 790 795 800
Trp Ser Lys Ser Ser Val Val Gly Trp Pro Thr Val Arg Glu Arg Met
805 810 815
Arg Arg Ala Glu Pro Ala Ala Asp Gly Val Gly Ala Ala Ser Arg Asp
820 825 830
Leu Glu Lys His Gly Ala Ile Thr Ser Ser Asn Thr Ala Ala Thr Asn
835 840 845
Ala Ala Cys Ala Trp Leu Glu Ala Gln Glu Glu Glu Glu Val Gly Phe
850 855 860
Pro Val Thr Pro Gln Val Pro Leu Arg Pro Met Thr Tyr Lys Ala Ala
865 870 875 880
Val Asp Leu Ser His Phe Leu Lys Glu Lys Gly Gly Leu Glu Gly Leu
885 890 895
Ile His Ser Gln Arg Arg Gln Asp Ile Leu Asp Leu Trp Ile Tyr His
900 905 910
Thr Gln Gly Tyr Phe Pro Asp Trp Gln Asn Tyr Thr Pro Gly Pro Gly
915 920 925
Val Arg Tyr Pro Leu Thr Phe Gly Trp Cys Tyr Lys Leu Val Pro Val
930 935 940
Glu Pro Asp Lys Val Glu Glu Ala Asn Lys Gly Glu Asn Thr Ser Leu
945 950 955 960
Leu His Pro Val Ser Leu His Gly Met Asp Asp Pro Glu Arg Glu Val
965 970 975
Leu Glu Trp Arg Phe Asp Ser Arg Leu Ala Phe His His Val Ala Arg
980 985 990
Glu Leu His Pro Glu Tyr Phe Lys Asn Cys Arg Pro Met Gly Ala Arg
995 1000 1005
Ala Ser Val Leu Ser Gly Gly Glu Leu Asp Arg Trp Glu Lys Ile Arg
1010 1015 1020
Leu Arg Pro Gly Gly Lys Lys Lys Tyr Lys Leu Lys His Ile Val Trp
1025 1030 1035 1040
Ala Ser Arg Glu Leu Glu Arg Phe Ala Val Asn Pro Gly Leu Leu Glu
1045 1050 1055
Thr Ser Glu Gly Cys Arg Gln Ile Leu Gly Gln Leu Gln Pro Ser Leu
1060 1065 1070
Gln Thr Gly Ser Glu Glu Leu Arg Ser Leu Tyr Asn Thr Val Ala Thr
1075 1080 1085
Leu Tyr Cys Val His Gln Arg Ile Glu Ile Lys Asp Thr Lys Glu Ala
1090 1095 1100
Leu Asp Lys Ile Glu Glu Glu Gln Asn Lys Ser Lys Lys Lys Ala Gln
1105 1110 1115 1120
Gln Ala Ala Ala Asp Thr Gly His Ser Asn Gln Val Ser Gln Asn Tyr
1125 1130 1135
<210> 11
<211> 1554
<212> PRT
<213> Artificial Sequence
<220>
<223> fusion protein
<400> 11
Met Ala Ala Arg Ala Ser Ile Leu Ser Gly Gly Lys Leu Asp Ala Trp
1 5 10 15
Glu Lys Ile Arg Leu Arg Pro Gly Gly Lys Lys Lys Tyr Arg Leu Lys
20 25 30
His Leu Val Trp Ala Ser Arg Glu Leu Asp Arg Phe Ala Leu Asn Pro
35 40 45
Ser Leu Leu Glu Thr Thr Glu Gly Cys Gln Gln Ile Met Asn Gln Leu
50 55 60
Gln Pro Ala Val Lys Thr Gly Thr Glu Glu Ile Lys Ser Leu Phe Asn
65 70 75 80
Thr Val Ala Thr Leu Tyr Cys Val His Gln Arg Ile Asp Val Lys Asp
85 90 95
Thr Lys Glu Ala Leu Asp Lys Ile Glu Glu Ile Gln Asn Lys Ser Lys
100 105 110
Gln Lys Thr Gln Gln Ala Ala Ala Asp Thr Gly Asp Ser Ser Lys Val
115 120 125
Ser Gln Asn Tyr Pro Ile Ile Gln Asn Ala Gln Gly Gln Met Ile His
130 135 140
Gln Asn Leu Ser Pro Arg Thr Leu Asn Ala Trp Val Lys Val Ile Glu
145 150 155 160
Glu Lys Ala Phe Ser Pro Glu Val Ile Pro Met Phe Ser Ala Leu Ser
165 170 175
Glu Gly Ala Thr Pro Gln Asp Leu Asn Val Met Leu Asn Ile Val Gly
180 185 190
Gly His Gln Ala Ala Met Gln Met Leu Lys Asp Thr Ile Asn Glu Glu
195 200 205
Ala Ala Glu Trp Asp Arg Leu His Pro Val Gln Ala Gly Pro Ile Pro
210 215 220
Pro Gly Gln Ile Arg Glu Pro Arg Gly Ser Asp Ile Ala Gly Thr Thr
225 230 235 240
Ser Thr Pro Gln Glu Gln Leu Gln Trp Met Thr Gly Asn Pro Pro Ile
245 250 255
Pro Val Gly Asn Ile Tyr Lys Arg Trp Ile Ile Leu Gly Leu Asn Lys
260 265 270
Ile Val Arg Met Tyr Ser Pro Val Ser Ile Leu Asp Ile Lys Gln Gly
275 280 285
Pro Lys Glu Pro Phe Arg Asp Tyr Val Asp Arg Phe Phe Lys Ala Leu
290 295 300
Arg Ala Glu Gln Ala Thr Gln Asp Val Lys Gly Trp Met Thr Glu Thr
305 310 315 320
Leu Leu Val Gln Asn Ala Asn Pro Asp Cys Lys Ser Ile Leu Lys Ala
325 330 335
Leu Gly Ser Gly Ala Thr Leu Glu Glu Met Met Thr Ala Cys Gln Gly
340 345 350
Val Gly Gly Pro Gly His Lys Ala Arg Val Leu Ala Glu Ala Met Ser
355 360 365
Gln Ala Gln Gln Thr Asn Ile Met Met Gln Arg Gly Asn Phe Arg Gly
370 375 380
Gln Lys Arg Ile Lys Cys Phe Asn Cys Gly Lys Glu Gly His Leu Ala
385 390 395 400
Arg Asn Cys Arg Ala Pro Arg Lys Lys Gly Cys Trp Lys Cys Gly Lys
405 410 415
Glu Gly His Gln Met Lys Asp Cys Thr Glu Arg Gln Ala Asn Phe Leu
420 425 430
Gly Lys Ile Trp Pro Ser Ser Lys Gly Arg Pro Gly Asn Phe Pro Gln
435 440 445
Ser Arg Pro Glu Pro Thr Ala Pro Pro Ala Glu Leu Phe Gly Met Gly
450 455 460
Glu Gly Ile Ala Ser Leu Pro Lys Gln Glu Gln Lys Asp Arg Glu Gln
465 470 475 480
Val Pro Pro Leu Val Ser Leu Lys Ser Leu Phe Gly Asn Asp Pro Leu
485 490 495
Ser Gln Gly Ser Pro Ile Ser Pro Ile Glu Thr Val Pro Val Thr Leu
500 505 510
Lys Pro Gly Met Asp Gly Pro Lys Val Lys Gln Trp Pro Leu Thr Glu
515 520 525
Glu Lys Ile Lys Ala Leu Thr Glu Ile Cys Thr Glu Met Glu Lys Glu
530 535 540
Gly Lys Ile Ser Lys Ile Gly Pro Glu Asn Pro Tyr Asn Thr Pro Ile
545 550 555 560
Phe Ala Ile Lys Lys Lys Asp Ser Thr Lys Trp Arg Lys Leu Val Asp
565 570 575
Phe Arg Glu Leu Asn Lys Arg Thr Gln Asp Phe Trp Glu Val Gln Leu
580 585 590
Gly Ile Pro His Pro Ala Gly Leu Lys Lys Lys Lys Ser Val Thr Val
595 600 605
Leu Asp Val Gly Asp Ala Tyr Phe Ser Val Pro Leu Asp Glu Asn Phe
610 615 620
Arg Lys Tyr Thr Ala Phe Thr Ile Pro Ser Thr Asn Asn Glu Thr Pro
625 630 635 640
Gly Val Arg Tyr Gln Tyr Asn Val Leu Pro Gln Gly Trp Lys Gly Ser
645 650 655
Pro Ala Ile Phe Gln Ser Ser Met Thr Lys Ile Leu Glu Pro Phe Arg
660 665 670
Ser Lys Asn Pro Glu Ile Ile Ile Tyr Gln Tyr Met Ala Ala Leu Tyr
675 680 685
Val Gly Ser Asp Leu Glu Ile Gly Gln His Arg Thr Lys Ile Glu Glu
690 695 700
Leu Arg Ala His Leu Leu Ser Trp Gly Phe Thr Thr Pro Asp Lys Lys
705 710 715 720
His Gln Lys Glu Pro Pro Phe Leu Trp Met Gly Tyr Glu Leu His Pro
725 730 735
Asp Lys Trp Thr Val Gln Pro Ile Met Leu Pro Asp Lys Glu Ser Trp
740 745 750
Thr Val Asn Asp Ile Gln Lys Leu Val Gly Lys Leu Asn Trp Ala Ser
755 760 765
Gln Ile Tyr Ala Gly Ile Lys Val Lys Gln Leu Cys Arg Leu Leu Arg
770 775 780
Gly Ala Lys Ala Leu Thr Asp Ile Val Thr Leu Thr Glu Glu Ala Glu
785 790 795 800
Leu Glu Leu Ala Glu Asn Arg Glu Ile Leu Lys Asp Pro Val His Gly
805 810 815
Val Tyr Tyr Asp Pro Ser Lys Asp Leu Val Ala Glu Ile Gln Lys Gln
820 825 830
Gly Gln Asp Gln Trp Thr Tyr Gln Ile Tyr Gln Glu Pro Phe Lys Asn
835 840 845
Leu Lys Thr Gly Lys Tyr Ala Arg Lys Arg Ser Ala His Thr Asn Asp
850 855 860
Val Arg Gln Leu Ala Glu Val Val Gln Lys Val Ala Met Glu Ser Ile
865 870 875 880
Val Ile Trp Gly Lys Thr Pro Lys Phe Lys Leu Pro Ile Gln Lys Glu
885 890 895
Thr Trp Glu Thr Trp Trp Met Asp Tyr Trp Gln Ala Thr Trp Ile Pro
900 905 910
Glu Trp Glu Phe Val Asn Thr Pro Pro Leu Val Lys Leu Trp Tyr Gln
915 920 925
Leu Glu Lys Asp Pro Ile Leu Gly Ala Glu Thr Phe Tyr Val Asp Gly
930 935 940
Ala Ala Asn Arg Glu Thr Lys Leu Gly Lys Ala Gly Tyr Val Thr Asp
945 950 955 960
Arg Gly Arg Gln Lys Val Val Ser Leu Thr Glu Thr Thr Asn Gln Lys
965 970 975
Thr Glu Leu His Ala Ile Leu Leu Ala Leu Gln Asp Ser Gly Ser Glu
980 985 990
Val Asn Ile Val Thr Asp Ser Gln Tyr Ala Leu Gly Ile Ile Gln Ala
995 1000 1005
Gln Pro Asp Arg Ser Glu Ser Glu Leu Val Asn Gln Ile Ile Glu Lys
1010 1015 1020
Leu Ile Gly Lys Asp Lys Ile Tyr Leu Ser Trp Val Pro Ala His Lys
1025 1030 1035 1040
Gly Ile Gly Gly Asn Glu Gln Val Asp Lys Leu Val Ser Ser Gly Ile
1045 1050 1055
Arg Lys Val Leu Phe Leu Asp Gly Ile Asp Lys Ala Gln Glu Asp His
1060 1065 1070
Glu Arg Tyr His Ser Asn Trp Arg Thr Met Ala Ser Asp Phe Asn Leu
1075 1080 1085
Pro Pro Ile Val Ala Lys Glu Ile Val Ala Ser Cys Asp Lys Cys Gln
1090 1095 1100
Leu Lys Gly Glu Ala Met His Gly Gln Val Asp Cys Ser Pro Gly Ile
1105 1110 1115 1120
Trp Gln Leu Ala Cys Thr His Leu Glu Gly Lys Val Ile Leu Val Ala
1125 1130 1135
Val His Val Ala Ser Gly Tyr Ile Glu Ala Glu Val Ile Pro Ala Glu
1140 1145 1150
Thr Gly Gln Glu Thr Ala Tyr Phe Leu Leu Lys Leu Ala Gly Arg Trp
1155 1160 1165
Pro Val Lys Val Val His Thr Ala Asn Gly Ser Asn Phe Thr Ser Ala
1170 1175 1180
Ala Val Lys Ala Ala Cys Trp Trp Ala Asn Ile Gln Gln Glu Phe Gly
1185 1190 1195 1200
Ile Pro Tyr Asn Pro Gln Ser Gln Gly Val Val Ala Ser Met Asn Lys
1205 1210 1215
Glu Leu Lys Lys Ile Ile Gly Gln Val Arg Asp Gln Ala Glu His Leu
1220 1225 1230
Lys Thr Ala Val Gln Met Ala Val Phe Ile His Asn Phe Lys Arg Lys
1235 1240 1245
Gly Gly Ile Gly Gly Tyr Ser Ala Gly Glu Arg Ile Ile Asp Ile Ile
1250 1255 1260
Ala Thr Asp Ile Gln Thr Lys Glu Leu Gln Lys Gln Ile Thr Lys Ile
1265 1270 1275 1280
Gln Asn Phe Arg Val Tyr Tyr Arg Asp Ser Arg Asp Pro Ile Trp Lys
1285 1290 1295
Gly Pro Ala Lys Leu Leu Trp Lys Gly Glu Gly Ala Val Val Ile Gln
1300 1305 1310
Asp Asn Ser Asp Ile Lys Val Val Pro Arg Arg Lys Ala Lys Ile Leu
1315 1320 1325
Arg Asp Tyr Gly Lys Gln Met Ala Gly Asp Asp Cys Val Ala Gly Arg
1330 1335 1340
Gln Asp Glu Asp Arg Ser Met Gly Gly Lys Trp Ser Lys Gly Ser Ile
1345 1350 1355 1360
Val Gly Trp Pro Glu Ile Arg Glu Arg Met Arg Arg Ala Pro Ala Ala
1365 1370 1375
Ala Pro Gly Val Gly Ala Val Ser Gln Asp Leu Asp Lys His Gly Ala
1380 1385 1390
Ile Thr Ser Ser Asn Ile Asn Asn Pro Ser Cys Val Trp Leu Glu Ala
1395 1400 1405
Gln Glu Glu Glu Glu Val Gly Phe Pro Val Arg Pro Gln Val Pro Leu
1410 1415 1420
Arg Pro Met Thr Tyr Lys Gly Ala Phe Asp Leu Ser His Phe Leu Lys
1425 1430 1435 1440
Glu Lys Gly Gly Leu Asp Gly Leu Ile Tyr Ser Arg Lys Arg Gln Glu
1445 1450 1455
Ile Leu Asp Leu Trp Val Tyr His Thr Gln Gly Tyr Phe Pro Asp Trp
1460 1465 1470
Gln Asn Tyr Thr Pro Gly Pro Gly Val Arg Tyr Pro Leu Thr Phe Gly
1475 1480 1485
Trp Cys Phe Lys Leu Val Pro Met Glu Pro Asp Glu Val Glu Lys Ala
1490 1495 1500
Thr Glu Gly Glu Asn Asn Ser Leu Leu His Pro Ile Cys Gln His Gly
1505 1510 1515 1520
Met Asp Asp Glu Glu Arg Glu Val Leu Ile Trp Lys Phe Asp Ser Arg
1525 1530 1535
Leu Ala Leu Lys His Arg Ala Gln Glu Leu His Pro Glu Phe Tyr Lys
1540 1545 1550
Asp Cys
<210> 12
<211> 127
<212> PRT
<213> Artificial Sequence
<220>
<223> fusion protein
<400> 12
Met Lys Leu Lys Thr Leu Ala Leu Ser Leu Leu Ala Ala Gly Val Leu
1 5 10 15
Ala Gly Cys Ser Ser His Ser Ser Asn Met Ala Asn Thr Gln Met Lys
20 25 30
Ser Asp Lys Ile Ile Ile Ala His Arg Gly Ala Ser Gly Tyr Leu Pro
35 40 45
Glu His Thr Leu Glu Ser Lys Ala Leu Ala Phe Ala Gln Gln Ala Asp
50 55 60
Tyr Leu Glu Gln Asp Leu Ala Met Thr Lys Asp Gly Arg Leu Val Val
65 70 75 80
Ile His Asp His Phe Leu Asp Gly Leu Thr Asp Val Ala Lys Lys Phe
85 90 95
Pro His Arg His Arg Lys Asp Gly Arg Tyr Tyr Val Ile Asp Phe Thr
100 105 110
Leu Lys Glu Ile Gln Ser Leu Glu Met Thr Glu Asn Phe Glu Thr
115 120 125
Claims (23)
- WT-1 및 이의 유도체 또는 단편을 포함하는 하나 이상의 항원 및 CpG 함유 면역자극성 올리고뉴클레오티드를 포함하는 동결건조 조성물로서,상기 유도체는 천연 항원과 충분히 유사하여 항원 특성을 보유하며 WT-1에 대하여 발생되는 면역 반응을 일으킬 수 있으며, 상기 단편은 8개 이상의 아미노산을 포함하고 천연적으로 발생되는 WT-1과 교차 반응하는 면역 반응을 유도할 수 있는 조성물.
- 삭제
- 제 1항에 있어서, 상기 CpG 함유 면역자극 올리고뉴클레오티드가 퓨린, 퓨린, C, G, 피리미딘, 피리미딘 서열을 포함하는 조성물.
- 제 1항 또는 제 3항에 있어서, 상기 CpG 함유 면역자극성 올리고뉴클레오티드가 하기 서열들을 포함하는 군에서 선택되는 조성물:TCC ATG ACG TTC CTG ACG TT(서열번호 1);TCT CCC AGC GTG CGC CAT(서열번호 2);ACC GAT GAC GTC GCC GGT GAC GGC ACC ACG(서열번호 3);TCG TCG TTT TGT CGT TTT GTC GTT(서열번호 4);TCC ATG ACG TTC CTG ATG CT(서열번호 5).
- 제 1항 또는 제 3항에 있어서, 상기 CpG 함유 면역자극성 올리고뉴클레오티드가 3개 이상의 뉴클레오티드에 의해 이격된 2개 이상의 비메틸화된 CG 반복부를 함유하는 조성물.
- 제 5항에 있어서, 상기 CpG 함유 면역자극 올리고뉴클레오티드가 6개의 뉴클레오티드에 의해 이격된 2개 이상의 비메틸화된 CG 반복부를 함유하는 조성물.
- 제 1항 및 제 3항 내지 제 6항 중 어느 한 항에 따른 동결건조 조성물을 제조하는 방법으로서,상기 항원과 CpG 함유 면역자극성 올리고뉴클레오티드를 부형제와 혼합하는 단계, 및그 결과 얻어진 제형이 동결건조 순환주기를 거치도록 하는 단계를 포함하는 방법.
- 제 1항 및 제 3항 내지 제 6항 중 어느 한 항의 동결건조 조성물을 담체로 재구성하는 단계를 포함하는 면역원성 조성물을 제조하는 방법.
- 제 8항에 있어서, 상기 담체가 미네랄 염, 에멀젼, 폴리머, 리포좀, ISCOM을 포함하는 군에서 선택된 미립자 담체인 방법.
- 제 9항에 있어서, 상기 담체가 리포좀 용액 또는 수중유 에멀젼인 방법.
- 제 8항에 있어서, 상기 담체가 하나 이상의 면역자극제를 추가로 포함하는 방법.
- 제 11항에 있어서, 상기 하나 이상의 면역자극제가 TLR 4 효능제, TLR4 길항제, 사포닌, TLR7 효능제, TLR8 효능제, TLR9 효능제로 이루어진 군에서 선택되는 방법.
- 제 12항에 있어서, 상기 TLR 4 길항제가 3-탈아실화된 MPL인 방법.
- 제 12항에 있어서, 상기 사포닌이 QS21인 방법.
- 제 11항에 있어서, 상기 담체가 2개의 면역자극제를 포함하는 방법.
- 제 15항에 있어서, 상기 면역자극제가 3-탈아실화된 MPL과 QS21인 방법.
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
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WOPCT/EP2007/055037 | 2007-05-24 | ||
PCT/EP2007/055037 WO2007137986A2 (en) | 2006-05-26 | 2007-05-24 | Vaccination against cancer |
GB0723044.4 | 2007-11-23 | ||
GB0723044A GB0723044D0 (en) | 2007-11-23 | 2007-11-23 | Lyophillised antigen composition |
GB0723900A GB0723900D0 (en) | 2007-12-06 | 2007-12-06 | Lyophillised antigen composition |
GB0723900.7 | 2007-12-06 | ||
PCT/EP2008/056305 WO2008142133A1 (en) | 2007-05-24 | 2008-05-22 | Lyophilised antigen composition |
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KR1020117016237A Division KR20110091817A (ko) | 2007-05-24 | 2008-05-22 | 동결건조 항원 조성물 |
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KR20100017519A KR20100017519A (ko) | 2010-02-16 |
KR101238795B1 true KR101238795B1 (ko) | 2013-03-07 |
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KR1020117016237A KR20110091817A (ko) | 2007-05-24 | 2008-05-22 | 동결건조 항원 조성물 |
KR1020097025005A KR101238795B1 (ko) | 2007-05-24 | 2008-05-22 | 동결건조 항원 조성물 |
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US (2) | US20090035360A1 (ko) |
EP (3) | EP2148697B1 (ko) |
JP (1) | JP5331105B2 (ko) |
KR (2) | KR20110091817A (ko) |
CN (1) | CN101678091A (ko) |
AR (1) | AR066676A1 (ko) |
AU (1) | AU2008252911B2 (ko) |
BR (1) | BRPI0811228A2 (ko) |
CA (1) | CA2687632C (ko) |
CL (1) | CL2008001491A1 (ko) |
CY (1) | CY1113446T1 (ko) |
DK (1) | DK2148697T3 (ko) |
EA (3) | EA201300102A1 (ko) |
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PL (1) | PL2148697T3 (ko) |
PT (1) | PT2148697E (ko) |
SI (1) | SI2148697T1 (ko) |
TW (1) | TW200911304A (ko) |
UY (1) | UY31101A1 (ko) |
WO (1) | WO2008142133A1 (ko) |
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- 2008-05-22 CN CN200880017245A patent/CN101678091A/zh active Pending
- 2008-05-22 EP EP12157796A patent/EP2476431A1/en not_active Withdrawn
- 2008-05-22 DK DK08759906.4T patent/DK2148697T3/da active
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- 2008-05-22 EP EP20120157797 patent/EP2489367A1/en not_active Withdrawn
- 2008-05-22 ES ES08759906T patent/ES2395333T3/es active Active
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1547581A1 (en) * | 2003-12-23 | 2005-06-29 | Vectron Therapeutics AG | Liposomal vaccine for the treatment of human hematological malignancies |
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