KR20210069651A - 항원 펩티드-아쥬반트 뉴클레오티드 컨쥬게이트체를 포함하는 면역 유도제 및 그것을 포함하는 의약 조성물 - Google Patents
항원 펩티드-아쥬반트 뉴클레오티드 컨쥬게이트체를 포함하는 면역 유도제 및 그것을 포함하는 의약 조성물 Download PDFInfo
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Abstract
본 발명은, CpG 모티프를 포함하는 1 본쇄 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체와, 항원성을 갖는 펩티드가, 일단측에서 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체와 공유 결합하고 타단측에서 항원성을 갖는 펩티드와 공유 결합한 스페이서를 통하여 결합한 폴리뉴클레오티드/펩티드 컨쥬게이트를 유효 성분으로서 포함하는 면역 유도제 및 그것을 포함하는 의약 조성물을 제공한다.
Description
본 발명은, 항원 펩티드에 특이적인 면역 응답을 유도하기 위한 신규 항원 펩티드-아쥬반트 뉴클레오티드 컨쥬게이트체를 포함하는 면역 유도제 및 그것을 포함하는 의약 조성물에 관한 것이다.
백신에 의한 감염 예방의 기본적인 원리는, 인위적인 의사 (擬似) 감염에 의해, 획득 면역을 유도하고, 특정 병원체에 대한 항체 산생이나 세포성 면역을 유도하는 것에 있다. 획득 면역에 있어서는, 면역의 「기억」을 담당하는 T 세포나 B 세포가 중심적인 역할을 하고, DNA 의 재구성에 의한 항체의 가변 영역의 다양성이, 무수한 항원에 대한 특이적인 면역 반응을 가능하게 하는 것이 알려져 있다. 한편, 백혈구, 마크로파지, 수지상 세포 등의 식세포가 중심적인 역할을 하고 있는 자연 면역은, 종래, 병원체나 이물질을 탐식하는 비특이적인 프로세스이고, 획득 면역 성립까지의 「임시방편」으로서의 역할만을 하고 있는 것으로 생각되었지만, 자연 면역의 분자 기구에 관한 연구의 진전에 의해, 자연 면역에 있어서도, 자기·비자기의 특이적 인식이 행해지고 있는 것이나, 자연 면역이 획득 면역의 성립에 필수인 것이 밝혀졌다. 보다 구체적으로는, 수지상 세포, 마크로파지, B 세포 등의 항원 제시 세포에 존재하는 Toll 유사 수용체 (TLR) 패밀리가, 다양한 병원체와 반응하여, 사이토카인의 산생을 유도하고, 나이브 T 세포의 Th1 세포로의 분화 촉진, 킬러 T 세포의 활성화 등을 통해 획득 면역을 유도하는 것이, 최근의 연구에 의해 밝혀졌다.
일련의 TLR 패밀리에 의해 인식되는 병원체의 구성 성분은 다방면에 걸치는데, 그 중의 하나로, TLR9 의 리간드인, CpG 모티프를 갖는 DNA (CpG DNA) 가 있다. CpG 모티프는 중심부에 시토신 (C) 과 구아닌 (G) 이 나열되고, 전후에 퓨린 염기 및 피리미딘 염기가 2 개씩 나열된 6 개의 염기를 기본으로 하고, -PuPu-CG-PyPy- (Pu 는 퓨린 염기를, Py 는 피리미딘 염기를 나타낸다.) 로 표시되는 서열로 (인간의 경우에는, GTCGTT 도 TLR9 에 대한 리간드 활성을 가지고 있는 것이 알려져 있다.), 포유류에는 적게, 미생물에는 많이 (확률에 의해 계산되는 빈도로) 보이는 염기 서열이다. 또한, 포유류에 있어서는, 소수 존재하는 CpG 모티프의 대부분이 메틸화가 되어 있다. 포유류 중에 거의 존재하지 않는 비메틸화 CpG 모티프는, 강력한 면역 부활 활성을 가지고 있다 (예를 들면, 비특허문헌 1 ∼ 3 참조). 엔도사이토시스에 의해 세포 내에 도입된 CpG DNA 는, 파고솜 유사 소포체에 존재하는 TLR9 에 의해 인식되어, Th1 반응을 강하게 유도한다. Th1 반응은, Th2 반응이 우위인 알레르기 반응을 억제함과 동시에, 강한 항종양 활성을 갖는다. 그 때문에, CpG DNA 는 감염 예방에 추가하여, 알레르기 질환, 종양성 질환에 대한 아쥬반트로서도 기대되고 있다 (예를 들어 비특허문헌 4 참조).
그러나, CpG DNA 를 면역 요법의 아쥬반트로서 사용하는 경우, 세포질이나 혈장 중의 뉴클레아제에 의한 분해나, 단백질과의 비특이적 결합을 회피하면서, 어떻게 표적 세포의 내부에 CpG DNA 를 도달시킬지가 문제가 된다.
본 발명자들은, 신규 유전자 캐리어로서 β-1,3-글루칸 골격을 갖는 다당 (이하, 「β-1,3-글루칸」이라고 약칭하는 경우가 있다) 에 착안하여, 지금까지, β-1,3-글루칸이 핵산 의약 (안티센스 DNA, CpG DNA) 을 비롯한 각종 핵산과 새로운 타입의 복합체를 형성하는 것을 알아내었다 (예를 들어, 특허문헌 1, 2, 비특허문헌 5 ∼ 7 참조).
천연에서는 3 중 나선으로 존재하는 β-1,3-글루칸을, 디메틸술폭시드 (DMSO) 등의 비프로톤성 극성 유기 용매, 혹은 0.1 N 이상의 알칼리 용액에 용해하여 1 본쇄로 해리시킨 후에, 1 본쇄의 핵산을 부가하고, 용매를 물 혹은 중성으로 되돌림으로써, 핵산 1 분자와 β-1,3-글루칸 2 분자로 이루어지는 3 중 나선 복합체가 형성되는 것을 발견하였다. 이 경우, 3 중 나선 복합체에 있어서의 β-1,3-글루칸 분자와 핵산 분자는, 주로 수소 결합과 소수성 상호 작용에 의해 분자간 결합을 형성하고 있는 것으로 생각되고 있다 (비특허문헌 8 참조).
상기 서술한 바와 같이, 핵산을 β-1,3-글루칸과 복합화함으로써, 뉴클레아제에 의한 핵산 분자의 가수분해나, 혈장 단백질과 핵산의 비특이적 결합 등의, 핵산 분자와 생체 내 단백질과의 바람직하지 않은 상호 작용을 억제하면서, 핵산을 세포의 내부에 도달시키는 것이 가능하게 되었다. β-1,3-글루칸과 핵산의 복합체, 나아가서는 항원성을 갖는 단백질을 포함하는 3 원 복합체를 이용하여, CpG DNA 의 세포 내로의 딜리버리에 성공하였다 (예를 들면, 특허문헌 3, 4, 비특허문헌 9 ∼ 11 참조).
그러나, 상기 종래의 기술은 다음과 같은 과제를 가지고 있었다. 예를 들어, 비특허문헌 11 에 기재된 β-1,3-글루칸/항원성을 갖는 단백질/CpG DNA 의 3 원 (元) 복합체의 제조 방법에 있어서는, 과요오드산 산화에 의해, β-1,3-글루칸의 측사슬의 글루코오스 잔기 상에 포르밀기를 생성시키고, 환원적 아미노화 반응에 의해, 포르밀기와 항원성을 갖는 펩티드 (이하, 「항원성 펩티드」라고 약칭하는 경우가 있다) 의 아미노기를 반응시켜, β-1,3-글루칸과 항원성을 갖는 펩티드가 공유 결합한 복합체를 형성하는데, 수율이 매우 낮다는 과제를 가지고 있었다. 이러한 사정을 감안하여, 예를 들어 특허문헌 4 에 기재된 β-1,3-글루칸/항원성 단백질 (항원성을 갖는 펩티드)/CpG DNA 의 3 원 복합체의 제조 방법에 있어서는, 측사슬에 포르밀기를 갖는 β-1,3-글루칸과 항원성을 갖는 펩티드를, 알칼리 수용액 중에서 반응시킴과 동시에 중화를 실시함으로써, 혹은 알칼리 수용액 중에서 반응시켜 축차 중화를 실시함으로써, β-1,3-글루칸의 측사슬 상의 포르밀기와 항원성을 갖는 펩티드의 아미노기와의 반응성 및 수율을 향상시키고 있다. 그러나, 펩티드에는 복수의 아미노기가 존재하기 때문에, 반응점의 제어가 곤란하다. 따라서, 항원성을 갖는 펩티드의 반응 위치에 따른 면역원성의 차이나, β-1,3-글루칸과의 반응 생성물이 복잡한 혼합물이 되는 것에서 기인하는 분리 정제의 곤란성 등의 문제의 발생이 우려된다. 또한, 수소 결합에 의한 복합체 형성을 이용한 β-1,3-글루칸과 DNA 와의 복합체의 형성에 비해, β-1,3-글루칸과 항원성을 갖는 펩티드의 공유 결합의 형성에 기초하는 복합체의 형성은 번잡하다. 이러한 점들에 있어서, 특허문헌 4 에 기재된 β-1,3-글루칸/항원성을 갖는 펩티드/CpG DNA 의 3 원 복합체의 제조 방법은, 생산성 등의 점에서 여전히 과제를 가지고 있다.
이러한 과제를 감안하여, 본 발명자들은 생산성이 우수하고, 높은 면역 부활 활성을 갖는 펩티드/β-1,3-글루칸 복합체로서, β-1,3-글루칸 골격을 갖는 다당과, 항원성을 갖는 펩티드가, 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체와 공유 결합을 통하여 결합한 펩티드/폴리뉴클레오티드 컨쥬게이트를 포함하고, 상기 펩티드/폴리뉴클레오티드 컨쥬게이트의 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체가, 상기 β-1,3-글루칸 골격을 갖는 다당과, 수소 결합을 통하여 결합하고, 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체의 분자쇄 1 개와 상기 β-1,3-글루칸 골격을 갖는 다당의 분자쇄 2 개로 이루어지는 삼중 나선 구조를 갖는 복합체를 형성하고 있는 것을 특징으로 하는 펩티드/β-1,3-글루칸 복합체를 제안하였다 (특허문헌 5 참조). 그러나, 특허문헌 5 에는 펩티드/β-1,3-글루칸 복합체를 구성하는 펩티드/폴리뉴클레오티드 컨쥬게이트 자체의 면역 유도 활성에 대해서는 기재되어 있지 않았다.
CpG DNA 와 항원성을 갖는 펩티드 또는 단백질과의 컨쥬게이트의 면역 유도 활성을 시사하는 몇 가지 보고는 존재한다 (비특허문헌 12, 13 참조). 그러나, 비특허문헌 12 에서는, CpG DNA 와 오보알부민 (OVA) 항원 유래의 18 ∼ 24 mer 의 펩티드의 컨쥬게이트의 투여에 의해, CD8 양성 T 세포 (CTL) 에서의 OVA 항원 제시 활성을 나타내고 있지만, 명확한 CTL 세포 장해 활성의 유도는 나타나 있지 않다. 또한 비특허문헌 13 에서는, CpG DNA 와 OVA 항원 단백질의 컨쥬게이트의 투여에 의해, CTL 세포 장해 활성의 유도가 나타나 있지만, 투여량이 10 ㎍/마우스로 높고, 또한 그 제조에 있어서는 DNA 의 화학 합성과 항원 단백질의 배양/정제에 의한 생산 및 이것들의 컨쥬게이트라는 복잡한 제조 공정을 필요로 하기 때문에, 저용량에서의 활성 및 생산성에 과제를 가지고 있다.
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Synthesis and in Vitro Characterization of Antigen-Conjugated Polysaccharide as a CpG DNA Carrier, N. Shimada, K. J. Ishii, Y. Takeda, C. Coban, Y. Torii, S. Shinkai, S. Akira and K. Sakurai, Bioconjugate Chem., 17 1136-1140 (2006).
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펩티드/폴리뉴클레오티드 컨쥬게이트 단독에서의 명확한 면역 유도 활성에 대해서는 알려져 있지 않았다.
본 발명자들은, β-1,3-글루칸과 복합체를 형성하고 있지 않은 펩티드/폴리뉴클레오티드 컨쥬게이트 자체, 특히 CpG 모티프를 포함하는 펩티드/폴리뉴클레오티드 컨쥬게이트가, 단독으로 높은 면역 유도 활성을 갖는 것을 알아내어, 본 발명을 완성하기에 이르렀다. 이렇게 하여, 본 발명은, 생산성이 우수하고, 높은 면역 부활 활성을 갖는 면역 유도체 및 그것을 포함하는 의약 조성물을 제공하는 것을 목적으로 한다.
상기 목적에 따른 본 발명의 제 1 양태는, CpG 모티프를 포함하는 1 본쇄 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체와, 항원성을 갖는 펩티드가, 일단측에서 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체와 공유 결합하고 타단측에서 상기 항원성을 갖는 펩티드와 공유 결합한 스페이서를 통하여 결합한 폴리뉴클레오티드/펩티드 컨쥬게이트를 유효 성분으로서 포함하는 면역 유도제를 제공함으로써 상기 과제를 해결하는 것이다.
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서, 상기 항원성을 갖는 펩티드의 아미노산 길이가 5 이상 30 이하여도 된다.
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서, 상기 항원성을 갖는 펩티드의 아미노산 길이가 8 이상 11 이하여도 된다.
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서, 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체가 2 이상의 CpG 모티프를 포함하는 폴리데옥시리보뉴클레오티드 (DNA) 또는 DNA 유도체여도 된다.
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서, 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체의 염기 길이가 15 이상 40 이하여도 된다.
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서, 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체의 염기 길이가 20 이상 30 이하여도 된다.
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서, 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체가, 인산디에스테르 결합의 적어도 일부가 포스포로티오에이트 결합으로 치환된 폴리뉴클레오티드 유도체여도 된다.
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서, 인산디에스테르 결합의 적어도 일부가 포스포로티오에이트 결합으로 치환된 폴리뉴클레오티드 유도체에 있어서, 인산디에스테르 결합의 50 % 이상이 포스포로티오에이트 결합으로 치환되어 있어도 된다.
상기 인산디에스테르 결합의 적어도 일부가 포스포로티오에이트 결합으로 치환된 폴리뉴클레오티드 유도체에 있어서, 인산디에스테르 결합의 90 % 이상이 포스포로티오에이트 결합으로 치환되어 있어도 된다.
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서, 상기 스페이서와 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체 사이의 공유 결합 및 상기 스페이서와 상기 항원성을 갖는 펩티드 사이의 공유 결합의 일방 또는 양방이 생체 환경 중에서 절단 가능한 공유 결합인 것이 바람직하다.
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서, 상기 폴리뉴클레오티드/펩티드 컨쥬게이트를 구성하는 상기 항원성을 갖는 펩티드와, 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체에 결합한 상기 스페이서가, 상기 항원성을 갖는 펩티드의 N 말단의 시스테인 잔기의 티올기와 상기 스페이서가 갖는 티올기의 반응에 의해 생성된 공유 결합 (디술피드 결합) 을 통하여 결합하고 있어도 된다.
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서, 상기 스페이서가, 하기 식으로 나타내는 반복 단위를 포함하고 있어도 된다.
[화학식 1]
상기 식에 있어서,
X 는, 산소 원자 또는 황 원자를 나타내고 (여기서 각 X 는 동일해도 되고 상이해도 된다),
R 은, (CH2)pO, (CH2)qNH, (CH2CH2O)m 의 어느 것을 나타내고 (m, p 및 q 는, 각각 독립적으로 10 이하의 자연수를 나타낸다),
n 은, 10 이하의 자연수를 나타낸다.
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서, 상기 스페이서가, 하기 중 어느 하나의 식으로 나타내는 구조를 가지고 있어도 된다.
[화학식 2]
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서,
상기 항원성을 갖는 펩티드의 아미노산 길이가 5 이상 30 이하이고,
상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체가 2 이상의 CpG 모티프를 포함하는 폴리데옥시리보뉴클레오티드 (DNA) 또는 DNA 유도체이고,
상기 폴리뉴클레오티드 유도체가, 인산디에스테르 결합의 적어도 일부가 포스포로티오에이트 결합으로 치환된 폴리뉴클레오티드 유도체이고, 및
상기 스페이서와 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체 사이의 공유 결합 및 상기 스페이서와 상기 항원성을 갖는 펩티드 사이의 공유 결합의 일방 또는 양방이 생체 환경 중에서 절단 가능한 공유 결합인 구조를 갖는 것이 바람직하다.
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서,
상기 항원성을 갖는 펩티드의 아미노산 길이가 8 이상 11 이하이고,
상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체가 2 이상의 CpG 모티프를 포함하고, 염기 길이가 20 이상 30 이하인 폴리데옥시리보뉴클레오티드 (DNA) 또는 DNA 유도체이고,
상기 폴리뉴클레오티드 유도체가, 인산디에스테르 결합의 90 % 이상이 포스포로티오에이트 결합으로 치환된 폴리뉴클레오티드 유도체이고,
상기 폴리뉴클레오티드/펩티드 컨쥬게이트를 구성하는 상기 항원성을 갖는 펩티드와, 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체에 결합한 상기 스페이서가, 상기 항원성을 갖는 펩티드의 N 말단의 시스테인 잔기의 티올기와 상기 스페이서가 갖는 티올기의 반응에 의해 생성한 공유 결합 (디술피드 결합) 을 통하여 결합하고 있고, 및
상기 스페이서가, 하기 중 어느 하나의 식
[화학식 3]
으로 나타내는 구조를 갖는 것이 보다 바람직하다.
본 발명의 제 1 양태에 관련된 면역 유도제에 있어서, 아쥬반트로서, 면역 부활 활성을 갖는 물질을 추가로 포함하고 있어도 된다.
본 발명의 제 2 양태는, 본 발명의 제 1 양태에 관련된 면역 유도제를 포함하는 의약 조성물을 제공함으로써 상기 과제를 해결하는 것이다.
본 발명의 제 2 양태는, 종양 치료를 위한 의약 조성물일 수 있다.
본 발명의 다른 양태에 따르면, 본 발명의 제 1 양태에 관련된 면역 유도제의 유효량을, 그것을 필요로 하는 대상에 투여하는 것을 포함하는, 질환을 치료 또는 예방하기 위한 방법이 제공된다. 이 양태에 있어서, 질환은 종양일 수 있다.
본 발명의 또 다른 양태에 따르면, 질환의 치료 또는 예방을 위한 의약의 제조를 위한, 본 발명의 제 1 양태에 관련된 면역 유도제의 사용이 제공된다. 이 양태에 있어서, 질환은 종양일 수 있다.
본 발명의 펩티드/폴리뉴클레오티드 컨쥬게이트는, 생산성이 우수한 고활성의 면역 유도제로 사용할 수 있다. 또한, 항원성을 갖는 펩티드 및 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체를 적절히 조합함으로써, 다양한 항원에 대하여 면역 유도 활성을 갖는 면역 유도제를 용이하게 설계할 수 있다.
도 1 은, 실시예 2 에 있어서의 플로 사이토메트리의 측정 결과를 나타내는 도면이다.
도 2 는, 실시예 3 에 있어서의 플로 사이토메트리의 측정 결과를 나타내는 도면이다.
도 3 은, 실시예 4 에 있어서의 플로 사이토메트리의 측정 결과를 나타내는 도면이다.
도 4 는, 실시예 4 에 있어서의 플로 사이토메트리의 측정 결과를 나타내는 도면이다.
도 5 는, 실시예 5 에 있어서의 플로 사이토메트리의 측정 결과를 나타내는 도면이다.
도 6 은, 실시예 7 에 있어서의 플로 사이토메트리의 측정 결과를 나타내는 도면이다.
도 7 은, 실시예 7 에 있어서의 플로 사이토메트리의 측정 결과를 나타내는 도면이다.
도 2 는, 실시예 3 에 있어서의 플로 사이토메트리의 측정 결과를 나타내는 도면이다.
도 3 은, 실시예 4 에 있어서의 플로 사이토메트리의 측정 결과를 나타내는 도면이다.
도 4 는, 실시예 4 에 있어서의 플로 사이토메트리의 측정 결과를 나타내는 도면이다.
도 5 는, 실시예 5 에 있어서의 플로 사이토메트리의 측정 결과를 나타내는 도면이다.
도 6 은, 실시예 7 에 있어서의 플로 사이토메트리의 측정 결과를 나타내는 도면이다.
도 7 은, 실시예 7 에 있어서의 플로 사이토메트리의 측정 결과를 나타내는 도면이다.
본 발명의 제 1 실시 형태에 관련된 면역 유도제 (이하, 「면역 유도제」라고 약칭하는 경우가 있다) 는, CpG 모티프를 포함하는 1 본쇄 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체와, 항원성을 갖는 펩티드가, 일단측에서 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체와 공유 결합하고 타단측에서 항원성을 갖는 펩티드와 공유 결합한 스페이서를 통하여 결합한 폴리뉴클레오티드/펩티드 컨쥬게이트를 유효 성분으로서 포함하고 있다.
펩티드/폴리뉴클레오티드 컨쥬게이트는, 항원성을 갖는 펩티드와, 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체가 공유 결합을 통하여 결합한 복합체이다. 「항원성을 갖는 펩티드」로는, 항원성을 갖는 것, 즉, 생체의 면역계에 있어서 이물질이라고 인식되고, 특이적인 항체 산생을 일으키는 (면역 응답을 유도하는) 것이면, 임의의 아미노산 서열 및 아미노산 잔기수를 갖는 것을, 특별히 제한없이 사용할 수 있다. 항원성을 갖는 펩티드의 서열에 시스테인 (Cys) 이 없는 경우에는, 본 실시 형태에서는, 항원 단백질 유래의 항원 에피토프 펩티드의 N 말단에 추가로 시스테인을 인위적으로 하나 부여한 펩티드를 항원성을 갖는 펩티드로서 사용할 수 있다. 본 실시형태에 관련된 면역 유도제의 유효 성분인 펩티드/폴리뉴클레오티드 컨쥬게이트의 제조에 사용되는 항원성을 갖는 펩티드로는, 식물 알레르기 등의 알레르기의 원인이 되는 단백질, 세균, 바이러스 등의 병원체, 종양 세포 등을 기원으로 하는 단백질 중, 에피토프로서 작용할 수 있는 부분 아미노산 서열을 갖는 것을 들 수 있다. 항원성을 갖는 펩티드를 구성하는 아미노산 잔기수는, 에피토프로서 작용할 수 있는 한에 있어서 특별히 제한되지 않지만, 대부분의 경우, 5 ∼ 30 의 범위 내이고, 대부분은 8 ∼ 17 정도의 범위 내에 있다.
항원성을 갖는 펩티드는, 기원이 되는 단백질의 효소 분해, 펩티드 합성 등의 임의의 공지된 방법을 사용하여 얻을 수 있다. 또한, 항원성을 갖는 펩티드의 아미노산 서열은, 펩티드 어레이를 이용한 에피토프 해석 등의 임의의 공지된 방법을 사용하여 결정할 수 있다.
항원성을 갖는 펩티드로서 사용할 수 있는 펩티드의 예시로는, 에피토프 펩티드 데이터베이스 IEDB (www.iedb.org, last accessed : 08/11/) 에 등록되어 있는 MHC-1 T cell Epitopes, Chowell 등의 논문 (TCR contact residue hydrophobicity is a hallmark of immunogenic CD8+ T cell epitopes PNAS April 7, 2015 112 (14) E1754-E1762), Table.S1) 에 기재된 펩티드, 하기 표 1 ∼ 7 에 나타내는 것을 들 수 있다. 이들 항원성 펩티드의 N 말단에 추가로 시스테인 잔기를 하나 부여한 펩티드가 본 실시 형태에 있어서, 항원성을 갖는 펩티드로서 사용할 수 있다 (단, 항원성 펩티드의 서열 중에 이미 시스테인 잔기가 있는 경우를 제외한다).
폴리뉴클레오티드/펩티드 컨쥬게이트를 구성하는 1 본쇄 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체는, 1 또는 복수 (바람직하게는 복수) 의 CpG 모티프를 포함하는 한에 있어서, 임의의 염기 서열 및 염기수를 갖는 폴리뉴클레오티드 또는 그 유도체를 특별히 제한없이 사용할 수 있다. CpG 모티프의 구체예로는, AGCGTT, GACGTT, GACGTC, GTCGTT 등을 들 수 있다. 폴리뉴클레오티드에 포함되는 CpG 모티프의 수는 특별히 제한되지 않지만, 1 내지 6 의 CpG 모티프를 포함하고 있는 것이 바람직하고, 2 내지 4 의 CpG 모티프를 포함하고 있는 것이 더욱 바람직하다. 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체는, 2 이상의 CpG 모티프를 포함하는 폴리데옥시리보뉴클레오티드 (DNA) 또는 포스포로티오에이트 수식된 DNA 유도체인 것이 바람직하지만, 일부에 RNA 또는 RNA 유도체가 포함되어 있어도 된다. RNA 또는 RNA 유도체가 포함되는 경우, 그것들 중 어느 하나 또는 복수의 함량이 20 % 이하 (구체적으로는, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 또는 1 % 이하) 인 것이 바람직하다.
폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체에 포함되는 염기수는, 15 ∼ 40 (구체적으로는, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 또는 40) 인 것이 바람직하고, 20 ∼ 30 (구체적으로는, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 또는 30) 인 것이 보다 바람직하다. 바람직한 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체의 구체예로는, 하기 표 8 에 나타내는 것을 들 수 있다.
폴리뉴클레오티드는, 생체 내에서 뉴클레아제에 의한 분해를 받기 쉬우므로, 생체 내에서의 안정성을 향상시키기 위하여, 폴리뉴클레오티드 대신에 폴리뉴클레오티드 유도체를 사용해도 된다. 폴리뉴클레오티드 유도체의 예로는, 리보뉴클레오티드의 2' 위치의 하이드록실기의 전부 또는 일부가 불소 또는 메톡시기로 치환되어 있는 것, 폴리리보뉴클레오티드 (RNA) 또는 폴리데옥시리보뉴클레오티드 (DNA) 의 인산디에스테르 결합의 전부 또는 일부가 포스포로티오에이트 결합으로 치환되어 있는 것 등을 들 수 있다. 폴리리보뉴클레오티드 또는 폴리데옥시리보뉴클레오티드의 인산디에스테르 결합의 일부가 포스포로티오에이트 결합으로 치환되어 있는 경우, 인산디에스테르 결합의 50 % 이상 (구체적으로는, 50, 60, 70, 80 또는 90 % 이상) 이 포스포로티오에이트 결합으로 치환되어 있는 것이 바람직하고, 90 % 이상 (구체적으로는, 90, 91, 92, 93, 94, 95, 96, 97, 98 또는 99 % 이상) 이 포스포로티오에이트 결합으로 치환되어 있는 것이 보다 바람직하고, 실질적으로 모두가 포스포로티오에이트 결합으로 치환되어 있어도 된다. 포스포로티오에이트 결합으로 치환되는 인산디에스테르 결합의 위치는 특별히 제한되지 않고, 연속된 복수의 인산디에스테르 결합이 치환되어 있어도 되고, 혹은 포스포로티오에이트 결합이 서로 이웃하지 않도록 치환되어 있어도 된다.
스페이서를 통하여 항원성을 갖는 펩티드와 공유 결합하는 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체는, 항원성을 갖는 펩티드의 N 말단, C 말단, 혹은 측사슬 중 어느 것에 결합하고 있어도 되지만, 항원성을 갖는 펩티드의 N 말단측에 결합하고 있는 것이 바람직하다. 항원성을 갖는 펩티드에 Cys 잔기가 포함되어 있지 않은 경우에는, N 말단측에 추가로 시스테인 잔기를 부여한 펩티드를 사용할 수 있다. 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체와 항원성을 갖는 펩티드는, 일단측에서 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체와 공유 결합하고, 타단측에서 항원성을 갖는 펩티드와 공유 결합한 스페이서를 통하여 결합하고 있다. 스페이서와 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체 및 항원성을 갖는 펩티드의 결합 형성에 사용되는 반응성 관능기로는, 항원성을 갖는 펩티드 및 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체에 존재하는 관능기를 그대로, 혹은 화학 수식에 의해 활성화한 것과 반응하여 공유 결합을 형성할 수 있는 임의의 것이 사용된다. 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체는 그 5' 말단측 또는 3' 말단의 수산기의 산소 원자 상에서, 스페이서와 결합하고 있는 것이 바람직하다. 항원성을 갖는 펩티드는, Cys 잔기 측사슬의 술프하이드릴기의 황 원자 상에서, 스페이서와 결합하고 있는 것이 바람직하다.
바람직한 펩티드/폴리뉴클레오티드 컨쥬게이트의 일례는, 하기 식 (A) 에 나타내는 바와 같이, 항원성을 갖는 펩티드의 N 말단측에, 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체의 3' 또는 5' 말단측이 스페이서 Sp 를 통하여 결합한 구조를 가지고 있다.
식 (A) : [폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체]-Sp-[항원성을 갖는 펩티드]
스페이서 Sp 의 일례로는, 알킬렌기, 폴리에틸렌글리콜 (PEG) 등을 들 수 있지만, 하기 식으로 나타내는 인산디에스테르 구조를 포함하는 반복 단위를 포함하고 있어도 된다.
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상기 식에 있어서, X 는, 산소 원자 또는 황 원자를 나타내고 (여기서 각 X 는 동일해도 되고 상이해도 된다), R 은, (CH2)pO, (CH2)qNH, (CH2CH2O)m 의 어느 것을 나타내고 (m, p 및 q 는, 각각 독립적으로 10 이하의 자연수를 나타낸다), n 은, 10 이하의 자연수를 나타낸다.
이들 반복 단위는, 뉴클레아제에 의한 가수분해를 받지 않기 때문에, X 가 산소 원자라도 생체 내에서의 안정성이 크게 저하되지 않는다. 예를 들면, R 이 (CH2)3 인 경우, 반복 단위의 사이즈가 리보뉴클레오티드 또는 데옥시리보뉴클레오티드의 사이즈와 거의 동일하게 되기 때문에, 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체의 일부를 이 스페이서로 치환하는 것에 의한 생산 비용의 저감을 기대할 수 있다. 스페이서 Sp 의 구체예로는 하기의 것을 들 수 있다.
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스페이서 Sp 의 보다 바람직한 예로는, 하기 중 어느 하나의 구조를 갖는 것을 들 수 있다.
[화학식 13]
스페이서와 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체 및 항원성을 갖는 펩티드의 결합 형성에 사용되는 반응성 관능기의 조합의 예로는, 에스테르 결합, 아미드 결합, 인산에스테르 결합 등에 추가하여, 예를 들면 바이오 칩 표면에 대한 생체 분자의 고정에 사용되는 반응성 관능기끼리의 조합을 들 수 있고, 보다 구체적으로는 하기에 나타내는 것을 들 수 있다.
(a) 알킨과 아지드 화합물
알킨과 아지드 화합물 (아지화물) 은, 하기에 나타내는 바와 같은 부가 고리화 반응 (휘스겐 반응) 에 의해, 1,2,3-트리아졸 고리를 형성한다. 양자는, 생체 분자를 포함하는 많은 유기 화합물에 도입 가능한 안정적인 관능기로, 물을 함유하는 용매 중에서도 신속하고 또한 거의 정량적으로 반응하고, 거의 부반응을 동반하지 않으며, 여분의 폐기물을 생성하지 않기 때문에, 소위 「클릭 케미스트리」의 중심적인 반응으로서, 생화학의 분야에서 널리 사용되고 있다. 알킨 유도체 및 아지드기는, 임의의 공지된 방법을 사용하여, 항원성을 갖는 펩티드 또는 폴리뉴클레오티드 혹은 폴리뉴클레오티드 유도체에 도입할 수 있다. 알킨 유도체로는, 프로파르길알코올, 프로파르길아민 등의 반응성 관능기를 갖는 것을 용이하게 입수할 수 있고, 이들을 카르복실기나 하이드록실기 등의 반응성 관능기와 직접 반응시키거나, 혹은 카르보닐디이미다졸 등과 함께 반응시켜, 생성되는 아미드 결합, 에스테르 결합, 우레탄 결합 등을 통하여 알킨 유도체를 도입할 수 있다. 아지드기에 대해서도, 임의의 공지된 방법을 사용하여, 항원성을 갖는 펩티드 또는 폴리뉴클레오티드 혹은 폴리뉴클레오티드 유도체에 도입할 수 있다. 또한, 휘스겐 반응은 구리 촉매의 존재하에서 실시되지만, 항원성을 갖는 펩티드 및 인산디에스테르 결합이 포스포로티오에이트 결합 등의 황 함유 관능기로 치환된 폴리뉴클레오티드 유도체에는, 구리 이온에 배위하는 황 원자가 존재하기 때문에, 구리의 촉매 활성이 저하될 우려가 있다. 반응률을 향상시키기 위해 과잉량의 구리를 첨가하는 것이 바람직하다.
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(b) 말레이미드 또는 비닐술폰과 티올기
전자 구인성의 카르보닐기 또는 술폰기에 인접하는 이중 결합을 갖는 말레이미드 또는 비닐술폰은, 중성 부근의 pH 에서, 하기에 나타내는 바와 같이, 티올기와의 부가 반응 (마이클 부가 반응) 에 의해, 안정적인 티오에테르 유도체를 생성한다. 적당한 스페이서를 갖는 말레이미드 및 비닐술폰 유도체가 시판되고 있기 때문에, 항원성을 갖는 펩티드 또는 폴리뉴클레오티드 혹은 폴리뉴클레오티드 유도체에 이들 관능기를 도입하는 것은 용이하다. 항원성을 갖는 펩티드에 티올기를 도입하는 경우, 시스테인을 포함하는 항원성을 갖는 펩티드의 경우에는, 시스테인 잔기 측사슬의 티올기를 이용할 수 있다. 단, 시스테인은, 존재비가 낮은 아미노산이기 때문에, 항원성을 갖는 펩티드의 N 말단측에 시스테인을 도입한 것을 사용한다. 티올기를 포함하는 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체로는, 이들 5' 말단의 하이드록실기를 티올기로 변환한 티올화 폴리뉴클레오티드가 사용된다.
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(c) 시스테인 측사슬의 티올기와 티올화 폴리뉴클레오티드의 티올기
상기 서술한 바와 같이, N 말단측에 시스테인을 도입한 항원성을 갖는 펩티드의 시스테인 잔기 측사슬의 티올기와, 티올화 폴리뉴클레오티드의 티올기를 반응시켜, 디술피드기를 형성시킨다. 디술피드 결합은, 환원제의 존재하에서 절단되기 때문에, 상기 양자에 비해, 안정성의 점에서 떨어진다. 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체로의 티올기의 도입은, 임의의 공지된 방법을 사용하여 실시할 수 있는데, 구체예로는, 하기 식에 나타내는 바와 같은, 아미노화 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체와, ω-(2-피리딜디티오) 지방산의 N-숙시이미딜에스테르와의 반응을 들 수 있다.
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이들 중, 생체 내에서 용이하게 절단 가능한 시스테인 측사슬의 티올기와 티올화 폴리뉴클레오티드의 티올기의 조합에 의한 디술피드 결합이 바람직하다.
본 실시형태에 관련된 면역 유도제의 유효 성분으로서 사용되는 폴리뉴클레오티드/펩티드 컨쥬게이트는, 프리체, 및 의약상 허용되는 염의 형태를 취할 수 있다. 의약상 허용되는 염으로는, 예를 들면 알칼리 금속 (칼륨, 나트륨, 리튬 등) 의 염, 알칼리 토금속 (칼슘, 마그네슘 등) 의 염, 암모늄염 (테트라메틸암모늄염, 테트라부틸암모늄염 등을 포함한다), 유기 아민 (트리에틸아민, 메틸아민, 디메틸아민, 시클로펜틸아민, 벤질아민, 페네틸아민, 피페리딘, 모노에탄올아민, 디에탄올아민, 트리스(하이드록시메틸)메틸아민, 리신, 아르기닌, N-메틸-D-글루카민 등) 의 염, 산부가물염 (염산염, 브롬화수소산염, 요오드화수소산염, 황산염, 인산염, 질산염 등의 무기산염 ; 및 아세트산염, 트리플루오로아세트산염, 락트산염, 타르타르산염, 옥살산염, 푸마르산염, 말레산염, 벤조산염, 시트르산염, 메탄술폰산 (메실산) 염, 에탄술폰산염, 벤젠술폰산염, 톨루엔술폰산염, 이세티온산염, 글루쿠론산염, 글루콘산염 등의 유기산염을 포함한다) 을 들 수 있다. 또한, 의약상 허용되는 염에는, 수화물도 포함된다.
본 발명의 제 2 실시 형태에 관련된 의약 조성물 (이하, 간단히 「의약 조성물」이라고 약칭하는 경우가 있다) 은, 본 발명의 제 1 실시 형태에 관련된 면역 유도제를 포함하고 있다. 의약 조성물의 제조에는, 유효 성분으로서의 펩티드/폴리뉴클레오티드 컨쥬게이트에 추가하여, 임의의 공지된 성분 (의약 용도로 허용되는 임의의 담체, 부형제 및 첨가물) 및 제제 방법을 사용할 수 있다. 면역 유도제를 포함하는 의약 조성물의 제조에는, 유효 성분으로서의 펩티드/폴리뉴클레오티드 컨쥬게이트에 추가하여, 임의의 공지된 성분 (의약 용도로 허용되는 임의의 담체, 부형제 및 첨가물) 및 제제 방법을 사용할 수 있다. 제제용의 물질로서 이하의 것을 들 수 있지만, 이들에 제한되지 않는다 : 글리신, 알라닌, 글루타민, 아스파라긴, 아르기닌 또는 리신 등의 아미노산류, 아스코르브산, 황산나트륨 또는 아황산수소나트륨 등의 항산화제, 인산, 시트르산, 붕산 버퍼, 탄산수소나트륨, 트리스-염산 (Tris-HCl) 용액 등의 완충제, 만니톨이나 글리신 등의 충전제, 에틸렌디아민사아세트산 (EDTA) 등의 킬레이트제, 카페인, 폴리비닐피롤리딘, β-시클로덱스트린이나 하이드록시프로필-β-시클로덱스트린 등의 착화제, 글루코오스, 만노오스 또는 덱스트린 등의 증량제, 단당류, 이당류 등의 다른 탄수화물, 착색제, 향미제, 희석제, 유화제나 폴리비닐피롤리딘 등의 친수 폴리머, 저분자량 폴리펩티드, 염 형성 카운터 이온, 염화벤잘코늄, 벤조산, 살리실산, 티메로살, 페네틸알코올, 메틸파라벤, 프로필파라벤, 클로르헥시딘, 소르브산 또는 과산화수소 등의 방부제, 글리세린, 프로필렌·글리콜 또는 폴리에틸렌글리콜 등의 용매, 만니톨 또는 소르비톨 등의 당알코올, 현탁제, 소르비탄에스테르, 폴리소르베이트 20 이나 폴리소르베이트 80 등의 폴리소르베이트, 트리톤 (triton), 트로메타민 (tromethamine), 레시틴 또는 콜레스테롤 등의 계면 활성제, 수크로오스나 소르비톨 등의 안정화 증강제, 염화나트륨, 염화칼륨이나 만니톨, 소르비톨 등의 탄성 증강제, 수송제, 부형제, 및/또는 약학상의 보조제. 이들 제제용의 물질의 첨가량은, 약제의 중량에 대하여 0.01 ∼ 100 배, 특히 0.1 ∼ 10 배 첨가하는 것이 바람직하다. 제제 중의 적합한 의약 조성물의 조성은 당업자에 의해, 적용 질환, 적용 투여 경로 등에 따라서 적절히 결정할 수 있다.
의약 조성물은, 경구 또는 비경구 투여에 적합한 제형으로 제공된다. 예를 들면, 주사제, 좌제 등이 사용되고, 주사제는 정맥 주사제, 피하 주사제, 피내 주사제, 근육 주사제, 점적 주사제 등의 제형을 포함해도 된다. 이러한 주사제는, 공지된 방법에 따라서 제조할 수 있다. 주사제의 조제 방법으로는, 예를 들어, 상기 본 발명의 폴리뉴클레오티드/펩티드 컨쥬게이트를 통상 주사제에 사용되는 무균의 수성 용매에 용해 또는 현탁함으로써 조제할 수 있다. 주사용의 수성 용매로는, 예를 들어 증류수, 생리적 식염수, 인산 완충액, 탄산 완충액, 트리스 완충액, 아세트산 완충액 등의 완충액 등을 사용할 수 있다. 이러한 수성 용매의 pH 는 5 ∼ 10 을 들 수 있고, 바람직하게는 6 ∼ 8 이다. 제조된 주사액은, 적당한 앰플에 충전되는 것이 바람직하다. 동결 건조 제제로 해도 된다. 주사 제제 외에는, 경피나 점막 흡수용의 제형 (액제 스프레이, 연고, 겔, 로션, 패치), 피하 국소 서방용의 제형 (나노겔이나 생분해성 마이크로/나노캡슐 등을 포함하는 현탁액, 온도 응답성 겔), 피부 투과용 경피 디바이스가 포함된 제제 (이온토포레시스, 마이크로니들), 분말제, 정제, 캡슐제, 시럽제, 에어졸이나 드라이 파우더 등의 흡입제, 등의 형태를 취할 수 있다.
의약 조성물은, 아쥬반트로서 면역 부활 활성을 갖는 물질을 추가로 포함하고 있어도 된다. 아쥬반트는 한정되지는 않으나, 자연 면역을 활성화하는 물질이다. 아쥬반트는, 바람직하게는 자연 면역 리셉터의 아고니스트이다. 자연 면역 리셉터 아고니스트로는, TLR 아고니스트 (예를 들면, TLR2 아고니스트, TLR3 아고니스트, TLR4 아고니스트, TLR7 아고니스트, TLR8 아고니스트, TLR9 아고니스트), RLR (retinoic acid-inducible gene I (RIG-1)-like receptors) 아고니스트, STING (stimulator of Interferon genes) 아고니스트, NLR (nucleotide-binding oligomerization domain (NOD)-like receptors) 아고니스트, CLR (C-type lectin receptors) 아고니스트 등이 예시된다. TLR 아고니스트로는, 예를 들어, 리포펩티드, Poly IC RNA, 이미퀴모드, 레시퀴모드, 모노포스포릴 리피드 A (MPL), CpG-ODN 등을 들 수 있다. RLR 아고니스트로는, pppRNA, Poly IC RNA 등, STING 아고니스트로는 cGAMP, c-di-AMP, c-di-GMP 등, NLR 아고니스트로는 iE-DAP, FK565, MDP, 무라부티드 등, CLR 아고니스트로는 베타글루칸, 트레할로스 6,6'-디미콜레이트 등을 들 수 있다. 아쥬반트는, 바람직하게는 TLR 아고니스트이고, 보다 바람직하게는 TLR4 아고니스트, TLR7 아고니스트 또는 TLR9 아고니스트이고, 보다 더 바람직하게는 이미퀴모드, 레시퀴모드, MPL 또는 CpG-ODN 이다. 어느 양태에 있어서, 아쥬반트는, 이미퀴모드, MPL 또는 CpG-ODN 이다. 아쥬반트로는, 펩티드/폴리뉴클레오티드 컨쥬게이트에 도입된 항원성을 갖는 펩티드 등에 따라서 적절히 선택되지만, 예를 들어 CpG DNA 등이어도 되고, 국제 공개 제2015/118789호에 기재된, 면역 부활 활성을 갖는 부분 염기 서열을 갖는 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체와, β-1,3-글루칸 골격을 갖는 다당이, 수소 결합을 통하여 결합하고, 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체의 분자쇄 1 개와 상기 β-1,3-글루칸 골격을 갖는 다당의 분자쇄 2 개로 이루어지는 삼중 나선 구조를 갖는 폴리뉴클레오티드/β-1,3-글루칸 복합체여도 된다.
의약 조성물은, 인간 또는 온혈 동물 (마우스, 래트, 토끼, 양, 돼지, 소, 말, 닭, 고양이, 개, 원숭이 등) 에 대하여, 경구 및 비경구 경로 중 어느 것에 의해서도 투여 가능하다. 비경구 투여 경로로는, 피하, 피내 및 근육중 주사, 복강내 투여, 점적, 비점막이나 인두부에 대한 분무 등을 들 수 있다.
의약 조성물의 유효 성분인 펩티드/폴리뉴클레오티드 컨쥬게이트의 용량은, 활성, 치료 대상이 되는 질환, 투여 대상이 되는 동물의 종류, 체중, 성별, 연령, 질환의 중증도, 투여 방법 등에 따라 상이하다. 체중 60 kg 의 성인을 예로 들면, 경구 투여의 경우, 1 일당 용량은 통상 약 0.1 ∼ 약 100 mg, 바람직하게는 약 1.0 ∼ 약 50 mg, 보다 바람직하게는 약 1.0 ∼ 약 20 mg 이고, 비경구 투여의 경우, 1 일당 용량은 통상 약 0.01 ∼ 약 30 mg, 바람직하게는 약 0.1 ∼ 약 20 mg, 보다 바람직하게는 약 0.1 ∼ 약 10 mg 이다. 다른 동물에 투여하는 경우에는, 상기 용량을 단위 체중당의 용량으로 환산 후, 투여 대상이 되는 동물의 체중을 곱하여 얻어진 용량을 사용한다.
본 실시 형태에 관련된 의약 조성물을, 병원체 감염증이나 암의 환자, 암이나 병원체 감염증으로 이환될 가능성이 있는 대상에 투여함으로써, 그 투여를 받은 대상 중의 세포 상해성 T 림프구 (CTL) 를 항원 특이적으로 활성화시켜, 상기 항원 특이적인 항체 생산을 유도하고, 즉, 온혈 동물 (바람직하게는, 인간) 의 방어 면역 반응을 유도함으로써, 그 감염증이나 암을 예방·치료할 수 있다. 즉, 상기 조성물은, 상기 감염증, 암 등의 질환의 예방 또는 치료를 위한 백신으로서 유용하다. 본 발명에서, 용어 「종양」 및 「암」은 교환 가능하게 사용된다. 또한, 본 발명에 있어서, 종양, 악성 종양, 암, 악성 신생물, 암종, 육종 등을 총칭하여, 「종양」 또는 「암」이라고 표현하는 경우가 있다. 또한, 용어 「종양」 및 「암」에는, 골수이형성 증후군 등, 경우에 따라서는 전암 단계로 구분되는 병태도 포함된다.
치료의 대상이 되는 종양의 종류는 본 발명의 의약 조성물에 감수성이 확인되는 종양이면 특별히 한정되지 않지만, 유방암, 결장암, 전립선암, 폐암 (소세포폐암, 비소세포폐암 등을 포함한다), 위암, 난소암, 자궁경부암, 자궁내막암, 자궁체암, 신장암, 간세포암, 갑상선암, 식도암, 골육종, 피부암 (멜라노마 등을 포함한다), 교아 세포종, 신경아 세포종, 난소암, 두경부암, 고환 종양, 대장암, 혈액암 (백혈병, 악성 림프종, 다발성 골수종 등을 포함한다), 망막아 세포종, 췌장암 등을 들 수 있다.
본 실시형태에 관련된 의약 조성물은, 다른 항종양제와 조합하여 사용해도 된다. 예를 들면, 항종양 항생 물질, 항종양성 식물 성분, BRM (Biological Response Modifier : 생물학적 응답성 제어 물질), 호르몬, 비타민, 항종양성 항체, 분자 표적약, 알킬화제, 대사 길항제 그 밖의 항종양제 등을 들 수 있다.
보다 구체적으로, 알킬화제로는, 예를 들면, 나이트로젠 머스타드, 나이트로젠 머스타드 N-옥시드, 벤다무스틴 또는 클로람부실 등의 알킬화제, 카르보콘 또는 티오테파 등의 아지리딘계 알킬화제, 디브로모만니톨 또는 디브로모둘시톨 등의 에폭사이드계 알킬화제, 카르무스틴, 로무스틴, 세무스틴, 니무스틴하이드로클로라이드, 스트렙토조신, 클로로조토신 또는 라니무스틴 등의 니트로소우레아계 알킬화제, 부술판, 토실산임프로술판, 테모졸로미드 또는 다카르바진 등을 들 수 있다.
각종 대사 길항제로는, 예를 들면 6-메르캅토퓨린, 6-티오구아닌 또는 티오이노신 등의 퓨린 대사 길항제, 플루오로우라실, 테가푸르, 테가푸르·우라실, 카르모푸르, 독시플루리딘, 브록스우리딘, 시타라빈 또는 에노시타빈 등의 피리미딘 대사 길항제, 메토트렉세이트 또는 트리메트렉세이트 등의 엽산 대사 길항제 등을 들 수 있다.
항종양성 항생 물질로는, 예를 들면, 마이토마이신 C, 블레오마이신, 페프로마이신, 다우노루비신, 아클라루비신, 독소루비신, 이다루비신, 피라루비신, THP-아드리아마이신, 4'-에피독소루비신 또는 에피루비신, 크로모마이신 A3 또는 악티노마이신 D 등을 들 수 있다.
항종양성 식물 성분 및 그들의 유도체로는, 예를 들어 빈데신, 빈크리스틴 혹은 빈블라스틴 등의 빈카 알카로이드류, 파클리탁셀, 도세탁셀, 카바지탁셀 등의 탁산류, 또는 에토포시드 혹은 테니포시드 등의 에피포도필로톡신류를 들 수 있다.
BRM 으로는, 예를 들면, 종양 괴사 인자 또는 인도메타신 등을 들 수 있다.
호르몬으로는, 예를 들어, 하이드로코르티손, 덱사메타손, 메틸프레드니솔론, 프레드니솔론, 프라스테론, 베타메타손, 트리암시놀론, 옥시메트론, 난드롤론, 메테놀론, 포스페스트롤, 에티닐에스트라디올, 클로르마디논, 메피티오스탄 또는 메드록시프로게스테론 등을 들 수 있다.
비타민으로는, 예를 들면 비타민 C 또는 비타민 A 등을 들 수 있다.
항종양성 항체, 분자 표적약으로는, 트라스투주맙, 리툭시맙, 세툭시맙, 파니투무맙, 니모투주맙, 데노수맙, 베바시주맙, 인플릭시맙, 이필리무맙, 니볼루맙, 펨브로리주맙, 아벨루맙, 피딜리주맙, 아테졸리주맙, 라무시루맙, 메실산이마티닙, 다사티닙, 수니티닙, 라파티닙, 다브라페닙, 트라메티닙, 코비메티닙, 파조파닙, 팔보시클립, 파노비노스탓, 소라페닙, 크리조티닙, 베무라페닙, 키잘티닙, 보테조밉, 카르필조밉, 익사조밉, 미도스타우린, 길테리티닙 등을 들 수 있다.
그 밖의 항종양제로는, 예를 들면 시스플라틴, 카르보플라틴, 옥살리플라틴, 타목시펜, 레트로졸, 아나스트로졸, 엑세메스탄, 토레미펜시트르산염, 풀베스트란트, 비카르타미드, 플루타미드, 미토탄, 류프로렐린, 고세렐린아세트산염, 캠토테신, 이포스파미드, 시클로포스파미드, 멜팔란, L-아스파라지나아제, 아세글라톤, 시조피란, 피시바닐, 프로카바진, 피포브로만, 네오카르지노스타틴, 하이드록시우레아, 우베니멕스, 탈리도마이드, 레날리도마이드, 포말리도마이드, 에리불린, 트레티노인 또는 크레스틴 등을 들 수 있다.
치료의 대상이 되는 감염증의 종류로는, 바이러스, 진균, 세균 등의 병원체에 의한 감염증이 예시된다. 바이러스로는, 인플루엔자 바이러스, 간염 바이러스, 인간 면역 부전 바이러스 (HIV), RS 바이러스, 풍진 바이러스, 홍역 바이러스, 유행성 이하선염 바이러스, 헤르페스 바이러스, 폴리오 바이러스, 로타 바이러스, 일본 뇌염 바이러스, 수두 바이러스, 아데노 바이러스, 광견병 바이러스, 황열병 바이러스 등이 예시된다. 세균으로는, 디프테리아균, 파상풍균, 백일해균, 인플루엔자균, 결핵균, 폐렴구균, 헬리코박터·필로리, 탄저균, 장티푸스균, 수막염균, 적리균, 콜레라균 등을 들 수 있다. 진균으로는, 칸디다 진균, 히스토플라즈마 진균, 크립토코커스 진균, 아스페르길루스 진균 등이 예시된다. 이들 감염증의 기존의 치료약과 본 발명의 의약 조성물은 조합하여 사용해도 된다.
본 실시 형태에 관련된 의약 조성물이, 아쥬반트나 다른 의약과 조합되어 투여되는 경우, 어느 일정 기간에 있어서, 피투여 대상이, 양 약제를 그 체내에 도입하는 것을 의미한다. 양 약제가 단일 제제 중에 포함된 제제가 투여되어도 되고, 또한 각각이 따로따로 제제화되어, 따로따로 투여되어도 된다. 따로따로 제제화되는 경우, 그 투여의 시기는 특별히 한정되지 않고, 동시에 투여되어도 되고, 시간을 두고 다른 시간에, 또는 다른 날에 투여되어도 된다. 각각 다른 시간 또는 날에 투여되는 경우, 그 투여의 순서는 특별히 한정되지 않는다. 통상, 각각의 제제는, 각각의 투여 방법에 따라서 투여되기 때문에, 그것들의 투여는, 동일 횟수가 되는 경우도 있고, 상이한 횟수가 되는 경우도 있다. 또한, 각각이 따로따로 제제화되는 경우, 각 제제의 투여 방법 (투여 경로) 은 동일해도 되고, 상이한 투여 방법 (투여 경로) 으로 투여되어도 된다. 또한, 양 약제가 동시에 체내에 존재할 필요는 없고, 어떤 일정 기간 (예를 들어 1 개월간, 바람직하게는 1 주일간, 더욱 바람직하게는 수 일간, 보다 더 바람직하게는 1 일간) 동안에 체내에 도입되어 있으면 되고, 어느 한쪽의 투여시에 다른 한쪽의 유효 성분이 체내로부터 소실되어 있어도 된다.
실시예
다음으로, 본 발명의 작용 효과를 확인하기 위해 실시한 실시예에 대해 설명한다. 또한, 본 실시예에 있어서, 「CpG DNA(S)」는 CpG 모티프를 포함하는 염기 서열을 갖고, 인산디에스테르 결합이 포스포로티오에이트 결합으로 치환된 DNA 유도체 (폴리뉴클레오티드 유도체의 일례) 를 나타낸다. 실시예에 기재한 화학 구조식에 있어서, 폴리뉴클레오티드 유도체는, 1 문자 염기 서열 표기 및 좌측이 5' 말단측 (우측이 3' 말단측) 이 되도록 표기하고, 펩티드는 N 말단의 시스테인 이외에는 3 문자 표기 및 좌측이 N 말단측 (우측이 C 말단측) 이 되도록 표기하고 있다. 1 문자 염기 서열 표기한 폴리뉴클레오티드 유도체에 있어서, 인산디에스테르 결합은 모두 포스포로티오에이트 결합으로 치환되어 있고, 또한 말단 구조는, 스페이서와 결합하고 있는 경우에는 말단 뉴클레오티드의 5' 또는 3' 수산기의 산소 원자까지를, 스페이서와 결합하고 있지 않은 경우에는 말단 뉴클레오티드의 5' 또는 3' 수산기 (수소 원자까지 포함한다) 를 의미한다. 또한, 본 실시예에 있어서의 CpG DNA(S)-펩티드 컨쥬게이트는, 트리에틸아민 및 아세트산이 부가된 염으로서 조제된다.
실시예 1 : CpG DNA(S)-펩티드 컨쥬게이트의 조제
임의의 공지된 방법으로 합성되는 아미노기 수식 CpG DNA(S) (5' 말단에 하기 식으로 나타내는 구조를 갖는 아미노기가 도입된 CpG DNA(S) 유도체. 염기 서열 : ATCGACTCTCGAGCGTTCTCATCGACTCTCGAGCGTTCTC (서열 번호 229 : 이하, 「CpG40(S)」라고 약칭한다」). 인산디에스테르 결합은 모두 포스포로티오에이트 결합이다.) 1 mol 과, 숙시이미딜 6-[3'-(2-피리딜디티오)-프로피온아미드]헥사노에이트 (LC-SPDP) 30 mol 을 인산 완충액 (pH 8.0) 중에서 혼합시켰다. 40 ℃ 에서 3 시간 가만히 정지시켜둔 후, NAP-5 칼럼을 사용하여 SPDP 수식 CpG DNA(S) 를 정제하였다.
[화학식 17]
하기 식으로 나타내는 구조를, 이하 「ssH 아미노 링커」라고 약칭한다.
[화학식 18]
SPDP 수식 CpG DNA(S) 1 mol 에 대하여, 25 mol 의 비율로, 오보알부민 (OVA) 유래의 항원성을 갖는 펩티드 (257 ∼ 264 번째의 아미노산; 아미노산 서열 : SIINFEKL : 서열 번호 196) 의 N 말단측에 시스테인을 부가한 펩티드 (아미노산 서열 : CSIINFEKL (서열 번호 250 : 이하, 「OVApep9」라고 약칭한다)) 를, 30 % N,N-디메틸포름아미드 (DMF) 수용액 중에서 혼합시켰다. 40 ℃ 에서 3 시간 가만히 정지시켜둔 후, HPLC 로 CpG DNA(S)-펩티드 컨쥬게이트를 분취하였다. HPLC 의 조건은 A 액을 0.1 M 아세트산트리에틸암모늄 (TEAA; pH 7.0), B 액을 아세토니트릴로 하고, 칼럼은 ZORBAX Eclipse Plus C18 을 사용하여 이하의 구배 조건으로 실시하였다.
0 분 A : 90 % B : 10 %
∼ 25 분 70 % 30 %
∼ 30 분 0 % 100 %
HPLC 를 사용한 SPDP 수식 CpG DNA(S) 와, OVA 유래 펩티드와의 반응 후의 용액의 분취에 있어서, 검출은 dA40(S) 의 260nm 의 흡수를 모니터함으로써 실시하였다. 분취 후의 CpG DNA(S)-펩티드 컨쥬게이트의 용출 시간은, SPDP 수식 CpG DNA(S) 보다 지연되는 것이 확인되었다. 이것은, 소수성의 펩티드와 결합함으로써 용출 시간이 지연되었기 때문으로 생각된다. 또한, 분취 후의 크로마토그램에는 미반응의 SPDP 수식 CpG DNA(S) 의 피크는 보이지 않고, CpG DNA(S)-펩티드 컨쥬게이트만의 피크가 검출된 것으로부터, 목적하는 CpG DNA(S)-펩티드 컨쥬게이트 (CpG40(S)-OVApep9 컨쥬게이트 : 구조식은 하기 참조) 가 순도높게 얻어진 것이 확인되었다.
[화학식 19]
실시예 2 : CpG DNA(S)-펩티드 컨쥬게이트에 의한 세포 상해성 T 세포 유도의 평가
항원으로서 CpG DNA(S)-펩티드 컨쥬게이트를, 마우스 (C57BL/6 마우스 (♂, 7 주령)) 에 피내 투여하였다 (1 마리당 20 ng, 1 회). 투여로부터 1 주일 후, 동 계통의 마우스 중, 투여를 실시하지 않은 개체로부터 비장 세포를 취출하고, 이것을 2 개의 군으로 나누어, 일방에, 항원으로서, 오보알부민 (난백 알부민, OVA) 유래의 항원성을 갖는 펩티드 (펩티드 서열; SIINFEKL : 서열 번호 196) 를 첨가하고, 90 분 가만히 정지시켜둠으로써 항원 보유 비장 세포를 제작하고, 펩티드를 첨가하지 않은 비장 세포를 항원 미보유 비장 세포로 하였다. 5,6-카르복시플루오레세인 숙시이미딜에스테르 (CFSE) 를 사용하여, 항원 보유 비장 세포 및 항원 미보유 비장 세포의 양자를 형광 수식하였다. 이때, CFSE 의 농도를 바꿈으로써, 항원 보유 비장 세포 (CFSE : 5 μM) 쪽이, 항원 미보유 비장 세포 (CFSE : 0.5 μM) 보다 형광 강도가 높아지도록 하였다. 투여 항원 보유 비장 세포, 항원 미보유 비장 세포를 각각 동수 혼합하고, 항원으로서 CpG DNA(S)-펩티드 컨쥬게이트를 투여한 마우스 개체에, 투여로부터 1 주일 후에 꼬리 정맥 투여하였다. CpG DNA(S)-펩티드 컨쥬게이트의 투여량은, 1 마리당 펩티드 환산으로 20 ng 으로 하였다 (이 경우, CpG40(S) 환산에서는 250 ng 이다).
상기한 꼬리 정맥 투여로부터 24 시간 경과 후에, 마우스로부터 비장 세포를 취출하고, 항원 보유 비장 세포와 항원 미보유 비장 세포의 비율을 플로 사이토메트리로 정량하여, 항원 보유 비장 세포의 감소량을 평가함으로써, 유도된 세포 상해성 T 세포의 활성을 평가하였다. 플로 사이토메트리의 측정 결과를 도 1 (도 1(b)) 에 나타낸다. 비교를 위해, CpG DNA(S)-펩티드 컨쥬게이트 대신에, 대조군으로서 PBS (인산 완충 생리 식염수) 를 투여한 마우스 개체 (도 1(a)), 항원성을 갖는 펩티드와 CpG DNA(S) 를 개별적으로 투여한 마우스 개체를 사용하여 동일한 조건으로 실시한 측정 결과를 함께 도 1 (도 1(c)) 에 나타낸다.
도 1(a) 에 나타내는 바와 같이, PBS 를 투여한 마우스 개체로부터 채취한 비장 세포에는, 항원 보유 비장 세포와 미보유 비장 세포의 비율이 동수 포함되어 있었지만, 도 1(b) 에 나타내는 바와 같이, CpG DNA(S)-펩티드 컨쥬게이트를 투여한 마우스 개체로부터 채취된 비장 세포로부터는, 항원 보유 비장 세포의 약 95 % 가 소실되어 있었다. 이것으로부터 CpG DNA(S)-펩티드 컨쥬게이트의 투여에 의해, 펩티드 항원에 특이적인 면역 응답이 유도되어 있음을 알 수 있다. 또한, 도 1(c) 와의 비교로부터, 그 효과는 항원성을 갖는 펩티드와 CpG DNA(S) 를 개별적으로 투여한 마우스 개체보다 높은 것을 알 수 있다.
실시예 3 : CpG DNA(S)-펩티드 컨쥬게이트의 투여량 의존성
CpG DNA(S)-펩티드 컨쥬게이트의 투여량을 변경하여 마우스에 면역시키고, 실시예 2 와 동일하게, 투여 항원 보유 비장 세포, 항원 미보유 비장 세포를 각각 동수 혼합한 것을 꼬리 정맥 투여한 마우스 개체로부터 채취한 비장 중의, 항원 보유 비장 세포, 항원 미보유 비장 세포의 비율을 플로 사이토메트리로 정량하여, 항원 보유 비장 세포의 감소량을 평가함으로써, 유도된 세포 상해성 T 세포의 활성을 평가하였다.
플로 사이토메트리의 측정 결과를 도 2 에 나타낸다. CpG DNA(S)-펩티드 컨쥬게이트의 투여량을 펩티드 환산으로 20 ng 보다 저감시키면, 서서히 그 효과가 없어지고 있는 것을 알 수 있다. 일반적인 펩티드 면역에서는 수 ㎍ 의 투여량을 필요로 하지만, 실시예 1 에서 제작한 CpG DNA(S)-펩티드 컨쥬게이트에서는, 그 투여량을 100 분의 1 ∼ 1000 분의 1 로 감소시키는 것에 성공하였다.
실시예 4 : CpG DNA(S)-펩티드 컨쥬게이트에 포함되는 CpG DNA(S) 의 염기 길이 및 염기 서열 의존성
CpG DNA(S)-펩티드 컨쥬게이트에 포함되는 CpG DNA(S) 로서, 실시예 1 에서 사용한 염기 길이 40 인 것 (염기 서열 : ATCGACTCTCGAGCGTTCTCATCGACTCTCGAGCGTTCTC (서열 번호 229 : 이하, 「CpG40(S)」라고 약칭한다)) 이외에, 염기 길이 30 인 것 (염기 서열 : GAGCGTTCTCATCGACTCTCGAGCGTTCTC (서열 번호 227 : 이하, 「CpG30(S)a」라고 약칭함) 인 것 및 염기 서열 : ATCGACTCTCGAGCGTTCTCGAGCGTTCTC (서열 번호 228 : 이하, 「CpG30(S)b」라고 약칭한다) 인 것, 염기 길이 24 인 것 (염기 서열 : TCTCGAGCGTTCTCGAGCGTTCTC (서열 번호 225 : 이하, 「CpG24(S)」라고 약칭한다) 인 것) 및 염기 길이 20 인 것 (서열 번호 222 : 염기 서열 : ATCGACTCTCGAGCGTTCTC (이하, 「CpG20(S)a」라고 약칭한다) 인 것 및 염기 서열 : GAGCGTTCTCGAGCGTTCTC (서열 번호 223 : 이하, 「CpG20(S)b」라고 약칭한다) 인 것) 대신에 (구조식은 하기 참조), 각각, 실시예 1 과 동일한 방법으로 CpG DNA(S)-펩티드 컨쥬게이트를 제작하였다 (구조식, 염기 서열에 대해서는 하기 식 및 하기 표 9 참조. 표 9 에 있어서, 굵은 글씨로 하선을 그은 염기 서열은 CpG 모티프이다. 인산디에스테르 결합은 모두 포스포로티오에이트 결합이다.)
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CpG DNA(S) 의 염기 길이가 상이한 CpG DNA(S)-펩티드 컨쥬게이트 (펩티드 환산으로 1 마리당 20 ng) 를 사용하여 마우스 개체를 면역시키고, 실시예 2 와 동일하게 마우스 개체에 꼬리 정맥 투여한 항원 보유 비장 세포, 항원 미보유 비장 세포의 비율을 플로 사이토메트리로 정량하여, 항원 보유 비장 세포의 감소량을 평가함으로써, 유도된 세포 상해성 T 세포의 활성을 평가하였다.
플로 사이토메트리의 측정 결과를 도 3, 4 에 나타낸다. CpG DNA(S) 의 염기 길이를 30 까지 짧게 해도, 항원 보유 비장 세포가 완전히 소실되어 있는 것을 알 수 있었다. CpG DNA(S) 의 염기 길이를 20 까지 감소시켰을 경우, CpG DNA(S) 에 포함되는 CpG 모티프의 수가 1 개뿐인 경우, 항원 보유 비장 세포의 감소는 보이지 않지만, CpG DNA(S) 에 포함되는 CpG 모티프의 수가 2 개인 경우, 항원 보유 비장 세포의 감소가 관측되어, 펩티드 특이적인 세포 장해성 T 세포의 활성이 유도되어 있는 것을 알 수 있다.
실시예 5 : CpG DNA(S)-펩티드 컨쥬게이트에 포함되는 펩티드의 아미노산 길이 의존성
실시예 1 에서 조제한 CpG DNA(S)-펩티드 컨쥬게이트에 있어서, 항원성을 갖는 펩티드를 N 말단측으로 연장하고, 아미노산 길이 18 (아미노산 서열 : CEVSGLEQLESIINFEKL (서열 번호 251 : 이하, 「OVApep18」이라고 약칭한다)), 아미노산 길이 27 (아미노산 서열 : CMSMLVLLPDEVSGLEQLESIINFEKL (서열 번호 252 : 이하, 「OVApep27」이라고 약칭한다)) 로 한 펩티드를 사용하여 CpG DNA(S)-펩티드 컨쥬게이트를 조제하고 (구조식은 하기 참조), 이것 (펩티드 환산으로 1 마리당 20 ng) 을 사용하여 마우스 개체를 면역시키고, 실시예 2 와 동일하게 마우스 개체에 꼬리 정맥 투여한 항원 보유 비세포, 항원 미보유 비장 세포의 비율을 플로 사이토메트리로 정량하여, 항원 보유 비장 세포의 감소량을 평가함으로써, 유도된 세포 상해성 T 세포의 활성을 평가하였다.
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플로 사이토메트리의 측정 결과를 도 5 에 나타낸다. 항원성을 갖는 펩티드의 아미노산 길이를 18 또는 27 까지 연장하면, 펩티드 특이적인 세포 장해성 T 세포의 활성이 저하되는 경향이 있는 것을 알 수 있다.
실시예 6 : CpG DNA(S)-펩티드 컨쥬게이트의 스페이서의 구조 및 펩티드의 결합 위치에 대한 의존성
실시예 1 에서 제조한 CpG DNA(S)-펩티드 컨쥬게이트에 있어서, ssH 아미노 링커를 하기 구조 (이하, 「C6 아미노 링커」라고 약칭한다) 로 변경한 CpG DNA(S)-펩티드 컨쥬게이트 (이하, 화합물 (I) 로 한다), CpG DNA(S) 와 ssH 아미노 링커 사이에 PEG 를 갖는 C18 스페이서를 삽입한 CpG DNA(S)-펩티드 컨쥬게이트, CpG DNA(S) 의 5' 측이 아니라 3' 말단에 화합물 (I) 과 동일한 스페이서 구조를 통하여 항원성을 갖는 펩티드가 공유 결합한 CpG DNA(S)-펩티드 컨쥬게이트를 사용하여, 실시예 2 와 동일한 순서에 의해, 유도된 세포 상해성 T 세포의 활성을 평가하였다. 그 결과, 어느 경우에 있어서도, 실시예 1 에서 조제한 CpG DNA(S)-펩티드 컨쥬게이트와 동일한 정도의 강한 펩티드 특이적인 세포 장해성 T 세포의 활성이 유도되어 있는 것이 확인되었다.
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실시예 7 : 복강 마크로파지에 있어서의 항원 제시량의 평가
마우스로부터 채취한 복강 마크로파지를 48 웰 플레이트에 취하고 (1.5 × 105 세포/웰), 아미노산 길이가 상이한 항원성을 갖는 펩티드 (OVApep9, OVApep18, OVApep27) 및 염기 길이가 상이한 CpG DNA(S) (CpG40(S), CpG30(S)a, CpG30(S)b, CpG20(S)a) 를 사용하여 조제한 CpG DNA(S)-펩티드 컨쥬게이트를 펩티드 환산 2 ㎍/㎖ 로 웰에 첨가하여, 24 시간 배양하였다. 배양 후, OVApep8 과 MHC 의 분자 복합체에 특이적인 항체 (피코에리트린 (PE) 으로 형광 표지 : (이하, 「PE labelled H-2Kb/FIINFEKL」이라고 약칭한다)) 를 첨가하고, 플로 사이토메트리로 항체가 결합된 복강 마크로파지의 정량을 실시하여, 항원 제시량의 평가를 실시하였다.
플로 사이토메트리의 측정 결과를 도 6 및 7 에 나타낸다. 이들 결과로부터, CpG DNA(S) 의 염기 길이가 항원 제시량에 미치는 영향은 거의 없는 것, 항원성을 갖는 펩티드의 아미노산 길이가 길어져 18 또는 27 이 되면, 항원 제시량이 감소하는 경향이 있는 것이 확인되었다. 또한, 도 7 에 「CpG40(S)-PEG-OVApep9」로 나타낸, 스페이서에 폴리옥시에틸렌기를 갖는 CpG40(S)-OVApep9 컨쥬게이트에 있어서, 스페이서에의 폴리옥시에틸렌기가 항원 제시량에 거의 영향을 미치지 않는 것이 확인되었다.
SEQUENCE LISTING
<110> The University of Kitakyushu
Daiichi Sankyo Company, Limited
<120> Immunostimulator containing immunogenic peptide-
ajuvant nucleotide conjugate and pharmaceutical
composition containing the same
<130> FA1511-19215
<150> JP 2018-186093
<151> 2018-09-28
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<212> PRT
<213> CMV
<400> 23
Gln Tyr Asp Pro Val Ala Ala Leu Phe
1 5
<210> 24
<211> 9
<212> PRT
<213> CMV
<400> 24
Val Leu Glu Glu Thr Ser Val Met Leu
1 5
<210> 25
<211> 9
<212> PRT
<213> CMV
<400> 25
Ala Tyr Ala Gln Lys Ile Phe Lys Ile
1 5
<210> 26
<211> 9
<212> PRT
<213> Influenza virus
<400> 26
Cys Thr Glu Leu Lys Leu Ser Asp Tyr
1 5
<210> 27
<211> 9
<212> PRT
<213> Influenza virus
<400> 27
Gly Ile Leu Gly Phe Val Phe Thr Leu
1 5
<210> 28
<211> 10
<212> PRT
<213> Influenza virus
<400> 28
Ile Leu Gly Phe Val Phe Thr Leu Thr Val
1 5 10
<210> 29
<211> 9
<212> PRT
<213> Influenza virus
<400> 29
Tyr Ile Gly Glu Val Leu Val Ser Val
1 5
<210> 30
<211> 10
<212> PRT
<213> Influenza virus
<400> 30
Lys Leu Gly Glu Phe Tyr Asn Gln Met Met
1 5 10
<210> 31
<211> 9
<212> PRT
<213> RSV
<400> 31
Tyr Leu Glu Lys Glu Ser Ile Tyr Tyr
1 5
<210> 32
<211> 9
<212> PRT
<213> RSV
<400> 32
Ser Tyr Ile Gly Ser Ile Asn Asn Ile
1 5
<210> 33
<211> 9
<212> PRT
<213> RSV
<400> 33
Lys Met Leu Lys Glu Met Gly Glu Val
1 5
<210> 34
<211> 9
<212> PRT
<213> RSV
<400> 34
Ala Ile Thr Thr Ile Leu Ala Ala Val
1 5
<210> 35
<211> 9
<212> PRT
<213> RSV
<400> 35
Ala Leu Leu Ser Thr Asn Lys Ala Val
1 5
<210> 36
<211> 9
<212> PRT
<213> RSV
<400> 36
Glu Leu Asp Lys Tyr Lys Asn Ala Val
1 5
<210> 37
<211> 9
<212> PRT
<213> RSV
<400> 37
Phe Leu Leu Gly Val Gly Ser Ala Ile
1 5
<210> 38
<211> 9
<212> PRT
<213> RSV
<400> 38
Phe Met Asn Tyr Thr Leu Asn Asn Thr
1 5
<210> 39
<211> 9
<212> PRT
<213> RSV
<400> 39
His Leu Glu Gly Glu Val Asn Lys Ile
1 5
<210> 40
<211> 9
<212> PRT
<213> RSV
<400> 40
Lys Ile Met Thr Ser Lys Thr Asp Val
1 5
<210> 41
<211> 9
<212> PRT
<213> RSV
<400> 41
Lys Ile Asn Gln Ser Leu Ala Phe Ile
1 5
<210> 42
<211> 9
<212> PRT
<213> RSV
<400> 42
Ser Val Tyr Asp Phe Phe Val Trp Leu
1 5
<210> 43
<211> 9
<212> PRT
<213> HIV
<400> 43
Arg Tyr Leu Lys Asp Gln Gln Leu Leu
1 5
<210> 44
<211> 10
<212> PRT
<213> HIV
<400> 44
Ser Leu Leu Asn Ala Thr Ala Ile Ala Val
1 5 10
<210> 45
<211> 9
<212> PRT
<213> HIV
<400> 45
Ser Leu Tyr Asn Thr Val Ala Thr Leu
1 5
<210> 46
<211> 9
<212> PRT
<213> HIV
<400> 46
Arg Thr Leu Asn Ala Trp Val Lys Val
1 5
<210> 47
<211> 8
<212> PRT
<213> HIV
<400> 47
Phe Leu Gly Lys Ile Trp Pro Ser
1 5
<210> 48
<211> 9
<212> PRT
<213> HIV
<400> 48
Thr Leu Asn Ala Trp Val Lys Val Val
1 5
<210> 49
<211> 9
<212> PRT
<213> HIV
<400> 49
Ser Leu Phe Asn Thr Val Ala Thr Leu
1 5
<210> 50
<211> 10
<212> PRT
<213> HIV
<400> 50
Ser Leu Tyr Asn Thr Val Ala Thr Leu Tyr
1 5 10
<210> 51
<211> 9
<212> PRT
<213> Polynomavirus
<400> 51
Leu Leu Met Trp Glu Ala Val Thr Val
1 5
<210> 52
<211> 9
<212> PRT
<213> Polynomavirus
<400> 52
Leu Leu Leu Ile Trp Phe Arg Pro Val
1 5
<210> 53
<211> 9
<212> PRT
<213> HTLV-1
<400> 53
Leu Leu Phe Gly Tyr Pro Val Tyr Val
1 5
<210> 54
<211> 9
<212> PRT
<213> HTLV-1
<400> 54
Ser Phe His Ser Leu His Leu Leu Phe
1 5
<210> 55
<211> 10
<212> PRT
<213> EBV
<400> 55
Asp Tyr Cys Asn Val Leu Asn Lys Glu Phe
1 5 10
<210> 56
<211> 9
<212> PRT
<213> EBV
<400> 56
Thr Leu Asp Tyr Lys Pro Leu Ser Val
1 5
<210> 57
<211> 9
<212> PRT
<213> EBV
<400> 57
Tyr Val Leu Asp His Leu Ile Val Val
1 5
<210> 58
<211> 9
<212> PRT
<213> EBV
<400> 58
Tyr Leu Leu Glu Met Leu Trp Arg Leu
1 5
<210> 59
<211> 9
<212> PRT
<213> EBV
<400> 59
Tyr Leu Gln Gln Asn Trp Trp Thr Leu
1 5
<210> 60
<211> 9
<212> PRT
<213> Homo sapiens
<400> 60
Gln Gln Ala His Cys Leu Trp Cys Val
1 5
<210> 61
<211> 9
<212> PRT
<213> Homo sapiens
<400> 61
Ala Leu Asp Val Tyr Asn Gly Leu Leu
1 5
<210> 62
<211> 9
<212> PRT
<213> Homo sapiens
<400> 62
Ala Leu Asn Val Tyr Asn Gly Leu Leu
1 5
<210> 63
<211> 9
<212> PRT
<213> Homo sapiens
<400> 63
Asn Leu Phe Glu Thr Pro Val Glu Ala
1 5
<210> 64
<211> 9
<212> PRT
<213> Homo sapiens
<400> 64
Gly Leu Gln His Trp Val Pro Glu Leu
1 5
<210> 65
<211> 9
<212> PRT
<213> Homo sapiens
<400> 65
Lys Leu Asp Val Gly Asn Ala Glu Val
1 5
<210> 66
<211> 10
<212> PRT
<213> Homo sapiens
<400> 66
Pro Leu Phe Asp Phe Ser Trp Leu Ser Leu
1 5 10
<210> 67
<211> 10
<212> PRT
<213> Homo sapiens
<400> 67
Tyr Leu Asn Arg His Leu His Thr Trp Ile
1 5 10
<210> 68
<211> 10
<212> PRT
<213> Homo sapiens
<400> 68
Trp Leu Ser Leu Lys Thr Leu Leu Ser Leu
1 5 10
<210> 69
<211> 9
<212> PRT
<213> Homo sapiens
<400> 69
Ala Leu Ser Pro Val Pro Pro Val Val
1 5
<210> 70
<211> 10
<212> PRT
<213> Homo sapiens
<400> 70
Tyr Leu Asn Asp His Leu Glu Pro Trp Ile
1 5 10
<210> 71
<211> 9
<212> PRT
<213> Homo sapiens
<400> 71
Cys Leu Pro Ser Pro Ser Thr Pro Val
1 5
<210> 72
<211> 9
<212> PRT
<213> Homo sapiens
<400> 72
Thr Leu Gln Asp Ile Val Tyr Lys Leu
1 5
<210> 73
<211> 11
<212> PRT
<213> Homo sapiens
<400> 73
Met Leu Met Ala Gln Glu Ala Leu Ala Phe Leu
1 5 10
<210> 74
<211> 9
<212> PRT
<213> Homo sapiens
<400> 74
Ala Leu Tyr Leu Met Glu Leu Thr Met
1 5
<210> 75
<211> 9
<212> PRT
<213> Homo sapiens
<400> 75
Tyr Leu Ile Ser Gly Asp Ser Pro Val
1 5
<210> 76
<211> 9
<212> PRT
<213> Homo sapiens
<400> 76
Tyr Leu Ser Gly Ala Asn Leu Asn Leu
1 5
<210> 77
<211> 9
<212> PRT
<213> Homo sapiens
<400> 77
Ile Leu Gly Val Leu Thr Ser Leu Val
1 5
<210> 78
<211> 10
<212> PRT
<213> Homo sapiens
<400> 78
Leu Leu Val Pro Thr Cys Val Phe Leu Val
1 5 10
<210> 79
<211> 9
<212> PRT
<213> Homo sapiens
<400> 79
Thr Leu Ala Asp Phe Asp Pro Arg Val
1 5
<210> 80
<211> 9
<212> PRT
<213> Homo sapiens
<400> 80
Tyr Met Cys Ser Phe Leu Phe Asn Leu
1 5
<210> 81
<211> 9
<212> PRT
<213> Homo sapiens
<400> 81
Ser Gln Ala Asp Ala Leu Lys Tyr Val
1 5
<210> 82
<211> 9
<212> PRT
<213> Homo sapiens
<400> 82
Ala Leu Val Cys Tyr Gly Pro Gly Ile
1 5
<210> 83
<211> 9
<212> PRT
<213> Homo sapiens
<400> 83
Gly Leu Phe Lys Cys Gly Ile Ala Val
1 5
<210> 84
<211> 8
<212> PRT
<213> Homo sapiens
<400> 84
Thr Leu Phe Trp Leu Leu Thr Leu
1 5
<210> 85
<211> 9
<212> PRT
<213> Homo sapiens
<400> 85
Glu Ile Trp Thr His Ser Tyr Lys Val
1 5
<210> 86
<211> 9
<212> PRT
<213> Homo sapiens
<400> 86
Phe Val Gly Glu Phe Phe Thr Asp Val
1 5
<210> 87
<211> 9
<212> PRT
<213> Homo sapiens
<400> 87
Lys Thr Trp Gly Gln Tyr Trp Gln Val
1 5
<210> 88
<211> 9
<212> PRT
<213> Homo sapiens
<400> 88
Ile Thr Asp Gln Val Pro Phe Ser Val
1 5
<210> 89
<211> 9
<212> PRT
<213> Homo sapiens
<400> 89
Ile Met Asp Gln Val Pro Phe Ser Val
1 5
<210> 90
<211> 9
<212> PRT
<213> Homo sapiens
<400> 90
Tyr Leu Glu Pro Gly Pro Val Thr Val
1 5
<210> 91
<211> 9
<212> PRT
<213> Homo sapiens
<400> 91
Gln Leu Phe Glu Glu Leu Gln Glu Leu
1 5
<210> 92
<211> 9
<212> PRT
<213> Homo sapiens
<400> 92
Leu Leu Leu Gly Pro Leu Gly Pro Leu
1 5
<210> 93
<211> 9
<212> PRT
<213> Homo sapiens
<400> 93
Ile Leu His Asp Gly Ala Tyr Ser Leu
1 5
<210> 94
<211> 10
<212> PRT
<213> Homo sapiens
<400> 94
Leu Ile Ala His Asn Gln Val Arg Gln Val
1 5 10
<210> 95
<211> 9
<212> PRT
<213> Homo sapiens
<400> 95
Lys Ile Phe Gly Ser Leu Ala Phe Leu
1 5
<210> 96
<211> 9
<212> PRT
<213> Homo sapiens
<400> 96
Ile Leu Ser Leu Glu Leu Met Lys Leu
1 5
<210> 97
<211> 9
<212> PRT
<213> Homo sapiens
<400> 97
Ala Leu Pro Phe Gly Phe Ile Leu Val
1 5
<210> 98
<211> 9
<212> PRT
<213> Homo sapiens
<400> 98
Ala Leu Leu Glu Ile Ala Ser Cys Leu
1 5
<210> 99
<211> 9
<212> PRT
<213> Homo sapiens
<400> 99
Ala Leu Met Glu Gln Gln His Tyr Val
1 5
<210> 100
<211> 10
<212> PRT
<213> Homo sapiens
<400> 100
Val Ile Ser Asn Asp Val Cys Ala Gln Val
1 5 10
<210> 101
<211> 10
<212> PRT
<213> Homo sapiens
<400> 101
Phe Ile Tyr Asp Phe Cys Ile Phe Gly Val
1 5 10
<210> 102
<211> 10
<212> PRT
<213> Homo sapiens
<400> 102
Gln Leu Cys Pro Ile Cys Arg Ala Pro Val
1 5 10
<210> 103
<211> 9
<212> PRT
<213> Homo sapiens
<400> 103
Tyr Leu Gln Gln Asn Trp Trp Thr Leu
1 5
<210> 104
<211> 10
<212> PRT
<213> Homo sapiens
<400> 104
Leu Leu Leu Ala Ser Ile Ala Ala Gly Leu
1 5 10
<210> 105
<211> 9
<212> PRT
<213> Homo sapiens
<400> 105
Gly Leu Tyr Asp Gly Met Glu His Leu
1 5
<210> 106
<211> 9
<212> PRT
<213> Homo sapiens
<400> 106
Lys Val Ala Glu Leu Val His Phe Leu
1 5
<210> 107
<211> 9
<212> PRT
<213> Homo sapiens
<400> 107
Phe Leu Ala Met Leu Lys Asn Thr Val
1 5
<210> 108
<211> 9
<212> PRT
<213> Homo sapiens
<400> 108
Phe Leu Trp Gly Pro Arg Ala Leu Val
1 5
<210> 109
<211> 10
<212> PRT
<213> Homo sapiens
<400> 109
Gly Val Tyr Asp Gly Arg Glu His Thr Val
1 5 10
<210> 110
<211> 9
<212> PRT
<213> Homo sapiens
<400> 110
Lys Val Leu Glu Tyr Val Ile Lys Val
1 5
<210> 111
<211> 10
<212> PRT
<213> Homo sapiens
<400> 111
Tyr Leu Gln Leu Val Phe Gly Ile Glu Val
1 5 10
<210> 112
<211> 10
<212> PRT
<213> Homo sapiens
<400> 112
Glu Leu Ala Gly Ile Gly Ile Leu Thr Val
1 5 10
<210> 113
<211> 9
<212> PRT
<213> Homo sapiens
<400> 113
Ser Leu Leu Phe Leu Leu Phe Ser Leu
1 5
<210> 114
<211> 9
<212> PRT
<213> Homo sapiens
<400> 114
Val Leu Pro Leu Thr Val Ala Glu Val
1 5
<210> 115
<211> 9
<212> PRT
<213> Homo sapiens
<400> 115
Ala Gln Cys Gln Glu Thr Ile Arg Val
1 5
<210> 116
<211> 9
<212> PRT
<213> Homo sapiens
<400> 116
Ser Leu Phe Leu Gly Ile Leu Ser Val
1 5
<210> 117
<211> 9
<212> PRT
<213> Homo sapiens
<400> 117
Gly Met Leu Gly Met Val Ser Gly Leu
1 5
<210> 118
<211> 9
<212> PRT
<213> Homo sapiens
<400> 118
Ser Leu Leu Met Trp Ile Thr Gln Cys
1 5
<210> 119
<211> 9
<212> PRT
<213> Homo sapiens
<400> 119
Ser Leu Leu Met Trp Ile Thr Gln Val
1 5
<210> 120
<211> 10
<212> PRT
<213> Homo sapiens
<400> 120
Tyr Leu Tyr Gln Trp Leu Gly Ala Pro Val
1 5 10
<210> 121
<211> 9
<212> PRT
<213> Homo sapiens
<400> 121
Tyr Leu Gly Ser Tyr Gly Phe Arg Leu
1 5
<210> 122
<211> 9
<212> PRT
<213> Homo sapiens
<400> 122
Lys Leu Cys Pro Val Gln Leu Trp Val
1 5
<210> 123
<211> 9
<212> PRT
<213> Homo sapiens
<400> 123
Ser Leu Pro Pro Pro Gly Thr Arg Val
1 5
<210> 124
<211> 11
<212> PRT
<213> Homo sapiens
<400> 124
Gly Leu Ala Pro Pro Gln His Leu Ile Arg Val
1 5 10
<210> 125
<211> 9
<212> PRT
<213> Homo sapiens
<400> 125
Leu Leu Gly Arg Asn Ser Phe Glu Val
1 5
<210> 126
<211> 9
<212> PRT
<213> Homo sapiens
<400> 126
Arg Met Pro Glu Ala Ala Pro Pro Val
1 5
<210> 127
<211> 9
<212> PRT
<213> Homo sapiens
<400> 127
Ser Thr Pro Pro Pro Gly Thr Arg Val
1 5
<210> 128
<211> 9
<212> PRT
<213> Homo sapiens
<400> 128
Tyr Leu Val Gly Asn Val Cys Ile Leu
1 5
<210> 129
<211> 10
<212> PRT
<213> Homo sapiens
<400> 129
Gln Leu Leu Asp Gly Phe Met Ile Thr Leu
1 5 10
<210> 130
<211> 9
<212> PRT
<213> Homo sapiens
<400> 130
Glu Leu Ser Asp Ser Leu Gly Pro Val
1 5
<210> 131
<211> 9
<212> PRT
<213> Homo sapiens
<400> 131
Ser Ile Asp Trp Phe Met Val Thr Val
1 5
<210> 132
<211> 9
<212> PRT
<213> Homo sapiens
<400> 132
Val Leu Gln Glu Leu Asn Val Thr Val
1 5
<210> 133
<211> 10
<212> PRT
<213> Homo sapiens
<400> 133
Ala Leu Tyr Val Asp Ser Leu Phe Phe Leu
1 5 10
<210> 134
<211> 9
<212> PRT
<213> Homo sapiens
<400> 134
Val Leu Asp Gly Leu Asp Val Leu Leu
1 5
<210> 135
<211> 9
<212> PRT
<213> Homo sapiens
<400> 135
Tyr Leu Gln Trp Ile Glu Phe Ser Ile
1 5
<210> 136
<211> 9
<212> PRT
<213> Homo sapiens
<400> 136
Lys Leu Gln Cys Val Asp Leu His Val
1 5
<210> 137
<211> 10
<212> PRT
<213> Homo sapiens
<400> 137
Phe Leu Thr Pro Lys Lys Leu Gln Cys Val
1 5 10
<210> 138
<211> 9
<212> PRT
<213> Homo sapiens
<400> 138
Ala Ile Leu Ala Leu Leu Pro Ala Leu
1 5
<210> 139
<211> 9
<212> PRT
<213> Homo sapiens
<400> 139
Gln Leu Gly Glu Gln Cys Trp Thr Val
1 5
<210> 140
<211> 9
<212> PRT
<213> Homo sapiens
<400> 140
Ser Leu Phe Glu Pro Pro Pro Pro Gly
1 5
<210> 141
<211> 9
<212> PRT
<213> Homo sapiens
<400> 141
Met Met Asn Asp Gln Leu Met Phe Leu
1 5
<210> 142
<211> 9
<212> PRT
<213> Homo sapiens
<400> 142
Val Leu Ala Gly Gly Phe Phe Leu Leu
1 5
<210> 143
<211> 10
<212> PRT
<213> Homo sapiens
<400> 143
Ala Leu Trp Pro Trp Leu Leu Met Ala Thr
1 5 10
<210> 144
<211> 9
<212> PRT
<213> Homo sapiens
<400> 144
Arg Leu Ala Glu Tyr Gln Ala Tyr Ile
1 5
<210> 145
<211> 9
<212> PRT
<213> Homo sapiens
<400> 145
Met Leu Ala Val Phe Leu Pro Ile Val
1 5
<210> 146
<211> 9
<212> PRT
<213> Homo sapiens
<400> 146
Leu Met Leu Gly Glu Phe Leu Lys Leu
1 5
<210> 147
<211> 9
<212> PRT
<213> Homo sapiens
<400> 147
Leu Thr Leu Gly Glu Phe Leu Lys Leu
1 5
<210> 148
<211> 10
<212> PRT
<213> Homo sapiens
<400> 148
Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu
1 5 10
<210> 149
<211> 9
<212> PRT
<213> Homo sapiens
<400> 149
Tyr Leu Ile Glu Leu Ile Asp Arg Val
1 5
<210> 150
<211> 10
<212> PRT
<213> Homo sapiens
<400> 150
Phe Leu Pro Ser Pro Leu Phe Phe Phe Leu
1 5 10
<210> 151
<211> 9
<212> PRT
<213> Homo sapiens
<400> 151
Phe Leu Phe Leu Arg Asn Phe Ser Leu
1 5
<210> 152
<211> 10
<212> PRT
<213> Homo sapiens
<400> 152
Tyr Leu Gln Val Asn Ser Leu Gln Thr Val
1 5 10
<210> 153
<211> 9
<212> PRT
<213> Homo sapiens
<400> 153
Ile Leu Ala Lys Phe Leu His Trp Leu
1 5
<210> 154
<211> 10
<212> PRT
<213> Homo sapiens
<400> 154
Ala Leu Leu Thr Ser Arg Leu Arg Phe Ile
1 5 10
<210> 155
<211> 9
<212> PRT
<213> Homo sapiens
<400> 155
Arg Leu Thr Ser Arg Val Lys Ala Leu
1 5
<210> 156
<211> 10
<212> PRT
<213> Homo sapiens
<400> 156
Gly Leu Leu Gly Ala Ser Val Leu Gly Leu
1 5 10
<210> 157
<211> 9
<212> PRT
<213> Homo sapiens
<400> 157
Arg Leu Ser Ser Cys Val Pro Val Ala
1 5
<210> 158
<211> 9
<212> PRT
<213> Homo sapiens
<400> 158
Phe Leu Tyr Asp Asp Asn Gln Arg Val
1 5
<210> 159
<211> 9
<212> PRT
<213> Homo sapiens
<400> 159
Gly Leu Ile Gln Leu Val Glu Gly Val
1 5
<210> 160
<211> 10
<212> PRT
<213> Homo sapiens
<400> 160
Ser Ile Leu Leu Arg Asp Ala Gly Leu Val
1 5 10
<210> 161
<211> 9
<212> PRT
<213> Homo sapiens
<400> 161
Leu Leu Leu Thr Val Leu Thr Val Val
1 5
<210> 162
<211> 9
<212> PRT
<213> Homo sapiens
<400> 162
Leu Leu Leu Leu Thr Val Leu Thr Val
1 5
<210> 163
<211> 9
<212> PRT
<213> Homo sapiens
<400> 163
Tyr Met Asp Gly Thr Met Ser Gln Val
1 5
<210> 164
<211> 9
<212> PRT
<213> Homo sapiens
<400> 164
Arg Met Phe Pro Asn Ala Pro Tyr Leu
1 5
<210> 165
<211> 9
<212> PRT
<213> Homo sapiens
<400> 165
Val Leu Asp Phe Ala Pro Pro Gly Ala
1 5
<210> 166
<211> 9
<212> PRT
<213> Homo sapiens
<400> 166
Ser Leu Gly Glu Gln Gln Tyr Ser Val
1 5
<210> 167
<211> 9
<212> PRT
<213> Homo sapiens
<400> 167
Cys Leu Trp Cys Val Pro Gln Leu Arg
1 5
<210> 168
<211> 9
<212> PRT
<213> Homo sapiens
<400> 168
Gly Val Arg Gly Arg Val Glu Glu Ile
1 5
<210> 169
<211> 9
<212> PRT
<213> Homo sapiens
<400> 169
Arg Leu Met Asn Asp Met Thr Ala Val
1 5
<210> 170
<211> 10
<212> PRT
<213> Homo sapiens
<400> 170
Lys Leu Met Ser Ser Asn Ser Thr Asp Leu
1 5 10
<210> 171
<211> 9
<212> PRT
<213> Homo sapiens
<400> 171
Leu Leu Thr Ala Ala Leu Trp Tyr Val
1 5
<210> 172
<211> 9
<212> PRT
<213> Homo sapiens
<400> 172
Asp Tyr Leu Gln Tyr Val Leu Gln Ile
1 5
<210> 173
<211> 9
<212> PRT
<213> Homo sapiens
<400> 173
Gly Tyr Cys Thr Gln Ile Gly Ile Phe
1 5
<210> 174
<211> 9
<212> PRT
<213> Homo sapiens
<400> 174
Glu Tyr Arg Ala Leu Gln Leu His Leu
1 5
<210> 175
<211> 9
<212> PRT
<213> Homo sapiens
<400> 175
Glu Tyr Tyr Glu Leu Phe Val Asn Ile
1 5
<210> 176
<211> 9
<212> PRT
<213> Homo sapiens
<400> 176
Ile Tyr Thr Trp Ile Glu Asp His Phe
1 5
<210> 177
<211> 9
<212> PRT
<213> Homo sapiens
<400> 177
Glu Tyr Ile Leu Ser Leu Glu Glu Leu
1 5
<210> 178
<211> 9
<212> PRT
<213> Homo sapiens
<400> 178
Val Tyr Phe Phe Leu Pro Asp His Leu
1 5
<210> 179
<211> 9
<212> PRT
<213> Homo sapiens
<400> 179
Lys Trp Leu Ile Ser Pro Val Lys Ile
1 5
<210> 180
<211> 10
<212> PRT
<213> Homo sapiens
<400> 180
Lys Leu Arg Gly Glu Val Lys Gln Asn Leu
1 5 10
<210> 181
<211> 9
<212> PRT
<213> Homo sapiens
<400> 181
Val Tyr Tyr Asn Trp Gln Tyr Leu Leu
1 5
<210> 182
<211> 10
<212> PRT
<213> Homo sapiens
<400> 182
Lys Tyr Tyr Leu Arg Val Arg Pro Leu Leu
1 5 10
<210> 183
<211> 9
<212> PRT
<213> Homo sapiens
<400> 183
Val Tyr Leu Arg Val Arg Pro Leu Leu
1 5
<210> 184
<211> 10
<212> PRT
<213> Homo sapiens
<400> 184
Arg Tyr Cys Asn Leu Glu Gly Pro Pro Ile
1 5 10
<210> 185
<211> 9
<212> PRT
<213> Homo sapiens
<400> 185
Glu Tyr Cys Pro Gly Gly Asn Leu Phe
1 5
<210> 186
<211> 10
<212> PRT
<213> Homo sapiens
<400> 186
Arg Tyr Asn Ala Gln Cys Gln Glu Thr Ile
1 5 10
<210> 187
<211> 9
<212> PRT
<213> Homo sapiens
<400> 187
Val Tyr Gly Ile Arg Leu Glu His Phe
1 5
<210> 188
<211> 9
<212> PRT
<213> Homo sapiens
<400> 188
Leu Tyr Gln Trp Leu Gly Ala Pro Val
1 5
<210> 189
<211> 10
<212> PRT
<213> Homo sapiens
<400> 189
Asp Tyr Leu Asn Glu Trp Gly Ser Arg Phe
1 5 10
<210> 190
<211> 9
<212> PRT
<213> Homo sapiens
<400> 190
Cys Tyr Ala Ser Gly Trp Gly Ser Ile
1 5
<210> 191
<211> 9
<212> PRT
<213> Homo sapiens
<400> 191
Asn Tyr Gln Pro Val Trp Leu Cys Leu
1 5
<210> 192
<211> 9
<212> PRT
<213> Homo sapiens
<400> 192
Ala Tyr Ala Cys Asn Thr Ser Thr Leu
1 5
<210> 193
<211> 9
<212> PRT
<213> Homo sapiens
<400> 193
Ser Tyr Arg Asn Glu Ile Ala Tyr Leu
1 5
<210> 194
<211> 9
<212> PRT
<213> Homo sapiens
<400> 194
Ala Phe Leu Pro Trp His Arg Leu Phe
1 5
<210> 195
<211> 9
<212> PRT
<213> Homo sapiens
<400> 195
Cys Tyr Thr Trp Asn Gln Met Asn Leu
1 5
<210> 196
<211> 8
<212> PRT
<213> Gallus gallus domesticus
<400> 196
Ser Ile Ile Asn Phe Glu Lys Leu
1 5
<210> 197
<211> 9
<212> PRT
<213> Mus musculus
<400> 197
Glu Gly Ser Arg Asn Gln Asp Trp Leu
1 5
<210> 198
<211> 9
<212> PRT
<213> Homo sapiens
<400> 198
Lys Val Pro Arg Asn Gln Asp Trp Leu
1 5
<210> 199
<211> 9
<212> PRT
<213> Homo sapiens
<400> 199
Ser Pro Ser Tyr Val Tyr His Gln Phe
1 5
<210> 200
<211> 9
<212> PRT
<213> Influenza A virus
<400> 200
Ile Tyr Ser Thr Val Ala Ser Ser Leu
1 5
<210> 201
<211> 9
<212> PRT
<213> Influenza A virus
<400> 201
Ala Ser Asn Glu Asn Met Asp Thr Met
1 5
<210> 202
<211> 10
<212> PRT
<213> Influenza A virus
<400> 202
Ser Ser Leu Glu Asn Phe Arg Ala Tyr Val
1 5 10
<210> 203
<211> 8
<212> PRT
<213> Homo sapiens
<400> 203
Asp Ala Pro Ile Tyr Thr Asn Val
1 5
<210> 204
<211> 8
<212> PRT
<213> Mouse leukemogenic retrovirus
<400> 204
Lys Ser Pro Trp Phe Thr Thr Leu
1 5
<210> 205
<211> 9
<212> PRT
<213> Sendai virus
<400> 205
Phe Ala Pro Gly Asn Tyr Pro Ala Leu
1 5
<210> 206
<211> 9
<212> PRT
<213> Mouse cytomegalovirus 1
<400> 206
Tyr Pro His Phe Met Pro Thr Asn Leu
1 5
<210> 207
<211> 9
<212> PRT
<213> Lymphocytic choriomeningitis virus
<400> 207
Lys Ala Val Tyr Asn Phe Ala Thr Met
1 5
<210> 208
<211> 9
<212> PRT
<213> Lymphocytic choriomeningitis virus
<400> 208
Phe Gln Pro Gln Asn Gly Gln Phe Ile
1 5
<210> 209
<211> 9
<212> PRT
<213> Lymphocytic choriomeningitis virus
<400> 209
Arg Pro Gln Ala Ser Gly Val Tyr Met
1 5
<210> 210
<211> 9
<212> PRT
<213> Plasmodium malariae
<400> 210
Ser Tyr Ile Pro Ser Ala Glu Lys Ile
1 5
<210> 211
<211> 10
<212> PRT
<213> Human immunodeficiency virus
<400> 211
Arg Gly Pro Gly Arg Ala Phe Val Thr Ile
1 5 10
<210> 212
<211> 9
<212> PRT
<213> Mycobacterium bovis
<400> 212
Gly Gly Pro His Ala Val Tyr Leu Leu
1 5
<210> 213
<211> 8
<212> PRT
<213> Homo sapiens
<400> 213
Glu Ala Gln Asn Thr Thr Tyr Leu
1 5
<210> 214
<211> 9
<212> PRT
<213> Mus musculus
<400> 214
Leu Pro Tyr Leu Gly Trp Leu Val Phe
1 5
<210> 215
<211> 12
<212> PRT
<213> Hepatitis B virus
<400> 215
Ile Pro Gln Ser Leu Asp Ser Trp Trp Thr Ser Leu
1 5 10
<210> 216
<211> 8
<212> PRT
<213> herpes simplex virus 1
<400> 216
Ser Ser Ile Glu Phe Ala Arg Leu
1 5
<210> 217
<211> 9
<212> PRT
<213> Homo sapiens
<400> 217
Trp Met His His Asn Met Asp Leu Ile
1 5
<210> 218
<211> 9
<212> PRT
<213> artificial
<220>
<223> an epitope derived from enhanced green fluorescent protein
<400> 218
His Tyr Leu Ser Thr Gln Ser Ala Leu
1 5
<210> 219
<211> 9
<212> PRT
<213> Homo sapiens
<400> 219
Thr Tyr Leu Pro Thr Asn Ala Ser Leu
1 5
<210> 220
<211> 8
<212> PRT
<213> Vesicular stomatitis virus
<400> 220
Arg Gly Tyr Val Tyr Gln Gly Leu
1 5
<210> 221
<211> 9
<212> PRT
<213> Polyomavirus
<400> 221
Arg Arg Leu Gly Arg Thr Leu Leu Leu
1 5
<210> 222
<211> 20
<212> DNA
<213> Artificial Sequence
<400> 222
atcgactctc gagcgttctc 20
<210> 223
<211> 20
<212> DNA
<213> Artificial Sequence
<400> 223
gagcgttctc gagcgttctc 20
<210> 224
<211> 21
<212> DNA
<213> Artificial Sequence
<400> 224
cgagcgttct cgagcgttct c 21
<210> 225
<211> 24
<212> DNA
<213> Artificial Sequence
<400> 225
tctcgagcgt tctcgagcgt tctc 24
<210> 226
<211> 27
<212> DNA
<213> Artificial Sequence
<400> 226
gactctcgag cgttctcgag cgttctc 27
<210> 227
<211> 30
<212> DNA
<213> Artificial Sequence
<400> 227
gagcgttctc atcgactctc gagcgttctc 30
<210> 228
<211> 30
<212> DNA
<213> Artificial Sequence
<400> 228
atcgactctc gagcgttctc gagcgttctc 30
<210> 229
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 229
atcgactctc gagcgttctc atcgactctc gagcgttctc 40
<210> 230
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 230
ctcagcgttc tcagcgttct cagcgttctc 30
<210> 231
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 231
tttagcgttt ttagcgtttt tagcgttttt 30
<210> 232
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 232
ttagcgttta gcgtttagcg tttagcgttt 30
<210> 233
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 233
ttagcgttta gcgtttagcg tttagcgttt 30
<210> 234
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 234
tcagcgtttc agcgtttcag cgtttc 26
<210> 235
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 235
ttagcgtttt agcgttttag cgtttt 26
<210> 236
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 236
tccatgacgt tcctgatgct 20
<210> 237
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 237
tgacgttcct tccatgacgt tcctgatgct 30
<210> 238
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 238
tccatgacgt tcctgatgct tccatgacgt tcctgatgct 40
<210> 239
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 239
tccatgacgt tcctgacgtt 20
<210> 240
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 240
tgacgttcct tccatgacgt tcctgacgtt 30
<210> 241
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 241
tccatgacgt tcctgacgtt tccatgacgt tcctgacgtt 40
<210> 242
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 242
tcgtcgtttt gtcgttttgt cgtt 24
<210> 243
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 243
gtcgtttcgt cgttttgtcg ttttgtcgtt 30
<210> 244
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 244
tcgtcgtttt gtcgtttcgt cgttttgtcg ttttgtcgtt 40
<210> 245
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 245
tcgacgttcg tcgttcgtcg ttc 23
<210> 246
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 246
tcgtcgttcg acgttcgtcg ttcgtcgttc 30
<210> 247
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 247
gttcgtcgtt tcgtcgttcg acgttcgtcg ttcgtcgttc 40
<210> 248
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 248
tcgcgacgtt cgcccgacgt tcggta 26
<210> 249
<211> 40
<212> DNA
<213> Artificial Sequence
<400> 249
tcgcgacgtt cgcgacgttc gcccgacgtt cggta 35
<210> 250
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 250
Cys Ser Ile Ile Asn Phe Glu Lys Leu
1 5
<210> 251
<211> 18
<212> PRT
<213> Artificial Sequence
<400> 251
Cys Glu Val Ser Gly Leu Glu Gln Leu Glu Ser Ile Ile Asn Phe Glu
1 5 10 15
Lys Leu
<210> 252
<211> 27
<212> PRT
<213> Artificial Sequence
<400> 252
Cys Met Ser Met Leu Val Leu Leu Pro Asp Glu Val Ser Gly Leu Glu
1 5 10 15
Gln Leu Glu Ser Ile Ile Asn Phe Glu Lys Leu
20 25
Claims (16)
- CpG 모티프를 포함하는 1 본쇄 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체와, 항원성을 갖는 펩티드가, 일단측에서 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체와 공유 결합하고 타단측에서 상기 항원성을 갖는 펩티드와 공유 결합한 스페이서를 통하여 결합한 폴리뉴클레오티드/펩티드 컨쥬게이트를 유효 성분으로서 포함하는 면역 유도제.
- 제 1 항에 있어서,
상기 항원성을 갖는 펩티드의 아미노산 길이가 5 이상 30 이하인 것을 특징으로 하는 면역 유도제. - 제 1 항 또는 제 2 항에 있어서,
상기 항원성을 갖는 펩티드의 아미노산 길이가 8 이상 11 이하인 것을 특징으로 하는 면역 유도제. - 제 1 항 내지 제 3 항 중 어느 한 항에 있어서,
상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체가 2 이상의 CpG 모티프를 포함하는 폴리데옥시리보뉴클레오티드 (DNA) 또는 DNA 유도체인 것을 특징으로 하는 면역 유도제. - 제 1 항 내지 제 4 항 중 어느 한 항에 있어서,
상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체의 염기 길이가 15 이상 40 이하인 것을 특징으로 하는 면역 유도제. - 제 1 항 내지 제 5 항 중 어느 한 항에 있어서,
상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체의 염기 길이가 20 이상 30 이하인 것을 특징으로 하는 면역 유도제. - 제 1 항 내지 제 6 항 중 어느 한 항에 있어서,
상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체가, 인산디에스테르 결합의 적어도 일부가 포스포로티오에이트 결합으로 치환된 폴리뉴클레오티드 유도체인 것을 특징으로 하는 면역 유도제. - 제 7 항에 있어서,
상기 인산디에스테르 결합의 적어도 일부가 포스포로티오에이트 결합으로 치환된 폴리뉴클레오티드 유도체에 있어서, 인산디에스테르 결합의 50 % 이상이 포스포로티오에이트 결합으로 치환되어 있는 것을 특징으로 하는 면역 유도제. - 제 7 항 또는 제 8 항에 있어서,
상기 인산디에스테르 결합의 적어도 일부가 포스포로티오에이트 결합으로 치환된 폴리뉴클레오티드 유도체에 있어서, 인산디에스테르 결합의 90 % 이상이 포스포로티오에이트 결합으로 치환되어 있는 것을 특징으로 하는 면역 유도제. - 제 1 항 내지 제 9 항 중 어느 한 항에 있어서,
상기 스페이서와 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체 사이의 공유 결합 및 상기 스페이서와 상기 항원성을 갖는 펩티드 사이의 공유 결합의 일방 또는 양방이 생체 환경 중에서 절단 가능한 공유 결합인 것을 특징으로 하는 면역 유도제. - 제 10 항에 있어서,
상기 폴리뉴클레오티드/펩티드 컨쥬게이트를 구성하는 상기 항원성을 갖는 펩티드와, 상기 폴리뉴클레오티드 또는 폴리뉴클레오티드 유도체에 결합한 상기 스페이서가, 상기 항원성을 갖는 펩티드의 N 말단의 시스테인 잔기의 티올기와 상기 스페이서가 갖는 티올기의 반응에 의해 생성된 공유 결합 (디술피드 결합) 을 통하여 결합하고 있는 것을 특징으로 하는 면역 유도제. - 제 1 항 내지 제 13 항 중 어느 한 항에 있어서,
아쥬반트로서, 면역 부활 활성을 갖는 물질을 추가로 포함하는 것을 특징으로 하는 면역 유도제. - 제 1 항 내지 제 14 항 중 어느 한 항에 기재된 면역 유도제를 포함하는 의약 조성물.
- 제 1 항 내지 제 14 항 중 어느 한 항에 기재된 면역 유도제를 포함하는 종양 치료를 위한 의약 조성물.
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- 2019-09-27 AU AU2019351458A patent/AU2019351458A1/en active Pending
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AU2019351458A1 (en) | 2021-05-20 |
EP3858383A1 (en) | 2021-08-04 |
JPWO2020067400A1 (ja) | 2021-08-30 |
EP3858383A4 (en) | 2022-09-21 |
JP7471600B2 (ja) | 2024-04-22 |
US20220031839A1 (en) | 2022-02-03 |
CA3114149A1 (en) | 2020-04-02 |
BR112021005601A2 (pt) | 2021-06-29 |
CN112839674A (zh) | 2021-05-25 |
WO2020067400A1 (ja) | 2020-04-02 |
TW202027786A (zh) | 2020-08-01 |
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