KR20180019543A - 캡시드(Capsid) - Google Patents
캡시드(Capsid) Download PDFInfo
- Publication number
- KR20180019543A KR20180019543A KR1020177035515A KR20177035515A KR20180019543A KR 20180019543 A KR20180019543 A KR 20180019543A KR 1020177035515 A KR1020177035515 A KR 1020177035515A KR 20177035515 A KR20177035515 A KR 20177035515A KR 20180019543 A KR20180019543 A KR 20180019543A
- Authority
- KR
- South Korea
- Prior art keywords
- gly
- asn
- pro
- thr
- ser
- Prior art date
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- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract description 33
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Abstract
본 발명은 서열번호 3의 서열과 98 % 이상의 상동성 또는 서열번호 4의 서열과 94 % 이상의 상동성을 갖는 아미노산 서열을 갖는, AAV 캡시드 단백질에 관한 것이다. 또한 약학적 조성물, AAV 캡시드 및 캡시드 단백질을 포함하는 바이러스 입자, 캡시드 단백질을 암호화하는 염기서열을 포함하는 재조합 AAV 벡터, 및 캡시드 단백질 또는 벡터를 포함하는 숙주 세포 및 형질전환 동물에 관한 것이다. 또한, 재조합 AAV 벡터를 포유류에 도입하는 단계;를 포함하는 목적 핵산을 포유류로 전달하는 방법으로, 상기 재조합 AAV 벡터는 캡시드 단백질을 포함하는 캡시드 내에 둘러싸여진 목적 유전자를 포함하는 것인, 방법에 관한 것이다.
Description
본 발명은 아데노-관련 바이러스(adeno-associated virus, AAV) 캡시드 변이체에 관한 것이다.
최근 여러 바이러스에 기초한 다중 재조합 유전자 전달 벡터(Multiple recombinant gene transfer vectors)가 개발되었다. 아데노-관련 바이러스 (AAV)에 기초한 유전자 전달 벡터, 즉 AAV 벡터는 상이한 조직의 분열 및 비분열 세포의 여러 다른 유형들에 형질을 도입시키는 능력과 안정적으로 장기간의 형질도입 유전자 발현을 확립하는 능력 때문에 바람직하다. 아데노바이러스(adenoviruses) 및 레트로바이러스(retroviruses)와 같은 다른 바이러스를 기초로 하는 벡터는 어떠한 바람직한 특성을 가질 수 있는 반면에, 바람직하지 않은 부작용들과도 관련되어 있다. 이러한 부작용들은 AAV 를 기초로 한 유전자 전달 벡터에서는 검출되지 않았다 (Manno et al., Nature Medicine, 12(3):342 (2006)).
많은 AAV 혈청형들이 확인되고, 복제되고, 서열화되었으며, 벡터로 변환되어 왔다. 이러한 혈청형은 AAV8, AAV5, AAV3B 및 더 최근에 기술된 AAV-LK03(WO 2013/029030)을 포함한다. 그러나, 본 발명자들은 현재 사용되는 많은 벡터들이 인간에 있어서 낮은 형질도입율을 갖는 것을 발견하였다. 예를 들어, AAV8 벡터는 마우스와 비교하여 사람에서 20 배 더 낮은 형질도입을 가질뿐만 아니라, 일시적이고, 프레드니솔론 반응성(prednisolone responsive) 및 고농도 코호트(cohort)의 2/3 에서 발생하는 트랜스아미니티스(transaminitis)를 갖는다. 따라서, 더 넓은 범위의 임상 적용성을 촉진시킬 뿐만 아니라 효능 및 안정성을 개선시킬 수 있는 새로운 AAV 벡터에 대한 필요성이 요구된다.
마침내 본 발명자들은 (1) AAV8, (2) AAV5, (3) AAV3B, 및 (4) AAV-LK03 4 개의 상이한 AAV 캡시드 유래의 다양한 도메인을 경험에 기인하여 맞바꿈으로써 새로운 하이브리드 캡시드를 개발하였다. 개발된 캡시드는 현재 사용되는 벡터들과 비교하여 유전자 전달을 5 배 더 높은 수준까지 달성할 수 있다.
본 발명자들은 상대적으로 높은 형질도입 속도 및 최소의 부작용을 갖는 AAV 벡터를 확립하기 위해 연구 프로그램을 설계하였다. 결과적으로, 본 발명자들은 새로운 하이브리드 캡시드 및 벡터를 개발하였다.
본 발명의 첫번째 양상은, 서열번호 3의 서열과 98 % 이상의 상동성 또는 서열번호 4의 서열과 94 % 이상의 상동성을 갖는 아미노산 서열을 갖는, AAV 캡시드 단백질을 제공하는 것이다.
본 발명자들은 놀랍게도 신규한 캡시드 단백질이 현재 사용되는 AAV 벡터보다 높은 형질도입 속도를 제공하는 캡시드를 생성한다는 것을 발견했다. 게다가, 환자 내 캡시드에 대한 항체의 보유 정도는 현재 사용되는 일부 AAV 벡터보다 더 낮다는 것을 확인하였다.
일부 실시 양태에서, 상기 아미노산 서열은 서열번호 4의 서열과 95 % 이상의 상동성을 갖는다. 특정 실시 양태에서, 상기 아미노산 서열은 서열번호 4의 서열과 96 % 이상의 상동성을 갖는다. 또다른 실시 양태에서, 상기 아미노산 서열은 서열번호 4의 서열과 97 % 이상의 상동성을 갖는다. 일부 실시 양태에서는, 상기 아미노산 서열은 서열번호 4의 서열과 98 % 이상의 상동성을 갖는다. 다른 실시 양태에서, 상기 아미노산 서열은 서열번호 4의 서열과 99 % 이상의 상동성을 갖는다. 특정 실시 양태에서, 상기 아미노산 서열은 서열번호 4의 서열을 갖는다.
일부 실시 양태에서, 상기 아미노산 서열은 서열번호 3의 서열과 98.5 % 이상의 상동성, 바람직하게는 서열번호 3의 서열과 99 % 이상의 상동성, 보다 바람직하게는 서열번호 3의 서열과 99.5 % 이상의 상동성을 갖는다. 특정 실시 양태에서, 상기 아미노산 서열은 서열번호 3의 서열을 갖는다.
일부 실시 양태에서, 상기 아미노산 서열은 서열번호 3의 서열과 상동성을 갖는다. 다른 실시 양태에서, 상기 아미노산 서열은 서열번호 4의 서열과 상동성을 갖는다. 바람직한 실시 양태에서, 상기 아미노산 서열은 서열번호 4의 서열을 갖는다. 더 바람직하게는, 상기 아미노산 서열은 서열번호 3의 서열을 갖는다.
상기 정의된 아미노산 서열을 갖는 캡시드 단백질은 다른 필요로 하는 캡시드 단백질에 덧붙여 기능성 캡시드를 형성할 수 있는 기능성 캡시드 단백질이다. 기능성 캡시드는 유전 물질을 둘러쌀 수 있고, 세포에 들어갈 수 있으며, 유전 물질과 함께 세포에 형질도입할 수 있는 것이다. 캡시드가 기능성인지의 여부를 확인하는 것은 숙련된 사람의 역량 내에서 충분할 것이다. 예를 들어, 본 발명의 상세한 설명에서 후술되는 실험들은 캡시드가 성공적으로 세포에 형질도입 할 수 있는지 여부를 확인하는 데 사용될 수 있다.
서열번호 3은 AAV8 VP1 영역을 포함하는 146 아미노산 영역을 AAV3B 캡시드의 VP2 및 VP3 도메인 업스트림에 클로닝함으로써 생성하였다. 서열번호 4는 AAV3B VP2 및 VP3 영역의 AAV5 VP1 영역 업스트림을 클로닝함으로써 생성하였다. AAV 혈청형 및 캡시드 단백질의 추가적인 세부사항은 하기에 제공한다.
본 발명의 두번째 양상은, 상기 AAV 캡시드 단백질을 포함하는, AAV 캡시드를 제공하는 것이다. AAV 캡시드는 VP1, VP2 및 VP3 단백질로 구성되며 바이러스의 유전 물질을 캡슐화(또는 포함)하는 단백질 껍질(protein shell)이다.
또한, 상기 AAV 캡시드 단백질을 포함하는, 바이러스 입자를 제공한다. 상기 바이러스 입자는 AAV 캡시드 및 바이러스의 유전 물질을 포함한다.
본 발명의 세번째 양상은, 상기 아미노산 서열을 암호화하는 염기서열을 포함하는, 재조합 AAV(recombinant AAV, rAAV) 벡터를 제공하는 것이다. 이는 상기 벡터가 기능성 캡시드 단백질을 암호화하는 염기서열을 포함한다는 것을 의미한다.
바람직하게는, 상기 벡터는 상기 염기서열이 발현 가능하도록 하는 프로모터를 더 포함한다. 바람직하게는, 상기 벡터는 대부분의 포유류 세포 유형 내에서 구조적으로 활성인 AAV2 p40 바이러스 프로모터를 포함한다.
따라서, 본 발명은 보통 인간(예를 들어, 혈청형 1, 2, 3A, 3B, 4, 5 및 6) 또는 영장류(예를 들어, 혈청형 1 및 4)를 감염시키는 아데노 관련 바이러스(AAV)를 기반으로 한 유전자 전달 벡터를 제공한다. 상기 바이러스에 대한 더 자세한 내용은 Kenneth I. Berns, "Parvoviridae : The Viruses and Their Replication", Fields Virology 챕터 69 (3d Ed. 1996)에 설명되어 있다.
알려져 있는 모든 AAV 혈청형의 게놈 구조는 매우 유사하다. AAV의 게놈은 길이가 약 5,000 뉴클레오티드(nt) 미만인 선형의 단일 가닥 DNA 분자이다. 역전된 말단 반복(Inverted terminal repeats, ITRs)은 비구조적 복제(Rep) 단백질 및 구조적(VP) 단백질의 독특한 코딩 염기서열의 측면에 위치한다. 상기 VP 단백질(VP1, VP2 및 VP3)은 캡시드를 형성한다. 말단 145 nt 는 자기 상보적(self-complementary)이고 T 자형 헤어핀 구조를 형성하는 에너지적으로 안정한 분자 내 이합체가 형성될 수 있도록 구성된다. 이 헤어핀 구조는 바이러스 DNA 복제를 위한 기점으로써 기능하여, 세포 DNA 중합효소 복합체(DNA polymerase complex)의 프라이머 역할을 한다. 포유류 세포 내 야생형(wt) AAV 감염에 뒤따라, Rep 유전자(즉, Rep78 및 Rep52 단백질의 암호화)는 P5 프로모터 및 P19 프로모터로부터 각각 발현되며, 두 Rep 단백질은 모두 바이러스 게놈 복제 기능을 갖는다. Rep ORF의 스플라이싱(splicing) 현상은 실제로 4 개의 Rep 단백질 (즉, Rep78, Rep68, Rep52 및 Rep40)의 발현을 초래한다. 그러나, 포유류 세포에서 스플라이싱 되지 않은 Rep78 및 Rep52 단백질을 암호화하는 mRNA는 AAV 벡터 생산에 충분하다는 것을 발견하였다. 또한, 곤충 세포에서도 Rep78 및 Rep52 단백질은 AAV 벡터 생산에 충분하다.
유전자 치료 벡터로 사용하기에 적합한 AAV 에서, 벡터 게놈은 전형적으로 표적 세포로 전달하기 위해 패키징 될 목적 핵산을 포함한다. 이 특정 실시 양태에 따르면, 상기 핵산은 벡터 게놈의 양 말단에서 바이러스의 역전된 말단 반복(inverted terminal repeats, ITR) 사이에 위치한다. AAV 게놈이 단지 하나의 ITR로 기능하는 것이 가능하다. 따라서, AAV 에 기초한 본 발명의 유전자 치료 벡터에서, 벡터 게놈은 적어도 하나의 ITR 이, 보다 전형적으로는 두 개의 AAV ITR (일반적으로 벡터 게놈의 어느 한쪽면, 즉 5' 말단 및 3' 말단)이 양쪽에 위치한다. 벡터 게놈 내의 핵산과 하나 이상의 ITR 사이에는 개재 배열(intervening sequences)이 있을 수 있다.
본 발명의 용어, "적어도 하나의 ITR" 은 "A", "B" 및 "C" 영역으로 지칭되는, 대부분 상보적이며 대칭으로 배열된 서열을 포함하는 대칭 구조(palindromic) 서열을 의미한다. ITR은 복제의 기점, 즉 복제 시 "시스(cis)" 역할을 갖는 부위, 즉 트랜스-작용(trans-acting) 복제 단백질, 예를 들어 대칭 구조(palindrome)와 대칭 구조 내의 특정 서열을 인식하는 Rep78 (또는 Rep68)과 같은 트랜스-작용(trans-acting) 복제 단백질의 인식 부위로써 기능한다. ITR 서열의 대칭에 대한 한 가지 예외는 ITR의 "D" 영역이다. 그것은 유일하다(하나의 ITR 내에 상등성(complement)을 갖지 않음). 단일 가닥 DNA의 니킹(Nicking)은 A 와 D 영역 사이의 교차점에서 발생한다. 그것은 새로운 DNA 합성이 시작되는 영역이다. D 영역은 일반적으로 대칭 구조의 한쪽면에 위치하고 핵산 복제 단계에서 방향성을 제공한다. 포유류 세포 내 AAV 복제는 전형적으로 2 개의 ITR 서열을 갖는다. 그러나 결합 부위가 A 영역의 양쪽 가닥에 있게 하고, D 영역이 대칭 구조의 각 면에 하나씩 대칭적으로 위치하게 하기 위해서 ITR 조작이 가능하다. 이중 가닥 원형 DNA 주형 (예컨대, 플라스미드)상에서, Rep78- 또는 Rep68-보조 핵산 복제는 양 방향으로 진행하고 단일 ITR은 원형 벡터의 파보바이러스(parvoviral) 복제에 충분하다. 즉, 하나의 ITR 뉴클레오티드 서열이 본 발명과 관련하여 사용될 수 있다. 그러나 바람직하게는, 두 개 또는 또다른 짝수 개의 정규 ITR 이 사용된다. 가장 바람직하게는, 두 개의 ITR 서열이 사용된다. 안전성의 이유로, 세포로의 초기 도입 후 추가로 증식할 수 없는 AAV 벡터를 구성하는 것이 바람직할 수 있다. 수용자 내 바람직하지 않은 벡터 증식을 제한하기 위한 이러한 안전 메카니즘은 US 2003148506에 기술된 바와 같은 키메라(chimeric) ITR 을 갖는 AAV 를 사용함으로써 제공될 수 있다.
당업자는 본 발명의 AAV 벡터를 생산하는데 사용되는 바이러스 Rep 단백질 (들)이 바이러스 ITR의 출처를 고려하여 선택될 수 있음을 이해할 것이다. 예를 들어, AAV5 ITR은 전형적으로 AAV5 Rep 단백질과 더 효율적으로 상호작용하지만, ITR 및 Rep 단백질(들)의 혈청형이 일치할 필요는 없다.
본 발명에서 사용되는 ITR(들)은 일반적으로 기능적이며, 즉 완전히 분해될 수 있고 AAV 서열이며, 혈청형 1, 2, 3, 4, 5 또는 6 이 바람직하다. 본 발명에 따른 분해 가능한 AAV ITR 은, ITR 이 원하는 기능, 예컨대 바이러스 패키징, 통합, 및/또는 프로바이러스 구제(provirus rescue) 등을 매개하는 한, 야생형 ITR 서열을 가질 필요는 없다 (예컨대 야생형 서열이 삽입, 결실, 절단 또는 미스센스 돌연변이에 의해 변경될 수 있다).
더 바람직한 실시 양태에서, AAV 캡 유전자 및 AAV rep 유전자는 주형 게놈으로부터 (따라서 이로부터 생성된 비리온(virion) DNA 로부터) 결실된다. 이러한 배열은 AAV 캡시드에 의해 운반될 수 있는 핵산 서열의 크기를 최대화한다.
AAV 유전자 치료 벡터의 생산을 위해 본 발명에서 사용될 수 있는 AAV 서열은 임의의 AAV 혈청형 게놈으로부터 유래될 수 있다. 일반적으로, AAV 혈청형은 아미노산 및 핵산 수준에서 현저한 상동성을 갖는 게놈 서열을 가지며, 동일한 유전 적 기능 세트를 제공하고, 본질적으로 물리적 및 기능적으로 동등한 비리온(virions)을 생성하며, 사실상 동일한 메카니즘에 의해 복제 및 조립한다. 다양한 AAV 혈청형의 게놈 서열 및 게놈 유사성의 개요에 대해서는 예컨대 GenBank Accession number U89790; GenBank Accession number J01901; GenBank Accession number AF043303; GenBank Accession number AF085716 을 참고하라. AAV 혈청형 1, 2, 3, 4, 5, 6, 7, 8 또는 9 가 본 발명에서 사용될 수 있다. 그러나, AAV 혈청형 1, 5 또는 8 은 본 발명과 관련하여 AAV 서열의 바람직한 공급원이다. AAV 혈청형 유래의 서열은 유전자 치료 벡터의 생산에 사용될 때 변이되거나 조작될 수 있다.
바람직하게 본 발명에서 사용하기 위한 AAV ITR 서열은 AAV1, AAV2, AAV4 및/또는 AAV6 으로부터 유래된다. 마찬가지로, Rep (Rep78 및 Rep52) 암호화 서열은 바람직하게는 AAV1, AAV2, AAV4 및/또는 AAV6으로부터 유래된다.
AAV Rep 및 ITR 서열은 대부분의 혈청형 사이에서 특히 보존되어 있다. 다양한 AAV 혈청형의 Rep78 단백질은 예컨대 89 % 이상의 상동성이고 AAV2, AAV3A, AAV3B 및 AAV6 사이의 게놈 수준에서 전체 염기서열 상동성은 약 82 % 이다. 게다가, 많은 AAV 혈청형의 Rep 서열 및 ITR 은 포유류 세포 내 AAV 입자의 생산에서 다른 혈청형으로부터 상응하는 서열을 효율적으로 교차-보완(cross-complement) (즉, 기능적 치환)하는 것으로 알려져 있다. US 2003148506 은 AAV Rep 및 ITR 서열이 곤충 세포에서 다른 AAV Rep 및 ITR 서열 또한 효율적으로 교차-보완한다는 것을 개시한다.
AAV VP 단백질은 AAV 비리온의 세포 친화성(cellular tropicity)을 결정하는 것으로 알려져 있다. VP 단백질-암호화 서열은 다른 AAV 혈청형 사이에서 Rep 단백질 및 유전자보다 유의적으로 덜 보존되어 있다. Rep 및 ITR 서열이 다른 혈청형의 상응하는 서열을 교차-보완할 수 있는 능력은 혈청형 (예컨대 AAV1, 5 또는 8)의 캡시드 단백질, Rep 및/또는 또다른 AAV 혈청형 (예컨대 AAV2)의 ITR 서열을 포함하는 슈도타입(pseudotyped) AAV 입자의 생산을 가능하게 한다. 이러한 슈도타입 rAAV 입자는 본 발명의 변형된 캡시드 단백질과 함께 사용될 수 있는 임의의 AAV 혈청형의 Rep 및/또는 ITR 서열로써 본 발명의 일부분이다.
변형된 "AAV" 서열은 또한 본 발명 예컨대, AAV 유전자 치료 벡터의 생산을 위해 본 발명에서 사용될 수 있다. 이러한 변형된 서열, 예컨대 AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9 ITR, 또는 Rep 와 약 70 % 이상, 약 75 % 이상, 약 80 % 이상, 약 85 % 이상, 약 90 % 이상, 약 95 % 이상, 또는 그 이상의 염기 및/또는 아미노산 서열 상동성, 예컨대 약 75-99 % 의 염기서열 상동성을 갖는 서열을 포함하는 서열이 야생형 AAV ITR 또는 Rep 서열 대신에 사용될 수 있다.
비록 많은 측면에서 다른 AAV 혈청형과 유사하지만, AAV5 는 다른 알려진 인간 및 유사 혈청형보다 더 기타 인간 및 유사 AAV 혈청형과는 다르다. 이를 고려하면, rAAV5 의 생산은 곤충 세포에서 다른 혈청형의 생산과 다를 수 있다. 본 발명의 방법을 rAAV5 생산에 적용하는 경우, 집합적으로 하나 이상의 구조체의 경우에서, AAV5 ITR 을 포함하는 염기서열 및 AAV5 Rep 암호화 서열을 포함하는 염기서열(즉 염기서열은 AAV5 Rep78 을 포함한다)을 포함하는 하나 이상의 구조체가 바람직하다. 이러한 ITR 및 Rep 서열은 AAV5 또는 슈도타입 AAV5 벡터의 효율적인 생산을 얻기 위해 원하는 대로 변형될 수 있다.
가장 적합한 바이러스, 바이러스 아형(subtype) 또는 바이러스 혈청형을 선택하는 것은 당업자의 기술적 능력범위 내에 있다. 일부 아형 또는 혈청형은 특정 유형의 조직에서는 다른 것들보다 더 적절할 수 있다.
예를 들어, 목적 핵산의 간 특이적 발현은 간세포의 AAV 매개 형질도입에 의해 유리하게 유도될 수 있다. 간은 AAV 매개 형질도입을 잘 받아들일 수 있고, 다른 혈청형(예컨대 AAV1, AAV5 또는 AAV8)들을 사용할 수 있다. 근육의 형질도입은 혈류를 통해 핵산을 암호화하는 AAV 를 투여함으로써 달성할 수 있다. 따라서, 정맥 내 또는 동맥 내로의 투여가 가능하다.
유리하게는, 본 발명의 벡터를 사용함으로써, 보다 큰 정도의 세포 형질도입을 얻을 수 있다. 이것은 특히 간세포에서의 경우이다.
따라서, 본 발명의 벡터는 간세포와 같은 적절한 세포 유형을 효율적으로 형질도입시키는 유전자 치료 벡터 내에서 핵산을 조작함으로써, 치료용 염기서열의 in vivo 전달을 위한 전략을 개발하기 위한 도구를 나타낸다.
상기 벡터는 기능성 치료용 단백질이 발현되도록 하는 다른 요소를 포함할 수 있다. 그러한 요소는 당업자에게 잘 알려져 있다.
바람직하게는, 상기 기재된 핵산 및 아미노산 서열은 단리된다.
전술한 핵산 분자 및 아미노산 서열을 생산하는 숙련자의 능력은 충분할 것이다. 이는 예를 들어, 주어진 서열의 화학적 합성을 이용하여 수행될 수 있다.
본 발명은 또한 재조합 AAV 벡터를 포유류에 도입하는 단계;를 포함하는 목적 핵산을 포유류로 전달하는 방법으로, 상기 재조합 AAV 벡터는 전술한 캡시드 단백질을 포함하는 캡시드 내에 둘러싸여진 목적 유전자를 포함하는 것인, 방법에 관한 것이다.
본 발명은 또한 상기 아미노산 서열을 갖는 캡시드 단백질 또는 상기 벡터를 포함하는 숙주 세포를 제공한다.
상기 용어 "숙주"는 재조합 유전자 또는 단백질 발현에 사용하기에 적합한 생물체(organisms) 및/또는 세포뿐만 아니라, 본 발명의 단백질 또는 벡터를 보유하는 생물체 및/또는 세포를 지칭한다. 본 발명이 임의의 특정 유형의 세포 또는 생물체에 한정되는 것은 아니다. 실제로, 임의의 적합한 생물체 및/또는 세포가 숙주로써 본 발명에 이용되는 것이 고려된다. 숙주 세포는 단일 세포의 형태, 유사하거나 상이한 세포의 집단, 예를 들어 배양물의 형태(액체 배양물 또는 고체 기질상의 배양물), 생물체 또는 이의 일부분일 수 있다.
본 발명에 따른 숙주 세포는 치료용 핵산 분자의 발현을 허용할 수 있다. 따라서, 숙주 세포는 예를 들어 박테리아, 효모, 곤충 또는 포유류 세포일 수 있다.
또한, 본 발명은 상기 아미노산 서열을 갖는 캡시드 단백질 또는 상기 벡터를 포함하는 세포를 포함하는 형질전환 동물을 제공한다. 바람직하게 상기 동물은 비인간 포유류, 특히 영장류이다. 대안으로, 상기 동물은 설치류, 특히 마우스일 수 있으며; 또는 개, 고양이, 양 또는 돼지일 수 있다.
일 양상에서 본 발명은, 본 발명의 아미노산 서열을 갖는 캡시드 단백질 또는 본 발명의 벡터; 및 하나 이상의 약학적으로 허용되는 부형제를 포함하는, 약학적 조성물을 제공한다. 하나 이상의 부형제는 담체, 희석제 및/또는 기타 다른 의학적 제제, 약학적 제제 또는 보조제 등을 포함한다.
본 발명의 서열로 달성된 유전자 전달의 더 높은 수준은 현재의 기술 수준을 넘어서는 진보를 나타낸다. 낮은 벡터 용량으로 유전자 전달을 가능하게 하는 효능 개선을 확인하였으며, 이에 따라 안정성을 향상시키고(특히 용량 의존적인 간 독성을 감소시킴), 비용을 절감할 수 있다.
본 발명의 서열 및 벡터에 따르면, 선천성 FVII 결핍(congenital FVII deficiency), 고세병(Gaucher's disease), OTC 결핍(OTC deficiency), 파브리 병(Fabry's disease), 글리코겐 저장 질환(glycogen storage diseases), α-1- 항트립신 결핍증(a-1-antitrypsin deficiency), 진행성 가족성 간내담즙정체증(progressive familial intrahepatic cholestasis), 윌슨병(Wilson's disease), 크리글러-나자르 증후군(Crigler Najjar syndrome) 및 간세포 암종(hepatocellular carcinoma) 등과 같은 장애의 임상 적용 가능성을 가질 수 있다.
따라서, 본 발명은 전술한 바와 같은 벡터의 치료적 유효량을 상기 질환을 앓고 있는 환자에게 투여하는 단계;를 포함하는, 상기 나열된 질병 중 하나 이상을 치료하는 방법을 제공할 수 있다. 바람직하게 상기 환자는 인간이다.
상기 질병이 상기 방법으로 "치료"된다고 할 때, 이것은 상기 질병의 하나 이상의 증상이 완화된다는 것을 의미한다. 이 질병의 증상이 완전히 치료되어 환자에게 더이상 존재하지 않는다는 것을 의미하는 것은 아니나, 일부 방법에서는 이는 그런 경우일 수 있다. 상기 치료 방법은 상기 질병의 하나 이상의 증상이 치료 전에 비해 덜 극심하게 하는 결과를 낳는다.
"치료적 유효량"은 필요한 투여량 및 필요한 시간 동안 원하는 치료 결과를 달성하는데에 효과적인 양을 지칭한다.
또한, 본 발명은 캡시드 단백질; 또는 치료에 사용할 수 있는 벡터;를 제공할 수 있으며, 바람직하게 상기 벡터는 전술한 질병들 중 하나에 사용할 수 있는 벡터이다.
또한, 본 발명은 상기 질환 중 하나를 치료하기 위한 제제의 제조에 있어서, 전술한 바와 같은 캡시드 단백질 또는 전술한 벡터의 용도를 제공할 수 있다.
상기 기재사항에서, 용어 "상동성"은 두 서열의 유사성을 나타내는 의미로 사용하였다. 본 발명의 목적을 위해, 두 개의 아미노산 서열의 상동성을 결정하기 위해서, 해당 서열은 최적의 비교 목적을 위해 정렬된다, 예컨대 갭이 두번째 아미노산 서열과의 최적 정렬을 위해 아미노산 서열에 도입될 수 있다. 그 후 아미노산 잔기가 비교된다. 첫번째 서열의 위치가 두번째 서열에서 대응하는 위치로 동일한 아미노산 또는 아미노산 잔기에 의해 점유되면, 상기 분자는 그 위치에서 동일하다. 두 서열간의 상동성은 상기 서열들에 의해 공유되는 동일한 위치의 수 (즉, 상동성 % = 동일한 위치의 수/총 위치 수(즉, 중첩 위치) × 100)의 함수이다. 바람직하게는, 2 개의 시퀀스는 동일한 길이이다.
서열 비교는 비교되는 두 서열의 전체 길이 또는 두 서열의 단편에 대해 수행될 수 있다. 일반적으로, 상기 비교는 비교되는 두 개의 서열의 전장(full length)에 걸쳐 수행될 것이다. 그러나, 서열 상동성 비교는 예를 들어 약 20 개, 약 50 개, 약 100 개, 약 200 개, 약 500 개, 약 1000 개 또는 약 2000 개 이상의 인접 아미노산 잔기의 영역에 걸쳐 수행될 수 있다.
당업자는 두 개의 서열 사이의 상동성 또는 동일성을 결정하기 위해 여러가지 다른 컴퓨터 프로그램을 이용할 수 있다는 사실을 인식할 것이다. 바람직한 실시 양태에서, 두 개의 서열 간의 상동성은 software package Clone Manager Professional version 9 (바람직하게는 version 9.4)를 사용하여 분석하였다. 이 분석 도구는 Sci-Ed Software (Scientific & Educational Software, 11010 Lake Grove Blvd, Ste 100, PMB 122, Morrisville, NC 27560, USA - http://www.scied.com/index.htm)에 의해 생산되었다. 서열을 비교하기 위해 사용된 설정은 바람직하게는 다음과 같다: 정렬: Global DNA 정렬; 매개 변수: 두 가닥; 채점 매트릭스: 선형(불일치 2, OpenGap 4, ExtGap 1). 대안으로 Fast Scan -MaxScore 및 Fast Scan MaxQual 와 같은 방법을 동일한 소프트웨어 및 로컬 설정으로 사용할 수 있다.
다른 방법들이 또한 서열 상동성을 결정하는데 사용될 수 있다. 예를 들어, 두 아미노산 또는 핵산 서열간의 상동성 비율은 Accelrys GCG 소프트웨어 패키지의 GAP 프로그램에 통합된 Needleman and Wunsch (1970) 알고리즘을 이용하여 Blosum 62 매트릭스 또는 PAM250 매트릭스, 및 16, 14, 12, 10, 8, 6 또는 4 의 갭 중량 및 1, 2, 3, 4, 5 또는 6 의 길이 가중치를 사용하여 결정될 수 있다.
본 명세서에 인용된 모든 특허 및 문헌은 이들 전체가 참고자료로써 포함되어 있다.
당업자라면 본 발명의 모든 양상, 예를 들어 아미노산, 바이러스 입자, 벡터, 숙주 세포 또는 그 용도에 관한 것이 본 발명의 모든 다른 양상에 동일하게 적용 가능하다는 것을 이해할 것이다. 특히, 치료 방법의 양상, 예를 들어, 벡터의 투여는, 예컨대 치료 용도의 벡터의 사용과 관련하여, 본 발명의 다른 양상 중 일부보다 더욱 상세하게 기술될 수 있다. 그러나, 당업자는 본 발명의 특정 양상에 대해 보다 상세한 정보가 주어졌을 때, 이 정보는 일반적으로 본 발명의 다른 양태에 동등하게 적용이 가능함을 인식할 것이다. 또한, 당업자는 치료 방법과 관련된 설명이 치료 용도의 벡터의 사용에도 동일하게 적용 가능함을 또한 인식할 것이다.
본 발명은 이제 도면을 단지 참고적인 예로 하여 상세하게 설명한다 :
도 1은 하이브리드 AAV 캡시드의 평가를 나타낸 도이다. 파트 a는 하이브리드 캡시드의 개략도를 나타내며 파트 b는 HUH7 세포 내 2 가지 상이한 MOIs (감염다중도)에서의 상이한 하이브리드 캡시드의 in vitro 전달 효율을 나타낸다.
도 2는 세포 형질도입 실험의 결과를 나타낸 도이다. 도 2a는 AAV8, AAV5, AAV-rh10, AAV-LK03 및 AAV 돌연변이 C 벡터를 갖는 HUH7 세포의 형질도입 결과를 나타낸다. 도 2b는 AAV8, AAV5, AAV-LK03 및 AAV 돌연변이 C 벡터를 갖는 부착성 HepG2 세포의 형질도입 결과를 나타낸다.
도 3a는 AAV8, AAV5, AAV-rh10 및 AAV 돌연변이 C 벡터를 갖는 일차 간세포의 형질도입 유동혈구 계산분석(flow-cytometric analysis) 결과를 나타낸다. 도 3b는 형질도입 된 간세포의 형광 현미경 이미지를 나타낸 도이다.
도 4a는 1x104 또는 1x105의 MOI에서 GFP 유전자를 포함하는 AAV8 및 AAV 돌연변이 C 벡터가 형질도입된 HepG2 세포의 3D 배양물로부터 야기된 485nm/535nm 에서의 GFP 여기/방출을 나타낸다. 도 4b는 형질도입된 3D HepG2 세포의 형광 현미경 이미지를 나타낸다 (5x 대물 렌즈(objective), GFP 노출시간 상수(exposure time constant)[300ms]).
도 5는 ELISA 면역 흡착법의 결과로써 중증 혈우병 환자 내 AAV 벡터에 대한 항체의 보유 정도를 나타낸 도이다.
도 1은 하이브리드 AAV 캡시드의 평가를 나타낸 도이다. 파트 a는 하이브리드 캡시드의 개략도를 나타내며 파트 b는 HUH7 세포 내 2 가지 상이한 MOIs (감염다중도)에서의 상이한 하이브리드 캡시드의 in vitro 전달 효율을 나타낸다.
도 2는 세포 형질도입 실험의 결과를 나타낸 도이다. 도 2a는 AAV8, AAV5, AAV-rh10, AAV-LK03 및 AAV 돌연변이 C 벡터를 갖는 HUH7 세포의 형질도입 결과를 나타낸다. 도 2b는 AAV8, AAV5, AAV-LK03 및 AAV 돌연변이 C 벡터를 갖는 부착성 HepG2 세포의 형질도입 결과를 나타낸다.
도 3a는 AAV8, AAV5, AAV-rh10 및 AAV 돌연변이 C 벡터를 갖는 일차 간세포의 형질도입 유동혈구 계산분석(flow-cytometric analysis) 결과를 나타낸다. 도 3b는 형질도입 된 간세포의 형광 현미경 이미지를 나타낸 도이다.
도 4a는 1x104 또는 1x105의 MOI에서 GFP 유전자를 포함하는 AAV8 및 AAV 돌연변이 C 벡터가 형질도입된 HepG2 세포의 3D 배양물로부터 야기된 485nm/535nm 에서의 GFP 여기/방출을 나타낸다. 도 4b는 형질도입된 3D HepG2 세포의 형광 현미경 이미지를 나타낸다 (5x 대물 렌즈(objective), GFP 노출시간 상수(exposure time constant)[300ms]).
도 5는 ELISA 면역 흡착법의 결과로써 중증 혈우병 환자 내 AAV 벡터에 대한 항체의 보유 정도를 나타낸 도이다.
이하, 본 발명을 실시예에 의거하여 보다 구체적으로 설명한다. 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.
실시예 1
새로운 하이브리드 캡시드는 4 개의 상이한 AAV 캡시드 유래의 다양한 도메인을 경험에 기인하여 맞바꿈으로써 생성하였다: (1) AAV8, (2) AAV5, (3) AAV3B, 및 (4) AAV-LK03 (도 1 참조). 이 중 AAV-LK03는 현재 이용 가능한 자연 발생 AAV 캡시드보다 더 효율적으로 인간 간세포에 형질도입하는 것으로 보고되었다. 특히, LK03은 AAV3B와 95 % 이상의 아미노산 서열 상동성을 갖는다. 본 발명의 캡시드 단백질은 야생형 AAV 캡시드 유래 모티프의 선택에 의해 혈청형 1-rh10으로부터 개발된 합성 캡시드이다. LK03의 VP2 및 VP3 영역은 돌연변이 A(서열번호 1)(Mut A) 및 B(서열번호 2)(Mut B)를 각각 생성하기 위해 AAV8 및 AAV5 유래 대응 영역으로 치환하였다. 돌연변이 C(서열번호 3)(Mut C)에서, AAV8 VP1 영역을 포함하는 146 아미노산 영역을 AAV3B 캡시드의 VP2 및 VP3 도메인의 업스트림(upstream)에 클로닝하였다. 유사하게 돌연변이 D(서열번호 4)(Mut D)에서 AAV5-VP1 영역은 AAV3B VP2 및 VP3 영역의 업스트림에 클로닝하였다. 돌연변이 E(서열번호 5)(Mut E)에서, AAV8의 도메인 v-I, v-II 및 v-IX는 AAV3B의 동족체(cognate)로 치환하였다. 돌연변이 F(서열번호 6)(Mut F)에서, AAV3B의 간세포 성장 인자 수용체 결합 부위를 함유하는 262 아미노산 영역은 AAV8 캡시드의 대응하는 영역 내로 클로닝하였다.
합성 캡시드, 특히 돌연변이 C 및 돌연변이 D에 대한 VP1, VP2 및 VP3의 비율은 AAV2, 3b, 5 또는 8에서 관찰된 것과 유사하다. 돌연변이 C 및 돌연변이 D는 인간 간 세포에 강한 친화성(tropism)을 가지고 있으며, AAV5와 AAV8을 포함한 야생형 AAV 캡시드와 비교했을 때 이들 세포로 더 높은 수준의 유전자 전달을 매개 할 수 있다.
캡시드 서열은 중첩 PCR(overlapping PCR)에 의해 조립하거나 유전자 합성(GenScript; Mut C, Mut E 및 F)을 통해 생성시켰다. 캡시드 서열은 변형된 개시 코돈(ATG 내지 ACG)을 갖는 AAV2의 Rep78 코딩 서열을 포함하는 AAV 헬퍼 플라스미드에 클로닝 하였다. 벡터 스톡은 HEK293 세포를 pCMV-eGFP, pRep2Cap 및 아데노바이러스 헬퍼 플라스미드 pHGTI로 표준 트리플 플라스미드 형질 감염시켜 제조하였다. 벡터는 이오딕사놀(iodixanol)을 이용한 밀도 구배 원심분리법으로 정제하였다. 벡터 게놈은 QPCR에 의해 eGFP에 특이적인 프라이머로 적정하였다. 하이브리드 AAV 벡터의 수율은 이전에 AAV8에서 관찰된 것과 유사하였다. 이들 하이브리드 캡시드의 유전자 전달 효율은 감염다중도(multiplicity of infection, MOI) 1x104 및 1x105에서 HUH7 간세포 암종 세포주를 사용하여 in vitro 평가하였다. 유전자 전달의 수준은 유세포 분석기(flow cytometry)를 이용한 리포터 유전자, eGFP의 검출에 의해 결정하였다. 가장 높은 수준의 유전자 전달은 AAV8보다 5 배 이상 높은 수준에서 돌연변이 C로 달성되었다(도 1b). 이 돌연변이는 AAV3B 및 신규한 혈청 형 LK03과 유사한 수준의 유전자 전달을 매개하였다. 돌연변이 D의 유전자 전달 효율은 돌연변이 C보다 낮았지만 부모 혈청형인 AAV5보다 3 배 더 높았다. 돌연변이 E 및 F는, 돌연변이 C와 비교했을 때 야생형 AAV8 및 AAV5 에서 볼 수 있는 GFP 양성 세포와 유사한 수준이 관찰되어, 유전자 전달 수준이 훨씬 낮은 것으로 확인하였다.
실시예 2
재조합 AAV 벡터의 생산.
AAV 벡터는 부착성 HEK293 T-세포를, CMV 프로모터 제어 하에 있는 EGFP 리포터 유전자를 포함한 벡터 플라스미드, 아데노바이러스 헬퍼 플라스미드 및 내인성(endogenous) 프로모터 제어 하에 있는 AAV2 Rep 유전자 다운스트림(downstream)에 있는 각각의 AAV cap 유전자를 포함한 패키징 플라스미드로 구성된 플라스미드 조합으로 형질전환시켜 제조하였다. 벡터를 AVB 컬럼 크로마토그래피를 사용하여 정제하였다. 모든 벡터의 적정은 알칼리 겔 분석 및 qPCR 분석에 의해 수행하였다.
In-vitro 형질도입.
단층에서 성장한 간암 세포주를 다양한 감염다중도(Multiplicity of infection, MOI)에서 AAV로 형질도입시킨 다음, 유전자 전달 후 72 시간 째에서 유세포 분석기(flow cytometry)을 사용하여 형질도입 효율성 평가를 실시하였다.
일차 인간 간세포는 Life-technologies로부터 얻었으며 공급 업체의 설명에 따라 배양하였다. 그 후, 일차 인간 간세포를 CMV 프로모터 하에서 GFP를 코딩하는 AAV에 노출시켰다. 유전자 전달 효율은 3-4 일 후 유세포 분석기 또는 다이렉트 형광 현미경을 사용하여 평가하였다.
캡슐화 된 HepG2 세포의 3D 배양물을 AAV의 상이한 MOI에 노출시킨 다음, 플레이트 판독기 또는 다이렉트 형광 현미경을 사용하여 녹색 형광을 정량함으로써 평가하였다.
항-AAV 항체 역가.
면역흡착법을 사용하여 중증 혈우병 환자로부터 얻은 혈장 샘플 내의 항 -AAV 항체 역가를 측정하였다. 항-AAV 항체 역가는 평균 흡광도 배경 값의 5 배에 해당하는 흡광도 값을 가진 보간된 희석(interpolated dilution)의 역수로서 정의되는 종점(end-point) 역가(Relative units/ml)로 표시하였다.
인간 간 세포주 및 일차 인간 간세포 내 다른 혈청형 대비 AAV 돌연변이 C 벡터의 형질도입 효율성
집중적인 연구에서, Huh7(간암 세포주) 및 HepG2 세포주(간암 세포주) 내 AAV8, AAV5, AAV-rh10, AAV-LK03 및 AAV Mut C의 in vitro 형질도입 효율성을 비교 하였다. 모든 벡터는 거대세포바이러스(cytomegalovirus, CMV) 프로모터의 제어 하에 녹색 형광 단백질 (GFP) 리포터 유전자를 포함하였다.
AAV8, AAV5 및 AAV-rh10 벡터는 평균 GFP 발현 범위가 15 내지 26 % 로, Huh7 세포 형질도입에 덜 효율적이었다. 이와 대조적으로 AAV-LK03와 Mut C의 형질도입 효율성은 70 % 에 이르러 이러한 캡시드 단백질을 가진 위형(pseudotyped) 벡터의 경우보다 높은 수준의 유전자 전달이 관찰되었다 (도 2a). Mut C와 AAV8 사이의 유전자 전달 효율성의 차이는 매우 유의적이었다 (p = 0.0012).
HepG2 세포주 (도 2b) 에서 AAV8 및 AAV5와 비교하였을 때, HepG2 세포에 AAV Mut C 및 AAV-LK03 을 형질도입한 경우, MOI 와 관계없이 거의 10 배 더 높은 유전자 전달 효율성이 관찰되는 유사한 결과를 확인하였다(P=<0.05 ).
다음으로 3명의 다른 기증자로부터 유래된 일차 인간 간세포의 유전자 전달 효율성을 평가하였다. 기증자는 모두 남성으로 백인 남성 2명과 아프리카계 카리브해인 1명이다. 기증자들의 나이는 21-52 세이다. CMV 프로모터의 조절 하에 GFP를 암호화하는 벡터를 사용하여 일차 간세포를 106의 MOI로 AAV 벡터에 노출시켰다. 유전자 전달 후 4-5 일째에 형광 현미경 또는 유세포 분석기로 형질도입 효율성을 평가하였다. 도 3에 나타난 바와 같이, AAV Mut C (32.06 ± 4 %)에서의 유전자 전달 효율은 AAV8 (7.3 ± 7 %)보다 4 배 이상 높았다. AAV Mut C와 AAV8 그룹 간의 일차 인간 간세포의 유전자 전달 효율의 차이는 매우 유의적이었다 (1 샘플 t- 테스트 시 p = 0.0015). 다이렉트 형광 이미지 분석은 AAV Mut C 로 형질도입된 세포에서 훨씬 높은 수준의 GFP 발현을 나타내는 유세포 분석기 데이터를 입증했다 (도 3b).
다음으로 본 발명자들은 JetCutter를 이용하여 알지네이트(alginate) 내에 캡슐화된 HepG2 세포의 3D 배양물로의 AAV 매개 유전자 이동을 확인하였고, HepG2 세포를 포함하는 대략 500㎛ 의 구형 비드를 ml 비드 당 대략 1.7M 농도로 생산하였다. 이 모델의 강점은 캡슐화된 세포가 증식하여 세포 간 접촉 및 세포 기능이 양호한 소형 세포 스페로이드(AELS)를 형성한다는 것이다. AELS는 단층 배양에 비해 전형적인 세포 구조를 보여주는 데스모솜들(desmosomes), 단단한 접합과 미세융털(micro-villi), 소포체와 미토콘드리아의 높은 발현 및 정상 간에서의 세포 외 매트릭스의 생성과 함께, 더 높은 성장과 상향 조절(upregulated)된 간 특이적 기능을 보인다.
3D 비드 배양물은 CMV GFP 발현 카세트를 포함하는 벡터를 사용하여 1x104 또는 1x105의 MOI에서 AAV8 또는 AAV Mut C로 형질도입되었다. 이전 실험과 마찬가지로 형질도입 효율성은 플레이트 판독기 (도 4a) 또는 다이렉트 형광 현미경 (도 4b)을 사용하여 녹색 형광을 정량함으로써 결정하였다. AAV8로 형질도입된 비드에서의 GFP 발현과 비교할 때, AAV Mut C로 형질도입된 3D 스페로이드의 유전자 전달 효율은 3-5 배 더 높게 확인되었다. 상기 유전자 전달 효율의 차이는 다이렉트 형광 현미경에서도 확인되었다.
중증 혈우병 환자 내 돌연변이 C에 대한 기존 항체의 평가
불특정한 중증 혈우병 환자의 혈장 샘플을 AAV Mut C에 대한 기존 항체의 보유 정도를 평가하기 위해 ELISA 면역 흡착법을 사용하여 스크리닝하였다. 63 %의 환자에게서 AAV Mut C에 대한 항체가 검출되지 않았다. AAV8 및 AAV-LK03에 대한 항체 보유 수준은 51 % 였다. 따라서 이는 보다 소수의 중증 혈우병 환자가 AAV Mut C에 대한 항체를 가짐을 나타낸다.
<110> UCL Business PLC
<120> Capsid
<130> IP-JAK1708
<150> GB1508026.0
<151> 2015-05-11
<160> 6
<170> PatentIn version 3.5
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Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
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Glu Gly Ile Arg Glu Trp Trp Ala Leu Gln Pro Gly Ala Pro Lys Pro
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Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
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Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
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Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
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Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
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Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
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Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ala Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
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Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr
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Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
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Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
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Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly
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Phe Ser Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala Lys Asn Trp
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Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Thr Gly
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Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Ala Gly Thr Lys Tyr His
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Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro Gly Ile Ala Met Ala Thr
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His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile
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Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val
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Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
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Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala
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Pro Gln Ile Gly Thr Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
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Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
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Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
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Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
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Pro Ala Asp Pro Pro Thr Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe
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Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
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Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
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Ser Asn Tyr Tyr Lys Ser Thr Ser Val Asp Phe Ala Val Asn Thr Glu
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Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
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Asn Leu
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Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
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Glu Gly Ile Arg Glu Trp Trp Ala Leu Gln Pro Gly Ala Pro Lys Pro
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Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
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Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
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Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
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Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
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Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
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Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Thr Gly Lys Arg
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Ile Asp Asp His Phe Pro Lys Arg Lys Lys Ala Arg Thr Glu Glu Asp
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Ser Lys Pro Ser Thr Ser Ser Asp Ala Glu Ala Gly Pro Ser Gly Ser
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Gln Gln Leu Gln Ile Pro Ala Gln Pro Ala Ser Ser Leu Gly Ala Asp
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Thr Met Ser Ala Gly Gly Gly Gly Pro Leu Gly Asp Asn Asn Gln Gly
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Ala Asp Gly Val Gly Asn Ala Ser Gly Asp Trp His Cys Asp Ser Thr
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Trp Met Gly Asp Arg Val Val Thr Lys Ser Thr Arg Thr Trp Val Leu
225 230 235 240
Pro Ser Tyr Asn Asn His Gln Tyr Arg Glu Ile Lys Ser Gly Ser Val
245 250 255
Asp Gly Ser Asn Ala Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly
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Tyr Phe Asp Phe Asn Arg Phe His Ser His Trp Ser Pro Arg Asp Trp
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Gln Arg Leu Ile Asn Asn Tyr Trp Gly Phe Arg Pro Arg Ser Leu Arg
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Val Lys Ile Phe Asn Ile Gln Val Lys Glu Val Thr Val Gln Asp Ser
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Thr Thr Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe Thr
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Asp Asp Asp Tyr Gln Leu Pro Tyr Val Val Gly Asn Gly Thr Glu Gly
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Cys Leu Pro Ala Phe Pro Pro Gln Val Phe Thr Leu Pro Gln Tyr Gly
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Tyr Ala Thr Leu Asn Arg Asp Asn Thr Glu Asn Pro Thr Glu Arg Ser
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Ser Phe Phe Cys Leu Glu Tyr Phe Pro Ser Lys Met Leu Arg Thr Gly
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Asn Asn Phe Glu Phe Thr Tyr Asn Phe Glu Glu Val Pro Phe His Ser
405 410 415
Ser Phe Ala Pro Ser Gln Asn Leu Phe Lys Leu Ala Asn Pro Leu Val
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Asp Gln Tyr Leu Tyr Arg Phe Val Ser Thr Asn Asn Thr Gly Gly Val
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Gln Phe Asn Lys Asn Leu Ala Gly Arg Tyr Ala Asn Thr Tyr Lys Asn
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Trp Phe Pro Gly Pro Met Gly Arg Thr Gln Gly Trp Asn Leu Gly Ser
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Gly Val Asn Arg Ala Ser Val Ser Ala Phe Ala Thr Thr Asn Arg Met
485 490 495
Glu Leu Glu Gly Ala Ser Tyr Gln Val Pro Pro Gln Pro Asn Gly Met
500 505 510
Thr Asn Asn Leu Gln Gly Ser Asn Thr Tyr Ala Leu Glu Asn Thr Met
515 520 525
Ile Phe Asn Ser Gln Pro Ala Asn Pro Gly Thr Thr Ala Thr Tyr Leu
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Glu Gly Asn Met Leu Ile Thr Ser Glu Ser Glu Thr Gln Pro Val Asn
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Arg Val Ala Tyr Asn Val Gly Gly Gln Met Ala Thr Asn Asn Gln Ser
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Ser Thr Thr Ala Pro Ala Thr Gly Thr Tyr Asn Leu Gln Glu Ile Val
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Pro Gly Ser Val Trp Met Glu Arg Asp Val Tyr Leu Gln Gly Pro Ile
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Trp Ala Lys Ile Pro Glu Thr Gly Ala His Phe His Pro Ser Pro Ala
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Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Met Met Leu Ile Lys
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Asn Thr Pro Val Pro Gly Asn Ile Thr Ser Phe Ser Asp Val Pro Val
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Ser Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Thr Val Glu Met
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Glu Trp Glu Leu Lys Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile
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Gln Tyr Thr Asn Asn Tyr Asn Asp Pro Gln Phe Val Asp Phe Ala Pro
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Asp Ser Thr Gly Glu Tyr Arg Thr Thr Arg Pro Ile Gly Thr Arg Tyr
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Leu Thr Arg Pro Leu
725
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Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
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Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
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Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
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Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
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Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
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Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
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Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
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Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
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Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
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Pro Val Asp Gln Ser Pro Gln Glu Pro Asp Ser Ser Ser Gly Val Gly
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Lys Ser Gly Lys Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
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Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro
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Ala Ala Pro Thr Ser Leu Gly Ser Asn Thr Met Ala Ser Gly Gly Gly
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Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
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Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
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Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Lys Leu Ser Phe Lys Leu Phe Asn Ile Gln Val
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Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
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Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
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Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
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Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Asn Arg Thr
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Gln Gly Thr Thr Ser Gly Thr Thr Asn Gln Ser Arg Leu Leu Phe Ser
450 455 460
Gln Ala Gly Pro Gln Ser Met Ser Leu Gln Ala Arg Asn Trp Leu Pro
465 470 475 480
Gly Pro Cys Tyr Arg Gln Gln Arg Leu Ser Lys Thr Ala Asn Asp Asn
485 490 495
Asn Asn Ser Asn Phe Pro Trp Thr Ala Ala Ser Lys Tyr His Leu Asn
500 505 510
Gly Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Asp Asp Glu Glu Lys Phe Phe Pro Met His Gly Asn Leu Ile Phe Gly
530 535 540
Lys Glu Gly Thr Thr Ala Ser Asn Ala Glu Leu Asp Asn Val Met Ile
545 550 555 560
Thr Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln
565 570 575
Tyr Gly Thr Val Ala Asn Asn Leu Gln Ser Ser Asn Thr Ala Pro Thr
580 585 590
Thr Arg Thr Val Asn Asp Gln Gly Ala Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
625 630 635 640
Lys His Pro Pro Pro Gln Ile Met Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asn Pro Pro Thr Thr Phe Ser Pro Ala Lys Phe Ala Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Asn Lys Ser Val Asn Val Asp Phe Thr Val Asp Thr Asn Gly Val
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Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
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<212> PRT
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Met Ser Phe Val Asp His Pro Pro Asp Trp Leu Glu Glu Val Gly Glu
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Gly Leu Arg Glu Phe Leu Gly Leu Glu Ala Gly Pro Pro Lys Pro Lys
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Pro Asn Gln Gln His Gln Asp Gln Ala Arg Gly Leu Val Leu Pro Gly
35 40 45
Tyr Asn Tyr Leu Gly Pro Gly Asn Gly Leu Asp Arg Gly Glu Pro Val
50 55 60
Asn Arg Ala Asp Glu Val Ala Arg Glu His Asp Ile Ser Tyr Asn Glu
65 70 75 80
Gln Leu Glu Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala Asp
85 90 95
Ala Glu Phe Gln Glu Lys Leu Ala Asp Asp Thr Ser Phe Gly Gly Asn
100 105 110
Leu Gly Lys Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro Phe
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Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg Pro
130 135 140
Val Asp Gln Ser Pro Gln Glu Pro Asp Ser Ser Ser Gly Val Gly Lys
145 150 155 160
Ser Gly Lys Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr Gly
165 170 175
Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro Ala
180 185 190
Ala Pro Thr Ser Leu Gly Ser Asn Thr Met Ala Ser Gly Gly Gly Ala
195 200 205
Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser Ser
210 215 220
Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile Thr
225 230 235 240
Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu Tyr
245 250 255
Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr Phe
260 265 270
Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His Cys
275 280 285
His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly
290 295 300
Phe Arg Pro Lys Lys Leu Ser Phe Lys Leu Phe Asn Ile Gln Val Lys
305 310 315 320
Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu Thr
325 330 335
Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr Val
340 345 350
Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp Val
355 360 365
Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser Gln
370 375 380
Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln
385 390 395 400
Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Thr Phe Glu Asp
405 410 415
Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg Leu
420 425 430
Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Asn Arg Thr Gln
435 440 445
Gly Thr Thr Ser Gly Thr Thr Asn Gln Ser Arg Leu Leu Phe Ser Gln
450 455 460
Ala Gly Pro Gln Ser Met Ser Leu Gln Ala Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Leu Ser Lys Thr Ala Asn Asp Asn Asn
485 490 495
Asn Ser Asn Phe Pro Trp Thr Ala Ala Ser Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Met His Gly Asn Leu Ile Phe Gly Lys
530 535 540
Glu Gly Thr Thr Ala Ser Asn Ala Glu Leu Asp Asn Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Thr Val Ala Asn Asn Leu Gln Ser Ser Asn Thr Ala Pro Thr Thr
580 585 590
Arg Thr Val Asn Asp Gln Gly Ala Leu Pro Gly Met Val Trp Gln Asp
595 600 605
Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr
610 615 620
Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys
625 630 635 640
His Pro Pro Pro Gln Ile Met Ile Lys Asn Thr Pro Val Pro Ala Asn
645 650 655
Pro Pro Thr Thr Phe Ser Pro Ala Lys Phe Ala Ser Phe Ile Thr Gln
660 665 670
Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys
675 680 685
Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr
690 695 700
Asn Lys Ser Val Asn Val Asp Phe Thr Val Asp Thr Asn Gly Val Tyr
705 710 715 720
Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Pro Leu
725 730 735
<210> 5
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<212> PRT
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Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
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Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
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Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His
260 265 270
Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe
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His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn
290 295 300
Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn Ile Gln
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Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala Asn Asn
325 330 335
Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro
340 345 350
Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala
355 360 365
Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly
370 375 380
Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro
385 390 395 400
Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr Thr Phe
405 410 415
Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp
420 425 430
Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg
435 440 445
Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly Phe Ser
450 455 460
Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala Lys Asn Trp Leu Pro
465 470 475 480
Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Thr Gly Gln Asn
485 490 495
Asn Asn Ser Asn Phe Ala Trp Thr Ala Gly Thr Lys Tyr His Leu Asn
500 505 510
Gly Arg Asn Ser Leu Ala Asn Pro Gly Ile Ala Met Ala Thr His Lys
515 520 525
Asp Asp Glu Glu Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Thr Ala Ser Asn Ala Glu Leu Asp Asn Val Met Ile
545 550 555 560
Thr Asp Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Glu
565 570 575
Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala Pro Gln
580 585 590
Ile Gly Thr Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val Trp Gln
595 600 605
Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asp Pro Pro Thr Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Asn Lys Ser Val Asn Val Asp Phe Thr Val Asp Thr Asn Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 6
<211> 736
<212> PRT
<213> Synthetic Protein
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Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His
260 265 270
Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe
275 280 285
His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn
290 295 300
Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn Ile Gln
305 310 315 320
Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala Asn Asn
325 330 335
Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro
340 345 350
Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala
355 360 365
Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly
370 375 380
Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro
385 390 395 400
Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr Thr Phe
405 410 415
Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp
420 425 430
Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg
435 440 445
Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly Phe Ser
450 455 460
Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala Lys Asn Trp Leu Pro
465 470 475 480
Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Thr Gly Gln Asn
485 490 495
Asn Asn Ser Asn Phe Ala Trp Thr Ala Gly Thr Lys Tyr His Leu Asn
500 505 510
Gly Arg Asn Ser Leu Ala Asn Pro Gly Ile Ala Met Ala Thr His Lys
515 520 525
Asp Asp Glu Glu Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile Phe Gly
530 535 540
Lys Gln Asn Ala Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val Met Leu
545 550 555 560
Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Glu
565 570 575
Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala Pro Gln
580 585 590
Ile Gly Thr Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val Trp Gln
595 600 605
Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asp Pro Pro Thr Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Tyr Lys Ser Thr Ser Val Asp Phe Ala Val Asn Thr Glu Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
Claims (11)
- 서열번호 3의 서열과 98 % 이상의 상동성 또는 서열번호 4의 서열과 94 % 이상의 상동성을 갖는 아미노산 서열을 갖는, AAV 캡시드 단백질.
- 제1항에 있어서,
상기 아미노산 서열은 서열번호 3의 서열과 99 % 이상의 상동성 또는 서열번호 4의 서열과 97 % 이상의 상동성을 갖는, AAV 캡시드 단백질.
- 제1항 또는 제2항에 있어서,
상기 아미노산 서열은 서열번호 3의 서열을 갖는, AAV 캡시드 단백질.
- 제1항 또는 제2항에 있어서,
상기 아미노산 서열은 서열번호 4의 서열을 갖는, AAV 캡시드 단백질.
- 제1항 내지 제4항 중 어느 한 항의 캡시드 단백질을 포함하는, AAV 캡시드.
- 제1항 내지 제4항 중 어느 한 항의 캡시드 단백질을 포함하는, 바이러스 입자.
- 제1항 내지 제4항 중 어느 한 항의 캡시드 단백질을 암호화하는 염기서열을 포함하는, 재조합 AAV 벡터.
- 재조합 AAV 벡터를 포유류에 도입하는 단계;를 포함하는 목적 핵산을 포유류로 전달하는 방법으로,
상기 재조합 AAV 벡터는 제1항 내지 제4항 중 어느 한 항의 캡시드 단백질을 포함하는 캡시드 내에 둘러싸여진 목적 유전자를 포함하는 것인, 방법.
- 제1항 내지 제4항 중 어느 한 항의 캡시드 단백질 또는 제7항의 벡터를 포함하는 숙주 세포.
- 제1항 내지 제4항 중 어느 한 항의 캡시드 단백질 또는 제7항의 벡터를 포함하는 세포를 포함하는 형질전환 동물.
- 제 1 항 내지 제 4 항 중 어느 한 항의 캡시드 단백질 또는 제 7 항의 벡터; 및 하나 이상의 약학적으로 허용되는 부형제를 포함하는, 약학적 조성물.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20200021765A (ko) | 2018-08-21 | 2020-03-02 | 코나아이 (주) | 가상 화폐 결제 방법 및 시스템 |
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| US20180111965A1 (en) | 2018-04-26 |
| JP6619454B2 (ja) | 2019-12-11 |
| US20200079821A1 (en) | 2020-03-12 |
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| HUE042693T2 (hu) | 2019-07-29 |
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| HRP20190442T1 (hr) | 2019-05-03 |
| CN107864653B (zh) | 2022-06-21 |
| LT3250239T (lt) | 2019-03-25 |
| PT3250239T (pt) | 2019-02-19 |
| DK3250239T3 (en) | 2019-03-11 |
| US10414803B2 (en) | 2019-09-17 |
| JP2018520997A (ja) | 2018-08-02 |
| EP3250239A1 (en) | 2017-12-06 |
| ES2711349T3 (es) | 2019-05-03 |
| CA2985945A1 (en) | 2016-11-17 |
| CN107864653A (zh) | 2018-03-30 |
| TR201901582T4 (tr) | 2019-02-21 |
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