KR20230145411A - 변형된 독소 폴리펩티드의 제조 방법 - Google Patents
변형된 독소 폴리펩티드의 제조 방법 Download PDFInfo
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- KR20230145411A KR20230145411A KR1020237031005A KR20237031005A KR20230145411A KR 20230145411 A KR20230145411 A KR 20230145411A KR 1020237031005 A KR1020237031005 A KR 1020237031005A KR 20237031005 A KR20237031005 A KR 20237031005A KR 20230145411 A KR20230145411 A KR 20230145411A
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Abstract
변형된 독소 폴리펩티드의 제조 방법이 제공되며, 상기 제조 방법은, 변형된 독소 폴리펩티드 전구체를 발현시키는 단계 1); 상기 독소 폴리펩티드 전구체를 농축시키는 단계 2); 상기 독소 폴리펩티드 전구체를 활성화시켜 변형된 독소 폴리펩티드를 얻는 단계 3)을 포함한다.
Description
본 발명은 생명 공학 기술 및 생체 공학 분야에 속하는 것으로, 구체적으로 변형된 독소 폴리펩티드의 제조 방법에 관한 것이다.
관련 출원의 상호 참조
본원 발명은 출원번호가 202110217756.1이고 출원일이 2021년 2월 26일인 출원을 본원 발명의 우선권으로 주장하는 바, 우선권 문서의 내용은 그 전체가 참조로서 여기에 인용된다.
폴리펩티드는 여러 아미노산이 펩티드 결합을 통해 연결되어 형성된 화합물의 한 종류로, 일반적으로 10~100개의 아미노산 분자로 구성되며, 그 연결 방식은 단백질과 동일하고, 상대 분자질량이 10000 미만이다. 폴리펩티드는 일반적으로 생물체 내에 존재하고, 지금까지 생물체 내에서 수만 종의 폴리펩티드가 발견되었으며, 이는 유기체 내 각 시스템, 기관, 조직 및 세포의 기능적 활동에 광범위하게 참여하고 조절하며 생명 활동에서 중요한 역할을 한다.
폴리펩티드계 약물은 화학적 합성, 유전자 재조합 또는 동식물로부터의 추출에 의한 특정 치료 효과를 갖는 폴리펩티드로, 의약 분야에서 폴리펩티드의 구체적인 용도를 의미한다. 폴리펩티드의 생물학적 활성은 광범위하고 중요하며, 내분비계, 면역계, 소화계, 심혈관계, 혈액계, 근골격계 등에 광범위하게 작용할 수 있으므로, 폴리펩티드는 약물로서의 개발 역사가 비교적 짧지만 그 발전 속도가 매우 빨라 현재 시장 개발의 핫이슈가 되었다. 폴리펩티드는 주로 암 및 대사 장애와 관련된 중대 질환을 치료하는데 사용되며 이러한 질환과 관련된 약물은 세계적으로 매우 중요한 시장을 가지고 있다.
폴리펩티드계 약물에서 독소 폴리펩티드는 천연 독소 폴리펩티드 또는 유전자 재조합에 의해 생성된 변형된 독소 폴리펩티드를 포함하여 일정한 점유율을 차지하는데, 경련, 미용 및 항종양 치료에서 천연 분자 또는 융합 단백질로서의 이러한 독소 폴리펩티드의 역할은 잘 알려져 있다.
클로스트리듐 독소(CNTs)는 7가지 상이한 혈청형의 보툴리눔 독소(BoNTs) 및 파상풍 독소(tetX, TeNT라고도 함)를 포함하는 것으로 알려져 있으며, 이들은 모두 이황화 결합으로 연결된 각각 약 50KDa의 경쇄(L) 및 약 100KDa의 중쇄(H)인 2개의 폴리펩티드 분자를 포함하고, 경쇄는 프로테아제 활성 영역을 포함하며, 중쇄는 전위 도메인(N-말단) 및 수용체 결합 도메인(C-말단)을 포함한다. 모든 혈청형의 보툴리눔 신경독소(BoNTs) 및 클로스트리듐 테타니에 의해 분비된 관련 파상풍 신경독소(tetX)는 모두 세포막 융합을 제어하는 SNARE 복합체의 형성에 관여하는 단백질을 절단하여 시냅스 엑소시토시스를 방지하고 신경전달물질의 방출을 억제하며 신경 신호 전달을 차단하는 Zn2+ 프로테아제이다. A형 보툴리눔 신경독소(BoNT/A)는 1989년 미국에서 사시, 안검 경련 및 다른 질환의 치료용으로 승인되었다. 일부 용도에서, 보툴리눔 독소는 추가적인 박테리아 단백질과의 복합체 형태로 치료하고자 하는 근육에 직접 주사되고, 생리학적 pH값에서, 독소는 단백질 복합체로부터 방출되어(Eisele et al.2011, Toxicon 57(4): 555-65.), 원하는 약리학적 효과를 생성한다. 또한, FDA는 B형 보툴리눔 독소를 경부 근육 긴장 이상 치료용으로 승인하였다.
디프테리아 독소 및 슈도모나스 외독소는 종종 독소 유사 융합 단백질 표적 약물을 구성하는데 사용된다. 천연 디프테리아 독소는 535개의 아미노산으로 구성되어 있으며 이황화 결합으로 연결된 총 2개의 서브유닛을 가지고 있고 14개의 아미노산의 고리와 결합된 2개의 이황화 결합을 포함하며, 디프테리아 독소의 2개의 서브유닛은 프로테아제 기능적 도메인, 수용체 결합 기능적 도메인 및 수송 기능적 도메인 이 3개의 단백질 도메인을 포함하고, 여기서, 프로테아제 기능적 도메인이 일단 세포질에 들어가면 촉매 인자-2의 ADP 리보실화 작용을 연장하여 단백질 합성 억제 및 세포 사멸을 초래할 수 있다. 따라서 사람들은 유전공학을 이용하여 디프테리아 독소 천연 수용체 결합 기능적 도메인을 종양 세포를 표적으로 하는 수용체 결합 기능적 도메인으로 대체하였는데, 이러한 융합 단백질은 특정 세포를 표적으로 하여 디프테리아 독소의 독성을 발휘시킨다("인터류킨 13과 디프테리아 독소 융합 단백질의 표적 치료 활성에 대한 연구”, Du Juan 등, "의학 연구 저널”, 2008(037)010, 3136).
슈도모나스 외독소는 디프테리아 독소의 구조와 유사하여 역시 프로테아제 기능적 도메인, 수용체 결합 기능적 도메인 및 수송 기능적 도메인 이 3개의 단백질 도메인을 포함한다. 현재, 슈도모나스 독소를 살상 그룹으로 사용하는 일련의 면역 융합 독소가 구축되었으며, 인터류킨, 성장 인자 및 단일 사슬 항체 등을 포함하여 특이성 리간드로서 선택하였다(재조합 인터류킨 2 슈도모나스 외독소 융합 단백질의 정제 및 재생, Hu Zhiming 등, "제1군 의과대학 저널”, 1000-2588(2002)03-0206-02).
콜레라 독소(CTX)는 콜레라균에 의해 생성된 독소 폴리펩티드로, 심각한 설사와 인체 탈수를 일으킬 수 있다. CTX는 분자량이 약 84kDa인 올리고단백질로, 하나의 A 서브유닛 및 주변에 둘러싸여 있는 5개의 B 서브유닛을 포함하여 구성된다. B 서브유닛은 홀로톡신 인식 및 포유동물 세포 표면의 GM1 강글리오시드 수용체에 대한 결합을 담당하고, A 서브유닛이 세포로 들어가는 것을 촉진하며; A 서브유닛은 ADP-리보실-트랜스퍼라제(ADP-ribosyl-transferase)의 활성을 담당하며, 이 효소는 Gs 단백질의 발현을 하향 조절하고 AC 효소를 활성화시켜 cAMP 수준의 향상을 촉진할 수 있다. A 서브유닛은 또한 ROS(rod outer segment)의 수송체를 ADP 리보실화하여 GTPase를 비활성화시킬 수 있다. GM1 강글리오시드 수용체가 일반적으로 진핵 세포막에 존재하기 때문에 CTX는 다양한 모델 시스템에서 아데닐레이트 시클라제(AC)를 활성화하는데 사용된다. CTX는 또한 IL-12 생성을 억제하여 2형 헬퍼 T 세포 면역 반응을 유도하는 점막 백신 보조제이다. 콜레라 독소의 A 서브유닛의 프로테아제 기능과 그 B 서브유닛의 표적 인식 및 결합 기능을 이용하여 제조된 융합 단백질은 항종양 분야에서 적용될 수 있다(CN201910673683.X).
의학적 및 미용적 측면에서 독소 폴리펩티드의 역할과 항종양에서의 융합 단백질의 역할이 인식되었지만, 그 독성으로 인해 제조 과정에서 환경 보호 및 조작자 보호를 고려해야 하므로, 독소 폴리펩티드의 제조는 일반적으로 BL-3 환경 또는 대형 아이솔레이터에서 수행되는데, 이는 의심할 여지 없이 생산 비용을 증가시키며, 이러한 독소의 대규모 산업적 생산에 불리하다.
선행기술의 결점을 극복하기 위해, 본 발명은 변형된 독소 폴리펩티드의 제조 방법을 제공하며, 구체적으로 다음과 같다.
본 발명의 제1 양태에서, 변형된 독소 폴리펩티드의 제조 방법을 제공하며, 여기서, 상기 제조 방법은, 변형된 독소 폴리펩티드 전구체를 발현시키는 단계 1); 상기 독소 폴리펩티드 전구체를 농축시키는 단계 2); 및 상기 독소 폴리펩티드 전구체를 활성화시켜 변형된 독소 폴리펩티드를 얻는 단계 3)을 포함한다.
바람직하게는, 상기 단계 1)은, (1) 상기 독소 폴리펩티드 전구체를 코딩하는 핵산 분자를 구축하는 단계; (2) 상기 핵산 분자를 포함하는 벡터를 구축하는 단계; (3) 상기 핵산 벡터를 적합한 숙주 세포에 형질전환하는 단계; 및 (4) 상기 숙주 세포를 배양하고, 숙주 세포가 상기 핵산 벡터에 의해 코딩된 독소 폴리펩티드 전구체를 발현하도록 허용 또는 유도하는 단계를 포함한다.
더 바람직하게는, 상기 단계 1)은, (5) 독소 폴리펩티드 전구체를 발현할 수 있는 세포를 발효시키는 단계를 더 포함한다.
보다 더 바람직하게는, 상기 단계 1)은, (6) 상기 독소 폴리펩티드를 발현하는 세포를 용해시켜 상기 독소 폴리펩티드 전구체를 포함하는 세포 용해 버퍼를 얻는 단계를 더 포함한다.
바람직하게는, 상기 단계 2)는 다중 여과 단계를 수행하여 상기 독소 폴리펩티드 전구체를 농축시키는 단계를 포함한다.
더 바람직하게는, 상기 다중 여과는 조액 여과 및 공급액 순환 여과를 포함한다.
보다 더 바람직하게는, 상기 조액 여과 단계에서 용해 버퍼를 공급액과 잔사로 나눈다.
보다 더 바람직하게는, 상기 조액 여과 재료의 기공 크기는 0.1~0.65μm이다.
보다 더 바람직하게는, 조액 여과에 의해 통과하지 못한 물질은 잔사로서 배출된다.
보다 더 바람직하게는, 상기 잔사는 완충액의 작용 하에 조액 여과 재료로부터 분리된다.
바람직하게는, 조액 여과 통과율 초기 속도의 50%보다 낮을 때 조액 여과에 들어가는 물질은 용해 버퍼에서 완충액으로 전환된다.
보다 더 바람직하게는, 상기 공급액 순환 여과 단계에서 공급액을 여러 번 여과하고, 여러 번 여과하는 과정에서, 완제품 액체 수집 조건에 부합되는 공급액을 완제품 액체로서 수집하며, 폐액 조건에 부합되는 공급액을 폐액으로서 배출시킨다.
보다 더 바람직하게는, 완제품 액체 수집 조건은 공급액의 탁도이고, OD600<0.1인 경우, 완제품 액체로서 수집된다.
보다 더 바람직하게는, 폐공급액 배출 조건은 공급액의 탁도이고, OD600>0.1인 경우, 폐공급액으로서 배출된다.
보다 더 바람직하게는, 폐공급액 배출 조건은 2회 이상 순환되어도 완제품 액체 수집 조건을 여전히 충족할 수 없는 공급액이다.
보다 더 바람직하게는, 상기 조액 여과 재료 및 공급액 순환 여과 재료는 친수성 여과 재료 또는 소수성 여과 재료로부터 선택된다.
보다 더 바람직하게는, 상기 친수성 여과 재료는 셀룰로오스 에스테르, 폴리에테르 술폰, 폴리에틸렌 등 또는 이들의 유도체로부터 선택된다.
보다 더 바람직하게는, 상기 소수성 여과 재료는 폴리비닐리덴 플루오라이드, 폴리프로필렌, 폴리테트라플루오로에틸렌 등 또는 이들의 유도체로부터 선택된다.
더 바람직하게는, 상기 용해 버퍼 분리 장비는 작동 시 완전히 밀폐된다.
보다 더 바람직하게는, 상기 용해 버퍼 분리 장비는 아이솔레이터와 같은 추가 격리 조치가 필요없다.
바람직하게는, 상기 단계 3)에서 프로테아제로 독소 폴리펩티드 전구체를 절단하여 변형된 독소 폴리펩티드를 얻는다.
더 바람직하게는, 상기 독소 폴리펩티드는 저독성 독소 폴리펩티드 전구체 형태로 세포 또는 용해 버퍼에 존재하고, 프로테아제 활성화 단계 후 독성이 높은 독소 폴리펩티드가 얻어진다.
보다 더 바람직하게는, 상기 저독성은 활성화 후 고독성에 비해 상대적이며, 구체적인 일 실시형태에서, 상기 활성화된 독소 폴리펩티드의 활성은 독소 폴리펩티드 전구체의 활성보다 적어도 5000배 더 높고, 더 나아가, 활성화된 독소 폴리펩티드의 활성은 독소 폴리펩티드 전구체의 활성보다 6000, 7000, 8000, 9000, 10000, 12000, 15000배, 심지어 더 높다.
바람직하게는, 상기 제조 방법은 상기 독소 폴리펩티드를 정제하는 단계 4)를 더 포함한다.
더 바람직하게는, 상기 단계 4)는 적어도 하나의 크로마토그래피 단계를 포함한다. 더 바람직하게는, 2개, 3개 또는 그 이상의 크로마토그래피 단계를 포함할 수 있다.
더 바람직하게는, 상기 다수의 크로마토그래피 단계는 동일하거나 상이할 수 있다.
더 바람직하게는, 상기 크로마토그래피 단계는 친화성 크로마토그래피, 겔 여과 크로마토그래피 및/또는 이온 크로마토그래피이다.
더 바람직하게는, 상기 단계 3)의 활성화 단계 및 단계 4)의 정제 단계는 아이솔레이터에서 수행된다.
바람직하게는, 상기 독소 폴리펩티드 전구체는 제2 폴리펩티드 단편을 포함하고, 상기 제2 폴리펩티드 단편은,
(a) 금속 이온 의존성 프로테아제 활성 도메인을 포함하는 제1 기능성 아미노산 구조 영역;
(b) 제2 프로테아제 절단 부위를 포함하는 구조 영역;
(c) 표적 세포 표면 수용체에 결합할 수 있는 수용체 결합 도메인 및/또는 소포 막을 가로지르는 폴리펩티드의 전위를 매개할 수 있는 전위 도메인을 포함하는 제2 기능성 아미노산 구조 영역을 포함한다.
더 바람직하게는, 상기 금속 이온 의존성 프로테아제 활성 도메인은 Zn2+ 의존성 프로테아제 활성 도메인이다.
더 바람직하게는, 상기 제1 기능성 아미노산 구조 영역 및/또는 제2 기능성 아미노산 구조 영역은 천연 서열 및/또는 인공 합성 서열에 의해 코딩된다.
보다 더 바람직하게는, 상기 독소 폴리펩티드 전구체의 제1 기능성 아미노산 구조 영역은 클로스트리듐 독소 경쇄의 Zn2+ 프로테아제 결합 도메인을 포함한다.
보다 더 바람직하게는, 상기 제2 기능성 아미노산 구조 영역에서 인체 세포 표면 항원의 수용체 결합 도메인에 결합할 수 있는 표적 세포는 SNARE 복합체에 존재하는 표적 세포를 의미한다. 예를 들어, 신경 세포, 췌장 세포 또는 다른 SNARE 복합체에 존재하는 세포이다.
보다 더 바람직하게는, 상기 제2 기능성 아미노산 구조 영역에서 표적 세포는 인간 신경 세포 또는 췌장 세포를 의미하며, 상기 수용체 결합 도메인은 인간 신경 세포 또는 췌장 세포에 특이적으로 결합할 수 있는 수용체 결합 도메인이다.
보다 더 바람직하게는, 상기 제2 기능성 아미노산 구조 영역의 수용체 결합 도메인은 클로스트리듐 독소의 중쇄의 세포 표면 항원 결합 도메인이고, 상기 제2 기능성 아미노산 구조 영역의 소포 막을 가로지르는 폴리펩티드의 전위를 매개하는 전위 도메인은 소포 막을 가로지르는 클로스트리듐 독소의 전위를 매개하는 도메인이다.
보다 더 바람직하게는, 상기 클로스트리듐 독소는 보툴리눔 독소 또는 파상풍 독소이다.
보다 더 바람직하게는, 상기 보툴리눔 독소는 선행기술에 공지된 혈청형 BoNT/A-BoNT/H 및 이들의 유도체 중 임의의 하나로부터 선택된다.
보다 더 바람직하게는, 상기 클로스트리듐 독소는 파상풍 독소 또는 이의 유도체 중 임의의 하나로부터 선택된다. 더 바람직하게는, 상기 제1 기능성 아미노산 구조 영역은 BoNT/A, BoNT/B, BoNT/C, BoNT/D, BoNT/E, BoNT/F, BoNT/G, BoNT/H 또는 파상풍 독소의 경쇄의 일부 또는 전부를 포함한다.
보다 더 바람직하게는, 상기 제2 기능성 아미노산 구조 영역은 BoNT/A, BoNT/B, BoNT/C, BoNT/D, BoNT/E, BoNT/F, BoNT/G, BoNT/H 또는 파상풍 독소의 중쇄의 일부 또는 전부를 포함한다.
구체적인 일 실시예에서, 상기 제1 기능성 아미노산 구조 영역은 BoNT/A의 경쇄이고, 상기 제2 기능성 아미노산 구조 영역은 BoNT/A의 중쇄이다.
보다 더 바람직하게는, 상기 제1 기능성 아미노산 구조 영역 및 제2 기능성 아미노산 구조 영역은 상이한 혈청형으로부터 유래될 수 있다. 상기 혈청형의 임의의 조합일 수 있으며, 예를 들어, 상기 제1 기능성 아미노산 구조 영역은 BoNT/A의 경쇄로부터 유래되고, 상기 제2 기능성 아미노산 구조 영역은 BoNT/B의 중쇄로부터 유래되거나, 또는, 상기 제1 기능성 아미노산 구조 영역은 BoNT/A의 경쇄로부터 유래되고, 상기 제2 기능성 아미노산 구조 영역은 BoNT/C의 중쇄로부터 유래된다.
보다 더 바람직하게는, 상기 제2 폴리펩티드 단편의 아미노산 서열은 서열번호 7로 표시되는 단편을 포함한다.
바람직하게는, 상기 독소 폴리펩티드 전구체는 제1 폴리펩티드 단편을 더 포함하고, 상기 제1 폴리펩티드 단편은 태그 단백질을 포함한다.
더 바람직하게는, 상기 제1 폴리펩티드 단편은 제1 프로테아제 절단 부위의 구조 영역을 더 포함한다.
더 바람직하게는, 상기 제1 폴리펩티드 단편은 링커 숏 펩티드를 더 포함한다.
구체적인 일 실시형태에서, 상기 독소 폴리펩티드 전구체는,
(I) 제1 폴리펩티드 단편;
(II) 제2 폴리펩티드 단편을 포함하고;
상기 제1 폴리펩티드 단편은,
(a) 태그 단백질,
(b) 제1 프로테아제 절단 부위를 포함하는 구조 영역;
(c) 링커 숏 펩티드를 포함하며;
상기 제2 폴리펩티드 단편은,
(d) 금속 이온 의존성 프로테아제 활성 도메인을 포함하는 제1 기능성 아미노산 구조 영역;
(e) 제2 프로테아제 절단 부위를 포함하는 구조 영역;
(f) 표적 세포 표면 수용체에 결합할 수 있는 수용체 결합 도메인 및/또는 소포 막을 가로지르는 폴리펩티드의 전위를 매개할 수 있는 전위 도메인을 포함하는 제2 기능성 아미노산 구조 영역을 포함한다.
용어 "태그 단백질”은 특정 리간드에 결합할 수 있는 한 종류의 단백질 분자를 의미한다.
상기 "태그 단백질”은 숙주에서 독소 폴리펩티드 전구체의 가용성을 증가시킬 수 있다.
상기 "태그 단백질”은 독소 폴리펩티드 전구체가 가용성 형태로 숙주 세포에 존재하도록 한다.
더 바람직하게는, 상기 태그 단백질은 당업자에게 공지된 태그 단백질 또는 컴퓨터 프로그램에 의해 설계된 태그 단백질로부터 선택될 수 있고, 상기 태그 단백질은 공지된 기질에 특이적으로 결합할 수 있다.
보다 더 바람직하게는, 상기 태그 단백질은 글루타티온 S-트랜스퍼라제(GSTs), C-myc, 키틴 결합 도메인, 말토스 결합 단백질(MBP), SUMO 이종 친화성 부분, 단클론 항체 또는 단백질 A, 스트렙타비딘 결합 단백질(SBP), 셀룰로오스 결합 도메인, 칼모듈린 결합 펩티드, S 태그, Strep 태그 II, FLA, 단백질 A, 단백질 G, 히스티딘 친화성 태그(HAT), 폴리히스티딘으로부터 선택되지만 이에 한정되지 않는다.
구체적인 일 실시예에서, 상기 태그 단백질은 독소 폴리펩티드 전구체의 N-말단에 위치한다.
구체적인 일 실시예에서, 상기 태그 단백질은 글루타티온 S-트랜스퍼라제(GSTs)이고, 더 바람직하게는, 상기 글루타티온 S-트랜스퍼라제의 아미노산 서열은 서열번호 2로 표시된다.
더 바람직하게는, 상기 제1 프로테아제 절단 부위 및 제2 프로테아제 절단 부위는 모두 인간 프로테아제, 또는 상기 독소 폴리펩티드 전구체를 발현하는 숙주 세포 자체에 의해 생성된 프로테아제에 의해 절단될 수 없다.
더 바람직하게는, 상기 제1 프로테아제 절단 부위와 제2 프로테아제 절단 부위는 동일하거나 상이하다.
상기 제1 프로테아제 절단 부위 및 제2 프로테아제 절단 부위는 발현 시 숙주 세포 또는 사용 시 유기체 내인성 프로테아제에 의해 인식 및 절단되지 않는다.
더 바람직하게는, 상기 단계 3)의 활성화는 제2 프로테아제를 사용하여 독소 폴리펩티드 전구체의 제2 프로테아제 절단 부위를 절단하는 것을 포함한다.
보다 더 바람직하게는, 상기 활성화는 제1 프로테아제를 사용하여 독소 폴리펩티드 전구체의 제1 프로테아제 절단 부위를 절단하는 것을 더 포함한다.
구체적인 일 실시형태에서, 상기 제1 프로테아제와 제2 프로테아제는 동일하다.
더 바람직하게는, 상기 특정 프로테아제는 비인간 엔테로키나제, 담배 식각 바이러스 프로테아제, 고초균 유래 프로테아제, 바실러스 아밀로리퀴파시엔스 유래 프로테아제, 리노바이러스 유래 프로테아제, 파파인, 곤충 파파인의 동족체 또는 갑각류 파파인의 동족체 중 하나 또는 둘의 조합으로부터 선택되지만 이에 한정되지 않는다.
구체적인 일 실시예에서, 상기 제1 프로테아제 절단 부위를 특이적으로 인식하는 프로테아제 및 상기 제2 프로테아제 절단 부위를 특이적으로 인식하는 프로테아제는 모두 리노바이러스 유래 프로테아제이다.
더 바람직하게는, 제2 절단 부위는 제1 기능성 펩티드 단편과 제2 기능성 펩티드 단편 사이의 자연 발생 루프에 삽입되거나 이를 부분적으로 대체하거나 완전히 대체한다. 상기 삽입은 상기 루프의 특정 두 아미노산 사이에 삽입되는 것을 의미하고; 상기 부분적으로 대체한다는 것은 상기 제2 절단 부위가 상기 루프의 일부 아미노산 서열을 대체하는 것을 의미하며; 상기 완전히 대체한다는 것은 자연 발생 루프의 아미노산 서열이 제2 절단 부위에 의해 완전히 대체되는 것을 의미한다.
더 바람직하게는, 상기 제1 프로테아제 절단 부위 및 제2 프로테아제 절단 부위는 DDDDK, EXXYXQS/G, HY, YH 또는 LEVLFQGP 중 하나 또는 둘의 조합으로부터 선택되지만 이에 한정되지 않는다.
구체적인 일 실시예에서, 상기 제1 프로테아제 절단 부위 및 제2 프로테아제 절단 부위는 모두 LEVLFQGP이다. 더 바람직하게는, 상기 링커 숏 펩티드는 5개의 아미노산을 초과하지 않는다.
보다 더 바람직하게는, 상기 링커 숏 펩티드는 제1 프로테아제 절단 부위가 프로테아제에 의해 더 쉽게 인식되거나 결합되도록 할 수 있다.
보다 더 바람직하게는, 상기 링커 숏 펩티드는 독소 폴리펩티드 전구체의 기능에 영향을 미치지 않는다.
보다 더 바람직하게는, 상기 제1 프로테아제 절단 부위가 절단된 후, 제2 폴리펩티드 단편의 N-말단에 보존된 링커 숏 펩티드는 제2 폴리펩티드 단편의 기능에 영향을 미치지 않는다.
보다 더 바람직하게는, 상기 링커 숏 펩티드의 GS 부분은 5개의 아미노산 잔기를 초과하지 않으며, 더 바람직하게는, 상기 링커 숏 펩티드는 글리신-세린(Glycine-Serine, 약칭 GS) 숏 펩티드, GGS, GGGS, GGGGS, GSGS, GGSGS, GSGGS, GGSGS, GGGSS 등 링커 숏 펩티드로부터 선택된다.
구체적인 일 실시예에서, 상기 제1 프로테아제 절단 부위를 포함하는 구조 영역 및 링커 숏 펩티드의 아미노산 서열은 LEVLFQGPLGS이다.
구체적인 일 실시형태에서, 상기 독소 폴리펩티드 전구체는 N-말단으로부터 시작하여 글루타티온 S-트랜스퍼라제, LEVLFQGPLGS, BoNT/A의 경쇄, LEVLFQGP 및 BoNT/A의 중쇄를 순차적으로 포함한다.
더 바람직하게는, 상기 독소 폴리펩티드 전구체의 아미노산 서열은 서열번호 11로 표시된다.
바람직하게는, 상기 독소 폴리펩티드 전구체를 코딩하는 핵산 분자를 구축하는 상기 단계 (1)에서 핵산 분자는 상기 독소 폴리펩티드 전구체를 코딩하는 핵산 분자이다. 더 바람직하게는, 상기 핵산 분자는 상기 독소 폴리펩티드 전구체의 각 부분을 코딩하는 뉴클레오티드 서열로 구성된다.
구체적인 일 실시예에서, 상기 태그 단백질을 코딩하는 서열은 서열번호 1로 표시되는 서열을 포함한다.
구체적인 일 실시예에서, 상기 제1 프로테아제 절단 부위를 포함하는 구조 영역을 코딩하는 뉴클레오티드 서열은 서열번호 3으로 표시되는 서열을 포함한다.
구체적인 일 실시예에서, 상기 제2 프로테아제 절단 부위를 포함하는 구조 영역을 코딩하는 뉴클레오티드 서열은 서열번호 8로 표시되는 서열을 포함한다.
구체적인 일 실시예에서, 상기 제2 폴리펩티드 단편의 아미노산 서열은 서열번호 7로 표시되는 서열을 포함한다.
구체적인 일 실시예에서, 상기 제2 폴리펩티드 단편을 코딩하는 뉴클레오티드 서열은 서열번호 6으로 표시되는 서열을 포함한다.
구체적인 일 실시예에서, 상기 독소 폴리펩티드 전구체를 코딩하는 뉴클레오티드 서열은 서열번호 10으로 표시된다.
바람직하게는, 상기 핵산 분자를 포함하는 벡터를 구축하는 단계 (2)에서, 상기 벡터는 상기 핵산 분자, 또는 상기 독소 폴리펩티드 전구체를 코딩하는 오픈 리딩 프레임을 포함한다.
더 바람직하게는, 상기 벡터는 플라스미드, 파지, 바이러스 벡터 등이다.
바람직하게는, 상기 핵산 벡터를 적합한 숙주 세포에 형질전환하는 단계 (3)에서, 상기 세포는 진핵 생물 세포 또는 원핵 생물 세포이다.
더 바람직하게는, 상기 세포는 대장균, 효모, 시아노박테리아 또는 포유동물 세포, 곤충 세포, 식물 세포 또는 양서류 세포로부터 선택된다.
보다 더 바람직하게는, 상기 세포는 대장균이다.
기존의 독소 폴리펩티드의 제조 방법과 비교하여 본 발명의 제조 방법은 독소 폴리펩티드를 먼저 저독성 독소 폴리펩티드 전구체로 발현하고, 대용량으로 농축시킨 후 활성화를 통해 활성이 있는 독소 폴리펩티드로 전환시킴으로써, 환경 및 작업자에 대한 대용량 조작 단계의 위험을 크게 감소시키고, 격리 장비 추가 비용을 절감하며; 대용량의 용해 버퍼를 처리할 때 독소 폴리펩티드 전구체의 농축 단계를 수행하고, 다중 여과 및 폐기물 등급화 배출 방법을 사용하여 목적 단백질의 수율을 향상시킬 수 있다. 이러한 방법은 특히 저독성 폴리펩티드에 적용되며, 완전히 밀폐된 세포 용해 버퍼 분리 단계를 거친 후 얻은 폐액은 저독성 독소 폴리펩티드 전구체를 거의 포함하지 않으며, 조작 환경에 대한 독성이 매우 낮아 간단한 소독 처리 후 직접 배출될 수 있다.
정제 단계를 추가로 결합한 후, 완제품 액체 내 독소 폴리펩티드의 함량은 90%보다 클 수 있으며, 수율이 더 높고 순도가 더 높으며 안전성도 더 높기 때문에 본 발명에 의해 제공되는 제조 방법은 선행기술에 비해 독소 폴리펩티드의 생산 및 정제를 더 쉽게 수행할 수 있으므로, 임상 사용을 위해 고순도 독소 폴리펩티드를 대규모로 제조할 수 있다.
도 1은 본 발명의 제조 방법의 흐름 모식도이다.
도 2는 GSTs-BoNT/A 예비 정제 및 GSTs 태그 추가 제거의 SDS-PAGE 결과이며, 여기서, 제1 레인은 GSTs 친화성 크로마토그래피 컬럼에 의한 예비 정제를 통해 얻은 GSTs-BoNT/A이고, 제2 레인은 예비 정제된 단백질을 리노바이러스 3C 프로테아제(Rinovirus 3C Protease)로 절단하여 GSTs 태그 단백질을 제거하여 얻은 GSTs가 절제된 BoNT/A이다.
도 3은 GSTs 태그가 절제된 생성물을 이온 교환 컬럼으로 추가 정제하여 얻은 고순도 BoNT/A 단백질의 SDS-PAGE 결과이다.
도 4는 환원 조건에서 BoNT/A의 이중 가닥 해리의 검증 결과이다.
도 2는 GSTs-BoNT/A 예비 정제 및 GSTs 태그 추가 제거의 SDS-PAGE 결과이며, 여기서, 제1 레인은 GSTs 친화성 크로마토그래피 컬럼에 의한 예비 정제를 통해 얻은 GSTs-BoNT/A이고, 제2 레인은 예비 정제된 단백질을 리노바이러스 3C 프로테아제(Rinovirus 3C Protease)로 절단하여 GSTs 태그 단백질을 제거하여 얻은 GSTs가 절제된 BoNT/A이다.
도 3은 GSTs 태그가 절제된 생성물을 이온 교환 컬럼으로 추가 정제하여 얻은 고순도 BoNT/A 단백질의 SDS-PAGE 결과이다.
도 4는 환원 조건에서 BoNT/A의 이중 가닥 해리의 검증 결과이다.
아래 구체적인 실시예와 결부하여 본 발명을 추가로 설명하며, 본 발명의 장점 및 특징은 설명과 함께 더욱 명확해질 것이다. 그러나 이러한 실시예는 단지 예시적인 것으로 본 발명의 범위를 어떠한 방식으로도 제한하지 않는다. 당업자는 본 발명의 사상 및 범위를 벗어나지 않고 본 발명의 기술적 해결수단의 세부 내용 및 형태를 수정 또는 대체할 수 있지만 이러한 수정 및 대체는 모두 본 발명의 보호 범위 내에 속하는 것으로 이해해야 한다.
실시예 1: GSTs-BoNT/A의 발현
본 발명의 제조 방법의 흐름 모식도는 도 1에 도시된 바와 같으며, 변형된 독소 폴리펩티드를 발현시키는 단계 1)은 구체적으로 다음과 같다.
(가): 변형된 독소 폴리펩티드 전구체를 코딩하는 핵산 분자의 설계 및 구축:
1. 핵산 분자는 5' 말단으로부터 시작하여 다음을 순차적으로 포함한다.
(a) 글루타티온 S-트랜스퍼라제를 코딩하는 뉴클레오티드 서열은 서열번호 1로 표시되고, 이에 의해 코딩된 글루타티온 S-트랜스퍼라제의 아미노산 서열은 서열번호 2로 표시되며;
(b) 제1 프로테아제 절단 부위를 코딩하는 뉴클레오티드 서열은 서열번호 3으로 표시되고, 이에 의해 코딩된 아미노산 서열은 서열번호 4로 표시되며;
(c) GS 링커 숏 펩티드를 코딩하는 뉴클레오티드 서열은 서열번호 5로 표시되며 GGATCC이고;
(d) 제2 폴리펩티드 단편을 코딩하는 뉴클레오티드 서열은 BoNT/A경쇄, 제2 프로테아제 절단 부위 및 BoNT/A중쇄의 뉴클레오티드 서열을 포함하고, 서열번호 6으로 표시되며, 이에 의해 코딩된 아미노산 서열은 서열번호 7로 표시되고; 여기서, 제2 프로테아제 절단 부위를 코딩하는 뉴클레오티드 서열은 서열번호 8로 표시되며, 이에 의해 코딩된 아미노산 서열은 서열번호 9로 표시되고;
제1 기능성 아미노산 구조 영역과 제2 기능성 아미노산 구조 영역 사이에는 자연 발생 루프가 존재하지 않을 수도 있으며, 예를 들어, 경쇄와 중쇄 사이의 KTKSLDKGYNK 연결 서열을 제거하여 비특이적 프로테아제 절단을 감소시킨다.
독소 폴리펩티드 전구체를 코딩하는 뉴클레오티드 서열은 서열번호 10으로 표시되고, 이에 의해 코딩된 독소 폴리펩티드 전구체의 아미노산 서열은 서열번호 11로 표시된다.
(나): 단계 1의 핵산 분자를 포함하는 플라스미드의 구축
단계 (가)에서 유전공학에 의해 최적화된 GSTs-BoNT/A를 인공 합성하고, 양 말단을 합성하여 NdeI 및 NotI 절단 부위를 추가하며, 37℃에서 NdeI 및 NotI를 통해 절단하고(뉴잉글랜드 바이오랩스(New England Biolabs)), QIquick 젤 추출 키트(QIquick gel extraction kit)(퀴아젠(Qiagen))를 사용하여 정제하며, T4 DNA 리가제(T4 DNA ligase)(NEB)를 사용하여 pET28a(노바겐(Novagen)) 플라스미드 벡터의 NdeI 및 NotI 부위에 삽입하였다.
(다): 단계 (나)에서 구축된 플라스미드를 숙주 세포에 형질감염
1. 컴피턴트 세포의 제조: 한 튜브의 대장균 세포 E.coli BL21 DE3(뉴잉글랜드 바이오랩스(New England Biolabs))을 취하여 3ml LB 배양액이 함유된 시험관에 접종하고, 37℃에서 밤새 진탕 배양하였다. 다음날 균액 0.5ml를 취하여 50ml LB 배지가 함유된 250ml 플라스크에 접종하고, 37℃에서 약 3~5시간 동안(250rpm) 격렬하게 진탕 배양하며, 콜로니 600nm OD 값이 0.3~0.4에 도달했을 때 플라스크를 꺼내 얼음 위에 10~15분 동안 두었다. 무균 조건에서 균액을 50ml 원심분리관에 부었다. 4℃, 1000g에서 10분 동안 원심분리하였다. 상청액을 버리고, 수집하여 0.1M의 CaCl2 10ml를 원심분리관에 넣고 흔들어 균일하게 혼합하며, 균체를 현탁하고, 아이스배스에 30분 동안 방치하며, 4℃, 1000g에서 10분 동안 원심분리하고, 상청액을 버리며, 수집하여 얼음으로 사전 냉각된 0.1M의 CaCl2 4ml를 넣고, 균체를 재현탁하였다. 각 튜브에 0.2ml씩 나누어 넣고, 나중에 사용하기 위해 4℃에서 보관하여 24시간 이내에 사용하였으며, 나머지는 -70℃의 저온 냉장고에 보관하였다.
2. 형질감염: 적당량의 DNA(ng)와 컴피턴트 대장균을 혼합하여 아이스배스에 15분 동안 방치하고, 42℃에서 30초 동안 열충격을 가하며, 아이스배스에 5분 동안 방치하고, SOC 배지에 넣어 250rpm으로 1시간 동안 진탕하며, 항생제가 있는 플레이트에 도말하여 37℃에서 밤새 배양하였다.
(라): 숙주 세포의 배양 및 독소 폴리펩티드 전구체 발현의 유도
배지의 성분 및 배합비: 11.8g/L 트립톤, 23.6g/L효모 추출물, 9.4g/L K2HPO4, 2.2g/L KH2PO4, 4ml/L 글리세린.
배양 조건: 37℃에서 250rpm으로 세포를 밤새 진탕 배양하였다.
발현 유도 및 발효: 세포를 발효조에 옮기고, 대장균이 OD600=1로 성장했을 때 1mM IPTG를 첨가하여 25℃에서 5시간 동안 발현하도록 발현을 유도하였다. OD600은 0.2~1.5로 선택할 수 있고, 온도는 37℃~10℃로 선택할 수 있으며, 발현 시간은 5~16시간일 수 있다.
세포 용해: 통상적인 방법에 따라 세포를 절단하고 탈기하며, 이 과정에서 세포를 용해시켜 세포 용해 버퍼를 얻었다.
실시예 2: GSTs-BoNT/A의 농축
조액 여과: 실시예 1의 세포 용해 버퍼는 세포 용해 버퍼 조액으로서 조액 여과를 거치고, 여과 기공 크기는 0.12~0.65μm이며, 조액 여과 재료를 통과할 수 있는 액체는 공급액으로서 추가 여과 단계에 진입하고, 조액 여과 재료를 통과할 수 없는 물질은 완충액의 작용 하에 잔사로서 잔사 배출 유로로 유입된다.
공급액 여과: 조액 여과 후 액체는 공급액으로서 공급액 여과 단계에 진입한다. 공급액은 순환 경로에서 여러 번 여과(최소 2번)되고, 여과 기공 크기는 0.2μm 이하이며, 이로써 완제품 액체가 얻어진다.
완전히 밀폐된 세포 용해 버퍼 분리를 거친 후, 얻은 폐액은 독소 폴리펩티드 전구체를 거의 포함하지 않으며, 조작 환경에 대한 독성이 매우 낮아 간단한 소독 처리 후 직접 배출될 수 있다.
실시예 3: GSTs-BoNT/A의 예비 정제
실시예 2에서 얻은 완제품 액체는 추가로 정제 모듈에 유입되고, 통상적인 친화성 크로마토그래피 방법을 통해 GSTs-BoNT/A를 얻었다.
통상적인 방법은 다음과 같은 바, 20배 컬럼 부피의 인산 완충액을 사용하여 크로마토그래피 컬럼을 세척하고, 10배 컬럼 부피의 새로 제조한 10mM 글루타티온 용출 완충액(50ml 50mM Tris-HCl(pH 8.0)에 용해된 0.154g 환원된 글루타티온)을 사용하여 GSTs-BoNT/A 용출을 수행하며, 280nm에서의 흡광도 판독값을 사용하여 융합 단백질의 용출을 모니터링하였다.
총 단백질 수준에서 GSTs-BoNT/A가 차지하는 비율의 측정: 200 볼트의 전압 하에, 정제된 GSTs-BoNT/A에 대해 4~12% SDS-PAGE(Biorad)를 사용하여 전기영동 분리를 수행하고, 175kd 분자량 주요 밴드는 GSTs-BoNT/A이다.
실시예 4: GSTs-BoNT/A 활성화 및 GSTs의 해리
젠스크립트(GenScript)의 3C 효소를 사용하여 글루타티온 정제 수지 크로마토그래피 컬럼에 재흡착된 GSTs-BoNT/A를 처리하면, 3C 효소의 작용 하에, GSTs와 BoNT/A 사이의 절단 부위가 끊어지고, GSTs가 탈리되며, 동시에 BoNT/A의 경쇄와 중쇄 사이의 절단 부위도 끊어진다.
인산 완충액으로 글루타티온 정제 수지 크로마토그래피 컬럼을 처리하면, 컬럼에 남아있는 GSTs 태그 단백질이 제거되고, BoNT/A의 경쇄 및 중쇄는 인산 완충액에 의해 용출된다.
GSTs 태그 단백질을 제거하기 전의 생성물 및 제거된 후의 생성물을 취하여 통상적인 SDS-PAGE 실험을 수행하였으며, 도 2에 도시된 바와 같이, 태그 단백질이 제거되지 않은 제1 레인과 비교하여, 리노바이러스 3C 프로테아제(Rinovirus 3C Protease)의 작용 하에 제1 레인의 GSTs 태그 단백질이 절제되어 GSTs가 없는 BoNT/A 분자가 얻어졌다.
실시예 5: BoNT/A의 추가 정제
실시예 4에서 얻은 BoNT/A를 통상적인 겔 여과 크로마토그래피 및 이온 크로마토그래피 컬럼으로 추가 정제하여 순도가 90% 이상인 BoNT/A를 얻었다.
GSTs가 제거된 생성물을 취하여 통상적인 SDS-PAGE 실험을 수행하였으며, 도 3에 도시된 바와 같이, 얻은 밴드에 GSTs 태그 단백질이 더 이상 없었는데, 이는 GSTs 태그 단백질이 완전히 제거되었음을 보여준다. SDS-PAGE를 사용하여 사진을 스캔하고, 밴드의 회색 밀도에 따라 계산한 결과 얻은 BoNT/A의 순도가 90% 이상이었다.
링커 숏 펩티드의 GS 부분 대신 GSS, GSGS, GGSGS 폴리펩티드를 사용하면, GS와 유사한 효과를 낼 수 있고, 태그 단백질은 잘 노출될 수 있어 완전히 절제될 수 있다.
실시예 6: 웨스턴 블롯(Western blot) 실험
실시예 4의 생성물에 대해 환원 실험을 수행하였다.
100mM의 디티오트레이톨을 사용하여 100℃에서 샘플을 5분 동안 처리하여 샘플을 환원시키고, 200 볼트의 전압 하에 4~12% SDS-PAGE(Biorad)를 사용하여 샘플에 대해 전기영동 분리를 수행하여 중쇄와 경쇄를 분리하였다.
도 4에 도시된 바와 같이, 실시예 4에서 얻은 생성물을 환원 조건에서 환원시키고, 얻은 생성물에 대해 통상적인 SDS-PAGE 실험을 수행하여 2개의 상이한 밴드를 얻었으며, 분자량은 각각 100Kda 및 50Kda인데, 이는 실시예 4에서 형성된 생성물이 2개의 펩티드 단편이 이황화 결합으로 연결된 이량체 구조임을 증명한다.
실시예 7: GSTs-BoNT/A와 BoNT/A의 독성 비교
실시예 3에서 얻은 GSTs-BoNT/A를 마우스에 복강내 주사했을 때 LD50은 45ng~450ng 사이이고; 주사된 보툴리눔 독소 단백질의 순도를 고려하면, 환산된 LD50은 22.5ng~225ng 사이이며, 중앙값은 123.75ng이다. 실시예 4에서 얻은 BoNT/A를 마우스에 복강내 주사했을 때 LD50은 0.02ng~0.05ng 사이이다. 주사된 보툴리눔 독소 단백질의 순도를 고려하면, 환산된 LD50은 0.006ng~0.015ng 사이이고, 중앙값은 0.0105ng이다(표 1 참조).
표 1. 마우스 생물학적 독성 실험에서 GSTs-BoNT/A와 BoNT/A 분자의 독성 비교
GSTs-BoNT/A는 보툴리눔 독소의 활성을 가지고 있으며, 마우스에 복강내 주사 후 반수 치사량(LD50)은 BoNT/A의 단백질 LD50보다 약 11786배 높은데, 이는 GSTs-BoNT/A 재조합 단백질 독소 전구체 분자의 활성이 최종 생성물 BoNT/A보다 약 11786배 약함을 보여준다. 이 실험은 GSTs-BoNT/A 재조합 단백질 독소 전구체 분자가 보툴리눔 독소의 활성을 가지고 있지만 그 독성이 활성화된 BoNT/A보다 훨씬 낮음을 증명한다. 보툴리눔 독소의 초고독성으로 인해 생산 과정에서 전구체 분자를 활성화 처리하기 전에 높은 수준의 안전 조작 보호가 필요하다.
본 발명의 실시예를 통해, 본 발명에서 청구하는 제조 방법은 특히 유전자 재조합 독소 폴리펩티드의 제조에 적용되며, 상기 독소 폴리펩티드가 숙주 세포에서 독성이 경미한 전구체 형태로 발현되고 세포 용해 버퍼에서 독성이 경미한 전구체 형태로 존재하는 경우, 특정 프로테아제의 가수분해를 거쳐야만 독성이 있는 독소 분자로 활성화될 수 있음을 증명하였다. 이 경우, 상기 제조 방법에서의 폴리펩티드 전구체의 농축 방법은 밀폐된 시스템에서 수행되는 장점이 있어, 이러한 독소 폴리펩티드의 산업적 생산 시 아이솔레이터와 같은 번거롭고 값비싼 격리 장비의 사용을 피하므로, 이러한 폴리펩티드의 대규모 산업적 생산에 더 적합하다.
위에서 본 발명의 바람직한 실시형태를 상세하게 설명하였지만, 본 발명은 상기 실시형태의 구체적인 세부 내용에 한정되지 않으며, 본 발명의 기술적 구상 범위 내에서 본 발명의 기술적 해결수단에 대해 다양한 간단한 변형이 이루어질 수 있으며, 이러한 간단한 변형은 모두 본 발명의 보호 범위에 속한다.
또한, 상기 구체적인 실시형태에 설명된 각 구체적인 기술적 특징은 모순되지 않는 한 임의의 적합한 방식으로 조합될 수 있으며, 불필요한 반복을 피하기 위해, 본 발명은 다양한 가능한 조합 방식을 더 이상 설명하지 않음에 유의해야 한다.
SEQUENCE LISTING
<110> CHONGQING CLARUVIS PHARMACEUTICAL CO., LTD.
<120> PREPARATION METHOD FOR MODIFIED TOXIN POLYPEPTIDE
<130> 1
<140> PCT/CN2022/077637
<141> 2022-02-24
<150> 202110217756.1
<151> 2021-02-26
<160> 11
<170> PatentIn version 3.5
<210> 1
<211> 654
<212> DNA
<213> Artificial Sequence
<400> 1
atgtccccta tactaggtta ttggaaaatt aagggccttg tgcaacccac tcgacttctt 60
ttggaatatc ttgaagaaaa atatgaagag catttgtatg agcgcgatga aggtgataaa 120
tggcgaaaca aaaagtttga attgggtttg gagtttccca atcttcctta ttatattgat 180
ggtgatgtta aattaacaca gtctatggcc atcatacgtt atatagctga caagcacaac 240
atgttgggtg gttgtccaaa agagcgtgca gagatttcaa tgcttgaagg agcggttttg 300
gatattagat acggtgtttc gagaattgca tatagtaaag actttgaaac tctcaaagtt 360
gattttctta gcaagctacc tgaaatgctg aaaatgttcg aagatcgttt atgtcataaa 420
acatatttaa atggtgatca tgtaacccat cctgacttca tgttgtatga cgctcttgat 480
gttgttttat acatggaccc aatgtgcctg gatgcgttcc caaaattagt ttgttttaaa 540
aaacgtattg aagctatccc acaaattgat aagtacttga aatccagcaa gtatatagca 600
tggcctttgc agggctggca agccacgttt ggtggtggcg accatcctcc aaaa 654
<210> 2
<211> 218
<212> PRT
<213> Artificial Sequence
<400> 2
Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro
1 5 10 15
Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu
20 25 30
Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu
35 40 45
Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys
50 55 60
Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn
65 70 75 80
Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu
85 90 95
Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser
100 105 110
Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu
115 120 125
Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn
130 135 140
Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp
145 150 155 160
Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu
165 170 175
Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr
180 185 190
Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala
195 200 205
Thr Phe Gly Gly Gly Asp His Pro Pro Lys
210 215
<210> 3
<211> 24
<212> DNA
<213> Artificial Sequence
<400> 3
ctggaagttc tgttccaggg gccc 24
<210> 4
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 4
Leu Glu Val Leu Phe Gln Gly Pro
1 5
<210> 5
<211> 6
<212> DNA
<213> Artificial Sequence
<400> 5
ggatcc 6
<210> 6
<211> 3882
<212> DNA
<213> Artificial Sequence
<400> 6
atgcctttcg ttaacaaaca gtttaactat aaggacccgg ttaacggtgt ggatattgca 60
tacattaaga tccctaacgc tggtcagatg cagccggtga aagcattcaa gatccacaat 120
aagatttggg tgatcccgga acgcgatacc tttaccaacc cggaagaagg cgatctgaac 180
ccccctccgg aggccaagca agttcccgtt agctattacg acagtaccta tttaagcacc 240
gataatgaga aagataacta tctgaagggt gttaccaaac tgttcgagcg catctacagc 300
acagacttag gccgcatgct gctgaccagt atcgttcgtg gtattccgtt ctggggcggc 360
agtaccatcg acaccgagct gaaagtgatc gacaccaatt gcattaacgt gatccagccc 420
gatggcagct atcgtagcga agagctgaat ctggttatca tcggccctag tgccgacatt 480
attcaattcg agtgtaaaag cttcggccat gaggtgctga atttaacccg taatggctat 540
ggcagtaccc agtacatccg cttcagcccg gattttacct tcggcttcga ggaatcttta 600
gaagtggata ccaatccgct gctgggcgcc ggcaaatttg caacagaccc cgctgttact 660
ttagcccatg agctgattca tgctggtcat cgtctgtacg gcatcgccat taacccgaac 720
cgtgtgttta aggttaacac caacgcctat tatgaaatga gtggtttaga ggtgagcttc 780
gaggagctgc gtacctttgg tggccatgat gccaagttca tcgatagtct gcaagaaaac 840
gagtttcgtc tgtattatta caacaagttc aaagatatcg caagcacctt aaataaagcc 900
aagagcatcg ttggcaccac cgcctcttta caatatatga aaaacgtttt caaggagaaa 960
tatctgctga gcgaggacac cagtggtaaa tttagtgttg acaaactgaa gttcgataaa 1020
ctgtataaga tgctgaccga gatctatacc gaagacaatt tcgtgaaatt ttttaaagtt 1080
ctgaatcgca aaacatattt aaacttcgac aaagcagtgt ttaaaatcaa catcgttccg 1140
aaggttaatt acacaatcta cgatggcttc aatttacgca acaccaattt agccgcaaac 1200
ttcaacggcc aaaataccga gatcaataac atgaatttca ccaaactgaa aaactttact 1260
ggtttatttg agttctacaa actgctgtgc gtgcgtggca ttatcaccag tttagaagtg 1320
ctgtttcaag gtccggcctt aaacgatctg tgtattaaag ttaacaattg ggatctgttt 1380
ttcagcccta gcgaggacaa ttttaccaac gatttaaaca aaggcgagga gatcaccagc 1440
gataccaata ttgaggccgc agaggagaat atcagtctgg atttaatcca gcaatattat 1500
ctgaccttta attttgacaa tgagccggag aacattagta tcgaaaattt aagtagcgac 1560
atcattggtc agctggagct gatgccgaac attgagcgct tcccgaatgg caaaaagtat 1620
gaattagata agtacaccat gtttcactat ttacgcgccc aagaatttga acacggtaaa 1680
agccgtattg ccttaaccaa cagcgtgaat gaagcactgc tgaacccgag ccgcgtgtat 1740
acctttttca gtagtgacta tgttaagaag gtgaataagg ccaccgaagc cgccatgttc 1800
ttaggctggg tggagcagct ggtgtatgat ttcaccgatg agaccagcga ggtgagcacc 1860
acagataaaa tcgcagatat tacaattatt attccgtaca tcggcccggc tttaaatatc 1920
ggtaacatgc tgtacaaaga tgatttcgtg ggcgctttaa tctttagcgg tgccgttatt 1980
ctgttagaat tcattcccga aattgcaatc ccggtgctgg gcacctttgc tttagttagc 2040
tatatcgcaa ataaagtgtt aaccgttcag accattgaca atgctttaag caagcgtaat 2100
gaaaagtggg atgaggttta taaatacatc gttacaaatt ggttagccaa agtgaacacc 2160
cagattgatt taatccgtaa gaaaatgaaa gaagccttag agaatcaagc tgaggccaca 2220
aaagcaatta tcaattacca gtacaatcag tataccgaag aagaaaagaa caatatcaac 2280
tttaatattg atgatttaag cagcaagctg aacgaaagca ttaataaagc catgattaat 2340
attaacaagt ttttaaacca gtgcagcgtg agctatttaa tgaacagcat gatcccttac 2400
ggtgtgaagc gtctggaaga tttcgatgcc tctttaaaag acgcactgtt aaagtatatt 2460
tatgacaatc gcggcacact gatcggtcaa gttgatcgtc tgaaagataa agttaataac 2520
acattaagca cagacattcc tttccagctg agtaaatacg tggacaatca acgtctgctg 2580
agcaccttta ccgaatacat taaaaacatt attaacacca gcattctgaa tttacgctac 2640
gagagcaacc atttaattga tctgagccgt tacgccagca agatcaatat cggtagcaag 2700
gttaacttcg acccgattga caaaaaccag atccagttat tcaatttaga gagtagtaag 2760
attgaggtta ttttaaaaaa cgccatcgtt tataacagca tgtacgaaaa ttttagcaca 2820
agcttttgga ttcgtatccc gaagtatttc aatagcatct ctttaaataa tgaatacaca 2880
atcattaatt gcatggaaaa caacagcggc tggaaggtgt ctttaaacta cggtgagatc 2940
atctggactt tacaagatac ccaagaaatc aagcagcgcg ttgtgttcaa atatagtcag 3000
atgatcaaca ttagtgacta tattaaccgc tggatttttg tgaccatcac aaataaccgt 3060
ttaaacaaca gcaaaattta tattaacggt cgtctgattg accagaagcc gattagcaat 3120
ttaggtaata tccatgccag caacaacatt atgttcaaac tggatggttg tcgcgatacc 3180
catcgctaca tctggattaa gtactttaac ttattcgaca aagaactgaa tgaaaaggag 3240
atcaaggact tatatgataa tcaaagcaat agcggcattt taaaagactt ttggggtgac 3300
tatctgcagt atgacaaacc ttactatatg ctgaacttat atgacccgaa caaatacgtt 3360
gacgtgaaca atgtgggtat tcgtggctac atgtatctga aaggcccgcg cggcagtgtt 3420
atgaccacaa atatttattt aaacagctct ttatatcgtg gcaccaagtt tatcatcaag 3480
aagtacgcaa gcggcaataa agacaatatt gtgcgtaaca acgatcgtgt gtacatcaac 3540
gttgtggtga agaacaaaga gtatcgttta gccaccaatg ccagccaagc tggtgtggaa 3600
aaaattttaa gcgcactgga gatccccgat gtgggcaatt taagtcaagt tgttgtgatg 3660
aaaagtaaga atgatcaagg catcaccaac aaatgtaaga tgaatttaca agacaataac 3720
ggcaatgaca ttggttttat tggtttccat cagttcaaca atatcgcaaa gctggtggcc 3780
agcaactggt acaaccgtca gatcgaacgt agcagccgta ctttaggttg cagctgggaa 3840
tttattccgg tggatgatgg ttggggtgag cgccctttat aa 3882
<210> 7
<211> 1293
<212> PRT
<213> Artificial Sequence
<400> 7
Met Pro Phe Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly
1 5 10 15
Val Asp Ile Ala Tyr Ile Lys Ile Pro Asn Ala Gly Gln Met Gln Pro
20 25 30
Val Lys Ala Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg
35 40 45
Asp Thr Phe Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu
50 55 60
Ala Lys Gln Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr
65 70 75 80
Asp Asn Glu Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu
85 90 95
Arg Ile Tyr Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val
100 105 110
Arg Gly Ile Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys
115 120 125
Val Ile Asp Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr
130 135 140
Arg Ser Glu Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile
145 150 155 160
Ile Gln Phe Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr
165 170 175
Arg Asn Gly Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe
180 185 190
Thr Phe Gly Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu
195 200 205
Gly Ala Gly Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu
210 215 220
Leu Ile His Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn
225 230 235 240
Arg Val Phe Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu
245 250 255
Glu Val Ser Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys
260 265 270
Phe Ile Asp Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn
275 280 285
Lys Phe Lys Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val
290 295 300
Gly Thr Thr Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys
305 310 315 320
Tyr Leu Leu Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu
325 330 335
Lys Phe Asp Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp
340 345 350
Asn Phe Val Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn
355 360 365
Phe Asp Lys Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr
370 375 380
Thr Ile Tyr Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn
385 390 395 400
Phe Asn Gly Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu
405 410 415
Lys Asn Phe Thr Gly Leu Phe Glu Phe Tyr Lys Leu Leu Cys Val Arg
420 425 430
Gly Ile Ile Thr Ser Leu Glu Val Leu Phe Gln Gly Pro Ala Leu Asn
435 440 445
Asp Leu Cys Ile Lys Val Asn Asn Trp Asp Leu Phe Phe Ser Pro Ser
450 455 460
Glu Asp Asn Phe Thr Asn Asp Leu Asn Lys Gly Glu Glu Ile Thr Ser
465 470 475 480
Asp Thr Asn Ile Glu Ala Ala Glu Glu Asn Ile Ser Leu Asp Leu Ile
485 490 495
Gln Gln Tyr Tyr Leu Thr Phe Asn Phe Asp Asn Glu Pro Glu Asn Ile
500 505 510
Ser Ile Glu Asn Leu Ser Ser Asp Ile Ile Gly Gln Leu Glu Leu Met
515 520 525
Pro Asn Ile Glu Arg Phe Pro Asn Gly Lys Lys Tyr Glu Leu Asp Lys
530 535 540
Tyr Thr Met Phe His Tyr Leu Arg Ala Gln Glu Phe Glu His Gly Lys
545 550 555 560
Ser Arg Ile Ala Leu Thr Asn Ser Val Asn Glu Ala Leu Leu Asn Pro
565 570 575
Ser Arg Val Tyr Thr Phe Phe Ser Ser Asp Tyr Val Lys Lys Val Asn
580 585 590
Lys Ala Thr Glu Ala Ala Met Phe Leu Gly Trp Val Glu Gln Leu Val
595 600 605
Tyr Asp Phe Thr Asp Glu Thr Ser Glu Val Ser Thr Thr Asp Lys Ile
610 615 620
Ala Asp Ile Thr Ile Ile Ile Pro Tyr Ile Gly Pro Ala Leu Asn Ile
625 630 635 640
Gly Asn Met Leu Tyr Lys Asp Asp Phe Val Gly Ala Leu Ile Phe Ser
645 650 655
Gly Ala Val Ile Leu Leu Glu Phe Ile Pro Glu Ile Ala Ile Pro Val
660 665 670
Leu Gly Thr Phe Ala Leu Val Ser Tyr Ile Ala Asn Lys Val Leu Thr
675 680 685
Val Gln Thr Ile Asp Asn Ala Leu Ser Lys Arg Asn Glu Lys Trp Asp
690 695 700
Glu Val Tyr Lys Tyr Ile Val Thr Asn Trp Leu Ala Lys Val Asn Thr
705 710 715 720
Gln Ile Asp Leu Ile Arg Lys Lys Met Lys Glu Ala Leu Glu Asn Gln
725 730 735
Ala Glu Ala Thr Lys Ala Ile Ile Asn Tyr Gln Tyr Asn Gln Tyr Thr
740 745 750
Glu Glu Glu Lys Asn Asn Ile Asn Phe Asn Ile Asp Asp Leu Ser Ser
755 760 765
Lys Leu Asn Glu Ser Ile Asn Lys Ala Met Ile Asn Ile Asn Lys Phe
770 775 780
Leu Asn Gln Cys Ser Val Ser Tyr Leu Met Asn Ser Met Ile Pro Tyr
785 790 795 800
Gly Val Lys Arg Leu Glu Asp Phe Asp Ala Ser Leu Lys Asp Ala Leu
805 810 815
Leu Lys Tyr Ile Tyr Asp Asn Arg Gly Thr Leu Ile Gly Gln Val Asp
820 825 830
Arg Leu Lys Asp Lys Val Asn Asn Thr Leu Ser Thr Asp Ile Pro Phe
835 840 845
Gln Leu Ser Lys Tyr Val Asp Asn Gln Arg Leu Leu Ser Thr Phe Thr
850 855 860
Glu Tyr Ile Lys Asn Ile Ile Asn Thr Ser Ile Leu Asn Leu Arg Tyr
865 870 875 880
Glu Ser Asn His Leu Ile Asp Leu Ser Arg Tyr Ala Ser Lys Ile Asn
885 890 895
Ile Gly Ser Lys Val Asn Phe Asp Pro Ile Asp Lys Asn Gln Ile Gln
900 905 910
Leu Phe Asn Leu Glu Ser Ser Lys Ile Glu Val Ile Leu Lys Asn Ala
915 920 925
Ile Val Tyr Asn Ser Met Tyr Glu Asn Phe Ser Thr Ser Phe Trp Ile
930 935 940
Arg Ile Pro Lys Tyr Phe Asn Ser Ile Ser Leu Asn Asn Glu Tyr Thr
945 950 955 960
Ile Ile Asn Cys Met Glu Asn Asn Ser Gly Trp Lys Val Ser Leu Asn
965 970 975
Tyr Gly Glu Ile Ile Trp Thr Leu Gln Asp Thr Gln Glu Ile Lys Gln
980 985 990
Arg Val Val Phe Lys Tyr Ser Gln Met Ile Asn Ile Ser Asp Tyr Ile
995 1000 1005
Asn Arg Trp Ile Phe Val Thr Ile Thr Asn Asn Arg Leu Asn Asn
1010 1015 1020
Ser Lys Ile Tyr Ile Asn Gly Arg Leu Ile Asp Gln Lys Pro Ile
1025 1030 1035
Ser Asn Leu Gly Asn Ile His Ala Ser Asn Asn Ile Met Phe Lys
1040 1045 1050
Leu Asp Gly Cys Arg Asp Thr His Arg Tyr Ile Trp Ile Lys Tyr
1055 1060 1065
Phe Asn Leu Phe Asp Lys Glu Leu Asn Glu Lys Glu Ile Lys Asp
1070 1075 1080
Leu Tyr Asp Asn Gln Ser Asn Ser Gly Ile Leu Lys Asp Phe Trp
1085 1090 1095
Gly Asp Tyr Leu Gln Tyr Asp Lys Pro Tyr Tyr Met Leu Asn Leu
1100 1105 1110
Tyr Asp Pro Asn Lys Tyr Val Asp Val Asn Asn Val Gly Ile Arg
1115 1120 1125
Gly Tyr Met Tyr Leu Lys Gly Pro Arg Gly Ser Val Met Thr Thr
1130 1135 1140
Asn Ile Tyr Leu Asn Ser Ser Leu Tyr Arg Gly Thr Lys Phe Ile
1145 1150 1155
Ile Lys Lys Tyr Ala Ser Gly Asn Lys Asp Asn Ile Val Arg Asn
1160 1165 1170
Asn Asp Arg Val Tyr Ile Asn Val Val Val Lys Asn Lys Glu Tyr
1175 1180 1185
Arg Leu Ala Thr Asn Ala Ser Gln Ala Gly Val Glu Lys Ile Leu
1190 1195 1200
Ser Ala Leu Glu Ile Pro Asp Val Gly Asn Leu Ser Gln Val Val
1205 1210 1215
Val Met Lys Ser Lys Asn Asp Gln Gly Ile Thr Asn Lys Cys Lys
1220 1225 1230
Met Asn Leu Gln Asp Asn Asn Gly Asn Asp Ile Gly Phe Ile Gly
1235 1240 1245
Phe His Gln Phe Asn Asn Ile Ala Lys Leu Val Ala Ser Asn Trp
1250 1255 1260
Tyr Asn Arg Gln Ile Glu Arg Ser Ser Arg Thr Leu Gly Cys Ser
1265 1270 1275
Trp Glu Phe Ile Pro Val Asp Asp Gly Trp Gly Glu Arg Pro Leu
1280 1285 1290
<210> 8
<211> 24
<212> DNA
<213> Artificial Sequence
<400> 8
ttagaagtgc tgtttcaagg tccg 24
<210> 9
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 9
Leu Glu Val Leu Phe Gln Gly Pro
1 5
<210> 10
<211> 4575
<212> DNA
<213> Artificial Sequence
<400> 10
atgtccccta tactaggtta ttggaaaatt aagggccttg tgcaacccac tcgacttctt 60
ttggaatatc ttgaagaaaa atatgaagag catttgtatg agcgcgatga aggtgataaa 120
tggcgaaaca aaaagtttga attgggtttg gagtttccca atcttcctta ttatattgat 180
ggtgatgtta aattaacaca gtctatggcc atcatacgtt atatagctga caagcacaac 240
atgttgggtg gttgtccaaa agagcgtgca gagatttcaa tgcttgaagg agcggttttg 300
gatattagat acggtgtttc gagaattgca tatagtaaag actttgaaac tctcaaagtt 360
gattttctta gcaagctacc tgaaatgctg aaaatgttcg aagatcgttt atgtcataaa 420
acatatttaa atggtgatca tgtaacccat cctgacttca tgttgtatga cgctcttgat 480
gttgttttat acatggaccc aatgtgcctg gatgcgttcc caaaattagt ttgttttaaa 540
aaacgtattg aagctatccc acaaattgat aagtacttga aatccagcaa gtatatagca 600
tggcctttgc agggctggca agccacgttt ggtggtggcg accatcctcc aaaatcggat 660
ctggaagttc tgttccaggg gcccctggga tccatgcctt tcgttaacaa acagtttaac 720
tataaggacc cggttaacgg tgtggatatt gcatacatta agatccctaa cgctggtcag 780
atgcagccgg tgaaagcatt caagatccac aataagattt gggtgatccc ggaacgcgat 840
acctttacca acccggaaga aggcgatctg aacccccctc cggaggccaa gcaagttccc 900
gttagctatt acgacagtac ctatttaagc accgataatg agaaagataa ctatctgaag 960
ggtgttacca aactgttcga gcgcatctac agcacagact taggccgcat gctgctgacc 1020
agtatcgttc gtggtattcc gttctggggc ggcagtacca tcgacaccga gctgaaagtg 1080
atcgacacca attgcattaa cgtgatccag cccgatggca gctatcgtag cgaagagctg 1140
aatctggtta tcatcggccc tagtgccgac attattcaat tcgagtgtaa aagcttcggc 1200
catgaggtgc tgaatttaac ccgtaatggc tatggcagta cccagtacat ccgcttcagc 1260
ccggatttta ccttcggctt cgaggaatct ttagaagtgg ataccaatcc gctgctgggc 1320
gccggcaaat ttgcaacaga ccccgctgtt actttagccc atgagctgat tcatgctggt 1380
catcgtctgt acggcatcgc cattaacccg aaccgtgtgt ttaaggttaa caccaacgcc 1440
tattatgaaa tgagtggttt agaggtgagc ttcgaggagc tgcgtacctt tggtggccat 1500
gatgccaagt tcatcgatag tctgcaagaa aacgagtttc gtctgtatta ttacaacaag 1560
ttcaaagata tcgcaagcac cttaaataaa gccaagagca tcgttggcac caccgcctct 1620
ttacaatata tgaaaaacgt tttcaaggag aaatatctgc tgagcgagga caccagtggt 1680
aaatttagtg ttgacaaact gaagttcgat aaactgtata agatgctgac cgagatctat 1740
accgaagaca atttcgtgaa attttttaaa gttctgaatc gcaaaacata tttaaacttc 1800
gacaaagcag tgtttaaaat caacatcgtt ccgaaggtta attacacaat ctacgatggc 1860
ttcaatttac gcaacaccaa tttagccgca aacttcaacg gccaaaatac cgagatcaat 1920
aacatgaatt tcaccaaact gaaaaacttt actggtttat ttgagttcta caaactgctg 1980
tgcgtgcgtg gcattatcac cagtttagaa gtgctgtttc aaggtccggc cttaaacgat 2040
ctgtgtatta aagttaacaa ttgggatctg tttttcagcc ctagcgagga caattttacc 2100
aacgatttaa acaaaggcga ggagatcacc agcgatacca atattgaggc cgcagaggag 2160
aatatcagtc tggatttaat ccagcaatat tatctgacct ttaattttga caatgagccg 2220
gagaacatta gtatcgaaaa tttaagtagc gacatcattg gtcagctgga gctgatgccg 2280
aacattgagc gcttcccgaa tggcaaaaag tatgaattag ataagtacac catgtttcac 2340
tatttacgcg cccaagaatt tgaacacggt aaaagccgta ttgccttaac caacagcgtg 2400
aatgaagcac tgctgaaccc gagccgcgtg tatacctttt tcagtagtga ctatgttaag 2460
aaggtgaata aggccaccga agccgccatg ttcttaggct gggtggagca gctggtgtat 2520
gatttcaccg atgagaccag cgaggtgagc accacagata aaatcgcaga tattacaatt 2580
attattccgt acatcggccc ggctttaaat atcggtaaca tgctgtacaa agatgatttc 2640
gtgggcgctt taatctttag cggtgccgtt attctgttag aattcattcc cgaaattgca 2700
atcccggtgc tgggcacctt tgctttagtt agctatatcg caaataaagt gttaaccgtt 2760
cagaccattg acaatgcttt aagcaagcgt aatgaaaagt gggatgaggt ttataaatac 2820
atcgttacaa attggttagc caaagtgaac acccagattg atttaatccg taagaaaatg 2880
aaagaagcct tagagaatca agctgaggcc acaaaagcaa ttatcaatta ccagtacaat 2940
cagtataccg aagaagaaaa gaacaatatc aactttaata ttgatgattt aagcagcaag 3000
ctgaacgaaa gcattaataa agccatgatt aatattaaca agtttttaaa ccagtgcagc 3060
gtgagctatt taatgaacag catgatccct tacggtgtga agcgtctgga agatttcgat 3120
gcctctttaa aagacgcact gttaaagtat atttatgaca atcgcggcac actgatcggt 3180
caagttgatc gtctgaaaga taaagttaat aacacattaa gcacagacat tcctttccag 3240
ctgagtaaat acgtggacaa tcaacgtctg ctgagcacct ttaccgaata cattaaaaac 3300
attattaaca ccagcattct gaatttacgc tacgagagca accatttaat tgatctgagc 3360
cgttacgcca gcaagatcaa tatcggtagc aaggttaact tcgacccgat tgacaaaaac 3420
cagatccagt tattcaattt agagagtagt aagattgagg ttattttaaa aaacgccatc 3480
gtttataaca gcatgtacga aaattttagc acaagctttt ggattcgtat cccgaagtat 3540
ttcaatagca tctctttaaa taatgaatac acaatcatta attgcatgga aaacaacagc 3600
ggctggaagg tgtctttaaa ctacggtgag atcatctgga ctttacaaga tacccaagaa 3660
atcaagcagc gcgttgtgtt caaatatagt cagatgatca acattagtga ctatattaac 3720
cgctggattt ttgtgaccat cacaaataac cgtttaaaca acagcaaaat ttatattaac 3780
ggtcgtctga ttgaccagaa gccgattagc aatttaggta atatccatgc cagcaacaac 3840
attatgttca aactggatgg ttgtcgcgat acccatcgct acatctggat taagtacttt 3900
aacttattcg acaaagaact gaatgaaaag gagatcaagg acttatatga taatcaaagc 3960
aatagcggca ttttaaaaga cttttggggt gactatctgc agtatgacaa accttactat 4020
atgctgaact tatatgaccc gaacaaatac gttgacgtga acaatgtggg tattcgtggc 4080
tacatgtatc tgaaaggccc gcgcggcagt gttatgacca caaatattta tttaaacagc 4140
tctttatatc gtggcaccaa gtttatcatc aagaagtacg caagcggcaa taaagacaat 4200
attgtgcgta acaacgatcg tgtgtacatc aacgttgtgg tgaagaacaa agagtatcgt 4260
ttagccacca atgccagcca agctggtgtg gaaaaaattt taagcgcact ggagatcccc 4320
gatgtgggca atttaagtca agttgttgtg atgaaaagta agaatgatca aggcatcacc 4380
aacaaatgta agatgaattt acaagacaat aacggcaatg acattggttt tattggtttc 4440
catcagttca acaatatcgc aaagctggtg gccagcaact ggtacaaccg tcagatcgaa 4500
cgtagcagcc gtactttagg ttgcagctgg gaatttattc cggtggatga tggttggggt 4560
gagcgccctt tataa 4575
<210> 11
<211> 1524
<212> PRT
<213> Artificial Sequence
<400> 11
Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro
1 5 10 15
Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu
20 25 30
Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu
35 40 45
Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys
50 55 60
Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn
65 70 75 80
Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu
85 90 95
Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser
100 105 110
Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu
115 120 125
Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn
130 135 140
Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp
145 150 155 160
Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu
165 170 175
Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr
180 185 190
Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala
195 200 205
Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Glu Val Leu
210 215 220
Phe Gln Gly Pro Leu Gly Ser Met Pro Phe Val Asn Lys Gln Phe Asn
225 230 235 240
Tyr Lys Asp Pro Val Asn Gly Val Asp Ile Ala Tyr Ile Lys Ile Pro
245 250 255
Asn Ala Gly Gln Met Gln Pro Val Lys Ala Phe Lys Ile His Asn Lys
260 265 270
Ile Trp Val Ile Pro Glu Arg Asp Thr Phe Thr Asn Pro Glu Glu Gly
275 280 285
Asp Leu Asn Pro Pro Pro Glu Ala Lys Gln Val Pro Val Ser Tyr Tyr
290 295 300
Asp Ser Thr Tyr Leu Ser Thr Asp Asn Glu Lys Asp Asn Tyr Leu Lys
305 310 315 320
Gly Val Thr Lys Leu Phe Glu Arg Ile Tyr Ser Thr Asp Leu Gly Arg
325 330 335
Met Leu Leu Thr Ser Ile Val Arg Gly Ile Pro Phe Trp Gly Gly Ser
340 345 350
Thr Ile Asp Thr Glu Leu Lys Val Ile Asp Thr Asn Cys Ile Asn Val
355 360 365
Ile Gln Pro Asp Gly Ser Tyr Arg Ser Glu Glu Leu Asn Leu Val Ile
370 375 380
Ile Gly Pro Ser Ala Asp Ile Ile Gln Phe Glu Cys Lys Ser Phe Gly
385 390 395 400
His Glu Val Leu Asn Leu Thr Arg Asn Gly Tyr Gly Ser Thr Gln Tyr
405 410 415
Ile Arg Phe Ser Pro Asp Phe Thr Phe Gly Phe Glu Glu Ser Leu Glu
420 425 430
Val Asp Thr Asn Pro Leu Leu Gly Ala Gly Lys Phe Ala Thr Asp Pro
435 440 445
Ala Val Thr Leu Ala His Glu Leu Ile His Ala Gly His Arg Leu Tyr
450 455 460
Gly Ile Ala Ile Asn Pro Asn Arg Val Phe Lys Val Asn Thr Asn Ala
465 470 475 480
Tyr Tyr Glu Met Ser Gly Leu Glu Val Ser Phe Glu Glu Leu Arg Thr
485 490 495
Phe Gly Gly His Asp Ala Lys Phe Ile Asp Ser Leu Gln Glu Asn Glu
500 505 510
Phe Arg Leu Tyr Tyr Tyr Asn Lys Phe Lys Asp Ile Ala Ser Thr Leu
515 520 525
Asn Lys Ala Lys Ser Ile Val Gly Thr Thr Ala Ser Leu Gln Tyr Met
530 535 540
Lys Asn Val Phe Lys Glu Lys Tyr Leu Leu Ser Glu Asp Thr Ser Gly
545 550 555 560
Lys Phe Ser Val Asp Lys Leu Lys Phe Asp Lys Leu Tyr Lys Met Leu
565 570 575
Thr Glu Ile Tyr Thr Glu Asp Asn Phe Val Lys Phe Phe Lys Val Leu
580 585 590
Asn Arg Lys Thr Tyr Leu Asn Phe Asp Lys Ala Val Phe Lys Ile Asn
595 600 605
Ile Val Pro Lys Val Asn Tyr Thr Ile Tyr Asp Gly Phe Asn Leu Arg
610 615 620
Asn Thr Asn Leu Ala Ala Asn Phe Asn Gly Gln Asn Thr Glu Ile Asn
625 630 635 640
Asn Met Asn Phe Thr Lys Leu Lys Asn Phe Thr Gly Leu Phe Glu Phe
645 650 655
Tyr Lys Leu Leu Cys Val Arg Gly Ile Ile Thr Ser Leu Glu Val Leu
660 665 670
Phe Gln Gly Pro Ala Leu Asn Asp Leu Cys Ile Lys Val Asn Asn Trp
675 680 685
Asp Leu Phe Phe Ser Pro Ser Glu Asp Asn Phe Thr Asn Asp Leu Asn
690 695 700
Lys Gly Glu Glu Ile Thr Ser Asp Thr Asn Ile Glu Ala Ala Glu Glu
705 710 715 720
Asn Ile Ser Leu Asp Leu Ile Gln Gln Tyr Tyr Leu Thr Phe Asn Phe
725 730 735
Asp Asn Glu Pro Glu Asn Ile Ser Ile Glu Asn Leu Ser Ser Asp Ile
740 745 750
Ile Gly Gln Leu Glu Leu Met Pro Asn Ile Glu Arg Phe Pro Asn Gly
755 760 765
Lys Lys Tyr Glu Leu Asp Lys Tyr Thr Met Phe His Tyr Leu Arg Ala
770 775 780
Gln Glu Phe Glu His Gly Lys Ser Arg Ile Ala Leu Thr Asn Ser Val
785 790 795 800
Asn Glu Ala Leu Leu Asn Pro Ser Arg Val Tyr Thr Phe Phe Ser Ser
805 810 815
Asp Tyr Val Lys Lys Val Asn Lys Ala Thr Glu Ala Ala Met Phe Leu
820 825 830
Gly Trp Val Glu Gln Leu Val Tyr Asp Phe Thr Asp Glu Thr Ser Glu
835 840 845
Val Ser Thr Thr Asp Lys Ile Ala Asp Ile Thr Ile Ile Ile Pro Tyr
850 855 860
Ile Gly Pro Ala Leu Asn Ile Gly Asn Met Leu Tyr Lys Asp Asp Phe
865 870 875 880
Val Gly Ala Leu Ile Phe Ser Gly Ala Val Ile Leu Leu Glu Phe Ile
885 890 895
Pro Glu Ile Ala Ile Pro Val Leu Gly Thr Phe Ala Leu Val Ser Tyr
900 905 910
Ile Ala Asn Lys Val Leu Thr Val Gln Thr Ile Asp Asn Ala Leu Ser
915 920 925
Lys Arg Asn Glu Lys Trp Asp Glu Val Tyr Lys Tyr Ile Val Thr Asn
930 935 940
Trp Leu Ala Lys Val Asn Thr Gln Ile Asp Leu Ile Arg Lys Lys Met
945 950 955 960
Lys Glu Ala Leu Glu Asn Gln Ala Glu Ala Thr Lys Ala Ile Ile Asn
965 970 975
Tyr Gln Tyr Asn Gln Tyr Thr Glu Glu Glu Lys Asn Asn Ile Asn Phe
980 985 990
Asn Ile Asp Asp Leu Ser Ser Lys Leu Asn Glu Ser Ile Asn Lys Ala
995 1000 1005
Met Ile Asn Ile Asn Lys Phe Leu Asn Gln Cys Ser Val Ser Tyr
1010 1015 1020
Leu Met Asn Ser Met Ile Pro Tyr Gly Val Lys Arg Leu Glu Asp
1025 1030 1035
Phe Asp Ala Ser Leu Lys Asp Ala Leu Leu Lys Tyr Ile Tyr Asp
1040 1045 1050
Asn Arg Gly Thr Leu Ile Gly Gln Val Asp Arg Leu Lys Asp Lys
1055 1060 1065
Val Asn Asn Thr Leu Ser Thr Asp Ile Pro Phe Gln Leu Ser Lys
1070 1075 1080
Tyr Val Asp Asn Gln Arg Leu Leu Ser Thr Phe Thr Glu Tyr Ile
1085 1090 1095
Lys Asn Ile Ile Asn Thr Ser Ile Leu Asn Leu Arg Tyr Glu Ser
1100 1105 1110
Asn His Leu Ile Asp Leu Ser Arg Tyr Ala Ser Lys Ile Asn Ile
1115 1120 1125
Gly Ser Lys Val Asn Phe Asp Pro Ile Asp Lys Asn Gln Ile Gln
1130 1135 1140
Leu Phe Asn Leu Glu Ser Ser Lys Ile Glu Val Ile Leu Lys Asn
1145 1150 1155
Ala Ile Val Tyr Asn Ser Met Tyr Glu Asn Phe Ser Thr Ser Phe
1160 1165 1170
Trp Ile Arg Ile Pro Lys Tyr Phe Asn Ser Ile Ser Leu Asn Asn
1175 1180 1185
Glu Tyr Thr Ile Ile Asn Cys Met Glu Asn Asn Ser Gly Trp Lys
1190 1195 1200
Val Ser Leu Asn Tyr Gly Glu Ile Ile Trp Thr Leu Gln Asp Thr
1205 1210 1215
Gln Glu Ile Lys Gln Arg Val Val Phe Lys Tyr Ser Gln Met Ile
1220 1225 1230
Asn Ile Ser Asp Tyr Ile Asn Arg Trp Ile Phe Val Thr Ile Thr
1235 1240 1245
Asn Asn Arg Leu Asn Asn Ser Lys Ile Tyr Ile Asn Gly Arg Leu
1250 1255 1260
Ile Asp Gln Lys Pro Ile Ser Asn Leu Gly Asn Ile His Ala Ser
1265 1270 1275
Asn Asn Ile Met Phe Lys Leu Asp Gly Cys Arg Asp Thr His Arg
1280 1285 1290
Tyr Ile Trp Ile Lys Tyr Phe Asn Leu Phe Asp Lys Glu Leu Asn
1295 1300 1305
Glu Lys Glu Ile Lys Asp Leu Tyr Asp Asn Gln Ser Asn Ser Gly
1310 1315 1320
Ile Leu Lys Asp Phe Trp Gly Asp Tyr Leu Gln Tyr Asp Lys Pro
1325 1330 1335
Tyr Tyr Met Leu Asn Leu Tyr Asp Pro Asn Lys Tyr Val Asp Val
1340 1345 1350
Asn Asn Val Gly Ile Arg Gly Tyr Met Tyr Leu Lys Gly Pro Arg
1355 1360 1365
Gly Ser Val Met Thr Thr Asn Ile Tyr Leu Asn Ser Ser Leu Tyr
1370 1375 1380
Arg Gly Thr Lys Phe Ile Ile Lys Lys Tyr Ala Ser Gly Asn Lys
1385 1390 1395
Asp Asn Ile Val Arg Asn Asn Asp Arg Val Tyr Ile Asn Val Val
1400 1405 1410
Val Lys Asn Lys Glu Tyr Arg Leu Ala Thr Asn Ala Ser Gln Ala
1415 1420 1425
Gly Val Glu Lys Ile Leu Ser Ala Leu Glu Ile Pro Asp Val Gly
1430 1435 1440
Asn Leu Ser Gln Val Val Val Met Lys Ser Lys Asn Asp Gln Gly
1445 1450 1455
Ile Thr Asn Lys Cys Lys Met Asn Leu Gln Asp Asn Asn Gly Asn
1460 1465 1470
Asp Ile Gly Phe Ile Gly Phe His Gln Phe Asn Asn Ile Ala Lys
1475 1480 1485
Leu Val Ala Ser Asn Trp Tyr Asn Arg Gln Ile Glu Arg Ser Ser
1490 1495 1500
Arg Thr Leu Gly Cys Ser Trp Glu Phe Ile Pro Val Asp Asp Gly
1505 1510 1515
Trp Gly Glu Arg Pro Leu
1520
Claims (10)
- 변형된 독소 폴리펩티드의 제조 방법으로서,
상기 제조 방법은,
변형된 독소 폴리펩티드 전구체를 발현시키는 단계 1);
상기 독소 폴리펩티드 전구체를 농축시키는 단계 2); 및
상기 독소 폴리펩티드 전구체를 활성화시켜 변형된 독소 폴리펩티드를 얻는 단계 3)을 포함하는 것을 특징으로 하는 제조 방법. - 제1항에 있어서,
상기 단계 1)은,
(1) 상기 독소 폴리펩티드 전구체를 코딩하는 핵산 분자를 설계하는 단계;
(2) 상기 핵산 분자를 포함하는 벡터를 구축하는 단계;
(3) 상기 핵산 벡터를 적합한 숙주 세포에 형질전환하는 단계; 및
(4) 상기 숙주 세포를 배양하고, 숙주 세포가 상기 핵산 벡터에 의해 코딩된 독소 폴리펩티드 전구체를 발현하도록 허용 또는 유도하는 단계를 포함하는 것을 특징으로 하는 제조 방법. - 제1항 내지 제2항 중 어느 한 항에 있어서,
상기 단계 2)는 다중 여과 단계를 수행하여 상기 독소 폴리펩티드 전구체를 농축시키는 단계를 포함하는 것을 특징으로 하는 제조 방법. - 제3항에 있어서,
상기 다중 여과는 조액 여과 및 공급액 순환 여과를 포함하는 것을 특징으로 하는 제조 방법. - 제4항에 있어서,
상기 조액 여과 재료의 기공 크기는 0.1~0.65μm인 것을 특징으로 하는 제조 방법. - 제4항 또는 제5항에 있어서,
상기 공급액 순환 여과 단계에서 공급액을 여러 번 여과하고, 상기 공급액 순환 여과 재료의 기공 크기는 0.2μm 이하인 것을 특징으로 하는 제조 방법. - 제1항 내지 제6항 중 어느 한 항에 있어서,
상기 단계 3)에서 프로테아제로 독소 폴리펩티드 전구체를 절단하여 변형된 독소 폴리펩티드를 얻는 것을 특징으로 하는 제조 방법. - 제7항에 있어서,
상기 독소 폴리펩티드 전구체는 프로테아제에 의해 절단된 후 적어도 하나의 이량체 구조를 형성하는 것을 특징으로 하는 제조 방법. - 제1항 내지 제8항 중 어느 한 항에 있어서,
상기 독소 폴리펩티드 전구체는 독소 폴리펩티드에 비해 낮은 독성을 갖는 것을 특징으로 하는 제조 방법. - 제1항 내지 제9항 중 어느 한 항에 있어서,
상기 제조 방법은 상기 독소 폴리펩티드를 정제하는 단계 4)를 더 포함하는 것을 특징으로 하는 제조 방법.
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PCT/CN2022/077637 WO2022179556A1 (zh) | 2021-02-26 | 2022-02-24 | 一种经修饰的毒素多肽的制备方法 |
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