KR101457753B1 - 결합 분자 - Google Patents
결합 분자 Download PDFInfo
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- KR101457753B1 KR101457753B1 KR1020117019563A KR20117019563A KR101457753B1 KR 101457753 B1 KR101457753 B1 KR 101457753B1 KR 1020117019563 A KR1020117019563 A KR 1020117019563A KR 20117019563 A KR20117019563 A KR 20117019563A KR 101457753 B1 KR101457753 B1 KR 101457753B1
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Abstract
Description
도 2A 및 2B는 결합 영역의 상이한 배치와 또 다른 결합영역에 의한 이펙터 부분의 대체를 보여준다. A. 동형이합체가 생산되는 바람직한 옵션. 생성물의 분리가 필요없음. B. 동형이합체와 이형이합체 혼합물이 생성. 생성물의 분리가 필요.
도 3은 이펙터 쇄와 회합된 중쇄 폴리펩티드 복합체를 보여준다. 이펙터 쇄는 상보적인 결합 영역(CBD)과 이펙터 부분(EM)을 포함한다. 상보적 결합 영역(CBD)은 중쇄의 EM(이펙터 부분)에 의해 인식된다. CBD는 이펙터, 예를 들면 효소, 톡신, 킬레이터, 영상제 또는 이들의 일부에 융합된다. 이펙터 쇄는 중쇄로부터 별도로 합성될 수 있다.
도 4는 J쇄와 회합된 2가의 분비성 IgA를 보여준다.
도 5는 J쇄를 통해 어셈블링된 다가의 중쇄만의 IgM-유사 폴리펩티드 복합체를 보여준다.
도 6은 IgG 유전자좌를 발현하는 형질전환 마우스의 생성을 위한 전략을 보여주고, 항원 노출의 결과로서 중쇄만의 항체들과 VH 영역의 작용적 생성을 위한 전략을 보여준다.
도 7은 IgM 유전자좌를 발현하는 형질전환 마우스의 생성 전략을 보여주고, 항원 노출의 결과로서 중쇄만의 항체와 VH 영역의 작용적 생성을 위한 전략을 보여준다.
도 8은 IgA 유전자좌를 발현하는 형질전환 마우스의 생성 전략을 보여주고, 항원 노출의 결과로서 중쇄만의 항체와 VH 영역의 작용적 생성을 위한 전략을 보여준다.
도 9는 PCR 생산물의 서열 정렬은 CH1을 제거하기 위해 카멜리드 스플라이스 변이를 갖는 불변 영역을 가지는 유전자좌를 포함하는 마우스로부터의 인간 Cγ2 프라이머와 조합된 VHH1과 VHH2 프라이머를 사용하여 골수 cDNA로부터 얻어졌다.
도 10~13은 VH/카멜리드 VH(VHH) 구조물의 구조이다. 1-n은 VH 유전자 또는 D 또는 J 단편의 어떤 수(number)를 의미한다. 인간 유전자좌의 정상적인 상보물은 51개의 V 유전자, 25개의 작용적 D 단편(+ 2개의 비작용적 D 단편) 및 6개의 J 단편이다. (IgM에 대한) Cμ 또는 (IgE에 대한) Cε 영역에서, H 영역은 없고, CH3과 M1 사이에는 부가적인 CH4 엑손이 있다. VH 유전자(들)은 공개된 영역에서 설명된 바와 같이 용해도를 제공하기 위하여 변이되었다.
바람직하게, VH 유전자, D와 J 단편 및 C 엑손은 인간이지만, 카멜리드를 포함하는 어떤 다른 종들로부터 일 수 있다. 후자의 경우에, 카멜리드 VH(VHH) 유전자는 그들이 자연적으로 가용성이기 때문에 변이될 수 없다.
도 14는 대장균 HSP70에 대한 중쇄만의 IgG 생성을 위한 마우스 면역화 스케쥴과 항체 검정을 나타낸다.
도 15는 형질전환 마우스 유래의 췌장 세포에 대한 플로우 사이토메트릭 분석(Flow cytometric analysis)과 면역조직화학 결과(immunohistochemistry results)이다.
도 16은 DKTP 면역화된 형질전환 마우스의 ELISA 분석의 결과와, 결과의 항체 라이브러리의 서열 분석을 보여준다.
도 17은 면역화된 형질전환 마우스에서 니타난 체세포 변이와 VDJ 재배열의 예를 보여준다.
도 18은 A5 항체를 포함하는 반응 플라즈미드로써 트랜스펙션된 Tet-on 세포주의 면역염색 검정의 결과를 나타낸다.
도 19는 형질전환 마우스 계통 혈청의 웨스턴 블랏 분석(Western blot analysis)의 결과를 나타낸다.
도 20은 IgM + IgG 유전자좌 마우스에 의해 생산된 인간 단일쇄 IgM과 혼합된 인간 IgM의 크기 분별을 나타낸다.
도 21은 인간 TNFα에 대한 단일쇄 IgM과 IgG 항체의 ELISA 분석의 결과를 나타낸다.
도 22는 HSP70과 αGAG에 대한 결합 친화성을 지닌 동형이합체 플라즈미드의 생성을 위한 전략을 보여준다.
도 23은 CHO 세포에서 동형이합체 폴리펩티드 복합체의 작용적 발현을 나타낸다.
도 24는 αGAG와 HSP70에 대한 동형이합체 폴리펩티드 복합체의 작용적 결합과 동시성을 나타낸다. 2가 이특이적 항체의 대표적인 도해. 제2의 가변 영역(VHH2는 gag를 향하고 있음)은 다른 특성(VHH1은 HSP70를 향하고 있음)을 포함하는 중쇄만의 항체의 카복시 말단으로 클로닝된다. CH3와 VHH2 사이에 있는 힌지 영역은 링커 영역에 의해 대체되었고, 여기에서 모든 시스테인은 프롤린(화살표)에 의해 대체되었다. Gag로써 ELISA 플레이트를 코팅하고, PBS 중의 1% 밀크/ 1% BSA로써 블로킹하고, 처음에는 디아바디 배지(1:2로 희석), 다음으로 BI21 세포 용해물(HSP 70을 포함)(1:2로 희석)로 항온처리했다. 용리액은 시료완충액=2-머캡토에탄올로 단백질에 결합되었고, 8%겔상으로 흘려보냈다. Gag, 디아바디 및 HSP70에 대해 폴리/단일클론항체로 염색했다. α Gag: 토끼 폴리클로날/돼지 α 토끼-AP(청색). α HSP70: 단일클론/염소 α 인간 IgG-HRP(갈색). α 디아바디: 염소 α 인간 IgG-HRP(갈색). 레인 1: Gag/디아바디/BI21 세포 용해물. 레인 2: Gag/배지(디아바디 음성 대조군)/BI21. 레인 3: -밀크-BSA/디아바디/BI21. 레인 4: -밀크-BSA/배지/BI21. 레인 5: Gag/디아바디/-밀크-BSA. 레인 6: Gag/배지/-밀크-BSA.
도 25는 선택적으로 IgA 이펙터 기능을 가지는 이펙터 쇄와 회합된 동형이합체 폴리펩티드 복합체의 생성을 위한 전략을 보여준다.
도 26은 선택적으로 IgA 이펙터 기능을 가지는 이펙터 쇄와 회합된 동형이합체 폴리펩티드 복합체의 생성을 위한 전략을 보여준다.
일반적인 기술
다르게 정의가 되지 않는다면, 여기에서 사용된 모든 기술적 및 과학적 용어들은 당업자들에 의해 통상적으로 이해되는 바와 같은 동일한 의미를 갖는다(예를 들어, 세포 배지에서, 분자유전학, 핵산화학, 잡종형성기술 및 생화학). 표준 기술은 분자, 유전학 및 생화학적 방법(Sambrook 등, Molecular Cloning: A Laboratory Manual, 2nd Ed.(1989) Cold Spring Harbor Lab. Press, Cold Spring Harbor, N.Y. 및 Ausubel 등, Short Protocols in Molecular Biology(1999) 4th Ed., John Wiley & Sons, Inc.)과 화학적 방법을 사용하였다. 추가적으로, Harlow & Lane, A Laboratory Manual, Cold Spring Harbor, N.Y.를 표준면역학적 기술에 대하여 참고하였다.
어떤 적당한 재조합 DNA 기술은 본 발명의 2가와 다가의 폴리펩티드 복합체, 단일 중쇄 항체 및 이들의 단편의 생산에 사용될 수 있다. 플라스미드와 같은 전형적인 발현 벡터는 폴리펩티드 복합체 또는 항체의 쇄 각각을 코딩하는 DNA 서열을 포함하여 구성된다. 면역글로불린의 효소적 절단 및 화학적 절단과 결과적으로 얻은 단편의 분리를 위한 어떤 적절한 확립된 기술이 사용될 수 있다.
또한, 본 발명은 형질전환 마우스에서 중쇄만의 항체의 발현과 본 발명의 폴리펩티드 복합체의 구성과 발현을 위한 구조물을 포함하는 벡터를 제공한다.
단일 벡터는 더 많은 폴리펩티드 사슬을 코딩하는 DNA 서열을 포함하여 구성될 수 있다는 것이 이해될 것이다. 예를 들면, 두 개의 상이한 중쇄를 코딩하는 DNA 서열은 동일한 플라스미드의 상이한 위치에 삽입될 수 있다.
택일적으로, 각각의 폴리펩티드 쇄를 코딩하는 DNA 서열은 플라스미드에 개별적으로 삽입될 수 있으므로, 다수의 구성된 플라스미드를 생성하고, 각각은 특별한 폴리펩티드 쇄를 코딩한다. 바람직하게는, 서열들이 삽입되는 플라스미드들이 양립가능하다.
다음으로, 각각의 플라스미드는 숙주세포를 형질전환시키기 위해 사용되므로 각각의 숙주세포는 폴리펩티드 복합체 내에서 폴리펩티드 쇄의 각각을 코딩하는 DNA 서열들을 포함한다.
박테리아 시스템에서 클로닝을 위해 사용될 수 있는 적당한 발현벡터는 Col E1, pcR1, pBR322, pACYC184 및 RP4, 파아지 DNA 또는 이들 중의 어느 것의 유도체를 포함한다.
효모 시스템에서 클로닝하기 위하여, 적절한 발현벡터는 2 마이크론 오리진(2 micron origin)에 기초한 플라스미드를 포함한다.
적절한 포유동물 유전자 프로모터 서열을 포함하는 어떤 플라스미드는 포유동물 시스템에서 클로닝에 사용될 수 있다. 곤충 또는 배큘로바이러스 프로모터 서열은 곤충세포 유전자 발현을 위해 사용될 수 있다. 이러한 벡터들은, 예를 들면, pBR322, 소과의 유두종 바이러스, 레트로바이러스, DNA 바이러스 및 우두 바이러스로부터 유래된 플라스미드를 포함한다.
폴리펩티드 복합체 또는 항체의 발현을 위해 사용될 수 있는 적절한 숙주세포는 박테리아, 효모 및 곤충 또는 포유동물 세포주와 같은 진핵세포, 형질전환 식물, 곤충, 포유동물 및 다른 무척추동물 또는 척추동물 발현 시스템을 포함한다.
본 발명의 폴리펩티드 복합체와 단일 중쇄 항체
또한, 본 발명의 용어 "폴리펩티드 복합체", "단일 중쇄 항체" 및 "이형 중쇄 유전자좌"는 어떤 소스, 예를 들면, 관련된 세포성 동종, 다른 종과 이들의 변종 또는 유도체로부터의 관련된 동종으로부터 얻어지는 동종 폴리펩티드와 핵산 서열을 포함한다.
따라서, 본 발명은 여기에서 설명된 바와 같은 폴리펩티드 복합체와 항체의 변종, 동종 또는 유도체를 포함한다.
본 발명에서, 상동 서열은 적어도 30, 바람직하게는 50, 70, 90 또는 100 아미노산을 넘는 아미노산 수준에서, 적어도 80, 85, 90, 95, 96, 97, 98, 99, 99.5, 99.6, 99.7, 99.8, 99.9% 동일성, 바람직하게는 적어도 98% 또는 99% 동일성이 있는 아미노산 서열을 포함하도록 취해진다. 또한, 비록 상동성이 유사성의 용어(즉, 유사한 화학적 성질/기능을 갖는 아미노산 잔기)로 나타나지만, 본 발명에서, 서열 동일성의 용어로 상동성으로 표현하는 것이 바람직하다.
또한, 본 발명은 본 발명의 폴리펩티드 복합체와 항체의 제조시에 사용하기 위한 구성된 발현 벡터와 형질전환된 숙주세포를 포함한다.
동일한 숙주세포 내에서 각각의 쇄의 발현 후, 이들은 완전한 폴리펩티드 복합체 또는 중쇄만의 항체를 활성 형태로 제공하도록 회수될 수 있다.
본 발명의 바람직한 형태에서, 개별적인 중쇄는 숙주세포에 의해 가공되어, 거기로부터 유리하게 분비되는 완전한 폴리펩티드 복합체 또는 항체를 만들 수 있다. 바람직하게, 이펙터 쇄는 숙주세포에 의해 또는 합성장치에 의해 각각 생성된다.
재조합 항체 폴리펩티드 복합체의 제조를 위한 기술은, 상기 참고내용에 설명되어 있고, 또한 EP-A-0 623 679; EP-A-0 368 684 및 EP-A-0 436 597에 설명되어 있다.
형질전환 생물의 면역화
또 다른 관점에서, 본 발명은 본 발명의 형질전환 생물에 항원을 투여하는 것을 포함하는 본 발명의 항체의 생산 방법을 제공한다.
본 발명의 형질전환 동물로부터 생산된 항체들과 폴리펩티드 복합체는 폴리클로날항체 및 단일클론항체와 이들의 단편을 포함한다. 폴리클로날항체를 원한다면, 형질전환 동물(예, 마우스, 토끼, 염소, 말 등)은 공지된 절차들에 의해 수집되고 처리된 면역화된 동물로부터의 항원과 혈청으로 면역시킬 수 있다. 폴리클로날항체를 포함하는 혈청이 다른 항원에 대한 항체를 포함한다면, 관심있는 폴리클로날항체는 당업자들에게는 친숙할 수 있는 면역친화성 크로마토그래피와 그와 유사한 기술들에 의해 정제될 수 있다. 또한, 폴리클로날 항혈청을 생산하고, 가공하기 위한 기술은 공지이다.
본 발명의 폴리펩티드 결합 복합체 및 항체의 사용
본 발명의 폴리펩티드 복합체와 이들의 단편을 포함하는 항체는, 생체 내 치료와 예방에 적용, 시험관 내와 생체 내에서의 진단에 적용, 시험관 내 검정 및 시약 적용 등에 이용될 수 있다.
본 발명의 폴리펩티드 복합체와 항체의 치료 및 예방을 위한 사용은, 인간과 같은 수령(recipient) 포유동물에 이들의 투여를 포함한다.
적어도 90~95% 상동성을 갖는 이들의 단편을 포함하는 실질적으로 순수한 폴리펩티드 복합체와 항체는 포유동물에 투여하기에 바람직하고, 98~99% 이상의 상동성은 약학적 사용, 특히 포유동물이 인간일 때 가장 바람직하다. 목표하는 부분적으로 또는 균질하게 일단 정제된 여기에서 설명된 바의 폴리펩티드 복합체와 중쇄만의 항체는 (여분의 유형을 포함하는) 진단 또는 치료 또는 당업자에게 공지된 방법을 사용하는 검정 과정을 개발하고 수행하는데 사용될 수 있다.
일반적으로, 본 발명의 폴리펩티드 복합체와 항체는 약학적으로 적절한 담체와 함께 정제된 형태로서 이용가능하다. 전형적으로, 이 담체는 염수 및/또는 완충 배지를 포함할 수 있는 수성 또는 알코올/수성 용액, 에멀젼 또는 현탁액을 포함한다. 비경구적 운반체는 염화나트륨용액, 링거 덱스트로오스, 덱스트로오스 및 염화나트륨 및 젖산화 링거를 포함한다.
현탁액 내에서 폴리펩티드 복합체를 유지하는 것이 필요하다면, 적당한 생리학적으로 허용가능한 보조제들이 카르복시메틸셀룰로오스, 폴리비닐피롤리돈, 젤라틴 및 알키네이트와 같은 농축제로부터 선택될 수 있다.
정맥용 운반체는 링거의 덱스트로오스에 기초를 둔 것들과 같은 유체와 영양보충제와 전해질 보충제를 포함한다. 또한, 항미생물제, 산화방지제, 킬레이팅제와 불활성 기체와 같은 방부제 및 다른 첨가제도 존재할 수 있다(Mack(1982) Remington's Pharmaceutical Science, 16th Edition).
본 발명의 폴리펩티드 복합체와 이들의 단편을 포함하는 항체는 따로 투여되는 조성물 또는 다른 약제들과 함께 사용가능하다. 이들은 시클로스포린, 메토트렉세이트, 아드리아마이신, 시스플라티늄 또는 이뮤노톡신과 같은 여러 가지의 면역치료용 약제를 포함할 수 있다. 택일적으로, 폴리펩티드 복합체는 그들의 작용 부위에서 프로드러그의 전환을 위해 효소들과 함께 사용될 수 있다.
약학적 조성물은 본 발명의 선별된 항체와 결합한 여러 가지의 세포독성제 또는 다른 제제와의 "칵테일" 또는 본 발명의 선별된 항체의 조합물을 포함할 수 있다.
본 발명의 약학적 조성물의 투여 경로는 당업자에게 통상적으로 공지된 것 중의 어느 것일 수 있다. 치료를 위하여, 면역치료에 제한 없이, 본 발명의 폴리펩티드 복합체 또는 항체는 표준기술에 따라서 어떤 환자에게도 투여될 수 있다. 투여는 비경구, 정맥 내, 근육 내, 복강 내, 피부, 폐 경로 또는 적절한 카테터로 직접 투여하는 것을 포함하는 어떤 적절한 방법에 의해 이루어질 수 있다. 투여량과 빈도는 환자의 나이, 성별 및 상태에 따라서 다른 약제의 동시 투여와 카운터-인디케이션(counter-indication) 및 의사에 의해 고려될 수 있는 다른 매개변수에 따라 달라질 수 있다.
본 발명의 폴리펩티드 복합체와 항체는 저장을 위해 동결건조될 수 있고, 사용하기 전에 적당한 담체에서 재구성될 수 있다. 공지된 동결건조 및 재구성 기술이 적용될 수 있다. 동결건조 및 재구성은 기능 활성도 손실의 정도 변화를 초래할 수 있고, 사용수준이 보상되도록 상향 조절되어야 한다는 것을 당업자는 이해할 것이다.
추가적으로, 본 발명의 폴리펩티드 복합체와 항체는 진단목적으로 사용가능하다. 예를 들면, 여기에서 설명된 바의 항체는 질병상태 동안 특별히 발현되거나, 또는 질병상태 동안에 그 수준이 변화하는 항원에 대해 생성 또는 발생할 수 있다.
진단 또는 추적 목적과 같은 특정한 목적을 위하여, 표지가 첨가될 수 있다. 적절한 표지는 제한되지는 않지만, 다음 중의 어떤 것을 포함한다: 방사성 표지, NMR 스핀 표지 및 형광 표지. 표지의 검출 방법은 당업자들에게는 익숙할 것이다.
본 발명의 폴리펩티드 복합체와 항체 또는 이들의 칵테일을 포함하는 조성물은 예방 및/또는 치료적 처치를 위해 투여될 수 있다.
본 발명의 하나 이상의 폴리펩티드 복합체 또는 항체를 포함하는 조성물은 포유동물에서 선택 표적 세포 집단의 변화, 불활성화, 사멸 또는 제거를 도와주기 위한 예방과 치료 세팅에 이용될 수 있다. 추가적으로, 여기에서 설명된 폴리펩티드 복합체와 항체의 선택된 레퍼토리는 세포의 이종 집단으로부터 표적 세포 집단을 죽이거나, 고갈시키거나, 또는 그렇지 않으면 효과적으로 제거시키는데 생체 외 또는 시험관 내에서 선택적으로 사용될 수 있다.
Claims (17)
- 다음의 단계들을 포함하는, VH 중쇄만의 항체 생산 방법:
(a) 이형 VH 중쇄 유전자좌를 발현하는 형질전환 비인간 포유동물을 항원으로 면역화하는 단계; 여기에서,
(i) 상기 VH 중쇄 유전자좌는 적어도 하나의 자연적으로 발생하는 VH 유전자 단편, 적어도 하나의 D 유전자 단편, 적어도 하나의 J 유전자 단편을 포함하는 가변 영역 및 적어도 하나의 중쇄 불변영역을 포함하고;
(ii) 각각의 불변 영역은 CH1 영역을 코딩하지 않고;
(iii) VH 유전자 단편, D 유전자 단편 및 J 유전자 단편은 VDJ 코딩 서열을 형성하기 위해 재조합이 가능하며;
(iv) 각 중쇄 불변 영역은 인간 기원이 아닌 척추동물 기원이고;
(v) 발현시 상기 재조합 VH 중쇄 유전자좌는, 가용성 항원특이적 VH 결합 영역 및 CH1 영역이 결여된 불변 영역 이펙터를 포함하는 가용성의 중쇄만의 항체 형성이 가능하다;
(b) 항체 생산 세포로부터 VH 중쇄만의 항체를 코딩하는 핵산 서열을 분리하는 단계; 및
(c) 재조합 DNA 기술을 사용하여 VH 중쇄만의 항체를 생산하는 단계. - 제 1항에 있어서, 상기 포유동물에 대해 내생적인 면역글로불린 경쇄 유전자좌는 결실 또는 사일런스되는 것을 특징으로 하는 방법.
- 제 1항에 있어서, 상기 포유동물에 대해 내생적인 면역글로불린 중쇄 유전자좌는 결실 또는 사일런스되는 것을 특징으로 하는 방법.
- 제 1항에 있어서, 상기 면역화는 항원을 형질전환 포유동물에 주입하는 것을 포함하고, 상기 단계 (b) 및 (c)는 다음의 단계들을 포함하는 것을 특징으로 하는 방법:
(ⅰ) 목적하는 항원특이적인 중쇄만의 항체를 발현하는 세포 또는 조직을 분리하는 단계;
(ⅱ) 상기 단계 (ⅰ)의 세포 또는 조직으로부터 하이브리도마를 생산하는 단계;
(ⅲ) 상기 하이브리도마로부터 상기 중쇄만의 항체 mRNA를 클로닝하는 단계; 및
(ⅳ) 상기 중쇄만의 항체를 이형 발현 시스템에서 생산하는 단계. - 제 1항의 단계 (a)를 포함하는, 가용성인 항원특이적 VH 결합 영역의 생산 방법으로서, 상기 면역화는 항원을 형질전환 포유동물에 주입하는 것을 포함하고, 상기 방법은 하기 추가의 단계들 (b1) 내지 (f1)를 더 포함하는 것을 특징으로 하는 방법:
(b1) 목적하는 항원특이적인 중쇄만의 항체를 발현하는 세포 또는 조직을 분리하는 단계;
(c1) 상기 단계 (b1)의 세포 또는 조직으로부터 하이브리도마를 생산하는 단계;
(d1) 상기 하이브리도마로부터 상기 중쇄만의 항체 mRNA를 클로닝하는 단계;
(e1) 상기 단계 (d1)의 클로닝된 mRNA로부터 항원특이적 VH 영역을 확인 및 분리하는 단계; 및
(f1) 상기 가용성인 항원특이적 VH 결합 영역을 이형 발현 시스템에서 생산하는 단계. - 제 1항의 단계 (a)를 포함하는, 가용성인 항원특이적 VH 결합 영역의 생산 방법으로서, 상기 면역화는 항원을 형질전환 포유동물에 주입하는 것을 포함하고, 상기 방법은 하기 추가의 단계들 (b2) 내지 (f2)를 더 포함하는 것을 특징으로 하는 방법:
(b2) 목적하는 항원특이적인 중쇄만의 항체를 발현하는 세포 또는 조직을 분리하는 단계;
(c2) 상기 분리된 세포 또는 조직으로부터 유래된 mRNA로부터 VH 유전자좌를 클로닝하는 단계;
(d2) 상기 VH 유전자좌에 의하여 코딩된 VH 영역을, 파지 또는 유사 라이브러리를 사용하여 디스플레이하는 단계;
(e2) 가용성의 항원특이적 VH 영역을 확인하는 단계; 및
(f2) 상기 가용성의 항원특이적 VH 영역을 단독으로 또는 융합체로서 발현하는 단계. - 제 1항에 있어서, 상기 VH 중쇄 유전자좌는 포유동물 VH, D 및 J 유전자 단편들을 포함하는 것을 특징으로 하는 방법.
- 제 1항에 있어서, 상기 VH 중쇄 유전자좌는 인간 VH, D 및 J 유전자 단편들을 포함하는 것을 특징으로 하는 방법.
- 제 1항에 있어서, 상기 VH 중쇄 유전자좌는 하나 이상의 VH 유전자 단편, 하나 이상의 D 유전자 단편 및 하나 이상의 J 유전자 단편을 포함하는 것을 특징으로 하는 방법.
- 제 1항 내지 제 4항 중 어느 한 항 또는 제 7항 내지 제 9항 중 어느 한 항의 방법에 따라 수득가능한 중쇄만의 항체.
- 제 5항 또는 제 6항의 방법에 따라 수득가능한 가용성 항원특이적 VH 결합 영역.
- 단독으로, 또는 상보적 어셈블리 영역과 조합되어, 이가 또는 다가 폴리펩티드 복합체의 생산을 위하여 사용되는, 제 11항에 따른 가용성 항원특이적 VH 결합 영역.
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