KR102112759B1 - 페리틴 자가조립체에 항원 펩타이드 및 면역 증강제가 결합된 나노 입자 및 이의 용도 - Google Patents
페리틴 자가조립체에 항원 펩타이드 및 면역 증강제가 결합된 나노 입자 및 이의 용도 Download PDFInfo
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Abstract
본 발명은 항원 펩타이드 및 면역 증강제가 결합되어 있는 페리틴 나노 입자에 관한 것으로, HTTcys 펩타이드와 VL12.3cys 펩타이드를 이용하여 페리틴 자가조립체에 항원 펩타이드 또는 면역 증강제를 간접적으로 결합시킴으로써, 항원 및 면역 증강제를 직접 융합시키는 경우보다 용이하게 융합 단백질을 생산할 수 있고, 또한 이를 통해 항원 및 면역 증강제의 상대적 몰비를 손쉽게 조절할 수 있어 백신 조성물로 유용하게 사용할 수 있다.
Description
본 발명은 페리틴 자가조립체에 항원 펩타이드 및 면역 증강제가 결합된 나노 입자에 관한 것이다.
백신이란 감염증의 예방을 위하여 동물을 능동적으로 면역하기 위하여 쓰이는 항원(antigen), 또는 항원을 유효성분으로 함유한 생물학적 제제로서 프랑스의 미생물학자 L.파스퇴르에 의하여 제창되었다. 통상 백신을 투여하면 생체에서는 해당 항체가 만들어져 면역이 획득되며, 일단 생성된 항체는 비교적 오랫동안 생체 안에 남아있게 되어, 해당 질병의 원인균에 의한 감염이 발생하더라도 이에 대한 방어가 가능하여 결과적으로 질병을 예방할 수 있다.
통상적으로 백신제제에는 세균을 사멸시켜 사용하는 사균백신(killed vaccine), 불활성 백신(inactivated vaccine), 살아있는 세균을 그대로 사용하는 생균백신(live vaccine), 생균을 약화시킨 약독균주(attenuated strain)를 사용하는 약독화 백신 (attenuated vaccine), 세균의 톡소이드(toxoid) 또는 이것의 유도체 등 다양한 종류가 존재하며, 효과적인 백신 개발을 위해서는 질병을 일으키는 원인체에 대해 항체의 형성을 원활하게 하여 생체 내 면역반응이 적절히 유도되도록 해야 하기 때문에, 가능한 질병 원인체에 유사한 형태로 개발되는 것이 바람직하다. 이 때문에 아무 처리도 하지 않고 생균을 그대로 사용하는 생균백신이 백신으로서는 가장 좋은 효과를 나타낼 수 있다. 하지만, 생균백신의 경우 질병을 야기하는 질병 원인체를 살아 있는 채로 이용하는 것이기 때문에, 향후 독성이 있는 균주로 전환되어 오히려 질병을 유발할 수 있는 위험성을 가지고 있어 극히 일부 감염성 질환에 있어서만 사용되고 있는 실정이다. 이런 단점을 극복하기 위한 대안으로 생균을 약독화시킨 약독화백신이 개발되어 사용되어지고 있지만, 이 경우 일반적으로 항원성이 생균백신에 비해 약화되어 백신으로서의 효과가 떨어지고, 또한 여전히 안전하다고도 할 수 없는 문제점을 가지고 있다. 사용상 안전성 때문에 개발된 사균백신은 비록 상기의 안전성 관점에서의 문제점을 해결할 수는 있지만 항원성이 생균백신이나 약독백신에 비해 크게 떨어지는 것이 일반적이다. 이에 따라, 사균백신처럼 사용상 안전하면서도 생균백신처럼 항원성이 뛰어난 이상적인 새로운 백신제제의 개발이 요구되고 있는 실정이다.
케이지(cage) 단백질은 저분자량 단일체들의 정밀한 자가조립 성질에 의하여 단일체 분자량의 수십에서 수백 배의 거대분자를 형성할 수 있는 단백질이다. 자연계에서 바이러스 capsid 단백질, 페리틴, 열충격 단백질 (heat shock protein), Dps 단백질 등이 이에 해당되며 케이지(cage)를 구성하는 각각의 단량체들은 인접 단량체들과 매우 규칙적이고 정밀한 상호작용을 이루어, 내부가 비어있는 구조를 형성한다.
페리틴은 철을 저장하는 단백질로써 원핵생물과 진핵생물에 널리 존재한다. 페리틴 케이지(cage)의 분자량은 약 500,000Da으로, 20 kDa의 동일한 단량체(중쇄 혹은 경쇄 중 하나로 구성된 단일 단량체 혹은 이종 단량체)가 자가 조립되어 거대한 구 형태의 삼차구조를 형성한 것으로, 인간 페리틴 케이지의 경우 외경은 약 12 nm 이고 내경은 약 8 nm이다. 페리틴은 pH 조건에 따라 단량체로 흩어지기도 하고 24개의 단량체가 결합한 나노 입자를 형성하기도 하는데 이러한 특성을 이용하면 페리틴 내에 다양한 물질을 포집할 수 있다.
그 외에도 페리틴 단량체의 N-말단에 인플루엔자 헤마글루티닌(hemagglutinin)을 유전적으로 융합하여 페리틴 케이지의 외부 표면에 나타낼 수 있고 (Kanekiyo, M et al., Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies, Nature 2013; 499: 102~6), 특히 헤마글루티닌의 불변 영역(invariable region)의 서열을 페리틴 표면에 발현시키는 경우, 광범위한 인플루엔자 균주에 대한 후보 백신을 생산하는 데에도 사용될 수 있다 (Yassine, HM et al., Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection, Nat Med 2015; 21: 1065~70).
이에 본 발명자들은 항원-항체 결합 및 이황화 결합을 형성하는 HTTcys 펩타이드와 VL12.3cys 펩타이드를 이용하여 페리틴 자가조립체에 항원 펩타이드 및 면역 증강제를 결합시킨 나노 입자를 제조하여, 항원 및 면역 증강 펩타이드를 직접 융합시키는 경우보다 용이하게 융합 단백질을 생산할 수 있고, 페리틴 자가조립체에 결합하는 항원 펩타이드 및 면역 증강제의 몰비(molar ratio)를 용이하게 조절할 수 있음을 확인하였다. 또한, 본 발명자들은 상기 나노 입자를 포함하는 조성물은 총 면역글로불린 수치를 증가시키고, 세포성 면역 및 체액성 면역을 증진시킬 수 있음을 확인함으로써 본 발명을 완성하였다.
본 발명의 목적은 페리틴 자가조립체에 항원 펩타이드 및 면역 증강제가 결합된 페리틴 나노 입자를 제공하는 것이다.
상기 목적을 달성하기 위하여, 본 발명은 HTTcys 펩타이드 및 페리틴 단량체의 융합 단백질 24개의 자가조립체; VL12.3cys 펩타이드 및 항원 펩타이드가 융합된 융합 단백질; 및 VL12.3cys 펩타이드 및 면역 증강제(adjuvant)의 융합 분자를 포함하는 나노 입자로서, 상기 항원 펩타이드 및 면역 증강제는 상기 HTTcys 펩타이드와 VL12.3cys 펩타이드 간의 결합에 의해 페리틴 자가조립체와 연결된 것인, 나노 입자를 제공한다.
또한, 본 발명은 상기 나노 입자를 포함하는, 백신 조성물을 제공한다.
본 발명의 나노 입자는 HTTcys 펩타이드와 VL12.3cys 펩타이드를 매개로 페리틴 자가조립체에 항원 펩타이드 또는 면역 증강제가 결합된 것으로, 항원 및 면역 증강제를 직접 융합시키는 경우보다 용이하게 융합 단백질을 생산할 수 있으며 항원 펩타이드 및 면역 증강제의 몰비를 용이하게 조절할 수 있으므로 백신 생산을 위한 조성물로 유용하게 이용될 수 있다.
도 1은 HTT 펩타이드 및 VL12.3 펩타이드 간의 항원-항체 결합에 이황화 결합을 추가적으로 도입시킬 수 있는 HTTcys 펩타이드 및 VL12.3cys 펩타이드의 서열을 나타낸 것이다.
도 2는 살모넬라 플라젤린(FliC), 대장균 페리틴(Ftn) 및 헤마글루티닌(인플루엔자 A 바이러스 (A/California/04/2009(H1N1), HA)의 융합 단백질 도메인을 도시적으로 나타낸 것이다.
도 3은 면역 증강 펩타이드인 플라젤린이 결합된 나노 입자를 나타낸 것으로, (A-1)은 Ftn-HA-ΔFliC 나노 입자, (B-1)은 Ftn-PA-ΔFliC 나노 입자 및 (C-1)은 I3-01-HA-ΔFliC 나노 입자를 나타낸 것이고, (A-2)는 (A-1)의 나노 입자의 크기 배제 크로마토그래피 프로파일, (B-2)는 (B-1)의 나노 입자의 크기 배제 크로마토그래피 프로파일 및 (C-2)는 (C-1)의 나노 입자의 크기 배제 크로마토그래피 프로파일을 나타낸 것이며, (A-3)은 (A-2)의 크로마토그래피로 정제된 나노 입자의 SDS-PAGE 분석 결과를 나타낸 것이다.
도 4는 Ftn, Ftn-ΔFliC(N) 및 Ftn-FliC 와 각각 배양된 HEK293 세포의 TLR5 활성화 정도를 나타낸 것이다.
도 5는 Ftn-HA-ΔFliC(N) 및 Ftn-HA-FliC(N)로 각각 면역화된 마우스 혈청의 총 IgG 및 IgG 서브클래스 수치를 나타낸 것이다
(Ftn : HA = 24:10;
HA : FliC(또는 ΔFliC) = 4:1).
도 6은 Ftn + ΔFliC, Ftn-ΔFliC(C), Ftn-ΔFliC(I) 및 Ftn-ΔFliC(N) 와 각각 배양된 HEK293 세포의 TLR5 활성화 정도를 나타낸 것이다.
도 7의 (A)는 HA, Ftn + ΔFliC + HA 및 Ftn-ΔFliC(I) + HA로 각각 면역화된 마우스 혈청의 총 IgG 및 IgG 서브클래스 수치를 나타낸 것이고, (B)는 Ftn-HA + ΔFliC 및 Ftn-HA-ΔFliC(I)로 각각 면역화된 마우스 혈청의 IgG 수치를 나타낸 것이다
(Ftn-ΔFliC에서 Ftn : ΔFliC = 24:10;
Ftn-HA에서 Ftn : HA = 24:10;
Ftn-HA-ΔFliC(I)에서 Ftn : HA : ΔFliC = 24:10:3.3).
도 8은 Ftn-HA 및 HA와 ΔFliC의 몰비를 다르게 조절하여 제조한 Ftn-HA-ΔFliC로 각각 면역화된 마우스 혈청의 IgG의 수치를 나타낸 것으로, (A)는 총 IgG, (B)는 IgG1, (C)는 IgG2a, (D)는 IgG2b 및 (E)는IgG1/IgG2a의 수치를 나타낸 것이다
(1:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:10;
2:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:5;
3:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:3.3;
4:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:2.5).
도 9는 Ftn-HA; 및 HA와 ΔFliC의 몰비를 다르게 조절하여 제조한 Ftn-HA-ΔFliC로 각각 면역화된 마우스의 비장 세포로부터 분비되는 사이토카인 IFN-γ 및 IL-4의 양을 나타낸 것이다
(1:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:10;
2:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:5;
4:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:2.5).
도 10은 Ftn와 HA의 몰비를 다르게 조절하여 제조한 Ftn-HA; 및 HA와 ΔFliC의 몰비를 3:1로 조절한 Ftn-HA-ΔFliC로 각각 면역화된 마우스 혈청의 총 IgG의 수치를 나타낸 것으로, (A)는 총 IgG, (B)는 IgG1, (C)는 IgG2a, (D)는 IgG2b 및 (E)는 IgG1/IgG2a의 수치를 나타낸 것이다
(Low의 Ftn-HA에서 Ftn : HA = 24:4;
High의 Ftn-HA에서 Ftn : HA = 24:24;
3:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:3.3).
도 2는 살모넬라 플라젤린(FliC), 대장균 페리틴(Ftn) 및 헤마글루티닌(인플루엔자 A 바이러스 (A/California/04/2009(H1N1), HA)의 융합 단백질 도메인을 도시적으로 나타낸 것이다.
도 3은 면역 증강 펩타이드인 플라젤린이 결합된 나노 입자를 나타낸 것으로, (A-1)은 Ftn-HA-ΔFliC 나노 입자, (B-1)은 Ftn-PA-ΔFliC 나노 입자 및 (C-1)은 I3-01-HA-ΔFliC 나노 입자를 나타낸 것이고, (A-2)는 (A-1)의 나노 입자의 크기 배제 크로마토그래피 프로파일, (B-2)는 (B-1)의 나노 입자의 크기 배제 크로마토그래피 프로파일 및 (C-2)는 (C-1)의 나노 입자의 크기 배제 크로마토그래피 프로파일을 나타낸 것이며, (A-3)은 (A-2)의 크로마토그래피로 정제된 나노 입자의 SDS-PAGE 분석 결과를 나타낸 것이다.
도 4는 Ftn, Ftn-ΔFliC(N) 및 Ftn-FliC 와 각각 배양된 HEK293 세포의 TLR5 활성화 정도를 나타낸 것이다.
도 5는 Ftn-HA-ΔFliC(N) 및 Ftn-HA-FliC(N)로 각각 면역화된 마우스 혈청의 총 IgG 및 IgG 서브클래스 수치를 나타낸 것이다
(Ftn : HA = 24:10;
HA : FliC(또는 ΔFliC) = 4:1).
도 6은 Ftn + ΔFliC, Ftn-ΔFliC(C), Ftn-ΔFliC(I) 및 Ftn-ΔFliC(N) 와 각각 배양된 HEK293 세포의 TLR5 활성화 정도를 나타낸 것이다.
도 7의 (A)는 HA, Ftn + ΔFliC + HA 및 Ftn-ΔFliC(I) + HA로 각각 면역화된 마우스 혈청의 총 IgG 및 IgG 서브클래스 수치를 나타낸 것이고, (B)는 Ftn-HA + ΔFliC 및 Ftn-HA-ΔFliC(I)로 각각 면역화된 마우스 혈청의 IgG 수치를 나타낸 것이다
(Ftn-ΔFliC에서 Ftn : ΔFliC = 24:10;
Ftn-HA에서 Ftn : HA = 24:10;
Ftn-HA-ΔFliC(I)에서 Ftn : HA : ΔFliC = 24:10:3.3).
도 8은 Ftn-HA 및 HA와 ΔFliC의 몰비를 다르게 조절하여 제조한 Ftn-HA-ΔFliC로 각각 면역화된 마우스 혈청의 IgG의 수치를 나타낸 것으로, (A)는 총 IgG, (B)는 IgG1, (C)는 IgG2a, (D)는 IgG2b 및 (E)는IgG1/IgG2a의 수치를 나타낸 것이다
(1:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:10;
2:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:5;
3:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:3.3;
4:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:2.5).
도 9는 Ftn-HA; 및 HA와 ΔFliC의 몰비를 다르게 조절하여 제조한 Ftn-HA-ΔFliC로 각각 면역화된 마우스의 비장 세포로부터 분비되는 사이토카인 IFN-γ 및 IL-4의 양을 나타낸 것이다
(1:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:10;
2:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:5;
4:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:2.5).
도 10은 Ftn와 HA의 몰비를 다르게 조절하여 제조한 Ftn-HA; 및 HA와 ΔFliC의 몰비를 3:1로 조절한 Ftn-HA-ΔFliC로 각각 면역화된 마우스 혈청의 총 IgG의 수치를 나타낸 것으로, (A)는 총 IgG, (B)는 IgG1, (C)는 IgG2a, (D)는 IgG2b 및 (E)는 IgG1/IgG2a의 수치를 나타낸 것이다
(Low의 Ftn-HA에서 Ftn : HA = 24:4;
High의 Ftn-HA에서 Ftn : HA = 24:24;
3:1의 Ftn-HA-ΔFliC에서 Ftn : HA : ΔFliC = 24:10:3.3).
이하, 본 발명을 상세히 설명한다.
본 발명은 HTTcys 펩타이드 및 페리틴 단량체의 융합 단백질 24개의 자가조립체; VL12.3cys 펩타이드 및 항원 펩타이드가 융합된 융합 단백질; 및 VL12.3cys 펩타이드 및 면역 증강제(adjuvant)의 융합 분자를 포함하는 나노 입자로서, 상기 항원 펩타이드 및 면역 증강제는 상기 HTTcys 펩타이드와 VL12.3cys 펩타이드 간의 결합에 의해 페리틴 자가조립체와 연결된 것인, 나노 입자를 제공한다.
본 발명에서 "융합 단백질"은 2개 이상의 단백질 또는 펩타이드가 서로 연결된 인위적으로 합성된 단백질을 의미한다. 본 발명의 융합 단백질은 당해 분야에 공지된 화학적 합성방법으로 제조하거나 본 발명의 융합 단백질을 코딩하는 폴리뉴클레오티드를 발현벡터에 클로닝하여 발현시켜서 제조할 수 있다. 상기 융합 단백질은 표적화 서열, 태그(tag), 표지된 잔기, 반감기 또는 펩타이드의 안정성을 증가시키기 위한 특정 목적으로 고안된 아미노산 서열을 추가로 포함할 수 있고, 공지된 아미노산 서열의 일부 아미노산이 부가, 치환, 결실 등의 방법으로 변이된 변이첸 단백질도 본 발명에서 제공하는 융합 단백질의 범주에 포함될 수 있다.
본 발명에서 페리틴(ferritin) 자가조립체는 생물 유래의 페리틴 단량체 24개가 자가조립(self-assembly)을 통하여 속이 빈 케이지(cage) 형태의 나노 입자를 형성한 것을 말한다.
상기 페리틴 단량체는 서로 동종 또는 이종일 수 있으며, 인간, 헬리코박터 균, 또는 대장균(E. coli) 유래의 것일 수 있으나, 이에 한정되는 것은 아니다. 바람직하게 상기 페리틴 단량체는 대장균 유래의 것일 수 있고 더 바람직하게는 서열번호 1의 아미노산 서열로 구성된 것일 수 있다.
서열번호 1:
MLKPEMIEKLNEQMNLELYSSLLYQQMSAWCSYHTFEGAAAFLRRHAQEEMTHMQRLFDYLTDTGNLPRINTVESPFAEYSSLDELFQETYKHEQLITQKINELAHAAMTNQDYPTFNFLQWYVSEQHEEEKLFKSIIDKLSLAGKSGEGLYFIDKELSTLDTQN
본 발명에서 HTTcys 펩타이드는 헌팅틴(huntingtin) 단백질에 존재하는 짧은 알파 나선의 헌팅틴 펩타이드(이하, HTT로 표기)의 변이체를 의미한다. 구체적으로, 상기 HTTcys 펩타이드는 서열번호 2의 아미노산 서열로 구성된 HTT 펩타이드의 6번째 아미노산인 알라닌(Alanine, A)을 시스테인(cysteine, C)으로 돌연변이시킨 것으로, 서열번호 3의 아미노산 서열로 구성된 것일 수 있다.
명칭 | 서열번호 | 서열종류 | 서열 |
HTT | 2 | 아미노산 서열 | EKLMK A FESLKSFQ |
HTTcys | 3 | 아미노산 서열 | EKLMK C FESLKSFQ |
상기 HTTcys 펩타이드는 페리틴 단량체의 N-말단 또는 C-말단에 융합되거나 내부에 삽입된 것일 수 있고, 바람직하게는 N-말단에 융합된 것일 수 있다. 상기 HTTcys 펩타이드가 페리틴 단량체의 N-말단에 융합된 융합 단백질로 페리틴 자가조립체 형성 시, HTTcys 펩타이드는 페리틴 자가조립체의 외부 표면에 위치할 수 있다. 본 발명의 구체적인 실시예에 의하면, 상기 HTTcys 펩타이드는 페리틴 단량체의 N-말단에 융합된 것이고, 상기 HTTcys 펩타이드가 페리틴 단량체의 N-말단에 융합된 융합 단백질은 서열번호 6의 아미노산 서열로 구성된 것일 수 있다.
상기 HTTcys 펩타이드 및 페리틴 단량체의 융합 단백질 24개로 이루어진 페리틴 자가조립체에서, 상기 HTTcys 펩타이드는 페리틴 자가조립체의 내부 또는 외부 표면에 위치할 수 있으며, 바람직하게는 페리틴 자가조립체의 외부 표면에 위치한 것일 수 있다.
본 발명에서 VL12.3cys 펩타이드는 상기 헌팅틴 펩타이드에 결합하는 면역글로불린 단편인 VL12.3 펩타이드의 변이체를 의미한다. 구체적으로, 상기 VL12.3cys 펩타이드는 서열번호 4의 아미노산 서열로 구성된 VL12.3 펩타이드의 53번째 아미노산인 타이로신(Tyrosine, Y)을 시스테인(C)으로 돌연변이시킨 것으로, 서열번호 5의 아미노산 서열로 구성된 것일 수 있다.
명칭 | 서열번호 | 서열종류 | 서열 |
VL12.3 | 4 | 아미노산 서열 | MGSQPVLTQSPSVSAAPRQRVTISVSGSNSNIGSNTVNWIQQLPGRAPELLM Y DDDLLAPGVSDRFSGSRSGTSASLTISGLQSEDEADYYAATWDDSLNGWVFGGGTKVTVLSA |
VL12.3cys | 5 | 아미노산 서열 | MGSQPVLTQSPSVSAAPRQRVTISVSGSNSNIGSNTVNWIQQLPGRAPELLM C DDDLLAPGVSDRFSGSRSGTSASLTISGLQSEDEADYYAATWDDSLNGWVFGGGTKVTVLSA |
상기 VL12.3cys 펩타이드는 항원 펩타이드의 N-말단 또는 C-말단에 융합되거나 내부에 삽입된 것일 수 있다.
상기 항원 펩타이드는 헤마글루티닌(Hemagglutinin, HA), PA(Protective antigen), PSA (prostate-specific antigen), 한타바이러스 당단백질 항원(Hantavirus glycoprotein antigen), SFTS 바이러스 당단백질 항원(virus glycoprotein antigen) 등일 수 있으나, 면역 반응을 유도할 수 있는 항원을 구성하는 펩타이드인 한, 제한없이 사용될 수 있다.
상기 면역 증강제(adjuvant)는 플라젤린(flagellin), MPL-A (monophosphoryl lipid A), 박테리아 리포단백질(bacterial lipoprotein) 등일 수 있으나, 면역 반응을 유도하는 항원 펩타이드의 기능을 직접적 또는 간접적인 방식으로 강화시킬 수 있는 한, 제한없이 사용될 수 있다. 바람직하게 상기 면역 증강제는 면역 증강 펩타이드일 수 있고, 더 바람직하게는 플라젤린(flagellin) 펩타이드일 수 있다.
명칭 | 서열번호 | 서열종류 | 서열 |
헤마글루티닌 (hemagglutinin,HA) |
8 | 아미노산 서열 | DTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDKHNGKLCKLRGVAPLHLGKCNIAGWILGNPECESLSTASSWSYIVETPSSDNGTCYPGDFIDYEELREQLSSVSSFERFEIFPKTSSWPNHDSNKGVTAACPHAGAKSFYKNLIWLVKKGNSYPKLSKSYINDKGKEVLVLWGIHHPSTSADQQSLYQNADTYVFVGSSRYSKKFKPEIAIRPKVRDQEGRMNYYWTLVEPGDKITFEATGNLVVPRYAFAMERNAGSGIIISDTPVHDCNTTCQTPKGAINTSLPFQNIHPITIGKCPKYVKSTKLRLATGLRNIPSIQSRGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADLKSTQNAIDEITNKVNSVIEKMNTQFTAVGKEFNHLEKRIENLNKKVDDGFLDIWTYNAELLVLLENERTLDYHDSNVKNLYEKVRSQLKNNAKEIGNGCFEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGVKLESTRIYQI |
전장 플라젤린 (full-length flagellin, Flic) |
9 | 아미노산 서열 | MAQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGCRINSAKDDAAGQAIANRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNVQQKYKVSDTAATVTGYADTTIALDNSTFKASATGLGGTDQKIDGDLKFDDTTGKYYAKVTVTGGTGKDGYYEVSVDKTNGEVTLAGGATSPLTGGLPATATEDVKNVQVANADLTEAKAALTAAGVTGTASVVKMSYTDNNGKTIDGGLAVKVGDDYYSATQNKDGSISINTTKYTADDGTSKTALNKLGGADGKTEVVSIGGKTYAASKAEGHNFKAQPDLAEAAATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIECSDYATEVSNMSRAQILQQAGTSVLAQANQVPQNVLSLLR |
절단된 플라젤린 (truncated flagellin, ΔFlic) |
10 | 아미노산 서열 | FTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNVQQKYKVSDTAATVTGYADTTIALDNSTFKASATGLGGTDQKIDGDLKFDDTTGKYYAKVTVTGGTGKDGYYEVSVDKTNGEVTLAGGATSPLTGGLPATATEDVKNVQVANADLTEAKAALTAAGVTGTASVVKMSYTDNNGKTIDGGLAVKVGDDYYSATQNKDGSISINTTKYTADDGTSKTALNKLGGADGKTEVVSIGGKTYAASKAEGHNFKAQPDLAEAAATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIECSDYATEVSNMSRAQILQQAGTSVLAQANQVPQNVLSLLR |
상기 VL12.3cys 펩타이드는 항원 펩타이드 또는 면역 증강 펩타이드의 N-말단 또는 C-말단에 융합되거나 내부에 삽입된 것일 수 있다. 본 발명의 구체적인 실시예에서, 상기 VL12.3cys 펩타이드는 항원 펩타이드인 헤마글루티닌의 C-말단 또는 면역 증강 펩타이드인 전장(full length) 플라젤린의 N-말단, C-말단 또는 내부에 융합된 것을 이용하였다.
상기 HTTcys 펩타이드는 헌팅틴(hungtingtin) 단백질에 존재하는 짧은 알파 나선의 헌팅틴(HTT) 펩타이드의 변이체이고, 상기 VL12.3cys 펩타이드는 상기 헌팅틴 펩타이드에 결합하는 면역글로불린 단편인 VL12.3 펩타이드의 변이체로서, 상기 HTTcys 펩타이드와 VL12.3cys 펩타이드는 항원-항체 반응에 의해 결합될 수 있다. 또한, 상기 HTTcys 펩타이드 및 VL12.3cys 펩타이드는 각각 HTT 펩타이드와 VL12.3 펩타이드 내에 시스테인이 도입된 변이체로서, 상기 HTTcys 펩타이드와 VL12.3cys 펩타이드는 이황화 결합에 의해 결합될 수 있다. 따라서 상기 VL12.3cys 펩타이드와 융합된 항원 펩타이드 및 면역 증강제는 상기 HTTcys 펩타이드와 VL12.3cys 펩타이드 간의 결합에 의해 페리틴 자가조립체에 연결될 수 있다. 따라서 상기 HTTcys 펩타이드와 VL12.3cys 펩타이드 간의 결합은 항원-항체 결합 및 이황화 결합을 포함할 수 있으며, 이에 상기 HTTcys 펩타이드와 VL12.3cys 펩타이드 간의 결합은 항원-항체 결합만 형성한 경우보다 견고한 결합을 형성할 수 있다.
상기 나노 입자 내의 항원 펩타이드와 면역 증강 펩타이드의 몰비(molar ratio)는 적절하게 조절될 수 있다. 바람직하게는 0.1~10 : 1 일 수 있으며, 보다 바람직하게는 1~4 : 1 일 수 있으며, 가장 바람직하게는 1~3 : 1 일 수 있다.
상기 나노 입자는 하기의 단계들을 포함하는 제조방법에 의해 제조될 수 있다:
1) HTTcys 펩타이드 및 페리틴 단량체의 융합 단백질 24개의 단량체로부터 페리틴 자가조립체를 얻는 단계; 및
2) 상기 1)의 페리틴 자가조립체에 VL12.3cys 펩타이드 및 항원 펩타이드가 융합된 융합 단백질; 및 VL12.3cys 펩타이드 및 면역 증강제(adjuvant)가 융합된 융합 분자를 혼합하는 단계.
또한, 본 발명은 본 발명의 나노 입자를 포함하는, 백신 조성물을 제공한다. 본 발명의 나노 입자는 항원 및 면역 증강제를 페리틴 단량체 단백질에 직접 융합시키는 경우 보다 제작이 용이하고 항원 펩타이드 및 면역 증강제의 몰비를 용이하게 조절할 수 있다.
상기 백신은 총 IgG 수치를 증가시킬 수 있다.
또한, 상기 백신은 세포성 면역 및 체액성 면역을 증진시킬 수 있다.
본 발명의 백신 조성물은 약학적 허용가능한 담체, 적절한 보조제, 기타 통상적인 물질들을 더욱 포함할 수 있고, 면역학적 효과량으로 투여될 수 있다. 본 발명에서 용어, "면역학적 효과량"이란 면역 증강 효과를 나타낼 수 있을 정도의 충분한 양과 부작용이나 심각한 또는 과도한 면역반응을 일으키지 않을 정도의 양을 의미하며, 정확한 투여 농도는 투여될 특정 면역원에 따라 달라지며 면역반응의 발생을 검사하기 위하여 당업자가 공지의 방법을 이용하여 이를 결정할 수 있다. 또한, 투여형태 및 경로, 수용자의 연령, 건강 및 체중, 증상의 특성 및 정도, 현재 치료법의 종류, 및 치료 횟수에 따라 변화될 수 있다.
담체는 당 분야에 공지의 것으로 안정화제, 희석제, 완충액을 포함할 수 있다. 적절한 안정화제는 솔비톨, 락토즈, 만니톨, 전분, 당, 덱스트란 및 포도당 같은 탄수화물; 알부민 또는 카제인 같은 단백질 등을 포함할 수 있다. 적절한 희석제에는 염, Hanks 균형 염, 링거액 등을 포함할 수 있다. 적절한 완충액에는 알칼리 금속 인산염, 알칼리 금속 탄산염, 알칼리 토금속 탄산염 등을 포함한다. 또한 백신에는 면역반응을 개선 또는 강화시키기 위하여 하나 이상의 면역 증강제(아쥬반트, adjuvant)를 포함할 수 있다. 적절한 면역 증강제의 예는 알루미늄 히드록시드, 프로이드 완전 또는 불완전 아쥬반트, DEAE 덱스트란, 레바미솔, PCG 및 poly I:C 또는 poly A:U를 포함할 수 있다. 본 발명의 백신 조성물은 공지의 투여 경로를 통하여 투여될 수 있다. 이와 같은 방법에는 경구, 경피, 근육, 복막, 정맥, 피하, 비강 경로를 이용할 수 있지만 이에 국한되지는 않으며, 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.
본 발명의 구체적인 실시예에 의하면, 본 발명자들은 HTTcys 펩타이드와 VL12.3cys 펩타이드를 매개로 페리틴 자가조립체에 헤마글루티닌 항원 펩타이드 및 플라젤린 면역 증강 펩타이드가 안정적으로 결합된 나노 입자를 제조하였다 (도 3 참조).
또한, 본 발명자들은 단백질 분해(proteolytic degradation) 및 중합화하는 경향을 가진 플라젤린 D0 도메인의 면역 반응 유도에 대한 영향을 시험하고자, 플라젤린의 D0 내지 D3 도메인을 포함하는 전장 플라젤린(이하, FliC로 표기)이 페리틴 자가조립체에 결합된 나노 입자(Ftn-FliC); 및 D0 도메인이 절단된 플라젤린(이하, ΔFliC로 표기)이 페리틴 자가조립체에 결합된 나노 입자(Ftn-ΔFliC)의 TLR5 활성화능과 상기 나노 입자로 유도된 마우스 혈청 내 면역글로불린 수치를 확인한 결과, 단백질 다량 생산에 제한이 될 수 있는 플라젤린의 D0 도메인은 IgG 반응에 미미한 영향을 끼치는 것을 확인하였다 (도 4 및 도 5 참조).
또한, 본 발명자들은 페리틴 자가조립체에 적합한 플라젤린(ΔFliC)의 부착 부위를 확인하고자, 플라젤린(ΔFliC)의 N-말단, C-말단 또는 내부(D3 도메인)에 VL12.3cys 펩타이드를 융합하여 페리틴 자가조립체에 결합시킨 나노 입자(각각 Ftn-ΔFliC(N), Ftn-ΔFliC(C) 및 Ftn-ΔFliC(I)로 표기)의 TLR5 활성화능을 확인한 결과, Ftn-ΔFliC(N) 및 Ftn-ΔFliC(I)는 Ftn-ΔFliC(C) 보다 TLR5 신호전달경로를 자극하는 데 효과적임을 확인하였다 (도 6 참조).
또한, 본 발명자들은 페리틴 자가조립체에 대해 헤마글루티닌과 플라젤린을 동시에 결합하는 경우, 결합하지 않고 헤마글루티닌과 플라젤린을 단순히 혼합하는 경우보다 강력한 면역 반응을 유도함을 확인하였다 (도 7 참조).
또한, 본 발명자들은 면역 증강 활성에 필요한 플라젤린의 최소량을 확인하고자, 페리틴 자가조립체에 결합한 헤마글루티닌 대 플라젤린의 몰비가 조절된 나노 입자로 유도된 마우스 혈청 내 면역글로불린 수치 및 비장세포의 사이토카인의 양을 측정한 결과, 페리틴 자가조립체에 결합한 헤마글루티닌 대 플라젤린의 몰비는 3:1까지 IgG2a 클래스 전환과 Th1 반응에 영향없이 플라젤린의 양을 줄일 수 있음을 확인하였다. 또한, 페리틴 자가조립체에 헤마글루티닌과 플라젤린을 동시 결합하는 것은 체액성 면역 반응을 증진시키고, 항원-특이적 T세포 반응을 자극하는 것임을 확인하였다 (도 8 및 도 9 참조).
또한, 본 발명자들은 4 분자 또는 24 분자 헤마글루티닌이 페리틴 자가조립체에 결합된 나노 입자(각각 Ftn-HA(Low), Ftn-HA(High))와, 헤마글루티닌과 플라젤린이 3:1의 몰비로 페리틴 자가조립체에 결합된 나노 입자(Ftn-HA-ΔFliC)로 유도된 마우스 혈청 내 면역글로불린 수치를 확인한 결과, 페리틴 자가조립체에 최대로 결합된 헤마글루티닌은 체액성 면역 반응을 유도하는 데 유용하지만, 자가 면역 증강 활성을 가진 나노 입자를 생산하기 위해서는 플라젤린이 결합되어야 함을 확인하였다 (도 10 참조).
따라서, 본 발명의 나노 입자는 HTTcys 펩타이드와 VL12.3cys 펩타이드를 매개로 페리틴 자가조립체에 항원 펩타이드 및 면역 증강제가 결합된 것으로, 나노 입자 내의 항원 펩타이드 및 면역 증강제의 몰비를 용이하게 조절할 수 있어, 독성을 나타낼 위험성이 있는 면역 증강제의 함량을 최적화할 수 있다. 또한, 항원 펩타이드와 면역 증강제를 함께 결합시킨 나노 입자를 투여한 경우, 전체(Total) IgG 뿐만 아니라 Th1 사이토카인 분비 및 IgG2a 클래스 전환을 크게 향상시킬 수 있으므로, 상기 나노 입자를 백신 조성물로 유용하게 이용할 수 있다.
이하, 본 발명을 하기 실시예에 의해 상세히 설명한다.
단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.
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이황화
결합 형성을 위한 아미노산 서열 설계
VL12.3은 115개의 아미노산(서열번호 4)으로 이루어진 단일 도메인 항체 단편으로, 인간 헌팅틴 단백질(human huntingtin protein) 내 HTT 펩타이드 서열(서열번호 2)과 항원-항체 결합에 의해 결합한다. Disulfide-by-Design 웹 서버를 사용하여 HTT 펩타이드와 VL12.3 에 각각 시스테인 서열을 도입한 VL12.3cys와 HTTcys 펩타이드를 제조하였다 (도 1, http://cptweb.cpt.wayne.edu/DbD2/). VL12.3cys와 HTTcys 펩타이드는 항원-항체 결합 이외에 추가적인 이황화 다리 형성을 통해 견고한 공유결합을 형성할 수 있다 (도 1, 표 1 및 표 2).
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자가조립체의
단량체 제조
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HTT
cys
펩타이드가
융합된 페리틴(
ferritin
) 단량체의 제조
대장균(E. coli) 페리틴 단량체(이하 Ftn로 표기)의 N-말단에 HTTcys를 융합시키고자(도 2), HTTcys가 융합된 페리틴 단량체를 암호화하는 폴리뉴클레오티드(표 4)를 PCR로 증폭하였다. 구체적으로, PCR 주형으로는 HTTcys 는 Addgene plasmid #23966 (Addgene, Cambridge, MA), 페리틴 단량체(Ftn)는 Addgene bacterial strain #61440를 사용하였으며, 하기 프라이머를 이용하여 95℃에서 30초, 58℃에서 30초, 72℃에서 30초 조건으로 PCR을 수행하였다.
(HTTcys 정방향 프라이머: ATC ATC CAT GGG CGA AAA GCT GAT GAA GTG TTT C(서열번호 25);
HTTcys 역방향 프라이머: ATC ACT CTA GAA CCA CCC TGG AAG GAC TTG AG(서열번호 26);
Ftn 정방향 프라이머: TGC GGT CTA GAA TGC TGA AAC CAG AAA TGA TTG AA(서열번호 27);
Ftn 역방향 프라이머: AGG CCA GCC ACT CGA GAC TAG TTC ATT AGT TTT GTG TGT C(서열번호 28))
증폭된 HTTcys-페리틴(HTTcys-Ftn)을 암호화하는 폴리뉴클레오티드를 pET28a 벡터(Addgene, Cambridge, MA)에 클로닝하였다.
명칭 | 서열번호 | 서열종류 | 서열 |
HTTcys-페리틴 단량체 (HTTcys-Ftn) |
6 | 아미노산 서열 | MGEKLMKCFESLKSFQGGSRMLKPEMIEKLNEQMNLELYSSLLYQQMSAWCSYHTFEGAAAFLRRHAQEEMTHMQRLFDYLTDTGNLPRINTVESPFAEYSSLDELFQETYKHEQLITQKINELAHAAMTNQDYPTFNFLQWYVSEQHEEEKLFKSIIDKLSLAGKSGEGLYFIDKELSTLDTQN |
7 | 염기서열 | atgggcgaaaagctgatgaagtgtttcgagtccctcaagtccttccagggtggttctagaatgctgaaaccagaaatgattgaaaaacttaatgagcagatgaacctggaactgtactcttcactgctttatcagcaaatgagcgcctggtgcagctatcataccttcgaaggtgctgccgcgttcctgcgccgtcacgcccaggaagagatgacgcatatgcagcgtctgtttgattacctgactgataccggcaatttaccgcgtattaataccgttgaatctccgtttgctgaatattcctcacttgatgaattattccaggaaacctataaacacgaacaattaatcacccagaaaattaacgaactggctcatgctgcaatgaccaatcaggactacccaacatttaatttcctgcagtggtatgtttctgagcagcatgaagaagagaaactgttcaaatcgattattgataaattaagcctggcaggcaaaagcggcgaaggtctgtattttatcgacaaagaactctctaccctcgacacacaaaactaa |
클로닝된 벡터를 E. coli BL21(DE3) 균주에 형질전환하고, 박테리아 배양액의 O.D.600 값이 0.7에 도달할 때, 1 mM IPTG를 첨가하여 HTTcys-페리틴 단량체 융합 단백질 생산을 유도하였다. 37℃에서 4시간 배양한 후, 4℃에서 4000 rpm, 30분 동안 원심분리를 통해 E. coli(DE3)를 수확하였다.
수확한 세포의 펠릿(pellet)을 20 mM Tris(pH 8.0), 200 mM NaCl, 10 mM β-메르캅토에탄올(β-mercaptoethanol) 및 0.1 mM PMSF를 포함한 용해 완충액(lysis buffer)에 재현탁하고, 마이크로플루다이저(microfludizer, Microfluidics, Westwood, MA)를 사용하여 균질화시킨 후 15,000 rpm으로 4℃에서 40분 동안 원심분리하였다. 상층액을 80℃에서 10분간 가열한 후 15,000 rpm으로 4℃에서 30분 동안 원심분리하고, Q-Sepharose 음이온 교환 컬럼으로 단백질을 정제하여 HTTcys-페리틴 단량체 융합 단백질을 함유하는 분획을 수득한 후 농축시켰다.
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HTT
cys
펩타이드가
융합된 I3-01 단량체의 제조
페리틴 자가조립체에 항원 또는 면역 증강 펩타이드를 부착하기 위한 HTTcys 펩타이드 및 VL12.3cys 펩타이드 간의 결합이 다른 단백질의 자가조립체에서도 유용한지 확인하기 위해, 인공 케이지 단백질 I3-01 단량체의 N-말단에도 HTTcys 서열을 융합시켰다. I3-01 자가조립체는 60개의 단량체 서브유닛으로 구성된 250 옹스트롬 케이지를 형성하는 컴퓨터로 설계된 단백질이다.
구체적으로, PCR 주형으로는 HTTcys 는 Addgene plasmid #23966 (Addgene, Cambridge, MA), I3-01 자가조립체는 워싱턴 대학교 Dr. Baker 실험실의 I3-01 cDNA를 사용하였으며, 하기 프라이머를 이용하여 95℃에서 30초, 62℃에서 60초, 72℃에서 30초 조건으로 PCR을 수행하였다.
(HTTcys-I3-01 정방향 프라이머: ATT ATC ATA TGC ATC ATC ATC ATC ATC ACG GTG GAA GCG GTG GAA GC(서열번호 29);
HTTcys-I3-01 역방향 프라이머: TGC GCC TCG AGC TAT TAT TCG GTG CAG CCA CGA ATC(서열번호 30))
이름 | 서열번호 | 서열종류 | 서열 |
HTTcys-I3-01 | 11 | 아미노산 서열 | MHHHHHHGGSGGSEKLMKCFESLKSFQGGSGGSMKMEELFKKHKIVAVLRANSVEEAKKKALAVFLGGVHLIEITFTVPDADTVIKELSFLKEMGAIIGAGTVTSVEQCRKAVESGAEFIVSPHLDEEISQFCKEKGVFYMPGVMTPTELVKAMKLGHTILKLFPGEVVGPQFVKAMKGPFPNVKFVPTGGVNLDNVCEWFKAGVLAVGVGSALVKGTPVEVAEKAKAFVEKIRGCTE |
12 | 염기서열 | atgcatcatcatcatcatcacggtggaagcggtggaagcgaaaagctgatgaagtgtttcgagtccctcaagtccttccagggtggtagcggcggttctatgaagatggaagagctgttcaagaaacacaagatcgttgccgtgctgcgtgccaatagtgtggaagaagcgaaaaagaaagcgctggcggttttcctgggcggcgttcatctgattgaaattacctttaccgtgccggatgcggataccgtgattaaggaactgagctttctgaaggaaatgggcgcgattattggtgcgggcaccgtgaccagcgtggagcagtgccgtaaagcggtggaaagtggcgccgaattcattgtgagtccgcacctggacgaggaaattagccaattttgcaaggagaagggtgtgttctatatgccaggcgttatgaccccgaccgaactggtgaaagccatgaaactgggccataccatcttaaaactgtttccgggtgaggtggtgggtccgcagtttgttaaagcgatgaaaggtccgtttccgaatgtgaaatttgtgccaaccggcggtgttaatctggacaatgtgtgcgaatggttcaaagcgggcgtgctggccgtgggcgtgggcagcgcgttagtgaaaggcaccccggtggaagtggcggaaaaggccaaggcgttcgttgagaagattcgtggctgcaccgaataa |
클로닝된 벡터를 E. coli BL21(DE3) 균주에 형질전환하고, 박테리아 배양액의 O.D.600 값이 0.5에 도달할 때, 0.5 mM IPTG를 첨가하여 HTTcys-I3-01 융합 단백질 생산을 유도하였다. 37℃에서 4시간 배양한 후, 4℃에서 4000 rpm, 30분 동안 원심분리를 통해 E. coli(DE3)를 수확하였다.
수확한 세포의 펠릿(pellet)을 20 mM Tris(pH 8.0), 200 mM NaCl, 10 mM β-메르캅토에탄올(β-mercaptoethanol) 및 0.1 mM PMSF를 포함한 용해 완충액(lysis buffer)에 재현탁하고, 마이크로플루다이저(microfludizer, Microfluidics, Westwood, MA)를 사용하여 균질화시킨 후, 15,000 rpm으로 4℃에서 40분 동안 원심분리하였다. 상층액을 80℃에서 5분간 가열한 후 15,000 rpm으로 4℃에서 30분 동안 원심분리하고, Q-Sepharose 음이온 교환 컬럼으로 단백질을 정제하여 HTT-I3-01 융합 단백질을 함유하는 분획을 수득한 후 농축시켰다.
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펩타이드의
제조
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펩타이드
및
헤마글루티닌
(
hemagglutinin
, HA) 항원이 융합된 융합 단백질의 제조
인플루엔자 A 바이러스의 헤마글루티닌(hemagglutinin, 이하 HA로 표기) (A/California/ 04/2009 (H1N1))의 단편(18D~530I)을 항원 펩타이드로 사용하였다 (도 2).
상기 HA 항원 단편의 C-말단에 VL12.3cys 도메인이 융합된 단백질을 얻기 위해, 이를 암호화하는 폴리뉴클레오티드(표 6)를 PCR로 증폭하였다. 구체적으로, PCR 주형으로는 HA 는 Swine Flu H1N1 hemagglutinin (a.a. 1-530)( A/California/04/2009)의 cDNA 클론, VL12.3cys 는 MIT(Massachusetts Institute of Technology) Dr Wittrup 실험실로부터 얻은 VL12.3 single domain intrabody의 cDNA를 사용하였으며, 하기 프라이머를 이용하여 95℃에서 30초, 58℃에서 30초, 72℃에서 1분 30초 조건으로 PCR을 수행하였다.
(HA-VL12.3cys 정방향 프라이머: AGG CCT CTA GAA GCA TGG GTA GTC AAC CAG TAC TT (서열번호 31);
HA-VL12.3cys 역방향 프라이머: GTG ATG ATG ATG ATG ATG GCT ACT GCC TGC GGA CAG CAC CGT (서열번호 32))
증폭된 HA-VL12.3cys 암호화 폴리뉴클레오티드를 pAcGP67A 바큘로바이러스 전달 벡터(baculovirus transfer vector, BD Biosciences, San Jose, CA)로 클로닝하였다.
이름 | 서열번호 | 서열종류 | 서열 |
HA-VL12.3cys | 13 | 아미노산 서열 | ADPDTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDKHNGKLCKLRGVAPLHLGKCNIAGWILGNPECESLSTASSWSYIVETPSSDNGTCYPGDFIDYEELREQLSSVSSFERFEIFPKTSSWPNHDSNKGVTAACPHAGAKSFYKNLIWLVKKGNSYPKLSKSYINDKGKEVLVLWGIHHPSTSADQQSLYQNADTYVFVGSSRYSKKFKPEIAIRPKVRDQEGRMNYYWTLVEPGDKITFEATGNLVVPRYAFAMERNAGSGIIISDTPVHDCNTTCQTPKGAINTSLPFQNIHPITIGKCPKYVKSTKLRLATGLRNIPSIQSRGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADLKSTQNAIDEITNKVNSVIEKMNTQFTAVGKEFNHLEKRIENLNKKVDDGFLDIWTYNAELLVLLENERTLDYHDSNVKNLYEKVRSQLKNNAKEIGNGCFEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGVKLESTRIYQIGSRSMGSQPVLTQSPSVSAAPRQRVTISVSGSNSNIGSNTVNWIQQLPGRAPELLMCDDDLLAPGVSDRFSGSRSGTSASLTISGLQSEDEADYYAATWDDSLNGWVFGGGTKVTVLSAGSSHHHHHH |
14 | 염기서열 | gcggatcccgacacattgtgcattgggtaccatgctaataactcaacagatacagtagatactgtgttggaaaaaaacgtaacggtaacacactcagtgaacttactagaagacaaacataatggaaagttatgtaaactaagaggggttgccccattacatctgggtaaatgcaatattgcagggtggattctaggaaacccagagtgtgagtcactatccactgcatcaagttggtcatacatcgtggaaactccaagctcagataatggcacatgttatccgggagactttatcgattatgaggaattaagggaacagttgagcagtgttagctcgttcgaaagattcgagatattccccaagacatcaagttggccaaatcatgactccaacaaaggagtaacagcggcatgccctcacgccggagctaaatcattctacaagaacctgatttggctagttaagaaaggcaattcttacccaaaactgtcaaagtcttatattaatgacaaaggtaaagaagtattggttctatgggggatacatcaccccagcacaagcgctgaccaacagtcactataccagaatgccgatacttacgtatttgtggggagtagcagatattctaaaaagttcaagccggaaattgcaattaggccgaaggtgagagaccaagaaggtagaatgaattactattggacattagtagagccgggtgataaaataacatttgaagcaactggaaatttggtggttccaagatacgcattcgctatggagagaaacgccggtagcggaatcattataagtgatacaccagtccacgactgtaacacaacctgccaaactcccaagggagcaataaacacgagcctaccgtttcaaaatattcacccaattacaatagggaaatgtccaaaatatgtaaaatcaacaaagttgagactggcaacagggctcagaaacataccctctattcagtccagaggtctatttggggcaattgccggattcatcgaggggggatggacaggtatggtcgatggctggtatgggtaccaccatcagaacgagcaaggatctggttacgccgcgatctaaagtcaacacaaaatgcaattgatgaaatcacaaataaggtaaattcagtaatagagaagatgaatacacagttcacagcagtaggcaaagaatttaatcacctggagaaaagaatagaaaacctcaataaaaaggtagacgatggtttcttagacatttggacatacaatgcagaactcctagtactactcgaaaatgaaaggacgctggactaccatgactcaaacgttaaaaatctatatgaaaaagtaagatcacagttgaaaaataatgccaaagagataggaaatggatgctttgaattttaccataaatgtgacaatacatgtatggaatcagttaaaaatgggacttacgattatccaaagtatagcgaagaagctaagctgaatagagaagaaatagatggggtaaaactagaatcaactaggatttatcagattggctctagaagcatgggtagtcaaccagtacttacacaaagcccgtctgtgtctgccgctccacgtcagagagtcaccatctcagttagtggttctaattcaaatataggatcgaacacagtgaactggattcagcagttgcctggccgtgccccggagttattaatgtgtgatgatgatttattagcacccggagtatcagatcgcttttcaggaagccgtagtggcactagtgcgtccttaaccattagcgggttacagtctgaagacgaagcggactattacgcagctacgtgggatgatagtttaaatggctgggtttttggtggtggtactaaagttacggtgctgtccgcaggcagtagccatcatcatcatcatcactaa |
클로닝된 벡터를 High Five 곤충 세포(High Five insect cells, Invitrogen, Waltham, MA)에 감염시키고, 28℃에서 2일 동안 배양 후 세포를 수득하였다. 세포 배양액을 4℃에서 4,000 rpm으로 30분 동안 원심분리하여 상등액을 얻은 후, 상등액에 0.1 mM PMSF, 10 mM β-메르캅토에탄올(β-mercaptoethanol)을 처리한 다음 상등액을 Ni-NTA 킬레이팅 아가로스 CL-6B 및 Q-Sepharose 음이온 교환 컬럼에 로딩하여 HA-VL12.3cys 융합 단백질을 정제하였다.
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펩타이드
및 PA(protective antigen) 항원이 융합된 융합 단백질의 제조
바실러스 안트라시스(Bacillus anthracis)의 방어항원(protective antigen, 이하 PA)의 도메인 4(596F-735G)를 항원 펩타이드로 사용하였다. PA의 도메인4는 모세혈관 형성 단백질2(capillary morphogenesis protein 2, CMG2) 수용체에 대한 PA의 결합을 중재하고, 탄저병 중화 항체(anthrax neutralizing antibody)의 인식 부위이다.
상기 PA 항원 단편의 C-말단에 VL12.3cys 도메인이 융합된 단백질을 얻기 위해, 이를 암호화하는 폴리뉴클레오티드(표 7)를 PCR로 증폭하였다. 구체적으로, PCR 주형으로는 PA 는 Addgene plasmid #11079, VL12.3cys 는 MIT(Massachusetts Institute of Technology) Dr Wittrup 실험실로부터 얻은 VL12.3 single domain intrabody의 cDNA를 사용하였으며, 하기 프라이머를 이용하여 95℃에서 30초, 58℃에서 30초, 72℃에서 30초 조건으로 PCR을 수행하였다.
(PA-VL12.3cys 정방향 프라이머: AAG AGC CAT GGG CTT TCA TTA TGA TAG AAA TAA C (서열번호 33);
PA-VL12.3cys 역방향 프라이머: AGC ATC TCG AGT GCG GAC AGC ACC GTA ACT TTA (서열번호 34))
증폭된 PA-VL12.3cys 암호화하는 폴리뉴클레오티드를 pET28a 벡터에 클로닝하였다.
이름 | 서열번호 | 서열종류 | 서열 | |
PA-VL12.3cys | 15 | 아미노산 서열 | MGFHYDRNNIAVGADESVVKEAHREVINSSTEGLLLNIDKDIRKILSGYIVEIEDTEGLKEVINDRYDMLNISSLRQDGKTFIDFKKYNDKLPLYISNPNYKVNVYAVTKENTIINPSENGDTSTNGIKKILIFSKKGYEIGSGGSMGSQPVLTQSPSVSAAPRQRVTISVSGSNSNIGSNTVNWIQQLPGRAPELLMCDDDLLAPGVSDRFSGSRSGTSASLTISGLQSEDEADYYAATWDDSLNGWVFGGGTKVTVLSALEHHHHHH | |
16 | 염기서열 | atgggctttcattatgatagaaataacatagcagttggggcggatgagtcagtagttaaggaggctcatagagaagtaattaattcgtcaacagagggattattgttaaatattgataaggatataagaaaaatattatcaggttatattgtagaaattgaagatactgaagggcttaaagaagttataaatgacagatatgatatgttgaatatttctagtttacggcaagatggaaaaacatttatagattttaaaaaatataatgataaattaccgttatatataagtaatcccaattataaggtaaatgtatatgctgttactaaagaaaacactattattaatcctagtgagaatggggatactagtaccaacgggatcaagaaaattttaatcttttctaaaaaaggctatgagataggatccggtggtagcatgggtagtcaaccagtacttacacaaagcccgtctgtgtctgccgctccacgtcagagagtcaccatctcagttagtggttctaattcaaatataggatcgaacacagtgaactggattcagcagttgcctggccgtgccccggagttattaatgtgtgatgatgatttattagcacccggagtatcagatcgcttttcaggaagccgtagtggcactagtgcgtccttaaccattagcgggttacagtctgaagacgaagcggactattacgcagctacgtgggatgatagtttaaatggctgggtttttggtggtggtactaaagttacggtgctgtccgcactcgagcaccaccaccaccaccactga |
클로닝된 벡터를 E. coli BL21(DE3) 균주에 형질전환하고, 박테리아 배양액의 O.D.600 값이 0.5에 도달할 때, 0.4 mM IPTG를 첨가하여 PA-VL12.3cys 융합 단백질 생산을 유도하였다. PA-VL12.3cys 융합 단백질은 30℃에서 3.5시간 배양한 후, 4℃에서 4000 rpm, 30분 동안 원심분리를 통해 E. coli(DE3)를 수확하였다.
PA-VL12.3cys 융합 단백질을 발현하는 세포 펠릿을 20 mM Tris(pH 8.0), 200 mM NaCl, 10 mM β-메르캅토에탄올(β-mercaptoethanol) 및 0.1 mM PMSF를 포함한 용해 완충액(lysis buffer)에 재현탁하고, 마이크로플루다이저(microfludizer, Microfluidics, Westwood, MA)를 사용하여 균질화시켰다. 15,000 rpm으로 4℃에서 40분 동안 원심분리한 후, 단백질을 Ni-NTA 킬레이팅 아가로스 CL-6B(Incospharm, Daejeon, Korea) 및 Q-Sepharose(GE Healthcare, Pittsburgh, PA) 음이온 교환 컬럼으로 정제하였다. PA-VL12.3cys 융합 단백질을 포함하는 분획을 수득한 후 농축시켰다.
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가
융합된
플라젤린(flagellin)의
제조
D0 도메인을 포함하는 전장(full-length) 플라젤린은 D0 도메인이 절단된(truncated) 플라젤린보다 면역 반응을 자극하는 활성이 더 높다고 알려져있으나, 플라젤린 D0 도메인은 단백질 분해 및 중합(polymerization)을 증가시키는 경향이 있어, D0 도메인을 포함한 재조합 단백질의 생산은 종종 어려움이 따른다.
본 발명의 나노 입자 시스템에서 D0 도메인의 영향을 테스트하기 위해, D0 내지 D3를 모두 포함하는 전장(full-length) 플라젤린(이하 FliC로 표기)과 D1 내지 D3를 포함하는 절단된 플라젤린(이하 ΔFliC로 표기)를 모두 사용하였다. 전장 플라젤린(FliC)의 경우, 단백질 분해를 감소시키기 위해 이황화 결합을 도입시킨 SS5 돌연변이를 포함한다. SS5 돌연변이는 플라젤린(FliC)의 L36C와 D456C 잔기의 이황화 결합이며, 플라젤린의 단백질 분해를 감소시킨다. 또한 플라젤린과의 가장 적합한 융합 부위를 확인하기 위해, VL12.3cys을 플라젤린의 N-말단, C-말단 또는 D3 도메인(238G와 239G 사이, I) 내부에 융합시켰다 (도 2).
표 8과 같이, 플라젤린과 VL12.3cys의 다양한 융합 단백질을 암호화하는 폴리뉴클레오티드를 PCR로 증폭하였다. 구체적으로, PCR 주형으로는 FliC 는 Addgene plasmid #85438, VL12.3cys 는 MIT(Massachusetts Institute of Technology) Dr Wittrup 실험실로부터 얻은 VL12.3 single domain intrabody의 cDNA를 사용하였으며, 하기 프라이머를 이용하여 95℃에서 30초, 58℃에서 30초, 72℃에서 30초 내지 1분 조건으로 PCR을 수행하였다.
(FliC(N)-VL12.3cys 정방향 프라이머: AGC GGC ATA TGG GTA GTC AAC CAG TAC TTA CAC AAA GCC CG (서열번호 35);
FliC(N)-VL12.3cys 역방향 프라이머: ATT ATG CGG CCG CTC AAC GCA GTA AAG AGA GGA CG (서열번호 36);
ΔFliC(N)-VL12.3cys 정방향 프라이머: ACT GGT GGT ACC ATG GGT AGT CAA CCA GTA CTT (서열번호 37);
ΔFliC(N)-VL12.3cys 역방향 프라이머: AGT TAC TCG AGA CGG GCA GAA GTC AGG TTG TT (서열번호 38);
ΔFliC(C)-VL12.3cys 정방향 프라이머: ATA ATC CAT GGG CTT TAC CGC GAA CAT CAA AGG T (서열번호 39);
ΔFliC(C)-VL12.3cys 역방향 프라이머: AGC ATC TCG AGT GCG GAC AGC ACC GTA AC (서열번호 40);
ΔFliC(I)-VL12.3cys 정방향 프라이머: ATA ATC CAT GGG CTT TAC CGC GAA CAT CAA AGG T (서열번호 41);
ΔFliC(I)-VL12.3cys 역방향 프라이머: AGT TAC TCG AGA CGG GCA GAA GTC AGG TTG TT (서열번호 42))
증폭된 폴리뉴클레오티드를 pET28a 벡터(Addgene, Cambridge, MA)에 클로닝하였다.
이름 | 서열번호 | 서열종류 | 서열 |
FliC | 9 | 아미노산 서열 | MAQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGCRINSAKDDAAGQAIANRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNVQQKYKVSDTAATVTGYADTTIALDNSTFKASATGLGGTDQKIDGDLKFDDTTGKYYAKVTVTGGTGKDGYYEVSVDKTNGEVTLAGGATSPLTGGLPATATEDVKNVQVANADLTEAKAALTAAGVTGTASVVKMSYTDNNGKTIDGGLAVKVGDDYYSATQNKDGSISINTTKYTADDGTSKTALNKLGGADGKTEVVSIGGKTYAASKAEGHNFKAQPDLAEAAATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIECSDYATEVSNMSRAQILQQAGTSVLAQANQVPQNVLSLLR |
ΔFliC | 10 | 아미노산 서열 |
FTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNVQQKYKVSDTAATVTGYADTTIALDNSTFKASATGLGGTDQKIDGDLKFDDTTGKYYAKVTVTGGTGKDGYYEVSVDKTNGEVTLAGGATSPLTGGLPATATEDVKNVQVANADLTEAKAALTAAGVTGTASVVKMSYTDNNGKTIDGGLAVKVGDDYYSATQNKDGSISINTTKYTADDGTSKTALNKLGGADGKTEVVSIGGKTYAASKAEGHNFKAQPDLAEAAATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSAR |
FliC(N)-VL12.3cys |
17 | 아미노산 서열 | MGSSHHHHHHSSGLVPRGSHMGSQPVLTQSPSVSAAPRQRVTISVSGSNSNIGSNTVNWIQQLPGRAPELLMCDDDLLAPGVSDRFSGSRSGTSASLTISGLQSEDEADYYAATWDDSLNGWVFGGGTKVTVLSAGGSAMAQVINTNSLSLLTQNNLNKSQSALGTAIERLSSGCRINSAKDDAAGQAIANRFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNVQQKYKVSDTAATVTGYADTTIALDNSTFKASATGLGGTDQKIDGDLKFDDTTGKYYAKVTVTGGTGKDGYYEVSVDKTNGEVTLAGGATSPLTGGLPATATEDVKNVQVANADLTEAKAALTAAGVTGTASVVKMSYTDNNGKTIDGGLAVKVGDDYYSATQNKDGSISINTTKYTADDGTSKTALNKLGGADGKTEVVSIGGKTYAASKAEGHNFKAQPDLAEAAATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARSRIECSDYATEVSNMSRAQILQQAGTSVLAQANQVPQNVLSLLR |
18 | 염기서열 | atgggtagtcaaccagtacttacacaaagcccgtctgtgtctgccgctccacgtcagagagtcaccatctcagttagtggttctaattcaaatataggatcgaacacagtgaactggattcagcagttgcctggccgtgccccggagttattaatgtgtgatgatgatttattagcacccggagtatcagatcgcttttcaggaagccgtagtggcactagtgcgtccttaaccattagcgggttacagtctgaagacgaagcggactattacgcagctacgtgggatgatagtttaaatggctgggtttttggtggtggtactaaagttacggtgctgtccgcaggtggtagcgccatggcacaagtcattaataccaacagcctgtcgctgttgacccagaataacctgaacaaatcccagtccgctctgggcaccgctatcgagcgtctgtcttcctgcctgcgtatcaacagcgcgaaagacgatgcggcaggtcaggcgattgctaaccgttttaccgcgaacatcaaaggtctgactcaggcttcccgtaacgctaacgacggtatctccattgcgcagaccactgaaggcgcgctgaacgaaatcaacaacaacctgcagcgtgtgcgtgaactggcggttcagtctgctaacagcaccaactcccagtctgacctcgactccatccaggctgaaatcacccagcgcctgaacgaaatcgaccgtgtatccggccagactcagttcaacggcgtgaaagtcctggcgcaggacaacaccctgaccatccaggttggtgccaacgacggtgaaactatcgatatcgatctgaagcagatcaactctcagaccctgggtctggatacgctgaatgtgcaacaaaaatataaggtcagcgatacggctgcaactgttacaggatatgccgatactacgattgctttagacaatagtacttttaaagcctcggctactggtcttggtggtactgaccagaaaattgatggcgatttaaaatttgatgatacgactggaaaatattacgccaaagttaccgttacggggggaactggtaaagatggctattatgaagtttccgttgataagacgaacggtgaggtgactcttgctggcggtgcgacttccccgcttacaggtggactacctgcgacagcaactgaggatgtgaaaaatgtacaagttgcaaatgctgatttgacagaggctaaagccgcattgacagcagcaggtgttaccggcacagcatctgttgttaagatgtcttatactgataataacggtaaaactattgatggtggtttagcagttaaggtaggcgatgattactattctgcaactcaaaataaagatggttccataagtattaatactacgaaatacactgcagatgacggtacatccaaaactgcactaaacaaactgggtggcgcagacggcaaaaccgaagttgtttctattggtggtaaaacttacgctgcaagtaaagccgaaggtcacaactttaaagcacagcctgatctggcggaagcggctgctacaaccaccgaaaacccgctgcagaaaattgatgctgctttggcacaggttgacacgttacgttctgacctgggtgcggtacagaaccgtttcaactccgctattaccaacctgggcaacaccgtaaacaacctgacttctgcccgtagccgtatcgaatgctccgactacgcgaccgaagtttccaacatgtctcgcgcgcagattctgcagcaggccggtacctccgttctggcgcaggcgaaccaggttccgcaaaacgtcctctctttactgcgttga | |
ΔFliC(N)-VL12.3cys |
19 | 아미노산 서열 | MGSQPVLTQSPSVSAAPRQRVTISVSGSNSNIGSNTVNWIQQLPGRAPELLMCDDDLLAPGVSDRFSGSRSGTSASLTISGLQSEDEADYYAATWDDSLNGWVFGGGTKVTVLSAGGSAMGFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNVQQKYKVSDTAATVTGYADTTIALDNSTFKASATGLGGTDQKIDGDLKFDDTTGKYYAKVTVTGGTGKDGYYEVSVDKTNGEVTLAGGATSPLTGGLPATATEDVKNVQVANADLTEAKAALTAAGVTGTASVVKMSYTDNNGKTIDGGLAVKVGDDYYSATQNKDGSISINTTKYTADDGTSKTALNKLGGADGKTEVVSIGGKTYAASKAEGHNFKAQPDLAEAAATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARLEHHHHHH |
20 | 염기서열 | atgggtagtcaaccagtacttacacaaagcccgtctgtgtctgccgctccacgtcagagagtcaccatctcagttagtggttctaattcaaatataggatcgaacacagtgaactggattcagcagttgcctggccgtgccccggagttattaatgtgtgatgatgatttattagcacccggagtatcagatcgcttttcaggaagccgtagtggcactagtgcgtccttaaccattagcgggttacagtctgaagacgaagcggactattacgcagctacgtgggatgatagtttaaatggctgggtttttggtggtggtactaaagttacggtgctgtccgcaggtggtagcgccatgggctttaccgcgaacatcaaaggtctgactcaggcttcccgtaacgctaacgacggtatctccattgcgcagaccactgaaggcgcgctgaacgaaatcaacaacaacctgcagcgtgtgcgtgaactggcggttcagtctgctaacagcaccaactcccagtctgacctcgactccatccaggctgaaatcacccagcgcctgaacgaaatcgaccgtgtatccggccagactcagttcaacggcgtgaaagtcctggcgcaggacaacaccctgaccatccaggttggtgccaacgacggtgaaactatcgatatcgatctgaagcagatcaactctcagaccctgggtctggatacgctgaatgtgcaacaaaaatataaggtcagcgatacggctgcaactgttacaggatatgccgatactacgattgctttagacaatagtacttttaaagcctcggctactggtcttggtggtactgaccagaaaattgatggcgatttaaaatttgatgatacgactggaaaatattacgccaaagttaccgttacggggggaactggtaaagatggctattatgaagtttccgttgataagacgaacggtgaggtgactcttgctggcggtgcgacttccccgcttacaggtggactacctgcgacagcaactgaggatgtgaaaaatgtacaagttgcaaatgctgatttgacagaggctaaagccgcattgacagcagcaggtgttaccggcacagcatctgttgttaagatgtcttatactgataataacggtaaaactattgatggtggtttagcagttaaggtaggcgatgattactattctgcaactcaaaataaagatggttccataagtattaatactacgaaatacactgcagatgacggtacatccaaaactgcactaaacaaactgggtggcgcagacggcaaaaccgaagttgtttctattggtggtaaaacttacgctgcaagtaaagccgaaggtcacaactttaaagcacagcctgatctggcggaagcggctgctacaaccaccgaaaacccgctgcagaaaattgatgctgctttggcacaggttgacacgttacgttctgacctgggtgcggtacagaaccgtttcaactccgctattaccaacctgggcaacaccgtaaacaacctgacttctgcccgtctcgagcaccaccaccaccaccactga | |
ΔFliC(C)-VL12.3cys | 21 | 아미노산 서열 | MGFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNVQQKYKVSDTAATVTGYADTTIALDNSTFKASATGLGGTDQKIDGDLKFDDTTGKYYAKVTVTGGTGKDGYYEVSVDKTNGEVTLAGGATSPLTGGLPATATEDVKNVQVANADLTEAKAALTAAGVTGTASVVKMSYTDNNGKTIDGGLAVKVGDDYYSATQNKDGSISINTTKYTADDGTSKTALNKLGGADGKTEVVSIGGKTYAASKAEGHNFKAQPDLAEAAATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARLEGGSMGSQPVLTQSPSVSAAPRQRVTISVSGSNSNIGSNTVNWIQQLPGRAPELLMCDDDLLAPGVSDRFSGSRSGTSASLTISGLQSEDEADYYAATWDDSLNGWVFGGGTKVTVLSALEHHHHHH |
22 | 염기서열 | atgggctttaccgcgaacatcaaaggtctgactcaggcttcccgtaacgctaacgacggtatctccattgcgcagaccactgaaggcgcgctgaacgaaatcaacaacaacctgcagcgtgtgcgtgaactggcggttcagtctgctaacagcaccaactcccagtctgacctcgactccatccaggctgaaatcacccagcgcctgaacgaaatcgaccgtgtatccggccagactcagttcaacggcgtgaaagtcctggcgcaggacaacaccctgaccatccaggttggtgccaacgacggtgaaactatcgatatcgatctgaagcagatcaactctcagaccctgggtctggatacgctgaatgtgcaacaaaaatataaggtcagcgatacggctgcaactgttacaggatatgccgatactacgattgctttagacaatagtacttttaaagcctcggctactggtcttggtggtactgaccagaaaattgatggcgatttaaaatttgatgatacgactggaaaatattacgccaaagttaccgttacggggggaactggtaaagatggctattatgaagtttccgttgataagacgaacggtgaggtgactcttgctggcggtgcgacttccccgcttacaggtggactacctgcgacagcaactgaggatgtgaaaaatgtacaagttgcaaatgctgatttgacagaggctaaagccgcattgacagcagcaggtgttaccggcacagcatctgttgttaagatgtcttatactgataataacggtaaaactattgatggtggtttagcagttaaggtaggcgatgattactattctgcaactcaaaataaagatggttccataagtattaatactacgaaatacactgcagatgacggtacatccaaaactgcactaaacaaactgggtggcgcagacggcaaaaccgaagttgtttctattggtggtaaaacttacgctgcaagtaaagccgaaggtcacaactttaaagcacagcctgatctggcggaagcggctgctacaaccaccgaaaacccgctgcagaaaattgatgctgctttggcacaggttgacacgttacgttctgacctgggtgcggtacagaaccgtttcaactccgctattaccaacctgggcaacaccgtaaacaacctgacttctgcccgtctcgagggtggtagcatgggtagtcaaccagtacttacacaaagcccgtctgtgtctgccgctccacgtcagagagtcaccatctcagttagtggttctaattcaaatataggatcgaacacagtgaactggattcagcagttgcctggccgtgccccggagttattaatgtgtgatgatgatttattagcacccggagtatcagatcgcttttcaggaagccgtagtggcactagtgcgtccttaaccattagcgggttacagtctgaagacgaagcggactattacgcagctacgtgggatgatagtttaaatggctgggtttttggtggtggtactaaagttacggtgctgtccgcactcgagcaccaccaccaccaccactga | |
ΔFliC(I)-VL12.3cys | 23 | 아미노산 서열 | MGFTANIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELAVQSANSTNSQSDLDSIQAEITQRLNEIDRVSGQTQFNGVKVLAQDNTLTIQVGANDGETIDIDLKQINSQTLGLDTLNVQQKYKVSDTAATVTGYADTTIALDNSTFKASATGLGGTDQKIDGDLKFDDTTGKYYAKVTVTGGSGGSMGSQPVLTQSPSVSAAPRQRVTISVSGSNSNIGSNTVNWIQQLPGRAPELLMCDDDLLAPGVSDRFSGSRSGTSASLTISGLQSEDEADYYAATWDDSLNGWVFGGGTKVTVLSAGHMLVPRGSGGSVDGTGKDGYYEVSVDKTNGEVTLAGGATSPLTGGLPATATEDVKNVQVANADLTEAKAALTAAGVTGTASVVKMSYTDNNGKTIDGGLAVKVGDDYYSATQNKDGSISINTTKYTADDGTSKTALNKLGGADGKTEVVSIGGKTYAASKAEGHNFKAQPDLAEAAATTTENPLQKIDAALAQVDTLRSDLGAVQNRFNSAITNLGNTVNNLTSARLEHHHHHH |
24 | 염기서열 | atgggctttaccgcgaacatcaaaggtctgactcaggcttcccgtaacgctaacgacggtatctccattgcgcagaccactgaaggcgcgctgaacgaaatcaacaacaacctgcagcgtgtgcgtgaactggcggttcagtctgctaacagcaccaactcccagtctgacctcgactccatccaggctgaaatcacccagcgcctgaacgaaatcgaccgtgtatccggccagactcagttcaacggcgtgaaagtcctggcgcaggacaacaccctgaccatccaggttggtgccaacgacggtgaaactatcgatatcgatctgaagcagatcaactctcagaccctgggtctggatacgctgaatgtgcaacaaaaatataaggtcagcgatacggctgcaactgttacaggatatgccgatactacgattgctttagacaatagtacttttaaagcctcggctactggtcttggtggtactgaccagaaaattgatggcgatttaaaatttgatgatacgactggaaaatattacgccaaagttaccgttacggggggatccggtggtagcatgggtagtcaaccagtacttacacaaagcccgtctgtgtctgccgctccacgtcagagagtcaccatctcagttagtggttctaattcaaatataggatcgaacacagtgaactggattcagcagttgcctggccgtgccccggagttattaatgtgtgatgatgatttattagcacccggagtatcagatcgcttttcaggaagccgtagtggcactagtgcgtccttaaccattagcgggttacagtctgaagacgaagcggactattacgcagctacgtgggatgatagtttaaatggctgggtttttggtggtggtactaaagttacggtgctgtccgcaggtcatatgctggtgccgcgcggcagcggtggtagcgtcgacggaactggtaaagatggctattatgaagtttccgttgataagacgaacggtgaggtgactcttgctggcggtgcgacttccccgcttacaggtggactacctgcgacagcaactgaggatgtgaaaaatgtacaagttgcaaatgctgatttgacagaggctaaagccgcattgacagcagcaggtgttaccggcacagcatctgttgttaagatgtcttatactgataataacggtaaaactattgatggtggtttagcagttaaggtaggcgatgattactattctgcaactcaaaataaagatggttccataagtattaatactacgaaatacactgcagatgacggtacatccaaaactgcactaaacaaactgggtggcgcagacggcaaaaccgaagttgtttctattggtggtaaaacttacgctgcaagtaaagccgaaggtcacaactttaaagcacagcctgatctggcggaagcggctgctacaaccaccgaaaacccgctgcagaaaattgatgctgctttggcacaggttgacacgttacgttctgacctgggtgcggtacagaaccgtttcaactccgctattaccaacctgggcaacaccgtaaacaacctgacttctgcccgtctcgagcaccaccaccaccaccactga |
클로닝된 벡터를 E. coli BL21(DE3) 균주에 형질전환하고, 박테리아의 O.D.600 값이 0.7에 도달할 때, 1 mM IPTG를 첨가하여 융합 단백질 생산을 유도하였다. 37℃에서 3시간 배양한 후, 4℃에서 4000 rpm, 30분 동안 원심분리를 통해 E. coli(DE3)를 수확하였다.
수확한 세포 펠릿을 20 mM Tris(pH 8.0), 200 mM NaCl, 10 mM β-메르캅토에탄올(β-mercaptoethanol) 및 0.1 mM PMSF를 포함한 용해 완충액(lysis buffer)에 재현탁하고, 마이크로플루다이저(microfludizer, Microfluidics, Westwood, MA)를 사용하여 균질화시켰다. 15,000 rpm으로 4℃에서 40분 동안 원심분리한 후, 단백질을 Ni-NTA 킬레이팅 아가로스 CL-6B(Incospharm, Daejeon, Korea) 및 Q-Sepharose(GE Healthcare, Pittsburgh, PA) 음이온 교환 컬럼으로 정제하였다. 플라젤린-VL12.3cys 융합 단백질을 포함하는 분획을 수득한 후 농축시켰다.
<
실험예
1> 나노 입자의 제조
실시예 2 내지 4에서 제조한 각 단백질의 정확한 농도는 SDS-PAGE와 농도계(densitometry)에 의해 계산되었고, 먼저 실시예 2에서 제조한 단량체 융합 단백질을 케이지 형태의 페리틴 자가조립체와 I3-01 자가조립체를 제조하였다. 제조한 자가조립체에 하기 표 9에 기재된 조합으로 실시예 3 및 4에서 제조한 항원 또는 플라젤린을 혼합하여 자가조립체에 결합시켜 나노 입자를 제조하였다.
혼합물 종류 | 생성물 |
HTTcys-Ftn 자가조립체, ΔFliC(I)-VL12.3cys , HA-VL12.3cys |
Ftn-HA-ΔFliC(I) |
HTTcys-Ftn 자가조립체, ΔFliC(I)-VL12.3cys , PA-VL12.3cys |
Ftn-PA-ΔFliC(I) |
HTTcys-I3-01 자가조립체, ΔFliC(I)-VL12.3cys , HA-VL12.3cys |
I3-01-HA-ΔFliC(I) |
제조한 나노 입자를 DPBS(Dulbecco 's phosphate-buffered saline, Welgene)를 완충제로 사용하여 Superdex 200(GE Healthcare) 크기 배제 크로마토그래피로 추가 정제하였다. 원하는 나노 입자를 포함하는 분획을 모아 농축시키고, High-Capacity Endotoxin Removal Resin(Pierce, Thermo Scientific, San Jose, CA)를 사용하여 엔도톡신을 제거하고, 농축된 단백질 용액을 여과멸균하였다. 자가조립된 나노 입자는 크기 배제 크로마토그래피를 통해 확인하였다.
크기 배제 크로마토그래피 용출 프로필에서 볼 수 있듯이, PA, HA 및 플라젤린은 페리틴 자가조립체에 안정적으로 결합하였고, HA 및 플라젤린은 또한 I3-01 자가조립체에 안정적으로 결합하였다 (도 3).
<
실험예
2> 면역증강제(Adjuvant)로서
플라젤린
선택
<
실험예
2-1>
FliC와
ΔFliC에
따른
TLR5
활성화 측정
면역증강제(adjuvant)로서 플라젤린 내의 D0 도메인의 효과를 조사하기 위해, D0 내지 D3를 모두 포함하는 전장(full-length) 플라젤린(FliC)과 D1 내지 D3를 포함하는 D0 도메인이 절단된 플라젤린(ΔFliC)의 TLR5 활성화능을 측정하였다. 이를 위해 실시예 2-1에서 제조한 HTTcys-Ftn 융합 단백질의 단량체로부터 제조한 페리틴 자가조립체에 실시예 4에서 제조한 VL12.3cys-FliC(N) 및 VL12.3cys-ΔFliC(N))을 각각 혼합하여, Ftn-FliC(N)과 Ftn-ΔFliC(N)을 제조하였다.
TLR5 활성화 측정 과정은 다음과 같다. 24-웰 플레이트의 2×105의 HEK293 세포를 X-tremeGENE HP DNA 형질 전환 시약(Roche, Basel, Switzerland)을 이용하여 500 ng의 hTLR5 발현벡터(pcDNA3.1/hTLR5), 200 ng pBII firefly NF-κB 리포터 벡터 및 10 ng pRL-TK Renilla 인터널 컨트롤 벡터(internal control vector)로 형질전환하였다. 24시간 후, Ftn-ΔFliC(N) 및 Ftn-FliC(N)를 처리하고 18시간 동안 추가 배양하였다. 각 세포의 상대적인 루시퍼라제 활성(RLU, firefly/renilla)은 듀얼 루시퍼라제 리포터 어세이(Promega, Madison, WI) 키트 및 VICTOR 3 멀티라벨 플레이트 리더(Wallac 1420, Perkin Elmer)로 제조사의 프로토콜에 따라 분석하였으며, 결과 수치는 DPBS 완충액으로 처리된 샘플의 RLU로 표준화하였다.
그 결과, 전장 플라젤린(FliC)은 절단된 플라젤린(ΔFliC)보다 단지 1.4 내지 2.3 배의 활성을 나타내었다 (도 4).
<
실험예
2-2>
FliC와
ΔFliC에
따른
IgG
수치 측정
시험관 내에서(in vitro) 전장(full-length) 플라젤린(FliC)과 절단된 플라젤린(ΔFliC)에 따른 면역 반응을 비교하고자 하였다. 이를 위해 상기 <실험예 2-1>에 기재된 바와 유사하게 HTTcys-Ftn 융합 단백질로 구성된 페리틴 자가조립체에 표 10에 기재된 바와 같이 HA-VL12.3cys와 ΔFliC(N)-VL12.3cys 또는 HA-VL12.3cys와 FliC(N)-VL12.3cys 를 혼합하여 Ftn-HA-ΔFliC(N) 및 Ftn-HA-FliC(N)를 제조하였다.
혼합물 종류 | 생성물 |
HTTcys-Ftn 자가조립체, ΔFliC(N)-VL12.3cys , HA-VL12.3cys |
Ftn-HA-ΔFliC(N) (Ftn : HA : ΔFliC = 24:10:2.5) |
HTTcys-Ftn 자가조립체, FliC(N)-VL12.3cys , HA-VL12.3cys |
Ftn-HA-FliC(N) (Ftn : HA : FliC = 24:10:2.5) |
마우스에 주사하기 전에 페리틴에 결합된 HA 항원 또는 플라젤린의 몰비(표 10)은 SDS-PAGE 및 농도계를 이용하여 확인하였으며, 조립된 나노 입자에서 페리틴과 HA의 몰비는 24:10이었다.
충남대학교 실험 동물 관리위원회의 승인을 얻은 후 대한 바이오 링크(Eumseong, Korea)로부터 구입한 후, 6주령의 암컷 BALB/c 마우스를 각 5마리의 두 그룹으로 나눈 후 3주 간격으로 Ftn-HA-ΔFliC(N) 및 Ftn-HA-FliC(N)을 포함한 PBS 용액(HA의 농도, 5.2 μg/100 μl PBS)으로 우측 측면에 2회 피하 주사하였다.
1차 면역 접종 1주일 전 그리고 1차 면역 접종 및 반복 접종(priming and boosting) 2주 후에 안구에서 혈액을 채혈한 후 혈청 내 IgG(Total IgG, IgG1 및 IgG2a) 수치를 하기에 기재된 바와 같이 ELISA로 측정하였다. 96웰 플레이트(microtiter plate; Komabiotech., Seoul, Korea)의 웰을 10 ㎍/ml의 HA 코팅 완충액(pH 9.6, Komabiotech) 100 ㎕로 4℃에서 밤새 코팅한 후, 세척 완충액(0.05 % Tween을 포함하는 1×PBS)으로 3회 세척하고 실온에서 2시간 동안 1% BSA를 함유한 PBS로 블로킹시켰다. 채취한 혈청을 0.1% BSA를 함유한 PBS에 1:100으로 희석하고, 추가로 연속 10배 희석한 샘플을 BSA-블로킹된 웰에 첨가하였다. 실온에서 2시간 동안 반응시킨 후, 플레이트를 세척 완충액으로 3회 세척하였다. 호스래디쉬페록시다제(Horseradish peroxidase; Abcam, Cambridge, UK)가 결합된 항체(conjugated with goat anti-mouse IgG, IgG1, IgG2a 또는 IgG2b)를 0.1% BSA를 함유한 PBS 에 1:10,000 으로 희석하여 첨가하였다. 실온에서 2시간 동안 반응시킨 후, 플레이트를 세척 완충액으로 3회 다시 세척하고, 100 ㎕ TMB 현상액(Komabiotech)을 첨가하였다. 10분 후에 0.5M 황산 100 ㎕로 반응을 정지시키고, 색상을 마이크로 플레이트 판독기(Tecan GENios Pro, Mannedorf, Switzerland)로 450 nm에서 측정하였다. 1:100으로 희석한 미리 면역화된 마우스 혈청보다 2배 높은 OD450을 나타낸 가장 많이 희석한 샘플을 항체의 최종 항체 역가로 정하였다.
그 결과, 혈청 IgG1 수치는 Ftn-HA-ΔFliC(N) 및 Ftn-HA-FliC(N) 모두 비슷했다(도 5). Ftn-HA-ΔFliC(N) 처리 시, 혈청 내 총 IgG 및 IgG2a의 양은 각각 2.1 및 2.7배 더 높은 수준을 나타내었다. 플라젤린의 D0 도메인은 본 발명의 플라젤린-페리틴 시스템에서 IgG 반응에 별 영향이 없는 것으로 결론을 내렸으며, 후속 실험에서 나노 입자를 만드는데 D0 도메인이 없는 플라젤린을 사용하였다.
<
실험예
3>
플라젤린에의
융합 부위(
ΔFliC
(C),
ΔFliC
(I) 및
ΔFliC
(N))에 따른 TLR5 활성화 측정
플라젤린(ΔFliC)에의 최적의 융합 부위를 확인하기 위해, 실시예 2-1에서 제조한 HTTcys-Ftn 융합 단백질의 단량체로부터 케이지 형태의 페리틴 자가조립체를 제조하였다. 제조한 자가조립체에 실시예 4에서 제조한 VL12.3cys-ΔFliC(N), VL12.3cys-ΔFliC(C) 및 VL12.3cys-ΔFliC(I)을 각각 혼합하여, Ftn:FliC(ΔFliC)가 24:10의 몰비인 Ftn-ΔFliC(N), Ftn-ΔFliC(C) 및 Ftn-ΔFliC(I)의 나노 입자를 제조하고, 이의 TLR5 활성화능을 측정하였다.
TLR5 활성화 측정은 실험예 2-1의 나노 입자 대신 Ftn-ΔFliC(N), Ftn-ΔFliC(C), Ftn-ΔFliC(I) 그리고 페리틴 나노 입자(Ftn)과 플라젤린(ΔFliC)의 비결합된 혼합물(Ftn + ΔFliC)을 사용한 것을 제외하고, 실험예 2-1에 기재된 방법과 동일한 방법으로 수행되었다.
그 결과, 페리틴과 플라젤린(ΔFliC)의 비결합된 혼합물(Ftn + ΔFliC)은 무시할 수 있을 정도의 활성을 나타내었고, 플라젤린이 결합된 모든 페리틴 나노 입자는 농도 의존적으로 TLR5를 활성화시켰다 (도 6). 특히 Ftn-ΔFliC(N) 또는 Ftn-ΔFliC(I) 경우, Ftn-ΔFliC(C) 보다 1.3 내지 1.9배 더 높게 TLR5를 활성화시켰는데, 이는 ΔFliC의 N-말단 또는 D3 도메인과 페리틴과의 결합이 TLR5 신호 전달 경로를 자극하는데 매우 효과적임을 제시한다. D3 도메인은 TLR5와의 상호 작용에 관여하지 않기 때문에, 후속 실험에서 ΔFliC의 238G와 238G 사이에 VL12.3cys 도메인과 융합시킨 페리틴 나노 입자를 선택했다.
<
실험예
4>
플라젤린이
결합된
페리틴
나노 입자의
면역 반응
실험예 3에서 플라젤린-페리틴 나노 입자는 플라젤린이 비결합된 나노 입자 보다 TLR5를 더 효과적으로 활성화시켰으므로, 플라젤린-페리틴 나노 입자가 보다 강력한 면역증강(adjuvant) 반응을 나타낼 수 있는지 조사하였다.
이를 위해, 실시예 2-1에서 제조한 HTTcys-Ftn 융합 단백질로부터 페리틴 자가조립체를 제조하였다. 제조한 자가조립체에 하기 표 11에 기재된 바와 같이 실시예 3 및 4에서 제조한 항원 또는 플라젤린을 혼합하여, Ftn-ΔFliC(I), Ftn-HA 및 Ftn-HA-ΔFliC(I)를 제조하였다.
혼합물 종류 | 생성물 |
HTTcys-Ftn 자가조립체, ΔFliC(I)-VL12.3cys | Ftn-ΔFliC(I) (Ftn : ΔFliC = 24:10) |
HTTcys-Ftn 자가조립체, HA-VL12.3cys | Ftn-HA (Ftn : HA = 24:10) |
HTTcys-Ftn 자가조립체, ΔFliC(I)-VL12.3cys, HA-VL12.3cys | Ftn-HA-ΔFliC(I) (Ftn : HA : ΔFliC = 24:10:3.3) |
마우스 혈청 내 IgG 수치 측정은 실험예 2-2의 나노 입자 대신 HA, Ftn+ΔFliC(I)+HA, Ftn-ΔFliC(I)+HA, Ftn-HA+ΔFliC(I), Ftn-HA-ΔFliC(I)을 사용한 것을 제외하고, 실험예 2-2에 기재된 방법과 동일한 방법으로 수행하였다. 결합(conjugated) 및 비결합(non-conjugated) 형태의 HA의 총 농도는 100 μl PBS 당 5.2 μg이었으며, 최종 조립된 나노 입자에서 페리틴 대 HA의 몰비(molar ratio)는 24:10 이었다.
시험관 내에서(in vitro) TLR5 활성화 분석에서 관찰된 것과는 달리, Ftn-ΔFliC(I) + HA(HA는 비결합된 형태로 처리)는 Ftn +ΔFliC + HA(ΔFliC 및 HA 모두 비결합된 형태로 처리)와 유사한 수준으로 마우스에서 약한 혈청 IgG 반응을 유도하였다(도 7의 (A)). 그러나 Ftn-HA-ΔFliC(I)는 Ftn-HA + ΔFliC(ΔFliC는 비결합된 형태로 처리) 보다 16.7 배 더 높은 IgG 반응을 유도하였다(도 7의 (B)). 이러한 결과는 항원과 플라젤린을 융합시키는 것이 항원과 플라젤린의 단순한 혼합보다 강력한 면역 반응을 유도함을 보여준다. 또한 HA와 플라젤린이 서로 간에 직접적으로 결합되지 않더라도 페리틴 자가조립체에 HA와 플라젤린의 동시 결합(simultaneous conjugation)은 강력한 혈청 항체 반응을 유도할 수 있으며, HA-페리틴 나노 입자에 부착된 플라젤린이 강력한 면역증강제(adjuvant)임을 제시한다.
<
실험예
5> 세포성 면역 반응(cellular immune response)에 필요한
플라젤린의
최소량 확인
<
실험예
5-1>
HA:ΔFliC의
몰비에 따른
IgG
수치 측정
면역증강(adjuvant) 활성에 필요한 HA-페리틴 나노 입자의 플라젤린의 최소량을 확인하기 위해, HA 대 플라젤린의 몰비에 따른 마우스의 면역 반응을 조사하였다.
이를 위해 실시예 2-1에서 제조한 HTTcys-Ftn 융합 단백질로부터 케이지 형태의 페리틴 자가조립체를 제조하였다. 제조한 자가조립체에 하기 표 12에 기재된 조합으로 VL12.3cys --ΔFliC(I)과 HA-VL12.3cys 융합 단백질을 혼합하여, HA 대 ΔFliC(I)의 몰비가 1:1 내지 4:1인 Ftn-HA-ΔFliC(I)을 제조하였다.
혼합물 종류 | 생성물 |
HTTcys-Ftn 자가조립체, HA-VL12.3cys | Ftn-HA (Ftn : HA = 24:10) |
HTTcys-Ftn 자가조립체, ΔFliC(I)-VL12.3cys , HA-VL12.3cys (혼합 시 HA-VL12.3cys : ΔFliC(I)-VL12.3cys = 3:1) |
Ftn-HA-ΔFliC(I) (Ftn: HA:ΔFliC = 24:10:10) |
HTTcys-Ftn 자가조립체, ΔFliC(I)-VL12.3cys , HA-VL12.3cys (혼합 시 HA-VL12.3cys : ΔFliC(I)-VL12.3cys = 6:1) |
Ftn-HA-ΔFliC(I) (Ftn: HA:ΔFliC = 24:10:5) |
HTTcys-Ftn 자가조립체, ΔFliC(I)-VL12.3cys , HA-VL12.3cys (혼합 시 HA-VL12.3cys : ΔFliC(I)-VL12.3cys = 9:1) |
Ftn-HA-ΔFliC(I) (Ftn: HA:ΔFliC = 24:10:3.3) |
HTTcys-Ftn 자가조립체, ΔFliC(I)-VL12.3cys , HA-VL12.3cys (혼합 시 HA-VL12.3cys : ΔFliC(I)-VL12.3cys = 12:1) |
Ftn-HA-ΔFliC(I) (Ftn: HA:ΔFliC = 24:10:2.5) |
마우스 혈청 내 IgG 수치 측정은 실험예 2-2의 나노 입자 대신 Ftn-HA, HA:ΔFliC(I)의 몰비가 1:1 내지 4:1인 Ftn-HA-ΔFliC(I)을 사용한 것을 제외하고, 실험예 2-2에 기재된 방법과 동일한 방법으로 수행하였다. HA의 총 농도는 100 μl PBS 당 5.2 μg이었으며, 최종 조립된 나노 입자에서 페리틴 대 HA의 몰비(molar ratio)는 24:10 이었다.
그 결과 도 8에 나타낸 바와 같이, 총 IgG 및 IgG1 생산은 HA:ΔFliC(I)의 몰비가 4:1 이어도 유의한 영향을 받지 않았다. 그러나 HA 대 ΔFliC의 몰비가 4:1인 경우의 IgG2a의 수치는 그의 몰비가 1:1인 경우 보다 4.8 배 낮았다. 따라서, HA:ΔFliC의 몰비가 4:1일 때, 혈청 내 IgG2a에 대한 IgG1의 비는 4배 증가하였다. 혈청 IgG2b 수준 또한 35.1% 감소했다.
면역 글로불린 IgG1으로의 클래스 전환은 인터루킨-4(IL-4), IgG2a으로의 클래스 전환은 인터페론-감마(IFN-γ)와 같은 사이토카인이 필요하므로, IgG1의 증가는 Th2 반응의 증가이며, IgG2a의 증가는 Th1 반응의 증가이다. 페리틴 자가조립체에 결합한 헤마글루티닌 대 플라젤린의 몰비는 3:1 까지 IgG2a 클래스 전환과 Th1 반응에 영향이 없이 플라젤린의 양을 줄일 수 있음을 확인하였다.
<
실험예
5-2>
HA:ΔFliC의
몰비에 따른 사이토카인 분비량 측정
면역 글로불린의 클래스 전환은 주로 B 림프구와 특이적인 사이토카인, 구체적으로 IgG1을 만드는데 필요한 인터루킨-4(IL-4) 및 IgG2a를 만드는데 요구되는 인터페론-감마(IFN-γ)와 같은 사이토카인과의 상호작용에 의해 영향을 받는다. 따라서 <실험예 5-1>에서 제조한 Ftn-HA 또는 Ftn-HA-ΔFliC 나노 입자가 주입된 마우스의 비장 세포에서 사이토카인을 측정하였다.
구체적으로, 마우스에 Ftn-HA 또는 Ftn-HA-ΔFliC 나노 입자를 반복 접종(boosting)하고 3주 후에 비장 세포를 분리하였다. RBC 용해 완충액(lysis buffer, Sigma)로 적혈구를 용해시킨 비장 세포(1 x 106 세포)를 96-웰 플레이트에 분주한 후, HA 캘리포니아(H1N1)의 100 μg/ml 농도의 139 15-mer 펩타이드의 혼합물(PM-INFA-HACal, JPT innovative peptide solutions, Berlin, Germany) 10 μg/ml로 자극하고, 37℃, 5% CO2에서 3일간 배양하였다. 상등액을 수득, INF-γ 및 IL-4의 양을 ELISA 키트(Komabiotech)를 이용하여 제조자의 프로토콜에 따라 측정하였다.
도 9에 나타낸 바와 같이, Ftn-HA-ΔFliC 나노 입자가 주입된 마우스의 비장 세포를 HA 펩티드로 자극하였을 때, IFN-γ 분비는 Ftn-HA가 투여된 마우스의 비장 세포보다 HA:ΔFliC의 몰비가 1:1 또는 2:1에서 각각 2.8배 또는 5.4배 더 높았다. 그러나 IFN-γ의 분비량은 HA:ΔFliC의 몰비가 4:1일 때, 유의하게 감소하였다. IL-4의 분비량도 ΔFliC을 페리틴 자가조립체에 결합시킨 경우 증가하였지만, 분비량은 4:1 까지의 HA:ΔFliC 비율에 민감하지 않았다.
종합적으로, 이러한 결과는 HA 및 플라젤린이 동시에 결합된 페리틴 나노 입자가 체액성 면역 반응 및 항원-특이적 T세포 반응을 자극하며, IgG2a 클래스 전환 및 Th1 반응에 영향 끼치는 것 없이 HA 대 플라젤린의 몰비를 3:1 까지 줄일 수 있음을 제시한다.
<
실험예
5-3> HA의
분자수에
따른
IgG
수치 확인
페리틴 자가조립체에 결합된 HA 분자의 수에 따라 혈청 IgG 수치에 미치는 영향을 조사하였다. 이를 위해 실시예 2-1에서 제조한 HTTcys-Ftn 단백질로부터 케이지 형태의 페리틴 자가조립체를 제조하고, 상기 제조한 자가조립체에 실시예 3-1에서 제조한 VL12.3cys 융합 단백질을 혼합하여 HA 4분자만 가진 Ftn-HA(low) 나노 입자와 HA 24분자를 가진 Ftn-HA(high) 나노 입자를 생산하고, 이들의 면역 자극 활성(immunostimulatory activities)을 비교했다.
마우스 혈청 내 IgG 수치 측정은 실험예 2-2의 나노 입자 대신 Ftn-HA(low), Ftn-HA(high) 및 HA:ΔFliC(I)의 몰비가 3:1인 Ftn-HA-ΔFliC(I)을 사용한 것을 제외하고, 실험예 2-2에 기재된 방법과 동일한 방법으로 수행하였다.
그 결과 도 10에 도시된 바와 같이, Ftn-HA(high) 나노 입자는 Ftn-HA(low) 나노 입자보다 강력한 총 IgG, IgG1, IgG2a 및 IgG2b 반응을 유도하였다. 그러나 IgG1 이외의 IgG 반응은 Ftn-HA-FliC의 3:1 비율(Ftn-HA-FliC 내 HA:플라젤린의 몰비=3:1)의 IgG 반응보다 유의하게 낮았다. 특히, Ftn-HA-ΔFliC 3:1 나노 입자에 의해 유도된 IgG2a 및 IgG2b 수준은 Ftn-HA(high) 나노 입자에 의해 유도된 것보다 각각 1.8 및 7 배 더 높았다. 이러한 결과는 최대로 결합된(conjugated) HA가 체액성 면역 반응을 유도하는데 유용하지만, 자가 면역 증강 활성(self-adjuvant activity)을 가진 매우 효과적인 나노 입자를 생산하기 위해서는 플라젤린이 페리틴 자가조립체에 결합되어야 함을 나타낸다.
<110> THE INDUSTRY & ACADEMIC COOPERATION IN CHUNGNAM NATIONAL UNIVERSITY
<120> Nano particle comprising self-assembled ferritin structure
conjugated with antigen peptide and adjuvant and use thereof
<130> 2018P-01-002
<160> 42
<170> KoPatentIn 3.0
<210> 1
<211> 165
<212> PRT
<213> Escherichia coli
<400> 1
Met Leu Lys Pro Glu Met Ile Glu Lys Leu Asn Glu Gln Met Asn Leu
1 5 10 15
Glu Leu Tyr Ser Ser Leu Leu Tyr Gln Gln Met Ser Ala Trp Cys Ser
20 25 30
Tyr His Thr Phe Glu Gly Ala Ala Ala Phe Leu Arg Arg His Ala Gln
35 40 45
Glu Glu Met Thr His Met Gln Arg Leu Phe Asp Tyr Leu Thr Asp Thr
50 55 60
Gly Asn Leu Pro Arg Ile Asn Thr Val Glu Ser Pro Phe Ala Glu Tyr
65 70 75 80
Ser Ser Leu Asp Glu Leu Phe Gln Glu Thr Tyr Lys His Glu Gln Leu
85 90 95
Ile Thr Gln Lys Ile Asn Glu Leu Ala His Ala Ala Met Thr Asn Gln
100 105 110
Asp Tyr Pro Thr Phe Asn Phe Leu Gln Trp Tyr Val Ser Glu Gln His
115 120 125
Glu Glu Glu Lys Leu Phe Lys Ser Ile Ile Asp Lys Leu Ser Leu Ala
130 135 140
Gly Lys Ser Gly Glu Gly Leu Tyr Phe Ile Asp Lys Glu Leu Ser Thr
145 150 155 160
Leu Asp Thr Gln Asn
165
<210> 2
<211> 14
<212> PRT
<213> Homo sapiens
<400> 2
Glu Lys Leu Met Lys Ala Phe Glu Ser Leu Lys Ser Phe Gln
1 5 10
<210> 3
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> HTTcys
<400> 3
Glu Lys Leu Met Lys Cys Phe Glu Ser Leu Lys Ser Phe Gln
1 5 10
<210> 4
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> VL12.3
<400> 4
Met Gly Ser Gln Pro Val Leu Thr Gln Ser Pro Ser Val Ser Ala Ala
1 5 10 15
Pro Arg Gln Arg Val Thr Ile Ser Val Ser Gly Ser Asn Ser Asn Ile
20 25 30
Gly Ser Asn Thr Val Asn Trp Ile Gln Gln Leu Pro Gly Arg Ala Pro
35 40 45
Glu Leu Leu Met Tyr Asp Asp Asp Leu Leu Ala Pro Gly Val Ser Asp
50 55 60
Arg Phe Ser Gly Ser Arg Ser Gly Thr Ser Ala Ser Leu Thr Ile Ser
65 70 75 80
Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Ala Ala Thr Trp Asp
85 90 95
Asp Ser Leu Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val
100 105 110
Leu Ser Ala
115
<210> 5
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> VL12.3cys
<400> 5
Met Gly Ser Gln Pro Val Leu Thr Gln Ser Pro Ser Val Ser Ala Ala
1 5 10 15
Pro Arg Gln Arg Val Thr Ile Ser Val Ser Gly Ser Asn Ser Asn Ile
20 25 30
Gly Ser Asn Thr Val Asn Trp Ile Gln Gln Leu Pro Gly Arg Ala Pro
35 40 45
Glu Leu Leu Met Cys Asp Asp Asp Leu Leu Ala Pro Gly Val Ser Asp
50 55 60
Arg Phe Ser Gly Ser Arg Ser Gly Thr Ser Ala Ser Leu Thr Ile Ser
65 70 75 80
Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Ala Ala Thr Trp Asp
85 90 95
Asp Ser Leu Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val
100 105 110
Leu Ser Ala
115
<210> 6
<211> 185
<212> PRT
<213> Artificial Sequence
<220>
<223> HTTcys-Ftn
<400> 6
Met Gly Glu Lys Leu Met Lys Cys Phe Glu Ser Leu Lys Ser Phe Gln
1 5 10 15
Gly Gly Ser Arg Met Leu Lys Pro Glu Met Ile Glu Lys Leu Asn Glu
20 25 30
Gln Met Asn Leu Glu Leu Tyr Ser Ser Leu Leu Tyr Gln Gln Met Ser
35 40 45
Ala Trp Cys Ser Tyr His Thr Phe Glu Gly Ala Ala Ala Phe Leu Arg
50 55 60
Arg His Ala Gln Glu Glu Met Thr His Met Gln Arg Leu Phe Asp Tyr
65 70 75 80
Leu Thr Asp Thr Gly Asn Leu Pro Arg Ile Asn Thr Val Glu Ser Pro
85 90 95
Phe Ala Glu Tyr Ser Ser Leu Asp Glu Leu Phe Gln Glu Thr Tyr Lys
100 105 110
His Glu Gln Leu Ile Thr Gln Lys Ile Asn Glu Leu Ala His Ala Ala
115 120 125
Met Thr Asn Gln Asp Tyr Pro Thr Phe Asn Phe Leu Gln Trp Tyr Val
130 135 140
Ser Glu Gln His Glu Glu Glu Lys Leu Phe Lys Ser Ile Ile Asp Lys
145 150 155 160
Leu Ser Leu Ala Gly Lys Ser Gly Glu Gly Leu Tyr Phe Ile Asp Lys
165 170 175
Glu Leu Ser Thr Leu Asp Thr Gln Asn
180 185
<210> 7
<211> 558
<212> DNA
<213> Artificial Sequence
<220>
<223> HTTcys-Ftn
<400> 7
atgggcgaaa agctgatgaa gtgtttcgag tccctcaagt ccttccaggg tggttctaga 60
atgctgaaac cagaaatgat tgaaaaactt aatgagcaga tgaacctgga actgtactct 120
tcactgcttt atcagcaaat gagcgcctgg tgcagctatc ataccttcga aggtgctgcc 180
gcgttcctgc gccgtcacgc ccaggaagag atgacgcata tgcagcgtct gtttgattac 240
ctgactgata ccggcaattt accgcgtatt aataccgttg aatctccgtt tgctgaatat 300
tcctcacttg atgaattatt ccaggaaacc tataaacacg aacaattaat cacccagaaa 360
attaacgaac tggctcatgc tgcaatgacc aatcaggact acccaacatt taatttcctg 420
cagtggtatg tttctgagca gcatgaagaa gagaaactgt tcaaatcgat tattgataaa 480
ttaagcctgg caggcaaaag cggcgaaggt ctgtatttta tcgacaaaga actctctacc 540
ctcgacacac aaaactaa 558
<210> 8
<211> 513
<212> PRT
<213> Influenza A virus
<400> 8
Asp Thr Leu Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asp Lys His Asn Gly Lys Leu Cys Lys Leu Arg Gly Val Ala
35 40 45
Pro Leu His Leu Gly Lys Cys Asn Ile Ala Gly Trp Ile Leu Gly Asn
50 55 60
Pro Glu Cys Glu Ser Leu Ser Thr Ala Ser Ser Trp Ser Tyr Ile Val
65 70 75 80
Glu Thr Pro Ser Ser Asp Asn Gly Thr Cys Tyr Pro Gly Asp Phe Ile
85 90 95
Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe Glu
100 105 110
Arg Phe Glu Ile Phe Pro Lys Thr Ser Ser Trp Pro Asn His Asp Ser
115 120 125
Asn Lys Gly Val Thr Ala Ala Cys Pro His Ala Gly Ala Lys Ser Phe
130 135 140
Tyr Lys Asn Leu Ile Trp Leu Val Lys Lys Gly Asn Ser Tyr Pro Lys
145 150 155 160
Leu Ser Lys Ser Tyr Ile Asn Asp Lys Gly Lys Glu Val Leu Val Leu
165 170 175
Trp Gly Ile His His Pro Ser Thr Ser Ala Asp Gln Gln Ser Leu Tyr
180 185 190
Gln Asn Ala Asp Thr Tyr Val Phe Val Gly Ser Ser Arg Tyr Ser Lys
195 200 205
Lys Phe Lys Pro Glu Ile Ala Ile Arg Pro Lys Val Arg Asp Gln Glu
210 215 220
Gly Arg Met Asn Tyr Tyr Trp Thr Leu Val Glu Pro Gly Asp Lys Ile
225 230 235 240
Thr Phe Glu Ala Thr Gly Asn Leu Val Val Pro Arg Tyr Ala Phe Ala
245 250 255
Met Glu Arg Asn Ala Gly Ser Gly Ile Ile Ile Ser Asp Thr Pro Val
260 265 270
His Asp Cys Asn Thr Thr Cys Gln Thr Pro Lys Gly Ala Ile Asn Thr
275 280 285
Ser Leu Pro Phe Gln Asn Ile His Pro Ile Thr Ile Gly Lys Cys Pro
290 295 300
Lys Tyr Val Lys Ser Thr Lys Leu Arg Leu Ala Thr Gly Leu Arg Asn
305 310 315 320
Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe
325 330 335
Ile Glu Gly Gly Trp Thr Gly Met Val Asp Gly Trp Tyr Gly Tyr His
340 345 350
His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Leu Lys Ser Thr
355 360 365
Gln Asn Ala Ile Asp Glu Ile Thr Asn Lys Val Asn Ser Val Ile Glu
370 375 380
Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn His Leu
385 390 395 400
Glu Lys Arg Ile Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Leu
405 410 415
Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu
420 425 430
Arg Thr Leu Asp Tyr His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys
435 440 445
Val Arg Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys
450 455 460
Phe Glu Phe Tyr His Lys Cys Asp Asn Thr Cys Met Glu Ser Val Lys
465 470 475 480
Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ala Lys Leu Asn
485 490 495
Arg Glu Glu Ile Asp Gly Val Lys Leu Glu Ser Thr Arg Ile Tyr Gln
500 505 510
Ile
<210> 9
<211> 495
<212> PRT
<213> Salmonella typhimurium
<400> 9
Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn
1 5 10 15
Asn Leu Asn Lys Ser Gln Ser Ala Leu Gly Thr Ala Ile Glu Arg Leu
20 25 30
Ser Ser Gly Cys Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln
35 40 45
Ala Ile Ala Asn Arg Phe Thr Ala Asn Ile Lys Gly Leu Thr Gln Ala
50 55 60
Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly
65 70 75 80
Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ala
85 90 95
Val Gln Ser Ala Asn Ser Thr Asn Ser Gln Ser Asp Leu Asp Ser Ile
100 105 110
Gln Ala Glu Ile Thr Gln Arg Leu Asn Glu Ile Asp Arg Val Ser Gly
115 120 125
Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ala Gln Asp Asn Thr Leu
130 135 140
Thr Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Asp Ile Asp Leu
145 150 155 160
Lys Gln Ile Asn Ser Gln Thr Leu Gly Leu Asp Thr Leu Asn Val Gln
165 170 175
Gln Lys Tyr Lys Val Ser Asp Thr Ala Ala Thr Val Thr Gly Tyr Ala
180 185 190
Asp Thr Thr Ile Ala Leu Asp Asn Ser Thr Phe Lys Ala Ser Ala Thr
195 200 205
Gly Leu Gly Gly Thr Asp Gln Lys Ile Asp Gly Asp Leu Lys Phe Asp
210 215 220
Asp Thr Thr Gly Lys Tyr Tyr Ala Lys Val Thr Val Thr Gly Gly Thr
225 230 235 240
Gly Lys Asp Gly Tyr Tyr Glu Val Ser Val Asp Lys Thr Asn Gly Glu
245 250 255
Val Thr Leu Ala Gly Gly Ala Thr Ser Pro Leu Thr Gly Gly Leu Pro
260 265 270
Ala Thr Ala Thr Glu Asp Val Lys Asn Val Gln Val Ala Asn Ala Asp
275 280 285
Leu Thr Glu Ala Lys Ala Ala Leu Thr Ala Ala Gly Val Thr Gly Thr
290 295 300
Ala Ser Val Val Lys Met Ser Tyr Thr Asp Asn Asn Gly Lys Thr Ile
305 310 315 320
Asp Gly Gly Leu Ala Val Lys Val Gly Asp Asp Tyr Tyr Ser Ala Thr
325 330 335
Gln Asn Lys Asp Gly Ser Ile Ser Ile Asn Thr Thr Lys Tyr Thr Ala
340 345 350
Asp Asp Gly Thr Ser Lys Thr Ala Leu Asn Lys Leu Gly Gly Ala Asp
355 360 365
Gly Lys Thr Glu Val Val Ser Ile Gly Gly Lys Thr Tyr Ala Ala Ser
370 375 380
Lys Ala Glu Gly His Asn Phe Lys Ala Gln Pro Asp Leu Ala Glu Ala
385 390 395 400
Ala Ala Thr Thr Thr Glu Asn Pro Leu Gln Lys Ile Asp Ala Ala Leu
405 410 415
Ala Gln Val Asp Thr Leu Arg Ser Asp Leu Gly Ala Val Gln Asn Arg
420 425 430
Phe Asn Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Asn Asn Leu Thr
435 440 445
Ser Ala Arg Ser Arg Ile Glu Cys Ser Asp Tyr Ala Thr Glu Val Ser
450 455 460
Asn Met Ser Arg Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu
465 470 475 480
Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Arg
485 490 495
<210> 10
<211> 442
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated flagellin
<400> 10
Phe Thr Ala Asn Ile Lys Gly Leu Thr Gln Ala Ser Arg Asn Ala Asn
1 5 10 15
Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly Ala Leu Asn Glu Ile
20 25 30
Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ala Val Gln Ser Ala Asn
35 40 45
Ser Thr Asn Ser Gln Ser Asp Leu Asp Ser Ile Gln Ala Glu Ile Thr
50 55 60
Gln Arg Leu Asn Glu Ile Asp Arg Val Ser Gly Gln Thr Gln Phe Asn
65 70 75 80
Gly Val Lys Val Leu Ala Gln Asp Asn Thr Leu Thr Ile Gln Val Gly
85 90 95
Ala Asn Asp Gly Glu Thr Ile Asp Ile Asp Leu Lys Gln Ile Asn Ser
100 105 110
Gln Thr Leu Gly Leu Asp Thr Leu Asn Val Gln Gln Lys Tyr Lys Val
115 120 125
Ser Asp Thr Ala Ala Thr Val Thr Gly Tyr Ala Asp Thr Thr Ile Ala
130 135 140
Leu Asp Asn Ser Thr Phe Lys Ala Ser Ala Thr Gly Leu Gly Gly Thr
145 150 155 160
Asp Gln Lys Ile Asp Gly Asp Leu Lys Phe Asp Asp Thr Thr Gly Lys
165 170 175
Tyr Tyr Ala Lys Val Thr Val Thr Gly Gly Thr Gly Lys Asp Gly Tyr
180 185 190
Tyr Glu Val Ser Val Asp Lys Thr Asn Gly Glu Val Thr Leu Ala Gly
195 200 205
Gly Ala Thr Ser Pro Leu Thr Gly Gly Leu Pro Ala Thr Ala Thr Glu
210 215 220
Asp Val Lys Asn Val Gln Val Ala Asn Ala Asp Leu Thr Glu Ala Lys
225 230 235 240
Ala Ala Leu Thr Ala Ala Gly Val Thr Gly Thr Ala Ser Val Val Lys
245 250 255
Met Ser Tyr Thr Asp Asn Asn Gly Lys Thr Ile Asp Gly Gly Leu Ala
260 265 270
Val Lys Val Gly Asp Asp Tyr Tyr Ser Ala Thr Gln Asn Lys Asp Gly
275 280 285
Ser Ile Ser Ile Asn Thr Thr Lys Tyr Thr Ala Asp Asp Gly Thr Ser
290 295 300
Lys Thr Ala Leu Asn Lys Leu Gly Gly Ala Asp Gly Lys Thr Glu Val
305 310 315 320
Val Ser Ile Gly Gly Lys Thr Tyr Ala Ala Ser Lys Ala Glu Gly His
325 330 335
Asn Phe Lys Ala Gln Pro Asp Leu Ala Glu Ala Ala Ala Thr Thr Thr
340 345 350
Glu Asn Pro Leu Gln Lys Ile Asp Ala Ala Leu Ala Gln Val Asp Thr
355 360 365
Leu Arg Ser Asp Leu Gly Ala Val Gln Asn Arg Phe Asn Ser Ala Ile
370 375 380
Thr Asn Leu Gly Asn Thr Val Asn Asn Leu Thr Ser Ala Arg Ser Arg
385 390 395 400
Ile Glu Cys Ser Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Arg Ala
405 410 415
Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln
420 425 430
Val Pro Gln Asn Val Leu Ser Leu Leu Arg
435 440
<210> 11
<211> 238
<212> PRT
<213> Artificial Sequence
<220>
<223> HTTcys-I3-01
<400> 11
Met His His His His His His Gly Gly Ser Gly Gly Ser Glu Lys Leu
1 5 10 15
Met Lys Cys Phe Glu Ser Leu Lys Ser Phe Gln Gly Gly Ser Gly Gly
20 25 30
Ser Met Lys Met Glu Glu Leu Phe Lys Lys His Lys Ile Val Ala Val
35 40 45
Leu Arg Ala Asn Ser Val Glu Glu Ala Lys Lys Lys Ala Leu Ala Val
50 55 60
Phe Leu Gly Gly Val His Leu Ile Glu Ile Thr Phe Thr Val Pro Asp
65 70 75 80
Ala Asp Thr Val Ile Lys Glu Leu Ser Phe Leu Lys Glu Met Gly Ala
85 90 95
Ile Ile Gly Ala Gly Thr Val Thr Ser Val Glu Gln Cys Arg Lys Ala
100 105 110
Val Glu Ser Gly Ala Glu Phe Ile Val Ser Pro His Leu Asp Glu Glu
115 120 125
Ile Ser Gln Phe Cys Lys Glu Lys Gly Val Phe Tyr Met Pro Gly Val
130 135 140
Met Thr Pro Thr Glu Leu Val Lys Ala Met Lys Leu Gly His Thr Ile
145 150 155 160
Leu Lys Leu Phe Pro Gly Glu Val Val Gly Pro Gln Phe Val Lys Ala
165 170 175
Met Lys Gly Pro Phe Pro Asn Val Lys Phe Val Pro Thr Gly Gly Val
180 185 190
Asn Leu Asp Asn Val Cys Glu Trp Phe Lys Ala Gly Val Leu Ala Val
195 200 205
Gly Val Gly Ser Ala Leu Val Lys Gly Thr Pro Val Glu Val Ala Glu
210 215 220
Lys Ala Lys Ala Phe Val Glu Lys Ile Arg Gly Cys Thr Glu
225 230 235
<210> 12
<211> 717
<212> DNA
<213> Artificial Sequence
<220>
<223> HTTcys-I3-01
<400> 12
atgcatcatc atcatcatca cggtggaagc ggtggaagcg aaaagctgat gaagtgtttc 60
gagtccctca agtccttcca gggtggtagc ggcggttcta tgaagatgga agagctgttc 120
aagaaacaca agatcgttgc cgtgctgcgt gccaatagtg tggaagaagc gaaaaagaaa 180
gcgctggcgg ttttcctggg cggcgttcat ctgattgaaa ttacctttac cgtgccggat 240
gcggataccg tgattaagga actgagcttt ctgaaggaaa tgggcgcgat tattggtgcg 300
ggcaccgtga ccagcgtgga gcagtgccgt aaagcggtgg aaagtggcgc cgaattcatt 360
gtgagtccgc acctggacga ggaaattagc caattttgca aggagaaggg tgtgttctat 420
atgccaggcg ttatgacccc gaccgaactg gtgaaagcca tgaaactggg ccataccatc 480
ttaaaactgt ttccgggtga ggtggtgggt ccgcagtttg ttaaagcgat gaaaggtccg 540
tttccgaatg tgaaatttgt gccaaccggc ggtgttaatc tggacaatgt gtgcgaatgg 600
ttcaaagcgg gcgtgctggc cgtgggcgtg ggcagcgcgt tagtgaaagg caccccggtg 660
gaagtggcgg aaaaggccaa ggcgttcgtt gagaagattc gtggctgcac cgaataa 717
<210> 13
<211> 644
<212> PRT
<213> Artificial Sequence
<220>
<223> HA-VL12.3cys
<400> 13
Ala Asp Pro Asp Thr Leu Cys Ile Gly Tyr His Ala Asn Asn Ser Thr
1 5 10 15
Asp Thr Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser
20 25 30
Val Asn Leu Leu Glu Asp Lys His Asn Gly Lys Leu Cys Lys Leu Arg
35 40 45
Gly Val Ala Pro Leu His Leu Gly Lys Cys Asn Ile Ala Gly Trp Ile
50 55 60
Leu Gly Asn Pro Glu Cys Glu Ser Leu Ser Thr Ala Ser Ser Trp Ser
65 70 75 80
Tyr Ile Val Glu Thr Pro Ser Ser Asp Asn Gly Thr Cys Tyr Pro Gly
85 90 95
Asp Phe Ile Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser
100 105 110
Ser Phe Glu Arg Phe Glu Ile Phe Pro Lys Thr Ser Ser Trp Pro Asn
115 120 125
His Asp Ser Asn Lys Gly Val Thr Ala Ala Cys Pro His Ala Gly Ala
130 135 140
Lys Ser Phe Tyr Lys Asn Leu Ile Trp Leu Val Lys Lys Gly Asn Ser
145 150 155 160
Tyr Pro Lys Leu Ser Lys Ser Tyr Ile Asn Asp Lys Gly Lys Glu Val
165 170 175
Leu Val Leu Trp Gly Ile His His Pro Ser Thr Ser Ala Asp Gln Gln
180 185 190
Ser Leu Tyr Gln Asn Ala Asp Thr Tyr Val Phe Val Gly Ser Ser Arg
195 200 205
Tyr Ser Lys Lys Phe Lys Pro Glu Ile Ala Ile Arg Pro Lys Val Arg
210 215 220
Asp Gln Glu Gly Arg Met Asn Tyr Tyr Trp Thr Leu Val Glu Pro Gly
225 230 235 240
Asp Lys Ile Thr Phe Glu Ala Thr Gly Asn Leu Val Val Pro Arg Tyr
245 250 255
Ala Phe Ala Met Glu Arg Asn Ala Gly Ser Gly Ile Ile Ile Ser Asp
260 265 270
Thr Pro Val His Asp Cys Asn Thr Thr Cys Gln Thr Pro Lys Gly Ala
275 280 285
Ile Asn Thr Ser Leu Pro Phe Gln Asn Ile His Pro Ile Thr Ile Gly
290 295 300
Lys Cys Pro Lys Tyr Val Lys Ser Thr Lys Leu Arg Leu Ala Thr Gly
305 310 315 320
Leu Arg Asn Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile
325 330 335
Ala Gly Phe Ile Glu Gly Gly Trp Thr Gly Met Val Asp Gly Trp Tyr
340 345 350
Gly Tyr His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Leu
355 360 365
Lys Ser Thr Gln Asn Ala Ile Asp Glu Ile Thr Asn Lys Val Asn Ser
370 375 380
Val Ile Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe
385 390 395 400
Asn His Leu Glu Lys Arg Ile Glu Asn Leu Asn Lys Lys Val Asp Asp
405 410 415
Gly Phe Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu
420 425 430
Glu Asn Glu Arg Thr Leu Asp Tyr His Asp Ser Asn Val Lys Asn Leu
435 440 445
Tyr Glu Lys Val Arg Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly
450 455 460
Asn Gly Cys Phe Glu Phe Tyr His Lys Cys Asp Asn Thr Cys Met Glu
465 470 475 480
Ser Val Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ala
485 490 495
Lys Leu Asn Arg Glu Glu Ile Asp Gly Val Lys Leu Glu Ser Thr Arg
500 505 510
Ile Tyr Gln Ile Gly Ser Arg Ser Met Gly Ser Gln Pro Val Leu Thr
515 520 525
Gln Ser Pro Ser Val Ser Ala Ala Pro Arg Gln Arg Val Thr Ile Ser
530 535 540
Val Ser Gly Ser Asn Ser Asn Ile Gly Ser Asn Thr Val Asn Trp Ile
545 550 555 560
Gln Gln Leu Pro Gly Arg Ala Pro Glu Leu Leu Met Cys Asp Asp Asp
565 570 575
Leu Leu Ala Pro Gly Val Ser Asp Arg Phe Ser Gly Ser Arg Ser Gly
580 585 590
Thr Ser Ala Ser Leu Thr Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala
595 600 605
Asp Tyr Tyr Ala Ala Thr Trp Asp Asp Ser Leu Asn Gly Trp Val Phe
610 615 620
Gly Gly Gly Thr Lys Val Thr Val Leu Ser Ala Gly Ser Ser His His
625 630 635 640
His His His His
<210> 14
<211> 1934
<212> DNA
<213> Artificial Sequence
<220>
<223> HA-VL12.3cys
<400> 14
gcggatcccg acacattgtg cattgggtac catgctaata actcaacaga tacagtagat 60
actgtgttgg aaaaaaacgt aacggtaaca cactcagtga acttactaga agacaaacat 120
aatggaaagt tatgtaaact aagaggggtt gccccattac atctgggtaa atgcaatatt 180
gcagggtgga ttctaggaaa cccagagtgt gagtcactat ccactgcatc aagttggtca 240
tacatcgtgg aaactccaag ctcagataat ggcacatgtt atccgggaga ctttatcgat 300
tatgaggaat taagggaaca gttgagcagt gttagctcgt tcgaaagatt cgagatattc 360
cccaagacat caagttggcc aaatcatgac tccaacaaag gagtaacagc ggcatgccct 420
cacgccggag ctaaatcatt ctacaagaac ctgatttggc tagttaagaa aggcaattct 480
tacccaaaac tgtcaaagtc ttatattaat gacaaaggta aagaagtatt ggttctatgg 540
gggatacatc accccagcac aagcgctgac caacagtcac tataccagaa tgccgatact 600
tacgtatttg tggggagtag cagatattct aaaaagttca agccggaaat tgcaattagg 660
ccgaaggtga gagaccaaga aggtagaatg aattactatt ggacattagt agagccgggt 720
gataaaataa catttgaagc aactggaaat ttggtggttc caagatacgc attcgctatg 780
gagagaaacg ccggtagcgg aatcattata agtgatacac cagtccacga ctgtaacaca 840
acctgccaaa ctcccaaggg agcaataaac acgagcctac cgtttcaaaa tattcaccca 900
attacaatag ggaaatgtcc aaaatatgta aaatcaacaa agttgagact ggcaacaggg 960
ctcagaaaca taccctctat tcagtccaga ggtctatttg gggcaattgc cggattcatc 1020
gaggggggat ggacaggtat ggtcgatggc tggtatgggt accaccatca gaacgagcaa 1080
ggatctggtt acgccgcgat ctaaagtcaa cacaaaatgc aattgatgaa atcacaaata 1140
aggtaaattc agtaatagag aagatgaata cacagttcac agcagtaggc aaagaattta 1200
atcacctgga gaaaagaata gaaaacctca ataaaaaggt agacgatggt ttcttagaca 1260
tttggacata caatgcagaa ctcctagtac tactcgaaaa tgaaaggacg ctggactacc 1320
atgactcaaa cgttaaaaat ctatatgaaa aagtaagatc acagttgaaa aataatgcca 1380
aagagatagg aaatggatgc tttgaatttt accataaatg tgacaataca tgtatggaat 1440
cagttaaaaa tgggacttac gattatccaa agtatagcga agaagctaag ctgaatagag 1500
aagaaataga tggggtaaaa ctagaatcaa ctaggattta tcagattggc tctagaagca 1560
tgggtagtca accagtactt acacaaagcc cgtctgtgtc tgccgctcca cgtcagagag 1620
tcaccatctc agttagtggt tctaattcaa atataggatc gaacacagtg aactggattc 1680
agcagttgcc tggccgtgcc ccggagttat taatgtgtga tgatgattta ttagcacccg 1740
gagtatcaga tcgcttttca ggaagccgta gtggcactag tgcgtcctta accattagcg 1800
ggttacagtc tgaagacgaa gcggactatt acgcagctac gtgggatgat agtttaaatg 1860
gctgggtttt tggtggtggt actaaagtta cggtgctgtc cgcaggcagt agccatcatc 1920
atcatcatca ctaa 1934
<210> 15
<211> 269
<212> PRT
<213> Artificial Sequence
<220>
<223> PA-VL12.3cys
<400> 15
Met Gly Phe His Tyr Asp Arg Asn Asn Ile Ala Val Gly Ala Asp Glu
1 5 10 15
Ser Val Val Lys Glu Ala His Arg Glu Val Ile Asn Ser Ser Thr Glu
20 25 30
Gly Leu Leu Leu Asn Ile Asp Lys Asp Ile Arg Lys Ile Leu Ser Gly
35 40 45
Tyr Ile Val Glu Ile Glu Asp Thr Glu Gly Leu Lys Glu Val Ile Asn
50 55 60
Asp Arg Tyr Asp Met Leu Asn Ile Ser Ser Leu Arg Gln Asp Gly Lys
65 70 75 80
Thr Phe Ile Asp Phe Lys Lys Tyr Asn Asp Lys Leu Pro Leu Tyr Ile
85 90 95
Ser Asn Pro Asn Tyr Lys Val Asn Val Tyr Ala Val Thr Lys Glu Asn
100 105 110
Thr Ile Ile Asn Pro Ser Glu Asn Gly Asp Thr Ser Thr Asn Gly Ile
115 120 125
Lys Lys Ile Leu Ile Phe Ser Lys Lys Gly Tyr Glu Ile Gly Ser Gly
130 135 140
Gly Ser Met Gly Ser Gln Pro Val Leu Thr Gln Ser Pro Ser Val Ser
145 150 155 160
Ala Ala Pro Arg Gln Arg Val Thr Ile Ser Val Ser Gly Ser Asn Ser
165 170 175
Asn Ile Gly Ser Asn Thr Val Asn Trp Ile Gln Gln Leu Pro Gly Arg
180 185 190
Ala Pro Glu Leu Leu Met Cys Asp Asp Asp Leu Leu Ala Pro Gly Val
195 200 205
Ser Asp Arg Phe Ser Gly Ser Arg Ser Gly Thr Ser Ala Ser Leu Thr
210 215 220
Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Ala Ala Thr
225 230 235 240
Trp Asp Asp Ser Leu Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Val
245 250 255
Thr Val Leu Ser Ala Leu Glu His His His His His His
260 265
<210> 16
<211> 810
<212> DNA
<213> Artificial Sequence
<220>
<223> PA-VL12.3cys
<400> 16
atgggctttc attatgatag aaataacata gcagttgggg cggatgagtc agtagttaag 60
gaggctcata gagaagtaat taattcgtca acagagggat tattgttaaa tattgataag 120
gatataagaa aaatattatc aggttatatt gtagaaattg aagatactga agggcttaaa 180
gaagttataa atgacagata tgatatgttg aatatttcta gtttacggca agatggaaaa 240
acatttatag attttaaaaa atataatgat aaattaccgt tatatataag taatcccaat 300
tataaggtaa atgtatatgc tgttactaaa gaaaacacta ttattaatcc tagtgagaat 360
ggggatacta gtaccaacgg gatcaagaaa attttaatct tttctaaaaa aggctatgag 420
ataggatccg gtggtagcat gggtagtcaa ccagtactta cacaaagccc gtctgtgtct 480
gccgctccac gtcagagagt caccatctca gttagtggtt ctaattcaaa tataggatcg 540
aacacagtga actggattca gcagttgcct ggccgtgccc cggagttatt aatgtgtgat 600
gatgatttat tagcacccgg agtatcagat cgcttttcag gaagccgtag tggcactagt 660
gcgtccttaa ccattagcgg gttacagtct gaagacgaag cggactatta cgcagctacg 720
tgggatgata gtttaaatgg ctgggttttt ggtggtggta ctaaagttac ggtgctgtcc 780
gcactcgagc accaccacca ccaccactga 810
<210> 17
<211> 634
<212> PRT
<213> Artificial Sequence
<220>
<223> full-length FliC(N)-VL12.3cys
<400> 17
Met Gly Ser Ser His His His His His His Ser Ser Gly Leu Val Pro
1 5 10 15
Arg Gly Ser His Met Gly Ser Gln Pro Val Leu Thr Gln Ser Pro Ser
20 25 30
Val Ser Ala Ala Pro Arg Gln Arg Val Thr Ile Ser Val Ser Gly Ser
35 40 45
Asn Ser Asn Ile Gly Ser Asn Thr Val Asn Trp Ile Gln Gln Leu Pro
50 55 60
Gly Arg Ala Pro Glu Leu Leu Met Cys Asp Asp Asp Leu Leu Ala Pro
65 70 75 80
Gly Val Ser Asp Arg Phe Ser Gly Ser Arg Ser Gly Thr Ser Ala Ser
85 90 95
Leu Thr Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Ala
100 105 110
Ala Thr Trp Asp Asp Ser Leu Asn Gly Trp Val Phe Gly Gly Gly Thr
115 120 125
Lys Val Thr Val Leu Ser Ala Gly Gly Ser Ala Met Ala Gln Val Ile
130 135 140
Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn Asn Leu Asn Lys Ser
145 150 155 160
Gln Ser Ala Leu Gly Thr Ala Ile Glu Arg Leu Ser Ser Gly Cys Arg
165 170 175
Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln Ala Ile Ala Asn Arg
180 185 190
Phe Thr Ala Asn Ile Lys Gly Leu Thr Gln Ala Ser Arg Asn Ala Asn
195 200 205
Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly Ala Leu Asn Glu Ile
210 215 220
Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ala Val Gln Ser Ala Asn
225 230 235 240
Ser Thr Asn Ser Gln Ser Asp Leu Asp Ser Ile Gln Ala Glu Ile Thr
245 250 255
Gln Arg Leu Asn Glu Ile Asp Arg Val Ser Gly Gln Thr Gln Phe Asn
260 265 270
Gly Val Lys Val Leu Ala Gln Asp Asn Thr Leu Thr Ile Gln Val Gly
275 280 285
Ala Asn Asp Gly Glu Thr Ile Asp Ile Asp Leu Lys Gln Ile Asn Ser
290 295 300
Gln Thr Leu Gly Leu Asp Thr Leu Asn Val Gln Gln Lys Tyr Lys Val
305 310 315 320
Ser Asp Thr Ala Ala Thr Val Thr Gly Tyr Ala Asp Thr Thr Ile Ala
325 330 335
Leu Asp Asn Ser Thr Phe Lys Ala Ser Ala Thr Gly Leu Gly Gly Thr
340 345 350
Asp Gln Lys Ile Asp Gly Asp Leu Lys Phe Asp Asp Thr Thr Gly Lys
355 360 365
Tyr Tyr Ala Lys Val Thr Val Thr Gly Gly Thr Gly Lys Asp Gly Tyr
370 375 380
Tyr Glu Val Ser Val Asp Lys Thr Asn Gly Glu Val Thr Leu Ala Gly
385 390 395 400
Gly Ala Thr Ser Pro Leu Thr Gly Gly Leu Pro Ala Thr Ala Thr Glu
405 410 415
Asp Val Lys Asn Val Gln Val Ala Asn Ala Asp Leu Thr Glu Ala Lys
420 425 430
Ala Ala Leu Thr Ala Ala Gly Val Thr Gly Thr Ala Ser Val Val Lys
435 440 445
Met Ser Tyr Thr Asp Asn Asn Gly Lys Thr Ile Asp Gly Gly Leu Ala
450 455 460
Val Lys Val Gly Asp Asp Tyr Tyr Ser Ala Thr Gln Asn Lys Asp Gly
465 470 475 480
Ser Ile Ser Ile Asn Thr Thr Lys Tyr Thr Ala Asp Asp Gly Thr Ser
485 490 495
Lys Thr Ala Leu Asn Lys Leu Gly Gly Ala Asp Gly Lys Thr Glu Val
500 505 510
Val Ser Ile Gly Gly Lys Thr Tyr Ala Ala Ser Lys Ala Glu Gly His
515 520 525
Asn Phe Lys Ala Gln Pro Asp Leu Ala Glu Ala Ala Ala Thr Thr Thr
530 535 540
Glu Asn Pro Leu Gln Lys Ile Asp Ala Ala Leu Ala Gln Val Asp Thr
545 550 555 560
Leu Arg Ser Asp Leu Gly Ala Val Gln Asn Arg Phe Asn Ser Ala Ile
565 570 575
Thr Asn Leu Gly Asn Thr Val Asn Asn Leu Thr Ser Ala Arg Ser Arg
580 585 590
Ile Glu Cys Ser Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Arg Ala
595 600 605
Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln
610 615 620
Val Pro Gln Asn Val Leu Ser Leu Leu Arg
625 630
<210> 18
<211> 1845
<212> DNA
<213> Artificial Sequence
<220>
<223> full-length FliC(N)-VL12.3cys
<400> 18
atgggtagtc aaccagtact tacacaaagc ccgtctgtgt ctgccgctcc acgtcagaga 60
gtcaccatct cagttagtgg ttctaattca aatataggat cgaacacagt gaactggatt 120
cagcagttgc ctggccgtgc cccggagtta ttaatgtgtg atgatgattt attagcaccc 180
ggagtatcag atcgcttttc aggaagccgt agtggcacta gtgcgtcctt aaccattagc 240
gggttacagt ctgaagacga agcggactat tacgcagcta cgtgggatga tagtttaaat 300
ggctgggttt ttggtggtgg tactaaagtt acggtgctgt ccgcaggtgg tagcgccatg 360
gcacaagtca ttaataccaa cagcctgtcg ctgttgaccc agaataacct gaacaaatcc 420
cagtccgctc tgggcaccgc tatcgagcgt ctgtcttcct gcctgcgtat caacagcgcg 480
aaagacgatg cggcaggtca ggcgattgct aaccgtttta ccgcgaacat caaaggtctg 540
actcaggctt cccgtaacgc taacgacggt atctccattg cgcagaccac tgaaggcgcg 600
ctgaacgaaa tcaacaacaa cctgcagcgt gtgcgtgaac tggcggttca gtctgctaac 660
agcaccaact cccagtctga cctcgactcc atccaggctg aaatcaccca gcgcctgaac 720
gaaatcgacc gtgtatccgg ccagactcag ttcaacggcg tgaaagtcct ggcgcaggac 780
aacaccctga ccatccaggt tggtgccaac gacggtgaaa ctatcgatat cgatctgaag 840
cagatcaact ctcagaccct gggtctggat acgctgaatg tgcaacaaaa atataaggtc 900
agcgatacgg ctgcaactgt tacaggatat gccgatacta cgattgcttt agacaatagt 960
acttttaaag cctcggctac tggtcttggt ggtactgacc agaaaattga tggcgattta 1020
aaatttgatg atacgactgg aaaatattac gccaaagtta ccgttacggg gggaactggt 1080
aaagatggct attatgaagt ttccgttgat aagacgaacg gtgaggtgac tcttgctggc 1140
ggtgcgactt ccccgcttac aggtggacta cctgcgacag caactgagga tgtgaaaaat 1200
gtacaagttg caaatgctga tttgacagag gctaaagccg cattgacagc agcaggtgtt 1260
accggcacag catctgttgt taagatgtct tatactgata ataacggtaa aactattgat 1320
ggtggtttag cagttaaggt aggcgatgat tactattctg caactcaaaa taaagatggt 1380
tccataagta ttaatactac gaaatacact gcagatgacg gtacatccaa aactgcacta 1440
aacaaactgg gtggcgcaga cggcaaaacc gaagttgttt ctattggtgg taaaacttac 1500
gctgcaagta aagccgaagg tcacaacttt aaagcacagc ctgatctggc ggaagcggct 1560
gctacaacca ccgaaaaccc gctgcagaaa attgatgctg ctttggcaca ggttgacacg 1620
ttacgttctg acctgggtgc ggtacagaac cgtttcaact ccgctattac caacctgggc 1680
aacaccgtaa acaacctgac ttctgcccgt agccgtatcg aatgctccga ctacgcgacc 1740
gaagtttcca acatgtctcg cgcgcagatt ctgcagcagg ccggtacctc cgttctggcg 1800
caggcgaacc aggttccgca aaacgtcctc tctttactgc gttga 1845
<210> 19
<211> 527
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated FliC(N)-VL12.3cys
<400> 19
Met Gly Ser Gln Pro Val Leu Thr Gln Ser Pro Ser Val Ser Ala Ala
1 5 10 15
Pro Arg Gln Arg Val Thr Ile Ser Val Ser Gly Ser Asn Ser Asn Ile
20 25 30
Gly Ser Asn Thr Val Asn Trp Ile Gln Gln Leu Pro Gly Arg Ala Pro
35 40 45
Glu Leu Leu Met Cys Asp Asp Asp Leu Leu Ala Pro Gly Val Ser Asp
50 55 60
Arg Phe Ser Gly Ser Arg Ser Gly Thr Ser Ala Ser Leu Thr Ile Ser
65 70 75 80
Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Ala Ala Thr Trp Asp
85 90 95
Asp Ser Leu Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val
100 105 110
Leu Ser Ala Gly Gly Ser Ala Met Gly Phe Thr Ala Asn Ile Lys Gly
115 120 125
Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln
130 135 140
Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val
145 150 155 160
Arg Glu Leu Ala Val Gln Ser Ala Asn Ser Thr Asn Ser Gln Ser Asp
165 170 175
Leu Asp Ser Ile Gln Ala Glu Ile Thr Gln Arg Leu Asn Glu Ile Asp
180 185 190
Arg Val Ser Gly Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ala Gln
195 200 205
Asp Asn Thr Leu Thr Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile
210 215 220
Asp Ile Asp Leu Lys Gln Ile Asn Ser Gln Thr Leu Gly Leu Asp Thr
225 230 235 240
Leu Asn Val Gln Gln Lys Tyr Lys Val Ser Asp Thr Ala Ala Thr Val
245 250 255
Thr Gly Tyr Ala Asp Thr Thr Ile Ala Leu Asp Asn Ser Thr Phe Lys
260 265 270
Ala Ser Ala Thr Gly Leu Gly Gly Thr Asp Gln Lys Ile Asp Gly Asp
275 280 285
Leu Lys Phe Asp Asp Thr Thr Gly Lys Tyr Tyr Ala Lys Val Thr Val
290 295 300
Thr Gly Gly Thr Gly Lys Asp Gly Tyr Tyr Glu Val Ser Val Asp Lys
305 310 315 320
Thr Asn Gly Glu Val Thr Leu Ala Gly Gly Ala Thr Ser Pro Leu Thr
325 330 335
Gly Gly Leu Pro Ala Thr Ala Thr Glu Asp Val Lys Asn Val Gln Val
340 345 350
Ala Asn Ala Asp Leu Thr Glu Ala Lys Ala Ala Leu Thr Ala Ala Gly
355 360 365
Val Thr Gly Thr Ala Ser Val Val Lys Met Ser Tyr Thr Asp Asn Asn
370 375 380
Gly Lys Thr Ile Asp Gly Gly Leu Ala Val Lys Val Gly Asp Asp Tyr
385 390 395 400
Tyr Ser Ala Thr Gln Asn Lys Asp Gly Ser Ile Ser Ile Asn Thr Thr
405 410 415
Lys Tyr Thr Ala Asp Asp Gly Thr Ser Lys Thr Ala Leu Asn Lys Leu
420 425 430
Gly Gly Ala Asp Gly Lys Thr Glu Val Val Ser Ile Gly Gly Lys Thr
435 440 445
Tyr Ala Ala Ser Lys Ala Glu Gly His Asn Phe Lys Ala Gln Pro Asp
450 455 460
Leu Ala Glu Ala Ala Ala Thr Thr Thr Glu Asn Pro Leu Gln Lys Ile
465 470 475 480
Asp Ala Ala Leu Ala Gln Val Asp Thr Leu Arg Ser Asp Leu Gly Ala
485 490 495
Val Gln Asn Arg Phe Asn Ser Ala Ile Thr Asn Leu Gly Asn Thr Val
500 505 510
Asn Asn Leu Thr Ser Ala Arg Leu Glu His His His His His His
515 520 525
<210> 20
<211> 1584
<212> DNA
<213> Artificial Sequence
<220>
<223> truncated FliC(N)-VL12.3cys
<400> 20
atgggtagtc aaccagtact tacacaaagc ccgtctgtgt ctgccgctcc acgtcagaga 60
gtcaccatct cagttagtgg ttctaattca aatataggat cgaacacagt gaactggatt 120
cagcagttgc ctggccgtgc cccggagtta ttaatgtgtg atgatgattt attagcaccc 180
ggagtatcag atcgcttttc aggaagccgt agtggcacta gtgcgtcctt aaccattagc 240
gggttacagt ctgaagacga agcggactat tacgcagcta cgtgggatga tagtttaaat 300
ggctgggttt ttggtggtgg tactaaagtt acggtgctgt ccgcaggtgg tagcgccatg 360
ggctttaccg cgaacatcaa aggtctgact caggcttccc gtaacgctaa cgacggtatc 420
tccattgcgc agaccactga aggcgcgctg aacgaaatca acaacaacct gcagcgtgtg 480
cgtgaactgg cggttcagtc tgctaacagc accaactccc agtctgacct cgactccatc 540
caggctgaaa tcacccagcg cctgaacgaa atcgaccgtg tatccggcca gactcagttc 600
aacggcgtga aagtcctggc gcaggacaac accctgacca tccaggttgg tgccaacgac 660
ggtgaaacta tcgatatcga tctgaagcag atcaactctc agaccctggg tctggatacg 720
ctgaatgtgc aacaaaaata taaggtcagc gatacggctg caactgttac aggatatgcc 780
gatactacga ttgctttaga caatagtact tttaaagcct cggctactgg tcttggtggt 840
actgaccaga aaattgatgg cgatttaaaa tttgatgata cgactggaaa atattacgcc 900
aaagttaccg ttacgggggg aactggtaaa gatggctatt atgaagtttc cgttgataag 960
acgaacggtg aggtgactct tgctggcggt gcgacttccc cgcttacagg tggactacct 1020
gcgacagcaa ctgaggatgt gaaaaatgta caagttgcaa atgctgattt gacagaggct 1080
aaagccgcat tgacagcagc aggtgttacc ggcacagcat ctgttgttaa gatgtcttat 1140
actgataata acggtaaaac tattgatggt ggtttagcag ttaaggtagg cgatgattac 1200
tattctgcaa ctcaaaataa agatggttcc ataagtatta atactacgaa atacactgca 1260
gatgacggta catccaaaac tgcactaaac aaactgggtg gcgcagacgg caaaaccgaa 1320
gttgtttcta ttggtggtaa aacttacgct gcaagtaaag ccgaaggtca caactttaaa 1380
gcacagcctg atctggcgga agcggctgct acaaccaccg aaaacccgct gcagaaaatt 1440
gatgctgctt tggcacaggt tgacacgtta cgttctgacc tgggtgcggt acagaaccgt 1500
ttcaactccg ctattaccaa cctgggcaac accgtaaaca acctgacttc tgcccgtctc 1560
gagcaccacc accaccacca ctga 1584
<210> 21
<211> 528
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated FliC(C)-VL12.3cys
<400> 21
Met Gly Phe Thr Ala Asn Ile Lys Gly Leu Thr Gln Ala Ser Arg Asn
1 5 10 15
Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly Ala Leu Asn
20 25 30
Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ala Val Gln Ser
35 40 45
Ala Asn Ser Thr Asn Ser Gln Ser Asp Leu Asp Ser Ile Gln Ala Glu
50 55 60
Ile Thr Gln Arg Leu Asn Glu Ile Asp Arg Val Ser Gly Gln Thr Gln
65 70 75 80
Phe Asn Gly Val Lys Val Leu Ala Gln Asp Asn Thr Leu Thr Ile Gln
85 90 95
Val Gly Ala Asn Asp Gly Glu Thr Ile Asp Ile Asp Leu Lys Gln Ile
100 105 110
Asn Ser Gln Thr Leu Gly Leu Asp Thr Leu Asn Val Gln Gln Lys Tyr
115 120 125
Lys Val Ser Asp Thr Ala Ala Thr Val Thr Gly Tyr Ala Asp Thr Thr
130 135 140
Ile Ala Leu Asp Asn Ser Thr Phe Lys Ala Ser Ala Thr Gly Leu Gly
145 150 155 160
Gly Thr Asp Gln Lys Ile Asp Gly Asp Leu Lys Phe Asp Asp Thr Thr
165 170 175
Gly Lys Tyr Tyr Ala Lys Val Thr Val Thr Gly Gly Thr Gly Lys Asp
180 185 190
Gly Tyr Tyr Glu Val Ser Val Asp Lys Thr Asn Gly Glu Val Thr Leu
195 200 205
Ala Gly Gly Ala Thr Ser Pro Leu Thr Gly Gly Leu Pro Ala Thr Ala
210 215 220
Thr Glu Asp Val Lys Asn Val Gln Val Ala Asn Ala Asp Leu Thr Glu
225 230 235 240
Ala Lys Ala Ala Leu Thr Ala Ala Gly Val Thr Gly Thr Ala Ser Val
245 250 255
Val Lys Met Ser Tyr Thr Asp Asn Asn Gly Lys Thr Ile Asp Gly Gly
260 265 270
Leu Ala Val Lys Val Gly Asp Asp Tyr Tyr Ser Ala Thr Gln Asn Lys
275 280 285
Asp Gly Ser Ile Ser Ile Asn Thr Thr Lys Tyr Thr Ala Asp Asp Gly
290 295 300
Thr Ser Lys Thr Ala Leu Asn Lys Leu Gly Gly Ala Asp Gly Lys Thr
305 310 315 320
Glu Val Val Ser Ile Gly Gly Lys Thr Tyr Ala Ala Ser Lys Ala Glu
325 330 335
Gly His Asn Phe Lys Ala Gln Pro Asp Leu Ala Glu Ala Ala Ala Thr
340 345 350
Thr Thr Glu Asn Pro Leu Gln Lys Ile Asp Ala Ala Leu Ala Gln Val
355 360 365
Asp Thr Leu Arg Ser Asp Leu Gly Ala Val Gln Asn Arg Phe Asn Ser
370 375 380
Ala Ile Thr Asn Leu Gly Asn Thr Val Asn Asn Leu Thr Ser Ala Arg
385 390 395 400
Leu Glu Gly Gly Ser Met Gly Ser Gln Pro Val Leu Thr Gln Ser Pro
405 410 415
Ser Val Ser Ala Ala Pro Arg Gln Arg Val Thr Ile Ser Val Ser Gly
420 425 430
Ser Asn Ser Asn Ile Gly Ser Asn Thr Val Asn Trp Ile Gln Gln Leu
435 440 445
Pro Gly Arg Ala Pro Glu Leu Leu Met Cys Asp Asp Asp Leu Leu Ala
450 455 460
Pro Gly Val Ser Asp Arg Phe Ser Gly Ser Arg Ser Gly Thr Ser Ala
465 470 475 480
Ser Leu Thr Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr
485 490 495
Ala Ala Thr Trp Asp Asp Ser Leu Asn Gly Trp Val Phe Gly Gly Gly
500 505 510
Thr Lys Val Thr Val Leu Ser Ala Leu Glu His His His His His His
515 520 525
<210> 22
<211> 1587
<212> DNA
<213> Artificial Sequence
<220>
<223> truncated FliC(C)-VL12.3cys
<400> 22
atgggcttta ccgcgaacat caaaggtctg actcaggctt cccgtaacgc taacgacggt 60
atctccattg cgcagaccac tgaaggcgcg ctgaacgaaa tcaacaacaa cctgcagcgt 120
gtgcgtgaac tggcggttca gtctgctaac agcaccaact cccagtctga cctcgactcc 180
atccaggctg aaatcaccca gcgcctgaac gaaatcgacc gtgtatccgg ccagactcag 240
ttcaacggcg tgaaagtcct ggcgcaggac aacaccctga ccatccaggt tggtgccaac 300
gacggtgaaa ctatcgatat cgatctgaag cagatcaact ctcagaccct gggtctggat 360
acgctgaatg tgcaacaaaa atataaggtc agcgatacgg ctgcaactgt tacaggatat 420
gccgatacta cgattgcttt agacaatagt acttttaaag cctcggctac tggtcttggt 480
ggtactgacc agaaaattga tggcgattta aaatttgatg atacgactgg aaaatattac 540
gccaaagtta ccgttacggg gggaactggt aaagatggct attatgaagt ttccgttgat 600
aagacgaacg gtgaggtgac tcttgctggc ggtgcgactt ccccgcttac aggtggacta 660
cctgcgacag caactgagga tgtgaaaaat gtacaagttg caaatgctga tttgacagag 720
gctaaagccg cattgacagc agcaggtgtt accggcacag catctgttgt taagatgtct 780
tatactgata ataacggtaa aactattgat ggtggtttag cagttaaggt aggcgatgat 840
tactattctg caactcaaaa taaagatggt tccataagta ttaatactac gaaatacact 900
gcagatgacg gtacatccaa aactgcacta aacaaactgg gtggcgcaga cggcaaaacc 960
gaagttgttt ctattggtgg taaaacttac gctgcaagta aagccgaagg tcacaacttt 1020
aaagcacagc ctgatctggc ggaagcggct gctacaacca ccgaaaaccc gctgcagaaa 1080
attgatgctg ctttggcaca ggttgacacg ttacgttctg acctgggtgc ggtacagaac 1140
cgtttcaact ccgctattac caacctgggc aacaccgtaa acaacctgac ttctgcccgt 1200
ctcgagggtg gtagcatggg tagtcaacca gtacttacac aaagcccgtc tgtgtctgcc 1260
gctccacgtc agagagtcac catctcagtt agtggttcta attcaaatat aggatcgaac 1320
acagtgaact ggattcagca gttgcctggc cgtgccccgg agttattaat gtgtgatgat 1380
gatttattag cacccggagt atcagatcgc ttttcaggaa gccgtagtgg cactagtgcg 1440
tccttaacca ttagcgggtt acagtctgaa gacgaagcgg actattacgc agctacgtgg 1500
gatgatagtt taaatggctg ggtttttggt ggtggtacta aagttacggt gctgtccgca 1560
ctcgagcacc accaccacca ccactga 1587
<210> 23
<211> 542
<212> PRT
<213> Artificial Sequence
<220>
<223> truncated FliC(I)-VL12.3cys
<400> 23
Met Gly Phe Thr Ala Asn Ile Lys Gly Leu Thr Gln Ala Ser Arg Asn
1 5 10 15
Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly Ala Leu Asn
20 25 30
Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ala Val Gln Ser
35 40 45
Ala Asn Ser Thr Asn Ser Gln Ser Asp Leu Asp Ser Ile Gln Ala Glu
50 55 60
Ile Thr Gln Arg Leu Asn Glu Ile Asp Arg Val Ser Gly Gln Thr Gln
65 70 75 80
Phe Asn Gly Val Lys Val Leu Ala Gln Asp Asn Thr Leu Thr Ile Gln
85 90 95
Val Gly Ala Asn Asp Gly Glu Thr Ile Asp Ile Asp Leu Lys Gln Ile
100 105 110
Asn Ser Gln Thr Leu Gly Leu Asp Thr Leu Asn Val Gln Gln Lys Tyr
115 120 125
Lys Val Ser Asp Thr Ala Ala Thr Val Thr Gly Tyr Ala Asp Thr Thr
130 135 140
Ile Ala Leu Asp Asn Ser Thr Phe Lys Ala Ser Ala Thr Gly Leu Gly
145 150 155 160
Gly Thr Asp Gln Lys Ile Asp Gly Asp Leu Lys Phe Asp Asp Thr Thr
165 170 175
Gly Lys Tyr Tyr Ala Lys Val Thr Val Thr Gly Gly Ser Gly Gly Ser
180 185 190
Met Gly Ser Gln Pro Val Leu Thr Gln Ser Pro Ser Val Ser Ala Ala
195 200 205
Pro Arg Gln Arg Val Thr Ile Ser Val Ser Gly Ser Asn Ser Asn Ile
210 215 220
Gly Ser Asn Thr Val Asn Trp Ile Gln Gln Leu Pro Gly Arg Ala Pro
225 230 235 240
Glu Leu Leu Met Cys Asp Asp Asp Leu Leu Ala Pro Gly Val Ser Asp
245 250 255
Arg Phe Ser Gly Ser Arg Ser Gly Thr Ser Ala Ser Leu Thr Ile Ser
260 265 270
Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Ala Ala Thr Trp Asp
275 280 285
Asp Ser Leu Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val
290 295 300
Leu Ser Ala Gly His Met Leu Val Pro Arg Gly Ser Gly Gly Ser Val
305 310 315 320
Asp Gly Thr Gly Lys Asp Gly Tyr Tyr Glu Val Ser Val Asp Lys Thr
325 330 335
Asn Gly Glu Val Thr Leu Ala Gly Gly Ala Thr Ser Pro Leu Thr Gly
340 345 350
Gly Leu Pro Ala Thr Ala Thr Glu Asp Val Lys Asn Val Gln Val Ala
355 360 365
Asn Ala Asp Leu Thr Glu Ala Lys Ala Ala Leu Thr Ala Ala Gly Val
370 375 380
Thr Gly Thr Ala Ser Val Val Lys Met Ser Tyr Thr Asp Asn Asn Gly
385 390 395 400
Lys Thr Ile Asp Gly Gly Leu Ala Val Lys Val Gly Asp Asp Tyr Tyr
405 410 415
Ser Ala Thr Gln Asn Lys Asp Gly Ser Ile Ser Ile Asn Thr Thr Lys
420 425 430
Tyr Thr Ala Asp Asp Gly Thr Ser Lys Thr Ala Leu Asn Lys Leu Gly
435 440 445
Gly Ala Asp Gly Lys Thr Glu Val Val Ser Ile Gly Gly Lys Thr Tyr
450 455 460
Ala Ala Ser Lys Ala Glu Gly His Asn Phe Lys Ala Gln Pro Asp Leu
465 470 475 480
Ala Glu Ala Ala Ala Thr Thr Thr Glu Asn Pro Leu Gln Lys Ile Asp
485 490 495
Ala Ala Leu Ala Gln Val Asp Thr Leu Arg Ser Asp Leu Gly Ala Val
500 505 510
Gln Asn Arg Phe Asn Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Asn
515 520 525
Asn Leu Thr Ser Ala Arg Leu Glu His His His His His His
530 535 540
<210> 24
<211> 1629
<212> DNA
<213> Artificial Sequence
<220>
<223> truncated FliC(I)-VL12.3cys
<400> 24
atgggcttta ccgcgaacat caaaggtctg actcaggctt cccgtaacgc taacgacggt 60
atctccattg cgcagaccac tgaaggcgcg ctgaacgaaa tcaacaacaa cctgcagcgt 120
gtgcgtgaac tggcggttca gtctgctaac agcaccaact cccagtctga cctcgactcc 180
atccaggctg aaatcaccca gcgcctgaac gaaatcgacc gtgtatccgg ccagactcag 240
ttcaacggcg tgaaagtcct ggcgcaggac aacaccctga ccatccaggt tggtgccaac 300
gacggtgaaa ctatcgatat cgatctgaag cagatcaact ctcagaccct gggtctggat 360
acgctgaatg tgcaacaaaa atataaggtc agcgatacgg ctgcaactgt tacaggatat 420
gccgatacta cgattgcttt agacaatagt acttttaaag cctcggctac tggtcttggt 480
ggtactgacc agaaaattga tggcgattta aaatttgatg atacgactgg aaaatattac 540
gccaaagtta ccgttacggg gggatccggt ggtagcatgg gtagtcaacc agtacttaca 600
caaagcccgt ctgtgtctgc cgctccacgt cagagagtca ccatctcagt tagtggttct 660
aattcaaata taggatcgaa cacagtgaac tggattcagc agttgcctgg ccgtgccccg 720
gagttattaa tgtgtgatga tgatttatta gcacccggag tatcagatcg cttttcagga 780
agccgtagtg gcactagtgc gtccttaacc attagcgggt tacagtctga agacgaagcg 840
gactattacg cagctacgtg ggatgatagt ttaaatggct gggtttttgg tggtggtact 900
aaagttacgg tgctgtccgc aggtcatatg ctggtgccgc gcggcagcgg tggtagcgtc 960
gacggaactg gtaaagatgg ctattatgaa gtttccgttg ataagacgaa cggtgaggtg 1020
actcttgctg gcggtgcgac ttccccgctt acaggtggac tacctgcgac agcaactgag 1080
gatgtgaaaa atgtacaagt tgcaaatgct gatttgacag aggctaaagc cgcattgaca 1140
gcagcaggtg ttaccggcac agcatctgtt gttaagatgt cttatactga taataacggt 1200
aaaactattg atggtggttt agcagttaag gtaggcgatg attactattc tgcaactcaa 1260
aataaagatg gttccataag tattaatact acgaaataca ctgcagatga cggtacatcc 1320
aaaactgcac taaacaaact gggtggcgca gacggcaaaa ccgaagttgt ttctattggt 1380
ggtaaaactt acgctgcaag taaagccgaa ggtcacaact ttaaagcaca gcctgatctg 1440
gcggaagcgg ctgctacaac caccgaaaac ccgctgcaga aaattgatgc tgctttggca 1500
caggttgaca cgttacgttc tgacctgggt gcggtacaga accgtttcaa ctccgctatt 1560
accaacctgg gcaacaccgt aaacaacctg acttctgccc gtctcgagca ccaccaccac 1620
caccactga 1629
<210> 25
<211> 34
<212> DNA
<213> Artificial Sequence
<220>
<223> HTTcys Forward primer
<400> 25
atcatccatg ggcgaaaagc tgatgaagtg tttc 34
<210> 26
<211> 32
<212> DNA
<213> Artificial Sequence
<220>
<223> HTTcys Reverse primer
<400> 26
atcactctag aaccaccctg gaaggacttg ag 32
<210> 27
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> Ftn Forward primer
<400> 27
tgcggtctag aatgctgaaa ccagaaatga ttgaa 35
<210> 28
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> Ftn Reverse primer
<400> 28
aggccagcca ctcgagacta gttcattagt tttgtgtgtc 40
<210> 29
<211> 47
<212> DNA
<213> Artificial Sequence
<220>
<223> HTTcys-I3-01 Forward primer
<400> 29
attatcatat gcatcatcat catcatcacg gtggaagcgg tggaagc 47
<210> 30
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> HTTcys-I3-01 Reverse primer
<400> 30
tgcgcctcga gctattattc ggtgcagcca cgaatc 36
<210> 31
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> HA-VL12.3cys Forward primer
<400> 31
aggcctctag aagcatgggt agtcaaccag tactt 35
<210> 32
<211> 42
<212> DNA
<213> Artificial Sequence
<220>
<223> HA-VL12.3cys Reverse primer
<400> 32
gtgatgatga tgatgatggc tactgcctgc ggacagcacc gt 42
<210> 33
<211> 34
<212> DNA
<213> Artificial Sequence
<220>
<223> PA-VL12.3cys Forward primer
<400> 33
aagagccatg ggctttcatt atgatagaaa taac 34
<210> 34
<211> 33
<212> DNA
<213> Artificial Sequence
<220>
<223> PA-VL12.3cys Reverse primer
<400> 34
agcatctcga gtgcggacag caccgtaact tta 33
<210> 35
<211> 41
<212> DNA
<213> Artificial Sequence
<220>
<223> FliC(N)-VL12.3cys Forward primer
<400> 35
agcggcatat gggtagtcaa ccagtactta cacaaagccc g 41
<210> 36
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> FliC(N)-VL12.3cys Reverse primer
<400> 36
attatgcggc cgctcaacgc agtaaagaga ggacg 35
<210> 37
<211> 33
<212> DNA
<213> Artificial Sequence
<220>
<223> truncated FliC(N)-VL12.3cys Forward primer
<400> 37
actggtggta ccatgggtag tcaaccagta ctt 33
<210> 38
<211> 32
<212> DNA
<213> Artificial Sequence
<220>
<223> truncated FliC(N)-VL12.3cys Reverse primer
<400> 38
agttactcga gacgggcaga agtcaggttg tt 32
<210> 39
<211> 34
<212> DNA
<213> Artificial Sequence
<220>
<223> truncated FliC(C)-VL12.3cys Forward primer
<400> 39
ataatccatg ggctttaccg cgaacatcaa aggt 34
<210> 40
<211> 29
<212> DNA
<213> Artificial Sequence
<220>
<223> truncated FliC(C)-VL12.3cys Reverse primer
<400> 40
agcatctcga gtgcggacag caccgtaac 29
<210> 41
<211> 34
<212> DNA
<213> Artificial Sequence
<220>
<223> truncated FliC(I)-VL12.3cys Forward primer
<400> 41
ataatccatg ggctttaccg cgaacatcaa aggt 34
<210> 42
<211> 32
<212> DNA
<213> Artificial Sequence
<220>
<223> truncated FliC(I)-VL12.3cys Reverse primer
<400> 42
agttactcga gacgggcaga agtcaggttg tt 32
Claims (11)
- 서열번호 3의 아미노산 서열로 구성되는 HTTcys 펩타이드 및 페리틴 단량체의 융합 단백질 24개의 자가조립체;
서열번호 5의 아미노산 서열로 구성되는 VL12.3cys 펩타이드 및 이를 N-말단 또는 C-말단에 융합하거나 내부에 삽입할 수 있는 항원 펩타이드가 융합된 융합 단백질; 및
상기 VL12.3cys 펩타이드 및 이를 N-말단 또는 C-말단에 융합하거나 내부에 삽입할 수 있는 면역 증강 펩타이드의 융합 단백질을 포함하는 나노 입자로서,
상기 항원 펩타이드 및 면역 증강 펩타이드는 상기 HTTcys 펩타이드와 VL12.3cys 펩타이드 간의 결합에 의해 페리틴 자가조립체와 연결된 것인, 나노 입자.
- 삭제
- 삭제
- 제1항에 있어서,
상기 HTTcys 펩타이드와 VL12.3cys 펩타이드 간의 결합은 항원-항체 결합 및 이황화 결합을 포함하는, 나노 입자.
- 삭제
- 제1항에 있어서,
상기 HTTcys 펩타이드는 페리틴 단량체의 N-말단에 융합된 것인, 나노 입자.
- 삭제
- 제1항에 있어서,
상기 나노 입자 내의 항원 펩타이드와 면역 증강 펩타이드의 몰비는 0.1~10 : 1인, 나노 입자.
- 제1항의 나노 입자를 포함하는, 백신 조성물.
- 제9항에 있어서,
상기 백신은 총 IgG 수치를 증가시키는 것인, 백신 조성물.
- 제9항에 있어서,
상기 백신은 세포성 면역 및 체액성 면역을 증진시키는 것인, 백신 조성물.
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PCT/KR2018/015938 WO2019194393A1 (ko) | 2018-04-02 | 2018-12-14 | 페리틴 자가조립체에 항원 펩타이드 및 면역 증강제가 결합된 나노 입자 및 이의 용도 |
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KR101630858B1 (ko) | 2014-01-24 | 2016-06-15 | 울산과학기술원 | 항원 펩타이드-페리틴 융합단백질 및 이를 포함하는 백신 조성물 |
KR101831483B1 (ko) | 2014-06-17 | 2018-02-23 | 이화여자대학교 산학협력단 | Mhc-페리틴 결합체, 이를 포함하는 나노파티클 및 이의 용도 |
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KR101831483B1 (ko) | 2014-06-17 | 2018-02-23 | 이화여자대학교 산학협력단 | Mhc-페리틴 결합체, 이를 포함하는 나노파티클 및 이의 용도 |
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