KR20230012100A - 수막구균 백신 - Google Patents
수막구균 백신 Download PDFInfo
- Publication number
- KR20230012100A KR20230012100A KR1020237001115A KR20237001115A KR20230012100A KR 20230012100 A KR20230012100 A KR 20230012100A KR 1020237001115 A KR1020237001115 A KR 1020237001115A KR 20237001115 A KR20237001115 A KR 20237001115A KR 20230012100 A KR20230012100 A KR 20230012100A
- Authority
- KR
- South Korea
- Prior art keywords
- gly
- ala
- lys
- leu
- asp
- Prior art date
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- 229960005486 vaccine Drugs 0.000 title description 28
- 101710186862 Factor H binding protein Proteins 0.000 claims abstract description 105
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 199
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 185
- 229920001184 polypeptide Polymers 0.000 claims description 184
- 239000000203 mixture Substances 0.000 claims description 95
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 57
- 230000004927 fusion Effects 0.000 claims description 51
- 230000002163 immunogen Effects 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 22
- 241000124008 Mammalia Species 0.000 claims description 19
- 239000012528 membrane Substances 0.000 claims description 18
- 230000027455 binding Effects 0.000 claims description 16
- 241000699670 Mus sp. Species 0.000 claims description 9
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims description 9
- 241000699666 Mus <mouse, genus> Species 0.000 claims description 8
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- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 claims description 4
- 230000001939 inductive effect Effects 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 208000034762 Meningococcal Infections Diseases 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 abstract description 23
- 102000004169 proteins and genes Human genes 0.000 abstract description 20
- 108700028369 Alleles Proteins 0.000 abstract description 2
- 229960005037 meningococcal vaccines Drugs 0.000 abstract description 2
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- 150000001413 amino acids Chemical class 0.000 description 66
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- 108010050848 glycylleucine Proteins 0.000 description 58
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Abstract
수막구균 백신은 fHbp의 다중 대립유전자 또는 변이체를 포함시켜, 이러한 단백질에 대해 알려진 다양성의 더 넓은 적용범위를 제공하고/거나, 각 용량에서 공지된 OMV 성분의 양을 감소시킴에 의해 개선될 수 있다.
Description
본 발명은 수막구균 백신화의 분야이다.
네이세리아 메닌지티디스(Neisseria meningitidis)는 인구의 약 10%의 상기도에 집락화된 그램-음성 캡슐화 박테리아이다. 컨쥬게이트 백신은 혈청군 A, C, W135 및 Y에 대해 이용가능하지만, 일반적으로 혈청군 B에 대한 보호에 이용가능한 유일한 백신은 2013년에 승인된 BEXSERO™ 제품이다. 이러한 제품은 4가지 주요 면역원성 성분을 포함한다: H 인자 결합 단백질, 'fHbp'; 헤파린 결합 단백질, NHBA; 네이세리아 부착소 A, NadA; 및 외막 소체 (OMV).
발명의 개요
본 발명의 양태는 (i) NHBA 폴리펩티드 (ii) NadA 폴리펩티드 및/또는 (iii) 수막구균 외막 소체 중 하나 이상과 함께, 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드를 포함하는 면역원성 조성물이다.
본 발명의 추가 양태는 (i) NHBA 폴리펩티드 (ii) NadA 폴리펩티드 및/또는 (iii) 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드 중 하나 이상과 함께, 수막구균 외막 소체를 포함하는 면역원성 조성물이고; 여기서 외막 소체 (OMV)는 5-30μg/ml의 농도로 존재한다. 특히, 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드는 안정화되고/거나 fHbp 비-결합 융합 폴리펩티드이다. 또한 보다 특히, v1 fHbp는 위치 R41에 돌연변이, 예를 들어 R41S 돌연변이를 포함한다. 여전히 또한 더욱 특히, v2 및 v3 fHbp 폴리펩티드는 전장 서열 (SEQ ID NO: 2 & 3)을 따라 및 또한 ΔG 서열 (SEQ ID NO: 8 & 9)을 따라 넘버링된 하기 위치에 하나 이상의 안정화 및/또는 H 인자 (fH) 비-결합 돌연변이를 포함한다:
본 발명의 추가 양태는 식 NH2-A-[-X-L]3-B-COOH의 아미노산 서열을 갖는 융합 폴리펩티드를 포함하는 면역원성 조성물이고, 상기 식에서 각 X는 상이한 변이체 fHbp 서열이고, L은 임의의 링커 아미노산 서열이고, A는 임의의 N-말단 아미노산 서열이고, B는 임의의 C-말단 아미노산 서열이다.
본 발명의 추가 양태는 본 발명에 따른 면역원성 조성물을 투여하는 것을 포함하는, 수막구균 감염에 대해 포유동물, 예컨대 인간을 보호하기 위한 방법이다.
도 1은 y-축 (0.0에서 1.0)이 비율이고 x-축 (0에서 256, 16 단계로)이 SBA 역가인 RCD 곡선을 도시한다. 맨 위 곡선은 그룹 C이고; 가장 빨리 0.0에 도달하는 그룹은 S이다.
도 2는 731 S 및 731 SNB 융합 단백질을 생산하기 위해 v1, v2 및 v3 fHbp 폴리펩티드에 도입된 안정화 및 H 인자 (fH) 비-결합 돌연변이의 도식을 제공한다.
도 3(a)-(g)는 741-231 융합체 (SEQ ID NO:10) 및 1/4OMV를 포함하는 조성물이 시험된 7개 균주 (3a=v2, 3b=v2, 3c=v3, 3d=v3, 3e=v2, 3f=v2, 3g=v3)에 대해 BEXSERO™보다 높은 GMT를 유도함을 나타낸다.
도 2는 731 S 및 731 SNB 융합 단백질을 생산하기 위해 v1, v2 및 v3 fHbp 폴리펩티드에 도입된 안정화 및 H 인자 (fH) 비-결합 돌연변이의 도식을 제공한다.
도 3(a)-(g)는 741-231 융합체 (SEQ ID NO:10) 및 1/4OMV를 포함하는 조성물이 시험된 7개 균주 (3a=v2, 3b=v2, 3c=v3, 3d=v3, 3e=v2, 3f=v2, 3g=v3)에 대해 BEXSERO™보다 높은 GMT를 유도함을 나타낸다.
상세한 설명
BEXSERO™ 제품을 개선시키기 위해 다양한 수막구균 균주에 대한 BEXSERO™의 적용범위를 추가로 향상시키고 (백신의 사용이 확산됨에 따라 잠재적인 변위 및 돌연변이의 발생시) 또한 백신이 통상적인 유아 백신과 함께 공동-투여될 때 가끔 나타나는 드문 발열을 감소시키는 것이 유리할 것이다[1]. 이러한 목표로 본 발명자들은 (i) 이러한 단백질에 대해 알려진 다양성의 더 넓은 적용범위를 제공하기 위해, fHbp의 다중 대립유전자 또는 변이체를 포함시키고; (ii) 각 용량에서 OMV 성분의 양을 감소시키는 2가지 방법으로 BEXSERO™을 변형시켰다. 본원에 제시된 대로, 이러한 2가지 변형은 실제 백신의 개선으로 이어졌다.
따라서, 첫 번째 구체예에서, 본 발명은 (i) NHBA 폴리펩티드 (ii) NadA 폴리펩티드 및/또는 (iii) 수막구균 외막 소체 중 하나 이상과 함께, 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드를 포함하는 면역원성 조성물을 제공한다.
게다가, 두 번째 구체예에서, 본 발명은 (i) NHBA 폴리펩티드 (ii) NadA 폴리펩티드 및/또는 (iii) 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드 중 하나 이상과 함께, 수막구균 외막 소체를 포함하는 면역원성 조성물을 제공하고; 여기서 외막 소체는 5-30μg/ml의 농도로 존재한다.
유사하게, 이러한 둘 모두의 구체예를 조합시켜, 본 발명은 (i) 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드, (ii) NHBA 폴리펩티드 (iii) NadA 폴리펩티드 및 (iv) 5-30μg/ml 수막구균 외막 소체를 포함하는 면역원성 조성물을 제공한다.
H 인자 결합 단백질 (fHbp)
본 발명의 조성물은 면역원성 fHbp 폴리펩티드를 포함할 수 있다. BEXSERO™ 제품은 fHbp 폴리펩티드를 포함하고, fHbp는 '741' (참고문헌 2에서 SEQ ID NO: 2536; 본원에서 SEQ ID 1), 'NMB1870', 'GNA1870' [3-5], 'P2086', 'LP2086' 또는 'ORF2086' [6-8]로도 공지되었다. 이러한 단백질의 3D 구조는 공지되어 있고 [9,10], 단백질은 짧은 링커에 의해 연결된 2개의 β-배럴을 갖는다. 많은 간행물은 수막구균 백신에서 이러한 단백질의 보호 효능을 보고하였다. 예컨대 참고문헌 11-15를 참조하라. 이러한 단백질은 모든 혈청군에 걸쳐 다수의 균주에서 지질화된 형태로 발현된다. fHbp 서열은 3개의 변이체로 그룹화되었고[3] (본원에서 v1, v2 및 v3으로서 언급됨), 일반적으로 주어진 변이체에 대해 생성된 혈청은 그 변이체를 발현시키는 균주에 대해서는 살균성이지만, 다른 두 변이체 중 하나를 발현시키는 균주에 대해서는 활성이 아니고, 즉, 변이체내 교차 보호는 존재하나 변이체간 교차 보호는 존재하지 않음이 발견되었다 (일부 v2 및 v3 교차-반응성은 예외임).
변이체간 교차-반응성을 증가시키기 위해 fHbp 서열은 3개 모두의 변이체에 대한 특이성을 포함하도록 공학처리되었다[16]. 그러나, 이 접근법을 따르는 대신에, 본 발명은 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드를 활용한다.
v1 fHbp
균주 MC58로부터의 v1의 전장 fHbp는 다음 아미노산 서열 (SEQ ID NO: 1)을 갖는다:
성숙한 지질단백질에는 SEQ ID NO: 1의 처음 19개 아미노산이 결여되어 있다 (밑줄로 표시됨; Cys-20에서 시작하여, SEQ ID NO: 4 제공). BEXSERO™ 제품은 전장 서열이 잔기 26까지 트렁케이션되어 (즉, 폴리-글리신 스트레치(stretch)를 제거하고, 대신 Val-27로 시작함) SEQ ID NO: 7을 제공하는 v1 fHbp의 'ΔG' 형태를 포함한다.
본 발명에 이용된 v1 수막구균 fHbp는 (i) SEQ ID NO: 7과 적어도 i%의 서열 동일성을 갖는 아미노산 서열을 포함하고/거나, (ii) SEQ ID NO: 7의 단편을 포함할 것이다.
i의 값은 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 또는 그 초과로부터 선택될 수 있다. 바람직하게는 90 (즉, 아미노산 서열은 SEQ ID NO: 7과 적어도 90%의 동일성을 갖는다)이고, 더욱 바람직하게는 95이다.
(ii)의 단편은 일반적으로 SEQ ID NO: 7로부터 적어도 7개 아미노산 길이, 예컨대 8개, 10개, 12개, 14개, 16개, 18개, 20개, 22개, 24개, 26개, 28개, 30개, 32개, 24개, 26개, 28개, 40개, 45개, 50개, 55개, 60개, 65개, 70개, 75개, 80개 이상의 연속적인 아미노산일 것이다. 단편은 전형적으로 SEQ ID NO: 7로부터의 적어도 하나의 에피토프를 포함할 것이다. 에피토프 식별 및 맵핑은 fHbp에 대해 확립되어 있다 [12; 17-21]. SEQ ID NO: 7과 적어도 30개의 연속적인 아미노산을 공유하는 것이 전형적일 것이며, 일반적으로 v1 fHbp 아미노산 서열은 SEQ ID NO: 7로부터의 여러 (예컨대, 2, 3, 4, 5개 이상) 단편을 포함할 것이다.
전반적으로, v1 fHbp 아미노산 서열은 SEQ ID NO: 7과 적어도 i%의 서열 동일성을 지닐 수 있고 SEQ ID NO: 7의 여러 단편을 포함할 수 있다.
v1 fHbp 서열은 일반적으로 SEQ ID NO: 2에 존재하지 않는 적어도 하나의 아미노산 서열 및/또는 SEQ ID NO: 3에 존재하지 않는 적어도 하나의 아미노산 서열을 포함한다.
본 발명에 이용되고 v1 서열을 포함하는 폴리펩티드는 적합한 숙주 포유동물 (예컨대, 마우스 또는 인간)로의 투여 후 SEQ ID NO: 4로 구성된 야생형 수막구균 폴리펩티드를 인지할 수 있는 항체를 유도할 수 있다. 이들 항체는, 비록 이들이 v2 및/또는 v3 폴리펩티드와 교차반응하는 일부 항체를 또한 포함할 수 있지만, v2 또는 v3 폴리펩티드를 인지하지 않는(예를 들어, SEQ ID NO: 5로 구성된 야생형 수막구균 폴리펩티드 및 SEQ ID NO: 6으로 구성된 야생형 수막구균 폴리펩티드를 인지하지 않을) 일부 항체를 포함할 것이다. 항체는 이상적으로는 v1 fHbp를 발현하는 수막구균 균주, 예를 들어, MC58 균주에 대해 살균성이다(하기 참조).
v2 fHbp
균주 2996으로부터의 v2의 전장 fHbp는 다음 아미노산 서열 (SEQ ID NO: 2)을 갖는다:
성숙한 지질단백질에는 SEQ ID NO: 2의 처음 19개 아미노산이 결여되어 있고 (밑줄로 표시됨; SEQ ID NO: 5 제공), SEQ ID NO: 2의 ΔG 형태에는 처음 26개 아미노산이 결여되어 있다 (SEQ ID NO: 8).
본 발명에 이용된 v2 수막구균 fHbp는 (i) SEQ ID NO: 8과 적어도 j%의 서열 동일성을 갖는 아미노산 서열을 포함하고/거나, (ii) SEQ ID NO: 8의 단편을 포함할 것이다.
j의 값은 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 또는 그 초과로부터 선택될 수 있다. 바람직하게는 90 (즉, 아미노산 서열은 SEQ ID NO: 8과 적어도 90%의 동일성을 갖는다)이고, 더욱 바람직하게는 95이다.
(ii)의 단편은 일반적으로 SEQ ID NO: 8로부터 적어도 7개 아미노산 길이, 예컨대 8개, 10개, 12개, 14개, 16개, 18개, 20개, 22개, 24개, 26개, 28개, 30개, 32개, 24개, 26개, 28개, 40개, 45개, 50개, 55개, 60개, 65개, 70개, 75개, 80개 이상의 연속적인 아미노산일 것이다. 단편은 전형적으로 SEQ ID NO: 8로부터의 적어도 하나의 에피토프를 포함할 것이다. 에피토프 식별 및 맵핑은 fHbp에 대해 확립되어 있다 (상기 참조). SEQ ID NO: 8과 적어도 30개의 연속적인 아미노산을 공유하는 것이 전형적일 것이며, 일반적으로 v2 fHbp 아미노산 서열은 SEQ ID NO: 8로부터의 여러 (예컨대, 2, 3, 4, 5개 이상) 단편을 포함할 것이다.
전반적으로, v2 fHbp 아미노산 서열은 SEQ ID NO: 8과 적어도 j%의 서열 동일성을 지닐 수 있고 SEQ ID NO: 8의 여러 단편을 포함할 수 있다.
v2 fHbp 서열은 일반적으로 SEQ ID NO: 1에 존재하지 않는 적어도 하나의 아미노산 서열 및/또는 SEQ ID NO: 3에 존재하지 않는 적어도 하나의 아미노산 서열을 포함한다.
본 발명에 이용되고 v2 서열을 포함하는 폴리펩티드는 적합한 숙주 포유동물 (예컨대, 마우스 또는 인간)로의 투여 후 SEQ ID NO: 5로 구성된 야생형 수막구균 폴리펩티드를 인지할 수 있는 항체를 유도할 수 있다. 이들 항체는, 비록 이들이 v1 및/또는 v3 폴리펩티드와 교차반응하는 일부 항체를 또한 포함할 수 있지만, v1 또는 v3 폴리펩티드를 인지하지 않는(예를 들어, SEQ ID NO: 4로 구성된 야생형 수막구균 폴리펩티드 및 SEQ ID NO: 6으로 구성된 야생형 수막구균 폴리펩티드를 인지하지 않을) 일부 항체를 포함할 것이다. 항체는 이상적으로는 v2 fHbp를 발현하는 수막구균 균주, 예를 들어, M2091 균주에 대해 살균성이다(하기 참조).
v3 fHbp
균주 M1239로부터의 v3의 전장 fHbp는 다음 아미노산 서열 (SEQ ID NO: 3)을 갖는다:
성숙한 지질단백질에는 SEQ ID NO: 3의 처음 19개 아미노산이 결여되어 있고 (밑줄로 표시됨; SEQ ID NO: 6 제공), SEQ ID NO: 3의 ΔG 형태에는 처음 31개 아미노산이 결여되어 있다 (SEQ ID NO: 9).
본 발명에 이용된 v3 수막구균 fHbp는 (i) SEQ ID NO: 9와 적어도 k%의 서열 동일성을 갖는 아미노산 서열을 포함하고/거나, (ii) SEQ ID NO: 9의 단편을 포함할 것이다.
k의 값은 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 이상으로부터 선택될 수 있다. 이는 바람직하게는 90이고(즉, 아미노산 서열은 SEQ ID NO: 9와 적어도 90%의 동일성을 가짐), 더욱 바람직하게는 95이다.
(ii)의 단편은 일반적으로 SEQ ID NO: 9로부터 적어도 7개 아미노산 길이, 예컨대 8개, 10개, 12개, 14개, 16개, 18개, 20개, 22개, 24개, 26개, 28개, 30개, 32개, 24개, 26개, 28개, 40개, 45개, 50개, 55개, 60개, 65개, 70개, 75개, 80개 이상의 연속적인 아미노산일 것이다. 단편은 전형적으로 SEQ ID NO: 9로부터의 적어도 하나의 에피토프를 포함할 것이다. 에피토프 식별 및 맵핑은 fHbp에 대해 확립되어 있다 (상기 참조). SEQ ID NO: 9와 적어도 30개의 연속적인 아미노산을 공유하는 것이 전형적일 것이며, 일반적으로 v3 fHbp 아미노산 서열은 SEQ ID NO: 9로부터의 여러 (예컨대, 2, 3, 4, 5개 이상) 단편을 포함할 것이다.
전반적으로, v3 fHbp 아미노산 서열은 SEQ ID NO: 9와 적어도 k%의 서열 동일성을 지닐 수 있고 SEQ ID NO: 9의 여러 단편을 포함할 수 있다.
v3 fHbp 서열은 일반적으로 SEQ ID NO: 1에 존재하지 않는 적어도 하나의 아미노산 서열 및/또는 SEQ ID NO: 2에 존재하지 않는 적어도 하나의 아미노산 서열을 포함한다.
본 발명에 이용되고 v3 서열을 포함하는 폴리펩티드는 적합한 숙주 포유동물(예컨대, 마우스 또는 인간)로의 투여 후 SEQ ID NO:6으로 구성된 야생형 수막구균 폴리펩티드를 인지할 수 있는 항체를 유도할 수 있다. 이들 항체는, 비록 이들이 v1 및/또는 v2 폴리펩티드와 교차반응하는 일부 항체를 또한 포함할 수 있지만, v1 또는 v2 폴리펩티드를 인지하지 않는(예를 들어, SEQ ID NO:4로 구성된 야생형 수막구균 폴리펩티드 및 SEQ ID NO:5로 구성된 야생형 수막구균 폴리펩티드를 인지하지 않을) 일부 항체를 포함할 것이다. 항체는 이상적으로는 v3 fHbp를 발현하는 수막구균 균주, 예를 들어, M01-240355 균주에 대해 살균성이다(하기 참조).
융합 폴리펩티드
본 발명은 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드를 활용한다. 결과적으로, 융합 폴리펩티드는 SEQ ID NO: 7, 8, 및 9 각각으로부터의 적어도 하나의 에피토프를 포함할 수 있고, 숙주 포유동물로의 투여 후, (i) SEQ ID NO: 4로 구성된 야생형 수막구균 폴리펩티드, (ii) SEQ ID NO: 5로 구성된 야생형 수막구균 폴리펩티드, 및 (iii) SEQ ID NO: 6으로 구성된 야생형 수막구균 폴리펩티드 3개 모두를 인지할 수 있는 항체를 유도할 수 있다. 이들 항체는 이상적으로는 v1 fHbp를 발현하는 수막구균 균주, v2 fHbp를 발현하는 수막구균 균주, 및 또한 v3 fHbp를 발현하는 수막구균 균주에 대해 (예컨대, MC58, M2091, 및 M01 240355 균주 각각에 대해) 살균성이다.
상기 주어진 정의와 관련하여, 적절한 경우, 융합 폴리펩티드에 대해 i=j=k인 것이 바람직하다.
일반적으로, 본 발명의 fHbp 융합 폴리펩티드는 하기 식의 아미노산 서열을 갖는다:
NH2―A-[-X-L-]3-B―COOH
상기 식에서, 각각의 X는 다양한 변이체 fHbp 서열이고, L은 임의의 링커 아미노산 서열이고, A는 임의의 N-말단 아미노산 서열이고, B는 임의의 C-말단 아미노산 서열이다.
3개의 X 모이어티는 상기 논의된 바와 같은 v1, v2, 및 v3 서열이다. 이들은 N-말단으로부터 C-말단으로 임의의 순서, 즉 v1-v2-v3, v1-v3-v2, v2-v1-v3, v2-v3-v1, v3-v1-v2, 또는 v3-v2-v1로 존재할 수 있다. 가장 바람직한 순서는 v2-v3-v1이다.
각 경우의 [-X-L-]에 대해, 링커 아미노산 서열 -L-은 존재하거나 부재할 수 있다. 링커 아미노산 서열(들) -L-은 전형적으로 짧을(예를 들어, 20개 이하의 아미노산, 즉, 19개, 18개, 17개, 16개, 15개, 14개, 13개, 12개, 11개, 10개, 9개, 8개, 7개, 6개, 5개, 4개, 3개, 2개, 1개) 것이다. 예로는 클로닝을 촉진하는 짧은 펩티드 서열, 폴리-글리신 링커(즉, Glyn, 여기서 n = 2, 3, 4, 5, 6, 7, 8, 9, 10 이상(SEQ ID NO:42)), 및 히스티딘 태그(즉, Hisn, 여기서 n = 3, 4, 5, 6, 7, 8, 9, 10 이상(SEQ ID NO:43))를 포함한다. 다른 적합한 링커 아미노산 서열은 당업자에게 명백할 것이다. 한 유용한 링커는 GSGGGG(SEQ ID NO:22)이며, Gly-Ser 디펩티드는 BamHI 제한 부위로부터 형성되어, 이에 따라 클로닝 및 조작을 돕는다. 또 다른 유용한 링커는 Gly-Ser 디펩티드(SEQ ID NO:24, BamHI로부터) 또는 Gly-Lys 디펩티드(SEQ ID NO:25, HindIII로부터)가 임의로 선행될 수 있는 SEQ ID NO:23이다.
-A-는 임의의 N-말단 아미노산 서열이다. 이는 통상적으로 짧을(예를 들어, 40개 이하의 아미노산, 즉, 39개, 38개, 37개, 36개, 35개, 34개, 33개, 32개, 31개, 30개, 29개, 28개, 27개, 26개, 25개, 24개, 23개, 22개, 21개, 20개, 19개, 18개, 17개, 16개, 15개, 14개, 13개, 12개, 11개, 10개, 9개, 8개, 7개, 6개, 5개, 4개, 3개, 2개, 1개) 것이다. 예로는 단백질 트래피킹(trafficking)을 유도하는 리더 서열을 포함한다. X1이 그 자체의 N-말단 메티오닌을 결여한 경우, -A-는 번역된 폴리펩티드에서 상기 메티오닌 잔기를 제공할 수 있다(예를 들어, -A-는 단일 Met 잔기이다). Met은 링커 서열, 예를 들어, SEQ ID NO: 23의 N-말단에 대해 존재할 수 있거나(즉, SEQ ID: 26), 짧은 서열의 N-말단에 존재할 수 있다(예를 들어, SEQ ID NO: 27).
-B-는 임의의 C-말단 아미노산 서열이다. 이는 통상적으로 짧을(예를 들어, 40개 이하의 아미노산, 즉, 39개, 38개, 37개, 36개, 35개, 34개, 33개, 32개, 31개, 30개, 29개, 28개, 27개, 26개, 25개, 24개, 23개, 22개, 21개, 20개, 19개, 18개, 17개, 16개, 15개, 14개, 13개, 12개, 11개, 10개, 9개, 8개, 7개, 6개, 5개, 4개, 3개, 2개, 1개) 것이다. 예로는 단백질 트래피킹을 유도하는 서열, 클로닝 또는 정제를 촉진하는 짧은 펩티드 서열(예를 들어, 히스티딘 태그, 즉, Hisn을 포함함, 여기서 n = 3, 4, 5, 6, 7, 8, 9, 10 이상(SEQ ID NO:43)), 또는 폴리펩티드 안정성을 향상시키는 서열을 포함한다. 다른 적합한 C-말단 아미노산 서열은 당업자에게 명백할 것이다. 하나의 적합한 -B- 모이어티는 SEQ ID NO: 28이고, 여기서 히스티딘 태그의 Leu-Glu 업스트림은 XhoI 제한 부위로부터 발생한다.
본 발명에 사용하기 적합한 한 융합 폴리펩티드는 SEQ ID NO: 10을 포함한다. 상기 식에 따라, SEQ ID NO: 10에서 -A-는 SEQ ID NO: 26이고, X1은 v2 fHbp 서열 (SEQ ID NO: 8)이고, -L1-은 SEQ ID NO: 24이고, X2는 v3 fHbp 서열 (SEQ ID NO: 9)이고, -L2-는 SEQ ID NO: 22이고, X3은 v1 fHbp 서열 (SEQ ID NO: 7)이고, L3 및 B는 존재하지 않는다. SEQ ID NO: 10에서 3개의 fHbp 서열은 하기에 밑줄로 표시된다:
본 발명에 사용하기 더욱 바람직한 융합 폴리펩티드는 SEQ ID NO: 29를 포함한다. 상기 식에 따라, SEQ ID NO: 29에서 -A-는 SEQ ID NO: 26이고, X1은 v2 fHbp 서열 (SEQ ID NO: 8)이고, -L1-은 SEQ ID NO: 22이고, X2는 v3 fHbp 서열 (SEQ ID NO: 9)이고, -L2-는 SEQ ID NO: 22이고, X3은 v1 fHbp 서열 (SEQ ID NO: 7)이고, L3 및 B는 존재하지 않는다. SEQ ID NO: 29에서 3개의 fHbp 서열은 하기에 밑줄로 표시된다:
따라서, 본 발명은 이상적으로는 아미노산 서열 SEQ ID NO: 10 또는 SEQ ID NO: 29를 갖는 폴리펩티드를 활용하지만, 본 발명은 또한 SEQ ID NO: 10 또는 SEQ ID NO: 29를 포함하나 폴리펩티드가 상기 논의된 대로 SEQ ID NO: 4-6의 3개 모두의 야생형 수막구균 폴리펩티드를 인지할 수 있는 항체를 유도할 수 있는 것을 조건으로 하여 10개 이하의 단일 아미노산 변화 (즉, 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10개의 단일 아미노산 치환, 결실 및/또는 삽입)에 의해 변형된 폴리펩티드를 이용할 수 있다. 더욱이, SEQ ID NO: 10 또는 SEQ ID NO: 29는 이들의 -A- 모이어티를 변화시키도록 변형될 수 있어서 (예컨대, SEQ ID NO: 26에 대한 대안을 사용하기 위해), 본 발명에 이용된 폴리펩티드는 임의로 10개 이하의 단일 아미노산 변화 (상기 논의된 바와 같음)에 의해 변형된 SEQ ID NO: 30을 포함할 수 있다.
예를 들어, SEQ ID NO: 30은 fH와 상호작용하는 각 fHbp의 능력을 파괴하는 점 돌연변이를 도입하도록 변형될 수 있다. 예를 들어, SEQ ID NO: 30은 잔기 E240, E496, 및 R543에서 돌연변이되어, SEQ ID NO: 31을 제공할 수 있다 (돌연변이 E240X, E496X 및 R543X 포함, 여기서 X는 열거된 아미노산 이외의 임의의 아미노산이고, 즉, E240X는 잔기 240에서 E 이외의 임의의 아미노산을 나타낸다). SEQ ID NO: 31의 바람직한 구체예는 SEQ ID NO: 32 (돌연변이 E240A, E496A, R543S 포함)이다. 본 발명은 잔기 E240, E496, 및 R543이 존재하지 않는 것을 조건으로 하여 임의로 5개 이하의 단일 아미노산 변화 (상기 논의된 바와 같음)에 의해 변형된 SEQ ID NO: 31 (예컨대, SEQ ID NO: 32)을 이용할 수 있다.
더욱이, SEQ ID NO: 30은 fHbp의 안정성을 증가시키는 점 돌연변이를 도입하도록 변형될 수 있다. 예를 들어, SEQ ID NO: 30은 잔기 S32, L123, S285, 및 L379에서 돌연변이되어, SEQ ID NO: 33을 제공할 수 있다 (돌연변이 S32X, L123X, S285X 및 L379X 포함). SEQ ID NO: 33의 바람직한 구체예는 SEQ ID NO: 34이다 (돌연변이 S32V, L123R, S285V, L379R 포함). 본 발명은 잔기 S32, L123, S285, 및 L379가 존재하지 않는 것을 조건으로 하여 임의로 5개 이하의 단일 아미노산 변화 (상기 논의된 바와 같음)에 의해 변형된 SEQ ID NO: 33 (예컨대, SEQ ID NO: 34)을 이용할 수 있다. 그러한 한 폴리펩티드는 SEQ ID NO: 35이며, 여기서 v1 서열은 참고문헌 22에 보고된 돌연변이, 예컨대 'R41S' 돌연변이 (SEQ ID NO: 36)를 포함하도록 변형되었다. SEQ ID NO:35는 돌연변이 S32X, L123X, S285X, L379X 및 R543X를 포함하고, SEQ ID NO:36은 돌연변이 S32V, L123R, S285V, L379R 및 R543S를 포함한다. 'R41S' 명명법은 성숙한 v1 폴리펩티드 (SEQ ID NO:4)에 관해 넘버링된 것이며, 따라서, 예컨대 이것은 SEQ ID NO:35 융합 폴리펩티드에 R543X로서 그리고 SEQ ID NO:36에 R543S로서 존재한다.
이러한 다양한 접근법은 조합될 수 있어서, 본 발명은 SEQ ID NO: 37을 포함하는 폴리펩티드 (예컨대, 아미노산 서열 SEQ ID NO: 38을 갖는 폴리펩티드)를 활용할 수 있다. SEQ ID NO: 37 및 SEQ ID NO: 38은 돌연변이 S32V, L123R, E240A, S285V, L379R, E496A 및 R543S를 포함한다. SEQ ID NO:38은 N-말단에 SEQ ID NO:26을 추가로 포함한다.
추가 구체예에서, 본 발명은 SEQ ID NO: 39 (돌연변이 L123X 및 L379X 포함), 예컨대 SEQ ID NO: 40 (돌연변이 L123R 및 L379R 포함)을 이용할 수 있다. 본 발명은 유사하게 잔기 L123 및 L379가 존재하지 않는 것을 조건으로 하여 (예컨대, 상기 언급한 2개의 S/V 치환을 포함함으로써 SEQ ID NO: 40과 상이한 SEQ ID NO: 34를 참조하라) 임의로 5개의 단일 아미노산 변화 (상기 논의된 바와 같음)에 의해 변형된 SEQ ID NO: 39 (예컨대, SEQ ID NO: 40)를 이용할 수 있다. 그러한 한 폴리펩티드는 SEQ ID NO: 41이고, 여기서 v1 서열은 'R41S' 돌연변이를 포함하도록 변형되었고, 이에 따라 L123R, L379R 및 R543S를 포함한다. 추가 구체예에서, 그러한 융합 단백질이 본 발명의 조성물에 존재할 때, OMV는 2.5μg/ml 내지 12.5μg/ml의 농도로 존재할 수 있다.
상기 돌연변이를 위해 언급된 아미노산 잔기는 구체적인 출발 서열에 대해 정의된다. 임의의 다른 fHbp 서열에서 상응하는 아미노산 잔기는 서열 정렬에 의해 용이하게 확인될 수 있고, 예를 들어, 쌍을 이룬 정렬 알고리즘(예를 들어, 하기에 상술되는 바와 같은 니들먼-분쉬(Needleman-Wunsch) 전체 정렬 알고리즘)을 이용하여 정렬될 때, 본원에 언급된 아미노산에 대해 정렬되는 아미노산이다. 종종 아미노산은 동일할 것이나, 그렇지 않은 경우 정렬에 의해 용이하게 확인될 것이다.
fHbp는 자연발생적인 N. 메닌지티디스의 지질단백질이다. 이는 천연 리더 서열 또는 이종 리더 서열에 의해 E. 콜리(E. coli)에서 발현되는 경우 지질화되는 것으로 또한 밝혀졌다. 본 발명의 폴리펩티드는, 예를 들어, 일반적으로 트리팔미토일-S-글리세릴-시스테인을 형성하는 팔미토일기를 포함하는, 지질화될 수 있는 N-말단 시스테인 잔기를 가질 수 있다. 그러나, 일반적인 구체예에서, 본 발명의 융합 폴리펩티드는 발현 숙주에서 지질화되지 않는다 (통상적으로 N-말단 -A- 모이어티가 지질화를 유도하지 않으므로).
네이세리아 헤파린 결합 항원 (NHBA)
본 발명의 조성물은 면역원성 NHBA 폴리펩티드를 포함할 수 있다. NHBA 항원은 수막구균 혈청군 B 균주 MC58에 대한 공개된 유전체 서열에[23] 유전자 NMB2132 (GenBank 수탁 번호 GI:7227388; 본원에서 SEQ ID NO: 11)로서 포함되었다. 다수의 균주로부터의 NHBA 항원의 서열은 그 이후에 공개되었다. 예를 들어, NHBA의 대립유전자 형태는 참고문헌 24의 도 5 및 15, 및 참고문헌 2의 실시예 13 및 도 21(그 안의 SEQ ID 3179 내지 3184)에서 볼 수 있다. SEQ ID NO: 12의 'ΔG' 단편을 포함하는 NHBA 항원의 다양한 면역원성 단편이 또한 보고되었다. 본 발명에 사용하기 바람직한 NHBA 항원은 (a) SEQ ID NO: 12와 60% 이상의 동일성 (예컨대, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% 이상)을 갖고/거나; (b) 'n'이 7 또는 그 초과(예컨대, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250 또는 그 초과)인 SEQ ID NO: 12의 적어도 'n'개의 연속 아미노산의 단편을 포함하는 아미노산 서열을 포함한다. (b)의 바람직한 단편은 SEQ ID NO: 12로부터의 에피토프를 포함한다.
본 발명의 가장 유용한 NHBA 항원은 적합한 숙주 포유동물 (예컨대, 마우스 또는 인간)로의 투여 후 아미노산 서열 SEQ ID NO: 13으로 구성된 수막구균 폴리펩티드에 결합할 수 있는 항체를 유도할 수 있다. 본 발명에 사용하기 유리한 NHBA 항원은 포유동물 대상체로의 투여 후 살균성 항-수막구균 항체를 유도할 수 있다.
본 발명에 사용하기 특히 바람직한 NHBA 폴리펩티드는 폴리펩티드가 상기 논의된 대로 SEQ ID NO: 13에 결합할 수 있는 항체를 유도할 수 있는 것을 조건으로 하여 임의로 3개 이하의 단일 아미노산 변화 (즉, 1, 2, 또는 3개의 단일 아미노산 치환, 결실 및/또는 삽입)에 의해 변형된 SEQ ID NO: 12를 포함한다.
BEXSERO™ 제품에서 보여진 대로, NHBA 폴리펩티드는, 예컨대 NMB1030 폴리펩티드에 융합된 융합 폴리펩티드로서 유용하게 존재할 수 있다. 그러한 융합 폴리펩티드에서 NMB1030은 바람직하게는 NHBA의 다운스트림에 있다. 균주 MC58로부터의 NMB1030은 GenBank 수탁 번호 GI:7226269를 갖는다 (본원에서 SEQ ID NO: 14). 본 발명에 사용하기 위한 NMB1030 서열은 (a) SEQ ID NO: 14와 60% 이상의 동일성 (예컨대, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% 이상)을 갖고/거나; (b) 'n'이 30 또는 그 초과인 SEQ ID NO: 14의 적어도 'n'개의 연속 아미노산의 단편을 포함하는 아미노산 서열을 포함할 수 있다. 한 유용한 NMB1030 단편은 SEQ ID NO: 15이다.
그러한 한 NHBA-NMB1030 융합 폴리펩티드는 아미노산 서열 SEQ ID NO: 16을 갖는다. 따라서, 본 발명은 폴리펩티드가 상기 논의된 대로 SEQ ID NO: 13에 결합할 수 있는 항체를 유도할 수 있는 것을 조건으로 하여 임의로 3개 이하의 단일 아미노산 변화 (즉, 1, 2, 또는 3개의 단일 아미노산 치환, 결실 및/또는 삽입)에 의해 변형된 SEQ ID NO: 16을 이용할 수 있다.
네이세리아 부착소 A (NadA)
본 발명의 조성물은 면역원성 NadA 폴리펩티드를 포함할 수 있다. NadA 항원은 수막구균 혈청군 B 균주 MC58에 대한 공개된 유전체 서열에[23] 유전자 NMB1994 (GenBank 수탁 번호 GI:7227256; 본원에서 SEQ ID NO: 17)로서 포함되었다. 다수의 균주로부터의 NadA 항원의 서열은 그 이후에 공개되었고, 네이세리아 부착소로서 단백질의 활성은 잘 문서화되었다. NadA의 다양한 면역원성 단편도 보고되었다. 본 발명에 사용하기 바람직한 NadA 항원은 (a) SEQ ID NO: 17과 60% 이상의 동일성 (예컨대, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% 이상)을 갖고/거나; (b) 'n'이 7 또는 그 초과(예컨대, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250 또는 그 초과)인 SEQ ID NO: 17의 적어도 'n'개의 연속 아미노산의 단편을 포함하는 아미노산 서열을 포함한다. (b)의 바람직한 단편은 SEQ ID NO: 17로부터의 에피토프를 포함한다.
본 발명의 가장 유용한 NadA 항원은 숙주 포유동물로의 투여 후 아미노산 서열 SEQ ID NO: 18로 구성된 수막구균 폴리펩티드에 결합할 수 있는 항체를 유도할 수 있다. 본 발명에 사용하기 유리한 NadA 항원은 숙주 포유동물로의 투여 후 살균성 항-수막구균 항체를 유도할 수 있다.
본 발명에 사용하기 특히 바람직한 NadA 폴리펩티드는 폴리펩티드가 상기 논의된 대로 SEQ ID NO: 18에 결합할 수 있는 항체를 유도할 수 있는 것을 조건으로 하여 임의로 3개 이하의 단일 아미노산 변화 (즉, 1, 2, 또는 3개의 단일 아미노산 치환, 결실 및/또는 삽입)에 의해 변형된 SEQ ID NO: 19를 갖는다.
수막구균 외막 소체 (OMV)
본 발명의 조성물은 수막구균 OMV, 즉 수막구균 외막의 파괴 또는 이로부터의 수포발생에 의해 수득되어 그로부터 외막의 단백질 성분 (예컨대, PorA, PorB, RmpM, Opa, Opc, Omp85, FetA/FrpB, NspA 등)을 보유하는, 직경이 50-200nm의 범위인 소체를 형성하는 임의의 단백질리포솜 소체를 포함한다. 따라서, 이 용어는 OMV (때로 '수포'로서 언급됨) 뿐만 아니라 미세소체 (MV [25]) 또는 '천연 OMV' ('NOMV' [26])로서 언급되는 소체도 포함할 수 있다. 또한 참고문헌 27 내지 33을 참조하라. 통상적인 외막 소체는 박테리아로부터 인공적으로 제조되며, 세제 처리(예를 들어, 데옥시콜레이트 이용)를 이용하거나 비-세제 수단에 의해 제조될 수 있다(예컨대, 참고문헌 37을 참조하라). OMV를 형성시키기 위한 기술은 세제를 침전시키지 않는 충분히 높은 pH에서 박테리아를 담즙산 염 세제(예를 들어, 리토콜산, 케노데옥시콜산, 우르소데옥시콜산, 데옥시콜산, 콜산, 우르소콜산 등의 염, 소듐 데옥시콜레이트[34 & 35]이 네이세리아를 치료하는데 바람직함)로 처리하는 것을 포함한다[36]. 다른 기술은 초음파처리, 균질화, 미세유동화, 공동화, 삼투압 충격, 분쇄, 프렌치 가압, 블렌딩 등과 같은 기술을 이용하여 실질적으로 세제의 부재하에서 수행될 수 있다[37,38]. 세제를 이용하지 않거나, 세제를 적게 이용하는 방법은 유용한 항원, 예를 들어, NspA 및 fHbp를 유지시킬 수 있다[37]. 따라서, 본 발명에 이용되는 OMV는 약 0.5%의 데옥시콜레이트 또는 그 미만, 예를 들어, 약 0.2%, 약 0.1%, <0.05% 또는 심지어 0의 데옥시콜레이트를 갖는 OMV 추출 완충제를 이용하여 제조될 수 있다.
MV 및 NOMV로 공지된 소체는 박테리아 성장 동안 자발적으로 형성되고, 배양 배지로 방출되는 천연-발생 막 소체이다. MV는 브로쓰 배양 배지에서 네이세리아를 배양하고, 브로쓰 배양 배지에서 더 작은 MV로부터 전체 세포를 분리(예를 들어, 세포만 펠렛화시키고 더 작은 소체는 펠렛화시키지 않기 위해 여과 또는 저속 원심분리에 의함)시키고, 이후 세포-고갈 배지로부터 MV를 수거(예를 들어, MV의 여과, 차별적 침전 또는 응집, MV를 펠렛화시키기 위한 고속 원심분리에 의함)함으로써 수득될 수 있다. MV의 생성에 사용하기 위한 균주는 일반적으로 배양 중에 생성된 MV의 양을 기초로 하여 선택될 수 있으며, 예를 들어, 참고문헌 45 & 46은 높은 MV 생성을 갖는 네이세리아를 기재한다.
예를 들어, 면역원성을 증가시키고(예를 들어, 과-발현 면역원), 독성을 감소시키고, 캡슐 다당류 합성을 억제하고, PorA 발현을 하향 조절하는 것 등을 위해 유전적으로 조작된 박테리아로부터 소체가 제조될 수 있다[39-42]. 이들은 과수포발생 균주로부터 제조될 수 있다[43-46]. 상이한 클래스 I 외막 단백질 서브타입을 갖는 박테리아로부터의 소체, 예를 들어, 각각 3개의 서브타입을 나타내는 2개의 상이한 유전적 처리된 소체 집단을 이용한 6개의 상이한 서브타입[47,48], 또는 각각 3개의 서브타입을 나타내는 3개의 상이한 유전적 처리된 소체 집단을 이용한 9개의 상이한 서브타입 등이 이용될 수 있다. 유용한 서브타입은 P1.7,16; P1.5-1,2-2; P1.19,15-1; P1.5-2,10; P1.12-1,13; P1.7-2,4; P1.22,14; P1.7-1,1; P1.18-1,3,6을 포함한다. 그러나, 일반적으로, 본 발명은 야생형 수막구균 균주로부터 OMV를 제조하는 것이 바람직하다.
따라서, 본 발명에 이용하기 위한 소체는 임의의 야생형 수막구균 균주로부터 제조될 수 있다. 소체는 일반적으로 혈청군 B 균주로부터의 소체일 것이나, 이들을 B가 아닌 혈청군(예를 들어, 참고문헌 36은 혈청군 A를 위한 방법을 기재함), 예를 들어, A, C, W135 또는 Y로부터 제조하는 것이 가능하다. 균주는 임의의 혈청형(예를 들어, 1, 2a, 2b, 4, 14, 15, 16 등), 임의의 혈청아형(예를 들어, P1.4), 및 임의의 면역형(예를 들어, L1; L2; L3; L3,7; L3,7,9; L10 등)의 균주일 수 있다. 수막구균은 임의의 적합한 계통, 예를 들어, 과침습성 및 과병독성 계통, 예를 들어, 서브그룹 I; 서브그룹 III; 서브그룹 IV-1; ET-5 복합체; ET-37 복합체; A4 클러스터; 계통 3의 7개의 과병독성 계통 중 어느 하나의 수막구균일 수 있다. 가장 바람직하게는, OMV는 균주 NZ98/254, 또는 P1.4 PorA 혈청아형을 갖는 또 다른 균주로부터 제조된다. 본 발명은 유리하게는 균주 NZ98/254로부터 제조된, BEXSERO™ 및 MENZB™ 제품에서 사용되는 것과 동일한 OMV를 이용한다.
소체는 일반적으로 수막구균 LOS(LPS로도 공지됨)를 포함할 것이나, OMV에서의 LOS의 발열 효과는 동일량의 정제된 LOS로 관찰되는 것보다 훨씬 적고, 알루미늄 하이드록시드로의 OMV의 흡착은 발열원성을 추가로 감소시킨다. LOS 수준은 내독소의 국제 단위(IU)로 표현되고, LAL 검정(리물러스 유주세포 용해질)에 의해 시험될 수 있다. 바람직하게는, LOS는 OMV 단백질의 μg 당 2000 IU 미만으로 존재한다.
LOS가 소체 내에 존재하는 경우, 이의 LOS와 단백질 성분을 연결시키기 위해 소체를 처리하는 것이 가능하다("수포내" 컨쥬게이션[49]).
OMV 정제를 위한 유용한 방법은 참고문헌 50에 기재되어 있고, 고속 원심분리 대신 미정제 OMV에 대한 초여과를 수반한다. 상기 방법은 초여과가 발생한 후에 초원심분리 단계를 수반할 수 있다. OMV는 또한 참고문헌 51에 기재된 2 단계 크기 여과 방법을 이용하여 정제될 수 있다.
OMV는 이들이 제조된 후에 수크로스 용액 중에 유용하게 현탁될 수 있다.
조합물
본 발명의 조성물은 (a) 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드, (b) NHBA 폴리펩티드, (c) NadA 폴리펩티드 및 (d) OMV의 각각을 포함할 수 있다.
그러한 조합물에서: (a) fHbp 융합 폴리펩티드는 이상적으로는 상기 논의된 대로 임의로 10개 이하의 단일 아미노산 변화에 의해 변형된 아미노산 서열 SEQ ID NO: 10을 포함하고; (b) NHBA 폴리펩티드는 이상적으로는 상기 논의된 대로 임의로 3개 이하의 단일 아미노산 변화에 의해 변형된 아미노산 서열 SEQ ID NO: 12를 포함하고; 그리고 (c) NadA 폴리펩티드는 이상적으로는 상기 논의된 대로 임의로 3개 이하의 단일 아미노산 변화에 의해 변형된 아미노산 서열 SEQ ID NO: 19를 포함한다.
보다 바람직하게는: (a) fHbp 융합 폴리펩티드는 아미노산 서열 SEQ ID NO: 10을 갖고; (b) NHBA 폴리펩티드는 아미노산 서열 SEQ ID NO: 12를 갖고; (c) NadA 폴리펩티드는 아미노산 서열 SEQ ID NO: 19를 갖는다.
심지어 더욱 바람직하게는: (a) fHbp 융합 폴리펩티드는 아미노산 서열 SEQ ID NO: 10을 갖고; (b) NHBA 폴리펩티드는 아미노산 서열 SEQ ID NO: 16을 갖고; (c) NadA 폴리펩티드는 아미노산 서열 SEQ ID NO: 19를 갖는다.
본 발명의 조성물 중 폴리펩티드는 숙주에서 효과적인 면역학적 반응을 발생시키는 임의의 농도로 존재할 수 있다. 이러한 용량은, 특히 각각 100μg/ml로 존재하는 fHbp, NHBA 및 NadA 폴리펩티드를 갖는 BEXSERO™ 제품에 의해 제공된 가이던스의 관점에서, 일상적인 시험을 통해 확립될 수 있다. 따라서, fHbp, NHBA 및/또는 NadA 폴리펩티드는 각각 본 발명의 조성물에 20μg/ml 내지 400μg/ml, 예컨대 50-150μg/ml, 80-120μg/ml, 또는 약 100μg/ml의 농도로 존재할 수 있다. 항원 농도는 표준 단백질 검정에 의해 용이하게 정량될 수 있다.
유사하게, 본 발명의 조성물 중 OMV는 숙주에서 효과적인 면역학적 반응을 발생시키는 임의의 농도로 존재할 수 있다. 이러한 용량은, 특히 OMV가 50μg/ml로 존재하는 BEXSERO™ 제품에 의해 제공된 가이던스의 관점에서, 일상적인 시험을 통해 확립될 수 있다. 따라서, 본 발명의 첫 번째 구체예에 따르면, OMV는 20μg/ml 내지 100μg/ml, 예컨대 30-75μg/ml, 40-60μg/ml, 또는 이상적으로 약 50μg/ml의 농도로 조성물에 존재할 수 있다. 그러나, 본 발명의 두 번째 구체예에서, OMV는 더 낮은 농도, 즉 5μg/ml 내지 30μg/ml, 예컨대 10μg/ml 내지 15μg/ml, 또는 이상적으로 약 12.5μg/ml로 존재한다. 특정 구체예에서, OMV는 2.5μg/ml 내지 12.5μg/ml의 더 낮은 농도, 예를 들어 2.5μg/ml, 3.0μg/ml, 3.5μg/ml, 4.0μg/ml, 4.5μg/ml, 5.0μg/ml, 5.5μg/ml, 6.0μg/ml, 6.5μg/ml, 7.0μg/ml, 7.5μg/ml, 8.0μg/ml, 8.5μg/ml, 9.0μg/ml, 9.5μg/ml 및 10μg/ml로 존재한다.
본 발명의 조성물 중 OMV 양 및 농도는 BEXSERO™ 제품과 동일한 방식으로, 즉 이들의 총 단백질 함량을 참고하여 정의된다. 이는 다양한 검정을 이용하여 평가될 수 있고, 예컨대 참고문헌 29는 Folin-Lowry 검정의 이용을 기재한다. 총 단백질은 문헌[European Pharmacopoeia, Ph. Eur. Assay 2.5.33]에 따라, 7가지 약전 방법 중 어느 하나를 이용하여 검정될 수 있다. 방법 2는 바람직한 Lowry 시험을 제공한다. 따라서, 본 발명의 두 번째 구체예의 조성물은 OMV를 5-30μg/총 단백질 ml로 포함한다.
폴리펩티드
본 발명의 폴리펩티드는 다양한 수단에 의해, 예를 들어, 화학적 합성(적어도 부분적으로)에 의해, 프로테아제를 이용한 더 긴 폴리펩티드의 분해에 의해, RNA로부터의 번역에 의해, 세포 배양액(예를 들어, 재조합 발현 또는 N. 메닌지티디스 배양액으로부터)으로부터 정제 등에 의해 제조될 수 있다. E. 콜리 숙주에서의 이종 발현이 바람직한 발현 경로이다.
본 발명의 폴리펩티드는 이상적으로는 적어도 100개 아미노산 길이, 예컨대 150aa, 175aa, 200aa, 225aa이거나, 더 길다. 예를 들어, fHbp 융합 폴리펩티드는 일반적으로 적어도 500aa 길이일 것이고, NHBA 폴리펩티드는 일반적으로 적어도 400aa 길이일 것이고, NadA 폴리펩티드는 일반적으로 적어도 250aa 길이일 것이다.
폴리펩티드는 바람직하게는 실질적으로 순수하거나 실질적으로 분리된 형태로 제조된다(즉, 실질적으로 다른 네이세리아 또는 숙주 세포 폴리펩티드가 없음). 일반적으로, 폴리펩티드는 비-자연 발생 환경으로 제공되며, 예를 들어, 이들은 이들의 자연 발생 환경으로부터 분리된다. 특정 구체예에서, 폴리펩티드는 출발 물질에 비해 폴리펩티드에 대해 풍부화된 조성물로 존재한다. 따라서, 정제된 폴리펩티드가 제공되며, 이 때 정제된이라 함은 폴리펩티드가 다른 발현된 폴리펩티드가 실질적으로 없는 조성물에 존재함을 의미하고, 실질적으로 없다는 것은 조성물의 총 폴리펩티드 중 50% 초과(예를 들어, ≥75%, ≥80%, ≥90%, ≥95%, 또는 ≥99%)가 본 발명의 폴리펩티드임을 의미한다.
폴리펩티드는 다양한 형태를 취할 수 있다(예를 들어, 천연, 융합, 비-당화, 지질화, 디설파이드 브릿지 등).
SEQ ID NO: 19와 같은 서열은 N-말단 메티오닌을 포함하지 않는다. 본 발명의 폴리펩티드가 생물학적 숙주에서 번역에 의해 생성되는 경우, 대부분의 숙주에서 N-말단 메티오닌을 제공할 개시 코돈을 필요로 한다. 따라서, 본 발명의 폴리펩티드는, 적어도 신생 단계에서, 상기 SEQ ID NO 서열의 업스트림에 메티오닌 잔기를 포함할 것이다.
일부 구체예에서 본 발명의 조성물 중 폴리펩티드는 (적절한 경우) fHbp, NHBA 또는 NadA 폴리펩티드 서열의 업스트림에 N-말단 서열을 포함할 수 있다. 일부 구체예에서, 폴리펩티드는 N-말단의 단일 메티오닌 바로 다음에 적절한 면역원의 아미노산 서열을 갖고; 다른 구체예에서, 더 긴 업스트림 서열이 이용될 수 있다. 그러한 업스트림 서열은 짧을(예를 들어, 40개 이하의 아미노산, 즉, 39개, 38개, 37개, 36개, 35개, 34개, 33개, 32개, 31개, 30개, 29개, 28개, 27개, 26개, 25개, 24개, 23개, 22개, 21개, 20개, 19개, 18개, 17개, 16개, 15개, 14개, 13개, 12개, 11개, 10개, 9개, 8개, 7개, 6개, 5개, 4개, 3개, 2개, 1개) 수 있다. 예로는 단백질 트래피킹을 유도하는 리더 서열, 또는 클로닝 또는 정제를 촉진하는 짧은 펩티드 서열(예를 들어, 히스티딘 태그, 즉, Hisn, 여기서 n = 4, 5, 6, 7, 8, 9, 10 이상(SEQ ID NO: 44))을 포함한다.
본 발명의 폴리펩티드는 또한 fHbp, NHBA 또는 NadA (적절한 경우) 아미노산 서열의 최종 아미노산의 다운스트림에 아미노산을 포함할 수 있다. 그러한 C-말단 신장은 짧을(예를 들어, 40개 이하의 아미노산, 즉, 39개, 38개, 37개, 36개, 35개, 34개, 33개, 32개, 31개, 30개, 29개, 28개, 27개, 26개, 25개, 24개, 23개, 22개, 21개, 20개, 19개, 18개, 17개, 16개, 15개, 14개, 13개, 12개, 11개, 10개, 9개, 8개, 7개, 6개, 5개, 4개, 3개, 2개, 1개) 수 있다. 예로는 단백질 트래피킹을 유도하는 서열, 클로닝 또는 정제를 촉진하는 짧은 펩티드 서열(예를 들어, 히스티딘 태그, 즉, Hisn을 포함함, 여기서 n = 4, 5, 6, 7, 8, 9, 10 이상(SEQ ID NO: 44)), 또는 폴리펩티드 안정성을 향상시키는 서열을 포함한다. 다른 적합한 C-말단 아미노산 서열은 당업자에게 명백할 것이다.
용어 "폴리펩티드"는 임의의 길이의 아미노산 중합체를 나타낸다. 중합체는 선형 또는 분지형일 수 있고, 이는 변형된 아미노산을 포함할 수 있고, 이는 비-아미노산에 의해 중단될 수 있다. 상기 용어는 또한 천연적으로 또는 개입에 의해, 예를 들어, 이황화 결합 형성, 당화, 지질화, 아세틸화, 인산화, 또는 임의의 다른 조작 또는 변형, 예를 들어, 표지 성분을 이용한 컨쥬게이션에 의해 변형된 아미노산 중합체를 포함한다. 예를 들어, 아미노산의 하나 이상의 유사체(예를 들어, 비천연 아미노산 등을 포함함), 뿐만 아니라 당 분야에 공지된 다른 변형을 함유하는 폴리펩티드가 또한 정의 내에 포함된다. 폴리펩티드는 단일 사슬 또는 회합된 사슬로 발생할 수 있다.
본 발명의 폴리펩티드는 바람직하게는 이종 숙주에서 (예를 들어, E.콜리에서) 재조합에 의해 발현된 다음, 정제되고, 이어서 조합되고 OMV로 제형화되어 본 발명의 조성물을 제공한다.
일부 구체예에서, 폴리펩티드는 N-말단에서 10개 이하의 아미노산(즉, 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 10개) 및/또는 C-말단에서 10개 이하의 아미노산(즉, 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 10개)이 결실된 것을 제외하고, 상기 기재된 바와 같은 아미노산 서열을 포함한다.
살균 반응
상기 언급된 대로, 본 발명의 바람직한 폴리펩티드 및 조성물은 수막구균에 대해 살균성인 항체 반응을 유도할 수 있다. 살균 항체 반응은 마우스의 면역화 후에 편리하게 측정되며, 백신 효능의 표준 지시자이다(예를 들어, 참고문헌 52의 말미의 주 14; 또한 참고문헌 53을 참조하라). 따라서, 항체는 적합한 혈청 살균 검정(SBA)에서 시험 균주에 대해 살균성일 것이다.
융합 fHbp 폴리펩티드는 바람직하게는 v1 fHbp를 발현하는 수막구균 균주, v2 fHbp를 발현하는 수막구균 균주, 및 또한 v3 fHbp를 발현하는 수막구균 균주에 대해 살균성인 항체를 유도할 수 있다. SBA 시험에 적합한 v1 균주는 MC58이고, 이는 광범하게 이용가능하며 (예컨대, ATCC BAA-335) 참고문헌 23에서 서열화된 균주였다. SBA 시험에 적합한 v2 균주는 M2091 (ATCC 13091)이다. SBA 시험에 적합한 v3 균주는 M01-240355이고, 이는 완전히 서열화된 (EMBL ID CP002422 [55]를 참조하라) 네이세리아 MLST 참조 균주 (참고문헌 54에서 id 19265)이다.
따라서, 바람직한 fHbp 융합 폴리펩티드는 혈청 살균성 검정에서 균주 MC58, M2091, 및 M01-240355 각각에 대해 살균성인 항체를 마우스에서 유도할 수 있다. 예를 들어, 본 발명의 조성물은 Goldschneider 검정을 이용하여 인간 보체 이용시 ≥1:4의 혈청 살균 역가[56-58], 및/또는 토끼 새끼 보체 이용시 ≥1:128의 혈청 살균 역가를 제공할 수 있다.
면역화
상기 논의된 폴리펩티드는 면역원성 조성물의 활성 성분(들)으로 이용될 수 있고, 따라서 본 발명은 상기 논의된 폴리펩티드를 포함하는 본 발명의 면역원성 조성물(예를 들어, 백신)을 제공한다.
본 발명은 또한 본 발명의 면역원성 조성물을 포유동물에 투여하는 것을 포함하는, 포유동물, 예컨대 마우스 또는 인간에서 항체 반응을 일으키는 방법을 제공한다. 항체 반응은 바람직하게는 보호 및/또는 살균성 항체 반응이다. 본 발명은 또한 이러한 방법에 사용하기 위한 본 발명의 조성물을 제공한다.
본 발명은 또한 본 발명의 면역원성 조성물을 포유동물에 투여하는 것을 포함하는, 네이세리아(예컨대, 수막구균) 감염에 대해 포유동물, 예를 들어 마우스 또는 인간을 보호하는 방법을 제공한다.
본 발명은 약제로서 사용되는 본 발명의 조성물을 제공한다 (예컨대, 면역원성 조성물로서 또는 백신으로서). 한 구체예에서, 본 발명은 또한 포유동물에서 네이세리아 (예컨대, 수막구균) 감염을 예방하기 위한 약제의 제조에서의 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드, 및 (i) NHBA 폴리펩티드 (ii) NadA 폴리펩티드 및/또는 (iii) 수막구균 외막 소체 중 하나 이상의 용도를 제공한다. 또 다른 구체예에서, 본 발명은 포유동물에서 네이세리아 (예컨대, 수막구균) 감염을 예방하기 위한 약제의 제조에서의 수막구균 외막 소체 및 (i) NHBA 폴리펩티드 (ii) NadA 폴리펩티드 및/또는 (iii) 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드 중 하나 이상의 용도를 제공하고, 이 때 약제 중 외막 소체의 농도는 5-30μg/ml이다.
포유동물은 바람직하게는 인간이다. 인간은 성인이거나, 바람직하게는, 소아일 수 있다. 백신이 예방용인 경우, 인간은 바람직하게는 소아이고(예를 들어, 영아 또는 유아); 백신이 치료용인 경우, 인간은 바람직하게는 성인이다. 아동에 대해 의도된 백신은 또한, 예를 들어, 안전성, 투여량, 면역원성 등을 평가하기 위해 성인에게 투여될 수 있다.
용도 및 방법은, 비제한적으로, 수막염(특히, 박테리아, 예를 들어, 수막구균, 수막염) 및 세균혈증을 포함하는 질병을 예방/치료하는데 특히 유용하다. 예를 들어, 이들은 N. 메닌지티디스(예를 들어, 혈청군 B)에 의해 야기된 침습성 수막구균 질병에 대한 개체의 능동 면역화에 적합하다.
치료적 치료의 효능은 본 발명의 조성물의 투여 후에 네이세리아 감염을 모니터함에 의해 시험될 수 있다. 예방적 치료의 효능은 본 조성물의 투여 후에 fHbp, NHBA, NadA 및 PorA (적절한 경우)에 대한 면역 반응을 모니터함에 의해 시험될 수 있다. 본 발명의 조성물의 면역원성은 이들을 시험 대상체(예를 들어, 소아 12-16개월, 또는 동물 모델)에 투여한 다음 혈청 살균성 항체(SBA) 및 ELISA 역가(GMT)를 포함하는 표준 파라미터를 측정함에 의해 결정될 수 있다. 이들 면역 반응은 일반적으로 본 조성물을 투여한 지 약 4주 후에 측정되고, 본 조성물의 투여 전에 측정된 값과 비교될 것이다. 적어도 4배 또는 8배의 SBA 증가가 바람직하다. 하나를 초과하는 본 조성물의 용량이 투여된 경우, 1회 초과의 투여-후 측정이 이루어질 수 있다.
본 발명의 바람직한 조성물은 허용되는 백분율의 인간 대상체에 대하여 각 항원성 성분에 대한 혈청보호를 위한 기준보다 우수한 항체 역가를 환자에서 제공할 수 있다. 숙주가 항원에 대해 혈청전환된 것으로 간주되는 것 이상의 관련 항체 역가를 갖는 항원은 널리 알려져 있고, 이러한 역가는 WHO와 같은 기구에 의해 공개되어 있다. 바람직하게는 대상체의 통계적으로 유의한 샘플의 80% 초과, 보다 바람직하게는 90% 초과, 더 더욱 바람직하게는 93% 초과 및 가장 바람직하게는 96-100%가 혈청전환된다.
본 발명을 이용하여 전신 및/또는 점막 면역을 유도할 수 있다.
본 발명의 조성물은 일반적으로 환자에 직접 투여될 것이다. 직접 전달은 비경구 주입(예를 들어, 피하, 복강내, 정맥내, 근내, 또는 조직의 사이질 공간으로), 또는 직장, 구강, 질, 국소, 경피, 비내, 안구, 귀, 폐 또는 다른 점막 투여에 의해 수행될 수 있다. 넙다리 또는 상지로의 근내 투여가 바람직하다. 주입은 바늘을 통해서일 수 있으나(예를 들어, 피부밑 바늘), 무침(needle-free) 주입이 대안적으로 이용될 수 있다. 통상적인 근내 용량은 약 0.5 ml(예를 들어, BEXSERO™ 제품에서 관찰되는 바와 같음)이다.
투여 치료는 단일 용량 스케줄 또는 다중 용량 스케줄일 수 있다. 다중 용량은 일차 면역화 스케줄 및/또는 부스터 면역화 스케줄에서 이용될 수 있다. 일차 용량 스케줄에 이어 부스터 용량 스케쥴이 올 수 있다. 프라이밍 용량 간의 적합한 타이밍(예를 들어, 4-16주), 및 프라이밍과 부스팅 간의 적합한 타이밍은 일상적으로 결정될 수 있다. 예를 들어, BEXSERO™ 제품은 대상체(예를 들어, 유아 또는 다른 대상체)에 따라 1개월 이상 또는 2개월 이상 떨어져 제공되는 2회 또는 3회 용량으로 투여된다.
본 발명의 면역원성 조성물은 일반적으로 조성물을 수용한 환자에 유해한 항체의 생성을 자체적으로 유도하지 않는 임의의 물질일 수 있고, 과도한 독성 없이 투여될 수 있는 약학적으로 허용되는 담체를 포함할 것이다. 약학적으로 허용되는 담체는 물, 염수, 글리세롤 및 에탄올과 같은 액체를 포함할 수 있다. 보조 물질, 예를 들어, 습윤제 또는 에멀젼화제, pH 완충 물질 등이 이러한 비히클에 또한 존재할 수 있다. 적합한 담체의 충분한 논의는 참고문헌 59에서 이용 가능하다. 예를 들어, BEXSERO™ 제품은 소듐 클로라이드, 히스티딘, 수크로스, 알루미늄 하이드록시드, 및 주사용수를 포함한다.
네이세리아 감염은 신체의 다양한 부위에 영향을 주므로 본 발명의 조성물은 다양한 형태로 제조될 수 있다. 예를 들어, 조성물은 액체 용액 또는 현탁액으로서, 주입가능물질로 제조될 수 있다. 주입 전에 액체 비히클에 용해 또는 현탁하기 적합한 고체 형태가 또한 제조될 수 있다. 비경구 주입(예를 들어, 근육으로)에 적합한 조성물이 가장 바람직하다.
조성물은 바람직하게는 멸균 조성물이다. 이는 바람직하게는 무-발열원이다. 이는 바람직하게는, 예를 들어, pH 6 내지 pH 8, 일반적으로 약 pH 7로 완충된다. 조성물이 알루미늄 하이드록시드 염을 포함하는 경우, 히스티딘 완충제를 이용하는 것이 바람직하다[60]. 본 발명의 조성물은 인간에 대해 등장성일 수 있다.
면역원성 조성물은 면역학적 유효량의 면역원, 뿐만 아니라 필요에 따라 임의의 다른 다른 명시된 성분들을 포함한다. '면역학적 유효량'은 단일 용량으로 또는 시리즈의 일부로서 개체로의 상기량의 투여가 치료 또는 예방에 효과적인 것을 의미한다. 상기량은 치료되는 개체의 건강 및 신체 상태, 연령, 치료되는 개체의 분류학적 그룹(예를 들어, 비-인간 영장류, 영장류 등), 항체를 합성하는 개체의 면역 반응의 능력, 요망되는 보호의 정도, 백신의 제형, 의학적 상황의 치료 의사의 평가, 및 다른 관련 요인에 따라 다양하다. 상기량이 일상적인 시험을 통해 결정될 수 있는 비교적 광범위한 범위 내에 해당할 것이 예상된다. 투여 치료는 단일 용량 스케줄 또는 다중 용량 스케줄일 수 있다(예를 들어, 부스터 용량 포함). 조성물은 다른 면역조절제와 함께 투여될 수 있다.
본 발명의 조성물에 이용될 수 있는 애쥬번트는, 비제한적으로, 불용성 금속염, 수중유 에멀젼(예를 들어, MF59 또는 AS03, 둘 모두는 스쿠알렌 함유), 사포닌, LPS의 무독성 유도체(예를 들어, 모노포스포릴 지질 A 또는 3-O-데아실화된 MPL), 면역자극성 올리고뉴클레오티드, 탈독화된 박테리아 ADP-리보실화 독소, 미세입자, 리포솜, 이미다조퀴놀론, 또는 이들의 혼합물을 포함한다. 면역자극제로서 작용하는 다른 물질은 참고문헌 61의 챕터 7에 기재되어 있다.
알루미늄 하이드록시드 및/또는 알루미늄 포스페이트 애쥬번트의 이용이 특히 바람직하고, 폴리펩티드는 일반적으로 이들 염에 흡착된다. 이들 염은 옥시하이드록시드 및 하이드록시포스페이트를 포함한다(예를 들어, 참고문헌 61의 챕터 8 & 9를 참조하라). 염은 임의의 적합한 형태를 취할 수 있다(예를 들어, 젤, 결정성, 무정형 등). Al+++은 <1 mg/용량으로 존재하여야 한다.
가장 바람직한 애쥬번트는 BEXSERO™ 제품에서 사용되는 바와 같은 알루미늄 하이드록시드이다. 본 발명의 조성물 내의 폴리펩티드 및 OMV는 BEXSERO™ 제품에서 관찰되는 바와 같이 상기 애쥬번트에 흡착될 수 있다. 알루미늄 하이드록시드는 약 1 mg/ml Al+++(즉 0.5ml 용량 당 0.5mg)으로 포함될 수 있다.
추가 항원성 성분
본 발명의 조성물은 fHbp, NHBA, NadA 및/또는 OMV 외에 추가의 수막구균 폴리펩티드 면역원을 포함할 수 있다. 에를 들어, 이는 NspA, App, NhhA, HmbR 등등 중 하나 이상을 포함할 수 있다.
본 발명의 조성물은 또한 '936' 항원을 포함할 수 있다. 936 항원은 수막구균 혈청군 B 균주 MC58에 대한 공개된 유전체 서열에[23] 유전자 NMB2091 (본원에서 SEQ ID NO: 20)로서 포함되었다. 본 발명에 사용하기 바람직한 936 항원은 (a) SEQ ID NO: 21과 50% 이상의 동일성 (예컨대, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% 이상)을 갖고/거나; (b) 'n'이 7 또는 그 초과(예컨대, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250 또는 그 초과)인 SEQ ID NO: 21의 적어도 'n'개의 연속 아미노산의 단편을 포함하는 아미노산 서열을 포함한다. (b)의 바람직한 단편은 SEQ ID NO: 21로부터의 에피토프를 포함한다. 본 발명의 가장 유용한 936 항원은 숙주 포유동물로의 투여 후 아미노산 서열 SEQ ID NO: 20으로 구성된 수막구균 폴리펩티드에 결합할 수 있는 항체를 유도할 수 있다. 936 항원은 fHbp에 대한 양호한 융합 파트너이다(예를 들어, 참고문헌 62 & 63을 참조하라).
본 조성물은 수막구균 폴리펩티드 항원 외에, 다른 질병 또는 감염에 대한 면역화를 위한 항원을 포함할 수 있다. 예를 들어, 본 조성물은 하기 추가 항원 중 하나 이상을 포함할 수 있다:
- N. 메닌지티디스 혈청군 A, C, W135 및/또는 Y로부터의 당류 항원, 예를 들어, 혈청군 C로부터 참고문헌 64(또한 참고문헌 65를 참조하라) 또는 참고문헌 66에 기재된 당류.
- 스트렙토코커스 뉴모니애(Streptococcus pneumoniae)로부터의 당류 항원[예를 들어, 67, 68, 69].
- A형 간염 바이러스, 예를 들어, 불활성화된 바이러스로부터의 항원[예를 들어, 70, 71].
- B형 간염 바이러스로부터의 항원, 예를 들어, 표면 및/또는 코어 항원[예를 들어, 71, 72].
- 디프테리아 항원, 예를 들어, 디프테리아 톡소이드[예를 들어, 참고문헌 73의 챕터 3], 예를 들어, CRM197 돌연변이체[예를 들어, 74].
- 파상풍 항원, 예를 들어, 파상풍 톡소이드(예를 들어, 참고문헌 73의 챕터 4).
- 보르데텔라 퍼투시스(Bordetella pertussis)로부터의 항원, 예를 들어, 임의로 또한 퍼탁틴 및/또는 아글루티노겐 2 및 3과 함께, B. 퍼투시스로부터의 백일해 홀로톡신(PT) 및 실모양 헤마글루티닌(FHA)(예를 들어, 참고문헌 75 & 76).
- 헤모필루스 인플루엔자(Haemophilus influenzae) B로부터의 당류 항원[예를 들어, 65].
- 소아마비 항원(들)[예를 들어, 77, 78], 예를 들어, IPV.
- 홍역, 볼거리 및/또는 풍진 항원(예를 들어, 참고문헌 73의 챕터 9, 10 & 11).
- 인플루엔자 항원(들)(예를 들어, 참고문헌 73의 챕터 19), 예를 들어, 헤마글루티닌 및/또는 뉴라미니다제 표면 단백질.
- 모락셀라 카타랄리스(Moraxella catarrhalis)로부터의 항원[예를 들어, 79].
- 스트렙토코커스 아갈락티아(Streptococcus agalactiae)(B그룹 스트렙토코커스)로부터의 단백질 항원[예를 들어, 80, 81].
- 스트렙토코커스 아갈락티아(B그룹 스트렙토코커스)로부터의 당류 항원.
- 스트렙토코커스 피오게네스(Streptococcus pyogenes)(A그룹 스트렙토코커스)로부터의 항원[예를 들어, 81, 82, 83].
- 스타필로코커스 아우레우스(Staphylococcus aureus)로부터의 항원[예를 들어, 84].
본 조성물은 이들 추가 항원 중 하나 이상을 포함할 수 있다.
독성 단백질 항원은 필요한 경우 탈독화될 수 있다(예를 들어, 화학적 및/또는 유전적 수단에 의한 백일해 독소의 탈독화[76]).
디프테리아 항원이 조성물에 포함되는 경우, 파상풍 항원 및 백일해 항원을 포함하는 것이 또한 바람직하다. 유사하게, 파상풍 항원이 포함되는 경우, 디프테리아 및 백일해 항원을 포함하는 것이 또한 바람직하다. 유사하게, 백일해 항원이 포함되는 경우, 디프테리아 및 파상풍 항원을 포함하는 것이 또한 바람직하다. 따라서 DTP 조합물이 바람직하다.
당류 항원은 바람직하게는 컨쥬게이트의 형태이다. 컨쥬게이트를 위한 담체 단백질은 하기에서 보다 자세하게 논의된다.
조성물 중 항원은 통상적으로 각각 적어도 1μg/ml의 농도로 존재할 것이다. 일반적으로, 임의의 주어진 항원의 농도는 그 항원에 대한 면역 반응을 유도하기에 충분할 것이다.
본 발명의 면역원성 조성물은 치료적으로(즉, 기존 감염을 치료하기 위해) 또는 예방적으로(즉, 앞으로의 감염을 예방하기 위해) 이용될 수 있다.
본 발명의 면역원성 조성물에 단백질 항원을 이용하는 것의 대안으로서, 항원을 인코딩하는 핵산(RNA, 예를 들어, 자기-복제 RNA, 또는 DNA, 예를 들어, 플라스미드일 수 있음)이 이용될 수 있다.
일부 구체예에서, 본 발명의 조성물은 수막구균 혈청군 A, C, W135 및 Y 중 1, 2, 3 또는 4개로부터의 컨쥬게이션된 캡슐 당류 항원을 포함한다. 다른 구체예에서, 본 발명의 조성물은 적어도 하나의 컨쥬게이션된 폐렴구균 캡슐 당류 항원을 포함한다.
수막구균 혈청군 Y, W135, C 및 A
현행 혈청군 C 백신(MENJUGATE™[64,85], MENINGITEC™ 및 NEISVAC-C™)은 컨쥬게이션된 당류를 포함한다. MENJUGATE™ 및 MeningitecMENINGITEC™은 CRM197 담체에 컨쥬게이션된 올리고당류 항원을 갖는 반면, NEISVAC-C™은 파상풍 톡소이드 담체에 컨쥬게이션된 완전한 다당류(데-O-아세틸화됨)를 이용한다. MENACTRA™ 백신은 혈청군 Y, W135, C 및 A의 각각으로부터의 컨쥬게이션된 캡슐 당류 항원을 함유한다.
본 발명의 조성물은 수막구균 혈청군 Y, W135, C 및 A 중 하나 이상으로부터의 캡슐 당류 항원을 포함할 수 있고, 여기서 항원은 담체 단백질(들)에 컨쥬게이션되고/거나 올리고당류이다. 예를 들어, 조성물은 혈청군 C; 혈청군 A 및 C; 혈청군 A, C 및 W135; 혈청군 A, C 및 Y; 혈청군 C, W135 및 Y로부터; 또는 4개 모두의 혈청군 A, C, W135 및 Y로부터의 캡슐 당류 항원을 포함할 수 있다.
용량 당 각각의 수막구균 당류 항원의 통상적인 양은 1μg 내지 20μg, 예를 들어, 약 1μg, 약 2.5μg, 약 4μg, 약 5μg, 또는 약 10μg이다(당류로서 표시됨).
혼합물이 혈청군 A 및 C 둘 모두로부터의 캡슐 당류를 포함하는 경우, MenA 당류:MenC 당류의 비율(w/w)은 1 초과일 수 있다(예를 들어, 2:1, 3:1, 4:1, 5:1, 10:1 또는 초과). 혼합물이 혈청군 Y 및 혈청군 C 및 W135 중 하나 또는 둘 모두로부터의 캡슐 당류를 포함하는 경우, MenY 당류:MenW135 당류의 비율(w/w)은 1 초과일 수 있고/거나(예를 들어, 2:1, 3:1, 4:1, 5:1, 10:1 또는 초과), MenY 당류:MenC 당류의 비율(w/w)은 1 미만일 수 있다(예를 들어, 1:2, 1:3, 1:4, 1:5, 또는 미만). 혈청군 A:C:W135:Y로부터의 당류에 대한 바람직한 비(w/w)는 1:1:1:1; 1:1:1:2; 2:1:1:1; 4:2:1:1; 8:4:2:1; 4:2:1:2; 8:4:1:2; 4:2:2:1; 2:2:1:1; 4:4:2:1; 2:2:1:2; 4:4:1:2; 및 2:2:2:1이다. 혈청군 C:W135:Y로부터의 당류에 대한 바람직한 비(w/w)는 1:1:1; 1:1:2; 1:1:1; 2:1:1; 4:2:1; 2:1:2; 4:1:2; 2:2:1; 및 2:1:1이다. 실질적으로 동등한 질량의 각 당류를 이용하는 것이 바람직하다.
캡슐 당류는 올리고당류의 형태로 이용될 수 있다. 이들은 정제된 캡슐 다당류의 단편화에 의해 편리하게 형성되고(예를 들어, 가수분해에 의해), 그 다음에 요망되는 크기의 단편의 정제가 일반적으로 이어질 것이다.
다당류의 단편화는 바람직하게는 30 미만(예를 들어, 혈청군 A에 대해 10 내지 20, 바람직하게는 약 10; 혈청군 W135 및 Y에 대해 15 내지 25, 바람직하게는 약 15-20; 혈청군 C에 대해 12 내지 22; 등등)의 올리고당류에서의 최종 평균 중합반응 정도(DP)를 제공하도록 수행된다. DP는 이온 교환 크로마토그래피 또는 비색 검정에 의해 편리하게 측정될 수 있다[86].
가수분해가 수행되면, 가수분해물은 일반적으로 짧은 길이 올리고당류를 제거하기 위해 크기조정될 것이다[65]. 이는 초미세여과 다음에 이온 교환 크로마토그래피와 같은, 다양한 방식으로 달성될 수 있다. 약 6 이하의 중합반응 정도를 갖는 올리고당류가 바람직하게는 혈청군 A에 대해 제거되고, 약 4 미만인 것들이 바람직하게는 혈청군 W135 및 Y에 대해 제거된다.
바람직한 MenC 당류 항원은 MENJUGATE™에서 이용된 바와 같이, 참고문헌 85에 기재되어 있다.
공유 컨쥬게이션
본 발명의 조성물의 캡슐 당류는 일반적으로 담체 단백질(들)에 컨쥬게이션될 것이다. 일반적으로, 컨쥬게이션은 이것이 T-독립적 항원으로부터 T-의존성 항원으로 당류를 전환시켜, 면역학적 기억에 대한 프라이밍을 허용함에 따라, 당류의 면역원성을 향상시킨다. 컨쥬게이션은 소아과 백신에 특히 유용하며 널리 알려진 기술이다.
통상적인 담체 단백질은 박테리아 독소, 예를 들어, 디프테리아 또는 파상풍 독소, 또는 이의 톡소이드 또는 돌연변이체이다. CRM197 디프테리아 독소 돌연변이체[87]가 유용하며, PREVNAR™ 제품의 담체이다. 다른 적합한 담체 단백질은 N. 메닌지티디스 외막 단백질 복합체[88], 합성 펩티드[89,90], 열 충격 단백질[91,92], 백일해 단백질[93,94], 사이토카인[95], 림포카인[95], 호르몬[95], 성장 인자[95], 다양한 병원체-유래 항원으로부터의 다수의 인간 CD4+ T 세포 에피토프를 포함하는 인공 단백질[96], 예를 들어, N19[97], H. 인플루엔자로부터의 단백질 D[98-100], 뉴몰리신[101] 또는 이의 무독성 유도체[102], 폐렴구균 표면 단백질 PspA[103], 철-흡수 단백질[104], C. 디피실레(C.difficile)로부터의 독소 A 또는 B[105], 재조합 P. 아에루기노사(P. aeruginosa) 엑소단백질 A(rEPA)[106] 등을 포함한다.
필요에 따라 임의의 적합한 링커를 이용하여, 임의의 적합한 컨쥬게이션 반응이 이용될 수 있다.
당류는 통상적으로 컨쥬게이션 전에 활성화되거나 작용기화될 것이다. 활성화는, 예를 들어, 시아닐화 시약, 예를 들어, CDAP(예를 들어, 1-시아노-4-디메틸아미노 피리디늄 테트라플루오로보레이트[107, 108, 등])를 수반할 수 있다. 다른 적합한 기술은 카르보디이미드, 하이드라지드, 활성 에스테르, 노르보란, p-니트로벤조산, N-하이드록시석신이미드, S-NHS, EDC, TSTU 등을 이용한다.
링커기를 통한 연결은 임의의 공지된 절차, 예를 들어, 참고문헌 109 및 110에 기재된 절차를 이용하여 이루어질 수 있다. 한 유형의 연결은 다당류의 환원성 아민화, 생성된 아미노기와 아디프산 링커기의 한 말단의 커플링, 및 이어서 아디프산 링커기의 다른 말단에 단백질 커플링을 포함한다[111,112]. 다른 링커는 B-프로피온아미도[113], 니트로페닐-에틸아민[114], 할로아실 할라이드[115], 글리코시드 연결[116], 6-아미노카프로산[117], ADH[118], C4 내지 C12 모이어티[119] 등을 포함한다. 링커를 이용하는 것에 대한 대안으로서, 직접 연결이 이용될 수 있다. 단백질로의 직접 연결은, 예를 들어, 참고문헌 120 및 121에 기재된 대로, 다당류의 산화 이후에 단백질에 의한 환원성 아민화를 포함할 수 있다.
아미노기를 당류에 도입시킨 다음(예를 들어, 말단 =O 기를 -NH2로 대체함에 의해) 아디프산 디에스테르(예를 들어, 아디프산 N-하이드록시석신이미도 디에스테르)에 의한 유도체화 및 담체 단백질과의 반응을 포함하는 공정이 바람직하다. 또 다른 바람직한 반응은, 예를 들어, MenA 또는 MenC의 경우 단백질 D 담체에 의한 CDAP 활성화를 이용한다.
총론
용어 "포함하는"은 "포함하는" 뿐만 아니라 "구성되는"을 포함하며, 예를 들어, X를 "포함하는" 조성물은 X만으로 구성될 수 있거나, 예를 들어, X + Y와 같이 추가적인 것을 포함할 수 있다. "포함하는"(또는 "포함하다" 등)에 대한 언급은 임의로 "구성된"(또는 "구성되다" 등)의 언급으로 대체될 수 있다.
숫자값 x와 관련된 용어 "약"은 임의적인 것이며, 예를 들어, x±10%를 의미한다.
용어 "실질적으로"는 "완전히"를 배제하지 않으며, 예를 들어, Y를 "실질적으로 함유하지 않는" 조성물은 Y를 완전히 함유하지 않을 수 있다. 필요한 경우, 용어 "실질적으로"는 본 발명의 정의로부터 생략될 수 있다.
"서열 동일성"은 바람직하게는 디폴트 파라미터(예를 들어, EBLOSUM62 스코어링 매트릭스를 이용하여 갭 오픈 페널티 = 10.0, 및 갭 신장 페널티 = 0.5를 지님)를 이용하는 니들먼-분쉬 전체 정렬 알고리즘[122]에 의해 결정된다. 이러한 알고리즘은 EMBOSS 패키지의 니들 툴[123]에서 편리하게 수행된다. 적용이 특정 SEQ ID에 대한 서열 동일성을 의미하는 경우, 동일성은 그 SEQ ID의 전체 길이에 걸쳐 계산되어야 한다.
혈청군 다음에, 수막구균 분류는 혈청형, 혈청아형 및 이어서 면역형을 포함하고, 표준 명명법은 각각이 B:4:P1.15:L3,7,9와 같이 콜론에 의해 분리된, 혈청군, 혈청형, 혈청아형, 및 면역형을 열거한다. 혈청군 B 내에서, 일부 계통은 종종 질병을 초래하고(과침습성), 일부 계통은 다른 것보다 더욱 심각한 형태의 질병을 초래하며(과병독성), 다른 것들은 질병을 거의 초래하지 않는다. 7개의 과병독성 계통이 인지되며, 즉 서브그룹 I, III 및 IV-1, ET-5 복합체, ET-37 복합체, A4 클러스터 및 계통 3이다. 이들은 다중좌(multilocus) 효소 전기영동(MLEE)에 의해 정의되었으나, 다중좌 서열 형결정(MLST)이 또한 수막구균을 분류하는데 이용되어 왔다. 4개의 주요 과병독성 클러스터는 ST32, ST44, ST8 및 ST11 복합체이다.
실시예
실시예 1:
BEXSERO™ 백신 (참조용)
BEXSERO™ 제품은 안전하고 효과적이며 유럽 및 다른 지역에서 인간에 대한 사용을 허가받았다. 이것은 0.5ml 용량 당 다음 면역원성 성분을 갖는다:
이들 면역원은 알루미늄 하이드록시드 애쥬번트 (용량 당 0.5mg Al+++)에 흡착된다. 조성물은 또한 NaCl, 히스티딘 완충제, 및 수크로스를 포함한다.
실시예 2: 안정화된 및 안정화된 비-결합 융합 폴리펩티드
본 발명자는 v2 및 v3에서 돌연변이의 두 상이한 유형을 연구하였다: 첫째로, 이들은 폴리펩티드의 안정성을 증가시키기 위해 변형될 수 있는 SEQ ID NO:2 및 SEQ ID NO:3 내의 잔기를 확인하였다. 둘째로, 이들은 인간 H 인자(fH)에 대한 결합을 감소시키는 잔기를 확인하였다. 둘 모두의 유형의 돌연변이를 포함하는 돌연변이체 fHbp 폴리펩티드는 향상된 특성을 갖는다. 특히, H 인자에 결합하지 않으나 면역원성을 보유한 fHbp 돌연변이체가 유리한데, 이는 결과로서 발생한 항체 반응이 fH-결합 부위 내 또는 근처의 에피토프에 대한 것이기 때문이다. 야생형 fHbp 백신 항원을 이용한 백신화 후, 상기 에피토프는 H 인자 결합에 의해 가려질 수 있다. 가장 흥미로운 아미노산은 하기와 같으며, 이는 전장 서열(SEQ ID NO:2 & 3) 및 또한 ΔG 서열(SEQ ID NO: 8 & 9)에 따라 넘버링된다.
** 이들 잔기 중 하나만이 돌연변이되는 경우, 이는 바람직하게는 류신이다.
안정성 및 fHbp 결합에 대한 돌연변이는 v2 및 v3의 돌연변이체 형태로 조합되고 R41S 돌연변이를 포함하는 돌연변이체 v1 서열과 융합되었다. 돌연변이체를 v2-v3-v1 순서로 융합시키고, 링커를 이용하여 연결시켜 731 SNB (SEQ ID NO: 38)를 제공하였다. 3개의 야생형 서열에 비해, 이러한 융합 폴리펩티드는 총 7개의 점 돌연변이를 포함한다 (도 2).
별도로, v2 및 v3의 안정성에 대한 돌연변이를 v2-v3-v1 순서로 'R41S' 돌연변이체 v1 서열과 융합시키고, 링커를 이용하여 연결시켜 731 S (SEQ ID NO: 40)를 제공하였다. 이에 따라, 3개의 야생형 서열에 비해, 이러한 융합 폴리펩티드는 총 5개의 점 돌연변이를 포함한다 (도 2).
SBA 역가를 유도하는 fHbp의 비-fH 결합 형태의 능력을 트랜스제닉(Tg) 마우스에서 시험하였다:
이들 데이터는 fHbp의 비-결합 형태가 더욱 면역원성일 수 있음을 나타낸다.
실시예 3:
NMB2091-fHbp 융합체의 치환
NMB2091-fHbp 융합 폴리펩티드를 N-말단으로부터 C-말단으로 v2-v3-v1을 갖는 fHbp 변이체의 "3중 융합" 폴리펩티드로 대체시킴에 의해 BEXSERO™ 제품을 변형시켰다. 이 융합 폴리펩티드는 아미노산 서열 SEQ ID NO: 10을 갖는다. 또한, OMV 성분을 제거하였다. 2개의 백신을 0, 21일 및 35일에 면역화된 마우스에서 비교하였고, 혈청을 다양한 클로날 복합체, MLST, 및 ET 분류의 15개 혈청군 B 균주의 패널에 대해 34일 및 49일에 평가하였다. 항원은 3mg/ml의 애쥬번트를 이용하여, 20μg/용량으로 투여되었다.
다양한 임계값 이상의 SBA 역가를 갖는 균주의 비율은 다음과 같았다:
이에 따라, v2-v3-v1 융합 폴리펩티드의 이용은 높은 항-MenB SBA 역가 (>4096)로 높은 비율의 패널 (60% vs. 53%)에 대한 커버를 제공할 수 있다.
실시예 4:
OMV 투여량의 4배 감소
NMB2091-fHbp 융합 폴리펩티드를 "3중 융합" fHbp v2-v3-v1 폴리펩티드 (SEQ ID NO:10)로 대체시키고 또한 (i) OMV 투여량을 12.5μg/ml로 4배 감소시키거나 (ii) OMV 성분을 제거함에 의해 BEXSERO™ 제품을 변형시켰다. 이에 따라 3개의 조성물이 제조되었다.
이러한 3개 백신의 면역원성을 평가하기 위해 인간 대상체는 매월 간격으로 3회 용량을 수용하였다 (0,1,2개월). 혈청을 관련 균주의 패널에 대한 평가를 위해 0, 1, 2 및 3개월, 및 이어서 세 번째 용량의 6개월 후 (8개월)에 취하였다. 역가(GMT)는 다음과 같았다.
풀링된 환자 혈청을 v1 fHbp를 발현하는 7개 MenB 균주 패널의 적용범위를 평가하는데 이용하였다. 각 그룹에서 유사한 수의 균주가 적절하게 커버되었으나, 역가(GMT)는 그룹 C에서 가장 높았다:
단일 환자 혈청을 v2 또는 v3 fHbp를 발현하는 6개 MenB 균주 패널에 대해 시험하였다 (한 균주가 2회 시험되었다). 역시, 역가(GMT)는 그룹 C에서 가장 높았다:
더욱이, 1:8 이상의 SBA 역가를 지닌 면역화된 대상체의 비율은 그룹 M 및 S에 비해 그룹 C에서 일반적으로 높았고, 예컨대 3회 용량 후 균주 M1239에 대해 80% 이상인데 반해, 다른 두 그룹에서는 50% 이하였다.
SBA 역가의 RCD 곡선 (역 누적 분포)은 또한 양호한 프로파일을 보여주었고, 예컨대 도 1은 균주 UK293에 대한 3개월 혈청 곡선을 도시하고, 그룹 C는 명백하게 다른 둘보다 높다.
풀링된 환자 혈청을 v2 또는 v3 fHbp를 발현하는 26개 MenB 균주 패널의 적용범위를 평가하는데 이용하였다. 역시, 역가(GMT)는 그룹 C에서 가장 높았다:
따라서, 이러한 데이터는 fHbp 면역원이 대체되고 OMV 투여량이 4배 감소된 백신 'C'가 BEXSERO™ 백신보다 열등하지 않음을 보여준다. 실제로, 단일-대상체 및 풀링된 혈청 둘 모두는 BEXSERO™ 백신에 비해 양호한 혈청반응률, 높은 GMT 및 백신 'C'에 대한 증가된 균주 적용범위를 보여준다.
실시예 5:
항체 결합활성(avidity)
그룹 'C' 및 'S'의 환자로부터의 항체의 결합활성을 항원으로부터 저 친화성 항체를 분리하기 위해 카오트로픽 시약을 이용하는 세척 단계를 포함하는 Gyrolab-기반 시스템을 이용하여 비교하여, 총 v1.fHbp-특이적 항체 중 고 친화성 항-v1.fHbp 항체의 비율로서 '결합활성 지수'를 제공하였다. 첫 번째 용량 1개월 후 및 세 번째 용량 1개월 후에 20개의 분리된 혈청을 평가하였다. 또한, SBA 역가를 균주 H44/76에 대해 평가하고, 결합활성 지수 및 SBA 역가 (log2) 간의 상관관계를 결정하였다.
결과 (Pearson 상관관계에 의한 R 및 p)는 다음과 같았다:
이에 따라, 그룹 'C'에서 두 시점 모두에 SBA 역가와 결합활성 지수 간에 현저한 상관관계가 존재하였으나, 그룹 'S'에서는 존재하지 않았다. 12.5μg/ml의 OMV를 갖는 백신을 수용한 대상체에서 결합활성 지수는 SBA 역가와 상관관계가 있었는데, 이는 OMV의 존재가 유도된 항체의 품질에 긍정적인 영향을 미침을 제안한다. 전반적으로, OMV를 수용한 대상체에서 살균성 역가가 높아지고 이는 백신 제형에 의해 유도된 항체의 결합활성과 상관관계를 갖는 경향이 있다
다음 기준을 기초로 하여 var2/3 균주의 서브패널을 단일 대상체 혈청 시험을 위해 선택하였다: (i) 종래 임상 시험에서 Bexsero에 의해 커버되지 않는 균주, (ii) 균주는 관련 클로날 복합체에 속함, (iii) 균주는 역학적으로 관련된 fHbp 서브변이체를 발현시킴, (iv) fHbp 발현 수준은 중간임, (v) 균주는 741-231 (경쟁적 hSBA)에 의해 특이적으로 사멸됨. 결과는 741-231+1/4OMV+alum이 시험된 7개 균주에 대해 더 높은 GMT를 유도함을 입증하는 도 3(a) 내지 3(g)에 도시된다. 따라서, hSBA 시험은 741-231 융합체를 포함하는 제형이 Bexsero에 비해 열등하지 않음을 나타낸다. 사실상, 단일 대상체 혈청 및 var2/3 균주에 대한 풀링된 혈청 분석 둘 모두는 양호한 혈청반응률, 높은 GMT 역가 및 741-231+1/4OMV+alum을 포함하는 제형에 대해 증가된 균주 적용범위를 나타낸다.
실시예 6:
OMV 투여량의 감소 및 731 'S' 및 731 'SNB'의 이용
NMB2091-fHbp 융합 폴리펩티드를 "3중 융합" 안정화된 또는 안정화된 비-결합 fHbp v2-v3-v1 폴리펩티드 (각각 SEQ ID NO:40 및 38)로 대체시키고 또한 OMV 투여량을 10μg/ml 또는 2.5μg/ml로 감소시켜 BEXSERO™ 제품을 변형시켰다.
마우스 항혈청을 제조하기 위해, 균주 NZ98/254로부터 유래된 10 μg 또는 2.5 ug의 OMV와 함께 20 μg의 NadA, NHBA-NMB1030 및 어느 하나의 NMB2091-fHbp, fHbp 231S 또는 fHbp 231SNB를 이용하여 6주령 CD1 암컷 마우스 (Charles River)를 면역시켰다. 그룹 당 8마리 마우스를 이용하였다. 항원을 0, 21일 및 35일에 알루미늄 하이드록시드 (3 mg/ml)와 함께 복강내 투여하였다. 최종 채혈 2주 후에 혈청을 수집하고 시험 전에 56℃에서 30분 동안 열-불활성화시켰다.
동물 혈청 및 인간 보체를 이용한 혈청 살균성 검정
Nm 균주에 대한 혈청 살균성 활성을 종래 기재된 대로 평가하였다. 건강한 성인 (25 또는 50%의 최종 농도로 시험시 내재적 살균 활성 갖지 않음)으로부터의 인간 혈청 또는 혈장을 보체 공급원으로서 이용하였다. 혈청 살균성 역가는, 0시에 ml 당 대조 집락 형성 단위(CFU)에 비해, 박테리아와 반응 혼합물의 60분 인큐베이션 후 ml 당 CFU에서 50% 감소를 발생시키는 혈청 희석율로서 정의되었다.
각 혈청에 대해 시험된 최저 희석율은 1:16이었다 (검출 한계). 검출 한계 미만의 역가는 분석의 목적으로 그 한계의 절반으로 설정되었고 양성 임계값은 이 값에 비해 4배 상승으로서 정의되었다 (즉, 32). Bexsero 제형으로 면역된 마우스로부터 유래된 풀링된 혈청은 시험된 34개 균주 중 14개 균주에 대해 양성 임계값 미만인 반면, 2세대 제형으로부터 유래된 풀링된 혈청은 fHbp 231SNB를 함유하는 백신 제형의 경우 단 1개의 균주 그리고 fHbp 231S를 함유하는 제형의 경우 1개의 균주에 대해 검출 한계 미만이었다.
하기 표에 보고된 hSBA 데이터는 시험된 34개 균주의 패널에서 Bexsero에 비해 fHbp 231S 또는 fHbp 231SNB를 함유하는 백신 제형에 의해 유도된 적용범위의 증가를 나타내었다:
본 발명은 단지 예시에 의해 상기와 같이 기재되었으며, 본 발명의 범위 및 사상 내에서 유지되면서 변형이 이루어질 수 있음이 이해될 것이다.
참고문헌
서열 목록
SEQUENCE LISTING
<110> GLAXOSMITHKLINE BIOLOGICALS S.A.
<120> MENINGOCOCCUS VACCINES
<130> VN56308 WO
<140>
<141>
<150> EP 14177563.5
<151> 2014-07-17
<160> 44
<170> PatentIn version 3.5
<210> 1
<211> 274
<212> PRT
<213> Neisseria meningitidis
<400> 1
Met Asn Arg Thr Ala Phe Cys Cys Leu Ser Leu Thr Thr Ala Leu Ile
1 5 10 15
Leu Thr Ala Cys Ser Ser Gly Gly Gly Gly Val Ala Ala Asp Ile Gly
20 25 30
Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His Lys Asp Lys
35 40 45
Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Arg Lys Asn Glu Lys
50 55 60
Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly Asn Gly Asp
65 70 75 80
Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser Arg Phe Asp
85 90 95
Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr Leu Glu Ser
100 105 110
Gly Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu Thr Ala Phe
115 120 125
Gln Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys Met Val Ala
130 135 140
Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His Thr Ser Phe
145 150 155 160
Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly Thr Ala Phe
165 170 175
Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile Asp Phe Ala
180 185 190
Ala Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser Pro Glu Leu
195 200 205
Asn Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly Lys Arg His
210 215 220
Ala Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu Lys Gly Ser
225 230 235 240
Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val Ala Gly Ser
245 250 255
Ala Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly Leu Ala Ala
260 265 270
Lys Gln
<210> 2
<211> 273
<212> PRT
<213> Neisseria meningitidis
<400> 2
Met Asn Arg Thr Ala Phe Cys Cys Leu Ser Leu Thr Ala Ala Leu Ile
1 5 10 15
Leu Thr Ala Cys Ser Ser Gly Gly Gly Gly Val Ala Ala Asp Ile Gly
20 25 30
Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His Lys Asp Lys
35 40 45
Ser Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Arg Lys Asn Glu Lys
50 55 60
Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly Asn Gly Asp
65 70 75 80
Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser Arg Phe Asp
85 90 95
Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr Leu Glu Ser
100 105 110
Gly Glu Phe Gln Ile Tyr Lys Gln Asp His Ser Ala Val Val Ala Leu
115 120 125
Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys Ile Asp Ser Leu Ile Asn
130 135 140
Gln Arg Ser Phe Leu Val Ser Gly Leu Gly Gly Glu His Thr Ala Phe
145 150 155 160
Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr His Gly Lys Ala Phe Ser
165 170 175
Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile Asp Phe Ala Ala
180 185 190
Lys Gln Gly His Gly Lys Ile Glu His Leu Lys Thr Pro Glu Gln Asn
195 200 205
Val Glu Leu Ala Ala Ala Glu Leu Lys Ala Asp Glu Lys Ser His Ala
210 215 220
Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser Glu Glu Lys Gly Thr Tyr
225 230 235 240
His Leu Ala Leu Phe Gly Asp Arg Ala Gln Glu Ile Ala Gly Ser Ala
245 250 255
Thr Val Lys Ile Gly Glu Lys Val His Glu Ile Gly Ile Ala Gly Lys
260 265 270
Gln
<210> 3
<211> 281
<212> PRT
<213> Neisseria meningitidis
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Met Asn Arg Thr Ala Phe Cys Cys Leu Ser Leu Thr Thr Ala Leu Ile
1 5 10 15
Leu Thr Ala Cys Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Val
20 25 30
Ala Ala Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu
35 40 45
Asp His Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Ser Ile
50 55 60
Pro Gln Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr
65 70 75 80
Phe Lys Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys
85 90 95
Asn Asp Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val Asp
100 105 110
Gly Gln Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln
115 120 125
Asn His Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro
130 135 140
Asp Lys Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Leu Val Ser Gly
145 150 155 160
Leu Gly Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala
165 170 175
Glu Tyr His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu
180 185 190
His Tyr Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu
195 200 205
His Leu Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu
210 215 220
Lys Ala Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr
225 230 235 240
Gly Ser Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg
245 250 255
Ala Gln Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val
260 265 270
His Glu Ile Gly Ile Ala Gly Lys Gln
275 280
<210> 4
<211> 255
<212> PRT
<213> Neisseria meningitidis
<400> 4
Cys Ser Ser Gly Gly Gly Gly Val Ala Ala Asp Ile Gly Ala Gly Leu
1 5 10 15
Ala Asp Ala Leu Thr Ala Pro Leu Asp His Lys Asp Lys Gly Leu Gln
20 25 30
Ser Leu Thr Leu Asp Gln Ser Val Arg Lys Asn Glu Lys Leu Lys Leu
35 40 45
Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly Asn Gly Asp Ser Leu Asn
50 55 60
Thr Gly Lys Leu Lys Asn Asp Lys Val Ser Arg Phe Asp Phe Ile Arg
65 70 75 80
Gln Ile Glu Val Asp Gly Gln Leu Ile Thr Leu Glu Ser Gly Glu Phe
85 90 95
Gln Val Tyr Lys Gln Ser His Ser Ala Leu Thr Ala Phe Gln Thr Glu
100 105 110
Gln Ile Gln Asp Ser Glu His Ser Gly Lys Met Val Ala Lys Arg Gln
115 120 125
Phe Arg Ile Gly Asp Ile Ala Gly Glu His Thr Ser Phe Asp Lys Leu
130 135 140
Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly Thr Ala Phe Gly Ser Asp
145 150 155 160
Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile Asp Phe Ala Ala Lys Gln
165 170 175
Gly Asn Gly Lys Ile Glu His Leu Lys Ser Pro Glu Leu Asn Val Asp
180 185 190
Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly Lys Arg His Ala Val Ile
195 200 205
Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu Lys Gly Ser Tyr Ser Leu
210 215 220
Gly Ile Phe Gly Gly Lys Ala Gln Glu Val Ala Gly Ser Ala Glu Val
225 230 235 240
Lys Thr Val Asn Gly Ile Arg His Ile Gly Leu Ala Ala Lys Gln
245 250 255
<210> 5
<211> 254
<212> PRT
<213> Neisseria meningitidis
<400> 5
Cys Ser Ser Gly Gly Gly Gly Val Ala Ala Asp Ile Gly Ala Gly Leu
1 5 10 15
Ala Asp Ala Leu Thr Ala Pro Leu Asp His Lys Asp Lys Ser Leu Gln
20 25 30
Ser Leu Thr Leu Asp Gln Ser Val Arg Lys Asn Glu Lys Leu Lys Leu
35 40 45
Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly Asn Gly Asp Ser Leu Asn
50 55 60
Thr Gly Lys Leu Lys Asn Asp Lys Val Ser Arg Phe Asp Phe Ile Arg
65 70 75 80
Gln Ile Glu Val Asp Gly Gln Leu Ile Thr Leu Glu Ser Gly Glu Phe
85 90 95
Gln Ile Tyr Lys Gln Asp His Ser Ala Val Val Ala Leu Gln Ile Glu
100 105 110
Lys Ile Asn Asn Pro Asp Lys Ile Asp Ser Leu Ile Asn Gln Arg Ser
115 120 125
Phe Leu Val Ser Gly Leu Gly Gly Glu His Thr Ala Phe Asn Gln Leu
130 135 140
Pro Asp Gly Lys Ala Glu Tyr His Gly Lys Ala Phe Ser Ser Asp Asp
145 150 155 160
Ala Gly Gly Lys Leu Thr Tyr Thr Ile Asp Phe Ala Ala Lys Gln Gly
165 170 175
His Gly Lys Ile Glu His Leu Lys Thr Pro Glu Gln Asn Val Glu Leu
180 185 190
Ala Ala Ala Glu Leu Lys Ala Asp Glu Lys Ser His Ala Val Ile Leu
195 200 205
Gly Asp Thr Arg Tyr Gly Ser Glu Glu Lys Gly Thr Tyr His Leu Ala
210 215 220
Leu Phe Gly Asp Arg Ala Gln Glu Ile Ala Gly Ser Ala Thr Val Lys
225 230 235 240
Ile Gly Glu Lys Val His Glu Ile Gly Ile Ala Gly Lys Gln
245 250
<210> 6
<211> 262
<212> PRT
<213> Neisseria meningitidis
<400> 6
Cys Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Val Ala Ala Asp
1 5 10 15
Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His Lys
20 25 30
Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Ser Ile Pro Gln Asn
35 40 45
Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys Ala
50 55 60
Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys
65 70 75 80
Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln Thr
85 90 95
Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His Ser
100 105 110
Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys Thr
115 120 125
Asp Ser Leu Ile Asn Gln Arg Ser Phe Leu Val Ser Gly Leu Gly Gly
130 135 140
Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr His
145 150 155 160
Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr Ser
165 170 175
Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu Lys
180 185 190
Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala Asp
195 200 205
Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser Glu
210 215 220
Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln Glu
225 230 235 240
Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu Ile
245 250 255
Gly Ile Ala Gly Lys Gln
260
<210> 7
<211> 248
<212> PRT
<213> Neisseria meningitidis
<400> 7
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser
20 25 30
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
35 40 45
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
50 55 60
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
65 70 75 80
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Val Tyr Lys Gln Ser His
85 90 95
Ser Ala Leu Thr Ala Phe Gln Thr Glu Gln Ile Gln Asp Ser Glu His
100 105 110
Ser Gly Lys Met Val Ala Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala
115 120 125
Gly Glu His Thr Ser Phe Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr
130 135 140
Tyr Arg Gly Thr Ala Phe Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr
145 150 155 160
Tyr Thr Ile Asp Phe Ala Ala Lys Gln Gly Asn Gly Lys Ile Glu His
165 170 175
Leu Lys Ser Pro Glu Leu Asn Val Asp Leu Ala Ala Ala Asp Ile Lys
180 185 190
Pro Asp Gly Lys Arg His Ala Val Ile Ser Gly Ser Val Leu Tyr Asn
195 200 205
Gln Ala Glu Lys Gly Ser Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala
210 215 220
Gln Glu Val Ala Gly Ser Ala Glu Val Lys Thr Val Asn Gly Ile Arg
225 230 235 240
His Ile Gly Leu Ala Ala Lys Gln
245
<210> 8
<211> 247
<212> PRT
<213> Neisseria meningitidis
<400> 8
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Ser
20 25 30
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
35 40 45
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
50 55 60
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
65 70 75 80
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His
85 90 95
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
100 105 110
Ile Asp Ser Leu Ile Asn Gln Arg Ser Phe Leu Val Ser Gly Leu Gly
115 120 125
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr
130 135 140
His Gly Lys Ala Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr
145 150 155 160
Thr Ile Asp Phe Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu
165 170 175
Lys Thr Pro Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
180 185 190
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
195 200 205
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
210 215 220
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
225 230 235 240
Ile Gly Ile Ala Gly Lys Gln
245
<210> 9
<211> 250
<212> PRT
<213> Neisseria meningitidis
<400> 9
Val Ala Ala Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Ser
20 25 30
Ile Pro Gln Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys
35 40 45
Thr Phe Lys Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu
50 55 60
Lys Asn Asp Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val
65 70 75 80
Asp Gly Gln Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys
85 90 95
Gln Asn His Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn
100 105 110
Pro Asp Lys Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Leu Val Ser
115 120 125
Gly Leu Gly Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys
130 135 140
Ala Glu Tyr His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg
145 150 155 160
Leu His Tyr Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile
165 170 175
Glu His Leu Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu
180 185 190
Leu Lys Ala Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg
195 200 205
Tyr Gly Ser Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp
210 215 220
Arg Ala Gln Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys
225 230 235 240
Val His Glu Ile Gly Ile Ala Gly Lys Gln
245 250
<210> 10
<211> 776
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 10
Met Gly Pro Asp Ser Asp Arg Leu Gln Gln Arg Arg Val Ala Ala Asp
1 5 10 15
Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His Lys
20 25 30
Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Arg Lys Asn
35 40 45
Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly Asn
50 55 60
Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser Arg
65 70 75 80
Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr Leu
85 90 95
Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His Ser Ala Val Val
100 105 110
Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys Ile Asp Ser Leu
115 120 125
Ile Asn Gln Arg Ser Phe Leu Val Ser Gly Leu Gly Gly Glu His Thr
130 135 140
Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr His Gly Lys Ala
145 150 155 160
Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile Asp Phe
165 170 175
Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu Lys Thr Pro Glu
180 185 190
Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala Asp Glu Lys Ser
195 200 205
His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser Glu Glu Lys Gly
210 215 220
Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln Glu Ile Ala Gly
225 230 235 240
Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu Ile Gly Ile Ala
245 250 255
Gly Lys Gln Gly Ser Gly Pro Asp Ser Asp Arg Leu Gln Gln Arg Arg
260 265 270
Val Ala Ala Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro
275 280 285
Leu Asp His Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Ser
290 295 300
Ile Pro Gln Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys
305 310 315 320
Thr Phe Lys Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu
325 330 335
Lys Asn Asp Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val
340 345 350
Asp Gly Gln Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys
355 360 365
Gln Asn His Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn
370 375 380
Pro Asp Lys Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Leu Val Ser
385 390 395 400
Gly Leu Gly Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys
405 410 415
Ala Glu Tyr His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg
420 425 430
Leu His Tyr Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile
435 440 445
Glu His Leu Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu
450 455 460
Leu Lys Ala Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg
465 470 475 480
Tyr Gly Ser Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp
485 490 495
Arg Ala Gln Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys
500 505 510
Val His Glu Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly
515 520 525
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
530 535 540
Leu Asp His Lys Asp Lys Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser
545 550 555 560
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
565 570 575
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
580 585 590
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
595 600 605
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Val Tyr Lys Gln Ser His
610 615 620
Ser Ala Leu Thr Ala Phe Gln Thr Glu Gln Ile Gln Asp Ser Glu His
625 630 635 640
Ser Gly Lys Met Val Ala Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala
645 650 655
Gly Glu His Thr Ser Phe Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr
660 665 670
Tyr Arg Gly Thr Ala Phe Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr
675 680 685
Tyr Thr Ile Asp Phe Ala Ala Lys Gln Gly Asn Gly Lys Ile Glu His
690 695 700
Leu Lys Ser Pro Glu Leu Asn Val Asp Leu Ala Ala Ala Asp Ile Lys
705 710 715 720
Pro Asp Gly Lys Arg His Ala Val Ile Ser Gly Ser Val Leu Tyr Asn
725 730 735
Gln Ala Glu Lys Gly Ser Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala
740 745 750
Gln Glu Val Ala Gly Ser Ala Glu Val Lys Thr Val Asn Gly Ile Arg
755 760 765
His Ile Gly Leu Ala Ala Lys Gln
770 775
<210> 11
<211> 488
<212> PRT
<213> Neisseria meningitidis
<400> 11
Met Phe Lys Arg Ser Val Ile Ala Met Ala Cys Ile Phe Ala Leu Ser
1 5 10 15
Ala Cys Gly Gly Gly Gly Gly Gly Ser Pro Asp Val Lys Ser Ala Asp
20 25 30
Thr Leu Ser Lys Pro Ala Ala Pro Val Val Ser Glu Lys Glu Thr Glu
35 40 45
Ala Lys Glu Asp Ala Pro Gln Ala Gly Ser Gln Gly Gln Gly Ala Pro
50 55 60
Ser Ala Gln Gly Ser Gln Asp Met Ala Ala Val Ser Glu Glu Asn Thr
65 70 75 80
Gly Asn Gly Gly Ala Val Thr Ala Asp Asn Pro Lys Asn Glu Asp Glu
85 90 95
Val Ala Gln Asn Asp Met Pro Gln Asn Ala Ala Gly Thr Asp Ser Ser
100 105 110
Thr Pro Asn His Thr Pro Asp Pro Asn Met Leu Ala Gly Asn Met Glu
115 120 125
Asn Gln Ala Thr Asp Ala Gly Glu Ser Ser Gln Pro Ala Asn Gln Pro
130 135 140
Asp Met Ala Asn Ala Ala Asp Gly Met Gln Gly Asp Asp Pro Ser Ala
145 150 155 160
Gly Gly Gln Asn Ala Gly Asn Thr Ala Ala Gln Gly Ala Asn Gln Ala
165 170 175
Gly Asn Asn Gln Ala Ala Gly Ser Ser Asp Pro Ile Pro Ala Ser Asn
180 185 190
Pro Ala Pro Ala Asn Gly Gly Ser Asn Phe Gly Arg Val Asp Leu Ala
195 200 205
Asn Gly Val Leu Ile Asp Gly Pro Ser Gln Asn Ile Thr Leu Thr His
210 215 220
Cys Lys Gly Asp Ser Cys Ser Gly Asn Asn Phe Leu Asp Glu Glu Val
225 230 235 240
Gln Leu Lys Ser Glu Phe Glu Lys Leu Ser Asp Ala Asp Lys Ile Ser
245 250 255
Asn Tyr Lys Lys Asp Gly Lys Asn Asp Lys Phe Val Gly Leu Val Ala
260 265 270
Asp Ser Val Gln Met Lys Gly Ile Asn Gln Tyr Ile Ile Phe Tyr Lys
275 280 285
Pro Lys Pro Thr Ser Phe Ala Arg Phe Arg Arg Ser Ala Arg Ser Arg
290 295 300
Arg Ser Leu Pro Ala Glu Met Pro Leu Ile Pro Val Asn Gln Ala Asp
305 310 315 320
Thr Leu Ile Val Asp Gly Glu Ala Val Ser Leu Thr Gly His Ser Gly
325 330 335
Asn Ile Phe Ala Pro Glu Gly Asn Tyr Arg Tyr Leu Thr Tyr Gly Ala
340 345 350
Glu Lys Leu Pro Gly Gly Ser Tyr Ala Leu Arg Val Gln Gly Glu Pro
355 360 365
Ala Lys Gly Glu Met Leu Ala Gly Ala Ala Val Tyr Asn Gly Glu Val
370 375 380
Leu His Phe His Thr Glu Asn Gly Arg Pro Tyr Pro Thr Arg Gly Arg
385 390 395 400
Phe Ala Ala Lys Val Asp Phe Gly Ser Lys Ser Val Asp Gly Ile Ile
405 410 415
Asp Ser Gly Asp Asp Leu His Met Gly Thr Gln Lys Phe Lys Ala Ala
420 425 430
Ile Asp Gly Asn Gly Phe Lys Gly Thr Trp Thr Glu Asn Gly Ser Gly
435 440 445
Asp Val Ser Gly Lys Phe Tyr Gly Pro Ala Gly Glu Glu Val Ala Gly
450 455 460
Lys Tyr Ser Tyr Arg Pro Thr Asp Ala Glu Lys Gly Gly Phe Gly Val
465 470 475 480
Phe Ala Gly Lys Lys Glu Gln Asp
485
<210> 12
<211> 464
<212> PRT
<213> Neisseria meningitidis
<400> 12
Ser Pro Asp Val Lys Ser Ala Asp Thr Leu Ser Lys Pro Ala Ala Pro
1 5 10 15
Val Val Ser Glu Lys Glu Thr Glu Ala Lys Glu Asp Ala Pro Gln Ala
20 25 30
Gly Ser Gln Gly Gln Gly Ala Pro Ser Ala Gln Gly Ser Gln Asp Met
35 40 45
Ala Ala Val Ser Glu Glu Asn Thr Gly Asn Gly Gly Ala Val Thr Ala
50 55 60
Asp Asn Pro Lys Asn Glu Asp Glu Val Ala Gln Asn Asp Met Pro Gln
65 70 75 80
Asn Ala Ala Gly Thr Asp Ser Ser Thr Pro Asn His Thr Pro Asp Pro
85 90 95
Asn Met Leu Ala Gly Asn Met Glu Asn Gln Ala Thr Asp Ala Gly Glu
100 105 110
Ser Ser Gln Pro Ala Asn Gln Pro Asp Met Ala Asn Ala Ala Asp Gly
115 120 125
Met Gln Gly Asp Asp Pro Ser Ala Gly Gly Gln Asn Ala Gly Asn Thr
130 135 140
Ala Ala Gln Gly Ala Asn Gln Ala Gly Asn Asn Gln Ala Ala Gly Ser
145 150 155 160
Ser Asp Pro Ile Pro Ala Ser Asn Pro Ala Pro Ala Asn Gly Gly Ser
165 170 175
Asn Phe Gly Arg Val Asp Leu Ala Asn Gly Val Leu Ile Asp Gly Pro
180 185 190
Ser Gln Asn Ile Thr Leu Thr His Cys Lys Gly Asp Ser Cys Ser Gly
195 200 205
Asn Asn Phe Leu Asp Glu Glu Val Gln Leu Lys Ser Glu Phe Glu Lys
210 215 220
Leu Ser Asp Ala Asp Lys Ile Ser Asn Tyr Lys Lys Asp Gly Lys Asn
225 230 235 240
Asp Lys Phe Val Gly Leu Val Ala Asp Ser Val Gln Met Lys Gly Ile
245 250 255
Asn Gln Tyr Ile Ile Phe Tyr Lys Pro Lys Pro Thr Ser Phe Ala Arg
260 265 270
Phe Arg Arg Ser Ala Arg Ser Arg Arg Ser Leu Pro Ala Glu Met Pro
275 280 285
Leu Ile Pro Val Asn Gln Ala Asp Thr Leu Ile Val Asp Gly Glu Ala
290 295 300
Val Ser Leu Thr Gly His Ser Gly Asn Ile Phe Ala Pro Glu Gly Asn
305 310 315 320
Tyr Arg Tyr Leu Thr Tyr Gly Ala Glu Lys Leu Pro Gly Gly Ser Tyr
325 330 335
Ala Leu Arg Val Gln Gly Glu Pro Ala Lys Gly Glu Met Leu Ala Gly
340 345 350
Ala Ala Val Tyr Asn Gly Glu Val Leu His Phe His Thr Glu Asn Gly
355 360 365
Arg Pro Tyr Pro Thr Arg Gly Arg Phe Ala Ala Lys Val Asp Phe Gly
370 375 380
Ser Lys Ser Val Asp Gly Ile Ile Asp Ser Gly Asp Asp Leu His Met
385 390 395 400
Gly Thr Gln Lys Phe Lys Ala Ala Ile Asp Gly Asn Gly Phe Lys Gly
405 410 415
Thr Trp Thr Glu Asn Gly Ser Gly Asp Val Ser Gly Lys Phe Tyr Gly
420 425 430
Pro Ala Gly Glu Glu Val Ala Gly Lys Tyr Ser Tyr Arg Pro Thr Asp
435 440 445
Ala Glu Lys Gly Gly Phe Gly Val Phe Ala Gly Lys Lys Glu Gln Asp
450 455 460
<210> 13
<211> 471
<212> PRT
<213> Neisseria meningitidis
<400> 13
Cys Gly Gly Gly Gly Gly Gly Ser Pro Asp Val Lys Ser Ala Asp Thr
1 5 10 15
Leu Ser Lys Pro Ala Ala Pro Val Val Ser Glu Lys Glu Thr Glu Ala
20 25 30
Lys Glu Asp Ala Pro Gln Ala Gly Ser Gln Gly Gln Gly Ala Pro Ser
35 40 45
Ala Gln Gly Ser Gln Asp Met Ala Ala Val Ser Glu Glu Asn Thr Gly
50 55 60
Asn Gly Gly Ala Val Thr Ala Asp Asn Pro Lys Asn Glu Asp Glu Val
65 70 75 80
Ala Gln Asn Asp Met Pro Gln Asn Ala Ala Gly Thr Asp Ser Ser Thr
85 90 95
Pro Asn His Thr Pro Asp Pro Asn Met Leu Ala Gly Asn Met Glu Asn
100 105 110
Gln Ala Thr Asp Ala Gly Glu Ser Ser Gln Pro Ala Asn Gln Pro Asp
115 120 125
Met Ala Asn Ala Ala Asp Gly Met Gln Gly Asp Asp Pro Ser Ala Gly
130 135 140
Gly Gln Asn Ala Gly Asn Thr Ala Ala Gln Gly Ala Asn Gln Ala Gly
145 150 155 160
Asn Asn Gln Ala Ala Gly Ser Ser Asp Pro Ile Pro Ala Ser Asn Pro
165 170 175
Ala Pro Ala Asn Gly Gly Ser Asn Phe Gly Arg Val Asp Leu Ala Asn
180 185 190
Gly Val Leu Ile Asp Gly Pro Ser Gln Asn Ile Thr Leu Thr His Cys
195 200 205
Lys Gly Asp Ser Cys Ser Gly Asn Asn Phe Leu Asp Glu Glu Val Gln
210 215 220
Leu Lys Ser Glu Phe Glu Lys Leu Ser Asp Ala Asp Lys Ile Ser Asn
225 230 235 240
Tyr Lys Lys Asp Gly Lys Asn Asp Lys Phe Val Gly Leu Val Ala Asp
245 250 255
Ser Val Gln Met Lys Gly Ile Asn Gln Tyr Ile Ile Phe Tyr Lys Pro
260 265 270
Lys Pro Thr Ser Phe Ala Arg Phe Arg Arg Ser Ala Arg Ser Arg Arg
275 280 285
Ser Leu Pro Ala Glu Met Pro Leu Ile Pro Val Asn Gln Ala Asp Thr
290 295 300
Leu Ile Val Asp Gly Glu Ala Val Ser Leu Thr Gly His Ser Gly Asn
305 310 315 320
Ile Phe Ala Pro Glu Gly Asn Tyr Arg Tyr Leu Thr Tyr Gly Ala Glu
325 330 335
Lys Leu Pro Gly Gly Ser Tyr Ala Leu Arg Val Gln Gly Glu Pro Ala
340 345 350
Lys Gly Glu Met Leu Ala Gly Ala Ala Val Tyr Asn Gly Glu Val Leu
355 360 365
His Phe His Thr Glu Asn Gly Arg Pro Tyr Pro Thr Arg Gly Arg Phe
370 375 380
Ala Ala Lys Val Asp Phe Gly Ser Lys Ser Val Asp Gly Ile Ile Asp
385 390 395 400
Ser Gly Asp Asp Leu His Met Gly Thr Gln Lys Phe Lys Ala Ala Ile
405 410 415
Asp Gly Asn Gly Phe Lys Gly Thr Trp Thr Glu Asn Gly Ser Gly Asp
420 425 430
Val Ser Gly Lys Phe Tyr Gly Pro Ala Gly Glu Glu Val Ala Gly Lys
435 440 445
Tyr Ser Tyr Arg Pro Thr Asp Ala Glu Lys Gly Gly Phe Gly Val Phe
450 455 460
Ala Gly Lys Lys Glu Gln Asp
465 470
<210> 14
<211> 187
<212> PRT
<213> Neisseria meningitidis
<400> 14
Met Lys Lys Ile Ile Phe Ala Ala Leu Ala Ala Ala Ala Ile Ser Thr
1 5 10 15
Ala Ser Ala Ala Thr Tyr Lys Val Asp Glu Tyr His Ala Asn Ala Arg
20 25 30
Phe Ala Ile Asp His Phe Asn Thr Ser Thr Asn Val Gly Gly Phe Tyr
35 40 45
Gly Leu Thr Gly Ser Val Glu Phe Asp Gln Ala Lys Arg Asp Gly Lys
50 55 60
Ile Asp Ile Thr Ile Pro Ile Ala Asn Leu Gln Ser Gly Ser Gln His
65 70 75 80
Phe Thr Asp His Leu Lys Ser Ala Asp Ile Phe Asp Ala Ala Gln Tyr
85 90 95
Pro Asp Ile Arg Phe Val Ser Thr Lys Phe Asn Phe Asn Gly Lys Lys
100 105 110
Leu Val Ser Val Asp Gly Asn Leu Thr Met His Gly Lys Thr Ala Pro
115 120 125
Val Lys Leu Lys Ala Glu Lys Phe Asn Cys Tyr Gln Ser Pro Met Glu
130 135 140
Lys Thr Glu Val Cys Gly Gly Asp Phe Ser Thr Thr Ile Asp Arg Thr
145 150 155 160
Lys Trp Gly Met Asp Tyr Leu Val Asn Val Gly Met Thr Lys Ser Val
165 170 175
Arg Ile Asp Ile Gln Ile Glu Ala Ala Lys Gln
180 185
<210> 15
<211> 168
<212> PRT
<213> Neisseria meningitidis
<400> 15
Ala Thr Tyr Lys Val Asp Glu Tyr His Ala Asn Ala Arg Phe Ala Ile
1 5 10 15
Asp His Phe Asn Thr Ser Thr Asn Val Gly Gly Phe Tyr Gly Leu Thr
20 25 30
Gly Ser Val Glu Phe Asp Gln Ala Lys Arg Asp Gly Lys Ile Asp Ile
35 40 45
Thr Ile Pro Ile Ala Asn Leu Gln Ser Gly Ser Gln His Phe Thr Asp
50 55 60
His Leu Lys Ser Ala Asp Ile Phe Asp Ala Ala Gln Tyr Pro Asp Ile
65 70 75 80
Arg Phe Val Ser Thr Lys Phe Asn Phe Asn Gly Lys Lys Leu Val Ser
85 90 95
Val Asp Gly Asn Leu Thr Met His Gly Lys Thr Ala Pro Val Lys Leu
100 105 110
Lys Ala Glu Lys Phe Asn Cys Tyr Gln Ser Pro Met Glu Lys Thr Glu
115 120 125
Val Cys Gly Gly Asp Phe Ser Thr Thr Ile Asp Arg Thr Lys Trp Gly
130 135 140
Met Asp Tyr Leu Val Asn Val Gly Met Thr Lys Ser Val Arg Ile Asp
145 150 155 160
Ile Gln Ile Glu Ala Ala Lys Gln
165
<210> 16
<211> 644
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 16
Met Ala Ser Pro Asp Val Lys Ser Ala Asp Thr Leu Ser Lys Pro Ala
1 5 10 15
Ala Pro Val Val Ser Glu Lys Glu Thr Glu Ala Lys Glu Asp Ala Pro
20 25 30
Gln Ala Gly Ser Gln Gly Gln Gly Ala Pro Ser Ala Gln Gly Gly Gln
35 40 45
Asp Met Ala Ala Val Ser Glu Glu Asn Thr Gly Asn Gly Gly Ala Ala
50 55 60
Ala Thr Asp Lys Pro Lys Asn Glu Asp Glu Gly Ala Gln Asn Asp Met
65 70 75 80
Pro Gln Asn Ala Ala Asp Thr Asp Ser Leu Thr Pro Asn His Thr Pro
85 90 95
Ala Ser Asn Met Pro Ala Gly Asn Met Glu Asn Gln Ala Pro Asp Ala
100 105 110
Gly Glu Ser Glu Gln Pro Ala Asn Gln Pro Asp Met Ala Asn Thr Ala
115 120 125
Asp Gly Met Gln Gly Asp Asp Pro Ser Ala Gly Gly Glu Asn Ala Gly
130 135 140
Asn Thr Ala Ala Gln Gly Thr Asn Gln Ala Glu Asn Asn Gln Thr Ala
145 150 155 160
Gly Ser Gln Asn Pro Ala Ser Ser Thr Asn Pro Ser Ala Thr Asn Ser
165 170 175
Gly Gly Asp Phe Gly Arg Thr Asn Val Gly Asn Ser Val Val Ile Asp
180 185 190
Gly Pro Ser Gln Asn Ile Thr Leu Thr His Cys Lys Gly Asp Ser Cys
195 200 205
Ser Gly Asn Asn Phe Leu Asp Glu Glu Val Gln Leu Lys Ser Glu Phe
210 215 220
Glu Lys Leu Ser Asp Ala Asp Lys Ile Ser Asn Tyr Lys Lys Asp Gly
225 230 235 240
Lys Asn Asp Gly Lys Asn Asp Lys Phe Val Gly Leu Val Ala Asp Ser
245 250 255
Val Gln Met Lys Gly Ile Asn Gln Tyr Ile Ile Phe Tyr Lys Pro Lys
260 265 270
Pro Thr Ser Phe Ala Arg Phe Arg Arg Ser Ala Arg Ser Arg Arg Ser
275 280 285
Leu Pro Ala Glu Met Pro Leu Ile Pro Val Asn Gln Ala Asp Thr Leu
290 295 300
Ile Val Asp Gly Glu Ala Val Ser Leu Thr Gly His Ser Gly Asn Ile
305 310 315 320
Phe Ala Pro Glu Gly Asn Tyr Arg Tyr Leu Thr Tyr Gly Ala Glu Lys
325 330 335
Leu Pro Gly Gly Ser Tyr Ala Leu Arg Val Gln Gly Glu Pro Ser Lys
340 345 350
Gly Glu Met Leu Ala Gly Thr Ala Val Tyr Asn Gly Glu Val Leu His
355 360 365
Phe His Thr Glu Asn Gly Arg Pro Ser Pro Ser Arg Gly Arg Phe Ala
370 375 380
Ala Lys Val Asp Phe Gly Ser Lys Ser Val Asp Gly Ile Ile Asp Ser
385 390 395 400
Gly Asp Gly Leu His Met Gly Thr Gln Lys Phe Lys Ala Ala Ile Asp
405 410 415
Gly Asn Gly Phe Lys Gly Thr Trp Thr Glu Asn Gly Gly Gly Asp Val
420 425 430
Ser Gly Lys Phe Tyr Gly Pro Ala Gly Glu Glu Val Ala Gly Lys Tyr
435 440 445
Ser Tyr Arg Pro Thr Asp Ala Glu Lys Gly Gly Phe Gly Val Phe Ala
450 455 460
Gly Lys Lys Glu Gln Asp Gly Ser Gly Gly Gly Gly Ala Thr Tyr Lys
465 470 475 480
Val Asp Glu Tyr His Ala Asn Ala Arg Phe Ala Ile Asp His Phe Asn
485 490 495
Thr Ser Thr Asn Val Gly Gly Phe Tyr Gly Leu Thr Gly Ser Val Glu
500 505 510
Phe Asp Gln Ala Lys Arg Asp Gly Lys Ile Asp Ile Thr Ile Pro Val
515 520 525
Ala Asn Leu Gln Ser Gly Ser Gln His Phe Thr Asp His Leu Lys Ser
530 535 540
Ala Asp Ile Phe Asp Ala Ala Gln Tyr Pro Asp Ile Arg Phe Val Ser
545 550 555 560
Thr Lys Phe Asn Phe Asn Gly Lys Lys Leu Val Ser Val Asp Gly Asn
565 570 575
Leu Thr Met His Gly Lys Thr Ala Pro Val Lys Leu Lys Ala Glu Lys
580 585 590
Phe Asn Cys Tyr Gln Ser Pro Met Ala Lys Thr Glu Val Cys Gly Gly
595 600 605
Asp Phe Ser Thr Thr Ile Asp Arg Thr Lys Trp Gly Val Asp Tyr Leu
610 615 620
Val Asn Val Gly Met Thr Lys Ser Val Arg Ile Asp Ile Gln Ile Glu
625 630 635 640
Ala Ala Lys Gln
<210> 17
<211> 364
<212> PRT
<213> Neisseria meningitidis
<400> 17
Met Ser Met Lys His Phe Pro Ser Lys Val Leu Thr Thr Ala Ile Leu
1 5 10 15
Ala Thr Phe Cys Ser Gly Ala Leu Ala Ala Thr Ser Asp Asp Asp Val
20 25 30
Lys Lys Ala Ala Thr Val Ala Ile Val Ala Ala Tyr Asn Asn Gly Gln
35 40 45
Glu Ile Asn Gly Phe Lys Ala Gly Glu Thr Ile Tyr Asp Ile Gly Glu
50 55 60
Asp Gly Thr Ile Thr Gln Lys Asp Ala Thr Ala Ala Asp Val Glu Ala
65 70 75 80
Asp Asp Phe Lys Gly Leu Gly Leu Lys Lys Val Val Thr Asn Leu Thr
85 90 95
Lys Thr Val Asn Glu Asn Lys Gln Asn Val Asp Ala Lys Val Lys Ala
100 105 110
Ala Glu Ser Glu Ile Glu Lys Leu Thr Thr Lys Leu Ala Asp Thr Asp
115 120 125
Ala Ala Leu Ala Asp Thr Asp Ala Ala Leu Asp Glu Thr Thr Asn Ala
130 135 140
Leu Asn Lys Leu Gly Glu Asn Ile Thr Thr Phe Ala Glu Glu Thr Lys
145 150 155 160
Thr Asn Ile Val Lys Ile Asp Glu Lys Leu Glu Ala Val Ala Asp Thr
165 170 175
Val Asp Lys His Ala Glu Ala Phe Asn Asp Ile Ala Asp Ser Leu Asp
180 185 190
Glu Thr Asn Thr Lys Ala Asp Glu Ala Val Lys Thr Ala Asn Glu Ala
195 200 205
Lys Gln Thr Ala Glu Glu Thr Lys Gln Asn Val Asp Ala Lys Val Lys
210 215 220
Ala Ala Glu Thr Ala Ala Gly Lys Ala Glu Ala Ala Ala Gly Thr Ala
225 230 235 240
Asn Thr Ala Ala Asp Lys Ala Glu Ala Val Ala Ala Lys Val Thr Asp
245 250 255
Ile Lys Ala Asp Ile Ala Thr Asn Lys Ala Asp Ile Ala Lys Asn Ser
260 265 270
Ala Arg Ile Asp Ser Leu Asp Lys Asn Val Ala Asn Leu Arg Lys Glu
275 280 285
Thr Arg Gln Gly Leu Ala Glu Gln Ala Ala Leu Ser Gly Leu Phe Gln
290 295 300
Pro Tyr Asn Val Gly Arg Phe Asn Val Thr Ala Ala Val Gly Gly Tyr
305 310 315 320
Lys Ser Glu Ser Ala Val Ala Ile Gly Thr Gly Phe Arg Phe Thr Glu
325 330 335
Asn Phe Ala Ala Lys Ala Gly Val Ala Val Gly Thr Ser Ser Gly Ser
340 345 350
Ser Ala Ala Tyr His Val Gly Val Asn Tyr Glu Trp
355 360
<210> 18
<211> 341
<212> PRT
<213> Neisseria meningitidis
<400> 18
Leu Ala Ala Thr Ser Asp Asp Asp Val Lys Lys Ala Ala Thr Val Ala
1 5 10 15
Ile Val Ala Ala Tyr Asn Asn Gly Gln Glu Ile Asn Gly Phe Lys Ala
20 25 30
Gly Glu Thr Ile Tyr Asp Ile Gly Glu Asp Gly Thr Ile Thr Gln Lys
35 40 45
Asp Ala Thr Ala Ala Asp Val Glu Ala Asp Asp Phe Lys Gly Leu Gly
50 55 60
Leu Lys Lys Val Val Thr Asn Leu Thr Lys Thr Val Asn Glu Asn Lys
65 70 75 80
Gln Asn Val Asp Ala Lys Val Lys Ala Ala Glu Ser Glu Ile Glu Lys
85 90 95
Leu Thr Thr Lys Leu Ala Asp Thr Asp Ala Ala Leu Ala Asp Thr Asp
100 105 110
Ala Ala Leu Asp Glu Thr Thr Asn Ala Leu Asn Lys Leu Gly Glu Asn
115 120 125
Ile Thr Thr Phe Ala Glu Glu Thr Lys Thr Asn Ile Val Lys Ile Asp
130 135 140
Glu Lys Leu Glu Ala Val Ala Asp Thr Val Asp Lys His Ala Glu Ala
145 150 155 160
Phe Asn Asp Ile Ala Asp Ser Leu Asp Glu Thr Asn Thr Lys Ala Asp
165 170 175
Glu Ala Val Lys Thr Ala Asn Glu Ala Lys Gln Thr Ala Glu Glu Thr
180 185 190
Lys Gln Asn Val Asp Ala Lys Val Lys Ala Ala Glu Thr Ala Ala Gly
195 200 205
Lys Ala Glu Ala Ala Ala Gly Thr Ala Asn Thr Ala Ala Asp Lys Ala
210 215 220
Glu Ala Val Ala Ala Lys Val Thr Asp Ile Lys Ala Asp Ile Ala Thr
225 230 235 240
Asn Lys Ala Asp Ile Ala Lys Asn Ser Ala Arg Ile Asp Ser Leu Asp
245 250 255
Lys Asn Val Ala Asn Leu Arg Lys Glu Thr Arg Gln Gly Leu Ala Glu
260 265 270
Gln Ala Ala Leu Ser Gly Leu Phe Gln Pro Tyr Asn Val Gly Arg Phe
275 280 285
Asn Val Thr Ala Ala Val Gly Gly Tyr Lys Ser Glu Ser Ala Val Ala
290 295 300
Ile Gly Thr Gly Phe Arg Phe Thr Glu Asn Phe Ala Ala Lys Ala Gly
305 310 315 320
Val Ala Val Gly Thr Ser Ser Gly Ser Ser Ala Ala Tyr His Val Gly
325 330 335
Val Asn Tyr Glu Trp
340
<210> 19
<211> 327
<212> PRT
<213> Neisseria meningitidis
<400> 19
Ala Thr Asn Asp Asp Asp Val Lys Lys Ala Ala Thr Val Ala Ile Ala
1 5 10 15
Ala Ala Tyr Asn Asn Gly Gln Glu Ile Asn Gly Phe Lys Ala Gly Glu
20 25 30
Thr Ile Tyr Asp Ile Asp Glu Asp Gly Thr Ile Thr Lys Lys Asp Ala
35 40 45
Thr Ala Ala Asp Val Glu Ala Asp Asp Phe Lys Gly Leu Gly Leu Lys
50 55 60
Lys Val Val Thr Asn Leu Thr Lys Thr Val Asn Glu Asn Lys Gln Asn
65 70 75 80
Val Asp Ala Lys Val Lys Ala Ala Glu Ser Glu Ile Glu Lys Leu Thr
85 90 95
Thr Lys Leu Ala Asp Thr Asp Ala Ala Leu Ala Asp Thr Asp Ala Ala
100 105 110
Leu Asp Ala Thr Thr Asn Ala Leu Asn Lys Leu Gly Glu Asn Ile Thr
115 120 125
Thr Phe Ala Glu Glu Thr Lys Thr Asn Ile Val Lys Ile Asp Glu Lys
130 135 140
Leu Glu Ala Val Ala Asp Thr Val Asp Lys His Ala Glu Ala Phe Asn
145 150 155 160
Asp Ile Ala Asp Ser Leu Asp Glu Thr Asn Thr Lys Ala Asp Glu Ala
165 170 175
Val Lys Thr Ala Asn Glu Ala Lys Gln Thr Ala Glu Glu Thr Lys Gln
180 185 190
Asn Val Asp Ala Lys Val Lys Ala Ala Glu Thr Ala Ala Gly Lys Ala
195 200 205
Glu Ala Ala Ala Gly Thr Ala Asn Thr Ala Ala Asp Lys Ala Glu Ala
210 215 220
Val Ala Ala Lys Val Thr Asp Ile Lys Ala Asp Ile Ala Thr Asn Lys
225 230 235 240
Asp Asn Ile Ala Lys Lys Ala Asn Ser Ala Asp Val Tyr Thr Arg Glu
245 250 255
Glu Ser Asp Ser Lys Phe Val Arg Ile Asp Gly Leu Asn Ala Thr Thr
260 265 270
Glu Lys Leu Asp Thr Arg Leu Ala Ser Ala Glu Lys Ser Ile Ala Asp
275 280 285
His Asp Thr Arg Leu Asn Gly Leu Asp Lys Thr Val Ser Asp Leu Arg
290 295 300
Lys Glu Thr Arg Gln Gly Leu Ala Glu Gln Ala Ala Leu Ser Gly Leu
305 310 315 320
Phe Gln Pro Tyr Asn Val Gly
325
<210> 20
<211> 202
<212> PRT
<213> Neisseria meningitidis
<400> 20
Met Lys Pro Lys Pro His Thr Val Arg Thr Leu Ile Ala Ala Ile Phe
1 5 10 15
Ser Leu Ala Leu Ser Gly Cys Val Ser Ala Val Ile Gly Ser Ala Ala
20 25 30
Val Gly Ala Lys Ser Ala Val Asp Arg Arg Thr Thr Gly Ala Gln Thr
35 40 45
Asp Asp Asn Val Met Ala Leu Arg Ile Glu Thr Thr Ala Arg Ser Tyr
50 55 60
Leu Arg Gln Asn Asn Gln Thr Lys Gly Tyr Thr Pro Gln Ile Ser Val
65 70 75 80
Val Gly Tyr Asn Arg His Leu Leu Leu Leu Gly Gln Val Ala Thr Glu
85 90 95
Gly Glu Lys Gln Phe Val Gly Gln Ile Ala Arg Ser Glu Gln Ala Ala
100 105 110
Glu Gly Val Tyr Asn Tyr Ile Thr Val Ala Ser Leu Pro Arg Thr Ala
115 120 125
Gly Asp Ile Ala Gly Asp Thr Trp Asn Thr Ser Lys Val Arg Ala Thr
130 135 140
Leu Leu Gly Ile Ser Pro Ala Thr Gln Ala Arg Val Lys Ile Val Thr
145 150 155 160
Tyr Gly Asn Val Thr Tyr Val Met Gly Ile Leu Thr Pro Glu Glu Gln
165 170 175
Ala Gln Ile Thr Gln Lys Val Ser Thr Thr Val Gly Val Gln Lys Val
180 185 190
Ile Thr Leu Tyr Gln Asn Tyr Val Gln Arg
195 200
<210> 21
<211> 178
<212> PRT
<213> Neisseria meningitidis
<400> 21
Ser Ala Val Ile Gly Ser Ala Ala Val Gly Ala Lys Ser Ala Val Asp
1 5 10 15
Arg Arg Thr Thr Gly Ala Gln Thr Asp Asp Asn Val Met Ala Leu Arg
20 25 30
Ile Glu Thr Thr Ala Arg Ser Tyr Leu Arg Gln Asn Asn Gln Thr Lys
35 40 45
Gly Tyr Thr Pro Gln Ile Ser Val Val Gly Tyr Asp Arg His Leu Leu
50 55 60
Leu Leu Gly Gln Val Ala Thr Glu Gly Glu Lys Gln Phe Val Gly Gln
65 70 75 80
Ile Ala Arg Ser Glu Gln Ala Ala Glu Gly Val Tyr Asn Tyr Ile Thr
85 90 95
Val Ala Ser Leu Pro Arg Thr Ala Gly Asp Ile Ala Gly Asp Thr Trp
100 105 110
Asn Thr Ser Lys Val Arg Ala Thr Leu Leu Gly Ile Ser Pro Ala Thr
115 120 125
Arg Ala Arg Val Lys Ile Val Thr Tyr Gly Asn Val Thr Tyr Val Met
130 135 140
Gly Ile Leu Thr Pro Glu Glu Gln Ala Gln Ile Thr Gln Lys Val Ser
145 150 155 160
Thr Thr Val Gly Val Gln Lys Val Ile Thr Leu Tyr Gln Asn Tyr Val
165 170 175
Gln Arg
<210> 22
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
peptide"
<400> 22
Gly Ser Gly Gly Gly Gly
1 5
<210> 23
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
peptide"
<400> 23
Gly Pro Asp Ser Asp Arg Leu Gln Gln Arg Arg
1 5 10
<210> 24
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
peptide"
<400> 24
Gly Ser Gly Pro Asp Ser Asp Arg Leu Gln Gln Arg Arg
1 5 10
<210> 25
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
peptide"
<400> 25
Gly Lys Gly Pro Asp Ser Asp Arg Leu Gln Gln Arg Arg
1 5 10
<210> 26
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
peptide"
<400> 26
Met Gly Pro Asp Ser Asp Arg Leu Gln Gln Arg Arg
1 5 10
<210> 27
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
peptide"
<400> 27
Met Ala Ser
1
<210> 28
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
peptide"
<400> 28
Leu Glu His His His His His His
1 5
<210> 29
<211> 769
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 29
Met Gly Pro Asp Ser Asp Arg Leu Gln Gln Arg Arg Val Ala Ala Asp
1 5 10 15
Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His Lys
20 25 30
Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Arg Lys Asn
35 40 45
Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly Asn
50 55 60
Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser Arg
65 70 75 80
Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr Leu
85 90 95
Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His Ser Ala Val Val
100 105 110
Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys Ile Asp Ser Leu
115 120 125
Ile Asn Gln Arg Ser Phe Leu Val Ser Gly Leu Gly Gly Glu His Thr
130 135 140
Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr His Gly Lys Ala
145 150 155 160
Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile Asp Phe
165 170 175
Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu Lys Thr Pro Glu
180 185 190
Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala Asp Glu Lys Ser
195 200 205
His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser Glu Glu Lys Gly
210 215 220
Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln Glu Ile Ala Gly
225 230 235 240
Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu Ile Gly Ile Ala
245 250 255
Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala Asp Ile Gly Thr
260 265 270
Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His Lys Asp Lys Gly
275 280 285
Leu Lys Ser Leu Thr Leu Glu Asp Ser Ile Pro Gln Asn Gly Thr Leu
290 295 300
Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys Ala Gly Asp Lys
305 310 315 320
Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Ile Ser Arg
325 330 335
Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln Thr Ile Thr Leu
340 345 350
Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His Ser Ala Val Val
355 360 365
Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys Thr Asp Ser Leu
370 375 380
Ile Asn Gln Arg Ser Phe Leu Val Ser Gly Leu Gly Gly Glu His Thr
385 390 395 400
Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr His Gly Lys Ala
405 410 415
Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr Ser Ile Asp Phe
420 425 430
Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu Lys Thr Leu Glu
435 440 445
Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala Asp Glu Lys Ser
450 455 460
His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser Glu Glu Lys Gly
465 470 475 480
Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln Glu Ile Ala Gly
485 490 495
Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu Ile Gly Ile Ala
500 505 510
Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala Asp Ile Gly Ala
515 520 525
Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His Lys Asp Lys Gly
530 535 540
Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Arg Lys Asn Glu Lys Leu
545 550 555 560
Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly Asn Gly Asp Ser
565 570 575
Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser Arg Phe Asp Phe
580 585 590
Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr Leu Glu Ser Gly
595 600 605
Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu Thr Ala Phe Gln
610 615 620
Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys Met Val Ala Lys
625 630 635 640
Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His Thr Ser Phe Asp
645 650 655
Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly Thr Ala Phe Gly
660 665 670
Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile Asp Phe Ala Ala
675 680 685
Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser Pro Glu Leu Asn
690 695 700
Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly Lys Arg His Ala
705 710 715 720
Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu Lys Gly Ser Tyr
725 730 735
Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val Ala Gly Ser Ala
740 745 750
Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly Leu Ala Ala Lys
755 760 765
Gln
<210> 30
<211> 757
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 30
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Ser
20 25 30
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
35 40 45
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
50 55 60
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
65 70 75 80
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His
85 90 95
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
100 105 110
Ile Asp Ser Leu Ile Asn Gln Arg Ser Phe Leu Val Ser Gly Leu Gly
115 120 125
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr
130 135 140
His Gly Lys Ala Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr
145 150 155 160
Thr Ile Asp Phe Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu
165 170 175
Lys Thr Pro Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
180 185 190
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
195 200 205
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
210 215 220
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
225 230 235 240
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
245 250 255
Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
260 265 270
Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Ser Ile Pro Gln
275 280 285
Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys
290 295 300
Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
305 310 315 320
Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln
325 330 335
Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His
340 345 350
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
355 360 365
Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Leu Val Ser Gly Leu Gly
370 375 380
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr
385 390 395 400
His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr
405 410 415
Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu
420 425 430
Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
435 440 445
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
450 455 460
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
465 470 475 480
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
485 490 495
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
500 505 510
Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
515 520 525
Lys Asp Lys Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Arg Lys
530 535 540
Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly
545 550 555 560
Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser
565 570 575
Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr
580 585 590
Leu Glu Ser Gly Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu
595 600 605
Thr Ala Phe Gln Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys
610 615 620
Met Val Ala Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His
625 630 635 640
Thr Ser Phe Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly
645 650 655
Thr Ala Phe Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile
660 665 670
Asp Phe Ala Ala Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser
675 680 685
Pro Glu Leu Asn Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly
690 695 700
Lys Arg His Ala Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu
705 710 715 720
Lys Gly Ser Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val
725 730 735
Ala Gly Ser Ala Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly
740 745 750
Leu Ala Ala Lys Gln
755
<210> 31
<211> 757
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<220>
<221> MOD_RES
<222> (240)..(240)
<223> Any amino acid except Glu
<220>
<221> MOD_RES
<222> (496)..(496)
<223> Any amino acid except Glu
<220>
<221> MOD_RES
<222> (543)..(543)
<223> Any amino acid except Arg
<400> 31
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Ser
20 25 30
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
35 40 45
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
50 55 60
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
65 70 75 80
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His
85 90 95
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
100 105 110
Ile Asp Ser Leu Ile Asn Gln Arg Ser Phe Leu Val Ser Gly Leu Gly
115 120 125
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr
130 135 140
His Gly Lys Ala Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr
145 150 155 160
Thr Ile Asp Phe Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu
165 170 175
Lys Thr Pro Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
180 185 190
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
195 200 205
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
210 215 220
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Xaa
225 230 235 240
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
245 250 255
Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
260 265 270
Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Ser Ile Pro Gln
275 280 285
Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys
290 295 300
Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
305 310 315 320
Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln
325 330 335
Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His
340 345 350
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
355 360 365
Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Leu Val Ser Gly Leu Gly
370 375 380
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr
385 390 395 400
His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr
405 410 415
Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu
420 425 430
Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
435 440 445
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
450 455 460
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
465 470 475 480
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Xaa
485 490 495
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
500 505 510
Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
515 520 525
Lys Asp Lys Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Xaa Lys
530 535 540
Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly
545 550 555 560
Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser
565 570 575
Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr
580 585 590
Leu Glu Ser Gly Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu
595 600 605
Thr Ala Phe Gln Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys
610 615 620
Met Val Ala Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His
625 630 635 640
Thr Ser Phe Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly
645 650 655
Thr Ala Phe Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile
660 665 670
Asp Phe Ala Ala Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser
675 680 685
Pro Glu Leu Asn Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly
690 695 700
Lys Arg His Ala Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu
705 710 715 720
Lys Gly Ser Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val
725 730 735
Ala Gly Ser Ala Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly
740 745 750
Leu Ala Ala Lys Gln
755
<210> 32
<211> 757
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 32
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Ser
20 25 30
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
35 40 45
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
50 55 60
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
65 70 75 80
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His
85 90 95
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
100 105 110
Ile Asp Ser Leu Ile Asn Gln Arg Ser Phe Leu Val Ser Gly Leu Gly
115 120 125
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr
130 135 140
His Gly Lys Ala Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr
145 150 155 160
Thr Ile Asp Phe Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu
165 170 175
Lys Thr Pro Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
180 185 190
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
195 200 205
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
210 215 220
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Ala
225 230 235 240
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
245 250 255
Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
260 265 270
Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Ser Ile Pro Gln
275 280 285
Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys
290 295 300
Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
305 310 315 320
Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln
325 330 335
Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His
340 345 350
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
355 360 365
Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Leu Val Ser Gly Leu Gly
370 375 380
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr
385 390 395 400
His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr
405 410 415
Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu
420 425 430
Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
435 440 445
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
450 455 460
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
465 470 475 480
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Ala
485 490 495
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
500 505 510
Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
515 520 525
Lys Asp Lys Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Ser Lys
530 535 540
Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly
545 550 555 560
Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser
565 570 575
Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr
580 585 590
Leu Glu Ser Gly Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu
595 600 605
Thr Ala Phe Gln Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys
610 615 620
Met Val Ala Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His
625 630 635 640
Thr Ser Phe Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly
645 650 655
Thr Ala Phe Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile
660 665 670
Asp Phe Ala Ala Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser
675 680 685
Pro Glu Leu Asn Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly
690 695 700
Lys Arg His Ala Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu
705 710 715 720
Lys Gly Ser Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val
725 730 735
Ala Gly Ser Ala Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly
740 745 750
Leu Ala Ala Lys Gln
755
<210> 33
<211> 757
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<220>
<221> MOD_RES
<222> (32)..(32)
<223> Any amino acid except Ser
<220>
<221> MOD_RES
<222> (123)..(123)
<223> Any amino acid except Leu
<220>
<221> MOD_RES
<222> (285)..(285)
<223> Any amino acid except Ser
<220>
<221> MOD_RES
<222> (379)..(379)
<223> Any amino acid except Leu
<400> 33
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Xaa
20 25 30
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
35 40 45
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
50 55 60
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
65 70 75 80
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His
85 90 95
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
100 105 110
Ile Asp Ser Leu Ile Asn Gln Arg Ser Phe Xaa Val Ser Gly Leu Gly
115 120 125
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr
130 135 140
His Gly Lys Ala Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr
145 150 155 160
Thr Ile Asp Phe Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu
165 170 175
Lys Thr Pro Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
180 185 190
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
195 200 205
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
210 215 220
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
225 230 235 240
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
245 250 255
Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
260 265 270
Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Xaa Ile Pro Gln
275 280 285
Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys
290 295 300
Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
305 310 315 320
Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln
325 330 335
Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His
340 345 350
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
355 360 365
Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Xaa Val Ser Gly Leu Gly
370 375 380
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr
385 390 395 400
His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr
405 410 415
Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu
420 425 430
Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
435 440 445
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
450 455 460
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
465 470 475 480
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
485 490 495
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
500 505 510
Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
515 520 525
Lys Asp Lys Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Arg Lys
530 535 540
Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly
545 550 555 560
Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser
565 570 575
Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr
580 585 590
Leu Glu Ser Gly Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu
595 600 605
Thr Ala Phe Gln Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys
610 615 620
Met Val Ala Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His
625 630 635 640
Thr Ser Phe Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly
645 650 655
Thr Ala Phe Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile
660 665 670
Asp Phe Ala Ala Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser
675 680 685
Pro Glu Leu Asn Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly
690 695 700
Lys Arg His Ala Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu
705 710 715 720
Lys Gly Ser Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val
725 730 735
Ala Gly Ser Ala Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly
740 745 750
Leu Ala Ala Lys Gln
755
<210> 34
<211> 757
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 34
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Val
20 25 30
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
35 40 45
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
50 55 60
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
65 70 75 80
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His
85 90 95
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
100 105 110
Ile Asp Ser Leu Ile Asn Gln Arg Ser Phe Arg Val Ser Gly Leu Gly
115 120 125
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr
130 135 140
His Gly Lys Ala Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr
145 150 155 160
Thr Ile Asp Phe Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu
165 170 175
Lys Thr Pro Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
180 185 190
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
195 200 205
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
210 215 220
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
225 230 235 240
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
245 250 255
Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
260 265 270
Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Val Ile Pro Gln
275 280 285
Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys
290 295 300
Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
305 310 315 320
Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln
325 330 335
Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His
340 345 350
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
355 360 365
Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Arg Val Ser Gly Leu Gly
370 375 380
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr
385 390 395 400
His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr
405 410 415
Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu
420 425 430
Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
435 440 445
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
450 455 460
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
465 470 475 480
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
485 490 495
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
500 505 510
Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
515 520 525
Lys Asp Lys Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Arg Lys
530 535 540
Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly
545 550 555 560
Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser
565 570 575
Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr
580 585 590
Leu Glu Ser Gly Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu
595 600 605
Thr Ala Phe Gln Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys
610 615 620
Met Val Ala Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His
625 630 635 640
Thr Ser Phe Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly
645 650 655
Thr Ala Phe Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile
660 665 670
Asp Phe Ala Ala Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser
675 680 685
Pro Glu Leu Asn Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly
690 695 700
Lys Arg His Ala Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu
705 710 715 720
Lys Gly Ser Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val
725 730 735
Ala Gly Ser Ala Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly
740 745 750
Leu Ala Ala Lys Gln
755
<210> 35
<211> 757
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<220>
<221> MOD_RES
<222> (32)..(32)
<223> Any amino acid except Ser
<220>
<221> MOD_RES
<222> (123)..(123)
<223> Any amino acid except Leu
<220>
<221> MOD_RES
<222> (285)..(285)
<223> Any amino acid except Ser
<220>
<221> MOD_RES
<222> (379)..(379)
<223> Any amino acid except Leu
<220>
<221> MOD_RES
<222> (543)..(543)
<223> Any amino acid except Arg
<400> 35
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Xaa
20 25 30
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
35 40 45
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
50 55 60
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
65 70 75 80
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His
85 90 95
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
100 105 110
Ile Asp Ser Leu Ile Asn Gln Arg Ser Phe Xaa Val Ser Gly Leu Gly
115 120 125
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr
130 135 140
His Gly Lys Ala Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr
145 150 155 160
Thr Ile Asp Phe Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu
165 170 175
Lys Thr Pro Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
180 185 190
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
195 200 205
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
210 215 220
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
225 230 235 240
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
245 250 255
Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
260 265 270
Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Xaa Ile Pro Gln
275 280 285
Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys
290 295 300
Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
305 310 315 320
Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln
325 330 335
Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His
340 345 350
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
355 360 365
Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Xaa Val Ser Gly Leu Gly
370 375 380
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr
385 390 395 400
His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr
405 410 415
Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu
420 425 430
Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
435 440 445
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
450 455 460
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
465 470 475 480
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
485 490 495
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
500 505 510
Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
515 520 525
Lys Asp Lys Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Xaa Lys
530 535 540
Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly
545 550 555 560
Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser
565 570 575
Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr
580 585 590
Leu Glu Ser Gly Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu
595 600 605
Thr Ala Phe Gln Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys
610 615 620
Met Val Ala Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His
625 630 635 640
Thr Ser Phe Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly
645 650 655
Thr Ala Phe Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile
660 665 670
Asp Phe Ala Ala Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser
675 680 685
Pro Glu Leu Asn Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly
690 695 700
Lys Arg His Ala Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu
705 710 715 720
Lys Gly Ser Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val
725 730 735
Ala Gly Ser Ala Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly
740 745 750
Leu Ala Ala Lys Gln
755
<210> 36
<211> 757
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 36
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Val
20 25 30
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
35 40 45
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
50 55 60
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
65 70 75 80
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His
85 90 95
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
100 105 110
Ile Asp Ser Leu Ile Asn Gln Arg Ser Phe Arg Val Ser Gly Leu Gly
115 120 125
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr
130 135 140
His Gly Lys Ala Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr
145 150 155 160
Thr Ile Asp Phe Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu
165 170 175
Lys Thr Pro Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
180 185 190
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
195 200 205
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
210 215 220
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
225 230 235 240
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
245 250 255
Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
260 265 270
Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Val Ile Pro Gln
275 280 285
Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys
290 295 300
Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
305 310 315 320
Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln
325 330 335
Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His
340 345 350
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
355 360 365
Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Arg Val Ser Gly Leu Gly
370 375 380
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr
385 390 395 400
His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr
405 410 415
Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu
420 425 430
Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
435 440 445
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
450 455 460
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
465 470 475 480
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
485 490 495
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
500 505 510
Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
515 520 525
Lys Asp Lys Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Ser Lys
530 535 540
Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly
545 550 555 560
Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser
565 570 575
Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr
580 585 590
Leu Glu Ser Gly Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu
595 600 605
Thr Ala Phe Gln Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys
610 615 620
Met Val Ala Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His
625 630 635 640
Thr Ser Phe Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly
645 650 655
Thr Ala Phe Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile
660 665 670
Asp Phe Ala Ala Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser
675 680 685
Pro Glu Leu Asn Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly
690 695 700
Lys Arg His Ala Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu
705 710 715 720
Lys Gly Ser Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val
725 730 735
Ala Gly Ser Ala Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly
740 745 750
Leu Ala Ala Lys Gln
755
<210> 37
<211> 757
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 37
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Val
20 25 30
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
35 40 45
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
50 55 60
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
65 70 75 80
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His
85 90 95
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
100 105 110
Ile Asp Ser Leu Ile Asn Gln Arg Ser Phe Arg Val Ser Gly Leu Gly
115 120 125
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr
130 135 140
His Gly Lys Ala Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr
145 150 155 160
Thr Ile Asp Phe Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu
165 170 175
Lys Thr Pro Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
180 185 190
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
195 200 205
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
210 215 220
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Ala
225 230 235 240
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
245 250 255
Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
260 265 270
Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Val Ile Pro Gln
275 280 285
Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys
290 295 300
Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
305 310 315 320
Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln
325 330 335
Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His
340 345 350
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
355 360 365
Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Arg Val Ser Gly Leu Gly
370 375 380
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr
385 390 395 400
His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr
405 410 415
Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu
420 425 430
Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
435 440 445
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
450 455 460
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
465 470 475 480
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Ala
485 490 495
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
500 505 510
Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
515 520 525
Lys Asp Lys Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Ser Lys
530 535 540
Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly
545 550 555 560
Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser
565 570 575
Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr
580 585 590
Leu Glu Ser Gly Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu
595 600 605
Thr Ala Phe Gln Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys
610 615 620
Met Val Ala Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His
625 630 635 640
Thr Ser Phe Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly
645 650 655
Thr Ala Phe Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile
660 665 670
Asp Phe Ala Ala Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser
675 680 685
Pro Glu Leu Asn Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly
690 695 700
Lys Arg His Ala Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu
705 710 715 720
Lys Gly Ser Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val
725 730 735
Ala Gly Ser Ala Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly
740 745 750
Leu Ala Ala Lys Gln
755
<210> 38
<211> 769
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 38
Met Gly Pro Asp Ser Asp Arg Leu Gln Gln Arg Arg Val Ala Ala Asp
1 5 10 15
Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His Lys
20 25 30
Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Val Val Arg Lys Asn
35 40 45
Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly Asn
50 55 60
Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser Arg
65 70 75 80
Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr Leu
85 90 95
Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His Ser Ala Val Val
100 105 110
Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys Ile Asp Ser Leu
115 120 125
Ile Asn Gln Arg Ser Phe Arg Val Ser Gly Leu Gly Gly Glu His Thr
130 135 140
Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr His Gly Lys Ala
145 150 155 160
Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile Asp Phe
165 170 175
Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu Lys Thr Pro Glu
180 185 190
Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala Asp Glu Lys Ser
195 200 205
His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser Glu Glu Lys Gly
210 215 220
Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln Glu Ile Ala Gly
225 230 235 240
Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Ala Ile Gly Ile Ala
245 250 255
Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala Asp Ile Gly Thr
260 265 270
Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His Lys Asp Lys Gly
275 280 285
Leu Lys Ser Leu Thr Leu Glu Asp Val Ile Pro Gln Asn Gly Thr Leu
290 295 300
Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys Ala Gly Asp Lys
305 310 315 320
Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Ile Ser Arg
325 330 335
Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln Thr Ile Thr Leu
340 345 350
Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His Ser Ala Val Val
355 360 365
Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys Thr Asp Ser Leu
370 375 380
Ile Asn Gln Arg Ser Phe Arg Val Ser Gly Leu Gly Gly Glu His Thr
385 390 395 400
Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr His Gly Lys Ala
405 410 415
Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr Ser Ile Asp Phe
420 425 430
Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu Lys Thr Leu Glu
435 440 445
Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala Asp Glu Lys Ser
450 455 460
His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser Glu Glu Lys Gly
465 470 475 480
Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln Glu Ile Ala Gly
485 490 495
Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Ala Ile Gly Ile Ala
500 505 510
Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala Asp Ile Gly Ala
515 520 525
Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His Lys Asp Lys Gly
530 535 540
Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Ser Lys Asn Glu Lys Leu
545 550 555 560
Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly Asn Gly Asp Ser
565 570 575
Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser Arg Phe Asp Phe
580 585 590
Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr Leu Glu Ser Gly
595 600 605
Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu Thr Ala Phe Gln
610 615 620
Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys Met Val Ala Lys
625 630 635 640
Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His Thr Ser Phe Asp
645 650 655
Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly Thr Ala Phe Gly
660 665 670
Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile Asp Phe Ala Ala
675 680 685
Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser Pro Glu Leu Asn
690 695 700
Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly Lys Arg His Ala
705 710 715 720
Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu Lys Gly Ser Tyr
725 730 735
Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val Ala Gly Ser Ala
740 745 750
Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly Leu Ala Ala Lys
755 760 765
Gln
<210> 39
<211> 757
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<220>
<221> MOD_RES
<222> (123)..(123)
<223> Any amino acid except Leu
<220>
<221> MOD_RES
<222> (379)..(379)
<223> Any amino acid except Leu
<400> 39
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Ser
20 25 30
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
35 40 45
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
50 55 60
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
65 70 75 80
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His
85 90 95
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
100 105 110
Ile Asp Ser Leu Ile Asn Gln Arg Ser Phe Xaa Val Ser Gly Leu Gly
115 120 125
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr
130 135 140
His Gly Lys Ala Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr
145 150 155 160
Thr Ile Asp Phe Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu
165 170 175
Lys Thr Pro Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
180 185 190
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
195 200 205
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
210 215 220
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
225 230 235 240
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
245 250 255
Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
260 265 270
Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Ser Ile Pro Gln
275 280 285
Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys
290 295 300
Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
305 310 315 320
Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln
325 330 335
Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His
340 345 350
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
355 360 365
Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Xaa Val Ser Gly Leu Gly
370 375 380
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr
385 390 395 400
His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr
405 410 415
Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu
420 425 430
Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
435 440 445
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
450 455 460
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
465 470 475 480
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
485 490 495
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
500 505 510
Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
515 520 525
Lys Asp Lys Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Arg Lys
530 535 540
Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly
545 550 555 560
Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser
565 570 575
Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr
580 585 590
Leu Glu Ser Gly Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu
595 600 605
Thr Ala Phe Gln Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys
610 615 620
Met Val Ala Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His
625 630 635 640
Thr Ser Phe Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly
645 650 655
Thr Ala Phe Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile
660 665 670
Asp Phe Ala Ala Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser
675 680 685
Pro Glu Leu Asn Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly
690 695 700
Lys Arg His Ala Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu
705 710 715 720
Lys Gly Ser Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val
725 730 735
Ala Gly Ser Ala Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly
740 745 750
Leu Ala Ala Lys Gln
755
<210> 40
<211> 757
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 40
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Ser
20 25 30
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
35 40 45
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
50 55 60
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
65 70 75 80
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His
85 90 95
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
100 105 110
Ile Asp Ser Leu Ile Asn Gln Arg Ser Phe Arg Val Ser Gly Leu Gly
115 120 125
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr
130 135 140
His Gly Lys Ala Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr
145 150 155 160
Thr Ile Asp Phe Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu
165 170 175
Lys Thr Pro Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
180 185 190
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
195 200 205
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
210 215 220
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
225 230 235 240
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
245 250 255
Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
260 265 270
Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Ser Ile Pro Gln
275 280 285
Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys
290 295 300
Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
305 310 315 320
Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln
325 330 335
Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His
340 345 350
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
355 360 365
Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Arg Val Ser Gly Leu Gly
370 375 380
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr
385 390 395 400
His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr
405 410 415
Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu
420 425 430
Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
435 440 445
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
450 455 460
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
465 470 475 480
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
485 490 495
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
500 505 510
Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
515 520 525
Lys Asp Lys Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Arg Lys
530 535 540
Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly
545 550 555 560
Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser
565 570 575
Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr
580 585 590
Leu Glu Ser Gly Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu
595 600 605
Thr Ala Phe Gln Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys
610 615 620
Met Val Ala Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His
625 630 635 640
Thr Ser Phe Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly
645 650 655
Thr Ala Phe Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile
660 665 670
Asp Phe Ala Ala Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser
675 680 685
Pro Glu Leu Asn Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly
690 695 700
Lys Arg His Ala Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu
705 710 715 720
Lys Gly Ser Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val
725 730 735
Ala Gly Ser Ala Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly
740 745 750
Leu Ala Ala Lys Gln
755
<210> 41
<211> 757
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
polypeptide"
<400> 41
Val Ala Ala Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro
1 5 10 15
Leu Asp His Lys Asp Lys Ser Leu Gln Ser Leu Thr Leu Asp Gln Ser
20 25 30
Val Arg Lys Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys
35 40 45
Thr Tyr Gly Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
50 55 60
Lys Val Ser Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln
65 70 75 80
Leu Ile Thr Leu Glu Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asp His
85 90 95
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
100 105 110
Ile Asp Ser Leu Ile Asn Gln Arg Ser Phe Arg Val Ser Gly Leu Gly
115 120 125
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Asp Gly Lys Ala Glu Tyr
130 135 140
His Gly Lys Ala Phe Ser Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr
145 150 155 160
Thr Ile Asp Phe Ala Ala Lys Gln Gly His Gly Lys Ile Glu His Leu
165 170 175
Lys Thr Pro Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
180 185 190
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
195 200 205
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
210 215 220
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
225 230 235 240
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
245 250 255
Asp Ile Gly Thr Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
260 265 270
Lys Asp Lys Gly Leu Lys Ser Leu Thr Leu Glu Asp Ser Ile Pro Gln
275 280 285
Asn Gly Thr Leu Thr Leu Ser Ala Gln Gly Ala Glu Lys Thr Phe Lys
290 295 300
Ala Gly Asp Lys Asp Asn Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp
305 310 315 320
Lys Ile Ser Arg Phe Asp Phe Val Gln Lys Ile Glu Val Asp Gly Gln
325 330 335
Thr Ile Thr Leu Ala Ser Gly Glu Phe Gln Ile Tyr Lys Gln Asn His
340 345 350
Ser Ala Val Val Ala Leu Gln Ile Glu Lys Ile Asn Asn Pro Asp Lys
355 360 365
Thr Asp Ser Leu Ile Asn Gln Arg Ser Phe Arg Val Ser Gly Leu Gly
370 375 380
Gly Glu His Thr Ala Phe Asn Gln Leu Pro Gly Gly Lys Ala Glu Tyr
385 390 395 400
His Gly Lys Ala Phe Ser Ser Asp Asp Pro Asn Gly Arg Leu His Tyr
405 410 415
Ser Ile Asp Phe Thr Lys Lys Gln Gly Tyr Gly Arg Ile Glu His Leu
420 425 430
Lys Thr Leu Glu Gln Asn Val Glu Leu Ala Ala Ala Glu Leu Lys Ala
435 440 445
Asp Glu Lys Ser His Ala Val Ile Leu Gly Asp Thr Arg Tyr Gly Ser
450 455 460
Glu Glu Lys Gly Thr Tyr His Leu Ala Leu Phe Gly Asp Arg Ala Gln
465 470 475 480
Glu Ile Ala Gly Ser Ala Thr Val Lys Ile Gly Glu Lys Val His Glu
485 490 495
Ile Gly Ile Ala Gly Lys Gln Gly Ser Gly Gly Gly Gly Val Ala Ala
500 505 510
Asp Ile Gly Ala Gly Leu Ala Asp Ala Leu Thr Ala Pro Leu Asp His
515 520 525
Lys Asp Lys Gly Leu Gln Ser Leu Thr Leu Asp Gln Ser Val Ser Lys
530 535 540
Asn Glu Lys Leu Lys Leu Ala Ala Gln Gly Ala Glu Lys Thr Tyr Gly
545 550 555 560
Asn Gly Asp Ser Leu Asn Thr Gly Lys Leu Lys Asn Asp Lys Val Ser
565 570 575
Arg Phe Asp Phe Ile Arg Gln Ile Glu Val Asp Gly Gln Leu Ile Thr
580 585 590
Leu Glu Ser Gly Glu Phe Gln Val Tyr Lys Gln Ser His Ser Ala Leu
595 600 605
Thr Ala Phe Gln Thr Glu Gln Ile Gln Asp Ser Glu His Ser Gly Lys
610 615 620
Met Val Ala Lys Arg Gln Phe Arg Ile Gly Asp Ile Ala Gly Glu His
625 630 635 640
Thr Ser Phe Asp Lys Leu Pro Glu Gly Gly Arg Ala Thr Tyr Arg Gly
645 650 655
Thr Ala Phe Gly Ser Asp Asp Ala Gly Gly Lys Leu Thr Tyr Thr Ile
660 665 670
Asp Phe Ala Ala Lys Gln Gly Asn Gly Lys Ile Glu His Leu Lys Ser
675 680 685
Pro Glu Leu Asn Val Asp Leu Ala Ala Ala Asp Ile Lys Pro Asp Gly
690 695 700
Lys Arg His Ala Val Ile Ser Gly Ser Val Leu Tyr Asn Gln Ala Glu
705 710 715 720
Lys Gly Ser Tyr Ser Leu Gly Ile Phe Gly Gly Lys Ala Gln Glu Val
725 730 735
Ala Gly Ser Ala Glu Val Lys Thr Val Asn Gly Ile Arg His Ile Gly
740 745 750
Leu Ala Ala Lys Gln
755
<210> 42
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
peptide"
<220>
<221> VARIANT
<222> (3)..(10)
<223> /replace=" "
<220>
<221> misc_feature
<222> (1)..(10)
<223> /note="Variant residues given in the sequence have no
preference with respect to those in the annotations
for variant positions"
<400> 42
Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly
1 5 10
<210> 43
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
peptide"
<220>
<221> VARIANT
<222> (4)..(10)
<223> /replace=" "
<220>
<221> misc_feature
<222> (1)..(10)
<223> /note="Variant residues given in the sequence have no
preference with respect to those in the annotations
for variant positions"
<400> 43
His His His His His His His His His His
1 5 10
<210> 44
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
peptide"
<220>
<221> VARIANT
<222> (5)..(10)
<223> /replace=" "
<220>
<221> misc_feature
<222> (1)..(10)
<223> /note="Variant residues given in the sequence have no
preference with respect to those in the annotations
for variant positions"
<400> 44
His His His His His His His His His His
1 5 10
Claims (15)
- (i) NHBA 폴리펩티드 (ii) NadA 폴리펩티드 및/또는 (iii) 수막구균 외막 소체 중 하나 이상과 함께 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드를 포함하는 면역원성 조성물.
- (i) NHBA 폴리펩티드 (ii) NadA 폴리펩티드 및/또는 (iii) 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드 중 하나 이상과 함께 수막구균 외막 소체를 포함하는 면역원성 조성물로서, 여기서 외막 소체 (OMV)가 5-30μg/ml의 농도로 존재하는, 면역원성 조성물.
- 제 1항 또는 제 2항에 있어서, (i) 3개 모두의 v1, v2 및 v3 수막구균 fHbp를 포함하는 융합 폴리펩티드, (ii) NHBA 폴리펩티드 (iii) NadA 폴리펩티드 및 (iv) 수막구균 외막 소체를 포함하는 조성물.
- 제 1항 내지 제 3항 중 어느 한 항에 있어서,
● 융합 폴리펩티드가 SEQ ID NO: 7, 8, 및 9 각각으로부터의 적어도 하나의 에피토프를 포함하고, 마우스로의 투여 후 (a) SEQ ID NO: 4로 구성된 폴리펩티드, (b) SEQ ID NO: 5로 구성된 폴리펩티드, (c) SEQ ID NO: 6으로 구성된 폴리펩티드 3개 모두를 인지할 수 있는 항체를 유도할 수 있고/거나;
● NHBA 폴리펩티드가 마우스로의 투여 후 아미노산 서열 SEQ ID NO: 13으로 구성된 폴리펩티드에 결합할 수 있는 항체를 유도할 수 있고/거나;
● NadA 폴리펩티드가 마우스로의 투여 후 아미노산 서열 SEQ ID NO: 18로 구성된 폴리펩티드에 결합할 수 있는 항체를 유도할 수 있는 조성물. - 제 1항 내지 제 4항 중 어느 한 항에 있어서, fHbp 융합 폴리펩티드가 식 NH2―A-[-X-L-]3-B―COOH의 아미노산 서열을 갖고, 여기서 각각의 X는 다양한 변이체 fHbp 서열이고, L은 임의의 링커 아미노산 서열이고, A는 임의의 N-말단 아미노산 서열이고, B는 임의의 C-말단 아미노산 서열인 조성물.
- 제 5항에 있어서, 변이체 fHbp 서열이 N-말단으로부터 C-말단으로 v2-v3-v1의 순서인 조성물.
- 제 6항에 있어서, 융합 폴리펩티드가 SEQ ID NO: 10, 29, 30, 31, 32, 33, 34, 35, 36, 37, 및 38로 구성된 군으로부터 선택된 아미노산 서열을 포함하는 조성물.
- 제 1항 내지 제 7항 중 어느 한 항에 있어서, (a) fHbp 융합 폴리펩티드가 아미노산 서열 SEQ ID NO: 10, SEQ ID NO: 36, 또는 SEQ ID NO: 38을 갖고; (b) NHBA 폴리펩티드가 아미노산 서열 SEQ ID NO: 12를 포함하고; 그리고 (c) NadA 폴리펩티드가 아미노산 서열 SEQ ID NO: 19를 갖는 조성물.
- 제 1항 내지 제 8항 중 어느 한 항에 있어서, OMV가 혈청군 B 균주로부터 유래되는 조성물.
- 제 9항에 있어서, OMV가 균주 NZ98/254로부터 제조되는 조성물.
- 제 1항 내지 제 10항 중 어느 한 항에 있어서, OMV가 10μg/ml 내지 15μg/ml의 농도로 존재하는 조성물.
- 제 1항 내지 제 11항 중 어느 한 항에 있어서, fHbp, NHBA 및 NadA 폴리펩티드가 50-150μg/ml의 농도로 존재하는 조성물.
- 제 1항 내지 제 12항 중 어느 한 항에 있어서, 알루미늄 하이드록시드 애쥬번트를 추가로 포함하는 조성물.
- 제 1항 내지 제 13항 중 어느 한 항의 면역원성 조성물을 포유동물에 투여하는 것을 포함하는, 수막구균 감염에 대해 포유동물을 보호하는 방법.
- 제 14항에 있어서, 상기 포유동물이 인간인 방법.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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EP14177563.5 | 2014-07-17 | ||
EP14177563 | 2014-07-17 | ||
PCT/EP2015/066229 WO2016008961A1 (en) | 2014-07-17 | 2015-07-16 | Meningococcus vaccines |
KR1020177004245A KR102626831B1 (ko) | 2014-07-17 | 2015-07-16 | 수막구균 백신 |
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KR1020177004245A Division KR102626831B1 (ko) | 2014-07-17 | 2015-07-16 | 수막구균 백신 |
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KR1020237001115A KR20230012100A (ko) | 2014-07-17 | 2015-07-16 | 수막구균 백신 |
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EP (1) | EP3169358A1 (ko) |
JP (2) | JP6687597B2 (ko) |
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CN (2) | CN113827712A (ko) |
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EA (1) | EA038940B1 (ko) |
IL (1) | IL249823B (ko) |
MX (1) | MX2017000775A (ko) |
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HUE052293T2 (hu) | 2014-02-28 | 2021-04-28 | Glaxosmithkline Biologicals Sa | Módosított fHbp meningococcus-polipeptidek |
BE1022641B1 (fr) | 2014-07-17 | 2016-06-23 | Glaxosmithkline Biologicals Sa | POLYPEPTIDES MENINGOCOCCIQUES fHbp MODIFIES |
SG11201610946YA (en) * | 2014-07-17 | 2017-01-27 | Glaxosmithkline Biolog Sa | Meningococcus vaccines |
US10975131B2 (en) * | 2015-10-27 | 2021-04-13 | University Of Massachusetts | Factor H-Fc immunotheraphy |
CN107961370B (zh) * | 2017-03-22 | 2020-08-11 | 武汉博沃生物科技有限公司 | 多价肺炎球菌缀合疫苗及其制备方法 |
CN108939061A (zh) * | 2018-08-03 | 2018-12-07 | 北京智飞绿竹生物制药有限公司 | 一种多组分b群脑膜炎球菌疫苗及其制备方法 |
EP3607967A1 (en) * | 2018-08-09 | 2020-02-12 | GlaxoSmithKline Biologicals S.A. | Modified meningococcal fhbp polypeptides |
US11014736B2 (en) | 2019-04-18 | 2021-05-25 | Altria Client Services Llc | Sliding packs with flip top hinged lids |
CN110804101A (zh) * | 2019-11-08 | 2020-02-18 | 苏州微超生物科技有限公司 | B群脑膜炎球菌相关融合蛋白、疫苗及其制备方法与应用 |
CA3162559A1 (en) * | 2019-11-25 | 2021-06-03 | Griffith University | Immunogenic protein against gonococcal infection |
GB202115151D0 (en) | 2021-10-21 | 2021-12-08 | Glaxosmithkline Biologicals Sa | Methods |
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US6747137B1 (en) | 1998-02-13 | 2004-06-08 | Genome Therapeutics Corporation | Nucleic acid sequences relating to Candida albicans for diagnostics and therapeutics |
US6551795B1 (en) | 1998-02-18 | 2003-04-22 | Genome Therapeutics Corporation | Nucleic acid and amino acid sequences relating to pseudomonas aeruginosa for diagnostics and therapeutics |
ES2507100T3 (es) * | 2000-01-17 | 2014-10-14 | Novartis Vaccines And Diagnostics S.R.L. | Vacuna OMV suplementada contra meningococo |
GB0227346D0 (en) * | 2002-11-22 | 2002-12-31 | Chiron Spa | 741 |
GB0419408D0 (en) * | 2004-09-01 | 2004-10-06 | Chiron Srl | 741 chimeric polypeptides |
GB0419627D0 (en) * | 2004-09-03 | 2004-10-06 | Chiron Srl | Immunogenic bacterial vesicles with outer membrane proteins |
GB0524066D0 (en) | 2005-11-25 | 2006-01-04 | Chiron Srl | 741 ii |
AR064642A1 (es) | 2006-12-22 | 2009-04-15 | Wyeth Corp | Polinucleotido vector que lo comprende celula recombinante que comprende el vector polipeptido , anticuerpo , composicion que comprende el polinucleotido , vector , celula recombinante polipeptido o anticuerpo , uso de la composicion y metodo para preparar la composicion misma y preparar una composi |
JP2013521770A (ja) * | 2010-03-10 | 2013-06-13 | グラクソスミスクライン バイオロジカルズ ソシエテ アノニム | ワクチン組成物 |
CA2790167C (en) | 2010-03-30 | 2021-02-09 | Children's Hospital & Research Center Oakland | Factor h binding proteins (fhbp) with altered properties and methods of use thereof |
CA2876138C (en) * | 2012-06-14 | 2023-09-19 | Novartis Ag | Vaccines for serogroup x meningococcus |
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HUE052293T2 (hu) * | 2014-02-28 | 2021-04-28 | Glaxosmithkline Biologicals Sa | Módosított fHbp meningococcus-polipeptidek |
EP2916512B1 (en) | 2014-03-07 | 2016-08-24 | Mitsubishi Electric R&D Centre Europe B.V. | Method for classifying a TCP connection carrying HTTP traffic as a trusted or an untrusted TCP connection |
SG11201610946YA (en) | 2014-07-17 | 2017-01-27 | Glaxosmithkline Biolog Sa | Meningococcus vaccines |
BE1022641B1 (fr) | 2014-07-17 | 2016-06-23 | Glaxosmithkline Biologicals Sa | POLYPEPTIDES MENINGOCOCCIQUES fHbp MODIFIES |
-
2015
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US11707513B2 (en) | 2023-07-25 |
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SG11201610946YA (en) | 2017-01-27 |
AR101225A1 (es) | 2016-11-30 |
EA038940B1 (ru) | 2021-11-12 |
JP2017522319A (ja) | 2017-08-10 |
WO2016008961A1 (en) | 2016-01-21 |
BE1022878B1 (fr) | 2016-09-30 |
AU2019201131B2 (en) | 2020-08-27 |
BR112017000519A2 (pt) | 2017-11-21 |
AU2019201131A1 (en) | 2019-03-07 |
IL249823B (en) | 2022-07-01 |
EP3169358A1 (en) | 2017-05-24 |
BE1022878A1 (fr) | 2016-09-30 |
CA2954729A1 (en) | 2016-01-21 |
AU2019201131C1 (en) | 2021-03-18 |
US20180214531A1 (en) | 2018-08-02 |
EA201692554A1 (ru) | 2017-07-31 |
MX2017000775A (es) | 2017-05-04 |
JP7074793B2 (ja) | 2022-05-24 |
KR102626831B1 (ko) | 2024-01-22 |
US20230414736A1 (en) | 2023-12-28 |
CN106659776A (zh) | 2017-05-10 |
KR20170029615A (ko) | 2017-03-15 |
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