KR20200090143A - 마이셀리오프쏘라 써모필라에서 독감 백신의 생산 - Google Patents
마이셀리오프쏘라 써모필라에서 독감 백신의 생산 Download PDFInfo
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Abstract
진균 마이셀리오프쏘라 써모필라 균주 C1에서 인플루엔자 바이러스 표면 단백질의 재조합 발현이 제공된다. 재조합 단백질은 인플루엔자 백신 조성물에 사용하기 위한 것이다.
Description
본 발명은 진균 마이셀리오프쏘라 써모필라 (Myceliophthora thermophila)에서 재조합 인플루엔자 바이러스 표면 단백질의 생산에 관한 것이다. 제조합 단백질은 인플루엔자 백신 조성물에 사용하기 위한 것이다.
인플루엔자 바이러스는 네거티브-센스, 단일-가닥, 분절된 RNA 게놈을 갖는 지질-외피 바이러스이다. 비리온의 외피는 2개 유형의 표면 당단백질인, 헤마글루티닌 및 뉴라미니다제를 함유하는데, 이들은 바이러스 감염에 필수적인 역할을 한다. 헤마글루티닌 (HA)은 그의 숙주 세포에 대한 바이러스의 부착 및 막 융합에 의한 바이러스 진입을 매개한다. 뉴라미니다제 (NA)는 새로운 자손의 방출과 이들의 응집 방지에 중요한 역할을 하는 효소이다.
인플루엔자 바이러스는 이들의 핵단백질과 매트릭스 단백질의 차이에 따라 타입 A, B 및 C로 분류된다. 각 타입은 그들의 표면에 존재하는 HA 및 NA의 조합에 따라 아형으로 더 분류된다. 인플루엔자 A 바이러스의 경우, HA의 16개 아형 및 NA의 9개 아형이 동정되었는데, 이들 중 3개의 HA 아형 (H1, H2 및 H3) 및 2개의 NA 아형 (N1 및 N2)은 인간에서 일반적으로 발견된다. 인플루엔자 B 바이러스의 경우, 단 하나의 HA 아형 및 하나의 NA 아형만이 인식된다.
인플루엔자 바이러스 균주의 명명법에 대한 세계보건기구 가이드라인은 다음과 같다: 먼저, 바이러스의 타입을 지정하고 (A, B, 또는 C), 이어서 숙주 (비-인간의 경우), 분리 장소, 분리 수, 및 분리 연도를 슬래시로 구분하여 지정한다. 인플루엔자 A의 경우, HA 및 NA 아형은 괄호 안에 표시된다. 예를 들어, 종종 인플루엔자 백신에 포함되는 균주는: A/뉴칼레도니아/20/1999 (H1N1)이다.
인플루엔자 시즌 전에 매년 고위험군의 백신 접종은 인플루엔자의 영향을 줄이는 가장 효과적인 방법이다. 가장 일반적인 인플루엔자 백신은 수정된 계란을 사용하여 생산된 비활성화 바이러스 입자로 구성된다. 매번 인플루엔자 시즌 전에, 특별 위원회는 다가오는 독감 시즌에 발생할 가능성이 가장 높은 바이러스를 나타내는 것으로 여겨지는 3개의 바이러스 균주를 선정한다. 선정된 바이러스의 샘플은 원하는 항원 특성을 갖는 종자 바이러스 스톡으로 제조사에게 제공된다. 이 종자 바이러스는 수정된 계란 내로 주입된다. 이들 계란을 인큐베이션하면서 인플루엔자 바이러스를 증식시킨다. 적절한 시간이 경과한 후 계란을 개봉하고 난백을 수확한다. 이 샘플에 바이러스가 포함되어 있다. 바이러스를 계란 물질로부터 정제하고 비활성화시킨다. 그 후에 개별 바이러스 스톡을 조합하여 통상의 3가 인플루엔자 백신을 생성한다.
계란에서 백신의 생산은 다수의 단점과 연관되어 있다. 첫째로, 1-2개 계란/용량만큼 굉장히 많은 계란이 요구된다. 또한, 예를 들어, 독감 시즌 동안에 백신 조성의 변화가 필요한 경우, 이 생산은 시간 소모적이고, 비용이 많이 들며, 융통성이 부족하다. 또한, 계란에서의 생산은 다양한 바이러스 수율을 초래하고 계란 단백질에 대한 알러지 반응과 관련이 있다.
계란의 사용을 피하기 위해, 인플루엔자 바이러스를 생산하기 위한 대안적인 방법이 제시되고 있다. 이들에는, 예를 들어, MDCK 세포 (Novartis) 또는 PERC.6 세포 (Crucell)와 같은 포유류 세포 배양물에서 바이러스를 번식시킴으로써 바이러스 입자를 생산하는 방법이 포함된다. 또한, 재조합 헤마글루티닌 및/또는 뉴라미니다제 단백질의 생산이, 예를 들어, 베큘로바이러스 발현 벡터를 사용하는 곤충 세포 (Flublok®, Protein Sciences Corp.), 식물 세포 (Medicago Inc.), 박테리아 시스템 (VaxInnate), 및 뉴로스포라 크라싸 (Neurospora crassa) (Intrexon/Neugenesis) 및 피치아 파스토리스 (Pichia pastoris) (예컨대, Murugan et al., 2013, Journal of Virological Methods, 187: 20-25 참조)와 같은 진균에서 제안되었다. 그러나, 지금까지 개시된 방법은 상대적으로 고가이고/이거나 이들의 수율이 비교적 낮다.
미국특허 제8,163,533호는 사상형 진균 이형다핵세포 (heterokaryon)를 사용하여 다가 재조합 백신을 신속하게 생산하기 위한 방법 및 조성물을 개시한다. 사상형 진균 이형다핵세포는 병원성 유기체로부터 유래하는 항원의 변이체를 인코딩하는 재조합 DNA가 도입된 2개 이상의 모균주의 조합으로부터 생성된다. 수득된 백신은 다가이다.
WO 2014/151488은 재조합 헤마글루티닌 제제, 특히 재조합 인플루엔자 헤마글루티닌 (rHA) 제제의 안정성을 개선하고 효능을 유지하는 방법을 개시한다. 구체적으로, rHA 제제의 안정성이 시스테인 잔기를 돌연변이시키거나 또는 환원제 및 시트르산나트륨과 함께 제제화함으로써 현저히 개선될 수 있는 것으로 나타났다.
이전에는 크리소스포리움 루크노웬세 (Chrysosporium lucknowense) 균주 C1로 불리던, 마이셀리오프쏘라 써모필라 균주 C1은 1990년대 초기에 발견된 사상형 고온성 진균이다. 야생형 C1은 자연적으로 높은 수준의 셀룰라제를 생산하여, 이 효소를 상업적 규모로 생산하는데 이 균주를 매력적이게 한다. 수년에 걸쳐 발현 시스템 및 몇몇 개선된 C1 균주가 C1에서 추가적인 효소 및 다른 산업적 단백질을 생산하기 위해 개발되었다. 예를 들어, 야생형 C1 단리물에 비해 더 높은 수준으로 셀룰라제 생산을 특징으로 하는 개선된 C1 균주가 개발되었고, "고-셀룰라제 (High Cellulase)" 또는 "HC"로 표시된다. 또한, 더 낮은 수준의 셀룰라제를 생산하는 C1 균주 역시 개발되었는데, 이는 "저 셀룰라제 (Low Cellulase)" 또는 "LC"로 표시되고, 더 순수한 효소의 상업적 생산을 가능케 한다.
야생형 C1을 부다페스트 조약에 따라 1996년 8월 29일자에, 기탁 번호 VKM F-3500 D로 기탁하였다. HC 및 LC 균주를 또한, 예를 들어, 다음과 같이 기탁하였다: 균주 UV13-6, 기탁 번호 VKM F-3632 D, 균주 NG7C-19, 기탁 번호 VKM F-3633 D, 균주 UV18-25, 기탁 번호 VKM F-3631 D. 기탁된 추가의 개선된 C1 균주에는 다음이 포함된다: (i) HC 균주 UV18-100f (△alp1△pyr5) - 기탁 번호 CBS141147; (ii) HC 균주 UV18-100f (△alp1△pep4△alp2△pyr5,△prt1) 기탁 번호 CBS141143; (iii) LC 균주 W1L#100I (△chi1△alp1△alp2△pyr5) - 기탁 번호 CBS141153; 및 (iv) LC 균주 W1L#100I (△chi1△alp1△pyr5) - 기탁 번호 CBS141149.
미국특허 제8,268,585호 및 미국특허 제8,871,493호는 사상형 진균 숙주 분야에서 이종 단백질 또는 폴리펩티드의 발현 및 분비를 위한 형질전환 시스템을 개시한다. 경제적인 방식으로 다량의 폴리펩티드 또는 단백질을 생산하는 방법을 또한 개시한다. 이 시스템은 크리소스포리움 속의 형질전환 또는 형질감염된 진균 균주, 보다 구체적으로 크리소스포리움 루크노웬세 및 이의 변이체 또는 유도체를 포함한다. 크리소스포리움 유전자의 발현-조절 서열뿐만 아니라, 크리소스포리움 코딩 서열을 함유하는 형질전환체를 또한 개시한다.
미국특허 제9,175,296호는 크리소스포리움 루크노웬세의 진균 숙주 균주를 개시한다. 75% 초과의 순도를 갖는 순수한 단백질의 동종 및/또는 이종 생산을 위한 방법, 인공 단백질 혼합물의 생산을 위한 방법, 및 원하는 효소를 기능적으로 발현하는 균주의 단순한 스크리닝 방법을 또한 개시한다. 미국특허 제9,175,296호는 크리소스포리움 루크노웬세에서 유전자 발현의 전사적 제어에 적합한 단리된 프로모터 서열, 및 프로테아제 분비가 크리소스포리움 루크노웬세 균주 UV 18-25의 프로테아제 분비의 20% 미만인 크리소스포리움 루크노웬세의 진균 숙주 균주를 단리하는 방법을 추가로 개시한다.
비용 효율적이고 시즌 인플루엔자 백신의 생산 요건을 충족하는 시간-제한적 방식으로 고 수율의 효과적인 면역원성 단백질을 제공하는, 인플루엔자 백신 조성물을 생산하는 개선된 방법이 요구된다.
본 발명은 일부 양태에 따라 인플루엔자 바이러스 표면 단백질 헤마글루티닌 및 뉴라미니다제를 생산하도록 유전적으로 변형된 마이셀리오프쏘라 써모필라 균주 C1을 제공한다.
본원에 기술된 바와 같이, 인플루엔자 바이러스 표면 단백질은 그의 엑토도메인 및 막횡단 도메인 둘 다를 함유하는, 전장의 막-결합 단백질로 생산된다. 놀랍게도 C1에 의해 생산된 전장의 막-결합 형태는 기능성 및 면역원성인 반면, 변형된 분비 형태는 비활성인 것으로 나타났다. 막-결합 형태는 마우스 모델에서 예시된 바와 같이, 특히 효과적이었고 상대적으로 낮은 농도에서 면역 반응을 이끌어 냈다. 유리하게는, C1은 상업적-규모의 생산에 적합한, 높은 수율로 막-결합 형태를 생산할 수 있다.
따라서 본 발명은 인플루엔자 백신 조성물에 사용하기 위한, 효과적인 면역원성 인플루엔자 바이러스 단백질을 높은 수율로 생산하는 효과적인 시스템을 제공한다.
일 양태에 따르면, 본 발명은 적어도 하나의 C1 조절 서열에 작동적으로 연결된 인플루엔자 바이러스 표면 단백질을 인코딩하는 핵산 서열을 포함하는 발현 컨스트럭트를 포함하는, 인플루엔자 바이러스 표면 단백질을 생산하도록 유전적으로 변형된 마이셀리오프쏘라 써모필라 C1을 제공하고, 상기 인플루엔자 바이러스 표면 단백질은 그의 엑토도메인 및 막횡단 도메인을 포함하고 막-결합 단백질로서 C1에서 발현된다.
일부 구현예에서, 인플루엔자 바이러스 표면 단백질은 헤마글루티닌 (HA)이다. 이들 구현예에 따르면, 발현 컨스트럭트는 HA를 인코딩하는 핵산 서열에 인-프레임으로 연결된 C1 시그널 펩티드를 인코딩하는 핵산 서열을 추가로 포함한다.
일부 구현예에서, HA 아형은 인플루엔자 A-H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15 및 H16; 및 인플루엔자 B 아형으로 구성된 군으로부터 선택된다.
일부 특정 구현예에서, HA 아형은 인플루엔자 A 아형 H1, H2 및 H3; 및 인플루엔자 B 아형로부터 선택되는 인간을 감염시키는 아형이다. 각각의 가능성은 본 발명의 개별 구현예를 나타낸다.
일부 구현예에서, HA는 A/뉴칼레도니아/20/99 (H1N1), A/캘리포니아/04/2009 (H1N1), A/우루과이/716/07 (H3N2) (A/브리스베인/10/07-유사), B/플로리다/04/2006: B 야마가타 계통, A/푸에르토리코/08/1934 (H1N1), 및 A/텍사스/50/2012 (H3N2)로 구성된 군으로부터 선택되는 인플루엔자 바이러스 균주로부터이다.
일부 구현예에서, 적어도 하나의 C1 조절 서열은 C1 프로모터를 포함한다. 일부 구현예에서, C1 프로모터는: hex1 (Woronin 체), cbh1 (셀로비오히드롤라제 1) 및 chi1 (키티나제 1) 프로모터로 구성된 군으로부터 선택된다. 각각의 가능성은 본 발명의 개별 구현예를 나타낸다. 일부 특정 구현예에서, C1 프로모터는 hex1 프로모터이다.
일부 구현예에서, C1 시그널 펩티드는 Cbh1 (셀로비오히드롤라제 1, C1), Gla1 (글루코아밀라제 1, C1) 및 GlaA (글루코아밀라제 A, 아스페르질러스)로 구성된 군으로부터 선택된 단백질로부터 유래한 시그널 펩티드이다. 각각의 가능성은 본 발명의 개별 구현예를 나타낸다. 일부 특정 구현예에서, C1 시그널 펩티드는 Cbh1로부터 유래한다.
일부 구현예에서, 발현 컨스트럭트는: HA에 융합된 Cbh1 시그널 펩티드를 인코딩하는 핵산 서열에 작동적으로 연결된 hex1 프로모터를 포함한다. 이들 구현예에 따르면, HA는 A/뉴칼레도니아/20/99 (H1N1), A/캘리포니아/04/2009 (H1N1), B/플로리다/04/2006: B 야마가타 계통, A/푸에르토리코/08/1934 (H1N1), 및 A/텍사스/50/2012 (H3N2)로 구성된 군으로부터 선택되는 인플루엔자 바이러스 균주로부터이다.
일부 구현예에서, 인플루엔자 바이러스 표면 단백질은 뉴라미니다제 (NA)이다.
일부 구현예에서, NA 아형은 인플루엔자 A-N1, N2, N3, N4, N5, N6, N7, N8 및 N9; 및 인플루엔자 B 아형으로 구성된 군으로부터 선택된다.
일부 특정 구현예에서, NA 아형은 인플루엔자 A 아형 N1 및 N2; 및 인플루엔자 B 아형으로부터 선택되는 인간을 감염시키는 아형이다. 각각의 가능성은 본 발명의 개별 구현예를 나타낸다.
일부 구현예에서, 발현 컨스트럭트는: NA를 인코딩하는 핵산 서열에 작동적으로 연결된 hex1 프로모터를 포함한다. 이들 구현예에 따르면, NA는 인플루엔자 바이러스 균주 A/뉴칼레도니아/20/99 (H1N1)로부터이다.
일부 구현예에서, C1 균주는: W1L#100I (prt-△alp1△chi1△alp2△pyr5) 기탁 번호 CBS141153, UV18-100f (prt-△alp1,△pyr5) 기탁 번호 CBS141147, W1L#100I (prt-△alp1△chi1△pyr5) 기탁 번호 CBS141149, 및 UV18-100f (prt-△alp1△pep4△alp2,△prt1△pyr5) 기탁 번호 CBS141143으로 구성된 군으로부터 선택된다. 일부 특정 구현예에서, C1 균주는 W1L#100I (prt-△alp1△chi1△alp2△pyr5) 기탁 번호 CBS141153이다. 추가의 특별 구현예에서, C1 균주는 UV18-100f (prt-△alp1,△pyr5) 기탁 번호 CBS141147이다.
일부 구현예에서, C1 균주는 내인성 프로테아제를 인코딩하는 하나 이상의 유전자를 결실시키도록 변이된 균주이다. 일부 구현예에서, C1 균주는 내인성 키티나제를 인코딩하는 유전자를 결실시키도록 변이된 균주이다.
추가 양태에 따르면, 본 발명은 인플루엔자 바이러스 표면 단백질을 생산하는 방법을 제공하고, 상기 방법은 본 발명의 유전적으로-변형된 마이셀리오프쏘라 써모필라 C1을 인플루엔자 바이러스 표면 단백질을 발현하기에 적합한 조건하에서 배양하는 단계; 및 인플루엔자 바이러스 표면 단백질을 회수하는 단계를 포함한다.
일부 구현예에서, 인플루엔자 바이러스 표면 단백질의 회수는 균사체로부터의 추출을 포함한다.
일부 구현예에서, 회수된 단백질의 수율은 적어도 80%이다. 특정 예시적인 구현예에 따르면, 수율은 80%이다.
다른 양태에 따르면, 마이셀리오프쏘라 써모필라 C1에서 막 결합 인플루엔자 바이러스 표면 단백질을 발현하기 위한 발현 컨스트럭트가 본원에 제공되고, 상기 발현 컨스트럭트는 인플루엔자 바이러스 표면 단백질을 인코딩하는 핵산 서열에 작동적으로 연결된 적어도 하나의 C1 조절 서열을 포함하고, 상기 인플루엔자 바이러스 표면 단백질은 그의 엑토도메인 및 막횡단 도메인을 포함한다.
또 다른 양태에 따르면, 본 발명의 변형된 마이셀리오프쏘라 써모필라 C1에 의해 생산된 실질적으로 순수한, 재조합 인플루엔자 바이러스 표면 단백질이 본원에 제공되고, 상기 인플루엔자 바이러스 표면 단백질은 95% 순도 이상으로 정제되고 활성 및 면역원성이며, 백신으로 사용되는 경우 보호 면역 반응을 유도한다.
본 발명의 변형된 마이셀리오프쏘라 써모필라 C1에 의해 생산된 인플루엔자 바이러스 표면 단백질을 포함하는 인플루엔자 백신 조성물이 본원에서 추가로 제공된다.
본 발명의 이들 및 추가 양태 및 특징은 하기의 상세한 설명, 실시예 및 청구범위로부터 명백할 것이다.
본 발명은 진균 마이셀리오프쏘라 써모필라, 특히 균주 C1에서 인플루엔자 바이러스 표면 단백질의 재조합 발현에 관한 것이다. 일부 구현예에 따르면 본 발명은 인플루엔자 바이러스 표면 단백질을 발현하는 유전적으로 변형된 C1 세포, 및이를 사용하여 인플루엔자 백신 조성물을 생산하는 방법을 제공한다.
이하에서는 C1에서 생산된 인플루엔자 항원이 마우스에서 산업 표준 항원과 동등하거나, 또는 이보다 훨씬 더 우수한 면역 반응을 생성함을 개시한다.
본원에 사용된 바와 같이 "C1" 또는 "마이셀리오프쏘라 써모필라 C1"은 부다페스트 조약에 따라 1996년 8월 29일자에, 번호 VKM F-3500 D로 기탁된, 이전에는 크리소스포리움 루크노웬세 균주 C1로 불리던, 마이셀리오프쏘라 써모필라 균주 C1을 지칭한다. 이 용어는 또한, 예를 들어, 하나 이상의 내인성 유전자를 결실하도록 변이된 이의 유전적으로 변형된 아-균주를 포함한다. 예를 들어, C1 균주 (아-균주)는 내인성 프로테아제를 인코딩하는 하나 이상의 유전자 및/또는 내인성 키티나제를 인코딩하는 하나 이상의 유전자를 결실하도록 변이된 균주일 수 있다. 예를 들어, 본 발명에 포함되는 C1 균주에는 W1L#100I (prt-△alp1△chi1△alp2△pyr5) 기탁 번호 CBS141153, UV18-100f (prt-△alp1,△pyr5) 기탁 번호 CBS141147, W1L#100I (prt-△alp1△chi1△pyr5) 기탁 번호 CBS141149, 및 UV18-100f (prt-△alp1△pep4△alp2,△prt1△pyr5) 기탁 번호 CBS141143가 포함된다.
최근 논문 (Marin-Felix et al., 2015, Mycologica, 3: 619-63)에서 온도 성장, 배양 중의 생식 형태 및 분생포자 (conidia) 특성과 같은 몇몇 기준에 근거한 마이셀리오프쏘라 속의 분열이 제안되었음이 주목된다. 제안된 기준에 따르면 C1은 써모셀로마이세스 (Thermothelomyces) 속 헤테로쌀리칼 써모필라 (heterothallica/ thermophila) 종에 속한다. 따라서, Marin-Felix 논문에 따르면, 업데이트된 C1 명칭은 써모셀로마이세스 써모필라 균주 C1이다.
발현 컨스트럭트
용어 "발현 컨스트럭트", "DNA 컨스트럭트" 또는 "발현 카세트"는 본원에서 호환적으로 사용되고 관심 단백질을 인코딩하는 핵산 서열을 포함하고 관심 단백질이 표적 숙주 세포에서 발현되도록 조립되는, 인공적으로 조립되거나 또는 단리된 핵산 분자를 지칭한다. 발현 컨스트럭트는 전형적으로 관심 단백질을 인코딩하는 핵산 서열에 작동적으로 연결되는 적합한 조절 서열을 포함한다. 발현 컨스트럭트는 선택 마커를 인코딩하는 핵산 서열을 추가로 포함할 수 있다.
용어 "핵산 서열", "뉴클레오티드 서열" 및 "폴리뉴클레오티드"는 본원에서 개별 단편의 형태로 또는 더 큰 컨스트럭트의 구성요소로 데옥시리보뉴클레오티드 (DNA), 리보뉴클레오티드 (RNA), 및 이들의 변형된 형태의 중합체를 지칭하기 위해 사용된다. 핵산 서열은 코딩 서열, 즉 세포에서 단백질과 같은 최종 산물을 인코딩하는 서열일 수 있다. 핵산 서열은 또한 예를 들어, 프로모터와 같은 조절 서열일 수 있다.
용어 "펩티드", "폴리펩티드" 및 "단백질"은 본원에서 아미노산 잔기의 중합체를 지칭하기 위해 사용된다. 용어 "펩티드'는 전형적으로 2 내지 50개 아미노산으로 구성된 아미노산 서열을 나타내는 반면, "단백질"은 50개 초과 아미노산 잔기로 구성된 아미노산 서열을 나타낸다.
참조 서열에 "상동성"인 서열 (예컨대, 핵산 서열 및 아미노산 서열)은 본원에서 서열간의 동일성 백분율을 지칭하며, 여기서 동일성 백분율은 적어도 70%, 바람직하게는 적어도 80%, 적어도 85%, 적어도 90%, 적어도 95%, 적어도 98% 또는 적어도 99%이다. 각각의 가능성은 본 발명의 개별 구현예를 나타낸다. 상동성 핵산 서열은 유전자 코드의 코돈 용법 및 축퇴성과 관련된 변이를 포함한다.
서열 동일성은 당해 분야에 공지된 바와 같은, 뉴클레오티드/아미노산 서열 비교 알고리즘을 사용하여 결정될 수 있다.
용어 "조절 서열"은 프로모터 및 터미네이터와 같이, 코딩 서열의 발현 (전사)을 제어하는 DNA 서열을 지칭한다.
용어 "프로모터"는 생체 내 또는 시험관 내에서 또 다른 DNA 서열의 전사를 제어 또는 지시하는 조절 DNA 서열에 관한 것이다. 일반적으로, 프로모터는 전사된 서열의 5' 영역에 위치한다 (즉, 그에 있고, 그에 선행하고, 그의 상류에 위치한다). 프로모터는 전부가 천연 공급원으로부터 유래할 수 있거나, 또는 자연계에서 발견되는 상이한 프로모터로부터 유래한 상이한 요소로 구성되거나, 또는 심지어 합성 뉴클레오티드 세그먼트를 포함할 수 있다. 프로모터는 구성적이거나 (즉, 프로모터 활성화가 유도제에 의해 조절되지 않고 따라서 전사 속도가 일정함), 또는 유도성일 수 있다 (즉, 프로모터 활성화가 유도제에 의해 조절됨). 대부분의 경우에 조절 서열의 정확한 경계는 완전히 정의되지 않았으며, 일부 경우에는 완전히 정의될 수 없고, 따라서 일부 변이의 DNA 서열이 동일한 프로모터 활성을 가질 수 있다.
용어 "터미네이터"는 전사 종결을 조절하는 또 다른 조절 DNA 서열에 관한 것이다. 터미네이터 서열은 전사되는 핵산 서열의 3' 말단에 작동적으로 연결된다.
용어 "C1 프로모터" 및 "C1 터미네이터"는 C1에 사용하기에 적합한, 즉 C1에서 유전자 발현을 지시할 수 있는 프로모터 및 터미네이터 서열을 나타낸다. 일부 구현예에 따르면, C1 프로모터/터미네이터는 마이셀리오프쏘라 써모필라 C1의 내인성 유전자로부터 유래한다. 예를 들어, 일부 구현예에서, C1 프로모터는 hex1 (Woronin 체) 프로모터이다. 예시적인 hex1 프로모터 서열이 서열번호: 1로 개시된다. 추가 구현예에서, C1 프로모터는 chi1 (키티나제 1) 프로모터이다. 예시적인 chi1 프로모터 서열이 서열번호: 2로 개시된다.
일부 구현예에 따르면, C1 프로모터/터미네이터는 마이셀리오프쏘라 써모필라 C1에 외인성인 유전자로부터 유래한다. 예를 들어, bgl 프로모터가 사용될 수 있다.
용어 "작동적으로 연결된"은 조절 요소 (프로모터 또는 터미네이터)와 근접해 있어 조절 요소가 선택된 핵산 서열의 발현 조절을 가능케 하는 것을 의미한다.
용어 "시그널 펩티드" 또는 "시그널 서열"은 본원에서 호환적으로 사용되고 숙주 세포에서 단백질을 분비 경로로 지시하는 새로 합성된 폴리펩티드 사슬의 N-말단에 전형적으로 존재하는 짧은 펩티드 (보통 5-30개 아미노산 길이)를 지칭한다. 시그널 펩티드는 전형적으로 이후에 제거된다. "C1 시그널 펩티드"는 C1과 사용하기에 적합한, 즉 C1에서 발현된 단백질을 C1의 분비 경로로 지시할 수 있는 시그널 펩티드를 나타낸다. 일부 구현예에 따르면, C1 시그널 펩티드는 마이셀리오프쏘라 써모필라 C1의 내인성 유전자로부터 유래한다. 예를 들어, 일부 구현예에서, C1 시그널 펩티드는 Gla1 (글루코아밀라제 1, C1)로부터 유래한 시그널 펩티드이다. Gla1 시그널 펩티드를 인코딩하는 예시적인 서열이 서열번호: 23의 위치 1-20에 개시된다. 추가 구현예에서, C1 시그널 펩티드는 Cbh1 (셀로비오히드롤라제 1, C1)로부터 유래한 시그널 펩티드이다. Cbh1 시그널 펩티드를 인코딩하는 예시적인 서열이 서열번호: 3으로 개시된다.
일부 구현예에 따르면, C1 시그널 펩티드는 마이셀리오프쏘라 써모필라 C1에 외인성인 유전자로부터 유래한다. 예를 들어, 일부 구현예에서, C1 시그널 펩티드는 GlaA (글루코아밀라제 A, 아스페르질러스)로부터 유래한다. GlaA 시그널 펩티드를 인코딩하는 예시적인 서열이 서열번호: 24의 위치 1-18에 개시된다.
본원에 사용된 바와 같이, 용어 "인-프레임"은, 하나 이상의 핵산 서열을 지칭하는 경우, 이들의 정확한 해독 틀이 유지되도록 이들 서열이 연결되는 것을 나타낸다.
본 발명의 일부 구현예에 따르면 발현 컨스트럭트는 인-프레임으로 융합된 C1 시그널 펩티드 및 인플루엔자 바이러스 표면 단백질을 인코딩하는 핵산 서열에 작동적으로 연결된 C1 프로모터 서열 및 C1 터미네이터 서열을 포함한다.
일부 구현예에서, 발현 컨스트럭트는 인플루엔자 바이러스 표면 단백질에 융합되어 이의 분비를 촉진하는 캐리어 단백질을 인코딩하는 핵산 서열을 함유하지 않는다.
특정 발현 컨스트럭트는 중합효소 연쇄 반응 (PCR), 제한 엔도뉴클리아제 분해, 시험관 내 및 생체 내 조립 방법뿐만 아니라, 유전자 합성 방법, 또는 이들의 조합과 같은 통상적인 분자 생물학적 방법을 포함하는 다양한 상이한 방법에 의해 조립될 수 있다.
인플루엔자 바이러스 표면 단백질
"HA"로 약칭되는 헤마글루티닌은 숙주 세포 상의 시알산-함유 수용체를 통해 그의 숙주 세포에 대한 바이러스의 부착을 매개하는 타입 I 막횡단 당단백질이다. HA 분자는 동형삼중체 (homotrimer)로서 바이러스 내에 존재한다. 각 단량체는 일반적으로 HA1 및 HA2로 명명된 2개의 도메인을 포함하는데, 여기서 HA2 도메인은 HA 단백질을 바이러스 막에 연결하는 막횡단 영역, 및 작은 세포질 꼬리 (cytoplasmic tail)를 포함한다. 단량체는 HA0으로 명명되는, 75 kDa 전구체 단백질로서 합성되는데, 이는 바이러스의 표면에서 삼중체 단백질로 조립된다. 시그널 펩티드는 HA0을 숙주 세포의 분비 경로로 지시하고 성숙 단백질에는 존재하지 않는다. 활성화되기 위해서, HA0 전구체는 숙주의 세포 프로테아제에 의해 절단되어야 한다. 절단 후, 이황화 결합에 의해 연결되는 (그리고 바이러스의 표면에 고정되는), HA1 및 HA2 도메인에 상응하는 2개의 아단위가 생성된다.
달리 정의되지 않는 한, 용어 "헤마글루티닌" 또는 "HA"는 본원에 사용된 바와 같이 인플루엔자 바이러스 헤마글루티닌, 특히 바이러스 입자 외부로 연장되는 엑토도메인, 막횡단 도메인 및 세포질 꼬리를 함유하는 전장 단백질을 지칭한다. 이 용어는 HA0 비절단 형태뿐만 아니라 성숙 HA1+HA2 형태를 포함한다.
본 발명의 HA의 아형은 인플루엔자 A 아형 H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15 또는 H16일 수 있다. HA 아형은 인플루엔자 B 아형일 수 있다. 특정 구현예에서, HA 아형은 인간을 감염시키는 아형이다. 일부 구현예에서, HA 아형은 인플루엔자 A 아형 H1, H2 및 H3으로부터 선택된다. 추가의 특별 구현예에서, HA 아형은 인플루엔자 B 아형이다.
"NA"로 약칭되는 뉴라미니다제는 숙주 세포로부터 새로운 바이러스 자손의 방출을 매개하는 타입 II 막-결합 효소이다. 이는 바이러스 표면에 4개의 동일한 단량체의 사량체로 존재하는데, 각 단량체는 보통 세포질 도메인, 막횡단 도메인, 줄기 (stalk) 도메인, 및 효소적 활성 부위를 운반하는 구형 헤드 (globular head) 도메인을 포함한다. 달리 정의되지 않는 한, 용어 "뉴라미니다제" 또는 "NA"는 본원에 사용된 바와 같이 전장 단백질을 지칭한다.
본 발명의 NA의 아형은 인플루엔자 A 아형 N1, N2, N3, N4, N5, N6, N7, N8 또는 N9, 또는 인플루엔자 B 아형일 수 있다. 특정 구현예에서, NA 아형은 인간을 감염시키는 아형이다. 일부 구현예에서, NA 아형은 인플루엔자 A 아형 N1 및 N2로부터 선택된다. 추가의 특별 구현예에서, NA 아형은 인플루엔자 B 아형이다.
다양한 인플루엔자 바이러스 균주로부터의 HA 및 NA의 뉴클레오티드 및 단백질 서열은 공개적으로, 예를 들어, National Center for Biotechnology Information (NCBI)의 데이터베이스에서 이용 가능하다. HA 및 NA 유전자/단백질의 예시적인 서열은 인플루엔자 균주 A/뉴칼레도니아/20/99 (H1N1), A/캘리포니아/04/2009 (H1N1), A/우루과이/716/07 (H3N2) (A/브리스베인/10/07-유사), B/플로리다/04/2006: B 야마가타 계통, A/푸에르토리코/08/1934 (H1N1), 및 A/텍사스/50/2012 (H3N2)로부터의 것들을 포함한다. 각각의 가능성은 본 발명의 개별 구현예를 나타낸다.
HA 및 NA의 유전적으로-변형된 변이체가 또한 본 발명에 따른 C1 내로 조작될 수 있는데, 이러한 변이체는 "범용 (universal)" HA 및 NA로 표시된다. 범용 HA 및 NA는, 예를 들어, 문헌 [Carter et al. (2016) Design and Characterization of a Computationally Optimized Broadly Reactive Hemaglutinin Vaccine for H1N1 Influenza Viruses., J Virol. 90(9). 4720-34]에 기술된 바와 같이, 다중 인플루엔자 균주에 대한 보호를 자극하는 교차-반응성 항원이다.
인플루엔자 바이러스 표면 단백질은 본 발명에 따라 클로닝되고 그의 엑토도메인 및 막횡단 도메인을 포함하는 막-결합 단백질로서 발현된다. 본 발명의 클로닝된 HA/NA 유전자는 전형적으로 천연 시그널 펩티드의 C1 시그널 펩티드로의 대체에 의해 변형된다.
일부 구현예에서, HA는 인플루엔자 바이러스 균주 A/뉴칼레도니아/20/99 (H1N1) ("HA 뉴칼레도니아")로부터이다. 천연 시그널 펩티드 없이, 그의 막횡단 도메인을 갖는, HA 뉴칼레도니아의 아미노산 서열은 서열번호: 4로 개시된다. 천연 시그널 펩티드 없이, 그의 막횡단 도메인을 갖는, HA 뉴칼레도니아를 인코딩하는 뉴클레오티드 서열은 서열번호: 5로 개시된다.
일부 구현예에서, HA는 인플루엔자 바이러스 균주 A/텍사스/50/2012 (H3N2) ("HA 텍사스")로부터이다. 천연 시그널 펩티드 없이, 그의 막횡단 도메인을 갖는, HA 텍사스의 아미노산 서열은 서열번호: 6으로 개시된다. 천연 시그널 펩티드 없이, 그의 막횡단 도메인을 갖는, HA 텍사스를 인코딩하는 뉴클레오티드 서열은 서열번호: 7로 개시된다.
일부 구현예에서, HA는 인플루엔자 바이러스 균주 A/푸에르토리코/08/1934 (H1N1) ("HA 푸에르토리코")로부터이다. 천연 시그널 펩티드 없이, 그의 막횡단 도메인을 갖는, HA 푸에르토리코의 아미노산 서열은 서열번호: 8로 개시된다. 천연 시그널 펩티드 없이, 그의 막횡단 도메인을 갖는, HA 푸에르토리코를 인코딩하는 뉴클레오티드 서열은 서열번호: 9로 개시된다.
일부 구현예에서, HA는 인플루엔자 바이러스 균주 B/플로리다/04/2006: B 야마가타 계통 ("HA 플로리다")으로부터이다. 천연 시그널 펩티드 없이, 그의 막횡단 도메인을 갖는, HA 플로리다의 아미노산 서열은 서열번호: 10으로 개시된다. 천연 시그널 펩티드 없이, 그의 막횡단 도메인을 갖는, HA 플로리다를 인코딩하는 뉴클레오티드 서열은 서열번호: 11로 개시된다.
일부 구현예에서, HA는 인플루엔자 바이러스 균주 A/캘리포니아/04/2009 (H1N1) ("HA 캘리포니아")로부터이다. 천연 시그널 펩티드 없이, 그의 막횡단 도메인을 갖는, HA 캘리포니아의 아미노산 서열은 서열번호: 12로 개시된다. 천연 시그널 펩티드 없이, 그의 막횡단 도메인을 갖는, HA 캘리포니아를 인코딩하는 뉴클레오티드 서열은 서열번호: 13으로 개시된다.
일부 구현예에서, NA는 인플루엔자 바이러스 균주 A/뉴칼레도니아/20/99 (H1N1) ("NA 뉴칼레도니아")로부터이다. 전장의 NA 뉴칼레도니아의 아미노산 서열은 서열번호: 14로 개시된다. 전장의 NA 뉴칼레도니아를 인코딩하는 뉴클레오티드 서열은 서열번호: 15로 개시된다.
C1에서 발현하는 경우, 클로닝된 HA/NA 유전자는 바람직하게는 C1 발현을 위해 코돈 최적화되고, 이는 클로닝된 유전자가 C1의 코돈 용법을 사용하여, 관심 인플루엔자 바이러스 표면 단백질의 아미노산 서열을 기준으로 고안됨을 의미한다.
특정 예시적인 구현예에 따르면, 유전자는 C1 프로모터 및 C1 터미네이터 하에서 클로닝된다.
Cbh 시그널 서열을 갖고, hex1 프로모터 및 cbh1 터미네이터 하에서 그의 막횡단 도메인을 갖는 HA 뉴칼레도니아를 인코딩하는 예시적인 발현 컨스트럭트는 서열번호: 16으로 개시된다. HA를 코딩하는 서열은 서열번호: 16의 위치 2920-4563에 상응한다. 이 세그먼트는 상이한 HA 단백질 또는 NA 단백질을 인코딩하는 발현 컨스트럭트를 수득하기 위해 상이한 HA 단백질 또는 NA 단백질을 인코딩하는 뉴클레오티드 서열로 대체될 수 있다.
서열번호: 16으로 개시되는 발현 컨스트럭트를 포함하는 예시적인 발현 벡터는 서열번호: 17로 개시되고 도 2cㅊ에 예시된다.
유전적으로-조작된 C1
본 발명에 따른 인플루엔자 바이러스 표면 단백질을 생산하도록 유전적으로 조작된 C1 세포는 상기에 기술된 바와 같은, 인플루엔자 바이러스 표면 단백질을 인코딩하는 핵산을 포함하는 발현 컨스트럭트를 C1 세포, 특히 C1 세포의 핵 내로 도입함으로써 생성된다. 구체적으로, 본 발명에 따른 유전적 변형은 숙주 게놈 내로 발현 컨스트럭트의 통합을 의미한다.
일부 구현예에서, C1은 단일 인플루엔자 바이러스 단백질을 생산하도록 유전적으로 조작된다. 다른 구현예에서, C1은 복수의 상이한 인플루엔자 바이러스 단백질을 생산하도록 유전적으로 조작된다. "복수"는 적어도 2개를 나타낸다.
C1 세포 내로의 발현 컨스트럭트의 도입, 즉 C1의 형질전환은 사상형 진균을 형질전환하는 당업계에 공지된 방법에 의해 수행될 수 있다. 예를 들어, 형질전환은 당업계에 공지되고 또한 하기 실시예 항목에 기술된 원형질체 형질전환 방법을 사용하여 수행될 수 있다.
형질전환된 세포의 용이한 선택을 위해, 선택 마커가 C1 세포 내로 형질전환될 수 있다. "선택 마커"는 항생제 내성 (내성 마커), 특정 자원을 활용하는 능력 (활용/영양요구성 마커) 또는, 예컨대 스펙트럼 측정에 의해 검출될 수 있는 리포터 단백질의 발현과 같이, 비-형질전환된 세포에는 존재하지 않는 특정 유형의 표현형을 부여하는 유전자 산물을 인코딩하는 폴리뉴클레오티드를 나타낸다. 영양요구성 마커는 전형적으로 식품 또는 제약 산업에서 선택 수단으로서 바람직하다. 선택 마커는 발현 컨스트럭트와 동시-형질전환된 개별 폴리뉴클레오티드 상에, 또는 발현 컨스트럭트의 동일한 폴리뉴클레오티드 상에 있을 수 있다.
형질전환 후, 양성 형질전환체는, 예컨대 선택된 선택 마커에 따른 선택적 배지에서 C1 세포를 배양함으로써 선택될 수 있다.
관심 단백질의 발현은 표준 방법을 사용하여 검출될 수 있다. 검출은, 예컨대 다양한 유형의 염색 또는 면역학적 방법에 의해 단백질 자체를 검출하거나, 또는 예컨대 혈구응집 분석에 의해 그의 활성을 검출함으로써 수행될 수 있다. 검출 전에, 단백질은 SDS-PAGE와 같은 다양한 기법을 사용하여 분리될 수 있다. 예시적인 절차가 하기 실시예 항목에 기술된다.
다량의 원하는 유전자 산물을 생산하기 위해 최고의 생산자가 선택되고 발효에 적용된다.
단백질의 생산
단백질 생산을 위해, 유전적으로 변형된 C1 세포를 인플루엔자 바이러스 표면 단백질을 인코딩하는 핵산의 발현을 허용하는 조건 하에서 배양한다. 진탕-플라스크 (shake-flask) 및 교반-탱크 (stirred-tank) 발효를 위한 예시적인 배양 조건이 하기 실시예 항목에 상세히 기술된다.
백신 조성물
본 발명에 따른 백신 또는 면역원성 조성물은 상기에 기술된 바와 같이 생산된 인플루엔자 바이러스 표면 단백질 및 약학적으로 허용가능한 담체를 포함한다.
용어 "면역원성" 또는 "면역성"은 면역 반응을 자극하거나 촉발하는 물질의 능력에 관한 것이다. 면역원성은, 예를 들어, 면역학적으로 적격인 유기체를 물질로 면역접종 후 그 물질에 대해 특이적인 항체의 존재를 결정함으로써 측정된다. 물질에 대해 특이적인 항체의 존재 및 그의 양은 당업계에 공지된 방법, 예를 들어, ELISA 분석을 사용하여 검출된다.
일부 구현예에서, 백신은 특정 인플루엔자 시즌에 대해 FDA에 의해 권고되는 인플루엔자 바이러스의 3개 균주로부터 유래하는 정제된 HA 단백질을 포함하는 면역 투여 형태로 제제화된다. 기능성 면역은 인플루엔자 헤마글루티닌에 결합하거나, 적혈구 세포를 응집시키는 인플루엔자 바이러스의 능력을 차단하거나, 또는 인플루엔자 바이러스를 중화시키는 항체의 양을 정량하는 분석을 이용하여 측정될 수 있다. 재조합 HA 백신을 이용한 보호 면역 반응이 또한 인플루엔자 감염에 취약한 동물에서 또는 인간 면역접종 연구에서 측정될 수 있다.
본 발명의 백신은 재조합 HA 및/또는 NA 단백질, 및 선택적으로, 아주반트를 포함한다. 이하에 예시된 바와 같이, 놀랍게도 본 발명에 따라 C1에서 생산된 재조합 HA 단백질은 아주반트 없이 투여되는 경우에서조차 마우스에서 체액성 반응을 촉발하는 것으로 나타났다.
백신은 근육 내, 비강 내, 피내, 경구, 복강 내, 피하 또는 경피 투여 방식을 비롯해, 다수의 상이한 방식 중 하나로의 투여를 위해 제제화될 수 있다.
일부 구현예에서, 백신은 비경구 투여용으로 제제화된다. 일부 특정 구현예에서, 백신은 근육 내 투여용으로 제제화된다. 다른 특정 구현예에서, 백신은 피내 투여용으로 제제화된다.
추가의 특별 구현예에서, 백신은 점막 전달, 특히 비강 내 전달용으로 제제화된다.
백신 조성물은 안정화제, 완충제 또는 보존제를 포함하는, 다양한 부형제를 함유할 수 있다.
일부 구현예에 따르면, 본 발명에 따른 백신 조성물은 아주반트를 함유하지 않는다.
일부 적용에서, 약제학적으로 허용가능한 아주반트가 백신 제제에 포함될 수 있다. 아주반트의 선택은 부분적으로 백신의 투여 방식에 의해 결정된다.
비강 내 아주반트의 비-제한적인 예시에는 키토산 분말, PLA 및 PLG 미세구체, QS-21, 인산칼슘 나노입자 (CAP) 및 mCTA/LTB (열 민감성 엔테로톡신의 오량체 B 아단위를 갖는 돌연변이 콜레라 독소 E112K)가 포함된다.
다른 투여 방식을 위한 아주반트의 예시에는 겔 형태의 무기 아주반트 (수산화알루미늄/인산알루미늄), 인산칼슘, 모노포스포릴 지질 A 및 뮤라밀 펩티드와 같은 박테리아 아주반트, ISCOMS ("면역자극 복합체"), 리포좀 및 생분해성 미세구체와 같은 미립자 아주반트, IFA ('불완전 Freund 아주반트"), SAF ("Syntex 아주반트 제제"), 사포닌 (예컨대, QS-21), 스쿠알렌/스쿠알란과 같은 오일 에멀젼 및 에멀젼화제 기반 아주반트, 비독성 블록 공중합체와 같은 합성 아주반트, 뮤라밀 펩티드 유사체, 합성 지질 A, 합성 폴리뉴클레오티드 및 폴리양이온성 아주반트가 포함된다.
아주반트는 아주반트 양으로 사용되며, 이는 아주반트, 숙주 동물 및 면역원에 따라 달라질 수 있다. 전형적인 양은 예방접종 당 약 1 μg 내지 약 1 mg으로 다양할 수 있다. 당업자는 적합한 농도 또는 양이 쉽게 결정될 수 있음을 알고 있다.
서열 목록
도 1a-1b. 고안되고 시험된 발현 컨스트럭트. 헤마글루티닌 (HA), 첫 번째 시리즈. P=프로모터, ss=시그널 서열, T=터미네이터. 각 컨스트럭트에 포함된 HA 타입은 굵은 글씨체로 표시된다.
도 2a-2b. 고안되고 시험된 발현 컨스트럭트. 헤마글루티닌 (HA), 두 번째 시리즈. P=프로모터, ss=시그널 서열, T=터미네이터. 각 컨스트럭트에 포함된 HA 타입은 굵은 글씨체로 표시된다. 도 2c. 컨스트럭트 Phex1-ssCbh-NC-TMD-Tcbh1을 함유하는 발현 벡터의 도해. 도 2d. 형질전환에 사용된 단편의 도해.
도 3. 고안되고 시험된 발현 컨스트럭트. 헤마글루티닌 (HA), 세 번째 시리즈. P=프로모터, ss=시그널 서열, T=터미네이터. 각 컨스트럭트에 포함된 HA 타입은 굵은 글씨체로 표시된다.
도 4. 고안되고 시험된 발현 컨스트럭트. 뉴라미니다제 (NA). P=프로모터, ss=시그널 서열, T=터미네이터. 각 컨스트럭트에 포함된 NA는 굵은 글씨체로 표시된다.
도 5. 약어 목록.
도 6. C1에서 이종 단백질 생산을 위한 예시적인 발현 벡터.
도 7. TMD-함유 HA의 정제 과정.
도 8. HA 세포 내 국소화 또는 세포-벽 부착 사이를 구별하기 위한 분획 연구의 흐름도.
도 9. rHA-TMD의 생화학적 평가.
도 10a-10b. 마우스에 주입 후 27일째 (도 10a) 및 49일째 (도 10b)에 C1에서 생산된 A/뉴칼레도니아/20/99 (H1N1)에 대해 촉발된 항체 반응.
도 11. 교반-탱크 발효를 사용한 C1에서 HA 생산의 웨스턴 블롯 분석.
도 2a-2b. 고안되고 시험된 발현 컨스트럭트. 헤마글루티닌 (HA), 두 번째 시리즈. P=프로모터, ss=시그널 서열, T=터미네이터. 각 컨스트럭트에 포함된 HA 타입은 굵은 글씨체로 표시된다. 도 2c. 컨스트럭트 Phex1-ssCbh-NC-TMD-Tcbh1을 함유하는 발현 벡터의 도해. 도 2d. 형질전환에 사용된 단편의 도해.
도 3. 고안되고 시험된 발현 컨스트럭트. 헤마글루티닌 (HA), 세 번째 시리즈. P=프로모터, ss=시그널 서열, T=터미네이터. 각 컨스트럭트에 포함된 HA 타입은 굵은 글씨체로 표시된다.
도 4. 고안되고 시험된 발현 컨스트럭트. 뉴라미니다제 (NA). P=프로모터, ss=시그널 서열, T=터미네이터. 각 컨스트럭트에 포함된 NA는 굵은 글씨체로 표시된다.
도 5. 약어 목록.
도 6. C1에서 이종 단백질 생산을 위한 예시적인 발현 벡터.
도 7. TMD-함유 HA의 정제 과정.
도 8. HA 세포 내 국소화 또는 세포-벽 부착 사이를 구별하기 위한 분획 연구의 흐름도.
도 9. rHA-TMD의 생화학적 평가.
도 10a-10b. 마우스에 주입 후 27일째 (도 10a) 및 49일째 (도 10b)에 C1에서 생산된 A/뉴칼레도니아/20/99 (H1N1)에 대해 촉발된 항체 반응.
도 11. 교반-탱크 발효를 사용한 C1에서 HA 생산의 웨스턴 블롯 분석.
하기 실시예는 본 발명의 특정 구현예를 더 완벽하게 설명하기 위해 제시된다. 그러나, 이들은 어떠한 방식으로도 발명의 범위를 제한하는 것으로 해석되어서는 안된다. 당업자는 발명의 범위를 벗어나지 않으면서 본원에 개시된 원리의 많은 변이 및 변형을 용이하게 고안할 수 있다.
실시예
실시예 1 -
마이셀리오프쏘라 써모필라
(C1)에서 헤마글루티닌 (HA) 및 뉴라미니다제 (NA)의 발현
C1에서 다양한 인플루엔자 바이러스 균주의 재조합 HA 단백질의 발현을 위해 여러 시리즈의 발현 컨스트럭트를 고안하였다. 본 연구에서 시험된 HA 단백질의 목록이 하기 표 1에 상세히 기술된다. 발현 컨스트럭트는 도 1-4 (도 1-3 - HA 함유 컨스트럭트; 도 4 - NA 함유 컨스트럭트. P=프로모터, ss=시그널 서열, T=터미네이터)에 상세히 도시된다. 각 컨스트럭트에 포함된 HA 타입 또는 NA는 굵은 글씨체로 표시된다. 컨스트럭트 내 다양한 요소를 설명하기 위해 사용된 약어의 목록이 도 5에 제공된다. 컨스트럭트의 생산은 하기 "재료 및 방법" 하에서 상세히 기술된다.
| 약칭 | 바이러스 균주 |
| NC | A/H1N1 A/뉴칼레도니아/20/99 |
| CA | A/H1N1 A/캘리포니아/04/2009 |
| UR | A/H3N2 A/우루과이/716/07 (A/브리스베인/10/07-유사) |
| FL | B/플로리다/04/2006: B 야마가타 계통 |
| PR | A/H1N1 A 푸에르토리코/08/1934 |
| Tex | A/ H3N2 A/텍사스/50/2012 |
초기에, 세포 외 기질 내로 HA의 분비를 촉진하기 위해 캐리어로서 잘-분비되는 A. 니거 글루코아밀라제 A (GlaA)에 융합된, cbh1 (셀로비오히드롤라제 1) 또는 chi1 (키티나제 1) 프로모터 하에서 HA를 발현시켰다. HA 유전자를 GlaA의 촉매 도메인을 인코딩하는 glaA 유전자의 일부에 융합시켰다. 골지체 내 부위의 절단 후 개별 HA 단백질을 수득하기 위해 KEX2 절단 부위 (VISKR)를 glaA와 HA 유전자 사이에 고안하였다. 컨스트럭트는 검출 및 정제 목적으로 C-말단 FLAG 태그를 추가로 포함하였다. 이 초기 시리즈의 발현 컨스트럭트에서, HA는 그들의 막횡단 도메인 (TMD) 및 세포질 꼬리 없이 발현되었다.
발현 컨스트럭트의 변형된 버전에서, hex1 (헥사고날 퍼옥시좀, Woronin 체) 프로모터가 시험되었는데, 이는 다른 2개의 프로모터보다 더 일찍 유도되는, 조기 구성적 프로모토로 간주된다.
HA 뉴칼레도니아의 경우, 추가 컨스트럭트 변이체가 하기와 같이 제조되었다:
- GlaA 캐리어 단백질 없이, 그러나 ER을 표적하기 위한 cbh1 시그널 서열을 갖는, cbh1 또는 chi1 프로모터 함유 컨스트럭트.
- chi1 프로모터 및 캐리어 단백질로서 Gla1 (C1 글루코아밀라제 1)을 갖는 컨스트럭트.
- 캐리어 단백질로서 EG2 (엔도글루카나제 2)를 갖는 컨스트럭트.
- hex1 프로모터, GlaA 캐리어 단백질을 갖고 FLAG 태그가 없는 컨스트럭트.
컨스트럭트의 발현을 위한 C1 숙주 균주를 단백분해 안정성 분석을 근거로 선택하였다. 간략히, 베큘로바이러스 발현 시스템 (Protein Sciences Corporation, Meriden USA)으로 생산된 HA를 몇몇 후보 C1 숙주 균주의 발효 종료 (end-of-fermentation, EOF) 배양 배지에서 단백분해 안정성에 대해 시험하였다 (하기 표 2 참조). 시험된 다른 균주에 비해 균주 D240 (고-셀룰라제 (HC) 균주) 및 D389 (저-셀룰라제 (LC) 균주)의 배양 여과물의 존재하에서 더 적은 HA 분해가 관찰되었다. 따라서 D240 및 D389를 재조합 HA의 생산을 위한 숙주 균주로 선택하였다. 이후 실험에서, D382를 또한 HA의 재조합 발현에 대해 시험하였다.
하기 "재료 및 방법"에 기술된 바와 같이 형질전환을 수행하였다.
형질전환 후, 형질전환체를 수집하고 96-웰 플레이트에서 배양하였다. 글루코아밀라제 (해당되는 경우) 및 헤마글루티닌의 발현에 대해 배지를 스크리닝하였다. 양성 형질전환체를 진탕 플라스크에서 추가 배양하고 HA의 발현을 블롯팅 기법 및 HA 활성 분석을 사용하여 평가하였다. 결과를 도 1a-b에 요약하였다.
수득된 형질전환체의 분석에 따르면 FLAG-태그 서열이 생략된 경우에 재조합 HA_NC가 C1에서 더 잘 발현되는 것으로 나타났다. 이 태그 없이 HA (130-160 kDa)를 함유하는 고 분자량 종이, HA_NC에 대한 단일클론 항체를 이용한 웨스턴 블롯에서 나타난 바와 같이, 진탕 플라스크 배양의 세포 외 기질에서 검출되었다. 시그널 강도를 기준으로 대규모 발효로 외삽하는 경우 이는 배양 배지에서 대략 30 mg/L를 나타내고, 총 세포 외 단백질 수준은 10 g/L에 이른다. HA_NC의 발현 수준은 HC 균주보다 LC 균주에서 더 높았다. 또한, 높은 수준의 HA가 세포 내에서 및/또는 세포-벽-연합으로 발견되었고, 이는 적어도 배지에서 발견되는 것만큼을 나타내는 것으로 추정된다.
hex1 프로모터를 갖는 컨스트럭트를 함유하는 형질전환체에서 가장 높은 발현이 달성되었다.
두 번째 시리즈의 발현 컨스트럭트를 고안하였고, HA의 천연 막횡단 도메인 (TMD) 또는 T4 박테리오파지 피브리틴 (fibritin)으로부터의 재조합 C-말단 사량체화 도메인 (T4 foldon 도메인)의 존재를 시험하였다. T4 foldon 도메인을 부가하여 세포 외 분비 시 HA의 안정성을 촉진하였다. 8개 Gly 잔기 ("8xG")의 링커를 HA 및 T4 foldon 도메인 사이에 클로닝하였다. TMD를 부가하여 수득된 HA의 발현 수준 및 활성에 대한 이의 효과를 시험하였다 (TMD 함유 HA 컨스트럭트는 분비될 것으로 예상되지 않았지만, 오히려 세포 내에서 또는 세포-벽-연합으로 발견되었음). 또한, HA와 GlaA 캐리어 단백질 사이에 5개 Gly 잔기 ("5xG")의 스트레치를 함유하는 변형된 KEX2 단백분해 부위를, 이러한 변형된 링커가 더 높은 수준의 개별 HA 단백질을 수득하는 결과를 초래할 수 있는지 여부를 조사하기 위해 시험하였다. 이 시리즈에 사용된 프로모터는 hex1이었는데, 이는 이전 시리즈에서 이 프로모터를 사용하여 수득된 더 강한 발현에 기초한 것이다. 시리즈 내 다양한 컨스트럭트가 도 2a-2b에 상세히 도시된다. 도 2c는 컨스트럭트 Phex1-ssCbh-NC-TMD-Tcbh1을 함유하는 발현 벡터 (발현 벡터의 서열은 서열번호: 17로 개시됨)를 설명한다. 도 2d는 형질전환에 사용된 단편을 설명한다.
첫 번째 시리즈에서 볼 수 있는 바와 같이, 캐리어 GlaA 없이 더 우수한 발현이 달성되었다. 캐리어가 존재하는 경우, 2개 모이어티 사이에 변형된 단백분해 부위가 사용된 경우에서조차 Gla-HA 융합 단백질만이 가시적이었다. C-말단 T4-foldon 도메인의 존재는 세포 외에서 검출되는 HA의 수준에 긍정적인 영향을 미쳤지만, 생성된 HA는 비활성인 것으로 보였다 (혈구응집 분석에서 음성 결과). T4 foldon 도메인에 융합된 HA의 활성을 더 평가하기 위하여, 컨스트럭트 Phex1-ssCbh-NC-8xG-T4 foldon-Tcbh1로부터 발현된 HA를 정제하여 마우스에서 면역원성 분석으로 시험하였다 (하기 실시예 2 참조). 기능적 면역원성은 전혀 관찰되지 않았다.
HA의 천연 막횡단 도메인은 발현 수준에 긍정적인 영향을 미쳤다 (세포 내 또는 세포-벽-연합). 또한, 생성된 단백질은 HA 활성 분석에서 매우 활성이었다. 그의 TMD를 갖는 HA의 활성을 추가로 평가하기 위해, 컨스트럭트 Phex1-ssCbh-NC-TMD-Tcbh1로부터 발현된 HA를 정제하고 마우스에서 면역원성 분석으로 시험하였다 (하기 실시예 2 참조). 기능적 면역원성이 관찰되었고, 이는 하기에 더 상세히 기술될 바와 같이, 특히 효과적이었다.
세 번째 시리즈의 발현 컨스트럭트를 고안하였는데, 지금까지 시험되지 않았던 유형을 비롯해 상이한 유형의 HA를 cbh 시그널 서열 함유, 캐리어 부재, 및 C-말단에서 T4 foldon 도메인 또는 TMD 함유로 hex1 프로모터 하에서 발현시켰다. 이 시리즈에서 T4 foldon 도메인을 Gly 링커 없이 또는 HA와 T4 foldon 도메인 사이에 변형된 링커와 함께 클로닝하였다. 또한, 뉴라미니다제 (NA)의 2개 변이체를 시험하였다. 이 시리즈의 다양한 컨스트럭트가 도 3-4에 상세히 도시된다.
C1은 상이한 유형의 HA를 생산할 수 있었다. 각각의 HA 유형에 대해 리터당 50 - 100 mg 사이의 단백질이 C1 균주에 의해 생산될 수 있음이 입증되었다. 하나 이상의 사례에서 ~ 300 mg/L의 발현 수준이 달성되었다.
두 번째 시리즈에서 볼 수 있는 바와 같이, C-말단 T4-foldon 도메인의 존재는 세포 외에서 검출되는 HA의 수준에 긍정적인 영향을 미쳤지만, 링커 없이 또는 HA와 T4 foldon 사이에 변형된 링커가 존재하는 경우에서조차, 생성된 HA는 비활성인 것으로 보였다 (혈구응집 분석에서 음성 결과). HA의 천연 막횡단 도메인은 또 다시 발현 수준에 긍정적인 영향을 나타내었다 (세포 내 또는 세포-벽-연합). 또한, 생성된 단백질은 HA 활성 분석에서 매우 활성이었다. 타입 A 및 타입 B 인플루엔자 단백질 둘 다가 성공적으로 발현되었고 생물학적으로 활성인 것으로 나타났다.
NA와 관련하여, 이는 C1에서 잘 발현되고 세포 외 및 세포 내 둘 다에서 검출될 수 있는 것으로 나타났다.
재료 및 방법
HA 단백질 표준품
HA 단백질 표준품을 Protein Sciences Corporation (Meriden, USA)으로부터 입수하였다. 이들 단백질을 베큘로바이러스 발현 벡터 시스템을 사용하여 곤충 세포에서 생산하였고 생물학적 활성 및 3차 구조를 보존하는 조건하에서 >90% 순도로 정제하였다. 단백질 표준품을 제조사에 의해 권고되는 바와 같이 4℃에서 저장하였다. 또한, A/H1N1 A/뉴칼레도니아/20/99 (NC)로부터의 계란-유래 HA의 배치를 National Institute for Biological Standards and Control (NIBSC)로부터 주문하였다. 이 샘플을 분취하고 제조사에 의해 권고되는 바와 같이 -20℃에서 저장하였다.
C1 균주
본 연구에서 시험된 후보 C1 생산 숙주를 표 2에 나타내었다. HC는 C1 고-셀룰라제 균주를 지칭하고 LC는 저-셀룰라제 균주를 지칭한다. Prt-는 프로테아제 결핍을 지칭하고, △alp1은 주요 분비 프로테아제의 유전자 파괴를 지칭하고, △alp2는 고도로 발현된 공포 (vacuolar) 프로테아제의 유전자 파괴를 지칭하고, △chi1은 C1에서 고도로 발현된 세포 외 C1 키티나제의 유전자 파괴를 지칭한다. 모든 균주는 △pyr5이다.
| C1 숙주 균주 | 기탁 정보 | 코드 |
| HC prt- | D202 | |
| HC prt-Δalp1 | "UV18-100f" 기탁 번호 CBS141147 | D240 |
| HC prt-Δalp1Δpep4 | D249 | |
| HC prt-Δalp1Δpep4Δalp2,Δprt1 | "UV18-100f" 기탁 번호 CBS141143 | D270 |
| LC prt-Δalp1 | D326 | |
| LC prt-Δalp1Δchi1 | "W1L#100I" 기탁 번호 CBS141149 | D382 |
| LC prt-Δalp1Δchi1Δalp2 | "W1L#100I" 기탁 번호 CBS141153 | D389 |
발현 벡터의 제작
C1에서 이종 단백질 생산을 위해 본원에 사용된 발현 벡터, pP-ssglaA-glaA-HA-FLAG-태그를 도 6에 나타내었다. 이 발현 벡터는 잘-분비된 A. 니거 글루코아밀라제 A 단백질을 캐리어로 사용하여, 이종 단백질의 세포 외 기질로의 분비를 촉진한다. HA 유전자를 A. 니거의 글루코아밀라제 A의 촉매 도메인을 인코딩하는 glaA 유전자의 일부에 융합하였다. FLAG-태그 서열을 C-말단에 융합하고 검출 및 정제 목적으로 포함시켰다. FLAG-태그는 서열 Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys (DYKDDDDK, 서열번호: 32)을 갖는 짧은, 친수성 8-아미노산 펩티드이다.
첫 번째 시리즈 컨스트럭트의 생성
HC 형질전환 실험을 위해 하기의 기본 클로닝 벡터를 사용하였다:
EcoRV - EcoRI로 소화된 pVJ1 (Pcbh1_glaA_kex2_GeneX_Tcbh1).
EcoRV는 kex2-부위 내에 위치하고 EcoRI은 GeneX의 정지 코돈 직후에 위치한다.
이 벡터를 사용하여 배양 배지 내로 분비된, 43개의 잘 발현된 유전자를 근거로 C1에 대해 코돈-최적화된, 하기의 합성 유전자 단편을 결찰시켰다 (모든 합성 단편은 GeneArt®에 의해 pMK 또는 pMS 셔틀 벡터에 서브-클로닝되었다):
- HA_NC_FLAG-태그 x EcoRV - EcoRI (1577 bp)
- HA_UR_FLAG-태그 x EcoRV - EcoRI (1586 bp)
- HA_FL_FLAG-태그 x EcoRV - EcoRI (1655 bp)
- HA_NC x EcoRV - EcoRI (1553 bp)
LC 형질전환 실험을 위해 하기의 기본 클로닝 벡터를 사용하였다:
EcoRV - EcoRI로 소화된 pVJ6 (Pchi1_glaA_kex2_관심 유전자_Tcbh1).
EcoRV는 kex2 부위 내에 위치하고 EcoRI은 관심 유전자의 정지 코돈 직후에 위치한다.
이 벡터를 사용하여 하기 합성 단편을 결찰시켰다 (모든 합성 단편은 GeneArt®에 의해 pMK 또는 pMS 셔틀 벡터에 서브-클로닝되었다):
- HA_NC_FLAG-태그 x EcoRV - EcoRI (1577 bp)
- HA_UR_FLAG-태그 x EcoRV - EcoRI (1586 bp)
- HA_FL_FLAG-태그 x EcoRV - EcoRI 1655 bp)
- HA_NC x EcoRV - EcoRI (1553 bp)
HA 뉴칼레도니아의 경우, 다음과 같이 추가 컨스트럭트 변이체를 제조하였다:
* GlaA 캐리어 단백질은 없지만, ER로의 표적화를 위한 cbh1 시그널 서열을 갖는, cbh1 프로모터 또는 chi1 프로모터 함유 벡터. 이 벡터를 다음과 같이 제조하였다:
클로닝 벡터 pCBHProm을 SacI - BspHI로 소화시키고 cbh1 프로모터를 함유하는 1819 bp 단편을 단리하였다.
클로닝 벡터 pVJ1을 SacI - EcoRI로 소화시키고 cbh1 터미네이터 및 pUC 백본을 함유하는 3896 bp 단편을 단리하였다.
이들 2개 단편을 sscbh1-HA_NC_FLAG-태그를 함유하는 PciI - EcoRI (1617 bp)로 소화된 합성 단편과 함께 3방향 결찰로 결찰시켰다.
클로닝 벡터 pPchi1-링커-Tcbh1을 NcoI - BspHI로 소화시키고 cbh1 프로모터 - cbh1 터미네이터 및 pUC 백본을 함유하는 5758 bp 단편을 단리하였다. 이 벡터를 sscbh1-HA_NC_FLAG-태그를 함유하는 PciI - EcoRI로 소화된 합성 단편 (1617 bp)과의 결찰에 사용하였다.
* chi1 프로모터 및 캐리어 단백질로서 Gla1 (C1 동족체)을 갖는 벡터를 다음과 같이 제조하였다:
클로닝 벡터 pPchi1-Gla1-XynB를 BsrGI - EcoRI로 소화시키고 chi1 프로모터, Gla1 캐리어 단백질의 일부, 및 cbh1 터미네이터를 함유하는 6609 bp 단편을 단리하였다.
클로닝 벡터 pPchi1-Gla1-XynB를 BsrGI - MabI로 소화시키고 Gla1 캐리어 단백질의 일부를 함유하는 783 bp 단편을 단리하였다.
이들 2개 단편을 Gla1의 일부, KEX2 부위, 및 HA_NC_FLAG-태그를 함유하는 MabI - EcoRI로 소화된 합성 단편 (1723 bp)과 함께 3방향 결찰로 결찰시켰다.
* 캐리어 단백질로서 EG2를 갖는 벡터를 다음과 같이 제조하였다:
클로닝 벡터 pPcbh1_EG2_Tcbh1을 SacI - PciI로 소화시키고 cbh1 프로모터 및 EG2 캐리어 단백질의 일부를 함유하는 3031 bp 단편을 단리하였다.
클로닝 벡터 pVJ1을 SacI - EcoRI로 소화시키고 cbh1 터미네이터 및 pUC 백본을 함유하는 3896 bp 단편을 단리하였다.
이들 2개 단편을 EG2의 일부, KEX2 부위, 및 HA_NC_FLAG-태그를 함유하는 PciI - EcoRI로 소화된 합성 단편 (1669 bp)과 함께 3방향 결찰로 결찰시켰다.
* FLAG-태그 없이 '조기 구성적' 프로모터 hex1, GlaA 캐리어 단백질 및 HA_NC를 갖는 벡터를 다음과 같이 제조하였다:
클로닝 벡터 pTcV1011을 SacI - EcoRV로 소화시키고 hex1 프로모터, GlaA 캐리어 단백질, 및 KEX2 부위의 일부를 함유하는 1643 bp 단편을 단리하였다.
클로닝 벡터 pVJ1을 SacI - EcoRI로 소화시키고 cbh1 터미네이터 및 pUC 백본을 함유하는 3896 bp 단편을 단리하였다.
이들 2개 단편을 sscbh1-HA_NC를 함유하는 EcoRV - EcoRI로 소화된 합성 단편 (1553 bp)과 함께 3방향 결찰로 결찰시켰다.
모든 벡터를 XL1-blue (Stratagene)에서 생성시켰다. 모든 벡터로부터 클로닝 접합은 서열 분석으로 확인하였다.
세 번째 시리즈 컨스트럭트의 생성
HA 또는 NA 발현 카세트를 NotI을 사용해 이들의 벡터로부터 잘라내었다. pyr5 선별 마커를 BglII를 사용해 그의 벡터 (DNL35)로부터 잘라내었다. 두 단편 모두를 플라스미드 백본으로부터 분리하고 Wizard® SV Gel 및 PCR Clean up System (Promega)을 사용해 겔로부터 정제하였다. C1 숙주 D389 및 D382를 단일 HA 또는 NA 발현 카세트 및 pyr5 마커로 동시-형질전환시켰다.
형질전환 및 미세역가 플레이트 (MTP) 배양
발현 벡터를 NotI로 소화시켜 외래-DNA 무함유 발현 카세트를 생성하였다. 이들 발현 카세트를 pyr5-결핍 C1 균주에 pyr5 마커와 함께 동시-형질전환시켰다.
각 균주의 96개 형질전환체의 정제 획선 (streak)을 수크로스 함유 최소 배지 플레이트 상에 그었고, 4일간 35℃에서 인큐베이션하였다. 순수한 콜로니를 Caylase 배지를 함유하는 96-웰 플레이트 (모 플레이트)로 옮기고 35℃에서 인큐베이션하였다. 3일 후 웰당 3 μl의 배양물을 생산 배지 ((NH4)2SO4, 35 mM, NaCl, 7 mM, KH2PO4, 55 mM, 글루코스, 0.5 %, MgSO4, 2 mM, 미량 원소 용액, 카사미노산 (casamino acids), 0.1 %, 비오틴, 4 μg/L, 페니실린 20 g/L, 스트렙토마이신 50 g/L, 10 mM. 10 M KOH를 이용해 5.5로 pH 설정)를 함유하는 새로운 96-웰 플레이트 (딸 플레이트)로 옮기고 플레이트를 72-96시간 동안 인큐베이션하였다. 이어서 상청액을 요구되는 표적 발현 또는 효소 활성에 대해 분석하였다. 일부 컨스트럭트의 경우, 생산 배지 또는 개조된 접종 배지 (aIM) 중 하나를 딸 플레이트 배지로 사용하였고, 성장 온도는 35℃, 30℃ 또는 30℃에 이은 35℃의 조합이었으며, 딸 플레이트를 48 및 72시간 (aIM) 동안 인큐베이션하였다.
TMD-함유 항원의 경우, 100 μl의 각 배양물 (웰)을 딸 플레이트 웰로부터 96-웰 PCR 플레이트의 웰로 옮겼다. 이를 4000 rpm에서 15분간 원심분리하였다. 배양액을 제거하고 100 μL의 추출 완충제 (50 mM Tris-Cl pH 7.5, 1 mM EDTA, 1% SDS, 0.2% CHAPS)를 각 웰에 첨가하였다. 이를 잘 혼합하고 96℃에서 5분간 인큐베이션하였다. 이어서 플레이트를 15분간 4000 rpm으로 원심분리하고 상청액을 새로운 96-웰 플레이트로 옮겼다. 20 μL의 이 상청액을 사용하여 PVDF 막 위에 스팟팅하였다. 이어서 스팟 블롯을 BSA로 차단하고 적합한 항체를 사용해 스크리닝하였다. HRP 접합된 이차 항체 기질 SuperSignalTM West Dura extended Duration Substrate (34075; ThermoFisher Scientific)을 사용하여 결합된 항체를 가시화하였다. Bio-Rad ChemiDoc를 사용해 이미지를 만들었다. 미세역가 플레이트 또는 진탕 플라스크 유래 중 하나인, 선택된 형질전환체 배양 샘플을 표준 기법에 따라서 SDS-PAGE 및 웨스턴 블롯팅 분석을 사용하여 더 연구하였다. 웨스턴 블롯을 스팟 블롯에 대해 수행된 것과 유사한 방식으로 동일한 항체를 사용하여 스크리닝하였다.
진탕 플라스크 배양 조건
진탕 플라스크 배양 실험을 50 ml 배지를 함유하는 300 ml 플라스크에서 수행하였다. LC 및 HC를 질소원으로 암모늄 및 0.5% 글루코스를 함유하는 생산 배지에서 상기에 기술된 바와 같이 표준 배양하였다. 두 균주 모두 1% 글루코스 외에, 질소원으로 질산염, 0.1% 카사미노산 (CM의 경우), 0.5% YE (CM의 경우) (및 비타민)을 함유하는 최소 배지 (MM)및 완전 배지 (CM)에서 또한 시험하였다. 250 rpm (1 인치/궤도) 및 35℃에서 배양을 수행하였다.
스팟블롯 분석
수득된 형질전환체 대부분을 스팟블롯 분석으로 스크리닝하였다. 미세역가 플레이트 배양 후, 플레이트를 원심분리로 수확하고 상청액을 새로운 96-웰 플레이트로 옮겼다. LC 균주의 경우, 25 μl의 상청액을 사용하고 HC 균주의 경우 12.5 μl를 사용하였다. 샘플을 96℃에서 5분간 변성시키고, 얼음 상에서 냉각시키고 PVDF 막으로 옮겼다. 스팟블롯을 mAb αGlaA 또는 mAb αHA_NC (AbCam ab66189)로 염색하였다.
SDS-PAGE 및 웨스턴 분석
SDS-PAGE 및 웨스턴 블롯팅을 표준 절차에 따라 수행하였다. 알칼라인 포스파타제를 이용한 웨스턴 블롯의 발색을 NBT 및 BCIP를 기질로 사용하여 수행하였다. 호스 래디쉬 퍼옥시다제를 이용한 웨스턴 블롯의 발색을 공급자 (Invitrogen: Novex®ECL #WP20005)의 지침에 따른 ECL 검출 시약을 사용하여 수행하였다. 발색된 웨스턴 블롯의 박리 (stripping)를 위해 하기 프로토콜을 사용하였다 (AbCam에 따른 경도 박리 절차):
신선한 박리 완충제를 제조하고 (1 L: 15 g 글리신, 1 g SDS, 10 ml Tween20, pH를 2.2로 조정함) 막을 박리 완충제 중에서 10분간 RT에서 인큐베이션하였다 (진탕). 완충제를 제거하고 신선한 박리 완충제를 사용하여 과정을 반복하였다. 그 다음에, 막을 PBS로 2회 세척하고 TBS-Tween20으로 2회 세척하였다.
2D 겔 전기영동
2D SDS-PAGE 전에, 샘플을 Amicon Ultra 0.5 ml 10K 원심 필터를 사용하여 10-20× 농축한 후 이어서 샘플을 BioRad micro Biospin 6 크로마토그래피 칼럼을 사용하여 탈염하였고, 단백질 농도를 BCA 분석 (Pierce)을 이용하여 결정하였다. 단백질 샘플을 공급자의 지침에 따라 BioRad ReadyPrep 2D 세정 키트를 사용하여 정제하였다. 정제 후, 단백질 펠렛 (~200 μg)을 7 M 우레아, 2 M 티오우레아, 4% CHAPS, 50 mM DTT, 0.2% Bio-Lyte 3/10 양성전해질 (20%), 및 0.002% 브로모페놀 블루를 함유하는 200 μl 2-D 재수화 완충제 1 (BioRad)에서 재수화시켰다. 재수화된 단백질 샘플을 BioRad Ready Strip IPG 스트립 (11 cm pH 4-7) 상에 로우딩하였고 RT에서 밤새 인큐베이션하였다. IPG 스트립의 완전 재수화 후, 공급자 (BioRad)에 따라 스트립을 집중시켰다. SDS-PAGE Criterion TGX 4-15% 구배 겔 (BioRad)을 이차원으로 수행하였다. 겔을 쿠마시 브릴리언트 블루 염색에 사용하거나 단백질을 PVDF로 옮겼다.
혈구응집 분석
일반적으로, 인플루엔자 바이러스 입자는 세포 상에 있는 시알산에 결합하는 HA를 그들의 표면에 갖는다. 이 바이러스는 적혈구 (적혈구 세포)에 결합하여, 격자 형성을 초래한다. 이러한 특성을 혈구응집이라고 한다. 기능성 HA가 적혈구 세포를 함유하는 샘플 내에 존재하는 경우, 격자는 적혈구 세포가 혈관의 바닥으로 침전하는 대신 "용액 중에 머무르는" 것으로 보이는 격자가 형성된다.
배양 배지 내로 HA 분비의 신속한 검출을 위해, 배양물을 V 바닥 96-웰 플레이트에서 연속 희석된 [1×PBS (Ca2+ 및 Mg2+ 부재) 중에 50 μl 최종 양], (여과된) 진균 배양 상청액을 1×PBS (Ca2+ 및 Mg2+ 부재) 중의 동량 (50 μl)의 세척된 0.5% 닭 적혈구 세포에 첨가하여 헤마글루티닌 활성에 대해 시험하였다. 그 후에 플레이트를 RT에서 1시간 동안 인큐베이션하였다. 샘플을 공지된 양의 정제된 HA 표준품 (Protein Sciences Corp. 또는 NIBSC)과 비교하였다.
EG2 활성 분석
EG2 활성을 제조사의 지침에 따라 azo-CMCase 분석 (MegaZyme)으로 측정하였다.
BCA 분석
단백질 함량을 제조사의 지침에 따라 BCA 분석 (Pierce)으로 정량하였다.
분비된 HA의 정제
진탕 플라스크 배양 후 발효 브로쓰를 원심분리하고 상청액을 수집하였다. 상청액의 35 ml 샘플을 Millipore Amicon Ultra 필터 (10 kDa의 컷 오프)를 사용하여 300 μl의 총 부피 (>100× 농축)로 농축하였다. 칼럼에 로우딩하기 전에, 원심분리 (14000 rpm에서 1분)에 의해 샘플을 제거하였다. PBS 중에서 겔 여과를 수행하고 100 μl의 샘플을 24-ml Superdex 200 칼럼 상에 로우딩하였다. 샘플을 1 ml/분의 유속으로 처리하고, 0.5 ml의 분획을 수집하였다 (AKTA Explorer 시스템 1). 분획을 HA_NC에 대한 단일클론 항체를 사용한 웨스턴 블롯으로 분석하였다.
TMD-함유 HA의 정제
TMD-함유 HA를 추출 완충제를 사용해 균사체 단편으로부터 추출한 후 이어서 AEX-Capto Q ImpRes를 사용해 정제하였다. 정제 절차는 도 7을 참조하시오.
탈당화 실험
세포 외 및 세포 내 분획 둘 다를 탈당화 실험에 사용하였다. EndoH (엔도-β-N아세틸글루코사미니다제; Roche 11 088 726 001) 탈당화를 공급자에 의해 권고되는 바와 같은 조건하에서 수행하였다. 따라서, 반응을: 20 mM NaOAc pH 5.5, 0.5 mM PMSF (페닐메틸설포닐플루오라이드), 0.1 M β-머캅토에탄올 및 0.02% SDS를 함유하는 완충제에서 37℃에서 밤새 수행하였다. 10 mU EndoH를 추가하기 전에, 단백질 샘플을 96℃에서 10분간 변성시켰다. 샘플을 SDS-PAGE 및 웨스턴 블롯팅으로 분석하고 HA_NC에 대한 mAb (AbCam ab66189)로 염색하였다. PNGaseF (Elizabethkingia miricola 유래 펩티드 N-글리코시다제 F; Sigma-Aldrich G5166) 탈당화를, 트리톤 X-100이 0.1%의 최종 농도로 첨가되는 유일한 차이점을 제외하고는 EndoH 탈당화와 유사한 조건하에서 수행하였다. 단백질 샘플의 변성 후 5 U의 PNGaseF를 첨가하고 샘플을 37℃에서 밤새 인큐베이션하였다. 샘플을 SDS-PAGE 및 웨스턴 블롯팅으로 분석하고 HA_NC에 대한 mAb (AbCam ab66189)로 염색하였다.
시험관 내
KEX2 처리
세포 외 및 세포 내 분획 둘 다를 KEX2 처리 실험에 사용하였다. 샘플을 천연- 및 변성된 형태 둘 다에서 시험하였다. 사카로마이세스 세레비지에 (Saccharomyces cerevisiae)로부터 유래한 KEX2 프로테아제 단백질을 High-5 곤충 세포 (AbCam; ab96554)에서 생산하였다. KEX2 단백질 절단을 하기 조건에 따라서 수행하였다: 분획을 50 mM Tris/HCl pH=7.5, 5 mM CaCl2 0.5 mM PMSF 및 0.1% Triton X-100 중에서 인큐베이션하였다. 단백질 샘플을 천연 또는 변성된 형태 중 하나로 80 mU KEX2와 함께 37℃에서 4시간 동안 인큐베이션하였다. 샘플을 SDS-PAGE 및 웨스턴 블롯팅으로 분석하고 HA_NC에 대한 mAb (AbCam ab66189) 및 GlaA에 대한 단일클론 항체로 염색하였다.
트립신 소화
부분적 트립신 소화를 50 mM NaOAc pH=5.5 완충제 중에서 RT로 수행하였다. 세포 외 샘플을 분석 완충제 및 트립신 [TPCK 트립신 (Pierce); 스톡 용액은 50 mg/ml임 (분취량을 -70℃에 저장함). 작업 용액은 50 ng/μl임]과 혼합하였다. 샘플을 t = 0, t = 2', t = 5', t = 10', t = 15', t = 20', t = 30', t = 45', 및 t = 60'에서 취하였다. 6× SDS-PAGE 로우딩 완충제를 첨가하여 소화를 중단시키고 96℃에서 5분간 변성시켰다. 샘플을 SDS-PAGE 및 웨스턴 블롯팅으로 분석하고 HA_NC에 대한 mAb (AbCam ab66189) 및 GlaA에 대한 단일클론 항체로 염색하였다.
진균 균사체 추출물
세포 내 국소화되거나 세포-벽 부착된 HA를 구별하기 위해 사용된 분획 연구가 도 8에 개략적으로 도시된 바와 같이 수행되었다. 간략히, 진탕 플라스크 배양물로부터 세포 외 기질 (Ex)을 수집하고 (측정 양) 균사체를 수확하였다. 균사체를 차가운 신선한 생산 배지로 세척하고, 무게를 잰 후 SDS 존재 또는 부재의 세척 완충제에서 동일한 부분으로 나누었다. 이 세척 단계를 RT에서 1시간 동안 수행하였고 세척 배지를 SDS-PAGE 상에서 분석하였다. 분쇄된 균사체를 최초 진탕 플라스크 배양물과 동일한 g/부피 비 추출 완충제 중에 재현탁하고, RT에서 회전 플랫폼 상에 10분간 방치한 후 이어서 튜브를 14000 rpm에서 5분간 원심분리하였다. 상청액을 SDS-PAGE 상에서 분석하였다. 잔여 펠렛을 다시 동일한 부피의 추출 완충제에 재현탁하고, 이제 Triton-X100을 첨가하여 막을 가용화시켰다. 원심분리에 의한 상청액의 제거 후, 최종 세포 펠렛을 SDS-PAGE 샘플 완충제에 재현탁하였다.
진균 원형질체의 제조
C1 LC 배양물을 상기에 기술된 바와 같이 완전 배지에서 2일간 성장시켰다. 원형질체를 생성시키고 정제하였다. 추가 세척 단계를 수행하여 원형질체를 오염시키는 세포벽 단편의 위험성을 감소시켰다.
실시예 2 -
마이셀리오프쏘라 써모필라
(C1)에서 생산된 HA의 면역원성
C1에서 생산된 막횡단 도메인 (rHA-TMD)을 보유하는 A/뉴칼레도니아/20/99 (H1N1) 인플루엔자 균주로부터의 전장의 재조합 헤마글루티닌 단백질의 면역원성을 시험하기 위해 동물 시험을 수행하였다. rHA-TMD의 생화학적 평가를 도 9에 나타내었는데, 이는 SDS-PAGE, 천연 PAGE 및 TEM 음성 염색을 이용한 올리고머 상태의 분석을 보여준다. TEM 이미지의 배율은 ×29000이다. 스케일 바=200 nm. 백색 화살표는 ~40 nm 올리고머를 가리킨다. 백색 원은 ~15 nm 올리고머를 표시한다.
C1에서 생산된 동일한 바이러스 균주로부터의 rHA의 분비된 형태로 전술한 면역원성 연구를 수행하였다. 이 rHA의 막횡단 도메인은 절두되어 있고 천연 HA에서는 발견되지 않는 추가 도메인을 함유하고 있다 (8-Gly 도메인 및 T4 foldon 도메인). rHA-8Gly-T4 컨스트럭트는 기능성 항체 반응을 유도하지 않았다. 그 후에 막횡단 도메인을 갖는 컨스트럭트 (rHA-TMD)가 더 우수한 면역원성을 유도할 수 있음이 제안되었다.
이를 위해, 8마리 Balb/C ByJ 마우스의 8개 그룹에 C1에서 생산된 rHA-TMD를 1 내지 30 μg 범위의 3-배 증가 용량을 4주 간격으로 2회 근육 내 (IM) 주사로 투여하였다. 음성 대조군으로서, 5마리 마우스를 표준 예방접종 스케쥴에 따라 PBS로 면역화하였다. 혈액 샘플을 혈구응집 억제 (HI) 분석에 의한 항체 반응 분석을 위해 27일째 및 49일째에 수집하였다.
하기에서 더욱 상세히 기술되는 바와 같이, 결과에 따르면 C1에서 제조된 전장 rHA의 마우스로의 단일 주사 후 초기에, 두 번째 주사 후 더 강화된 특정 기능성 항체 반응이 유도되었음을 보여준다.
재료 및 방법
시험된 조성물
표 3은 본 연구에서 시험된 조성물을 열거한다. 브래드포드 기법으로 정량된 단백질 함량을 주사 용량 제제에 사용하였다. 모든 조성물은 사용 전까지 +5℃±3℃에 저장하였다.
| 조성물 | 설명 | 농도/순도 |
내독소 함량*
(EU/mL) |
순도 |
| rHA-TMD C1 | C1에서 생산된 막횡단 도메인을 갖는 A/뉴칼레도니아/20/99 (H1N1)로부터의 재조합 HA | BCA (BRD sp): 791μg/mL μ브래드포드 (ARD sp): 627 μg/mL 순도: 80% |
12 | >96% |
| PBS (Eurobio) | N/A |
*sp에서 Endosafe 시험
동물 정보
동물 종: 마우스
상태: SPF
주: Balb/c ByJ 마우스
공급자: Charles River
연령: 0일째 9주령
성별: 암컷
체중: 20-22 g
채색에 의한 개인 식별
관리 및 유지: 매일
사육시설
위치: 모든 그룹의 경우 4마리 동물 / 케이지 / L2 생체안전 요구사항을 준수하는 에어컨이 설치된 빌딩 내 케이지.
동물의 수 / 케이지: 4
식이: 과립화 사료 (M20, SDS, DIETEX France, St Gratien, France)
물: 수돗물, 임의 섭취, 자동 급수 시스템을 통함
검역: N/A
순응: 연구에 배정된 마우스를 예방접종 전 5일간 이들의 설계된 사육시설에 순응시켰다.
그룹 정의
그룹 정의를 표 4에 요약하였다.
| 그룹 | 시험 조성물 | W0 및 W4에서의 주입 | ||
| 명칭 | 양 | 경로 |
주입된 부피
(100 μL /주입) |
|
| A (8마리 마우스) | rHA-TMD C1 | 1 μg | IM | 2×50 μL |
| B (8마리 마우스) | rHA-TMD C1 | 3.33 μg | IM | 2×50 μL |
| C (8마리 마우스) | rHA-TMD C1 | 10 μg | IM | 2×50 μL |
| D (8마리 마우스) | rHA-TMD C1 | 30 μg | IM | 2×50 μL |
| M (8마리 마우스) | PBS | - | IM | 2×50 μL |
연구 일정
연구 일정이 표 5에 상세히 기술된다.
| 일자 | 그룹 번호 | 동물 수 | 조치 | 특이적 특성 |
| -1일째 | A 내지 M | 88 | 체중 측정 및 면도 | N/A |
| 0일째 | A 내지 M | 88 | 프라임 IM 예방접종 | rHAs로 예방접종 |
| 27 일째 | A 내지 M | 88 | 체중 측정, 혈액 샘플링 | 턱밑 정맥에서 혈액 샘플링 |
| 28 일째 | A 내지 M | 88 | 부스트 IM 예방접종 | rHAs로 예방접종 |
| 49 일째 | A 내지 M | 88 | 혈액 샘플링 및 동물 희생 | 마취에 의한 최종 출혈 경추 탈구에 의한 동물 희생 |
임상 모니터링
예방접종 후 작업일 (월요일부터 금요일까지)에 매일 동물을 관찰하였고 -1일째 및 27일째에 체중을 측정하였다.
생물학적 샘플링
모든 동물로부터 27일째, 및 49일째 경동맥 절개에 의한 발기 후 이소플루란 마취 하에 레트로-오비탈 부비동 (retro-orbital sinus, ROS) 또는 턱밑 정맥으로부터 혈액 샘플을 채취하였다. 49일째에, 복강 내 경로에 의해 200 μL의 부피로 투여된 이말겐 (Imalgene) (1.6 mg의 케타민) 및 롬푼 (Rompun) (0.32 mg의 자일라진)으로 마취를 수행하였다.
체액 반응 분석을 위해, 27일째에 200 μL의 혈액을 응고 활성제 및 혈청 분리제 (BD Microtainer SST ref 365951)를 함유하는 바이알에 수집하였다. +37℃에서 2시간 후, 혈액을 10,000 rpm에서 5분간 원심분리하고 혈청을 분석 전까지 -20℃에 보관하였다.
49일째에: 1 mL의 혈액을 응고 활성제 및 혈청 분리제 (BD Vacutainer SST II Advance ref 367957)를 함유하는 바이알에 수집하였다. +5℃에서 2일 후, 혈액을 20분간 2000 g로 원심분리하고 혈청을 분석 전까지 -20℃에 보관하였다.
혈구응집 억제 (HI) 분석
이 분석은 적혈구 세포를 응집시키는 인플루엔자 바이러스의 능력을 기준으로 한다. HA에 대한 기능성 항체를 함유하는 혈청은 혈구응집 활성을 억제한다. 이 분석에서, 기능성 항-HA 항체의 농도를 특성화하기 위해 인플루엔자-예방접종된 동물로부터의 혈청을 인플루엔자 바이러스로 처리한다.
시약:
- 96-웰 V-바닥 플레이트, (NUNC)
- RDE (Receptor Destroying Enzyme): 비브리오 콜레라 (Vibrio cholerae) 타입 III로부터의 뉴라미니다제 10 mU/mL (Sigma)
- Ca++ 및 Mg++ 미함유 PBS (Gibco)
- TPCK 트립신 (Thermo Scientific)
- 닭 적혈구 세포 ("cRBCs"): 혈청 처리용의 경우 PBS 중의 10%, HI 분석용의 경우 PBS 중의 0.5% (Sanofi Pasteur)
- 인플루엔자 균주 A/뉴칼레도니아/20/99, 정화된 요막액 (allantoic fluid) 1900 혈구응집 단위 (HAU)/50 μL
하기와 같이 적정을 수행한다: 바이러스 현탁액을 보정하고 4 HAU/50 μL의 농도를 얻기 위해 바이러스의 연속 희석 (2배)을 PBS 중에서 수행하였다. 그 후에 보정된 바이러스 (50 μL)를 1/10에서 시작하여 PBS 중의 50 μL의 혈청 연속 희석액 (2배)으로 V-모양의 96-웰 플레이트에 첨가하고, 실온에서 1시간 동안 인큐베이션하였다. 이어서 닭의 적혈구 세포 (PBS 중의 0.5%) (50 μL)를 각 웰에 첨가하고 혈구응집의 억제 (적색 점) 또는 혈구응집 (분홍색 네트워크)을 실온에서 1시간 후 시각적으로 판독하였다.
HA에 대해 지시된 혈청 비-특이적 억제제를 제거하기 위해, 각 혈청을 HI 분석 전에 수용체-파괴 효소 (RDE), 닭 적혈구 세포 및 TPCK 트립신으로 처리하였다. 간략히, 10 mU/mL의 RDE를 각 혈청에 첨가하였다 (1 부피의 혈청에 대해 5 부피의 RDE). 그 후에 혼합물을 +37℃에서 18시간 동안 인큐베이션하고, 이어서 +56℃에서 1시간 동안 인큐베이션하였다. 냉각시키기 위해, 혼합물 "혈청-RDE"를 30분 내지 4시간 사이 동안 +4℃에 놓아두었다. 이어서 "혈청-RDE" 혼합물을 실온에서 30분간 PBS 중의 10% cRBCs (1 부피의 혈청에 대해 5 부피의 cRBCs) 상에 흡착시킨 후, +5℃에서 10분간 700 g로 원심분리하였다. 상청액을 수집하고 10 부피의 RDE-RBC-열 비활성화 혈청 (희석 혈청 1:10)을 1 부피의 0.4% 트립신 (식염수 중 w/v)과 +56℃에서 30분간 혼합하여 트립신 처리를 수행하였다. 그 후에 HI를 수행하고 최종 혈청 희석액은 여전히 1:10에서 고려되었다.
바이러스 현탁액을 보정하고 4 HAU/50 μL의 농도를 얻기 위해 바이러스의 연속 희석 (2배)을 PBS 중에서 수행하였다. 그 후에 보정된 바이러스 (50 μL)를 1/10에서 시작하여 PBS 중의 50 μL의 혈청 연속 희석액 (2배)으로 V-모양의 96-웰 플레이트에 첨가하고, 실온에서 1시간 동안 인큐베이션하였다. 이어서 닭의 적혈구 세포 (PBS 중의 0.5%) (50 μL)를 각 웰에 첨가하고 혈구응집의 억제 (적색 점) 또는 혈구응집 (분홍색 네트워크)을 실온에서 1시간 후 시각적으로 판독하였다.
HI 적정 값은 혈구응집을 완전히 억제한 혈청의 마지막 희석의 역수이다. 초기 희석 (1/10)의 절반에 상응하는, 5의 값이 통계학적 분석을 수행하기 위해 음성으로 결정된 모든 혈청에 대해 임의적으로 주어졌다.
비-특이적 응집소의 부재가 각 혈청에 대해 대조되었다 (바이러스 없이 각 혈청 및 cRBCs의 4 연속 희석). cRBCs의 대조군 (단지 cRBCs 및 PBS만) 및 바이러스 작업 희석의 4 HAU의 존재의 대조군을 각 플레이트에서 수행하였다.
관찰 및 편차
턱밑 정맥으로부터 혈액을 샘플링한 다음날인 28일째에, 그룹 A로부터의 마우스가 이러한 개입으로부터 회복되지 않아 병에 걸렸고 이에 안락사시켰다.
결과
임상 모니터링
평균 체중의 증가가 27일째에 모든 그룹에서 관찰되었다.
체액 반응
A/뉴칼레도니아/20/99 (H1N1)에 대해 촉발된 항체 반응을 HI 분석에 의해 27일째 및 49일째에 모든 동물로부터 수집된 개별 혈청에서 측정하였다. 도 10a-10b에 결과를 나타내었다.
rHA의 최초 주입 후, 통계학적 분석을 배제한, 2개의 최저 용량의 C1-rHA에서 HI 반응이 없거나 낮게 유도되었다. 그럼에도 불구하고, 결과는 C1-rHA가 실제로 항체 반응을 유도함을 강력히 제안하였다.
부스터 주입 후, 반응이 더욱 강화되었다. 상당한 용량-의존적 HI 효과가 1 및 30 μg 용량 각각에 대해 108 내지 830 범위의 평균 HI 역가를 갖고 C1-rHA에 의해 유도되었다.
C1에서 생산된 전장의 재조합 HA가 마우스에서 어떠한 부정적인 임상적 징후도 유도하지 않았음이 주목된다.
따라서 C1은 5일 발효에서 1 g/L 수준의 HAs 및 다른 항원을 쉽게 생산할 수 있다:
시즌 인플루엔자 백신에서 - 분포된 총 용량 = 146 M/년
각각의 0.5 mL 용량이: 각 균주에 대해 15 μg의 HA를 함유하도록 제제화된다.
따라서, 3×1000 L 규모의 발효 가동은 2,175 g의 인플루엔자에 대한 연간 전세계 HA/균주 수요를 공급할 수 있을 것이다.
실시예 3 - HA의 교반-탱크 발효
배치 및 유가식 기법으로 교반-탱크 발효기에서 더 큰 규모로 상기에 기술된 rHA-TMD의 생산 수준을 측정하기 위해 실험을 수행하였다. 이를 위해, MiniforsTM 3 L 생물반응기를 rHA-TMD를 발현하는 C1 균주 D389를 배양하기 위해 사용하였다.
표 6은 50시간 동안 수행된, 초기 실험 설정의 발효 조건을 요약한다. "배치" - 발표 초기에 표시된 탄수화물의 농도. "유가식 (Fed-batch)" - 사료 중 탄수화물의 농도. 1.5 리터의 시작 부피로 pH 7.5에서 발효를 수행하였다.
| 가동 # | 온도 (℃) | 배치 | 유가식 |
| R465F2 | 25 | 4% 자일로스 | 없음 |
| R465F4 | 35 | 1% 자일로스 | 47% 자일로스 |
| R465F5 | 35 | 1% 글루코스 | 50% 글루코스 |
| R465F6 | 35 | 4.7% 글루코스 | 없음 |
발효 후, 균사체를 수집하고 HA를 추출하였다.
균사체 농도를 평가하기 위해, 균사체의 건조 중량을 측정하였다. 간략히, 특정 양의 발효 브로쓰를 수집하고 수회 세척하여 발효 중간산물 및 분비 단백질과 같은 배지 및 배지 성분을 제거하였다. 그 후에 생성된 물질을 90℃에서 24시간 동안 건조시키고 중량을 측정하였다. 모든 발효 샘플은 대략 동일한 균사체 농도를 함유하는 것으로 나타났다.
추출된 HA에 대해 얻어진 웨스턴 블롯 신호를 공지된 양의 HA 표준품과 비교함으로써 HA의 정량을 수행하였다 (도 13).
최상의 배치의 생산 수준은 대략 375 mg/l로 계산되었고, 이는 170 mg/l/일이다.
표 7은 98-137시간 동안 수행된, 두 번째 실험 설정의 발효 조건 및 생성된 HA 생산 수준을 요약한다. 표는 발효 종료 (EOF) 결과를 보여준다.
| 가동 # | 시간 (h) |
온도
(℃) |
C-공급원 |
공급률
(%) |
DM* (g/L) | HA (mg/L) |
HA**
(mg/g DM) |
C-공급원 (g/L) |
| R481F1 | 98 | 35 | 글루코스 | 1 | 37.9 | 47.3 | 1.2 | 0.8 |
| R481F2 | 98 | 35 | 자일로스 | 1 | 34.0 | 35.0 | 1.0 | 0.5 |
| R481F5 | 98 | 30 | 자일로스 | 1 | 25.0 | 62.9 | 2.5 | 66.9 |
| R481F6 | 98 | 35-25 | 글루코스 | 1 | 33.6 | 29.0 | 0.9 | 17.2 |
| R481F7 | 98 | 35-25 | 자일로스 | 1 | 13.3 | 27.6 | 2.1 | 42.2 |
| R482F1 | 102 | 35 | 글루코스 | 1 | 56.6 | 50.6 | 0.9 | 0.1 |
| R482F2 | 102 | 30 | 글루코스 | 1 | 61.1 | 49.0 | 0.8 | 0.2 |
| R483F1 | 140 | 30 | 글루코스 | 1 | 47.6 | 124 | 5.4 | 0.1 |
| R483F2 | 140 | 30 | 자일로스 | 1 | 46.7 | 171.4 | 3.7 | 0.1 |
| R483F4 | 140 | 35-25 | 글루코스 | 1 | 56.5 | 62.8 | 1.1 | 0.1 |
| R483F5 | 140 | 35-25 | 자일로스 | 1 | 51.7 | 86.0 | 1.7 | 1.2 |
| R484F2 | 137 | 30 | 글루코스 | 1 | 48.9 | 51.8 | 1.2 | 0.1 |
| R484F5 | 137 | 35 | 글루코스 | 2 | 33.6 | 106.8 | 4.0 | 6.5 |
| R484F6 | 137 | 35 | 자일로스 | 2 | 56.7 | 169,6 | 3.6 | 12.8 |
| R484F7 | 137 | 30 | 글루코스 | 2 | 76.6 | 413.4 | 5.4 | 0.1 |
* 건조 세포 중량
** 측정치.
특정 구현예에 대한 전술한 설명은 다른 사람들이 현재의 지식을 적용함으로써 과도한 실험 없이, 그리고 일반적인 개념을 벗어나지 않으면서 이러한 특정 구현예와 같은 다양한 응용에 대해 쉽게 수정 및/또는 개조할 수 있도록 본 발명의 일반적인 특성을 충분히 드러낼 것이고, 따라서 이러한 개조 및 변경은 기술된 구현예의 의미 및 균등 범위 내에서 이해되어야 하고 이해되는 것으로 의도된다. 본원에 사용된 어구 또는 용어는 설명의 목적을 위한 것으로 제한하려는 것이 아님을 이해해야 한다. 기술된 다양한 화학 구조 및 기능을 수행하기 위한 수단, 재료 및 단계는 본 발명을 벗어나지 않으면서 다양한 대안적인 형태를 취할 수 있다.
SEQUENCE LISTING
<110> DYADIC INTERNATIONAL INC.
<120> PRODUCTION OF FLU VACCINE IN MYCELIOPHTHORA THERMOPHILA
<130> IPA200175-IL
<150> US 62/547,885
<151> 2017-08-21
<160> 32
<170> PatentIn version 3.5
<210> 1
<211> 2869
<212> DNA
<213> Artificial Sequence
<220>
<223> Promoter
<400> 1
ggccgctcta gaactagtac ggcgtgcaag tagtgtcttt ctttgcactc ccgccgtccc 60
agaagacgcc gcaacaagct gagcttgctg gaagccgaac aaaggcgtta cagagcacaa 120
acatagtggc agtgtaggaa ctctaactgg gaccaaaact acgggcccgg cagaaacgtt 180
ccccgccccg aagcgaaggc gaacgtcgaa aagcaagacc gggaccgctc gtcccaggat 240
tagccacgaa gttccagacc aagtatagga gtaaacgctc gctcgtcaaa acaattgtca 300
ccaatcagca ccacatcggc acataacaac cggttgcgga actcgcatgt gaacaacaag 360
cggctccggg ggagtgatcg gctcgggcgg atgacccgga ctcttccgcg cagcaactcg 420
gcgtgttgtt gacggcagta ctccgtagtt gccatgacaa cagtcaatgg cgtgcttcac 480
aaggtggaga gccgagaaag cacctcggca tgtacgagta tgtagatagt gtatcaagca 540
ggaagatggg ggttacttta tctcaatcag atgcctgtaa gcgagagccg agagcctgcc 600
ctgttgttga cacaattctg gcctgataac gagtgacaag cgctgggacg gcggctgggg 660
tcttttgctc gcggcttcag ctcaattcca atcctgggcc ggtgccgaac ggcccaatcg 720
cgagcgccca cgaaatcgga ggtcgaggaa agaaggctgg gcgagacgcg gcgacaagct 780
gtggcaaaat ggccaattga ggttctgggt cggctggtga tcaaccatgc atttcccagc 840
ccgcagattc tctttctctc tcgtgcagca gcggcaccag cagcagcagc agccaggggt 900
ttgaccaacc tctccgccca gccaccgata gtaaagatgc tgcctgcgta ttctgggctg 960
caggagttcc aagatctttc ggtctggcca ccagctgtca cgtcaccctc cacctttgga 1020
cgacgttgct ggaaaattcg aagccttcac taagataact atgccgtagc acttgcagcc 1080
ccggaagctg caagttgatt cttggagggc tctctccacc accaatacgg gagatctggc 1140
cccgcacttg aggaggctgg agtctcggat cgcccacttc gcgtcgccct gggccctggg 1200
ccctggggtg atgggcccgt tgccgtggtg gatggcagga gcttttcagc tctcaatggg 1260
cgaatgctac tccgtaggtc ggagtggctg gaagcggcgg aacggacagg gggaggttgg 1320
ggaaaatgct ccgcaggaag agcagggagt ggggagctgc ggtcggccct gtggagcccg 1380
tgcagggcca gctaatccaa ttcgggccac aataaacaag agagggcccc acatcatgta 1440
aacagaggct cagaagctcc tgccacactg ggagggtttc gaagtctgac gactgccaat 1500
ggaccccagc catcgcgagc acacagcagt tcgcacgctc ccattgggtt cctcatcacg 1560
cagtcgctct ccccgccaac cagcgccagg tccgggaaca gcggcgcaaa tgcgtatttg 1620
agggcgcctc gctcgagcaa cctgtgcctg accttctcct cctccttctg caccttgcat 1680
ctcgtcgcgt ccactcgcag gcaaccacac atcctcctcc tctcccaaaa cccccccgct 1740
ttttctttcc cttgttggaa ttcgattgaa aaagaagacg ggtccgtcta gagaccgcct 1800
tctcaccttt ctctcgactt ctttctagga aaagaagcaa gagtcattct tcttgtccac 1860
cttctggttc acggaaggtc gaggagaaga ttgcctctgc ccccaaagtc gccaacctgg 1920
actttgaagc acgtgttccg gtccctttca gtgtcttccc gtcctcgtac agggagtccg 1980
agaccgccac ccaaacccac tcccacgaag aggttgagat caagctcccc cagctcgccg 2040
gacgggaagg tcaacactct tcattccaag cccaagcaca tcttcctccc agcggagagg 2100
gtcgcttcag agaagaagag gtccgcatca ctcgtcaaga ggaacatcac cgccgtcccg 2160
gcatccgtga agagttcgtt caccgcgagg agcgtcaccg gtaagtttag tttttgtttt 2220
gattcaccac ccattgtctt ccccgccttt ttctttttct tcccttgctc tcttgcccct 2280
gtctagtgta gggcattgcc aaggccatct tcacacacac acaccccccc ccccccccac 2340
cctcagctgg gggggggggt ggcctgggtt gaccaaggga cggtgaagac tactactact 2400
tgagccactc aaacccatgc atgacacagg gttttccttt ttcttttctc ttttccttta 2460
actaaccaac cactccaaca ttagccctca gtcaacctac tccgagtctc gcatcgagtt 2520
cgatactgag caccgcactc acaactccgt cattgacgtt gctgagagcg agtatcgtgc 2580
ccgtgtccag cccaactacc gcaaggaagc ttccgtagtc ggtaccaccg tcgacggatc 2640
ccgcttcagc cacagccgca aggccagcag caccacctcc acccacaccg acgagtacac 2700
cgtcgatccc cctagccacc gccccgtcta caagaaggag tcggttgaag tcgccggtac 2760
cactgttgac ccccctgctc ctcgttcgac ctaccacgag caggtgaaca ttgttgaaga 2820
gaccgttgac gctcaccgtt acgctcctca acccaacaac aacaacacc 2869
<210> 2
<211> 1162
<212> DNA
<213> Artificial Sequence
<220>
<223> Promoter
<400> 2
gactagcagc acgcggcagg attcttcaaa attggctaaa acgcgttggc ggggtgctcc 60
aagctcgagt gtgatcgaat gggagcaaag catcgccgct tgagtcagcc cgggctcggc 120
cattgattgg gggtgcccat gtcagctcaa ggcagcaagc ggatagaagc gccgtgggaa 180
gactagcaac gcctgctctg ggcatggccg ctgaatgtct gctggttctc aacgacgcgg 240
ggaacttgtg caactggagc gaaatatcgg cttggcaggg gctccttcta ctttgggagg 300
agaactggca tcacccactc ggctctacgg cttgaagatg ccgtgtgtgg caaccaacag 360
gcactgaaaa ttcatgcagg cagaccccgt tctgggaagc aaaatgcagc agcgccttcc 420
ttggctctcg cgagctgtta gtagagcacg aacgaaactc gaccagtttg agggtctatc 480
acgctcccgt accgcaagaa ggatctcatg tagtaggact gagatgtttt ttttcttccc 540
ttcctacttt tttgtgcgct cttgaaggta ttaagaccat cacgatggga tacctacctc 600
ttcaaagcat acatggcacg gcaaccgacc ccccaaacgt taggtagcac gccagcgggc 660
ggatggccca tcgtggaatt cacggtctgg gcccgcggga ggattgcttg cacctgcgtg 720
ataatttcct gggacacccc cctgttcgcg gacagcgagc ccggatgtca acgacagcgg 780
acgcatcgtg gaagcgggtt gccgttctcc ctcccccccc cccccttttc tctccagggg 840
tggccctttt cccttctgag ctggcttggc taagttgggc ctcctcctat gaaaggctgc 900
cgttcccttt gcctccctag ggccgtcttc ttcccgccgc ctccctcttg gttcctgttc 960
aattcaacac cagacggcgt gctctccccg gccgttgcaa acgtcttgtt tgcgtccttt 1020
cgttgtgtgc ttctgccgtt gcagctcatc agtcgctcct ttactacggc ccggccatcc 1080
tcggccattc actcgttttc cgtgtgtgca gacgaacaaa cacatactca ccttgtattg 1140
ttaatatcac gtctcgtcca ta 1162
<210> 3
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Signal sequence
<400> 3
atgtacgcca agttcgcgac cctcgccgcc cttgtggctg gcgccgctgc t 51
<210> 4
<211> 548
<212> PRT
<213> Influenza virus
<400> 4
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asp Ser His Asn Gly Lys Leu Cys Leu Leu Lys Gly Ile Ala
35 40 45
Pro Leu Gln Leu Gly Asn Cys Ser Val Ala Gly Trp Ile Leu Gly Asn
50 55 60
Pro Glu Cys Glu Leu Leu Ile Ser Lys Glu Ser Trp Ser Tyr Ile Val
65 70 75 80
Glu Thr Pro Asn Pro Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe Ala
85 90 95
Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe Glu
100 105 110
Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Thr Val
115 120 125
Thr Gly Val Ser Ala Ser Cys Ser His Asn Gly Lys Ser Ser Phe Tyr
130 135 140
Arg Asn Leu Leu Trp Leu Thr Gly Lys Asn Gly Leu Tyr Pro Asn Leu
145 150 155 160
Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val Leu Trp
165 170 175
Gly Val His His Pro Pro Asn Ile Gly Asn Gln Arg Ala Leu Tyr His
180 185 190
Thr Glu Asn Ala Tyr Val Ser Val Val Ser Ser His Tyr Ser Arg Arg
195 200 205
Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Asp Gln Glu Gly
210 215 220
Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr Ile Ile
225 230 235 240
Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe Ala Leu
245 250 255
Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Pro Met Asp
260 265 270
Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn Ser Ser
275 280 285
Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys Pro Lys
290 295 300
Tyr Val Arg Ser Ala Lys Leu Arg Met Val Thr Gly Leu Arg Asn Ile
305 310 315 320
Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe Ile
325 330 335
Glu Gly Gly Trp Thr Gly Met Val Asp Gly Trp Tyr Gly Tyr His His
340 345 350
Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr Gln
355 360 365
Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu Lys
370 375 380
Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu Glu
385 390 395 400
Arg Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Leu Asp
405 410 415
Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu Arg
420 425 430
Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys Val
435 440 445
Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys Phe
450 455 460
Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys Asn
465 470 475 480
Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn Arg
485 490 495
Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr Gln Ile
500 505 510
Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val Ser
515 520 525
Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu Gln Cys
530 535 540
Arg Ile Cys Ile
545
<210> 5
<211> 1644
<212> DNA
<213> Artificial Sequence
<220>
<223> Polynucleotide
<400> 5
gacaccatct gcatcggcta ccacgccaac aacagcaccg acaccgtcga cacggtcctc 60
gagaagaacg tcaccgtcac ccacagcgtc aacctgctcg aggacagcca caacggcaag 120
ctctgcctcc tcaagggcat cgcccccctc cagctcggca actgcagcgt cgccggctgg 180
atcctcggca accccgagtg cgagctgctc atcagcaagg agagctggtc gtacatcgtc 240
gagaccccca accccgagaa cggcacgtgc taccccggct acttcgccga ctacgaggag 300
ctgcgcgagc agctcagcag cgtcagctcg ttcgagcgct tcgagatctt ccccaaggag 360
agcagctggc ccaaccacac cgtcaccggc gtcagcgcca gctgctcgca caacggcaag 420
agcagcttct accgcaacct cctctggctc accggcaaga acggcctcta cccgaacctc 480
agcaagagct acgtcaacaa caaggagaag gaggtcctcg tcctctgggg cgtccaccac 540
ccccccaaca tcggcaacca gcgcgccctc taccacaccg agaacgccta cgtcagcgtc 600
gtcagcagcc actacagccg ccgcttcacc cccgagatcg ccaagcgccc caaggtccgc 660
gaccaggagg gccgcatcaa ctactactgg accctcctcg agcccggcga caccatcatc 720
ttcgaggcca acggcaacct gatcgccccc tggtacgcct tcgccctcag ccgcggcttc 780
ggcagcggca tcatcaccag caacgccccc atggacgagt gcgacgccaa gtgccagacc 840
ccccagggcg ccatcaacag cagcctcccg ttccagaacg tccaccccgt caccatcggc 900
gagtgcccca agtacgtccg cagcgccaag ctccgcatgg tcaccggcct ccgcaacatc 960
cccagcatcc agagccgcgg cctcttcggc gccatcgccg gcttcatcga gggcggctgg 1020
accggcatgg tcgacggctg gtacggctac caccaccaga acgagcaggg cagcggctac 1080
gccgccgacc agaagtcgac ccagaacgcc atcaacggca tcaccaacaa ggtcaacagc 1140
gtcatcgaga agatgaacac ccagttcacc gccgtcggca aggagttcaa caagctcgag 1200
cgccgcatgg agaacctcaa caagaaggtc gacgacggct tcctcgacat ctggacctac 1260
aacgccgagc tgctcgtcct cctcgagaac gagcgcaccc tcgacttcca cgacagcaac 1320
gtcaagaacc tgtacgagaa ggtcaagagc cagctcaaga acaacgccaa ggagatcggc 1380
aacggctgct tcgagttcta ccacaagtgc aacaacgagt gcatggagag cgtcaagaac 1440
ggcacctacg actaccccaa gtacagcgag gagagcaagc tcaaccgcga gaagatcgac 1500
ggcgtcaagc tcgagagcat gggcgtctac cagatcctcg ccatctacag caccgtcgcc 1560
agcagcctcg tcctcctggt cagcctcggc gccatctcgt tctggatgtg cagcaacggc 1620
agcctccagt gccgcatctg catc 1644
<210> 6
<211> 550
<212> PRT
<213> Influenza virus
<400> 6
Gln Lys Leu Pro Gly Asn Asp Asn Ser Thr Ala Thr Leu Cys Leu Gly
1 5 10 15
His His Ala Val Pro Asn Gly Thr Ile Val Lys Thr Ile Thr Asn Asp
20 25 30
Arg Ile Glu Val Thr Asn Ala Thr Glu Leu Val Gln Asn Ser Ser Ile
35 40 45
Gly Glu Ile Cys Asp Ser Pro His Gln Ile Leu Asp Gly Glu Asn Cys
50 55 60
Thr Leu Ile Asp Ala Leu Leu Gly Asp Pro Gln Cys Asp Gly Phe Gln
65 70 75 80
Asn Lys Lys Trp Asp Leu Phe Val Glu Arg Ser Lys Ala Tyr Ser Asn
85 90 95
Cys Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Ser Leu Arg Ser Leu Val
100 105 110
Ala Ser Ser Gly Thr Leu Glu Phe Asn Asn Glu Ser Phe Asn Trp Asn
115 120 125
Gly Val Thr Gln Asn Gly Thr Ser Ser Ala Cys Ile Arg Arg Ser Asn
130 135 140
Asn Ser Phe Phe Ser Arg Leu Asn Trp Leu Thr His Leu Asn Phe Lys
145 150 155 160
Tyr Pro Ala Leu Asn Val Thr Met Pro Asn Asn Glu Gln Phe Asp Lys
165 170 175
Leu Tyr Ile Trp Gly Val His His Pro Gly Thr Asp Lys Asp Gln Ile
180 185 190
Phe Leu Tyr Ala Gln Pro Ser Gly Arg Ile Thr Val Ser Thr Lys Arg
195 200 205
Ser Gln Gln Ala Val Ile Pro Asn Ile Gly Ser Arg Pro Arg Ile Arg
210 215 220
Asn Ile Pro Ser Arg Ile Ser Ile Tyr Trp Thr Ile Val Lys Pro Gly
225 230 235 240
Asp Ile Leu Leu Ile Asn Ser Thr Gly Asn Leu Ile Ala Pro Arg Gly
245 250 255
Tyr Phe Lys Ile Arg Ser Gly Lys Ser Ser Ile Met Arg Ser Asp Ala
260 265 270
Pro Ile Gly Lys Cys Lys Ser Glu Cys Ile Thr Pro Asn Gly Ser Ile
275 280 285
Pro Asn Asp Lys Pro Phe Gln Asn Val Asn Arg Ile Thr Tyr Gly Ala
290 295 300
Cys Pro Arg Tyr Val Lys Gln Ser Thr Leu Lys Leu Ala Thr Gly Met
305 310 315 320
Arg Asn Val Pro Glu Lys Gln Thr Arg Gly Ile Phe Gly Ala Ile Ala
325 330 335
Gly Phe Ile Glu Asn Gly Trp Glu Gly Met Val Asp Gly Trp Tyr Gly
340 345 350
Phe Arg His Gln Asn Ser Glu Gly Arg Gly Gln Ala Ala Asp Leu Lys
355 360 365
Ser Thr Gln Ala Ala Ile Asp Gln Ile Asn Gly Lys Leu Asn Arg Leu
370 375 380
Ile Gly Lys Thr Asn Glu Lys Phe His Gln Ile Glu Lys Glu Phe Ser
385 390 395 400
Glu Val Glu Gly Arg Ile Gln Asp Leu Glu Lys Tyr Val Glu Asp Thr
405 410 415
Lys Ile Asp Leu Trp Ser Tyr Asn Ala Glu Leu Leu Val Ala Leu Glu
420 425 430
Asn Gln His Thr Ile Asp Leu Thr Asp Ser Glu Met Asn Lys Leu Phe
435 440 445
Glu Lys Thr Lys Lys Gln Leu Arg Glu Asn Ala Glu Asp Met Gly Asn
450 455 460
Gly Cys Phe Lys Ile Tyr His Lys Cys Asp Asn Ala Cys Ile Gly Ser
465 470 475 480
Ile Arg Asn Gly Thr Tyr Asp His Asp Val Tyr Arg Asp Glu Ala Leu
485 490 495
Asn Asn Arg Phe Gln Ile Lys Gly Val Glu Leu Lys Ser Gly Tyr Lys
500 505 510
Asp Trp Ile Leu Trp Ile Ser Phe Ala Ile Ser Cys Phe Leu Leu Cys
515 520 525
Val Ala Leu Leu Gly Phe Ile Met Trp Ala Cys Gln Lys Gly Asn Ile
530 535 540
Arg Cys Asn Ile Cys Ile
545 550
<210> 7
<211> 1650
<212> DNA
<213> Artificial Sequence
<220>
<223> Polynucleotide
<400> 7
caaaaacttc ctggaaatga caatagcacg gcaacgctgt gccttgggca ccatgcagta 60
ccaaacggaa cgatagtgaa aacaatcacg aatgaccgaa ttgaagttac taatgctact 120
gaactggttc agaattcctc aataggtgaa atatgcgaca gtcctcatca gatccttgat 180
ggagaaaact gcacactaat agatgctcta ttgggagacc ctcagtgtga tggcttccaa 240
aataagaaat gggacctttt tgttgaacga agcaaagcct acagcaactg ttacccttat 300
gatgtgccgg attatgcctc ccttaggtca ctagttgcct catccggcac actggagttt 360
aacaatgaaa gcttcaattg gaatggagtc actcaaaacg gaacaagttc tgcttgcata 420
aggagatcta ataatagttt ctttagtaga ttaaattggt tgacccactt aaacttcaaa 480
tacccagcat tgaacgtgac tatgccaaac aatgaacaat ttgacaaatt gtacatttgg 540
ggggttcacc acccgggtac ggacaaggac caaatcttcc tgtatgctca accatcagga 600
agaatcacag tatctaccaa aagaagccaa caagctgtaa tcccgaatat cggatctaga 660
cccagaataa ggaatatccc tagcagaata agcatctatt ggacaatagt aaaaccggga 720
gacatacttt tgattaacag cacagggaat ctaattgctc ctaggggtta cttcaaaata 780
cgaagtggga aaagctcaat aatgagatca gatgcaccca ttggcaaatg caagtctgaa 840
tgcatcactc caaatggaag cattcccaat gacaaaccat tccaaaatgt aaacaggatc 900
acatacgggg cctgtcccag atatgttaag caaagcactc tgaaattggc aacaggaatg 960
cggaatgtac cagagaaaca aactagaggc atatttggcg caatagcggg tttcatagaa 1020
aatggttggg agggaatggt ggatggttgg tacggtttca ggcatcaaaa ttctgaggga 1080
agaggacaag cagcagatct caaaagcact caagcagcaa tcgatcaaat caatgggaag 1140
ctgaatcgat tgatcgggaa aaccaacgag aaattccatc agattgaaaa agaattctca 1200
gaagtagaag ggagaattca ggaccttgag aaatatgttg aggacactaa aatagatctc 1260
tggtcataca acgcggagct tcttgttgcc ctggagaacc aacatacaat tgatctaact 1320
gactcagaaa tgaacaaact gtttgaaaaa acaaagaagc aactgaggga aaatgctgag 1380
gatatgggca atggttgttt caaaatatac cacaaatgtg acaatgcctg cataggatca 1440
atcagaaatg gaacttatga ccacgatgta tacagagatg aagcattaaa caaccggttc 1500
cagatcaagg gagttgagct gaagtcaggg tacaaagatt ggatcctatg gatttccttt 1560
gccatatcat gttttttgct ttgtgttgct ttgttggggt tcatcatgtg ggcctgccaa 1620
aagggcaaca ttaggtgcaa catttgcatt 1650
<210> 8
<211> 548
<212> PRT
<213> Influenza virus
<400> 8
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asp Ser His Asn Gly Lys Leu Cys Arg Leu Lys Gly Ile Ala
35 40 45
Pro Leu Gln Leu Gly Lys Cys Asn Ile Ala Gly Trp Leu Leu Gly Asn
50 55 60
Pro Glu Cys Asp Pro Leu Leu Pro Val Arg Ser Trp Ser Tyr Ile Val
65 70 75 80
Glu Thr Pro Asn Ser Glu Asn Gly Ile Cys Tyr Pro Gly Asp Phe Ile
85 90 95
Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe Glu
100 105 110
Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Asn Thr
115 120 125
Asn Gly Val Thr Ala Ala Cys Ser His Glu Gly Lys Ser Ser Phe Tyr
130 135 140
Arg Asn Leu Leu Trp Leu Thr Glu Lys Glu Gly Ser Tyr Pro Lys Leu
145 150 155 160
Lys Asn Ser Tyr Val Asn Lys Lys Gly Lys Glu Val Leu Val Leu Trp
165 170 175
Gly Ile His His Pro Pro Asn Ser Lys Glu Gln Gln Asn Leu Tyr Gln
180 185 190
Asn Glu Asn Ala Tyr Val Ser Val Val Thr Ser Asn Tyr Asn Arg Arg
195 200 205
Phe Thr Pro Glu Ile Ala Glu Arg Pro Lys Val Arg Asp Gln Ala Gly
210 215 220
Arg Met Asn Tyr Tyr Trp Thr Leu Leu Lys Pro Gly Asp Thr Ile Ile
225 230 235 240
Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Met Tyr Ala Phe Ala Leu
245 250 255
Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Ser Met His
260 265 270
Glu Cys Asn Thr Lys Cys Gln Thr Pro Leu Gly Ala Ile Asn Ser Ser
275 280 285
Leu Pro Tyr Gln Asn Ile His Pro Val Thr Ile Gly Glu Cys Pro Lys
290 295 300
Tyr Val Arg Ser Ala Lys Leu Arg Met Val Thr Gly Leu Arg Asn Ile
305 310 315 320
Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe Ile
325 330 335
Glu Gly Gly Trp Thr Gly Met Ile Asp Gly Trp Tyr Gly Tyr His His
340 345 350
Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr Gln
355 360 365
Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Thr Val Ile Glu Lys
370 375 380
Met Asn Ile Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu Glu
385 390 395 400
Lys Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Leu Asp
405 410 415
Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu Arg
420 425 430
Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys Val
435 440 445
Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys Phe
450 455 460
Glu Phe Tyr His Lys Cys Asp Asn Glu Cys Met Glu Ser Val Arg Asn
465 470 475 480
Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn Arg
485 490 495
Glu Lys Val Asp Gly Val Lys Leu Glu Ser Met Gly Ile Tyr Gln Ile
500 505 510
Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Leu Val Ser
515 520 525
Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu Gln Cys
530 535 540
Arg Ile Cys Ile
545
<210> 9
<211> 1647
<212> DNA
<213> Artificial Sequence
<220>
<223> Polynucleotide
<400> 9
gacacaatat gtataggcta ccatgcgaac aattcaaccg acactgttga cacagtactc 60
gagaagaatg tgacagtgac acactctgtt aacctgctcg aagacagcca caacggaaaa 120
ctatgtagat taaaaggaat agccccacta caattgggga aatgtaacat cgccggatgg 180
ctcttgggaa acccagaatg cgacccactg cttccagtga gatcatggtc ctacattgta 240
gaaacaccaa actctgagaa tggaatatgt tatccaggag atttcatcga ctatgaggag 300
ctgagggagc aattgagctc agtgtcatca ttcgaaagat tcgaaatatt tcccaaagaa 360
agctcatggc ccaaccacaa cacaaacgga gtaacggcag catgctccca tgaggggaaa 420
agcagttttt acagaaattt gctatggctg acggagaagg agggctcata cccaaagctg 480
aaaaattctt atgtgaacaa aaaagggaaa gaagtccttg tactgtgggg tattcatcac 540
ccgcctaaca gtaaggaaca acagaatctc tatcagaatg aaaatgctta tgtctctgta 600
gtgacttcaa attataacag gagatttacc ccggaaatag cagaaagacc caaagtaaga 660
gatcaagctg ggaggatgaa ctattactgg accttgctaa aacccggaga cacaataata 720
tttgaggcaa atggaaatct aatagcacca atgtatgctt tcgcactgag tagaggcttt 780
gggtccggca tcatcacctc aaacgcatca atgcatgagt gtaacacgaa gtgtcaaaca 840
cccctgggag ctataaacag cagtctccct taccagaata tacacccagt cacaatagga 900
gagtgcccaa aatacgtcag gagtgccaaa ttgaggatgg ttacaggact aaggaacatt 960
ccgtccattc aatccagagg tctatttgga gccattgccg gttttattga agggggatgg 1020
actggaatga tagatggatg gtatggttat catcatcaga atgaacaggg atcaggctat 1080
gcagcggatc aaaaaagcac acaaaatgcc attaacggga ttacaaacaa ggtgaacact 1140
gttatcgaga aaatgaacat tcaattcaca gctgtgggta aagaattcaa caaattagaa 1200
aaaaggatgg aaaatttaaa taaaaaagtt gatgatggat ttctggacat ttggacatat 1260
aatgcagaat tgttagttct actggaaaat gaaaggactc tggatttcca tgactcaaat 1320
gtgaagaatc tgtatgagaa agtaaaaagc caattaaaga ataatgccaa agaaatcgga 1380
aatggatgtt ttgagttcta ccacaagtgt gacaatgaat gcatggaaag tgtaagaaat 1440
gggacttatg attatcccaa atattcagaa gagtcaaagt tgaacaggga aaaggtagat 1500
ggagtgaaat tggaatcaat ggggatctat cagattctgg cgatctactc aactgtcgcc 1560
agttcactgg tgcttttggt ctccctgggg gcaatcagtt tctggatgtg ttctaatgga 1620
tctttgcagt gcagaatatg catctga 1647
<210> 10
<211> 569
<212> PRT
<213> Influenza virus
<400> 10
Asp Arg Ile Cys Thr Gly Ile Thr Ser Ser Asn Ser Pro His Val Val
1 5 10 15
Lys Thr Ala Thr Gln Gly Glu Val Asn Val Thr Gly Val Ile Pro Leu
20 25 30
Thr Thr Thr Pro Thr Lys Ser Tyr Phe Ala Asn Leu Lys Gly Thr Arg
35 40 45
Thr Arg Gly Lys Leu Cys Pro Asp Cys Leu Asn Cys Thr Asp Leu Asp
50 55 60
Val Ala Leu Gly Arg Pro Met Cys Val Gly Thr Thr Pro Ser Ala Lys
65 70 75 80
Ala Ser Ile Leu His Glu Val Lys Pro Val Thr Ser Gly Cys Phe Pro
85 90 95
Ile Met His Asp Arg Thr Lys Ile Arg Gln Leu Pro Asn Leu Leu Arg
100 105 110
Gly Tyr Glu Asn Ile Arg Leu Ser Thr Gln Asn Val Ile Asp Ala Glu
115 120 125
Lys Ala Pro Gly Gly Pro Tyr Arg Leu Gly Thr Ser Gly Ser Cys Pro
130 135 140
Asn Ala Thr Ser Lys Ser Gly Phe Phe Ala Thr Met Ala Trp Ala Val
145 150 155 160
Pro Lys Asp Asn Asn Lys Asn Ala Thr Asn Pro Leu Thr Val Glu Val
165 170 175
Pro Tyr Ile Cys Thr Glu Gly Glu Asp Gln Ile Thr Val Trp Gly Phe
180 185 190
His Ser Asp Asp Lys Thr Gln Met Lys Asn Leu Tyr Gly Asp Ser Asn
195 200 205
Pro Gln Lys Phe Thr Ser Ser Ala Asn Gly Val Thr Thr His Tyr Val
210 215 220
Ser Gln Ile Gly Ser Phe Pro Asp Gln Thr Glu Asp Gly Gly Leu Pro
225 230 235 240
Gln Ser Gly Arg Ile Val Val Asp Tyr Met Met Gln Lys Pro Gly Lys
245 250 255
Thr Gly Thr Ile Val Tyr Gln Arg Gly Val Leu Leu Pro Gln Lys Val
260 265 270
Trp Cys Ala Ser Gly Arg Ser Lys Val Ile Lys Gly Ser Leu Pro Leu
275 280 285
Ile Gly Glu Ala Asp Cys Leu His Glu Lys Tyr Gly Gly Leu Asn Lys
290 295 300
Ser Lys Pro Tyr Tyr Thr Gly Glu His Ala Lys Ala Ile Gly Asn Cys
305 310 315 320
Pro Ile Trp Val Lys Thr Pro Leu Lys Leu Ala Asn Gly Thr Lys Tyr
325 330 335
Arg Pro Pro Ala Lys Leu Leu Lys Glu Arg Gly Phe Phe Gly Ala Ile
340 345 350
Ala Gly Phe Leu Glu Gly Gly Trp Glu Gly Met Ile Ala Gly Trp His
355 360 365
Gly Tyr Thr Ser His Gly Ala His Gly Val Ala Val Ala Ala Asp Leu
370 375 380
Lys Ser Thr Gln Glu Ala Ile Asn Lys Ile Thr Lys Asn Leu Asn Ser
385 390 395 400
Leu Ser Glu Leu Glu Val Lys Asn Leu Gln Arg Leu Ser Gly Ala Met
405 410 415
Asp Glu Leu His Asn Glu Ile Leu Glu Leu Asp Glu Lys Val Asp Asp
420 425 430
Leu Arg Ala Asp Thr Ile Ser Ser Gln Ile Glu Leu Ala Val Leu Leu
435 440 445
Ser Asn Glu Gly Ile Ile Asn Ser Glu Asp Glu His Leu Leu Ala Leu
450 455 460
Glu Arg Lys Leu Lys Lys Met Leu Gly Pro Ser Ala Val Glu Ile Gly
465 470 475 480
Asn Gly Cys Phe Glu Thr Lys His Lys Cys Asn Gln Thr Cys Leu Asp
485 490 495
Arg Ile Ala Ala Gly Thr Phe Asn Ala Gly Glu Phe Ser Leu Pro Thr
500 505 510
Phe Asp Ser Leu Asn Ile Thr Ala Ala Ser Leu Asn Asp Asp Gly Leu
515 520 525
Asp Asn His Thr Ile Leu Leu Tyr Tyr Ser Thr Ala Ala Ser Ser Leu
530 535 540
Ala Val Thr Leu Met Leu Ala Ile Phe Ile Val Tyr Met Val Ser Arg
545 550 555 560
Asp Asn Val Ser Cys Ser Ile Cys Leu
565
<210> 11
<211> 1707
<212> DNA
<213> Artificial Sequence
<220>
<223> Polynucleotide
<400> 11
gatcgaatct gcactggaat aacatcttca aactcacctc atgtggtcaa aacagccact 60
caaggggagg tcaatgtgac tggtgtgata ccactaacaa caacaccaac aaaatcttat 120
tttgcaaatc tcaaaggaac aaggaccaga gggaaactat gcccagactg tctcaactgc 180
acagatctgg atgtggcttt gggcagacca atgtgtgtgg ggaccacacc ttcggcgaaa 240
gcttcaatac tccacgaagt caaacctgtt acatccgggt gctttcctat aatgcacgac 300
agaacaaaaa tcaggcaact acccaatctt ctcagaggat atgaaaatat caggctatca 360
acccaaaacg tcatcgatgc ggaaaaggca ccaggaggac cctacagact tggaacctca 420
ggatcttgcc ctaacgctac cagtaagagc ggatttttcg caacaatggc ttgggctgtc 480
ccaaaggaca acaacaaaaa tgcaacgaac ccactaacag tagaagtacc atacatttgt 540
acagaagggg aagaccaaat cactgtttgg gggttccatt cagatgacaa aacccaaatg 600
aagaacctct atggagactc aaatcctcaa aagttcacct catctgctaa tggagtaacc 660
acacactatg tttctcagat tggcagcttc ccagatcaaa cagaagacgg aggactacca 720
caaagcggca ggattgttgt tgattacatg atgcaaaaac ctgggaaaac aggaacaatt 780
gtctaccaaa gaggtgtttt gttgcctcaa aaggtgtggt gcgcgagtgg caggagcaaa 840
gtaataaaag ggtccttgcc tttaattggt gaagcagatt gccttcatga aaaatacggt 900
ggattaaaca aaagcaagcc ttactacaca ggagaacatg caaaagccat aggaaattgc 960
ccaatatggg tgaaaacacc tttgaagctt gccaatggaa ccaaatatag acctcctgca 1020
aaactattaa aggaaagggg tttcttcgga gctattgctg gtttcctaga aggaggatgg 1080
gaaggaatga ttgcaggctg gcacggatac acatctcacg gagcacatgg agtggcagtg 1140
gcggcggacc ttaagagtac gcaagaagct ataaacaaga taacaaaaaa tctcaattct 1200
ttgagtgagc tagaagtaaa gaatcttcaa agactaagtg gtgccatgga tgaactccac 1260
aacgaaatac tcgagctgga tgagaaagtg gatgatctca gagctgacac tataagctcg 1320
caaatagaac ttgcagtctt gctttccaac gaaggaataa taaacagtga agatgagcat 1380
ctattggcac ttgagagaaa actaaagaaa atgctgggtc cctctgctgt agagatagga 1440
aatggatgct tcgaaaccaa acacaagtgc aaccagacct gcttagacag gatagctgct 1500
ggcaccttta atgcaggaga attttctctc cccacttttg attcactgaa cattactgct 1560
gcatctttaa atgatgatgg attggataac catactatac tgctctatta ctcaactgct 1620
gcttctagtt tggctgtaac attgatgcta gctattttta ttgtttatat ggtctccaga 1680
gacaacgttt catgctccat ctgtcta 1707
<210> 12
<211> 549
<212> PRT
<213> Influenza virus
<400> 12
Asp Thr Leu Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asp Lys His Asn Gly Lys Leu Cys Lys Leu Arg Gly Val Ala
35 40 45
Pro Leu His Leu Gly Lys Cys Asn Ile Ala Gly Trp Ile Leu Gly Asn
50 55 60
Pro Glu Cys Glu Ser Leu Ser Thr Ala Ser Ser Trp Ser Tyr Ile Val
65 70 75 80
Glu Thr Pro Ser Ser Asp Asn Gly Thr Cys Tyr Pro Gly Asp Phe Ile
85 90 95
Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe Glu
100 105 110
Arg Phe Glu Ile Phe Pro Lys Thr Ser Ser Trp Pro Asn His Asp Ser
115 120 125
Asn Lys Gly Val Thr Ala Ala Cys Pro His Ala Gly Ala Lys Ser Phe
130 135 140
Tyr Lys Asn Leu Ile Trp Leu Val Lys Lys Gly Asn Ser Tyr Pro Lys
145 150 155 160
Leu Ser Lys Ser Tyr Ile Asn Asp Lys Gly Lys Glu Val Leu Val Leu
165 170 175
Trp Gly Ile His His Pro Ser Thr Ser Ala Asp Gln Gln Ser Leu Tyr
180 185 190
Gln Asn Ala Asp Ala Tyr Val Phe Val Gly Ser Ser Arg Tyr Ser Lys
195 200 205
Lys Phe Lys Pro Glu Ile Ala Ile Arg Pro Lys Val Arg Asp Gln Glu
210 215 220
Gly Arg Met Asn Tyr Tyr Trp Thr Leu Val Glu Pro Gly Asp Lys Ile
225 230 235 240
Thr Phe Glu Ala Thr Gly Asn Leu Val Val Pro Arg Tyr Ala Phe Ala
245 250 255
Met Glu Arg Asn Ala Gly Ser Gly Ile Ile Ile Ser Asp Thr Pro Val
260 265 270
His Asp Cys Asn Thr Thr Cys Gln Thr Pro Lys Gly Ala Ile Asn Thr
275 280 285
Ser Leu Pro Phe Gln Asn Ile His Pro Ile Thr Ile Gly Lys Cys Pro
290 295 300
Lys Tyr Val Lys Ser Thr Lys Leu Arg Leu Ala Thr Gly Leu Arg Asn
305 310 315 320
Ile Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe
325 330 335
Ile Glu Gly Gly Trp Thr Gly Met Val Asp Gly Trp Tyr Gly Tyr His
340 345 350
His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Leu Lys Ser Thr
355 360 365
Gln Asn Ala Ile Asp Glu Ile Thr Asn Lys Val Asn Ser Val Ile Glu
370 375 380
Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn His Leu
385 390 395 400
Glu Lys Arg Ile Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Leu
405 410 415
Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu
420 425 430
Arg Thr Leu Asp Tyr His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys
435 440 445
Val Arg Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys
450 455 460
Phe Glu Phe Tyr His Lys Cys Asp Asn Thr Cys Met Glu Ser Val Lys
465 470 475 480
Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ala Lys Leu Asn
485 490 495
Arg Glu Glu Ile Asp Gly Val Lys Leu Glu Ser Thr Arg Ile Tyr Gln
500 505 510
Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Val Val
515 520 525
Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu Gln
530 535 540
Cys Arg Ile Cys Ile
545
<210> 13
<211> 1590
<212> DNA
<213> Artificial Sequence
<220>
<223> Polynucleotide
<400> 13
gacacattat gtataggtta tcatgcgaac aattcaacag acactgtaga cacagtacta 60
gaaaagaatc taagaggggt agccccattg catttgggta aatgtaacat tgctggctgg 120
atcctgggaa atccagagtg tgaatcactc tccacagcaa gctcatggtc ctacattgtg 180
gaaacaccta gttcagacaa tggaacgtgt tacccaggag atttcatcga ttatgaggag 240
ctaagagagc aattgagctc agtgtcatca tttgaaaggt ttgagatatt ccccaagaca 300
agttcatggc ccaatcatga ctcgaacaaa ggtgtaacgg cagcatgtcc tcatgctgga 360
gcaaaaagct tctacaaaaa tttaatatgg ctagttaaaa aaggaaattc atacccaaag 420
ctcagcaaat cctacattaa tgataaaggg aaagaagtcc tcgtgctatg gggcattcac 480
catccatcta ctagtgctga ccaacaaagt ctctatcaga atgcagatgc atatgttttt 540
gtggggtcat caagatacag caagaagttc aagccggaaa tagcaataag acccaaagtg 600
agggatcaag aagggagaat gaactattac tggacactag tagagccggg agacaaaata 660
acattcgaag caactggaaa tctagtggta ccgagatatg cattcgcaat ggaaagaaat 720
gctggatctg gtattatcat ttcagataca ccagtccacg attgcaatac aacttgtcaa 780
acacccaagg gtgctataaa caccagcctc ccatttcaga atatacatcc gatcacaatt 840
ggaaaatgtc caaaatatgt aaaaagcaca aaattgagac tggccacagg attgaggaat 900
atcccgtcta ttcaatctag aggcctattt ggggccattg ccggtttcat tgaagggggg 960
tggacaggga tggtagatgg atggtacggt tatcaccatc aaaatgagca ggggtcagga 1020
tatgcagccg acctgaagag cacacagaat gccattgacg agattactaa caaagtaaat 1080
tctgttattg aaaagatgaa tacacagttc acagcagtag gtaaagagtt caaccacctg 1140
gaaaaaagaa tagagaattt aaataaaaaa gttgatgatg gtttcctgga catttggact 1200
tacaatgccg aactgttggt tctattggaa aatgaaagaa ctttggacta ccacgattca 1260
aatgtgaaga acttatatga aaaggtaaga agccagctaa aaaacaatgc caaggaaatt 1320
ggaaacggct gctttgaatt ttaccacaaa tgcgataaca cgtgcatgga aagtgtcaaa 1380
aatgggactt atgactaccc aaaatactca gaggaagcaa aattaaacag agaagaaata 1440
gatggggtaa agctggaatc aacaaggatt taccagattt tggcgatcta ttcaactgtc 1500
gccagttcat tggtactggt agtctccctg ggggcaatca gtttctggat gtgctctaat 1560
gggtctctac agtgtagaat atgtatttaa 1590
<210> 14
<211> 470
<212> PRT
<213> Influenza virus
<400> 14
Met Asn Pro Asn Gln Lys Ile Ile Thr Ile Gly Ser Ile Ser Ile Ala
1 5 10 15
Ile Gly Ile Ile Ser Leu Met Leu Gln Ile Gly Asn Ile Ile Ser Ile
20 25 30
Trp Ala Ser His Ser Ile Gln Thr Gly Ser Gln Asn His Thr Gly Val
35 40 45
Cys Asn Gln Arg Ile Ile Thr Tyr Glu Asn Ser Thr Trp Val Asn His
50 55 60
Thr Tyr Val Asn Ile Asn Asn Thr Asn Val Val Ala Gly Lys Asp Lys
65 70 75 80
Thr Ser Val Thr Leu Ala Gly Asn Ser Ser Leu Cys Ser Ile Ser Gly
85 90 95
Trp Ala Ile Tyr Thr Lys Asp Asn Ser Ile Arg Ile Gly Ser Lys Gly
100 105 110
Asp Val Phe Val Ile Arg Glu Pro Phe Ile Ser Cys Ser His Leu Glu
115 120 125
Cys Arg Thr Phe Phe Leu Thr Gln Gly Ala Leu Leu Asn Asp Lys His
130 135 140
Ser Asn Gly Thr Val Lys Asp Arg Ser Pro Tyr Arg Ala Leu Met Ser
145 150 155 160
Cys Pro Leu Gly Glu Ala Pro Ser Pro Tyr Asn Ser Lys Phe Glu Ser
165 170 175
Val Ala Trp Ser Ala Ser Ala Cys His Asp Gly Met Gly Trp Leu Thr
180 185 190
Ile Gly Ile Ser Gly Pro Asp Asn Gly Ala Val Ala Val Leu Lys Tyr
195 200 205
Asn Gly Ile Ile Thr Glu Thr Ile Lys Ser Trp Lys Lys Arg Ile Leu
210 215 220
Arg Thr Gln Glu Ser Glu Cys Val Cys Val Asn Gly Ser Cys Phe Thr
225 230 235 240
Ile Met Thr Asp Gly Pro Ser Asn Gly Ala Ala Ser Tyr Lys Ile Phe
245 250 255
Lys Ile Glu Lys Gly Lys Val Thr Lys Ser Ile Glu Leu Asn Ala Pro
260 265 270
Asn Phe His Tyr Glu Glu Cys Ser Cys Tyr Pro Asp Thr Gly Thr Val
275 280 285
Met Cys Val Cys Arg Asp Asn Trp His Gly Ser Asn Arg Pro Trp Val
290 295 300
Ser Phe Asn Gln Asn Leu Asp Tyr Gln Ile Gly Tyr Ile Cys Ser Gly
305 310 315 320
Val Phe Gly Asp Asn Pro Arg Pro Lys Asp Gly Glu Gly Ser Cys Asn
325 330 335
Pro Val Thr Val Asp Gly Ala Asp Gly Val Lys Gly Phe Ser Tyr Lys
340 345 350
Tyr Gly Asn Gly Val Trp Ile Gly Arg Thr Lys Ser Asn Arg Leu Arg
355 360 365
Lys Gly Phe Glu Met Ile Trp Asp Pro Asn Gly Trp Thr Asp Thr Asp
370 375 380
Ser Asp Phe Ser Val Lys Gln Asp Val Val Ala Ile Thr Asp Trp Ser
385 390 395 400
Gly Tyr Ser Gly Ser Phe Val Gln His Pro Glu Leu Thr Gly Leu Asp
405 410 415
Cys Ile Arg Pro Cys Phe Trp Val Glu Leu Val Arg Gly Leu Pro Arg
420 425 430
Glu Asn Thr Thr Ile Trp Thr Ser Gly Ser Ser Ile Ser Phe Cys Gly
435 440 445
Val Asn Ser Asp Thr Ala Asn Trp Ser Trp Pro Asp Gly Ala Glu Leu
450 455 460
Pro Phe Thr Ile Asp Lys
465 470
<210> 15
<211> 1410
<212> DNA
<213> Artificial Sequence
<220>
<223> Polynucleotide
<400> 15
atgaatccaa atcaaaaaat aataaccatt ggatcaatca gtatagcaat cggaataatt 60
agtctaatgt tgcaaatagg aaatattatt tcaatatggg ctagtcactc aatccaaact 120
ggaagtcaaa accacactgg agtatgcaac caaagaatca tcacatatga aaacagcacc 180
tgggtgaatc acacatatgt taatattaac aacactaatg ttgttgctgg aaaggacaaa 240
acttcagtga cattggccgg caattcatct ctttgttcta tcagtggatg ggctatatac 300
acaaaagaca acagcataag aattggctcc aaaggagatg tttttgtcat aagagaacct 360
ttcatatcat gttctcactt ggaatgcaga accttttttc tgacccaagg tgctctatta 420
aatgacaaac attcaaatgg gaccgttaag gacagaagtc cttatagggc cttaatgagc 480
tgtcctctag gtgaagctcc gtccccatac aattcaaagt ttgaatcagt tgcatggtca 540
gcaagcgcat gccatgatgg catgggctgg ttaacaatcg gaatttctgg tccagacaat 600
ggagctgtgg ctgtactaaa atacaacggc ataataactg aaaccataaa aagttggaaa 660
aagcgaatat taagaacaca agagtctgaa tgtgtctgtg tgaacgggtc atgtttcacc 720
ataatgaccg atggcccgag taatggggcc gcctcgtaca aaatcttcaa gatcgaaaag 780
gggaaggtta ctaaatcaat agagttgaat gcacccaatt ttcattatga ggaatgttcc 840
tgttacccag acactggcac agtgatgtgt gtatgcaggg acaactggca tggttcaaat 900
cgaccttggg tgtcttttaa tcaaaacctg gattatcaaa taggatacat ctgcagtggg 960
gtgttcggtg acaatccgcg tcccaaagat ggagagggca gctgtaatcc agtgactgtt 1020
gatggagcag acggagtaaa ggggttttca tacaaatatg gtaatggtgt ttggatagga 1080
aggactaaaa gtaacagact tagaaagggg tttgagatga tttgggatcc taatggatgg 1140
acagataccg acagtgattt ctcagtgaaa caggatgttg tggcaataac tgattggtca 1200
gggtacagcg gaagtttcgt tcaacatcct gagttaacag gattggactg tataagacct 1260
tgcttctggg ttgagttagt cagaggactg cctagagaaa atacaacaat ctggactagt 1320
gggagcagca tttctttttg tggcgtaaat agtgatactg caaactggtc ttggccagac 1380
ggtgctgagt tgccgttcac cattgacaag 1410
<210> 16
<211> 5589
<212> DNA
<213> Artificial Sequence
<220>
<223> Polynucleotide
<220>
<221> misc_feature
<222> (4774)..(4774)
<223> n is a, c, g, or t
<400> 16
ggccgctcta gaactagtac ggcgtgcaag tagtgtcttt ctttgcactc ccgccgtccc 60
agaagacgcc gcaacaagct gagcttgctg gaagccgaac aaaggcgtta cagagcacaa 120
acatagtggc agtgtaggaa ctctaactgg gaccaaaact acgggcccgg cagaaacgtt 180
ccccgccccg aagcgaaggc gaacgtcgaa aagcaagacc gggaccgctc gtcccaggat 240
tagccacgaa gttccagacc aagtatagga gtaaacgctc gctcgtcaaa acaattgtca 300
ccaatcagca ccacatcggc acataacaac cggttgcgga actcgcatgt gaacaacaag 360
cggctccggg ggagtgatcg gctcgggcgg atgacccgga ctcttccgcg cagcaactcg 420
gcgtgttgtt gacggcagta ctccgtagtt gccatgacaa cagtcaatgg cgtgcttcac 480
aaggtggaga gccgagaaag cacctcggca tgtacgagta tgtagatagt gtatcaagca 540
ggaagatggg ggttacttta tctcaatcag atgcctgtaa gcgagagccg agagcctgcc 600
ctgttgttga cacaattctg gcctgatacg agtgacaagc gctgggacgg cggctggggt 660
cttttgctcg cggcttcagc tcaattccaa tcctgggccg gtgccgaacg gcccaatcgc 720
gagcgcccac gaaatcggag gtcgaggaaa gaaggctggg cgagacgcgg cgacaagctg 780
tggcaaaatg gccaattgag gttctgggtc ggctggtgat caaccatgca tttcccagcc 840
cgcagattct ctttctctct cgtgcagcag cggcaccagc agcagcagca gccaggggtt 900
tgaccaacct ctccgcccag ccaccgatag taaagatgct gcctgcgtat tctgggctgc 960
aggagttcca agatctttcg gtctggccac cagctgtcac gtcaccctcc acctttggac 1020
gacgttgctg gaaaattcga agccttcact aagataacta tgccgtagca cttgcagccc 1080
cggaagctgc aagttgattc ttggagggct ctctccacca ccaatacggg agatctggcc 1140
ccgcacttga ggaggctgga gtctcggatc gcccacttcg cgtcgccctg ggccctgggc 1200
cctggggtga tgggcccgtt gccgtggtgg atggcaggag cttttcagct ctcaatgggc 1260
gaatgctact ccgtaggtcg gagtggctgg aagcggcgga acggacaggg ggaggttggg 1320
gaaaatgctc cgcaggaaga gcagggagtg gggagctgcg gtcggccctg tggagcccgt 1380
gcagggccag ctaatccaat tcgggccaca ataaacaaga gagggcccca catcatgtaa 1440
acagaggctc agaagctcct gccacactgg gagggtttcg aagtctgacg actgccaatg 1500
gaccccagcc atcgcgagca cacagcagtt cgcacgctcc cattgggttc ctcatcacgc 1560
agtcgctctc cccgccaacc agcgccaggt ccgggaacag cggcgcaaat gcgtatttga 1620
gggcgcctcg ctcgagcaac ctgtgcctga ccttctcctc ctccttctgc accttgcatc 1680
tcgtcgcgtc cactcgcagg caaccacaca tcctcctcct ctcccaaaac ccccccgctt 1740
tttctttccc ttgttggaat tcgattgaaa aagaagacgg gtccgtctag agaccgcctt 1800
ctcacctttc tctcgacttc tttctaggaa aagaagcaag agtcattctt cttgtccacc 1860
ttctggttca cggaaggtcg aggagaagat tgcctctgcc cccaaagtcg ccaacctgga 1920
ctttgaagca cgtgttccgg tccctttcag tgtcttcccg tcctcgtaca gggagtccga 1980
gaccgccacc caaacccact cccacgaaga ggttgagatc aagctccccc agctcgccgg 2040
acgggaaggt caacactctt cattccaagc ccaagcacat cttcctccca gcggagaggg 2100
tcgcttcaga gaagaagagg tccgcatcac tcgtcaagag gaacatcacc gccgtcccgg 2160
catccgtgaa gagttcgttc accgcgagga gcgtcaccgg taagtttagt ttttgttttg 2220
attcaccacc cattgtcttc cccgcctttt tctttttctt cccttgctct cttgcccctg 2280
tctagtgtag ggcattgcca aggccatctt cacacacaca cacccccccc cccccccacc 2340
ctcagctggg ggggggggtg gcctgggttg accaagggac ggtgaagact actactactt 2400
gagccactca aacccatgca tgacacaggg ttttcctttt tcttttctct tttcctttaa 2460
ctaaccaacc actccaacat tagccctcag tcaacctact ccgagtctcg catcgagttc 2520
gatactgagc accgcactca caactccgtc attgacgttg ctgagagcga gtatcgtgcc 2580
cgtgtccagc ccaactaccg caaggaagct tccgtagtcg gtaccaccgt cgacggatcc 2640
cgcttcagcc acagccgcaa ggccagcagc accacctcca cccacaccga cgagtacacc 2700
gtcgatcccc ctagccaccg ccccgtctac aagaaggagt cggttgaagt cgccggtacc 2760
actgttgacc cccctgctcc tcgttcgacc taccacgagc aggtgaacat tgttgaagag 2820
accgttgacg ctcaccgtta cgctcctcaa cccaacaaca acaacaccat gtacgccaag 2880
ttcgcgaccc tcgccgccct tgtggctggc gccgctgctg acaccatctg catcggctac 2940
cacgccaaca acagcaccga caccgtcgac acggtcctcg agaagaacgt caccgtcacc 3000
cacagcgtca acctgctcga ggacagccac aacggcaagc tctgcctcct caagggcatc 3060
gcccccctcc agctcggcaa ctgcagcgtc gccggctgga tcctcggcaa ccccgagtgc 3120
gagctgctca tcagcaagga gagctggtcg tacatcgtcg agacccccaa ccccgagaac 3180
ggcacgtgct accccggcta cttcgccgac tacgaggagc tgcgcgagca gctcagcagc 3240
gtcagctcgt tcgagcgctt cgagatcttc cccaaggaga gcagctggcc caaccacacc 3300
gtcaccggcg tcagcgccag ctgctcgcac aacggcaaga gcagcttcta ccgcaacctc 3360
ctctggctca ccggcaagaa cggcctctac ccgaacctca gcaagagcta cgtcaacaac 3420
aaggagaagg aggtcctcgt cctctggggc gtccaccacc cccccaacat cggcaaccag 3480
cgcgccctct accacaccga gaacgcctac gtcagcgtcg tcagcagcca ctacagccgc 3540
cgcttcaccc ccgagatcgc caagcgcccc aaggtccgcg accaggaggg ccgcatcaac 3600
tactactgga ccctcctcga gcccggcgac accatcatct tcgaggccaa cggcaacctg 3660
atcgccccct ggtacgcctt cgccctcagc cgcggcttcg gcagcggcat catcaccagc 3720
aacgccccca tggacgagtg cgacgccaag tgccagaccc cccagggcgc catcaacagc 3780
agcctcccgt tccagaacgt ccaccccgtc accatcggcg agtgccccaa gtacgtccgc 3840
agcgccaagc tccgcatggt caccggcctc cgcaacatcc ccagcatcca gagccgcggc 3900
ctcttcggcg ccatcgccgg cttcatcgag ggcggctgga ccggcatggt cgacggctgg 3960
tacggctacc accaccagaa cgagcagggc agcggctacg ccgccgacca gaagtcgacc 4020
cagaacgcca tcaacggcat caccaacaag gtcaacagcg tcatcgagaa gatgaacacc 4080
cagttcaccg ccgtcggcaa ggagttcaac aagctcgagc gccgcatgga gaacctcaac 4140
aagaaggtcg acgacggctt cctcgacatc tggacctaca acgccgagct gctcgtcctc 4200
ctcgagaacg agcgcaccct cgacttccac gacagcaacg tcaagaacct gtacgagaag 4260
gtcaagagcc agctcaagaa caacgccaag gagatcggca acggctgctt cgagttctac 4320
cacaagtgca acaacgagtg catggagagc gtcaagaacg gcacctacga ctaccccaag 4380
tacagcgagg agagcaagct caaccgcgag aagatcgacg gcgtcaagct cgagagcatg 4440
ggcgtctacc agatcctcgc catctacagc accgtcgcca gcagcctcgt cctcctggtc 4500
agcctcggcg ccatctcgtt ctggatgtgc agcaacggca gcctccagtg ccgcatctgc 4560
atctgagaat tcggatccta agtaagtaaa cgaacctctc tgaaggaggt tctgagacac 4620
gcgcgattct tctgtatata gttttatttt tcactctgga gtgcttcgct ccaccagtac 4680
ataaaccttt tttttcacgt aacaaaatgg cttcttttca gaccatgtga accatcttga 4740
tgccttgacc tcttcagttc tcactttaac gtanttcgcg ttagtctgta tgtcccagtt 4800
gcatgtagtt gagataaata cccctggaag tgggtctggg cctttgtggg acggagccct 4860
ctttctgtgg tctggagagc ccgctctcta ccgcctacct tcttaccaca gtacactact 4920
cacacattgc tgaactgacc catcataccg tactttatcc tgttaattcg tggtgctgtc 4980
gactattcta tttgctcaaa tggagagcac attcatcggc gcagggatac acggtttatg 5040
gaccccaaga gtgtaaggac tattattagt aatattatat gcctctaggc gccttaactt 5100
caacaggcga gcactactaa tcaacttttg gtagacccaa ttacaaacga ccatacgtgc 5160
cggaaatttt gggattccgt ccgctctccc caaccaagct agaagaggca acgaacagcc 5220
aatcccggtg ctaattaaat tatatggttc atttttttta aaaaaatttt ttcttcccat 5280
tttcctctcg cttttctttt tcgcatcgta gttgatcaaa gtccaagtca agcgagctat 5340
ttgtgctata gctcggtggc tataatcagt acagcttaga gaggctgtaa aggtatgata 5400
ccacagcagt attcgcgcta taagcggcac tcctagacta attgttacgg tctacagaag 5460
taggtaataa aagcgttaat tgttctaaat actagaggca cttagagaag ctatctaaat 5520
atatattgac cctagcttat tatccctatt agtaagttag ttagctctaa cctatagata 5580
gatgcatgc 5589
<210> 17
<211> 5589
<212> DNA
<213> Artificial Sequence
<220>
<223> Vector
<220>
<221> misc_feature
<222> (4774)..(4774)
<223> n is a, c, g, or t
<400> 17
ggccgctcta gaactagtac ggcgtgcaag tagtgtcttt ctttgcactc ccgccgtccc 60
agaagacgcc gcaacaagct gagcttgctg gaagccgaac aaaggcgtta cagagcacaa 120
acatagtggc agtgtaggaa ctctaactgg gaccaaaact acgggcccgg cagaaacgtt 180
ccccgccccg aagcgaaggc gaacgtcgaa aagcaagacc gggaccgctc gtcccaggat 240
tagccacgaa gttccagacc aagtatagga gtaaacgctc gctcgtcaaa acaattgtca 300
ccaatcagca ccacatcggc acataacaac cggttgcgga actcgcatgt gaacaacaag 360
cggctccggg ggagtgatcg gctcgggcgg atgacccgga ctcttccgcg cagcaactcg 420
gcgtgttgtt gacggcagta ctccgtagtt gccatgacaa cagtcaatgg cgtgcttcac 480
aaggtggaga gccgagaaag cacctcggca tgtacgagta tgtagatagt gtatcaagca 540
ggaagatggg ggttacttta tctcaatcag atgcctgtaa gcgagagccg agagcctgcc 600
ctgttgttga cacaattctg gcctgatacg agtgacaagc gctgggacgg cggctggggt 660
cttttgctcg cggcttcagc tcaattccaa tcctgggccg gtgccgaacg gcccaatcgc 720
gagcgcccac gaaatcggag gtcgaggaaa gaaggctggg cgagacgcgg cgacaagctg 780
tggcaaaatg gccaattgag gttctgggtc ggctggtgat caaccatgca tttcccagcc 840
cgcagattct ctttctctct cgtgcagcag cggcaccagc agcagcagca gccaggggtt 900
tgaccaacct ctccgcccag ccaccgatag taaagatgct gcctgcgtat tctgggctgc 960
aggagttcca agatctttcg gtctggccac cagctgtcac gtcaccctcc acctttggac 1020
gacgttgctg gaaaattcga agccttcact aagataacta tgccgtagca cttgcagccc 1080
cggaagctgc aagttgattc ttggagggct ctctccacca ccaatacggg agatctggcc 1140
ccgcacttga ggaggctgga gtctcggatc gcccacttcg cgtcgccctg ggccctgggc 1200
cctggggtga tgggcccgtt gccgtggtgg atggcaggag cttttcagct ctcaatgggc 1260
gaatgctact ccgtaggtcg gagtggctgg aagcggcgga acggacaggg ggaggttggg 1320
gaaaatgctc cgcaggaaga gcagggagtg gggagctgcg gtcggccctg tggagcccgt 1380
gcagggccag ctaatccaat tcgggccaca ataaacaaga gagggcccca catcatgtaa 1440
acagaggctc agaagctcct gccacactgg gagggtttcg aagtctgacg actgccaatg 1500
gaccccagcc atcgcgagca cacagcagtt cgcacgctcc cattgggttc ctcatcacgc 1560
agtcgctctc cccgccaacc agcgccaggt ccgggaacag cggcgcaaat gcgtatttga 1620
gggcgcctcg ctcgagcaac ctgtgcctga ccttctcctc ctccttctgc accttgcatc 1680
tcgtcgcgtc cactcgcagg caaccacaca tcctcctcct ctcccaaaac ccccccgctt 1740
tttctttccc ttgttggaat tcgattgaaa aagaagacgg gtccgtctag agaccgcctt 1800
ctcacctttc tctcgacttc tttctaggaa aagaagcaag agtcattctt cttgtccacc 1860
ttctggttca cggaaggtcg aggagaagat tgcctctgcc cccaaagtcg ccaacctgga 1920
ctttgaagca cgtgttccgg tccctttcag tgtcttcccg tcctcgtaca gggagtccga 1980
gaccgccacc caaacccact cccacgaaga ggttgagatc aagctccccc agctcgccgg 2040
acgggaaggt caacactctt cattccaagc ccaagcacat cttcctccca gcggagaggg 2100
tcgcttcaga gaagaagagg tccgcatcac tcgtcaagag gaacatcacc gccgtcccgg 2160
catccgtgaa gagttcgttc accgcgagga gcgtcaccgg taagtttagt ttttgttttg 2220
attcaccacc cattgtcttc cccgcctttt tctttttctt cccttgctct cttgcccctg 2280
tctagtgtag ggcattgcca aggccatctt cacacacaca cacccccccc cccccccacc 2340
ctcagctggg ggggggggtg gcctgggttg accaagggac ggtgaagact actactactt 2400
gagccactca aacccatgca tgacacaggg ttttcctttt tcttttctct tttcctttaa 2460
ctaaccaacc actccaacat tagccctcag tcaacctact ccgagtctcg catcgagttc 2520
gatactgagc accgcactca caactccgtc attgacgttg ctgagagcga gtatcgtgcc 2580
cgtgtccagc ccaactaccg caaggaagct tccgtagtcg gtaccaccgt cgacggatcc 2640
cgcttcagcc acagccgcaa ggccagcagc accacctcca cccacaccga cgagtacacc 2700
gtcgatcccc ctagccaccg ccccgtctac aagaaggagt cggttgaagt cgccggtacc 2760
actgttgacc cccctgctcc tcgttcgacc taccacgagc aggtgaacat tgttgaagag 2820
accgttgacg ctcaccgtta cgctcctcaa cccaacaaca acaacaccat gtacgccaag 2880
ttcgcgaccc tcgccgccct tgtggctggc gccgctgctg acaccatctg catcggctac 2940
cacgccaaca acagcaccga caccgtcgac acggtcctcg agaagaacgt caccgtcacc 3000
cacagcgtca acctgctcga ggacagccac aacggcaagc tctgcctcct caagggcatc 3060
gcccccctcc agctcggcaa ctgcagcgtc gccggctgga tcctcggcaa ccccgagtgc 3120
gagctgctca tcagcaagga gagctggtcg tacatcgtcg agacccccaa ccccgagaac 3180
ggcacgtgct accccggcta cttcgccgac tacgaggagc tgcgcgagca gctcagcagc 3240
gtcagctcgt tcgagcgctt cgagatcttc cccaaggaga gcagctggcc caaccacacc 3300
gtcaccggcg tcagcgccag ctgctcgcac aacggcaaga gcagcttcta ccgcaacctc 3360
ctctggctca ccggcaagaa cggcctctac ccgaacctca gcaagagcta cgtcaacaac 3420
aaggagaagg aggtcctcgt cctctggggc gtccaccacc cccccaacat cggcaaccag 3480
cgcgccctct accacaccga gaacgcctac gtcagcgtcg tcagcagcca ctacagccgc 3540
cgcttcaccc ccgagatcgc caagcgcccc aaggtccgcg accaggaggg ccgcatcaac 3600
tactactgga ccctcctcga gcccggcgac accatcatct tcgaggccaa cggcaacctg 3660
atcgccccct ggtacgcctt cgccctcagc cgcggcttcg gcagcggcat catcaccagc 3720
aacgccccca tggacgagtg cgacgccaag tgccagaccc cccagggcgc catcaacagc 3780
agcctcccgt tccagaacgt ccaccccgtc accatcggcg agtgccccaa gtacgtccgc 3840
agcgccaagc tccgcatggt caccggcctc cgcaacatcc ccagcatcca gagccgcggc 3900
ctcttcggcg ccatcgccgg cttcatcgag ggcggctgga ccggcatggt cgacggctgg 3960
tacggctacc accaccagaa cgagcagggc agcggctacg ccgccgacca gaagtcgacc 4020
cagaacgcca tcaacggcat caccaacaag gtcaacagcg tcatcgagaa gatgaacacc 4080
cagttcaccg ccgtcggcaa ggagttcaac aagctcgagc gccgcatgga gaacctcaac 4140
aagaaggtcg acgacggctt cctcgacatc tggacctaca acgccgagct gctcgtcctc 4200
ctcgagaacg agcgcaccct cgacttccac gacagcaacg tcaagaacct gtacgagaag 4260
gtcaagagcc agctcaagaa caacgccaag gagatcggca acggctgctt cgagttctac 4320
cacaagtgca acaacgagtg catggagagc gtcaagaacg gcacctacga ctaccccaag 4380
tacagcgagg agagcaagct caaccgcgag aagatcgacg gcgtcaagct cgagagcatg 4440
ggcgtctacc agatcctcgc catctacagc accgtcgcca gcagcctcgt cctcctggtc 4500
agcctcggcg ccatctcgtt ctggatgtgc agcaacggca gcctccagtg ccgcatctgc 4560
atctgagaat tcggatccta agtaagtaaa cgaacctctc tgaaggaggt tctgagacac 4620
gcgcgattct tctgtatata gttttatttt tcactctgga gtgcttcgct ccaccagtac 4680
ataaaccttt tttttcacgt aacaaaatgg cttcttttca gaccatgtga accatcttga 4740
tgccttgacc tcttcagttc tcactttaac gtanttcgcg ttagtctgta tgtcccagtt 4800
gcatgtagtt gagataaata cccctggaag tgggtctggg cctttgtggg acggagccct 4860
ctttctgtgg tctggagagc ccgctctcta ccgcctacct tcttaccaca gtacactact 4920
cacacattgc tgaactgacc catcataccg tactttatcc tgttaattcg tggtgctgtc 4980
gactattcta tttgctcaaa tggagagcac attcatcggc gcagggatac acggtttatg 5040
gaccccaaga gtgtaaggac tattattagt aatattatat gcctctaggc gccttaactt 5100
caacaggcga gcactactaa tcaacttttg gtagacccaa ttacaaacga ccatacgtgc 5160
cggaaatttt gggattccgt ccgctctccc caaccaagct agaagaggca acgaacagcc 5220
aatcccggtg ctaattaaat tatatggttc atttttttta aaaaaatttt ttcttcccat 5280
tttcctctcg cttttctttt tcgcatcgta gttgatcaaa gtccaagtca agcgagctat 5340
ttgtgctata gctcggtggc tataatcagt acagcttaga gaggctgtaa aggtatgata 5400
ccacagcagt attcgcgcta taagcggcac tcctagacta attgttacgg tctacagaag 5460
taggtaataa aagcgttaat tgttctaaat actagaggca cttagagaag ctatctaaat 5520
atatattgac cctagcttat tatccctatt agtaagttag ttagctctaa cctatagata 5580
gatgcatgc 5589
<210> 18
<211> 545
<212> PRT
<213> Artificial Sequence
<220>
<223> Polypeptide
<400> 18
Asp Thr Ile Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr Val
1 5 10 15
Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn Leu
20 25 30
Leu Glu Asp Ser His Asn Gly Lys Leu Cys Leu Leu Lys Gly Ile Ala
35 40 45
Pro Leu Gln Leu Gly Asn Cys Ser Val Ala Gly Trp Ile Leu Gly Asn
50 55 60
Pro Glu Cys Glu Leu Leu Ile Ser Lys Glu Ser Trp Ser Tyr Ile Val
65 70 75 80
Glu Thr Pro Asn Pro Glu Asn Gly Thr Cys Tyr Pro Gly Tyr Phe Ala
85 90 95
Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe Glu
100 105 110
Arg Phe Glu Ile Phe Pro Lys Glu Ser Ser Trp Pro Asn His Thr Val
115 120 125
Thr Gly Val Ser Ala Ser Cys Ser His Asn Gly Lys Ser Ser Phe Tyr
130 135 140
Arg Asn Leu Leu Trp Leu Thr Gly Lys Asn Gly Leu Tyr Pro Asn Leu
145 150 155 160
Ser Lys Ser Tyr Val Asn Asn Lys Glu Lys Glu Val Leu Val Leu Trp
165 170 175
Gly Val His His Pro Pro Asn Ile Gly Asn Gln Arg Ala Leu Tyr His
180 185 190
Thr Glu Asn Ala Tyr Val Ser Val Val Ser Ser His Tyr Ser Arg Arg
195 200 205
Phe Thr Pro Glu Ile Ala Lys Arg Pro Lys Val Arg Asp Gln Glu Gly
210 215 220
Arg Ile Asn Tyr Tyr Trp Thr Leu Leu Glu Pro Gly Asp Thr Ile Ile
225 230 235 240
Phe Glu Ala Asn Gly Asn Leu Ile Ala Pro Trp Tyr Ala Phe Ala Leu
245 250 255
Ser Arg Gly Phe Gly Ser Gly Ile Ile Thr Ser Asn Ala Pro Met Asp
260 265 270
Glu Cys Asp Ala Lys Cys Gln Thr Pro Gln Gly Ala Ile Asn Ser Ser
275 280 285
Leu Pro Phe Gln Asn Val His Pro Val Thr Ile Gly Glu Cys Pro Lys
290 295 300
Tyr Val Arg Ser Ala Lys Leu Arg Met Val Thr Gly Leu Arg Asn Ile
305 310 315 320
Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly Phe Ile
325 330 335
Glu Gly Gly Trp Thr Gly Met Val Asp Gly Trp Tyr Gly Tyr His His
340 345 350
Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Gln Lys Ser Thr Gln
355 360 365
Asn Ala Ile Asn Gly Ile Thr Asn Lys Val Asn Ser Val Ile Glu Lys
370 375 380
Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn Lys Leu Glu
385 390 395 400
Arg Arg Met Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe Leu Asp
405 410 415
Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn Glu Arg
420 425 430
Thr Leu Asp Phe His Asp Ser Asn Val Lys Asn Leu Tyr Glu Lys Val
435 440 445
Lys Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly Cys Phe
450 455 460
Glu Phe Tyr His Lys Cys Asn Asn Glu Cys Met Glu Ser Val Lys Asn
465 470 475 480
Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ser Lys Leu Asn Arg
485 490 495
Glu Lys Ile Asp Gly Val Lys Leu Glu Ser Met Gly Val Tyr Gln Gly
500 505 510
Gly Gly Gly Gly Gly Gly Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly
515 520 525
Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Leu Leu Ser Thr Phe
530 535 540
Leu
545
<210> 19
<211> 1690
<212> DNA
<213> Artificial Sequence
<220>
<223> Polynucleotide
<400> 19
atgtacgcca agttcgcgac cctcgccgcc cttgtggctg gcgccgctgc tgacaccatc 60
tgcatcggct accacgccaa caacagcacc gacaccgtcg acacggtcct cgagaagaac 120
gtcaccgtca cccacagcgt caacctgctc gaggacagcc acaacggcaa gctctgcctc 180
ctcaagggca tcgcccccct ccagctcggc aactgcagcg tcgccggctg gatcctcggc 240
aaccccgagt gcgagctgct catcagcaag gagagctggt cgtacatcgt cgagaccccc 300
aaccccgaga acggcacgtg ctaccccggc tacttcgccg actacgagga gctgcgcgag 360
cagctcagca gcgtcagctc gttcgagcgc ttcgagatct tccccaagga gagcagctgg 420
cccaaccaca ccgtcaccgg cgtcagcgcc agctgctcgc acaacggcaa gagcagcttc 480
taccgcaacc tcctctggct caccggcaag aacggcctct acccgaacct cagcaagagc 540
tacgtcaaca acaaggagaa ggaggtcctc gtcctctggg gcgtccacca cccccccaac 600
atcggcaacc agcgcgccct ctaccacacc gagaacgcct acgtcagcgt cgtcagcagc 660
cactacagcc gccgcttcac ccccgagatc gccaagcgcc ccaaggtccg cgaccaggag 720
ggccgcatca actactactg gaccctcctc gagcccggcg acaccatcat cttcgaggcc 780
aacggcaacc tgatcgcccc ctggtacgcc ttcgccctca gccgcggctt cggcagcggc 840
atcatcacca gcaacgcccc catggacgag tgcgacgcca agtgccagac cccccagggc 900
gccatcaaca gcagcctccc gttccagaac gtccaccccg tcaccatcgg cgagtgcccc 960
aagtacgtcc gcagcgccaa gctccgcatg gtcaccggcc tccgcaacat ccccagcatc 1020
cagagccgcg gcctcttcgg cgccatcgcc ggcttcatcg agggcggctg gaccggcatg 1080
gtcgacggct ggtacggcta ccaccaccag aacgagcagg gcagcggcta cgccgccgac 1140
cagaagtcga cccagaacgc catcaacggc atcaccaaca aggtcaacag cgtcatcgag 1200
aagatgaaca cccagttcac cgccgtcggc aaggagttca acaagctcga gcgccgcatg 1260
gagaacctca acaagaaggt cgacgacggc ttcctcgaca tctggaccta caacgccgag 1320
ctgctcgtcc tcctcgagaa cgagcgcacc ctcgacttcc acgacagcaa cgtcaagaac 1380
ctgtacgaga aggtcaagag ccagctcaag aacaacgcca aggagatcgg caacggctgc 1440
ttcgagttct accacaagtg caacaacgag tgcatggaga gcgtcaagaa cggcacctac 1500
gactacccca agtacagcga ggagagcaag ctcaaccgcg agaagatcga cggcgtcaag 1560
ctcgagagca tgggcgtcta ccagggcggc ggcggcggcg gcggcggcta catccccgag 1620
gccccccgcg acggccaggc ctacgtccgc aaggacggcg agtgggtcct cctcagcacc 1680
ttcctgtgag 1690
<210> 20
<211> 571
<212> PRT
<213> Artificial Sequence
<220>
<223> Polypeptide
<400> 20
Asp Arg Ile Cys Thr Gly Ile Thr Ser Ser Asn Ser Pro His Val Val
1 5 10 15
Lys Thr Ala Thr Gln Gly Glu Val Asn Val Thr Gly Val Ile Pro Leu
20 25 30
Thr Thr Thr Pro Thr Lys Ser Tyr Phe Ala Asn Leu Lys Gly Thr Arg
35 40 45
Thr Arg Gly Lys Leu Cys Pro Asp Cys Leu Asn Cys Thr Asp Leu Asp
50 55 60
Val Ala Leu Gly Arg Pro Met Cys Val Gly Thr Thr Pro Ser Ala Lys
65 70 75 80
Ala Ser Ile Leu His Glu Val Lys Pro Val Thr Ser Gly Cys Phe Pro
85 90 95
Ile Met His Asp Arg Thr Lys Ile Arg Gln Leu Pro Asn Leu Leu Arg
100 105 110
Gly Tyr Glu Asn Ile Arg Leu Ser Thr Gln Asn Val Ile Asp Ala Glu
115 120 125
Lys Ala Pro Gly Gly Pro Tyr Arg Leu Gly Thr Ser Gly Ser Cys Pro
130 135 140
Asn Ala Thr Ser Lys Ser Gly Phe Phe Ala Thr Met Ala Trp Ala Val
145 150 155 160
Pro Lys Asp Asn Asn Lys Asn Ala Thr Asn Pro Leu Thr Val Glu Val
165 170 175
Pro Tyr Ile Cys Thr Glu Gly Glu Asp Gln Ile Thr Val Trp Gly Phe
180 185 190
His Ser Asp Asp Lys Thr Gln Met Lys Asn Leu Tyr Gly Asp Ser Asn
195 200 205
Pro Gln Lys Phe Thr Ser Ser Ala Asn Gly Val Thr Thr His Tyr Val
210 215 220
Ser Gln Ile Gly Ser Phe Pro Asp Gln Thr Glu Asp Gly Gly Leu Pro
225 230 235 240
Gln Ser Gly Arg Ile Val Val Asp Tyr Met Met Gln Lys Pro Gly Lys
245 250 255
Thr Gly Thr Ile Val Tyr Gln Arg Gly Val Leu Leu Pro Gln Lys Val
260 265 270
Trp Cys Ala Ser Gly Arg Ser Lys Val Ile Lys Gly Ser Leu Pro Leu
275 280 285
Ile Gly Glu Ala Asp Cys Leu His Glu Lys Tyr Gly Gly Leu Asn Lys
290 295 300
Ser Lys Pro Tyr Tyr Thr Gly Glu His Ala Lys Ala Ile Gly Asn Cys
305 310 315 320
Pro Ile Trp Val Lys Thr Pro Leu Lys Leu Ala Asn Gly Thr Lys Tyr
325 330 335
Arg Pro Pro Ala Lys Leu Leu Lys Glu Arg Gly Phe Phe Gly Ala Ile
340 345 350
Ala Gly Phe Leu Glu Gly Gly Trp Glu Gly Met Ile Ala Gly Trp His
355 360 365
Gly Tyr Thr Ser His Gly Ala His Gly Val Ala Val Ala Ala Asp Leu
370 375 380
Lys Ser Thr Gln Glu Ala Ile Asn Lys Ile Thr Lys Asn Leu Asn Ser
385 390 395 400
Leu Ser Glu Leu Glu Val Lys Asn Leu Gln Arg Leu Ser Gly Ala Met
405 410 415
Asp Glu Leu His Asn Glu Ile Leu Glu Leu Asp Glu Lys Val Asp Asp
420 425 430
Leu Arg Ala Asp Thr Ile Ser Ser Gln Ile Glu Leu Ala Val Leu Leu
435 440 445
Ser Asn Glu Gly Ile Ile Asn Ser Glu Asp Glu His Leu Leu Ala Leu
450 455 460
Glu Arg Lys Leu Lys Lys Met Leu Gly Pro Ser Ala Val Glu Ile Gly
465 470 475 480
Asn Gly Cys Phe Glu Thr Lys His Lys Cys Asn Gln Thr Cys Leu Asp
485 490 495
Arg Ile Ala Ala Gly Thr Phe Asn Ala Gly Glu Phe Ser Leu Pro Thr
500 505 510
Phe Asp Ser Leu Asn Ile Thr Ala Ala Ser Leu Asn Asp Asp Gly Leu
515 520 525
Asp Asn His Thr Ile Leu Leu Tyr Tyr Gly Gly Gly Gly Gly Gly Gly
530 535 540
Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys
545 550 555 560
Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu
565 570
<210> 21
<211> 1768
<212> DNA
<213> Artificial Sequence
<220>
<223> Polynucleotide
<400> 21
atgtacgcca agttcgcgac cctcgccgcc cttgtggctg gcgccgctgc tgaccgcatc 60
tgcaccggca tcaccagcag caacagcccc cacgtcgtca agaccgccac ccagggcgag 120
gtcaacgtca cgggcgtcat ccccctcacc accaccccca ccaagagcta cttcgccaac 180
ctcaagggca cccgcacccg cggcaagctc tgccccgact gcctcaactg caccgacctc 240
gacgtcgccc tcggccgccc catgtgcgtc ggcaccaccc ccagcgccaa ggccagcatc 300
ctccacgagg tcaagcccgt caccagcggc tgcttcccca tcatgcacga ccgcaccaag 360
atccgccagc tccccaacct cctccgcggc tacgagaaca tccgcctcag cacccagaac 420
gtcatcgacg ccgagaaggc ccccggcggc ccctaccgcc tcggcaccag cggctcgtgc 480
cccaacgcca ccagcaagag cggcttcttc gccaccatgg cctgggccgt ccccaaggac 540
aacaacaaga acgccaccaa ccccctgacc gtcgaggtcc cctacatctg caccgagggc 600
gaggaccaga tcaccgtctg gggcttccac agcgacgaca agacccagat gaagaacctc 660
tacggcgaca gcaaccccca gaagttcacc agcagcgcca acggcgtcac cacccactac 720
gtcagccaga tcggcagctt ccccgaccag accgaggacg gcggcctccc ccagtcgggc 780
cgcatcgtcg tcgactacat gatgcagaag cccggcaaga ccggcaccat cgtctaccag 840
cgcggcgtcc tcctgcccca gaaggtctgg tgcgcctcgg gccgcagcaa ggtcatcaag 900
ggcagcctcc cgctcatcgg cgaggccgac tgcctccacg agaagtacgg cggcctcaac 960
aagagcaagc cctactacac gggcgagcac gccaaggcca tcggcaactg ccccatctgg 1020
gtcaagaccc ccctcaagct cgccaacggc accaagtacc gcccccccgc caagctcctc 1080
aaggagcggg gcttcttcgg cgccatcgcc ggcttcctcg agggcggctg ggagggcatg 1140
atcgccggct ggcacggcta caccagccac ggcgcccacg gcgtcgccgt cgccgccgac 1200
ctcaagtcga cccaggaggc catcaacaag atcaccaaga acctcaacag cctcagcgag 1260
ctggaggtca agaacctcca gcgcctctcg ggcgccatgg acgagctgca caacgagatc 1320
ctcgagctgg acgagaaggt cgacgacctc cgcgccgaca ccatcagcag ccagatcgag 1380
ctggccgtcc tcctcagcaa cgagggcatc atcaacagcg aggacgagca cctcctggcc 1440
ctcgagcgca agctcaagaa gatgctcggc cccagcgccg tcgagatcgg caacggctgc 1500
ttcgagacca agcacaagtg caaccagacc tgcctcgacc ggatcgccgc cggcaccttc 1560
aacgccggcg agttcagcct ccccaccttc gacagcctca acatcaccgc cgccagcctc 1620
aacgacgacg gcctcgacaa ccacaccatc ctgctctact acggcggcgg cggcggcggc 1680
ggcggctaca tccccgaggc cccccgcgac ggccaggcct acgtccgcaa ggacggcgag 1740
tgggtcctcc tcagcacctt cctgtgag 1768
<210> 22
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Polypeptide
<400> 22
Met Tyr Ala Lys Phe Ala Thr Leu Ala Ala Leu Val Ala Gly Ala Ala
1 5 10 15
Ala Ser Ser Ser Asp Tyr Ser Asp Leu Gln Arg Val Lys Gln Glu Leu
20 25 30
Leu Glu Glu Val Lys Lys Glu Leu Gln Lys Val Lys Glu Glu Ile Ile
35 40 45
Glu Ala Phe Val Gln Glu Leu Arg Lys Arg Gly Gly Ser Val Thr Leu
50 55 60
Ala Gly Asn Ser Ser Leu Cys Ser Ile Ser Gly Trp Ala Ile Tyr Thr
65 70 75 80
Lys Asp Asn Ser Ile Arg Ile Gly Ser Lys Gly Asp Val Phe Val Ile
85 90 95
Arg Glu Pro Phe Ile Ser Cys Ser His Leu Glu Cys Arg Thr Phe Phe
100 105 110
Leu Thr Gln Gly Ala Leu Leu Asn Asp Lys His Ser Asn Gly Thr Val
115 120 125
Lys Asp Arg Ser Pro Tyr Arg Ala Leu Met Ser Cys Pro Leu Gly Glu
130 135 140
Ala Pro Ser Pro Tyr Asn Ser Lys Phe Glu Ser Val Ala Trp Ser Ala
145 150 155 160
Ser Ala Cys His Asp Gly Met Gly Trp Leu Thr Ile Gly Ile Ser Gly
165 170 175
Pro Asp Asn Gly Ala Val Ala Val Leu Lys Tyr Asn Gly Ile Ile Thr
180 185 190
Glu Thr Ile Lys Ser Trp Lys Lys Arg Ile Leu Arg Thr Gln Glu Ser
195 200 205
Glu Cys Val Cys Val Asn Gly Ser Cys Phe Thr Ile Met Thr Asp Gly
210 215 220
Pro Ser Asn Gly Ala Ala Ser Tyr Lys Ile Phe Lys Ile Glu Lys Gly
225 230 235 240
Lys Val Thr Lys Ser Ile Glu Leu Asn Ala Pro Asn Phe His Tyr Glu
245 250 255
Glu Cys Ser Cys Tyr Pro Asp Thr Gly Thr Val Met Cys Val Cys Arg
260 265 270
Asp Asn Trp His Gly Ser Asn Arg Pro Trp Val Ser Phe Asn Gln Asn
275 280 285
Leu Asp Tyr Gln Ile Gly Tyr Ile Cys Ser Gly Val Phe Gly Asp Asn
290 295 300
Pro Arg Pro Lys Asp Gly Glu Gly Ser Cys Asn Pro Val Thr Val Asp
305 310 315 320
Gly Ala Asp Gly Val Lys Gly Phe Ser Tyr Lys Tyr Gly Asn Gly Val
325 330 335
Trp Ile Gly Arg Thr Lys Ser Asn Arg Leu Arg Lys Gly Phe Glu Met
340 345 350
Ile Trp Asp Pro Asn Gly Trp Thr Asp Thr Asp Ser Asp Phe Ser Val
355 360 365
Lys Gln Asp Val Val Ala Ile Thr Asp Trp Ser Gly Tyr Ser Gly Ser
370 375 380
Phe Val Gln His Pro Glu Leu Thr Gly Leu Asp Cys Ile Arg Pro Cys
385 390 395 400
Phe Trp Val Glu Leu Val Arg Gly Leu Pro Arg Glu Asn Thr Thr Ile
405 410 415
Trp Thr Ser Gly Ser Ser Ile Ser Phe Cys Gly Val Asn Ser Asp Thr
420 425 430
Ala Asn Trp Ser Trp Pro Asp Gly Ala Glu Leu Pro Phe Thr Ile Asp
435 440 445
Lys
<210> 23
<211> 628
<212> PRT
<213> Myceliophthora thermophila
<400> 23
Met His Ala Leu Ser Ser Leu Ala Val Leu Gly Ala Trp Ala Val Gln
1 5 10 15
Thr Val Leu Gly Arg Pro Ala Thr Leu Ser Lys Arg Ala Thr Asp Ser
20 25 30
Phe Ile Glu Thr Glu Thr Pro Ile Ala Trp Glu Lys Leu Arg Cys Asn
35 40 45
Ile Gly Ala Asn Gly Cys Ala Ala Ser Gly Ala Ala Ala Gly Val Val
50 55 60
Ile Ala Ser Pro Ser Lys Ser Asp Pro Asp Tyr Phe Tyr Thr Trp Thr
65 70 75 80
Arg Asp Ala Gly Leu Val Leu Thr Gly Ile Val Asp Ala Leu Ser Gln
85 90 95
Asn Tyr Ser Ala Ala Leu Gln Thr Asn Ile Gln Asp Tyr Ile Ile Ala
100 105 110
Gln Ala Lys Leu Gln Gly Val Ser Asn Pro Ser Gly Ser Leu Ser Asp
115 120 125
Gly Thr Gly Leu Gly Glu Pro Lys Phe Asn Val Asp Leu Thr Gln Phe
130 135 140
Thr Gly Asp Trp Gly Arg Pro Gln Arg Asp Gly Pro Pro Leu Arg Ala
145 150 155 160
Ile Ala Leu Ile Arg Tyr Ala Lys Trp Leu Ala Ser Asn Gly Tyr Lys
165 170 175
Asp Thr Ala Asn Ser Val Val Trp Pro Val Ile Lys Asn Asp Leu Ala
180 185 190
Tyr Ala Ala Gln Tyr Trp Asn Glu Thr Gly Phe Asp Leu Trp Glu Glu
195 200 205
Val Pro Gly Ser Ser Phe Phe Thr Ile Ala Ser Thr His Arg Ala Leu
210 215 220
Val Glu Gly Ala Ala Leu Ala Ala Gln Leu Gly Thr Glu Cys Ser Ala
225 230 235 240
Cys Ile Thr Val Ala Pro Gln Val Leu Cys Phe Gln Gln Ser Phe Trp
245 250 255
Asn Pro Ser Gly Gly Tyr Val Val Ser Asn Ile Asn Gly Gly Asn Asn
260 265 270
Arg Ser Gly Lys Asp Leu Asn Ser Val Leu Ala Ser Ile His Thr Phe
275 280 285
Asp Pro Ala Val Gly Cys Asp Ser Val Thr Phe Gln Pro Cys Ser Asp
290 295 300
Lys Ala Leu Ser Asn His Lys Ala Tyr Val Asp Ser Phe Arg Ser Val
305 310 315 320
Tyr Ala Ile Asn Ser Gly Ile Ala Gln Gly Lys Ala Val Ala Val Gly
325 330 335
Arg Tyr Ser Glu Asp Val Tyr Tyr Asn Gly Asn Pro Trp Tyr Leu Ala
340 345 350
Asn Phe Ala Ala Ala Glu Gln Leu Tyr Asp Ala Val Phe Val Trp Lys
355 360 365
Lys Gln Gln Ser Ile Glu Val Thr Gln Leu Ser Leu Pro Phe Phe Lys
370 375 380
Asp Leu Leu Pro Gly Ile Ser Thr Gly Thr Tyr Thr Pro Ser Ser Ser
385 390 395 400
Thr Tyr Gln Gln Ile Leu Asp Ala Val Ser Ala Tyr Ala Asp Gly Phe
405 410 415
Ile Asp Val Ala Ala Lys Tyr Thr Pro Ser Asp Gly Ser Leu Ala Glu
420 425 430
Gln Tyr Thr Arg Asp Ser Gly Gln Pro Ile Ser Ala Lys Asp Leu Thr
435 440 445
Trp Ser Tyr Ala Ala Phe Leu Ser Ala Ala Asp Arg Arg Ala Gly Ile
450 455 460
Val Pro Ala Gly Trp Ser Ala Glu His Gly Lys Thr Leu Pro Gly Ser
465 470 475 480
Cys Ser Ala Val Gln Val Ala Gly Thr Tyr Thr Gln Ala Thr Ala Thr
485 490 495
Ser Phe Pro Pro Gly Gln Thr Pro Asn Pro Thr Ser Asp Thr Pro Ala
500 505 510
Pro Phe Pro Thr Ala Cys Ala Asp Ser Thr Gln Val Phe Val Thr Phe
515 520 525
Arg Ala Glu Val Thr Thr Gln Trp Gly Gln Ser Val Lys Val Val Gly
530 535 540
Ser Ser Ser Glu Leu Gly Asn Trp Asp Val Ser Lys Ala Pro Arg Leu
545 550 555 560
Ser Ala Ser Ala Tyr Thr Ala Ser Asp Pro Leu Trp Ala Ile Thr Val
565 570 575
Pro Met Lys Ala Gly Gln Ser Val Gln Tyr Lys Phe Val Lys Val Asn
580 585 590
Gly Asp Gly Ser Ile Gln Trp Glu Ser Asp Pro Asn Arg Gln Phe Thr
595 600 605
Val Ser Ser Ser Ser Thr Ala Ser Gly Cys Ala Trp Gln Thr Ile Glu
610 615 620
Ala Thr Trp Arg
625
<210> 24
<211> 640
<212> PRT
<213> Aspergillus niger
<400> 24
Met Ser Phe Arg Ser Leu Leu Ala Leu Ser Gly Leu Val Cys Thr Gly
1 5 10 15
Leu Ala Asn Val Ile Ser Lys Arg Ala Thr Leu Asp Ser Trp Leu Ser
20 25 30
Asn Glu Ala Thr Val Ala Arg Thr Ala Ile Leu Asn Asn Ile Gly Ala
35 40 45
Asp Gly Ala Trp Val Ser Gly Ala Asp Ser Gly Ile Val Val Ala Ser
50 55 60
Pro Ser Thr Asp Asn Pro Asp Tyr Phe Tyr Thr Trp Thr Arg Asp Ser
65 70 75 80
Gly Leu Val Leu Lys Thr Leu Val Asp Leu Phe Arg Asn Gly Asp Thr
85 90 95
Ser Leu Leu Ser Thr Ile Glu Asn Tyr Ile Ser Ala Gln Ala Ile Val
100 105 110
Gln Gly Ile Ser Asn Pro Ser Gly Asp Leu Ser Ser Gly Ala Gly Leu
115 120 125
Gly Glu Pro Lys Phe Asn Val Asp Glu Thr Ala Tyr Thr Gly Ser Trp
130 135 140
Gly Arg Pro Gln Arg Asp Gly Pro Ala Leu Arg Ala Thr Ala Met Ile
145 150 155 160
Gly Phe Gly Gln Trp Leu Leu Asp Asn Gly Tyr Thr Ser Thr Ala Thr
165 170 175
Asp Ile Val Trp Pro Leu Val Arg Asn Asp Leu Ser Tyr Val Ala Gln
180 185 190
Tyr Trp Asn Gln Thr Gly Tyr Asp Leu Trp Glu Glu Val Asn Gly Ser
195 200 205
Ser Phe Phe Thr Ile Ala Val Gln His Arg Ala Leu Val Glu Gly Ser
210 215 220
Ala Phe Ala Thr Ala Val Gly Ser Ser Cys Ser Trp Cys Asp Ser Gln
225 230 235 240
Ala Pro Glu Ile Leu Cys Tyr Leu Gln Ser Phe Trp Thr Gly Ser Phe
245 250 255
Ile Leu Ala Asn Phe Asp Ser Ser Arg Ser Gly Lys Asp Ala Asn Thr
260 265 270
Leu Leu Gly Ser Ile His Thr Phe Asp Pro Glu Ala Ala Cys Asp Asp
275 280 285
Ser Thr Phe Gln Pro Cys Ser Pro Arg Ala Leu Ala Asn His Lys Glu
290 295 300
Val Val Asp Ser Phe Arg Ser Ile Tyr Thr Leu Asn Asp Gly Leu Ser
305 310 315 320
Asp Ser Glu Ala Val Ala Val Gly Arg Tyr Pro Glu Asp Thr Tyr Tyr
325 330 335
Asn Gly Asn Pro Trp Phe Leu Cys Thr Leu Ala Ala Ala Glu Gln Leu
340 345 350
Tyr Asp Ala Leu Tyr Gln Trp Asp Lys Gln Gly Ser Leu Glu Val Thr
355 360 365
Asp Val Ser Leu Asp Phe Phe Lys Ala Leu Tyr Ser Asp Ala Ala Thr
370 375 380
Gly Thr Tyr Ser Ser Ser Ser Ser Thr Tyr Ser Ser Ile Val Asp Ala
385 390 395 400
Val Lys Thr Phe Ala Asp Gly Phe Val Ser Ile Val Glu Thr His Ala
405 410 415
Ala Ser Asn Gly Ser Met Ser Glu Gln Tyr Asp Lys Ser Asp Gly Glu
420 425 430
Gln Leu Ser Ala Arg Asp Leu Thr Trp Ser Tyr Ala Ala Leu Leu Thr
435 440 445
Ala Asn Asn Arg Arg Asn Ser Val Val Pro Ala Ser Trp Gly Glu Thr
450 455 460
Ser Ala Ser Ser Val Pro Gly Thr Cys Ala Ala Thr Ser Ala Ile Gly
465 470 475 480
Thr Tyr Ser Ser Val Thr Val Thr Ser Trp Pro Ser Ile Val Ala Thr
485 490 495
Gly Gly Thr Thr Thr Thr Ala Thr Pro Thr Gly Ser Gly Ser Val Thr
500 505 510
Ser Thr Ser Lys Thr Thr Ala Thr Ala Ser Lys Thr Ser Thr Ser Thr
515 520 525
Ser Ser Thr Ser Cys Thr Thr Pro Thr Ala Val Ala Val Thr Phe Asp
530 535 540
Leu Thr Ala Thr Thr Thr Tyr Gly Glu Asn Ile Tyr Leu Val Gly Ser
545 550 555 560
Ile Ser Gln Leu Gly Asp Trp Glu Thr Ser Asp Gly Ile Ala Leu Ser
565 570 575
Ala Asp Lys Tyr Thr Ser Ser Asp Pro Leu Trp Tyr Val Thr Val Thr
580 585 590
Leu Pro Ala Gly Glu Ser Phe Glu Tyr Lys Phe Ile Arg Ile Glu Ser
595 600 605
Asp Asp Ser Val Glu Trp Glu Ser Asp Pro Asn Arg Glu Tyr Thr Val
610 615 620
Pro Gln Ala Cys Gly Thr Ser Thr Ala Thr Val Thr Asp Thr Trp Arg
625 630 635 640
<210> 25
<211> 1920
<212> DNA
<213> Artificial Sequence
<220>
<223> Polynucleotide
<400> 25
atgtcgttcc gatctctact cgccctgagc ggcctcgtct gcacagggtt ggcaaatgtg 60
atttccaagc gcgcgacctt ggattcatgg ttgagcaacg aagcgaccgt ggctcgtact 120
gccatcctga ataacatcgg ggcggacggt gcttgggtgt cgggcgcgga ctctggcatt 180
gtcgttgcta gtcccagcac ggataacccg gactacttct acacctggac tcgcgactct 240
ggtctcgtcc tcaagaccct cgtcgatctc ttccgaaatg gagataccag tctcctctcc 300
accattgaga actacatctc cgcccaggca attgtccagg gtatcagtaa cccctctggt 360
gatctgtcca gcggcgctgg tctcggtgaa cccaagttca atgtcgatga gactgcctac 420
actggttctt ggggacggcc gcagcgagat ggtccggctc tgagagcaac tgctatgatc 480
ggcttcgggc agtggctgct tgacaatggc tacaccagca ccgcaacgga cattgtttgg 540
cccctcgtta ggaacgacct gtcgtatgtg gctcaatact ggaaccagac aggatatgat 600
ctctgggaag aagtcaatgg ctcgtctttc tttacgattg ctgtgcaaca ccgcgccctt 660
gtcgaaggta gtgccttcgc gacggccgtc ggctcgtcct gctcctggtg tgattctcag 720
gcacccgaaa ttctctgcta cctgcagtcc ttctggaccg gcagcttcat tctggccaac 780
ttcgatagca gccgttccgg caaggacgca aacaccctcc tgggaagcat ccacaccttt 840
gatcctgagg ccgcatgcga cgactccacc ttccagccct gctccccgcg cgcgctcgcc 900
aaccacaagg aggttgtaga ctctttccgc tcaatctata ccctcaacga tggtctcagt 960
gacagcgagg ctgttgcggt gggtcggtac cctgaggaca cgtactacaa cggcaacccg 1020
tggttcctgt gcaccttggc tgccgcagag cagttgtacg atgctctata ccagtgggac 1080
aagcaggggt cgttggaggt cacagatgtg tcgctggact tcttcaaggc actgtacagc 1140
gatgctgcta ctggcaccta ctcttcgtcc agttcgactt atagtagcat tgtagatgcc 1200
gtgaagactt tcgccgatgg cttcgtctct attgtggaaa ctcacgccgc aagcaacggc 1260
tccatgtccg agcaatacga caagtctgat ggcgagcagc tttccgctcg cgacctgacc 1320
tggtcttatg ctgctctgct gaccgccaac aaccgtcgta actccgtcgt gcctgcttct 1380
tggggcgaga cctctgccag cagcgtgccc ggcacctgtg cggccacatc tgccattggt 1440
acctacagca gtgtgactgt cacctcgtgg ccgagtatcg tggctactgg cggcaccact 1500
acgacggcta cccccactgg atccggcagc gtgacctcga ccagcaagac caccgcgact 1560
gctagcaaga ccagcaccag tacgtcatca acctcctgta ccactcccac cgccgtggct 1620
gtgactttcg atctgacagc taccaccacc tacggcgaga acatctacct ggtcggatcg 1680
atctctcagc tgggtgactg ggaaaccagc gacggcatag ctctgagtgc tgacaagtac 1740
acttccagcg acccgctctg gtatgtcact gtgactctgc cggctggtga gtcgtttgag 1800
tacaagttta tccgcattga gagcgatgac tccgtggagt gggagagtga tcccaaccga 1860
gaatacaccg ttcctcaggc gtgcggaacg tcgaccgcga cggtgactga cacctggcgg 1920
<210> 26
<211> 389
<212> PRT
<213> Myceliophthora thermophila
<400> 26
Met Lys Ser Ser Ile Leu Ala Ser Val Phe Ala Thr Gly Ala Val Ala
1 5 10 15
Gln Ser Gly Pro Trp Gln Gln Cys Gly Gly Ile Gly Trp Gln Gly Ser
20 25 30
Thr Asp Cys Val Ser Gly Tyr His Cys Val Tyr Gln Asn Asp Trp Tyr
35 40 45
Ser Gln Cys Val Pro Gly Ala Ala Ser Thr Thr Leu Gln Thr Ser Thr
50 55 60
Thr Ser Arg Pro Thr Ala Thr Ser Thr Ala Pro Pro Ser Ser Thr Thr
65 70 75 80
Ser Pro Ser Lys Gly Lys Leu Lys Trp Leu Gly Ser Asn Glu Ser Gly
85 90 95
Ala Glu Phe Gly Glu Gly Asn Tyr Pro Gly Leu Trp Gly Lys His Phe
100 105 110
Ile Phe Pro Ser Thr Ser Ala Ile Gln Thr Leu Ile Asn Asp Gly Tyr
115 120 125
Asn Ile Phe Arg Ile Asp Phe Ser Met Glu Arg Leu Val Pro Asn Gln
130 135 140
Leu Thr Ser Ser Phe Asp Glu Gly Tyr Leu Arg Asn Leu Thr Glu Val
145 150 155 160
Val Asn Phe Val Thr Asn Ala Gly Lys Tyr Ala Val Leu Asp Pro His
165 170 175
Asn Tyr Gly Arg Tyr Tyr Gly Asn Val Ile Thr Asp Thr Asn Ala Phe
180 185 190
Arg Thr Phe Trp Thr Asn Leu Ala Lys Gln Phe Ala Ser Asn Ser Leu
195 200 205
Val Ile Phe Asp Thr Asn Asn Glu Tyr Asn Thr Met Asp Gln Thr Leu
210 215 220
Val Leu Asn Leu Asn Gln Ala Ala Ile Asp Gly Ile Arg Ala Ala Gly
225 230 235 240
Ala Thr Ser Gln Tyr Ile Phe Val Glu Gly Asn Ala Trp Ser Gly Ala
245 250 255
Trp Ser Trp Asn Thr Thr Asn Thr Asn Met Ala Ala Leu Thr Asp Pro
260 265 270
Gln Asn Lys Ile Val Tyr Glu Met His Gln Tyr Leu Asp Ser Asp Ser
275 280 285
Ser Gly Thr His Ala Glu Cys Val Ser Ser Asn Ile Gly Ala Gln Arg
290 295 300
Val Val Gly Ala Thr Gln Trp Leu Arg Ala Asn Gly Lys Leu Gly Val
305 310 315 320
Leu Gly Glu Phe Ala Gly Gly Ala Asn Ala Val Cys Gln Gln Ala Val
325 330 335
Thr Gly Leu Leu Asp His Leu Gln Asp Asn Ser Asp Val Trp Leu Gly
340 345 350
Ala Leu Trp Trp Ala Ala Gly Pro Trp Trp Gly Asp Tyr Met Tyr Ser
355 360 365
Phe Glu Pro Pro Ser Gly Thr Gly Tyr Val Asn Tyr Asn Ser Ile Leu
370 375 380
Lys Lys Tyr Leu Pro
385
<210> 27
<211> 1167
<212> DNA
<213> Artificial Sequence
<220>
<223> Polynucleotide
<400> 27
atgaagtcct ccatcctcgc cagcgtcttc gccacgggcg ccgtggctca aagtggtccg 60
tggcagcaat gtggtggcat cggatggcaa ggatcgaccg actgtgtgtc gggttaccac 120
tgcgtctacc agaacgattg gtacagccag tgcgtgcctg gcgcggcgtc gacaacgctc 180
cagacatcta ccacgtccag gcccaccgcc accagcaccg cccctccgtc gtccaccacc 240
tcgcctagca agggcaagct caagtggctc ggcagcaacg agtcgggcgc cgagttcggg 300
gagggcaact accccggcct ctggggcaag cacttcatct tcccgtcgac ttcggcgatt 360
cagacgctca tcaatgatgg atacaacatc ttccggatcg acttctcgat ggagcgtctg 420
gtgcccaacc agttgacgtc gtccttcgac gagggctacc tccgcaacct gaccgaggtg 480
gtcaacttcg tgacgaacgc gggcaagtac gccgtcctgg acccgcacaa ctacggccgg 540
tactacggca acgtcatcac ggacacgaac gcgttccgga ccttctggac caacctggcc 600
aagcagttcg cctccaactc gctcgtcatc ttcgacacca acaacgagta caacacgatg 660
gaccagaccc tggtgctcaa cctcaaccag gccgccatcg acggcatccg ggccgccggc 720
gcgacctcgc agtacatctt cgtcgagggc aacgcgtgga gcggggcctg gagctggaac 780
acgaccaaca ccaacatggc cgccctgacg gacccgcaga acaagatcgt gtacgagatg 840
caccagtacc tcgactcgga cagctcgggc acccacgccg agtgcgtcag cagcaacatc 900
ggcgcccagc gcgtcgtcgg agccacccag tggctccgcg ccaacggcaa gctcggcgtc 960
ctcggcgagt tcgccggcgg cgccaacgcc gtctgccagc aggccgtcac cggcctcctc 1020
gaccacctcc aggacaacag cgacgtctgg ctgggtgccc tctggtgggc cgccggtccc 1080
tggtggggcg actacatgta ctcgttcgag cctccttcgg gcaccggcta tgtcaactac 1140
aactcgatcc taaagaagta cttgccg 1167
<210> 28
<211> 281
<212> PRT
<213> Artificial Sequence
<220>
<223> Polypeptide
<400> 28
Met Ser Glu Tyr Gln Pro Ser Leu Phe Ala Leu Asn Pro Met Gly Phe
1 5 10 15
Ser Pro Leu Asp Gly Ser Lys Ser Thr Asn Glu Asn Val Ser Ala Ser
20 25 30
Thr Ser Thr Ala Lys Pro Met Val Gly Gln Leu Ile Phe Asp Lys Phe
35 40 45
Ile Lys Thr Glu Glu Asp Pro Ile Ile Lys Gln Asp Thr Pro Ser Asn
50 55 60
Leu Asp Phe Asp Phe Ala Leu Pro Gln Thr Ala Thr Ala Pro Asp Ala
65 70 75 80
Lys Thr Val Leu Pro Ile Pro Glu Leu Asp Asp Ala Val Val Glu Ser
85 90 95
Phe Phe Ser Ser Ser Thr Asp Ser Thr Pro Met Phe Glu Tyr Glu Asn
100 105 110
Leu Glu Asp Asn Ser Lys Glu Trp Thr Ser Leu Phe Asp Asn Asp Ile
115 120 125
Pro Val Thr Thr Asp Asp Val Ser Leu Ala Asp Lys Ala Ile Glu Ser
130 135 140
Thr Glu Glu Val Ser Leu Val Pro Ser Asn Leu Glu Val Ser Thr Thr
145 150 155 160
Ser Phe Leu Pro Thr Pro Val Leu Glu Asp Ala Lys Leu Thr Gln Thr
165 170 175
Arg Lys Val Lys Lys Pro Asn Ser Val Val Lys Lys Ser His His Val
180 185 190
Gly Lys Asp Asp Glu Ser Arg Leu Asp His Leu Gly Val Val Ala Tyr
195 200 205
Asn Arg Lys Gln Arg Ser Ile Pro Leu Ser Pro Ile Val Pro Glu Ser
210 215 220
Ser Asp Pro Ala Ala Leu Lys Arg Ala Arg Asn Thr Glu Ala Ala Arg
225 230 235 240
Arg Ser Arg Ala Arg Lys Leu Gln Arg Met Lys Gln Leu Glu Asp Lys
245 250 255
Val Glu Glu Leu Leu Ser Lys Asn Tyr His Leu Glu Asn Glu Val Ala
260 265 270
Arg Leu Lys Lys Leu Val Gly Glu Arg
275 280
<210> 29
<211> 27
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide
<400> 29
Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys
1 5 10 15
Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu
20 25
<210> 30
<211> 85
<212> PRT
<213> Artificial Sequence
<220>
<223> Polynucleotide
<400> 30
Gly Gly Cys Thr Ala Cys Ala Thr Cys Cys Cys Cys Gly Ala Gly Gly
1 5 10 15
Cys Cys Cys Cys Cys Cys Gly Cys Gly Ala Cys Gly Gly Cys Cys Ala
20 25 30
Gly Gly Cys Cys Thr Ala Cys Gly Thr Cys Cys Gly Cys Ala Ala Gly
35 40 45
Gly Ala Cys Gly Gly Cys Gly Ala Gly Thr Gly Gly Gly Thr Cys Cys
50 55 60
Thr Cys Cys Thr Cys Ala Gly Cys Ala Cys Cys Thr Thr Cys Cys Thr
65 70 75 80
Gly Thr Gly Ala Gly
85
<210> 31
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide
<400> 31
Val Ile Ser Lys Arg
1 5
<210> 32
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide
<400> 32
Asp Tyr Lys Asp Asp Asp Asp Lys
1 5
Claims (24)
- 인플루엔자 바이러스 표면 단백질을 생산하도록 유전적으로 조작된 마이셀리오프쏘라 써모필라 (Myceliophthora thermophila) C1로서, 적어도 하나의 C1 조절 서열에 작동적으로 연결된 인플루엔자 바이러스 표면 단백질을 인코딩하는 핵산 서열을 포함하는 발현 컨스트럭트를 포함하고, 인플루엔자 바이러스 표면 단백질이 그의 엑토도메인 및 막횡단 도메인을 포함하고 막-결합 단백질로서 C1에서 발현되는 것인, 마이셀리오프쏘라 써모필라 C1.
- 제1항에 있어서, 인플루엔자 바이러스 표면 단백질이 헤마글루티닌 (HA)인 것인, C1.
- 제2항에 있어서, 발현 컨스트럭트가 HA를 인코딩하는 핵산 서열에 인-프레임으로 연결된 C1 시그널 펩티드를 인코딩하는 핵산 서열을 추가로 포함하는 것인, C1.
- 제2항에 있어서, HA 아형이 인플루엔자 A-H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15 및 H16; 및 인플루엔자 B 아형으로 구성된 군으로부터 선택되는 것인, C1.
- 제2항에 있어서, HA 아형이 인플루엔자 A 아형 H1, H2 및 H3; 및 인플루엔자 B 아형으로부터 선택되는 인간을 감염시키는 아형인 것인, C1.
- 제2항에 있어서, HA가 A/뉴칼레도니아/20/99 (H1N1), A/캘리포니아/04/2009 (H1N1), A/우루과이/716/07 (H3N2)(A/브리스베인/10/07-유사), B/플로리다/04/2006: B 야마가타 계통, A/푸에르토리코/08/1934 (H1N1), 및 A/텍사스/50/2012 (H3N2)로 구성된 군으로부터 선택되는 인플루엔자 바이러스 균주로부터인 것인, C1.
- 제1항에 있어서, 적어도 하나의 C1 조절 서열이 C1 프로모터를 포함하는 것인, C1.
- 제7항에 있어서, C1 프로모터가: hex1 (Woronin 체), cbh1 (셀로비오히드롤라제 1) 및 chi1 (키티나제 1) 프로모터로 구성된 군으로부터 선택되는 것인, C1.
- 제7항에 있어서, C1 프로모터가 hex1 프로모터인 것인, C1.
- 제3항에 있어서, C1 시그널 펩티드가 Gla1 (글루코아밀라제 1, C1), GlaA (글루코아밀라제 A, 아스페르질러스) 및 Cbh1 (셀로비오히드롤라제 1, C1)로 구성된 군으로부터 선택되는 단백질로부터 유래하는 시그널 펩티드인 것인, C1.
- 제10항에 있어서, C1 시그널 펩티드가 Cbh1로부터 유래하는 것인, C1.
- 제1항에 있어서, 발현 컨스트럭트가: HA에 융합된 Cbh1 시그널 펩티드를 인코딩하는 핵산 서열에 작동적으로 연결된 hex1 프로모터를 포함하는 것인, C1.
- 제12항에 있어서, HA가 A/뉴칼레도니아/20/99 (H1N1), A/캘리포니아/04/2009 (H1N1), B/플로리다/04/2006: B 야마가타 계통, A/푸에르토리코/08/1934 (H1N1), 및 A/텍사스/50/2012 (H3N2)로 구성된 군으로부터 선택되는 인플루엔자 바이러스 균주로부터인 것인, C1.
- 제1항에 있어서, 인플루엔자 바이러스 표면 단백질이 뉴라미니다제 (NA)인 것인, C1.
- 제14항에 있어서, NA 아형이 인플루엔자 A-N1, N2, N3, N4, N5, N6, N7, N8 및 N9; 및 인플루엔자 B 아형으로 구성된 군으로부터 선택되는 것인, C1.
- 제14항에 있어서, NA 아형이 인플루엔자 A 아형 N1 및 N2; 및 인플루엔자 B 아형으로부터 선택되는 인간을 감염시키는 아형인 것인, C1.
- 제14항에 있어서, 발현 컨스트럭트가: NA를 인코딩하는 핵산 서열에 작동적으로 연결된 hex1 프로모터를 포함하는 것인, C1.
- 제17항에 있어서, NA가 인플루엔자 바이러스 균주 A/뉴칼레도니아/20/99 (H1N1)로부터인 것인, C1.
- 제1항에 있어서, C1 균주가: W1L#100I (prt-△alp1△chi1△alp2△pyr5) 기탁 번호 CBS141153, UV18-100f (prt-△alp1,△pyr5) 기탁 번호 CBS141147, W1L#100I (prt-△alp1△chi1△pyr5) 기탁 번호 CBS141149, 및 UV18-100f (prt-△alp1△pep4△alp2,△prt1△pyr5) 기탁 번호 CBS141143으로 구성된 군으로부터 선택되는 것인, C1.
- 인플루엔자 바이러스 표면 단백질을 발현하기에 적합한 조건하에서 제1항의 마이셀리오프쏘라 써모필라 C1을 배양하는 단계; 및 인플루엔자 바이러스 표면 단백질을 회수하는 단계를 포함하는, 인플루엔자 바이러스 표면 단백질을 생산하는 방법.
- 제20항에 있어서, 인플루엔자 바이러스 표면 단백질을 회수하는 단계가 균사체로부터의 추출을 포함하는 것인, 방법.
- 마이셀리오프쏘라 써모필라 C1에서 막 결합 인플루엔자 바이러스 표면 단백질을 발현하기 위한 발현 컨스트럭트로서, 인플루엔자 바이러스 표면 단백질을 인코딩하는 핵산 서열에 작동적으로 연결된 적어도 하나의 C1 조절 서열을 포함하고, 인플루엔자 바이러스 표면 단백질이 그의 엑토도메인 및 막횡단 도메인을 포함하는 것인, 발현 컨스트럭트.
- 제1항의 변형된 마이셀리오프쏘라 써모필라 C1에 의해 생산된 실질적으로 순수한, 재조합 인플루엔자 바이러스 표면 단백질로서, 인플루엔자 바이러스 표면 단백질이 95% 순도 이상으로 정제되고 활성 및 면역원성이며, 백신으로 사용되는 경우 보호 면역반응을 유도하는, 재조합 인플루엔자 바이러스 표면 단백질.
- 제1항의 변형된 마이셀리오프쏘라 써모필라 C1에 의해 생산된 인플루엔자 바이러스 표면 단백질을 포함하는 인플루엔자 백신 조성물.
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| US62/547,885 | 2017-08-21 | ||
| PCT/IB2018/056003 WO2019038623A1 (en) | 2017-08-21 | 2018-08-09 | PRODUCTION OF AN INFLUENZA VACCINE IN MYCELIOPHTHORA THERMOPHILA |
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| CA2190581A1 (en) | 1994-05-20 | 1995-11-30 | Peter Palese | Treatment of influenza virus infection using antivirals that inhibit acylation/palmitylation of hemagglutinin |
| KR100618495B1 (ko) | 1998-10-06 | 2006-08-31 | 마크 아론 에말파브 | 섬유상의 진균성 숙주 영역에서의 형질전환 시스템:크리소스포륨속에서 |
| CZ303980B6 (cs) * | 2000-04-13 | 2013-07-31 | Dyadic International (Usa), Inc. | Expresi regulující sekvence nukleové kyseliny a produkty exprese v oblasti vláknitých plísní |
| US8506967B2 (en) * | 2003-07-11 | 2013-08-13 | Novavax, Inc. | Functional influenza virus like particles (VLPs) |
| CA2584249C (en) * | 2004-10-15 | 2013-01-08 | Neugenesis Corporation | Methods and compositions for combinatoral-based production of multivalent recombinant antigens |
| EP2102366A4 (en) | 2006-12-10 | 2010-01-27 | Dyadic International Inc | EXPRESSION AND HIGH-DROP SCREENING OF COMPLEX EXPRESSED DNA LIBRARIES IN FADENED MUSHROOMS |
| WO2008073490A1 (en) * | 2006-12-12 | 2008-06-19 | Carrington Laboratories Inc., | Purification of influenza viral antigens |
| WO2010107303A2 (en) * | 2009-03-16 | 2010-09-23 | Dyadic Nederland B.V. | New fungal production system |
| WO2010117786A1 (en) | 2009-03-30 | 2010-10-14 | Mount Sinai School Of Medicine Of New York University | Influenza virus vaccines and uses thereof |
| WO2010150982A2 (ko) | 2009-06-23 | 2010-12-29 | 한밭대학교 산학협력단 | 안전성이 뛰어난 인플루엔자 바이러스 백신용 재조합 헤마글루티닌 단백질 및 이를 함유하는 생분해성 ｐｌｇａ 미립자의 제조 방법 |
| WO2011091376A2 (en) | 2010-01-24 | 2011-07-28 | Biological Mimetics, Inc. | Immunogenic influenza composition |
| WO2013138357A1 (en) * | 2012-03-12 | 2013-09-19 | Codexis, Inc. | Cbh1a variants |
| US20130315955A1 (en) | 2012-04-13 | 2013-11-28 | Protein Sciences Corporation | Stability and potency of hemagglutinin |
| WO2016097369A1 (en) * | 2014-12-19 | 2016-06-23 | Sanofi Pasteur | Multimerization of recombinant protein by fusion to a sequence from lamprey |
| KR20180084135A (ko) | 2015-12-02 | 2018-07-24 | 바스프 에스이 | 감소된 clr2 활성을 갖는 사상 진균에서 단백질을 생산하는 방법 |
-
2018
- 2018-08-09 CA CA3073646A patent/CA3073646A1/en not_active Abandoned
- 2018-08-09 JP JP2020510102A patent/JP2020533966A/ja active Pending
- 2018-08-09 CN CN201880053773.2A patent/CN111315408A/zh active Pending
- 2018-08-09 WO PCT/IB2018/056003 patent/WO2019038623A1/en unknown
- 2018-08-09 KR KR1020207004901A patent/KR20200090143A/ko not_active Application Discontinuation
- 2018-08-09 AU AU2018319501A patent/AU2018319501A1/en not_active Abandoned
- 2018-08-09 EP EP18848087.5A patent/EP3672630A4/en active Pending
- 2018-08-09 US US16/640,483 patent/US11738080B2/en active Active
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2020
- 2020-02-09 IL IL272568A patent/IL272568A/en unknown
-
2023
- 2023-07-11 US US18/350,646 patent/US20230346913A1/en active Pending
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|---|---|
| US20230346913A1 (en) | 2023-11-02 |
| AU2018319501A1 (en) | 2020-04-02 |
| CA3073646A1 (en) | 2019-02-28 |
| WO2019038623A1 (en) | 2019-02-28 |
| US20200215183A1 (en) | 2020-07-09 |
| JP2020533966A (ja) | 2020-11-26 |
| EP3672630A1 (en) | 2020-07-01 |
| CN111315408A (zh) | 2020-06-19 |
| EP3672630A4 (en) | 2021-06-02 |
| IL272568A (en) | 2020-03-31 |
| US11738080B2 (en) | 2023-08-29 |
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