KR20220030217A - 개선된 백신 제형 - Google Patents
개선된 백신 제형 Download PDFInfo
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Abstract
원치 않은 면역 반응을 치료 또는 예방하는데 사용하기 위한 약학적으로 양립 가능한 산화 방지제, 상응하는 약학적 및 백신 조성물, 및 상응하는 임상적 및 생체 외 응용.
Description
본 발명은 자가 면역 질환 및 만성 조직 염증과 연관된 질환을 치료하는데 유용하거나 대체 요법에 사용되는 생물 펩타이드와 함께 투여되는 환원성 화합물 내에 농축된 새로운 백신 접종 조성물에 관한 것이다.
자가 면역 질환은 항체의 생산 및 자가 항원에 대한 림프구의 활성화를 특징으로 하며, 이는 표적 장기의 점진적인 기능 상실을 초래한다.
사이토카인을 표적화하는 항체의 비특이적 면역 억제 또는 투여에 기반을 둔 용법의 상대적 효능에 의해 뒷받침되는, 자가 면역 질환의 촉발(triggering) 및 유지에서의 자가 항체 및 자가 반응성 면역 세포의 병원성 역할에 대한 명확한 증거가 존재하지만, 이 같은 질환에 대한 치료책은 존재하지 않는다. 이는 꾸준히 증가하는 자가 면역의 발생과 결합된 것으로, 매우 유의한 미충족 의료(unmet medical need)를 구성하고 있다. 실제로, 전체 면역 시스템에 영향을 미치지 않으면서 자가 면역 반응을 억제하는 것이 가능할 수 있는 전략에 대한 요구가 많다.
현재, 자가 면역 반응을 선택적으로 억제하려는 시도로 한정된 수의 전략이 정의되어 있다. 그러나, 이들 접근법은 실시하기에 매우 복잡하고, 종종 천이 효과(transient effect)에만 연관되어 있으며, 이들의 상당한 유용성에 대한 증명이 종종 빠져 있다.
특허 출원 제WO2008/017517 A1호(면역원성 펩타이드 및 면역 질병에서의 이들의 용도)에는 펩타이드 및 방법이 기술되어 있으며, 여기서 산화/환원(redox) (티오리덕타아제) 모티프 C-X-X-C(여기서, C는 시스테인을 나타내고, X는 임의의 아미노산을 나타냄)를 함유하는 II형 MHC 에피토프는 세포 용해 특성을 갖는 에피토프-특이적 CD4+ T 세포를 유발하기 위해 사용된다. 활성화 APC 및 방관자 T 세포의 세포 용해에 의한 제거는 면역 질병, 및 특히 자가 면역 및 알레르기성 질환을 치료하는데 효과적인 것으로 여겨진다. 이들 펩타이드는 아미노산 링커의 유무에 따라 에피토프 서열의 양측 중 하나 상에 공유 아미드 연결(펩타이드 결합)에 의해 부착되는 티오리덕타아제 모티프를 함유한다. MHC II형 분자의 개방형 구조로 인해, 실제로 II형 제한 요소의 개열부(cleft) 내로 삽입된 서열에 의해 길이가 제한될 수 있는 경우에 허용 가능한 펩타이드보다 훨씬 긴 펩타이드를 사용하는 것이 가능하다.
명백한 자가 면역 질환 분야에서 확장하여, 만성 염증을 특징으로 하는 다수의 병리 조건이 존재하지만, 특이적 자가 항원은 확실하게 증명된 바는 없다. 일례가 비만이다. 지방 조직의 만성 염증은 이 같은 조건에서 현저하며, 최근 증거에 따르면 이 같은 염증이 억제 특성을 갖는 T 세포의 존재와 반비례 관계가 있는 것으로 강력히 시사된다.
자가 면역 질환 외에, (주입된) 생물 분자에 대한 면역 반응 또한 지금까지 전혀 해결되지 않은 주요 문제를 나타낸다.
T 림프구는 자가 면역 반응 또는 조직-특이적 염증이 시작할 때 여전히 주요 세포이다. 항원-특이적 T 세포는 이들이 활성화되는 제한 요소에 의해 정의되는 3개의 별도의 계통으로 나누어진다. CD4+ T 세포는 MHC II형 복합체에 의한 제시의 맥락에서 유발되고, CD8+ T 세포는 MHC I형 제시를 통해 활성화되며, 자연 살해 T(NKT) 세포는 MHC-유사 CD1 분자에 의한 제시에 의해 활성화된다.
항원 또는 이의 에피토프에 노출되는 경우, 고전적으로 3개의 단계, 즉 (1) APC에 의해 가공되고 MHC 분자의 맥락에서 제시된 바와 같이 항원 에피토프와 이의 항원-특이적 수용체(CD3)를 통한 T 세포 사이의 접촉(신호 1); (2) APC 표면에서 발현되는 동시 자극 신호와 T 세포 표면에서의 이들 개개의 리간드 또는 수용체 사이의 상호작용(신호 2); 및 (3) APC에 의한 사이토카인 및 케모카인을 포함한 용해성 인자의 생산(신호 3)으로 기술되는 시나리오로, 항원 제시 세포(APC)는 항원을 가공하고 이를 특이적 T 세포 활성화를 위한 이들의 표면에 노출시킨다.
자가 면역 질환 또는 조직-연관 만성 염증의 환경에서, 원치 않은 반응을 억제하는 것을 겨냥한 백신 접종 전략은 이들 신호를 고려한다. 요약하면, 고유 내성은 주로 보조제의 부재 하에 얻어지는 반면, 외인성 내성은 활성화가 일어나는 사이토카인 환경을 조작함으로써 얻어진다.
그러나, 이들 방법은 복합 질환을 치료하기에 충분한 정도로 만능이거나 강력하지 않다.
증가하는 수의 질환에 대한 요법제로서 투여되는 생물학제의 효능은 종종 면역 반응의 발생에 의해 제한되며, 그 결과 치료 효과의 중화, 소거율(clearance rate)의 증가 및/또는 다양한 과민 반응 모드(혈청병(serum sickness), 초과민 반응(anaphylactic reaction) 및 피부 발진을 포함함) 중 하나가 초래된다. 이 같은 반응을 방지하면 부작용이 줄어들고, 생물학제의 투여량이 감소하여 이의 비용이 감소하며, 보다 많은 환자가 생물학제에 따른 혜택을 얻게 된다.
WO2016/162495에는 자가 면역 질환을 치료하기 위해 자가 항원 펩타이드를 함유하는 글루타티온-코로네이티드 나노입자(glutathione-coronated nanoparticle)가 개시되어 있다. 그러나, 이러한 문헌으로부터 자명한 것은, 글루타티온이 이 같은 입자에 혼입되는 경우에 유리 -SH 기가 상기 입자와 반응하고 공유 연결에 의해 포매(embedding)되기 때문에, 더 이상 산화 방지제로서 적합하지 않다는 것이다.
문헌[Blessin N.C. et al., 2019, "Patterns of TIGIT Expression in Lymphatic Tissue, Inflammation, and Cancer" Disease Markers, vol. 2019, ISSN: 0278-0240]에는 조직 구획화의 기능 및 염증성 질환과 관련한 TIGIT 발현이 개시되어 있다. 그러나, 이 문헌에는 환원 조건 하에 특이 항원과의 접촉 이후에 T 림프구의 TIGIT 발현의 변화(즉, 보다 높은 표면 발현)가 개시되어 있지 않다.
문헌[Quinn J.F. et al., 2017, "Glutathione responsive polymers and their application in drug delivery systems" Polymer Chemistry]에는 글루타티온을 밀리몰 농도로 갖는 시스템이 개시되어 있지만, 백신 제형의 맥락에서의 시스템은 개시되어 있지 않다.
본 특허 출원은 원치 않은 면역 반응을 치료 또는 예방하는데 사용하기 위한 약학적으로 양립 가능한 산화 방지제에 관한 것이다.
바람직하게는, 이러한 약학적으로 양립 가능한 산화 방지제는 약학적 (주사 가능한) 펩타이드 분자를 더 포함하는 약학 조성물(또는 부분의 약학적 키트(kit of parts)) 내에 존재(혼입)하며, 이러한 약학적 (주사 가능한) 펩타이드 분자는 바람직하게는 자가 면역 및/또는 만성 염증성 질환과 연관된 항원, 에피토프, 항체, 대체 요법을 위한 생물학제(리소솜 효소, 사이토카인, 호르몬, 응고 인자)으로 이루어진 군으로부터 선택되며, 이때 에피토프는 대체 요법을 위한 생물학제의 일부이다.
약학적 펩타이드가 산화 방지제에 의해 영향을 받을 위험성이 있는 경우, 예를 들어 약학적 펩타이드가 중요한 이황화 가교(disulphide bridge)를 포함하는 경우, 약학적 산화 방지제는 약학적 펩타이드에 비가역적으로 영향을 주지 않도록 온화한 조건에서 혼입된다. 이를 달성하기 위한 하나의 방법은, 산화 방지제를 부분의 약학적 키트에 혼입시키는 것이고; 약학적 펩타이드 및 약학적 산화 방지제는 환자에 투여되기 직전에 혼합된다.
바람직하게는, 이러한 약학적으로 양립 가능한 산화 방지제(가능하게는, 약학적 펩타이드 분자가 구비됨)는 자가 면역 질환의 치료에 사용하거나 대체 요법에서 사용되는 펩타이드계 생물학제에 대한 내성을 유도하는데 사용하기 위한 것이다.
유리하게는, 이러한 약학적으로 양립 가능한 산화 방지제 또는 이러한 약학 조성물은 피하 경로에 의한 투여를 위한 것이다.
본 발명의 관련 양태는 펩타이드계 항원 및 약학적으로 양립 가능한 산화 방지제를 포함하는 백신 조성물이다.
바람직하게는, 이러한 백신 조성물은 백신 보조제, 보다 바람직하게는 박테리아성 지질 다당류, CpG 올리고뉴클레오타이드 및 수산화알루미늄으로 이루어진 군으로부터 선택되는 백신 보조제를 더 포함한다.
유리하게는, 이러한 백신 조성물(펩타이드계 항원 및 약학적으로 양립 가능한 산화 방지제를 포함함)은 자가 면역 질환, 바람직하게는 1형 당뇨병, 만성 염증성 탈수초성 신경병증(예를 들어, 다발성 경화증), 신경근 접합부 질환(예를 들어, 중증 근무력증), 갑상선 질환(예를 들어, 하시모토병(Hashimoto's disease) 및 그레이브병(Grave's disease)), 염증성 장 질환(크론병(Crohn's disease), 궤양성 직장염 및 셀리악병(celiac disease)을 포함함)으로 이루어진 군으로부터 선택되는 자가 면역 질환을 치료하는데 사용하기 위한 것이다.
바람직하게는, 이러한 백신 조성물은 국부 주사를 위한 것이다.
바람직하게는, 약학적으로 양립 가능한 산화 방지제(이러한 백신 조성물 내에 존재함)는 (국부) 주사 부위의 세포 외 기질에서 환원 조건을 부여하기에 충분한 양이다.
본 발명의 관련 양태는 CD4, CD8 및/또는 NKT인 억제성 항원-특이적 T 림프구를 유발하기 위한 생체 외 방법으로서, 이 방법은 환원 조건 하에 생체 외 T 림프구를 특이 항원과 접촉시키는 단계, 및 바람직하게는 TIGIT, DLL4 및 CTLA2로 이루어진 군으로부터 선택되는 분자의 표면 발현이 보다 높고/높거나 IL-13, IL-10, 프로스타글란딘 E2, TGF-베타, 암피레귤린(amphiregulin), MMP9 및 ADAM33으로 이루어진 군으로부터 선택되는 분자의 분비가 보다 높은 처리된 림프구를 선택하는 단계를 포함한다.
이에 반해, 본 발명은 또한 이 같은 생체 외 방법에 의해 바람직하게는 약학 조성물의 형태로 수득 가능한 T 림프구를 포함한다.
본 발명의 다른 관련 양태는, 바람직하게는 1형 당뇨병, 만성 염증성 탈수초성 (다발) 신경병증(예를 들어, 다발성 경화증), 신경근 접합부 질환(예를 들어, 중증 근무력증), 갑상선 질환(예를 들어, 하시모토병 및 그레이브병), 염증성 장 질환(크론병, 궤양성 직장염 및 셀리악병을 포함함), 비만, 또는 환자에 투여된 펩타이드성 생물 분자의 원치 않은 면역 반응으로 이루어진 군으로부터 선택되는, 포유류 환자에 영향을 미치는 (특이적 조직의) 자가 면역 질환 또는 만성 염증성 질환을 치료하기 위한 방법으로서, 이 방법은 산화 방지제 화합물(약학적으로 허용 가능한 산화 방지제 화합물)을 이러한 자가 면역 질환으로부터 설계된 에피토프 또는 이러한 펩타이드성 생물 분자와 함께 이러한 포유류 환자에게 국부 투여하는 단계를 포함한다.
본 발명의 다른 관련 양태는 이러한 생물 제제를 필요로 하는 환자에서 투여된 생물 제제에 대한 이상 면역 반응(adverse immune response)을 예방 및/또는 치료하기 위한 방법으로서, 이 방법은,
- 생물 제제에 대해 이상 면역 반응을 나타내는 환자 또는 생물 제제에 대해 이상 면역 반응을 나타낼 위험성 있는 환자를 확인하는 단계,
- 이러한 이상 면역 반응을 야기하거나 이를 야기할 위험성이 있는 생물 제제로부터 에피토프를 식별하는 단계,
- 산화 방지제 화합물을 포함하는 약학 조성물에 이러한 에피토프를 혼입시키는 단계,
- 산화 방지제 화합물을 포함하는 이러한 약학 조성물을 이러한 환자에게 투여하는 단계, 가능하게는 산화 방지제 화합물을 포함하는 이러한 약학 조성물을 이러한 환자에게 투여하는 단계를 반복하는 단계,
- 이러한 생물 제제를 이러한 환자에게 투여하는 단계를 포함한다.
바람직하게는, 백신 보조제가 상기 약학 조성물에 첨가된다.
바람직하게는, 이러한 (약학적으로-양립 가능한) 산화 방지제 화합물은 0.1 μM과 5 mM 사이, 바람직하게는 0.3 μM과 1 mM 사이, 보다 바람직하게는 1 μM과 0.3 mM 사이, 더욱 더 바람직하게는 3 μM과 100 μM 사이 또는 5 μM과 50 μM 사이로 이루어진 농도로 존재한다.
바람직하게는, 이러한 (약학적으로-양립 가능한) 산화 방지제 화합물은 N-아세틸 시스테인(이의 염을 포함함), 글루타티온, 티오레독신, 티오레독신 유도체, 글루타레독신, 페록시레독신 및 감마 인터페론-유도성 리소솜성 티올 리덕타아제(GILT) 및 이들의 혼합물로 이루어진 군으로부터 선택되며, 바람직하게는 이러한 산화 방지제는 NADH 및/또는 NADPH를 유리하게는 0.1 μM과 5 mM 사이, 바람직하게는 0.3 μM과 1 mM 사이, 보다 바람직하게는 1 μM과 0.3 mM 사이, 더욱 더 바람직하게는 3 μM과 100 μM 사이 또는 5 μM과 50 μM 사이로 이루어진 농도로 더 포함하며, 유리하게는 티오리덕타아제를 더 포함한다.
본 발명자는 특히 T 세포 계통 CD4, CD8 및 또는 NKT의 특이적 표적화에 의해 면역 반응을 미세 조정하기 위한 몇몇 방법을 개발해 왔다.
본 발명자는, 본 발명의 효능을 증강시키기 위해 본 발명자가 보여주었던, 펩타이드 및 심지어는 백신 보조제를 포함하는 국부 주사용 조성물에 (적어도 이황화 가교를 감소시키기에 충분히 강한) 환원성 화합물의 첨가가 자가 면역 및/또는 염증성 질환을 치료하거나 대체 요법을 위한 펩타이드 생물학제와 함께 사용하는데 특히 유리한 특이적 면역 보호를 유발하는 것을 허용한다는 예상치 못한 발견을 하였다. 대체 요법을 위한 생물 펩타이드(여기서, 보조제 부재) (및 이에 따른 산화 방지제)의 국부 주사는 피하에서 이루어질 수 있으며, 이는 놀라운 일이다: 심지어 보조제의 부재 하에서, 피하 공간에서의 항원 제시 세포(APC)의 높은 밀도로 인해이곳에서 면역 반응을 유발할 위험성은 실제 존재한다. 따라서, 본 발명은 환자에 대한 생물학제(펩타이드의 형태)의 보다 편리한 투여 및/또는 시간의 경과에 따른 개선된 효능을 허용하며, 부작용이 거의 없이 자가 면역 또는 염증성 질환을 특이적으로 치료하는 것을 추가로 허용한다.
따라서, 본 발명의 제1 양태는 원치 않은 면역 반응을 치료 또는 예방하는데 사용하기 위한 약학적으로 양립 가능한 산화 방지제(적어도 펩타이드의 이황화 가교를 감소시킬 수 있음)이다.
바람직하게는, 약학적으로 양립 가능한 산화 방지제는 0.1 μM과 5 mM 사이, 바람직하게는 0.3 μM과 1 mM 사이, 보다 바람직하게는 1 μM과 0.3 mM 사이, 더욱 더 바람직하게는 3 μM과 100 μM 사이, 또는 5 μM과 50 μM 사이로 이루어진 농도로 존재한다(환자에 투여된다).
산화 방지제는 바람직하게는 N-아세틸 시스테인, 글루타티온, 티오레독신, 티오레독신 유도체, 글루타레독신, 페록시레독신 및 감마 인터페론-유도성 리소솜성 티올 리덕타아제(GILT) 및 이들의 혼합물로 이루어진 군으로부터 선택된다.
바람직하게는, 산화 방지제 화합물의 효과를 증강시키기 위해, 추가로 NADH 및/또는 NADPH가 유리하게는 0.1 μM과 5 mM 사이, 바람직하게는 0.3 μM과 1 mM 사이, 보다 바람직하게는 1 μM과 0.3 mM 사이, 더욱 더 바람직하게는 3 μM과 100 μM 사이, 또는 5 μM과 50 μM 사이로 이루어진 농도로 존재한다. 가능하게는, 티오리덕타아제 효소는, 특히 NAD(P)H가 존재하는 경우에 추가로 첨가된다.
바람직하게는, 이러한 약학적으로 양립 가능한 산화 방지제는 약학적 펩타이드 분자를 더 포함하는 조성물 또는 부분의 약학적 키트 내에 존재하거나, 약학적 펩타이드 분자를 포함하는 이 같은 조성물과 함께 투여된다.
이러한 약학적 펩타이드 분자는 바람직하게는 (백신 접종, 예를 들어 원치 않은 면역 반응을 억제하기 위한 백신 접종에 사용하기 위한) 에피토프(예를 들어, 자가 항원, 또는 비만을 비롯한 만성 염증성 질환(예를 들어, 특이적 조직)에 연관된 항원), 항체, 대체 요법을 위한 생물학제(리소솜 효소, 사이토카인, 호르몬, 응고 인자 등)로 이루어진 군으로부터 선택된다.
펩타이드의 크기는 수개의 아미노산 내지 1,000개를 훨씬 초과하는 아미노산의 범위일 수 있다. 실제로, 본 발명의 펩타이드 중 일부는 에피토프(통상 7개 내지 50개 사이의 아미노산 범위의 크기를 의미함), 생물 분자(예를 들어, 응고 인자 VIII(2,300개의 아미노산의 크기임)) 또는 항체이다.
이러한 약학적으로 양립 가능한 산화 방지제 및/또는 이러한 약학 조성물은 유리하게는 피하 경로에 의한 (피하) 투여에 적합하고/하거나 적용된다.
이러한 약학적으로 양립 가능한 산화 방지제는 자가 면역 질환을 치료하는데 사용하거나 대체 요법에서 사용되는 펩타이드계 생물학제에 대한 내성의 유도에 사용하는데 유리하다.
이러한 접근법에 있어서, 유리하게는 내성 유도와 시너지 효과를 내기 위해 백신 보조제가 첨가될 수 있는데, 백신 보조제가 면역 반응을 증강시키는데 사용되기 때문에 이는 본 발명 없이는 역설적이다.
본 발명의 산화 방지제((주사 가능한) 약학 조성물)에 의해 치료되는 자가 면역 질환들 중에는, 1형 당뇨병, 만성 염증성 탈수초성 다발 신경병증 및 다발성 경화증, 신경근 접합부 질환(예를 들어, 중증 근무력증), 갑상선 질환(예를 들어, 하시모토병 및 그레이브병), 염증성 장 질환(크론병, 궤양성 직장염 및 셀리악병을 포함함)이 있다. 또한, 본 발명은 외상 또는 허혈성 사건(ischemic event) 이후의 원치 않은 염증성 상태뿐만 아니라, 항원에 대한 원치 않은 반응과 연관된 (특이적 조직의) 만성 염증(비만을 포함함)의 치료를 포함한다.
보다 일반적으로, 본 발명의 산화 방지제((주사 가능한) 약학 조성물)에 의해 치료되는 자가 면역 질환에는,
ㆍ 다체계 질환(multisystem disease): 류머티즘성 관절염, 다발성 근염 및 피부근염;
ㆍ 내분비 질환: 갑상선염, 1형 당뇨병, 부신염, 다발성 내분비 증후군, 뇌하수체염;
ㆍ 혈액 질환: 용혈성 빈혈, 혈소판 감소성 자반(thrombocytopenic purpura), 호중구 감소증, 재생 불량성 빈혈(aplastic anaemia), 항인지질 증후군, 응고 질병;
ㆍ 신경계 질환: 다발성 경화증, 말초 신경병증, 안질환, 내이 질환, 중증 근무력증;
ㆍ 장 질환: 크론병, 궤양성 장염, 셀리악병, 원발성 담즙성 간경변, 원발성 경화 담관염, 위염 및 악성 빈혈;
ㆍ 피부 질환: 수포창(pemphigus), 유천포창(pemphigoid), 탈모, 백반(vitiligo), 건선, 두드러기(urticaria);
ㆍ 신장 질환: 굿파스튜어병(Goodpasture's disease), ANCA-연관 사구체 신염;
ㆍ 심장 및 폐 질환: 심근염, 괴사성 동맥염(necrotizing arteritis), 혈관염;
ㆍ 부신 신생물 질환(paraneoplastic disease)이 있다.
이에 반해, 증가하는 수의 생물학제가 매우 다양한 질환에 사용되지만; 상당한 규모의 환자 집단에 의해, 치료 효능을 감소시키거나 이를 강제로 중단시키는, 이들 펩타이드성 생물학제에 대한 면역 반응이 조만간에 확립된다.
따라서, 본 발명자에 의한 발견의 결과로서, 본 발명의 산화 방지제는 이러한 생물 펩타이드 분자에 대한 환자의 이 같은 이상 면역 반응을 차단할 때 이 같은 생물학제와 시너지 효과를 낸다.
이러한 연관 양태에서, 본 발명은 심지어 피하 또는 근육 내 경로에 의해 투여되는 생물학제에 적용 가능하다.
산화 방지제와 생물학제의 조합은 2개의 방법으로 달성될 수 있다: 둘 모두를 함께 투여하거나, 먼저 이러한 생물학제에 대한 (확립된) 이상 면역 반응을 낮추기 위해 생물학제로부터의 에피토프(예를 들어, 7개의 아미노산만큼 짧은 에피토프 또는 20개 초과, 50개 초과, 100개 초과, 200개 초과, 500개 초과 또는 심지어 1,000개 초과의 아미노산보다 훨씬 더 큰 분자)가 산화 방지제와 함께 투여되는 백신 접종 단계, 및 그 이후에 (가능하게는 가능한 낮은 이상 면역 반응을 보장하기 위해 산화 방지제와 함께) 생물학제의 투여가 존재한다. 약학적 산화 방지제가 이황화 가교를 비가역적으로 분해하지 않도록 이를 갖는 생물학제에 대해 주의한다. 이를 피하기 위한 하나의 편리한 방법은, 환자에게 투여할 때까지 2개의 화합물을 (예를 들어, 부분의 키트의 2개의 상이한 바이얼 내에) 분리된 상태로 유지하는 것이다.
본 발명의 산화 방지제 화합물과 함께 사용될 생물학제, 즉 주사 가능한 생물학제 중에는,
ㆍ 인자 VIII, 인자 IX 및 스타필로키나아제(staphylokinase)를 비롯한 응고 또는 섬유 용해성 결함에 대한 대체 요법제;
ㆍ 성장 호르몬 또는 인슐린과 같은 호르몬;
ㆍ 인터페론, GM-CSF 및 G-CSF와 같은 사이토카인 및 성장 인자;
ㆍ 항-CD3, 항-CD4 및 항-CD20 항체, 항-사이토카인 또는 사이토카인 수용체 항체 및 항-관문 억제제(anti-checkpoint inhibitor)를 비롯한 면역 반응 조정용 항체;
ㆍ 신부전에서의 에리트로포이에틴(erythropoietin);
ㆍ 리소솜 축적병에 사용되는 리소솜 효소;
ㆍ 유전자 요법에 사용되는 바이러스 벡터;
ㆍ 유전자 편집에 사용되는 뉴클레아제가 있다.
본 발명의 다른 관련 양태는 펩타이드계 항원 및 약학적으로 양립 가능한 산화 방지제(적어도 이황화 가교를 감소시킬 수 있음)를 포함하는 백신 조성물이다.
이러한 백신 조성물은 유리하게는 자가 면역 질환(본원에서 상기에 언급된 바와 같음)의 치료 및/또는 만성 염증성 질환의 치료에 사용하기 위한 것으로, 이 만성 염증성 질환으로는 1형 당뇨병, 만성 염증성 탈수초성 (다발) 신경병증(예를 들어, 다발성 경화증), 신경근 접합부 질환(예를 들어, 중증 근무력증), 갑상선 질환(예를 들어, 하시모토병 및 그레이브병), 염증성 장 질환(크론병, 궤양성 직장염 및 셀리악병을 포함함)으로 이루어진 군으로부터 선택되는 특이적 조직의 만성 염증성 질환을 들 수 있다.
백신 조성물은 바람직하게는 국부 (피하) 주사를 위한 것이고; 이로 인해 약학적으로 양립 가능한 산화 방지제는 주사 부위의 세포 외 기질에서 환원 조건을 부여하기에 충분하고/하거나 면역 시냅스(immune synapse)에서 유리 티올 잔기를 유지하기(즉, 이황화 가교를 감소시키기)에 충분한 양이다.
바람직하게는, 약학적으로 양립 가능한 산화 방지제는 이러한 백신 조성물내에 0.1 μM과 5 mM 사이, 바람직하게는 0.3 μM과 1 mM 사이, 보다 바람직하게는 1 μM과 0.3 mM 사이, 더욱 더 바람직하게는 3 μM과 100 μM 사이, 또는 5 μM과 50 μM 사이로 이루어진 농도로 존재한다.
산화 방지제는 바람직하게는 글루타티온, 티오레독신, 티오레독신 유도체, 글루타레독신, 페록시레독신 및 감마 인터페론-유도성 리소솜성 티올 리덕타아제(GILT) 및 이들의 혼합물로 이루어진 군으로부터 선택된다.
바람직하게는, 본원에서 상기에 기술되어 있는 산화 방지제의 효과를 증강시키기 위해, NADH 및/또는 NADPH는 유리하게는 이러한 조성물 내에 0.1 μM과 5 mM 사이, 바람직하게는 0.3 μM과 1 mM 사이, 보다 바람직하게는 1 μM과 0.3 mM 사이, 더욱 더 바람직하게는 3 μM과 100 μM 사이, 또는 5 μM과 50 μM 사이로 이루어진 농도로 첨가된다.
가능하게는, 티오리덕타아제 효소는, 특히 NAD(P)H가 존재하는 경우에 이러한 조성물에 첨가된다.
바람직하게는, 이러한 백신 조성물은 백신 보조제를 더 포함한다.
본 발명의 맥락에서, "백신 보조제"란 용어는 바람직하게는 면역 세포의 수용체, 예를 들어 패턴 인식 수용체에 작용하는 분자를 지칭한다. 바람직한 백신 보조제들 중에는 결정(예를 들어, 수산화알루미늄 및 요소) 및 톨-유사 수용체(Toll-like receptor) 활성화제(예를 들어, 지질 다당류(LPS), CpG 올리고뉴클레오타이드, RNA(dsRNA 또는 심지어 DNA를 포함함))가 있다. 바람직하게는, 오일 및 유화제(종종 백신 접종에 사용됨)는 본 발명의 맥락에서 백신 보조제로서 간주되지 않는다. 보다 바람직하게는, 본 발명의 조성물은 유중수 또는 수중유 유화액의 형태가 아니다.
본 발명의 또 다른 양태는 CD4, CD8 및/또는 NKT인 억제성 항원-특이적 T 림프구를 유발하기 위한 생체 외 방법으로서, 이 같은 방법에 의해 수득 가능한 T 림프구 또는 T 림프구를 포함하는 약학 조성물뿐만 아니라 생체 외 T 림프구를 환원 조건 하에 특이적 항원에 접촉시키는 단계를 포함한다.
본 발명에 의해 (백신 접종을 통한 생체 내에서 또는 생체 외에서) 수득된 세포의 특성의 일례가 제공된다:
본 발명에 따른 백신 접종에 의해 수득된 CD4+ T 세포는 환원제 또는 이 같은 환원제의 조합의 첨가에 의해 FoxP3 전사 인자를 발현하지 않으며, 이들에게 하기 특성들 중 하나 또는 수개(바람직하게는 적어도 2개)를 부여하는 다수의 특징을 제시한다:
ㆍ IL-6, IL-1알파 및 LIF의 생산을 감소시키기 위해 단핵구에 작용하는 IL-13의 생산에 의한 염증의 감소;
ㆍ IL-1베타, TNF, IL-6 및 MCP-1과 같은 전염증성 사이토카인의 생산을 억제하는 전사 인자 ROR알파(NR1F1)의 발현;
ㆍ 아르기닌 1의 생산에 의해 조절 특성을 갖는 골수 세포의 유집(attraction) 및 컨디셔닝(conditioning);
ㆍ IL-10, 프로스타글란딘 E2 및 TGF-베타의 생산에 의한 조절 T 세포의 생성;
ㆍ 통상적인 T 세포 활성화를 억제할 때의 조절 T 세포의 기능을 위해 기질로서의 프로스타글란딘 E2의 제공;
ㆍ 암피레귤린의 생산에 의한 조직 복구에 참여;
ㆍ 항-염증, 전-신생혈관 생성(pro-angiogenesis) 및 조직 복구 특성을 갖는 MMP9 및 ADAM(예를 들어, ADAM33)과 같은 메탈로프로테이나아제(metalloproteinase)의 생산;
ㆍ 대식세포(M2 전환)에 작용하는 항-염증 특성 및 복구 기작 및 조직 재생의 활성화 특성을 갖는 키티나아제(chitinase)-유사 단백질(예를 들어, 키티나아제 3-유사-3) 또는 인간에서의 등가의 유전자 산물의 생산;
ㆍ 신경 발생(neurogenesis) 및 축삭돌기 신장(axonal extension)을 위한 전구 세포, 근육 세포 복원에서의 근세포 및 연골 재건에서의 연골세포의 분화가 증가된 메테오린(meteorin)의 생산.
또한, 이 같은 세포는 TIGIT, DLL4 및 CTLA2를 비롯한 억제 기능에 관련된 다수의 표면 분자를 발현한다.
실시예
실시예 1
만성 염증성 탈수초성 다발 신경병증(CIDP)의 치료를 위한 억제성 CD4+ T 세포의 유도
미엘린 단백질 제로(0)(myelin protein zero; 미엘린 0)는 말초 신경계에서 발현된다. 미엘린 0에 대한 자가 면역 반응성은 만성 염증성 탈수초성 다발 신경병증(CIDP)의 발병의 원인이 되며, 자가 반응성 CD4+ T 림프구와 관련된다.
NOD 품종의 마우스(주로 암컷)는 B7.2 KO 하위 품종에서 인간 병리상태를 모방하는 자발적 CIPD에 민감하지만, 능동 면역화가 일어나는 경우 수주 이내에 질환이 발병한다. CD4+ T 세포 활성화와 연관된 주요 미엘린 0 에피토프들 중 하나는 상기 단백질의 180번 내지 199번째 카르복시 말단의 끝에 위치한다.
서열: SSKRGRQTPVLYAMLDHSRS(서열 번호 1)를 갖는 펩타이드는 화학적 합성에 의해 생산된다.
백신 접종 제형은 수산화알루미늄과 혼합되고 50 μM의 글루타티온이 첨가된 서열 번호 1의 100 ㎍의 펩타이드를 이용하여 제조된다.
이러한 제형은 B7.2 KO 암컷 NOD 마우스 군에서 1주 간격으로 4회에 나눠 피하 주사한다. B7.2 KO 암컷 NOD 마우스 대조군은 수산화알루미늄이 혼합된 100 ㎍의 펩타이드로 주사한다.
마우스는 꼬리 축 늘어짐의 발생 및 마비의 정도 및 강도를 비롯한 신경병증의 징후에 대해 정규적으로 추적한다. 마지막으로 주사한지 6주 후, 신경병증의 징후에 대한 최종 평가를 실시하고, 신경병증의 조직학적 징후 및 T 림프구의 특성분석을 위해 마우스를 희생시킨다.
글루타티온을 함유하는 펩타이드 제형으로 백신 접종된 마우스는 신경병증의 어떠한 징후도 나타내지 않는 반면, 글루타티온의 첨가 없이 백신 접종된 대조군 마우스 100%는 이 같은 징후를 나타내는 것으로 나타난다.
포름알데히드에 고정한 후 조직 검사를 위해 좌골 신경의 절편을 준비한다. 헤마톡실린 및 에오신으로 염색한 이후 신경 말단의 끝 주변에 집중된 세포 침윤물을 관찰한다. 침윤물의 강도에 상응하는 0 내지 3의 점수가 확립된다. 항-CD3 항체를 이용한 염색에 의해 T 림프구가 식별된다. 놀랍게도, 글루타티온-함유 제형으로 처리된 마우스의 경우 세포 침윤에 대하여 평균 점수 1이 계산되는 반면, 글루타티온이 없는 백신 접종 제형으로 처리된 모든 마우스에서 점수 3이 확립되었다.
룩솔 패스트 블루(Luxol fast blue)로 염색된 절편에 대해 탈미엘린화(demyelination)를 평가하였다. 실제로, 글루타티온 군에서는 어떠한 미엘린 분절화도 관찰되지 않는 반면, 대조군 마우스에서 수득된 모든 신경 절편에서 이 같은 분절화가 관찰되었다.
각 군으로부터 CD4+ 비장세포 T 세포를 준비하고, 서열 번호 1의 펩타이드를 이용하여 활성화를 위한 배양에서 시험하였다. 대조군에서, IFN-γ의 생산 및 Tbet(Tbx21) 전사 인자의 발현을 특징으로 하는 바와 같이, 펩타이드에 특이적인 Th1 세포가 수득된다. 이에 반해, 글루타티온으로 처리된 마우스 군에서 수득된 T 세포는 효과기 기억 세포(CD62L(-)) 및 표면 마커(AREG(암피레귤린), TIGIT 및 DLL4를 포함함)의 발현을 특징으로 한다. 전사 수준에서, 세포는 Foxp3(-), IL-10+, IL-13+ 및 PGE2+이다.
따라서, 결론은, 백신 접종 제형 내로의 글루타티온의 첨가가 이들 세포가 항-염증성 특성 및 치유 특성을 발휘하는 조직에서 축적할 수 있는, 억제 및 항-염증 특성이 부여된 T 세포 개체군을 유발하기에 충분하다는 것이다.
실시예 2
1형 당뇨병 모델에서의 억제성 CD8+ T 세포의 유도
인간에서 1형 당뇨병은 인슐린 에피토프의 제시에 의해 활성화되고, 소도 베타 세포(islet beta cell)를 파괴하는 세포 독성 활성을 발휘하는 I형-제한 CD8+ T 세포의 존재를 특징으로 한다. 마우스(NOD 품종)에서의 1형 당뇨병의 자발적 모델이 본질적으로 II형-제한 CD4+ T 세포에 의해 유도됨에 따라, 난백 알부민이 래트 전인슐린(RIP)의 프로모터 하에 소도에서 발현되는 동물 모델이 사용되었다. 이어서, I형-제한 난백 알부민 에피토프에 대한 형질전환 수용체를 갖고 있는 OT-I 세포(따라서 CD8+ T 세포로서 분류함)를 사용하여 베타 세포 파괴 및 당뇨병을 유발하였다.
난백 알부민의 I형-제한 에피토프에 대한 CD8+ T 세포를 갖고 있는 OT-I C57BL/6 마우스를 에피토프(SIINFEKL, 서열 번호 2)를 투여하여 처리하였다. 시험군에서, 이 같은 투여는 수산화알루미늄 중의 100 ㎍의 펩타이드, 및 글루타티온(50 μM) 및 NADPH(50 μM)로 만들어진 환원성 화합물을 포함하는 제형을 이용하여 피하(SC) 경로에 의해 이루어졌다. 대조군에서는 글루타티온 및 NADPH 없이 동일한 절차가 사용되었다.
10일 간격으로 3회 주사 후, 마우스를 희생시키고, 개개의 비장세포 개체군을 준비하였다. 시험관 내에서 2회의 자극 이후에 CD8+ T 세포를 준비하고, 특성 분석하였다. 대조군으로부터 수득된 세포는 CD103의 발현 및 그랜자임 B(granzyme B) 및 퍼포린(perforin)에 대한 양성의 세포 내 염색을 비롯한 활성화 징후 및 세포 독성 잠재성을 나타낸다. 대조적으로, 글루타티온 및 NADPH의 존재 하에 면역화된 마우스로부터 수득된 세포는 이들의 억제 표현형을 나타내는 CTLA2 및 TIGIT와 같은 마커를 발현한다.
췌장 소도에서 OVA를 발현하는 RIP-OVA 마우스내에 CD8+ T 세포의 개개의 제제를 정맥 내(IV) 경로로 투여하였다(50 x 103개의 세포). 대조군으로부터의 CD8+ T 세포를 이용하여 재건된 모든 마우스는 혈당증으로 평가할 때 급격히 당뇨병에 걸렸다. 글루타티온 및 NADPH를 함유하는 제형으로 처리된 OT-1 마우스로부터의 CD8+ T 세포를 수용한 마우스 중 소수는 지연형 및 경미한 당뇨병에 걸렸다.
따라서, 결론은, 글루타티온과 NADPH의 혼합물의 존재 하에 CD8+ T 세포를 활성화하는 것이 인슐린 의존성 당뇨병의 맥락에서 이 같은 세포의 세포 독성 잠재성을 현저히 줄이기에 충분하다는 것이다.
실시예 3
마우스 모델에서 중증 근무력증의 예방
중증 근무력증(MG)은 점진적인 근육 쇠약 및 호흡곤란을 초래하는 신경근 접합부의 자가 면역 공격을 특징으로 한다. 자가 면역 반응의 체계에서 생산되는 병원성 항체는 니코틴성 아세틸콜린 수용체(nAchR), LRP4, Musk 및 아그린(agrin)을 포함하는 신경근 접합부의 다양한 성분을 대상으로 한다.
실험적으로, MG는 토르페도(Torpedo fish) 아세틸-콜린 수용체에 대항하여 생산된 항체가 래트 또는 마우스 수용체와 교차 반응하는 한 이 같은 수용체를 이용한 면역화에 의해 래트 또는 마우스에서 유도될 수 있다.
마우스 nAchR의 서열은 MHC-유사 CD1d 분자에 의해 제시되는 에피토프를 함유한다. 이 같은 에피토프는 서열: FAI VKF TKV LL(100-110: 서열 번호 3)을 갖는다.
C57BL/6 마우스 대조군은 10일 간격으로 복강 내(IP) 경로(NKT 세포가 풍부한 신체 구획)로 수산화알루미늄 상에 흡착된 100 ㎍의 펩타이드(서열 번호 3)를 2회 주사함으로써 처리한다. 제2군은 동일한 프로토콜에 따라 처리하지만, 제형 내에 GILT(감마 인터페론-유도성 리소솜성 티올 리덕타아제, 50 μM)를 첨가한다.
마지막 IP 주사 10일 후, 2개 군의 마우스를 프로이드 보조제(Freund's adjuvant)에서 유화된 20 ㎍의 토르페도 AchR로 피하 경로에 의해 면역화한다. 4주 후에 불완전 프로이드 보조제를 이용하여 1회의 부가적인 20 ㎍의 주사를 실시한다.
토르페도 AchR를 마지막으로 주사한 6주 후, 근육 쇠약의 첫 번째 징후가 관찰되며, 0(정상); 1(운동 후 쇠약, 움직임 감소); 2(휴식에도 쇠약) 또는 3(빈사, 탈수 및 마비 상태)의 점수에 따라 점수를 매긴다. 대조군 제형으로 처리된 마우스는 2와 3 사이에 있는 점수를 나타내는 반면, GILT를 함유하는 제형으로 처리된 마우스는 0 또는 1의 점수를 나타내는 것으로 나타난다.
AchR에 대한 특이적 항체의 평가를 위해, 관찰 기간(3개월, 3점에 도달한 즉시 희생된 마우스를 제외함)이 끝날 무렵에 개개의 마우스로부터 혈청을 수집하였다. 이는 폴리스티렌 플레이트를 코팅하기 위해 토르페도 AchR을 이용하여 ELISA에서 수행되며, 개개 혈청의 일련의 희석액과 함께 배양한다. GILT의 존재 하에 서열 번호 3의 펩타이드로 예비 면역화된 마우스 군에서의 12 ㎍의 총 IgG와 비교할 때, 대조군에서는 혈청 1 ㎖ 당 총 IgG 항체가 200 ㎍의 평균 농도로 관찰된다.
실시예 4
실험용 셀리악병의 맥락에서의 항-글리아딘 면역 반응의 예방
셀리악병은 글루텐의 성분인 글리아딘으로부터의 에피토프에 대한 자가 면역 반응으로부터 발생한다. 특히, 인간 DQ2.5 HLA 분자에 대한 높은 친화도를 부여하는 칼슘의 존재 하에, 알파-글리아딘 단편 알파-1/알파-2(QLQ PFP QPE LPY PQP QS; 서열 번호 4)의 57번 내지 73번의 에피토프가 트랜스글루타미나아제(transglutaminase)에 의해 4번 위치(밑줄 친 부분은 코어 서열임)에서 탈아미드화(deamidation)된다. 이는 셀리악병 증상 초기에 장 점막에서 II형-제한 T 세포의 활성화 및 염증을 초래한다.
이 같은 질환에 대한 간단한 마우스 모델은 존재하지 않는다. 그러나, 면역 병리학의 적어도 일부를 탐구하고 잠재적이고 신규한 요법을 규명하기에 적합한 몇몇 형질 전환 모델이 기술되어 있다. 글리아딘 에피토프에 대한 내성을 수득할 수 있는지를 증명하기 위해, 인간 DR3-DQ2.5 MHC 반수체형을 발현하는 형질 전환 마우스를 이용할 수 있다.
서열 번호 4의 펩타이드가 효소인 조직 트랜스글루타미나아제에 의해 자연적으로 탈아미드화되는 인간 상황을 모방하기 위해, 글루타민(Q)이 7번 위치에서 하전된 글루타메이트 잔기(E)로 교체되어 있는 펩타이드의 탈아미드화 버전이 사용된다.
서열 번호 5: QLQ PFP EPE LPY PQP QS
프로이드 보조제 내에서 유화되고 발바닥으로 주사되는 50 ㎍의 펩타이드(서열 번호 5)를 사용하여 C57BL/6 DR3-DQ2 형질 전환 마우스를 면역화시킨다. 2주 후에 불완전 프로이드 보조제 내 50 ㎍을 2번째로 주사하였다. 1개월 후, 마우스를 살해하고, T 세포 자극 검정을 위해 비장세포를 준비한다. 이를 위해, 특이적 항-CD4+ 항체를 이용하여 FACS 분류에 의해 비장세포 개체군으로부터의 CD4+ T 세포를 준비한다. 이어서, 면역화를 위해 사용되는 펩타이드(서열 번호 5)가 적재된 수지상 세포의 존재 하에 이들 세포를 배양하고, 배양 1주 후에 펩타이드 특이적 CD4+ T 세포의 존재를 검출한다. 제2 마우스 군을 동일한 방식으로 처리하지만, 면역화 기간이 끝날 무렵에 귀 피부에 펩타이드를 주사하고, 3일 후에 국부적 팽창 반응의 발달을 지연형 과민 반응의 존재로서 판독한다.
먼저, 마우스 실험군을 수산화알루미늄 및 100 μM의 글루타티온과 혼합된 100 ㎍을 사용하여 서열 번호 5의 펩타이드를 피하 주사함으로써 처리한다. 10일 간격으로 이 주사를 4회 실시한다. 마지막 주사 15일 후, 대조군에 대해 발바닥 면역화 절차를 개시한다. 비장세포로부터의 CD4+ 세포는 서열 번호 5의 펩타이드의 탈아미드화 버전의 존재 하에 증식하지 않는 것으로 나타난다. 더욱이, 지연형 반응에 대한 시험은 이 군에서 음성으로 유지된다.
따라서, 결론은, 강력한 보조제를 이용한 활성의 전신 (풋패스) 면역화의 맥락에서도, 환원제의 존재 하에 글리아딘 에피토프를 이용한 면역화가 이 같은 에피토프에 대한 내성을 유도하기에 충분하다는 것이다.
실시예 5
피하 경로에 의해 투여된 응고 인자 VIII에 대한 면역화의 방지
응고 인자 VIII에 대한 항체의 발생이 여전히 혈우병 A 환자의 치료에서 주요 부작용으로 여겨진다. 이 같은 항체는 인자 VIII(억제제 항체로서 지칭됨)의 기능 활성을 중화시키는 잠재성을 가지며, 이로 인해 환자는 심각한 출혈 위험성에 처하게 된다.
선천성 및 적응성 면역 반응 둘 모두를 특징으로 하는 바와 같이, 인자 VIII은 면역원성이다. 특허 WO2012/069575에는 MHC-유사 CD1d 분자에 의해 제시되는 인자 VIII 에피토프의 결실에 의해 억제제 항체를 유도하는 위험성이 제거되는 방법이 개시되어 있다.
그러나, 혈우병 A 환자의 치료에 있어서 최근 개발에서는 정맥 내 대신 피하 투여를 위한 인자 VIII 제형이 다루어지고 있다. 피하 경로는 대식세포 및 수지상 세포를 비롯한 고밀도의 항원 제시 세포의 존재로 인해 IV 경로보다 더 면역원성이다.
인간 재조합(r) 인자 VIII의 페길화 형태(pegylated form)는 총 6주 동안에 매주 2회 100 IU/㎏의 투여량으로 인자 VIII KO 마우스내 피하 투여용으로 사용되었다.
혈우병 A 마우스 대조군은 인자 VIII(유전자은행 등록 번호(GenBank accession reference): AAA52484.1; 서열 번호 6)의 제제를 투여 받은 반면, 시험군은 200 μM의 글루타티온이 첨가된 동일한 제제를 투여 받았다. 6주 후, 마우스를 출혈시켜 고상 ELISA에 의해 항-인자 VIII 항체의 농도를 측정하였으며, 상업적으로 이용 가능한 발색 검정(chromogenic assay)을 이용하여 억제제의 농도를 측정하였다. 항체에 대한 결과는 인자 VIII-특이적 단클론성 항체의 일련의 희석에 의해 수득된 형광 수준을 참고하여 확립된 1 ㎖ 당 임의의 단위로 표시된다. 억제제 검정에 대한 결과는 1 ㎖ 당 베테스다(Bethesda) 단위로 표시된다.
r인자 VIII로 주사된 마우스는 항-인자 VIII 항체를 평균 750 ㎍/㎖로 생산하고, 억제제를 1,200 BU/㎖의 평균 역가로 생산하는 것으로 나타난다. 글루타티온-함유 인자 VIII 제제를 이용하여 처리된 마우스는 평균 150 ㎍/㎖의 항-인자 VIII 항체 및 억제제에 대해 225 BU/㎖의 평균 역가를 나타낸다.
따라서, 결론은, 인자 VIII 제형에 환원성 화합물을 첨가하는 것이 인자 VIII-특이적 면역 반응을 유의하게 감소시키기에 충분하다는 것이다. 인자 VIII에 대한 면역 반응이 특이적 NKT 세포의 후속적인 활성화를 포함하므로, 추가적인 결론은 환원성 화합물이 특이적 NKT 세포 활성화를 방지하는 능력을 갖는다는 것이다.
실시예 6
마우스 모델에서 TNF-알파에 대한 항체의 독성에 대한 장기간 평가
종양 괴사 인자(TNF) 알파에 대한 항체는 흔히 류머티즘성 관절염과 같은 다수의 만성 염증성 질환(중쇄 Fab 단편: 서열 번호 7; 경쇄 Fab 단편: 서열 번호 8)의 치료에 사용된다. 대부분의 환자에서 효능이 있지만, 이들 항체의 반복 투여에 의해 감염 및 종양 발병의 위험이 증가하게 된다. 현재, 그 중에서도 상업적으로 이용 가능한 항-TNF-알파 항체가 TNF-알파의 모든 활성을 억제하지 못하고 여전히 조절 T 세포 활성화를 위해 요구되는 TNF 수용체 2(TNFR2)에 대한 TNF의 결합을 억제한다는 사실로 인해, 이 같은 합병증이 발병할 위험성이 있는 환자를 확인할 가능성이 없다. 게다가, TNF-알파의 농도는 항-항체의 존재 또는 부재 하에 TNF-알파/항-TNF-알파 복합체가 지속됨에 따라 환자들 사이에서 상당한 변화를 보인다.
항-TNF 알파 항체 투여의 장기간 결과(단일 표적 상의 TNF 알파를 평가하기 위한 이의 유전자 조작 순응성을 포함함)를 예측하는 것이 가능한 동물 모델이 많은 도움이 될 것이다. 그러나, 동물에서 항-TNF 알파 항체를 투여하면 곧이어 임의의 장기간 효과 평가를 방해하는 면역 반응이 일어난다. 이는 임상적 이용을 모방한 피하 투여에 특히 관련된다.
C57BL/6 품종의 마우스를 50 ㎍의 항-TNF-알파 항체로 주사하여 처리하고, 주사는 1주 간격으로 4회 이루어졌다. 대조군은 임상에서 사용되는 항체 제형을 투여 받는 반면, 제2 마우스 군은 동일한 제형을 투여받지만 각각의 주사에 50 μM 글루타티온이 첨가된다.
마지막으로 주사한 4주 후, 글루타티온-함유 제형에 의해 처리된 마우스 군에서 TNF-알파 및 항-TNF-알파 항체의 순환성 복합체의 수준이 높은 수준(평균 200 ng/㎖)으로 남아 있는 반면, 대조군에서는 TNF-알파/항-TNF-알파 항체가 현저히 낮은 농도(평균 7 ng/㎖)로 측정되는 것으로 나타난다.
이러한 결과는 대조군에서 항-항체의 유도에 의해 혈류로부터 항-TNF-알파/TNF-알파 복합체가 신속하게 소거된다는 것을 보여주는 것으로 해석된다. 이러한 결론은, 플레이트를 코팅하기 위해 항-TNF-알파 항체를 사용하는 고상 ELISA에서 항-항체를 검출한 후, 마우스 혈청을 희석하고 인간 항-TNF-알파 항체에 결합된 마우스 항체를 검출함으로써 확인된다. 글루타티온 제형을 투여 받은 군에서 1 ㎖ 당 평균 6의 임의 단위가 확인되며, 대조군에서는 1 ㎖ 당 평균 145의 단위가 계산된다.
따라서, 항-TNF-알파 항체 제형에 대한 환원성 화합물의 첨가는 이의 면역원성을 현저히 감소시키는데 효과적이다.
SEQUENCE LISTING
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Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val
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Glu Thr Phe Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn
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Ser Leu Ser Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly
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Asp Met Val Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu
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Leu Ala Ala Gly Thr Asp Asn Thr Ser Ser Leu Gly Pro Pro Ser Met
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Ser Asp Thr Glu Phe Lys Lys Val Thr Pro Leu Ile His Asp Arg
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Ser Asn Lys Thr Thr Ser Ser Lys Asn Met Glu Met Val Gln Gln
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Lys Lys Glu Gly Pro Ile Pro Pro Asp Ala Gln Asn Pro Asp Met
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Ser Phe Phe Lys Met Leu Phe Leu Pro Glu Ser Ala Arg Trp Ile
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Gln Arg Thr His Gly Lys Asn Ser Leu Asn Ser Gly Gln Gly Pro
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Ser Pro Lys Gln Leu Val Ser Leu Gly Pro Glu Lys Ser Val Glu
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Gly Gln Asn Phe Leu Ser Glu Lys Asn Lys Val Val Val Gly Lys
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Gly Glu Phe Thr Lys Asp Val Gly Leu Lys Glu Met Val Phe Pro
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Ser Ser Arg Asn Leu Phe Leu Thr Asn Leu Asp Asn Leu His Glu
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Asn Asn Thr His Asn Gln Glu Lys Lys Ile Gln Glu Glu Ile Glu
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Lys Lys Glu Thr Leu Ile Gln Glu Asn Val Val Leu Pro Gln Ile
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His Thr Val Thr Gly Thr Lys Asn Phe Met Lys Asn Leu Phe Leu
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Leu Ser Thr Arg Gln Asn Val Glu Gly Ser Tyr Glu Gly Ala Tyr
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Ala Pro Val Leu Gln Asp Phe Arg Ser Leu Asn Asp Ser Thr Asn
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Arg Thr Lys Lys His Thr Ala His Phe Ser Lys Lys Gly Glu Glu
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Glu Asn Leu Glu Gly Leu Gly Asn Gln Thr Lys Gln Ile Val Glu
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Lys Tyr Ala Cys Thr Thr Arg Ile Ser Pro Asn Thr Ser Gln Gln
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Asn Phe Val Thr Gln Arg Ser Lys Arg Ala Leu Lys Gln Phe Arg
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Leu Pro Leu Glu Glu Thr Glu Leu Glu Lys Arg Ile Ile Val Asp
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Asp Thr Ser Thr Gln Trp Ser Lys Asn Met Lys His Leu Thr Pro
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Ser Thr Leu Thr Gln Ile Asp Tyr Asn Glu Lys Glu Lys Gly Ala
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Ile Thr Gln Ser Pro Leu Ser Asp Cys Leu Thr Arg Ser His Ser
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Ile Pro Gln Ala Asn Arg Ser Pro Leu Pro Ile Ala Lys Val Ser
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Ser Phe Pro Ser Ile Arg Pro Ile Tyr Leu Thr Arg Val Leu Phe
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Gln Asp Asn Ser Ser His Leu Pro Ala Ala Ser Tyr Arg Lys Lys
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Asp Ser Gly Val Gln Glu Ser Ser His Phe Leu Gln Gly Ala Lys
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Lys Asn Asn Leu Ser Leu Ala Ile Leu Thr Leu Glu Met Thr Gly
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Asp Gln Arg Glu Val Gly Ser Leu Gly Thr Ser Ala Thr Asn Ser
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Val Thr Tyr Lys Lys Val Glu Asn Thr Val Leu Pro Lys Pro Asp
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Leu Pro Lys Thr Ser Gly Lys Val Glu Leu Leu Pro Lys Val His
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Ile Tyr Gln Lys Asp Leu Phe Pro Thr Glu Thr Ser Asn Gly Ser
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Pro Gly His Leu Asp Leu Val Glu Gly Ser Leu Leu Gln Gly Thr
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Glu Gly Ala Ile Lys Trp Asn Glu Ala Asn Arg Pro Gly Lys Val
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Pro Phe Leu Arg Val Ala Thr Glu Ser Ser Ala Lys Thr Pro Ser
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Lys Leu Leu Asp Pro Leu Ala Trp Asp Asn His Tyr Gly Thr Gln
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Ile Pro Lys Glu Glu Trp Lys Ser Gln Glu Lys Ser Pro Glu Lys
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Thr Ala Phe Lys Lys Lys Asp Thr Ile Leu Ser Leu Asn Ala Cys
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Glu Ser Asn His Ala Ile Ala Ala Ile Asn Glu Gly Gln Asn Lys
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Pro Glu Ile Glu Val Thr Trp Ala Lys Gln Gly Arg Thr Glu Arg
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Leu Cys Ser Gln Asn Pro Pro Val Leu Lys Arg His Gln Arg Glu
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Ile Thr Arg Thr Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp Tyr
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Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile
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Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys
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Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr
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Gly Met Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser
1730 1735 1740
Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr
1745 1750 1755
Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu
1760 1765 1770
His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp
1775 1780 1785
Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser
1790 1795 1800
Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly
1805 1810 1815
Ala Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr
1820 1825 1830
Tyr Phe Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu
1835 1840 1845
Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu
1850 1855 1860
Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His
1865 1870 1875
Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val Thr Val Gln
1880 1885 1890
Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp
1895 1900 1905
Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys Asn
1910 1915 1920
Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His
1925 1930 1935
Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met
1940 1945 1950
Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser
1955 1960 1965
Asn Glu Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr
1970 1975 1980
Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr
1985 1990 1995
Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly
2000 2005 2010
Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His Ala Gly
2015 2020 2025
Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro
2030 2035 2040
Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala
2045 2050 2055
Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His
2060 2065 2070
Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser
2075 2080 2085
Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile
2090 2095 2100
Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser
2105 2110 2115
Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr
2120 2125 2130
Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe Gly Asn
2135 2140 2145
Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile
2150 2155 2160
Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg
2165 2170 2175
Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys
2180 2185 2190
Ser Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln
2195 2200 2205
Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser
2210 2215 2220
Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp
2225 2230 2235
Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe
2240 2245 2250
Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly Val Lys
2255 2260 2265
Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser
2270 2275 2280
Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys
2285 2290 2295
Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val
2300 2305 2310
Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His
2315 2320 2325
Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu
2330 2335 2340
Gly Cys Glu Ala Gln Asp Leu Tyr
2345 2350
<210> 7
<211> 228
<212> PRT
<213> artificial sequence
<220>
<223> Heavy chain Fab fragment anti TNF alpha
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Val Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Gly Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Met Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Leu Ser Asn Arg Leu Ser Gly Gly Gly Thr Phe Asp Ile
100 105 110
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Ser Ala Ser Ala
115 120 125
Pro Thr Leu Phe Pro Leu Val Ser Cys Glu Asn Ser Pro Ser Asp Thr
130 135 140
Ser Ser Val Ala Val Gly Cys Leu Ala Gln Asp Phe Leu Pro Asp Ser
145 150 155 160
Ile Thr Phe Ser Trp Lys Tyr Lys Asn Asn Ser Asp Ile Ser Ser Thr
165 170 175
Arg Gly Phe Pro Ser Val Leu Arg Gly Gly Lys Tyr Ala Ala Thr Ser
180 185 190
Gln Val Leu Leu Pro Ser Lys Asp Val Met Gln Gly Thr Asp Glu His
195 200 205
Val Val Cys Lys Val Gln His Pro Asn Gly Asn Lys Glu Lys Asn Val
210 215 220
Pro Leu Pro Val
225
<210> 8
<211> 213
<212> PRT
<213> Artificial sequence
<220>
<223> Light chain Fab fragment anti TNF alpha
<400> 8
Asp Ile Glu Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Leu Asn Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Ala Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Pro Trp Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
Claims (15)
- 원치 않은 면역 반응을 치료 또는 예방하는데 사용하기 위한 약학적으로 양립 가능한 산화 방지제.
- 제1항에 있어서, 약학적 펩타이드 분자를 추가로 포함하는 약학 조성물 내에 존재하거나 부분의 약학적 키트 내에 혼입되며, 상기 약학적 펩타이드 분자는 바람직하게는 자가 면역 및/또는 만성 염증성 질환과 연관된 항원, 주사 가능한 생물학제, 및 상기 생물학제의 일부인 에피토프로 이루어진 군으로부터 선택되는 것인 약학적으로 양립 가능한 산화 방지제.
- 제1항 또는 제2항에 있어서, 바람직하게는 백신 보조제와 함께 자가 면역 질환을 치료하거나, 펩타이드계 생물학제에 대한 내성을 유도하는데 사용하기 위한 것인 약학적으로 양립 가능한 산화 방지제.
- 제1항, 제2항 또는 제3항에 있어서, 피하 경로에 의한 투여용인 것인 약학적으로 양립 가능한 산화 방지제 또는 약학 조성물 또는 부분의 키트.
- 펩타이드계 항원 및 약학적으로 양립 가능한 산화 방지제를 포함하는 백신 조성물.
- 제5항에 있어서, 바람직하게는 1형 당뇨병, 만성 염증성 탈수초성 신경병증(예를 들어, 다발성 경화증), 신경근 접합부 질환(예를 들어, 중증 근무력증), 갑상선 질환(예를 들어, 하시모토병(Hashimoto's disease) 및 그레이브병(Grave's disease)), 염증성 장 질환(크론병(Crohn's disease), 궤양성 직장염 및 셀리악병(celiac disease)을 포함함)으로 이루어진 군으로부터 선택되는 자가 면역 질환을 치료하는데 사용하기 위한 것인 백신 조성물.
- 제5항 또는 제6항에 있어서, 국부 주사용이며, 상기 약학적으로 양립 가능한 산화 방지제가 주사 부위의 세포 외 기질에서 환원 조건을 부여하기에 충분한 양인 것인 백신 조성물.
- 제5항 내지 제7항 중 어느 한 항에 있어서, 바람직하게는 박테리아성 지질 다당류, CpG 올리고뉴클레오타이드, 이중 가닥 RNA 및 수산화알루미늄으로 이루어진 군으로부터 선택되는 백신 보조제를 더 포함하는 것인 백신 조성물.
- CD4, CD8 및/또는 NKT인 억제성 항원-특이적 T 림프구를 유발하기 위한 생체 외 방법으로서,
환원 조건 하에 생체 외 T 림프구를 특이 항원과 접촉시키는 단계;
바람직하게는 TIGIT, DLL4 및 CTLA2로 이루어진 군으로부터 선택되는 분자의 표면 발현이 보다 높고/높거나 IL-13, IL-10, 프로스타글란딘 E2, TGF-베타, 암피레귤린(amphiregulin), MMP9 및 ADAM33으로 이루어진 군으로부터 선택되는 분자의 분비가 보다 높은 처리된 림프구를 선택하는 단계를 포함하는 것인 억제성 항원-특이적 T 림프구를 유도하기 위한 생체 외 방법. - 제9항의 방법에 의해 수득 가능한 T 림프구.
- 제10항의 T 림프구를 포함하는 약학 조성물.
- 제1항 내지 제11항 중 어느 한 항에 있어서, 0.1 μM과 5 mM 사이, 바람직하게는 0.3 μM과 1 mM 사이, 보다 바람직하게는 1 μM과 0.3 mM 사이, 더욱 더 바람직하게는 3 μM과 100 μM 사이, 또는 5 μM과 50 μM 사이로 이루어진 농도로 존재하는 것인 산화 방지제.
- 제1항 내지 제12항 중 어느 한 항에 있어서, N-아세틸 시스테인, 글루타티온, 티오레독신, 티오레독신 유도체, 글루타레독신, 페록시레독신 및 감마 인터페론-유도성 리소솜성 티올 리덕타아제(GILT) 및 이들의 혼합물로 이루어진 군으로부터 선택되는 것인 산화 방지제.
- 제13항에 있어서, 유리하게는 0.1 μM과 5 mM 사이, 바람직하게는 0.3 μM과 1 mM 사이, 보다 바람직하게는 1 μM과 0.3 mM 사이, 더욱 더 바람직하게는 3 μM과 100 μM 사이, 또는 5 μM과 50 μM 사이로 이루어진 농도로 NADH 및/또는 NADPH를 더 포함하는 것인 산화 방지제.
- 제13항 또는 제14항에 있어서, 티오리덕타아제를 더 포함하는 것인 산화 방지제.
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EP19182807.8 | 2019-06-27 | ||
EP19182807.8A EP3756648A1 (en) | 2019-06-27 | 2019-06-27 | Improved vaccine formulations |
PCT/EP2020/068270 WO2020260699A1 (en) | 2019-06-27 | 2020-06-29 | Improved vaccine formulations |
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CA2387666A1 (en) * | 1999-10-27 | 2001-05-03 | Innogenetics N.V. | Redox reversible hcv proteins with native-like conformation |
DE10306075A1 (de) * | 2003-02-06 | 2004-08-19 | Hans-Knöll-Institut für Naturstoff-Forschung e.V. | Neue Antioxidantien, Verfahren zu deren Herstellung und deren Verwendung |
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BR112013010926A2 (pt) * | 2010-11-01 | 2016-08-23 | Univ Technology Sidney | agentes imunomoduladores e seus usos |
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