KR20180116925A - 암 또는 면역 질환의 예방 또는 치료용 약학 조성물 - Google Patents
암 또는 면역 질환의 예방 또는 치료용 약학 조성물 Download PDFInfo
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- KR20180116925A KR20180116925A KR1020170049856A KR20170049856A KR20180116925A KR 20180116925 A KR20180116925 A KR 20180116925A KR 1020170049856 A KR1020170049856 A KR 1020170049856A KR 20170049856 A KR20170049856 A KR 20170049856A KR 20180116925 A KR20180116925 A KR 20180116925A
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Abstract
본 발명은 암 또는 면역 질환의 예방 또는 치료용 약학 조성물 및 세포 치료제에 관한 것으로, Lrig-1+ 면역세포를 포함하는 약학 조성물 및 세포 치료제는 면역세포를 특이적으로 선별하여 암 또는 면역 질환을 효과적으로 예방 또는 치료할 수 있다.
Description
본 발명은 암 또는 면역 질환의 예방 또는 치료용 약학 조성물에 관한 것이다.
모든 정상 개체에 있어서 가장 중요한 특성 중 하나는, 자기(self)를 구성하고 있는 항원 물질에 대해서는 해롭게 반응하지 않는 반면, 자기가 아닌(non-self)항원에 대해서는 이를 인식하고 제거할 수 있는 능력을 갖는 것이다. 이처럼 자기 항원에 대한 생체의 무반응을 면역학적 무반응성(immunologic unresponsiveness) 또는 관용(tolerance)이라 한다. 자기 관용은 자기 항원의 특이적인 수용체를 가지고 있을지 모르는 림프구를 제거함으로써, 또는 자기 항원에 접한 후 스스로 반응하는 기능이 불활성화됨으로써 발생한다. 자기 관용을 유도하거나 계속 유지하는데 있어서 문제가 생기게 되면 자기 항원에 대하여 면역반응이 일어나게 되고, 이로 인하여 초래되는 질환을 자가면역질환(autoimmune disease)이라 한다.
상기 자가면역질환의 치료를 위하여, 970년대 초 Gershon에 의해 고식적 T 세포(conventional T cells)의 효과 기능(effector function)을 제어 및 억제할 수 있는 T 세포의 존재 가능성이 있는 억제 T 세포라는 개념을 도입하여, 처음으로 제시된 이래(R. K. Gershon and K. Kondo, Immunology, 1970, 18: 723-37), 면역학의 많은 분야에서 조절 T 세포의 생물학적 특성 및 기능을 규명하기 위한 연구가 이루어져 왔다.
이에, 상기 조절 T 세포(Treg)는 과다한 염증과 면역반응의 발생을 자연적으로 방지하는 중요한 역할을 하지만, 자가면역질환과 만성염증질환이 발생하는 경우 조절 T 세포의 기능과 숫자가 현저하게 줄어드는 것이 보고되었다. 따라서, 면역 질환과 염증 질환이 있는 환자의 경우, 조절 T 세포가 정상적인 수준으로 생성되는 것이 중요하며, 이는 상기 질환의 치료법 중 하나가 될 수 있다.
현재까지 조절 T 세포에 특이적으로 존재하는 유전자 및 단백질에 대한 연구가 진행되어, CD25, CTLA4, CD62L, CD38, CD103, GITR 및 CD45RB 등의 물질이 표지 물질에 해당할 수 있음이 제시되어 왔지만, 아직 조절 T 세포만을 단독으로 표적화 할 수 있는 유전자 및 단백질은 존재하지 않는다.
한편, 면역관련 질환 중 자가면역질환의 치료는 자가면역반응을 조절하고, 신체의 손상된 면역기능을 회복시키는 것을 목적으로 이루어지며, 이는 다양한 자가면역질환의 종류에 따라 치료의 방법에 차이가 있다. 예를 들어, 혈액에 문제가 생긴 경우에는 수혈을 하고, 뼈, 관절 혹은 근육에 문제가 발생한 경우에는 운동 혹은 다른 기능적인 치료를 받아야 한다. 또한, 면역 체계의 반응을 조절하기 위해서는 약물이 처방되고 있다. 하지만, 상기 약물인 면역 억제약이라고 불리우는 코르티코스테로이드(corticosteroids) 약물인 프레드니손(prednisone)과 비스테로이드성(nonsteroid) 약물인 시클로포스파미드(cyclophosphamide), 아자티오프린(azathioprine), 및 타크로리무스(tacrolimus) 등은 안정성과 효용성의 문제가 존재하여 면역관련 질환의 치료제 개발이 시급한 실정이다.
본 발명의 일 목적은 Lrig-1+ 면역세포를 포함하는 면역관련 질환 예방 또는 치료용 약학 조성물을 제공하는 것이다.
본 발명의 다른 목적은 Lrig-1+ 면역세포를 포함하는 면역관련 질환 예방 또는 치료용 세포 치료제를 제공하는 것이다.
본 발명의 또 다른 목적은 Lrig-1+ 면역세포를 포함하는 세포 치료제의 제조방법을 제공하는 것이다.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당 업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.
본 발명자들은 면역세포, 특히 조절 T 세포의 표면에 특이적으로 존재하는 Lrig-1 단백질을 발견하고, 상기 단백질의 항원 결정 부위를 선별하여 상기 Lrig-1 단백질에 특이적으로 결합할 수 있는 단일 클론 항체를 제작하여, Lrig-1 단백질이 발현되는 면역세포, 특히 조절 T 세포를 선택적으로 선별하여 이를 효과 T 세포(effector T cell)과 공동 배양 하는 경우 효과 T 세포의 활성을 억제 시킬 수 있음을 발견하여 본 발명을 완성하게 되었다.
본 발명의 일 구현 예에서는 Lrig-1+ 면역세포를 포함하는 면역관련 질환 예방 또는 치료용 약학 조성물을 제공한다. 본 발명의 목적상 상기 Lrig-1+ 면역세포는 조절 T 세포의 표면에 Lrig-1 단백질이 존재하는 것일 수 있고, 더욱 바람직하게는 상기 조절 T 세포는 CD4+ T 세포일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서, 상기 “Lrig-1+ 면역세포”란, 표면에 Lrig-1 단백질이 발현되는 면역세포를 의미한다. 상기 Lrig-1+ 면역세포는 목적하는 개체의 비장 또는 혈액에서 수득한 면역세포를 Lrig-1 단백질에 특이적인 항체를 이용하여 염색한 뒤, 세포 분류기를 통해 수득한 세포일 수 있다. 바람직하게는, 상기 세포의 수를 증가시키기 위하여 통상의 방법에 의해 세포 외(In vitro) 배양을 수행할 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 Lrig-1 단백질은 서열번호 1 또는 3으로 표시되는 아미노산 서열을 포함할 수 있으나, 이에 제한되는 것은 아니다.
또한, 본 발명에서 상기 Lrig-1 단백질은 서열번호 2 또는 4로 표시되는 유전자에 의해 코딩될 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서, 상기 Lrig-1 단백질은 면역세포, 특히 조절 T 세포의 표면에 존재하는 1091개의 아미노산으로 이루어진 막관통 단백질로서, 세포 외 혹은 루멘 쪽의 루신 반복 서열(Leucine-rich repeat(LRR))과 세개의 면역 체 유사 도메인(Immunoglobulin-Like Domains), 세포막 관통 서열 및 세포질 꼬리부분으로 구성되어 있다. LRIG 유전자 패밀리는 LRIG1, LRIG2와 LRIG3이 존재하며, 이들간의 아미노산들은 매우 보전적으로 구성되어 있다. 상기 LRIG1 유전자는 정상 피부에서 높게 발현하고 있으며, 기저와 모낭 세포에 발현하여 상피 줄기세포의 증식을 조절할 수 있다. 따라서, 표피의 항상성 유지에 중요한 역할을 하며, 부존재 시 건선이나 피부암으로 발전할 수 있다. LRIG1이 위치한 염색체 3p14.3 부분이 잘리는 경우에는 암세포로 발전할 가능성이 많은 것으로 보고되어 있으며, 실제로 신장암(Renal cell Carcinoma)과 편평상피암(Cutaneous Squamous Cell Carcinoma)에서는 LRIG1의 발현이 매우 감소되어 있는 것으로 확인되었다. 현재, LRIG1은 c-Cbl을 통해 EGFR(Epidermarl growth factor receptor)의 유비퀴틴화를 통해 단백질 분해시킴으로써 그 하위에 존재하고 세포 증식에 관여하는 MAPK 및 AKT의 인산화에 의한 신호전달을 차단하고, 카스파아제(Caspase)-8의 분비를 증가시켜 세포사멸(Apoptosis)을 일으킴으로써 암 억제제로써의 가능성이 제기되고 있다. 본 발명의 목적상 상기 Lrig-1 단백질은 인간 또는 쥐에 존재하는 단백질 일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서, 상기 암이란, 유방암, 담도암, 담낭암, 췌장암, 대장암, 자궁암, 식도암, 위암, 뇌암, 직장암, 폐암, 방광암, 신장암, 난소암, 전립선암, 자궁암, 두경부암, 피부암, 백혈병, 림프종, 혈액암 및 간암으로 이루어진 군으로부터 선택되는 하나 이상의 암일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서, 상기 면역 질환이란 알로페시아 그레아타(Alopecia Greata), 강직성 척추염, 항 인지질 증후군, 자가면역 아디슨 질환, 부신의 자가면역 질환, 자가면역 용혈성 빈혈, 자가면역 간염, 자가면역 난소염 및 고환염, 자가면역 혈소판감소증, 베체트병, 수포성 유천포창, 심근병증, 복강 스프루우-피부염(celiac spruedermatitis), 만성 피로 면역이상 증후군, 만성염증성 탈수초 다발성 신경병증, Churg-Strauss 증후군, 반흔성유천포창, CREST 증후군, 한냉 응집소 질환, 크론씨병, 원판성 낭창, 복태성복합한냉글로불린혈증, 섬유근통-섬유근염, 사구체신염, 그레이브스 질환, 귈레인 바레 증후군, 하시모토 갑상선염, 특발성 폐섬유화증, 특발성 혈소판 감소성 자반증, IgA 신경염, 연소자성 관절염, 편평태선, 홍반성 루푸스, 메니에르병, 혼합성 연결 조직질환, 다발성 경화증, 타입 I 또는 면역-매개 당뇨병, 중증근무력증, 심상성 천포창, 악성 빈혈, 결정성 다발동맥염, 다발연골염, 자가면역성 다선 증후군, 류마티스 다발성근통, 다발성 근염과 피부근염, 일차성 무감마글로불린혈증, 일차성 담증성 간경변, 건선, 건선성 관절염, 레이노 현상, 라이터 증후군, 류마티스 관절염, 사르코이드증, 공피증, 강직인간 증후군, 전신성 홍반성 루푸스, 홍반성 루푸스, 다가야스 동맥염, 일시적 동맥염, 거대세포 동맥염, 궤양성 대장염, 포도막염, 백반증 및 베게너 육아종증으로 구성된 군으로부터 선택되는 어느 1종 이상일 수 있으나, 이에 제한되는 것은 아니다.
한편, 본 발명에서, "예방"은 본 발명에 따른 약학 조성물을 이용하여 암 또는 면역 질환의 증상을 차단하거나, 그 증상의 억제 또는 지연시키는 모든 행위라면 제한 없이 포함할 수 있다.
또한, 본 발명에서, "치료"는 본 발명에 따른 약학 조성물을 이용하여 암 또는 면역 질환의 증상이 호전되거나 이롭게 되는 모든 행위라면 제한 없이 포함할 수 있다.
본 발명에서, 상기 약학 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. 바람직하게는 본 발명에 따른 약학 조성물은 주사제 형태로 제조되어 암 또는 면역 질환이 발생된 부위에 직접적으로 주사될 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 약학 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사 용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 약학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 약학적 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여 시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형화할 수 있다.
한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.
본 발명에 따른 약학 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. 본원에 사용된 용어 "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.
본 발명의 약학 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여 시간, 투여 경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약무 형태, 투여 경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50mg/kg 또는 0.001 내지 50mg/kg 으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 의약 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형화될 수 있다.
본 발명의 약학 조성물은 추가로 다른 항암제 또는 면역 질환 치료제와 병용 투여할 수 있으며, 이를 통해서 일반적인 암세포 증식 및 암 전이를 효과적으로 억제하여 암의 치료에 사용될 수 있다.
여기서 상기 항암제로는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 소라페닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴 키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 카페시타빈, 데시타빈, 머캅토푸린, 티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈블라스틴, 이다루비신, 미토마이신, 블레로마이신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 올라파립, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴, 5FU, 보리노스텟, 엔티노스텟 및 카르무스틴으로 이루어진 군에서 선택된 1종 이상을 사용할 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 다른 구현 예에서는 Lrig-1+ 면역세포를 포함하는 암 또는 면역 질환 예방 또는 치료용 세포 치료제를 제공한다.
본 발명에서, 상기 “세포 치료제”란, 살아있는 세포를 환자에게 직접 주입하는 세포치료에 사용되는 살아있는 세포를 말하며 의약품 등의 안전에 관한 규칙에서 살아있는 자가세포, 동종세포, 또는 이종세포를 체외에서 배양, 증식하거나 선별하는 등의 방법으로 조작 제조하는 의약품을 말한다. 본 발명의 목적상 상기 세포 치료제는 T 세포의 표면에 Lrig-1 단백질이 발현되는 세포일 수 있고, 더욱 바람직하게는 상기 조절 T 세포는 CD4+ T 세포일 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 Lrig-1+ 면역세포를 포함하는 암 또는 면역 질환 예방 또는 치료용 세포 치료제에서 상기 Lrig-1+ 면역세포, 암, 면역 질환, 예방 및 치료에 관한 내용은 상기 약학 조성물에서 기재한 바와 중복되어, 이하 구체적인 기재를 생략한다.
본 발명의 또 다른 구현 예에서는 Lrig-1+ 면역세포를 포함하는 암 또는 면역 질환 예방 또는 치료용 세포 치료제의 제조방법을 제공한다.
본 발명에서 상기 세포 치료제의 제조방법은 a) 목적하는 개체로부터 분리된 생물학적 시료로부터 면역세포를 획득하는 단계; 및 b) 상기 면역세포로부터 Lrig-1 단백질이 표면에 발현되는 세포를 분리하는 단계를 포함할 수 있다.
단, 본 발명의 상기 "목적하는 개체"란, 암 또는 면역 질환 치료용 약물에 의한 치료 전 또는 후의 개체, 바람직하게는 암 또는 면역 질환 환자를 의미한다.
또한, 본 발명에서 상기 개체로부터 얻어진 "생물학적 시료"란 본 발명에 따른 상기 유전자, 단백질 및/또는 마이크로 RNA의 수준 차이가 존재하는 조직, 세포, 혈액, 혈청, 혈장, 타액, 객담, 뇌척수액, 분변 또는 소변과 같은 시료 등을 포함하나, 이에 제한되지 않는다.
본 발명에서 상기 b) 단계는 Lrig-1 단백질에 특이적으로 결합하는 단일 클론 항체를 이용하여 수행될 수 있다.
본 발명에서 상기 단일 클론 항체는 아고니스트(agonist) 또는 길항제(antagonist)일 수 있다.
본 발명에서 상기 단일 클론 항체가 아고니스트로 또는 길항제로 사용되는 경우에는 본 발명에 따른 상기 Lrig-1+ 면역세포가 활성 또는 억제되어 있는 상태를 특징적으로 선별할 수 있다.
본 발명의 상기 단일 클론 항체는 서열번호 5로 표시되는 CDR1, 서열번호 6으로 표시되는 CDR2, 서열번호 7로 표시되는 CDR3을 포함하는 중쇄 영역; 및
서열번호 9로 표시되는 CDR1, 서열번호 10으로 표시되는 CDR2, 서열번호 11로 표시되는 CDR3를 포함하는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 8로 표시되는 중쇄 영역; 및 서열번호 12로 표시되는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 13으로 표시되는 CDR1, 서열번호 14로 표시되는 CDR2, 서열번호 15로 표시되는 CDR3을 포함하는 중쇄 영역; 및
서열번호 17로 표시되는 CDR1, 서열번호 18로 표시되는 CDR2, 서열번호 19로 표시되는 CDR3를 포함하는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 16으로 표시되는 중쇄 영역; 및 서열번호 20으로 표시되는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 21로 표시되는 CDR1, 서열번호 22로 표시되는 CDR2, 서열번호 23으로 표시되는 CDR3을 포함하는 중쇄 영역; 및
서열번호 25로 표시되는 CDR1, 서열번호 26으로 표시되는 CDR2, 서열번호 27로 표시되는 CDR3를 포함하는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 24로 표시되는 중쇄 영역; 및 서열번호 28로 표시되는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 29로 표시되는 CDR1, 서열번호 30으로 표시되는 CDR2, 서열번호 31로 표시되는 CDR3을 포함하는 중쇄 영역; 및
서열번호 33으로 표시되는 CDR1, 서열번호 34로 표시되는 CDR2, 서열번호 35으로 표시되는 CDR3를 포함하는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 32로 표시되는 중쇄 영역; 및 서열번호 36으로 표시되는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 37로 표시되는 CDR1, 서열번호 38로 표시되는 CDR2, 서열번호 39로 표시되는 CDR3을 포함하는 중쇄 영역; 및
서열번호 41로 표시되는 CDR1, 서열번호 42로 표시되는 CDR2, 서열번호 43로 표시되는 CDR3를 포함하는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 40으로 표시되는 중쇄 영역; 및 서열번호 44로 표시되는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 45로 표시되는 CDR1, 서열번호 46으로 표시되는 CDR2, 서열번호 47로 표시되는 CDR3을 포함하는 중쇄 영역; 및
서열번호 49로 표시되는 CDR1, 서열번호 50으로 표시되는 CDR2, 서열번호 51로 표시되는 CDR3를 포함하는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 48로 표시되는 중쇄 영역; 및 서열번호 52로 표시되는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 53으로 표시되는 CDR1, 서열번호 54로 표시되는 CDR2, 서열번호 55로 표시되는 CDR3을 포함하는 중쇄 영역; 및
서열번호 57로 표시되는 CDR1, 서열번호 58로 표시되는 CDR2, 서열번호 59로 표시되는 CDR3를 포함하는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 56로 표시되는 중쇄 영역; 및 서열번호 60으로 표시되는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 61로 표시되는 CDR1, 서열번호 62로 표시되는 CDR2, 서열번호 63으로 표시되는 CDR3을 포함하는 중쇄 영역; 및
서열번호 65로 표시되는 CDR1, 서열번호 66으로 표시되는 CDR2, 서열번호 67로 표시되는 CDR3를 포함하는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
또한, 본 발명의 상기 단일 클론 항체는 서열번호 64로 표시되는 중쇄 영역; 및 서열번호 68로 표시되는 경쇄 영역을 포함하는 면역세포, 특히 조절 T 세포(Regulatory T cell; Treg)의 표면 단백질에 특이적인 단일클론 항체일 수 있다.
본 발명에서, 상기 "항체"는 면역학적으로 특정 항원과 반응성을 갖는 면역글로블린 분자를 포함하는, 항원을 특이적으로 인식하는 수용체 역할을 하는 단백질 분자를 의미한다. 본 발명의 목적상 상기 항원은 면역세포, 바람직하게는 조절 T 세포(Regulatory T cell)의 표면에 존재하는 Lrig-1 단백질일 수 있다. 더욱 바람직하게는 상기 Lrig-1 단백질의 류신 리치 구역(Leucine Rich Region) 또는 면역글로블린 유사 도메인을 특이적으로 인식하는 것일 수 있으나, 이에 제한되지 아니한다.
본 발명에서 상기 면역글로불린은 중쇄 및 경쇄를 가지며 각각의 중쇄 및 경쇄는 불변 영역 및 가변 영역을 포함한다. 경쇄 및 중쇄의 가변 영역은, 상보성 결정 영역(Complementarity Determining Region, 이하 "CDR"이라 함)이라 불리우는 3개의 다변 가능한 영역 및 4개의 구조 영역(Framework region)을 포함한다. 상기 CDR은 주로 항원의 항원 결정기(Epitope)에 결합하는 역할을 한다. 각각의 사슬의 CDR은 전형적으로 N-말단으로부터 시작하여 순차적으로 CDR1, CDR2 및 CDR3로 지칭하고, 또한 특정 CDR이 위치하고 있는 사슬에 의해서 식별된다.
본 발명에서 상기 항체는, 예를 들면 단일 클론 항체, 전장 항체 (Full-length antibody) 및 항체의 단편을 모두 포함한다.
본 발명에서 상기 "전장 항체"는 2개의 전체 길이의 경쇄 및 2개의 전체 길이의 중쇄를 가지는 구조이며, 각각의 경쇄는 중쇄와 다이설파이드(Disulfide) 결합으로 연결되어 있으며, IgA, IgD, IgE, IgM, 및 IgG를 포함한다. 상기 IgG는 그 아형(subtype)으로, IgG1, IgG2, IgG3 및 IgG4를 포함한다.
또한, 본 발명에서 상기 "항체의 단편"은 항원 결합 기능을 보유하고 있는 단편을 의미하며, Fab, Fab', F(ab')2 및 Fv 등을 포함한다. 상기 Fab는 경쇄 및 중쇄의 가변 영역과 경쇄의 불변 영역 및 중쇄의 첫 번째 불변 영역(CH1 도메인)을 가지는 구조로 1개의 항원 결합 부위를 가진다. 또한, Fab'는 중쇄 CH1 도메인의 C 말단에 하나 이상의 시스테인 잔기를 포함하는 힌지 영역(hinge region)을 가진다는 점에서 Fab와 차이가 있다. F(ab')2 항체는 Fab'의 힌지 영역의 시스테인 잔기가 다이설파이드 결합을 이루면서 생성된다. Fv(variable fragment)는 중쇄 가변부위 및 경쇄 가변부위만을 가지고 있는 최소의 항체 조각을 의미한다. 이중쇄 Fv(dsFv)는 다이설파이드 결합으로 중쇄 가변 부위와 경쇄 가변 부위가 연결되어 있고 단쇄 Fv(scFv)는 일반적으로 펩타이드 링커를 통하여 중쇄의 가변 영역과 경쇄의 가변 영역이 공유 결합으로 연결되어 있다. 상기 항체 단편은 단백질 가수분해 효소, 예를 들면 파파인 또는 펩신을 이용하는 경우 Fab 또는 F(ab')2의 단편을 얻을 수 있으며, 유전자 재조합 기술을 통하여 제작할 수 있다.
본 발명에서, 상기 항체는 키메라 항체, 인간화 항체(humanized antibody), 이가(bivalent) 또는 양특이성 분자, 디아바디, 트리아바디 및 테트라바디를 포함할 수 있다.
본 발명에서 상기 "키메라 항체"는, 생쥐 항체의 가변 영역 및 인간 항체의 불변 영역을 재조합시킨 항체로서, 생쥐 항체에 비하여 면역 반응이 크게 개선된 항체이다.
또한, 본 발명에서 상기 "단일 클론 항체"는, 실질적으로 동일한 항체 집단에서 수득한 단일 분자 조성의 항체 분자를 일컫는 말로, 특정 항원 결정기(Epitope)에 대해 단일 결합 특이성 및 친화도를 나타낸다.
또한, 본 발명에서 상기 "인간화 항체"는 인간이 아닌 종에서 유래한 항체의 단백질 서열을 인간에서 자연적으로 생산된 항체 변이체와 유사하도록 변형시킨 항체를 의미한다. 그 예로 상기 인간화 항체는 생쥐 유래의 CDR을 인간 항체 유래의 FR과 재조합시켜 인간화 가변 영역을 제조하고, 이를 바람직한 인간 항체의 불변 영역과 재조합시켜 인간화 항체를 제조할 수 있다.
본 발명에서 상기 항체는 항체를 생산하는 통상의 방법에 의해 생성될 수 있지만, 친화도 성숙(Affinity maturation)에 의해 생성될 수 있다.
본 발명에서 상기 "친화도 성숙(Affinity maturation)"은, 활성화된 B 세포가 면역 반응 과정에서 항원에 대한 친화도가 증가된 항체를 생산하는 과정을 의미한다. 본 발명의 목적상 상기 친화도 성숙은 자연에서 일어나는 과정과 동일하게, 돌연변이와 선택의 원리에 기초하여 친화도 성숙으로 인해 생성된 항체 또는 항체 단편을 생성할 수 있다.
본 발명에서, 상기 b) 단계는 세포를 분리하는 기술은 FACS(Fluorescence-activated cell sorting), MACS(Magnetic-activated cell sorting) 및 친화 크로마토그래피(affinity chromatography) 중 어느 하나 이상일 수 있으나, 단일 세포를 분리하는 방법은 모두 포함될 수 있다. 바람직하게는 MACS를 이용하여 수행될 수 있다. 상기 MACS를 사용하는 경우에는 분리된 세포의 수 및 정확도를 높일 수 있다.
단, 본 발명에서, 상기 “MACS”이란, 마그네틱 비드(Magnetic bead)를 이용한 세포의 분리 방법으로, 자성 입자를 사용하여 이들에 항체를 부착하여 세포와 반응시키거나, 혹은 비드를 엔도시토시스(Endocytosis)에 의해서 세포를 연결 시키고, 이에 따라서 자기장을 통해 세포를 분리해 내는 방법을 의미한다.
또한, 본 발명에서, 상기 “FACS”란, 살아있는 세포를 형광 표지시킨 뒤, 유동세포계수기 원리를 응용하여 각각의 세포를 레이져로 선별, 분취하는 장치를 의미한다.
본 발명에 따른 Lrig-1+ 면역세포를 포함하는 약학 조성물 및 세포 치료제는 면역세포를 특이적으로 선별하여 암 또는 면역 질환을 효과적으로 예방 또는 치료할 수 있다.
도 1은 본 발명의 일 실시예에 따른 Lrig-1 단백질의 구조를 나타낸 것이다.
도 2는 본 발명의 일 실시예에 따른 Lrig-1 단백질의 구조를 나타낸 것이다.
도 3은 본 발명의 일 실시예에 따른 Lrig-1 단백질의 항원 결정기(epitope)를 예측한 결과를 나타낸 것이다.
도 4는 본 발명의 일 실시예에 따른 Lrig-1 단백질의 항원 결정기(epitope)를 예측한 결과를 나타낸 것이다.
도 5는 본 발명의 일 실시예에 따른 Lrig-1 mRNA의 발현 정도를 나타낸 것이다.
도 6은 본 발명의 일 실시예에 따른 Lrig-1 mRNA의 발현 정도를 나타낸 것이다.
도 7은 본 발명의 일 실시예에 따른 Lrig-1 mRNA의 발현 정도를 나타낸 것이다.
도 8은 본 발명의 일 실시예에 따른 Lrig-1, Lrig-2 및 Lrig-3 mRNA의 발현 정도를 나타낸 것이다.
도 9는 본 발명의 일 실시예에 따른 조절 T 세포와 비 조절 T 세포 내 Lrig-1 단백질의 발현량 비교 결과를 나타낸 것이다.
도 10은 본 발명의 일 실시예에 따른 조절 T 세포의 표면에 Lrig-1 단백질의 발현을 나타낸 것이다.
도 11은 본 발명의 일 실시예에 따른 세포 증식 억제 효과를 나타낸 것이다.
도 2는 본 발명의 일 실시예에 따른 Lrig-1 단백질의 구조를 나타낸 것이다.
도 3은 본 발명의 일 실시예에 따른 Lrig-1 단백질의 항원 결정기(epitope)를 예측한 결과를 나타낸 것이다.
도 4는 본 발명의 일 실시예에 따른 Lrig-1 단백질의 항원 결정기(epitope)를 예측한 결과를 나타낸 것이다.
도 5는 본 발명의 일 실시예에 따른 Lrig-1 mRNA의 발현 정도를 나타낸 것이다.
도 6은 본 발명의 일 실시예에 따른 Lrig-1 mRNA의 발현 정도를 나타낸 것이다.
도 7은 본 발명의 일 실시예에 따른 Lrig-1 mRNA의 발현 정도를 나타낸 것이다.
도 8은 본 발명의 일 실시예에 따른 Lrig-1, Lrig-2 및 Lrig-3 mRNA의 발현 정도를 나타낸 것이다.
도 9는 본 발명의 일 실시예에 따른 조절 T 세포와 비 조절 T 세포 내 Lrig-1 단백질의 발현량 비교 결과를 나타낸 것이다.
도 10은 본 발명의 일 실시예에 따른 조절 T 세포의 표면에 Lrig-1 단백질의 발현을 나타낸 것이다.
도 11은 본 발명의 일 실시예에 따른 세포 증식 억제 효과를 나타낸 것이다.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.
실시예
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준비예
1] T 세포 아형 세포 배양
조절 T 세포(Treg)에서만 Lrig-1 단백질이 발현되는지 확인하기 위하여, T 세포의 아형(subset)인 Th0, Th1, Th2, Th17 및 iTreg을 준비하였다. 상기 iTreg은 자연적으로 분리한 nTreg과는 달리하기 조성을 포함하는 배지에서 분화를 인공적으로 유도한 세포를 의미한다.
T 세포의 아형은 우선, 쥐의 비장으로부터 얻은 나이브(naive) T 세포를 분리한 뒤, 우태아혈청(FBS; hyclone, logan, UT) 10%를 포함하는 RPMI1640(Invitrogen Gibco, Grand Island, NY) 영양 배지에 하기 표 1의 성분을 각각 더 포함하도록 하여, 37℃, 5 % CO2 배양기 내에서 72시간 배양을 통해 각각의 세포로 분화 유도 하였다.
분화 세포 | 조성 |
Th0 | anti-CD3, anti-CD28 |
Th1 | IL-12, anti-IL-4 항체 |
Th2 | IL-4, anti-IFNβ |
Th17 | IL-6, TGFβ, anti-IFNβ, anti-IL-4 |
iTreg | IL-2, TGFβ |
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Lrig
-1 구조 분석
조절 T 세포의 표면 단백질인 Lrig-1 단백질에 특이적인 항체를 제작하기 위하여 Lrig-1 단백질의 세포외 도메인의 3차원 입체 구조를 예측하였다.
우선, 항원 결정기(Epitope) 염기서열 예측을 위해 Lrig-1 단백질의 세포외 도메인(Extracellular domain; ECD)의 구조를 확인하기 위하여 Uniprot(http://www.uniprot.org)과 RCSB Protein Data Bank (http://www.rcsb.org/pdb)툴을 이용하여 3차원 입체 구조를 예측한 뒤, 그 결과를 도 1 및 2에 나타내었다.
도 1에서 보는 바와 같이, Lrig-1 단백질의 세포외 도메인 중 Lrig-LRR 도메인(아미노산 서열 41 ~ 494번) 내에는 LRR1 내지 LRR15의 총 15개의 류신 리치 부위(Leucine rich region)가 존재하였다. 상기 LRR 도메인 각각은 23 내지 27개의 아미노산으로 구성되고, 류신은 3 내지 5개가 존재하였다.
또한, 도 2에서 보는 바와 같이, Lrig-1 단백질의 세포외 도메인 중 Lrig-1 단백질의 아미노산 서열 494 내지 781번에는 면역글로블린 유사 도메인(Immunoglobulin-like domain)이 3개 존재하였다.
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Lrig
-1 항원
결정기
(
epitope
) 아미노산 서열 예측
상기 염기서열의 예측은 Lrig-1 단백질의 구조를 기반으로 하는 항원 결정기 예측 소프트웨어(epitope prediction software)인 Ellipro 서버(http://tools.iedb.org/ellipro/)를 이용하였다. 상기 Ellipro 검색 엔진은 현존하는 항원 결정기를 예측하는 알고리즘 중에서 가장 신뢰도가 높다고 알려진 검색엔진에 해당하여 이를 이용하였다.
항원 결정기 예측 소프트웨어에 상기 실시예 1에서 분석된 세포외 도메인을 입력한 뒤, 예측된 항원 결정기의 예측된 연속 또는 불연속 아미노산 서열을 도 3 및 4에 나타내었다.
도 3 및 4에서 보는 바와 같이, 연속된 항원 결정기 아미노산 서열은 총 22개가 예측되었고, 불연속된 항원 결정기 아미노산 서열은 총 8개가 예측되었다.
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Lrig
-1 항체의 제조
본 발명에 따른 Lrig-1 단백질에 특이적인 항체를 제작하였다. 본 항체는 특정 항원 결정기를 정하여 생산하지 않고, Lrig-1 단백질에 어느 부위든지 결합할 수 있는 항체를 생산하였다.
상기 항체를 제작하기 위하여 Lrig-1 단백질이 발현되는 세포를 제작하였다. 서열번호 2에 해당하는 DNA 단편 및 pcDNA(hygro)를 절단 효소로 절단한 뒤, 37도씨에서 배양하여 라이게이션(Lrigation) 하여, Lrig-1 단백질의 DNA 서열이 삽입(insert) 되어 있는 pcDNA를 제작하였다. 상기 제작된 서열번호 2가 삽입된 pcDNA는 L세포에 형질주입(transfection)을 통해 도입되어 L 세포의 표면에 Lrig-1 단백질이 발현될 수 있도록 하였다.
상기 세포 표면에 발현되는 Lrig-1 에 결합할 수 있는 경쇄(Lright chain) 및 중쇄(heavy chain) 아미노산의 서열을 Human scFv library에서 선별하여, 총 8개의 중쇄 및 경쇄를 선별하였다.
상기 선별된 중쇄 및 경쇄 아미노산 서열을 mlgG2a Fc region과 융합하여 단일 클론(mono clonal) 항체를 제작하였다. 상기 단일 클론 항체의 서열은 하기 표 2와 같다.
구분 | 클론 | 위치 | 아미노산 서열 |
제조예 1 | A7 clone | 중쇄 | METDTLLLWVLLLWVPGSTWEVQLLESGGGLVQPGGSLRLSCAASGFTFSGYDMSWV RQAPGKGLEWVSLIYPDSGNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY YCARDAGLSWAGAFDYWGQGTLVTVSSTTAPSVYPLAPVCGDTTGSSVTLGCLVKGY FPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPAS STKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVV VDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFK CKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDI YVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHN HHTTKSFSRTPGK |
경쇄 | METDTLLLWVLLLWVPGSTWQSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVTWY QQLPGTAPKLLIYSDSHRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCGSWDY SLSAYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKW KIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPI VKSFNRNEC |
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제조예 2 | A8 clone | 중쇄 | METDTLLLWVLLLWVPGSTWEVQLLESGGGLVQPGGSLRLSCAASGFTFSDYDMSWV RQVPGKGLEWVSWISHGGGSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY YCARGLGLCKTGLCYYYDAMDVWGQGTLVTVSSTTAPSVYPLAPVCGDTTGSSVTLG CLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCN VAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSP IVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWM SGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTD FMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVV HEGLHNHHTTKSFSRTPGK |
경쇄 | METDTLLLWVLLLWVPGSTWQSVLTQPPSASGTPGQRVTISCTGSSSNIGNNSVTWY QQLPGTAPKLLIYADNNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDS SLSAYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKW KIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPI VKSFNRNEC |
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제조예 3 | B8 clone | 중쇄 | METDTLLLWVLLLWVPGSTWEVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWV RQAPGKGLEWVSGISHDSGSKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY YCARHWTTFDYWGQGTLVTVSSTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPV TLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVD KKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSE DDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNN KDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWT NNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTK SFSRTPGK |
경쇄 | METDTLLLWVLLLWVPGSTWQSVLTQPPSASGTPGQRVTISCSGSSSNIGSNNVTWY QQLPGTAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGAWDY SLSAYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKW KIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPI VKSFNRNEC |
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제조예 4 | C8 clone | 중쇄 | METDTLLLWVLLLWVPGSTWEVQLLESGGGLVQPGGSLRLSCAASGFTFSNYYMSWV RQAPGKGLEWVSGISPGDSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY YCAKGLYSNPNEPFDYWGQGTLVTVSSTTAPSVYPLAPVCGDTTGSSVTLGCLVKGY FPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPAS STKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVV VDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFK CKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDI YVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHN HHTTKSFSRTPGK |
경쇄 | METDTLLLWVLLLWVPGSTWQSVLTQPPSASGTPGQRVTISCTGSSSNIGSNYVSWY QQLPGTAPKLLIYDDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGTWDY SLNGYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKW KIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPI VKSFNRNEC |
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제조예 5 | D9 clone | 중쇄 | METDTLLLWVLLLWVPGSTWEVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWV RQAPGKGLEWVSAIYPGGGSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY YCARDILPCPWGRCYYDYAMDVWGQGTLVTVSSTTAPSVYPLAPVCGDTTGSSVTLG CLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCN VAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSP IVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWM SGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTD FMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVV HEGLHNHHTTKSFSRTPGK |
경쇄 | METDTLLLWVLLLWVPGSTWQSVLTQPPSASGTPGQRVTISCSDSSSNIGSNTVSWY QQLPGTAPKLLIYADNNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGTWDY SLSGYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKW KIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPI VKSFNRNEC |
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제조예 6 | E7 clone | 중쇄 | METDTLLLWVLLLWVPGSTWEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWV RQAPGKGLEWVSGISPDGSNIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY YCAKVGLRCRYEACSYAYGMDVWGQGTLVTVSSTTAPSVYPLAPVCGDTTGSSVTLG CLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCN VAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSP IVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWM SGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTD FMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVV HEGLHNHHTTKSFSRTPGK |
경쇄 | METDTLLLWVLLLWVPGSTWQSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVSWY QQLPGTAPKLLIYSDSHRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDS SLNGYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKW KIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPI VKSFNRNEC |
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제조예 7 | G3 clone | 중쇄 | METDTLLLWVLLLWVPGSTWEVQLLESGGGLVQPGGSLRLSCAASGFTFSNYDMSWVR QAPGKGLEWVSSISPSSGSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC AKDLDAFWRPSFDYWGQGTLVTVSSTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPE PVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKV DKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSE DDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNK DLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNN GKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFS RTPGK |
경쇄 | METDTLLLWVLLLWVPGSTWQSVLTQPPSASGTPGQRVTISCTGSSSNIGNNNVNWYQ QLPGTAPKLLIYSDSHRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGSWDDSL SAYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKID GSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSF NRNEC |
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제조예 8 | H6 clone | 중쇄 | METDTLLLWVLLLWVPGSTWEVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQ APGKGLEWVSVISHGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR VISNCHLGVCYYSNGMDVWGQGTLVTVSSTTAPSVYPLAPVCGDTTGSSVTLGCLVKGY FPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASST KVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVS EDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNK DLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNG KTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRT PGK |
경쇄 | METDTLLLWVLLLWVPGSTWQSVLTQPPSASGTPGQRVTISCSGSSSNIGNNDVYWYQQ LPGTAPKLLIYSDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGTWDYSLSG YVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSE RQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC |
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Lrig
-1
mRNA의
조절 T 세포에서의 특이적 발현 확인
Lrig-1 단백질이 조절 T 세포에 특이적인 바이오마커(biomarker)로 작용할 수 있는지 검증하였다.
상기 검증을 위하여, 쥐의 비장으로부터 CD4 비드를 통해 자석 활성 세포 분류기(magnet-activated cell sorting; MACS)를 이용하여 CD4+ T 세포를 분리하였다. 이후, CD25 항체를 이용하여 형광 활성 세포 분류기(FACS)를 이용해 조절 T (CD4+CD25+ T)세포 및 비 조절 T (CD4+CD25- T)세포를 분리하였다. 각각의 세포 및 상기 준비예 1에서 분화된 세포는 트리졸(Trizol)을 이용하여 mRNA를 추출한 뒤, 게노믹 RNA는 gDNA 추출 키트(Qiagen)를 이용하여 업체에서 제공한 프로토콜에 의해 gDNA를 제거하였다. gDNA가 제거된 mRNA는 BDsprint cDNA 합성 키트 (Clonetech)를 통해 cDNA로 합성하였다.
상기 cDRNA에서 Lrig-1 mRNA의 발현량을 정량적으로 확인하기 위하여 실시간 중합효소연쇄반응(real time PCR)을 수행하였다.
상기 실시간 중합효소연쇄반응은 SYBR Green (Molecular Probes)을 이용하여 업체에서 제공한 프로토콜에 의해 95 에서 3분, 61 에서 15초, 72 에서 30초씩 40 사이클의 조건으로, 하기 표 3의 프라이머를 이용하여 수행하였고, 상대적인 유전자 발현량은 ΔCT 방법을 이용하여 계산하였으며, HPRT를 이용하여 일반화(normalization) 하여, 그 결과를 도 5 내지 8에 나타내었다.
프라이머 | 서열 |
쥐 Lrig-1 | Forward 5' - GAC GGA ATT CAG TGA GGA GAA CCT - 3' |
Reverse 5' - CAA CTG GTA GTG GCA GCT TGT AGG - 3' | |
쥐 Lrig-2 | forward 5' - TCA CAA GGA ACA TTG TCT GAA CCA- 3' |
reverse 5' - GCC TGA TCT AAC ACA TCC TCC TCA- 3' | |
쥐 Lrig-3 | forward 5' - CAG CAC CTT GAG CTG AAC AGA AAC - 3' |
reverse 5' - CCA GCC TTT GGT AAT CTC GGT TAG - 3' | |
쥐 FOXP3 | forward 5' - CTT TCA CCT ATC CCA CCC TTA TCC - 3' |
reverse 5' - ATT CAT CTA CGG TCC ACA CTG CTC - 3' | |
ACTG1 | forward 5' - GGC GTC ATG GTG GGC ATG GG - 3' |
reverse 5' - ATG GCG TGG GGA AGG GCG TA - 3' |
도 5에서 보는 바와 같이, 비 조절 T (CD4+CD25- T)세포에 비하여 조절 T((CD4+CD25+ T) 세포에서 Lrig-1의 발현이 18.1배 높은 것을 알 수 있다. 이는, 기존에 알려져 있는 조절 T 세포의 마커인 Lag3 및 Ikzf4와 비교하였을 때 약 10배 정도 발현양이 높은 수준이었다.
또한, 도 6 및 7에서 보는 바와 같이, 다른 종류의 면역세포에 비하여 조절 T 세포, 특히 유도된 조절 T 세포(iTreg)에 비해 자연적으로 분리한 조절 T 세포(nTreg)에서 Lrig-1 mRNA의 발현이 현저하게 높았다.
또한, 도 8에서 보는 바와 같이, Lrig 패밀리에 해당하는 Lrig-1, Lrig-2 및 Lrig-3 중에서 Lrig-1의 발현이 가장 높았다.
상기 결과를 통해 본 발명에 따른 Lrig-1 단백질은 조절 T 세포, 특히 자연적으로 존재하는 조절 T 세포에서 특이적으로 발현하는 것을 알 수 있다.
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Lrig
-1 단백질의 조절 T 세포에서의 특이적 발현 확인
Lrig-1 mRNA로부터 발현된 Lrig-1 단백질이 조절 T 세포에서만 특이적으로 발현되는지 확인하였다.
조절 T 세포 특이적인 전사인자인 FOXP3 프로모터에 RFP(Red fluorescence protein)이 결합된 FOXP3-RFP 주입(Knock-in) 쥐를 이용하여, 상기 쥐의 비장으로부터 CD4 비드로 자석 활성 세포 분류기(magnet-activated cell sorting; MACS)를 이용하여 CD4+ T 세포를 분리하였다. 이후, RFP 단백질을 이용하여, 형광 활성 세포 분류기(FACS)를 통해 조절 T (CD4+RFP+ T)세포 및 비 조절 T(CD4+RFP- T)를 분리하여 얻었다. 각각의 상기 세포는 구입한 Lrig-1 항체 및 음성 대조군은 아이소타입(isotype)을 통해 염색하여 형광 활성 세포 분류기로 Lrig-1의 발현량을 측정하여, 그 결과를 도 9에 나타내었다.
도 9에서 보는 바와 같이, 점선으로 표시되는 비 조절 T 세포의 경우 음성 대조군과 거의 동일한 Lrig-1의 발현 수준을 보였지만, 조절 T 세포의 경우 Lrig-1의 발현 수준이 높은 세포가 다수 존재하였다.
상기 결과를 통해 본 발명에 따른 Lrig-1 단백질은 조절 T 세포에서 특이적으로 발현하는 것을 알 수 있다.
[
실시예
5] 조절 T 세포 표면에서의
Lrig
-1 단백질 특이적 발현 확인
Lrig-1 단백질이 세포 치료의 타겟이 되기 위해서는 조절 T 세포의 표면에 발현되어야 더욱 효과적으로 타겟 치료를 할 수 있으므로, Lrig-1 단백질이 표면에서의 발현 여부를 확인하였다.
상기 준비예 1의 각각의 분화된 T 세포 아형을 항-CD4-APC 및 항 Lrig-1-PE 항체로 염색하고, 형광 이용 세포 분류기(Fluorescence-Activated Cell Sorter; FACS)를 이용하여 각각의 세포 표면에서 Lrig-1의 발현량을 측정하여, 그 결과를 도 10에 나타내었다.
도 10에서 보는 바와 같이, 활성화된 T 세포(activated T cell), Th1 세포, Th2 세포, Th17 세포 및 나이브(Na?ve) T 세포에서는 Lrig-1의 발현이 0.77 내지 15.3의 양으로 발현되는 반면, 분화가 유도된 T 세포(iTreg)에서는 83.9로 높게 발현되었다.
상기 결과를 통해 본 발명에 따른 Lrig-1 단백질은 조절 T 세포(Treg) 세포에서 특이적으로 발현될 뿐만 아니라, 특히 Treg 세포의 표면에서 더욱 높게 발현되는 것을 알 수 있다.
[
실시예
6]
Lrig
-1 단백질 기능 확인
Lrig-1 단백질이 조절 T 세포의 주요 기능인 효과 T 세포(effector T cell)의 증식 억제를 조절하는지 여부를 확인하였다.
상기 실시예 4에서와 같이 조절 T (CD4+FOXP3+ T)세포를 얻어 이를 조절 T 세포의 양성 대조군으로 사용하였고, 정상 쥐의 비장에서 추출한 CD4+ T 세포를 구입한 항 Lrig-1-PE 항체로 염색한 뒤, 형광 이용 세포 분류기를 이용하여 CD4+Lrig-1+-PE 세포 및 CD4+Lrig-1―-PE 세포를 각각 분리하였다. 분리된 각각의 세포는 정상 쥐의 비장에서 자석 활성 분류기(MACS)를 통해 분리된 나이브 T 세포와 항원 제시 세포(APC) 및 항-CD3과 함께 72시간 동안 공동 배양을 진행하였다.
상기 공동 배양은 ⅰ) 나이브 T 세포만 배양, ⅱ)나이브 T 세포와 조절 T 세포 공동 배양, ⅲ) 나이브 T 세포 및 CD4+Lrig-1+ T 세포 공동 배양, 및 ⅳ) 나이브 T 세포 및 CD4+Lrig-1- T 세포를 공동 배양으로 4개의 군을 나눠 각각 조절 T 세포: 효과 T 세포 = 1:4 또는 1:1의 세포의 비율로 72시간 배양한 뒤, 상기 나이브 세포는 증식을 확인할 수 있도록 CFSE(Carboxyfluorescein succinimidyl ester)를 통해 염색하여 형광 이용 세포 분류기를 통해 측정하여, 그 결과를 도 11에 나타내었다.
도 11에서 보는 바와 같이, 나이브 T 세포의 활성 및 증식 억제 효과가 있다고 알려져 있는 양성 대조군인 CD4+FOXP3+ T 세포와 유사한 수준으로 CD4+Lrig-1+ T 세포는 나이브 T 세포의 증식을 억제하였다. 반면, CD4+Lrig-1- T세포는 나이브 T 세포의 증식 억제 효과를 나타내지 않았다.
상기 결과를 통해 조절 T 세포의 표면에 존재하는 Lrig-1 단백질은 나이브 T 세포의 증식을 억제하여 활성을 억제하는 기능을 하는 것을 알 수 있다.
이상에서 본 발명에 대하여 상세하게 설명하였지만 본 발명의 권리범위는 이에 한정되는 것은 아니고, 청구범위에 기재된 본 발명의 기술적 사상을 벗어나지 않는 범위 내에서 다양한 수정 및 변형이 가능하다는 것은 당 기술분야의 통상의 지식을 가진 자에게는 자명할 것이다.
<110> Good T cells
<120> A monoclonal antibody having complementarity determining region
binding to extracellular protein of regulatory T cell and use
thereof
<130> DPB172433
<160> 68
<170> KoPatentIn 3.0
<210> 1
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Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr Leu
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Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg Leu
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Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu Pro
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agttacaaca aactctctga gattgaccct gctggttttg aggacttgcc gaacctacag 180
gaagtgtacc tcaataataa tgagttgaca gcggtaccat ccctgggcgc tgcttcatca 240
catgtcgtct ctctctttct gcagcacaac aagattcgca gcgtggaggg gagccagctg 300
aaggcctacc tttccttaga agtgttagat ctgagtttga acaacatcac ggaagtgcgg 360
aacacctgct ttccacacgg accgcctata aaggagctca acctggcagg caatcggatt 420
ggcaccctgg agttgggagc atttgatggt ctgtcacggt cgctgctaac tcttcgcctg 480
agcaaaaaca ggatcaccca gcttcctgta agagcattca agctacccag gctgacacaa 540
ctggacctca atcggaacag gattcggctg atagagggcc tcaccttcca ggggctcaac 600
agcttggagg tgctgaagct tcagcgaaac aacatcagca aactgacaga tggggccttc 660
tggggactgt ccaagatgca tgtgctgcac ctggagtaca acagcctggt agaagtgaac 720
agcggctcgc tctacggcct cacggccctg catcagctcc acctcagcaa caattccatc 780
gctcgcattc accgcaaggg ctggagcttc tgccagaagc tgcatgagtt ggtcctgtcc 840
ttcaacaacc tgacacggct ggacgaggag agcctggccg agctgagcag cctgagtgtc 900
ctgcgtctca gccacaattc catcagccac attgcggagg gtgccttcaa gggactcagg 960
agcctgcgag tcttggatct ggaccataac gagatttcgg gcacaataga ggacacgagc 1020
ggcgccttct cagggctcga cagcctcagc aagctgactc tgtttggaaa caagatcaag 1080
tctgtggcta agagagcatt ctcggggctg gaaggcctgg agcacctgaa ccttggaggg 1140
aatgcgatca gatctgtcca gtttgatgcc tttgtgaaga tgaagaatct taaagagctc 1200
catatcagca gcgacagctt cctgtgtgac tgccagctga agtggctgcc cccgtggcta 1260
attggcagga tgctgcaggc ctttgtgaca gccacctgtg cccacccaga atcactgaag 1320
ggtcagagca ttttctctgt gccaccagag agtttcgtgt gcgatgactt cctgaagcca 1380
cagatcatca cccagccaga aaccaccatg gctatggtgg gcaaggacat ccggtttaca 1440
tgctcagcag ccagcagcag cagctccccc atgacctttg cctggaagaa agacaatgaa 1500
gtcctgacca atgcagacat ggagaacttt gtccacgtcc acgcgcagga cggggaagtg 1560
atggagtaca ccaccatcct gcacctccgt caggtcactt tcgggcacga gggccgctac 1620
caatgtgtca tcaccaacca ctttggctcc acctattcac ataaggccag gctcaccgtg 1680
aatgtgttgc catcattcac caaaacgccc cacgacataa ccatccggac caccaccgtg 1740
gcccgcctcg aatgtgctgc cacaggtcac ccaaaccctc agattgcctg gcagaaggat 1800
ggaggcacgg atttccccgc tgcccgtgag cgacgcatgc atgtcatgcc ggatgacgac 1860
gtgtttttca tcactgatgt gaaaatagat gacgcagggg tttacagctg tactgctcag 1920
aactcagccg gttctatttc agctaatgcc accctgactg tcctagagac cccatccttg 1980
gtggtcccct tggaagaccg tgtggtatct gtgggagaaa cagtggccct ccaatgcaaa 2040
gccacgggga accctccgcc ccgcatcacc tggttcaagg gggaccgccc gctgagcctc 2100
actgagcggc accacctgac ccctgacaac cagctcctgg tggttcagaa cgtggtggca 2160
gaggatgcgg gccgatatac ctgtgagatg tccaacaccc tgggcacgga gcgagctcac 2220
agccagctga gcgtcctgcc cgcagcaggc tgcaggaagg atgggaccac ggtaggcatc 2280
ttcaccattg ctgtcgtgag cagcatcgtc ctgacgtcac tggtctgggt gtgcatcatc 2340
taccagacca ggaagaagag tgaagagtac agtgtcacca acacagatga aaccgtc 2397
<210> 3
<211> 761
<212> PRT
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Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu
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Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe Lys
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Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu
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Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu Arg
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Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His
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Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser Phe
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Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr Arg
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Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu Arg
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Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly
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Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn Ala
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Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile Arg
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Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala
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Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile Ala
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Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly His
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Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro
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Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe
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Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys Thr
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Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr Val
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Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr Glu
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<210> 4
<211> 2283
<212> DNA
<213> Mus musculus
<400> 4
caggctggcc cgcgggcccc ctgcgcggcc gcctgcactt gcgccgggga ctcgctggac 60
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aacctgagtt ataacagact ctccgagatc gactctgctg cttttgagga cttgacgaat 180
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cagctgaagt cgtacctgtc cttggaagtg ctggatctga gttccaacaa catcacggaa 360
attcggagct cctgtttccc gaacggcctg cgtataaggg aactcaactt ggcgagcaac 420
cgcatcagca tcctggagtc tggagcattt gatggtctgt cgcggtcact gctgactctc 480
cgtctgagca aaaacaggat cacccagctt cctgtgaaag cgttcaagct acccaggctg 540
acacaactag acctgaatcg gaatcggatt cggctgattg aaggcctcac gttccagggg 600
ctcgacagct tagaggtgct gaggcttcag aggaacaaca tcagcaggct gacggacggg 660
gccttctggg ggctgtctaa gatgcacgtg ctgcacctgg agtacaacag tctggtggaa 720
gtgaacagtg gctccctcta tggcctcaca gccctgcacc agctgcacct cagcaacaac 780
tccatctctc gaattcagcg tgatggctgg agcttctgcc aaaagctgca tgagttgatt 840
ctgtccttca acaacctcac gcggctggat gaggagagtc tagcggagtt gagcagcctc 900
agtatcctgc gcctcagtca caacgccatc agtcacattg ctgaaggcgc cttcaaggga 960
ctcaagagtc tgcgggtctt ggacctggac cataacgaga tctcgggtac aatcgaggat 1020
accagtggtg cctttacggg gcttgacaac ctcagcaagc tgactctgtt tggaaacaag 1080
atcaaatctg tggctaagag agccttctcg ggcctggaaa gcctggaaca cctgaacctt 1140
ggagagaatg caatcaggtc tgtccagttt gatgcctttg caaagatgaa gaaccttaaa 1200
gagctctaca tcagcagtga gagcttcctg tgtgactgcc agctcaagtg gctgccccca 1260
tggctaatgg gtaggatgct gcaggccttt gtgacagcca cctgtgccca tccagagtcg 1320
ctgaagggcc agagcatttt ctcagtgctg ccagacagct ttgtgtgtga tgactttcca 1380
aagccacaga tcatcaccca gcctgagacg accatggctg tggtgggcaa ggacatccgt 1440
ttcacatgct ccgcagccag cagcagcagc tcaccaatga ccttcgcctg gaagaaggac 1500
aatgaggtcc tggccaatgc agacatggag aactttgccc acgtccgtgc acaggacggc 1560
gaagtgatgg agtataccac tatcctgcac ctccgtcacg tcacctttgg gcacgagggc 1620
cgctaccagt gtatcatcac aaaccacttt ggctccacat actcccacaa agccaggctc 1680
actgtgaatg tgttgccatc attcactaaa ataccccatg acattgccat ccggactggc 1740
accacagccc gcctcgagtg tgctgccacg ggccacccta accctcagat tgcctggcag 1800
aaggatggag gcaccgattt cccggcagct cgtgagcgac gcatgcatgt tatgccagac 1860
gatgatgtgt tcttcatcac tgatgtgaaa atagacgaca tgggggtcta cagctgcact 1920
gcccagaact cggcaggctc ggtttcagcc aacgctaccc tcacagtctt agaaactcca 1980
tccttggcag tgcctctgga agaccgtgtg gtaactgtgg gagaaacagt ggccttccag 2040
tgcaaagcaa ccgggagccc cacaccacgc atcacctggc ttaagggagg tcgcccattg 2100
agcctcacag agcgccacca tttcactcca ggcaaccagc tgctggttgt tcagaatgtg 2160
atgatagacg atgcagggcg gtatacctgt gagatgtcta atcccctggg cactgagcga 2220
gcacatagcc agctgagcat tttacctacc cctggctgcc ggaaggatgg gaccaccgta 2280
ggc 2283
<210> 5
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> A7 Heavy chain CDR1
<400> 5
Gly Tyr Asp Met Ser
1 5
<210> 6
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> A7 heavy chain CDR2
<400> 6
Leu Ile Tyr Pro Asp Ser Gly Asn Lys
1 5
<210> 7
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> A7 light chain CDR3
<400> 7
Leu Ile Tyr Pro Asp Ser Gly Asn Lys
1 5
<210> 8
<211> 469
<212> PRT
<213> Artificial Sequence
<220>
<223> A7 heavy chain
<400> 8
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
20 25 30
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
35 40 45
Phe Ser Gly Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
50 55 60
Leu Glu Trp Val Ser Leu Ile Tyr Pro Asp Ser Gly Asn Lys Tyr Tyr
65 70 75 80
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
85 90 95
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Arg Asp Ala Gly Leu Ser Trp Ala Gly Ala Phe
115 120 125
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Ala
130 135 140
Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser
145 150 155 160
Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
165 170 175
Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
195 200 205
Val Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala
210 215 220
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly
225 230 235 240
Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu
245 250 255
Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val
260 265 270
Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val
275 280 285
Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val
290 295 300
Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser
305 310 315 320
Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met
325 330 335
Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala
340 345 350
Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro
355 360 365
Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln
370 375 380
Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr
385 390 395 400
Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr
405 410 415
Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu
420 425 430
Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser
435 440 445
Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser
450 455 460
Arg Thr Pro Gly Lys
465
<210> 9
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> A7 Heavy chain CDR1
<400> 9
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Thr
1 5 10
<210> 10
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> A7 Light chain CDR2
<400> 10
Ser Asp Ser His
1
<210> 11
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> A7 Light chain CDR3
<400> 11
Gly Ser Trp Asp Tyr Ser Leu Ser Ala
1 5
<210> 12
<211> 237
<212> PRT
<213> Artificial Sequence
<220>
<223> A7 Light chain
<400> 12
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly
20 25 30
Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn
35 40 45
Ile Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala
50 55 60
Pro Lys Leu Leu Ile Tyr Ser Asp Ser His Arg Pro Ser Gly Val Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile
85 90 95
Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp
100 105 110
Asp Tyr Ser Leu Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
115 120 125
Val Leu Arg Thr Val Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser
130 135 140
Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn
145 150 155 160
Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser
165 170 175
Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys
180 185 190
Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu
195 200 205
Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser
210 215 220
Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 13
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> A8 Heavy chain CDR1
<400> 13
Asp Tyr Asp Met Ser
1 5
<210> 14
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> A8 Heavy chain CDR2
<400> 14
Trp Ile Ser His Gly Gly Gly Ser Ile
1 5
<210> 15
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> A8 Heavy chain CDR3
<400> 15
Arg Gly Leu Gly Leu Cys Lys Thr Gly Leu Cys Tyr Tyr Tyr Asp Ala
1 5 10 15
Met Asp Val
<210> 16
<211> 475
<212> PRT
<213> Artificial Sequence
<220>
<223> A8 Heavy chain
<400> 16
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
20 25 30
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
35 40 45
Phe Ser Asp Tyr Asp Met Ser Trp Val Arg Gln Val Pro Gly Lys Gly
50 55 60
Leu Glu Trp Val Ser Trp Ile Ser His Gly Gly Gly Ser Ile Tyr Tyr
65 70 75 80
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
85 90 95
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Arg Gly Leu Gly Leu Cys Lys Thr Gly Leu Cys
115 120 125
Tyr Tyr Tyr Asp Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr
130 135 140
Val Ser Ser Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys
145 150 155 160
Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly
165 170 175
Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser
180 185 190
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr
195 200 205
Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser
210 215 220
Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys
225 230 235 240
Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys
245 250 255
Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro
260 265 270
Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr
275 280 285
Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser
290 295 300
Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His
305 310 315 320
Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile
325 330 335
Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn
340 345 350
Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys
355 360 365
Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu
370 375 380
Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe
385 390 395 400
Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu
405 410 415
Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr
420 425 430
Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg
435 440 445
Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His
450 455 460
Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
465 470 475
<210> 17
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> A8 Light chain CDR1
<400> 17
Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn Ser Val Thr
1 5 10
<210> 18
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> A8 Light chain CDR2
<400> 18
Ala Asp Asn Asn
1
<210> 19
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> A8 Light chain CDR3
<400> 19
Ala Ala Trp Asp Ser Ser Leu Ser Ala
1 5
<210> 20
<211> 237
<212> PRT
<213> Artificial Sequence
<220>
<223> A8 Light chain
<400> 20
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly
20 25 30
Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn
35 40 45
Ile Gly Asn Asn Ser Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala
50 55 60
Pro Lys Leu Leu Ile Tyr Ala Asp Asn Asn Arg Pro Ser Gly Val Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile
85 90 95
Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp
100 105 110
Asp Ser Ser Leu Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
115 120 125
Val Leu Arg Thr Val Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser
130 135 140
Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn
145 150 155 160
Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser
165 170 175
Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys
180 185 190
Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu
195 200 205
Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser
210 215 220
Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 21
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> B8 Heavy chain CDR1
<400> 21
Asp Tyr Tyr Met Ser
1 5
<210> 22
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> B8 Heavy chain CDR2
<400> 22
Gly Ile Ser His Asp Ser Gly Ser Lys
1 5
<210> 23
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> B8 Heavy chain CDR3
<400> 23
Arg His Trp Thr Thr Phe Asp Tyr
1 5
<210> 24
<211> 464
<212> PRT
<213> Artificial Sequence
<220>
<223> B8 Heavy chain
<400> 24
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
20 25 30
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
35 40 45
Phe Ser Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
50 55 60
Leu Glu Trp Val Ser Gly Ile Ser His Asp Ser Gly Ser Lys Tyr Tyr
65 70 75 80
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
85 90 95
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Arg His Trp Thr Thr Phe Asp Tyr Trp Gly Gln
115 120 125
Gly Thr Leu Val Thr Val Ser Ser Thr Thr Ala Pro Ser Val Tyr Pro
130 135 140
Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly
145 150 155 160
Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn
165 170 175
Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
180 185 190
Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr
195 200 205
Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser
210 215 220
Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro
225 230 235 240
Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser
245 250 255
Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu
260 265 270
Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro
275 280 285
Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala
290 295 300
Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val
305 310 315 320
Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe
325 330 335
Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr
340 345 350
Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu
355 360 365
Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys
370 375 380
Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn
385 390 395 400
Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp
405 410 415
Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys
420 425 430
Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly
435 440 445
Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
450 455 460
<210> 25
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> B8 Light chain CDR1
<400> 25
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Asn Val Thr
1 5 10
<210> 26
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> B8 Light chain CDR2
<400> 26
Ala Asn Ser Asn
1
<210> 27
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> B8 Light chain CDR3
<400> 27
Gly Ala Trp Asp Tyr Ser Leu Ser Ala
1 5
<210> 28
<211> 237
<212> PRT
<213> Artificial Sequence
<220>
<223> B8 Light chain
<400> 28
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly
20 25 30
Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn
35 40 45
Ile Gly Ser Asn Asn Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala
50 55 60
Pro Lys Leu Leu Ile Tyr Ala Asn Ser Asn Arg Pro Ser Gly Val Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile
85 90 95
Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp
100 105 110
Asp Tyr Ser Leu Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
115 120 125
Val Leu Arg Thr Val Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser
130 135 140
Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn
145 150 155 160
Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser
165 170 175
Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys
180 185 190
Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu
195 200 205
Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser
210 215 220
Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 29
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> C8 Heavy chain CDR1
<400> 29
Asn Tyr Tyr Met Ser
1 5
<210> 30
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> C8 Heavy chain CDR2
<400> 30
Gly Ile Ser Pro Gly Asp Ser Ser Thr
1 5
<210> 31
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> C8 Heavy chain CDR3
<400> 31
Lys Gly Leu Tyr Ser Asn Pro Asn Glu Pro Phe Asp Tyr
1 5 10
<210> 32
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> C8 Heavy chain
<400> 32
Gly Ile Ser Pro Gly Asp Ser Ser Thr
1 5
<210> 33
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> C8 Light chain CDR1
<400> 33
Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Ser
1 5 10
<210> 34
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> C8 Light chain CDR2
<400> 34
Asp Asp Ser Gln
1
<210> 35
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> C8 Light chain CDR3
<400> 35
Gly Thr Trp Asp Tyr Ser Leu Asn Gly
1 5
<210> 36
<211> 237
<212> PRT
<213> Artificial Sequence
<220>
<223> C8 Light chain
<400> 36
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly
20 25 30
Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn
35 40 45
Ile Gly Ser Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala
50 55 60
Pro Lys Leu Leu Ile Tyr Asp Asp Ser Gln Arg Pro Ser Gly Val Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile
85 90 95
Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp
100 105 110
Asp Tyr Ser Leu Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
115 120 125
Val Leu Arg Thr Val Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser
130 135 140
Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn
145 150 155 160
Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser
165 170 175
Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys
180 185 190
Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu
195 200 205
Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser
210 215 220
Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 37
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> D9 Heavy chain CDR1
<400> 37
Asn Tyr Ala Met Ser
1 5
<210> 38
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> D9 Heavy chain CDR2
<400> 38
Ala Ile Tyr Pro Gly Gly Gly Ser Ile
1 5
<210> 39
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> D9 Heavy chain CDR3
<400> 39
Arg Asp Ile Leu Pro Cys Pro Trp Gly Arg Cys Tyr Tyr Asp Tyr Ala
1 5 10 15
Met Asp Val
<210> 40
<211> 475
<212> PRT
<213> Artificial Sequence
<220>
<223> D9 Heavy chain
<400> 40
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
20 25 30
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
35 40 45
Phe Ser Asn Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
50 55 60
Leu Glu Trp Val Ser Ala Ile Tyr Pro Gly Gly Gly Ser Ile Tyr Tyr
65 70 75 80
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
85 90 95
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Arg Asp Ile Leu Pro Cys Pro Trp Gly Arg Cys
115 120 125
Tyr Tyr Asp Tyr Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr
130 135 140
Val Ser Ser Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys
145 150 155 160
Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly
165 170 175
Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser
180 185 190
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr
195 200 205
Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser
210 215 220
Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys
225 230 235 240
Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys
245 250 255
Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro
260 265 270
Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr
275 280 285
Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser
290 295 300
Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His
305 310 315 320
Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile
325 330 335
Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn
340 345 350
Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys
355 360 365
Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu
370 375 380
Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe
385 390 395 400
Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu
405 410 415
Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr
420 425 430
Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg
435 440 445
Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His
450 455 460
Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
465 470 475
<210> 41
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> D9 Light chain CDR1
<400> 41
Ser Asp Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Ser
1 5 10
<210> 42
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> D9 Light chain CDR2
<400> 42
Ala Asp Asn Asn
1
<210> 43
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> D9 Light chain CDR3
<400> 43
Gly Thr Trp Asp Tyr Ser Leu Ser Gly
1 5
<210> 44
<211> 237
<212> PRT
<213> Artificial Sequence
<220>
<223> D9 Light chain
<400> 44
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly
20 25 30
Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Asp Ser Ser Ser Asn
35 40 45
Ile Gly Ser Asn Thr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala
50 55 60
Pro Lys Leu Leu Ile Tyr Ala Asp Asn Asn Arg Pro Ser Gly Val Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile
85 90 95
Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp
100 105 110
Asp Tyr Ser Leu Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
115 120 125
Val Leu Arg Thr Val Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser
130 135 140
Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn
145 150 155 160
Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser
165 170 175
Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys
180 185 190
Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu
195 200 205
Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser
210 215 220
Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 45
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> E7 Heavy chain CDR1
<400> 45
Ser Tyr Asp Met Ser
1 5
<210> 46
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> E7 Heavy chain CDR2
<400> 46
Gly Ile Ser Pro Asp Gly Ser Asn Ile
1 5
<210> 47
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> E7 Heavy chain CDR3
<400> 47
Lys Val Gly Leu Arg Cys Arg Tyr Glu Ala Cys Ser Tyr Ala Tyr Gly
1 5 10 15
Met Asp Val
<210> 48
<211> 475
<212> PRT
<213> Artificial Sequence
<220>
<223> E7 Heavy chain
<400> 48
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
20 25 30
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
35 40 45
Phe Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
50 55 60
Leu Glu Trp Val Ser Gly Ile Ser Pro Asp Gly Ser Asn Ile Tyr Tyr
65 70 75 80
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
85 90 95
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Lys Val Gly Leu Arg Cys Arg Tyr Glu Ala Cys
115 120 125
Ser Tyr Ala Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr
130 135 140
Val Ser Ser Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys
145 150 155 160
Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly
165 170 175
Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser
180 185 190
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr
195 200 205
Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser
210 215 220
Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys
225 230 235 240
Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys
245 250 255
Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro
260 265 270
Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr
275 280 285
Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser
290 295 300
Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His
305 310 315 320
Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile
325 330 335
Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn
340 345 350
Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys
355 360 365
Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu
370 375 380
Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe
385 390 395 400
Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu
405 410 415
Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr
420 425 430
Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg
435 440 445
Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His
450 455 460
Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
465 470 475
<210> 49
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> E7 Light chain CDR1
<400> 49
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Ser
1 5 10
<210> 50
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> E7 Light chain CDR2
<400> 50
Ser Asp Ser His
1
<210> 51
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> E7 Light chain CDR3
<400> 51
Ala Thr Trp Asp Ser Ser Leu Asn Gly
1 5
<210> 52
<211> 237
<212> PRT
<213> Artificial Sequence
<220>
<223> E7 Light chain
<400> 52
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly
20 25 30
Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn
35 40 45
Ile Gly Ser Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala
50 55 60
Pro Lys Leu Leu Ile Tyr Ser Asp Ser His Arg Pro Ser Gly Val Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile
85 90 95
Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp
100 105 110
Asp Ser Ser Leu Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
115 120 125
Val Leu Arg Thr Val Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser
130 135 140
Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn
145 150 155 160
Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser
165 170 175
Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys
180 185 190
Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu
195 200 205
Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser
210 215 220
Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 53
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> G3 Heavy chain CDR1
<400> 53
Asn Tyr Asp Met Ser
1 5
<210> 54
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> G3 Heavy chain CDR2
<400> 54
Ser Ile Ser Pro Ser Ser Gly Ser Ile
1 5
<210> 55
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> G3 Heavy chain CDR3
<400> 55
Lys Asp Leu Asp Ala Phe Trp Arg Pro Ser Phe Asp Tyr
1 5 10
<210> 56
<211> 469
<212> PRT
<213> Artificial Sequence
<220>
<223> G3 Heavy chain
<400> 56
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
20 25 30
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
35 40 45
Phe Ser Asn Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
50 55 60
Leu Glu Trp Val Ser Ser Ile Ser Pro Ser Ser Gly Ser Ile Tyr Tyr
65 70 75 80
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
85 90 95
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Lys Asp Leu Asp Ala Phe Trp Arg Pro Ser Phe
115 120 125
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Ala
130 135 140
Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser
145 150 155 160
Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
165 170 175
Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
195 200 205
Val Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala
210 215 220
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly
225 230 235 240
Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu
245 250 255
Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val
260 265 270
Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val
275 280 285
Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val
290 295 300
Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser
305 310 315 320
Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met
325 330 335
Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala
340 345 350
Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro
355 360 365
Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln
370 375 380
Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr
385 390 395 400
Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr
405 410 415
Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu
420 425 430
Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser
435 440 445
Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser
450 455 460
Arg Thr Pro Gly Lys
465
<210> 57
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> G3 Light chain CDR1
<400> 57
Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn Asn Val Asn
1 5 10
<210> 58
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> G3 Light chain CDR2
<400> 58
Ser Asp Ser His
1
<210> 59
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> G3 Light chain CDR3
<400> 59
Gly Ser Trp Asp Asp Ser Leu Ser Ala
1 5
<210> 60
<211> 237
<212> PRT
<213> Artificial Sequence
<220>
<223> G3 Light chain
<400> 60
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly
20 25 30
Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn
35 40 45
Ile Gly Asn Asn Asn Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala
50 55 60
Pro Lys Leu Leu Ile Tyr Ser Asp Ser His Arg Pro Ser Gly Val Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile
85 90 95
Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp
100 105 110
Asp Asp Ser Leu Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
115 120 125
Val Leu Arg Thr Val Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser
130 135 140
Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn
145 150 155 160
Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser
165 170 175
Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys
180 185 190
Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu
195 200 205
Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser
210 215 220
Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 61
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> H6 Heavy chain CDR1
<400> 61
Asn Tyr Ala Met Ser
1 5
<210> 62
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> H6 Heavy chain CDR2
<400> 62
Val Ile Ser His Gly Gly Gly Ser Thr
1 5
<210> 63
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> H6 Heavy chain CDR3
<400> 63
Arg Val Ile Ser Asn Cys His Leu Gly Val Cys Tyr Tyr Ser Asn Gly
1 5 10 15
Met Asp Val
<210> 64
<211> 475
<212> PRT
<213> Artificial Sequence
<220>
<223> H6 Heavy chain
<400> 64
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
20 25 30
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
35 40 45
Phe Ser Asn Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
50 55 60
Leu Glu Trp Val Ser Val Ile Ser His Gly Gly Gly Ser Thr Tyr Tyr
65 70 75 80
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
85 90 95
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Arg Val Ile Ser Asn Cys His Leu Gly Val Cys
115 120 125
Tyr Tyr Ser Asn Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr
130 135 140
Val Ser Ser Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys
145 150 155 160
Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly
165 170 175
Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser
180 185 190
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr
195 200 205
Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser
210 215 220
Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys
225 230 235 240
Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys
245 250 255
Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro
260 265 270
Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr
275 280 285
Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser
290 295 300
Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His
305 310 315 320
Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile
325 330 335
Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn
340 345 350
Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys
355 360 365
Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu
370 375 380
Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe
385 390 395 400
Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu
405 410 415
Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr
420 425 430
Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg
435 440 445
Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His
450 455 460
Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
465 470 475
<210> 65
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> H6 Light chain CDR1
<400> 65
Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Asp Val Tyr
1 5 10
<210> 66
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> H6 Light chain CDR2
<400> 66
Ser Asp Ser Gln
1
<210> 67
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> H6 Light chain CDR3
<400> 67
Ser Asp Ser His
1
<210> 68
<211> 237
<212> PRT
<213> Artificial Sequence
<220>
<223> H6 Light chain
<400> 68
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly
20 25 30
Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn
35 40 45
Ile Gly Asn Asn Asp Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala
50 55 60
Pro Lys Leu Leu Ile Tyr Ser Asp Ser Gln Arg Pro Ser Gly Val Pro
65 70 75 80
Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile
85 90 95
Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp
100 105 110
Asp Tyr Ser Leu Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
115 120 125
Val Leu Arg Thr Val Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser
130 135 140
Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn
145 150 155 160
Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser
165 170 175
Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys
180 185 190
Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu
195 200 205
Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser
210 215 220
Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
Claims (5)
- Lrig-1+ 면역세포를 포함하는 암 또는 면역 질환 예방 또는 치료용 약학 조성물.
- 제 1항에 있어서,
상기 Lrig-1+ 면역 세포는 조절 T (Regulatory T)세포인 것인, 약학 조성물. - Lrig-1+ 면역세포를 포함하는 암 또는 면역 질환 예방 또는 치료용 세포 치료제.
- a) 환자로부터 분리된 생물학적 시료로부터 면역세포를 획득하는 단계; 및
b) 상기 면역세포들로부터 Lrig-1 단백질이 표면에 발현되는 세포를 분리하는 단계를 포함하는 세포 치료제의 제조방법. - 제 4항에 있어서,
상기 b) 단계는 세포를 분리하는 기술은 FACS(fluorescence-activated cell sorting), MACS(Magnetic-activated cell sorting) 및 친화 크로마토그래피(affinity chromatography) 중 어느 하나 이상인 것인, 세포 치료제의 제조방법.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020170049856A KR20180116925A (ko) | 2017-04-18 | 2017-04-18 | 암 또는 면역 질환의 예방 또는 치료용 약학 조성물 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020170049856A KR20180116925A (ko) | 2017-04-18 | 2017-04-18 | 암 또는 면역 질환의 예방 또는 치료용 약학 조성물 |
Publications (1)
Publication Number | Publication Date |
---|---|
KR20180116925A true KR20180116925A (ko) | 2018-10-26 |
Family
ID=64099215
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020170049856A KR20180116925A (ko) | 2017-04-18 | 2017-04-18 | 암 또는 면역 질환의 예방 또는 치료용 약학 조성물 |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR20180116925A (ko) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021002735A1 (ko) * | 2019-07-04 | 2021-01-07 | 주식회사 굳티셀 | T 세포의 세포 표면 항원 및 이의 다양한 용도 |
WO2021091359A1 (ko) * | 2019-11-08 | 2021-05-14 | 주식회사 굳티셀 | 조절 t 세포 표면 항원의 에피토프 및 이에 특이적으로 결합하는 항체 |
CN113811330A (zh) * | 2019-03-20 | 2021-12-17 | 古德T细胞有限公司 | 预防或治疗脑和神经系统疾病的组合物 |
CN114173814A (zh) * | 2019-07-11 | 2022-03-11 | 古德T细胞有限公司 | 用于预防、改善或治疗免疫检查点抑制剂耐药癌症的组合物 |
WO2022086197A1 (ko) * | 2020-10-22 | 2022-04-28 | 주식회사 굳티셀 | 활성화된 면역 세포의 세포 표면 항원 및 이의 다양한 용도 |
-
2017
- 2017-04-18 KR KR1020170049856A patent/KR20180116925A/ko unknown
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113811330A (zh) * | 2019-03-20 | 2021-12-17 | 古德T细胞有限公司 | 预防或治疗脑和神经系统疾病的组合物 |
EP3943107A4 (en) * | 2019-03-20 | 2022-12-07 | Good T Cells, Inc. | COMPOSITION FOR PREVENTING OR TREATING DISEASE OF THE BRAIN AND NERVOUS SYSTEM |
WO2021002735A1 (ko) * | 2019-07-04 | 2021-01-07 | 주식회사 굳티셀 | T 세포의 세포 표면 항원 및 이의 다양한 용도 |
CN114173814A (zh) * | 2019-07-11 | 2022-03-11 | 古德T细胞有限公司 | 用于预防、改善或治疗免疫检查点抑制剂耐药癌症的组合物 |
WO2021091359A1 (ko) * | 2019-11-08 | 2021-05-14 | 주식회사 굳티셀 | 조절 t 세포 표면 항원의 에피토프 및 이에 특이적으로 결합하는 항체 |
WO2022086197A1 (ko) * | 2020-10-22 | 2022-04-28 | 주식회사 굳티셀 | 활성화된 면역 세포의 세포 표면 항원 및 이의 다양한 용도 |
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