KR20210007916A - 면역체크포인트 억제제 저항성 암의 예방, 개선 또는 치료용 조성물 - Google Patents
면역체크포인트 억제제 저항성 암의 예방, 개선 또는 치료용 조성물 Download PDFInfo
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Abstract
본 발명은 본 발명은 조절 T 세포(Regulatory T cell; Treg)의 표면에 존재하는 단백질인 Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질에 특이적으로 결합할 수 있는 결합 분자를 유효성분으로 포함하는 면역체크포인트 억제제 저항성 암의 예방, 개선 또는 치료용 조성물에 관한 것으로서, 본 발명에 따른 Lrig-1 단백질에 특이적인 결합 분자는 Lrig-1 단백질이 높은 수준으로 발현되어 있는 조절 T 세포, 즉 종양 침윤 림프구(tumor infiltrating lymphocytes; TIL)에 속하는 조절 T 세포 또는 활성화된 조절 T 세포의 기능을 억제하여, 조절 T 세포에 의해 효과 T 세포의 기능이 억제되는 현상을 매우 효과적으로 차단함으로써 면역 회피 암, 즉 면역 체크 포인트 억제제에 내성이 존재하는 암을 효과적으로 예방, 개선 또는 치료할 수 있다.
Description
본 발명은 조절 T 세포(Regulatory T cell; Treg)의 표면에 존재하는 단백질인 Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질에 특이적으로 결합할 수 있는 결합 분자를 유효성분으로 포함하는 면역체크포인트 억제제 저항성 암의 예방, 개선 또는 치료용 조성물에 관한 것이다.
면역항암제는 암 자체를 공격하는 기존 항암제와는 달리 인공면역 단백질을 체내에 주입하여 면역체계를 자극함으로써 면역세포가 선택적으로 암세포만을 공격하도록 유도하는 치료약제이다. 이들 면역항암제에는 면역체크포인트 억제제, 면역세포치료제, 면역바이러스치료제 등이 있다.
면역항암제 등과 같은 항체 기반 암 치료법은 통상적인 약물에 비해 잠재적으로 특이성이 높고 부작용이 낮다는 특성을 갖는다. 그 이유는 항체에 의한 정상 세포와 신생 세포 간의 정밀한 구별이 가능하다는 것과 이들의 작용 방식이 세포독성 면역 세포의 유입 및 상보적인 활성화와 같은 독성이 덜한 면역학적 항종양 메카니즘에 의존하기 때문이다.
항체 기반 요법을 위한 표적은 정상 세포와 신생 세포를 적절하게 구별 지을 만한 기초가 되는 특정한 성질을 가져야만 한다. 효과적이고도 안전한 항체 요법을 개발하는데 있어서, 종양 세포에만 독점적으로 국한되거나, 정상 조직상에서는 전혀 검출되지 않는 표적이 이상적일 것은 두 말 할 필요도 없다. 다른 측면에서, 고도의 과발현은 치료 창의 기초가 될 수 있고 유전자 증폭의 결과로서 인간 상피성장인자 수용체 타입 2(HER-2)에 의해 예시되는 낮은 부작용은 항체 트라스투주맙(헤르셉틴)의 우수한 표적이다.
종양 치료법에서 이미 승인받았거나 임상 개발 중에 있는 항체들의 다른 표적들은 종양 세포 상의 표적 분자의 수치상의 과발현에 기초하지 않는, 고유한 특성을 갖는다. 프로테오글리칸 MUC-1에 대한 항체의 경우, 표적의 골격 중에 존재하는 펩타이드 반복 에피토프가 종양 세포에서 언더글리코실화되어 그의 정상적인 카운터파트로 변경된다. CD20(리툭시맙), CD52(캄파트-1H) 및 CD22(에프라투주맙)에 대한 항체의 경우, 항체 표적들은 종양 세포과 정상적인 임파구 상에서 필적할만한 발현 수준을 보인다. 이와 관련해서, 표적-음성적인 줄기 세포들이 정상적인 임파구 레파토리를 복구시켜주기 때문에, 항체에 의한 정상 세포의 제거는 관용될 수 있다. 항체 표적의 서로 다른 접근성의 또 다른 예는 암배아성 항원(CEA)와 카보안하이드라제 IX(CA9)이다. 이들 두 가지 항원은 모두 각각 결장과 신장의 정상적인 상피에서 발현된다. 그러나, 방사능 표지된 조영 항체들은 종양 조직과 정상 조직을 잘 구별해 내기 때문에, 세포독성 항체들은 잘 관용된다. 이는 아마도 IgG 항체가 접근하지 못하는 정상적인 상피 조직의 관강 쪽에만 CA9와 CEA의 발현이 국한되기 때문인 것으로 여겨진다. 항원 상피 세포 부착 분자(Ep-CAM) 역시도 이 카테고리에 속한다. 상피 세포에 대한 상동기관 세포 부착 분자로서, 이것은 세포간 공간에 위치한다. 흥미로운 것은, 고친화성 항Ep CAM 항체들은 매우 독성이 높은 반면, 중간 정도의 친화성 항체들은 잘 관용된다는 점이다. 이는, 정상 세포에 대한 Ep-CAM 표적의 접근성뿐만 아니라, 항체 결합의 동역학(kinetics)이 새로운 치료 창을 열어줄 수 있음을 시사하는 것이다.
신생조직과 관련한 질병을 치료하는데 있어서 8 가지 항체가 승인되었지만, 이들 대부분은 임파종과 백혈병에 대한 것이다(Adams, G. P. & Weiner, L. M. (2005) Nat. Biotechnol.23, 1147-1157). 단 3개의 단일클론항체, 즉, 허셉틴(Herceptin), 아바스틴 및 에르비툭스만이 암사망률의 90% 이상을 차지하는 고형암 종류에 듣는다. 실질적으로 잔존하는 의학적 요청, 현저한 임상적 장점이 인정된 mAb가 이미 제공되었고 이들의 상당한 상업적 성공 역시 여러 그룹의 환자들에 대한 항체 기반 요법 개발과 이들의 효능 증강이 잘 균형을 이룬 새로운 혁신적인 접근법을 개발하는 동기를 제공하였다(Brekke, O. H. & Sandlie, I. (2003) Nat. Rev. Drug Discov.2, 52-62; Carter, P. (2001) Nat. Rev. Cancer1, 118-129).
그러나, 폐암 등의 경우 PD-1/PD-L1 억제제의 전체적인 반응율(overall response rate (ORR)이 15-20% 미만에 이르고 있다. 이러한 PD-1/PD-L1 억제제를 이용한 치료적 효능의 한계성을 적절히 설명하는 현상은 종양 미세환경에서 형성된 면역억제 기작들로 제시되어왔다. 이에, 종양 미세환경을 개선하면서 면역체크포인트 억제제의 반응율을 높이기 위하여 종양 항원을 인지하는 T 세포의 수를 증가시키거나, TNFRS 자극제를 이용하는 전략 및 종양에 특정한 항원 백신을 추가적으로 주사하는 등의 전략 등이 사용되고 있으나, 아직까지 그 효용성이 미비한 실정이다.
본 발명의 일 목적은 Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질에 특이적으로 결합하는 결합 분자를 유효성분으로 포함하는 면역체크포인트 억제제 저항성 암의 예방, 개선 또는 치료용 조성물을 제공하는 것이다.
본 발명의 다른 목적은 항체-약물 결합체(Antibody-Drug Conjugate, ADC)를 유효성분으로 포함하는 면역체크포인트 억제제 저항성 암의 예방, 개선 또는 치료용 조성물을 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.
1.
Lrig-1 단백질에 특이적으로 결합하는 결합 분자를 유효성분으로 포함하는 면역체크포인트 억제제 저항성 암의 예방, 개선 또는 치료용 조성물
본 발명의 일 구현 예에 따르면, Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질에 특이적으로 결합하는 결합 분자를 유효성분으로 포함하는 면역체크포인트 억제제 저항성 암의 예방, 개선 또는 치료용 조성물에 관한 것이다.
본 발명의 상기 조성물은 약학 조성물 또는 식품 조성물로 사용될 수 있다.
본 발명에서 상기 결합 분자는 Lrig-1 단백질이 높은 수준으로 발현되어 있는 조절 T 세포(Regulatory T cell; Treg), 즉 종양 침윤 림프구(tumor infiltrating lymphocytes; TIL)에 속하는 조절 T 세포 또는 활성화된 조절 T 세포의 기능을 억제하여, 조절 T 세포에 의해 효과 T 세포의 기능이 억제되는 현상을 매우 효과적으로 차단함으로써 면역 회피 암, 즉 면역체크 포인트 억제제에 내성이 존재하는 암을 효과적으로 예방, 개선 또는 치료할 수 있다.
본 발명에서 상기 Lrig-1 단백질이 표면에 존재하는 조절 T 세포는 종양 침윤 림프구 또는 활성화된 조절 T 세포인 것일 수 있다.
본 발명에서 상기 "종양 침윤 림프구"란, 혈류로부터 종양 조직이 있는 부위로 이동되어 암 조직 또는 종양미세환경(Tumor microenvironment; TME)에 침윤된 림프구를 의미한다. 상기 종양 침윤 림프구에 의해 세포독성 면역 반응이 유발될 수 있으나, Lrig-1 단백질이 표면에 존재하는 조절 T 세포의 경우에는 효과 T 세포의 작용을 억제하는 기능이 활성화(활성화된 조절 T 세포)되어 있으므로 세포독성 면역 반응을 오히려 억제할 수 있다.
본 발명에서 상기 "활성화된 조절 T 세포"란, 효과 T 세포(effector T cell)의 유도와 확산을 억제하거나, 하향 조절할 수 있는 기능이 활성화된 조절 T 세포를 의미한다. 상기 Lrgi-1 단백질이 표면에 존재하지 않는 조절 T 세포와는 달리, Lrig-1 단백질이 표면에 존재하는 경우에는 효과 T 세포의 유도와 확산을 억제하는 기능이 활성화되어 있을 수 있다.
본 발명에서 상기 "면역체크포인트 억제제 저항성"이란, 면역체크포인트 억제제, 예를 들면, PD-1 억제제(pembrolizumab과 nivolumab) 또는 PD-L1 억제제(atezolizumab) 등에 의해 처음부터 약물에 대한 반응이 없는 비 반응군이거나, 약물의 오랜 처치로 인해 면역체크포인트 억제제를 외부 물질로 인식하여 이를 제거하는 면역반응이 유도되는 등의 기작을 통해 약물에 대한 반응이 감소 또는 사라지는 현상을 갖게 되는 것을 의미한다.
본 발명에서 상기 "암"은 포유류에서 전형적으로 조절되지 않는 세포 성장으로 특징 지어진 생리적 상태를 나타내거나 가리킨다. 본 발명에서 예방, 개선 또는 치료의 대상이 되는 암은 고형 장기(solid organ)에서 비정상적으로 세포가 성장하여 발생한 덩어리로 이루어진 고형암(solid tumor)일 수 있고, 예를 들면, 고형 장기의 부위에 따라 위암, 간암, 교세포종, 난소암, 대장암, 두경부암, 방광암, 신장세포암, 유방암, 전이암, 전립선암, 췌장암, 흑색종 또는 폐암 등일 수 있으며, 예를 들면, 흑색종일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 "Lrig-1 단백질"은 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 LRIG3 유전자가 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. LRIG1 유전자가 위치한 염색체 3p14.3 부분이 잘리는 경우에는 암세포로 발전할 가능성이 있는 것으로 보고된 바 있으며, 실제로 신장암(renal cell carcinoma)과 편평상피암(cutaneous squamous cell carcinoma)에서는 LRIG1 유전자의 발현이 매우 감소되어 있는 것으로 확인되었다. 그런데 최근에는 상기 Lrig-1 단백질을 발현하는 암은 20~30% 정도에 불과하다고 밝혀지기도 하였다. 한편, 본 발명의 목적상 상기 Lrig-1 단백질은 인간 또는 쥐에 존재하는 단백질 일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 Lrig-1 단백질은 인간 유래인 서열번호 1로 표시되는 폴리펩티드이거나, 마우스 유래인 서열번호 3으로 표시되는 폴리펩티드일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 서열번호 1로 표시되는 Lrig-1 단백질은 서열번호 2로 표시되는 폴리뉴클레오티드에 의해 암호화되는 것일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 서열번호 3으로 표시되는 Lrig-1 단백질은 서열번호 4로 표시되는 폴리뉴클레오티드에 의해 암호화되는 것일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 사용되는 "결합 분자"는 키메라, 인간화 또는 인간 단일클론 항체와 같은 단일클론 항체를 포함하는 온전한(intact) 이뮤노글로블린(immunoglobulin), 또는 항원에 결합하는 이뮤노글로믈린, 예를 들면 인플루엔자 A 바이러스의 단량체 HA 또는 삼량체 HA와의 결합을 위해 온전한(intact) 이뮤노글로블린과 경쟁하는 이뮤노글로블린 단편을 포함하는 가변성 도메인을 뜻한다. 구조와는 상관없이 항원-결합 단편은 온전한(intact) 이뮤노글로블린에 의해 인식된 동일한 항원과 결합된다. 항원-결합 단편은 결합 분자의 아미노산 서열의 2개 이상의 연속기, 20개 이상의 연속 아미노산 잔기, 25개 이상의 연속 아미노산 잔기, 30개 이상의 연속 아미노산 잔기, 35개 이상의 연속 아미노산 잔기, 40개 이상의 연속 아미노산 잔기, 50개 이상의 연속 아미노산 잔기, 60개 이상의 연속 아미노산 잔기, 70개 이상의 연속 아미노산 잔기, 80개 이상의 연속 아미노산 잔기, 90개 이상의 연속 아미노산 잔기, 100개 이상의 연속 아미노산 잔기, 125개 이상의 연속 아미노산 잔기, 150개 이상의 연속 아미노산 잔기, 175개 이상 연속 아미노산 잔기, 200개 이상의 연속 아미노산 잔기, 또는 250개 이상의 연속 아미노산 잔기의 아미노산 서열을 포함하는 펩티드 또는 폴리펩티드를 포함할 수 있다.
본 발명에서 상기"항원-결합 단편"은 특히 Fab, F(ab'), F(ab')2, Fv, dAb, Fd, 상보성 결정 영역(CDR) 단편, 단일-쇄 항체(scFv), 2가(bivalent) 단일-쇄 항체, 단일-쇄 파지 항체, 유니바디(unibody), 디아바디(diabody), 트리아바디, 테트라바디, 폴리펩티드로의 특정 항원에 결합하기에 충분한 이뮤노글로블린의 하나 이상의 단편을 함유하는 폴리펩티드 등을 포함한다. 상기 단편은 합성으로 또는 완전한 이뮤노글로블린의 효소적 또는 화학적 분해에 의해 생성되거나, 재조합 DNA 기술에 의해 유전공학적으로 생성될 수 있다. 생성 방법은 당업계에 잘 알려져 있다.
본 발명에서 상기 결합 분자는 항체 또는 그 단편일 수 있다.
본 발명에서 상기 항체는 키메라 항체, 인간화 항체(humanized antibody), 인간 항체(human antibody), 이가(bivalent) 항체, 양특이성 분자, 미니바디(minibody), 도메인 항체, 이중특이적 항체(bispecific antibody), 항체 모방체, 유니바디(unibody), 디아바디(diabody), 트리아바디(triabody), 테트라바디(tetrabody) 또는 이의 단편일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에 있어서, 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 조절 T 세포(regulatory T cell)의 표면에 존재하는 Lrig-1 단백질일 수 있다. 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 항체는 2개의 전장의 경쇄 및 2개의 전장의 중쇄를 갖는 완전한 형태뿐만 아니라, 항체 분자의 기능적인 단편을 포함한다. 상기 항체 분자의 기능적인 단편이란, 적어도 항원 결합 기능을 보유하고 있는 단편을 의미하며, Fab, F(ab'), F(ab')2 및 Fv 등이 있다.
본 발명에서 상기 항체는 길항성(antagonist) 항체일 수 있다.
본 발명에서 상기 “길항성(antagonist) 항체”란 세포 표면의 특정 분자 또는 세포 내 특정 분자와 결합하는 것에 의해, 길항성 항체와 리간드의 결합에 의해 발생되는 세포 내의 생물학적 작용 또는 활성을 억제하는 작용을 하는 항체를 말한다. 예컨대, 본 발명에서 상기 길항성 항체는 조절 T 세포의 표면에 존재하는 Lrig-1 단백질과 결합하여 세포 내 혹은 세포 간에서 Lrig-1 단백질에 의한 하나 이상의 생물학적 작용들을 감소 또는 억제시킬 수 있다.
본 발명에서 상기 "면역글로불린"은 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.
또한, 본 발명에서 상기 "단일클론항체"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.
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 기능적인 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 영역과 경쇄 영역이 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 "키메라 항체"는, 생쥐 항체의 가변 영역 및 인간 항체의 불변 영역을 재조합 시킨 항체로서, 생쥐 항체에 비하여 면역 반응이 크게 개선된 항체이다.
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 "유니바디"는 일반적인 항체에 비하여 더 오랜 시간 동안 치료 효과 등이 발휘될 수 있도록 안정적인 작은 항체 형식을 생산하는 기술에 의해 제작된 것으로서, 유니바디는 IgG4 항체의 힌지 영역을 제거하여, 표적에 결합할 수 있는 영역이 하나만 존재하도록 제작된 것일 수 있다. 전체 크기의 IgG4 항체와 비교하여 상기 유니바디는 안정성 측면에서 매우 뛰어나다. 이와 같은 유니바디는 제 WO2007/059782 호 및 (Kolfschoten et al. (2007) Science 317: 1554-1557)를 참고하여 제작할 수 있다.
본 발명에서 상기 결합 분자는,
서열번호 5, 13, 21 및 29로 이루어진 군에서 선택되는 아미노산 서열로 이루어지는 중쇄 CDR1; 서열번호 6, 14, 22 및 30으로 이루어진 군에서 선택된 아미노산 서열로 이루어지는 중쇄 CDR2; 서열번호 7, 15, 23 및 31로 이루어진 군에서 선택된 아미노산 서열로 이루어지는 중쇄 CDR3;을 포함하는 중쇄 가변 영역; 및
서열번호 8, 16, 24 및 32로 이루어진 군에서 선택되는 아미노산 서열로 이루어지는 경쇄 CDR1; 서열번호 9, 17, 25 및 33으로 이루어진 군에서 선택되는 아미노산 서열로 표시되는 경쇄 CDR2; 서열번호 10, 18, 26 및 34로 이루어진 군에서 선택되는 아미노산 서열로 이루어지는 경쇄 CDR3;를 포함하는 경쇄 가변 영역을 포함하는 결합 분자일 수 있다.
본 발명에서 상기 결합 분자는,
(a) 서열번호 5로 표시되는 중쇄 CDR1, 서열번호 6으로 표시되는 중쇄 CDR2, 및 서열번호 7로 표시되는 중쇄 CDR3를 포함하는 중쇄 가변 영역;
(b) 서열번호 13으로 표시되는 중쇄 CDR1, 서열번호 14로 표시되는 중쇄 CDR2, 및 서열번호 15로 표시되는 중쇄 CDR3를 포함하는 중쇄 가변 영역;
(c) 서열번호 21로 표시되는 중쇄 CDR1, 서열번호 22로 표시되는 중쇄 CDR2, 및 서열번호 23으로 표시되는 중쇄 CDR3를 포함하는 중쇄 가변 영역; 및
(d) 서열번호 29로 표시되는 중쇄 CDR1, 서열번호 30으로 표시되는 중쇄 CDR2, 및 서열번호 31로 표시되는 중쇄 CDR3를 포함하는 중쇄 영역;으로 이루어진 군에서 선택되는 중쇄 가변 영역; 및
(e) 서열번호 8로 표시되는 경쇄 CDR1, 서열번호 9로 표시되는 경쇄 CDR2, 및 서열번호 10으로 표시되는 경쇄 CDR3를 포함하는 경쇄 가변 영역;
(f) 서열번호 16으로 표시되는 경쇄 CDR1, 서열번호 17로 표시되는 경쇄 CDR2, 및 서열번호 18로 표시되는 경쇄 CDR3를 포함하는 경쇄 가변 영역;
(g) 서열번호 24로 표시되는 경쇄 CDR1, 서열번호 25로 표시되는 경쇄 CDR2, 및 서열번호 26으로 표시되는 경쇄 CDR3를 포함하는 경쇄 가변 영역; 및
(h) 서열번호 32로 표시되는 경쇄 CDR1, 서열번호 33으로 표시되는 경쇄 CDR2, 및 서열번호 34로 표시되는 경쇄 CDR3를 포함하는 경쇄 가변 영역;으로 이루어진 군에서 선택되는 경쇄 가변 영역;을 포함하는 결합 분자일 수 있다.
본 발명에서 상기 결합 분자는,
(1) 서열번호 5로 표시되는 중쇄 CDR1, 서열번호 6으로 표시되는 중쇄 CDR2, 및 서열번호 7로 표시되는 중쇄 CDR3를 포함하는 중쇄 가변 영역; 및 서열번호 8로 표시되는 경쇄 CDR1, 서열번호 9로 표시되는 경쇄 CDR2, 및 서열번호 10으로 표시되는 경쇄 CDR3를 포함하는 경쇄 가변 영역을 포함하는 결합 분자;
(2) 서열번호 13으로 표시되는 중쇄 CDR1, 서열번호 14로 표시되는 중쇄 CDR2, 및 서열번호 15로 표시되는 중쇄 CDR3를 포함하는 중쇄 가변 영역; 및 서열번호 16으로 표시되는 경쇄 CDR1, 서열번호 17로 표시되는 경쇄 CDR2, 및 서열번호 18로 표시되는 경쇄 CDR3를 포함하는 경쇄 가변 영역을 포함하는 결합 분자;
(3) 서열번호 21로 표시되는 중쇄 CDR1, 서열번호 22로 표시되는 중쇄 CDR2, 및 서열번호 23으로 표시되는 중쇄 CDR3를 포함하는 중쇄 가변 영역; 및 서열번호 24로 표시되는 경쇄 CDR1, 서열번호 25로 표시되는 경쇄 CDR2, 및 서열번호 26으로 표시되는 경쇄 CDR3를 포함하는 경쇄 가변 영역을 포함하는 결합 분자; 및
(4) 서열번호 29로 표시되는 중쇄 CDR1, 서열번호 30으로 표시되는 중쇄 CDR2, 및 서열번호 31로 표시되는 중쇄 CDR3를 포함하는 중쇄 가변 영역; 및 서열번호 32로 표시되는 경쇄 CDR1, 서열번호 33으로 표시되는 경쇄 CDR2, 및 서열번호 34로 표시되는 경쇄 CDR3를 포함하는 경쇄 가변 영역을 포함하는 결합 분자;로 이루어진 군에서 선택되는 결합 분자일 수 있다.
본 발명에서, 상기 결합 분자는,
서열번호 11, 19, 27 및 35로 이루어진 군에서 선택되는 어느 하나의 아미노산 서열로 이루어지는 중쇄 가변 영역; 및
서열번호 12, 20, 28 및 36으로 이루어진 군에서 선택되는 어느 하나의 아미노산 서열로 이루어지는 경쇄 가변 영역;을 포함하는 결합 분자일 수 있다.
본 발명에서 상기 결합 분자는,
① 서열번호 11로 표시되는 중쇄 가변 영역, 및 서열번호 12로 표시되는 경쇄 가변 영역을 포함하는 결합 분자;
② 서열번호 19로 표시되는 중쇄 가변 영역, 및 서열번호 20으로 표시되는 경쇄 가변 영역을 포함하는 결합 분자;
③ 서열번호 27로 표시되는 중쇄 가변 영역, 및 서열번호 28로 표시되는 경쇄 가변 영역을 포함하는 결합 분자; 및
④ 서열번호 35로 표시되는 중쇄 가변 영역, 및 서열번호 36으로 표시되는 경쇄 가변 영역을 포함하는 결합 분자;로 이루어진 군에서 선택되는 결합 분자일 수 있다.
본 발명에서 상기 결합 분자는 Fc 영역(Fragment crystallization region) 또는 불변 영역(constant region)을 더 포함할 수 있다. 이때 상기 Fc 영역은 IgA, IgD, IgE, IgM, IgG1, IgG2, IgG3 또는 IgG4 항체의 Fc 영역이거나, 그로부터 유래된 것일 수 있고, 혹은 하이브리드 Fc(hybrid Fc) 영역일 수 있다.
본 발명에서 상기 Fc 영역은 포유동물 유래 IgA, IgD, IgE, IgM, IgG1, IgG2, IgG3 또는 IgG4 항체의 Fc 영역일 수 있고, 바람직하게는 인간 유래 IgA, IgD, IgE, IgM, IgG1, IgG2, IgG3 또는 IgG4 항체의 Fc 영역일 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 일 예시로서, 상기 불변 영역은 서열번호 37로 표시되는 마우스 유래 IgG2a 불변 영역일 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 일 예시로서, 상기 불변 영역은 서열번호 38로 표시되는 마우스 유래 면역글로불린 카파(kappa) 불변 영역일 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 일 예시로서, 상기 불변 영역은 서열번호 39 또는 40으로 표시되는 인간 유래 IgG1 불변 영역일 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 일 예시로서, 상기 불변 영역은 서열번호 41로 표시되는 인간 유래 면역글로불린 카파(kappa) 불변 영역일 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 일 예시로서, 상기 불변 영역은 서열번호 42로 표시되는 인간 유래 IgG2 불변 영역일 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 일 예시로서, 상기 불변 영역은 서열번호 43으로 표시되는 인간 유래 IgG3 불변 영역일 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 일 예시로서, 상기 불변 영역은 서열번호 44로 표시되는 인간 유래 IgG4 불변 영역일 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 일 예시로서, 상기 불변 영역은 인간 유래 면역글로불린 람다(lambda) 불변 영역일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 "하이브리드 Fc"는 인간 IgG 서브클래스의 조합 또는 인간 IgD 및 IgG의 조합으로부터 유도될 수 있다. 상기 하이브리드 Fc는 생물학적 활성 분자, 폴리펩티드 등에 결합하는 경우, 생물학적 활성 분자의 혈청 반감기를 증가시킬 뿐만 아니라 Fc-폴리펩타이드 융합 단백질을 코딩하는 뉴클레오티드가 발현될 때 폴리펩타이드의 발현 수준을 높이는 효과가 있다.
본 발명의 일 예시로서, 상기 하이브리드 Fc 영역은 서열번호 45로 표시되는 하이브리드 Fc일 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 상기 결합 분자에서 상기 Fc 또는 불변 영역은 상기 가변 영역에 링커(linker)로 연결될 수 있다. 이때 상기 Fc의 C-말단에 링커가 연결되며, 상기 링커에 본 발명의 결합 분자의 N-말단이 연결될 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 "링커(linker)"는 목적하는 질환의 조직 또는 세포 내에서 과발현되는 효소에 의해 절단될 수 있는 서열을 포함할 수 있다. 상기와 같이 과발현되는 효소에 의해 절단될 수 있는 경우에는 Fc 부분으로 인하여 폴리펩티드의 활성이 저하되는 것을 효과적으로 방지할 수 있다. 본 발명에서는 링커의 바람직한 예로, 혈액 내에 가장 많이 존재하는 인간 알부민의 282번 내지 314번째 부분에 위치한 33개의 아미노산으로 이루어진 펩티드 링커, 보다 바람직하게는 292번 내지 304번째 부분에 위치한 13개의 아미노산으로 이루어진 펩티드 링커일 수 있으며, 이러한 부분은 3차원적인 구조상 대부분 외부에 노출된 부분으로서 체내에서 면역반응을 유도할 가능성이 최소화된 부분이다. 단, 이에 제한되는 것은 아니다.
본 발명의 결합 분자는, 서열번호 37, 39, 40, 42, 43, 44 및 45로 이루어진 군에서 선택되는 아미노산 서열로 이루어지는 중쇄 불변 영역을 더 포함할 수 있다.
본 발명의 결합 분자는, 서열번호 38 또는 41로 표시되는 아미노산 서열로 이루어지는 경쇄 불변 영역을 더 포함할 수 있다.
본 발명의 결합 분자는,
서열번호 37로 표시되는 아미노산 서열로 이루어지는 중쇄 불변 영역; 및
서열번호 38로 표시되는 아미노산 서열로 이루어지는 경쇄 불변 영역을 더 포함할 수 있다.
본 발명의 결합 분자는,
서열번호 39, 40, 42, 43 또는 44로 표시되는 아미노산 서열로 이루어지는 중쇄 불변 영역; 및
서열번호 41로 표시되는 아미노산 서열로 이루어지는 경쇄 불변 영역을 더 포함할 수 있다.
본 발명의 결합 분자는,
서열번호 45로 표시되는 아미노산 서열로 이루어지는 중쇄 불변 영역을 더 포함할 수 있다.
본 발명의 결합 분자는,
서열번호 46으로 표시되는 중쇄, 및 서열번호 47로 표시되는 경쇄를 포함하는 결합 분자;
서열번호 48로 표시되는 중쇄, 및 서열번호 49로 표시되는 경쇄를 포함하는 결합 분자;
서열번호 50으로 표시되는 중쇄, 및 서열번호 51로 표시되는 경쇄를 포함하는 결합 분자; 및
서열번호 52로 표시되는 중쇄, 및 서열번호 53으로 표시되는 경쇄를 포함하는 결합 분자;로 이루어진 군에서 선택되는 결합 분자일 수 있다.
본 발명의 결합 분자는,
서열번호 90으로 표시되는 중쇄, 및 서열번호 91로 표시되는 경쇄를 포함하는 결합분자일 수 있다.
본 발명의 결합 분자는 항체인 것을 특징으로 하나 이에 한정되는 것은 아니다. 상기 항체는 단일클론항체(monoclonal antibody), 전장 항체 (full-length antibody) 또는 항체의 일부분으로써 Lrig-1 단백질에 결합할 능력을 가지며 본 발명의 결합 분자와 경쟁적으로 Lrig-1 항원 결정 부위에 결합하는 항체 단편 모두를 포함한다.
본 발명에서 상기 결합 분자는 Lrig-1 단백질에 결합할 수 있고, 그 외의 다른 단백질에도 결합할 수 있는 이중특이적 항체 또는 이중특이적 항원 결합 단편으로도 제공될 수 있다.
본 발명에서 상기 이중특이적 항체 및 이중특이적 항원 결합 단편은 본 발명에 따르는 결합 분자를 포함할 수 있다. 본 발명에서 일 예시로, 상기 이중특이적 항체 및 이중특이적 항원 결합 단편은 Lrig-1 단백질에 결합할 수 있는 항원 결합 도메인을 포함하고, 여기서 Lrig-1에 결합할 수 있는 항원 결합 도메인은 본 발명에 따르는 결합 분자를 포함하거나 이로 구성될 수 있다.
본 발명에서 제공하는 이중특이적 항체 및 이중특이적 항원 결합 단편은 본 발명에 따른 Lrig-1 단백질에 결합할 수 있는 결합 분자인 항원 결합 도메인, 및 다른 표적 단백질에 결합할 수 있는 항원 결합 도메인을 포함한다. 여기서, 다른 표적 단백질에 결합할 수 있는 항원 결합 도메인은 Lrig-1 단백질 이외의 다른 단백질로, 예를 들면, PD-1 또는 세포 표면 수용체일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에 따르는 이중특이적 항체 및 이중특이적 항원 결합 단편은 임의의 적합한 포맷, 예를 들면, 전문이 본원에 참조로 인용된 문헌(참조: Kontermann MAbs 2012, 4(2): 182-197)에 기재된 포맷으로 제공될 수 있다. 예를 들면, 이중특이적 항체 또는 이중특이적 항원 결합 단편은 이중특이적 항체 접합체(예: IgG2, F(ab')2 또는 CovX-바디), 이중특이적 IgG 또는 IgG-형 분자(예: IgG, scFv4-Ig, IgG-scFv, scFv-IgG, DVD-Ig, IgG-sVD, sVD-IgG, 또는 2 인(in) 1-IgG, mAb2, 또는 Tandemab common LC), 비대칭성 이중특이적 IgG 또는 IgG-형 분자(예: kih IgG, kih IgG common LC, CrossMab, kih IgG-scFab, mAb-Fv, 전하쌍 또는 SEED-바디), 소형 이중특이적 항체 분자(예: 디아바디(Db), dsDb, DART, scDb, tandAbs, 탠덤 scFv (taFv), 탠덤 dAb/VHH, 트리플 바디, 트리플 헤드, Fab-scFv, 또는 F(ab')2-scFv2), 이중특이적 Fc 및 CH3 융합 단백질(예: taFv-Fc, 디-디아바디, scDb-CH3, scFv-Fc-scFv, HCAb-VHH, scFv-kih-Fc, 또는 scFv-kih-CH3), 또는 이중특이적 융합 단백질(예: scFv2-알부민, scDb-알부민, taFv-독소, DNL-Fab3, DNL-Fab4-IgG, DNL-Fab4-IgG-사이토카인2)일 수 있다. 특히, 문헌(참조: Kontermann MAbs 2012, 4(2): 182-19)의 도 2를 참조한다. 당업자는 본 발명에 따르는 이중특이적 항체 및 이중특이적 항원 결합 단편을 설계하고 제조할 수 있다.
본 발명에서 상기 이중특이적 항체를 생산하는 방법은, 예를 들면, 전문이 본원에 참조로 인용된 문헌(참조: Segal and Bast, 2001. Production of Bispecific Antibodies. Current Protocols in Immunology. 14:IV:2.13:2.13.1-2.13.16)에 기재된 바와 같이 환원성 디설파이드 또는 비환원성 티오에테르 결합과 항체 또는 항체 단편의 화학적 가교결합을 포함한다. 예를 들면, N-석신이미딜-3-(-2-피리딜디티오)-프로피오네이트(SPDP)는 디설파이드 연결된 이중특이적 F(ab)2 헤테로다이머를 생성하기 위해, 예를 들면, 힌지 영역 SH- 그룹을 통해 Fab 단편을 화학적으로 가교결합시키는데 사용될 수 있다.
또한, 본 발명에서 상기 이중특이적 항체를 생산하기 위한 다른 방법은, 예를 들면, 문헌(참조: D. M. and Bast, B. J. 2001. Production of Bispecific Antibodies. Current Protocols in Immunology. 14:IV:2.13:2.13.1-2.13.16)에 기재된 바와 같이, 이중특이적 항체를 분비할 수 있는 쿼드로마 세포를 생성하기 위해 항체-생산 하이브리도마를, 예를 들면, 폴리에틸렌 글리콜과 융합시키는 과정을 포함한다.
본 발명에서 상기 이중특이적 항체 및 이중특이적 항원 결합 단편은 또한, 예를 들면, 둘 다 전문이 본원에 참조로 인용된 문헌(참조: Antibody Engineering: Methods and Protocols, Second Edition (Humana Press, 2012), at Chapter 40: Production of Bispecific Antibodies: Diabodies and Tandem scFv (Hornig and Farber-Schwarz), 또는 French, How to make bispecific antibodies, Methods Mol. Med. 2000; 40:333-339)에 기재된 바와 같이, 예를 들면, 항원 결합 분자를 위한 폴리펩티드를 암호화하는 핵산 작제물로부터 발현에 의해 재조합으로 생산될 수 있다. 예를 들면, 2개의 항원 결합 도메인(즉, PD-1에 결합할 수 있는 항원 결합 도메인을 위한 경쇄 및 중쇄 가변 도메인, 및 다른 표적 단백질에 결합할 수 있는 항원 결합 도메인을 위한 경쇄 및 중쇄 가변 도메인)을 위한 경쇄 및 중쇄 가변 도메인을 암호화하고, 항원 결합 도메인 사이의 적합한 링커 또는 이량체화 도메인을 암호화하는 서열을 포함하는 DNA 작제물은 분자 클로닝 기술에 의해 제조될 수 있다. 재조합 이중특이적 항체는 이후 적합한 숙주 세포(예: 포유류 숙주 세포) 중에서 작제물의 발현(예: 시험관내)에 의해 생산될 수 있고, 이어서 발현된 재조합 이중특이적 항체는 임의로 정제될 수 있다.
본 발명에서 상기 항체는, 비변형된 부모 항체와 비교하여 항원에 대한 항체의 친화도가 개선된 변형된 항체가 생성되는 친화도 성숙 공정에 의해 생성될 수 있다. 친화도 성숙 항체는 당해 기술 분야, 예를 들면, 문헌(참조: Marks et al., Rio/Technology 10:779-783 (1992); Barbas et al. Proc Nat. Acad. Sci. USA 91:3809-3813 (1994); Schier et al. Gene 169:147-155 (1995); Yelton et al. J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):3310-159 (1995); 및 Hawkins et al, J. Mol. Biol. 226:889-896 (1992))에 공지된 절차로 생산될 수 있다.
본 발명에서 제공하는 결합 분자는, Lrig-1 단백질에 특이적으로 결합할 수 있는 한, 상기 아미노산 서열의 변이체를 포함할 수 있다. 예를 들면, 항체의 결합 친화도 및/또는 기타 생물학적 특성을 개선시키기 위하여 항체의 아미노산 서열에 변화를 줄 수 있다. 이러한 변형은, 예를 들어 항체의 아미노산 서열 잔기의 결실, 삽입 및/또는 치환을 포함한다.
본 발명에서 상기 아미노산 변이는 아미노산 곁사슬 치환체의 상대적 유사성, 예컨대, 소수성, 친수성, 전하, 크기 등에 기초하여 이루어진다. 아미노산 곁사슬 치환체의 크기, 모양 및 종류에 대한 분석에 의하여, 아르기닌, 라이신과 히스티딘은 모두 양전하를 띤 잔기이고; 알라닌, 글라이신과 세린은 유사한 크기를 갖으며; 페닐알라닌, 트립토판과 타이로신은 유사한 모양을 갖는다는 것을 알 수 있다. 따라서 이러한 고려 사항에 기초하여, 아르기닌, 라이신 및 히스티딘; 알라닌, 글라이신 및 세린; 그리고 페닐알라닌, 트립토판 및 타이로신은 생물학적으로 기능 균등물이라 할 수 있다.
본 발명에서 상기 변이를 도입하는 데 있어서, 아미노산의 소수성 인덱스 (hydropathic index)가 고려될 수 있다. 각각의 아미노산은 소수성과 전하에 따라 소수성 인덱스가 부여되어 있다: 아이소루이신(+4.5); 발린(+4.2); 루이신(+3.8); 페닐알라닌(+2.8); 시스테인/시스타인(+2.5); 메티오닌(+1.9); 알라닌(+1.8); 글라이신(-0.4); 쓰레오닌(-0.7); 세린(-0.8); 트립토판(-0.9); 타이로신(-1.3); 프롤린(-1.6); 히스티딘(-3.2); 글루타메이트(-3.5); 글루타민(-3.5); 아스파르테이트(-3.5); 아스파라긴(-3.5); 라이신(-3.9); 및 아르기닌(-4.5). 단백질의 상호적인 생물학적 기능(interactive biological function)을 부여하는 데 있어서 소수성 아미노산 인덱스는 매우 중요하다. 유사한 소수성 인덱스를 가지는 아미노산으로 치환하여야 유사한 생물학적 활성을 보유할 수 있다는 것은 공지된 사실이다. 소수성 인덱스를 참조하여 변이를 도입시키는 경우, 바람직하게는 ±2 이내, 보다 바람직하게는 ± 1 이내, 보다 더 바람직하게는 ± 0.5 이내의 소수성 인덱스 차이를 나타내는 아미노산 사이에 치환을 한다.
본 발명에서 유사한 친수성 값(hydrophilicity value)을 가지는 아미노산 사이의 치환이 균등한 생물학적 활성을 갖는 단백질을 초래한다는 것도 잘 알려져 있다. 미국 특허 제4,554,101호에 개시된 바와 같이, 다음의 친수성 값이 각각의 아미노산 잔기에 부여되어 있다: 아르기닌(+3.0); 라이신(+3.0); 아스팔테이트(+3.0± 1); 글루타메이트(+3.0±1); 세린(+0.3); 아스파라긴(+0.2); 글루타민(+0.2); 글라이신(0); 쓰레오닌(-0.4); 프롤린(-0.5±1); 알라닌(-0.5); 히스티딘(-0.5); 시스테인(-1.0); 메티오닌(-1.3); 발린(-1.5); 루이신(-1.8); 아이소루이신(-1.8); 타이로신(-2.3); 페닐알라닌(-2.5); 트립토판(-3.4). 친수성 값을 참조하여 변이를 도입시키는 경우, 바람직하게는 ± 2 이내, 보다 바람직하게는 ± 1 이내, 보다 더 바람직하게는 ± 0.5 이내의 친수성 값 차이를 나타내는 아미노산 사이에서 치환을 수행할 수 있다.
본 발명에서 상기 분자의 활성을 전체적으로 변경시키지 않는 단백질에서의 아미노산 교환은 당해 분야에 공지되어 있다(H. Neurath, R.L.Hill, The Proteins, Academic Press, New York (1979)). 가장 통상적으로 일어나는 교환은 아미노산 잔기 Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr, Ser/Asn, Ala/Val, Ser/Gly, Tyr/Phe, Ala/Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Gln/Glu 간의 교환이다.
본 발명에서 상기 Lrig-1 단백질에 특이적으로 결합하는 결합 분자는 하기 식 1로 표시되는 아미노산 서열로 이루어지는 폴리펩티드를 포함하는 에피토프에 특이적으로 결합하는 것일 수 있다:
[식 1]
Lx1Lx2x3N
상기 식 1에서,
x1 내지 x3는 각각 독립적으로 중성 아미노산, 산성 아미노산, 염기성 아미노산 또는 방향족 아미노산일 수 있다. 여기서 상기 중성 아미노산은, 글리신(glycine; G), 알라닌(alanine; A), 발린(valine, V), 류신(leucine, L), 아이소류신(isoleucine, I), 세린(serine, S) 또는 트레오닌(threonine, T)일 수 있고, 상기 산성 아미노산은 아스파트산(aspartic acid; D), 글루탐산(glutamic acid; E), 아스파라긴(asparagine; N) 또는 글루타민(glutamine; Q)일 수 있으며, 상기 염기성 아미노산은 라이신(lysine, K), 아르기닌(arginine; R) 또는 히스티딘(histidine; H)일 수 있고, 상기 방향족 아미노산은 페닐알라닌(phenylalanine; F) 또는 티로신(tyrosine; Y)일 수 있다.
본 발명의 일 예시로, 상기 x1 내지 x3는 각각 독립적으로 아스파라긴(asparagine; N), 아스파트산(aspartic acid; D), 세린(serine; S), 티로신(tyrosine; Y), 아르기닌(arginine; R), 페닐알라닌(phenylalanine; F), 라이신(lysine, K), 히스티딘(histidine; H), 류신(leucine, L), 발린(valine, V), 트레오닌(threonine, T), 알라닌(alanine; A), 글루타민(glutamine; Q), 글루탐산(glutamic acid; E) 및 글리신(glycine; G)으로 이루어진 군에서 선택되는 아미노산일 수 있다.
본 발명의 다른 예시로, 상기 x1은 아스파라긴(asparagine; N), 페닐알라닌(phenylalanine; F), 아스파트산(aspartic acid; D), 라이신(lysine, K), 히스티딘(histidine; H), 발린(valine, V), 아르기닌(arginine; R) 및 트레오닌(threonine, T)으로 이루어진 군에서 선택되는 아미노산이고, 상기 x2는 세린(serine; S), 글루타민(glutamine; Q), 알라닌(alanine; A), 아스파라긴(asparagine; N), 글루탐산(glutamic acid; E), 아스파트산(aspartic acid; D), 페닐알라닌(phenylalanine; F) 및 글리신(glycine; G)으로 이루어진 군에서 선택되는 아미노산이며, 상기 x3는 티로신(tyrosine; Y), 히스티딘(histidine; H), 글리신(glycine; G), 아르기닌(arginine; R), 아스파라긴(asparagine; N), 류신(leucine, L), 라이신(lysine, K) 및 페닐알라닌(phenylalanine; F)으로 이루어진 군에서 선택되는 아미노산일 수 있다.
본 발명의 또 다른 예시로, 상기 x1 내지 x3는 각각 독립적으로 각각 독립적으로 아스파라긴(asparagine; N), 아스파트산(aspartic acid; D), 세린(serine; S), 티로신(tyrosine; Y) 및 아르기닌(arginine; R)으로 이루어진 군에서 선택되는 아미노산일 수 있다.
본 발명의 또 다른 예시로, 상기 x1은 아스파라긴(asparagine; N) 또는 아스파트산(aspartic acid; D)이고, 상기 x2는 세린(serine; S) 또는 아스파라긴(asparagine; N)이며, 상기 x3는 티로신(tyrosine; Y) 또는 아르기닌(arginine; R)이다.
본 발명에서 상기 에피토프는 상기 식 1로 표시되는 아미노산 서열로 이루어지는 폴리펩티드를 포함하는 것으로, 10 내지 20 mer, 바람직하게는 10 내지 15 mer, 보다 바람직하게는 11 내지 14 mer로 이루어질 수 있다.
또한, 본 발명에서 상기 에피토프에서 상기 식 1로 표시되는 아미노산 서열로 이루어지는 폴리펩티드는, 상기 에피토프의 N-터미널로부터 3 내지 6 번째, 바람직하게는 4 내지 6 번째, 보다 바람직하게는 5 번째에 위치할 수 있다.
본 발명의 일 예시로서, 상기 식 1로 표시되는 아미노산 서열로 이루어진 폴리펩티드는 하기 표 1의 서열번호 54 내지 67 중 어느 하나의 아미노산 서열로 표시될 수 있으나, 이에 제한되는 것은 아니다:
서열목록 | 서열정보 |
서열번호 54 | LNLSYN |
서열번호 55 | LDLNRN |
서열번호 56 | LFLQHN |
서열번호 57 | LNLAGN |
서열번호 58 | LDLSLN |
서열번호 59 | LRLSKN |
서열번호 60 | LKLQRN |
서열번호 61 | LHLEYN |
서열번호 62 | LHLSNN |
서열번호 63 | LVLSFN |
서열번호 64 | LRLSHN |
서열번호 65 | LDLDHN |
서열번호 66 | LTLFGN |
서열번호 67 | LNLGGN |
본 발명에서 상기 Lrig-1 단백질의 에피토프는 하기 표 2의 서열번호 68 내지 79 중 어느 하나의 아미노산 서열로 표시되는 폴리펩티드를 포함하는 것일 수 있다:
서열목록 | 서열정보 |
서열번호 68 | WTRSLNLSYNKL |
서열번호 69 | TEVRNTCFPHGPPI |
서열번호 70 | RLTQLDLNRNRIR |
서열번호 71 | DLNRNRIRLIEGLTF |
서열번호 72 | NSIARIHRKGW |
서열번호 73 | WLPPWLIGRMLQAF |
서열번호 74 | RQVTFGHEGRY |
서열번호 75 | FGHEGRYQCVITNHF |
서열번호 76 | RLTVNVLPSFTKTPH |
서열번호 77 | RRMHVMPDDDVFF |
서열번호 78 | FFITDVKIDDAGVYS |
서열번호 79 | KGDRPLSLTERHH |
본 발명의 다른 일 예시로서, 상기 에피토프는 서열번호 66 또는 68의 아미노산 서열로 표시될 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상술한 생물학적 균등 활성을 갖는 변이를 고려한다면, 본 발명의 결합 분자는 서열목록에 기재된 서열과 실질적인 동일성(substantial identity)을 나타내는 서열도 포함하는 것으로 해석된다.
본 발명에서 용어 "실질적인 동일성"이란, 본 발명의 서열과 임의의 다른 서열을 최대한 대응되도록 병렬하고, 당업계에서 통상적으로 이용되는 알고리즘을 이용하여 병렬된 서열을 분석한 경우에, 최소 61%의 상동성, 보다 바람직하게는 70%의 상동성, 보다 더 바람직하게는 80%의 상동성, 가장 바람직하게는 90%의 상동성을 나타내는 서열을 의미한다. 서열비교를 위한 얼라인먼트 방법은 당업계에 공지되어 있다. 얼라인먼트에 대한 다양한 방법 및 알고리즘은 Smith and Waterman, Adv. Appl. Math. 2:482(1981); Needleman and Wunsch, J. Mol. Bio.48:443(1970); Pearson and Lipman, Methods in Mol. Biol. 24: 307-31(1988); Higgins and Sharp, Gene 73:237-44(1988); Higgins and Sharp, CABIOS 5:151-3(1989); Corpet et al., Nuc. Acids Res. 16:10881-90(1988); Huang et al., Comp. Appl. BioSci. 8:155-65(1992) and Pearson et al., Meth. Mol. Biol. 24:307-31(1994)에 개시되어 있다. NCBI Basic Local Alignment Search Tool (BLAST) (Altschul et al., J. Mol. Biol. 215:403-10(1990))은 NBCI (National Center for Biological Information) 등에서 접근 가능하며, 인터넷상에서 blastp, blasm, blastx, tblastn and tblastx와 같은 서열 분석 프로그램과 연동되어 이용할 수 있다. BLSAT는 http://www.ncbi.nlm.nih.gov/BLAST/에서 접속 가능하다. 이 프로그램을 이용한 서열 상동성 비교 방법은 온라인(http://www.ncbi.nlm.nih.gov/BLAST/ blast_help.html)을 통해 확인할 수 있다.
본 발명에서 상기 결합 분자, 바람직하게 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 항암제는 기타 공지의 항암 치료제와 조합하여 사용될 수 있다.
본 발명에서 상기 "항암 치료제"는 예를 들면, 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, 카르무스틴, VEGF 항체(베바시주맙), EGFR 항체(세툭시맙), HER-2 항체(트라스투주맙), PD-1 저해제(펨브롤리주맙, 니볼루맙), PD-L1 저해제(아테졸리주맙, 아벨루맙, 더발루맙, STI-1014, CX-072), CTLA-4 항체(이필리무맙), LAG-3 항체(BMS-986016, IMP-731, IMP-321), CD137 항체(우렐루맙, PF-05082566), GITR 항체(BMS-986153, BMS-986156, TRX-518, MK-4166), IDO 길항제(INCB-024360, 인독시모드, NLG-919), OXO 항체(MEDI-6383 또는 MEDI-6469), OXO40L 길항제(RG-7888), CD40 길항제(루카투무맙, 다세투주맙) 및 CD27 항체(바를리루맙), ), CD20 항체(리툭시맙), CD52 항체(캄파트-1H), CD22 항체(에프라투주맙), CD25 항체, TIGIT 항체(tiragolumab), CCR4 항체, FR4 항체, CD15s 항체, PI-16 항체 및 LAIR-1 항체로 이루어진 군에서 선택될 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서, "예방" 또는 "개선"은 본 발명의 약학 조성물을 이용하여 질환의 증상을 차단하거나, 그 증상을 억제 또는 지연시키는 모든 행위라면 제한없이 포함할 수 있다.
또한, 본 발명에서, "치료"는 본 발명의 약학 조성물을 이용하여 질환의 증상이 호전되거나 이롭게 되는 모든 행위라면 제한없이 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.
본 발명에서 상기 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 약학 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 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, 말티톨, 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, 항 응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.
본 발명에 상기 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.
본 발명에서 상기 "비경구"란, 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 상기 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 50 mg/kg 또는 0.001 내지 50 mg/kg으로 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 상기 식품 조성물은 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다.
본 발명에서 상기 유효성분이 식품 조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 50%의 비율로 첨가할 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 식품 조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 포함하는 것 외에 특별한 제한점은 없으며, 통상의 음료와 같이 다양한 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 구체적으로, 천연 탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등) 등일 수 있다.
본 발명에서 상기 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 더 포함할 수 있다.
본 발명에서 상기 성분은 독립적 또는 조합하여 사용할 수 있다. 상기 첨가제의 비율은 본 발명의 핵심적인 요소에 해당하지 아니하지만, 본 발명의 식품 조성물 100 중량부 당 0.1 내지 약 50 중량부의 범위에서 선택될 수 있으나, 이에 제한되는 것은 아니다.
2.
항체-약물 결합체를 유효성분으로 포함하는 면역체크포인트 억제제 저항성 암의 예방, 개선 또는 치료용 조성물
본 발명의 다른 구현 예에 따르면, Lrig-1 단백질에 특이적으로 결합하는 항체 또는 항원 결합 단편; 및 약물을 포함하는 항체-약물 결합체를 유효성분으로 포함하는 조성물을 제공한다.
본 발명에서 상기 항체-약물 결합체를 유효성분으로 포함하는 면역체크포인트 억제제 저항성 암의 예방, 개선 또는 치료용 약학 조성물에서, 항체, 면역체크포인트 억제제 저항성, 암, 예방, 개선 등과 관련된 내용은 앞서 기재한 바와 동일하여, 그 기재를 생략한다.
본 발명에서 상기 "항체-약물 결합체(Antibody-Drug Conjugate, ADC)"란, 항체와 약물의 생물학적 활성을 저하시키지 않으면서 약물과 항체를 화학적으로 연결한 형태를 지칭한다. 본 발명에서 상기 항체-약물 결합체는 항체의 중쇄 및/또는 경쇄의 N-말단의 아미노산 잔기에 약물이 결합된 형태, 구체적으로는 항체의 중쇄 및/또는 경쇄의 N-말단, α-아민기에 약물이 결합된 형태를 말한다.
본 발명에서 상기 "약물"은 세포에 특정 생물학적 활성을 가지는 임의의 물질을 의미할 수 있으며, 이는 DNA, RNA 또는 펩타이드(Peptide)를 포함하는 개념이다. 상기 약물은 α-아민기와 반응하여 가교할 수 있는 반응기를 포함하는 형태일 수 있으며, α-아민기와 반응하여 가교할 수 있는 반응기를 포함하는 링커가 연결되어 있는 형태 역시 포함한다.
본 발명에서 상기 α-아민기와 반응하여 가교할 수 있는 반응기의 예로는, 항체의 중쇄 또는 경쇄의 N-말단의 α-아민기와 반응하여 가교할 수 있다면 그 종류는 특별히 제한되지 않으며, 당업계에 공지된 아민기와 반응하는 종류를 모두 포함한다. 그 예로 아이소티오시아네이트(Isothiocyanate), 아이소시아네이트(Isocyanates), 아실 아자이드(Acyl azide), NHS 에스터(NHS ester), 설포닐 클로라이드(Sulfonyl chloride), 알데하이드(Aldehyde), 글리옥살(Glyoxal), 에폭사이드(Epoxide), 옥시레인(Oxirane), 칼보네이트(Carbonate), 아릴 할라이드(Aryl halide), 이미도에스터(Imidoester), 카보이미드(Carbodiimide), 안하이드라이드(Anhydride) 및 플루오로페닐 에스터(Fluorophenyl ester) 중 어느 하나 일 수 있으나, 이에 제한되는 것은 아니다.
본 발명에서 상기 항암제는 이에 제한되는 것은 아니지만, 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 선택될 수 있다.
본 발명에 따른 Lrig-1 단백질에 특이적인 결합 분자, 바람직하게는 항체는, Lrig-1 단백질이 높은 수준으로 발현되어 있는 조절 T 세포(Regulatory T cell; Treg), 즉 종양 침윤 림프구(tumor infiltrating lymphocytes; TIL)에 속하는 조절 T 세포 또는 활성화된 조절 T 세포의 기능을 억제하여, 조절 T 세포에 의해 효과 T 세포의 기능이 억제되는 현상을 매우 효과적으로 차단함으로써 면역 회피 암, 즉 면역 체크 포인트 억제제에 내성이 존재하는 암을 효과적으로 예방, 개선 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 발현 정도를 나타낸 것이다.
도 4는 본 발명의 일 실시예에 따른 Lrig-1 mRNA의 발현 정도를 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, Lrig-2 및 Lrig-3 mRNA의 발현 정도를 나타낸 것이다.
도 7은 본 발명의 일 실시예에 따른 조절 T 세포와 비 조절 T 세포내 Lrig-1 단백질의 발현량 비교 결과를 나타낸 것이다.
도 8a 및 8b는 본 발명의 일 실시예에 따른 조절 T 세포의 표면에 Lrig-1 단백질의 발현을 나타낸 것이다.
도 9는 본 발명의 일 실시예에 따른 Lrig-1 단백질 특이적인 단일클론항체(GTC110-01, GTC110-02, GTC110-03 및 GTC110-04)의 Lrig-1 단백질에 대한 결합력을 분석한 결과를 나타낸 것이다.
도 10은 일 실시예에서 마이크로어레이를 이용하여 Lrig-1 단백질에 대한 단일클론항체(GTC110-04) 10 ㎍/ml의 에피토프 맵핑 결과를 나타낸 것이다.
도 11은 본 발명의 일 실시예에서 마이크로어레이를 이용하여 Lrig-1 단백질에 대한 단일클론항체(GTC110-04) 100 ㎍/ml의 에피토프 맵핑 결과를 나타낸 것이다.
도 12는 본 발명의 일 실시예에서 마이크로어레이를 이용하여 Lrig-1 단백질에 대한 단일클론항체(GTC110-04)의 에피토프 맵핑 결과를 나타낸 것이다. 여기서, 인간 항체 04(Human antibody 04)는 단일클론항체 GTC110-04를 의미한다.
도 13은 본 발명의 일 실시예에 따른 Lrig-1 단백질 특이적인 단일클론항체(GTC110-01, GTC110-02, GTC110-03 및 GTC110-04)의 조절 T 세포내에서 Lrig-1 단백질 유도 Stat3 인산화 조절 기작을 분석한 결과를 나타낸 것이다. 여기서, 01은 GTC110-01, 02는 GTC110-02, 03은 GTC110-03 및 04는 GTC110-04를 의미한다.
도 14a 및 도 14b는 본 발명의 일 실시예에 따른 Lrig-1 단백질의 발현 수준에 따른 Treg의 효과 T 세포(effector T cell)의 억제 효과를 확인한 결과를 나타낸 것이다.
도 15는 본 발명의 일 실시예에 따른 Lrig-1 단백질 특이적인 단일클론항체(GTC110-04) 또는 PD-1 항체를 이용한 면역체크포인트억제제 저항성 암 치료 효과의 실험 설계도를 간략히 나타낸 것이다.
도 16은 본 발명의 일 실시예에 따른 Lrig-1 단백질 특이적인 단일클론항체(GTC110-04) 또는 PD-1 항체를 이용한 면역체크포인트억제제 저항성 암 치료에 따른 종양 크기의 감소를 확인한 결과를 나타낸 것이다.
도 17은 본 발명의 일 실시예에 따른 Lrig-1 단백질에 특이적인 단일클론항체(GTC110-04) 또는 PD-1 항체를 이용한 면역체크포인트억제제 저항성 암 치료에 따른 종양 침윤 림프구의 세포 분포를 유세포분석(FACS)을 통해 확인한 결과를 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 발현 정도를 나타낸 것이다.
도 4는 본 발명의 일 실시예에 따른 Lrig-1 mRNA의 발현 정도를 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, Lrig-2 및 Lrig-3 mRNA의 발현 정도를 나타낸 것이다.
도 7은 본 발명의 일 실시예에 따른 조절 T 세포와 비 조절 T 세포내 Lrig-1 단백질의 발현량 비교 결과를 나타낸 것이다.
도 8a 및 8b는 본 발명의 일 실시예에 따른 조절 T 세포의 표면에 Lrig-1 단백질의 발현을 나타낸 것이다.
도 9는 본 발명의 일 실시예에 따른 Lrig-1 단백질 특이적인 단일클론항체(GTC110-01, GTC110-02, GTC110-03 및 GTC110-04)의 Lrig-1 단백질에 대한 결합력을 분석한 결과를 나타낸 것이다.
도 10은 일 실시예에서 마이크로어레이를 이용하여 Lrig-1 단백질에 대한 단일클론항체(GTC110-04) 10 ㎍/ml의 에피토프 맵핑 결과를 나타낸 것이다.
도 11은 본 발명의 일 실시예에서 마이크로어레이를 이용하여 Lrig-1 단백질에 대한 단일클론항체(GTC110-04) 100 ㎍/ml의 에피토프 맵핑 결과를 나타낸 것이다.
도 12는 본 발명의 일 실시예에서 마이크로어레이를 이용하여 Lrig-1 단백질에 대한 단일클론항체(GTC110-04)의 에피토프 맵핑 결과를 나타낸 것이다. 여기서, 인간 항체 04(Human antibody 04)는 단일클론항체 GTC110-04를 의미한다.
도 13은 본 발명의 일 실시예에 따른 Lrig-1 단백질 특이적인 단일클론항체(GTC110-01, GTC110-02, GTC110-03 및 GTC110-04)의 조절 T 세포내에서 Lrig-1 단백질 유도 Stat3 인산화 조절 기작을 분석한 결과를 나타낸 것이다. 여기서, 01은 GTC110-01, 02는 GTC110-02, 03은 GTC110-03 및 04는 GTC110-04를 의미한다.
도 14a 및 도 14b는 본 발명의 일 실시예에 따른 Lrig-1 단백질의 발현 수준에 따른 Treg의 효과 T 세포(effector T cell)의 억제 효과를 확인한 결과를 나타낸 것이다.
도 15는 본 발명의 일 실시예에 따른 Lrig-1 단백질 특이적인 단일클론항체(GTC110-04) 또는 PD-1 항체를 이용한 면역체크포인트억제제 저항성 암 치료 효과의 실험 설계도를 간략히 나타낸 것이다.
도 16은 본 발명의 일 실시예에 따른 Lrig-1 단백질 특이적인 단일클론항체(GTC110-04) 또는 PD-1 항체를 이용한 면역체크포인트억제제 저항성 암 치료에 따른 종양 크기의 감소를 확인한 결과를 나타낸 것이다.
도 17은 본 발명의 일 실시예에 따른 Lrig-1 단백질에 특이적인 단일클론항체(GTC110-04) 또는 PD-1 항체를 이용한 면역체크포인트억제제 저항성 암 치료에 따른 종양 침윤 림프구의 세포 분포를 유세포분석(FACS)을 통해 확인한 결과를 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
[준비예 1] T 세포 아형 세포 배양
조절 T 세포(Regulatory T cell; Treg, 이하, 'Treg'이라 함)에서만 Lrig-1 단백질이 발현되는지 확인하기 위하여, T 세포의 아형(subset)인 Th0, Th1, Th2, Th17 및 iTreg을 준비하였다. 여기서, iTreg은 자연적으로 분리한 nTreg과는 달리 하기 조성을 포함하는 배지에서 분화를 인공적으로 유도한 세포를 의미한다.
T 세포의 아형은 우선, 쥐의 비장으로부터 나이브(naive) T 세포를 분리한 뒤, 우태아혈청(FBS; hyclone, logan, UT) 10%를 포함하는 RPMI1640(Invitrogen Gibco, Grand Island, NY) 영양배지에 하기 표 3의 성분을 각각 더 포함하도록 하여, 37℃ 5% CO2 배양기 내에서 72시간 배양을 통해 각각의 세포로 분화 유도하였다.
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 |
[준비예 2] Lrig-1 단백질의 발현 정도에 따른 Treg 분리
Foxp3-GFP KI 쥐의 비장으로부터 나이브 T 세포를 분리한 뒤, 상기 분리된 나이브 T 세포를 상기 준비예 1의 표 1에 기재되어 있는 iTreg 조성에서 4일 또는 6일 동안 배양함으로써 나이브 T 세포를 iTreg으로 분화시켰다. 그런 다음, 상기 iTreg을 Lrig-1 PE 항체(R&D system FAB3688P)를 이용하여 염색한 뒤, 형광 이용 세포 분류기(Fluorescence-Activated Cell Sorter; FACS)를 이용하여 FOXP3+인 세포 중에서 Lrig-1의 발현 정도에 따라, 4일 동안 배양된 iTreg Lrig-1low 및 iTreg Lrig-1high와, 6일 동안 배양된 iTreg Lrig-1low로 분리하였다.
[실시예 1] Lrig-1 구조 분석
조절 T 세포의 표면 단백질인 Lrig-1 단백질에 특이적인 항체를 제작하기 위하여 Lrig-1 단백질의 세포 외 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 세포 외 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 세포 외 도메인 중 Lrig-1 단백질의 아미노산 서열 494 내지 781번에는 면역글로블린 유사 도메인(Immunoglobulin-like domain)이 3개 존재하였다.
[제조예 1 내지 8] Lrig-1 단백질에 특이적인 단일클론항체의 제작
본 발명에 따른 Lrig-1 단백질에 결합하는 결합분자인 항체를 제작하였다.
상기 항체를 제작하기 위하여 Lrig-1 단백질이 발현되는 세포를 제작하였다. 구체적으로, 서열번호 2에 해당하는 DNA 단편 및 pcDNA(hygro)를 절단 효소로 절단한 뒤, 37℃에서 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 단백질에 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 영역 또는 인간 IgG1과 융합하여 제조예 1 내지 5에 해당하는 단일클론항체(monoclonal antibody)를 제작하였다. 상기 단일 클론 항체의 서열은 하기 표 4와 같다.
구분 | 클론 | 위치 | 아미노산 서열 | 서열번호 |
제조예 1 | GTC110-01 clone | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYDMSWVRQVPGKGLEWVSWISHGGGSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGLGLCKTGLCYYYDAMDVWGQGTLVTVSSASTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK | 서열번호 46 |
경쇄 | QSVLTQPPSASGTPGQRVTISCTGSSSNIGNNSVTWYQQLPGTAPKLLIYADNNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDSSLSAYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC | 서열번호 47 | ||
제조예 2 | GTC110-02 clone | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWVRQAPGKGLEWVSGISHDSGSKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHWTTFDYWGQGTLVTVSSASTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK | 서열번호 48 |
경쇄 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNNVTWYQQLPGTAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGAWDYSLSAYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC | 서열번호 49 | ||
제조예 3 | GTC110-03 clone | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSAIYPGGGSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDILPCPWGRCYYDYAMDVWGQGTLVTVSSASTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK | 서열번호 50 |
경쇄 | QSVLTQPPSASGTPGQRVTISCSDSSSNIGSNTVSWYQQLPGTAPKLLIYADNNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGTWDYSLSGYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC | 서열번호 51 | ||
제조예 4 | GTC110-04 clone | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSVISHGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVISNCHLGVCYYSNGMDVWGQGTLVTVSSASTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK | 서열번호 52 |
경쇄 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNDVYWYQQLPGTAPKLLIYSDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGTWDYSLSGYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC | 서열번호 53 | ||
제조예 5 | GTC110-04 인간화 항체 | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSVISHGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVISNCHLGVCYYSNGMDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKY | 서열번호 90 |
경쇄 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNDVYWYQQLPGTAPKLLIYSDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGTWDYSLSGYVFGGGTKLTVLRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 서열번호 91 |
[실시예 2] Lrig-1 mRNA의 Treg에서의 특이적 발현 확인
Lrig-1 단백질이 Treg에 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 Treg (CD4+CD25+ T) 및 비 조절 T (CD4+CD25- T)세포를 분리하였다. 각각의 세포 및 상기 준비예 1에서 분화된 세포는 트리졸(Trizol)을 이용하여 mRNA를 추출하고, 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 cDNA에서 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 5의 프라이머를 이용하여 수행하였고, 상대적인 유전자 발현량은 ΔΔCT 방법을 이용하여 계산하였으며, HPRT를 이용하여 일반화(normalization) 하여, 그 결과를 도 3 내지 6에 나타내었다.
프라이머 | 서열번호 | 서열 |
쥐 Lrig-1 | 서열번호 80 | Forward 5' - GAC GGA ATT CAG TGA GGA GAA CCT - 3' |
서열번호 81 | Reverse 5' - CAA CTG GTA GTG GCA GCT TGT AGG - 3' | |
쥐 Lrig-2 | 서열번호 82 | forward 5' - TCA CAA GGA ACA TTG TCT GAA CCA- 3' |
서열번호 83 | reverse 5' - GCC TGA TCT AAC ACA TCC TCC TCA- 3' | |
쥐 Lrig-3 | 서열번호 84 | forward 5' - CAG CAC CTT GAG CTG AAC AGA AAC - 3' |
서열번호 85 | reverse 5' - CCA GCC TTT GGT AAT CTC GGT TAG - 3' | |
쥐 FOXP3 | 서열번호 86 | forward 5' - CTT TCA CCT ATC CCA CCC TTA TCC - 3' |
서열번호 87 | reverse 5' - ATT CAT CTA CGG TCC ACA CTG CTC - 3' | |
ACTG1 | 서열번호 88 | forward 5' - GGC GTC ATG GTG GGC ATG GG - 3' |
서열번호 89 | reverse 5' - ATG GCG TGG GGA AGG GCG TA - 3' |
도 3에서 보는 바와 같이, 비 조절 T (CD4+CD25- T)세포에 비하여 Treg (CD4+CD25+ T)에서 Lrig-1의 발현이 18.1배 높은 것을 알 수 있다. 이는, 기존에 알려져 있는 Treg의 마커인 Lag3 및 Ikzf4와 비교하였을 때 약 10배 정도 발현양이 높은 수준이었다.
또한, 도 4 및 5에서 보는 바와 같이, 다른 종류의 면역세포에 비하여 Treg, 특히 분화가 유도된 조절 T 세포(iTreg)에 비해 자연적으로 분리한 Treg (nTreg)에서 Lrig-1 mRNA의 발현이 현저하게 높았다. 또한, 도 6에서 보는 바와 같이, Lrig 패밀리에 해당하는 Lrig-1, Lrig-2 및 Lrig-3의 mRNA 중에서 Lrig-1의 mRNA 발현 수준이 가장 높았다.
상기 결과를 통해 본 발명에 따른 Lrig-1 단백질은 Treg, 특히 자연적으로 존재하는 Treg에서 특이적으로 발현하는 것을 알 수 있다.
[실시예 3] Lrig-1 단백질의 Treg에서의 특이적 발현 확인
Lrig-1 mRNA로부터 발현된 Lrig-1 단백질이 Treg에서만 특이적으로 발현되는지 확인하였다.
Treg 특이적인 전사 인자인 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-1 단백질의 발현량을 측정하여, 그 결과를 도 7에 나타내었다.
도 7에서 보는 바와 같이, 점선으로 표시되는 비-조절 T 세포의 경우 음성 대조군과 거의 동일한 Lrig-1 단백질의 발현 수준을 보였지만, Treg의 경우 Lrig-1 단백질의 발현 수준이 높은 세포가 다수 존재하였다.
상기 결과를 통해 본 발명에 따른 Lrig-1 단백질은 Treg에서 특이적으로 발현하는 것을 알 수 있다.
[실시예 4] Treg 표면에서의 Lrig-1 단백질 특이적 발현 확인
Lrig-1 단백질이 세포 치료의 타겟이 되기 위해서는 Treg의 표면에 발현되어야 더욱 효과적으로 타겟 치료를 할 수 있으므로, Lrig-1 단백질이 Treg의 표면에서 발현되는지 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-1 단백질의 발현량을 측정하여, 그 결과를 도 8a 및 8b에 나타내었다.
도 8a 및 8b에서 보는 바와 같이, 활성화된 T 세포(activated T cell), Th1 세포, Th2 세포, Th17 세포 및 나이브(Naive) T 세포에서는 Lrig-1 단백질의 발현이 0.77 내지 15.3의 양으로 발현되는 반면, iTreg에서는 83.9로 높게 발현되었다.
상기 결과를 통해 본 발명에 따른 Lrig-1 단백질은 Treg에서 특이적으로 발현될 뿐만 아니라, 특히 Treg의 세포 표면에서 더욱 높게 발현되는 것을 알 수 있다.
[실시예 5] 본 발명에 따른 항체의 Lrig-1 단백질에 대한 결합능 평가
상기 제조예 1 내지 4에서 제작된 본 발명에 따른 단일클론항체가 Lrig-1 단백질을 잘 인식하는 지를 확인하기 위하여, Lrig-1 단백질을 안정하게 발현하는 L 세포에 상기 제조예 1 내지 4의 항체 각각을 결합시킨 뒤 마우스 항체를 인식할 수 있으면서 eFlour 670이 컨쥬게이션(conjugation)된 2차 항체(secondary antibody)를 넣은 후 FACS를 이용하여 상기 단일클론항체의 Lrig-1 단백질에 대한 결합능을 분석하여 그 결과를 도 9에 나타내었다.
도 9에서 보는 바와 같이, 본 발명에 따른 Lrig-1 단백질 특이적인 제조예 1 내지 4 모두 L 세포의 표면에 존재하는 Lrig-1 단백질을 효과적으로 인식하여 결합한 것을 확인할 수 있었다.
[실시예 6] 본 발명에 따른 Lrig-1 단백질의 에피토프 결정
조절 T 세포 표면에 존재하는 Lrig-1 단백질에서 각 LRR 도메인과 Ig-like 도메인에 존재하는 상기 제조예 4인 GTC110-04 클론 항체의 결합 에피토프를 발굴하기 위하여 하기의 실험을 수행하였다.
1. 실험 준비
(1) 마이크로어레이
Lrig-1 단백질의 펩타이드 절단을 방지하기 위하여 상기 Lrig-1 단백질의 C- 및 N-터미널에 GSGSGSG 링커를 신장시켰다. 신장된 항원 서열은 14개 아미노산의 펩타이드-펩타이드 중복으로 인하여 15개 아미노산으로 번역되었다. 최종 LRIG1 펩타이드의 마이크로어레이 결과 1,091개의 상이한 펩타이드가 듀플리케이트(duplicate)로 확인되었고, 추가적인 HA (YPYDVPDYAG, 102 spots) 컨트롤 펩타이드에 의해 프레임(framed) 되었다.
(2) 실험 재료
시료:
제조예 4의 GTC110-04 단일클론항체
세척 버퍼: PBS, 0.05% Tween 20 (각 배양 후 10초 경과하였을 때, 3회)에 의한 pH 7.4
블러킹 버퍼(Blocking Buffer): Rockland 블러킹 버퍼 MB-070 (첫 어세이 30분 전)
배양 버퍼: 10% 블러킹 버퍼를 추가한 세척 버퍼
어세이 조건: 배양 버퍼 내 항체의 농도를 1 ㎍/ml, 10 ㎍g/ml 및 100 ㎍/ml로 조절; 4℃에서 16 시간 동안 배양하고, 140 rpm으로 교반
2차 항체: 염소 항-인간 IgG (H+L) DyLight680 (0.2 ㎍/ml); 상온에서 배양 버퍼 내 45분간 염색
대조군 항체: 마우스 단일클론성 항-HA (12CA5) DyLight800 (0.5 ㎍/ml); 상온에서 배양 버퍼 내 45분간 염색
스캐너: LI-COR Odyssey Imaging System; 스캐닝 오프세트(scanning offset) 0.65 mm, 해상도 21 μm, 7/7 (red = 700 nm/green = 800 nm)의 스캐닝 강도
2. 실험 방법
메인 어세이에서 간섭을 일으킬 수 있는 항원-유래 펩타이드와 상호 작용을 일으킬 수 있는 지 확인하기 위하여, 배양 버퍼 내에서 2차 항체 및 대조군 항체를 사용해 Lrig-1 펩타이드의 마이크로어레이 복제의 전-염색(pre-staining)을 수행하였다. 이후, 배양 버퍼 내에서 제조예 4인 GTC110-04 단일클론항체(1 ㎍/ml, 10 ㎍/ml 및 100 ㎍/ml)와 함께 다른 Lrig-1 펩타이드의 마이크로어레이 복제의 추가적 배양을 수행한 뒤, 2차 항체 및 대조군 항체를 사용하여 염색하였다. LI-COR Odyssey Imaging System을 이용하여 7/7 (red/green)의 스캐닝 강도로 판독(read-out)을 수행하였다. 스팟 강도의 정량화 및 펩타이드 해독(peptide annotation)은 16-비트 회색 스케일 TIFF 파일로 나타내었다. PepSlide® Analyzer를 이용하여 마이크로어레이 이미지를 분석하였다. 그 결과는 도 10 내지 12에 나타내었고, 분석된 에피토프 서열은 하기 표 6에 나타내었다.
서열목록 | 서열정보 |
서열번호 68 | WTRSLNLSYNKL |
서열번호 69 | TEVRNTCFPHGPPI |
서열번호 70 | RLTQLDLNRNRIR |
서열번호 71 | DLNRNRIRLIEGLTF |
서열번호 72 | NSIARIHRKGW |
서열번호 73 | WLPPWLIGRMLQAF |
서열번호 74 | RQVTFGHEGRY |
서열번호 75 | FGHEGRYQCVITNHF |
서열번호 76 | RLTVNVLPSFTKTPH |
서열번호 77 | RRMHVMPDDDVFF |
서열번호 78 | FFITDVKIDDAGVYS |
서열번호 79 | KGDRPLSLTERHH |
3. 실험 결과
도 10 내지 12에서 보는 바와 같이, 조절 T 세포상에 존재하는 Lrig-1 단백질에 특이적으로 결합하여 암을 효과적으로 치료하는 단일클론항체(GTC110-04)는, Lrig-1 단백질 중 서열번호 68 내지 79로 표시되는 아미노산 서열로 이루어지는 에피토프에 특이적으로 결합하여 상기의 기능을 발휘하는 것임을 확인할 수 있었다. 더욱이, 서열번호 66 및 68로 표시되는 에피토프는 류신-풍부 단백질(leucine rich repeat)을 공통으로 하고 있으며, 구체적으로는 N-터미널로부터 5번째 아미노산 위치에 하기 식 1의 아미노산 서열로 표시될 수 있는 공통된 서열(consensus sequence)을 포함하고 있음을 수 있었다.
[식 1]
Lx1Lx2x3N
상기 식 1에서,
x1 내지 x3는 각각 독립적으로 중성 아미노산, 산성 아미노산, 염기성 아미노산 또는 방향족 아미노산일 수 있다. 여기서 상기 중성 아미노산은, 글리신(glycine; G), 알라닌(alanine; A), 발린(valine, V), 류신(leucine, L), 아이소류신(isoleucine, I), 세린(serine, S) 또는 트레오닌(threonine, T)일 수 있고, 상기 산성 아미노산은 아스파트산(aspartic acid; D), 글루탐산(glutamic acid; E), 아스파라긴(asparagine; N) 또는 글루타민(glutamine; Q)일 수 있으며, 상기 염기성 아미노산은 라이신(lysine, K), 아르기닌(arginine; R) 또는 히스티딘(histidine; H)일 수 있고, 상기 방향족 아미노산은 페닐알라닌(phenylalanine; F) 또는 티로신(tyrosine; Y)일 수 있다.
[실시예 7] 본 발명에 따른 항체의 Treg 내 신호전달경로의 조절
상기 제조예 1 내지 4에서 제작된 본 발명에 따른 단일클론항체가 Lrig-1 단백질을 통하여 Treg 내의 신호전달경로에 어떠한 영향을 미치는지를 분석하기 위하여, 상기 제조예 1 내지 4의 항체를 Treg에 처리하여 상기 Treg의 표면에 존재하는 Lrig-1 단백질을 자극한 뒤, 포스포티로신 면역 블롯(phosphotyrosine immunoblot)을 통하여 자극받은 Treg 내에 존재하는 Stat3 단백질의 티로신 인산화(tyrosine phosphorylation) 정도를 분석하고, 그 결과를 도 13에 나타내었다.
도 13에서 보는 바와 같이, 본 발명에 따른 Lrig-1 단백질에 특이적으로 결합하는 결합 분자인 단일클론항체(GTC110-01, GTC110-02, GTC110-03 및 GTC110-04)는 Stat3의 인산화(phosphorylation)를 iTreg 세포와 같은 수준으로 계속하여 유지 및 감소시키는 것을 확인할 수 있었다.
[실시예 8] Lrig-1 발현 수준에 따른 Treg의 기능 확인
상기 준비예 2에서 분리한 4일 동안 배양된 iTreg Lrig-1low (이하, '4d iTreg Lrig-1low'라 함), 4일 동안 배양된 iTreg Lrig-1high(이하, '4d iTreg Lrig-1high'라 함) 또는 6일 동안 배양된 iTreg Lrig-1low(이하, '6d iTreg Lrig-1low'라 함)와 C57BL/6 쥐에서 분리된 효과 T 세포(effector T cell)을 1:1 또는 2:1의 비율로 혼합한 배양하고, 상기 Treg 각각에 의한 효과 T 세포의 억제 정도를 FACS를 통해 분석하여, 그 결과를 도 14a 및 14b에 나타내었다.
도 14a 및 14b에서 보는 바와 같이, 효과 T 세포가 4d iTreg Lrig-1low 및 6d iTreg Lrig-1low와 혼합된 경우에는 15.3%(2:1) 24.4%(2:1)의 효과 T 세포가 그 기능이 억제된 반면, 4d iTreg Lrig-1high와 혼합된 경우에는 45.1%(2:1) 또는 34.2%(1:1)의 효과 T 세포가 기능이 억제되었다.
이를 통해, 본 발명에 따른 Lrig-1 단백질이 표면에 발현되어 있는 Treg은 효과 T 세포를 억제할 수 있는 활성화된 Treg이며, 종양 침윤 림프구(tumor infiltrating lymphocytes; TIL)임을 알 수 있다. 따라서, Treg의 표면에 발현되어 있는 Lrig-1 단백질에 특이적으로 결합하는 결합 분자는 Treg이 효과 T 세포를 억제하는 기능을 효과적으로 억제함으로써, 궁극적으로 효과 T 세포에 의해 암 세포의 사멸을 유도할 수 있다.
나아가, 이는 암 세포와 효과 T 세포 사이에 일어나는 종양세포의 면역체크포인트 회피와는 별개의 메커니즘으로 효과 T 세포의 활성을 유지시킴으로써 면역체크포인트 억제제에 의해 저항성이 있는 암에도 매우 유용하게 적용하여 암을 예방, 개선 또는 치료할 수 있음을 알 수 있다.
[실시예 9] 면역체크포인트 억제제 저항성 암 치료 효과 확인(1)
상기 제조예에서 제작된 본 발명에 따른 단일클론항체(GTC110-04)와 기존의 면역체크포인트억제제인 PD-1 항체의 고형암에 대한 치료 효과를 비교하기 위하여, 도 15에서 보는 바와 같이, B16F10 흑색종 세포(melanoma cell)를 마우스 등에 3× 105 세포의 양으로 피하 주사(subcutaneous injection)한 뒤, 4일, 8일, 12일 째에 상기 단일클론항체(GTC110-04) 또는 PD-1 항체를 200 ㎍의 양으로 복강 내 주사하였다. 상기 흑색종 세포 이식 후 시간의 경과에 따른 종양의 부피 변화를 측정하여 그 결과를 도 16에 나타내었다.
도 16에서 보는 바와 같이, PD-1 항체를 주사한 경우에는 종양의 크기가 음성 대조군과 유사한 정도에 불과하였으나, 본 발명에 따른 Lrig-1 단백질에 특이적으로 결합하는 결합 분자인 단일클론항체(GTC110-04)를 주사한 경우에는 음성 대조군에 비하여 종양의 크기가 현저하게 감소되었다.
이를 통하여, 본 발명에 따른 Lrig-1 단백질 특이적인 단일클론항체는 PD-1에 의해 치료될 수 없는 면역체크포인트 억제제 저항성이 존재하는 고형암 세포의 성장을 억제할 수 있고, 이를 통해 면역체크포인트 억제제 저항성이 존재하는 고형암을 효과적으로 예방, 개선 또는 치료할 수 있음을 알 수 있다.
[실시예 10] 면역체크포인트 억제제 저항성 암 치료 효과 확인(2)
상기 실시예 9의 흑색종 동물 모델의 종양 침윤 림프구의 세포 분포를 확인하였다.
구체적으로, 상기 흑색종 마우스 모델에서 종양 조직을 적출한 뒤, 2 ml의 PBS(2%의 FBS 포함)가 담겨 있는 6웰 플레이트에 상기 적출된 종양 조직을 넣고 e-튜브를 이용하여 잘게 갈았다. 이때, 종양 조직의 크기가 너무 클 경우에는 가위를 이용하여 1차 절단을 하였다. 상기 잘게 갈린 종양 조직과, e-튜브의 벽에 붙어 있는 모든 조직을 스트레이너(strainer)를 통해 걸러 50 ml 튜브에 넣은 뒤, 최종 볼륨을 20 ml로 맞추어 4도씨에서 2000 rpm으로 10분 동안 원심분리하였다. 이후, 석션을 통해 상층액을 제거하고, 3 ml의 RBC 용해 버퍼(lysis buffer)를 넣고 상온에서 30초 동안 반응시킨 뒤, 2%의 RPMI를 넣어 비활성화 시켰다. 그런 다음, 원심분리를 수행하고 상층액을 제거한 뒤에, 스트레이너를 이용하여 재 현탁된 펠렛을 거른 뒤 원심분리를 수행하였다. 이후, 8 ml의 붉은색의 44% 퍼콜(percoll, percoll : RPMI = 11 : 14)을 이용하여 재 현탁된 펠렛을 15 ml 튜브로 옮기고, 5 ml의 깨끗한 67% 퍼콜(percoll : PBS = 67 : 33)을 파스테르 파이펫을 이용하여 천천히 상기 15 ml 튜브의 아래층에 넣었다. 상기 15 ml 튜브를 4도씨 2000 rpm에서 20분 동안 브레이크가 걸리지 않는 조건의 원심분리를 수행하고, 버피 코트(buffy coat) 위 약 1 ml까지 제거한 뒤에, 버피 코트를 분리하여 15 ml 튜브에 옮겨 담았다. 이후, 버피 코트가 포함된 15 ml 튜브에 2%의 FBS가 포함된 PBS를 이용하여 재 현탁 시킨 뒤에 종양 침윤 림프구의 세포 수를 측정하였다.
이렇게 얻어진 종양 침윤 림프구 세포를 1 × 106 세포수/200 ㎕의 양으로 둥근 바닥의 96웰 세포 배양 플레이트의 각 웰에 분주하고, 2500 rpm에서 2분동안 원심분리를 수행하였다. 이후, 상층액을 제거하고, PBS에 희석된 1차 마커(CD4, CD8, Lrig-1)를 표적으로 하는 항체를 각 웰에 50 ㎕씩 분주한 뒤에 파이펫팅하여 잘 섞어주었다. 그런 다음, 호일을 이용하여 플레이트에 빛을 차단하고 4도씨 냉장고에서 30분 동안 배양하고, 150 ㎕의 PBS를 추가로 넣고 원심분리를 수행하였다. 이후, 고정화/펌(perm) 시약을 각 웰당 80 ㎕씩 분주하고, 4도씨에서 30분 동안 배양한 뒤에 120 ㎕의 1× 펌 버퍼를 넣고 원심분리를 수행하였다. 마지막으로, 1× 펌 버퍼에 포함된 1 ㎕의 2차 마커(Foxp3)를 각 웰당 50 ㎕씩 분주하고, 4도씨에서 30분 동안 배양한 뒤에 원심분리를 수행하여 얻어진 세포를 200 ㎕의 PBS에 재 현탁 시킨 뒤에 통상의 방법에 따라 FACS를 측정하여, 그 결과를 도 17에 나타내었다.
도 17에서 보는 바와 같이, PD-1 항체를 주사한 경우에는 종양으로 침윤된 CD8+ T 세포의 수가 대조군(Control)과 비교하여 그 증가가 미비한 반면, 본 발명에 따른 Lrig-1 단백질에 특이적으로 결합하는 결합 분자인 단일클론항체(GTC110-04)를 주사한 경우에는 음성 대조군과 비교하여 약 2배 이상 종양으로 침윤된 CD8+ T 세포의 수가 증가되었다. 나아가, PD-1 항체에 의해서는 종양으로 침윤된 CD4+Foxp3+ T 세포의 수가 변화되지 않는 반면, 상기 단일클론항체(GTC110-04)에 의해서는 종양으로 침윤된 CD4+Foxp3+ T 세포의 수가 현저하게 감소되는 것을 확인하였다.
상기 결과를 통해 본 발명에 따른 Lrig-1 단백질에 특이적으로 결합하는 결합분자는 종양으로 침윤된 CD4+Foxp3+ T 세포의 수를 현저하게 감소시켜, 효과 T 세포의 기능을 향상시킴으로써 매우 효과적으로 면역체크포인트 억제제 저항성 암의 예방 또는 치료에 시너지 효과가 발휘되도록 할 수 있음을 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, Inc.
<120> A composition for preventing, alleviating or treating immune
checkpoint inhibitor resistant cancer
<130> PDPB194136k01
<150> KR 10-2019-0084098
<151> 2019-07-11
<160> 91
<170> KoPatentIn 3.0
<210> 1
<211> 759
<212> PRT
<213> Homo sapiens
<400> 1
Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp Ser
1 5 10 15
Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu Pro
20 25 30
Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu Ile
35 40 45
Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr Leu
50 55 60
Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser Ser
65 70 75 80
His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val Glu
85 90 95
Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu Ser
100 105 110
Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly Pro
115 120 125
Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu Glu
130 135 140
Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg Leu
145 150 155 160
Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu Pro
165 170 175
Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile Glu
180 185 190
Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu Gln
195 200 205
Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu Ser
210 215 220
Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val Asn
225 230 235 240
Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu Ser
245 250 255
Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys Gln
260 265 270
Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu Asp
275 280 285
Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu Ser
290 295 300
His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu Arg
305 310 315 320
Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr Ile
325 330 335
Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys Leu
340 345 350
Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe Ser
355 360 365
Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile Arg
370 375 380
Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu Leu
385 390 395 400
His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp Leu
405 410 415
Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala Thr
420 425 430
Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val Pro
435 440 445
Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile Thr
450 455 460
Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe Thr
465 470 475 480
Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp Lys
485 490 495
Lys Asp Asn Glu Val Leu Thr Asn Ala Asp Met Glu Asn Phe Val His
500 505 510
Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu His
515 520 525
Leu Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys Val Ile
530 535 540
Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu Thr Val
545 550 555 560
Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His Asp Ile Thr Ile Arg
565 570 575
Thr Thr Thr Val Ala Arg Leu Glu Cys Ala Ala Thr Gly His Pro Asn
580 585 590
Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro Ala Ala
595 600 605
Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe Ile
610 615 620
Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser Cys Thr Ala Gln
625 630 635 640
Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr Leu Thr Val Leu Glu
645 650 655
Thr Pro Ser Leu Val Val Pro Leu Glu Asp Arg Val Val Ser Val Gly
660 665 670
Glu Thr Val Ala Leu Gln Cys Lys Ala Thr Gly Asn Pro Pro Pro Arg
675 680 685
Ile Thr Trp Phe Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg His
690 695 700
His Leu Thr Pro Asp Asn Gln Leu Leu Val Val Gln Asn Val Val Ala
705 710 715 720
Glu Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Thr Leu Gly Thr
725 730 735
Glu Arg Ala His Ser Gln Leu Ser Val Leu Pro Ala Ala Gly Cys Arg
740 745 750
Lys Asp Gly Thr Thr Val Gly
755
<210> 2
<211> 2397
<212> DNA
<213> Homo sapiens
<400> 2
ggcccgcggg cgccctgcgc ggccgcctgc acttgcgctg gggactcgct ggactgcggt 60
gggcgcgggc tggctgcgtt gcccggggac ctgccctcct ggacgcggag cctaaacctg 120
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
<213> Mus musculus
<400> 3
Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly
1 5 10 15
Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg Asp
20 25 30
Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu Ser
35 40 45
Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu Val
50 55 60
Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala Ala
65 70 75 80
Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu Ser
85 90 95
Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu Asp
100 105 110
Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro Asn
115 120 125
Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser Ile
130 135 140
Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu
145 150 155 160
Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe Lys
165 170 175
Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu
180 185 190
Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu Arg
195 200 205
Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp Gly
210 215 220
Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu
225 230 235 240
Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His
245 250 255
Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser Phe
260 265 270
Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr Arg
275 280 285
Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu Arg
290 295 300
Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly
305 310 315 320
Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly
325 330 335
Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu Ser
340 345 350
Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala
355 360 365
Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn Ala
370 375 380
Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu Lys
385 390 395 400
Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu Lys
405 410 415
Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val Thr
420 425 430
Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser
435 440 445
Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln Ile
450 455 460
Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile Arg
465 470 475 480
Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala
485 490 495
Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn Phe
500 505 510
Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile
515 520 525
Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys
530 535 540
Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu
545 550 555 560
Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile Ala
565 570 575
Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly His
580 585 590
Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro
595 600 605
Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe
610 615 620
Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys Thr
625 630 635 640
Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr Val
645 650 655
Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val Thr
660 665 670
Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro Thr
675 680 685
Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr Glu
690 695 700
Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn Val
705 710 715 720
Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro Leu
725 730 735
Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro Gly
740 745 750
Cys Arg Lys Asp Gly Thr Thr Val Gly
755 760
<210> 4
<211> 2283
<212> DNA
<213> Mus musculus
<400> 4
caggctggcc cgcgggcccc ctgcgcggcc gcctgcactt gcgccgggga ctcgctggac 60
tgcagtgggc gcgggctggc gacgctgccc cgggacctgc cctcctggac gcgcagccta 120
aacctgagtt ataacagact ctccgagatc gactctgctg cttttgagga cttgacgaat 180
ctgcaggaag tgtacctcaa cagcaatgag ctgacagcca taccatcact gggcgctgct 240
tccataggag ttgtctctct ctttttgcag cacaacaaga tccttagtgt ggatgggagc 300
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> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-01 heavy chain CDR1
<400> 5
Gly Phe Thr Phe Ser Asp Tyr Asp
1 5
<210> 6
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-01 heavy chain CDR2
<400> 6
Trp Ile Ser His Gly Gly Gly Ser Ile
1 5
<210> 7
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-01 heavy chain CDR3
<400> 7
Ala Arg Gly Leu Gly Leu Cys Lys Thr Gly Leu Cys Tyr Tyr Tyr Asp
1 5 10 15
Ala Met Asp Val
20
<210> 8
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-01 light chain CDR1
<400> 8
Ser Ser Asn Ile Gly Asn Asn Ser
1 5
<210> 9
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-01 light chain CDR2
<400> 9
Ala Asp Asn
1
<210> 10
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-01 light chain CDR3
<400> 10
Ala Ala Trp Asp Ser Ser Leu Ser Ala Tyr Val
1 5 10
<210> 11
<211> 127
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-01 heavy chain_variable region
<400> 11
Glu Val Gln Leu Leu Glu 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 Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Trp Ile Ser His Gly Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys 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 Arg Gly Leu Gly Leu Cys Lys Thr Gly Leu Cys Tyr Tyr Tyr Asp
100 105 110
Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 12
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-01 light chain_variable region
<400> 12
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Ser Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Asn Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 13
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-02 heavy chain CDR1
<400> 13
Gly Phe Thr Phe Ser Asp Tyr Tyr
1 5
<210> 14
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-02 heavy chain CDR2
<400> 14
Gly Ile Ser His Asp Ser Gly Ser Lys
1 5
<210> 15
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-02 heavy chain CDR3
<400> 15
Ala Arg His Trp Thr Thr Phe Asp Tyr
1 5
<210> 16
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-02 light chain CDR1
<400> 16
Ser Ser Asn Ile Gly Ser Asn Asn
1 5
<210> 17
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-02 light chain CDR2
<400> 17
Ala Asn Ser
1
<210> 18
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-02 light chain CDR3
<400> 18
Gly Ala Trp Asp Tyr Ser Leu Ser Ala Tyr Val
1 5 10
<210> 19
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-02 heavy chain_variable region
<400> 19
Glu Val Gln Leu Leu Glu 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 Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser His Asp Ser Gly Ser Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys 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 Arg His Trp Thr Thr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 20
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-02 light chain_variable region
<400> 20
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Asn Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Tyr Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 21
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-03 heavy chain CDR1
<400> 21
Gly Phe Thr Phe Ser Asn Tyr Ala
1 5
<210> 22
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-03 heavy chain CDR2
<400> 22
Ala Ile Tyr Pro Gly Gly Gly Ser Ile
1 5
<210> 23
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-03 heavy chain CDR3
<400> 23
Ala Arg Asp Ile Leu Pro Cys Pro Trp Gly Arg Cys Tyr Tyr Asp Tyr
1 5 10 15
Ala Met Asp Val
20
<210> 24
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-03 light chain CDR1
<400> 24
Ser Ser Asn Ile Gly Ser Asn Thr
1 5
<210> 25
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-03 light chain CDR2
<400> 25
Ala Asp Asn
1
<210> 26
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-03 light chain CDR3
<400> 26
Gly Thr Trp Asp Tyr Ser Leu Ser Gly Tyr Val
1 5 10
<210> 27
<211> 127
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-03 heavy chain_variable region
<400> 27
Glu Val Gln Leu Leu Glu 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 Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Tyr Pro Gly Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys 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 Arg Asp Ile Leu Pro Cys Pro Trp Gly Arg Cys Tyr Tyr Asp Tyr
100 105 110
Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 28
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-03 light chain_variable region
<400> 28
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Asp Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Asn Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 29
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-04 heavy chain CDR1
<400> 29
Gly Phe Thr Phe Ser Asn Tyr Ala
1 5
<210> 30
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-04 heavy chain CDR2
<400> 30
Val Ile Ser His Gly Gly Gly Ser Thr
1 5
<210> 31
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-04 heavy chain CDR3
<400> 31
Ala Arg Val Ile Ser Asn Cys His Leu Gly Val Cys Tyr Tyr Ser Asn
1 5 10 15
Gly Met Asp Val
20
<210> 32
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-04 light chain CDR1
<400> 32
Ser Ser Asn Ile Gly Asn Asn Asp
1 5
<210> 33
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-04 light chain CDR2
<400> 33
Ser Asp Ser
1
<210> 34
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-04 light chain CDR3
<400> 34
Gly Thr Trp Asp Tyr Ser Leu Ser Gly Tyr Val
1 5 10
<210> 35
<211> 127
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-04 heavy chain_variable region
<400> 35
Glu Val Gln Leu Leu Glu 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 Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser His 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 Lys 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 Arg Val Ile Ser Asn Cys His Leu Gly Val Cys Tyr Tyr Ser Asn
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 36
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-04 light chain_variable region
<400> 36
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Asp Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Ser Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 37
<211> 328
<212> PRT
<213> Mus musculus
<400> 37
Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr
1 5 10 15
Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro
20 25 30
Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val
35 40 45
His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser
50 55 60
Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys
65 70 75 80
Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu
85 90 95
Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala
100 105 110
Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile
115 120 125
Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val
130 135 140
Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val
145 150 155 160
Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp
165 170 175
Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln
180 185 190
Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp
195 200 205
Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val
210 215 220
Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr
225 230 235 240
Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu
245 250 255
Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr
260 265 270
Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr
275 280 285
Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr
290 295 300
Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys
305 310 315 320
Ser Phe Ser Arg Thr Pro Gly Lys
325
<210> 38
<211> 107
<212> PRT
<213> Mus musculus
<400> 38
Arg Thr Val Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
1 5 10 15
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
20 25 30
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
35 40 45
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
65 70 75 80
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
85 90 95
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
100 105
<210> 39
<211> 330
<212> PRT
<213> Homo sapiens
<400> 39
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 40
<211> 330
<212> PRT
<213> Homo sapiens
<400> 40
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 41
<211> 107
<212> PRT
<213> Homo sapiens
<400> 41
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 42
<211> 326
<212> PRT
<213> Homo sapiens
<400> 42
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ser Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly Lys
325
<210> 43
<211> 377
<212> PRT
<213> Homo sapiens
<400> 43
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro
100 105 110
Arg Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg
115 120 125
Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys
130 135 140
Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro
145 150 155 160
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
165 170 175
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
180 185 190
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr
195 200 205
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
210 215 220
Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His
225 230 235 240
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
245 250 255
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
260 265 270
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
275 280 285
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
290 295 300
Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn
305 310 315 320
Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
325 330 335
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile
340 345 350
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln
355 360 365
Lys Ser Leu Ser Leu Ser Pro Gly Lys
370 375
<210> 44
<211> 327
<212> PRT
<213> Homo sapiens
<400> 44
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 45
<211> 245
<212> PRT
<213> Artificial Sequence
<220>
<223> Hybrid Fc_Heavy region
<400> 45
Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys
1 5 10 15
Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His
20 25 30
Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
35 40 45
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
50 55 60
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
65 70 75 80
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
85 90 95
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
100 105 110
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
115 120 125
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
130 135 140
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
145 150 155 160
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
165 170 175
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
180 185 190
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
195 200 205
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
210 215 220
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
225 230 235 240
Leu Ser Leu Gly Lys
245
<210> 46
<211> 457
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-01 heavy chain_mouse IgG2 Fc_full sequence
<400> 46
Glu Val Gln Leu Leu Glu 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 Asp Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Trp Ile Ser His Gly Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys 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 Arg Gly Leu Gly Leu Cys Lys Thr Gly Leu Cys Tyr Tyr Tyr Asp
100 105 110
Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp
130 135 140
Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly
165 170 175
Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser
180 185 190
Ser Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr
195 200 205
Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile
210 215 220
Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro
225 230 235 240
Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys
245 250 255
Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val
260 265 270
Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe
275 280 285
Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu
290 295 300
Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His
305 310 315 320
Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys
325 330 335
Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser
340 345 350
Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met
355 360 365
Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro
370 375 380
Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn
385 390 395 400
Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met
405 410 415
Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser
420 425 430
Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr
435 440 445
Lys Ser Phe Ser Arg Thr Pro Gly Lys
450 455
<210> 47
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-01 light chain_mouse IgG2 Fc_full sequence
<400> 47
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Ser Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Asn Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Ser Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Thr
100 105 110
Val Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu
115 120 125
Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro
130 135 140
Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn
145 150 155 160
Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His
180 185 190
Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile
195 200 205
Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 48
<211> 446
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-02 heavy chain_mouse IgG2 Fc_full sequence
<400> 48
Glu Val Gln Leu Leu Glu 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 Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser His Asp Ser Gly Ser Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys 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 Arg His Trp Thr Thr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala
115 120 125
Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu
130 135 140
Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly
145 150 155 160
Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp
165 170 175
Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp Pro
180 185 190
Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys
195 200 205
Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro
210 215 220
Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro
245 250 255
Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val
260 265 270
Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr
275 280 285
Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala
290 295 300
Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys
305 310 315 320
Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser
325 330 335
Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro
340 345 350
Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val
355 360 365
Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly
370 375 380
Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp
405 410 415
Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His
420 425 430
Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
435 440 445
<210> 49
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-02 light chain_mouse IgG2 Fc_full sequence
<400> 49
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Asn Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Tyr Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Thr
100 105 110
Val Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu
115 120 125
Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro
130 135 140
Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn
145 150 155 160
Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His
180 185 190
Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile
195 200 205
Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 50
<211> 457
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-03 heavy chain_mouse IgG2 Fc_full sequence
<400> 50
Glu Val Gln Leu Leu Glu 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 Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Tyr Pro Gly Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys 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 Arg Asp Ile Leu Pro Cys Pro Trp Gly Arg Cys Tyr Tyr Asp Tyr
100 105 110
Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp
130 135 140
Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly
165 170 175
Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser
180 185 190
Ser Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr
195 200 205
Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile
210 215 220
Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro
225 230 235 240
Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys
245 250 255
Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val
260 265 270
Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe
275 280 285
Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu
290 295 300
Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His
305 310 315 320
Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys
325 330 335
Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser
340 345 350
Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met
355 360 365
Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro
370 375 380
Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn
385 390 395 400
Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met
405 410 415
Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser
420 425 430
Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr
435 440 445
Lys Ser Phe Ser Arg Thr Pro Gly Lys
450 455
<210> 51
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-03 light chain_mouse IgG2 Fc_full sequence
<400> 51
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Asp Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Asn Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Thr
100 105 110
Val Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu
115 120 125
Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro
130 135 140
Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn
145 150 155 160
Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His
180 185 190
Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile
195 200 205
Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 52
<211> 457
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-04 heavy chain_mouse IgG2 Fc_full sequence
<400> 52
Glu Val Gln Leu Leu Glu 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 Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser His 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 Lys 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 Arg Val Ile Ser Asn Cys His Leu Gly Val Cys Tyr Tyr Ser Asn
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp
130 135 140
Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly
165 170 175
Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser
180 185 190
Ser Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr
195 200 205
Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile
210 215 220
Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro
225 230 235 240
Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys
245 250 255
Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val
260 265 270
Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe
275 280 285
Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu
290 295 300
Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His
305 310 315 320
Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys
325 330 335
Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser
340 345 350
Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met
355 360 365
Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro
370 375 380
Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn
385 390 395 400
Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met
405 410 415
Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser
420 425 430
Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr
435 440 445
Lys Ser Phe Ser Arg Thr Pro Gly Lys
450 455
<210> 53
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-04 light chain_mouse IgG2 Fc_full sequence
<400> 53
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Asp Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Ser Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Thr
100 105 110
Val Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu
115 120 125
Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro
130 135 140
Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn
145 150 155 160
Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His
180 185 190
Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile
195 200 205
Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 54
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 54
Asn Leu Ser Tyr Asn
1 5
<210> 55
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 55
Leu Asp Leu Asn Arg Asn
1 5
<210> 56
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 56
Leu Phe Leu Gln His Asn
1 5
<210> 57
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 57
Leu Asn Leu Ala Gly Asn
1 5
<210> 58
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 58
Leu Asp Leu Ser Leu Asn
1 5
<210> 59
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 59
Leu Arg Leu Ser Lys Asn
1 5
<210> 60
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 60
Leu Lys Leu Gln Arg Asn
1 5
<210> 61
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 61
Leu His Leu Glu Tyr Asn
1 5
<210> 62
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 62
Leu His Leu Ser Asn Asn
1 5
<210> 63
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 63
Leu Val Leu Ser Phe Asn
1 5
<210> 64
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 64
Leu Arg Leu Ser His Asn
1 5
<210> 65
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 65
Leu Asp Leu Asp His Asn
1 5
<210> 66
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 66
Leu Thr Leu Phe Gly Asn
1 5
<210> 67
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 67
Leu Asn Leu Gly Gly Asn
1 5
<210> 68
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 68
Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu
1 5 10
<210> 69
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 69
Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly Pro Pro Ile
1 5 10
<210> 70
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 70
Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg
1 5 10
<210> 71
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 71
Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile Glu Gly Leu Thr Phe
1 5 10 15
<210> 72
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 72
Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp
1 5 10
<210> 73
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 73
Trp Leu Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe
1 5 10
<210> 74
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 74
Arg Gln Val Thr Phe Gly His Glu Gly Arg Tyr
1 5 10
<210> 75
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 75
Phe Gly His Glu Gly Arg Tyr Gln Cys Val Ile Thr Asn His Phe
1 5 10 15
<210> 76
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 76
Arg Leu Thr Val Asn Val Leu Pro Ser Phe Thr Lys Thr Pro His
1 5 10 15
<210> 77
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 77
Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe Phe
1 5 10
<210> 78
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 78
Phe Phe Ile Thr Asp Val Lys Ile Asp Asp Ala Gly Val Tyr Ser
1 5 10 15
<210> 79
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Lrig-1 epitope
<400> 79
Lys Gly Asp Arg Pro Leu Ser Leu Thr Glu Arg His His
1 5 10
<210> 80
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> mouse Lrig-1 forward primer
<400> 80
gacggaattc agtgaggaga acct 24
<210> 81
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> mouse Lrig-1 reverse primer
<400> 81
caactggtag tggcagcttg tagg 24
<210> 82
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> mouse Lrig-2 forward primer
<400> 82
tcacaaggaa cattgtctga acca 24
<210> 83
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> mouse Lrig-2 reverse primer
<400> 83
gcctgatcta acacatcctc ctca 24
<210> 84
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> mouse Lrig-3 forward primer
<400> 84
cagcaccttg agctgaacag aaac 24
<210> 85
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> mouse Lrig-3 reverse primer
<400> 85
ccagcctttg gtaatctcgg ttag 24
<210> 86
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> mouse Foxp3 forward primer
<400> 86
ctttcaccta tcccaccctt atcc 24
<210> 87
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> mouse Foxp3 reverse primer
<400> 87
attcatctac ggtccacact gctc 24
<210> 88
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> ACTG1 Forward primer
<400> 88
ggcgtcatgg tgggcatggg 20
<210> 89
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> ACTG1 reverse primer
<400> 89
atggcgtggg gaagggcgta 20
<210> 90
<211> 458
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-04 heavy chain_human IgG1
<400> 90
Glu Val Gln Leu Leu Glu 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 Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser His 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 Lys 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 Arg Val Ile Ser Asn Cys His Leu Gly Val Cys Tyr Tyr Ser Asn
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
130 135 140
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
165 170 175
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
180 185 190
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
195 200 205
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
210 215 220
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
225 230 235 240
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
245 250 255
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
260 265 270
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
275 280 285
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
290 295 300
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
305 310 315 320
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
325 330 335
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
340 345 350
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
355 360 365
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
370 375 380
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
385 390 395 400
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
405 410 415
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
420 425 430
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
435 440 445
Lys Ser Leu Ser Leu Ser Pro Gly Lys Tyr
450 455
<210> 91
<211> 217
<212> PRT
<213> Artificial Sequence
<220>
<223> GTC110-04 Light chain_human IgG1
<400> 91
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Asp Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Ser Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Ser Leu
85 90 95
Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
Claims (13)
- Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질에 특이적으로 결합하는 결합 분자를 유효성분으로 포함하는 면역체크포인트 억제제 저항성 암의 예방 또는 치료용 약학 조성물.
- 제1항에 있어서,
상기 Lrig-1 단백질은 서열번호 1 또는 3으로 표시되는 아미노산 서열로 이루어지는 것인, 약학 조성물. - 제1항에 있어서,
상기 Lrig-1 단백질은 서열번호 2 또는 4로 표시되는 폴리뉴클레오티드에 의해 암호화되는 것인, 약학 조성물. - 제1항에 있어서,
상기 Lrig-1 단백질은 조절 T 세포(Regulatory T cell; Treg)의 표면에 존재하는 것인, 약학 조성물. - 제4항에 있어서,
상기 조절 T 세포는 종양 침윤 림프구(tumor infiltrating lymphocytes; TIL) 또는 활성화된 조절 T 세포인 것인, 약학 조성물. - 제1항에 있어서,
상기 결합 분자는 항체 또는 그 단편인 것인, 약학 조성물. - 제6항에 있어서,
상기 항체는 키메라 항체, 인간화 항체(humanized antibody), 인간 항체(human antibody), 이가(bivalent) 항체, 양특이성 분자, 미니바디(minibody), 도메인 항체, 이중특이적 항체(bispecific antibody), 항체 모방체, 유니바디(unibody), 디아바디(diabody), 트리아바디(triabody), 테트라바디(tetrabody) 또는 이의 단편인 것인, 약학 조성물. - 제1항에 있어서,
상기 약학 조성물은 항암 치료제를 더 포함하는 것인, 약학 조성물. - 제1항에 있어서,
상기 암은 고형암인 것인, 약학 조성물. - 제1항에 있어서,
상기 암은 위암, 간암, 교세포종, 난소암, 대장암, 두경부암, 방광암, 신장세포암, 유방암, 전이암, 전립선암, 췌장암, 흑색종 또는 폐암인, 약학 조성물. - Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질에 특이적으로 결합하는 항체 또는 항원 결합 단편; 및 약물을 포함하는 항체-약물 결합체를 유효성분으로 포함하는 면역체크포인트 억제제 저항성 암의 예방 또는 치료용 약학 조성물.
- 제11항에 있어서,
상기 암은 고형암인, 약학 조성물. - 제11항에 있어서,
상기 암은 위암, 간암, 교세포종, 난소암, 대장암, 두경부암, 방광암, 신장세포암, 유방암, 전이암, 전립선암, 췌장암, 흑색종 또는 폐암인, 약학 조성물.
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EP (1) | EP3998284A4 (ko) |
JP (1) | JP2022539831A (ko) |
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KR101847523B1 (ko) * | 2011-01-24 | 2018-05-28 | 연세대학교 산학협력단 | 조절자 T 세포에 특이적으로 존재하는 새로운 표면단백질 Lrig-1의 용도 |
KR101938699B1 (ko) * | 2012-07-23 | 2019-01-16 | 삼성전자주식회사 | Lrig1의 항 c―met 항체 적용 대상 환자 선별을 위한 용도 |
CA2949947A1 (en) * | 2014-06-04 | 2015-12-10 | Ngm Biopharmaceuticals, Inc. | Compositions and methods for targeting a pathway |
CN108697777A (zh) * | 2016-02-08 | 2018-10-23 | 国立大学法人三重大学 | 对免疫检查点抑制剂抵抗性肿瘤的t细胞输注疗法的预处理药物 |
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US11365249B2 (en) * | 2017-04-18 | 2022-06-21 | Good T Cells, Inc. | Binding molecule specific for Lrig-1 protein and use thereof |
KR20180116924A (ko) * | 2017-04-18 | 2018-10-26 | 주식회사 굳티셀 | 면역 세포 표면 단백질의 항원 결정기인 폴리펩티드 |
KR20180116925A (ko) * | 2017-04-18 | 2018-10-26 | 주식회사 굳티셀 | 암 또는 면역 질환의 예방 또는 치료용 약학 조성물 |
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- 2020-07-13 CN CN202080050262.2A patent/CN114173814A/zh active Pending
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US20220249684A1 (en) | 2022-08-11 |
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