KR20220144777A - Asymmetric antibody with enhanced target cell clearance - Google Patents
Asymmetric antibody with enhanced target cell clearance Download PDFInfo
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- KR20220144777A KR20220144777A KR1020220048257A KR20220048257A KR20220144777A KR 20220144777 A KR20220144777 A KR 20220144777A KR 1020220048257 A KR1020220048257 A KR 1020220048257A KR 20220048257 A KR20220048257 A KR 20220048257A KR 20220144777 A KR20220144777 A KR 20220144777A
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- antibody
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Abstract
Description
본 발명은 보체 의존 세포사멸능 (Complement Dependent Cytotoxicity, CDC)이 향상된 신규한 항-CD20 비대칭 항체 또는 이의 항원 결합 단편 및/또는 이를 이용한 암의 예방, 치료 및/또는 진단용 조성물에 관한 것이다.The present invention relates to a novel anti-CD20 asymmetric antibody or antigen-binding fragment thereof with improved complement dependent cytotoxicity (CDC) and/or a composition for preventing, treating and/or diagnosing cancer using the same.
전세계 항암제 시장은 지난 10년 간 연평균 10 - 13%의 성장률을 보여 왔으며, 2022년에는 총 2,000억 달러에 달할 것으로 예상된다. 2020년 현재 전세계 남성은 5명 중 1명, 여성은 6명 중 1명이 평생 1회 이상의 암 발병을 경험하고 있으며, 남성 8명 중 1명과 여성 11명 중 1명이 암으로 사망하고 있을 만큼 암의 유병률과 사망률은 지속적으로 증가하고 있다. The global anticancer drug market has grown at a CAGR of 10 - 13% over the past decade, and is expected to reach a total of $200 billion by 2022. As of 2020, 1 in 5 men and 1 in 6 women worldwide will experience cancer at least once in their lifetime, and 1 in 8 men and 1 in 11 women will die from cancer. The morbidity and mortality rates are continuously increasing.
전 세계 항암제 시장은 1세대 화학요법을 시작으로 2세대 표적 항암제와 3세대 면역 항암제까지 패러다임 전환이 이루어지고 있다. 초창기 단순한 암의 축소·억제를 목적으로 하던 치료 방법에서 벗어나 정상적으로 빠르게 분열하는 세포에 대한 손상이 가해지지 않고 암세포만을 선택적으로 공격하는 표적 항암 치료 기술이 활발하게 연구되고 있으며, 이러한 표적 항암치료 기술의 개발은 암세포를 선택적으로 표적화할 수 있도록 하는, 암세포에서 특이적으로 발현되는 수용체의 선별과 수용체와 결합하는 표적화 화합물의 개발의 두 단계로 이루어진다. The global anticancer drug market is undergoing a paradigm shift from first-generation chemotherapy to second-generation targeted anticancer drugs and third-generation immune anticancer drugs. In the early stage, away from the treatment methods aimed at reducing and suppressing simple cancers, targeted anticancer treatment technologies that selectively attack only cancer cells without damaging normally rapidly dividing cells are being actively studied. Development consists of two steps: the selection of a receptor specifically expressed on the cancer cell and the development of a targeting compound that binds to the receptor, which allows for the selective targeting of the cancer cell.
리툭시맙은 chimeric anti-CD20 단일클론 항체로서 종양 치료목적으로 상용화되어 미국 FDA로부터 최초로 승인된 단일클론 항체 치료제이다. 1980년대 초기의 CD20 항원의 항체는 마우스로부터 만들어진 단일클론 항체로서 항원과의 반응성은 우수하지만 생체 반감기가 짧고 이종 항원으로 인한 항원성(HAMA,human anti-mouse antibody)이 유발되는 단점이 있었다. 이러한 마우스 기원 항체의 결점을 보안하고 생물학적 효과를 높이기 위하여 항원 인식이 이루어지는 가변부위(variable region)는 마우스 기원이고 항체의 불변부위(constant region)는 인간 기원인 키메라 항체인 리툭시맙이 유전자 재조합 기술을 통하여 합성되었다.Rituximab is a chimeric anti-CD20 monoclonal antibody that has been commercialized for the purpose of treating tumors and is the first monoclonal antibody treatment approved by the US FDA. The CD20 antigen antibody in the early 1980s was a monoclonal antibody made from a mouse, and although it had excellent reactivity with the antigen, it had a short half-life and a disadvantage of inducing antigenicity (HAMA, human anti-mouse antibody) due to a heterologous antigen. In order to secure the defects of the mouse-origin antibody and increase the biological effect, the variable region where antigen recognition is made is of mouse origin, and the constant region of the antibody is a chimeric antibody rituximab of human origin. was synthesized through
CD20 항원은 B세포 계열이 세포주기(cell-cycle entry)에 들어가거나 B세포로 분화하는데 관여하는 것으로 알려져 있다. CD20 항원은 세포 표면으로부터 쉽게 탈각되거나 변형 혹은 함입되지 않는 특성을 지니고 있어 표적 분자로서 활용하기에 적당한 특징을 갖고 있다. CD20 항원의 분포는 정상 세포의 경우, pre-B 세포 단계에서 활성화된 B 세포(activated B cell) 단계까지 광범위하게 분포하지만 조혈모세포, 형질세포와 다른 계열의 세포에는 분포하지 않으며 림프종의 경우는 B 세포 림프종과 만성 림프구성 백혈병의 대부분과 pre-B cell 급성림프구성 백혈병의 50%에서 CD20 항원이 발현되어 단일클론 항체를 이용한 종양특이적 면역반응을 유도하는데 적절한 표적이 될 수 있다(Maloney DG et al., IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed lowgrade non-Hodgkin's lymphoma. Blood, 90:2188-2195, 1997; McLaughlin P et al., Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol, 16:2825-2833, 1998).CD20 antigen is known to be involved in the entry of the B cell lineage into the cell cycle (cell-cycle entry) or differentiation into B cells. The CD20 antigen has a characteristic that it is not easily dislodged, modified, or incorporated from the cell surface, so it has suitable characteristics for use as a target molecule. The distribution of CD20 antigen is widely distributed from the pre-B cell stage to the activated B cell stage in normal cells, but not in hematopoietic stem cells, plasma cells and other cell types. CD20 antigen is expressed in most of cell lymphoma and chronic lymphocytic leukemia and 50% of pre-B cell acute lymphocytic leukemia, so it can be an appropriate target for inducing a tumor-specific immune response using a monoclonal antibody (Maloney DG et al. al., IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed lowgrade non-Hodgkin's lymphoma.Blood, 90: 2188-2195 , 1997; McLaughlin P et al., Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol , 16:2825-2833, 1998).
하지만, 상기 리툭시맙의 경우 약 절반 정도의 저도 림프종 환자 및 약 60-70% 정도의 고도 림프종 환자에서 내성을 보이며, CD55 또는 CD59 등의 발현이 많은 경우 보체 매개성 세포독성이 감소한다는 일부 보고가 있으나, 상당수의 환자에서 반응하지 않는 이유에 대해 확실하지 않은 상황이다.However, some reports that rituximab is resistant to about half of low-grade lymphoma patients and about 60-70% of high-grade lymphoma patients, and that complement-mediated cytotoxicity decreases when CD55 or CD59 expression is high. However, it is not clear why the majority of patients do not respond.
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.Numerous papers and patent documents are referenced throughout this specification and citations thereof are indicated. The disclosure contents of the cited papers and patent documents are incorporated herein by reference in their entirety to more clearly describe the level of the technical field to which the present invention pertains and the content of the present invention.
이에 본 발명자들은 리툭시맙에 반응성을 나타내지 않거나 이에 내성을 갖는 암세포를 효과적으로 사멸할 수 있는 치료제를 개발하기 위하여 예의 연구 노력하였다. 그 결과, 한쪽은 scFv 및 다른 한쪽은 Fab을 포함하는 항-CD20 비대칭 항체를 이용할 경우 현저히 향상된 보체 의존 세포사멸능 (Complement Dependent Cytotoxicity, CDC)을 갖는다는 것을 발견함으로써, 본 발명을 완성하게 되었다. Accordingly, the present inventors made intensive research efforts to develop a therapeutic agent capable of effectively killing cancer cells that are not responsive to rituximab or have resistance thereto. As a result, when an anti-CD20 asymmetric antibody containing scFv on one side and Fab on the other side is used, it has been found that it has significantly improved Complement Dependent Cytotoxicity (CDC), thereby completing the present invention.
따라서 본 발명의 목적은, scFv (Single-chain variable fragment) 및 Fab (Fragment antigen-binding)을 포함하는, 보체 의존 세포사멸능 (CDC)이 향상된 항-CD20 비대칭 항체 (asymmetric antibody) 또는 이의 항원 결합 단편을 제공하는데 있다.Therefore, an object of the present invention, complement-dependent apoptosis (CDC), including scFv (Single-chain variable fragment) and Fab (Fragment antigen-binding), improved anti-CD20 asymmetric antibody (asymmetric antibody) or antigen binding thereof It is to provide a snippet.
본 발명의 다른 목적은, 상기 항-CD20 비대칭 항체 또는 이의 항원 결합 단편을 코딩하는 핵산분자를 제공하는데 있다.Another object of the present invention is to provide a nucleic acid molecule encoding the anti-CD20 asymmetric antibody or antigen-binding fragment thereof.
본 발명의 또 다른 목적은, 상기 핵산분자를 포함하는 벡터를 제공하는데 있다.Another object of the present invention is to provide a vector containing the nucleic acid molecule.
본 발명의 또 다른 목적은, 상기 벡터로 형질전환된 숙주세포를 제공하는데 있다.Another object of the present invention is to provide a host cell transformed with the vector.
본 발명의 또 다른 목적은, 상기 항-CD20 비대칭 항체 또는 이의 항원 결합 단편, 상기 항체 또는 이의 항원 결합 단편을 코딩하는 핵산분자, 또는 상기 핵산분자를 포함하는 벡터를 유효성분으로 포함하는 암의 예방 또는 치료용 약제학적 조성물을 제공하는데 있다.Another object of the present invention is to prevent cancer comprising the anti-CD20 asymmetric antibody or antigen-binding fragment thereof, a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof, or a vector containing the nucleic acid molecule as an active ingredient Or to provide a pharmaceutical composition for treatment.
본 발명의 또 다른 목적은, 상기 항-CD20 비대칭 항체 또는 이의 항원 결합 단편, 상기 항체 또는 이의 항원 결합 단편을 코딩하는 핵산분자, 또는 상기 핵산분자를 포함하는 벡터의 약제학적 유효량을 대상체에게 투여하는 단계를 포함하는 암의 예방 또는 치료방법을 제공하는데 있다.Another object of the present invention is to administer to a subject a pharmaceutically effective amount of the anti-CD20 asymmetric antibody or antigen-binding fragment thereof, a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof, or a vector comprising the nucleic acid molecule. To provide a method for preventing or treating cancer comprising the steps.
본 발명의 또 다른 목적은, 상기 항-CD20 비대칭 항체 또는 이의 항원 결합 단편, 상기 항체 또는 이의 항원 결합 단편을 코딩하는 핵산분자, 또는 상기 핵산분자를 포함하는 벡터의 치료용도(for use in therapy)를 제공하는데 있다.Another object of the present invention is the anti-CD20 asymmetric antibody or antigen-binding fragment thereof, a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof, or a vector containing the nucleic acid molecule for use in therapy. is to provide
본 발명의 또 다른 목적은, 상기 항-CD20 비대칭 항체 또는 이의 항원 결합 단편, 상기 항체 또는 이의 항원 결합 단편을 코딩하는 핵산분자, 또는 상기 핵산분자를 포함하는 벡터를 유효성분으로 포함하는 암의 진단용 조성물을 제공하는데 있다.Another object of the present invention is to diagnose cancer comprising the anti-CD20 asymmetric antibody or antigen-binding fragment thereof, a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof, or a vector including the nucleic acid molecule as an active ingredient To provide a composition.
본 발명의 또 다른 목적은, scFv를 제조하는 단계 및 Fab을 제조하는 단계를 포함하는, 보체 의존 세포사멸능이 향상된 항-CD20 비대칭 항체 또는 이의 항원 결합 단편의 제조방법을 제공하는데 있다.Another object of the present invention is to provide a method for preparing an anti-CD20 asymmetric antibody or antigen-binding fragment thereof with improved complement-dependent apoptosis, comprising preparing an scFv and preparing a Fab.
본 발명의 또 다른 목적은, scFv를 코딩하는 핵산분자를 제조하는 단계 및 Fab을 코딩하는 핵산분자를 제조하는 단계를 포함하는, 보체 의존 세포사멸능이 향상된 항-CD20 비대칭 항체 또는 이의 항원 결합 단편을 코딩하는 핵산분자의 제조방법을 제공하는데 있다.Another object of the present invention is to prepare an anti-CD20 asymmetric antibody or antigen-binding fragment thereof with improved complement-dependent apoptosis, comprising preparing a nucleic acid molecule encoding an scFv and preparing a nucleic acid molecule encoding a Fab. An object of the present invention is to provide a method for producing an encoding nucleic acid molecule.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
본 발명의 일 양태에 따르면, 본 발명은 하기의 단계를 포함하는, 보체 의존 세포사멸능 (Complement Dependent Cytotoxicity, CDC)이 향상된 항-CD20 비대칭 항체 (asymmetric antibody) 또는 이의 항원 결합 단편을 코딩하는 핵산분자의 제조방법을 제공한다:According to one aspect of the present invention, the present invention is an anti-CD20 asymmetric antibody with improved complement dependent cytotoxicity (CDC), comprising the steps of: nucleic acid encoding an antigen-binding fragment thereof A method of making a molecule is provided:
(a) 서열번호 16의 LCDR1, 서열번호 18의 LCDR2, 서열번호 20의 LCDR3, 서열번호 24의 HCDR1, 서열번호 26의 HCDR2 및 서열번호 28의 HCDR3 서열을 포함하는 scFv (Single-chain variable fragment)를 코딩하는 핵산분자를 제조하는 단계; 및(a) LCDR1 of SEQ ID NO: 16, LCDR2 of SEQ ID NO: 18, LCDR3 of SEQ ID NO: 20, HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 26 and HCDR3 of SEQ ID NO: 28 scFv (Single-chain variable fragment) encoding preparing a nucleic acid molecule; and
(b) 서열번호 33의 LCDR1, 서열번호 35의 LCDR2, 서열번호 37의 LCDR3, 서열번호 42의 HCDR1, 서열번호 44의 HCDR2 및 서열번호 46의 HCDR3 서열을 포함하는 Fab (Fragment antigen-binding)을 코딩하는 핵산분자를 제조하는 단계.(b) A nucleic acid encoding Fab (Fragment antigen-binding) comprising the sequence of LCDR1 of SEQ ID NO: 33, LCDR2 of SEQ ID NO: 35, LCDR3 of SEQ ID NO: 37, HCDR1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44 and HCDR3 of SEQ ID NO: 46 Steps to make a molecule.
본 발명자들은 리툭시맙에 반응성을 나타내지 않거나 이에 내성을 갖는 암세포를 효과적으로 사멸할 수 있는 치료제를 개발하기 위하여 예의 연구 노력하였다. 그 결과, 한쪽은 scFv 및 다른 한쪽은 Fab을 포함하는 항-CD20 비대칭 항체를 이용할 경우 현저히 증가된 보체 의존 세포사멸능을 갖는다는 것을 발견하였다.The present inventors made intensive research efforts to develop a therapeutic agent capable of effectively killing cancer cells that are not responsive to rituximab or have resistance thereto. As a result, it was found that when using an anti-CD20 asymmetric antibody comprising scFv on one side and Fab on the other side, it has a significantly increased complement-dependent apoptosis ability.
본 명세서에서 용어 "항체(antibody)"는 면역학적으로 특정 항원과 반응성을 갖는 면역글로불린 분자를 포함하는, 항원을 특이적으로 인식하는 수용체 역할을 하는 단백질 분자를 의미하며 다클론항체 및 단클론항체를 모두 포함한다.As used herein, the term "antibody" refers to a protein molecule serving as a receptor that specifically recognizes an antigen, including immunoglobulin molecules having immunological reactivity with a specific antigen, and includes polyclonal antibodies and monoclonal antibodies. include all
항체는 완전한 전장(full-length) 항체 형태뿐만 아니라 항체 분자의 항원 결합 단편(항체 단편)을 포함한다. 완전한 항체는 2개의 전체 길이의 경쇄 및 2개의 전체 길이의 중쇄를 가지는 구조로서 각각의 경쇄는 중쇄와 이황화 결합으로 연결되어 있다. 중쇄 불변영역은 감마(γ), 뮤(μ), 알파(α), 델타(δ) 및 엡실론(ε) 타입을 가지고 서브클래스로 감마1(γ1), 감마2(γ2), 감마3(γ3), 감마4(γ4), 알파1(α1) 및 알파2(α2)를 가진다. 경쇄의 불변영역은 카파(kappa, κ) 및 람다(lambda, λ) 타입을 가진다.Antibodies include antigen-binding fragments (antibody fragments) of antibody molecules as well as full-length antibody forms. A complete antibody has a structure having two full-length light chains and two full-length heavy chains, and each light chain is linked to a heavy chain by a disulfide bond. The heavy chain constant region has gamma (γ), mu (μ), alpha (α), delta (δ) and epsilon (ε) types and subclasses gamma 1 (γ1), gamma 2 (γ2), gamma 3 (γ3). ), gamma 4 (γ4), alpha 1 (α1) and alpha 2 (α2). The constant region of the light chain has kappa (kappa, κ) and lambda (lambda, λ) types.
본 명세서에서 용어 "항체의 항원 결합 단편"은 전체 항체 분자 내에서 항원을 특이적으로 인식하고 항원-항체 결합 기능을 보유하는 단편을 의미하며, 단일-도메인 항체(sdAb), 단일쇄 항체(scFv), Fab, F(ab'), F(ab')2 및 Fv 등을 포함한다. 단편의 예로는, VL, VH, Cκ (또는 CL) 및 CH1 도메인으로 구성된 1가 단편(Fab 단편); 힌지 영역에서 이황화물 브릿지에 의해 연결된 2개의 Fab 단편을 포함하는 2가 단편(F(ab')2 단편); VH 및 CH1 도메인으로 구성된 Fd 단편; 항체의 하나의 암(arm)의 VL 및 VH 도메인, 및 이황화물-연결된 Fv(sdFv)로 구성된 Fv 단편; VH 도메인으로 구성된 dAb 단편; 및 분리된 상보성 결정 영역(CDR) 또는 링커에 의해 선택적으로 이어질 수 있는 둘 이상의 분리된 CDR의 조합을 포함한다. 또한, scFv는 VL과 VH 영역이 쌍을 이루어 1가 분자를 형성한 단일 단백질 사슬을 이루도록 링커에 의해 이어질 수 있다. 이러한 단일쇄 항체도 항체의 단편에 포함된다. 또한, 상기 항체 또는 항체의 단편은 2개의 중쇄 분자와 2개의 경쇄 분자를 포함하는 테트라머 항체; 항체 경쇄 모노머; 항체 중쇄 모노머; 항체 경쇄 다이머, 항체 중쇄 다이머; 인트라바디; 1가 항체; 낙타 항체; 및 단일-도메인 항체(sdAb)를 포함한다. As used herein, the term “antigen-binding fragment of an antibody” refers to a fragment that specifically recognizes an antigen within an entire antibody molecule and retains an antigen-antibody-binding function, and includes a single-domain antibody (sdAb), a single-chain antibody (scFv). ), Fab, F(ab'), F(ab')2 and Fv, and the like. Examples of fragments include monovalent fragments consisting of VL, VH, CK (or CL) and CH1 domains (Fab fragments); a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region (F(ab')2 fragment); Fd fragment consisting of VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of one arm of an antibody, and a disulfide-linked Fv (sdFv); a dAb fragment consisting of a VH domain; and separate complementarity determining regions (CDRs) or combinations of two or more separate CDRs optionally followed by a linker. In addition, the scFv may be linked by a linker such that the VL and VH regions are paired to form a single protein chain forming a monovalent molecule. Such single-chain antibodies are also included in antibody fragments. In addition, the antibody or fragment of the antibody may be a tetrameric antibody comprising two heavy chain molecules and two light chain molecules; antibody light chain monomers; antibody heavy chain monomers; antibody light chain dimers, antibody heavy chain dimers; Intrabody; monovalent antibody; camel antibody; and single-domain antibodies (sdAbs).
Fv는 중쇄 가변영역 및 경쇄 가변영역만을 가지고 있는 최소의 항체조각으로 Fv 단편을 생성하는 재조합 기술은 PCT 국제 공개특허출원 WO 88/10649, WO 88/106630, WO 88/07085, WO 88/07086 및 WO 88/09344에 개시되어 있다. 이중쇄 Fv(two-chain Fv)는 비공유 결합으로 중쇄 가변영역과 경쇄 가변영역이 연결되어 있고 단쇄 Fv(single-chain Fv)는 일반적으로 펩타이드 링커를 통하여 중쇄의 가변영역과 단쇄의 가변영역이 공유결합으로 연결되거나 또는 C-말단에서 바로 연결되어 있어서 이중쇄 Fv와 같이 다이머와 같은 구조를 이룰 수 있다. 이러한 항체 단편은 단백질 가수분해 효소를 이용해서 얻을 수 있고(예를 들어, 전체 항체를 파파인으로 제한 절단하면 Fab를 얻을 수 있고 펩신으로 절단하면 F(ab')2 단편을 얻을 수 있다), 유전자 재조합 기술을 통하여 제작할 수도 있다.Fv is a minimal antibody fragment having only a heavy chain variable region and a light chain variable region, and recombinant technology for generating Fv fragments is described in PCT International Patent Application Publications WO 88/10649, WO 88/106630, WO 88/07085, WO 88/07086 and WO 88/09344. In a double-chain Fv (two-chain Fv), the heavy chain variable region and the light chain variable region are connected by a non-covalent bond, and in a single-chain Fv (single-chain Fv), the heavy chain variable region and the single chain variable region are generally shared through a peptide linker. They are linked by a bond or are linked directly at the C-terminus to form a dimer-like structure like a double-stranded Fv. Such antibody fragments can be obtained using proteolytic enzymes (for example, by restriction digestion of the entire antibody with papain to obtain Fab, and by digestion with pepsin to obtain F(ab')2 fragments), gene It can also be produced through recombinant technology.
본 명세서에서 용어 "중쇄"는 항원에 특이성을 부여하기 위한 충분한 가변영역 서열을 갖는 아미노산 서열을 포함하는 가변영역 도메인 VH 및 3개의 불변영역 도메인 CH1, CH2 및 CH3을 포함하는 전체길이 중쇄 및 이의 단편을 모두 의미한다. 또한, 본 명세서 용어 "경쇄"는 항원에 특이성을 부여하기 위한 충분한 가변영역 서열을 갖는 아미노산 서열을 포함하는 가변영역 도메인 VL 및 불변영역 도메인 Cκ (또는 CL)를 포함하는 전체길이 경쇄 및 이의 단편을 모두 의미한다.As used herein, the term "heavy chain" refers to a full-length heavy chain comprising a variable region domain VH comprising an amino acid sequence having a sufficient variable region sequence to confer specificity to an antigen and three constant domain domains CH1, CH2 and CH3, and fragments thereof. means all In addition, as used herein, the term "light chain" refers to a full-length light chain comprising a variable region domain VL comprising an amino acid sequence having a sufficient variable region sequence to confer specificity to an antigen and a constant region domain CK (or CL), and fragments thereof. all means
본 명세서에서, 용어 "CDR(complementarity determining region)"은 면역글로블린의 중쇄 및 경쇄의 고가변 영역(hypervariable region)의 아미노산 서열을 의미한다(Kabat et al. Sequences of Proteins of Immunological Interest, 4th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1987)). 중쇄(HCDR1, HCDR2 및 HCDR3) 및 경쇄(LCDR1, LCDR2 및 LCDR3)에는 각각 3개의 CDR이 포함되어 있으며, 이들 CDR은 항체가 항원 또는 에피토프에 결합하는 데 있어서 주요한 접촉 잔기를 제공한다. 상기 CDR은 프레임워크 영역(FR)이라고 명명된 더 보존된 영역들에 산재된다. 각 VH 및 VL은 3개의 CDR과 4개의 FR로 이루어지며, 이들은 FR1, CDR1, FR2, CDR2, FR3, CDR3 및 FR4 순서로 아미노-말단에서 카복시-말단으로 배열된다.As used herein, the term "complementarity determining region (CDR)" refers to the amino acid sequence of the hypervariable region of the heavy and light chains of immunoglobulin (Kabat et al . Sequences of Proteins of Immunological Interest , 4th Ed., US Department of Health and Human Services, National Institutes of Health (1987)). The heavy (HCDR1, HCDR2 and HCDR3) and light chains (LCDR1, LCDR2 and LCDR3) each contain three CDRs, which provide key contact residues for the binding of the antibody to antigen or epitope. The CDRs are interspersed with more conserved regions termed framework regions (FR). Each VH and VL consists of 3 CDRs and 4 FRs, arranged amino-terminus to carboxy-terminus in the order FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
본 발명의 항체 또는 항체 단편의 범위에는 CDR 영역에 보존적 아미노산 치환을 갖는 변이체가 포함되며, CD20을 특이적으로 인식할 수 있는 범위 내에서 첨부한 서열목록에 기재된 아미노산 서열에 대한 변이체를 포함할 수 있다. 예를 들면, 항체의 결합 친화도 외에 반감기, 생체 적합성 기타 생물학적 특성을 보다 개선시키기 위하여 항체의 아미노산 서열에 추가적인 변화를 줄 수 있다. 이러한 생물학적 균등 활성을 갖는 변이를 고려한다면, 본 발명의 항체 또는 이를 코딩하는 핵산 분자는 서열목록에 기재된 서열과 실질적인 동일성(substantial identity)을 나타내는 서열도 포함하는 것으로 해석된다. 상기의 실질적인 동일성은, 상기한 본 발명의 서열과 임의의 다른 서열을 최대한 대응되도록 얼라인 하고, 당업계에서 통상적으로 이용되는 알고리즘을 이용하여 얼라인 된 서열을 분석한 경우에, 최소 61%의 상동성, 일 특정예에 따르면 70%의 상동성, 다른 특정예에 따르면 80%의 상동성, 또 다른 특정예에 따르면 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. (1981) 2:482 Needleman and Wunsch, J. Mol. Bio. (1970) 48:443; Pearson and Lipman, Methods in Mol. Biol. (1988) 24: 307-31; Higgins and Sharp, Gene (1988) 73:237-44; Higgins and Sharp, CABIOS (1989) 5:151-3; Corpet et al. Nuc. Acids Res. (1988) 16:10881-90; Huang et al. Comp. Appl. BioSci. (1992) 8:155-65 및 Pearson et al. Meth. Mol. Biol. (1994) 24:307-31에 개시되어 있다. The scope of the antibody or antibody fragment of the present invention includes variants having conservative amino acid substitutions in the CDR regions, and variants to the amino acid sequences set forth in the accompanying sequence listing within the scope capable of specifically recognizing CD20. can For example, additional changes may be made to the amino acid sequence of the antibody in order to further improve the half-life, biocompatibility, and other biological properties in addition to the binding affinity of the antibody. In consideration of such mutations having biological equivalent activity, it is construed that the antibody or nucleic acid molecule encoding the same of the present invention includes a sequence exhibiting substantial identity to the sequence listed in the sequence listing. The substantial identity is at least 61% when the aligned sequence is analyzed using an algorithm commonly used in the art after aligning the sequence of the present invention and any other sequences as much as possible. homology, according to one specific example, 70% homology, according to another specific example, 80% homology, according to another specific example, 90% homology. Alignment methods for sequence comparison are known in the art. Various methods and algorithms for alignment are described in Smith and Waterman, Adv. Appl. Math . (1981) 2:482 Needleman and Wunsch, J. Mol. Bio . (1970) 48:443; Pearson and Lipman, Methods in Mol. Biol . (1988) 24: 307-31; Higgins and Sharp, Gene (1988) 73:237-44; Higgins and Sharp, CABIOS (1989) 5:151-3; Corpet et al . Nuc. Acids Res . (1988) 16:10881-90; Huang et al . Comp. Appl. BioSci . (1992) 8:155-65 and Pearson et al . Meth. Mol. Biol . (1994) 24:307-31.
본 명세서에서 용어 "대칭 항체"는 2개의 경쇄 및 2개의 중쇄를 가지는 항체가 한쪽 및 다른 쪽이 서로 대칭된 구조(예를 들어, 한쪽 및 다른 쪽이 동일한 경쇄 가변 영역 및 동일한 중쇄 가변 영역을 갖는 항체)를 갖는 항체를 의미한다.As used herein, the term "symmetric antibody" means that an antibody having two light chains and two heavy chains has a structure in which one and the other are symmetric to each other (e.g., one and the other have the same light chain variable region and the same heavy chain variable region) antibody).
본 명세서에서 용어 "비대칭 항체"는 상기 "대칭 항체"가 아닌 비대칭 구조의 항체를 의미한다. 예를 들어, 한쪽은 VL-링커-VH를 포함하는 단편(즉, scFv) 및 다른 한쪽은 VL-Cκ(또는 CL)-링커-VH-CH1를 포함하는 단편(즉, Fab)을 포함할 수 있다. 또한, 한쪽은 Fab을 포함하는 단편 및 다른 한쪽은 Fab과 scFv를 포함하는 단편을 포함할 수 있다. 상기 비대칭 항체는 추가로 Fc 부위를 포함할 수도 있다. 예를 들어, 한쪽은 VL-링커-VH-CH2-CH3를 포함하는 단편 및 다른 한쪽은 VL-Cκ(또는 CL)-링커-VH-CH1-CH2-CH3를 포함하는 단편을 포함하여 비 대칭 구조의 항체를 제작할 수도 있다.As used herein, the term “asymmetric antibody” refers to an antibody having an asymmetric structure, not the “symmetric antibody”. For example, one may contain a fragment comprising a VL-linker-VH (i.e., scFv) and the other comprising a fragment comprising a VL-Cκ (or CL)-linker-VH-CH1 (i.e., Fab). have. In addition, one side may contain a fragment containing Fab and the other side may contain a fragment containing Fab and scFv. The asymmetric antibody may further comprise an Fc region. asymmetric structures, including, for example, a fragment comprising a VL-linker-VH-CH2-CH3 on one side and a fragment comprising a VL-Cκ (or CL)-linker-VH-CH1-CH2-CH3 on the other side antibodies can also be produced.
본 명세서에서 용어 "친화도(affinity)"는 항체 또는 이의 항원결합 단편과 항원 간의 결합 강도를 의미하며, 이에 "결합력"으로도 표현될 수 있다. As used herein, the term “affinity” refers to the binding strength between an antibody or antigen-binding fragment thereof and an antigen, and may also be expressed as “binding strength”.
본 발명의 구체적인 구현예에 따르면, 상기 scFv는 서열번호 51의 경쇄 가변 영역 (VL) 서열을 포함한다.According to a specific embodiment of the present invention, the scFv comprises a light chain variable region (VL) sequence of SEQ ID NO: 51.
본 발명의 구체적인 구현예에 따르면, 상기 scFv는 서열번호 52의 중쇄 가변 영역 (VH) 서열을 포함한다.According to a specific embodiment of the present invention, the scFv comprises a heavy chain variable region (VH) sequence of SEQ ID NO: 52.
본 발명의 구체적인 구현예에 따르면, 상기 scFv는 서열번호 15의 LFR1, 서열번호 17의 LFR2, 서열번호 19의 LFR3, 서열번호 21의 LFR4, 서열번호 23의 HFR1, 서열번호 25의 HFR2, 서열번호 27의 HFR3 및 서열번호 29의 HFR4로 구성된 군으로부터 선택되는 서열을 포함한다.According to a specific embodiment of the present invention, the scFv is LFR1 of SEQ ID NO: 15, LFR2 of SEQ ID NO: 17, LFR3 of SEQ ID NO: 19, LFR4 of SEQ ID NO: 21, HFR1 of SEQ ID NO: 23, HFR2 of SEQ ID NO: 25, SEQ ID NO: and a sequence selected from the group consisting of HFR3 of 27 and HFR4 of SEQ ID NO:29.
본 발명의 구체적인 구현예에 따르면, 상기 scFv는 VL-링커-VH 형태이다.According to a specific embodiment of the present invention, the scFv is in the form of VL-linker-VH.
본 발명의 구체적인 구현예에 따르면, 상기 링커는 Gly 및 Ser의 조합일 수 있다.According to a specific embodiment of the present invention, the linker may be a combination of Gly and Ser.
본 발명의 구체적인 구현예에 따르면, 상기 Fab은 서열번호 53의 경쇄 가변 영역 (VL) 서열을 포함한다.According to a specific embodiment of the present invention, the Fab comprises a light chain variable region (VL) sequence of SEQ ID NO: 53.
본 발명의 구체적인 구현예에 따르면, 상기 Fab은 서열번호 54의 중쇄 가변 영역 (VH) 서열을 포함한다.According to a specific embodiment of the present invention, the Fab comprises a heavy chain variable region (VH) sequence of SEQ ID NO: 54.
본 발명의 구체적인 구현예에 따르면, 상기 Fab은 서열번호 32의 LFR1, 서열번호 34의 LFR2, 서열번호 36의 LFR3, 서열번호 38의 LFR4, 서열번호 41의 HFR1, 서열번호 43의 HFR2, 서열번호 45의 HFR3 및 서열번호 47의 HFR4로 구성된 군으로부터 선택되는 서열을 포함한다.According to a specific embodiment of the present invention, the Fab is LFR1 of SEQ ID NO: 32, LFR2 of SEQ ID NO: 34, LFR3 of SEQ ID NO: 36, LFR4 of SEQ ID NO: 38, HFR1 of SEQ ID NO: 41, HFR2 of SEQ ID NO: 43, SEQ ID NO: and a sequence selected from the group consisting of HFR3 of 45 and HFR4 of SEQ ID NO:47.
본 발명의 구체적인 구현예에 따르면, 상기 Fab은 서열번호 39의 Cκ (C kappa) 서열을 포함한다.According to a specific embodiment of the present invention, the Fab comprises a Cκ (C kappa) sequence of SEQ ID NO: 39.
본 발명의 구체적인 구현예에 따르면, 상기 Fab은 서열번호 48의 CH1 서열을 포함한다.According to a specific embodiment of the present invention, the Fab comprises the CH1 sequence of SEQ ID NO: 48.
본 발명의 구체적인 구현예에 따르면, 상기 VL-Cκ-링커-VH-CH1 형태이다.According to a specific embodiment of the present invention, the VL-Cκ-linker-VH-CH1 form.
본 발명의 구체적인 구현예에 따르면, 상기 링커는 Gly 및 Ser의 조합일 수 있다.According to a specific embodiment of the present invention, the linker may be a combination of Gly and Ser.
본 발명의 구체적인 구현예에 따르면, 본 발명의 비대칭 항체는 중쇄끼리의 원치 않는 쌍의 결합을 막기 위해 10 내지 100개, 보다 구체적으로는 15 내지 60개의 Gly과 Ser으로 구성된 링커를 사용할 수 있다. According to a specific embodiment of the present invention, the asymmetric antibody of the present invention may use a linker composed of 10 to 100, more specifically 15 to 60 Gly and Ser, in order to prevent undesirable pairing of heavy chains.
구체적으로는, 본 발명의 이중특이적 항체는 CD20-scFv-knob(VL-linker20-VH-CH2-CH3)과 CD20-Fab-hole(VL-Cκ-linker40-VH-CH1-CH2-CH3)이 결합된 형태일 수 있다.Specifically, the bispecific antibody of the present invention contains CD20-scFv-knob (VL-linker20-VH-CH2-CH3) and CD20-Fab-hole (VL-Cκ-linker40-VH-CH1-CH2-CH3). It may be in a combined form.
linker20은 상기 Gly 또는 Ser을 20개 포함하는 것으로, 이의 예로는 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Gly Ser을 포함할 수 있으나, 이에 제한되는 것은 아니다.Linker20 includes 20 Glys or Sers, and examples thereof include, but are not limited to, Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Gly Ser.
linker40은 상기 Gly 또는 Ser을 40개 포함하는 것으로, 이의 예로는 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Ser Ser을 포함할 수 있으나, 이에 제한되는 것은 아니다.linker40 includes 40 Gly or Ser, for example, Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Ser Ser may include, but is not limited thereto.
본 발명의 다른 양태에 따르면, 본 발명은 전술한 본 발명의 항체 또는 이의 항원 결합 단편을 코딩하는 핵산분자를 제공한다.According to another aspect of the present invention, the present invention provides a nucleic acid molecule encoding the aforementioned antibody or antigen-binding fragment thereof of the present invention.
본 명세서에서 용어 "핵산 분자"는 DNA(gDNA 및 cDNA) 그리고 RNA 분자를 포괄적으로 포함하는 의미를 가지며, 핵산 분자에서 기본 구성단위인 뉴클레오타이드는 자연의 뉴클레오타이드뿐만 아니라, 당 또는 염기 부위가 변형된 유사체(analogue)도 포함한다(Scheit, Nucleotide Analogs, John Wiley, New York(1980); Uhlman 및 Peyman, Chemical Reviews, (1990) 90:543-584). 본 발명의 중쇄 및 경쇄 가변영역을 코딩하는 핵산 분자의 서열은 변형될 수 있다. 상기 변형은 뉴클레오타이드의 추가, 결실, 또는 비보존적 치환 또는 보존적 치환을 포함한다.As used herein, the term "nucleic acid molecule" has a meaning comprehensively including DNA (gDNA and cDNA) and RNA molecules, and nucleotides, which are basic structural units in nucleic acid molecules, include natural nucleotides as well as analogs in which sugar or base sites are modified. (analogue) (Scheit, Nucleotide Analogs, John Wiley, New York (1980); Uhlman and Peyman, Chemical Reviews, (1990) 90:543-584). The sequence of the nucleic acid molecule encoding the heavy and light chain variable regions of the present invention may be modified. Such modifications include additions, deletions, or non-conservative or conservative substitutions of nucleotides.
본 발명의 핵산 분자는 상기한 뉴클레오타이드 서열에 대하여 실질적인 동일성을 나타내는 뉴클레오타이드 서열도 포함하는 것으로 해석된다. 상기의 실질적인 동일성은, 상기한 본 발명의 뉴클레오타이드 서열과 임의의 다른 서열을 최대한 대응되도록 얼라인하고, 당업계에서 통상적으로 이용되는 알고리즘을 이용하여 얼라인 된 서열을 분석한 경우에, 최소 80%의 상동성, 일 특정예에서는 최소 90%의 상동성, 다른 특정예에서는 최소 95%의 상동성을 나타내는 뉴클레오타이드 서열을 의미한다.The nucleic acid molecule of the present invention is construed to include a nucleotide sequence exhibiting substantial identity to the above-described nucleotide sequence. The substantial identity is at least 80% when the nucleotide sequence of the present invention and any other sequences are aligned as much as possible, and the aligned sequence is analyzed using an algorithm commonly used in the art. of homology, in one specific example, at least 90% homology, in another specific example, at least 95% homology.
본 발명의 또 다른 양태에 따르면, 본 발명은 전술한 본 발명의 항체 또는 이의 항원 결합 단편을 코딩하는 핵산분자를 포함하는 벡터를 제공한다.According to another aspect of the present invention, the present invention provides a vector comprising a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof of the present invention as described above.
본 명세서에서 용어 "벡터"는 상기 폴리뉴클레오타이드(핵산) 서열을 복제할 수 있는 세포로의 도입을 위해서 폴리뉴클레오타이드 서열을 삽입할 수 있는 전달체를 의미한다. 폴리뉴클레오타이드 서열은 외생(Exogenous) 또는 이종(Heterologous)일 수 있다. 벡터로서는 플라스미드, 코스미드 벡터 및 바이러스 벡터(레트로바이러스, 아데노바이러스 및 아데노-부속 바이러스 벡터 등)를 들 수 있으나, 이에 제한되지 않는다. 당업자는 표준적인 재조합 기술에 의해 벡터를 구축할 수 있다(Maniatis, et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, N.Y., 1988; 및 Ausubel et al., In: Current Protocols in Molecular Biology, John, Wiley & Sons, Inc, NY, 1994 등).As used herein, the term "vector" refers to a carrier capable of inserting a polynucleotide sequence for introduction into a cell capable of replicating the polynucleotide (nucleic acid) sequence. The polynucleotide sequence may be exogenous or heterologous. Vectors include, but are not limited to, plasmids, cosmid vectors, and viral vectors (such as retroviruses, adenoviruses and adeno-associated viral vectors). One skilled in the art can construct vectors by standard recombinant techniques (Maniatis, et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, N.Y., 1988; and Ausubel et al., In: Current Protocols in Molecular Biology, John, Wiley & Sons, Inc, NY, 1994 et al.).
본 명세서에서 용어 "발현 벡터"는 전사되는 유전자 산물 중 적어도 일부분을 코딩하는 뉴클레오타이드 서열을 포함한 벡터를 의미한다. 일부의 경우에는 그 후 RNA 분자가 단백질, 폴리펩타이드, 또는 펩타이드로 번역된다. 발현 벡터에는 다양한 조절서열을 포함할 수 있다. 전사 및 번역을 조절하는 조절서열과 함께 벡터 및 발현 벡터에는 또 다른 기능도 제공하는 핵산 서열도 포함될 수 있다.As used herein, the term "expression vector" refers to a vector comprising a nucleotide sequence encoding at least a portion of a transcribed gene product. In some cases, the RNA molecule is then translated into a protein, polypeptide, or peptide. The expression vector may include various regulatory sequences. In addition to regulatory sequences that control transcription and translation, vectors and expression vectors may contain nucleic acid sequences that also serve other functions.
본 발명의 또 다른 양태에 따르면, 본 발명은 전술한 벡터로 형질전환된 숙주세포를 제공한다.According to another aspect of the present invention, the present invention provides a host cell transformed with the vector described above.
본 명세서에서 용어 "세포"는 진핵세포 및 원핵세포를 포함하며, 상기 벡터를 복제할 수 있거나 벡터에 의해 코딩되는 유전자를 발현할 수 있는 임의의 형질 전환 가능한 세포를 의미한다. 세포는 상기 벡터에 의해 형질감염(Transfected), 형질도입(Transduced) 또는 형질전환(Transformed) 될 수 있으며, 이는 외생의 폴리뉴클레오타이드(핵산분자)가 숙주세포 내에 전달되거나 도입되는 과정을 의미한다. 본 명세서에서 용어 "형질전환"은 상기 형질감염(Transfected) 및 형질도입(Transduced)을 포함하는 의미로 사용된다.As used herein, the term "cell" includes eukaryotic cells and prokaryotic cells, and refers to any transformable cell capable of replicating the vector or expressing a gene encoded by the vector. Cells may be transfected, transduced, or transformed by the vector, which means a process in which an exogenous polynucleotide (nucleic acid molecule) is delivered or introduced into a host cell. In the present specification, the term "transformation" is used in the meaning including the transfection (Transfected) and transduction (Transduced).
본 발명의(숙주)세포는 제한되지 않으나, 바람직하게는 곤충세포 또는 포유동물 세포, 보다 바람직하게는 곤충세포의 경우 Sf9, 포유동물 세포의 경우 HEK293 세포, HeLa 세포, ARPE-19 세포, RPE-1 세포, HepG2 세포, Hep3B 세포, Huh-7 세포, C8D1a 세포, Neuro2A 세포, CHO 세포, MES13 세포, BHK-21 세포, COS7 세포, COP5 세포, A549 세포, MCF-7 세포, HC70 세포, HCC1428 세포, BT-549 세포,PC3 세포, LNCaP 세포, Capan-1 세포, Panc-1 세포, MIA PaCa-2 세포, SW480 세포, HCT166 세포, LoVo 세포, A172 세포, MKN-45 세포, MKN-74 세포, Kato-III 세포, NCI-N87 세포, HT-144 세포, SK-MEL-2 세포, SH-SY5Y 세포, C6 세포, HT-22 세포, PC-12 세포, NIH3T3 세포 등을 이용할 수 있다.The (host) cells of the present invention are not limited, but preferably insect cells or mammalian cells, more preferably insect cells, Sf9, mammalian cells, HEK293 cells, HeLa cells, ARPE-19 cells, RPE- 1 cell, HepG2 cell, Hep3B cell, Huh-7 cell, C8D1a cell, Neuro2A cell, CHO cell, MES13 cell, BHK-21 cell, COS7 cell, COP5 cell, A549 cell, MCF-7 cell, HC70 cell, HCC1428 cell , BT-549 cells, PC3 cells, LNCaP cells, Capan-1 cells, Panc-1 cells, MIA PaCa-2 cells, SW480 cells, HCT166 cells, LoVo cells, A172 cells, MKN-45 cells, MKN-74 cells, Kato-III cells, NCI-N87 cells, HT-144 cells, SK-MEL-2 cells, SH-SY5Y cells, C6 cells, HT-22 cells, PC-12 cells, NIH3T3 cells and the like can be used.
본 발명의 숙주세포는 바람직하게는 단리된 숙주세포이다.The host cell of the present invention is preferably an isolated host cell.
본 발명의 또 다른 양태에 따르면, 본 발명은 전술한 본 발명의 항체 또는 이의 항원 결합 단편, 상기 항체 또는 이의 항원 결합 단편을 코딩하는 핵산분자, 또는 상기 핵산분자를 포함하는 벡터를 유효성분으로 포함하는 암의 예방 또는 치료용 약제학적 조성물을 제공한다.According to another aspect of the present invention, the present invention includes the above-described antibody or antigen-binding fragment thereof of the present invention, a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof, or a vector comprising the nucleic acid molecule as an active ingredient. It provides a pharmaceutical composition for the prevention or treatment of cancer.
본 발명의 또 다른 양태에 따르면, 본 발명은 전술한 본 발명의 항체 또는 이의 항원 결합 단편, 상기 항체 또는 이의 항원 결합 단편을 코딩하는 핵산분자, 또는 상기 핵산분자를 포함하는 벡터의 약제학적 유효량을 대상체에게 투여하는 단계를 포함하는 암의 예방 또는 치료방법을 제공한다.According to another aspect of the present invention, the present invention provides a pharmaceutically effective amount of the above-described antibody or antigen-binding fragment thereof of the present invention, a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof, or a vector comprising the nucleic acid molecule. It provides a method for preventing or treating cancer comprising administering to a subject.
본 발명의 또 다른 양태에 따르면, 본 발명은 전술한 본 발명의 항체 또는 이의 항원 결합 단편, 상기 항체 또는 이의 항원 결합 단편을 코딩하는 핵산분자, 또는 상기 핵산분자를 포함하는 벡터의 치료용도(for use in therapy)를 제공한다. According to another aspect of the present invention, the present invention provides a therapeutic use of the aforementioned antibody or antigen-binding fragment thereof of the present invention, a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof, or a vector comprising the nucleic acid molecule (for use in therapy).
본 명세서에서 용어 "예방"은 질환 또는 질병을 보유하고 있다고 진단된 적은 없으나, 이러한 질환 또는 질병에 걸릴 가능성이 있는 대상체에서 질환 또는 질병의 발생을 억제하는 것을 의미한다. As used herein, the term “prevention” refers to inhibiting the occurrence of a disease or disease in a subject who has not been diagnosed as possessing the disease or disease, but is likely to be afflicted with the disease or disease.
본 명세서에서 용어 "치료"는 (a) 질환, 질병 또는 증상의 발전의 억제; (b) 질환, 질병 또는 증상의 경감; 또는 (c) 질환, 질병 또는 증상을 제거하는 것을 의미한다. 본 발명의 조성물을 대상체에 투여하면 CD20에 대하여 rituximab과 동등 수준의 결합력을 나타내며, rituximab 대비 유의미한 보체 활성능 및/또는 이로 인한 CDC 효과로 인하여 암세포의 증식을 억제하여 암의 진행을 저해하거나, 이로 인한 증상을 제거하거나 또는 경감시키는 역할을 한다. 따라서, 본 발명의 조성물은 그 자체로 암 치료용 조성물이 될 수도 있고, 혹은 다른 약리성분과 함께 투여되어 이의 치료 반응성을 향상시키는 치료 보조제로 적용될 수도 있다. 이에, 본 명세서에서 용어 "치료" 또는 "치료제"는 "치료 보조" 또는 "치료 보조제"의 의미를 포함한다. As used herein, the term “treatment” refers to (a) inhibiting the development of a disease, disorder or condition; (b) alleviation of the disease, condition or condition; or (c) eliminating the disease, condition or symptom. When the composition of the present invention is administered to a subject, it exhibits an equivalent level of binding to CD20 with rituximab, and inhibits the proliferation of cancer cells due to a significant complement activation ability and/or the resulting CDC effect compared to rituximab, thereby inhibiting the progression of cancer, or It plays a role in eliminating or alleviating symptoms caused by Accordingly, the composition of the present invention may be a composition for cancer treatment by itself, or may be administered as a therapeutic adjuvant to improve its therapeutic responsiveness by being administered with other pharmacological components. Accordingly, as used herein, the term “treatment” or “therapeutic agent” includes the meaning of “therapeutic adjuvant” or “therapeutic adjuvant”.
본 명세서에서 용어 "투여" 또는 "투여하다"는 본 발명의 조성물의 치료적 유효량을 대상체에 직접적으로 투여함으로써 대상체의 체내에서 동일한 양이 형성되도록 하는 것을 말한다.As used herein, the term “administration” or “administering” refers to administering a therapeutically effective amount of the composition of the present invention directly to a subject so that the same amount is formed in the subject's body.
본 발명에서 용어 "치료적 유효량"은 본 발명의 약제학적 조성물을 투여하고자 하는 개체에게 조성물 내의 약리성분이 치료적 또는 예방적 효과를 제공하기에 충분한 정도로 함유된 조성물의 함량을 의미하며, 이에 "예방적 유효량"을 포함하는 의미이다. In the present invention, the term "therapeutically effective amount" means the content of the composition in which the pharmacological component in the composition is sufficient to provide a therapeutic or prophylactic effect to an individual to whom the pharmaceutical composition of the present invention is administered, and thus " prophylactically effective amount".
본 명세서에서 용어 "대상체"는 제한없이 인간, 마우스, 래트, 기니아 피그, 개, 고양이, 말, 소, 돼지, 원숭이, 침팬지, 비비 또는 붉은털 원숭이를 포함한다. 구체적으로는, 본 발명의 대상체는 인간이다. As used herein, the term “subject” includes, without limitation, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon or rhesus monkey. Specifically, the subject of the present invention is a human.
본 발명의 구체적인 구현예에 따르면, 본 발명의 조성물로 예방 또는 치료될 수 있는 암은 CD20 양성 암이다.According to a specific embodiment of the present invention, the cancer that can be prevented or treated by the composition of the present invention is a CD20-positive cancer.
CD20 양성 암은 예를 들어, 림프종, 백혈병 등의 혈액암 및 흑색종, 폐암, 갑상선암, 유방암, 대장암, 전립선암, 두경부암, 위암, 간장암, 방광암, 신장암, 자궁경부암, 췌장암, 난소암, 자궁경부암, 자궁내막세포암 등의 고형암을 포함하며, 바람직하게는 B 세포 비호지킨 림프종 (non-Hodgkin's lymphomas) (NHL), 여포성 림프종(follicular lymphoma), 확산 거대 B-세포 림프종(diffuse large B cell lymphoma), 외투세포 림프종(mantle cell lymphoma), 만성 림프성 백혈병(chronic lymphocytic leukemia), 소림프구성 림프종[small lymphocytic lymphoma (SLL)], 변연부 림프종 [marginal zone lymphoma (MZL)], 림프구형 질세포성림프종[Lymphoplasmacytic lymphoma (LDL)], 거대글로블린혈증 [Waldenstrom macroglobulinemia (WM)] 등을 포함하나 이에 제한되는 것은 아니다.CD20-positive cancers include, for example, lymphoma, hematologic cancer such as leukemia and melanoma, lung cancer, thyroid cancer, breast cancer, colorectal cancer, prostate cancer, head and neck cancer, stomach cancer, liver cancer, bladder cancer, kidney cancer, cervical cancer, pancreatic cancer, ovarian cancer solid cancers such as cancer, cervical cancer, and endometrial cell carcinoma, preferably B-cell non-Hodgkin's lymphoma (NHL), follicular lymphoma, diffuse large B-cell lymphoma (diffuse) large B cell lymphoma), mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), lymphocytes including, but not limited to, Lymphoplasmacytic lymphoma (LDL), Waldenstrom macroglobulinemia (WM), and the like.
본 발명의 또 다른 양태에 따르면, 본 발명은 전술한 본 발명의 항체 또는 이의 항원 결합 단편, 상기 항체 또는 이의 항원 결합 단편을 코딩하는 핵산분자, 또는 상기 핵산분자를 포함하는 벡터를 유효성분으로 포함하는 암의 진단용 조성물을 제공한다. According to another aspect of the present invention, the present invention includes the above-described antibody or antigen-binding fragment thereof of the present invention, a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof, or a vector comprising the nucleic acid molecule as an active ingredient. To provide a composition for diagnosis of cancer.
본 발명에서 사용되는 항체 또는 그의 항원결합 단편과 대상이 되는 암에 대해서는 이미 상술하였으므로, 과도한 중복을 피하기 위하여 그 기재를 생략한다.Since the antibody or antigen-binding fragment thereof used in the present invention and the target cancer have already been described above, description thereof will be omitted to avoid excessive overlap.
본 명세서에서 용어 "진단"은 특정 질환에 대한 개체의 감수성(susceptibility)의 판정, 특정 질환을 현재 개체가 가지고 있는 지 여부의 판정, 및 특정 질환에 걸린 한 객체의 예후(prognosis)의 판정을 포함한다. As used herein, the term "diagnosis" includes determination of an individual's susceptibility to a particular disease, determination of whether an individual currently has a particular disease, and determination of the prognosis of a subject with a particular disease. do.
CD20은 B 세포 림프종 및 만성 림프구성 백혈병과 같은 암 조직에서 정상수준에 비해 높은 발현 수준을 보이는 전형적인 암 진단 마커로서, CD20에 특이적으로 결합하는 본 발명의 항체는 생물학적 시료 내 종양의 존재를 정확하게 판정할 수 있다. 아울러, 본 발명의 항체는 다양한 면역 어세이 방법을 통해 종양 내 CD55의 발현 수준을 정확히 측정하여 해당 종양의 CDC 약물에 대한 치료 민감성을 예측함으로써, 암의 성격에 따른 맞춤형 치료 전략을 조기에 수립하는 데에 유용하게 이용될 수 있다. CD20 is a typical cancer diagnostic marker that shows high expression levels compared to normal levels in cancer tissues such as B-cell lymphoma and chronic lymphocytic leukemia. can be judged. In addition, the antibody of the present invention accurately measures the expression level of CD55 in the tumor through various immunoassay methods to predict the therapeutic sensitivity of the tumor to the CDC drug, thereby establishing a customized treatment strategy according to the nature of the cancer at an early stage. can be usefully used for
본 명세서에서 용어 "진단용 조성물"은 대상체의 암 발병 여부를 판단하거나 CDC 약물에 대한 치료 민감성을 예측하기 위해 CD20 단백질의 발현량 측정수단으로서 본 발명의 항체를 포함하는 통합적인 혼합물(mixture) 또는 장비(device)를 의미하며, 이에 "진단용 키트"로 표현될 수도 있다.As used herein, the term "diagnostic composition" refers to an integrated mixture or equipment comprising the antibody of the present invention as a means for measuring the expression level of CD20 protein in order to determine whether a subject has cancer or predict treatment sensitivity to a CDC drug. (device), which may be expressed as a “diagnostic kit”.
본 명세서에서 용어 "생물학적 시료"란 조직, 세포, 전혈, 혈청, 혈장, 타액, 뇨, 림프액, 척수액, 조직 부검 시료(뇌, 피부, 림프절, 척수 등), 세포 배양 상등액, 파열된 진핵세포 및 세균 발현계를 포함하나, 이에 제한되지는 않는다. As used herein, the term "biological sample" means tissue, cells, whole blood, serum, plasma, saliva, urine, lymph, spinal fluid, tissue autopsy sample (brain, skin, lymph node, spinal cord, etc.), cell culture supernatant, ruptured eukaryotic cells and Bacterial expression systems include, but are not limited to.
생물학적 시료에서 CD20 단백질의 검출은, 비색법(colormetric method), 전기화학법(electrochemical method), 형광법(fluorimetric method), 발광법(luminometry), 입자계수법(particle counting method), 육안측정법(visual assessment) 또는 섬광계수법(scintillation counting method)을 이용한 항원-항체 복합체 형성의 검출을 통하여 수행할 수 있다. 본 명세서에서 용어 "검출"은 항원-항체 복합체의 형성 여부를 판정하기 위한 일련의 과정을 의미한다. 검출은 효소, 형광물, 리간드, 발광물, 미소입자 또는 방사성 동위원소를 포함하는 다양한 표지체를 사용하여 실시할 수 있다. The detection of CD20 protein in a biological sample may be performed by a colormetric method, an electrochemical method, a fluorimetric method, a luminometry, a particle counting method, a visual assessment or Detection of antigen-antibody complex formation using a scintillation counting method can be performed. As used herein, the term “detection” refers to a series of processes for determining whether an antigen-antibody complex is formed. Detection can be carried out using various labels including enzymes, fluorescent substances, ligands, luminescent substances, microparticles, or radioactive isotopes.
검출 표지체로서 사용되는 효소는 예를 들어 아세틸콜린에스테라제, 알칼라인 포스파타제, β-D-갈락토시다제, 호스래디쉬 퍼옥시다제 및 β-라타마제를 포함하며, 형광물로는 플루오레세인, Eu3+, Eu3+ 킬레이트 또는 크립테이트 등을 포함하고, 리간드로는 바이오틴 유도체 등을 포함하며, 발광물로는 아크리디늄 에스테르 및 이소루미놀 유도체 등을 포함하고, 미소입자로는 콜로이드 금 및 착색된 라텍스 등을 포함하며, 방사성 동위원소로는 57Co, 3H, 125I 및 125I-볼톤(Bonton) 헌터(Hunter) 시약 등을 포함할 수 있다.Enzymes used as detection labels include, for example, acetylcholinesterase, alkaline phosphatase, β-D-galactosidase, horseradish peroxidase and β-latamase, and the fluorescent substance is fluoro Contains resinein, Eu 3+ , Eu 3+ chelate or cryptate, etc., as ligands, including biotin derivatives, etc., as luminescent materials, including acridinium esters and isoluminol derivatives, and the like, and as microparticles. colloidal gold and colored latex, and the like, and radioactive isotopes may include 57 Co, 3 H, 125 I and 125 I-Bonton Hunter reagents.
본 발명의 일구현예에 따르면, 항원-항체 복합체를 효소면역흡착법(ELISA) 을 이용하여 검출할 수 있다. 본 발명의 항체는 검출 표지를 가질 수 있으며, 검출표지를 가지지 않을 경우는 본 발명의 항체를 포획할 수 있고 검출 표지를 가지는 또 다른 항체를 처리하여 확인할 수 있다.According to one embodiment of the present invention, the antigen-antibody complex can be detected using enzyme immunosorbent assay (ELISA). The antibody of the present invention may have a detection label, and when it does not have a detection label, the antibody of the present invention can be captured and confirmed by treating another antibody having a detection label.
본 발명의 또 다른 양태에 따르면, 본 발명은 하기의 단계를 포함하는, 보체 의존 세포사멸능 (Complement Dependent Cytotoxicity, CDC)이 향상된 항-CD20 비대칭 항체 (asymmetric antibody) 또는 이의 항원 결합 단편의 제조방법을 제공한다:According to another aspect of the present invention, the present invention provides a method for producing an anti-CD20 asymmetric antibody or antigen-binding fragment thereof with improved complement dependent cytotoxicity (CDC), comprising the steps of: provides:
(a) 서열번호 16의 LCDR1, 서열번호 18의 LCDR2, 서열번호 20의 LCDR3, 서열번호 24의 HCDR1, 서열번호 26의 HCDR2 및 서열번호 28의 HCDR3 서열을 포함하는 scFv (Single-chain variable fragment)를 제조하는 단계; 및(a) LCDR1 of SEQ ID NO: 16, LCDR2 of SEQ ID NO: 18, LCDR3 of SEQ ID NO: 20, HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 26 and HCDR3 of SEQ ID NO: 28 for preparing scFv (Single-chain variable fragment) step; and
(b) 서열번호 33의 LCDR1, 서열번호 35의 LCDR2, 서열번호 37의 LCDR3, 서열번호 42의 HCDR1, 서열번호 44의 HCDR2 및 서열번호 46의 HCDR3 서열을 포함하는 Fab (Fragment antigen-binding)을 제조하는 단계. (b) LCDR1 of SEQ ID NO: 33, LCDR2 of SEQ ID NO: 35, LCDR3 of SEQ ID NO: 37, HCDR1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44 and HCDR3 of SEQ ID NO: 46 Preparing Fab (Fragment antigen-binding) .
본 발명의 또 다른 양태에 따르면, 본 발명은 하기의 단계를 포함하는, 보체 의존 세포사멸능 (Complement Dependent Cytotoxicity, CDC)이 향상된 항-CD20 비대칭 항체 (asymmetric antibody) 또는 이의 항원 결합 단편을 코딩하는 핵산분자의 제조방법을 제공한다:According to another aspect of the present invention, the present invention comprises the following steps, Complement Dependent Cytotoxicity (CDC) improved anti-CD20 asymmetric antibody (asymmetric antibody) or antigen-binding fragment thereof encoding A method for preparing a nucleic acid molecule is provided:
(a) 서열번호 16의 LCDR1, 서열번호 18의 LCDR2, 서열번호 20의 LCDR3, 서열번호 24의 HCDR1, 서열번호 26의 HCDR2 및 서열번호 28의 HCDR3 서열을 포함하는 scFv (Single-chain variable fragment)를 코딩하는 핵산분자를 제조하는 단계; 및(a) LCDR1 of SEQ ID NO: 16, LCDR2 of SEQ ID NO: 18, LCDR3 of SEQ ID NO: 20, HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 26 and HCDR3 of SEQ ID NO: 28 scFv (Single-chain variable fragment) encoding preparing a nucleic acid molecule; and
(b) 서열번호 33의 LCDR1, 서열번호 35의 LCDR2, 서열번호 37의 LCDR3, 서열번호 42의 HCDR1, 서열번호 44의 HCDR2 및 서열번호 46의 HCDR3 서열을 포함하는 Fab (Fragment antigen-binding)을 코딩하는 핵산분자를 제조하는 단계. (b) A nucleic acid encoding Fab (Fragment antigen-binding) comprising the sequence of LCDR1 of SEQ ID NO: 33, LCDR2 of SEQ ID NO: 35, LCDR3 of SEQ ID NO: 37, HCDR1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44 and HCDR3 of SEQ ID NO: 46 Steps to make a molecule.
본 발명의 비대칭 항체는 안정하게 회합할 수 있는 제 1 및 제 2 서브유닛으로 이루어진 Fc 영역을 포함할 수 있다. 본 명세서에서 용어 "Fc 영역"은 전장 항체의 불변 영역 중 적어도 일부분을 함유하는 항체 중쇄의 C-말단 영역을 의미하며, 이는 야생형 서열 Fc 영역과 변이체 Fc 영역을 모두 포함한다. IgG의 Fc 영역은 IgG CH2 및 IgG CH3 도메인을 포함한다. 본 발명의 비대칭 항체의 CH3 영역은 야생형 또는 변이체 CH3 도메인(예를 들어, 그의 한 쇄에 도입된 "돌출부"("놉") 및 그의 다른 쇄에 상응하는 도입된 "공동(cavity)"("홀")을 갖는 CH3 도메인일 수 있다.The asymmetric antibody of the present invention may comprise an Fc region consisting of first and second subunits capable of stably associating. As used herein, the term “Fc region” refers to the C-terminal region of an antibody heavy chain containing at least a portion of the constant region of a full-length antibody, and includes both a wild-type sequence Fc region and a mutant Fc region. The Fc region of an IgG comprises an IgG CH2 and an IgG CH3 domain. The CH3 region of an asymmetric antibody of the present invention has a wild-type or mutant CH3 domain (eg, an introduced "overhang" ("knob") on one chain thereof and an introduced "cavity" (") corresponding to its other chain. a CH3 domain with a hole").
본 발명의 구체적인 구현예에 따르면, 본 발명의 비대칭 항체는 중쇄끼리의 원치 않는 쌍의 결합을 막기 위해 놉-인투 홀(knob-into-hole)방법을 사용할 수 있다. "놉-인투-홀" 방법[US 5,731,168; US7,695,936; Ridgway et al., Prot Eng 9, 617-621 (1996); Carter, J Immunol Meth 248, 7-15 (2001)]은 이종이량체 생성을 촉진하고 동종이량체 생성을 저해하기 위해 돌출부가 공동에 위치할 수 있도록, 제 1 폴리펩타이드의 계면에 돌출부("놉") 및 제 2 폴리펩타이드의 계면에 상응하는 공동("홀")을 도입한다. 돌출부는 제 1 폴리펩타이드의 계면으로부터 작은 아미노산 측쇄를 보다 큰 측쇄(예, 티로신 또는 트립토판)로 치환시킴으로써 구성된다. 큰 아미노산 측쇄를 보다 작은 측쇄(예, 알라닌 또는 트레오닌)로 치환시킴으로써, 돌출부와 동일하거나 유사한 크기의 상호보완적 공동이 제 2 폴리펩타이드의 계면에 생성된다. According to a specific embodiment of the present invention, the asymmetric antibody of the present invention may use a knob-into-hole method to prevent unwanted pairing of heavy chains between each other. The “knob-into-hole” method [US 5,731,168; US 7,695,936; Ridgway et al., Prot Eng 9, 617-621 (1996); Carter, J Immunol Meth 248, 7-15 (2001)] described a protrusion at the interface of a first polypeptide (“knob ") and a cavity ("hole") corresponding to the interface of the second polypeptide. The overhang is constructed by substituting a smaller amino acid side chain from the interface of the first polypeptide with a larger side chain (eg, tyrosine or tryptophan). By substituting a larger amino acid side chain with a smaller side chain (eg, alanine or threonine), a complementary cavity of the same or similar size as the overhang is created at the interface of the second polypeptide.
본 발명의 구체적인 구현예에 따르면, 본 발명의 비대칭 항체는 VL-linker-VH-CH2-CH3 형태의 scFv 및 VL-Cκ-linker-VH-CH1-CH2-CH3 형태의 Fab이 결합된 형태일 수 있다.According to a specific embodiment of the present invention, the asymmetric antibody of the present invention may be a VL-linker-VH-CH2-CH3 form of scFv and VL-Cκ-linker-VH-CH1-CH2-CH3 form of a Fab bound form. have.
본 발명의 특징 및 이점을 요약하면 다음과 같다: The features and advantages of the present invention are summarized as follows:
(i) 본 발명은 한쪽은 scFv (Single-chain variable fragment) 및 다른 한쪽은 Fab (Fragment antigen-binding)을 포함하는, 보체 의존 세포사멸능 (Complement Dependent Cytotoxicity, CDC)이 향상된 항-CD20 비대칭 항체 (asymmetric antibody) 또는 이의 항원 결합 단편을 제공한다.(i) the present invention is one side scFv (Single-chain variable fragment) and the other side comprising Fab (Fragment antigen-binding), complement-dependent apoptosis (Complement Dependent Cytotoxicity, CDC) improved anti-CD20 asymmetric antibody (asymmetric antibody) or antigen-binding fragment thereof.
(ii) 본 발명의 비대칭 항체는 대칭구조의 항체와 비교하여 현저히 향상된 보체 의존 세포사멸능 (Complement Dependent Cytotoxicity, CDC)을 나타내는 바, 리툭시맙 등의 항암제에 내성이 유도된 다양한 질환에서 약물의 내성을 근원적으로 제거하고 치료 반응성을 현저히 개선시키는 효율적인 치료제 또는 치료 보조제로 유용하게 이용될 수 있다.(ii) the asymmetric antibody of the present invention shows significantly improved complement-dependent apoptosis (Complement Dependent Cytotoxicity, CDC) compared to the antibody of the symmetric structure, and resistance to anticancer drugs such as rituximab is induced in various diseases of the drug It can be usefully used as an effective therapeutic agent or therapeutic adjuvant that fundamentally eliminates resistance and significantly improves therapeutic responsiveness.
도 1은 IgG와 비대칭 형태의 항체의 모식도를 나타낸다.
도 2는 비대칭 형태의 anti-CD20 항체의 SDS-PAGE 분석 결과이다.
도 3은 비대칭 형태의 anti-CD20 항체의 CD20에 대한 친화도 분석 ELISA 결과이다.
도 4는 rituximab과 비대칭 형태의 anti-CD20 항체의 보체 활성능을 C4d 농도 측정으로 비교한 ELISA 결과이다.
도 5는 rituximab에 대한 내성을 나타내는 Ramos-RR 세포에서 rituximab과 비대칭 형태의 anti-CD20 항체의 CDC 효과를 비교한 결과이다.1 shows a schematic diagram of an antibody in an asymmetric form with IgG.
2 is an SDS-PAGE analysis result of an asymmetric anti-CD20 antibody.
3 shows the results of an affinity analysis ELISA for CD20 of an asymmetric anti-CD20 antibody.
4 is an ELISA result comparing the complement activity ability of rituximab and an asymmetric anti-CD20 antibody by measuring the C4d concentration.
5 is a result of comparing the CDC effect of rituximab and an asymmetric anti-CD20 antibody in Ramos-RR cells showing resistance to rituximab.
이하, 실시 예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시 예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시 예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example
실시예 1. 동물 세포 발현을 위한 비대칭 형태의 anti-CD20 항체 클로닝Example 1. Cloning of anti-CD20 antibody in asymmetric form for expression in animal cells
비대칭 형태의 anti-CD20 항체는 중쇄끼리의 원하지 않는 pair와 결합하는 것을 막기 위해 knob-into-hole 기법을 사용하였으며, 경쇄끼리의 잘못된 결합을 막기 위해서는 Gly과 Ser으로 구성된 linker를 사용하였다. CD20-scFv-knob (VL-linker20-VH-CH2-CH3) 과 CD20-Fab-hole (VL-Cκ-linker40-VH-CH1-CH2-CH3) 형태로 각각 클로닝을 진행하였으며, CD20-scFv-knob의 경우에는 Drug Data Bank에 나온 Rituximab sequence를 토대로 표 1의 프라이머 조합을 이용하여 PCR을 수행하였다. 증폭된 유전체는 BssHII 와 XbaI (New England Biolab, 영국) 효소를 처리하였고, 마찬가지로 동일한 제한효소로 처리된 동물세포 발현용 벡터인 pMAZ 벡터에 라이게이션 하였다. 라이게이션이 완료된 플라스미드는 DH5α competent cell (New England Biolab, 영국)에 열충격을 가하여 형질전환 하였고, 확보한 콜로니를 대량 배양하여 플라스미드를 수득하였다. The asymmetric anti-CD20 antibody used a knob-into-hole technique to prevent undesirable binding of heavy chains to each other, and a linker composed of Gly and Ser was used to prevent erroneous binding between light chains. Cloning was carried out in the form of CD20-scFv-knob (VL-linker20-VH-CH2-CH3) and CD20-Fab-hole (VL-Cκ-linker40-VH-CH1-CH2-CH3), respectively, and CD20-scFv-knob In the case of , PCR was performed using the primer combinations in Table 1 based on the Rituximab sequence from the Drug Data Bank. The amplified genome was treated with Bss HII and Xba I (New England Biolab, UK) enzymes, and was ligated to pMAZ vector, a vector for expression of animal cells treated with the same restriction enzyme. The ligation-completed plasmid was transformed by applying heat shock to DH5α competent cells (New England Biolab, UK), and the obtained colonies were mass-cultured to obtain a plasmid.
CD20-Fab-hole (VL-Cκ-linker40-VH-CH1-CH2-CH3) 형태를 만들기 위해서는 CD20-scFv-knob와 마찬가지로 Drug Data Bank에 나온 Rituximab sequence를 토대로 표 2의 프라이머 조합을 이용해서 PCR을 수행하였다. 증폭된 유전체는 BssHII와 XbaI 효소를 처리하였고, 마찬가지로 동일한 제한효소로 처리된 동물세포 발현용 벡터인 pMAZ 벡터에 라이게이션 하였다. 라이게이션이 완료된 플라스미드는 DH5α competent cell (New England Biolab, 영국)에 열충격을 가하여 형질전환 하였고, 확보한 콜로니를 대량 배양하여 플라스미드를 수득하여 sequence 분석(표 3)을 완료하였다. To create the CD20-Fab-hole (VL-Cκ-linker40-VH-CH1-CH2-CH3) form, PCR was performed using the primer combination in Table 2 based on the Rituximab sequence from the Drug Data Bank as in the CD20-scFv-knob. carried out. The amplified genome was treated with Bss HII and Xba I enzymes, and was ligated to the pMAZ vector, a vector for expression of animal cells treated with the same restriction enzyme. The ligation-completed plasmid was transformed by applying heat shock to DH5α competent cells (New England Biolab, UK), and the obtained colonies were mass-cultured to obtain a plasmid and sequence analysis (Table 3) was completed.
실시예 2. 동물세포에서 발현 및 정제Example 2. Expression and purification in animal cells
비대칭 형태의 anti-CD20 항체는 서열번호 13 및 14의 서열을 이용하여 각각의 플라스미드를 Polyethylenimine (PEI) (Polysciences, 미국)와 150 mM NaCl을 이용하여 HEK293F 세포 (Invitrogen, 미국)에 transfection 시키고 Freestyle 293 expression medium (Invitrogen, 미국)에서 37℃의 온도, 8% CO2 그리고 55% Humidity 조건으로 7일간 배양하였다. 발현 세포 배양액을 4,000 rpm, 10분간 원심분리한 후, 상등액을 취해 0.22 μm filter를 통해 여과하였다. 여과된 상등액은 4℃에서 KappaSelect (GE Healthcare, 미국) 레진 1 ml에 결합 유도하였다. 결합된 resin은 10 cv (column volume)의 PBS 용액으로 세척 후, 100 mM glycine-HCl (pH 2.7) 용액을 사용하여 결합된 항체를 용출한 후, 1 M Tris-HCL (pH 9.0)으로 중화하였다. pH 7.2~7.4 PBS로 buffer change 진행 후 SDS-PAGE를 통해 정제된 항체의 경쇄와 중쇄의 크기와 순도를 확인하였고 그 결과 이론적 계산치와 일치하는 분자량과 높은 순도를 확인할 수 있었다 (도 2). Anti-CD20 antibody in asymmetric form was transfected into HEK293F cells (Invitrogen, USA) using Polyethylenimine (PEI) (Polysciences, USA) and 150 mM NaCl, each plasmid using the sequences of SEQ ID NOs: 13 and 14, and Freestyle 293 In an expression medium (Invitrogen, USA) at 37°C, 8% CO 2 and 55% Humidity were cultured for 7 days. After centrifuging the expression cell culture at 4,000 rpm for 10 minutes, the supernatant was taken and filtered through a 0.22 μm filter. The filtered supernatant was induced to bind to 1 ml of KappaSelect (GE Healthcare, USA) resin at 4°C. The bound resin was washed with 10 cv (column volume) PBS solution, then the bound antibody was eluted using 100 mM glycine-HCl (pH 2.7) solution, and then neutralized with 1 M Tris-HCL (pH 9.0). . After buffer change with PBS at pH 7.2 to 7.4, the size and purity of the light and heavy chains of the purified antibody were confirmed through SDS-PAGE. As a result, the molecular weight and high purity consistent with the theoretical calculated values were confirmed (FIG. 2).
비대칭 형태의 anti-CD20 항체는 한쪽의 결합부위가 Fab이고 다른 한쪽의 결합부위가 scFv인 hetero form이다. Fab의 C kappa 부분을 이용하여 KappaSelect 로 정제를 하면 이중항체 정제 시 생성 가능성이 가장 높다고 알려진 knob-knob homodimer 또는 knob monomer (Giese, et al., Bispecific antibody process development: Assembly and purification of knob and hole bispecific antibodies. Biotechnol Prog, 34(2)397-404)의 생성을 억제하고 원하는 형태인 heterodimer만은 얻을 수 있다. The asymmetric form of the anti-CD20 antibody is a hetero form in which one binding site is Fab and the other binding site is scFv. When purified by KappaSelect using the C kappa portion of the Fab, a knob-knob homodimer or knob monomer (Giese, et al., Bispecific antibody process development: Assembly and purification of knob and hole bispecific that is known to be most likely to be produced during diabody purification) It inhibits the production of antibodies.Biotechnol Prog, 34(2)397-404) and only the heterodimer in the desired form can be obtained.
실시예 3. ELISA를 통한 비대칭 형태의 anti-CD20 항체의 CD20 결합력 확인Example 3. Confirmation of CD20 binding affinity of asymmetric anti-CD20 antibody through ELISA
상기 실시예 2에서 제작한 비대칭 형태의 anti-CD20 항체가 타겟하는 항원인 CD20에 대한 친화도를 indirect ELISA로 확인하였다. The affinity of the asymmetric anti-CD20 antibody prepared in Example 2 to CD20, the target antigen, was confirmed by indirect ELISA.
Indirect ELISA는 50 μl의 PBS에 1 ug/ml로 CD20 ectodomain loop 영역 항원을 희석하여 96웰 면역 플레이트 (Corning, 미국)에 넣고, 4℃에서 보관하여 밤새 흡착시켰다. 4% skim milk (BD, 미국)가 포함된 완충용액으로 상온에서 1시간 반응시킨 후, 0.5% Tween 20 (Amresco, 미국)이 포함된 완충용액으로 3회 세척하고, 순차적 농도 (0.1, 0.3, 1, 3, 11, 33, 100 nM)로 희석한 각각의 항체를 웰 당 50μl씩 처리하였다. 항원에 항체가 결합할 수 있도록 상온에서 2시간 반응시킨 후, 0.5% Tween 20 (Amresco, 미국)이 포함된 완충용액으로 3회 세척하였다. 항-인간 면역글로불린 Fc-HRP 항체 (Jackson Immunoresearch, 미국)를 1:3,000으로 2% skim milk (BD, 미국)가 포함된 완충용액을 이용하여 희석하고 웰 당 50 μl씩 처리한 후, 상온에서 1시간 반응시켰다. 반응이 끝난 후, 0.5% Tween 20 (Amresco, 미국)이 포함된 완충용액으로 3회 세척한 후, 3,3',5,5'-Tetramethylbenzidine (TMB) (ThermoFisher Scientific, 미국) 50 μl씩 넣고 10분간 발색 시켰다. 분광 광도계 (Biotek, 미국)를 이용하여 450 nm에서 흡광도를 측정하여 그 결과를 도 3에 나타내었다. 그 결과, 비대칭 형태의 anti-CD20 항체는 CD20에 대하여 rituximab과 동등 수준의 결합력을 나타냈다.Indirect ELISA was performed by diluting the CD20 ectodomain loop region antigen at 1 ug/ml in 50 μl of PBS, putting it in a 96-well immune plate (Corning, USA), and storing it at 4° C. for adsorption overnight. After reacting for 1 hour at room temperature with a buffer containing 4% skim milk (BD, USA), it was washed three times with a buffer containing 0.5% Tween 20 (Amresco, USA), and sequential concentrations (0.1, 0.3, 1, 3, 11, 33, 100 nM) of each antibody was treated at 50 μl per well. After reacting for 2 hours at room temperature so that the antibody can bind to the antigen, it was washed 3 times with a buffer containing 0.5% Tween 20 (Amresco, USA). Anti-human immunoglobulin Fc-HRP antibody (Jackson Immunoresearch, USA) was diluted 1:3,000 using a buffer containing 2% skim milk (BD, USA), treated with 50 μl per well, and then at room temperature. The reaction was carried out for 1 hour. After the reaction, after washing 3 times with a buffer containing 0.5% Tween 20 (Amresco, USA), 50 μl of 3,3',5,5'-Tetramethylbenzidine (TMB) (ThermoFisher Scientific, USA) is added. Color was developed for 10 minutes. Absorbance was measured at 450 nm using a spectrophotometer (Biotek, USA), and the results are shown in FIG. 3 . As a result, the asymmetric form of the anti-CD20 antibody exhibited the same level of binding to CD20 as that of rituximab.
실시예 4. C4d ELISA를 통한 비대칭 형태의 anti-CD20 항체의 보체 활성능 확인Example 4. Confirmation of complement activity of anti-CD20 antibody in asymmetric form through C4d ELISA
상기 실시예 2에서 제작한 비대칭 형태의 anti-CD20 항체의 보체 활성능을 C4d ELISA를 통하여 확인하였다. C4d는 보체 고전 경로의 활성화에 대한 marker로 (Cohen, et al., Pros and cons for C4d as a biomarker. Kidney Int., 81(7)628-39) C4d 농도 측정으로 보체 활성능 확인이 가능하다.The complement activity ability of the asymmetric anti-CD20 antibody prepared in Example 2 was confirmed through C4d ELISA. C4d is a marker for activation of the classical complement pathway (Cohen, et al., Pros and cons for C4d as a biomarker. Kidney Int., 81(7)628-39). Complement activity can be confirmed by measuring the C4d concentration. .
먼저 100 μg/ml 농도의 Rituximab 또는 비대칭 형태의 anti-CD20 항체 10 μl를 1 mg/ml 농도의보체 (Quidel, 미국) 90 ul 1시간 반응시킨 후, 10배 희석하여 MicroVue Complement C4d Fragment EIA kit (Quidel, 미국)를 이용하여 C4d 농도를 확인하여 그 결과를 도 4에 나타내었다. 그 결과 비대칭 형태의 anti-CD20 항체는 보체 의존 세포사멸 (Complement Dependent Cytotoxicity, CDC)이 주요 치료 기작인 rituximab에 비하여 C4d 농도를 증가시켰다. 이는 비대칭 형태의 anti-CD20 항체의 보체 활성능이 rituximab에 비하여 우수함을 의미한다. First, 10 μl of Rituximab at a concentration of 100 μg/ml or an asymmetric form of anti-CD20 antibody was reacted with 90 μl of complement (Quidel, USA) at a concentration of 1 mg/ml for 1 hour, diluted 10-fold with MicroVue Complement C4d Fragment EIA kit ( Quidel, USA) was used to check the C4d concentration, and the results are shown in FIG. 4 . As a result, the asymmetric anti-CD20 antibody increased the C4d concentration compared to rituximab, whose main treatment mechanism is complement dependent cytotoxicity (CDC). This means that the complement activity of the asymmetric anti-CD20 antibody is superior to that of rituximab.
실시예 5. Rituximab 내성 세포주인 Ramos-RR에서 비대칭 형태의 anti-CD20 항체의 CDC 효과 확인Example 5. Confirmation of CDC effect of asymmetric anti-CD20 antibody in Ramos-RR, a Rituximab-resistant cell line
Rituximab에 대한 내성을 나타내는 Ramos-RR에서 rituximab과 비대칭 형태의 anti-CD20 항체의 CDC 효과를 확인하였다. 샘플 당 5x105개의 Ramos-RR 세포에 rituximab 또는 비대칭 형태의 anti-CD20 항체를 각각 20 μg/ml 농도가 되도록 20% complement sera human (Sigma, 미국)이 첨가된 RPMI 배지로 희석하여 최종 100 μl를 처리한 후, 37℃/5%/CO2조건에서 2시간 동안 배양하였다. 그 후, FITC Annexin V Apoptosis Detection Kit with 7-AAD (BioLegend, 미국)를 이용하여 FACS 분석 장비인 Attune NxT (ThermoFisher Scientific, 미국)로 사멸 세포를 확인하여 CDC를 관찰하였다 (도 5). Ramos-RR 세포는 rituximab에 대한 CDC 효과가 낮았으나, 비대칭 형태의 anti-CD20 항체는 그 효과를 증가시켰다. In Ramos-RR showing resistance to rituximab, the CDC effect of rituximab and an asymmetric anti-CD20 antibody was confirmed. 5x10 5 Ramos-RR cells per sample by diluting rituximab or asymmetric anti-CD20 antibody in RPMI medium with 20% complement sera human (Sigma, USA) to a concentration of 20 μg/ml, respectively, and finally 100 μl After treatment, incubated for 2 hours at 37° C./5%/CO 2 conditions. Thereafter, CDC was observed by confirming apoptotic cells with Attune NxT (ThermoFisher Scientific, USA), a FACS analysis equipment, using the FITC Annexin V Apoptosis Detection Kit with 7-AAD (BioLegend, USA) (FIG. 5). Ramos-RR cells had a low CDC effect on rituximab, but an asymmetric anti-CD20 antibody increased the effect.
이러한 결과는 IgG 항체에 비하여 비대칭 형태의 항체가 보체를 효과적으로 활성화하여 CDC를 효과적으로 유도하는 것을 보여주며, CDC가 주요 치료 기작인 암 치료용 항체의 경우 비대칭 형태의 항체가 암 치료에 더 유리함을 의미한다.These results show that an asymmetric antibody effectively induces CDC by activating complement effectively compared to an IgG antibody. do.
이상, 본 발명의 실시예들에 대하여 설명하였으나, 해당 기술 분야에서 통상의 지식을 가진 자라면 특허청구범위에 기재된 본 발명의 사상으로부터 벗어나지 않는 범위 내에서, 구성 요소의 부가, 변경, 삭제 또는 추가 등에 의해 본 발명을 다양하게 수정 및 변경시킬 수 있을 것이며, 이 또한 본 발명의 권리범위 내에 포함된다고 할 것이다. In the above, although embodiments of the present invention have been described, those of ordinary skill in the art can add, change, delete or add components within the scope that does not depart from the spirit of the present invention described in the claims. The present invention may be variously modified and changed by such as, and it will be said that it is also included within the scope of the present invention.
<110> SG Medical, Inc. <120> Asymmetric antibody with enhanced target cell clearance <130> HPC-10589 <150> KR 10-2021-005092 <151> 2021-04-20 <160> 54 <170> KoPatentIn 3.0 <210> 1 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> VL Primer (F) CD20-scFv-knob <400> 1 cgcagcgagc gcgcactccc agatcgtcct gagtcagagc c 41 <210> 2 <211> 86 <212> DNA <213> Artificial Sequence <220> <223> VL Primer (R) CD20-scFv-knob <400> 2 agagccgcca gatccactgc ctcctccacc gctaccgcca ccaccactcc cgcctccgcc 60 cttaatctcc aatttagttc ccccgc 86 <210> 3 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> VH Primer (F) CD20-scFv-knob <400> 3 gcagtggatc tggcggctct caggtccagc tccaacagcc c 41 <210> 4 <211> 55 <212> DNA <213> Artificial Sequence <220> <223> VH Primer (R) CD20-scFv-knob <400> 4 ggtgggcatg tgtgagtttt gtctgagccg ccagcactca ccgtcacagt ggtac 55 <210> 5 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> CH Primer (F) CD20-scFv-knob <400> 5 gacaaaactc acacatgccc acc 23 <210> 6 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> CH Primer (R) CD20-scFv-knob <400> 6 ctctccctgt ccccgggtaa atgactagaa cta 33 <210> 7 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> VL- CK Primer (F) CD20-Fab-hole <400> 7 cgcagcgagc gcgcactccc agattgtcct gtctcagtct cctgc 45 <210> 8 <211> 44 <212> DNA <213> Artificial Sequence <220> <223> VL- CK Primer (R) CD20-Fab-hole <400> 8 cggccgccgt gcgagatctt ttgatttcca gtttagttcc gccg 44 <210> 9 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> VH Primer (F) CD20-Fab-hole <400> 9 caagtccaac tgcaacaacc ggg 23 <210> 10 <211> 50 <212> DNA <213> Artificial Sequence <220> <223> VH Primer (R) CD20-Fab-hole <400> 10 ggaagaccga tgggcccttg aagctagcgg cggaaaccgt tgtgccagag 50 <210> 11 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> CH Primer (F) CD20-Fab-hole <400> 11 gcaagcttca agggc 15 <210> 12 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> CH Primer (R) CD20-Fab-hole <400> 12 ctctccctgt ccccgggtaa atgactagaa cta 33 <210> 13 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> CD20-scFv-knob <400> 13 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly 100 105 110 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Gly Ser Gln Val 115 120 125 Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val 130 135 140 Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met 145 150 155 160 His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly Ala 165 170 175 Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly 180 185 190 Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln 195 200 205 Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 210 215 220 Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly 225 230 235 240 Thr Thr Val Thr Val Ser Ala Gly Gly Ser Asp Lys Thr His Thr Cys 245 250 255 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 260 265 270 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 275 280 285 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 290 295 300 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 305 310 315 320 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 325 330 335 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 340 345 350 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 355 360 365 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 370 375 380 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys 385 390 395 400 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 405 410 415 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 420 425 430 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 435 440 445 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 450 455 460 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 14 <211> 706 <212> PRT <213> Artificial Sequence <220> <223> CD20-Fab-hole <400> 14 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ser Arg Thr Ala Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly 210 215 220 Ser Gly Gly Gly Gly Ser Gly Ser Gly Gly Ser Gly Gly Gly Gly Ser 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Ser Ser Gln 245 250 255 Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser 260 265 270 Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn 275 280 285 Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly 290 295 300 Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys 305 310 315 320 Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met 325 330 335 Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala 340 345 350 Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala 355 360 365 Gly Thr Thr Val Thr Val Ser Ala Ala Ser Phe Lys Gly Pro Ser Val 370 375 380 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 385 390 395 400 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 405 410 415 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 420 425 430 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 435 440 445 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 450 455 460 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 465 470 475 480 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 485 490 495 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 500 505 510 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 515 520 525 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 530 535 540 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 545 550 555 560 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 565 570 575 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 580 585 590 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 595 600 605 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 610 615 620 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 625 630 635 640 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 645 650 655 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 660 665 670 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 675 680 685 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 690 695 700 Gly Lys 705 <210> 15 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> LFR1 of CD20-scFv-knob <400> 15 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys 20 <210> 16 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 of CD20-scFv-knob <400> 16 Arg Ala Ser Ser Ser Val Ser Tyr Ile His 1 5 10 <210> 17 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> LFR2 of CD20-scFv-knob <400> 17 Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 1 5 10 15 <210> 18 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 of CD20-scFv-knob <400> 18 Ala Thr Ser Asn Leu Ala Ser 1 5 <210> 19 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> LFR3 of CD20-scFv-knob <400> 19 Gly Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser 1 5 10 15 Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys 20 25 30 <210> 20 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 of CD20-scFv-knob <400> 20 Gln Gln Trp Thr Ser Asn Pro Pro Thr 1 5 <210> 21 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LFR4 of CD20-scFv-knob <400> 21 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 1 5 10 <210> 22 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> Linker of CD20-scFv-knob <400> 22 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Ser Gly Gly Ser 20 <210> 23 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> HFR1 of CD20-scFv-knob <400> 23 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 20 25 30 <210> 24 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 of CD20-scFv-knob <400> 24 Ser Tyr Asn Met His 1 5 <210> 25 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> HFR2 of CD20-scFv-knob <400> 25 Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly 1 5 10 <210> 26 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 of CD20-scFv-knob <400> 26 Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 27 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> HFR3 of CD20-scFv-knob <400> 27 Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln 1 5 10 15 Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 28 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 of CD20-scFv-knob <400> 28 Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val 1 5 10 <210> 29 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HFR4 of CD20-scFv-knob <400> 29 Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala 1 5 10 <210> 30 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> CH2 of CD20-scFv-knob <400> 30 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys 115 120 <210> 31 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> CH3 of CD20-scFv-knob <400> 31 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 1 5 10 15 Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe 20 25 30 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 35 40 45 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 50 55 60 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 65 70 75 80 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 85 90 95 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 100 105 <210> 32 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> LFR1 of CD20-Fab-hole <400> 32 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys 20 <210> 33 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 of CD20-Fab-hole <400> 33 Arg Ala Ser Ser Ser Val Ser Tyr Ile His 1 5 10 <210> 34 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> LFR2 of CD20-Fab-hole <400> 34 Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 1 5 10 15 <210> 35 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 of CD20-Fab-hole <400> 35 Ala Thr Ser Asn Leu Ala Ser 1 5 <210> 36 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> LFR3 of CD20-Fab-hole <400> 36 Gly Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser 1 5 10 15 Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys 20 25 30 <210> 37 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 of CD20-Fab-hole <400> 37 Gln Gln Trp Thr Ser Asn Pro Pro Thr 1 5 <210> 38 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LFR4 of CD20-Fab-hole <400> 38 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 1 5 10 <210> 39 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Ckappa of CD20-Fab-hole <400> 39 Arg Thr Ala 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> 40 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Linker of CD20-Fab-hole <400> 40 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 20 25 30 Gly Gly Ser Gly Ser Gly Ser Ser 35 40 <210> 41 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> HFR1 of CD20-Fab-hole <400> 41 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 20 25 30 <210> 42 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 of CD20-Fab-hole <400> 42 Ser Tyr Asn Met His 1 5 <210> 43 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> HFR2 of CD20-Fab-hole <400> 43 Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly 1 5 10 <210> 44 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 of CD20-Fab-hole <400> 44 Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 45 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> HFR3 of CD20-Fab-hole <400> 45 Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln 1 5 10 15 Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 46 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 of CD20-Fab-hole <400> 46 Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val 1 5 10 <210> 47 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HFR4 of CD20-Fab-hole <400> 47 Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala 1 5 10 <210> 48 <211> 103 <212> PRT <213> Artificial Sequence <220> <223> CH1 of CD20-Fab-hole <400> 48 Ala Ser Phe 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 100 <210> 49 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> CH2 of CD20-Fab-hole <400> 49 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys 115 120 <210> 50 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> CH3 of CD20-Fab-hole <400> 50 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 1 5 10 15 Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 20 25 30 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 35 40 45 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 50 55 60 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 65 70 75 80 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 85 90 95 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 100 105 <210> 51 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL of CD20-scFv-knob <400> 51 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 52 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> VH of CD20-scFv-knob <400> 52 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala 115 120 <210> 53 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL of CD20-Fab-hole <400> 53 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 54 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> VH of CD20-Fab-hole <400> 54 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala 115 120 <110> SG Medical, Inc. <120> Asymmetric antibody with enhanced target cell clearance <130> HPC-10589 <150> KR 10-2021-005092 <151> 2021-04-20 <160> 54 <170> KoPatentIn 3.0 <210> 1 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> VL Primer (F) CD20-scFv-knob <400> 1 cgcagcgagc gcgcactccc agatcgtcct gagtcagagc c 41 <210> 2 <211> 86 <212> DNA <213> Artificial Sequence <220> <223> VL Primer (R) CD20-scFv-knob <400> 2 agagccgcca gatccactgc ctcctccacc gctaccgcca ccaccactcc cgcctccgcc 60 cttaatctcc aatttagttc ccccgc 86 <210> 3 <213> 41 <212> DNA <220> <223> VH Primer (F) CD20-scFv-knob <400> 3 gcagtggatc tggcggctct caggtccagc tccaacagcc c 41 <210> 4 <211> 55 <212> DNA <213> Artificial Sequence <220> <223> VH Primer (R) CD20-scFv-knob <400> 4 ggtgggcatg tgtgagtttt gtctgagccg ccagcactca ccgtcacagt ggtac 55 <210> 5 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> CH Primer (F) CD20- scFv-knob <400> 5 gacaaaactc acacatgccc acc 23 <210> 6 <211> 33 <212> DNA <213> Artificial Seque nce <220> <223> CH Primer (R) CD20-scFv-knob <400> 6 ctctccctgt ccccgggtaa atgactagaa cta 33 <210> 7 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> VL - CK Primer (F) CD20-Fab-hole <400> 7 cgcagcgagc gcgcactccc agattgtcct gtctcagtct cctgc 45 <210> 8 <211> 44 <212> DNA <213> Artificial Sequence <220> <223> VL- CK Primer (R ) CD20-Fab-hole <400> 8 cggccgccgt gcgagatctt ttgatttcca gtttagttcc gccg 44 <210> 9 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> VH Primer (F) CD20-Fab-hole < 400> 9 caagtccaac tgcaacaacc ggg 23 <210> 10 <211> 50 <212> DNA <213> Artificial Sequence <220> <223> VH Primer (R) CD20-Fab-hole <400> 10 ggaagaccga tgggcccttg aagctagcgg cggaaaccgt tgtgccagag 50 <210> 11 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> CH Primer (F) CD20-Fab-hole <400> 11 gcaagcttca agggc 15 <210> 12 <211> 33 <212 > DNA <213> Artificial Sequence <220> <223> CH Primer (R) CD20-Fab-hole <400> 12 ctctccctgt ccccgggtaa atgactagaa cta 33 <210> 13 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> CD20-scFv-knob <400> 13 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly 100 105 110 Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Gly Ser Gly Gly Ser Gln Val 115 120 125 Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val 130 135 140 Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met 145 150 155 160 His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly Ala 165 170 175 Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly 180 185 190 Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln 195 200 205 Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 210 215 220 Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly 225 230 235 240 Thr Thr Val Thr Val Ser Ala Gly Gly Ser Asp Lys Thr His Thr Cys 245 250 255 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 260 265 270 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 275 280 285 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 290 295 300 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 305 310 315 320 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 325 330 335 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 340 345 350 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 355 360 365 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 370 375 380 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys 385 390 395 400 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 405 410 415 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 420 425 430 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 435 440 445 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 450 455 460 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 14 <211> 706 <212> PRT <213> Artificial Sequence <220> <223> CD20-Fab-hole <400> 14 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ser Arg Thr Ala Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 13 0 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly 210 215 220 Ser Gly Gly Gly Gly Ser Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Ser Ser Gln 245 250 255 Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser 260 265 270 Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Se r Tyr Asn 275 280 285 Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly 290 295 300 Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys 305 310 315 320 Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met 325 330 335 Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala 340 345 350 Arg Ser Thr Tyr Tyr Gly Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala 355 360 365 Gly Thr Thr Val Thr Val Ser Ala Ala Ser Phe Lys Gly Pro Ser Val 370 375 380 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 385 390 395 400 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 405 410 415 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val Hi s Thr Phe Pro Ala Val 420 425 430 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 435 440 445 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 450 455 460 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 465 470 475 480 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 485 490 495 Pro Ser Val Phe Leu Phe Pro Lys Pro Lys Asp Thr Leu Met Ile 500 505 510 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 515 520 525 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 530 535 540 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 545 550 555 560 Val Val Ser Val Leu Thr Val Le u His Gln Asp Trp Leu Asn Gly Lys 565 570 575 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 580 585 590 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 595 600 605 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 610 615 620 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 625 630 635 640 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 645 650 655 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 660 665 670 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 675 680 685 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 690 695 700 Gly Lys 705 <210> 15 <211> 23 <212> PR T <213> Artificial Sequence <220> <223> LFR1 of CD20-scFv-knob <400> 15 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys 20 <210> 16 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 of CD20-scFv-knob <400> 16 Arg Ala Ser Ser Ser Val Ser Tyr Ile His 1 5 10 <210 > 17 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> LFR2 of CD20-scFv-knob <400> 17 Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 1 5 10 15 <210> 18 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 of CD20-scFv-knob <400> 18 Ala Thr Ser Asn Leu Ala Ser 1 5 <210> 19 <211 > 32 <212> PRT <213> Artificial Sequence <220> <223> LFR3 of CD20-scFv-knob <400> 19 Gly Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser 1 5 10 15 Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys 20 25 30 <210> 20 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 of CD20-scFv-knob <400> 20 Gln Gln Trp Thr Ser Asn Pro Pro Thr 1 5 <210> 21 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LFR4 of CD20-scFv -knob <400> 21 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 1 5 10 <210> 22 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> Linker of CD20-scFv-knob < 400> 22 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Ser Gly Gly Ser 20 <210> 23 <211> 30 <212> PRT <213> Artificial Sequence <220> <223 > HFR1 of CD20-scFv-knob <400> 23 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 20 25 30 < 210> 24 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 of CD20-scFv-knob <400> 24 Ser Tyr Asn Met His 1 5 <210> 25 <211> 14 <212 > PRT <213> Artificial Sequence <220> <223> HFR2 of CD20-scFv-knob <400> 25 Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly 1 5 10 <210> 26 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 of CD20-scFv-knob <400> 26 Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 27 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> HFR3 of CD20-scFv-knob <400> 27 Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln 1 5 10 15 Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 28 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 of CD20-scFv-knob <400> 28 Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val 1 5 10 <210> 29 <211> 11 <212> PRT <213> Artificial Sequence <220> < 223> HFR4 of CD20-scFv-knob <400> 29 Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala 1 5 10 <210> 30 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> CH2 of CD20-scFv-knob <400> 30 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val P he Leu Phe Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys 115 120 <210> 31 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> CH3 of CD20-scFv- knob <400> 31 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 1 5 10 15 Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe 20 25 30 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 35 40 45 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 50 55 60 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 65 70 75 80 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 85 90 95 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 100 105 <210> 32 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> LFR1 of CD20-Fab-hole <400> 32 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys 20 <210> 33 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 of CD20-Fab-hole <400> 33 Arg Ala Ser Ser Ser Val Ser Tyr Ile His 1 5 10 <210> 34 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> LFR2 of CD20-Fab -hole <400> 34 Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 1 5 10 15 <210> 35 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 of CD20-Fab-hole <400> 35 Ala Thr Ser Asn Leu Ala Ser 1 5 <210> 36 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> LFR3 of CD20-Fab-hole <400> 36 Gly Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser 1 5 10 15 Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys 20 25 30 <210> 37 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 of CD20-Fab-hole < 400> 37 Gln Gln Trp Thr Ser Asn Pro Pro Thr 1 5 <210> 38 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LFR4 of CD20-Fab-hole <400> 38 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 1 5 10 <210> 39 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Ckappa of CD20-Fab-hole <400> 39 Arg Thr Ala 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 G lu 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> 40 <211> 40 <212> PRT < 213> Artificial Sequence <220> <223> Linker of CD20-Fab-hole <400> 40 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 20 25 30 Gly Gly Ser Gly Ser Gly Ser Ser 35 40 <210> 41 <211> 30 <212> PRT <213> Artificial Sequence <220> < 223> HFR1 of CD20-Fab-hole <400> 41 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 20 25 30 <210> 42 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 of CD20-Fab-hole <400> 42 Ser Tyr Asn Met His 1 5 <210> 43 <211> 14 < 212> PRT <213> Artificial Sequence <220> <223> HFR2 of CD20-Fab-hole <400> 43 Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly 1 5 10 <210> 44 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 of CD20-Fab-hole <400> 44 Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 45 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> HFR3 of CD20-Fab-hole <400> 45 Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Ser Thr Ala Tyr Met Gln 1 5 10 15 Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 46 <211> 12 <212> PRT <213> Artificial Sequence <220> <223 > HCDR3 of CD20-Fab-hole <400> 46 Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val 1 5 10 <210> 47 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HFR4 of CD20-Fab-hole <400> 47 Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala 1 5 10 <210> 48 <211> 103 <212> PRT <213> Artificial Sequence <220> <223> CH1 of CD20-Fab-hole <400> 48 Ala Ser Phe 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 100 <210> 49 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> CH2 of CD20-Fab-hole <400> 49 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys 115 120 <210> 50 <211> 107 <212> PRT < 213> Artificial Sequence <220> <223> CH3 of CD20-Fab-hole <400> 50 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 1 5 10 15 Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 20 25 30 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 35 40 45 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 50 55 60 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 65 70 75 80 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 85 90 95 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 100 105 <210> 51 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL of CD20-scFv-knob <400> 51 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 52 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> VH of CD20-scFv-knob <400> 52 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala 115 120 <210> 53 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL of CD20-Fab-hole <400> 53 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Me t Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 54 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> VH of CD20-Fab-hole <400> 54 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly As p Trp Tyr Phe Asn Val Trp Gly 100 105 110Ala Gly Thr Thr Val Thr Val Ser Ala 115 120
Claims (22)
(a) 서열번호 16의 LCDR1, 서열번호 18의 LCDR2, 서열번호 20의 LCDR3, 서열번호 24의 HCDR1, 서열번호 26의 HCDR2 및 서열번호 28의 HCDR3 서열을 포함하는 scFv (Single-chain variable fragment); 및
(b) 서열번호 33의 LCDR1, 서열번호 35의 LCDR2, 서열번호 37의 LCDR3, 서열번호 42의 HCDR1, 서열번호 44의 HCDR2 및 서열번호 46의 HCDR3 서열을 포함하는 Fab (Fragment antigen-binding).
An anti-CD20 asymmetric antibody or antigen-binding fragment thereof with improved Complement Dependent Cytotoxicity (CDC), comprising the following configuration:
(a) scFv (Single-chain variable fragment) comprising the sequences of LCDR1 of SEQ ID NO: 16, LCDR2 of SEQ ID NO: 18, LCDR3 of SEQ ID NO: 20, HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 26 and HCDR3 of SEQ ID NO: 28 ; and
(b) Fab (Fragment antigen-binding) comprising the sequence of LCDR1 of SEQ ID NO: 33, LCDR2 of SEQ ID NO: 35, LCDR3 of SEQ ID NO: 37, HCDR1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44 and HCDR3 of SEQ ID NO: 46.
The anti-CD20 asymmetric antibody or antigen-binding fragment thereof according to claim 1, wherein the scFv comprises the light chain variable region (VL) sequence of SEQ ID NO:51.
The anti-CD20 asymmetric antibody or antigen-binding fragment thereof according to claim 1, wherein the scFv comprises a heavy chain variable region (VH) sequence of SEQ ID NO: 52.
The method of claim 1, wherein the scFv is LFR1 of SEQ ID NO: 15, LFR2 of SEQ ID NO: 17, LFR3 of SEQ ID NO: 19, LFR4 of SEQ ID NO: 21, HFR1 of SEQ ID NO: 23, HFR2 of SEQ ID NO: 25, HFR3 of SEQ ID NO: 27 And an anti-CD20 asymmetric antibody or antigen-binding fragment thereof, characterized in that it comprises a sequence selected from the group consisting of HFR4 of SEQ ID NO: 29.
The anti-CD20 asymmetric antibody or antigen-binding fragment thereof according to claim 1, wherein the scFv is in the form of a VL-linker-VH.
The anti-CD20 asymmetric antibody or antigen-binding fragment thereof according to claim 5, wherein the linker is a combination of Gly and Ser.
The anti-CD20 asymmetric antibody or antigen-binding fragment thereof according to claim 1, wherein the Fab comprises the light chain variable region (VL) sequence of SEQ ID NO: 53.
The anti-CD20 asymmetric antibody or antigen-binding fragment thereof according to claim 1, wherein the Fab comprises a heavy chain variable region (VH) sequence of SEQ ID NO: 54.
According to claim 1, wherein the Fab is LFR1 of SEQ ID NO: 32, LFR2 of SEQ ID NO: 34, LFR3 of SEQ ID NO: 36, LFR4 of SEQ ID NO: 38, HFR1 of SEQ ID NO: 41, HFR2 of SEQ ID NO: 43, HFR3 of SEQ ID NO: 45 and a sequence selected from the group consisting of HFR4 of SEQ ID NO: 47. An anti-CD20 asymmetric antibody or antigen-binding fragment thereof.
The anti-CD20 asymmetric antibody or antigen-binding fragment thereof according to claim 1, wherein the Fab comprises the C kappa (C kappa) sequence of SEQ ID NO: 39.
The anti-CD20 asymmetric antibody or antigen-binding fragment thereof according to claim 1, wherein the Fab comprises the CH1 sequence of SEQ ID NO: 48.
The anti-CD20 asymmetric antibody or antigen-binding fragment thereof according to claim 1, wherein the Fab is in the form of VL-Cκ-linker-VH-CH1.
The anti-CD20 asymmetric antibody or antigen-binding fragment thereof according to claim 12, wherein the linker is a combination of Gly and Ser.
A nucleic acid molecule encoding the anti-CD20 asymmetric antibody of claim 1 or an antigen-binding fragment thereof.
A vector comprising the nucleic acid molecule of claim 14 .
An isolated host cell transformed with the vector of claim 15 .
The anti-CD20 asymmetric antibody or antigen-binding fragment thereof of claim 1, a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof, or a pharmaceutical composition for the prevention or treatment of cancer comprising a vector containing the nucleic acid molecule as an active ingredient .
The method of claim 1, comprising administering to a subject a pharmaceutically effective amount of the anti-CD20 asymmetric antibody or antigen-binding fragment thereof, a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof, or a vector comprising the nucleic acid molecule. Prevention or treatment methods.
The anti-CD20 asymmetric antibody or antigen-binding fragment thereof of claim 1, a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof, or a vector containing the nucleic acid molecule for use in therapy.
The composition for diagnosis of cancer comprising the anti-CD20 asymmetric antibody or antigen-binding fragment thereof of claim 1, a nucleic acid molecule encoding the antibody or antigen-binding fragment thereof, or a vector containing the nucleic acid molecule as an active ingredient.
(a) 서열번호 16의 LCDR1, 서열번호 18의 LCDR2, 서열번호 20의 LCDR3, 서열번호 24의 HCDR1, 서열번호 26의 HCDR2 및 서열번호 28의 HCDR3 서열을 포함하는 scFv (Single-chain variable fragment)를 제조하는 단계; 및
(b) 서열번호 33의 LCDR1, 서열번호 35의 LCDR2, 서열번호 37의 LCDR3, 서열번호 42의 HCDR1, 서열번호 44의 HCDR2 및 서열번호 46의 HCDR3 서열을 포함하는 Fab (Fragment antigen-binding)을 제조하는 단계.
A method for producing an anti-CD20 asymmetric antibody or antigen-binding fragment thereof with improved complement dependent cytotoxicity (CDC), comprising the steps of:
(a) scFv (Single-chain variable fragment) comprising the sequences of LCDR1 of SEQ ID NO: 16, LCDR2 of SEQ ID NO: 18, LCDR3 of SEQ ID NO: 20, HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 26 and HCDR3 of SEQ ID NO: 28 preparing a; and
(b) Fab (Fragment antigen-binding) comprising the sequence of LCDR1 of SEQ ID NO: 33, LCDR2 of SEQ ID NO: 35, LCDR3 of SEQ ID NO: 37, HCDR1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44 and HCDR3 of SEQ ID NO: 46 manufacturing steps.
(a) 서열번호 16의 LCDR1, 서열번호 18의 LCDR2, 서열번호 20의 LCDR3, 서열번호 24의 HCDR1, 서열번호 26의 HCDR2 및 서열번호 28의 HCDR3 서열을 포함하는 scFv (Single-chain variable fragment)를 코딩하는 핵산분자를 제조하는 단계; 및
(b) 서열번호 33의 LCDR1, 서열번호 35의 LCDR2, 서열번호 37의 LCDR3, 서열번호 42의 HCDR1, 서열번호 44의 HCDR2 및 서열번호 46의 HCDR3 서열을 포함하는 Fab (Fragment antigen-binding)을 코딩하는 핵산분자를 제조하는 단계. A method for producing a nucleic acid molecule encoding an anti-CD20 asymmetric antibody or antigen-binding fragment thereof having improved complement dependent cytotoxicity (CDC), comprising the steps of:
(a) scFv (Single-chain variable fragment) comprising the sequences of LCDR1 of SEQ ID NO: 16, LCDR2 of SEQ ID NO: 18, LCDR3 of SEQ ID NO: 20, HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 26 and HCDR3 of SEQ ID NO: 28 preparing a nucleic acid molecule encoding and
(b) Fab (Fragment antigen-binding) comprising the sequence of LCDR1 of SEQ ID NO: 33, LCDR2 of SEQ ID NO: 35, LCDR3 of SEQ ID NO: 37, HCDR1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 44 and HCDR3 of SEQ ID NO: 46 A step of preparing the encoding nucleic acid molecule.
Priority Applications (4)
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EP22792028.7A EP4328243A1 (en) | 2021-04-20 | 2022-04-20 | Asymmetric antibody with improved cytotoxicity against cancer cell |
JP2023562971A JP2024514890A (en) | 2021-04-20 | 2022-04-20 | Asymmetric antibodies with improved efficacy in killing cancer cells |
CN202280029122.6A CN117440971A (en) | 2021-04-20 | 2022-04-20 | Asymmetric antibodies with improved cancer cell killing efficacy |
PCT/KR2022/005661 WO2022225329A1 (en) | 2021-04-20 | 2022-04-20 | Asymmetric antibody with improved cytotoxicity against cancer cell |
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KR1020210050921 | 2021-04-20 | ||
KR20210050921 | 2021-04-20 |
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