KR20230143869A - Antibody-drug conjugate comprising antibody against human TROP2 and its use - Google Patents
Antibody-drug conjugate comprising antibody against human TROP2 and its use Download PDFInfo
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- KR20230143869A KR20230143869A KR1020220043049A KR20220043049A KR20230143869A KR 20230143869 A KR20230143869 A KR 20230143869A KR 1020220043049 A KR1020220043049 A KR 1020220043049A KR 20220043049 A KR20220043049 A KR 20220043049A KR 20230143869 A KR20230143869 A KR 20230143869A
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
Abstract
본 발명은 인간 TROP2(tumor-associated calcium signal transducer 2, TACSTD2)를 타겟팅하는 항체-약물 접합체(antibody-drug conjugate, ADC) 및 이의 용도에 관한 것으로, 보다 상세하게는 인간 TROP2에 결합하는 항체 또는 이의 항원 결합 단편을 포함하는 ADC 및 병, 더 상세하게는 과증식 및/또는 혈관신생질환 예컨대, 암 질환의 치료 및/또는 예방을 위한 약제를 생산하기 위한 이들 ADC의 용도에 관한 것이다.The present invention relates to an antibody-drug conjugate (ADC) targeting human TROP2 (tumor-associated calcium signal transducer 2, TACSTD2) and its use. More specifically, it relates to an antibody that binds to human TROP2 or its use. It relates to ADCs comprising antigen-binding fragments and the use of these ADCs to produce medicaments for the treatment and/or prevention of diseases, more particularly hyperproliferative and/or angiogenic diseases, such as cancer diseases.
Description
본 발명은 인간 TROP2(tumor-associated calcium signal transducer 2, TACSTD2)를 타겟팅하는 항체-약물 접합체(antibody-drug conjugate, ADC) 및 이의 용도에 관한 것으로, 보다 상세하게는 인간 TROP2에 결합하는 항체 또는 이의 항원 결합 단편을 포함하는 ADC 및 병, 더 상세하게는 과증식 및/또는 혈관신생질환 예컨대, 암 질환의 치료 및/또는 예방을 위한 약제를 생산하기 위한 이들 ADC의 용도에 관한 것이다.The present invention relates to an antibody-drug conjugate (ADC) targeting human TROP2 (tumor-associated calcium signal transducer 2, TACSTD2) and its use. More specifically, it relates to an antibody that binds to human TROP2 or its use. It relates to ADCs comprising antigen-binding fragments and the use of these ADCs to produce medicaments for the treatment and/or prevention of diseases, more particularly hyperproliferative and/or angiogenic diseases, such as cancer diseases.
암(cancer)은 신체 조직의 자율적인 과잉 성장에 의해 비정상적으로 자라난 덩어리로 인한 질환을 말하며, 다양한 조직에서 조절되지 않는 세포 성장의 결과이다. 초기 단계 종양은 수술 및 방사선치료 조치에 의해 제거될 수 있으며, 전이된 종양의 경우 일반적으로 화학요법제에 의해 완화치료를 하게 된다. Cancer refers to a disease caused by abnormally growing lumps caused by autonomous overgrowth of body tissues and is the result of uncontrolled cell growth in various tissues. Early-stage tumors can be removed by surgery and radiotherapy, and metastatic tumors are generally treated with chemotherapy.
비경구로 투여되는 대다수 화학요법제는 전신 투여의 결과로서 원치 않는 부작용 및 심지어 독성이라는 심각한 효과를 유도할 수 있다. 따라서 종양 세포 또는 바로 인접한 조직에서 이들 화학요법제의 개선된 효능 및 선택적인 적용을 통해 약효 증가 및 독성/부작용의 최소화를 동시에 이루기 위한 신규한 화학요법제의 개발에 초점이 맞추어져 왔다. Many parenterally administered chemotherapy drugs can induce serious effects, such as unwanted side effects and even toxicity, as a result of systemic administration. Therefore, focus has been placed on the development of novel chemotherapy agents to simultaneously increase drug efficacy and minimize toxicity/side effects through improved efficacy and selective application of these chemotherapy agents in tumor cells or immediately adjacent tissues.
항체-약물 접합체(antibody-drug conjugate, ADC)는 항원과 결합하는 항체에 독소 또는 약물을 결합시킨 후 세포 내부에서 독성물질을 방출하면서 암 세포 등을 사멸에 이르게 하는 표적지향성 신기술이다. 건강한 세포에는 최소한으로 영향을 주면서 약물을 타겟 암세포에 정확하게 전달하고, 특정한 조건하에서만 방출되도록 해주기 때문에 항체 치료제 자체보다 효능이 우수하고 기존의 항암제들에 비해 부작용의 위험성을 크게 낮출 수 있는 기술이다. Antibody-drug conjugate (ADC) is a target-oriented new technology that combines a toxin or drug with an antibody that binds to an antigen, then releases toxic substances inside the cell and kills cancer cells. It is a technology that accurately delivers drugs to target cancer cells with minimal impact on healthy cells and releases them only under specific conditions, making them more effective than antibody treatments themselves and significantly lowering the risk of side effects compared to existing anticancer drugs.
이러한 항체-약물 접합체의 기본 구조는 "항체-링커-저분자 약물(독소)"로 구성되어 있다. 여기서 링커는 단순히 항체와 약물을 연결시켜 주는 기능적인 역할뿐 아니라, 체내 순환시 안정하게 타겟 세포까지 도달 후 항체-약물 접합체가 세포 내로 들어가 항체-약물간 해리현상(예, 효소에 의한 가수분해에 의한 결과)에 의해 약물이 잘 떨어지면서 타겟 암세포에 약효를 나타내도록 해야 한다. 즉 링커의 안정성에 따라 항체-약물 접합체의 효능 및 전신독성(systemic toxicity) 등의 안전성 면에서 링커는 매우 중요한 역할을 한다(Discovery Medicine 2010, 10(53): 329-39).The basic structure of this antibody-drug conjugate is composed of “antibody-linker-low molecule drug (toxin).” Here, the linker not only plays a functional role in connecting the antibody and the drug, but also stably reaches the target cell when circulating in the body, and then the antibody-drug conjugate enters the cell, causing dissociation between the antibody and drug (e.g., due to hydrolysis by enzymes). As a result, the drug must be absorbed well and exert its effect on the target cancer cells. In other words, the linker plays a very important role in terms of safety, such as efficacy and systemic toxicity of the antibody-drug conjugate, depending on the stability of the linker (Discovery Medicine 2010, 10(53): 329-39).
한편 암 치료를 위한 단일클론 항체의 사용은 상당한 성공을 거두고 있다. 단일클론 항체는 종양 조직 및 종양 세포의 표적-지향된 어드레싱(addressing)에 적당하다. 항체-약물 접합체들은 림프종과 고형암 치료를 위해 강력하고 새로운 치료의 옵션이 되었으며, 최근 들어 면역 조절 항체들도 임상에서 상당한 성공을 거두고 있다. 치료 항체들의 개발은 암 혈청학, 단백질 엔지니어링 기술과 그 작용, 저항성의 기작들 및 면역 시스템과 암세포들 간의 상호 작용에 대한 깊은 이해를 바탕으로 한다. Meanwhile, the use of monoclonal antibodies for cancer treatment is achieving considerable success. Monoclonal antibodies are suitable for target-directed addressing of tumor tissue and tumor cells. Antibody-drug conjugates have become a powerful new therapeutic option for the treatment of lymphoma and solid tumors, and recently, immunomodulatory antibodies have also achieved significant clinical success. The development of therapeutic antibodies is based on a deep understanding of cancer serology, protein engineering techniques and their actions, mechanisms of resistance, and interactions between the immune system and cancer cells.
인간 암의 세포 표면에서 발현되는 항원의 정의는 정상 조직에 비해 과다 발현되거나 돌연변이 및 선택적으로 발현되는 광범위한 목표물들을 의미한다. 핵심적인 문제는 항체를 기반으로 한 치료법들에 적절한 항원을 동정하는 것이다. 이러한 치료제들은 항원이나 수용체 기능(즉, 자극제로서나 길항제로서의 기능)의 변화를 매개하고 Fc와 T 세포 활성화를 통해 면역 시스템을 조절하며 특정한 항원을 목표로 하는 항체에 결합되는 특정한 약물의 전달을 통해 그 효능을 발휘한다. 항체 약동학(pharmacokinetics), 작용 기능, 사이즈와 면역 자극성을 변화시킬 수 있는 분자 기술들은 새로운 항체를 기반으로 한 치료법들의 개발에서 핵심적인 요소로 등장하고 있다. 암 환자들을 대상으로 한 치료 항체들의 임상 시도에서 얻은 증거들은 목표 항원과 항체들의 친화성 및 결합성, 항체 구조의 선택, 치료적 접근법(신호전달 차단이나 면역 작용 기능)을 포함하는 최적화된 항체들의 선택을 위한 접근법들의 중요성을 강조하고 있다.The definition of antigens expressed on the cell surface of human cancer refers to a wide range of targets that are overexpressed, mutated, or selectively expressed compared to normal tissues. A key problem is identifying appropriate antigens for antibody-based therapies. These therapeutics mediate changes in antigen or receptor function (i.e., function as stimulator or antagonist), modulate the immune system through Fc and T cell activation, and deliver specific drugs that bind to antibodies targeting specific antigens. It exerts its effectiveness. Molecular technologies that can alter antibody pharmacokinetics, action function, size and immunostimulatory properties are emerging as key elements in the development of new antibody-based therapies. Evidence from clinical trials of therapeutic antibodies in cancer patients provides guidance on the optimization of antibodies, including their affinity and binding to target antigens, choice of antibody structure, and therapeutic approach (signal transduction blockade or immunogenic function). The importance of approaches for selection is emphasized.
인간 유래 TROP2(tumor-associated calcium signal transducer 2, TACSTD2)는 323개의 아미노산(274개의 세포외 영역, 23개의 막관통영역, 26개의 세포내 영역)을 가지는 35-46 kDa의 세포막 관통 칼슘신호전달 당단백질로, 세포 신호 전달이나 증식, 분화에 중요한 구성 요소인 EpCAM(Epithelial cell adhesion molecule) family에 속한다. TROP2의 발현이 다양한 암종에서 종양 유발 혹은 종양 억제와 관련이 있으나 대체로 종양 유발 인자로 작용하는 것으로 알려져 있다. Human-derived TROP2 (tumor-associated calcium signal transducer 2, TACSTD2) is a 35-46 kDa transmembrane calcium signaling sugar with 323 amino acids (274 extracellular domains, 23 transmembrane domains, and 26 intracellular domains). With protein, It belongs to the EpCAM (Epithelial cell adhesion molecule) family, which is an important component in cell signaling, proliferation, and differentiation. The expression of TROP2 is associated with tumor induction or tumor suppression in various carcinomas, but it is generally known to act as a tumor inducing factor.
274개의 세포외 영역 중 R87과 T88 사이 영역이 잘리면 TROP2 구조의 재배열이 일어나 생물학적 활성에 변화가 일어난다. 정상 조직에서는 이러한 절단이 일어나지 않지만 피부, 난소, 대장, 유방암을 포함한 대부분의 암종에서는 TROP2 절단이 일어나 종양 유발 인자로 작용하게 된다.Among the 274 extracellular regions, truncation of the region between R87 and T88 causes rearrangement of the TROP2 structure, resulting in changes in biological activity. Although this cleavage does not occur in normal tissues, TROP2 cleavage occurs in most carcinomas, including skin, ovary, colon, and breast cancer, and acts as a tumor-inducing factor.
이러한 기술적 배경하에서, 본 출원의 발명자들은 종양에서 치료 효과를 더욱 강화할 수 있는 치료제를 개발하기 위해 노력한 결과, 혈장 내에서 뿐만 아니라 체내 순환시에도 안정적이며 약물이 암세포에서 쉽게 방출되어 약효를 나타낼 수 있는 효과적인 자가-희생기(self-immolative group)을 포함하는 링커를 종양에서 주로 발현되는 TROP2 형태에 특이적으로 더 강하게 결합하는 항-TROP2 항체에 적용하여, 과증식 및/또는 전이암 질환의 치료 및/또는 예방에 보다 효과적인 TROP2를 타겟팅하는 항체-약물 접합체(ADC)를 제공할 수 있음을 확인함으로써, 본 발명을 완성하게 되었다.Under this technical background, the inventors of the present application made efforts to develop a therapeutic agent that can further enhance the therapeutic effect in tumors, and as a result, a drug that is stable not only in plasma but also when circulating in the body and that can be easily released from cancer cells to exhibit medicinal effects A linker containing an effective self-immolative group is applied to an anti-TROP2 antibody that specifically binds more strongly to the TROP2 form mainly expressed in tumors, thereby treating hyperproliferative and/or metastatic cancer diseases and/ Alternatively, the present invention was completed by confirming that an antibody-drug conjugate (ADC) targeting TROP2 that is more effective in prevention can be provided.
본 발명에서는 혈장 내에서 보다 안정하고 체내 순환시에도 안정적이며, 약물이 암세포 내에서 쉽게 방출되어 약효를 극대화할 수 있는 자가-희생기를 포함하는 링커 기술을 접목시켜, 약물 및/또는 톡신이 표적 세포에 안정적으로 도달하여 약효를 효과적으로 발휘하면서도 독성을 크게 낮출 수 있는, 항체-링커-약물(톡신) 시스템을 제공하고자 한다.In the present invention, a linker technology is applied that includes a self-sacrificial group that is more stable in plasma and stable in body circulation and allows the drug to be easily released within cancer cells to maximize drug efficacy, so that the drug and/or toxin is transferred to the target cell. The goal is to provide an antibody-linker-drug (toxin) system that can stably achieve drug efficacy and significantly reduce toxicity.
이에, 본 발명의 목적은 인간 TROP2(tumor-associated calcium signal transducer 2, TACSTD2)를 타겟팅하는 항체-약물 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물을 제공하는 것이다.Accordingly, the purpose of the present invention is to provide an antibody-drug conjugate targeting human TROP2 (tumor-associated calcium signal transducer 2, TACSTD2), or a pharmaceutically acceptable salt or solvate thereof.
본 발명의 다른 목적은 상기 항체-약물 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물을 포함하는 약학 조성물을 제공하는 것이다. Another object of the present invention is to provide a pharmaceutical composition comprising the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof.
본 발명의 목적을 달성하기 위하여, 본 발명은 하기 일반식 I로 표시되는 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물을 제공한다:In order to achieve the object of the present invention, the present invention provides a conjugate represented by the following general formula (I) or a pharmaceutically acceptable salt or solvate thereof:
[일반식 I][General formula I]
Ab-[LINKER-(B)l]m Ab-[LINKER-(B) l ] m
상기 식에서,In the above equation,
Ab는 중쇄 가변영역 및 경쇄 가변영역을 포함하는 인간 TROP2(tumor-associated calcium signal transducer 2, TACSTD2)에 특이적으로 결합하는 항체 또는 이의 항원 결합 단편이고,Ab is an antibody or antigen-binding fragment thereof that specifically binds to human TROP2 (tumor-associated calcium signal transducer 2, TACSTD2), which includes a heavy chain variable region and a light chain variable region,
상기 항체 또는 이의 항원 결합 단편은The antibody or antigen-binding fragment thereof is
서열번호 2의 아미노산 서열로 이루어진 중쇄 CDR1; 서열번호 4의 아미노산 서열로 이루어진 중쇄 CDR2; 서열번호 6의 아미노산 서열로 이루어진 중쇄 CDR3을 포함하는 중쇄 가변영역; 및Heavy chain CDR1 consisting of the amino acid sequence of SEQ ID NO: 2; Heavy chain CDR2 consisting of the amino acid sequence of SEQ ID NO: 4; A heavy chain variable region comprising a heavy chain CDR3 consisting of the amino acid sequence of SEQ ID NO: 6; and
서열번호 9의 아미노산 서열로 이루어진 경쇄 CDR1; 서열번호 11의 아미노산 서열로 이루어진 경쇄 CDR2; 서열번호 13의 아미노산 서열로 이루어진 경쇄 CDR3을 포함하는 경쇄 가변영역을 포함하며,Light chain CDR1 consisting of the amino acid sequence of SEQ ID NO: 9; Light chain CDR2 consisting of the amino acid sequence of SEQ ID NO: 11; It contains a light chain variable region including a light chain CDR3 consisting of the amino acid sequence of SEQ ID NO: 13,
LINKER는 링커이고,LINKER is a linker,
B는 활성제 모이어티이며,B is the activator moiety,
l 및 m은 각각 독립적으로 1 내지 20 중에서 선택되는 정수이며,l and m are each independently integers selected from 1 to 20,
l이 2 이상의 정수인 경우, B는 각각 서로 동일하거나 상이할 수 있다.When l is an integer of 2 or more, B may be the same or different from each other.
본 발명의 일 양태에서, 상기 항체 또는 이의 항원 결합 단편은 서열번호 15 또는 20의 아미노산 서열; 또는 상기 서열번호 15 또는 20의 아미노산 서열과 적어도 80% 이상의 상동성을 갖는 서열로 이루어진 중쇄 가변영역을 포함할 수 있다.In one aspect of the invention, the antibody or antigen-binding fragment thereof has the amino acid sequence of SEQ ID NO: 15 or 20; Alternatively, it may include a heavy chain variable region consisting of a sequence having at least 80% homology to the amino acid sequence of SEQ ID NO: 15 or 20.
보다 구체적으로, 상기 항체 또는 이의 항원 결합 단편은 서열번호 15 또는 20의 아미노산 서열; 또는 상기 서열번호 15 또는 20의 아미노산 서열과 적어도 80% 이상, 85% 이상, 90% 이상, 95% 이상의 상동성을 갖는 서열로 이루어진 중쇄 가변영역을 포함할 수 있다.More specifically, the antibody or antigen-binding fragment thereof has the amino acid sequence of SEQ ID NO: 15 or 20; Alternatively, it may include a heavy chain variable region consisting of a sequence having at least 80%, 85%, 90%, or 95% homology to the amino acid sequence of SEQ ID NO: 15 or 20.
보다 더 구체적으로, 상기 항체 또는 이의 항원 결합 단편은 서열번호 15 또는 20의 아미노산 서열; 상기 서열번호 15 또는 20의 아미노산 서열과 적어도 90% 이상의 상동성을 갖는 서열; 또는 상기 서열번호 15 또는 20의 아미노산 서열과 적어도 95% 이상의 상동성을 갖는 서열로 이루어진 중쇄 가변영역을 포함할 수 있다.More specifically, the antibody or antigen-binding fragment thereof has the amino acid sequence of SEQ ID NO: 15 or 20; A sequence having at least 90% homology to the amino acid sequence of SEQ ID NO: 15 or 20; Alternatively, it may include a heavy chain variable region consisting of a sequence having at least 95% homology to the amino acid sequence of SEQ ID NO: 15 or 20.
본 발명의 일 양태에서, 상기 항체 또는 이의 항원 결합 단편은 서열번호 16의 아미노산 서열; 또는 상기 서열번호 16의 아미노산 서열과 적어도 80% 이상의 상동성을 갖는 서열로 이루어진 경쇄 가변영역을 포함할 수 있다.In one aspect of the invention, the antibody or antigen-binding fragment thereof has the amino acid sequence of SEQ ID NO: 16; Alternatively, it may include a light chain variable region consisting of a sequence having at least 80% homology to the amino acid sequence of SEQ ID NO: 16.
보다 구체적으로, 상기 항체 또는 이의 항원 결합 단편은 서열번호 16의 아미노산 서열; 또는 상기 서열번호 16의 아미노산 서열과 적어도 80% 이상, 85% 이상, 90% 이상, 95% 이상의 상동성을 갖는 서열로 이루어진 경쇄 가변영역을 포함할 수 있다.More specifically, the antibody or antigen-binding fragment thereof has the amino acid sequence of SEQ ID NO: 16; Alternatively, it may include a light chain variable region consisting of a sequence having at least 80%, 85%, 90%, or 95% homology to the amino acid sequence of SEQ ID NO: 16.
보다 더 구체적으로, 상기 항체 또는 이의 항원 결합 단편은 서열번호 16의 아미노산 서열; 상기 서열번호 16의 아미노산 서열과 적어도 90% 이상의 상동성을 갖는 서열; 또는 상기 서열번호 16의 아미노산 서열과 적어도 95% 이상의 상동성을 갖는 서열로 이루어진 경쇄 가변영역을 포함할 수 있다.More specifically, the antibody or antigen-binding fragment thereof has the amino acid sequence of SEQ ID NO: 16; A sequence having at least 90% homology to the amino acid sequence of SEQ ID NO: 16; Alternatively, it may include a light chain variable region consisting of a sequence having at least 95% homology to the amino acid sequence of SEQ ID NO: 16.
본 발명의 일 양태에서, 상기 항체 또는 이의 항원 결합 단편은 서열번호 15 및 16의 아미노산 서열로 이루어진 중쇄 가변영역 및 경쇄 가변영역 조합; 또는 서열번호 15 및 16의 아미노산 서열에 대해 적어도 80% 이상의 상동성을 갖는 아미노산 서열로 이루어진 중쇄 가변영역 및 경쇄 가변영역 조합을 포함하고, 인간 TROP2에 특이적으로 결합한다.In one aspect of the invention, the antibody or antigen-binding fragment thereof includes a combination of a heavy chain variable region and a light chain variable region consisting of the amino acid sequences of SEQ ID NOs: 15 and 16; or a combination of a heavy chain variable region and a light chain variable region consisting of an amino acid sequence having at least 80% homology to the amino acid sequences of SEQ ID NOs: 15 and 16, and binds specifically to human TROP2.
보다 구체적으로, 상기 항체 또는 이의 항원 결합 단편은 서열번호 15 및 16의 아미노산 서열로 이루어진 중쇄 가변영역 및 경쇄 가변영역 조합; 또는 서열번호 15 및 16의 아미노산 서열에 대해 적어도 80% 이상, 85% 이상, 90% 이상, 95% 이상의 상동성을 갖는 아미노산 서열로 이루어진 중쇄 가변영역 및 경쇄 가변영역 조합을 포함하고, 인간 TROP2에 특이적으로 결합한다.More specifically, the antibody or antigen-binding fragment thereof includes a combination of a heavy chain variable region and a light chain variable region consisting of the amino acid sequences of SEQ ID NOs: 15 and 16; or a combination of a heavy chain variable region and a light chain variable region consisting of an amino acid sequence having at least 80%, 85%, 90%, or 95% homology to the amino acid sequences of SEQ ID NOs: 15 and 16, and human TROP2 Binds specifically.
보다 더 구체적으로, 상기 항체 또는 이의 항원 결합 단편은 서열번호 15 및 16의 아미노산 서열로 이루어진 중쇄 가변영역 및 경쇄 가변영역 조합; 또는 서열번호 15 및 16의 아미노산 서열에 대해 적어도 80% 이상, 81% 이상, 82% 이상, 83% 이상, 84% 이상, 85% 이상, 86% 이상, 87% 이상, 88% 이상, 89% 이상, 90% 이상, 91% 이상, 92% 이상, 93% 이상, 94% 이상, 95% 이상, 96% 이상, 97% 이상, 98% 이상, 99% 이상, 99.5% 이상의 상동성을 갖는 아미노산 서열로 이루어진 중쇄 가변영역 및 경쇄 가변영역 조합을 포함하고, 인간 TROP2에 특이적으로 결합한다.More specifically, the antibody or antigen-binding fragment thereof includes a combination of a heavy chain variable region and a light chain variable region consisting of the amino acid sequences of SEQ ID NOs: 15 and 16; or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% of the amino acid sequences of SEQ ID NOs: 15 and 16. Amino acids with homology of more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, more than 99.5% It contains a combination of heavy chain variable region and light chain variable region sequence, and binds specifically to human TROP2.
본 발명의 일 양태에서, 상기 항체는 인간화 항체(humanized antibody)이다.In one aspect of the invention, the antibody is a humanized antibody.
본 발명의 일 양태에서, 상기 인간화 항체는 In one aspect of the invention, the humanized antibody is
(a)(i) 인간 항체의 중쇄 또는 인간 컨센서스 프레임워크(consensus framework)로부터의 가변 도메인 프레임워크 영역; 및 (ii) 인간 항체의 경쇄 또는 인간 컨센서스 프레임워크로부터의 가변 도메인 프레임워크 영역을 포함하고,(a) (i) the heavy chain of a human antibody or variable domain framework region from the human consensus framework; and (ii) a light chain of a human antibody or a variable domain framework region from a human consensus framework,
(b)(i) 상기 중쇄로부터의 가변 도메인 프레임워크 영역의 적어도 하나의 아미노산은 마우스 항체 또는 마우스 컨센서스 프레임워크의 중쇄로부터의 상응하는 아미노산으로 치환되거나; (ii) 상기 경쇄로부터의 가변 도메인 프레임워크 영역은 마우스 항체 또는 마우스 컨센서스 프레임워크의 경쇄로부터 상응하는 아미노산으로 치환되고, 및(b)(i) at least one amino acid in the variable domain framework region from said heavy chain is replaced with a corresponding amino acid from the heavy chain of a mouse antibody or mouse consensus framework; (ii) the variable domain framework region from the light chain is replaced with the corresponding amino acid from the light chain of the mouse antibody or mouse consensus framework, and
(c) (i) 상기 중쇄의 아미노산 치환은 하기 아미노산 치환으로부터 선택되고:(c) (i) the amino acid substitutions in the heavy chain are selected from the following amino acid substitutions:
위치 27에서 Y(인간) 대신 F(마우스)로 치환;Substitute F (mouse) for Y (human) in position 27;
위치 30에서 T(인간) 대신 S(마우스)로 치환;Substitute S (mouse) for T (human) in position 30;
위치 37에서 V(인간) 대신 L(마우스)로 치환;Substitute L (mouse) for V (human) in position 37;
위치 48에서 M(인간) 대신 I(마우스)로 치환; Substitute I (mouse) for M (human) in position 48;
위치 49에서 G(인간) 대신 A(마우스)로 치환;Substitute A (mouse) for G (human) in position 49;
위치 70에서 I(인간) 대신 L(마우스)로 치환; 및Substitute L (mouse) for I (human) at position 70; and
위치 72에서 R(인간) 대신 V(마우스)로 치환Substitute V (mouse) for R (human) at position 72
(ii) 상기 경쇄의 아미노산 치환은 위치 49에서 Y(인간) 대신 S(마우스)로 치환이다.(ii) The amino acid substitution in the light chain is S (mouse) instead of Y (human) at position 49.
또한, 추가적인 양태에서, 상기 중쇄의 아미노산 치환은 하기 아미노산 치환을 더 포함할 수 있다:Additionally, in a further aspect, the amino acid substitution in the heavy chain may further include the following amino acid substitution:
위치 67에서 R(인간) 대신 K(마우스)로 치환; 및/또는Substitute K (mouse) for R (human) in position 67; and/or
위치 68에서 V(인간) 대신 A(마우스)로 치환.Substitute A (mouse) for V (human) at position 68.
또한, 추가적인 양태에서, 상기 경쇄의 아미노산 치환은 하기 아미노산 치환을 더 포함할 수 있다:Additionally, in a further aspect, the amino acid substitution in the light chain may further include the following amino acid substitution:
위치 67에서 S(인간) 대신 Y(마우스)로 치환;Substitute Y (mouse) for S (human) in position 67;
위치 2에서 I(인간) 대신 T(마우스)로 치환 및 위치 67에서 S(인간) 대신 Y(마우스)로 치환;Substitute T (mouse) for I (human) at position 2 and Y (mouse) for S (human) at position 67;
위치 22에서 T(인간) 대신 R(마우스)로 치환 및 위치 67에서 S(인간) 대신 Y(마우스)로 치환;Substitute R (mouse) for T (human) at position 22 and Y (mouse) for S (human) at position 67;
위치 42에서 K(인간) 대신 E(마우스)로 치환 및 위치 67에서 S(인간) 대신 Y(마우스)로 치환;Substitute E (mouse) for K (human) at position 42 and Y (mouse) for S (human) at position 67;
위치 64에서 G(인간) 대신 S(마우스)로 치환 및 위치 67에서 S(인간) 대신 Y(마우스)로 치환;Substitute S (mouse) for G (human) at position 64 and Y (mouse) for S (human) at position 67;
위치 67에서 S(인간) 대신 Y(마우스)로 치환 및 위치 72에서 T(인간) 대신 V(마우스)로 치환; 또는 Substitute Y (mouse) for S (human) at position 67 and V (mouse) for T (human) at position 72; or
위치 67에서 S(인간) 대신 Y(마우스)로 치환 및 위치 85에서 T(인간) 대신 D(마우스)로 치환.Substitute Y (mouse) for S (human) at position 67 and D (mouse) for T (human) at position 85.
본 발명의 일 양태에서, 상기 항체 또는 이의 항원 결합 단편은 단일클론 항체(monoclonal antibody), 도메인 항체(domain antibody; dAb), 단일 사슬 항체(single chain antibody; scAb), Fab 단편, Fab'단편, F(ab')2 단편, scFab 단편, Fv 단편, dsFv 단편, 단일 사슬 가변 항체(single chain variable fragment; scFv), scFv-Fc 단편, 단일 도메인 중쇄 항체(single domain heavy chain antibody), 단일 도메인 경쇄 항체(single domain light chain antibody), 항체 변이체(variant antibody), 다중 결합 항체(multimeric antibody), 미니바디, 다이아바디, 이중 특이적 항체(bispecific antibody) 및 다중 특이적 항체로 이루어진 군으로부터 선택될 수 있다.In one aspect of the invention, the antibody or antigen-binding fragment thereof is a monoclonal antibody, a domain antibody (dAb), a single chain antibody (scAb), a Fab fragment, a Fab' fragment, F(ab')2 fragment, scFab fragment, Fv fragment, dsFv fragment, single chain variable fragment (scFv), scFv-Fc fragment, single domain heavy chain antibody, single domain light chain Antibodies may be selected from the group consisting of single domain light chain antibodies, antibody variants, multimeric antibodies, minibodies, diabodies, bispecific antibodies, and multispecific antibodies. there is.
본 명세서에서 "링커"는 세포독성 화합물을 항체에 공유결합시키는 화합물을 말한다.As used herein, “linker” refers to a compound that covalently binds a cytotoxic compound to an antibody.
본 발명에 기재된 링커는 절단성, 비절단성, 친수성 또는 소수성 일 수 있다.Linkers described herein may be cleavable, non-cleavable, hydrophilic or hydrophobic.
절단성 링커는 세포 내 조건들 하에서 절단 가능하여 상기 링커의 절단으로 세포 내 환경에서 항체 구조물-활성제 접합체로부터 활성제를 방출한다.A cleavable linker is cleavable under intracellular conditions such that cleavage of the linker releases the activator from the antibody construct-activator conjugate in the intracellular environment.
절단성 링커는 세포 내 환경(예를 들어, 리소좀 또는 엔도좀 또는 카베올레아 (caveolea) 내)에 존재하는 절단제에 의해 절단 가능하다. 절단성 링커는, 예컨대, 리소좀의 또는 엔도좀의 프로테아제를 포함하는 이에 제한되지 않는 세포 내 펩티다아제 또는 프로테아제 효소에 의해 절단되는 펩티딜 링커(peptidyl linker)일 수 있다. 일반적으로, 상기 펩티딜 링커는 적어도 2개의 아미노산 길이 또는 적어도 3개의 아미노산 길이이다. 절단제들은 카텝신 B 및 D 및 플라스민을 포함할 수 있으며, 이들 모두는 디펩타이드 약물 유도체들 가수분해하여 표적 세포들 내에서 활성 약물을 방출하는 것으로 알려져 있다(예를 들어, Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123 참조). 항원 발현 세포들 내에 존재하는 효소들에 의해 절단 가능한 펩티딜 링커들이 가장 일반적이다. 예를 들어, 암 조직에서 고도로 발현되는 티올-의존성 프로테아제 카텝신-B에 의해 절단 가능한 펩티딜 링커가 사용될 수 있다(예를 들어, Phe-Leu 또는 Gly-Phe-Leu-Gly 링커). 다른 이러한 링커들은, 예를 들어, 미국 등록특허 제6,214,345호에서 설명된다. 또한, 세포 내 프로테아제에 의해 절단 가능한 상기 펩티딜 링커는 예를 들어, Val-Cit 링커, Phe-Lys 링커(예를 들어, Val-Cit 링커를 이용한 독소루비신의 합성을 설명하는 미국 등록특허 제6,214,345호 참조) 또는 Val-Ala 링커일 수 있다. Val-Cit 링커 또는 Val-Ala 링커는 펜타플루오로페닐 그룹을 함유할 수 있고, 숙신이미드 그룹 또는 말레이미드 그룹을 함유할 수 있다. 또는, PABA 그룹 및 펜타플루오로페닐 그룹을 함유할 수 있고, 4-아미노벤조산(4-Aminobenzoic acid, PABA) 그룹 및 말레이미드 그룹을 함유할 수 있으며, PABA 그룹 및 숙신이미드 그룹을 함유할 수 있다.Cleavable linkers are cleavable by cleavage agents present in the intracellular environment (e.g., within lysosomes or endosomes or caveolea). Cleavable linkers may be, for example, peptidyl linkers that are cleaved by intracellular peptidase or protease enzymes, including but not limited to lysosomal or endosomal proteases. Typically, the peptidyl linker is at least 2 amino acids long or at least 3 amino acids long. Cleaving agents may include cathepsins B and D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives to release the active drug within target cells (e.g., Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123). Peptidyl linkers that are cleavable by enzymes present in antigen-expressing cells are the most common. For example, a peptidyl linker that is cleavable by the thiol-dependent protease cathepsin-B, which is highly expressed in cancer tissues, can be used (e.g., a Phe-Leu or Gly-Phe-Leu-Gly linker). Other such linkers are described, for example, in US Pat. No. 6,214,345. In addition, the peptidyl linker that is cleavable by intracellular proteases includes, for example, a Val-Cit linker, a Phe-Lys linker (e.g., U.S. Patent No. 6,214,345, which describes the synthesis of doxorubicin using a Val-Cit linker) Reference) or it may be a Val-Ala linker. The Val-Cit linker or Val-Ala linker may contain a pentafluorophenyl group and may contain a succinimide group or a maleimide group. Alternatively, it may contain a PABA group and a pentafluorophenyl group, may contain a 4-Aminobenzoic acid (PABA) group and a maleimide group, and may contain a PABA group and a succinimide group. there is.
본 발명의 명세서에서 사용된 용어 "세포 내 절단된(intracellularly cleaved)" 및 "세포 내 절단(intracellular cleavage)"은 항체 구조물-활성제 접합체에 대한 세포 내부의 대사 과정 또는 반응을 지칭하며, 이로써 활성제(B) 및 항체 구조물(Ab) 사이의 공유 부착, 예를 들어, 링커가 파괴되어 유리 약물 또는 세포 내 항체로부터 분리된 접합체의 다른 대사 산물이 야기된다.As used herein, the terms “intracellularly cleaved” and “intracellular cleavage” refer to a metabolic process or reaction inside a cell for an antibody construct-activator conjugate, thereby producing an activator ( B) and the covalent attachment between the antibody construct (Ab), e.g. the linker, is broken resulting in free drug or other metabolites of the conjugate being separated from the intracellular antibody.
또한, 절단성 링커는 pH-민감, 즉, 특정 pH 값에서 쉽게 가수분해 될 수 있다. 일반적으로, 상기 pH-민감성 링커는 산성 조건들에서 가수분해될 수 있다. 예를 들어, 리소좀에서 가수분해될 수 있는 산-불안정성 링커(예를 들어, 하이드라존(hydrazone), 세미카르바존(semicarbazone), 티오세미카르바존 (thiosemicarbazone), 시스-아코니틱 아미드(cis-aconitic amide), 오쏘에스테르(orthoester), 아세탈, 케탈 등)가 사용될 수 있다 (예를 들어, 미국 등록특허 제5,122,368호; 제5,824,805호; 제5,622,929호; Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123; Neville et al., 1989, Biol. Chem. 264:14653-14661 참조). 이러한 링커들은 혈액과 같은 중성 pH 조건들에서 비교적 안정적이지만 리소좀의 대략적인 pH인 pH 5.5 또는 5.0 미만에서는 불안정하다. 가수분해성 링커의 예로는 티오에테르 링커(예를 들어, 아실하이드라존 결합을 통해 치료제에 부착된 티오에테르와 같은(예를 들어, 미국 등록 특허 제5,622,929호 참조)를 들 수 있다.Additionally, the cleavable linker is pH-sensitive, i.e., can be easily hydrolyzed at certain pH values. In general, the pH-sensitive linker can be hydrolyzed in acidic conditions. For example, acid-labile linkers that can be hydrolyzed in lysosomes (e.g., hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide) -aconitic amide), orthoester, acetal, ketal, etc.) may be used (e.g., U.S. Patent Nos. 5,122,368; 5,824,805; 5,622,929; Dubowchik and Walker, 1999, Pharm. Therapeutics 83 :67-123; Neville et al., 1989, Biol. Chem. 264:14653-14661). These linkers are relatively stable at neutral pH conditions, such as blood, but are unstable at pH 5.5 or below 5.0, which is approximately the pH of lysosomes. Examples of hydrolyzable linkers include thioether linkers (e.g., such as a thioether attached to a therapeutic agent through an acylhydrazone linkage (see, e.g., U.S. Pat. No. 5,622,929).
또한, 링커는 환원 조건들 하에서 절단 가능하다(예를 들어, 디설파이드 링커). 예를 들어, SATA(N-숙신이미딜-5-아세틸티오아세테이트), SPDP(N-숙신이미딜-3-(2-피리딜디티오)프로피오네이트), SPDB(N-숙신이미딜-3-(2-피리딜디티오)부티레이트) 및 SMPT(N-숙신이미딜-옥시카보닐-알파-메틸-알파-(2-피리딜-티오)톨루엔)-, SPDB 및 SMPT를 사용하여 형성될 수 있는 것들을 포함하는 다양한 디설파이드 링커들이 공지되어 있다(예를 들어, Thorpe et al., 1987, Cancer Res. 47:5924-5931; 미국 등록 특허 제4,880,935호 참조).Additionally, the linker is cleavable under reducing conditions (eg, a disulfide linker). For example, SATA (N-succinimidyl-5-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N-succinimidyl- 3-(2-pyridyldithio)butyrate) and SMPT (N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-thio)toluene)-, formed using SPDB and SMPT A variety of disulfide linkers are known, including those that can be (see, e.g., Thorpe et al., 1987, Cancer Res. 47:5924-5931; U.S. Pat. No. 4,880,935).
또한, 링커는 말로네이트 링커(Johnson et al., 1995, Anticancer Res. 15:1387-93), 말레이미도벤조일 링커(Lau et al., 1995, Bioorg-Med-Chem. 3(10):1299-1304), 3'-N-아미드 유사체(Lau et al., 1995, Bioorg-Med-Chem. 3(10):1305-12), 베타-글루쿠로나이드(β-Glucuronide) 링커(Jeffery et al., 2006, Bioconjug Chem. 17(3):832-40), 또는 베타-갈락토사이드(β-galactoside) 링커(Kolodych et al., 2017, Eur J Med Chem. Dec 15;142:376-382)일 수 있다.In addition, the linker is a malonate linker (Johnson et al., 1995, Anticancer Res. 15:1387-93), a maleimidobenzoyl linker (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1299- 1304), 3'-N-amide analog (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1305-12), beta-glucuronide linker (Jeffery et al. ., 2006, Bioconjug Chem. 17(3):832-40), or beta-galactoside linker (Kolodych et al., 2017, Eur J Med Chem. Dec 15;142:376-382 ) can be.
비절단성 링커는 말레이미도카프로일 링커일 수 있다. 말레이미도카프로일 링커는 N-말레이미도메틸사이클로헥산-1-카복실레이트를 포함할 수 있다. 말레이미도카프로일 링커는 숙신이미드 그룹을 함유할 수 있다. 말레이미도카프로일 링커는 펜타플루오로페닐 그룹을 함유할 수 있다. 링커는 말레이미드 그룹과 하나 이상의 폴리에틸렌 글리콜 분자의 조합일 수 있다. 링커는 말레이미도카프로일 그룹과 하나 이상의 폴리에틸렌 글리콜 분자의 조합일 수 있다. 링커는 말레이미드-PEG4 링커일 수 있다. 링커는 숙신이미드 그룹을 함유하는 말레이미도카프로일 링커 및 하나 이상의 폴리에틸렌 글리콜 분자의 조합일 수 있다. 링커는 펜타플루오로페닐 그룹 및 하나 이상의 폴리에틸렌 글리콜 분자를 함유하는 말레이미도카프로일 링커의 조합일 수 있다. 링커는 폴리에틸렌 글리콜 분자에 연결된 말레이미드를 함유할 수 있으며, 여기서 폴리에틸렌 글리콜은 더 많은 링커 가요성을 허용하거나 링커를 길게 사용할 수 있다. 링커는 (말레이미도카프로일)-(발린-시트룰린)-(파라-아미노벤질옥시카보닐) 링커일 수 있다.The non-cleavable linker may be a maleimidocaproyl linker. The maleimidocaproyl linker may include N-maleimidomethylcyclohexane-1-carboxylate. The maleimidocaproyl linker may contain a succinimide group. The maleimidocaproyl linker may contain a pentafluorophenyl group. The linker may be a combination of a maleimide group and one or more polyethylene glycol molecules. The linker may be a combination of a maleimidocaproyl group and one or more polyethylene glycol molecules. The linker may be a maleimide-PEG4 linker. The linker may be a combination of a maleimidocaproyl linker containing a succinimide group and one or more polyethylene glycol molecules. The linker may be a combination of a maleimidocaproyl linker containing a pentafluorophenyl group and one or more polyethylene glycol molecules. The linker may contain a maleimide linked to a polyethylene glycol molecule, where the polyethylene glycol allows for more linker flexibility or the linker may be used as a long linker. The linker may be a (maleimidocaproyl)-(valine-citrulline)-(para-aminobenzyloxycarbonyl) linker.
본 발명의 일 양태에서, 링커는 절단성 링커일 수 있다.In one aspect of the invention, the linker may be a cleavable linker.
본 발명의 일 양태에서, 링커는 프로테아제 절단성 링커, 산-절단성 링커, 디설파이드 링커, 자기-희생기 링커(self-immolative linker) 또는 자기-안정화 링커(self-stabilizing linker), 말로네이트 링커, 말레이미도벤조일 링커, 3'-N-아미드 유사체, 베타-글루쿠로나이드(β-Glucuronide) 링커, 또는 베타-갈락토사이드(β-galactoside) 링커일 수 있다. In one aspect of the invention, the linker is a protease cleavable linker, an acid-cleavable linker, a disulfide linker, a self-immolative linker or a self-stabilizing linker, a malonate linker, It may be a maleimidobenzoyl linker, a 3'-N-amide analog, a beta-glucuronide linker, or a beta-galactoside linker.
본 발명의 일 양태에서, 상기 프로테아제 절단성 링커는 티올반응성 스페이서(thiol-reactive spacer) 또는 디펩타이드를 포함할 수 있고, 보다 구체적으로, 상기 프로테아제 절단성 링커는 티올반응성 말레이미도카프로일 스페이서, 발린-시트룰린 디펩타이드 또는 p-아미노-벤질옥시카보닐 스페이서를 포함할 수 있다.In one aspect of the present invention, the protease cleavable linker may include a thiol-reactive spacer or a dipeptide, and more specifically, the protease cleavable linker may include a thiol-reactive maleimidocaproyl spacer and valine. -citrulline dipeptide or p-amino-benzyloxycarbonyl spacer.
본 발명의 일 양태에서, 상기 산 절단성 링커는 하이드라진(hydrazine) 링커 또는 제4급 암모늄 링커일 수 있다.In one aspect of the present invention, the acid cleavable linker may be a hydrazine linker or a quaternary ammonium linker.
본 발명의 일 양태에서, 상기 링커는 일반식 Ⅱ의 구조를 갖는 것일 수 있다.In one aspect of the present invention, the linker may have a structure of general formula II.
[일반식 Ⅱ][General formula Ⅱ]
상기 식에서, In the above equation,
물결표시는 인간 TROP2에 특이적으로 결합하는 항체 또는 항원 결합단편과 연결되는 부위, * 표시는 활성제와 연결되는 부위를 나타내며;The tilde indicates the site connected to an antibody or antigen-binding fragment that specifically binds to human TROP2, and the * mark indicates the site connected to the activator;
G는 글루쿠론산(glucuronic acid) moiety 또는 이고, 상기 R3은 수소 또는 카르복실 보호기이며, 상기 각각의 R4는 독립적으로 수소 또는 하이드록실 보호기이고;G is a glucuronic acid moiety or and R 3 is hydrogen or a carboxyl protecting group, and each R 4 is independently a hydrogen or hydroxyl protecting group;
R1 및 R2는 각각 독립적으로 수소, C1-8 알킬 또는 C3-8 사이클로알킬이며;R 1 and R 2 are each independently hydrogen, C 1-8 alkyl, or C 3-8 cycloalkyl;
W는 -C(O)-, -C(O)NR'-, -C(O)O-, -SO2NR'-, -P(O)R''NR'-, -SONR'- 또는 -PO2NR'-이고, 상기 C, S 또는 P는 직접적으로 페닐링(phenyl ring)에 결합하며, 상기 R' 및 R''는 각각 독립적으로 수소, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, 모노- 또는 다이- C1-8 알킬아미노, C3-20 헤테로아릴 또는 C6-20아릴인 화합물이고;W is -C(O)-, -C(O)NR'-, -C(O)O-, -SO 2 NR'-, -P(O)R''NR'-, -SONR'- or -PO 2 NR'-, wherein C, S or P is directly bonded to a phenyl ring, and R' and R'' are each independently hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl or C 6-20 aryl;
Z는 독립적으로 수소, C1-8 알킬, 할로겐, 시아노 또는 나이트로이며;Z is independently hydrogen, C 1-8 alkyl, halogen, cyano or nitro;
n은 0 내지 3의 정수이고; n is an integer from 0 to 3;
L은, 하기 A) 또는 B) 중 어느 하나이다:L is either A) or B) below:
A) C1-50 알킬렌 또는 1-50 원자 헤테로알킬렌이며, 하기 중 하나 이상을 만족한다:A) C 1-50 alkylene or 1-50 atom heteroalkylene, satisfying one or more of the following:
(i) L은 하나 이상의 불포화 결합을 포함하고;(i) L contains one or more unsaturated bonds;
(ii) L 내의 2 개의 원자가 치환체와 같은 2가 치환체로 치환되고, 이는 헤테로아릴렌(heteroarylene)을 완성시키며;(ii) two atoms in L are substituted with a divalent substituent, such as a substituent, resulting in a heteroarylene;
(iii) L은 1 내지 50 원자 헤테로알킬렌이고;(iii) L is 1 to 50 atom heteroalkylene;
(iv) 상기 알킬렌은 하나 이상의 C1-20 알킬로 치환되고;(iv) the alkylene is substituted with one or more C 1-20 alkyl;
B) 이소프레노이드 트랜스퍼라제에 의하여 인식될 수 있는 하기 일반식 Ⅲ의 이소프레닐 유도체 유닛을 적어도 하나 이상 포함한다:B) It contains at least one isoprenyl derivative unit of the following general formula III that can be recognized by isoprenoid transferase:
[일반식 Ⅲ][General formula Ⅲ]
본 발명의 일 양태에서, 상기 접합체는 하기 일반식 IIa의 구조를 갖는 것일 수 있다.In one aspect of the present invention, the conjugate may have the structure of the following general formula IIa.
[일반식 IIa][Formula IIa]
상기 식에서,In the above equation,
Ab는 인간 TROP2에 특이적으로 결합하는 항체 또는 이의 항원 결합 단편이고,Ab is an antibody or antigen-binding fragment thereof that specifically binds to human TROP2,
B'는 각각 독립적으로 동일하거나 상이한 활성제이며,B' is each independently the same or different activator,
G는 각각 독립적으로 글루쿠론산 모이어티(glucuronic acid moiety) 또는 이고; G is each independently a glucuronic acid moiety or ego;
상기 R3은 수소 또는 카복실 보호기이며, 상기 각각의 R4는 독립적으로 수소 또는 하이드록실 보호기이고;wherein R 3 is hydrogen or a carboxyl protecting group, and each R 4 is independently a hydrogen or hydroxyl protecting group;
R1 및 R2은 각각 독립적으로 수소, C1-8 알킬 또는 C3-8 사이클로알킬이며;R 1 and R 2 are each independently hydrogen, C 1-8 alkyl, or C 3-8 cycloalkyl;
W은 각각 독립적으로 -C(O)-, -C(O)NR'-, -C(O)O-, -SO2NR'-, -P(O)R''NR'-, -SONR'- 또는 -PO2NR'-이고, 상기 C, S 또는 P는 직접적으로 페닐링(phenyl ring)에 결합하며, 상기 NR'은 L에 결합하고, 상기 R' 및 R''는 각각 독립적으로 수소, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, 모노- 또는 다이-C1-8 알킬아미노, C3-20 헤테로아릴 또는 C6-20아릴이며;.W is each independently -C(O)-, -C(O)NR'-, -C(O)O-, -SO 2 NR'-, -P(O)R''NR'-, -SONR '- or -PO 2 NR'-, wherein C, S or P is directly bonded to a phenyl ring, NR' is bonded to L, and R' and R'' are each independently Hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl or C 6- 20 Aryl;.
Z는 각각 독립적으로 수소, C1-8 알킬, 할로겐, 시아노 또는 나이트로이고;Z is each independently hydrogen, C 1-8 alkyl, halogen, cyano or nitro;
n은 0 내지 3의 정수이며, n이 2 이상의 정수인 경우 각각의 Z는 서로 동일하거나 상이할 수 있고; n is an integer from 0 to 3, and when n is an integer of 2 or more, each Z may be the same or different;
L은 각각 독립적으로, 하기 A) 또는 B) 중 어느 하나이고:L is each independently, either A) or B) below:
A) C1-50 알킬렌 또는 1-50 원자 헤테로알킬렌이며, 하기 중 하나 이상을 만족한다:A) C 1-50 alkylene or 1-50 atom heteroalkylene, satisfying one or more of the following:
(i) L은 하나 이상의 불포화 결합을 포함하고;(i) L contains one or more unsaturated bonds;
(ii) L 내의 2개의 원자가 치환체와 같은 2가 치환체로 치환되고; 이는 헤테로아릴렌(heteroarylene)을 완성시키며;(ii) two atoms in L are substituted with a divalent substituent, such as the substituent; This completes heteroarylene;
(iii) L은 1 내지 50 원자 헤테로알킬렌이고;(iii) L is 1 to 50 atom heteroalkylene;
(iv) 상기 알킬렌은 하나 이상의 C1-20 알킬로 더 치환된다;(iv) said alkylene is further substituted with one or more C 1-20 alkyl;
B) 이소프레노이드 트랜스퍼라제에 의하여 인식될 수 있는 하기 일반식 Ⅲ의 이소프레닐 유도체 유닛을 하나 이상 포함한다:B) comprises at least one isoprenyl derivative unit of the general formula III:
[일반식 Ⅲ][General formula Ⅲ]
; ;
Ab는 물결표시된 부분에 결합되고;Ab is bound to the tilde portion;
l 및 m은 각각 독립적으로 1 내지 20 중에서 선택되는 정수이고,l and m are each independently integers selected from 1 to 20,
l이 2 이상인 경우, 활성제는 각각 동일하거나 상이할 수 있다.When l is 2 or more, the active agents may be the same or different, respectively.
또한, 본 발명은 하기 일반식 IIa로 표시되는 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물을 제공한다:Additionally, the present invention provides a conjugate represented by the following general formula IIa, or a pharmaceutically acceptable salt or solvate thereof:
[일반식 IIa][Formula IIa]
상기 식에서,In the above equation,
Ab는 인간 TROP2에 특이적으로 결합하는 항체 또는 이의 항원 결합 단편이고,Ab is an antibody or antigen-binding fragment thereof that specifically binds to human TROP2,
G는 각각 독립적으로 글루쿠론산 모이어티(glucuronic acid moiety) 또는 이고; G is each independently a glucuronic acid moiety or ego;
상기 R3은 수소 또는 카복실 보호기이며, 상기 각각의 R4는 독립적으로 수소 또는 하이드록실 보호기이고;wherein R 3 is hydrogen or a carboxyl protecting group, and each R 4 is independently a hydrogen or hydroxyl protecting group;
R1 및 R2은 각각 독립적으로 수소, C1-8 알킬 또는 C3-8 사이클로알킬이며;R 1 and R 2 are each independently hydrogen, C 1-8 alkyl, or C 3-8 cycloalkyl;
W은 각각 독립적으로 -C(O)-, -C(O)NR'-, -C(O)O-, -SO2NR'-, -P(O)R''NR'-, -SONR'- 또는 -PO2NR'-이고, 상기 C, S 또는 P는 직접적으로 페닐링(phenyl ring)에 결합하며, 상기 NR'은 L에 결합하고, 상기 R' 및 R''는 각각 독립적으로 수소, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, 모노- 또는 다이-C1-8 알킬아미노, C3-20 헤테로아릴 또는 C6-20아릴이며;W is each independently -C(O)-, -C(O)NR'-, -C(O)O-, -SO 2 NR'-, -P(O)R''NR'-, -SONR '- or -PO 2 NR'-, wherein C, S or P is directly bonded to a phenyl ring, NR' is bonded to L, and R' and R'' are each independently Hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl or C 6- 20 is aryl;
Z는 각각 독립적으로 수소, C1-8 알킬, 할로겐, 시아노 또는 나이트로이고;Z is each independently hydrogen, C 1-8 alkyl, halogen, cyano or nitro;
n은 0 내지 3의 정수이며; n is an integer from 0 to 3;
L은 각각 독립적으로, 하기 A) 또는 B) 중 어느 하나이고:L is each independently, either A) or B) below:
A) C1-50 알킬렌 또는 1-50 원자 헤테로알킬렌이며, 하기 중 하나 이상을 만족한다:A) C 1-50 alkylene or 1-50 atom heteroalkylene, satisfying one or more of the following:
(i) L은 하나 이상의 불포화 결합을 포함하고;(i) L contains one or more unsaturated bonds;
(ii) L 내의 2개의 원자가 치환체와 같은 2가 치환체로 치환되고; 이는 헤테로아릴렌(heteroarylene)을 완성시키며;(ii) two atoms in L are substituted with a divalent substituent, such as the substituent; This completes heteroarylene;
(iii) L은 1 내지 50 원자 헤테로알킬렌이고;(iii) L is 1 to 50 atom heteroalkylene;
(iv) 상기 알킬렌은 하나 이상의 C1-20 알킬로 치환된다;(iv) the alkylene is substituted with one or more C 1-20 alkyl;
B) 이소프레노이드 트랜스퍼라제에 의하여 인식될 수 있는 하기 일반식 Ⅲ의 이소프레닐 유도체 유닛을 하나 이상 포함한다:B) comprises at least one isoprenyl derivative unit of the general formula III:
[일반식 Ⅲ][General formula Ⅲ]
; ;
B'는 활성제이고,B' is the activator,
Ab는 물결표시된 부분에 결합되고;Ab is bound to the tilde portion;
l 및 m은 각각 독립적으로 1 내지 20 중에서 선택되는 정수이고,l and m are each independently integers selected from 1 to 20,
l이 2 이상인 경우, 활성제는 각각 동일하거나 상이할 수 있다.When l is 2 or more, the active agents may be the same or different, respectively.
본 발명의 일 양태에서, 상기 G는 글루쿠론산 모이어티(glucuronic acid moiety) 또는 하기 화학식 (IIIa) 구조의 화합물이다:In one aspect of the invention, G is a glucuronic acid moiety or a compound having the structure of formula (IIIa):
[화학식 (IIIa)][Formula (IIIa)]
여기에서,From here,
R3는 수소 또는 카르복실 보호기이고,R 3 is hydrogen or a carboxyl protecting group,
각 R4는 각각 독립적으로 수소 또는 하이드록실 보호기이다.Each R 4 is independently a hydrogen or hydroxyl protecting group.
본 발명의 일 양태에서, 상기 G는 각각 독립적으로 이고,In one aspect of the present invention, each G is independently ego,
R3은 수소 또는 카복실 보호기이며,R 3 is hydrogen or a carboxyl protecting group,
상기 각각의 R4는 독립적으로 수소 또는 하이드록실 보호기이다.Each of R 4 is independently hydrogen or hydroxyl protecting group.
본 발명의 일 양태에서, 상기 R3는 수소이고, 각 R4는 수소이다. In one aspect of the present invention, R 3 is hydrogen, and each R 4 is hydrogen.
본 발명의 일 양태에서, 상기 R1 및 R2는 각각 수소이다.In one aspect of the present invention, R 1 and R 2 are each hydrogen.
또한, 상기 Z는 각각 독립적으로 수소, C1-8 알킬, 할로겐, 시아노 또는 니트로이다.Additionally, Z is each independently hydrogen, C 1-8 alkyl, halogen, cyano, or nitro.
또한, 상기 W는 -C(O)-, -C(O)NR'- 또는 -C(O)O-이고, 보다 구체적으로 상기 W는 -C(O)NR'-이며, 여기에서 C(O)가 페닐링과 연결되고, NR'은 L에 결합된다. 여기에서, 상기 R'은 수소, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, 모노- 또는 다이- C1-8 알킬아미노, C3-20 헤테로아릴 또는 C6-20아릴이다.In addition, the W is -C(O)-, -C(O)NR'-, or -C(O)O-, and more specifically, the W is -C(O)NR'-, where C ( O) is connected to the phenyl ring, and NR' is connected to L. Here, R' is hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di- C 1-8 alkylamino, C 3- 20 heteroaryl or C 6-20 aryl.
또한, 상기 n은 0, 1, 2 또는 3이고, 보다 구체적으로 0, 1 또는 2이며, 보다 더 구체적으로 0이다.In addition, n is 0, 1, 2 or 3, more specifically 0, 1 or 2, and even more specifically 0.
보다 구체적으로, 상기 G는 하기 화학식 (IIIa) 구조의 화합물이고:More specifically, G is a compound having the structure of formula (IIIa):
[화학식 (IIIa)][Formula (IIIa)]
여기에서,From here,
R3는 수소 또는 카르복실 보호기이고,R 3 is hydrogen or a carboxyl protecting group,
각 R4는 각각 독립적으로 수소 또는 하이드록실 보호기이며,Each R 4 is independently a hydrogen or hydroxyl protecting group,
W는 -C(O)NR'-이고, 여기에서 C(O)가 페닐링과 연결되며 NR'은 L에 결합하며, 각 Z는 C1-8 알킬, 할로겐, 시아노 또는 니트로이며, n은 0이고, m은 1이며, R1 및 R2는 각각 수소이다.W is -C(O)NR'-, wherein C(O) is linked to the phenyl ring and NR' is linked to L, each Z is C 1-8 alkyl, halogen, cyano or nitro, and n is 0, m is 1, and R 1 and R 2 are each hydrogen.
본 발명의 일 양태에서, 최소 하나의 L은 1 내지 100개의 탄소 원자를 갖는 알킬렌이고, 여기에서 알킬렌의 탄소 원자는, N, O 및 S로 이루어진 그룹으로부터 선택되는 하나 또는 그 이상의 헤테로원자로 치환될 수 있으며, 알킬렌은 1 내지 20개의 탄소원자를 갖는 하나 이상의 알킬로 더 치환될 수 있다.In one aspect of the invention, at least one L is an alkylene having 1 to 100 carbon atoms, wherein the carbon atoms of the alkylene are one or more heteroatoms selected from the group consisting of N, O and S. Alkylene may be further substituted with one or more alkyls having 1 to 20 carbon atoms.
구체적으로, 최소 하나의 L은 C1-50 알킬렌 또는 1-50 원자 헤테로알킬렌이고, 하기 중 하나 이상을 만족할 수 있다:Specifically, at least one L is C 1-50 alkylene or 1-50 atom heteroalkylene, and may satisfy one or more of the following:
(i) 하나 이상의 불포화 결합을 포함하고;(i) contains one or more unsaturated bonds;
(ii) L 내의 2 개의 원자가 치환체와 같은 2가 치환체로 치환되고; 이는 헤테로아릴렌(heteroarylene)을 완성시키며(ii) two atoms in L are substituted with a divalent substituent, such as the substituent; This completes heteroarylene and
(iii) L은 1 내지 50 원자 헤테로알킬렌이고;(iii) L is 1 to 50 atom heteroalkylene;
(iv) 상기 알킬렌은 하나 이상의 C1-20 알킬로 치환된다.(iv) the alkylene is substituted with one or more C 1-20 alkyl.
또한, 상기 최소 하나의 L은 질소 함유 1-50 원자 헤테로알킬렌이고, 링커는 친수성 아미노산의 2 이상의 원자를 포함하며, 상기 질소는 친수성 아미노산의 카르보닐과 펩타이드 결합을 형성할 수 있다. In addition, the at least one L is a nitrogen-containing 1-50 atom heteroalkylene, the linker includes two or more atoms of a hydrophilic amino acid, and the nitrogen can form a peptide bond with the carbonyl of the hydrophilic amino acid.
본 발명의 일 양태에서, L은 C2-50 알킬렌, C2-50 헤테로알킬렌, 친수성 아미노산, -C(O)-, -C(O)NR''-, -C(O)O-, -(CH2)s-NHC(O)-(CH2)t-, -(CH2)u-C(O)NH-(CH2)v-, -(CH2)s-NHC(O)-(CH2)t-C(O)-, -(CH2)u-C(O)NH-(CH2)v-C(O)-, -S(O)2NR''-, -P(O)R'''NR''-, -S(O)NR''-, 또는 -PO2NR''- 이고, In one aspect of the invention, L is C 2-50 alkylene, C 2-50 heteroalkylene, hydrophilic amino acid, -C(O)-, -C(O)NR''-, -C(O)O -, -(CH 2 ) s -NHC(O)-(CH 2 ) t -, -(CH 2 ) u -C(O)NH-(CH 2 ) v -, -(CH 2 ) s -NHC( O)-(CH 2 ) t -C(O)-, -(CH 2 ) u -C(O)NH-(CH 2 ) v -C(O)-, -S(O) 2 NR''- , -P(O)R'''NR''-, -S(O)NR''-, or -PO 2 NR''-,
여기에서, R'' 및 R'''는 각각 독립적으로 수소, C1-8알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, 모노- 또는 디-C1-8 알킬아미노, C3-20 헤테로아릴 또는 C5-20 아릴이며, s, t, u 및 v는 각각 독립적으로 0 내지 10의 정수이다.Here, R'' and R''' are each independently hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1 -8 alkylamino, C 3-20 heteroaryl or C 5-20 aryl, and s, t, u and v are each independently integers from 0 to 10.
본 발명의 일 양태에서, 상기 L은 질소 함유 1-5 원자 헤테로 알킬렌이고, 상기 링커는 친수성 아미노산의 2 이상의 원자를 포함하며, 상기 질소는 친수성 아미노산의 카르보닐과 펩타이드 결합을 형성한다.In one aspect of the present invention, L is a nitrogen-containing 1-5 membered heteroalkylene, the linker includes two or more atoms of a hydrophilic amino acid, and the nitrogen forms a peptide bond with the carbonyl of the hydrophilic amino acid.
본 발명의 일 양태에서, 상기 L은 티오에테르 결합에 의해 항체와 공유결합하고, 상기 티오에테르 결합은 항체의 시스테인의 황원자를 포함한다.In one aspect of the present invention, L is covalently bonded to the antibody through a thioether bond, and the thioether bond includes a sulfur atom of the cysteine of the antibody.
본 발명의 일 양태에서, 최소 하나의 L은 친수성 아미노산(hydrophilic amino acid)이다.In one aspect of the invention, at least one L is a hydrophilic amino acid.
본 발명의 일 양태에서, 친수성 아미노산은 아르기닌, 아스파테이트, 아스파라긴, 글루타메이트, 글루타민, 히스티딘, 리신, 오르니틴, 프롤린, 세린, 또는 트레오닌일 수 있다.In one aspect of the invention, the hydrophilic amino acid may be arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine, or threonine.
본 발명의 일 양태에서, 친수성 아미노산은 수용액에서 중성 pH에서 전하를 갖는 잔기를 갖는 측쇄를 포함하는 아미노산일 수 있다.In one aspect of the invention, the hydrophilic amino acid may be an amino acid comprising a side chain having a charged residue at neutral pH in aqueous solution.
본 발명의 일 양태에서, 친수성 아미노산은 아스파테이트 또는 글루타메이트이다.In one aspect of the invention, the hydrophilic amino acid is aspartate or glutamate.
본 발명의 일 양태에서, 친수성 아미노산은 오르니틴 또는 리신이다.In one aspect of the invention, the hydrophilic amino acid is ornithine or lysine.
본 발명의 일 양태에서, 친수성 아미노산은 아르기닌이다.In one aspect of the invention, the hydrophilic amino acid is arginine.
본 발명의 일 양태에서, 최소 하나의 L은 -C(O)-, -C(O)NR''-, -C(O)O-, -S(O)2NR''-, -P(O)R'''NR''-, -S(O)NR''-, 또는 -PO2NR''-이고, R'' 및 R'''은 각각 독립적으로 수소, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, 모노- 또는 디-C1-8 알킬아미노, C3-20 헤테로아릴, 또는 C6-20 아릴이다.In one aspect of the invention, at least one L is -C(O)-, -C(O)NR''-, -C(O)O-, -S(O) 2 NR''-, -P (O)R'''NR''-, -S(O)NR''-, or -PO 2 NR''-, and R'' and R''' are each independently hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl, or C 6-20 aryl.
본 발명의 일 양태에서, 최소 하나의 L은 -C(O)NR''-, -(CH2)s-NHC(O)-(CH2)t-, -(CH2)u-C(O)NH-(CH2)v-, -(CH2)s-NHC(O)-(CH2)t-C(O)-, 또는 -(CH2)u-C(O)NH-(CH2)v-C(O)-이고, 여기에서, R''은 수소, C1-5 알킬, C3-8 사이클로알킬, C1-5 알콕시, C3-20 헤테로아릴, 또는 C6-20 아릴이며, s, t, u 및 v는 각각 독립적으로 0 내지 10의 정수이다.In one aspect of the invention, at least one L is -C(O)NR''-, -(CH 2 ) s -NHC(O)-(CH 2 ) t -, -(CH 2 ) u -C( O)NH-(CH 2 ) v -, -(CH 2 ) s -NHC(O)-(CH 2 ) t -C(O)-, or -(CH 2 ) u -C(O)NH-( CH 2 ) v -C(O)-, where R'' is hydrogen, C 1-5 alkyl, C 3-8 cycloalkyl, C 1-5 alkoxy, C 3-20 heteroaryl, or C 6 -20 is aryl, and s, t, u and v are each independently integers from 0 to 10.
본 발명의 일 양태에서, 최소 하나의 L은 -C(O)NR''- 이고, R''은 수소이다.In one aspect of the invention, at least one L is -C(O)NR''- and R'' is hydrogen.
본 발명의 일 양태에서, 최소 하나의 L은 -(CH2)s-NHCO-이고, s는 1 내지 5의 정수이다.In one aspect of the invention, at least one L is -(CH 2 ) s -NHCO-, and s is an integer from 1 to 5.
본 발명의 일 양태에서, 최소 하나의 L은 -(CH2)u-C(O)NH-(CH2)v-C(O)-이고, u는 1 내지 5의 정수이며, v는 1 내지 5의 정수이다.In one aspect of the invention, at least one L is -(CH 2 ) u -C(O)NH-(CH 2 ) v -C(O)-, u is an integer from 1 to 5, and v is 1. It is an integer from 5 to 5.
본 발명의 일 양태에서, L은, In one aspect of the present invention, L is,
, , 또는 을 포함하고, , , or Including,
여기에서 L1은 직접 결합 또는 1 내지 30개의 탄소원자를 갖는 알킬렌이고, R11은 수소 또는 1 내지 10개의 탄소원자를 갖는 알킬이며, L2는 1 내지 30개의 탄소원자를 갖는 알킬렌이다.Here, L 1 is a direct bond or alkylene having 1 to 30 carbon atoms, R 11 is hydrogen or alkyl having 1 to 10 carbon atoms, and L 2 is alkylene having 1 to 30 carbon atoms.
본 발명의 일 양태에서, 상기 L은 일반식 VIII 또는 일반식 IX로 표시되는 제2 유닛을 더 포함한다.In one aspect of the present invention, L further includes a second unit represented by Formula VIII or Formula IX.
본 발명의 일 양태에서, 최소 하나의 제2 유닛은 일반식 VIII 또는 일반식 IX로 표시된다:In one aspect of the invention, the at least one second unit is represented by Formula VIII or Formula IX:
[일반식 VIII][Formula VIII]
-(CH2)r(V(CH2)p)q--(CH 2 ) r (V(CH 2 ) p ) q -
[일반식 IX][Formula IX]
-(CH2CH2X)w--( CH 2 CH 2
상기 V는 단일결합, -O-, -S-, -NR21-, -C(O)NR22-, -NR23C(O)-, -NR24SO2- 또는 -SO2NR25-이고;The V is a single bond, -O-, -S-, -NR 21 -, -C(O)NR 22 -, -NR 23 C(O)-, -NR 24 SO 2 - or -SO 2 NR 25 - ego;
X는 -O-, C1-8 알킬렌 또는 -NR21-이며; X is -O-, C 1-8 alkylene or -NR 21 -;
R21 내지 R25는 각각 독립적으로 수소, C1-6 알킬, C1-6 알킬 C6-20 아릴 또는 C1-6 알킬 C3-20 헤테로아릴이고;R 21 to R 25 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkyl C 6-20 aryl, or C 1-6 alkyl C 3-20 heteroaryl;
r은 0 내지 10의 정수이며;r is an integer from 0 to 10;
p는 0 내지 10의 정수이고;p is an integer from 0 to 10;
q는 1 내지 20의 정수이며; 및q is an integer from 1 to 20; and
w는 1 내지 20의 정수이다.w is an integer from 1 to 20.
본 발명의 일 양태에서, q는 4 내지 20일 수 있고, 보다 구체적으로 5 내지 20일 수 있다. 또한, q는 1 내지 10, 또는 2 내지 12일 수 있고, 보다 구체적으로 2, 4, 5, 또는 11일 수 있다. 또한, r은 1 또는 2일 수 있다. 또한, p는 1 또는 2일 수 있다. 또한, V는 -O-일 수 있다.In one aspect of the present invention, q may be 4 to 20, more specifically 5 to 20. Additionally, q may be 1 to 10, or 2 to 12, and more specifically may be 2, 4, 5, or 11. Additionally, r may be 1 or 2. Additionally, p may be 1 or 2. Additionally, V may be -O-.
보다 구체적으로, r은 2이고, p는 2이며, q는 2, 4, 5 또는 11이고, V는 -O-일 수 있다.More specifically, r may be 2, p may be 2, q may be 2, 4, 5, or 11, and V may be -O-.
또한, 본 발명의 일 양태에서, X는 -O-일 수 있다. 또한, w는 4 내지 20의 정수일 수 있다.Additionally, in one aspect of the present invention, X may be -O-. Additionally, w may be an integer of 4 to 20.
보다 구체적으로, X는 -O-이고, w는 1 내지 10, 또는 4 내지 20일 수 있다.More specifically, X may be -O-, and w may be 1 to 10, or 4 to 20.
본 발명의 일 양태에서, 최소 하나의 제2 유닛은 최소 하나의 폴리에틸렌 글리콜 유닛이고, 또는 의 구조를 가지며, 여기서 n은 1 내지 12이다.In one aspect of the invention, the at least one second unit is at least one polyethylene glycol unit, or It has the structure of, where n is 1 to 12.
본 발명의 일 양태에서, 최소 하나의 제2 유닛은 1 내지 12 -OCH2CH2-유닛, 또는 3 내지 12 -OCH2CH2-유닛, 또는 5 내지 12 -OCH2CH2-유닛, 또는 6 내지 12 -OCH2CH2-유닛, 또는 3 -OCH2CH2-유닛이다.In one aspect of the invention, the at least one second unit is 1 to 12 -OCH 2 CH 2 -units, or 3 to 12 -OCH 2 CH 2 -units, or 5 to 12 -OCH 2 CH 2 -units, or 6 to 12 -OCH 2 CH 2 -units, or 3 -OCH 2 CH 2 -units.
본 발명의 일 양태에서, 최소 하나의 제2 유닛은 -(CH2CH2X)w-이고, In one aspect of the invention, the at least one second unit is -(CH 2 CH 2
여기에서 X는 단일 결합, -O-, C1-8 알킬렌, 또는 -NR21-이고;where X is a single bond, -O-, C 1-8 alkylene, or -NR 21 -;
R21은 수소, C1-6 알킬, C1-6 알킬-C6-20아릴, 또는 C1-6알킬-C3-20 헤테로아릴이며, w는 1 내지 20의 정수이고, 구체적으로는 1, 3, 6, 또는 12이다.R 21 is hydrogen, C 1-6 alkyl, C 1-6 alkyl-C 6-20 aryl, or C 1-6 alkyl-C 3-20 heteroaryl, w is an integer of 1 to 20, specifically It is 1, 3, 6, or 12.
본 발명의 일 양태에서 X는 -O-이고, w는 6 내지 20의 정수이다.In one aspect of the invention, X is -O-, and w is an integer from 6 to 20.
구체적인 본 발명의 일 양태에서, 상기 L은 옥심을 포함하고, 적어도 하나의 폴리에틸렌 글리콜 유닛은 옥심을 활성제에 공유 결합시킨다.In one specific aspect of the present invention, L comprises an oxime, and at least one polyethylene glycol unit covalently binds the oxime to the active agent.
본 발명의 일 양태에서, 링커는 1,3-양극성고리 첨가반응(1,3-dipolar cycloaddition reactions), 헤테로-디엘스-올더 반응(hetero-Diels-Alder reactions), 친핵성 치환(nucleophilic substitution) 반응, 비-알돌형 카르보닐 반응(non-aldol type carbonyl reactions), 탄소-탄소 다중 결합 첨가(addition to carbon-carbon multiple bond), 산화 반응(osidation reactions) 또는 클릭 반응(click reactions)에 의해 형성된 제3 유닛을 포함한다.In one aspect of the invention, the linker undergoes 1,3-dipolar cycloaddition reactions, hetero-Diels-Alder reactions, and nucleophilic substitution. reactions, non-aldol type carbonyl reactions, addition to carbon-carbon multiple bond, oxidation reactions or click reactions. Includes a third unit.
본 발명의 일 양태에서, 제3 유닛은 알카인 및 아자이드 사이의 반응, 또는 알데하이드 또는 케톤기 및 하이드라진 또는 알콕시아민 사이의 반응에 의해 형성된다.In one aspect of the invention, the third unit is formed by a reaction between an alkyne and an azide, or between an aldehyde or ketone group and a hydrazine or alkoxyamine.
본 발명의 일 양태에서, 상기 L은 하기 일반식 Ⅳa, Ⅳb, Ⅳc, Ⅳd, 또는 Ⅳe로 표시되는 제3 유닛을 더 포함한다.In one aspect of the present invention, L further includes a third unit represented by the following general formula IVa, IVb, IVc, IVd, or IVe.
[일반식 Ⅳa][General formula Ⅳa]
[일반식 Ⅳb][General formula Ⅳb]
[일반식 Ⅳc][General formula Ⅳc]
[일반식 Ⅳd][General formula Ⅳd]
[일반식 Ⅳe][General formula Ⅳe]
상기 식에서, L1은 단일 결합 또는 1 내지 30개의 탄소원자를 갖는 알킬렌이고,In the above formula, L 1 is a single bond or alkylene having 1 to 30 carbon atoms,
R11은 수소 또는 C1-10의 알킬이다.R 11 is hydrogen or C 1-10 alkyl.
본 발명의 일 양태에서, 제3 유닛은,In one aspect of the invention, the third unit is:
, , 또는 을 포함하고, , , or Including,
여기에서,From here,
L1은 단일 결합 또는 1 내지 30개의 탄소원자를 갖는 알킬렌이고, 바람직하게는 10, 11, 12, 13, 14, 15 또는 16개의 탄소원자를 갖는 알킬렌이며;L 1 is a single bond or alkylene having 1 to 30 carbon atoms, preferably alkylene having 10, 11, 12, 13, 14, 15 or 16 carbon atoms;
R11은 수소 또는 1 내지 10개의 탄소원자를 갖는 알킬이고, 구체적으로 메틸이고,R 11 is hydrogen or alkyl having 1 to 10 carbon atoms, specifically methyl,
L2는 1 내지 30개의 탄소원자를 갖는 알킬렌이다.L 2 is alkylene having 1 to 30 carbon atoms.
본 발명의 일 양태에서, 상기 L1 및 L2는 각각 독립적으로 단일결합 또는 C1-30의 알킬렌이고; R11은 수소 또는 C1-10의 알킬이다.In one aspect of the present invention, L 1 and L 2 are each independently a single bond or C 1-30 alkylene; R 11 is hydrogen or C 1-10 alkyl.
본 발명의 일 양태에서, L1은 단일 결합, 또는 11개의 탄소원자를 갖는 알킬렌, 또는 12개의 탄소원자를 갖는 알킬렌이다.In one aspect of the invention, L 1 is a single bond, or alkylene having 11 carbon atoms, or alkylene having 12 carbon atoms.
또한, 본 발명의 일 양태에서, 제3 유닛은 또는 을 포함하고,Additionally, in one aspect of the invention, the third unit is or Including,
상기 V는 단일 결합 , -O-, -S-, -NR21-, -C(O)NR22-, -NR23C(O)-, -NR24SO2-, 또는 -SO2NR25-이며;The V is a single bond, -O-, -S-, -NR 21 -, -C(O)NR 22 -, -NR 23 C(O)-, -NR 24 SO 2 -, or -SO 2 NR 25 -is;
R21 내지 R25는 각각 독립적으로 수소, C1-6 알킬, C1-6 알킬 C6-20 아릴, 또는 C1-6 알킬 C3-20 헤테로아릴이고;R 21 to R 25 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkyl C 6-20 aryl, or C 1-6 alkyl C 3-20 heteroaryl;
r은 1 내지 10의 정수이며;r is an integer from 1 to 10;
p는 0 내지 10의 정수이고;p is an integer from 0 to 10;
q는 1 내지 20의 정수이며; 및q is an integer from 1 to 20; and
L1은 단일결합이다.L 1 is a single bond.
본 발명의 일 양태에서, 상기 r은 2 또는 3일 수 있다. 또한, p는 1 또는 2일 수 있다. 또한, q는 1 내지 6일 수 있다.In one aspect of the present invention, r may be 2 or 3. Additionally, p may be 1 or 2. Additionally, q may be 1 to 6.
보다 구체적으로, 상기 제3 유닛에서 r은 2 또는 3; p는 1 또는 2; q는 1 내지 6일 수 있다.More specifically, in the third unit r is 2 or 3; p is 1 or 2; q may be 1 to 6.
또한, 본 발명의 일 양태에서, 상기 제3 유닛을 포함하는 링커는 Additionally, in one aspect of the present invention, the linker comprising the third unit is
, , 또는 일 수 있고, 여기에서 물결표시는 항체 구조물과 연결되는 부위, * 표시는 활성제와 연결되는 부위를 나타내며, n은 0 내지 20의 정수이다. , , or It may be, where the tilde indicates the site connected to the antibody structure, the * sign indicates the site connected to the activator, and n is an integer from 0 to 20.
본 발명의 일 양태에서, 제3 유닛은 또는 을 포함한다.In one aspect of the invention, the third unit is or Includes.
또한, 본 발명의 일 양태에서, 링커는 전구체 상태에서 를 포함한다. 또한, 상기 구조에서 알카인 및 아자이드 사이의 반응, 상세하게는 클릭 반응에 의해 제3 유닛을 형성할 수 있다.Additionally, in one aspect of the present invention, the linker is in the precursor state. Includes. Additionally, in the above structure, a third unit can be formed through a reaction between an alkyne and an azide, specifically a click reaction.
본 발명의 일 양태에서, 링커는 전구체 상태에서 를 포함하고, 상기 구조를 통해 제3 유닛을 형성할 수 있으며, 제3 유닛은 를 포함한다.In one aspect of the invention, the linker is in the precursor state It includes, and a third unit can be formed through the structure, and the third unit is Includes.
본 발명의 일 양태에서, 상기 L은 옥심을 포함하는 3 내지 50 헤테로알킬렌이고, In one aspect of the present invention, L is 3 to 50 heteroalkylene containing an oxime,
상기 옥심의 산소 원자는 W와 연결된 L의 측면에 있으며, 옥심의 탄소 원자는 Ab에 연결된 L의 측면에 있거나; 또는The oxygen atom of the oxime is on the side of L linked to W, and the carbon atom of the oxime is on the side of L linked to Ab; or
상기 옥심의 탄소 원자는 W에 연결된 L의 측면에 있으며, 옥심의 산소 원자는 Ab에 연결된 L의 측면에 있는 것이다.The carbon atom of the oxime is on the side of L connected to W, and the oxygen atom of the oxime is on the side of L connected to Ab.
본 발명의 일 양태에서, 상기 L은 옥심을 포함하고, 하나 이상의 이소프레닐 유닛은 옥심을 Ab에 공유 결합시키는 것이다.In one aspect of the invention, L comprises an oxime, and one or more isoprenyl units covalently bind the oxime to the Ab.
본 발명의 일 양태에서, 링커는 의 구조를 갖는 최소 하나 이상의 이소프레닐 유닛을 추가로 함유할 수 있으며, 여기에서 n은 최소 2 이상이다.In one aspect of the invention, the linker is It may additionally contain at least one isoprenyl unit having the structure, where n is at least 2 or more.
본 발명의 일 양태에서, 최소 하나의 이소프레닐 유닛은 이소프레노이드 트랜스퍼라제의 기질 또는 이소프레노이드 트랜스퍼라제의 생성물이다.In one aspect of the invention, the at least one isoprenyl unit is a substrate of isoprenoid transferase or a product of isoprenoid transferase.
본 발명의 일 양태에서, 링커의 이소프레닐 유닛은 티오에테르 결합에 의해 항체와 공유결합하며, 티오에테르 결합은 항체 구조물의 시스테인의 황원자를 포함한다.In one aspect of the invention, the isoprenyl unit of the linker is covalently bound to the antibody by a thioether bond, and the thioether bond includes a sulfur atom of cysteine of the antibody structure.
또한, 이소프레닐 유닛은 링커에 포함된 옥심을 항체 구조물에 공유 결합시킬 수 있다.Additionally, the isoprenyl unit can covalently link the oxime included in the linker to the antibody structure.
본 발명의 일 양태에서, 항체 구조물은 이소프레노이드 트랜스퍼라제에 의해 인식되는 아미노산 모티프를 포함하고, 티오에테르 결합은 아미노산 모티프의 시스테인의 황원자를 포함한다.In one aspect of the invention, the antibody construct includes an amino acid motif recognized by isoprenoid transferase, and the thioether bond includes the sulfur atom of the cysteine of the amino acid motif.
본 발명의 일 양태에서, 항체 구조물은 이소프레노이드 트랜스퍼라제에 의해 인식되는 아미노산 모티프를 포함하고, 티오에테르 결합은 아미노산 모티프의 시스테인의 황원자를 포함한다.In one aspect of the invention, the antibody construct includes an amino acid motif recognized by isoprenoid transferase, and the thioether bond includes the sulfur atom of the cysteine of the amino acid motif.
본 발명의 일 양태에서, 아미노산 모티프는 CXX, CXC, XCXC, XXCC, 및 CYYX로 이루어진 그룹으로부터 선택되는 서열이고, 여기에서 C는 시스테인을 나타내며; Y는 각 경우 독립적으로 지방족 아미노산을 나타내고; X는 각 경우 독립적으로 글루타민, 글루타메이트, 세린, 시스테인, 메티오닌, 알라닌, 또는 루신을 나타내고; 티오에테르 결합은 아미노산 모티프의 시스테인의 황원자를 포함한다.In one aspect of the invention, the amino acid motif is a sequence selected from the group consisting of CXX, CXC, XCXC, XXCC, and CYYX, where C represents cysteine; Y independently represents an aliphatic amino acid at each occurrence; X independently represents glutamine, glutamate, serine, cysteine, methionine, alanine, or leucine at each occurrence; The thioether bond involves the sulfur atom of the cysteine of the amino acid motif.
본 발명의 일 양태에서, 아미노산 모티프는 CYYX 서열이고, Y는 각 경우 독립적으로 알라닌, 이소루신, 루신, 메티오닌 또는 발린이다.In one aspect of the invention, the amino acid motif is a CYYX sequence, and Y at each occurrence is independently alanine, isoleucine, leucine, methionine or valine.
본 발명의 일 양태에서, 아미노산 모티프는 CVIM 또는 CVLL 서열이다.In one aspect of the invention, the amino acid motif is a CVIM or CVLL sequence.
본 발명의 일 양태에서, 상기 아미노산 모티프에 선행하는 1 내지 20 개의 아미노산 중 적어도 글리신, 아르기닌, 아스파르트산 및 세린으로부터 각각 독립적으로 선택될 수 있다.In one aspect of the present invention, among 1 to 20 amino acids preceding the amino acid motif, each may be independently selected from at least glycine, arginine, aspartic acid, and serine.
본 발명의 일 양태에서, 상기 아미노산 모티프에 선행하는 1 내지 20 개의 아미노산 중 적어도 하나가 글리신이다.In one aspect of the invention, at least one of the 1 to 20 amino acids preceding the amino acid motif is glycine.
본 발명의 일 양태에서, 아미노산 모티프에 선행하는 1 내지 10개의 아미노산 중 하나 이상이 글리신, 아르기닌, 아스파르트산 및 세린으로부터 각각 독립적으로 선택될 수 있다. 예컨대, 본 발명의 일 양태에서, 아미노산 모티프에 선행하는 7개의 아미노산 중 적어도 하나는 글리신이다. 또는, 아미노산 모티프에 선행하는 7개의 아미노산 중 3개 이상이 글리신, 아르기닌, 아스파르트산 및 세린으로부터 각각 독립적으로 선택된다. 또는, 아미노산 모티프에 선행하는 1 내지 10개의 아미노산이 글리신, 구체적으로는 아미노산 모티프에 선행하는 최소 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 10개의 아미노산은 글리신이다.In one aspect of the invention, one or more of the 1 to 10 amino acids preceding the amino acid motif may each be independently selected from glycine, arginine, aspartic acid, and serine. For example, in one aspect of the invention, at least one of the seven amino acids preceding the amino acid motif is glycine. Alternatively, three or more of the seven amino acids preceding the amino acid motif are each independently selected from glycine, arginine, aspartic acid, and serine. Alternatively, 1 to 10 amino acids preceding the amino acid motif are glycine, specifically at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids preceding the amino acid motif are glycine.
본 발명의 일 양태에서, 항체는 GGGGGGGCVIM의 아미노산 서열을 포함할 수 있다.In one aspect of the invention, the antibody may comprise the amino acid sequence of GGGGGGGCVIM.
본 발명의 일 양태에서, 상기 L이 C-말단에 아미노산 서열 GGGGGGGCVIM을 포함하는 것일 수 있다.In one aspect of the present invention, the L may include the amino acid sequence GGGGGGGCVIM at the C-terminus.
본 발명의 일 구현예에서 상기 아미노산 서열 GGGGGGGCVIM은 서열번호 22로 나타낸다. 또한, 일 구현예에서 상기 아미노산 서열은 항체의 경쇄 C-말단에 포함된다.In one embodiment of the present invention, the amino acid sequence GGGGGGGCVIM is represented by SEQ ID NO: 22. Additionally, in one embodiment, the amino acid sequence is included in the C-terminus of the light chain of the antibody.
본 발명의 또 다른 일 양태에서, Linker는,In another aspect of the present invention, Linker,
(a) 하나 이상의 L; (b) 하나 이상의 제2 유닛; (c) 하나 이상의 제3 유닛; 및 (d) 하나 이상의 제4 유닛을 함유하는 것일 수 있다.(a) one or more L; (b) one or more second units; (c) one or more third units; and (d) one or more fourth units.
여기에서 제2 유닛은 L과 제3 유닛, L과 제4 유닛 또는 제3 유닛과 제4 유닛을 연결하고,Here, the second unit connects L and the third unit, L and the fourth unit, or the third unit and the fourth unit,
여기에서 하나 이상의 제4 유닛은 하나 이상의 약물 또는 톡신을 방출할 수 있으며,wherein the one or more fourth units are capable of releasing one or more drugs or toxins,
여기에서 L은 제2 유닛과 제4 유닛, 제2 유닛과 제3 유닛 또는 제2 유닛을 또 다른 제2 유닛과 연결하는 것이다.Here, L connects the second unit and the fourth unit, the second unit and the third unit, or the second unit with another second unit.
본 발명의 일 양태에서, 제4 유닛은 다음 화학식 (IIb)의 구조를 갖는다:In one aspect of the invention, the fourth unit has the structure of formula (IIb):
[화학식 (IIb)][Formula (IIb)]
상기 식에서,In the above equation,
G는 당(sugar), 당산(sugar acid), 또는 당 유도체(sugar derivatives)이고,G is sugar, sugar acid, or sugar derivatives,
W는 -C(O)-, -C(O)NR'-, -C(O)O-, -S(O)2NR'-, -P(O)R''NR'-, -S(O)NR'-, 또는 -PO2NR'-이고,W is -C(O)-, -C(O)NR'-, -C(O)O-, -S(O) 2 NR'-, -P(O)R''NR'-, -S (O)NR'-, or -PO 2 NR'-,
C(O), S, 또는 P가 페닐환과 바로 연결되는 경우, R' 및 R''은 각각 독립적으로 수소, (C1-8)알킬, (C3-8)사이클로알킬, (C1-8)알콕시, (C1-8)알킬티오, 모노- 또는 디-(C1-8)알킬아미노, (C3-20)헤테로아릴, 또는 (C6-20)아릴이며, W는 L 또는 제2 유닛과 연결되고,When C(O), S, or P is directly connected to the phenyl ring, R' and R'' are each independently hydrogen, (C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C 1- 8 )alkoxy, (C 1-8 )alkylthio, mono- or di-(C 1-8 )alkylamino, (C 3-20 )heteroaryl, or (C 6-20 )aryl, W is L or connected to the second unit,
각 Z는 각각 독립적으로 수소, (C1-8)알킬, 할로겐, 시아노 또는 나이트로이고,Each Z is independently hydrogen, (C 1-8 )alkyl, halogen, cyano or nitro,
n은 1 내지 3의 정수이며,n is an integer from 1 to 3,
m은 0 또는 1이고,m is 0 or 1,
R1 및 R2는 각각 독립적으로 수소, (C1-8)알킬 또는 (C3-8)사이클로알킬이거나, 또는 R1 및 R2는 이들이 부착된 탄소 원자와 함께 (C3-8)사이클로알킬 환을 형성한다.R 1 and R 2 are each independently hydrogen, (C 1-8 )alkyl or (C 3-8 )cycloalkyl, or R 1 and R 2 together with the carbon atom to which they are attached are (C 3-8 )cyclo. Forms an alkyl ring.
본 발명의 일 양태에서, 상기 당 또는 당산은 모노사카라이드이다.In one aspect of the invention, the sugar or sugar acid is a monosaccharide.
본 발명의 일 양태에서, G는 하기 화학식 (IIIa) 구조의 화합물이다:In one aspect of the invention, G is a compound of the structure (IIIa):
[화학식 (IIIa)][Formula (IIIa)]
여기에서,From here,
R3는 수소 또는 카르복실 보호기이고,R 3 is hydrogen or a carboxyl protecting group,
각 R4는 각각 독립적으로 수소 또는 하이드록실 보호기이다.Each R 4 is independently a hydrogen or hydroxyl protecting group.
본 발명의 일 양태에서, R3는 수소이고, 각 R4는 수소이다.In one aspect of the invention, R 3 is hydrogen and each R 4 is hydrogen.
본 발명의 일 양태에서, W는 -C(O)NR'-이고, 여기에서 C(O)가 페닐환과 연결되며, NR'은 L 또는 제2 유닛과 연결된다.In one aspect of the invention, W is -C(O)NR'-, wherein C(O) is linked to the phenyl ring and NR' is linked to L or the second unit.
본 발명의 일 양태에서, Z는 수소이다.In one aspect of the invention, Z is hydrogen.
본 발명의 일 양태에서, R1 및 R2는 각각 수소이다.In one aspect of the invention, R 1 and R 2 are each hydrogen.
본 발명의 일 양태에서, 제2 유닛은 -(CH2)r(V(CH2)p)q-, -((CH2)pV)q-, -(CH2)r(V(CH2)p)qY-, -((CH2)pV)q(CH2)r-, -Y((CH2)pV)q- 또는 -(CH2)r(V(CH2)p)qYCH2-로 나타내지며,In one aspect of the invention, the second unit is -(CH 2 ) r (V(CH 2 ) p ) q -, -((CH 2 ) p V) q -, -(CH 2 ) r (V(CH 2 ) p ) q Y-, -((CH 2 ) p V) q (CH 2 ) r -, -Y((CH 2 ) p V) q - or -(CH 2 ) r (V(CH 2 ) p ) q YCH 2 -,
여기에서,From here,
r은 0 내지 10의 정수이고;r is an integer from 0 to 10;
p는 1 내지 10의 정수이며;p is an integer from 1 to 10;
q는 1 내지 20의 정수이고,q is an integer from 1 to 20,
V 및 Y는 각각 독립적으로 단일결합, -O-, -S-, -NR21-, -C(O)NR22-, -NR23C(O)-, -NR24SO2-, 또는 -SO2NR25-이고,V and Y are each independently a single bond, -O-, -S-, -NR 21 -, -C(O)NR 22 -, -NR 23 C(O)-, -NR 24 SO 2 -, or - SO 2 NR 25 -,
R21 내지 R25는 각각 독립적으로 수소, (C1-6)알킬, (C1-6)알킬(C6-20)아릴 또는 (C1-6)알킬(C3-20)헤테로아릴이다.R 21 to R 25 are each independently hydrogen, (C 1-6 )alkyl, (C 1-6 )alkyl(C 6-20 )aryl, or (C 1-6 )alkyl(C 3-20 )heteroaryl. .
본 발명의 일 양태에서, r은 2이다.In one aspect of the invention, r is 2.
본 발명의 일 양태에서, p는 2이다.In one aspect of the invention, p is 2.
본 발명의 일 양태에서, q는 6 내지 20의 정수이다.In one aspect of the invention, q is an integer from 6 to 20.
본 발명의 일 양태에서, q는 2, 5, 또는 11이다.In one aspect of the invention, q is 2, 5, or 11.
본 발명의 일 양태에서, V 및 Y는 각각 독립적으로 -O-이다.In one aspect of the invention, V and Y are each independently -O-.
본 발명의 일 양태에서, L 또는 제3 유닛은, In one aspect of the invention, L or the third unit is:
, , 또는 을 포함하고, 여기에서 L1은 직접 결합 또는 1 내지 30개의 탄소원자를 갖는 알킬렌이고, R11은 수소 또는 1 내지 10개의 탄소원자를 갖는 알킬이며, 구체적으로 메틸이고, L2는 1 내지 30개의 탄소원자를 갖는 알킬렌이다. , , or Includes, where L 1 is a direct bond or alkylene having 1 to 30 carbon atoms, R 11 is hydrogen or alkyl having 1 to 10 carbon atoms, specifically methyl, and L 2 is 1 to 30 carbon atoms It is an alkylene with a carbon atom.
본 발명의 일 양태에서, L1은 12개의 탄소원자를 갖는 알킬렌이다.In one aspect of the invention, L 1 is alkylene having 12 carbon atoms.
본 발명의 일 양태에서, R11은 메틸이다.In one aspect of the invention, R 11 is methyl.
본 발명의 일 양태에서, L2는 11개의 탄소원자를 갖는 알킬렌이다.In one aspect of the invention, L 2 is alkylene having 11 carbon atoms.
본 발명의 일 양태에서, 바인딩 유닛은 티오에테르 결합에 의해 항체와 공유결합하며, 티오에테르 결합은 항체의 시스테인의 황원자를 포함한다.In one aspect of the invention, the binding unit is covalently linked to the antibody by a thioether bond, the thioether bond comprising a sulfur atom of the cysteine of the antibody.
본 발명의 일 양태에서, 항체는 이소프레노이드 트랜스퍼라제에 의해 인식되는 아미노산 모티프를 포함하고, 티오에테르 결합은 아미노산 모티프의 시스테인의 황원자를 포함한다.In one aspect of the invention, the antibody comprises an amino acid motif recognized by isoprenoid transferase, and the thioether bond comprises the sulfur atom of the cysteine of the amino acid motif.
본 발명의 일 양태에서, 아미노산 모티프는 CXX, CXC, XCXC, XXCC, 및 CYYX로 이루어진 그룹으로부터 선택되는 서열이고, 여기에서 C는 시스테인을 나타내며; Y는 각 경우 독립적으로 지방족 아미노산을 나타내고; X는 각 경우 독립적으로 글루타민, 글루타메이트, 세린, 시스테인, 메티오닌, 알라닌, 또는 루신을 나타내고; 티오에테르 결합은 아미노산 모티프의 시스테인의 황원자를 포함한다.In one aspect of the invention, the amino acid motif is a sequence selected from the group consisting of CXX, CXC, XCXC, XXCC, and CYYX, where C represents cysteine; Y independently represents an aliphatic amino acid at each occurrence; X independently represents glutamine, glutamate, serine, cysteine, methionine, alanine, or leucine at each occurrence; The thioether bond involves the sulfur atom of the cysteine of the amino acid motif.
본 발명의 일 양태에서, 아미노산 모티프는 CYYX 서열이고, Y는 각 경우 독립적으로 알라닌, 이소루신, 루신, 메티오닌 또는 발린이다.In one aspect of the invention, the amino acid motif is a CYYX sequence, and Y at each occurrence is independently alanine, isoleucine, leucine, methionine or valine.
본 발명의 일 양태에서, 아미노산 모티프는 CVIM 또는 CVLL 서열이다.In one aspect of the invention, the amino acid motif is a CVIM or CVLL sequence.
본 발명의 일 양태에서, 아미노산 모티프에 선행하는 1 내지 20개의 아미노산 중 적어도 하나는 글리신이다.In one aspect of the invention, at least one of the 1 to 20 amino acids preceding the amino acid motif is glycine.
본 발명의 일 양태에서, 아미노산 모티프에 선행하는 1 내지 20개의 아미노산 중 1개 이상이 글리신, 아르기닌, 아스파르트산 및 세린으로부터 각각 독립적으로 선택될 수 있다.In one aspect of the invention, one or more of the 1 to 20 amino acids preceding the amino acid motif may each be independently selected from glycine, arginine, aspartic acid, and serine.
본 발명의 일 양태에서, 아미노산 모티프에 선행하는 1 내지 20개의 아미노산이 글리신, 구체적으로는 아미노산 모티프에 선행하는 최소 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 또는 20개의 아미노산은 글리신이다.In one aspect of the invention, 1 to 20 amino acids preceding the amino acid motif are glycine, specifically at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 amino acids preceding the amino acid motif. , 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids are glycine.
본 발명의 일 양태에서, 항체는 GGGGGGGCVIM의 아미노산 서열을 포함할 수 있다.In one aspect of the invention, the antibody may comprise the amino acid sequence of GGGGGGGCVIM.
본 발명의 일 양태에서, 상기 이소프레노이드 트랜스퍼라제는 파네실 단백질 트랜스퍼라아제(FTase) 또는 게라닐게라닐 트랜스퍼라제(GGTase)이다.In one aspect of the invention, the isoprenoid transferase is farnesyl protein transferase (FTase) or geranylgeranyl transferase (GGTase).
본 발명의 일 양태에서, L은 Ab에 공유 결합된 하나 이상의 분지형 링커를 포함하고,In one aspect of the invention, L comprises one or more branched linkers covalently linked to the Ab,
i) 각각의 분지형 링커는 제1 링커(PL)에 의해 Ab에 공유 결합된 제5 유닛을 포함하고;i) each branched linker comprises a fifth unit covalently linked to the Ab by a first linker (PL);
ii) 각각의 분지형 링커는 제1 활성제가 제2 링커 (SL) 및 절단 그룹(CG)에 의해 제5 유닛에 공유 결합된 제1 분지(B1)를 포함하며; 및ii) each branched linker comprises a first branch (B1) in which a first active agent is covalently linked to a fifth unit by a second linker (SL) and a cleavage group (CG); and
iii) 각각의 분지형 링커는 a) 제2 활성제가 제2 링커 (SL) 및 절단 그룹(CG)에 의해 제5 유닛에 공유 결합된 제2 분지 (B2); 또는 b) 폴리에틸렌 글리콜 모이어티가 제5 유닛에 공유 결합된 있는 제2 분지(B2)를 더 포함하고,iii) each branched linker has a) a second branch (B2) wherein a second active agent is covalently linked to the fifth unit by a second linker (SL) and a cleavage group (CG); or b) further comprising a second branch (B2) wherein a polyethylene glycol moiety is covalently attached to the fifth unit,
상기 각각의 절단 그룹은 항체 구조물-활성제 접합체부터 활성제를 방출하기 위해 가수분해되는 것일 수 있다.Each of the cleavage groups may be hydrolyzed to release the activator from the antibody structure-activator conjugate.
본 발명의 일 양태에서, i) 분지된 링커는 제1 링커(PL)에 의해 반응성 모이어티에 공유 결합된 제5 유닛(BR)을 포함하고;In one aspect of the invention, i) the branched linker comprises a fifth unit (BR) covalently linked to the reactive moiety by a first linker (PL);
ii) 제5 유닛은 제1 분지(B1)에 공유 결합되고, 제2 링커(SL) 및 절단 그룹(CG)에 공유 결합된 제1 활성제를 포함하며;ii) the fifth unit comprises a first activator covalently linked to a first branch (B1), a second linker (SL) and a cleavage group (CG);
iii) 제5 유닛은 제2 분지(B2)와 공유 결합되고, a) 제2 링커(SL) 및 절단 그룹(CG)과 공유 결합된 제2 활성제 또는 b) 폴리에틸렌 글리콜 모이어티를 포함하며, 여기에서 각 절단 그룹은 가수분해되어 활성제를 방출시킬 수 있다.iii) the fifth unit is covalently linked to a second branch (B2) and comprises a) a second activator covalently linked to a second linker (SL) and a cleavage group (CG) or b) a polyethylene glycol moiety, wherein Each cleavage group can be hydrolyzed to release the active agent.
본 발명의 일 양태에서, 상기 절단 그룹은 상기 화학식 II와 같다.In one aspect of the invention, the cleavage group is as shown in Formula II above.
본 발명에서, 제2링커(예를 들어, 활성제를 제5 유닛과 연결하는 것)은 1,3-쌍극 부가환화 반응(1,3-dipolar cycloaddition reaction), 헤테로-디엘스-엘더 반응(hetero-Diels-Alder reaction), 친핵성 치환 반응(nucleophilic substitution reaction), 비-알돌형 카보닐 반응(non-aldol type carbonyl reaction), 탄소-탄소 다중 결합에의 첨가(addition to a carbon-carbon multiple bond), 산화 반응(oxidation reaction) 또는 클릭 반응(click reaction)에 의하여 형성된 제3 유닛을 포함할 수 있다. 여기에서, 제3 유닛은 상기와 같이 알카인과 아자이드와의 반응, 또는 비-알돌형 카보닐 반응, 예컨대 알데하이드 또는 케톤 그룹과 하이드라진 또는 하이드록실아민과의 반응으로 형성될 수 있으며, 이는 활성제 및/또는 절단 그룹과 L을 마일드 커플링(mild coupling)하도록 해준다.In the present invention, the second linker (e.g., connecting the activator with the fifth unit) is 1,3-dipolar cycloaddition reaction, hetero-Diels-Elder reaction. -Diels-Alder reaction, nucleophilic substitution reaction, non-aldol type carbonyl reaction, addition to a carbon-carbon multiple bond ), and may include a third unit formed by an oxidation reaction or a click reaction. Here, the third unit may be formed by the reaction of an alkyne with an azide, as above, or by a non-aldol-type carbonyl reaction, such as the reaction of an aldehyde or ketone group with hydrazine or hydroxylamine, which may be formed by the activator. and/or allows mild coupling between the cutting group and L.
본 발명의 일 양태에서, 상기 제5 유닛은 , , , , 또는 이고,In one aspect of the invention, the fifth unit is , , , , or ego,
상기 L2, L3, L4 는 각각 독립적으로 직접 결합 또는 -CnH2n-이며, 상기 n은 1 내지 30의 정수이고,The L 2 , L 3 , and L 4 are each independently a direct bond or -C n H 2n -, where n is an integer from 1 to 30,
상기 G1, G2, G3은 독립적으로 직접 결합, , , 또는 이며,G 1 , G 2 , and G 3 are independently directly bonded, , , or and
상기 R30은 수소 또는 C1-30 알킬이고,R 30 is hydrogen or C 1-30 alkyl,
상기 R40은 수소, C1-10 알킬 또는 -L5-COOR50이며, 여기에서 L5는 직접 결합 또는 -CnH2n-이고,R 40 is hydrogen, C 1-10 alkyl or -L 5 -COOR 50 , where L 5 is a direct bond or -C n H 2n -,
여기에서 n은 1 내지 10의 정수이고, R50은 수소 또는 C1-30 알킬이다.Here, n is an integer from 1 to 10, and R 50 is hydrogen or C 1-30 alkyl.
본 발명의 일 양태에서, 상기 제5 유닛은 , , 또는 이고,In one aspect of the invention, the fifth unit is , , or ego,
상기 L2, L3, L4 ,G1, G2, G3, R30, R40, 및 L5는 상기와 동일할 수 있다.The L 2 , L 3 , L 4 , G 1 , G 2 , G 3 , R 30 , R 40 , and L 5 may be the same as above.
본 발명의 일 양태에서, 상기 절단 그룹은 표적 세포 내에서 절단가능하다.In one aspect of the invention, the cleavage group is cleavable within the target cell.
본 발명의 일 양태에서, 상기 절단 그룹은 하나 이상의 활성제를 방출시킬 수 있다.In one aspect of the invention, the cleavage group is capable of releasing one or more active agents.
또한, 본 발명의 일 양태에서, 상기 접합체는 Ab를 포함하고; Additionally, in one aspect of the invention, the conjugate includes Ab;
Ab에 공유 결합 된 1, 2, 3 또는 4개 이상의 분지형 링커를 포함하며; Contains 1, 2, 3, or 4 or more branched linkers covalently attached to the Ab;
각 분지형 링커가 1 또는 2개 이상의 활성제와 결합하고;Each branched linker binds one or two or more activators;
여기에서 활성제는 각각 동일하거나, 상이한 것이다.Here, the activators are the same or different.
또한, 본 발명의 일 양태에서, 상기 각각의 활성제는 절단 가능한 결합에 의해 분지형 링커에 결합된다.Additionally, in one aspect of the invention, each of the above active agents is linked to a branched linker by a cleavable bond.
본 발명의 일 양태에서, 상기 L은 적어도 하나의 제5 유닛 및 제1 링커(PL)을 포함하는 링커이다.In one aspect of the present invention, L is a linker including at least one fifth unit and a first linker (PL).
본 발명의 일 양태에서, 항체-약물 접합체의 제1 링커는 1 내지 100개, 바람직하게는 1 내지 50개의 탄소원자를 갖는 알킬렌을 포함하고, 또는:In one aspect of the invention, the first linker of the antibody-drug conjugate comprises an alkylene having 1 to 100 carbon atoms, preferably 1 to 50 carbon atoms, or:
알킬렌은 적어도 하나의 불포화 결합을 포함하고;Alkylene contains at least one unsaturated bond;
알킬렌은 적어도 하나의 헤테로아릴렌을 포함하며;Alkylene includes at least one heteroarylene;
알킬렌의 탄소원자는 질소(N), 산소(O), 및 황(S)으로부터 선택되는 하나 이상의 헤테로원자에 의해 대체되고; 또는The carbon atom of the alkylene is replaced by one or more heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S); or
알킬렌은 1 내지 20개의 탄소원자를 갖는 하나 이상의 알킬로 더욱 치환된다.Alkylene is further substituted with one or more alkyls having 1 to 20 carbon atoms.
또한, 본 발명의 일 양태에서, 상기 각각의 분지형 링커는 제5 유닛을 포함하고, 각각의 활성제는 2차 링커를 통해 제5 유닛에 결합하고, 상기 제5 유닛은 1차 링커에 의해 항체에 결합된다.Additionally, in one aspect of the invention, each branched linker comprises a fifth unit, each activator is bound to the fifth unit through a secondary linker, and the fifth unit binds to the antibody via a primary linker. is combined with
본 발명의 일 양태에서, 상기 제5 유닛은 아미드이고, 1차 링커는 아미드의 카르보닐을 포함한다.In one aspect of the invention, the fifth unit is an amide and the primary linker includes the carbonyl of the amide.
본 발명의 일 양태에서, 상기 제5 유닛은 리신(lysine) 유닛이다.In one aspect of the invention, the fifth unit is a lysine unit.
구체적인 본 발명의 일 양태에서, 알킬렌의 적어도 하나의 탄소원자는 질소로 대체되고, 제1 링커는 친수성 아미노산의 적어도 두 개의 원자를 포함하며, 그리고 질소는 친수성 아미노산의 주쇄 카보닐과 함께 펩타이드 결합을 형성한다. 친수성 아미노산은, 예를 들면, 아르기닌, 아스파테이트, 아스파라긴, 글루타메이트, 글루타민, 히스티딘, 리신, 오르니틴, 프롤린, 세린 또는 트레오닌일 수 있다.In one specific aspect of the invention, at least one carbon atom of the alkylene is replaced with a nitrogen, the first linker includes at least two atoms of a hydrophilic amino acid, and the nitrogen forms a peptide bond with the main chain carbonyl of the hydrophilic amino acid. form Hydrophilic amino acids may be, for example, arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine or threonine.
본 발명의 일 양태에서, 항체-활성제의 분지형 링커는 수용액 중의 중성 pH에서 전하를 갖는 모이어티를 갖는 측쇄를 갖는 아미노산, 바람직하게는 아르기닌, 아스파테이트, 글루타메이트, 리신 또는 오르니틴을 포함한다. 아미노산은 분지된 링커의 어느 곳에도 위치될 수 있다. 예를 들면, 분지형 링커의 옥심을 분지형 링커의 폴리에틸렌 글리콜 유닛에 공유 결합시킬 수 있다. 택일적으로 또는 부가적으로, 이러한 아미노산은 제2 링커에, 임의로 각각의 제2 링커 내에 존재할 수 있다.In one aspect of the invention, the branched linker of the antibody-active agent comprises an amino acid having a side chain with a charged moiety at neutral pH in aqueous solution, preferably arginine, aspartate, glutamate, lysine or ornithine. Amino acids can be positioned anywhere on the branched linker. For example, the oxime of the branched linker can be covalently linked to the polyethylene glycol unit of the branched linker. Alternatively or additionally, such amino acids may be present in the second linker, optionally within each second linker.
구체적인 본 발명의 일 양태에서, 상기 링커-활성제는 하기 구조식 화합물을 포함한다:In one specific aspect of the invention, the linker-activator comprises a compound of the structure:
을 포함하고, Including,
상기 B' 및 B''는 동일하거나 상이할 수 있는 활성제를 나타내며;wherein B' and B'' represent active agents which may be the same or different;
n1 내지 n3은 각각 독립적으로 0 내지 30의 정수를 나타내고;n1 to n3 each independently represent an integer from 0 to 30;
AA는 아미노산 그룹을 나타낸다.AA represents an amino acid group.
본 발명의 일 양태에서, 상기 AA는 아미노산 그룹을 나타내며, 아미노산 그룹은 하나 이상의 아미노산이 결합된 형태를 의미한다.In one aspect of the present invention, AA represents an amino acid group, and the amino acid group refers to a form in which one or more amino acids are combined.
본 발명의 일 양태에서, i) 링커는 다수의 아미노산의 펩타이드 서열을 포함하고; ii) 적어도 두 개의 활성제는 아미노산의 측쇄와 공유 결합으로 연결된다.In one aspect of the invention, i) the linker comprises a peptide sequence of multiple amino acids; ii) At least two activators are covalently linked to the side chains of amino acids.
구체적인 본 발명의 일 양태에서, 상기 아미노산 그룹은 1 내지 20의 아미노산의 주쇄 결합되거나; 또는 측쇄 결합이다.In one specific aspect of the present invention, the amino acid group is bonded to the main chain of 1 to 20 amino acids; or a side chain bond.
구체적인 본 발명의 일 양태에서, 상기 아미노산 그룹은 1 내지 20의 아르기닌, 아스파테이트, 아스파라긴, 글루타메이트, 글루타민, 히스티틴, 리신, 오르니틴, 프롤린, 세린 또는 트레오닌의 주쇄 결합; 또는 측쇄 결합에 의한 그룹이다.In one specific aspect of the present invention, the amino acid group is a main chain bond of 1 to 20 arginine, aspartate, asparagine, glutamate, glutamine, histitine, lysine, ornithine, proline, serine, or threonine; Or it is a group by side chain bonding.
구체적인 본 발명의 일 양태에서, 상기 아미노산 그룹은 1 내지 20의 아르기닌, 아스파테이트, 글루타메이트, 리신 또는 오르니틴의 주쇄 결합; 또는 측쇄 결합에 의한 그룹이다.In one specific aspect of the present invention, the amino acid group is a main chain bond of 1 to 20 arginine, aspartate, glutamate, lysine or ornithine; Or it is a group by side chain bonding.
구체적인 본 발명의 일 양태에서, 상기 아미노산 그룹은 1 내지 20의 아미노산 하나 이상의 리신을 포함한다. In one specific aspect of the invention, the group of amino acids includes amino acids 1 to 20 and at least one lysine.
또한, 상기 아미노산 그룹은 리신의 주쇄, 측쇄 결합을 포함한다.Additionally, the amino acid group includes the main chain and side chain bonds of lysine.
본 발명의 일 양태에서, 상기 제5 유닛을 포함하는 분지형 링커는 일 수 있다.In one aspect of the invention, the branched linker comprising the fifth unit is It can be.
본 명세서에서, '활성제 모이어티'는 활성제를 포함하여 링커 또는 링커 일부에 공유결합시키는 화합물을 말한다.In this specification, 'activator moiety' refers to a compound that includes an activator and is covalently bonded to a linker or part of a linker.
본 발명에서, 활성제 모이어티는 링커에 직접결합할 수 있고, 링커에 하나 이상, 구체적으로, 2개 이상, 3개 이상, 4개 이상의 활성제 모이어티가 링커에 직접결합할 수 있다. In the present invention, the activator moiety may be directly bound to the linker, and one or more, specifically, 2 or more, 3 or more, or 4 or more activator moieties may be directly bound to the linker.
또한, 본 발명에서 활성제 모이어티는 활성제를 링커에 직접결합시키기 위한 화합물 단위를 포함할 수 있다. 또한, 본 발명에서 활성제 모이어티의 일부는 절단가능하고, 일부분이 절단되어 세포내 환경에서 활성제를 방출할 수 있다. 또한, 본 발명에서 활성제 모이어티 및 링커는 접합체의 DAR, 약리활성 등을 고려하여 결합개수를 정할 수 있다. 일 예에서, 활성제 모이어티는 하기 구조 및 활성제를 포함한 전체를 의미할 수 있고, 이를 통해 활성제와 링커를 직접결합할 수 있다. 다만, 이는 예시적인 것으로 이에 제한되는 것은 아니다.Additionally, in the present invention, the activator moiety may include a compound unit for directly binding the activator to the linker. Additionally, some of the active agent moieties in the present invention are cleavable, and some parts may be cleaved to release the active agent in the intracellular environment. Additionally, in the present invention, the number of bonds between the activator moiety and the linker can be determined by considering the DAR and pharmacological activity of the conjugate. In one example, the activator moiety may refer to the entire structure including the following structure and the activator, through which the activator and the linker can be directly combined. However, this is an example and is not limited thereto.
(여기에서, 각 부분은 상기 정의와 같다)(where each part is as defined above)
본 발명의 일 양태에서, 활성제는 각각 독립적으로 화학요법제 및 톡신으로부터 선택된다.In one aspect of the invention, the active agents are each independently selected from chemotherapeutic agents and toxins.
또한, 활성제는 면역 조절 화합물, 항암제, 항바이러스제, 항균제, 항진균제, 항기생충제 또는 이들의 조합일 수 있고, 하기 나열된 활성제 중 선택적으로 사용할 수 있다:Additionally, the active agent may be an immunomodulatory compound, an anticancer agent, an antiviral agent, an antibacterial agent, an antifungal agent, an antiparasitic agent, or a combination thereof, and may be selectively used among the active agents listed below:
(a) 엘로티닙(erlotinib), 보르테조밉(bortezomib), 풀베스트란트(fulvestrant), 수텐트(sutent), 레트로졸(letrozole), 이마티닙 메실레이트(imatinib mesylate), PTK787/ZK 222584, 옥살리플라틴(oxaliplatin), 5-플루오로우라실(5-fluorouracil), 루코보린(leucovorin), 라파마이신(rapamycin), 라파티닙(lapatinib), 로나파르닙(lonafarnib), 소라페닙(sorafenib), 제피티닙(gefitinib), AG1478, AG1571, 티오테파(thiotepa), 사이클로포스파마이드(cyclophosphamide), 부술판(busulfan), 임프로술판(improsulfan), 피포술판(piposulfan), 벤조도파(benzodopa), 카르보콘(carboquone), 메츄도파(meturedopa), 유레도파(uredopa), 에틸렌이민(ethylenimine), 알트레타민(altretamine), 트리에틸렌멜라민(triethylenemelamine), 트리에틸렌포스포라미드(trietylenephosphoramide), 트리에틸렌티오포스포라미드(triethiylenethiophosphoramide), 트리메틸롤로멜라민(trimethylolomelamine), 불라타신(bullatacin), 불라타시논(bullatacinone), 캄토테신(camptothecin), 토포테칸(topotecan), 브리오스타틴(bryostatin), 칼리스타틴(callystatin), CC-1065, 아도젤레신(adozelesin), 카르젤레신(carzelesin), 비젤레신(bizelesin), 크립토피신 1(cryptophycin 1), 크립토피신 8(cryptophycin 8), 돌라스타틴(dolastatin), 듀오카마이신(duocarmycin), KW-2189, CB1-TM1, 엘루테로빈(eleutherobin), 판크라티스타틴(pancratistatin), 사르코딕티인(sarcodictyin), 스폰지스타틴(spongistatin), 클로람부실(chlorambucil), 클로르나파진(chlornaphazine), 클로로포스파미드(cholophosphamide), 에스트라무스틴(estramustine), 이포스파미드(ifosfamide), 메클로르에타민(mechlorethamine), 멜팔란(melphalan), 노벰비킨(novembichin), 페네스테린(phenesterine), 프레드니무스틴(prednimustine), 트로포스파미드(trofosfamide), 우라실 머스타드(uracil mustard), 카르무스틴(carmustine), 클로로코토신(chlorozotocin), 포테쿠스틴(fotemustine), 로무스틴(lomustine), 니무스틴(nimustine), 라니무스틴(ranimnustine), 칼리키아미신(calicheamicin), 칼리키아미신 감마 1(calicheamicin gamma 1), 칼리키아미신 오메가 1(calicheamicin omega 1), 디네미신(dynemicin), 디네미신 A(dynemicin A), 클로드로네이트(clodronate), 에스페르아미신(esperamicin), 네오카르지노스타틴크로모포어(neocarzinostatin chromophore), 아클라시노마이신(aclacinomysins), 악티노마이신(actinomycin), 안트르마이신(antrmycin), 아자세린(azaserine), 블레오마이신(bleomycins), 칵티노마이신(cactinomycin), 카라비신(carabicin), 카르니노마이신(carninomycin), 카르지노필린(carzinophilin), 크로모마이신(chromomycins), 닥티노마이신(dactinomycin), 다우노루비신(daunorubicin), 데토루부신(detorubucin), 6-디아조-5-옥소-L-노르루신(6-diazo-5-oxo-L-norleucine), 독소루비신(doxorubicin), 모르폴리노-독소루비신(morpholino-doxorubicin), 시아노모르폴리노-독소루비신(cyanomorpholino-doxorubicin), 2-피롤리노-독소루비신(2-pyrrolino-doxorubucin), 리포소말 독소루비신(liposomal doxorubicin), 데옥시독소루비신(deoxydoxorubicin), 에피루비신(epirubicin), 에소루비신(esorubicin), 마르셀로마이신(marcellomycin), 미토마이신 C(mitomycin C), 미코페놀산(mycophenolic acid), 노갈라마이신(nogalamycin), 올리보마이신(olivomycins), 페플로마이신(peplomycin), 포트피로마이신(potfiromycin), 퓨로마이신(puromycin), 쿠엘라마이신(quelamycin), 로도루비신(rodorubicin), 스트렙토미그린(streptomigrin), 스트렙토조신(streptozocin), 투베르시딘(tubercidin), 우베니멕스(ubenimex), 지노스타틴(zinostatin), 조루비신(zorubicin), 5-플루오로우라신(5-fluorouracil), 데노프테린(denopterin), 메토트렉세이트(methotrexate), 프테로프테린(pteropterin), 트리메트렉세이트(trimetrexate), 플루다라빈(fludarabine), 6-머캅토퓨린(6-mercaptopurine), 티아미프린(thiamiprine), 티구아닌(thiguanine), 안시타빈(ancitabine), 아자시티딘(azacitidine), 6-아자유리딘(6-azauridine), 카르모푸르(carmofur), 시타라빈(cytarabine), 디데옥시유리딘(dideoxyuridine), 독시플루리딘(doxifluridine), 에노시타빈(enocitabine), 플록수리딘(floxuridine), 칼루스테론(calusterone), 드로모스타놀론(dromostanolone), 프로피오네이트(propionate), 에피티오스타놀(epitiostanol), 메피티오스테인(mepitiostane), 테스토락톤(testolactone), 아미노글루테티미드(aminoglutethimide), 미토테인(mitotane), 트릴로스테인(trilostane), 폴린산(folinic acid), 아세글라톤(aceglatone), 알도포스파미드 글리코사이드(aldophosphamide glycoside), 아미노레불린산(aminolevulinic acid), 에닐우라실(eniluracil), 암사크린(amsacrine), 베스트라부실(bestrabucil), 비산트렌(bisantrene), 에다트락세이트(edatraxate), 데포파민(defofamine), 데메콜신(demecolcine), 디아지콘(diaziquone), 엘포르니틴(elfornithine), 엘립티니움 아세테이트(elliptinium acetate), 에토글루시드(etoglucid), 갈리움 나이트레이트(gallium nitrate), 하이드록시우레아(hydroxyurea), 렌티난(lentinan), 로니다이닌(lonidainine), 메이탄신(maytansine), 안사미토신(ansamitocins), 미토구아존(mitoguazone), 미토잔트론(mitoxantrone), 모피단몰(mopidanmol), 니트라에린(nitraerine), 펜토스타틴(pentostatin), 페나메트(phenamet), 피라루비신(pirarubicin), 로소잔트론(losoxantrone), 2-에틸하이드라지드(2-ethylhydrazide), 프로카르바진(procarbazine), 폴리사카라이드-k(polysaccharidek), 라족세인(razoxane), 리조신(rhizoxin), 시조피란(sizofiran), 스피로게르마늄(spirogermanium), 테누아존산(tenuazonic acid), 트리아지콘(triaziquone), 2,2',2''-트리클로로트리에틸아민(2,2',2''-trichlorotriethylamine), T-2 톡신, 베라큐린 A(verracurin A), 로리딘 A(roridin A), 안구이딘(anguidine), 우레탄(urethane), 빈데신(vindesine), 다카르바진(dacarbazine), 만노무스틴(mannomustine), 미토브로니톨(mitobronitol), 미토락톨(mitolactol), 피포브로만(pipobroman), 가시토신(gacytosine), 아라비노사이드(arabinoside), 사이클로포스파미드(cyclophosphamide), 티오테파(thiotepa), 파클리탁셀(paclitaxel), 파클리탁셀, 파클리탁셀의 알부민-엔지니어드 나노파티클(albumin-engineered nanoparticle formulation of paclitaxel), 도세탁셀, 클로람부실, 젬시타빈, 6-티오구아닌, 머캅토퓨린, 시스플라틴, 카보플라틴(carboplatin), 빈블라스틴(vinblastine), 플래티늄(platinum), 에토포사이드(etoposide), 이포스파미드(ifosfamide), 미톡산트론(mitoxantrone), 빈크리스틴, 비노렐빈(vinorelbine), 노반트론(novantrone), 테니포사이드(teniposide), 에다트렉세이트(edatrexate), 다우노마이신(daunomycin), 아미노프테린(aminopterin), 젤로다(xeloda), 이반드로네이트(ibandronate), CPT-11, 토포이소머라아제 저해제 RFS 2000, 디플루오로메틸오르니틴(difluoromethylornithine), 레티노산(retinoic acid), 카페시타빈(capecitabine), 또는 이의 약학적으로 허용되는 염, 용매화물 또는 산;(a) erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787/ZK 222584, oxaliplatin ( oxaliplatin, 5-fluorouracil, leucovorin, rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib , AG1478, AG1571, thiotepa, cyclophosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, Meturedopa, uredopa, ethylenimine, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide , trimethylolomelamine, bullatacin, bullatacinone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, Ado adozelesin, carzelesin, bizelesin, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, KW- 2189, CB1-TM1, eleutherobin, pancratistatin, sarcodictyin, spongestatin, chlorambucil, chlornaphazine, chlorophos Cholophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, novembichin, phenesterine, prednimustine (prednimustine), trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine , ranimnustine, calicheamicin, calicheamicin gamma 1, calicheamicin omega 1, dynemicin, dynemicin A , clodronate, esperamicin, neocarzinostatin chromophore, alacinomysins, actinomycin, antrmycin, Azaserine, bleomycins, cactinomycin, carabicin, carninomycin, carzinophilin, chromomycins, dactinomycin ( dactinomycin), daunorubicin, detorubucin, 6-diazo-5-oxo-L-norleucine, doxorubicin, mor Morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubucin, liposomal doxorubicin, deoxydoxorubicin ( deoxydoxorubicin, epirubicin, esorubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins ), peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, 5-fluorouracil, denopterin, methotrexate, pte Pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thiguanine, ancitabine , azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocy. Enocitabine, floxuridine, calusterone, dromostanolone, propionate, epitiostanol, mepitiostane, testolactone (testolactone), aminoglutethimide, mitotane, trilostane, folinic acid, aceglatone, aldophosphamide glycoside, amino Aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine ), diaziquone, elfornithine, elliptinium acetate, etoglucid, gallium nitrate, hydroxyurea, lentinan ( lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pento Statin (pentostatin), phenamet, pirarubicin, losoxantrone, 2-ethylhydrazide, procarbazine, polysaccharide-k ( polysaccharidek, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid, triaziquone, 2,2',2'' -Trichlorotriethylamine (2,2',2''-trichlorotriethylamine), T-2 toxin, verracurin A, roridin A, anguidine, urethane, Vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside ), cyclophosphamide, thiotepa, paclitaxel, paclitaxel, albumin-engineered nanoparticle formulation of paclitaxel, docetaxel, chlorambucil, gemcitabine, 6 -Thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vin. Christine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate (ibandronate), CPT-11, topoisomerase inhibitor RFS 2000, difluoromethylornithine, retinoic acid, capecitabine, or a pharmaceutically acceptable salt or solvent thereof. cargo or mountains;
(b) 모노카인(monokine), 림포카인(lympokine), 폴리펩타이드 호르몬(traditional polypeptide hormone), 부갑상선 호르몬(parathyroid hormone), 티록신(thyroxine), 릴렉신(relaxin), 프로릴렉신(prorelaxin), 당단백 호르몬(glycoprotein hormone), 여포자극호르몬(follicle stimulating hormone), 갑상샘자극호르몬(thyroid stimulating hormone), 황체형성호르몬(luteinizing hormone), 간 성장인자 섬유모세포성장인자(hepatic growth factor fibroblast growth factor), 프롤락틴(prolactin), 태반성 락토젠(placental lactogen), 종양괴사인자 (tumor necrosis factor), 종양괴사인자-α, 종양괴사인자-β, 뮐러관 억제물질(mullerian inhibiting substance), 마우스 고나도트로핀-연관 펩타이드(mouse gonadotropin associated peptide), 인히빈(inhibin), 액티빈(activin), 혈관내피증식인자(vascular endothelial growth factor), 트롬보포이에틴(thrombopoietin), 에리스로포이에틴(erythropoietin), 골유도 인자(osteoinductive factor), 인터페론, 인터페론-α, 인터페론-β, 인터페론-γ, 콜로니자극인자(colony stimulating factor, CSF), 마크로파지-CSF, 과립구-마크로파지-CSF(granulocyte-macrophage-CSF), 과립구-CSF, 인터루킨(IL), IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, 종양괴사인자(tumor necrosis factor), 폴리펩타이드 인자, LIF, 키트 리간드(kit ligand), 또는 이들의 배합물;(b) monokine, lymphokine, traditional polypeptide hormone, parathyroid hormone, thyroxine, relaxin, prorelaxin, Glycoprotein hormone, follicle stimulating hormone, thyroid stimulating hormone, luteinizing hormone, liver growth factor fibroblast growth factor, prolactin (prolactin), placental lactogen, tumor necrosis factor, tumor necrosis factor-α, tumor necrosis factor-β, Mullerian inhibiting substance, mouse gonadotropin- Mouse gonadotropin associated peptide, inhibin, activin, vascular endothelial growth factor, thrombopoietin, erythropoietin, osteoinductive factor factor), interferon, interferon-α, interferon-β, interferon-γ, colony stimulating factor (CSF), macrophage-CSF, granulocyte-macrophage-CSF, granulocyte-CSF, interleukin (IL), IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL- 11, IL-12, tumor necrosis factor, polypeptide factor, LIF, kit ligand, or combinations thereof;
(c) 디프테리아 톡신, 보툴리눔 톡신, 테타누스 톡신, 디센터리 톡신, 콜레라 톡신, 아마니틴, α-아마니틴, 피롤로벤조디아제핀, 피롤로벤조디아제핀 유도체, 인돌리노벤조디아제핀, 피리디노벤조디아제핀, 테트로도톡신, 브레베톡신(brevetoxin), 시구아톡신(ciguatoxin), 리신(ricin), AM 톡신, 오리스타틴(auristatin), 투불리신(tubulysin), 겔다나마이신(geldanamycin), 메이탄시노이드(maytansinoid), 칼리케아마이신(calicheamycin), 다우노마이신(daunomycin), 독소루비신(doxorubicin), 메토트렉세이트(methotrexate), 빈데신(vindesine), SG2285, 돌라스타틴(dolastatin), 돌라스타틴 유사체(dolastatin analog), 오리스타틴(auristatin), 크립토피신(cryptophycin), 캄토테신(camptothecin), 리족신(rhizoxin), 리족신 유도체(rhizoxin derivatives), CC-1065, CC-1065, 유사체 또는 유도체, 듀오카마이신(duocarmycin), 에네다인 항생제(enediyne antibiotic), 에스페라마이신(esperamicin), 에포틸론(epothilone), 톡소이드(toxoid), 또는 이들의 배합물;(c) Diphtheria toxin, botulinum toxin, tetanus toxin, decentritoxin, cholera toxin, amanitin, α-amanitin, pyrrolobenzodiazepine, pyrrolobenzodiazepine derivatives, indolinobenzodiazepine, pyridinobenzodiazepine, tetrodotoxin, breve Toxins (brevetoxin), ciguatoxin, ricin, AM toxin, auristatin, tubulysin, geldanamycin, maytansinoid, calichea calicheamycin, daunomycin, doxorubicin, methotrexate, vindesine, SG2285, dolastatin, dolastatin analog, auristatin, Cryptophycin, camptothecin, rhizoxin, rhizoxin derivatives, CC-1065, CC-1065, analogs or derivatives, duocarmycin, enediyne antibiotic antibiotic, esperamicin, epothilone, toxoid, or combinations thereof;
(d) 친화성 리간드(affinity ligand), 여기에서 친화성 리간드는 기질, 저해제, 활성화제, 신경전달물질, 방사성 동위원소, 또는 이들의 배합물;(d) affinity ligand, wherein the affinity ligand is a substrate, inhibitor, activator, neurotransmitter, radioisotope, or combination thereof;
(e) 방사능표지(radioactive label), 32P, 35S, 형광다이, 전자밀도 반응제(electron dense reagent), 효소, 비오틴, 스트렙타비딘(streptavidin), 디옥시제닌(dioxigenin), 햅텐(hapten), 면역성 단백질(immunogenic protein), 타겟에 컴플러멘터리한 서열을 갖는 핵산 분자(nucleic acid molecule with a sequence complementary to a target) 또는 이들의 배합물;(e) Radioactive label, 32P, 35S, fluorescent die, electron dense reagent, enzyme, biotin, streptavidin, dioxigenin, hapten, an immunogenic protein, a nucleic acid molecule with a sequence complementary to a target, or a combination thereof;
(f) 면역조절 화합물(immunomodulatory compound), 항-암제(anticancer agent), 항-바이러스제(anti-viral agent), 항-박테리아제(anti-bacterial agent), 항-곰팡이제(anti-fungal agent), 및 항-기생충제(anti-parasitic agent), 또는 이들의 배합물;(f) immunomodulatory compound, anticancer agent, anti-viral agent, anti-bacterial agent, anti-fungal agent , and anti-parasitic agents, or combinations thereof;
(g) 타목시펜(tamoxifen), 랄록시펜(raloxifene), 드롤록시펜(droloxifene), 4-하이드록시타목시펜(4-hydroxytamoxifen), 트리옥시펜(trioxifene), 케옥시펜(keoxifene), LY117018, 오나프리스톤(onapristone) 또는 토레미펜(toremifene);(g) Tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone ( onapristone) or toremifene;
(h) 4(5)-이미다졸, 아미노글루테티미드(aminoglutethimide), 메제스톨 아세테이트(megestrol acetate), 엑스메스탄(exemestane), 레트로졸(letrozole), 또는 아나스트로졸(anastrozole);(h) 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, letrozole, or anastrozole;
(i) 플루타미드(flutamide), 닐루타미드(nilutamide), 비칼루타미드(bicalutamide), 리우프롤라이드(leuprolide), 고세렐린(goserelin), 또는 트록사시타빈(troxacitabine);(i) flutamide, nilutamide, bicalutamide, leuprolide, goserelin, or troxacitabine;
(j) 아로마타아제 저해제;(j) aromatase inhibitor;
(k) 단백질 키나아제 저해제;(k) protein kinase inhibitors;
(l) 리피드 키나아제 저해제;(l) lipid kinase inhibitors;
(m) 안티센스 올리고뉴클레오티드;(m) antisense oligonucleotide;
(n) 리보자임;(n) ribozyme;
(o) 백신; 및(o) Vaccines; and
(p) 항-맥관형성제(anti-angiogenic agent).(p) Anti-angiogenic agent.
본 발명의 일 양태에서, 활성제는 In one aspect of the invention, the active agent is
, , , , , , , , , , , , , , , 또는 이고, , , , , , , , , , , , , , , , or ego,
여기에서 y는 1 내지 10의 정수이다.Here y is an integer from 1 to 10.
또한, 본 발명의 다른 일 양태에서, 활성제는 피롤로벤조디아제핀 다이머이고, 상기 피롤로벤조디아제핀 다이머의 N10 또는 N10' 위치를 통해 링커와 항체가 연결된다.Additionally, in another aspect of the present invention, the active agent is a pyrrolobenzodiazepine dimer, and the linker and the antibody are connected through the N10 or N10' position of the pyrrolobenzodiazepine dimer.
피롤로벤조디아제핀 다이머의 N10 및 N10' 위치에 각각 독립적으로 -C(O)O-*, -S(O)O-*, -C(O)-*, -C(O)NR-*, -S(O)2NR-*, -(P(O)R')NR-*, -S(O)NR-*, 및 -PO2NR-*기로 이루어진 그룹으로부터 선택되는 어느 하나가 부착되며,-C(O)O-*, -S(O)O-*, -C(O)-*, -C(O)NR-*, - independently at the N10 and N10' positions of the pyrrolobenzodiazepine dimer, respectively. Any one selected from the group consisting of S(O) 2 NR-*, -(P(O)R')NR-*, -S(O)NR-*, and -PO 2 NR-* groups is attached,
여기에서 *은 링커가 부착되는 부분이고,Here, * is the part where the linker is attached,
여기에서, R 및 R'은 각각 독립적으로 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, 치환되거나 비치환된 C1-8알킬, 치환되거나 비치환된 C3-8사이클로알킬, 치환되거나 비치환된 C1-8알콕시, 치환되거나 비치환된 C1-8알킬티오, 치환되거나 비치환된 C3-20헤테로아릴, 치환되거나 비치환된 C5-20아릴 또는 모노- 또는 다이-C1-8알킬아미노이고,Here, R and R' are each independently H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted Substituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted C 1-8 alkylthio, substituted or unsubstituted C 3-20 heteroaryl, substituted or unsubstituted C 5-20 aryl or mono- or di-C 1-8 alkylamino,
여기에서 C1-8알킬, C3-8사이클로알킬, C1-8알콕시, C1-8알킬티오, C3-20헤테로아릴, C5-20아릴이 치환되는 경우, H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, 할로, C1-6알킬, C1-6알콕시 및 C6-12아릴로 이루어진 그룹으로부터 선택되는 치환기로 치환되는,Where C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl are substituted, H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NNH 2 , halo, C 1-6 alkyl, C 1-6 alkoxy and C 6-12 aryl,
피롤로벤조디아제핀 다이머 전구체(pyrrolobenzodiazepine dimer prodrug), 이의 약학적으로 허용되는 염 또는 용매화물은 활성제로 사용할 수 있다.Pyrrolobenzodiazepine dimer prodrug, its pharmaceutically acceptable salt or solvate can be used as an active agent.
보다 구체적으로, 피롤로벤조디아제핀 다이머의 N10 위치에서 X 또는 N'10 위치에서 X '로 치환되고, 여기서 X 또는 X'는 피롤로벤조디아제핀 다이머를 링커에 연결하며;More specifically, the pyrrolobenzodiazepine dimer is substituted with
X 및 X'는 각각 독립적으로 -C(O)O*, -S(O)O-*, -C(O)-*, -C(O)NRX-*, -S(O)2NRX-*, -P(O)R'NRX-*, -S(O)NRX-*, 또는 -PO2NRX-*로부터 선택되고;X and X' are each independently -C(O)O*, -S(O)O-*, -C(O)-*, -C (O) NR is selected from X -*, -P(O)R'NR X -*, -S(O)NR X -*, or -PO 2 NR X -*;
RX 및 RX'는 독립적으로 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, C3-20 헤테로아릴, C5-20 아릴 또는 모노- 또는 디(di)-C1-8 알킬아미노로부터 선택된다. R _ _ _ _ _ _ _ _ _ 8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkylamino.
본 발명의 일 양태에서, 상기 활성제로 피롤로벤조디아제핀 다이머 전구체가 제공된다. 본 발명에 따른 전구체 형태로 투여하는 경우, 혈중 노출 시 추가적인 반응에 의해 유효한 약물로 전환되어야 할 필요가 있기 때문에 예상치 못한 링커의 분해 시에 생길 수 있는 부작용의 발생가능성을 미연에 방지할 수 있고, 정상세포에 대한 독성이 감소하며, 약물이 보다 안정적이라는 점에서 기존 PBD 약물에 비해 유리한 점이 있다.In one aspect of the invention, a pyrrolobenzodiazepine dimer precursor is provided as the activator. When administered in the form of a precursor according to the present invention, it needs to be converted into an effective drug by an additional reaction when exposed to the blood, so the possibility of side effects that may occur due to unexpected decomposition of the linker can be prevented. It has an advantage over existing PBD drugs in that toxicity to normal cells is reduced and the drug is more stable.
또한 항체-약물 접합체 제조 시, 기존 방법으로 제조한 항체-약물 접합체의 경우 불순물의 함량이 높고 노출된 이민 그룹이 뉴클레오필(nucleophile)의 공격을 받아 원치 않는 구조의 약물이 생성될 우려가 있는 반면, 본 발명에 따른 방법으로 제조된 항체-약물 접합체는 순도가 높아 분리가 용이하다는 장점이 있고, 기존 PBD 또는 PBD 다이머에 비하여 물성이 보다 향상되는 것으로 나타났다.In addition, when manufacturing an antibody-drug conjugate, there is a risk that the antibody-drug conjugate prepared by the existing method may have a high content of impurities and the exposed imine group may be attacked by nucleophiles, creating a drug with an unwanted structure. On the other hand, the antibody-drug conjugate prepared by the method according to the present invention has the advantage of being easy to separate due to its high purity, and its physical properties were shown to be improved compared to existing PBD or PBD dimer.
본 발명의 일 양태에서, 피롤로벤조디아제핀 다이머 전구체는 하기 일반식 X 또는 일반식 XI 구조를 갖는 것을 특징으로 하는, 피롤로벤조디아제핀 다이머 전구체, 이의 약학적으로 허용되는 염 또는 용매화물이다:In one aspect of the invention, the pyrrolobenzodiazepine dimer precursor is a pyrrolobenzodiazepine dimer precursor, a pharmaceutically acceptable salt or solvate thereof, characterized by having the following general formula
[일반식 X][General formula
[일반식 XI][General Formula XI]
상기 식에서,In the above equation,
상기 점선은 C1과 C2 사이, C2와 C3 사이, C'1과 C'2 사이, 또는 C'2과 C'3 사이의 이중 결합의 선택적 존재를 나타내며;The dotted line indicates the optional presence of a double bond between C1 and C2, C2 and C3, C'1 and C'2, or C'2 and C'3;
RX1 및 RX1'는 독립적으로 H, OH, =O, =CH2, CN, Rm, ORm, =CH-Rm' =C(Rm')2, O-SO2-Rm, CO2Rm, CORm, 할로 및 디할로로부터 선택되고; R _ _ _ _ _ _ _ _ _ , CO 2 R m , COR m , halo and dihalo;
Rm'는 Rm, CO2Rm, CORm, CHO, CO2H, 및 할로로부터 선택되며,R m ' is selected from R m , CO 2 R m , COR m , CHO, CO 2 H, and halo,
각각의 Rm는 독립적으로 C1-12 알킬, C2-12 알케닐, C2-12 알키닐, C5-20 아릴, C5-20 헤테로아릴, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 및 5 내지 7-원 헤테로아릴로 이루어진 군으로부터 선택되고;Each R m is independently C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl, 3 to 7 - is selected from the group consisting of one-membered heterocyclyl, 3- to 7-membered heterocycloalkyl, and 5- to 7-membered heteroaryl;
RX2, RX2' RX3, RX3', RX5, 및 RX5'는 독립적으로 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm 2, NO2, 및 할로로부터 선택되며; R _ _ _ _ _ _ _ _ _ _ _ _ _ , and halo;
RX4 및 RX4'는 독립적으로 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm 2, NO2, 할로, C1-6 알킬 C1-6 알콕시, C2-6 알케닐, C2-6 알키닐, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-12 아릴, 5 내지 7-원 헤테로아릴, -CN, -NCO, -ORn, -OC(O)Rn, -OC(O)NRnRn', -OS(O)Rn, -OS(O)2Rn, -SRn, -S(O)Rn, -S(O)2Rn, -S(O)NRnRn', -S(O)2NRnRn', -OS(O)NRnRn', -OS(O)2NRnRn', -NRnRn', -NRnC(O)Ro, -NRnC(O)ORo, -NRnC(O)NRoRo', -NRnS(O)Ro, -NRnS(O)2Ro, -NRnS(O)NRoRo', -NRnS(O)2NRoRo', -C(O)Rn, -C(O)ORn 및 -C(O)NRnRn'로 부터 선택되고; R _ _ _ _ _ _ _ _ _ _ _ C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5-12 aryl, 5 to 7-membered heteroaryl, -CN, -NCO, -OR n , -OC(O)R n , -OC(O)NR n R n ', -OS(O)R n , -OS(O) 2 R n , -SR n , -S(O)R n , -S(O) 2 R n , -S(O)NR n R n ', -S(O) 2 NR n R n ', -OS(O)NR n R n ', -OS(O) 2 NR n R n ', -NR n R n ', -NR n C(O)R o , -NR n C(O)OR o , -NR n C(O)NR o R o ', -NR n S(O)R o , -NR n S(O) 2 R o , -NR n S(O)NR o R o ', -NR n S(O) 2 NR o R o ', -C(O) R n , -C(O)OR n and -C(O)NR n R n ';
X 및 X'는 독립적으로 -C(O)O*, -S(O)O-*, -C(O)-*, -C(O)NRX-*, -S(O)2NRX-*, -P(O)R'NRX-*, -S(O)NRX-*, 또는 -PO2NRX-*로부터 선택되며;X and X' are independently -C(O)O*, -S(O ) O-*, -C(O)- * , -C(O) NR - * , -P( O ) R'NR
RX 및 RX'는 독립적으로 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, C3-20 헤테로아릴, C5-20 아릴 또는 모노- 또는 디(di)-C1-8 알킬아미노로 부터 선택되며; R _ _ _ _ _ _ _ _ _ 8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkylamino;
Y 및 Y'는 독립적으로 O, S, 및 N(H)으로 부터 선택되고;Y and Y' are independently selected from O, S, and N(H);
RX6는 독립적으로 C3-12 알킬렌, C3-12 알케닐렌, 또는 C3-12 헤테로알킬렌으로 부터 선택되며; R _ _ _
RX7 및 RX7' 는 독립적으로 H, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-6 사이클로 알킬, 3 내지 7-원 헤테로사이클로알킬, C6-10 아릴, 5 내지 7-원 헤테로아릴, -ORr, -OC(O)Rr, -OC(O)NRrRr', -OS(O)Rr, -OS(O)2Rr, -SRr, -S(O)Rr, -S(O)2Rr, -S(O)NRrRr', -S(O)2NRrRr', -OS(O)NRrRr', -OS(O)2NRrRr', -NRrRr', -NRrC(O)Rs, -NRrC(O)ORs, -NRrC(O)NRsRs', -NRrS(O)Rs, -NRrS(O)2Rs, -NRrS(O)NRsRs', -NRrS(O)2NRsRs, -C(O)Rr, -C(O)ORs 또는 -C(O)NRrRr'으로 부터 선택되고; R _ _ _ _ _ _ 10 aryl, 5 to 7-membered heteroaryl, -OR r , -OC(O)R r , -OC(O)NR r R r ', -OS(O)R r , -OS(O) 2 R r , -SR r , -S(O)R r , -S(O) 2 R r , -S(O)NR r R r ', -S(O) 2 NR r R r ', -OS(O) NR r R r ', -OS(O) 2 NR r R r ', -NR r R r ', -NR r C(O)R s , -NR r C(O)OR s , -NR r C( O)NR s R s ', -NRr S (O)R s , -NRr S (O) 2 R s , -NRr S (O)NR s R s ', -NRr S (O) 2 NR s R s , -C(O)R r , -C(O)OR s or -C(O)NR r R r ';
각각의 Rr, Rr', Rs, 및 Rs' 은 독립적으로 H, C1-7 알킬, C2-7 알케닐, C2-7 알키닐, C3-13 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10 아릴, 및 5 내지 7-원 헤테로아릴로 부터 선택되며;Each of R r , R r ', R s , and R s ' is independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3 to selected from 7-membered heterocycloalkyl, C 5-10 aryl, and 5 to 7-membered heteroaryl;
각 RX8 및 RX8'는 독립적으로 H, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-6 헤테로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10 아릴, 5 내지 7-원 헤테로아릴, -S(O)Rm, -S(O)2Rm, -S(O)NRmRm', -S(O)2NRmRm', -NRmRm', -NRmC(O)Rm, -NRmC(O)ORn, -NRmC(O)NRnRn', -NRmS(O)Rn, -NRmS(O)2Rn, -NRmS(O)NRnRn', -NRmS(O)2NRnRn', -C(O)Rm, -C(O)ORm 및 -C(O)NRmRm'로 부터 선택되고; Each R _ _ _ _ _ -10 aryl, 5 to 7-membered heteroaryl, -S(O)R m , -S(O) 2 R m , -S(O)NR m R m ', -S(O) 2 NR m R m ', -NR m R m ', -NR m C(O)R m , -NR m C(O)OR n , -NR m C(O)NR n R n ', -NR m S(O)R n , -NR m S(O) 2 R n , -NR m S(O)NR n R n ', -NR m S(O) 2 NR n R n ', -C(O)R m , -C (O)OR m and -C(O)NR m R m ';
Za 는 ORX12a, NRX12aRX12a, 또는 SRX12a로 부터 선택되며;Z a is selected from OR X12a , NR X12a R X12a , or SR X12a ;
Zb 는 ORX13a, NRX13aRX13a, 또는 SRX13a로 부터 선택되고;Z b is selected from OR X13a , NR X13a R X13a , or SR X13a ;
Za'는 ORX12a', NRX12a'RX12a', 또는 SRX12a'로 부터 선택되며;Z a 'is selected from OR X12a ', NR X12a 'R X12a ', or SR X12a ';
Zb'는 ORX13a', NRX13'RX13a' 또는 SRX13a'로 부터 선택되고;Z b 'is selected from OR X13a ', NR X13 'R X13a ' or SR X13a ';
각 RX12a, RX12a', RX13a' 및 RX13a'는 독립적으로 H, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10 아릴, 5 내지 7-원 헤테로아릴, -C(O)RX15a, -C(O)ORX15a 및 -C(O)NRX15aRX15a'로 부터 선택되고; 및 Each R _ _ _ _ _ _ -one-membered heterocycloalkyl, C 5-10 aryl , 5 to 7-membered heteroaryl , -C(O) R ; and
각각의 RX15a 및 RX15a' 는 독립적으로 C1-12 알킬, C2-12 알케닐, C2-12 알키닐, C5-20 아릴, C5-20 헤테로아릴, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 및 5 내지 7-원 헤테로아릴로부터 선택되며; Each R _ _ _ _ _ _ , 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl;
상기 Za 및 Zb는 이들이 부착된 원자와 함께 임의적으로 결합하여 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 또는 3 내지 7-원 헤테로아릴을 형성하고, 및 Za' 및 Zb'는 이들이 부착된 원자와 함께 임의적으로 결합하여 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 또는 3 내지 7-원 헤테로 아릴을 형성하며; 및wherein Z a and Z b are optionally combined together with the atoms to which they are attached to form 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, or 3 to 7-membered heteroaryl, and Z a ' and Z b ' are They optionally join together with the atoms to which they are attached to form a 3 to 7-membered heterocyclyl, a 3 to 7-membered heterocycloalkyl, or a 3 to 7-membered heteroaryl; and
상기 각각의 Rn, Rn', Ro, Ro', Rp, 및 Rp' 는 독립적으로 H, C1-7 알킬, C2-7 알케닐, C2-7 알키닐, C3-13 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10 아릴, 및 5 내지 7-원 헤테로아릴로부터 선택된다.Each of R n , R n ', R o , Ro ' , R p , and R p ' is independently H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C is selected from 3-13 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5-10 aryl, and 5 to 7-membered heteroaryl.
본 발명의 일 양태에서, 상기 Rm는 독립적으로 C1-12 알킬, C2-12 알케닐, C2-12 알키닐, C5-20 아릴, C5-20 헤테로아릴, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 및 5 내지 7-원 헤테로아릴로 이루어진 군으로부터 선택되고,In one aspect of the invention, R m is independently C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 selected from the group consisting of cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl,
본 발명의 일 양태에서, Rm는 추가적으로 C1-12 알킬, C2-12 알케닐, C2-12 알키닐, C5-20 아릴, C5-20 헤테로아릴, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 또는 5 내지 7-원 헤테로아릴로 치환된다.In one aspect of the invention, R m is additionally C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl. , 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, or 5 to 7-membered heteroaryl.
본 발명의 일 양태에서, 상기 RX4 및 RX4'는 독립적으로 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRmRm', NO2, 할로, C1-6 알킬 C1-6 알콕시, C2-6 알케닐, C2-6 알키닐, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-12 아릴, 5 내지 7-원 헤테로아릴, -CN, -NCO, -ORn, -OC(O)Rn, -OC(O)NRnRn', -OS(O)Rn, -OS(O)2Rn, -SRn, -S(O)Rn, -S(O)2Rn, -S(O)NRnRn', -S(O)2NRnRn', -OS(O)NRnRn', -OS(O)2NRnRn', -NRnRn', -NRnC(O)Ro, -NRnC(O)ORo, -NRnC(O)NRoRo', -NRnS(O)Ro, -NRnS(O)2Ro, -NRnS(O)NRoRo', -NRnS(O)2NRoRo', -C(O)Rn, -C(O)ORn 및 -C(O)NRnRn'로 부터 선택되고, In one aspect of the invention , R _ _ 1-6 alkyl C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5-12 aryl, 5 to 7- One heteroaryl, -CN, -NCO, -OR n , -OC(O)R n , -OC(O)NR n R n ', -OS(O)R n , -OS(O) 2 R n , -SR n , -S(O)R n , -S(O) 2 R n , -S(O)NR n R n ', -S(O) 2 NR n R n ', -OS(O)NR n R n ', -OS(O) 2 NR n R n ', -NR n R n ', -NR n C(O)Ro, -NR n C(O)ORo, -NR n C(O)NR o R o ', -NR n S(O)R o , -NR n S(O) 2 R o , -NR n S(O)NR o R o ', -NR n S(O) 2 NR o R o ', -C(O)R n , -C(O)OR n and -C(O)NR n R n ',
상기 RX4 또는 RX4'는 C1-6 알킬, C1-6 알콕시, C2-6 알케닐, C2-6 알키닐, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-12 아릴 또는 5 내지 7-원 헤테로아릴이고, 추가적으로 하나 이상의 C1-6 알킬, C1-6 알콕시, C2-6 알케닐, C2-6 알키닐, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10 아릴, 5 내지 7-원 헤테로아릴, -ORp, -OC(O)Rp, -OC(O)NRpRp', -OS(O)Rp, -OS(O)2Rp, -SRp, -S(O)Rp, -S(O)2Rp, -S(O)NRpRp', -S(O)2NRpRp', -OS(O)NRpRp', -OS(O)2NRpRp', -NRpRp', -NRpC(O)Rq, -NRpC(O)ORq, -NRpC(O)NRqRq', -NRpS(O)Rq, -NRpS(O)2Rq, -NRpS(O)NRqRq', -NRpS(O)2NRqRq', -C(O)Rp, -C(O)ORp 또는 -C(O)NRpRp로 치환된다. Said R _ _ _ _ _ C 5-12 aryl or 5 to 7-membered heteroaryl, and additionally one or more C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl , 3 to 7-membered heterocycloalkyl, C 5-10 aryl, 5 to 7-membered heteroaryl, -OR p , -OC(O)R p , -OC(O)NR p R p ', -OS( O)R p , -OS(O) 2 R p , -SR p , -S(O)R p , -S(O) 2 R p , -S(O)NR p R p ', -S(O ) 2 NR p R p ', -OS(O)NR p R p ', -OS(O) 2 NR p R p ', -NR p R p ', -NR p C(O)R q , -NR p C(O)OR q , -NR p C(O)NR q R q ', -NR p S(O)R q , -NR p S(O) 2 R q , -NR p S(O)NR q R q ', -NR p S(O) 2 NR q R q ', -C(O)R p , -C(O)OR p or -C(O)NR p R p .
본 발명의 일 양태에서, 상기 RX7 및 RX7' 는 독립적으로 H, C1-6 알킬, C2-6 알케닐, C2-6알키닐, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C6-10 아릴, 5 내지 7-원 헤테로아릴, -ORr, -OC(O)Rr, -OC(O)NRrRr', -OS(O)Rr, -OS(O)2Rr, -SRr, -S(O)Rr, -S(O)2Rr, -S(O)NRrRr', -S(O)2NRrRr', -OS(O)NRrRr', -OS(O)2NRrRr', -NRrRr', -NRrC(O)Rs, -NRrC(O)ORs, -NRrC(O)NRsRs', -NRrS(O)Rs, -NRrS(O)2Rs, -NRrS(O)NRsRs', -NRrS(O)2NRsRs, -C(O)Rr, -C(O)ORs 또는 -C(O)NRrRr'으로부터 선택되고, In one aspect of the invention , R One-membered heterocycloalkyl, C 6-10 aryl, 5 to 7-membered heteroaryl, -OR r , -OC(O)R r , -OC(O)NR r R r ', -OS(O)R r , -OS(O) 2 R r , -SR r , -S(O)R r , -S(O) 2 R r , -S(O)NR r R r ', -S(O) 2 NR r R r ', -OS(O)NR r R r ', -OS(O) 2 NR r R r ', -NR r R r ', -NR r C(O)R s , -NR r C(O) OR s , -NR r C(O)NR s R s ', -NR r S(O)R s , -NR r S(O) 2 R s , -NR r S(O)NR s R s ', -NR r S(O) 2 NR s R s , -C(O)R r , -C(O)OR s or -C(O)NR r R r ',
상기 RX7 또는 RX7' 는 C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C6-10 아릴, 5 내지 7-원 헤테로아릴이고, 추가적으로 C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C6-10 아릴, 5 내지 7-원 헤테로아릴, -ORt, -OC(O)Rt, -OC(O)NRtRt', -OS(O)Rt, -OS(O)2Rt, -SRt, -S(O)Rt, -S(O)2Rt, -S(O)NRtRt', -S(O)2NRtRt', -OS(O)NRtRt', -OS(O)2NRtRt', -NRtRt', -NRtC(O)Ru, -NRtC(O)ORu, -NRtC(O)NRuRu', -NRtS(O)Ru, -NRtS(O)2Ru, -NRtS(O)NRuRu', -NRtS(O)2NRuRu', -C(O)Rt, -C(O)ORt 또는 -C(O)NRtRt'로 치환되며, The R _ _ _ _ _ 5 to 7-membered heteroaryl, and additionally C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6-10 Aryl, 5 to 7-membered heteroaryl, -OR t , -OC(O)R t , -OC(O)NR t R t ', -OS(O)R t , -OS(O) 2 R t , -SR t , -S(O)R t , -S(O) 2 R t , -S(O)NR t R t ', -S(O) 2 NR t R t ', -OS(O)NR t R t ', -OS(O) 2 NR t R t ', -NR t R t ', -NR t C(O)R u , -NR t C(O)OR u , -NR t C(O )NR u R u ', -NR t S(O)R u , -NR t S(O) 2 R u , -NR t S(O)NR u R u ', -NR t S(O) 2 NR u R u ', -C(O)R t , -C(O)OR t or -C(O)NR t R t ',
상기 Rr, Rr', Rs, Rs', Rt, Rt', Ru 및 Ru'는 독립적으로 H, C1-7 알킬, C2-7 알케닐, C2-7 알키닐, C3-13 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10 아릴, 및 5 내지 7-원 헤테로아릴로부터 선택된다.The R r , R r ', R s , R s ', R t , R t ', R u and R u ' are independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 is selected from alkynyl, C 3-13 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5-10 aryl, and 5 to 7-membered heteroaryl.
본 발명의 일 양태에서, 상기 RX1 및 RX1' 는 독립적으로 Rm 으로부터 선택되고; 및In one aspect of the invention , R and
Rm은 C1-6 알킬, C2-6 알케닐, C5-7 아릴 및 C3-6 헤테로아릴로부터 선택된다.R m is selected from C 1-6 alkyl, C 2-6 alkenyl, C 5-7 aryl and C 3-6 heteroaryl.
본 발명의 일 양태에서, 상기 RX2 , RX2', RX3, RX3', RX5, 및 RX5'은 독립적으로 H 또는 OH로부터 선택된다.In one aspect of the invention , R
본 발명의 일 양태에서, RX4 및 RX4'는 독립적으로 Rm으로부터 선택되고; 및In one aspect of the invention, R and
Rm 은 C1-6 알콕시이다.R m is C 1-6 alkoxy.
본 발명의 일 양태에서, 상기 RX4 및 RX4' 는 독립적으로 메톡시, 에톡시 및 부톡시로 이루어진 군으로부터 선택되는 어느 하나이다.In one aspect of the present invention, R
본 발명의 일 양태에서, 상기 Y 및 Y'는 O이다.In one aspect of the present invention, Y and Y' are O.
본 발명의 일 양태에서, 상기 RX6 는 C3-12 알킬렌, C3-12 알케닐렌 또는 C3-12 헤테로알킬렌이고, 상기 RX6은 -NH2, -NHRm, -NHC(O)Rm, -NHC(O)CH2-[OCH2CH2]n-RXX, 또는 -[CH2CH2O]n-RXX치환되고;In one aspect of the present invention , R )R m , -NHC(O)CH 2 -[OCH 2 CH 2 ] n -R XX , or -[CH 2 CH 2 O] n -R XX substituted;
상기 RXX는 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, C3-20 헤테로아릴, C5-20 아릴 또는 모노- 또는 디-C1-8 알킬 아미노; 및The R XX is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1 -8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkylamino; and
n은 1 내지 6의 정수이다.n is an integer from 1 to 6.
본 발명의 일 양태에서, 상기 피롤로벤조디아제핀 다이머는 하기 일반식 X로 표현되는 것이다:In one aspect of the present invention, the pyrrolobenzodiazepine dimer is represented by the following general formula
[일반식 X][General formula
상기 식에서,In the above equation,
상기 점선은 C1과 C2 사이, C2와 C3 사이, C'1과 C'2 사이, 또는 C'2과 C'3 사이의 이중 결합의 선택적 존재를 나타내며;The dotted line indicates the optional presence of a double bond between C1 and C2, C2 and C3, C'1 and C'2, or C'2 and C'3;
RX1 및 RX1'는 각각 독립적으로 H, OH, =O, =CH2, CN, Rm, ORm, =CH-Rm, =C(Rm')2, OSO2-Rm, CO2Rm, CORm, 할로 또는 디할로로부터 선택되고; R _ _ _ _ _ _ _ _ _ is selected from CO 2 R m , COR m , halo or dihalo;
RX2, RX2' RX3, 및 RX3'는 각각 독립적으로 H, Rm, OH, ORm, NRm 2, NO2, 및 할로로부터 선택되며; R _ _ _ _ _ _ _ _
RX4 및 RX4'는 각각 독립적으로 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm 2, 할로, 및 C1-6 알킬로부터 선택되고; RX4 and R _ _ _ _ _ _ _
RX5 및 RX5'는 각각 독립적으로 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm 2, -NRmRm', NO2, -NRmC(O)Rm', -NRmC(O)ORm', -NRmC(O)NRmRm', -S(O)Rm, -S(O)2Rm, -S(O)NRmRm', -S(O)2NRmRm', -NRmS(O)Rm', -NRmS(O)2Rm', -P(O)Rm, -P(O)2Rm, -P(O)NRmRm', -P(O)2NRmRm', -NRmP(O)Rm', -NRmP(O)2Rm', 및 할로로부터 선택되며; R _ _ _ _ _ _ _ _ _ _ _ _ O)R m' , -NR m C(O)OR m' , -NR m C(O)NR m R m' , -S(O)R m , -S(O) 2 R m , -S( O)NR m R m ', -S(O) 2 NR m R m ', -NR m S(O)R m ', -NR m S(O) 2 R m ', -P(O)R m , -P(O) 2 R m , -P(O)NR m R m ', -P(O) 2 NR m R m ', -NR m P(O)R m ', -NR m P(O ) 2 R m ', and halo;
Y 및 Y'는 각각 독립적으로 O, S, 또는 N(H)이고;Y and Y' are each independently O, S, or N(H);
RX6는 독립적으로 C3-12 알킬렌, C3-12 알케닐렌, 또는 C3-12 헤테로알킬렌이며; RX6은 -NH2, -NHRm, -NHC(O)Rm, -NHC(O)CH2-[OCH2CH2]n-RXX, 또는 -[CH2CH2O]n-RXX로 치환되거나 비치환되고; R _ _ _ R _ _ _ _ _ _ _ _ _ _ _ substituted or unsubstituted with XX ;
상기 RXX는 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, C1-8 알킬, C3-8 시클로알킬, C1-8 알콕시, C1-8 알킬 티오, C3-20 헤테로아릴, C5-20 아릴 또는 모노- 또는 디-C1-8 알킬아미노이고, 여기에서 n은 1 내지 6의 정수이며;The R XX is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy , C 1 -8 alkyl thio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkylamino, where n is an integer from 1 to 6;
RX7 및 RX7'는 각각 독립적으로 H, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, -C(O)Rr, -C(O)ORs 또는 -C(O)NRrRr'이고; R _ _ _ _ _ _ (O)NR r R r ';
Rr, Rr', 및 Rs는 각각 독립적으로 H, C1-7 알킬, C2-7 알케닐, C2-7 알키닐, C3-13 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10 아릴 또는 5 내지 7-원 헤테로아릴로이며;R r , R r ', and R s are each independently H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3 to 7-membered heterocyclo alkyl, C 5-10 aryl or 5 to 7-membered heteroarylo;
각 Rm'는 독립적으로 Rm, CO2Rm, CORm, CHO, CO2H, 및 할로로부터 선택되며,each R m' is independently selected from R m , CO 2 R m , COR m , CHO, CO 2 H, and halo;
각 Rm은 독립적으로 H, OH, C1-12 알킬, C1-12 알콕시, C2-12 알케닐, C2-12 알키닐, C5-20 아릴, C5-20 헤테로아릴, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 및 5 내지 7-원 헤테로아릴로 이루어진 군으로부터 선택되고, 여기에서 C5-20 아릴, C5-20 헤테로아릴, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 및 5 내지 7-원 헤테로아릴의 하나 이상의 수소원자는 OH, =O, C1-12 알킬, 또는 C1-12 알콕시로 치환될 수 있다.Each R m is independently H, OH, C 1-12 alkyl, C 1-12 alkoxy, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C selected from the group consisting of 3-6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl, wherein C 5-20 aryl, C 5- 20 Heteroaryl, C 3-6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl, one or more hydrogen atoms are OH, =O, C 1 It may be substituted with -12 alkyl, or C 1-12 alkoxy.
본 발명의 일 양태에서, 상기 RX1 및 RX1'는 각각 독립적으로 =CH2; C1-6 알킬; C1-6 알콕시; C2-6 알케닐; C5-7 아릴; C3-6 헤테로아릴; 또는 C1-6 알킬, 또는 C1-6 알콕시로 치환된 C5-7 아릴로부터 선택된다.In one aspect of the present invention, R C 1-6 alkyl; C 1-6 alkoxy; C 2-6 alkenyl; C 5-7 aryl; C 3-6 heteroaryl; or C 1-6 alkyl, or C 5-7 aryl substituted with C 1-6 alkoxy.
본 발명의 일 양태에서, 상기 RX2, RX2', RX3, 및 RX3'은 각각 독립적으로 H 또는 OH로부터 선택된다.In one aspect of the invention , R
본 발명의 일 양태에서, 상기 RX5, 및 RX5'은 각각 독립적으로 H, OH, -S(O)Rm, S(O)2Rm, -P(O)Rm, 및 -P(O)2Rm로 이루어진 군에서 선택되고, 여기에서 Rm은 H, OH, C1-12 알킬, C1-12 알콕시, C2-12 알케닐, 또는 C2-12 알키닐이다. In one aspect of the invention , R (O) 2 R m , wherein R m is H, OH, C 1-12 alkyl, C 1-12 alkoxy, C 2-12 alkenyl, or C 2-12 alkynyl.
본 발명의 일 양태에서, 상기 RX4 및 RX4'는 각각 독립적으로 C1-6 알콕시이다.In one aspect of the invention, R X4 and R X4 ' are each independently C 1-6 alkoxy.
본 발명의 일 양태에서, 상기 RX4 및 RX4' 는 독립적으로 메톡시, 에톡시 및 부톡시로 이루어진 군으로부터 선택되는 어느 하나이다.In one aspect of the present invention, R
본 발명의 일 양태에서, 상기 Y 및 Y'는 O이다.In one aspect of the present invention, Y and Y' are O.
본 발명의 일 양태에서, 상기 RX6는 C3-12 알킬렌, C3-12 알케닐렌 또는 C3-12 헤테로알킬렌이고, 상기 RX6은 -NH2, -NHRm, -NHC(O)Rm, -NHC(O)CH2-[OCH2CH2]n-RXX, 또는 -[CH2CH2O]n-RXX로 치환되며;In one aspect of the present invention , R )R m , -NHC(O)CH 2 -[OCH 2 CH 2 ] n -R XX , or -[CH 2 CH 2 O] n -R XX ;
상기 RXX는 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, C3-20 헤테로아릴, C5-20 아릴 또는 모노- 또는 디-C1-8 알킬 아미노이고; 및The R XX is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1 -8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkylamino; and
n은 1 내지 6의 정수이다.n is an integer from 1 to 6.
본 발명의 일 양태에서, 상기 피롤로벤조디아제핀 다이머는 하기 일반식 X로 표현되는 것이다:In one aspect of the present invention, the pyrrolobenzodiazepine dimer is represented by the following general formula
[일반식 X][General formula
상기 식에서,In the above equation,
상기 점선은 C1과 C2 사이, C2와 C3 사이, C'1과 C'2 사이, 또는 C'2과 C'3 사이의 이중 결합의 선택적 존재를 나타내며;The dotted line indicates the optional presence of a double bond between C1 and C2, C2 and C3, C'1 and C'2, or C'2 and C'3;
RX1 및 RX1'는 각각 독립적으로 H, OH, =O, =CH2, CN, Rm, ORm, =CH-Rm, =C(Rm')2, OSO2-Rm, CO2Rm, CORm, 할로 또는 디할로로부터 선택되고; R _ _ _ _ _ _ _ _ _ is selected from CO 2 R m , COR m , halo or dihalo;
RX2, RX2' RX3, 및 RX3'는 각각 독립적으로 H, Rm, OH, ORm, NRm 2, NO2, 및 할로로부터 선택되며; R _ _ _ _ _ _ _ _
RX4 및 RX4'는 각각 독립적으로 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm 2, 할로, 및 C1-6 알킬로부터 선택되고; RX4 and R _ _ _ _ _ _ _
RX5 및 RX5'는 각각 독립적으로 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm 2, -NRmRm', NO2, -NRmC(O)Rm', -NRmC(O)ORm', -NRmC(O)NRmRm', -S(O)Rm, -S(O)2Rm, -S(O)NRmRm', -S(O)2NRmRm', -NRmS(O)Rm', -NRmS(O)2Rm', -P(O)Rm, -P(O)2Rm, -P(O)NRmRm', -P(O)2NRmRm', -NRmP(O)Rm', -NRmP(O)2Rm', 및 할로로부터 선택되며; R _ _ _ _ _ _ _ _ _ _ _ _ O)R m' , -NR m C(O)OR m' , -NR m C(O)NR m R m' , -S(O)R m , -S(O) 2 R m , -S( O)NR m R m ', -S(O) 2 NR m R m ', -NR m S(O)R m ', -NR m S(O) 2 R m ', -P(O)R m , -P(O) 2 R m , -P(O)NR m R m ', -P(O) 2 NR m R m ', -NR m P(O)R m ', -NR m P(O ) 2 R m ', and halo;
Y 및 Y'는 각각 독립적으로 O, S, 또는 N(H)이고;Y and Y' are each independently O, S, or N(H);
RX6는 독립적으로 C3-12 알킬렌, C3-12 알케닐렌, 또는 C3-12 헤테로알킬렌이며; RX6은 -NH2, -NHRm, -NHC(O)Rm, -NHC(O)CH2-[OCH2CH2]n-RXX, 또는 -[CH2CH2O]n-RXX로 치환되거나 비치환되고; R _ _ _ R _ _ _ _ _ _ _ _ _ _ _ substituted or unsubstituted with XX ;
상기 RXX는 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, C1-8 알킬, C3-8 시클로알킬, C1-8 알콕시, C1-8 알킬 티오, C3-20 헤테로아릴, C5-20 아릴 또는 모노- 또는 디-C1-8 알킬아미노이고, 여기에서 n은 1 내지 6의 정수이며;The R XX is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy , C 1 -8 alkyl thio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkylamino, where n is an integer from 1 to 6;
RX7 및 RX7'는 각각 독립적으로 H, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, -C(O)Rr, -C(O)ORs 또는 -C(O)NRrRr'이고; R _ _ _ _ _ _ (O)NR r R r ';
Rr, Rr', 및 Rs는 각각 독립적으로 H, C1-7 알킬, C2-7 알케닐, C2-7 알키닐, C3-13 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10 아릴 또는 5 내지 7-원 헤테로아릴로이며;R r , R r ', and R s are each independently H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3 to 7-membered heterocyclo alkyl, C 5-10 aryl or 5 to 7-membered heteroarylo;
각 Rm'는 독립적으로 Rm, CO2Rm, CORm, CHO, CO2H, 및 할로로부터 선택되며,each R m' is independently selected from R m , CO 2 R m , COR m , CHO, CO 2 H, and halo;
각 Rm은 독립적으로 H, OH, C1-12 알킬, C1-12 알콕시, C2-12 알케닐, C2-12 알키닐, C5-20 아릴, C5-20 헤테로아릴, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 및 5 내지 7-원 헤테로아릴로 이루어진 군으로부터 선택되고, 여기에서 C5-20 아릴, C5-20 헤테로아릴, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 및 5 내지 7-원 헤테로아릴의 하나 이상의 수소원자는 OH, =O, C1-12 알킬, 또는 C1-12 알콕시로 치환될 수 있다.Each R m is independently H, OH, C 1-12 alkyl, C 1-12 alkoxy, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C selected from the group consisting of 3-6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl, wherein C 5-20 aryl, C 5- 20 Heteroaryl, C 3-6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl, one or more hydrogen atoms are OH, =O, C 1 It may be substituted with -12 alkyl, or C 1-12 alkoxy.
본 발명의 일 양태에서, 상기 RX1 및 RX1'는 각각 독립적으로 =CH2; C1-6 알킬; C1-6 알콕시; C2-6 알케닐; C5-7 아릴; C3-6 헤테로아릴; 또는 C1-6 알킬, 또는 C1-6 알콕시로 치환된 C5-7 아릴로부터 선택된다.In one aspect of the present invention, R C 1-6 alkyl; C 1-6 alkoxy; C 2-6 alkenyl; C 5-7 aryl; C 3-6 heteroaryl; or C 1-6 alkyl, or C 5-7 aryl substituted with C 1-6 alkoxy.
본 발명의 일 양태에서, 상기 RX2, RX2', RX3, 및 RX3'은 각각 독립적으로 H 또는 OH로부터 선택된다.In one aspect of the invention , R
본 발명의 일 양태에서, 상기 RX5, 및 RX5'은 각각 독립적으로 H, OH, -S(O)Rm, S(O)2Rm, -P(O)Rm, 및 -P(O)2Rm로 이루어진 군에서 선택되고, 여기에서 Rm은 H, OH, C1-12 알킬, C1-12 알콕시, C2-12 알케닐, 또는 C2-12 알키닐이다. In one aspect of the invention , R (O) 2 R m , wherein R m is H, OH, C 1-12 alkyl, C 1-12 alkoxy, C 2-12 alkenyl, or C 2-12 alkynyl.
본 발명의 일 양태에서, 상기 RX4 및 RX4'는 각각 독립적으로 C1-6 알콕시이다.In one aspect of the invention, R X4 and R X4 ' are each independently C 1-6 alkoxy.
본 발명의 일 양태에서, 상기 RX4 및 RX4' 는 독립적으로 메톡시, 에톡시 및 부톡시로 이루어진 군으로부터 선택되는 어느 하나이다.In one aspect of the present invention, R
본 발명의 일 양태에서, 상기 Y 및 Y'는 O이다.In one aspect of the present invention, Y and Y' are O.
본 발명의 일 양태에서, 상기 RX6는 C3-12 알킬렌, C3-12 알케닐렌 또는 C3-12 헤테로알킬렌이고, 상기 RX6은 -NH2, -NHRm, -NHC(O)Rm, -NHC(O)CH2-[OCH2CH2]n-RXX, 또는 -[CH2CH2O]n-RXX로 치환되며;In one aspect of the present invention , R )R m , -NHC(O)CH 2 -[OCH 2 CH 2 ] n -R XX , or -[CH 2 CH 2 O] n -R XX ;
상기 RXX는 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, C3-20 헤테로아릴, C5-20 아릴 또는 모노- 또는 디-C1-8 알킬 아미노이고; 및The R XX is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1 -8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkylamino; and
n은 1 내지 6의 정수이다.n is an integer from 1 to 6.
또한, 본 발명의 일 양태에서, 상기 활성제는 일반식 XII 또는 일반식 XIII로 기재되는 피롤로벤조디아제핀 다이머이다:Additionally, in one aspect of the invention, the active agent is a pyrrolobenzodiazepine dimer represented by Formula XII or Formula XIII:
[일반식 XII][General Formula XII]
[일반식 XIII][General Formula XIII]
상기 Xa 및 Xa'는 독립적으로 결합 또는 C1-6 알킬렌으로부터 선택되고;wherein X a and X a ' are independently selected from a bond or C 1-6 alkylene;
ZX' 및 ZX 는 독립적으로 수소, C1-8 알킬, 할로겐, 시아노, 나이트로, , 또는 -(CH2)m-OCH3로부터 선택되며; Z _ _ , or -(CH 2 ) m -OCH 3 ;
각각의 R80, R90 및 R100 는 수소, C1-8 알킬, C2-6 알케닐, 및 C1-6 알콕시로부터 선택되고; 및Each of R 80 , R 90 and R 100 is selected from hydrogen, C 1-8 alkyl, C 2-6 alkenyl, and C 1-6 alkoxy; and
m은 0 내지 12의 정수이다.m is an integer from 0 to 12.
상기 ZX' 및 ZX 는 독립적으로 수소, , 및 -(CH2)m-OCH3로 이루어진 군으로 부터 선택되는 어느 하나이고,Z X ' and Z X are independently hydrogen, , and -(CH 2 ) m -OCH 3 ,
상기 각각의 R80, R90 및 R100 는 수소, C1-3 알킬 및 C1-3 알콕시로 이루어진 군으로부터 선택되는 어느 하나이며,Each of R 80 , R 90 and R 100 is selected from the group consisting of hydrogen, C 1-3 alkyl and C 1-3 alkoxy,
m은 1 내지 6의 정수이다.m is an integer from 1 to 6.
본 발명의 일 양태에서, 상기 [LINKER-(B)l] 전구체는In one aspect of the present invention, the [LINKER-(B) l ] precursor is
, , , , , , , , , , , , , , , , , , , , , , , , 및 으로 이루어진 군으로부터 선택되는 어느 하나이다. , , , , , , , , , , , , , , , , , , , , , , , , and It is any one selected from the group consisting of.
또한, 본 발명의 일 양태에서, 상기 [LINKER-(B)l] 전구체는 ,Additionally, in one aspect of the present invention, the [LINKER-(B) l ] precursor is ,
, ,
, ,
, 또는 , or
이고, ego,
여기에서, MMAE는 모노메틸 오리스타틴 E(monomethyl auristatin E)이며,Here, MMAE is monomethyl auristatin E,
MMAF는 모노메틸 오리스타틴 F(monomethyl auristatin F)이다.MMAF is monomethyl auristatin F.
본 발명의 일 양태에서, 상기 [LINKER-(B)l] 전구체는 하기 구조를 포함한다:In one aspect of the invention, the [LINKER-(B) l ] precursor comprises the following structure:
, ,
, 또는 , or
이고, ego,
상기 B' 및 B''는 동일하거나 상이할 수 있는 활성제를 나타내고;wherein B' and B'' represent active agents which may be the same or different;
m 및 n은 각각 독립적으로 0 내지 30의 정수를 나타낸다.m and n each independently represent an integer from 0 to 30.
구체적으로, 상기는 일반식 X의 X 및 X'와 연결되는 부분을 의미한다. 더 구체적으로는 이다.Specifically, the above means the part connected to X and X' of general formula More specifically am.
또한, 본 발명은 상기 접합체를 포함하는 과증식, 암 또는 혈관신생질환의 예방 또는 치료용 약학적 조성물을 제공한다.Additionally, the present invention provides a pharmaceutical composition containing the above conjugate for preventing or treating hyperproliferation, cancer, or angiogenic disease.
본 발명의 일 양태에서, 상기 약학적 조성물은 추가적으로 약학적으로 유효한 양의 화학 치료제(chemotherapeutic agent)를 포함한다.In one aspect of the invention, the pharmaceutical composition additionally includes a pharmaceutically effective amount of a chemotherapeutic agent.
본 발명의 일 양태에서, 상기 암은 폐암, 소세포성 폐암, 위장관암, 대장암, 장암, 유방암, 난소암, 전립선암, 고환암, 간암, 신장암, 방광암, 췌장암, 뇌암, 육종, 골육종, 카포시 육종 및 흑색종으로 이루어진 군으로부터 선택되는 어느 하나이다.In one aspect of the invention, the cancer is lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's It is any one selected from the group consisting of sarcoma and melanoma.
아울러, 본 발명은 상기 접합체를 포함하는 약학 제제를 제공한다.In addition, the present invention provides a pharmaceutical formulation containing the above conjugate.
본 발명에 따른 항체-약물 접합체는 종양에서 주로 발현되는 TROP2 형태에 특이적으로 더 강하게 결합하는 항-TROP2 항체를 포함함으로써, 약물을 효과적이면서도 특이적 및 선택적으로 전달할 수 있으며, 항체에 약물이 안정적으로 결합되어 생체내 안정성을 유지하면서 목적하는 세포독성을 나타낼 수 있도록 하며, 특히 혈장 내에서 보다 안정하고 체내 순환시에도 안정적이며, 약물이 암세포 내에서 쉽게 방출되어 약효를 극대화할 수 있는 자가-희생기를 포함하는 링커 기술을 접목시킴으로써, 약물 및/또는 톡신이 표적 세포에 안정적으로 도달하여 약효를 효과적으로 발휘하면서도 독성을 크게 낮출 수 있는, 항체-링커-약물 시스템을 제공하는 효과를 나타낸다.The antibody-drug conjugate according to the present invention contains an anti-TROP2 antibody that specifically binds more strongly to the TROP2 form mainly expressed in tumors, thereby enabling effective, specific and selective delivery of the drug, and the drug is stable in the antibody. It is combined to maintain in vivo stability and exhibit the desired cytotoxicity. In particular, it is more stable in plasma and stable during circulation in the body, and the drug is easily released within cancer cells to maximize drug efficacy through self-sacrifice. By incorporating a linker technology containing a group, the drug and/or toxin can stably reach the target cells, effectively demonstrating drug efficacy while providing an antibody-linker-drug system that can significantly reduce toxicity.
도 1은 본 발명의 일 실시예에 따른 항체-약물 접합체 ADC1의 제조방법을 모식화한 도이다.
도 2는 본 발명의 일 실시예에 따른 항체-약물 접합체 ADC2의 제조방법을 모식화한 도이다.
도 3은 본 발명의 일 실시예에 따른 항체-약물 접합체 ADC3의 제조방법을 모식화한 도이다.
도 4는 본 발명의 일 실시예에 따른 항체-약물 접합체 ADC4의 제조방법을 모식화한 도이다.
도 5a 및 도 5b는 1차 in vivo 실험으로 췌장암 세포주 BxPC-3 이식 마우스 모델(도 5a) 및 유방암 세포주 MDA-MB-468 이식 마우스 모델(도 5b)에서 본 발명의 일 실시예에 따라 제조한 항체-약물 접합체의 종양 생장 억제 효능을 확인한 도이다.
도 6a 내지 도 6d는 2차 in vivo 실험으로 유방암 세포주 MDA-MB-468 이식 마우스 모델(도 6a), 췌장암 세포주 BxPC-3 이식 마우스 모델(도 6b), 위암 세포주 NCI-N87 이식 마우스 모델(도 6c) 및 비소세포폐암 세포주 HCC827 이식 마우스 모델(도 6d)에서 본 발명의 일 실시예에 따라 제조한 항체-약물 접합체의 종양 생장 억제 효능을 확인한 도이다.
도 7a 내지 도 7e는 3차 in vivo 실험으로 췌장암 세포주 BxPC-3 이식 마우스 모델(도 7a), 비소세포폐암 세포주 HCC827 이식 마우스 모델(도 7b), 췌장암 세포주 Capan-1 이식 마우스 모델(도 7c), 비소세포폐암 세포주 NCI-H2170 이식 마우스 모델(도 7d) 및 대장암 세포주 HT29 이식 마우스 모델(도 7e)에서 본 발명의 일 실시예에 따라 제조한 항체-약물 접합체의 종양 생장 억제 효능을 확인한 도이다. Figure 1 is a diagram schematically illustrating a method for producing antibody-drug conjugate ADC1 according to an embodiment of the present invention.
Figure 2 is a diagram schematically illustrating the manufacturing method of antibody-drug conjugate ADC2 according to an embodiment of the present invention.
Figure 3 is a diagram schematically illustrating the manufacturing method of antibody-drug conjugate ADC3 according to an embodiment of the present invention.
Figure 4 is a diagram schematically illustrating the manufacturing method of antibody-drug conjugate ADC4 according to an embodiment of the present invention.
Figures 5a and 5b show the first in vivo experiment, showing the pancreatic cancer cell line BxPC-3 transplant mouse model (Figure 5A) and the breast cancer cell line MDA-MB-468 transplant mouse model (Figure 5B) prepared according to an embodiment of the present invention. This diagram confirms the tumor growth inhibition efficacy of the antibody-drug conjugate.
Figures 6a to 6d show the second in vivo experiment, showing the breast cancer cell line MDA-MB-468 transplant mouse model (Figure 6A), the pancreatic cancer cell line BxPC-3 transplant mouse model (Figure 6B), and the stomach cancer cell line NCI-N87 transplant mouse model (Figure 6B). 6c) and a non-small cell lung cancer cell line HCC827 transplant mouse model (FIG. 6d) confirm the tumor growth inhibition efficacy of the antibody-drug conjugate prepared according to an embodiment of the present invention.
Figures 7a to 7e show the third in vivo experiment, showing the pancreatic cancer cell line BxPC-3 transplant mouse model (Figure 7a), the non-small cell lung cancer cell line HCC827 transplant mouse model (Figure 7b), and the pancreatic cancer cell line Capan-1 transplant mouse model (Figure 7c). , Figure confirming the tumor growth inhibition efficacy of the antibody-drug conjugate prepared according to an embodiment of the present invention in the non-small cell lung cancer cell line NCI-H2170 transplant mouse model (FIG. 7D) and the colon cancer cell line HT29 transplant mouse model (FIG. 7E) am.
본 발명은 인간 TROP2(tumor-associated calcium signal transducer 2, TACSTD2)에 특이적으로 결합할 수 있는 항체의 개발을 근거로 한 것이다.The present invention is based on the development of an antibody that can specifically bind to human TROP2 (tumor-associated calcium signal transducer 2, TACSTD2).
본 항목에서 사용된 제목은 명세서 기재의 편리성을 위한 것일 뿐, 본 발명을 이로 제한하는 것은 아니다.The titles used in this item are only for convenience of description and do not limit the present invention thereto.
본 발명에서 달리 정의하지 않는 한, 본 발명에서 사용된 과학 및 기술적 용어는 본 기술분야의 당업자가 통상적으로 이해하는 대로의 의미를 가진다. 나아가 문맥상 특별히 요구되지 않는다면, 단수는 복수를 포함하고, 복수는 단수를 포함한다.Unless otherwise defined in the present invention, scientific and technical terms used in the present invention have meanings as commonly understood by those skilled in the art. Furthermore, unless otherwise specifically required by context, the singular includes the plural and the plural includes the singular.
[정의][Justice]
본 명세서에서 하기 정의가 적용된다:The following definitions apply herein:
본 명세서에서 "접합체(conjugates)"는 세포독성 화합물의 하나 이상의 분자에 공유결합되는 세포 결합제를 말한다. 여기서, "세포 결합제"는 생물학적 타깃에 대한 친화도를 갖는 분자로서, 예를 들어 항체, 구체적으로 모노클로날 항체, 항체 단편일 수 있으며, 결합제는 생물학적 활성 화합물을 생물학적 타깃으로 유도하는 기능을 한다. 본 발명의 일 양태에서, 접합체는 세포 표면 항원을 통해 종양 세포를 표적화하도록 설계될 수 있다. 항원은 비정상적인 세포 타입에서 과다발현되거나 또는 발현되는 세포 표면 항원일 수 있다. 구체적으로, 표적 항원은 증식성 세포(예컨대 종양 세포) 상에서만 발현되는 것일 수 있다. 표적 항원은 통상 증식성 조직 및 정상 조직 사이의 상이한 발현에 기초하여 선택될 수 있다. 본 발명에서 항체는 링커에 결합된다.As used herein, “conjugates” refers to cell binding agents that are covalently linked to one or more molecules of a cytotoxic compound. Here, the “cell binding agent” is a molecule with affinity for a biological target, and may be, for example, an antibody, specifically a monoclonal antibody or antibody fragment, and the binding agent functions to guide the biologically active compound to the biological target. . In one aspect of the invention, conjugates can be designed to target tumor cells via cell surface antigens. The antigen may be a cell surface antigen that is overexpressed or expressed on abnormal cell types. Specifically, the target antigen may be expressed only on proliferating cells (eg, tumor cells). Target antigens can usually be selected based on differential expression between proliferative and normal tissues. In the present invention, the antibody is coupled to a linker.
본 발명에서 예를 들면 항원 결합 단편, 단백질, 또는 항체와 같은 폴리펩타이드의 "변이체"는 다른 폴리펩타이드 서열과 비교하여 하나 이상의 아미노산 잔기에 삽입, 결실, 부가 및/또는 치환이 발생한 폴리펩타이드이며, 융합 폴리펩타이드를 포함한다. 또한 단백질 변이체는 단백질 효소 절단, 인산화 또는 기타 후번역 변형에 의해 변형되었으나, 본 발명에 개시된 항체의 생물학적 활성 예를 들면 ROR1에 결합 및 특이성을 유지하는 것을 포함한다. 변이체는 본 발명에 개시된 항체 또는 그 항원 결합단편의 서열과 약 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 또는 80% 동일한 것일 수 있다. 퍼센트 동일성(%) 또는 상동성은 후술하는 바를 참조하여 계산할 수 있다.In the present invention, a "variant" of a polypeptide, for example, an antigen-binding fragment, protein, or antibody, is a polypeptide in which insertions, deletions, additions, and/or substitutions occur at one or more amino acid residues compared to other polypeptide sequences, Contains fusion polypeptides. Protein variants also include those that have been modified by protein enzymatic cleavage, phosphorylation, or other post-translational modifications, but retain the biological activities of the antibodies disclosed herein, such as binding and specificity to ROR1. The variant is about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88% of the sequence of the antibody or antigen-binding fragment thereof disclosed in the present invention. %, 87%, 86%, 85%, 84%, 83%, 82%, 81%, or 80% may be the same. Percent identity (%) or homology can be calculated with reference to what is described below.
일 구현예에서 퍼센트 상동성 또는 동일성은 100Х[(동일한 위치)/min(TGA, TGB)]으로 계산될 수 있으며, 상기 식에서 TGA, TGB 는 비교되는 서열 A 및 B의 잔기의 수 및 내부갭 위치의 합이다 (Russell et al., J. Mol Biol., 244: 332-350 (1994).In one embodiment, percent homology or identity can be calculated as 100Х[(same position)/min(TGA, TGB)], where TGA, TGB are the number of residues in sequences A and B being compared and the internal gap position. It is the sum of (Russell et al., J. Mol Biol., 244: 332-350 (1994).
본 발명에서 보존적 아미노산 치환은 폴리펩타이드의 활성 또는 항원선을 실질적으로 영향을 미치지 않는 치환을 의미한다. 폴리펩타이드는 하나 이상의 보존적 치환을 포함할 수 있다. 비제한적 예는 하기 표 3에 개시되어 있다.In the present invention, conservative amino acid substitution refers to a substitution that does not substantially affect the activity or antigen function of the polypeptide. A polypeptide may contain one or more conservative substitutions. Non-limiting examples are set forth in Table 3 below.
본 발명에서 폴리펩타이드의 "유도체"는, 삽입, 결실, 부가 또는 치환 변이체와는 상이한, 다른 화학적 모이어티와의 컨쥬게에션을 통해 하나 이상의 잔기에서 화학적으로 변형된 폴리펩타이드를 의미한다.As used herein, a “derivative” of a polypeptide refers to a polypeptide that has been chemically modified at one or more residues through conjugation with another chemical moiety, which is different from the insertion, deletion, addition, or substitution variant.
본 발명에서 폴리펩타이드, 핵산, 숙주 세포 등과 관련하여 사용된 용어 "자연에서 발견되는"은 자연적으로 존재하는 물질을 의미한다.As used herein in relation to polypeptides, nucleic acids, host cells, etc., the term “found in nature” refers to substances that exist naturally.
본 발명에서 "동일성"은 두 개 이상의 폴리펩타이드 또는 두 개 이상의 폴리뉴클레오타이드 서열을 정렬하고 비교하여 결정되는, 두 개 이상 폴리펩타이드 또는 두 개 이상 폴리뉴클레오타이드의 서열 유사성을 의미한다. 이러한 서열간 동일성은 일반적으로 "동일성 퍼센트"로 표시되며, 이는 비교되는 분자 간의 동일한 아미노산 또는 뉴클레오타이드 비율을 의미하며, 비교되는 분자 중, 가장 작은 크기의 분자를 기초로 계산된다. 핵산 또는 폴리펩타이드를 정렬하여 다 분자간의 동일성을 계산하는데 사용될 수 있는 방법은 당업자에게 공지되어 있다.In the present invention, “identity” refers to the sequence similarity of two or more polypeptides or two or more polynucleotides, which is determined by aligning and comparing the sequences of two or more polypeptides or two or more polynucleotides. Identity between these sequences is generally expressed as “percent identity,” which refers to the proportion of amino acids or nucleotides that are identical between the molecules being compared, calculated based on the smallest molecule being compared. Methods that can be used to calculate identity between multiple molecules by aligning nucleic acids or polypeptides are known to those skilled in the art.
본 발명에서 "친화성" 또는 "친화도"는 항체 또는 그 항원 결합단편과 항원 사이의 상호작용의 강도이며, 항원의 크기, 모양 및/또는 전하와 같은 항원의 특징 및 항체 또는 항원결합 단편의 CDR 서열에 의해 결정된다. 이러한 친화도를 결정하는 방법은 당업계에 공지되어 있으며, 또한 하기를 참조할 수 있다.In the present invention, "affinity" or "affinity" is the strength of interaction between an antibody or an antigen-binding fragment thereof and an antigen, and the characteristics of the antigen such as the size, shape and/or charge of the antibody or antigen-binding fragment. Determined by CDR sequence. Methods for determining such affinities are known in the art and may also be referenced below.
항체 또는 이의 항원 결합 단편은 해리 상수(dissociation constant, KD)가 ≤10-6 M일 때, 항원과 같은 이의 표적에 "특이적으로 결합한다"라고 일컬어진다. 항체는 KD가 ≤1x 10-8 M일 때, "높은 친화성"으로 표적에 특이적으로 결합한다.An antibody or antigen-binding fragment thereof is said to “specifically bind” its target, such as an antigen, when its dissociation constant (KD) is ≦10 -6 M. An antibody binds specifically to its target with “high affinity” when its KD is ≤1x 10 -8 M.
본 발명에 사용된, 항체 또는 면역글로불린의 사슬(중쇄 또는 경쇄)의 "항원 결합 단편"은 전장 사슬과 비교하여 일부 아미노산이 결여되었지만, 항원에 특이적으로 결합할 수 있는 항체의 일부를 포함하는 것이다. 이러한 단편은 표적 항원에 특이적으로 결합할 수 있고, 또는 다른 항체 또는 항원 결합 단편과 특정 에피토프에 결합하기 위해 경쟁할 수 있다는 측면에서 생물학적으로 활성이 있다고 할 수 있다. 한 양태에서, 이러한 단편은 전장 경쇄 또는 중쇄 내에 존재하는 적어도 하나의 CDR을 포함하고, 일부 구현예에서, 단쇄 중쇄 및/또는 경쇄, 또는 이의 일부를 포함한다. 이러한 생물학적 활성 단편은 재조합 DNA 기술에 의해 생산되거나, 또는 예를 들면 온전한 항체를 효소적 또는 화학적 절단하여 생산될 수 있다. 면역학적으로 기능적인 면역글로불린 단편에는 이로 제한하는 것은 아니나, Fab, Fab, F(ab)2, scFab, dsFv, Fv, scFV, scFV-Fc, 다이아바디, 미니바디, scAb, 및 dAb를 포함하나 이로 제한하는 것은 아니나, 인간, 마우스, 랫트, 카멜리드 또는 토끼를 포함하는 임의의 포유동물에서 유래될 수 있다. 본 발명에 개시된 하나 이상의 CDR과 같은 항체의 기능적인 부분은 제2의 단백질 또는 저분자 화합물과 공유결합으로 연결되어 특정 표적에 대한 표적 치료제로서 사용될 수 있다.As used in the present invention, an "antigen-binding fragment" of a chain (heavy or light chain) of an antibody or immunoglobulin is a fragment that lacks some amino acids compared to the full-length chain, but contains a portion of the antibody that is capable of specifically binding to the antigen. will be. These fragments can be said to be biologically active in that they can specifically bind to a target antigen or compete with other antibodies or antigen-binding fragments for binding to a specific epitope. In one aspect, such fragments comprise at least one CDR present in a full-length light or heavy chain, and in some embodiments, comprise short heavy and/or light chains, or portions thereof. These biologically active fragments may be produced by recombinant DNA techniques or, for example, by enzymatic or chemical cleavage of intact antibodies. Immunologically functional immunoglobulin fragments include, but are not limited to, Fab, Fab, F(ab)2, scFab, dsFv, Fv, scFV, scFV-Fc, diabody, minibody, scAb, and dAb. It may be derived from any mammal including, but not limited to, human, mouse, rat, camelid or rabbit. The functional portion of the antibody, such as one or more CDRs disclosed in the present invention, can be covalently linked to a second protein or small molecule compound and used as a targeted therapeutic agent for a specific target.
본 발명에서 "Fc" 영역은 항체의 CH2 및 CH3 도메인을 포함하는 2개의 중쇄 단편을 포함한다. 이들 2개의 중쇄 단편은 2개 이상의 디설파이드 결합 및 CH3 도메인의 소수성 상호작용에 의해 서로 결합되어 있다.In the present invention, the “Fc” region includes two heavy chain fragments comprising the CH2 and CH3 domains of an antibody. These two heavy chain fragments are linked to each other by two or more disulfide bonds and hydrophobic interactions of the CH3 domain.
본 발명에서 "Fab 단편"은 1개의 경쇄와 가변 영역 및 CH1만을 포함하는 1개 중쇄로 구성된다. Fab 분자의 중쇄는 다른 중쇄 분자와 디설파이드 결합을 형성할 수 없다. scFab은 두 분자의 Fab이 유연한 링커에 의해 연결된 것이다.In the present invention, the “Fab fragment” consists of one light chain and one heavy chain containing only the variable region and CH1. The heavy chain of a Fab molecule cannot form disulfide bonds with other heavy chain molecules. scFab is two Fab molecules connected by a flexible linker.
본 발명에서 "Fab' 단편"은 Fab 단편에 추가적으로 중쇄의 CH1과 CH2 도메인 사이의 영역을 포함하여, 두 분자의 Fab' 단편의 두 개의 중쇄사이에서 사슬간 다이설파이드 결합이 형성되어, F(ab')2 분자를 형성할 수 있다.In the present invention, the "Fab' fragment" includes a region between the CH1 and CH2 domains of the heavy chain in addition to the Fab fragment, and an interchain disulfide bond is formed between the two heavy chains of the two molecules of the Fab' fragment, F (ab ')2 molecules can be formed.
본 발명에서 "F(ab')2 단편"은 앞서 기술한 바와 같이, 2개의 경쇄, 및 가변영역, CH1 및 CH1과 CH2 도메인 사이에 불변 영역의 일부를 포함하는 2개의 중쇄를 포함하여, 2개의 중쇄 사이에서 사슬간 다이설파이드 결합이 형성된다. 따라서, F(ab')2 단편은 2개의 Fab' 단편으로 구성되며, 상기 두 개의 Fab' 단편은 이들 간의 다이설파이드 결합에 의해 서로 회합되어 있다.As described above, the "F(ab')2 fragment" in the present invention includes two light chains and two heavy chains including a variable region, CH1, and a portion of the constant region between the CH1 and CH2 domains, 2 Interchain disulfide bonds are formed between the heavy chains. Therefore, the F(ab')2 fragment is composed of two Fab' fragments, and the two Fab' fragments are associated with each other by a disulfide bond between them.
본 발명에서 "Fv 영역"은 중쇄 및 경쇄의 각 가변 영역을 포함하지만 불변 영역은 포함하지 않는 항체의 단편이다. sdFV는 중쇄 및 경쇄가 이황화결합에 의해 연결된 것이다. scFv는 Fv가 유연한 링커에 의해 연결된 것이다. scFv-Fc는 scFV에 Fc가 연결된 것이다. 미니바디는 scFV에 CH3가 연결된 것이다. 다이아바디는 두분자의 scFV를 포함한다.In the present invention, the “Fv region” is a fragment of an antibody that includes the variable regions of the heavy and light chains, but does not include the constant region. sdFV has heavy and light chains connected by disulfide bonds. scFv is Fv linked by a flexible linker. scFv-Fc is where Fc is connected to scFV. The minibody is one where CH3 is connected to scFV. The diabody contains two molecules of scFV.
본 발명에서 "단일쇄 Fv" 또는 "scFv" 항체 단편은 항체의 VH 및 VL 도메인을 포함하는데, 이들 도메인은 단일폴리펩티드 쇄 내에 존재한다. Fv 폴리펩티드는 scFv가 항원 결합을 위해 목적하는 구조를 형성할 수 있도록 하는 VH 도메인과 VL 도메인 사이에 폴리펩티드 링커를 추가로 포함할 수 있다.In the present invention, a “single chain Fv” or “scFv” antibody fragment comprises the VH and VL domains of an antibody, which domains are present in a single polypeptide chain. The Fv polypeptide may further include a polypeptide linker between the VH and VL domains that allows the scFv to form the desired structure for antigen binding.
본 발명에서 "단쇄항체"(scAb)는 중쇄 및 경쇄 가변영역이 유연한 링커에 의해 연결된 중쇄의 하나의 불변영역 또는 경쇄 불변영역을 포함하는 단일 폴리펩타이드 사슬이다. 단쇄 항체는 예를 들면 미국 특허 제5,260,203호를 참조할 수 있으며, 이는 참조에 의해 본 발명에 개시된다.In the present invention, a "single chain antibody" (scAb) is a single polypeptide chain containing one constant region of a heavy chain or a light chain constant region where the heavy chain and light chain variable regions are connected by a flexible linker. For single chain antibodies, see, for example, U.S. Pat. No. 5,260,203, which is incorporated herein by reference.
본 발명에서 "도메인 항체"(dAb)는 중쇄의 가변 영역 또는 경쇄의 가변 영역만을 포함하는 면역학적으로 기능적인 면역글로불린 단편이다. 일 구현예에서는 2개 이상의 VH 영역이 펩타이드 링커에 의한 공유결합으로 연결되어, 2가(bivalent)의 도메인 항체를 형성한다. 이러한 2가 도메인 항체의 2개의 VH 영역은 동일 또는 상이한 항원을 표적으로 할 수 있다.In the present invention, a “domain antibody” (dAb) is an immunologically functional immunoglobulin fragment containing only the variable region of a heavy chain or the variable region of a light chain. In one embodiment, two or more VH regions are covalently linked by a peptide linker to form a bivalent domain antibody. The two VH regions of these bivalent domain antibodies can target the same or different antigens.
본 발명에서 "상보성 결정 영역" (CDR; 즉, CDR1, CDR2, 및 CDR3)은 항원 결합을 위해 필요한 존재인 항체 가변도메인의 아미노산 잔기를 지칭한다. 각 가변 도메인은 전형적으로 CDR1, CDR2 및 CDR3으로서 확인된 3개의 CDR 영역을 갖는다.In the present invention, “complementarity determining region” (CDR; i.e., CDR1, CDR2, and CDR3) refers to amino acid residues of an antibody variable domain that are required for antigen binding. Each variable domain typically has three CDR regions identified as CDR1, CDR2 and CDR3.
본 발명에서 "골격 영역" (FR)은 CDR 잔기 이외의 가변 도메인 잔기이다. 각 가변 도메인은 전형적으로, FR1, FR2, FR3 및 FR4로서 확인된 4개의 FR을 가진다.In the present invention, “framework region” (FR) is variable domain residues other than CDR residues. Each variable domain typically has four FRs, identified as FR1, FR2, FR3 and FR4.
본 발명에서 "2가의 항원 결합 단백질" 또는 "2가 항체"는 2개의 항원 결합 부위를 포함한다. 이러한 2가 항체에 포함된 2개의 항원 결합 부위는 동일한 항원 특이성을 갖거나, 또는 각각 상이한 항원에 결합하는 이중특이적 항체일 수 있다.In the present invention, a “bivalent antigen binding protein” or “bivalent antibody” includes two antigen binding sites. The two antigen binding sites included in such a bivalent antibody may have the same antigen specificity, or may be bispecific antibodies that each bind to different antigens.
본 발명에서 "다중 특이적 항원 결합 단백질" 또는 "다중 특이적 항체"는 두 개 이상의 항원 또는 에피토프를 표적으로 하는 것이다.In the present invention, “multispecific antigen binding protein” or “multispecific antibody” targets two or more antigens or epitopes.
본 발명에서 "링커"는 세포독성 화합물을 항체에 공유결합시키는 화합물을 말한다.In the present invention, “linker” refers to a compound that covalently binds a cytotoxic compound to an antibody.
본 발명에서 "비치환되거나 치환된"은 비치환될 수 있거나 또는 치환될 수 있는 모기(parent group)를, "치환된"은 1 이상의 치환기를 갖는 모기(parent group)를, 치환기는 모기(parent group)에 공유결합되거나 모기(parent group)에 융합된 화학적 부분을 의미한다.In the present invention, “unsubstituted or substituted” refers to a parent group that may be unsubstituted or substituted, “substituted” refers to a parent group having one or more substituents, and a substituent refers to a parent group. refers to a chemical moiety covalently bonded to a group or fused to a parent group.
본 발명에서 "할로"는 플루오린, 클로라인, 브로마인, 요오드 등을 말한다.In the present invention, “halo” refers to fluorine, chlorine, bromine, iodine, etc.
본 발명에서 "알킬"은 지방족 또는 지환족, 포화 또는 불포화(불포화, 완전 불포화) 탄화수소 화합물의 탄소 원자로부터 수소 원자를 제거하여 얻어진 1가 부분으로서, 포화 알킬의 예로는 메틸, 에틸, 프로필, 부틸, 펜틸, 헥실, 헵틸 등을, 포화 직쇄형 알킬의 예로는 메틸, 에틸, n-프로필, n-부틸, n-펜틸(아밀), n-헥실, n-헵틸 등, 포화 분지쇄형 알킬의 예로는 이소프로필, 이소부틸, sec-부틸, tert-부틸, 이소펜틸, 네오펜틸 등을 들 수 있다.In the present invention, "alkyl" is a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an aliphatic or alicyclic, saturated or unsaturated (unsaturated, fully unsaturated) hydrocarbon compound. Examples of saturated alkyl include methyl, ethyl, propyl, and butyl. , pentyl, hexyl, heptyl, etc., examples of saturated straight-chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl (amyl), n-hexyl, n-heptyl, etc., examples of saturated branched-chain alkyls. Examples include isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, etc.
본 발명에서 "알콕시"는 -OR[여기서, R은 알킬기]을 의미하며, 예로는 메톡시, 에톡시, n-프로폭시, 이소프로폭시, n-부톡시, sec-부톡시, 이소부톡시, tert-부톡시 등을 들 수 있다.In the present invention, “alkoxy” means -OR [where R is an alkyl group], examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, etc. can be mentioned.
본 발명에서 "아릴"은 고리 원자를 갖는 방향족 화합물의 방향족 고리 원자로부터 수소 원자를 제거하여 얻어진 1가 부분을 의미한다.In the present invention, “aryl” refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound having a ring atom.
본 발명에서 "알케닐"은 1 이상의 탄소-탄소 이중 결합을 갖는 알킬로서, 불포화 알케닐기의 예로는 에테닐(비닐, -CH=CH2), 1-프로페닐(-CH=CHCH3), 2-프로페닐, 이소프로페닐, 부테닐, 펜테닐, 헥세닐 등을 들 수 있다.In the present invention, “alkenyl” refers to alkyl having one or more carbon-carbon double bonds. Examples of unsaturated alkenyl groups include ethenyl (vinyl, -CH=CH 2 ), 1-propenyl (-CH=CHCH 3 ), Examples include 2-propenyl, isopropenyl, butenyl, pentenyl, and hexenyl.
본 발명에서 "알키닐"은 1 이상의 탄소-탄소 삼중 결합을 갖는 알킬기로서, 불포화 알키닐기의 예는 에티닐 및 2-프로피닐 등을 들 수 있다.In the present invention, “alkynyl” refers to an alkyl group having one or more carbon-carbon triple bonds, and examples of unsaturated alkynyl groups include ethynyl and 2-propynyl.
본 발명에서 "카르복시"는 -C(=O)OH를 말한다.In the present invention, “carboxy” refers to -C(=O)OH.
본 발명에서 "포르밀"은 -C(=O)H를 말한다.In the present invention, “formyl” refers to -C(=O)H.
본 발명에서 "아릴"은 방향족 화합물의 방향족 고리 원자로부터 수소 원자를 제거하여 얻어진 1가 모이어티에 관한 것이다. 예를 들어 "C5-7아릴"은 모이어티가 5 내지 7 개의 고리 원자를 갖는 것으로서, 방향족 화합물의 방향족 고리 원자로부터 수소 원자를 제거함으로써 수득되는 1 가 모이어티를 의미하고,"C5-10아릴"은 모이어티가 5 내지 10 개의 고리 원자를 갖는 것으로서, 방향족 화합물의 방향족 고리 원자로부터 수소 원자를 제거함으로써 수득되는 1 가 모이어티를 의미한다. 여기에서 접두사(C5-7, C5-10 등)는 탄소 원자 또는 헤테로 원자인지 여부와 상관없이 고리원자의 수 또는 고리 원자의 수의 범위를 지칭한다. 예를 들어 "C5-6아릴"은 5 또는 6개의 고리 원자를 갖는 아릴기에 관한 것이다. 여기에서, 고리 원자는 "카르보아릴기"에서와 같이 모두 탄소 원자일 수 있다. 카르보아릴기의 예는 벤젠, 나프탈렌, 아줄렌, 안트라센, 페난트렌, 나프타센 및 피렌으로부터 유도된 것들을 포함하나, 이로 제한되지 않는다. 적어도 하나가 방향족 고리인 융합 고리를 포함하는 아릴기의 예는 인단, 인덴, 이소인덴, 테트랄린, 아세나프텐, 플루오렌, 페날렌, 아세페난트렌 및 아세안트렌으로부터 유도된 기를 포함하나, 이로 제한되지 않는다. 또는, 고리 원자는 "헤테로아릴기"에서와 같이 하나 이상의 헤테로 원자를 포함할 수 있다.In the present invention, “aryl” relates to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound. For example, “C 5-7 aryl” means a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, where the moiety has 5 to 7 ring atoms, and “C 5- “10 aryl” means a monovalent moiety in which the moiety has 5 to 10 ring atoms and is obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound. Here, the prefix (C 5-7 , C 5-10, etc.) refers to the number of ring atoms or a range of the number of ring atoms, regardless of whether they are carbon atoms or heteroatoms. For example, “C 5-6 aryl” refers to an aryl group having 5 or 6 ring atoms. Here, the ring atoms may be all carbon atoms, as in a “carboaryl group”. Examples of carboaryl groups include, but are not limited to, those derived from benzene, naphthalene, azulene, anthracene, phenanthrene, naphthacene, and pyrene. Examples of aryl groups containing fused rings, at least one of which is an aromatic ring, include groups derived from indane, indene, isoindene, tetralin, acenaphthene, fluorene, phenalene, acephenanthrene, and aceanthrene, such as Not limited. Alternatively, the ring atom may contain one or more heteroatoms, such as in a “heteroaryl group”.
본 발명에서 "헤테로아릴"은 1 이상의 헤테로 원자를 포함하는 아릴로서, 예로는 피리딘, 피리미딘, 벤조티오펜, 푸릴, 디옥살라닐, 피롤릴, 옥사졸릴, 피리딜, 피리다지닐, 피리미디닐 등, 보다 구체적으로 벤조푸란, 이소벤조푸란, 인돌, 이소인돌, 인돌리진, 인돌린, 이소인돌린, 푸린(아데닌 또는 구아닌), 벤즈이미다졸, 인다졸, 벤즈옥사졸, 벤즈이속사졸, 벤조디옥솔, 벤조푸란, 벤조트리아졸, 벤조티오푸란, 벤조티아졸, 벤조티아디아졸로부터 유도된 2개의 융합고리를 갖는 C9, 크로멘, 이소크로멘, 크로만, 이소크로만, 벤조디옥산, 퀴놀린, 이소퀴놀린, 퀴놀리진, 벤족사진, 벤조디아진, 피리도피리딘, 퀴녹살린, 퀴나졸린, 신놀린, 프탈라진, 나프티리딘, 프테리딘으로부터 유도된 2개의 융합고리를 갖는 C10, 벤조디아제핀으로부터 유도된 2개의 융합고리를 갖는 C11, 카르바졸, 디벤조푸란, 디벤조티오펜, 카르볼린, 페리미딘, 피리도인돌로부터 유도된 3개의 융합고리를 갖는 C13, 아크리딘, 크산텐, 티오크산텐, 옥산트렌, 페녹사티인, 페나진, 페녹사진, 페노티아진, 티안트렌, 페난트리딘, 페난트롤린, 페나진으로부터 유도된 3개의 융합고리를 갖는 C14를 들 수 있다.In the present invention, “heteroaryl” refers to aryl containing one or more heteroatoms, examples of which include pyridine, pyrimidine, benzothiophene, furyl, dioxalanyl, pyrrolyl, oxazolyl, pyridyl, pyridazinyl, and pyrimidi. Neel et al., more specifically benzofuran, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (adenine or guanine), benzimidazole, indazole, benzoxazole, benzisoxazole, Benzodioxole, benzofuran, benzotriazole, benzothiofuran, benzothiazole, C 9 with two fused rings derived from benzothiadiazole, chromene, isochromene, chroman, isochroman, benzo Two fused rings derived from dioxane, quinoline, isoquinoline, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, and pteridine. C 10 with two fused rings derived from benzodiazepines, C 11 with two fused rings derived from benzodiazepines, C 13 with three fused rings derived from carbazole, dibenzofuran, dibenzothiophene, carboline, perimidine, and pyridoindole, Three fused rings derived from acridine, Examples include C 14 .
본 발명에서 "사이클로알킬"은 시클릴기인 알킬기이고, 고리(cyclic) 탄화수소 화합물의 지환족 고리 원자로부터 수소 원자를 제거하여 얻어진 1가 부분에 관한 것이다. 사이클로알킬기의 예는 하기로부터 유도된 것들을 포함하나, 이로 제한되지 않는다:In the present invention, “cycloalkyl” refers to an alkyl group, which is a cyclyl group, and relates to a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon compound. Examples of cycloalkyl groups include, but are not limited to, those derived from:
포화 단일고리 탄화수소 화합물: 사이클로프로판, 사이클로부탄, 사이클로펜탄, 사이클로헥산, 사이클로헵탄, 메틸사이클로프로판, 디메틸사이클로프로판, 메틸사이클로부탄, 디메틸사이클로부탄, 메틸사이클로펜탄, 디메틸사이클로펜탄 및 메틸사이클로헥산;Saturated monocyclic hydrocarbon compounds: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane and methylcyclohexane;
불포화 단일고리 탄화수소 화합물: 사이클로프로펜, 사이클로부텐, 사이클로펜텐, 사이클로헥센, 메틸사이클로프로펜, 디메틸사이클로프로펜, 메틸사이클로부텐, 디메틸사이클로부텐, 메틸사이클로펜텐, 디메틸사이클로펜텐 및 메틸사이클로헥센; 및 포화 헤테로사이클릭 탄화수소 화합물: 노르카란, 노르피난, 노르보르난.Unsaturated monocyclic hydrocarbon compounds: cyclopropene, cyclobutene, cyclopentene, cyclohexene, methylcyclopropene, dimethylcyclopropene, methylcyclobutene, dimethylcyclobutene, methylcyclopentene, dimethylcyclopentene and methylcyclohexene; and saturated heterocyclic hydrocarbon compounds: norcarane, norpinene, norbornane.
본 발명에서 "헤테로사이클릴"은 헤테로사이클릭 화합물의 고리 원자로부터 수소 원자를 제거하여 얻어진 1가 부분에 관한 것이다.In the present invention, “heterocyclyl” relates to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound.
본 발명에서 접두사(예를 들어 C1-12, C3-8 등)는 탄소 원자 또는 헤테로 원자인지 여부와 상관없이 고리 원자의 수 또는 고리 원자의 수의 범위를 지칭한다. 예를 들어 본 명세서에서 사용된 용어 "C3-6헤테로사이클릴"은 3 내지 6개의 고리 원자를 갖는 헤테로사이클릴기에 관한 것이다.In the present invention, a prefix (eg C 1-12 , C 3-8 , etc.) refers to the number of ring atoms or a range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term “C 3-6 heterocyclyl” as used herein refers to a heterocyclyl group having 3 to 6 ring atoms.
단일고리 헤테로사이클릴기의 예는 하기로부터 유도된 것들을 포함하지만, 이로 제한되지 않는다:Examples of single ring heterocyclyl groups include, but are not limited to, those derived from:
N1: 아지리딘, 아제티딘, 피롤리딘, 피롤린, 2H- 또는 3H-피롤, 피페리딘, 디하이드로피리딘, 테트라하이드로피리딘, 아제핀;N 1 : aziridine, azetidine, pyrrolidine, pyrroline, 2H- or 3H-pyrrole, piperidine, dihydropyridine, tetrahydropyridine, azepine;
N2: 이미다졸리딘, 피라졸리딘, 이미다졸린, 피라졸린, 피페라진;N 2 : imidazolidine, pyrazolidine, imidazoline, pyrazoline, piperazine;
O1: 옥시란, 옥세탄, 옥솔란, 옥솔, 옥산, 디하이드로피란, 피란, 옥세핀;O 1 : oxirane, oxetane, oxolane, oxol, oxane, dihydropyran, pyran, oxepin;
O2: 디옥솔란, 디옥산 및 디옥세판;O 2 : dioxolane, dioxane and dioxepane;
O3: 트리옥산;O 3 : trioxane;
N1O1: 테트라하이드로옥사졸, 디하이드로옥사졸, 테트라하이드로이속사졸, 디하이드로이속사졸, 모르폴린, 테트라하이드로옥사진, 디하이드로옥사진, 옥사진;N 1 O 1 : tetrahydroxazole, dihydroxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydroxazine, dihydroxazine, oxazine;
S1: 티이란, 티에탄, 티올란, 티안, 티에판;S 1 : thiiran, thietane, thiolan, thian, thiophane;
N1S1: 티아졸린, 티아졸리딘, 티오모르폴린;N 1 S 1 : Thiazoline, thiazolidine, thiomorpholine;
N2O1: 옥사디아진;N 2 O 1 : Oxadiazine;
O1S1: 옥사티올, 옥사티안; 및O 1 S 1 : oxathiol, oxathian; and
N1O1S1: 옥사티아진.N 1 O 1 S 1 : Oxathiazine.
본 발명에서 "전구체(prodrug)"는 생체내 생리학적 조건 하(예를 들어 효소 산화(enzymatic oxidation), 환원(reduction) 및/또는 가수분해 등)에서 효소, 위산의 작용에 의해 피롤로벤조다이아제핀 약물로 직접적으로 또는 간접적으로 변환할 수 있는 화합물을 말한다.In the present invention, "prodrug" refers to pyrrolobenzodiacephalic acid by the action of enzymes and gastric acid under physiological conditions in vivo (e.g., enzymatic oxidation, reduction and/or hydrolysis, etc.). Zepine refers to a compound that can be converted directly or indirectly into a drug.
본 발명에서 "약학적으로 허용되는 염"으로는 약학적으로 허용가능한 유리산(free acid)에 의하여 형성된 산 부가염을 사용할 수 있고, 상기 유리 산으로는 유기산 또는 무기산을 사용할 수 있다.In the present invention, the “pharmaceutically acceptable salt” may be an acid addition salt formed from a pharmaceutically acceptable free acid, and the free acid may be an organic acid or an inorganic acid.
상기 유기산은 이로 제한되는 것은 아니나, 구연산, 초산, 젖산, 주석산, 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플로오로아세트산, 벤조산, 글루콘산, 메타술폰산, 글리콜산, 숙신산, 4-톨루엔술폰산, 글루탐산 및 아스파르트산을 포함한다. 또한 상기 무기산은 이로 제한되는 것은 아니나, 염산, 브롬산, 황산 및 인산을 포함한다.The organic acids include, but are not limited to, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, Includes glutamic acid and aspartic acid. Additionally, the inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid.
예컨대, 화합물이 음이온이거나 또는 음이온일 수 있는 작용기를 갖는 경우(예컨대 -COOH는 -COO-일 수 있음), 적절한 양이온으로 염을 형성할 수 있다. 적절한 무기 양이온의 예는 알칼리 금속 이온, 예컨대 Na+ 및 K+, 알칼리 토금속 양이온, 예컨대 Ca2+ 및 Mg2+ 및 다른 양이온, 예컨대 Al3+을 포함하지만, 이에 한정되지 않는다. 적절한 유기 양이온의 예는 암모늄 이온(즉, NH4 +) 및 치환된 암모늄 이온(예컨대 NH3R+, NH2R2 +, NHR3 +, NR4 +)을 포함하지만, 이에 한정되지 않는다.For example, if a compound is anionic or has a functional group that may be anionic (e.g., -COOH can be -COO-), a salt can be formed with the appropriate cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth metal cations such as Ca 2+ and Mg 2+ and other cations such as Al 3+ . Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
일부 적절한 치환된 암모늄 이온의 예는 하기로부터 유도된 것들이다: 에틸아민, 디에틸아민, 디사이클로헥실아민, 트리에틸아민, 부틸아민, 에틸렌디아민, 에탄올아민, 디에탄올아민, 피페라진, 벤질아민, 페닐벤질아민, 콜린, 메글루민 및 트로메타민 뿐 아니라, 아미노산, 예컨대 리신 및 아르기닌. 통상적인 4급 암모늄 이온의 예는 N(CH3)4 +이다.Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine. , phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
화합물이 양이온이거나 또는 양이온일 수 있는 작용기를 갖는 경우(예컨대 -NH2는 -NH3 + 일 수 있음), 적절한 음이온으로 염을 형성할 수 있다. 적절한 무기 음이온의 예는 하기 무기 산으로부터 유도된 것들을 포함하지만, 이에 한정되지 않는다: 염산, 브롬화수소산, 요오드화수소산, 황산, 아황산, 질산, 아질산, 인산 및 아인산 등을 예로 들 수 있다.If the compound is cationic or has a functional group that may be cationic (e.g. -NH 2 may be -NH 3 + ), salts can be formed with the appropriate anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid.
적절한 유기 음이온의 예는 하기 유기산으로부터 유도된 것들을 포함하지만, 이로 한정되지 않는다: 2-아세티옥시벤조산, 아세트산, 아스코르브산, 아스파르트산, 벤조산, 캠퍼설폰산, 신남산, 시트르산, 에데트산, 에탄디설폰산, 에탄설폰산, 푸마르산, 글루쳅톤산, 글루콘산, 글루탐산, 글리콜산, 히드록시말레산, 히드록시나프탈렌 카르복실산, 이세티온산, 락트산, 락토비온산, 라우르산, 말레산, 말산, 메탄설폰산, 점액산, 올레산, 옥살산, 팔미트산, 팜산, 판토텐산, 페닐아세트산, 페닐설폰산, 프로피온산, 피루브산, 살리실산, 스테아르산, 숙신산, 설파닐산, 타르타르산, 톨루엔설폰산 및 발레르산 등을 예로 들 수 있다. 적절한 중합체 유기 음이온의 예는 하기 중합체 산으로부터 유도된 것들을 포함하지만, 이에 한정되지 않는다: 타닌산, 카르복시메틸 셀룰로오스 등을 예로 들 수 있다.Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetioxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethane. Disulfonic acid, ethanesulfonic acid, fumaric acid, gluteptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalene carboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, Malic acid, methanesulfonic acid, mucilic acid, oleic acid, oxalic acid, palmitic acid, palmic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid and valeric acid. Examples include: Examples of suitable polymer organic anions include, but are not limited to, those derived from the following polymer acids: tannic acid, carboxymethyl cellulose, etc.
본 발명에서 "용매화물(solvate)"은 본 발명에 따른 화합물과 용매 분자(solvent molecules) 사이의 분자 복합체(molecular complex)를 말하며, 용매화물의 예는 물, 이소프로판올, 에탄올, 메탄올, 디메틸설폭사이드(dimethylsulfoxide), 에틸 아세테이트, 아세트산, 에탄올아민 또는 이의 혼합용매와 결합한 본 발명에 따른 화합물을 포함하나, 이로 제한되는 것은 아니다.In the present invention, “solvate” refers to a molecular complex between the compound according to the present invention and solvent molecules. Examples of solvates include water, isopropanol, ethanol, methanol, and dimethyl sulfoxide. It includes, but is not limited to, the compound according to the present invention combined with (dimethylsulfoxide), ethyl acetate, acetic acid, ethanolamine, or a mixed solvent thereof.
활성 화합물의 상당하는 용매화물을 제조, 정제 및/또는 취급하는 것이 편리하거나 또는 바람직할 수 있다. 용어 "용매화물"은 본 명세서에서 용질(예컨대 활성 화합물, 활성 화합물의 염) 및 용매의 착체를 지칭하기 위해 통상적인 의미로 사용된다. 용매가 물인 경우, 용매화물을 편리하게 수화물, 예컨대 일수화물, 이수화물, 삼수화물 등으로 지칭할 수 있다.It may be convenient or desirable to prepare, purify and/or handle corresponding solvates of the active compounds. The term “solvate” is used herein in its conventional sense to refer to a complex of a solute (eg an active compound, a salt of an active compound) and a solvent. When the solvent is water, the solvate may conveniently be referred to as a hydrate, such as monohydrate, dihydrate, trihydrate, etc.
본 발명에서 사용된 어구 "유효량" 또는 "치료 유효량"은 목적 치료결과를 달성하는데 (투여량 및 투여 기간 및 수단에 대해) 필요한 양을 지칭한다. 유효량은 적어도 대상체에게 치료 이익을 부여하는데 필요한 활성제의 최소량이며, 독성량 미만이다. 예를 들어 투여량은 환자 당 약 100 ng 내지 약 100 mg/kg 범위로, 보다 전형적으로 약 1 μg/kg 내지 약 10 mg/kg의 범위로 투여할 수 있다. 활성 화합물이 염, 에스테르, 아미드, 전구체약물(prodrug) 등인 경우에 투여양은 모화합물을 기준으로 계산되므로, 사용되는 실제 중량은 비례하여 증가된다. 본 발명에 따른 피롤로벤조디아제핀 화합물은 단위 제형(dosage form)당 활성 성분 0.1 mg 내지 3000 mg, 1 mg 내지 2000 mg, 10 mg 내지 1000 mg을 포함하도록 제형화될 수 있으나 이로 한정되지 않는다. 활성 성분은 약 0.05 μM 내지 100 μM, 1 μM 내지 50 μM, 5 μM 내지 30 μM의 활성 화합물의 피크 플라즈마 농도를 얻도록 투여될 수 있다. 예를 들어 임의로 식염수내에서 활성 성분 0.1 w/v% 내지 5 w/v% 용액의 정맥 주사에 의해 투여될 수 있다.As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount (with respect to dosage and period and means of administration) necessary to achieve the desired therapeutic result. An effective amount is at least the minimum amount of active agent necessary to confer therapeutic benefit to the subject and is less than a toxic amount. For example, dosages may range from about 100 ng to about 100 mg/kg per patient, more typically from about 1 μg/kg to about 10 mg/kg. When the active compound is a salt, ester, amide, prodrug, etc., the dosage is calculated based on the parent compound, so the actual weight used is proportionally increased. The pyrrolobenzodiazepine compound according to the present invention may be formulated to contain 0.1 mg to 3000 mg, 1 mg to 2000 mg, or 10 mg to 1000 mg of the active ingredient per unit dosage form (dosage form), but is not limited thereto. The active ingredient may be administered to obtain a peak plasma concentration of the active compound of about 0.05 μM to 100 μM, 1 μM to 50 μM, or 5 μM to 30 μM. For example, it can be administered by intravenous injection of a 0.1 w/v% to 5 w/v% solution of the active ingredient, optionally in saline solution.
약학 조성물에서 활성 화합물의 농도는 약물의 흡수, 불활성화 및 배출율 및 당 기술분야의 숙련자에게 알려진 다른 인자에 의해 결정될 수 있다. 투여량은 증상/질환의 심각도에 따라 달라질 수 있다. 또한 어떤 특정 환자에 대한 투여량 및 투여요법은 환자의 증상/질환의 정도, 필요성, 나이, 약물에 대한 반응성 등을 종합적으로 고려하여 투여 감독자의 직업적 판단에 따라 조정될 수 있으며, 본 발명에서 제시된 농도 범위는 단지 일 예이며 청구된 조성물의 실시양태를 이로 한정하는 것을 의도하지 않는다. 또한 활성 성분은 1회 투여될 수 있거나, 보다 적은 투여량을 수 회 나누어 투여할 수도 있다.The concentration of the active compound in a pharmaceutical composition can be determined by the rate of absorption, inactivation and excretion of the drug and other factors known to those skilled in the art. Dosage may vary depending on the severity of symptoms/disease. In addition, the dosage and administration regimen for a specific patient can be adjusted according to the professional judgment of the administration supervisor by comprehensively considering the patient's symptoms/disease severity, necessity, age, responsiveness to the drug, etc., and the concentration suggested in the present invention The ranges are by way of example only and are not intended to limit embodiments of the claimed compositions. Additionally, the active ingredient may be administered once, or smaller doses may be administered in several divided doses.
항체 또는 항원 결합 단편Antibody or antigen-binding fragment
본 발명은 인간 TROP2(tumor-associated calcium signal transducer 2, TACSTD2)에 특이적으로 결합하는 항체를 개시한다. 본 발명에 따른 항체는 본 발명에 개시된 바와 같이, 하나 이상의 상보성 결정영역 또는 부위(CDR)를 포함하는 폴리펩타이드이다.The present invention discloses an antibody that specifically binds to human TROP2 (tumor-associated calcium signal transducer 2, TACSTD2). An antibody according to the invention is a polypeptide comprising one or more complementarity determining regions or regions (CDRs), as disclosed herein.
일부 구현예에서, CDR은 "프레임워크" 영역에 포함되며, 프레임워크는 이러한 CDR(들)이 적절한 항원 결합 특성을 가질 수 있도록 CDR(들)을 배향한다.In some embodiments, the CDRs are comprised in a “framework” region, wherein the framework orients the CDR(s) such that they can have appropriate antigen binding properties.
본 발명에 개시된 항체는 종양에서 주로 발현되는 TROP2 형태에 특이적으로 더 강하게 결합할 수 있어, 인간 TROP2를 표적으로 하는 암의 표적 치료에 유용하게 사용될 수 있다. 예를 들면, 본 발명에 따른 항체와 항암제를 결합시켜, 특정 암의 치료에 사용될 수 있다.The antibody disclosed in the present invention can specifically bind more strongly to the TROP2 form mainly expressed in tumors, and can be usefully used for targeted treatment of cancer targeting human TROP2. For example, the antibody according to the present invention can be combined with an anticancer agent and used to treat specific cancer.
일 구현예에서, 항체는 모노클로날 항체, 이중특이적 항체, 이중항체, 다중특이적 항체, 다중항체, 미니바디, 도메인 항체, 항체 모방체(또는 합성 항체), 키메라 항체, 인간화 항체, 인간 항체 또는 항체 융합체(또는 항체 접합체), 및 이의 단편을 포함하나, 이에 국한되지 않으며 본 발명에 개시된 다양한 형태의 항체를 포함한다.In one embodiment, the antibody is a monoclonal antibody, bispecific antibody, diabody, multispecific antibody, polyantibody, minibody, domain antibody, antibody mimetic (or synthetic antibody), chimeric antibody, humanized antibody, human Various forms of antibodies disclosed herein include, but are not limited to, antibodies or antibody fusions (or antibody conjugates), and fragments thereof.
일 구현예에서, 본 발명에 개시된 항체의 항체 단편은 Fab, Fab', F(ab')2, scFab, Fv, dsFv, scFV, scFV-Fc, 미니바디, 다이아바디, scAb 또는 dAb를 포함한다.In one embodiment, the antibody fragment of an antibody disclosed herein comprises Fab, Fab', F(ab')2, scFab, Fv, dsFv, scFV, scFV-Fc, minibody, diabody, scAb, or dAb. .
또 다른 구현예에서, 본 발명에 개시된 항체는 표 1 내지 표 3에 개시된 가변영역을 포함하는 경쇄만의 또는 중쇄만의 폴리펩타이드로 이루어질 수 있다.In another embodiment, the antibody disclosed in the present invention may be composed of a light chain-only or heavy chain-only polypeptide comprising the variable regions disclosed in Tables 1 to 3.
본 발명의 일 구현예에 따른 항체 또는 항원 결합 단편의 중쇄 및 경쇄가변 영역에 포함될 수 있는 CDR 서열은 각각 표 1 내지 표 3에 개시된다.CDR sequences that may be included in the heavy chain and light chain variable regions of the antibody or antigen-binding fragment according to one embodiment of the present invention are disclosed in Tables 1 to 3, respectively.
본 발명에 개시된 일 항체는 본 발명에 개시된 다른 항체와 특정 영역 또는 서열을 공유한다. 일 구현예에서는 항체 또는 항원결합단편의 불변영역을 공유할 수 있다. 다른 구현예에서는 Fc 영역을 공유할 수 있다. 또 다른 구현예에서는 가변영역의 프레임을 공유할 수 있다.One antibody disclosed herein shares certain regions or sequences with other antibodies disclosed herein. In one embodiment, the constant region of the antibody or antigen-binding fragment may be shared. In other embodiments, the Fc region may be shared. In another implementation, frames in the variable region can be shared.
본 발명에 따른 중쇄 가변영역 및 경쇄 가변영역은 인간 불변영역의 적어도 일부에 연결될 수 있다. 불변영역의 선택은 부분적으로 항체 의존적 세포 매개 세포독성, 항체 의존적 세포 식균작용 및/또는 보체 의존적 세포독성이 요구되는지에 의해 결정될 수 있다. 예를 들면, 인간 동종형 IgGl 및 IgG3은 보체 의존적 세포독성을 갖고, 인간 동종형 IgG2 및 IgG4는 이러한 세포독성을 갖지 않는다. 또한, 인간 IgGl 및 IgG3은 인간 IgG2 및 IgG4보다 더 강한 세포 매개 이펙터 기능을 유도한다. 경쇄 불변영역은 람다 또는 카파일 수 있다.The heavy chain variable region and light chain variable region according to the present invention may be linked to at least a portion of the human constant region. The choice of constant region may be determined in part by whether antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell phagocytosis, and/or complement-dependent cytotoxicity is desired. For example, human isotypes IgG1 and IgG3 have complement dependent cytotoxicity, while human isotypes IgG2 and IgG4 do not have such cytotoxicity. Additionally, human IgGl and IgG3 induce stronger cell-mediated effector functions than human IgG2 and IgG4. The light chain constant region can be lambda or kappa.
면역글로불린 사슬의 가변영역은 일반적으로 전체적 구조가 동일하며, "상보적 결정부위 또는 영역 또는 도메인" 또는 CDR(Complementary Determining Region)로 지칭되는 3개의 초가변영역에 의해 이어지는 비교적 보존된 프레임워크 영역(FR)을 포함한다. 중쇄/경쇄 쌍을 구성하는 각 사슬 유래의 가변영역의 CDR은 전형적으로 프레임워크 영역에 의해 정렬되어 표적 단백질의 특정 에피토프와 특이적으로 결합하는 구조를 형성한다. 자연 발생 경쇄 및 중쇄 가변영역의 이러한 요소는 N-말단으로부터 C-말단까지 전형적으로 다음 순서로 포함된다: FR1, CDR1, FR2, CDR2, FR3, CDR3 및 FR4. 가변영역에서 이들 각각에 해당하는 아미노산 서열의 위치는 Kabat(Kabat et al.,(1983) U.S. Dept, of Health and Human Services, "Sequences of Proteins of Immunological Interest"), Chothia(Chothia and Lesk, J. Mol. Biol. 196:901-917(1987)) 또는 OPAL 라이브러리와 관련된 방식(Hye Young Yang et. al., 2009 Mol. Cells 27: 225)에 의해 결정될 수 있다. 상기 각 정의에 의해 결정된 CDR은 서로 비교하면, 중첩되거나 하나가 다른 하나를 포함하는 서브세트일 수 있다. 하지만 본 발명에는 상기 각 방법에 의해 정의되는 모든 CDR이 본 발명의 범위에 포함된다. 당업자라면 항체의 가변영역 서열이 주어지면, 여기에서 상기 각 정의에 의한 CDR 서열을 용이하게 선택할 수 있을 것이다.The variable regions of immunoglobulin chains are generally identical in overall structure and consist of a relatively conserved framework region (sequenced by three hypervariable regions), called "complementary determining regions or domains" or CDRs (Complementary Determining Regions). FR). The CDRs of the variable regions derived from each chain constituting the heavy chain/light chain pair are typically aligned with the framework region to form a structure that specifically binds to a specific epitope of the target protein. These elements of naturally occurring light and heavy chain variable regions are typically included in the following order from N-terminus to C-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The positions of the amino acid sequences corresponding to each of these in the variable region are listed in Kabat (Kabat et al., (1983) U.S. Dept, of Health and Human Services, "Sequences of Proteins of Immunological Interest"), Chothia (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)) or by a method involving the OPAL library (Hye Young Yang et. al., 2009 Mol. Cells 27: 225). When compared to each other, the CDRs determined by each of the above definitions may overlap or be a subset containing one another. However, in the present invention, all CDRs defined by each of the above methods are included in the scope of the present invention. Given the variable region sequence of an antibody, those skilled in the art will be able to easily select the CDR sequence according to each of the above definitions.
일 구현예에서 본 발명에 따른 항체는 인간화 항체이다. 인간화 항체는 비-인간 항체의 불변 영역이 불변 영역의 인간 형태로 완전히 치환되고, 표적 구조에 결합하는 각 가변 영역의 외부에서 아미노산 서열의 3개의 루프를 제외한 비-인간 항체의 가변 영역의 적어도 일부가 인간 항체의 상응하는 부분으로 완전히 또는 부분적으로 치환된 임의의 항체를 의미한다. In one embodiment, the antibody according to the invention is a humanized antibody. A humanized antibody is one in which the constant region of the non-human antibody is completely replaced with the human form of the constant region, and at least a portion of the variable region of the non-human antibody excluding three loops of amino acid sequence outside each variable region that binds to the target structure. refers to any antibody that has been completely or partially replaced by a corresponding part of a human antibody.
일 구현예에서 본 발명에 따른 인간화 항체는In one embodiment, the humanized antibody according to the present invention is
(a)(i) 인간 항체의 중쇄 또는 인간 컨센서스 프레임워크(consensus framework)로부터의 가변 도메인 프레임워크 영역; 및 (ii) 인간 항체의 경쇄 또는 인간 컨센서스 프레임워크로부터의 가변 도메인 프레임워크 영역을 포함하고,(a) (i) the heavy chain of a human antibody or variable domain framework region from the human consensus framework; and (ii) a light chain of a human antibody or a variable domain framework region from a human consensus framework,
(b)(i) 상기 중쇄로부터의 가변 도메인 프레임워크 영역의 적어도 하나의 아미노산은 마우스 항체 또는 마우스 컨센서스 프레임워크의 중쇄로부터의 상응하는 아미노산으로 치환되거나; (ii) 상기 경쇄로부터의 가변 도메인 프레임워크 영역은 마우스 항체 또는 마우스 컨센서스 프레임워크의 경쇄로부터 상응하는 아미노산으로 치환되고, 및(b)(i) at least one amino acid in the variable domain framework region from said heavy chain is replaced with a corresponding amino acid from the heavy chain of a mouse antibody or mouse consensus framework; (ii) the variable domain framework region from the light chain is replaced with the corresponding amino acid from the light chain of the mouse antibody or mouse consensus framework, and
(c) (i) 상기 중쇄의 아미노산 치환은 하기 아미노산 치환으로부터 선택되고:(c) (i) the amino acid substitutions in the heavy chain are selected from the following amino acid substitutions:
위치 27에서 Y(인간) 대신 F(마우스)로 치환;Substitute F (mouse) for Y (human) in position 27;
위치 30에서 T(인간) 대신 S(마우스)로 치환;Substitute S (mouse) for T (human) in position 30;
위치 37에서 V(인간) 대신 L(마우스)로 치환;Substitute L (mouse) for V (human) in position 37;
위치 48에서 M(인간) 대신 I(마우스)로 치환; Substitute I (mouse) for M (human) in position 48;
위치 49에서 G(인간) 대신 A(마우스)로 치환;Substitute A (mouse) for G (human) in position 49;
위치 70에서 I(인간) 대신 L(마우스)로 치환; 및Substitute L (mouse) for I (human) at position 70; and
위치 72에서 R(인간) 대신 V(마우스)로 치환Substitute V (mouse) for R (human) at position 72
(ii) 상기 경쇄의 아미노산 치환은 위치 49에서 Y(인간) 대신 S(마우스)로 치환일 수 있다.(ii) The amino acid substitution of the light chain may be substitution of S (mouse) instead of Y (human) at position 49.
추가로 상기 중쇄의 아미노산 치환은 하기 아미노산 치환을 더 포함할 수 있다:Additionally, the amino acid substitution of the heavy chain may further include the following amino acid substitutions:
위치 67에서 R(인간) 대신 K(마우스)로 치환; 및/또는Substitute K (mouse) for R (human) in position 67; and/or
위치 68에서 V(인간) 대신 A(마우스)로 치환.Substitute A (mouse) for V (human) at position 68.
추가로 상기 경쇄의 아미노산 치환은 하기 아미노산 치환을 더 포함할 수 있다:Additionally, the amino acid substitution of the light chain may further include the following amino acid substitutions:
위치 67에서 S(인간) 대신 Y(마우스)로 치환;Substitute Y (mouse) for S (human) in position 67;
위치 2에서 I(인간) 대신 T(마우스)로 치환 및 위치 67에서 S(인간) 대신 Y(마우스)로 치환;Substitute T (mouse) for I (human) at position 2 and Y (mouse) for S (human) at position 67;
위치 22에서 T(인간) 대신 R(마우스)로 치환 및 위치 67에서 S(인간) 대신 Y(마우스)로 치환;Substitute R (mouse) for T (human) at position 22 and Y (mouse) for S (human) at position 67;
위치 42에서 K(인간) 대신 E(마우스)로 치환 및 위치 67에서 S(인간) 대신 Y(마우스)로 치환;Substitute E (mouse) for K (human) at position 42 and Y (mouse) for S (human) at position 67;
위치 64에서 G(인간) 대신 S(마우스)로 치환 및 위치 67에서 S(인간) 대신 Y(마우스)로 치환;Substitute S (mouse) for G (human) at position 64 and Y (mouse) for S (human) at position 67;
위치 67에서 S(인간) 대신 Y(마우스)로 치환 및 위치 72에서 T(인간) 대신 V(마우스)로 치환; 또는 Substitute Y (mouse) for S (human) at position 67 and V (mouse) for T (human) at position 72; or
위치 67에서 S(인간) 대신 Y(마우스)로 치환 및 위치 85에서 T(인간) 대신 D(마우스)로 치환.Substitute Y (mouse) for S (human) at position 67 and D (mouse) for T (human) at position 85.
본 발명의 일 구현예에서, 상기 치환을 포함하는 중쇄 및 경쇄 가변영역 서열을 각각 표 1 내지 표 3에 개시된다. 또한, 일 구현예에서 상기 치환은 표 1 내지 표 3에 개시된 FR 영역의 치환을 포함한다.In one embodiment of the present invention, the heavy chain and light chain variable region sequences containing the above substitutions are disclosed in Tables 1 to 3, respectively. Additionally, in one embodiment, the substitution includes substitution of the FR region disclosed in Tables 1 to 3.
본 발명은 또한 본 발명에 개시된 하나 이상의 아미노산 서열과 실질적인 서열 동일성을 갖는 하나 이상의 아미노산 서열을 포함한다. 실질적 동일성이란 본 발명은 서열변이가 존재하는 본 발명에 개시된 효과를 유지하는 것을 의미한다. 일 구현예에서 표 1 내지 표 3에 개시된 중쇄 가변영역과 약 90%, 95%, 또는 99% 동일성을 가진다. 다른 구현예에서 표 1 내지 표 3에 개시된 경쇄 가변영역과 약 90%, 95%, 또는 99% 동일성을 가진다. 예를 들면 본 발명에 개시된 항체 또는 항원 결합단편의 서열과 90%, 95%, 또는 99% 동일성을 나타내는 변이체의 경우, 임의의 변이는 CDR 보다는 가변영역의 골격에서 발생된다.The invention also includes one or more amino acid sequences that have substantial sequence identity to one or more amino acid sequences disclosed herein. Substantial identity means that the present invention maintains the effects disclosed in the present invention even when sequence variations exist. In one embodiment, it has about 90%, 95%, or 99% identity with the heavy chain variable region disclosed in Tables 1 to 3. In other embodiments, it has about 90%, 95%, or 99% identity with the light chain variable region disclosed in Tables 1 to 3. For example, in the case of a variant showing 90%, 95%, or 99% identity to the sequence of the antibody or antigen-binding fragment disclosed in the present invention, any mutation occurs in the framework of the variable region rather than the CDR.
일 구현예에서 본 발명에 개시된 항체 또는 그 단편을 코딩하는 핵산은 본 발명에 개시된 CDR, 상기 CDR을 포함하는 가변영역, 상기 가변영역 및 불변영역을 포함하는 전장 항체를 코딩하는 핵산이다. 아미노산 서열이 결정되면, 핵산서열은 공지의 역전사 프로그램 및 코돈사용빈도(codon usage) 등을 고려하여 용이하게 결정될 수 있다. In one embodiment, the nucleic acid encoding the antibody or fragment thereof disclosed in the present invention is a nucleic acid encoding a full-length antibody comprising the CDRs disclosed in the present invention, a variable region including the CDRs, and the variable region and constant region. Once the amino acid sequence is determined, the nucleic acid sequence can be easily determined by considering known reverse transcription programs and codon usage.
항체의 항원 대한 특이성 및 친화도Specificity and affinity of antibody to antigen
본 발명에 따른 항체 또는 항원 결합단편은 특히 인간 TROP2 항원에 대한 특이성 및 항체 치료제/진단제로서 사용되기에 적절한 친화도를 가진다. 일 구현예에서, 응집체에 대한 친화도는 KD < 1,000 nM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM 또는 < 0.001 nM일 수 있고, 예컨대 10-6 M 내지 10-12 M일 수 있다.The antibody or antigen-binding fragment according to the present invention has specificity and affinity suitable for use as an antibody therapeutic/diagnostic agent, particularly for the human TROP2 antigen. In one embodiment, the affinity for aggregates may be KD <1,000 nM, <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM or <0.001 nM, such as from 10 -6 M to 10 It could be -12 M.
항체의 제조Preparation of Antibodies
본 발명에서 비-인간 항체는, 예를 들면, 임의의 항체-생성 동물, 예를 들면, 마우스, 랫트, 토끼, 염소, 당나귀, 또는 비-인간 영장류(예를 들면, 시노몰구스 또는 붉은털 원숭이와 같은 원숭이) 또는 유인원(예를 들면 침팬지))로부터유래될 수 있다. 비인간 항체는 당해 기술 분야에 공지된 방법을 사용하여 동물을 면역화시킴으로써 생성될 수 있다. 본 발명의 일 구현예에서 인간화 항체의 제조방법은 미국 출원번호 15/532598를 참조한다. 완전 인간항체는 인간 면역글로불린 유전자 좌를 포함하는 형질전환 동물에 항원을 투여하거나, 또는 인간 항체의 레퍼토리를 발현하는 파지 디스플레이 라이브러리를 항원으로 처리하여, 목적하는 항체를 선택함으로써 제조될 수 있다. 항체는 폴리클로날, 모노클로날일 수 있거나, 또는 재조합 DNA를 발현시킴으로써 숙주 세포 내에서 합성될 수 있다. Non-human antibodies in the present invention include, for example, any antibody-producing animal, such as a mouse, rat, rabbit, goat, donkey, or non-human primate (e.g., cynomolgus or rhesus). It may be derived from a monkey (such as a monkey) or an ape (such as a chimpanzee). Non-human antibodies can be generated by immunizing animals using methods known in the art. For a method of producing a humanized antibody in one embodiment of the present invention, see US Application No. 15/532598. Fully human antibodies can be produced by administering an antigen to a transgenic animal containing a human immunoglobulin locus, or by treating a phage display library expressing a repertoire of human antibodies with an antigen to select the desired antibody. Antibodies can be polyclonal, monoclonal, or synthesized within host cells by expressing recombinant DNA.
모노클로날 항체(mAb)는 종래의 모노클로날 항체 방법, 예를 들면, 문헌(참조: Kohler and Milstein, 1975, Nature 256:495)의 표준 체세포 혼성화 기술을 비롯한 다양한 기술에 의해 생성될 수 있다.Monoclonal antibodies (mAbs) can be generated by a variety of techniques, including conventional monoclonal antibody methods, such as the standard somatic cell hybridization technique of Kohler and Milstein, 1975, Nature 256:495. .
항체를 발현하는 방법How to Express Antibodies
본 발명에 개시된 항체는 하이브리도마 세포주 또는 하이브리도마 이외의 발현 세포주에서 발현될 수 있다. 항체를 코딩하는 발현 구축물은 포유동물, 곤충 또는 미생물 숙주 세포를 형질전환시키는데 사용될 수 있다. 플라스미드와 같은 구축물은 앞서 기술된 바와 같이 폴리뉴클레오티드를 숙주 세포 내로 도입하기 위한 다양한 임의의 공지된 방법을 사용하여 수행될 수 있다. 구체적인 방법은 숙주세포의 종류에 따라 달라질 수 있을 것이다. 이종 폴리뉴클레오티드를 포유동물 세포 내로 도입하는 방법은 당해 기술 분야에 널리 공지되어 있고, 예를 들면 덱스트란 매개 전달이입, 인산칼슘 침전, 폴리브렌 매개 전달이입, 원형질체(protoplast) 융합, 전기천공, 리포좀을 이용한 전달되는 폴리뉴클레오티드의 캡슐화, 핵산과 양으로 하전된 지질의 혼합, 및 핵 내로 DNA의 직접적인 미세주입에 의해 수행될 수 있지만, 이로 제한되는 것은 아니다.Antibodies disclosed in the present invention may be expressed in hybridoma cell lines or non-hybridoma expression cell lines. Expression constructs encoding antibodies can be used to transform mammalian, insect, or microbial host cells. Constructs such as plasmids can be made using any of a variety of known methods for introducing polynucleotides into host cells, as previously described. The specific method may vary depending on the type of host cell. Methods for introducing heterologous polynucleotides into mammalian cells are well known in the art and include, for example, dextran-mediated transfection, calcium phosphate precipitation, polybrene-mediated transfection, protoplast fusion, electroporation, and liposomes. This can be accomplished by, but is not limited to, encapsulation of the delivered polynucleotide, mixing of nucleic acid with positively charged lipids, and direct microinjection of DNA into the nucleus.
치료 목적을 위한 항-인간 TROP2 항체 약물-접합체의 용도Use of anti-human TROP2 antibody drug-conjugate for therapeutic purposes
암에서 TROP2의 발현은 암환자의 좋지 않은 예후와 관련이 있으며, 암 전이에도 영향을 미치는 것으로 알려져 있다. 예를 들면 TROP2는 폐암, 소세포성 폐암, 위장관암, 대장암, 장암, 유방암, 난소암, 전립선암, 고환암, 간암, 신장암, 방광암, 췌장암, 뇌암, 육종, 골육종, 카포시 육종 및 흑색종 등에서 과발현된다. 항암 항체 치료를 위해 예를 들면 항-인간 TROP2 항체는 본 발명에 기술한 바와 같이 링커를 통해 다양한 세포독성제제와 연결된 형태로 TROP2를 과발현하는 암 세포의 제거에 사용될 수 있다. 따라서, TROP2에 결합하는 항체는 항체 단독 또는 항암화학요법제, 세포독성제 또는 방사선 물질과 결합되어 사용될 수 있거나 또는 CAR-T 세포와 같은 세포치료제로서, 항암 표적에 대한 표적화의 목적으로 구현되어, TROP2를 발현하는 세포로 유도하는 표적 치료제로 사용될 수 있다.Expression of TROP2 in cancer is associated with poor prognosis of cancer patients and is known to affect cancer metastasis. For example, TROP2 is used in lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. It is overexpressed. For anti-cancer antibody treatment, for example, an anti-human TROP2 antibody can be used to eliminate cancer cells overexpressing TROP2 in a form linked to various cytotoxic agents through a linker as described in the present invention. Therefore, the antibody that binds to TROP2 can be used alone or in combination with anticancer chemotherapy agents, cytotoxic agents, or radioactive substances, or is implemented as a cell therapy agent such as CAR-T cells for the purpose of targeting an anticancer target, It can be used as a targeted treatment that induces cells expressing TROP2.
치료 방법: 약학적 제형, 투여 경로Treatment method: pharmaceutical formulation, route of administration
본 발명의 일 구현예에서는 항체-약물 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물을 사용한 치료 방법이 또한 제공된다. 일 구현예에서 항체-약물 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물은 환자에 제공된다. 항체-약물 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물은 암세포 표면에 발현되는 인간 TROP2에 결합함으로써, 암세포의 전이를 억제한다. 일 구현예에서 항체는 세포독성제와 결합한 형태로 암세포 표면에 발현되는 인간 TROP2에 결합함으로써, 항체에 결합된 세포독성제를 암세포에 특이적으로 전달하여 암세포의 사멸을 유도한다. 일 구현예에서 항체는 같은 표적 또는 다른 표적에 특이적인 항체의 형태로 암세포 표면에 발현되는 인간 TROP2에 결합함으로써, 다중항체의 암세포에 대한 특이성을 높이거나 암세포와 면역세포등의 다른 종류의 세포간의 연결을 유도하여 암세포의 사멸을 유도한다.In one embodiment of the present invention, a treatment method using an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof is also provided. In one embodiment, the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof is provided to a patient. The antibody-drug conjugate or its pharmaceutically acceptable salt or solvate inhibits the metastasis of cancer cells by binding to human TROP2 expressed on the surface of cancer cells. In one embodiment, the antibody binds to human TROP2 expressed on the surface of cancer cells in a form bound to a cytotoxic agent, thereby specifically delivering the cytotoxic agent bound to the antibody to the cancer cells, thereby inducing death of the cancer cells. In one embodiment, the antibody binds to human TROP2 expressed on the surface of cancer cells in the form of an antibody specific for the same target or a different target, thereby increasing the specificity of the polyantibody to cancer cells or increasing the specificity of the antibody to cancer cells and other types of cells such as immune cells. Induces the death of cancer cells by inducing connection.
항체-약물 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물의 치료적 유효량, 및 약학적으로 허용가능한 희석제, 담체, 가용화제, 유화제, 방부제 및/또는 보조제를 포함하는 약학적 조성물도 또한 제공된다. 또한, 예를 들면, 이러한 약학적 조성물을 투여함으로써 암 환자를 치료하는 방법이 포함된다. 용어 "환자"는 인간 환자를 포함한다.Also provided is a pharmaceutical composition comprising a therapeutically effective amount of an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative and/or adjuvant. do. Also included are methods of treating cancer patients, for example, by administering such pharmaceutical compositions. The term “patient” includes human patients.
상기 약학적 조성물은 약학적으로 허용가능한 담체를 포함할 수 있다. 상기 담체는 부형제, 희석제 또는 보조제를 포함하는 의미로 사용된다. 상기 담체는 예를 들면, 락토스, 덱스트로스, 수크로스, 소르비톨, 만니톨, 자일리톨, 에리트리톨, 말티톨, 전분, 아카시아 고무, 알기네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 폴리비닐 피롤리돈, 물, 생리식염수, PBS와 같은 완충액, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트, 및 미네랄 오일로 이루어진 군으로부터 선택된 것일 수 있다. 상기 조성물은 충진제, 항응집제, 윤활제, 습윤제, 풍미제, 유화제, 보존제, 또는 이들의 조합을 포함할 수 있다.The pharmaceutical composition may include a pharmaceutically acceptable carrier. The carrier is used to include an excipient, diluent, or auxiliary agent. The carriers include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl chloride. It may be selected from the group consisting of rolidone, water, physiological saline, buffer solutions such as PBS, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil. The composition may include fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, or combinations thereof.
상기 약학적 조성물은 통상의 방법에 따라 임의의 제형으로 준비될 수 있다. 상기 조성물은 예를 들면, 경구 투여 제형(예를 들면, 분말, 정제, 캡슐, 시럽, 알약, 또는 과립), 또는 비경구 제형(예를 들면, 주사제)으로 제형화될 수 있다. 또한, 상기 조성물은 전신 제형, 또는 국부 제형으로 제조될 수 있다.The pharmaceutical composition can be prepared in any dosage form according to conventional methods. The composition may be formulated, for example, as an oral dosage form (e.g., powder, tablet, capsule, syrup, pill, or granule), or a parenteral dosage form (e.g., injection). Additionally, the composition may be prepared as a systemic formulation or a topical formulation.
상기 약학적 조성물은 상기 항체 또는 그의 항원 결합 단편, 항암제, 또는 이들의 조합을 유효한 양으로 포함할수 있다. 용어 "유효한 양"은 예방 또는 치료를 필요로 하는 개체에게 투여되는 경우 예방 또는 치료의 효과를 나타내기에 충분한 양을 말한다. 상기 유효한 양은 당업자가 선택되는 세포 또는 개체에 따라 적절하게 선택할 수 있다. 질환의 중증도, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 사용된 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. The pharmaceutical composition may contain an effective amount of the antibody or antigen-binding fragment thereof, an anticancer agent, or a combination thereof. The term “effective amount” refers to an amount sufficient to produce a prophylactic or therapeutic effect when administered to an individual in need of such prophylaxis or treatment. The effective amount can be appropriately selected by a person skilled in the art depending on the cell or organism selected. Factors including the severity of the disease, the patient's age, weight, health, gender, the patient's sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs combined or used simultaneously with the composition used, and other fields of medicine. It can be determined according to well-known factors.
상기 약학적 조성물의 투여량은 예를 들어, 성인 기준으로 10 ㎍/kg 내지 약 30 ㎎/kg, 선택적으로 0.1 ㎎/kg 내지 약 30 ㎎/kg, 또는 대안적으로 0.3 ㎎/kg 내지 약 20 ㎎/kg의 범위일 수 있다. 상기 투여는 1일 1회, 1일 다회, 또는 1주일 내지 4주일에 1회, 또는 1년에 1회 내지 12회 투여될 수 있다.The dosage of the pharmaceutical composition may be, for example, 10 μg/kg to about 30 mg/kg, optionally 0.1 mg/kg to about 30 mg/kg, or alternatively 0.3 mg/kg to about 20 mg/kg, for an adult. It may be in the range of mg/kg. The administration may be administered once a day, multiple times a day, once a week to four weeks, or once a year to 12 times.
이하 본 발명을 실시예 및 실험예를 통해 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail through examples and experimental examples.
하기 실시예 및 실험예는 본 발명의 이해를 돕기 위한 것이고, 본 발명의 권리범위를 이로 한정하려는 의도를 갖는 것은 아니다.The following examples and experimental examples are intended to aid understanding of the present invention, and are not intended to limit the scope of the present invention.
<실시예 1> 인간 TROP2(tumor-associated calcium signal transducer 2, TACSTD2) 특이적 항체 제조<Example 1> Preparation of human TROP2 (tumor-associated calcium signal transducer 2, TACSTD2) specific antibody
종양에서 주로 발현되는 TROP2(tumor-associated calcium signal transducer 2, TACSTD2) 형태에 특이적으로 더 강하게 결합하는 항-TROP2 인간화 항체 2G10-5 및 2G10-6은 미국 출원번호 15/532598에 기재된 방법으로 제조하였다. 또한, 상기 항체의 아미노산 서열은 하기 표 1 및 표 2에 나타내었다.Anti-TROP2 humanized antibodies 2G10-5 and 2G10-6 bind more strongly to the TROP2 (tumor-associated calcium signal transducer 2, TACSTD2) form that is mainly expressed in tumors. It was prepared by the method described in US Application No. 15/532598. Additionally, the amino acid sequences of the antibodies are shown in Tables 1 and 2 below.
또한, ADC 합성을 위해 상기 항체 2G10-5의 경쇄(서열번호 18) C-말단에 CaaX 펩타이드 모이어티(GGGGGGGCVIM; 서열번호 22)를 융합한 형태의 항체 클론 2G10-5-CaaX 제작하고, CHO 세포 기반의 임시발현을 통해 항체를 생산하였다. 생산된 항체 2G10-5-CaaX를 ADC 합성에 사용하였다. 상기 항체의 아미노산 서열은 표 3에 나타내었다.In addition, for ADC synthesis, antibody clone 2G10-5-CaaX was prepared by fusing the CaaX peptide moiety (GGGGGGGCVIM; SEQ ID NO: 22) to the C-terminus of the light chain (SEQ ID NO: 18) of the antibody 2G10-5, and grown in CHO cells. Antibodies were produced through transient expression. The produced antibody 2G10-5-CaaX was used for ADC synthesis. The amino acid sequence of the antibody is shown in Table 3.
<실시예 2> 화합물 1, 2, 3 및 4의 제조<Example 2> Preparation of compounds 1, 2, 3 and 4
<2-1> 화합물 1의 제조<2-1> Preparation of Compound 1
상기 화합물 1은 대한민국 출원번호 10-2018-7018068에 기재된 방법으로 제조하였다.Compound 1 was prepared by the method described in Korean Application No. 10-2018-7018068.
상기 화합물 1에서 MMAE(Monomethyl auristatin E)의 구조는 다음과 같다: The structure of MMAE (Monomethyl auristatin E) in Compound 1 is as follows:
<2-2> 화합물 2의 제조<2-2> Preparation of compound 2
상기 화합물 2는 대한민국 출원번호 10-2018-0036895에 기재된 방법으로 제조하였다.The compound 2 was prepared by the method described in Korean Application No. 10-2018-0036895.
<2-3> 화합물 3의 제조<2-3> Preparation of compound 3
상기 화합물 3은 대한민국 출원번호 10-2020-0188314에 기재된 방법으로 제조하였다.The compound 3 was prepared by the method described in Korean Application No. 10-2020-0188314.
<2-4> 화합물 4의 제조<2-4> Preparation of compound 4
상기 화합물 4는 대한민국 출원번호 10-2018-0036895에 기재된 방법으로 제조하였다.The compound 4 was prepared by the method described in Korean Application No. 10-2018-0036895.
<실시예 3> ADC의 제조<Example 3> Preparation of ADC
ADC의 제조는 다음의 두 단계를 거쳐 제조되었으며, 공통적으로 사용한 LCB14-0606과 LCB14-0512는 대한민국 출원번호 10-2013-7032628에 기재된 방법으로 제조하였다. LCB14-0606과 LCB14-0512의 구조식은 다음과 같다:The ADC was manufactured through the following two steps, and the commonly used LCB14-0606 and LCB14-0512 were manufactured by the method described in Korean Application No. 10-2013-7032628. The structural formulas of LCB14-0606 and LCB14-0512 are as follows:
1단계 : 프레닐화 항체(prenylated antibody)의 제조 Step 1: Preparation of prenylated antibody
<LCB14-0606를 이용한 프레닐화 항체 제조><Manufacture of prenylated antibody using LCB14-0606>
실시예 1의 항체 2G10-5-CaaX의 프레닐레이션(prenylation) 반응 혼합물을 제조하여 30℃에서 16시간 반응하였다. 반응 혼합물은 24 μM 항체, 600 nM FTase(Genscript)와 144 μM LCB14-0606을 포함하는 완충용액(50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 10 μM ZnCl2, 0.5 mM DTT)으로 구성하였다. 반응 종료 후 프레닐레이션된 항체는 PBS 완충용액으로 평형화된 G25 Sepharose 컬럼(AKTA purifier, GE healthcare)으로 제염시켰다.A prenylation reaction mixture of the antibody 2G10-5-CaaX of Example 1 was prepared and reacted at 30°C for 16 hours. The reaction mixture was buffered (50 mM Tris-HCl (pH 7.4), 5 mM MgCl 2 , 10 μM ZnCl 2 , 0.5 mM DTT) containing 24 μM antibody, 600 nM FTase (Genscript), and 144 μM LCB14-0606. It was composed. After completion of the reaction, the prenylated antibody was decontaminated using a G25 Sepharose column (AKTA purifier, GE healthcare) equilibrated with a PBS buffer solution.
<LCB14-0512를 이용한 프레닐화 항체 제조><Production of prenylated antibody using LCB14-0512>
실시예 1의 항체 2G10-5-CaaX의 프레닐레이션 반응 혼합물을 제조하여 30℃에서 2시간 반응하였다. 반응 혼합물은 24 μM 항체, 600 nM FTase(Genscript)와 200 μM LCB14-0512을 포함하는 완충용액(50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 10 μM ZnCl2, 0.1 mM DTT)으로 구성하였다. 반응 종료 후 프레닐레이션된 항체는 PBS 완충용액으로 평형화된 G25 Sepharose 컬럼(AKTA purifier, GE healthcare)으로 제염시켰다.A prenylation reaction mixture of the antibody 2G10-5-CaaX of Example 1 was prepared and reacted at 30°C for 2 hours. The reaction mixture was a buffer solution (50 mM Tris-HCl (pH 7.4), 5 mM MgCl 2 , 10 μM ZnCl 2 , 0.1 mM DTT) containing 24 μM antibody, 600 nM FTase (Genscript), and 200 μM LCB14-0512. It was composed. After completion of the reaction, the prenylated antibody was decontaminated using a G25 Sepharose column (AKTA purifier, GE healthcare) equilibrated with a PBS buffer solution.
2단계 : 약물-컨쥬게이션(drug-conjugation) 방법Step 2: Drug-conjugation method
<옥심 결합 반응(conjugation by oxime bond formation)><Conjugation by oxime bond formation>
프레닐레이션된 항체와 링커-약물간의 옥심 결합 생성반응 혼합물은 100 μM Na-아세테이트 완충용액 pH 5.2, 10% DMSO, 24 μM 프레닐레이션된 항체와 240 μM 링커-약물(in house, 실시예 2의 화합물 1, 2 또는 3)을 섞어 제조하였으며 30℃에서 약하게 교반하였다. 6시간 또는 24시간 반응 후에 FPLC(AKTA purifier, GE healthcare) 과정을 거쳐 사용된 과량의 저분자 화합물들을 제거하였으며 단백질 분획은 수집하여 농축하였다.The oxime bond formation reaction mixture between the prenylated antibody and the linker-drug was 100 μM Na-acetate buffer pH 5.2, 10% DMSO, 24 μM prenylated antibody and 240 μM linker-drug (in house, Example 2) Compounds 1, 2 or 3) were mixed and stirred gently at 30°C. After reaction for 6 or 24 hours, excess low-molecular-weight compounds used were removed through FPLC (AKTA purifier, GE healthcare), and protein fractions were collected and concentrated.
<Copper-free 클릭 결합 반응(conjugation by Copper-free click reaction)><Copper-free click reaction (conjugation by Copper-free click reaction)>
프레닐레이션된 항체와 링커-약물간의 Copper-free 클릭 결합 반응을 이용한 ADC는 PBS 완충용액 (pH 7.4), 1% DMSO, 10 μM 프레닐레이션된 항체와 100 μM 링커-약물(in house, 실시예 2의 화합물 4번)을 섞어서 반응 혼합물을 제조하고 25℃에서 6 시간 반응 후에 FPLC(AKTA purifier, GE healthcare) 또는 G25 Sepharose 컬럼 과정을 거쳐 사용된 과량의 저분자 화합물들을 제거하였으며 단백질 분획은 수집하여 농축하였다.ADC using copper-free click coupling reaction between prenylated antibody and linker-drug was performed in PBS buffer solution (pH 7.4), 1% DMSO, 10 μM prenylated antibody and 100 μM linker-drug (in house, A reaction mixture was prepared by mixing Compound No. 4 in Example 2, and after reaction at 25°C for 6 hours, excess low molecular weight compounds used were removed through FPLC (AKTA purifier, GE healthcare) or G25 Sepharose column, and the protein fraction was collected. Concentrated.
상기 두 단계를 거쳐 제조된 ADC는 하기 표 4 및 도 1 내지 도 4에 나타내었다.The ADC prepared through the above two steps is shown in Table 4 and Figures 1 to 4 below.
2G10-5
2G10-5
LCB12-0606
LCB12-0606
<실험예 1> <Experimental Example 1> In vitroIn vitro 세포 독성 평가 Cytotoxicity evaluation
상기 <실시예 2>에서 제조한 ADC 및 상기 ADC에 포함된 약물 단독의 암세포주에 대한 세포증식억제 활성을 측정하였다. The cytostatic activity of the ADC prepared in <Example 2> and the drug contained in the ADC alone was measured against cancer cell lines.
구체적으로, 암세포주로 시판 중인 사람 췌장암 세포주(BxPC-3, Capan-1, PATU-8988s), 유방암 세포주(JIMT-1, MDA-MB-468), 위암 세포주(NCI-N87, SNU-601, SNU-620), 대장암 세포주(HCT15, HT29, DLD-1, SW480, COLO205), 난소암 세포주(OVCAR-3), 전립선암 세포주(PC-3, LNCaP), 비소세포폐암 세포주(NCI-H1781, HCC827, Calu-1, Calu-3)를 사용하였다. 상기 실시예 3에서 제조한 ADC에 포함된 약물 단독으로 MMAE 및 PBD dimer인 SG2057(CAS#: 260417-62-7, MedKoo Biosciences)을 사용하였다. 96-웰 플레이트에 각 암세포주를 웰당 500 ~ 5,000개씩 접종(seeding)하여 24시간 동안 배양한 뒤, ADC로 상기 실시예 3에서 제조한 ADC1, ADC2 및 ADC3, 약물 단독으로 MMAE 및 SG2057 약물 각각을 0.256 pM ~ 100 nM(5배 연속 희석) 농도로 처리하였다. 144시간 뒤에 살아있는 세포수를 SRB(Sulforhodamine B) 염료 혹은 Cell titer glo를 사용하여 정량하였다.Specifically, commercially available cancer cell lines include human pancreatic cancer cell lines (BxPC-3, Capan-1, PATU-8988s), breast cancer cell lines (JIMT-1, MDA-MB-468), and gastric cancer cell lines (NCI-N87, SNU-601, SNU). -620), colon cancer cell line (HCT15, HT29, DLD-1, SW480, COLO205), ovarian cancer cell line (OVCAR-3), prostate cancer cell line (PC-3, LNCaP), non-small cell lung cancer cell line (NCI-H1781, HCC827, Calu-1, Calu-3) were used. SG2057 (CAS#: 260417-62-7, MedKoo Biosciences), an MMAE and PBD dimer, was used as the only drug included in the ADC prepared in Example 3. 500 to 5,000 cells per well of each cancer cell line were seeded in a 96-well plate and cultured for 24 hours. Then, ADC1, ADC2, and ADC3 prepared in Example 3 were used as ADCs, and MMAE and SG2057 drugs were used alone. It was treated at a concentration of 0.256 pM to 100 nM (5-fold serial dilution). After 144 hours, the number of living cells was quantified using SRB (Sulforhodamine B) dye or Cell titer glo.
그 결과, 표 5 내지 표 7에 나타낸 바와 같이, 대부분의 암세포주에서 옥심 반응을 이용한 피롤로벤조디아제핀 계열의 항체-약물 접합체(ADC2, ADC3)가 오리스타틴 계열의 항체-약물 접합체(ADC1) 대비 훨씬 강한 세포 독성을 보이는 것을 확인하였다. As a result, as shown in Tables 5 to 7, in most cancer cell lines, the pyrrolobenzodiazepine series antibody-drug conjugate (ADC2, ADC3) using oxime reaction is much stronger than the auristatin series antibody-drug conjugate (ADC1). It was confirmed that it exhibited strong cytotoxicity.
<실험예 2> <Experimental Example 2> In vivoIn vivo 종양 생장 억제 효능 분석 Tumor growth inhibition efficacy analysis
종양 이식 마우스 모델에서 상기 실시예 3에서 제조한 ADC의 종양 생장 억제 효능을 분석하였다.The tumor growth inhibition efficacy of the ADC prepared in Example 3 was analyzed in a tumor transplant mouse model.
구체적으로, 췌장암 세포주(BxPC-3, Capan-1), 유방암 세포주(MDA-MB-468), 위암 세포주(NCI-N87), 대장암 세포주(HT29), 비소세포폐암 세포주(HCC827, NCI-H2170)를 세포배양하였다. 배양한 세포를 1 × 106 ~ 7 ×106 세포 수가 되도록 100 μl의 PBS로 현탁하고, Matrigel 100 μl을 섞은 후 Balb/c-nude 마우스에 생착하였다. 종양의 크기가 100 ~ 200 mm3가 되었을 때 하기 표 8 내지 표 10의 투여용법으로 상기 실시예 3에서 제조한 ADC를 정맥 내로 투여하였다. 마우스에 이식된 종양 크기를 최초 투여(Day 1) 직전에 측정하고, 그 후 56일 동안 주기적으로 측정하였다. 비교군의 경우 Trodelvy(sacituzumab govitecan-hziy) 또는 DS-1062BS(Datopotamab deruxtecan)를 투여하였다.Specifically, pancreatic cancer cell lines (BxPC-3, Capan-1), breast cancer cell lines (MDA-MB-468), stomach cancer cell lines (NCI-N87), colon cancer cell lines (HT29), and non-small cell lung cancer cell lines (HCC827, NCI-H2170). ) was cultured. The cultured cells were suspended in 100 μl of PBS to reach a cell count of 1 × 10 6 to 7 × 10 6 , mixed with 100 μl of Matrigel, and engraftd into Balb/c-nude mice. When the size of the tumor reached 100 to 200 mm 3 , the ADC prepared in Example 3 was administered intravenously using the administration regimen shown in Tables 8 to 10 below. The size of the tumor transplanted into the mouse was measured immediately before the first administration (Day 1) and measured periodically for 56 days thereafter. For the comparison group, Trodelvy (sacituzumab govitecan-hziy) or DS-1062BS (Datopotamab deruxtecan) was administered.
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그 결과, 도 5a 및 도 5b에 나타낸 바와 같이, 1차 실험 결과 췌장암 세포주 이식 마우스 모델에 옥심 반응을 이용한 오리스타틴 계열의 항체-약물 접합체 (ADC1)를 투여한 경우 2, 4 mg/kg에서 모두 대조군 대비 용량 의존적으로 종양 생장 억제 효능을 확인하였다(도 5a). 유방암 세포주 이식 마우스 모델에서는 옥심 반응을 이용한 오리스타틴 계열의 항체-약물 접합체(ADC1) 투여군과 피롤로벤조디아제핀 계열의 항체-약물 접합체(ADC2, ADC3) 투여군 모두 대조군 대비 종양 생장 억제 효능을 확인하였다. As a result, as shown in Figures 5a and 5b, when the auristatin antibody-drug conjugate (ADC1) using the oxime reaction was administered to the pancreatic cancer cell line transplant mouse model as a result of the first experiment, both at 2 and 4 mg/kg Tumor growth inhibition efficacy was confirmed in a dose-dependent manner compared to the control group (Figure 5a). In the breast cancer cell line transplant mouse model, tumor growth inhibition efficacy was confirmed in both the auristatin-based antibody-drug conjugate (ADC1) administration group and the pyrrolobenzodiazepine-based antibody-drug conjugate (ADC2, ADC3) administration group using oxime reaction compared to the control group.
또한, 도 6a 내지 도 6d에 나타낸 바와 같이, 2차 실험 결과 4가지 암세포주 이식 마우스 모델(MDA-MB-468, BxPC-3, NCI-N87, HCC827) 모두에서 시판약물인 Trodelvy 대비 ADC1의 우수한 효능을 확인하였다.In addition, as shown in Figures 6a to 6d, the results of the second experiment showed that ADC1 was superior to Trodelvy, a commercially available drug, in all four cancer cell line transplant mouse models (MDA-MB-468, BxPC-3, NCI-N87, HCC827). Efficacy was confirmed.
또한, 도 7a 내지 도 7e에 나타낸 바와 같이, 3차 실험 결과 5가지 암세포주 이식 마우스 모델(BxPC-3, HCC827, Capan-1, NCI-H2170, HT-29) 모두에서 시판약물인 Trodelvy 대비 ADC1의 우수한 효능을 확인하였으며, 경쟁약물인 DS-1062BS 대비 동등 이상의 효능을 확인하였다. In addition, as shown in Figures 7a to 7e, the results of the third experiment showed that ADC1 compared to Trodelvy, a commercially available drug, in all five cancer cell line transplant mouse models (BxPC-3, HCC827, Capan-1, NCI-H2170, HT-29) The excellent efficacy of was confirmed, and the efficacy was confirmed to be equal or better than that of the competing drug DS-1062BS.
<110> LEGOCHEM BIOSCIENCES, INC. <120> Antibody-drug conjugate comprising antibody against human TROP2 and its use <130> KP2260105-LEGC <160> 23 <170> KoPatentIn 3.0 <210> 1 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_HFR1 <400> 1 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Ser 20 25 30 <210> 2 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_HCDR1 <400> 2 Ser Ser Tyr Ile Ser 1 5 <210> 3 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_HFR2 <400> 3 Trp Leu Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Ala 1 5 10 <210> 4 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_HCDR2 <400> 4 Trp Ile Tyr Ala Gly Thr Gly Gly Thr Ser Tyr Asn Gln Lys Phe Thr 1 5 10 15 Gly <210> 5 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_HFR3 <400> 5 Lys Ala Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu 1 5 10 15 Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 6 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_HCDR3 <400> 6 His Asn Pro Arg Tyr Tyr Ala Met Asp Tyr 1 5 10 <210> 7 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_HFR4 <400> 7 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 1 5 10 <210> 8 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_LFR1 <400> 8 Asp Thr Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr 20 <210> 9 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_LCDR1 <400> 9 Ile Thr Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp Met Asn 1 5 10 <210> 10 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_LFR2 <400> 10 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Ser 1 5 10 15 <210> 11 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_LCDR2 <400> 11 Glu Gly Asn Thr Leu Arg Pro 1 5 <210> 12 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_LFR3 <400> 12 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Tyr Gly Thr Asp Phe Thr 1 5 10 15 Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 20 25 30 <210> 13 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_LCDR3 <400> 13 Leu Gln Ser Asp Asn Leu Pro Tyr Thr 1 5 <210> 14 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_LFR4 <400> 14 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 1 5 10 <210> 15 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_VH <400> 15 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Ser Ser Ser 20 25 30 Tyr Ile Ser Trp Leu Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Ala Trp Ile Tyr Ala Gly Thr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Asn Pro Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> 16 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_VL <400> 16 Asp Thr Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp 20 25 30 Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Ser Asp Asn Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 17 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_HC <400> 17 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Ser Ser Ser 20 25 30 Tyr Ile Ser Trp Leu Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Ala Trp Ile Tyr Ala Gly Thr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Asn Pro Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 18 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-6_LC <400> 18 Asp Thr Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp 20 25 30 Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Ser Asp Asn Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 19 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> 2G10-6_HFR3 <400> 19 Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu 1 5 10 15 Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 20 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> 2G10-6_VH <400> 20 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Ser Ser Ser 20 25 30 Tyr Ile Ser Trp Leu Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Ala Trp Ile Tyr Ala Gly Thr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Asn Pro Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> 21 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> 2G10-6_HC <400> 21 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Ser Ser Ser 20 25 30 Tyr Ile Ser Trp Leu Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Ala Trp Ile Tyr Ala Gly Thr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Asn Pro Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 22 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> CaaX peptide moiety <400> 22 Gly Gly Gly Gly Gly Gly Gly Cys Val Ile Met 1 5 10 <210> 23 <211> 225 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5-CaaX_LC <400> 23 Asp Thr Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp 20 25 30 Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Ser Asp Asn Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Gly Gly Gly Cys Val Ile 210 215 220 Met 225 <110> LEGOCHEM BIOSCIENCES, INC. <120> Antibody-drug conjugate comprising antibody against human TROP2 and its use <130> KP2260105-LEGC <160> 23 <170> KoPatentIn 3.0 <210> 1 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_HFR1 <400> 1 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Ser 20 25 30 <210> 2 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_HCDR1 <400> 2 Ser Ser Tyr Ile Ser 1 5 <210> 3 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_HFR2 <400> 3 Trp Leu Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Ala 1 5 10 < 210> 4 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_HCDR2 <400> 4 Trp Ile Tyr Ala Gly Thr Gly Gly Thr Ser Tyr Asn Gln Lys Phe Thr 1 5 10 15 Gly <210> 5 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_HFR3 <400> 5 Lys Ala Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu 1 5 10 15 Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 6 <211> 10 <212> PRT <213> Artificial Sequence <220> < 223> 2G10-5_2G10-5-CaaX_2G10-6_HCDR3 <400> 6 His Asn Pro Arg Tyr Tyr Ala Met Asp Tyr 1 5 10 <210> 7 <211> 11 <212> PRT <213> Artificial Sequence <220> <223 > 2G10-5_2G10-5-CaaX_2G10-6_HFR4 <400> 7 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 1 5 10 <210> 8 <211> 20 <212> PRT <213> Artificial Sequence <220> <223 > 2G10-5_2G10-5-CaaX_2G10-6_LFR1 <400> 8 Asp Thr Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr 20 <210> 9 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_LCDR1 <400> 9 Ile Thr Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp Met Asn 1 5 10 <210> 10 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_LFR2 <400> 10 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Ser 1 5 10 15 <210> 11 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_LCDR2 <400> 11 Glu Gly Asn Thr Leu Arg Pro 1 5 <210> 12 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_LFR3 <400> 12 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Tyr Gly Thr Asp Phe Thr 1 5 10 15 Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 20 25 30 <210> 13 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_LCDR3 < 400> 13 Leu Gln Ser Asp Asn Leu Pro Tyr Thr 1 5 <210> 14 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_LFR4 <400> 14 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 1 5 10 <210> 15 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_VH <400> 15 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Ser Ser Ser 20 25 30 Tyr Ile Ser Trp Leu Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Ala Trp Ile Tyr Ala Gly Thr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Asn Pro Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> 16 <211> 107 <212 > PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_2G10-6_VL <400> 16 Asp Thr Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp 20 25 30 Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Ser Asp Asn Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 17 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5_2G10-5-CaaX_HC <400> 17 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Ser Ser Ser 20 25 30 Tyr Ile Ser Trp Leu Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Ala Trp Ile Tyr Ala Gly Thr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Asn Pro Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 18 <211> 214 <212> PRT <213> Artificial Sequence <220> <223 > 2G10-5_2G10-6_LC <400> 18 Asp Thr Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp 20 25 30 Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Ser Asp Asn Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 19 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> 2G10-6_HFR3 <400> 19 Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu 1 5 10 15 Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 20 <211> 119 <212> PRT <213 > Artificial Sequence <220> <223> 2G10-6_VH <400> 20 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Ser Ser Ser 20 25 30 Tyr Ile Ser Trp Leu Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Ala Trp Ile Tyr Ala Gly Thr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Asn Pro Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> 21 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> 2G10-6_HC <400> 21 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Ser Ser Ser 20 25 30 Tyr Ile Ser Trp Leu Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Ala Trp Ile Tyr Ala Gly Thr Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Arg Val Thr Leu Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Asn Pro Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 22 <211> 11 <212> PRT <213> Artificial Sequence <220> <223 > CaaX peptide moiety <400> 22 Gly Gly Gly Gly Gly Gly Gly Cys Val Ile Met 1 5 10 <210> 23 <211> 225 <212> PRT <213> Artificial Sequence <220> <223> 2G10-5-CaaX_LC <400> 23 Asp Thr Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp 20 25 30 Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Ser Asp Asn Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Gly Gly Gly Cys Val Ile 210 215 220Met 225
Claims (54)
[일반식 I]
Ab-[LINKER-(B)l]m
상기 식에서,
Ab는 중쇄 가변영역 및 경쇄 가변영역을 포함하는 인간 TROP2(tumor-associated calcium signal transducer 2, TACSTD2)에 특이적으로 결합하는 항체 또는 이의 항원 결합 단편이고,
상기 항체 또는 이의 항원 결합 단편은
서열번호 2의 아미노산 서열로 이루어진 중쇄 CDR1; 서열번호 4의 아미노산 서열로 이루어진 중쇄 CDR2; 서열번호 6의 아미노산 서열로 이루어진 중쇄 CDR3을 포함하는 중쇄 가변영역; 및
서열번호 9의 아미노산 서열로 이루어진 경쇄 CDR1; 서열번호 11의 아미노산 서열로 이루어진 경쇄 CDR2; 서열번호 13의 아미노산 서열로 이루어진 경쇄 CDR3을 포함하는 경쇄 가변영역을 포함하며,
LINKER는 링커이고,
B는 활성제 모이어티이며,
l 및 m은 각각 독립적으로 1 내지 20 중에서 선택되는 정수이며,
l이 2 이상의 정수인 경우, B는 각각 서로 동일하거나 상이할 수 있다.
A conjugate represented by the following general formula (I) or a pharmaceutically acceptable salt or solvate thereof:
[General formula I]
Ab-[LINKER-(B) l ] m
In the above equation,
Ab is an antibody or antigen-binding fragment thereof that specifically binds to human TROP2 (tumor-associated calcium signal transducer 2, TACSTD2), which includes a heavy chain variable region and a light chain variable region,
The antibody or antigen-binding fragment thereof is
Heavy chain CDR1 consisting of the amino acid sequence of SEQ ID NO: 2; Heavy chain CDR2 consisting of the amino acid sequence of SEQ ID NO: 4; A heavy chain variable region comprising a heavy chain CDR3 consisting of the amino acid sequence of SEQ ID NO: 6; and
Light chain CDR1 consisting of the amino acid sequence of SEQ ID NO: 9; Light chain CDR2 consisting of the amino acid sequence of SEQ ID NO: 11; It contains a light chain variable region including a light chain CDR3 consisting of the amino acid sequence of SEQ ID NO: 13,
LINKER is a linker,
B is the activator moiety,
l and m are each independently integers selected from 1 to 20,
When l is an integer of 2 or more, B may be the same or different from each other.
서열번호 15 또는 20의 아미노산 서열;
상기 서열번호 15 또는 20의 아미노산 서열과 적어도 90% 이상의 상동성을 갖는 서열; 또는
상기 서열번호 15 또는 20의 아미노산 서열과 적어도 95% 이상의 상동성을 갖는 서열로 이루어진 중쇄 가변영역을 포함하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
The method of claim 1, wherein the antibody or antigen-binding fragment thereof is
Amino acid sequence of SEQ ID NO: 15 or 20;
A sequence having at least 90% homology to the amino acid sequence of SEQ ID NO: 15 or 20; or
A conjugate or a pharmaceutically acceptable salt or solvate thereof comprising a heavy chain variable region consisting of a sequence having at least 95% homology to the amino acid sequence of SEQ ID NO: 15 or 20.
서열번호 16의 아미노산 서열;
상기 서열번호 16의 아미노산 서열과 적어도 90% 이상의 상동성을 갖는 서열; 또는
상기 서열번호 16의 아미노산 서열과 적어도 95% 이상의 상동성을 갖는 서열로 이루어진 경쇄 가변영역을 포함하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
The method of claim 1, wherein the antibody or antigen-binding fragment thereof is
Amino acid sequence of SEQ ID NO: 16;
A sequence having at least 90% homology to the amino acid sequence of SEQ ID NO: 16; or
A conjugate or a pharmaceutically acceptable salt or solvate thereof comprising a light chain variable region consisting of a sequence having at least 95% homology to the amino acid sequence of SEQ ID NO: 16.
The conjugate or pharmaceutically acceptable salt or solvent thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises a combination of a heavy chain variable region and a light chain variable region consisting of the amino acid sequences of SEQ ID NOs: 15 and 16. freight.
The conjugate or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the antibody is a humanized antibody.
(a)(i) 인간 항체의 중쇄 또는 인간 컨센서스 프레임워크(consensus framework)로부터의 가변 도메인 프레임워크 영역; 및 (ii) 인간 항체의 경쇄 또는 인간 컨센서스 프레임워크로부터의 가변 도메인 프레임워크 영역을 포함하고,
(b)(i) 상기 중쇄로부터의 가변 도메인 프레임워크 영역의 적어도 하나의 아미노산은 마우스 항체 또는 마우스 컨센서스 프레임워크의 중쇄로부터의 상응하는 아미노산으로 치환되거나; (ii) 상기 경쇄로부터의 가변 도메인 프레임워크 영역은 마우스 항체 또는 마우스 컨센서스 프레임워크의 경쇄로부터 상응하는 아미노산으로 치환되고, 및
(c) (i) 상기 중쇄의 아미노산 치환은 하기 아미노산 치환으로부터 선택되고:
위치 27에서 Y(인간) 대신 F(마우스)로 치환;
위치 30에서 T(인간) 대신 S(마우스)로 치환;
위치 37에서 V(인간) 대신 L(마우스)로 치환;
위치 48에서 M(인간) 대신 I(마우스)로 치환;
위치 49에서 G(인간) 대신 A(마우스)로 치환;
위치 70에서 I(인간) 대신 L(마우스)로 치환; 및
위치 72에서 R(인간) 대신 V(마우스)로 치환
(ii) 상기 경쇄의 아미노산 치환은 위치 49에서 Y(인간) 대신 S(마우스)로 치환인,
접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
The method of claim 5, wherein the humanized antibody is
(a) (i) the heavy chain of a human antibody or variable domain framework region from the human consensus framework; and (ii) a light chain of a human antibody or a variable domain framework region from a human consensus framework,
(b)(i) at least one amino acid in the variable domain framework region from said heavy chain is replaced with a corresponding amino acid from the heavy chain of a mouse antibody or mouse consensus framework; (ii) the variable domain framework region from the light chain is replaced with the corresponding amino acid from the light chain of the mouse antibody or mouse consensus framework, and
(c) (i) the amino acid substitutions in the heavy chain are selected from the following amino acid substitutions:
Substitute F (mouse) for Y (human) in position 27;
Substitute S (mouse) for T (human) in position 30;
Substitute L (mouse) for V (human) in position 37;
Substitute I (mouse) for M (human) in position 48;
Substitute A (mouse) for G (human) in position 49;
Substitute L (mouse) for I (human) at position 70; and
Substitute V (mouse) for R (human) at position 72
(ii) the amino acid substitution of the light chain is substitution of S (mouse) for Y (human) at position 49,
Conjugate or pharmaceutically acceptable salt or solvate thereof.
The method of claim 1, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody, a domain antibody (dAb), a single chain antibody (scAb), a Fab fragment, a Fab' fragment, or an F (ab')2 fragment, scFab fragment, Fv fragment, dsFv fragment, single chain variable fragment (scFv), scFv-Fc fragment, single domain heavy chain antibody, single domain light chain antibody Any one selected from the group consisting of (single domain light chain antibody), antibody variant, multimeric antibody, minibody, diabody, bispecific antibody, and multispecific antibody. Phosphorus, conjugate or pharmaceutically acceptable salt or solvate thereof.
상기 항체와 활성제 사이의 링커는 절단 가능한 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to paragraph 1,
A conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the linker between the antibody and the active agent is cleavable.
상기 접합체는 하기 일반식 IIa의 구조를 갖는 것인, 항체 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물:
[일반식 IIa]
상기 식에서,
Ab는 중쇄 가변영역 및 경쇄 가변영역을 포함하는 인간 TROP2에 특이적으로 결합하는 항체 또는 이의 항원 결합 단편이고,
B'은 각각 독립적으로 동일하거나 상이한 활성제이며,
G 및 G'은 각각 독립적으로 글루쿠론산 모이어티(glucuronic acid moiety) 또는 이고;
상기 R3은 수소 또는 카복실 보호기이며, 상기 각각의 R4는 독립적으로 수소 또는 하이드록실 보호기이고;
R1 및 R2은 각각 독립적으로 수소, C1-8 알킬 또는 C3-8 사이클로알킬이며;
W은 각각 독립적으로 -C(O)-, -C(O)NR'-, -C(O)O-, -SO2NR'-, -P(O)R''NR'-, -SONR'- 또는 -PO2NR'-이고, 상기 C, S 또는 P는 직접적으로 페닐링(phenyl ring)에 결합하며, 상기 NR'은 L에 결합하고, 상기 R' 및 R''는 각각 독립적으로 수소, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, 모노- 또는 다이-C1-8 알킬아미노, C3-20 헤테로아릴 또는 C6-20아릴이며;.
Z는 각각 독립적으로 수소, C1-8 알킬, 할로겐, 시아노 또는 나이트로이고;
n은 0 내지 3의 정수이며, n이 2 이상의 정수인 경우 각각의 Z는 서로 동일하거나 상이할 수 있고;
L은 각각 독립적으로, 하기 A) 또는 B) 중 어느 하나이고:
A) C1-50 알킬렌 또는 1-50 원자 헤테로알킬렌이며, 하기 중 하나 이상을 만족한다:
(i) L은 하나 이상의 불포화 결합을 포함하고;
(ii) L 내의 2개의 원자가 치환체와 같은 2가 치환체로 치환되고; 이는 헤테로아릴렌(heteroarylene)을 완성시키며;
(iii) L은 1 내지 50 원자 헤테로알킬렌이고;
(iv) 상기 알킬렌은 하나 이상의 C1-20 알킬로 더 치환된다;
B) 이소프레노이드 트랜스퍼라제에 의하여 인식될 수 있는 하기 일반식 Ⅲ의 이소프레닐 유도체 유닛을 하나 이상 포함한다:
[일반식 Ⅲ]
;
Ab는 물결표시된 부분에 결합되고;
l 및 m은 각각 독립적으로 1 내지 20 중에서 선택되는 정수이고,
l이 2 이상인 경우, 활성제는 각각 동일하거나 상이할 수 있다.
According to paragraph 1,
The conjugate is an antibody conjugate or a pharmaceutically acceptable salt or solvate thereof having the structure of the following general formula IIa:
[Formula IIa]
In the above equation,
Ab is an antibody or antigen-binding fragment thereof that specifically binds to human TROP2 including a heavy chain variable region and a light chain variable region,
B' is each independently the same or different activator,
G and G' are each independently a glucuronic acid moiety or ego;
wherein R 3 is hydrogen or a carboxyl protecting group, and each R 4 is independently a hydrogen or hydroxyl protecting group;
R 1 and R 2 are each independently hydrogen, C 1-8 alkyl, or C 3-8 cycloalkyl;
W is each independently -C(O)-, -C(O)NR'-, -C(O)O-, -SO 2 NR'-, -P(O)R''NR'-, -SONR '- or -PO 2 NR'-, wherein C, S or P is directly bonded to a phenyl ring, NR' is bonded to L, and R' and R'' are each independently Hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl or C 6- 20 Aryl;.
Z is each independently hydrogen, C 1-8 alkyl, halogen, cyano or nitro;
n is an integer from 0 to 3, and when n is an integer of 2 or more, each Z may be the same or different;
L is each independently, either A) or B) below:
A) C 1-50 alkylene or 1-50 atom heteroalkylene, satisfying one or more of the following:
(i) L contains one or more unsaturated bonds;
(ii) two atoms in L are substituted with a divalent substituent, such as the substituent; This completes heteroarylene;
(iii) L is 1 to 50 atom heteroalkylene;
(iv) said alkylene is further substituted with one or more C 1-20 alkyl;
B) comprises at least one isoprenyl derivative unit of the general formula III:
[General formula Ⅲ]
;
Ab is bound to the tilde portion;
l and m are each independently integers selected from 1 to 20,
When l is 2 or more, the active agents may be the same or different, respectively.
[일반식 IIa]
상기 식에서,
Ab는 인간 TROP2(tumor-associated calcium signal transducer 2, TACSTD2)에 특이적으로 결합하는 항체 또는 이의 항원 결합 단편이고,
G는 각각 독립적으로 글루쿠론산 모이어티(glucuronic acid moiety) 또는 이고;
상기 R3은 수소 또는 카복실 보호기이며, 상기 각각의 R4는 독립적으로 수소 또는 하이드록실 보호기이고;
R1 및 R2은 각각 독립적으로 수소, C1-8 알킬 또는 C3-8 사이클로알킬이며;
W은 각각 독립적으로 -C(O)-, -C(O)NR'-, -C(O)O-, -SO2NR'-, -P(O)R''NR'-, -SONR'- 또는 -PO2NR'-이고, 상기 C, S 또는 P는 직접적으로 페닐링(phenyl ring)에 결합하며, 상기 NR'은 L에 결합하고, 상기 R' 및 R''는 각각 독립적으로 수소, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, 모노- 또는 다이-C1-8 알킬아미노, C3-20 헤테로아릴 또는 C6-20아릴이며;
Z는 각각 독립적으로 수소, C1-8 알킬, 할로겐, 시아노 또는 나이트로이고;
n은 0 내지 3의 정수이며;
L은 각각 독립적으로, 하기 A) 또는 B) 중 어느 하나이고:
A) C1-50 알킬렌 또는 1-50 원자 헤테로알킬렌이며, 하기 중 하나 이상을 만족한다:
(i) L은 하나 이상의 불포화 결합을 포함하고;
(ii) L 내의 2개의 원자가 치환체와 같은 2가 치환체로 치환되고; 이는 헤테로아릴렌(heteroarylene)을 완성시키며;
(iii) L은 1 내지 50 원자 헤테로알킬렌이고;
(iv) 상기 알킬렌은 하나 이상의 C1-20 알킬로 치환된다;
B) 이소프레노이드 트랜스퍼라제에 의하여 인식될 수 있는 하기 일반식 Ⅲ의 이소프레닐 유도체 유닛을 하나 이상 포함한다:
[일반식 Ⅲ]
;
B'는 활성제이고,
Ab는 물결표시된 부분에 결합되고;
l 및 m은 각각 독립적으로 1 내지 20 중에서 선택되는 정수이고,
l이 2 이상인 경우, 활성제는 각각 동일하거나 상이할 수 있다.
A conjugate represented by the following general formula IIa or a pharmaceutically acceptable salt or solvate thereof:
[Formula IIa]
In the above equation,
Ab is an antibody or antigen-binding fragment thereof that specifically binds to human TROP2 (tumor-associated calcium signal transducer 2, TACSTD2),
G is each independently a glucuronic acid moiety or ego;
wherein R 3 is hydrogen or a carboxyl protecting group, and each R 4 is independently a hydrogen or hydroxyl protecting group;
R 1 and R 2 are each independently hydrogen, C 1-8 alkyl, or C 3-8 cycloalkyl;
W is each independently -C(O)-, -C(O)NR'-, -C(O)O-, -SO 2 NR'-, -P(O)R''NR'-, -SONR '- or -PO 2 NR'-, wherein C, S or P is directly bonded to a phenyl ring, NR' is bonded to L, and R' and R'' are each independently Hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl or C 6- 20 is aryl;
Z is each independently hydrogen, C 1-8 alkyl, halogen, cyano or nitro;
n is an integer from 0 to 3;
L is each independently, either A) or B) below:
A) C 1-50 alkylene or 1-50 atom heteroalkylene, satisfying one or more of the following:
(i) L contains one or more unsaturated bonds;
(ii) two atoms in L are substituted with a divalent substituent, such as the substituent; This completes heteroarylene;
(iii) L is 1 to 50 atom heteroalkylene;
(iv) the alkylene is substituted with one or more C 1-20 alkyl;
B) comprises at least one isoprenyl derivative unit of the general formula III:
[General formula Ⅲ]
;
B' is the activator,
Ab is bound to the tilde portion;
l and m are each independently integers selected from 1 to 20,
When l is 2 or more, the active agents may be the same or different, respectively.
상기 G는 각각 독립적으로 이고,
R3은 수소 또는 카복실 보호기이며,
상기 각각의 R4는 독립적으로 수소 또는 하이드록실 보호기인 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to claim 9 or 10,
The G is each independently ego,
R 3 is hydrogen or a carboxyl protecting group,
Wherein each R 4 is independently hydrogen or a hydroxyl protecting group, a conjugate or a pharmaceutically acceptable salt or solvate thereof.
상기 R1 및 R2은 모두 수소이고;
n은 0이며;
상기 W는 각각 독립적으로 -C(O)NR'-이고, 상기 C는 직접적으로 페닐링(phenyl ring)에 결합하며, 상기 R'은 수소, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, 모노- 또는 다이- C1-8 알킬아미노, C3-20 헤테로아릴 또는 C6-20아릴이며, NR'은 L에 결합하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to claim 9 or 10,
Both R 1 and R 2 are hydrogen;
n is 0;
Each W is independently -C(O)NR'-, C is directly bonded to a phenyl ring, and R' is hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di- C 1-8 alkylamino, C 3-20 heteroaryl or C 6-20 aryl, and NR' is bonded to L. Or a pharmaceutically acceptable salt or solvate thereof.
상기 L은 질소 함유 1-5 원자 헤테로 알킬렌이고,
상기 링커는 친수성 아미노산의 2 이상의 원자를 포함하며,
상기 질소는 친수성 아미노산의 카르보닐과 펩타이드 결합을 형성하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to claim 9 or 10,
wherein L is a nitrogen-containing 1-5 membered heteroalkylene,
The linker contains two or more atoms of hydrophilic amino acid,
The nitrogen forms a peptide bond with the carbonyl of a hydrophilic amino acid, or a pharmaceutically acceptable salt or solvate thereof.
상기 L은 티오에테르 결합에 의해 항체와 공유결합하고,
상기 티오에테르 결합은 항체의 시스테인의 황원자를 포함하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to claim 9 or 10,
The L is covalently bound to the antibody by a thioether bond,
The conjugate or pharmaceutically acceptable salt or solvate thereof, wherein the thioether bond includes a sulfur atom of cysteine of the antibody.
상기 항체는 이소프레노이드 트랜스퍼라제에 의하여 인식될 수 있는 아미노산 모티프를 항체의 C-말단에 포함하고,
상기 티오에테르 결합은 상기 아미노산 모티프의 시스테인의 황원자를 포함하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 14,
The antibody contains an amino acid motif at the C-terminus of the antibody that can be recognized by isoprenoid transferase,
The thioether bond includes a sulfur atom of cysteine of the amino acid motif, or a pharmaceutically acceptable salt or solvate thereof.
상기 아미노산 모티프는 CYYX 서열이고, C가 시스테인이고, Y가 지방족 아미노산이며, X가 글루타민, 글루타메이트, 세린, 시스테인, 메티오닌, 알라닌 및 루신으로 이루어진 군으로부터 선택되는 어느 하나이며; 및
상기 티오에테르 결합은 상기 아미노산 모티프의 시스테인의 황원자를 포함하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 15,
The amino acid motif is a CYYX sequence, where C is cysteine, Y is an aliphatic amino acid, and X is any one selected from the group consisting of glutamine, glutamate, serine, cysteine, methionine, alanine, and leucine; and
The thioether bond includes a sulfur atom of cysteine of the amino acid motif, or a pharmaceutically acceptable salt or solvate thereof.
상기 아미노산 모티프는 CYYX 서열이고, Y가 알라닌, 이소루이신, 류신, 메티오닌 및 발린으로 이루어진 군으로부터 선택되는 어느 하나이거나; 또는
CVIM 또는 CVLL 서열인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 15,
The amino acid motif is a CYYX sequence, and Y is any one selected from the group consisting of alanine, isoleucine, leucine, methionine, and valine; or
A conjugate having a CVIM or CVLL sequence, or a pharmaceutically acceptable salt or solvate thereof.
아미노산 모티프에 선행하는 1 내지 20 개의 아미노산 중 적어도 하나가 글리신인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 15,
A conjugate or pharmaceutically acceptable salt or solvate thereof, wherein at least one of the 1 to 20 amino acids preceding the amino acid motif is glycine.
상기 L은 C-말단에 아미노산 서열 GGGGGGGCVIM을 포함하는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to claim 9 or 10,
Wherein L is a conjugate or a pharmaceutically acceptable salt or solvate thereof comprising the amino acid sequence GGGGGGGCVIM at the C-terminus.
상기 L은 옥심을 포함하는 3 내지 50 헤테로알킬렌이고,
상기 옥심의 산소 원자는 W와 연결된 L의 측면에 있으며,
옥심의 탄소 원자는 Ab에 연결된 L의 측면에 있거나; 또는
상기 옥심의 탄소 원자는 W에 연결된 L의 측면에 있으며,
옥심의 산소 원자는 Ab에 연결된 L의 측면에 있는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to claim 9 or 10,
Wherein L is 3 to 50 heteroalkylene containing oxime,
The oxygen atom of the oxime is on the side of L connected to W,
The carbon atom of the oxime is on the side of L linked to Ab; or
The carbon atom of the oxime is on the side of L connected to W,
A conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the oxygen atom of the oxime is on the side of L linked to Ab.
상기 L은 옥심을 포함하고, 하나 이상의 이소프레닐 유닛은 옥심을 Ab에 공유 결합시키는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to claim 9 or 10,
Wherein L includes an oxime, and at least one isoprenyl unit covalently binds the oxime to Ab, or a pharmaceutically acceptable salt or solvate thereof.
상기 L은 일반식 VIII 또는 일반식 IX로 표시되는 제2 유닛을 더 포함하는 것인, 항체 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물:
[일반식 VIII]
-(CH2)r(V(CH2)p)q-
[일반식 IX]
-(CH2CH2X)w-
상기 V는 단일결합, -O-, -S-, -NR21-, -C(O)NR22-, -NR23C(O)-, -NR24SO2- 또는 -SO2NR25-이고;
X는 -O-, C1-8 알킬렌 또는 -NR21-이고;
R21 내지 R25는 각각 독립적으로 수소, C1-6 알킬, C1-6 알킬 C6-20 아릴 또는 C1-6 알킬 C3-20 헤테로아릴이고;
r은 0 내지 10의 정수이고;
p는 0 내지 10의 정수이고;
q는 1 내지 20의 정수이고; 및
w는 1 내지 20의 정수이다.
According to claim 9 or 10,
wherein L further comprises a second unit represented by Formula VIII or Formula IX, or a pharmaceutically acceptable salt or solvate thereof:
[Formula VIII]
-(CH 2 ) r (V(CH 2 ) p ) q -
[Formula IX]
-( CH 2 CH 2
The V is a single bond, -O-, -S-, -NR 21 -, -C(O)NR 22 -, -NR 23 C(O)-, -NR 24 SO 2 - or -SO 2 NR 25 - ego;
X is -O-, C 1-8 alkylene or -NR 21 -;
R 21 to R 25 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkyl C 6-20 aryl, or C 1-6 alkyl C 3-20 heteroaryl;
r is an integer from 0 to 10;
p is an integer from 0 to 10;
q is an integer from 1 to 20; and
w is an integer from 1 to 20.
상기 q는 1 내지 10의 정수이고;
r 및 p는 각각 1 또는 2이며;
V는 -O-인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 22,
where q is an integer from 1 to 10;
r and p are each 1 or 2;
V is -O-, a conjugate or a pharmaceutically acceptable salt or solvate thereof.
상기 X는 -O-이고;
w는 1 내지 10의 정수인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 22,
X is -O-;
w is an integer from 1 to 10, or a conjugate or a pharmaceutically acceptable salt or solvate thereof.
상기 L은 또는 로 표시되는 적어도 하나의 폴리에틸렌 글리콜 유닛을 포함하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 21,
The L is or A conjugate or a pharmaceutically acceptable salt or solvate thereof comprising at least one polyethylene glycol unit represented by .
상기 L은 옥심을 포함하고,
적어도 하나의 폴리에틸렌 글리콜 유닛은 옥심을 활성제에 공유 결합시키는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 21,
The L includes an oxime,
A conjugate or pharmaceutically acceptable salt or solvate thereof, wherein at least one polyethylene glycol unit covalently binds an oxime to an active agent.
상기 L은 알카인과 아지드와의 반응, 또는 알데히드 또는 케톤 그룹과 하이드라진 또는 하이드록실아민과의 반응으로 형성되는 제3 유닛을 더 포함하는 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to claim 9 or 10,
Wherein L further comprises a third unit formed by reaction of an alkyne with an azide, or a reaction of an aldehyde or ketone group with hydrazine or hydroxylamine, a conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Solvate.
상기 L은 하기 일반식 Ⅳa, Ⅳb, Ⅳc, Ⅳd, 또는 Ⅳe로 표시되는 L 또는 제3 유닛을 더 포함하는 것을 특징으로 하는, 항체 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물:
[일반식 Ⅳa]
[일반식 Ⅳb]
[일반식 Ⅳc]
[일반식 Ⅳd]
[일반식 Ⅳe]
상기 식에서,
상기 L1 및 L2는 각각 독립적으로 단일결합 또는 C1-30의 알킬렌이고;
R11은 수소 또는 C1-10의 알킬이다.
According to claim 9 or 10,
An antibody conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein L further comprises L or a third unit represented by the following general formulas IVa, IVb, IVc, IVd, or IVe:
[General formula Ⅳa]
[General formula Ⅳb]
[General formula Ⅳc]
[General formula Ⅳd]
[General formula Ⅳe]
In the above equation,
L 1 and L 2 are each independently a single bond or C 1-30 alkylene;
R 11 is hydrogen or C 1-10 alkyl.
상기 L1 및 L2는 각각 독립적으로 단일결합; 또는 C11의 알킬렌; 또는 C12의 알킬렌인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 28,
Wherein L 1 and L 2 are each independently a single bond; or C 11 alkylene; or C 12 alkylene, conjugate or pharmaceutically acceptable salt or solvate thereof.
이소프레노이드 트랜스퍼라제는 파네실 단백질 트랜스퍼라아제(FTase) 또는 게라닐게라닐 트랜스퍼라제(GGTase)인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to claim 9 or 10,
The isoprenoid transferase is a conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the isoprenoid transferase is farnesyl protein transferase (FTase) or geranylgeranyl transferase (GGTase).
L은 Ab에 공유 결합된 하나 이상의 분지형 링커를 포함하고,
i) 각각의 분지형 링커는 제1 링커(PL)에 의해 Ab에 공유 결합된 제5 유닛을 포함하고;
ii) 각각의 분지형 링커는 제1 활성제가 제2 링커 (SL) 및 절단 그룹(CG)에 의해 제5 유닛에 공유결합된 제1 분지(B1)를 포함하며; 및
iii) 각각의 분지형 링커는 a) 제2 활성제가 제2 링커 (SL) 및 절단 그룹(CG)에 의해 제5 유닛에 공유 결합된 제2 분지 (B2); 또는 b) 폴리에틸렌 글리콜 모이어티(moiety)가 제5 유닛에 공유 결합되어 있는 제2 분지를 포함하고,
상기 각각의 절단 그룹은 접합체부터 활성제를 방출하기 위해 가수분해되는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to claim 9 or 10,
L contains one or more branched linkers covalently linked to the Ab,
i) each branched linker comprises a fifth unit covalently linked to the Ab by a first linker (PL);
ii) each branched linker comprises a first branch (B1) in which a first active agent is covalently linked to a fifth unit by a second linker (SL) and a cleavage group (CG); and
iii) each branched linker has a) a second branch (B2) wherein a second active agent is covalently linked to the fifth unit by a second linker (SL) and a cleavage group (CG); or b) a second branch wherein a polyethylene glycol moiety is covalently attached to the fifth unit,
The conjugate or pharmaceutically acceptable salt or solvate thereof, wherein each cleavage group is hydrolyzed to release the active agent from the conjugate.
상기 제5 유닛은 , , 또는 이고,
상기 L2, L3, 및 L4는 각각 독립적으로 직접 결합 또는 -CnH2n-이며, 상기 n은 1 내지 30의 정수이고,
상기 G1, G2, 및 G3은 각각 독립적으로 직접 결합, , , 또는 이며,
상기 R30은 수소 또는 C1-30 알킬이고;
상기 R40은 수소 또는 L5-COOR6이며;
상기 L5는 직접 결합 또는 -Cn'H2n'-이고, 여기에서 n'은 1 내지 10의 정수이고, R6는 수소 또는 C1-30 알킬인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 31,
The fifth unit is , , or ego,
L 2 , L 3 , and L 4 are each independently a direct bond or -C n H 2n -, where n is an integer of 1 to 30,
Wherein G 1 , G 2 , and G 3 are each independently directly bonded, , , or and
R 30 is hydrogen or C 1-30 alkyl;
R 40 is hydrogen or L 5 -COOR 6 ;
L 5 is a direct bond or -C n' H 2n' -, where n' is an integer of 1 to 10, and R 6 is hydrogen or C 1-30 alkyl, a conjugate or a pharmaceutically acceptable salt thereof. or a solvate thereof.
상기 절단 그룹은 표적 세포 내에서 절단가능하거나; 또는 하나 이상의 활성제를 방출시킬 수 있는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 31,
The cleavage group is cleavable within the target cell; or a conjugate or pharmaceutically acceptable salt or solvate thereof capable of releasing one or more active agents.
접합체는 Ab를 포함하고;
Ab에 공유 결합 된 1, 2, 3 또는 4개 이상의 분지형 링커를 포함하며;
각 분지형 링커가 1 또는 2개 이상의 활성제와 결합하고;
여기에서 활성제는 각각 동일하거나, 상이한 것인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 33,
The conjugate contains Ab;
Contains 1, 2, 3, or 4 or more branched linkers covalently attached to the Ab;
Each branched linker binds one or two or more activators;
wherein the active agents are the same or different, respectively, a conjugate or a pharmaceutically acceptable salt or solvate thereof.
각각의 분지형 링커는 제5 유닛을 포함하고, 각각의 활성제는 2차 링커를 통해 제5 유닛에 결합하고, 상기 제5 유닛은 1차 링커에 의해 항체에 결합되는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 32,
Each branched linker comprises a fifth unit, each active agent is bound to the fifth unit through a secondary linker, and the fifth unit is bound to the antibody by a primary linker. An acceptable salt or solvate thereof.
상기 제5 유닛은 아미드이고, 1차 링커는 아미드의 카르보닐을 포함하는 것이거나; 또는
리신(lysine) 유닛인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 35,
the fifth unit is an amide and the primary linker includes the carbonyl of the amide; or
A lysine unit, a conjugate or a pharmaceutically acceptable salt or solvate thereof.
하기 구조식:
을 포함하고,
상기 B' 및 B''는 동일하거나 상이할 수 있는 활성제를 나타내며;
n1 내지 n3은 각각 독립적으로 0 내지 30의 정수를 나타내고;
AA는 아미노산 그룹을 나타내는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 33,
The following structural formula:
Including,
wherein B' and B'' represent active agents which may be the same or different;
n1 to n3 each independently represent an integer from 0 to 30;
AA represents an amino acid group, a conjugate or a pharmaceutically acceptable salt or solvate thereof.
,
, 또는
이고,
상기 B' 및 B''는 동일하거나 상이할 수 있는 활성제를 나타내고;
m 및 n은 각각 독립적으로 0 내지 30의 정수를 나타낸다.
A conjugate containing the [LINKER-B] structure, or a pharmaceutically acceptable salt or solvate thereof, represented by the following structural formula:
,
, or
ego,
wherein B' and B'' represent active agents which may be the same or different;
m and n each independently represent an integer from 0 to 30.
상기 활성제는 화학요법제 또는 톡신인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to claim 9 or 10,
The active agent is a chemotherapeutic agent or a toxin, a conjugate or a pharmaceutically acceptable salt or solvate thereof.
상기 활성제는 면역 조절 화합물, 항암제, 항바이러스제, 항균제, 항진균제, 항기생충제 또는 이들의 조합인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to claim 9 or 10,
The active agent is an immunomodulatory compound, an anticancer agent, an antiviral agent, an antibacterial agent, an antifungal agent, an antiparasitic agent, or a combination thereof, a conjugate, or a pharmaceutically acceptable salt or solvate thereof.
상기 활성제는 하기로부터 선택되는 어느 하나인, 항체 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물:
(a) 엘로티닙(erlotinib), 보르테조밉(bortezomib), 풀베스트란트(fulvestrant), 수텐트(sutent), 레트로졸(letrozole), 이마티닙 메실레이트(imatinib mesylate), PTK787/ZK 222584, 옥살리플라틴(oxaliplatin), 5-플루오로우라실(5-fluorouracil), 루코보린(leucovorin), 라파마이신(rapamycin), 라파티닙(lapatinib), 로나파르닙(lonafarnib), 소라페닙(sorafenib), 제피티닙(gefitinib), AG1478, AG1571, 티오테파(thiotepa), 사이클로포스파마이드(cyclophosphamide), 부술판(busulfan), 임프로술판(improsulfan), 피포술판(piposulfan), 벤조도파(benzodopa), 카르보콘(carboquone), 메츄도파(meturedopa), 유레도파(uredopa), 에틸렌이민(ethylenimine), 알트레타민(altretamine), 트리에틸렌멜라민(triethylenemelamine), 트리에틸렌포스포라미드(trietylenephosphoramide), 트리에틸렌티오포스포라미드(triethiylenethiophosphoramide), 트리메틸롤로멜라민(trimethylolomelamine), 불라타신(bullatacin), 불라타시논(bullatacinone), 캄토테신(camptothecin), 토포테칸(topotecan), 브리오스타틴(bryostatin), 칼리스타틴(callystatin), CC-1065, 아도젤레신(adozelesin), 카르젤레신(carzelesin), 비젤레신(bizelesin), 크립토피신 1(cryptophycin 1), 크립토피신 8(cryptophycin 8), 돌라스타틴(dolastatin), 듀오카마이신(duocarmycin), KW-2189, CB1-TM1, 엘루테로빈(eleutherobin), 판크라티스타틴(pancratistatin), 사르코딕티인(sarcodictyin), 스폰지스타틴(spongistatin), 클로람부실(chlorambucil), 클로르나파진(chlornaphazine), 클로로포스파미드(cholophosphamide), 에스트라무스틴(estramustine), 이포스파미드(ifosfamide), 메클로르에타민(mechlorethamine), 멜팔란(melphalan), 노벰비킨(novembichin), 페네스테린(phenesterine), 프레드니무스틴(prednimustine), 트로포스파미드(trofosfamide), 우라실 머스타드(uracil mustard), 카르무스틴(carmustine), 클로로코토신(chlorozotocin), 포테쿠스틴(fotemustine), 로무스틴(lomustine), 니무스틴(nimustine), 라니무스틴(ranimnustine), 칼리키아미신(calicheamicin), 칼리키아미신 감마 1(calicheamicin gamma 1), 칼리키아미신 오메가 1(calicheamicin omega 1), 디네미신(dynemicin), 디네미신 A(dynemicin A), 클로드로네이트(clodronate), 에스페르아미신(esperamicin), 네오카르지노스타틴크로모포어(neocarzinostatin chromophore), 아클라시노마이신(aclacinomysins), 악티노마이신(actinomycin), 안트르마이신(antrmycin), 아자세린(azaserine), 블레오마이신(bleomycins), 칵티노마이신(cactinomycin), 카라비신(carabicin), 카르니노마이신(carninomycin), 카르지노필린(carzinophilin), 크로모마이신(chromomycins), 닥티노마이신(dactinomycin), 다우노루비신(daunorubicin), 데토루부신(detorubucin), 6-디아조-5-옥소-L-노르루신(6-diazo-5-oxo-L-norleucine), 독소루비신(doxorubicin), 모르폴리노-독소루비신(morpholino-doxorubicin), 시아노모르폴리노-독소루비신(cyanomorpholino-doxorubicin), 2-피롤리노-독소루비신(2-pyrrolino-doxorubucin), 리포소말 독소루비신(liposomal doxorubicin), 데옥시독소루비신(deoxydoxorubicin), 에피루비신(epirubicin), 에소루비신(esorubicin), 마르셀로마이신(marcellomycin), 미토마이신 C(mitomycin C), 미코페놀산(mycophenolic acid), 노갈라마이신(nogalamycin), 올리보마이신(olivomycins), 페플로마이신(peplomycin), 포트피로마이신(potfiromycin), 퓨로마이신(puromycin), 쿠엘라마이신(quelamycin), 로도루비신(rodorubicin), 스트렙토미그린(streptomigrin), 스트렙토조신(streptozocin), 투베르시딘(tubercidin), 우베니멕스(ubenimex), 지노스타틴(zinostatin), 조루비신(zorubicin), 5-플루오로우라신(5-fluorouracil), 데노프테린(denopterin), 메토트렉세이트(methotrexate), 프테로프테린(pteropterin), 트리메트렉세이트(trimetrexate), 플루다라빈(fludarabine), 6-머캅토퓨린(6-mercaptopurine), 티아미프린(thiamiprine), 티구아닌(thiguanine), 안시타빈(ancitabine), 아자시티딘(azacitidine), 6-아자유리딘(6-azauridine), 카르모푸르(carmofur), 시타라빈(cytarabine), 디데옥시유리딘(dideoxyuridine), 독시플루리딘(doxifluridine), 에노시타빈(enocitabine), 플록수리딘(floxuridine), 칼루스테론(calusterone), 드로모스타놀론(dromostanolone),프로피오네이트(propionate), 에피티오스타놀(epitiostanol), 메피티오스테인(mepitiostane), 테스토락톤(testolactone), 아미노글루테티미드(aminoglutethimide), 미토테인(mitotane), 트릴로스테인(trilostane), 폴린산(folinic acid), 아세글라톤(aceglatone), 알도포스파미드 글리코사이드(aldophosphamide glycoside), 아미노레불린산(aminolevulinic acid), 에닐우라실(eniluracil), 암사크린(amsacrine), 베스트라부실(bestrabucil), 비산트렌(bisantrene), 에다트락세이트(edatraxate), 데포파민(defofamine), 데메콜신(demecolcine), 디아지콘(diaziquone), 엘포르니틴(elfornithine), 엘립티니움 아세테이트(elliptinium acetate), 에토글루시드(etoglucid), 갈리움 나이트레이트(gallium nitrate), 하이드록시우레아(hydroxyurea), 렌티난(lentinan), 로니다이닌(lonidainine), 메이탄신(maytansine), 안사미토신(ansamitocins), 미토구아존(mitoguazone), 미토잔트론(mitoxantrone), 모피단몰(mopidanmol), 니트라에린(nitraerine), 펜토스타틴(pentostatin), 페나메트(phenamet), 피라루비신(pirarubicin), 로소잔트론(losoxantrone), 2-에틸하이드라지드(2-ethylhydrazide), 프로카르바진(procarbazine), 폴리사카라이드-k(polysaccharidek), 라족세인(razoxane), 리조신(rhizoxin), 시조피란(sizofiran), 스피로게르마늄(spirogermanium), 테누아존산(tenuazonic acid), 트리아지콘(triaziquone),2,2',2''-트리클로로트리에틸아민(2,2',2''-trichlorotriethylamine), T-2 톡신, 베라큐린 A(verracurin A), 로리딘 A(roridin A), 안구이딘(anguidine), 우레탄(urethane), 빈데신(vindesine), 다카르바진(dacarbazine), 만노무스틴(mannomustine), 미토브로니톨(mitobronitol), 미토락톨(mitolactol), 피포브로만(pipobroman), 가시토신(gacytosine), 아라비노사이드(arabinoside), 사이클로포스파미드(cyclophosphamide), 티오테파(thiotepa), 파클리탁셀(paclitaxel), 파클리탁셀, 파클리탁셀의 알부민-엔지니어드 나노파티클(albumin-engineered nanoparticle formulation of paclitaxel), 도세탁셀, 클로람부실, 젬시타빈, 6-티오구아닌, 머캅토퓨린, 시스플라틴, 카보플라틴(carboplatin), 빈블라스틴(vinblastine), 플래티늄(platinum), 에토포사이드(etoposide), 이포스파미드(ifosfamide), 미톡산트론(mitoxantrone), 빈크리스틴, 비노렐빈(vinorelbine), 노반트론(novantrone), 테니포사이드(teniposide), 에다트렉세이트(edatrexate), 다우노마이신(daunomycin), 아미노프테린(aminopterin), 젤로다(xeloda), 이반드로네이트(ibandronate), CPT-11, 토포이소머라아제 저해제 RFS 2000, 디플루오로메틸오르니틴(difluoromethylornithine), 레티노산(retinoic acid), 카페시타빈(capecitabine), 또는 이의 약학적으로 허용되는 염, 용매화물 또는 산;
(b) 모노카인(monokine), 림포카인(lympokine), 폴리펩타이드 호르몬(traditional polypeptide hormone), 부갑상선 호르몬(parathyroid hormone), 티록신(thyroxine), 릴렉신(relaxin), 프로릴렉신(prorelaxin), 당단백 호르몬(glycoprotein hormone), 여포자극호르몬(follicle stimulating hormone), 갑상샘자극호르몬(thyroid stimulating hormone), 황체형성호르몬(luteinizing hormone), 간 성장인자 섬유모세포성장인자(hepatic growth factor fibroblast growth factor), 프롤락틴(prolactin), 태반성 락토젠(placental lactogen), 종양괴사인자 (tumor necrosis factor), 종양괴사인자-α, 종양괴사인자-β, 뮐러관 억제물질(mullerian inhibiting substance), 마우스 고나도트로핀-연관 펩타이드(mouse gonadotropin associated peptide), 인히빈(inhibin), 액티빈(activin), 혈관내피증식인자(vascular endothelial growth factor), 트롬보포이에틴(thrombopoietin), 에리스로포이에틴(erythropoietin), 골유도 인자(osteoinductive factor), 인터페론, 인터페론-α, 인터페론-β, 인터페론-γ, 콜로니자극인자(colony stimulating factor, CSF), 마크로파지-CSF, 과립구-마크로파지-CSF(granulocyte-macrophage-CSF), 과립구-CSF, 인터루킨(IL), IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, 폴리펩타이드 인자, LIF, 키트 리간드(kit ligand), 또는 이들의 배합물;
(c) 디프테리아 톡신, 보툴리눔 톡신, 테타누스 톡신, 디센터리 톡신, 콜레라 톡신, 아마니틴, α-아마니틴, 피롤로벤조디아제핀, 피롤로벤조디아제핀 유도체, 인돌리노벤조디아제핀, 피리디노벤조디아제핀, 테트로도톡신, 브레베톡신(brevetoxin), 시구아톡신(ciguatoxin), 리신(ricin), AM 톡신, 오리스타틴(auristatin), 투불리신(tubulysin), 겔다나마이신(geldanamycin), 메이탄시노이드(maytansinoid), 칼리케아마이신(calicheamycin), 다우노마이신(daunomycin), 독소루비신(doxorubicin), 메토트렉세이트(methotrexate), 빈데신(vindesine), SG2285, 돌라스타틴(dolastatin), 돌라스타틴유사체(dolastatin analog), 크립토피신(cryptophycin), 캄토테신(camptothecin), 리족신(rhizoxin), 리족신 유도체(rhizoxin derivatives), CC-1065, CC-1065 유사체 또는 유도체, 듀오카마이신(duocarmycin), 에네다인 항생제(enediyne antibiotic), 에스페라마이신(esperamicin), 에포틸론(epothilone), 톡소이드(toxoid), 또는 이들의 배합물;
(d) 친화성 리간드(affinity ligand), 여기에서 친화성 리간드는 기질, 저해제, 활성화제, 신경전달물질, 방사성 동위원소, 또는 이들의 배합물;
(e) 방사능표지(radioactive label), 32P, 35S, 형광다이, 전자밀도 반응제(electron dense reagent), 효소, 비오틴, 스트렙타비딘(streptavidin), 디옥시제닌(dioxigenin), 햅텐(hapten), 면역성 단백질(immunogenic protein), 타겟에 컴플러멘터리한 서열을 갖는 핵산 분자(nucleic acid molecule with a sequence complementary to a target) 또는 이들의 배합물;
(f) 면역조절 화합물(immunomodulatory compound), 항-암제(anti-cancer agent), 항-바이러스제(anti-viral agent), 항-박테리아제(anti-bacterial agent), 항-곰팡이제(anti-fungal agent), 및 항-기생충제(anti-parasitic agent), 또는 이들의 배합물;
(g) 타목시펜(tamoxifen), 랄록시펜(raloxifene), 드롤록시펜(droloxifene), 4-하이드록시타목시펜(4-hydroxytamoxifen), 트리옥시펜(trioxifene), 케옥시펜(keoxifene), LY117018, 오나프리스톤(onapristone) 또는 토레미펜(toremifene);
(h) 4(5)-이미다졸, 아미노글루테티미드(aminoglutethimide), 메제스톨 아세테이트(megestrol acetate), 엑스메스탄(exemestane), 레트로졸(letrozole), 또는 아나스트로졸(anastrozole);
(i) 플루타미드(flutamide), 닐루타미드(nilutamide), 비칼루타미드(bicalutamide), 리우프롤라이드(leuprolide), 고세렐린(goserelin), 또는 트록사시타빈(troxacitabine);
(j) 아로마타아제 저해제;
(k) 단백질 키나아제 저해제;
(l) 리피드 키나아제 저해제;
(m) 안티센스 올리고뉴클레오티드;
(n) 리보자임;
(o) 백신; 및
(p) 항-맥관형성제(anti-angiogenic agent).
According to claim 9 or 10,
The active agent is any one selected from the following: an antibody conjugate or a pharmaceutically acceptable salt or solvate thereof:
(a) erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787/ZK 222584, oxaliplatin ( oxaliplatin, 5-fluorouracil, leucovorin, rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib , AG1478, AG1571, thiotepa, cyclophosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, Meturedopa, uredopa, ethylenimine, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide , trimethylolomelamine, bullatacin, bullatacinone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, Ado adozelesin, carzelesin, bizelesin, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, KW- 2189, CB1-TM1, eleutherobin, pancratistatin, sarcodictyin, spongestatin, chlorambucil, chlornaphazine, chlorophos Cholophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, novembichin, phenesterine, prednimustine (prednimustine), trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine , ranimnustine, calicheamicin, calicheamicin gamma 1, calicheamicin omega 1, dynemicin, dynemicin A , clodronate, esperamicin, neocarzinostatin chromophore, alacinomysins, actinomycin, antrmycin, Azaserine, bleomycins, cactinomycin, carabicin, carninomycin, carzinophilin, chromomycins, dactinomycin ( dactinomycin), daunorubicin, detorubucin, 6-diazo-5-oxo-L-norleucine, doxorubicin, mor Morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubucin, liposomal doxorubicin, deoxydoxorubicin ( deoxydoxorubicin, epirubicin, esorubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins ), peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, 5-fluorouracil, denopterin, methotrexate, pte Pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thiguanine, ancitabine , azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocy. Enocitabine, floxuridine, calusterone, dromostanolone, propionate, epitiostanol, mepitiostane, testolactone (testolactone), aminoglutethimide, mitotane, trilostane, folinic acid, aceglatone, aldophosphamide glycoside, amino Aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine ), diaziquone, elfornithine, elliptinium acetate, etoglucid, gallium nitrate, hydroxyurea, lentinan ( lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pento Statin (pentostatin), phenamet, pirarubicin, losoxantrone, 2-ethylhydrazide, procarbazine, polysaccharide-k ( polysaccharidek, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid, triaziquone, 2,2',2'' -Trichlorotriethylamine (2,2',2''-trichlorotriethylamine), T-2 toxin, verracurin A, roridin A, anguidine, urethane, Vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside ), cyclophosphamide, thiotepa, paclitaxel, paclitaxel, albumin-engineered nanoparticle formulation of paclitaxel, docetaxel, chlorambucil, gemcitabine, 6 -Thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vin. Christine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate (ibandronate), CPT-11, topoisomerase inhibitor RFS 2000, difluoromethylornithine, retinoic acid, capecitabine, or a pharmaceutically acceptable salt or solvent thereof. cargo or mountains;
(b) monokine, lymphokine, traditional polypeptide hormone, parathyroid hormone, thyroxine, relaxin, prorelaxin, Glycoprotein hormone, follicle stimulating hormone, thyroid stimulating hormone, luteinizing hormone, liver growth factor fibroblast growth factor, prolactin (prolactin), placental lactogen, tumor necrosis factor, tumor necrosis factor-α, tumor necrosis factor-β, Mullerian inhibiting substance, mouse gonadotropin- Mouse gonadotropin associated peptide, inhibin, activin, vascular endothelial growth factor, thrombopoietin, erythropoietin, osteoinductive factor factor), interferon, interferon-α, interferon-β, interferon-γ, colony stimulating factor (CSF), macrophage-CSF, granulocyte-macrophage-CSF, granulocyte-CSF, interleukin (IL), IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL- 11, IL-12, polypeptide factor, LIF, kit ligand, or combinations thereof;
(c) Diphtheria toxin, botulinum toxin, tetanus toxin, decentritoxin, cholera toxin, amanitin, α-amanitin, pyrrolobenzodiazepine, pyrrolobenzodiazepine derivatives, indolinobenzodiazepine, pyridinobenzodiazepine, tetrodotoxin, breve Toxins (brevetoxin), ciguatoxin, ricin, AM toxin, auristatin, tubulysin, geldanamycin, maytansinoid, calichea calicheamycin, daunomycin, doxorubicin, methotrexate, vindesine, SG2285, dolastatin, dolastatin analog, cryptophycin, Camptothecin, rhizoxin, rhizoxin derivatives, CC-1065, CC-1065 analogs or derivatives, duocarmycin, enediyne antibiotic, esperamycin ( esperamicin), epothilone, toxoid, or combinations thereof;
(d) affinity ligand, wherein the affinity ligand is a substrate, inhibitor, activator, neurotransmitter, radioisotope, or combination thereof;
(e) Radioactive label, 32P, 35S, fluorescent die, electron dense reagent, enzyme, biotin, streptavidin, dioxigenin, hapten, an immunogenic protein, a nucleic acid molecule with a sequence complementary to a target, or a combination thereof;
(f) immunomodulatory compound, anti-cancer agent, anti-viral agent, anti-bacterial agent, anti-fungal agent agent), and anti-parasitic agent, or combinations thereof;
(g) Tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone ( onapristone) or toremifene;
(h) 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, letrozole, or anastrozole;
(i) flutamide, nilutamide, bicalutamide, leuprolide, goserelin, or troxacitabine;
(j) aromatase inhibitor;
(k) protein kinase inhibitors;
(l) lipid kinase inhibitors;
(m) antisense oligonucleotide;
(n) ribozyme;
(o) Vaccines; and
(p) Anti-angiogenic agent.
상기 활성제는 피롤로벤조디아제핀 다이머이고;
상기 피롤로벤조디아제핀 다이머는 N10 위치에서 X 또는 N'10 위치에서 X'로 치환되고, 여기서 X 또는 X'는 피롤로벤조디아제핀 다이머를 링커에 연결하며;
X 및 X'는 각각 독립적으로 -C(O)O-*, -또는 -C(O)-*이고;
*는 피롤로벤조디아제핀 다이머와 링커 사이의 결합 지점인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to paragraph 1,
The active agent is a pyrrolobenzodiazepine dimer;
The pyrrolobenzodiazepine dimer is substituted with X at the N10 position or X' at the N'10 position, where X or
X and X' are each independently -C(O)O-*, -or -C(O)-*;
* is the binding point between the pyrrolobenzodiazepine dimer and the linker, the conjugate or a pharmaceutically acceptable salt or solvate thereof.
상기 피롤로벤조디아제핀 다이머는 하기 일반식 X 또는 일반식 XI로 표현되는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물:
[일반식 X]
상기 식에서,
상기 점선은 C1과 C2 사이, C2와 C3 사이, C'1과 C'2 사이, 또는 C'2과 C'3 사이의 이중 결합의 선택적 존재를 나타내며;
RX1 및 RX1'는 각각 독립적으로 H, OH, =O, =CH2, CN, Rm, ORm, =CH-Rm, =C(Rm')2, OSO2-Rm, CO2Rm, CORm, 할로 또는 디할로로부터 선택되고;
RX2, RX2' RX3, 및 RX3'는 각각 독립적으로 H, Rm, OH, ORm, NRm 2, NO2, 및 할로로부터 선택되며;
RX4 및 RX4'는 각각 독립적으로 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm 2, 할로, 및 C1-6 알킬로부터 선택되고;
RX5 및 RX5'는 각각 독립적으로 H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm 2, -NRmRm', NO2, -NRmC(O)Rm', -NRmC(O)ORm', -NRmC(O)NRmRm', -S(O)Rm, -S(O)2Rm, -S(O)NRmRm', -S(O)2NRmRm', -NRmS(O)Rm', -NRmS(O)2Rm', -P(O)Rm, -P(O)2Rm, -P(O)NRmRm', -P(O)2NRmRm', -NRmP(O)Rm', -NRmP(O)2Rm', 및 할로로부터 선택되며;
Y 및 Y'는 각각 독립적으로 O, S, 또는 N(H)이고;
RX6는 독립적으로 C3-12 알킬렌, C3-12 알케닐렌, 또는 C3-12 헤테로알킬렌이며; RX6은 -NH2, -NHRm, -NHC(O)Rm, -NHC(O)CH2-[OCH2CH2]n-RXX, 또는 -[CH2CH2O]n-RXX로 치환되거나 비치환되고;
상기 RXX는 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, C1-8 알킬, C3-8 시클로알킬, C1-8 알콕시, C1-8 알킬 티오, C3-20 헤테로아릴, C5-20 아릴 또는 모노- 또는 디-C1-8 알킬아미노이고, 여기에서 n은 1 내지 6의 정수이며;
RX7 및 RX7'는 각각 독립적으로 H, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, -C(O)Rr, -C(O)ORs 또는 -C(O)NRrRr'이고;
Rr, Rr', 및 Rs는 각각 독립적으로 H, C1-7 알킬, C2-7 알케닐, C2-7 알키닐, C3-13 사이클로알킬, 3 내지 7-원 헤테로사이클로알킬, C5-10 아릴 또는 5 내지 7-원 헤테로아릴로이며;
각 Rm'는 독립적으로 Rm, CO2Rm, CORm, CHO, CO2H, 및 할로로부터 선택되며,
각 Rm은 독립적으로 H, OH, C1-12 알킬, C1-12 알콕시, C2-12 알케닐, C2-12 알키닐, C5-20 아릴, C5-20 헤테로아릴, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 및 5 내지 7-원 헤테로아릴로 이루어진 군으로부터 선택되고, 여기에서 C5-20 아릴, C5-20 헤테로아릴, C3-6 사이클로알킬, 3 내지 7-원 헤테로사이클릴, 3 내지 7-원 헤테로사이클로알킬, 및 5 내지 7-원 헤테로아릴의 하나 이상의 수소원자는 OH, =O, C1-12 알킬, 또는 C1-12 알콕시로 치환될 수 있다.
According to clause 42,
The pyrrolobenzodiazepine dimer is a conjugate or a pharmaceutically acceptable salt or solvate thereof, represented by the following general formula
[General formula
In the above equation,
The dotted line indicates the optional presence of a double bond between C1 and C2, C2 and C3, C'1 and C'2, or C'2 and C'3;
R _ _ _ _ _ _ _ _ _ is selected from CO 2 R m , COR m , halo or dihalo;
R _ _ _ _ _ _ _ _
RX4 and R _ _ _ _ _ _ _
R _ _ _ _ _ _ _ _ _ _ _ _ O)R m' , -NR m C(O)OR m' , -NR m C(O)NR m R m' , -S(O)R m , -S(O) 2 R m , -S( O)NR m R m ', -S(O) 2 NR m R m ', -NR m S(O)R m ', -NR m S(O) 2 R m ', -P(O)R m , -P(O) 2 R m , -P(O)NR m R m ', -P(O) 2 NR m R m ', -NR m P(O)R m ', -NR m P(O ) 2 R m ', and halo;
Y and Y' are each independently O, S, or N(H);
R _ _ _ R -NH 2 , -NHR m , -NHC(O)R m , -NHC(O)CH 2 -[OCH 2 CH 2 ] n -R XX , or -[CH 2 CH 2 O] n -R XX Substituted or unsubstituted;
The R XX is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy , C 1 -8 alkyl thio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkylamino, where n is an integer from 1 to 6;
R _ _ _ _ _ _ (O)NR r R r ';
R r , R r ', and R s are each independently H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3 to 7-membered heterocyclo alkyl, C 5-10 aryl or 5 to 7-membered heteroarylo;
each R m' is independently selected from R m , CO 2 R m , COR m , CHO, CO 2 H, and halo;
Each R m is independently H, OH, C 1-12 alkyl, C 1-12 alkoxy, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C selected from the group consisting of 3-6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl, wherein C 5-20 aryl, C 5- 20 Heteroaryl, C 3-6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7-membered heteroaryl, one or more hydrogen atoms are OH, =O, C 1 It may be substituted with -12 alkyl, or C 1-12 alkoxy.
상기 RX1 및 RX1'는 각각 독립적으로 =CH2; C1-6 알킬; C1-6 알콕시; C2-6 알케닐; C5-7 아릴; C3-6 헤테로아릴; 또는 C1-6 알킬, 또는 C1-6 알콕시로 치환된 C5-7 아릴로부터 선택되는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 43,
R X1 and R X1 'are each independently =CH 2 ; C 1-6 alkyl; C 1-6 alkoxy; C 2-6 alkenyl; C 5-7 aryl; C 3-6 heteroaryl; or a conjugate or pharmaceutically acceptable salt or solvate thereof selected from C 1-6 alkyl, or C 5-7 aryl substituted with C 1-6 alkoxy.
상기 RX2, RX2', RX3, 및 RX3'은 각각 독립적으로 H 또는 OH로부터 선택되는, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 43,
Wherein R _ _
RX5, 및 RX5'은 각각 독립적으로 H, OH, -S(O)Rm, S(O)2Rm, -P(O)Rm, 및 -P(O)2Rm로 이루어진 군에서 선택되고, 여기에서 Rm은 H, OH, C1-12 알킬, C1-12 알콕시, C2-12 알케닐, 또는 C2-12 알키닐인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 43,
R _ _ _ _ _ _ _ selected from the group wherein R m is H, OH, C 1-12 alkyl, C 1-12 alkoxy, C 2-12 alkenyl, or C 2-12 alkynyl, or a pharmaceutically acceptable conjugate thereof. Salt or solvate thereof.
상기 RX4 및 RX4'는 각각 독립적으로 C1-6 알콕시인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 43,
Wherein R _
상기 Y 및 Y'는 O인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 43,
Y and Y' are O, a conjugate or a pharmaceutically acceptable salt or solvate thereof.
RX6는 C3-12 알킬렌, C3-12 알케닐렌 또는 C3-12 헤테로알킬렌이고, 상기 RX6은 -NH2, -NHRm, -NHC(O)Rm, -NHC(O)CH2-[OCH2CH2]n-RXX, 또는 -[CH2CH2O]n-RXX로 치환되며;
상기 RXX는 H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, 할로, C1-8 알킬, C3-8 사이클로알킬, C1-8 알콕시, C1-8 알킬티오, C3-20 헤테로아릴, C5-20 아릴 또는 모노- 또는 디-C1-8 알킬 아미노이고; 및
n은 1 내지 6의 정수인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to clause 43,
R _ _ _ _ _ _ _ )CH 2 -[OCH 2 CH 2 ] n -R XX , or -[CH 2 CH 2 O] n -R XX ;
The R XX is H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy , C 1 -8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl or mono- or di-C 1-8 alkylamino; and
n is an integer of 1 to 6, or a conjugate or a pharmaceutically acceptable salt or solvate thereof.
상기 [Linker-(B)l]는, 다음 구조식:
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
, 및
로 이루어진 군에서 선택되고,
여기에서, MMAE는 모노메틸 오리스타틴 E(monomethyl auristatin E)이며,
MMAF는 모노메틸 오리스타틴 F(monomethyl auristatin F)인, 접합체 또는 이의 약학적으로 허용되는 염 또는 이의 용매화물.
According to claim 1 or 10,
The [Linker-(B) l ] has the following structural formula:
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
, and
is selected from the group consisting of,
Here, MMAE is monomethyl auristatin E,
MMAF is monomethyl auristatin F, a conjugate or a pharmaceutically acceptable salt or solvate thereof.
A pharmaceutical composition for preventing or treating hyperproliferation, cancer, or angiogenic disease, comprising the conjugate of claim 1 or 10.
추가적으로 약학적으로 유효한 양의 화학 치료제(chemotherapeutic agent)를 포함하는, 약학적 조성물.
According to clause 51,
A pharmaceutical composition further comprising a pharmaceutically effective amount of a chemotherapeutic agent.
상기 암은 폐암, 소세포성 폐암, 위장관암, 대장암, 장암, 유방암, 난소암, 전립선암, 고환암, 간암, 신장암, 방광암, 췌장암, 뇌암, 육종, 골육종, 카포시 육종 및 흑색종으로 이루어진 군으로부터 선택되는 어느 하나인, 약학적 조성물.
According to clause 51,
The cancer includes lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. Any one pharmaceutical composition selected from.
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