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US-12622977-B2 - Antibody drug conjugate

US12622977B2US 12622977 B2US12622977 B2US 12622977B2US-12622977-B2

Abstract

Provided is an antibody drug conjugate, specifically comprising a therapeutic antibody moiety, an intermediate linker moiety and a cytotoxic drug moiety which are linked. The therapeutic antibody moiety is an antibody against an HER2 target. The cytotoxic drug moiety is a camptothecin topoisomerase I inhibitor. The cytotoxic drug moiety or the linker-cytotoxic drug moiety is modified by means of deuterium substitution. The antibody drug conjugate can be used for the prevention or treatment of cancers.

Inventors

  • Xiquan Zhang
  • Hua Wang
  • Yong Gao
  • Tianxi CHEN
  • WeiWei FENG
  • Bing Zhang
  • Xiaoqi TANG
  • Tongjie XU
  • Xiaojin Wang
  • Huace SHENG
  • Zhengping Zhang

Assignees

  • CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD.
  • NANJING SHUNXIN PHARMACEUTICALS CO., LTD. OF CHIATAI TIANQING PHARMACEUTICAL GROUP

Dates

Publication Date
20260512
Application Date
20210813
Priority Date
20200813

Claims (12)

  1. 1 . An antibody-drug conjugate of general formula Ab-(L-U) n, wherein Ab represents an antibody moiety, L represents a linker moiety, U represents a cytotoxic drug moiety, and wherein the antibody-drug conjugate has a structure of formula VII below: wherein the Ab represents an antibody moiety comprising a first antigen-binding fragment that binds to ECD4 epitope of HER2 and a second antigen-binding fragment that binds to ECD2 epitope of HER2, wherein the first antigen-binding fragment is an scFv and comprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3, a light chain CDR1, a light chain CDR2 and a light chain CDR3, the heavy chain CDR1, the heavy chain CDR2 and the heavy chain CDR3 comprising amino acid sequences set forth in SEQ ID NOs: 43, 28 and 29, respectively, and the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising amino acid sequences set forth in SEQ ID NOs: 30, 31 and 32, respectively, the second antigen-binding fragment is an Fab and comprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3, a light chain CDR1, a light chain CDR2 and a light chain CDR3, the heavy chain CDR1, the heavy chain CDR2 and the heavy chain CDR3 comprising amino acid sequences set forth in SEQ ID NOs: 45, 46 and 47, respectively, and the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising amino acid sequences set forth in SEQ ID NOs: 48, 49 and 50, respectively, n is an integer or a decimal selected from the group consisting of 1 to 10, and R 1 and R 2 are each independently selected from the group consisting of hydrogen (H) and deuterium (D).
  2. 2 . The antibody-drug conjugate according to claim 1 , wherein the first antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising amino acid sequence set forth in SEQ ID No: 35, and the light chain variable region comprising amino acid sequence set forth in SEQ ID No: 36.
  3. 3 . The antibody-drug conjugate according to claim 2 , wherein a VH and VL of the first antigen-binding fragment is arranged from N-terminus to C-terminus in the following order: VH-linker-VL.
  4. 4 . The antibody-drug conjugate according to claim 1 , wherein the second antigen-binding fragment comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences set forth in SEQ ID NOs: 37 and 38, respectively.
  5. 5 . The antibody-drug conjugate according to claim 1 , wherein the antibody moiety Ab comprises an immunoglobulin functional domain operably linked to the first antigen-binding fragment and/or the second antigen-binding fragment, the immunoglobulin functional domain comprising: i. one or more of CL, CH1, CH2 or CH3, or ii. an Fc.
  6. 6 . The antibody-drug conjugate according to claim 5 , wherein the CL, CH1, CH2, CH3 and Fc are derived from CL, CH1, CH2, CH3 and Fc of human IgG, respectively; the CL, CH1, CH2, CH3 or Fc has a modification or does not have a modification.
  7. 7 . The antibody-drug conjugate according to claim 5 , wherein the Fc is a dimeric Fc comprising a first Fc polypeptide and a second Fc polypeptide, the first antigen-binding fragment is operably linked to the first Fc polypeptide, and the second antigen-binding fragment is operably linked to the second Fc polypeptide.
  8. 8 . The antibody-drug conjugate according to claim 1 , wherein the antibody moiety Ab is a bivalent bispecific antibody, comprising: a heavy chain set forth in SEQ ID NO: 11, a heavy chain set forth in SEQ ID NO: 13, and a light chain set forth in SEQ ID NO: 15.
  9. 9 . The antibody-drug conjugate according to claim 1 , wherein the formula VII is of a structure of VII-1, VII 2, VII 3, or VII-4 below:
  10. 10 . A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the antibody-drug conjugate according to claim 1 , or a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.
  11. 11 . The method according to claim 10 , wherein the cancer is HER2 positive cancer.
  12. 12 . A pharmaceutical composition comprising the antibody-drug conjugate according to claim 1 , and a pharmaceutically acceptable carrier.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a U.S. National Stage Entry of International Application No. PCT/CN2021/112462 filed on Aug. 13, 2021, which claims the benefit of and priority to Chinese Patent Application No. 202010814877.X filed with China National Intellectual Property Administration on Aug. 13, 2020, which are incorporated herein by reference in their entireties. SEQUENCE LISTING The instant application contains a Sequence Listing that has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Feb. 2, 2023, is named “059541-000099USPX_SL.txt” and is 89,398 bytes in size. TECHNICAL FIELD The present application relates to an antibody-drug conjugate comprising a therapeutic antibody moiety, an intermediate linker moiety and a cytotoxic drug moiety which are linked. The present application further relates to use of the antibody-drug conjugate in preparing a medicament for preventing and treating cancer. BACKGROUND Antibody-drug conjugates (ADCs) are a class of drugs that combine the high specificity of therapeutic antibodies and the high killing activity of cytotoxic drugs, where the therapeutic antibody moiety is linked to the cytotoxic drug moiety via an intermediate linker moiety. Currently, at least eight ADC drugs are marketed globally, among which antibody moieties of brentuximab vedotin, polatuzumab vedotin and enfortumab vedotin are directed against targets CD30, CD79b and Nectin-4, respectively; antibody moieties of trastuzumab emtansine and trastuzumab deruxtecan are directed against target HER2; antibody moieties of gemtuzumab ozogamicin and inotuzumab ozogamicin are directed against targets CD33 and CD22, respectively; antibody moiety of sacituzumab govitecan is directed against target TROP2. For the cytotoxic drug moieties, brentuximab vedotin, polatuzumab vedotin and enfortumab vedotin adopt auristatin toxin molecules acting on microtubules, trastuzumab emtansine adopts maytansinoid toxin molecules acting on microtubules, gemtuzumab ozogamicin and inotuzumab ozogamicin adopts calicheamicin toxin molecules acting on DNA, and the lastest marketed trastuzumab deruxtecan and sacituzumab govitecan adopt camptothecin analog toxin molecules. For the intermediate linker moiety, trastuzumab emtansine adopts a non-cleavable linker, while the remaining seven of the above ADC drugs adopt cleavable linkers. Camptothecin (CPT) analogs and derivatives exert anti-tumor activity by binding to topoisomerase I, which exhibits significant activity against a wide variety of tumor types. To overcome the poor water solubility of CPT, researchers have synthesized a variety of CPT derivatives, of which irinotecan hydrochloride (CPT-11) is a water-soluble prodrug that has been approved for the treatment of metastatic colorectal cancer. However, CPT-11 must be catalyzed by carboxylesterase in vivo before it can be converted to its active form SN-38 (formula I), this conversion is extremely inefficient, and SN38 itself is difficult to be prepared as drugs due to its poor solubility. Exatecan (formula II), another water-soluble CPT derivative, had been attempted for development as an anti-tumor drug, however, the development had been ceased by 2004, and exatecant does not need to be activated by enzymes. In addition, compared with SN-38, which is the pharmacodynamic ontology of irinotecan, exatecan has a stronger inhibitory effect on the activity of topoisomerase I. ADC drugs combine the dual advantages of high potency of cytotoxic small molecules and high selectivity of antibodies to specific tumor cells, however, there is still a need to develop highly potent and low-toxic ADC drugs that can target more indications. BRIEF SUMMARY In one aspect, the present application provides an antibody-drug conjugate containing a deuterated modification, or a pharmaceutically acceptable salt or a solvate thereof, and specifically relates to a deuterated modification of a linker or a cytotoxic drug moiety. In one aspect, the present application provides an antibody-drug conjugate of general formula Ab-(L-U)n, or a pharmaceutically acceptable salt or a solvate thereof, wherein Ab represents an antibody moiety, L represents a linker moiety, U represents a cytotoxic drug moiety, and n is an integer or a decimal selected from the group consisting of 1 to 10. In one aspect, the present application provides an antibody-drug conjugate of general formula Ab-(L-U)n, or a pharmaceutically acceptable salt or a solvate thereof, wherein Ab (an antibody moiety) can specifically bind to a tumor antigen (including a tumor specific antigen and a tumor-associated antigen), which can be selected from any tumor prevention or treatment target known in the art, for example, can be selected from the group consisting of HER2, EGFR, CD20, CD30, CD33, CD47, CD79b, VEGF, VEGFR, MET, RET, PD-1, PD-L1, and the like. In some embodiments, the present applica