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KR-20260065820-A - Drug conjugate and method of preparation and use thereof

KR20260065820AKR 20260065820 AKR20260065820 AKR 20260065820AKR-20260065820-A

Abstract

The present invention provides a novel linker, a linker conjugate, and a drug conjugate thereof, as well as a method for manufacturing the same and a method for using the same to treat various diseases and disorders.

Inventors

  • 구오 마오준
  • 리 리차드 후이
  • 이동준
  • 루오 웬룽
  • 하오 후이

Assignees

  • 애드센트릭스 테라퓨틱스 잉크.
  • 애드센트릭스 테라퓨틱스 상하이 컴퍼니 리미티드

Dates

Publication Date
20260511
Application Date
20240731
Priority Date
20230803

Claims (20)

  1. Drug-linker conjugate having the structural formula of chemical formula I: [Chemical Formula I] or its salt or ester (In the above formula, Each D is independently a drug moiety; X is a conjugating functional group capable of forming a covalent linkage with an antigen-binding moiety; Each L C is a moiety formed independently by a click chemical reaction between an alkyne and an azide; Each of L D , L X 1 , and L X 2 is independently a linker or spacer moiety, wherein at least one of L D , L X 1 , and L X 2 comprises the following phosphorylcholine (PC) group: ; i is an integer selected from 0 to 8; Each j and k is independently 0 or 1, provided that j and k are not both 0).
  2. A drug-linker conjugate according to claim 1, wherein j is 0.
  3. In paragraph 1, a drug-linker conjugate in which j is 1.
  4. In paragraph 3, k is a drug-linker conjugate of 1.
  5. A drug-linker conjugate according to any one of paragraphs 1 to 4, wherein i is 1.
  6. A drug-linker conjugate, wherein i is 2 in any one of paragraphs 1 to 4.
  7. A drug-linker conjugate according to any one of paragraphs 1 to 4, wherein i is greater than 2.
  8. A drug-linker conjugate according to any one of claims 1 to 7, wherein each L C is as follows: or .
  9. In paragraph 8, L C is a drug-linker conjugate as follows: .
  10. In paragraph 8, L C is a drug-linker conjugate as follows: .
  11. In any one of claims 1 to 10, X is a drug-linker conjugate selected from the following:
  12. In any one of paragraphs 1 through 11, -L D - is -L D 2 -L D 1 -, and Here, L D 1 is And; L D 2 is And, Here, L p is a di-, tri-, or tetra-peptide linker; Each R1 and R2 is H, C1-3 alkyl, or LPC- (PC), where LPC is as follows: , Each p and q is independently 0 or 1, provided that p and q are not both 0; R is H or C 1-3 alkyl and; m is 0, 1, 2, or 3 and; n is 0 or 1 and; A drug-linker conjugate where t is 0 or 1.
  13. In paragraph 12, each R 1 and R 2 is a drug-linker conjugate that is L PC -(PC).
  14. In paragraph 12 or 13, L PC -(PC) is a drug-linker conjugate selected from the following:
  15. A drug-linker conjugate according to any one of claims 1 to 14, wherein L X 1 is (CH 2 ) g (where g is an integer selected from 0 to 6).
  16. In paragraph 15, g is a drug-linker conjugate of 1.
  17. A drug-linker conjugate according to any one of claims 1 to 16, wherein L X 2 is as follows: or (In the above formula, L X a is a substituted or unsubstituted C 1-6 alkyl or PEG group; L X b is -C(=O)-, CH or CH 2 ).
  18. In paragraph 17, L X 2 is a drug-linker conjugate as follows:
  19. In paragraph 17, L X 2 is a drug-linker conjugate as follows:
  20. A drug-linker conjugate according to any one of claims 1 to 19, wherein the spacer moiety is selected from the group consisting of alkyl, heteroalkyl, polyethylene glycol (PEG), and peptide.

Description

Drug conjugate and method of preparation and use thereof Priority Claim and Related Patent Application This application claims the benefit of priority to PCT/CN2023/110989 filed on August 3, 2023, the entire contents of which are incorporated herein by reference. Technology field The present invention generally relates to novel compounds, methods for preparing the same, and therapeutic uses thereof. More specifically, the present invention provides novel linkers, linker conjugates, and drug conjugates thereof, as well as methods for preparing the same and methods for using the same to treat various diseases and disorders. Drug conjugates (e.g., antibody-drug conjugates (ADCs) or immunoconjugates) can provide an effective means of delivering drugs to targeted sites within tissues or organisms. To date, 13 ADCs have been approved by the FDA, including gemtuzumab ozogamicin (Mylotarg™), the first ADC approved by the FDA in 2000. (See, for example, [Drago et al . 2021 Nature Reviews 18, 327-344]; [Mckertish et al . 2021 Biomedicines 9, 872]; [Khongorzui et al . 2020 Molecular Cancer Res. 18:3-19]; [Bross et al . 2001 Clin. Cancer Res . 7, 1490-1496]; [Hamann et al . 2002 Bioconjug. Chem . 13, 47-58]; [Lamb, 2017 Drugs 77, 1603-1610].) Lessons learned from the development of these ADCs highlight the importance of optimized methods for attaching drugs to proteins. There remains a need for drug conjugates and conjugation methods characterized by improved efficiency, drug loading rate (loading amount), stability, and other properties. Novel building blocks, drug-linker conjugates, and conjugation methods that enable improved conjugation efficiency, drug loading rate, product stability, and other characteristics are provided herein. The present invention further provides a novel immunoconjugate, a method for manufacturing the same, a kit comprising a drug conjugate and components thereof, and a method for using the drug conjugate and the kit for the treatment of a disease or disorder. Specifically, through novel building blocks that are modular and well-matched to click chemistry, the present invention enables significantly improved conjugation efficiency, increased drug loading rates, and higher selectivity for more extended electrophilic chemotypes and thiols (e.g., cysteine). As a key feature of the present invention, introducing phosphorylcholine (PC) groups onto the backbone of a building scaffold or within a drug linker component provides a convenient mechanism for efficiently adjusting the hydrophilicity of the building blocks and the resulting conjugate. In one aspect, the present invention generally relates to a drug-linker conjugate having the structural formula of chemical formula I: [Chemical Formula I] or its salt or ester (In the above formula, Each D is independently a drug moiety; X is a conjugating functional group capable of forming a covalent link with an antigen-binding moiety; Each L C is a moiety formed independently by a click chemical reaction between an alkyne and an azide; Each of L D , L X 1 , and L X 2 is independently a linker or spacer moiety, wherein at least one of L D , L X 1 , and L X 2 comprises the following PC group: ; i is an integer selected from 0 to 8; Each j and k is independently 0 or 1, provided that j and k are not both 0). In another aspect, the present invention generally relates to a compound having the structural formula of Chemical Formula II: [Chemical Formula II] or its salt or ester (In the above formula, X is a conjugating functional group capable of forming a covalent link with an antigen-binding moiety; Each L Ca is independently an alkyne or azide group; Each L X1 and L X 2 is independently a linker or spacer moiety, wherein at least one of L X 1 and L X 2 comprises the following PC group: ; i is an integer selected from 0 to 8; Each j and k is independently 0 or 1, provided that j and k are not both 0). In another aspect, the present invention generally relates to a compound having the structural formula of Chemical Formula III: [Chemical Formula III] or its salt or ester (In the above formula, D is a drug moiety; L D is a linker or spacer moiety containing a PC group; L Cb is an alkyne or azide group). In another aspect, the present invention relates to an immunoconjugate comprising a drug-linker conjugate or building block, or a moiety or derivative thereof, generally disclosed herein. In another aspect, the present invention relates to an immunoconjugate prepared from a drug-linker conjugate or building block, or a moiety or derivative thereof, generally disclosed herein. In another aspect, the present invention generally relates to an immunoconjugate having the structural formula of Chemical Formula IV: [Chemical Formula IV] or a pharmaceutically acceptable salt thereof (In the above formula, Ab represents an antigen-binding moiety; Each D is independently a drug moiety; X' is a single bond or junction; Each L C is a moiety formed independently by a click