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CN-121985963-A - Antibody-conjugated drugs and uses thereof

CN121985963ACN 121985963 ACN121985963 ACN 121985963ACN-121985963-A

Abstract

In particular, antibody conjugated drugs (ADC) that bind to B7-H3 antigen are provided. Further disclosed are pharmaceutical compositions and methods for treating cancer using the ADCs provided herein.

Inventors

  • Y.Fu
  • HONG YUFENG
  • E.W. Kovac
  • LIU MOLI
  • ZHANG HONG
  • LI LINGNA
  • A. Springer

Assignees

  • 维硕公司

Dates

Publication Date
20260505
Application Date
20240401
Priority Date
20230405

Claims (20)

  1. 1. An antibody conjugated drug (ADC) of formula (I), formula (II) or formula (III): or a pharmaceutically acceptable salt thereof, wherein: ab is an anti-B7-H3 antibody; m is an integer from 1 to 8; L 1 is a linker that binds to the anti-B7-H3 antibody; l 2 is a bond, -C (O) -, -NH-, an amino acid unit, - (CH 2 CH 2 O) n -、-(CH 2 ) n -, -O-, -4-aminobenzyloxycarbonyl) -, - (C (O) CH 2 CH 2 NH)-、-(C(O)N(R 2 )CH 2 CH 2 N(R 5 )) -, or any combination thereof, wherein n is an integer from 1 to 24; Each R 2 and R 5 is independently H or substituted or unsubstituted alkyl; L 3 is a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted heteroarylene, or L 3 is a substituted or unsubstituted-OCH 2 - (heterocycloalkylene) or a substituted or unsubstituted-OCH 2 - (heteroarylene) wherein L 3 is linked to D via oxygen, or L 3 is a substituted or unsubstituted-CH 2 NCH 2 - (heteroaryl) or a substituted or unsubstituted-CH 2 NCH 2 - (heterocycloalkyl) wherein L 3 is linked to D via-CH 2 -and to L 2 via nitrogen; R * is substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; D is ; D' is Wherein D' is linked to R * via its amide group and to L 2 via oxygen, and D '' is Or (b) Wherein: R 1 is H or-C 1 -C 8 alkyl; R 3 is H, halogen 、-CCl 3 、-CBr 3 、-CF 3 、-CI 3 、-CHCl 2 、-CHBr 2 、-CHF 2 、-CHI 2 、-CH 2 Cl、-CH 2 Br、-CH 2 F、-CH 2 I、-CN、-OR 3A 、-NR 3A R 3B 、-(CH 2 ) v OR 6 、 substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R 4 is H, halogen, -OR 4A 、-NR 4A R 4B , substituted OR unsubstituted alkyl OR substituted OR unsubstituted heteroalkyl; v is N, O or C; Z 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; z 2 is substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene; R 6 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl 、-CO(CH 2 CH 2 O) w CH 2 CH 2 M、-CONH(CH 2 CH 2 O) w CH 2 CH 2 M、 A charged group or sugar derivative; v is an integer from 1 to 24; w is an integer from 1 to 24; M is-NH 2 , -OH, -COOH or-OCH 3 ;R 10 is-OH-OCH 3 or-COOH; and Each R 3A 、R 3B 、R 4A and R 4B is independently H or substituted or unsubstituted alkyl.
  2. 2. The ADC of claim 1, or a pharmaceutically acceptable salt thereof, wherein L 1 is a linker that binds to one or two sulfur or nitrogen atoms of the anti-B7-H3 antibody.
  3. 3. The ADC of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L 1 is: 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  4. 4. The ADC of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein m is 1,2, 3, 4, 5, 6, 7, or 8.
  5. 5. The ADC of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 4.
  6. 6. The ADC of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein L 2 is a bond, -C (O) -, -NH-, -Val-, -Phe-, -Lys-, -4-aminobenzyloxycarbonyl) -, -Gly-, -Ser-, -Thr-, -Ala-, β -Ala-, -citrulline -(-Cit-)、-(CH 2 ) n -、-(CH 2 CH 2 O) n -、-O-、-(C(O)N(CH 3 )CH 2 CH 2 N(CH 3 ))-, or any combination thereof.
  7. 7. The ADC of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein L 2 is-C (O) -, -NH-, -Val-, - (4-aminobenzyloxycarbonyl) -, -Gly-, -citrulline- (-Cit-), - (CH 2 ) n -、-(CH 2 CH 2 O) n -, or any combination thereof.
  8. 8. The ADC of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein L 2 is: 、 Or (b) 。
  9. 9. The ADC of claim 8, or a pharmaceutically acceptable salt thereof, wherein L 2 is 。
  10. 10. The ADC of claim 8, or a pharmaceutically acceptable salt thereof, wherein L 2 is 。
  11. 11. The ADC of claim 8, or a pharmaceutically acceptable salt thereof, wherein L 2 is 。
  12. 12. The ADC of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein D "is Wherein: R 1 is H or-C 1 -C 8 alkyl; R 3 is H, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R 4 is H, halogen or substituted or unsubstituted alkyl; v is N, and Z 2 is a substituted or unsubstituted arylene group.
  13. 13. The ADC of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R 1 is H.
  14. 14. The ADC of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R 3 is H, methyl, ethyl, propyl, butyl 、-CH 2 OH、-CH 2 CH 2 OH、-CH 2 N 3 、-CH 2 CH 2 N 3 、-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 , or-CH 2 CH 2 OCH 3 .
  15. 15. The ADC of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl, -CH 2 OH, or-CH 2 N 3 .
  16. 16. The ADC of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R 4 is H or substituted or unsubstituted alkyl.
  17. 17. The ADC of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R 4 is H or methyl.
  18. 18. The ADC of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R 4 is H.
  19. 19. The ADC of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein Z 2 is unsubstituted arylene.
  20. 20. The ADC of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein Z 2 is 。

Description

Antibody-conjugated drugs and uses thereof The present application claims the benefit of priority from U.S. provisional patent application No. 63/457,196 filed 4/5 of 2023, which is incorporated herein by reference for all purposes. Throughout this disclosure, various publications, patents, and/or patent applications are referenced. The disclosures of these publications, patents, and/or patent applications are hereby incorporated by reference in their entireties into this application in order to more fully describe the state of the art to which this disclosure pertains. Technical Field The present disclosure relates to antibody conjugated drugs (ADCs) comprising anti-B7-H3 antibodies and methods of making the same. Also provided herein are methods of treating cancer using the ADCs described herein. Background of the inventiondescription of the invention Antibody conjugated drugs (ADCs) allow targeted delivery of drug moieties to tumors and, in some embodiments, allow for intracellular accumulation thereof, wherein systemic administration of unconjugated drugs may result in unacceptable levels of toxicity to normal cells (Polakis p. (2005) pharmacology latest view (Current Opinion in Pharmacology) 5:382-387). ADC is a targeted chemotherapeutic molecule that combines the properties of both antibodies and cytotoxic drugs by targeting potent cytotoxic drugs to tumor cells expressing the antigen (Teicher, B.A. (2009) current cancer drug targets (Current Cancer Drug Targets) 9:982-1004), thereby enhancing the therapeutic index by maximizing efficacy and minimizing off-target toxicity (Carter, P.J. and Senter P.D. (2008) journal of cancer (THE CANCER journal) 14 (3): 154-169; chari, R.V. (2008) chemical research review (Acc.chem. Res.)) 41:98-107. The present disclosure provides ADCs comprising an anti-B7-H3 antibody conjugated to a camptothecin derivative toxin or a dolastatin (duostatin) derivative toxin via a linker moiety. In embodiments, the anti-B7-H3 antibodies bind to B7-H3 expressing cancer cells and allow for selective uptake of the ADC into the cancer cells. In embodiments, the ADCs provided herein selectively deliver an effective amount of a camptothecin derivative toxin or a dolastatin derivative toxin to tumor tissue and reduce non-specific toxicity associated with the associated ADC. The ADC compounds described herein comprise compounds with anticancer activity. The B7 family checkpoint molecules have become the leading edge of cancer research, the concept of which is that tumor cells use them to evade immune surveillance. The B7 family of molecules are capable of controlling and suppressing the immune response of T cells and NK cells. The growing family of B7 now includes 10 members, which are CD80 (also known as B7.1), CD86 (also known as B7.2), B7-H1 (also known as PD-L1 or CD 274), B7-DC (also known as PD-L2 or CD 273), B7-H2 (also known as ICOSL), B7-H3 (also known as CD 276), B7-H4 (also known as B7S1, B7x or Vtcn), B7-H5 (also known as VISTA, GI24, dies1 or PD-1H), B7-H6 (also known as NCR3LG 1) and B7-H7 (also known as HHLA 2). Convincing evidence suggests that the B7 molecule not only provides a key positive signal that stimulates and supports T cell action, but also a negative signal that controls and suppresses T cell responses. The B7 homologous 3 protein (B7-H3) (also known as CD276 and B7RP-2, and herein referred to as "B7-H3") is a type I transmembrane glycoprotein of the immunoglobulin superfamily. Human B7-H3 contains a signal peptide at the N-terminus, extracellular immunoglobulin-like variable (Ig-like V-1 type) and constant (Ig-like C2-1 type), a transmembrane region and a cytoplasmic tail with 45 amino acids (Zhou Y.H. Et al, 2007, tissue antigen (Tissue Antigens). 70 (2): 96-104). B7-H3 has three splice variants, B7-H3 alpha and B7-H3 beta. The extracellular domain of B7-h3α consists of two Ig domains of an immunoglobulin-like V-Ig-like C-type (also known as 2 IgB-H3), while the extracellular domain of B7-h3β consists of four immunoglobulin domains of Ig-like V-Ig-like C-type (also known as 4IgB 7-H3). The major B7-H3 isoform in human tissues and cell lines is the 4 IgB-H3 isoform (Steinberger et al, 2004, J. Immunol.) (172 (4): 2352-9). B7-H3 is reported to have co-stimulatory and co-inhibitory signaling functions (see, e.g., chapoval et al, 2001, & gt, nat. Immunol.) & gt, 2:269-74, & gt, suh et al, 2003, & gt, nat. Immunol. 4:899-906, & gt, prasad et al, 2004, & gt, J.Immunol. 173:2500-6, and Wang et al, 2005, & gt, european J.Immunol. & gt, 35:428-38, & gt, yang, S. Et al, 2020, & gt, J.Biol. Sci.) & gt, 16 (11) & gt 1767-1773. For example, in vitro studies have shown co-stimulatory function of B7-H3, as B7-H3 is shown to induce proliferation of Cytotoxic T Lymphocytes (CTL) and up-regulate production of interferon gamma (IFN-gamma) in the presence of stimulatory anti-CD 3 antibodies to mimic T cell receptor signaling (Chapoval et al, 2001, nature immunology 2:269-74). Furt