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EP-4736885-A1 - ANTIBODY-DRUG CONJUGATE AND USE THEREOF

EP4736885A1EP 4736885 A1EP4736885 A1EP 4736885A1EP-4736885-A1

Abstract

Provided are an antibody-drug conjugate and the use thereof, in particular an antibody-drug conjugate targeting B7H3. Also provided are an antibody targeting B7H3 and the use thereof.

Inventors

  • GAO, XIAO
  • YAO, BING
  • PAN, Fujun
  • HUI, Xiwu
  • ZHAO, LU
  • FAN, Lixue
  • DAN, Mo
  • WU, Yufen
  • SUN, Xiongfei
  • WANG, Mingxiao

Assignees

  • CSPC Megalith Biopharmaceutical Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. An antibody-drug conjugate having a structure represented by formula (I), and a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or an isotopically labeled compound thereof: A-(L-D) d (I) wherein A is selected from an antibody (e.g., a monoclonal antibody) or an antigen-binding fragment thereof; L is a linker moiety, with one end linked to A and the other end linked to a bioactive molecule D; D is a bioactive molecule; d represents the molar ratio of the bioactive molecule to A (also known as DAR, i.e., drug-to-antibody ratio), and is an integer or a decimal selected from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12); when d is a decimal, it refers to the average number of linker-bioactive molecules (L-D) conjugated per A.
  2. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to claim 1, wherein A is selected from an antibody or an antigen-binding fragment thereof targeting HER2 (ErbB2), HER3 (ErbB3), HER4 (ErbB4), EGFR, DLL3, TROP2, B7H3, B7H4, TF (Tissue factor), c-Met, CD20, CD22, CD30, CD33, CD44, CD47, CD56, CD70, CD73, CD79b, CD105, CEA, A33, Cripto, EphA2, G250, MUC1, Lewis Y, EDB-FN, VEGFR, VEGF, PD-1, PD-L1, MET, RET, GPNMB, Integrin, PSMA, Tenascin-C, SLC44A4, Claudin18.2, and Mesothelin.
  3. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to any one of claims 1-2, wherein A is an antibody or an antigen-binding fragment thereof targeting B7H3; the antibody or the antigen-binding fragment thereof comprises a heavy chain and/or a light chain, wherein the heavy chain comprises 3 complementarity determining regions (CDRs), wherein the amino acid sequence of the heavy chain complementarity determining region 1 (HCDR1) is set forth in SEQ ID NO. 1, the amino acid sequence of the heavy chain complementarity determining region 2 (HCDR2) is set forth in SEQ ID NO. 2, and the amino acid sequence of the heavy chain complementarity determining region 3 (HCDR3) is set forth in SEQ ID NO. 3; the light chain comprises 3 complementarity determining regions (CDRs), wherein the amino acid sequence of the light chain complementarity determining region 1 (LCDR1) is set forth in SEQ ID NO. 4, the amino acid sequence of the light chain complementarity determining region 2 (LCDR2) is set forth in SEQ ID NO. 5, and the amino acid sequence of the light chain complementarity determining region 3 (LCDR3) is set forth in SEQ ID NO. 6; the CDRs are determined according to the Kabat numbering scheme.
  4. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to any one of claims 1-3, wherein A is an antibody or an antigen-binding fragment thereof targeting B7H3; the anti-B7H3 antibody or the antigen-binding fragment thereof comprises a heavy chain and/or a light chain, wherein the sequence of a variable region of the heavy chain (HV) is set forth in SEQ ID NO. 7, and the sequence of a variable region of the light chain (LV) is set forth in SEQ ID NO. 8.
  5. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to any one of claims 1-4, wherein A is an antibody targeting B7H3, wherein the anti-B7H3 antibody further comprises a heavy chain constant region sequence or a variant thereof, and/or a light chain constant region sequence or a variant thereof.
  6. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to any one of claims 1-5, wherein A is an antigen-binding fragment targeting B7H3, wherein the antigen-binding fragment is selected from a Fab, a Fab', a Fab'-SH, an Fv, an scFv, and a F(ab') 2 .
  7. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to any one of claims 1-6, wherein A is an antibody or an antigen-binding fragment thereof targeting B7H3, wherein the anti-B7H3 antibody or the antigen-binding fragment thereof is a humanized or fully human antibody or an antigen-binding fragment thereof.
  8. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to any one of claims 1-7, wherein A is an antibody or an antigen-binding fragment thereof targeting B7H3; the anti-B7H3 antibody comprises a heavy chain and/or a light chain, wherein the amino acid sequence of the heavy chain is set forth in SEQ ID NO. 9 or SEQ ID NO. 10, and the amino acid sequence of the light chain is set forth in SEQ ID NO. 11.
  9. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to claim 1, wherein A is selected from 43A or 43B targeting B7H3, DP001 targeting HER2, sacituzumab targeting TROP2, alsevalimab targeting B7H4, tisotumab targeting TF, L19A targeting EDB-FN, zolbetuximab targeting Claudin18.2, and biosimilar thereof, wherein 43A comprises 2 identical heavy chains and 2 identical light chains, wherein the amino acid sequence of the heavy chain is set forth in SEQ ID NO. 9, and the amino acid sequence of the light chain is set forth in SEQ ID NO. 11; 43B comprises 2 identical heavy chains and 2 identical light chains, wherein the amino acid sequence of the heavy chain is set forth in SEQ ID NO. 10, and the amino acid sequence of the light chain is set forth in SEQ ID NO. 11.
  10. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to any one of claims 1-9, wherein -L- is selected from -L 1 -L 2 -L 3 -L 4 -L 5 -, wherein L 1 is a covalent linker unit covalently linked to A, L 2 is an extension unit, L 3 is selected from a bond and an amino acid residue optionally substituted with a polar hydrophilic group, L 4 is selected from a peptide residue consisting of 2-8 amino acids, and L 5 is a bond, a self-immolative fragment, or a self-immolative fragment substituted with a polar hydrophilic group.
  11. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to claim 10, wherein L 1 is selected from wherein * indicates linkage to A; L 2 is selected from -L 2a -, -L 2a -C(O)-, -C(O)-L 2a -C(O)-NH-L 2b -C(O)-, and -L 2a -NH-C(O)-L 2b -C(O)-, wherein L 2a and L 2b are each independently selected from -C 1 -C 8 alkylene-, -C 1 -C 8 alkylene-C 3 -C 8 cycloalkylene-, -alkynylene-C 1 -C 6 alkylene-, -phenylene-, -phenylene-C 1 -C 3 alkylene-, and linear or branched heteroalkylene having 1-50 (preferably 9-30, and more preferably 9-26, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) atoms, wherein the alkylene, cycloalkylene, and heterocyclylene are each optionally substituted with one or more substituents independently selected from C 1 -C 6 alkyl, heteroalkyl having 1-6 atoms, C 1 -C 6 alkoxy, hydroxyl, amino, carboxyl, and C 3 -C 8 cycloalkyl, and the heteroalkylene contains 1-12 (preferably 1-8, and more preferably 3-8, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) heteroatoms selected from one or more of N, O, and S (preferably O); L 3 is selected from a bond and an amino acid residue substituted with a polar hydrophilic group, wherein the polar hydrophilic group comprises a saccharide residue and a derivative thereof, a polyethylene glycol residue and a derivative thereof, a polysarcosine residue and a derivative thereof, or a combination thereof; L 4 is selected from a peptide residue consisting of 2-8 amino acids selected from phenylalanine, isoleucine, leucine, tryptophan, valine, methionine, tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartic acid, and glycine; L 5 is selected from a bond, wherein R 3 is selected from hydrogen and m is an integer selected from 3-50, preferably an integer selected from 8-24, and further preferably 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24; * indicates linkage to D; preferably, L 5 is selected from
  12. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to claim 11, wherein L 2 is selected from -L 2a -, -L 2a -C(O)-, -C(O)-L 2a -C(O)-NH-L 2b -C(O)-, and -L 2a -NH-C(O)-L 2b -C(O)-, wherein L 2a and L 2b are each independently selected from -C 1 -C 6 alkylene-, -C 1 -C 3 alkylene-C 3 -C 6 cycloalkylene-, -ethynylene-C 1 -C 6 alkylene-, -(CH 2 CH 2 O) s -, -(CH 2 CH 2 O) s C 1-3 alkylene-, -C 1-3 alkylene(CH 2 CH 2 O) s C 1-3 alkylene-, phenylene, and phenylenemethylene, wherein s is an integer selected from 1-12 (preferably 3-8, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12).
  13. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to claims 11-12, wherein L 2 is selected from -L 2a -, -L 2a -C(O)-, -C(O)-L 2a -C(O)-NH-L 2b -C(O)-, and -L 2a -NH-C(O)-L 2b -C(O)-, wherein L 2a and L 2b are each independently selected from methylene, ethylene, n-propylene, isopropylene, n-pentylene, methylenecyclohexylene, ethynylenemethylene, ethynyleneethylene, ethynylenen-n-propylene, ethynylenen-n-butylene, ethynylenen-n-pentylene, ethynylenen-n-hexylene, phenylene, phenylenemethylene, -(CH 2 CH 2 O) s CH 2 -, -(CH 2 CH 2 O) s CH 2 CH 2 -, -CH 2 (OCH 2 CH 2 ) s -, -CH 2 CH 2 (OCH 2 CH 2 ) s -, -CH 2 CH 2 (OCH 2 CH 2 ) s CH 2 -, -CH 2 CH 2 (OCH 2 CH 2 ) s CH 2 CH 2 -, and -CH 2 (OCH 2 CH 2 ) s CH 2 -, wherein s is an integer selected from 1-12 (preferably 3-8, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12).
  14. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to claims 11-13, wherein L 2 is selected from: -(CH 2 CH 2 O) s CH 2 C(O)-, -(CH 2 CH 2 O) s CH 2 CH 2 -, wherein s is an integer selected from 1-12 (preferably 3-8, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12).
  15. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to claims 11-14, wherein L 3 is selected from glutamic acid substituted with a polar hydrophilic group, wherein the polar hydrophilic group comprises a saccharide residue and a derivative thereof, a polyethylene glycol residue and a derivative thereof, a polysarcosine residue and a derivative thereof, or a combination thereof.
  16. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to claims 11-15, wherein L 3 is selected from: wherein HG is selected from a group comprising a saccharide residue and a derivative thereof, a group comprising a polyethylene glycol residue and a derivative thereof, a group comprising a polysarcosine residue and a derivative thereof, and a combination thereof; * indicates linkage to L 2 .
  17. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to claims 11-16, wherein HG is selected from: -NH(CH 2 CH 2 O)nCH 3 , and wherein n and q are each independently an integer selected from 1-50 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50), preferably 1-24, and further preferably 3-12.
  18. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to claims 11-17, wherein L 4 is selected from: and wherein * indicates linkage to L 3 .
  19. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to any one of claims 1-9, wherein -L- is selected from: and wherein s is an integer selected from 1-12 (preferably 3-8, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12), HG is as defined in claim 17, and * indicates linkage to A.
  20. The antibody-drug conjugate having the structure represented by formula (I), and the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopically labeled compound thereof according to any one of claims 1-9, wherein -L- is selected from -L 1 -L 2 -L 4 -L 5 -, wherein L 1 , L 2 , L 4 , and L 5 are as defined in claims 11-18.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims priority to the prior application with the patent application No. 2023107806802 filed with China National Intellectual Property Administration on June 29, 2023, and the prior application with the patent application No. 2024101255800 filed with China National Intellectual Property Administration on January 30, 2024, both of which are entitled "ANTIBODY-DRUG CONJUGATE" and are incorporated herein by reference in their entirety. TECHNICAL FIELD The present disclosure relates to the field of biopharmaceuticals, and in particular to an antibody-drug conjugate, a preparation method therefor, and use thereof. BACKGROUND An antibody-drug conjugate (ADC) consists of three different components: an antibody, a linker, and a bioactive molecule (drug). The ADC technology conjugates an antibody and a drug molecule together via a linker, utilizing the specificity of the antibody to achieve targeted delivery of the drug molecule to a target tissue to exert its effect, thereby reducing the systemic toxic and side effects of the drug, widening the therapeutic window of the drug, and expanding the therapeutic potential of the antibody. Bioactive molecules (drugs) are essential for ADC drugs to function. Camptothecin compounds have attracted widespread attention due to their excellent anti-tumor effects. The marketed ADC drugs Trodelvy and Enhertu adopt camptothecin compounds SN38 and Dxd as cytotoxic substances, respectively. Among them, Dxd exhibits 10 times higher activity compared to the common chemotherapeutic drug irinotecan; it has a strong ability to penetrate cell membranes, which enables it to kill nearby cancer cells after killing cancer cells that have ingested the ADC, thereby producing a "bystander effect"; its half-life in blood is significantly shortened, which helps to reduce the generation of toxic and side effects. However, ADCs ultimately prepared using camptothecin compounds greatly alter the properties of monoclonal antibodies, resulting in a relatively considerable degree of degradation in both stability and half-life. Although Enhertu achieved a confirmed objective response rate (ORR) of up to 79.7% in the DESTINY-Breast 03 clinical study, the DS8201-A-J101 clinical study demonstrated that for breast cancer with low HER2 expression, Enhertu only achieved a confirmed ORR of 37.0%, indicating a significantly lower treatment efficacy compared to breast cancer with high or medium HER2 expression. Furthermore, ADC drugs have exhibited new symptoms in terms of toxic and side effects. For example, Enhertu has shown side effects such as pneumonia, interstitial lung disease, etc. WO2020233174A1 discloses a camptothecin compound containing a valine-citrulline (Val-Cit)-PAB linker; however, this molecule cannot yield an ADC molecule of qualified quality after conjugation with an antibody (a qualified ADC product requires an aggregate content of less than 5%). Therefore, there is an urgent need in the art to provide more suitable antibody-drug conjugates based on camptothecin drugs (e.g., exatecan, belotecan, etc.) to achieve efficient, simple, and practical chemical preparation and conjugation, and to improve the pharmaceutical properties, metabolic properties, efficacy, safety, etc., of existing antibody-drug conjugates, such as improving the stability of ADC molecules, widening the therapeutic window, etc. B7H3 (full name: B7 homolog 3), also known as CD276, is a newly identified ligand of the B7 family belonging to type I transmembrane glycoproteins. Its extracellular domain is composed of two immunoglobulin constant (IgC) and variable (IgV) domains. It primarily exists in two splice isomers: 2IgB7H3 whose extracellular region is composed of IgV-IgC and 4IgB7H3 whose extracellular region is composed of IgV-IgC-IgV-IgC. Both murine and human B7H3 include 2IgB7-H3, but humans and other primates also have the four immunoglobulin-like domain structure of 4IgB7H3. The receptor for B7H3 has not been clearly identified, and its mechanism of action is not fully understood. Current research indicates that B7H3 possesses both immunosuppressive and immune-activating functions, with the prevailing view being that B7H3 primarily plays an immunosuppressive role. Some studies report that B7H3 is a negative regulator of T cell function, mainly affecting Th1. However, some studies have shown that it mainly inhibits CD8+ T cells and NK cells, directly suppresses NK cell activation, and has no significant effect on CD4+ T cells. B7H3 exerts its inhibitory effect on T cells by suppressing IL-2 secretion, and this effect can be reversed by exogenous addition of IL-2, indicating that B7H3 is an upstream regulatory molecule of IL-2. When DCs are co-cultured with Tregs, the DCs up-regulate B7H3 and reduce pMHC expression, resulting in impaired T cell stimulation function. B7H3 expression is negatively correlated with the response to PD-1 therapy in NSCLC. B7H3 expr