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EP-4741393-A2 - NOVEL COMPOUNDS AND THEIR USE IN THERAPY

EP4741393A2EP 4741393 A2EP4741393 A2EP 4741393A2EP-4741393-A2

Abstract

The present invention relates to ADCs comprising a NMT inhibitor conjugated to an antibody via a linker, and related uses.

Inventors

  • CARR, ROBIN
  • SOLARI, ROBERTO
  • TATE, EDWARD, WILLIAM
  • BELL, ANDREW, SIMON
  • BONNERT, ROGER

Assignees

  • MyricX Pharma Limited
  • Imperial College Innovations Limited

Dates

Publication Date
20260513
Application Date
20230908

Claims (16)

  1. An antibody drug conjugate (ADC) comprising a NMT inhibitor conjugated to an antibody via a linker, or a salt thereof, wherein the antibody binds to HER2.
  2. The ADC or salt thereof according to claim 1, wherein the linker is a cleavable linker, for example wherein the linker is cleavable by an enzyme.
  3. The ADC or salt thereof according to claim 1 or claim 2, wherein the linker has the following formula (VII): -A a -W w -Y y - (formula (VII)) wherein: A is a first stretcher unit which when present forms a covalent bond with a chain terminus (such as a N-terminus) or a functional group of an amino acid side chain of the antibody; a is 0 or 1; each W is independently an amino acid unit or a glucuronide unit which when A and/or Y are absent forms a covalent bond with a chain terminus (such as a N-terminus) or a functional group of an amino acid side chain of the antibody and/or with a functional group of the NMT inhibitor respectively; when W is an amino acid, w is 1 to 12; when W is a glucuronide unit, w is 1 or 2; Y is a second stretcher unit which when present forms a covalent bond with a functional group of the NMT inhibitor; and y is 0 or 1.
  4. The ADC or salt thereof according to claim 3, wherein the functional group on the amino acid side chain of the antibody is an amino or sulfhydryl, for example a sulfhydryl.
  5. The ADC or salt thereof according to claim 3 or claim 4, wherein the functional group on the NMT inhibitor is an amino or alcohol, for example an amino.
  6. The ADC or salt thereof according to any one of claims 1 to 5, wherein the antibody is a humanised, chimeric, human antibody or an antibody fragment.
  7. The ADC or salt thereof according to any one of claims 1 to 6, wherein the antibody antibody can bind HER2 with a K D equal to or less than about 10 -6 M, such as 1 x 10 -6 , 1 x 10 -7 , 1 x 10 -8 , 1 x 10 -9 , 1 x 10 -10 , 1 x 10 -11 , 1 x 10 -12 , 1 x 10 -13 or 1 x 10 -14 M.
  8. The ADC or salt thereof according to any one of claims 1 to 7, wherein the antibody is trastuzumab, pertuzumab, margetuximab, ertumaxomab, MM-111, HER2Bi-aATCs, MCLA-128, ZW25, MDX-210, ado-trastuzumab or fam-trastuzumab,
  9. The ADC or salt thereof according to claim 8, wherein the antibody is trastuzumab.
  10. The ADC or salt thereof according to any one of claims 1 to 7, wherein the antibody has the CDRs of trastuzumab, and in particular has the CDRs of the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2.
  11. The ADC of salt thereof according to any one of claims 1 to 10, wherein the drug loading (p) of NMT inhibitor to antibody is between 1 to 10 NMT inhibitor(s) to antibody, such as between 2 and 6, 4 and 6, 8 and 10, or 6 and 8 NMT inhibitors to antibody.
  12. A pharmaceutical composition comprising the ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11.
  13. The ADC or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, or pharmaceutical composition according to claim 12, for use as a medicament.
  14. The ADC or pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to claim 13, for use in the treatment of cancer.
  15. The ADC or pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to claim 14, wherein the cancer is breast cancer, bladder cancer, lung cancer, prostate cancer, kidney cancer, esophageal carcinoma, colorectal cancer, gallbladder carcinoma, brain tumor, lymphoma (such as B-cell lymphoma or disuse large B-cell lymphoma), leukemia (such as AML) or neuroblastoma.
  16. The ADC or pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to claim 15, wherein the cancer is breast cancer, prostate cancer, gastric cancer, or lung cancer.

Description

Field of Invention This invention relates to novel antibody drug conjugates (ADC) comprising an inhibitor of the human N-myristoyl transferases (human NMT). The invention also inter alia relates to such ADCs for use as medicaments, in particular, in the treatment or prevention of hyperproliferative disorders such as cancer. Background to the invention Antibody therapy has been established for the targeted treatment of patients with cancer, immunological and angiogenic disorders (Carter, P. (2006) Nature Reviews Immunology 6:343-357). The use of antibody-drug conjugates (ADC), i.e. immunoconjugates, for the local delivery of cytotoxic or cytostatic agents, i.e. drugs to kill or inhibit tumor cells in the treatment of cancer, targets delivery of the drug moiety to tumors, and intracellular accumulation therein, whereas systemic administration of these unconjugated drug agents may result in unacceptable levels of toxicity to normal cells (Xie et al (2006) Expert. Opin. Biol. Ther. 6(3):281-291; Kovtun e tal (2006) Cancer Res. 66(6):3214-3121; Law et a/ (2006) Cancer Res. 66(4):2328-2337; Wu et al (2005) Nature Biotech. 23(9):1137-1145; Lambert J. (2005) Current Opin. in Pharmacol. 5:543-549; Hamann P. (2005) Expert Opin. Ther. Patents 15(9):1087-1103; Payne, G. (2003) Cancer Cell 3:207-212; Trail etal (2003) Cancer Immunol. Immunother. 52:328-337; Syrigos and Epenetos (1999) Anticancer Research 19:605-614). Maximal efficacy with minimal toxicity is sought thereby. Efforts to design and refine ADC have focused on the selectivity of monoclonal antibodies (mAbs) as well as drug mechanism of action, drug-linking, drug/antibody ratio (loading), and drug-releasing properties (Junutula, et al., 2008b Nature Biotech., 26(8):925-932; Dornan et al (2009) Blood 114(13):2721-2729; US 7521541; US 7723485; WO2009/052249; McDonagh (2006) Protein Eng. Design & Sei. 19(7): 299-307; Doronina etal (2006) Bioconj. Chem. 17:114-124; Erickson etal (2006) Cancer Res. 66(8):1-8; Sanderson etal (2005) Clin. Cancer Res. 11:843-852; Jeffrey etal (2005) J. Med. Chem. 48:1344-1358; Hamblett etal (2004) Clin. Cancer Res. 10:7063- 7070). Drug moieties may impart their cytotoxic and cytostatic effects by mechanisms including tubulin binding, DNA binding, proteasome and/or topoisomerase inhibition. Some cytotoxic drugs tend to be inactive or less active when conjugated to large antibodies or protein receptor ligands. N-myristoyl transferase (NMT) is a monomeric enzyme, which is ubiquitous in eukaryotes. NMT catalyses an irreversible co-translational transfer of myristic acid (a saturated 14-carbon fatty acid) from myristoyl-Coenzyme A (myr-CoA) to a protein substrate containing an N-terminal glycine with formation of an amide bond (Farazi, T.A., G. Waksman, and J.I. Gordon, J. Biol. Chem., 2001. 276(43): p. 39501-39504). There are two types of human NMT, human NMT1 (HsNMT1) and human NMT2 (HsNMT2). Inhibition of human NMT has been suggested as a target for treating or preventing various diseases or disorders, for example hyperproliferative disorders (for example cancers, e.g. human colorectal cancer, gallbladder carcinoma, brain tumors, and lymphomas such as B-cell lymphoma) (Resh MD. 1993. Biochern. Biophys.Acta 1115, 307-22; Bertiaume LG, Beuachamp E, WO2017011907), and viral infections such as HIV (Gottlinger HG, Sodroski JG, Haseltine WA. 1989. Proc. Nat. Acad. Sci. USA 86:5781-85; Bryant ML, Ratner L. 1990. Proc. Natl. Acad. Sci. USA 87:523-27) and human rhinovirus (HRV) (Davis MP, Bottley, G, Beales LP, Killington, RA, Rowlands DJ, Tuthill, TJ, 2008 Journal of Virology 82 4169-4174; Mousnier A, Bell AS, Swieboda DP, Morales-Sanfrutos J, Perez-Dorado I, Brannigan JA, Newman J, Ritzefeld M, Hutton, JA, Guedan A, Asfor AS, Robinson, SW, Hopkins-Navratilova I, Wilkinson AJ, Johnston SL, Leatherbarrow RJ, Tuthill TJ, Solari R, Tate EW 2018 Nature Chemistry 10 (6) 599-606), Corbic Ramljak I, Stanger J, Real-Hohn A. Dreier D, Wimmer L., Redlberger-Fritz M, Fischl W, Klingel K, Mihovilovic MD, Blaas D, Kowalski H, PLOS Pathogens 14(8): e1007203. As NMT plays a key role in protein trafficking, mediation of protein-protein interactions, stabilization of protein structures and signal transduction in living systems, inhibition of the HsNMT1 and/or HsNMT2 enzyme(s) has the potential to disrupt multi-protein pathways. Although it is expected that inhibitors of human NMT will inhibit both HsNMT1 and HsNMT2, their therapeutic and/or prophylactic activity is believed to primarily derive from inhibition of HsNMT1. The above characteristics are believed to be desirable to reduce the risk of the development of resistance in, for example, treatment or prevention of microbial infections and hyperproliferative disorders. There are two known binding pockets in NMT. One is the myr-CoA binding pocket and the other is the peptide binding pocket. Most NMT inhibitors reported to date target the peptide binding pocket. Compounds active as inhibitors of NMT have prev