CTLA4-targeted drug conjugates, products containing the same, and their therapeutic use

Abstract

The present invention relates to a novel drug conjugate comprising a CTLA4-targeting molecule, at least one cytotoxic substance, and a linker that links the CTLA4-targeting molecule and the cytotoxic substance, as well as compositions and kits comprising such drug conjugates, and their use in particular for the treatment of cancer and / or prevention of cancer recurrence in subjects requiring it.

Claims

1. i) a monoclonal antibody against anticytotoxic T lymphocyte antigen 4 protein (anti-CTLA4), ii) at least one cytotoxic substance, and iii) a linker that links a CTLA4 targeting molecule to the cytotoxic substance.

2. The drug conjugate according to claim 1, wherein the anti-CTLA4 monoclonal antibody is ipilimumab or tremelimumab.

3. The drug conjugate according to claim 1 or 2, wherein the linker is a cleavable linker such as an acid-unstable linker, an enzyme-cleavable linker, a lysosomal protease-sensitive linker, a disulfide linker, or a β-glucuronide linker.

4. The drug conjugate according to any one of claims 1 to 3, wherein the cytotoxic substance is selected from microtubule inhibitors; DNA damaging substances such as alkylating agents or platinum complexes; cytotoxic antibiotics; antimetabolites; topoisomerase inhibitors; RNA polymerase inhibitors; mitotic inhibitors; and combinations thereof.

5. The drug conjugate according to claim 4, wherein the microtubule inhibitor is selected from emtansine (DM1), auristatin, and derivatives thereof such as monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF), preferably MMAF.

6. The drug complex according to claim 2, wherein the complex comprises i) ipilimumab, ii) a cytotoxic substance, preferably an MMAF, and iii) a cleavable linker, preferably a linker comprising valine-citrulline dipeptide or phenylalanine-lysine dipeptide.

7. A pharmaceutical composition comprising, for example, at least one drug conjugate according to any one of claims 1 to 6, for example, at least two different drug conjugates, the first conjugate comprising a first cytotoxic substance and the second conjugate comprising a different cytotoxic substance, or, for example, at least one drug conjugate and different therapeutic substances selected from immune checkpoint targeting substances, anti-angiogenic substances, cytotoxic substances and hormonal substances, as well as a pharmaceutically acceptable carrier.

8. A kit comprising at least two drug conjugates according to any one of claims 1 to 6, or at least one drug conjugate according to any one of claims 1 to 6 and different therapeutic substances selected from immune checkpoint targeting substances, anti-angiogenic substances, cytotoxic substances, hormonal substances, and any combination thereof.

9. A drug conjugate according to any one of claims 1 to 6, a composition according to claim 7, or a kit according to claim 8, for use in treating cancer or preventing cancer recurrence in a subject that requires it.

10. A drug conjugate, composition, or kit for use according to claim 9, wherein the cancer is a solid tumor selected from melanoma, renal cell carcinoma (RCC), colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer (NSCLC), mesothelioma (MM), or a hematological malignancy selected from lymphoma and leukemia.

11. A drug conjugate, composition, or kit for use according to claim 9 or 10, wherein cancer cells or the tumor microenvironment (TME) of cancer contain CTLA4-expressing cells.

12. A drug conjugate, composition, or kit for use according to claim 11, wherein the CTLA4-expressing cells are regulatory T cells, preferably CD4+FOXP3+CTLA4+ T cells and / or CD4+CD25+CD39+ T cells containing tumor antigen-specific clonal proliferating Treg cells.

13. A drug conjugate, composition, or kit for use according to any one of claims 9 to 12, wherein the drug conjugate or composition is administered to a target as a neoadjuvant therapeutic agent, preferably as monotherapy or in combination with different anticancer therapeutic agents prior to any partial or total tumor surgical resection or local destruction by any cytoreductive strategy, preferably by local delivery including an intratumor (IT) route, an intravascular route, or a local route.

14. A drug conjugate, composition, or kit for use according to any one of claims 9 to 13, wherein approximately 0.01 mg to approximately 1 mg of the drug conjugate is administered to the subject per kilogram of the subject's body weight.

15. A drug complex, composition, or kit for use according to any one of claims 9 to 14, wherein the target is a mammal, preferably a human.

16. A drug conjugate, composition, or kit for use according to any one of claims 9 to 15, wherein the subject is a tumor or tumor microenvironment (TME) comprising CTLA4+ tumor cells and / or CTLA4+ immune cells.

17. A drug conjugate, composition, or kit for use according to claim 16, wherein the target is a target resistant to bare anti-CTLA4 and / or anti-PD(L)1 substance.

18. A drug conjugate, composition, or kit for use according to claim 16 or 17, wherein the subject tumor and / or TME does not exhibit myeloid cells that do not express or exhibit low levels of Fcγ receptor I ("CD64"), Fcγ receptor IIIa ("CD16a"), and / or Fcγ receptor IIIb ("CD16b"), exhibits low levels of said myeloid cells, or exhibits dysfunctional said myeloid cells.

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