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1. WO2016145536 - CONJUGATES FOR THE TREATMENT OF CANCER TARGETED AT INTRACELLULAR TUMOR-ASSOCIATED ANTIGENS

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CLAIMS

1. A conjugate comprising:

a. a targeting agent that specifically binds a target antigen, optionally a lysosomal aspartic protease, optionally human cathepsin D;

b. a cytotoxic moiety, optionally linked directly or indirectly to the targeting agent; c. and, optionally, a linker linking the targeting agent and cytotoxic moiety.

2. The conjugate of claim 1, wherein the target antigen is a lysosomal aspartic protease selected from human cathepsin D human cathepsin E.

3. The conjugate of claim 1 or 2, wherein the targeting agent specifically binds human cathepsin D.

4. The conjugate of any one of claims 1 to 3, wherein the targeting agent specifically binds human pro-cathepsin D.

5. The conjugate of any of the claims 2-4, wherein the targeting agent binds to an epitope excluding a cathepsin D receptor binding site, optionally mannose-6-phosphote (M6P) receptor, L P1, or sortilin, optionally where the epitope excludes residues Asn70 and Asnl99 of human cathepsin D.

6. The conjugate of any of the preceding claims, wherein the conjugate also comprises a cell- penetrating peptide moiety.

7. The conjugate of any of the preceding claims, wherein the linker is a stable linker.

8. The conjugate of any of the preceding claims, wherein the linker is a labile linker.

9. The conjugate of claim 8, wherein said linker is an enzymatically cleavable linker.

10. The conjugate of any one of the claims 8-9, wherein the linker is a self-immolating linker.

11. The conjugate of any one of the claims 8-9, wherein the linker is cleavable by an intracellular protease.

12. . The conjugate of any of the preceding claims, wherein the linker is derived from a cross- linking reagent selected from the group consisting of N-succinimidyl-3-(2- pyridyldithio)propionate (SPDP), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP), N- succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-succinimidyl-4-(2-pyridyldithio)2-sulfo- butanoate (sulfo-SPDB), N-succinimidyl iodoacetate (SIA), N-succinimidyl(4-

iodoacetyl)aminobenzoate (SIAB), N-succinimidyl bromoacetate (SBA), N-succinimidyl 3- (bromoacetamido)propionate (SBAP), maleimide PEG NHS, N- succinimidyl 4- (maleimidomethyl) cyclohexanecarboxylate (SMCC), N-succinimidyl-4-(N-maleimidomethyl)- cyclohexane- 1 -carboxy-(6-amidocaproate) (LC- SMCC), N-sulfosuccinimidyl 4- (maleimidomethyl) cyclohexanecarboxylate (sulfo-SMCC) or 2,5-dioxopyrrolidin-l-yl 17-(2,5- dioxo- 2,5 -dihydro- 1 H-pyrrol- 1 -yl)-5 ,8, ll,14-tetraoxo-4,7, 10, 13-tetraazaheptadecan- 1 - oate (CXI - 1 ), K-maleimidoundecanoic acid N-succinimidyl ester (KM UA), γ- maleimidobutyric acid N-succinimidyl ester (GMBS), ε-maleimidcaproic acid N- hydroxysuccinimide ester (EMCS), m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), N-(a-maleimidoacetoxy)-succinimide ester (AMAS), succinimidyl-6-(P- maleimidopropionamido)hexanoate (SMPH), N-succinimidyl 4-(p-maleimidophenyl)- butyrate (SMPB), or N-(p-maleimidophenyl)isocyanate (PMPI).

13. The conjugate of any of the preceding claims, wherein said cytotoxic moiety is selected from a group consisting of a microtubule stabilizer, a microtubule destabilizer, an auristatin, a dolastatin, a maytansinoid, a tubulysin, a cryptophycins , a methionine aminopeptidase, a calicheamicin, an inhibitor of nuclear export of proteins C M1, a DPPIV inhibitor, proteasome inhibitors, inhibitors of phosphoryl transfer reactions, a protein synthesis inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, a kinesin inhibitor, an HDAC inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA intercalator, a DNA minor groove binder, a DHFR inhibitor, a pro-apoptotic agent, a Bcl2 inhibitor, an MCL1 inhibitor, a HSP90 inhibitor, an IAP inhibitor, and an mTor inhibitor, N(2')- deacetyl-N(2')-(3- mercapto-l-oxopropyl)- maytansine (DM1), or N(2')-deacetyl-N2-(4- mercapto-4-methyl- 1 - oxopentyl)-maytansine (DM4).

14. The conjugate of any one of claims 1 to 6, wherein the cytotoxic moiety and linker comprises a compound of Formula III or IV.

15. The conjugate of any of the preceding claims, wherein the targeting agent is selected from a binding protein and a nucleic acid, such as DNA, RNA or an aptamer.

16. The conjugate of claim 15, wherein the binding protein is selected from an antibody, affimer and receptor.

17. The conjugate of claim 16, wherein the antibody is selected from the group consisting of a monoclonal antibody, a polyclonal antibody, an antibody fragment, a chimeric antibody, a

humanized antibody, a human antibody, a single chain Fv (scFv), a nanobody, a single-domain antibody (sdAb), and an antibody fragment such as an Fab fragment, and an F(ab')2 fragment.

18. The conjugate of claim 17, wherein the antibody is a monoclonal antibody.

19. The conjugate of any of the preceding claims administered to or for use in a subject in need thereof optionally in combination with another therapeutic agent.

20. A composition comprising an effective amount of the conjugate of any one of claims 1 to 19, a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

21. The composition of claim 20, wherein the composition is a pharmaceutical composition.

22. A method of delivering a cytotoxin selectively to cancer cells, the method comprising contacting the cell with the conjugate of any one of claims 1 to 19 or the composition of claim 20 or 21.

23. The method of claim 20 wherein the cancer cells to be targeted are in a subject and the cells are contacted by administering the conjugate or composition to the subject in need thereof.

24. The method of claim 22 or 23, wherein the method is for treating cancer.

25. A method of treating cancer comprising administering to a subject in need thereof an effective amount of the conjugate of any one of claims 1 to 19 or the composition of claim 20 or 21.

26. The method of claim 24 or 25 wherein the conjugate or composition is

administered systemically or locally to the subject.

27. The method of any of the claims 22-26, wherein the subject is a human.

28. The method of any of the claims 22-27, wherein the conjugate or composition is administered by injection.

29. The method of any one of claims 24 to 28, wherein the cancer is a solid tumor.

30. The method of any one of claims 24 to 29 wherein the subject has one or more metastasis.

31. The method of any one of claims 24 to 30, wherein a sample of the cancer is assessed for cathepsin D or cathepsin E expression prior to administration of the conjugate or the composition.

32. The method of claim 31, wherein the cancer overexpresses cathepsin D.

33. The method of using of any one of claims 24-31, wherein the cancer is selected from the group consisting of breast cancer, such as triple-negative breast cancer, prostate cancer, ovarian cancer, endometrial cancer, non-small cell lung cancer (NSCLC), hepatocellular carcinoma

(HCC), head & neck squamous cell carcinoma (HNSCC), bladder cancer, pancreatic cancer, glioblastoma multiforme (GBM), small-cell lung cancer, melanoma, and renal cell carcinoma.

34. The method of claim 32, wherein the cancer is breast cancer.

35. The method of claim 32, wherein the breast cancer is a triple-negative breast cancer.

36. The method of claims 32, wherein the cancer is prostate cancer.

37. The method of any one of claims 22-36, wherein the conjugate or composition is parenterally administered.

38. A method of making the conjugate of any one of claims 1 to 19, wherein the method comprises either:

a. reacting the targeting agent with a linker precursor reagent to form a targeting agent-linker pre-conjugate comprising 1 to 20 linker molecules;

b. reacting the targeting agent-linker pre-conjugate with the cytotoxic moiety to form the conjugate, the conjugate comprising 1 to 20 molecules of the cytotoxic moiety; or

a. reacting the cytotoxic moiety with a linker precursor reagent to form a linker- cytotoxic moiety pre-conjugate;

b. reacting the linker-cytotoxic moiety pre-conjugate with the targeting agent to form the conjugate, the conjugate comprising 1 to 20 linker-cytotoxic moiety molecules.

39. A method for selecting a candidate target intracellular tumor antigen as a target antigen comprising:

a. testing non-cancer cells for a candidate antigen to determine if it is intracellular and/or normally non-secreted by non-cancer cells;

b. testing cancer cells for the candidate antigen to determine if it is secreted by cancer cells;

c. if the target antigen is secreted by cancer cells in an amount greater than the non- cancer cells, testing cancer cells for the candidate antigen to determine if it can be re-internalized by cancer cells; and

d. identifying a target antigen that is secreted by cancer cells in an amount greater than non-cancer cells and is reinternalizable by cancer cells as a candidate target intracellular tumor antigen.

40. The method of claim 39, wherein the non-cancer cells of step a) and the cancer cells of step b) are each cultured in culture media for a period of time and the culture media of each is measured for the level of target antigen.

41. The method of claim 40 wherein mass spectrometry is used to measure the level of the target antigen.

42. The method of any one of claims 39 to 41, wherein the method further comprises preparing a conjugate.

43. The method of claim 42, wherein the method of preparing the conjugate comprises either:

a. reacting a targeting agent that specifically binds the candidate target intracellular tumor antigen with a linker precursor reagent to form a targeting agent-linker pre- conjugate comprising 1 to 20 linker molecules;

b. reacting the targeting agent-linker pre-conjugate with the cytotoxic moiety to form the conjugate, the conjugate comprising 1 to 20 molecules of the cytotoxic moiety; or

a. reacting the cytotoxic moiety with a linker precursor reagent to form a linker- cytotoxic moiety pre-conjugate;

b. reacting the linker-cytotoxic moiety pre-conjugate with a targeting agent that specifically binds the candidate target intracellular tumor antigen to form the conjugate, the conjugate comprising 1 to 20 linker-cytotoxic moiety molecules.

44. A companion diagnostic kit for use with the method of claim 31, the kit comprising a detection agent that specifically binds to cathepsin D, optionally procathepsin D, or cathepsin E.