Beta-glucuronide-linker drug conjugates

1. A method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a ligand drug conjugate compound having the formula:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

L- is a Ligand Unit selected from the group consisting of a protein, a polypeptide, and a peptide that specifically binds to an antigen expressed on cells of the cancer;

-A a -W w —Y y - is a Linker Unit (LU) linking a Drug Unit to a Ligand Unit,

-A- is an optional Stretcher Unit,

a is 0, 1 or 2;

each —W— is independently a Glucuronide Unit having one of the formulae:

Su is a Sugar moiety,

—O′— represents an oxygen atom of an O-glycosidic bond cleavable by beta-glucoronidase;

each R is independently hydrogen, a halogen, —CN, or —NO 2 ;

w is 1,

—Y— is an optional Self-Immolative Spacer Unit,

y is 0, 1 or 2;

p ranges from 1 to 20; and

-D is a Drug Unit selected from the group consisting of a cytotoxic, a cytostatic and an immunomodulatory drug and wherein the wavy lines indicate covalent bonds within the rest of the compound.

2. The method of claim 1 , wherein the Ligand Unit is an antibody.

3. The method of claim 2 , wherein the antibody is a humanized or chimeric antibody or an antigen binding fragment of an antibody.

4. The method of claim 1 , wherein the ligand drug conjugate compound has the following formula:

or a pharmaceutically acceptable salt or solvate thereof.

5. The method of claim 4 , wherein the ligand drug conjugate compound has the following formula:

or a pharmaceutically acceptable salt or solvate thereof.

6. The method of claim 5 , wherein the ligand drug conjugate compound has the following formula:

or a pharmaceutically acceptable salt or solvate thereof.

7. The method of claim 6 , wherein the ligand drug conjugate compound has the following formula:

or a pharmaceutically acceptable salt or solvate thereof; wherein the wavy line indicates attachment to the remainder of the Stretcher Unit or to the Ligand Unit, and wherein from 1 to 20 Drug Units are linked to the Ligand Unit and L is a monoclonal antibody.

8. The method of claim 1 , wherein p is 2 to 6.

9. The method of claim 1 , wherein p is 2 or 4.

10. The method of claim 1 , wherein A is present and selected from the formulae:

wherein R 17 is —C 1 -C 10 alkylene-, —C 3 -C 8 carbocyclo-, —O—(C 1 -C 8 alkyl)-, -arylene-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-, —(CH 2 CH 2 O) r —, —(CH 2 CH 2 O) r CH 2 —; or —(CH 2 CH 2 O) r CH 2 CH 2 —, and r is an integer ranging from 1-10.

11. The method of claim 10 , wherein A is:

12. The method of claim 1 , wherein a is 1 or 2.

13. The method of claim 1 , wherein Y is a carbonyl group (—CO)— or a p-aminobenzyl alcohol group whose phenylene portion is substituted with Q m wherein Q is C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), -halogen, -nitro or -cyano; and m is an integer ranging from 0-4.

14. The method of claim 1 , wherein the ligand drug conjugate compound has the following formula:

or a pharmaceutically acceptable salt or solvate thereof wherein mAb is a monoclonal antibody.

15. The method of claim 1 , further comprising administering a therapeutically effective amount of an additional anticancer gent or an immunosuppressant agent.

16. The method of any one of claim 1 , wherein the ligand drug conjugate compound is in a formulation further comprising a pharmaceutically acceptable diluent, carrier or excipient.

17. The method of claim 16 , wherein the ligand drug conjugate compound is formulated in a unit dosage injectable form.

18. The method of claim 1 , wherein the cytotoxic drug is a DNA replication inhibitor.

19. The method of claim 1 , wherein the cytotoxic drug is a DNA minor groove binder.

20. The method of claim 1 , wherein the cytotoxic drug is an alkylating agent.

21. The method of claim 1 , wherein the cytotoxic drug is an antitubulin agent.

22. The method of claim 21 , wherein the antitubulin agent is a maytansinoid.

23. The method of claim 21 , wherein the cytotoxic drug is an auristatin.

24. The method of claim 23 , wherein D has the formula:

or a pharmaceutically acceptable salt or solvate thereof.

25. The method of claim 23 , wherein D has the formula:

or a pharmaceutically acceptable salt or solvate thereof.