Methods of treating drug-resistant cancers

1. A method of treating refractory or drug-resistant cancer cells in a patient in need of such treatment, said method comprising:

(a) evaluating whether the patient has a refractory or drug-resistant cancer,

(b) administering to the patient having a refractory or drug-resistant cancer an effective amount of a Drug-Linker-Ligand conjugate of the following formula:

L-(LU-D) p   I

or a pharmaceutically acceptable salt or solvate thereof

wherein,

L- is a Ligand unit;

LU is a Linker unit;

p is an integer from 1 to about 20; and

-D is a Drug unit having the Formula D F :

wherein, independently at each location:

R 2 is selected from the group consisting of H and C 1 -C 10 alkyl;

R 3 is selected from the group consisting of H, C 1 -C 10 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 10 alkyl-aryl, C 1 -C 10 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 10 alkyl-(C 3 -C 8 heterocycle);

R 4 is selected from the group consisting of H, C 1 -C 10 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 10 alkyl-aryl, C 1 -C 10 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 10 alkyl-(C 3 -C 8 heterocycle);

R 5 is selected from the group consisting of H and methyl;

or R 4 and R 5 jointly form a carbocyclic ring and have the formula —(CR a R b ) n1 — wherein R a and R b are independently selected from the group consisting of H, C 1 -C 10 alkyl and C 3 -C 8 carbocycle and n1 is selected from the group consisting of 2, 3, 4, 5 and 6;

R 6 is selected from the group consisting of H and C 1 -C 10 alkyl;

R 7 is selected from the group consisting of H, C 1 -C 10 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 10 alkyl-aryl, C 1 -C 10 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 10 alkyl-(C 3 -C 8 heterocycle);

each R 8 is independently selected from the group consisting of H, OH, C 1 -C 10 alkyl, C 3 -C 8 carbocycle and O—(C 1 -C 10 alkyl);

R 9 is selected from the group consisting of H and C 1 -C 10 alkyl;

R 10 is selected from the group consisting of aryl and C 3 -C 8 heterocycle;

Z is O;

R 11 is H or Me; and

(c) monitoring the patient to determine the status of the cancer;

wherein administration of the Drug-Linker-Ligand conjugate kills or inhibits the proliferation of the cancer cells.

2. The method of claim 1 , wherein the Drug comprises the following formula:

wherein R 11 ═H or Me.

3. The method of claim 2 , wherein the Drug comprises the following formula:

4. The method of claim 1 , wherein the Linker unit has the formula:

-A a -W w —Y y —

wherein:

-A- is a Stretcher unit;

a is 0 or 1;

each —W— is independently an Amino Acid unit;

w is independently an integer ranging from 0 to 12;

—Y— is a Spacer unit; and

y is 0, 1 or 2.

5. The method of claim 4 , wherein each W in the Amino Acid unit is independently selected from the group consisting of valine citrulline, 5-aminovaleric acid, homo phenylalanine lysine, tetraisoquinolinecarboxylate lysine, cyclohexylalanine lysine, isonipecotic acid lysine, beta-alanine lysine, glycine serine valine glutamine (SEQ ID NO:1) and isonipecotic acid.

6. The method of claim 1 , wherein the Ligand is an antibody or antibody fragment.

7. The method of claim 6 , wherein the antibody is a monoclonal antibody that is chimeric, humanized or human antibody, or an antigen-binding fragment thereof.

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

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

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

11. The method of claim 4 wherein -A a - has the formula:

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 —, or —(CH 2 CH 2 O) r —CH 2 —; r is an integer ranging from 1 to 10; and the Ligand unit is an antibody or antibody fragment; the succinimido terminus of -A a - forming a bond with the Ligand unit and the carbonyl terminus of -A a - forming a bond with the remainder of the Linker unit or the Drug unit.

12. The method of claim 11 , wherein the Drug-Linker-Ligand conjugate has the formula:

wherein Ab is the antibody or antibody fragment and S is a sulfur atom of a sulfhydryl group of the antibody or antibody fragment.

13. The method of claim 12 , wherein the Drug-Linker-Ligand conjugate has the formula:

.

14. The method of claim 4 , wherein the Drug-Linker-Ligand conjugate has the formula:

wherein the Ligand unit is represented by Ab and Ab is an antibody or antibody fragment.

15. The method of claim 4 , wherein W w is -valine-citrulline-.

16. The method of claim 6 , wherein the Drug-Ligand-Linker unit has the formula:

wherein Ab is the antibody or antibody fragment and S is a sulfur atom of a sulfhydryl group of the antibody or antibody fragment.

17. The method of claim 6 , wherein the Drug-Linker-Ligand unit has the formula:

wherein Ab is the antibody or antibody fragment and S is a sulfur atom of a sulfhydryl group of the antibody or antibody fragment.

18. The method of claim 6 , wherein the antibody is selected from the group consisting of chimeric or humanized AC10, chimeric or humanized 1F6, and chimeric or humanized 2F2.

19. The method of claim 1 , comprising administering the Drug-Linker-Ligand conjugate as a pharmaceutical composition comprising an effective amount of the Drug-Linker-Ligand conjugate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient.

20. The method of claim 19 , wherein the cancer is selected from the group consisting of breast, ovarian, stomach, endometrial, salivary gland, lung, kidney, colon, colorectal, thyroid, pancreatic, prostate and bladder cancer.