Synergistic effects between auristatin-based antibody drug conjugates and inhibitors of the PI3K-AKT mTOR pathway

1. A method for treating cancer in a subject, the method comprising the step of administering to the subject an auristatin-based antibody-drug conjugate and an inhibitor of the PI3K-AKT-mTOR pathway, which is a PI3K inhibitor, wherein the PI3K inhibitor is BKM120, XL147, GDC0941, GSK1059615, PX-866, or CAL-101, wherein cells of the cancer express a cell-surface antigen internalizable on selective binding by the antibody of the auristatin-based antibody-drug conjugate, which antigen is CD19, CD30 or CD70, and wherein the cells are characterized by constitutive activation of the PI3K-AKT-mTOR pathway, and the cancer is a hematological malignancy expressing CD19, CD30 or CD70 or renal cell carcinoma expressing CD70, wherein the auristatin-based antibody drug conjugate and the inhibitor of the PI3K-AKT-mTOR pathway act synergistically in killing cancer cells in an in vitro or animal model of the cancer.

2. The method of claim 1 wherein the auristatin-based antibody-drug conjugate has the following formula:

L -( LU - D ) p   (I)

or a pharmaceutically acceptable salt thereof;

wherein:

L is the antibody that selectively binds to the internalizable cancer cell antigen expressed on the surface of the cancer cell; and

(LU-D) is a drug-linker moiety, wherein:

LU- is a Linker unit;

-D is an auristatin having cytostatic or cytotoxic activity against the target cells; and

subscript p ranges from 1 to 20.

3. The method of claim 2 wherein the auristatin has the formula:

or a pharmaceutically acceptable salt form thereof.

4. The method of claim 2 wherein the auristatin has the formula:

or a pharmaceutically acceptable salt form thereof.

5. The method of claim 2 , wherein the Linker Unit has the formula:

- A a - W w - Y y -

or a pharmaceutically acceptable salt form thereof,

wherein:

-A- is a Stretcher Unit;

subscript a is 0 or 1;

each —W— is independently an Amino Acid Unit;

subscript w is an integer ranging from 0 to 12;

-Y- is a Spacer unit; and

subscript y is 0, 1 or 2.

6. The method of claim 5 wherein the auristatin-based antibody drug conjugate has the formula:

or a pharmaceutically acceptable salt form thereof.

7. The method of claim 5 wherein the auristatin-based antibody drug conjugate has the formula:

or a pharmaceutically acceptable salt form thereof.

8. The method of claim 7 wherein the auristatin-based antibody drug conjugate has the formula

or a pharmaceutically acceptable salt form thereof.

9. The method of claim 8 wherein the auristatin-based antibody drug conjugate has the formula:

or a pharmaceutically acceptable salt form thereof, wherein mAb is a monoclonal antibody, S is a sulfur atom of the antibody, and subscript p ranges from 1 to 8.

10. The method of claim 2 wherein the auristatin-based antibody-drug conjugate has the formula:

or a pharmaceutically acceptable salt form thereof.

11. The method of claim 10 wherein the auristatin-based antibody-drug conjugate has the formula:

or a pharmaceutically acceptable salt form thereof wherein mAb is a monoclonal antibody, S is a sulfur atom of the antibody, and subscript p ranges from 1 to 8.

12. The method of claim 2 wherein the administered auristatin-based antibody-drug conjugate is in a composition comprising a collection of such conjugates in which the average number of drug molecules per antibody ranges from about 2 to about 6.