Antibody-drug conjugates and methods
The present invention relates to antibody-drug conjugate compounds of Formula I: Ab-(L-D) p I where one or more maytansinoid drug moieties (D) are covalently linked by L to an antibody (Ab) which binds to an ErbB receptor, or which binds to one or more tumor-associated antigens or cell-surface receptors. These compounds may be used in methods of diagnosis or treatment of cancer, and other diseases and disorders.
1. A method of treating breast cancer comprising administering to a patient a formulation of trastuzumab-SMCC-DM1 and a pharmaceutically acceptable diluent, carrier or excipient, in combination with lapatinib;
wherein trastuzumab-SMCC-DM1 has the structure:
and p is 1 to 8;
the breast cancer overexpresses ErbB2 at a 2+level or more; and
the patient is administered a dose of 3 to 10 mg/kg of trastuzumab-SMCC-DM1 by infusion about every 7 to about every 21 days.
2. The method of claim 1 wherein trastuzumab-SMCC-DM1 is formulated with a pharmaceutically acceptable parenteral vehicle.
3. The method of claim 1 wherein the formulation comprises about 10 to 30 mg per ml of trastuzumab-SMCC-DM1.
4. The method of claim 3 wherein the formulation comprises about 20 mg per ml of trastuzumab-SMCC-DM1.
5. The method of claim 1 wherein the formulation comprises up to 10% molar equivalent of DM1-SMCC.
6. The method of claim 1 wherein the pharmaceutically acceptable diluent, carrier or excipient is selected from one or more of succinate, polysorbate 20, and trehalose.
7. The method of claim 1 further comprising measuring thrombocytopenia.
8. The method of claim 7 further comprising the step of adjusting the dose of trastuzumab-SMCC-DM1 to the patient to lessen thrombocytopenia.
9. The method of claim 1 wherein the formulation of trastuzumab-SMCC-DM1 and lapatinib are administered sequentially.
10. The method of claim 1 wherein the formulation of trastuzumab-SMCC-DM1 and lapatinib are coadministered in separate formulations.
11. The method of claim 1 wherein the formulation of trastuzumab-SMCC-DM1 and lapatinib are coadministered in a single formulation.
12. The method of claim 1 wherein the patient failed to respond or responded poorly to prior HERCEPTIN®treatment.