Cancer is the second most common cause of death in the U.S., exceeded only by heart disease, accounting for approximately 1 in 4 deaths. In 2014, about 585,720 Americans are expected to die of cancer, almost 1,600 people per day. As of Jan. 1, 2012, there were approximately 13.7 million Americans living with cancer, or with a history of cancer (American Cancer Society, Cancer Facts & Figures, 2014).
The majority of cancer therapies are severely limited by significant side effects due to non-specific tissue toxicity. The identification and development of therapeutic agents that are selectively toxic to malignant cells is a key goal in cancer research. Many tumors harbor genetic defects that distinguish them from normal cells, and some of these defects have the potential to be exploited in the development of targeted therapies for cancer. A number of tumor-specific targets are located inside cells and nuclei, and numerous types of cancer that are selectively toxic to cancer cells with pre-existing deficiencies in DNA repair are particularly vulnerable to treatments that inhibit DNA repair.
A significant amount of work has focused on applying the specific binding activity of monoclonal antibodies to the development of tumor-specific therapies. Select antibodies such as trastuzumab (HERCEPTIN®), rituximab (RITUXAN®), and cetuximab (ERBITUX®) have received approval for use in human cancer therapy. However, all of these therapeutic antibodies lack the ability to penetrate into cancer cells and are therefore limited to attacking cells with the specific antigens located on the external surface of tumor cells.
It is therefore an object of the invention to provide cell-penetrating antibodies that are selectively cytotoxic to cancer cells that are deficient in DNA repair.
It is also an object of the invention to provide compositions and methods to sensitize specific target cells to enhance and augment the efficacy of conventional therapeutic agents.