A One-Two Punch Against Cancer

Scientists at Genentech have devised a novel approach to developing antibodies to combat cancer, based on differences in the way cancer and normal cells respond to chemotherapy. First, they identified cell-surface antigens that were induced by the topoisomerase inhibitor CPT-11 in metastatic colorectal cancer. This was accomplished by nude mice innoculated with human colorectal cancer cells with CPT-11 or saline. An analysis of RNA transcripts revealed several cell surface proteins that were induced by the chemotherapeutic agent, including E48 antigen (LY6D), which was the most consistently elevated. This induction showed specificity, as neither prostate nor embryonic kidney cell lines responded in this manner, while three different human colorectal cancer cell lines increased LY6D/E48 mRNA in response to CPT-11. The induction was also specific for cancer cells, as CPT-11 did not induce these cell-surface proteins in the intestines of normal mice.

Antibodies to LY6D/E48, which were raised in mice immunized with the purified protein, showed specific reactivity but no cytotoxicity. A conjugated antibody was then prepared with the cytotoxin monomethyl auristatin E, which binds to and disrupts the polymerization of tubulin. Treatment of tumor-bearing mice with CPT-11 and the conjugate showed minimal tumor mass for 8 weeks, while treatment with the conjugate alone had no effect and CPT-11 alone retarded tumor growth for about three weeks.

This work identifies a new avenue to developing anticancer drugs, based on the unique response to chemotherapy by cancer cells. The results suggest that antibodies targeting cell-surface antigens induced by chemotherapeutic agents may be used in combination therapies that may be more effective than either component alone.

Message posted by: Keith Markey