Conjugates of mitomycin C with the immunoglobulin M monomer fragment of a monoclonal anti-MM46 immunoglobulin M antibody with or without serum albumin as intermediary.

Abstract

In studies on antitumor antibody-drug conjugates as potential antitumor agents with improved tumor specificity, conjugates of mitomycin C (MMC) with the IgMs fragment of a monoclonal IgM antibody to a tumor-associated antigen (MM antigen) on mouse mammary tumor MM46 cell (anti-MM46 IgMs) were prepared by direct and bovine serum albumin (BSA)-mediated indirect conjugation. MMC was linked to the IgMs and BSA by the use of 1a-[4-(N-succinimidoxycarbonyl)butyryl]mitomycin C, which allowed the slow release of MMC. In the indirect conjugation, the thiol group of BSA was first protected as the 2-pyridyldithio group and, after the MMC binding, regenerated with dithiothreitol, and the resulting BSA-MMC was reacted with the IgMs having the maleimide group introduced with N-succinimidyl m-(N-maleimido)benzoate. Anti-MM46 IgMs-MMC was more cytotoxic against the target MM antigen-positive but Thy 1.2 antigen-negative MM46 cells than control anti-Thy 1.2 IgM-MMC. No such selective cytotoxicity was observed between anti-MM46 IgMs-MMC and anti-Thy 1.2 IgMs-MMC against the MM antigen- and Thy 1.2 antigen-negative MM48 cells. Anti-MM46 IgMs-BSA-MMC was more cytotoxic against MM46 cells than was a mixture of unconjugated anti-MM46 IgMs and BSA-MMC.