Modification of methyliminodiacetato-trans-R,R-1,2-diamminocyclohexane platinum(II) pharmacology using a platinum-specific monoclonal antibody.

Platinum complexes are extremely active chemotherapeutic agents. A murine monoclonal antibody designated 1C1 was developed that binds to the third-generation platinum complex methyliminodiacetato-trans-R,R-1,2-diamminocyclohexane platinum(II) (MIDP). Competitive enzyme-linked immunosorbent assay (ELISA) shows that antibody 1C1 binds preferentially to the 1,2-diamminocyclohexane (DACH) side-chain of the platinum complex, although non-DACH-containing platinum complexes can compete for binding at high concentrations. When tested against MCF-7 breast carcinoma cells, the 1C1-MIDP complex caused 50% growth inhibition at 0.63 micrograms Pt/ml, whereas MIDP alone caused 50% growth inhibition at a concentration of 0.16 micrograms Pt/ml. Pharmacokinetic studies in rats using [3H]-MIDP showed that the drug was cleared triphasically from plasma, with elimination-phase half-lives (t1/2) of 1.2, 10.2, and 243 min for alpha, beta, and gamma phases, respectively. The MIDP-1C1 complex was cleared with longer half-lives of 5, 26, and 291 min, respectively. The overall clearance rate from plasma of the MIDP-1C1 complex was 10-fold lower than that of MIDP alone (0.37 vs 3.01 ml/kg x min). Tissue concentrations of [3H]-MIDP 3 h after administration showed that 1C1 antibody prevented MIDP distribution to most organs and dramatically reduced [3H] concentration in the intestine, liver, kidney, heart, and skeletal muscles. Studies are under way to determine the relative therapeutic activity of the 1C1 antibody-MIDP complex and assess whether the 1C1 antibody may be useful for antibody-directed delivery of platinum complexes to tumors.