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.
Rosenblum
M G
MG
Department of Clinical Immunology and Biological Therapy, University of Texas, M. D. Anderson Cancer Center, Houston 77030.
Murray
J L
JL
Stuckey
S
S
Newman
R A
RA
Chaney
S
S
Khokhar
A R
AR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000970:Antineoplastic Agents; D001666:Binding Sites, Antibody; D055598:Chemical Phenomena; D002621:Chemistry; D006207:Half-Life; D000922:Immunotoxins / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D009944:Organoplatinum Compounds / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D010984:Platinum / Q000276:immunology*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000922:Immunotoxins; D009944:Organoplatinum Compounds; D010984:Platinum; C049496:N-methyliminodiacetato-1,2-diaminocyclohexane platinum(II)