REDUCTION IN THE TOXICITY OF AMINOPTERIN - MONOCLONAL-ANTIBODY CONJUGATES BY LEUCOVORIN

Although aminopterin(AMN)-antibody drug conjugates have been demonstra ted to have a greatly increased antitumour efficacy compared to the fr ee drug, their use is limited by an increase in systemic toxicity mani fested by weight loss and bone marrow suppression. Using a murine thym oma model (E3) in inbred mice, the toxicity of a sublethal dose of fre e AMN could be prevented by the administration of leucovorin 24 h foll owing drug treatment, whilst maintaining the antitumour effect of the drug. The same rescue protocol completely abrogated the antitumour eff icacy of AMN-antibody, although toxicity was also diminished. However, the later administration of leucovorin 48-72 h following a sublethal dose of AMN-antibody conjugates resulted in a maintenance of the antit umour efficacy of the immunoconjugates and a reduction in toxicity, wi th a mean percentage change in mouse weight not significantly differen t from that of the controls. These studies demonstrate that reversal o f toxicity caused by AMN-antibody conjugates can be achieved by leucov orin while maintaining a powerful antitumour effect provided that the dose of leucovorin is administered 48-72 h after the conjugate.