Comparative clinical pharmacology of [111In]-labeled murine monoclonal antibodies.
Patients with metastatic melanoma received either the murine antimelanoma antibody ZME-018 (20 patients) or antibody 96.5 (26 patients) at doses ranging from 1 to 20 mg and coupled to 2.5 or 5 mCi of [111In]. The pharmacokinetics and tissue disposition of these antibodies were measured at various times after infusion of the radiolabel. The clearance of the [111In]label from plasma closely fit (r2 greater than 0.90) an open, one-compartment mathematical model after administration of antibody 96.5. Clearance of [111In] from plasma after administration of ZME-018 fit a one-compartment model in some patients and a two-compartment model in others. The terminal phase half-lives of 96.5 and ZME-018 antibodies at the 20-mg dose were almost identical (27 +/- 2 h and 29 +/- 5 h, respectively). The half-lives calculated for 96.5 were not dependent upon the total antibody dose; however, with increasing doses of ZME-018 there was a dose-dependent increase in t 1/2 (from 17.8 +/- 2 h at the 2.5-mg dose to 29 +/- 5 h at the 20-mg dose). For 96.5 antibody, the apparent volume of distribution (Vd) approximated the total blood volume (7.8 +/- 0.71) at the 1-mg dose and decreased significantly at the 20-mg dose, suggesting saturation of extravascular antigen sites. In contrast, the Vd calculated for ZME-018 did not appear to be dependent upon the administered dose. Improved imaging occurred with increasing doses of unlabeled 96.5 above 2 mg, a finding not observed with ZME-018. The cumulative urine excretion of [111In] after administration of 96.5 or ZME-018 was 10%-14% of the total dose. These studies show that murine monoclonal antibodies of the same subtype but recognizing different surface antigens can exhibit markedly different in vivo pharmacokinetic behavior, which may partially explain differences in imaging noted with increasing doses of monoclonal antibody.
D000911:Antibodies, Monoclonal / Q000097:blood / Q000378:metabolism*; D001682:Biological Availability; D004797:Enzyme-Linked Immunosorbent Assay; D006207:Half-Life; D006801:Humans; D007204:Indium; D007262:Infusions, Intravenous; D007700:Kinetics; D008545:Melanoma / Q000378:metabolism*; D011868:Radioisotopes; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D011868:Radioisotopes; D007204:Indium