The pharmacokinetics and toxicity of murine monoclonal antibodies and of gelonin conjugates of these antibodies.
We studied in mice the in vivo pharmacokinetics and toxicity of murine monoclonal antibodies (MCA) and of disulfide-linked MCA conjugates of gelonin, a ribosomal inhibitor prepared from the seeds of Gelonium multiflorum. Iodinated MCA with specificity for human determinants and of gamma 1 or gamma 2a isotype had a circulatory half life (T 1/2) in the mouse of 4 days, which is consistent with previously published estimates of the circulatory T 1/2 of heterogeneous murine IgG. Iodinated murine MCA with specificity for murine determinants had a much shorter T 1/2, probably reflecting antigen binding. This effect could be partially overcome by the simultaneous injection of unlabeled MCA of identical specificity. Clearance of MCA-gelonin conjugates was characterized by an initial rapid phase lasting 8-12 h with a T 1/2 or from 4 to 7 h, followed by a slower clearance phase with T 1/2 approaching that of MCA. Moreover, the presence of significant amounts of intact conjugate in the murine circulation was demonstrable, by SDS gel electrophoresis, for up to 48 h post injection. Intraperitoneal injection of MCA-gelonin conjugate resulted in circulating levels identical to those achieved after i.v. administration after an initial 4 h equilibration. The LD50 of MCA-gelonin conjugates was approximately 25 mg/kg (i.v.) while that of gelonin was approximately 75 mg/kg (i.v.) MCA alone showed no toxicity in doses in excess of 150 mg/kg. At doses below the LD50 immunoconjugates caused a dose-dependent reversible weight loss. The main site of toxicity of MCA-gelonin conjugates was the liver; histopathological examination revealed dose-dependent foci of necrosis and acute inflammation. No pathology was observed in lung, spleen, kidney, gut or brain. The relationship to previous work in this area is discussed.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000633:toxicity*; D006207:Half-Life; D000922:Immunotoxins / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D010940:Plant Proteins / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D054789:Ribosome Inactivating Proteins, Type 1
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C025674:GEL protein, Gelonium multiflorum