Effect of linkage variation on pharmacokinetics of ricin A chain-antibody conjugates in normal rats.
We have investigated the pharmacokinetics of three ricin A chain-antibody conjugates having different bridging structures. Conjugate 1 has a disulphide linkage and was prepared with the N-succinimidyl-3-(2-pyridyldithio)propionate cross-linking reagent. Conjugate 2 has a protected disulphide linkage with a methyl group substituted on the carbon atom of the bridging structure adjacent to the disulphide linkage. Its preparation necessitated the synthesis of a new cross-linking reagent N-succinimidyl 3-(2-pyridyldithio)-butyrate. Conjugate 3 has a sulphide linkage and was prepared with the cross-linking reagent N-succinimidyl 4-(iodoacetylamino)benzoate which was synthesized by a novel route. Conjugate 1 is reducible, conjugate 2 less easily reducible and conjugate 3 nonreducible. On administration to animals all three conjugates displayed biphasic kinetics. The reducibility of the bond had no significant effect on the early disappearance of the conjugate from the circulation. However, at the later time points ease of reduction of the bond was associated with a more rapid disappearance of conjugate.
D000818:Animals; D004220:Disulfides; D006207:Half-Life; D000922:Immunotoxins / Q000493:pharmacokinetics*; D051381:Rats; D012276:Ricin / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship
D004220:Disulfides; D000922:Immunotoxins; D012276:Ricin