SYNTHESIS AND BIODISTRIBUTION OF IMMUNOCONJUGATES OF A HUMAN-IGM AND POLYMERIC DRUG CARRIERS

The synthesis and purification of radiolabelled immunoconjugates, comp osed of a human IgM monoclonal antibody directed against an intracellu lar tumour-associated antigen and either poly(alpha-L-glutamic acid) ( PGA) or poly[N5-(2-hydroxyethyl)-L-glutamine] (PHEG) is described. Cou pling of polymers to the antibody was performed through disulfide bond formation involving a single thiol group at the C-terminus of the pol ymer chain and 2-pyridyldisulfide groups introduced onto the antibody. The antibody was iodinated with I-131 before conjugation. The polymer s contained tyrosinamide in a low degree of substitution and were radi olabelled with I-125. I-125-labelled PGA and PHEG were found to be sta ble for at least 3 days in murine and human plasma. The biodistributio n in mice of the doubly labelled immunoconjugates was studied and was compared with the pharmacokinetics of the individual components. PHEG showed a relatively slow blood clearance, the half-life being approxim ately 10 h with low uptake in liver, kidneys and spleen. PGA was rapid ly cleared from the circulation and was significantly taken up in live r, kidneys and spleen. The biodistribution of both immunoconjugates wa s indistinguishable from that of the IgM proper, with plasma half-live s of approximately 6 h, indicating that the pharmacokinetic properties of the immunoconjugates are largely determined by the antibody part.