Synthesis and biological evaluation of immunoconjugates of adriamycin and a human IgM linked by poly[N-5-(2-hydroxyethyl)-L-glutamine]

The synthesis and purification of radiolabelled immunoconjugates, composed of a human IgM monoclonal antibody (IgM 16.88) directed against an intracellular tumour-associated antigen, the drug carrier poly [N-5-(2-hydroxyethyl)-L-glutamine] (PHEG) and the cytostatic drug adriamycin (ADR) are described. The immunoconjugates were constructed to allow selective release of ADR in the putatively acidic environment of the tumour through a novel acid-labile maleamic acid linker. The conjugate of PHEG and the acid-labile ADR derivative effectively released ADR in cytotoxic amounts at a pH of 6.0 as judged from incubation in buffer and from inhibition of the growth of HT-29 colon tumour cells in vitro. Immunoconjugates were prepared by coupling of PHEG-ADR having a hydrolytically stable amide bond with I-131-labelled antibody through thioether bond formation involving a single thiol group at the C-terminus of the polymer chain and maleimido groups introduced onto the antibody. The immunoreactivity of IgM-PHEG-ADR conjugate was almost fully preserved. Tumour uptake and biodistribution of I-125-labelled PHEG-ADR and of I-131-labelled IgM-PHEG-ADR, which was co-administered with H-3-labelled IgM 16.88, in nude mice carrying MRI-H-207 human ovarian tumour xenografts were studied. I-125 bound to PHEG-ADR was cleared relatively slowly from the circulation and significant tumour uptake was maintained during the period studied. The drug immunoconjugate was cleared more rapidly frolic the circulation with a concomitant decrease in tumour uptake as compared with unmodified IgM. The biodistribution data indicate that targeting of ADR with IgM 16.88 in this tumour model is not feasible.