SYNTHESIS AND BIOLOGICAL EVALUATION OF IMMUNOCONJUGATES OF ADRIAMYCINAND A HUMAN-IGM LINKED BY POLY[N-5-(2-HYDROXYETHYL)-L-GLUTAMINE]

The synthesis and purification of radiolabelled immunoconjugates, comp osed of a human IgM monoclonal antibody (IgM 16.88) directed against a n intracellular tumour-associated antigen, the drug carrier poly [N-5- (2-hydroxyethyl)-L-glutamine] (PHEG) and the cytostatic drug adriamyci n (ADR) are described. The immunoconjugates were constructed to allow selective release of ADR in the putatively acidic environment of the t umour 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 hydr olytically stable amide bond with I-131-labelled antibody through thio ether 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 pres erved. Tumour uptake and biodistribution of I-125-labelled PHEG-ADR an d of I-131-labelled IgM-PHEG-ADR, which was co-administered with H-3-l abelled IgM 16.88, in nude mice carrying MRI-H-207 human ovarian tumou r xenografts were studied. I-125 bound to PHEG-ADR was cleared relativ ely slowly from the circulation and significant tumour uptake was main tained during the period studied. The drug immunoconjugate was cleared more rapidly frolic the circulation with a concomitant decrease in tu mour 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.