Tolerogenic polyethylene glycol derivatives of xenogeneic monoclonal immunoglobulins.

It is becoming apparent that the effectiveness of xenogeneic monoclonal antibodies (XIg), which are increasingly used for diverse therapeutic purposes in man, may be counteracted by their inherent immunogenicity. Since conjugates of proteins with monomethoxypolyethylene glycol (mPEG) have proved to be effective tolerogens in other systems, we have used an experimental model in mice to explore the tolerogenicity of mPEG conjugates of a human monoclonal IgG (HIgG), i.e. a myeloma protein. Administration of these conjugates prior to immunization with heat aggregated HIgG (ha-HIgG) resulted in specific tolerance, as manifested by a marked reduction in the level of antibodies to HIgG, which was related to the degree of conjugation and the dose of conjugate administered. Thus, administration of HIgG(mPEG)20 6 to 43 days prior to immunization with ha-HIgG resulted in an inhibition of anti-HIgG antibody formation of the order of 85-90%, in relation to the titres of mice receiving PBS in lieu of HIgG(mPEG)20; these results hold the promise that mPEG conjugates of XIg may prove therapeutically useful in man in relation to organ transplantation, localization of tumours by immuno-imaging and tumour destruction by immunotoxins.