Tolerogenic conjugates of xenogeneic monoclonal antibodies with monomethoxypolyethylene glycol. I. Induction of long-lasting tolerance to xenogeneic monoclonal antibodies

Abstract

The therapeutic effectiveness of xenogeneic monoclonal antibodies (MAbs) (xlg) or their conjugates with toxins (xlg-Tx) is undermined because of their inherent immunogenicity. This complication may be overcome by converting the antigenic xlg to tolerogenic derivatives by coupling an appropriate number of monomethoxypolyethylene glycol (mPEG) chains (MW 6400) onto an xlg molecule. In our study, the test system consisted of inbred mice and human (myeloma) monoclonal immunoglobulins (HlgG) which were used in lieu of xlg; the immunizing antigen was heat-aggregated HlgG. The results of a variety of experimental protocols demonstrate that a long-lasting suppression (>95%) of anti HlgG antibodies for periods in excess of 300 days was achieved by administration of tolerogenic HlgG(mPEG)_n conjugates in spite of multiple injections of the immunizing antigen. Thus, pre-treatment of hosts with mPEG conjugates of xlg or of xlg-Tx is envisaged as a potential method for overcoming the antigenicity of these anti-tumour agents.