Suppression of Antibody Responses by Conjugates of Antigens and Monomethoxypoly(Ethylene Glycol)

The possibility of selectively downregulating the host’s immune response to a given antigen represents one of the most formidable challenges of modern immunology in relation to the development of new therapies for IgE-mediated allergies, autoimmune diseases, and the prevention of immune rejection of organ transplants. Similar considerations apply to an increasing number of promising therapeutic modalities for a broad spectrum of diseases, which would involve the use of foreign biologically active agents potentially capable of modulating the immune response, provided they were not also immunogenic. Among these agents, one may cite (1) xenogeneic monoclonal or polyclonal antibodies (collectively referred to here as xIg) against different epitopes of the patients’ CD4+ cells,1,2 administered alone or in combination with immunosuppressive drugs for treatment of rheumatoid arthritis and other autoimmune diseases, or for the suppression of graft versus host reactions and of the immune rejection of organ transplants,1,2 and (2) “magic bullets” for the destruction of tumor cells,3–5 which consist of anti-tumor xIg to which are coupled toxins (Tx), or radionuclides, or chemotherapeutic drugs. However, in most cases the patients produce antibodies to the injected xIg and to the even more immunogenic immunotoxins (xIg-Tx); consequently, the therapeutic effectiveness of these immunological strategies is undermined by the patients’ antibodies which prevent these “bullets” from reaching their target cells. In addition, the repeated administration of these agents may result in serious complications, namely, serum sickness, anaphylactic symptoms (i.e., bronchospasm, dyspnea, and hypotension), and/or the deposition in the liver of toxic immune complexes leading frequently to hepatotoxicity.6,7 Similar limitations apply to the use of hormones or other regulatory factors, such as lymphokines and growth factors, synthesized by recombinant DNA technology, which are often immunogenic8 probably because of small differences in their conformational characteristics or in their glycosidic constituents in relation to their natural, human counterparts.