The discovery of monoclonal antibodies by Kohler and Milstein in 1975 sparked the generation of novel drugs that could be used to antagonize functional receptors of the immune system. The anti-CD3 antibody, OKT3, was the first of these drugs to be exploited clinically in the treatment of acute allograft rejection. Although the antibody was efficacious, neutralizing immunogenicity and, in particular, the often severe “flu-like” cytokine-release syndrome associated with initial doses of the antibody limited its application to other indications. As a consequence, the emergence of other immune-modulating CD3 or T cell-directed antibodies as therapeutics took a surprisingly long time. Three scientific developments rekindled interest in immune-modulating therapeutic antibodies resulting in many more antibody candidates entering clinical trials. The first development was the discovery that co-receptor CD4 antibodies could be used to tolerize to other proteins, thus establishing tolerance as a therapeutic paradigm. The second development was the discovery that rodent antibodies could be reengineered or reshaped to minimize their immunogenicity. Finally, the third development was the discovery that transplantation tolerance induced by co-receptor blockade was “dominant” and dependent on the induction of CD4+ regulatory T cells through so-called infectious tolerance. These findings together suggested that antibodies might be used sparingly to recruit the host's own tolerance mechanisms without evoking neutralizing responses.

Further studies in transplant models indicated that anti-CD4 therapeutic antibodies alone were insufficient when CD8+ T cells were also involved. In those circumstances, antagonism of CD8 function was also required.