CHIMERIC INTERLEUKIN-2 RECEPTOR-ALPHA CHAIN ANTIBODY DERIVATIVES WITH FUSED MU-CHAINS AND GAMMA-CHAINS PERMIT IMPROVED RECRUITMENT OF EFFECTOR FUNCTIONS

In order to investigate the feasibility of shuffling effector functions of monoclonal antibodies, we constructed chimeric antibodies with fused heavy chains. The derivatives studied are based on a monoclonal antibody directed against the alpha chain of the human Il2-R. Derivatives studied were the IgG1 and IgM isotypes; IgM Delta, lacking the ability of multimerization due to a deletion; IgMc gamma 1 and IgG1c mu, with fused mu and gamma 1 chains and vice versa. IgG1, IgM Delta and IgMc gamma 1 were secreted as monomers, IgM and IgG1c mu as polymers. The K-i values for competition with radio-iodinated Il2 with respect to binding to the Il2-R were markedly lower for polymeric than for monomeric derivatives (300-400 pM versus 2500-6500 pM). Recruitment of complement mediated by the deposition of C3 fragments, either of heterologous (rabbit) or homologous (human) origin, was mediated only by the polymeric derivatives IgM and IgGlc mu. ADCC was mediated by monomeric IgG1 and polymeric IgG1c mu, the latter derivative being active at concentrations 100-fold lower than the former. Together, the results demonstrate that both CDC and ADCC effector functions can be combined on a polymeric antibody derivative with fused gamma 1 and mu chains. In addition, such a derivative, due to its polymeric nature, has a high binding affinity. These properties may be important for the elimination of target cells in vivo.