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

In order to investigate the feasibility of shuffling effector function s of monoclonal antibodies, we constructed chimeric antibodies with fu sed heavy chains. The derivatives studied are based on a monoclonal an tibody directed against the alpha chain of the human Il2-R. Derivative s studied were the IgG1 and IgM isotypes; IgM Delta, lacking the abili ty of multimerization due to a deletion; IgMc gamma 1 and IgG1c mu, wi th fused mu and gamma 1 chains and vice versa. IgG1, IgM Delta and IgM c 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 b inding to the Il2-R were markedly lower for polymeric than for monomer ic derivatives (300-400 pM versus 2500-6500 pM). Recruitment of comple ment mediated by the deposition of C3 fragments, either of heterologou s (rabbit) or homologous (human) origin, was mediated only by the poly meric derivatives IgM and IgGlc mu. ADCC was mediated by monomeric IgG 1 and polymeric IgG1c mu, the latter derivative being active at concen trations 100-fold lower than the former. Together, the results demonst rate that both CDC and ADCC effector functions can be combined on a po lymeric antibody derivative with fused gamma 1 and mu chains. In addit ion, such a derivative, due to its polymeric nature, has a high bindin g affinity. These properties may be important for the elimination of t arget cells in vivo.