Changes in complementarity-determining regions significantly alter IgG binding to the neonatal Fc receptor

A large body of data exists demonstrating the key role of FcRn in extending the half-life of therapeutic antibodies by rescuing them from lysosomal degradation. This led to the widely accepted hypothesis that FcRn binding of an IgG via the CH2-CH3 interface of Fc correlates with IgG half-life. Several studies have demonstrated that in vivo half-life can be modified by changing the binding affinity of IgG to FcRn. These modifications were generated by mutating the coding sequence for the Fc region that resulted in enhanced or reduced FcRn binding at endosomal pH without enhancing binding at neutral pH. In contrast to this, we have observed that the half-lifes of IgG molecules that had showed no target-mediated disposition or off-target binding varies widely, even when they share identical Fc domains. This led us to hypothesize that domains of IgG molecules other than Fc could contribute to the modulation of FcRn binding and affect in vivo half-life. This hypothesis was strengthened by recent publications by other groups showing a correlation between antibody charge and the FcRn affinity and/or in vivo half-life.