SignificanceTherapeutic antibodies of the immunoglobulin G (IgG) isotype show a pharmacokinetic (PK) profile that is strongly mediated by the interaction with the neonatal Fc receptor (FcRn). Therefore, modulating the FcRn–IgG interaction allows altering PK characteristics of therapeutic antibodies. So far, engineering the crystallizable fragment (Fc) is known to affect PK, and, although the influence of the antigen binding fragment (Fab) on FcRn interactions has been reported, the underlying mechanism remains unknown. Here, we demonstrate that the charge distribution in the distal variable fragment (Fv) of IgGs is involved in excessive binding to the FcRn, thereby reducing FcRn-dependent terminal half-lives in vivo. These findings contribute to a better understanding of the FcRn–IgG interaction.

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This study shows that not all protein drug aggregates are equally immunogenic.

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