Mechanistic modeling of a human IgG(4) monoclonal antibody (tralokinumab) Fab‐arm exchange with endogenous IgG(4) in healthy volunteers

Therapeutic IgG(4) antibodies engage in Fab‐arm exchange with endogenous human immunoglobulin G4 (IgG(4)) to form monovalent hybrid molecules. A mechanistic population model was developed to quantitatively characterize the dynamic Fab‐arm exchange of tralokinumab, a human IgG(4) monoclonal antibody currently being developed for the treatment of atopic dermatitis, with endogenous IgG(4) in healthy volunteers. The estimated pharmacokinetic parameters for IgG(4) were similar to those of immunoglobulin G1 or immunoglobulin G2 in humans. However, the mechanistically modeled clearance of half molecules is 21‐fold higher, likely due to the loss of avidity for the neonatal Fc receptor. Half molecules of tralokinumab randomly associate with those of endogenous IgG(4) to form monovalent hybrid molecules, which became the dominant form of tralokinumab within 1 day postdose in healthy volunteers. As the potency of monovalent tralokinumab is comparable with that of bivalent tralokinumab, the IgG(4) Fab‐arm exchange with endogenous IgG(4) is not expected to affect the potency of neutralization of interleukin‐13 in vivo.