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.
(© 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)