Biophysical differences in IgG1 Fc-based therapeutics relate to their cellular handling, interaction with FcRn and plasma half-life

Analysis of clinically approved antibody-based therapeutics reveals different structural designs, such as full-length IgG1 or Fc-fusions, entail distinct biophysical properties that affect FcRn binding, intracellular transport and plasma half-life. Antibody-based therapeutics (ABTs) are used to treat a range of diseases. Most ABTs are either full-length IgG1 antibodies or fusions between for instance antigen (Ag)-binding receptor domains and the IgG1 Fc fragment. Interestingly, their plasma half-life varies considerably, which may relate to how they engage the neonatal Fc receptor (FcRn). As such, there is a need for an in-depth understanding of how different features of ABTs affect FcRn-binding and transport behavior. Here, we report on how FcRn-engagement of the IgG1 Fc fragment compare to clinically relevant IgGs and receptor domain Fc fusions, binding to VEGF or TNF-alpha. The results reveal FcRn-dependent intracellular accumulation of the Fc, which is in line with shorter plasma half-life than that of full-length IgG1 in human FcRn-expressing mice. Receptor domain fusion to the Fc increases its half-life, but not to the extent of IgG1. This is mirrored by a reduced cellular recycling capacity of the Fc-fusions. In addition, binding of cognate Ag to ABTs show that complexes of similar size undergo cellular transport at different rates, which could be explained by the biophysical properties of each ABT. Thus, the study provides knowledge that should guide tailoring of ABTs regarding optimal cellular sorting and plasma half-life.

Automated summary

The analysis of clinically approved antibody-based therapeutics reveals that different structural designs have distinct biophysical properties affecting FcRn binding, intracellular transport, and plasma half-life. Understanding the impact of different features of antibody-based therapeutics on FcRn binding and transport is crucial for optimizing cellular sorting and plasma half-life. This study compares the FcRn engagement of IgG1 Fc fragment to clinically relevant IgGs and receptor domain Fc fusions, binding to VEGF or TNF-alpha, and provides insights into their intracellular accumulation, plasma half-life, and cellular transportation.