Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics

Abstract

Nearly 350 IgG-based therapeutics are approved for clinical use or are under development for many diseases lacking adequate treatment options. These include molecularly engineered biologicals comprising the IgG Fc-domain fused to various effector molecules (so-called Fc-fusion proteins) that confer the advantages of IgG, including binding to the neonatal Fc receptor (FcRn) to facilitate in vivo stability, and the therapeutic benefit of the specific effector functions. Advances in IgG structure-function relationships and an understanding of FcRn biology have provided therapeutic opportunities for previously unapproachable diseases. This article discusses approved Fc-fusion therapeutics, novel Fc-fusion proteins and FcRn-dependent delivery approaches in development, and how engineering of the FcRn–Fc interaction can generate longer-lasting and more effective therapeutics.

High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer

“…We also noted that the scFvD2 antibody formats did not present any detectable agonist activity at the concentration tested. In the context of the potential therapeutic application the Fc-fusion format shows several advantages, including higher tumor uptake due to prolonged circulation half-life, Fc-mediated effector functions (47) and convenient drug conjugation possibilities (30).…”

Monomeric IgG1 Fc molecules displaying unique Fc receptor interactions that are exploitable to treat inflammation-mediated diseases

“…[3][4][5] One very promising field that could benefit from Fc engineering is the development of therapeutic Fc-fusion proteins. [6][7][8] There are currently six Fc fusion proteins approved by the US Food and Drug Administration for clinical use, and many more are in clinical trials. A major advantage of Fc fusion is the half-life extension to biologically active proteins, which usually display very short half-life and would otherwise be quickly eliminated in vivo.…”

Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A

“…6 Fc fusion prolongs the half-life of rFVIIIFc by utilizing the neonatal Fc receptor and endogenous IgG recycling pathway, which delays lysosomal degradation of IgG and Fc fusion proteins, and cycles them back into the circulation. 2,7 The pharmacokinetics and safety of rFVIIIFc were previously evaluated in a single-dose phase 1/2a study in severe hemophilia A. 8 Here, we report the results of a phase 3 open-label, multicenter, partially randomized study that evaluated the comparative pharmacokinetics of rFVIIIFc and rFVIII, and the safety, tolerability, and efficacy of repeated rFVIIIFc dosing for prophylaxis, treatment of acute bleeding, and perioperative management in previously treated adolescents and adults with hemophilia A.…”

“…3 Extending FVIII half-life can reduce injection frequency, which may lessen treatment burden, improve compliance with prophylaxis, and positively impact therapeutic outcomes. 1,2,4,5 A protein composed of a single molecule of recombinant FVIII (rFVIII) covalently fused to the Fc domain of IgG 1 , recombinant FVIII Fc fusion protein (rFVIIIFc) (efraloctocog alfa), has been developed. 6 Fc fusion prolongs the half-life of rFVIIIFc by utilizing the neonatal Fc receptor and endogenous IgG recycling pathway, which delays lysosomal degradation of IgG and Fc fusion proteins, and cycles them back into the circulation.…”