Next-generation Fc receptor-targeting biologics for autoimmune diseases

Abstract

In recent years, there has been a surge in the research and development of novel molecules as potential therapeutic alternatives to traditional treatments (such as intravenous immunoglobulins) for autoimmune disorders. The aim of this review is to describe different drug development strategies and evaluate how various molecules have performed in clinical trials to date. Broadly, three main approaches have been pursued. Recombinant fragment crystallisable (rFc) multimers primarily target Fcγ receptors (FcγRs) but may also affect the complement system. These include PF-06755347 (GL-2045), CSL730 (M230), CSL777 and Pan Fc Receptor Interacting Molecule (PRIM). Neonatal Fc receptor (FcRn)-targeting therapeutics block the FcRn receptor and are represented by candidate drugs such as the Fc fragment efgartigimod and the monoclonal antibodies rozanolixizumab (UCB7665), M281 and SYNT001. Finally, Fc and FcγR-targeting therapeutics, comprise molecules that target the Fc of IgG, such as the recombinant soluble FcγIIb receptor valziflocept (SM101/SHP652) and various monoclonal antibodies directed against the receptors. The developmental status of these three classes of molecules ranges from preclinical to ongoing phase 3 clinical studies. Efgartigimod and rozanolixizumab are the most advanced and have demonstrated encouraging results from phase 2 trials in immune thrombocytopenia and myasthenia gravis. Although initial results are promising, further long-term data and a better understanding of the unique mechanisms of action of the different molecules are needed. The efficacy, safety, convenience of administration, duration of effects, and cost will all contribute to determining which of the molecules will be successful in the clinic.

Keywords: Autoimmune disease; Fcγ receptor; Monoclonal antibodies; Neonatal Fc receptor; Recombinant Fc multimers.