Scientific Publications by FDA Staff

AAPS J 2019 May 6;21(4):62

Fc-Fusion drugs have FcgammaR/C1q binding and signaling properties that may affect their immunogenicity.

Lagasse HAD, Hengel H, Golding B, Sauna ZE

Fusing the human immunoglobulin G1 (IgG1) constant region (Fc-domain) to therapeutic proteins or peptides increases their circulating plasma half-life via neonatal Fc receptor (FcRn) binding and recycling. However, Fc-mediated interactions with other molecules including complement C1q and Fc gamma receptors (FcgammaRs) can have immunological consequences and the potential to modulate the immunogenicity of Fc-fusion therapeutics. In a comparative study, we carried out a comprehensive assessment of Fc-mediated interactions for five FDA-approved Fc-fusion therapeutics. C1q binding and complement activation were measured by ELISA, while FcgammaR binding and signaling were evaluated using BW5147:FcgammaR-zeta reporter cell lines. We demonstrate that FIX-Fc and FVIII-Fc bound C1q as well as activating and inhibitory FcgammaRs (I, IIA, IIB, IIIA). These coagulation factor Fc-fusions also signaled via FcgammaRIIIA, and to a lesser extent via FcgammaRI and FcgammaRIIB. TNFR-Fc and CTLA4-Fc bound FcgammaRI, while TNFR-Fc also bound FcgammaRIIIA, but these interactions did not result in FcgammaR signaling. Our comprehensive assessment demonstrates that (i) different Fc-fusion drugs have distinct C1q/FcgammaR binding and signaling properties, (ii) FcgammaR binding does not predict signaling, and (iii) the fusion partner (effector molecule) can influence Fc-mediated interactions.