The AAPS Journal

, 21:62 | Cite as

Fc-Fusion Drugs Have FcγR/C1q Binding and Signaling Properties That May Affect Their Immunogenicity

  • H. A. Daniel Lagassé
  • Hartmut Hengel
  • Basil Golding
  • Zuben E. SaunaEmail author
Research Article


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 (FcγRs) 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 FcγR binding and signaling were evaluated using BW5147:FcγR-ζ reporter cell lines. We demonstrate that FIX-Fc and FVIII-Fc bound C1q as well as activating and inhibitory FcγRs (I, IIA, IIB, IIIA). These coagulation factor Fc-fusions also signaled via FcγRIIIA, and to a lesser extent via FcγRI and FcγRIIB. TNFR-Fc and CTLA4-Fc bound FcγRI, while TNFR-Fc also bound FcγRIIIA, but these interactions did not result in FcγR signaling. Our comprehensive assessment demonstrates that (i) different Fc-fusion drugs have distinct C1q/FcγR binding and signaling properties, (ii) FcγR binding does not predict signaling, and (iii) the fusion partner (effector molecule) can influence Fc-mediated interactions.


Fc-fusion Immunogenicity Fc gamma receptors Complement C1q 



B.G. and Z.E.S. are funded by intramural grants from the US FDA. We thank Biogen for providing the coagulation factor Fc-fusions (FIX-Fc [efmoroctocog alfa] and FVIII-Fc [eftrenonacog alfa]) through a Material Transfer Agreement.

Compliance with Ethical Standards


My comments are an informal communication and represent my own best judgment. These comments do not bind or obligate FDA.


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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • H. A. Daniel Lagassé
    • 1
  • Hartmut Hengel
    • 2
    • 3
  • Basil Golding
    • 1
  • Zuben E. Sauna
    • 1
    Email author
  1. 1.Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced TherapiesCenter for Biologics Evaluation and Research, US Food and Drug AdministrationSilver SpringUSA
  2. 2.Institute of VirologyUniversity Medical CenterFreiburgGermany
  3. 3.Faculty of MedicineAlbert-Ludwigs-UniversityFreiburgGermany

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