Skip to main content
SpringerLink
Log in

The FcγR/IgG Interaction as Target for the Treatment of Autoimmune Diseases

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

FcγRs are a crucial component of the antibody response as they mediate the cellular effector functions in response to IgG-containing immune complexes (ICs). Therefore, they also play a central role in the pathogenesis of autoimmune diseases which offers an attractive option to specifically target this class of molecules and their interaction with IgG for treatment of immune disorders. In detail, two strategies are discussed in this article. SM101, a soluble FcγR that is already in clinical development competes with the interaction of IgG with membrane FcγRs. Oppositely, SM201 recruits the inhibitory FcγRIIB for a broad down-modulation of the immune system. The presented approaches for the treatment of autoimmune diseases have the potential be more efficacious with fewer side effects than the currently used therapeutic options.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Nimmerjahn F, Ravetch JV. Fcγ receptors as regulators of immune responses. Nat Rev Immunol. 2008;8:34–47.

    Article  CAS  PubMed  Google Scholar 

  2. Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. 2014. doi:10.3389/fimmu.2014.00520.

    PubMed  PubMed Central  Google Scholar 

  3. Jefferis R. Glycosylation as a strategy to improve antibody-based therapeutics. Nat Rev Drug Discov. 2009;8:226–34.

    Article  CAS  PubMed  Google Scholar 

  4. Schmidt RE, Gessner JE. Fc receptors and their interaction with complement in autoimmunity. Immunol Lett. 2005;100:56–67.

    Article  CAS  PubMed  Google Scholar 

  5. Pricop L, Redecha P, Teillaud J-L, Frey J, Fridman WH, Sautes-Fridman C, et al. Differential modulation of stimulatory and inhibitory Fc receptors on human monocytes by Th1 and Th2 cytokines. J Immunol. 2001;166:531–7.

    Article  CAS  PubMed  Google Scholar 

  6. Takai T. Roles of Fc receptors in autoimmunity. Nat Rev Immunol. 2002;2:580–92.

    CAS  PubMed  Google Scholar 

  7. van de Winkel JG, Capel PJ. Human IgG Fc receptor heterogeneity: molecular aspects and clinical implications. Immunol Today. 1993;14:215–21.

    Article  PubMed  Google Scholar 

  8. de la Salle C, Esposito-Farese M-E, Bieber T, Moncuit J, Morales M, Wollenberg A, et al. Release of soluble FcgammaRII/CD32 molecules by human Langerhans cells: a subtle balance between shedding and secretion? J Investig Dermatol. 1992;99:15S–7S.

    Article  PubMed  Google Scholar 

  9. Rappaport EF, Cassel DL, Walterhouse DO, McKenzie SE, Surrey S, Keller MA, et al. A soluble form of the human Fc receptor Fc gamma RIIA: cloning, transcript analysis and detection. Exp Hematol. 1993;21:689–96.

    CAS  PubMed  Google Scholar 

  10. Calvo CF, Watanabe S, Mètivier D, Senik A. Human monocyte cell line (U937) releases suppressive IgG-binding factor(s). Eur J Immunol. 1986;16:25–30.

    Article  CAS  PubMed  Google Scholar 

  11. Bazil V, Strominger JL. Metalloprotease and serine protease are involved in cleavage of CD43, CD44, and CD16 from stimulated human granulocytes. Induction of cleavage of L-selectin via CD16. J Immunol. 1994;152:1314–22.

    CAS  PubMed  Google Scholar 

  12. Fridman WH, Golstein P. Immunoglobulin-binding factor present on and produced by thymus-processed lymphocytes (T cells). Cell Immunol. 1974;11:442–55.

    Article  CAS  PubMed  Google Scholar 

  13. Ierino FL, Powell MS, McKenzie IF, Hogarth PM. Recombinant soluble human Fc gamma RII: production, characterization, and inhibition of the Arthus reaction. J Exp Med. 1993;178:1617–28.

    Article  CAS  PubMed  Google Scholar 

  14. Varin N, Sautès C, Galinha A, Even J, Hogarth PM, Fridman WH. Recombinant soluble receptors for the Fcγ portion inhibit antibody productionin vitro. Eur J Immunol. 1989;19:2263–8.

    Article  CAS  PubMed  Google Scholar 

  15. Sautès C, Galinha A, Bouchard C, Mazières N, Spagnoli R, Fridman WH. Recombinant soluble Fcγ receptors: production, purification and biological activities. J Chromatogr B Biomed Sci Appl. 1994;662:197–207.

    Article  Google Scholar 

  16. Watanabe H, Sherris D, Gilkeson GS. Soluble CD16 in the treatment of murine lupus nephritis. Clin Immunol Immunopathol. 1998;88:91–5.

    Article  CAS  PubMed  Google Scholar 

  17. Galon J, Bouchard C, Fridman WH, Sautès C. Ligands and biological activities of soluble Fcγ receptors. Immunol Lett. 1995;44:175–81.

    Article  CAS  PubMed  Google Scholar 

  18. Sondermann P, Jacob U. Human Fc gamma receptor IIb expressed in Escherichia coli reveals IgG binding capability. Biol Chem. 1999;380:717–21.

    Article  CAS  PubMed  Google Scholar 

  19. Sondermann P, Jacob U, Kutscher C, Frey J. Characterization and crystallization of soluble human Fcγ receptor II (CD32) isoforms produced in insect cells. Biochemistry. 1999;38:8469–77.

    Article  CAS  PubMed  Google Scholar 

  20. Maenaka K, van der Merwe PA, Stuart DI, Jones EY, Sondermann P. The human low affinity Fcgamma receptors IIa, IIb, and III bind IgG with fast kinetics and distinct thermodynamic properties. J Biol Chem. 2001;276:44,898–904.

    Article  CAS  Google Scholar 

  21. Sondermann P, Huber R, Jacob U. Crystal structure of the soluble form of the human Fcgamma -receptor IIb: a new member of the immunoglobulin superfamily at 1.7 A resolution. EMBO J. 1999;18:1095–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sondermann P, Huber R, Oosthuizen V, Jacob U. The 3.2-Å crystal structure of the human IgG1 Fc ragment–FcγRIII complex. Nature. 2000;406:267–73.

  23. Werwitzke S, Trick D, Sondermann P, Kamino K, Schlegelberger B, Kniesch K, et al. Treatment of lupus-prone NZB/NZW F1 mice with recombinant soluble Fc receptor II (CD32). Ann Rheum Dis. 2008;67:154–61.

    Article  CAS  PubMed  Google Scholar 

  24. Magnusson SE, Andrén M, Nilsson KE, Sondermann P, Jacob U, Kleinau S. Amelioration of collagen-induced arthritis by human recombinant soluble FcγRIIb. Clin Immunol. 2008;127:225–33.

    Article  CAS  PubMed  Google Scholar 

  25. Iwata H, Pipi E, Möckel N, Sondermann P, Vorobyev A, Beek NV, et al. Recombinant soluble CD32 suppresses disease progression in experimental epidermolysis bullosa acquisita. J Investig Dermatol. 2015;135:916–9.

    Article  CAS  PubMed  Google Scholar 

  26. Smith KGC, Clatworthy MR. FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat Rev Immunol. 2010;10:328–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tillmanns S, Sondermann P, Schrödter A, Schubert C, Nilius S, Buckel P. Soluble Fc-gamma IIb receptor SM101 as potential therapy in autoimmune diseases – results from a Phase 0/Ia clinical trial in healthy volunteers. Ann Rheum Dis. 2011;70:618.

    Google Scholar 

  28. Konstaninova TS, Leonidovna IV, Hellmann A, Kyrcz-Krzemien S, Tillmanns S, Sondermann P, et al. Interim results from a phase Ib/IIa clinical trial with the soluble Fc-gamma IIb receptor SM101 for the treatment of primary immune thrombocytopenia. Blood. 2012;120:3388.

    Google Scholar 

  29. Tillmanns S, Kolligs C, DP D’C, Doria A, Hachulla E, Voll RE, et al. SM101, a novel recombinant, soluble, human Fc gamma IIb receptor, in the treatment of systemic lupus erythematosus: results of a double-blind, placebo-controlled multicenter study. Arthritis Rheum. 2014;66:S1238.

    Google Scholar 

  30. Idusogie EE, Presta LG, Gazzano-Santoro H, Totpal K, Wong PY, Ultsch M, et al. Mapping of the C1q binding site on Rituxan, a chimeric antibody with a human IgG1 Fc. J Immunol. 2000;164:4178–84.

    Article  CAS  PubMed  Google Scholar 

  31. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7:715–25.

    Article  CAS  PubMed  Google Scholar 

  32. Weflen AW, Baier N, Tang Q-J, Van den Hof M, Blumberg RS, Lencer WI, et al. Multivalent immune complexes divert FcRn to lysosomes by exclusion from recycling sorting tubules. Mol Biol Cell. 2013;24:2398–405.

  33. Sondermann P, Oosthuizen V. X-ray crystallographic studies of IgG-FcγR interactions. Biochem Soc Trans. 2002;30:481–6.

    Article  CAS  PubMed  Google Scholar 

  34. Chen W, Nordstrom J, Burke S, Shah K, Ciccarone V, Li H, et al. Development of human B-lymphocyte targeted bi-specific DART® molecules for the treatment of autoimmune disorders (THER5P. 830). J Immunol. 2014;192(1 Supplement):200–9.

    Google Scholar 

  35. Chu SY, Yeter K, Kotha R, Pong E, Miranda Y, Phung S, et al. Suppression of rheumatoid arthritis B cells by XmAb5871, an anti-CD19 antibody that coengages B cell antigen receptor complex and Fcγ receptor IIb inhibitory receptor. Arthritis Rheum. 2014;66:1153–64.

    Article  CAS  Google Scholar 

  36. Rieth N, Carle A, Müller M, Meer DT, Direnberger C, Pohl T, et al. Characterization of SM201, an anti-hFcγRIIB antibody not interfering with ligand binding that mediates immune complex dependent inhibition of B cells. Immunol Lett. 2014;160:145–50.

    Article  CAS  PubMed  Google Scholar 

  37. Pearse RN, Kawabe T, Bolland S, Guinamard R, Kurosaki T, Ravetch JV. SHIP recruitment attenuates FcγRIIB-induced B cell apoptosis. Immunity. 1999;10:753–60.

    Article  CAS  PubMed  Google Scholar 

  38. Xiang Z, Cutler AJ, Brownlie RJ, Fairfax K, Lawlor KE, Severinson E, et al. FcγRIIb controls bone marrow plasma cell persistence and apoptosis. Nat Immunol. 2007;8:419–29.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The author likes to thank Nicole Rieth for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. SuppreMol GmbH, Am Klopferspitz 19a, Martinsried, D-82152, Germany

    Peter Sondermann

Authors
  1. Peter Sondermann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Sondermann.

Additional information

SuppreMol GmbH is a wholly-owned subsidiary of Baxalta Incorporated.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sondermann, P. The FcγR/IgG Interaction as Target for the Treatment of Autoimmune Diseases. J Clin Immunol 36 (Suppl 1), 95–99 (2016). https://doi.org/10.1007/s10875-016-0272-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-016-0272-7

Keywords

Search

Navigation