Mabs. 2014 July-Aug;6(4):991-9.

Suppression of innate and adaptive B cell activation pathways by antibody coengagement of FcγRIIb and CD19.

Szili D1, Cserhalmi M1, Bankó Z1, Nagy G2, Szymkowski DE3, Sármay G1

1Department of Immunology; Eötvös Loránd University; Budapest, Hungary

2Department of Rheumatology; Polyclinic of the Hospitaller Brothers of St. John of God; Budapest, Hungary

3Xencor Inc.; Monrovia, CA USA

 

ABSTRACT

The Fc receptor (FcγRIIb) inhibits B cell responses when coengaged with B cell receptor (BCR), and has become a target for new autoimmune disease therapeutics. For example, BCR and FcγRIIb coengagement via the Fc-engineered anti-CD19 XmAb5871 suppresses humoral immune responses. We now assess effects of XmAb5871 on other activation pathways, including the pathogen-associated molecular pattern receptor, TLR9. Since TLR9 signaling is implicated in autoimmune diseases, we asked if XmAb5871 could inhibit TLR9 stimulation. We show that XmAb5871 decreases ERK and AKT activation, cell proliferation, cytokine, and IgG production induced by BCR and/or TLR9 signals. XmAb5871 also inhibited differentiation of citrullinated peptide-specific plasma cells from rheumatoid arthritis (RA) patients. XmAb5871 may therefore have potential to suppress pathogenic B cells in autoimmune diseases.

 

SUPPLEMENTARY:

FcγRIIb is a low affinity receptor for the Fc part of IgG on B cells. The coengagement of the antigen-specific B cell receptor (BCR) and FcγRIIb by an immune complex suppresses B cell activation thus downregulates antigen-specific immune response (Fig. 1A). In order to mimic the inhibitory effect of immune complexes, Xencor Inc. had modified the Fc part of an anti-human CD19 antibody to enhance its binding affinity to FcγRIIb (XmAb5871) (Fig. 1B) [1]. XmAb5871 has >400 higher affinity to FcγRIIb than its wild type counterpart and is now in clinical trials as a treatment for RA.

 

fig1

Figure. 1. XmAb5871 mimics the inhibitory function of immune complexes, and besides BCR-delivered signals, it also suppresses TLR9-mediated stimulation of human B cells.

 

Besides BCR, Toll like receptor 9 (TLR9) plays a crucial role in breaking tolerance since it may rescue B cells from apoptosis and induce signals leading to proliferation, cytokine and antibody production. Therefore we decided to assess the inhibitory potential of XmAb5871 both on BCR- and TLR9-mediated activation of primary human B cells.

We have shown that XmAb5871 induces a robust phosphorylation of FcγRIIb, which is a prerequisite of the inhibition. Since BCR and TLR9 induce partly different activation pathways that meet at the level of MAPK activation [2], and the interaction between FcγRIIb and TLR9 on B cells has not yet been studied, we aimed to examine co-signaling between BCR, TLR9 and FcγRIIb, and its functional consequences on B cells.

XmAb5871 successfully reduced BCR- and/or TLR9-induced proliferation, cytokine production and plasma cell differentiation. Since anti-citrullinated protein/peptide-specific antibodies (ACPAs) play a central role in the pathogenesis of RA, we have measured the inhibitory effect of XmAb5871 on the antibody response against the RA-specific citrullinated filaggrin peptide. XmAb5871 significantly diminished the number of citrullinated filaggrin peptide-specific spots, indicating that FcγRIIb-dependent inhibition of B cells may indeed block autoantibody production (Fig. 2) [3].

 

 

fig2

Figure. 2. XmAb5871 activates the inhibitory machinery of FcγRIIb, resulting in the inhibition of BCR- and TLR9-mediated responses.

 

Collectively, XmAb5871 has at least three simultaneous mechanisms of action: it inhibits proliferation, cytokine and antibody production of B cells. We provide data that activating FcγRIIb with XmAb5871 not only inhibits BCR-dependent activation, but also diminishes TLR9-mediated response as well. In addition, XmAb5871 hampers B cell functions without B cell depletion [1, 4], thus it has a potential as an alternative B cell suppressive therapy in autoimmune diseases such as RA.

 

REFRENCES:

  1. Chu, S.Y., et al., Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcgRIIb with Fc-engineered antibodies. Mol Immunol, 2008. 45(15): p. 3926-33.
  2. Szili, D., et al., TGFbeta activated kinase 1 (TAK1) at the crossroad of B cell receptor and Toll-like receptor 9 signaling pathways in human B cells. PLoS One, 2014. 9(5): p. e96381.
  3. Szili, D., et al., Suppression of innate and adaptive B cell activation pathways by antibody coengagement of FcgammaRIIb and CD19. MAbs, 2014. 6(4): p. 991-9.
  4. Horton, H.M., et al., Antibody-mediated coengagement of FcgRIIb and B cell receptor complex suppresses humoral immunity in systemic lupus erythematosus. J Immunol, 2011. 186(7): p. 4223-33.

 

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