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A1.84 Switching off B cells by Fc-engineered anti-CD19 antibody (XmAb5871)
  1. Daniel Szili1,
  2. Marcell Cserhalmi1,
  3. Zsuzsanna Bankó1,
  4. Gyorgy Nagy2,
  5. David E Szymkowski3,
  6. Gabriella Sármay1
  1. 1Department of Immunology, Eötvös Loránd University, Budapest, Hungary;
  2. 2Department of Rheumatology, Buda Hospital of Hospitaller Brothers of St. John, Budapest, Hungary
  3. 3Xencor Inc., Monrovia, CA USA

Abstract

Background and Objectives CD19 is a B cell-specific marker present on pre-B cells, immature and mature B cells but lacking on plasma cells. CD19 is a positive co-receptor of B cell receptors (BCR) and a target of the tyrosine kinase Lyn in activated B cells. Phosphorylated CD19 recruits Lyn, PI3K and Vav, enhancing B cell activation. In contrast, FcgRIIb is also a target of Lyn, but when co-engaged with BCR is phosphorylated, recruits SHP2 and SHIP phosphatases, and inhibits B cell activation. XmAb5871 is an Fc engineered anti-CD19 that binds to FcgRIIb with approximately 400 higher affinity as compared to its native IgG1 Fc counterpart (Horton HM et al. J. Immunol. 2011, 186:4223-4233). Our aim was to clarify if Fc-engineered CD19 antibody amplifying the FcgRIIb-mediated inhibitory pathway in activated B cells is able to inhibit not only BCR-mediated but also TLR9-stimulated signals. The innate receptor TLR9 plays a role in the etiology of systemic autoimmune diseases by lowering the signalling threshold of B cells. An agent that could inhibit both BCR- and TLR9-mediated signals may block autoantibody production without B cell depletion, and have therapeutic potential in systemic autoimmune diseases.

Materials and Methods We studied early and late signalling events in B cells purified from human blood or tonsils by negative selection. The cells were stimulated by single, double or triple combined signals via BCR, TLR9 and CD19. We monitored the phosphorylation of FcgRIIb and ERK, induction of the activation marker CD38, cell proliferation, cytokine and antibody production of B cells.

Results We show that XmAb5871 decreases BCR-induced ERK and AKT activation in B cells. In functional assays, we found that cell proliferation, plasma cell differentiation and cytokine production induced by the combined BCR and TLR9-mediated signals were inhibited by XmAb5871. The synergistically enhanced secretion of IL-6, IL-10 and TNFα induced by the BCR and TLR9 double signals was almost completely blocked by XmAb5871. Moreover, the Fc-engineered anti-CD19 inhibited the differentiation of citrullinated filaggrin peptide-specific antibody-forming cells from rheumatoid arthritis patients.

Conclusion These data indicate that an Fc-engineered anti-CD19 antibody amplifying FcgRIIb inhibits activated B cells including autoantibody as well as cytokine production, and thus might be a useful new therapeutic strategy to suppress pathogenic B cells in autoimmune disease.

Acknowledgement The work was supported by the National Development Agency OTKA 80689 fund.

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