A Novel Role for Galectin-3 Binding Protein in B Cell Biology and Antibody Secretion

Shinji Okitsu¹, Melinda Genest¹, Nuruddeen Lewis¹, Evgeni Tzvetkov¹, Yin Wu², Andrew Bender¹, Arnon Arazi³, Thomas Eisenhaure³, Edward Browne⁴, Alex Rolfe⁵, Jonathan Derry⁶, William Pendergraft III⁷, Nir Hacohen⁸, Julie DeMartino⁵ and Jaromir Vlach⁵, ¹TIP Immunology, EMD Serono Research and Development Institute, Billerica, MA, ²TIP Immunology, EMD Serono Research & Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, ³Broad Institute, Cambridge, MA, ⁴Massachusetts General Hospital, Boston, MA, ⁵EMD Serono Research and Development Institute, Billerica, MA, ⁶Iris Bioconsulting, Bainbridge Island, WA, ⁷Kidney Center, University of North Carolina, Chapel Hill, NC, ⁸Harvard Medical School, Boston, MA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: B cell targeting, B cells, Gene Expression, Lupus and basic research

Session Information

Date: Sunday, November 5, 2017

Title: B Cell Biology and Targets in Autoimmune Disease Poster

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Antibodies are important in protection against pathogens, but also harbor the potential to cause autoimmune disease when directed against self-antigens. Systemic lupus erythematosus (SLE) is an autoimmune disease where antibodies recognizing nucleic acids and associated proteins form immune complexes that drive inflammation and disease progression. Consequently, targeting B cells and antibody production is a main focus in SLE drug development and we have endeavored to discover new targets in this pathway.

Methods: Here we show results from screening a secreted protein library for effects on Ig secretion by primary human B cells.

Results: We identified galectin-3 binding protein (G3BP) as a soluble factor that enhances antibody production induced by a variety of stimuli in vitro. In an orthogonal translational study we found that the G3BP gene (LGALS3BP) was one of the most upregulated genes across 14 different immune cell types isolated from lupus nephritis (LN) patient blood. LGALS3BP contains an IRF7 binding site in its promoter and we observed increased expression in TLR7-stimulated PBMCs. SLE is characterized by RNAs that induce type I interferon (IFN) inflammation through the innate receptor TLR7. LGALS3BP expression in LN patients correlated with type I interferon-inducible genes indicating that G3BP is part of this pathological process. Indeed, in support of this hypothesis, other investigators have documented upregulated LGALS3BP in active IFN high SLE patients versus healthy controls (Merrill, J.T. et al., ACR abstract 1809, 2013). We found the same LGALS3BP upregulation and correlation with type I IFN in a mouse model of LN. Moreover, upregulation in mouse kidneys correlated with nephritis development. In in vitro studies we found that antibodies against G3BP led to defects in human B cell survival and loss of antibody production.

Conclusion: We hypothesize that targeting G3BP may be a novel approach to inhibit autoantibody production and may benefit patients suffering from antibody-mediated autoimmune diseases, including lupus nephritis.

Disclosure: S. Okitsu, EMD Serono Inc., 3,EMD Serono Inc, 1; M. Genest, EMD Serono Inc, 3; N. Lewis, EMD Serono Inc, 3; E. Tzvetkov, EMD Serono Inc, 3; Y. Wu, EMD Serono, Inc, 3; A. Bender, EMD Serono, Inc, 3; A. Arazi, None; T. Eisenhaure, None; E. Browne, None; A. Rolfe, EMD Serono Inc, 3; J. Derry, Amgen, Merck and Co, 1,EMD Serono, Inc; Curis, Inc; ITeos Therapeutics; Lumos Pharma; Aptevo Therapeutics, 5; W. Pendergraft III, EMD Serono, Inc, 2; N. Hacohen, EMD Serono, Inc, 2; J. DeMartino, EMD Serono Inc, 3,EMD Serono, Novartis, 1,Merck and Co, 1; J. Vlach, Jaromir Vlach, 3.

To cite this abstract in AMA style:

Okitsu S, Genest M, Lewis N, Tzvetkov E, Wu Y, Bender A, Arazi A, Eisenhaure T, Browne E, Rolfe A, Derry J, Pendergraft W III, Hacohen N, DeMartino J, Vlach J. A Novel Role for Galectin-3 Binding Protein in B Cell Biology and Antibody Secretion [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/a-novel-role-for-galectin-3-binding-protein-in-b-cell-biology-and-antibody-secretion/. Accessed .

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