Povetacicept, an Enhanced Dual APRIL/BAFF Antagonist That Modulates B Lymphocytes and Pathogenic Autoantibodies for the Treatment of Lupus and Other B Cell-Related Autoimmune Diseases

  • Arthritis Rheumatol. 2023 Jul;75(7):1187-1202. doi: 10.1002/art.42462.
Lawrence S Evans  1 ,  Katherine E Lewis  1 ,  Daniel DeMonte  1 ,  Janhavi G Bhandari  1 ,  Logan B Garrett  1 ,  Joseph L Kuijper  1 ,  Daniel Ardourel  1 ,  Martin F Wolfson  1 ,  Susan Debrot  1 ,  Sherri Mudri  1 ,  Kayla Kleist  1 ,  Luana L Griffin  1 ,  LuAnne Hebb  1 ,  Russell J Sanderson  1 ,  NingXin Wang  1 ,  Michelle Seaberg  1 ,  Allison G Chunyk  1 ,  Jing Yang  1 ,  Youji Hong  1 ,  Zahra Maria  1 ,  David J Messenheimer  1 ,  Pamela M Holland  1 ,  Stanford L Peng  1 ,  Mark W Rixon  1 ,  Stacey R Dillon  1
Affiliations
  • 1. Alpine Immune Sciences, Inc., Seattle, Washington.
PMID: 36705554 DOI: 10.1002/art.42462
Abstract

Objective: Dysregulated APRIL/BAFF signaling is implicated in the pathogenesis of multiple autoimmune diseases, including systemic lupus erythematosus and lupus nephritis. We undertook this study to develop and evaluate a high-affinity APRIL/BAFF antagonist to overcome the clinical limitations of existing B cell inhibitors.

Methods: A variant of TACI-Fc generated by directed evolution showed enhanced binding for both APRIL and BAFF and was designated povetacicept (ALPN-303). Povetacicept was compared to wild-type (WT) TACI-Fc and related molecules in vitro and in vivo.

Results: Povetacicept inhibited APRIL and BAFF more effectively than all evaluated forms of WT TACI-Fc and selective APRIL and BAFF inhibitors in cell-based reporter assays and primary human B cell assays, mediating potent suppression of B cell proliferation, differentiation, and immunoglobulin (Ig) secretion. In mouse immunization models, povetacicept significantly reduced serum immunoglobulin titers and antibody-secreting cells more effectively than anti-CD20 monoclonal antibodies, WT TACI-Fc, or APRIL and BAFF inhibitors. In the NZB × NZW mouse lupus nephritis model, povetacicept significantly enhanced survival and suppressed proteinuria, anti-double-stranded DNA antibody titers, blood urea nitrogen, glomerulonephritis, and renal immunoglobulin deposition. In the bm12 mouse lupus model, povetacicept significantly reduced splenic plasmablasts, follicular helper T cells, and germinal center B cells. In non-human primates, povetacicept was well tolerated, exhibited high serum exposure, and significantly decreased serum IgM, IgA, and IgG levels after a single dose.

Conclusion: Enhanced APRIL and BAFF inhibition by povetacicept led to greater inhibition of B cell populations critical for autoantibody production compared to WT TACI-Fc and CD20-, APRIL-, or BAFF-selective inhibitors. Potent, dual inhibition by povetacicept has the potential to significantly improve clinical outcomes in autoantibody-related autoimmune diseases.

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