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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.
- Source :
- Arthritis & Rheumatology; Jul2023, Vol. 75 Issue 7, p1187-1202, 16p
- Publication Year :
- 2023
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- SYSTEMIC lupus erythematosus treatment
AUTOANTIBODIES
IN vitro studies
CELL differentiation
B cells
LUPUS nephritis
IN vivo studies
IMMUNOGLOBULINS
ANIMAL experimentation
CELL receptors
AUTOIMMUNE diseases
CELLULAR signal transduction
RESEARCH funding
CELL proliferation
MEMBRANE proteins
IMMUNOGLOBULIN producing cells
Subjects
Details
- Language :
- English
- ISSN :
- 23265191
- Volume :
- 75
- Issue :
- 7
- Database :
- Complementary Index
- Journal :
- Arthritis & Rheumatology
- Publication Type :
- Academic Journal
- Accession number :
- 164633488
- Full Text :
- https://doi.org/10.1002/art.42462