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

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 highaffinity 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.

Effectiveness and safety of telitacicept for refractory generalized myasthenia gravis: a retrospective study

“…This approach is further justified by telitacicept’s mechanism of action, which includes the dual inhibition of APRIL/BAFF and suppression of LLPC, potentially contributing to its lasting therapeutic effects even after cessation of treatment. 30 Consequently, while our study presents compelling evidence of telitacicept’s effectiveness in the management of MG, the cautious discontinuation reflects a prudent balance between maximizing clinical benefits and minimizing safety risks, underscoring the need for additional research to establish its optimal duration of use and long-term safety profile in this patient population.…”

“…While the detection of telitacicept at such a late stage does not directly correlate to ongoing therapeutic effectiveness, this pharmacokinetic profile suggests a potential for sustained efficacy beyond the immediate treatment period. Importantly, the long-term impact of telitacicept, attributable to its dual inhibition of APRIL/BAFF and suppression of long-lived plasma cells (LLPC), 30 posits a rationale for evaluating the timing of treatment cessation, especially in light of observed clinical improvements.…”

The role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapies

“…Results from a recent clinical trial in China in IgAN patients indicate that telitacicept reduced proteinuria and was well tolerated ( 33 ). Another dual inhibition agent, povetacicept, was shown to inhibit BAFF and APRIL in a mouse lupus nephritis model, with significant reductions in serum IgM, IgA, and IgG levels after a single dose ( 111 ). Povetacicept is currently being evaluated in an open-label Phase 2 study in adult patients with IgAN, membranous nephropathy, or lupus nephritis to determine its safety, efficacy, and optimum dose in these autoimmune renal diseases ( https://clinicaltrials.gov/study/NCT05732402 ).…”

Biologics and Non-Biologics Immunosuppressive Treatments for IgA Nephropathy in Both Adults and Children

“…Povetacicept (ALPN-303), a dual BAFF/APRIL antagonist, showed an increased binding affinity and inhibitor activity compared to the previous agents [54]. An openlabel study, is currently recruiting patients to evaluate multiple doses of povetacicept in subjects with IgAN and other autoantibody-associated glomerular diseases (RUBY-3, NCT05732402).…”