[Pubmed] Povetacicept (ALPN-303; TACI vTD-Fc), an enhanced, potent dual inhibitor of BAFF and APRIL, ameliorates experim

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Front Immunol. 2025 Jun 6;16:1533093. doi: 10.3389/fimmu.2025.1533093. eCollection 2025.

ABSTRACT

BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is a T cell-dependent, B cell-mediated autoimmune disease targeting the acetylcholine receptor (AChR) and other proteins of the neuromuscular junction postsynaptic membrane. Production of pathogenic autoantibodies results from B cell activation and expansion of antibody-secreting cells, including plasma cells, whose differentiation and survival are reliant on the TNF family cytokines APRIL and BAFF. Povetacicept (ALPN-303; TACI vTD-Fc) is an Fc fusion protein of an engineered TACI domain with significantly more potent dual inhibition of APRIL and BAFF than wild-type (WT) TACI-Fc (e.g., telitacicept).

METHODS: In this study, the activity of povetacicept was evaluated in the mouse experimental autoimmune MG (EAMG) model, compared to (i) telitacicept, (ii) a depleting anti-CD20 antibody, (iii) neonatal Fc receptor blocker efgartigimod, (iv) a matched Fc control protein, and (v) PBS as vehicle.

RESULTS: Therapeutic administration of povetacicept ameliorated clinical manifestations in EAMG mice and was associated with significantly lower levels of immunoglobulin subclasses and anti-AChR antibody titers in serum, along with increased muscle AChR content - superior to the evaluated comparators. Povetacicept treatment also reduced the number of total B220+ and Ki67+ proliferating cells in draining lymph node follicles and resulted in modifications of splenic T and B cell subset frequencies, compared to controls.

DISCUSSION: The potent, dual BAFF/APRIL inhibitor povetacicept significantly improves clinical disease activity in EAMG, associated with reductions in pathogenic anti-AChR autoantibodies and superior to comparator therapeutic interventions based on WT TACI-Fc, CD20 depletion, or FcRn inhibition. Povetacicept may therefore confer beneficial clinical outcomes in the treatment of MG and other autoantibody-related neurological diseases.

PMID:40547042 | PMC:PMC12179661 | DOI:10.3389/fimmu.2025.1533093


Source: https://pubmed.ncbi.nlm.nih.gov/4054704 ... t9+e462414