Povetacicept (ALPN-303; TACI vTD-Fc), an enhanced, potent dual inhibitor of BAFF and APRIL, ameliorates experimental autoimmune myasthenia gravis in C57BL/6N mice

TL;DR

Povetacicept, a new drug that blocks two proteins involved in autoimmunity, shows better results than existing treatments in a mouse model of myasthenia gravis.

Contribution

Povetacicept demonstrates superior efficacy in reducing autoantibodies and disease activity in experimental autoimmune myasthenia gravis compared to existing therapies.

Findings

Povetacicept reduced anti-AChR antibody levels and improved muscle AChR content in EAMG mice.

The drug decreased B and T cell activity in lymph nodes and spleen compared to controls.

Povetacicept outperformed telitacicept, anti-CD20 antibodies, and FcRn inhibitors in treating EAMG.

Abstract

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).

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.

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.

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.

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