To explore the role of the BAFF and APRIL cytokines in the pathogenesis of anti-N-methyl-D-aspartate receptor (NMDAR) autoimmune encephalitis.

BAFF and APRIL are cytokines that signal through TACI, BCMA, and/or BAFF-R and play important roles in the activation, differentiation and/or survival of B cells, particularly antibody-secreting cells, as well as T cells and innate immune cells. Povetacicept is an Fc fusion protein of an engineered TACI domain which mediates significantly more potent dual inhibition of APRIL and BAFF than WT TACI-Fc, which has shown promise in the treatment of myasthenia gravis and other antibody-related diseases. Povetacicept may provide a more efficacious treatment option for autoimmune encephalitis and other antibody-related neurological diseases.

Mice (female C57BL/6NJ) were immunized every 4 weeks for a total of 3 immunizations with an encephalitogenic peptide (GluN1_356-385) of the human/mouse NMDAR subunit. At the 2^nd immunization, when high circulating levels of anti-GluN1 antibodies were detected, mice were placed into two treatment groups in a balanced manner, such that each had similar anti-GluN1 levels. Mice were treated 2x/week with povetacicept (10 mg/kg) or a molar-matched dose of Fc control over 5 weeks, then evaluated at Week 10 for anti-GluN1 titers and cerebral IgG deposits. Splenocytes were also evaluated by flow cytometry to track immune cell subsets important for antibody production.

Povetacicept treatment was associated with significantly lower serum anti-GluN1 antibodies (p=0.0003) and IgG deposition in brains (p=0.0009) than Fc control-treated mice. Moreover, total numbers of splenic B, germinal center, T follicular helper, and plasma cells were significantly lower in povetacicept-treated mice than Fc control-treated mice (p≤0.0003).

Povetacicept demonstrates promising efficacy in a preclinical model of autoimmune encephalitis, reducing pathogenic autoantibodies and cerebral Ig deposition. Povetacicept may hold promise in the treatment of autoimmune encephalitis and other autoantibody-related neurological diseases.