P104 Upregulation of both APRIL and BAFF in systemic lupus erythematosus suggests non-redundant roles, further revealed by potent dual inhibition with povetacicept (TACI vTD-Fc; ALPN-303)

Objective BAFF and APRIL 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. Therapeutic agents targeting BAFF and/or APRIL have demonstrated promising clinical potential in systemic lupus erythematosus (SLE), lupus nephritis (LN), and other B cell-related diseases; however, these inhibit only BAFF, only APRIL, or predominantly BAFF, and more potent inhibition of both cytokines is likely required for optimal efficacy. Our objectives were to ascertain the importance of BAFF and APRIL in the inflammatory processes associated with SLE via transcriptional datasets and in vitro assays, and to evaluate the efficacy of povetacicept, a potent dual BAFF/APRIL antagonist, against wild-type TACI-Ig and B cell depletion in a mouse lupus model. Methods APRIL and BAFF gene expression was assessed in published transcriptional datasets from healthy donors and SLE patients. PBMCs from healthy donors were stimulated with CD40L, IL-21, BAFF, and APRIL prior to treatment with Fc control, povetacicept, belimumab (anti-BAFF), anti-APRIL mAb, telitacicept (WT TACI-Ig), or combined anti-BAFF/anti-APRIL, then harvested for flow cytometry and RNA-seq analyses. Povetacicept was also evaluated in an IFNα-accelerated NZB/W mouse model of SLE alongside a matched Fc control, telitacicept, a depleting anti-mouse CD20 mAb, and cyclophosphamide. Results In publicly available RNA-Seq datasets, BAFF- and APRIL-related gene expression is increased in SLE patients versus healthy adults. Povetacicept, as compared to single BAFF or APRIL pathway inhibitors, more potently downregulated genes associated with B cell activation in cultured PBMC. In the IFNα-accelerated NZB/W lupus model, povetacicept significantly suppressed multiple disease parameters (figure 1) and reduced key immune cell subsets (including plasma cells) more effectively than telitacicept or conventional B cell depletion. Conclusion Dual, potent inhibition of both BAFF and APRIL may be required to achieve optimal suppression of pathogenic pathways in SLE and related diseases. These results strongly support the clinical evaluation of povetacicept in SLE and other B cell- and/or autoantibody-related diseases. A clinical study of povetacicept in SLE is in preparation; clinical trials are ongoing in autoimmune cytopenias (NCT05757570) and glomerulonephritides, including LN (NCT05732402). Acknowledgements This work was wholly funded by Alpine Immune Sciences, Inc.