Povetacicept: An enhanced dual BAFF/APRIL inhibitor for treatment of SLE

• Publicly available RNA-Seq datasets from healthy donors and patients with SLE were used to assess the gene expression of APRIL and BAFF. 

• In vivo biodistribution was assessed by intravenously injecting povetacicept (10 mg/kg) or matching dose of WT TACI-Ig (telitacicept) to healthy C57BL/6 mice. Lupus-related tissues were collected after 18 hours, and quantitative immunohistochemistry was performed for human Fc staining. 

• The study objectives were to ascertain the expression of BAFF and APRIL in patients with SLE using transcriptional datasets; and to compare povetacicept to WT TACI-Ig in tissue distribution and lupus efficacy using mouse models. 

• Povetacicept was also tested in an interferon-α-accelerated NZB/W mouse model of SLE, compared with matched Fc control, WT TACI-Ig, a depleting anti-mouse CD20 mAb (anti-mCD20), and cyclophosphamide. 

• In the transcriptional datasets, genes related to BAFF (TNFSF13B), APRIL (TNFSF13), BAFF-receptor (TNFRSF13C), BCMA (TNFRSF17), and TACI (TNFRSF13B) were increased in myeloid lineage cells and B cells in patients with SLE compared with healthy adults. 

• Povetacicept, compared with WC TACI-Ig, is smaller in size (molecular weight: 62.6 kDA vs 75.3–75.4, respectively), has a lower isoelectric point (6.5–7.0 vs 7.1–8.4, respectively), and higher target affinity. Consequently, povetacicept exhibited greater distribution to lupus-related organs in normal mice than WT TACI-Ig (Figure 1). 

Figure 1. Distribution of povetacicept and WT TACI-Ig to lupus-related organs* 

TACI, transmembrane activator and CAML interactor; SEM, standard error of the mean; WT, wild-type. 
*Data from Simsek.¹ 

 Flow cytometric analysis of spleens collected at Day 50 revealed that povetacicept: