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Povetacicept: An enhanced dual BAFF/APRIL inhibitor for treatment of SLE
B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) signal through B-cell maturation antigen (BCMA), TACI (transmembrane activator and CAML interactor), and/or BAFF-receptor plays important role in the pathogenesis of systemic lupus erythematosus (SLE). Povetacicept, a potent enhanced dual BAFF/APRIL inhibitor, has demonstrated efficacy, enhanced serum exposure, and pharmacodynamics in previous preclinical studies.
At the 14th European Lupus Meeting, Simsek.1 presented the analysis of published transcriptional datasets to ascertain the gene expression of BAFF and APRIL in patients with SLE. A comparison of povetacicept to wild-type (WT) TACI-Ig in tissue distribution and SLE disease activity in murine models was also discussed.1 Here, we summarize the key findings.
Methods
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Publicly available RNA-Seq datasets from healthy donors and patients with SLE were used to assess the gene expression of APRIL and BAFF.
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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.
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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.
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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.
Key findings
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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.
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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:
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reduced the frequency of total B cells (CD19+B220+CD11b-), plasma cells (live TACI+CD138+ cells), and anti-double stranded DNA as compared with Fc control, anti-mCD20, or WT TACI-Ig groups; and
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increased hemoglobin levels as compared with Fc control, WT TACI-Ig, or cyclophosphamide groups.
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In the histopathology analysis, povetacicept showed a significant reduction in:
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proteinuria scores on Day 48 and total lesion scores (glomerular + tubular/interstitial lesions) in kidney, as compared with Fc control and WT TAC-Ig;
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glomerular IgG deposition, compared with Fc control, anti-mCD20, and WT TACI-Ig; and
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numbers of inflammatory foci in submandibular gland, compared with Fc control and anti-mCD20.
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Key learnings |
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- Simsek I. 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). Abstract #P104. 14th European Lupus Meeting; March 21, 2024; Bruges, BE.
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