Abstract: FR-PO114
BION-1301: A Novel Fully Blocking APRIL Antibody for the Treatment of IgA Nephropathy
Session Information
- Molecular Mechanisms of CKD - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Dulos, John, Aduro Biotech Europe, Oss, Netherlands
- Vink, Paul, Aduro Biotech Europe, Oss, Netherlands
- Van eenennaam, Hans, Aduro Biotech Europe, Oss, Netherlands
- Van elsas, Andrea, Aduro Biotech Europe, Oss, Netherlands
Background
A PRoliferation Inducing Ligand (APRIL, TNFSF13) is a ligand for the receptors B cell maturation antigen (BCMA) and Transmembrane activator and CAML interactor (TACI). APRIL serum levels were found to be enhanced in patients diagnosed with IgA Nephropathy (IgAN) and treatment with an anti-mouse APRIL antibody reduced serum IgA and proteinuria increase in an IgAN mouse model (Kim Y.G. et al. PLOS one Sep 8, 2015). Altogether suggesting that the APRIL-axis is important in IgAN pathology and strongly supporting the development of our anti-APRIL antibody, BION-1301 to treat IgA nephropathy (IgAN).
Methods
BION-1301 affinity, binding to APRIL and blocking capacity to BCMA and TACI was characterized using Biolayer Interferometry and ELISA. A sinlge-dose non-human primate (NHP) PK and tolerability study was performed administering intravenous (i.v.) BION-1301 at 0.3, 3 and 30 mg/kg. Preclinical safety was assessed in a 4-week repeat-dose NHP study using weekly i.v. doses of 10, 30 and 100 mg/kg. In human primary B-cell cultures the effect of (anti-)APRIL on IgA production, BCMA and TACI expression was assessed.
Results
We developed a novel humanized high-affinity anti-APRIL antibody BION-1301 (KD 0.4 ± 0.15 nM, EC50 0.29 ± 0.05 nM). Its epitope was mapped to the BCMA and TACI binding site conferring fully blocking capacity to BION-1301. Blocking potency (IC50) was 1.61± 0.78 nM (BCMA) and 1.29 ± 0.89 nM (TACI) respectively. The mouse anti-human parental antibody hAPRIL.01A inhibited APRIL-dependent B-cell proliferation and IgA production in vitro and in vivo (Guadagnoli et al. Blood Jun 23;117, 2011). In B-cell cultures, hAPRIL.01A reduced IgM, IgA and IgG-secreting cells after CpG pulse and APRIL stimulation.
Following administration of a single-dose of BION-1301 to NHP, PK parameters typical for human IgG4 antibodies were observed, and confirmed a lack of tolerability issues. In a 4-week repeat dose NHP study BION-1301 demonstrated a favorable safety profile (No Observed Adverse Event Level was 100 mg/kg). Chronic exposure to BION-1301 led to a significantly reduced IgA level vs baseline of -50±14, -52±14, -59±7 % at 10, 30 and 100 mg/kg respectively.
Conclusion
Here, we report the in vivo and in vitro mechanism of action of a novel humanized APRIL neutralizing antibody modulating IgA, support the development of BION-1301 for the treatment of IgAN.
Funding
- Commercial Support –