Abstract: FR-PO709

Antibody-Based Targeting of APRIL as a Therapeutic Strategy in the Treatment of IgA Nephropathy—A Case Study in a Grouped ddY Mouse Model

Session Information

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • Myette, James R., Visterra, Inc., Cambridge, Massachusetts, United States
  • Kano, Toshiki, Juntendo University Faculty of Medicine, Tokyo, Japan
  • Suzuki, Hitoshi, Juntendo University Faculty of Medicine, Tokyo, Japan
  • Adari, Hedy, Visterra, Inc., Cambridge, Massachusetts, United States
  • Deotale, Ketan, Visterra, Inc., Cambridge, Massachusetts, United States
  • Pereira, Brian J.G., Visterra, Inc., Cambridge, Massachusetts, United States
  • Suzuki, Yusuke, Juntendo University Faculty of Medicine, Tokyo, Japan
Background

IgA nephropathy (IgAN) is a chronic, “autoimmune” glomerular disease of high unmet medical need. The cytokine APRIL (TNFSF13) is emerging as a key player in disease onset and progression, based on a recent convergence of biological and translational data. The pathogenic role of APRIL in IgAN has been previously established in grouped ddY (gddY) mice, an early-onset disease model which recapitulates many of the clinical hallmarks of IgAN pathophysiology and progression. VIS649, a humanized IgG2 specifically targeting human APRIL, is being developed as a therapy for IgA nephropathy. Based on its overlapping epitope and functional attributes, surrogate antibody mAb 4540, which neutralizes mouse APRIL, was used to evaluate anti-APRIL intervention in controlling disease in gddY mice.

Methods

6-7 week old female mice were administered mAb 4540 (10-20 mg/kg) once weekly for up to eight weeks by i.p. injection. Relevant endpoints included serum immunoglobulin profiling by ELISA; IgA, IgG, and C3 deposition in kidney by IFC; proteinuria based on albumin:creatinine ratios (uACR) from spot urine; and glomerular histopathology by PAS staining. Cellular B-cell profiling in bone marrow was completed by flow cytometry.

Results

Treatment of gddY mice with mAb 4540, relative to the control groups, resulted in the suppression of serum IgA profiles and a markedly lower deposition of IgA, IgG, and C3 in the kidney mesangium. These observations correlated with a better glomerular histopathology profile and a lower uACR profile, indicative of reduced kidney injury. Treatment efficacy was observed as early as 4 weeks after the start of intervention and was sustained during the recovery phase of this study. Targeting APRIL with mAb 4540 demonstrated no overt differences in serum IgG levels or plasma cell profiles.

Conclusion

This study both confirms and extends the rationale for targeting the cytokine APRIL for treatment of IgAN. The demonstrated efficacy of mAb4540 in this model also highlights the potential therapeutic benefit of VIS649, a first-in-class human monoclonal antibody being developed for the treatment of IgAN.

Funding

  • Commercial Support