Abstract: TH-PO046

Preclinical Safety Profile of VIS649, a First-in-Class Humanized IgG2 Targeting APRIL for the Treatment of IgA Nephropathy

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Szretter, Kristy J, Visterra, Inc., Cambridge, Massachusetts, United States
  • Myette, James R., Visterra, Inc., Cambridge, Massachusetts, United States
  • Helger, Emily A, Visterra, Inc., Cambridge, Massachusetts, United States
  • Trevejo, Jose, Visterra, Inc., Cambridge, Massachusetts, United States
  • Sloan, Susan E, Visterra, Inc., Cambridge, Massachusetts, United States
  • Pereira, Brian J.G., Visterra, Inc., Cambridge, Massachusetts, United States
Background

IgA Nephropathy (IgAN) is the most common cause of glomerulonephritis worldwide, with no disease-specific therapies currently available. VIS649 is a humanized IgG2 monoclonal antibody targeting the cytokine named A PRoliferation Inducing Ligand (APRIL) that has been implicated in the pathophysiology of IgAN disease and progression. The preclinical effect of inhibiting APRIL activity by VIS649 was evaluated in nonhuman primates (NHP) to better understand the safety and tolerability profile of this development candidate.

Methods

Preclinical safety assessments of VIS649 included off-target binding analysis, cytokine release, and in vivo tolerability in a NHP study. Off-target binding analysis utilized the Retrogenix cell microarray platform, in which human plasma membrane proteins were transiently expressed on HEK293 cells and therapeutic antibody binding was measured by fluorescent staining. Cytokine release was assessed with whole blood from human donors and cytokines were measured by Luminex. In vivo safety and tolerability were evaluated in cynomolgus monkeys administered 25 mg/kg of VIS649 intravenously weekly for 8 weeks, followed by a 3 week recovery period. Clinical chemistry, clinical pathology, hematology, immune cell profiling by flow cytometry, and histopathology were assessed.

Results

VIS649 did not demonstrate off-target binding in the Retrogenix cell microarray platform including over 3,300 unique membrane-associated human proteins. Preliminary cytokine release assays demonstrated that compared to negative controls, VIS649 did not induce secretion of cytokines. Treatment of NHP with VIS649 as compared to the control group resulted in no significant abnormalities in clinical observations, clinical chemistry, clinical pathology, hematology, or pathology. Despite a ~70% reduction in serum IgA levels, no perturbations in immune cell populations in peripheral blood or lymphoid organs were observed.

Conclusion

VIS649 has a preclinical safety profile that supports its further development as a therapeutic monoclonal antibody candidate for the treatment of IgAN. Furthermore, targeting APRIL at a dose that reduced IgA levels by 70% did not result in any safety or tolerability findings in NHP.

Funding

  • Other U.S. Government Support