Nonclinical Safety Profile of JADE101, a Half-Life Extended Fully Human Monoclonal Antibody Targeting APRIL for the Treatment of IgAN

Background: IgA nephropathy (IgAN) is a chronic autoimmune kidney disease characterized by mesangial deposition of immune complexes containing IgA and Gd-IgA1. A proliferation-inducing ligand (APRIL) is critical in driving production of Gd-IgA1. Blocking APRIL reduces Gd-IgA1 levels resulting in reduced proteinuria and preservation of kidney function in IgAN patients. Evaluation of anti-APRIL therapies has consistently shown a favorable safety profile in healthy volunteers and IgAN patients. JADE101 is a fully human anti-APRIL monoclonal antibody (mAb) engineered for high affinity, to limit effector function, and extend half-life. Studies were conducted to characterize the nonclinical safety profile of JADE101. Methods: Nonclinical safety studies conducted with JADE101 included an in vitro membrane protein array, a human tissue cross-reactivity assay, an in vitro cytokine release assay, and repeat-dose studies in non-human primates (NHP). In vivo studies included evaluation of immunoglobulins (Ig), cytokines, and immunophenotyping. Results: Fc receptor and C1q binding studies confirm that JADE101 has minimal effector function. No off-target binding of JADE101 was observed against a panel of over 6000 human proteins. JADE101 was not associated with cytokine release in human whole blood and showed no specific cell membrane binding in a panel of 37 human tissues. JADE101 was well tolerated in NHP studies up to the highest dose tested providing wide safety margins above the anticipated therapeutic dose. As anticipated, JADE101 treatment resulted in significant reductions in IgA and IgM, more modest reductions in IgG, and did not elicit significant cytokine release or effects on T, B, or NK cells. Conclusion: Nonclinical studies demonstrate that JADE101 binds APRIL with high specificity and has low potential for off-target binding to human proteins and low potential to induce cytokine release. Additionally, JADE101 demonstrated a clean safety profile in NHPs at high dose levels, providing wide safety margins above the anticipated human doses. By potently blocking APRIL-mediated signaling, JADE101 has the potential to provide disease-modifying treatment to IgAN patients with low risk of toxicity and no impact on circulating immune cells. Funding: Commercial Support - Jade Biosciences