Abstract: SA-PO0253
Development and Characterization of CLYM116, a Novel Fc-Engineered Anti-APRIL Monoclonal Antibody (mAb) with pH-Dependent Binding for IgAN
Session Information
- Pharmacology
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Beeck, Stefan, Climb Bio, Inc, Wellesley Hills, Massachusetts, United States
- Lin, Guangzhong, Beijing Mabworks Biotech Co Ltd, Beijing, China
- Li, Jiangmei, Beijing Mabworks Biotech Co Ltd, Beijing, China
- Li, Feng, Beijing Mabworks Biotech Co Ltd, Beijing, China
- Mack, Timothy, Climb Bio, Inc, Wellesley Hills, Massachusetts, United States
- Hao, Gary, Climb Bio, Inc, Wellesley Hills, Massachusetts, United States
Background
IgA Nephropathy (IgAN) is an autoantibody-mediated disease caused by deposition of immune complexes in the glomeruli and is the most common primary glomerulonephritis worldwide. Elevated levels of A Proliferation-Inducing Ligand (APRIL) have been linked to disease severity in IgAN and inhibition of APRIL is a potentially disease-modifying approach. CLYM116/MIL116 is a novel, Fc-engineered mAb designed to employ a pH-dependent bind-and-release mechanism to enhance antibody recycling and enable half-life extension. CLYM116’s unique approach may result in rapid, deep, and durable inhibition of APRIL signaling and enhanced APRIL degradation, which may provide prolonged IgA suppression.
Methods
Binding of CLYM116 to APRIL and its effect on APRIL-TACI/BCMA interactions were assessed via ELISA and SPR. Rate of APRIL degradation was assessed in vitro. The PK of APRIL and antibodies were evaluated post-subcutaneous (SC) administration in mice. Free APRIL, IgA, IgM, and IgG levels were measured with ELISA following SC administration to non-human primates (NHPs).
Results
CLYM116 exhibited strict pH-dependent binding, with high affinity for human and NHP APRIL at pH 7.4 and negligible binding below pH 5.5. Control antibodies did not exhibit this pH-dependent binding. CLYM116 blocked APRIL-BCMA/TACI interactions and promoted APRIL degradation in human endothelial cells. In mice, CLYM116 administration enhanced degradation of exogenously administered human APRIL. In NHPs, CLYM116 administration led to rapid, deep, and sustained reductions of free APRIL, IgA, IgM, and IgG.
Conclusion
In preclinical models, CLYM116’s pH-dependent binding profile promoted APRIL degradation and CLYM116 recycling, enabling deep and durable IgA, IgM, and IgG reduction. IND-enabling NHP studies are currently underway. CLYM116’s unique profile may provide robust inhibition of APRIL signaling with potential impact on IgAN pathophysiology.
Funding
- Commercial Support – Mabworks Biotech, Climb Bio