Abstract: SA-PO714
Stabilization of Integrin a3b1 with Novel Activating Antibodies Protects against FSGS
Session Information
- Glomerular Diseases: Therapeutic Strategies
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Balza Pineda, Santiago, 149 Bio, LLC, Miami, Florida, United States
- Lopez-Rodriguez, Darlah M., 149 Bio, LLC, Miami, Florida, United States
- Youssef, Mohamed, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Brackman, Sheri, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Barbosa, Antonio, 149 Bio, LLC, Miami, Florida, United States
- Gupta, Vineet, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
Background
Healthy podocytes maintain the normal function of the glomerulus. The cell surface integrin a3b1 helps podocytes adhere to the extracellular basement membranes. Inflammatory injury, mutations in a3b1 or associated protein CD151, or defects in the integrin-linked cytoskeleton result in reduced cell adhesion, podocyte detachment and urinary loss. This weakening of the filtration barrier contributes to progressive glomerular diseases, including focal segmental glomerulosclerosis (FSGS). Enhancing podocyte retention through increased integrin-mediated cell adhesion presents a promising therapeutic strategy in FSGS.
Methods
Podocytes were used in High-Content Screening (HCS) assays to measure cell damage induced by puromycin aminonucleoside (PAN) and measure the protective effects of integrin agonists. To identify a3b1-activating antibodies (Abs), we employed a naive human phage display library. For discovery and in vitro characterization assays, we used recombinant integrin constructs, K562 cells stably expressing a3b1, differentiated podocytes, and human SK-OV3 cells. Albuminuria was assessed in a lipopolysaccharide (LPS)-induced mouse model of FSGS.
Results
Results from the HCS assay revealed observable changes in F-actin fiber formation, focal adhesion formation, and active integrin levels in podocytes following PAN injury. Notably, known b1 integrin agonists (Ab 9EG7 and Pyrintegrin) and novel a3 Abs demonstrated protective effects against PAN-induced injury in podocytes. The agonist Abs also increased cell adhesion and decreased cell migration in vitro. Ab mapping experiments show selective and allosteric binding of the new Abs to the a3 head-domain, away from the ligand binding pocket. In an animal model of FSGS, treatment with the new a3 Ab resulted in a significant reduction in albuminuria compared to control groups, highlighting the therapeutic potential of a3b1 activation in mitigating glomerular dysfunction.
Conclusion
Activation of integrin a3b1 in podocytes enhances adhesion to matrix proteins and confers protection against cellular damage. Ongoing in vivo efficacy studies will provide additional insights into the therapeutic potential of this approach, offering a promising strategy against various glomerular diseases.
Funding
- Commercial Support – 149 Bio, LLC