Abstract: FR-PO0786
Integrin α3 Targeting Antibodies for Podocyte-Specific Delivery of Nanoparticles for Treatment of Glomerular Diseases
Session Information
- Glomerular Diseases: Cell Homeostasis and Novel Injury Mechanisms
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Brown, Sherlene L, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Balza Pineda, Santiago, Allosite Therapeutics, Miami, Florida, United States
- Machineni, Prathyushasai, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Lopez-Rodriguez, Darlah M., Allosite Therapeutics, Miami, Florida, United States
- Gupta, Vineet, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
Group or Team Name
- University of Texas Medical Branch (UTMB Health).
Background
Focal segmental glomerulosclerosis (FSGS), a major cause of chronic kidney disease, is a heterogeneous disorder driven by podocyte injury that leads to foot process effacement, proteinuria, and glomerular scarring. In the USA, it contributes to 20% of idiopathic nephrotic syndrome cases in children and 40% in adults. Integrin α3β1, the most abundant renal integrin, is crucial for podocyte integrity. Loss of its α3 subunit leads to proteinuria, glomerular damage and disease progression. Despite advances in understanding FSGS, targeted therapies remain limited. Current therapies like glucocorticoids have significant toxicity and limited efficacy. To address this, we are developing antibody-conjugated lipid nanoparticles (ALNPs) that target podocytes and deliver therapeutic agents via podocyte-expressed integrin α3β1, offering a promising approach for improving treatment outcomes in FSGS.
Methods
Using a human phage display library and cell-based screening, we developed novel allosteric agonist targeting integrin α3β1. Structural modeling, epitope mapping, and in vitro binding assays were used to identify the agonist binding site on integrin α3β1. Confocal microscopy confirmed binding in cultured podocytes and human/mouse tissues. Antibodies were conjugated using covalent coupling strategies and incorporated into LNPs via post-insertion. ALNPs' physicochemical properties were characterized by DLS, NTA, and electron microscopy.
Results
Allosteric antibodies exhibited strong binding to podocyte-expressed integrin α3β1 in vitro and in tissue samples. They selectively target active conformation of α3β1 and bound the α3 head domain, distinct from the ligand-binding site. LNPs were successfully conjugated with the agonist antibodies, and conjugation efficiency was confirmed by SDS-PAGE and mass spectrometry. Ongoing studies are evaluating the cellular uptake of ALNPs carrying firefly luciferase mRNA in cultured podocytes and in mice.
Conclusion
This study presents a novel ALNP-based delivery platform targeting podocyte integrin α3β1. This approach highlights integrin activation as a precise strategy to treat glomerular dysfunction and proteinuric disease, offering a promising new therapeutic paradigm for FSGS.
Funding
- NIDDK Support