Abstract: TH-PO1146
Defining the Cytoskeletal Interactome of the Proximal Tubule: A Network Analysis of Payload-Specific Antibody-Drug Conjugate Nephrotoxicity
Session Information
- Onconephrology: Emerging Biomarkers, Preclinical Models, Clinical Challenges, and Therapeutic Strategies
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onconephrology
- 1600 Onconephrology
Authors
- Capriles, Guido M., TriHealth Inc, Cincinnati, Ohio, United States
- Abdeltawwab, Mohannad, TriHealth Inc, Cincinnati, Ohio, United States
- Rajput, Amit K., TriHealth Inc, Cincinnati, Ohio, United States
Background
The clinical integration of Monomethyl Auristatin E (MMAE)-based antibody-drug conjugates (ADCs) has revealed unexpected acute kidney injury (AKI) (Atemnkeng et al., 2023). Unlike Topoisomerase-I (Topo-I) ADCs, MMAE payloads function as microtubule depolymerizing agents. Because the proximal tubule (PT) relies heavily on dynamic cytoskeletal networks to maintain a polarized reabsorptive phenotype, we hypothesized MMAE-induced microtubule inhibition disproportionately dismantles the functional PT interactome compared to nuclear-targeted therapies.
Methods
To explore structural dependencies of PT physiology on distinct ADC targets, an in-silico protein-protein interaction (PPI) network analysis was conducted (STRING v12.5). Structural interactomes of MMAE targets (TUBB/TUBA1A) and Topo-I targets (TOP1) were modeled against core PT functional mediators: apical endocytosis (LRP2), vesicular recycling (RAB11A), and solute transport (SLC9A3, ATP1A1). Networks were filtered for high-confidence human interactions (>0.700). Functional integration was quantified via False Discovery Rate (FDR).
Results
Network modeling revealed a payload-specific structural vulnerability. The MMAE target network demonstrated highly significant functional integration with core PT mediators, forming a tightly bound structural interactome (26 nodes, 50 edges; PPI enrichment p=3.19e-08). Disruption of this cytoskeletal node mathematically destabilized networks essential for 'apical part of cell' maintenance (FDR=5.99e-06), 'brush border membrane' scaffolding (FDR=0.0014), and 'endocytic vesicle' localization (FDR=0.0016). Conversely, the TOP1 interactome remained structurally segregated, exhibiting zero high-confidence interactions bridging the nuclear target to PT transport or polarity networks.
Conclusion
This computational interactome analysis provides a physiological framework for MMAE-associated AKI. The proximal tubule’s absolute reliance on intact microtubule networks for polarized vesicular transport represents a profound structural vulnerability to tubulin-inhibiting ADCs. These in-silico findings propose targeted disruption of the PT cytoskeletal interactome as a primary mechanism for payload-specific tubular toxicity, establishing a foundation for in-vitro validation.