Abstract: SA-PO0267
Novel Neutralizing Monoclonal Antibody (mAb) Against Pregnancy-Associated Plasma Protein A (PAPPA) for the Treatment of ADPKD
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
- Hu, Erding, GSK, Philadelphia, Pennsylvania, United States
- Gardener, Matthew James, GlaxoSmithKline Research & Development Limited, London, England, United Kingdom
- Luo, Guizhen, GSK, Philadelphia, Pennsylvania, United States
- Kotzer, Charles J, GSK, Philadelphia, Pennsylvania, United States
- Mallick, Emily Rose, GSK, Philadelphia, Pennsylvania, United States
- Alsaid, Hasan, GSK, Philadelphia, Pennsylvania, United States
- Doan, Minh, GSK, Philadelphia, Pennsylvania, United States
- Srinivasan, Arun, GSK, Philadelphia, Pennsylvania, United States
- Swerdlow, Daniel I, GlaxoSmithKline Research & Development Limited, London, England, United Kingdom
- Roberts, Juliet, GlaxoSmithKline Research & Development Limited, London, England, United Kingdom
Background
ADPKD is the most common inherited cause of kidney failure. It is characterized by relentless growth of tubular cysts, leading to structural damage/functional decline. Tolvaptan is the sole medicine approved for ADPKD but has aquaresis side effects and risk of liver injury. PAPPA regulates insulin-like growth factor 1 (IGF1) bioavailability through cleavage of IGF1 binding protein (IGFBP) 2, 4 and 5. IGF1 accelerates cyst growth via increased cell proliferation and hypertrophy. Inhibition of PAPPA cleavage of IGFBPs, thereby sequestering IGF1, may delay ADPKD cyst expansion and slow disease progression.
Methods
A yeast-based expression platform was utilized to generate mAbs that neutralize PAPPA-mediated IGFBP2, 4 and 5 cleavage. Optimized PAPPA mAbs were evaluated in human epithelial cells and by a quantitative ELISA to quantify full-length IGFBP4 (IGFBP4-Fl) and PAPPA-cleaved C-terminal fragment (IGFBP4-Ct). Juvenile cystic kidney (JCK) mice were utilized to determine the efficacy on slowing cyst growth.
Results
Potent PAPPA neutralizing mAbs were identified with sub-nM binding affinity. These mAbs blocked PAPPA-mediated cleavage of IGFBP2, 4 and 5 in biochemical assays and in a cell-based recombinant PAPPA activity assay. In A549 cells, dose-dependent inhibition of IGFBP4 cleavage by the PAPPA mAbs was demonstrated . In JCK mice, the administration of two PAPPA neutralizing mAbs demonstrated up to 90% lower total kidney volume (tKV) growth than controls along with reduction in markers of tubular injury and cystic index.
Conclusion
Novel PAPPA neutralizing mAbs were developed, which blocked PAPPA-mediated cleavage of IGFBP2, 4 and 5 in vitro, and reduced cyst growth in JCK mice in vivo. These data support the further exploration of PAPPA inhibition as a therapeutic approach for the treatment of ADPKD.
Figure 1: Reduction of tKV growth in JCK mice after PAPPA mAb treatments
Funding
- Commercial Support – Internally funded by GlaxoSmithKline PLC