Abstract: FR-PO0079
Comparing Pregnancy-Associated Plasma Protein A Inhibition vs. Tolvaptan in a Mouse Model of ADKPD
Session Information
- ADPKD and Cystic Kidney Disease - 2
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)
Authors
- Zhou, Alex Xianghua, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden
- Cederblad, Linda, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden
- Todkar, Abhijeet, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden
- Wennberg Huldt, Charlotte, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden
- Tesan Tomic, Tajana, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden
- Cavallin, Anders, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden
- Ingelsten, Madeleine, AstraZeneca Pharmaceuticals LP, Boston, Massachusetts, United States
- Pfeiff, Janice Marie, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden
- Bilkei-Gorzo, Orsolya, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden
- Matadamas-Guzman, Meztli, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden
- Holmgren, Gustav, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden
- Sundqvist, Monika, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden
- Murray, Thomas V., AstraZeneca PLC, Gothenburg, Sweden
- Gonzalez-Villalobos, Romer Andres, AstraZeneca Pharmaceuticals LP, Boston, Massachusetts, United States
Background
Autosomal dominant polycystic kidney disease (ADPKD) is driven by progressive cyst growth causing renal function decline. Tolvaptan, the only FDA-approved therapy, slows progression but causes polyuria, underscoring the need for novel treatments. Elevated pregnancy-associated plasma protein A (PAPPA) in cyst epithelia cleaves IGF binding proteins (IGFBPs), increasing local IGF1 bioavailability and promoting cyst expansion. We evaluated PAPPA inhibition in a KspCad-driven Pkd1 knockout mouse model and compared efficacy and tolerability with tolvaptan.
Methods
Pappa expression was determined by RNAscope. IGFBP4 proteolysis was quantified by MSD assay in WT9-12 cystic cells and mouse plasma. Six-week-old ADPKD mice received weekly subcutaneous anti-PAPPA mAb (0.1–3 mg/kg) for 10 weeks versus isotype IgG control; parallel cohorts received tolvaptan (75 mg/kg daily plus 0.1% in chow) or control chow. Kidney volume and blood urea nitrogen (BUN) were monitored by ultrasound and biochemical assay. Kidneys were assessed by microscopy with H&E staining, transcriptomics, proteomics, and western blotting.
Results
In ADPKD mice, Pappa mRNA was upregulated in cystic epithelium, accompanied by elevated plasma levels of cleaved IGFBP4. PAPPA mAb dose-dependently blocked IGFBP4 cleavage both in vitro and in vivo in ADPKD mice. Correspondingly, PAPPA mAb demonstrated dose-dependent efficacy in reducing kidney enlargement, cystic index, and normalizing BUN. At 3 mg/kg, PAPPA mAb matched tolvaptan efficacy without reducing urine osmolarity. Transcriptomics and proteomics revealed that both treatments improved mitochondrial function and inhibited cell cycle pathways, though PAPPA mAb showed more pronounced effects. The treatments also exhibited distinct pathway modulation; notably, PAPPA mAb specifically targeted "IGF transport and uptake by IGFBPs". In addition, PAPPA mAb more potently inhibited phosphorylation of ERK, AKT, and S6K compared to tolvaptan.
Conclusion
PAPPA inhibition slows disease progression in Pkd1 knockout mice with clear dose-dependent target engagement and therapeutic responses. PAPPA mAb delivered comparable renal benefits vs. tolvaptan while achieving broader molecular normalization and preserving urine osmolality, suggesting a lower polyuria risk. These findings support PAPPA blockade as a promising disease-modifying strategy for ADPKD warranting clinical investigation.
Funding
- Commercial Support – AstraZeneca R&D Gothenburg