Kidney Week

Abstract: FR-OR053

Protective Effect of a Human Pregnancy-Associated Plasma Protein A IgG Monoclonal Antibody in an Orthologous ADPKD Mouse Model

Session Information

• Monogenic Kidney Disease: Mechanistic Insights and Therapeutic Approaches
  November 07, 2025 | Location: Room 360A, Convention Center
  Abstract Time: 05:40 PM - 05:50 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases

Authors

• Wang, Xiaofang, Robert M. and Billie J. Pirnie Mayo Translational PKD Center; Mayo Clinic Minnesota, Rochester, Minnesota, United States

Xiaofang Wang

• Jiang, Li, Robert M. and Billie J. Pirnie Mayo Translational PKD Center; Mayo Clinic Minnesota, Rochester, Minnesota, United States

Li Jiang

• Nanayakkara, Kavini, Robert M. and Billie J. Pirnie Mayo Translational PKD Center; Mayo Clinic Minnesota, Rochester, Minnesota, United States

Kavini Nanayakkara, MS

• Kotzer, Charles J, Respiratory, Immunology and Inflammation Research Biology Unit GlaxoSmithKline PLC, Collegeville, Pennsylvania, United States

Charles J Kotzer

• Mallick, Emily Rose, Respiratory, Immunology and Inflammation Research Biology Unit GlaxoSmithKline PLC, Collegeville, Pennsylvania, United States

Emily Rose Mallick, MS

• Srinivasan, Arun, Research and MDS Statistics GlaxoSmithKline PLC, Collegeville, Pennsylvania, United States

Arun Srinivasan, PhD

• Hu, Erding, Respiratory, Immunology and Inflammation Research Biology Unit GlaxoSmithKline PLC, Collegeville, Pennsylvania, United States

Erding Hu, PhD

• Torres, Vicente E., Robert M. and Billie J. Pirnie Mayo Translational PKD Center; Mayo Clinic Minnesota, Rochester, Minnesota, United States

Vicente E. Torres, MD, PhD

Background

Pregnancy-associated plasma protein A (PAPPA), a metalloproteinase that cleaves IGF binding protein-2,4,5, and IGF-1 pathway genes are overexpressed in Pkd1^RC/RC mouse kidneys. Administration of anti-PAPPA mAb ameliorated PKD in this model (PMID: 31990681). We wanted to confirm this observation using a human anti-PAPPA IgG mAb.

Methods

Pkd1^RC/RC had kidney MRIs to measure total kidney volume (TKV) at 3-4 weeks of age, were randomized into 5 groups (10 males, 10 females each) matched by TKV and body weight, and randomly assigned to control (i.p. human IgG, chow), tolvaptan (i.p. human IgG, chow containing 0.2% tolvaptan), and three human anti-PAPPA mAb (i.p. 0.3, 3, 30 mg/kg) treatments. IgG or GSK mAb were administered weekly. Body weights were recorded weekly, urines collected at 8 and 12 weeks, kidney MRIs at 15-16 weeks, bloods and tissues at sacrifice at 16 weeks of age.

Results

Anti-PAPPA mAb plasma levels were markedly higher in the 30 mg than in the 3 mg group, and in the 3 mg than in the 0.3 mg group. GSK anti-PAPPA mAb (0.3, 3, and 30 mg) and tolvaptan reduced TKV growth and TKV at end of study (EOS) compared to control (Figure 1). Effect sizes were not significantly different between the 3 doses of anti-PAPPA mAb, despite marked differences in plasma levels. Kidney PAPPA levels (a marker for mAb target engagement) were significantly higher in the anti-PAPPA mAb and lower in the tolvaptan treated mice compared to controls. There were no significant differences in liver weights or plasma creatinine and urea values.

Conclusion

Human anti-PAPPA mAb markedly inhibits PKD development in Pkd1^RC/RC mice even at a low dose of 0.3 mg/kg. Anti-PAPPA mAb increases the level of PAPPA in the kidney, whereas tolvaptan has the opposite effect (consistent with the reported PKA/CREB driven expression of PAPPA). This points to possible additive or synergistic effects of anti-PAPPA mAb and tolvaptan.

Figure 1. A) Trajectory of TKV by treatment B) EOS TKV relative to control (means, 95% CI)

Funding

• Commercial Support – GSK

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20256862yj2c