靶向妊娠相关血浆蛋白 A 的新型人源中和单克隆抗体用于治疗常染色体显性多囊肾病

INTRODUCTION: Pregnancy-associated plasma protein A (PAPPA) cleaves insulin-like growth factor (IGF) binding proteins (IGFBP) 2, 4, 5, releasing IGF1. PAPPA is overexpressed in polycystic kidneys and its genetic elimination or suppression by mouse Ansh Labs PAPPA-mAb, which blocks IGFBP4 but not IGFBP5 cleavage, ameliorates polycystic kidney disease (PKD) in Pkd1RC/RC mice. Here, we sought to generate human pan-selective PAPPA-mAbs and test their efficacy in models of advanced and early PKD, using a wide range of doses in mice.

METHODS: Yeast-based expression platforms were used to generate mAbs neutralizing PAPPA-mediated cleavage of IGFBP2, 4, 5 in human epithelial cells (IGF1-induced Akt phosphorylation or ELISAs of full length and PAPPA cleaved C-terminal IGFBP4 fragments as readouts). Hydrogen deuterium exchange (HDX) and cryo-EM were used to map PAPPA and mAb interacting sites. PAPPA-mAb1 (15 or 50 mg/kg/week) and -mAb2 (1, 5 or 50 mg/kg/week) were administered intraperitoneally to male jck mice with advanced PKD from six to 12 weeks; PAPPA-mAb2 (0.3, 3 or 30 mg/kg/week) was administered to male and female Pkd1RC/RC mice with early PKD from four to 16 weeks of age.

RESULTS: PAPPA-mAb1 and -mAb2 blocked PAPPA mediated cleavage of IGFBP2, 4, 5. HDX and cryo-EM identified PAPPA regions interacting with IGFBP2, 4, 5 protected by both PAPPA-mAbs. All doses administered to male mice equally demonstrated excellent target engagement and ameliorated cystic disease, inflammation, fibrosis, and inhibited IGF1Rβ and downstream signaling. PAPPA-mAb2 protected female less than male Pkd1RC/RC mice. Both mAbs compared favorably to Ansh Labs mAb in cell systems and in vivo.

CONCLUSION: Our study confirms that PAPPA-mAbs are a promising new targeted therapy for autosomal dominant PKD. Excellent target engagement and low dose effectiveness of novel human PAPPA-mAbs, with implications for long-term safety, and sexual dimorphism of the therapeutic response should be considered in the design of clinical trials.