Weekly issue 2026-W41 ·
Novel human neutralizing monoclonal antibodies against Pregnancy-Associated Plasma Protein A for the treatment of Autosomal Dominant Polycystic Kidney Disease
Plain language
PAPP-A is a protein that frees a growth signal called IGF-1, and polycystic kidneys have more of it. Researchers made new human antibodies that block PAPP-A and tested them in two mouse models of PKD, one with advanced and one with early disease. In male mice, all doses tested reduced cyst disease, inflammation and scarring in the kidney. In one of the models, female mice were protected less than males. These are mouse results; the authors say the difference between sexes should be taken into account when planning trials in people.
Clinical note
Preclinical therapeutic study. PAPPA cleaves IGFBP2, 4 and 5, releasing IGF1, and is overexpressed in polycystic kidneys. Human PAPPA-mAbs generated on yeast-based platforms blocked PAPPA-mediated cleavage of IGFBP2, 4 and 5; HDX and cryo-EM mapped the protected PAPPA regions. PAPPA-mAb1 (15 or 50 mg/kg/week) and -mAb2 (1, 5 or 50 mg/kg/week) were given intraperitoneally to male jck mice with advanced PKD from 6 to 12 weeks; -mAb2 (0.3, 3 or 30 mg/kg/week) to male and female Pkd1RC/RC mice with early PKD from 4 to 16 weeks. All doses in males showed target engagement, ameliorated cystic disease, inflammation and fibrosis, and inhibited IGF1Rβ and downstream signalling; females were less protected than males. Both mAbs compared favourably with the earlier Ansh Labs mAb. The authors flag low-dose effectiveness and sexual dimorphism for clinical trial design.
Question for your next visit
How do researchers check that a medicine that works in mice is safe to test in people?