Erin E Olsan, Tamami Matsushita, Mina Rezaei, Thomas Weimbs

Autosomal-dominant polycystic kidney disease (ADPKD) is a common life-threatening genetic disease that leads to renal failure. No treatment is yet available to effectively slow disease progression. Renal cyst growth is, at least in part, driven by the presence of growth factors in the lumens of renal cysts which are enclosed spaces lacking connections to the tubular system. We have previously shown that IL13 in cyst fluid leads to aberrant activation of STAT6 via the IL4/13 receptor. While antagonistic antibodies against many of the growth factors implicated in ADPKD are already available, they are IgG isotype antibodies which are not expected to gain access to renal cyst lumens. Here, we demonstrate that targeting of antibodies to renal cyst lumens is possible with the use of dimeric IgA (dIgA) antibodies. Using human ADPKD tissues and PKD mouse models we show that the polymeric immunoglobulin receptor (pIgR) is highly expressed by renal cyst-lining cells. pIgR expression is in part driven by aberrant STAT6 pathway activation. pIgR actively transports dIgA from the circulation across the cyst epithelium and releases it into the cyst lumen as secretory IgA. dIgA administered by i.p. injection is preferentially targeted to polycystic kidneys while injected IgG is not. Our results suggest that pIgR-mediated transcytosis of antagonistic antibodies in dIgA format can be exploited for targeted therapy in ADPKD.