Development of a cyst-targeted therapy for polycystic kidney disease using an antagonistic dimeric IgA monoclonal antibody against cMET

Polycystic kidney disease (PKD) is characterized by the development of fluid-filled kidney cysts and relentless progression to renal failure. Current treatments have adverse effects and limited efficacy, enhancing the need for improved therapeutics. Here, we provide a proof of concept for the use of dimeric immunoglobulin A (IgA) (dIgA) monoclonal antibodies (mAbs) to target epithelial-enclosed cysts, by exploiting their ability to transcytose via the polymeric immunoglobulin receptor highly expressed on renal cyst-lining cells. We engineered an antagonistic dIgA mAb against the cell mesenchymal-epithelial transition (cMET) receptor, a driver of cyst progression, and demonstrated its specific binding and inhibition of cMET in vitro. In vivo studies in PKD rodent models showed efficient targeting of the mAb to renal cyst lumens and its ability to slow disease progression without apparent adverse effects. This study presents an intriguing avenue for developing antibody-based therapies for PKD and similar diseases by repurposing existing immunoglobulin G (IgG) mAbs into dIgA mAbs for superior targeting to epithelial-enclosed compartments.