Novel Use of Recombinant Dimeric IgA Monoclonal Antibodies as Cyst-Targeted Therapeutics in Polycystic Kidney Disease

Background: The sole approved treatment for autosomal dominant polycystic kidney disease demonstrates limited efficacy and causes adverse side effects1. Urgent development of more effective therapies is imperative. While biological drugs, such as IgG monoclonal antibodies, offer increased target specificity and decreased off-target effects compared to small molecule drugs, they are unable to reach a large portion of target proteins present in cyst lumen due to their structure. Thus, we engineered a human dimeric IgA1 (dIgA) antibody - an isotype that is naturally secreted onto luminal surfaces, to target the cMET receptor on cyst-lining epithelial cells of Pkd kidneys. dIgAs have the unique ability to cross epithelial barriers via binding the polymeric immunoglobulin receptor (pIgR). We previously found pIgR highly upregulated in Pkd cyst-lining cells, giving rise to this novel dIgA targeting approach. Methods: Human IgA1 chains are co-expressed in HEK293F cells and purified using Ni-NTA and AEX chromatography to obtain dimeric IgA suitable for in vitro functional testing as well as preliminary preclinical studies. Cystic (Bpk) and wildtype (WT) mice were treated once daily for 1 week with vehicle (PBS) or 20mg/kg anti-cMET dIgA. Results: Our anti-cMET dIgA mAb has shown potent antagonistic function in the nanomolar range in vitro, and the ability to transytose via pIgR. The dIgA accumulated and remained stable for multiple days in cyst lumen after a single injection. 1-week cMET-dIgA treatment slowed cyst growth and improved kidney function in a rapid-onset Pkd mouse model. Conclusion: We have shown it is feasible to utilize antagonistic mAbs against a number of growth factors/receptors implicated in PKD to slow cyst progression and even ameliorate kidney dysfunction, provided they are in dIgA format. This approach has the potential to eliminate all extra-renal side effects seen with small molecule drugs, and thus, would be tolerable and effective during long-term treatment in PKD clinical trials. Funding: Other NIH Support - NIH (R01DK109563, R01DK124895), Commercial Support - Chinook Therapeutics, Other U.S. Government Support, Private Foundation Support