(W1430-02-07) Novel Use of Recombinant Dimeric IgA Monoclonal Antibodies as Cyst-Targeted Therapeutics in Polycystic Kidney Disease

Purpose: The first, and sole approved pharmacological treatment for autosomal dominant polycystic kidney disease, or PKD, demonstrates limited efficacy and causes adverse effects on patients’ quality of life1. Urgent development of more effective therapies with less extra-renal side effects is imperative. While biological drugs, such as IgG monoclonal antibodies, offer increased target specificity compared to small molecules drugs, they face challenges reaching most targets due to their inability to cross epithelial barriers. These targets implicated in PKD predominantly reside in cyst lumen, accessible only to drugs that can traverse epithelial cells2. Addressing this limitation, we engineered a human dimeric IgA1 antibody, an isotype that is naturally secreted onto luminal surfaces, to target the overactive cMET receptor tyrosine kinase present on cyst-lining cells. Short-term preclinical trials in PKD rodents revealed that the dimeric IgA effectively inhibits membrane-bound cMET receptors specifically in renal cyst luminal spaces. Within one week in a rapidly progressing PKD mouse model, treatment slowed cyst progression with no observed extra-renal side effects. These findings suggest a promising avenue for expanding the repertoire of specific PKD therapies by repurposing previously characterized IgG antibodies into cyst-targeting dimeric IgA antibodies.

Methods: Human IgA1 alpha heavy (H) and kappa light (L) chains are co-expressed with the joining chain (J chain), which contains a Myc and histidine tag, in HEK293F cells to obtain monomeric and dimeric IgA. Supernatants are purified using Ni-NTA and AEX chromatography (Fig 1a, b). 10 cystic and 10 wildtype 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 in vitro target binding (Fig. 1c), and specific antagonistic function in the nanomolar range (Fig. 1d). With a single injection, these dIgA mAbs accumulate in CF and are present in serum for up to 5 days post injection (fig 2a,b). This dIgA recovered from CF shows a size shift due to attachment of secretory component during pIgR mediated transcytosis (Fig. 2c). 1 week anti-cMET treatment showed an improvement in kidney-to-body weight, cystic index, and serum creatinine (Fig. 2d,f,g,h). The dIgA inhibited its target in cyst-lining cells of Bpk mice and showed attenuated downstream ERK activation in dIgA positive cysts (Fig. 2e).

Conclusion: Our lab has recently devised a strategy of combining the molecular specificity of monoclonal antibodies (mAbs) with a method of targeting such antibodies specifically to renal cyst lumens in ADPKD with the use of dimeric immunoglobulin A (dIgA) antibodies and the unique expression of the polymeric immunoglobulin receptor (pIgR) on cyst-lining epithelial cells3. The findings from this study suggest that it is feasible to utilize antagonistic mAbs against a number of growth factors/receptors implicated in ADPKD for long term therapy, provided that the mAbs are in dIgA format.

References: 1. Anderson CL. Doubts about the efficacy of tolvaptan for polycystic kidney disease. Clin Nephrol. 2020;93(6):307-309.
2. Weimbs T, Shillingford JM, Torres J, Kruger SL, Bourgeois BC. Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease. Clin Kidney J. 2018;11(Suppl 1):i27-i38.
3. Olsan EE, Matsushita T, Rezaei M, Weimbs T. Exploitation of the Polymeric Immunoglobulin Receptor for Antibody Targeting to Renal Cyst Lumens in Polycystic Kidney Disease. J Biol Chem. 2015;290(25):15679-15686.

Acknowledgements: This project was partially funded by Chinook Therapeutics. Dr. Stefan Lohse generously provided the joining-chain plasmid used to make the dIgA antibody. All animal studies adhered to the rules and regulations of the National Institutes of Health with the approval of the Institutional Animal Care and Use Committee of the University of California, Santa Barbara.