Filtration and tubular handling of EWE‐hC3Nb1, a complement inhibitor nanobody, in wild type mice and a mouse model of proteinuric kidney disease

Author:

Fast Morten Schøler1ORCID,Weyer Kathrin1,Pedersen Henrik2,Andersen Gregers Rom2,Birn Henrik13

Affiliation:

1. Department of Biomedicine Aarhus University Denmark

2. Department of Molecular Biology and Genetics – Protein Science Aarhus University Denmark

3. Departments of Clinical Medicine Aarhus University and Renal Medicine, Aarhus University Hospital Denmark

Abstract

Tubular activation and deposition of filtered complement proteins have been implicated in the progression of proteinuric kidney disease. The potent C3b‐specific nanobody inhibitor of the alternative pathway, EWE‐hC3Nb1, is likely freely filtered in the glomerulus to allow complement inhibition in the tubular lumen and may provide a novel treatment option to prevent tubulointerstitial injury. However, more information on the pharmacokinetic properties and renal tubular handling of EWE‐hC3Nb1 nanobody is required for its pharmacological application in relation to kidney disease. Here, we examined the pharmacokinetic properties of free EWE‐hC3Nb1 in mouse plasma and urine, following subcutaneous injection in wild‐type control and podocin knock out (KO) mice with severe proteinuria. Tubular handling of filtered EWE‐hC3Nb1 was assessed by immunohistochemistry (IHC) on kidney tissue from control, proteinuric mice, and KO mice deficient in the proximal tubule endocytic receptor megalin. Rapid plasma absorption and elimination of EWE‐hC3Nb1 was observed in both control and proteinuric mice; however, urinary excretion of EWE‐hC3Nb1 was markedly increased in proteinuric mice. Urinary EWE‐hC3Nb1 excretion was amplified in megalin KO mice, and substantial accumulation of EWE‐hC3Nb1 was observed in megalin‐expressing renal proximal tubules by IHC. Moreover, free EWE‐hC3Nb1 was found to be rapidly cleared from plasma. In conclusion, filtered EWE‐hC3Nb1 is reabsorbed by a megalin‐dependent process in the proximal tubules. Increased load of filtered proteins in the tubular fluid may inhibit the megalin‐dependent uptake of EWE‐hC3Nb1 in proteinuric mice. Treatment with EWE‐hC3Nb1 may allow investigation of the effects of complement inhibition in the tubular fluid.

Funder

Aarhus Universitets Forskningsfond

Danmarks Frie Forskningsfond

Publisher

Wiley

Subject

General Biochemistry, Genetics and Molecular Biology

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