Engineering Proteins for Reabsorption in the Renal Proximal Tubule

1264807

Lazzara, Matthew J.

The clearance of proteins from plasma by the kidneys constitutes one of the most significant pathways leading to reduced bioavailability of protein-based therapeutics. The loss of such proteins via the renal system is greatest for proteins which are not efficiently retained by the filtration apparatus of the glomerular capillary wall and which are not efficiently reabsorbed from the primary urine within the proximal tubule. While some protein-based therapeutics have been engineered for reduced renal clearance by covalent modification or fusion to bulky inert proteins, such modifications may alter therapeutic availability to intended target tissues. The investigators propose to identify minimal epitopes within albumin that trigger the efficient proximal tubule reabsorption of this abundant plasma protein through cognate transport receptors expressed in the proximal epithelium and to use this information to engineer generic peptides that can be fused to any therapeutic protein to reduce its renal clearance by causing its intact reabsorption. The experimental aims will leverage tools within the investigators? laboratories to engineer proteins, analyze protein interactions with cells and receptors, and measure intracellular protein trafficking processes. The computational aim will leverage mass transport and kinetic modeling approaches to create a quantitative framework for predicting how changes to protein binding and endocytosis will improve therapeutic bioavailability and how to optimally engineer proteins. In addition, this project will have broader impact through integrated educational programs in which the science behind the research objectives will be disseminated to students and teachers in multiple educational settings.

Protein-based therapeutics are becoming increasingly common due to their exquisite biological functions and specificities. The investigators? work will have broad implications for enhancing therapeutic protein efficacy. Indeed, the successful engineering of the intact reabsorption of model proteins will enable the application of this technology to any protein-based therapeutic and create a fundamentally new modularity for protein-based drugs. This has potential for tremendous societal impact through enhancement of therapeutic efficacy and patient treatment regimens, as well as reduction in the financial burden associated with production and administration of protein-based drugs.