A biomimetic chip to assess subcutaneous bioavailability of monoclonal antibodies in humans

Abstract

Subcutaneous injection is a common route for delivering biotherapeutics, wherein pharmacokinetics is largely influenced by drug transport in a complex subcutaneous tissue microenvironment. The selection of good drug candidates with beneficial pharmacokinetics for subcutaneous injections is currently limited by a lack of reliable testing models. To address this limitation, we report here a Subcutaneous Co-Culture Tissue-on-a-chip for Injection Simulation (SubCuTIS). Sub-CuTIS possesses a three-dimensional co-culture tissue architecture, and it allows facile quantitative determination of relevant scale independent drug transport rate constants. SubCuTIS captures key in vivo physiological characteristics of the subcutaneous tissues, and it differentiates the transport behavior of various chemically distinct molecules. We supplemented the transport measurements with theoretical modeling, which identified subtle differences in the local absorption rate constants of seven clinically available mAbs. Accounting for first order proteolytic catabolism, we established a mathematical framework to assess clinical bioavailability using the local absorption rate constants obtained from SubCuTIS. Taken together, the technology described here broadens the applicability of organson-chips as a standardized and easy-to-use device for quantitative analysis of subcutaneous drug transport.