Utility of an in vitro lymphatics on-chip model for rank ordering subcutaneous absorption of monoclonal antibodies

Abstract

The lymphatic vasculature plays a key role in the subcutaneous absorption of macromolecules (>16 kDa). Recent trends toward subcutaneous delivery of macromolecular therapeutics have brought awareness to the need for preclinical estimation of subcutaneous bioavailability prior to first in human studies. In vitro tools offer a low cost means to inform molecule design and formulation and mitigate costly mistakes of under- or overestimation of therapeutic dose and exposure in clinical studies. Building on a previous engineered on-chip lymphatics platform, the utility of an in vitro model to rank therapeutic proteins based on lymphatic absorption was investigated. Lymphatics grown under a combination of interstitial flow and growth factor supplementation on-chip demonstrated in vivo-like morphology, phenotypic marker expression, and solute drainage rates. Dextrans of increasing molecular weight were assessed on the model and demonstrated an inverse relationship between size and diffusion coefficient. More importantly, lymphatic transport of a panel of nine therapeutic proteins and monoclonal antibodies successfully rank ordered subcutaneous bioavailability in human (Pearson r = 0.8929). The on-chip lymphatics model described here bridges a pharmaceutical industry gap for estimating the relative subcutaneous bioavailability during early drug development increasing the potential for successful candidate selection and more accurate dose and exposure estimates.