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

ABSTRACT: Subcutaneous (subQ) injection is a common route for delivering biotherapeutics, wherein pharmacokinetics is largely influenced by drug transport in a complex subQ tissue microenvironment. The selection of good drug candidates with beneficial pharmacokinetics for subQ 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). SubCuTIS possesses a 3D coculture 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 subQ 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 organs-on-chips as a standardized and easy-to-use device for quantitative analysis of subQ drug transport.

SUBMITTER: Chandran Suja V

PROVIDER: S-EPMC10612570 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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

Chandran Suja Vineeth V Qi Qin M QM Halloran Kevin K Zhang Jifeng J Shaha Suyog S Prakash Supriya S Kumbhojkar Ninad N Deslandes Antoine A Huille Sylvain S Gokarn Yatin R YR Mitragotri Samir S

PNAS nexus 20231009 10

Subcutaneous (subQ) injection is a common route for delivering biotherapeutics, wherein pharmacokinetics is largely influenced by drug transport in a complex subQ tissue microenvironment. The selection of good drug candidates with beneficial pharmacokinetics for subQ 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). SubC ...[more]

PMID: 37901442

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Project description:Mycobacterium ulcerans is the bacillus responsible for Buruli ulcer, an infectious disease and the third most important mycobacterial disease worldwide, after tuberculosis and leprosy. M. ulcerans infection is a type of panniculitis beginning mostly with a nodule or an oedema, which can progress to large ulcerative lesions. The lesions are caused by mycolactone, the polyketide toxin of M. ulcerans. Mycolactone plays a central role for host colonization as it has immunomodulatory and analgesic effects. On one hand, mycolactone induces analgesia by targeting type-2 angiotensin II receptors (AT2R), causing cellular hyperpolarization and neuron desensitization. Indeed, a single subcutaneous injection of mycolactone into the mouse footpad induces a long-lasting hypoesthesia up to 48 h. It was suggested that the long-lasting hypoesthesia may result from the persistence of a significant amount of mycolactone locally following its injection, which could be probably due to its slow elimination from tissues. To verify this hypothesis, we investigated the correlation between hypoesthesia and mycolactone bioavailability directly at the tissue level. Various quantities of mycolactone were then injected in mouse tissue and hypoesthesia was recorded with nociception assays over a period of 48 h. The hypoesthesia was maximal 6 h after the injection of 4 μg mycolactone. The basal state was reached 48 h after injection, which demonstrated the absence of nerve damage. Surprisingly, mycolactone levels decreased strongly during the first hours with a reduction of 70 and 90% after 4 and 10 h, respectively. Also, mycolactone did not diffuse in neighboring skin tissue and only poorly into the bloodstream upon direct injection. Nevertheless, the remaining amount was sufficient to induce hypoesthesia during 24 h. Our results thus demonstrate that intact mycolactone is rapidly eliminated and that very small amounts of mycolactone are sufficient to induce hypoesthesia. Taken together, our study points out that mycolactone ought to be considered as a promising analgesic.

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

Publications

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

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