Pharmacokinetics and Pharmacodynamics of T-Cell Bispecifics in the Tumour Interstitial Fluid

Autor: Miro Julian Eigenmann, Tine Veronica Karlsen, Marek Wagner, Olav Tenstad, Tina Weinzierl, Tanja Fauti, Hans Peter Grimm, Trude Skogstrand, Christian Klein, Johannes Sam, Pablo Umana, Marina Bacac, Helge Wiig, Antje-Christine Walz
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Pharmaceutics, Vol 13, Iss 12, p 2105 (2021)
Druh dokumentu: article
ISSN: 1999-4923
DOI: 10.3390/pharmaceutics13122105
Popis: The goal of this study is to investigate the pharmacokinetics in plasma and tumour interstitial fluid of two T-cell bispecifics (TCBs) with different binding affinities to the tumour target and to assess the subsequent cytokine release in a tumour-bearing humanised mouse model. Pharmacokinetics (PK) as well as cytokine data were collected in humanised mice after iv injection of cibisatamab and CEACAM5-TCB which are binding with different binding affinities to the tumour antigen carcinoembryonic antigen (CEA). The PK data were modelled and coupled to a previously published physiologically based PK model. Corresponding cytokine release profiles were compared to in vitro data. The PK model provided a good fit to the data and precise estimation of key PK parameters. High tumour interstitial concentrations were observed for both TCBs, influenced by their respective target binding affinities. In conclusion, we developed a tailored experimental method to measure PK and cytokine release in plasma and at the site of drug action, namely in the tumour. Integrating those data into a mathematical model enabled to investigate the impact of target affinity on tumour accumulation and can have implications for the PKPD assessment of the therapeutic antibodies.
Databáze: Directory of Open Access Journals
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