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

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)...

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Published inPharmaceutics Vol. 13; no. 12; p. 2105
Main Authors Eigenmann, Miro Julian, Karlsen, Tine Veronica, Wagner, Marek, Tenstad, Olav, Weinzierl, Tina, Fauti, Tanja, Grimm, Hans Peter, Skogstrand, Trude, Klein, Christian, Sam, Johannes, Umana, Pablo, Bacac, Marina, Wiig, Helge, Walz, Antje-Christine
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 07.12.2021
MDPI
Subjects
Antibodies
Biodistribution
Cytokines
Immunotherapy
interstitial space
Labeling
Laboratory animals
PBPK modelling
Pharmacodynamics
Pharmacokinetics
Plasma
Quality control
T-cell bispecifics
tumour uptake
United States > US
pharmacokinetics
tumour uptake
cytokines
interstitial space
PBPK modelling
T-cell bispecifics
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Summary: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.
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M.J.E. and T.V.K. contributed equally.
M.B., H.W. and A.-C.W. contributed equally.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics13122105