Abstract
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.
Highlights
Immune modulatory drugs are an important pillar for anticancer treatment [1]
We assessed if the tissue centrifugation method yields fluid samples of sufficient volume, which could be used as surrogate for native tumour interstitial fluid
We combined a single-dose PKPD study with a tissue centrifugation methodology with the main objective to compare the distribution of two T-cell bispecifics (TCBs) with different binding affinities to the same tumour target and evaluate how this affects their distribution to the tumour interstitial space
Summary
Immune modulatory drugs are an important pillar for anticancer treatment [1]. Therapeutic antibodies, which are often used for immunotherapy, have an uneven distribution in plasma and tissue sub compartments [2,3,4,5]. A combination of preclinical in vitro and in vivo data together with mathematical modelling is commonly used in order to define a safe and efficacious human dose and dosing schedule. Translation based on preclinical in vivo data can be limited in cases lacking cross-reactivity of the antibody or relevant differences in target expression in preclinical animals [8,9]. In such cases, the ability of a mathematical model to predict the distribution of an antibody to the target site in vivo represents a crucial aspect
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