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- W4308394489 abstract "<h3>Background</h3> NM32-2668 is a fragment-based multispecific antibody therapeutic<sup>1</sup> that has been designed to activate T-cells (via CD3) in the presence of tumour antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1). The objective of this work was to build a mathematical model to establish a PKPD relationship using both <i>in vitro</i> and <i>in vivo</i> data for NM32-2668. <h3>Methods</h3> Data were collected from<i> in vitro</i> studies measuring CD4/8 activation and cytotoxicity from a panel of cell lines and patient samples to increasing concentrations of NM32-2668, and from <i>in vivo</i> tumour growth inhibition (TGI) data from a humanised mouse model in one cell line with two different donors with increasing doses of NM32-2668. Nonlinear mixed-effects models were used to assess the variability in cytotoxicity as a function of drug concentration and immune system activation. The translatability of <i>in vitro</i> potency values for immune system activation was assessed by linking PK to <i>in vitro</i> data and to TGI <i>in vivo</i> data. <h3>Results</h3> The combination of ROR1 expression and CD8 activation fully explained the variance in cytotoxicity across all <i>in vitro</i> data. The estimated <i>in vitro</i> potency for CD8 activation could successfully be used to provide a link between PK and TGI in vivo. <h3>Conclusions</h3> A PK-PD-Efficacy model based on the <i>in vitro</i> data was established showing that the cytotoxicity response was strongly correlated to ROR1 expression and CD8 activation. Building on this <i>in vitro</i> model, we developed an <i>in vivo</i> PK-TGI model that can link immune system activation to TGI. <h3>Reference</h3> Egan TJ, Diem D, Weldon R, Neumann Y, Meyer S, Urech DM. Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments. <i>MABS</i>. 2017;<b>9</b>(1):68–84" @default.
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- W4308394489 date "2022-11-01" @default.
- W4308394489 modified "2023-09-25" @default.
- W4308394489 title "1293 Establishing the preclinical PKPD relationship for NM32–2668 a ROR1 targeting T cell engager" @default.
- W4308394489 doi "https://doi.org/10.1136/jitc-2022-sitc2022.1293" @default.
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