Abstract
<div>Abstract<p><b>Purpose:</b> CEA TCB (RG7802, RO6958688) is a novel T-cell bispecific antibody, engaging CD3ϵ upon binding to carcinoembryonic antigen (CEA) on tumor cells. Containing an engineered Fc region, conferring an extended blood half-life while preventing side effects due to activation of innate effector cells, CEA TCB potently induces tumor lysis in mouse tumors. Here we aimed to characterize the pharmacokinetic profile, the biodistribution, and the mode of action of CEA TCB by combining <i>in vitro</i> and <i>in vivo</i> fluorescence imaging readouts.</p><p><b>Experimental Design:</b> CEA-expressing tumor cells (LS174T) and human peripheral blood mononuclear cells (PBMC) were cocultured <i>in vitro</i> or cografted into immunocompromised mice. Fluorescence reflectance imaging and intravital 2-photon (2P) microscopy were employed to analyze <i>in vivo</i> tumor targeting while <i>in vitro</i> confocal and intravital time-lapse imaging were used to assess the mode of action of CEA TCB.</p><p><b>Results:</b> Fluorescence reflectance imaging revealed increased ratios of extravascular to vascular fluorescence signals in tumors after treatment with CEA TCB compared with control antibody, suggesting specific targeting, which was confirmed by intravital microscopy. Confocal and intravital 2P microscopy showed CEA TCB to accelerate T-cell–dependent tumor cell lysis by inducing a local increase of effector to tumor cell ratios and stable crosslinking of multiple T cells to individual tumor cells.</p><p><b>Conclusions:</b> Using optical imaging, we demonstrate specific tumor targeting and characterize the mode of CEA TCB–mediated target cell lysis in a mouse tumor model, which supports further clinical evaluation of CEA TCB. <i>Clin Cancer Res; 22(17); 4417–27. ©2016 AACR</i>.</p><p><i>See related commentary by Teijeira et al., p. 4277</i></p></div>
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