In Vivo Fluorescence Imaging of the Activity of CEA TCB, a Novel T-Cell Bispecific Antibody, Reveals Highly Specific Tumor Targeting and Fast Induction of T-Cell-Mediated Tumor Killing

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...

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Published in:	Clinical cancer research Vol. 22; no. 17; pp. 4417 - 4427
Main Authors:	Lehmann, Steffi, Perera, Ramanil, Grimm, Hans-Peter, Sam, Johannes, Colombetti, Sara, Fauti, Tanja, Fahrni, Linda, Schaller, Teilo, Freimoser-Grundschober, Anne, Zielonka, Jörg, Stoma, Szymon, Rudin, Markus, Klein, Christian, Umana, Pablo, Gerdes, Christian, Bacac, Marina
Format:	Journal Article
Language:	English
Published:	United States 01-09-2016
Subjects:	Animals Antibodies, Bispecific - immunology Antibodies, Bispecific - metabolism Antibodies, Bispecific - pharmacology Antibody Specificity - immunology Antineoplastic Agents, Immunological - metabolism Antineoplastic Agents, Immunological - pharmacology Biomarkers Carcinoembryonic Antigen - immunology Cell Communication - immunology Cell Line, Tumor Cell Survival - drug effects Cell Survival - immunology Cytotoxicity, Immunologic Disease Models, Animal Female Humans Mice Microscopy, Confocal Molecular Imaging - methods Neoplasms - diagnostic imaging Neoplasms - immunology Neoplasms - metabolism Neoplasms - therapy T-Lymphocytes - immunology T-Lymphocytes - metabolism T-Lymphocytes, Cytotoxic - immunology T-Lymphocytes, Cytotoxic - metabolism Time Factors Tissue Distribution
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Summary:	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 in vitro and in vivo fluorescence imaging readouts. CEA-expressing tumor cells (LS174T) and human peripheral blood mononuclear cells (PBMC) were cocultured in vitro or cografted into immunocompromised mice. Fluorescence reflectance imaging and intravital 2-photon (2P) microscopy were employed to analyze in vivo tumor targeting while in vitro confocal and intravital time-lapse imaging were used to assess the mode of action of CEA TCB. 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. 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. Clin Cancer Res; 22(17); 4417-27. ©2016 AACRSee related commentary by Teijeira et al., p. 4277.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-15-2622