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Redirected T-cell cytotoxicity to epithelial cell adhesion molecule-overexpressing adenocarcinomas by a novel recombinant antibody, E3Bi, in vitro and in an animal model
Article first published online: 26 JAN 2004
Copyright © 2004 American Cancer Society
Volume 100, Issue 5, pages 1095–1103, 1 March 2004
How to Cite
Ren-Heidenreich, L., Davol, P. A., Kouttab, N. M., Elfenbein, G. J. and Lum, L. G. (2004), Redirected T-cell cytotoxicity to epithelial cell adhesion molecule-overexpressing adenocarcinomas by a novel recombinant antibody, E3Bi, in vitro and in an animal model. Cancer, 100: 1095–1103. doi: 10.1002/cncr.20060
- Issue published online: 18 FEB 2004
- Article first published online: 26 JAN 2004
- Manuscript Accepted: 11 DEC 2003
- Manuscript Revised: 18 NOV 2003
- Manuscript Received: 1 AUG 2003
- Adele R. Decof Cancer Center
- Roger Williams Hospital
- Rhode Island Foundation. Grant Number: 20020742
- National Institutes of Health. Grant Number: R01 CA92344
- Department of Defense. Grant Number: BC996442
- recombinant bispecific antibody;
- cytotoxic T lymphocyte;
- epithelial cell adhesion molecule;
- CD3 receptor;
- severe-combined immunodeficient tumor model
To redirect cytotoxic T cells to target a broad range of adenocarcinomas, the authors constructed a novel, recombinant, bispecific antibody, E3Bi, directed at the tumor-associated antigen, epithelial cell adhesion molecule (EpCAM), and the CD3 receptor on T cells.
T cells were prepared from healthy blood donors. The cytotoxicity of activated T cells (ATC) redirected to tumor cells by E3Bi was measured with in vitro 51Cr release assays. In vivo studies were performed in a severe combined immunodeficient (SCID)/Beige mouse xenograft model. Tumor-bearing mice were treated with low doses (1 mg/kg) or high doses (10 mg/kg) of E3Bi along with ATC (2 × 109 cells/kg), and treatment efficacy was evaluated both by ex vivo tumor cell survival assay after in vivo treatments and by in vivo tumor growth delay studies.
In vitro, targeting the EpCAM-overexpressing human tumor cell lines with E3Bi increased specific cytotoxicity of ATC by > 70% at an effector-to-target ratio of 2.5 (P < 0.001); this cytotoxicity was abolished competitively in the presence of an anti-EpCAM monoclonal antibody. In contrast, E3Bi did not enhance ATC cytotoxicity toward the low EpCAM-expressing tumor cell line. In ex vivo tumor cytotoxicity assays, a significant reduction in tumor cell survival (40% with low-dose E3Bi; 90% with high-dose E3Bi) was observed in E3Bi/ATC-treated mice compared with control mice that were treated with ATC only. In addition, SCID/Beige mice xenografted with LS174T tumors demonstrated a significant tumor growth delay (P = 0.0139) after receiving E3Bi/ATC/interleukin 2 (IL-2) compared with mice that received ATC/IL-2 alone.
E3Bi specifically and very efficiently redirected T cells to destroy EpCAM-overexpressing tumors both in vitro and in an animal model. These results suggest a therapeutic utility for E3Bi in the treatment of adenocarcinomas. Cancer 2004;100:1095–103. © 2004 American Cancer Society.