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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
Author(s) -
RenHeidenreich Lifen,
Davol Pamela A.,
Kouttab Nicola M.,
Elfenbein Gerald J.,
Lum Lawrence G.
Publication year - 2004
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.20060
Subject(s) - epithelial cell adhesion molecule , cytotoxicity , in vivo , cytotoxic t cell , cancer research , ex vivo , monoclonal antibody , in vitro , antibody , microbiology and biotechnology , cell culture , immunology , biology , biochemistry , genetics
BACKGROUND 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. METHODS 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 51 Cr 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 × 10 9 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. RESULTS 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. CONCLUSIONS 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.