Li, Jing, Knee, Deborah, Wang, Youzhen, Zhang, Qingxiu, Johnson, Jennifer, Cheng, Jane, He, Helen, Miller, Christine, Li, Zhifang, Kowal, Colleen, Eckman Iii, Joseph, Tang, Betty, Yuan, Jing, Chen, Liqing, Deveraux, Quinn, Nasoff, Marc and Stover, David (2008) LBY135, a Novel Anti-DR5 Agonistic Antibody Induces Tumor Cell–Specific Cytotoxic Activity in Human Colon Tumor Cell Lines and Xenografts. Drug Development Research, 69 (2). pp. 69-82. ISSN 0272-4391

Abstract

ABSTRACT TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis on binding to DR4 and
DR5 receptors on the surface of tumor cells. These receptors are of particular interest in the development
of cancer therapeutics as they preferentially mediate tumor cell apoptosis. We have generated a chimeric
anti-DR5 agonistic antibody, LBY135, from its murine parental antibody, LCR211, identified using
hybridoma technology. Both LCR211 and LBY135 specifically bind to DR5 with nanomolar affinity, mimic
TRAIL to induce cell death in tumor cells, and have little effect on non-transformed cells in vitro. The anti-
DR5 antibody reduced viability in 45% of a panel of 40 human colon cancer cell lines with IC50 values of
20nM or less. In vivo, using human colorectal tumor xenograft mouse models, LCR211 induced tumor
regression and showed enhanced efficacy when combined with 5-FU. Both in vitro evaluation of ADCC
(antibody-dependent cell-mediated cytotoxicity) and CDC (complement-dependent cytotoxicity), and in
vivo studies using a non-functional DR5 specific antibody or SCID-Beige mice, suggested ADCC and CDC
are unlikely to be the mechanism to ablate tumors in vivo. LBY135 and LCR211 appear to mediate cell
death and tumor regression mainly through apoptosis, as demonstrated by the activation of caspase 3,
caspase 8, M30, and TUNEL assay. In addition, the discovery of synergy between cross-linked LBY135 and
TRAIL not only revealed the unique epitope of LBY135, but also demonstrated an additional mechanism of
action for LBY135 in vivo. LBY135 demonstrates promise as a novel therapeutic for cancer treatment and
is currently in Phase I clinical trials. Drug Dev Res 69: 69–82, 2008.

Item Type:	Article
Additional Information:	archiving not allowed on institutional repository
Keywords:	TRAIL; R5; agonistic antibody; anti-tumor; xenograft model
Date Deposited:	14 Dec 2009 13:56
Last Modified:	31 Jan 2013 01:09
URI:	https://oak.novartis.com/id/eprint/682