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A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors

Authors :
Bridget Chappell
Antony W. Burgess
Anthony T. Papenfuss
Gerd Ritter
Andrew M. Scott
A. M. T. Poon
Wendie Hopkins
Lloyd J. Old
Lawrence M Cher
T. Saunder
Eric W. Hoffman
Fiona E Smyth
Zhanqi Liu
Martin W. Brechbiel
Effie Skrinos
Roger Murphy
Fook-Thean Lee
Carmel Murone
Duncan MacGregor
R. A. Herbertson
Niall C. Tebbutt
Achim A. Jungbluth
S Gill
Terrance Grant Johns
Source :
Proceedings of the National Academy of Sciences. 104:4071-4076
Publication Year :
2007
Publisher :
Proceedings of the National Academy of Sciences, 2007.

Abstract

An array of cell-surface antigens expressed by human cancers have been identified as targets for antibody-based therapies. The great majority of these antibodies do not have specificity for cancer but recognize antigens expressed on a range of normal cell types (differentiation antigens). Over the past two decades, our group has analyzed thousands of mouse monoclonal antibodies for cancer specificity and identified a battery of antibodies with limited representation on normal human cells. The most tumor-specific of these antibodies is 806, an antibody that detects a unique epitope on the epidermal growth factor receptor (EGFR) that is exposed only on overexpressed, mutant, or ligand-activated forms of the receptor in cancer. In vitro immunohistochemical specificity analysis shows little or no detectable 806 reactivity with normal tissues, even those with high levels of wild-type (wt)EGFR expression. Preclinical studies have demonstrated that 806 specifically targets a subset of EGFR expressed on tumor cells, and has significant anti-tumor effects on human tumor xenografts, primarily through abrogation of signaling pathways. The present clinical study was designed to examine the in vivo specificity of a chimeric form of mAb 806 (ch806) in a tumor targeting/biodistribution/pharmacokinetic analysis in patients with diverse tumor types. ch806 showed excellent targeting of tumor sites in all patients, no evidence of normal tissue uptake, and no significant toxicity. These in vitro and in vivo characteristics of ch806 distinguish it from all other antibodies targeting EGFR.

Details

ISSN :
10916490 and 00278424
Volume :
104
Database :
OpenAIRE
Journal :
Proceedings of the National Academy of Sciences
Accession number :
edsair.doi.dedup.....f3e28e712a4f814ec60667b9de4160ed
Full Text :
https://doi.org/10.1073/pnas.0611693104