A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors.
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.
Scott
Andrew M
AM
Ludwig Institute for Cancer Research, 143-165 Studley Road, Heidelberg, Melbourne, Victoria 3084, Australia. andrew.scott@ludwig.edu.au
Lee
Fook-Thean
FT
Tebbutt
Niall
N
Herbertson
Rebecca
R
Gill
Sanjeev S
SS
Liu
Zhanqi
Z
Skrinos
Effie
E
Murone
Carmel
C
Saunder
Timothy H
TH
Chappell
Bridget
B
Papenfuss
Anthony T
AT
Poon
Aurora M T
AM
Hopkins
Wendie
W
Smyth
Fiona E
FE
MacGregor
Duncan
D
Cher
Lawrence M
LM
Jungbluth
Achim A
AA
Ritter
Gerd
G
Brechbiel
Martin W
MW
Murphy
Roger
R
Burgess
Antony W
AW
Hoffman
Eric W
EW
Johns
Terrance G
TG
Old
Lloyd J
LJ
D000368:Aged; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000295:instrumentation / Q000379:methods*; D007205:Indium Radioisotopes / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007205:Indium Radioisotopes; C518939:monoclonal antibody 806; D066246:ErbB Receptors