Phase I trial and tumour localisation of the anti-EGFR monoclonal antibody ICR62 in head and neck or lung cancer.
The purpose of this study was to determine the effect of the first rat monoclonal antibody (MAb ICR62) to the epidermal growth factor receptor (EGFR) in a phase I clinical trial in patients with unresectable squamous cell carcinomas. This antibody effectively blocks the binding of EGF, transforming growth factor (TGF)-alpha and HB-EGF to the EGFR, inhibits the growth in vitro of tumour cell lines which overexpress the EGFR and eradicates such tumours when grown as xenografts in athymic mice. Eleven patients with squamous cell carcinoma of the head and neck and nine patients with squamous cell carcinoma of the lung, whose tumours expressed EGFR, were recruited. Groups of three patients were treated with 2.5 mg, 10 mg, 20 mg or 40 mg of ICR62 and a further eight patients received 100 mg. All patients were evaluated for toxicity using WHO criteria. Patients' sera were tested for the clearance of MAb ICR62 and the development of human anti-rat antibodies (HARA). No serious (WHO Grade III-IV) toxicity was observed in patients treated with up to 100 mg of antibody ICR62. Antibody ICR62 could be detected at 4 h and 24 h in the sera of patients treated with 40 mg or 100 mg of ICR62. Only 4/20 patients showed HARA responses (one at 20 mg, one at 40 mg and two at 100 mg doses) and of these only the former two were anti-idiotypic responses. In four patients receiving doses of ICR62 at 40 mg or greater, biopsies were obtained from metastatic lesions 24 h later and examined for the localisation of ICR62 using anti-rat antibody reagent. In these patients we showed the localisation of MAb ICR62 to the membranes of tumour cells; this appeared to be more prominent at the higher dose of 100 mg. On the basis of these data we conclude that MAb ICR62 can be administered safely to patients with squamous cell carcinomas and that it can localise efficiently to metastases even at relatively low doses.
Modjtahedi
H
H
Section of Immunology, McElwain Laboratories, Institute of Cancer Research, Sutton, UK.
Hickish
T
T
Nicolson
M
M
Moore
J
J
Styles
J
J
Eccles
S
S
Jackson
E
E
Salter
J
J
Sloane
J
J
Spencer
L
L
Priest
K
K
Smith
I
I
Dean
C
C
Gore
M
M
D000328:Adult; D000368:Aged; D000818:Animals; D000910:Antibodies, Heterophile / Q000097:blood; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D002462:Cell Membrane / Q000378:metabolism; D066246:ErbB Receptors / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D051381:Rats
D000910:Antibodies, Heterophile; D000911:Antibodies, Monoclonal; D066246:ErbB Receptors