Targeting of cells expressing wild-type EGFR and type-III mutant EGFR (EGFRvIII) by anti-EGFR MAb ICR62: a two-pronged attack for tumour therapy.
With a view to their use in cancer therapy, we have produced rat monoclonal antibodies (MAbs) directed against 5 distinct epitopes (A-E) on the external domain of the wild-type human EGF receptor (EGFR). Here, we have investigated the relative binding and anti-tumour activity of our anti-EGFR MAbs against HC2 20d2/c cells, which have been engineered to overexpress the type-III mutated form of the human EGFR (EGFRvIII). We found that anti-EGFR MAbs that are the most effective antagonists of EGFR ligands (e.g., ICR16, ICR62 and ICR80) also bind to cells that overexpress the EGFRvIII. Although these antibodies are potent inhibitors of the growth of cells which express wild-type EGFR, they did not directly inhibit the growth in vitro of EGFRvIII expressing HC2 20d2/c cells, or the constitutive tyrosine kinase activity of this receptor. However, in the presence of human peripheral blood mononuclear cells (PBMC), the rat IgG2b MAb ICR62 induced strong antibody-dependent cell-mediated cytotoxicity (ADCC) against HC2 20d2/c cells in culture. Interestingly, MAb ICR62 also inhibited very effectively experimental lung metastases of HC2 20d2/c cells in athymic nude mice. Our results suggest that anti-EGFR MAb ICR62, which binds to the EGFRvIII, may have potential in the treatment of tumors which overexpress the EGFRvIII via immunological mechanisms such as ADCC. Since tumours that are EGFRvIII positive may also overexpress the wild-type EGFR, the use of anti-EGFR MAbs that target both wild-type and mutant receptors may have advantages over those that target only1form.
Modjtahedi
Helmout
H
Division of Oncology, Postgraduate Medical School, Guildford, United Kingdom. H.Modtjahedi@surrey.ac.uk
Moscatello
David K
DK
Box
Gary
G
Green
Margaret
M
Shotton
Christine
C
Lamb
David J
DJ
Reynolds
Lesley J
LJ
Wong
Albert J
AJ
Dean
Christopher
C
Thomas
Hilary
H
Eccles
Suzanne
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D000939:Epitopes / Q000276:immunology; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D011233:Precipitin Tests; D011863:Radioimmunoassay; D051381:Rats; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*
D000911:Antibodies, Monoclonal; D000939:Epitopes; D007457:Iodine Radioisotopes; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors