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.