Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy

Overexpression of epidermal growth factor receptor (EGFr) has been demonstr ated on many human tumors, and the increase in receptor expression levels h as been linked with a poor clinical prognosis. Blocking the interaction of EGFr and the growth factors could lead to the arrest of tumor growth and po ssibly result in tumor cell death. To this end, using XenoMouse(TM) technol ogy. ABX-EGF. a human IgG2 monoclonal antibody (mAb) specific to human EGFr , has been generated. ABX-EGF binds EGFr with high affinity (5 x 10(-11) M) , blocks the binding of both EGF and transforming growth factor-alpha (TCF- alpha) to various EGFr-expressing human carcinoma cell lines, and inhibits EGF-dependent tumor cell activation, including EGFr tyrosine phosphorylatio n, increased extracellular acidification rate, and cell proliferation. In v ivo ABX-EGF prevents completely the formation of human epidermoid carcinoma A431 xenografts in athymic mice. More importantly, administration of ABX-E GF without concomitant chemotherapy results in complete eradication of esta blished tumors. No tumor recurrence was observed for more than 8 months fol lowing the last antibody injection, further indicating complete tumor cell elimination by the antibody. Inhibition of human pancreatic, renal, breast and prostate tumor xenografts which express different levels of EGFr by ABX -EGF was also achieved. Tumor expressing more than 17 000 ECFr molecules pe r cell showed significant growth inhibition when treated with ABX-EGF. ABX- EGF had no effect on EGFr-negative tumors. The potency of ABX-EGF in eradic ating well-established tumors without concomitant chemotherapy indicates it s potential as a monotherapeutic agent For treatment of multiple EGFr-expre ssing human solid tumors, including those where no effective chemotherapy i s available. Utilization of mAbs directed to growth factor receptors as can cer therapeutics has been validated recently by the tumor responses obtaine d from clinical trials with Herceptin, the humanized anti-HER2 antibody, in patients with HER2 overexpressing metastatic breast cancer. Being a fully human antibody. ABX-EGF is anticipated to exhibit a long serum half-life an d minimal immunogenicity with repeated administration, even in immunocompet ent patients. These results demonstrate the potent anti-tumor activity of A BX-EGF and its therapeutic potential for the treatment of multiple human so lid tumors that overexpress EGFr. (C) 2001 Elsevier Science Ireland Ltd. Al l rights reserved.