Gisela Schwab¹, R. Figlin², A. Belldegrun², J. Crawford³, M. Lohner¹, L. Roskos¹, X-D. Yang¹, K. Foon¹, L. Weiner^4 
1Abgenix, Inc., Fremont, CA; ²University of California, Los Angeles, CA; ³Duke University, Durham, NC; ⁴Fox Chase Cancer Center, Philadelphia, PA

Effects of ABX-EGF, A Fully Human Anti-EGFr Antibody, in Patients with Advanced Cancer

The major impediment to the development of murine monoclonal anti-bodies (mAbs) for therapy in humans has been their potential immunogenicity. XenoMouse strains include YACs carrying germline-configured portions of the human IgH and Ig kappa loci, including the majority of the variable region repertoire. Immunization of XenoMouse mice with human antigens routinely results in a robust secondary immune response, which can ultimately be captured as a large panel of antigen-specific fully human IgG kappa mAbs of sub-nanomolar affinities. A fully human antibody derived from XenoMouse mice, ABX-EGF, shows anti-cancer activity in a Phase 1 trial.

The epidermal growth factor receptor (EGFr) is a transmembrane glycoprotein that promotes cell growth in a variety of normal and transformed tissues. Autocrine stimulation via EGFr is thought to play a critical role in tumor progression. Antibodies that bind to EGFr and block ligand binding have been shown to inhibit tumor growth in vitro and in vivo. ABX-EGF is a high-affinity, fully human IgG2 monoclonal antibody to EGFr generated in transgenic XenoMouseTM animals. This antibody blocks tumor growth and elicits tumor eradication in xenograft tumor models. A Phase 1 multiple-dose clinical trial of ABX-EGF is being conducted to examine the tolerability of ABX-EGF in patients with refractory cancer. Patients enrolled in this trial have received ABX-EGF weekly for 4 weeks. The patients’ cancer types include renal, prostate, non-small cell lung, pancreatic, esophageal, and colorectal. Doses up to 1.0 mg/kg have been administered with a 2x loading dose; doses of 1.0 and 1.5 mg/kg have also been administered without a loading dose. ABX-EGF has been well tolerated with no dose limiting toxicities observed up to 1.5 mg/kg. Skin rashes were observed in patients receiving higher doses of ABX-EGF. Rashes improved within one week following interruption of dosing and completely resolved within 4 weeks. No other toxicities have been observed to date. No related serious adverse experiences have been reported, and no allergic reactions or infusion-related reactions have been observed in patients receiving ABX-EGF. Human anti-human antibodies (HAHA) have not been detected in any patient receiving ABX-EGF. Stable disease has been seen in patients with prostate and esophageal cancers. Additional patients are currently being evaluated at the 2.0 mg/kg dose level, without a loading dose, in order to further determine the maximum tolerated dose. This high affinity, fully human antibody offers potential promise as a means of inhibiting signaling through the EGF receptor.