A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors

Abstract

An array of cell-surface antigens expressed by human cancers have been identified as targets for antibody-based therapies. The great majority of these antibodies do not have specificity for cancer but recognize antigens expressed on a range of normal cell types (differentiation antigens). Over the past two decades, our group has analyzed thousands of mouse monoclonal antibodies for cancer specificity and identified a battery of antibodies with limited representation on normal human cells. The most tumor-specific of these antibodies is 806, an antibody that detects a unique epitope on the epidermal growth factor receptor (EGFR) that is exposed only on overexpressed, mutant, or ligand-activated forms of the receptor in cancer. In vitro immunohistochemical specificity analysis shows little or no detectable 806 reactivity with normal tissues, even those with high levels of wild-type (wt)EGFR expression. Preclinical studies have demonstrated that 806 specifically targets a subset of EGFR expressed on tumor cells, and has significant anti-tumor effects on human tumor xenografts, primarily through abrogation of signaling pathways. The present clinical study was designed to examine the in vivo specificity of a chimeric form of mAb 806 (ch806) in a tumor targeting/biodistribution/pharmacokinetic analysis in patients with diverse tumor types. ch806 showed excellent targeting of tumor sites in all patients, no evidence of normal tissue uptake, and no significant toxicity. These in vitro and in vivo characteristics of ch806 distinguish it from all other antibodies targeting EGFR.

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

“…Thus mAb806 has tumor-specific binding properties and would not be expected to elicit the side effects, including skin rash, observed with other cetuximab-like EGFR targeting (mAbs) associated with targeting of normal tissues. Consistent with these expectations, in a phase I trial, a radiolabeled chimeric version of mAb806 (ch806) demonstrated tumor uptake in multiple tumor types with minimal evidence of normal tissue uptake (11).…”

“…The ability of ABT-806 to cross the BBB and specifically target glioblastoma in patients is supported by the selective imaging of [ 111 In]ABT-806 in a GBM orthotopic mouse model. Phase I clinical observations with both radiolabeled ch806 and ABT-806 also indicate excellent uptake in GBM patients demonstrating that this antibody can effectively cross the BBB or that the BBB is sufficiently comprised in these patients to allow antibody uptake (11,30).…”

Cetuximab and Other Anti–Epidermal Growth Factor Receptor Monoclonal Antibodies in the Treatment of Non-Small Cell Lung Cancer

“…At doses up to 40 mg/m 2 , ch806 was well tolerated; no dose-limiting toxicity was observed and the maximum-tolerated dose was not reached. One case of SD and one progression were registered in the two patients diagnosed with advanced NSCLC [51]. The almost complete absence of EGFRvIII in NSCLC reduces the interest of ch806 in the treatment of NSCLC.…”

Antibodies specifically targeting a locally misfolded region of tumor associated EGFR

“…EGFR over-expression and mutation occur in tumor cells but are rare in normal tissues. The results from our completed Phase I clinical trial with a radio-labeled, chimeric version of mAb806 demonstrated that this antibody targets the EGFR on tumors (14). Interestingly, mAb806 also shows synergistic anti-tumor activity in animal models when used in combination with other EGFR therapeutics, including EGFR kinase inhibitors (15) and antibodies to unrelated EGFR epitopes (16).…”