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.

Fig. 1.

Biodistribution and tumor localization of ¹¹¹In-ch806. (A and B) Whole body gamma camera images of patient 7, anterior (A) and posterior (B), on day 5 after infusion of ¹¹¹In-ch806. High uptake of ¹¹¹In-ch806 in metastatic lesions in the lungs (arrows) is evident. (C and D) Metastatic lesions (arrows) on scan. (E) 3D SPECT images of the chest. (F) Coregistered transaxial images of SPECT and CT showing specific uptake of ¹¹¹In-ch806 in metastatic lesions.

Fig. 2.

ch806 targeting of glioma. (A–C) Planar images of the head and neck of patient 8 obtained on day 0 (A), day 3 (B), and day 7 (C) after infusion of ¹¹¹In-ch806. Initial blood pool activity is seen on day 0, and uptake of ¹¹¹In-ch806 in an anaplastic astrocytoma in the right frontal lobe is evident by day 3 (arrow) and increases by day 7. (D–F) Specific uptake of ¹¹¹In-ch806 is confirmed in SPECT image of the brain (D) (arrow), at the site of tumor (arrow) evident in ¹⁸F-FDG (FDG, Fluorodeoxyglucose) positron emission tomography (E), and MRI (F).

Fig. 3.

Individual patient results for normalized whole body clearance (A) and hepatic clearance (B) of ¹¹¹In-ch806 at the 5 mg/m² (■), 10 mg/m² (▵), 20 mg/m² (▿), and 40 mg/m² (⧫) dose levels. Linear regression for data sets is indicated in each image [r² = 0.9595 (A); r² = 0.9415 (B)].