Abstract
Anti-EGF receptor (EGFR) antibodies and small-molecule tyrosine kinase inhibitors have shown activity in epithelial tumors; however, agents that work by blocking the EGFR growth signal are ineffective when the oncogenic stimulus arises downstream, such as in tumors with KRAS mutations. Antibodies of the IgG1 subclass can also kill tumor cells directly through antibody-dependent cell-mediated cytotoxicity (ADCC), and the efficacy of this is determined by the interaction of the Fc portion of the target cell-bound antibody and Fc receptors present on immune effector cells. We report the development of GA201, a novel anti-EGFR monoclonal antibody with enhanced ADCC properties. GA201 was derived by humanization of the rat ICR62 antibody. The Fc region of GA201 was glycoengineered to contain bisected, afucosylated carbohydrates for enhanced binding to FcγRIIIA. In vitro binding of GA201 to EGFR inhibited EGF ligand binding, EGFR/HER2 heterodimerization, downstream signaling, and cell proliferation to a similar extent as cetuximab. However, GA201 exhibited superior binding to both the low- and high-affinity variants of FcγRIIIA. This resulted in significantly enhanced induction of ADCC compared with cetuximab against both KRAS-wild-type and -mutant tumor cells lines. This enhanced ADCC translated into superior in vivo efficacy in a series of mouse xenograft models. Efficacy of GA201 was further increased when administered in combination with chemotherapy (irinotecan). These data suggest that GA201 may be more effective than cetuximab in patients with EGFR-positive solid tumors and may also represent a first-in-class treatment of patients with KRAS-mutated tumors. Clin Cancer Res; 19(5); 1126-38. ©2012 AACR.
Highlights
The expression or activation of the EGF receptor (EGFR)has been shown in various epithelial malignancies including colorectal cancer (CRC), squamous cell carcinoma of the head and neck (HNSCC), and carcinomas of the pancreas, lung, cervix, renal cell, prostate, bladder, and breast [1]
GA201 exhibited superior binding to both the low- and high-affinity variants of FcgRIIIA. This resulted in significantly enhanced induction of antibody-dependent cell-mediated cytotoxicity (ADCC) compared with cetuximab against both KRAS-wild-type and -mutant tumor cells lines
Efficacy of GA201 was further increased when administered in combination with chemotherapy
Summary
The expression or activation of the EGF receptor (EGFR)has been shown in various epithelial malignancies including colorectal cancer (CRC), squamous cell carcinoma of the head and neck (HNSCC), and carcinomas of the pancreas, lung, cervix, renal cell, prostate, bladder, and breast [1]. The small-molecule EGFR tyrosine kinase inhibitors (TKI) erlotinib (Tarceva) and gefitinib (Iressa) have shown activity in multiple epithelial tumor types and have provided a scientific rationale for the development of EGFR antagonists as targeted therapeutics [3]. These compounds reversibly bind to the ATP-binding site of the EGFR tyrosine kinase domain and inhibit autophosphorylation [4]. Initial results with these molecules as monotherapy or in combination with chemotherapy in unselected populations were disappointing. It is known that mutations in the EGFR gene alter the tumor phenotype and predict response to treatment, allowing the molecular selection of a subset of patients in which TKI are highly efficacious [5, 6]
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