Distinguishing features of a novel humanized anti-EGFR monoclonal antibody based on cetuximab with superior antitumor efficacy

Abstract

ABSTRACT Background Cetuximab, the first approved EGFR targeting therapeutic antibody, is currently used to treat colorectal cancer and head and neck cancer. While effective, cetuximab is associated with a higher rate of skin rash, infusion reactions, and gastrointestinal toxicity, which was suggested to be linked to the presence of heterogeneous glycan contents on the Fab of the SP2/0-produced cetuximab. Objective and Methods To improve efficacy and minimize toxicity of EGFR inhibition treatment, we re-engineered cetuximab by humanizing its Fab regions and minimizing its glycan contents to generate HLX07. Results HLX07 binds to EGFR with similar affinity as cetuximab and shows better bioactivity compared to cetuximab in vitro. In vivo studies demonstrated that HLX07 significantly inhibited the growth of A431, FaDu, NCI-H292, and WiDr tumor cells and synergized them with chemotherapeutics and immune simulator agents such as anti-PD-1. In cynomolgus monkeys, 13-week repeat-dose GLP toxicokinetic studies showed minimal-to-mild toxicities in the dose range of up to 60 mg/kg/wk. In the preliminary phase 1 dose-escalation study, HLX07 had showed lower incidence of skin rashes with grade >2 severities. Conclusion HLX07 is currently under phase 1/2 clinical development. We believe HLX07 would potentially be an alternative for patients who have been suffering from cetuximab-mediated toxicity.