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

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.

KEYWORDS:

• EGFR
• cetuximab
• monoclonal antibody (mAb)
• safety
• humanization
• antibody-dependent cell mediated cytotoxicity (ADCC)
• NSCLC
• combination therapy
• PD-1
• HLX07

Declaration of interests

P Lin, Y Wang and H Issafras are employees of Hengenix Biotech. E Liu is an employee of Henlix Biotech. C-L Tseng, Y Cheng and C-H Ho are also employed by HanchorBio Co., Ltd and Henlix Biotech. S Chen is an employee of Anwita Biosciences, Inc. and Hengenix Biotech. W Jiang is an employee of Shanghai Henlius Biotech Inc. and Hengenix Biotech, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Author contributions

Weidong Jiang conceived of the presented work; Weidong Jiang, Pei-Hua Lin, Chi-Ling Tseng were involved in the design of sequences and planning of experiments; Pei-Hua Lin, Chi-Ling Tseng, Yun-Chih Cheng, Chieh-Hsin Ho, Shih Chieh Chen, Yanling Wang contributed to the generation, analysis and interpretation of the data; Eugene Liu led the conduct of clinical trials and was responsible for all clinical research activities at study sites; Hassan Issafras and Pei-Hua Lin were involved in the drafting of the paper or revising it critically for intellectual content; Weidong Jiang gave the final approval of the version to be published; All authors agree to be accountable for all aspects of the work.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This paper is funded by the China National Scientific and Technological Key Project of ‘Significant New Drug Development’ (2019ZX09201003-001-005) and Hengenix Biotech, Inc. Milpitas, CA, USA