Gastric cancer is the second highest cause of cancer mortality in Asia. Over-expression of ErbB3, a cell surface RTK, occurs in ~60% of mGC patients where it is significantly associated with poorer survival. Ligand binding to ErbB3 triggers heterodimerization and downstream signaling through Akt. Neutralizing antibodies that inhibit ligand binding show poor efficacy in clinical trials, likely due to high levels of ligand independent activation in many tumor types. Directly inhibiting heterodimerization could be more effective, however, current methods of antibody isolation offer limited control over the site of antibody binding and, therefore, mechanism of action, requiring extensive screening of antibodies and posing significant challenges to identifying suitable candidates for therapeutic development.
Hummingbird Bioscience has used its proprietary Rational Antibody Development Platform for the design and development of novel therapeutic antibodies against ErbB3. Computational sequence and structural analyses predicted highly specific surface epitopes, with strong antigenicity and good safety profiles, where antibody binding would inhibit dimerization. Subsequently, Hummingbird’s directed evolution mouse immunization strategy efficiently isolated monoclonal antibodies that bound with low nM (Kd < 5nM) affinity to these epitopes on native folded ErbB3. Furthermore, these mAbs showed ELISA cross-reactivity to ErbB3 in model organisms (mouse, rat, monkey) but no binding to other EGFR family proteins.
Antibody HMBD001 was found to strongly inhibit the phosphorylation of ErbB3 and decrease downstream signaling through the Akt pathway (90% decrease in p-ErbB3 and 60% decrease in p-AKT observed at 24 hrs) resulting in the inhibition of tumor cell proliferation in models of ErbB3+ gastric cancer (over 90% inhibition of NCI-N87 proliferation after 5 days) and breast cancer (up to 85% inhibition of BT474 proliferation after 5 days). In mouse NCI-N87 gastric cancer CDX models, weekly doses of HMBD001 achieved greater than 90% inhibition of tumor growth (at 25 days) with no observable adverse toxicity.
The first in-human trial of HMBD001 is planned for 2018.
Citation Format: Jerome D. Boyd-Kirkup, Dipti Thakkar, Piers J. Ingram. HMBD001, a novel anti-ErbB3 antibody with a unique mechanism of action, effectively inhibits tumor growth in pre-clinical models of ErbB3+ solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 24. doi:10.1158/1538-7445.AM2017-24