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RN765C, a low affinity EGFR antibody drug conjugate with potent anti-tumor activity in preclinical solid tumor models


The cover for issue 71 of Oncotarget features Figure 1B, "Schematic representation to illustrate the differential binding and internalization of low affinity EGFR-ADC on normal cells versus tumor cells that express higher level of the receptors," by Wong, et al.

Potent in vitro cytotoxicity of RN765C, with nanomolar to subnanomolar EC50, was observed on a panel of cancer cell lines expressing moderate to high level of EGFR. Mechanistically, RN765C has multiple modes of action: inducing payload mediated mitotic arrest and cell death, blocking EGFR pathway signal and mediating antibody dependent cell cytotoxicity.

Dr. Oi Kwan Wong from the Oncology R&D, Cancer Immunology Discovery Unit, Pfizer Inc., South San Francisco, CA, USA and Allogene Therapeutics, South San Francisco, CA, USA said, "It plays essential roles in the development and normal physiology of epithelial cells, including cell proliferation, growth, differentiation, migration and inhibition of apoptosis."

Figure 1: Strategy to develop an effective EGFR ADC. (A) EGFR antibodies only partially inhibit growth of A431 cells. The ability of mAb-D (our in-house monoclonal anti-EGFR antibody) and cetuximab to inhibit A431 cell growth was performed over a treatment time of 5 days in DMEM medium + 5% FBS. Viable cell number remaining in the cultures was assessed using CellTiter-Glo® and normalized to the value from wells treated with isotype control antibody. Each treatment was done in triplicate. (B) Schematic representation to illustrate the differential binding and internalization of low affinity EGFR-ADC on normal cells versus tumor cells that express higher level of the receptors.

A clinically proven strategy to treat EGFR driven tumors is to block the EGFR pathway signaling. To this end, both monoclonal lig and blocking antibodies such as cetuximab and panitumumab as well as EGFR tyrosine kinase inhibitors have been approved. EGFR is widely overexpressed in many types of solid tumor, the researchers aimed to develop a more broadly applicable therapy that does not solely rely on blocking of the EGFR signaling. Antibody drug conjugates exploit the binding specificity of monoclonal antibodies as a mechanism for selective delivery of cytotoxic agents to kill tumor cells. In contrast, on EGFR overexpressing tumor cells, the high receptor density allows RN765C to establish stable bivalent binding leading to efficient ADC internalization and release of the payload to kill tumor cells. Indeed, RN765C showed potent in vitro cell killing activity in EGFR high tumor cell lines, even in those that were non-responsive to cetuximab.

The Oi Kwan Wong research team concluded, "Among them, three are for hematologic malignances and only one is for solid tumor indication. As most solid tumor antigens have normal tissue expression, one of the major obstacles for ADCs in solid tumors is to deliver sufficient toxic payload to tumor cells without causing serious normal tissue toxicity."

Full text - https://doi.org/10.18632/oncotarget.26002

Correspondence to - Oi Kwan Wong - oikwan@gmail.com

Keywords - EGFR, antibody-drug conjugate, site-specific conjugation, non-small cell lung cancer, target therapy

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