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

Oi Kwan Wong,Pavel Strop,Melinda Au,Meritxell Galindo Casas,Arvind Rajpal,Thomas-Toan Tran,Marjorie Bateman,Shu-Hui Liu,Wei-Hsien Ho,Kevin C Lindquist,David L Shelton

doi:10.18632/oncotarget.26002

Abstract

Epidermal growth factor receptor (EGFR) is a clinically validated target and often overexpressed in some solid tumors. Both EGFR tyrosine kinase inhibitors and ligand-blocking antibodies have been approved for treatment of NSCLC, head and neck cancers and colorectal cancers. However, clinical response is limited and often accompanied by significant toxicities due to normal tissue expression. To improve the effectiveness of targeting EGFR while minimizing the toxicities on normal tissues, we developed a low-affinity anti-EGFR antibody drug conjugate (ADC), RN765C. 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. In contrast, RN765C was less effective in killing normal human keratinocytes, presumably due to its lower receptor expression. 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. In preclinical studies, a single dose of RN765C at 1.5-3 mg/kg was generally sufficient to induce tumor regression in multiple cell line and patient-derived xenograft models, including those that are resistant to EGFR-directed tyrosine kinase inhibitors. Our data support further investigation of RN765C in the clinic to treat EGFR expressing solid tumors.

Highlights

Epidermal growth factor receptor (EGFR) is a member of the ErbB family of type I receptor tyrosine kinases
We described here a novel low affinity anti-EGFR antibody drug conjugate (ADC), RN765C, designed to have potent anti-tumor activity in tumors with medium to high EGFR expression
RN765C is able to utilize three mechanisms to inhibit tumor growth: 1) active cell killing mediated by its potent payload PF-06380101, 2) blocking of EGFR signaling pathway due to ligand blocking property of its parental antibody, and 3) antibody dependent cell cytotoxicity provided by human IgG1 backbone (Table 2, Figure 3 and Supplementary Figure 2)

Summary

Introduction

EGFR is a member of the ErbB family of type I receptor tyrosine kinases. It plays essential roles in the development and normal physiology of epithelial cells, including cell proliferation, growth, differentiation, migration and inhibition of apoptosis [1]. A clinically proven strategy to treat EGFR driven tumors is to block the EGFR pathway signaling. To this end, both monoclonal ligand blocking antibodies such as cetuximab and panitumumab as well as EGFR tyrosine kinase inhibitors (TKIs; erlotinib, gefitinib, lapatinib, afatinib, osimertinib) have been approved [2]. In www.oncotarget.com addition, treatment related moderate to severe cutaneous and gastrointestinal toxicities were often observed [5]. More effective treatment of EGFR positive tumors is needed

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