Oncotarget

Priority Research Papers:

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

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

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Oncotarget. 2018; 9:33446-33458. https://doi.org/10.18632/oncotarget.26002

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Abstract

Oi Kwan Wong1,6, Thomas-Toan Tran1,3, Wei-Hsien Ho1,4, Meritxell Galindo Casas1,5, Melinda Au1,6, Marjorie Bateman1, Kevin C. Lindquist1, Arvind Rajpal1,2, David L. Shelton1, Pavel Strop1,2 and Shu-Hui Liu1,7

1 Oncology R&D, Cancer Immunology Discovery Unit, Pfizer Inc., South San Francisco, CA, USA

2 Bristol-Myers Squibb, Redwood City, CA, USA

3 NGM Biopharmaceuticals, South San Francisco, CA, USA

4 Alector Inc., South San Francisco, CA, USA

5 acib GmbH Graz, Graz, Austria

6 Allogene Therapeutics, South San Francisco, CA, USA

7 Abmart Inc., Redwood City, CA, USA

Correspondence to:

Oi Kwan Wong, email: [email protected]

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

Received: June 26, 2018    Accepted: August 06, 2018    Published: September 11, 2018

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.


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