An anti-EGFR\u2009\xd7\u2009cotinine bispecific antibody complexed with cotinine-conjugated duocarmycin inhibits growth of EGFR-positive cancer cells with KRAS mutations

Junyeong Jin,Gunwoo Park,Jong Bae Park,Junho Chung,Soohyun Kim,Hyori Kim

doi:10.1038/s12276-018-0096-z

Abstract

Antibody-drug conjugates (ADCs) can selectively deliver cytotoxic agents to tumor cells and are frequently more potent than naked antibodies. However, optimization of the conjugation process between antibodies and cytotoxic agents and characterization of ADCs are laborious and time-consuming processes. Here, we describe a novel ADC platform using a tetravalent bispecific antibody that simultaneously binds to the tumor-associated antigen and a hapten conjugated to a cytotoxic agent. We selected cotinine as the hapten because it is not present in biological systems and is inert and nontoxic. We prepared an anti-epidermal growth factor receptor (EGFR) × cotinine bispecific antibody and mixed it with an equimolar amount of cotinine-conjugated duocarmycin to form the ADC. This ADC showed significant in vitro and in vivo antitumor activity against EGFR-positive, cetuximab-refractory lung adenocarcinoma cells with KRAS mutations.

Highlights

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase in the ErbB family
ERC6 was designed in an IgG-based tetravalent bispecific format by fusing anti-cotinine single chain variable fragments to the CH3 domains of cetuximab (Fig. 1a)[16]
In this study, we developed a new Antibody-drug conjugates (ADCs) platform composed of an antitumor-associated antigen × cotinine bispecific antibody and cotinine-cytotoxic agent

Summary

Introduction

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase in the ErbB family. Two pharmacological approaches for cancer treatment have been used to block EGFR: (1) monoclonal antibodies, including cetuximab (Erbitux), panitumumab (Vectibix), and necitumumab (Portrazza); and (2) small-molecule tyrosine kinase inhibitors, including gefitinib (Iressa), erlotinib (Tarceva), afatinib (Gilotrif), and osimertinib (Tagrisso)[2]. Mutations in EGFR and its downstream signaling molecules are associated with poor clinical response and resistance to EGFR-targeted therapy[3]. Among these oncogene aberrations, KRAS mutations are one of the most commonly occurring and are found in 25% of non-small cell lung cancers and 39% of colorectal cancers[4]. KRAS mutations play a critical role in primary resistance to EGFR-targeted therapy among

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Conclusion