An anti-EGFR × cotinine bispecific antibody complexed with cotinine-conjugated duocarmycin inhibits growth of EGFR-positive cancer cells with KRAS mutations

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. A new method for producing antibody-drug conjugates (ADCs), pairing anti-cancer drugs with antibodies that deliver them specifically to cancer cells, may help to develop therapies for hard-to-treat cancers. ADCs show promise for treating several cancers, but are difficult to produce. Junho Chung at the Seoul National University College of Medicine in South Korea and co-workers tested a new way of forming the conjugates, using cotinine, a non-toxic molecule related to nicotine, as a link. They bound cotinine to the anti-cancer drug duocarmycin, then formulated an antibody with two binding sites, one for cotinine, one for tumor cells. Combining the drug−cotinine complex with the antibody resulted in a drug–cotinine-antibody ADC that delivered duocarmycin exclusively to cancer cells and inhibited tumor growth in mice. This simplified method may help develop treatments for other drug-resistant cancers.