Abstract 5467: IMGN289, an EGFR-targeting antibody-maytansinoid conjugate with potent activity against non-small cell lung cancer (NSCLC) regardless of dependency on EGFR pathway.
Authors: Chittenden Thomas D. , Setiady Yulius Y. , Park Peter U. , Ponte Jose F. , Dong Ling , Skaletskaya Anna , Carrigan Christina N. , Villaluz Alfred A. , Pinkas Jan , Lutz Robert J. , Lambert John M. 
Published: August 2014

Abstract
NSCLC accounts for approximately 85% of all lung cancers. Based on tumor histology, NSCLC can be subdivided into adenocarcinoma (AC), squamous cell carcinoma (SCC), and large cell carcinoma (LCC), which account for 40%, 25-30% and 10-15% of NSCLC cases, respectively. In a fraction of AC cases, driver oncogenes have been identified that enable effective treatment with targeted therapies. For most NSCLC cases, however, etiology is still unknown and effective targeted therapies have yet to be achieved. Additionally, even cancers that initially respond to targeted therapies eventually develop resistance, creating the need for other therapeutic approaches.
EGFR is one of the best characterized driver oncogenes in NSCLC and also is frequently expressed at high levels in this indication. In house immunohistochemical analysis found EGFR to be highly expressed in 23.8% of AC (n = 21), 60% of SCC (n = 10) and 50% of LCC (n = 8), confirming published data that EGFR represents an attractive therapeutic target for NSCLC. As a novel approach to targeting EGFR-expressing tumors, we have developed IMGN289, an antibody-“drug” conjugate (ADC) consisting of the J2898A antibody (Ab), which selectively binds to EGFR and inhibits EGFR-driven tumor cell growth, conjugated to the maytansinoid DM1, a potent anti-microtubule agent, via the SMCC thioether linker. IMGN289 showed significantly enhanced cytotoxic activity, relative to cetuximab or unconjugated J2898A, against a panel of NSCLC cell lines dependent on EGFR signaling. In vitro, anti-EGFR Abs typically inhibit less than 70% of tumor cell growth at 30 nM concentration, whereas IMGN289 exposure approached 100% inhibition at a significantly lower concentration. Enhanced potency of IMGN289 against EGFR-dependent tumors was demonstrated in vivo in the H292 xenograft tumor model, where the minimally effective doses of IMGN289 and its J2898A Ab were 1 and 3 mg/kg, respectively. In addition, IMGN289 was effective against EGFR-expressing NSCLC cells that are not dependent on EGFR signaling and therefore resistant to anti-EGFR Abs. For example, IMGN289 was active against H226 and H1703 mesenchymal cell lines in vitro and H1703 xenograft tumor in vivo, while neither cetuximab nor J2898A alone was active. IMGN289 was also active against EGFR mutant HCC827 cell lines that have acquired resistance to EGFR tyrosine kinase inhibitors through T790M EGFR mutation or MET gene amplification. Thus, EGFR-targeting IMGN289 achieves a distinct anti-tumor mechanism that is independent of EGFR pathway inhibition.
In summary, IMGN289 is highly active against EGFR-positive NSCLC cells regardless of dependency on the EGFR pathway and represents a promising therapeutic candidate for NSCLC.
Citation Format: Thomas D. Chittenden, Yulius Y. Setiady, Peter U. Park, Jose F. Ponte, Ling Dong, Anna Skaletskaya, Christina N. Carrigan, Alfred A. Villaluz, Jan Pinkas, Robert J. Lutz, John M. Lambert. IMGN289, an EGFR-targeting antibody-maytansinoid conjugate with potent activity against non-small cell lung cancer (NSCLC) regardless of dependency on EGFR pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5467. doi:10.1158/1538-7445.AM2013-5467