Abstract 5483: Preclinical evaluation of IMGN289, an anti-EGFR antibody-maytansinoid conjugate for the treatment of squamous cell carcinoma of the head and neck.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Squamous cell carcinoma of the head and neck (SCCHN) include cancers that affect the squamous epithelium of the mouth, larynx, nasal passages, sinuses and pharynx. The epidermal growth factor receptor (EGFR) has emerged as an important antigen for novel targeted therapies in SCCHN, where EGFR overexpression correlates with aggressive disease, resistance to standard therapies and a poor prognosis. EGFR expression was evaluated on a panel of SCCHN xenografts and primary SCCHN tumors using a calibrated immunohistochemical (IHC) staining method on formalin-fixed paraffin-embedded sections. The results demonstrated that 83 of 85 (98%) SCCHN tumors stained positive for EGFR and, of the 83 positive tumors, 80 (96%) had high EGFR expression, confirming that EGFR represents an attractive therapeutic target for SCCHN. IMGN289 is an antibody-“drug” conjugate (ADC) consisting of the humanized monoclonal antibody, J2898A, which selectively binds to EGFR, linked to the potent cytotoxic maytansinoid, DM1, via a SMCC thioether linker. The cytotoxic activity of IMGN289 was evaluated against a panel of SCCHN cell lines in vitro. IMGN289 was active in 9 of 13 cell lines assayed, including 5 of 8 that were resistant to cetuximab. Cytotoxic activity was observed against cell lines originating from multiple anatomic sites including the pharynx, oral cavity, larynx and tongue. The anti-tumor activity of IMGN289 was evaluated in EGFR-positive SCCHN xenograft models with expression levels comparable to patient tumors. Immunodeficient mice bearing established subcutaneous xenograft tumors were treated with a single intravenous injection of IMGN289 at 1, 2.5 or 5.0 mg/kg (based on antibody concentration). A group of mice dosed with the J2898A antibody at 5 mg/kg was included in the study. In the FaDu xenograft model, IMGN289 was active with a minimally efficacious dose (MED) of 1 mg/kg, highly active at 2.5, and at 5 mg/kg 5/6 partial regressions (PR) and 2/6 complete regressions (CR) were observed. Conjugation of DM1 to J2898A achieved greater anti-tumor activity than J2898A, which was active in the study but without regressions. In the HSC-2 xenograft model, IMGN289 was also highly active, with a MED of 2.5 mg/kg and tumor regression at 5 mg/kg with 6/6 PR and 4/6 CR. Once again, the activity of IMGN289 was more robust than naked J2898A antibody, which was active with 2/6 PR and 1/6 CR. The strong anti-tumor activity of IMGN289 against SCCHN xenograft tumors with EGFR expression levels comparable to patient tumors suggests that IMGN289 may be a promising compound for the treatment of SCCHN. Citation Format: Jose F. Ponte, Yulius Y. Setiady, Ling Dong, Anna Skaletskaya, Christina N. Carrigan, Alfred Anderson-Villaluz, Robert J. Lutz, Jan Pinkas. Preclinical evaluation of IMGN289, an anti-EGFR antibody-maytansinoid conjugate for the treatment of squamous cell carcinoma of the head and neck. [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 5483. doi:10.1158/1538-7445.AM2013-5483