Abstract
Abstract Bispecific T cell engager (BiTE®) antibody constructs redirect T cells to induce lysis of tumor cells. The anti-CD19/CD3 BiTE® Blincyto® can deplete target cells in both the blood and tissue compartment in B cell malignancies, suggesting that the BiTE® mechanism of action will also be effective against solid tumors. The tumor differentiation antigen mesothelin (MSLN) is an attractive target for the BiTE® approach. MSLN is highly expressed in >80% of ovarian and pancreatic tumors and mesothelioma. Expression of MSLN in normal tissues appears restricted to mesothelial cell surfaces such as the pleural, pericardial, and peritoneal layer. Here, we report the preclinical characterization of an anti-MSLN/CD3 BiTE® antibody construct with extended half-life. The BiTE® antibody construct binds MSLN and CD3 with low nM affinity and has low pM cytotoxic activity against MSLN-positive ovarian, pancreatic and lung cancer cell lines in vitro. Activity of the anti-MSLN/CD3 BiTE® antibody construct is observed at low effector to target cell ratios, and in cancer cells that express low levels of MSLN. This BiTE® antibody construct is also cytotoxic to cell lines that are resistant to chemotherapy. In mice, significant tumor growth inhibition of an established ovarian tumor xenograft model was achieved by IV dosing of the anti-MSLN/CD3 BiTE® antibody construct every 5 days. Pharmacokinetic evaluation of the anti-MSLN/CD3 BiTE® antibody construct in non-human primates demonstrated a half-life of 4-10 days. The potency and specificity of the anti-MSLN/CD3 BiTE® antibody construct, together with projected ability to dose once a week IV in humans, supports development of this BiTE® for treatment of MSLN-positive tumors. Citation Format: Alexander Sternjak, Fei Lee, Joachim Wahl, Dan Rock, Oliver Thomas, Sabine Stienen, Ralf Lutterbuese, Patrick Hoffmann, Tobias Raum, Peter Kufer, Benno Rattel, Angela Coxon, Matthias Friedrich, Julie Bailis. Preclinical evaluation of a BiTE® antibody construct with extended half-life that targets the tumor differentiation marker mesothelin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3630. doi:10.1158/1538-7445.AM2017-3630
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