Preclinical characterization of therapeutic antibodies targeted at the carboxy-terminus of Sonic hedgehog
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Bhairavi Tolani1, Ngoc T. Hoang1, Luis A. Acevedo1, Etienne Giroux Leprieur1,2, Hui Li1, Biao He1 and David M. Jablons1
1Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
2Respiratory Diseases and Thoracic Oncology Department, APHP-Ambroise Pare Hospital, Boulogne-Billancourt, France
Bhairavi Tolani, email: Bhairavi.Tolani@ucsf.edu
David M. Jablons, email: David.Jablons@ucsf.edu
Keywords: sonic hedgehog (Shh); cancer stem cells (CSCs); therapeutic antibody; targeted therapy; non-small cell lung cancer (NSCLC)
Received: September 29, 2017 Accepted: February 10, 2018 Epub: February 16, 2018 Published: March 06, 2018
The Sonic Hedgehog (Shh) signaling pathway has been implicated in the development and tumor progression of a number of human cancers. Using synthetic peptide mimics to mount an immune response, we generated a mouse mAb to the carboxy (C)-terminus of the Shh protein and characterized its preclinical antitumor effects. In vitro screening guided selection of the best candidate for mAb scale-up production and therapeutic development. C-term anti-Shh, Ab 1C11-2G4 was selected based on ELISA screens, Western blotting, and flow cytometric analyses. Purified Ab 1C11-2G4 was shown to recognize and bind both Shh peptide mimics and cell surface Shh. Administration of Ab 1C11-2G4 not only reduced cell viability in 7 cancer cell lines but also significantly inhibitted tumor growth in a xenograft model of A549 lung cancer cells. Ex vivo analyses of xenograft tumors revealed a reduction in Shh signal transduction and apoptosis in 2G4-treated mice. Collectively, our results provide early demonstration of the antitumor utility of antibodies specific for the C-terminal region of Shh, and support continued development to evaluate their potential efficacy in cancers in which Shh activity is elevated.
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