Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy
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Geoffrey S. Williams1, Bina Mistry1, Sandrine Guillard1, Jane Coates Ulrichsen1, Alan M. Sandercock1, Jun Wang2, Andrea González-Muñoz1, Julie Parmentier3, Chelsea Black4, Jo Soden5, Jim Freeth5, Jelena Jovanović1, Rebecca Leyland1, Rafia S. Al-Lamki2, Andrew J. Leishman1, Steven J. Rust1, Ross Stewart1, Lutz Jermutus1, John R. Bradley2, Vahe Bedian3, Viia Valge-Archer1, Ralph Minter1, Robert W. Wilkinson1
1MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK
2Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK
3Oncology iMED, AstraZeneca-R&D Boston, Waltham, MA 02451, USA
4MedImmune LLC, Gaithersburg, MD 20878, USA
5Retrogenix Ltd, Whaley Bridge, High Peak, SK23 7LY, UK
Geoffrey S. Williams, email: email@example.com
Keywords: TNFR2, regulatory T cell, cancer immunotherapy, drug discovery, phenotypic screening
Received: May 27, 2016 Accepted: August 13, 2016 Published: September 10, 2016
Antibodies that target cell-surface molecules on T cells can enhance anti-tumor immune responses, resulting in sustained immune-mediated control of cancer. We set out to find new cancer immunotherapy targets by phenotypic screening on human regulatory T (Treg) cells and report the discovery of novel activators of tumor necrosis factor receptor 2 (TNFR2) and a potential role for this target in immunotherapy. A diverse phage display library was screened to find antibody mimetics with preferential binding to Treg cells, the most Treg-selective of which were all, without exception, found to bind specifically to TNFR2. A subset of these TNFR2 binders were found to agonise the receptor, inducing iκ-B degradation and NF-κB pathway signalling in vitro. TNFR2 was found to be expressed by tumor-infiltrating Treg cells, and to a lesser extent Teff cells, from three lung cancer patients, and a similar pattern was also observed in mice implanted with CT26 syngeneic tumors. In such animals, TNFR2-specific agonists inhibited tumor growth, enhanced tumor infiltration by CD8+ T cells and increased CD8+ T cell IFN-γ synthesis. Together, these data indicate a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy, and demonstrate the utility of target-agnostic screening in highlighting important targets during drug discovery.
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