title: Development of a T-cell Receptor Mimic Antibody against Wild-Type p53 for Cancer Immunotherapy.
abstract: The tumor suppressor p53 is widely dysregulated in cancer and represents an attractive target for immunotherapy. Because of its intracellular localization, p53 is inaccessible to classical therapeutic monoclonal antibodies, an increasingly successful class of anticancer drugs. However, peptides derived from intracellular antigens are presented on the cell surface in the context of MHC I and can be bound by T-cell receptors (TCR). Here, we report the development of a novel antibody, T1-116C, that acts as a TCR mimic to recognize an HLA-A*0201-presented wild-type p53 T-cell epitope, p5365-73(RMPEAAPPV). The antibody recognizes a wide range of cancers, does not bind normal peripheral blood mononuclear cells, and can activate immune effector functions to kill cancer cellsin vitroIn vivo, the antibody targets p5365-73peptide-expressing breast cancer xenografts, significantly inhibiting tumor growth. This represents a promising new agent for future cancer immunotherapy.Cancer Res; 77(10); 2699-711. ©2017 AACR.
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom. alison.banham@ndcls.ox.ac.uk demin.li@ndcls.ox.ac.uk.
authors.forename: Demin
authors.initials: D
authors.lastname: Li
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
authors.forename: Carol
authors.initials: C
authors.lastname: Bentley
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
authors.forename: Amanda
authors.initials: A
authors.lastname: Anderson
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wiblin
authors.affiliation: Antibody & Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Kirstie L S
authors.initials: KLS
authors.lastname: Cleary
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Sofia
authors.initials: S
authors.lastname: Koustoulidou
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
authors.forename: Tasneem
authors.initials: T
authors.lastname: Hassanali
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
authors.forename: Jenna
authors.initials: J
authors.lastname: Yates
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
authors.forename: Jenny
authors.initials: J
authors.lastname: Greig
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
authors.forename: Marloes Olde
authors.initials: MO
authors.lastname: Nordkamp
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
authors.forename: Iva
authors.initials: I
authors.lastname: Trenevska
authors.affiliation: The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ternette
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Bart
authors.initials: B
authors.lastname: Cornelissen
authors.affiliation: Antibody & Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cragg
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom. alison.banham@ndcls.ox.ac.uk demin.li@ndcls.ox.ac.uk.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Banham
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D051379:Mice; D018716:Molecular Mimicry; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53