879 A promising cancer immunotherapy target: novel fully human agonist antibodies against the human T-cell costimulatory receptor CD27
| Autor: | Thierry Guillaudeux, Yulia Ovechkina, Eric J. Tarcha, David Jurchen, Shawn P. Iadonato, David Peckham, Emily Frazier, Shaarwari Sridhar |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Agonist Cancer Research medicine.drug_class Chemistry T cell Immunology T-cell receptor CD28 Neoplasms. Tumors. Oncology. Including cancer and carcinogens hemic and immune systems chemical and pharmacologic phenomena Monoclonal antibody Jurkat cells medicine.anatomical_structure Oncology Cancer research medicine Molecular Medicine Immunology and Allergy Cytotoxic T cell Receptor RC254-282 |
| Zdroj: | Journal for ImmunoTherapy of Cancer, Vol 9, Iss Suppl 2 (2021) |
| ISSN: | 2051-1426 |
| Popis: | BackgroundCD27 is a member of the TNF receptor superfamily and plays a critical role in T-cell activation by providing a costimulatory signal. CD27 signaling enhances T-cell proliferation, activation and differentiation of effector and memory T cells and therefore promotes cytotoxic T cell (CTL)-based anti-tumor immunity.1 Agonistic stimulation of CD27 is a promising cancer immunotherapy approach to boost specific T cell driven anti-tumor responses.MethodsIn this study, we generated a series of 147 fully human monoclonal anti-CD27 antibodies and tested their agonist properties to stimulate T cell activation.ResultsUsing a NF-κB reporter Jurkat cell line, we evaluated in vitro the ability of anti-CD27 antibodies to induce CD27 receptor activation. With this assay, five antibodies have been selected for their agonist properties. When combined with suboptimal T cell receptor (TCR) stimulation, agonist antibodies induced CD27 receptor activation with an EC50 of 1–5 ug/mL. We also used human peripheral blood T cells to characterize the CD27-mediated costimulatory effects of agonist antibodies in combination with TCR stimulation. Our anti-CD27 monoclonal antibodies boosted T cell proliferation and induced IL-2 and TNFalpha secretion only in a presence of TCR engagement. Moreover, CD27 agonists induce strong T cell proliferation in a Mixed Lymphocyte Reaction. CD27 antibodies were shown to bind human and cynomolgus monkey CD27 with a KD value of 5–20 nM as determined by BioLayer Interferometry, but do not bind to mouse CD27. In vivo experiments are currently ongoing to demonstrate the efficient anti-tumor activity of the selected CD27 agonist antibodies in different mice tumor models.ConclusionsIn conclusion, we have developed and successfully selected efficient fully human immuno-stimulatory agonist CD27 mAbs as a promising cancer immunotherapy.ReferenceHendriks J, Xiao Y, Borst J. CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool. J Exp Med 2003;Volume 198, Number 9:1369–1380. |
| Databáze: | OpenAIRE |
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