Engineering a Single-Agent Cytokine/Antibody Fusion That Selectively Expands Regulatory T Cells for Autoimmune Disease Therapy

0494805 - MBÚ 2019 RIV US eng J - Článek v odborném periodiku
Spangler, J.B. - Trotta, E. - Tomala, Jakub - Peck, A. - Young, T.A. - Savvides, Ch.S. - Silveria, S. - Votavová, Petra - Salafsky, J. - Pande, V.S. - Kovář, Marek - Bluestone, J.A. - Garcia, K.Ch.
Engineering a Single-Agent Cytokine/Antibody Fusion That Selectively Expands Regulatory T Cells for Autoimmune Disease Therapy.
Journal of Immunology. Roč. 201, č. 7 (2018), s. 2094-2106. ISSN 0022-1767. E-ISSN 1550-6606
Grant CEP: GA ČR GA13-12885S; GA ČR(CZ) GA18-12973S
Institucionální podpora: RVO:61388971
Klíčová slova: IL-2/ANTI-IL-2 MAB COMPLEXES * LOW-DOSE INTERLEUKIN-2 * CYTOKINE-RECEPTOR
Obor OECD: Microbiology
Impakt faktor: 4.718, rok: 2018

IL-2 has been used to treat diseases ranging from cancer to autoimmune disorders, but its concurrent immunostimulatory and immunosuppressive effects hinder efficacy. IL-2 orchestrates immune cell function through activation of a high-affinity heterotrimeric receptor (composed of IL-2R alpha, IL-2R beta, and common gamma [gamma(c)]). IL-2R alpha, which is highly expressed on regulatory T (T-Reg) cells, regulates IL-2 sensitivity. Previous studies have shown that complexation of IL-2 with the JES6-1 Ab preferentially biases cytokine activity toward T-Reg cells through a unique mechanism whereby IL-2 is exchanged from the Ab to IL-2R alpha. However, clinical adoption of a mixed Ab/cytokine complex regimen is limited by stoichiometry and stability concerns. In this study, through structure-guided design, we engineered a single agent fusion of the IL-2 cytokine and JES6-1 Ab that, despite being covalently linked, preserves IL-2 exchange, selectively stimulating T-Reg expansion and exhibiting superior disease control to the mixed IL-2/JES6-1 complex in a mouse colitis model. These studies provide an engineering blueprint for resolving a major barrier to the implementation of functionally similar IL-2/Ab complexes for treatment of human disease.
Trvalý link: http://hdl.handle.net/11104/0289054