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

JB. Spangler, E. Trotta, J. Tomala, A. Peck, TA. Young, CS. Savvides, S. Silveria, P. Votavova, J. Salafsky, VS. Pande, M. Kovar, JA. Bluestone, KC. Garcia,

. 2018 ; 201 (7) : 2094-2106. [pub] 20180813

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem, Research Support, U.S. Gov't, Non-P.H.S.

Perzistentní odkaz   https://www.medvik.cz/link/bmc19035074

Grantová podpora
Howard Hughes Medical Institute - United States
Howard Hughes Medical Institute - United States
R01 AI051321 NIAID NIH HHS - United States
R37 AI051321 NIAID NIH HHS - United States
UC4 DK116264 NIDDK NIH HHS - United States

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-2Rα, IL-2Rβ, and common γ [γc]). IL-2Rα, which is highly expressed on regulatory T (TReg) cells, regulates IL-2 sensitivity. Previous studies have shown that complexation of IL-2 with the JES6-1 Ab preferentially biases cytokine activity toward TReg cells through a unique mechanism whereby IL-2 is exchanged from the Ab to IL-2Rα. 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 TReg 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.

Citace poskytuje Crossref.org

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