TY - JOUR
T1 - Engineering a single-agent cytokine/antibody fusion that selectively expands regulatory t cells for autoimmune disease therapy
AU - Spangler, Jamie B.
AU - Trotta, Eleonora
AU - Tomala, Jakub
AU - Peck, Ariana
AU - Young, Tracy A.
AU - Savvides, Christina S.
AU - Silveria, Stephanie
AU - Votavova, Petra
AU - Salafsky, Joshua
AU - Pande, Vijay S.
AU - Kovar, Marek
AU - Bluestone, Jeffrey A.
AU - Christopher Garcia, K.
N1 - Funding Information:
Health Service, the National Institute for Health Research, or the Department of Health. K.C.G. is an investigator of the Howard Hughes Medical Institute, J.B.S. is the recipient of a Leukemia & Lymphoma Society Career Development Program fellowship, and A.P. is a recipient of a National Science Foundation Graduate Research fellowship.
Funding Information:
This work was supported by the U.S. National Institutes of Health (NIH) (R01 AI51321 to K.C.G.), NIH UC4DK116264 to K.C.G. and J.A.B., the Jordan Fund, and the Czech Science Foundation (Grants 13-12885S and 18-12973S to M.K.). The views expressed are those of the authors and not necessarily those of the National
Publisher Copyright:
© 2018 by The American Association of Immunologists, Inc.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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-2Ra, IL-2Rb, and common g [gc]). IL-2Ra, 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-2Ra. 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.
AB - 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-2Ra, IL-2Rb, and common g [gc]). IL-2Ra, 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-2Ra. 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.
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U2 - 10.4049/jimmunol.1800578
DO - 10.4049/jimmunol.1800578
M3 - Article
C2 - 30104245
AN - SCOPUS:85053437035
SN - 0022-1767
VL - 201
SP - 2094
EP - 2106
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -