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

Autor: Marek Kovar, Vijay S. Pande, Jamie B. Spangler, Christina S. Savvides, Stephanie L. Silveria, K. Christopher Garcia, Ariana Peck, Joshua Salafsky, Eleonora Trotta, Jakub Tomala, Jeffrey A. Bluestone, Tracy A. Young, Petra Votavova
Rok vydání: 2018
Předmět:
0301 basic medicine
T-Lymphocytes
medicine.medical_treatment
Protein Engineering
Lymphocyte Activation
T-Lymphocytes
Regulatory
Mice
0302 clinical medicine
Heterotrimeric G protein
Receptors
Immunology and Allergy
Receptor
Cells
Cultured
Cultured
Chemistry
Colitis
Regulatory
Infectious Diseases
Cytokine
Cytokines
Immunotherapy
Cells
Recombinant Fusion Proteins
1.1 Normal biological development and functioning
Immunology
Autoimmune Disease
Article
Antibodies
Autoimmune Diseases
03 medical and health sciences
Underpinning research
medicine
Animals
Humans
Cytokine Antibody
Cell Proliferation
Autoimmune disease
Animal
Cell growth
Receptors
Interleukin-2
Protein engineering
medicine.disease
Disease Models
Animal
030104 developmental biology
Disease Models
Cancer research
Interleukin-2
030215 immunology
Zdroj: Journal of immunology (Baltimore, Md. : 1950), vol 201, iss 7
Spangler, JB; Trotta, E; Tomala, J; Peck, A; Young, TA; Savvides, CS; et al.(2018). Engineering a Single-Agent Cytokine/Antibody Fusion That Selectively Expands Regulatory T Cells for Autoimmune Disease Therapy. JOURNAL OF IMMUNOLOGY, 201(7), 2094-2106. doi: 10.4049/jimmunol.1800578. UCSF: Retrieved from: http://www.escholarship.org/uc/item/30160235
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.1800578
Popis: 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.
Databáze: OpenAIRE
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