Potent antitumour activity of interleukin-2-Fc fusion proteins requires Fc-mediated depletion of regulatory T-cells
| Autor: | Kylie E. Webster, Tri Giang Phan, Daniel Christ, Jonathan Sprent, Daniela Zinkl, Jennifer Jackson, Elissa K. Deenick, Rodrigo Vazquez-Lombardi, Claudia Loetsch, Cecile King, Peter R. Schofield |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Melanoma Experimental General Physics and Astronomy CD8-Positive T-Lymphocytes Lymphocyte Activation T-Lymphocytes Regulatory Mice Cancer immunotherapy Neoplasms Cytotoxic T cell IL-2 receptor Immunoglobulin Fragments Mice Inbred BALB C Multidisciplinary biology Antibodies Monoclonal Recombinant Proteins Killer Cells Natural Cytokines Female Immunotherapy Antibody medicine.drug Interleukin 2 Science Antineoplastic Agents Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences medicine Animals Interleukin-2 Receptor alpha Subunit General Chemistry Fusion protein Lymphocyte Subsets Mice Inbred C57BL 030104 developmental biology Mutagenesis Immunoglobulin G Immunology Leukocytes Mononuclear biology.protein Cancer research Interleukin-2 Immunologic Memory Spleen CD8 |
| Zdroj: | Nature Communications, Vol 8, Iss 1, Pp 1-12 (2017) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Interleukin-2 (IL-2) is an established therapeutic agent used for cancer immunotherapy. Since treatment efficacy is mediated by CD8+ and NK cell activity at the tumour site, considerable efforts have focused on generating variants that expand these subsets systemically, as exemplified by IL-2/antibody complexes and ‘superkines'. Here we describe a novel determinant of antitumour activity using fusion proteins consisting of IL-2 and the antibody fragment crystallizable (Fc) region. Generation of long-lived IL-2-Fc variants in which CD25 binding is abolished through mutation effectively prevents unwanted activation of CD25+ regulatory T-cells (Tregs) and results in strong expansion of CD25− cytotoxic subsets. Surprisingly, however, such variants are less effective than wild-type IL-2-Fc in mediating tumour rejection. Instead, we report that efficacy is crucially dependent on depletion of Tregs through Fc-mediated immune effector functions. Our results underpin an unexpected mechanism of action and provide important guidance for the development of next generation IL-2 therapeutics. Interleukin-2 (IL-2) is a T-cell proliferating factor used for cancer immunotherapy. Here, the authors develop a long-lived variant of IL-2 that, mutated in its binding domain, drives a much more potent tumour regression by depleting CD25+ CD4+ regulatory T-cells via targeting them for phagocytosis. |
| Databáze: | OpenAIRE |
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