Engineered interleukin-2 antagonists for the inhibition of regulatory T cells.
The immunosuppressive effects of CD4+ CD25 high regulatory T cells (Tregs) interfere with antitumor immune responses in cancer patients. Here, we present a novel class of engineered human interleukin (IL)-2 analogs that antagonizes the IL-2 receptor, for inhibiting regulatory T cell suppression. These antagonists have been engineered for high affinity to the alpha subunit of the IL-2 receptor and very low affinity to either the beta or gamma subunit, resulting in a signaling-deficient IL-2 analog that sequesters the IL-2 receptor alpha subunit from wild type IL-2. Two variants, "V91R" and "Q126T" with residue substitutions that disrupt the beta and gamma subunit binding interfaces, respectively, have been characterized in both a T cell line and in human primary Tregs. These mutants retain their high affinity binding to IL-2 receptor alpha subunit, but do not activate STAT5 phosphorylation or stimulate T cell growth. The 2 mutants competitively antagonize wild-type IL-2 signaling through the IL-2 receptor with similar efficacy, with inhibition constants of 183 pM for V91R and 216 pM for Q126T. Here, we present a novel approach to CD25-mediated Treg inhibition, with the use of an engineered human IL-2 analog that antagonizes the IL-2 receptor.
Liu
David V
DV
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Maier
Lisa M
LM
Hafler
David A
DA
Wittrup
K Dane
KD
D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D007376:Interleukin-2 / Q000031:analogs & derivatives* / Q000235:genetics / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors*; D053612:Janus Kinases / Q000276:immunology / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D015202:Protein Engineering; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D050505:Mutant Proteins; D050799:STAT5 Transcription Factor; D053612:Janus Kinases