An immune cell-selective interleukin 4 agonist.
Interleukin 4 (IL-4) is a pleiotropic cytokine. Of the cell types responsive to IL-4, T cells express one IL-4 receptor (IL-4R) type, IL-4Ralpha/IL-2Rgamma (class I IL-4R), whereas endothelial cells express another type, IL-4Ralpha/IL-13Ralpha (class II IL-4R). It was hypothesized that IL-4 variants could be generated that would be selective for cell types expressing the different IL-4Rs. A series of IL-4 muteins were generated that were substituted in the region of IL-4 implicated in interactions with IL-2Rgamma. These muteins were evaluated in T cell and endothelial cell assays. One of these muteins, containing the mutation Arg-121 to Glu (IL-4/R121E), exhibited complete biological selectivity for T cells, B cells, and monocytes, but showed no activity on endothelial cells. Receptor binding studies indicated that IL-4/R121E retained physical interaction with IL-2Rgamma but not IL-13Ralpha; consistent with this observation, IL-4/R121E was an antagonist of IL-4-induced activity on endothelial cells. IL-4/R121E exhibits a spectrum of activities in vitro that suggest utility in the treatment of certain autoimmune diseases.
Bayer Corporation, Pharmaceutical Division, Biotechnology, 800 Dwight Way, Berkeley, CA 94710, USA. Shanafelt.B@bayer.com
A B
AB
Shanafelt
C P
CP
Forte
J J
JJ
Kasper
L
L
Sanchez-Pescador
M
M
Wetzel
R
R
Gundel
J M
JM
Greve
D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001667:Binding, Competitive; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000819:agonists* / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D019948:Receptors, Interleukin-4; D015847:Interleukin-4