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Department of Inflammation/Autoimmune Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110
IL-12 is a heterodimeric cytokine, composed of a p40 and a p35
subunit, that exerts its biological effects by binding to specific cell
surface receptors. Two IL-12R proteins, designated human IL-12
(huIL-12) receptor ß1 (huIL-12Rß1) and huIL-12Rß2, have been
previously identified. These IL-12R individually bind huIL-12 with low
affinity and in combination bind huIL-12 with high affinity and confer
IL-12 responsiveness. In this study the interactions of huIL-12 with
these two identified human IL-12R protein subunits are examined. The
heterodimer-specific anti-huIL-12 mAb 20C2, which neutralizes
huIL-12 bioactivity but does not block 125I-huIL-12
binding to huIL-12Rß1, blocked binding of huIL-12 to huIL-12Rß2. In
contrast, anti-huIL-12Rß1 mAb 2B10 and mouse IL-12 p40 subunit
homodimer (mo(p40)2) blocked 125I-huIL-12
binding to huIL-12Rß1, but not to huIL-12Rß2. Therefore, two
classes of IL-12 inhibitors can be identified that differ in their
ability to block huIL-12 interaction with either huIL-12Rß1 or
huIL-12Rß2. Both mo(p40)2 and 20C2 blocked high affinity
binding to huIL-12Rß1/ß2-cotransfected COS-7 cells, although, as
previously reported, mo(p40)2 does not block high affinity
binding to IL-12R on PHA-activated human lymphoblasts. Furthermore,
these two classes of IL-12 inhibitors synergistically decreased
huIL-12-stimulated proliferation and IFN-
production. Therefore,
IL-12, in binding to the high affinity IL-12R, interacts with
IL-12Rß1 primarily via regions on the IL-12 p40 subunit and with
IL-12Rß2 via 20C2-reactive, heterodimer-specific regions of IL-12 to
which the p35 and p40 subunits both contribute.
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