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Receptor (hIFNAR1) Using Blocking Monoclonal Antibodies: The Role of Domains 1 and 21
*
Department of Antibody and Bioassay Technology, Process Science, Molecular Biology and Protein Engineering, Genentech Inc., South San Francisco, CA 94080; and
San Francisco Veterans Administration Medical Center, San Francisco, CA 94121
We have performed a structure-function analysis of extracellular
domain regions of the human IFN-
receptor (hIFNAR1) using mAbs
generated by immunizing mice with a soluble hIFNAR1-IgG. Five mAbs
described in this study recognize different epitopes as determined by a
competitive binding ELISA and by alanine substitution mutant analyses
of the hIFNAR1-IgG. Two mAbs, 2E1 and 4A7, are able to block
IFN-stimulated gene factor 3 (ISGF3) formation and inhibit the
antiviral cytopathic effect induced by several IFN- (IFN-2/1,
-1, -2, -5, and -8). None of these anti-IFNAR1 mAbs
were able to block activity of IFN-ß. mAb 4A7 binds to a domain
1-hIFNAR1-IgG but not to a domain 2-hIFNAR1-IgG, which suggests that
its binding region is located in domain 1. The binding of the most
potent blocking mAb, 2E1, requires the presence of domain 1 and domain
2. The most critical residue for 2E1 binding is a lysine residue at
position 249, which is in domain 2. These findings suggest that both
domain 1 and domain 2 are necessary to form a functional receptor and
that a region in domain 2 is important. IFN-ß recognizes regions of
the hIFNAR complex that are distinct from those important for the
IFN-.
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