In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 51 ( 2008-12-23), p. 20251-20256
Abstract:
TGF-β isoforms are key modulators of a broad range of biological pathways and increasingly are exploited as therapeutic targets. Here, we describe the crystal structures of a pan-TGF-β neutralizing antibody, GC-1008, alone and in complex with TGF-β3. The antibody is currently in clinical evaluation for idiopathic pulmonary fibrosis, melanoma, and renal cell cancer. GC-1008 recognizes an asymmetric binding interface across the TGF-β homodimer with high affinity. Whereas both cognate receptors, TGF-β-receptor types I and II, are required to recognize all 3 TGF-β isoforms, GC-1008 has been engineered to bind with high affinity to TGF-β1, 2, and 3 via a single interaction surface. Comparison with existing structures and models of TGF-β interaction with its receptors suggests that the antibody binds to a similar epitope to the 2 receptors together and is therefore a structurally different but functionally identical mimic of the binding mode of both receptors.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0807200106
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2008
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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