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| Article Authors: | Christian Grütter; Trevor Wilkinson; Richard Turner; Sadhana Podichetty; Donna Finch; Matthew McCourt; Scott Loning; Lutz Jermutus; Markus G Grütter |
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| Article Title: | A cytokine-neutralizing antibody as a structural mimetic of 2 receptor interactions. |
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| Reference ID: | 1018813 |
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| Abstract: | TGF-beta 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-beta neutralizing antibody, GC-1008, alone and in complex with TGF-beta3. 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-beta homodimer with high affinity. Whereas both cognate receptors, TGF-beta-receptor types I and II, are required to recognize all 3 TGF-beta isoforms, GC-1008 has been engineered to bind with high affinity to TGF-beta1, 2, and 3 via a single interaction surface. Comparison with existing structures and models of TGF-beta 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. |
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| Affiliations: | Biochemisches Institut, Universität Zürich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. |
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| Date: | 2008 |
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| Reference Type: | Literature |
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| PubMed ID: | 19073914 |
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| Journal: | Proc Natl Acad Sci U S A |
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| Journal Volume: | 105 |
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| Article Pages: | 20251-6 |
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| Journal ISSN: | 1091-6490 |
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| Article Chemical List: | Antibodies;Cytokines;Epitopes;Receptors, Transforming Growth Factor beta;Transforming Growth Factor beta;Transforming Growth Factor beta1;Transforming Growth Factor beta2;Transforming Growth Factor beta3;TGF-beta type I receptor;Protein-Serine-Threonine Kinases;transforming growth factor-beta type II receptor |
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| Article MeSH List: | Antibodies(metabolism); Cytokines(immunology); Epitopes; Humans; Molecular Mimicry; Protein Binding; Protein-Serine-Threonine Kinases(metabolism); Receptors, Transforming Growth Factor beta(metabolism); Transforming Growth Factor beta(immunology); Transforming Growth Factor beta1(metabolism); Transforming Growth Factor beta2(metabolism); Transforming Growth Factor beta3(metabolism) |
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| Curation Last Updated: | 2012-05-31 20:43:21 |
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