Epitopes described in "A cytokine-neutralizing antibody as a structural mimetic of 2 receptor interactions."

Article Authors:Christian Grütter; Trevor Wilkinson; Richard Turner; Sadhana Podichetty; Donna Finch; Matthew McCourt; Scott Loning; Lutz Jermutus; Markus G Grütter
Article Title:A cytokine-neutralizing antibody as a structural mimetic of 2 receptor interactions.
Reference Detail
Reference ID:1018813
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.
Affiliations:Biochemisches Institut, Universität Zürich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Reference Type:Literature
PubMed ID:19073914
Journal:Proc Natl Acad Sci U S A
Journal Volume:105
Article Pages:20251-6
Journal ISSN:0027-8424
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
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)
Curation Last Updated:2015-06-05 01:57:34