A cytokine-neutralizing antibody as a structural mimetic of 2 receptor interactions

作者：Gruetter Christian; Wilkinson Trevor; Turner Richard; Podichetty Sadhana; Finch Donna; McCourt Matthew; Loning Scott; Jermutus Lutz^*; Gruetter Markus G

来源：Proceedings of the National Academy of Sciences of the United States of America, 2008, 105(51): 20251-20256.

DOI：10.1073/pnas.0807200106

• cancer
• fibrotic diseases
• TGF-beta/antibody complex
• TGF-beta signaling
• X-ray structure

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-beta 3. 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-beta 1, 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.

• 出版日期2008-12-23