3KR3

Crystal structure of IGF-II antibody complex

Summary for 3KR3

• Entry DOI: 10.2210/pdb3kr3/pdb
• Descriptor: Insulin-like growth factor II, antibody-Fab (heavy chain), antibody-Fab (light chain), ... (5 entities in total)
• Functional Keywords: antibody-target complex, carbohydrate metabolism, glucose metabolism, glycoprotein, growth factor, hormone, mitogen, osteogenesis, secreted, immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P01344
• Total number of polymer chains: 3
• Total formula weight: 57898.48

Authors

Peat, T.S.,Newman, J.,Adams, T.E. (deposition date: 2009-11-17, release date: 2010-06-16, Last modification date: 2024-10-30)

Primary citation

Dransfield, D.T.,Cohen, E.H.,Chang, Q.,Sparrow, L.G.,Bentley, J.D.,Dolezal, O.,Xiao, X.,Peat, T.S.,Newman, J.,Pilling, P.A.,Phan, T.,Priebe, I.,Brierley, G.V.,Kastrapeli, N.,Kopacz, K.,Martik, D.,Wassaf, D.,Rank, D.,Conley, G.,Huang, Y.,Adams, T.E.,Cosgrove, L.
A human monoclonal antibody against insulin-like growth factor-II blocks the growth of human hepatocellular carcinoma cell lines in vitro and in vivo.
Mol.Cancer Ther., 9:1809-1819, 2010

PubMed Abstract: Elevated expression of insulin-like growth factor-II (IGF-II) is frequently observed in a variety of human malignancies, including breast, colon, and liver cancer. As IGF-II can deliver a mitogenic signal through both IGF-IR and an alternately spliced form of the insulin receptor (IR-A), neutralizing the biological activity of this growth factor directly is a potential alternative option to IGF-IR-directed agents. Using a Fab-displaying phage library and a biotinylated precursor form of IGF-II (1-104 amino acids) as a target, we isolated Fabs specific for the E-domain COOH-terminal extension form of IGF-II and for mature IGF-II. One of these Fabs that bound to both forms of IGF-II was reformatted into a full-length IgG, expressed, purified, and subjected to further analysis. This antibody (DX-2647) displayed a very high affinity for IGF-II/IGF-IIE (K(D) value of 49 and 10 pmol/L, respectively) compared with IGF-I (approximately 10 nmol/L) and blocked binding of IGF-II to IGF-IR, IR-A, a panel of insulin-like growth factor-binding proteins, and the mannose-6-phosphate receptor. A crystal complex of the parental Fab of DX-2647 bound to IGF-II was resolved to 2.2 A. DX-2647 inhibited IGF-II and, to a lesser extent, IGF-I-induced receptor tyrosine phosphorylation, cellular proliferation, and both anchorage-dependent and anchorage-independent colony formation in various cell lines. In addition, DX-2647 slowed tumor progression in the Hep3B xenograft model, causing decreased tumoral CD31 staining as well as reduced IGF-IIE and IGF-IR phosphorylation levels. Therefore, DX-2647 offers an alternative approach to targeting IGF-IR, blocking IGF-II signaling through both IGF-IR and IR-A.

PubMed: 20515953
DOI: 10.1158/1535-7163.MCT-09-1134

Experimental method

X-RAY DIFFRACTION (2.2 Å)