title: Human monoclonal antibody fragments binding to insulin-like growth factors I and II with picomolar affinity.
abstract: The type 1 insulin-like growth factor receptor (IGF1R) and its ligands (IGF-I and IGF-II) have been implicated in a variety of physiologic processes and in diseases such as cancer. In addition to IGF1R, IGF-II also activates the insulin receptor (IR) isoform A, and therefore, antibodies against IGF-II can inhibit cell proliferation mediated by the signaling through both IGF1R and IR triggered by IGF-II. We identified a new human monoclonal antibody (mAb), m708.2, which is bound to IGF-I and IGF-II but not to insulin. m708.2 potently inhibited signal transduction mediated by the interaction of IGF-I or IGF-II with the IGF1R and IGF-II with the IR. It also inhibited the growth of the breast cancer cell line MCF-7. An affinity-matured derivative of m708.2, m708.5, bound to IGF-I with equilibrium dissociation constant, K(D) = 200 pmol/L and to IGF-II with K(D) = 60 pmol/L. m708.5 inhibited signal transduction mediated by IGF-I and IGF-II and cancer cell growth more potently than m708.2. These results suggest that m708.5 could have potential as a candidate therapeutic for cancers driven by the IGF-I and IGF-II interactions with IGF1R and IR.
authors.affiliation: Protein Interactions Group, National Cancer Institute-Frederick, NIH, Bldg 469, Rm 150B, Frederick, MD 21702, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Zhu
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000915:Antibody Affinity / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003429:Cross Reactions / Q000276:immunology; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007074:Immunoglobulin G / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D019151:Peptide Library; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000276:immunology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D019151:Peptide Library; D057127:Single-Chain Antibodies; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin