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.
Publication types
-
Research Support, N.I.H., Intramural
MeSH terms
-
Amino Acid Sequence
-
Antibodies, Monoclonal / genetics
-
Antibodies, Monoclonal / metabolism
-
Antibodies, Monoclonal / pharmacology*
-
Antibody Affinity / immunology*
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Cross Reactions / immunology
-
Humans
-
Immunoglobulin Fragments / genetics
-
Immunoglobulin Fragments / metabolism
-
Immunoglobulin Fragments / pharmacology
-
Immunoglobulin G / metabolism
-
Insulin-Like Growth Factor I / antagonists & inhibitors*
-
Insulin-Like Growth Factor I / immunology
-
Insulin-Like Growth Factor I / metabolism
-
Insulin-Like Growth Factor II / antagonists & inhibitors*
-
Insulin-Like Growth Factor II / immunology
-
Insulin-Like Growth Factor II / metabolism
-
Peptide Library
-
Phosphorylation / drug effects
-
Protein Binding / immunology
-
Receptor, IGF Type 1 / antagonists & inhibitors
-
Receptor, IGF Type 1 / metabolism
-
Receptor, Insulin / antagonists & inhibitors
-
Receptor, Insulin / metabolism
-
Single-Chain Antibodies / genetics
-
Single-Chain Antibodies / metabolism
-
Single-Chain Antibodies / pharmacology
Substances
-
Antibodies, Monoclonal
-
Immunoglobulin Fragments
-
Immunoglobulin G
-
Peptide Library
-
Single-Chain Antibodies
-
Insulin-Like Growth Factor I
-
Insulin-Like Growth Factor II
-
Receptor, IGF Type 1
-
Receptor, Insulin