title: Human monoclonal antibodies targeting nonoverlapping epitopes on insulin-like growth factor II as a novel type of candidate cancer therapeutics.
abstract: Soluble ligands are important targets for therapy of cancers and other diseases. Therapeutic monoclonal antibodies (mAb) against such ligands block their interactions with corresponding receptors but do not enhance their removal from the circulation and can increase their half-lives because of the long half-lives of the antibodies. We have hypothesized that mAbs targeting two or more nonoverlapping epitopes on the same ligand could form oligomeric antibody-ligand complexes that can bind to cells expressing Fc gamma receptors (FcγRs) with high avidity leading to their fast and irreversible removal from the circulation. Insulin-like growth factor II (IGF-II) is an example of such ligands and an important target for human cancer therapy. We identified two mAbs, m610.27 and m630.3, which bound to nonoverlapping epitopes on IGF-II with nanomolar affinity, and generated a bispecific antibody, m660. m660 inhibited the interaction of human IGF-II (hIGF-II) with the human breast cancer cell line MCF-7, hIGF-II-mediated IGF receptor type I and insulin receptor phosphorylation, and cell growth. In the presence of hIGF-II, large complexes of m660 were formed that bound to FcγRII-expressing BJAB cells much more efficiently than the monospecific antibody-hIGF-II complexes and were presumably phagocytosed by phorbol 12-myristate 13-acetate-stimulated macrophage-like U937 cells. A mixture of m610.27 and m630.3 exhibited similar properties. To our knowledge, these mAbs are the first reported to target nonoverlapping epitopes on a cancer-related ligand and could represent a novel class of candidate therapeutics against cancers. This approach could also be used to irreversibly eliminate other disease-related soluble ligands.
authors.affiliation: Protein Interactions Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland 21702, USA.
authors.forename: Weizao
authors.initials: W
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Zhu
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D000915:Antibody Affinity; D000918:Antibody Specificity; D000936:Antigen-Antibody Complex; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000737:chemistry / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D000939:Epitopes; D007074:Immunoglobulin G; D017452:Receptors, IgG; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1