title: Quantification of binding of IGF-1 to BI 836845, a candidate therapeutic antibody against IGF-1 and IGF-2, and effects of this antibody on IGF-1:IGFBP-3 complexes in vitro and in male C57BL/6 mice.
abstract: IGF-1 and IGF-2 are potent mitogens acting through the IGF-1 receptor (IGF-1R). The importance of the IGF system in neoplasia has been demonstrated in several models, and IGF-1 signaling has become a target for drug development. The drug candidate BI 836845 is a fully human IgG1 ligand-neutralizing antibody that cross-reacts with IGF-1 and IGF-2. It has been shown to reduce both IGF-1R phosphorylation and cellular proliferation in preclinical studies. In rodent studies, administration of BI 836845 leads to large increases in total IGF-1 concentration in serum, despite reduced serum IGF-1 activity as measured by a kinase activation assay. Despite the fact that anti-IGF-ligand antibodies have entered clinical trials, their effect on IGF-binding proteins has not been described. In this report, we developed a novel technique to measure ligand-BI 836845 binding, and we apply it to a mouse model in various contexts. We show that although large increases in total serum IGF-1 levels are observed, the vast majority of ligand is present as a complex with BI 836845, and total serum IGF-binding protein-3 levels are decreased. Finally, we show that BI 836845 treatment induces an increase in GH levels, a finding consistent with attempted compensation at the level of the pituitary. Our results reveal complexities in the physiologic sequelae of BI 836845 administration that have implications for determination of optimal dosing regimens and for development of pharmacodynamic endpoints for clinical trials.
authors.affiliation: Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Jewish General Hospital and McGill University, Montreal, Quebec, Canada H3T 1E2.
authors.forename: Matei
authors.initials: M
authors.lastname: Mireuta
authors.forename: Elena
authors.initials: E
authors.lastname: Birman
authors.forename: Melinda
authors.initials: M
authors.lastname: Barmash
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000737:chemistry*; D007334:Insulin-Like Growth Factor I / Q000737:chemistry*; D007335:Insulin-Like Growth Factor II / Q000737:chemistry*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011485:Protein Binding; D017526:Receptor, IGF Type 1 / Q000737:chemistry
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D007074:Immunoglobulin G; D018972:Insulin-Like Growth Factor Binding Protein 3; D008024:Ligands; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; C588089:xentuzumab