title: Pharmacodynamic and antineoplastic activity of BI 836845, a fully human IGF ligand-neutralizing antibody, and mechanistic rationale for combination with rapamycin.
abstract: Insulin-like growth factor (IGF) signaling is thought to play a role in the development and progression of multiple cancer types. To date, therapeutic strategies aimed at disrupting IGF signaling have largely focused on antibodies that target the IGF-I receptor (IGF-IR). Here, we describe the pharmacologic profile of BI 836845, a fully human monoclonal antibody that utilizes an alternative approach to IGF signaling inhibition by selectively neutralizing the bioactivity of IGF ligands. Biochemical analyses of BI 836845 demonstrated high affinity to human IGF-I and IGF-II, resulting in effective inhibition of IGF-induced activation of both IGF-IR and IR-A in vitro. Cross-reactivity to rodent IGFs has enabled rigorous assessment of the pharmacologic activity of BI 836845 in preclinical models. Pharmacodynamic studies in rats showed potent reduction of serum IGF bioactivity in the absence of metabolic adverse effects, leading to growth inhibition as evidenced by reduced body weight gain and tail length. Moreover, BI 836845 reduced the proliferation of human cell lines derived from different cancer types and enhanced the antitumor efficacy of rapamycin by blocking a rapamycin-induced increase in upstream signaling in vitro as well as in human tumor xenograft models in nude mice. Our data suggest that BI 836845 represents a potentially more effective and tolerable approach to the inhibition of IGF signaling compared with agents that target the IGF-I receptor directly, with potential for rational combinations with other targeted agents in clinical studies.
authors.affiliation: Corresponding Author: Paul J. Adam, Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer Gasse 5-11, A-1121, Vienna, Austria. paul.adam@boehringer-ingelheim.com.
authors.forename: Katrin
authors.initials: K
authors.lastname: Friedbichler
authors.forename: Marco H
authors.initials: MH
authors.lastname: Hofmann
authors.forename: Monika
authors.initials: M
authors.lastname: Kroez
authors.forename: Elinborg
authors.initials: E
authors.lastname: Ostermann
authors.forename: Herbert R
authors.initials: HR
authors.lastname: Lamche
authors.forename: Christian
authors.initials: C
authors.lastname: Koessl
authors.forename: Eric
authors.initials: E
authors.lastname: Borges
authors.forename: Michael N
authors.initials: MN
authors.lastname: Pollak
authors.forename: Günther
authors.initials: G
authors.lastname: Adolf
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Adam
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006801:Humans; 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; D008297:Male; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020123:Sirolimus / Q000008:administration & dosage; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; C588089:xentuzumab