title: Anti-insulin-like growth factor 1 receptor antibody EM164 (murine AVE1642) exhibits anti-tumour activity alone and in combination with temozolomide against neuroblastoma.
abstract: Insulin-like growth factor 1 receptor (IGF-1R) is overexpressed in many tumours and contributes to tumourigenicity, cell proliferation, metastasis and resistance, thus representing a promising therapeutic target. The human IGF-1R antagonistic monoclonal antibody EM164 (murine AVE1642) has shown activity in adult cancers and is being evaluated in patients with advanced malignancies. We investigated the EM164 for its therapeutic potential against childhood neuroblastoma. EM164 at 0.07, 0.7 and 7 μg/mL exhibited anti-proliferative activity against all nine cell lines tested in (3)H-thymidine incorporation assay in vitro. Cell proliferation after EM164 exposure ranged between 24% and 80% compared to controls. Sensitivity was independent from culture serum conditions, intensity of IGF-1R expression and IGF-II secretion, although associated with inhibition of AKT activation. In vivo, EM164 administered intravenously at 40 mg/kg twice weekly for 4 weeks yielded significant tumour growth delays (TGD) of 13.4d in advanced stage IGR-N91 and 12.9 d in SK-N-AS tumours compared to controls (p = 0.02 and p = 0.0059, respectively). Simultaneous treatment of EM164 0.7 μg/mL and temozolomide resulted in enhanced activity in vitro. In vivo, treatment with temozolomide at the maximum tolerated dose (100mg/kg/d for 5 consecutive days) and EM164 yielded a significantly greater TGD of 29.1d (p<0.01) and two complete tumour regressions (CR) compared to 18.1d (p = ns) and one CR for EM164 alone and 16.1d (p = ns) for temozolomide alone. Our results demonstrate the potential of the anti-IGF-1R antibody alone and in combination with alkylating agents and support the therapeutic development of the AVE1642 for aggressive neuroblastoma.
authors.affiliation: UPRES EA 3535, Pharmacology and New Treatments of Cancer, Université Paris-Sud XI, Institut Gustave Roussy, 94805 Villejuif, France. geoerger@igr.fr
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Brasme
authors.forename: Estelle
authors.initials: E
authors.lastname: Daudigeos-Dubus
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.forename: Corinne
authors.initials: C
authors.lastname: Venot
authors.forename: Laurent
authors.initials: L
authors.lastname: Debussche
authors.forename: Patricia
authors.initials: P
authors.lastname: Vrignaud
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D009447:Neuroblastoma / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D000077204:Temozolomide; C545477:AVE1642