Functional responses and in vivo anti-tumour activity of h7C10: A humanised monoclonal antibody with neutralising activity against the insulin-like growth factor-1 (IGF-1) receptor and insulin/IGF-1 hybrid receptors Giuseppe Pandini a , Thierry Wurch b, *, Barbara Akla b , Nathalie Corvaia b , Antonino Belfiore c , Liliane Goetsch b a Dipartimento di Medicina Interna e Medicine Specialistiche, Ospedale Garibaldi, University of Catania, Italy b Centre d’Immunologie Pierre Fabre, 5 Avenue Napoleon III, 74164 Saint Julien en Genevois, France c Department of Experimental and Clinical Medicine, Campus Universitario di Germaneto, University of Catanzaro, Catanzaro, Italy ARTICLE INFO Article history: Received 1 December 2006 Received in revised form 14 February 2007 Accepted 5 March 2007 Keywords: Monoclonal antibody IGF-1R Hybrid receptor Ligand binding Phosphorylation Mouse xenograft model ABSTRACT A novel humanised monoclonal antibody (Mab, h7C10) was raised against the human insulin-like growth factor-1 receptor (IGF-1R); it exhibited potent inhibition of tumour growth in animal models. Further evaluation of its inhibitory activity at hybrid receptors (Hybrid-Rs) composed of the association between IGF-1R and insulin receptor (IR) was performed. Selective, potent and efficacious inhibition of [ 125 I]IGF-1 binding as well as IGF-1- and IGF-2-mediated receptor phosphorylation was demonstrated at both IGF-1R and Hybrid-Rs, without activity at IR. Ligand-independent down-regulation of both IGF- 1R and Hybrid-Rs was obtained upon long-term association with h7C10. In vivo evaluation was performed in a MDA-MB-231 xenograft mouse model, showing a 14-fold higher level of Hybrid-Rs as compared to IGF-1R. A more potent anti-tumoural response was obtained for h7C10 as compared to Mabs targeting solely IGF-1R or Hybrid-Rs. The herewith described neutralising properties of h7C10 as potent inhibitor of both IGF-1R and Hybrid-Rs are likely to participate in its anti-tumoural activities and maybe of interest for therapeutic applications. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction The insulin-like growth factor-1 (IGF-1) receptor (IGF-1R) is a member of the receptor tyrosine kinase family. Numerous lines of evidence point to major and central implications of this receptor type in both tumour establishment and maintenance of a tumourigenic phenotype in animal mod- els and human cancer (for recent reviews 1–3 ). Therapeutic interventions, dealing with inhibition of IGF-1R signalling by various approaches such as antisense oligonucleotides, 4 tyrosine kinase inhibitors 5,6 and more recently monoclonal antibodies (Mabs, 7–14 ), demonstrated efficient anti-tumoural activities both in in vitro experiments and in animal models. As a consequence of these studies, several of these com- pounds are actually under clinical investigations in humans. The IGF-1R, as well as its close structural homologue, insu- lin receptor (IR), contains two a-and two b-chains, associated in a hetero-tetrameric functional structure via covalent disul- phide bridges. 15 Human IR exists in two isoforms determined 0959-8049/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2007.03.009 * Corresponding author: Tel.: +33 450 35 35 78; fax: +33 450 35 35 90. E-mail address: thierry.wurch@pierre-fabre.com (T. Wurch). EUROPEAN JOURNAL OF CANCER 43 (2007) 1318 – 1327 available at www.sciencedirect.com journal homepage: www.ejconline.com