A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts.
Interaction of insulin-like growth factor receptor I (IGF-IR) with its ligands has been reported to induce cell proliferation, transformation and blockade of cell apoptotic functions. IGF-IR is overexpressed on numerous tumor cell types and its blockade could be of importance for anti-cancer therapy. We have generated a humanized anti-IGF-IR antibody h7C10 that blocks in vitro IGF-I and IGF-II-induced cell proliferation of MCF-7 breast cancer cells. Analysis of the IGF-I transduction cascade demonstrated that the humanized anti-IGF-IR antibody and its murine parental form block IGF-I-induced tyrosine phosphorylation, both its beta-chain and IRS-1 tyrosine phosphorylation. This presumably leads to cell cycle arrest and, consequently, growth inhibition. Treatment of nude mice bearing either human breast cancer cells (MCF-7) or non small lung cancer cells (A549) with h7C10, or its murine parental form 7C10, inhibited significantly tumor growth. An almost complete inhibition of A549 tumor growth was observed when mice were treated with the anti-IGF-IR antibody combined with either a chemotherapeutic agent, Vinorelbine or an anti-epidermal growth factor receptor (EGFR) antibody, 225. Combined therapy prolonged significantly the life span of mice in an orthotopic in vivo model of A549; the combination of the anti-IGF-IR antibody with an anti-EGFR antibody was superior to the Vinorelbine combination. The present results indicate that the humanized anti-IGF-IR antibody h7C10 has a great potential for cancer therapy when combined with either a chemotherapeutic agent or an antibody that targets other growth factor receptors, such as the epidermal growth factor receptor.
Goetsch
Liliane
L
Centre d'Immunologie Pierre Fabre, 5 Avenue Napoléon III, 74160, St. Julien en Genevois, France. Liliane.Goetsch@pierre-fabre.com
Gonzalez
Alexandra
A
Leger
Olivier
O
Beck
Alain
A
Pauwels
Petrus J
PJ
Haeuw
Jean François
JF
Corvaia
Nathalie
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D004347:Drug Interactions; D066246:ErbB Receptors / Q000502:physiology*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D017526:Receptor, IGF Type 1 / Q000276:immunology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000077235:Vinorelbine
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D000077235:Vinorelbine