1. ¹Centre de Biophysique Moléculaire CNRS UPR 4301, University of Orléans and INSERM, Orléans cedex 2, France
2. ²Division of Lipid Science and Technology, Indian Institute of Chemical Technology, Hyderabad, India
3. ³Laboratoire de Microscopie Moléculaire et Cellulaire, CNRS UMR 8126, Institut Gustave Roussy, Villejuif, France
4. ⁴Laboratoire d'Immunologie et d'Embryologie Moléculaire, CNRS UMR 6218, Institut de Transgénose, Orléans cedex 2, France

Correspondence: Dr P Midoux, Centre de Biophysique Moléculaire CNRS UPR4301, University of Orléans and INSERM, rue Charles Sadron, Orléans cedex 2 45071, France. E-mail: midoux@cnrs-orleans.fr

Received 20 December 2006; Revised 2 April 2007; Accepted 19 April 2007; Published online 22 June 2007.

Abstract

Immunization with mRNA encoding tumor antigen is an emerging vaccine strategy for cancer. In this paper, we demonstrate that mice receiving systemic injections of MART1 mRNA histidylated lipopolyplexes were specifically and significantly protected against B16F10 melanoma tumor progression. The originality of this work concerns the use of a new tumor antigen mRNA formulation as vaccine, which allows an efficient protection against the growth of a highly aggressive tumor model after its delivery by intravenous route. Synthetic melanoma-associated antigen MART1 mRNA was formulated with a polyethylene glycol (PEG)ylated derivative of histidylated polylysine and L-histidine-(N,N-di-n-hexadecylamine)ethylamide liposomes (termed histidylated lipopolyplexes). Lipopolyplexes comprised mRNA/polymer complexes encapsulated by liposomes. The tumor protective effect was induced with MART1 mRNA carrying a poly(A) tail length of 100 adenosines at an optimal dose of 12.5 g per mouse. MART1 mRNA lipopolyplexes elicited a cellular immune response characterized by the production of interferon- and the induction of cytotoxic T lymphocytes. Finally, the anti-B16 response was enhanced using a formulation containing both MART1 mRNA and MART1-LAMP1 mRNA encoding the antigen targeted to the major histocompatibility complex class II compartments by the lysosomal sorting signal of LAMP1 protein. Our results provide a basis for the development of mRNA histidylated lipopolyplexes for cancer vaccine.