Domaines scientifiques
Mots-clés
Claude LECLERC Dr es Sciences, Professeur, Institut Pasteur
Parcours et situation actuelle
Dr. Claude Leclerc is Professor and Head of Immune Regulation and Vaccinology Unit at the Pasteur Institute, Paris, France. She is also the Director of U883 INSERM and exerts various responsibilities in the administration of research in France. Dr Leclerc received her Masters degrees in Biochemistry and Immunology in 1973 and 1974, followed by her PhD in Immunology in 1981, all from the University of Paris VII (Paris, France). Dr Leclerc is an expert in cancer vaccine development and tumor immunology.
Dr Leclerc has worked in vaccinology for 37 years and has contributed to the development of synthetic adjuvants, synthetic peptide vaccines and of several innovative delivery systems. In particular, she was the first to propose that muramyl dipeptide (MDP) activates macrophages, through interaction with an intracellular receptor. She has also pioneered the field of immunoadjuvants by establishing that MDP, a synthetic ligand of NOD2, can induce both activation and suppression of immune responses, introducing the notion of immunomodulation. She has demonstrated that fully efficient vaccines can be prepared by chemical linkage of synthetic peptides, each containing only a single B or T cell epitope from unrelated pathogens. Her group has also recently discovered a new mechanism by which CD5+ regulatory B cells, abundant in the first days of life, controls TLR induced inflammatory responses of newborns and subsequent T cell response development.
Dr Leclerc has published over 260 papers in renowned scientific journals including Nature Medicine, Nature Reviews Immunology, Immunity, The Journal of Experimental Medicine and Cancer Research. She holds 25 patents, several of which enabled the creation of Genticel (formerly, BT Pharma), a biopharmaceutical company that develops therapeutic anti-cancer vaccines. Procervix, the first product of this company, developed in collaboration with Dr Leclerc, is a bivalent vaccine for individuals infected with the most common oncogenic genotypes, HPV 16 and/or HPV 18, which cause approximately 70% of cervical cancers worldwide. A phase I/II clinical trial with ProCervix is scheduled for 2010.
Dr Leclerc sits on the Editorial Board of several journals, including Microbes and Infection and the International Journal of Oncology.
For her research in immunology and vaccinology, Dr. Leclerc has received numerous awards and honors, such as the Cancer Paris Distinction by the League against Cancer in 2004. She has been nominated Chevalier of the Legion of Honour by the French Republic in 2008.
Résumé scientifique
Claude Leclerc’s laboratory at the Pasteur Institute is presently focusing its activity on the understanding of the mechanisms that control the activation and regulation of T cell responses and on the development of new strategies of vaccination against tumors. Her lab recently developed new strategies to deliver antigen to dendritic cells (DC). Indeed, DC are well recognized as the most potent professional APCs, with a unique capacity to interact with naive T cells to initiate primary immune responses. Thus, targeting DC represents the main objective in designing new delivery systems for vaccine development. Dr Leclerc has developed a new proteinic vector based on the adenylate cyclase (CyaA) from Bordetella pertussis. CyaA uses a unique mechanism of cell invasion in which the catalytic domain is delivered from cell surface directly to the cytosol of target cells, through the cytoplasmatic membrane. In collaboration with Drs Daniel Ladant and Peter Sebo, she has shown that CyaA binds specifically to the CD11b/CD18 integrin expressed on DC. This ability of CyaA to deliver genetically grafted epitopes or antigens to the DC MHC class I and class II pathways, leading to protective CTL and/or Th cellular immunity, has been well documented in mice and primates. Based on this technology, she developed several therapeutic anti-cancer vaccine candidates, targeting in particular melanoma and cervical cancer, which will enter clinical trials in 2010. Importantly, Dr Leclerc has established that the therapeutic efficacy of CyaA-based anti-cancer vaccines is progressively lost as the tumor grows. The tumor resistance to therapeutic vaccination was shown to be due to the recruitment of regulatory CD25+FoxP3+ T cells and CD11b+GR1+ myeloid suppressor cells. Using this experimental model, she has developed combined therapies targeting innate, adaptive and regulatory components of the immune system, which induce the full eradication of large, established tumors.
Dr Leclerc has also developed an exciting innovative approach to induce immune responses against most adenocarcinomas. Indeed, a hallmark of cancer cells is a change in glycosylation processes leading to the abnormal expression of carbohydrate chains, such as antigens of the T family (Tn, sialyl-Tn and T) on many carcinomas. Such tumor-associated carbohydrate antigens, are potential targets for immune intervention because they are exposed at the surface of tumor cells but hidden in normal cells. In collaboration with Dr Sylvie Bay at the Pasteur Institute, she has developed a fully synthetic glycopeptide structure, which does not require a protein carrier, for the induction of antibodies against the Tn antigen expressed by tumor cells. This molecule, namely MAG-Tn, is a glycopeptidic dendrimer including the Tn Ag and a pan-DR T cell epitope from tetanus toxin and represents the first example of a fully synthetic glycosidic vaccine with immunotherapeutic potential against cancer.
