Institut Pasteur

Centre National De La Recherche Scientifique

Institut National De La Sante Et De La Recherche Medicale

Assistance Publique-hopitaux De Paris

Institut National De La Santéde La Recherche Médicale

Hüseyin Firat

Pierre Charneau

Véronique Zennou

François Lemonnier

Etienne Vilmer

Pierre Rohrlich

Patricia Yotnda

Pierre Langlade-Demoyan

Marie-Louise Michel

Andreas Suhrbier

Pierre Langlade-Demoyen

Franç Is Lemonnier

Langlade-Demoyen Pierre

Patricia c/o Institut Pasteur Yotnda

The invention relates to an immunogenic composition comprising a recombinant vector characterized in that it comprises a polynucleotide comprising the cis-acting central initiation region (cPPT) and the cis-acting termination region (CTS), these regions being of retroviral or retroviral-like origin, said vector comprising in addition a defined nucleotide sequence (transgene or sequence of interest) and regulatory signals of retrotranscription, expression and encapsidation of retroviral or retroviral-like origin, wherein the composition is capable of inducing or of stimulating a cell-mediated response for instance a CTL (Cytotoxic T Lymphocytes) response or a CD4 response, against one or several epitopes encoded by the transgene sequence present in the vector.

Lentiviral vectors for the preparation of immunotherapeutical compositions

The invention concerns a recombinant vector characterized in that it comprises a polynucleotide comprising a central initiation cis-active region (cPPT) and a termination cis-active region (CTS), the regions being of retroviral or retroviral-like origin, and the vector further comprising a predetermined nucleotide sequence (transgene or nucleotide sequence of interest) and retrotranscription regulating, expressing, and packaging signals of retroviral or retroviral-like origin.

Use of triplex structure DNA in transferring nucleotide sequences

A method to induce an immune response in a host in need thereof, comprises administering to the host, recombinant lentiviral vector particles comprising:

The invention concerns the optimization of the wild R9M peptide and the use of the resulting peptides for therapeutic vaccination and/or preventive vaccination against leukaemia in humans. More particularly, the invention concerns mutated immunogenic peptides derived from the human TEL/AML1 fusion protein comprising the wild R9M peptide sequence Arg-Ile-Ala-Glu-Czs-Ile-Leu-Gly-Met. The invention also concerns polynucleotides coding for the mutated R9M immunogenic peptides, cellular expression vectors comprising nucleic acid sequences expressing the mutated R9M immunogenic peptides and polyclonal or monoclonal antibodies capable of being fixed on at least one of said peptides/polynucleotides. The invention further concerns the use of said peptides, polynucleotides and/or antibodies for preparing vaccines, anti-tumoral medicines and compositions and for in vitro and in vivo stimulation of the immune response in humans.

Mutated immunogenic peptides derived from R9M, polynucleotides coding for same and therapeutic uses thereof

The invention concerns a recombinant vector characterized in that it comprises a polynucleotide comprising a central initiation cis-active region (cPPT) and a termination cis-active region (CTS) of retroviral or retroviral-like origin, further comprising a predetermined nucleotide sequence (transgene or nucleotide sequence of interest) and retrotranscription regulating, expressing and packaging signals of retroviral or retroviral-like origin.

The invention concerns the optimisation of the wild R9M peptide and the use of the resulting peptides for therapeutic vaccination and/or preventive vaccination against leukemia in humans. More particularly, the invention concerns mutated immunogenic peptides derived from the human TEL/AML1 fusion protein comprising the wild R9M peptide sequence Arg-Ile-Ala-Glu-Czs-Ile-Leu-Gly-Met. The invention also concerns polynucleotides coding for the mutated R9M immunogenic peptides, cellular expression vectors comprising nucleic acid sequences expressing the mutated R9M immunogenic peptides and polyclonal or monoclonal antibodies capable of being fixed on at least one of said peptides/polynucleotides. The invention further concerns the use of said peptides, polynucleotides and/or antibodies for preparing vaccines, anti-tumoral medicines and compositions and for in vitro and in vivo stimulation of the immune response in humans.

H-2 class I negative, HLA-A2.1 transgeniic HHD mice were used for a comparative evaluation of the immunogenicity of HLA-A2.1 restricted human tumor-associated CTL epitopes. A hierarchy was established among these epitopic peptides injected into mice in IFA which correlates globally with their capacity to bind and stabilize HLA-A2.1 molecules. Co-injection of a helper peptide enhanced most CTL responses. In contrast, classical HLA class I transgenic mice which still express their own class I molecules did not, in most cases, develop H.A.-A2.1-restricted CTL responses under the same experimental conditions. Different monoepitopic immunization strategies of acceptable clinical usage were compared in HHD mice. Recombinant Ty-virus-like particles, or DNA encoding epitopes fused to the hepatitis B virus middle envelope protein gave the best results. Using this latter approach and a melanoma-based polyepitope construct, CTL responses against five distinct epitopes could be elicited simultaneously in a single animal. Thus, HHD mice provide a versatile animal model for preclinical evaluation of peptide-based cancer immunotherapy.

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Paris, France

Hüseyin Firat