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  • Technology offers portfolio

    CNRS ONCOLOGY

    16/02/2017 Emmanuelle Le Coz V2

    83 Bd Exelmans, 75016 PARIS Tel + 33 (0) 1 40 51 00 90 Fax + 33 (0) 1 40 51 78 58 Email : frinnov@fist.fr web : www.fist.fr S.A. au capital de 1 128 122 R.C.S B 388 461 154 SIREN 388 461 154 00030 Code APE 6630Z TVA CEE FR 60 388 461 154

  • 2 Table of content

    Table of contents Part 1: Therapy ....................................................................................................................................................... 3

    Part 1.1: Small molecules ........................................................................................................................................ 4

    A potential first-in-class drug for the treatment of leukemia ................................................................................. 5

    Targeted drugs for brain cancer .............................................................................................................................. 7

    Platinum-based n-heterocylic carbenic complexes showing very efficient anti-cancer activity ........................... 10

    Part 1.2: Antibodies .............................................................................................................................................. 12

    LLT1 Antibodies with new functional properties .................................................................................................. 13

    Part 1.3: Peptides .................................................................................................................................................. 14

    Chimeric molecule involving oligomerized FasL extracellular domain ................................................................. 15

    Tumor vaccine for immunotherapy of tumoral pathologies related to EBV latency infections ........................... 16

    Novel recombinant lectins and applications for the detection of pathological state markers ............................. 18

    Part 1.4: Biomarkers (targets) ............................................................................................................................... 20

    New target involved in DNA replication for diagnosing and treating cancers ...................................................... 21

    Part 2: Pronostic .................................................................................................................................................... 22

    Development of Anti Trio antibody to detect Trio as a potential pronostic marker for cancer ........................... 23

    Part 3: Theranostic ................................................................................................................................................ 24

    A novel methodology to predict the response to HER2 bloking agent treatment in cancer ................................ 25

    Part 4: Diagnostic .................................................................................................................................................. 27

    Use of an inhibitory protein of cell migration as a diagnostic marker for metastastic progression ..................... 28

    Mannose 6-phosphate receptor, new target for prostate cancer diagnosis ........................................................ 29

    Novel recombinant lectins and applications for the detection of pathological state markers ............................. 30

    CNRS Key figures ................................................................................................................................................... 32

    Budget forecast for 2014 ................................................................................................................... 32

    Personnel ........................................................................................................................................... 32

    Organization ...................................................................................................................................... 32

    International relations ....................................................................................................................... 32

    Industrial relations ............................................................................................................................ 32

    Awards ............................................................................................................................................... 32

  • 3 Table of content

    Part 1: Therapy

  • 4 Table of content

    Part 1.1: Small molecules

  • 5 Table of content

    A potential first-in-class drug for the

    treatment of leukemia

    CONTEXT The expression level of the cytosolic 5-nucleotidase II (cN-II) is of crucial interest for patients treated with nucleoside analogue-based chemotherapy. Indeed, a high level of expression of cN-II mRNA in blasts is predictive of worse outcome in patients receiving cytarabine-based regimens (a well-known nucleoside analogue used to treat acute myeloid leukemia, AML). In addition, the inhibition of cN-II expression by short hairpin RNA was associated with the induction of apoptosis in human astrocytoma cells, suggesting that cN-II could be a therapeutic target in brain tumors. Finally, recent reports showed that hyperactive mutated cN-II in relapsed children with acute lymphoblastic leukemia, and treated with the anti-metabolite 6-mercaptopurine, was associated with a worse survival. In this context, cN-II has been shown to be an attractive molecular target for the development of novel drugs circumventing resistance to cytotoxic nucleoside analogues currently used for treating leukemia and other hematological malignancies.

    TECHNICAL DESCRIPTION In light of the various structural, functional and regulatory properties of cN-II, the inventors considered cN-II as an attractive therapeutic target for developing different types of inhibitors that could interfere with protein function or regulation. Altering the enzymatic function of cN-II has an indirect effect on nucleotide pools and is supposed to enhance the therapeutic efficiency of cytotoxic nucleosides (by decreasing the competition with endogenous nucleotides). Indeed, numerous experimental evidences indicated that cN-II is interfering with anticancer treatment based on this class of therapeutics (nucleoside analogs) and therefore also governing the final outcome of patients. The main evidence is the relationship between the expression level of cN-II and the patient outcome. This feature is reinforced by the recent discovery of hyperactive mutants of cN-II that induce a similar response. The development of potent inhibitors against cN-II has been carried out and a family of small size compounds (designed for an oral delivery) has been characterized for their capability in blocking the cN-II enzymatic function and also in sensitizing the anti-proliferative effects of some cancer drugs using preclinical models.

    DEVELOPMENT STAGE Multi-step chemical synthesis was been optimized, all intermediates and

    final compounds were fully characterized. Synthesis has been carried out on mg to gram scale.

    Reference 06043-01

    Keywords [cN-II]; [5-nucleotidases]; [nucleotides]; [Enzyme inhibitors]; [small molecule inhibitors]; [AML]; [Leukemia]; [cancer]. Status of Patent French priority patent application filed on October 1rst, 2013 and entitled Inhibiteurs de 5-nuclotidases et leurs utilisations thrapeutiques

    Inventors Suzanne PEYROTTES, Laurent CHALOIN & al. Commercial Status Exclusive or non-exclusive license Laboratory Institut des Biomolcules Max Mousseron (IBMM), UMR5247

  • 6 Table of content

    In vitro evaluation towards the recombinant purified cN-II (Nucleotidase activity inhibition assays). Two different in vitro assays were used for evaluating the inhibition of compounds. A colorimetric assays based on the dosage of inorganic phosphate produced by the reaction and a kinetic assay for the characterization of the inhibition mode and constant (Ki). Several compounds described in the invention have shown a potent inhibition of the cN-II activity (up to 90% of inhibition at 200 M)

    Cytotoxic activity validated on several tumor cell lines. Direct cytotoxicity was determined using cell survival assays on a large panel of cancer cell lines, showing IC50 in low micromolar range for the most potent inhibitors. Synergy with nucleoside analogues was shown for several associations.

    Ex vivo PoC. The most potent cN-II inhibitors are also cytotoxic on human cancer cells obtained from patients with AML or CLL as shown by ex vivo incubation and cell survival analysis.

    In vivo efficacy PoC. Initial experiments in a mouse model showed an antitumoral activity of cN-II inhibitors and a slight increase in the activity of associated nucleoside analogues.

    BENEFITS The originality of the invention lies in the nature of the drug target (cytosolic and not membrane). No inhibitor of intracellular 5'-nucleotidases (cytosolic) is described to date for the treatment of human blood diseases (Acute lymphoblastic or myeloblastic leukemia and chronic lymphoid leukemia) for children and adult patients. The unique combination of the compounds of the invention, 5'-nucleotidases inhibitors, with cytotoxic nucleoside analogs known to date, increases the effectiveness of this drug class by several mechanisms: (1) by the intrinsic inhibition cN-II inducing a shorter cell survival ; (2) by increasing the intracellular concentration of phosphorylated forms (nucleotide) of associated nucleoside analogues, these entities bei