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WO2017207040A1 - Thérapie anticancéreuse utilisant un antagoniste de la leptine et un activateur des cellules inkt - Google Patents

Thérapie anticancéreuse utilisant un antagoniste de la leptine et un activateur des cellules inkt Download PDF

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Publication number
WO2017207040A1
WO2017207040A1 PCT/EP2016/062322 EP2016062322W WO2017207040A1 WO 2017207040 A1 WO2017207040 A1 WO 2017207040A1 EP 2016062322 W EP2016062322 W EP 2016062322W WO 2017207040 A1 WO2017207040 A1 WO 2017207040A1
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inkt
leptin
cells
pharmaceutical composition
cell activator
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Inventor
Dirk Elewaut
Koen VENKEN
Jan Tavernier
Lennart Zabeau
Eline MENU
Mérédis FAVREAU
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Universiteit Gent
Vlaams Instituut voor Biotechnologie VIB
Vrije Universiteit Brussel VUB
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Universiteit Gent
Vlaams Instituut voor Biotechnologie VIB
Vrije Universiteit Brussel VUB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5158—Antigen-pulsed cells, e.g. T-cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/22—Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Anti-cancer therapy using a leptin antagonist and an iNKT-cell activator using a leptin antagonist and an iNKT-cell activator
  • the present invention relates to the treatment of cancer. More specifically the invention shows that the anti-cancer activity in mammals can be augmented by administering to the mammalian host a combination of a synergistically effective amount of a leptin antagonist and an invariant natural killer T (iNKT) cell activator.
  • a synergistically effective amount of a leptin antagonist and an invariant natural killer T (iNKT) cell activator.
  • the anti-cancer drugs may be anti-metabolites, alkylating agents, antibiotics, antibodies, immune-stimulants, cytokines and the like. Combinations of said drugs are administered in an attempt to obtain a synergistic, cytotoxic effect on most cancers, e.g., carcinomas, myelomas, melanomas, lymphomas and sarcomas, and to reduce or eliminate emergence of drug-resistant cells and to reduce side effects of each drug.
  • MM multiple myeloma
  • BM bone marrow
  • Fatty deposits can occupy up to 70% of the BM cavity with aging, yet little attention has been given to the role of adipocytes and adipokines in MM development.
  • Adipocytes may contribute to MM by promoting migration and proliferation through secretion of adipokines such as leptin and are known to be negative regulators of the hematopoietic environment (Naveiras O, Nardi V, Wenzel PL, Fahey F, Daley GQ, Nature. 2009;460(7252):259-263). Recently, it became clear that adipose tissue contains a wide range of immune cells. Reciprocal interactions of immune mediators with adipocytes have been described giving rise to the emerging field of the immunometabolism (Mathis D, Shoelson S., Nat. Rev. Immunol. 2011 ;11 (2):81 doi).
  • Invariant natural killer T (iNKT) cells a prototypic T cell subset with important roles in anti-tumour immunity, have been shown to closely interact with adipocytes in a CD1d dependent manner (Huh JY, Kim I, Park J, et al., Mol. Cell. Biol. 2013;33(2):328-339).
  • MM defective IFN- ⁇ production by iNKT cells and reduced iNKT cell frequencies are observed in patients and different animal models (Dhodapkar M V, Geller MD, Chang DH, et al., J. Exp. Med. 2003; 197(12): 1667-76).
  • CD1d expression levels on antigen presenting cells are progressively downregulated upon MM progression (Spanoudakis E, Hu M, Naresh K, et al., Blood. 2009;113(11):2498— 507).
  • a crosstalk between adipose tissue and iNKT cell function plays a crucial role in MM development through release of the adipokine leptin.
  • iNKT cells have been shown to be involved in various immune responses, both in mice and in humans, ranging from self-tolerance to development of autoimmunity and responses to pathogens and tumours (Taniguchi, M. et al., Annu Rev Immunol. 2003;21 :483).
  • ⁇ -galactosylceramides (a -GalCer) have originally been isolated from a marine sponge Agelas mauritianus and it was found that these compounds exhibit anti-tumour and immuno-stimulating activity in pre-clinical animal models (see for example patent EP0609437B1).
  • the use of a-GalCer and analogous CD1d ligands has allowed to define iNKT cells as potent immunoregulatory cells that bridge the innate and adaptive response.
  • the design of various analogs of a-GalCer and its non-glycosidic analogues is extensively described in literature (Kerzerho, J. et al., J Immunol.
  • Modifications include either the lipid tails responsible for CD1d binding or the sugar moiety that directly interacts with the TCR.
  • KRN7000 is a synthetic a -GalCer that has been most frequently used in experimental studies. Clinical studies using KRN7000 have been disappointing since no clinical anti-tumour effects were recorded (Giaccone G et al (2002) Clin Cancer Res 8: 3702). Furthermore, it was observed that the use of sequential doses of a -GalCer can lead to an anergic state of T-cells (Parekh W et al (2005) J Clin. Invest. 115(9):2572-83).
  • BM changes occurring during aging is the increase in adipocyte numbers.
  • Leptin an adipokine released by adipocytes crucial in energy homeostasis, also displays immune modulatory properties but its role in anti-tumour immunity is unclear.
  • leptin and iNKT leptin receptor (LR) levels are linked to disease progression.
  • Leptin controls iNKT cells by inhibiting their function, preventing long term anti-tumour effects in MM.
  • LR signaling on activated iNKT cells markedly promotes tumour protection by alleviating iNKT cell anergy.
  • leptin-leptin receptor as a novel check point inhibitor strategy to target MM.
  • blocking leptin receptor signalling on activated iNKT cells protects against multiple myeloma by modulating iNKT anergy.
  • the use of a therapeutic amount of a leptin antagonist in combination with an iNKT-cell activator provides a surprising synergism in treating various forms of cancer.
  • compositions which comprise a leptin antagonist and an iNKT-cell activator.
  • said iNKT-cell activator is a-galactosylceramide or a functional derivative thereof.
  • a functional derivative retains the capacity to activate invariant natural killer cells.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a leptin antagonist and a-galactosylceramide.
  • said pharmaceutical composition comprises a leptin antagonist and a functional derivative of ⁇ -galactosylceramide capable of activating invariant natural killer T cells.
  • said leptin antagonist is a leptin receptor antagonist.
  • the invention provides a pharmaceutical composition which comprises an antagonist of the leptin receptor and an iNKT-cell activator.
  • said antagonist of the leptin receptor is an antibody with a specificity for the leptin receptor.
  • said pharmaceutical composition comprising a leptin antagonist and an iNKT-cell activator further comprises a chemotherapeutic agent.
  • This invention also relates to a pharmaceutical composition, comprising the particular components as described above, and one or more physiologically acceptable excipients.
  • the pharmaceutical composition according to the invention is particularly useful in treating cancer.
  • the pharmaceutical composition can be used to treat multiple myeloma.
  • the pharmaceutical composition is useful in the treatment of melanoma.
  • the pharmaceutical composition according to the invention can be used to treat breast cancer.
  • the leptin antagonist and the iNKT-cell activator are simultaneously administered. In another aspect according to the invention, administration of the leptin antagonist and the iNKT-cell activator takes place successively. In yet another aspect according to the invention, the leptin antagonist and the iNKT-cell activator are sequentially administered.
  • simultaneous, successive and sequential administration of the leptin antagonist and the iNKT-cell activator can be combined.
  • the leptin antagonist and the iNKT-cell activator can alternatingly be administered simultaneously, successively and sequentially.
  • Figure 1 The effect of leptin and its receptor on iNKT cells in MM.
  • B) Mean Fluorescence Intensity (MFI) of the leptin receptor expression on iNKT cells in the liver, bone marrow, spleen and blood at week 1 , 2 and 3 after inoculation with 5T33MM cells. The MFI is compared to leptin receptor levels in na ' ive C57BL/KaLwRij mice (n 3).
  • Respective conditions are MM cells + iNKT cells; iNKT cells + a- GalCer- loaded Dc's; iNKT cells + a-GalCer- loaded Dc's + MM cells; iNKT cells + a-GalCer- loaded Dc's + MM cells + leptin receptor antagonist; iNKT cells + a-GalCer- loaded Dc's + leptin receptor antagonist; iNKT cells + a-GalCer- loaded Dc's + leptin; iNKT cells + a-GalCer- loaded Dc's + leptin + MM.
  • Natural killer T cells (NKT); Dendritic cells (DC); Alpha- Galactosylceramide (a-G); Leptin Receptor antagonist (2.17-mAlb); Leptin (L). * p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.001
  • Figure 2 The combination effects of blocking the leptin receptor and iNKT cell activation in MM in vivo.
  • the present invention relates to a combination of a leptin antagonist and an iNKT-cell activator and the use of said combination as an anti-tumour therapeutic agent.
  • the present invention provides a pharmaceutical composition comprising a leptin antagonist and an iNKT-cell activator.
  • said pharmaceutical composition comprises synergistically effective amounts of the leptin antagonist and the iNKT-cell activator.
  • said leptin antagonist is from mammalian species, preferably human.
  • said leptin antagonist is recombinant.
  • said leptin antagonist is a leptin receptor antagonist.
  • said leptin receptor antagonist is an antibody which provides a specificity for the leptin receptor.
  • said iNKT-cell activator is a-galactosylceramide or a functional derivative thereof capable of activating invariant natural killer T cells.
  • the pharmaceutical composition comprising a leptin receptor antagonist and an iNKT-cell activator further comprises a chemotherapeutic agent.
  • the invention provides the use of a pharmaceutical composition comprising a leptin receptor antagonist and an iNKT-cell activator for the treatment of cancer.
  • the invention provides the use of a pharmaceutical composition comprising a leptin receptor antagonist and an iNKT-cell activator for the therapeutic treatment of MM.
  • the invention provides the use of a pharmaceutical composition comprising a leptin receptor antagonist and an iNKT-cell activator for the therapeutic treatment of melanoma.
  • the invention provides the use of a pharmaceutical composition comprising a leptin receptor antagonist and an iNKT-cell activator for the therapeutic treatment of breast cancer.
  • the invention provides the use of a pharmaceutical composition comprising a leptin receptor antagonist and an iNKT-cell activator for the treatment of metastasis.
  • said leptin receptor antagonist and said iNKT-cell activator are administered simultaneously. In a particular embodiment said leptin receptor antagonist and said iNKT-cell activator are administered successively.
  • the administration of the leptin receptor antagonist precedes the administration of the iNKT-cell activator.
  • the administration of the iNKT-cell activator precedes the administration of the leptin receptor antagonist.
  • said leptin receptor antagonist and said iNKT-cell activator are administered sequentially.
  • the administration of the leptin receptor antagonist precedes the administration of the iNKT-cell activator wherein said leptin receptor antagonist is administered sequentially and the first dose is administered at least one hour before the administration of the iNKT-cell activator.
  • said first dose of the leptin receptor antagonist is administered at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours before the administration of the iNKT-cell activator.
  • said first dose of the leptin receptor antagonist is administered at least one day before the administration of the iNKT-cell activator.
  • said first dose of the leptin receptor antagonist is administered at least two days before the administration of the iNKT-cell activator.
  • the leptin receptor antagonist is administered daily for at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 consecutive days.
  • the leptin receptor antagonist can also be administered over a long period, for example over weeks, months or even years. This can be useful to suppress tumour development and tumour growth.
  • the administration with the iNKT-cell activator is weekly for at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 consecutive weeks.
  • the iNKT-cell activator can also be administered over a long period, for example over months or even years. This can be useful to suppress tumour development and tumour growth.
  • the dose and dosage regimen will depend mainly on whether the leptin receptor antagonist and iNKT-cell activator are being administered separately or as a mixture, the type of cancer, the patient, and the patient's history. The amount must be effective to achieve a tumour reduction that is synergistic. If multiple doses are employed (such as preferred with the leptin receptor antagonist) the frequency of administration will depend, for example, on the type of host and type of cancer, dosage amounts, etc. For some types of cancers, daily administration will be effective, whereas for others, administration every other day or every third day will be effective, but daily administration will be ineffective. The practitioner will be able to ascertain upon routine experimentation which route of administration and frequency of administration are most effective in any particular case.
  • leptin receptor antagonist By a “leptin receptor antagonist” are meant the various forms of leptin receptor antagonists as described in the non- limiting examples below:
  • Leptin shows three binding sites for the interaction with the leptin receptor, sites l-lll.
  • the leptin receptor antagonist binds to the leptin receptor on binding site II, but fails to induce receptor clustering and thus signaling.
  • leptin site III leptin S120A/T121A; Peelman, F. et al., J Biol Chem. 2004; 279(39):41038-41046
  • leptin site I leptin L39A/D40A/F41A; Niv-Spector, L. et al., Biochem J.
  • the leptin receptor antagonist can also be synthesized based on the wild-type sequence of leptin binding sites I and III.
  • the preparation of a leptin receptor antagonist based on site I is disclosed in Catalano, S. et al., J Cell Mol Med. 2015 May;19(5):1122-32, and based on site III in Otvos, L. et al., Biopolymers. 2011 ;96(2):117-125.
  • a nanobody-based approach for the design of a leptin receptor antagonist is applied. Methods for this approach can be found in Zabeau, L. et al., Biochem J. 2012 Jan 1 ;441 (1):425-34.
  • leptin receptor antagonists are modified with polyethylene glycol (PEG) and the like as known in the art.
  • PEG polyethylene glycol
  • the leptin receptor antagonist comprises an antibody binding to albumin.
  • the preferred range of the leptin receptor antagonist used in the pharmaceutical composition of the present invention is between 1-100 mg/kg.
  • Any compound activating iNKT cell function can be used in the scope of the present invention. In view of the person skilled in the art, those compounds can be easily selected or designed. A broad range of these compounds is commonly available as well.
  • iNKT-cell activator has its general meaning in the art and refers to any derivative or analogue derived from a lipid, that is typically presented in a CD1d context by antigen presentating cells (APCs) and that can activate iNKT cells, i.e. promote, in a specific manner, cytokine production by iNKT cells, "a- galactosylceramide or "a -GalCer” can be seen as an example of a compound activating iNKT cell function.
  • APCs antigen presentating cells
  • a-galactosylceramide compound or "a-GalCer compound” has its general meaning in the art and refers to any functional derivative or analogue derived from a glycosphingolipid that contains a galactose carbohydrate attached by an a-linkage to a ceramide lipid that has an acyl and sphingosine chains of variable lengths (Van Kaer L. a - Galactosylceramide therapy for autoimmune diseases: Prospects and obstacles. Nat. Rev. Immunol. 2005; 5: 31-42).
  • a functional derivative retains the capacity to activate iNKT cells.
  • Examples of patents and patent applications describing instances of a -GalCer compounds include U.S. Pat. No. 5,936,076; U.S. Pat. No. 6,531 ,453 U.S. Pat. No. 5.S53.737, U.S. Pat. No. 8,022,043, US Patent Application 2003030611 , US Patent Application 20030157135, US Patent Application 20040242499, US Patent Application 20040127429, US Patent Application 20100104590, EP0609437, EP2958595 and International patent application W02006026389.
  • a typical -GalCer compound is KRN7000 ((2S 3S, 4R)-1-0-(alfaD-galactopyranosyl)-N - hexacosanoyl-2-amino- 1 ,3,4-octadecanetriol)) (KRN7000, a novel immunomodulator, and its antitumour activities.
  • KRN7000 ((2S 3S, 4R)-1-0-(alfaD-galactopyranosyl)-N - hexacosanoyl-2-amino- 1 ,3,4-octadecanetriol)) (KRN7000, a novel immunomodulator, and its antitumour activities.
  • Kobayashi E Motoki K, Uchida T, Fukushima H, Koezuka Y. Oncol Res. 1995;7(10-l l):529-34).
  • a -GalCer compounds are modified with polyethylene glycol (PEG) and the like as known in the art.
  • PEG polyethylene glycol
  • pegylated refers to the conjugation of a compound moiety (i.e. a -GalCer compound) with conjugate moiety(ies) containing at least one polyalkylene unit.
  • pegylated refers to the conjugation of the compound moiety (i.e. a -GalCer compound) with a conjugate moiety having at least one polyethylene glycol unit.
  • Derivatives of a -GalCer also include functional derivatives of a -GalCer which have been modified for chemical coupling (conjugation) to another molecule.
  • activate iNKT cells refers for instance to the observed induction of cytokine production, such as IFN- ⁇ in iNKT cells by an iNKT-cell activator.
  • the particulate entity according to the invention comprises (2S,3S,4R)-l-0-(alpha-D- galactosyl)-N-hexacosanoyl-2-amino-l,3,4-octadecanetriol or its functional derivative.
  • iNKT-cell activators are non-limiting.
  • the skilled person has access to suitable iNKT-cell activators as their design and optimization is extensively spread in both scientific and patent literature. Any compound activating iNKT-cell function is envisaged by the present invention.
  • the preferred range of a -GalCer used in the pharmaceutical composition of the present invention is between 20-200 g/kg.
  • the combination of the iNKT-cell activator and the leptin receptor antagonist is found to provide a surprising synergism in treating various forms of cancer such as myeloma, melanoma and breast cancer.
  • the term "therapeutic" treatment refers to administration to the host of the leptin receptor antagonist and the iNKT-cell activator after or before the host has contracted cancer, as determined by any means.
  • the treatment is not considered therapeutic if an existing tumour burden is not decreased or more preferentially eliminated.
  • the treatment is also not considered therapeutic if the development of a tumour burden is not decreased or more preferentially prevented.
  • cancer refers to any neoplastic disorder, including such cellular disorders as, for example, renal cell cancer, Kaposi's sarcoma, chronic leukemia, breast cancer, sarcoma, ovarian carcinoma, rectal cancer, throat cancer, myeloma, melanoma, colon cancer, bladder cancer, mastocytoma, lung cancer, mammary adenocarcinoma, pharyngeal squamous cell carcinoma, and gastrointestinal or stomach cancer. Metastasis of said various forms of cancer are also envisaged by the term "cancer".
  • the cancer is myeloma, melanoma and breast cancer.
  • the term "synergistically effective amount" as applied to the leptin receptor antagonist and the iNKT- cell activator refers to the amount of each component of the pharmaceutical composition which is effective for a decrease of tumour cells and which produces an effect which does not intersect, in a dose-response plot of the dose of the leptin receptor antagonist versus a dose of the iNKT-cell activator versus decrease of tumour cells, either the dose leptin receptor antagonist axis or the dose iNKT-cell activator axis.
  • the dose response curve used to determine synergy in the art is fully described in A. Goodman etal, ed.
  • the optimum synergistic amounts can be determined, using a 95% confidence limit, by varying factors such as dose level, schedule and response, and using a computer-generated model that generates isobolograms from the dose response curves for various combinations of the iNKT-cell activator and the leptin receptor antagonist. The highest decrease in tumour cells on the dose response curve correlates with the optimum dosage levels.
  • the term "recombinant" refers to a leptin receptor antagonist produced by recombinant DNA techniques wherein generally the gene coding for the leptin receptor antagonist is cloned by known recombinant DNA technology.
  • the recombinant host may be eucaryotic or procaryotic host.
  • the term “pharmaceutically acceptable” refers to a carrier medium that does not interfere with the effectiveness of the biological activity of the active ingredients and that is not toxic to the hosts to which it is administered.
  • parenteral administration examples include subcutaneous, intravenous, intraarterial, intramuscular, and intraperitoneal administration(s).
  • the dosage amount which appears to be most effective herein is one which results in tumour regression or complete regression and is not toxic to the host. This optimum level will depend on many factors, for example, on the type of host and type of cancer, route, schedule of administration, existing tumour burden, the type of iNKT-cell activator and the leptin receptor antagonist, and the definition of toxicity. Toxicity to the host may be defined by the extent and type of side effects or by the amount of body weight loss or by death after a certain period of time. If body weight loss is the criterion for toxicity, typically a loss of 10-20% by weight will be tolerated, with greater than 20% loss being considered toxic.
  • the pharmaceutical composition will generally be formulated in a unit dosage injectable form (solution, suspension, emulsion), preferably in a pharmaceutically acceptable carrier medium that is inherently non-toxic and non-therapeutic.
  • a pharmaceutically acceptable carrier medium that is inherently non-toxic and non-therapeutic.
  • examples of such vehicles include saline, Ringer's solution, dextrose solution, mannitol and normal serum albumin.
  • Non-aqueous vehicles such as fixed oils and ethyl oleate may also be used.
  • the carrier medium may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives.
  • the leptin receptor antagonist will typically be formulated in such carriers at a concentration of about 0.01 mg/ml to 20 mg/ml.
  • the pharmaceutical composition may be made into a sterile, stable lyophilized formulation in which the purified compounds (i.e. leptin receptor antagonist and iNKT-cell activator) can be mixed with a water-soluble carrier such as mannitol, which provides bulk, and a sufficient amount of a surfactant (such as for example sodium dodecyl sulfate) to ensure the solubility of the iNKT-cell activator in water.
  • a surfactant such as for example sodium dodecyl sulfate
  • the pharmaceutical composition and its uses can also be applied for the treatment of veterinary animals.
  • the leptin receptor antagonist may be prepared from tissue cultures or by recombinant techniques, and from any mammalian source, such as, e.g. rabbit, primate, pig, cow, cat and dog.
  • mice lymphocytes were stained with CD1d/a-GalCer tetramer, mouse anti-leptin receptor biotinylated antibody (R&D Systems), TCRp, CD3, NK1.1 , anti-APC HRP conjugated antibody (all eBioscience), CD4 and 7-AAD (Both BD Biosciences) and acquired on a FACSCanto II (BD Biosciences).
  • Human mononuclear cells were stained with CD3, CD4, CD8 (eBioscience), anti-human leptin receptor (R&D Systems) and acquired on a FACSLSRII (BD Biosciences). Analyses were performed using FlowJo software (Tree Star Inc.).
  • 5x10 4 5T33MMW cells, 5x10 4 iNKT cells, 10 5 a-GalCer loaded or vehicle loaded DCs were co-cultured in supplemented RPMI-1640 medium.
  • Leptin (0,25 ⁇ / ⁇ ) and/or bispecific nanobody 2.17m-Alb ( ⁇ / ⁇ ) were added. Construction, production, and purification of the nanobody 2.17m-Alb was described elsewhere (Zabeau L, Verhee A, Catteeuw D, et al., Biochem. J. 2011 ;441 :425-434).
  • Supernatants of co-cultures were collected after 72 h for IFN- Y measurements by ELISA (eBioscience), following manufacturer's instructions.
  • mice C57BL/KaLwRij mice were inoculated as described previously and weekly i.p. injected with 2 ⁇ g a-GalCer (Vanderkerken K, Croucher P., Immunol. Rev. 2003;194:196-206; Radl J, Glopper E De, Schuit HRE, Zucher C, J. Immunol. 1979;122(2):609— 613).
  • Serum IFN- ⁇ levels were determined by ELISA. Mice were treated during 10 days with 2.17m-Alb or control BclL10-mAlb (i.p., 200 g mouse -1 day -1 ) and weighed daily.
  • the melanin-positive melanoma B16BI6 cells (Hart ef al., 1979) are cultured in RPM1 1640 (Invitrogen) supplemented with 10% FCS, 50 lU/ml penicillin G, 50 ⁇ g/ml streptomycin sulphate, 2 mM L-glutamine and 0,4 mM Na-pyruvate.
  • tumour inoculation cells are detached from the culture flask by a short EDTA treatment, washed three times in endotoxin-free sterile PBS (Sigma), and resuspended in PBS at 12x10 6 cells/ml.
  • mice are inoculated with 6x10 5 cells (in 50 ⁇ PBS) subcutaneously in the back just in front of the hind limb. Treatment is started when the tumour size index (TSI), i.e. the product of the largest perpendicular diameters in mm, reached 10-50 (day 7-12).
  • TTI tumour size index
  • mice are inoculated with 1x10 5 cells (in 50 ⁇ PBS) subcutaneously in the back just in front of the hind limb. Treatment is started when the tumour size index (TSI), i.e. the product of the largest perpendicular diameters in mm, reached 10-50 (day 8-14).
  • TTI tumour size index
  • mice receive a-GalCer, 2.17m-Alb or control BclM O- mAlb (i.p., 200 g mouse-1 day-1) according to the treatment scheme above.
  • DCa-G dendritic cells
  • LR could be a potential target in MM by using a 2.17-mAlb nanobody which inhibits binding of leptin to the leptin receptor (Zabeau, L. et al., Biochem. J. 2011 ;441 :425-434).
  • a-GalCer stimulated iNKT cells significantly decreased BM tumour load and serum M-spike in MM diseased mice (Nur, H. et al., PLoS One. 2013;8(5):e65075; Mattarollo, S.R. et al., Blood. 2012;120(15):3019-3029).
  • mice receiving the combined regimen with LR antagonist displayed intact IFN- ⁇ levels after a second restimulation ( Figure 2E).
  • LR antagonists therefore bypass hypo- activation of iNKT cells ( Figure 2E). This maintained iNKT activity had effects on tumour burden, as measured by the serum M spike.
  • C57BL/6 mice bearing a subcutaneously growing B16BI6 tumour are treated with a combination of the specific iNKT cell agonist alfa-GalCer and a leptin receptor antagonist.
  • Treatment with either a-GalCer or a leptin receptor antagonist alone has no significant effect on tumour growth, while the combination of a-GalCer and the leptin receptor antagonist results in reduced tumour growth.
  • mice bearing a subcutaneously growing 4T1 tumour are treated with a combination of the specific iNKT cell agonist alfa-GalCer and a leptin receptor antagonist.
  • Treatment with either a-GalCer or a leptin receptor antagonist alone has no significant effect on tumour growth, while the combination of a-GalCer and the leptin receptor antagonist results in reduced tumour growth.

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Abstract

La présente invention concerne le traitement du cancer. Plus spécifiquement, l'invention révèle que l'activité anticancéreuse chez les mammifères peut être augmentée par l'administration à l'hôte mammifère d'une quantité synergétiquement efficace d'une combinaison d'un antagoniste de la leptine et d'un activateur des cellules T "tueuses naturelles" (de l'anglais "Natural Killer T cell") invariantes (iNKT).
PCT/EP2016/062322 2016-06-01 2016-06-01 Thérapie anticancéreuse utilisant un antagoniste de la leptine et un activateur des cellules inkt Ceased WO2017207040A1 (fr)

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