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AssigneeEnzo Therapeutics, Inc.
InventorsYaron Ilan, Eran Elinav
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Leptin was previously demonstrated to exert potent immune modulatory properties in several immune mediated disorders. The aim of the study was to determine leptin's anti-tumor effect in a murine model of human hepatocellular carcinoma (HCC). In vivo, Athymic T cell deficient (nude) mice transplanted with 1×106 human Hep3B cells, followed by administration of two daily intraperitoneal doses of 0.5 mg/gram leptin for 6 weeks. Leptin administration induced a significant reduction in tumor size and improved survival in nude mice. Histologically, tumors of leptin-administered mice featured increased inflammatory exudate in interphase areas. Leptin-induced tumor suppression was associated with a significant increase in peripheral natural killer (NK) cell number. Splenocytes from leptin-treated mice featured decreased expression of CIS mRNA. To determine which lymphocyte subset is a prerequisite for the anti tumor effect of leptin, T&B cell deficient (Scid) mice and T,B& NK deficient (Scid-Beige) mice were subcutaneously implanted with Hep3B tumor cells, with and without the daily intraperitoneal administration of 0.5 mg/gram leptin for 6 weeks. SCID mice featured leptin-associated tumor suppression similar to those of nude mice. In contrast, NK-deficient SCID-Beige mice developed larger tumors. To further establish natural killer cell's central role in mediation of leptin's anti-tumor effect, NK cells were incubated in vitro with increasing doses of leptin, demonstrating a dose-dependent increase in cytotoxic activity. Incubation of leptin with hepatoma cell line was found to induce a dose-dependent reduction in hepatoma cell proliferation, suggesting an additive direct anti-tumor effect. Further synergism in inhibition of hepatoma cell proliferation in vitro was achieved following addition of natural killer cells. HCC cells expressed leptin receptor mRNA, while addition of leptin induced increased mRMA expression of STAT2 and SOCS1 on tumor cell lines. Leptin administration induces a significant suppression of human HCC. This effect is mediated by induction of natural killer cell proliferation and activation, and by direct inhibition of tumor growth. Decreased natural killer cell expression of inhibitory CIS protein and over expression of the anti-proliferative STAT2 and SOCS1 proteins in HCC lines may underline both anti cancerous effects of leptin.
A method for modulating the Th1/Th2 cell balance in a subject in need thereof, wherein said modulating comprises adjusting the amount, the expression, the activity, and/or any combination thereof of leptin in said subject.
A method for the treatment of an immune-related disorder in a subject comprising administering to said subject an effective amount of leptin, any homologue, derivative, functional fragment of leptin, an expression vector comprising a nucleic acid sequence encoding for leptin or any functional fragments thereof, a protein, a peptide, an anti-idiotype antibody to leptin, or any combination of any of the foregoing.
A therapeutic composition for modulating the Th1/Th2 cell balance in a subject in need thereof comprising adjusting the level, the expression, the activity and/or any combination thereof, of leptin in said subject.
A method for the treatment of an immune-related disorder in a subject comprising administering to said subject an effective amount of an antibody specific for leptin, a fragment of an antibody to leptin, an antibody to the leptin receptor, a fragment of an antibody to the leptin receptor, soluble leptin receptor, a fragment of leptin, a fragment of leptin receptor, a protein or peptide capable of inhibiting the expression of leptin, a nucleic acid or an oligonucleotide comprising sequences complementary to leptin or leptin receptor mRNA sequences, or any combination of any of the foregoing.
A method for the treatment of immune-related disorders in a mammalian subject in need of such treatment, by manipulating NKT cell population of said subject, wherein manipulation of said NKT cell population results in modulation of the Th1/Th2 cell balance, said method comprises the steps of:
A therapeutic composition for the treatment of an immune-related disorder in a mammalian subject, wherein said composition comprises as an effective ingredient ex vivo educated autologous NKT cells capable of modulating the Th1/Th2 cell balance, and optionally further comprises a pharmaceutically acceptable carrier, diluent, excipient and/or additive.
Dependencies are inferred from the claim text.