Beta-glucan methods and compositions that affect the tumor microenvironment

A glucopyranose and glucopyranose-based technology, applied in the field of serial number 62/115,895 submitted on February 13, 2015, can solve the problem of reducing the overall survival rate of tumor growth

Active Publication Date: 2021-05-07
百奥赛诺公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Numerous animal tumor models have demonstrated that administration of soluble β-glucan in combination with complement-activating, tumor-targeting antibodies results in significantly reduced tumor growth and improved overall survival compared to either agent alone

Method used

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  • Beta-glucan methods and compositions that affect the tumor microenvironment
  • Beta-glucan methods and compositions that affect the tumor microenvironment
  • Beta-glucan methods and compositions that affect the tumor microenvironment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Establishment and Characterization of Human M1 and M2 Macrophages Cultured in Vitro: Enrichment of CD14 from Human Whole Blood Using Ficoll Gradients and Magnetic Bead Separation + monocytes. Then the enriched monocytes (5×10 5 cells / mL) in M1-polarized (XVivo 10 medium (Lonza Group) supplemented with 5% autologous serum and 100 ng / mL recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) (R&D Systems)) or M2-polarization (XVivo 10 medium supplemented with 10% autologous serum and 50 ng / mL recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) (R&D Systems) was cultured for 6 days. In experiments performed to evaluate the effect of β-glucan, whole blood was first incubated with vehicle (sodium citrate buffer) or 25 μg / mL soluble β-glucan at 37°C for 2 hours, then Monocytes were isolated and allowed to differentiate. Macrophages were examined for morphology prior to collection for phenotypic analysis. Media from day 6 mac...

Embodiment 2

[0071] Effect of β-glucan on M2 to M1 repolarization: M1 and M2 macrophages from vehicle-treated or β-glucan-treated whole blood were prepared as described above. Expression of a panel of M1 / M2-specific markers, including HLA-DR, CD163, CD206, CD209, CD80, CD86, and PD-L1, was measured by flow cytometry. β-glucan pretreatment did not affect the M1 macrophage phenotype, but did affect the M2 macrophage phenotype. Such as Figure 2A As shown, the mean fluorescence intensity (MFI) of CD163 was downregulated in β-glucan-treated M2 macrophages. In addition, the surface expression of CD86 and the protein and mRNA levels of PD-L1 were enhanced ( Figure 2B ).

[0072] Next, vehicle-treated or β-glucan-treated M1 or M2 macrophages were cultured with CD3- and CD28-stimulated, carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled autologous CD4 T cells , and T cell proliferation was measured by flow cytometry at the end of the experiment, and the results were quantitatively...

Embodiment 3

[0075] Effect of β-glucan on M2 to M1 repolarization in cells from strongly bound versus weakly bound subjects: assessment of soluble β-glucan in relation to neutrophils and monocytes Early studies of binding revealed that subjects have different binding abilities. Further studies found that soluble beta-glucan bound to at least some immune cells of the strongly bound subjects, and that the strongly bound subjects also had higher levels of natural anti-beta-glucan antibodies. Functional studies identified general cut-offs for binding and antibody levels that were used to differentiate subjects as strong binders (high responsiveness to β-glucan) and weak binders (low responsiveness to β-glucan) .

[0076] To this end, M1 / M2 macrophages derived from monocytes from strong and weak binders treated with soluble β-glucan were assessed. M1 and M2 macrophages from strong and weak binders were subsequently assessed for A) phenotype, B) enhancement of CD4 T cell proliferation, and C) ...

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Abstract

The present invention relates to the combination of soluble β-glucan and immunosuppressive alleviating agents affecting the tumor microenvironment. Soluble β-glucans promote an immunostimulatory environment that increases the effectiveness of anti-angiogenic agents, checkpoint inhibitors including non-tumor-targeting antibodies.

Description

[0001] Cross References to Related Applications [0002] This application claims serial numbers 62 / 076,094 filed November 6, 2014, 62 / 115,895 filed February 13, 2015, 62 / 149,892 filed April 20, 2015, 2015 Priority to U.S. Provisional Patent Applications Serial No. 62 / 234,276, filed September 29, 2015 and Serial No. 62 / 239,005, filed October 8, 2015, all of which are incorporated herein by reference. Background technique [0003] The present invention relates to combinations of soluble β-glucans with anticancer agents that affect the tumor microenvironment, including anticancer agents that alleviate immunosuppression. β-glucan is a fungal PAMP and is detected by the pattern recognition molecule C3 in serum and the pattern recognition receptor, complement receptor 3, on innate immune cells including neutrophils and monocytes ( CR3) recognition. Yeast-derived polysaccharide β-glucan - β-glucan (β(1,6)-[poly-(1,3)-D-glucopyranosyl]-poly-β(1,3) -D-glucopyranose) is being develo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/716C07K16/28
CPCA61K39/3955C07K16/2818C07K16/2827C07K16/2863C12N5/0639C12N5/0645A61K2039/505C07K2317/24C07K2317/76C12N5/0636C12N2500/34C12N2501/052C12N2501/22C12N2501/2304C12N2501/24C12N2501/51C12N2502/1114A61K31/716A61P35/00A61K2300/00C07K16/3015C07K16/3023C07K16/303C07K16/3038C07K16/3046C07K16/3053C07K16/3061
Inventor N·波斯基思·戈登阿尼萨·SH·陈史蒂文·莱昂纳多杰里米·格拉夫邱晓红塔卡什·坎加斯凯瑟琳·A·弗雷泽阿德里亚·拜科夫斯基乔纳斯纳丁·奥特森
Owner 百奥赛诺公司
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