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Modulation of tumor immunity by protein-mediated 02 delivery

a tumor immunity and protein-mediated technology, applied in the field of tumor immunity modulation, can solve the problems of limiting the penetration depth of hypoxic tumor tissue, and achieve the effects of enhancing the immune response to the tumor, increasing lymphocyte infiltration, and modulating tumor immunity

Inactive Publication Date: 2018-08-30
OMNIOX
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides methods for using a protein called O2 carrier polypeptide to enhance the immune response to tumors and improve the infiltration of lymphocytes, such as CD4, CD8, or NK cells, into tumors. This approach also inhibits the growth of tumor-associated cells that can suppress the immune system. The invention also enhances antigen processing and improves the ability of dendritic cells to present antigens to the immune system. Overall, the patent provides a novel approach to improve the immunity against tumors and avenge their growth.

Problems solved by technology

This is likely due to the inability of soluble oxygen to effectively diffuse beyond ˜80 μm from blood vessels, limiting its penetration deep into hypoxic tumor tissue.

Method used

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  • Modulation of tumor immunity by protein-mediated 02 delivery
  • Modulation of tumor immunity by protein-mediated 02 delivery
  • Modulation of tumor immunity by protein-mediated 02 delivery

Examples

Experimental program
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Effect test

example 1

bles Efficient Oxygenation of Hypoxic Tumor Microenvironments

[0229]A PEGylated trimeric Thermoanaerobacter tengcongensis (Tt.) H-NOX bearing a L144F substitution in the distal pocket (FIG. 6B) was evaluated for the ability to oxygenate tumor microenvironments and increase radiation sensitity. Administration of the PEGylated trimeric Tt H-NOX L144F to mice bearing hypoxic tumors induces rapid and sustained oxygenation of the tumors as directly measured by the external hypoxia marker, pimonidazole, hypoxia inducible transcription factor 1 alpha, HIF-1-α, and OxyLite oxygen-sensing nanofiber (FIGS. 2 and 3, respectively).

[0230]Mice bearing H460 subcutaneous xenograft tumors were injected i.v. with PEGylated trimer H-NOX (L144F) at 650 mg / kg when tumor volume reached ˜300-350 mm3 (˜10-14 days after tumor cell subcutaneous implantation). Prior to euthanasia, mice were injected with the exogenous hypoxia marker pimonidazole at 60 mg / kg and tumors were harvested. Pimonidazole (FIG. 2A) (Hy...

example 2

s as an Immunoactivator Enhancing Host Anti-Tumor Responses

[0238]PEGylated trimer Tt H-NOX L144F-induced oxygenation inhibits the HIF-1α pathway (FIG. 2B) and relieves HIF-1α-dependent and HIF-1α-independent tumor immunosuppression. Mice bearing H460 subcutaneous xenograft tumors (200-350 mm3) were either treated with vehicle alone or with PEGylated trimer H-NOX (L144F) and harvested 7, 16 or 24 hours after injection for qRT-PCR analysis. Mean values+ / −SEM. N=5-6 per group, *p<0.05 by t-test. Treatment with a single dose of H-NOX resulted in significant downregulation of HIF-1α and its effectors including direct and indirect modulators of the host's immune response: PD / PDL-1 and VEGF signaling, metabolic and growth factor regulators (FIG. 5).

[0239]Seven to eight week old Nu / Nu female mice were subcutaneously implanted with 3×106 of H460 human lung cancer cells and monitored until the tumors reached average size of ˜300 mm3 (10-14 days post-implantation of tumor cells). Mice bearing ...

example 3

nt of Hypoxia and T Cells in B16F10 and CT26 Subcutaneous Tumors and Intracranial GL261-Luciferase Tumors

[0242]Generation of B16F10 and CT26 Subcutaneous Tumors and Intracranial GL261-Luciferase Tumors.

[0243]Six to eight week old C57BL / 6J female mice were subcutaneously implanted with 1×106 B16F10 mouse melanoma cancer cells on the flank (FIG. 7A). Six to eight week old BALB / c female mice were subcutaneously implanted with 1×106 CT26 colon tumor cells on the flank (FIG. 7B). Male C57BL / 6J weighting 20 g were injected with 3×105 GL261-luc cells intracranially into the right caudate nucleus (+0.5 mm A / P, +2.3 mm M / L and −3.2 mm D / V) (FIG. 7C). Intracranial tumors were allowed to grow for 21 days before sacrifice. Subcutaneous tumors were measured 3 times a week using calipers and tumor size was calculated based on the formula: (length x width2)+0.5. Once the tumors reached an average size of −300 mm3 (10-14 days post-implantation of tumor cells), treatment was initiated.

[0244]Treatmen...

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Abstract

The invention provides methods to modulate hypoxia-mediated tumor immunity by administration of an O2 carrier polypeptide (e.g., an H-NOX protein). The methods of the invention target both hypoxia inducible factor 1 alpha (HIF-1α) pathways and non-HIF-1α pathways of tumor immunity. Such methods are useful in the treatment of a wide variety of cancers and may be used alone or in combination with other anti-cancer therapies.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Patent Application No. 62 / 134,523, filed Mar. 17, 2015, the disclosure of which is hereby incorporated by reference in its entirety for all purposes.SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE[0002]The content of the following submission on ASCII text file is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name: 627042000940SeqList.txt, date recorded: Mar. 17, 2016, size: 41 KB).TECHNICAL FIELD[0003]This application pertains to the modulation of tumor immunity by delivering oxygen to the tumor by way of a protein O2 carrier polypeptide; for example an H-NOX protein.BACKGROUND OF THE INVENTION[0004]The hypoxic tumor microenvironment suppresses the host's immune anti-tumor defenses by modulating multiple signaling pathways including, but not limited to, hypoxia inducible factor (HIF-1) signaling (Codo et al., 2014 Onc...

Claims

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Application Information

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IPC IPC(8): A61K38/16A61K45/06A61K47/60A61P35/00A61K39/39
CPCA61K38/164A61K45/06A61K47/60A61P35/00A61K39/39A61N5/10A61N2005/1098A61K38/00A61K38/16
Inventor CARY, STEPHEN P. L.KRTOLICA, ANALE MOAN, NATACHAWINGER, JONATHAN A.LEONG, KEVIN G.
Owner OMNIOX
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