Modulation of tumor immunity by protein-mediated O2 delivery
Inventors
Cary, Stephen P. L. • Krtolica, Ana • LE MOAN, NATACHA • Winger, Jonathan A • Leong, Kevin G.
Assignees
Publication Number
US-12285463-B2
Publication Date
2025-04-29
Expiration Date
2036-03-17
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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.
Core Innovation
The invention provides methods for modulating hypoxia-mediated tumor immunity by administration of an O2 carrier polypeptide, such as an H-NOX protein. These methods enhance an immune response to tumors by targeting both hypoxia inducible factor 1 alpha (HIF-1α)-mediated pathways and non-HIF-1α-mediated pathways of tumor immunity. The O2 carrier polypeptide is delivered to the tumor to increase lymphocyte infiltration, including CD4, CD8, and NK cells, inhibit suppressive cells such as regulatory T cells (Treg), tumor associated macrophages (TAM), and myeloid-derived suppressor cells (MDSC), and enhance antigen processing and dendritic cell presentation capabilities.
The background identifies that hypoxia in tumor microenvironments suppresses host anti-tumor immune defenses by modulating multiple signaling pathways including HIF-1 signaling, adenosinergic A2 and PD-L1 pathways, recruitment of inhibitory cell types, and direct inhibition of tumor recognition by the immune system. Previous supplemental oxygen therapies failed to effectively improve tumor oxygenation due to poor diffusion limits. The invention addresses this problem by using protein-based O2 carriers, such as H-NOX proteins, which can deliver oxygen beyond normal diffusion limits to hypoxic tumor tissues, thus better reversing immunosuppression.
Claims Coverage
The independent claims focus on methods of treating cancer in humans involving administration of specific trimeric H-NOX proteins with defined features, in combination with immunotherapy.
Trimeric H-NOX protein with specific T. tengcongensis H-NOX domain and foldon trimerization domain
A trimeric H-NOX protein comprising three monomers, each comprising a T tengcongensis H-NOX domain with a L144F amino acid substitution, covalently linked to a foldon domain of bacteriophage T4 fibritin, with each monomer covalently bound to polyethylene glycol (PEG).
Combination cancer treatment method
A method of treating glioblastoma in a human individual comprising administering an effective amount of the trimeric H-NOX protein in combination with immunotherapy, wherein the immunotherapy is an anti-PD-1 antibody therapy or a dual PD-1/PD-L1 blockade antibody therapy.
Structural linkage and modification features
The H-NOX domain is covalently linked to the trimerization (foldon) domain, optionally via an amino acid linker of 3-10 residues such as Gly-Ser-Gly, and each monomer can carry multiple PEG molecules (e.g., three per monomer within 1-10 kDa molecular weight range).
Administration details
The trimeric H-NOX protein is administered intravenously, via bolus or infusion, preferably prior to or concurrently (within 60 minutes) with the immunotherapy.
The claims cover the method of treating glioblastoma in humans by administering a PEGylated trimeric H-NOX protein composed of T. tengcongensis H-NOX L144F monomers linked to a foldon domain, in combination with immunotherapy targeting PD-1/PD-L1 checkpoints, including specific structural and administration features.
Stated Advantages
The protein-mediated oxygen delivery overcomes diffusion limitations of soluble oxygen leading to improved oxygenation of hypoxic tumor microenvironments.
It enhances anti-tumor immune responses by increasing lymphocyte infiltration and reducing immunosuppressive cells within tumors.
It decreases expression of hypoxia-induced immunosuppressive factors such as HIF-1α, PD-L1, A2AR, VEGF, and GLUT1 within tumors.
It synergizes with other cancer therapies including radiation, chemotherapy, and various immunotherapies to improve therapeutic efficacy.
H-NOX proteins have lower NO reactivity than hemoglobin, reducing side effects associated with NO scavenging and making them suitable as oxygen carriers.
Documented Applications
Cancer treatment involving administration of O2 carrier polypeptides such as H-NOX proteins to modulate tumor immunity and enhance immune responses.
Treatment of a wide variety of cancers including glioblastoma, brain tumors, bone tumors, pancreatic tumors, skin tumors, head and neck tumors, melanoma, lung tumors, uterine tumors, ovarian tumors, colorectal tumors, liver tumors, stomach tumors, testicular tumors, endometrial tumors, cervical tumors, vaginal tumors, Hodgkin's and non-Hodgkin's lymphomas, esophageal tumors, intestinal tumors, thyroid tumors, adrenal tumors, bladder tumors, kidney tumors, breast tumors, multiple myeloma tumors, sarcomas, and squamous cell tumors.
Combination therapies of H-NOX proteins with radiation therapy, chemotherapy, and immunotherapies such as immune checkpoint inhibitors (e.g., anti-PD1, anti-PD-L1, anti-CTLA-4), adoptive immune cell therapies, anticancer vaccines, oncolytic viruses, and BiTEs.
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