Polymeric forms of H-NOX proteins
Inventors
KAPP, Gregory • SERWER, LAURA • LE MOAN, NATACHA • Cary, Stephen P. L.
Assignees
Publication Number
US-11987614-B2
Publication Date
2024-05-21
Expiration Date
2033-01-07
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Abstract
The invention provides polymeric H-NOX proteins for the delivery of oxygen with longer circulation half-lives compared to monomeric H-NOX proteins. Polymeric H-NOX proteins extravasate into and preferentially accumulate in tumor tissue for sustained delivery of oxygen. The invention also provides the use of H-NOX proteins as radiosensitizers for the treatment of brain cancers.
Core Innovation
The invention provides polymeric H-NOX proteins comprising two or more H-NOX domains for the delivery of oxygen with longer circulation half-lives compared to monomeric H-NOX proteins. These polymeric proteins extravasate into and preferentially accumulate in tumor tissue, enabling sustained oxygen delivery to hypoxic tumor regions. The invention also includes recombinant monomeric H-NOX proteins comprising an H-NOX domain and a polymerization domain that associate to form these polymeric proteins.
H-NOX proteins bind nitric oxide and oxygen via their heme domain and have been engineered through mutations to optimize oxygen affinity and minimize nitric oxide reactivity, addressing limitations of existing hemoglobin-based oxygen carriers. The invention introduces polymeric forms, such as trimers formed by fusing an H-NOX domain to a trimerization foldon domain, increasing molecular weight beyond renal filtration limits, thereby extending circulation time and improving tissue accumulation and oxygen delivery, particularly into tumors.
The problem addressed is the short circulation half-life of monomeric H-NOX proteins due to their small size and kidney filtration. There is a need for oxygen carriers with prolonged circulation that can deliver oxygen effectively to distal tissues and specifically permeate hypoxic tumor zones to enhance therapies such as radiotherapy and chemotherapy. The invention provides polymeric H-NOX proteins that persist longer in circulation, preferentially accumulate in tumors, and maintain oxygen binding properties within desired ranges to modify hypoxic tumor niches and improve treatment efficacy.
Claims Coverage
The patent claims focus on a method of delivering oxygen to brain tumors in individuals with brain cancer by administering trimeric H-NOX proteins, highlighting combinations with radiation or chemotherapy and defining specific inventive features regarding the protein composition and treatment parameters.
Oxygen delivery using trimeric H-NOX proteins
A method of delivering oxygen to a brain tumor in an individual with brain cancer comprising administering an effective amount of a trimeric H-NOX protein comprising three H-NOX monomers.
Combination with radiation therapy or chemotherapy
The administration of the H-NOX protein is used in combination with radiation therapy or chemotherapy, where radiation or chemotherapy can be administered 1 to 6 hours post H-NOX administration, including X-radiation at doses from about 0.5 gray to about 75 gray.
Repeated administration of H-NOX protein and/or radiation
The method includes repeated administration of the H-NOX protein and/or radiation treatment in multiple cycles.
Treatment specificity for brain cancer and mammalian individuals
The brain cancer treated is glioblastoma, and the individual subject is a mammal.
Use of H-NOX proteins from various species and specific mutations
The H-NOX protein used can be from Thermoanaerobacter tengcongensis, Legionella pneumophilia 2, Homo sapiens β1, Rattus norvegicus β1, Canis lupus, Drosophila melanogaster β1, D. melanogaster CG14885-PA, Caenorhabditis elegans GCY-35, Nostoc punctiforme, Caulobacter crescentus, Shewanella oneidensis, or Clostridium acetobutylicum. The H-NOX domain may correspond to T. tengcongensis SEQ ID NO:2.
Inclusion of distal pocket mutations in H-NOX proteins
The H-NOX protein can comprise one or more distal pocket amino acid substitutions, specifically at position L144 of T. tengcongensis H-NOX, including the L144F substitution.
The claims cover therapeutic methods employing trimeric H-NOX proteins with defined compositions and mutations, particularly for brain cancer treatment through oxygen delivery, optionally combined with radiation or chemotherapy with specified timing, dosage, and repeated administration.
Stated Advantages
Polymeric H-NOX proteins provide longer circulation half-lives than monomeric forms.
They preferentially accumulate in tumor tissues, enabling sustained oxygen delivery.
The H-NOX proteins have lower nitric oxide reactivity than hemoglobin, reducing related side effects.
Polymeric H-NOX proteins improve oxygen delivery deep within hypoxic tumor zones.
The invention enhances efficacy of radiotherapy, chemotherapy, and other oxygen-dependent anticancer treatments.
Documented Applications
Delivery of oxygen to brain tumors, especially glioblastoma.
Use as radiosensitizers in combination with radiation therapy or chemotherapy for treatment of brain cancers.
Methods to treat brain cancer and reduce tumor growth via administration of H-NOX proteins and radiation.
Use in treatment of other cancers including lung, colorectal, and skin cancers.
Use of H-NOX proteins in veterinary medicine for animals such as dogs, cats, horses, monkeys, rabbits, rats, mice, guinea pigs, hamsters, pigs, and cows.
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