# US 10,766,947 B2 · Polymeric forms of H-NOX proteins

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- Number: US 10,766,947 B2
- Document ID: US10766947B2
- Status: Granted
- Kind: B2
- Application number: 16/450,913
- Filed: 2019-06-24
- Published: 2020-01-16
- Granted: 2020-09-08
- Earliest claimed: 2019-06-24
- Assignees: Omniox, Inc.
- Applicants: Omniox, Inc.
- Inventors: Gregory Kapp; Laura Serwer; Natacha Le Moan; Stephen P. L. Cary
- Web page: https://patentgrep.com/patent/US10766947B2

## CPC

- C07K 14/795: Porphyrin- or corrin-ring-containing peptides
- A61K 38/164: {from bacteria}
- A61K 38/41: Porphyrin- or corrin-ring-containing peptides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- A61P 7/06: Antianaemics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- G01N 33/53: Immunoassay; Biospecific binding assay; Materials therefor
- G01N 33/57557: {of other specific parts of the body, e.g. brain}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61N 2005/1098: {Enhancing the effect of the particle by an injected agent or implanted device}
- C07K 2319/21: containing a His-tag
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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.

## Claims

### Claim 1

A method of treating a disease or condition in a mammal in need thereof comprising administering to the mammal a trimeric H-NOX protein comprising three H-NOX monomers, wherein each H-NOX monomer comprises a T. tengcongensis H-NOX domain and a trimerization domain, wherein the H-NOX domain in each H-NOX monomer comprises a L144F substitution, and wherein the trimerization domain in each H-NOX monomer is a foldon domain of bacteriophage T4 fibritin,
wherein the disease or condition is a cardiovascular disease in which blood volume is lost or O2 carrying capacity is reduced, loss of blood, a trauma in which blood volume is lost or O2 carrying capacity is reduced, hemorrhage, hemorrhagic shock, a surgery, hemodilution, a wound, a diabetic ulcer, anemia, a tissue ischemia, a stroke, a transient ischemic attack, myocardial stunning and hibernation, acute angina, unstable angina, emerging angina, myocardial infarction, cardioplegia, or traumatic brain injury.

### Claim 2 (depends on 1)

The method of claim 1, wherein the disease or condition is a stroke.

### Claim 3 (depends on 2)

The method of claim 2, wherein the stroke is an ischemic stroke.

### Claim 4 (depends on 2)

The method of claim 2, wherein the stroke is an emerging stroke.

### Claim 5 (depends on 1)

The method of claim 1, wherein the disease or condition is myocardial infarction.

### Claim 6 (depends on 1)

The method of claim 1, wherein the disease or condition is a surgery.

### Claim 7 (depends on 6)

The method of claim 6, wherein the surgery is abdominal aneurysm surgery, orthopedic surgery, or a surgery that produces high blood loss.

### Claim 8 (depends on 1)

The method of claim 1, wherein the disease or condition is loss of blood.

### Claim 9 (depends on 1)

The method of claim 1, wherein the disease or condition is a tissue ischemia.

### Claim 10 (depends on 9)

The method of claim 9, wherein the tissue ischemia is perioperative ischemia.

### Claim 11 (depends on 1)

The method of claim 1, wherein the disease or condition is a trauma in which blood volume is lost or O2 carrying capacity is reduced.

### Claim 12 (depends on 1)

The method of claim 1, wherein the disease or condition is hemorrhagic shock.

### Claim 13 (depends on 1)

The method of claim 1, wherein the disease or condition is traumatic brain injury.

### Claim 14 (depends on 1)

The method of claim 1, wherein the disease or condition is a wound.

### Claim 15 (depends on 13)

The method of claim 13, wherein the wound is a post-radiation wound, a post-surgical wound, or a burn wound.

### Claim 16 (depends on 1)

The method of claim 1, wherein the disease or condition is anemia.

### Claim 17 (depends on 1)

The method of claim 1, wherein each of the three H-NOX monomers of the trimeric H-NOX protein is PEGylated.

### Claim 18 (depends on 1)

The method of claim 1, wherein the C-terminus of the H-NOX domain of each of the three H-NOX monomers of the trimeric H-NOX protein is covalently linked to the trimerization domain.

### Claim 19 (depends on 1)

The method of claim 1, wherein the H-NOX domain in each of the three H-NOX monomers of the trimeric H-NOX protein is fused via an amino acid linker to the foldon domain of bacteriophage T4 fibritin.

### Claim 20 (depends on 19)

The method of claim 19, wherein the amino acid linker is three, four, five, six, seven, eight, nine, or ten amino acids in length.

### Claim 21 (depends on 19)

The method of claim 19, wherein the amino acid linker is three amino acids in length.

### Claim 22 (depends on 19)

The method of claim 19, wherein the amino acid linker is a Gly-Ser-Gly linker.

### Claim 23 (depends on 1)

The method of claim 1, wherein each of the three H-NOX monomers of the trimeric H-NOX protein comprises the amino acid sequence of SEQ ID NO:8.

### Claim 24 (depends on 23)

The method of claim 23, wherein each of the three H-NOX monomers of the trimeric H-NOX protein is PEGylated.

### Claim 25 (depends on 1)

The method of claim 1, wherein the T tengcongensis H-NOX domain has the amino acid sequence of SEQ ID NO:2, except for a L144F amino acid substitution in SEQ ID NO:2.

### Claim 26 (depends on 25)

The method of claim 25, wherein each of the three H-NOX monomers of the trimeric H-NOX protein is PEGylated.

### Claim 27 (depends on 1)

The method of claim 1, wherein the mammal is a human.

### Claim 28 (depends on 1)

The method of claim 1, wherein the administering is intravenous.