# US 11,078,471 B2 · Active low molecular weight variants of angiotensin converting enzyme 2 (ACE2)

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- Number: US 11,078,471 B2
- Document ID: US11078471B2
- Status: Granted
- Kind: B2
- Application number: 16/601,545
- Filed: 2019-10-14
- Published: 2020-06-11
- Granted: 2021-08-03
- Earliest claimed: 2017-01-24
- Assignees: Northwestern University
- Applicants: Northwestern University
- Inventors: Daniel Batlle; Jan Wysocki
- Web page: https://patentgrep.com/patent/US11078471B2

## CPC

- C12N 9/485: {Exopeptidases (3.4.11-3.4.19)}
- A61K 38/4813: {Exopeptidases (3.4.11. to 3.4.19)}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/68: the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K 47/6929: {the form being a nanoparticle, e.g. an immuno-nanoparticle}
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- C07K 14/315: from Streptococcus (G), e.g. Enterococci
- C07K 14/765: Serum albumin, e.g. HSA
- C12Y 304/17023: Angiotensin-converting enzyme 2 (3.4.17.23)
- C07K 2319/02: containing a signal sequence
- C07K 2319/21: containing a His-tag
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/31: fusions, other than Fc, for prolonged plasma life, e.g. albumin
- C07K 2319/70: containing domain for protein-protein interaction
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)
- C12Y: ENZYMES

## Abstract

Disclosed are variants of ACE2, pharmaceutical compositions comprising the variants of ACE2, and treatment methods for reducing Angiotensin II (1-8) plasma levels and/or increasing Angiotensin (1-7) plasma levels in a subject in need thereof. The disclosed variants of ACE2 may include polypeptide fragments of ACE2 having ACE2 activity for converting AngII (1-8) to Ang(1-7). Suitable subjects suitable for the disclosed methods of treatment may include subjects having or at risk for developing diabetic and non-diabetic chronic kidney disease, acute renal failure and its prevention, chronic kidney disease, severe hypertension, scleroderma and its skin, pulmonary, kidney and hypertensive complications, malignant hypertension, renovascular hypertension secondary to renal artery stenosis, idiopathic pulmonary fibrosis, liver fibrosis such as in liver cirrhosis patients, an aortic aneurysm, cardiac fibrosis and remodeling, left ventricular hypertrophy, and an acute stroke.

## Claims

### Claim 1

A fusion protein comprising a variant of ACE2 fused at its C-terminus via a linker amino acid sequence to a heterologous amino acid sequence, wherein the variant and linker amino acid sequence consist of the amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 11 and the variant has ACE2 activity.

### Claim 2 (depends on 1)

The fusion protein of claim 1, wherein the heterologous amino acid sequence comprises an amino acid sequence selected from the group consisting of (i) an amino acid sequence of the Fc portion of an antibody or a fragment thereof, which is devoid of its hinge region to prevent dimerization of the fusion polypeptide; (ii) an amino acid sequence of domain III of human serum albumin or a fragment thereof; and (iii) an amino acid sequence of the C-terminal albumin binding domain 3 (ABD3) of streptococcal protein G.

### Claim 3 (depends on 1)

The fusion protein of claim 1, further comprising an N-terminal or C-terminal histidine tag.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising: (i) the fusion protein of claim 1; and (ii) a suitable pharmaceutical carrier.

### Claim 5 (depends on 1)

The fusion protein of claim 1, wherein the variant of ACE2 is glycosylated.