# US 10,870,689 B2 · ApoM-Fc fusion proteins, complexes thereof with sphingosine 1-phosphate (S1P), and methods for treating vascular and non-vascular diseases

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- Number: US 10,870,689 B2
- Document ID: US10870689B2
- Status: Granted
- Kind: B2
- Application number: 16/326,089
- Filed: 2017-08-15
- Published: 2019-06-20
- Granted: 2020-12-22
- Earliest claimed: 2016-08-15
- Assignees: Children's Medical Center Corporation
- Applicants: Children's Medical Center Corporation
- Inventors: Timothy T. Hla; Steven L. Swendeman; Annarita DiLorenzo; Teresa Sanchez
- Web page: https://patentgrep.com/patent/US10870689B2

## CPC

- C07K 14/775: Apolipopeptides
- A61K 8/553: {Phospholipids, e.g. lecithin}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 38/1709: {from mammals}
- A61K 47/544: {Phospholipids}
- A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- 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 9/12: Antihypertensives
- C07K 14/00: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes}
- 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)
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure is directed to an engineered phospholipid or lysophospholipid (e.g., sphingosine 1-phosphate (S1P)) chaperone derived from an Apolipoprotein M (ApoM)-Fc fusion protein having an extended half life in vivo. The disclosed ApoM-Fc fusion protein provides a safe, efficient and effective means of delivering S1P to endothelial cells and to all tissues of the body.

## Claims

### Claim 1

A fusion protein comprising an Apolipoprotein M (ApoM) polypeptide fused to a fragment crystallizable (Fc) region of an antibody, wherein the ApoM polypeptide comprises amino acids 21-188 of SEQ ID NO: 9 and does not comprise amino acids 1-20 of SEQ ID NO: 9.

### Claim 2 (depends on 1)

The fusion protein of claim 1, wherein the fusion protein further comprises an IL-2 signal peptide at the amino-terminus.

### Claim 3 (depends on 1)

The fusion protein of claim 1, wherein the Fc region is fused to the amino terminus of the ApoM polypeptide.

### Claim 4 (depends on 2)

The fusion protein of claim 2, wherein the Fc region is fused to the carboxyl terminus of the ApoM polypeptide.

### Claim 5 (depends on 1)

The fusion protein of claim 1, wherein the Fc region is an Fc region selected from the group consisting of an IgG antibody, an IgM antibody, an IgA antibody, an IgE antibody, and an IgD antibody.

### Claim 6 (depends on 5)

The fusion protein of claim 5, wherein the Fc region is an IgG1-Fc.

### Claim 7 (depends on 1)

A composition comprising the fusion protein of claim 1 in complex with phospholipids or lysophospholipids.

### Claim 8 (depends on 7)

The composition of claim 7, wherein the phospholipids comprise phosphocholine.

### Claim 9 (depends on 7)

The composition of claim 7, wherein the phospholipids comprise sphingosine 1-phosphate (S1P).

### Claim 10 (depends on 7)

The composition of claim 7, wherein the composition is formed by mixing the fusion protein with the phospholipids or the lysophospholipids, incubating the mixture to allow the complex to form, and purifying the complex.

### Claim 11 (depends on 10)

The composition of claim 10, wherein the phospholipids comprise phosphocholine.

### Claim 12 (depends on 10)

The composition of claim 10, wherein the phospholipids comprise sphingosine 1-phosphate (S1P).

### Claim 13 (depends on 9)

A method of treating a condition in a subject, comprising administering a composition according to claim 9 to the subject, wherein said condition is selected from the group consisting of hypertension, ischemia of the heart, ischemia of the brain, accelerated atherosclerosis, non-cardiac reperfusion injury and peripheral vascular disease.

### Claim 14 (depends on 13)

The method of claim 13, wherein said hypertension comprises conditions selected from the group consisting of primary resistant hypertension, secondary resistant hypertension, neurogenic hypertension, gestational hypertension (pre-eclempsia), diabetic pre-eclempsia, and hypertension of chronic kidney disease.

### Claim 15 (depends on 13)

The method of claim 13, wherein said ischemia of the heart comprises diseases selected from the group consisting of cardiac reperfusion injury, myocardial infarction, acute coronary syndrome and angina.

### Claim 16 (depends on 13)

The method of claim 13, wherein said non-cardiac reperfusion injury comprises an injury as a result of an ischemia selected from the group consisting of liver ischemia, kidney ischemia, intestinal ischemia, and muscle ischemia.

### Claim 17 (depends on 1)

A method of reducing a side effect of Fingolimod in a patient being treated with Fingolimod comprising administering the ApoM-Fc fusion protein of claim 1 to the patient.