# US 8,772,234 B2 · BMP10 propeptides and related methods

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- Number: US 8,772,234 B2
- Document ID: US8772234B2
- Status: Granted
- Kind: B2
- Application number: 13/442,479
- Filed: 2012-04-09
- Published: 2012-08-23
- Granted: 2014-07-08
- Earliest claimed: 2004-05-12
- Assignees: Acceleron Pharma Inc.
- Applicants: Jasbir Seehra; John Knopf
- Inventors: Jasbir Seehra; John Knopf
- Web page: https://patentgrep.com/patent/US8772234B2

## CPC

- A61K 38/1875: {Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- C07K 14/51: Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
- C07K 2319/00: Fusion polypeptide
- 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)

## Abstract

In certain aspects, the present invention provides BMP10 propeptides for use in treating a variety of disorders including heart disorders and other disorders associated with unwanted activity of the mature BMP10 polypeptide. The present invention also provides methods of screening compounds that modulate activity of BMP10.

## Claims

### Claim 1

A pharmaceutical preparation comprising:
a) a polypeptide comprising a bone morphogenetic protein-10 (BMP10) propeptide; and
b) a pharmaceutically acceptable carrier,
wherein the BMP10 propeptide comprises an amino acid sequence at least 98% identical to the amino acid sequence of SEQ ID NO: 1, wherein the BMP10 propeptide contains no more than 20 contiguous amino acids of a mature portion of a BMP10 polypeptide and comprises an alteration in the amino acid sequence that alters glycosylation of the BMP10 propeptide relative to the naturally occurring BMP10 propeptide when produced in a mammalian cell, and
wherein said BMP10 propeptide has one or more of the following characteristics:
i) binds to mature BMP10 with a Kd of at least 10−5 M; and
ii) inhibits BMP10 signaling in a cell.

### Claim 2 (depends on 1)

The pharmaceutical preparation of claim 1, wherein the BMP10 propeptide comprises a sequence alteration that decreases proteolytic cleavage of the BMP10 propeptide relative to the naturally occurring BMP10 propeptide.

### Claim 3 (depends on 1)

The pharmaceutical preparation of claim 1, wherein said BMP10 propeptide is a fusion protein including, in addition to said BMP10 propeptide domain, one or more polypeptide portions that enhance one or more of in vivo half life, uptake, tissue localization or distribution, formation of protein complexes, and purification.

### Claim 4 (depends on 3)

The pharmaceutical preparation of claim 3, wherein said fusion protein includes a polypeptide portion selected from the group consisting of: an immunoglobulin Fc domain and a serum albumin.

### Claim 5 (depends on 3)

The pharmaceutical preparation of claim 3, wherein said fusion protein includes a purification subsequence selected from: an epitope tag, a FLAG tag, a polyhistidine sequence, and a GST fusion.

### Claim 6 (depends on 1)

The pharmaceutical preparation of claim 1, wherein said BMP10 propeptide includes one or more modified amino acid residues selected from: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, and an amino acid conjugated to an organic derivatizing agent.

### Claim 7 (depends on 1)

The pharmaceutical preparation of claim 1, wherein said preparation is substantially pyrogen free.

### Claim 8 (depends on 1)

The pharmaceutical preparation of claim 1, wherein the BMP10 propeptide binds to a mature BMP10 polypeptide with a Kd of less than 1 micromolar.

### Claim 9

A BMP10 propeptide fusion protein comprising: a BMP10 propeptide and an IgG Fc portion; wherein the BMP10 propeptide comprises an amino acid sequence at least 98% identical to the amino acid sequence of SEQ ID NO: 1, wherein the BMP10 propeptide contains no more than 20 contiguous amino acids of a mature portion of a BMP10 polypeptide and comprises an alteration in the amino acid sequence that alters glycosylation of the BMP10 propeptide relative to the naturally occurring BMP10 propeptide when produced in a mammalian cell, and
wherein said BMP10 propeptide has one or more of the following characteristics:
i) binds to mature BMP10 with a Kd of at least 10−5M; and
ii) inhibits BMP10 signaling in a cell.

### Claim 10 (depends on 9)

The BMP10 propeptide fusion protein of claim 9, wherein the BMP10 propeptide comprises a sequence alteration that decreases proteolytic cleavage of the BMP10 propeptide relative to the naturally occurring BMP10 propeptide.