# US 10,765,626 B2 · Methods for treatment of charcot-marie-tooth disease with follistatin polypeptides

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- Number: US 10,765,626 B2
- Document ID: US10765626B2
- Status: Granted
- Kind: B2
- Application number: 15/983,191
- Filed: 2018-05-18
- Published: 2018-11-15
- Granted: 2020-09-08
- Earliest claimed: 2014-06-04
- Assignees: Acceleron Pharma Inc.
- Applicants: Acceleron Pharma Inc.
- Inventors: Ravindra Kumar; Asya Grinberg
- Web page: https://patentgrep.com/patent/US10765626B2

## CPC

- A61K 38/1709: {from mammals}
- A61K 47/68: the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61P 21/06: Anabolic agents (androgens A61P5/26)
- C07K 14/4703: {Inhibitors; Suppressors}
- 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 38/00: 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 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes}
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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

The disclosure provides, in part, follistatin polypeptides that are suitable for use in local administration and methods for use.

## Claims

### Claim 1

A method of treating a patient having Charcot-Marie-Tooth disease, the method comprising administering an effective amount of a follistatin fusion protein by an intramuscular route of administration to a targeted muscle of a patient in need thereof, wherein the follistatin fusion protein comprises a first amino acid sequence and a second amino acid sequence, wherein the first amino acid sequence comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 15 or 16, wherein the first amino acid sequence ends at the amino acid corresponding to any one of amino acids 291-302 of SEQ ID NO: 4; wherein the second amino acid sequence comprises a constant domain of an immunoglobulin G (IgG); and wherein the follistatin fusion protein inhibits signaling by myostatin in a cell-based assay.

### Claim 2 (depends on 1)

The method of claim 1, wherein the first amino acid sequence comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 15 or 16.

### Claim 3 (depends on 1)

The method of claim 1, wherein the first amino acid sequence ends at the amino acid corresponding to position 291 of SEQ ID NO: 4.

### Claim 4 (depends on 2)

The method of claim 2, wherein the first amino acid sequence ends at the amino acid corresponding to position 291 of SEQ ID NO: 4.

### Claim 5 (depends on 1)

The method of claim 1, wherein an increase in muscle size or strength occurs in the targeted muscle.

### Claim 6 (depends on 1)

The method of claim 1, wherein the follistatin fusion protein does not have a substantial systemic effect on muscle size or strength.

### Claim 7 (depends on 1)

The method of claim 1, wherein the follistatin fusion protein is administered to only one targeted muscle.

### Claim 8 (depends on 1)

The method of claim 1, wherein the follistatin fusion protein is administered to more than one targeted muscle.

### Claim 9 (depends on 1)

The method of claim 1, wherein a muscle that is contralateral to a targeted muscle does not substantially increase in size or strength.

### Claim 10 (depends on 1)

The method of claim 1, wherein the follistatin fusion protein binds to one or more ligands selected from the group consisting of: myostatin, growth differentiation factor 11 (GDF-11), activin A and activin B with a dissociation constant (KD) less than 1 nM, 100 pM, 50 pM or 10 pM.

### Claim 11 (depends on 1)

The method of claim 1, wherein the follistatin fusion protein forms a dimer.

### Claim 12 (depends on 1)

The method of claim 1, wherein the follistatin fusion protein comprises an Fc portion of an IgG.

### Claim 13 (depends on 1)

The method of claim 1, wherein the follistatin fusion protein does not mediate substantial antibody-dependent cell-mediated toxicity (ADCC).

### Claim 14 (depends on 1)

The method of claim 1, wherein the follistatin fusion protein does not mediate substantial complement-dependent cytotoxicity (CDC).

### Claim 15 (depends on 1)

The method of claim 1, wherein the constant domain of the IgG is selected so as to mediate no substantial antibody-dependent cell-mediated cytotoxicity (ADCC) and/or no substantial complement dependent cytotoxicity (CDC).

### Claim 16 (depends on 1)

The method of claim 1, wherein the method causes no substantial effect in the patient on a measure selected from the group consisting of: serum follicle stimulating hormone (FSH) levels, liver size, hematocrit and reticulocyte levels.

### Claim 17 (depends on 1)

The method of claim 1, wherein the constant domain of the IgG is a constant domain of an IgG1.

### Claim 18 (depends on 17)

The method of claim 17, wherein the constant domain of the IgG1 comprises the amino acid sequence of SEQ ID NO: 17.

### Claim 19 (depends on 1)

The method of claim 1, wherein the constant domain of the IgG is a constant domain of an IgG2.

### Claim 20 (depends on 18)

The method of claim 18, wherein the constant domain of the IgG2 comprises the amino acid sequence of SEQ ID NO: 18.

### Claim 21 (depends on 1)

The method of claim 1, wherein a linker directly connects the C-terminal portion of the first amino acid sequence to the N-terminal portion of the second amino acid sequence.

### Claim 22 (depends on 21)

The method of claim 21, wherein the linker is 1-10 amino acids in length.

### Claim 23 (depends on 21)

The method of claim 21, wherein the linker comprises the sequence of SEQ ID NO: 46.

### Claim 24 (depends on 21)

The method of claim 21, wherein the linker consists of the sequence of SEQ ID NO: 46.

### Claim 25 (depends on 1)

The method of claim 1, wherein the first amino acid sequence comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 15 or 16; wherein a linker directly connects the C-terminal portion of the first amino acid sequence to the N-terminal portion of the second amino acid sequence; wherein the linker is 1-10 amino acids in length; wherein the constant domain of the IgG is a constant domain of an IgG2 comprising the amino acid sequence of SEQ ID NO: 18.

### Claim 26 (depends on 1)

The method of claim 1, wherein the follistatin fusion protein comprises the amino acid sequence of SEQ ID NO: 43, but wherein the final (carboxy-terminal) lysine (K) of SEQ ID NO: 43 is optionally absent.

### Claim 27 (depends on 26)

The method of claim 26, wherein the final (carboxy-terminal) lysine (K) of SEQ ID NO: 43 is absent.