# US 7,070,788 B2 · Follicle stimulating hormone superagonists

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- Number: US 7,070,788 B2
- Document ID: US7070788B2
- Status: Granted
- Kind: B2
- Application number: 10/057,113
- Filed: 2002-01-25
- Published: 2002-08-15
- Granted: 2006-07-04
- Earliest claimed: 1996-05-08
- Assignees: The United States of America as represented by the Department of Health and Human Services
- Inventors: Mariusz W. Szkudlinski; Bruce D. Weintraub; Mathis Grossmann
- Web page: https://patentgrep.com/patent/US7070788B2

## CPC

- C07K 14/59: Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g.hCG [human chorionic gonadotropin]; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
- 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)
- Y10S 530/85: Reproductive organs or embryos
- 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)
- Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

## Abstract

The invention is directed toward a human glycoprotein hormone having at least one, two, three, four, or five basic amino acids in the α-subunit at positions selected from the group consisting of positions 11, 13, 14, 16, 17, and 20. The inventions is also directed to a human glycoprotein where at least one of the amino acids at position 58, 63, and 69 of the β-subunit of the human thyroid stimulating hormone are basic amino acids. The invention is further directed to a modified human glycoprotein hormone having increased activity over a wild-type human glycoprotein hormone, where the modified human glycoprotein comprises a basic amino acid substituted at a position corresponding to the same amino acid position in a non-human glycoprotein hormone having an increased activity over the wild-type human glycoprotein hormone. The invention is also directed to a method of constructing superactive nonchimeric analogs of human hormones comprising comparing the amino acid sequence of a more active homolog from another species to the human hormone, and selecting superactive analogs from the substituted human hormones. The invention is also directed to nucleic acids encoding the modified human glycoprotein hormones, vectors containing those nucleic acids, and host cells containing those vectors.

## Claims

### Claim 1

A modified human follicle stimulating hormone (FSH), which differs from the wild-type human FSH, said modified human FSH comprising an α-subunit and a β-subunit, said α-subunit comprising at least three basic amino acids in the α-subunit at positions selected from the group consisting of positions 11, 13, 14, 16, 17, and 20, wherein by human is meant the number of amino acid substitutions in the wild-type sequence does not exceed one-half the number of amino acid differences at corresponding positions in the FSH subunits between human and bovine species.

### Claim 2 (depends on 1)

The modified human FSH of claim 1, said α-subunit further comprising a fourth basic amino acid at a position selected from the group consisting of positions 11, 13, 14, 16, 17, and 20.

### Claim 3 (depends on 2)

The modified human FSH of claim 2, wherein said basic amino acids of the α-subunit are at positions 11, 13, 16, and 20.

### Claim 4 (depends on 2)

The modified human FSH of claim 2, wherein said basic amino acids of the α-subunit are at positions 11, 13, 17, and 20.

### Claim 5 (depends on 2)

The modified human FSH of claim 2, wherein said basic amino acids of the α-subunit are at positions 13, 14, 16, and 20.

### Claim 6 (depends on 2)

The modified human FSH of claim 2, wherein said basic amino acids of the α-subunit are at positions 13, 14, 17, and 20.

### Claim 7 (depends on 2)

The modified human FSH of claim 2, said α-subunit further comprising a fifth basic amino acid at a position selected from the group consisting of positions 11, 13, 14, 16, 17, and 20.

### Claim 8 (depends on 7)

The modified human FSH of claim 7, wherein said basic amino acids of the α-subunit are at positions 13, 14, 16, 17, and 20.

### Claim 9 (depends on 7)

The modified human FSH of claim 7, wherein said basic amino acids of the α-subunit are at positions 11, 13, 14, 16, and 20.

### Claim 10 (depends on 1)

The modified human FSH of claim 1, wherein said basic amino acids of the α-subunit are at positions 11, 13, 14, 16, 17, and 20.

### Claim 11 (depends on 1)

The modified human FSH of claim 1, wherein said basic amino acids of the α-subunit are at positions 13, 16, and 20.

### Claim 12 (depends on 1)

The modified human FSH of claim 1, wherein said basic amino acids of the α-subunit are at positions 14, 16, and 20.

### Claim 13 (depends on 1)

The modified human FSH of claim 1, wherein said basic amino acids are selected from the group consisting of lysine and arginine.

### Claim 14 (depends on 1)

A nucleic acid encoding the modified human FSH α-subunit of claim 1.

### Claim 15 (depends on 14)

A vector comprising the nucleic acid of claim 14, wherein the vector is suitable for expressing the nucleic acid.

### Claim 16 (depends on 15)

A host cell comprising the vector of claim 15, wherein the host cell is suitable for expressing the nucleic acid.

### Claim 17 (depends on 1)

The modified human FSH of claim 1, wherein said modified human FSH has less than five amino acid substitutions in said α-subunit in positions other than positions 11, 13, 14, 16, 17, and 20.

### Claim 18 (depends on 1)

The modified human FSH of claim 1, wherein said modified human FSH has less than four amino acid substitutions in said α-subunit in positions other than positions 11, 13, 14, 16, 17, and 20.

### Claim 19 (depends on 1)

The modified human FSH of claim 1, wherein said modified human FSH has less than three amino acid substitutions in said α-subunit in positions other than positions 11, 13, 14, 16, 17, and 20.

### Claim 20 (depends on 1)

The modified human FSH of claim 1, wherein said modified human FSH has less than two amino acid substitutions in said α-subunit in positions other than positions 11, 13, 14, 16, 17, and 20.

### Claim 21 (depends on 1)

The modified human FSH of claim 1, wherein said modified human FSH has complete amino acid sequence identity with the corresponding wild-type human FSH in said α-subunit in positions other than positions 11, 13, 14, 16, 17, and 20.

### Claim 22

A modified human follicle stimulating hormone (FSH), which differs from the wild-type human FSH, said modified human FSH comprising an α-subunit and a β-subunit, said α-subunit comprising a basic amino acid in the α-subunit in at least one position selected from the group consisting of positions 11, 13, 14, 16, 17, and 20, wherein by human is meant the number of amino acid substitutions in the wild-type sequence does not exceed one-half the number of amino acid differences at corresponding positions in the FSH subunits between human and bovine species.

### Claim 23 (depends on 22)

The modified human FSH of claim 22, wherein a basic amino acid of the α-subunit is at position 11.

### Claim 24 (depends on 22)

The modified human FSH of claim 22, wherein a basic amino acid of the α-subunit is at position 13.

### Claim 25 (depends on 22)

The modified human FSH of claim 22, wherein a basic amino acid of the α-subunit is at position 14.

### Claim 26 (depends on 22)

The modified human FSH of claim 22, wherein a basic amino acid of the α-subunit is at position 16.

### Claim 27 (depends on 22)

The modified human FSH of claim 22, wherein a basic amino acid of the α-subunit is at position 17.

### Claim 28 (depends on 22)

The modified human FSH of claim 22, wherein a basic amino acid of the α-subunit is at position 20.

### Claim 29 (depends on 22)

The modified human FSH of claim 22, wherein said basic amino acid is selected from the group consisting of lysine and arginine.

### Claim 30 (depends on 22)

The modified human FSH of claim 22, further modified so that said α-subunit comprises a basic amino acid in at least two positions selected from the group consisting of positions 11, 13, 14, 16, 17, and 20.

### Claim 31 (depends on 30)

The modified FSH of claim 30, wherein said basic amino acids of the α-subunit are at positions 14 and 20.

### Claim 32 (depends on 30)

The modified human FSH of claim 30, wherein said basic amino acids of the α-subunit are at positions 16 and 20.

### Claim 33 (depends on 30)

The modified human FSH of claim 30, wherein said basic amino acids of the α-subunit are at positions 13 and 14.

### Claim 34 (depends on 30)

The modified human FSH of claim 30, wherein said basic amino acids of the α-subunit are at positions 13 and 16.

### Claim 35 (depends on 30)

The modified human FSH of claim 30, wherein said basic amino acids of the α-subunit are at positions 13 and 20.

### Claim 36 (depends on 30)

The modified human FSH of claim 30 wherein said basic amino acids of the α-subunit are at positions 14 and 16.

### Claim 37 (depends on 30)

The modified human FSH of claim 30, wherein said basic amino acid is selected from the group consisting of lysine and arginine.

### Claim 38 (depends on 22)

A nucleic acid encoding the modified human FSH α-subunit of claim 22.

### Claim 39 (depends on 38)

A vector comprising the nucleic acid of claim 38, wherein the vector is suitable for expressing the nucleic acid.

### Claim 40 (depends on 39)

A host cell comprising the vector of claim 39, wherein the host cell is suitable for expressing the nucleic acid.

### Claim 41 (depends on 22)

The modified human FSH of claim 22, wherein said modified human FSH has less than five amino acid substitutions in said α-subunit in positions other than positions 11, 13, 14, 16, 17, and20.

### Claim 42 (depends on 22)

The modified human FSH of claim 22, wherein said modified human FSH has less than four amino acid substitutions in said α-subunit in positions other than positions 11, 13, 14, 16, 17, and 20.

### Claim 43 (depends on 22)

The modified human FSH of claim 22, wherein said modified human FSH has less than three amino acid substitutions in said α-subunit in positions other than positions 11, 13, 14, 16, 17, and20.

### Claim 44 (depends on 22)

The modified human FSH of claim 22, wherein said modified human FSH has less than two amino acid substitutions in said α-subunit in positions other than positions 11, 13, 14, 16, 17, and 20.

### Claim 45 (depends on 22)

The modified human FSH of claim 22, wherein said modified human FSH has complete amino acid sequence identity with the corresponding wild-type human FSH in said α-subunit in positions other than positions 11, 13, 14, 16, 17, and 20.