# US 2023/0265152 A1 · Glp-1r agonist / fgf21 fusion proteins

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- Number: US 2023/0265152 A1
- Document ID: US20230265152A1
- Status: Published application
- Kind: A1
- Application number: 18/013,462
- Filed: 2020-07-02
- Published: 2023-08-24
- Earliest claimed: 2020-07-02
- Assignees: Sanofi
- Applicants: Sanofi
- Inventors: Oliver BOSCHEINEN; Werner DITTRICH; Andreas EVERS; Thomas LANGER; Christine RUDOLPH; Uwe SCHWAHN; Mark SOMMERFELD
- Web page: https://patentgrep.com/patent/US20230265152A1

## CPC

- C07K 14/605: Glucagons
- A61K 38/1825: {Fibroblast growth factor [FGF]}
- A61K 38/26: Glucagons
- A61P 3/04: Anorexiants; Antiobesity agents
- C07K 14/50: Fibroblast growth factor [FGF]
- 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 invention relates to fusion proteins comprising a Glucagon-Like Peptide-1 Receptor 5 (GLP-1R) agonistic peptide and a variant of human Fibroblast Growth Factor 21 (FGF21). The present invention further relates to the use of fusion proteins comprising a GLP-1R agonistic peptide and a variant of FGF21 as medicaments, in particular for the treatment of obesity, being overweight, metabolic syndrome, diabetes mellitus, diabetic retinopathy, hyperglycemia, dyslipidemia, non-alcoholic steatohepatitis (NASH) and/or atherosclerosis in a subject. The present invention also relates to pharmaceutical compositions comprising fusion proteins including a GLP-1R agonistic peptide and a variant of FGF21.

## Claims

### Claim 1

A fusion protein comprising a GLP-1R (glucagon-like peptide-1 receptor) agonistic peptide and a functionally active variant of human FGF21 (fibroblast growth factor 21),
wherein the GLP-1R agonistic peptide is a variant of native GLP-1(7-36) comprising up to about 15 substitutions of amino acid residues in the amino acid sequence of native GLP-1(7-36) (SEQ ID NO: 260);
wherein the functionally active variant of human FGF21 comprises an amino acid sequence being at least about 96% identical to the amino acid sequence of SEQ ID NO: 250 or SEQ ID NO: 251 and comprises
(i) substitutions Q55C and P147C or substitutions Q55C and N149C, and
(ii) a substitution or deletion of G198 and/or P199,
wherein numbering of the amino acid residues is in accordance with SEQ ID NO: 250; and
wherein the GLP-1R agonistic peptide and the functionally active variant of human FGF21 are linked via a linker molecule comprising a structure selected from the group consisting of L - Fc, Fc - L, L1 - Fc - L2 and Fc, wherein L, L1 and L2 are independently selected from the group consisting of single amino acids and peptides, and Fc is an Fc domain of an immunoglobulin or a variant thereof.

### Claim 2 (depends on 1)

The fusion protein according to claim 1, having a GLP-1R agonistic activity which is about 9- to about 531-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36).

### Claim 3 (depends on 1)

The fusion protein according to claim 1, wherein the GLP-1R agonistic peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 261 to 565.

### Claim 4 (depends on 1)

The fusion protein according to claim 1, wherein the GLP-1R agonistic peptide comprises the amino acid sequence H-G-E-G-T-F-T-S-D-X10-S-K-Q-L-E-E-E-X18-V-X20-L-F-I-E-W-L-K-A-X29-G (SEQ ID NO: 4079), wherein
X10 is K or L,
X18 is A or R,
X20 is R or Q, and
X29 is G or T;
wherein, optionally, the amino acid sequence further comprises at least one additional amino acid residue at its N-terminus; and
wherein, optionally, the amino acid sequence further comprises a peptide extension consisting of up to about 12, about 11 or about 10 amino acid residues at its C-terminus.

### Claim 5 (depends on 1)

The fusion protein according to claim 1, wherein the GLP-1R agonistic peptide comprises the amino acid sequence of SEQ ID NO: 261 or 262.

### Claim 6 (depends on 1)

The fusion protein according to claim 1, wherein the functionally active variant of human FGF21 comprises a substitution or deletion selected from the group consisting of G198R, G198K, G198Y and P199 deleted.

### Claim 7 (depends on 1)

The fusion protein according to claim 1, wherein the functionally active variant of human FGF21 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 253, 254, 255 and 256.

### Claim 8 (depends on 1)

The fusion protein according to claim 1, wherein the Fc domain of an immunoglobulin or a variant thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 257, 258 and 259.

### Claim 9

A fusion protein comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-8, 18-31, 39, 40, 42-72, 74, 76, 78-84, 88-90, 92-97, 100-102, 105-109, 112, 113, 115, 116, 118, 120-124, 126-130, 132-136, 139, 142-148, 150-153, 155-158, 161-172, 174-177, 180-188, 190, 192-209, 211, 212, 216, 217 and 219-229, or a functionally active variant thereof which comprises an amino acid sequence at least about 96% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 1-8, 18-31, 39, 40, 42-72, 74, 76, 78-84, 88-90, 92-97, 100-102, 105-109, 112, 113, 115, 116, 118, 120-124, 126-130, 132-136, 139, 142-148, 150-153, 155-158, 161-172, 174-177, 180-188, 190, 192-209, 211, 212, 216, 217 and 219-229.

### Claim 10

A fusion protein comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 7 and 8, or a functionally active variant thereof which comprises an amino acid sequence at least about 96% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 7 and 8.

### Claim 11 (depends on 1)

The fusion protein according to claim 1, wherein said fusion protein can activate human GLP-1R with an EC50 of about 15 pmol/L to about 400 pmol/L, or about 20 pmol/L to about 400 pmol/L, or about 50 pmol/L to about 400 pmol/L, or about 100 pmol/L to about 400 pmol/L, as determined by measuring the cAMP response of cells stably expressing human GLP-1R.

### Claim 12 (depends on 1)

The fusion protein according to claim 1, wherein said fusion protein can induce (i) autophosphorylation of human FGF Receptor 1c (FGFR1c) with an EC50 of about 250 nmol/L or lower, or about 200 nmol/L or lower, or about 150 nmol/L or lower, or about 100 nmol/L or lower, or about 75 nmol/L or lower, or about 50 nmol/L or lower; and/or (ii) phosphorylation of Mitogen-Activated Protein Kinase (MAPK) ERK½ with an EC50 of about 100 nmol/L or lower, or about 75 nmol/L or lower, or about 50 nmol/L or lower, or about 25 nmol/L or lower, or about 20 nmol/L or lower, or about 15 nmol/L or lower, or about 10 nmol/L or lower.

### Claim 13 (depends on 1)

A nucleic acid molecule encoding a fusion protein according to claim 1.

### Claim 14 (depends on 13)

A host cell containing a nucleic acid molecule according to claim 13.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising a fusion protein according to claim 1.

### Claim 16 (depends on 1)

A kit comprising a fusion protein according to claim 1.

### Claim 17 (depends on 1)

A fusion protein according to claim 1 for use as a medicament.

### Claim 18 (depends on 1)

A fusion protein according to claim 1 for use in the treatment of a disease or disorder selected from the group consisting of obesity, being overweight, metabolic syndrome, diabetes mellitus, diabetic retinopathy, hyperglycemia, dyslipidemia, Non-Alcoholic SteatoHepatitis (NASH) and atherosclerosis.

### Claim 19 (depends on 18)

The fusion protein, the nucleic acid molecule, the host cell or the pharmaceutical composition for use according to claim 18, wherein the diabetes mellitus is type 1 diabetes mellitus or type 2 diabetes mellitus.