US20110034373A1 - Use of an fgf-21 compound and a glp-1 compound for the treatment of obesity - Google Patents

Use of an fgf-21 compound and a glp-1 compound for the treatment of obesity Download PDF

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US20110034373A1
US20110034373A1 US12/668,475 US66847508A US2011034373A1 US 20110034373 A1 US20110034373 A1 US 20110034373A1 US 66847508 A US66847508 A US 66847508A US 2011034373 A1 US2011034373 A1 US 2011034373A1
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xaa
cys
seq
gly
glp
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Tamer Coskun
Wolfgang Glaesner
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Eli Lilly and Co
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Eli Lilly and Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1825—Fibroblast growth factor [FGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to compositions that comprise an FGF-21 compound and a GLP-1 compound. These compositions can be used to lower body weight and treat obesity.
  • Current methods for promoting weight loss are not completely satisfactory.
  • an estimated 33 billion dollars a year are spent on weight-loss measures that are largely futile.
  • new methods and compositions such as pharmaceutical agents that promote weight-loss are urgently needed to complement old approaches.
  • Fibroblast growth factor 21 belongs to a family of large polypeptides widely expressed in developing and adult tissues that play crucial roles in multiple physiological functions. FGF-21 has been reported to stimulate glucose-uptake in mouse adipocytes after prolonged treatment, in the presence and absence of insulin, and to decrease fed and fasting blood glucose, triglycerides, and glucagon levels in oh/oh and db/db mice in a dose-dependent manner, thus, providing the basis for the use of FGF-21 as a therapy for treating, diabetes and obesity (WO03/011213).
  • Glucagon-like peptide-1 (GLP-1) compounds have been described for the treatment of obesity. (WO98/019698). Although both FGF-21 and GLP-1 compounds have shown positive effects in treating obesity, there has not been any indication that a combination of FGF-21 compounds and GLP-1 compounds would provide a synergistic effect on lowering body weight. There is thus, still a need for additional beneficial therapeutics for weight loss.
  • Applicants have determined that a combination of an FGF-21 compound and a GLP-1 compound have an unexpected synergistic effect on lowering body weight.
  • the present invention relates to compositions comprising a FGF-21 compound and a GLP-1 compound.
  • the present invention also provides a method of lowering body weight comprising administering an FGF-21 compound in combination with a GLP-1 compound.
  • the present invention provides a method of treating obesity comprising administering a FGF-21 compound in combination with a GLP-1.
  • the present invention also provides compositions comprising a FGF-21 compound and an exendin compound.
  • the present invention also provides a method of lowering body weight comprising administering an FGF-21 compound in combination with an exendin compound.
  • the present invention provides a method of treating obesity comprising administering a FGF-21 compound in combination with an exendin compound.
  • FGF-21 compound is defined as a compound comprising native human FGF-21 (SEQ ID NO: 2), an FGF-21 analog, or an FGF-21 derivative.
  • the FGF-21 compounds of the present invention retain FGF-21 activity as measured in assays as described in Kharitonenkov, et al. (Journal of Clinical Investigation, 115(6): 1627 (2005)).
  • FGF 21 analog is defined as a molecule having a modification including one or more amino acid substitutions, deletions, inversions or additions when compared with SEQ ID NO: 2.
  • a “FGF-21 derivative” is defined as a molecule having the amino acid sequence of human FGF-21 (SEQ ID NO: 2) or of a FGF-21 analog but additionally having at least one chemical modification of one or more of its amino acid side groups, ⁇ -carbon atoms, terminal amino group, or terminal carboxylic acid group. Modifications at amino acid side groups include acylation of lysine e-amino groups, N-alkylation of arginine, histidine, or lysine, alkylation of glutamic or aspartic carboxylic acid groups, and deamidation of glutamine or asparagine.
  • Modifications of the terminal amino include the des-amino, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications.
  • Modifications of the terminal carboxy group include the amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications.
  • a lower alkyl is a C 1 -C 4 alkyl.
  • one or more side groups, or terminal groups may be protected by protective groups known to the ordinarily-skilled protein chemist.
  • the ⁇ -carbon of an amino acid may be mono- or di-methylated.
  • the chemical modification may also include “pegylation.”
  • GLP-1 compound is defined as a compound comprising the amino acid sequence of native human GLP-1 (SEQ ID NO: 3), a GLP-1 analog or GLP-1 derivative, which maintains GLP-1 activity.
  • GLP-1 activity may be measured by methods known in the art, including using in vivo experiments and in vitro assays that measure GLP-1 receptor binding activity or receptor activation, e, g., assays employing pancreatic islet cells or insulinoma cells, as described in EP 619,322, Gelfand, et al., and U.S. Pat. No. 5,120,712, respectively.
  • GLP-1 compounds are well known in the art. See, e.g. PCT International Application. Publication Nos. WO 03/040309, U.S. Pat. Nos. 6,593,295, 7,141,547, and 7,176,278.
  • GLP-1 analog is defined as a molecule having a modification including one or more amino acid substitutions, deletions, inversions, or additions when compared with SEQ ID NO: 3.
  • GLP-1 analog also includes “GLP-1 fusion proteins” where the GLP-1 fusion protein is a heterologous protein comprising a GLP-1 or GLP-1 analog and a second polypeptide selected from the group consisting of human albumin, human albumin analogs, fragments of human albumin, transferrin, transferrin analogs, transferrin derivatives, fragments of transferring, the Fc portion of an immunoglobulin, an analog of the Fc portion of an immunoglobulin, and fragments of the Fc portion of an immunoglobulin, and wherein the C-terminus of the first polypeptide is fused to the N-terminus of the second polypeptide.
  • the GLP-1 or GLP-1 analog may be fused to the second polypeptide via a peptide linker.
  • the GLP-1 fusion proteins of the present invention contain an Fc portion which is derived from human IgG4 but comprises one or more substitutions compared to the wild-typo human sequence (SEQ ID NO: 5).
  • a “GLP-1 derivative” is defined as a molecule having the amino acid sequence of native human GLP-1 or of a GLP-1 analog, but additionally having at least one chemical modification of one or more of its amino acid side groups, a-carbon atoms, terminal amino group, or terminal carboxylic acid group.
  • Modifications at amino acid side groups include acylation of lysine e-amino groups, N-alkylation of arginine, histidine, or lysine, alkylation of glutamic or aspartic carboxylic acid groups, and deamidation of glutamine or asparagine.
  • Modifications of the terminal amino include the des-amino, N-lower alkyl, N-d-lower alkyl, and N-acyl modifications.
  • Modifications of the terminal carboxy group include the amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications,
  • a lower alkyl is a C 1 -C 4 alkyl.
  • one or more side groups, or terminal groups may be protected by protective groups known to the ordinarily-skilled protein chemist.
  • the ⁇ -carbon of an amino acid may be mono- or di-methylated.
  • the chemical modification may also include the pegylation of an amino acid of the peptide or polypeptide.
  • GLP-1(7-37) indicates that the GLP-1 analog, portion of the mature fusion protein begins with His at position 7 and ends with Gly at position 37.
  • the added amino acid is indicated followed by the position at which it is present.
  • Ser 38 -Ser 39 -GLP-1 the addition of two serine residues to the C-terminus of wild type GLP-1.
  • exendin compound is defined as a compound comprising the amino acid sequence of exendin-4 (SEQ ID NO: 4), an exendin-4 analog or exendin-4 derivative, wherein the exendin compound maintains exendin-4 activity.
  • exendin-4 analog is defined as a compound having a modification including one or more amino acid substitutions, deletions, inversions, or additions when compared with the amino acid sequence of exendin-4 (SEQ ID NO: 4).
  • Exendin-4 analog also includes “exendin fusion proteins” where the “exendin fusion protein” is a heterologous protein comprising an exendin-4 or exendin-4 analog and a second polypeptide selected from the group consisting of human albumin, human albumin analogs, fragments of human albumin, transferrin, transferrin analogs, transferrin derivatives, fragments of transferring, the Fc portion of an immunoglobulin, an analog of the Fc portion of an immunoglobulin, and fragments of the Fc portion of an immunoglobulin, and wherein the C-terminus of the first polypeptide is fused to the N-terminus of the second polypeptide.
  • exendin-4 or exendin-4 analog may be fused to the second poly peptide via a peptide linker.
  • the exendin-4 fusion proteins of the present invention may contain an Fc portion which is derived from human IgG4 but comprises one or more substitutions compared to the wild-type human sequence (SEQ ID NO: 5).
  • exendin-4 derivative is defined as a compound having the amino acid sequence of exendin-4 or of an exendin-4 analog, but additionally having at least one chemical modification of one or more of its amino acid side groups, a-carbon atoms, terminal amino group, or terminal carboxylic acid group.
  • Modifications at amino acid side groups include acylation of lysine e-amino groups, N-alkylation of arginine, histidine, or lysine, alkylation of glutamic or aspartic carboxylic acid groups, and deamidation of glutamine or asparagine.
  • Modifications of the terminal amino include the des-amino, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications.
  • Modifications of the terminal carboxy group include the amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications.
  • a lower alkyl is a C 1 -C 4 alkyl.
  • one or more side groups, or terminal groups may be protected by protective groups known to the ordinarily-skilled protein chemist.
  • the ⁇ -carbon of an amino acid may be mono- or di-methylated.
  • the chemical modification may also include pegylation.
  • the Fc portion of an immunoglobulin has the meaning commonly given to the term in the field of immunology. Specifically, this term refers to an antibody fragment which does not contain the two antigen binding regions the Fab fragments) from the antibody.
  • the Fc portion consists of the constant region of an antibody from both heavy chains, which associate through non-covalent interactions and disulfide bonds.
  • the Fc portion can include the hinge regions and extend through the CH2 and CH3 domains to the c-terminus of the antibody.
  • the Fc portion can further include one or more glycosylation sites.
  • the fusion proteins described herein may also contain a linker (“L”).
  • the linker may comprise the sequence Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Gly-Gly-Ser SEQ ID NO: 6).
  • the number immediately preceding the L refers to the number of linkers separating the particular peptide or protein portion from the Fc portion.
  • a linker specified as 1.5L refers to the sequence Gly-Ser-Gly-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Gly-Gly-Gly-Gly-Gly-Gly-Ser (SEQ ID NO: 7).
  • IgG4 refers to an analog of the human IgG4 Fc sequence specified as SEQ ID NO: 5. Substitutions in the IgG4 Fc portion of the fusion protein are indicated in parenthesis.
  • the wild-type amino acid is specified by its common abbreviation followed by the position number in the context of the entire IgG4 sequence using the EU numbering system followed by the amino acid being substituted at that position specified by its common abbreviation.
  • PEG polyethylene glycol or a derivative thereof as are known in the art.
  • PEG is a linear polymer with terminal hydroxyl groups and has the formula HO—CH 2 CH 2 —(CH 2 CH 2 O)n-CH 2 CH 2 —OH, where n is from about 8 to about 4000.
  • the terminal hydrogen may be substituted with a protective group such as an alkyl or aryl group.
  • PEG has at least one hydroxy group, more preferably it is a terminal hydroxy group. It is this hydroxy group which is preferably activated to react with the peptide.
  • PEG useful for the present invention. Numerous derivatives of PEG exist in the art and are suitable for use in the invention.
  • the PEG molecule covalently attached to compounds in the present invention is not intended to be limited to a particular type. PEG's molecular weight is preferably from 500-100,000 daltons and more preferably from 20,000-60,000 daltons and most preferably from 20,000-40,000 daltons.
  • PEG may be linear or branched.
  • “In combination with” or “coadministration” refers to the administration of a FGF-21 compound with a GLP-1 compound either simultaneously, sequentially or a combination thereof.
  • the combination therapy of a FGF-21 compound with a GLP-1 compound results in a synergistic effect in lowering body weight and thus, in the treatment of obesity.
  • the combination therapy also results in a synergistic effect on lower elevated blood glucose levels and thus, a potential use in the treatment of diabetes.
  • effect refers to a loss in body weight, lowering of body weight or a reduction in blood glucose levels.
  • the FGF-21 compounds, the GLP-1 compounds and the exendin compounds of the present invention may be made using various techniques known to one of skill in the art.
  • the FGF-21, GLP-1 and exendin compounds may be made using recombinant techniques.
  • DNA sequences of mature human FGF-21 SEQ ID NO: 1
  • native GLP-1 native GLP-1
  • exendin-4 are known
  • PCR methodology may be used to isolate genes encoding the corresponding, gene.
  • one of skill in the art is aware of various methods to introduce changes in the DNA sequence so as to effect desired changes in the amino acid sequence of the resulting FGF-21. GLP-1 or exendin compounds.
  • the GLP-1 and the exendin peptides of the present invention can also be prepared by using standard methods of solid-phase peptide synthesis techniques.
  • Peptide synthesizers are commercially available from, for example, Applied Biosystems in Foster City, Calif. Reagents for solid phase synthesis are commercially available, for example, from Midwest Biotech (Fishers, Ind.).
  • Solid phase peptide synthesizers can be used according to manufacturer's instructions for blocking interfering groups, protecting the amino acid to be reacted, coupling, decoupling, and capping of unreacted amino acids.
  • Pegylation of peptides at the carboxy-terminus may be performed via enzymatic coupling using recombinant compounds of the present invention as a precursor or alternative methods known in the art and described. See e.g. U.S. Pat. No. 4,343,898 or International Journal of Peptide & Protein Research, 43:127-38, 1994.
  • fusion proteins comprising an Fc fragment can be effectively purified using a Protein A or Protein G affinity matrix.
  • Low or high pH buffers can be used to elute the fusion protein from the affinity matrix Mild elution conditions will aid in preventing irreversible denaturation of the fusion protein.
  • Coadministration of FGF-21 compounds, GLP-1 compounds and exendin compounds of the present invention may be via any route known to be effective by the physician of ordinary skill.
  • Peripheral parenteral is one such method. Parenteral administration is commonly understood in the medical literature as the injection of a dosage form into the body by a sterile syringe or some other mechanical device such as an infusion pump. Peripheral parenteral routes can include intravenous, intramuscular, subcutaneous, and intraperitoneal routes of administration.
  • a typical dose range for the FGF-21 compounds of the present invention will range from about 0.01 mg per day to about 1000 mg per day for an adult.
  • a typical dose range for the GLP-1 derivative compounds of the present invention will range from about 0.01 mg per day to about 1000 mg per day for an adult.
  • doses may be in the range of 0.01 to 1 mg/kg body weight, preferably in the range of 0.05 to 0.5 mg/kg body weight.
  • the present invention provides a composition comprising a FGF-21 compound and a GLP-1 compound.
  • the present invention provides a composition comprising a FGF-21 compound and a GLP-1 compound, wherein the FGF-21 compound is selected from the group consisting of human FGF-21, an FGF-21 analog and an FGF-21 derivative and wherein the GLP-1 compound is selected from the group consisting of GLP-1 analog, GLP-1 derivative and GLP-1 fusion proteins.
  • the composition comprises an FGF-21 analog and a GLP-1 analog.
  • the composition comprises a FGF-21 analog and a GLP-1 derivative.
  • the composition comprises a FGF-21 analog and a GLP-1 fusion protein.
  • the present invention provides a composition comprising FGF-21 compound and an exendin compound.
  • the composition comprises a FGF-21 compound and an exendin compound, wherein the FGF-21 compound is selected from the group consisting of human FGF-21, an FGF-21 analog and an FGF-21 derivative and wherein the exendin compound is selected from the group consisting of exendin-4, an exendin-4 analog, an exendin-4 derivative, and an exendin-4 agonist.
  • the composition comprises a FGF-21 analog and exendin-4.
  • the composition comprises a FGF-21 analog and an exendin-4 analog.
  • the composition comprises a FGF-21 analog and an exendin-4 derivative.
  • the composition comprises a FGF-21 analog and an exendin-4 agonist.
  • the present invention also provides a method of lowering body weight comprising administering a FGF 21 compound in combination with a GLP-1 compound.
  • administering a FGF-21 compound in combination with a GLP-1 compound results in a synergistic effect on weight loss.
  • the method of lowering body weight comprises administering a FGF-21 compound in combination with a GLP-1 compound, wherein the FGF-21 compound is selected from the group consisting of human FGF-21, an FGF 21 analog and an FGF-21 derivative and wherein the GLP-1 compound is selected from the group consisting of GLP-1 analog, GLP-1 derivative and GLP-1 fusion protein.
  • the method of lowering body weight comprises administering a FGF-21 analog in combination with a GLP-1 analog. In another preferred embodiment, the method of lowering body weight comprises administering a FGF-21 analog in combination with a GLP-1 derivative. In another preferred embodiment, the method of lowering, body weight comprises administering a FGF-21 analog and a GLP-1 fusion protein.
  • the present invention also provides a method of lowering body weight comprising administering a FGF-21 compound in combination with an exendin compound.
  • administering a FGF-21 compound in combination with an exendin compound results in a synergistic effect on weight loss.
  • the method of lowering body weight comprises administering a FGF-21 compound in combination with an exendin compound, wherein the FGF-21 compound is selected from the group consisting of human FGF-21, an FGF-21 analog and an FGF-21 derivative and wherein the exendin compound is selected from the group consisting of exendin-4, an exendin-4 analog, an exendin-4 derivative, and an exendin-4 agonist.
  • the method of lowering body weight comprises administering a FGF-21 analog in combination with exendin-4. In another preferred embodiment, the method of lowering body weight comprises administering a FGF-21 analog in combination with an exendin-4 analog. In another preferred embodiment, the method of lowering body weight comprises administering a FGF-21 analog and an exendin-4 derivative. In another preferred embodiment, the method of lowering body weight comprises administering a FGF-21 analog and an exendin-4 agonist.
  • the present invention also provides a method of treating obesity comprising administering a FGF-21 compound in combination with a GLP-1 compound.
  • administering a FGF-21 compound in combination with a GLP-1 compound results in a synergistic effect on weight loss.
  • the method of treating obesity comprises administering a FGF-21 compound in combination with a GLP-1 compound, wherein the FGF-21 compound is selected, from the group consisting of human FGF-21, an FGF-21 analog and an FGF-21 derivative and wherein the GLP-1 compound is selected from the group consisting of GLP-1 analog, GLP-1 derivative and GLP-1 fusion protein.
  • the method of treating obesity comprises administering a FGF-21 analog in combination with a GLP-1 analog.
  • the method of treating obesity comprises administering a FGF-21 analog in combination with a GLP-1 derivative.
  • the method of treating obesity comprises administering a FGF-21 analog and a GLP-1 fusion protein.
  • the present invention also provides a method of treating obesity comprising administering a FGF-21 compound in combination with an exendin compound.
  • administering a FGF-21 compound in combination with an exendin compound results in a synergistic effect on weight loss.
  • the method of treating obesity comprises administering a FGF-21 compound in combination with an exendin compound, wherein the FGF-21 compound is selected from the group consisting of human FGF-21, an FGF-21 analog and an FGF-21 derivative and wherein the exendin compound is selected from the group consisting of exendin-4, an exendin-4 analog, an exendin-4 derivative, and exendin-4 agonist.
  • the method of treating obesity comprises administering a FGF-21 analog in combination with exendin-4. In another preferred embodiment, the method of treating obesity comprises administering a FGF-21 analog in combination with an exendin-4 analog. In another preferred embodiment, the method of treating obesity comprises administering a FGF-21 analog and an exendin-4 derivative. In another preferred embodiment, the method of treating obesity comprises administering a FGF-21 analog and an exendin-4 agonist.
  • the present invention also provides for the use of a FGF-21 compound and a GLP-1 compound in the manufacture of a medicament to lower body weight.
  • the present invention also provides for the use of a FGF-21 compound and a GLP-1 compound in the manufacture of a medicament to lower body weight, wherein the FGF-21 compound is selected from the group consisting of human FGF-21, an FGF-21 analog and an FGF-21 derivative and wherein the GLP-1 compound is selected from the group consisting of a GLP-1 analog, a GLP-1 derivative and a GLP-1 fusion protein.
  • the present invention provides for the use of a FGF-21 analog and a GLP-1 analog in the manufacture of a medicament to lower body weight.
  • the present invention provides for the use of a FGF-21 analog and a GLP-1 derivative in the manufacture of a medicament to lower body weight. In another preferred embodiment, the present invention provides for the use of a FGF-21 analog and a GLP-1 fusion protein in the manufacture of a medicament to lower body weight.
  • the present invention also provides for the use of a FGF-21 compound and an exendin compound in the manufacture of a medicament to lower body weight.
  • the present invention also provides for the use of a FGF-21 compound and an exendin compound in the manufacture of a medicament to lower body weight, wherein the FGF-21 compound is selected from the group consisting of human FGF-21, an FGF-21 analog and an FGF-21 derivative and wherein the exendin compound is selected from the group consisting of exendin-4, an exendin-4 analog, an exendin-4 derivative, and an exendin-4 agonist.
  • the present invention provides for the use of a FGF-21 analog and an exendin-4 analog in the manufacture of a medicament to lower body weight.
  • the present invention provides for the use of a FGF-21 analog and an exendin-4 derivative in the manufacture of a medicament to lower body weight. In another preferred embodiment, the present invention provides for the use of a FGF-21 analog and an exendin-4 agonist in the manufacture of a medicament to lower body weight.
  • the present invention also provides for the use of a FGF-21 compound and a GLP-1 compound in the manufacture of a medicament for the treatment of obesity.
  • the present invention also provides for the use of a FGF-21 compound and a GLP-1 compound in the manufacture of a medicament for the treatment of obesity, wherein the FGF-21 compound is selected from the group consisting of human FGF-21, an FGF-21 analog and an FGF-21 derivative and wherein the GLP-1 compound is selected from the group consisting of a GLP-1 analog, a GLP-1 derivative and a GLP-1 fusion protein.
  • the present invention provides for the use of a FGF-21 analog and a GLP-1 analog in the manufacture of a medicament for the treatment of obesity.
  • the present invention provides for the use of a FGF-21 analog and a GLP-1 derivative in the manufacture of a medicament for the treatment of obesity. In another preferred embodiment, the present invention provides for the use of a FGF-21 analog and a GLP-1 fusion protein in the manufacture of a medicament for the treatment of obesity.
  • the present invention also provides for the use of a FGF-21 compound and an exendin compound in the manufacture of a medicament to treat obesity.
  • the present invention also provides for the use of a FGF-21 compound and an exendin compound in the manufacture of a medicament to lower body weight, wherein the FGF-21 compound is selected from the group consisting of human FGF-21, an FGF-21 analog and an FGF-21 derivative and wherein the exendin compound is selected from the group consisting of exendin-4, an exendin-4 analog, an exendin-4 derivative, and an exendin-4 agonist.
  • the present invention provides for the use of a FGF-21 analog and an exendin-4 analog in the manufacture of a medicament to treat obesity.
  • the present invention provides for the use of a FGF-21 analog and an exendin-4 derivative in the manufacture of a medicament to treat obesity. In another preferred embodiment, the present invention provides for the use of a FGF-21 analog and an exendin-4 agonist in the manufacture of a medicament to treat obesity.
  • the FGF-21 compounds of the present invention may be human FGF-21, a FGF-21 analog or a FGF-21 derivative.
  • the FGF-21 compound of the present invention is a FGF-21 analog.
  • the present invention provides FGF-21 compounds comprising one or two engineered disulfide bonds.
  • the present invention provides FGF-21 compounds which comprise an amino acid sequence comprising a cysteine substitution at positions 21, 26, 33, 118, 119, 121, 122, or 134 of FGF-21 (SEQ ID NO: 2).
  • the FGF-21 compound comprises an amino acid sequence comprising an amino acid substitution at position 167 of FGF-21 (SEQ ID NO: 2), wherein the substitution is not Ser or Tyr.
  • the FGF-21 compound comprises an amino acid sequence comprising an amino acid substitution at position 121 of FGF-21 (SEQ ID NO: 2), wherein the substitution is any amino acid except Gln or Asn.
  • the amino acid at position 121 of FGF-21 (SD) ID NO: 2) is selected from the group consisting of Ala, Val, Ser, Asp, or Glu.
  • the FGF-21 compound comprises an amino acid sequence selected from the group consisting of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9), Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10), Cys 21 -Cys 33 -Ala 167 -FGF-21 (SEQ ID NO: 11), Cys 26 -Cys 122 -Ala 167 -FGF-21 (SEQ ID NO: 12), and Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO:13).
  • the FGF-21 compound consists of an amino acid sequence selected from the group consisting of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9), Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10), Cys 21 -Cys 33 -Ala 167 -FGF-21 (SEQ ID NO: 11), Cys 26 -Cys 122 -Ala 167 -FGF-21 (SEQ ID NO: 12), and Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO:13).
  • the present invention provides FGF-21 compounds which consist of a cysteine substitution at positions 21, 26, 33, 118, 119, 121, 122, or 134 of FGF-21 (SEQ ID NO: 2).
  • the FGF-21 compound consist of an amino acid substitution at position 167 of FGF-21 (SEQ ID NO: 2), wherein the substitution is not Ser or Tyr.
  • the FGF-21 compound consists of a substitution at position 121 of FGF-21 (SEQ ID NO: 2), wherein the substitution is any amino acid except Gln or Asn.
  • the amino acid at position 121 of FGF-21 (SEQ ID NO: 2) is selected from the group consisting of Ala, Val, Ser, Asp, or Glu.
  • the FGF-21 compound consists of an amino acid sequence selected from the group consisting of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9), Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10). Cys 21 -Cys 33 -Ala 167 -FGF-21 (SEQ ID NO: 11), Cys 26 -Cys 122 -Ala 167 -FGF-21 (SEQ ID NO: 12), and Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13).
  • the present invention provides GLP-1 compounds to be used in combination with the FGF-21 compounds of the present invention.
  • the GLP-1 compound is a GLP-1 analog, GLP-1 derivative, or a GLP-1 fusion protein.
  • the GLP-1 compound is a GLP-1 analog or derivative.
  • the GLP-1 compound is a GLP-1 analog.
  • the GLP-1 compound comprises of an amino acid sequence of SEQ ID NO: 14
  • Xaa at position 8 is Gly, Ala, Val, Xaa at position 22 is Gly, Glu, Asp, or Lys, Xaa at position 33 is Val, or Ile, Xaa at position 34 is Lys or Arg, Xaa at position 36 is Arg or Gly, Xaa at position 17 is selected from the group consisting of NH 2 , Gly and Pro, Xaa at position 38 is Ser or absent, Xaa at position 19 is Ser or absent, Xaa at position 40 is Gly or absent, Xa
  • the GLP-1 compound comprises Ala at Xaa 8 . In another embodiment, the GLP-1 compound comprises Val at Xaa 8 . In another embodiment, the GLP-1 compound comprises Gly at Xaa 22 . In a preferred embodiment, the (LP-1 compound comprises Gly at Xaa 22 . In a preferred embodiment, the GLP-1 compound comprises Lys at Xaa 34 . In another preferred embodiment, the GLP-1 compound comprises Arg at Xaa 34 .
  • the amino acid sequence of the GLP-1 analog comprises Val 8 -Glu 22 -Ile 33 -Gly 36 -Pro 37 -Ser 38 -Ser 39 -Gly 40 -Ala 41 -Pro 42 -Pro 43 -Pro 44 -Ser 45 -GLP-1 (SEQ ID NO: 19).
  • the amino acid sequence of the GLP-1 analog consists of Val 8 -Glu 22 -Ile 33 -Gly 36 -Pro 37 -Ser 38 -Ser 39 -Gly 40 -Ala 41 -Pro 42 -Pro 43 -Pro 44 -Ser 45 -GLP-1 (SEQ ID NO: 19).
  • the amino acid sequence of the GLP-1 compound comprises Val 8 -GLP-1 (SEQ ID NO: 15). In a preferred embodiment, the amino acid sequence of the GLP-1 compound consists of the amino acid sequence Val 8 -GLP-1 (SEQ ID NO: 15). In another preferred embodiment, the amino acid sequence of the GLP-1 compound comprises Arg 34 -GLP-1 (SEQ ID NO: 16). In another preferred embodiment, the amino acid sequence of the GLP-1 compound consists of Arg 34 -GLP-1 (SEQ ID NO: 16). In another preferred embodiment, the amino acid sequence of the GLP-1 compound comprises Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17).
  • the amino acid sequence of the GLP-1 compound consists of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17).
  • the amino acid sequence of Val 8 -Glu 22 -GLP-1 comprises of five additional amino acid sequence substitutions.
  • the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) consists of five additional amino acid sequence substitutions.
  • the amino acid sequence of Val 8 -Glu 22 -GLP-1 comprises of four additional amino acid sequence substitutions
  • the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) consists of four additional amino acid sequence substitutions.
  • the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) comprises of three additional amino acid sequence substitutions.
  • the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) consists of three additional amino acid sequence substitutions.
  • the amino acid sequence of Val 8 -Glu 22 -GLP-1 comprises of two additional amino acid sequence substitutions. In another preferred embodiment, the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) consists of two additional amino acid sequence substitutions. In another preferred embodiment, the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) comprises of one additional amino acid sequence substitution. In another preferred embodiment, the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) consists of one additional amino acid sequence substitution.
  • the present invention also provides GLP-1 derivatives in combination with FGF-21 compounds.
  • the GLP-1 derivative is pegylated.
  • the GLP-1 derivative comprises of an amino acid sequence of SEQ ID NO: 20
  • Xaa at position 8 is: Gly, Val, Leu, Ile, Ser, or Thr
  • Xaa at position 22 is: Gly Glu, Asp, or Lys
  • Xaa at position 33 is: Val or file Xaa at position 46 is: Cys or Cys-NH 2 and wherein one PEG molecule is covalently attached to Cys 45 and one PEG molecule is covalently attached to Cys 46 or Cys 46 -NH 2 .
  • the GLP-1 derivative consists of the amino acid sequence of SEQ ID NO: 20.
  • Xaa 8 is Val or Gly. In another embodiment, Xaa 22 is Gly or Glu. In another embodiment, Xaa 33 is Ile. In an embodiment, Xaa 46 is Cys-NH 2 .
  • the GLP-1 derivative comprises of the amino acid sequence of Val 8 -Glu 22 -Ile 33 -Cys-NH 2 46 -GLP-1 (SEQ ID NO: 21). In a preferred embodiment, the GLP-1 derivative consists of the amino acid sequence of Val 8 -Glu 22 -Ile 33 -Cys-NH 2 46 -GLP-1 (SEQ ID NO: 21).
  • the GLP-1 compound is a GLP-1 fusion protein in a preferred embodiment, the GLP-1 fusion protein comprises a GLP-1 portion and an Fc portion of an immunoglobulin. In a preferred embodiment, the GLP-1 fusion protein comprises a GLP-1 analog and the Fc portion of an immunoglobulin wherein the GLP-1 analog comprises an amino acid sequence of SEQ ID NO: 22
  • Xaa at position 8 is Gly or Val
  • Xaa at position 33 is Val or Lys
  • Xaa at position 34 is Lys or Asn
  • Xaa at position 37 is Gly, Pro or is absent, and wherein the GLP analog is fused to the Fc portion of an immunoglobulin comprising the amino acid sequence of Formula IV (SEQ ID NO: 23)
  • the C-terminus of the GLP-1 analog and the N-terminus of the Fc portion of an immunoglobulin are preferably fused together via 1, 1.5 (SEQ ID NO: 7) or 2 repeats (SEQ ID NO: 8) of a G-rich peptide linker having the sequence Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Gly-Gly-Gly-Ser (SEQ ID NO: 6).
  • the GLP-1 fusion protein comprises a GLP-1 analog and the Fc portion of an immunoglobulin wherein the GLP-1 analog consists of an amino acid sequence of SEQ ID NO: 22 and wherein the GLP analog is fused to the Fc portion of an immunoglobulin consisting of the amino acid sequence of SEQ ID NO: 23.
  • the GLP-1 fusion protein further comprises a linker.
  • the GLP-1 fusion protein further comprises a linker, wherein the linker comprises an amino acid sequence is selected from the group consisting of SEQ ID NO: 6, SEQ ID NO:7 and SEQ ID NO:8.
  • the GLP-1 fusion protein further comprises a linker, wherein the linker consists of an amino acid sequence is selected from the group consisting of SEQ ID NO: 6: SEQ ID NO:7 and SEQ ID NO:8.
  • the linker comprises an amino acid sequence of SEQ ID NO:6.
  • the linker comprises an amino acid sequence of SEQ ID NO:7:
  • the linker comprises an amino acid sequence of SEQ ID NO: 8.
  • the linker consists of an amino acid sequence of SEQ ID NO:6.
  • the linker consists of an amino acid sequence of SEQ ID NO:7.
  • the linker consists of an amino acid sequence of SEQ ID NO:8
  • the GLP-1 portion comprises Gly at Xaa 8 . In another embodiment, the GLP-1 portion comprises Val at Xaa 8 . In an embodiment, the GLP-1 portion comprises Gly at Xaa 22 . In a preferred embodiment, the GLP-1 portion comprises Glu at Xaa 22 . In an embodiment, the GLP-1 portion comprises Lys at Xaa 34 . In another embodiment, the GLP-1 portion comprises Asn at Xaa 34 . In an embodiment, Xaa 37 of the GLP-1 portion is absent. In a preferred embodiment, the GLP-1 portion comprises Gly at Xaa 37 . In another preferred embodiment, the GLP-1 portion comprises Pro at Xaa 37 .
  • Preferred GLP-1 fusion proteins of the present invention include the following. proteins: Gly 8 -Glu 22 -Gly 36 -GLP-1-1L-IgG4 (S228P) (SEQ ID NO: 24), Gly 8 -Glu 22 -Gly 36 -GLP-1-1L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 24), Gly 8 -Glu 22 -Gly 36 -GLP-1-1L-IgG4 (S228P, N297A) (SEQ ID NO: 26), Gly 8 -Glu 22 -Gly 36 -GLP-1-1L-IgG4 (S228P, F234A, L235A, N297A) (SEQ ID NO: 27), Gly 8 -Glu 22 -Gly 36 -GLP-1-1L-IgG4 (S228P, des K) (SEQ ID NO: 28), Gly 8 -Glu 22 -Gly 36 -G
  • the present invention also includes FGF-21 compounds in combination with GLP-1 compounds, wherein the GLP-1 compound comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 5-4, SEQ ID NO: 55, SEQ ID NO: 56, and SEQ ID NO: 57.
  • the present invention also includes FGF-21 compounds in combination with GLP-1 compounds, wherein the GLP-1 compound consists of an amino acid sequence selected from the group consisting of SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, and SEQ ID NO: 57.
  • Preferred FGF-21 compound and (LP-1 compound combinations of the present invention include, Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9) in combination with Val 8 -GLP-1 (SEQ ID NO: 15), Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9) in combination with Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17), Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9) in combination with is Val 8 -Glu 22 -Ile 33 -Gly 36 -Pro 37 -Ser 38 -Ser 39 -Gly 40 -Ala 41 -Pro 42 -Pro 43 -Pro 44 -Ser 45 -GLP-1 (SEQ ID NO: 19), Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9) in combination with pegylated.
  • the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with five additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with five additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SE) ID NO: 17) with four additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with four additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with three additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -FGF-1 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with three additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with two additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with two additional amino acid sequence substitutions
  • the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with one additional amino acid sequence substitution.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with one additional amino acid sequence substitution.
  • More preferred FGF-21 compound and GLP-1 compound combinations of the present invention include Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with Val 8 -GLP-1 (SEQ ID NO: 17), Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEX) ID NO: 10) in combination with Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17), Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with is Val 8 -Glu 22 -Ile 33 -Gly 36 -Pro 37 -Ser 38 -Ser 39 -Gly 40 -Ala 41 -Pro 42 -Pro 43 -Pro 44 -Ser 45 -GLP-1 (SEQ ID NO: 19).
  • Cys 118 -Cys 134 -Ala 167 -FGF-21 in combination with pegylated Val 8 -Glu 22 -Ile 33 -Cys-NH 2 46 -GLP-1 (SEQ ID NO: 21), Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with Arg 34 -GLP-1 (SEQ ID NO: 16), Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with acylated Arg 34 -GLP-1 (SEQ ID NO: 16), Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with Arg 34 -Lys 26 -(N- ⁇ -( ⁇ -Glu(N- ⁇ -hexadecanoyl)))-GLP-1 (SEQ ID NO: 18), Cys 118 -Cy
  • Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with Gly 8 -Glu 22 -Gly 36 -GLP-1-2L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 41), Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO:10) in combination with Gly 8 -Glu 22 -Gly 36 -GLP-1-2L-IgG4 (S228P, N297A) (SEQ ID NO: 42), Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO:10) in combination with Gly 8 -Glu 22 -Gly 36 -GLP-1(7-37)-2L4-IgG4 (S228P, F234A, L235A, N297A) (SEQ ID NO: 43), Cys 118 -Cys
  • Cys 118 -Cys 134 -Ala 167 -FGF-21 in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 55, Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 55, Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO:10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 56.
  • Cys 118 -Cys 134 -Ala 167 -FGF-21 in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 56, Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO:10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 57 and Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO:10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 57.
  • the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with five additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with five additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with four additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with four additional amino acid sequence substitutions
  • the combination of the present invention Comprises an FGF-21 analog comprising the ammo acid sequence of Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises an amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with three additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog consist of an amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with three additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with two additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with two additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with one additional amino acid sequence substitution.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with one additional amino acid sequence substitution.
  • Preferred FGF-21 compound and GLP-1 compound combinations of the present invention include, Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEC ID NO: 13) in combination with Val 8 -GLP-1 (SEQ ID NO: 15), Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13) in combination with Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17), Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13) in combination with is Val 8 -Glu 22 Ile 33 -Gly 36 -Pro 37 -Ser 38 -Ser 39 -Gly 40 -Ala 41 -Pro 42 -Pro 43 -Pro 44 -Ser 45 -GLP-1 (SEQ ID NO: 19), Cys 118 -Cys 134 -Ala
  • the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with five additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 1 in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID M): 17) with five additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with four additional amino acid sequence substitutions: in another preferred embodiment, the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with four additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog composing the amino acid sequence of Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 anal on, wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with three additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with three additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with two additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) with two additional amino acid sequence substitutions.
  • the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 7) comprises one additional amino acid sequence substitution.
  • the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 analog, wherein the GLP-1 analog consists of the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17) comprises one additional amino acid sequence substitution.
  • DIO Diet-induced obese (DIO) male C57/B16 mice (Harlan: Va.) maintained on a calorie rich diet (TD95217, Teklad, Madison, Wis.) since weaning are used, DIO is established by ad libitum feeding for at least 7 weeks of a diet consisting of 40% fat, 39% carbohydrate, and 21% protein caloric content (TD95217). Animals are individually housed in a temperature-controlled (24° C.) facility with 12 hour light/dark cycle (lights on 2200) and free access to food (TD95217) and water. After a minimum of 2 weeks acclimation to the facility, the mice are randomized according to their body weight, so each experimental group of animals would have similar body weight.
  • Body composition of DIO male C57/B16 mice is determined by using QNMR analysis 1 day prior to initiation of treatment. Combination treatment is administered with two delivery methods.
  • a FGF-21 compound (1 mg/kg) is subcutaneously injected once a day and a GLP-1 compound (3 nmol/kg/day) is delivered by continuous subcutaneous infusion with alzet pump.
  • Another group (“FGF-21”) of mice receives 11.4 ⁇ L/day of PBS using the alzet pump and a daily subcutaneous injection of 1 mg/kg of FGF-21.
  • the “GLP-1” group of mice receives 3 nmol/kg/day of a GLP-1 compound through an alzet pump and a daily subcutaneous injection of 0.05 mL/10 g of PBS.
  • the “GLP-1+FGF-21” group of mice receives 3 nmol/kg/day of a GLP-1 compound through an alzet pump and a daily subcutaneous injection of 1 mg/kg of a FGF-21 compound. Injections occur prior to the onset of the dark photoperiod.
  • Data in Table 1 represent results where the FGF-21 compound is human FGF-2 (SEQ ID NO: 1) and where the GLP-1 compound is Val 8 -Glu 22 -Ile 33 -Pro 37 -Ser 38 -Ser 39 -Gly 40 -Ala 41 -Pro 42 -Pro 43 -Pro 44 -Ser 45 -GLP-1 (SEQ ID NO: 19).
  • the data demonstrate that the use of a FGF-21 compound in combination with a GLP-1 con pound results in a synergistic effect on weight loss.

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US20140024586A1 (en) 2014-01-23
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