USE OF AN FGF-21 COMPOUND AND A GLP-1 COMPOUND FOR THE TREATMENT OF OBESITY

Abstract

The present invention provides methods of lowering body weight by administering an FGF-21 compound in combination with a GLP-1 compound. In addition, the present invention also provides methods to treat obesity by administering an FGF-21 compound in combination with a GLP-1 compound. The present invention also discloses combinations useful in the methods of the present invention.

Description

[0001] 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

BACKGROUND OF THE INVENTION

[0002] Obesity, and especially upper body obesity, is the most common nutritional disorder in the over-nourished populations of the world. Current methods for promoting weight loss are not completely satisfactory. Unfortunately, an estimated 33 billion dollars a year are spent on weight-loss measures that are largely futile. Thus, new methods and compositions such as pharmaceutical agents that promote weight-loss are urgently needed to complement old approaches.

[0003] Fibroblast growth factor 21 (FGF-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 ob/ob 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).

[0004] In addition to its beneficial effects on Type 2 diabetes, 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.

[0005] 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.

SUMMARY OF THE INVENTION

[0006] 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. In another embodiment, the present invention provides a method of treating obesity comprising administering a FGF-21 compound in combination with a GLP-1 compound.

[0007] 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. In another embodiment, the present invention provides a method of treating obesity comprising administering a FGF-21 compound in combination with an exendin compound.

DETAILED DESCRIPTION

[0008] A "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)).

[0009] A "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.

[0010] 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, α-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 C₁-C₄alkyl. Furthermore, one or more side groups, or terminal groups, may be protected by protective groups known to the ordinarily-skilled protein chemist. The α-carbon of an amino acid may be mono- or di-methylated. The chemical modification may also include "pegylation."

[0011] Specific substitutions to human FGF-21, FGF-21 analog or FGF-21 derivative indicated using the specific amino acid present after substitution or modification at a particular residue followed by the residue number. For example, Cys¹¹⁸-FGF-21 indicates that there has been a cysteine introduced at position 118 of human FGF-21.

[0012] A "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.

[0013] A "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-type human sequence (SEQ ID NO: 5).

[0014] 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-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 C₁-C₄alkyl. Furthermore, one or more side groups, or terminal groups, may be protected by protective groups known to the ordinarily-skilled protein chemist. The α-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.

[0015] The nomenclature used herein to refer to specific GLP-1 analogs and GLP-1 derivatives is defined as follows: Specific substitutions to a GLP-1 analog and GLP-1 derivative are indicated using the specific amino acid being substituted followed by the residue number. 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. In the case of additions of amino acids to a GLP-1 amino acid sequence, the added amino acid is indicated followed by the position at which it is present. For example, the addition of two serine residues to the C-terminus of wild type GLP-1 will be referred to as Ser³⁸-Ser³⁹-GLP-1.

[0016] An "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.

[0017] An "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. The exendin-4 or exendin-4 analog may be fused to the second polypeptide 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).

[0018] An "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 glulamic 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 C₁-C₄alkyl. Furthermore, one or more side groups, or terminal groups, may be protected by protective groups known to the ordinarily-skilled protein chemist. The α-carbon of an amino acid may be mono- or di-methylated. The chemical modification may also include pegylation.

[0019] As used herein, 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.

[0020] 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-Ser-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-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-G- ly-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.

[0021] "Pegylation" or "Pegylated" refers to a compound of the present invention that is chemically modified by covalent attachment of a molecule or molecules of polyethylene glycol or a derivative thereof. Furthermore, it is intended that the term "PEG" refers to polyethylene glycol or a derivative thereof as are known in the art. In its typical form, PEG is a linear polymer with terminal hydroxyl groups and has the formula HO--CH₂CH₂--(CH₂CH₂O)_n--CH₂CH₂- --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. Preferably, 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. There are many forms of 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.

[0022] "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.

[0023] The term "synergy" or "synergistic" as used herein is defined to mean a combination of components wherein the effect of the combination is greater than the additive individual effects of each component of the combination. For purposes of the present invention, "effect" refers to a loss in body weight, lowering of body weight or a reduction in blood glucose levels.

[0024] 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. For example, the FGF-21, GLP-1 and exendin compounds may be made using recombinant techniques. As the DNA sequences of mature human FGF-21 (SEQ ID NO: 1), native GLP-1, and exendin-4 are known, PCR methodology may be used to isolate genes encoding the corresponding gene. Further, 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.

[0025] 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.

[0026] A wide variety of methods have been described in the art to covalently conjugate PEGs to peptides (for review article see, Roberts, M. et al. Advanced Drug Delivery Reviews, 54:459-476, 2002). 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.

[0027] Various methods of protein purification may be employed and such methods are known in the art and described, for example, in Deutscher, Methods in Enzymology 182: 83-9 (1990) and Scopes, Protein Purification: Principles and Practice, Springer-Verlag, NY (1982). The purification step(s) selected will depend on the nature of the production process used and the particular protein produced. For example, 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.

[0028] 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.

[0029] Those skilled in the art can readily optimize pharmaceutically effective dosages and administration regimens for the combinations of the present invention, as determined by good medical practice and the clinical condition of the individual patient. For example, 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. For GLP-1 fusion proteins, 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.

[0030] In an embodiment, the present invention provides a composition comprising a FGF-21 compound and a GLP-1 compound. In another embodiment, 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. In a preferred embodiment, the composition comprises an FGF-21 analog and a GLP-1 analog. In another preferred embodiment, the composition comprises a FGF-21 analog and a GLP-1 derivative. In another preferred embodiment, the composition comprises a FGF-21 analog and a GLP-1 fusion protein.

[0031] In another embodiment, the present invention provides a composition comprising an FGF-21 compound and an exendin compound. In a preferred embodiment, 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. In a preferred embodiment, the composition comprises a FGF-21 analog and exendin-4. In another preferred embodiment, the composition comprises a FGF-21 analog and an exendin-4 analog. In another preferred embodiment, the composition comprises a FGF-21 analog and an exendin-4 derivative. In another preferred embodiment, the composition comprises a FGF-21 analog and an exendin-4 agonist.

[0032] The present invention also provides a method of lowering body weight comprising administering a FGF-21 compound in combination with a GLP-1 compound. In a more preferred embodiment, administering a FGF-21 compound in combination with a GLP-1 compound results in a synergistic effect on weight loss. In another embodiment, 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. In a preferred embodiment, 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.

[0033] The present invention also provides a method of lowering body weight comprising administering a FGF-21 compound in combination with an exendin compound. In more preferred embodiment, administering a FGF-21 compound in combination with an exendin compound results in a synergistic effect on weight loss. In an embodiment, 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. In a preferred embodiment, 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.

[0034] The present invention also provides a method of treating obesity comprising administering a FGF-21 compound in combination with a GLP-1 compound. In more preferred embodiment, administering a FGF-21 compound in combination with a GLP-1 compound results in a synergistic effect on weight loss. In an embodiment, 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. In a preferred embodiment, the method of treating obesity comprises administering a FGF-21 analog in combination with a GLP-1 analog. In another preferred embodiment, the method of treating obesity comprises administering a FGF-21 analog in combination with a GLP-1 derivative. In another preferred embodiment, the method of treating obesity comprises administering a FGF-21 analog and a GLP-1 fusion protein.

[0035] The present invention also provides a method of treating obesity comprising administering a FGF-21 compound in combination with an exendin compound. In more preferred embodiment, administering a FGF-21 compound in combination with an exendin compound results in a synergistic effect on weight loss. In an embodiment, 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. In a preferred embodiment, 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.

[0036] 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. In a preferred embodiment, 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. In another preferred embodiment, 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.

[0037] 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. In a preferred embodiment, 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. In another preferred embodiment, 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.

[0038] 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-L compound is selected from the group consisting of a GLP-1 analog, a GLP-1 derivative and a GLP-1 fusion protein. In a preferred embodiment, 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. In another preferred embodiment, 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.

[0039] 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. In a preferred embodiment, 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. In another preferred embodiment, 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.

[0040] The FGF-21 compounds of the present invention may be human FGF-21, a FGF-21 analog or a FGF-21 derivative. In a preferred embodiment, the FGF-21 compound of the present invention is a FGF-21 analog in a more preferred embodiment, the present invention provides FGF-21 compounds comprising one or two engineered disulfide bonds. In a more preferred embodiment, 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). In another preferred embodiment, 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. In another preferred embodiment, the FGF-2 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. In a more preferred embodiment, 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. In a more preferred embodiment, the FGF-21 compound comprises an amino acid sequence selected from the group consisting of Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10), Cys²¹-Cys³³-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 11), Cys²⁶-Cys¹²²-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 12), and Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO:13). In a more preferred embodiment, the FGF-21 compound consists of an amino acid sequence selected from the group consisting of Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9), Cys²⁶-Cys¹²²-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10), Cys²¹-Cys³³-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 11), Cys²⁶-Cys¹²²-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 12), and Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO:13).

[0041] In an embodiment, 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). In another embodiment, 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. In another preferred embodiment, 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. In a more preferred embodiment, 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. In a more preferred embodiment, the FGF-21 compound consists of an amino acid sequence selected from the group consisting of Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10), Cys²¹-Cys³³-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 11), Cys²⁶-Cys¹²²-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 12), and Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO; 13).

[0042] Further, the present invention provides GLP-1 compounds to be used in combination with the FGF-21 compounds of the present invention. In an embodiment, the GLP-1 compound is a GLP-1 analog, GLP-1 derivative, or a GLP-1 fusion protein. In a more preferred embodiment, the GLP-1 compound is a GLP-1 analog or derivative. In a preferred embodiment, the GLP-1 compound is a GLP-1 analog. In a more preferred embodiment, the GLP-1 compound comprises of an amino acid sequence of SEQ ID NO:

TABLE-US-00001 His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser 10 15 Tyr Leu Glu Xaa Gln Ala Ala Lys Glu Phe Ile Ala 20 25 30 Trp Leu Xaa Xaa Gly Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 40 Xaa Xaa Xaa 45

wherein 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 37 is selected from the group consisting of NH₂, Gly and Pro, Xaa at position 38 is Ser or absent, Xaa at position 39 is Ser or absent, Xaa at position 40 is Gly or absent, Xaa at position 41 is Ala or absent, Xaa at position 42 is Pro or absent, Xaa at position 43 is Pro or absent, Xaa at position 44 is Pro or absent, and Xaa at position 45 is Ser or absent.

[0043] In an embodiment, the GLP-1 compound comprises Ala at Xaa₈. In another embodiment, the GLP-1 compound comprises Val at Xaa₈. In another embodiment, the GLP-1 compound comprises Gly at Xaa₂₂. In a preferred embodiment, the GLP-1 compound comprises Gly at Xaa₂₂. In a preferred embodiment, the GLP-1 compound comprises Lys at Xaa₃₄. In another preferred embodiment, the GLP-1 compound comprises Arg at Xaa₃₄. In a more preferred embodiment, the amino acid sequence of the GLP-1 analog comprises Val⁸-Glu²²-Ile³³-Gly³⁶-Pro³⁷-Ser³⁸-Ser³⁹-Gly⁴⁰-Ala⁴¹-Pro⁴²-Pro⁴³-Pro⁴⁴-Ser⁴⁵-GLP-1 (SEQ ID NO: 19). In another embodiment, the amino acid sequence of the GLP-1 analog consists of Val⁸-Glu²²-Ile³³-Gly³⁶-Pro³⁷-Ser³⁸-Ser³⁹-Gly⁴⁰-Ala⁴¹-Pro⁴²-Pro⁴³-Pro⁴⁴-Ser⁴⁵-GLP-1 (SEQ ID NO: 19).

[0044] In a preferred embodiment, the amino acid sequence of the GLP-1 compound comprises Val⁸-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 Val⁸-GLP-1 (SEQ ID NO: 15). In another preferred embodiment, the amino acid sequence of the GLP-1 compound comprises Arg³⁴-GLP-1 (SEQ ID NO: 16). In another preferred embodiment, the amino acid sequence of the GLP-1 compound consists of Arg³⁴-GLP-1 (SEQ ID NO: 16). In another preferred embodiment, the amino acid sequence of the GLP-1 compound comprises Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17). In another preferred embodiment, the amino acid sequence of the GLP-1 compound consists of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17). In another preferred embodiment, the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) comprises of five additional amino acid sequence substitutions. In another preferred embodiment, the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) consists of five additional amino acid sequence substitutions. In another preferred embodiment, the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) comprises of four additional amino acid sequence substitutions. In another preferred embodiment, the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) consists of four additional amino acid sequence substitutions. In another preferred embodiment, the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) comprises of three additional amino acid sequence substitutions. In another preferred embodiment, the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) consists of three additional amino acid sequence substitutions. In another preferred embodiment, the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) comprises of two additional amino acid sequence substitutions. In another preferred embodiment, the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) consists of two additional amino acid sequence substitutions. In another preferred embodiment, the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) comprises of one additional amino acid sequence substitution In another preferred embodiment, the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) consists of one additional amino acid sequence substitution.

[0045] The present invention also provides GLP-1 derivatives in combination with FGF-21 compounds. In another preferred embodiment, the GLP-1 derivative is pegylated. In a preferred embodiment, the GLP-1 derivative comprises of an amino acid sequence of SEQ ID NO: 20

TABLE-US-00002 His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser 10 15 Tyr Leu Glu Xaa Gln Ala Ala Lys Glu Phe Ile Ala 20 25 30 Trp Leu Xaa Lys Gly Gly Pro Ser Ser Gly Ala Pro 35 40 Pro Pro Cys Xaa 45

wherein Xaa at position 8 is: D-Ala, Gly, Val, Leu, Ile, Ser, or Thr; Xaa at position 22 is: Gly, Glu, Asp, or Lys; Xaa at position 33 is: Val or Ile Xaa at position 46 is: Cys or Cys-NH₂ and wherein one PEG molecule is covalently attached to Cys⁴⁵ and one PEG molecule is covalently attached to Cys⁴⁶ or Cys⁴⁶-NH₂. In another embodiment, the GLP-1 derivative consists of the amino acid sequence of SEQ ID NO: 20.

[0046] In an embodiment, Xaa₈ is Val or Gly. In another embodiment, Xaa₂₂ is Gly or Glu. In another embodiment, Xaa₃₃ is Ile. In an embodiment, Xaa₄ is Cys-NH₂. In a preferred embodiment, the GLP-1 derivative comprises of the amino acid sequence of Val⁸-Glu²²-Ile³³-Cys-NH₂⁴⁶-GLP-1 (SEQ ID NO: 21). In a preferred embodiment, the GLP-1 derivative consists of the amino acid sequence of Val⁸-Glu²²-Ile³³-Cys-NH₂⁴⁶-GLP-1 (SEQ ID NO: 21).

[0047] In another embodiment, 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-t 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

TABLE-US-00003 His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser 10 15 Tyr Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala 20 25 30 Trp Leu Xaa Xaa Gly Gly Xaa 35

wherein 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)

TABLE-US-00004 Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys 5 10 Pro Ala Pro Xaa Xaa Xaa Gly Gly Pro Ser Val Phe 15 20 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 25 30 35 Ser Arg Thr Pro Gln Val Thr Cys Val Val Val Asp 40 45 Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp 50 55 60 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 65 70 Lys Pro Arg Glu Glu Gln Phe Xaa Ser Thr Tyr Arg 75 80 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 85 90 95 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 100 105 Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 110 115 120 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 125 130 Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 135 140 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 145 150 155 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 160 165 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 170 175 180 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 185 190 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn 195 200 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 205 210 215 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 220 225 Gly Xaa 230

wherein: Xaa at position 16 is Pro or Glu; Xaa at position 17 is Phe, Val, or Ala; Xaa at position 18 is Leu, Glu, or Ala; Xaa at position 80 is Asn or Ala; and Xaa at position 230 is Lys or is absent.

[0048] In a preferred embodiment, 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-Ser (SEQ ID NO: 6).

[0049] 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 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. In another embodiment, the GLP-1 fusion protein further comprises a linker. In another embodiment, 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. In another embodiment, 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. In an embodiment, the linker comprises an amino acid sequence of SEQ ID NO:6. In an embodiment, the linker comprises an amino acid sequence of SEQ ID NO:7. In an embodiment, the linker comprises an amino acid sequence of SEQ ID NO: 8. In an embodiment, the linker consists of an amino acid sequence of SEQ ID NO:6. In an embodiment, the linker consists of an amino acid sequence of SEQ ID NO:7. In an embodiment, the linker consists of an amino acid sequence of SEQ ID NO:8

[0050] In an embodiment of the present invention, the GLP-1 portion comprises Gly at Xaa₈. In another embodiment, the GLP-1 portion comprises Val at Xaa₈. In an embodiment, the GLP-1 portion comprises Gly at Xaa₂₂. In a preferred embodiment, the GLP-1 portion comprises Glu at Xaan. In an embodiment, the GLP-1 portion comprises Lys at Xaa₃₄. In another embodiment, the GLP-1 portion comprises Asn at Xaa₃₄. In an embodiment, Xaa₃₇ of the GLP-1 portion is absent. In a preferred embodiment, the GLP-1 portion comprises Gly at Xaa₃₇. In another preferred embodiment, the GLP-1 portion comprises Pro at Xaa₃₇.

[0051] Preferred GLP-1 fusion proteins of the present invention include the following proteins: Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P) (SEQ ID NO: 24), Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 25), Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P, N297A) (SEQ ID NO: 26), Gly⁸-Glu²²-Gly³⁶-GLP-1-IgG4 (S228P, F234A, L235A, N297A) (SEQ ID NO: 27), Gly⁸-Glu²²-Gly³⁶-GLP-1L-IgG4 (S228P, des K) (SEQ ID NO: 28), Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P, F234A, L235A, des K) (SEQ ID NO: 29), Gly⁸-Glu²²-Gly³⁶-GLP-1-1 L-IgG4 (S228P, N297A,des K) (SEQ ID NO: 30), Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P, F234A, L235A, N297A, des K) (SEQ ID NO: 31), Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-LgG4 (S228P) (SEQ ID NO: 32), Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 33), Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, N297A) (SEQ ID NO: 34), Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A, N297A) (SEQ ID NO: 35), Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, des K) (SEQ ID NO: 36), Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A, des K) (SEQ ID NO: 37), Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, N297A des K) (SEQ ID NO: 38), Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A, N297A, des K) (SEQ ID NO: 39), Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P) (SEQ ID NO: 40), Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 41), Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, N297A) (SEQ ID NO: 42), Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A, N297A) (SEQ ID NO: 43), (Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, des K) (SEQ ID NO: 44), Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A, des K) (SEQ ID NO: 45), Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, N297A, des K) (SEQ ID NO: 46), Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A, N297A, des K) (SEQ ID NO: 47), and the Val⁸ forms of all of the above.

[0052] 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: 54, 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.

[0053] Preferred FGF-21 compound and GLP-1 compound combinations of the present invention include. Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Val⁸-GLP-1 (SEQ ID NO: 15), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with is Val⁸-Glu²²-Ile³³-Gly³⁶-Pro³⁷-Ser³⁸-Ser³⁹-Gly⁴⁰-Ala⁴¹-Pro⁴²-Pro⁴³-Pro⁴⁴-Ser⁴⁵-GLP-1 (SEQ ID NO: 19), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with pegylated Val⁸-Glu²²-Ile³³-Cys-NH₂-GLP-1 (SEQ ID NO: 21), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Arg-GLP-1 (SEQ ID NO: 16), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with acylated Arg³⁴-GLP-1 (SEQ ID NO: 16), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Arg³⁴-Lys²⁶-(N-ε-(γ-Glu (N-α-hexadecanoyl)))-GLP-1 (SEQ ID NO: IS), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P) (SEQ ID NO: 24), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 25), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-L-IgG4 (S228P, N297A) (SEQ ID NO: 26), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-L-IgG4 (S228P, F234A, L235A, N297A) (SEQ ID NO: 27), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1 L-IgG4 (S228P, des K) (SEQ ID NO: 28), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P, F234A, L235A, des K) (SEQ ID NO: 29), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P, N297A, des K) (SEQ ID NO: 30). Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P, F234A, L235A, N297A, des K) (SEQ ID NO: 31), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P) (SEQ ID NO: 32), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 33), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, N297A) (SEQ ID NO: 34), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A, N297A) (SEQ ID NO: 35), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, des K) (SEQ ID NO: 36), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A, des K) (SEQ ID NO: 37), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, N297A, des K) (SEQ ID NO: 38), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A, N297A, des K) (SEQ ID NO: 39), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P) (SEQ ID NO: 40), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 41), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, N297A) (SEQ ID NO: 42), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A, N297A) (SEQ ID NO: 43), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, des K) (SEQ ID NO: 44), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A, des K) (SEQ ID NO: 45), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, N297A, des K) (SEQ ID NO: 46), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A, N297A, des K) (SEQ ID NO: 47), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with exendin-4 (SEQ ID NO: 4), Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with albiglutide (SEQ ID NO: 48). Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 47, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 47, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 48, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 48, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 49, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 49, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 50, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 50, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 51, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 51, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 52, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 52, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 53, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 53, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 54, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 54, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 55, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 55, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 56, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 56, Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 57, and Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 57

[0054] In a preferred embodiment, the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with five additional amino acid sequence substitutions. In a preferred embodiment, the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-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 Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with five additional amino acid sequence substitutions. In another preferred embodiment, the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-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 Cys¹¹⁸-Cys¹³⁴-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 Val⁸-Glu²²-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-2 analog comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with three 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 Cys¹¹⁸-Cys¹³⁴-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 Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with three additional amino acid sequence substitutions. In another preferred embodiment, the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with two 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 Cys¹¹⁸-Cys¹³⁴-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 Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with two additional amino acid sequence substitutions. In another preferred embodiment, the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-FGF-21 (SEQ ID NO: 9) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with one additional amino acid sequence substitution. In another preferred embodiment, the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-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 Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with one additional amino acid sequence substitution.

[0055] More preferred FGF-21 compound and GLP-1 compound combinations of the present invention include Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Val⁸-GLP-1 (SEQ ID NO: 17), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with is Val⁸-Glu²²-Ile³³-Gly³⁶-Pro³⁷-Ser³⁸-- Ser³⁹-Gly⁴⁰-Ala⁴¹-Pro⁴²-Pro⁴³-Pro⁴⁴-Ser⁴⁵-GLP-1 (SEQ ID NO: 19), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with pegylated Val⁸-Glu²²-Ile³³-Cys-NH₂-GLP-1 (SEQ ID NO: 21), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Arg³⁴-GLP-1 (SEQ ID NO: 16), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with acylated Arg-GLP-1 (SEQ ID NO: 16), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Arg³⁴-Lys²⁶-(N-ε-(γ-Glu (N-α-hexadecanoyl)))-GLP-1 (SEQ ID NO: 18), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1L-IgG4 (S228P) (SEQ ID NO: 24), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 25), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1L-IgG4 (S228P, N297A) (SEQ ID NO: 26), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1L-IgG4 (S228P, F234A, L235A, N297A) (SEQ ID NO: 27), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1L-IgG4 (S228P, des K) (SEQ ID NO: 28), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1L-IgG4 (S228P, F234A, L235A, des K) (SEQ ID NO: 29), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1L-IgG4 (S228P, N297A, des K) (SEQ ID NO: 30), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1L-IgG4 (S228P, F234A, L235A, N297A, des K) (SEQ ID NO: 31), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1.5L-IgG4 (S228P) (SEQ ID NO: 32), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1.5L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 33), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1.5L-IgG4 (S228P, N297A) (SEQ ID NO: 34), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A, N297A) (SEQ ID NO: 35), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1.5L-IgG4 (S228P, des K) (SEQ ID NO: 36), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1.5L-IgG4 (S228P, F234A, L235A, des K) (SEQ ID NO: 37), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-1.5L-IgG4 (S228P, N297A, des K) (SEQ ID NO: 38), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A, N297A, des K) (SEQ ID NO: 39), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P) (SEQ ID NO: 40), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with (Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 41), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, N297A) (SEQ ID NO: 42), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1 (7-37)-2L-IgG4 (S228P, F234A, L235A, N297A) (SEQ ID NO: 43), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, des K) (SEQ ID NO 44), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A, des K) (SEQ ID NO: 45), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, N297A, des K) (SEQ ID NO: 46), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1(7-37)-2L-IgG4 (S228P, F234A, L235A, N297A, des K) (SEQ ID NO: 47), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with exendin-4 (SEQ ID NO: 4), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with albiglutide (SEQ ID NO: 48). Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 47, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 47, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 48, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 48, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 49, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 49. Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 50, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 50, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 51, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 51, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 52, Cys¹¹⁸-Cys¹¹⁸-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 52, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 53, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 53, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 54, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 54, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 55, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 55, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 56, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 56, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 57 and Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 57.

[0056] In a preferred embodiment, the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with five additional amino acid sequence substitutions. In a preferred embodiment, the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-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 Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with five additional amino acid sequence substitutions. In another preferred embodiment, the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-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 Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-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 Val⁸-Glu²²-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 comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises an amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with three 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 Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-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 Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with three additional amino acid sequence substitutions. In another preferred embodiment, the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with two 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 Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-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 Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with two additional amino acid sequence substitutions. In another preferred embodiment, the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 10) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with one additional amino acid sequence substitution. In another preferred embodiment, the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-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 Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with one additional amino acid sequence substitution.

[0057] Preferred FGF-21 compound and GLP-1 compound combinations of the present invention include, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Val⁸-GLP-1 (SEQ ID NO: 15), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17). Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with is Val⁸-Glu²²-Ile³³-Gly³⁶-Pro³⁷-Ser³⁸-Ser³⁹-Gly⁴¹-Ala⁴¹-Pro⁴²-Pro⁴³-Pro⁴⁴-Ser⁴⁵-GLP-1 (SEQ ID NO: 19), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with pegylated Val⁸-Glu²²-Ile³³-Cys-NH₂⁴⁶-GLP-1 (SEQ ID NO: 21), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Arg³⁴-GLP-1 (SEQ ID NO: 16), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷ FGF-21 (SEQ ID NO: 13) in combination with acylated Arg³⁴-GLP-1 (SEQ ID NO: 16), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Arg³⁴-Lys²⁶-(N-ε-(γ-Glu (N-α-hexadecanoyl)))-GLP-1 (SEQ ID NO: 18). Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Gly²²-GLP-1-1L-IgG4 (S228P) (SEQ ID NO: 24), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) with Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 25), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1 L-IgG4 (S228P, N297A) (SEQ ID NO: 26), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P, F234A. L235A, N297A) (SEQ ID NO: 27), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1 L-IgG4 (S228P, des K) (SEQ ID NO: 28), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) with Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P: F234A, L235A, des K) (SEQ ID NO: 29), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1L-IgG4 (S228P, N297A, des K) (SEQ ID NO: 30), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-L-IgG4 (S228P, F234A, L235A, N297A, des K) (SEQ ID NO: 31), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO:13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P) (SEQ ID NO: 32), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 33). Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, N297A) (SEQ ID NO: 34), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A, N297A) (SEQ ID NO: 35), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, des K) (SEQ ID NO: 36), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A, des K) (SEQ ID NO: 37), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, N297A, des K) (SEQ ID NO: 38), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-1.5L-IgG4 (S228P, F234A, L235A, N297A, des K) (SEQ ID NO: 39), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P) (SEQ ID NO: 40), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A) (SEQ ID NO: 41), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, N297A) (SEQ ID NO: 42), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A, N297A) (SEQ ID NO: 43), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, des K) (SEQ ID NO: 44), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A, des K) (SEQ ID NO: 45), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, N297A, des K) (SEQ ID NO: 46). Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with Gly⁸-Glu²²-Gly³⁶-GLP-1-2L-IgG4 (S228P, F234A, L235A, N297A, des K) (SEQ ID NO: 47), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with exendin-4 (SEQ ID NO: 4), Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with albiglutide (SEQ ID NO: 49), Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 47, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO:10) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 47, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 48, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 48, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 49, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 49, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 50, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 50, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 51, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 51, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 52. Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 52, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 53, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 53, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 54, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 54, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 55, Cys¹¹⁸-Cys¹³⁴-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 55, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 56, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 56, Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 57, and Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 compound consisting of the amino acid sequence of SEQ ID NO: 57.

[0058] In a preferred embodiment, the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with five additional amino acid sequence substitutions. In a preferred embodiment, the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-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 Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with five additional amino acid sequence substitutions. In another preferred embodiment, the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-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 Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-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 Val⁸-Glu²²-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 comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with three 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 Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-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 Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with three additional amino acid sequence substitutions. In another preferred embodiment, the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with two 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 Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-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 Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) with two additional amino acid sequence substitutions. In another preferred embodiment, the combination of the present invention comprises an FGF-21 analog comprising the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-FGF-21 (SEQ ID NO: 13) in combination with a GLP-1 analog, wherein the GLP-1 analog comprises the amino acid sequence of Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) comprises one additional amino acid sequence substitution. In another preferred embodiment, the combination of the present invention comprises an FGF-21 analog consisting of the amino acid sequence of Cys¹¹⁸-Cys¹³⁴-Ala¹²¹-Ala¹⁶⁷-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 Val⁸-Glu²²-GLP-1 (SEQ ID NO: 17) comprises one additional amino acid sequence substitution.

Example 1

Effect of Combination Treatment with GLP-1 and FGF-21 on Body Weight and on Blood Glucose Levels

[0059] Diet-induced obese (DIO) male C57/Bl6 mice (Harlan: Virginia) 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 (TD)95217). 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.

[0060] 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. The experimental groups are as follow: One group ("Vehicle") of mice (n=8) receives PBS (11.4 μL/day) and a daily subcutaneous injection of 0.05 mL/10 g of PBS. Another group ("FGF-21") of mice (n=8) receives 11.4 μL/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. Starting weight values are measured after implantation of alzet pumps on Day 1. Body weights are recorded in conjunction with daily dosing. Average weight changes compared to starting weights of a particular treatment group, including vehicle, are determined. Average daily weight changes are normalized to average of daily weight change of Vehicle group and are reported in Table 1 (i.e., (Average weight change of Treatment group)-(Average weight change of Vehicle group)). For all treatment groups n=8.

[0061] Data in Table 1 represent results where the FGF-21 compound is human FGF-21 (SEQ ID NO: 1) and where the GLP-1 compound is Val⁸-Glu²²-Ile³³-Gly³⁶-Pro³⁷-Ser³⁸-Ser³⁹-Gly⁴⁰-Ala⁴¹-Pro⁴²-Pro⁴³-Pro³⁴-Ser⁴⁵-GLP-1 (SEQ ID NO: 19). The data demonstrate that the use of a FGF-21 compound in combination with a GLP-1 compound results in a synergistic effect on weight loss.

TABLE-US-00005 TABLE 1 Average Weight Change Normalized to Vehicle Treated Mice Treatment FGF-21 GLP-1 GLP-1 + FGF-21 Day (g) (g) (g) Day 1 0 0 0 Day 5 -0.45 -1.01 -2.62 Day 10 -1.94 -1.99 -5.16 Day 15 -2.85 -2.50 -6.94

Sequence CWU 1

1

571624DNAHomo sapiens 1atggactcgg acgagaccgg gttcgagcac tcaggactgt gggtttctgt gctggctggt 60ctgctgggag cctgccaggc acaccccatc cctgactcca gtcctctcct gcaattcggg 120ggccaagtcc ggcagcggta cctctacaca gatgatgccc agcagacaga agcccacctg 180gagatcaggg aggatgggac ggtggggggc gctgctgacc agagccccga aagtctcctg 240cagctgaaag ccttgaagcc gggagttatt caaatcttgg gagtcaagac atccaggttc 300ctgtgccagc ggccagatgg ggccctgtat ggatcgctcc actttgaccc tgaggcctgc 360agcttccggg agctgcttct tgaggacgga tacaatgttt accagtccga agcccacggc 420ctcccgctgc acctgccagg gaacaagtcc ccacaccggg accctgcacc ccgaggacca 480gctcgcttcc tgccactacc aggcctgccc cccgcactcc cggagccacc cggaatcctg 540gccccccagc cccccgatgt gggctcctcg gaccctctga gcatggtggg accttcccag 600ggccgaagcc ccagctacgc ttcc 6242181PRTHomo sapiens 2His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val 1 5 10 15 Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His 20 25 30 Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser 35 40 45 Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln 50 55 60 Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly 65 70 75 80 Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg 85 90 95 Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His 100 105 110 Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro 115 120 125 Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro 130 135 140 Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val 145 150 155 160 Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser 165 170 175 Pro Ser Tyr Ala Ser 180 331PRTHomo sapiens 3His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 439PRTHeloderma suspectumMOD_RES(39)..(39)Xaa at position 39 is amidated 4His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Xaa 35 5230PRTHomo sapiens 5Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu 1 5 10 15 Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 20 25 30 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 35 40 45 Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 50 55 60 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 65 70 75 80 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 85 90 95 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 100 105 110 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 115 120 125 Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 130 135 140 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 145 150 155 160 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 165 170 175 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 180 185 190 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys 195 200 205 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 210 215 220 Ser Leu Ser Leu Gly Lys 225 230 615PRTArtificial SequenceSynthetic Construct 6Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 722PRTArtificial SequenceSynthetic Construct 7Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1 5 10 15 Ser Gly Gly Gly Gly Ser 20 830PRTArtificial SequenceSynthetic Construct 8Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 20 25 30 9181PRTArtificial SequenceSynthetic Construct 9His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val 1 5 10 15 Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His 20 25 30 Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser 35 40 45 Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln 50 55 60 Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly 65 70 75 80 Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Cys Ala Cys Ser Phe Arg 85 90 95 Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His 100 105 110 Gly Leu Pro Leu His Cys Pro Gly Asn Lys Ser Pro His Arg Asp Pro 115 120 125 Ala Pro Arg Gly Pro Cys Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro 130 135 140 Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val 145 150 155 160 Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser 165 170 175 Pro Ser Tyr Ala Ser 180 10181PRTArtificial SequenceSynthetic Construct 10His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val 1 5 10 15 Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His 20 25 30 Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser 35 40 45 Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln 50 55 60 Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly 65 70 75 80 Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Cys Ala Cys Ser Phe Arg 85 90 95 Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His 100 105 110 Gly Leu Pro Leu His Cys Pro Gly Asn Lys Ser Pro His Arg Asp Pro 115 120 125 Ala Pro Arg Gly Pro Cys Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro 130 135 140 Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val 145 150 155 160 Gly Ser Ser Asp Pro Leu Ala Met Val Gly Pro Ser Gln Gly Arg Ser 165 170 175 Pro Ser Tyr Ala Ser 180 11181PRTArtificial SequenceSynthetic Construct 11His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val 1 5 10 15 Arg Gln Arg Tyr Cys Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His 20 25 30 Cys Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser 35 40 45 Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln 50 55 60 Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly 65 70 75 80 Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg 85 90 95 Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His 100 105 110 Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro 115 120 125 Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro 130 135 140 Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val 145 150 155 160 Gly Ser Ser Asp Pro Leu Ala Met Val Gly Pro Ser Gln Gly Arg Ser 165 170 175 Pro Ser Tyr Ala Ser 180 12181PRTArtificial SequenceSynthetic Construct 12His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val 1 5 10 15 Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Cys Gln Gln Thr Glu Ala His 20 25 30 Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser 35 40 45 Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln 50 55 60 Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly 65 70 75 80 Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg 85 90 95 Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His 100 105 110 Gly Leu Pro Leu His Leu Pro Gly Asn Cys Ser Pro His Arg Asp Pro 115 120 125 Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro 130 135 140 Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val 145 150 155 160 Gly Ser Ser Asp Pro Leu Ala Met Val Gly Pro Ser Gln Gly Arg Ser 165 170 175 Pro Ser Tyr Ala Ser 180 13181PRTArtificial SequenceSynthetic Construct 13His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val 1 5 10 15 Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His 20 25 30 Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser 35 40 45 Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln 50 55 60 Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly 65 70 75 80 Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg 85 90 95 Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His 100 105 110 Gly Leu Pro Leu His Cys Pro Gly Ala Lys Ser Pro His Arg Asp Pro 115 120 125 Ala Pro Arg Gly Pro Cys Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro 130 135 140 Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val 145 150 155 160 Gly Ser Ser Asp Pro Leu Ala Met Val Gly Pro Ser Gln Gly Arg Ser 165 170 175 Pro Ser Tyr Ala Ser 180 1439PRTArtificial SequenceSynthetic Construct 14His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Xaa 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Xaa Xaa Gly Xaa Xaa Xaa 20 25 30 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 1531PRTArtificial SequenceSynthetic Construct 15His Val Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 1631PRTArtificial SequenceSynthetic Construct 16His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Arg Gly Arg Gly 20 25 30 1731PRTArtificial SequenceSynthetic Construct 17His Val Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 1831PRTArtificial SequenceSynthetic Construct 18His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Xaa Glu Phe Ile Ala Trp Leu Val Arg Gly Arg Gly 20 25 30 1939PRTArtificial SequenceSynthetic Construct 19His Val Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Ile Lys Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 2040PRTArtificial SequenceSynthetic Construct 20His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Xaa 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Xaa Lys Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Cys Xaa 35 40 2140PRTArtificial SequenceSynthetic Construct 21His Val Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Ile Lys Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Cys Xaa 35 40 2231PRTArtificial SequenceSynthetic Construct 22His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Xaa Xaa Gly Gly Xaa 20 25 30 23230PRTArtificial SequenceSynthetic Construct 23Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Xaa 1 5 10 15 Xaa Xaa Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 20 25 30 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 35 40 45 Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 50 55 60 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Xaa 65 70 75 80 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 85 90 95 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 100 105 110 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 115 120 125 Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 130 135 140 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 145 150 155 160 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 165 170 175 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 180 185 190 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys 195 200 205 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 210 215 220 Ser Leu Ser Leu Gly Xaa 225 230 24276PRTArtificial SequenceSynthetic Construct 24His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu 35 40 45 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 50 55 60 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

Lys Asp Thr Leu 65 70 75 80 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 85 90 95 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 100 105 110 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 115 120 125 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 130 135 140 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 145 150 155 160 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 165 170 175 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 180 185 190 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 195 200 205 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 210 215 220 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 225 230 235 240 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 245 250 255 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 260 265 270 Ser Leu Gly Lys 275 25276PRTArtificial SequenceSynthetic Construct 25His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu 35 40 45 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 50 55 60 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 65 70 75 80 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 85 90 95 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 100 105 110 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 115 120 125 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 130 135 140 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 145 150 155 160 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 165 170 175 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 180 185 190 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 195 200 205 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 210 215 220 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 225 230 235 240 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 245 250 255 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 260 265 270 Ser Leu Gly Lys 275 26276PRTArtificial SequenceSynthetic Construct 26His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu 35 40 45 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 50 55 60 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 65 70 75 80 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 85 90 95 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 100 105 110 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr 115 120 125 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 130 135 140 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 145 150 155 160 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 165 170 175 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 180 185 190 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 195 200 205 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 210 215 220 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 225 230 235 240 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 245 250 255 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 260 265 270 Ser Leu Gly Lys 275 27276PRTArtificial SequenceSynthetic Construct 27His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu 35 40 45 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 50 55 60 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 65 70 75 80 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 85 90 95 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 100 105 110 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr 115 120 125 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 130 135 140 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 145 150 155 160 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 165 170 175 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 180 185 190 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 195 200 205 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 210 215 220 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 225 230 235 240 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 245 250 255 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 260 265 270 Ser Leu Gly Lys 275 28275PRTArtificial SequenceSynthetic Construct 28His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu 35 40 45 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 50 55 60 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 65 70 75 80 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 85 90 95 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 100 105 110 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 115 120 125 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 130 135 140 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 145 150 155 160 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 165 170 175 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 180 185 190 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 195 200 205 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 210 215 220 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 225 230 235 240 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 245 250 255 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 260 265 270 Ser Leu Gly 275 29275PRTArtificial SequenceSynthetic Construct 29His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu 35 40 45 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 50 55 60 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 65 70 75 80 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 85 90 95 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 100 105 110 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 115 120 125 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 130 135 140 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 145 150 155 160 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 165 170 175 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 180 185 190 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 195 200 205 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 210 215 220 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 225 230 235 240 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 245 250 255 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 260 265 270 Ser Leu Gly 275 30275PRTArtificial SequenceSynthetic Construct 30His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu 35 40 45 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 50 55 60 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 65 70 75 80 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 85 90 95 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 100 105 110 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr 115 120 125 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 130 135 140 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 145 150 155 160 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 165 170 175 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 180 185 190 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 195 200 205 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 210 215 220 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 225 230 235 240 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 245 250 255 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 260 265 270 Ser Leu Gly 275 31275PRTArtificial SequenceSynthetic Construct 31His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu 35 40 45 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 50 55 60 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 65 70 75 80 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 85 90 95 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 100 105 110 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr 115 120 125 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 130 135 140 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 145 150 155 160 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 165 170 175 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 180 185 190 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 195 200 205 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 210 215 220 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 225 230 235 240 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 245 250 255 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 260 265 270 Ser Leu Gly 275 32283PRTArtificial SequenceSynthetic Construct 32His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 35 40 45 Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 50 55 60 Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 65 70 75 80 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 85 90 95 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 100 105 110 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

Arg 115 120 125 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 130 135 140 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 145 150 155 160 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 165 170 175 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 180 185 190 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 195 200 205 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 210 215 220 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 225 230 235 240 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 245 250 255 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 260 265 270 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 275 280 33283PRTArtificial SequenceSynthetic Construct 33His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 35 40 45 Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 50 55 60 Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro 65 70 75 80 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 85 90 95 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 100 105 110 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 115 120 125 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 130 135 140 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 145 150 155 160 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 165 170 175 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 180 185 190 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 195 200 205 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 210 215 220 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 225 230 235 240 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 245 250 255 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 260 265 270 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 275 280 34283PRTArtificial SequenceSynthetic Construct 34His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 35 40 45 Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 50 55 60 Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 65 70 75 80 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 85 90 95 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 100 105 110 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 115 120 125 Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 130 135 140 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 145 150 155 160 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 165 170 175 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 180 185 190 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 195 200 205 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 210 215 220 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 225 230 235 240 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 245 250 255 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 260 265 270 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 275 280 35283PRTArtificial SequenceSynthetic Construct 35His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 35 40 45 Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 50 55 60 Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro 65 70 75 80 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 85 90 95 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 100 105 110 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 115 120 125 Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 130 135 140 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 145 150 155 160 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 165 170 175 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 180 185 190 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 195 200 205 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 210 215 220 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 225 230 235 240 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 245 250 255 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 260 265 270 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 275 280 36282PRTArtificial SequenceSynthetic Construct 36His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 35 40 45 Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 50 55 60 Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 65 70 75 80 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 85 90 95 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 100 105 110 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 115 120 125 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 130 135 140 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 145 150 155 160 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 165 170 175 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 180 185 190 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 195 200 205 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 210 215 220 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 225 230 235 240 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 245 250 255 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 260 265 270 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 275 280 37282PRTArtificial SequenceSynthetic Construct 37His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 35 40 45 Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 50 55 60 Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro 65 70 75 80 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 85 90 95 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 100 105 110 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 115 120 125 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 130 135 140 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 145 150 155 160 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 165 170 175 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 180 185 190 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 195 200 205 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 210 215 220 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 225 230 235 240 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 245 250 255 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 260 265 270 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 275 280 38282PRTArtificial SequenceSynthetic Construct 38His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 35 40 45 Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 50 55 60 Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 65 70 75 80 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 85 90 95 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 100 105 110 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 115 120 125 Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 130 135 140 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 145 150 155 160 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 165 170 175 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 180 185 190 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 195 200 205 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 210 215 220 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 225 230 235 240 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 245 250 255 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 260 265 270 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 275 280 39282PRTArtificial SequenceSynthetic Construct 39His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 35 40 45 Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 50 55 60 Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro 65 70 75 80 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 85 90 95 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 100 105 110 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 115 120 125 Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 130 135 140 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 145 150 155 160 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 165 170 175 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 180 185 190 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 195 200 205 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 210 215 220 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 225 230 235 240 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 245 250 255 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 260 265 270 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 275 280 40291PRTArtificial SequenceSynthetic Construct 40His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 35 40 45 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser 50 55 60 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly 65 70 75 80 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 85 90 95 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 100 105 110 Glu Asp

Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 115 120 125 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 130 135 140 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 145 150 155 160 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 165 170 175 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 180 185 190 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 195 200 205 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 210 215 220 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 225 230 235 240 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 245 250 255 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 260 265 270 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 275 280 285 Leu Gly Lys 290 41291PRTArtificial SequenceSynthetic Construct 41His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 35 40 45 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser 50 55 60 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 65 70 75 80 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 85 90 95 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 100 105 110 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 115 120 125 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 130 135 140 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 145 150 155 160 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 165 170 175 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 180 185 190 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 195 200 205 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 210 215 220 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 225 230 235 240 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 245 250 255 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 260 265 270 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 275 280 285 Leu Gly Lys 290 42291PRTArtificial SequenceSynthetic Construct 42His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 35 40 45 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser 50 55 60 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly 65 70 75 80 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 85 90 95 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 100 105 110 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 115 120 125 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr Tyr 130 135 140 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 145 150 155 160 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 165 170 175 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 180 185 190 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 195 200 205 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 210 215 220 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 225 230 235 240 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 245 250 255 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 260 265 270 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 275 280 285 Leu Gly Lys 290 43291PRTArtificial SequenceSynthetic Construct 43His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 35 40 45 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser 50 55 60 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 65 70 75 80 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 85 90 95 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 100 105 110 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 115 120 125 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr Tyr 130 135 140 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 145 150 155 160 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 165 170 175 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 180 185 190 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 195 200 205 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 210 215 220 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 225 230 235 240 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 245 250 255 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 260 265 270 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 275 280 285 Leu Gly Lys 290 44290PRTArtificial SequenceSynthetic Construct 44His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 35 40 45 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser 50 55 60 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly 65 70 75 80 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 85 90 95 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 100 105 110 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 115 120 125 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 130 135 140 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 145 150 155 160 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 165 170 175 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 180 185 190 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 195 200 205 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 210 215 220 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 225 230 235 240 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 245 250 255 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 260 265 270 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 275 280 285 Leu Gly 290 45290PRTArtificial SequenceSynthetic Construct 45His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 35 40 45 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser 50 55 60 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 65 70 75 80 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 85 90 95 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 100 105 110 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 115 120 125 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 130 135 140 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 145 150 155 160 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 165 170 175 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 180 185 190 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 195 200 205 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 210 215 220 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 225 230 235 240 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 245 250 255 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 260 265 270 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 275 280 285 Leu Gly 290 46290PRTArtificial SequenceSynthetic Construct 46His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 35 40 45 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser 50 55 60 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly 65 70 75 80 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 85 90 95 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 100 105 110 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 115 120 125 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr Tyr 130 135 140 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 145 150 155 160 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 165 170 175 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 180 185 190 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 195 200 205 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 210 215 220 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 225 230 235 240 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 245 250 255 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 260 265 270 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 275 280 285 Leu Gly 290 47290PRTArtificial SequenceSynthetic Construct 47His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 35 40 45 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser 50 55 60 Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 65 70 75 80 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 85 90 95 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 100 105 110 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 115 120 125 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr Tyr 130 135 140 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 145 150 155 160 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 165 170 175 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 180 185 190 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 195 200 205 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 210 215 220 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 225 230 235 240 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 245 250 255 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 260 265 270 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 275 280 285 Leu Gly 290 4831PRTArtificial SequenceSynthetic Construct 48His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Lys 20 25 30 49645PRTArtificial SequenceSynthetic Construct 49His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser

Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg His Gly 20 25 30 Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala 35 40 45 Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Asp Ala His Lys 50 55 60 Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys 65 70 75 80 Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe 85 90 95 Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr 100 105 110 Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr 115 120 125 Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr 130 135 140 Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu 145 150 155 160 Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val 165 170 175 Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu 180 185 190 Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr 195 200 205 Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala 210 215 220 Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro 225 230 235 240 Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln 245 250 255 Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys 260 265 270 Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe 275 280 285 Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu 290 295 300 Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu 305 310 315 320 Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys 325 330 335 Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu 340 345 350 Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp 355 360 365 Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp 370 375 380 Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp 385 390 395 400 Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr 405 410 415 Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys 420 425 430 Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile 435 440 445 Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln 450 455 460 Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr 465 470 475 480 Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys 485 490 495 Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr 500 505 510 Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro 515 520 525 Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg 530 535 540 Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys 545 550 555 560 Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu 565 570 575 Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu 580 585 590 Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met 595 600 605 Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys 610 615 620 Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln 625 630 635 640 Ala Ala Leu Gly Leu 645 5044PRTArtificial SequenceSynthetic Construct 50His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys 35 40 5150PRTArtificial SequenceSynthetic Construct 51Lys Lys Lys Lys Lys Lys His Gly Glu Gly Thr Phe Thr Ser Asp Leu 1 5 10 15 Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu 20 25 30 Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys 35 40 45 Lys Lys 50 5238PRTArtificial SequenceSynthetic Construct 52His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Trp Leu Lys Asn Gly Gly 20 25 30 Pro Ser Ser Gly Ala Ser 35 5342PRTArtificial SequenceSynthetic Construct 53Lys Lys Lys Lys Lys Lys His Gly Glu Gly Thr Phe Thr Ser Asp Leu 1 5 10 15 Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu 20 25 30 Lys Asn Gly Gly Pro Ser Ser Gly Ala Ser 35 40 5442PRTArtificial SequenceSynthetic Construct 54Asn Glu Glu Glu Glu Glu His Gly Glu Gly Thr Phe Thr Ser Asp Leu 1 5 10 15 Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu 20 25 30 Lys Asn Gly Gly Pro Ser Ser Gly Ala Ser 35 40 5542PRTArtificial SequenceSynthetic Construct 55His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Ser Lys Lys Lys Lys Lys Lys 35 40 5648PRTArtificial SequenceSynthetic Construct 56Lys Lys Lys Lys Lys Lys His Gly Glu Gly Thr Phe Thr Ser Asp Leu 1 5 10 15 Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu 20 25 30 Lys Asn Gly Gly Pro Ser Ser Gly Ala Ser Lys Lys Lys Lys Lys Lys 35 40 45 5748PRTArtificial SequenceSynthetic Construct 57Asp Glu Glu Glu Glu Glu His Gly Glu Gly Thr Phe Thr Ser Asp Leu 1 5 10 15 Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu 20 25 30 Lys Asn Gly Gly Pro Ser Ser Gly Ala Ser Lys Lys Lys Lys Lys Lys 35 40 45

Claims

1-15. (canceled)

16. A method of treating diabetes comprising administering an FGF-21 compound in combination with a GLP-1 compound, wherein the GLP-1 compound comprises an amino acid sequence of SEQ ID NO: 20: TABLE-US-00006 His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser 10 15 Tyr Leu Glu Xaa Gln Ala Ala Lys Glu Phe Ile Ala 20 25 30 Trp Leu Xaa Lys Gly Gly Pro Ser Ser Gly Ala Pro 35 40 Pro Pro Cys Xaa 45

wherein Xaa at position 8 is: D-Ala, Gly, Val, Leu, Ile, Ser, or Thr, Xaa at position 22 is: Gly, Glu, Asp, or Lys; Xaa at position 33 is: Val or Ile Xaa at position 46 is: Cys or Cys-NH₂ and wherein one PEG molecule is covalently attached to Cys⁴⁵ and one PEG molecule is covalently attached to Cys⁴⁶ or Cys⁴⁶-NH.sub.2.

17. A method of treating diabetes comprising administering an FGF-21 compound in combination with a GLP-1 compound, wherein the GLP-1 compound is a fusion protein comprising a GLP-1 analog fused via a linker to an FC portion of an immunoglobulin, wherein the GLP-1 analog comprises an amino acid sequence of SEQ ID NO:22: TABLE-US-00007 His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser 10 15 Tyr Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala 20 25 30 Trp Leu Xaa Xaa Gly Gly Xaa 35

wherein 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; the linker comprises an amino acid sequence of SEQ ID NO:6: Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser, and the Fc portion comprises an amino acid sequence of SEQ ID NO: 23: TABLE-US-00008 Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys 5 10 Pro Ala Pro Xaa Xaa Xaa Gly Gly Pro Ser Val Phe 15 20 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 25 30 35 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 40 45 Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp 50 55 60 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 65 70 Lys Pro Arg Glu Glu Gln Phe Xaa Ser Thr Tyr Arg 75 80 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 85 90 95 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 100 105 Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 110 115 120 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 125 130 Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 135 140 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 145 150 155 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 160 165 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 170 175 180 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 185 190 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn 195 200 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 205 210 215 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 220 225 Gly Xaa 230

wherein: Xaa at position 16 is Pro or Glu; Xaa at position 17 is Phe, Val, or Ala; Xaa at position 18 is Leu, Glu, or Ala; Xaa at position 80 is Asn or Ala; and Xaa at position 230 is Lys or is absent.

18. A method of lowering blood glucose levels comprising administering an FGF-21 compound in combination with a GLP-1 compound, wherein the GLP-1 compound comprises an amino acid sequence of SEQ ID NO: 20: TABLE-US-00009 His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser 10 15 Tyr Leu Glu Xaa Gln Ala Ala Lys Glu Phe Ile Ala 20 25 30 Trp Leu Xaa Lys Gly Gly Pro Ser Ser Gly Ala Pro 35 40 Pro Pro Cys Xaa 45

wherein Xaa at position 8 is: D-Ala, Gly, Val, Leu, Ile, Ser, or Thr, Xaa at position 22 is: Gly, Glu, Asp, or Lys; Xaa at position 33 is: Val or Ile Xaa at position 46 is: Cys or Cys-NH₂ and wherein one PEG molecule is covalently attached to Cys⁴⁵ and one PEG molecule is covalently attached to Cys⁴⁶ or Cys⁴⁶-NH.sub.2.

19. A method of lowering blood glucose levels comprising administering an FGF-21 compound in combination with a GLP-1 compound, wherein the GLP-1 compound is a fusion protein comprising a GLP-1 analog fused via a linker to an FC portion of an immunoglobulin, wherein the GLP-1 analog comprises an amino acid sequence of SEQ ID NO: 22: TABLE-US-00010 His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser 10 15 Tyr Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala 20 25 30 Trp Leu Xaa Xaa Gly Gly Xaa 35

wherein 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; the linker comprises an amino acid sequence of SEQ ID NO:6: Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser, and the Fc portion comprises an amino acid sequence of SEQ ID NO:23: TABLE-US-00011 Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys 5 10 Pro Ala Pro Xaa Xaa Xaa Gly Gly Pro Ser Val Phe 15 20 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 25 30 35 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 40 45 Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp 50 55 60 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 65 70 Lys Pro Arg Glu Glu Gln Phe Xaa Ser Thr Tyr Arg 75 80 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 85 90 95 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 100 105 Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 110 115 120 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 125 130 Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 135 140 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 145 150 155 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 160 165 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 170 175 180 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 185 190 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn 195 200 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 205 210 215 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 220 225 Gly Xaa 230

wherein: Xaa at position 16 is Pro or Glu; Xaa at position 17 is Phe, Val, or Ala; Xaa at position 18 is Leu, Glu, or Ala; Xaa at position 80 is Asn or Ala; and Xaa at position 230 is Lys or is absent.

20. The method according to claim 16, wherein the FGF21 compound comprises 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).

21. The method according to claim 17, wherein the FGF21 compound comprises 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).

22. The method according to claim 18, wherein the FGF21 compound comprises 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).

23. The method according to claim 19, wherein the FGF21 compound comprises 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).

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