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WO2018018010A1 - Mutants de fgf et leurs utilisations - Google Patents

Mutants de fgf et leurs utilisations Download PDF

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Publication number
WO2018018010A1
WO2018018010A1 PCT/US2017/043383 US2017043383W WO2018018010A1 WO 2018018010 A1 WO2018018010 A1 WO 2018018010A1 US 2017043383 W US2017043383 W US 2017043383W WO 2018018010 A1 WO2018018010 A1 WO 2018018010A1
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Prior art keywords
modification
polypeptide
amino acid
fgf
isolated
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Inventor
Mack Flinspach
Ross FELLOWS
Andrew PIEKARZ
Matt LUNDBERG
James MARION
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Metacrine Inc
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Metacrine Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/50—Fibroblast growth factor [FGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Metabolic diseases or conditions such as diabetes and obesity are growing health problems worldwide. In some instances, it is estimated that more than 250 million adults worldwide have diabetes and the figure is projected to increase to 380 million by 2025.
  • FGF mutants include FGF mutants and their use in the treatment of one or more metabolic diseases or conditions.
  • the FGF mutant is an FGF1 mutant.
  • an FGF1 mutant is used for the treatment of one or more metabolic diseases or conditions.
  • an isolated and purified FGF polypeptide comprising at least 80% sequence identity to SEQ ID NOs: 3-25917 and 25922-25974.
  • the FGF polypeptide comprises at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NOs: 3-25917 and 25922-25974.
  • the FGF polypeptide consists of SEQ ID NOs: 3-25917 and 25922-25974.
  • the FGF polypeptide comprises at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NOs: 130, 131, 132, 133, 134, 135, 139, 141, 142, 143, 144, 146, 147, 148, 149, 150, 151, 152, 153, 156, 157, 158, 159, 163, 165, 168, 170, 171, 174, 177, 284, 286, 290, 401, 484, 488, or 518.
  • the FGF polypeptide further comprises a modification at amino acid residue T30, T34, A48, E53, K57, Q63, T78, P79, L84, L89, T96, K128, or a combination thereof, wherein the numbering of the amino acid residue corresponds to SEQ ID NO: 2.
  • the FGF polypeptide further comprises a modification at amino acid residue T30, T34, A48, E53, K57, Q63, T78, P79, L89, T96, K128, or a combination thereof, wherein the numbering of the amino acid residue corresponds to SEQ ID NO: 2.
  • the FGF polypeptide further comprises a modification at amino acid residue L84, wherein the numbering of the amino acid residue corresponds to SEQ ID NO: 2.
  • the modification comprises a mutation to a non-polar residue or a charged residue.
  • the modification comprises a mutation to alanine.
  • the isolated and purified FGF polypeptide comprises a modification of T30A, T34A, A48G, E53A, K57A, K57E, Q63A, T78A, P79A, L84A, L89A, T96A, K128E, or a combination thereof.
  • the isolated and purified FGF polypeptide has enhanced stability relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has enhanced thermostability relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has enhanced pH stability relative to a wild- type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has reduced or impaired mitogenic activity relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has enhanced FGF receptor interaction relative to a wild-type FGF polypeptide.
  • the isolated and purified FGF polypeptide has increased in vivo half-life relative to a wild-type FGF polypeptide when administered to a subject in need thereof. In some embodiments, the isolated and purified FGF polypeptide has increased resistance to proteolysis relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide is an FGF1 mutant.
  • the FGF polypeptide comprises a modification at amino acid residue L84, wherein the numbering of the amino acid residue corresponds to SEQ ID NO: 2.
  • the isolated and purified FGF polypeptide further comprises a modification at amino acid residue H41, 142, or Q43, wherein the numbering of the amino acid residue corresponds to SEQ ID NO: 2.
  • the isolated and purified FGF polypeptide further comprises a modification at amino acid residue K10, Y15, S17, N18, H21, L26, P27, D28, R35, D36, R37, S38, D39, Q40, Q43, S47, Y55, E60, T61, Y64, D68, E81, E87, R88, E90, E91, N92, Y94, N95, K100, K101, H102, K105, Kl 13, S I 16, CI 17, Kl 18, P121, R122, H124, Q127, or L133, wherein the numbering of the amino acid residue corresponds to SEQ ID NO: 2.
  • the isolated and purified FGF polypeptide has enhanced pH stability relative to a wild- type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has reduced or impaired mitogenic activity relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has enhanced FGF receptor interaction relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has increased in vivo half-life relative to a wild-type FGF polypeptide when administered to a subject in need thereof. In some embodiments, the isolated and purified FGF polypeptide has increased resistance to proteolysis relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide is an FGF1 mutant.
  • an isolated and purified FGF polypeptide comprising: one or more modified amino acids selected from Group 1 amino acid residues: P27, R35, D36, R37, Y55, K57, T61, E81, E87, R88, N92, T96, K101, H102, and L133; and one or more modified amino acids selected from Group 2 amino acid residues: L26, T30, D39, Q43, Y64, D68, Q77, N80, E82, L84, L86, K105, G120, Q127, and K128; wherein the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • an isolated and purified FGF polypeptide comprising two or more modifications, the polypeptide comprising: a first modification at an amino acid residue selected from: Y15, R35, R37, K57, R88, N92, T96, R122, and L133; and a second modification at an amino acid residue selected from: Fl, N2, P5, G6, N7, K9, K10, S 17, R35, R37, S38, Q40, Q43, Q45, S47, A48, E49, S50, V51, E53, K57, S58, T59, D70, L72, S76, Q77, T78, P79, N80, E81, E82, E90, E91, N92, H93, T96, 198, K101, E104, Kl 12, SI 16, Rl 19, H124, Y125, P136, V137, S138, S139, and D140; wherein the numbering of the amino acid residues corresponds to S
  • the first modification is at R88, and the second modification is at an amino acid residue selected from the group consisting of E91 and T96.
  • the first modification is at K57, and the second modification is at an amino acid residue selected from the group consisting of: K10, A48, E90, and E91.
  • the first modification is at K57, and the second modification is at an amino acid residue selected from the group consisting of: K10, A48, and E90.
  • the first modification is at T96, and the second modification is at Q43. In some embodiments, the first modification is at Y 15, and the second modification is at Q43.
  • the first modification is at R122
  • the second modification is at an amino acid residue selected from the group consisting of: R35, R37, and K57.
  • the FGF polypeptide further comprises a truncation.
  • the truncation is an N-terminal truncation.
  • the N-terminal truncation is a deletion of amino acid residues 1-9.
  • the modification comprises a mutation to a non- polar residue or a charged residue.
  • the modification comprises a mutation to alanine.
  • K57 is mutated to an amino acid selected from the group consisting of: alanine (A), asparagine (N), glutamic acid (E), and histidine (H).
  • R88 is mutated to leucine (L).
  • N92 is mutated to an amino acid selected from the group consisting of: alanine (A) and threonine (T).
  • T96 is mutated to alanine (A).
  • the FGF polypeptide is an FGFl polypeptide.
  • the isolated and purified FGF polypeptide has enhanced thermostability relative to a wild-type FGF polypeptide.
  • the isolated and purified FGF polypeptide has enhanced pH stability relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has reduced or impaired mitogenic activity relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has enhanced FGF receptor interaction relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has increased in vivo half-life relative to a wild-type FGF polypeptide when administered to a subject in need thereof. In some embodiments, the isolated and purified FGF polypeptide has increased resistance to proteolysis relative to a wild-type FGF polypeptide.
  • the modification comprises a mutation to a non-polar residue or a charged residue. In some embodiments, the modification comprises a mutation to alanine.
  • the FGF polypeptide is an FGFl polypeptide. In some embodiments, the isolated and purified FGF polypeptide has enhanced thermostability relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has enhanced pH stability relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has reduced or impaired mitogenic activity relative to a wild-type FGF polypeptide.
  • the isolated and purified FGF polypeptide has enhanced FGF receptor interaction relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has increased in vivo half-life relative to a wild-type FGF polypeptide when administered to a subject in need thereof. In some embodiments, the isolated and purified FGF polypeptide has increased resistance to proteolysis relative to a wild-type FGF polypeptide.
  • an isolated and purified FGF polypeptide comprising at least 80% sequence identity to a sequence selected from SEQ ID NOs: 3-25917 and 25922-25974.
  • the FGF polypeptide comprises at least 85%, 90%, 95%, 96%), 97%), 98%o, 99%o, or more sequence identity to a sequence selected from SEQ ID NOs: 3- 25917 and 25922-25974.
  • the FGF polypeptide consists of a sequence selected from SEQ ID NOs: 3-25917 and 25922-25974.
  • the FGF polypeptide is an FGFl polypeptide.
  • the isolated and purified FGF polypeptide has enhanced thermostability relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has enhanced pH stability relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has reduced or impaired mitogenic activity relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has enhanced FGF receptor interaction relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has increased in vivo half-life relative to a wild-type FGF polypeptide when administered to a subject in need thereof. In some embodiments, the isolated and purified FGF polypeptide has increased resistance to proteolysis relative to a wild-type FGF polypeptide.
  • an isolated and purified FGF polypeptide having an FGFR interaction activity that is equivalent to the FGFR interaction activity of FGF 1 polypeptide of SEQ ID NO: 2; and a mitogenicity that is at least 1-fold lower than the mitogenicity of the FGFl polypeptide of SEQ ID NO: 2.
  • the FGFR interaction activity of the isolated and purified FGF polypeptide is about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% to the FGFR interaction activity of FGF 1 polypeptide of SEQ ID NO: 2.
  • the mitogenicity is at least 2-fold lower, 3 -fold lower, 4-fold lower, 5 -fold lower, 6-fold lower, 7-fold lower, 8-fold lower, 9-fold lower, or 10-fold lower than the mitogenicity of the FGF1 polypeptide of SEQ ID NO: 2.
  • the isolated and purified FGF polypeptide is an isolated and purified FGF polypeptide described supra.
  • the FGF polypeptide is an FGF1 polypeptide.
  • the isolated and purified FGF polypeptide has enhanced thermostability relative to a wild-type FGF polypeptide.
  • the isolated and purified FGF polypeptide has enhanced pH stability relative to a wild-type FGF polypeptide.
  • the isolated and purified FGF polypeptide has reduced or impaired mitogenic activity relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has enhanced FGF receptor interaction relative to a wild-type FGF polypeptide. In some embodiments, the isolated and purified FGF polypeptide has increased in vivo half-life relative to a wild-type FGF polypeptide when administered to a subject in need thereof. In some embodiments, the isolated and purified FGF polypeptide has increased resistance to proteolysis relative to a wild-type FGF polypeptide.
  • the at least one additional FGF polypeptide comprises at least one modification, a truncation, or a combination thereof.
  • the truncation is an N-terminal truncation, a C-terminal truncation, or a combination thereof.
  • the pharmaceutical composition is formulated for oral or parenteral administration.
  • a method of treating a metabolic disease or condition in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an isolated and purified FGF polypeptide described above.
  • the metabolic disease or condition comprises FGF 1 -related disease or condition.
  • the metabolic disease or condition comprises diabetes, polycystic ovary syndrome (PCOS), metabolic syndrome (MetS), obesity, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), dyslipidemia, a cardiovascular disease, Hurler syndrome, Huntington's disease, Alzheimer's disease, Parkinson's disease, Crohn's disease, Fabry disease, or galactosemia.
  • the metabolic disease or condition comprises impaired insulin sensitivity or glucose intolerance.
  • the subject has diabetes.
  • the diabetes comprises type 1 diabetes, type 2 diabetes, type 3 diabetes, type 4 diabetes, double diabetes, latent autoimmune diabetes (LAD), gestational diabetes, neonatal diabetes mellitus (NDM), maturity onset diabetes of the young
  • the subject has type 1 diabetes. In some embodiments, the subject has type 2 diabetes. In some embodiments, the subject has type 4 diabetes. In some embodiments, the subject has prediabetes. In some embodiments, the subject has polycystic ovary syndrome. In some embodiments, the subject has metabolic syndrome. In some embodiments, the subject has obesity. In some embodiments, the subject has non-alcoholic fatty liver disease. In some embodiments, the subject has insulin resistance. In some embodiments, the subject has lipodystrophy. In some embodiments, the subject has a cardiovascular disease.
  • the cardiovascular disease comprises hypertension, coronary artery diseases (CAD), stroke, rheumatic heart disease, hypertensive heart disease, cardiomyopathy, heart arrhythmia, congenital heart disease, carditis, aortic aneurysms, renal artery stenosis, peripheral artery disease, venous thrombosis, heart valve disease, deep vein thrombosis, cerebrovascular disease, cardiac dysrhythmia, chronic obstructive pulmonary disease, or inflammatory heart disease.
  • the subject has hypertension.
  • the method further comprises administration of an additional therapeutic agent.
  • the additional therapeutic agent comprises thiazolidinedione.
  • thiazolidinedione comprises pioglitazone, rosiglitazone, lobeglitazone, and troglitazone.
  • the FGF polypeptide and the additional therapeutic agent are administered
  • kits comprising an isolated and purified FGF polypeptide described above.
  • kits comprising a polynucleic acid molecule encoding an FGF polypeptide described above.
  • Fig. lA-Fig. IB illustrate the location of the FGF1 Group 1 residues with respect to a FGFl-FGFRlc complex (PDB: 30JV.pdb) in a first orientation.
  • Fig. 1A shows the FGFl-FGFRlc complex and
  • Fig. IB shows a close-up of the positions of the Group 1A, Group IB, and Group 1C residues on FGF1.
  • Fig. 2A-Fig. 2B illustrate the location of the FGF1 Group 1 residues with respect to a FGFl-FGFRlc complex (PDB: 30JV.pdb) in a second orientation.
  • Fig. 2A shows the FGFl-FGFRlc complex and
  • Fig. 2B shows a close-up of the positions of the Group 1A, Group IB, and Group 1C residues on FGF1.
  • Fig. 3A-Fig. 3B illustrate the location of the FGF1 Group 1 and Group 2 residues with respect to a FGFl-FGFRlc complex (PDB: 30JV.pdb) in a first orientation.
  • Fig. 3A shows the FGFl-FGFRlc complex and
  • Fig. 3B shows a close-up of the positions of the Group 1 and Group 2 residues on FGF1.
  • Fig. 4A-Fig. 4B illustrate the location of the FGF1 Group 1 and Group 2 residues with respect to a FGFl-FGFRlc complex (PDB: 30JV.pdb) in a second orientation.
  • Fig. 4A shows the FGFl-FGFRlc complex and
  • Fig. 4B shows a close-up of the positions of the Group 1 and Group 2 residues on FGF1.
  • Fig. 6 illustrates the mitogenic activity of exemplary FGF1 polypeptides in zona glomerulosa.
  • Fig. 7 illustrates the mitogenic activity of exemplary FGF1 polypeptides in zona fasciculata/reticularis.
  • Fig. 9 illustrates the mitogenic activity of exemplary FGF1 polypeptides in hepatocytes.
  • Fig. 13A-Fig. 13C illustrate in-vivo mitogenicity and in-vivo efficacy of exemplary FGF1 polypeptides.
  • Fig. 13A shows the in-vivo mitogenicity of exemplary FGF1 polypeptides.
  • Fig. 13B and Fig. 13C show the in-vivo efficacy of exemplary FGF1 polypeptides.
  • Fibroblast growth factors are a family of growth factors that are involved in endocrine signaling pathways, wound healing, angiogenesis, and embryonic development. There are 22 structurally related members in the FGF family, which are further classified as intracrine, paracrine, and endocrine FGFs, based on their action mechanism. Paracrine and endocrine FGFs are extracellular signaling molecules that interact with fibroblast growth factor receptors (FGFRs).
  • FGFRs fibroblast growth factor receptors
  • FGF19/FGF15 FGF 15 is the mouse homolog of human FGF 19
  • FGF21 FGF23
  • Intracrine FGFs are FGFR-independent intracellular molecules that regulate the function of voltage gated sodium channels and the members include FGF11, FGF12, FGF13, and FGF14.
  • FGF1 interacts with all four FGFRs, fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), and fibroblast growth factor receptor 4 (FGFR4), and in particular, isoforms FGFRlb (FGFRlIIIb), FGFRlc (FGFRlIIIc), FGFR2b (FGFR2IIIb), FGFR2c (FGFR2IIIc), FGFR3b (FGFR3IIIb), FGFR3c (FGFR3IIIc), and FGFR4.
  • FGFRlb fibroblast growth factor receptor 1
  • FGFR2b fibroblast growth factor receptor 2
  • FGFR3 fibroblast growth factor receptor 3
  • FGFR4 fibroblast growth factor receptor 4
  • the full length FGF1 (GenBank Accession Nos: BC032697.1 and AAH32697.1) comprises a non-glycosylated 155 amino acid residue polypeptide (SEQ ID NO: 1).
  • the mature FGF1 comprises 140 amino acid residues in length (SEQ ID NO: 2), which is resulted from the truncation of the first 15 residues from the N-terminus of the full length FGF1.
  • FGF1 is expressed in metabolic tissues such as liver, kidney, muscle, and white adipose tissue (WAT).
  • WAT white adipose tissue
  • FGF1 is upregulated in WAT following a high-fat food intake.
  • Each cell of the white adipose tissue, or white fat comprises a single large droplet of fat with a nucleus encircling the droplet as a thin rim.
  • WAT is further grouped into visceral or gonadal WAT (gWAT) or inguinal white adipose tissue (iWAT).
  • gWAT visceral or gonadal WAT
  • iWAT inguinal white adipose tissue
  • FGF1 has been observed in the adipocyte fraction but not in the stromal vascular fraction (SVF) of gWAT and in the adipocyte fraction of iWAT.
  • SVF stromal vascular fraction
  • FGF1 knockout mice has been characterized by aberrant WAT expansion, impaired WAT vascularization, and rapid development of severe diabetes upon high-fat diet (HFD) challenge and defective WAT reduction upon HFD withdrawal (Jonker, et al, "A PPARy-FGFl axis is required for adaptive adipose remodeling and metabolic homeostasis," Nature 485(7398): 391-394 (2012)).
  • Fibroblast growth factor 2 also known as basic fibroblast growth factor, bFGF, FGF2, or FGF- ⁇
  • FGF2 is a 288 amino acid polypeptide that comprises about 5 different isoforms. The C-terminal portion of FGF2 shares about 48% sequence identity to FGF 1. Similar to FGF 1 , FGF2 is involved in cellular developmental processes such as proliferation, migration, differentiation, and survival. In some instances, FGF2 has been implicated in the pathogenesis of vascular dysfunction induced by hyperglycemia, such as vascular
  • the mitogenic activity of FGF 1 is potentiated by heparan sulfate or a heparan sulfate analogue, leading to cellular developments such as proliferation, migration, and differentiation.
  • the mitogenic activity of FGF 1 has also been linked to increased tumorigenicity. Indeed, studies have shown that FGF1 stimulate the cell growth of breast cancer, prostate cancer, and bladder cancer. See, e.g., Fernig, et al., "Differential regulation of FGF-1 and -2 mitogenic activity is related to their kinetics of binding to heparan sulfate in MDA-MB-231 human breast cancer cells," Biochemical and Biophysical Research Comm. 267(3): 770-776 (2000);
  • FGF mutants and methods of use in the treatment of a metabolic disease exhibit low mitogenicity. In some cases, the FGF mutants further exhibit near wild-type FGFR interaction. In additional cases, the FGF mutants further induces and/or enhances insulin sensitivity in a subject. In some instances, the FGF mutant is an FGF1 mutant. In some instances, described herein are FGF1 mutants and methods of use in the treatment of a metabolic disease. In some cases, the FGF1 mutants exhibit low mitogenicity and near wild-type FGFR interaction, and further optionally induces and/or enhances insulin sensitivity in a subject.
  • an isolated and purified FGF polypeptide such as an isolated and purified FGF polypeptide which comprises at least 80% sequence identity to SEQ ID NOs: 3-25917 and 25922- 25974; an isolated and purified FGF polypeptide comprising a modification at amino acid residue T30, T34, A48, E53, K57, Q63, T78, P79, L84, L89, T96, K128, or a combination thereof; or an isolated and purified FGF polypeptide that comprises a modification at amino acid residue K10, Y15, S 17, N18, H21, L26, P27, D28, R35, D36, R37, S38, D39, Q40, Q43, S47, Y55, E60, T61, Y64, D68, E81, E87, R88, E90, E91
  • FGF mutants and methods of use in the treatment of a metabolic disease.
  • the FGF mutant is an FGFl or FGF2 mutant.
  • the FGF mutant is an FGF 1 mutant.
  • the FGF mutant is an FGFl polypeptide that comprises 155 amino acid residues (or comprises the full length FGFl sequence; SEQ ID NO: 1). In some instances, the FGF mutant is an FGFl polypeptide that comprises 140 amino acid residues (or comprises the mature FGFl sequence; SEQ ID NO: 2). In some instances, the FGF mutant is a mature FGFl (140 amino acid residues) that further comprises a truncation at the N-terminus, the C-terminus, or truncations at both termini. In some instances, the truncation is a truncation of about 1 to about 30 amino acid residues.
  • the FGF mutant is an FGFl polypeptide that comprises about 14 modifications. In some instances, the FGF mutant is an FGFl polypeptide that comprises about 15 modifications. In some instances, the FGF mutant is an FGFl polypeptide that comprises about 16 modifications. In some instances, the FGF mutant is an FGFl polypeptide that comprises about 17 modifications. In some instances, the FGF mutant is an FGFl polypeptide that comprises about 18 modifications. In some instances, the FGF mutant is an FGFl polypeptide that comprises about 19 modifications. In some instances, the FGF mutant is an FGFl polypeptide that comprises about 20 modifications. In some cases, a modification comprises an insertion, a deletion, or a mutation.
  • the mutation is a missense mutation or a nonsense mutation.
  • the insertion comprises a duplication or one or more amino acid residues or a repeat expansion of one or more amino acid residues.
  • the FGF mutant is a truncated FGF 1 polypeptide that further comprises one or more modifications described herein.
  • the FGF mutant is a N- terminus truncated FGFl polypeptide that further comprises about 1 to about 20 modifications.
  • the FGF mutant is a C-terminus truncated FGFl polypeptide that further comprises about 1 to about 20 modifications.
  • dicyclohexyl ammonium salt L-cyclohexylglycine, L- phenylglycine, L-propargylglycine, L-norvaline, N-a-aminomethyl-L-alanine, D-a,y-diaminobutyric acid, L-a,y-diaminobutyric acid, ⁇ -cyclopropyl-L-alanine, ( ⁇ -(2,4-dinitrophenyl))-L-a ⁇ - diaminopropionic acid, ( ⁇ - ⁇ - 1 -(4,4-dimethyl-2,6-dioxocyclohex- 1 -ylidene)ethyl)-D-a ⁇ - diaminopropionic acid, ( ⁇ - ⁇ - 1 -(4,4-dimethyl-2,6-dioxocyclohex- 1 -ylidene)ethyl)-L-a ⁇ - diaminopropi
  • Exemplary amino acid analogs of aspartic and glutamic acids include, but are not limited to, a-methyl-D-aspartic acid, a-methyl-glutamic acid, a-methyl-L-aspartic acid, ⁇ -methylene-glutamic acid, (N-Y-ethyl)-L-glutamine, [N-a-(4-aminobenzoyl)]-L-glutamic acid, 2,6-diaminopimelic acid, L- a-aminosuberic acid, D-2-aminoadipic acid, D-a-aminosuberic acid, a-aminopimelic acid, iminodiacetic acid, L-2-aminoadipic acid, threo- -methyl-aspartic acid, ⁇ -carboxy-D-glutamic acid ⁇ , ⁇ -di-t-butyl ester, ⁇ -carboxy-L-glutamic acid ⁇ , ⁇ -di-t-
  • the modification comprises a mutation to a charged amino acid residue.
  • charged amino acids include lysine, arginine, histidine, aspartate, glutamate, or analog thereof.
  • a FGF mutant described herein comprises a mutation to a charged amino acid residue (e.g., a mutation to lysine, arginine, histidine, aspartate, glutamate, or analog thereof).
  • the FGF mutant is an FGFl polypeptide that comprises a modification at at least one amino acid position: 30, 34, 41, 42, 43, 48, 53, 57, 63, 78, 79, 84, 89, 96, or 128, according to the amino acid residue position of SEQ ID NO: 2.
  • the FGF mutant is an FGFl polypeptide that comprises a modification at at least one amino acid position: 30, 34, 48, 53, 57, 63, 78, 79, 84, 89, 96, or 128, according to the amino acid residue position of SEQ ID NO: 2.
  • the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 34, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 41, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 42, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 43, according to the amino acid residue position of SEQ ID NO: 2.
  • the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 48, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 53, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 57, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 63, according to the amino acid residue position of SEQ ID NO: 2.
  • the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 78, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 79, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 84, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 89, according to the amino acid residue position of SEQ ID NO: 2.
  • the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 96, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 128, according to the amino acid residue position of SEQ ID NO: 2.
  • the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 26, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 27, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 28, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid positions 35, according to the amino acid residue position of SEQ ID NO: 2.
  • the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 64, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 68, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 81, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 87, according to the amino acid residue position of SEQ ID NO: 2.
  • the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 93, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 94, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 95, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 100, according to the amino acid residue position of SEQ ID NO: 2.
  • the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 101, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 102, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 105, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 108, according to the amino acid residue position of SEQ ID NO: 2.
  • the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 133, according to the amino acid residue position of SEQ ID NO: 2. In some embodiments, the FGF mutant is an FGFl polypeptide that comprises a modification at amino acid position 134, according to the amino acid residue position of SEQ ID NO: 2.
  • an isolated and purified FGF polypeptide described herein comprises a modification at amino acid residue T30, T34, H41, 142, Q43, A48, E53, K57, Q63, T78, P79, L84, L89, T96, K128, or a combination thereof, according to the amino acid residue numbering of SEQ ID NO: 2.
  • an isolated and purified FGF polypeptide described herein comprises a modification at amino acid residue T30, T34, A48, E53, K57, Q63, T78, P79, L84, L89, T96, K128, or a combination thereof, according to the amino acid residue numbering of SEQ ID NO: 2.
  • the isolated and purified FGF polypeptide comprising a modification at amino acid residue T30, T34, H41, 142, Q43, A48, E53, K57, Q63, T78, P79, L84, L89, T96, K128, or a combination thereof further comprises at least one additional modification.
  • the at least one additional modification comprises an insertion, a deletion, or a mutation.
  • the mutation comprises a mutation to a polar residue, a non-polar residue, or a charged residue.
  • the isolated and purified FGF polypeptide further comprises a truncation.
  • the truncation is an N-terminal truncation, a C-terminal truncation, or a combination thereof.
  • the isolated and purified FGF polypeptide comprises a modification of T30A, T34A, A48G, E53A, K57A, K57E, Q63A, T78A, P79A, L84A, L89A, T96A, K128E, or a combination thereof.
  • the isolated and purified FGF polypeptide comprises T30A modification.
  • the isolated and purified FGF polypeptide comprises T34A modification.
  • the isolated and purified FGF polypeptide comprises A48G modification.
  • the isolated and purified FGF polypeptide comprises E53A modification.
  • the isolated and purified FGF polypeptide comprises K57A modification.
  • the mutation comprises a mutation to a polar residue, a non-polar residue, or a charged residue.
  • the isolated and purified FGF polypeptide further comprises a truncation.
  • the truncation is an N-terminal truncation, a C-terminal truncation, or a combination thereof.
  • the mutation comprises a mutation to a polar residue, a non- polar residue, or a charged residue.
  • the isolated and purified FGF polypeptide further comprises a truncation.
  • the truncation is an N-terminal truncation, a C- terminal truncation, or a combination thereof.
  • an isolated and purified FGF polypeptide described herein comprises a modification at amino acid residue Kl 18, according to the amino acid residue numbering of SEQ ID NO: 2.
  • the modification comprises a mutation to a polar residue.
  • the modification comprises a mutation to a non-polar residue.
  • a FGF polypeptide comprising one or more modified amino acids at Group 1 amino acid positions: 27, 35, 36, 37, 55, 57, 61, 81, 87, 88, 92, 96, 101, 102, and 133; and one or more modified amino acids at Group 2 amino acid positions: 26, 30, 39, 43, 64, 68, 77, 80, 82, 84, 86, 105, 120, 127, and 128, in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • the FGF polypeptide comprises one or more modified amino acids at Group 1C amino acid positions: 27, 55, 57, 61, 81, 101, and 102; and one or more modified amino acids at Group 2 amino acid positions: 26, 30, 39, 43, 64, 68, 77, 80, 82, 84, 86, 105, 120, 127, and 128, in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • the FGF polypeptide is an FGF1 polypeptide.
  • a FGF polypeptide described herein comprises one or more modified amino acids selected from Group 1 amino acid residues: P27, R35, D36, R37, Y55, K57, T61, E81, E87, R88, N92, T96, K101, H102, and L133; and one or more modified amino acids selected from Group 2 amino acid residues: L26, T30, D39, Q43, Y64, D68, Q77, N80, E82, L84, L86, K105, G120, Q127, and K128; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • the Group 1 modified amino acids are further divided into Group 1A amino acids: R35, D36, and R37; Group IB amino acids: E87, R88, N92, T96, and L133; and Group IC amino acids: P27, Y55, K57, T61, E81, K101, and H102.
  • the FGF polypeptide comprises one or more modified amino acids selected from Group 1A amino acid residues: R35, D36, and R37; and one or more modified amino acids selected from Group 2 amino acid residues: L26, T30, D39, Q43, Y64, D68, Q77, N80, E82, L84, L86, K105, G120, Q127, and K128; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • the FGF polypeptide comprises a Group 1 modified amino acid at T96 and one or more modified amino acids selected from Group 2 amino acid residues: L26, T30, D39, Q43, Y64, D68, Q77, N80, E82, L84, L86, K105, G120, Q127, and K128; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • Group 1 modified amino acids are further divided into Group 1A amino acids: R35, D36, and R37; Group IB amino acids: E87, R88, N92, T96, and L133; and Group IC amino acids: P27, Y55, K57, T61, E81, K101, and HI 02.
  • the FGF polypeptide comprises a first modification at R35, and a second modification at S38; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2. In some cases, the FGF polypeptide comprises a first modification at R35, and a second modification at Q40; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2. In some cases, the FGF polypeptide comprises a first modification at R35, and a second modification at D 140; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2. In some cases, the FGF polypeptide comprises a first modification at R35, and a second modification at E81; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • R122 is mutated to an amino acid selected from: : aspartic acid (D), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), glutamine (Q), serine (S), valine (V), and tyrosine (Y).
  • R122 is mutated to an amino acid selected from: alanine (A), glutamic acid (E), histidine (H), leucine (L), and phenylalanine (F).
  • R122 is mutated to glutamic acid (E).
  • the first modification is Y15.
  • the FGFl polypeptide comprises a first modification at Y15, and a second modification at an amino acid residue selected from: Fl, N2, P5, G6, N7, K9, K10, S17, R35, R37, S38, Q40, Q43, Q45, S47, A48, E49, S50, V51, E53, K57, S58, T59, D70, L72, S76, Q77, T78, P79, N80, E81, E82, E90, E91, N92, H93, T96, 198, K101, E104, Kl 12, S I 16, Rl 19, H124, Y125, P136, V137, S138, S139, D140; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • the FGFl polypeptide comprises a first modification at R35, and a second modification at an amino acid residue selected from: A48, E91, N92, H93, 198, K101, and V137; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • the FGFl polypeptide comprises a first modification at R35, and a second modification at an amino acid residue selected from: G6, K9, and S I 7; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • the FGFl polypeptide comprises a first modification at R35, and a second modification at E81; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • the FGFl polypeptide comprises a first modification at R35, and a second modification at R37; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • R35 is mutated to an amino acid selected from: alanine (A), glutamic acid (E), histidine (H), leucine (L), and phenylalanine (F).
  • R35 is mutated to alanine (A) or glutamic acid (E).
  • the first modification is K57.
  • the FGF1 polypeptide comprises a first modification at K57, and a second modification at an amino acid residue selected from: Fl, N2, P5, G6, N7, K9, K10, S17, R35, R37, S38, Q40, Q43, Q45, S47, A48, E49, S50, V51, E53, S58, T59, D70, L72, S76, Q77, T78, P79, N80, E81, E82, E90, E91, N92, H93, T96, 198, K101, E104, Kl 12, S I 16, Rl 19, H124, Y125, P136, V137, S 138, S 139, D140; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • alanine A
  • aspartic acid D
  • glutamic acid E
  • phenylalanine F
  • G G
  • histidine H
  • isoleucine I
  • lysine K
  • leucine L
  • methionine M
  • asparagine N
  • glutamine Q
  • S serine
  • V valine
  • Y tyrosine
  • R122 is mutated to an amino acid selected from: : aspartic acid (D), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), glutamine (Q), serine (S), valine (V), and tyrosine (Y).
  • R122 is mutated to an amino acid selected from: alanine (A), glutamic acid (E), histidine (H), leucine (L), and phenylalanine (F).
  • R122 is mutated to glutamic acid (E).
  • R122 is mutated to alanine (A). In some cases, R122 is mutated to aspartic acid (D). In some cases, R122 is mutated to phenylalanine (F). In some cases, R122 is mutated to glycine (G). In some cases, R122 is mutated to histidine (H). In some cases, R122 is mutated to isoleucine (I). In some cases, R122 is mutated to lysine (K). In some cases, R122 is mutated to leucine (L). In some cases, R122 is mutated to methionine (M). In some cases, R122 is mutated to asparagine (N).
  • the FGF polypeptide comprises a modification at amino acid position 72. In some cases, the FGF polypeptide comprises a modification at amino acid position 76. In some cases, the FGF polypeptide comprises a modification at amino acid position 77. In some cases, the FGF polypeptide comprises a modification at amino acid position 78. In some cases, the FGF polypeptide comprises a modification at amino acid position 79. In some cases, the FGF polypeptide comprises a modification at amino acid position 96. In some cases, the FGF polypeptide comprises a modification at amino acid position 98. In some cases, the modification comprises a mutation to a non-polar residue or a charged residue. In some cases, the modification comprises a mutation to alanine.
  • the modification comprises a mutation to a non-polar residue or a charged residue. In some cases, the modification comprises a mutation to alanine. In some cases, the FGF polypeptide further comprises a truncation. In some cases, the truncation is an N- terminal truncation, a C-terminal truncation, or a combination thereof. In some cases, the truncation is an N-terminal truncation. In some cases, the N-terminal truncation comprises a deletion of amino acid residues 1-9.
  • the FGF polypeptide comprises a first modification at R35 and a second modification at E53. In some instances, the FGF polypeptide comprises a first modification at R35 and a second modification at Y55. In some instances, the FGF polypeptide comprises a first modification at R35 and a second modification at K57. In some instances, the FGF polypeptide comprises a first modification at R35 and a second modification at E60. In some instances, the FGF polypeptide comprises a first modification at R35 and a second modification at T61. In some instances, the FGF polypeptide comprises a first modification at R35 and a second modification at Q63. In some instances, the FGF polypeptide comprises a first modification at R35 and a second modification at D68.
  • the FGFl polypeptide comprises a first modification at R35 and a second modification at H102. In some instances, the FGFl polypeptide comprises a first modification at R35 and a second modification at K 105. In some instances, the FGFl polypeptide comprises a first modification at R35 and a second modification at N 106. In some instances, the FGFl polypeptide comprises a first modification at R35 and a second modification at F 108. In some instances, the FGFl polypeptide comprises a first modification at R35 and a second modification at Kl 12. In some instances, the FGFl polypeptide comprises a first modification at R35 and a second modification at Kl 13.
  • a FGF polypeptide comprising a first modification at amino acid position 133 and a second modification at an amino acid position selected from: 34, 37, 43, 84, 88, 95, and 118; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • the modification comprises a mutation to a non-polar residue or a charged residue.
  • the modification comprises a mutation to alanine.
  • the FGF polypeptide further comprises a truncation.
  • the truncation is an N-terminal truncation, a C-terminal truncation, or a combination thereof.
  • the truncation is an N- terminal truncation.
  • the N-terminal truncation comprises a deletion of amino acid residues 1-9.
  • the FGF polypeptide comprises a first modification at K10 and a second modification at SI 16. In some instances, the FGF polypeptide comprises a first modification at K10 and a second modification at Kl 18. In some cases, the modification comprises a mutation to a non- polar residue or a charged residue. In some cases, the modification comprises a mutation to alanine. In some cases, the FGF polypeptide further comprises a truncation. In some cases, the truncation is an N- terminal truncation, a C-terminal truncation, or a combination thereof. In some cases, the truncation is an N-terminal truncation. In some cases, the N-terminal truncation comprises a deletion of amino acid residues 1-9.
  • the truncation is an N-terminal truncation. In some cases, the N-terminal truncation comprises a deletion of amino acid residues 1-9.
  • described herein is a FGF polypeptide comprising a first modification at S I 16 and a second modification at an amino acid residue selected from: Y15, D28, R35, D36, L84, E87, R88, Y94, N95, K101, and Kl 18; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • the FGF polypeptide comprises a first modification at S I 16 and a second modification at Y 15.
  • the truncation is an N-terminal truncation, a C-terminal truncation, or a combination thereof. In some cases, the truncation is an N- terminal truncation. In some cases, the N-terminal truncation comprises a deletion of amino acid residues 1-9.
  • the FGF polypeptide comprises a first modification at R122 and a second modification at D36. In some instances, the FGF polypeptide comprises a first modification at R122 and a second modification at L84. In some instances, the FGF polypeptide comprises a first modification at R122 and a second modification at E87. In some instances, the FGF polypeptide comprises a first modification at R122 and a second modification at R88. In some instances, the FGF polypeptide comprises a first modification at R122 and a second modification at Y94. In some instances, the FGF polypeptide comprises a first modification at R122 and a second modification at N95. In some instances, the FGF polypeptide comprises a first modification at R122 and a second modification at K101.
  • the FGF polypeptide comprises a first modification at R122 and a second modification at Kl 18.
  • the modification comprises a mutation to a non-polar residue or a charged residue.
  • the modification comprises a mutation to alanine.
  • the FGF polypeptide further comprises a truncation.
  • the truncation is an N-terminal truncation, a C-terminal truncation, or a combination thereof.
  • the truncation is an N- terminal truncation.
  • the N-terminal truncation comprises a deletion of amino acid residues 1-9.
  • the FGFl polypeptide comprises a first modification at R122 and a second modification at R35. In some instances, the FGFl polypeptide comprises a first modification at R122 and a second modification at D36. In some instances, the FGFl polypeptide comprises a first modification at R122 and a second modification at L84. In some instances, the FGFl polypeptide comprises a first modification at R122 and a second modification at E87. In some instances, the FGFl polypeptide comprises a first modification at R122 and a second modification at R88. In some instances, the FGFl polypeptide comprises a first modification at R122 and a second modification at Y94.
  • the FGF polypeptide comprises a first modification at H124 and a second modification at D36. In some instances, the FGF polypeptide comprises a first modification at H124 and a second modification at L84. In some instances, the FGF polypeptide comprises a first modification at H124 and a second modification at E87. In some instances, the FGF polypeptide comprises a first modification at HI 24 and a second modification at R88. In some instances, the FGF polypeptide comprises a first modification at H124 and a second modification at Y94. In some instances, the FGF polypeptide comprises a first modification at H124 and a second modification at N95. In some instances, the FGF polypeptide comprises a first modification at H124 and a second modification at K101.
  • the FGF polypeptide comprises a first modification at Y64 and a second modification at D36. In some instances, the FGF polypeptide comprises a first modification at Y64 and a second modification at L84. In some instances, the FGF polypeptide comprises a first modification at Y64 and a second modification at E87. In some instances, the FGF polypeptide comprises a first modification at Y64 and a second modification at R88. In some instances, the FGF polypeptide comprises a first modification at Y64 and a second modification at Y94. In some instances, the FGF polypeptide comprises a first modification at Y64 and a second modification at N95.
  • a FGF polypeptide comprising a first modification at amino acid position 53 and a second modification at an amino acid position selected from: 15, 28, 35, 36, 84, 87, 88, 94, 95, 101, 116, and 118; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • the modification comprises a mutation to a non-polar residue or a charged residue.
  • the modification comprises a mutation to alanine.
  • the FGF polypeptide further comprises a truncation.
  • the truncation is an N-terminal truncation, a C-terminal truncation, or a combination thereof.
  • the truncation is an N-terminal truncation.
  • the N-terminal truncation comprises a deletion of amino acid residues 1-9.
  • the FGF polypeptide comprises a first modification at E53 and a second modification at Kl 18.
  • the modification comprises a mutation to a non-polar residue or a charged residue.
  • the modification comprises a mutation to alanine.
  • the FGF polypeptide further comprises a truncation.
  • the truncation is an N-terminal truncation, a C-terminal truncation, or a combination thereof.
  • the truncation is an N- terminal truncation.
  • the N-terminal truncation comprises a deletion of amino acid residues 1-9.
  • a FGF polypeptide comprising a first modification at amino acid position 47 and a second modification at an amino acid position selected from: 15, 28, 35, 36, 84, 87, 88, 94, 95, 101, 116, and 118; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • the modification comprises a mutation to a non-polar residue or a charged residue.
  • the modification comprises a mutation to alanine.
  • the FGF polypeptide further comprises a truncation.
  • the truncation is an N-terminal truncation, a C-terminal truncation, or a combination thereof.
  • the truncation is an N-terminal truncation.
  • the N-terminal truncation comprises a deletion of amino acid residues 1-9.
  • the FGF polypeptide comprises a first modification at S47 and a second modification at Kl 18.
  • the modification comprises a mutation to a non-polar residue or a charged residue.
  • the modification comprises a mutation to alanine.
  • the FGF polypeptide further comprises a truncation.
  • the truncation is an N-terminal truncation, a C-terminal truncation, or a combination thereof.
  • the truncation is an N-terminal truncation.
  • the N-terminal truncation comprises a deletion of amino acid residues 1-9.
  • the FGF1 polypeptide comprises a first modification at S47 and a second modification at R35. In some instances, the FGF1 polypeptide comprises a first modification at S47 and a second modification at D36. In some instances, the FGF1 polypeptide comprises a first modification at S47 and a second modification at L84. In some instances, the FGF1 polypeptide comprises a first modification at S47 and a second modification at E87. In some instances, the FGF1 polypeptide comprises a first modification at S47 and a second modification at R88. In some instances, the FGF 1 polypeptide comprises a first modification at S47 and a second modification at Y94.
  • the FGF1 polypeptide comprises a first modification at Q40 and a second modification at N95. In some instances, the FGF1 polypeptide comprises a first modification at Q40 and a second modification at K101. In some instances, the FGF1 polypeptide comprises a first modification at Q40 and a second modification at Kl 18. In some cases, the modification comprises a mutation to a non-polar residue or a charged residue. In some cases, the modification comprises a mutation to alanine. In some cases, the FGF1 polypeptide further comprises a truncation. In some cases, the truncation is an N-terminal truncation, a C-terminal truncation, or a combination thereof. In some cases, the truncation is an N-terminal truncation. In some cases, the N-terminal truncation comprises a deletion of amino acid residues 1-9.
  • a FGF polypeptide comprising a first modification at S 17 and a second modification at an amino acid residue selected from: Y15, D28, R35, D36, L84, E87, R88, Y94, N95, K101, S I 16, and Kl 18; in which the numbering of the amino acid residues corresponds to SEQ ID NO: 2.
  • the FGF polypeptide comprises a first modification at S 17 and a second modification at Y 15.
  • the FGF polypeptide comprises a first modification at S17 and a second modification at D28.
  • the FGF polypeptide comprises a first modification at S 17 and a second modification at R35.
  • the FGF mutant is an FGFl polypeptide comprising about 94% sequence identity to a polypeptide of SEQ ID NOs: 3-25917 and 25922-25974. In some instances, the FGF mutant is an FGFl polypeptide comprising about 95% sequence identity to a polypeptide of SEQ ID NOs: 3-25917 and 25922-25974. In some instances, the FGF mutant is an FGFl polypeptide comprising about 96% sequence identity to a polypeptide of SEQ ID NOs: 3-25917 and 25922-25974. In some instances, the FGF mutant is an FGFl polypeptide comprising about 97% sequence identity to a polypeptide of SEQ ID NOs: 3-25917 and 25922-25974.
  • the FGF mutant is an FGFl polypeptide comprising about 98% sequence identity to a polypeptide of SEQ ID NOs: 3-25917 and 25922-25974. In some instances, the FGF mutant is an FGFl polypeptide comprising about 99% sequence identity to a polypeptide of SEQ ID NOs: 3-25917 and 25922-25974. In some instances, the FGF mutant is an FGFl polypeptide comprising about 100% sequence identity to a polypeptide of SEQ ID NOs: 3-25917 and 25922-25974. In some instances, the FGF mutant is an FGFl polypeptide consists of a polypeptide of SEQ ID NOs: 3-25917 and 25922-25974.
  • the FGF mutant is an FGFl polypeptide comprising about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to a polypeptide of SEQ ID NO: 134. In some embodiments, the FGF mutant is an FGFl polypeptide comprising about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to a polypeptide of SEQ ID NO: 135.
  • the FGF mutant is an FGF1 polypeptide comprising about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to a polypeptide of SEQ ID NO: 159. In some embodiments, the FGF mutant is an FGF1 polypeptide comprising about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to a polypeptide of SEQ ID NO: 163.
  • the FGF mutant is an FGF1 polypeptide comprising about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to a polypeptide of SEQ ID NO: 165. In some embodiments, the FGF mutant is an FGF1 polypeptide comprising about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to a polypeptide of SEQ ID NO: 168.
  • the FGF mutant is an FGF1 polypeptide consists of a polypeptide of SEQ ID NOs: 130, 131, 132, 133, 134, 135, 139, 141, 142, 143, 144, 146, 147, 148, 149, 150, 151, 152, 153, 156, 157, 158, 159, 163, 165, 168, 170, 171, 174, 177, 284, 286, 290, 401, 484, 488, or 518.
  • the FGF mutant is an FGF1 polypeptide comprising about 80%, 85%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 25851. In some instances, the FGF mutant comprises about 80% or more sequence identity to SEQ ID NO: 25851. In some instances, the FGF mutant comprises about 85% or more sequence identity to SEQ ID NO: 25851. In some instances, the FGF mutant comprises about 90% or more sequence identity to SEQ ID NO: 25851. In some instances, the FGF mutant comprises about 91% or more sequence identity to SEQ ID NO: 25851.
  • the FGF mutant comprises about 92% or more sequence identity to SEQ ID NO: 25851. In some instances, the FGF mutant comprises about 93% or more sequence identity to SEQ ID NO: 25851. In some instances, the FGF mutant comprises about 94% or more sequence identity to SEQ ID NO: 25851. In some instances, the FGF mutant comprises about 95% or more sequence identity to SEQ ID NO: 25851. In some instances, the FGF mutant comprises about 96% or more sequence identity to SEQ ID NO: 25851. In some instances, the FGF mutant comprises about 97% or more sequence identity to SEQ ID NO: 25851. In some instances, the FGF mutant comprises about 98% or more sequence identity to SEQ ID NO: 25851.
  • the FGF mutant has a FGFR interaction activity that is about 20% greater than the FGFR interaction activity of FGF 1 polypeptide of SEQ ID NO: 2. In some cases, the FGF mutant has a FGFR interaction activity that is about 30% greater than the FGFR interaction activity of FGF 1 polypeptide of SEQ ID NO: 2. In some cases, the FGF mutant has a FGFR interaction activity that is about 40% greater than the FGFR interaction activity of FGF 1 polypeptide of SEQ ID NO: 2. In some cases, the FGF mutant has a FGFR interaction activity that is about 50% greater than the FGFR interaction activity of FGF 1 polypeptide of SEQ ID NO: 2.
  • FGF polypeptides described herein are generated recombinantly through a host cell system.
  • the host cell is a eukaryotic cell (e.g., mammalian cell, insect cells, yeast cells or plant cell) or a prokaryotic cell (e.g., gram -positive bacterium or a gram-negative bacterium).
  • a eukaryotic host cell is an insect host cell.
  • exemplary insect host cell include Drosophila S2 cells, Sf9 cells, Sf21 cells, High FiveTM cells, and expresSF+® cells.
  • Bacterial vectors include, for example, pACYC177, pASK75, pBAD vector series, pBADM vector series, pET vector series, pETM vector series, pGEX vector series, pHAT, pHAT2, pMal-c2, pMal-p2, pQE vector series, pRSET A, pRSET B, pRSET C, pTrcHis2 series, pZA31-Luc, pZE21-MCS-l, pFLAG ATS, pFLAG CTS, pFLAG MAC, pFLAG Shift- 12c, pTAC-MAT-1, pFLAG CTC, or pTAC-MAT-2.
  • Insect vectors include, for example, pFastBacl, pFastBac DUAL, pFastBac ET, pFastBac HTa, pFastBac HTb, pFastBac HTc, pFastBac M30a, pFastBact M30b, pFastBac, M30c, pVL1392, pVL1393, pVL1393 M10, pVL1393 Mi l, pVL1393 M12, FLAG vectors such as pPolh-FLAGl or pPolh-MAT 2, or MAT vectors such as pPolh-MATl, or pPolh-MAT2.
  • FLAG vectors such as pPolh-FLAGl or pPolh-MAT 2
  • MAT vectors such as pPolh-MATl, or pPolh-MAT
  • a FGF mutant described herein is used for the treatment of a metabolic disease or condition, such as an FGFl -related disease or condition or a FGF2-related disease or condition. In some instances, a FGF mutant described herein is used for the treatment of an FGF1- related disease or condition.
  • administration of a FGF mutant described herein reduces blood glucose, improves insulin sensitivity, improves glucose tolerance, reduces systemic chronic inflammation, ameliorate hepatic steatosis, reduces food intake, or combinations thereof.
  • administration of a FGF mutant described herein reduces blood glucose.
  • administration of a FGF mutant described herein improves insulin sensitivity.
  • administration of a FGF mutant described herein improves glucose tolerance.
  • administration of a FGF mutant described herein reduces systemic chronic inflammation.
  • administration of a FGF mutant described herein ameliorate hepatic steatosis.
  • administration of a FGF mutant described herein reduces food intake.
  • Type 1 diabetes also called insulin-dependent diabetes, comprises about 5% to 10% of all diabetes cases.
  • Type 1 diabetes is an autoimmune disease where T cells attack and destroy insulin- producing beta cells in the pancreas.
  • Type 1 diabetes is caused by genetic and environmental factors.
  • double diabetes is used to describe patients diagnosed with both type 1 and 2 diabetes.
  • Type 4 diabetes is a recently discovered type of diabetes affecting about 20% of diabetic patients age 65 and over. In some embodiments, type 4 diabetes is characterized by age-associated insulin resistance.
  • Diabetes insipidus is a rare disorder affecting 3 in about 100,000 people each year worldwide.
  • diabetes insipidus is further classified into neurogenic DI, nephrogenic DI, dipsogenic DI, and gestational DI.
  • neurogenic DI also known as central DI, is characterized by damage to the pituitary gland, which results in disruption of antidiuretic hormone (ADH) storage and release.
  • ADH antidiuretic hormone
  • nephrogenic DI is characterized by the inability of the kidneys to respond to ADH.
  • dipsogenic DI is characterized by a defect or damage in the thirst mechanism governed by the hypothalamus, which results in suppression of ADH and an increase in urine output.
  • gestational DI is characterized by degradation of vasopressin in the mother by placental vasopressinase.
  • an FGFl mutant described herein is used for the treatment of type 1 diabetes, type 2 diabetes, type 3 diabetes, type 4 diabetes, double diabetes, latent autoimmune diabetes (LAD), gestational diabetes, neonatal diabetes mellitus (NDM), maturity onset diabetes of the young (MODY), Wolfram syndrome, Alstrom syndrome, prediabetes, or diabetes insipidus.
  • LAD latent autoimmune diabetes
  • NDM neonatal diabetes mellitus
  • MODY maturity onset diabetes of the young
  • an FGFl mutant described herein is used for the treatment of type 1 diabetes.
  • an FGFl mutant described herein is used for the treatment of type 2 diabetes.
  • an FGFl mutant described herein is used for the treatment of type 3 diabetes.
  • an FGFl mutant described herein is used for the treatment of type 4 diabetes. In some cases, an FGFl mutant described herein is used for the treatment of double diabetes. In some cases, an FGFl mutant described herein is used for the treatment of latent autoimmune diabetes (LAD) (e.g., LADA, LADY, or LADC). In some cases, an FGFl mutant described herein is used for the treatment of gestational diabetes. In some cases, an FGFl mutant described herein is used for the treatment of neonatal diabetes mellitus (NDM) (e.g., PNDM or TNDM).
  • NDM neonatal diabetes mellitus
  • a FGF mutant described herein is used for the treatment of NAFLD.
  • the FGF mutant is an FGF 1 mutant.
  • an FGF 1 mutant described herein is used for the treatment of NAFLD.
  • a FGF mutant described herein is used for the treatment of lipodystrophy.
  • the FGF mutant is an FGF1 mutant.
  • an FGF1 mutant described herein is used for the treatment of lipodystrophy.
  • a metabolic disease or condition is a cardiovascular disease.
  • a FGF mutant e.g., FGF1 mutant
  • the additional therapeutic agent is a therapeutic agent for the treatment of a metabolic disease selected from diabetes, polycystic ovary syndrome (PCOS), metabolic syndrome (MetS), obesity, non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), dyslipidemia, a cardiovascular disease, Hurler syndrome, Huntington's disease, Alzheimer's disease, Parkinson's disease, Crohn's disease, Fabry disease, and galactosemia.
  • a metabolic disease selected from diabetes, polycystic ovary syndrome (PCOS), metabolic syndrome (MetS), obesity, non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), dyslipidemia, a cardiovascular disease, Hurler syndrome, Huntington's disease, Alzheimer's disease, Parkinson's disease, Crohn's disease, Fabry disease, and galactosemia.
  • a FGF mutant (e.g., FGF1 mutant) described herein is used in combination with a therapeutic agent for the treatment of a metabolic disease selected from diabetes, polycystic ovary syndrome (PCOS), metabolic syndrome (MetS), obesity, non-alcoholic alcoholic fibrosis, diabetes, diabetes, polycystic ovary syndrome (PCOS), metabolic syndrome (MetS), obesity, non-alcoholic fibrosis, diabetes, diabetes, polycystic ovary syndrome (PCOS), metabolic syndrome (MetS), obesity, non-alcoholic ovary syndrome (PCOS), diabetes, diabetes, polycystic ovary syndrome (PCOS), metabolic syndrome (MetS), obesity, non-alcoholic a metabolic disease, and others.
  • the additional therapeutic agent is a therapeutic agent for the treatment of Crohn's disease and includes: 5 -aminosalicylates such as sulfasalazine or mesalamine; corticosteroids such as prednisone, methylprednisolone, hydrocortisone, or budesonide; immune system suppressors such as azathioprine, mercaptopurine, infliximab, adalimumab, certolizumab pegol, methotrexate, cyclosporine, tracrolimus, natalizumab, vedolizumab, or ustekinumab;
  • 5 -aminosalicylates such as sulfasalazine or mesalamine
  • corticosteroids such as prednisone, methylprednisolone, hydrocortisone, or budesonide
  • immune system suppressors such as azathioprine, mercaptopur
  • the additional therapeutic agent is a therapeutic agent for the treatment of Fabry disease and includes: agalsidase beta or alpha-galactosidase.
  • the additional therapeutic agent is a glucagon-like peptide- 1 receptor
  • a FGF mutant described herein is modified by myristoylation, palmitoylation, isoprenylation (or prenylation) (e.g., farnesylation or geranylgeranylation), glypiation, acylation (e.g., O-acylation, N-acylation, S-acylation), alkylation (e.g., additional of alkyl groups such as methyl or ethyl groups), amidation, glycosylation, hydroxylation, iodination, nucleotide addition, oxidation, phosphorylation, succinylation, sulfation, glycation, carbamylation, glutamylation, or deamidation.
  • myristoylation, palmitoylation, isoprenylation (or prenylation) e.g., farnesylation or geranylgeranylation
  • acylation e.g., O-acylation, N-acylation, S-acylation
  • alkylation
  • a conjugating moiety comprises a polymer.
  • a polymer is a natural or synthetic polymer, consisting of, e.g., long chains of branched or unbranched monomers, and/or cross-linked network of monomers in two or three dimensions.
  • a polymer comprises a water soluble polymer or a water insoluble polymer.
  • a FGF polypeptide conjugate comprises a FGF-polymer conjugate.
  • a polymer conjugate alters one or more properties (e.g., biological properties and/or physicochemical properties) of a FGF polypeptide.
  • polyamination modification of a FGF polypeptide described herein by a polyamine is referred to as polyamination.
  • polyamination is an enzyme -mediated conjugation, in which transglutaminase (Tgase) catalyzes the transfer of a primary amino group to an acyl group.
  • Tgase transglutaminase
  • polyamination is as described in Zhang, et al, "Synthesis and applications of polyamine amino acid residues: improving the bioactivity of an analgesic neuropeptide, Neurotensin," J Med Chem 52(6): 1514-1517 (2009).
  • a FGF polypeptide described herein is modified by polyamination.
  • a FGF polypeptide of SEQ ID NOs: 3-25917 and 25922-25974 is modified by polyamination.
  • a polymer comprises a lipid moiety.
  • Lipid is a broad family of small molecules capable of forming structures such as vesicles, multilamellar/unilamellar liposomes, or membranes in an aqueous environment.
  • a lipid comprises a fatty acid.
  • a lipid comprises a short chain fatty acid (less than C6), a medium chain fatty acid (C6-C14), or a long chain fatty acid (C15 or longer).
  • a fatty acid comprises a saturated fatty acid or an unsaturated fatty acid.
  • a lipid comprises an unsaturated fatty acid.
  • unsaturated fatty acid comprises monounsaturated fatty acid such as palmitoleic acid, vaccenic acid, oleic acid, eicosenoic acid, erucic acid, gadoleic acid, myristoleic acid, or nervonic acid; and polyunsaturated fatty acid such as hexadecatrienoic acid, alpha-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, linoleic acid, gamma-linolenic acid,
  • a FGF-polymer conjugate comprises a FGF-lipid conjugate. In some cases, a FGF-polymer conjugate comprises a FGF-fatty acid conjugate.
  • a FGF polypeptide described herein is conjugated to a functional fragment of albumin.
  • a functional fragment of albumin comprises an albumin with a N-terminal truncation, a C-terminal truncation or a truncation of both termini.
  • a functional fragment of albumin comprises domain I, domain II, domain III, or a combination thereof.
  • a functional fragment of albumin comprises a polypeptide of at least 70%, 80%, 90%, or 95% sequence identity to the full-length wild type albumin (e.g., HSA).
  • a FGF polypeptide described herein is conjugated to a functional fragment of HSA.
  • a conjugating moiety comprises a conjugating peptide.
  • a conjugating peptide modulates one or more biological properties and/or physicochemical properties of a target molecule of interest (e.g., a FGF polypeptide).
  • a conjugating peptide enhances pharmacokinetics, pharmacodynamics, metabolic stability, biodistribution, water solubility, lipophilicity, or tissue targeting capabilities of a target molecule of interest (e.g., a FGF polypeptide).
  • a XTENTM peptide is selected based on properties such as expression, genetic stability, solubility, aggregation resistance, enhanced half- life, increased potency, and/or increased in vitro activity in combination with a polypeptide of interest.
  • a FGF polypeptide of SEQ ID NOs: 3-25917 and 25922-25974 is modified by XTENylation.
  • modification of a FGF polypeptide described herein by an elastin- like polypeptide (ELP) is referred to as ELPylation.
  • a FGF polypeptide described herein is conjugated to an antibody or its binding fragments thereof.
  • a FGF polypeptide described herein is conjugated to an antibody or its binding fragments thereof selected from a humanized antibody or binding fragment thereof, murine antibody or binding fragment thereof, chimeric antibody or binding fragment thereof, monoclonal antibody or binding fragment thereof, monovalent Fab', divalent Fab 2 , F(ab)'3 fragments, single-chain variable fragment (scFv), bis-scFv, (scFv) 2 , diabody, minibody, nanobody, triabody, tetrabody, humabody, disulfide stabilized Fv protein (dsFv), single-domain antibody (sdAb), Ig NAR, camelid antibody or binding fragment thereof, bispecific antibody or biding fragment thereof, or a chemically modified derivative thereof.
  • a FGF polypeptide selected from SEQ ID NOs: 3-25917 and 25922-25974 is conjugated to an antibody or its binding fragments thereof selected from a humanized antibody or binding fragment thereof, murine antibody or binding fragment thereof, chimeric antibody or binding fragment thereof, monoclonal antibody or binding fragment thereof, monovalent Fab', divalent Fab 2 , F(ab)'3 fragments, single-chain variable fragment (scFv), bis-scFv, (scFv) 2 , diabody, minibody, nanobody, triabody, tetrabody, humabody, disulfide stabilized Fv protein (dsFv), single-domain antibody (sdAb), Ig NAR, camelid antibody or binding fragment thereof, bispecific antibody or biding fragment thereof, or a chemically modified derivative thereof.
  • the conjugation is a covalent conjugation.
  • the conjugation is genetic linkage of an antibody or its binding fragments thereof to a FGF polypeptide.
  • Affimer is derived from cystatins, a family of cysteine protease inhibitors.
  • the Affimer structure comprises two peptide loops and an N-terminal sequence which in some cases are randomized to generate a target site of interest.
  • Alphabodies or cell-penetrating alphabodies or CPAB
  • Alphabodies are small proteins of about 10 kDa in size.
  • Alphabodies comprise coiled-coil structures and the sequences are modified, e.g., by phase display, to generate target site of interest.
  • Avimers comprise two or more peptide sequences of about 30 to about 35 amino acid residues in length.
  • each peptide sequence interacts with an epitope of a target protein of interest, and the combination of peptides to different epitopes of a target protein of interest increases affinity to the target protein.
  • a nanoparticle includes a core or a core and a shell, as in a core-shell nanoparticle.
  • a nanoparticle has at least one dimension of less than about 500nm, 400nm, 300nm, 200nm, or lOOnm.
  • a FGF mutant is encapsulated within a hydrogel or a scaffold.
  • the hydrogels or scaffolds are comprised of synthetic polymers such as, but not limited to, poly(a-hydroxy acids), poly(orthoesters), poly(anhydrides), poly(amino acids), dextrin, poly(glycoside) (PGA), poly(L-lactide) (PLA) and their copolymers poly(D,L-lactic-co-glycolic) acid (PLGA); naturally occurring polymers such as, but not limited to, silk, keratin, collagen, denatured collagen, atelocollagen, gelatin, fibrinogen, fibrin, laminin, elastin, chitosan, hyaluronic acid, starch, carrageenan, cellulose, alginate, perlecan (PLC), heparin or heparin sulfate, chondroitin sulfate, fibronectin, and
  • the pharmaceutical formulations include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations (e.g., nanoparticle formulations), and mixed immediate and controlled release formulations.
  • aqueous liquid dispersions self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations (e.g., nanoparticle formulations), and mixed immediate and controlled release formulations.
  • Pharmaceutically compatible carrier materials include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, polyvinylpyrrollidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphotidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack
  • the pharmaceutical formulations include, but are not limited to, sugars like trehalose, sucrose, mannitol, maltose, glucose, or salts like potassium phosphate, sodium citrate, ammonium sulfate and/or other agents such as heparin to increase the solubility and in vivo stability of polypeptides.
  • Such compounds can include e.g., lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel ® , dibasic calcium phosphate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium phosphate, anhydrous lactose, spray-dried lactose, pregelatinized starch, compressible sugar, such as Di-Pac ® (Amstar), mannitol,
  • hydroxypropylmethylcellulose hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, mannitol, sodium chloride, inositol, bentonite, and the like.
  • the pharmaceutical formulations include disintegration agents or disintegrants to facilitate the breakup or disintegration of a substance.
  • disintegrate include both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid.
  • Lubricants and glidants are also optionally included in the pharmaceutical formulations described herein for preventing, reducing or inhibiting adhesion or friction of materials.
  • Exemplary lubricants include, e.g., stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex ® ), higher fatty acids and their alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet ® , boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol (e.g., PEG-4000) or a methoxypolyethylene glycol such as CarbowaxTM, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene
  • Cab-O-Sil ® a starch such as corn starch, silicone oil, a surfactant, and the like.
  • Plasticizers include compounds used to soften the microencapsulation material or film coatings to make them less brittle. Suitable plasticizers include, e.g., polyethylene glycols such as
  • Solubilizers include compounds such as triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide, N- methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide and the like.
  • Suspending agents include compounds such as polyvinylpyrrolidone, e.g.,
  • kits and articles of manufacture for use with one or more methods and compositions described herein.
  • Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers are formed from a variety of materials such as glass or plastic.
  • a label is on or associated with the container.
  • a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.
  • the pack for example, contains metal or plastic foil, such as a blister pack.
  • the terms "individual(s)", “subject(s)” and “patient(s)” mean any mammal.
  • the mammal is a human.
  • the mammal is a non-human. None of the terms require or are limited to situations characterized by the supervision (e.g. constant or intermittent) of a health care worker (e.g. a doctor, a registered nurse, a nurse practitioner, a physician's assistant, an orderly or a hospice worker).
  • a health care worker e.g. a doctor, a registered nurse, a nurse practitioner, a physician's assistant, an orderly or a hospice worker.

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Abstract

L'invention concerne des compositions de FGF et des méthodes de traitement d'une maladie ou d'un état métabolique. L'invention concerne également des mutants de FGF1, des formulations pharmaceutiques et leur utilisation dans le traitement d'une maladie ou d'un état métabolique.
PCT/US2017/043383 2016-07-21 2017-07-21 Mutants de fgf et leurs utilisations Ceased WO2018018010A1 (fr)

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US20190284252A1 (en) * 2018-03-16 2019-09-19 The Board Of Trustees Of The University Of Arkansas Engineered fgf1 and fgf2 compositions and methods of use thereof
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US10159711B2 (en) 2010-04-16 2018-12-25 Salk Institute For Biological Studies Methods for treating metabolic disorders using FGF
US10293027B2 (en) 2010-04-16 2019-05-21 Salk Institute For Biological Studies Methods for treating metabolic disorders using FGF
US10398759B2 (en) 2010-04-16 2019-09-03 Salk Institute For Biological Studies Methods for treating metabolic disorders using FGF
US10695404B2 (en) 2015-10-30 2020-06-30 Salk Institute For Biological Studies Treatment of steroid-induced hyperglycemia with fibroblast growth factor (FGF) 1 analogs
US20190284252A1 (en) * 2018-03-16 2019-09-19 The Board Of Trustees Of The University Of Arkansas Engineered fgf1 and fgf2 compositions and methods of use thereof
US11267855B2 (en) * 2018-03-16 2022-03-08 The Board Of Trustees Of The University Of Arkansas Engineered FGF1 and FGF2 compositions and methods of use thereof
CN113194980A (zh) * 2018-10-09 2021-07-30 利兰斯坦福初级大学董事会 作为受体拮抗剂的工程化纤维细胞生长因子变体
WO2021011878A1 (fr) * 2019-07-18 2021-01-21 Venturis Therapeutics, Inc. Procédé de traitement de la maladie de parkinson
US11542309B2 (en) 2019-07-31 2023-01-03 Salk Institute For Biological Studies Fibroblast growth factor 1 (FGF1) mutant proteins that selectively activate FGFR1B to reduce blood glucose
WO2021239046A1 (fr) * 2020-05-28 2021-12-02 江苏康缘瑞翱生物医药科技有限公司 Protéine de fusion rhfgf21, polynucléotide codant pour la protéine de fusion rhfgf21, composition contenant la protéine de fusion rhfgf21, et utilisation de la protéine de fusion rhfgf21
WO2022035849A1 (fr) * 2020-08-10 2022-02-17 Venturis Therapeutics, Inc. Méthodes permettant de réduire la chute des cheveux et/ou d'augmenter la repousse des cheveux

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