EP2480579A2 - Verfahren zur behandlung von entzündungen - Google Patents

Verfahren zur behandlung von entzündungen

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Publication number
EP2480579A2
EP2480579A2 EP10819481A EP10819481A EP2480579A2 EP 2480579 A2 EP2480579 A2 EP 2480579A2 EP 10819481 A EP10819481 A EP 10819481A EP 10819481 A EP10819481 A EP 10819481A EP 2480579 A2 EP2480579 A2 EP 2480579A2
Authority
EP
European Patent Office
Prior art keywords
peptide
mif
seq
motif
disease
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10819481A
Other languages
English (en)
French (fr)
Other versions
EP2480579A4 (de
Inventor
Jurgen Bernhagen
Christian Weber
Benedikt Vollrath
Court Turner
Joshua Robert Schultz
Alma Zernecke
Sergio Duron
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Carolus Therapeutics Inc
Original Assignee
Carolus Therapeutics Inc
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Filing date
Publication date
Application filed by Carolus Therapeutics Inc filed Critical Carolus Therapeutics Inc
Publication of EP2480579A2 publication Critical patent/EP2480579A2/de
Publication of EP2480579A4 publication Critical patent/EP2480579A4/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • 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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Inflammatory diseases, disorders, conditions and symptoms are characterized, in part, by the migration lymphocytes and monocytes into the affected tissue.
  • the migration of lymphocytes and monocytes induces tissue damage and exacerbates inflammatory diseases, disorders, conditions and symptoms.
  • Many leukocytes and monocytes follow a MIF gradient to the affected tissue.
  • MIF interacts with CXCR2 and CXCR4 receptors on leukocytes and monocytes to trigger and maintain leukocyte and monocyte migration.
  • MIF and CXCR2, CXCR4, CD44, and CD74 will inhibit the ability of MIF to bind to CXCR2, CXCR4, CD44, and CD74 (thus, preventing undesired inflammation) without affecting other (e.g., desired and beneficial) interactions of MIF, CXCR2, CXCR4, CD44, and CD74.
  • peptides that competitively bind with a binding partner of one of the following domains of MIF: the N-terminal/pseudo-ELR motif/domain, the alpha-helix #1 motif/domain, the MIF N-loop motif/domain, the loop-barrel-loop motif/domain, the C-terminal motif/domain, or a combination thereof.
  • the peptide competitively binds with a binding partner of the N-loop domain.
  • the peptide comprises an amino acid that competitively binds with a binding partner of MIF leu47.
  • the peptide competitively binds with a binding partner of the pseudo-ELR domain.
  • the peptide is selected from: LMAFGGSSEP (SEQ ID NO. 18); LMAFGGSS (SEQ ID NO. 20); cyclic CLMAFGGSSEPCALC (SEQ ID NO. 423);
  • VHVVPDQLMA (SEQ ID NO. 465); QLMAFGGSSE (SEQ ID NO. 468); VNTNVPRASVPDG (SEQ ID NO. 437); NVPRASVPDG (SEQ ID NO. 172); cyclic CNVPRASVPDGC (SEQ ID NO. 440); NVPRASVPD (SEQ ID NO. 82); cyclic CLMAFGGSSEP[Abu]ALC (SEQ ID NO. 429), wherein Abu is isosteric L-amino acid, alpha- aminobutyric acid; or cyclic CLMAFGGSSEPSALC (SEQ ID NO. 469).
  • peptides that competitively bind with a binding partner of one motif/domain of CXCR2.
  • the peptide competitively binds with a binding partner of one of the following domains: CXCR2 extracellular loop 1, CXCR2 extracellular loop 2, CXCR2 extracellular loop 3, or the CXCR2 N-terminus/domain.
  • peptides that competitively bind with a binding partner of one motif/domain of CXCR4.
  • the peptide competitively binds with a binding partner of: SEADDRYICDRFYPNDLWVVV; or DDRYICDRFYPNDLW.
  • peptides that competitively bind with a binding partner of one motif/domain of CD44.
  • peptides that competitively bind with a binding partner of one motif/domain of CD74.
  • a fusion peptide comprising (a) a first peptide that competitively binds with a binding partner of the N-loop motif of MIF; and (b) a second peptide that competitively binds with a binding partner of the pseudo ELR motif of MIF; wherein the first peptide and the second peptide retain their activity in the fusion peptide.
  • the fusion peptide comprises (a) a first peptide that competitively binds with a binding partner of the N- loop motif of MIF; (b) a second peptide that competitively binds with a binding partner of the pseudo ELR motif of MIF; and (c) a third peptide that competitively binds with a binding partner of the pseudo ELR motif of MIF; and wherein the first peptide and the second peptide retain their activity in the fusion peptide.
  • the fusion peptide comprises a peptide selected from: LMAFGGSSEP (SEQ ID NO. 18); LMAFGGSS (SEQ ID NO. 20); cyclic
  • CLMAFGGSSEPCALC SEQ ID NO. 423; VHVVPDQLMA (SEQ ID NO. 465); QLMAFGGSSE (SEQ ID NO. 468); VNTNVPRASVPDG (SEQ ID NO. 437); NVPRASVPDG (SEQ ID NO. 172); cyclic CNVPRASVPDGC (SEQ ID NO. 440); NVPRASVPD (SEQ ID NO. 82); cyclic
  • the fusion peptide is given by Formula (IV):
  • the fusion peptide is given by Formula (V): Peptide 1— Linker— Peptide 2
  • the linker comprises an alkyl, a heteroalkyl, an alkylene, an alkenylene, an alkynylene, a heteroalkylene, a carbocycle, a heterocycle, an aromatic ring, a non-aromatic ring, a substituted ring, a monocyclic ring, a polycyclic ring, or a combination thereof.
  • a peptibody comprising (a) an antibody, (b) a peptide described herein, and (c) a linker binding the peptide to the Fab region of the antibody; wherein the peptide and the antibody retain their activity in the peptibody.
  • the linker binds the peptide to an antigen binding site.
  • the linker comprises an alkyl, a heteroalkyl, an alkylene, an alkenylene, an alkynylene, a heteroalkylene, a carbocycle, a heterocycle, an aromatic ring, a non-aromatic ring, a substituted ring, a monocyclic ring, a polycyclic ring, or a combination thereof.
  • the antibody is an IgA, IgD, IgE, IgG, or IgM.
  • the inflammatory disease, disorder or condition is Atherosclerosis; Abdominal aortic aneurysm; Acute disseminated encephalomyelitis; Moyamoya disease; Takayasu disease; Acute coronary syndrome; Cardiac- allograft vasculopathy; Pulmonary inflammation; Acute respiratory distress syndrome; Pulmonary fibrosis; Acute disseminated encephalomyelitis; Addison's disease; Ankylosing spondylitis;
  • Antiphospholipid antibody syndrome Autoimmune hemolytic anemia; Autoimmune hepatitis; Autoimmune inner ear disease; Bullous pemphigoid; Chagas disease; Chronic obstructive pulmonary disease; Coeliac disease; Dermatomyositis; Diabetes mellitus type 1; Diabetes mellitus type 2; Endometriosis; Goodpasture's syndrome; Graves' disease; Guillain-Barre syndrome;
  • Hashimoto's disease Idiopathic thrombocytopenic purpura; Interstitial cystitis; Systemic lupus erythematosus (SLE); Metabolic syndrome; Multiple sclerosis; Myasthenia gravis; Myocarditis; Narcolepsy; Obesity; Pemphigus Vulgaris; Pernicious anaemia; Polymyositis; Primary biliary cirrhosis; Rheumatoid arthritis; Schizophrenia; Scleroderma; Sjogren's syndrome; Vasculitis;
  • Vitiligo Surprivo; Wegener's granulomatosis; Allergic rhinitis; Prostate cancer; Non-small cell lung carcinoma; Ovarian cancer; Breast cancer; Melanoma; Gastric cancer; Colorectal cancer; Brain cancer; Metastatic bone disorder; Pancreatic cancer; bladder cancer; hepatocellular cancer; liver cancer; adenocarcinoma of the lung; esophageal squamous cell carcinoma; CNS tumors;
  • hematological tumors a Lymphoma; Nasal polyps; Gastrointestinal cancer; Ulcerative colitis; Crohn's disorder; Collagenous colitis; Lymphocytic colitis; Ischaemic colitis; Diversion colitis; Behcet's syndrome; Infective colitis; Indeterminate colitis; Inflammatory liver disorder; Endotoxin shock; Septic shock; Rheumatoid spondylitis; Ankylosing spondylitis; Gouty arthritis; Polymyalgia rheumatica; Alzheimer's disorder; Parkinson's disorder; Epilepsy; AIDS dementia; Asthma; Adult respiratory distress syndrome; Bronchitis; Cystic fibrosis; Acute leukocyte-mediated lung injury; Distal proctitis; Wegener's granulomatosis; Fibromyalgia; Bronchitis; ;Uveitis; Conjunctivitis; Psoriasis; Eczema; Dermatitis; Smooth
  • Encephalitis Nephritis; Tuberculosis; Retinitis; Atopic dermatitis; Pancreatitis; Periodontal gingivitis; Coagulative Necrosis; Liquefactive Necrosis; Fibrinoid Necrosis; Neointimal hyperplasia; Myocardial infarction; Stroke; organ transplant rejection; influenza, or combinations thereof.
  • the inflammatory, disease, disorder, or condition is: Prostate cancer; Non-small cell lung carcinoma; Ovarian cancer; Breast cancer; Melanoma; Gastric cancer; Colorectal cancer; Brain cancer; Metastatic bone disorder; Pancreatic cancer; bladder cancer; hepatocellular cancer; liver cancer; adenocarcinoma of the lung; esophageal squamous cell carcinoma; CNS tumors;
  • the inflammatory, disease, disorder, or condition is rehumatoid arthritis. In some embodiments, the inflammatory, disease, disorder, or condition is acute respiratory distress syndrome. In some embodiments, the inflammatory, disease, disorder, or condition is glomerulonephritis. In some embodiments, the inflammatory, disease, disorder, or condition is inflammatory bowel disease. In some embodiments, the inflammatory, disease, disorder, or condition is abdominal aortic aneurysm disease. In some embodiments, the inflammatory, disease, disorder, or condition is chronic obstructive pulmonary disease. In some embodiments, the inflammatory, disease, disorder, or condition is asthma. In some embodiments, the inflammatory, disease, disorder, or condition is lupus. In some embodiments, the inflammatory, disease, disorder, or condition is sepsis.
  • composition of matter described herein to treat, prevent or reduce angiogenesis.
  • compositions for treating an inflammatory disease, disorder, condition or symptom in an individual in need thereof comprising a composition of matter described herein.
  • Figure 1 illustrates the crystal structure of a MIF trimer.
  • the pseudo-ELR motif/domains form a ring in the trimer while the N-loop motif/domains extend outward from the pseudo-ELR ring.
  • Figure 2 illustrates the nucleotide sequence of MIF annotated to show the sequences that correspond to the N-Loop motif/domain and the pseudo-ELR motif/domain.
  • Figure 3 shows the nucleic acid sequence of human MIF and the corresponding MIF motif/domains.
  • FIGURE 4 shows that the peptide of SEQ ID No. 18 blocks chemotaxis in human peripheral blood mononuclear cells (PBMC).
  • PBMC peripheral blood mononuclear cells
  • FIGURE 5 shows that the peptide of SEQ ID NO. 423 significantly antagonizes MIF- induced chemotaxis in PMBCs.
  • FIGURE 6 shows that the peptide of SEQ ID NO. 423 significantly antagonizes MIF- induced chemotaxis in PMBCs in a dose dependent manner.
  • FIGURE 9 presents the results of probing the MIF-MIF interface with Peptide SPOT arrays. luM of MIF was incubated overnight. Streptavidin-POD (1 : 10000) was incubated for 2 hours at room temperature.
  • FIGURE 10 presents the results of probing the MIF-CXCR2 interface with Peptide SPOT arrays. luM of MIF was incubated overnight. Streptavidin-POD (1 : 10000) was incubated for 2 hours at room temperature.
  • FIGURE 1 1 presents the results of probing the MIF-CXCR2 interface with Peptide SPOT arrays using wildtype MIF (1 ⁇ Biotin-monoQ-MIF:Streptavidin-POD) and mutant MIF (1 ⁇ biotin-Rl 1A-D44A-MIF Streptavidin-POD).Streptavidin-POD (1 : 10000) was incubated for 2 hours at room temperature. Wildtype MIF and mutant MIF were incubated overnight at room temperature.
  • FIGURE 12 presents the results of probing the MIF-CXCR4 interface with Peptide SPOT arrays using wildtype MIF (1 ⁇ Biotin- MIF:Streptavidin-POD).Streptavidin-POD (1 : 10000) was incubated for 2 hours at room temperature. Wildtype MIF was incubated overnight at 4°C.
  • HPF high power fields
  • FIGURE 14 shows that SEQ ID NO 18 reduces TNFa and MCP- 1 in mouse peritonitis model.
  • FIGURE 15 shows that SEQ ID NO 18 reduces MCP- 1 and monocyte levels in mouse peritonitis model.
  • Vehicle, SEQ ID NO. 422, SEQ ID NO. 421, SEQ ID NO. 45 land Dex: 30 min prior to and 30 min post TG challenge. 2hr post TG, peritoneal lavage for cell counts and chemokines.
  • FIGURE 16 presents a proposed mechanism of MIF signalling modulation.
  • FIGURE 17 illustrates the structure and surface exposure of the MIF-N-loop and schematic of the two-site binding model for MIF/CXCR2.
  • A 3 D-architectural homology between CXCL8 and MIF with a focus on the receptor interaction motifs. Binding of the canonical ligand CXCL8 to CXCR2 involves the N-loop and the ELR motif. MIF contains an N-like-loop (sequence stretch 47- 56) and a pseudo-(E)LR motif (amino acids R12 and D45, constituting a 3D-ELR motif). For clarity reasons, only the monomeric structures of CXCL8 and MIF are depicted.
  • B Schematic showing the structure of MIF.
  • FIGURE 18 is a peptide SPOT array analysis identifying the interaction sites between MIF and the extracellular domains of CXCR2 by peptide spot array analysis.
  • Short 15-mer peptides representing full-length human MIF (A) and the CXCR2 extracellular domains (B and C) were directly synthesized onto amino-cellulose membranes.
  • CXCR2 peptides correspond to the N- terminus (N-term) and extracellular loops (EL) 1-3.
  • Peptide strips were incubated with 1 ⁇ biotin- MIF (A and B) or biotin-R12A/D45A-MIF (C) and detected using streptavidin-POD.
  • A MIFstrip developed with biotin-MIF.
  • B CXCR2-strip developed with biotin-MIF.
  • C CXCR2-strip developed with biotin-R12A/D45A-MIF.
  • FIG. 19 illustrates that MIF N-loop peptides inhibit the interaction between MIF and CXCR2.
  • the effect of the peptides was examined by a competitive receptor binding assay measuring the reversal by the N-loop peptides of the inhibitory effect of MIF on tracer binding.
  • HEK293 cells stably overexpressing CXCR2 were incubated with radioiodinated I125CXCL8 tracer together with 1 ⁇ human MIF and 100 ⁇ of the indicated N-like-loop peptides of MIF as competitor.
  • Plots represent percent of specific I125-CXCL8 binding.
  • FIGURE 20 is a model depicting the interactions at the MIF/CXCR2 interface according to the general two-site binding mechanism.
  • FIGURE 21 is a model depicting a peptibody. DETAILED DESCRIPTION OF THE INVENTION
  • compositions of matter for treating inflammatory diseases, disorders, conditions and symptoms.
  • compositions of matter for treating inflammatory diseases, disorders, conditions and symptoms.
  • pharmaceutical compositions and methods of treating inflammatory diseases, disorders, conditions and symptoms are characterized by undesired MIF signaling.
  • the inflammatory disease, disorder, condition or symptom is characterized by MIF-mediated leukocyte recruitment.
  • peptides that competitively bind with a binding partner of one of the following domains of MIF: the N-terminal/pseudo-ELR motif/domain, the alpha-helix #1 motif/domain, the MIF N-loop motif/domain, the loop-barrel-loop motif/domain, the C-terminal motif/domain, or a combination thereof.
  • the peptide competitively binds with a binding partner of the N-loop domain.
  • the peptide comprises an amino acid that competitively binds with a binding partner of MIF leu47.
  • the peptide competitively binds with a binding partner of the pseudo-ELR domain.
  • the peptide is selected from: LMAFGGSSEP (SEQ ID NO. 18); LMAFGGSS (SEQ ID NO. 20); cyclic CLMAFGGSSEPCALC (SEQ ID NO. 423);
  • VHVVPDQLMA (SEQ ID NO. 465); QLMAFGGSSE (SEQ ID NO. 468); VNTNVPRASVPDG (SEQ ID NO. 437); NVPRASVPDG (SEQ ID NO. 172); cyclic CNVPRASVPDGC (SEQ ID NO. 440); NVPRASVPD (SEQ ID NO. 82); cyclic CLMAFGGSSEP[Abu]ALC (SEQ ID NO. 429), wherein Abu is isosteric L-amino acid, alpha- aminobutyric acid; or cyclic CLMAFGGSSEPSALC (SEQ ID NO. 469).
  • peptides that competitively bind with a binding partner of one motif/domain of CXCR2.
  • the peptide competitively binds with a binding partner of one of the following domains: CXCR2 extracellular loop 1, CXCR2 extracellular loop 2, CXCR2 extracellular loop 3, or the CXCR2 N-terminus/domain.
  • peptides that competitively bind with a binding partner of one motif/domain of CXCR4.
  • the peptide competitively binds with a binding partner of: SEADDRYICDRFYPNDLWVVV; or DDRYICDRFYPNDLW.
  • peptides that competitively bind with a binding partner of one motif/domain of CD44 are peptides that competitively bind with a binding partner of one motif/domain of CD74.
  • a fusion peptide comprising (a) a first peptide that competitively binds with a binding partner of the N-loop motif of MIF; and (b) a second peptide that competitively binds with a binding partner of the pseudo ELR motif of MIF; wherein the first peptide and the second peptide retain their activity in the fusion peptide.
  • the fusion peptide comprises (a) a first peptide that competitively binds with a binding partner of the N- loop motif of MIF; (b) a second peptide that competitively binds with a binding partner of the pseudo ELR motif of MIF; and (c) a third peptide that competitively binds with a binding partner of the pseudo ELR motif of MIF; and wherein the first peptide and the second peptide retain their activity in the fusion peptide.
  • the fusion peptide comprises a peptide selected from: LMAFGGSSEP (SEQ ID NO. 18); LMAFGGSS (SEQ ID NO. 20); cyclic
  • CLMAFGGSSEPCALC SEQ ID NO. 423; VHVVPDQLMA (SEQ ID NO. 465); QLMAFGGSSE (SEQ ID NO. 468); VNTNVPRASVPDG (SEQ ID NO. 437); NVPRASVPDG (SEQ ID NO. 172); cyclic CNVPRASVPDGC (SEQ ID NO. 440); NVPRASVPD (SEQ ID NO. 82); cyclic
  • the fusion peptide is given by Formula (IV):
  • the fusion peptide is given by Formula (V):
  • the linker comprises an alkyl, a heteroalkyl, an alkylene, an alkenylene, an alkynylene, a heteroalkylene, a carbocycle, a heterocycle, an aromatic ring, a non-aromatic ring, a substituted ring, a monocyclic ring, a polycyclic ring, or a combination thereof.
  • a peptibody comprising (a) an antibody, (b) a peptide described herein, and (c) a linker binding the peptide to the Fab region of the antibody; wherein the peptide and the antibody retain their activity in the peptibody.
  • the linker binds the peptide to an antigen binding site.
  • the linker comprises an alkyl, a heteroalkyl, an alkylene, an alkenylene, an alkynylene, a heteroalkylene, a carbocycle, a heterocycle, an aromatic ring, a non-aromatic ring, a substituted ring, a monocyclic ring, a polycyclic ring, or a combination thereof.
  • the antibody is an IgA, IgD, IgE, IgG, or IgM.
  • the inflammatory disease, disorder or condition is Atherosclerosis; Abdominal aortic aneurysm; Acute disseminated encephalomyelitis; Moyamoya disease; Takayasu disease; Acute coronary syndrome; Cardiac- allograft vasculopathy; Pulmonary inflammation; Acute respiratory distress syndrome; Pulmonary fibrosis; Acute disseminated encephalomyelitis; Addison's disease; Ankylosing spondylitis;
  • Antiphospholipid antibody syndrome Autoimmune hemolytic anemia; Autoimmune hepatitis; Autoimmune inner ear disease; Bullous pemphigoid; Chagas disease; Chronic obstructive pulmonary disease; Coeliac disease; Dermatomyositis; Diabetes mellitus type 1; Diabetes mellitus type 2; Endometriosis; Goodpasture's syndrome; Graves' disease; Guillain-Barre syndrome;
  • Hashimoto's disease Idiopathic thrombocytopenic purpura; Interstitial cystitis; Systemic lupus erythematosus (SLE); Metabolic syndrome; Multiple sclerosis; Myasthenia gravis; Myocarditis; Narcolepsy; Obesity; Pemphigus Vulgaris; Pernicious anaemia; Polymyositis; Primary biliary cirrhosis; Rheumatoid arthritis; Schizophrenia; Scleroderma; Sjogren's syndrome; Vasculitis;
  • Vitiligo Surprivo; Wegener's granulomatosis; Allergic rhinitis; Prostate cancer; Non-small cell lung carcinoma; Ovarian cancer; Breast cancer; Melanoma; Gastric cancer; Colorectal cancer; Brain cancer; Metastatic bone disorder; Pancreatic cancer; bladder cancer; hepatocellular cancer; liver cancer; adenocarcinoma of the lung; esophageal squamous cell carcinoma; CNS tumors;
  • hematological tumors a Lymphoma; Nasal polyps; Gastrointestinal cancer; Ulcerative colitis;
  • Encephalitis Nephritis; Tuberculosis; Retinitis; Atopic dermatitis; Pancreatitis; Periodontal gingivitis; Coagulative Necrosis; Liquefactive Necrosis; Fibrinoid Necrosis; Neointimal hyperplasia; Myocardial infarction; Stroke; organ transplant rejection; influenza, or combinations thereof.
  • composition of matter described herein to treat, prevent or reduce angiogenesis.
  • compositions for treating an inflammatory disease, disorder, condition or symptom in an individual in need thereof comprising a composition of matter described herein.
  • the terms "individual,” “subject,” or “patient” are used interchangeably. As used herein, they mean any mammal (i.e. species of any orders, families, and genus within the taxonomic classification animalia: chordata: vertebrata: mammalia). In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human. In some embodiments, the mammal is a member of the taxonomic orders: primates (e.g. lemurs, lorids, galagos, tarsiers, monkeys, apes, and humans); rodentia (e.g.
  • mice, rats, squirrels, chipmunks, and gophers mice, rats, squirrels, chipmunks, and gophers); lagomorpha (e.g. hares, rabbits, and pika); erinaceomorpha (e.g. hedgehogs and gymnures); soricomorpha (e.g. shrews, moles, and solenodons); chiroptera (e.g., bats); cetacea (e.g. whales, dolphins, and porpoises); carnivora (e.g. cats, lions, and other feliformia; dogs, bears, weasels, and seals); perissodactyla (e.g.
  • artiodactyla e.g. pigs, camels, cattle, and deer
  • proboscidea e.g. elephants
  • sirenia e.g. manatees, dugong, and sea cows
  • cingulata e.g. armadillos
  • pilosa e.g. anteaters and sloths
  • didelphimorphia e.g. american opossums
  • paucituberculata e.g. shrew opossums
  • microbiotheria e.g. Monito del Monte
  • notoryctemorphia e.g.
  • the animal is a reptile (i.e. species of any orders, families, and genus within the taxonomic classification animalia: chordata: vertebrata: reptilia). In some embodiments, the animal is a bird (i.e. animalia: chordata: vertebrata: aves).
  • a health care worker e.g. a doctor, a registered nurse, a nurse practitioner, a physician's assistant, an orderly, or a hospice worker.
  • the specified antibodies or binding molecules bind to a particular polypeptide, protein or epitope yet does not bind in a significant or undesirable amount to other molecules present in a sample.
  • the specified antibody or binding molecule does not undesirably cross-react with non-target antigens and/or epitopes.
  • a variety of immunoassay formats are used to select antibodies or other binding molecule that are immunoreactive with a particular polypeptide and have a desired specificity.
  • solid-phase ELISA immunoassays, BIAcore, flow cytometry and radioimmunoassays are used to select monoclonal antibodies having a desired immunoreactivity and specificity. See, Harlow, 1988, ANTIBODIES, A LABORATORY MANUAL, Cold Spring Harbor Publications, New York (hereinafter, "Harlow”), for a description of immunoassay formats and conditions that are used to determine or assess immunoreactivity and specificity.
  • “Selective binding,” “selectivity,” and the like refer the preference of agent to interact with one molecule as compared to another. Preferably, interactions between an agent disclosed herein and proteins are both specific and selective. Note that in some embodiments an agent is designed to "specifically bind” and “selectively bind” two distinct, yet similar targets without binding to other undesirable targets.
  • polypeptide peptide
  • protein protein
  • the terms apply to naturally occurring amino acid polymers as well as amino acid polymers in which one or more amino acid residues is a non-naturally occurring amino acid (e.g., an amino acid analog).
  • the terms encompass amino acid chains of any length, including full length proteins (i.e., antigens), wherein the amino acid residues are linked by covalent peptide bonds.
  • motif and domain are used interchangeably. As used herein, they mean a discrete, contiguous or non-contiguous portion of a polypeptide that folds independently of the rest of the polypeptide and possesses its own function.
  • disruption means to interfere with the function of.
  • to disrupt a motif/domain means to interfere with the function of the motif/domain.
  • an antigen refers to a substance that is capable of inducing the production of an antibody.
  • an antigen is a substance that specifically binds to an antibody variable region.
  • antibody refers to monoclonal antibodies, polyclonal antibodies, bi-specific antibodies, multispecific antibodies, grafted antibodies, human antibodies, humanized antibodies, synthetic antibodies, chimeric antibodies, camelized antibodies, single-chain Fvs (scFv), single chain antibodies, Fab fragments, F(ab') fragments, disulfide- linked Fvs (sdFv), intrabodies, and anti-idiotypic (anti-Id) antibodies and antigen-binding fragments of any of the above.
  • antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen binding site.
  • immunoglobulins can be assigned to different classes.
  • the heavy-chain constant motif/domains (Fc) that correspond to the different classes of immunoglobulins are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
  • Immunoglobulin molecules are of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG i ; IgG 2, IgG 3, IgG , IgA 1 and IgA 2 ) or subclass.
  • variable motif/domain refers to the variable motif/domains of antibodies that are used in the binding and specificity of each particular antibody for its particular antigen.
  • variability is not evenly distributed throughout the variable motif/domains of antibodies. Rather, it is concentrated in three segments called hypervariable regions (also known as CDRs) in both the light chain and the heavy chain variable motif/domains.
  • variable motif/domains More highly conserved portions of variable motif/domains are called the "framework regions" or "FRs.”
  • the variable motif/domains of unmodified heavy and light chains each contain four FRs (FR1, FR2, FR3 and FR4), largely adopting a ⁇ -sheet configuration interspersed with three CDRs which form loops connecting and, in some cases, part of the ⁇ -sheet structure.
  • the CDRs in each chain are held together in close proximity by the FRs and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), pages 647-669).
  • hypervariable region refers to the amino acid residues of an antibody which are responsible for antigen-binding.
  • the CDRs comprise amino acid residues from three sequence regions which bind in a complementary manner to an antigen and are known as CDRl, CDR2, and CDR3 for each of the V H and V L chains.
  • the CDRs typically correspond to approximately residues 24-34 (CDRLl), 50-56 (CDRL2) and 89-97 (CDRL3), and in the heavy chain variable motif/domain the CDRs typically correspond to approximately residues 31-35 (CDRHl), 50-65 (CDRH2) and 95-102 (CDRH3) according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). It is understood that the CDRs of different antibodies may contain insertions, thus the amino acid numbering may differ.
  • the Kabat numbering system accounts for such insertions with a numbering scheme that utilizes letters attached to specific residues (e.g., 27A, 27B, 27C, 27D, 27E, and 27F of CDRLl in the light chain) to reflect any insertions in the numberings between different antibodies.
  • the CDRs typically correspond to approximately residues 26-32 (CDRLl), 50-52 (CDRL2) and 91-96 (CDRL3)
  • the CDRs typically correspond to approximately residues 26-32 (CDRHl), 53-55 (CDRH2) and 96- 101 (CDRH3) according to Chothia and Lesk, J. Mol. Biol., 196: 901-917 (1987)).
  • Constant motif/domains (Fc) of antibodies are not involved directly in binding an antibody to an antigen but, rather, exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity via interactions with, for example, Fc receptors (FcR). Fc motif/domains can also increase bioavailability of an antibody in circulation following administration to a patient.
  • affinity refers to the equilibrium constant for the reversible binding of two agents and is expressed as Kd.
  • Affinity of a binding protein to a ligand such as affinity of an antibody for an epitope can be, for example, from about 100 nanomolar (nM) to about 0.1 nM, from about 100 nM to about 1 picomolar (pM), or from about 100 nM to about 1 femtomolar (flVI).
  • nM nanomolar
  • pM picomolar
  • flVI femtomolar
  • the term "avidity” refers to the resistance of a complex of two or more agents to dissociation after dilution.
  • peptide refers to a molecule comprising peptide(s) fused either directly or indirectly to an antibody or one or more antibody motif/domains (e.g., an Fc motif/domain of an antibody), where the peptide moiety specifically binds to a desired target.
  • the peptide(s) may be fused to either an Fc region or inserted into an Fc- Loop, a modified Fc molecule.
  • “peptibody” does not include Fc-fusion proteins (e.g., full length proteins fused to an Fc motif/domain).
  • isolated and purified refer to a material that is substantially or essentially removed from or concentrated in its natural environment.
  • an isolated nucleic acid is one that is separated from at least some of the nucleic acids that normally flank it or other nucleic acids or components (proteins, lipids, etc.) in a sample.
  • a polypeptide is purified if it is substantially removed from or concentrated in its natural environment. Methods for purification and isolation of nucleic acids and proteins are documented methodologies.
  • Embodiments of "substantially” include at least 20%, at least 40%, at least 50%, at least 75%, at least 85%, at least 90%, at least 95%, or at least 99%.
  • the terms "treat,” “treating” or “treatment,” and other grammatical equivalents as used herein, include alleviating, inhibiting or reducing symptoms, reducing or inhibiting severity of, reducing incidence of, prophylactic treatment of, reducing or inhibiting recurrence of, preventing, delaying onset of, delaying recurrence of, abating or ameliorating a disease or condition symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • the terms further include achieving a therapeutic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated, and/or the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual.
  • compositions include preventing additional symptoms, preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition and are intended to include prophylaxis.
  • the terms further include achieving a prophylactic benefit.
  • the compositions are optionally administered to an individual at risk of developing a particular disease, to an individual reporting one or more of the physiological symptoms of a disease, or to an individual at risk of reoccurrence of the disease.
  • the terms "effective amount” or "therapeutically effective amount” as used herein, refer to a sufficient amount of at least one agent being administered which achieve a desired result, e.g., to relieve to some extent one or more symptoms of a disease or condition being treated.
  • the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • the result is a decrease in the growth of, the killing of, or the inducing of apoptosis in at least one abnormally proliferating cell, e.g., a cancer stem cell.
  • an "effective amount” for therapeutic uses is the amount of the composition comprising an agent as set forth herein required to provide a clinically significant decrease in a disease.
  • An appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.
  • administer refers to the methods that are used to enable delivery of agents or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Administration techniques that are optionally employed with the agents and methods described herein, include e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In some embodiments, the agents and compositions described herein are administered orally.
  • pharmaceutically acceptable refers to a material that does not abrogate the biological activity or properties of the agents described herein, and is relatively nontoxic (i.e., the toxicity of the material significantly outweighs the benefit of the material). In some instances, a pharmaceutically acceptable material is administered to an individual without causing significant undesirable biological effects or significantly interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • MIF Macrophage Migration Inhibitory Factor
  • compositions of matter for treating inflammatory diseases, disorders, conditions and symptoms.
  • compositions of matter for treating inflammatory diseases, disorders, conditions and symptoms.
  • pharmaceutical compositions and methods of treating inflammatory diseases, disorders, conditions and symptoms are disclosed herein.
  • MIF is a pro-inflammatory cytokine. In certain instances, it is secreted by activated immune cells (e.g. a lymphocyte (T-cell)) in response to an infection, inflammation, or tissue injury. In certain instances, MIF is a ligand for the receptors CXCR2, CXCR4, CD44, and CD74. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits (partially or fully) the activity of CXCR2 CXCR4, CD44, and/or CD 74.
  • activated immune cells e.g. a lymphocyte (T-cell)
  • T-cell lymphocyte
  • MIF is a ligand for the receptors CXCR2, CXCR4, CD44, and CD74.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits (partially or fully) the activity of CXCR2 CXCR4, CD44, and/or CD 74.
  • MIF induces chemotaxis in nearby leukocytes (e.g. lymphocytes, granulocytes, monocytes/macrophages, and TH- 17 cells) along a MIF gradient.
  • leukocytes e.g. lymphocytes, granulocytes, monocytes/macrophages, and TH- 17 cells
  • a composition of matter, method and/or pharmaceutical composition disclosed herein prevents chemotaxis along a MIF gradient, or reduces chemotaxis along a MIF gradient.
  • MIF induces the chemotaxis of a leukocyte (e.g. lymphocytes, granulocytes,
  • a composition of matter, method and/or pharmaceutical composition disclosed herein prevents or decreases the chemotaxis of a leukocyte to the site of an infection, inflammation or tissue injury.
  • the chemotaxis of a leukocyte e.g. lymphocytes, granulocytes, monocytes/macrophages, and TH- 17 cells
  • a composition of matter, method and/or pharmaceutical composition disclosed herein treats inflammation at the site of infection, inflammation, or tissue injury.
  • the chemotaxis of monocytes along a RANTES gradient results in monocyte arrest (i.e., the deposition of monocytes on epithelium) at the site of injury or inflammation.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein prevents or decreases monocyte arrest at the site of injury or inflammation.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits treats a lymphocyte mediated disorder.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein treats a granulocyte mediated disorder.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein treats a macrophage mediated disorder.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein treats a Th- 17 mediated disorder.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein treats a pancreatic beta-cell mediated disorder.
  • MIF is inducible by glucocorticoids, a mechanism implicated in an acceleration of atherosclerosis associated with many diseases requiring glucocorticoid therapy.
  • the compositions and methods described herein inhibit the induction of MIF expression by glucocorticoids.
  • Human MIF peptide is encoded by a nucleotide sequence located on chromosome 22 at the cytogenic band 22ql 1.23.
  • a mature MIF protein is a homotrimer comprising three polypeptides of about 1 14 amino acids; the first methionine having been removed during translation from each of the MIF peptide monomers.
  • a human MIF peptide is encoded by the nucleic acid sequence SEQ ID No. 422:
  • a human MIF peptide is encoded by SEQ ID No. 1 :
  • a porcine MIF peptide is encoded by SEQ ID No. 2:
  • a bovine MIF peptide is encoded by SEQ ID No. 3:
  • a murine MIF peptide is encoded by SEQ ID No. 4:
  • a rat MIF peptide is encoded by SEQ ID No. 5:
  • a peptide disclosed herein comprises a sequence that competitively binds with a binding partner of the MIF pseudo ELR motif/domain .
  • the pseudo ELR motif/domain comprises two nonadjacent but adequately spaced residues (Argl2 and Asp45 & see Fig. 1 1).
  • the pseudo ELR motif/domain comprises the amino acid sequence from amino acid 12 to amino acid 45 (this numbering includes the first methionine residue). This is equivalent to a pseudo ELR motif/domain from amino acid 11 to amino acid 44 in which the first methionine residue is not counted (in such instances, the pseudo ELR motif/domain comprises Arg 1 1 and Asp 44).
  • a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits binding of the pseudo ELR motif/domain to CXCR2 and/or CXCR4. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein treats inflammatory diseases, disorders, conditions and symptoms by inhibiting binding of the pseudo ELR motif/domain to CXCR2 and/or CXCR4.
  • a MIF peptide comprises a 10- to 20-residue N-terminal Loop motif/domain (N-loop).
  • N-loop mediates binding to a CXCR2 and/or CXCR4 receptor.
  • the N-loop motif/domain of MIF comprises the sequential residues 44-57 of MIF (i.e., P45 D45 Q46 L47 M48 A49 F50 G51 G52 S53 S54 E55 P56 C57; see FIG. 1 1), where the first methionine is included. This is equivalent to amino acid 43 to amino acid 56 in which the first methionine residue is not counted.
  • the N-loop motif/domain of MIF comprises amino acids 45-60, where the first methionine is included. In certain instances, the N-loop motif/domain of MIF comprises amino acids 44-61 , where the first methionine is included. In certain instances, the N-loop motif/domain of MIF comprises amino acids 43-62. In certain instances, the N-loop motif/domain of MIF comprises amino acids 42-63, where the first methionine is included. In certain instances, the N-loop motif/domain of MIF comprises amino acids 41 -64, where the first methionine is included. In certain instances, the N-loop motif/domain of MIF comprises amino acids 40-65, where the first methionine is included.
  • the N-loop motif/domain of MIF comprises amino acids 46-59, where the first methionine is included. In certain instances, the N-loop motif/domain of MIF comprises amino acids 47-59, where the first methionine is included. In certain instances, the N-loop motif/domain of MIF comprises amino acids 48-59, where the first methionine is included. In certain instances, the N-loop motif/domain of MIF comprises amino acids 50-59, where the first methionine is included. In certain instances, the N-loop motif/domain of MIF comprises amino acids 47-58, where the first methionine is included. In certain instances, the N-loop motif/domain of MIF comprises amino acids 47-57, where the first methionine is included.
  • the N-loop motif/domain of MIF comprises amino acids 47-56, where the first methionine is included. In certain instances, the N-loop motif/domain of MIF comprises amino acids 48-58, where the first methionine is included. In some embodiments the N- loop motif/domain comprises amino acids 48-57, where the first methionine is included.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits binding of the N-loop motif/domain to CXCR2 and/or CXCR4. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein treats inflammatory diseases, disorders, conditions and symptoms by inhibiting binding of the N-loop motif/domain to CXCR2 and/or CXCR4.
  • a MIF polypeptide comprises the following motifs/domains: an N-terminal/pseudo-ELR motif/domain (MIFi_i 7 ), an alpha-helix #1 motif/domain (i.e., MIFi 8 _ 3 i), an MIF N-loop motif/domain (i.e., MIF 3 2_6o), a loop-barrel-loop motif/domain (i.e., MIF 64 _ 93 ), and a C-terminal motif/domain (i.e., MIF 90 - 114 ).
  • MIFi_i 7 N-terminal/pseudo-ELR motif/domain
  • MIFi 8 _ 3 i alpha-helix #1 motif/domain
  • MIF N-loop motif/domain i.e., MIF 3 2_6o
  • a loop-barrel-loop motif/domain i.e., MIF 64 _ 93
  • C-terminal motif/domain i.e., M
  • a MIF polypeptide comprises the following motifs/domains: an N-terminal tail (i.e., MIFi_ 7 ), a pseudo ELR-loop (i.e., MIF 7 7 ), an alpha-helix #1 motif/domain (i.e., MIF 18 .
  • a PPQ-loop i.e., MIF32-38
  • a PDQ-loop i.e., MIF43-56
  • an IGK- loop i.e., MIF 64 _ 71
  • an NRS-helix i.e., MIF 72 _ 89
  • a SPDR-loop i.e., MIF 90 _ 94
  • a C-terminal tail i.e., MIFioi.114.
  • a peptide disclosed herein competitively binds with a binding partner of one of the following domains: N-terminal/pseudo-ELR motif/domain ( ⁇ 447 ), the alpha-helix #1 motif/domain (i.e., MIFi 8 _ 3 i), the MIF N-loop motif/domain (i.e., MIF 32 _6o), the loop-barrel-loop motif/domain (i.e., MIF 64 _ 93 ), the C-terminal motif/domain (i.e., MIF 90414 ), or a combination of any of the aforementioned domains.
  • N-terminal/pseudo-ELR motif/domain ⁇ 447
  • the alpha-helix #1 motif/domain i.e., MIFi 8 _ 3 i
  • the MIF N-loop motif/domain i.e., MIF 32 _6o
  • the loop-barrel-loop motif/domain i.e.,
  • a peptide disclosed herein competitively binds with a binding partner of one of the following domains: N-terminal tail (i.e., MIFi_ 7 ), the pseudo ELR-loop (i.e., MIF 747 ), the alpha-helix #1 motif/domain (i.e., MIFi 8 _ 3 i), the PPQ-loop (i.e., MIF 32 - 3 8), the PDQ-loop (i.e., MIF 43 _ 56 ), the IGK-loop (i.e., MIF ⁇ i), the NRS- helix (i.e., MIF 72 _ 8 9), the SPDR-loop (i.e., MIF90-9 4 ), the C-terminal tail (i.e., MIF 10 i_ii 4 ), or a combination of any of the aforementioned domains.
  • a peptide disclosed herein competitively binds with a binding partner of MIF
  • a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits (1) binding of the N-loop motif/domain to CXCR2 and/or CXCR4; and (2) binding of the pseudo ELR motif/domain to CXCR2 and/or CXCR4.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein treats inflammatory diseases, disorders, conditions and symptoms by inhibiting (1) binding of the N-loop motif/domain to CXCR2 and/or CXCR4; and (2) binding of the pseudo ELR motif/domain to CXCR2 and/or CXCR4.
  • compositions of matter for treating inflammatory diseases, disorders, conditions and symptoms.
  • compositions of matter for treating inflammatory diseases, disorders, conditions and symptoms.
  • pharmaceutical compositions and methods of treating inflammatory diseases, disorders, conditions and symptoms are disclosed herein.
  • compositions of matter, methods, and pharmaceutical compositions that inhibit the ability of MIF to bind to CXCR2, CXCR4, CD44, CD74, or a combination thereof.
  • compositions of matter, methods, and pharmaceutical compositions that treat inflammatory diseases, disorders, conditions and symptoms by inhibiting the ability of MIF to bind to CXCR2, CXCR4, CD44, CD74, or a combination thereof.
  • occupying, masking, or otherwise disrupting motif/domains on MIF does not affect CXCR2, CXCR4, CD44 and/or CD74 signaling mediated by other agonists/ligands (e.g., CXCR2 interactions with IL-8/CXCL8, GROp/CXCL2, GROa, GROy, ENA78, NAP2; and CXCR4 interactions with Stromal Cell-Derived Factor- la (SDF- la)/CXCL12, and GP120).
  • CXCR2 interactions with IL-8/CXCL8, GROp/CXCL2, GROa, GROy, ENA78, NAP2 and CXCR4 interactions with Stromal Cell-Derived Factor- la (SDF- la)/CXCL12, and GP120.
  • Any amino acid in any of the peptides disclosed herein may be substituted with an unnatural or natural amino acid that corresponds to and functions as an effective substitute for the original amino acid, but does not substantially diminish binding or bioactivity relative to the parent peptide sequence.
  • the phrase "does not substantially diminish binding or bioactivity relative to the parent peptide sequence” means the modified peptide sequence has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the same activity of the parent peptide sequence.
  • Unnatural amino acids include, but are not limited to: D-amino acids such as D- phenylalanine (D-F) and D-cyclohexyl alanine (D-CA); norLeucine (NLe), L-cyclohexyl alanine (L- CA), and L-amino acid, alpha-aminobutyric acid (Abu).
  • D-amino acids such as D- phenylalanine (D-F) and D-cyclohexyl alanine (D-CA); norLeucine (NLe), L-cyclohexyl alanine (L- CA), and L-amino acid, alpha-aminobutyric acid (Abu).
  • an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid.
  • an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
  • a composition of matter inhibits the ability of MIF to interact with CXCR2, CXCR4, CD74, CD44 or a combination thereof.
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed, or monitored by disrupting the ability of MIF to interact with CXCR2, CXCR4, CD74, CD44 or a combination thereof.
  • the ability of MIF to interact with CXCR2, CXCR4, CD74, CD44 or a combination thereof is inhibited by occupying, masking, or otherwise disrupting motif/domains on MIF to which CXCR2, CXCR4, CD74 and/or CD44 bind.
  • the ability of MIF to interact with CXCR2, CXCR4, CD74, CD44 or a combination thereof is inhibited by occupying, masking, or otherwise disrupting all or a portion of a motif/domain selected from: an N-terminal/pseudo-ELR motif/domain (MIF ⁇ n), an alpha-helix #1 motif/domain (i.e., MIF 18 _ 31 ), an MIF N-loop
  • MIF 32 _ 6 o a loop-barrel-loop motif/domain
  • MIF 64 _ 93 a loop-barrel-loop motif/domain
  • C-terminal motif/domain i.e., MIFgo-m
  • the ability of MIF to interact with CXCR2, CXCR4, CD74, CD44 or a combination thereof is inhibited by occupying, masking, or otherwise disrupting all or a portion of a motif/domain selected from: an N-terminal tail (i.e., MIFi_ 7 ), a pseudo ELR-loop (i.e., MIF 7 _i 7 ), an alpha-helix #1 motif/domain (i.e., MIF 18êt 3 i), a PPQ-loop (i.e., MIF32- 38), a PDQ-loop (i.e., MIF43-56), an IGK-loop (i.e., MIF ⁇ i), an NRS-helix (i.e., MIF 72 .
  • a motif/domain selected from: an N-terminal tail (i.e., MIFi_ 7 ), a pseudo ELR-loop (i.e., MIF 7 _i 7 ), an alpha-helix #1
  • MIF 90 - 94 a SPDR-loop
  • C-terminal tail i.e., MIF 101 14 .
  • the ability of MIF to interact with CXCR2, CXCR4, CD74, CD44 or a combination thereof is inhibited by occupying, masking, or otherwise disrupting MIF 47 (leucine).
  • the ability of MIF to interact with CXCR2, CXCR4, CD74, CD44 or a combination thereof is inhibited by a small molecule, peptide, antibody, and/or peptibody occupying, masking, or otherwise disrupting one or more motifs/domains on MIF to which CXCR2, CXCR4, CD74 and/or CD44 bind.
  • occupying, masking, or otherwise disrupting one or more motifs/domains on MIF does not affect CXCR2 and CXCR4 signaling mediated by other agonists/ligands (e.g., IL-8/CXCL8, GRObeta/CXCL2 and/or Stromal Cell-Derived Factor- la (SDF- la)/CXCL12).
  • agonists/ligands e.g., IL-8/CXCL8, GRObeta/CXCL2 and/or Stromal Cell-Derived Factor- la (SDF- la)/CXCL12.
  • the pseudo-ELR motif/domain of MIF mediates ligand (e.g., CD44, CD74, CXCR2, CXCR4) binding to MIF.
  • ligand e.g., CD44, CD74, CXCR2, CXCR4
  • the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of thepseudo ELR motif/domain of MIF inhibits the ability of MIF to bind to CXCR2, CXCR4, CD74, CD44 or a combination thereof.
  • the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of theN-terminal tail (i.e., MIFi_ 7 ) and/or all or a portion of thepseudo ELR-loop (i.e., MIF 7 _ 17 ) inhibits the ability of MIF to bind to CXCR2, CXCR4, CD74, CD44 or a combination thereof.
  • the N-loop motif/domain of MIF mediates ligand (e.g., CD44, CD74, CXCR2, CXCR4) binding to MIF.
  • ligand e.g., CD44, CD74, CXCR2, CXCR4
  • the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of theN-loop motif/domain of MIF inhibits the ability of MIF to bind to CXCR2, CXCR4, CD74, CD44 or a combination thereof.
  • the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of thePPQ- loop (i.e., MIF 32 _38) and/or all or a portion of thePDQ-loop (i.e., MIF 4 3_5 6 ) inhibits the ability of MIF to to bind to CXCR2, CXCR4, CD74, CD44 or a combination thereof.
  • the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of theN-loop motif/domain of MIF invokes a conformational change in MIF that prevents receptor or substrate interactions.
  • the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of thePPQ-loop (i.e., MIF 32 _38) and/or all or a portion of thePDQ-loop (i.e., MIF 43 _ 56 ) invokes a conformational change in MIF that prevents receptor or substrate interactions.
  • amino acids 65-94 of MIF e.g., amino acids 65-94 of MIF
  • IGKIGGAQNRSYSKLLCGLLAERLRISPDR (SEQ ID No. 8); numbering includes the first methionine) mediate CXCR2 binding to MIF.
  • the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of amino acids 65-94 of MIF inhibits the ability of MIF to bind to CXCR2.
  • the binding of a peptide to all or a portion of amino acids 65-94 of MIF inhibits the ability of MIF to bind to CXCR2.
  • the binding of an antibody to all or a portion of amino acids 65-94 of MIF inhibits the ability of MIF to bind to CXCR2.
  • the binding of a peptibody to all or a portion of amino acids 65-94 of MIF inhibits the ability of MIF to bind to CXCR2. In some embodiments, the binding of a small molecule to amino acids all or a portion of 65-94 of MIF inhibits the ability of MIF to bind to CXCR2. [0089] In certain instances, amino acids 80-95 of MIF (e.g., LCGLLAERLRISPDRV (SEQ ID No. 9); numbering includes the first methionine) mediate ligand binding to MIF.
  • MIF e.g., LCGLLAERLRISPDRV (SEQ ID No. 9); numbering includes the first methionine
  • the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of amino acids 80-95 of MIF inhibits the ability of MIF to bind to a ligand. In some embodiments, the binding of a peptide to all or a portion of amino acids 80-95 of MIF inhibits the ability of MIF to bind to a ligand. In some embodiments, the binding of an antibody to all or a portion of amino acids 80-95 of MIF inhibits the ability of MIF to bind to a ligand.
  • the binding of a peptibody to all or a portion of amino acids 80-95 of MIF inhibits the ability of MIF to bind to a ligand. In some embodiments, the binding of a small molecule to all or a portion of amino acids 80-95 of MIF inhibits the ability of MIF to bind to a ligand.
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed or monitored by administering a peptide that occupies, masks, or otherwise disrupts all or a portion of a motif/domain on MIF to which CXCR2, CXCR4, CD74 and/or CD44 binds.
  • the peptide specifically binds to all or a portion of the pseudo ELR motif/domain of MIF.
  • the peptide specifically binds to all or a portion of the N-loop motif/domain of MIF.
  • the peptide specifically binds to all or a portion of both the pseudo-ELR and N-loop motifs.
  • the agent is a peptide that specifically binds to all or a portion of a peptide sequence as follows: VNTNVPPRASVPDGFLSELTQQLAQATGKPPQYIAVHVVPDQL (SEQ ID No. 10) and the corresponding feature/domain of at least one of a MIF monomer or MIF trimer; a peptide that specifically binds to all or a portion of a peptide sequence as follows:
  • PDQLMAFGGSSEPCALCSL SEQ ID No. 1 1
  • MIF monomer or MIF trimer a peptide that specifically binds to all or a portion of a peptide sequence as follows:
  • PDQLMAFGGSSEPCALCSLHSI SEQ ID No. 13
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed or monitored by administering an antibody that occupies, masks, or otherwise disrupts all or a portion of amotif/domain on MIF to which CXCR2, CXCR4, CD74 and/or CD44 binds.
  • the antibody specifically binds to all or a portion of the pseudo ELR motif/domain of MIF.
  • the antibody specifically binds to all or a portion of the N-loop motif/domain of MIF.
  • the antibody specifically binds to all or a portion of both the pseudo-ELR and N-loop motifs.
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed or monitored by administering a peptibody that occupies, masks, or otherwise disrupts all or a portion of a motif/domain on MIF to which CXCR2, CXCR4, CD74 and/or CD44 binds.
  • the peptibody specifically binds to all or a portion of the pseudo ELR motif/domain of MIF.
  • the peptibody specifically binds to all or a portion of the N-loop motif/domain of MIF.
  • the peptibody specifically binds to all or a portion of both the pseudo-ELR and N-loop motifs.
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed or monitored by administering a small molecule that occupies, masks, or otherwise disrupts all or a portion of a motif/domain on MIF to which CXCR2, CXCR4, CD 74 and/or CD44 binds.
  • the small molecule specifically binds to all or a portion of the pseudo ELR motif/domain of MIF.
  • the small molecule specifically binds to all or a portion of the N-loop motif/domain of MIF.
  • the small molecule specifically binds to all or a portion of both the pseudo-ELR and N-loop motifs.
  • composition of matter disrupts all or a portion of a motif/domain on CXCR2 to which CXCR4, MIF, CD44 and/or CD74 bind.
  • inflammatory disease, disorder, condition and symptom is treated, diagnosed, or monitored by administering an agent that occupies, masks, or otherwise disrupts all or a portion of a motif/domain on CXCR2 to which CXCR4, MIF, CD44 and/or CD74 bind.
  • composition of matter disrupts all or a portion of a motif/domain on CXCR4 to which CXCR2, MIF, CD44 and/or CD74 bind.
  • an XCR4 to which CXCR2, MIF, CD44 and/or CD74 bind.
  • inflammatory disease, disorder, condition and symptom is treated, diagnosed, or monitored by administering an agent that occupies, masks, or otherwise disrupts all or a portion of a motif/domain on CXCR4 to which CXCR2, MIF, CD44 and/or CD74 bind.
  • the agent that inhibits the binding of CXCR4, MIF, CD74 and/or CD44 to CXCR2 is a peptide. In some embodiments, the agent that inhibits the binding of CXCR2, MIF, CD74 and/or CD44 to CXCR4 is a peptide.
  • the agent that inhibits the binding of CXCR4, MIF, CD74 and/or CD44 to CXCR2 is an antibody.
  • the agent that inhibits the binding of CXCR2, MIF, CD74 and/or CD44 to CXCR4 is an antibody.
  • the agent that inhibits the binding of CXCR4, MIF, CD74 and/or CD44 to CXCR2 is a peptibody. In some embodiments, the agent that inhibits the binding of CXCR2, MIF, CD74 and/or CD44 to CXCR4 is a peptibody. [00100] In some embodiments, the agent that inhibits the binding of MIF, CD74 and/or CD44 to CXCR2 and/or CXCR4 is a derivative of hydroxycinnamate, Schiff-based tryptophan analogs, or imino-quinone metabolites of acetaminophen.
  • the agent that inhibits the binding of MIF, CD74 and/or CD44 to CXCR2 and/or CXCR4 is glyburide, probenicide, DIDS (4, 4- diisothiocyanatostilbene-2, 2- disulfonic acid), bumetanide, furosemide, sulfobromophthalein, diphenylamine-2-carboxylic acid, flufenamic acid, or combinations thereof.
  • the agent that inhibits the binding of MIF, CD74 and/or CD44 to CXCR2 is CXCL8(3-74) 11R/G31P; IL-8 (4 - 7 2); IL-8 (6 . 12) ; recombinant IL-8 (rIL-8); recombinant IL- 8,NMeLeu (rhIL-8 with an N-methylated leucine at position 25); (AAR)IL-8 (IL-8 with N-terminal Ala4-Ala5 instead of Glu4-Leu5); GRO-alpha (1 _ 73) (also known as CXCL1); GRO-alpha ( 4_7 3) ; GRO- alpha (5 _73); GRO-alpha (6 _ 7 3); recombinant GRO (rGRO); (ELR)PF4 (PF4 with an ELR seq.
  • PF4 recombinant PF4
  • Antileukinate Sch527123 (-hydroxy-N,N-dimethyl-3- ⁇ 2-[[(R)- 1 -(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut- 1 -enylamino ⁇ -benzamide); N-(3- (aminosulfonyl)-4-chloro-2-hydroxyphenyl)-N'-(2,3-dichlorophenyl) urea; SB-517785-M (GSK); SB 265610 (N-(2-Bromophenyl)-N'-(7-cyano-lH-benzotriazol-4-yl)urea); SB225002 (N-(2- Bromophenyl)-N'-(2-hydroxy-4-nitrophenyl)urea); SB455821 (GSK), SB272844 (GSK); DF2162 (4
  • the agent that inhibits the binding of MIF, CD74 and/or CD44 to CXCR4 is ALX40-4C (N-alpha-acetyl-nona-D-arginine amide acetate); AMD-070 (AMD 11070, AnorMED); Plerixafor (AMD3100); AMD3465(AnorMED); AMD8664 (l-pyridin-2-yl-N-[4- (l,4,7-triazacyclotetradecan-4-ylmethyl)benzyl]methanamine); KRH- 1636 (Kureha Chemical Industry Co. Limited); KRH-2731 (Kureha Chemical Industry Co. Limited); KRH-3955 (Kureha Chemical Industry Co.
  • T134 L- citrulline 16-TW70 substituted for the C-terminal amide by a carboxylic acid
  • T22 [Tyr 5 12 , Lys 7 ]- polyphemusin II
  • TW70 des-[Cys8, 13, Tyr9,12]-[D-LyslO, Prol 1]-T22
  • T140 H-Arg-Arg-Nal- Cys-Tyr- Arg-Lys-DLys-Pro-Tyr-Arg-Cit-Cys-Arg-OH
  • the agent that inhibits the binding of MIF, CD74 and/or CD44 to CXCR2 and/or CXCR4 is MIF is COR100140 (Genzyme Corp/Cortical Pty Ltd.); ISO-1 ((S,R)-3- (4-Hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid, methyl ester); 4-IPP (4-iodo-6- phenylpyrimidine); or combinations thereof.
  • a composition of matter disrupts all or a portion of a motif/domain on CD74 to which MIF, CD44, CXCR2, and/or CXCR4 bind.
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed, or monitored by administering an agent that occupies, masks, or otherwise disrupts all or a portion of a motif/domain on CD74 to which MIF, CD44, CXCR2, and/or CXCR4 bind.
  • the agent that inhibits the binding of MIF, CD44, CXCR2, CXCR4, or a combination thereof to CD74 is a peptide.
  • the agent that inhibits the binding of MIF, CD44, CXCR2, CXCR4, or a combination thereof to CD74 is an antibody. In some embodiments, the agent that inhibits the binding of MIF, CD44, CXCR2, CXCR4, or a combination thereof to CD74 is M-B741, 555538 (BD Pharmingen).
  • the agent that inhibits the binding of MIF, CD44, CXCR2, CXCR4, or a combination thereof to CD74 is a peptibody.
  • the agent that inhibits the binding of MIF, CD44, CXCR2, CXCR4, or a combination thereof to CD74 is a small molecule.
  • occupying, masking, or otherwise disrupting all or a portion of motifs/domains on MIF does not affect CD74 signaling mediated by other agonists/ligands (e.g., IL- 8/CXCL8, GRObeta/CXCL2 and/or Stromal Cell-Derived Factor- 1 a (SDF- 1 a)/CXCL 12).
  • agonists/ligands e.g., IL- 8/CXCL8, GRObeta/CXCL2 and/or Stromal Cell-Derived Factor- 1 a (SDF- 1 a)/CXCL 12).
  • a composition of matter disrupts all or a portion of a motif/domain on CD44 to which MIF, CD74, CXCR2, and/or CXCR4 bind.
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed, or monitored by administering an agent that occupies, masks, or otherwise disrupts all or a portion of a motif/domain on CD44 to which MIF, CD74, CXCR2, and/or CXCR4 bind.
  • the agent that inhibits the binding of MIF, CD74, CXCR2, CXCR4, or a combination thereof to CD44 is a peptide.
  • the agent that inhibits the binding of MIF, CD74, CXCR2, CXCR4, or a combination thereof to CD44 is an antibody.
  • the agent that inhibits the binding of MIF, CD74, CXCR2, CXCR4, or a combination thereof to CD44 is a peptibody.
  • the agent that inhibits the binding of MIF, CD74, CXCR2, CXCR4, or a combination thereof to CD44 is a small molecule.
  • a composition of matter disrupts the ability of MIF to bind to CXCR2, CXCR4, CD74, CD 44 or a combination thereof.
  • the composition of matter is a peptide that competitively binds with a binding partner of a MIF motif/domain (e.g., the pseudo-ELR, or N-Loop motif/domains).
  • a MIF motif/domain e.g., the pseudo-ELR, or N-Loop motif/domains.
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed, or monitored by disrupting the ability of MIF to bind to CXCR2, CXCR4, CD74, CD 44 or a combination thereof.
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed, or monitored by administering to an individual in need thereof a peptide that competitively binds with a binding partner of a MIF motif/domain (e.g., the pseudo-ELR, or N-Loop motif/domains).
  • a MIF motif/domain e.g., the pseudo-ELR, or N-Loop motif/domains.
  • the Peptide binds to CXCR2, CXCR4, CD74, CD44 or a combination thereof and thus prevents CXCR2, CXCR4, CD44 or CD74 from binding to MIF.
  • the Peptide adopts structural or functional features similar to the N- Loop motif/domain of MIF.
  • the peptide comprises the sequence of Formula (I):
  • X 1 is selected from the group consisting of threonine, glycine, proline and alanine;
  • X 2 is selected from the group consisting of glycine, asparagine, aspartic acid, and serine;
  • X 3 is selected from the group consisting of methionine, isoleucine, leucine, alanine, proline, lysine, glutamine, arginine and lysine;
  • X 4 is selected from the group consisting of methionine, isoleucine and leucine;
  • X 5 is selected from the group consisting of alanine, threonine, methionine, serine and valine;
  • X 6 is selected from the group consisting of phenylalanine, histidine, arginine and lysine;
  • X 7 is selected from the group consisting of aspartic acid, glutamic acid, threonine, glycine and alanine;
  • X 8 is selected from the group consisting of serine, threonine, lysine and arginine;
  • X 9 is selected from the group consisting of serine, asparagine, glycine, threonine, aspartic acid, glutamic acid, glutamine and histidine;
  • X 10 is selected from the group consisting of aspartic acid, glutamic acid, alanine and asparagine; and X 11 is selected from the group consisting of cysteine, alanine, serine, threonine and valine.
  • X 1 is proline.
  • X 2 is aspartic acid.
  • X 3 is leucine.
  • X 4 is methionine.
  • X 5 is alanine.
  • X 6 is phenylalanine.
  • X 7 is glycine.
  • X 8 is serine.
  • X 9 is serine.
  • X 10 is glutamic acid.
  • X 11 is serine cysteine.
  • the Peptide comprises 3 or more consecutive amino acids of human MIF 44 _57 (numbering includes the first methionine). In some embodiments, the Peptide comprises 3 or more consecutive amino acids of murine MIF 4 4_5 7 . In some embodiments, the Peptide comprises 3 or more consecutive amino acids of porcine MIF 44 _ 57 . In some embodiments, the Peptide comprises 3 or more consecutive amino acids of bovine MIF 4 4_5 7 . In some embodiments, the Peptide comprises 3 or more consecutive amino acids of rat MIF 44 _ 57 .
  • the peptide is selected from Table 1. Any amino acid in any of the peptides disclosed herein may be substituted with an unnatural or natural amino acid that corresponds to and functions as an effective substitute for the original amino acid, but does not substantially diminish binding or bioactivity relative to the parent peptide sequence.
  • Unnatural amino acids include, but are not limited to: D-amino acids such as D-phenylalanine (D-F) and D- cyclohexyl alanine (D-CA); norLeucine (NLe), L-cyclohexyl alanine (L-CA), and L-amino acid, alpha- aminobutyric acid (Abu).
  • an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid.
  • an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
  • LMAFGG (SEQ ID No. 22)
  • QLMAFGGSS (SEQ ID No. cyclo(SEPCAL) (SEQ ID No.
  • MAFGGSSEPCAL SEQ ID QLMAFGG (SEQ ID No. 72) cyclo(QLMAFGGSSEPCALC) No. 24) (SEQ ID No. 120)
  • MAFGGS SEPCA SEQ ID QLMAFG (SEQ ID No. 73) cyclo(QLMAFGGS SEPCAL) No. 25) (SEQ ID No. 121)
  • MAFGGS SEPC SEQ ID No. CSSEPCALC (SEQ ID No. 74) cyclo(QLMAFGGSSEPCA) 26) (SEQ ID No. 122)
  • MAFGGS SEP (SEQ ID No. CFGGSSEPCALC (SEQ ID No. cyclo(QLMAFGGSSEPC) 27) 75) (SEQ ID No. 123)
  • MAFGGS SE SEQ ID No. CLMAFGGSSEPCALC (SEQ cyclo(QLMAFGGSSEP) (SEQ 28) ID No. 76) ID No. 124)
  • AFGGSSEPCALC SEQ ID CAFGGSSEPCAC (SEQ ID cyclo(QLMAFGGS) (SEQ ID No. 31) No. 79) No. 127)
  • AFGGSSEPCAL SEQ ID CMAFGGSSEPC (SEQ ID No. cyclo(QLMAFGG) (SEQ ID No. 32) 80) No. 128)
  • AFGGSSEPCA SEQ ID No. CGGSSEPCAC (SEQ ID No. cyclo(QLMAFG) (SEQ ID No. 33) 81) 129)
  • AFGGSSEPC (SEQ ID No. NVPRASVPD (SEQ ID No. 82) cyclo(AFGGSSEPCALC) 34) (SEQ ID No. 130)
  • AFGGSSEP (SEQ ID No. 35)
  • VPDGFLSEL (SEQ ID No. 83)
  • cyclo(AFGGSSEPCAL) (SEQ ID No. 35)
  • AFGGSSE (SEQ ID No. 36)
  • CFGGSSEPC (SEQ ID No. 84) cyclo(AFGGSSEPCA) (SEQ ID No. 84)
  • AFGGSS (SEQ ID No. 37) lAVHVVPDQLMAFGGSSEPC cyclo(AFGGSSEPC) (SEQ ID No. 37)
  • FGGSSEPCALC SEQ ID CLHSIGKIGGAQNPvSYSKLL cyclo(AFGGSSEP) (SEQ ID No. 38) (SEQ ID No. 86) No. 134)
  • FGGSSEPCAL SEQ ID No. PCALLCSLHSIGKIG (SEQ ID cyclo(AFGGSSE) (SEQ ID 39) No. 87) No. 135)
  • FGGSSEPCA SEQ ID No. CSLHSIGKIGGAQNPv (SEQ cyclo(AFGGSS) (SEQ ID No. 40) ID No. 88) 136)
  • FGGSSEP (SEQ ID No. 42) GAQNRSYSKLLCGLLA cyclo(FGGSSEPCAL) (SEQ ID No. 42)
  • GGSSEPCALC SEQ ID No. ERLRISPDRVYINYY (SEQ ID cyclo(FGGSSEPC) (SEQ ID 44) No. 92) No. 140)
  • GGSSEPCAL SEQ ID No. cyclo(LMAFGGSSEPCALC) cyclo(FGGSSEP) (SEQ ID No. 45) (SEQ ID No. 93) 141)
  • GGSSEPCA (SEQ ID No. 46) cyclo(LMAFGGSSEPCAL) cyclo(FGGSSE) (SEQ ID No.
  • GGSSEPC (SEQ ID No. 47) cyclo(LMAFGGSSEPCA) cyclo(GGSSEPCALC) (SEQ ID No. 47)
  • GGSSEP (SEQ ID No. 48) cyclo(LMAFGGSSEPC) (SEQ cyclo(GGSSEPCAL) (SEQ ID NO: 48)
  • GSSEPCALC SEQ ID No. cyclo(LMAFGGSSEP) (SEQ ID cyclo(GGSSEPCA) (SEQ ID 49) No. 97) No. 145)
  • GSSEPCAL (SEQ ID No. 50) cyclo(LMAFGGSSE) (SEQ ID cyclo(GGSSEPC) (SEQ ID No.
  • GSSEPCA (SEQ ID No. 51) cyclo(LMAFGGSS) (SEQ ID cyclo(GGSSEP) (SEQ ID No.
  • GSSEPC (SEQ ID No. 52) cyclo(LMAFGGS) (SEQ ID No. cyclo(CSSEPCALC) (SEQ ID No.
  • GSSEPCALC SEQ ID No. cyclo(MAFGGSSEPCALC) cyclo(CFGGSSEPCC) (SEQ 54) (SEQ ID No. 102) ID No. 150
  • GSSEPCAL (SEQ ID No. 55) cyclo(MAFGGSSEPCAL) cyclo(CFGGSSEPC) (SEQ ID NO: 55)
  • GSSEPCA (SEQ ID No. 56) cyclo(MAFGGSSEPCA) (SEQ cyclo(CGSSEPCALC) (SEQ ID No. 104) ID No. 152)
  • the peptide is cyclic: CLMAFGGS SEPC (SEQ ID No. 422);
  • CGGLMAFGGS SEPGGC (SEQ ID NO. 425); CGGSLMAFGGSSEPSGGC (SEQ ID NO. 426); CGGSGLMAFGGSSEPGSGGC (SEQ ID NO. 427); CGGSGGLMAFGGSSEPGGSGGC (SEQ ID NO. 428); CLMAFGGS SEP [Abu] ALC (SEQ ID NO. 429); wherein Abu is isosteric L-amino acid, alpha-aminobutyric acid; CFGGSSEPCALC (SEQ ID NO. 441); CSSEPCALC (SEQ ID NO. 443); CFGGSSEPCC (SEQ ID NO. 444); CFGGSSEPC (SEQ ID NO. 445); CGSSEPCALCC (SEQ ID NO. 446); CAFGGSSEPCAC (SEQ ID NO. 449); CAFGGSSC (SEQ ID NO. 450);
  • CLMAFGGSSEC SEQ ID NO. 463
  • cyclic CLMAFGGSSEPSALC SEQ ID NO. 469
  • the peptide is linear: CLMAFGGSSEPCALC (SEQ ID No. 442); linera CAFGGSSC (SEQ ID No. 447); CAFGGSSEPCAC (SEQ ID NO. 448); CLMAFGGSSEC (SEQ ID NO. 464).
  • the peptide is: LMA[NLe]AFGGSSEPC[NLe] (SEQ ID NO. 430), wherein NLe is norLeucine; LMA[L-CA]AFGGSSEPC[L-CA] (SEQ ID NO. 431), wherein L-CA is
  • CLMAFGGS SEPCCGG SEQ ID NO. 453
  • CLMAFGGS SEPCGGG SEQ ID NO. 454)
  • a peptide disclosed herein competitively binds with a binding partner of of MIF 40 -49 (i.e., the peptide has the sequence VHVVPDQLMA (SEQ ID NO. 465)). In some embodiments, a peptide disclosed herein competitively binds with a binding partner of MIF 42 -51 (i.e., the peptide has the sequence VVPDQLMAFG (SEQ ID NO. 466)). In some embodiments, a peptide disclosed herein competitively binds with all or a portion of MIF 4 5_5 7 (i.e., the peptide has the sequence DQLMAFGGSSEPC (SEQ ID NO. 467)).
  • a peptide disclosed herein competitively binds with a binding partner of MIF 46 _ 55 (i.e., the peptide has the sequence QLMAFGGSSE (SEQ ID NO. 468)). In some embodiments, the peptide has the sequence:
  • VHVVPDQLMA (SEQ ID NO. 421), VVPDQLMAFG (SEQ ID NO. 461), DQLMAFGGSSEPC (SEQ ID NO. 462), or QLMAFGGSSE (SEQ ID NO. 69).
  • the peptide comprises the sequence of Formula (II):
  • X 1 is selected from the group consisting of valine, isoleucine, threonine, phenylalanine and leucine
  • X 2 is selected from the group asparagine, arginine, aspartic acid, glutamic acid, serine and alanine
  • X 3 is selected from the group valine, isoleucine, arginine, lysine and leucine
  • X 4 is selected from the group proline, alanine, cysteine and leucine;
  • X 5 is selected from the group arginine, lysine, glutamine, serine, alanine, aspartic acid, glutamic acid and asparagine;
  • X 6 is selected from the group alanine, aspartic acid, glutamic acid, asparagine, serine and glutamine
  • X 7 is selected from the group serine, glutamic acid, aspartic acid, asparagine, arginine, glycine, lysine and arginine;
  • X 8 is selected from the group valine, isoleucine and phenylalanine
  • X 9 is selected from the group aspartic acid, glutamic acid, valine, serine and threonine;
  • X 10 is selected from the group glycine, alanine, threonine, aspartic acid and glutamic acid.
  • X 1 is valine.
  • X 2 is asparagine.
  • X 3 is valine.
  • X 4 is proline.
  • X 5 is arginine.
  • X 6 is alanine.
  • X 7 is serine.
  • X 8 is valine.
  • X 9 is aspartic acid.
  • X 10 is glycine.
  • the Peptide comprises 3 or more consecutive amino acids of human MIFi_45 (numbering includes the first methionine). In some embodiments, the Peptide comprises 3 or more consecutive amino acids of murine MIFi_ 45 . In some embodiments, the Peptide comprises 3 or more consecutive amino acids of porcine MIFi ⁇ 5 . In some embodiments, the Peptide comprises 3 or more consecutive amino acids of bovine MIFi_ 45 . In some embodiments, the Peptide comprises 3 or more consecutive amino acids of rat MIFi ⁇ 5 .
  • the peptide is selected from Table 2 Any amino acid in any of the peptides disclosed herein may be substituted with an unnatural or natural amino acid that corresponds to and functions as an effective substitute for the original amino acid, but does not substantially diminish binding or bioactivity relative to the parent peptide sequence.
  • Unnatural amino acids include, but are not limited to: D-amino acids such as D-phenylalanine (D-F) and D- cyclohexyl alanine (D-CA); norLeucine (NLe), L-cyclohexyl alanine (L-CA), and L-amino acid, alpha- aminobutyric acid (Abu).
  • an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid.
  • an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
  • Peptide is cyclic: CPRASVPDGC (SEQ ID NO. 438),
  • CGGSGGPRASVPDGGGSGGC SEQ ID NO. 439
  • CNVPRASVPDGC SEQ ID NO. 440
  • the Peptide adopts structural or functional features similar to the amino acid residues 65-94 (numbering includes the first methionine).
  • the Peptide comprises a peptide of Formula (III): I/L-G-X ⁇ -X'-X ⁇ -X ⁇ N-X 7 ⁇
  • X I is selected from the group consisting of lysine, arginine, cysteine, serine and alanine;
  • X 2 is selected from the group consisting of isoleucine, valine and phenylalanine;
  • X 3 is selected from the group consisting of glycine, asparagine and serine;
  • X 4 is selected from the group consisting of glycine, proline, alanine, aspartic acid and glutamic acid
  • X 5 is selected from the group consisting of alanine, proline, lysine, arginine, asparagine, aspartic acid and glutamic acid;
  • X 6 is selected from the group consisting of glutamine, valine, lysine, arginine, leucine, aspartic acid and glutamic acid;
  • X 7 is selected from the group consisting of lysine, arginine, asparagine, isoleucine and valine;
  • X 8 is selected from the group consisting of serine, asparagine, glutamine, aspartic acid, glutamic acid, lysine and arginine;
  • X 9 is selected from the group consisting of tyrosine, histidine and asparagine;
  • X 10 is selected from the group consisting of serine, threonine and alanine;
  • X I I is selected from the group consisting of lysine, aspartic acid, glutamic acid, alanine, serine and glycine;
  • X 12 is selected from the group consisting of leucine, glutamine, lysine, arginine, leucine, serine and alanine;
  • X 13 is selected from the group consisting of cysteine, tyrosine, phenylalanine, serine, alanine and threonine;
  • X 14 is selected from the group consisting of glycine, aspartic acid, glutamic acid, lysine and arginine;
  • X 15 is selected from the group consisting of leucine, glutamine, isoleucine, histidine and phenylalanine;
  • X 16 is selected from the group consisting of leucine, methionine, isoleucine and cysteine;
  • X 17 is selected from the group consisting of alanine, threonine, serine, arginine, lysine, alanine, glutamine and glycine;
  • X 18 is selected from the group consisting of glutamic acid, aspartic acid, lysine and arginine;
  • X 19 is selected from the group consisting of arginine, histidine, glutamine, aspartic acid, glutamic acid, glycine, threonine and lysine;
  • X 20 is selected from the group consisting of arginine, histidine, glycine, asparagine, lysine, arginine, aspartic acid and glutamic acid;
  • X 21 is selected from the group consisting of serine, aspartic acid, glutamic acid, lysine, arginine and proline; X is selected from the group consisting of proline, alanine, lysine, arginine and glycine;
  • X 23 is selected from the group consisting of aspartic acid, glutamic acid, asparagine and alanine; and X 24 is selected from the group consisting of histidine, tyrosine, lysine and arginine.
  • X 1 is lysine.
  • X 2 is isoleucine.
  • X 3 is glycine.
  • X 4 is glycine.
  • X 5 is alanine.
  • X 6 is glutamine.
  • X 7 is arginine.
  • X 8 is serine.
  • X 9 is tyrosine.
  • X 10 is serine.
  • X 11 is lysine.
  • X 12 is leucine.
  • X 13 is cysteine.
  • X 14 is glycine. In some embodiments, X 15 is leucine. In some embodiments, X 16 is leucine. In some embodiments, X 17 is alanine. In some embodiments, X 18 is glutamic acid. In some embodiments, X 19 is arginine. In some embodiments,
  • X is arginine. In some embodiments, X is serine. In some embodiments, X is proline. In some embodiments, X 23 is aspartic acid. In some embodiments, X 24 is arginine.
  • the Peptide comprises 3 or more consecutive amino acids of human MIF 6 5_94. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of murine MIF 6 5_94. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of porcine MIF 6 5_94. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of bovine MIF 6 5_94. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of rat [00133] In some embodiments, the peptide is selected from Table 3.
  • Any amino acid in any of the peptides disclosed herein may be substituted with an unnatural or natural amino acid that corresponds to and functions as an effective substitute for the original amino acid, but does not substantially diminish binding or bioactivity relative to the parent peptide sequence.
  • Unnatural amino acids include, but are not limited to: D-amino acids such as D-phenylalanine (D-F) and D- cyclohexyl alanine (D-CA); norLeucine (NLe), L-cyclohexyl alanine (L-CA), and L-amino acid, alpha- aminobutyric acid (Abu).
  • an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid.
  • an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
  • GAQNRSYSKLLCGLLAE SEQ ALCSLHSIGKIGGAQNRSYSKLL (SEQ ID No. 232)
  • Peptide is: CVHVVPDQLMAC (SEQ ID NO. 451).
  • CD74 is transmembrane protein that binds MIF.
  • CD74 is a receptor for MIF.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits binding of the CD74 to CXCR2, CXCR4, MIF, CD44 or a combination thereof.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein treats inflammatory diseases, disorders, conditions and symptoms by inhibiting the binding of the CD74 to CXCR2, CXCR4, MIF, CD44.
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed, or monitored by administering to an individual in need thereof a peptide that competitively binds with a binding partner of a CD74 motif/domain (e.g., the C- terminal/extracellular (lumenal) motif/domain).
  • a CD74 motif/domain e.g., the C- terminal/extracellular (lumenal) motif/domain.
  • the peptide competitively binds with MIF, CD44, CXCR2, and/or CXCR4 and thus prevents CD74 from binding to MIF, CD44, CXCR2, and/or CXCR4.
  • the peptide- adopts structural or functional features similar to CD74.
  • the -peptide comprises 3 or more consecutive amino acids of human CD74. In some embodiments, the comprises 3 or more consecutive amino acids of bovine CD74. In some embodiments, the peptide comprises 3 or more consecutive amino acids of porcine CD74. In some embodiments, the peptide comprises 3 or more consecutive amino acids of murine CD74. In some embodiments, the peptide comprises 3 or more consecutive amino acids of rat CD74.
  • the peptide is selected from Table 4. Any amino acid in any of the peptides disclosed herein may be substituted with an unnatural or natural amino acid that corresponds to and functions as an effective substitute for the original amino acid, but does not substantially diminish binding or bioactivity relative to the parent peptide sequence.
  • Unnatural amino acids include, but are not limited to: D-amino acids such as D-phenylalanine (D-F) and D- cyclohexyl alanine (D-CA); norLeucine (NLe), L-cyclohexyl alanine (L-CA), and L-amino acid, alpha- aminobutyric acid (Abu).
  • an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid.
  • an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
  • KLPKPPKPVSKMRMA SEQ ID NO. 276
  • CVFPNGTEVPHTKSR SEQ ID NO. 309
  • a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits binding of the CXCR2 to CXCR4, MIF, CD44, CD74 or a combination thereof.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein treats inflammatory diseases, disorders, conditions and symptoms by inhibiting the binding of the CXCR2 to CXCR4, MIF, CD44, CD74 or a combination thereof.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits binding of the CXCR4 to CXCR2, MIF, CD44, CD74 or a combination thereof.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein treats inflammatory diseases, disorders, conditions and symptoms by inhibiting the binding of the CXCR4 to CXCR2, MIF, CD44, CD74 or a combination thereof.
  • a peptide disclosed herein competitively binds with a binding partner of a CXCR2 domain/motif.
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed or monitored by administering to an individual in need thereof a peptide that competitively binds with a binding partner of a CXCR2 motif/domain.
  • the peptide binds to MIF, CD74 and/or CD44 and thus prevents CXCR2 from binding to MIF, CD74 and/or CD44.
  • a peptide disclosed herein competitively binds with a binding partner of the CXCR2 extracellular loop 1 (i.e., CXCR2 108 -i2o), the extracellular loop 2 (i.e., CXCR2 184 _2i 2 ), and/or the extracellular loop 3 (i.e., CXCR2286-300) ⁇
  • a peptide disclosed herein competitively binds with a binding partner of the extracellular loop 2 (i.e., CXCR2i 84 _2i2), and/or CXCR2 extracellular loop 3 (i.e., CXCR2 2 86-3oo).
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed or monitored by administering to an individual in need thereof a peptide that competitively binds with a binding partner of the CXCR2 extracellular loop 1 (i.e., CXCR2i 0 8-i2o), the extracellular loop 2 (i.e., CXCR2i 84 _ 2 i2), and/or the extracellular loop 3 (i.e., CXCR2 286 _3oo).
  • CXCR2 extracellular loop 1 i.e., CXCR2i 0 8-i2o
  • the extracellular loop 2 i.e., CXCR2i 84 _ 2 i2
  • the extracellular loop 3 i.e., CXCR2 286 _3oo
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed or monitored by administering to an individual in need thereof a peptide that competitively binds with a binding partner of the CXCR2 extracellular loop 2 (i.e., CXCR2 184 _ 212 ), and/or CXCR2 extracellular loop 3 (i.e., CXCR2 286 _ 300 ).
  • a peptide disclosed herein competitively binds with a binding partner of CXCR2 N-terminus/domain (i.e., CXCR2 1 _ 39 ).
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed or monitored by administering to an individual in need thereof a peptide that competitively binds with a binding partner of the CXCR2 N-terminus/domain (i.e., CXCR2i_ 39 ).
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed or monitored by administering to an individual in need thereof a peptide that
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed or monitored by administering to an individual in need thereof a peptide that competitively binds with a binding partner of the CXCR4 extracellular loop 1 and/or extracellular loop 2.
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed or monitored by administering to an individual in need thereof a peptide that competitively binds with a binding partner of CXCR4 amino acids 182-202 (SEADDRYICDRFYPNDLWVVV).
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed or monitored by administering to an individual in need thereof a peptide that competitively binds with a binding partner of CXCR4 amino acids 185-199 (DDRYICDRF YPNDL W) .
  • the peptide binds to MIF, CD74 and/or CD44 and thus prevents CXCR4 from binding to MIF, CD74 and/or CD44.
  • the peptide comprises 3 or more consecutive amino acids of human CXCR2. In some embodiments, the peptide comprises 3 or more consecutive amino acids of bovine CXCR2. In some embodiments, the peptide comprises 3 or more consecutive amino acids of porcine CXCR2. In some embodiments, the peptide comprises 3 or more consecutive amino acids of murine CXCR2. In some embodiments, the peptide comprises 3 or more consecutive amino acids of rat CXCR2.
  • the peptide comprises 3 or more consecutive amino acids of human CXCR4. In some embodiments, the peptide comprises 3 or more consecutive amino acids of bovine CXCR4. In some embodiments, the peptide comprises 3 or more consecutive amino acids of porcine CXCR4. In some embodiments, the peptide comprises 3 or more consecutive amino acids of murine CXCR4. In some embodiments, the peptide comprises 3 or more consecutive amino acids of rat CXCR4. [00147] In some embodiments, the peptide is selected from Table 5.
  • Any amino acid in any of the peptides disclosed herein may be substituted with an unnatural or natural amino acid that corresponds to and functions as an effective substitute for the original amino acid, but does not substantially diminish binding or bioactivity relative to the parent peptide sequence.
  • Unnatural amino acids include, but are not limited to: D-amino acids such as D-phenylalanine (D-F) and D- cyclohexyl alanine (D-CA); norLeucine (NLe), L-cyclohexyl alanine (L-CA), and L-amino acid, alpha- aminobutyric acid (Abu).
  • an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid.
  • an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
  • CD44 is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion and migration.
  • human CD44 has the sequence:
  • murine CD44 has the sequence:
  • TRNLQSVDMKIGV SEQ ID No. 359
  • CD44 forms a complex with CD74.
  • inhibiting the binding of CD44 and CD74 reduces or inhibits (partially or fully) inflammation.
  • inhibiting the binding of CD44 and MIF reduces or inhibits (partially or fully) inflammation.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits binding of the CD44 to CXCR2, CXCR4, MIF, CD74 or a combination thereof. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein treats inflammatory diseases, disorders, conditions and symptoms by inhibiting the binding of the CD44 to CXCR2, CXCR4, MIF, CD74 or a combination thereof.
  • an inflammatory disease, disorder, condition and symptom is treated, diagnosed, or monitored by administering to an individual in need thereof a peptide that competitively binds with a binding partner of a CD44 motif/domain.
  • the Peptide binds to MIF, CXCR2, CXCR4, CD74, or a combination thereof.
  • the Peptide comprises 3 or more consecutive amino acids of human CD44. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of bovine CD44. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of porcine CD44. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of murine CD44. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of rat CD44.
  • the peptide is selected from Table 6. Any amino acid in any of the peptides disclosed herein may be substituted with an unnatural or natural amino acid that corresponds to and functions as an effective substitute for the original amino acid, but does not substantially diminish binding or bioactivity relative to the parent peptide sequence.
  • Unnatural amino acids include, but are not limited to: D-amino acids such as D-phenylalanine (D-F) and D- cyclohexyl alanine (D-CA); norLeucine (NLe), L-cyclohexyl alanine (L-CA), and L-amino acid, alpha- aminobutyric acid (Abu).
  • an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid.
  • an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
  • MDKFWWHTAWGLC SEQ ID NO. 388
  • MTADETRNLQ S VD SEQ ID NO. 419)
  • composition of matter disrupts the ability of MIF to bind to CXCR2, CXCR4, CD74, or a combination thereof.
  • the composition of matter is a fusion peptide that binds both the N-loop motif/domain of MIF and the pseudo-ELR
  • an inflammatory disease, disorder, condition, or symptom is treated by disrupting the ability of MIF to bind to CXCR2, CXCR4, CD74, or a combination thereof.
  • an inflammatory disease, disorder, condition, or symptom is treated by administering to an individual in need thereof a fusion peptide that binds both the N-loop motif/domain of MIF and the pseudo-ELR motif/domain of MIF.
  • the peptides that comprise the fusion peptide are derived from human MIF, bovine MIF, porcine MIF, murine MIF, rat MIF, or a combination thereof. In some embodiments, the peptides that comprise the fusion peptide are artificially constructed.
  • the fusion peptide comprises at least one peptide that competitively binds with a binding partner of the N-loop motif/domain of MIF, and at least one peptide that competitively binds with a binding partner of the pseudo ELR motif/domain of MIF.
  • the fusion peptide comprises (a) a first peptide that competitively binds with a binding partner of the N-loop motif/domain of MIF; and (b) a second peptide that competitively binds with a binding partner of the pseudo ELR motif/domain of MIF.
  • the fusion peptide comprise (a) a first peptide that competitively binds with a binding partner of the N- loop motif/domain of MIF; (b) a second peptide that competitively binds with a binding partner of the pseudo ELR motif/domain of MIF; and (c) a third peptide that competitively binds with a binding partner of the pseudo ELR motif/domain of MIF.
  • the fusion peptide comprise (a) a first peptide that competitively binds with a binding partner of the N-loop motif/domain of MIF; and (b) a second peptide that competitively binds with a binding partner of the pseudo ELR motif/domain of MIF; wherein the first peptide and the second peptide are chemically linked.
  • the fusion peptide comprise (a) a first peptide that competitively binds with a binding partner of the N-loop motif/domain of MIF; (b) a second peptide that that competitively binds with a binding partner of the pseudo ELR motif/domain of MIF; and (c) a third peptide that that competitively binds with a binding partner of the e pseudo ELR motif/domain of MIF; wherein the first peptide, the second peptide, and the third peptide are chemically linked.
  • the fusion peptide comprises (a) a first peptide having the sequence MAFGGSSEPC; and (b) a second peptide having the sequence NVPRA. In some embodiments, the fusion peptide comprises (a) a first peptide having the sequence MAFGGSSEPC; (b) a second peptide having the sequence NVPRA; and (c) a third peptide having the sequence SVPDG.
  • the methods and compositions disclosed herein comprise (a) a first peptide having the sequence LQDP; and (b) a second peptide having the sequence NVPRA.
  • the first peptide and the second peptide are directly bound to each other (e.g., via a covalent or ionic bond).
  • At least one peptide that competitively binds with a binding partner of the N-loop motif/domain of MIF and at least one peptide that competitively binds with a binding partner of the pseudo ELR motif/domain of MIF are indirectly bound to each other (e.g., via a linker).
  • at least one peptide that competitively binds with a binding partner of the N-loop motif/domain of MIF and at least one peptide that competitively binds with a binding partner of the pseudo ELR motif/domain of MIF are bound by a linker.
  • the linker binds (a) a first peptide that competitively binds with a binding partner of the N-loop motif/domain of MIF; and (b) a second peptide that competitively binds with a binding partner of the pseudo ELR motif/domain of MIF.
  • the fusion peptide is a peptide of Formula (IV):
  • Peptide 1 and Peptide 2 are selected from any peptide disclosed herein.
  • the linker binds (a) a first peptide that competitively binds with a binding partner of the N-loop motif/domain of MIF; (b) a second peptide that adopts structural or functional features similar to a first portion of the pseudo ELR motif/domain of MIF; and (c) a third peptide that adopts structural or functional features similar to a second portion of the pseudo ELR motif/domain of MIF.
  • the fusion peptide is a peptide of Formula (V):
  • a "linker” is any molecule capable of binding (e.g., covalently) to multiple peptides.
  • the linker binds to the peptide by a covalent linkage.
  • the covalent linkage comprises a ether bond, thioether bond, amine bond, amide bond, carbon-carbon bond, carbon-nitrogen bond, carbon-oxygen bond, or carbon-sulfur bond.
  • the linker is flexible. In some embodiments, the linker is rigid. In some embodiments, the linker is long enough to allow the fusion peptide to bind to both the pseudo- ELR and N-loop motif/domains of MIF.
  • the linker binds to two peptides. In some embodiments, the linker binds to three peptides.
  • a linker described herein binds to the C-terminus of one or more of the peptides that form the fusion peptide. In some embodiments, the linker binds to the N-terminus of one or more of the peptides that form the fusion peptide. In some embodiments, a linker described herein binds to the C-terminus of one or more of the peptides and the N-terminus of any remaining peptides.
  • the linker comprises a linear structure. In some embodiments, the linker comprises a non-linear structure. In some embodiments, the linker comprises a branched structure. In some embodiments, the linker comprises a cyclic structure.
  • the linker is an alkyl. In some embodiments, the linker is heteroalkyl.
  • the linker is an alkylene. In some embodiments, the linker is an alkenylene. In some embodiments, the linker is an alkynylene. In some embodiments, the linker is a heteroalkylene.
  • alkyl refers to an aliphatic hydrocarbon group.
  • the alkyl moiety may be a saturated alkyl or an unsaturated alkyl.
  • an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).
  • the "alkyl” moiety may have 1 to 10 carbon atoms (whenever it appears herein, a numerical range such as “1 to 10" refers to each integer in the given range; e.g. , "1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group could also be a "lower alkyl” having 1 to 6 carbon atoms.
  • the alkyl group of the compounds described herein may be designated as "C 1 -C 4 alkyl" or similar designations.
  • C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t- butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.
  • the linker comprises a ring structure (e.g., an aryl).
  • ring refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings can be optionally substituted. Rings can be monocyclic or polycyclic.
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms.
  • Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.
  • an aryl group can be a monoradical or a diradical (i.e., an arylene group).
  • cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms. Cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the ring is a cycloalkane. In some embodiments, the ring is a cycloalkene.
  • the ring is an aromatic ring.
  • aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer.
  • Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted.
  • aromatic includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic") groups (e.g., pyridine).
  • heterocyclic aryl or “heteroaryl” or “heteroaromatic” groups
  • pyridine e.g., pyridine
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
  • the ring is a heterocycle.
  • heterocycle refers to heteroaromatic and heteroalicyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • An example of a 3-membered heterocyclic group is aziridinyl.
  • An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine).
  • An example of a 5-membered heterocyclic group is thiazolyl.
  • An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl.
  • non- aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl,
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzo furazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol- 1 -yl or imidazol- 3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • a heterocycle group can be a monoradical or a diradical (i.e., a heterocyclene group).
  • the ring is fused.
  • fused refers to structures in which two or more rings share one or more bonds.
  • the ring is a dimer.
  • the ring is a trimer.
  • the ring is a substituted.
  • Carbocyclic or “carbocycle” refers to a ring wherein each of the atoms forming the ring is a carbon atom.
  • Carbocycle includes aryl and cycloalkyl. The term thus distinguishes carbocycle from heterocycle ("heterocyclic") in which the ring backbone contains at least one atom which is different from carbon (i.e., a heteroatom).
  • Heterocycle includes heteroaryl and
  • heterocycloalkyl Carbocycles and heterocycles can be optionally substituted.
  • the linker is substituted.
  • the term "optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from Ci-Cealkyl, C 3 -Cgcycloalkyl, aryl, heteroaryl, C2-C 6 heteroalicyclic, hydroxy, Ci-Cealkoxy, aryloxy, Ci-Cealkylthio, arylthio, Ci-Cealkylsulfoxide, arylsulfoxide, Ci-Cealkylsulfone, arylsulfone, cyano, halo, C 2 -Cgacyl, C 2 -Cgacyloxy, nitro, Cr
  • the protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art.
  • the linker is an amino acid.
  • the fusion peptide is a peptide of Formula (VI):
  • Peptide 1 and Peptide 2 are selected from any peptide disclosed herein.
  • the linker is an artificial amino acid. In some embodiments, the linker is a ⁇ -amino acid. In some embodiments, the linker is a ⁇ -amino acid.
  • the linker is a polyethylene glycol (PEG). In some embodiments, the linker is a diamino acid. In some embodiments, the linker is diaminopropionic acid.
  • the linker is hydrolyzible.
  • the fusion peptide is:
  • Peptide 1 , Peptide 2, and Peptide 3 are se ected from any peptide disclosed herein.
  • an inflammatory disease, disorder, condition, or symptom is treated by modulating the ability of MIF to form a homo-multimer. In some embodiments, an inflammatory disease, disorder, condition, or symptom is treated by disrupting the ability of MIF to form a trimer. In some embodiments, an inflammatory disease, disorder, condition, or symptom is treated by promoting MIF trimerization.
  • functionally-active (or, mature) MIF comprises three MIF peptide sequences (i.e., a trimer).
  • the pseudo ELR motif/domains of each MIF polypeptide form a ring in the trimer.
  • the N-loop motifs/domains of each MIF polypeptide extend outwards from the pseudo-ELR ring (see Figure 1).
  • residues 38-44 of one subunit interact with residues 48-50 of a second subunit.
  • residues 96-102 of one subunit interact with residues 107-109 of a second subunit.
  • a motif/domain on one subunit formed by N73 R74 S77 K78 C81 (numbering includes the first methionine) interacts with N110 S111 T112 (numbering includes the first methionine) of a second subunit.
  • a MIF trimerization disrupting agent is derived from and/or incorporates any or all of amino acid residues 38-44 of MIF (e.g., human, bovine, procine, murine, or rat).
  • a MIF trimerization disrupting agent is a peptide derived from and/or incorporates any or all of amino acid residues 48-50 of MIF (e.g., human, bovine, procine, murine, or rat).
  • a MIF trimerization disrupting agent is a peptide derived from and/or incorporates any or all of amino acid residues 57-66 of MIF (e.g., human, bovine, procine, murine, or rat).
  • a MIF trimerization disrupting agent is a peptide derived from and/or incorporates any or all of amino acid residues 61-70 of MIF (e.g., human, bovine, procine, murine, or rat). In some embodiments, a MIF trimerization disrupting agent is a peptide derived from and/or incorporates any or all of amino acid residues 96-102 of MIF (e.g., human, bovine, procine, murine, or rat).
  • a MIF trimerization disrupting agent is a peptide derived from and/or incorporates any or all of amino acid residues 107-109 of MIF (e.g., human, bovine, procine, murine, or rat).
  • a MIF trimerization disrupting agent is a peptide derived from and/or incorporates any or all of amino acid residues N73, R74, S77, K78, and C81 of MIF (e.g., human, bovine, procine, murine, or rat) (numbering includes the first methionine).
  • a MIF trimerization disrupting agent is a peptide derived from and/or incorporates any or all of amino acid residues Nl 10, SI 1 1, and Tl 12 of MIF (e.g., human, bovine, procine, murine, or rat) (numbering includes the first methionine).
  • a MIF trimerization disrupting agent is a peptide derived from and/or incorporates any or all of amino acid residues 57-66 of MIF (numbering includes the first methionine).
  • a MIF trimerization disrupting agent is a peptide of Formula (VII):
  • X 1 is selected from the group consisting of cysteine, alanine, serine, and threonine;
  • X 2 is selected from the group consisting of alanine, proline, glycine and cysteine;
  • X 3 is selected from the group consisting of leucine, valine and phenylalanine;
  • X 4 is selected from the group consisting of cysteine, glycine, threonine and isoleucine;
  • X 5 is selected from the group consisting of serine, valine, glutamine and asparagine;
  • X 6 is selected from the group consisting of leucine, valine, isoleucine and methionine;
  • X 7 is selected from the group consisting of histidine, cysteine, lysine, arginine, and leucine.
  • the MIF trimerization disrupting agent comprises 3 or more consecutive amino acids of human MIF 57 _ 6 6. In some embodiments, the MIF trimerization disrupting agent comprises 3 or more consecutive amino acids of murine MIF 57 _ 6 6. In some embodiments, the MIF trimerization disrupting agent comprises 3 or more consecutive amino acids of porcine MIF 57 _
  • the MIF trimerization disrupting agent comprises 3 or more consecutive amino acids of bovine MIF 57 _66. In some embodiments, the MIF trimerization disrupting agent comprises 3 or more consecutive amino acids of rat MIF 57 _ 6 6.
  • a MIF trimerization disrupting agent is an antibody that binds to any or all of amino acid residues 38-44 of MIF. In some embodiments, a MIF trimerization disrupting agent is an antibody that binds to any or all of amino acid residues 48-50 of MIF. In some embodiments, a MIF trimerization disrupting agent is an antibody that binds to any or all of amino acid residues 57-66 of MIF. In some embodiments, a MIF trimerization disrupting agent is an antibody that binds to any or all of amino acid residues 61 -70 of MIF.
  • a MIF trimerization disrupting agent is an antibody that binds to any or all of amino acid residues 96- 102 of MIF. In some embodiments, a MIF trimerization disrupting agent is an antibody that binds to any or all of amino acid residues 107- 109 of MIF. In some embodiments, a MIF trimerization disrupting agent is an antibody that binds to any or all of amino acid residues N73, R74, S77, K78, and C81 of MIF. In some embodiments, a MIF trimerization disrupting agent is an antibody that binds to any or all of amino acid residues Nl 10, S I 1 1, and Tl 12 of MIF.
  • a MIF trimerization disrupting agent is a small molecule that binds to any or all of amino acid residues 38-44 of MIF. In some embodiments, a MIF trimerization disrupting agent is a small molecule that binds to any or all of amino acid residues 48-50 of MIF. In some embodiments, a MIF trimerization disrupting agent is a small molecule that binds to any or all of amino acid residues 57-66 of MIF. In some embodiments, a MIF trimerization disrupting agent is a small molecule that binds to any or all of amino acid residues 61-70 of MIF. In some
  • a MIF trimerization disrupting agent is a small molecule that binds to any or all of amino acid residues 96- 102 of MIF. In some embodiments, a MIF trimerization disrupting agent is a small molecule that binds to any or all of amino acid residues 107- 109 of MIF. In some
  • a MIF trimerization disrupting agent is a small molecule that binds to any or all of amino acid residues N73, R74, S77, K78, and C81 of MIF. In some embodiments, a MIF trimerization disrupting agent is a small molecule that binds to any or all of amino acid residues N1 10, Si l l, and T1 12 of MIF.
  • a MIF trimerization disrupting agent is a peptibody that binds to any or all of amino acid residues 38-44 of MIF. In some embodiments, a MIF trimerization disrupting agent is a peptibody that binds to any or all of amino acid residues 48-50 of MIF. In some embodiments, a MIF trimerization disrupting agent is a peptibody that binds to any or all of amino acid residues 57-66 of MIF. In some embodiments, a MIF trimerization disrupting agent is a peptibody that binds to any or all of amino acid residues 61-70 of MIF.
  • a MIF trimerization disrupting agent is a peptibody that binds to any or all of amino acid residues 96- 102 of MIF. In some embodiments, a MIF trimerization disrupting agent is a peptibody that binds to any or all of amino acid residues 107- 109 of MIF. In some embodiments, a MIF trimerization disrupting agent is a peptibody that binds to any or all of amino acid residues N73, R74, S77, K78, and C81 of MIF. In some embodiments, a MIF trimerization disrupting agent is a peptibody that binds to any or all of amino acid residues N1 10, Si l l, and Tl 12 of MIF.
  • a peptide mimetic is used in place of the peptides described herein, including for use in the treatment or prevention of an inflammatory disorder.
  • such peptide mimetics have greater chemical stability, enhanced pharmacological properties (half- life, absorption, potency, efficacy, etc.), altered specificity (e.g., a broad-spectrum of biological activities), reduced antigenicity, and are more economically prepared.
  • peptide mimetics include covalent attachment of one or more labels or conjugates, directly or through a spacer (e.g., an amide group), to non-interfering positions(s) on the analog that are predicted by quantitative structure-activity data and/or molecular modeling. Such non-interfering positions generally are positions that do not form direct contacts with the receptor(s) to which the peptide mimetic specifically binds to produce the therapeutic effect.
  • Phage display peptide libraries have emerged as a technique in generating peptide mimetics (Scott, J. K. et al. (1990) Science 249:386; Devlin, J. J. et al. (1990) Science 249:404; US5,223,409, US5,733,731 ; US5,498,530; US5,432,018;US5,338,665;US5,922,545; WO 96/40987and WO 98/15833 (each of which is incorporated by reference for such disclosure).
  • random peptide sequences are displayed by fusion with coat proteins of filamentous phage.
  • the displayed peptides are affinity-eluted against an antibody-immobilized extracellular motif/domain (in this case PF4 or RANTES.
  • peptide mimetics are isolated by biopanning (Nowakowski, G.S, et al. (2004) Stem Cells 22: 1030-1038).
  • whole cells expressing MIF are used to screen the library utilizing FACs to isolate phage specifically bound cells.
  • the retained phages are enriched by successive rounds of biopanning and repropagation.
  • the best binding peptides are sequenced to identify key residues within one or more structurally related families of peptides.
  • the peptide sequences also suggest which residues to replace by alanine scanning or by mutagenesis at the DNA level.
  • mutagenesis libraries are created and screened to further optimize the sequence of the best binders. Lowman (1997)
  • structural analysis of protein-protein interaction is used to suggest peptides that competitiveky bind with a binding partners of polypeptides described herein.
  • the crystal structure resulting from such an analysis suggests the identity and relative orientation of critical residues of the polypeptide, from which a peptide is designed. See, e.g., Takasaki, et al. (1997) Nature Biotech, 15: 1266-70.
  • the agent is a peptide or polypeptide.
  • the peptide is: a peptide that competitively binds with a binding partner of
  • VNTNVPPRASVPDGFLSELTQQLAQATGKPPQYIAVHVVPDQL (SEQ ID No. 10); a peptide that competitively binds with a binding partner of PDQLMAFGGSSEPCALCSL (SEQ ID No. 1 1); a peptide that competitively binds with a binding partner of
  • VNTNVPPPvASVPDGFLSELTQQLAQATGKPPQYIAVHVVPDQLMAFGGSSEPCALCSL (SEQ ID No. 12); a peptide that competitively binds with a binding partner of
  • PDQLMAFGGSSEPCALCSLHSI (SEQ ID No. 13); or combinations thereof.
  • an inflammatory disease, disorder, condition, or symptom is treated by disrupting the ability of MIF to bind to CXCR2, CXCR4, CD74, or a combination thereof.
  • an inflammatory disease, disorder, condition, or symptom is treated by administering to an individual in need an antibody that binds to MIF, one or more MIF motifs.
  • an inflammatory disease, disorder, condition, or symptom is treated by administering to an individual in need an antibody that binds to CD44.
  • an inflammatory disease, disorder, condition, or symptom is treated by administering to an individual in need an antibody that binds to CD74.
  • an inflammatory disease, disorder, condition, or symptom is treated by administering to an individual in need an antibody that binds to CXCR2. In some embodiments, an inflammatory disease, disorder, condition, or symptom is treated by administering to an individual in need an antibody that binds to CXCR4.
  • the antibody is a human antibody or a humanized antibody.
  • the antibody is a human IgG.
  • the antibody is or comprises one or more polypeptides derived from a human IgGl , IgG4, IgG2, IgD, IgA or IgM.
  • An antibody disclosed herein is generated by any suitable method.
  • an antibody disclosed herein is generated by contacting a host (e.g., a mouse or rabbit) with an antigen.
  • the antigen is a MIF monomer.
  • the antigen is a MIF trimer.
  • the antigen is a fragment of a full- length MIF polypeptide.
  • the antigen is a polypeptide that encompasses all or part of MIF 50 -65.
  • the antigen is a polypeptide that encompasses all or part of the MIF N-terminal/pseudo-ELR motif/domain (MIF 1 7 ).
  • the antigen is a polypeptide that encompasses all or part of the MIF alpha-helix #1 motif/domain (i.e., MIFi 8 _ 3 i). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF N-loop motif/domain (i.e., MIF 3 2_6o). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF loop-barrel-loop motif/domain (i.e., MIF 6 4_93). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF C-terminal motif/domain (i.e., MIF 90 14 ).
  • the antigen is a polypeptide that encompasses all or part of the MIF N-terminal tail (i.e., MIF ⁇ ). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF pseudo ELR-loop (i.e., MIF 7 _ 17 ). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF PPQ-loop (i.e., MIF 32 _38). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF PDQ-loop (i.e., MIF 4 3_5 6 ).
  • the antigen is a polypeptide that encompasses all or part of the MIF IGK-loop (i.e., MIF 64 -71). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF NRS-helix (i.e., MIF 72 _89). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF SPDR-loop (i.e., MIF 90 - 94 ). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF C-terminal tail (i.e., MIF 101414 ).
  • an antibody disclosed herein is generated by contacting a host (e.g., a mouse or rabbit) with at least two antigens.
  • the antigens are selected from: a polypeptide that encompasses all or part of the MIF N-terminal/pseudo-ELR motif; a polypeptide that encompasses all or part of the MIF N-loop motif; a polypeptide that encompasses all or part of the MIF loop-barrel-loop motif; a polypeptide that encompasses all or part of the MIF C-terminal motif; a polypeptide that encompasses all or part of the MIF alpha-helix #1 motif; a polypeptide that encompasses all or part of the MIF N-terminal tail; a polypeptide that encompasses al or part of the MIF pseudo ELR motif/domain; a polypeptide that encompasses all or part of the MIF PPQ-loop; a polypeptide that
  • an antibody disclosed herein is generated by contacting a host (e.g., a mouse or rabbit) with at least three antigens.
  • the antigens are selected from: a polypeptide that encompasses all or part of the MIF N-terminal/pseudo-ELR motif; a polypeptide that encompasses all or part of the MIF N-loop motif; a polypeptide that encompasses all or part of the MIF loop-barrel-loop motif; a polypeptide that encompasses all or part of the MIF C-terminal motif; a polypeptide that encompasses all or part of the MIF alpha-helix #1 motif; a polypeptide that encompasses all or part of the MIF N-terminal tail; a polypeptide that encompasses al or part of the MIF pseudo ELR motif/domain; a polypeptide that encompasses all or part of the MIF PPQ-loop; a polypeptide that
  • an antibody disclosed herein is generated by contacting a host with a nucleic acid sequence encoding part or all of a MIF polypeptide (alternatively, "MIF nucleic acid sequence").
  • the MIF nucleic acid sequence has been cloned into an expression vector (e.g., a plasmid).
  • an expression vector e.g., a plasmid
  • the host is a mammal. In some embodiments, the host is a mouse, a rabbit, or a rat. In some embodiments, the host is a mammalian cell. In some embodiments, the host is a bacterial cell.
  • the MIF nucleic acid sequence is contacted with the host by injecting the MIF nucleic acid sequence into the host intramuscularly or intradermally. In some embodiments, the contacting further comprises applying an electric current to the site of injection (i.e., electroporation). In some embodiments, the MIF nucleic acid sequence is contacted with the host by use of a gene gun.
  • the nucleic acid sequence encoding part or all of a MIF polypeptide is expressed by a host cell (or a plurality of host cells) to generate an expressed MIF polypeptide.
  • the expressed MIF polypeptide is cysteinylated.
  • the expressed MIF polypeptide is phosphorylated.
  • the expressed MIF polypeptide is glycosylated.
  • a method of generating an antibody disclosed herein further comprises contacting the host with an adjuvant.
  • the adjuvant is administered as a nucleic acid sequence.
  • the adjuvant is administered as a polypeptide or polysaccharide.
  • the adjuvant is a cytokine, a lymphokine, or a combination thereof.
  • the adjuvant is an interleukin, a tumor necrosis factor, GM-CSF, or a combination thereof.
  • the adjuvant is B7-1, B7-2, CD40L, or a combination thereof.
  • the expression vector containing the MIF nucleic acid sequence further comprises a nucleic acid sequence encoding an adjuvant.
  • the host is contacted with a second expression vector encoding an adjuvant.
  • the nucleic acid sequence encodes the MIF N-terminal tail/pseudo- ELR motif. In some embodiments, the nucleic acid sequence encodes MIF 50 _65. In some
  • the nucleic acid sequence encodes the MIF N-loop motif. In some embodiments, the nucleic acid sequence encodes the MIF loop-barrel-loop motif. In some embodiments, the nucleic acid sequence encodes the MIF C-terminal motif. In some embodiments, the nucleic acid sequence encodes the MIF alpha-helix #1 motif/domain (i.e., TTCCTGAGCGAGCTGACACAGCAGCTGGCCCAGGCCACCGGC). In some embodiments, the nucleic acid sequence encodes the MIF N-terminal tail (i.e., CCC ATGTTC ATCGTGAAC ACC) .
  • the nucleic acid sequence encodes the MIF pseudo ELR motif/domain (i.e., AACGTGCCCAGAGCCAGCGTGCCCGACGGC). In some embodiments, the nucleic acid sequence encodes the MIF PPQ loop (i.e., AAGCCCCCTCAGTAT ATCGCC) . In some embodiments, the nucleic acid sequence encodes the MIF PDQ loop (i.e.,
  • the nucleic acid sequence encodes the MIF IGK-loop (i.e., ATCGGCAAGATCGGCGGAGCCC AG) . In some embodiments, the nucleic acid sequence encodes the MIF NRS-helix (i.e.,
  • the nucleic acid sequence encodes the SPDR loop (i.e.,
  • the nucleic acid sequence encodes the C-terminal tail (i.e.,
  • an antibody disclosed herein is generated by contacting a host with at least two nucleic acid sequences selected from: a sequence encoding the MIF N-terminal tail/pseudo-ELR motif, a sequence encoding the MIF N-loop motif, a sequence encoding the MIF loop-barrel-loop motif, a sequence encoding the MIF C-terminal motif, a sequence encoding the MIF alpha-helix #1 motif, a sequence encoding the MIF N-terminal tail, a sequence encoding the MIF pseudo ELR motif/domain, a sequence encoding the MIF PPQ loop, a sequence encoding the MIF PDQ loop, a sequence encoding the MIF IGK loop, a sequence encoding the MIF NRS helix, a sequence encoding the MIF SPDR loop, a sequence encoding the MIF C-terminal tail, and a sequence encoding MIF 50
  • an antibody disclosed herein is generated by contacting a host with a nucleic acid sequence encoding at least two MIF polypeptide motifs selected from: a sequence encoding the MIF N-terminal tail/pseudo-ELR motif, a sequence encoding the MIF N-loop motif, a sequence encoding the MIF loop-barrel-loop motif, a sequence encoding the MIF C-terminal motif, a sequence encoding the MIF alpha-helix #1 motif, a sequence encoding the MIF N-terminal tail, a sequence encoding the MIF pseudo ELR motif/domain, a sequence encoding the MIF PPQ loop, a sequence encoding the MIF PDQ loop, a sequence encoding the MIF IGK loop, a sequence encoding the MIF NRS helix, a sequence encoding the MIF SPDR loop, a sequence encoding the MIF C-terminal tail, and a sequence encoding the M
  • an antibody disclosed herein is generated by contacting a host with at least three nucleic acid sequences selected from: a sequence encoding the MIF N-terminal tail/pseudo-ELR motif, a sequence encoding the MIF N-loop motif, a sequence encoding the MIF loop-barrel-loop motif, a sequence encoding the MIF C-terminal motif, a sequence encoding the MIF alpha-helix #1 motif, a sequence encoding the MIF N-terminal tail, a sequence encoding the MIF pseudo ELR motif/domain, a sequence encoding the MIF PPQ loop, a sequence encoding the MIF PDQ loop, a sequence encoding the MIF IGK loop, a sequence encoding the MIF NRS helix, a sequence encoding the MIF SPDR loop, a sequence encoding the MIF C-terminal tail, and a sequence encoding MIF 50 _
  • an antibody disclosed herein is generated by contacting a host with a nucleic acid sequence encoding at least three MIF polypeptide motifs selected from: a sequence encoding the MIF N-terminal tail/pseudo-ELR motif, a sequence encoding the MIF N-loop motif, a sequence encoding the MIF loop-barrel-loop motif, a sequence encoding the MIF C-terminal motif, a sequence encoding the MIF alpha-helix #1 motif, a sequence encoding the MIF N-terminal tail, a sequence encoding the MIF pseudo ELR motif/domain, a sequence encoding the MIF PPQ loop, a sequence encoding the MIF PDQ loop, a sequence encoding the MIF IGK loop, a sequence encoding the MIF NRS helix, a sequence encoding the MIF SPDR loop, a sequence encoding the MIF C-terminal tail, and a sequence encoding the M
  • an antibody disclosed herein is produced via the use of a hybridoma.
  • a "hybridoma" is an immortalized antibody producing cell.
  • a host e.g., a mouse or a rabbit
  • B-cells from the host's spleen are extracted.
  • a hybridoma is generated by fusing (1) an extracted B-cell with (2) a myeloma cell (i.e., hypoxanthine-guanine-phosphoribosyl transferase negative, immortalized myeloma cells).
  • the B-cell and the myeloma cells are cultured together and exposed to an agent that renders their cell membranes more permeable (e.g., PEG).
  • the culture comprises a plurality of hybridoma, a plurality of myeloma cells, and a plurality of B-cells.
  • the cells are individual to culturing conditions that select for hybridoma (e.g., culturing with HAT media).
  • an individual hybridoma i.e., the clone
  • the hybridoma are isolated and cultured.
  • the hybridoma are injected into a laboratory animal.
  • the hybridoma are cultured in a cell culture.
  • the methods described herein comprise a humanized monoclonal antibody.
  • a humanized monoclonal antibody comprises heavy and light chain constant regions from a human source and variable regions from a murine source.
  • humanized immunoglobulins are constructed by genetic engineering.
  • humanized immunoglobulins comprise a framework that is identical to the framework of a particular human immunoglobulin chain (i.e., an acceptor or recipient), and three CDRs from a non-human (donor) immunoglobulin chain.
  • a limited number of amino acids in the framework of a humanized immunoglobulin chain are identified and chosen to be the same as the amino acids at those positions in the donor rather than in the acceptor.
  • a framework is used from a particular human immunoglobulin that is homologous to the donor immunoglobulin to be humanized. For example, comparison of the sequence of a mouse heavy (or light) chain variable region against human heavy (or light) variable regions in a data bank (for example, the National Biomedical Research Foundation Protein
  • immunoglobulin comprises light and heavy chains from different human antibody germline sequences as acceptor sequences; when such combinations are used, one can readily determine whether the VH and VL bind an epitope of interest using conventional assays (e.g., an ELISA).
  • the human antibody will be chosen in which the light and heavy chain variable regions sequences, taken together, are overall most homologous to the donor light and heavy chain variable region sequences.
  • higher affinity is achieved by selecting a small number of amino acids in the framework of the humanized immunoglobulin chain to be the same as the amino acids at those positions in the donor rather than in the acceptor.
  • the relevant framework amino acids to change are selected based on differences in amino acid framework residues between the donor and acceptor molecules.
  • the amino acid positions to change are residues known to be important or to contribute to CDR conformation (e.g., canonical framework residues are important for CDR conformation and/or structure).
  • the relevant framework amino acids to change are selected based on frequency of an amino acid residue at a particular framework position (e.g., comparison of the selected framework with other framework sequences within its subfamily can reveal residues that occur at minor frequencies at a particular position or positions).
  • the relevant framework amino acids to change are selected based on proximity to a CDR. In some embodiments, the relevant framework amino acids to change are selected based on known or predicted proximity to the antigen-CDR interface or predicted to modulate CDR activity. In some embodiments, the relevant framework amino acids to change are framework residues that are known to, or predicted to, form contacts between the heavy (VH) and light (VL) chain variable region interface. In some embodiments, the relevant framework amino acids to change are framework residues that are inaccessible to solvent.
  • amino acid changes at some or all of the selected positions are incorporated into encoding nucleic acids for the acceptor variable region framework and donor CDRs.
  • altered framework or CDR sequences are individually made and tested, or are sequentially or simultaneously combined and tested.
  • the variability at any or all of the altered positions is from a few to a plurality of different amino acid residues, including all twenty naturally occurring amino acids or functional equivalents and analogues thereof. In some embodiments, non-naturally occurring amino acids are considered.
  • the humanized antibody sequence is cloned into a vector.
  • any suitable vector is used.
  • the vector is a plasmid, viral e.g.
  • any suitable host cell is transformed with the vector expressing the humanized antibody sequence.
  • the host cell is bacteria, mammalian cells, yeast and baculovirus systems.
  • the expression of antibodies and antibody fragments in prokaryotic cells such as E. coli is well established in the art. For a review, see for example Pluckthun, A.
  • a mammalian expression system is used.
  • the mammalian expression system is dehydrofolate reductase deficient ("dhfr- ") Chinese hamster ovary cells.
  • dhfr- CHO cells are transfected with an expression vector containing a functional DHFR gene, together with a gene that encodes a desired humanized antibody.
  • DNA is transformed by any suitable method.
  • suitable techniques include, for example, calcium phosphate transfection, DEAE Dextran, electroporation, liposome-mediated transfection and transduction using retrovirus or other virus, e.g., vaccinia or, for insect cells, baculovirus.
  • suitable techniques include, for example, calcium chloride transformation, electroporation and transfection using bacteriophage.
  • a DNA sequence encoding an antibody or antigen-binding fragment thereof is prepared synthetically rather than cloned.
  • the DNA sequence is designed with the appropriate codons for the antibody or antigen-binding fragment amino acid sequence. In general, one will select preferred codons for the intended host if the sequence will be used for expression.
  • the complete sequence is assembled from overlapping oligonucleotides prepared by standard methods and assembled into a complete coding sequence. See, e.g., Edge, Nature, 292:756 (1981); Nambair et al., Science, 223: 1299 (1984); Jay et al., J. Biol. Chem., 259:631 1 (1984), each of which is which is incorporated herein by reference for such disclosure.
  • a composition of matter disrupts the ability of MIF to bind to CXCR2, CXCR4, CD74, or a combination thereof.
  • the composition of matter is a peptibody.
  • an inflammatory disease, disorder, condition, or symptom is treated by disrupting the ability of MIF to bind to CXCR2, CXCR4, CD 74, or a combination thereof.
  • an inflammatory disease, disorder, condition, or symptom is treated by administering to an individual in need thereof a peptibody.
  • the term "peptibody” refers to a molecule comprising peptide(s) bound (e.g., covalenly) either directly or indirectly to an antibody or one or more antibody motif/domains (e.g., an Fc motif/domain of an antibody), where the peptide moiety specifically binds to a desired target.
  • the peptide(s) may be fused to either an Fc region or inserted into an Fc- Loop, a modified Fc molecule.
  • the term “peptibody” does not include Fc-fusion proteins (e.g., full length proteins fused to an Fc motif/domain).
  • the peptibody comprises (a) an antibody, and (b) a peptide disclosed herein; wherein the peptide and the antibody retain their activity in the peptibody.
  • the peptide is bound (directly or indirectly) to the antibody.
  • the peptide is covalently bound (directly or indirectly) to the antibody.
  • the peptide is bound (directly or indirectly) to the Fab region of the antibody.
  • the peptide is bound (directly or indirectly) to the antigen binding site of the antibody.
  • the peptide binds to the antibody via a reactive side chain.
  • a reactive side chain may be present naturally or may be placed in an antibody by mutation.
  • the reactive residue of the antibody combining site may be associated with the antibody, such as when the residue is encoded by nucleic acid present in the lymphoid cell first identified to make the antibody.
  • the amino acid residue may arise by purposely mutating the DNA so as to encode the particular residue.
  • the reactive residue may be a non-natural residue arising, for example, by biosynthetic incorporation using a unique codon, tRNA, and aminoacyl-tRNA as discussed herein.
  • the amino acid residue or its reactive functional groups e.g., a nucleophilic amino group or sulfhydryl group
  • Catalytic antibodies are one source of antibodies that comprise one or more reactive amino acid side chains. Such antibodies include aldolase antibodies, beta lactamase antibodies, esterase antibodies, amidase antibodies, and the like.
  • the peptide is indirectly bound to the antibody via a linker.
  • the linker comprises an alkyl, a heteroalkyl, an alkylene, an alkenylene, an alkynylene, a heteroalkylene, a carbocycle, a heterocycle, an aromatic ring, a non-aromatic ring, a substituted ring, a monocyclic ring, a polycyclic ring, or a combination thereof.
  • the antibody is an IgA, IgD, IgE, IgG, or IgM. In some embodiments, the antibody is an IgA, IgD, IgE, IgG, or IgM. In some embodiments,
  • the antibody is a humanized antibody.
  • the peptibody is a CovXTM body.
  • an agent that binds to a MIF motif/domain disclosed herein is identified. In some embodiments, an agent that binds to a MIF motif/domain disclosed herein does not influence MIF-independent signaling events at CXCR2 and CXCR4.
  • a library of peptides covering the extracellular N-terminal motif/domain and/or the extracellular loops of CXCR2 and CXCR4 is generated.
  • the peptides range in size from about 5 amino acids to about 20 amino acid; from about 7 amino acids to about 18 amino acids; from about 10 amino acids to about 15 amino acids.
  • the peptide library is screened for inhibition of MIF -mediated signaling through CXCR2 and CXCR4 using any suitable method (e.g., HTS GPCR screening technology).
  • the peptide library is further screened for inhibition of 11-8 and/or SDF- 1 mediated signaling on CXCR2 and CXCR4.
  • a peptide is identified as a MIF motif/domain disrupting peptide if it inhibits MIF- signaling through CXCR2 and CXCR4 but allows SDF-1- and IL-8-mediated signaling through CXCR2 and CXCR4.
  • peptide sequences from the extracellular N-terminal motif/domain and the extracellular loops of CXCR2 and CXCR4 are arrayed onto a membrane.
  • the peptide sequences from the extracellular N-terminal motif/domain and the extracellular loops of CXCR2 and CXCR4 are arrayed onto a membrane are probed with full-length MIF.
  • the MIF is labeled (e.g., isotopically labeled, radioactively labeled, or fluorophore labeled).
  • peptide sequences to which labeled MIF specifically bound are assayed for inhibition of MIF-mediated signaling of CXCR2 and CXCR4.
  • the peptide sequences that inhibit MIF-mediated signaling of CXCR2 and CXCR4 are screened using any suitable method (e.g., GPCR screening assay).
  • any of the aforementioned peptides and/or polypeptides is used as a "model" to do structure- activity relationship (SAR) chemistry (as provided in detail herein).
  • SAR structure- activity relationship
  • the SAR chemistry yields smaller peptides.
  • the smaller peptides yield small molecules that disrupt the ability of MIF to bind to CXCR2 and/or CXCR4 (e.g., by determining the amino acid residues involved in disrupting the ability of MIF to bind to CXCR2 and/or CXCR4).
  • a MIF trimerization disrupting peptide is identified. In some embodiments, a MIF motif/domain trimerization disrupting peptide does not influence MIF- independent signaling events at CXCR2 and CXCR4.
  • a peptide and/or polypeptide derived from any of the aforementioned amino acid sequences is screened for inhibition of MIF-mediated signaling through CXCR2 and CXCR4 using any suitable method (e.g., HTS GPCR screening technology).
  • a peptide and/or polypeptide derived from any of the aforementioned amino acid sequences is used as a "model" to do structure- activity relationship (SAR) chemistry.
  • the SAR chemistry yields smaller peptides.
  • the smaller peptides yield small molecules that disrupt the ability of MIF to form a homotrimer (e.g., by figuring out the amino acid residues involved in disrupting the ability of MIF to form a homotrimer).
  • a MIF small molecule, peptide, and/or antibody antagonist is derived from and/or incorporates any or all of amino acid residues 1-45 of SEQ. ID. NO. 1.
  • a MIF small molecule, peptide, and/or antibody antagonist is a peptide derived from and/or incorporates any or all of amino acid residues 2-45 of SEQ. ID. NO. 1.
  • a MIF small molecule, peptide, and/or antibody antagonist is a peptide derived from and/or incorporates any or all of amino acid residues 3-45 of SEQ. ID. NO. 1.
  • a MIF small molecule, peptide, and/or antibody antagonist is a peptide derived from and/or incorporates any or all of amino acid residues 4-45 of SEQ. ID. NO. 1.
  • a MIF small molecule, peptide, and/or antibody antagonist is a peptide derived from and/or incorporates any or all of amino acid residues 5-45 of SEQ. ID. NO. 1.
  • a MIF small molecule, peptide, and/or antibody antagonist is a peptide derived from and/or incorporates any or all of amino acid residues 6-45 of SEQ. ID. NO.
  • a MIF small molecule, peptide, and/or antibody antagonist is a peptide derived from and/or incorporates any or all of amino acid residues 7-45 of SEQ. ID. NO.
  • a MIF small molecule, peptide, and/or antibody antagonist is a peptide derived from and/or incorporates any or all of amino acid residues 8-45 of SEQ. ID. NO.
  • a MIF small molecule, peptide, and/or antibody antagonist is a peptide derived from and/or incorporates any or all of amino acid residues 9-45 of SEQ. ID. NO. In some embodiments, a MIF small molecule, peptide, and/or antibody antagonist is a peptide derived from and/or incorporates any or all of amino acid residues 10-45 of SEQ. ID. NO.
  • a peptide and/or polypeptide derived from any of the aforementioned amino acid sequences e.g., amino acid residues 1 -45 of SEQ. ID. NO. 1 ; amino acid residues 2-45 of SEQ. ID. NO. 1 ; amino acid residues 3-45 of SEQ. ID. NO. 1 ; amino acid residues 4-45 of SEQ. ID. NO. 1 ; amino acid residues 5-45 of SEQ. ID. NO. 1 ; amino acid residues 6-45 of SEQ. ID. NO. 1 ; amino acid residues 7-45 of SEQ. ID. NO. 1 ; amino acid residues 8-45 of SEQ. ID. NO. 1 ; amino acid residues 9-45 of SEQ.
  • SAR structure-activity relationship
  • the SAR chemistry yields smaller peptides.
  • the smaller peptides yield small molecules that disrupt the ability of MIF to form a homotrimer (e.g., by determining the amino acid residues involved in disrupting the ability of MIF to form a homotrimer).
  • the antagonist of MIF is an siRNA molecule and/or an antisense molecule complementary to a MIF gene and/or MIF RNA sequence.
  • the siRNA and/or antisense molecule decreases the level or half- life of MIF mRNA and/or protein by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 80%, at least about 90%, at least about 95%, or substantially 100%.
  • a cell line that expresses a recombinant human CXCR4 plus human CD74 is a cell line (e.g., HEK293).
  • the cell line that expresses a recombinant human CXCR4 plus human CD74 is a non-human cell line (e.g., CHO).
  • inflammatory disease e.g., acute or chronic.
  • disorder e.g., acute or chronic.
  • symptom e.g., acute or chronic.
  • the methods and compositions described herein treat an inflammatory disease, disorder, condition, or symptom resulting from (either partially or fully) an infection.
  • the methods and compositions described herein treat an inflammatory disease, disorder, condition, or symptom resulting from (either partially or fully) damage to a tissue (e.g., by a burn, by frostbite, by exposure to a cytotoxic agent, or by trauma).
  • the methods and compositions described herein treat an inflammatory disease, disorder, condition, or symptom resulting from (either partially or fully) an autoimmune disorder.
  • the methods and compositions described herein treat an inflammatory disease, disorder, condition, or symptom resulting from (either partially or fully) the presence of a foreign body (e.g., a splinter). In some embodiments, the methods and compositions described herein treat an inflammatory disease, disorder, condition, or symptom resulting from exposure to a toxin and/or chemical irritant.
  • acute inflammation refers to inflammation characterized in that it develops over the course of a few minutes to a few hours, and ceases once the stimulus has been removed (e.g., an infectious agent has been killed by an immune response or administration of a therapeutic agent, a foreign body has been removed by an immune response or extraction, or damaged tissue has healed).
  • the short duration of acute inflammation results from the short half- lives of most inflammatory mediators.
  • acute inflammation begins with the activation of leukocytes (e.g., dendritic cells, endothelial cells and mastocytes).
  • leukocytes e.g., dendritic cells, endothelial cells and mastocytes.
  • the leukocytes release inflammatory mediators (e.g., histamines, proteoglycans, serine proteases, eicosanoids, and cytokines).
  • inflammatory mediators result in (either partially or fully) the symptoms associated with inflammation.
  • an inflammatory mediator dilates post capillary venules, and increases blood vessel permeability.
  • the increased blood flow that follows vasodilation results in (either partially or fully) rubor and calor.
  • permeability of the blood vessels results in an exudation of plasma into the tissue leading to edema. In certain instances, the latter allows leukocytes to migrate along a chemotactic gradient to the site of the inflammatory stimulant.
  • structural changes to blood vessels e.g., capillaries and venules
  • the structural changes are induced (either partially or fully) by monocytes and/or macrophages.
  • the structural changes include, but are not limited to, remodeling of vessels, and angiogenesis.
  • angiogenesis contributes to the maintenance of chronic inflammation by allowing for increased transport of leukocytes.
  • histamines and bradykinin irritate nerve endings leading to itching and/or pain.
  • chronic inflammation results from the presence of a persistent stimulant (e.g., persistent acute inflammation, bacterial infection (e.g., by Mycobacterium tuberculosis), prolonged exposure to chemical agents (e.g., silica, or tobacco smoke) and autoimmune reactions (e.g., rheumatoid arthritis)).
  • a persistent stimulant e.g., persistent acute inflammation, bacterial infection (e.g., by Mycobacterium tuberculosis), prolonged exposure to chemical agents (e.g., silica, or tobacco smoke) and autoimmune reactions (e.g., rheumatoid arthritis)
  • the persistent stimulant results in continuous inflammation (e.g., due to the continuous recruitment of monocytes, and the proliferation of macrophages).
  • the continuous inflammation further damages tissues which results in the additional recruitment of mononuclear cells thus maintaining and exacerbating the inflammation.
  • physiological responses to inflammation further include angiogenesis and fibrosis.
  • inflammatory diseases, disorders and conditions include, but are not limited to, Atherosclerosis; Abdominal aortic aneurysm; Acute disseminated encephalomyelitis; Moyamoya disease; Takayasu disease; Acute coronary syndrome; Cardiac-allograft vasculopathy; Pulmonary inflammation; Acute respiratory distress syndrome; Pulmonary fibrosis; Acute disseminated encephalomyelitis; Addison's disease; Ankylosing spondylitis; Antiphospholipid antibody syndrome; Autoimmune hemolytic anemia; Autoimmune hepatitis; Autoimmune inner ear disease; Bullous pemphigoid; Chagas disease; Chronic obstructive pulmonary disease; Coeliac disease; Dermatomyositis; Diabetes mellitus type 1; Diabetes mellitus type 2; Endometriosis; Goodpasture's syndrome; Grav
  • Gastrointestinal cancer Ulcerative colitis; Crohn's disorder; Collagenous colitis; Lymphocytic colitis; Ischaemic colitis; Diversion colitis; Behcet's syndrome; Infective colitis; Indeterminate colitis; Inflammatory liver disorder, Endotoxin shock, Septic shock, Rheumatoid spondylitis,
  • the inflammatory disease, disorder, or condition is a cancer.
  • the inflammatory disease, disorder or condition is Prostate cancer; Non-small cell lung carcinoma; Ovarian cancer; Breast cancer; Melanoma; Gastric cancer; Colorectal cancer; Brain cancer; Metastatic bone disorder; Pancreatic cancer; bladder cancer; hepatocellular cancer; liver cancer; adenocarcinoma of the lung; esophageal squamous cell carcinoma; CNS tumors (e.g., Glioblastoma and neuroblastoma); hematological tumors; a Lymphoma;, or combinations thereof.
  • the inflammatory disease, disorder, or conditionis is a cardiovascular disorder.
  • the inflammatory disease, disorder, or condition is: Atherosclerosis, peripheral vascular diseases, cerebrovascular disease (i.e., stroke), hypertension (i.e., high blood pressure), heart failure, rheumatic heart disease, bacterial endocarditis, cardiomyopathy, pulmonary circulation diseases, vein & lympatics diseases, or combinations thereof.
  • the methods and compositions described herein treat atherosclerosis.
  • atherosclerosis means inflammation of an arterial wall and includes all phases of atherogenesis (e.g., lipid deposition, intima-media thickening, and subintimal infiltration with monocytes) and all atherosclerotic lesions (e.g., Type I lesions to Type VIII lesions).
  • atherosclerosis results from (partially or fully) the accumulation of macrophages.
  • the methods and compositions described herein prevent the accumulation of macrophages, decrease the number of accumulated macrophages, and/or decrease the rate at which macrophages accumulate.
  • Atherosclerosis results from (partially or fully) the presence of oxidized LDL.
  • oxidized LDL damages an arterial wall.
  • the methods and compositions described herein prevent oxidized LDL-induced damage to an arterial wall, decrease the portion of an arterial wall damaged by oxidized LDL, decrease the severity of the damage to an arterial wall, and/or decrease the rate at which an arterial wall is damaged by oxidized LDL.
  • monocytes respond to (i.e., follow a chemotactic gradient to) the damaged arterial wall. In certain instances, the monocytes differentiate macrophages.
  • macrophages endocytose the oxidized-LDL (cells such as macrophages with endocytosed LDL are called "foam cells").
  • the methods and compositions described herein prevent the formation of foam cells, decrease the number of foam cells, and/or decrease the rate at which foam cells are formed.
  • a foam cell dies and subsequently ruptures.
  • the rupture of a foam cell deposits oxidized cholesterol into the artery wall.
  • the methods and compositions described herein prevent the deposition of oxidized cholesterol deposited onto an artery wall, decrease the amount of oxidized cholesterol deposited onto an artery wall, and/or decrease the rate at which oxidized cholesterol is deposited onto an arterial wall.
  • the arterial wall becomes inflamed due to the damage caused by the oxidized LDL.
  • the methods and compositions described herein prevent arterial wall inflammation, decrease the portion of an arterial wall that is inflamed, and/or decrease the severity of the inflammation.
  • the inflammation of arterial walls results in (either partially or full) the expression of matrix
  • MMP metalloproteinase
  • CD40 ligand CD40 ligand
  • TNF tumor necrosis factor
  • the methods and compositions described herein prevent the expression of matrix metalloproteinase (MMP)-2, CD40 ligand, and tumor necrosis factor (TNF)-a, or decrease the amount of matrix metalloproteinase (MMP)-2, CD40 ligand, and tumor necrosis factor (TNF)-a expressed.
  • cells form a hard covering over the inflamed area.
  • the methods and compositions described herein prevent the formation of the hard covering, decrease the portion of an arterial wall affected by the hard covering, and/or decrease the rate at which the hard covering is formed.
  • the cellular covering narrows an artery.
  • the methods and compositions described herein prevent arterial narrowing, decrease the portion of an artery that is narrowed, decrease the severity of the narrowing, and/or decrease the rate at which the artery is narrowed.
  • an atherosclerotic plaque results (partially or fully) in stenosis (i.e., the narrowing of blood vessel).
  • stenosis results (partially or fully) in decreased blood flow.
  • the methods and compositions described herein treat stenosis and/or restinosis.
  • the mechanical injury of stenotic atherosclerotic lesions by percutaneous intervention induces the development of neointimal hyperplasia.
  • the acute injury of the vessel wall induces acute endothelial denudation and platelet adhesion, as well as apoptosis of SMCs in the medial vessel wall.
  • the accumulation of phenotypically unique SMCs within the intimal layer in response to injury functions to restore the integrity of the arterial vessel wall but subsequently leads to the progressive narrowing of the vessel.
  • monocyte recruitment triggers a more sustained and chronic inflammatory response.
  • methods and compositions disclosed herein inhibit the accumulation of phenotypically unique SMCs within the intimal layer.
  • methods and compositions disclosed herein inhibit the accumulation of phenotypically unique SMCs within the intimal layer in an individual treated by balloon angioplasty or stenting.
  • the rupture of an atherosclerotic plaque results (partially or fully) in an infarction (e.g., myocardial infarction or stroke) to a tissue.
  • myocardial MIF expression is upregulated in surviving cardiomyocytes and macrophages following cute myocardial ischemic injury.
  • hypoxia and oxidative stress induce the secretion of MIF from cardiomyocytes through an atypical protein kinase C-dependent export mechanism and result in extracellular signal-regulated kinase activation.
  • increased serum concentrations of MIF are detected in individuals with acute myocardial infarction.
  • MIF contributes to macrophage accumulation in infarcted regions and to the proinflammatory role of myocyte-induced damage during infarction.
  • the methods and compositions described herein treat an infarction.
  • reperfusion injury follows an infarction.
  • the methods and compositions described herein treat reperfusion injury.
  • an antibody disclosed herein is administered to identify and/or locate an atherosclerotic plaque.
  • the antibody is labeled for imaging.
  • the antibody is labeled for medical imaging.
  • the antibody is labeled for radio-imaging, PET imaging, MRI imaging, and fluorescent imaging.
  • the antibody localizes to areas of the circulatory system with high concentrations of MIF.
  • an area of the circulatory system with high concentrations of MIF is an atherosclerotic plaque.
  • the labeled antibodies are detected by any suitable method (e.g., by use of a gamma camera, MRI, PET scanner, x-ray computed tomography (CT), functional magnetic resonance imaging (fMRI), and single photon emission computed tomography (SPECT)).
  • a gamma camera e.g., by use of a gamma camera, MRI, PET scanner, x-ray computed tomography (CT), functional magnetic resonance imaging (fMRI), and single photon emission computed tomography (SPECT)
  • CT x-ray computed tomography
  • fMRI functional magnetic resonance imaging
  • SPECT single photon emission computed tomography
  • an atherosclerotic plaque results (partially or fully) in the development of an aneurysm.
  • the methods and compositions described herein are administered to treat an aneurysm.
  • the methods and compositions described herein are administered to treat an abdominal aortic aneurysm ("AAA").
  • AAA abdominal aortic aneurysm
  • an "abdominal aortic aneurysm” is a localized dilatation of the abdominal aorta characterized by at least a 50% increase over normal arterial diameter.
  • the methods and compositions described herein decrease the dilation of the abdominal aorta.
  • abdominal aortic aneurysms result (partially or fully) from a breakdown of structural proteins (e.g., elastin and collagen).
  • a composition of matter, method and/or pharmaceutical composition disclosed herein partially or fully inhibits the breakdown of a structural protein (e.g., elastin and collagen).
  • a composition of matter, method and/or pharmaceutical composition disclosed herein facilitates the regeneration of a structural protein (e.g., elastin and collagen).
  • the breakdown of structural proteins is caused by activated MMPs.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein partially or fully inhibits the activation of an MMP.
  • a composition and/or method disclosed herein inhibits the upregulation of MMP- 1 , MMP-9 or MMP- 12.
  • MMPs are activated following infiltration of a section of the abdominal aorta by leukocytes (e.g., macrophages and neutrophils).
  • the methods and compositions described herein decrease the infiltration of leukocytes.
  • the MIF is upregulated in early abdominal aortic aneurysm.
  • leukocytes follow a MIF gradient to a section of the abdominal aorta that is susceptible to the development of an AAA (e.g., the section of the aorta affected by an atherosclerotic plaque, infection, cystic medial necrosis, arteritis, trauma, an anastomotic disruption producing pseudoaneurysms).
  • a composition of matter, method and/or pharmaceutical composition disclosed herein partially or fully inhibits the activity of MIF.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein partially or fully inhibits the ability of MIF to function as a chemokine for macrophages and neutrophils.
  • an antibody disclosed herein is administered to identify and/or locate an AAA in an individual in need thereof.
  • an individual in need thereof displays one or more risk factors for developing an AAA (e.g., 60 years of age or older; male; cigarette smoking; high blood pressure; high serum cholesterol; diabetes mellitus; atherosclerosis).
  • the antibody is labeled for imaging.
  • the antibody is labeled for medical imaging.
  • the antibody is labeled for radio-imaging, PET imaging, MRI imaging, and fluorescent imaging.
  • the antibody localizes to areas of the circulatory system with high concentrations of MIF.
  • an area of the circulatory system with high concentrations of MIF is a AAA.
  • the labeled antibodies are detected by any suitable method (e.g., by use of a gamma camera, MRI, PET scanner, x-ray computed tomography (CT), functional magnetic resonance imaging (fMRI), and single photon emission computed tomography (SPECT)).
  • CT computed tomography
  • fMRI functional magnetic resonance imaging
  • SPECT single photon emission computed tomography
  • a T-cell mediated autoimmune disorder is characterized by a T-cell mediated immune response against self (e.g., native cells and tissues).
  • T-cell mediated autoimmune disorders include, but are not limited to colitis, multiple sclerosis, arthritis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, acute pancreatitis, chronic pancreatitis, diabetes, insulin-dependent diabetes mellitus (IDDM or type I diabetes), insulitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, autoimmune hemolytic syndromes, autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, reactive arthritis, ankylosing spondylitis, silicone implant associated autoimmune disease, Sjogren's syndrome, systemic lupus erythematosus (SLE), vasculitis syndromes (e.g., giant cell arteritis, Behcet's disease & Wegener's granulomatosis), vitiligo, secondary hematologic manifestation of autoimmune diseases (e.g., anemia
  • Pain includes, but is not limited to acute pain, acute inflammatory pain, chronic inflammatory pain and neuropathic pain.
  • hypersensitivity refers to an undesireable immune system response. Hypersensitivity is divided into four categories. Type I hypersensitivity includes allergies (e.g., Atopy, Anaphylaxis, or Asthma). Type II hypersensitivity is cytotoxic/antibody mediated (e.g., Autoimmune hemolytic anemia, Thrombocytopenia, Erythroblastosis fetalis, or Goodpasture's syndrome). Type III is immune complex diseases (e.g., Serum sickness, Arthus reaction, or SLE). Type IV is delayed-type hypersensitivity (DTH), Cell-mediated immune memory response, and antibody-independent (e.g., Contact dermatitis, Tuberculin skin test, or Chronic transplant rejection).
  • DTH delayed-type hypersensitivity
  • DTH Cell-mediated immune memory response
  • antibody-independent e.g., Contact dermatitis, Tuberculin skin test, or Chronic transplant rejection.
  • allergy means a disorder characterized by excessive activation of mast cells and basophils by IgE.
  • the excessive activation of mast cells and basophils by IgE results (either partially or fully) in an inflammatory response.
  • the inflammatory response is local.
  • the inflammatory response results in the narrowing of airways (i.e., bronchoconstriction).
  • the inflammatory response results in inflammation of the nose (i.e., rhinitis).
  • the inflammatory response is systemic (i.e., anaphylaxis).
  • angiogenesis refers to the formations of new blood vessels.
  • angiogenesis occurs with chronic inflammation.
  • angiogenesis is induced by monocytes and/or macrophages.
  • a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits angiogenesis.
  • MIF is expressed in endothelial progenitor cells.
  • MIF is expressed in tumor-associated neovasculature.
  • the present invention comprises a method of treating a neoplasia.
  • a neoplastic cell induces an inflammatory response.
  • part of the inflammatory response to a neoplastic cell is angiogenesis.
  • angiogenesis facilitates the development of a neoplasia.
  • the neoplasia is: angiosarcoma, Ewing sarcoma, osteosarcoma, and other sarcomas, breast carcinoma, cecum carcinoma, colon carcinoma, lung carcinoma, ovarian carcinoma, pharyngeal carcinoma, rectosigmoid carcinoma, pancreatic carcinoma, renal carcinoma, endometrial carcinoma, gastric carcinoma, liver carcinoma, head and neck carcinoma, breast carcinoma and other carcinomas, Hodgkins lymphoma and other lymphomas, malignant and other melanomas, parotid tumor, chronic lymphocytic leukemia and other leukemias, astrocytomas, gliomas, hemangiomas, retinoblastoma, neuroblastoma, acoustic neuroma, neurofibroma, trachoma and pyogenic granulomas.
  • neovascularization comprising administering to said individual MIF or a MIF analogue.
  • sepsis is a disorder characterized by whole-body inflammation. In certain instances, inhibiting the expression or activity of MIF increases the survival rate of individuals with sepsis. In some embodiments, the methods and compositions described herein treat sepsis. In certain instances, sepsis results in (either partially or fully) myocardial dysfunction (e.g., myocardial dysfunction). In some embodiments, the methods and compositions described herein treat myocardial dysfunction (e.g., myocardial dysfunction) resulting from sepsis.
  • MIF induces kinase activation and phosphorylation in the heart (i.e., indicators of cardiac depression).
  • the methods and compositions described herein treat myocardial dysfunction (e.g., myocardial dysfunction) resulting from sepsis.
  • LPS induces the expression of MIF.
  • MIF is induced by endotoxins during sepsis and functions as an initiating factor in myocardial
  • the methods and compositions described herein inhibit myocardial inflammatory responses resulting from endotoxin exposure. In some embodiments, the methods and compositions described herein inhibit cardiac myocyte apoptosis resulting from endotoxin exposure. In some embodiments, the methods and compositions described herein inhibit cardiac dysfunction resulting from endotoxin exposure.
  • inhibition of MIF results in (either partially or fully) a significant increase in survival factors (e.g., Bcl-2, Bax, and phospho-Akt) and an improvement in
  • the methods and compositions described herein increase the expression of Bcl-2, Bax or phospho-Akt.
  • MIF mediates the late and prolonged cardiac depression after burn injury associated and/or major tissue damage.
  • the methods and compositions described herein treat prolonged cardiac depression after burn injury.
  • the methods and compositions described herein treat prolonged cardiac depression after major tissue damage.
  • MIF is released from the lungs during sepsis.
  • antibody neutralization of MIF inhibits the onset of and reduced the severity of autoimmune myocarditis.
  • the methods and compositions described herein treat autoimmune myocarditis.
  • compositions for modulating a disorder of a cardiovascular system comprising a synergistic combination of (a) agent that inhibits (i) MIF binding to CXCR2 and CXCR4 and/or (ii) MIF-activation of CXCR2 and CXCR4; (iii) the ability of MIF to form a homomultimer; or a combination thereof; and (b) a second agent selected from an agent that treats inflammatory diseases, disorders, conditions and symptoms (the "MIF-mediated disorder agent").
  • compositions for modulating a disorder of a cardiovascular system comprising a synergistic combination of (a) agent that inhibits (i) MIF binding to CXCR2 and CXCR4 and/or (ii) MIF-activation of CXCR2 and CXCR4; (iii) the ability of MIF to form a homomultimer; or a combination thereof; and (b) a second agent selected from an agent that treats a disorder a component of which is inflammation.
  • compositions for modulating a disorder of a cardiovascular system comprising a synergistic combination of (a) agent that inhibits (i) MIF binding to CXCR2 and CXCR4 and/or (ii) MIF-activation of CXCR2 and CXCR4; (iii) the ability of MIF to form a homomultimer; or a combination thereof ; and (b) a second agent selected from an agent a side-effect of which is undesired inflammation.
  • statins e.g., atorvastatin, lovastatin and simvastatin
  • administration of a statin results (partially or fully) in myositis.
  • the terms “pharmaceutical combination,” “administering an additional therapy,” “administering an additional therapeutic agent” and the like refer to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • the term “fixed combination” means that at least one of the agents described herein, and at least one co-agent, are both administered to an individual simultaneously in the form of a single entity or dosage.
  • non- fixed combination means that at least one of the agents described herein, and at least one co- agent, are administered to an individual as separate entities either simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more agents in the body of the individual.
  • the co-agent is administered once or for a period of time, after which the agent is administered once or over a period of time. In other instances, the co-agent is administered for a period of time, after which, a therapy involving the administration of both the co-agent and the agent are administered. In still other embodiments, the agent is administered once or over a period of time, after which, the co- agent is administered once or over a period of time.
  • cocktail therapies e.g. the administration of three or more active ingredients.
  • the terms "co-administration,” “administered in combination with” and their grammatical equivalents are meant to encompass administration of the selected therapeutic agents to a single individual, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • the agents described herein will be co-administered with other agents.
  • These terms encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
  • the agents described herein and the other agent(s) are administered in a single composition.
  • the agents described herein and the other agent(s) are admixed in the composition.
  • the agents described herein are not intended that the agents described herein be limited by the particular nature of the combination.
  • the agents described herein are optionally administered in combination as simple mixtures as well as chemical hybrids.
  • An example of the latter is where the agent is covalently linked to a targeting carrier or to an active pharmaceutical.
  • Covalent binding can be accomplished in many ways, such as, though not limited to, the use of a commercially available cross-linking agent.
  • combination treatments are optionally administered separately or concomitantly.
  • the co-administration of (a) agent disclosed herein; and (b) a second agent allows (partially or fully) a medical professional to increase the prescribed dosage of the MIF- mediated disorder agent.
  • statin-induced myositis is dose-dependent.
  • prescribing the agent allows (partially or fully) a medical professional to increase the prescribed dosage of statin.
  • the co-administration of (a) agent; and (b) a second agent enables (partially or fully) a medical professional to prescribe the second agent (i.e., co-administration rescues the MIF-mediated disorder agent).
  • the second agent is an agent that targets HDL levels by indirect means (e.g. CETP inhibition).
  • indirect means e.g. CETP inhibition.
  • combining a non-selective HDL therapy with agent disclosed herein; (2) a modulator of an interaction between RANTES and Platelet Factor 4; or (3) combinations thereof converts the second agent that targets HDL levels by indirect means into a more efficacious therapy.
  • the second agent is administered before, after, or simultaneously with the modulator of inflammation.
  • the second agent is niacin, a fibrate, a statin, a Apo-Al mimetic peptide (e.g., DF-4, Novartis), an apoA-I transcriptional up-regulator, an AC AT inhibitor, a CETP modulator, Glycoprotein (GP) Ilb/IIIa receptor antagonists, P2Y12 receptor antagonists, Lp-PLA2- inhibitors, an anti-TNF agent, an IL- 1 receptor antagonist, an IL-2 receptor antagonist, a cytotoxic agent, an immunomodulatory agent, an antibiotic, a T-cell co-stimulatory blocker, a disorder- modifying anti-rheumatic agent, a B cell depleting agent, an immunosuppressive agent, an anti- lymphocyte antibody, an alkylating agent, an anti-metabolite, a plant alkaloid, a terpenoids, a topoisomerase inhibitor, an antitumor antibiotic, a monoclonal antibody
  • the second active is niacin, bezafibrate; ciprofibrate; clofibrate; gemfibrozil; fenofibrate; DF4 (Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2); DF5; RVX- 208 (Resverlogix); avasimibe; pactimibe sulfate (CS-505); CI- 101 1 (2,6-diisopropylphenyl [(2, 4,6- triisopropylphenyl)acetyl]sulfamate); CI-976 (2,2-dimethyl-N-(2,4,6- trimethoxyphenyl)dodecanamide); VULM1457 (l -(2,6-diisopropyl-phenyl)-3-[4-(4'- nitrophenyl
  • XV 459 N(3)-(2-(3-(4-formamidinophenyl)isoxazolin-5-yl)acetyl)-N(2)-(l - butyloxycarbonyl)-2,3-diaminopropionate
  • SR 121566A (3-[N- ⁇ 4-[4-(aminoiminomethyl)phenyl ]- 1 ,3-thiazol-2-yl ⁇ -N-(l -carboxymethylpiperid-4-yl) aminol propionic acid, trihydrochloride);
  • FK419 ((S)-2-acetylamino-3-[(R)-[l -[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate); clopidogrel; prasugrel; cangrelor; AZD6140 (AstraZeneca); MRS 2395 (2,2-Dimethyl-propionic acid 3-(2-chloro-6-methylaminopurin-9-yl)- 2-(2,2-dimethyl- propionyloxymethyl) -propyl ester); BX 667 (Berlex Biosciences); BX 048 (Berlex Biosciences); darapladib (SB 480848); SB-435495 (Glaxo SmithKline); SB-222657 (Glaxo SmithKline); SB- 253514 (Glaxo SmithKline); alefacept, efalizumab, methotrexate, aci
  • NCI antibody anti-anb3 integrin
  • BIW-8962 BioWa Inc.
  • Antibody BC8 NCI
  • antibody muJ591 NCI
  • indium In 1 1 1 monoclonal antibody MN-14 NCI
  • yttrium Y 90 monoclonal antibody MN-14 NCI
  • F105 Monoclonal Antibody NIAID
  • Monoclonal Antibody RAV12 Raven Biotechnologies
  • CAT-192 Human Anti-TGF-Betal Monoclonal Antibody, Genzyme
  • antibody 3F8 NCI
  • 177Lu-J591 Weill Medical College of Cornell University
  • TB-403 Biolnvent International AB
  • anakinra azathioprine
  • cyclophosphamide cyclosporine A
  • leflunomide d-penicillamine
  • amitriptyline amitriptyline
  • nortriptyline chlorambucil
  • chlorambucil nitrogen mustard
  • prasterone
  • CNTO 328 Anti IL-6 Monoclonal Antibody, Centocor
  • ACZ885 fully human anti-interleukin-lbeta monoclonal antibody, Novartis
  • CNTO 1275 Full Human Anti-IL- 12 Monoclonal Antibody, Centocor
  • methylprednisolone aceponate mometasone furoate, paramethasone, prednicarbate, prednisone, rimexolone, tixocortol, triamcinolone, ulobetasol; cisplatin; carboplatin; oxaliplatin;
  • bleomycin plicamycin; mitomycin; trastuzumab; cetuximab; rituximab; bevacizumab; finasteride; goserelin; aminoglutethimide; anastrozole; letrozole; vorozole; exemestane; 4-androstene-3,6, 17- trione ("6-OXO"; l ,4,6-androstatrien-3, 17-dione (ATD); formestane; testolactone; fadrozole;
  • milatuzumab milatuzumab conjugated to doxorubicin; or combinations thereof.
  • composition for modulating an MIF -mediated disorder comprising a combination of (a) agent disclosed herein; and (b) gene therapy.
  • methods for modulating an MIF-mediated disorder comprising co-administering a combination of (a) agent disclosed herein; and (b) gene therapy.
  • the gene therapy comprises modulating the concentration of a lipid and/or lipoprotein (e.g., HDL) in the blood of an individual in need thereof.
  • modulating the concentration of a lipid and/or lipoprotein (e.g., HDL) in the blood comprises transfecting DNA into an individual in need thereof.
  • the DNA encodes an Apo Al gene, an LCAT gene, an LDL gene, an 11-4 gene, an IL-10 gene, an IL-lra gene, a galectin- 3 gene, or combinations thereof.
  • the DNA is transfected into a liver cell.
  • the DNA is transfected into a liver cell via use of ultrasound.
  • ultrasound For disclosures of techniques related to transfecting ApoAl DNA via use of ultrasound see U.S. Patent No. 7,21 1,248, which is hereby incorporated by reference for those disclosures.
  • an individual is administered a vector engineered to carry the human gene (the "gene vector").
  • the gene vector is a retrovirus.
  • the gene vector is not a retrovirus (e.g. it is an adenovirus; a lentivirus; or a polymeric delivery system such as
  • a retrovirus, adenovirus, or lentivirus will have a mutation such that the virus is rendered incompetent.
  • the vector is administered in vivo (i.e., the vector is injected directly into the individual, for example into a liver cell), ex vivo (i.e., cells from the individual are grown in vitro and transduced with the gene vector, embedded in a carrier, and then implanted in the individual), or a combination thereof.
  • the gene vector infects the cells at the site of administration (e.g. the liver).
  • the gene sequence is incorporated into the individual's genome (e.g. when the gene vector is a retrovirus).
  • the therapy will need to be periodically re-administered (e.g. when the gene vector is not a retrovirus).
  • the therapy is re-administered annually.
  • the therapy is re-administered semi-annually.
  • the therapy is re-administered when the individual's HDL level decreases below about 60 mg/dL.
  • the therapy is re- administered when the individual's HDL level decreases below about 50 mg/dL. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 45 mg/dL. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 40 mg/dL. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 35 mg/dL. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 30 mg/dL.
  • composition for modulating an MIF-mediated disorder comprising a combination of (a) agent disclosed herein; and (b) an RNAi molecule designed to silence the expression of a gene that participates in the development and/or progression of an MIF-mediated disorder (the "target gene”).
  • methods for modulating an MIF-mediated disorder comprising administering a combination of (a) agent disclosed herein; and (b) ) an RNAi molecule designed to silence the expression of a gene that participates in the development and/or progression of an MIF-mediated disorder (the "target gene”).
  • the target gene is Apolipoprotein B (Apo B), Heat Shock Protein 1 10 (Hsp 1 10), Proprotein Convertase Subtilisin Kexin 9 (Pcsk9), CyDl, TNF-a, IL- ⁇ , Atrial Natriuretic Peptide Receptor A (NPRA), GAT A- 3, Syk, VEGF, MIP-2, FasL, DDR- 1 , C5aR, AP- 1, or combinations thereof.
  • Apolipoprotein B Apolipoprotein B
  • Hsp 1 10 Heat Shock Protein 1 10
  • Pcsk9 Proprotein Convertase Subtilisin Kexin 9
  • CyDl CyDl
  • TNF-a TNF-a
  • IL- ⁇ Atrial Natriuretic Peptide Receptor A
  • NPRA Atrial Natriuretic Peptide Receptor A
  • GAT A- 3 Syk
  • VEGF FasL
  • DDR- 1 C5aR
  • the target gene is silenced by RNA interference (RNAi).
  • RNAi therapy comprises use of an siRNA molecule.
  • a double stranded RNA (dsRNA) molecule with sequences complementary to an mRNA sequence of a gene to be silenced e.g., Apo B, Hsp 1 10 and Pcsk9 is generated (e.g by PCR).
  • dsRNA double stranded RNA
  • a 20-25 bp siRNA molecule with sequences complementary to an mRNA sequence of a gene to be silenced is generated.
  • the 20-25 bp siRNA molecule has 2-5 bp overhangs on the 3' end of each strand, and a 5' phosphate terminus and a 3' hydroxyl terminus. In some embodiments, the 20-25 bp siRNA molecule has blunt ends.
  • Molecular Cloning A Laboratory Manual, second edition (Sambrook et al., 1989) and Molecular Cloning: A Laboratory Manual, third edition (Sambrook and Russel, 2001), jointly referred to herein as "Sambrook”); Current Protocols in Molecular Biology (F. M. Ausubel et al., eds., 1987, including supplements through 2001); Current Protocols in Nucleic Acid Chemistry John Wiley & Sons, Inc., New York, 2000) which are hereby incorporated by reference for such disclosure.
  • an siRNA molecule is "fully complementary" (i.e., 100%
  • an antisense molecule is "mostly complementary” (e.g., 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, or 70% complementary) to the target gene.
  • dsRNA or siRNA molecule after administration of the dsRNA or siRNA molecule, cells at the site of administration (e.g. the cells of the liver and/or small intestine) are transformed with the dsRNA or siRNA molecule.
  • the dsRNA molecule is cleaved into multiple fragments of about 20-25 bp to yield siRNA molecules.
  • the fragments have about 2bp overhangs on the 3 ' end of each strand.
  • an siRNA molecule is divided into two strands (the guide strand and the anti-guide strand) by an RNA-induced Silencing Complex (RISC).
  • the guide strand is incorporated into the catalytic component of the RISC (i.e. argonaute).
  • the guide strand specifically binds to a complementary RB 1 mRNA sequence.
  • the RISC cleaves an mRNA sequence of a gene to be silenced.
  • the expression of the gene to be silenced is down-regulated.
  • a sequence complementary to an mRNA sequence of a target gene is incorporated into a vector.
  • the sequence is placed between two promoters. In some embodiments, the promoters are orientated in opposite directions.
  • the vector is contacted with a cell. In certain instances, a cell is transformed with the vector. In certain instances following transformation, sense and anti-sense strands of the sequence are generated. In certain instances, the sense and anti-sense strands hybridize to form a dsRNA molecule which is cleaved into siRNA molecules. In certain instances, the strands hybridize to form an siRNA molecule.
  • the vector is a plasmid (e.g pSUPER; pSUPER.neo;
  • an siRNA molecule is administered to in vivo (i.e., the vector is injected directly into the individual, for example into a liver cell or a cell of the small intestine, or into the blood stream).
  • a siRNA molecule is formulated with a delivery vehicle (e.g., a liposome, a biodegradable polymer, a cyclodextrin, a PLGA microsphere, a PLCA microsphere, a biodegradable nanocapsule, a bioadhesive microsphere, or a proteinaceous vector), carriers and diluents, and other pharmaceutically-acceptable excipients.
  • a delivery vehicle e.g., a liposome, a biodegradable polymer, a cyclodextrin, a PLGA microsphere, a PLCA microsphere, a biodegradable nanocapsule, a bioadhesive microsphere, or a proteinaceous vector
  • a delivery vehicle e.g., a liposome, a biodegradable polymer, a cyclodextrin, a PLGA microsphere, a PLCA microsphere, a biodegradable nanocapsule
  • an siRNA molecule described herein is administered to the liver by any suitable manner (see e.g., Wen et al., 2004, World J Gastroenterol., 10, 244-9; Murao et al., 2002, Pharm Res., 19, 1808-14; Liu et al., 2003, Gene Ther., 10, 180-7; Hong et al., 2003, J Pharm Pharmacol., 54, 51-8; Herrmann et al., 2004, Arch Virol., 149, 161 1-7; and Matsuno et al., 2003, Gene Ther., 10, 1559-66).
  • an siRNA molecule described herein is administered
  • an siRNA molecule described herein is administered systemically (i.e., in vivo systemic absorption or accumulation of an siRNA molecule in the blood stream followed by distribution throughout the entire body).
  • Administration routes contemplated for systemic administration include, but are not limited to, intravenous, subcutaneous, portal vein, intraperitoneal, and intramuscular. Each of these administration routes exposes the siRNA molecules of the invention to an accessible diseased tissue (e.g., liver).
  • the therapy will need to be periodically re- administered.
  • the therapy is re-administered annually.
  • the therapy is re- administered semi-annually.
  • the therapy is administered monthly.
  • the therapy is administered weekly.
  • the therapy is re- administered when the individual's HDL level decreases below about 60 mg/dL.
  • the therapy is re-administered when the individual's HDL level decreases below about 50 mg/dL.
  • the therapy is re-administered when the individual's HDL level decreases below about 45 mg/dL.
  • the therapy is re-administered when the individual's HDL level decreases below about 40 mg/dL. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 35 mg/dL. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 30 mg/dL.
  • compositions for modulating an MIF-mediated disorder comprising a combination of (a) agent disclosed herein; and (b) an antisense molecule designed to inhibit the expression of and/or activity of a DNA or RNA sequence that participates in the development and/or progression of an MIF-mediated disorder (the "target sequence”).
  • methods for modulating an MIF-mediated disorder comprising co-administering (a) agent disclosed herein; and (b) an antisense molecule designed to inhibit the expression of and/or activity of a DNA or RNA sequence that participates in the development and/or progression of an MIF-mediated disorder (the "target sequence”).
  • inhibiting the expression of and/or activity of a target sequence comprises use of an antisense molecule complementary to the target sequence.
  • the target sequence is microRNA- 122 (miRNA- 122 or mRNA-122), secretory phospholipase A2 (sPLA2), intracellular adhesion molecule-1 (ICAM-1), GATA-3, NF- ⁇ B, Syk, or combinations thereof.
  • sPLA2 secretory phospholipase A2
  • ICAM-1 intracellular adhesion molecule-1
  • GATA-3 GATA-3
  • NF- ⁇ B NF- ⁇ B
  • Syk secretory phospholipase A2
  • inhibiting the expression of and/or activity of miR A-122 results (partially or fully) in a decrease in the concentration of cholesterol and/or lipids in blood.
  • an antisense molecule that is complementary to a target sequence is generated (e.g. by PCR). In some embodiments, the antisense molecule is about 15 to about 30 nucleotides. In some embodiments, the antisense molecule is about 17 to about 28 nucleotides. In some embodiments, the antisense molecule is about 19 to about 26 nucleotides. In some
  • the antisense molecule is about 21 to about 24 nucleotides.
  • RNA sequences See Molecular Cloning: A Laboratory Manual, second edition
  • the antisense molecules are single- stranded, double- stranded, circular or hairpin. In some embodiments, the antisense molecules contain structural elements (e.g., internal or terminal bulges, or loops).
  • an antisense molecule is "fully complementary” (i.e., 100% complementary) to the target sequence.
  • an antisense molecule is "mostly complementary” (e.g., 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, or 70% complementary) to the target RNA sequence.
  • the antisense molecule hybridizes to the target sequence.
  • hybridize means the pairing of nucleotides of an antisense molecule with corresponding nucleotides of the target sequence.
  • hybridization involves the formation of one or more hydrogen bonds (e.g., Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding) between the pairing nucleotides.
  • hybridizing results (partially or fully) in the degradation, cleavage, and/or sequestration of the RNA sequence.
  • a siRNA molecule is formulated with a delivery vehicle (e.g., a liposome, a biodegradable polymer, a cyclodextrin, a PLGA microsphere, a PLCA microsphere, a biodegradable nanocapsule, a bioadhesive microsphere, or a proteinaceous vector), carriers and diluents, and other pharmaceutically-acceptable excipients.
  • a delivery vehicle e.g., a liposome, a biodegradable polymer, a cyclodextrin, a PLGA microsphere, a PLCA microsphere, a biodegradable nanocapsule, a bioadhesive microsphere, or a proteinaceous vector
  • a delivery vehicle e.g., a liposome, a biodegradable polymer, a cyclodextrin, a PLGA microsphere, a PLCA microsphere, a biodegradable nanocapsule
  • an siRNA molecule described herein is administered to the liver by any suitable manner (see e.g., Wen et al., 2004, World J Gastroenterol., 10, 244-9; Murao et al., 2002, Pharm Res., 19, 1808-14; Liu et al., 2003, Gene Ther., 10, 180-7; Hong et al., 2003, J Pharm Pharmacol., 54, 51-8; Herrmann et al., 2004, Arch Virol., 149, 161 1-7; and Matsuno et al., 2003, Gene Ther., 10, 1559-66).
  • an siRNA molecule described herein is administered
  • iontophoretically for example to a particular organ or compartment (e.g., the liver or small intestine).
  • a particular organ or compartment e.g., the liver or small intestine.
  • Non- limiting examples of iontophoretic delivery are described in, for example, WO 03/043689 and WO 03/030989, which are hereby incorporated by reference for such disclosures.
  • an siRNA molecule described herein is administered systemically (i.e., in vivo systemic absorption or accumulation of an siRNA molecule in the blood stream followed by distribution throughout the entire body).
  • Administration routes contemplated for systemic administration include, but are not limited to, intravenous, subcutaneous, portal vein, intraperitoneal, and intramuscular. Each of these administration routes exposes the siRNA molecules of the invention to an accessible diseased tissue (e.g., liver).
  • the therapy will need to be periodically re- administered.
  • the therapy is re-administered annually.
  • the therapy is re- administered semi-annually.
  • the therapy is administered monthly.
  • the therapy is administered weekly.
  • the therapy is re- administered when the individual's HDL level decreases below about 60 mg/dL.
  • the therapy is re-administered when the individual's HDL level decreases below about 50 mg/dL.
  • the therapy is re-administered when the individual's HDL level decreases below about 45 mg/dL.
  • the therapy is re-administered when the individual's HDL level decreases below about 40 mg/dL. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 35 mg/dL. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 30 mg/dL.
  • the device mediated strategy comprises removing a lipid from an HDL molecule in an individual in need thereof (delipification), removing an LDL molecule from the blood or plasma of an individual in need thereof (delipification), or a combination thereof.
  • delivery removing a lipid from an HDL molecule in an individual in need thereof
  • LDL molecule from the blood or plasma of an individual in need thereof
  • delivery removing an LDL molecule from the blood or plasma of an individual in need thereof
  • the delipification therapy will need to be periodically re- administered.
  • the delipification therapy is re-administered annually.
  • the delipification therapy is re-administered semi-annually.
  • the delipification therapy is re-administered monthly.
  • the delipification therapy is re- administered semi-weekly.
  • the therapy is re- administered when the individual's HDL level decreases below about 60 mg/dL.
  • the therapy is re- administered when the individual's HDL level decreases below about 50 mg/dL.
  • the therapy is re-administered when the individual's HDL level decreases below about 45 mg/dL. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 40 mg/dL. In some embodiments, the therapy is re- administered when the individual's HDL level decreases below about 35 mg/dL. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 30 mg/dL.
  • compositions for treating an inflammatory disease, disorder, condition, or symptom comprising a therapeutically-effective amount of agent disclosed herein.
  • compositions herein are formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the agents into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).
  • the pharmaceutical composition for modulating a disorder of a cardiovascular system further comprises a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s).
  • the pharmaceutical compositions includes other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and/or buffers.
  • the pharmaceutical compositions also contain other therapeutically valuable substances.
  • the pharmaceutical formulations described herein are optionally administered to an individual by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
  • the pharmaceutical formulations described herein 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, and mixed immediate and controlled release formulations.
  • compositions described herein are formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by an individual to be treated, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
  • aqueous oral dispersions liquids, gels, syrups, elixirs, slurries, suspensions and the like
  • solid oral dosage forms aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, modified release formulations, delayed release formulations,
  • the pharmaceutical compositions described herein are formulated as multiparticulate formulations.
  • the pharmaceutical compositions described herein comprise a first population of particles and a second population of particles.
  • the first population comprises an agent.
  • the second population comprises an agent.
  • the dose of agent in the first population is equal to the dose of agent in the second population.
  • the dose of agent in the first population is not equal to (e.g., greater than or less than) the dose of agent in the second population.
  • the agent of the first population is released before the agent of the second population.
  • the second population of particles comprises a modified- release (e.g., delayed-release, controlled-release, or extended release) coating.
  • the second population of particles comprises a modified-release (e.g., delayed-release, controlled-release, or extended release) matrix.
  • a modified-release e.g., delayed-release, controlled-release, or extended release
  • Coating materials for use with the pharmaceutical compositions described herein include, but are not limited to, polymer coating materials (e.g., cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate); ammonio methacrylate copolymers (e.g., Eudragit® RS and RL); poly acrylic acid and poly acrylate and methacrylate copolymers (e.g., Eudragite S and L, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate, shellac); hydrogels and gel-forming materials (e.g., carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, poly vinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch, hydoxypropyl cellulose, hydroxypropyl
  • poly(hydroxyalkyl methacrylate) (m. wt. ⁇ 5 k-5,000 k), polyvinylpyrrolidone (m. wt. ⁇ 10 k-360 k), anionic and cationic hydrogels, polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (m. wt.
  • polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, Polyox® polyethylene oxides (m. wt.
  • AquaKeep® acrylate polymers diesters of polyglucan, crosslinked polyvinyl alcohol and poly N- vinyl-2-pyrrolidone, sodium starch; hydrophilic polymers (e.g., polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers, polyethylene oxides, methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of methacrylic acid or methacrylic acid, other acrylic
  • the second population of particles comprises a modified release matrix material.
  • Materials for use with the pharmaceutical compositions described herein include, but are not limited to microcrytalline cellulose, sodium carboxymethylcellulose,
  • hydoxyalkylcelluloses e.g., hydroxypropylmethylcellulose and hydroxypropylcellulose
  • polyethylene oxide alkylcelluloses (e.g., methylcellulose and ethylcellulose), polyethylene glycol, polyvinylpyrrolidone, cellulose acteate, cellulose acetate butyrate, cellulose acteate phthalate, cellulose acteate trimellitate, polyvinylacetate phthalate, polyalkylmethacrylates, polyvinyl acetate, or combinations thereof.
  • the first population of particles comprises a cardiovascular disorder agent.
  • the second population of particles comprises a (1) a modulator of MIF; (2) a modulator of an interaction between RANTES and Platelet Factor 4; or (3) combinations thereof.
  • the first population of particles comprises a (1) a modulator of MIF; (2) a modulator of an interaction between RANTES and Platelet Factor 4; or (3) combinations thereof.
  • the second population of particles comprises a cardiovascular disorder agent.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions are generally used, which optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments are optionally added to the tablets or dragee coatings for identification or to characterize different combinations of agent doses.
  • the solid dosage forms disclosed herein are in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol.
  • a tablet including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet
  • a pill including a sterile packaged powder,
  • the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast-melt tablet. Additionally, pharmaceutical formulations disclosed herein are optionally administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.
  • dosage forms include microencapsulated formulations.
  • one or more other compatible materials are present in the microencapsulation material.
  • Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti- foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.
  • Exemplary microencapsulation materials useful for delaying the release of the formulations including a MIF receptor inhibitor include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF- LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such as Opa
  • HPC
  • Liquid formulation dosage forms for oral administration are optionally aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).
  • the liquid dosage forms optionally include additives, such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancing agents, (f) at least one sweetening agent, and (g) at least one flavoring agent.
  • the aqueous dispersions further include a crystal- forming inhibitor.
  • the pharmaceutical formulations described herein are elf-emulsifying drug delivery systems (SEDDS).
  • SEDDS elf-emulsifying drug delivery systems
  • Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets.
  • emulsions are created by vigorous mechanical dispersion.
  • SEDDS as opposed to emulsions or microemulsions, spontaneously form emulsions when added to an excess of water without any external mechanical dispersion or agitation.
  • An advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. Additionally, water or the aqueous phase is optionally added just prior to administration, which ensures stability of an unstable or hydrophobic active ingredient.
  • the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients.
  • SEDDS provides improvements in the bioavailability of hydrophobic active ingredients.
  • Methods of producing self-emulsifying dosage forms include, but are not limited to, for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.
  • Suitable intranasal formulations include those described in, for example, U.S. Pat. Nos.
  • Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents are optionally present.
  • the pharmaceutical compositions disclosed herein are optionally in a form of an aerosol, a mist or a powder.
  • Pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit is determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix and a suitable powder base such as lactose or star
  • buccal formulations include, but are not limited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739, 136.
  • the buccal dosage forms described herein optionally further include a bioerodible (hydro lysable) polymeric carrier that also serves to adhere the dosage form to the buccal mucosa.
  • the buccal dosage form is fabricated so as to erode gradually over a
  • the bioerodible (hydrolysable) polymeric carrier generally comprises hydrophilic (water-soluble and water-swellable) polymers that adhere to the wet surface of the buccal mucosa.
  • examples of polymeric carriers useful herein include acrylic acid polymers and co, e.g., those known as "carbomers” (Carbopol®, which is obtained from B.F. Goodrich, is one such polymer).
  • compositions optionally take the form of tablets, lozenges, or gels formulated in a conventional manner.
  • Transdermal formulations of a pharmaceutical compositions disclosed here are administered for example by those described in U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230, 105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144.
  • transdermal formulations described herein include at least three components: (1) an agent; (2) a penetration enhancer; and (3) an aqueous adjuvant.
  • transdermal formulations include components such as, but not limited to, gelling agents, creams and ointment bases, and the like.
  • the transdermal formulation further includes a woven or non-woven backing material to enhance absorption and prevent the removal of the transdermal formulation from the skin.
  • the transdermal formulations described herein maintain a saturated or supersaturated state to promote diffusion into the skin.
  • formulations suitable for transdermal administration employ transdermal delivery devices and transdermal delivery patches and are lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.
  • patches are optionally constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • transdermal delivery is optionally accomplished by means of iontophoretic patches and the like.
  • transdermal patches provide controlled delivery. The rate of absorption is optionally slowed by using rate-controlling membranes or by trapping an agent within a polymer matrix or gel.
  • absorption enhancers are used to increase absorption.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing an agent optionally with carriers, optionally a rate controlling barrier to deliver a an agent to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Formulations suitable for intramuscular, subcutaneous, or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Formulations suitable for subcutaneous injection also contain optional additives such as preserving, wetting, emulsifying, and dispensing agents.
  • an agent is optionally formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • appropriate formulations include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients.
  • Parenteral injections optionally involve bolus injection or continuous infusion.
  • Formulations for injection are optionally presented in unit dosage form, e.g., in ampoules or in multi dose containers, with an added preservative.
  • the pharmaceutical composition described herein are in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of an agent in water soluble form. Additionally, suspensions are optionally prepared as appropriate oily injection suspensions.
  • an agent disclosed herein is administered topically and formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.
  • Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • An agent disclosed herein is also optionally formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • An agent disclosed herein is optionally used in the preparation of medicaments for the prophylactic and/or therapeutic treatment of inflammatory diseases, disorders, conditions and symptoms or conditions that would benefit, at least in part, from amelioration.
  • a method for treating any of the diseases or conditions described herein in an individual in need of such treatment involves administration of pharmaceutical compositions containing an agent disclosed herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide,
  • an agent disclosed herein is optionally administered chronically, that is, for an extended period of time, including throughout the duration of the individual's life in order to ameliorate or otherwise control or limit the symptoms of the individual's disease or condition.
  • the administration of an agent disclosed herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a length of time (i.e., a "drug holiday").
  • the length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday includes from 10%- 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
  • individuals require intermittent treatment on a long- term basis upon any recurrence of symptoms.
  • the pharmaceutical composition described herein is in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of an agent disclosed herein.
  • the unit dosage is in the form of a package containing discrete quantities of the formulation.
  • Non- limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • aqueous suspension compositions are packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection are presented in unit dosage form, which include, but are not limited to ampoules, or in multi dose containers, with an added preservative.
  • the daily dosages appropriate for an agent disclosed herein are from about 0.01 to 3 mg/kg per body weight.
  • An indicated daily dosage in the larger mammal, including, but not limited to, humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered in divided doses, including, but not limited to, up to four times a day or in extended release form.
  • Suitable unit dosage forms for oral administration include from about 1 to 50 mg active ingredient. The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon.
  • Such dosages are optionally altered depending on a number of variables, not limited to the activity of the MIF receptor inhibitor used, the disease or condition to be treated, the mode of administration, the requirements of the individual, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50.
  • An agent disclosed herein exhibiting high therapeutic indices is preferred.
  • the data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human.
  • the dosage of such an agent disclosed herein lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.
  • MonoMac6 cells (Weber, C, et al. (1993) Eur. J. Immunol. 23, 852-859) and Chinese hamster ovary (CHO) ICAM- 1 -transfectants (Ostermann, G., et al. (2002) Nat. Immunol. 3, 151-158) were used as described.
  • Jurkat cells and RAW264.7 macrophages were transfected with pcDNA3- CXCR2.
  • HL-60 cells were transfected with pcDNA3.1/V5- HisTOPO-TA-CD74 or vector control (Nucleofector Kit V, Amaxa).
  • L1.2 cells were transfected with pcDNA3-CXCRs or pcDNA-CCR5 (UMR cDNA Resource Center) for assays on simian virus-40-transformed mouse microvascular endothelial cells (SVECs).
  • SVECs mouse microvascular endothelial cells
  • Peripheral blood mononuclear cells were prepared from buffy coats, monocytes by adherence or immunomagnetic separation (Miltenyi), primary T cells by
  • Recombinant MIF was expressed and purified as described (Bernhagen, J., et al. (1993) Nature 365, 756-759).
  • Chemokines were from PeproTech. Human VCAM-l .Fc chimera, blocking antibodies to CXCR1 (42705, 5A12), CXCR2 (48311), CXCR4 (44708, FABSP2 cocktail, R&D), human MIF and mouse MIF (NIHIII.D.9) (Lan, H.Y., et al. (1997) J. Exp. Med.
  • CHO- ICAM-1 cells incubated with MIF (2 h) were stained with antibody to MIF Ka565 (Leng, L., et al. (2003) J. Exp. Med. 197, 1467-1476) and FITC-conjugated antibody. Chemotaxis assays.
  • lymphocytes 3 ⁇ and 1.5 h (T cells), and 3 mm and 1 h (neutrophils).
  • Monocytes stimulated with MIF or Mg 2+ /EGTA were fixed, reacted with the agent 327C and an FITC-conjugated antibody to mouse IgG.
  • LFA-1 activation analyzed by flow cytometry is reported as the increase in mean fluorescent intensity (MFI) or relative to the positive control (Shamri, R., et al. (2005) Nat. Immunol. 6, 497-506).
  • HEK293-CXCR2 transfectants or controls were incubated with biotin-labeled MIF (Kleemann, R., et al. (2002) J. Interferon Cytokine Res. 22, 351-363), washed and lysed with coimmunoprecipitation (CoIP) buffer.
  • CoIP coimmunoprecipitation
  • HEK293-CXCR2 transfectants or Jurkat cells pretreated with AMD3465 and/or a 20-fold excess of unlabeled MIF were incubated with fluorescein-labeled MIF and analyzed using a BD FACSCalibur.
  • HEK293-CXCR2 or Jurkat cells were treated with CXCL8 or CXCL12, respectively, treated with MIF, washed with acidic glycine-buffer, stained with antibodies to CXCR2 or CXCR4, and analyzed by flow cytometry. Internalization was calculated relative to surface expression of buffer-treated cells (100% control) and isotype control staining (0% control): geometric
  • RAW264.7-CXCR2 transfectants were co stained with CXCR2 and rat antibody to mouse CD74 (In- 1 , Pharmingen), followed by FITC-conjugated antibody to rat IgG and Cy3-conjugated antibody to mouse IgG, and were analyzed by confocal laser scanning microscopy (Zeiss).
  • l/V5-HisTOPO-TA-CD74 were lysed in nondenaturing CoIP buffer. Supernatants were incubated with the CXCR2 antibody Rill 15 or an isotype control, and were preblocked with protein G-sepharose overnight. Proteins were analyzed by western blots using agent to the His-tag (Santa Cruz). Similarly, CoIPs and immunoblots were performed with antibodies to the His-tag and CXCR2, respectively. L1.2-CXCR2 cells were subjected to immunoprecipitation with antibody to CXCR2 and immunoblotting with an antibody to mouse CD74.
  • Mif'-Ldlr-'- mice and Mif l+ Ldlr 1 littermate controls crossbred from Mif 1 (Fingerle- Rowson, G., et al. (2003) Proc. Natl. Acad. Sci. USA 100, 9354-9359) and Ldlr mice (Charles River), and Apoe ⁇ ' ⁇ mice were fed an atherogenic diet (21% fat; Altromin) for 6 weeks. All single knockout strains had been back-crossed in the C57BL/6 background ten times.
  • Mif l+ and Mif' ⁇ mice were treated with TNF-a (intraperitoneally (i.p.), 4 h). Explanted arteries were transferred onto the stage of an epifluorescence microscope and perfused at 4 ⁇ /min with calcein-AM-labeled
  • MonoMac6 cells treated with antibodies to CD74 or CXCR2, isotype control IgG, or left untreated (Huo, Y., et al. (2001) J. Clin. Invest. 108, 1307-1314). Untreated monocytic cells were perfused after blockade with antibody to MIF for 30 min.
  • rhodamine-G (Molecular Probes) was administered intravenously (i.v.), and carotid arteries were exposed in anesthetized mice.
  • Arrest (>30 s) of labeled leukocytes was analyzed by epifluorescence microscopy (Zeiss Axiotech, 20x water immersion). All studies were approved by local authorities (Bezirksreg réelle Koln), and complied with German animal protection law Az: 50.203.2-AC 36, 19/05.
  • Aortic roots were fixed by in situ perfusion and atherosclerosis was quantified by staining transversal sections with Oil-Red-O.
  • Relative macrophage and T-cell contents were determined by staining with antibodies to MOMA-2 (MCA519, Serotec) or to CD3 (PC3/ 188A, Dako) and FITC-conjugated antibody.
  • Axioplan; 20x was performed in postcapillary venules (Gregory, J.L., et al. (2004) Arthritis Rheum. 50, 3023-3034; Keane, M.P., et al. (2004) J. Immunol. 172, 2853-2860). Adhesion was measured as leukocytes stationary for more than 30 s, emigration as the number of extravascular leukocytes per field.
  • Femurs and tibias were aseptically removed from donor Il8rb ⁇ ' ⁇ (Jackson Laboratories) or BALB/c mice.
  • the cells, flushed from the marrow cavities, were administered i.v. into Mif l+ or Mif _ mice 24 h after ablative whole-body irradiation (Zernecke, A., et al. (2005) Circ. Res. 96, 784- 791).
  • CXCR2 substantially but not fully impaired MIF-triggered and CXCL8-triggered monocytic cell arrest. Addition of antibodies to both CXCRl and CXCR2 completely inhibited the arrest functions of MIF or CXCL8 (Fig. I d & Fig. 8). The use of antibodies to CD74 implicated this protein, along with CXCR2, in MIF-induced arrest (Fig. I d). Spontaneous arrest was unaffected (Fig. 8). Thus, CXCR2 assisted by CD74 mediates MIF-induced arrest.
  • Chemokines have been eponymously defined as inducers of chemotaxis (Baggiolini, M., et al. (1994) Adv. Immunol. 55, 97-179; Weber, C, et al. (2004) Arterioscler. Thromb. Vase. Biol. 24, 1997-2008). Paradoxically, MIF was initially thought to interfere with 'random' migration
  • MIF-induced monocyte chemotaxis was sensitive to PTX and abrogated by Ly294002 (Fig. 2d). Both CXCR2 and CD74 specifically contributed to MIF-triggered monocyte chemotaxis (Fig. 2e). The role for CXCR2 was confirmed by showing MIF-mediated cross- desensitization of CXCL8-induced chemotaxis in CXCR2-transfected LI .2 cells. The chemotactic activity of MIF was verified in RAW264.7 macrophages (Fig. 8) and THP-1 monocytes. These data demonstrate that MIF triggers monocyte chemotaxis through CXCR2.
  • MIF exerted CXCR2- but not CXCR1 -mediated chemotactic activity, exhibiting a bell-shaped dose-response curve and cross-densensitizing CXCL8 (Fig. 2g,h).
  • the moderate chemotactic activity of neutrophils towards MIF is likely to be related to an absence of CD74 on neutrophils, as its ectopic expression in CD74 ⁇ promyelocytic HL-60 cells enhanced MIF-induced migration (Fig. 8).
  • MIF like other CXCR2 ligands, functions as an arrest chemokine, the present data revealed that MIF also has appreciable chemotactic properties on mononuclear cells and neutrophils.
  • MIF triggers rapid integrin activation and calcium flux
  • integrin ligands for example, vascular cell adhesion molecule (VCAM)-l
  • VCAM vascular cell adhesion molecule
  • MIF was labeled with biotin or fluorescein, which, in contrast to iodinated MIF, allows for direct receptor-binding assays.
  • the specific binding of fluorescein-MIF to CXCR4-bearing Jurkat cells was inhibited by the CXCR4 antagonist AMD3465.
  • CXCR2 mediates MIF-induced monocyte arrest in arteries
  • MIF promotes the formation of complex plaques with abundant cell proliferation, macrophage infiltration and lipid deposition (Weber, C, et al. (2004) Arterioscler. Thromb. Vase. Biol. 24, 1997-2008; Morand, E.F., et al. (2006) Nat. Rev. Drug Discov. 5, 399 ⁇ 110). This has been related to the induction of endothelial MIF by oxLDL, triggering monocyte arrest (Schober, A., et al. (2004) Circulation 109, 380-385). The CXCR2 ligand CXCL1 can also elicit
  • Intravital microscopy of microcirculation in the cremaster muscle revealed that injecting MIF adjacent to the muscle caused a marked increase in (mostly CD68 ) leukocyte adhesion and emigration in postcapillary venules, which was inhibited by an antibody to CXCR2 (Fig. 6b,c). Circulating monocyte counts were unaffected.
  • MIF acted through both CXCR2 and CXCR4.
  • CXCR2 CXCR2 + monocytes and CXCR4 + T cells.
  • Apoe ⁇ ' ⁇ mice which had received a high- fat diet for 12 weeks and had developed severe atherosclerotic lesions, were treated with neutralizing antibodies to MIF, CXCL1 or CXCL12 for 4 weeks.
  • Immunoblotting and adhesion assays were used to verify the specificity of the MIF antibody. These assays confirmed that the MIF antibody blocked MIF- induced, but not CXCL1 - or CXCL8-induced, arrest (Fig. 10).
  • Blockade of MIF, but not CXCL1 or CXCL12 resulted in a reduced plaque area in the aortic root at 16 weeks and a significant (P ⁇ 0.05) plaque regression compared to baseline at 12 weeks (Fig. 6e,f).
  • blockade of MIF, but not CXCL1 or CXCL12 was associated with less of an inflammatory plaque phenotype at 16 weeks, as evidenced by a lower content of both macrophages and CD3 + T cells (Fig. 6g,h). Therefore, by targeting MIF and inhibiting the activation of CXCR2 and CXCR4, therapeutic regression and stabilization of advanced atherosclerotic lesions was achieved.
  • the present invention comprises a method of reducing plaque area in an individual in need thereof, comprising administering to said individual one or more agents that inhibit (i) MIF binding to CXCR2 and/or CXCR4 and/or (ii) MIF-activation of CXCR2 and/or CXCR4; or (iii) any combination of (i) and (ii).
  • peptide and M. tuberculosis are 150 ⁇ g/mouse and 1 mg/mouse, respectively.
  • PTX 400 ng; LIST Biological Laboratories Inc.
  • mice are compared to group 1 mice to determine the efficacy of an agent that blocks MIF binding and/or activation of CXCR2 and CXCR4, for treating or preventing EAE.
  • Group 5 mice are compared to groups 3 & 4 to determine the effect of blocking MIF binding and/or activation of both CXCR2 and CXCR4 to the effect of blocking CXCR2 or CXCR4 individually.
  • T cells are prepared from draining lymph nodes and spleen on day 7-1 1 after immunization.
  • Viable cells (3.75 x 10 6 /ml) are cultured in complete medium with (re-stimulated) or without MOG peptide (amino acids 35-55) at various concentrations.
  • Supernatants from activated cells are collected 72 h later and TNF, IFN- ⁇ , IL-23 & IL-17 are measured by ELISA (BD
  • IL-17 and IL-23 levels indicate the development of a Th-17 cells and a Th-17 mediated disease phenotype.
  • Inhibition of these cytokines by treatment of mice or cell cultures with MIF blocking antibodies (group 2), or by blocking MIF binding and/or activation of both CXCR2 and CXCR4 (group 5) illustrates a key regulatory role of MIF in the development of Th-17 cells and in the progression of a Th- 17 mediated inflammatory disease (i.e. multiple sclerosis).
  • cytokine staining For intracellular cytokine staining, spleen and lymph node cells from immunized mice are stimulated for 24 h with peptide antigen, and GolgiPlug (BD Pharmingen) is added in the last 5 h or GolgiPlug plus 500 ng/ml of ionomycin and 50 ng/ml of phorbol 12-myristate 13-acetate (PMA; Sigma- Aldrich) are added for 5 h.
  • GolgiPlug BD Pharmingen
  • PMA phorbol 12-myristate 13-acetate
  • CD4- posivtive T-cells are analyzed for the presence of intracellular IL- 17, IL-23 or cell surface IL23 receptor (IL23R) by flow cytometry.
  • IL23R cell surface IL23 receptor
  • the presence of CD4+, IL-17+ double positive T-cells indicates development of a Th- 17 phenotype that is driving disease progression. Further the up- regulation of IL-23Rs on CD4+, IL-17 double positive cells provides supportive evidence of a Th-17 phenotype.
  • Th- 17 cell development and the inhibition of the progression of EAE in mice by blocking MIF demonstrates the valuable utility of agents that inhibit (i) MIF binding to CXCR2 and/or CXCR4 and/or (ii) MIF-activation of CXCR2 and/or CXCR4; or (iii) any combination of (i) and (ii) for the treatment and/or prevention of Th- 17 mediated autoimmune diseases such as multiple sclerosis.
  • a library of peptides covering the extracellular N-terminal motif/domain of CXCR2 is generated.
  • the peptides range in size from about 12 amino acids to about 15 amino acids.
  • the peptide library is screened for inhibition of MIF-mediated signaling through CXCR2 using HTS GPCR screening technology.
  • peptides that inhibit MIF-mediated signaling are next screened from inhibition of 11-8 and/or SDF-1 mediated signaling on CXCR2.
  • Polypeptides are generated that comprise amino acid residues 38-44 (beta-2 strand) of MIF.
  • polypeptides are screened for inhibition of MIF-mediated signaling through CXCR2 using HTS GPCR screening technology.
  • polypeptides that inhibit MIF-mediated signaling are next screened for inhibition of 11-8 and/or SDF-1 mediated signaling on CXCR2.
  • LMAFGGSSEP (PI; 20 mg, 40 mg, 80 mg) in individuals with homozygous familial
  • hypercholesterolemia HHT
  • Study Design This is a multi-center, open-label, single-group forced titration study of fixed combination P2 in male and female individuals >18 years of age with HoFH. After initial screening, eligible individuals enter a 4-week screening period, consisting of 2 visits (Weeks -4 and -1), during which all lipid-lowering drugs are discontinued (except for bile acid sequestrants and cholesterol absorption inhibitors) and therapeutic lifestyle change counseling (TLC) according to National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP-III) clinical guidelines or equivalent are initiated. Individuals already on apheresis continue their treatment regimen maintaining consistent conditions and intervals during the study.
  • the primary endpoints are the mean percent changes in HDL-C and LDL-C from baseline to the end of each treatment period (ie, Weeks 6, 12 and 18). A lipid profile which includes HDL-C and LDL-C is obtained at each study visit.
  • the primary efficacy endpoints are the percent changes in HDL-C and LDL-C from baseline to the end of each treatment period (ie, Weeks 6, 12, and 18).
  • the primary efficacy analysis population is the full analysis set (FAS) which included all individuals who received at least 1 dose of study drug and had both a baseline and at least 1 valid post-baseline measurement at each analysis period.
  • Animal models are prepared as follows. An adult, male rat at is subjected to infusion of elastase for 2 hours. Histological analysis is performed 12-24 hours after infusion to confirm presence of fragmented and disorganized elastin. Ultrasound is performed daily to identify and monitor areas of aortic enlargement.
  • P1 (LMAFGGSSEP).
  • the initial administration of P2 is infused into subject at a rate of 0.5 mg/hr.
  • increase infusion rate by 0.5 mg/hr increments every 30 minutes, to a maximum of 2.0 mg/hr.
  • P2 is infused at a rate of 1.0 mg/hr.
  • increase rate by 1.0 mg/hr increments at 30-minute intervals, to a maximum of 4.0 mg/hr.
  • the primary endpoints are the mean percent changes in AAA size (i.e., aortic diameter) from baseline to weeks 3, 6, and 12.
  • Study Design This is a multi-center, open-label, single-group study of P2in male and female individuals >18 years of age with early AAA. Presence of early AAA is confirmed with serial cross-sectional imaging. At Week 0, baseline efficacy/safety values are determined and individuals begin treatment with the initial dose of P2. Subjects are administered P2once a week for 12 weeks.
  • Study Treatment The initial administration of P2is infused into subject at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. Each week thereafter, P2 is infused at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr.
  • Efficacy Evaluations The primary endpoints are the mean percent changes in AAA size (i.e., aortic diameter) from baseline to weeks 3, 6, and 12.
  • EXAMPLE 15 Human Clinical Trial for Treatment of Rheumatoid Arthritis
  • Study Objective(s) The primary objective of this study is to assess efficacy of Peptide 2 (P2; cyclic CNVPRASVPDGC) in individuals with rheumatoid arthritis (RA).
  • Intervention Model Single Group Assignment
  • TJC Tender Joint Count
  • ACR American College of Rheumatology
  • DI-HAQ Mean Change From Baseline in the Disability Index of the Health Assessment Questionaire (DI-HAQ, a Component of the American College of Rheumatology (ACR) Criteria by Visit
  • CRP C-reactive Protein
  • Presence of Morning Stiffness [00443] Presence of Morning Stiffness [00444] Mean Change From Baseline in the Duration (Minutes) of Morning Stiffness by Visit
  • Peptide 2 will be administered as a single oral dose (10 mg/Kg) once per day
  • Placebo will be administered via oral administration once per day

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