CA2773978A1 - Methods of treating inflammation - Google Patents
Methods of treating inflammation Download PDFInfo
- Publication number
- CA2773978A1 CA2773978A1 CA2773978A CA2773978A CA2773978A1 CA 2773978 A1 CA2773978 A1 CA 2773978A1 CA 2773978 A CA2773978 A CA 2773978A CA 2773978 A CA2773978 A CA 2773978A CA 2773978 A1 CA2773978 A1 CA 2773978A1
- Authority
- CA
- Canada
- Prior art keywords
- peptide
- seq
- mif
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title abstract description 116
- 230000004054 inflammatory process Effects 0.000 title description 33
- 206010061218 Inflammation Diseases 0.000 title description 32
- 230000027455 binding Effects 0.000 claims abstract description 203
- 108010018951 Interleukin-8B Receptors Proteins 0.000 claims abstract description 154
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims abstract description 125
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims abstract description 121
- 230000001404 mediated effect Effects 0.000 claims abstract description 38
- 102100028989 C-X-C chemokine receptor type 2 Human genes 0.000 claims abstract 7
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 562
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 169
- 150000001413 amino acids Chemical class 0.000 claims description 158
- 208000035475 disorder Diseases 0.000 claims description 126
- 239000000203 mixture Substances 0.000 claims description 111
- 102100030595 HLA class II histocompatibility antigen gamma chain Human genes 0.000 claims description 100
- 101001082627 Homo sapiens HLA class II histocompatibility antigen gamma chain Proteins 0.000 claims description 100
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 claims description 89
- 102100032912 CD44 antigen Human genes 0.000 claims description 87
- 208000027866 inflammatory disease Diseases 0.000 claims description 87
- 208000024891 symptom Diseases 0.000 claims description 75
- 125000005647 linker group Chemical group 0.000 claims description 48
- 230000004927 fusion Effects 0.000 claims description 45
- 239000000427 antigen Substances 0.000 claims description 41
- 108091007433 antigens Proteins 0.000 claims description 41
- 102000036639 antigens Human genes 0.000 claims description 41
- 201000010099 disease Diseases 0.000 claims description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims description 41
- 210000004899 c-terminal region Anatomy 0.000 claims description 37
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 claims description 35
- 125000004122 cyclic group Chemical group 0.000 claims description 34
- 230000002757 inflammatory effect Effects 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 210000000265 leukocyte Anatomy 0.000 claims description 19
- 230000000694 effects Effects 0.000 claims description 17
- 208000002223 abdominal aortic aneurysm Diseases 0.000 claims description 16
- 201000001320 Atherosclerosis Diseases 0.000 claims description 14
- 150000008575 L-amino acids Chemical class 0.000 claims description 14
- 230000033115 angiogenesis Effects 0.000 claims description 14
- 208000014018 liver neoplasm Diseases 0.000 claims description 14
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 13
- 206010028851 Necrosis Diseases 0.000 claims description 13
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 11
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 10
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 10
- 206010040047 Sepsis Diseases 0.000 claims description 10
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 10
- 208000007474 aortic aneurysm Diseases 0.000 claims description 10
- 125000002950 monocyclic group Chemical group 0.000 claims description 10
- 125000003367 polycyclic group Chemical group 0.000 claims description 10
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- 230000017074 necrotic cell death Effects 0.000 claims description 9
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- 201000004624 Dermatitis Diseases 0.000 claims description 8
- 206010025323 Lymphomas Diseases 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 206010033128 Ovarian cancer Diseases 0.000 claims description 8
- 206010040070 Septic Shock Diseases 0.000 claims description 8
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 claims description 8
- 125000004450 alkenylene group Chemical group 0.000 claims description 8
- 125000004419 alkynylene group Chemical group 0.000 claims description 8
- 206010006451 bronchitis Diseases 0.000 claims description 8
- 206010017758 gastric cancer Diseases 0.000 claims description 8
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 8
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 8
- 125000004474 heteroalkylene group Chemical group 0.000 claims description 8
- 201000001441 melanoma Diseases 0.000 claims description 8
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 8
- 206010005003 Bladder cancer Diseases 0.000 claims description 7
- 208000020084 Bone disease Diseases 0.000 claims description 7
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 7
- 208000011231 Crohn disease Diseases 0.000 claims description 7
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 7
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 claims description 7
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 7
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 7
- 230000001154 acute effect Effects 0.000 claims description 7
- 208000006673 asthma Diseases 0.000 claims description 7
- 208000025997 central nervous system neoplasm Diseases 0.000 claims description 7
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 claims description 7
- 201000005787 hematologic cancer Diseases 0.000 claims description 7
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 7
- 201000007270 liver cancer Diseases 0.000 claims description 7
- 201000005249 lung adenocarcinoma Diseases 0.000 claims description 7
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 7
- 230000001394 metastastic effect Effects 0.000 claims description 7
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 7
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 7
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 7
- 201000002528 pancreatic cancer Diseases 0.000 claims description 7
- 201000011549 stomach cancer Diseases 0.000 claims description 7
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 7
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 6
- 208000024869 Goodpasture syndrome Diseases 0.000 claims description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 206010003827 Autoimmune hepatitis Diseases 0.000 claims description 5
- 208000023328 Basedow disease Diseases 0.000 claims description 5
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
- 208000015023 Graves' disease Diseases 0.000 claims description 5
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 5
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 claims description 5
- 206010033645 Pancreatitis Diseases 0.000 claims description 5
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 5
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 5
- 206010052779 Transplant rejections Diseases 0.000 claims description 5
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
- 206010047115 Vasculitis Diseases 0.000 claims description 5
- 206010047642 Vitiligo Diseases 0.000 claims description 5
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 claims description 5
- 206010009887 colitis Diseases 0.000 claims description 5
- 206010020718 hyperplasia Diseases 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 206010028417 myasthenia gravis Diseases 0.000 claims description 5
- 208000010125 myocardial infarction Diseases 0.000 claims description 5
- 230000035755 proliferation Effects 0.000 claims description 5
- 208000030507 AIDS Diseases 0.000 claims description 4
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 4
- 208000026872 Addison Disease Diseases 0.000 claims description 4
- 206010001935 American trypanosomiasis Diseases 0.000 claims description 4
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 claims description 4
- 208000027496 Behcet disease Diseases 0.000 claims description 4
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 4
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 4
- 208000024699 Chagas disease Diseases 0.000 claims description 4
- 208000015943 Coeliac disease Diseases 0.000 claims description 4
- 206010009895 Colitis ischaemic Diseases 0.000 claims description 4
- 206010056979 Colitis microscopic Diseases 0.000 claims description 4
- 206010010741 Conjunctivitis Diseases 0.000 claims description 4
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 4
- 206010012289 Dementia Diseases 0.000 claims description 4
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 4
- 201000009273 Endometriosis Diseases 0.000 claims description 4
- 208000001640 Fibromyalgia Diseases 0.000 claims description 4
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 4
- 201000005569 Gout Diseases 0.000 claims description 4
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 4
- 208000035895 Guillain-Barré syndrome Diseases 0.000 claims description 4
- 208000001204 Hashimoto Disease Diseases 0.000 claims description 4
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims description 4
- 208000005615 Interstitial Cystitis Diseases 0.000 claims description 4
- 208000004852 Lung Injury Diseases 0.000 claims description 4
- 201000009906 Meningitis Diseases 0.000 claims description 4
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 4
- 206010049567 Miller Fisher syndrome Diseases 0.000 claims description 4
- 208000009433 Moyamoya Disease Diseases 0.000 claims description 4
- 208000009525 Myocarditis Diseases 0.000 claims description 4
- 208000000592 Nasal Polyps Diseases 0.000 claims description 4
- 208000008589 Obesity Diseases 0.000 claims description 4
- 206010034277 Pemphigoid Diseases 0.000 claims description 4
- 201000011152 Pemphigus Diseases 0.000 claims description 4
- 208000031845 Pernicious anaemia Diseases 0.000 claims description 4
- 206010035664 Pneumonia Diseases 0.000 claims description 4
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 claims description 4
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 4
- 206010036774 Proctitis Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 206010038910 Retinitis Diseases 0.000 claims description 4
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 4
- 206010039710 Scleroderma Diseases 0.000 claims description 4
- 208000001106 Takayasu Arteritis Diseases 0.000 claims description 4
- 206010069363 Traumatic lung injury Diseases 0.000 claims description 4
- 241000223109 Trypanosoma cruzi Species 0.000 claims description 4
- 206010046851 Uveitis Diseases 0.000 claims description 4
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 4
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 4
- 201000010105 allergic rhinitis Diseases 0.000 claims description 4
- 201000008937 atopic dermatitis Diseases 0.000 claims description 4
- 208000010668 atopic eczema Diseases 0.000 claims description 4
- 208000027625 autoimmune inner ear disease Diseases 0.000 claims description 4
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 4
- 208000000594 bullous pemphigoid Diseases 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 claims description 4
- 230000001112 coagulating effect Effects 0.000 claims description 4
- 208000008609 collagenous colitis Diseases 0.000 claims description 4
- 201000001981 dermatomyositis Diseases 0.000 claims description 4
- 201000008243 diversion colitis Diseases 0.000 claims description 4
- 206010014599 encephalitis Diseases 0.000 claims description 4
- 206010015037 epilepsy Diseases 0.000 claims description 4
- 208000007565 gingivitis Diseases 0.000 claims description 4
- 208000027138 indeterminate colitis Diseases 0.000 claims description 4
- 230000001524 infective effect Effects 0.000 claims description 4
- 206010022000 influenza Diseases 0.000 claims description 4
- 208000019423 liver disease Diseases 0.000 claims description 4
- 231100000515 lung injury Toxicity 0.000 claims description 4
- 208000004341 lymphocytic colitis Diseases 0.000 claims description 4
- 201000000083 maturity-onset diabetes of the young type 1 Diseases 0.000 claims description 4
- 201000003631 narcolepsy Diseases 0.000 claims description 4
- 201000008383 nephritis Diseases 0.000 claims description 4
- 235000020824 obesity Nutrition 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- 201000001976 pemphigus vulgaris Diseases 0.000 claims description 4
- 230000003239 periodontal effect Effects 0.000 claims description 4
- 208000005987 polymyositis Diseases 0.000 claims description 4
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 4
- 201000000980 schizophrenia Diseases 0.000 claims description 4
- 230000036303 septic shock Effects 0.000 claims description 4
- 210000002460 smooth muscle Anatomy 0.000 claims description 4
- 201000008827 tuberculosis Diseases 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
- 206010003246 arthritis Diseases 0.000 claims description 3
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
- 206010025135 lupus erythematosus Diseases 0.000 claims description 2
- QWCKQJZIFLGMSD-VKHMYHEASA-N L-alpha-aminobutyric acid Chemical compound CC[C@H](N)C(O)=O QWCKQJZIFLGMSD-VKHMYHEASA-N 0.000 claims 2
- 230000004913 activation Effects 0.000 abstract description 7
- 229940024606 amino acid Drugs 0.000 description 160
- 235000001014 amino acid Nutrition 0.000 description 159
- 102000002791 Interleukin-8B Receptors Human genes 0.000 description 147
- 239000003795 chemical substances by application Substances 0.000 description 138
- 102000004196 processed proteins & peptides Human genes 0.000 description 124
- 125000000539 amino acid group Chemical group 0.000 description 79
- 229920001184 polypeptide Polymers 0.000 description 72
- 238000005829 trimerization reaction Methods 0.000 description 44
- 150000003384 small molecules Chemical class 0.000 description 41
- -1 MIF Proteins 0.000 description 38
- 150000007523 nucleic acids Chemical group 0.000 description 38
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 37
- 108090000623 proteins and genes Proteins 0.000 description 34
- 210000004027 cell Anatomy 0.000 description 32
- 229930182817 methionine Natural products 0.000 description 32
- 235000006109 methionine Nutrition 0.000 description 32
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 31
- 108091028043 Nucleic acid sequence Proteins 0.000 description 31
- 230000007423 decrease Effects 0.000 description 30
- 239000004475 Arginine Substances 0.000 description 29
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 29
- 235000009697 arginine Nutrition 0.000 description 29
- 229960003121 arginine Drugs 0.000 description 29
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 28
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 28
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 28
- 235000004279 alanine Nutrition 0.000 description 28
- 229960003767 alanine Drugs 0.000 description 28
- 235000004400 serine Nutrition 0.000 description 28
- 229960001153 serine Drugs 0.000 description 28
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 26
- 239000004472 Lysine Substances 0.000 description 26
- 229960003646 lysine Drugs 0.000 description 26
- 108060003951 Immunoglobulin Proteins 0.000 description 25
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 25
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 25
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 25
- 102000018358 immunoglobulin Human genes 0.000 description 25
- 235000018977 lysine Nutrition 0.000 description 25
- 235000003704 aspartic acid Nutrition 0.000 description 24
- 229960005261 aspartic acid Drugs 0.000 description 24
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 24
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 22
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 22
- 101710176384 Peptide 1 Proteins 0.000 description 22
- 235000013922 glutamic acid Nutrition 0.000 description 22
- 239000004220 glutamic acid Substances 0.000 description 22
- 210000001616 monocyte Anatomy 0.000 description 22
- 241001529936 Murinae Species 0.000 description 20
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 19
- 229960003136 leucine Drugs 0.000 description 19
- 235000005772 leucine Nutrition 0.000 description 19
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 18
- 239000004471 Glycine Substances 0.000 description 18
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 18
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 18
- ORQXBVXKBGUSBA-UHFFFAOYSA-N cyclohexyl D-alanine Natural products OC(=O)C(N)CC1CCCCC1 ORQXBVXKBGUSBA-UHFFFAOYSA-N 0.000 description 18
- 230000002401 inhibitory effect Effects 0.000 description 18
- 210000002540 macrophage Anatomy 0.000 description 18
- ORQXBVXKBGUSBA-QMMMGPOBSA-N β-cyclohexyl-alanine Chemical compound OC(=O)[C@@H](N)CC1CCCCC1 ORQXBVXKBGUSBA-QMMMGPOBSA-N 0.000 description 18
- 235000018102 proteins Nutrition 0.000 description 17
- 102000004169 proteins and genes Human genes 0.000 description 17
- 238000002560 therapeutic procedure Methods 0.000 description 17
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 16
- 241000700159 Rattus Species 0.000 description 16
- 235000009582 asparagine Nutrition 0.000 description 16
- 229960001230 asparagine Drugs 0.000 description 16
- 239000013598 vector Substances 0.000 description 16
- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical compound C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 description 15
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 15
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 15
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 15
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 15
- 239000004473 Threonine Substances 0.000 description 15
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 15
- 230000006870 function Effects 0.000 description 15
- 230000014509 gene expression Effects 0.000 description 15
- 230000003993 interaction Effects 0.000 description 15
- 235000008521 threonine Nutrition 0.000 description 15
- 229960002898 threonine Drugs 0.000 description 15
- 235000014393 valine Nutrition 0.000 description 15
- 239000004474 valine Substances 0.000 description 15
- 229960004295 valine Drugs 0.000 description 15
- 241000283690 Bos taurus Species 0.000 description 14
- 239000003446 ligand Substances 0.000 description 14
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 13
- QWCKQJZIFLGMSD-GSVOUGTGSA-N D-alpha-aminobutyric acid Chemical compound CC[C@@H](N)C(O)=O QWCKQJZIFLGMSD-GSVOUGTGSA-N 0.000 description 12
- 235000018417 cysteine Nutrition 0.000 description 12
- 230000006378 damage Effects 0.000 description 12
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 12
- 235000004554 glutamine Nutrition 0.000 description 12
- 229960000310 isoleucine Drugs 0.000 description 12
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 12
- 235000014705 isoleucine Nutrition 0.000 description 12
- 230000011664 signaling Effects 0.000 description 12
- 108010010234 HDL Lipoproteins Proteins 0.000 description 11
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 11
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 11
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 11
- 239000005557 antagonist Substances 0.000 description 11
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 11
- 229960002433 cysteine Drugs 0.000 description 11
- 238000011161 development Methods 0.000 description 11
- 230000018109 developmental process Effects 0.000 description 11
- 235000013930 proline Nutrition 0.000 description 11
- 229960002429 proline Drugs 0.000 description 11
- 239000013638 trimer Substances 0.000 description 11
- 102000004890 Interleukin-8 Human genes 0.000 description 10
- 108090001007 Interleukin-8 Proteins 0.000 description 10
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 10
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 10
- 125000003275 alpha amino acid group Chemical group 0.000 description 10
- 230000035605 chemotaxis Effects 0.000 description 10
- 230000002107 myocardial effect Effects 0.000 description 10
- 150000008574 D-amino acids Chemical class 0.000 description 9
- 108020004414 DNA Proteins 0.000 description 9
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 9
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 230000008859 change Effects 0.000 description 9
- 230000028709 inflammatory response Effects 0.000 description 9
- 102000039446 nucleic acids Human genes 0.000 description 9
- 108020004707 nucleic acids Proteins 0.000 description 9
- 238000005556 structure-activity relationship Methods 0.000 description 9
- 229930182832 D-phenylalanine Natural products 0.000 description 8
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 8
- 239000002671 adjuvant Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 230000004064 dysfunction Effects 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 235000014304 histidine Nutrition 0.000 description 8
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 8
- 229960002885 histidine Drugs 0.000 description 8
- 210000004408 hybridoma Anatomy 0.000 description 8
- 210000004698 lymphocyte Anatomy 0.000 description 8
- 230000000873 masking effect Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 101001055222 Homo sapiens Interleukin-8 Proteins 0.000 description 7
- 101001011645 Homo sapiens Muellerian-inhibiting factor Proteins 0.000 description 7
- 102100026236 Interleukin-8 Human genes 0.000 description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 7
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 7
- 238000007385 chemical modification Methods 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 208000015181 infectious disease Diseases 0.000 description 7
- 208000014674 injury Diseases 0.000 description 7
- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 7
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 7
- 235000008729 phenylalanine Nutrition 0.000 description 7
- 229960005190 phenylalanine Drugs 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 6
- 208000023275 Autoimmune disease Diseases 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 6
- 210000001744 T-lymphocyte Anatomy 0.000 description 6
- 238000009825 accumulation Methods 0.000 description 6
- 210000001367 artery Anatomy 0.000 description 6
- 230000001363 autoimmune Effects 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 210000000497 foam cell Anatomy 0.000 description 6
- 229960002989 glutamic acid Drugs 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000000178 monomer Substances 0.000 description 6
- 241001430294 unidentified retrovirus Species 0.000 description 6
- 102100039398 C-X-C motif chemokine 2 Human genes 0.000 description 5
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 5
- 101000889128 Homo sapiens C-X-C motif chemokine 2 Proteins 0.000 description 5
- 206010020751 Hypersensitivity Diseases 0.000 description 5
- 102100030304 Platelet factor 4 Human genes 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 210000003719 b-lymphocyte Anatomy 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 210000004413 cardiac myocyte Anatomy 0.000 description 5
- 239000002158 endotoxin Substances 0.000 description 5
- 229940072221 immunoglobulins Drugs 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 208000037816 tissue injury Diseases 0.000 description 5
- WAFNZAURAWBNDZ-UHFFFAOYSA-N 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide Chemical compound CCCCCCCCCCC(C)(C)C(=O)NC1=C(OC)C=C(OC)C=C1OC WAFNZAURAWBNDZ-UHFFFAOYSA-N 0.000 description 4
- 208000009137 Behcet syndrome Diseases 0.000 description 4
- 108010029697 CD40 Ligand Proteins 0.000 description 4
- 102100032937 CD40 ligand Human genes 0.000 description 4
- 102000019034 Chemokines Human genes 0.000 description 4
- 108010012236 Chemokines Proteins 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 102100021242 Dymeclin Human genes 0.000 description 4
- 102100034221 Growth-regulated alpha protein Human genes 0.000 description 4
- 101000817629 Homo sapiens Dymeclin Proteins 0.000 description 4
- 101000950847 Homo sapiens Macrophage migration inhibitory factor Proteins 0.000 description 4
- 206010061216 Infarction Diseases 0.000 description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- 108010067902 Peptide Library Proteins 0.000 description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 description 4
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 description 4
- 101710172711 Structural protein Proteins 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 208000038016 acute inflammation Diseases 0.000 description 4
- 230000006022 acute inflammation Effects 0.000 description 4
- 208000026935 allergic disease Diseases 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 210000000702 aorta abdominal Anatomy 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 238000003491 array Methods 0.000 description 4
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 230000003684 cardiac depression Effects 0.000 description 4
- GGCLNOIGPMGLDB-GYKMGIIDSA-N cholest-5-en-3-one Chemical compound C1C=C2CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 GGCLNOIGPMGLDB-GYKMGIIDSA-N 0.000 description 4
- 238000011260 co-administration Methods 0.000 description 4
- 238000002591 computed tomography Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000013604 expression vector Substances 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 238000002599 functional magnetic resonance imaging Methods 0.000 description 4
- 238000001415 gene therapy Methods 0.000 description 4
- 210000003714 granulocyte Anatomy 0.000 description 4
- 102000053523 human CXCR4 Human genes 0.000 description 4
- 102000057097 human MIF Human genes 0.000 description 4
- 230000007574 infarction Effects 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 238000002595 magnetic resonance imaging Methods 0.000 description 4
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 4
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 4
- 238000013508 migration Methods 0.000 description 4
- 201000000050 myeloid neoplasm Diseases 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- 230000007115 recruitment Effects 0.000 description 4
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 235000002374 tyrosine Nutrition 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 4
- 229960004441 tyrosine Drugs 0.000 description 4
- DKVSUQWCZQBWCP-QAGGRKNESA-N (8R,9S,10R,13S,14S)-10,13-dimethyl-9,10,11,12,13,14,15,16-octahydro-3H-cyclopenta[alpha]phenanthrene-3,17(8H)-dione Natural products O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3C=CC2=C1 DKVSUQWCZQBWCP-QAGGRKNESA-N 0.000 description 3
- PTQXTEKSNBVPQJ-UHFFFAOYSA-N Avasimibe Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1CC(=O)NS(=O)(=O)OC1=C(C(C)C)C=CC=C1C(C)C PTQXTEKSNBVPQJ-UHFFFAOYSA-N 0.000 description 3
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 3
- 108010055166 Chemokine CCL5 Proteins 0.000 description 3
- 241000251556 Chordata Species 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 102000016942 Elastin Human genes 0.000 description 3
- 108010014258 Elastin Proteins 0.000 description 3
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 3
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 3
- 208000007514 Herpes zoster Diseases 0.000 description 3
- 101001069921 Homo sapiens Growth-regulated alpha protein Proteins 0.000 description 3
- 101000617130 Homo sapiens Stromal cell-derived factor 1 Proteins 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 108010007622 LDL Lipoproteins Proteins 0.000 description 3
- 206010029260 Neuroblastoma Diseases 0.000 description 3
- 244000061176 Nicotiana tabacum Species 0.000 description 3
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 3
- 208000031481 Pathologic Constriction Diseases 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 3
- 241000283083 Sirenia Species 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 210000000748 cardiovascular system Anatomy 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 208000037976 chronic inflammation Diseases 0.000 description 3
- 230000006020 chronic inflammation Effects 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 229920002549 elastin Polymers 0.000 description 3
- 238000004520 electroporation Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 230000009368 gene silencing by RNA Effects 0.000 description 3
- 239000003862 glucocorticoid Substances 0.000 description 3
- 229960002449 glycine Drugs 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 210000003630 histaminocyte Anatomy 0.000 description 3
- 230000009610 hypersensitivity Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 238000003018 immunoassay Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 150000002541 isothioureas Chemical class 0.000 description 3
- 210000005229 liver cell Anatomy 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 238000002703 mutagenesis Methods 0.000 description 3
- 231100000350 mutagenesis Toxicity 0.000 description 3
- 230000009826 neoplastic cell growth Effects 0.000 description 3
- 230000002085 persistent effect Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000000700 radioactive tracer Substances 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 230000036262 stenosis Effects 0.000 description 3
- 208000037804 stenosis Diseases 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 239000011885 synergistic combination Substances 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 230000000451 tissue damage Effects 0.000 description 3
- 231100000827 tissue damage Toxicity 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- LGLVVVCSQBZONM-HCCLCSBVSA-N (2r)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentano Chemical group NC(N)=NCCC[C@@H](NC(=O)C)C(=O)N[C@H](CCCN=C(N)N)C(=O)N[C@H](CCCN=C(N)N)C(=O)N[C@H](CCCN=C(N)N)C(=O)N[C@H](CCCN=C(N)N)C(=O)N[C@H](CCCN=C(N)N)C(=O)N[C@H](CCCN=C(N)N)C(=O)N[C@H](CCCN=C(N)N)C(=O)N[C@H](CCCN=C(N)N)C(N)=O LGLVVVCSQBZONM-HCCLCSBVSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- MQBZVUNNWUIPMK-UHFFFAOYSA-N 1-(2-bromophenyl)-3-(2-hydroxy-4-nitrophenyl)urea Chemical compound OC1=CC([N+]([O-])=O)=CC=C1NC(=O)NC1=CC=CC=C1Br MQBZVUNNWUIPMK-UHFFFAOYSA-N 0.000 description 2
- SEDUMQWZEOMXSO-UHFFFAOYSA-N 1-(2-bromophenyl)-3-(7-cyano-2h-benzotriazol-4-yl)urea Chemical compound BrC1=CC=CC=C1NC(=O)NC1=CC=C(C#N)C2=C1NN=N2 SEDUMQWZEOMXSO-UHFFFAOYSA-N 0.000 description 2
- NQZTZGNLFLQHKG-UHFFFAOYSA-N 1-butyl-3-[2-[3-(5-ethyl-4-phenylimidazol-1-yl)propoxy]-6-methylphenyl]urea Chemical compound CCCCNC(=O)NC1=C(C)C=CC=C1OCCCN1C(CC)=C(C=2C=CC=CC=2)N=C1 NQZTZGNLFLQHKG-UHFFFAOYSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- MKJQESRCXYYHFR-UHFFFAOYSA-N 2-[7-(2,2-dimethylpropanoylamino)-4,6-dimethyl-1-octyl-2,3-dihydroindol-5-yl]acetic acid;sulfuric acid Chemical compound OS(O)(=O)=O.CC(C)(C)C(=O)NC1=C(C)C(CC(O)=O)=C(C)C2=C1N(CCCCCCCC)CC2.CC(C)(C)C(=O)NC1=C(C)C(CC(O)=O)=C(C)C2=C1N(CCCCCCCC)CC2 MKJQESRCXYYHFR-UHFFFAOYSA-N 0.000 description 2
- PJMNEPMSGCRSRC-IEVKOWOJSA-N 4-androstene-3,6,17-trione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=O)C2=C1 PJMNEPMSGCRSRC-IEVKOWOJSA-N 0.000 description 2
- KEWSCDNULKOKTG-UHFFFAOYSA-N 4-cyano-4-ethylsulfanylcarbothioylsulfanylpentanoic acid Chemical compound CCSC(=S)SC(C)(C#N)CCC(O)=O KEWSCDNULKOKTG-UHFFFAOYSA-N 0.000 description 2
- WVLHHLRVNDMIAR-IBGZPJMESA-N AMD 070 Chemical compound C1CCC2=CC=CN=C2[C@H]1N(CCCCN)CC1=NC2=CC=CC=C2N1 WVLHHLRVNDMIAR-IBGZPJMESA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- 206010002329 Aneurysm Diseases 0.000 description 2
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 2
- 206010064539 Autoimmune myocarditis Diseases 0.000 description 2
- 101000950850 Bos taurus Macrophage migration inhibitory factor Proteins 0.000 description 2
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 2
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 2
- 108010061299 CXCR4 Receptors Proteins 0.000 description 2
- 102000012000 CXCR4 Receptors Human genes 0.000 description 2
- 241001466804 Carnivora Species 0.000 description 2
- 241000283153 Cetacea Species 0.000 description 2
- 241000288673 Chiroptera Species 0.000 description 2
- 102100037637 Cholesteryl ester transfer protein Human genes 0.000 description 2
- UDKCHVLMFQVBAA-UHFFFAOYSA-M Choline salicylate Chemical compound C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O UDKCHVLMFQVBAA-UHFFFAOYSA-M 0.000 description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 2
- 241000230159 Crocidura phaeura Species 0.000 description 2
- 241000938605 Crocodylia Species 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 2
- 241000289427 Didelphidae Species 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 241000289659 Erinaceidae Species 0.000 description 2
- 108010087819 Fc receptors Proteins 0.000 description 2
- 102000009109 Fc receptors Human genes 0.000 description 2
- 108091006020 Fc-tagged proteins Proteins 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 2
- 101000880514 Homo sapiens Cholesteryl ester transfer protein Proteins 0.000 description 2
- 101000713585 Homo sapiens Tubulin beta-4A chain Proteins 0.000 description 2
- 206010065390 Inflammatory pain Diseases 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- 241000713666 Lentivirus Species 0.000 description 2
- 102000004895 Lipoproteins Human genes 0.000 description 2
- 108090001030 Lipoproteins Proteins 0.000 description 2
- 241000289619 Macropodidae Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 201000002481 Myositis Diseases 0.000 description 2
- 108010056642 N-alpha-acetyl-nona-D-arginine amide acetate Proteins 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 238000012879 PET imaging Methods 0.000 description 2
- 241000283080 Proboscidea <mammal> Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 101001018880 Rattus norvegicus Macrophage migration inhibitory factor Proteins 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- 241000555745 Sciuridae Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- 102100036788 Tubulin beta-4A chain Human genes 0.000 description 2
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- NASABYJQIYJDID-UHFFFAOYSA-N [2-[[2-chloro-6-(methylamino)purin-9-yl]methyl]-3-(2,2-dimethylpropanoyloxy)propyl] 2,2-dimethylpropanoate Chemical compound CNC1=NC(Cl)=NC2=C1N=CN2CC(COC(=O)C(C)(C)C)COC(=O)C(C)(C)C NASABYJQIYJDID-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 230000001494 anti-thymocyte effect Effects 0.000 description 2
- 230000003143 atherosclerotic effect Effects 0.000 description 2
- 230000005784 autoimmunity Effects 0.000 description 2
- 229960002170 azathioprine Drugs 0.000 description 2
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 210000003651 basophil Anatomy 0.000 description 2
- 229960002537 betamethasone Drugs 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229960001838 canakinumab Drugs 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 229960003115 certolizumab pegol Drugs 0.000 description 2
- 230000003399 chemotactic effect Effects 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- 229960004630 chlorambucil Drugs 0.000 description 2
- 229960002688 choline salicylate Drugs 0.000 description 2
- 229960002436 cladribine Drugs 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 229960002806 daclizumab Drugs 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000002059 diagnostic imaging Methods 0.000 description 2
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 2
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 230000008029 eradication Effects 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 238000012632 fluorescent imaging Methods 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 229960002743 glutamine Drugs 0.000 description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 2
- 229960001743 golimumab Drugs 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 102000048851 human CD44 Human genes 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 229960004963 mesalazine Drugs 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 229950003734 milatuzumab Drugs 0.000 description 2
- 238000000302 molecular modelling Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- HYEIHNVWTVQZFH-UHFFFAOYSA-N n-(4,6-dimethyl-1-pentyl-2,3-dihydroindol-7-yl)-2,2-dimethylpropanamide Chemical compound CC(C)(C)C(=O)NC1=C(C)C=C(C)C2=C1N(CCCCC)CC2 HYEIHNVWTVQZFH-UHFFFAOYSA-N 0.000 description 2
- CWJJHESJXJQCJA-UHFFFAOYSA-N n-(pyridin-2-ylmethyl)-1-[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methanamine Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CNCC1=CC=CC=N1 CWJJHESJXJQCJA-UHFFFAOYSA-N 0.000 description 2
- 210000005170 neoplastic cell Anatomy 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 238000012831 peritoneal equilibrium test Methods 0.000 description 2
- 206010034674 peritonitis Diseases 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 238000012636 positron electron tomography Methods 0.000 description 2
- 238000012877 positron emission topography Methods 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000005180 public health Effects 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000007781 signaling event Effects 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- VIDRYROWYFWGSY-UHFFFAOYSA-N sotalol hydrochloride Chemical compound Cl.CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 VIDRYROWYFWGSY-UHFFFAOYSA-N 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229960001940 sulfasalazine Drugs 0.000 description 2
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 2
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 2
- 229940037128 systemic glucocorticoids Drugs 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- 229960001278 teniposide Drugs 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- FQCQGOZEWWPOKI-UHFFFAOYSA-K trisalicylate-choline Chemical compound [Mg+2].C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O FQCQGOZEWWPOKI-UHFFFAOYSA-K 0.000 description 2
- 230000005951 type IV hypersensitivity Effects 0.000 description 2
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 241000701447 unidentified baculovirus Species 0.000 description 2
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 210000000264 venule Anatomy 0.000 description 2
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- JCORQAPHJGHVGK-JUQOVJQISA-N (2s)-2-acetamido-3-[[(3r)-1-(3-piperidin-4-ylpropanoyl)piperidine-3-carbonyl]amino]propanoic acid;trihydrate Chemical compound O.O.O.C1[C@H](C(=O)NC[C@H](NC(=O)C)C(O)=O)CCCN1C(=O)CCC1CCNCC1 JCORQAPHJGHVGK-JUQOVJQISA-N 0.000 description 1
- XAMYAYIMCKELIP-FQEVSTJZSA-N (2s)-2-hexylsulfanyl-n-[6-methyl-2,4-bis(methylsulfanyl)pyridin-3-yl]decanamide Chemical compound CCCCCCCC[C@H](SCCCCCC)C(=O)NC1=C(SC)C=C(C)N=C1SC XAMYAYIMCKELIP-FQEVSTJZSA-N 0.000 description 1
- JOEHPBQVSCDCHE-BKGQOYFSSA-N (4r,7s,10s,13s,19s,22s,25s,28s,31s,34r)-34-amino-22-(4-aminobutyl)-10-(3-amino-3-oxopropyl)-31-benzyl-13,19-bis[3-(diaminomethylideneamino)propyl]-25-[(1r)-1-hydroxyethyl]-28-(2-methylpropyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-7-propan-2-yl-1,2-dithia-5, Chemical compound N1C(=O)[C@@H](N)CSSC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCCN)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CC1=CC=CC=C1 JOEHPBQVSCDCHE-BKGQOYFSSA-N 0.000 description 1
- HPVSJNGZYYDDMU-UHFFFAOYSA-N (5Z)-5-[(6E,10E)-13-(3-furyl)-2,6,10-trimethyltrideca-6,10-dien-1-ylidene]-4-hydroxy-3-methylfuran-2(5H)-one Natural products O1C(=O)C(C)=C(O)C1=CC(C)CCCC(C)=CCCC(C)=CCCC=1C=COC=1 HPVSJNGZYYDDMU-UHFFFAOYSA-N 0.000 description 1
- HMLGSIZOMSVISS-ONJSNURVSA-N (7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2,2-dimethylpropanoyloxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(C=C)CSC21)C(O)=O)=O)C(=O)\C(=N/OCOC(=O)C(C)(C)C)C1=CSC(N)=N1 HMLGSIZOMSVISS-ONJSNURVSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- WTLRWOHEKQGKDS-UHFFFAOYSA-N 1-(4-chloro-2-hydroxy-3-sulfamoylphenyl)-3-(2,3-dichlorophenyl)urea Chemical compound NS(=O)(=O)C1=C(Cl)C=CC(NC(=O)NC=2C(=C(Cl)C=CC=2)Cl)=C1O WTLRWOHEKQGKDS-UHFFFAOYSA-N 0.000 description 1
- XWMKELOZYZOSKN-UHFFFAOYSA-N 1-[1-butyl-2-oxo-4-[3-(pyridin-3-ylmethoxy)phenyl]-1,8-naphthyridin-3-yl]-3-[2,6-di(propan-2-yl)phenyl]urea Chemical compound CC(C)C=1C=CC=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C(C=1)=CC=CC=1OCC1=CC=CN=C1 XWMKELOZYZOSKN-UHFFFAOYSA-N 0.000 description 1
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- YCAMCDZPALUJIJ-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid;n-[[4-[[1h-imidazol-2-ylmethyl-[(1-methylimidazol-2-yl)methyl]amino]methyl]phenyl]methyl]-n-methyl-n',n'-dipropylbutane-1,4-diamine Chemical compound OC(=O)C(O)C(O)C(O)=O.C1=CC(CN(C)CCCCN(CCC)CCC)=CC=C1CN(CC=1N(C=CN=1)C)CC1=NC=CN1 YCAMCDZPALUJIJ-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- MDKVDJZIHRFUBO-UHFFFAOYSA-N 2-amino-3-benzoyl-4-(2-benzoylphenyl)iminocyclohexa-2,5-dien-1-one Chemical class C1=CC=C(C=C1)C(=O)C2=CC=CC=C2N=C3C=CC(=O)C(=C3C(=O)C4=CC=CC=C4)N MDKVDJZIHRFUBO-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- RXIUEIPPLAFSDF-CYBMUJFWSA-N 2-hydroxy-n,n-dimethyl-3-[[2-[[(1r)-1-(5-methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]benzamide Chemical compound N([C@H](CC)C=1OC(C)=CC=1)C(C(C1=O)=O)=C1NC1=CC=CC(C(=O)N(C)C)=C1O RXIUEIPPLAFSDF-CYBMUJFWSA-N 0.000 description 1
- YZQLWPMZQVHJED-UHFFFAOYSA-N 2-methylpropanethioic acid S-[2-[[[1-(2-ethylbutyl)cyclohexyl]-oxomethyl]amino]phenyl] ester Chemical compound C=1C=CC=C(SC(=O)C(C)C)C=1NC(=O)C1(CC(CC)CC)CCCCC1 YZQLWPMZQVHJED-UHFFFAOYSA-N 0.000 description 1
- RKAKHLWCVBGMID-FQEVSTJZSA-N 2-phenyl-n-[[(3s)-1-[2-[5-(1,2,4-triazol-4-yl)-1h-indol-3-yl]ethyl]pyrrolidin-3-yl]methyl]propan-2-amine Chemical compound C([C@H](C1)CNC(C)(C)C=2C=CC=CC=2)CN1CCC(C1=C2)=CNC1=CC=C2N1C=NN=C1 RKAKHLWCVBGMID-FQEVSTJZSA-N 0.000 description 1
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000001627 3 membered heterocyclic group Chemical group 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- PYSICVOJSJMFKP-UHFFFAOYSA-N 3,5-dibromo-2-chloropyridine Chemical compound ClC1=NC=C(Br)C=C1Br PYSICVOJSJMFKP-UHFFFAOYSA-N 0.000 description 1
- LYIQNVKSTSEEEG-UHFFFAOYSA-N 3-[[4-(4-carbamimidoylphenyl)-1,3-thiazol-2-yl]-[1-(carboxymethyl)piperidin-4-yl]amino]propanoic acid Chemical compound C1=CC(C(=N)N)=CC=C1C1=CSC(N(CCC(O)=O)C2CCN(CC(O)=O)CC2)=N1 LYIQNVKSTSEEEG-UHFFFAOYSA-N 0.000 description 1
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical group [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001963 4 membered heterocyclic group Chemical group 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- YSCNMFDFYJUPEF-OWOJBTEDSA-N 4,4'-diisothiocyano-trans-stilbene-2,2'-disulfonic acid Chemical compound OS(=O)(=O)C1=CC(N=C=S)=CC=C1\C=C\C1=CC=C(N=C=S)C=C1S(O)(=O)=O YSCNMFDFYJUPEF-OWOJBTEDSA-N 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- ZTCJXHNJVLUUMR-UHFFFAOYSA-N 4-iodo-6-phenylpyrimidine Chemical compound C1=NC(I)=CC(C=2C=CC=CC=2)=N1 ZTCJXHNJVLUUMR-UHFFFAOYSA-N 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- ODZGXAJXTPWPBC-UHFFFAOYSA-N 5,5-diisothiocyanato-2-(2-phenylethenyl)cyclohex-3-ene-1,1-disulfonic acid Chemical compound OS(=O)(=O)C1(S(O)(=O)=O)CC(N=C=S)(N=C=S)C=CC1C=CC1=CC=CC=C1 ODZGXAJXTPWPBC-UHFFFAOYSA-N 0.000 description 1
- SRHSMXLXWORYJK-SSDOTTSWSA-N 5-[(2,3-difluorophenyl)methylsulfanyl]-7-[[(2r)-1-hydroxypropan-2-yl]amino]-3h-[1,3]thiazolo[4,5-d]pyrimidin-2-one Chemical compound N=1C=2NC(=O)SC=2C(N[C@@H](CO)C)=NC=1SCC1=CC=CC(F)=C1F SRHSMXLXWORYJK-SSDOTTSWSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- MJZJYWCQPMNPRM-UHFFFAOYSA-N 6,6-dimethyl-1-[3-(2,4,5-trichlorophenoxy)propoxy]-1,6-dihydro-1,3,5-triazine-2,4-diamine Chemical compound CC1(C)N=C(N)N=C(N)N1OCCCOC1=CC(Cl)=C(Cl)C=C1Cl MJZJYWCQPMNPRM-UHFFFAOYSA-N 0.000 description 1
- QNQZWEGMKJBHEM-UHFFFAOYSA-N 6-methyl-5-(2-methylpyrazol-3-yl)-n-[(5-methylsulfonylpyridin-2-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(C=2N(N=CC=2)C)C=C1C(=O)NCC1=CC=C(S(C)(=O)=O)C=N1 QNQZWEGMKJBHEM-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 101150037123 APOE gene Proteins 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- 108700023418 Amidases Proteins 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 101710095342 Apolipoprotein B Proteins 0.000 description 1
- 102100040202 Apolipoprotein B-100 Human genes 0.000 description 1
- MAVDNGWEBZTACC-HNNXBMFYSA-N Apratastat Chemical compound ONC(=O)[C@H]1C(C)(C)SCCN1S(=O)(=O)C1=CC=C(OCC#CCO)C=C1 MAVDNGWEBZTACC-HNNXBMFYSA-N 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- 208000000104 Arthus reaction Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 102100039339 Atrial natriuretic peptide receptor 1 Human genes 0.000 description 1
- 101710082924 Atypical protein kinase C Proteins 0.000 description 1
- 206010050245 Autoimmune thrombocytopenia Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 239000005465 B01AC22 - Prasugrel Substances 0.000 description 1
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 101100059517 Bos taurus CD44 gene Proteins 0.000 description 1
- 101100168975 Bos taurus CXCR2 gene Proteins 0.000 description 1
- 101100168990 Bos taurus CXCR4 gene Proteins 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 102400000967 Bradykinin Human genes 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- 102100036150 C-X-C motif chemokine 5 Human genes 0.000 description 1
- GHTGYZMBQPXTCQ-UHFFFAOYSA-N CC1(C)Cc2c(sc(NC(=O)c3ccn[nH]3)c2C(N)=O)C(C)(C)O1 Chemical compound CC1(C)Cc2c(sc(NC(=O)c3ccn[nH]3)c2C(N)=O)C(C)(C)O1 GHTGYZMBQPXTCQ-UHFFFAOYSA-N 0.000 description 1
- 101100112679 Caenorhabditis elegans cyd-1 gene Proteins 0.000 description 1
- 101100124795 Caenorhabditis elegans hsp-110 gene Proteins 0.000 description 1
- 101100289894 Caenorhabditis elegans lys-7 gene Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000010667 Carcinoma of liver and intrahepatic biliary tract Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 102000009410 Chemokine receptor Human genes 0.000 description 1
- 108050000299 Chemokine receptor Proteins 0.000 description 1
- 208000000668 Chronic Pancreatitis Diseases 0.000 description 1
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 1
- 241000688200 Cingulata Species 0.000 description 1
- KPSRODZRAIWAKH-JTQLQIEISA-N Ciprofibrate Natural products C1=CC(OC(C)(C)C(O)=O)=CC=C1[C@H]1C(Cl)(Cl)C1 KPSRODZRAIWAKH-JTQLQIEISA-N 0.000 description 1
- ARPLCFGLEYFDCN-CDACMRRYSA-N Clocortolone acetate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(Cl)[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)COC(C)=O)[C@@]2(C)C[C@@H]1O ARPLCFGLEYFDCN-CDACMRRYSA-N 0.000 description 1
- 101710094648 Coat protein Proteins 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 241000759568 Corixa Species 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 241001125840 Coryphaenidae Species 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- 101150074155 DHFR gene Proteins 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 101100216294 Danio rerio apoeb gene Proteins 0.000 description 1
- 241001520250 Dasyuromorphia Species 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 241001520234 Didelphimorphia Species 0.000 description 1
- WYQPLTPSGFELIB-JTQPXKBDSA-N Difluprednate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2CC[C@@](C(=O)COC(C)=O)(OC(=O)CCC)[C@@]2(C)C[C@@H]1O WYQPLTPSGFELIB-JTQPXKBDSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241001520243 Diprotodontia Species 0.000 description 1
- 241001147101 Dugong Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014666 Endocarditis bacterial Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 108010056764 Eptifibatide Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000283070 Equus zebra Species 0.000 description 1
- 206010015251 Erythroblastosis foetalis Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 101100169267 Escherichia coli (strain K12) cydA gene Proteins 0.000 description 1
- 241000283257 Eschrichtius robustus Species 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 1
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 1
- 208000009087 False Aneurysm Diseases 0.000 description 1
- 102100027286 Fanconi anemia group C protein Human genes 0.000 description 1
- 241000212015 Feliformia Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 241000724791 Filamentous phage Species 0.000 description 1
- WJOHZNCJWYWUJD-IUGZLZTKSA-N Fluocinonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WJOHZNCJWYWUJD-IUGZLZTKSA-N 0.000 description 1
- POPFMWWJOGLOIF-XWCQMRHXSA-N Flurandrenolide Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O POPFMWWJOGLOIF-XWCQMRHXSA-N 0.000 description 1
- 208000001034 Frostbite Diseases 0.000 description 1
- 102000001390 Fructose-Bisphosphate Aldolase Human genes 0.000 description 1
- 108010068561 Fructose-Bisphosphate Aldolase Proteins 0.000 description 1
- 101800002469 GRO-alpha(4-73) Proteins 0.000 description 1
- 102400000482 GRO-alpha(4-73) Human genes 0.000 description 1
- 101800003150 GRO-alpha(5-73) Proteins 0.000 description 1
- 102400000481 GRO-alpha(5-73) Human genes 0.000 description 1
- 101800003860 GRO-alpha(6-73) Proteins 0.000 description 1
- 102400000485 GRO-alpha(6-73) Human genes 0.000 description 1
- 241000122126 Galagidae Species 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- 208000007465 Giant cell arteritis Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 102100021181 Golgi phosphoprotein 3 Human genes 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 206010069767 H1N1 influenza Diseases 0.000 description 1
- 102000007369 HSP110 Heat-Shock Proteins Human genes 0.000 description 1
- 108010032952 HSP110 Heat-Shock Proteins Proteins 0.000 description 1
- MUQNGPZZQDCDFT-JNQJZLCISA-N Halcinonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]1(C)C[C@@H]2O MUQNGPZZQDCDFT-JNQJZLCISA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 206010073069 Hepatic cancer Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000916059 Homo sapiens C-X-C chemokine receptor type 2 Proteins 0.000 description 1
- 101100441523 Homo sapiens CXCL5 gene Proteins 0.000 description 1
- 101000973997 Homo sapiens Nucleosome assembly protein 1-like 4 Proteins 0.000 description 1
- FOGXJPFPZOHSQS-AYVLZSQQSA-N Hydrocortisone butyrate propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CC)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O FOGXJPFPZOHSQS-AYVLZSQQSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 108010091358 Hypoxanthine Phosphoribosyltransferase Proteins 0.000 description 1
- 102100029098 Hypoxanthine-guanine phosphoribosyltransferase Human genes 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- 208000001718 Immediate Hypersensitivity Diseases 0.000 description 1
- 208000024781 Immune Complex disease Diseases 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 241000289658 Insectivora Species 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 1
- 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 description 1
- 102100026018 Interleukin-1 receptor antagonist protein Human genes 0.000 description 1
- 101710144554 Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
- 102000013691 Interleukin-17 Human genes 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000010781 Interleukin-6 Receptors Human genes 0.000 description 1
- 108010038501 Interleukin-6 Receptors Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 101710172072 Kexin Proteins 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical class C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 101150002998 LCAT gene Proteins 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 108010070919 LJP 1082 Proteins 0.000 description 1
- 241000283953 Lagomorpha Species 0.000 description 1
- 241000288903 Lemuridae Species 0.000 description 1
- 241001446569 Lepus granatensis Species 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 101150058224 MIF gene Proteins 0.000 description 1
- 108010048043 Macrophage Migration-Inhibitory Factors Proteins 0.000 description 1
- 102000009073 Macrophage Migration-Inhibitory Factors Human genes 0.000 description 1
- 102100027998 Macrophage metalloelastase Human genes 0.000 description 1
- 101710187853 Macrophage metalloelastase Proteins 0.000 description 1
- 241000289569 Macropus robustus Species 0.000 description 1
- 241000318926 Macrotis lagotis Species 0.000 description 1
- MQHWFIOJQSCFNM-UHFFFAOYSA-L Magnesium salicylate Chemical compound [Mg+2].OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O MQHWFIOJQSCFNM-UHFFFAOYSA-L 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 1
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- GZENKSODFLBBHQ-ILSZZQPISA-N Medrysone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@H](C(C)=O)CC[C@H]21 GZENKSODFLBBHQ-ILSZZQPISA-N 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 208000027530 Meniere disease Diseases 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 241001520247 Microbiotheria Species 0.000 description 1
- 241001416521 Microbiotheriidae Species 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 241000428199 Mustelinae Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 241000289692 Myrmecophagidae Species 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N N-acetyl-para-amino-phenol Natural products CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 201000004404 Neurofibroma Diseases 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- 241001520370 Notoryctemorphia Species 0.000 description 1
- 241001416525 Notoryctidae Species 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 101710141454 Nucleoprotein Proteins 0.000 description 1
- 102100022396 Nucleosome assembly protein 1-like 4 Human genes 0.000 description 1
- 241000283965 Ochotona princeps Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 206010033165 Ovarian failure Diseases 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 229940127424 P2Y12 Receptor Antagonists Drugs 0.000 description 1
- 101150094724 PCSK9 gene Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- 206010033649 Pancreatitis chronic Diseases 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- HYRKAAMZBDSJFJ-LFDBJOOHSA-N Paramethasone acetate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)COC(C)=O)(O)[C@@]2(C)C[C@@H]1O HYRKAAMZBDSJFJ-LFDBJOOHSA-N 0.000 description 1
- 241001520236 Paucituberculata Species 0.000 description 1
- 241000721454 Pemphigus Species 0.000 description 1
- 241001520373 Peramelemorphia Species 0.000 description 1
- 241000289702 Peramelidae Species 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 241000283089 Perissodactyla Species 0.000 description 1
- 241001520316 Phascolarctidae Species 0.000 description 1
- 241000283216 Phocidae Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000688197 Pilosa Species 0.000 description 1
- 108090000778 Platelet factor 4 Proteins 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 241001074346 Priodontes maximus Species 0.000 description 1
- 101710083689 Probable capsid protein Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102220537320 Protein NDRG2_G31P_mutation Human genes 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 206010037649 Pyogenic granuloma Diseases 0.000 description 1
- 101100168983 Rattus norvegicus Cxcr2 gene Proteins 0.000 description 1
- 101100497630 Rattus norvegicus Cxcr4 gene Proteins 0.000 description 1
- 230000010799 Receptor Interactions Effects 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 241000282806 Rhinoceros Species 0.000 description 1
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 102220506570 Small ubiquitin-related modifier 2_K11R_mutation Human genes 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- 241001327471 Solenodon Species 0.000 description 1
- 206010041662 Splinter Diseases 0.000 description 1
- 101710088580 Stromal cell-derived factor 1 Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 241001493546 Suina Species 0.000 description 1
- 108010045306 T134 peptide Proteins 0.000 description 1
- 108010025037 T140 peptide Proteins 0.000 description 1
- 108010043065 TC14012 Proteins 0.000 description 1
- 108010037529 TN14003 Proteins 0.000 description 1
- 108700012920 TNF Proteins 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 241000283068 Tapiridae Species 0.000 description 1
- 241000288942 Tarsiidae Species 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 206010045240 Type I hypersensitivity Diseases 0.000 description 1
- 206010054000 Type II hypersensitivity Diseases 0.000 description 1
- 206010053614 Type III immune complex mediated reaction Diseases 0.000 description 1
- 241000282458 Ursus sp. Species 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- RILSEMQQYBRWTN-UHFFFAOYSA-N Variabiline+ Natural products C1=C2C(C=34)=C(O)C(OC)=CC=3CCN(C)C4CC2=CC=C1N(CC=1C=CC=CC=1)CC1=CC=CC=C1 RILSEMQQYBRWTN-UHFFFAOYSA-N 0.000 description 1
- 208000014070 Vestibular schwannoma Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 241000289674 Vombatidae Species 0.000 description 1
- 235000021068 Western diet Nutrition 0.000 description 1
- OGQICQVSFDPSEI-UHFFFAOYSA-N Zorac Chemical compound N1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SCCC2(C)C)C2=C1 OGQICQVSFDPSEI-UHFFFAOYSA-N 0.000 description 1
- NWLFOBZKYXKBOF-NSVAZKTRSA-N [(1s,2s)-2-[[2,2-dimethylpropyl(nonyl)carbamoyl]amino]cyclohexyl] 3-[[(4r)-2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl]amino]propanoate Chemical compound CCCCCCCCCN(CC(C)(C)C)C(=O)N[C@H]1CCCC[C@@H]1OC(=O)CCNC(=O)[C@H]1C(C)(C)COC(C)(C)O1 NWLFOBZKYXKBOF-NSVAZKTRSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- UVKSSLZRUNYLIM-ZCFIWIBFSA-N [4-[(2r)-1-amino-1-oxopropan-2-yl]phenyl] trifluoromethanesulfonate Chemical compound NC(=O)[C@H](C)C1=CC=C(OS(=O)(=O)C(F)(F)F)C=C1 UVKSSLZRUNYLIM-ZCFIWIBFSA-N 0.000 description 1
- 229960003697 abatacept Drugs 0.000 description 1
- 229960000446 abciximab Drugs 0.000 description 1
- 229960003146 abetimus sodium Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960005339 acitretin Drugs 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 238000011374 additional therapy Methods 0.000 description 1
- 101150115889 al gene Proteins 0.000 description 1
- 238000012867 alanine scanning Methods 0.000 description 1
- 229960000552 alclometasone Drugs 0.000 description 1
- DJHCCTTVDRAMEH-DUUJBDRPSA-N alclometasone dipropionate Chemical compound C([C@H]1Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O DJHCCTTVDRAMEH-DUUJBDRPSA-N 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 229960002459 alefacept Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- IHUNBGSDBOWDMA-AQFIFDHZSA-N all-trans-acitretin Chemical compound COC1=CC(C)=C(\C=C\C(\C)=C\C=C\C(\C)=C\C(O)=O)C(C)=C1C IHUNBGSDBOWDMA-AQFIFDHZSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229960003099 amcinonide Drugs 0.000 description 1
- ILKJAFIWWBXGDU-MOGDOJJUSA-N amcinonide Chemical compound O([C@@]1([C@H](O2)C[C@@H]3[C@@]1(C[C@H](O)[C@]1(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]13)C)C(=O)COC(=O)C)C12CCCC1 ILKJAFIWWBXGDU-MOGDOJJUSA-N 0.000 description 1
- 102000005922 amidase Human genes 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960004238 anakinra Drugs 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000781 anti-lymphocytic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 108010086127 antileukinate Proteins 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 210000002403 aortic endothelial cell Anatomy 0.000 description 1
- NETXMUIMUZJUTB-UHFFFAOYSA-N apabetalone Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C1=CC(C)=C(OCCO)C(C)=C1 NETXMUIMUZJUTB-UHFFFAOYSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229950002842 apratastat Drugs 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 125000005362 aryl sulfone group Chemical group 0.000 description 1
- 125000005361 aryl sulfoxide group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229940072224 asacol Drugs 0.000 description 1
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 1
- 229940092117 atgam Drugs 0.000 description 1
- 230000036523 atherogenesis Effects 0.000 description 1
- 208000010216 atopic IgE responsiveness Diseases 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 201000004339 autoimmune neuropathy Diseases 0.000 description 1
- 229950010046 avasimibe Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 229960000794 baclofen Drugs 0.000 description 1
- 208000009361 bacterial endocarditis Diseases 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 229960004168 balsalazide Drugs 0.000 description 1
- IPOKCKJONYRRHP-FMQUCBEESA-N balsalazide Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1\N=N\C1=CC=C(O)C(C(O)=O)=C1 IPOKCKJONYRRHP-FMQUCBEESA-N 0.000 description 1
- 229960004669 basiliximab Drugs 0.000 description 1
- 229960004495 beclometasone Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 229960000516 bezafibrate Drugs 0.000 description 1
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008275 binding mechanism Effects 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- GHAFORRTMVIXHS-UHFFFAOYSA-L bromosulfophthalein sodium Chemical compound [Na+].[Na+].C1=C(S([O-])(=O)=O)C(O)=CC=C1C1(C=2C=C(C(O)=CC=2)S([O-])(=O)=O)C(C(Br)=C(Br)C(Br)=C2Br)=C2C(=O)O1 GHAFORRTMVIXHS-UHFFFAOYSA-L 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 1
- 229960004064 bumetanide Drugs 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000035571 calor Effects 0.000 description 1
- 229960001080 cangrelor Drugs 0.000 description 1
- PAEBIVWUMLRPSK-IDTAVKCVSA-N cangrelor Chemical compound C1=NC=2C(NCCSC)=NC(SCCC(F)(F)F)=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)C(Cl)(Cl)P(O)(O)=O)[C@@H](O)[C@H]1O PAEBIVWUMLRPSK-IDTAVKCVSA-N 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 208000025188 carcinoma of pharynx Diseases 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 201000003959 cecum carcinoma Diseases 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000017455 cell-cell adhesion Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- AIXMJTYHQHQJLU-UHFFFAOYSA-N chembl210858 Chemical compound O1C(CC(=O)OC)CC(C=2C=CC(O)=CC=2)=N1 AIXMJTYHQHQJLU-UHFFFAOYSA-N 0.000 description 1
- FZDJFSFPMBLXMO-ADZSTZGASA-N chembl2370108 Chemical compound C([C@H]1C(=O)N[C@@H](CCCNC(N)=O)C(=O)N[C@H](C(N[C@H](CCCCN)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCNC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CC=1C=C2C=CC=CC2=CC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=O)CCCCN)C1=CC=C(O)C=C1 FZDJFSFPMBLXMO-ADZSTZGASA-N 0.000 description 1
- WGGSNNMSSGLKHI-HLICZWCASA-N chembl525205 Polymers C([C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@@H]2C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CC=3C=CC=CC=3)C(=O)N[C@H](C(N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CSSC2)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)=O)CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCCNC(N)=N)=O)C(C)C)C1=CC=CC=C1 WGGSNNMSSGLKHI-HLICZWCASA-N 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 239000002561 chemical irritant Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000012085 chronic inflammatory response Effects 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229960003728 ciclesonide Drugs 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229960002174 ciprofibrate Drugs 0.000 description 1
- KPSRODZRAIWAKH-UHFFFAOYSA-N ciprofibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1C1C(Cl)(Cl)C1 KPSRODZRAIWAKH-UHFFFAOYSA-N 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960002842 clobetasol Drugs 0.000 description 1
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 description 1
- 229960001146 clobetasone Drugs 0.000 description 1
- XXIFVOHLGBURIG-OZCCCYNHSA-N clobetasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)CC2=O XXIFVOHLGBURIG-OZCCCYNHSA-N 0.000 description 1
- 229960004299 clocortolone Drugs 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 229960002219 cloprednol Drugs 0.000 description 1
- YTJIBEDMAQUYSZ-FDNPDPBUSA-N cloprednol Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3C=C(Cl)C2=C1 YTJIBEDMAQUYSZ-FDNPDPBUSA-N 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- BMCQMVFGOVHVNG-TUFAYURCSA-N cortisol 17-butyrate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O BMCQMVFGOVHVNG-TUFAYURCSA-N 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 229960003840 cortivazol Drugs 0.000 description 1
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 150000001925 cycloalkenes Chemical class 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 150000001945 cysteines Chemical class 0.000 description 1
- 230000002559 cytogenic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- ZESRJSPZRDMNHY-UHFFFAOYSA-N de-oxy corticosterone Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 ZESRJSPZRDMNHY-UHFFFAOYSA-N 0.000 description 1
- 231100000895 deafness Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229960001145 deflazacort Drugs 0.000 description 1
- FBHSPRKOSMHSIF-GRMWVWQJSA-N deflazacort Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O FBHSPRKOSMHSIF-GRMWVWQJSA-N 0.000 description 1
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 229940027008 deltasone Drugs 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 229940119740 deoxycorticosterone Drugs 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 229960003662 desonide Drugs 0.000 description 1
- WBGKWQHBNHJJPZ-LECWWXJVSA-N desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 description 1
- 229960002593 desoximetasone Drugs 0.000 description 1
- VWVSBHGCDBMOOT-IIEHVVJPSA-N desoximetasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@H](C(=O)CO)[C@@]1(C)C[C@@H]2O VWVSBHGCDBMOOT-IIEHVVJPSA-N 0.000 description 1
- 229960003654 desoxycortone Drugs 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960004154 diflorasone Drugs 0.000 description 1
- BOBLHFUVNSFZPJ-JOYXJVLSSA-N diflorasone diacetate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)COC(C)=O)(OC(C)=O)[C@@]2(C)C[C@@H]1O BOBLHFUVNSFZPJ-JOYXJVLSSA-N 0.000 description 1
- 229960004091 diflucortolone Drugs 0.000 description 1
- OGPWIDANBSLJPC-RFPWEZLHSA-N diflucortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O OGPWIDANBSLJPC-RFPWEZLHSA-N 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- 229960004875 difluprednate Drugs 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229940075049 dovonex Drugs 0.000 description 1
- 229960002224 eculizumab Drugs 0.000 description 1
- 229960000284 efalizumab Drugs 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 150000002066 eicosanoids Chemical class 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229950009760 epratuzumab Drugs 0.000 description 1
- GLGOPUHVAZCPRB-LROMGURASA-N eptifibatide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCCNC(=N)N)NC(=O)CCSSC[C@@H](C(N)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@@H]1CC1=CN=C2[C]1C=CC=C2 GLGOPUHVAZCPRB-LROMGURASA-N 0.000 description 1
- 229960004468 eptifibatide Drugs 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 229960005293 etodolac Drugs 0.000 description 1
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- 229960004945 etoricoxib Drugs 0.000 description 1
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229950011548 fadrozole Drugs 0.000 description 1
- ZWJINEZUASEZBH-UHFFFAOYSA-N fenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC=C1 ZWJINEZUASEZBH-UHFFFAOYSA-N 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 229960005341 fenoprofen calcium Drugs 0.000 description 1
- VHUXSAWXWSTUOD-UHFFFAOYSA-L fenoprofen calcium (anhydrous) Chemical compound [Ca+2].[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1.[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1 VHUXSAWXWSTUOD-UHFFFAOYSA-L 0.000 description 1
- 208000001031 fetal erythroblastosis Diseases 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000007519 figuring Methods 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- 229960001440 fluclorolone Drugs 0.000 description 1
- VTWKPILBIUBMDS-OTJLYDAYSA-N fluclorolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(Cl)[C@@H](Cl)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3C[C@H](F)C2=C1 VTWKPILBIUBMDS-OTJLYDAYSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960002011 fludrocortisone Drugs 0.000 description 1
- AAXVEMMRQDVLJB-BULBTXNYSA-N fludrocortisone Chemical compound O=C1CC[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 AAXVEMMRQDVLJB-BULBTXNYSA-N 0.000 description 1
- 229960004511 fludroxycortide Drugs 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- 229960003469 flumetasone Drugs 0.000 description 1
- WXURHACBFYSXBI-GQKYHHCASA-N flumethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-GQKYHHCASA-N 0.000 description 1
- 229960000676 flunisolide Drugs 0.000 description 1
- 229960001347 fluocinolone acetonide Drugs 0.000 description 1
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 1
- 229960000785 fluocinonide Drugs 0.000 description 1
- 229960005355 fluocortin Drugs 0.000 description 1
- XWTIDFOGTCVGQB-FHIVUSPVSA-N fluocortin butyl Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)C(=O)OCCCC)[C@@]2(C)C[C@@H]1O XWTIDFOGTCVGQB-FHIVUSPVSA-N 0.000 description 1
- 229960003973 fluocortolone Drugs 0.000 description 1
- GAKMQHDJQHZUTJ-ULHLPKEOSA-N fluocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O GAKMQHDJQHZUTJ-ULHLPKEOSA-N 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229960001048 fluorometholone Drugs 0.000 description 1
- FAOZLTXFLGPHNG-KNAQIMQKSA-N fluorometholone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@]2(F)[C@@H](O)C[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FAOZLTXFLGPHNG-KNAQIMQKSA-N 0.000 description 1
- 229960003590 fluperolone Drugs 0.000 description 1
- HHPZZKDXAFJLOH-QZIXMDIESA-N fluperolone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](C(=O)[C@@H](OC(C)=O)C)(O)[C@@]1(C)C[C@@H]2O HHPZZKDXAFJLOH-QZIXMDIESA-N 0.000 description 1
- 229960003238 fluprednidene Drugs 0.000 description 1
- YVHXHNGGPURVOS-SBTDHBFYSA-N fluprednidene Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](C(=C)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 YVHXHNGGPURVOS-SBTDHBFYSA-N 0.000 description 1
- 229960002714 fluticasone Drugs 0.000 description 1
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 229960000671 formocortal Drugs 0.000 description 1
- QNXUUBBKHBYRFW-QWAPGEGQSA-N formocortal Chemical compound C1C(C=O)=C2C=C(OCCCl)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O QNXUUBBKHBYRFW-QWAPGEGQSA-N 0.000 description 1
- 229960002848 formoterol Drugs 0.000 description 1
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N gamma-butyrolactam Natural products O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical group COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229960002383 halcinonide Drugs 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 229960002475 halometasone Drugs 0.000 description 1
- GGXMRPUKBWXVHE-MIHLVHIWSA-N halometasone Chemical compound C1([C@@H](F)C2)=CC(=O)C(Cl)=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O GGXMRPUKBWXVHE-MIHLVHIWSA-N 0.000 description 1
- 201000003911 head and neck carcinoma Diseases 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 102000055357 human CXCR2 Human genes 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229960002453 hydrocortisone aceponate Drugs 0.000 description 1
- MFBMYAOAMQLLPK-FZNHGJLXSA-N hydrocortisone aceponate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(C)=O)(OC(=O)CC)[C@@]1(C)C[C@@H]2O MFBMYAOAMQLLPK-FZNHGJLXSA-N 0.000 description 1
- 229960001524 hydrocortisone butyrate Drugs 0.000 description 1
- 229960002846 hydrocortisone probutate Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 1
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000000899 immune system response Effects 0.000 description 1
- 230000006054 immunological memory Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 201000001371 inclusion conjunctivitis Diseases 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- APFVFJFRJDLVQX-AHCXROLUSA-N indium-111 Chemical compound [111In] APFVFJFRJDLVQX-AHCXROLUSA-N 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 201000007119 infective endocarditis Diseases 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 230000008611 intercellular interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960004384 ketorolac tromethamine Drugs 0.000 description 1
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000023404 leukocyte cell-cell adhesion Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000002250 liver carcinoma Diseases 0.000 description 1
- 229960001798 loteprednol Drugs 0.000 description 1
- YPZVAYHNBBHPTO-MXRBDKCISA-N loteprednol Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)OCCl)[C@@H]4[C@@H]3CCC2=C1 YPZVAYHNBBHPTO-MXRBDKCISA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 229960000994 lumiracoxib Drugs 0.000 description 1
- KHPKQFYUPIUARC-UHFFFAOYSA-N lumiracoxib Chemical compound OC(=O)CC1=CC(C)=CC=C1NC1=C(F)C=CC=C1Cl KHPKQFYUPIUARC-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229940072082 magnesium salicylate Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940013798 meclofenamate Drugs 0.000 description 1
- 229960001011 medrysone Drugs 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 229960005108 mepolizumab Drugs 0.000 description 1
- 229960001810 meprednisone Drugs 0.000 description 1
- PIDANAQULIKBQS-RNUIGHNZSA-N meprednisone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)CC2=O PIDANAQULIKBQS-RNUIGHNZSA-N 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- IRAXRQFCCSHQDX-WBVHZDCISA-N methyl (2s)-2-(butoxycarbonylamino)-3-[[2-[(5r)-3-(4-carbamimidoylphenyl)-4,5-dihydro-1,2-oxazol-5-yl]acetyl]amino]propanoate Chemical compound O1[C@@H](CC(=O)NC[C@H](NC(=O)OCCCC)C(=O)OC)CC(C=2C=CC(=CC=2)C(N)=N)=N1 IRAXRQFCCSHQDX-WBVHZDCISA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960002037 methylprednisolone aceponate Drugs 0.000 description 1
- DALKLAYLIPSCQL-YPYQNWSCSA-N methylprednisolone aceponate Chemical compound C1([C@@H](C)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@](C(=O)COC(C)=O)(OC(=O)CC)[C@@]2(C)C[C@@H]1O DALKLAYLIPSCQL-YPYQNWSCSA-N 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 108091005601 modified peptides Proteins 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 229960002744 mometasone furoate Drugs 0.000 description 1
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 229960003816 muromonab-cd3 Drugs 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- 230000010016 myocardial function Effects 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- HSQAARMBHJCUOK-UHFFFAOYSA-N n-(1-adamantylmethyl)-2-chloro-5-[3-(3-hydroxypropylamino)propyl]benzamide Chemical compound OCCCNCCCC1=CC=C(Cl)C(C(=O)NCC23CC4CC(CC(C4)C2)C3)=C1 HSQAARMBHJCUOK-UHFFFAOYSA-N 0.000 description 1
- AVMFPLAFTONVSZ-UHFFFAOYSA-N n-(pyridin-2-ylmethyl)-1-[4-(1,4,7-triazacyclotetradec-4-ylmethyl)phenyl]methanamine Chemical compound C=1C=C(CN2CCNCCCCCCCNCC2)C=CC=1CNCC1=CC=CC=N1 AVMFPLAFTONVSZ-UHFFFAOYSA-N 0.000 description 1
- UYMDKKVILQGGBT-ZTOMLWHTSA-N n-[(2s)-5-(diaminomethylideneamino)-1-[[(1s)-1-naphthalen-1-ylethyl]amino]-1-oxopentan-2-yl]-4-[(pyridin-2-ylmethylamino)methyl]benzamide Chemical compound N([C@@H](CCCN=C(N)N)C(=O)N[C@@H](C)C=1C2=CC=CC=C2C=CC=1)C(=O)C(C=C1)=CC=C1CNCC1=CC=CC=N1 UYMDKKVILQGGBT-ZTOMLWHTSA-N 0.000 description 1
- VBFPXFNZWSRGTJ-UHFFFAOYSA-N n-[2,6-di(propan-2-yl)phenyl]hexadecanethioamide Chemical compound CCCCCCCCCCCCCCCC(=S)NC1=C(C(C)C)C=CC=C1C(C)C VBFPXFNZWSRGTJ-UHFFFAOYSA-N 0.000 description 1
- WDPFJWLDPVQCAJ-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-2-[2-[(4-fluorophenyl)methylsulfanyl]-4-oxo-6,7-dihydro-5h-cyclopenta[d]pyrimidin-1-yl]-n-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]acetamide Chemical compound C1=2CCCC=2C(=O)N=C(SCC=2C=CC(F)=CC=2)N1CC(=O)N(CCN(CC)CC)CC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=C1 WDPFJWLDPVQCAJ-UHFFFAOYSA-N 0.000 description 1
- QZECRCLSIGFCIO-RISCZKNCSA-N n-[2-[(2,3-difluorophenyl)methylsulfanyl]-6-[(2r,3s)-3,4-dihydroxybutan-2-yl]oxypyrimidin-4-yl]azetidine-1-sulfonamide Chemical compound N=1C(SCC=2C(=C(F)C=CC=2)F)=NC(O[C@H](C)[C@@H](O)CO)=CC=1NS(=O)(=O)N1CCC1 QZECRCLSIGFCIO-RISCZKNCSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229960005027 natalizumab Drugs 0.000 description 1
- 102000027424 natriuretic peptide receptors Human genes 0.000 description 1
- 108091008599 natriuretic peptide receptors Proteins 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- QQBDLJCYGRGAKP-FOCLMDBBSA-N olsalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=C(C(O)=CC=2)C(O)=O)=C1 QQBDLJCYGRGAKP-FOCLMDBBSA-N 0.000 description 1
- 229960004110 olsalazine Drugs 0.000 description 1
- 229950010444 onercept Drugs 0.000 description 1
- 201000005737 orchitis Diseases 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 201000004535 ovarian dysfunction Diseases 0.000 description 1
- 231100000539 ovarian failure Toxicity 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 229960002858 paramethasone Drugs 0.000 description 1
- 229960004662 parecoxib Drugs 0.000 description 1
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 description 1
- 208000024011 parotid gland neoplasm Diseases 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- 229940072223 pentasa Drugs 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 239000003358 phospholipase A2 inhibitor Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 229960005330 pimecrolimus Drugs 0.000 description 1
- KASDHRXLYQOAKZ-ZPSXYTITSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-ZPSXYTITSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- YIQPUIGJQJDJOS-UHFFFAOYSA-N plerixafor Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CN1CCCNCCNCCCNCC1 YIQPUIGJQJDJOS-UHFFFAOYSA-N 0.000 description 1
- 229960002169 plerixafor Drugs 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229960002847 prasterone Drugs 0.000 description 1
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 1
- 229960004197 prasugrel Drugs 0.000 description 1
- 229960002794 prednicarbate Drugs 0.000 description 1
- FNPXMHRZILFCKX-KAJVQRHHSA-N prednicarbate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CC)(OC(=O)OCC)[C@@]1(C)C[C@@H]2O FNPXMHRZILFCKX-KAJVQRHHSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 230000004088 pulmonary circulation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 1
- 229960000611 pyrimethamine Drugs 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-YZRHJBSPSA-N pyrrolidin-2-one Chemical group O=C1CC[14CH2]N1 HNJBEVLQSNELDL-YZRHJBSPSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 108010003189 recombinant human tumor necrosis factor-binding protein-1 Proteins 0.000 description 1
- 208000028165 rectosigmoid carcinoma Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- KQDRVXQXKZXMHP-LLVKDONJSA-N reparixin Chemical compound CC(C)CC1=CC=C([C@@H](C)C(=O)NS(C)(=O)=O)C=C1 KQDRVXQXKZXMHP-LLVKDONJSA-N 0.000 description 1
- 229950005650 reparixin Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000008458 response to injury Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 208000004124 rheumatic heart disease Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 229960004181 riluzole Drugs 0.000 description 1
- 229960001487 rimexolone Drugs 0.000 description 1
- QTTRZHGPGKRAFB-OOKHYKNYSA-N rimexolone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CC)(C)[C@@]1(C)C[C@@H]2O QTTRZHGPGKRAFB-OOKHYKNYSA-N 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229950002267 roxifiban Drugs 0.000 description 1
- 230000036185 rubor Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229960004540 secukinumab Drugs 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 206010040400 serum sickness Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229960003323 siltuximab Drugs 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000002966 stenotic effect Effects 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960001734 sulfobromophthalein Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 238000004416 surface enhanced Raman spectroscopy Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 201000010740 swine influenza Diseases 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940057780 taclonex Drugs 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960000565 tazarotene Drugs 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000002446 thrombocytic effect Effects 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 229940107955 thymoglobulin Drugs 0.000 description 1
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 1
- 229960002528 ticagrelor Drugs 0.000 description 1
- MIMJSJSRRDZIPW-UHFFFAOYSA-N tilmacoxib Chemical compound C=1C=C(S(N)(=O)=O)C(F)=CC=1C=1OC(C)=NC=1C1CCCCC1 MIMJSJSRRDZIPW-UHFFFAOYSA-N 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 description 1
- 229960003425 tirofiban Drugs 0.000 description 1
- 229960004631 tixocortol Drugs 0.000 description 1
- BISFDZNIUZIKJD-XDANTLIUSA-N tixocortol pivalate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CSC(=O)C(C)(C)C)(O)[C@@]1(C)C[C@@H]2O BISFDZNIUZIKJD-XDANTLIUSA-N 0.000 description 1
- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 1
- 229960000488 tizanidine Drugs 0.000 description 1
- 229960003989 tocilizumab Drugs 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- CMSGWTNRGKRWGS-NQIIRXRSSA-N torcetrapib Chemical compound COC(=O)N([C@H]1C[C@@H](CC)N(C2=CC=C(C=C21)C(F)(F)F)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CMSGWTNRGKRWGS-NQIIRXRSSA-N 0.000 description 1
- 229950004514 torcetrapib Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 206010044325 trachoma Diseases 0.000 description 1
- NGSWKAQJJWESNS-ZZXKWVIFSA-N trans-4-coumaric acid Chemical group OC(=O)\C=C\C1=CC=C(O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-N 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- 230000009959 type I hypersensitivity Effects 0.000 description 1
- 230000008026 type II hypersensitivity Effects 0.000 description 1
- 229960002249 ulobetasol Drugs 0.000 description 1
- BDSYKGHYMJNPAB-LICBFIPMSA-N ulobetasol propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]2(C)C[C@@H]1O BDSYKGHYMJNPAB-LICBFIPMSA-N 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229960003824 ustekinumab Drugs 0.000 description 1
- 108010054167 vMIP-II Proteins 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 108010045161 variabilin Proteins 0.000 description 1
- HPVSJNGZYYDDMU-FECKPXKMSA-N variabilin Chemical compound O\1C(=O)C(C)=C(O)C/1=C/C(C)CCC\C(C)=C\CC\C(C)=C\CCC=1C=COC=1 HPVSJNGZYYDDMU-FECKPXKMSA-N 0.000 description 1
- VVPGAJNPGZZNBM-UHFFFAOYSA-N variabilin Natural products C1=C(OC)C=C2OCC3(O)C4=CC=C(OC)C=C4OC3C2=C1 VVPGAJNPGZZNBM-UHFFFAOYSA-N 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
Disclosed herein, in some embodiments, are methods for treating an MIF-mediated disorder. In some embodiments, the method comprises administering an 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.
Description
METHODS OF TREATING INFLAMMATION
CROSS-REFERNCE
[0001] This application claims priority to US Provisional Application 61/245,214, filed September 23, 2009;
and to US Provisional Application 61/319,039, filed March 30, 2010; both of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
CROSS-REFERNCE
[0001] This application claims priority to US Provisional Application 61/245,214, filed September 23, 2009;
and to US Provisional Application 61/319,039, filed March 30, 2010; both of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 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. In general, MIF interacts with CXCR2 and CXCR4 receptors on leukocytes and monocytes to trigger and maintain leukocyte and monocyte migration.
SUMMARY OF THE INVENTION
SUMMARY OF THE INVENTION
[0003] There is a need for new methods of treating inflammatory diseases, disorders, conditions (e.g., atherosclerosis) and symptoms that do not interfere with (a) non-inflammatory processes or (b) desired-inflammatory processes. The inventors have discovered that undesired and harmful inflammation can be treated by inhibiting the ability of MIF to bind to CXCR2, CXCR4, CD44, and CD74. Further, the inventors have discovered that targeting precise regions of 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.
[0004] Disclosed herein, in certain embodiments, are 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. In some embodiments, the peptide that competitively binds with a binding partner of one of the following domains: N-terminal tail, the pseudo ELR-loop, the alpha-helix #1 motif/domain, the PPQ-loop, the PDQ-loop, the IGK-loop, the NRS-helix, the SPDR-loop, the C-terminal tail, or the combination thereof. In some embodiments, the peptide competitively binds with a binding partner of the N-loop domain.
In some embodiments, the peptide comprises an amino acid that competitively binds with a binding partner of MIF 1eu47.
In some embodiments, the peptide competitively binds with a binding partner of the pseudo-ELR
domain. In some embodiments, 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).
In some embodiments, the peptide comprises an amino acid that competitively binds with a binding partner of MIF 1eu47.
In some embodiments, the peptide competitively binds with a binding partner of the pseudo-ELR
domain. In some embodiments, 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).
[0005] Disclosed herein, in certain embodiments, are peptides that competitively bind with a binding partner of one motif/domain of CXCR2. In some embodiments, 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.
[0006] Disclosed herein, in certain embodiments, are peptides that competitively bind with a binding partner of one motif/domain of CXCR4. In some embodiments, the peptide competitively binds with a binding partner of. SEADDRYICDRFYPNDLWVVV; or DDRYICDRFYPNDLW.
[0007] Disclosed herein, in certain embodiments, are peptides that competitively bind with a binding partner of one motif/domain of CD44.
[0008] Disclosed herein, in certain embodiments, are peptides that competitively bind with a binding partner of one motif/domain of CD74.
[0009] Disclosed herein, in certain embodiments, is 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. In some embodiments, 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. In some embodiments, 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 CLMAFGGSSEP[Abu]ALC (SEQ ID NO. 429), wherein Abu is isosteric L-amino acid, alpha-aminobutyric acid; or cyclic CLMAFGGSSEPSALC (SEQ ID NO. 469). In some embodiments, the fusion peptide is given by Formula (IV):
Peptide 1 Linker Peptide 2 In some embodiments, the fusion peptide is given by Formula (V):
Peptide 1 Linker Peptide 2 Peptide 3 In some embodiments, 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.
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. In some embodiments, 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. In some embodiments, 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 CLMAFGGSSEP[Abu]ALC (SEQ ID NO. 429), wherein Abu is isosteric L-amino acid, alpha-aminobutyric acid; or cyclic CLMAFGGSSEPSALC (SEQ ID NO. 469). In some embodiments, the fusion peptide is given by Formula (IV):
Peptide 1 Linker Peptide 2 In some embodiments, the fusion peptide is given by Formula (V):
Peptide 1 Linker Peptide 2 Peptide 3 In some embodiments, 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.
[0010] Disclosed herein, in certain embodiments, is 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.
In some embodiments, the linker binds the peptide to an antigen binding site. In some embodiments, 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. In some embodiments, the antibody is an IgA, IgD, IgE, IgG, or IgM.
Disclosed herein, in certain embodiments, is the use of a composition of matter described herein for treating an inflammatory disease, disorder or condition. In some embodiments, 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; 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 muscle proliferation disorders;
Meningitis; Shingles;
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. In some embodiments, 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;
hematological tumors; a Lymphoma; or a combination thereof. In some embodiments, 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.
wherein the peptide and the antibody retain their activity in the peptibody.
In some embodiments, the linker binds the peptide to an antigen binding site. In some embodiments, 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. In some embodiments, the antibody is an IgA, IgD, IgE, IgG, or IgM.
Disclosed herein, in certain embodiments, is the use of a composition of matter described herein for treating an inflammatory disease, disorder or condition. In some embodiments, 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; 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 muscle proliferation disorders;
Meningitis; Shingles;
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. In some embodiments, 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;
hematological tumors; a Lymphoma; or a combination thereof. In some embodiments, 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.
[0011] Disclosed herein, in certain embodiments, is the use of a composition of matter described herein to treat, prevent or reduce angiogenesis.
[0012] Disclosed herein, in certain embodiments, is a pharmaceutical composition for treating an inflammatory disease, disorder, condition or symptom in an individual in need thereof, comprising a composition of matter described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The novel features of the invention are set forth with particularity in the appended claims. A
better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
[0014] 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.
[0015] 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.
[0016] Figure 3 shows the nucleic acid sequence of human MIF and the corresponding MIF
motif/domains.
motif/domains.
[0017] FIGURE 4 shows that the peptide of SEQ ID No. 18 blocks chemotaxis in human peripheral blood mononuclear cells (PBMC).
[0018] FIGURE 5 shows that the peptide of SEQ ID NO. 423 significantly antagonizes MIF-induced chemotaxis in PMBCs.
[0019] FIGURE 6 shows that the peptide of SEQ ID NO. 423 significantly antagonizes MIF-induced chemotaxis in PMBCs in a dose dependent manner.
[0020] FIGURE 7 shows that peptides disclosed herein block MIF-mediated monocyte arrest on human aortic endothelial cells (under flow). 4nM of MIF were used. 5uM of peptide were used. *p<
0.05; ** p< 0.01; *** = p< 0.005.
0.05; ** p< 0.01; *** = p< 0.005.
[0021] FIGURE 8 sgows that the peptide of SE ID NO. 18 blocks MIF-mediated monocyte arrest HuAoECs in a dose dependent manner. 4nM of MIF were used. *p< 0.05; ** p<
0.01; *** = p<
0.005.
0.01; *** = p<
0.005.
[0022] 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.
luM of MIF was incubated overnight. Streptavidin-POD (1:10000) was incubated for 2 hours at room temperature.
[0023] 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.
arrays. luM of MIF was incubated overnight. Streptavidin-POD (1:10000) was incubated for 2 hours at room temperature.
[0024] FIGURE 11 presents the results of probing the MIF-CXCR2 interface with Peptide SPOT
arrays using wildtype MIF (1 M Biotin-monoQ-MIF:Streptavidin-POD) and mutant MIF (1 M
biotin-R 11A-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.
arrays using wildtype MIF (1 M Biotin-monoQ-MIF:Streptavidin-POD) and mutant MIF (1 M
biotin-R 11A-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.
[0025] FIGURE 12 presents the results of probing the MIF-CXCR4 interface with Peptide SPOT
arrays using wildtype MIF (1 M Biotin- MIF: Streptavidin-POD). Streptavidin-POD (1:10000) was incubated for 2 hours at room temperature. Wildtype MIF was incubated overnight at 4 C.
arrays using wildtype MIF (1 M Biotin- MIF: Streptavidin-POD). Streptavidin-POD (1:10000) was incubated for 2 hours at room temperature. Wildtype MIF was incubated overnight at 4 C.
[0026] FIGURE 13 shows that SEQ ID NO. 18 inhibits leukocyte adhesion to carotid arteries of Apoe-deficient mice. Deficient and age matched controls on Western diet for 8 wks. n=5 for each group; quantification from 10 high power fields (HPF) throughout carotid artery. lx injection per day of SEQ ID NO 18 or scrambled SEQ ID NO 18 for 3 days prior to adhesion expt& IVM.
[0027] FIGURE 14 shows that SEQ ID NO 18 reduces TNFa and MCP-1 in mouse peritonitis model. Thioglycollate (TG): (3% IP). Vehicle, SEQ ID NO 18, SEQ ID NO 85 and Dex: 30 min prior to and 30 min post TG challenge. 2hr post TG, peritoneal lavage for cell counts and chemokines.
[0028] FIGURE 15 shows that SEQ ID NO 18 reduces MCP-1 and monocyte levels in mouse peritonitis model. Thioglycollate (TG): (3% IP). Vehicle, SEQ ID NO. 422, SEQ
ID NO. 421, SEQ
ID NO. 45l and Dex: 30 min prior to and 30 min post TG challenge. 2hr post TG, peritoneal lavage for cell counts and chemokines.
ID NO. 421, SEQ
ID NO. 45l and Dex: 30 min prior to and 30 min post TG challenge. 2hr post TG, peritoneal lavage for cell counts and chemokines.
[0029] FIGURE 16 presents a proposed mechanism of MIF signalling modulation.
[0030] 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. C, Application of the two-site binding model of chemokine/chemokine receptor binding to MIF. The proposed interaction interface between MIF and CXCR2 (site 1: interaction between the N-like-loop of MIF and the receptor N-terminus; site 2:
interaction between the pseudo-(E)LR-motif of MIF and the receptor exoloops EL2 and 3). D, Trimeric structure of MIF depicted in surface mode.
motif). For clarity reasons, only the monomeric structures of CXCL8 and MIF are depicted. B, Schematic showing the structure of MIF. C, Application of the two-site binding model of chemokine/chemokine receptor binding to MIF. The proposed interaction interface between MIF and CXCR2 (site 1: interaction between the N-like-loop of MIF and the receptor N-terminus; site 2:
interaction between the pseudo-(E)LR-motif of MIF and the receptor exoloops EL2 and 3). D, Trimeric structure of MIF depicted in surface mode.
[0031] 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 M biotin-MIF (A and B) or biotin-Rl2A/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.
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 M biotin-MIF (A and B) or biotin-Rl2A/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.
[0032] Figure 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 M human MIF and 100 M of the indicated N-like-loop peptides of MIF as competitor. Plots represent percent of specific 1125-CXCL8 binding. Tracer binding in the absence of MIF and peptide (buffer) was set at 100% and the competitive effect of MIF
in the absence of peptide at 0%. Data represent means SEM of 3 independent experiments, each performed in duplicate measurements (* = p<0.01).
on tracer binding.
HEK293 cells stably overexpressing CXCR2 were incubated with radioiodinated I125CXCL8 tracer together with 1 M human MIF and 100 M of the indicated N-like-loop peptides of MIF as competitor. Plots represent percent of specific 1125-CXCL8 binding. Tracer binding in the absence of MIF and peptide (buffer) was set at 100% and the competitive effect of MIF
in the absence of peptide at 0%. Data represent means SEM of 3 independent experiments, each performed in duplicate measurements (* = p<0.01).
[0033] FIGURE 20 is a model depicting the interactions at the MIF/CXCR2 interface according to the general two-site binding mechanism.
[0034] FIGURE 21 is a model depicting a peptibody.
DETAILED DESCRIPTION OF THE INVENTION
DETAILED DESCRIPTION OF THE INVENTION
[0035] Disclosed herein, in some embodiments, are peptides, small molecules, antibodies, and peptibodies (collectively, "compositions of matter") for treating inflammatory diseases, disorders, conditions and symptoms. Further disclosed herein are pharmaceutical compositions and methods of treating inflammatory diseases, disorders, conditions and symptoms. In some embodiments, the inflammatory disease, disorder, condition or symptom is characterized by undesired MIF signaling.
In some embodiments, the inflammatory disease, disorder, condition or symptom is characterized by MIF-mediated leukocyte recruitment.
In some embodiments, the inflammatory disease, disorder, condition or symptom is characterized by MIF-mediated leukocyte recruitment.
[0036] Disclosed herein, in certain embodiments, are 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. In some embodiments, the peptide that competitively binds with a binding partner of one of the following domains: N-terminal tail, the pseudo ELR-loop, the alpha-helix #1 motif/domain, the PPQ-loop, the PDQ-loop, the IGK-loop, the NRS-helix, the SPDR-loop, the C-terminal tail, or the combination thereof. In some embodiments, the peptide competitively binds with a binding partner of the N-loop domain.
In some embodiments, the peptide comprises an amino acid that competitively binds with a binding partner of MIF 1eu47.
In some embodiments, the peptide competitively binds with a binding partner of the pseudo-ELR
domain. In some embodiments, 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).
In some embodiments, the peptide comprises an amino acid that competitively binds with a binding partner of MIF 1eu47.
In some embodiments, the peptide competitively binds with a binding partner of the pseudo-ELR
domain. In some embodiments, 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).
[0037] Disclosed herein, in certain embodiments, are peptides that competitively bind with a binding partner of one motif/domain of CXCR2. In some embodiments, 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.
[0038] Disclosed herein, in certain embodiments, are peptides that competitively bind with a binding partner of one motif/domain of CXCR4. In some embodiments, the peptide competitively binds with a binding partner of. SEADDRYICDRFYPNDLWVVV; or DDRYICDRFYPNDLW.
[0039] Disclosed herein, in certain embodiments, are peptides that competitively bind with a binding partner of one motif/domain of CD44.
[0040] Disclosed herein, in certain embodiments, are peptides that competitively bind with a binding partner of one motif/domain of CD74.
[0041] Disclosed herein, in certain embodiments, is 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. In some embodiments, 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. In some embodiments, 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 CLMAFGGSSEP[Abu]ALC (SEQ ID NO. 429), wherein Abu is isosteric L-amino acid, alpha-aminobutyric acid; or cyclic CLMAFGGSSEPSALC (SEQ ID NO. 469). In some embodiments, the fusion peptide is given by Formula (IV):
Peptide 1 Linker Peptide 2 In some embodiments, the fusion peptide is given by Formula (V):
Peptide 1 Linker Peptide 2 Peptide 3 In some embodiments, 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.
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. In some embodiments, 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. In some embodiments, 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 CLMAFGGSSEP[Abu]ALC (SEQ ID NO. 429), wherein Abu is isosteric L-amino acid, alpha-aminobutyric acid; or cyclic CLMAFGGSSEPSALC (SEQ ID NO. 469). In some embodiments, the fusion peptide is given by Formula (IV):
Peptide 1 Linker Peptide 2 In some embodiments, the fusion peptide is given by Formula (V):
Peptide 1 Linker Peptide 2 Peptide 3 In some embodiments, 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.
[0042] Disclosed herein, in certain embodiments, is 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.
In some embodiments, the linker binds the peptide to an antigen binding site. In some embodiments, 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. In some embodiments, the antibody is an IgA, IgD, IgE, IgG, or IgM.
wherein the peptide and the antibody retain their activity in the peptibody.
In some embodiments, the linker binds the peptide to an antigen binding site. In some embodiments, 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. In some embodiments, the antibody is an IgA, IgD, IgE, IgG, or IgM.
[0043] Disclosed herein, in certain embodiments, is the use of a composition of matter described herein for treating an inflammatory disease, disorder or condition. In some embodiments, the inflammatory, disease, disorder, or condition is a cancer. In some embodiments, 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; 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 muscle proliferation disorders;
Meningitis; Shingles;
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.
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; 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 muscle proliferation disorders;
Meningitis; Shingles;
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.
[0044] Disclosed herein, in certain embodiments, is the use of a composition of matter described herein to treat, prevent or reduce angiogenesis.
[0045] Disclosed herein, in certain embodiments, is a pharmaceutical composition for treating an inflammatory disease, disorder, condition or symptom in an individual in need thereof, comprising a composition of matter described herein.
Definitions [0046] 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);
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.
horse, zebra, tapir, and rhinoceros); 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.
marsupial moles);
dasyuromorphia (e.g. marsupial carnivores); peramelemorphia (e.g. bandicoots and bilbies); or diprotodontia (e.g. wombats, koalas, possums, gliders, kangaroos, wallaroos, and wallabies). In some embodiments, 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: ayes). None of the terms require or are limited to situation characterized by the supervision (e.g. constant or intermittent) of a health care worker (e.g.
a doctor, a registered nurse, a nurse practitioner, a physician's assistant, an orderly, or a hospice worker).
Definitions [0046] 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);
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.
horse, zebra, tapir, and rhinoceros); 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.
marsupial moles);
dasyuromorphia (e.g. marsupial carnivores); peramelemorphia (e.g. bandicoots and bilbies); or diprotodontia (e.g. wombats, koalas, possums, gliders, kangaroos, wallaroos, and wallabies). In some embodiments, 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: ayes). None of the terms require or are limited to situation characterized by the supervision (e.g. constant or intermittent) of a health care worker (e.g.
a doctor, a registered nurse, a nurse practitioner, a physician's assistant, an orderly, or a hospice worker).
[0047] The phrase "specifically binds" when referring to the interaction between a binding molecule (i.e., the agent; e.g., a peptide or peptide mimetic) and a protein or polypeptide or epitope, typically refers to a binding molecule that recognizes and detestably specifically binds with high affinity to the target of interest. Preferably, under designated or physiological conditions, 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. In other words 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. For example, solid-phase ELISA immunoassays, BlAcore, 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.
[0048] "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.
[0049] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. 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.
[0050] The terms "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.
[0051] The term "disruption" means to interfere with the function of. For example, to disrupt a motif/domain means to interfere with the function of the motif/domain.
[0052] The term "antigen" refers to a substance that is capable of inducing the production of an antibody. In some embodiments an antigen is a substance that specifically binds to an antibody variable region.
[0053] The terms "antibody" and "antibodies" refer 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. In particular, antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen binding site.
Depending on the amino acid sequence of the constant motif/domain of their heavy chains, immunoglobulins can be assigned to different classes. The heavy-chain constant motif/domains (Fc) that correspond to the different classes of immunoglobulins are called a., 6, c, y, 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 4, IgA 1 and IgA 2) or subclass. The terms "antibody" and "immunoglobulin" are used interchangeably in the broadest sense. In some embodiments an antibody is part of a larger molecule, formed by covalent or non-covalent association of the antibody with one or more other proteins or peptides.
[00541 With respect to antibodies, the term "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. However, the 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.
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 (FRI, FR2, FR3 and FR4), largely adopting a (3-sheet configuration interspersed with three CDRs which form loops connecting and, in some cases, part of the (3-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).
[00551 The terms "hypervariable region" and "CDR" when used herein, refer 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 CDRI, CDR2, and CDR3 for each of the VH and VL chains. In the light chain variable motif/domain, the CDRs typically correspond to approximately residues 24-34 (CDRL1), 50-56 (CDRL2) and 89-97 (CDRL3), and in the heavy chain variable motif/domain the CDRs typically correspond to approximately residues 31-35 (CDRHI), 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 CDRLI
in the light chain) to reflect any insertions in the numberings between different antibodies.
Alternatively, in the light chain variable motif/domain, the CDRs typically correspond to approximately residues 26-32 (CDRL1), 50-52 (CDRL2) and 91-96 (CDRL3), and in the heavy chain variable motif/domain, the CDRs typically correspond to approximately residues 26-32 (CDRHI), 53-55 (CDRH2) and 96-101 (CDRH3) according to Chothia and Lesk, J. Mol. Biol., 196: 901-917 (1987)).
[00561 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.
[0057] As used herein, the term "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 (fM). As used herein, the term "avidity" refers to the resistance of a complex of two or more agents to dissociation after dilution.
[0058] The term "peptibody" 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. The term "peptibody" does not include Fc-fusion proteins (e.g., full length proteins fused to an Fc motif/domain).
[0059] The terms "isolated" and "purified" refer to a material that is substantially or essentially removed from or concentrated in its natural environment. For example, 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. In another example, 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%.
[0060] 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. By 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.
[0061] The terms "prevent," "preventing" or "prevention," and other grammatical equivalents as used herein, 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. For 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.
[0062] 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. In certain instances, 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. In specific instances, 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. In certain instances, 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.
[0063] The terms "administer," "administering," "administration," and the like, as used herein, refer 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.
[0064] The term "pharmaceutically acceptable" as used herein, 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.
1. Macrophage Migration Inhibitory Factor (MIF) [0065] Disclosed herein, in some embodiments, are peptides, small molecules, antibodies, and peptibodies (collectively, "compositions of matter") for treating inflammatory diseases, disorders, conditions and symptoms. Further disclosed herein are pharmaceutical compositions and methods of treating inflammatory diseases, disorders, conditions and symptoms.
[0066] 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 CD74.
[0067] In certain instances, MIF induces chemotaxis in nearby leukocytes (e.g.
lymphocytes, granulocytes, monocytes/macrophages, and TH- 17 cells) along a MIF gradient.
In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein prevents chemotaxis along a MIF gradient, or reduces chemotaxis along a MIF
gradient. In certain instances, MIF induces the chemotaxis of a leukocyte (e.g. lymphocytes, granulocytes, monocytes/macrophages, and TH- 17 cells) to the site of an infection, inflammation or tissue injury.
In some embodiments, 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. In certain instances, the chemotaxis of a leukocyte (e.g. lymphocytes, granulocytes, monocytes/macrophages, and TH- 17 cells) along a MIF gradient results in inflammation at the site of infection, inflammation, or tissue injury. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein treats inflammation at the site of infection, inflammation, or tissue injury. In certain instances, 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. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein prevents or decreases monocyte arrest at the site of injury or inflammation. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits treats a lymphocyte mediated disorder. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein treats a granulocyte mediated disorder. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein treats a macrophage mediated disorder. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein treats a Th- 17 mediated disorder. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein treats a pancreatic beta-cell mediated disorder.
[0068] In certain instances, MIF is inducible by glucocorticoids, a mechanism implicated in an acceleration of atherosclerosis associated with many diseases requiring glucocorticoid therapy.
Thus, in some embodiments, the compositions and methods described herein inhibit the induction of MIF expression by glucocorticoids.
[0069] Human MIF peptide is encoded by a nucleotide sequence located on chromosome 22 at the cytogenic band 22g11.23.
[0070] In certain instances, a mature MIF protein is a homotrimer comprising three polypeptides of about 114 amino acids; the first methionine having been removed during translation from each of the MIF peptide monomers.
[0071] In certain instances, a human MIF peptide is encoded by the nucleic acid sequence SEQ ID
No. 422:
GGTACCGGATCCCCCATGTTCATCGTGAACACCAACGTGCCCAGAGCCAGCGTGCCCGAC
GCTTCCTGAGCGAGCTGACACAGCAGCTGGCCCAGGCCACCGGCAAGCCCCCTCAGTAT
ATCGCCGTGCACGTGGTGCCCGACCAGCTGATGGCCTTCGGCGGCAGCAGCGAGCCTTGC
GCCCTGTGTAGCCTGCACAGCATCGGCAAGATCGGCGGAGCCCAGAACAGAAGCTACAGC
AAGCTGCTGTGCGGCCTGCTGGCCGAGAGACTGAGAATCAGCCCCGACAGAGTGTACATC
AACTACTACGACATGAACGCCGCCAACGTGGGCTGGAACAACAGCACCTTCGCCCTCGAG
CTC
[0072] In certain instances, a human MIF peptide is encoded by SEQ ID No. 1:
MPMFIVNTNVPRASVPDGFLSELTQQLAQATGKPPQYIAVHVVPDQLMA
FGGSSEPCALCSLHSIGKIGGAQNRSYSKLLCGLLAERLRISPDRVYINYY
DMNAANVGWNGSTFAL (SEQ ID 1).
[0073] In certain instances, a porcine MIF peptide is encoded by SEQ ID No. 2:
MPMFVVNTNVPRASVPDGFLSELTQQLVQAMGKPAQYIAVHVVPDQLM
AFGGSSEPCALCSLHSIGKIGGAQNRSYSKLLCGLLAERLRISPDRIYINYY
DMNAANVGWNGSTFAL (SEQ ID No. 2).
[0074] In certain instances, a bovine MIF peptide is encoded by SEQ ID No. 3:
MPMFV VNTNVPRASV PDGLLSELTQQLAQATGKPAQYIAVHV VPDQLM
TFGGSSEPCALCSLHSIGKIGGAQNRSYSKLLCGLLTERLRISPDRIYINFC
DMNAANVGWNGSTFAL (SEQ ID No. 3).
[0075] In certain instances, a murine MIF peptide is encoded by SEQ ID No. 4:
MPMFIVNTNVPRAS VPEGFLSELTQQLAQATGKPPAYIAVHV VPDQLMT
FS GTNDPCALC SLHSIGKIGGAQNRNYSKLLCGLLSDRLHISPDRVYINYY
DMNAANVGWGNSTFAL (SEQ ID No. 4).
[0076] In certain instances, a rat MIF peptide is encoded by SEQ ID No. 5:
MPMFIVNTNVPRAS VPEGFLSELTQQLAQATGKPPAYIAVHV VPDQLMT
FSGTSDPCALCSLHSIGKIGGAQNRNYSKLLCGLLSDRLHISPDRVYINYY
DMNAANVGWGNSTFAL (SEQ ID No. 5).
[0077] In some embodiments, 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 (Arg12 and Asp45 &
see Fig. 11). 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 11 and Asp 44). In some embodiments, 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.
[0078] A MIF peptide comprises a 10- to 20-residue N-terminal Loop motif/domain (N-loop). In certain instances, a MIF N-loop mediates binding to a CXCR2 and/or CXCR4 receptor. In certain instances, 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. 11), 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. In certain instances, 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. In certain instances, 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. In certain instances, 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. In some embodiments, 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.
[0079] A MIF polypeptide comprises the following motifs/domains: an N-terminal/pseudo-ELR
motif/domain (MIFi_17), an alpha-helix #1 motif/domain (i.e., MIF18_31), an MIF N-loop motif/domain (i.e., MIF32_60), a loop-barrel-loop motif/domain (i.e., MIF64_93), and a C-terminal motif/domain (i.e., MIF90_114). Alternatively, a MIF polypeptide comprises the following motifs/domains: an N-terminal tail (i.e., MIF1_7), a pseudo ELR-loop (i.e., MIF7_17), an alpha-helix #1 motif/domain (i.e., MIF18_31), a PPQ-loop (i.e., MIF32-38), a PDQ-loop (i.e., MIF43-56), an IGK-loop (i.e., MIF64_71), an NRS-helix (i.e., MIF72_89), a SPDR-loop (i.e., MIF90_94), and a C-terminal tail (i.e., MlF1o1_114). In some embodiments, a peptide disclosed herein competitively binds with a binding partner of one of the following domains: N-terminal/pseudo-ELR
motif/domain (MIF1_17), the alpha-helix #1 motif/domain (i.e., M1F18-31), the MIF N-loop motif/domain (i.e., MIF32-60), the loop-barrel-loop motif/domain (i.e., MIF64_93), the C-terminal motif/domain (i.e., MIF9o_114), or a combination of any of the aforementioned domains. In some embodiments, a peptide disclosed herein competitively binds with a binding partner of one of the following domains: N-terminal tail (i.e., MIF1_7), the pseudo ELR-loop (i.e., MIF7_17), the alpha-helix #1 motif/domain (i.e., MIF18_31), the PPQ-loop (i.e., MIF32-38), the PDQ-loop (i.e., MIF43-56), the IGK-loop (i.e., MIF64.71), the NRS-helix (i.e., MIF72_89), the SPDR-loop (i.e., MIF90_94), the C-terminal tail (i.e., MIF101-114), or a combination of any of the aforementioned domains. In some embodiments, a peptide disclosed herein competitively binds with a binding partner of MIF47 (leucine).
[0080] In some embodiments, 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. In some embodiments, 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.
II. Active Agents [0081] Disclosed herein, in some embodiments, are peptides, small molecules, antibodies, and peptibodies (collectively, "compositions of matter") for treating inflammatory diseases, disorders, conditions and symptoms. Further disclosed herein are pharmaceutical compositions and methods of treating inflammatory diseases, disorders, conditions and symptoms.
[0082] Additionally disclosed herein, in some embodiments, are compositions of matter, methods, and pharmaceutical compositions that inhibit the ability of MIF to bind to CXCR2, CXCR4, CD44, CD74, or a combination thereof. Further disclosed herein, are 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.
In certain instances, 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, GROG/CXCL2, GROa., GRO-y, ENA78, NAP2; and CXCR4 interactions with Stromal Cell-Derived Factor-la (SDF-la)/CXCL12, and GP120).
[0083] 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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
Disruption of MIF Motifs/Domains [0084] In some embodiments, a composition of matter inhibits the ability of MIF to interact with CXCR2, CXCR4, CD74, CD44 or a combination thereof. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 (MIF1_17), an alpha-helix #1 motif/domain (i.e., MIF18_31), an MIF N-loop motif/domain (i.e., MIF32_60), a loop-barrel-loop motif/domain (i.e., MIF64_93), and a C-terminal motif/domain (i.e., MIF90_ii4). In some embodiments, 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., MIF1_7), a pseudo ELR-loop (i.e., MIF7_17), an alpha-helix #1 motif/domain (i.e., MIF18_31), a PPQ-loop (i.e., MIF32-38), a PDQ-loop (i.e., MIF43-56), an IGK-loop (i.e., MIF64_71), an NRS-helix (i.e., MIF72_89), a SPDR-loop (i.e., MIF90_94), and a C-terminal tail (i.e., MlFioi_114). In some embodiments, the ability of MIF to interact with CXCR2, CXCR4, CD74, CD44 or a combination thereof is inhibited by occupying, masking, or otherwise disrupting MIF47 (leucine).
[0085] In some embodiments, 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. In certain instances, 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).
[0086] In certain instances, the pseudo-ELR motif/domain of MIF mediates ligand (e.g., CD44, CD74, CXCR2, CXCR4) binding to MIF. In some embodiments, 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. In some embodiments, the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of theN-terminal tail (i.e., MIF1_7) and/or all or a portion of thepseudo ELR-loop (i.e., MIF7_ 17) inhibits the ability of MIF to bind to CXCR2, CXCR4, CD74, CD44 or a combination thereof.
[0087] In certain instances, the N-loop motif/domain of MIF mediates ligand (e.g., CD44, CD74, CXCR2, CXCR4) binding to MIF. In some embodiments, 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. In some embodiments, the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of thePPQ-loop (i.e., MIF32_38) and/or all or a portion of thePDQ-loop (i.e., MIF43.56) inhibits the ability of MIF
to to bind to CXCR2, CXCR4, CD74, CD44 or a combination thereof. In some embodiments, 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. In some embodiments, the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of thePPQ-loop (i.e., MIF32_38) and/or all or a portion of thePDQ-loop (i.e., MIF43-56) invokes a conformational change in MIF that prevents receptor or substrate interactions.
[0088] In certain instances, amino acids 65-94 of MIF (e.g., IGKIGGAQNRSYSKLLCGLLAERLRISPDR (SEQ ID No. 8); numbering includes the first methionine) mediate CXCR2 binding to MIF. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
[0090] In some embodiments, 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. In some embodiments, the peptide specifically binds to all or a portion of the pseudo ELR motif/domain of MIF. In some embodiments, the peptide specifically binds to all or a portion of the N-loop motif/domain of MIF. In some embodiments, the peptide specifically binds to all or a portion of both the pseudo-ELR and N-loop motifs.
[0091] In some embodiments, 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. 11) 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:
VNTNVPPRASVPDGFLSELTQQLAQATGKPPQYIAVHVVPDQLMAFGGSSEPCALCSL
(SEQ ID No. 12) 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:
PDQLMAFGGSSEPCALCSLHSI (SEQ ID No. 13) and the corresponding feature/domain of at least one of a MIF monomer or MIF trimer; or combinations thereof.
[0092] In some embodiments, 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. In some embodiments, the antibody specifically binds to all or a portion of the pseudo ELR
motif/domain of MIF. In some embodiments, the antibody specifically binds to all or a portion of the N-loop motif/domain of MIF. In some embodiments, the antibody specifically binds to all or a portion of both the pseudo-ELR and N-loop motifs.
[0093] In some embodiments, 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. In some embodiments, the peptibody specifically binds to all or a portion of the pseudo ELR
motif/domain of MIF. In some embodiments, the peptibody specifically binds to all or a portion of the N-loop motif/domain of MIF. In some embodiments, the peptibody specifically binds to all or a portion of both the pseudo-ELR and N-loop motifs.
[0094] In some embodiments, 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, CD74 and/or CD44 binds. In some embodiments, the small molecule specifically binds to all or a portion of the pseudo ELR motif/domain of MIF. In some embodiments, the small molecule specifically binds to all or a portion of the N-loop motif/domain of MIF. In some embodiments, the small molecule specifically binds to all or a portion of both the pseudo-ELR and N-loop motifs.
Disruption of CXCR2 and CXCR4 Motifs/Domains [0095] In some embodiments, a composition of matter disrupts all or a portion of a motif/domain on CXCR2 to which CXCR4, MIF, CD44 and/or CD74 bind. In some embodiments, 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 CXCR2 to which CXCR4, MIF, CD44 and/or CD74 bind.
[0096] In some embodiments, a composition of matter disrupts all or a portion of a motif/domain on CXCR4 to which CXCR2, MIF, CD44 and/or CD74 bind. In some embodiments, 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 CXCR4 to which CXCR2, MIF, CD44 and/or CD74 bind.
[0097] In some embodiments, 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.
[0098] In some embodiments, the agent that inhibits the binding of CXCR4, MIF, CD74 and/or CD44 to CXCR2 is an antibody. In some embodiments, the agent that inhibits the binding of CXCR2, MIF, CD74 and/or CD44 to CXCR4 is an antibody.
[0099] In some embodiments, 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.
[00101] In some embodiments, 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.
[00102] In some embodiments, the agent that inhibits the binding of MIF, CD74 and/or CD44 to CXCR2 is CXCL8(3_74)K11R/G31P; IL-8(4_72); IL-8 (6-72); 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_73); GRO-alpha(5_73); GRO-alpha(6_73); recombinant GRO (rGRO); (ELR)PF4 (PF4 with an ELR seq. at the N-terminus); recombinant PF4 (rPF4); Antileukinate; Sch527123 (-hydroxy-N,N-dimethyl-3-{2-[[(R)-1 -(5-methyl-furan-2-yl)-propyl]amino] -3,4-dioxo-cyclobut-l-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- [(1R)-2-amino-l-methyl-2-oxoethyl]phenyl trifluoromethanesulphonate);
Reparixin; or combinations thereof.
[00103] In some embodiments, 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 (AMD3 100); AMD3465(AnorMED); AMD8664 (1-pyridin-2-yl-N-[4-(1,4,7-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. Limited); KRH-3140 (Kureha Chemical Industry Co.
Limited); T134 (L-citrullinel6-TW70 substituted for the C-terminal amide by a carboxylic acid);
T22 ([Tyr5"2, Lys7]-polyphemusin II); TW70 (des-[Cys8,13, Tyr9,12]-[D-Lys10, Prol l]-T22); T140 (H-Arg-Arg-Nal-Cys-Tyr- Arg-Lys-DLys-Pro-Tyr-Arg-Cit-Cys-Arg-OH); TC14012 (R-R-Nal-C-Y-(L)Cit-K-(D)Cit-P-Y-R-(L)citrulline-C-R-NH2, where Nal=L-3-(2-naphthylalanine), Cit=citruline and the peptide is cyclized with the cysteines); TN14003; RCP168 (vMIP-II (11_71) with D-amino acids added to the N
terminus); POL3026 (Arg(*)-Arg-Nal(2)-Cys(1x)-Tyr-Gln-Lys-(d-Pro)-Pro-Tyr-Arg-Cit-Cys(lx)-Arg-Gly-(d-Pro)(*)); POL2438; compound 3 (N-(1-methyl-l-phenylethyl)-N-[((3S)-1-{2-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]ethyl}pyrrolidin-3-yl)methyl]amine);
isothioureas la-lu (for information regarding isothioureas la-lu see Gebhard Thoma, et al., Orally Bioavailable Isothioureas Block Function of the Chemokine Receptor CXCR4 In Vitro and In Vivo, J. Med.
Chem., Article ASAP (2008), which is herein incorporated by reference for such disclosures); or combinations thereof.
[00104] In some embodiments, 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.
Disruption of CD74 Motifs/Domains [00105] In some embodiments, a composition of matter disrupts all or a portion of a motif/domain on CD74 to which MIF, CD44, CXCR2, and/or CXCR4 bind. In some embodiments, 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.
[00106] In some embodiments, the agent that inhibits the binding of MIF, CD44, CXCR2, CXCR4, or a combination thereof to CD74 is a peptide.
[00107] In some embodiments, 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).
[00108] In some embodiments, the agent that inhibits the binding of MIF, CD44, CXCR2, CXCR4, or a combination thereof to CD74 is a peptibody.
[00109] In some embodiments, the agent that inhibits the binding of MIF, CD44, CXCR2, CXCR4, or a combination thereof to CD74 is a small molecule.
[00110] In certain instances, 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-la (SDF-la)/CXCL12).
Disruption of CD44 Motifs/Domains [00111] In some embodiments, a composition of matter disrupts all or a portion of a motif/domain on CD44 to which MIF, CD74, CXCR2, and/or CXCR4 bind. In some embodiments, 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.
[00112] In some embodiments, the agent that inhibits the binding of MIF, CD74, CXCR2, CXCR4, or a combination thereof to CD44 is a peptide.
[00113] In some embodiments, the agent that inhibits the binding of MIF, CD74, CXCR2, CXCR4, or a combination thereof to CD44 is an antibody.
[00114] In some embodiments, the agent that inhibits the binding of MIF, CD74, CXCR2, CXCR4, or a combination thereof to CD44 is a peptibody.
[00115] In some embodiments, the agent that inhibits the binding of MIF, CD74, CXCR2, CXCR4, or a combination thereof to CD44 is a small molecule.
MIF Mimics [00116] In some embodiments, a composition of matter disrupts the ability of MIF to bind to CXCR2, CXCR4, CD74, CD 44 or a combination thereof. In some embodiments, 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). In some embodiments, 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. In some embodiments, 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).
In some embodiments, the Peptide binds to CXCR2, CXCR4, CD74, CD44 or a combination thereof and thus prevents CXCR2, CXCR4, CD44 or CD74 from binding to MIF.
[00117] In some embodiments, the Peptide adopts structural or functional features similar to the N-Loop motif/domain of MIF. In some embodiments, the peptide comprises the sequence of Formula (I):
XI-X2-Q/A-X3-X4-X5-X6-G/S-X7-X8-X9-Xl0-P-X11 wherein:
X1 is selected from the group consisting of threonine, glycine, proline and alanine;
X2 is selected from the group consisting of glycine, asparagine, aspartic acid, and serine;
X3 is selected from the group consisting of methionine, isoleucine, leucine, alanine, proline, lysine, glutamine, arginine and lysine;
X4 is selected from the group consisting of methionine, isoleucine and leucine;
X5 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;
X7 is selected from the group consisting of aspartic acid, glutamic acid, threonine, glycine and alanine;
X8 is selected from the group consisting of serine, threonine, lysine and arginine;
X9 is selected from the group consisting of serine, asparagine, glycine, threonine, aspartic acid, glutamic acid, glutamine and histidine;
X10 is selected from the group consisting of aspartic acid, glutamic acid, alanine and asparagine; and X11 is selected from the group consisting of cysteine, alanine, serine, threonine and valine.
[00118] In some embodiments, X1 is proline. In some embodiments, X2 is aspartic acid. In some embodiments, X3 is leucine. In some embodiments, X4 is methionine. In some embodiments, X5 is alanine. In some embodiments, X6 is phenylalanine. In some embodiments, X7 is glycine. In some embodiments, X8 is serine. In some embodiments, X9 is serine. In some embodiments, X10 is glutamic acid. In some embodiments, X11 is serine cysteine.
[00119] In some embodiments, the Peptide comprises 3 or more consecutive amino acids of human MIF44_57 (numbering includes the first methionine). In some embodiments, the Peptide comprises 3 or more consecutive amino acids of murine MIF44_57. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of porcine MIF44_57. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of bovine MIF44_57. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of rat MIF44_57.
[00120] In some embodiments, 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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
LMAFGGSSEPCALC (SEQ SEPCAL (SEQ ID No. 62) cyclo(GSSEPCALC) (SEQ ID
ID No. 14) No. 110) LMAFGGSSEPCAL (SEQ EPCALC (SEQ ID No. 63) cyclo(GSSEPCAL) (SEQ ID
ID No. 15) No. 111) LMAFGGSSEPCA (SEQ ID QLMAFGGSSEPCALC (SEQ cyclo(GSSEPCA) (SEQ ID No.
No. 16) ID No. 64) 112) LMAFGGSSEPC (SEQ ID QLMAFGGSSEPCAL (SEQ ID cyclo(GSSEPC) (SEQ ID No.
No. 17) No. 65) 113) LMAFGGSSEP (SEQ ID No. QLMAFGGSSEPCA (SEQ ID cyclo(SSEPCALC) (SEQ ID
18) No. 66) No. 114) LMAFGGSSE (SEQ ID No. QLMAFGGSSEPC (SEQ ID cyclo(SSEPCAL) (SEQ ID No.
19) No. 67) 115) LMAFGGSS (SEQ ID No. QLMAFGGSSEP (SEQ ID No. cyclo(SSEPCA) (SEQ ID No.
20) 68) 116) LMAFGGS (SEQ ID No. 21) QLMAFGGSSE (SEQ ID No. cyclo(SEPCALC) (SEQ ID No.
69) 117) LMAFGG (SEQ ID No. 22) QLMAFGGSS (SEQ ID No. cyclo(SEPCAL) (SEQ ID No.
70) 118) MAFGGSSEPCALC (SEQ QLMAFGGS (SEQ ID No. 71) cyclo(EPCALC) (SEQ ID No.
ID No. 23) 119) MAFGGSSEPCAL (SEQ ID QLMAFGG (SEQ ID No. 72) cyclo(QLMAFGGSSEPCALC) No. 24) (SEQ ID No. 120) MAFGGSSEPCA (SEQ ID QLMAFG (SEQ ID No. 73) cyclo(QLMAFGGSSEPCAL) No. 25) (SEQ ID No. 121) MAFGGSSEPC (SEQ ID No. CSSEPCALC (SEQ ID No. 74) cyclo(QLMAFGGSSEPCA) 26) (SEQ ID No. 122) MAFGGSSEP (SEQ ID No. CFGGSSEPCALC (SEQ ID No. cyclo(QLMAFGGSSEPC) 27) 75) (SEQ ID No. 123) MAFGGSSE (SEQ ID No. CLMAFGGSSEPCALC (SEQ cyclo(QLMAFGGSSEP) (SEQ
28) ID No. 76) ID No. 124) MAFGGSS (SEQ ID No. 29) CAFGGSSC (SEQ ID No. 77) cyclo(QLMAFGGSSE) (SEQ
ID No. 125) MAFGGS (SEQ ID No. 30) CLMAFGGSSEPCC (SEQ ID cyclo(QLMAFGGSS) (SEQ ID
No. 78) No. 126) 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. 131) AFGGSSE (SEQ ID No. 36) CFGGSSEPC (SEQ ID No. 84) cyclo(AFGGSSEPCA) (SEQ
ID No. 132) AFGGSS (SEQ ID No. 37) IAVHVVPDQLMAFGGSSEPC cyclo(AFGGSSEPC) (SEQ ID
(SEQ ID No. 85) No. 133) FGGSSEPCALC (SEQ ID CLHSIGKIGGAQNRSYSKLL 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. CSLHSIGKIGGAQNR (SEQ cyclo(AFGGSS) (SEQ ID No.
40) ID No. 88) 136) FGGSSEPC (SEQ ID No. 41) IGKIGGAQNRSYSKL (SEQ cyclo(FGGSSEPCALC) (SEQ
ID No. 89) ID No. 137) FGGSSEP (SEQ ID No. 42) GAQNRSYSKLLCGLLA cyclo(FGGSSEPCAL) (SEQ
(SEQ ID No. 90) ID No. 138) FGGSSE (SEQ ID No. 43) CGLLAERLRISPDRV (SEQ cyclo(FGGSSEPCA) (SEQ ID
ID No. 91) No. 139) 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.
(SEQ ID No. 94) 142) GGSSEPC (SEQ ID No. 47) cyclo(LMAFGGSSEPCA) cyclo(GGSSEPCALC) (SEQ
(SEQ ID No. 95) ID No. 143) GGSSEP (SEQ ID No. 48) cyclo(LMAFGGSSEPC) (SEQ cyclo(GGSSEPCAL) (SEQ ID
ID No. 96) No. 144) 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.
No. 98) 146) GSSEPCA (SEQ ID No. 51) cyclo(LMAFGGSS) (SEQ ID cyclo(GGSSEP) (SEQ ID No.
No. 99) 147) GSSEPC (SEQ ID No. 52) cyclo(LMAFGGS) (SEQ ID No. cyclo(CSSEPCALC) (SEQ ID
100) No. 148) SSEPCALC (SEQ ID No. 53) cyclo(LMAFGG) (SEQ ID No. cyclo(CFGGSSEPCALC) 101) (SEQ ID No. 149) GSSEPCALC (SEQ ID No. cyclo(MAFGGSSEPCALC) cyclo(CFGGSSEPCC) (SEQ
Depending on the amino acid sequence of the constant motif/domain of their heavy chains, immunoglobulins can be assigned to different classes. The heavy-chain constant motif/domains (Fc) that correspond to the different classes of immunoglobulins are called a., 6, c, y, 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 4, IgA 1 and IgA 2) or subclass. The terms "antibody" and "immunoglobulin" are used interchangeably in the broadest sense. In some embodiments an antibody is part of a larger molecule, formed by covalent or non-covalent association of the antibody with one or more other proteins or peptides.
[00541 With respect to antibodies, the term "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. However, the 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.
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 (FRI, FR2, FR3 and FR4), largely adopting a (3-sheet configuration interspersed with three CDRs which form loops connecting and, in some cases, part of the (3-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).
[00551 The terms "hypervariable region" and "CDR" when used herein, refer 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 CDRI, CDR2, and CDR3 for each of the VH and VL chains. In the light chain variable motif/domain, the CDRs typically correspond to approximately residues 24-34 (CDRL1), 50-56 (CDRL2) and 89-97 (CDRL3), and in the heavy chain variable motif/domain the CDRs typically correspond to approximately residues 31-35 (CDRHI), 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 CDRLI
in the light chain) to reflect any insertions in the numberings between different antibodies.
Alternatively, in the light chain variable motif/domain, the CDRs typically correspond to approximately residues 26-32 (CDRL1), 50-52 (CDRL2) and 91-96 (CDRL3), and in the heavy chain variable motif/domain, the CDRs typically correspond to approximately residues 26-32 (CDRHI), 53-55 (CDRH2) and 96-101 (CDRH3) according to Chothia and Lesk, J. Mol. Biol., 196: 901-917 (1987)).
[00561 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.
[0057] As used herein, the term "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 (fM). As used herein, the term "avidity" refers to the resistance of a complex of two or more agents to dissociation after dilution.
[0058] The term "peptibody" 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. The term "peptibody" does not include Fc-fusion proteins (e.g., full length proteins fused to an Fc motif/domain).
[0059] The terms "isolated" and "purified" refer to a material that is substantially or essentially removed from or concentrated in its natural environment. For example, 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. In another example, 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%.
[0060] 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. By 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.
[0061] The terms "prevent," "preventing" or "prevention," and other grammatical equivalents as used herein, 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. For 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.
[0062] 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. In certain instances, 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. In specific instances, 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. In certain instances, 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.
[0063] The terms "administer," "administering," "administration," and the like, as used herein, refer 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.
[0064] The term "pharmaceutically acceptable" as used herein, 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.
1. Macrophage Migration Inhibitory Factor (MIF) [0065] Disclosed herein, in some embodiments, are peptides, small molecules, antibodies, and peptibodies (collectively, "compositions of matter") for treating inflammatory diseases, disorders, conditions and symptoms. Further disclosed herein are pharmaceutical compositions and methods of treating inflammatory diseases, disorders, conditions and symptoms.
[0066] 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 CD74.
[0067] In certain instances, MIF induces chemotaxis in nearby leukocytes (e.g.
lymphocytes, granulocytes, monocytes/macrophages, and TH- 17 cells) along a MIF gradient.
In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein prevents chemotaxis along a MIF gradient, or reduces chemotaxis along a MIF
gradient. In certain instances, MIF induces the chemotaxis of a leukocyte (e.g. lymphocytes, granulocytes, monocytes/macrophages, and TH- 17 cells) to the site of an infection, inflammation or tissue injury.
In some embodiments, 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. In certain instances, the chemotaxis of a leukocyte (e.g. lymphocytes, granulocytes, monocytes/macrophages, and TH- 17 cells) along a MIF gradient results in inflammation at the site of infection, inflammation, or tissue injury. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein treats inflammation at the site of infection, inflammation, or tissue injury. In certain instances, 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. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein prevents or decreases monocyte arrest at the site of injury or inflammation. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits treats a lymphocyte mediated disorder. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein treats a granulocyte mediated disorder. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein treats a macrophage mediated disorder. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein treats a Th- 17 mediated disorder. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein treats a pancreatic beta-cell mediated disorder.
[0068] In certain instances, MIF is inducible by glucocorticoids, a mechanism implicated in an acceleration of atherosclerosis associated with many diseases requiring glucocorticoid therapy.
Thus, in some embodiments, the compositions and methods described herein inhibit the induction of MIF expression by glucocorticoids.
[0069] Human MIF peptide is encoded by a nucleotide sequence located on chromosome 22 at the cytogenic band 22g11.23.
[0070] In certain instances, a mature MIF protein is a homotrimer comprising three polypeptides of about 114 amino acids; the first methionine having been removed during translation from each of the MIF peptide monomers.
[0071] In certain instances, a human MIF peptide is encoded by the nucleic acid sequence SEQ ID
No. 422:
GGTACCGGATCCCCCATGTTCATCGTGAACACCAACGTGCCCAGAGCCAGCGTGCCCGAC
GCTTCCTGAGCGAGCTGACACAGCAGCTGGCCCAGGCCACCGGCAAGCCCCCTCAGTAT
ATCGCCGTGCACGTGGTGCCCGACCAGCTGATGGCCTTCGGCGGCAGCAGCGAGCCTTGC
GCCCTGTGTAGCCTGCACAGCATCGGCAAGATCGGCGGAGCCCAGAACAGAAGCTACAGC
AAGCTGCTGTGCGGCCTGCTGGCCGAGAGACTGAGAATCAGCCCCGACAGAGTGTACATC
AACTACTACGACATGAACGCCGCCAACGTGGGCTGGAACAACAGCACCTTCGCCCTCGAG
CTC
[0072] In certain instances, a human MIF peptide is encoded by SEQ ID No. 1:
MPMFIVNTNVPRASVPDGFLSELTQQLAQATGKPPQYIAVHVVPDQLMA
FGGSSEPCALCSLHSIGKIGGAQNRSYSKLLCGLLAERLRISPDRVYINYY
DMNAANVGWNGSTFAL (SEQ ID 1).
[0073] In certain instances, a porcine MIF peptide is encoded by SEQ ID No. 2:
MPMFVVNTNVPRASVPDGFLSELTQQLVQAMGKPAQYIAVHVVPDQLM
AFGGSSEPCALCSLHSIGKIGGAQNRSYSKLLCGLLAERLRISPDRIYINYY
DMNAANVGWNGSTFAL (SEQ ID No. 2).
[0074] In certain instances, a bovine MIF peptide is encoded by SEQ ID No. 3:
MPMFV VNTNVPRASV PDGLLSELTQQLAQATGKPAQYIAVHV VPDQLM
TFGGSSEPCALCSLHSIGKIGGAQNRSYSKLLCGLLTERLRISPDRIYINFC
DMNAANVGWNGSTFAL (SEQ ID No. 3).
[0075] In certain instances, a murine MIF peptide is encoded by SEQ ID No. 4:
MPMFIVNTNVPRAS VPEGFLSELTQQLAQATGKPPAYIAVHV VPDQLMT
FS GTNDPCALC SLHSIGKIGGAQNRNYSKLLCGLLSDRLHISPDRVYINYY
DMNAANVGWGNSTFAL (SEQ ID No. 4).
[0076] In certain instances, a rat MIF peptide is encoded by SEQ ID No. 5:
MPMFIVNTNVPRAS VPEGFLSELTQQLAQATGKPPAYIAVHV VPDQLMT
FSGTSDPCALCSLHSIGKIGGAQNRNYSKLLCGLLSDRLHISPDRVYINYY
DMNAANVGWGNSTFAL (SEQ ID No. 5).
[0077] In some embodiments, 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 (Arg12 and Asp45 &
see Fig. 11). 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 11 and Asp 44). In some embodiments, 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.
[0078] A MIF peptide comprises a 10- to 20-residue N-terminal Loop motif/domain (N-loop). In certain instances, a MIF N-loop mediates binding to a CXCR2 and/or CXCR4 receptor. In certain instances, 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. 11), 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. In certain instances, 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. In certain instances, 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. In certain instances, 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. In some embodiments, 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.
[0079] A MIF polypeptide comprises the following motifs/domains: an N-terminal/pseudo-ELR
motif/domain (MIFi_17), an alpha-helix #1 motif/domain (i.e., MIF18_31), an MIF N-loop motif/domain (i.e., MIF32_60), a loop-barrel-loop motif/domain (i.e., MIF64_93), and a C-terminal motif/domain (i.e., MIF90_114). Alternatively, a MIF polypeptide comprises the following motifs/domains: an N-terminal tail (i.e., MIF1_7), a pseudo ELR-loop (i.e., MIF7_17), an alpha-helix #1 motif/domain (i.e., MIF18_31), a PPQ-loop (i.e., MIF32-38), a PDQ-loop (i.e., MIF43-56), an IGK-loop (i.e., MIF64_71), an NRS-helix (i.e., MIF72_89), a SPDR-loop (i.e., MIF90_94), and a C-terminal tail (i.e., MlF1o1_114). In some embodiments, a peptide disclosed herein competitively binds with a binding partner of one of the following domains: N-terminal/pseudo-ELR
motif/domain (MIF1_17), the alpha-helix #1 motif/domain (i.e., M1F18-31), the MIF N-loop motif/domain (i.e., MIF32-60), the loop-barrel-loop motif/domain (i.e., MIF64_93), the C-terminal motif/domain (i.e., MIF9o_114), or a combination of any of the aforementioned domains. In some embodiments, a peptide disclosed herein competitively binds with a binding partner of one of the following domains: N-terminal tail (i.e., MIF1_7), the pseudo ELR-loop (i.e., MIF7_17), the alpha-helix #1 motif/domain (i.e., MIF18_31), the PPQ-loop (i.e., MIF32-38), the PDQ-loop (i.e., MIF43-56), the IGK-loop (i.e., MIF64.71), the NRS-helix (i.e., MIF72_89), the SPDR-loop (i.e., MIF90_94), the C-terminal tail (i.e., MIF101-114), or a combination of any of the aforementioned domains. In some embodiments, a peptide disclosed herein competitively binds with a binding partner of MIF47 (leucine).
[0080] In some embodiments, 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. In some embodiments, 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.
II. Active Agents [0081] Disclosed herein, in some embodiments, are peptides, small molecules, antibodies, and peptibodies (collectively, "compositions of matter") for treating inflammatory diseases, disorders, conditions and symptoms. Further disclosed herein are pharmaceutical compositions and methods of treating inflammatory diseases, disorders, conditions and symptoms.
[0082] Additionally disclosed herein, in some embodiments, are compositions of matter, methods, and pharmaceutical compositions that inhibit the ability of MIF to bind to CXCR2, CXCR4, CD44, CD74, or a combination thereof. Further disclosed herein, are 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.
In certain instances, 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, GROG/CXCL2, GROa., GRO-y, ENA78, NAP2; and CXCR4 interactions with Stromal Cell-Derived Factor-la (SDF-la)/CXCL12, and GP120).
[0083] 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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
Disruption of MIF Motifs/Domains [0084] In some embodiments, a composition of matter inhibits the ability of MIF to interact with CXCR2, CXCR4, CD74, CD44 or a combination thereof. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 (MIF1_17), an alpha-helix #1 motif/domain (i.e., MIF18_31), an MIF N-loop motif/domain (i.e., MIF32_60), a loop-barrel-loop motif/domain (i.e., MIF64_93), and a C-terminal motif/domain (i.e., MIF90_ii4). In some embodiments, 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., MIF1_7), a pseudo ELR-loop (i.e., MIF7_17), an alpha-helix #1 motif/domain (i.e., MIF18_31), a PPQ-loop (i.e., MIF32-38), a PDQ-loop (i.e., MIF43-56), an IGK-loop (i.e., MIF64_71), an NRS-helix (i.e., MIF72_89), a SPDR-loop (i.e., MIF90_94), and a C-terminal tail (i.e., MlFioi_114). In some embodiments, the ability of MIF to interact with CXCR2, CXCR4, CD74, CD44 or a combination thereof is inhibited by occupying, masking, or otherwise disrupting MIF47 (leucine).
[0085] In some embodiments, 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. In certain instances, 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).
[0086] In certain instances, the pseudo-ELR motif/domain of MIF mediates ligand (e.g., CD44, CD74, CXCR2, CXCR4) binding to MIF. In some embodiments, 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. In some embodiments, the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of theN-terminal tail (i.e., MIF1_7) and/or all or a portion of thepseudo ELR-loop (i.e., MIF7_ 17) inhibits the ability of MIF to bind to CXCR2, CXCR4, CD74, CD44 or a combination thereof.
[0087] In certain instances, the N-loop motif/domain of MIF mediates ligand (e.g., CD44, CD74, CXCR2, CXCR4) binding to MIF. In some embodiments, 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. In some embodiments, the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of thePPQ-loop (i.e., MIF32_38) and/or all or a portion of thePDQ-loop (i.e., MIF43.56) inhibits the ability of MIF
to to bind to CXCR2, CXCR4, CD74, CD44 or a combination thereof. In some embodiments, 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. In some embodiments, the binding of a small molecule, peptide, antibody, and/or peptibody to all or a portion of thePPQ-loop (i.e., MIF32_38) and/or all or a portion of thePDQ-loop (i.e., MIF43-56) invokes a conformational change in MIF that prevents receptor or substrate interactions.
[0088] In certain instances, amino acids 65-94 of MIF (e.g., IGKIGGAQNRSYSKLLCGLLAERLRISPDR (SEQ ID No. 8); numbering includes the first methionine) mediate CXCR2 binding to MIF. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
[0090] In some embodiments, 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. In some embodiments, the peptide specifically binds to all or a portion of the pseudo ELR motif/domain of MIF. In some embodiments, the peptide specifically binds to all or a portion of the N-loop motif/domain of MIF. In some embodiments, the peptide specifically binds to all or a portion of both the pseudo-ELR and N-loop motifs.
[0091] In some embodiments, 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. 11) 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:
VNTNVPPRASVPDGFLSELTQQLAQATGKPPQYIAVHVVPDQLMAFGGSSEPCALCSL
(SEQ ID No. 12) 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:
PDQLMAFGGSSEPCALCSLHSI (SEQ ID No. 13) and the corresponding feature/domain of at least one of a MIF monomer or MIF trimer; or combinations thereof.
[0092] In some embodiments, 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. In some embodiments, the antibody specifically binds to all or a portion of the pseudo ELR
motif/domain of MIF. In some embodiments, the antibody specifically binds to all or a portion of the N-loop motif/domain of MIF. In some embodiments, the antibody specifically binds to all or a portion of both the pseudo-ELR and N-loop motifs.
[0093] In some embodiments, 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. In some embodiments, the peptibody specifically binds to all or a portion of the pseudo ELR
motif/domain of MIF. In some embodiments, the peptibody specifically binds to all or a portion of the N-loop motif/domain of MIF. In some embodiments, the peptibody specifically binds to all or a portion of both the pseudo-ELR and N-loop motifs.
[0094] In some embodiments, 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, CD74 and/or CD44 binds. In some embodiments, the small molecule specifically binds to all or a portion of the pseudo ELR motif/domain of MIF. In some embodiments, the small molecule specifically binds to all or a portion of the N-loop motif/domain of MIF. In some embodiments, the small molecule specifically binds to all or a portion of both the pseudo-ELR and N-loop motifs.
Disruption of CXCR2 and CXCR4 Motifs/Domains [0095] In some embodiments, a composition of matter disrupts all or a portion of a motif/domain on CXCR2 to which CXCR4, MIF, CD44 and/or CD74 bind. In some embodiments, 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 CXCR2 to which CXCR4, MIF, CD44 and/or CD74 bind.
[0096] In some embodiments, a composition of matter disrupts all or a portion of a motif/domain on CXCR4 to which CXCR2, MIF, CD44 and/or CD74 bind. In some embodiments, 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 CXCR4 to which CXCR2, MIF, CD44 and/or CD74 bind.
[0097] In some embodiments, 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.
[0098] In some embodiments, the agent that inhibits the binding of CXCR4, MIF, CD74 and/or CD44 to CXCR2 is an antibody. In some embodiments, the agent that inhibits the binding of CXCR2, MIF, CD74 and/or CD44 to CXCR4 is an antibody.
[0099] In some embodiments, 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.
[00101] In some embodiments, 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.
[00102] In some embodiments, the agent that inhibits the binding of MIF, CD74 and/or CD44 to CXCR2 is CXCL8(3_74)K11R/G31P; IL-8(4_72); IL-8 (6-72); 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_73); GRO-alpha(5_73); GRO-alpha(6_73); recombinant GRO (rGRO); (ELR)PF4 (PF4 with an ELR seq. at the N-terminus); recombinant PF4 (rPF4); Antileukinate; Sch527123 (-hydroxy-N,N-dimethyl-3-{2-[[(R)-1 -(5-methyl-furan-2-yl)-propyl]amino] -3,4-dioxo-cyclobut-l-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- [(1R)-2-amino-l-methyl-2-oxoethyl]phenyl trifluoromethanesulphonate);
Reparixin; or combinations thereof.
[00103] In some embodiments, 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 (AMD3 100); AMD3465(AnorMED); AMD8664 (1-pyridin-2-yl-N-[4-(1,4,7-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. Limited); KRH-3140 (Kureha Chemical Industry Co.
Limited); T134 (L-citrullinel6-TW70 substituted for the C-terminal amide by a carboxylic acid);
T22 ([Tyr5"2, Lys7]-polyphemusin II); TW70 (des-[Cys8,13, Tyr9,12]-[D-Lys10, Prol l]-T22); T140 (H-Arg-Arg-Nal-Cys-Tyr- Arg-Lys-DLys-Pro-Tyr-Arg-Cit-Cys-Arg-OH); TC14012 (R-R-Nal-C-Y-(L)Cit-K-(D)Cit-P-Y-R-(L)citrulline-C-R-NH2, where Nal=L-3-(2-naphthylalanine), Cit=citruline and the peptide is cyclized with the cysteines); TN14003; RCP168 (vMIP-II (11_71) with D-amino acids added to the N
terminus); POL3026 (Arg(*)-Arg-Nal(2)-Cys(1x)-Tyr-Gln-Lys-(d-Pro)-Pro-Tyr-Arg-Cit-Cys(lx)-Arg-Gly-(d-Pro)(*)); POL2438; compound 3 (N-(1-methyl-l-phenylethyl)-N-[((3S)-1-{2-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]ethyl}pyrrolidin-3-yl)methyl]amine);
isothioureas la-lu (for information regarding isothioureas la-lu see Gebhard Thoma, et al., Orally Bioavailable Isothioureas Block Function of the Chemokine Receptor CXCR4 In Vitro and In Vivo, J. Med.
Chem., Article ASAP (2008), which is herein incorporated by reference for such disclosures); or combinations thereof.
[00104] In some embodiments, 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.
Disruption of CD74 Motifs/Domains [00105] In some embodiments, a composition of matter disrupts all or a portion of a motif/domain on CD74 to which MIF, CD44, CXCR2, and/or CXCR4 bind. In some embodiments, 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.
[00106] In some embodiments, the agent that inhibits the binding of MIF, CD44, CXCR2, CXCR4, or a combination thereof to CD74 is a peptide.
[00107] In some embodiments, 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).
[00108] In some embodiments, the agent that inhibits the binding of MIF, CD44, CXCR2, CXCR4, or a combination thereof to CD74 is a peptibody.
[00109] In some embodiments, the agent that inhibits the binding of MIF, CD44, CXCR2, CXCR4, or a combination thereof to CD74 is a small molecule.
[00110] In certain instances, 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-la (SDF-la)/CXCL12).
Disruption of CD44 Motifs/Domains [00111] In some embodiments, a composition of matter disrupts all or a portion of a motif/domain on CD44 to which MIF, CD74, CXCR2, and/or CXCR4 bind. In some embodiments, 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.
[00112] In some embodiments, the agent that inhibits the binding of MIF, CD74, CXCR2, CXCR4, or a combination thereof to CD44 is a peptide.
[00113] In some embodiments, the agent that inhibits the binding of MIF, CD74, CXCR2, CXCR4, or a combination thereof to CD44 is an antibody.
[00114] In some embodiments, the agent that inhibits the binding of MIF, CD74, CXCR2, CXCR4, or a combination thereof to CD44 is a peptibody.
[00115] In some embodiments, the agent that inhibits the binding of MIF, CD74, CXCR2, CXCR4, or a combination thereof to CD44 is a small molecule.
MIF Mimics [00116] In some embodiments, a composition of matter disrupts the ability of MIF to bind to CXCR2, CXCR4, CD74, CD 44 or a combination thereof. In some embodiments, 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). In some embodiments, 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. In some embodiments, 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).
In some embodiments, the Peptide binds to CXCR2, CXCR4, CD74, CD44 or a combination thereof and thus prevents CXCR2, CXCR4, CD44 or CD74 from binding to MIF.
[00117] In some embodiments, the Peptide adopts structural or functional features similar to the N-Loop motif/domain of MIF. In some embodiments, the peptide comprises the sequence of Formula (I):
XI-X2-Q/A-X3-X4-X5-X6-G/S-X7-X8-X9-Xl0-P-X11 wherein:
X1 is selected from the group consisting of threonine, glycine, proline and alanine;
X2 is selected from the group consisting of glycine, asparagine, aspartic acid, and serine;
X3 is selected from the group consisting of methionine, isoleucine, leucine, alanine, proline, lysine, glutamine, arginine and lysine;
X4 is selected from the group consisting of methionine, isoleucine and leucine;
X5 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;
X7 is selected from the group consisting of aspartic acid, glutamic acid, threonine, glycine and alanine;
X8 is selected from the group consisting of serine, threonine, lysine and arginine;
X9 is selected from the group consisting of serine, asparagine, glycine, threonine, aspartic acid, glutamic acid, glutamine and histidine;
X10 is selected from the group consisting of aspartic acid, glutamic acid, alanine and asparagine; and X11 is selected from the group consisting of cysteine, alanine, serine, threonine and valine.
[00118] In some embodiments, X1 is proline. In some embodiments, X2 is aspartic acid. In some embodiments, X3 is leucine. In some embodiments, X4 is methionine. In some embodiments, X5 is alanine. In some embodiments, X6 is phenylalanine. In some embodiments, X7 is glycine. In some embodiments, X8 is serine. In some embodiments, X9 is serine. In some embodiments, X10 is glutamic acid. In some embodiments, X11 is serine cysteine.
[00119] In some embodiments, the Peptide comprises 3 or more consecutive amino acids of human MIF44_57 (numbering includes the first methionine). In some embodiments, the Peptide comprises 3 or more consecutive amino acids of murine MIF44_57. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of porcine MIF44_57. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of bovine MIF44_57. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of rat MIF44_57.
[00120] In some embodiments, 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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
LMAFGGSSEPCALC (SEQ SEPCAL (SEQ ID No. 62) cyclo(GSSEPCALC) (SEQ ID
ID No. 14) No. 110) LMAFGGSSEPCAL (SEQ EPCALC (SEQ ID No. 63) cyclo(GSSEPCAL) (SEQ ID
ID No. 15) No. 111) LMAFGGSSEPCA (SEQ ID QLMAFGGSSEPCALC (SEQ cyclo(GSSEPCA) (SEQ ID No.
No. 16) ID No. 64) 112) LMAFGGSSEPC (SEQ ID QLMAFGGSSEPCAL (SEQ ID cyclo(GSSEPC) (SEQ ID No.
No. 17) No. 65) 113) LMAFGGSSEP (SEQ ID No. QLMAFGGSSEPCA (SEQ ID cyclo(SSEPCALC) (SEQ ID
18) No. 66) No. 114) LMAFGGSSE (SEQ ID No. QLMAFGGSSEPC (SEQ ID cyclo(SSEPCAL) (SEQ ID No.
19) No. 67) 115) LMAFGGSS (SEQ ID No. QLMAFGGSSEP (SEQ ID No. cyclo(SSEPCA) (SEQ ID No.
20) 68) 116) LMAFGGS (SEQ ID No. 21) QLMAFGGSSE (SEQ ID No. cyclo(SEPCALC) (SEQ ID No.
69) 117) LMAFGG (SEQ ID No. 22) QLMAFGGSS (SEQ ID No. cyclo(SEPCAL) (SEQ ID No.
70) 118) MAFGGSSEPCALC (SEQ QLMAFGGS (SEQ ID No. 71) cyclo(EPCALC) (SEQ ID No.
ID No. 23) 119) MAFGGSSEPCAL (SEQ ID QLMAFGG (SEQ ID No. 72) cyclo(QLMAFGGSSEPCALC) No. 24) (SEQ ID No. 120) MAFGGSSEPCA (SEQ ID QLMAFG (SEQ ID No. 73) cyclo(QLMAFGGSSEPCAL) No. 25) (SEQ ID No. 121) MAFGGSSEPC (SEQ ID No. CSSEPCALC (SEQ ID No. 74) cyclo(QLMAFGGSSEPCA) 26) (SEQ ID No. 122) MAFGGSSEP (SEQ ID No. CFGGSSEPCALC (SEQ ID No. cyclo(QLMAFGGSSEPC) 27) 75) (SEQ ID No. 123) MAFGGSSE (SEQ ID No. CLMAFGGSSEPCALC (SEQ cyclo(QLMAFGGSSEP) (SEQ
28) ID No. 76) ID No. 124) MAFGGSS (SEQ ID No. 29) CAFGGSSC (SEQ ID No. 77) cyclo(QLMAFGGSSE) (SEQ
ID No. 125) MAFGGS (SEQ ID No. 30) CLMAFGGSSEPCC (SEQ ID cyclo(QLMAFGGSS) (SEQ ID
No. 78) No. 126) 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. 131) AFGGSSE (SEQ ID No. 36) CFGGSSEPC (SEQ ID No. 84) cyclo(AFGGSSEPCA) (SEQ
ID No. 132) AFGGSS (SEQ ID No. 37) IAVHVVPDQLMAFGGSSEPC cyclo(AFGGSSEPC) (SEQ ID
(SEQ ID No. 85) No. 133) FGGSSEPCALC (SEQ ID CLHSIGKIGGAQNRSYSKLL 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. CSLHSIGKIGGAQNR (SEQ cyclo(AFGGSS) (SEQ ID No.
40) ID No. 88) 136) FGGSSEPC (SEQ ID No. 41) IGKIGGAQNRSYSKL (SEQ cyclo(FGGSSEPCALC) (SEQ
ID No. 89) ID No. 137) FGGSSEP (SEQ ID No. 42) GAQNRSYSKLLCGLLA cyclo(FGGSSEPCAL) (SEQ
(SEQ ID No. 90) ID No. 138) FGGSSE (SEQ ID No. 43) CGLLAERLRISPDRV (SEQ cyclo(FGGSSEPCA) (SEQ ID
ID No. 91) No. 139) 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.
(SEQ ID No. 94) 142) GGSSEPC (SEQ ID No. 47) cyclo(LMAFGGSSEPCA) cyclo(GGSSEPCALC) (SEQ
(SEQ ID No. 95) ID No. 143) GGSSEP (SEQ ID No. 48) cyclo(LMAFGGSSEPC) (SEQ cyclo(GGSSEPCAL) (SEQ ID
ID No. 96) No. 144) 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.
No. 98) 146) GSSEPCA (SEQ ID No. 51) cyclo(LMAFGGSS) (SEQ ID cyclo(GGSSEP) (SEQ ID No.
No. 99) 147) GSSEPC (SEQ ID No. 52) cyclo(LMAFGGS) (SEQ ID No. cyclo(CSSEPCALC) (SEQ ID
100) No. 148) SSEPCALC (SEQ ID No. 53) cyclo(LMAFGG) (SEQ ID No. cyclo(CFGGSSEPCALC) 101) (SEQ ID No. 149) 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
(SEQ ID No. 103) No. 151) GSSEPCA (SEQ ID No. 56) cyclo(MAFGGSSEPCA) (SEQ cyclo(CGSSEPCALC) (SEQ
ID No. 104) ID No. 152) GSSEPC (SEQ ID No. 57) cyclo(MAFGGSSEPC) (SEQ cyclo(CAFGGSSEPCAC) ID No. 105) (SEQ ID No. 153) SSEPCALC (SEQ ID No. 58) cyclo(MAFGGSSEP) (SEQ ID cyclo(CLMAFGGSSEPCALC) No. 106) (SEQ ID No. 154) SSEPCAL (SEQ ID No. 59) cyclo(MAFGGSSE) (SEQ ID cyclo(CAFGGSSC) (SEQ ID
No. 107) No. 155) SSEPCA (SEQ ID No. 60) cyclo(MAFGGSS) (SEQ ID No. VVPDQLMAFG (SEQ ID No.
108) 461) SEPCALC (SEQ ID No. 61) cyclo(MAFGGS) (SEQ ID No. DQLMAFGGSSEPC (SEQ ID
109) NO. 462) Table 1 [00121] In some embodiments, the peptide is cyclic: CLMAFGGSSEPC (SEQ ID No.
422);
CLMAFGGSSEPCALC (SEQ ID No. 423); CGLMAFGGSSEPGC (SEQ ID NO. 424);
CGGLMAFGGSSEPGGC (SEQ ID NO. 425); CGGSLMAFGGSSEPSGGC (SEQ ID NO. 426);
CGGSGLMAFGGSSEPGSGGC (SEQ ID NO. 427); CGGSGGLMAFGGSSEPGGSGGC (SEQ ID
NO. 428); CLMAFGGSSEP[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); or cyclic CLMAFGGSSEPSALC (SEQ ID NO. 469).
[00122] In some embodiments, 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).
[00123] In some embodiments, 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 L-cyclohexylalanine; LMA[D-CA]AFGGSSEPC[D-CA] (SEQ ID NO. 432), wherein D-CA
is D-cyclohexylalanine; LMA[D-F]AFGGSSEPC[D-F] (SEQ ID NO. 433), wherein D-F is D-phenylalanine; (D)-MAFGGSSEPC (SEQ ID NO. 434); (D)-CPESSGGFAML (SEQ ID NO.
435);
(L)-CPESSGGFAML (SEQ ID NO. 436); CLMAFGGSSEPCACG (SEQ ID NO. 452);
CLMAFGGSSEPCCGG (SEQ ID NO. 453); CLMAFGGSSEPCGGG (SEQ ID NO. 454);
CLMAFGGSSECGGGG (SEQ ID NO. 455); CLMAFGGSSCGGGGG (SEQ ID NO. 456);
CLMAFGGSCGGGGG (SEQ ID NO. 457); CLMAFGGCGGGGGGG (SEQ ID NO. 458);
CLMAFGCGGGGGGGG (SEQ ID NO. 459); or CLMAFGGSSEPCALG (SEQ ID NO. 460).
[00124] In some embodiments, a peptide disclosed herein competitively binds with a binding partner of of MIF40_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 MIF42-51 (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 MIF45.57 (i.e., the peptide has the sequence DQLMAFGGSSEPC (SEQ ID NO. 467)). In some embodiments, a peptide disclosed herein competitively binds with a binding partner of MIF46-55 (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).
[00125] In some embodiments, the peptide comprises the sequence of Formula (II):
XI-X2-T/S-N-X3-X4-X5-X6-X7-Xg-P/S-X9-Xl wherein:
X1 is selected from the group consisting of valine, isoleucine, threonine, phenylalanine and leucine;
x2 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;
X4 is selected from the group proline, alanine, cysteine and leucine;
X5 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;
X7 is selected from the group serine, glutamic acid, aspartic acid, asparagine, arginine, glycine, lysine and arginine;
X8 is selected from the group valine, isoleucine and phenylalanine;
X9 is selected from the group aspartic acid, glutamic acid, valine, serine and threonine; and X10 is selected from the group glycine, alanine, threonine, aspartic acid and glutamic acid.
[00126] In some embodiments, X1 is valine. In some embodiments, X2 is asparagine. In some embodiments, X3 is valine. In some embodiments, X4 is proline. In some embodiments, X5 is arginine. In some embodiments, X6 is alanine. In some embodiments, X7 is serine. In some embodiments, X8 is valine. In some embodiments, X9 is aspartic acid. In some embodiments, X10 is glycine.
[00127] In some embodiments, the Peptide comprises 3 or more consecutive amino acids of human MIF1_45 (numbering includes the first methionine). In some embodiments, the Peptide comprises 3 or more consecutive amino acids of murine MIF1_45. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of porcine MIF1-45. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of bovine M1F1_45. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of rat MIF1-45.
[00128] In some embodiments, 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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
CTNVPRASVPDGC (SEQ ID No. 156) NVPRASVPD (SEQ ID No. 173) CVPRASC (SEQ ID No. 157) NVPRASVP (SEQ ID No. 174) VNTNVPRASVPDGFLSEL (SEQ ID No. VPRASVP (SEQ ID No. 175) 158) NTNVPRASVPDGFLSEL (SEQ ID No. PRASVP (SEQ ID No. 176) 159) TNVPRASVPDGFLSEL (SEQ ID No. 160) VPRASVPDGFL (SEQ ID No. 177) NVPRASVPDGFLSEL (SEQ ID No. 161) VPRASVPDGF (SEQ ID No. 178) VPRASVPDGFLSEL (SEQ ID No. 162) VPRASVPDG (SEQ ID No. 179) PRASVPDGFLSEL (SEQ ID No. 163) VPRASVPD (SEQ ID No. 180) RASVPDGFLSEL (SEQ ID No. 164) VPRASVP (SEQ ID No. 181) ASVPDGFLSEL (SEQ ID No. 165) VPRAS (SEQ ID No. 182) SVPDGFLSEL (SEQ ID No. 166) MPMFIVNTNVPRASVPDGFLSEC (SEQ
ID No. 183) VPDGFLSEL (SEQ ID No. 167) MPMFIVNTNVPRASV (SEQ ID No. 184) NVPRASVPDGFLSE (SEQ ID No. 168) FIVNTNVPRASVPDG (SEQ ID No. 185) NVPRASVPDGFLS (SEQ ID No. 169) NTNVPRASVPDGFLS (SEQ ID No. 186) NVPRASVPDGFL (SEQ ID No. 170) VPRASVPDGFLSELT (SEQ ID No. 187) NVPRASVPDGF (SEQ ID No. 171) PRASVPDG (SEQ ID NO. 436) NVPRASVPDG (SEQ ID No. 172) VNTNVPRASVPDG (SEQ ID NO. 437) Table 2 [00129] In some embodiments, Peptide is cyclic: CPRASVPDGC (SEQ ID NO. 438), CGGSGGPRASVPDGGGSGGC (SEQ ID NO. 439); or CNVPRASVPDGC (SEQ ID NO. 440).
[00130] In some embodiments, the Peptide adopts structural or functional features similar to the amino acid residues 65-94 (numbering includes the first methionine). In some embodiments, the Peptide comprises a peptide of Formula (III):
I/L-G-Xl-X2-X3-X4-Xs-X6-N-X7-Xs-X9-X10-Xl1-X12-L/I-X13-X14-X'5-X16-X'7-X'8-X19-wherein:
X1 is selected from the group consisting of lysine, arginine, cysteine, serine and alanine;
X2 is selected from the group consisting of isoleucine, valine and phenylalanine;
X3 is selected from the group consisting of glycine, asparagine and serine;
X4 is selected from the group consisting of glycine, proline, alanine, aspartic acid and glutamic acid;
X5 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;
X7 is selected from the group consisting of lysine, arginine, asparagine, isoleucine and valine;
X8 is selected from the group consisting of serine, asparagine, glutamine, aspartic acid, glutamic acid, lysine and arginine;
X9 is selected from the group consisting of tyrosine, histidine and asparagine;
X10 is selected from the group consisting of serine, threonine and alanine;
X11 is selected from the group consisting of lysine, aspartic acid, glutamic acid, alanine, serine and glycine;
X12 is selected from the group consisting of leucine, glutamine, lysine, arginine, leucine, serine and alanine;
X13 is selected from the group consisting of cysteine, tyrosine, phenylalanine, serine, alanine and threonine;
X14 is selected from the group consisting of glycine, aspartic acid, glutamic acid, lysine and arginine;
X15 is selected from the group consisting of leucine, glutamine, isoleucine, histidine and phenylalanine;
X16 is selected from the group consisting of leucine, methionine, isoleucine and cysteine;
X17 is selected from the group consisting of alanine, threonine, serine, arginine, lysine, alanine, glutamine and glycine;
X'8 is selected from the group consisting of glutamic acid, aspartic acid, lysine and arginine;
X19 is selected from the group consisting of arginine, histidine, glutamine, aspartic acid, glutamic acid, glycine, threonine and lysine;
X20 is selected from the group consisting of arginine, histidine, glycine, asparagine, lysine, arginine, aspartic acid and glutamic acid;
X21 is selected from the group consisting of serine, aspartic acid, glutamic acid, lysine, arginine and proline;
X22 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.
[00131] In some embodiments, X1 is lysine. In some embodiments, X2 is isoleucine. In some embodiments, X3 is glycine. In some embodiments, X4 is glycine. In some embodiments, X5 is alanine. In some embodiments, X6 is glutamine. In some embodiments, X7 is arginine. In some embodiments, X8 is serine. In some embodiments, X9 is tyrosine. In some embodiments, X10 is serine. In some embodiments, X11 is lysine. In some embodiments, X12 is leucine. In some embodiments, X13 is cysteine. In some embodiments, X14 is glycine. In some embodiments, X15 is leucine. In some embodiments, X16 is leucine. In some embodiments, X17 is alanine. In some embodiments, X'8 is glutamic acid. In some embodiments, X19 is arginine. In some embodiments, X20 is arginine. In some embodiments, X21 is serine. In some embodiments, X22 is proline. In some embodiments, X23 is aspartic acid. In some embodiments, X24 is arginine.
[00132] In some embodiments, the Peptide comprises 3 or more consecutive amino acids of human MIF65-94. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of murine MIF65-94. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of porcine MIF65-94. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of bovine MIF65-94. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of rat MIF65-94=
[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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
CSLHSIGKIGGAQNR (SEQ ID IAVHVVPDQLMAFGGSSEPCALCSLHSIGKIGGAQNRSYSKLL
No. 188) (SEQ ID No. 218) IGKIGGAQNRSYSKL (SEQ ID IAVHVVPDQLMAFGGSSEPCALCSLHSIGKIGGAQNRSY (SEQ
No. 189) ID No. 219) HSIGKIGGAQNRSYSKLLCGLL IAVHVVPDQLMAFGGSSEPCALCSLHSIGKIGGAQ (SEQ ID
(SEQ ID No. 190) No. 220) HSIGKIGGAQNRSYSKLLCG IAVHVVPDQLMAFGGSSEPCALCSLHSIGKI (SEQ ID No. 221) (SEQ ID No. 191) HSIGKIGGAQNRSYSKLL (SEQ IAVHVVPDQLMAFGGSSEPCALCSLHS (SEQ ID No. 222) ID No. 192) HSIGKIGGAQNRSYSK (SEQ ID IAVHVVPDQLMAFGGSSEPCALC (SEQ ID No. 223) No. 193) HSIGKIGGAQNRSYS (SEQ ID IAVHVVPDQLMAFGGSSEP (SEQ ID No. 224) No. 194) IGKIGGAQNRSYSKLLC (SEQ IAVHVVPDQLMAFGG (SEQ ID No. 225) ID No. 195) KIGGAQNRSYSKLLC (SEQ ID IAVHVVPDQLM (SEQ ID No. 226) No. 196) GGAQNRSYSKLLCGLLAERLRI IAVHVVPDQLMAFGGSSEPCALCSLHSIGKIGGAQNRSYSKLL
(SEQ ID No. 197) (SEQ ID No. 227) AQNRSYSKLLCGLLAERLRI VVPDQLMAFGGSSEPCALCSLHSIGKIGGAQNRSYSKLL (SEQ
(SEQ ID No. 198) ID No. 228) NRSYSKLLCGLLAERLRI (SEQ QLMAFGGSSEPCALCSLHSIGKIGGAQNRSYSKLL (SEQ ID
ID No. 199) No. 229) SYSKLLCGLLAERLRI (SEQ ID FGGSSEPCALCSLHSIGKIGGAQNRSYSKLL (SEQ ID No. 230) No. 200) YSKLLCGLLAERLRI (SEQ ID SEPCALCSLHSIGKIGGAQNRSYSKLL (SEQ ID No. 231) No. 201) GAQNRSYSKLLCGLLAE (SEQ ALCSLHSIGKIGGAQNRSYSKLL (SEQ ID No. 232) ID No. 202) GAQNRSYSKLLCGLL (SEQ ID LHSIGKIGGAQNRSYSKLL (SEQ ID No. 233) No. 203) QNRSYSKLLCGLLAE (SEQ ID GKIGGAQNRSYSKLL (SEQ ID No. 234) No. 204) HSIGKIGGAQNRSY (SEQ ID IGGAQNRSYSKLL (SEQ ID No. 235) No. 205) HSIGKIGGAQNR (SEQ ID No. QNRSYSKLL (SEQ ID No. 236) 206) HSIGKIGGAQNRSYSK (SEQ ID IGKIGGAQNRSYSKL (SEQ ID No. 237) No. 207) IGKIGGAQNRSYSKLLC (SEQ IGKIGGAQ (SEQ ID No. 238) ID No. 208) KIGGAQNRSYSKLLC (SEQ ID linear (CIGKIGGAQC) (SEQ ID No. 239) No. 209) KIGGAQNRSYS (SEQ ID No. cyclo (CIGKIGGAQC) (SEQ ID No. 240) 210) GAQNRSYSKLLCGLLAE (SEQ RSYSKLLCGLLAE (SEQ ID No. 241) ID No. 211) GAQNRSYSKLLCGLL (SEQ ID linear (CRSYSKLLCGLLAEC) (SEQ ID No. 242) No. 212) GAQNRSYSKLLCG (SEQ ID No. cyclo (CRSYSKLLCGLLAEC) (SEQ ID No. 243) 213) GAQNRSYSKLL (SEQ ID No. CGLLAERLRISPDR (SEQ ID No. 244) 214) QNRSYSKLLCGLLAE (SEQ ID linear(CGLLAERLRISPDRC) (SEQ ID No. 245) No. 215) RSYSKLLCGLLAE (SEQ ID No. Cyclo (CGLLAERLRISPDRC) (SEQ ID No. 246) 216) YSKLLCGLLAE (SEQ ID No. VHVVPDQLMA (SEQ ID No. 421) 217) Table 3 [00134] In some embodiments, Peptide is: CVHVVPDQLMAC (SEQ ID NO. 451).
CD74 Mimics [00135] CD74 is transmembrane protein that binds MIF. In some embodiments, CD74 is a receptor for MIF. In some embodiments, 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. 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 CD74 to CXCR2, CXCR4, MIF, CD44.
[00136] In some embodiments, 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). In some embodiments, the peptide competitively binds with MIF, CD44, CXCR2, and/or CXCR4 and thus prevents CD74 from binding to MIF, CD44, CXCR2, and/or CXCR4.
[00137] In some embodiments, the peptide- adopts structural or functional features similar to CD74.
[00138] In some embodiments, 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.
[00139] In some embodiments, 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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
AYFLYQQQ (SEQ ID NO. 247) TKYGNMTEDHVMHLL (SEQ ID NO. 280) QQQGRLDKLTVTGRL (SEQ ID NO. 248) HVMHLLQNADPLKVY (SEQ ID NO. 281) GRLDKLTVTSQNLQL (SEQ ID NO. 249) DPLKVYPPLKGSFPE (SEQ ID NO. 282) SQNLQLENLRM (SEQ ID NO. 250) KGSFPENLRHLKNTM (SEQ ID NO. 283) TVTGRLDKLTVTSQN (SEQ ID NO. 251) HLKNTMETIDWKVFE (SEQ ID NO. 284) TVTSQNLQLENLRM (SEQ ID NO. 252) DWKVFESWMHHWLLF (SEQ ID NO. 285) LENLRMKLPKPPKPV (SEQ ID NO. 253) HHWLLFEMSRHSLEQ (SEQ ID NO. 286) KLPKPPKPVSKMRMA (SEQ ID NO. 254) RHSLEQKPTDAPPKE (SEQ ID NO. 287) SKMRMATPL (SEQ ID NO. 255) DAPPKESLELEDPSS (SEQ ID NO. 288) LMQALPMGALPQGPM (SEQ ID NO. 256) LEDPSSGLGVTKQDL (SEQ ID NO. 289) LPQGPMQNATKYGNM (SEQ ID NO. 257) SGLGVTKQDLGPVPM (SEQ ID NO. 290) TKYGNMTEDHVMHLL (SEQ ID NO. 258) MDDQRDLISNHEQLP (SEQ ID NO. 291) HVMHLLQNADPLKVY (SEQ ID NO. 259) LPILGNRPREPERCS (SEQ ID NO. 292) DPLKVYPPLKGSFPE (SEQ ID NO. 260) CSRGALYTGVSVLVA (SEQ ID NO. 293) KGSFPENLRHLKNTM (SEQ ID NO. 261) VSVLVALLLAGQATT (SEQ ID NO. 294) HLKNTMETIDWKVFE (SEQ ID NO. 262) AYFLYQQQGRLDKLT (SEQ ID NO. 295) DWKVFESWMHHWLLF (SEQ ID NO. 263) LTITSQNLQLESLRM (SEQ ID NO. 296) HHWLLFEMSRHSLEQ (SEQ ID NO. 264) RMKLPKSAKPVSQMR (SEQ ID NO. 297) RHSLEQKPTDAPPKE (SEQ ID NO. 265) MRMATPLLMRPMSMD (SEQ ID NO. 298) DAPPKESLELEDPSS (SEQ ID NO. 266) MDNMLLGPVKNVTKY (SEQ ID NO. 299) LEDPSSGLGVTKQDL (SEQ ID NO. 267) KYGNMTQDHVMHLLT (SEQ ID NO. 300) VTKQDLGPVPM (SEQ ID NO. 268) RSGPLEYPQLKGTFP (SEQ ID NO. 301) MDDQRDLISNNEQLP (SEQ ID NO. 269) FPENLKHLKNSMDGV (SEQ ID NO. 302) LPMLGRRPGAPESKC (SEQ ID NO. 270) GVNWKIFESWMKQWL (SEQ ID NO. 303) CSRGALYTGFSILVT (SEQ ID NO. 271) WLLFEMSKNSLEEKK (SEQ ID NO. 304) FSILVTLLLAGQATT (SEQ ID NO. 272) EKKPTEAPPKVLTKC (SEQ ID NO. 305) AYFLYQQQGRLDKLT (SEQ ID NO. 273) CQEEVSHIPAVYPGA (SEQ ID NO. 306) GRLDKLTVTSQNLQL (SEQ ID NO. 274) GAFRPKCDENGNYLP (SEQ ID NO. 307) SQNLQLENLRMKLPK (SEQ ID NO. 275) LPLQCHGSTGYCWCV (SEQ ID NO. 308) KLPKPPKPVSKMRMA (SEQ ID NO. 276) CVFPNGTEVPHTKSR (SEQ ID NO. 309) SKMRMATPLLMQALP (SEQ ID NO. 277) SRGRHNCSEPLDMED (SEQ ID NO. 310) LMQALPMGALPQGPM (SEQ ID NO. 278) EDLSSGLGVTRQELG (SEQ ID NO. 311) LPQGPMQNATKYGNM (SEQ ID NO. 279) SGLGVTRQELGQVTL (SEQ ID NO. 312) Table 4 CXCR2/CXCR4 Mimics [00140] In some embodiments, 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. 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 CXCR2 to CXCR4, MIF, CD44, CD74 or a combination thereof. In some embodiments, 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. 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 CXCR4 to CXCR2, MIF, CD44, CD74 or a combination thereof.
[00141] In some embodiments, a peptide disclosed herein competitively binds with a binding partner of a CXCR2 domain/motif. In some embodiments, 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. In some embodiments, the peptide binds to MIF, CD74 and/or CD44 and thus prevents CXCR2 from binding to MIF, CD74 and/or CD44.
[00142] In some embodiments, a peptide disclosed herein competitively binds with a binding partner of the CXCR2 extracellular loop 1 (i.e., CXCR2108 120), the extracellular loop 2 (i.e., CXCR2184-212), and/or the extracellular loop 3 (i.e., CXCR2286-300)= In some embodiments, a peptide disclosed herein competitively binds with a binding partner of the extracellular loop 2 (i.e., CXCR2184-212), and/or CXCR2 extracellular loop 3 (i.e., CXCR2286-300)= In some embodiments, 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., CXCR2108-120), the extracellular loop 2 (i.e., CXCR2184-212), and/or the extracellular loop 3 (i.e., CXCR2286-300). In some embodiments, 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., CXCR2i84-212), and/or CXCR2 extracellular loop 3 (i.e., CXCR2286-300)=
[00143] In some embodiments, a peptide disclosed herein competitively binds with a binding partner of CXCR2 N-terminus/domain (i.e., CXCR21-39). In some embodiments, 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., CXCR21-39).
[00144] In some embodiments, 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 CXCR4 motif/domain. In some embodiments, 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. In some embodiments, 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). In some embodiments, 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 (DDRYICDRFYPNDLW). In some embodiments, the peptide binds to MIF, CD74 and/or CD44 and thus prevents CXCR4 from binding to MIF, CD74 and/or CD44.
[00145] In some embodiments, 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.
[00146] In some embodiments, 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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
DLSNYSYSSTLPPFL (SEQ ID NO. 313) MRTQVIQ (SEQ ID NO. 336) DLSNYSYSSTLPP (SEQ ID NO. 314) MRTQV (SEQ ID NO. 337) DLSNYSYSSTL (SEQ ID NO. 315) CERRNHIDRALDA (SEQ ID NO. 338) DLSNYSYSS (SEQ ID NO. 316) CERRNHIDRAL (SEQ ID NO. 339) DLSNYSY (SEQ ID NO. 317) CERRNHIDR (SEQ ID NO. 340) DLSNY (SEQ ID NO. 318) CERRNHI (SEQ ID NO. 341) KVNGWIFGTFL (SEQ ID NO. 319) CERRN (SEQ ID NO. 342) KVNGWIFGT (SEQ ID NO. 320) DRYICDRFYPNDL (SEQ ID NO. 343) KVNGWIF (SEQ ID NO. 321) DRYICDRFYPN (SEQ ID NO. 344) KVNGW (SEQ ID NO. 322) DRYICDRFY (SEQ ID NO. 345) RRTVYSSNVSPAC (SEQ ID NO. 323) DRYICDR (SEQ ID NO. 346) RRTVYSSNVSP (SEQ ID NO. 324) DRYIC (SEQ ID NO. 347) RRTVYSSNV (SEQ ID NO. 325) ICDRFYPNDLWVV (SEQ ID NO. 348) RRTVYSS (SEQ ID NO. 326) ICDRFYP (SEQ ID NO. 349) RRTVY (SEQ ID NO. 327) ICDRF (SEQ ID NO. 350) EDMGNNTANWRML (SEQ ID NO. 328) RFYPNDLWVVVFQ (SEQ ID NO. 351) EDMGNNTANWR (SEQ ID NO. 329) RFYPNDLWVVV (SEQ ID NO. 352) EDMGNNTAN (SEQ ID NO. 330) RFYPNDLWV (SEQ ID NO. 353) EDMGNNT (SEQ ID NO. 331) RFYPNDL (SEQ ID NO. 354) EDMGN (SEQ ID NO. 332) RFYPN (SEQ ID NO. 355) MRTQVIQETCERR (SEQ ID NO. 333) ICDRFYPNDLW (SEQ ID NO. 356) MRTQVIQETCE (SEQ ID NO. 334) ICDRFYPND (SEQ ID NO. 357) MRTQVIQET (SEQ ID NO. 335) Table 5 CD44 Mimics [00148] CD44 is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion and migration. In certain instances, human CD44 has the sequence:
MDKFWWHAAWGLCLVPLSLAQIDLNITCRFAGVFHVEKNGRYSISRTEA
ADLCKAFNSTLPTMAQMEKALSIGFETCRYGFIEGHVVIPRIHPNSICAAN
NTGVYILTSNTSQYDTYCFNASAPPEEDCTSVTDLPNAFDGPITITIVNRD
GTRYV QKGEYRTNPEDIYPSNPTDDDV S SGS S SERS STSGGYIFYTFSTVH
PIPDEDSPWITDSTDRIPATRDQDTFHPSGGSHTTHGSESDGHSHGSQEGG
ANTTSGPIRTPQIPEWLIILASLLALALILAVCIAVNSRRRCGQKKKLVINS
GNGAVEDRKPSGLNGEASKSQEMVHLVNKESSETPDQFMTADETRNLQ
NVDMKIGV (SEQ ID No. 358).
In certain instances, murine CD44 has the sequence:
MDKFWWHTAWGLCLLQLSLAHPHQQIDLNVTCRYAGVFHVEKNGRYSI
SRTEAADLCQAFNSTLPTMDQMKLALSKGFETCRYGFIEGNVVIPRIHPN
AICAANHTGVYILVTSNTSHYDTYCFNASAPPEEDCTSVTDLPNSFDGPV
TITIVNRDGTRYSKKGEYRTHQEDIDASNIIDDDVSSGSTIEKSTPESYILHT
YLPTEQPTGDQDDSFFIRSTLATRDRDSSKDSRGSSRTVTHGSELAGHSSA
NQDSGVTTTSGPMRRPQIPEWLIILASLLALALILAVCIAVNSRRRCGQKK
KLVINGGNGTVEDRKPSELNGEASKSQEMVHLVNKEPSETPDQCMTADE
TRNLQSVDMKIGV (SEQ ID No. 359).
[00149] In certain instances, CD44 forms a complex with CD74. In some embodiments, inhibiting the binding of CD44 and CD74 reduces or inhibits (partially or fully) inflammation. In some embodiments, inhibiting the binding of CD44 and MIF reduces or inhibits (partially or fully) inflammation.
[00150] In some embodiments, 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.
[00151] In some embodiments, 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. In some embodiments, the Peptide binds to MIF, CXCR2, CXCR4, CD74, or a combination thereof.
[00152] In some embodiments, 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.
[00153] In some embodiments, 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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
MDKFWWHAAWGLCLV (SEQ ID NO. 360) GVFHVEKNGRYSI (SEQ ID NO. 391) LVPLSLAQIDLNITC (SEQ ID NO. 361) SISRTEAADLCQA (SEQ ID NO. 392) CRFAGVFHVEKNGRY (SEQ ID NO. 362) QAFNSTLPTMDQM (SEQ ID NO. 393) RYSISRTEAADLCKA (SEQ ID NO. 363) QMKLALSKGFETC (SEQ ID NO. 394) KAAFNSTLPTMAQME (SEQ ID NO. 364) CRYGFIEGNVVIP (SEQ ID NO. 395) KALSIGFETCRYGFI (SEQ ID NO. 365) IPRIHPNAICAAN (SEQ ID NO. 396) FIEGHVVIPRIHPNS (SEQ ID NO. 366) ANHTGVYILVTSN (SEQ ID NO. 397) NSICAANNTGVYILT (SEQ ID NO. 367) SNTSHYDTYCFNA (SEQ ID NO. 398) LTSNTSQYDTYCFNA (SEQ ID NO. 368) NASAPPEEDCTSV (SEQ ID NO. 399) NASAPPEEDCTSVTD (SEQ ID NO. 369) SVTDLPNSFDGPV (SEQ ID NO. 400) TDLPNAFDGPITITI (SEQ ID NO. 370) PVTITIVNRDGTR (SEQ ID NO. 401) TIVNRDGTRYVQKGE (SEQ ID NO. 371) TRYSKKGEYRTHQ (SEQ ID NO. 402) GEYRTNPEDIYPSNP (SEQ ID NO. 372) HQEDIDASNIIDD (SEQ ID NO. 403) NPTDDDVSSGSSSER (SEQ ID NO. 373) DDVSSGSTIEKST (SEQ ID NO. 404) ERSSTSGGYIFYTFS (SEQ ID NO. 374) STPESYILHTYLP (SEQ ID NO. 405) FSTVHPIPDEDSPWI (SEQ ID NO. 375) LPTEQPTGDQDDS (SEQ ID NO. 406) WITDSTDRIPATRDQ (SEQ ID NO. 376) DSFFIRSTLATRD (SEQ ID NO. 407) DQDTFHPSGGSHTTH (SEQ ID NO. 377) RDRDSSKDSRGSS (SEQ ID NO. 408) THGSESDGHSHGSQE (SEQ ID NO. 378) SSRTVTHGSELAG (SEQ ID NO. 409) QEGGANTTSGPIRTP (SEQ ID NO. 379) AGHSSANQDSGVT (SEQ ID NO. 410) TPQIPEWLIILASLL (SEQ ID NO. 380) TTSGPMRRPQIPE (SEQ ID NO. 411) LLALALILAVCIAVN (SEQ ID NO. 381) PEWLIILASLLAL (SEQ ID NO. 412) VNSRRRCGQKKKLVI (SEQ ID NO. 382) ALALILAVCIAVN (SEQ ID NO. 413) VINSGNGAVEDRKPS (SEQ ID NO. 383) VNSRRRCGQKKKL (SEQ ID NO. 414) PSGLNGEASKSQEMV (SEQ ID NO. 384) KLVINGGNGTVED (SEQ ID NO. 415) MVHLVNKESSETPDQ (SEQ ID NO. 385) EDRKPSELNGEAS (SEQ ID NO. 416) DQFMTADETRNLQNV (SEQ ID NO. 386) ASKSQEMVHLVNK (SEQ ID NO. 417) DETRNLQNVDMKIGV (SEQ ID NO. 387) NKEPSETPDQCMT (SEQ ID NO. 418) MDKFWWHTAWGLC (SEQ ID NO. 388) MTADETRNLQSVD (SEQ ID NO. 419) LLQLSLAHPHQQI (SEQ ID NO. 389) TRNLQSVDMKIGV (SEQ ID NO. 420) QIDLNVTCRYAGV (SEQ ID NO. 390) Table 6 F. Fusion Peptide [00154] In some embodiments, a composition of matter disrupts the ability of MIF to bind to CXCR2, CXCR4, CD74, or a combination thereof. In some embodiments, the composition of matter is a fusion peptide that binds both the N-loop motif/domain of MIF and the pseudo-ELR
motif/domain of MIF. In some embodiments, 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. In some embodiments, 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.
[00155] In some embodiments, 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.
[00156] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
[00157] In some embodiments, 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. In some embodiments, 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.
[00158] In some embodiments, 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.
[00159] In some embodiments, the methods and compositions disclosed herein comprise (a) a first peptide having the sequence LQDP; and (b) a second peptide having the sequence NVPRA.
[00160] In some embodiments, the first peptide and the second peptide are directly bound to each other (e.g., via a covalent or ionic bond).
Linkers [00161] In some embodiments, 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). In some embodiments, 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.
[00162] In some embodiments, 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. In some embodiments, the fusion peptide is a peptide of Formula (IV):
Peptide 1 -Linker Peptide 2 Formula (IV) wherein Peptide 1, and Peptide 2 are selected from any peptide disclosed herein.
[00163] In some embodiments, 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. In some embodiments, the fusion peptide is a peptide of Formula (V):
Peptide 1 Linker Peptide 2 Peptide 3 Formula (V) wherein Peptide 1, Peptide 2, and Peptide 3 are selected from any peptide disclosed herein.
[00164] As used herein, a "linker" is any molecule capable of binding (e.g., covalently) to multiple peptides. In some embodiments, the linker binds to the peptide by a covalent linkage. In some embodiments, 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.
[00165] In some embodiments, 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.
[00166] In some embodiments, the linker binds to two peptides. In some embodiments, the linker binds to three peptides.
[00167] In some embodiments, 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.
[00168] In some embodiments, 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.
[00169] In some embodiments, the linker is an alkyl. In some embodiments, the linker is heteroalkyl.
[00170] In some embodiments, 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.
[00171] An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl moiety may be a saturated alkyl or an unsaturated alkyl. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).
[00172] 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 "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 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.
[00173] In some embodiments, the linker comprises a ring structure (e.g., an aryl). As used herein, the term "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.
[00174] As used herein, the term "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.
Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).
[00175] The term "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.
[00176] In some embodiments, the ring is a cycloalkane. In some embodiments, the ring is a cycloalkene.
[00177] In some embodiments, the ring is an aromatic ring. The term "aromatic"
refers to a planar ring having a delocalized t-electron system containing 4n+2 t 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. The term "aromatic" includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
[00178] In some embodiments, the ring is a heterocycle. The term "heterocycle"
refers to heteroaromatic and heteroalicyclic groups containing one to four heteroatoms each selected from 0, 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 0 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.
Examples of 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, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of 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, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-l-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo (=O) moieties such as pyrrolidin-2-one. Depending on the structure, a heterocycle group can be a monoradical or a diradical (i.e., a heterocyclene group).
[00179] In some embodiments, the ring is fused. The term "fused" refers to structures in which two or more rings share one or more bonds. In some embodiments, the ring is a dimer. In some embodiments, the ring is a trimer. In some embodiments, the ring is a substituted.
[00180] The term "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.
[00181] In some embodiments, 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-C6alkyl, C3-Cgcycloalkyl, aryl, heteroaryl, C2-C6heteroalicyclic, hydroxy, Ci-C6alkoxy, aryloxy, Ci-C6alkylthio, arylthio, Ci-C6alkylsulfoxide, arylsulfoxide, Ci-C6alkylsulfone, arylsulfone, cyano, halo, C2-Cgacyl, C2-Cgacyloxy, nitro, Ci-C6haloalkyl, Ci-C6fluoroalkyl, and amino, including Ci-C6alkylamino, and the protected derivatives thereof. By way of example, an optional substituents may be LSRS, wherein each Ls is independently selected from a bond, -0-, -C(=O)-, -S-, -S(=O)-, -S(=0)2-, -NH-, -NHC(=O)-, -C(=O)NH-, S(=0)2NH-, -NHS(=0)2-, -OC(=O)NH-, -NHC(=O)O-, -(Ci-C6alkyl)-, or -(C2-C6alkenyl)-; and each Rs is independently selected from H, (Ci-C4alkyl), (C3-Cgcycloalkyl), heteroaryl, aryl, and Ci-C6heteroalkyl. Optionally substituted non-aromatic groups may be substituted with one or more oxo (=O). The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art.
[00182] In some embodiments, the linker is an amino acid. In some embodiments, the fusion peptide is a peptide of Formula (VI):
O H
Peptide 1,N N,Pe Peptide 2 H p r, r2 Formula (VI) wherein Peptide 1, and Peptide 2 are selected from any peptide disclosed herein.
[00183] In some embodiments, the linker is an artificial amino acid. In some embodiments, the linker is a (3-amino acid. In some embodiments, the linker is a y-amino acid.
[00184] In some embodiments, the linker is a polyethylene glycol (PEG). In some embodiments, the linker is a diamino acid. In some embodiments, the linker is diaminopropionic acid.
[00185] In some embodiments, the linker is hydrolyzible.
[00186] By way of non-limiting example, the fusion peptide is:
O H
O Peptide 1, ~--~ NPeptide 2 H N N, Peptide 2 Peptide1v H
Peptide 3' NH
0 Peptide 1 Peptide 1 I \N HN O
/ ,Peptide 2 HNUN'Peptide 2 H I H
Peptide 3 H
Peptide 1' TO H
Peptide 1 I" N, N-Peptide 2 Peptide 3 NzzN O 0 HN,Peptide 2 Peptide 1, NH
O H
N, N,Peptide 2 Peptide 1 Peptide 2 H
HN
Peptide 3 O O Peptide 1 O
Peptide 1, Peptide 2 HN N N' H / H Peptide 2 HN N' H
HN 0 Peptide 3 Peptide 3 O O Peptide 1 Peptide 1, Peptide 2 HN N N' H
H H HN N, Peptide 2 Peptide 3'NH Peptide 3 H H Peptide 1 O
Peptide 1'N N, Peptide 2 HN
HN N' Peptide 2 NH I O
Peptide 3' Peptide 3 wherein Peptide 1, Peptide 2, and Peptide 3 are selected from any peptide disclosed herein.
E. MIF Trimerization Modulating Agents [00187] In some embodiments, 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.
[00188] In certain instances, functionally-active (or, mature) MIF comprises three MIF peptide sequences (i.e., a trimer). In certain instances, the pseudo ELR motif/domains of each MIF
polypeptide form a ring in the trimer. In certain instances, the N-loop motifs/domains of each MIF
polypeptide extend outwards from the pseudo-ELR ring (see Figure 1).
[00189] In certain instances, residues 38-44 of one subunit interact with residues 48-50 of a second subunit. In certain instances, residues 96-102 of one subunit interact with residues 107-109 of a second subunit. In certain instances, a motif/domain on one subunit formed by C81 (numbering includes the first methionine) interacts with N110 Sill T112 (numbering includes the first methionine) of a second subunit.
[00190] In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, a MIF trimerization disrupting agent is a peptide derived from and/or incorporates any or all of amino acid residues N110, S111, and T112 of MIF (e.g., human, bovine, procine, murine, or rat) (numbering includes the first methionine).
[00191] In some embodiments, 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). In some embodiments, a MIF trimerization disrupting agent is a peptide of Formula (VII):
Xl -XZ-X3-X4-X5-X6-X7-S/A-I-G
wherein:
X' is selected from the group consisting of cysteine, alanine, serine, and threonine;
x2 is selected from the group consisting of alanine, proline, glycine and cysteine;
X3 is selected from the group consisting of leucine, valine and pheynylalanine;
X4 is selected from the group consisting of cysteine, glycine, threonine and isoleucine;
X5 is selected from the group consisting of serine, valine, glutamine and asparagine;
X6 is selected from the group consisting of leucine, valine, isoleucine and methionine; and X7 is selected from the group consisting of histidine, cysteine, lysine, arginine, and leucine.
[00192] In some embodiments, the MIF trimerization disrupting agent comprises 3 or more consecutive amino acids of human MIF57-66- In some embodiments, the MIF
trimerization disrupting agent comprises 3 or more consecutive amino acids of murine MIF57-66- In some embodiments, the MIF trimerization disrupting agent comprises 3 or more consecutive amino acids of porcine MIF57_ 66= In some embodiments, the MIF trimerization disrupting agent comprises 3 or more consecutive amino acids of bovine MIF57-66- In some embodiments, the MIF trimerization disrupting agent comprises 3 or more consecutive amino acids of rat MIF57-66=
[00193] In some embodiments, 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. In some embodiments, 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 N 110, S 111, and T 112 of MIF.
[00194] In some embodiments, 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 embodiments, 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 embodiments, 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 N110, S111, and T112 of MIF.
[00195] In some embodiments, 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. In some embodiments, 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 N110, S111, and T112 of MIF.
F. Peptide Mimetics [00196] In some embodiments, a peptide mimetic is used in place of the peptides described herein, including for use in the treatment or prevention of an inflammatory disorder.
[00197] Peptide mimetics (and peptide-based inhibitors) are developed using, for example, computerized molecular modeling. Peptide mimetics are designed to include structures having one or more peptide linkages optionally replaced by a linkage selected from the group consisting of. -CH2NH-, -CH2S-, -CH2 -CH2 -, -CH=CH-(cis and trans), -CH=CF-(trans), -CoCH2 -, -CH(OH)CH2 -, and -CH2SO-, by methods well known in the art. In some embodiments 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. In some embodiments 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. In some embodiments, systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) are used to generate more stable peptides with desired properties.
[00198] 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, U55,733,731; 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). In such libraries, random peptide sequences are displayed by fusion with coat proteins of filamentous phage. Typically, the displayed peptides are affinity-eluted against an antibody-immobilized extracellular motif/domain (in this case PF4 or RANTES. In some embodiments peptide mimetics are isolated by biopanning (Nowakowski, G.S, et al. (2004) Stem Cells 22:1030-1038). In some embodiments 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. In some embodiments mutagenesis libraries are created and screened to further optimize the sequence of the best binders.
Lowman (1997) Ann.Rev.Biophys.Biomol.Struct. 26:401-24.
[00199] In some embodiments structural analysis of protein-protein interaction is used to suggest peptides that competitiveky bind with a binding partners of polypeptides described herein. In some embodiments 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.
[00200] In some embodiments, the agent is a peptide or polypeptide. In some embodiments, 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. 11);
a peptide that competitively binds with a binding partner of VNTNVPPRASVPDGFLSELTQQLAQATGKPPQYIAVHVVPDQLMAFGGSSEPCALCSL
(SEQ ID No. 12); a peptide that competitively binds with a binding partner of PDQLMAFGGSSEPCALCSLHSI (SEQ ID No. 13); or combinations thereof.
G. Antibodies [00201] In some embodiments, 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. In some embodiments, 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. In some embodiments, an inflammatory disease, disorder, condition, or symptom is treated by administering to an individual in need an antibody that binds to CD44. In some embodiments, an inflammatory disease, disorder, condition, or symptom is treated by administering to an individual in need an antibody that binds to CD74. In some embodiments, 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.
[00202] In some embodiments, the antibody is a human antibody or a humanized antibody. In some embodiments, the antibody is a human IgG. In some embodiments, the antibody is or comprises one or more polypeptides derived from a human IgGI, IgG4, IgG2, IgD, IgA or IgM.
An antibody disclosed herein is generated by any suitable method.
Antigen-Based Antibody Development [00203] In some embodiments, an antibody disclosed herein is generated by contacting a host (e.g., a mouse or rabbit) with an antigen. In some embodiments, the antigen is a MIF
monomer. In some embodiments, the antigen is a MIF trimer. In some embodiments, the antigen is a fragment of a full-length MIF polypeptide. In some embodiments, the antigen is a polypeptide that encompasses all or part of MIF50-65. In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF N-terminal/pseudo-ELR motif/domain (MIF1-17). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF alpha-helix #1 motif/domain (i.e., MIF18-31). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF N-loop motif/domain (i.e., MIF32_60). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF loop-barrel-loop motif/domain (i.e., MIF64-93)= In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF C-terminal motif/domain (i.e., MIF90_114). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF N-terminal tail (i.e., M1F1_7). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF pseudo ELR-loop (i.e., MIF7_17). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF PPQ-loop (i.e., MIF32-38)= In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF PDQ-loop (i.e., MIF43_56). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF
IGK-loop (i.e., MIF64_71). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF NRS-helix (i.e., MIF72_89). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF SPDR-loop (i.e., MIF90_94). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF C-terminal tail (i.e., M1F1o1-114).
[00204] In some embodiments, an antibody disclosed herein is generated by contacting a host (e.g., a mouse or rabbit) with at least two antigens. In some embodiments, 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 encompasses all or part of the MIF PDQ-loop; a polypeptide that encompasses all or part of the MIF IGK loop; a polypeptide that encompasses all or part of the MIF NRS helix; a polypeptide that encompasses all or part of the MIF SPDR loop; a polypeptide that encompasses all or part of the C-terminal tail; a polypeptide that encompasses all or part of MIF50-65=
[00205] In some embodiments, an antibody disclosed herein is generated by contacting a host (e.g., a mouse or rabbit) with at least three antigens. In some embodiments, 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 encompasses all or part of the MIF PDQ-loop; a polypeptide that encompasses all or part of the MIF IGK loop; a polypeptide that encompasses all or part of the MIF NRS helix; a polypeptide that encompasses all or part of the MIF SPDR loop; a polypeptide that encompasses all or part of the C-terminal tail; and a polypeptide that encompasses all or part of MIF50-65=
DNA-Based Antibody Development [00206] In some embodiments, 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").
[00207] In some embodiments, the MIF nucleic acid sequence has been cloned into an expression vector (e.g., a plasmid).
[00208] In some embodiments, 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.
[00209] In some embodiments, 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.
[00210] In some embodiments, 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. In some embodiments, the expressed MIF polypeptide is cysteinylated. In some embodiments, the expressed MIF polypeptide is phosphorylated. In some embodiments, the expressed MIF
polypeptide is glycosylated.
[00211] In some embodiments, a method of generating an antibody disclosed herein further comprises contacting the host with an adjuvant. In some embodiments, the adjuvant is administered as a nucleic acid sequence. In some embodiments, the adjuvant is administered as a polypeptide or polysaccharide. In some embodiments, the adjuvant is a cytokine, a lymphokine, or a combination thereof. In some embodiments, the adjuvant is an interleukin, a tumor necrosis factor, GM-CSF, or a combination thereof. In some embodiments, the adjuvant is B7-1, B7-2, CD40L, or a combination thereof. In some embodiments, the expression vector containing the MIF nucleic acid sequence further comprises a nucleic acid sequence encoding an adjuvant. In some embodiments, the host is contacted with a second expression vector encoding an adjuvant.
[00212] In some embodiments, the nucleic acid sequence encodes the MIF N-terminal tail/pseudo-ELR motif. In some embodiments, the nucleic acid sequence encodes MIF50-65. In some embodiments, 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., CCCATGTTCATCGTGAACACC). In some embodiments, 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., AAGCCCCCTCAGTATATCGCC). In some embodiments, the nucleic acid sequence encodes the MIF PDQ loop (i.e., CCCGACCAGCTGATGGCCTTCGGCGGCAGCAGCGAGCCTTGC). In some embodiments, the nucleic acid sequence encodes the MIF IGK-loop (i.e., ATCGGCAAGATCGGCGGAGCCCAG). In some embodiments, the nucleic acid sequence encodes the MIF NRS-helix (i.e., AACAGAAGCTACAGCAAGCTGCTGTGCGGCCTGCTGGCCGAGAGACTGAGAATC). In some embodiments, the nucleic acid sequence encodes the SPDR loop (i.e., AGCCCCGACAGAGTGTACATCAACTACTACGAC). In some embodiments, the nucleic acid sequence encodes the C-terminal tail (i.e., ATGAACGCCGCCAACGTGGGCTGGAACAACAGCACCTTCGCC).
[00213] In some embodiments, 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 MIF50-65. In some embodiments, 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 MIF50-65=
[00214] In some embodiments, 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 MIF50-65. In some embodiments, 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 MIF50-65==
Production of Antibodies [00215] In some embodiments, an antibody disclosed herein is produced via the use of a hybridoma.
As used herein, a "hybridoma" is an immortalized antibody producing cell. In some embodiments, a host (e.g., a mouse or a rabbit) is inoculated with an antigen or a nucleic acid. In some embodiments, B-cells from the host's spleen are extracted. In some embodiments, 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). In some embodiments, 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).
[00216] In some embodiments, the culture comprises a plurality of hybridoma, a plurality of myeloma cells, and a plurality of B-cells. In some embodiments, the cells are individual to culturing conditions that select for hybridoma (e.g., culturing with HAT media).
[00217] In some embodiments, an individual hybridoma (i.e., the clone) is isolated and cultured. In some embodiments, the hybridoma are injected into a laboratory animal. In some embodiments, the hybridoma are cultured in a cell culture.
Humanized Antibodies [00218] In some embodiments, the methods described herein comprise a humanized monoclonal antibody. In some embodiments, a humanized monoclonal antibody comprises heavy and light chain constant regions from a human source and variable regions from a murine source.
[00219] In some embodiments, humanized immunoglobulins, including humanized antibodies, are constructed by genetic engineering. In some embodiments, 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. In some embodiments, 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.
[00220] In some embodiments, 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 Identification Resource or the protein sequence database of the National Center for Biotechnology Information - NCBI) shows that the extent of homology to different human regions can vary greatly, for example from about 40% to about 60%, about 70%, about 80%, or higher. By choosing as the acceptor immunoglobulin one of the human heavy chain variable regions that is most homologous to the heavy chain variable region of the donor immunoglobulin, fewer amino acids will be changed in going from the donor immunoglobulin to the humanized immunoglobulin. By choosing as the acceptor immunoglobulin one of the human light chain variable regions that is most homologous to the light chain variable region of the donor immunoglobulin, fewer amino acids will be changed in going from the donor immunoglobulin to the humanized immunoglobulin.
[00221] In some embodiments, a humanized immunoglobulin comprises light and heavy chains from the same human antibody as acceptor sequences. In some embodiments, a humanized 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). In some embodiments, 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. In some embodiments, 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.
[00222] Any suitable method of modifying a framework region is contemplated herein. In some embodiments, the relevant framework amino acids to change are selected based on differences in amino acid framework residues between the donor and acceptor molecules. In some embodiments, 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). In some embodiments, 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). In some embodiments, 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.
[00223] In some embodiments, 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. In some embodiments, altered framework or CDR sequences are individually made and tested, or are sequentially or simultaneously combined and tested.
[00224] In some embodiments, 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.
[00225] In some embodiments, the humanized antibody sequence is cloned into a vector. In some embodiments, any suitable vector is used. In some embodiments, the vector is a plasmid, viral e.g.
`phage, or phagemid, as appropriate. For further details see, for example, Molecular Cloning: a Laboratory Manual: 2nd edition, Sambrook et al., 1989, Cold Spring Harbor Laboratory Press.
Many known techniques and protocols for manipulation of nucleic acid, for example in preparation of nucleic acid constructs, mutagenesis, sequencing, introduction of DNA into cells and gene expression, and analysis of proteins, are described in detail in Short Protocols in Molecular Biology, Second Edition, Ausubel et al. eds., John Wiley & Sons, 1992. The disclosures of Sambrook et al.
and Ausubel et al. are incorporated herein by reference for such disclosure.
[00226] In some embodiments, any suitable host cell is transformed with the vector expressing the humanized antibody sequence. In some embodiments, 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 Pliickthun, A.
Bio/Technology 9: 545-551 (1991). Expression in eukaryotic cells in culture is also available to those skilled in the art as an option for production of the antibodies and antigen-binding fragments described herein, see for recent reviews, for example Raff, M.E. (1993) Curr.
Opinion Biotech. 4:
573-576; Trill J.J. et al. (1995) Curr. Opinion Biotech 6: 553-560, each of which is which is incorporated herein by reference for such disclosure.
[00227] In some embodiments, a mammalian expression system is used. In some embodiments, the mammalian expression system is dehydrofolate reductase deficient ("dhfr- ") Chinese hamster ovary cells. In some embodiments, dhfr- CHO cells are transfected with an expression vector containing a functional DHFR gene, together with a gene that encodes a desired humanized antibody.
(SEQ ID No. 103) No. 151) GSSEPCA (SEQ ID No. 56) cyclo(MAFGGSSEPCA) (SEQ cyclo(CGSSEPCALC) (SEQ
ID No. 104) ID No. 152) GSSEPC (SEQ ID No. 57) cyclo(MAFGGSSEPC) (SEQ cyclo(CAFGGSSEPCAC) ID No. 105) (SEQ ID No. 153) SSEPCALC (SEQ ID No. 58) cyclo(MAFGGSSEP) (SEQ ID cyclo(CLMAFGGSSEPCALC) No. 106) (SEQ ID No. 154) SSEPCAL (SEQ ID No. 59) cyclo(MAFGGSSE) (SEQ ID cyclo(CAFGGSSC) (SEQ ID
No. 107) No. 155) SSEPCA (SEQ ID No. 60) cyclo(MAFGGSS) (SEQ ID No. VVPDQLMAFG (SEQ ID No.
108) 461) SEPCALC (SEQ ID No. 61) cyclo(MAFGGS) (SEQ ID No. DQLMAFGGSSEPC (SEQ ID
109) NO. 462) Table 1 [00121] In some embodiments, the peptide is cyclic: CLMAFGGSSEPC (SEQ ID No.
422);
CLMAFGGSSEPCALC (SEQ ID No. 423); CGLMAFGGSSEPGC (SEQ ID NO. 424);
CGGLMAFGGSSEPGGC (SEQ ID NO. 425); CGGSLMAFGGSSEPSGGC (SEQ ID NO. 426);
CGGSGLMAFGGSSEPGSGGC (SEQ ID NO. 427); CGGSGGLMAFGGSSEPGGSGGC (SEQ ID
NO. 428); CLMAFGGSSEP[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); or cyclic CLMAFGGSSEPSALC (SEQ ID NO. 469).
[00122] In some embodiments, 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).
[00123] In some embodiments, 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 L-cyclohexylalanine; LMA[D-CA]AFGGSSEPC[D-CA] (SEQ ID NO. 432), wherein D-CA
is D-cyclohexylalanine; LMA[D-F]AFGGSSEPC[D-F] (SEQ ID NO. 433), wherein D-F is D-phenylalanine; (D)-MAFGGSSEPC (SEQ ID NO. 434); (D)-CPESSGGFAML (SEQ ID NO.
435);
(L)-CPESSGGFAML (SEQ ID NO. 436); CLMAFGGSSEPCACG (SEQ ID NO. 452);
CLMAFGGSSEPCCGG (SEQ ID NO. 453); CLMAFGGSSEPCGGG (SEQ ID NO. 454);
CLMAFGGSSECGGGG (SEQ ID NO. 455); CLMAFGGSSCGGGGG (SEQ ID NO. 456);
CLMAFGGSCGGGGG (SEQ ID NO. 457); CLMAFGGCGGGGGGG (SEQ ID NO. 458);
CLMAFGCGGGGGGGG (SEQ ID NO. 459); or CLMAFGGSSEPCALG (SEQ ID NO. 460).
[00124] In some embodiments, a peptide disclosed herein competitively binds with a binding partner of of MIF40_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 MIF42-51 (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 MIF45.57 (i.e., the peptide has the sequence DQLMAFGGSSEPC (SEQ ID NO. 467)). In some embodiments, a peptide disclosed herein competitively binds with a binding partner of MIF46-55 (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).
[00125] In some embodiments, the peptide comprises the sequence of Formula (II):
XI-X2-T/S-N-X3-X4-X5-X6-X7-Xg-P/S-X9-Xl wherein:
X1 is selected from the group consisting of valine, isoleucine, threonine, phenylalanine and leucine;
x2 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;
X4 is selected from the group proline, alanine, cysteine and leucine;
X5 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;
X7 is selected from the group serine, glutamic acid, aspartic acid, asparagine, arginine, glycine, lysine and arginine;
X8 is selected from the group valine, isoleucine and phenylalanine;
X9 is selected from the group aspartic acid, glutamic acid, valine, serine and threonine; and X10 is selected from the group glycine, alanine, threonine, aspartic acid and glutamic acid.
[00126] In some embodiments, X1 is valine. In some embodiments, X2 is asparagine. In some embodiments, X3 is valine. In some embodiments, X4 is proline. In some embodiments, X5 is arginine. In some embodiments, X6 is alanine. In some embodiments, X7 is serine. In some embodiments, X8 is valine. In some embodiments, X9 is aspartic acid. In some embodiments, X10 is glycine.
[00127] In some embodiments, the Peptide comprises 3 or more consecutive amino acids of human MIF1_45 (numbering includes the first methionine). In some embodiments, the Peptide comprises 3 or more consecutive amino acids of murine MIF1_45. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of porcine MIF1-45. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of bovine M1F1_45. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of rat MIF1-45.
[00128] In some embodiments, 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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
CTNVPRASVPDGC (SEQ ID No. 156) NVPRASVPD (SEQ ID No. 173) CVPRASC (SEQ ID No. 157) NVPRASVP (SEQ ID No. 174) VNTNVPRASVPDGFLSEL (SEQ ID No. VPRASVP (SEQ ID No. 175) 158) NTNVPRASVPDGFLSEL (SEQ ID No. PRASVP (SEQ ID No. 176) 159) TNVPRASVPDGFLSEL (SEQ ID No. 160) VPRASVPDGFL (SEQ ID No. 177) NVPRASVPDGFLSEL (SEQ ID No. 161) VPRASVPDGF (SEQ ID No. 178) VPRASVPDGFLSEL (SEQ ID No. 162) VPRASVPDG (SEQ ID No. 179) PRASVPDGFLSEL (SEQ ID No. 163) VPRASVPD (SEQ ID No. 180) RASVPDGFLSEL (SEQ ID No. 164) VPRASVP (SEQ ID No. 181) ASVPDGFLSEL (SEQ ID No. 165) VPRAS (SEQ ID No. 182) SVPDGFLSEL (SEQ ID No. 166) MPMFIVNTNVPRASVPDGFLSEC (SEQ
ID No. 183) VPDGFLSEL (SEQ ID No. 167) MPMFIVNTNVPRASV (SEQ ID No. 184) NVPRASVPDGFLSE (SEQ ID No. 168) FIVNTNVPRASVPDG (SEQ ID No. 185) NVPRASVPDGFLS (SEQ ID No. 169) NTNVPRASVPDGFLS (SEQ ID No. 186) NVPRASVPDGFL (SEQ ID No. 170) VPRASVPDGFLSELT (SEQ ID No. 187) NVPRASVPDGF (SEQ ID No. 171) PRASVPDG (SEQ ID NO. 436) NVPRASVPDG (SEQ ID No. 172) VNTNVPRASVPDG (SEQ ID NO. 437) Table 2 [00129] In some embodiments, Peptide is cyclic: CPRASVPDGC (SEQ ID NO. 438), CGGSGGPRASVPDGGGSGGC (SEQ ID NO. 439); or CNVPRASVPDGC (SEQ ID NO. 440).
[00130] In some embodiments, the Peptide adopts structural or functional features similar to the amino acid residues 65-94 (numbering includes the first methionine). In some embodiments, the Peptide comprises a peptide of Formula (III):
I/L-G-Xl-X2-X3-X4-Xs-X6-N-X7-Xs-X9-X10-Xl1-X12-L/I-X13-X14-X'5-X16-X'7-X'8-X19-wherein:
X1 is selected from the group consisting of lysine, arginine, cysteine, serine and alanine;
X2 is selected from the group consisting of isoleucine, valine and phenylalanine;
X3 is selected from the group consisting of glycine, asparagine and serine;
X4 is selected from the group consisting of glycine, proline, alanine, aspartic acid and glutamic acid;
X5 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;
X7 is selected from the group consisting of lysine, arginine, asparagine, isoleucine and valine;
X8 is selected from the group consisting of serine, asparagine, glutamine, aspartic acid, glutamic acid, lysine and arginine;
X9 is selected from the group consisting of tyrosine, histidine and asparagine;
X10 is selected from the group consisting of serine, threonine and alanine;
X11 is selected from the group consisting of lysine, aspartic acid, glutamic acid, alanine, serine and glycine;
X12 is selected from the group consisting of leucine, glutamine, lysine, arginine, leucine, serine and alanine;
X13 is selected from the group consisting of cysteine, tyrosine, phenylalanine, serine, alanine and threonine;
X14 is selected from the group consisting of glycine, aspartic acid, glutamic acid, lysine and arginine;
X15 is selected from the group consisting of leucine, glutamine, isoleucine, histidine and phenylalanine;
X16 is selected from the group consisting of leucine, methionine, isoleucine and cysteine;
X17 is selected from the group consisting of alanine, threonine, serine, arginine, lysine, alanine, glutamine and glycine;
X'8 is selected from the group consisting of glutamic acid, aspartic acid, lysine and arginine;
X19 is selected from the group consisting of arginine, histidine, glutamine, aspartic acid, glutamic acid, glycine, threonine and lysine;
X20 is selected from the group consisting of arginine, histidine, glycine, asparagine, lysine, arginine, aspartic acid and glutamic acid;
X21 is selected from the group consisting of serine, aspartic acid, glutamic acid, lysine, arginine and proline;
X22 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.
[00131] In some embodiments, X1 is lysine. In some embodiments, X2 is isoleucine. In some embodiments, X3 is glycine. In some embodiments, X4 is glycine. In some embodiments, X5 is alanine. In some embodiments, X6 is glutamine. In some embodiments, X7 is arginine. In some embodiments, X8 is serine. In some embodiments, X9 is tyrosine. In some embodiments, X10 is serine. In some embodiments, X11 is lysine. In some embodiments, X12 is leucine. In some embodiments, X13 is cysteine. In some embodiments, X14 is glycine. In some embodiments, X15 is leucine. In some embodiments, X16 is leucine. In some embodiments, X17 is alanine. In some embodiments, X'8 is glutamic acid. In some embodiments, X19 is arginine. In some embodiments, X20 is arginine. In some embodiments, X21 is serine. In some embodiments, X22 is proline. In some embodiments, X23 is aspartic acid. In some embodiments, X24 is arginine.
[00132] In some embodiments, the Peptide comprises 3 or more consecutive amino acids of human MIF65-94. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of murine MIF65-94. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of porcine MIF65-94. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of bovine MIF65-94. In some embodiments, the Peptide comprises 3 or more consecutive amino acids of rat MIF65-94=
[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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
CSLHSIGKIGGAQNR (SEQ ID IAVHVVPDQLMAFGGSSEPCALCSLHSIGKIGGAQNRSYSKLL
No. 188) (SEQ ID No. 218) IGKIGGAQNRSYSKL (SEQ ID IAVHVVPDQLMAFGGSSEPCALCSLHSIGKIGGAQNRSY (SEQ
No. 189) ID No. 219) HSIGKIGGAQNRSYSKLLCGLL IAVHVVPDQLMAFGGSSEPCALCSLHSIGKIGGAQ (SEQ ID
(SEQ ID No. 190) No. 220) HSIGKIGGAQNRSYSKLLCG IAVHVVPDQLMAFGGSSEPCALCSLHSIGKI (SEQ ID No. 221) (SEQ ID No. 191) HSIGKIGGAQNRSYSKLL (SEQ IAVHVVPDQLMAFGGSSEPCALCSLHS (SEQ ID No. 222) ID No. 192) HSIGKIGGAQNRSYSK (SEQ ID IAVHVVPDQLMAFGGSSEPCALC (SEQ ID No. 223) No. 193) HSIGKIGGAQNRSYS (SEQ ID IAVHVVPDQLMAFGGSSEP (SEQ ID No. 224) No. 194) IGKIGGAQNRSYSKLLC (SEQ IAVHVVPDQLMAFGG (SEQ ID No. 225) ID No. 195) KIGGAQNRSYSKLLC (SEQ ID IAVHVVPDQLM (SEQ ID No. 226) No. 196) GGAQNRSYSKLLCGLLAERLRI IAVHVVPDQLMAFGGSSEPCALCSLHSIGKIGGAQNRSYSKLL
(SEQ ID No. 197) (SEQ ID No. 227) AQNRSYSKLLCGLLAERLRI VVPDQLMAFGGSSEPCALCSLHSIGKIGGAQNRSYSKLL (SEQ
(SEQ ID No. 198) ID No. 228) NRSYSKLLCGLLAERLRI (SEQ QLMAFGGSSEPCALCSLHSIGKIGGAQNRSYSKLL (SEQ ID
ID No. 199) No. 229) SYSKLLCGLLAERLRI (SEQ ID FGGSSEPCALCSLHSIGKIGGAQNRSYSKLL (SEQ ID No. 230) No. 200) YSKLLCGLLAERLRI (SEQ ID SEPCALCSLHSIGKIGGAQNRSYSKLL (SEQ ID No. 231) No. 201) GAQNRSYSKLLCGLLAE (SEQ ALCSLHSIGKIGGAQNRSYSKLL (SEQ ID No. 232) ID No. 202) GAQNRSYSKLLCGLL (SEQ ID LHSIGKIGGAQNRSYSKLL (SEQ ID No. 233) No. 203) QNRSYSKLLCGLLAE (SEQ ID GKIGGAQNRSYSKLL (SEQ ID No. 234) No. 204) HSIGKIGGAQNRSY (SEQ ID IGGAQNRSYSKLL (SEQ ID No. 235) No. 205) HSIGKIGGAQNR (SEQ ID No. QNRSYSKLL (SEQ ID No. 236) 206) HSIGKIGGAQNRSYSK (SEQ ID IGKIGGAQNRSYSKL (SEQ ID No. 237) No. 207) IGKIGGAQNRSYSKLLC (SEQ IGKIGGAQ (SEQ ID No. 238) ID No. 208) KIGGAQNRSYSKLLC (SEQ ID linear (CIGKIGGAQC) (SEQ ID No. 239) No. 209) KIGGAQNRSYS (SEQ ID No. cyclo (CIGKIGGAQC) (SEQ ID No. 240) 210) GAQNRSYSKLLCGLLAE (SEQ RSYSKLLCGLLAE (SEQ ID No. 241) ID No. 211) GAQNRSYSKLLCGLL (SEQ ID linear (CRSYSKLLCGLLAEC) (SEQ ID No. 242) No. 212) GAQNRSYSKLLCG (SEQ ID No. cyclo (CRSYSKLLCGLLAEC) (SEQ ID No. 243) 213) GAQNRSYSKLL (SEQ ID No. CGLLAERLRISPDR (SEQ ID No. 244) 214) QNRSYSKLLCGLLAE (SEQ ID linear(CGLLAERLRISPDRC) (SEQ ID No. 245) No. 215) RSYSKLLCGLLAE (SEQ ID No. Cyclo (CGLLAERLRISPDRC) (SEQ ID No. 246) 216) YSKLLCGLLAE (SEQ ID No. VHVVPDQLMA (SEQ ID No. 421) 217) Table 3 [00134] In some embodiments, Peptide is: CVHVVPDQLMAC (SEQ ID NO. 451).
CD74 Mimics [00135] CD74 is transmembrane protein that binds MIF. In some embodiments, CD74 is a receptor for MIF. In some embodiments, 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. 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 CD74 to CXCR2, CXCR4, MIF, CD44.
[00136] In some embodiments, 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). In some embodiments, the peptide competitively binds with MIF, CD44, CXCR2, and/or CXCR4 and thus prevents CD74 from binding to MIF, CD44, CXCR2, and/or CXCR4.
[00137] In some embodiments, the peptide- adopts structural or functional features similar to CD74.
[00138] In some embodiments, 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.
[00139] In some embodiments, 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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
AYFLYQQQ (SEQ ID NO. 247) TKYGNMTEDHVMHLL (SEQ ID NO. 280) QQQGRLDKLTVTGRL (SEQ ID NO. 248) HVMHLLQNADPLKVY (SEQ ID NO. 281) GRLDKLTVTSQNLQL (SEQ ID NO. 249) DPLKVYPPLKGSFPE (SEQ ID NO. 282) SQNLQLENLRM (SEQ ID NO. 250) KGSFPENLRHLKNTM (SEQ ID NO. 283) TVTGRLDKLTVTSQN (SEQ ID NO. 251) HLKNTMETIDWKVFE (SEQ ID NO. 284) TVTSQNLQLENLRM (SEQ ID NO. 252) DWKVFESWMHHWLLF (SEQ ID NO. 285) LENLRMKLPKPPKPV (SEQ ID NO. 253) HHWLLFEMSRHSLEQ (SEQ ID NO. 286) KLPKPPKPVSKMRMA (SEQ ID NO. 254) RHSLEQKPTDAPPKE (SEQ ID NO. 287) SKMRMATPL (SEQ ID NO. 255) DAPPKESLELEDPSS (SEQ ID NO. 288) LMQALPMGALPQGPM (SEQ ID NO. 256) LEDPSSGLGVTKQDL (SEQ ID NO. 289) LPQGPMQNATKYGNM (SEQ ID NO. 257) SGLGVTKQDLGPVPM (SEQ ID NO. 290) TKYGNMTEDHVMHLL (SEQ ID NO. 258) MDDQRDLISNHEQLP (SEQ ID NO. 291) HVMHLLQNADPLKVY (SEQ ID NO. 259) LPILGNRPREPERCS (SEQ ID NO. 292) DPLKVYPPLKGSFPE (SEQ ID NO. 260) CSRGALYTGVSVLVA (SEQ ID NO. 293) KGSFPENLRHLKNTM (SEQ ID NO. 261) VSVLVALLLAGQATT (SEQ ID NO. 294) HLKNTMETIDWKVFE (SEQ ID NO. 262) AYFLYQQQGRLDKLT (SEQ ID NO. 295) DWKVFESWMHHWLLF (SEQ ID NO. 263) LTITSQNLQLESLRM (SEQ ID NO. 296) HHWLLFEMSRHSLEQ (SEQ ID NO. 264) RMKLPKSAKPVSQMR (SEQ ID NO. 297) RHSLEQKPTDAPPKE (SEQ ID NO. 265) MRMATPLLMRPMSMD (SEQ ID NO. 298) DAPPKESLELEDPSS (SEQ ID NO. 266) MDNMLLGPVKNVTKY (SEQ ID NO. 299) LEDPSSGLGVTKQDL (SEQ ID NO. 267) KYGNMTQDHVMHLLT (SEQ ID NO. 300) VTKQDLGPVPM (SEQ ID NO. 268) RSGPLEYPQLKGTFP (SEQ ID NO. 301) MDDQRDLISNNEQLP (SEQ ID NO. 269) FPENLKHLKNSMDGV (SEQ ID NO. 302) LPMLGRRPGAPESKC (SEQ ID NO. 270) GVNWKIFESWMKQWL (SEQ ID NO. 303) CSRGALYTGFSILVT (SEQ ID NO. 271) WLLFEMSKNSLEEKK (SEQ ID NO. 304) FSILVTLLLAGQATT (SEQ ID NO. 272) EKKPTEAPPKVLTKC (SEQ ID NO. 305) AYFLYQQQGRLDKLT (SEQ ID NO. 273) CQEEVSHIPAVYPGA (SEQ ID NO. 306) GRLDKLTVTSQNLQL (SEQ ID NO. 274) GAFRPKCDENGNYLP (SEQ ID NO. 307) SQNLQLENLRMKLPK (SEQ ID NO. 275) LPLQCHGSTGYCWCV (SEQ ID NO. 308) KLPKPPKPVSKMRMA (SEQ ID NO. 276) CVFPNGTEVPHTKSR (SEQ ID NO. 309) SKMRMATPLLMQALP (SEQ ID NO. 277) SRGRHNCSEPLDMED (SEQ ID NO. 310) LMQALPMGALPQGPM (SEQ ID NO. 278) EDLSSGLGVTRQELG (SEQ ID NO. 311) LPQGPMQNATKYGNM (SEQ ID NO. 279) SGLGVTRQELGQVTL (SEQ ID NO. 312) Table 4 CXCR2/CXCR4 Mimics [00140] In some embodiments, 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. 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 CXCR2 to CXCR4, MIF, CD44, CD74 or a combination thereof. In some embodiments, 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. 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 CXCR4 to CXCR2, MIF, CD44, CD74 or a combination thereof.
[00141] In some embodiments, a peptide disclosed herein competitively binds with a binding partner of a CXCR2 domain/motif. In some embodiments, 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. In some embodiments, the peptide binds to MIF, CD74 and/or CD44 and thus prevents CXCR2 from binding to MIF, CD74 and/or CD44.
[00142] In some embodiments, a peptide disclosed herein competitively binds with a binding partner of the CXCR2 extracellular loop 1 (i.e., CXCR2108 120), the extracellular loop 2 (i.e., CXCR2184-212), and/or the extracellular loop 3 (i.e., CXCR2286-300)= In some embodiments, a peptide disclosed herein competitively binds with a binding partner of the extracellular loop 2 (i.e., CXCR2184-212), and/or CXCR2 extracellular loop 3 (i.e., CXCR2286-300)= In some embodiments, 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., CXCR2108-120), the extracellular loop 2 (i.e., CXCR2184-212), and/or the extracellular loop 3 (i.e., CXCR2286-300). In some embodiments, 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., CXCR2i84-212), and/or CXCR2 extracellular loop 3 (i.e., CXCR2286-300)=
[00143] In some embodiments, a peptide disclosed herein competitively binds with a binding partner of CXCR2 N-terminus/domain (i.e., CXCR21-39). In some embodiments, 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., CXCR21-39).
[00144] In some embodiments, 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 CXCR4 motif/domain. In some embodiments, 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. In some embodiments, 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). In some embodiments, 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 (DDRYICDRFYPNDLW). In some embodiments, the peptide binds to MIF, CD74 and/or CD44 and thus prevents CXCR4 from binding to MIF, CD74 and/or CD44.
[00145] In some embodiments, 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.
[00146] In some embodiments, 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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
DLSNYSYSSTLPPFL (SEQ ID NO. 313) MRTQVIQ (SEQ ID NO. 336) DLSNYSYSSTLPP (SEQ ID NO. 314) MRTQV (SEQ ID NO. 337) DLSNYSYSSTL (SEQ ID NO. 315) CERRNHIDRALDA (SEQ ID NO. 338) DLSNYSYSS (SEQ ID NO. 316) CERRNHIDRAL (SEQ ID NO. 339) DLSNYSY (SEQ ID NO. 317) CERRNHIDR (SEQ ID NO. 340) DLSNY (SEQ ID NO. 318) CERRNHI (SEQ ID NO. 341) KVNGWIFGTFL (SEQ ID NO. 319) CERRN (SEQ ID NO. 342) KVNGWIFGT (SEQ ID NO. 320) DRYICDRFYPNDL (SEQ ID NO. 343) KVNGWIF (SEQ ID NO. 321) DRYICDRFYPN (SEQ ID NO. 344) KVNGW (SEQ ID NO. 322) DRYICDRFY (SEQ ID NO. 345) RRTVYSSNVSPAC (SEQ ID NO. 323) DRYICDR (SEQ ID NO. 346) RRTVYSSNVSP (SEQ ID NO. 324) DRYIC (SEQ ID NO. 347) RRTVYSSNV (SEQ ID NO. 325) ICDRFYPNDLWVV (SEQ ID NO. 348) RRTVYSS (SEQ ID NO. 326) ICDRFYP (SEQ ID NO. 349) RRTVY (SEQ ID NO. 327) ICDRF (SEQ ID NO. 350) EDMGNNTANWRML (SEQ ID NO. 328) RFYPNDLWVVVFQ (SEQ ID NO. 351) EDMGNNTANWR (SEQ ID NO. 329) RFYPNDLWVVV (SEQ ID NO. 352) EDMGNNTAN (SEQ ID NO. 330) RFYPNDLWV (SEQ ID NO. 353) EDMGNNT (SEQ ID NO. 331) RFYPNDL (SEQ ID NO. 354) EDMGN (SEQ ID NO. 332) RFYPN (SEQ ID NO. 355) MRTQVIQETCERR (SEQ ID NO. 333) ICDRFYPNDLW (SEQ ID NO. 356) MRTQVIQETCE (SEQ ID NO. 334) ICDRFYPND (SEQ ID NO. 357) MRTQVIQET (SEQ ID NO. 335) Table 5 CD44 Mimics [00148] CD44 is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion and migration. In certain instances, human CD44 has the sequence:
MDKFWWHAAWGLCLVPLSLAQIDLNITCRFAGVFHVEKNGRYSISRTEA
ADLCKAFNSTLPTMAQMEKALSIGFETCRYGFIEGHVVIPRIHPNSICAAN
NTGVYILTSNTSQYDTYCFNASAPPEEDCTSVTDLPNAFDGPITITIVNRD
GTRYV QKGEYRTNPEDIYPSNPTDDDV S SGS S SERS STSGGYIFYTFSTVH
PIPDEDSPWITDSTDRIPATRDQDTFHPSGGSHTTHGSESDGHSHGSQEGG
ANTTSGPIRTPQIPEWLIILASLLALALILAVCIAVNSRRRCGQKKKLVINS
GNGAVEDRKPSGLNGEASKSQEMVHLVNKESSETPDQFMTADETRNLQ
NVDMKIGV (SEQ ID No. 358).
In certain instances, murine CD44 has the sequence:
MDKFWWHTAWGLCLLQLSLAHPHQQIDLNVTCRYAGVFHVEKNGRYSI
SRTEAADLCQAFNSTLPTMDQMKLALSKGFETCRYGFIEGNVVIPRIHPN
AICAANHTGVYILVTSNTSHYDTYCFNASAPPEEDCTSVTDLPNSFDGPV
TITIVNRDGTRYSKKGEYRTHQEDIDASNIIDDDVSSGSTIEKSTPESYILHT
YLPTEQPTGDQDDSFFIRSTLATRDRDSSKDSRGSSRTVTHGSELAGHSSA
NQDSGVTTTSGPMRRPQIPEWLIILASLLALALILAVCIAVNSRRRCGQKK
KLVINGGNGTVEDRKPSELNGEASKSQEMVHLVNKEPSETPDQCMTADE
TRNLQSVDMKIGV (SEQ ID No. 359).
[00149] In certain instances, CD44 forms a complex with CD74. In some embodiments, inhibiting the binding of CD44 and CD74 reduces or inhibits (partially or fully) inflammation. In some embodiments, inhibiting the binding of CD44 and MIF reduces or inhibits (partially or fully) inflammation.
[00150] In some embodiments, 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.
[00151] In some embodiments, 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. In some embodiments, the Peptide binds to MIF, CXCR2, CXCR4, CD74, or a combination thereof.
[00152] In some embodiments, 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.
[00153] In some embodiments, 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). In some embodiments, an amino acid of a peptide disclosed herein is substituted with a non-natural amino acid. In some embodiments, an amino acid of a peptide disclosed herein comprises N- and/or C-terminal chemical modifications to improve ADME-PK.
MDKFWWHAAWGLCLV (SEQ ID NO. 360) GVFHVEKNGRYSI (SEQ ID NO. 391) LVPLSLAQIDLNITC (SEQ ID NO. 361) SISRTEAADLCQA (SEQ ID NO. 392) CRFAGVFHVEKNGRY (SEQ ID NO. 362) QAFNSTLPTMDQM (SEQ ID NO. 393) RYSISRTEAADLCKA (SEQ ID NO. 363) QMKLALSKGFETC (SEQ ID NO. 394) KAAFNSTLPTMAQME (SEQ ID NO. 364) CRYGFIEGNVVIP (SEQ ID NO. 395) KALSIGFETCRYGFI (SEQ ID NO. 365) IPRIHPNAICAAN (SEQ ID NO. 396) FIEGHVVIPRIHPNS (SEQ ID NO. 366) ANHTGVYILVTSN (SEQ ID NO. 397) NSICAANNTGVYILT (SEQ ID NO. 367) SNTSHYDTYCFNA (SEQ ID NO. 398) LTSNTSQYDTYCFNA (SEQ ID NO. 368) NASAPPEEDCTSV (SEQ ID NO. 399) NASAPPEEDCTSVTD (SEQ ID NO. 369) SVTDLPNSFDGPV (SEQ ID NO. 400) TDLPNAFDGPITITI (SEQ ID NO. 370) PVTITIVNRDGTR (SEQ ID NO. 401) TIVNRDGTRYVQKGE (SEQ ID NO. 371) TRYSKKGEYRTHQ (SEQ ID NO. 402) GEYRTNPEDIYPSNP (SEQ ID NO. 372) HQEDIDASNIIDD (SEQ ID NO. 403) NPTDDDVSSGSSSER (SEQ ID NO. 373) DDVSSGSTIEKST (SEQ ID NO. 404) ERSSTSGGYIFYTFS (SEQ ID NO. 374) STPESYILHTYLP (SEQ ID NO. 405) FSTVHPIPDEDSPWI (SEQ ID NO. 375) LPTEQPTGDQDDS (SEQ ID NO. 406) WITDSTDRIPATRDQ (SEQ ID NO. 376) DSFFIRSTLATRD (SEQ ID NO. 407) DQDTFHPSGGSHTTH (SEQ ID NO. 377) RDRDSSKDSRGSS (SEQ ID NO. 408) THGSESDGHSHGSQE (SEQ ID NO. 378) SSRTVTHGSELAG (SEQ ID NO. 409) QEGGANTTSGPIRTP (SEQ ID NO. 379) AGHSSANQDSGVT (SEQ ID NO. 410) TPQIPEWLIILASLL (SEQ ID NO. 380) TTSGPMRRPQIPE (SEQ ID NO. 411) LLALALILAVCIAVN (SEQ ID NO. 381) PEWLIILASLLAL (SEQ ID NO. 412) VNSRRRCGQKKKLVI (SEQ ID NO. 382) ALALILAVCIAVN (SEQ ID NO. 413) VINSGNGAVEDRKPS (SEQ ID NO. 383) VNSRRRCGQKKKL (SEQ ID NO. 414) PSGLNGEASKSQEMV (SEQ ID NO. 384) KLVINGGNGTVED (SEQ ID NO. 415) MVHLVNKESSETPDQ (SEQ ID NO. 385) EDRKPSELNGEAS (SEQ ID NO. 416) DQFMTADETRNLQNV (SEQ ID NO. 386) ASKSQEMVHLVNK (SEQ ID NO. 417) DETRNLQNVDMKIGV (SEQ ID NO. 387) NKEPSETPDQCMT (SEQ ID NO. 418) MDKFWWHTAWGLC (SEQ ID NO. 388) MTADETRNLQSVD (SEQ ID NO. 419) LLQLSLAHPHQQI (SEQ ID NO. 389) TRNLQSVDMKIGV (SEQ ID NO. 420) QIDLNVTCRYAGV (SEQ ID NO. 390) Table 6 F. Fusion Peptide [00154] In some embodiments, a composition of matter disrupts the ability of MIF to bind to CXCR2, CXCR4, CD74, or a combination thereof. In some embodiments, the composition of matter is a fusion peptide that binds both the N-loop motif/domain of MIF and the pseudo-ELR
motif/domain of MIF. In some embodiments, 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. In some embodiments, 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.
[00155] In some embodiments, 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.
[00156] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
[00157] In some embodiments, 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. In some embodiments, 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.
[00158] In some embodiments, 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.
[00159] In some embodiments, the methods and compositions disclosed herein comprise (a) a first peptide having the sequence LQDP; and (b) a second peptide having the sequence NVPRA.
[00160] In some embodiments, the first peptide and the second peptide are directly bound to each other (e.g., via a covalent or ionic bond).
Linkers [00161] In some embodiments, 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). In some embodiments, 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.
[00162] In some embodiments, 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. In some embodiments, the fusion peptide is a peptide of Formula (IV):
Peptide 1 -Linker Peptide 2 Formula (IV) wherein Peptide 1, and Peptide 2 are selected from any peptide disclosed herein.
[00163] In some embodiments, 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. In some embodiments, the fusion peptide is a peptide of Formula (V):
Peptide 1 Linker Peptide 2 Peptide 3 Formula (V) wherein Peptide 1, Peptide 2, and Peptide 3 are selected from any peptide disclosed herein.
[00164] As used herein, a "linker" is any molecule capable of binding (e.g., covalently) to multiple peptides. In some embodiments, the linker binds to the peptide by a covalent linkage. In some embodiments, 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.
[00165] In some embodiments, 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.
[00166] In some embodiments, the linker binds to two peptides. In some embodiments, the linker binds to three peptides.
[00167] In some embodiments, 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.
[00168] In some embodiments, 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.
[00169] In some embodiments, the linker is an alkyl. In some embodiments, the linker is heteroalkyl.
[00170] In some embodiments, 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.
[00171] An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl moiety may be a saturated alkyl or an unsaturated alkyl. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).
[00172] 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 "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 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.
[00173] In some embodiments, the linker comprises a ring structure (e.g., an aryl). As used herein, the term "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.
[00174] As used herein, the term "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.
Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).
[00175] The term "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.
[00176] In some embodiments, the ring is a cycloalkane. In some embodiments, the ring is a cycloalkene.
[00177] In some embodiments, the ring is an aromatic ring. The term "aromatic"
refers to a planar ring having a delocalized t-electron system containing 4n+2 t 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. The term "aromatic" includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
[00178] In some embodiments, the ring is a heterocycle. The term "heterocycle"
refers to heteroaromatic and heteroalicyclic groups containing one to four heteroatoms each selected from 0, 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 0 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.
Examples of 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, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of 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, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-l-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo (=O) moieties such as pyrrolidin-2-one. Depending on the structure, a heterocycle group can be a monoradical or a diradical (i.e., a heterocyclene group).
[00179] In some embodiments, the ring is fused. The term "fused" refers to structures in which two or more rings share one or more bonds. In some embodiments, the ring is a dimer. In some embodiments, the ring is a trimer. In some embodiments, the ring is a substituted.
[00180] The term "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.
[00181] In some embodiments, 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-C6alkyl, C3-Cgcycloalkyl, aryl, heteroaryl, C2-C6heteroalicyclic, hydroxy, Ci-C6alkoxy, aryloxy, Ci-C6alkylthio, arylthio, Ci-C6alkylsulfoxide, arylsulfoxide, Ci-C6alkylsulfone, arylsulfone, cyano, halo, C2-Cgacyl, C2-Cgacyloxy, nitro, Ci-C6haloalkyl, Ci-C6fluoroalkyl, and amino, including Ci-C6alkylamino, and the protected derivatives thereof. By way of example, an optional substituents may be LSRS, wherein each Ls is independently selected from a bond, -0-, -C(=O)-, -S-, -S(=O)-, -S(=0)2-, -NH-, -NHC(=O)-, -C(=O)NH-, S(=0)2NH-, -NHS(=0)2-, -OC(=O)NH-, -NHC(=O)O-, -(Ci-C6alkyl)-, or -(C2-C6alkenyl)-; and each Rs is independently selected from H, (Ci-C4alkyl), (C3-Cgcycloalkyl), heteroaryl, aryl, and Ci-C6heteroalkyl. Optionally substituted non-aromatic groups may be substituted with one or more oxo (=O). The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art.
[00182] In some embodiments, the linker is an amino acid. In some embodiments, the fusion peptide is a peptide of Formula (VI):
O H
Peptide 1,N N,Pe Peptide 2 H p r, r2 Formula (VI) wherein Peptide 1, and Peptide 2 are selected from any peptide disclosed herein.
[00183] In some embodiments, the linker is an artificial amino acid. In some embodiments, the linker is a (3-amino acid. In some embodiments, the linker is a y-amino acid.
[00184] In some embodiments, the linker is a polyethylene glycol (PEG). In some embodiments, the linker is a diamino acid. In some embodiments, the linker is diaminopropionic acid.
[00185] In some embodiments, the linker is hydrolyzible.
[00186] By way of non-limiting example, the fusion peptide is:
O H
O Peptide 1, ~--~ NPeptide 2 H N N, Peptide 2 Peptide1v H
Peptide 3' NH
0 Peptide 1 Peptide 1 I \N HN O
/ ,Peptide 2 HNUN'Peptide 2 H I H
Peptide 3 H
Peptide 1' TO H
Peptide 1 I" N, N-Peptide 2 Peptide 3 NzzN O 0 HN,Peptide 2 Peptide 1, NH
O H
N, N,Peptide 2 Peptide 1 Peptide 2 H
HN
Peptide 3 O O Peptide 1 O
Peptide 1, Peptide 2 HN N N' H / H Peptide 2 HN N' H
HN 0 Peptide 3 Peptide 3 O O Peptide 1 Peptide 1, Peptide 2 HN N N' H
H H HN N, Peptide 2 Peptide 3'NH Peptide 3 H H Peptide 1 O
Peptide 1'N N, Peptide 2 HN
HN N' Peptide 2 NH I O
Peptide 3' Peptide 3 wherein Peptide 1, Peptide 2, and Peptide 3 are selected from any peptide disclosed herein.
E. MIF Trimerization Modulating Agents [00187] In some embodiments, 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.
[00188] In certain instances, functionally-active (or, mature) MIF comprises three MIF peptide sequences (i.e., a trimer). In certain instances, the pseudo ELR motif/domains of each MIF
polypeptide form a ring in the trimer. In certain instances, the N-loop motifs/domains of each MIF
polypeptide extend outwards from the pseudo-ELR ring (see Figure 1).
[00189] In certain instances, residues 38-44 of one subunit interact with residues 48-50 of a second subunit. In certain instances, residues 96-102 of one subunit interact with residues 107-109 of a second subunit. In certain instances, a motif/domain on one subunit formed by C81 (numbering includes the first methionine) interacts with N110 Sill T112 (numbering includes the first methionine) of a second subunit.
[00190] In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, a MIF trimerization disrupting agent is a peptide derived from and/or incorporates any or all of amino acid residues N110, S111, and T112 of MIF (e.g., human, bovine, procine, murine, or rat) (numbering includes the first methionine).
[00191] In some embodiments, 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). In some embodiments, a MIF trimerization disrupting agent is a peptide of Formula (VII):
Xl -XZ-X3-X4-X5-X6-X7-S/A-I-G
wherein:
X' is selected from the group consisting of cysteine, alanine, serine, and threonine;
x2 is selected from the group consisting of alanine, proline, glycine and cysteine;
X3 is selected from the group consisting of leucine, valine and pheynylalanine;
X4 is selected from the group consisting of cysteine, glycine, threonine and isoleucine;
X5 is selected from the group consisting of serine, valine, glutamine and asparagine;
X6 is selected from the group consisting of leucine, valine, isoleucine and methionine; and X7 is selected from the group consisting of histidine, cysteine, lysine, arginine, and leucine.
[00192] In some embodiments, the MIF trimerization disrupting agent comprises 3 or more consecutive amino acids of human MIF57-66- In some embodiments, the MIF
trimerization disrupting agent comprises 3 or more consecutive amino acids of murine MIF57-66- In some embodiments, the MIF trimerization disrupting agent comprises 3 or more consecutive amino acids of porcine MIF57_ 66= In some embodiments, the MIF trimerization disrupting agent comprises 3 or more consecutive amino acids of bovine MIF57-66- In some embodiments, the MIF trimerization disrupting agent comprises 3 or more consecutive amino acids of rat MIF57-66=
[00193] In some embodiments, 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. In some embodiments, 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 N 110, S 111, and T 112 of MIF.
[00194] In some embodiments, 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 embodiments, 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 embodiments, 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 N110, S111, and T112 of MIF.
[00195] In some embodiments, 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. In some embodiments, 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 N110, S111, and T112 of MIF.
F. Peptide Mimetics [00196] In some embodiments, a peptide mimetic is used in place of the peptides described herein, including for use in the treatment or prevention of an inflammatory disorder.
[00197] Peptide mimetics (and peptide-based inhibitors) are developed using, for example, computerized molecular modeling. Peptide mimetics are designed to include structures having one or more peptide linkages optionally replaced by a linkage selected from the group consisting of. -CH2NH-, -CH2S-, -CH2 -CH2 -, -CH=CH-(cis and trans), -CH=CF-(trans), -CoCH2 -, -CH(OH)CH2 -, and -CH2SO-, by methods well known in the art. In some embodiments 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. In some embodiments 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. In some embodiments, systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) are used to generate more stable peptides with desired properties.
[00198] 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, U55,733,731; 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). In such libraries, random peptide sequences are displayed by fusion with coat proteins of filamentous phage. Typically, the displayed peptides are affinity-eluted against an antibody-immobilized extracellular motif/domain (in this case PF4 or RANTES. In some embodiments peptide mimetics are isolated by biopanning (Nowakowski, G.S, et al. (2004) Stem Cells 22:1030-1038). In some embodiments 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. In some embodiments mutagenesis libraries are created and screened to further optimize the sequence of the best binders.
Lowman (1997) Ann.Rev.Biophys.Biomol.Struct. 26:401-24.
[00199] In some embodiments structural analysis of protein-protein interaction is used to suggest peptides that competitiveky bind with a binding partners of polypeptides described herein. In some embodiments 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.
[00200] In some embodiments, the agent is a peptide or polypeptide. In some embodiments, 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. 11);
a peptide that competitively binds with a binding partner of VNTNVPPRASVPDGFLSELTQQLAQATGKPPQYIAVHVVPDQLMAFGGSSEPCALCSL
(SEQ ID No. 12); a peptide that competitively binds with a binding partner of PDQLMAFGGSSEPCALCSLHSI (SEQ ID No. 13); or combinations thereof.
G. Antibodies [00201] In some embodiments, 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. In some embodiments, 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. In some embodiments, an inflammatory disease, disorder, condition, or symptom is treated by administering to an individual in need an antibody that binds to CD44. In some embodiments, an inflammatory disease, disorder, condition, or symptom is treated by administering to an individual in need an antibody that binds to CD74. In some embodiments, 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.
[00202] In some embodiments, the antibody is a human antibody or a humanized antibody. In some embodiments, the antibody is a human IgG. In some embodiments, the antibody is or comprises one or more polypeptides derived from a human IgGI, IgG4, IgG2, IgD, IgA or IgM.
An antibody disclosed herein is generated by any suitable method.
Antigen-Based Antibody Development [00203] In some embodiments, an antibody disclosed herein is generated by contacting a host (e.g., a mouse or rabbit) with an antigen. In some embodiments, the antigen is a MIF
monomer. In some embodiments, the antigen is a MIF trimer. In some embodiments, the antigen is a fragment of a full-length MIF polypeptide. In some embodiments, the antigen is a polypeptide that encompasses all or part of MIF50-65. In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF N-terminal/pseudo-ELR motif/domain (MIF1-17). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF alpha-helix #1 motif/domain (i.e., MIF18-31). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF N-loop motif/domain (i.e., MIF32_60). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF loop-barrel-loop motif/domain (i.e., MIF64-93)= In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF C-terminal motif/domain (i.e., MIF90_114). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF N-terminal tail (i.e., M1F1_7). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF pseudo ELR-loop (i.e., MIF7_17). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF PPQ-loop (i.e., MIF32-38)= In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF PDQ-loop (i.e., MIF43_56). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF
IGK-loop (i.e., MIF64_71). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF NRS-helix (i.e., MIF72_89). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF SPDR-loop (i.e., MIF90_94). In some embodiments, the antigen is a polypeptide that encompasses all or part of the MIF C-terminal tail (i.e., M1F1o1-114).
[00204] In some embodiments, an antibody disclosed herein is generated by contacting a host (e.g., a mouse or rabbit) with at least two antigens. In some embodiments, 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 encompasses all or part of the MIF PDQ-loop; a polypeptide that encompasses all or part of the MIF IGK loop; a polypeptide that encompasses all or part of the MIF NRS helix; a polypeptide that encompasses all or part of the MIF SPDR loop; a polypeptide that encompasses all or part of the C-terminal tail; a polypeptide that encompasses all or part of MIF50-65=
[00205] In some embodiments, an antibody disclosed herein is generated by contacting a host (e.g., a mouse or rabbit) with at least three antigens. In some embodiments, 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 encompasses all or part of the MIF PDQ-loop; a polypeptide that encompasses all or part of the MIF IGK loop; a polypeptide that encompasses all or part of the MIF NRS helix; a polypeptide that encompasses all or part of the MIF SPDR loop; a polypeptide that encompasses all or part of the C-terminal tail; and a polypeptide that encompasses all or part of MIF50-65=
DNA-Based Antibody Development [00206] In some embodiments, 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").
[00207] In some embodiments, the MIF nucleic acid sequence has been cloned into an expression vector (e.g., a plasmid).
[00208] In some embodiments, 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.
[00209] In some embodiments, 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.
[00210] In some embodiments, 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. In some embodiments, the expressed MIF polypeptide is cysteinylated. In some embodiments, the expressed MIF polypeptide is phosphorylated. In some embodiments, the expressed MIF
polypeptide is glycosylated.
[00211] In some embodiments, a method of generating an antibody disclosed herein further comprises contacting the host with an adjuvant. In some embodiments, the adjuvant is administered as a nucleic acid sequence. In some embodiments, the adjuvant is administered as a polypeptide or polysaccharide. In some embodiments, the adjuvant is a cytokine, a lymphokine, or a combination thereof. In some embodiments, the adjuvant is an interleukin, a tumor necrosis factor, GM-CSF, or a combination thereof. In some embodiments, the adjuvant is B7-1, B7-2, CD40L, or a combination thereof. In some embodiments, the expression vector containing the MIF nucleic acid sequence further comprises a nucleic acid sequence encoding an adjuvant. In some embodiments, the host is contacted with a second expression vector encoding an adjuvant.
[00212] In some embodiments, the nucleic acid sequence encodes the MIF N-terminal tail/pseudo-ELR motif. In some embodiments, the nucleic acid sequence encodes MIF50-65. In some embodiments, 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., CCCATGTTCATCGTGAACACC). In some embodiments, 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., AAGCCCCCTCAGTATATCGCC). In some embodiments, the nucleic acid sequence encodes the MIF PDQ loop (i.e., CCCGACCAGCTGATGGCCTTCGGCGGCAGCAGCGAGCCTTGC). In some embodiments, the nucleic acid sequence encodes the MIF IGK-loop (i.e., ATCGGCAAGATCGGCGGAGCCCAG). In some embodiments, the nucleic acid sequence encodes the MIF NRS-helix (i.e., AACAGAAGCTACAGCAAGCTGCTGTGCGGCCTGCTGGCCGAGAGACTGAGAATC). In some embodiments, the nucleic acid sequence encodes the SPDR loop (i.e., AGCCCCGACAGAGTGTACATCAACTACTACGAC). In some embodiments, the nucleic acid sequence encodes the C-terminal tail (i.e., ATGAACGCCGCCAACGTGGGCTGGAACAACAGCACCTTCGCC).
[00213] In some embodiments, 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 MIF50-65. In some embodiments, 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 MIF50-65=
[00214] In some embodiments, 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 MIF50-65. In some embodiments, 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 MIF50-65==
Production of Antibodies [00215] In some embodiments, an antibody disclosed herein is produced via the use of a hybridoma.
As used herein, a "hybridoma" is an immortalized antibody producing cell. In some embodiments, a host (e.g., a mouse or a rabbit) is inoculated with an antigen or a nucleic acid. In some embodiments, B-cells from the host's spleen are extracted. In some embodiments, 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). In some embodiments, 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).
[00216] In some embodiments, the culture comprises a plurality of hybridoma, a plurality of myeloma cells, and a plurality of B-cells. In some embodiments, the cells are individual to culturing conditions that select for hybridoma (e.g., culturing with HAT media).
[00217] In some embodiments, an individual hybridoma (i.e., the clone) is isolated and cultured. In some embodiments, the hybridoma are injected into a laboratory animal. In some embodiments, the hybridoma are cultured in a cell culture.
Humanized Antibodies [00218] In some embodiments, the methods described herein comprise a humanized monoclonal antibody. In some embodiments, a humanized monoclonal antibody comprises heavy and light chain constant regions from a human source and variable regions from a murine source.
[00219] In some embodiments, humanized immunoglobulins, including humanized antibodies, are constructed by genetic engineering. In some embodiments, 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. In some embodiments, 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.
[00220] In some embodiments, 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 Identification Resource or the protein sequence database of the National Center for Biotechnology Information - NCBI) shows that the extent of homology to different human regions can vary greatly, for example from about 40% to about 60%, about 70%, about 80%, or higher. By choosing as the acceptor immunoglobulin one of the human heavy chain variable regions that is most homologous to the heavy chain variable region of the donor immunoglobulin, fewer amino acids will be changed in going from the donor immunoglobulin to the humanized immunoglobulin. By choosing as the acceptor immunoglobulin one of the human light chain variable regions that is most homologous to the light chain variable region of the donor immunoglobulin, fewer amino acids will be changed in going from the donor immunoglobulin to the humanized immunoglobulin.
[00221] In some embodiments, a humanized immunoglobulin comprises light and heavy chains from the same human antibody as acceptor sequences. In some embodiments, a humanized 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). In some embodiments, 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. In some embodiments, 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.
[00222] Any suitable method of modifying a framework region is contemplated herein. In some embodiments, the relevant framework amino acids to change are selected based on differences in amino acid framework residues between the donor and acceptor molecules. In some embodiments, 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). In some embodiments, 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). In some embodiments, 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.
[00223] In some embodiments, 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. In some embodiments, altered framework or CDR sequences are individually made and tested, or are sequentially or simultaneously combined and tested.
[00224] In some embodiments, 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.
[00225] In some embodiments, the humanized antibody sequence is cloned into a vector. In some embodiments, any suitable vector is used. In some embodiments, the vector is a plasmid, viral e.g.
`phage, or phagemid, as appropriate. For further details see, for example, Molecular Cloning: a Laboratory Manual: 2nd edition, Sambrook et al., 1989, Cold Spring Harbor Laboratory Press.
Many known techniques and protocols for manipulation of nucleic acid, for example in preparation of nucleic acid constructs, mutagenesis, sequencing, introduction of DNA into cells and gene expression, and analysis of proteins, are described in detail in Short Protocols in Molecular Biology, Second Edition, Ausubel et al. eds., John Wiley & Sons, 1992. The disclosures of Sambrook et al.
and Ausubel et al. are incorporated herein by reference for such disclosure.
[00226] In some embodiments, any suitable host cell is transformed with the vector expressing the humanized antibody sequence. In some embodiments, 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 Pliickthun, A.
Bio/Technology 9: 545-551 (1991). Expression in eukaryotic cells in culture is also available to those skilled in the art as an option for production of the antibodies and antigen-binding fragments described herein, see for recent reviews, for example Raff, M.E. (1993) Curr.
Opinion Biotech. 4:
573-576; Trill J.J. et al. (1995) Curr. Opinion Biotech 6: 553-560, each of which is which is incorporated herein by reference for such disclosure.
[00227] In some embodiments, a mammalian expression system is used. In some embodiments, the mammalian expression system is dehydrofolate reductase deficient ("dhfr- ") Chinese hamster ovary cells. In some embodiments, dhfr- CHO cells are transfected with an expression vector containing a functional DHFR gene, together with a gene that encodes a desired humanized antibody.
[00228] In some embodiments, DNA is transformed by any suitable method. For eukaryotic cells, 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. For bacterial cells, suitable techniques include, for example, calcium chloride transformation, electroporation and transfection using bacteriophage.
[00229] In some embodiments, a DNA sequence encoding an antibody or antigen-binding fragment thereof is prepared synthetically rather than cloned. In some embodiments, 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. In some embodiments, 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., 259:6311 (1984), each of which is which is incorporated herein by reference for such disclosure.
H. Peptibodies [00230] In some embodiments, a composition of matter disrupts the ability of MIF to bind to CXCR2, CXCR4, CD74, or a combination thereof. In some embodiments, the composition of matter is a peptibody. In some embodiments, 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. In some embodiments, an inflammatory disease, disorder, condition, or symptom is treated by administering to an individual in need thereof a peptibody.
[00231] 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).
[00232] In some embodiments, the peptibody comprises (a) an antibody, and (b) a peptide disclosed herein; wherein the peptide and the antibody retain their activity in the peptibody. In some embodiments, the peptide is bound (directly or indirectly) to the antibody. In some embodiments, the peptide is covalently bound (directly or indirectly) to the antibody. In some embodiments, the peptide is bound (directly or indirectly) to the Fab region of the antibody.
In some embodiments, the peptide is bound (directly or indirectly) to the antigen binding site of the antibody.
[00233] In some embodiments, 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.
Alternatively, 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.
In another approach, the amino acid residue or its reactive functional groups (e.g., a nucleophilic amino group or sulfhydryl group) may be attached to an amino acid residue in the antibody combining site.
[00234] 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.
[00235] In some embodiments, the peptide is indirectly bound to the antibody via a linker. In some embodiments, 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.
[00236] In some embodiments, the antibody is an IgA, IgD, IgE, IgG, or IgM. In some embodiments, the antibody is a humanized antibody.
[00237] In some embodiments, the peptibody is a CovXTM body.
III. Assays for Identifying MIF motif/domain Disrupting Agents [00238] In some embodiments, 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.
[00239] In some embodiments, a library of peptides covering the extracellular N-terminal motif/domain and/or the extracellular loops of CXCR2 and CXCR4 is generated.
In some embodiments, 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. In some embodiments, 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). In some embodiments, the peptide library is further screened for inhibition of 11-8 and/or SDF-1 mediated signaling on CXCR2 and CXCR4. In some embodiments, 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.
[00240] In some embodiments, peptide sequences from the extracellular N-terminal motif/domain and the extracellular loops of CXCR2 and CXCR4 are arrayed onto a membrane. In some embodiments, 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. In some embodiments, the MIF is labeled (e.g., isotopically labeled, radioactively labeled, or fluorophore labeled). In some embodiments, peptide sequences to which labeled MIF specifically bound are assayed for inhibition of MIF-mediated signaling of CXCR2 and CXCR4.
In some embodiments, the peptide sequences that inhibit MIF-mediated signaling of CXCR2 and CXCR4 are screened using any suitable method (e.g., GPCR screening assay).
[00241] In some embodiments, any of the aforementioned peptides and/or polypeptides (e.g., a peptide derived from a pseudo ELR motif/domain of MIF or an N-loop motif/domain of MIF) is used as a "model" to do structure-activity relationship (SAR) chemistry (as provided in detail herein). In some embodiments, the SAR chemistry yields smaller peptides. In some embodiments, 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).
IV. Assays for Identifying MIF Trimerization Disrupting Agents [00242] In some embodiments, 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. In some embodiments, a peptide and/or polypeptide derived from any of the aforementioned amino acid sequences (e.g., amino acid residues 38-44 (beta-2 strand) of MIF, amino acid residues 48-50 (beta-3 strand) of MIF, amino acid residues 96-102 (beta-5 strand) of MIF, amino acid residues 107-109 (beta-6 strand) of MIF, amino acid residues N73, R74, S77, K78, and C81 of MIF, and/or amino acid residues N110, S111, and T112 of MIF) is screened for inhibition of MIF-mediated signaling through CXCR2 and CXCR4 using any suitable method (e.g., HTS GPCR screening technology).
[00243] In some embodiments, a peptide and/or polypeptide derived from any of the aforementioned amino acid sequences (e.g., amino acid residues 3 8-44 (beta-2 strand) of MIF, amino acid residues 48-50 (beta-3 strand) of MIF, amino acid residues 96-102 (beta-5 strand) of MIF, amino acid residues 107-109 (beta-6 strand) of MIF, amino acid residues N73, R74, S77, K78, and C81 of MIF, and/or amino acid residues N110, S 111, and T112 of MIF) is used as a "model"
to do structure-activity relationship (SAR) chemistry. In some embodiments, the SAR chemistry yields smaller peptides. In some embodiments, 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).
[00244] In some embodiments, 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. 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 2-45 of SEQ. ID. NO. 1.
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 3-45 of SEQ. ID. NO. 1.
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 4-45 of SEQ. ID. NO. 1.
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 5-45 of SEQ. ID. NO. 1.
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 6-45 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 7-45 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 8-45 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 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.
[00245] In some embodiments, 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. ID. NO. 1; or amino acid residues 10-45 of SEQ. ID.
NO. 1) is used as a "model" to do structure-activity relationship (SAR) chemistry. In some embodiments, the SAR
chemistry yields smaller peptides. In some embodiments, 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).
[00246] In some embodiments, the antagonist of MIF is an siRNA molecule and/or an antisense molecule complementary to a MIF gene and/or MIF RNA sequence. In some embodiments, 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%.
V. Cell Lines [00247] Disclosed herein, in some embodiments, is a cell line that expresses a recombinant human CXCR4 plus human CD74. In some embodiments, the cell line that expresses a recombinant human CXCR4 plus human CD74 is a human cell line (e.g., HEK293). In some embodiments, the cell line that expresses a recombinant human CXCR4 plus human CD74 is a non-human cell line (e.g., CHO).
VI. Inflammation [00248] In some embodiments, the methods and compositions described herein treat an inflammatory disease, disorder, condition, or symptom (e.g., acute or chronic). In some embodiments, the methods and compositions described herein treat an inflammatory disease, disorder, condition, or symptom resulting from (either partially or fully) an infection. In some embodiments, 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). In some embodiments, the methods and compositions described herein treat an inflammatory disease, disorder, condition, or symptom resulting from (either partially or fully) an autoimmune disorder. In some embodiments, 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.
[00249] As used herein, "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.
[00250] In certain instances, acute inflammation begins with the activation of leukocytes (e.g., dendritic cells, endothelial cells and mastocytes). In certain instances, the leukocytes release inflammatory mediators (e.g., histamines, proteoglycans, serine proteases, eicosanoids, and cytokines). In certain instances, inflammatory mediators result in (either partially or fully) the symptoms associated with inflammation. For example, In certain instances an inflammatory mediator dilates post capillary venules, and increases blood vessel permeability. In certain instances, the increased blood flow that follows vasodilation results in (either partially or fully) rubor and calor. In certain instances, increased 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.
Further, In certain instances, structural changes to blood vessels (e.g., capillaries and venules) occur. In certain instances, the structural changes are induced (either partially or fully) by monocytes and/or macrophages. In certain instances, the structural changes include, but are not limited to, remodeling of vessels, and angiogenesis. In certain instances, angiogenesis contributes to the maintenance of chronic inflammation by allowing for increased transport of leukocytes. Additionally, In certain instances, histamines and bradykinin irritate nerve endings leading to itching and/or pain.
[00251] In certain instances, 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)). In certain instances, the persistent stimulant results in continuous inflammation (e.g., due to the continuous recruitment of monocytes, and the proliferation of macrophages). In certain instances, the continuous inflammation further damages tissues which results in the additional recruitment of mononuclear cells thus maintaining and exacerbating the inflammation. In certain instances, physiological responses to inflammation further include angiogenesis and fibrosis.
[00252] In some embodiments, the methods and compositions described herein treat an inflammatory disease, disorder, condition, or symptom. By way of non-limiting example, 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; 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; 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 (e.g., Glioblastoma and neuroblastoma); 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, Acute leukocyte-mediated lung injury, Distal proctitis, Wegener's granulomatosis, Fibromyalgia, Bronchitis, Cystic fibrosis, Uveitis, Conjunctivitis, Psoriasis, Eczema, Dermatitis, Smooth muscle proliferation disorders, Meningitis, Shingles, Encephalitis, Nephritis, Tuberculosis, Retinitis, Atopic dermatitis, Pancreatitis, Periodontal gingivitis, Coagulative Necrosis, Liquefactive Necrosis, Fibrinoid Necrosis, Neointimal hyperplasia, Myocardial infarction; Stroke;
organ transplant rejection; influenza (e.g., H1N1 influenza A), or combinations thereof. In some embodiments, methods and compositions disclosed herein treat, reduce or prevent angiogenesis.
[00253] In some embodiments, the inflammatory disease, disorder, or condition is a cancer. In some embodiments, 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.
[00254] In some embodiments, the inflammatory disease, disorder, or conditionis is a cardiovascular disorder. In some 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.
Atherosclerosis [00255] In some embodiments, the methods and compositions described herein treat atherosclerosis.
As used herein, "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). In instance, atherosclerosis results from (partially or fully) the accumulation of macrophages. In some embodiments, 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. In certain instances, atherosclerosis results from (partially or fully) the presence of oxidized LDL. In certain instances, oxidized LDL damages an arterial wall. In some embodiments, 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. In certain instances, monocytes respond to (i.e., follow a chemotactic gradient to) the damaged arterial wall. In certain instances, the monocytes differentiate macrophages. In certain instances, macrophages endocytose the oxidized-LDL
(cells such as macrophages with endocytosed LDL are called "foam cells"). In some embodiments, 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. In certain instances, a foam cell dies and subsequently ruptures. In certain instances, the rupture of a foam cell deposits oxidized cholesterol into the artery wall. In some embodiments, 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. In certain instances, the arterial wall becomes inflamed due to the damage caused by the oxidized LDL. In some embodiments, 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. In certain instances, the inflammation of arterial walls results in (either partially or full) the expression of matrix metalloproteinase (MMP)-2, CD40 ligand, and tumor necrosis factor (TNF)-a. In some embodiments, 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. In certain instances, cells form a hard covering over the inflamed area. In some embodiments, 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. In certain instances, the cellular covering narrows an artery. In some embodiments, 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..
[00256] In certain instances, an atherosclerotic plaque results (partially or fully) in stenosis (i.e., the narrowing of blood vessel). In certain instances, stenosis results (partially or fully) in decreased blood flow. In some embodiments, the methods and compositions described herein treat stenosis and/or restinosis. In certain instances, the mechanical injury of stenotic atherosclerotic lesions by percutaneous intervention (e.g., balloon angioplasty or stenting) induces the development of neointimal hyperplasia. In certain instances, 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. In certain instances, 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. In certain instances, monocyte recruitment triggers a more sustained and chronic inflammatory response. In some embodiments, methods and compositions disclosed herein inhibit the accumulation of phenotypically unique SMCs within the intimal layer. In some embodiments, 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.
[00257] In certain instances, the rupture of an atherosclerotic plaque results (partially or fully) in an infarction (e.g., myocardial infarction or stroke) to a tissue. In certain instances, myocardial MIF
expression is upregulated in surviving cardiomyocytes and macrophages following cute myocardial ischemic injury. In certain instances, 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. In certain instances, increased serum concentrations of MIF are detected in individuals with acute myocardial infarction. In certain instances, MIF
contributes to macrophage accumulation in infarcted regions and to the proinflammatory role of myocyte-induced damage during infarction. In some embodiments, the methods and compositions described herein treat an infarction. In certain instances, reperfusion injury follows an infarction. In some embodiments, the methods and compositions described herein treat reperfusion injury.
[00258] In some embodiments, an antibody disclosed herein is administered to identify and/or locate an atherosclerotic plaque. In some embodiments, the antibody is labeled for imaging. In some embodiments, the antibody is labeled for medical imaging. In some embodiments, the antibody is labeled for radio-imaging, PET imaging, MRI imaging, and fluorescent imaging.
In some embodiments, the antibody localizes to areas of the circulatory system with high concentrations of MIF. In some embodiments, an area of the circulatory system with high concentrations of MIF is an atherosclerotic plaque. In some embodiments, 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)).
Abdominal Aortic Aneurysm [00259] In certain instances, an atherosclerotic plaque results (partially or fully) in the development of an aneurysm. In some embodiments, the methods and compositions described herein are administered to treat an aneurysm. In some embodiments, the methods and compositions described herein are administered to treat an abdominal aortic aneurysm ("AAA"). As used herein, an "abdominal aortic aneurysm" is a localized dilatation of the abdominal aorta characterized by at least a 50% increase over normal arterial diameter. In some embodiments, the methods and compositions described herein decrease the dilation of the abdominal aorta.
[00260] In certain instances, abdominal aortic aneurysms result (partially or fully) from a breakdown of structural proteins (e.g., elastin and collagen). In some embodiments, 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). In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein facilitates the regeneration of a structural protein (e.g., elastin and collagen). In certain instances, the breakdown of structural proteins is caused by activated MMPs. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein partially or fully inhibits the activation of an MMP. In some embodiments, a composition and/or method disclosed herein inhibits the upregulation of MMP-1, MMP-9 or MMP-12. In certain instances, MMPs are activated following infiltration of a section of the abdominal aorta by leukocytes (e.g., macrophages and neutrophils).
[00261] In some embodiments, the methods and compositions described herein decrease the infiltration of leukocytes. In certain instances, the MIF is upregulated in early abdominal aortic aneurysm. In certain instances, 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). In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein partially or fully inhibits the activity of MIF. In some embodiments, 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.
[00262] In some embodiments, an antibody disclosed herein is administered to identify and/or locate an AAA in an individual in need thereof. In some embodiments, 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).
In some embodiments, the antibody is labeled for imaging. In some embodiments, the antibody is labeled for medical imaging. In some embodiments, the antibody is labeled for radio-imaging, PET
imaging, MRI imaging, and fluorescent imaging. In some embodiments, the antibody localizes to areas of the circulatory system with high concentrations of MIF. In some embodiments, an area of the circulatory system with high concentrations of MIF is a AAA. In some embodiments, 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)).
Miscellaneous Disorders [00263] In some embodiments, the methods and compositions described herein treat a T-cell mediated autoimmune disorder. In certain instances, a T-cell mediated autoimmune disorder is characterized by a T-cell mediated immune response against self (e.g., native cells and tissues).
Examples of 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., anemias), drug-induced autoimmunity, Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytic pupura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune deafness (e.g., Meniere's disease), Goodpasture's syndrome, Graves' disease, HIV-related autoimmune syndromes and Gullain-Barre disease.
[00264] In some embodiments, the methods and compositions described herein treat pain. Pain includes, but is not limited to acute pain, acute inflammatory pain, chronic inflammatory pain and neuropathic pain.
[00265] In some embodiments, the methods and compositions described herein treat hypersensitivity. As used herein, "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).
[00266] As used herein, "allergy" means a disorder characterized by excessive activation of mast cells and basophils by IgE. In certain instances, the excessive activation of mast cells and basophils by IgE results (either partially or fully) in an inflammatory response. In certain instances, the inflammatory response is local. In certain instances, the inflammatory response results in the narrowing of airways (i.e., bronchoconstriction). In certain instances, the inflammatory response results in inflammation of the nose (i.e., rhinitis). In certain instances, the inflammatory response is systemic (i.e., anaphylaxis).
[00267] In some embodiments, the methods and compositions described herein treat angiogenesis.
As used herein, "angiogenesis" refers to the formations of new blood vessels.
In certain instances, angiogenesis occurs with chronic inflammation. In certain instances, angiogenesis is induced by monocytes and/or macrophages. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits angiogenesis. In certain instances, MIF is expressed in endothelial progenitor cells. In certain instances, MIF is expressed in tumor-associated neovasculature.
[00268] In some embodiments the present invention comprises a method of treating a neoplasia. In certain instances, a neoplastic cell induces an inflammatory response. In certain instances, part of the inflammatory response to a neoplastic cell is angiogenesis. In certain instances, angiogenesis facilitates the development of a neoplasia. In some embodiments, 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.
[00269] Disclosed herein, in some embodiments, are methods of promoting neovascularization comprising administering to said individual MIF or a MIF analogue.
[00270] As used herein, "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.
[00271] In certain instances, MIF induces kinase activation and phosphorylation in the heart (i.e., indicators of cardiac depression). In some embodiments, the methods and compositions described herein treat myocardial dysfunction (e.g., myocardial dysfunction) resulting from sepsis.
[00272] In certain instances, LPS induces the expression of MIF. In certain instances, MIF is induced by endotoxins during sepsis and functions as an initiating factor in myocardial inflammatory responses, cardiac myocyte apoptosis, and cardiac dysfunction.
[00273] In some embodiments, 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.
[00274] In certain instances, 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 cardiomyocyte survival and myocardial function. In some embodiments, the methods and compositions described herein increase the expression of Bcl-2, Bax or phospho-Akt.
[00275] In certain instances, MIF mediates the late and prolonged cardiac depression after burn injury associated and/or major tissue damage. In some embodiments, the methods and compositions described herein treat prolonged cardiac depression after burn injury. In some embodiments, the methods and compositions described herein treat prolonged cardiac depression after major tissue damage.
[00276] In certain instances, MIF is released from the lungs during sepsis.
[00277] In certain instances, antibody neutralization of MIF inhibits the onset of and reduced the severity of autoimmune myocarditis. In some embodiments, the methods and compositions described herein treat autoimmune myocarditis.
VII. Combinations [00278] Disclosed herein, in some embodiments, are methods and pharmaceutical 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").
[00279] Disclosed herein, in some embodiments, are methods and pharmaceutical 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.
[00280] Disclosed herein, in some embodiments, are methods and pharmaceutical 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. In certain instances, statins (e.g., atorvastatin, lovastatin and simvastatin) induce inflammation. In certain instances, administration of a statin results (partially or fully) in myositis.
[00281] As used herein, 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. The term "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. In some instances, 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. These also apply to cocktail therapies, e.g. the administration of three or more active ingredients.
[00282] As used herein, 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. In some embodiments 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. Thus, in some embodiments, the agents described herein and the other agent(s) are administered in a single composition. In some embodiments, the agents described herein and the other agent(s) are admixed in the composition.
[00283] Where combination treatments or prevention methods are contemplated, it is not intended that the agents described herein be limited by the particular nature of the combination. For example, 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. Furthermore, combination treatments are optionally administered separately or concomitantly.
[00284] In some embodiments, 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. In certain instances, statin-induced myositis is dose-dependent. In some embodiments, prescribing the agent allows (partially or fully) a medical professional to increase the prescribed dosage of statin.
[00285] In some embodiments, 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).
[00286] In some embodiments, the second agent is an agent that targets HDL
levels by indirect means (e.g. CETP inhibition). In some embodiments, 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.
[00287] In some embodiments, the second agent is administered before, after, or simultaneously with the modulator of inflammation.
VIII. Pharmaceutical Therapies [00288] In some embodiments, 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 ACAT inhibitor, a CETP
modulator, Glycoprotein (GP) IIb/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, a hormonal therapy (e.g., aromatase inhibitors), or combinations thereof.
[00289] In some embodiments, 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-1011 (2,6-diisopropylphenyl [(2, 4,6-triisopropylphenyl)acetyl]sulfamate); CI-976 (2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide); VULM1457 (1-(2,6-diisopropyl-phenyl)-3-[4-(4'-nitrophenylthio)phenyl] urea); CI-976 (2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide); E-5324 (n-butyl-N'-(2-(3-(5-ethyl-4-phenyl-lH-imidazol-1-yl)propoxy)-6-methylphenyl)urea); HL-004 (N-(2,6-diisopropylphenyl) tetradecylthioacetamide); KY-455 (N-(4,6-dimethyl-l-pentylindolin-7-yl)-2,2-dimethylpropanamide); FY-087 (N-[2-[N'-pentyl-(6,6-dimethyl-2,4-heptadiynyl)amino]ethyl] -(2-methyl-l-naphthyl-thio)acetamide); MCC- 147 (Mitsubishi Pharma); F
12511 ((S)-2',3',5'-trimethyl-4'-hydroxy-alpha-dodecylthioacetanilide); SMP-500 (Sumitomo Pharmaceuticals); CL 277082 (2,4-difluoro-phenyl-N[[4-(2,2-dimethylpropyl)phenyl]methyl]-N-(hepthyl)urea); F-1394 ((ls,2s)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]aminocyclohexane-1-y13-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate); CP- 113818 (N-(2,4-bis(methylthio)-6-methylpyridin-3-yl)-2-(hexylthio)decanoic acid amide); YM-750; torcetrapib;
anacetrapid; JTT-705 (Japan Tobacco/Roche); abciximab; eptifibatide;
tirofiban; roxifiban;
variabilin; XV 459 (N(3)-(2-(3-(4-formamidinophenyl)isoxazolin-5-yl)acetyl)-N(2)-(1-butyloxycarbonyl)-2,3-diaminopropionate); SR 121566A (3-[N- {4-[4-(aminoiminomethyl)phenyl ]-1 ,3-thiazol-2-yl}-N-(1 -carboxymethylpiperid-4-yl) aminol propionic acid, trihydrochloride);
FK419 ((S)-2-acetylamino-3-[(R)-[1-[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 (G1axoSmithKline); SB-222657 (G1axoSmithKline); SB-253514 (G1axoSmithKline); alefacept, efalizumab, methotrexate, acitretin, isotretinoin, hydroxyurea, mycophenolate mofetil, sulfasalazine, 6-Thioguanine, Dovonex, Taclonex, betamethasone, tazarotene, hydroxychloroquine, sulfasalazine, etanercept, adalimumab, infliximab, abatacept, rituximab, trastuzumab, Anti-CD45 monoclonal antibody AHN-12 (NCI), Iodine-131 Anti-B1 Antibody (Corixa Corp.), anti-CD66 monoclonal antibody BW 250/183 (NCI, Southampton General Hospital), anti-CD45 monoclonal antibody (NCI, Baylor College of Medicine), antibody anti-anb3 integrin (NCI), BIW-8962 (BioWa Inc.), Antibody BC8 (NCI), antibody muJ591 (NCI), indium In 111 monoclonal antibody MN-14 (NCI), yttrium monoclonal antibody MN-14 (NCI), F105 Monoclonal Antibody (NIAID), Monoclonal Antibody RAV12 (Raven Biotechnologies), CAT-192 (Human Anti-TGF-Beta l 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, or nortriptyline, chlorambucil, nitrogen mustard, prasterone, LJP 394 (abetimus sodium), LJP 1082 (La Jolla Pharmaceutical), eculizumab, belibumab, rhuCD40L (NIAID), epratuzumab, sirolimus, tacrolimus, pimecrolimus, thalidomide, antithymocyte globulin-equine (Atgam, Pharmacia Upjohn), antithymocyte globulin-rabbit (Thymoglobulin, Genzyme), Muromonab-CD3 (FDA Office of Orphan Products Development), basiliximab, daclizumab, riluzole, cladribine, natalizumab, interferon beta-lb, interferon beta-la, tizanidine, baclofen, mesalazine, asacol, pentasa, mesalamine, balsalazide, olsalazine, 6-mercaptopurine, AIN457 (Anti IL-17 Monoclonal Antibody, Novartis), theophylline, D2E7 (a human anti-TNF mAb from Knoll Pharmaceuticals), Mepolizumab (Anti-IL-S
antibody, SB
240563), Canakinumab (Anti-IL-1 Beta Antibody, NIAMS), Anti-IL-2 Receptor Antibody (Daclizumab, NHLBI), CNTO 328 (Anti IL-6 Monoclonal Antibody, Centocor), ACZ885 (fully human anti-interleukin-l beta monoclonal antibody, Novartis), CNTO 1275 (Fully Human Anti-IL-12 Monoclonal Antibody, Centocor), (3 S)-N-hydroxy-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl} sulfonyl)-2,2-dimet- hyl-3-thiomorpholine carboxamide (apratastat), golimumab (CNTO 148), Onercept, BG9924 (Biogen Idec), Certolizumab Pegol (CDP870, UCB
Pharma), AZD9056 (AstraZeneca), AZD5069 (AstraZeneca), AZD9668 (AstraZeneca), (AstraZeneca), AZD2914 (AstraZeneca), AZD6067 (AstraZeneca), AZD3342 (AstraZeneca), AZD8309 (AstraZeneca), ), [(1R)-3-methyl-l-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid (Bortezomib), AMG-714, (Anti-IL 15 Human Monoclonal Antibody, Amgen), ABT-874 (Anti IL-12 monoclonal antibody, Abbott Labs), MRA(Tocilizumab, an Anti IL-6 Receptor Monoclonal Antibody, Chugai Pharmaceutical), CAT-354 (a human anti-interleukin- 13 monoclonal antibody, Cambridge Antibody Technology, Medlmmune), aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, flurobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502 (Sankyo), JTE-522 (Japan Tobacco Inc.), L-745,337 (Almirall), NS398 (Sigma), betamethasone (Celestone), prednisone (Deltasone), alclometasone, aldosterone, amcinonide, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, cortivazol, deflazacort, deoxycorticosterone, desonide, desoximetasone, desoxycortone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone, fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene, fluticasone, formocortal, formoterol, halcinonide, halometasone, hydrocortisone, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone, meprednisone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, paramethasone, prednicarbate, prednisone, rimexolone, tixocortol, triamcinolone, ulobetasol; cisplatin; carboplatin;
oxaliplatin;
mechlorethamine; cyclophosphamide; chlorambucil; vincristine; vinblastine;
vinorelbine; vindesine;
azathioprine; mercaptopurine; fludarabine; pentostatin; cladribine; 5-fluorouracil (5FU); floxuridine (FUDR); cytosine arabinoside; methotrexate; trimethoprim; pyrimethamine;
pemetrexed; paclitaxel;
docetaxel; etoposide; teniposide; irinotecan; topotecan; amsacrine; etoposide;
etoposide phosphate;
teniposide; dactinomycin; doxorubicin; daunorubicin; valrubicine; idarubicine;
epirubicin;
bleomycin; plicamycin; mitomycin; trastuzumab; cetuximab; rituximab;
bevacizumab; finasteride;
goserelin; aminoglutethimide; anastrozole; letrozole; vorozole; exemestane; 4-androstene-3,6,17-trione ("6-OXO' ; 1,4,6-androstatrien-3,17-dione (ATD); formestane;
testolactone; fadrozole;
milatuzumab; milatuzumab conjugated to doxorubicin; or combinations thereof.
Gene Therapy [00290] Disclosed herein, in some embodiments, is a composition for modulating an MIF-mediated disorder, comprising a combination of (a) agent disclosed herein; and (b) gene therapy. Disclosed herein, in some embodiments, are methods for modulating an MIF-mediated disorder, comprising co-administering a combination of (a) agent disclosed herein; and (b) gene therapy.
[00291] In some embodiments, 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.
In some embodiments, modulating the concentration of a lipid and/or lipoprotein (e.g., HDL) in the blood comprises transfecting DNA into an individual in need thereof. In some embodiments, the DNA encodes an Apo Al gene, an LCAT gene, an LDL gene, an 11-4 gene, an IL-10 gene, an IL-Ira gene, a galectin-3 gene, or combinations thereof. In some embodiments, the DNA is transfected into a liver cell.
[00292] In some embodiments, the DNA is transfected into a liver cell via use of ultrasound. For disclosures of techniques related to transfecting ApoAl DNA via use of ultrasound see U.S. Patent No. 7,211,248, which is hereby incorporated by reference for those disclosures.
[00293] In some embodiments, an individual is administered a vector engineered to carry the human gene (the "gene vector"). For disclosures of techniques for creating an LDL
gene vector see U.S.
Patent No. 6,784,162, which is hereby incorporated by reference for those disclosures. In some embodiments, the gene vector is a retrovirus. In some embodiments, the gene vector is not a retrovirus (e.g. it is an adenovirus; a lentivirus; or a polymeric delivery system such as METAFECTENE, SUPERFECT , EFFECTENE , or MIRUS TRANSIT). In certain instances, a retrovirus, adenovirus, or lentivirus will have a mutation such that the virus is rendered incompetent.
[00294] In some embodiments, 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.
[00295] In certain instances, after administration of the gene vector, the gene vector infects the cells at the site of administration (e.g. the liver). In certain instances the gene sequence is incorporated into the individual's genome (e.g. when the gene vector is a retrovirus). In certain instances the therapy will need to be periodically re-administered (e.g. when the gene vector is not a retrovirus).
In some embodiments, the therapy is re-administered annually. In some embodiments, the therapy is re-administered semi-annually. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 60 mg/dL. In some embodiments, 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.
RNAi Therapies [00296] Disclosed herein, in some embodiments, is 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"). Disclosed herein, in some embodiments, are 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").
In some embodiments, the target gene is Apolipoprotein B (Apo B), Heat Shock Protein 110 (Hsp 110), Proprotein Convertase Subtilisin Kexin 9 (Pcsk9), CyD1, TNF-a, IL-1(3, Atrial Natriuretic Peptide Receptor A (NPRA), GATA-3, Syk, VEGF, MIP-2, FasL, DDR-1, C5aR, AP-1, or combinations thereof.
[00297] In some embodiments, the target gene is silenced by RNA interference (RNAi). In some embodiments, the RNAi therapy comprises use of an siRNA molecule. In some embodiments, a double stranded RNA (dsRNA) molecule with sequences complementary to an mRNA
sequence of a gene to be silenced (e.g., Apo B, Hsp 110 and Pcsk9) is generated (e.g by PCR). In some embodiments, a 20-25 bp siRNA molecule with sequences complementary to an mRNA
sequence of a gene to be silenced is generated. In some embodiments, 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. For techniques for generating RNA sequences see 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.
[00298] In some embodiments, an siRNA molecule is "fully complementary" (i.e., 100%
complementary) to the target gene. In some embodiments, 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. In some embodiments, there is a 1 bp mismatch, a 2 bp mismatch, a 3 bp mismatch, a 4 bp mismatch, or a 5 bp mismatch.
[00299] In certain instances, 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. In certain instances following transformation, the dsRNA
molecule is cleaved into multiple fragments of about 20-25 bp to yield siRNA molecules. In certain instances, the fragments have about 2bp overhangs on the 3' end of each strand.
[00300] In certain instances, an siRNA molecule is divided into two strands (the guide strand and the anti-guide strand) by an RNA-induced Silencing Complex (RISC). In certain instances, the guide strand is incorporated into the catalytic component of the RISC (i.e.
argonaute). In certain instances, the guide strand specifically binds to a complementary RBI mRNA sequence. In certain instances, the RISC cleaves an mRNA sequence of a gene to be silenced. In certain instances, the expression of the gene to be silenced is down-regulated.
Dextran, electroporation, liposome-mediated transfection and transduction using retrovirus or other virus, e.g., vaccinia or, for insect cells, baculovirus. For bacterial cells, suitable techniques include, for example, calcium chloride transformation, electroporation and transfection using bacteriophage.
[00229] In some embodiments, a DNA sequence encoding an antibody or antigen-binding fragment thereof is prepared synthetically rather than cloned. In some embodiments, 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. In some embodiments, 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., 259:6311 (1984), each of which is which is incorporated herein by reference for such disclosure.
H. Peptibodies [00230] In some embodiments, a composition of matter disrupts the ability of MIF to bind to CXCR2, CXCR4, CD74, or a combination thereof. In some embodiments, the composition of matter is a peptibody. In some embodiments, 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. In some embodiments, an inflammatory disease, disorder, condition, or symptom is treated by administering to an individual in need thereof a peptibody.
[00231] 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).
[00232] In some embodiments, the peptibody comprises (a) an antibody, and (b) a peptide disclosed herein; wherein the peptide and the antibody retain their activity in the peptibody. In some embodiments, the peptide is bound (directly or indirectly) to the antibody. In some embodiments, the peptide is covalently bound (directly or indirectly) to the antibody. In some embodiments, the peptide is bound (directly or indirectly) to the Fab region of the antibody.
In some embodiments, the peptide is bound (directly or indirectly) to the antigen binding site of the antibody.
[00233] In some embodiments, 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.
Alternatively, 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.
In another approach, the amino acid residue or its reactive functional groups (e.g., a nucleophilic amino group or sulfhydryl group) may be attached to an amino acid residue in the antibody combining site.
[00234] 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.
[00235] In some embodiments, the peptide is indirectly bound to the antibody via a linker. In some embodiments, 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.
[00236] In some embodiments, the antibody is an IgA, IgD, IgE, IgG, or IgM. In some embodiments, the antibody is a humanized antibody.
[00237] In some embodiments, the peptibody is a CovXTM body.
III. Assays for Identifying MIF motif/domain Disrupting Agents [00238] In some embodiments, 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.
[00239] In some embodiments, a library of peptides covering the extracellular N-terminal motif/domain and/or the extracellular loops of CXCR2 and CXCR4 is generated.
In some embodiments, 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. In some embodiments, 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). In some embodiments, the peptide library is further screened for inhibition of 11-8 and/or SDF-1 mediated signaling on CXCR2 and CXCR4. In some embodiments, 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.
[00240] In some embodiments, peptide sequences from the extracellular N-terminal motif/domain and the extracellular loops of CXCR2 and CXCR4 are arrayed onto a membrane. In some embodiments, 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. In some embodiments, the MIF is labeled (e.g., isotopically labeled, radioactively labeled, or fluorophore labeled). In some embodiments, peptide sequences to which labeled MIF specifically bound are assayed for inhibition of MIF-mediated signaling of CXCR2 and CXCR4.
In some embodiments, the peptide sequences that inhibit MIF-mediated signaling of CXCR2 and CXCR4 are screened using any suitable method (e.g., GPCR screening assay).
[00241] In some embodiments, any of the aforementioned peptides and/or polypeptides (e.g., a peptide derived from a pseudo ELR motif/domain of MIF or an N-loop motif/domain of MIF) is used as a "model" to do structure-activity relationship (SAR) chemistry (as provided in detail herein). In some embodiments, the SAR chemistry yields smaller peptides. In some embodiments, 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).
IV. Assays for Identifying MIF Trimerization Disrupting Agents [00242] In some embodiments, 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. In some embodiments, a peptide and/or polypeptide derived from any of the aforementioned amino acid sequences (e.g., amino acid residues 38-44 (beta-2 strand) of MIF, amino acid residues 48-50 (beta-3 strand) of MIF, amino acid residues 96-102 (beta-5 strand) of MIF, amino acid residues 107-109 (beta-6 strand) of MIF, amino acid residues N73, R74, S77, K78, and C81 of MIF, and/or amino acid residues N110, S111, and T112 of MIF) is screened for inhibition of MIF-mediated signaling through CXCR2 and CXCR4 using any suitable method (e.g., HTS GPCR screening technology).
[00243] In some embodiments, a peptide and/or polypeptide derived from any of the aforementioned amino acid sequences (e.g., amino acid residues 3 8-44 (beta-2 strand) of MIF, amino acid residues 48-50 (beta-3 strand) of MIF, amino acid residues 96-102 (beta-5 strand) of MIF, amino acid residues 107-109 (beta-6 strand) of MIF, amino acid residues N73, R74, S77, K78, and C81 of MIF, and/or amino acid residues N110, S 111, and T112 of MIF) is used as a "model"
to do structure-activity relationship (SAR) chemistry. In some embodiments, the SAR chemistry yields smaller peptides. In some embodiments, 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).
[00244] In some embodiments, 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. 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 2-45 of SEQ. ID. NO. 1.
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 3-45 of SEQ. ID. NO. 1.
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 4-45 of SEQ. ID. NO. 1.
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 5-45 of SEQ. ID. NO. 1.
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 6-45 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 7-45 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 8-45 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 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.
[00245] In some embodiments, 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. ID. NO. 1; or amino acid residues 10-45 of SEQ. ID.
NO. 1) is used as a "model" to do structure-activity relationship (SAR) chemistry. In some embodiments, the SAR
chemistry yields smaller peptides. In some embodiments, 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).
[00246] In some embodiments, the antagonist of MIF is an siRNA molecule and/or an antisense molecule complementary to a MIF gene and/or MIF RNA sequence. In some embodiments, 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%.
V. Cell Lines [00247] Disclosed herein, in some embodiments, is a cell line that expresses a recombinant human CXCR4 plus human CD74. In some embodiments, the cell line that expresses a recombinant human CXCR4 plus human CD74 is a human cell line (e.g., HEK293). In some embodiments, the cell line that expresses a recombinant human CXCR4 plus human CD74 is a non-human cell line (e.g., CHO).
VI. Inflammation [00248] In some embodiments, the methods and compositions described herein treat an inflammatory disease, disorder, condition, or symptom (e.g., acute or chronic). In some embodiments, the methods and compositions described herein treat an inflammatory disease, disorder, condition, or symptom resulting from (either partially or fully) an infection. In some embodiments, 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). In some embodiments, the methods and compositions described herein treat an inflammatory disease, disorder, condition, or symptom resulting from (either partially or fully) an autoimmune disorder. In some embodiments, 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.
[00249] As used herein, "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.
[00250] In certain instances, acute inflammation begins with the activation of leukocytes (e.g., dendritic cells, endothelial cells and mastocytes). In certain instances, the leukocytes release inflammatory mediators (e.g., histamines, proteoglycans, serine proteases, eicosanoids, and cytokines). In certain instances, inflammatory mediators result in (either partially or fully) the symptoms associated with inflammation. For example, In certain instances an inflammatory mediator dilates post capillary venules, and increases blood vessel permeability. In certain instances, the increased blood flow that follows vasodilation results in (either partially or fully) rubor and calor. In certain instances, increased 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.
Further, In certain instances, structural changes to blood vessels (e.g., capillaries and venules) occur. In certain instances, the structural changes are induced (either partially or fully) by monocytes and/or macrophages. In certain instances, the structural changes include, but are not limited to, remodeling of vessels, and angiogenesis. In certain instances, angiogenesis contributes to the maintenance of chronic inflammation by allowing for increased transport of leukocytes. Additionally, In certain instances, histamines and bradykinin irritate nerve endings leading to itching and/or pain.
[00251] In certain instances, 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)). In certain instances, the persistent stimulant results in continuous inflammation (e.g., due to the continuous recruitment of monocytes, and the proliferation of macrophages). In certain instances, the continuous inflammation further damages tissues which results in the additional recruitment of mononuclear cells thus maintaining and exacerbating the inflammation. In certain instances, physiological responses to inflammation further include angiogenesis and fibrosis.
[00252] In some embodiments, the methods and compositions described herein treat an inflammatory disease, disorder, condition, or symptom. By way of non-limiting example, 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; 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; 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 (e.g., Glioblastoma and neuroblastoma); 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, Acute leukocyte-mediated lung injury, Distal proctitis, Wegener's granulomatosis, Fibromyalgia, Bronchitis, Cystic fibrosis, Uveitis, Conjunctivitis, Psoriasis, Eczema, Dermatitis, Smooth muscle proliferation disorders, Meningitis, Shingles, Encephalitis, Nephritis, Tuberculosis, Retinitis, Atopic dermatitis, Pancreatitis, Periodontal gingivitis, Coagulative Necrosis, Liquefactive Necrosis, Fibrinoid Necrosis, Neointimal hyperplasia, Myocardial infarction; Stroke;
organ transplant rejection; influenza (e.g., H1N1 influenza A), or combinations thereof. In some embodiments, methods and compositions disclosed herein treat, reduce or prevent angiogenesis.
[00253] In some embodiments, the inflammatory disease, disorder, or condition is a cancer. In some embodiments, 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.
[00254] In some embodiments, the inflammatory disease, disorder, or conditionis is a cardiovascular disorder. In some 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.
Atherosclerosis [00255] In some embodiments, the methods and compositions described herein treat atherosclerosis.
As used herein, "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). In instance, atherosclerosis results from (partially or fully) the accumulation of macrophages. In some embodiments, 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. In certain instances, atherosclerosis results from (partially or fully) the presence of oxidized LDL. In certain instances, oxidized LDL damages an arterial wall. In some embodiments, 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. In certain instances, monocytes respond to (i.e., follow a chemotactic gradient to) the damaged arterial wall. In certain instances, the monocytes differentiate macrophages. In certain instances, macrophages endocytose the oxidized-LDL
(cells such as macrophages with endocytosed LDL are called "foam cells"). In some embodiments, 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. In certain instances, a foam cell dies and subsequently ruptures. In certain instances, the rupture of a foam cell deposits oxidized cholesterol into the artery wall. In some embodiments, 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. In certain instances, the arterial wall becomes inflamed due to the damage caused by the oxidized LDL. In some embodiments, 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. In certain instances, the inflammation of arterial walls results in (either partially or full) the expression of matrix metalloproteinase (MMP)-2, CD40 ligand, and tumor necrosis factor (TNF)-a. In some embodiments, 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. In certain instances, cells form a hard covering over the inflamed area. In some embodiments, 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. In certain instances, the cellular covering narrows an artery. In some embodiments, 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..
[00256] In certain instances, an atherosclerotic plaque results (partially or fully) in stenosis (i.e., the narrowing of blood vessel). In certain instances, stenosis results (partially or fully) in decreased blood flow. In some embodiments, the methods and compositions described herein treat stenosis and/or restinosis. In certain instances, the mechanical injury of stenotic atherosclerotic lesions by percutaneous intervention (e.g., balloon angioplasty or stenting) induces the development of neointimal hyperplasia. In certain instances, 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. In certain instances, 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. In certain instances, monocyte recruitment triggers a more sustained and chronic inflammatory response. In some embodiments, methods and compositions disclosed herein inhibit the accumulation of phenotypically unique SMCs within the intimal layer. In some embodiments, 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.
[00257] In certain instances, the rupture of an atherosclerotic plaque results (partially or fully) in an infarction (e.g., myocardial infarction or stroke) to a tissue. In certain instances, myocardial MIF
expression is upregulated in surviving cardiomyocytes and macrophages following cute myocardial ischemic injury. In certain instances, 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. In certain instances, increased serum concentrations of MIF are detected in individuals with acute myocardial infarction. In certain instances, MIF
contributes to macrophage accumulation in infarcted regions and to the proinflammatory role of myocyte-induced damage during infarction. In some embodiments, the methods and compositions described herein treat an infarction. In certain instances, reperfusion injury follows an infarction. In some embodiments, the methods and compositions described herein treat reperfusion injury.
[00258] In some embodiments, an antibody disclosed herein is administered to identify and/or locate an atherosclerotic plaque. In some embodiments, the antibody is labeled for imaging. In some embodiments, the antibody is labeled for medical imaging. In some embodiments, the antibody is labeled for radio-imaging, PET imaging, MRI imaging, and fluorescent imaging.
In some embodiments, the antibody localizes to areas of the circulatory system with high concentrations of MIF. In some embodiments, an area of the circulatory system with high concentrations of MIF is an atherosclerotic plaque. In some embodiments, 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)).
Abdominal Aortic Aneurysm [00259] In certain instances, an atherosclerotic plaque results (partially or fully) in the development of an aneurysm. In some embodiments, the methods and compositions described herein are administered to treat an aneurysm. In some embodiments, the methods and compositions described herein are administered to treat an abdominal aortic aneurysm ("AAA"). As used herein, an "abdominal aortic aneurysm" is a localized dilatation of the abdominal aorta characterized by at least a 50% increase over normal arterial diameter. In some embodiments, the methods and compositions described herein decrease the dilation of the abdominal aorta.
[00260] In certain instances, abdominal aortic aneurysms result (partially or fully) from a breakdown of structural proteins (e.g., elastin and collagen). In some embodiments, 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). In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein facilitates the regeneration of a structural protein (e.g., elastin and collagen). In certain instances, the breakdown of structural proteins is caused by activated MMPs. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein partially or fully inhibits the activation of an MMP. In some embodiments, a composition and/or method disclosed herein inhibits the upregulation of MMP-1, MMP-9 or MMP-12. In certain instances, MMPs are activated following infiltration of a section of the abdominal aorta by leukocytes (e.g., macrophages and neutrophils).
[00261] In some embodiments, the methods and compositions described herein decrease the infiltration of leukocytes. In certain instances, the MIF is upregulated in early abdominal aortic aneurysm. In certain instances, 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). In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein partially or fully inhibits the activity of MIF. In some embodiments, 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.
[00262] In some embodiments, an antibody disclosed herein is administered to identify and/or locate an AAA in an individual in need thereof. In some embodiments, 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).
In some embodiments, the antibody is labeled for imaging. In some embodiments, the antibody is labeled for medical imaging. In some embodiments, the antibody is labeled for radio-imaging, PET
imaging, MRI imaging, and fluorescent imaging. In some embodiments, the antibody localizes to areas of the circulatory system with high concentrations of MIF. In some embodiments, an area of the circulatory system with high concentrations of MIF is a AAA. In some embodiments, 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)).
Miscellaneous Disorders [00263] In some embodiments, the methods and compositions described herein treat a T-cell mediated autoimmune disorder. In certain instances, a T-cell mediated autoimmune disorder is characterized by a T-cell mediated immune response against self (e.g., native cells and tissues).
Examples of 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., anemias), drug-induced autoimmunity, Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytic pupura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune deafness (e.g., Meniere's disease), Goodpasture's syndrome, Graves' disease, HIV-related autoimmune syndromes and Gullain-Barre disease.
[00264] In some embodiments, the methods and compositions described herein treat pain. Pain includes, but is not limited to acute pain, acute inflammatory pain, chronic inflammatory pain and neuropathic pain.
[00265] In some embodiments, the methods and compositions described herein treat hypersensitivity. As used herein, "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).
[00266] As used herein, "allergy" means a disorder characterized by excessive activation of mast cells and basophils by IgE. In certain instances, the excessive activation of mast cells and basophils by IgE results (either partially or fully) in an inflammatory response. In certain instances, the inflammatory response is local. In certain instances, the inflammatory response results in the narrowing of airways (i.e., bronchoconstriction). In certain instances, the inflammatory response results in inflammation of the nose (i.e., rhinitis). In certain instances, the inflammatory response is systemic (i.e., anaphylaxis).
[00267] In some embodiments, the methods and compositions described herein treat angiogenesis.
As used herein, "angiogenesis" refers to the formations of new blood vessels.
In certain instances, angiogenesis occurs with chronic inflammation. In certain instances, angiogenesis is induced by monocytes and/or macrophages. In some embodiments, a composition of matter, method and/or pharmaceutical composition disclosed herein inhibits angiogenesis. In certain instances, MIF is expressed in endothelial progenitor cells. In certain instances, MIF is expressed in tumor-associated neovasculature.
[00268] In some embodiments the present invention comprises a method of treating a neoplasia. In certain instances, a neoplastic cell induces an inflammatory response. In certain instances, part of the inflammatory response to a neoplastic cell is angiogenesis. In certain instances, angiogenesis facilitates the development of a neoplasia. In some embodiments, 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.
[00269] Disclosed herein, in some embodiments, are methods of promoting neovascularization comprising administering to said individual MIF or a MIF analogue.
[00270] As used herein, "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.
[00271] In certain instances, MIF induces kinase activation and phosphorylation in the heart (i.e., indicators of cardiac depression). In some embodiments, the methods and compositions described herein treat myocardial dysfunction (e.g., myocardial dysfunction) resulting from sepsis.
[00272] In certain instances, LPS induces the expression of MIF. In certain instances, MIF is induced by endotoxins during sepsis and functions as an initiating factor in myocardial inflammatory responses, cardiac myocyte apoptosis, and cardiac dysfunction.
[00273] In some embodiments, 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.
[00274] In certain instances, 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 cardiomyocyte survival and myocardial function. In some embodiments, the methods and compositions described herein increase the expression of Bcl-2, Bax or phospho-Akt.
[00275] In certain instances, MIF mediates the late and prolonged cardiac depression after burn injury associated and/or major tissue damage. In some embodiments, the methods and compositions described herein treat prolonged cardiac depression after burn injury. In some embodiments, the methods and compositions described herein treat prolonged cardiac depression after major tissue damage.
[00276] In certain instances, MIF is released from the lungs during sepsis.
[00277] In certain instances, antibody neutralization of MIF inhibits the onset of and reduced the severity of autoimmune myocarditis. In some embodiments, the methods and compositions described herein treat autoimmune myocarditis.
VII. Combinations [00278] Disclosed herein, in some embodiments, are methods and pharmaceutical 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").
[00279] Disclosed herein, in some embodiments, are methods and pharmaceutical 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.
[00280] Disclosed herein, in some embodiments, are methods and pharmaceutical 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. In certain instances, statins (e.g., atorvastatin, lovastatin and simvastatin) induce inflammation. In certain instances, administration of a statin results (partially or fully) in myositis.
[00281] As used herein, 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. The term "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. In some instances, 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. These also apply to cocktail therapies, e.g. the administration of three or more active ingredients.
[00282] As used herein, 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. In some embodiments 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. Thus, in some embodiments, the agents described herein and the other agent(s) are administered in a single composition. In some embodiments, the agents described herein and the other agent(s) are admixed in the composition.
[00283] Where combination treatments or prevention methods are contemplated, it is not intended that the agents described herein be limited by the particular nature of the combination. For example, 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. Furthermore, combination treatments are optionally administered separately or concomitantly.
[00284] In some embodiments, 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. In certain instances, statin-induced myositis is dose-dependent. In some embodiments, prescribing the agent allows (partially or fully) a medical professional to increase the prescribed dosage of statin.
[00285] In some embodiments, 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).
[00286] In some embodiments, the second agent is an agent that targets HDL
levels by indirect means (e.g. CETP inhibition). In some embodiments, 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.
[00287] In some embodiments, the second agent is administered before, after, or simultaneously with the modulator of inflammation.
VIII. Pharmaceutical Therapies [00288] In some embodiments, 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 ACAT inhibitor, a CETP
modulator, Glycoprotein (GP) IIb/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, a hormonal therapy (e.g., aromatase inhibitors), or combinations thereof.
[00289] In some embodiments, 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-1011 (2,6-diisopropylphenyl [(2, 4,6-triisopropylphenyl)acetyl]sulfamate); CI-976 (2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide); VULM1457 (1-(2,6-diisopropyl-phenyl)-3-[4-(4'-nitrophenylthio)phenyl] urea); CI-976 (2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide); E-5324 (n-butyl-N'-(2-(3-(5-ethyl-4-phenyl-lH-imidazol-1-yl)propoxy)-6-methylphenyl)urea); HL-004 (N-(2,6-diisopropylphenyl) tetradecylthioacetamide); KY-455 (N-(4,6-dimethyl-l-pentylindolin-7-yl)-2,2-dimethylpropanamide); FY-087 (N-[2-[N'-pentyl-(6,6-dimethyl-2,4-heptadiynyl)amino]ethyl] -(2-methyl-l-naphthyl-thio)acetamide); MCC- 147 (Mitsubishi Pharma); F
12511 ((S)-2',3',5'-trimethyl-4'-hydroxy-alpha-dodecylthioacetanilide); SMP-500 (Sumitomo Pharmaceuticals); CL 277082 (2,4-difluoro-phenyl-N[[4-(2,2-dimethylpropyl)phenyl]methyl]-N-(hepthyl)urea); F-1394 ((ls,2s)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]aminocyclohexane-1-y13-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate); CP- 113818 (N-(2,4-bis(methylthio)-6-methylpyridin-3-yl)-2-(hexylthio)decanoic acid amide); YM-750; torcetrapib;
anacetrapid; JTT-705 (Japan Tobacco/Roche); abciximab; eptifibatide;
tirofiban; roxifiban;
variabilin; XV 459 (N(3)-(2-(3-(4-formamidinophenyl)isoxazolin-5-yl)acetyl)-N(2)-(1-butyloxycarbonyl)-2,3-diaminopropionate); SR 121566A (3-[N- {4-[4-(aminoiminomethyl)phenyl ]-1 ,3-thiazol-2-yl}-N-(1 -carboxymethylpiperid-4-yl) aminol propionic acid, trihydrochloride);
FK419 ((S)-2-acetylamino-3-[(R)-[1-[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 (G1axoSmithKline); SB-222657 (G1axoSmithKline); SB-253514 (G1axoSmithKline); alefacept, efalizumab, methotrexate, acitretin, isotretinoin, hydroxyurea, mycophenolate mofetil, sulfasalazine, 6-Thioguanine, Dovonex, Taclonex, betamethasone, tazarotene, hydroxychloroquine, sulfasalazine, etanercept, adalimumab, infliximab, abatacept, rituximab, trastuzumab, Anti-CD45 monoclonal antibody AHN-12 (NCI), Iodine-131 Anti-B1 Antibody (Corixa Corp.), anti-CD66 monoclonal antibody BW 250/183 (NCI, Southampton General Hospital), anti-CD45 monoclonal antibody (NCI, Baylor College of Medicine), antibody anti-anb3 integrin (NCI), BIW-8962 (BioWa Inc.), Antibody BC8 (NCI), antibody muJ591 (NCI), indium In 111 monoclonal antibody MN-14 (NCI), yttrium monoclonal antibody MN-14 (NCI), F105 Monoclonal Antibody (NIAID), Monoclonal Antibody RAV12 (Raven Biotechnologies), CAT-192 (Human Anti-TGF-Beta l 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, or nortriptyline, chlorambucil, nitrogen mustard, prasterone, LJP 394 (abetimus sodium), LJP 1082 (La Jolla Pharmaceutical), eculizumab, belibumab, rhuCD40L (NIAID), epratuzumab, sirolimus, tacrolimus, pimecrolimus, thalidomide, antithymocyte globulin-equine (Atgam, Pharmacia Upjohn), antithymocyte globulin-rabbit (Thymoglobulin, Genzyme), Muromonab-CD3 (FDA Office of Orphan Products Development), basiliximab, daclizumab, riluzole, cladribine, natalizumab, interferon beta-lb, interferon beta-la, tizanidine, baclofen, mesalazine, asacol, pentasa, mesalamine, balsalazide, olsalazine, 6-mercaptopurine, AIN457 (Anti IL-17 Monoclonal Antibody, Novartis), theophylline, D2E7 (a human anti-TNF mAb from Knoll Pharmaceuticals), Mepolizumab (Anti-IL-S
antibody, SB
240563), Canakinumab (Anti-IL-1 Beta Antibody, NIAMS), Anti-IL-2 Receptor Antibody (Daclizumab, NHLBI), CNTO 328 (Anti IL-6 Monoclonal Antibody, Centocor), ACZ885 (fully human anti-interleukin-l beta monoclonal antibody, Novartis), CNTO 1275 (Fully Human Anti-IL-12 Monoclonal Antibody, Centocor), (3 S)-N-hydroxy-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl} sulfonyl)-2,2-dimet- hyl-3-thiomorpholine carboxamide (apratastat), golimumab (CNTO 148), Onercept, BG9924 (Biogen Idec), Certolizumab Pegol (CDP870, UCB
Pharma), AZD9056 (AstraZeneca), AZD5069 (AstraZeneca), AZD9668 (AstraZeneca), (AstraZeneca), AZD2914 (AstraZeneca), AZD6067 (AstraZeneca), AZD3342 (AstraZeneca), AZD8309 (AstraZeneca), ), [(1R)-3-methyl-l-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid (Bortezomib), AMG-714, (Anti-IL 15 Human Monoclonal Antibody, Amgen), ABT-874 (Anti IL-12 monoclonal antibody, Abbott Labs), MRA(Tocilizumab, an Anti IL-6 Receptor Monoclonal Antibody, Chugai Pharmaceutical), CAT-354 (a human anti-interleukin- 13 monoclonal antibody, Cambridge Antibody Technology, Medlmmune), aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, flurobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502 (Sankyo), JTE-522 (Japan Tobacco Inc.), L-745,337 (Almirall), NS398 (Sigma), betamethasone (Celestone), prednisone (Deltasone), alclometasone, aldosterone, amcinonide, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, cortivazol, deflazacort, deoxycorticosterone, desonide, desoximetasone, desoxycortone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone, fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene, fluticasone, formocortal, formoterol, halcinonide, halometasone, hydrocortisone, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone, meprednisone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, paramethasone, prednicarbate, prednisone, rimexolone, tixocortol, triamcinolone, ulobetasol; cisplatin; carboplatin;
oxaliplatin;
mechlorethamine; cyclophosphamide; chlorambucil; vincristine; vinblastine;
vinorelbine; vindesine;
azathioprine; mercaptopurine; fludarabine; pentostatin; cladribine; 5-fluorouracil (5FU); floxuridine (FUDR); cytosine arabinoside; methotrexate; trimethoprim; pyrimethamine;
pemetrexed; paclitaxel;
docetaxel; etoposide; teniposide; irinotecan; topotecan; amsacrine; etoposide;
etoposide phosphate;
teniposide; dactinomycin; doxorubicin; daunorubicin; valrubicine; idarubicine;
epirubicin;
bleomycin; plicamycin; mitomycin; trastuzumab; cetuximab; rituximab;
bevacizumab; finasteride;
goserelin; aminoglutethimide; anastrozole; letrozole; vorozole; exemestane; 4-androstene-3,6,17-trione ("6-OXO' ; 1,4,6-androstatrien-3,17-dione (ATD); formestane;
testolactone; fadrozole;
milatuzumab; milatuzumab conjugated to doxorubicin; or combinations thereof.
Gene Therapy [00290] Disclosed herein, in some embodiments, is a composition for modulating an MIF-mediated disorder, comprising a combination of (a) agent disclosed herein; and (b) gene therapy. Disclosed herein, in some embodiments, are methods for modulating an MIF-mediated disorder, comprising co-administering a combination of (a) agent disclosed herein; and (b) gene therapy.
[00291] In some embodiments, 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.
In some embodiments, modulating the concentration of a lipid and/or lipoprotein (e.g., HDL) in the blood comprises transfecting DNA into an individual in need thereof. In some embodiments, the DNA encodes an Apo Al gene, an LCAT gene, an LDL gene, an 11-4 gene, an IL-10 gene, an IL-Ira gene, a galectin-3 gene, or combinations thereof. In some embodiments, the DNA is transfected into a liver cell.
[00292] In some embodiments, the DNA is transfected into a liver cell via use of ultrasound. For disclosures of techniques related to transfecting ApoAl DNA via use of ultrasound see U.S. Patent No. 7,211,248, which is hereby incorporated by reference for those disclosures.
[00293] In some embodiments, an individual is administered a vector engineered to carry the human gene (the "gene vector"). For disclosures of techniques for creating an LDL
gene vector see U.S.
Patent No. 6,784,162, which is hereby incorporated by reference for those disclosures. In some embodiments, the gene vector is a retrovirus. In some embodiments, the gene vector is not a retrovirus (e.g. it is an adenovirus; a lentivirus; or a polymeric delivery system such as METAFECTENE, SUPERFECT , EFFECTENE , or MIRUS TRANSIT). In certain instances, a retrovirus, adenovirus, or lentivirus will have a mutation such that the virus is rendered incompetent.
[00294] In some embodiments, 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.
[00295] In certain instances, after administration of the gene vector, the gene vector infects the cells at the site of administration (e.g. the liver). In certain instances the gene sequence is incorporated into the individual's genome (e.g. when the gene vector is a retrovirus). In certain instances the therapy will need to be periodically re-administered (e.g. when the gene vector is not a retrovirus).
In some embodiments, the therapy is re-administered annually. In some embodiments, the therapy is re-administered semi-annually. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 60 mg/dL. In some embodiments, 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.
RNAi Therapies [00296] Disclosed herein, in some embodiments, is 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"). Disclosed herein, in some embodiments, are 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").
In some embodiments, the target gene is Apolipoprotein B (Apo B), Heat Shock Protein 110 (Hsp 110), Proprotein Convertase Subtilisin Kexin 9 (Pcsk9), CyD1, TNF-a, IL-1(3, Atrial Natriuretic Peptide Receptor A (NPRA), GATA-3, Syk, VEGF, MIP-2, FasL, DDR-1, C5aR, AP-1, or combinations thereof.
[00297] In some embodiments, the target gene is silenced by RNA interference (RNAi). In some embodiments, the RNAi therapy comprises use of an siRNA molecule. In some embodiments, a double stranded RNA (dsRNA) molecule with sequences complementary to an mRNA
sequence of a gene to be silenced (e.g., Apo B, Hsp 110 and Pcsk9) is generated (e.g by PCR). In some embodiments, a 20-25 bp siRNA molecule with sequences complementary to an mRNA
sequence of a gene to be silenced is generated. In some embodiments, 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. For techniques for generating RNA sequences see 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.
[00298] In some embodiments, an siRNA molecule is "fully complementary" (i.e., 100%
complementary) to the target gene. In some embodiments, 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. In some embodiments, there is a 1 bp mismatch, a 2 bp mismatch, a 3 bp mismatch, a 4 bp mismatch, or a 5 bp mismatch.
[00299] In certain instances, 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. In certain instances following transformation, the dsRNA
molecule is cleaved into multiple fragments of about 20-25 bp to yield siRNA molecules. In certain instances, the fragments have about 2bp overhangs on the 3' end of each strand.
[00300] In certain instances, an siRNA molecule is divided into two strands (the guide strand and the anti-guide strand) by an RNA-induced Silencing Complex (RISC). In certain instances, the guide strand is incorporated into the catalytic component of the RISC (i.e.
argonaute). In certain instances, the guide strand specifically binds to a complementary RBI mRNA sequence. In certain instances, the RISC cleaves an mRNA sequence of a gene to be silenced. In certain instances, the expression of the gene to be silenced is down-regulated.
[00301] In some embodiments, a sequence complementary to an mRNA sequence of a target gene is incorporated into a vector. In some embodiments, the sequence is placed between two promoters. In some embodiments, the promoters are orientated in opposite directions. In some embodiments, 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. In some embodiments, the vector is a plasmid (e.g pSUPER;
pSUPER.neo;
pSUPER.neo+gfp).
[00302] In some embodiments, 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).
[00303] In some embodiments, 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. For methods of formulating and administering a nucleic acid molecule to an individual in need thereof see Akhtar et al., 1992, Trends Cell Bio., 2, 139; Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed.
Akhtar, 1995; Maurer et al., 1999, Mol. Membr. Biol., 16, 129-140; Hofland and Huang, 1999, Handb. Exp. Pharmacol., 137, 165-192; Lee et al., 2000, ACS Symp. Ser., 752, 184-192; Beigelman et al., U.S. Pat. No. 6,395,713; Sullivan et al., PCT WO 94/02595; Gonzalez et al., 1999, Bioconjugate Chem., 10, 1068-1074; Wang et al., International PCT publication Nos. WO 03/47518 and WO 03/46185; U.S. Pat. No. 6,447,796; US Patent Application Publication No. US
2002130430; O'Hare and Normand, International PCT Publication No. WO 00/53722;
and U.S.
Patent Application Publication No. 20030077829; U.S. Provisional patent application No.
60/678,53 1, all of which are hereby incorporated by reference for such disclosures.
[00304] In some embodiments, 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, 1611-7; and Matsuno et al., 2003, Gene Ther., 10, 1559-66).
[00305] In some embodiments, an siRNA molecule described herein is administered iontophoretically, for example to 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.
molecule which is cleaved into siRNA molecules. In certain instances, the strands hybridize to form an siRNA
molecule. In some embodiments, the vector is a plasmid (e.g pSUPER;
pSUPER.neo;
pSUPER.neo+gfp).
[00302] In some embodiments, 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).
[00303] In some embodiments, 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. For methods of formulating and administering a nucleic acid molecule to an individual in need thereof see Akhtar et al., 1992, Trends Cell Bio., 2, 139; Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed.
Akhtar, 1995; Maurer et al., 1999, Mol. Membr. Biol., 16, 129-140; Hofland and Huang, 1999, Handb. Exp. Pharmacol., 137, 165-192; Lee et al., 2000, ACS Symp. Ser., 752, 184-192; Beigelman et al., U.S. Pat. No. 6,395,713; Sullivan et al., PCT WO 94/02595; Gonzalez et al., 1999, Bioconjugate Chem., 10, 1068-1074; Wang et al., International PCT publication Nos. WO 03/47518 and WO 03/46185; U.S. Pat. No. 6,447,796; US Patent Application Publication No. US
2002130430; O'Hare and Normand, International PCT Publication No. WO 00/53722;
and U.S.
Patent Application Publication No. 20030077829; U.S. Provisional patent application No.
60/678,53 1, all of which are hereby incorporated by reference for such disclosures.
[00304] In some embodiments, 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, 1611-7; and Matsuno et al., 2003, Gene Ther., 10, 1559-66).
[00305] In some embodiments, an siRNA molecule described herein is administered iontophoretically, for example to 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.
[00306] In some embodiments, 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).
[00307] In certain instances the therapy will need to be periodically re-administered. In some embodiments, the therapy is re-administered annually. In some embodiments, the therapy is re-administered semi-annually. In some embodiments, the therapy is administered monthly. In some embodiments, the therapy is administered weekly. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 60 mg/dL.
In some embodiments, 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.
[00308] For disclosures of techniques related to silencing the expression of Apo B and/or Hsp 110 see U.S. Pub. No. 2007/0293451 which is hereby incorporated by reference for such disclosures. For disclosures of techniques related to silencing the expression of Pcsk9 see U.S. Pub. No.
2007/0173473 which is hereby incorporated by reference for such disclosures.
Antisense Therapies [00309] Disclosed herein, in some embodiments, is a composition 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"). Disclosed herein, in some embodiments, are 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"). In some embodiments, inhibiting the expression of and/or activity of a target sequence comprises use of an antisense molecule complementary to the target sequence. In some embodiments, the target sequence is microRNA- 122 (miRNA-122 or mRNA-122), secretory phospholipase A2 (sPLA2), intracellular adhesion molecule-1 (ICAM-1), GATA-3, NF-x B, Syk, or combinations thereof. In certain instances, inhibiting the expression of and/or activity of miRNA-122 results (partially or fully) in a decrease in the concentration of cholesterol and/or lipids in blood.
[00310] In some embodiments, 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 embodiments, the antisense molecule is about 21 to about 24 nucleotides. For techniques for generating RNA sequences see 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.
[00311] In some embodiments, 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).
[00312] In some embodiments, an antisense molecule is "fully complementary"
(i.e., 100%
complementary) to the target sequence. In some embodiments, 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. In some embodiments, there is a 1 bp mismatch, a 2 bp mismatch, a 3 bp mismatch, a 4 bp mismatch, or a 5 bp mismatch.
[00313] In some embodiments, the antisense molecule hybridizes to the target sequence. As used herein, "hybridize" means the pairing of nucleotides of an antisense molecule with corresponding nucleotides of the target sequence. In certain instances, hybridization involves the formation of one or more hydrogen bonds (e.g., Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding) between the pairing nucleotides.
[00314] In certain instances, hybridizing results (partially or fully) in the degradation, cleavage, and/or sequestration of the RNA sequence.
[00315] In some embodiments, 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. For methods of formulating and administering a nucleic acid molecule to an individual in need thereof see Akhtar et al., 1992, Trends Cell Bio., 2, 139; Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed.
Akhtar, 1995; Maurer et al., 1999, Mol. Membr. Biol., 16, 129-140; Hofland and Huang, 1999, Handb. Exp. Pharmacol., 137, 165-192; Lee et al., 2000, ACS Symp. Ser., 752, 184-192; Beigelman et al., U.S. Pat. No. 6,395,713; Sullivan et al., PCT WO 94/02595; Gonzalez et al., 1999, Bioconjugate Chem., 10, 1068-1074; Wang et al., International PCT publication Nos. WO 03/47518 and WO 03/46185; U.S. Pat. No. 6,447,796; US Patent Application Publication No. US
2002130430; O'Hare and Normand, International PCT Publication No. WO 00/53722;
and U.S.
Patent Application Publication No. 20030077829; U.S. Provisional patent application No.
60/678,53 1, all of which are hereby incorporated by reference for such disclosures.
[00316] In some embodiments, 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, 1611-7; and Matsuno et al., 2003, Gene Ther., 10, 1559-66).
[00317] In some embodiments, an siRNA molecule described herein is administered iontophoretically, for example to 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.
[00318] In some embodiments, 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).
[00319] In certain instances the therapy will need to be periodically re-administered. In some embodiments, the therapy is re-administered annually. In some embodiments, the therapy is re-administered semi-annually. In some embodiments, the therapy is administered monthly. In some embodiments, the therapy is administered weekly. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 60 mg/dL.
In some embodiments, 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.
[00320] For disclosures of techniques related to silencing the expression of miRNA-122 see WO
07/027775A2 which is hereby incorporated by reference for such disclosures.
Device-Mediated Therapies [00321] In some embodiments, 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. For disclosures of techniques for removing a lipid from an HDL molecule and removing an LDL
molecule from the blood or plasma of an individual in need thereof see U.S.
Pub. No.
2008/0230465, which is hereby incorporated by reference for those disclosures.
[00322] In certain instances, the delipification therapy will need to be periodically re-administered.
In some embodiments, the delipification therapy is re-administered annually.
In some embodiments, the delipification therapy is re-administered semi-annually. In some embodiments, the delipification therapy is re-administered monthly. In some embodiments, the delipification therapy is re-administered semi-weekly. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 60 mg/dL. In some embodiments, 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.
Pharmaceutical Compositions [00323] Disclosed herein, in some embodiments, is a pharmaceutical composition for treating an inflammatory disease, disorder, condition, or symptom comprising a therapeutically-effective amount of agent disclosed herein.
[00324] Pharmaceutical 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).
[00325] In some embodiments, the pharmaceutical composition for modulating a disorder of a cardiovascular system further comprises a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In some embodiments, 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. In addition, the pharmaceutical compositions also contain other therapeutically valuable substances.
[00326] 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.
[00327] The pharmaceutical 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.
[00328] In some embodiments, the pharmaceutical compositions described herein are formulated as multiparticulate formulations. In some embodiments, the pharmaceutical compositions described herein comprise a first population of particles and a second population of particles. In some embodiments, the first population comprises an agent. In some embodiments, the second population comprises an agent. In some embodiments, the dose of agent in the first population is equal to the dose of agent in the second population. In some embodiments, 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.
[00329] In some embodiments, the agent of the first population is released before the agent of the second population. In some embodiments, the second population of particles comprises a modified-release (e.g., delayed-release, controlled-release, or extended release) coating. In some embodiments, the second population of particles comprises a modified-release (e.g., delayed-release, controlled-release, or extended release) matrix.
[00330] 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 methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, aminoacryl-methacrylate copolymer, pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers) 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. -30 k-300 k), polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, Polyox polyethylene oxides (m.
wt. -100 k-5,000 k), 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 acid derivatives, sorbitan esters, natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, arabic gum, karaya gum, locust bean gum, tragacanth gum, carrageens gum, guar gum, xanthan gum, scleroglucan gum); or combinations thereof. In some embodiments, the coating comprises a plasticiser, a lubricant, a solvent, or combinations thereof. Suitable plasticisers include, but are not limited to, acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol;
triacetin; citrate; tripropioin;
diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols;
castor oil; triethyl citrate;
polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate.
[00331] In some embodiments, 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.
[00332] In some embodiments, the first population of particles comprises a cardiovascular disorder agent. In some embodiments, 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. In some embodiments, 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. In some embodiments, the second population of particles comprises a cardiovascular disorder agent.
[00333] Dragee cores are provided with 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.
[00334] In some embodiments, 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.
In other embodiments, 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.
[00335] In another aspect, dosage forms include microencapsulated formulations. In some embodiments, 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.
[00336] 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 E46 1, Ethocel , Aqualon -EC, Surelease , Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosol , carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon -CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR , monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit EPO, Eudragit L30D-55, Eudragit FS 30D Eudragit L100-55, Eudragit L100, Eudragit 5100, Eudragit RD 100, Eudragit E l00, Eudragit L12.5, Eudragit S12.5, Eudragit NE30D, and Eudragit NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.
[00337] 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). In addition to a MIF
receptor inhibitor, 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. In some embodiments, the aqueous dispersions further include a crystal-forming inhibitor.
[00338] In some embodiments, the pharmaceutical formulations described herein are elf-emulsifying drug delivery systems (SEDDS). Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets. Generally, 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. Thus, the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. In some embodiments, 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.
[00339] Suitable intranasal formulations include those described in, for example, U.S. Pat. Nos.
4,476,116, 5,116,817 and 6,391,452. 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.
[00340] For administration by inhalation, 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. In the case of a pressurized aerosol, 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 starch.
[00341] 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. In addition, the buccal dosage forms described herein optionally further include a bioerodible (hydrolysable) 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 predetermined time period. Buccal drug delivery avoids the disadvantages encountered with oral drug administration, e.g., slow absorption, degradation of the agent by fluids present in the gastrointestinal tract and/or first-pass inactivation in the liver. 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). Other components also be incorporated into the buccal dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like. For buccal or sublingual administration, the compositions optionally take the form of tablets, lozenges, or gels formulated in a conventional manner.
[00342] 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.
[00343] The transdermal formulations described herein include at least three components: (1) an agent; (2) a penetration enhancer; and (3) an aqueous adjuvant. In addition, transdermal formulations include components such as, but not limited to, gelling agents, creams and ointment bases, and the like. In some embodiments, 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. In other embodiments, the transdermal formulations described herein maintain a saturated or supersaturated state to promote diffusion into the skin.
[00344] In some embodiments, 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. Such patches are optionally constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Still further, transdermal delivery is optionally accomplished by means of iontophoretic patches and the like. Additionally, 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. Conversely, absorption enhancers are used to increase absorption. An absorption enhancer or carrier includes absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, 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.
[00345] 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.
Examples of 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. Proper fluidity is maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
Formulations suitable for subcutaneous injection also contain optional additives such as preserving, wetting, emulsifying, and dispensing agents.
[00346] For intravenous injections, 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. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. For other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients.
[00347] 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. In some embodiments, 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.
[00348] In some embodiments, 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.
[00349] 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. In suppository forms of the compositions, 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.
[00350] 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. In addition, 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, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said individual.
[00351] In the case wherein the individual's condition does not improve, upon the doctor's discretion the administration of 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.
[00352] In the case wherein the individual's status does improve, upon the doctor's discretion 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%.
[00307] In certain instances the therapy will need to be periodically re-administered. In some embodiments, the therapy is re-administered annually. In some embodiments, the therapy is re-administered semi-annually. In some embodiments, the therapy is administered monthly. In some embodiments, the therapy is administered weekly. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 60 mg/dL.
In some embodiments, 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.
[00308] For disclosures of techniques related to silencing the expression of Apo B and/or Hsp 110 see U.S. Pub. No. 2007/0293451 which is hereby incorporated by reference for such disclosures. For disclosures of techniques related to silencing the expression of Pcsk9 see U.S. Pub. No.
2007/0173473 which is hereby incorporated by reference for such disclosures.
Antisense Therapies [00309] Disclosed herein, in some embodiments, is a composition 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"). Disclosed herein, in some embodiments, are 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"). In some embodiments, inhibiting the expression of and/or activity of a target sequence comprises use of an antisense molecule complementary to the target sequence. In some embodiments, the target sequence is microRNA- 122 (miRNA-122 or mRNA-122), secretory phospholipase A2 (sPLA2), intracellular adhesion molecule-1 (ICAM-1), GATA-3, NF-x B, Syk, or combinations thereof. In certain instances, inhibiting the expression of and/or activity of miRNA-122 results (partially or fully) in a decrease in the concentration of cholesterol and/or lipids in blood.
[00310] In some embodiments, 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 embodiments, the antisense molecule is about 21 to about 24 nucleotides. For techniques for generating RNA sequences see 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.
[00311] In some embodiments, 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).
[00312] In some embodiments, an antisense molecule is "fully complementary"
(i.e., 100%
complementary) to the target sequence. In some embodiments, 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. In some embodiments, there is a 1 bp mismatch, a 2 bp mismatch, a 3 bp mismatch, a 4 bp mismatch, or a 5 bp mismatch.
[00313] In some embodiments, the antisense molecule hybridizes to the target sequence. As used herein, "hybridize" means the pairing of nucleotides of an antisense molecule with corresponding nucleotides of the target sequence. In certain instances, hybridization involves the formation of one or more hydrogen bonds (e.g., Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding) between the pairing nucleotides.
[00314] In certain instances, hybridizing results (partially or fully) in the degradation, cleavage, and/or sequestration of the RNA sequence.
[00315] In some embodiments, 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. For methods of formulating and administering a nucleic acid molecule to an individual in need thereof see Akhtar et al., 1992, Trends Cell Bio., 2, 139; Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed.
Akhtar, 1995; Maurer et al., 1999, Mol. Membr. Biol., 16, 129-140; Hofland and Huang, 1999, Handb. Exp. Pharmacol., 137, 165-192; Lee et al., 2000, ACS Symp. Ser., 752, 184-192; Beigelman et al., U.S. Pat. No. 6,395,713; Sullivan et al., PCT WO 94/02595; Gonzalez et al., 1999, Bioconjugate Chem., 10, 1068-1074; Wang et al., International PCT publication Nos. WO 03/47518 and WO 03/46185; U.S. Pat. No. 6,447,796; US Patent Application Publication No. US
2002130430; O'Hare and Normand, International PCT Publication No. WO 00/53722;
and U.S.
Patent Application Publication No. 20030077829; U.S. Provisional patent application No.
60/678,53 1, all of which are hereby incorporated by reference for such disclosures.
[00316] In some embodiments, 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, 1611-7; and Matsuno et al., 2003, Gene Ther., 10, 1559-66).
[00317] In some embodiments, an siRNA molecule described herein is administered iontophoretically, for example to 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.
[00318] In some embodiments, 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).
[00319] In certain instances the therapy will need to be periodically re-administered. In some embodiments, the therapy is re-administered annually. In some embodiments, the therapy is re-administered semi-annually. In some embodiments, the therapy is administered monthly. In some embodiments, the therapy is administered weekly. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 60 mg/dL.
In some embodiments, 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.
[00320] For disclosures of techniques related to silencing the expression of miRNA-122 see WO
07/027775A2 which is hereby incorporated by reference for such disclosures.
Device-Mediated Therapies [00321] In some embodiments, 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. For disclosures of techniques for removing a lipid from an HDL molecule and removing an LDL
molecule from the blood or plasma of an individual in need thereof see U.S.
Pub. No.
2008/0230465, which is hereby incorporated by reference for those disclosures.
[00322] In certain instances, the delipification therapy will need to be periodically re-administered.
In some embodiments, the delipification therapy is re-administered annually.
In some embodiments, the delipification therapy is re-administered semi-annually. In some embodiments, the delipification therapy is re-administered monthly. In some embodiments, the delipification therapy is re-administered semi-weekly. In some embodiments, the therapy is re-administered when the individual's HDL level decreases below about 60 mg/dL. In some embodiments, 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.
Pharmaceutical Compositions [00323] Disclosed herein, in some embodiments, is a pharmaceutical composition for treating an inflammatory disease, disorder, condition, or symptom comprising a therapeutically-effective amount of agent disclosed herein.
[00324] Pharmaceutical 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).
[00325] In some embodiments, the pharmaceutical composition for modulating a disorder of a cardiovascular system further comprises a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In some embodiments, 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. In addition, the pharmaceutical compositions also contain other therapeutically valuable substances.
[00326] 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.
[00327] The pharmaceutical 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.
[00328] In some embodiments, the pharmaceutical compositions described herein are formulated as multiparticulate formulations. In some embodiments, the pharmaceutical compositions described herein comprise a first population of particles and a second population of particles. In some embodiments, the first population comprises an agent. In some embodiments, the second population comprises an agent. In some embodiments, the dose of agent in the first population is equal to the dose of agent in the second population. In some embodiments, 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.
[00329] In some embodiments, the agent of the first population is released before the agent of the second population. In some embodiments, the second population of particles comprises a modified-release (e.g., delayed-release, controlled-release, or extended release) coating. In some embodiments, the second population of particles comprises a modified-release (e.g., delayed-release, controlled-release, or extended release) matrix.
[00330] 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 methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, aminoacryl-methacrylate copolymer, pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers) 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. -30 k-300 k), polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, Polyox polyethylene oxides (m.
wt. -100 k-5,000 k), 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 acid derivatives, sorbitan esters, natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, arabic gum, karaya gum, locust bean gum, tragacanth gum, carrageens gum, guar gum, xanthan gum, scleroglucan gum); or combinations thereof. In some embodiments, the coating comprises a plasticiser, a lubricant, a solvent, or combinations thereof. Suitable plasticisers include, but are not limited to, acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol;
triacetin; citrate; tripropioin;
diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols;
castor oil; triethyl citrate;
polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate.
[00331] In some embodiments, 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.
[00332] In some embodiments, the first population of particles comprises a cardiovascular disorder agent. In some embodiments, 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. In some embodiments, 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. In some embodiments, the second population of particles comprises a cardiovascular disorder agent.
[00333] Dragee cores are provided with 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.
[00334] In some embodiments, 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.
In other embodiments, 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.
[00335] In another aspect, dosage forms include microencapsulated formulations. In some embodiments, 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.
[00336] 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 E46 1, Ethocel , Aqualon -EC, Surelease , Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosol , carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon -CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR , monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit EPO, Eudragit L30D-55, Eudragit FS 30D Eudragit L100-55, Eudragit L100, Eudragit 5100, Eudragit RD 100, Eudragit E l00, Eudragit L12.5, Eudragit S12.5, Eudragit NE30D, and Eudragit NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.
[00337] 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). In addition to a MIF
receptor inhibitor, 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. In some embodiments, the aqueous dispersions further include a crystal-forming inhibitor.
[00338] In some embodiments, the pharmaceutical formulations described herein are elf-emulsifying drug delivery systems (SEDDS). Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets. Generally, 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. Thus, the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. In some embodiments, 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.
[00339] Suitable intranasal formulations include those described in, for example, U.S. Pat. Nos.
4,476,116, 5,116,817 and 6,391,452. 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.
[00340] For administration by inhalation, 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. In the case of a pressurized aerosol, 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 starch.
[00341] 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. In addition, the buccal dosage forms described herein optionally further include a bioerodible (hydrolysable) 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 predetermined time period. Buccal drug delivery avoids the disadvantages encountered with oral drug administration, e.g., slow absorption, degradation of the agent by fluids present in the gastrointestinal tract and/or first-pass inactivation in the liver. 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). Other components also be incorporated into the buccal dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like. For buccal or sublingual administration, the compositions optionally take the form of tablets, lozenges, or gels formulated in a conventional manner.
[00342] 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.
[00343] The transdermal formulations described herein include at least three components: (1) an agent; (2) a penetration enhancer; and (3) an aqueous adjuvant. In addition, transdermal formulations include components such as, but not limited to, gelling agents, creams and ointment bases, and the like. In some embodiments, 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. In other embodiments, the transdermal formulations described herein maintain a saturated or supersaturated state to promote diffusion into the skin.
[00344] In some embodiments, 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. Such patches are optionally constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Still further, transdermal delivery is optionally accomplished by means of iontophoretic patches and the like. Additionally, 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. Conversely, absorption enhancers are used to increase absorption. An absorption enhancer or carrier includes absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, 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.
[00345] 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.
Examples of 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. Proper fluidity is maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
Formulations suitable for subcutaneous injection also contain optional additives such as preserving, wetting, emulsifying, and dispensing agents.
[00346] For intravenous injections, 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. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. For other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients.
[00347] 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. In some embodiments, 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.
[00348] In some embodiments, 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.
[00349] 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. In suppository forms of the compositions, 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.
[00350] 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. In addition, 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, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said individual.
[00351] In the case wherein the individual's condition does not improve, upon the doctor's discretion the administration of 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.
[00352] In the case wherein the individual's status does improve, upon the doctor's discretion 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%.
[00353] Once improvement of the individual's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, 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. In some embodiments, individuals require intermittent treatment on a long-term basis upon any recurrence of symptoms.
[00354] In some embodiments, the pharmaceutical composition described herein is in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of an agent disclosed herein. In some embodiments, 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. In some embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition. By way of example only, 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.
[00355] 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.
[00356] 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.
[00354] In some embodiments, the pharmaceutical composition described herein is in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of an agent disclosed herein. In some embodiments, 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. In some embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition. By way of example only, 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.
[00355] 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.
[00356] 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.
EXAMPLES
[00357] The following specific examples are to be construed as illustrative, and not limiting of the disclosure or the claims.
Cell Lines and Reagents [00358] Human aortic (Schober, A., et al. (2004) Circulation 109, 380-385) and umbilical vein (Weber, K.S., et al. (1999) Eur. J. Immunol. 29, 700-712) endothelial cells (PromoCell), 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). Peripheral blood mononuclear cells were prepared from buffy coats, monocytes by adherence or immunomagnetic separation (Miltenyi), primary T
cells by phytohaemaglutinin/interleukin-2 (Biosource) stimulation and/or immunomagnetic selection (antibody to CD3/ M-450 Dynabeads), and neutrophils by Ficoll gradient centrifugation. Human embryonal kidney-CXCR2 transfectants (HEK293-CXCR2) have been described previously (Ben-Baruch, A., et al. (1997) Cytokine 9, 37-45).
[00359] Recombinant MIF was expressed and purified as described (Bernhagen, J., et al. (1993) Nature 365, 756-759). Chemokines were from PeproTech. Human VCAM-1.Fc chimera, blocking antibodies to CXCRI (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.
185, 1455-1465), CD74 (M-B741, Pharmingen), R2 integrin (TS 1/18), a4 integrin (HP2/1) (Weber, C., et al. (1996) J.
Cell Biol. 134, 1063-1073) and CXCR2 (RII115), and antibody to aL integrin (327C) (Shamri, R., et al. (2005) Nat. Immunol. 6, 497-506) were used. PTX and B-oligomer were from Merck.
Methods Used in Examples Adhesion assays.
[00360] Arrest of calcein-AM (Molecular Probes)-labeled monocytes, T cells and L1.2 transfectants was quantified in parallel-wall chambers in flow (1.5 dynes/cm2, 5 min) (Schober, A., et al. (2004) Circulation 109, 380-385; Ostermann, G., et al. (2002) Nat. Immunol. 3, 151-158; Weber, C., et al.
(1996) J. Cell Biol. 134, 1063-1073). Confluent endothelial cells, CHO-ICAM-1 cells, VCAM-1.Fc-coated plates and leukocytes were pretreated with MIF, chemokines or antibodies. 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.
[00357] The following specific examples are to be construed as illustrative, and not limiting of the disclosure or the claims.
Cell Lines and Reagents [00358] Human aortic (Schober, A., et al. (2004) Circulation 109, 380-385) and umbilical vein (Weber, K.S., et al. (1999) Eur. J. Immunol. 29, 700-712) endothelial cells (PromoCell), 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). Peripheral blood mononuclear cells were prepared from buffy coats, monocytes by adherence or immunomagnetic separation (Miltenyi), primary T
cells by phytohaemaglutinin/interleukin-2 (Biosource) stimulation and/or immunomagnetic selection (antibody to CD3/ M-450 Dynabeads), and neutrophils by Ficoll gradient centrifugation. Human embryonal kidney-CXCR2 transfectants (HEK293-CXCR2) have been described previously (Ben-Baruch, A., et al. (1997) Cytokine 9, 37-45).
[00359] Recombinant MIF was expressed and purified as described (Bernhagen, J., et al. (1993) Nature 365, 756-759). Chemokines were from PeproTech. Human VCAM-1.Fc chimera, blocking antibodies to CXCRI (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.
185, 1455-1465), CD74 (M-B741, Pharmingen), R2 integrin (TS 1/18), a4 integrin (HP2/1) (Weber, C., et al. (1996) J.
Cell Biol. 134, 1063-1073) and CXCR2 (RII115), and antibody to aL integrin (327C) (Shamri, R., et al. (2005) Nat. Immunol. 6, 497-506) were used. PTX and B-oligomer were from Merck.
Methods Used in Examples Adhesion assays.
[00360] Arrest of calcein-AM (Molecular Probes)-labeled monocytes, T cells and L1.2 transfectants was quantified in parallel-wall chambers in flow (1.5 dynes/cm2, 5 min) (Schober, A., et al. (2004) Circulation 109, 380-385; Ostermann, G., et al. (2002) Nat. Immunol. 3, 151-158; Weber, C., et al.
(1996) J. Cell Biol. 134, 1063-1073). Confluent endothelial cells, CHO-ICAM-1 cells, VCAM-1.Fc-coated plates and leukocytes were pretreated with MIF, chemokines or antibodies. 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.
[00361] Using Transwell chambers (Costar), we quantified primary leukocyte migration toward MIF
or chemokines by fluorescence microscopy or using calcein-AM labeling and FluoroBlok filters (Falcon). Cells were pretreated with PTX/B-oligomer, Ly294002, MIF (for desensitization), antibodies to CXCRs or CD74, or isotype IgG. Pore sizes and intervals were 5 m and 3 h (monocytes), 3 m and 1.5 h (T cells), and 3 mm and 1 h (neutrophils).
Q-PCR and ELISA.
[00362] RNA was reverse-transcribed using oligo-dT primers. RTPCR was performed using QuantiTect Kit with SYBRGreen (Qiagen), specific primers and an MJ Opticon2 (Biozym). CXCL8 was quantified by Quantikine ELISA (R&D).
aL(32 integrin activation assay.
[00363] Monocytes stimulated with MIF or Mg2+/EGTA (positive control) 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).
Calcium mobilization.
[00364] Neutrophils or L1.2 CXCR2 transfectants were labeled with Fluo-4 AM
(Molecular Probes).
After the addition of the first or a subsequent stimulus (MIF, CXCL8 or CXCL7), MFI was monitored as a measure of cytosolic Ca 2+ concentrations for 120 s using a BD
FACSAria. L1.2 controls showed negligible calcium influx.
Receptor-binding assays.
[00365] Because iodinated MIF is inactive (Leng, L., et al. (2003) J. Exp.
Med. 197, 1467-1476;
Kleemann, R., et al. (2002) J. Interferon Cytokine Res. 22, 351-363), competitive receptor binding (Hayashi, S., et al. (1995) J. Immunol. 154, 814-824) were performed using radioiodinated tracers (Amersham): [1125]CXCL8, reconstituted at 4 nM (80 &i/ml) to a final concentration of 40 pM;
[1125]CXCL12, reconstituted at 5 nM (100 Ci/ml) to a final concentration of 50 pM. For competition of [1125]CXCL8 with MIF for CXCR2 binding or competition of [1125]CXCL12 with MIF for CXCR4 binding in equilibrium binding assays, cold MIF and/or CXCL with tracers to HEK293-CXCR2 or CXCR4-bearing Jurkat cells were added. The analysis was performed by liquid scintillation counting. To calculate EC50 and Kd values, a one-site receptor-ligand binding model was assumed and the Cheng/Prusoff-equation and GraphPad Prism were used.
[00366] For pull-down of biotin-MIF-CXCR complexes, 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. Complexes were isolated from cleared lysates by streptavidin-coated magnetic beads (M280, Dynal) and analyzed by western blotting with antibody to CXCR2 or streptavidin-peroxidase. For flow cytometry, 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.
CXCR internalization assays.
[00367] 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 MFI[experimental]-MFI[0% control]/MFI[100% control]-MFI[0% control] x 100.
Co localization of CXCR2 and CD74.
[00368] 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).
Coimmunoprecipitation of CXCR2 and CD74.
[00369] HEK293-CXCR2 cells transiently transfected with pcDNA3.1/V5-HisTOPO-TA-were lysed in nondenaturing CoIP buffer. Supernatants were incubated with the CXCR2 antibody Rll115 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.
Ex vivo perfusion and intravital microscopy of carotid arteries.
[00370] Mil-I Ldlr /- mice and M I+Ldlr / littermate controls, crossbred from Mil-1- (Fingerle-Rowson, G., et al. (2003) Proc. Natl. Acad. Sci. USA 100, 9354-9359) and Ldlr/
mice (Charles River), and Apoe i- 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.
Mit i+ and M ' 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 l/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. For intravital microscopy, 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 (Bezirksregierung Koln), and complied with German animal protection law Az: 50.203.2-AC 36, 19/05.
Mouse model of atherosclerotic disease progression.
[00361] Using Transwell chambers (Costar), we quantified primary leukocyte migration toward MIF
or chemokines by fluorescence microscopy or using calcein-AM labeling and FluoroBlok filters (Falcon). Cells were pretreated with PTX/B-oligomer, Ly294002, MIF (for desensitization), antibodies to CXCRs or CD74, or isotype IgG. Pore sizes and intervals were 5 m and 3 h (monocytes), 3 m and 1.5 h (T cells), and 3 mm and 1 h (neutrophils).
Q-PCR and ELISA.
[00362] RNA was reverse-transcribed using oligo-dT primers. RTPCR was performed using QuantiTect Kit with SYBRGreen (Qiagen), specific primers and an MJ Opticon2 (Biozym). CXCL8 was quantified by Quantikine ELISA (R&D).
aL(32 integrin activation assay.
[00363] Monocytes stimulated with MIF or Mg2+/EGTA (positive control) 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).
Calcium mobilization.
[00364] Neutrophils or L1.2 CXCR2 transfectants were labeled with Fluo-4 AM
(Molecular Probes).
After the addition of the first or a subsequent stimulus (MIF, CXCL8 or CXCL7), MFI was monitored as a measure of cytosolic Ca 2+ concentrations for 120 s using a BD
FACSAria. L1.2 controls showed negligible calcium influx.
Receptor-binding assays.
[00365] Because iodinated MIF is inactive (Leng, L., et al. (2003) J. Exp.
Med. 197, 1467-1476;
Kleemann, R., et al. (2002) J. Interferon Cytokine Res. 22, 351-363), competitive receptor binding (Hayashi, S., et al. (1995) J. Immunol. 154, 814-824) were performed using radioiodinated tracers (Amersham): [1125]CXCL8, reconstituted at 4 nM (80 &i/ml) to a final concentration of 40 pM;
[1125]CXCL12, reconstituted at 5 nM (100 Ci/ml) to a final concentration of 50 pM. For competition of [1125]CXCL8 with MIF for CXCR2 binding or competition of [1125]CXCL12 with MIF for CXCR4 binding in equilibrium binding assays, cold MIF and/or CXCL with tracers to HEK293-CXCR2 or CXCR4-bearing Jurkat cells were added. The analysis was performed by liquid scintillation counting. To calculate EC50 and Kd values, a one-site receptor-ligand binding model was assumed and the Cheng/Prusoff-equation and GraphPad Prism were used.
[00366] For pull-down of biotin-MIF-CXCR complexes, 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. Complexes were isolated from cleared lysates by streptavidin-coated magnetic beads (M280, Dynal) and analyzed by western blotting with antibody to CXCR2 or streptavidin-peroxidase. For flow cytometry, 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.
CXCR internalization assays.
[00367] 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 MFI[experimental]-MFI[0% control]/MFI[100% control]-MFI[0% control] x 100.
Co localization of CXCR2 and CD74.
[00368] 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).
Coimmunoprecipitation of CXCR2 and CD74.
[00369] HEK293-CXCR2 cells transiently transfected with pcDNA3.1/V5-HisTOPO-TA-were lysed in nondenaturing CoIP buffer. Supernatants were incubated with the CXCR2 antibody Rll115 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.
Ex vivo perfusion and intravital microscopy of carotid arteries.
[00370] Mil-I Ldlr /- mice and M I+Ldlr / littermate controls, crossbred from Mil-1- (Fingerle-Rowson, G., et al. (2003) Proc. Natl. Acad. Sci. USA 100, 9354-9359) and Ldlr/
mice (Charles River), and Apoe i- 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.
Mit i+ and M ' 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 l/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. For intravital microscopy, 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 (Bezirksregierung Koln), and complied with German animal protection law Az: 50.203.2-AC 36, 19/05.
Mouse model of atherosclerotic disease progression.
[00371] Apoe i- mice fed an atherogenic diet for 12 weeks were injected (3 injections per week, each 50 g) with antibodies to MIF (NIHIIID.9), CXCL12 (79014) or CXCLI (124014, R&D) (n = 6-10 mice) for an additional 4 weeks. 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. In Mif4 Ldl and Mif~I+Ldlr 1 mice fed a chow diet for 30 weeks, the abundance of luminal monocytes and lesional macrophages in aortic roots was determined as described (Verschuren, L., et al. (2005) Arterioscler. Thromb.
Vasc. Biol. 25, 161-167).
Cremaster microcirculation model.
[00372] Human MIF (1 g) was injected intra-scrotally and the cremaster muscle was exteriorized in mice treated with antibody to CXCR2 (100 g i.p.). After 4 h, intravital microscopy (Zeiss 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.
Bone marrow transplantation.
[00373] Femurs and tibias were aseptically removed from donor Il8rb_1-(Jackson Laboratories) or BALB/c mice. The cells, flushed from the marrow cavities, were administered i.v. into Mifl+ or Mif i mice 24 h after ablative whole-body irradiation (Zernecke, A., et al. (2005) Circ. Res. 96, 784-791).
Model of acute peritonitis.
[00374] Mice repopulated with Il8rb+i+ or Il8rb/- bone marrow were injected i.p. with MIF (200 ng).
After 4 h, peritoneal lavage was performed and Gr-1+CD 115-F4/80- neutrophils were quantified by flow cytometry using the relevant conjugated antibodies.
Statistical analysis.
[00375] Statistical analysis was performed using either a one-way analysis of variance (ANOVA) and Newman-Keuls post-hoc test or an unpaired Student's t-test with Welch's correction (GraphPad Prism).
EXAMPLE 2:
Surface-bound MIF induced monocyte arrest through CXCR2 [00376] Monoclonal antibodies and pertussis toxin (PTX) were used to explore whether MIF-induced monocyte arrest depends on Ga,1-coupled activities of CXCR2. Human aortic endothelial cells that had been pretreated with recombinant MIF for 2 h substantially increased the arrest of primary human monocytes under flow conditions, an effect blocked by an antibody to MIF (Fig. 1 a).
188A, Dako) and FITC-conjugated antibody. In Mif4 Ldl and Mif~I+Ldlr 1 mice fed a chow diet for 30 weeks, the abundance of luminal monocytes and lesional macrophages in aortic roots was determined as described (Verschuren, L., et al. (2005) Arterioscler. Thromb.
Vasc. Biol. 25, 161-167).
Cremaster microcirculation model.
[00372] Human MIF (1 g) was injected intra-scrotally and the cremaster muscle was exteriorized in mice treated with antibody to CXCR2 (100 g i.p.). After 4 h, intravital microscopy (Zeiss 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.
Bone marrow transplantation.
[00373] Femurs and tibias were aseptically removed from donor Il8rb_1-(Jackson Laboratories) or BALB/c mice. The cells, flushed from the marrow cavities, were administered i.v. into Mifl+ or Mif i mice 24 h after ablative whole-body irradiation (Zernecke, A., et al. (2005) Circ. Res. 96, 784-791).
Model of acute peritonitis.
[00374] Mice repopulated with Il8rb+i+ or Il8rb/- bone marrow were injected i.p. with MIF (200 ng).
After 4 h, peritoneal lavage was performed and Gr-1+CD 115-F4/80- neutrophils were quantified by flow cytometry using the relevant conjugated antibodies.
Statistical analysis.
[00375] Statistical analysis was performed using either a one-way analysis of variance (ANOVA) and Newman-Keuls post-hoc test or an unpaired Student's t-test with Welch's correction (GraphPad Prism).
EXAMPLE 2:
Surface-bound MIF induced monocyte arrest through CXCR2 [00376] Monoclonal antibodies and pertussis toxin (PTX) were used to explore whether MIF-induced monocyte arrest depends on Ga,1-coupled activities of CXCR2. Human aortic endothelial cells that had been pretreated with recombinant MIF for 2 h substantially increased the arrest of primary human monocytes under flow conditions, an effect blocked by an antibody to MIF (Fig. 1 a).
Notably, MIF-triggered, but not spontaneous, monocyte arrest was ablated by an antibody to CXCR2 or by PTX, implicating Ga,1-coupled CXCR2. The ability of MIF to induce monocyte arrest through CXCR2 was confirmed using monocytic Mono-Mach cells and this activity was associated with an immobilization of MIF on aortic endothelial cells (Fig. lb). This data indicated that MIF
was presented on the endothelial cell surface and exerted a chemokine-like arrest function as a noncognate CXCR2 ligand. Blocking classical CXCR2 agonists (CXCL1/CXCL8) failed to interfere with these effects of MIF (Fig. I a).
[00377] Chinese hamster ovary (CHO) transfectants that express the R2 integrin ligand, ICAM-1 (intercellular adhesion molecule 1), were used to dissect the mechanisms by which MIF promotes integrin-dependent arrest. As quantified under flow conditions, the exposure of CHO transfectants to MIF for 2 h resulted in its surface presentation (Fig. lb) and, like exposure of the transfectants to CXCL8, increased monocytic cell arrest (Fig. lc). This effect was fully sensitive to PTX and an antibody to R2 integrin (Fig. lc), confirming a role of Ga1 1 in R2 integrin-mediated arrest induced by MIF. Primary monocytes and MonoMac6 cells express both CXCRI and CXCR2 (Weber, K.S., et al. (1999) Eur. J. Immunol. 29, 700-712). Whereas blocking CXCR1 had no effect, blocking CXCR2 substantially but not fully impaired MIF-triggered and CXCL8-triggered monocytic cell arrest. Addition of antibodies to both CXCRI 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. 1 d). Spontaneous arrest was unaffected (Fig. 8). Thus, CXCR2 assisted by CD74 mediates MIF-induced arrest.
MIF induced T-Cell arrest through CXCR4 [00378] Either MIF or CXCL12 immobilized on aortic endothelial cells triggered the arrest of primary human effector T cells (Fig. 1 e). MIF-induced, but not spontaneous, T-cell arrest was sensitive to PTX and was inhibited by an antibody to CXCR4 (Fig. 1 e).
Although less pronounced than in monocytes expressing CXCR2 (Fig. ld), presentation of MIF (or CXCL12) on CHO
transfectants expressing ICAM-1 elicited aL(32-dependent arrest of Jurkat T
cells, an effect mediated by CXCR4 (Fig. If).
[00379] Ectopic expression of CXCR2 in Jurkat T cells increased MIF-triggered arrest (Fig. lg), corroborating the idea that CXCR2 imparts responsiveness to MIF in leukocytes.
L1.2 pre-B
lymphoma transfectants expressing CXCR1, CXCR2 or CXCR3, and controls using cells expressing endogenous CXCR4 only were used in the presence of the CXCR4 antagonist AMD3465. MIF
triggered the arrest of CXCR2 transfectants and CXCR4-bearing controls on endothelial cells with a similar efficacy to that of the canonical ligands CXCL8 and CXCL12, whereas CXCR1 and CXCR3 transfectants were responsive to CXCL8 and CXCL10, respectively, but not to MIF (Fig. lh). This data established that CXCR2 and CXCR4, but not CXCRI or CXCR3, support MIF-induced arrest.
was presented on the endothelial cell surface and exerted a chemokine-like arrest function as a noncognate CXCR2 ligand. Blocking classical CXCR2 agonists (CXCL1/CXCL8) failed to interfere with these effects of MIF (Fig. I a).
[00377] Chinese hamster ovary (CHO) transfectants that express the R2 integrin ligand, ICAM-1 (intercellular adhesion molecule 1), were used to dissect the mechanisms by which MIF promotes integrin-dependent arrest. As quantified under flow conditions, the exposure of CHO transfectants to MIF for 2 h resulted in its surface presentation (Fig. lb) and, like exposure of the transfectants to CXCL8, increased monocytic cell arrest (Fig. lc). This effect was fully sensitive to PTX and an antibody to R2 integrin (Fig. lc), confirming a role of Ga1 1 in R2 integrin-mediated arrest induced by MIF. Primary monocytes and MonoMac6 cells express both CXCRI and CXCR2 (Weber, K.S., et al. (1999) Eur. J. Immunol. 29, 700-712). Whereas blocking CXCR1 had no effect, blocking CXCR2 substantially but not fully impaired MIF-triggered and CXCL8-triggered monocytic cell arrest. Addition of antibodies to both CXCRI 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. 1 d). Spontaneous arrest was unaffected (Fig. 8). Thus, CXCR2 assisted by CD74 mediates MIF-induced arrest.
MIF induced T-Cell arrest through CXCR4 [00378] Either MIF or CXCL12 immobilized on aortic endothelial cells triggered the arrest of primary human effector T cells (Fig. 1 e). MIF-induced, but not spontaneous, T-cell arrest was sensitive to PTX and was inhibited by an antibody to CXCR4 (Fig. 1 e).
Although less pronounced than in monocytes expressing CXCR2 (Fig. ld), presentation of MIF (or CXCL12) on CHO
transfectants expressing ICAM-1 elicited aL(32-dependent arrest of Jurkat T
cells, an effect mediated by CXCR4 (Fig. If).
[00379] Ectopic expression of CXCR2 in Jurkat T cells increased MIF-triggered arrest (Fig. lg), corroborating the idea that CXCR2 imparts responsiveness to MIF in leukocytes.
L1.2 pre-B
lymphoma transfectants expressing CXCR1, CXCR2 or CXCR3, and controls using cells expressing endogenous CXCR4 only were used in the presence of the CXCR4 antagonist AMD3465. MIF
triggered the arrest of CXCR2 transfectants and CXCR4-bearing controls on endothelial cells with a similar efficacy to that of the canonical ligands CXCL8 and CXCL12, whereas CXCR1 and CXCR3 transfectants were responsive to CXCL8 and CXCL10, respectively, but not to MIF (Fig. lh). This data established that CXCR2 and CXCR4, but not CXCRI or CXCR3, support MIF-induced arrest.
MIF-induced leukocyte chemotaxis through CXCR2/4 activation [00380] 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. Vasc. Biol. 24, 1997-2008). Paradoxically, MIF was initially thought to interfere with `random' migration (Calandra, T., et al. (2003) Nat. Rev. Immunol. 3, 791-800). Although this may be attributable to active repulsion or desensitization of directed emigration, specific mechanisms evoked by MIF to regulate migration remain to be clarified. Our results showing that MIF
induced Ga,1-mediated functions of CXCR2 and CXCR4 prompted us to test if MIF directly elicits leukocyte chemotaxis through these receptors.
[00381] Using a transwell system, the promigratory effects of MIF and CXCL8 were compared on primary human peripheral blood mononuclear cell-derived monocytes. CCL2 was also used as a prototypic chemokine for monocytes. Similar to CXCL8 and CCL2, adding MIF to the lower chamber induced migration, which followed a bell-shaped dose-response curve typical for chemokines, with an optimum at 25-50 ng/ml, albeit with a lower peak migratory index (Fig. 2a).
Heat treatment or a neutralizing antibody to MIF abolished MIF-induced transmigration. In contrast, isotype-matched immunoglobulin (IgG) had no effect (Fig. 2b). When added to the upper chamber, MIF dose-dependently desensitized migration toward MIF in the lower chamber (Fig. 2c) but did not elicit migration when present in the upper chamber only, suggesting that MIF evokes true chemotaxis rather than chemokinesis. Consistent with Ga,1-dependent signaling through phosphoinositide-3-kinase, 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 L1.2 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.
[00382] To substantiate functional MIF-CXCR4 interactions, the transmigration of primary CD3+ T
lymphocytes devoid of CXCRI and CXCR2 was evaluated. Similar to CXCL12, a known CXCR4 ligand and T-cell chemoattractant, MIF dose-dependently induced transmigration, a process that was chemotactic and transduced through CXCR4, as shown by antibody blockade and cross-desensitization of CXCL12 (Fig. 2f & Fig. 8). Thus, MIF elicits directed T-cell migration through CXCR4. In primary human neutrophils, a major cell type bearing CXCR2, MIF
exerted CXCR2-but not CXCR I -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). Although 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 [00383] Arrest functions of MIF may reflect direct MIF/CXCR signaling, but it cannot be entirely excluded that MIF induces other arrest chemokines during the time required for MIF
immobilization. To consolidate evidence that MIF directly induces leukocyte arrest (Fig. 1), real-time PCR and ELISAs were performed and found that 2-h-long preincubation of human aortic (or venous) endothelial cells with MIF failed to upregulate typical arrest chemokines known to engage CXCR2 (Fig. 3a).
[00384] Short-term exposure to chemokines present in solution or immobilized in juxtaposition to integrin ligands (for example, vascular cell adhesion molecule (VCAM)- 1) can rapidly upregulate integrin activity, which mediates leukocyte arrest (Laudanna, C., et al.
(2006) Thromb. Haemost. 95, 5-11). This is accomplished by clustering (for example, a4(3i) or conformational changes (for example, aL(32) immediately preceding ligand binding. Stimulation of monocytic cells with MIF (or CXCL8) for 1-5 min triggered aLR2-dependent arrest on CHO/ICAM-1 cells (Fig.
3b). To obtain evidence for a direct stimulation of monocyte integrins, the reporter antibody 327C, which recognizes an extended high-affinity conformation of aL(32, was used (Shamri, R., et al. (2005) Nat.
Immunol. 6, 497-506). These assays revealed that aL(32 activation in MonoMac6 cells (Fig. 3c) and human blood monocytes (Fig. 3d) occurred as early as 1 min after exposure to MIF and persisted over 30 min. To evaluate whether MIF's effects were restricted to aLR2, a4(3i-dependent monocytic cell arrest on VCAM-1 was studied. Exposure to MIF for 1-5 min induced marked arrest, which was mediated by CXCR2, CD74 and a4(3i (Fig. 3e). Similarly to the effect of CXCL12, stimulation of Jurkat T cells with MIF for 1-5 min triggered CXCR4-dependent adhesion on VCAM-1 (Fig. 8).
[00385] As CXCR2 can mediate increases in cytosolic calcium elicited by CXCL8 (Jones, S.A., et al. (1997) J. Biol. Chem. 272, 16166-16169), the ability of MIF to stimulate calcium influx and desensitize CXCL8 signals was tested. Indeed, like CXCL8, MIF induced calcium influx in primary human neutrophils and desensitized calcium transients in response to either CXCL8 or MIF (Fig.
3f), confirming that MIF activates GPCR/G,,; signaling. The partial desensitization of CXCL8 signaling by MIF seen in neutrophils parallels findings with other CXCR2 ligands (Jones, S.A., et al.
(1997) J. Biol. Chem. 272, 16166-16169) and reflects the presence of CXCR1. In L1.2 transfectants expressing CXCR2, MIF fully desensitized CXCL8-induced calcium influx, and in neutrophils, MIF
desensitized transients induced by the selective CXCR2 ligand CXCL7 (and CXCL7 desensitized transients induced by MIF) (Fig. 3f). In CXCR2 transfectants, MIF dose-dependently induced calcium influx, and was slightly less potent and effective than CXCL8 or CXCL7 (Fig. 3g). In conclusion, MIF acted on CXCR2 and CXCR4 to elicit rapid integrin activation and calcium influx.
MIF interacts with CXCR2 and CXCR4 [00386] To assess the physical interactions of MIF with CXCR2 and CXCR4, we performed receptor-binding competition and internalization studies. In HEK293 cells ectopically expressing CXCR2, MIF strongly competed with 125I-labeled CXCL8 for CXCR2 binding under equilibrium conditions. Binding of the CXCL8 tracer to CXCR2 was inhibited by MIF with an effector concentration for half-maximum response (EC50) of 1.5 nM (Fig. 4a). The affinity of CXCR2 for MIF (Kd = 1.4 nM) was close to that for CXCL8 (Kd = 0.7 nM) and within the range of the MIF
concentration that induced optimal chemotaxis (2-4 nM). To confirm binding to CXCR2, we used a receptor internalization assay that reports specific receptor-ligand interactions. FACS analysis of surface CXCR2 on stable HEK293 transfectants showed that MIF induced CXCR2 internalization with a dose response resembling that of CXCL8 (Fig. 4b). Comparable data was obtained in CXCR2-transfected RAW264.7 macrophages (inset in Fig. 4b).
[00387] To verify an interaction of MIF with CXCR4, receptor-binding studies were performed in Jurkat T cells, which endogenously express CXCR4. MIF competed with 125I-labeled CXCL12 for CXCR4 binding (Kd for CXCL12 = 1.5 nM; EC50 = 19.9 nM, Kd for MIF = 19.8 nM) (Fig. 4c). The Kd was in accordance with MIF concentrations that induce T-cell chemotaxis.
Consistently, MIF, like CXCL12, elicited CXCR4 internalization in a dose-dependent fashion (Fig.
4d). MIF-induced internalization of CXCR2 and CXCR4 was specific to these receptors, as MIF, unlike the cognate ligand CCL5, was unable to induce CCR5 internalization in L1.2 CCR5 transfectants.
[00388] To corroborate its interactions with CXCRs, MIF was labeled with biotin or fluorescein, which, in contrast to iodinated MIF, allows for direct receptor-binding assays. CXCR2 transfectants, but not vector controls, supported direct binding of labeled MIF, as evidenced by flow cytometry (Fig. 4e), pull down with streptavidin beads (inset in Fig. 4e) and fluorescence microscopy. In addition, the specific binding of fluorescein-MIF to CXCR4-bearing Jurkat cells was inhibited by the CXCR4 antagonist AMD3465.
Complex formation between CXCR2 and CD74 [00389] Our data suggests the possibility that a functional MIF receptor complex involves both GPCRs and CD74. Thus, the colocalization of endogenous CD74 and CXCR2 was visualized using confocal fluorescence microscopy in RAW264.7 macrophages expressing human CXCR2. Using this technique, prominent colocalization was observed in a polarized pattern in -50% of cells (Fig.
4f).
Thromb. Vasc. Biol. 24, 1997-2008). Paradoxically, MIF was initially thought to interfere with `random' migration (Calandra, T., et al. (2003) Nat. Rev. Immunol. 3, 791-800). Although this may be attributable to active repulsion or desensitization of directed emigration, specific mechanisms evoked by MIF to regulate migration remain to be clarified. Our results showing that MIF
induced Ga,1-mediated functions of CXCR2 and CXCR4 prompted us to test if MIF directly elicits leukocyte chemotaxis through these receptors.
[00381] Using a transwell system, the promigratory effects of MIF and CXCL8 were compared on primary human peripheral blood mononuclear cell-derived monocytes. CCL2 was also used as a prototypic chemokine for monocytes. Similar to CXCL8 and CCL2, adding MIF to the lower chamber induced migration, which followed a bell-shaped dose-response curve typical for chemokines, with an optimum at 25-50 ng/ml, albeit with a lower peak migratory index (Fig. 2a).
Heat treatment or a neutralizing antibody to MIF abolished MIF-induced transmigration. In contrast, isotype-matched immunoglobulin (IgG) had no effect (Fig. 2b). When added to the upper chamber, MIF dose-dependently desensitized migration toward MIF in the lower chamber (Fig. 2c) but did not elicit migration when present in the upper chamber only, suggesting that MIF evokes true chemotaxis rather than chemokinesis. Consistent with Ga,1-dependent signaling through phosphoinositide-3-kinase, 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 L1.2 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.
[00382] To substantiate functional MIF-CXCR4 interactions, the transmigration of primary CD3+ T
lymphocytes devoid of CXCRI and CXCR2 was evaluated. Similar to CXCL12, a known CXCR4 ligand and T-cell chemoattractant, MIF dose-dependently induced transmigration, a process that was chemotactic and transduced through CXCR4, as shown by antibody blockade and cross-desensitization of CXCL12 (Fig. 2f & Fig. 8). Thus, MIF elicits directed T-cell migration through CXCR4. In primary human neutrophils, a major cell type bearing CXCR2, MIF
exerted CXCR2-but not CXCR I -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). Although 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 [00383] Arrest functions of MIF may reflect direct MIF/CXCR signaling, but it cannot be entirely excluded that MIF induces other arrest chemokines during the time required for MIF
immobilization. To consolidate evidence that MIF directly induces leukocyte arrest (Fig. 1), real-time PCR and ELISAs were performed and found that 2-h-long preincubation of human aortic (or venous) endothelial cells with MIF failed to upregulate typical arrest chemokines known to engage CXCR2 (Fig. 3a).
[00384] Short-term exposure to chemokines present in solution or immobilized in juxtaposition to integrin ligands (for example, vascular cell adhesion molecule (VCAM)- 1) can rapidly upregulate integrin activity, which mediates leukocyte arrest (Laudanna, C., et al.
(2006) Thromb. Haemost. 95, 5-11). This is accomplished by clustering (for example, a4(3i) or conformational changes (for example, aL(32) immediately preceding ligand binding. Stimulation of monocytic cells with MIF (or CXCL8) for 1-5 min triggered aLR2-dependent arrest on CHO/ICAM-1 cells (Fig.
3b). To obtain evidence for a direct stimulation of monocyte integrins, the reporter antibody 327C, which recognizes an extended high-affinity conformation of aL(32, was used (Shamri, R., et al. (2005) Nat.
Immunol. 6, 497-506). These assays revealed that aL(32 activation in MonoMac6 cells (Fig. 3c) and human blood monocytes (Fig. 3d) occurred as early as 1 min after exposure to MIF and persisted over 30 min. To evaluate whether MIF's effects were restricted to aLR2, a4(3i-dependent monocytic cell arrest on VCAM-1 was studied. Exposure to MIF for 1-5 min induced marked arrest, which was mediated by CXCR2, CD74 and a4(3i (Fig. 3e). Similarly to the effect of CXCL12, stimulation of Jurkat T cells with MIF for 1-5 min triggered CXCR4-dependent adhesion on VCAM-1 (Fig. 8).
[00385] As CXCR2 can mediate increases in cytosolic calcium elicited by CXCL8 (Jones, S.A., et al. (1997) J. Biol. Chem. 272, 16166-16169), the ability of MIF to stimulate calcium influx and desensitize CXCL8 signals was tested. Indeed, like CXCL8, MIF induced calcium influx in primary human neutrophils and desensitized calcium transients in response to either CXCL8 or MIF (Fig.
3f), confirming that MIF activates GPCR/G,,; signaling. The partial desensitization of CXCL8 signaling by MIF seen in neutrophils parallels findings with other CXCR2 ligands (Jones, S.A., et al.
(1997) J. Biol. Chem. 272, 16166-16169) and reflects the presence of CXCR1. In L1.2 transfectants expressing CXCR2, MIF fully desensitized CXCL8-induced calcium influx, and in neutrophils, MIF
desensitized transients induced by the selective CXCR2 ligand CXCL7 (and CXCL7 desensitized transients induced by MIF) (Fig. 3f). In CXCR2 transfectants, MIF dose-dependently induced calcium influx, and was slightly less potent and effective than CXCL8 or CXCL7 (Fig. 3g). In conclusion, MIF acted on CXCR2 and CXCR4 to elicit rapid integrin activation and calcium influx.
MIF interacts with CXCR2 and CXCR4 [00386] To assess the physical interactions of MIF with CXCR2 and CXCR4, we performed receptor-binding competition and internalization studies. In HEK293 cells ectopically expressing CXCR2, MIF strongly competed with 125I-labeled CXCL8 for CXCR2 binding under equilibrium conditions. Binding of the CXCL8 tracer to CXCR2 was inhibited by MIF with an effector concentration for half-maximum response (EC50) of 1.5 nM (Fig. 4a). The affinity of CXCR2 for MIF (Kd = 1.4 nM) was close to that for CXCL8 (Kd = 0.7 nM) and within the range of the MIF
concentration that induced optimal chemotaxis (2-4 nM). To confirm binding to CXCR2, we used a receptor internalization assay that reports specific receptor-ligand interactions. FACS analysis of surface CXCR2 on stable HEK293 transfectants showed that MIF induced CXCR2 internalization with a dose response resembling that of CXCL8 (Fig. 4b). Comparable data was obtained in CXCR2-transfected RAW264.7 macrophages (inset in Fig. 4b).
[00387] To verify an interaction of MIF with CXCR4, receptor-binding studies were performed in Jurkat T cells, which endogenously express CXCR4. MIF competed with 125I-labeled CXCL12 for CXCR4 binding (Kd for CXCL12 = 1.5 nM; EC50 = 19.9 nM, Kd for MIF = 19.8 nM) (Fig. 4c). The Kd was in accordance with MIF concentrations that induce T-cell chemotaxis.
Consistently, MIF, like CXCL12, elicited CXCR4 internalization in a dose-dependent fashion (Fig.
4d). MIF-induced internalization of CXCR2 and CXCR4 was specific to these receptors, as MIF, unlike the cognate ligand CCL5, was unable to induce CCR5 internalization in L1.2 CCR5 transfectants.
[00388] To corroborate its interactions with CXCRs, MIF was labeled with biotin or fluorescein, which, in contrast to iodinated MIF, allows for direct receptor-binding assays. CXCR2 transfectants, but not vector controls, supported direct binding of labeled MIF, as evidenced by flow cytometry (Fig. 4e), pull down with streptavidin beads (inset in Fig. 4e) and fluorescence microscopy. In addition, the specific binding of fluorescein-MIF to CXCR4-bearing Jurkat cells was inhibited by the CXCR4 antagonist AMD3465.
Complex formation between CXCR2 and CD74 [00389] Our data suggests the possibility that a functional MIF receptor complex involves both GPCRs and CD74. Thus, the colocalization of endogenous CD74 and CXCR2 was visualized using confocal fluorescence microscopy in RAW264.7 macrophages expressing human CXCR2. Using this technique, prominent colocalization was observed in a polarized pattern in -50% of cells (Fig.
4f).
[00390] In addition, coimmunoprecipitation assays revealed that CXCR2 physically interacts with CD74. CXCR2/CD74 complexes were detected in HEK293 cells stably overexpressing CXCR2 and transiently expressing His-tagged CD74. These complexes were observed by precipitation with an antibody to CXCR2 and by detecting coprecipitated CD74 by western blot against the His-tag.
Coprecipitation was also seen when the order of the antibodies used was reversed (Fig. 4g).
Complexes were also detected with CD74 in L1.2 transfectants stably expressing human CXCR2, as assessed by coimmunoprecipitation with an antibody to CXCR2. In contrast, no complexes were observed with L1.2 controls or the isotype control (Fig. 4h). The data are consistent with a model in which CD74 forms a signaling complex with CXCR2 to mediate MIF functions.
CXCR2 mediates MIF-induced monocyte arrest in arteries [00391] MIF promotes the formation of complex plaques with abundant cell proliferation, macrophage infiltration and lipid deposition (Weber, C., et al. (2004) Arterioscler. Thromb. Vasc.
Biol. 24, 1997-2008; Morand, E.F., et al. (2006) Nat. Rev. Drug Discov. 5, 399-4 10). 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 a4(3i-dependent monocyte accumulation in ex vivo-perfused carotid arteries of mice with early atherosclerotic endothelium (Huo, Y., et al. (2001) J. Clin. Invest. 108, 1307-1314). This system was used to test whether MIF acts via CXCR2 to induce recruitment. Monocyte arrest in carotid arteries of Apoe i-mice fed a high-fat diet was inhibited by antibodies to CXCR2, CD74 or MIF
(Fig. 5a & Fig. 9), indicating that MIF contributed to atherogenic recruitment via CXCR2 and CD74.
Following the blockade of MIF, CXCR2 and CD74 for 24 h, a similar pattern was observed for monocyte arrest in arteries of wild-type mice treated with tumor necrosis factor (TNF)- a, mimicking acute vascular inflammation (Fig. 5b). In arteries of TNF-a-treated Milmice, inhibitory effects on CD74 were attenuated and blocking MIF was ineffective, whereas there was residual CXCR2 inhibition, implying the involvement of other inducible ligands (Fig. 5c). Compared to the effect of MIF
deficiency observed with TNF- a stimulation, monocyte accumulation was more clearly impaired by MIF deficiency in arteries of Mii Ldlr / mice (compared to atherogenic M
1+Ldlr / mice; Fig.
5d,e). In the absence of MIF, there was no apparent contribution of CXCR2.
Moreover, blocking MIF had no effect (Fig. 5d,e). The inhibitory effects of blocking CXCR2 were restored by loading exogenous MIF (Fig. 5f).
[00392] To provide further evidence for the idea that CXCR2 is required for MIF-mediated monocyte recruitment in vivo, intravital microscopy was performed on carotid arteries of chimeric wild-type Mif"+ and Mil-- mice reconstituted with wild-type or Il8rb-~- bone marrow (Il8rb encodes CXCR2; Fig. 5g,h). After treatment with TNF- a for 4 h, the accumulation of rhodamine G-labeled leukocytes was attenuated in Mil'- mice reconstituted with wild-type bone marrow compared to that in wild-type mice reconstituted with wild-type bone marrow. The reduction in leukocyte accumulation due to deficiency in bone marrow CXCR2 was more marked in chimeric wild-type mice than in chimeric Mif mice (Fig. 5g,h).
MIF-induced inflammation in vivo relied on CXCR2 [00393] The importance of CXCR2 for MIF-mediated leukocyte recruitment under atherogenic or inflammatory diseases, disorders, conditions and symptoms was corroborated in vivo. The adhesion of monocytes to the luminal surface of aortic roots was reduced in Mif/ Ldlr /
versus M1+Ldlr mice with primary atherosclerosis, and this was mirrored by a marked decrease in lesional macrophage content (Fig. 6a). 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.
[00394] Next a model of MIF-induced peritonitis was used in chimeric mice reconstituted with wild-type or I18rb-/- bone marrow. Intraperitoneal injection of MIF elicited neutrophil recruitment after 4 h in mice with wild-type bone marrow, which was abrogated in mice with Il8rb/-bone marrow (Fig.
6d). Collectively, these results demonstrated that MIF triggers leukocyte recruitment under atherogenic and inflammatory diseases, disorders, conditions and symptoms in vivo through CXCR2.
Targeting MIF resulted in regression of atherosclerosis [00395] As described herein, MIF acted through both CXCR2 and CXCR4. Given the role of MIF
and CXCR2 in the development of atherosclerotic lesions, targeting MIF, rather than CXCL1 or CXCL 12, was investigated as a method to modify advanced lesions and their content of CXCR2+
monocytes and CXCR4+ T cells. Apoe i- 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).
[00396] 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). In addition, 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. In some embodiments, 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).
Interference with CXCR4 aggravates atherosclerosis.
[00397] To explore the role of CXCR4 in atherosclerosis, Apoe-/- mice fed an atherogenic diet are continuously treated with the CXCR4 antagonist AMD3465 or vehicle (controls) via osmotic minipumps, and atherosclerotic plaque formation is analyzed after 12 weeks.
Compared with controls, AMD3465 treatment significantly exacerbates lesion formation in oil red O-stained aortic root sections (Figure 9a) and in thoracoabdominal aortas prepared en face (Figure 9b). In addition continuous treatment of Apoe-/- mice with AMD3465 induces a pronounced peripheral blood leukocytosis within 2 days, which is sustained throughout the study period, and an expansion in the relative number of circulating neutrophils, which further increases during disease progression (Figure 9c).
Blocking Th-17 development in a mouse model of Multiple Sclerosis [00398] Eight- to twelve-week-old C57BL/6 mice ( obtained from The Jackson Laboratory, Bar Harbor, Main, USA) are pretreated on day -1 and weekly thereafter with intraperitoneal injections of 5 mg/kg of either a control antibody (group 1), an antagonistic anti-mouse MIF antibody (group 2), an antibody to CXCR2 that blocks MIF binding and/or activation of CXCR2 (group 3), an antibody to CXCR4 that blocks MIF binding and/or activation of CXCR4 (group 4) or an antibody to CXCR4 that blocks MIF binding and/or activation of CXCR4 and an antibody to CXCR2 that blocks MIF binding and/or activation of CXCR2 (group 5). Mice (n = 30 per group) are immunized the following day (day 0) by two subcutaneous injections on the back totaling 200 l of an emulsification of MOG35-55 peptide (MEVGWYRSPFSRVVHLYRNGK; Bachem AG, Bubendorf, Switzerland) in CFA. The final concentrations of peptide and M.
tuberculosis are 150 g/mouse and 1 mg/mouse, respectively. PTX (400 ng; LIST Biological Laboratories Inc., Campbell, California, USA) is injected intraperitoneally on days 0 and 2. The disease is monitored daily by measuring paralysis on a 0-6 scale as described above. Average maximal disease scores are compared between groups using a one-way ANOVA.
[00399] Paralysis measurements are compared between group 2 mice and group 1 to determine the efficacy of an antagonistic anti-MIF antibody, for treating or preventing EAE.
Group 5 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.
[00400] Mixed T cells are prepared from draining lymph nodes and spleen on day 7-11 after immunization. Viable cells (3.75 x 106/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--y, IL-23 & IL- 17 are measured by ELISA (BD
Pharmingen). High 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).
[00401] 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. For cell staining, cells are permeabilized with the Cytofix/Cytoperm Plus Kit (BD Pharmingen) according to the manufacturer's protocol. Gated CD4-posivtive T-cells are analyzed for the presence of intracellular IL- 17, IL-23 or cell surface IL23 receptor (IL23R) by flow cytometry. 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. The presence of high intracellular IL-23 in CD4+, IL- 17 double positive cells or in any leukocyte provides additional supportive evidence for IL-23 driving Th- 17 cell expansion and/or maintenance. Inhibition of Th-17 cell development, as determined by lower levels of IL-17, IL-23R
or IL-23, as described in the above experiment, by treating mice with MIF
blocking agents (group 2 mice) or agents that block MIF binding/or activation of CXCR2 and CXCR4 (group 5 mice) demonstrates a dominant role for MIF in driving the progression of Th- 17 mediated autoimmune disease. The inhibition of 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.
Identification of an Agent that Disrupts MIF Signaling [00402] 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.
[00403] The peptide library is screened for inhibition of MIF-mediated signaling through CXCR2 using HTS GPCR screening technology.
[00404] The peptides that inhibit MIF-mediated signaling are next screened from inhibition of 11-8 and/or SDF-1 mediated signaling on CXCR2.
[00405] Peptides that inhibit MIF- signaling through CXCR2 but allow SDF-1 and IL-8-mediated signaling through CXCR2 are selected for further investigation.
Identification of a MIF Trimerization Disrupting Agent [00406] Polypeptides are generated that comprise amino acid residues 38-44 (beta-2 strand) of MIF.
[00407] The polypeptides are screened for inhibition of MIF-mediated signaling through CXCR2 using HTS GPCR screening technology.
[00408] The polypeptides that inhibit MIF-mediated signaling are next screened for inhibition of 11-8 and/or SDF-1 mediated signaling on CXCR2.
[00409] Peptides that inhibit MIF- signaling through CXCR2 but allow SDF-1-and IL-8-mediated signaling through CXCR2 are selected for further investigation.
Human Clinical Trial [00410] Study Objective(s): The primary objective of this study is to assess efficacy of (P1;
LMAFGGSSEP) (P1; 20 mg, 40 mg, 80 mg) in individuals with homozygous familial hypercholesterolemia (HoFH).
METHODS
[00411] 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. At Visit 3 (Week 0), baseline efficacy/safety values are determined and individuals begin treatment with the initial dose of P2 (20 mg) once daily (QD) for 6 weeks. At Week 6 (Visit 4) doses are titrated to P2 40 mg QD for 6 weeks, and titrated again at Week 12 (Visit 5) to P2 80 mg QD, for 6 weeks, if individuals tolerate the previous dose. Final visit (Visit 6) occurrs at Week 18. Study visits are timed with individuals' apheresis treatments to occur immediately before the visit procedures, where applicable. When the intervals between aphereses are misaligned with a study drug treatment period, the individuals are kept in the same drug treatment period until the next scheduled apheresis, and until the intervals are brought back to the original length of time. Efficacy measures are done at least 2 weeks after the previous apheresis and just before the apheresis procedure scheduled for the day of study visit.
[00412] Number of Participants: Between 30 and 50 individuals.
[00413] Diagnosis and Main Criteria for Inclusion: Men and women 18 years of age or older with definite evidence of the familial hypercholesterolemia (FH) homozygote per World Health Organization guidelines, and with serum fasting triglyceride (TG) <400 mg/dL
(4.52 mmol/L) for individuals aged >20 years and 200 mg/dL (2.26 mmol/L) for individuals aged 18-20 years, are screened for study participation.
[00414] Study Treatment: During the three 6-week open-label treatment periods, individuals take 1 tablet QD, with food, immediately after the morning meal. No down titration is permitted. If individuals are unable to tolerate dose increases, they are discontinued from the study.
[00415] Efficacy Evaluations: 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.
[00416] Safety Evaluations: Safety is assessed using routine clinical laboratory evaluations (hematology and urinalysis panels at Weeks -4, 0 and 18, and chemistry also at Weeks 6 and 12).
Vital signs are monitored at every visit, and physical examinations and electrocardiograms (ECGs) are performed at Weeks 0 and 18. Urine pregnancy testing is carried out at every visit except Week -1. Individuals are monitored for adverse events (AEs) from Week 0 to Week 18.
Week 18 safety assessments are completed at early termination if this took place.
[00417] Statistical Methods: 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.
[00418] The primary efficacy endpoints are analyzed through the computation of sample means of percent (or nominal) changes, their 95% confidence intervals (CIs), 1-sample t-test statistics, and corresponding p-values. Incremental treatment differences between different dose levels are also estimated and 95% CIs obtained. Hypothesis testing is 2-sided with an overall family-wise type I
error rate of 5% (ie, p = 0.05 significance level). Hochberg's procedure is used to control the family-wise error rate for multiple comparisons.
Coprecipitation was also seen when the order of the antibodies used was reversed (Fig. 4g).
Complexes were also detected with CD74 in L1.2 transfectants stably expressing human CXCR2, as assessed by coimmunoprecipitation with an antibody to CXCR2. In contrast, no complexes were observed with L1.2 controls or the isotype control (Fig. 4h). The data are consistent with a model in which CD74 forms a signaling complex with CXCR2 to mediate MIF functions.
CXCR2 mediates MIF-induced monocyte arrest in arteries [00391] MIF promotes the formation of complex plaques with abundant cell proliferation, macrophage infiltration and lipid deposition (Weber, C., et al. (2004) Arterioscler. Thromb. Vasc.
Biol. 24, 1997-2008; Morand, E.F., et al. (2006) Nat. Rev. Drug Discov. 5, 399-4 10). 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 a4(3i-dependent monocyte accumulation in ex vivo-perfused carotid arteries of mice with early atherosclerotic endothelium (Huo, Y., et al. (2001) J. Clin. Invest. 108, 1307-1314). This system was used to test whether MIF acts via CXCR2 to induce recruitment. Monocyte arrest in carotid arteries of Apoe i-mice fed a high-fat diet was inhibited by antibodies to CXCR2, CD74 or MIF
(Fig. 5a & Fig. 9), indicating that MIF contributed to atherogenic recruitment via CXCR2 and CD74.
Following the blockade of MIF, CXCR2 and CD74 for 24 h, a similar pattern was observed for monocyte arrest in arteries of wild-type mice treated with tumor necrosis factor (TNF)- a, mimicking acute vascular inflammation (Fig. 5b). In arteries of TNF-a-treated Milmice, inhibitory effects on CD74 were attenuated and blocking MIF was ineffective, whereas there was residual CXCR2 inhibition, implying the involvement of other inducible ligands (Fig. 5c). Compared to the effect of MIF
deficiency observed with TNF- a stimulation, monocyte accumulation was more clearly impaired by MIF deficiency in arteries of Mii Ldlr / mice (compared to atherogenic M
1+Ldlr / mice; Fig.
5d,e). In the absence of MIF, there was no apparent contribution of CXCR2.
Moreover, blocking MIF had no effect (Fig. 5d,e). The inhibitory effects of blocking CXCR2 were restored by loading exogenous MIF (Fig. 5f).
[00392] To provide further evidence for the idea that CXCR2 is required for MIF-mediated monocyte recruitment in vivo, intravital microscopy was performed on carotid arteries of chimeric wild-type Mif"+ and Mil-- mice reconstituted with wild-type or Il8rb-~- bone marrow (Il8rb encodes CXCR2; Fig. 5g,h). After treatment with TNF- a for 4 h, the accumulation of rhodamine G-labeled leukocytes was attenuated in Mil'- mice reconstituted with wild-type bone marrow compared to that in wild-type mice reconstituted with wild-type bone marrow. The reduction in leukocyte accumulation due to deficiency in bone marrow CXCR2 was more marked in chimeric wild-type mice than in chimeric Mif mice (Fig. 5g,h).
MIF-induced inflammation in vivo relied on CXCR2 [00393] The importance of CXCR2 for MIF-mediated leukocyte recruitment under atherogenic or inflammatory diseases, disorders, conditions and symptoms was corroborated in vivo. The adhesion of monocytes to the luminal surface of aortic roots was reduced in Mif/ Ldlr /
versus M1+Ldlr mice with primary atherosclerosis, and this was mirrored by a marked decrease in lesional macrophage content (Fig. 6a). 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.
[00394] Next a model of MIF-induced peritonitis was used in chimeric mice reconstituted with wild-type or I18rb-/- bone marrow. Intraperitoneal injection of MIF elicited neutrophil recruitment after 4 h in mice with wild-type bone marrow, which was abrogated in mice with Il8rb/-bone marrow (Fig.
6d). Collectively, these results demonstrated that MIF triggers leukocyte recruitment under atherogenic and inflammatory diseases, disorders, conditions and symptoms in vivo through CXCR2.
Targeting MIF resulted in regression of atherosclerosis [00395] As described herein, MIF acted through both CXCR2 and CXCR4. Given the role of MIF
and CXCR2 in the development of atherosclerotic lesions, targeting MIF, rather than CXCL1 or CXCL 12, was investigated as a method to modify advanced lesions and their content of CXCR2+
monocytes and CXCR4+ T cells. Apoe i- 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).
[00396] 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). In addition, 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. In some embodiments, 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).
Interference with CXCR4 aggravates atherosclerosis.
[00397] To explore the role of CXCR4 in atherosclerosis, Apoe-/- mice fed an atherogenic diet are continuously treated with the CXCR4 antagonist AMD3465 or vehicle (controls) via osmotic minipumps, and atherosclerotic plaque formation is analyzed after 12 weeks.
Compared with controls, AMD3465 treatment significantly exacerbates lesion formation in oil red O-stained aortic root sections (Figure 9a) and in thoracoabdominal aortas prepared en face (Figure 9b). In addition continuous treatment of Apoe-/- mice with AMD3465 induces a pronounced peripheral blood leukocytosis within 2 days, which is sustained throughout the study period, and an expansion in the relative number of circulating neutrophils, which further increases during disease progression (Figure 9c).
Blocking Th-17 development in a mouse model of Multiple Sclerosis [00398] Eight- to twelve-week-old C57BL/6 mice ( obtained from The Jackson Laboratory, Bar Harbor, Main, USA) are pretreated on day -1 and weekly thereafter with intraperitoneal injections of 5 mg/kg of either a control antibody (group 1), an antagonistic anti-mouse MIF antibody (group 2), an antibody to CXCR2 that blocks MIF binding and/or activation of CXCR2 (group 3), an antibody to CXCR4 that blocks MIF binding and/or activation of CXCR4 (group 4) or an antibody to CXCR4 that blocks MIF binding and/or activation of CXCR4 and an antibody to CXCR2 that blocks MIF binding and/or activation of CXCR2 (group 5). Mice (n = 30 per group) are immunized the following day (day 0) by two subcutaneous injections on the back totaling 200 l of an emulsification of MOG35-55 peptide (MEVGWYRSPFSRVVHLYRNGK; Bachem AG, Bubendorf, Switzerland) in CFA. The final concentrations of peptide and M.
tuberculosis are 150 g/mouse and 1 mg/mouse, respectively. PTX (400 ng; LIST Biological Laboratories Inc., Campbell, California, USA) is injected intraperitoneally on days 0 and 2. The disease is monitored daily by measuring paralysis on a 0-6 scale as described above. Average maximal disease scores are compared between groups using a one-way ANOVA.
[00399] Paralysis measurements are compared between group 2 mice and group 1 to determine the efficacy of an antagonistic anti-MIF antibody, for treating or preventing EAE.
Group 5 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.
[00400] Mixed T cells are prepared from draining lymph nodes and spleen on day 7-11 after immunization. Viable cells (3.75 x 106/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--y, IL-23 & IL- 17 are measured by ELISA (BD
Pharmingen). High 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).
[00401] 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. For cell staining, cells are permeabilized with the Cytofix/Cytoperm Plus Kit (BD Pharmingen) according to the manufacturer's protocol. Gated CD4-posivtive T-cells are analyzed for the presence of intracellular IL- 17, IL-23 or cell surface IL23 receptor (IL23R) by flow cytometry. 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. The presence of high intracellular IL-23 in CD4+, IL- 17 double positive cells or in any leukocyte provides additional supportive evidence for IL-23 driving Th- 17 cell expansion and/or maintenance. Inhibition of Th-17 cell development, as determined by lower levels of IL-17, IL-23R
or IL-23, as described in the above experiment, by treating mice with MIF
blocking agents (group 2 mice) or agents that block MIF binding/or activation of CXCR2 and CXCR4 (group 5 mice) demonstrates a dominant role for MIF in driving the progression of Th- 17 mediated autoimmune disease. The inhibition of 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.
Identification of an Agent that Disrupts MIF Signaling [00402] 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.
[00403] The peptide library is screened for inhibition of MIF-mediated signaling through CXCR2 using HTS GPCR screening technology.
[00404] The peptides that inhibit MIF-mediated signaling are next screened from inhibition of 11-8 and/or SDF-1 mediated signaling on CXCR2.
[00405] Peptides that inhibit MIF- signaling through CXCR2 but allow SDF-1 and IL-8-mediated signaling through CXCR2 are selected for further investigation.
Identification of a MIF Trimerization Disrupting Agent [00406] Polypeptides are generated that comprise amino acid residues 38-44 (beta-2 strand) of MIF.
[00407] The polypeptides are screened for inhibition of MIF-mediated signaling through CXCR2 using HTS GPCR screening technology.
[00408] The polypeptides that inhibit MIF-mediated signaling are next screened for inhibition of 11-8 and/or SDF-1 mediated signaling on CXCR2.
[00409] Peptides that inhibit MIF- signaling through CXCR2 but allow SDF-1-and IL-8-mediated signaling through CXCR2 are selected for further investigation.
Human Clinical Trial [00410] Study Objective(s): The primary objective of this study is to assess efficacy of (P1;
LMAFGGSSEP) (P1; 20 mg, 40 mg, 80 mg) in individuals with homozygous familial hypercholesterolemia (HoFH).
METHODS
[00411] 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. At Visit 3 (Week 0), baseline efficacy/safety values are determined and individuals begin treatment with the initial dose of P2 (20 mg) once daily (QD) for 6 weeks. At Week 6 (Visit 4) doses are titrated to P2 40 mg QD for 6 weeks, and titrated again at Week 12 (Visit 5) to P2 80 mg QD, for 6 weeks, if individuals tolerate the previous dose. Final visit (Visit 6) occurrs at Week 18. Study visits are timed with individuals' apheresis treatments to occur immediately before the visit procedures, where applicable. When the intervals between aphereses are misaligned with a study drug treatment period, the individuals are kept in the same drug treatment period until the next scheduled apheresis, and until the intervals are brought back to the original length of time. Efficacy measures are done at least 2 weeks after the previous apheresis and just before the apheresis procedure scheduled for the day of study visit.
[00412] Number of Participants: Between 30 and 50 individuals.
[00413] Diagnosis and Main Criteria for Inclusion: Men and women 18 years of age or older with definite evidence of the familial hypercholesterolemia (FH) homozygote per World Health Organization guidelines, and with serum fasting triglyceride (TG) <400 mg/dL
(4.52 mmol/L) for individuals aged >20 years and 200 mg/dL (2.26 mmol/L) for individuals aged 18-20 years, are screened for study participation.
[00414] Study Treatment: During the three 6-week open-label treatment periods, individuals take 1 tablet QD, with food, immediately after the morning meal. No down titration is permitted. If individuals are unable to tolerate dose increases, they are discontinued from the study.
[00415] Efficacy Evaluations: 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.
[00416] Safety Evaluations: Safety is assessed using routine clinical laboratory evaluations (hematology and urinalysis panels at Weeks -4, 0 and 18, and chemistry also at Weeks 6 and 12).
Vital signs are monitored at every visit, and physical examinations and electrocardiograms (ECGs) are performed at Weeks 0 and 18. Urine pregnancy testing is carried out at every visit except Week -1. Individuals are monitored for adverse events (AEs) from Week 0 to Week 18.
Week 18 safety assessments are completed at early termination if this took place.
[00417] Statistical Methods: 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.
[00418] The primary efficacy endpoints are analyzed through the computation of sample means of percent (or nominal) changes, their 95% confidence intervals (CIs), 1-sample t-test statistics, and corresponding p-values. Incremental treatment differences between different dose levels are also estimated and 95% CIs obtained. Hypothesis testing is 2-sided with an overall family-wise type I
error rate of 5% (ie, p = 0.05 significance level). Hochberg's procedure is used to control the family-wise error rate for multiple comparisons.
Animal Model for Treatment of Abdominal Aortic Aneurysms (AAA) [00419] 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.
[00420] 2 weeks after administration of elastase, the rat is administered Peptide 2 (PI;LMAFGGSSEP). The initial administration of P2 is infused into subject at a rate of 0.5 mg/hr.
In the absence of infusion toxicity, increase infusion rate by 0.5 mg/hr increments every 30 minutes, to a maximum of 2.0 mg/hr. Each week thereafter, P2 is infused at a rate of 1.0 mg/hr. In the absence of infusion toxicity, increase rate by 1.0 mg/hr increments at 30-minute intervals, to a maximum of 4.0 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.
Human Clinical Trial for Treatment of Abdominal Aortic Aneurysms (AAA) [00421] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 1 (P1; LMAFGGSSEP) in individuals with early AAA.
METHODS
[00422] 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.
[00423] Number of Participants: Between 30 and 50 individuals.
[00424] 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.
[00425] 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 [00426] 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).
Study Type:
[00427] Interventional Study Design:
[00428] Allocation: Non-Randomized [00429] Control: Uncontrolled [00430] Endpoint Classification: Safety Study [00431] Intervention Model: Single Group Assignment [00432] Masking: Open Label [00433] Primary Purpose: Treatment Primary Outcome Measures:
[00434] Number of Subjects With American College of Rheumatology (ACR) Criteria Improvement Consisting of 20%, 50%, and 70% (ACR20/50/70 Responders, Respectively) [00435] Number of responders with ACR criteria improvement consisting of 20%, 50%, and 70%
(ACR20/50/70, respectively) reduction in tender or swollen joint counts (TJC
or SJC, respectively) and 20%, 50%, and 70% improvement, respectively, in 3 of the following 5 criteria: 1) physician's global assessment of disease activity (PGA), 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire (DI-HAQ), and 5) C-reactive protein (CRP) at each visit.
Secondary Outcome Measures:
[00436] Mean Change From Baseline in Tender Joint Count (TJC, Max=68), a Component of the American College of Rheumatology (ACR) by Visit [00437] Mean Change From Baseline in Swollen Joint Count (SJC, Max=66), a Component of the American College of Rheumatology (ACR) by Visit [00438] Mean Change From Baseline in Physician Global Assessment of Disease Activity (PGA), a Component of the ACR Criteria by Visit [00439] Mean Change From Baseline in Subject's Global Assessment of Disease Activity Using a Visual Analog Scale, a Component of the ACR Criteria by Visit [00440] Mean Change From Baseline in Subject's Assessment of Pain Using a Visual Analog Scale, a Component of the ACR Criteria by Visit [00441] 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 [00442] Mean Change From Baseline in C-reactive Protein (CRP), a Component of the American College of Rheumatology (ACR) Criteria by Visit [00443] Presence of Morning Stiffness [00444] Mean Change From Baseline in the Duration (Minutes) of Morning Stiffness by Visit [00445] Presence of Rheumatoid Factor (RF) [00446] Mean Change From Baseline in Rheumatoid Factor (IU/ML) by Visit Arms [00447] Peptide 2 will be administered as a single oral dose (10 mg/Kg) once per day [00448] Placebo will be administered via oral administration once per day Elegibility Criteria [00449] 20 Years and older [00450] Male and female Inclusion Criteria:
[00451] Participation and completion until Week 24 of the prior adalimumab dose-ranging study.
[00452] Females must be postmenopausal for at least 1 year, surgically sterile, or practicing birth control throughout the study and for 90 days after study completion.
[00453] Female subjects tested negative in pregnancy test (serum test) at Week 24 in prior adalimumab study, if capable of pregnancy.
Exclusion Criteria:
[00454] A subject who experienced any of the following during prior study:
[00455] Advanced or poorly controlled diabetes [00456] Joint surgery (joint evaluated in this study) [00457] A subject who has been prescribed excluded medications during prior study [00458] History of following during prior study:
[00459] Clinically significant drug or alcohol abuse [00460] Intravenous (iv) drug abuse [00461] Active infection with listeria or tuberculosis (TB) [00462] Lymphoma, leukemia [00463] And, any malignancy with the exception of successfully treated non-metastatic basal cell carcinoma of the skin.
[00464] A subject who has been administered a live vaccine during prior study, or subject scheduled to complete the administration of a live vaccine during the study period EXAMPLE 16: Human Clinical Trial for Treatment of Acute Respiratory Distress Syndrome (ARDS) [00465] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 2 (P3; LMAFGGSS) in individuals with ARDS.
Study Type:
[00466] Interventional Study Design:
[00467] Allocation: Randomized [00468] Control: Placebo Control [00469] Endpoint Classification: Safety/Efficacy Study [00470] Intervention Model: Parallel Assignment [00471] Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) [00472] Primary Purpose: Treatment Primary Outcome Measures:
[00473] Safety profile of the study drug [
[00474] Number of ventilator-free days at Day 28 Secondary Outcome Measures:
[00475] Mortality at Day 28 [00476] Length of hospitalization at Day 28 [00477] Length of ICU stay at Day 28 [00478] Number of Non-pulmonary organ failure free days at Day 28 [00479] Changes in physiological variables of lung injury [00480] Changes in disease severity and lung injury scores [00481] Effects of the study drug and the etiology of the disease (i.e.
pulmonary or extra-pulmonary origin) [00482] Pharmacokinetics & Pharmacodynamics [00483] Immunogenicity Arms [00484] Peptide 3 will be administered as a single dose (0.06 mg/Kg) via intravenous infusion over 15 minutes.
[00485] Placebo will be administered via intravenous infusion over 15 minutes Elegibility Criteria [00486] 18 years or older [00487] Male and Female [00488] Accepts Healthy Volunteers: No INCLUSION CRITERIA:
[00489] Suspected or proven infection [00490] Hypoxemia: Pa02/FiO2is <300 mm Hg [00491] Bilateral infiltrates consistent with pulmonary edema [00492] Positive-pressure mechanical ventilation through an endotracheal tube [00493] No clinical evidence of left atrial hypertension to explain bilateral infiltrates [00494] Presence of at least three of the four SIRS criteria. If only two criteria are evidenced, one must be temperature or WBC
[00495] Criteria 2 and 3 must occur within a 24-hour interval. The 48-hour enrollment time window begins when criteria 2, 3, and 4 are met.
EXCLUSION CRITERIA:
[00496] <18 years [00497] Inability to obtain consent [00498] Patient, surrogate, or physician not committed to full support [00499] Moribund state in which death was perceived to be imminent [00500] Morbid obesity [00501] Malignancy or other irreversible disease or condition for which 6-month mortality is estimated to be >50%
[00502] Known HIV positive with known end stage processes [00503] Prior cardiac arrest requiring CPR without fully demonstrated neurological recovery; or New York Heart Association Class IV
[00504] Pregnant or nursing [00505] Mechanically or chemically-induced ALI/ARDS (including burns, trauma, and near drowning) [00506] >48 hours since all inclusion criteria are met [00507] Neuromuscular disease that impairs ability to ventilate without assistance [00508] Severe chronic respiratory disease, severe pulmonary hypertension, or ventilator dependency [00509] Chest wall deformity resulting in severe exercise restriction, secondary polycythemia, or respirator dependent [00510] History of organ transplant (including bone marrow) [00511] Severe chronic liver disease, as determined by a Child-Pugh Score >10 [00512] Hemoglobin persistently < 8.0 g/dL
[00513] Platelet count <50,000/mm3 [00514] Prolonged INR >3 [00515] Bleeding disorders unless corrective surgery has been performed [00516] Active internal bleeding [00517] Major surgery within 48 hours before study drug infusion, or evidence of active bleeding postoperatively, or plan for any major surgery within 3 days after study drug infusion.
[00518] Diffuse alveolar hemorrhage from vasculitis [00519] Known bleeding diathesis [00520] Presence of an epidural catheter or lumbar puncture within 48 hours before study drug infusion or anticipation of receiving an epidural catheter or a lumbar puncture within 48 hours after study drug infusion [00521] Stroke within 3 months of study entry [00522] Trauma with an increased risk of life-threatening bleeding [00523] A history of severe head trauma that required hospitalization, or intracranial surgery within two months of study entry [00524] Any history of intracerebral arteriovenous malformation, cerebral neurysm, or central nervous system mass lesion [00525] Uses of certain medications or treatment regimens such as chemotherapy, unfractionated heparin, low-molecular-weight heparin, Warfarin, antithrombin III, acetylsalicylic acid, glycoprotein IIb/IIIa antagonists, thrombolytic therapy, and activated Protein C are restricted.
[00526] Participation in another experimental medication study within 30 days of study entry with the exception of the ARDSNet pharmaconutrient nutrition trial (OMEGA) EXAMPLE 17: Human Clinical Trial for Treatment of Glomerulonephritis [00527] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 2 (P4; VHVVPDLLMA) in individuals with Glomerulonephritis.
Study Type:
[00528] Interventional Study Design:
[00529] Allocation: Randomized [00530] Control: Active Control [00531] Endpoint Classification: Efficacy Study [00532] Intervention Model: Parallel Assignment [00533] Masking: Open Label [00534] Primary Purpose: Treatment Primary Outcome Measures:
[00535] Initiation of acute dialysis or doubling of serum creatinine levels [
Time Frame: 3 months ] [
Designated as safety issue: Yes ]
Secondary Outcome Measures:
[00536] ESRD (defined by the need for long-term dialysis) Detailed Description [00537] This study is a randomized, open-label, comparative study.
[00420] 2 weeks after administration of elastase, the rat is administered Peptide 2 (PI;LMAFGGSSEP). The initial administration of P2 is infused into subject at a rate of 0.5 mg/hr.
In the absence of infusion toxicity, increase infusion rate by 0.5 mg/hr increments every 30 minutes, to a maximum of 2.0 mg/hr. Each week thereafter, P2 is infused at a rate of 1.0 mg/hr. In the absence of infusion toxicity, increase rate by 1.0 mg/hr increments at 30-minute intervals, to a maximum of 4.0 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.
Human Clinical Trial for Treatment of Abdominal Aortic Aneurysms (AAA) [00421] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 1 (P1; LMAFGGSSEP) in individuals with early AAA.
METHODS
[00422] 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.
[00423] Number of Participants: Between 30 and 50 individuals.
[00424] 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.
[00425] 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 [00426] 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).
Study Type:
[00427] Interventional Study Design:
[00428] Allocation: Non-Randomized [00429] Control: Uncontrolled [00430] Endpoint Classification: Safety Study [00431] Intervention Model: Single Group Assignment [00432] Masking: Open Label [00433] Primary Purpose: Treatment Primary Outcome Measures:
[00434] Number of Subjects With American College of Rheumatology (ACR) Criteria Improvement Consisting of 20%, 50%, and 70% (ACR20/50/70 Responders, Respectively) [00435] Number of responders with ACR criteria improvement consisting of 20%, 50%, and 70%
(ACR20/50/70, respectively) reduction in tender or swollen joint counts (TJC
or SJC, respectively) and 20%, 50%, and 70% improvement, respectively, in 3 of the following 5 criteria: 1) physician's global assessment of disease activity (PGA), 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire (DI-HAQ), and 5) C-reactive protein (CRP) at each visit.
Secondary Outcome Measures:
[00436] Mean Change From Baseline in Tender Joint Count (TJC, Max=68), a Component of the American College of Rheumatology (ACR) by Visit [00437] Mean Change From Baseline in Swollen Joint Count (SJC, Max=66), a Component of the American College of Rheumatology (ACR) by Visit [00438] Mean Change From Baseline in Physician Global Assessment of Disease Activity (PGA), a Component of the ACR Criteria by Visit [00439] Mean Change From Baseline in Subject's Global Assessment of Disease Activity Using a Visual Analog Scale, a Component of the ACR Criteria by Visit [00440] Mean Change From Baseline in Subject's Assessment of Pain Using a Visual Analog Scale, a Component of the ACR Criteria by Visit [00441] 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 [00442] Mean Change From Baseline in C-reactive Protein (CRP), a Component of the American College of Rheumatology (ACR) Criteria by Visit [00443] Presence of Morning Stiffness [00444] Mean Change From Baseline in the Duration (Minutes) of Morning Stiffness by Visit [00445] Presence of Rheumatoid Factor (RF) [00446] Mean Change From Baseline in Rheumatoid Factor (IU/ML) by Visit Arms [00447] Peptide 2 will be administered as a single oral dose (10 mg/Kg) once per day [00448] Placebo will be administered via oral administration once per day Elegibility Criteria [00449] 20 Years and older [00450] Male and female Inclusion Criteria:
[00451] Participation and completion until Week 24 of the prior adalimumab dose-ranging study.
[00452] Females must be postmenopausal for at least 1 year, surgically sterile, or practicing birth control throughout the study and for 90 days after study completion.
[00453] Female subjects tested negative in pregnancy test (serum test) at Week 24 in prior adalimumab study, if capable of pregnancy.
Exclusion Criteria:
[00454] A subject who experienced any of the following during prior study:
[00455] Advanced or poorly controlled diabetes [00456] Joint surgery (joint evaluated in this study) [00457] A subject who has been prescribed excluded medications during prior study [00458] History of following during prior study:
[00459] Clinically significant drug or alcohol abuse [00460] Intravenous (iv) drug abuse [00461] Active infection with listeria or tuberculosis (TB) [00462] Lymphoma, leukemia [00463] And, any malignancy with the exception of successfully treated non-metastatic basal cell carcinoma of the skin.
[00464] A subject who has been administered a live vaccine during prior study, or subject scheduled to complete the administration of a live vaccine during the study period EXAMPLE 16: Human Clinical Trial for Treatment of Acute Respiratory Distress Syndrome (ARDS) [00465] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 2 (P3; LMAFGGSS) in individuals with ARDS.
Study Type:
[00466] Interventional Study Design:
[00467] Allocation: Randomized [00468] Control: Placebo Control [00469] Endpoint Classification: Safety/Efficacy Study [00470] Intervention Model: Parallel Assignment [00471] Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) [00472] Primary Purpose: Treatment Primary Outcome Measures:
[00473] Safety profile of the study drug [
[00474] Number of ventilator-free days at Day 28 Secondary Outcome Measures:
[00475] Mortality at Day 28 [00476] Length of hospitalization at Day 28 [00477] Length of ICU stay at Day 28 [00478] Number of Non-pulmonary organ failure free days at Day 28 [00479] Changes in physiological variables of lung injury [00480] Changes in disease severity and lung injury scores [00481] Effects of the study drug and the etiology of the disease (i.e.
pulmonary or extra-pulmonary origin) [00482] Pharmacokinetics & Pharmacodynamics [00483] Immunogenicity Arms [00484] Peptide 3 will be administered as a single dose (0.06 mg/Kg) via intravenous infusion over 15 minutes.
[00485] Placebo will be administered via intravenous infusion over 15 minutes Elegibility Criteria [00486] 18 years or older [00487] Male and Female [00488] Accepts Healthy Volunteers: No INCLUSION CRITERIA:
[00489] Suspected or proven infection [00490] Hypoxemia: Pa02/FiO2is <300 mm Hg [00491] Bilateral infiltrates consistent with pulmonary edema [00492] Positive-pressure mechanical ventilation through an endotracheal tube [00493] No clinical evidence of left atrial hypertension to explain bilateral infiltrates [00494] Presence of at least three of the four SIRS criteria. If only two criteria are evidenced, one must be temperature or WBC
[00495] Criteria 2 and 3 must occur within a 24-hour interval. The 48-hour enrollment time window begins when criteria 2, 3, and 4 are met.
EXCLUSION CRITERIA:
[00496] <18 years [00497] Inability to obtain consent [00498] Patient, surrogate, or physician not committed to full support [00499] Moribund state in which death was perceived to be imminent [00500] Morbid obesity [00501] Malignancy or other irreversible disease or condition for which 6-month mortality is estimated to be >50%
[00502] Known HIV positive with known end stage processes [00503] Prior cardiac arrest requiring CPR without fully demonstrated neurological recovery; or New York Heart Association Class IV
[00504] Pregnant or nursing [00505] Mechanically or chemically-induced ALI/ARDS (including burns, trauma, and near drowning) [00506] >48 hours since all inclusion criteria are met [00507] Neuromuscular disease that impairs ability to ventilate without assistance [00508] Severe chronic respiratory disease, severe pulmonary hypertension, or ventilator dependency [00509] Chest wall deformity resulting in severe exercise restriction, secondary polycythemia, or respirator dependent [00510] History of organ transplant (including bone marrow) [00511] Severe chronic liver disease, as determined by a Child-Pugh Score >10 [00512] Hemoglobin persistently < 8.0 g/dL
[00513] Platelet count <50,000/mm3 [00514] Prolonged INR >3 [00515] Bleeding disorders unless corrective surgery has been performed [00516] Active internal bleeding [00517] Major surgery within 48 hours before study drug infusion, or evidence of active bleeding postoperatively, or plan for any major surgery within 3 days after study drug infusion.
[00518] Diffuse alveolar hemorrhage from vasculitis [00519] Known bleeding diathesis [00520] Presence of an epidural catheter or lumbar puncture within 48 hours before study drug infusion or anticipation of receiving an epidural catheter or a lumbar puncture within 48 hours after study drug infusion [00521] Stroke within 3 months of study entry [00522] Trauma with an increased risk of life-threatening bleeding [00523] A history of severe head trauma that required hospitalization, or intracranial surgery within two months of study entry [00524] Any history of intracerebral arteriovenous malformation, cerebral neurysm, or central nervous system mass lesion [00525] Uses of certain medications or treatment regimens such as chemotherapy, unfractionated heparin, low-molecular-weight heparin, Warfarin, antithrombin III, acetylsalicylic acid, glycoprotein IIb/IIIa antagonists, thrombolytic therapy, and activated Protein C are restricted.
[00526] Participation in another experimental medication study within 30 days of study entry with the exception of the ARDSNet pharmaconutrient nutrition trial (OMEGA) EXAMPLE 17: Human Clinical Trial for Treatment of Glomerulonephritis [00527] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 2 (P4; VHVVPDLLMA) in individuals with Glomerulonephritis.
Study Type:
[00528] Interventional Study Design:
[00529] Allocation: Randomized [00530] Control: Active Control [00531] Endpoint Classification: Efficacy Study [00532] Intervention Model: Parallel Assignment [00533] Masking: Open Label [00534] Primary Purpose: Treatment Primary Outcome Measures:
[00535] Initiation of acute dialysis or doubling of serum creatinine levels [
Time Frame: 3 months ] [
Designated as safety issue: Yes ]
Secondary Outcome Measures:
[00536] ESRD (defined by the need for long-term dialysis) Detailed Description [00537] This study is a randomized, open-label, comparative study.
[00538] Group A is treated by three monthly standard intravenous pulse-dose methylprednisolone (15 mg/kg/day or a maximum of 1 g/day from days 1 to 3) followed by oral prednisolone 0.5-1.0 mg/kg/day (from days 4-30).
[00539] Group B is treated by the same corticosteroid regimen plus intravenous Peptide 4 (0.33-0.66 mg/kg/h from days 1 to 7) followed by oral Peptide 4 400-800 mg/day (from days 8-90). The dose of intravenous pentoxifylline will be determined by estimated GFR, patients whose GFRs are 30-59 ml/min/1.73 m2 will be given 0.66 mg/kg/h, and those below 30 ml/min/1.73 m2 will be given 0.33 mg/kg/h. The oral dose of Peptid 4 will also be determined by estimated GFR.
Patients whose estimated GFRs are between 30-59 ml/min/1.73 m2 will be given 800 mg/day, and those below 30 ml/min/1.73 m2 will be given 400 mg/day.
[00540] Serum and single-voided urine specimens will be collected at the hospital before initiation of therapy (day 0), and at days 8, 15, 30, and 90 after the commencement of therapy. Renal function will be calculated by Cockcroft-Gault and simplified MDRD formula. Serum and urine samples will be measured for inflammatory mediators such as TNF-alpha, IL-lbeta, IL-6, MCP-1, CX3CL1 (fractalkine), IL-8 by using commercial ELISA kits.
Elegibility Criteria [00541] 20 Years to 80 Years [00542] Male and female Inclusion Criteria:
[00543] Biopsied-proved crescentic glomerulonephritis, with rapidly progressive renal failure Exclusion Criteria:
[00544] Anti-GBM disease, [00545] Dialysis-dependency or pulmonary hemorrhage, [00546] Females are nursing or pregnant, [00547] Congestive heart failure, [00548] Unstable angina, myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention, within the past 6 months prior to signing the informed consent form, [00549] Cerebral hemorrhage within the past 6 months prior to signing the informed consent form, [00550] Retinal hemorrhage within the past 6 months prior to signing the informed consent form, [00551] Known or suspected secondary hypertension, [00552] Uncontrolled hypertension or diabetes, [00553] Liver cirrhosis or hepatic dysfunction as defined by ALT or AST > 2 times the upper limit of the normal range, [00554] Biliary obstructive disorders, [00555] Active malignancy or infection EXAMPLE 18: Human Clinical Trial for Treatment of Inflammatory Bowel Disease (IBD) [00556] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 2 (P5; QLMAFGGSSE) in individuals with IBD.
[00557] This is an exploratory, open-label, uncontrolled, multi-center, 1-arm study [00558] A total of 24 patients will receive P5 tablets, 35 mg once daily for 12 weeks. First of all the patients will undergo a screening period of 1 week and a follow-up visit will be performed 4 weeks after study drug discontinuation or earlier in case of relapse during follow up. Total study duration will be up to 17 weeks.
[00559] There will be 8 study visits: one screening visit, 6 visits during the treatment period and one follow-up visit. Two telephone visits will be performed at Week 6 and Week 10.
[00560] The duration of the entire study (first patient in till last patient out) is expected to be about 13 months.
Primary Outcome Measures:
[00561] Efficacy of P5 at a dose of 35 mg once daily in patients with Crohn's Disease (CD) or Ulcerative Colitis (UC) after a 12 week therapy as measured by the number of patients with complete or partial response.
Secondary Outcome Measures:
[00562] The secondary objective of this study is to evaluate the safety and tolerability of P5 at a dose of 35 mg once daily in patients with CD or UC and to explore plasma levels (trough values) of P5.
Elegibility Criteria [00563] 18 Years to 70 Years [00564] Male and femals Inclusion Criteria:
[00565] Criteria regarding Crohn's Disease:
[00566] Established diagnosis of CD, confirmed by standard criteria (e.g.
endoscopy, ultrasound, X-ray) [00567] Patients must be in clinical remission (Crohn's Disease Activity Index [CDAI] <150 points) on steroid therapy for at least 2 weeks [00568] Confirmed steroid-dependency of CD: patients who are either unable to taper steroids completely within 3 months of starting steroids, without recurrent active disease, or who have a relapse within 2 months of stopping steroids [00569] Individual threshold* dose of previous relapses should be equal or less than 20 mg/day Prednisolone or equivalent steroid dose [00570] Patients with stable glucocorticosteroid therapy between 20 and 40 mg/day Prednisolone or equivalent steroid dose for the previous week [00571] Criteria regarding Ulcerative Colitis:
[00539] Group B is treated by the same corticosteroid regimen plus intravenous Peptide 4 (0.33-0.66 mg/kg/h from days 1 to 7) followed by oral Peptide 4 400-800 mg/day (from days 8-90). The dose of intravenous pentoxifylline will be determined by estimated GFR, patients whose GFRs are 30-59 ml/min/1.73 m2 will be given 0.66 mg/kg/h, and those below 30 ml/min/1.73 m2 will be given 0.33 mg/kg/h. The oral dose of Peptid 4 will also be determined by estimated GFR.
Patients whose estimated GFRs are between 30-59 ml/min/1.73 m2 will be given 800 mg/day, and those below 30 ml/min/1.73 m2 will be given 400 mg/day.
[00540] Serum and single-voided urine specimens will be collected at the hospital before initiation of therapy (day 0), and at days 8, 15, 30, and 90 after the commencement of therapy. Renal function will be calculated by Cockcroft-Gault and simplified MDRD formula. Serum and urine samples will be measured for inflammatory mediators such as TNF-alpha, IL-lbeta, IL-6, MCP-1, CX3CL1 (fractalkine), IL-8 by using commercial ELISA kits.
Elegibility Criteria [00541] 20 Years to 80 Years [00542] Male and female Inclusion Criteria:
[00543] Biopsied-proved crescentic glomerulonephritis, with rapidly progressive renal failure Exclusion Criteria:
[00544] Anti-GBM disease, [00545] Dialysis-dependency or pulmonary hemorrhage, [00546] Females are nursing or pregnant, [00547] Congestive heart failure, [00548] Unstable angina, myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention, within the past 6 months prior to signing the informed consent form, [00549] Cerebral hemorrhage within the past 6 months prior to signing the informed consent form, [00550] Retinal hemorrhage within the past 6 months prior to signing the informed consent form, [00551] Known or suspected secondary hypertension, [00552] Uncontrolled hypertension or diabetes, [00553] Liver cirrhosis or hepatic dysfunction as defined by ALT or AST > 2 times the upper limit of the normal range, [00554] Biliary obstructive disorders, [00555] Active malignancy or infection EXAMPLE 18: Human Clinical Trial for Treatment of Inflammatory Bowel Disease (IBD) [00556] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 2 (P5; QLMAFGGSSE) in individuals with IBD.
[00557] This is an exploratory, open-label, uncontrolled, multi-center, 1-arm study [00558] A total of 24 patients will receive P5 tablets, 35 mg once daily for 12 weeks. First of all the patients will undergo a screening period of 1 week and a follow-up visit will be performed 4 weeks after study drug discontinuation or earlier in case of relapse during follow up. Total study duration will be up to 17 weeks.
[00559] There will be 8 study visits: one screening visit, 6 visits during the treatment period and one follow-up visit. Two telephone visits will be performed at Week 6 and Week 10.
[00560] The duration of the entire study (first patient in till last patient out) is expected to be about 13 months.
Primary Outcome Measures:
[00561] Efficacy of P5 at a dose of 35 mg once daily in patients with Crohn's Disease (CD) or Ulcerative Colitis (UC) after a 12 week therapy as measured by the number of patients with complete or partial response.
Secondary Outcome Measures:
[00562] The secondary objective of this study is to evaluate the safety and tolerability of P5 at a dose of 35 mg once daily in patients with CD or UC and to explore plasma levels (trough values) of P5.
Elegibility Criteria [00563] 18 Years to 70 Years [00564] Male and femals Inclusion Criteria:
[00565] Criteria regarding Crohn's Disease:
[00566] Established diagnosis of CD, confirmed by standard criteria (e.g.
endoscopy, ultrasound, X-ray) [00567] Patients must be in clinical remission (Crohn's Disease Activity Index [CDAI] <150 points) on steroid therapy for at least 2 weeks [00568] Confirmed steroid-dependency of CD: patients who are either unable to taper steroids completely within 3 months of starting steroids, without recurrent active disease, or who have a relapse within 2 months of stopping steroids [00569] Individual threshold* dose of previous relapses should be equal or less than 20 mg/day Prednisolone or equivalent steroid dose [00570] Patients with stable glucocorticosteroid therapy between 20 and 40 mg/day Prednisolone or equivalent steroid dose for the previous week [00571] Criteria regarding Ulcerative Colitis:
[00572] Established diagnosis of UC, confirmed by standard criteria (e.g.
endoscopy, ultrasound, X-ray) [00573] Patients must be in clinical remission (Clinical Activity Index [CAI]
<4 points) on steroid therapy for at least 2 weeks [00574] Confirmed steroid-dependency of UC: patients who are either unable to taper steroids completely within 3 months of starting steroids, without recurrent active disease, or who have a relapse within 2 months of stopping steroids [00575] Individual threshold* dose of previous relapses should be equal or less than 20 mg/day Prednisolone or equivalent steroid dose [00576] Patients with stable glucocorticosteroid therapy between 20 and 40 mg/day Prednisolone or equivalent steroid dose for the previous week Exclusion Criteria:
[00577] Short bowel syndrome [00578] Ileostomy, colostomy or rectal pouch [00579] Relapse during screening EXAMPLE 19: Human Clinical Trial for Treatment of Sepsis [00580] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 2 (P6; NVPRASVPDG) in individuals with sepsis.
Study Type:
[00581] Interventional Study Design:
[00582] Allocation: Randomized [00583] Control: Placebo Control [00584] Endpoint Classification: Safety/Efficacy Study [00585] Intervention Model: Single Group Assignment [00586] Masking: Double-Blind [00587] Primary Purpose: Treatment Arms [00588] P7 0.5 by IV infusion twice daily for 1 week [00589] P7 1 mg by IV infusion twice daily for 1 week [00590] Placebo by IV infusion twice daily for 1 week Eligibility Criteria [00591] 18 Years to 85 Years [00592] Male and femal Inclusion Criteria:
endoscopy, ultrasound, X-ray) [00573] Patients must be in clinical remission (Clinical Activity Index [CAI]
<4 points) on steroid therapy for at least 2 weeks [00574] Confirmed steroid-dependency of UC: patients who are either unable to taper steroids completely within 3 months of starting steroids, without recurrent active disease, or who have a relapse within 2 months of stopping steroids [00575] Individual threshold* dose of previous relapses should be equal or less than 20 mg/day Prednisolone or equivalent steroid dose [00576] Patients with stable glucocorticosteroid therapy between 20 and 40 mg/day Prednisolone or equivalent steroid dose for the previous week Exclusion Criteria:
[00577] Short bowel syndrome [00578] Ileostomy, colostomy or rectal pouch [00579] Relapse during screening EXAMPLE 19: Human Clinical Trial for Treatment of Sepsis [00580] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 2 (P6; NVPRASVPDG) in individuals with sepsis.
Study Type:
[00581] Interventional Study Design:
[00582] Allocation: Randomized [00583] Control: Placebo Control [00584] Endpoint Classification: Safety/Efficacy Study [00585] Intervention Model: Single Group Assignment [00586] Masking: Double-Blind [00587] Primary Purpose: Treatment Arms [00588] P7 0.5 by IV infusion twice daily for 1 week [00589] P7 1 mg by IV infusion twice daily for 1 week [00590] Placebo by IV infusion twice daily for 1 week Eligibility Criteria [00591] 18 Years to 85 Years [00592] Male and femal Inclusion Criteria:
[00593] Presently admitted, or about to be transferred, to the ICU.
[00594] Women of Child-bearing potential must have a negative serum (or urine) hCG assay within 24 hours prior to drug administration.
[00595] Any Race.
[00596] Severe Sepsis [newly developed respiratory failure, refractory shock, renal dysfunction, hepatic dysfunction, or metabolic acidosis and at least three signs of SIRS
(systematic inflammatory response syndrome)].
[00597] Objective signs of infection likely to be caused by a bacterial or fungal pathogen.
[00598] Patients must receive study medication within 8 to 12 hours of recognition of the initial sepsis-related organ failure.
[00599] APACHE Predicted risk of mortality score between 20% and 80%.
[00600] An intent by physicians and family to aggressively treat the patient for the 28 day study period.
Exclusion Criteria:
[00601] Cardiogenic or hypovolemic shock.
[00602] Acute third degree burns involving >20% of body surface.
[00603] Recipients of non-autologous organ transplants within the past year.
[00604] Pregnancy.
[00605] Chronic vegetative state.
[00606] Uncontrolled serious hemorrhage (.2 units of blood/platelets in the previous 24 hours).
Patients may be considered for enrollment if bleeding has stopped and patients are still otherwise qualified.
[00607] Unwilling or unable to be fully evaluated for all follow-up visits.
[00608] Patients who are classified as "Do not resusitate" or "Do not treat."
[00609] Patients who develop severe sepsis <36 hours post trauma or post-surgery. Patients may be considered for enrollment >36 hours post-trauma or post-surgery, if they meet other inclusion criteria.
[00610] Patients with a predicted risk of mortality score of <20% or >80%
after recognition of qualifying organ failure.
[00611] Patients with a predicted risk of mortality of <51% for whom Xigris use is planned.
EXAMPLE 20: Human Clinical Trial for Treatment of Lupus [00612] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 2 (P7; NVPRASVPD) in individuals with lupus.
Study Type:
[00613] Interventional Study Design:
[00614] Allocation: Randomized [00615] Endpoint Classification: Safety/Efficacy Study [00616] Intervention Model: Parallel Assignment [00617] Masking: Double Blind (Subject, Investigator, Outcomes Assessor) [00618] Primary Purpose: Treatment Primary Outcome Measures:
[00619] Safety, Tolerability, Change in swollen and tender joint counts Arms [00620] P7 0.5 mg once daily for 12 weeks [00621] P7 1 mg oral once daily for 12 weeks [00622] Placebo oral once daily for 12 weeks Eligibility Criteria [00623] 18 Years to 75 Years [00624] Male and female Inclusion Criteria:
[00625] Subjects diagnosed with SLE.
[00626] Subjects with active lupus arthritis as evident by [00627] At least 4 tender and 4 swollen joints [00628] Active synovitis > 1 joint with some loss of functional range of movement Exclusion Criteria:
[00629] Subjects with severe renal impairment or dialysis [00630] Severe, unstable and/or progressive CNS lupus [00631] Subjects with a clinically significant or unstable medical or surgical condition [00632] Women who are pregnant or nursing or who intend to be during the study period.
[00633] Women of child-bearing potential who do not practice an acceptable method of birth control EXAMPLE 21: Human Clinical Trial for Treatment of Asthma [00634] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 2 (P8; cyclic CLMAFGGSSEPCALC) in individuals with asthma.
[00635] Study Type: Interventional [00636] Study Design: Allocation: Randomized [00637] Control: Placebo Control [00638] Endpoint Classification: Safety/Efficacy Study [00639] Intervention Model: Parallel Assignment [00640] Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) [00641] Primary Purpose: Treatment Primary Outcome Measures:
[00642] Airway reactivity will be measured with methacholine challenge testing following ATS
guidelines Secondary Outcome Measures:
[00643] Pulmonary function as measured by FEV 1 and FVC following ATS
guidelines [00644] Asthma symptoms and control will be objectively monitored using the Juniper Questionnaire, Asthma Quality of Life Questionnaire, and St. George Respiratory Questionnaire Detailed Description:
[00645] Participants in this study will be randomly assigned to P8 or placebo (an inactive pill). They will be given study medication to take every day for 12 weeks (3 months).
[00646] Participants will complete a number of asthma-related questionnaires and a variety of pulmonary function tests. Participants will undergo physical exams, an electrocardiogram, and blood sampling to measure leptin, adiponectin, markers of inflammation, blood cell counts, glucose levels, BNP hormone levels, and liver function.
[00647] To monitor participants throughout the study, follow-up visits will be done at 2, 6, and 12 weeks after starting study drug. At these visits many of the pulmonary function tests and questionnaires will be repeated.
Eligibility Criteria [00648] 18 Years to 60 Years [00649] Male and femal Inclusion Criteria:
[00650] Asthma diagnosed by a physician at least 1 year prior to study enrollment [00651] Poorly-controlled asthma at study enrollment [00652] Non smokers (stopped smoking at least 1 year ago) and limited lifetime history of smoking [00653] Body mass index 30-60 [00654] Responds to methacholine challenge test with PC20 of <16 mg/ml [00655] On a stable dose of inhaled corticosteroid for at least 4 weeks prior to study entry [00656] FEV 1 > 60% predicted [00657] Able to obtain weekly weights at home Exclusion Criteria:
[00658] Systemic steroids within the past 4 weeks [00659] Lung pathology other than asthma [00660] Other significant non-pulmonary co-morbidities such as: coronary artery disease, peripheral vascular disease, cerebrovascular disease, congestive heart failure with an ejection fraction <50%, liver disease or elevated liver enzymes at baseline, malignancy (excluding non-melanoma skin cancers), AIDS, renal failure with serum creatinine >3.0, or disorders requiring steroid treatment such as vasculitis, lupus, rheumatoid arthritis [00661] B-type natriuretic peptide (BNP) >400pg/ml [00662] Pregnant or lactating [00663] Currently taking a beta blocker, a CYP2C8 inhibitor or inducer such as gemfibrozil or rifampin, a TZD (thiazolidinedione), or allergic to TZD
[00664] Taking antioxidants (if taking a multivitamin must be on a stable regimen prior to enrollment) [00665] Illicit drug use within the past year [00666] Current/active upper respiratory infection (if active URI, wait until asymptomatic for 1 week to enroll) [00667] Asthma exacerbation within the past 4 weeks (includes ER, urgent care, or hospital visits due to asthma resulting in an increase in asthma-related medications) [00668] Undergoing evaluation for sleep apnea, or plans to institute treatment for sleep apnea (patients on a stable treatment regimen for sleep apnea for the last 3 months will be allowed to participate) [00669] Clinically significant abnormalities present on screening 12-lead electrocardiogram [00670] Women of childbearing potential using oral contraceptives who are not willing to use a second method of contraception during the study EXAMPLE 22: Human Clinical Trial for Treatment of Colon Cancer [00671] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 1 (P1; LMAFGGSSEP) in individuals with colon cancer Study Type:
[00672] Interventional Study Design:
[00673] Allocation: Non-Randomized [00674] Control: Uncontrolled [00675] Endpoint Classification: Efficacy Study [00676] Intervention Model: Single Group Assignment [00677] Masking: Open Label [00678] Primary Purpose: Treatment Arms [00679] Oral peptide 1 (15 mg/kg), once daily, for 4 months [00680] Oral placebo, once daily, for 4 months Elegibility Criteria [00681] 18 Years and older [00682] Male and female Inclusion Criteria:
[00683] Has undergone complete resection of stage I or II adenocarcinoma of the colon with curative intent within the past year [00684] Has undergone either a preoperative or postoperative colonoscopy to the cecum (or small bowel anastomosis) with adequate bowel preparation within the past 180 days [00685] Distal border of the tumor located > 12 cm from the anal verge [00686] No classic familial adenomatous polyposis, attenuated familial adenomatous polyposis (i.e., > 20 adenomas, either synchronous or metachronous), or hereditary nonpolyposis colorectal cancer (Lynch syndrome) PATIENT CHARACTERISTICS:
[00687] ECOG performance status 0-1 [00688] Serum creatinine < 1.5 times upper limit of normal (ULN) [00689] AST and/or ALT < 3.0 times ULN
[00690] Total bilirubin < 1.5 times ULN
[00691] Not pregnant or nursing [00692] Negative pregnancy test [00693] Fertile patients must use effective contraception during and for > 3 months after completion of study treatment [00694] Able to swallow oral medication [00695] No malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease significantly affecting gastrointestinal (GI) function [00696] No history of documented upper GI bleeding or upper GI ulcerative disease [00697] No hyperlipidemia with clinical indication for statin therapy (determination of acceptable fasting lipid values should be in accordance with current dyslipidemia management guidelines) [00698] No inadequately treated hypothyroidism, as determined by the investigator [00699] No history of myopathy or rhabdomyolysis [00700] No other malignancy within the past 5 years except for in situ cancers or basal cell or squamous cell carcinoma of the skin [00701] No hypersensitivity or intolerance to statins [00702] No other non-malignant systemic disease that would preclude rosuvastatin administration or prolonged follow-up PRIOR CONCURRENT THERAPY:
[00703] See Disease Characteristics [00704] More than 30 days since prior statins [00705] More than 30 days since prior investigational agents [00706] No prior total colectomy or total proctocolectomy [00707] No concurrent chronic use of NSAIDs [00708] No concurrent chronic drug therapy with cyclosporine, coumarin anticoagulants, gemfibrozil, other lipid-lowering therapies (e.g., fibrates or niacin), lopinavir/ritonavir, or drugs (e.g., ketoconazole, spironolactone, or cimetidine) that lower levels or activity of steroid hormones [00709] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
[00594] Women of Child-bearing potential must have a negative serum (or urine) hCG assay within 24 hours prior to drug administration.
[00595] Any Race.
[00596] Severe Sepsis [newly developed respiratory failure, refractory shock, renal dysfunction, hepatic dysfunction, or metabolic acidosis and at least three signs of SIRS
(systematic inflammatory response syndrome)].
[00597] Objective signs of infection likely to be caused by a bacterial or fungal pathogen.
[00598] Patients must receive study medication within 8 to 12 hours of recognition of the initial sepsis-related organ failure.
[00599] APACHE Predicted risk of mortality score between 20% and 80%.
[00600] An intent by physicians and family to aggressively treat the patient for the 28 day study period.
Exclusion Criteria:
[00601] Cardiogenic or hypovolemic shock.
[00602] Acute third degree burns involving >20% of body surface.
[00603] Recipients of non-autologous organ transplants within the past year.
[00604] Pregnancy.
[00605] Chronic vegetative state.
[00606] Uncontrolled serious hemorrhage (.2 units of blood/platelets in the previous 24 hours).
Patients may be considered for enrollment if bleeding has stopped and patients are still otherwise qualified.
[00607] Unwilling or unable to be fully evaluated for all follow-up visits.
[00608] Patients who are classified as "Do not resusitate" or "Do not treat."
[00609] Patients who develop severe sepsis <36 hours post trauma or post-surgery. Patients may be considered for enrollment >36 hours post-trauma or post-surgery, if they meet other inclusion criteria.
[00610] Patients with a predicted risk of mortality score of <20% or >80%
after recognition of qualifying organ failure.
[00611] Patients with a predicted risk of mortality of <51% for whom Xigris use is planned.
EXAMPLE 20: Human Clinical Trial for Treatment of Lupus [00612] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 2 (P7; NVPRASVPD) in individuals with lupus.
Study Type:
[00613] Interventional Study Design:
[00614] Allocation: Randomized [00615] Endpoint Classification: Safety/Efficacy Study [00616] Intervention Model: Parallel Assignment [00617] Masking: Double Blind (Subject, Investigator, Outcomes Assessor) [00618] Primary Purpose: Treatment Primary Outcome Measures:
[00619] Safety, Tolerability, Change in swollen and tender joint counts Arms [00620] P7 0.5 mg once daily for 12 weeks [00621] P7 1 mg oral once daily for 12 weeks [00622] Placebo oral once daily for 12 weeks Eligibility Criteria [00623] 18 Years to 75 Years [00624] Male and female Inclusion Criteria:
[00625] Subjects diagnosed with SLE.
[00626] Subjects with active lupus arthritis as evident by [00627] At least 4 tender and 4 swollen joints [00628] Active synovitis > 1 joint with some loss of functional range of movement Exclusion Criteria:
[00629] Subjects with severe renal impairment or dialysis [00630] Severe, unstable and/or progressive CNS lupus [00631] Subjects with a clinically significant or unstable medical or surgical condition [00632] Women who are pregnant or nursing or who intend to be during the study period.
[00633] Women of child-bearing potential who do not practice an acceptable method of birth control EXAMPLE 21: Human Clinical Trial for Treatment of Asthma [00634] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 2 (P8; cyclic CLMAFGGSSEPCALC) in individuals with asthma.
[00635] Study Type: Interventional [00636] Study Design: Allocation: Randomized [00637] Control: Placebo Control [00638] Endpoint Classification: Safety/Efficacy Study [00639] Intervention Model: Parallel Assignment [00640] Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) [00641] Primary Purpose: Treatment Primary Outcome Measures:
[00642] Airway reactivity will be measured with methacholine challenge testing following ATS
guidelines Secondary Outcome Measures:
[00643] Pulmonary function as measured by FEV 1 and FVC following ATS
guidelines [00644] Asthma symptoms and control will be objectively monitored using the Juniper Questionnaire, Asthma Quality of Life Questionnaire, and St. George Respiratory Questionnaire Detailed Description:
[00645] Participants in this study will be randomly assigned to P8 or placebo (an inactive pill). They will be given study medication to take every day for 12 weeks (3 months).
[00646] Participants will complete a number of asthma-related questionnaires and a variety of pulmonary function tests. Participants will undergo physical exams, an electrocardiogram, and blood sampling to measure leptin, adiponectin, markers of inflammation, blood cell counts, glucose levels, BNP hormone levels, and liver function.
[00647] To monitor participants throughout the study, follow-up visits will be done at 2, 6, and 12 weeks after starting study drug. At these visits many of the pulmonary function tests and questionnaires will be repeated.
Eligibility Criteria [00648] 18 Years to 60 Years [00649] Male and femal Inclusion Criteria:
[00650] Asthma diagnosed by a physician at least 1 year prior to study enrollment [00651] Poorly-controlled asthma at study enrollment [00652] Non smokers (stopped smoking at least 1 year ago) and limited lifetime history of smoking [00653] Body mass index 30-60 [00654] Responds to methacholine challenge test with PC20 of <16 mg/ml [00655] On a stable dose of inhaled corticosteroid for at least 4 weeks prior to study entry [00656] FEV 1 > 60% predicted [00657] Able to obtain weekly weights at home Exclusion Criteria:
[00658] Systemic steroids within the past 4 weeks [00659] Lung pathology other than asthma [00660] Other significant non-pulmonary co-morbidities such as: coronary artery disease, peripheral vascular disease, cerebrovascular disease, congestive heart failure with an ejection fraction <50%, liver disease or elevated liver enzymes at baseline, malignancy (excluding non-melanoma skin cancers), AIDS, renal failure with serum creatinine >3.0, or disorders requiring steroid treatment such as vasculitis, lupus, rheumatoid arthritis [00661] B-type natriuretic peptide (BNP) >400pg/ml [00662] Pregnant or lactating [00663] Currently taking a beta blocker, a CYP2C8 inhibitor or inducer such as gemfibrozil or rifampin, a TZD (thiazolidinedione), or allergic to TZD
[00664] Taking antioxidants (if taking a multivitamin must be on a stable regimen prior to enrollment) [00665] Illicit drug use within the past year [00666] Current/active upper respiratory infection (if active URI, wait until asymptomatic for 1 week to enroll) [00667] Asthma exacerbation within the past 4 weeks (includes ER, urgent care, or hospital visits due to asthma resulting in an increase in asthma-related medications) [00668] Undergoing evaluation for sleep apnea, or plans to institute treatment for sleep apnea (patients on a stable treatment regimen for sleep apnea for the last 3 months will be allowed to participate) [00669] Clinically significant abnormalities present on screening 12-lead electrocardiogram [00670] Women of childbearing potential using oral contraceptives who are not willing to use a second method of contraception during the study EXAMPLE 22: Human Clinical Trial for Treatment of Colon Cancer [00671] Study Objective(s): The primary objective of this study is to assess efficacy of Peptide 1 (P1; LMAFGGSSEP) in individuals with colon cancer Study Type:
[00672] Interventional Study Design:
[00673] Allocation: Non-Randomized [00674] Control: Uncontrolled [00675] Endpoint Classification: Efficacy Study [00676] Intervention Model: Single Group Assignment [00677] Masking: Open Label [00678] Primary Purpose: Treatment Arms [00679] Oral peptide 1 (15 mg/kg), once daily, for 4 months [00680] Oral placebo, once daily, for 4 months Elegibility Criteria [00681] 18 Years and older [00682] Male and female Inclusion Criteria:
[00683] Has undergone complete resection of stage I or II adenocarcinoma of the colon with curative intent within the past year [00684] Has undergone either a preoperative or postoperative colonoscopy to the cecum (or small bowel anastomosis) with adequate bowel preparation within the past 180 days [00685] Distal border of the tumor located > 12 cm from the anal verge [00686] No classic familial adenomatous polyposis, attenuated familial adenomatous polyposis (i.e., > 20 adenomas, either synchronous or metachronous), or hereditary nonpolyposis colorectal cancer (Lynch syndrome) PATIENT CHARACTERISTICS:
[00687] ECOG performance status 0-1 [00688] Serum creatinine < 1.5 times upper limit of normal (ULN) [00689] AST and/or ALT < 3.0 times ULN
[00690] Total bilirubin < 1.5 times ULN
[00691] Not pregnant or nursing [00692] Negative pregnancy test [00693] Fertile patients must use effective contraception during and for > 3 months after completion of study treatment [00694] Able to swallow oral medication [00695] No malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease significantly affecting gastrointestinal (GI) function [00696] No history of documented upper GI bleeding or upper GI ulcerative disease [00697] No hyperlipidemia with clinical indication for statin therapy (determination of acceptable fasting lipid values should be in accordance with current dyslipidemia management guidelines) [00698] No inadequately treated hypothyroidism, as determined by the investigator [00699] No history of myopathy or rhabdomyolysis [00700] No other malignancy within the past 5 years except for in situ cancers or basal cell or squamous cell carcinoma of the skin [00701] No hypersensitivity or intolerance to statins [00702] No other non-malignant systemic disease that would preclude rosuvastatin administration or prolonged follow-up PRIOR CONCURRENT THERAPY:
[00703] See Disease Characteristics [00704] More than 30 days since prior statins [00705] More than 30 days since prior investigational agents [00706] No prior total colectomy or total proctocolectomy [00707] No concurrent chronic use of NSAIDs [00708] No concurrent chronic drug therapy with cyclosporine, coumarin anticoagulants, gemfibrozil, other lipid-lowering therapies (e.g., fibrates or niacin), lopinavir/ritonavir, or drugs (e.g., ketoconazole, spironolactone, or cimetidine) that lower levels or activity of steroid hormones [00709] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Claims (44)
1. A peptide that competitively binds 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.
2. The peptide of claim 1, wherein the peptide that competitively binds with a binding partner of one of the following domains: N-terminal tail, the pseudo ELR-loop, the alpha-helix #1 motif/domain, the PPQ-loop, the PDQ-loop, the IGK-loop, the NRS-helix, the SPDR-loop, the C-terminal tail, or the combination thereof.
3. The peptide of claim 1, wherein the peptide competitively binds with a binding partner of the N-loop domain.
4. The peptide of claim 2, wherein the peptide comprises an amino acid that competitively binds with a binding partner of MIF leu47.
5. The peptide of claim 1, wherein the peptide competitively binds with a binding partner of the pseudo-ELR domain.
6. The peptide of claim 1, wherein 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).
(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).
7. A peptide that that competitively binds with a binding partner of one motif/domain of CXCR2.
8. The peptide of claim 7, wherein 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.
9. A peptide that that competitively binds with a binding partner of one motif/domain of CXCR4.
10. The peptide of claim 9, wherein the peptide competitively binds with a binding partner of:
SEADDRYICDRFYPNDLWVVV; or DDRYICDRFYPNDLW.
SEADDRYICDRFYPNDLWVVV; or DDRYICDRFYPNDLW.
11. A peptide that that competitively binds with a binding partner of one motif/domain of CD44.
12. A peptide that that competitively binds with a binding partner of one motif/domain of CD74.
13. 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.
14. The fusion peptide of claim 13, wherein the 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 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
15. The fusion peptide of claim 13 or claim 14, wherein 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 CLMAFGGSSEP[Abu]ALC (SEQ ID NO. 429), wherein Abu is isosteric L-amino acid, alpha-aminobutyric acid; or cyclic CLMAFGGSSEPSALC (SEQ ID NO. 469).
(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).
16. The fusion peptide of any of claims 13-15, wherein the fusion peptide is given by Formula (IV):
17. The fusion peptide of any of claims 13-15, wherein the fusion peptide is given by Formula (V):
18. The fusion peptide of claim 16 or claim 17, wherein 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.
19. A peptibody comprising (a) an antibody, and (b) a peptide disclosed herein; wherein the peptide and the antibody retain their activity in the peptibody.
20. The peptibody of claim 19, wherein the peptide is indirectly bound to the antibody.
21. The peptibody of claim 19, wherein the peptide is directly bound to the antibody.
22. The peptibody of claim 19, wherein the peptide is covalently bound to the antibody.
23. The peptibody of claim 19, wherein the peptide is bound to the Fab region of the antibody.
24. The peptibody of claim 19, wherein the peptide is bound to the antigen binding site of the antibody.
25. The peptibody of claim 19, wherein the peptide is bound to the antibody via a reactive side chain.
26. The peptibody of claim 19, wherein the peptide is indirectly bound to the antibody via a linker.
27. The peptibody of claim 19, wherein 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.
28. The peptibody of claim 19, wherein the antibody is an IgA, IgD, IgE, IgG, or IgM. In some embodiments, the antibody is a humanized antibody.
29. The peptibody of claim 19, wherein the peptibody is a CovX.TM. body.
30. Use of a composition of matter of any of claims 1-29, for treating an inflammatory disease, disorder or condition.
31. The use of claim 30, wherein 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-Barré 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; Sjögren's syndrome; Vasculitis; Vitiligo;
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; Behçet'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 muscle proliferation disorders; Meningitis; Shingles; 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.
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-Barré 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; Sjögren's syndrome; Vasculitis; Vitiligo;
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; Behçet'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 muscle proliferation disorders; Meningitis; Shingles; 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.
32. The use of claim 30, wherein the inflammatory, disease, disorder, or condition is a cancer.
33. The use of claim 30, wherein 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; hematological tumors; a Lymphoma; or a combination thereof.
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; or a combination thereof.
34. The use of claim 30, wherein the inflammatory, disease, disorder, or condition is rehumatoid arthritis.
35. The use of claim 30, wherein the inflammatory, disease, disorder, or condition is acute respiratory distress syndrome.
36. The use of claim 30, wherein the inflammatory, disease, disorder, or condition is glomerulonephritis.
37. The use of claim 30, wherein the inflammatory, disease, disorder, or condition is inflammatory bowel disease.
38. The use of claim 30, wherein the inflammatory, disease, disorder, or condition is abdominal aortic aneurysm disease.
39. The use of claim 30, wherein the inflammatory, disease, disorder, or condition is chronic obstructive pulmonary disease.
40. The use of claim 30, wherein the inflammatory, disease, disorder, or condition is asthma.
41. The use of claim 30, wherein the inflammatory, disease, disorder, or condition is lupus.
42. The use of claim 30, wherein the inflammatory, disease, disorder, or condition is sepsis.
43. Use of a composition of matter of claims 1-29 to treat, prevent or reduce angiogenesis.
44. A pharmaceutical composition for treating an inflammatory disease, disorder, condition or symptom in an individual in need thereof, comprising a composition of matter of any of claims 1-29.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US24521409P | 2009-09-23 | 2009-09-23 | |
US61/245,214 | 2009-09-23 | ||
US31903910P | 2010-03-30 | 2010-03-30 | |
US61/319,039 | 2010-03-30 | ||
PCT/US2010/050047 WO2011038149A2 (en) | 2009-09-23 | 2010-09-23 | Methods of treating inflammation |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2773978A1 true CA2773978A1 (en) | 2011-03-31 |
Family
ID=43796491
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2773978A Abandoned CA2773978A1 (en) | 2009-09-23 | 2010-09-23 | Methods of treating inflammation |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP2480579A4 (en) |
KR (1) | KR20120105429A (en) |
CN (1) | CN102725311A (en) |
AU (1) | AU2010298249A1 (en) |
BR (1) | BR112012006468A2 (en) |
CA (1) | CA2773978A1 (en) |
IN (1) | IN2012DN02423A (en) |
MX (1) | MX2012003514A (en) |
WO (1) | WO2011038149A2 (en) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2731970B1 (en) | 2011-07-15 | 2018-11-28 | MorphoSys AG | Antibodies that are cross-reactive for macrophage migration inhibitory factor (mif) and d-dopachrome tautomerase (d-dt) |
US9328174B2 (en) | 2012-05-09 | 2016-05-03 | Novartis Ag | Chemokine receptor binding polypeptides |
WO2013170367A1 (en) * | 2012-05-17 | 2013-11-21 | The University Of British Columbia | Methods and uses for proprotein convert ase subtilisin kexin 9 (pcsk9) inhibitors |
AR098418A1 (en) * | 2013-11-14 | 2016-05-26 | Baxter Healthcare Sa | INHIBITORY FACTOR OF IMMIGRATION OF MACROPHAGUS (MIF) AS THERAPEUTIC OBJECTIVE |
EP3426253A4 (en) | 2016-03-11 | 2019-11-06 | Ardea Biosciences, Inc. | Cxcr-2 inhibitors for treating crystal arthropathy disorders |
AU2019282132A1 (en) | 2018-06-05 | 2020-12-17 | Anji Pharmaceuticals Inc. | Compositions and methods for treating pancreatitis |
CN113383235A (en) * | 2018-12-26 | 2021-09-10 | 高露洁-棕榄公司 | Biomarkers of neutrophil dysregulation as a diagnostic of gingivitis |
WO2021181398A1 (en) * | 2020-03-11 | 2021-09-16 | Biolinerx Ltd. | Cxcr4 inhibitor for the treatment of acute respiratory distress syndrome and viral infections |
WO2021219495A1 (en) * | 2020-04-28 | 2021-11-04 | Dalcor Pharma Uk Ltd., Leatherhead, Zug Branch | Methods for treating or preventing a viral infection or inhibiting viral replication |
CN112656934A (en) * | 2021-01-22 | 2021-04-16 | 深圳市图微安创科技开发有限公司 | Application of polypeptide AT03 in medicine for treating primary biliary cholangitis |
EP4378319A1 (en) * | 2022-12-01 | 2024-06-05 | Bioiberica, S.A.U. | Composition comprising bioactive peptides |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7534605B2 (en) * | 1999-06-08 | 2009-05-19 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | CD44 polypeptides, polynucleotides encoding same, antibodies directed thereagainst and method of using same for diagnosing and treating inflammatory diseases |
AU2003213647A1 (en) * | 2002-02-27 | 2003-09-09 | Emory University | Multimeric binding complexes |
CA2478012C (en) * | 2002-03-01 | 2012-06-19 | Immunomedics, Inc. | Internalizing anti-cd74 antibodies and methods of use |
WO2005065328A2 (en) * | 2003-12-30 | 2005-07-21 | The United States Of America, As Represented By The Department Of Veterans Affairs | Macrophage migration inhibitory factor (mif) as marker for urological inflammatory disease |
US7612181B2 (en) * | 2005-08-19 | 2009-11-03 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
CN102088993A (en) * | 2008-03-20 | 2011-06-08 | 卡罗勒斯治疗公司 | Methods of treating inflammation |
WO2010056910A2 (en) * | 2008-11-12 | 2010-05-20 | Carolus Therapeutics, Inc. | Methods of treating cardiovascular disorders |
-
2010
- 2010-09-23 CA CA2773978A patent/CA2773978A1/en not_active Abandoned
- 2010-09-23 AU AU2010298249A patent/AU2010298249A1/en not_active Abandoned
- 2010-09-23 EP EP10819481.2A patent/EP2480579A4/en not_active Withdrawn
- 2010-09-23 BR BR112012006468A patent/BR112012006468A2/en not_active IP Right Cessation
- 2010-09-23 KR KR1020127010455A patent/KR20120105429A/en not_active Application Discontinuation
- 2010-09-23 IN IN2423DEN2012 patent/IN2012DN02423A/en unknown
- 2010-09-23 WO PCT/US2010/050047 patent/WO2011038149A2/en active Application Filing
- 2010-09-23 CN CN2010800526286A patent/CN102725311A/en active Pending
- 2010-09-23 MX MX2012003514A patent/MX2012003514A/en unknown
Also Published As
Publication number | Publication date |
---|---|
BR112012006468A2 (en) | 2016-08-09 |
AU2010298249A1 (en) | 2012-04-19 |
MX2012003514A (en) | 2012-04-19 |
WO2011038149A3 (en) | 2011-10-27 |
IN2012DN02423A (en) | 2015-08-21 |
CN102725311A (en) | 2012-10-10 |
EP2480579A2 (en) | 2012-08-01 |
KR20120105429A (en) | 2012-09-25 |
WO2011038149A2 (en) | 2011-03-31 |
EP2480579A4 (en) | 2013-07-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20110262386A1 (en) | Methods of treating inflammation | |
CA2773978A1 (en) | Methods of treating inflammation | |
US20100093636A1 (en) | Methods of treating inflammation | |
US20110256130A1 (en) | Methods of treating inflammatory disorders | |
TWI434854B (en) | Monoclonal antibodies that bind to hgm-csf and medical compositions comprising same | |
US20190375844A1 (en) | Antibodies and polypeptides directed against cd127 | |
TW201008580A (en) | Dual variable domain immunoglobulin and uses thereof | |
WO2019137397A1 (en) | Pd-l1 antibody, antigen-binding fragment thereof, and pharmaceutical use thereof | |
US20150291689A1 (en) | Compositions and Methods for Treating Rheumatoid Arthritis | |
KR20210005169A (en) | Optimized anti-TL1A antibody | |
BR112020020118A2 (en) | anti-cmklr1 compound, nucleic acid molecule, vector, host cell, combination product, compound combination, method for selecting an anti-cmklr1 compound, and, cmklr1 agonist compound. | |
JP2021506748A (en) | Fusion of anti-PD-L1 antibody and IL-7 | |
KR20200076731A (en) | Safe and effective way to treat psoriatic arthritis with anti-IL23 specific antibodies | |
WO2011116245A2 (en) | Methods of treating inflammation | |
EP4301774A1 (en) | Methods of treating cancer using multi-specific binding proteins that bind nkg2d, cd16 and a tumor-associated antigen | |
WO2024005204A1 (en) | Fusion protein | |
US20230140694A1 (en) | Combination treatment for cancer involving anti-icos and anti-pd1 antibodies, optionally further involving anti-tim3 antibodies | |
US20230149543A1 (en) | Combination treatment for cancer based upon an icos antbody and a pd-l1 antibody tgf-bets-receptor fusion protein | |
JP5476310B2 (en) | Monoclonal antibody binding to hGM-CSF and pharmaceutical composition comprising said antibody | |
WO2022256739A2 (en) | Antibody specific for bcl-6 and methods of use | |
CA3164126A1 (en) | Antibodies for the treatment of chronic graft versus host disease | |
JP2012105657A (en) | MONOCLONAL ANTIBODY BINDING TO hGM-CSF AND MEDICAL COMPOSITION CONTAINING THE SAME |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued |
Effective date: 20140923 |