US2018214543A1PendingUtilityA1
Motile Sperm Domain Containing Protein 2 and Inflammation
Est. expiryJul 31, 2035(~9 yrs left)· nominal 20-yr term from priority
A61P 37/06A61P 29/00A61K 39/0008A61K 39/3955A61K 2039/505C12N 2310/531C12N 2310/14C07K 16/28A61K 48/00C12N 15/113A61K 48/0016A61K 39/001102Y02A50/30A61K 31/7105
39
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Claims
Abstract
Disclosed herein are methods of treating, preventing, or reducing the incidence of an inflammatory disease or disorder and methods of inhibiting, preventing, or reducing the incidence of one or more activities in a cell with an inhibitor of a Motile Sperm Domain containing Protein 2 (MOSPD2). Also disclosed are inhibitors of MOSPD2 and pharmaceutical compositions containing MOSPD2 inhibitors.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating or preventing an inflammatory disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of an inhibitor of Motile Sperm Domain containing Protein 2 (MOSPD2).
2 . The method of claim 1 , wherein the inhibitor is a polypeptide, DNA, or RNA.
3 . The method of claim 1 , wherein the inhibitor is (i) an isolated binding molecule that specifically binds to a MOSPD2 polypeptide, (ii) an isolated binding molecule that specifically binds to a ligand of a MOSPD2 polypeptide, (iii) an antisera raised against a MOSPD2 polypeptide, (iv) a soluble MOSPD2 polypeptide, or (v) a soluble MOSPD2 polypeptide comprising, consisting essentially of, or consisting of an extracellular domain of a MOSPD2 polypeptide.
4 . The method of claim 1 , wherein the inhibitor is an antibody that specifically binds to a MOSPD2 polypeptide.
5 . The method of claim 1 , wherein the inhibitor is an antigen binding fragment of an antibody that specifically binds to a MOSPD2 polypeptide.
6 . The method of claim 4 , wherein the antibody is a polyclonal, monoclonal, murine, human, humanized, or chimeric antibody.
7 . The method of claim 5 , wherein the antigen binding fragment is a Fab, Fab′, F(ab′) 2 , Fv, scFv, sdFv fragment, VH domain, or VL domain.
8 . The method of claim 1 , wherein the inhibitor is an RNAi, miRNA, siRNA, shRNA, an antisense RNA, an antisense DNA, a decoy molecule, a decoy DNA, a double-stranded DNA, a single-stranded DNA, a complexed DNA, an encapsulated DNA, a viral DNA, a plasmid DNA, a naked RNA, an encapsulated RNA, a viral RNA, a double-stranded RNA, a molecule capable of generating RNA interference, or combinations thereof, that hybridizes to a nucleotide sequence encoding a MOSPD2 polypeptide under a stringent condition.
9 . The method of any one of claims 2 - 7 , wherein the MOSPD2 polypeptide has a sequence at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs:1-4.
10 . The method of any one of claims 2 - 7 , wherein the MOSPD2 polypeptide is encoded by a sequence at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs:5-8.
11 . The method of any one of claims 1 - 10 , wherein the inflammatory disease or disorder is an idiopathic inflammatory disease or disorder, a chronic inflammatory disease or disorder, an acute inflammatory disease or disorder, an autoimmune disease or disorder, an infectious disease or disorder, an inflammatory malignant disease or disorder, an inflammatory transplantation-related disease or disorder, an inflammatory degenerative disease or disorder, a disease or disorder associated with a hypersensitivity, an inflammatory cardiovascular disease or disorder, an inflammatory cerebrovascular disease or disorder, a peripheral vascular disease or disorder, an inflammatory glandular disease or disorder, an inflammatory gastrointestinal disease or disorder, an inflammatory cutaneous disease or disorder, an inflammatory hepatic disease or disorder, an inflammatory neurological disease or disorder, an inflammatory musculo-skeletal disease or disorder, an inflammatory renal disease or disorder, an inflammatory reproductive disease or disorder, an inflammatory systemic disease or disorder, an inflammatory connective tissue disease or disorder, necrosis, an inflammatory implant-related disease or disorder, an inflammatory aging process, an immunodeficiency disease or disorder, or an inflammatory pulmonary disease or disorder.
12 . The method of claim 11 , wherein the hypersensitivity is Type I hypersensitivity, Type II hypersensitivity, Type III hypersensitivity, Type IV hypersensitivity, immediate hypersensitivity, antibody mediated hypersensitivity, immune complex mediated hypersensitivity, T lymphocyte mediated hypersensitivity, delayed type hypersensitivity, helper T lymphocyte mediated hypersensitivity, cytotoxic T lymphocyte mediated hypersensitivity, TH1 lymphocyte mediated hypersensitivity, or TH2 lymphocyte mediated hypersensitivity.
13 . The method of claim 11 , wherein the inflammatory cardiovascular disease or disorder is an occlusive disease or disorder, atherosclerosis, a cardiac valvular disease, stenosis, restenosis, in-stent-stenosis, myocardial infarction, coronary arterial disease, acute coronary syndromes, congestive heart failure, angina pectoris, myocardial ischemia, thrombosis, Wegener's granulomatosis, Takayasu's arteritis, Kawasaki syndrome, anti-factor VIII autoimmune disease or disorder, necrotizing small vessel vasculitis, microscopic polyangiitis, Churg and Strauss syndrome, pauci-immune focal necrotizing glomerulonephritis, crescentic glomerulonephritis, antiphospholipid syndrome, antibody induced heart failure, thrombocytopenic purpura, autoimmune hemolytic anemia, cardiac autoimmunity, Chagas' disease or disorder, or anti-helper T lymphocyte autoimmunity.
14 . The method of claim 11 , wherein the inflammatory cerebrovascular disease or disorder is stroke, cerebrovascular inflammation, cerebral hemorrhage, or vertebral arterial insufficiency.
15 . The method of claim 11 , wherein the peripheral vascular disease or disorder is gangrene, diabetic vasculopathy, ischemic bowel disease, thrombosis, diabetic retinopathy, or diabetic nephropathy.
16 . The method of claim 11 , wherein the autoimmune disease or disorder is chronic rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma, mixed connective tissue disease, polyarteritis nodosa, polymyositis/dermatomyositis, Sjogren's syndrome, Bechet's disease, multiple sclerosis, autoimmune diabetes, Hashimoto's disease, psoriasis, primary myxedema, pernicious anemia, myasthenia gravis, chronic active hepatitis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, uveitis, vasculitides, or heparin induced thrombocytopenia.
17 . The method of claim 11 , wherein the inflammatory glandular disease or disorder is a pancreatic disease or disorder, Type I diabetes, thyroid disease or disorder, Graves' disease or disorder, thyroiditis, spontaneous autoimmune thyroiditis, Hashimoto's thyroiditis, idiopathic myxedema, ovarian autoimmunity, autoimmune anti-sperm infertility, autoimmune prostatitis, or Type I autoimmune polyglandular syndrome.
18 . The method of claim 11 , wherein the inflammatory gastrointestinal disease or disorder is colitis, ileitis, Crohn's disease, chronic inflammatory intestinal disease, inflammatory bowel syndrome, inflammatory bowel disease, celiac disease, ulcerative colitis, an ulcer, a skin ulcer, a bed sore, a gastric ulcer, a peptic ulcer, a buccal ulcer, a nasopharyngeal ulcer, an esophageal ulcer, a duodenal ulcer, or a gastrointestinal ulcer.
19 . The method of claim 11 , wherein the inflammatory cutaneous disease or disorder is acne, autoimmune bullous skin disease or disorder, pemphigus vulgaris, bullous pemphigoid, pemphigus foliaceus, contact dermatitis, or drug eruption.
20 . The method of claim 11 , wherein the inflammatory hepatic disease or disorder is autoimmune hepatitis, hepatic cirrhosis, or biliary cirrhosis.
21 . The method of claim 11 , wherein the inflammatory neurological disease or disorder is multiple sclerosis, Alzheimer's disease, Parkinson's disease, myasthenia gravis, motor neuropathy, Guillain-Barre syndrome, autoimmune neuropathy, Lambert-Eaton myasthenic syndrome, paraneoplastic neurological disease or disorder, paraneoplastic cerebellar atrophy, non-paraneoplastic stiff man syndrome, progressive cerebellar atrophy, Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydeham chorea, Gilles de la Tourette syndrome, autoimmune polyendocrinopathy, dysimmune neuropathy, acquired neuromyotonia, arthrogryposis multiplex, Huntington's disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis, stroke, an inflammatory retinal disease or disorder, an inflammatory ocular disease or disorder, optic neuritis, spongiform encephalopathy, migraine, headache, cluster headache, or stiff-man syndrome.
22 . The method of claim 11 , wherein the inflammatory connective tissue disease or disorder is Duchenne muscular dystrophy (DMD), autoimmune myositis, primary Sjogren's syndrome, smooth muscle autoimmune disease or disorder, myositis, tendinitis, a ligament inflammation, chondritis, a joint inflammation, a synovial inflammation, carpal tunnel syndrome, arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, a skeletal inflammation, an autoimmune ear disease or disorder, or an autoimmune disease or disorder of the inner ear.
23 . The method of claim 11 , wherein the inflammatory renal disease or disorder is autoimmune interstitial nephritis.
24 . The method of claim 11 , wherein the inflammatory reproductive disease or disorder is repeated fetal loss, ovarian cyst, or a menstruation associated disease or disorder.
25 . The method of claim 11 , wherein the inflammatory systemic disease or disorder is systemic lupus erythematosus, systemic sclerosis, septic shock, toxic shock syndrome, or cachexia.
26 . The method of claim 11 , wherein the infectious disease or disorder is a chronic infectious disease or disorder, a subacute infectious disease or disorder, an acute infectious disease or disorder, a viral disease or disorder, a bacterial disease or disorder, a protozoan disease or disorder, a parasitic disease or disorder, a fungal disease or disorder, a mycoplasma disease or disorder, gangrene, sepsis, a prion disease or disorder, influenza, tuberculosis, malaria, acquired immunodeficiency syndrome, or severe acute respiratory syndrome.
27 . The method of claim 11 , wherein the inflammatory transplantation-related disease or disorder is graft rejection, chronic graft rejection, subacute graft rejection, acute graft rejection hyperacute graft rejection, or graft versus host disease or disorder.
28 . The method of claim 11 , wherein the implant is a prosthetic implant, a breast implant, a silicone implant, a dental implant, a penile implant, a cardiac implant, an artificial joint, a bone fracture repair device, a bone replacement implant, a drug delivery implant, a catheter, a pacemaker, an artificial heart, an artificial heart valve, a drug release implant, an electrode, or a respirator tube.
29 . The method of claim 11 , wherein the inflammatory pulmonary disease or disorder is asthma, allergic asthma, emphysema, chronic obstructive pulmonary disease or disorder, sarcoidosis, or bronchitis.
30 . The method of any one of claims 1 - 10 , wherein the inflammatory disease or disorder is fibrosis.
31 . The method of any one of claims 1 - 10 , wherein the inflammatory disease or disorder is vascular inflammation in a subject suffering from a chronic autoimmune or chronic inflammatory disease.
32 . The method of claim 31 , wherein the chronic autoimmune or inflammatory disease is psoriasis.
33 . The method of claim 31 , wherein the vascular inflammation is associated with a cardiovascular disease, a peripheral vascular disease, a coronary artery disease, a cerebral vascular disease, a renal artery stenosis, an ischemic disease, or an aortic aneurism.
34 . The method of claim 31 , wherein the vascular inflammation is associated with an ischemic heart disease, atherosclerosis, acute coronary syndrome, unstable angina, stable angina, or stroke.
35 . The method of claim 31 , wherein the vascular inflammation is inflammation of a carotid artery.
36 . The method of claim 31 , wherein the vascular inflammation is inflammation of an aorta.
37 . The method of any one of claims 1 - 10 , wherein the inflammatory disease or disorder is inflammation associated with an implant.
38 . The method of claim 37 , wherein the inflammation associated with an implant is a local inflammation or a systemic inflammatory reaction.
39 . The method of claim 37 or 38 , wherein the implant is a silicone, a saline, a metal, a plastic, or a polymeric implant.
40 . The method of any one of claims 37 - 39 , wherein the implant is a cosmetic implant, a prosthetic implant, a subdermal implant, a transdermal implant, a bone replacement implant, or a bone fracture repair device.
41 . The method of any one of claims 37 - 39 , wherein the implant is a drug delivery implant or a drug release implant.
42 . The method of any one of claims 37 - 39 , wherein the implant is an artificial joint, an artificial heart, an artificial heart valve, a testicular prosthesis, a breast implant, a dental implant, an ocular implant, a cochlear implant, a penile implant, a cardiac implant, a catheter, an implantable urinary continence device, a pacemaker, an electrode, a Hernia support device, or a respirator tube.
43 . The method of any one of claims 1 - 10 , wherein the inflammatory disease or disorder is hepatitis.
44 . The method of any one of claims 1 - 10 , wherein the inflammatory disease or disorder is steatohepatitis.
45 . The method of any one of claims 1 - 10 , wherein the inflammatory disease or disorder is nonalcoholic steatohepatitis (NASH).
46 . The method of any one of claims 1 - 10 , wherein the inflammatory disease or disorder is glomerulonephritis.
47 . The method of any one of claims 1 - 10 , wherein the inflammatory disease or disorder is focal segmental glomerulosclerosis (FSGS).
48 . The method of any one of claims 1 - 10 , wherein the inflammatory disease or disorder is osteoporosis.
49 . The method of any one of claims 1 - 48 , wherein the subject is a human.
50 . A method of inhibiting one or more activities in a cell, comprising administering to a subject in need thereof a therapeutically effective amount of an inhibitor of MOSPD2, wherein the one or more activities is one or more of: leukocyte migration, leukocyte chemotaxis, a chemokine signaling pathway, EGF receptor phosphorylation, ERK phosphorylation, AKT phosphorylation, and FAK phosphorylation.
51 . The method of claim 50 , wherein the inhibitor is a polypeptide, DNA, or RNA.
52 . The method of claim 50 , wherein the leukocyte migration is monocyte migration.
53 . The method of claim 50 , wherein at least leukocyte chemotaxis and a chemokine signaling pathway are inhibited.
54 . The method of claim 50 or 53 , wherein the leukocyte chemotaxis is monocyte chemotaxis.
55 . The method of claim 50 or 53 , wherein the inhibiting of a chemokine signaling pathway is the inhibiting of ERK phosphorylation and/or AKT phosphorylation.
56 . The method of claim 50 or 53 , wherein the leukocyte chemotaxis is induced by more than one chemokine or chemokine receptor.
57 . The method of any one of claims 50 - 56 , wherein the inhibitor is (i) an isolated binding molecule that specifically binds to a MOSPD2 polypeptide, (ii) an isolated binding molecule that specifically binds to a ligand of a MOSPD2 polypeptide, (iii) an antisera raised against a MOSPD2 polypeptide, (iv) a soluble MOSPD2 polypeptide, or (v) a soluble MOSPD2 polypeptide comprising, consisting essentially of, or consisting of an extracellular domain of a MOSPD2 polypeptide.
58 . The method of claim 57 , wherein the inhibitor is an antibody that specifically binds to a MOSPD2 polypeptide.
59 . The method of claim 57 , wherein the inhibitor is an antigen binding fragment of an antibody that specifically binds to a MOSPD2 polypeptide.
60 . The method of claim 58 , wherein the antibody is a polyclonal, monoclonal, murine, human, humanized, or chimeric antibody.
61 . The method of claim 59 , wherein the antigen binding fragment is a Fab, Fab′, F(ab′) 2 , Fv, scFv, sdFv fragment, VH domain, or VL domain.
62 . The method of any one of claims 50 - 56 , wherein the inhibitor is an RNAi, miRNA, siRNA, shRNA, an antisense RNA, an antisense DNA, a decoy molecule, a decoy DNA, a double-stranded DNA, a single-stranded DNA, a complexed DNA, an encapsulated DNA, a viral DNA, a plasmid DNA, a naked RNA, an encapsulated RNA, a viral RNA, a double-stranded RNA, a molecule capable of generating RNA interference, or combinations thereof, that hybridizes to a nucleotide sequence encoding a MOSPD2 polypeptide under a stringent condition, or a gene editing system.
63 . The method of any one of claims 51 - 61 , wherein the MOSPD2 polypeptide has a sequence at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs:1-4.
64 . The method of any one of claims 51 - 61 , wherein the MOSPD2 polypeptide is encoded by a sequence at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs:5-8.
65 . The method of any one of claims 50 - 64 , wherein the subject is a human.
66 . An isolated polypeptide that inhibits MOSPD2.
67 . The isolated polypeptide of claim 66 , wherein the polypeptide (i) specifically binds to a MOSPD2 polypeptide, (ii) specifically binds to a ligand of a MOSPD2 polypeptide, (iii) is an antisera raised against a MOSPD2 polypeptide, (iv) is a soluble MOSPD2 polypeptide, or (v) is a soluble MOSPD2 polypeptide comprising, consisting essentially of, or consisting of an extracellular domain of a MOSPD2 polypeptide.
68 . The isolated polypeptide of claim 66 or 67 , wherein the MOSPD2 polypeptide has a sequence at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs:1-4.
69 . The isolated polypeptide of claim 66 or 67 , wherein the MOSPD2 polypeptide is encoded by a nucleotide sequence at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs:5-8.
70 . A pharmaceutical composition comprising the isolated polypeptide of any of claims 66 - 69 , and a pharmaceutically acceptable carrier.
71 . A pharmaceutical composition comprising an isolated polypeptide that inhibits MOSPD2, and a pharmaceutically acceptable carrier.
72 . The pharmaceutical composition of claim 70 or 71 , suitable for systemic or local administration.
73 . The pharmaceutical composition of claim 70 or 71 , suitable for nasal, oral, or intra-peritoneal administration.
74 . The pharmaceutical composition of claim 70 or 71 , suitable for intravenous administration, intramuscular administration or subcutaneous administration.
75 . A method of inhibiting MOSPD2 of a cell, comprising contacting the cell with an effective amount of a MOSPD2 inhibitor comprising an oxidized phospholipid having a structure according to Formula I:
or a pharmaceutically acceptable salt, a hydrate or a solvate thereof,
wherein:
n is an integer from 1 to 6, wherein when n is 1, Cn, Bn, Rn, and Y are absent, and C 1 is attached to R′n;
each of B 1 , B 2 , . . . Bn-1 and Bn is independently selected from the group consisting of oxygen, sulfur, nitrogen, phosphorus and silicon, whereby each of said nitrogen, phosphorus and silicon is optionally substituted by one substituent selected from the group consisting of alkyl, halo, cycloalkyl, aryl, hydroxy, thiohydroxy, alkoxy, aryloxy, thioaryloxy, thioalkoxy and oxo;
each of A 1 , A 2 , . . . An-1 and An is independently selected from the group consisting of CR″R′″, C═O and C═S,
Y is selected from the group consisting of hydrogen, acyl, alkyl, aryl, cycloalkyl, carboxy, saccharide, phosphoric acid, phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-glutaric acid, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4-phosphate, phosphoinositol-4,5-biphosphonate, phosphoinositol-4,5-bisphosphate, pyrophosphate, phosphoethanolamine-diethylenetriamine-pentaacetate, dinitrophenyl-phosphoethanolamine, phosphoglycerol and a moiety having the general formula:
wherein:
each of B′ and B″ is independently selected from the group consisting of sulfur and oxygen; and
each of D′ and D″ is independently selected from the group consisting of hydrogen, alkyl, amino substituted alkyl, cycloalkyl, phosphonate and thiophosphonate; and
each of X 1 , X 2 , . . . Xn-1 is independently a saturated or unsaturated hydrocarbon having the general Formula II:
wherein m is an integer from 1 to 26; and
Z is selected from the group consisting of:
wherein W is selected from the group consisting of oxygen and sulfur;
wherein at least one of X 1 , X 2 , . . . Xn-1 comprises a Z other than hydrogen,
and wherein:
each of R 1 , R′ 1 , R 2 , . . . Rn-1, Rn, R′n, each of R″ and R′″ and each of Ra, R′a, Rb, R′b , . . . Rm-1, R′m-1, Rm and R′m is independently selected from the group consisting of a bond, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfinyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy and amino, or, alternatively, at least two of R 1 , R′ 1 , R2, . . . Rn-1, Rn and R′n and/or at least two of Ra, R′a, Rb, R′b , . . . Rm-1, R′m-1, Rm and R′m form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring, or a pharmaceutically acceptable salt, a hydrate or a solvate thereof.
76 . The method of claim 75 , wherein the oxidized phospholipid has a structure according to Formula III:
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
wherein n is an integer selected from 1 to 4;
B 1 , each B 2 , and B 3 are independently selected from the group consisting of oxygen, sulfur, and NR 4 , wherein R 4 is selected from hydrogen, alkyl, cycloalkyl, aryl, and acyl;
A 1 and each A 2 are independently selected from the group consisting of CR e R ee , CR e ═CR ee , C═O and C═S, wherein R e and R ee are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl;
Y is selected from the group consisting of hydrogen, acyl, alkyl, aryl, cycloalkyl, carboxy, saccharide, phosphoric acid, phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-glutaric acid, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4-phosphate, phosphoinositol-4,5-bisphosphate, pyrophosphate, phosphoethanolamine-diethylenetriamine-pentaacetate, dinitrophenyl-phosphoethanolamine, phosphoglycerol, and a moiety having the general formula:
wherein: each of B and B a is independently selected from the group consisting of sulfur and oxygen; and D and D a are independently selected from the group consisting of hydrogen, alkyl, aminoalkyl, cycloalkyl, phosphonate and thiophosphonate;
X 1 and each X 2 are independently a saturated or unsaturated, linear or branched hydrocarbon, wherein at least one of X 1 and X 2 is substituted with an oxidized moiety Z selected from the group consisting of:
wherein W is oxygen or sulfur; and R d and R dd are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl;
R 1 , R 1a , each R 2 , R 3 , and R 3a are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfinyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy and amino, wherein at least two of R 1 , R 1a , R 2 , R 3 and R 3a are optionally joined to form a four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring.
77 . The method of claim 76 , wherein the oxidized phospholipid has a structure according to Formula III, and wherein X1 and each X2 in Formula III independently have the general Formula IV:
wherein m is an integer selected from 1 to 26;
Z is selected from the group consisting of:
wherein W is oxygen or sulfur; and R d and R dd are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, and wherein at least one of X 1 and X 2 comprises a Z other than hydrogen; and
R a , R aa , each R b , each R bb , R c and R cc are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfinyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy and amino, wherein at least two of R a , R aa , R b , R bb , R c , and R cc are optionally joined to form a four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring.
78 . The method of any one of claims 75 - 77 , wherein n in Formula I is 3 or n in Formula III is 1.
79 . The method of any one of claims 75 - 78 , wherein Y is selected from the group consisting of hydrogen, acyl, alkyl, aryl, cycloalkyl, carboxy, saccharide, phosphoric acid, phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-glutaric acid, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4-phosphate, phosphoinositol-4,5-bisphosphate, pyrophosphate, phosphoethanolamine-diethylenetriamine-pentaacetate, dinitrophenyl-phosphoethanolamine, and phosphoglycerol.
80 . The method of any one of claims 75 - 79 , wherein Y is selected from the group consisting of hydrogen, phosphoryl choline, and phosphoryl ethanolamine.
81 . The method of any one of claims 75 - 80 , wherein each of B 1 , B 2 , and B 3 is oxygen.
82 . The method of any one of claims 75 - 81 , wherein Z is
wherein W is oxygen.
83 . The method of claim 75 , wherein the oxidized phospholipid has a structure according to Formula IIIa:
or a pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein B 1 , B 2 , and B 3 are independently selected from oxygen and sulfur,
A 1 and A 2 are independently selected from the group consisting of CH 2 , CH═CH, C═O and C═S;
Y is selected from the group consisting of hydrogen, acyl, alkyl, aryl, cycloalkyl, carboxy, saccharide, phosphoric acid, phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-glutaric acid, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4-phosphate, phosphoinositol-4,5-bisphosphate, pyrophosphate, phosphoethanolamine-diethylenetriamine-pentaacetate, dinitrophenyl-phosphoethanolamine, and phosphoglycerol;
R 1 , R 1a , R 2 , R 3 , and R 3a , are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfinyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy and amino, wherein at least two of R 1 , R 1a , R 2 , R 3 and R 3a are optionally joined to form a four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring,
and wherein X 1 and X 2 are independently a saturated or unsaturated, linear or branched hydrocarbon, wherein at least one of X 1 and X 2 is substituted with an oxidized moiety Z having a formula selected from:
wherein W is oxygen or sulfur; and R d and R dd are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl.
84 . The method of claim 83 , wherein R 1 , R 1a , R 2 , R 3 , and R 3a are each hydrogen.
85 . The method of claim 83 or 84 , wherein X 1 and X 2 independently have a structure according to Formula IVa:
wherein m is an integer selected from 1 to 26,
R a , R aa , each R b , each R bb , R c , and R c are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfinyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy and amino, wherein at least two of R a , R aa , R b , R bb , R c , and R cc are optionally joined to form a four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring;
Z is selected from the group consisting of:
wherein W is oxygen or sulfur; and R d and R dd are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, wherein at least one of X 1 and X 2 comprises a Z other than hydrogen.
86 . The method of any one of claims 83 - 85 , wherein Z is
and wherein W is oxygen.
87 . The method of any one of claims 83 - 86 , wherein Y is selected from the group consisting of hydrogen, phosphoryl choline, and phosphoryl ethanolamine.
88 . The method of any one of claims 83 - 87 , wherein each of B 1 , B 2 , and B 3 is oxygen.
89 . The method of claim 75 , wherein the oxidized phospholipid has a structure according to the Formula VI:
wherein A 1 is selected from the group consisting of CH 2 , CH═CH and C═O; A 2 is absent or CH 2 ; X 1 is an alkyl having from 1 to 30 carbon atoms; X 2 is
wherein
E is absent or is an alkyl chain having from 1 to 24 carbon atoms;
F is selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, halide, acetoxy and aryl; and
Z is selected from the group consisting of:
wherein R d is selected from H, alkyl and aryl; and
Y is selected from the group consisting of hydrogen, alkyl, aryl, phosphoric acid, phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl serine, phosphatidyl cardiolipin, phosphatidyl inositol, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4-phosphate, phosphoinositol-4,5-bisposphate, pyrophosphate, phosphoethanolamine-diethylenetriamine-pentaacetate, dinitrophenyl-phosphoethanolamine, phosphoglycerol.
90 . The method of claim 89 , wherein X 1 is alkyl having from 10 to 30 carbon atoms.
91 . The method of claim 89 or 90 , wherein E is alkyl having from 1 to 10 carbon atoms.
92 . The method of any one of claims 89 - 91 , wherein Y is phosphocholine.
93 . The method of any one of claims 75 - 92 , wherein the oxidized phospholipid is
or a pharmaceutically acceptable salt thereof.
94 . The method of any one of claims 75 - 93 , wherein the oxidized phospholipid is
or a pharmaceutically acceptable salt thereof.
95 . The method of any one of claims 4 - 7 , wherein the antibody or antigen binding fragment thereof binds to MOSPD2 with a binding affinity (K D ) of from about 10 −6 M to about 10 −12 M.
96 . The method of any one of claim 4 - 7 or 95 , wherein the MOSPD2 is human MOSPD2.
97 . The method of any one of claims 4 - 7 , 95 and 96 , wherein the antibody or antigen binding fragment thereof specifically binds to one or more of the following amino acid regions of human MOSPD2, numbered according to SEQ ID NO:1: about 508 to about 517, about 501 to about 514, about 233 to about 241, about 509 to about 517, about 212 to about 221, about 13 to about 24, about 505 to about 517, about 505 to about 514, about 89 to about 100, about 506 to about 517, about 233 to about 245, about 504 to about 514, about 128 to about 136, about 218 to about 226, about 15 to about 24, about 83 to about 96, about 42 to about 50, about 462 to 474, about 340 to about 351, about 504 to about 517, about 462 to about 470, about 327 to about 337, about 21 to about 32, about 217 to about 226, about 510 to about 517, about 178 to about 190, about 497 to about 509, about 504 to about 516, about 64 to about 77, about 504 to about 515, about 147 to about 159, about 503 to about 515, about 88 to about 97, about 208 to about 218, about 178 to about 191, about 502 to about 515, about 503 to about 516, about 497 to about 505, about 500 to about 509, about 189 to about 202, about 189 to about 197, about 505 to about 516, about 1 to about 63, about 82 to about 239, about 93 to about 234, about 327 to about 445, about 327 to about 431, and about 497 to about 517.
98 . The method of any one of claims 4 - 7 and 95 - 97 , wherein the antibody or antigen binding fragment thereof specifically binds to one or more of the following amino acid regions of human MOSPD2, numbered according to SEQ ID NO:1: about 505 to about 515, about 500 to about 515, about 230 to about 240, about 510 to about 520, about 210 to about 220, about 15 to about 25, about 505 to about 520, about 505 to about 515, about 90 to about 100, about 505 to about 525, about 230 to about 245, about 505 to about 510, about 130 to about 140, about 220 to about 230, about 15 to about 30, about 80 to about 95, about 40 to about 50, about 460 to about 475, about 340 to about 350, about 500 to about 515, about 460 to about 470, about 325 to about 335, about 20 to about 35, about 215 to about 225, about 510 to about 520, about 175 to about 190, about 500 to about 510, about 505 to about 530, about 60 to about 75, about 500 to about 520, about 145 to about 160, about 502 to about 515, about 85 to about 100, about 205 to about 220, about 175 to about 190, about 500 to about 505, about 500 to about 525, about 495 to about 505, about 495 to about 510, about 190 to about 200, about 190 to about 198, about 502 to about 515, about 1 to about 60, about 80 to about 240, about 90 to about 235, about 330 to about 445, about 330 to about 430, and about 495 to about 515.
99 . The method of any one of claims 4 - 7 and 95 - 98 , wherein the antibody is an IgG, IgM, IgE, IgA or IgD molecule, or is derived therefrom.
100 . The method of any one of claims 4 - 7 and 95 - 99 , wherein the antibody comprises an Fc region.Join the waitlist — get patent alerts
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