WO2018053143A1 - Composition et procédé permettant de provoquer une anti-apoptose, la survie ou la prolifération de la cellule - Google Patents

Composition et procédé permettant de provoquer une anti-apoptose, la survie ou la prolifération de la cellule Download PDF

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Publication number
WO2018053143A1
WO2018053143A1 PCT/US2017/051582 US2017051582W WO2018053143A1 WO 2018053143 A1 WO2018053143 A1 WO 2018053143A1 US 2017051582 W US2017051582 W US 2017051582W WO 2018053143 A1 WO2018053143 A1 WO 2018053143A1
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cell
composition
factors
disease
target cell
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PCT/US2017/051582
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English (en)
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Jason LAPETODA
Lee Landeen
Patricia Bedard
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Vital Therapies, Inc.
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Publication of WO2018053143A1 publication Critical patent/WO2018053143A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/37—Digestive system
    • A61K35/407—Liver; Hepatocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/178—Lectin superfamily, e.g. selectins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1858—Platelet-derived growth factor [PDGF]
    • A61K38/1866—Vascular endothelial growth factor [VEGF]

Definitions

  • the present invention relates generally to cell biology and more particularly to a composition and method for inducing anti-apoptosis, anti-pyroptosis, anti-necroptosis, survival, protection, proliferation, and/or phenotypic modulation of a cell, as well as treating disease in a subject.
  • vasodilators induce increased blood flow and permeability of the blood vessels in the vicinity of the injury. This, in turn, results in the increased movement of plasma and leukocytes (including neutrophils and macrophages) from the blood into the injured tissue. Because inflammatory mediators are, in general, rapidly degraded, acute inflammation requires constant stimulation in order to be sustained. As a result, acute inflammation ends once the harmful stimulus is removed.
  • Chronic inflammation is believed to be a contributing factor to many widespread and debilitating diseases, including liver diseases, such as hepatitis, cirrhosis and fatty liver disease, heart disease, cancer, respiratory disease, stroke, neurological diseases such as Alzheimer's disease, diabetes, and kidney disease.
  • liver diseases such as hepatitis, cirrhosis and fatty liver disease
  • heart disease such as hepatitis, cirrhosis and fatty liver disease
  • heart disease such as hepatitis, cirrhosis and fatty liver disease
  • heart disease such as hepatitis and cirrhosis and fatty liver disease
  • heart disease such as hepatitis, cirrhosis and fatty liver disease
  • heart disease such as hepatitis, cirrhosis and fatty liver disease
  • heart disease such as hepatitis, cirrhosis and fatty liver disease
  • heart disease such as hepatitis, cirrhosis and fatty liver disease
  • heart disease such as hepatit
  • Fibrosis is among the common symptoms of diseases affecting the lungs, skin, liver, heart, and bone marrow, and is a critical factor in diseases such as idiopathic pulmonary fibrosis, scleroderma, keloids, liver cirrhosis, myocardial fibrosis, diabetic kidney disease, myelodysplastic syndrome, and other disorders.
  • the processing of blood has been performed to remove a variety of blood constituents for therapeutic purposes including inflammatory liver diseases, such as hepatitis.
  • blood processing methods include hemodialysis that allows to remove metabolic waste products from the blood of patients suffering from inadequate kidney function. Blood flowing from the patient is filtrated to remove these waste products, and then returned to the patient.
  • the method of plasmapheresis also processes blood using tangential flow membrane separation, to treat a wide variety of disease states. Membrane pore sizes can be selected to remove the unwanted plasma constituents.
  • Blood can be also processed using various devices utilizing biochemical reactions to modify biological constituents that are present in blood. For instance, blood components such as bilirubin or phenols can be gluconized or sulfated by the in vitro circulation of blood plasma across enzymes that are bonded to membrane surfaces.
  • Hepatocytes provide the majority of liver functions and respond to regenerative stimuli primarily through cell-surface receptor activation, such as MET (the receptor for hepatocyte growth factor (HGF) and epidermal growth factor receptor (EGFR) which interacts with various ligands). If resident hepatocytes are unable to proliferate, hepatocyte function can be replaced from a regenerative cell pool that is believed to derive from transdifferentated biliary epithelial cells located near the bile ducts. In patients with hepatitis due to chronic alcohol consumption, viral infection, or fulminant toxicants, the resident hepatocytes have a diminished replicative capacity.
  • MET the receptor for hepatocyte growth factor (HGF) and epidermal growth factor receptor (EGFR) which interacts with various ligands).
  • HGF hepatocyte growth factor
  • EGFR epidermal growth factor receptor
  • the present disclosure provides a composition for inducing anti- apoptosis, anti-pyroptosis, anti-necroptosis, survival, protection, proliferation, and/or phenotypic modulation of a cell.
  • the composition includes one or more anti-apoptotic, anti- pyroptotic, anti-necroptotic, surviving, protective, proliferative, and/or phenotypic modulative factors, such as an inhibitor of Fas mediated apoptosis (i.e., soluble Fas (sFas)), an activator of epidermal growth factor receptor (EGFR) mediated signal transduction (i.e., an EGFR agonist), and a molecule that promotes a reducing environment thereby inhibiting oxidative stress-mediated apoptosis (i.e., glutathione).
  • Fas mediated apoptosis i.e., soluble Fas (sFas)
  • EGFR epidermal growth factor receptor
  • a molecule that promotes a reducing environment thereby inhibiting oxidative stress-mediated apoptosis i.e., glutathione
  • the present disclosure provides a method of inducing anti- apoptosis, anti-pyroptosis, anti-necroptosis, protection, survival, and/or proliferation, and/or phenotypic modulation of a cell.
  • the method includes contacting the cell with a composition of the disclosure, thereby inducing anti-apoptosis, anti-pyroptosis, anti-necroptosis, protection, survival, and/or proliferation, and/or phenotypic modulation of the cell.
  • the present disclosure provides a method of treating a disease or disorder in a subject.
  • the method includes administering a composition of the disclosure to the subject, thereby treating the disease or disorder.
  • the disease, disorder, condition or undesired process is inflammation, infection, metastasis, an undesired immunological process, or an undesired thrombotic process.
  • the disease, disorder, condition or undesired process is atherosclerosis, restenosis, myocardial infarction, Reynauld's syndrome, inflammatory bowel disease, osteoarthritis, acute respiratory distress syndrome, asthma, emphysema, delayed type hypersensitivity reaction, thermal injury, experimental allergic encephalomyelitis, multiple organ injury syndrome secondary to trauma, neutrophilic dermatosis (Sweet's disease), glomerulonephritis, ulcerative colitis, Crohn's disease, necrotizing enterocolitis, cytokine- induced toxicity, gingivitis, periodontitis, hemolytic uremic syndrome, psoriasis, systemic lupus erythematosus, autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis, Grave's disease, immunological-mediated side effects of treatment associated with hemodialysis or leukapheresis, granulocyte transfusion associated syndrome
  • the disease, disorder, condition or undesired process is an undesired infection process mediated by a bacteria, a virus, or a parasite, for example gingivitis, periodontitis, hemolytic uremic syndrome, or granulocyte transfusion associated syndrome.
  • the disease, disorder, condition or undesired process is metastasis associated with cancer.
  • the disease, disorder, condition or undesired process is a disease or disorder associated with an undesired immunological process, for example psoriasis, systemic lupus erythematosus, autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis, Grave's disease and immunological-mediated side effects of treatment associated with hemodialysis or leukapheresis.
  • an undesired immunological process for example psoriasis, systemic lupus erythematosus, autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis, Grave's disease and immunological-mediated side effects of treatment associated with hemodialysis or leukapheresis.
  • the disease, disorder, condition or undesired process is a condition associated with an undesired thrombotic process, for example deep vein thrombosis, unstable angina, transient ischemic attacks, peripheral vascular disease, or congestive heart failure.
  • the invention provides methods of ameliorating an undesired immunological process in a transplanted organ comprising administering to the organ a composition of the invention.
  • the invention provides methods for treating, or ameliorating a symptom of a sickle syndrome, for example sickle cell anemia, comprising administering a composition of the invention to a patient in need thereof.
  • FIGURE 1 is a graphical plot depicting data relating to an embodiment of the invention.
  • FIGURE 2 is a graphical plot depicting data relating to an embodiment of the invention.
  • FIGURE 3 is a simplified block diagram illustrating a prior art extracorporeal filtration and detoxification system (also referred to herein as ELAD).
  • ELAD extracorporeal filtration and detoxification system
  • FIGURE 4 is a graphical plot depicting data relating to an embodiment of the invention.
  • FIGURE 5 is a series of images depicting data relating to an embodiment of the invention.
  • FIGURE 6 is a representation of a gel depicting data relating to an embodiment of the invention along with a schematic diagram.
  • FIGURE 7 is a representation of a gel depicting data relating to an embodiment of the invention along with a schematic diagram.
  • FIGURE 8 is a graphical plot depicting data relating to an embodiment of the invention.
  • FIGURE 9 is a graphical plot depicting data relating to an embodiment of the invention.
  • FIGURE 10 is a graphical plot depicting data relating to an embodiment of the invention.
  • FIGURE 11 is a tabular plot depicting data relating to an embodiment of the invention.
  • FIGURE 12 is a series of images depicting data relating to an embodiment of the invention showing that CM inhibits LPS-induced cell death in human aortic endothelial cells (HAEC).
  • FIGURE 13 is a series of images depicting data relating to an embodiment of the invention showing that VEGF contributes to anti-apoptotic effects in in human aortic endothelial cells (HAEC)
  • the present invention is based on the unexpected finding that cells of a certain C3A clonal cell line are capable of producing a variety of secreted factors with involvement in liver regeneration and hepatocyte proliferation, as well as inhibition of endothelial cell associated inflammation. These factors facilitate liver regeneration, either directly through direct stimulation of hepatocytes or indirectly through interactions with other resident cell populations upon introduction into the circulatory system of a subject.
  • This knowledge forms the basis for providing a composition and method for inducing anti-apoptosis, anti- pyroptosis, anti-necroptosis, protection, survival, and/or proliferation, and/or phenotypic modulation of a cell, as well as treatment of disease.
  • the invention described herein relates to a composition which includes one or more anti-apoptotic, pro-survival, and/or pro-regeneration factors.
  • the composition may be used to produce pharmaceutical compositions for use in treating a disease, disorder, or otherwise abnormal condition, such as an inflammatory disease or disorder.
  • the term "subject" refers to a mammalian subject
  • treatment of any animal in the order mammalian is envisioned.
  • animals include, but are not limited to horses, cats, dogs, rabbits, mice, goats, sheep, non-human primates and humans.
  • the method of the present disclosure is contemplated for use in veterinary applications as well as human use.
  • Treatment of a subject herein refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with a disease or disorder as well as those in which it is to be prevented. Hence, the subject may have been diagnosed as having a disease or disorder or may be predisposed or susceptible to a disease or disorder.
  • an effective amount refers to an amount of an anti-apoptotic, pro- survival, and/or pro-regeneration factor, that is effective for preventing, ameliorating or treating a disease or disorder. Such an effective amount will generally result in an improvement in the signs, symptoms or other indicators of a disease or disorder. For example, in liver diseases, an effective amount results in the reduction of biochemical markers indicative or poor hepatic function.
  • a "symptom" of a disease or disorder is any morbid phenomenon or departure from the normal in structure, function, or sensation, experienced by the subject and indicative of a disease or disorder.
  • inflammatory disease, disorder, or otherwise abnormal condition may include disorders associated with inflammation or have an inflammation component, such as, but are not limited to: sepsis, infection (such as viral, bacterial or fungal infection), acne vulgaris, asthma, chronic obstructive pulmonary disease (COPD), autoimmune diseases, celiac disease, chronic (plaque) prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel diseases (IBD, Crohn's disease, ulcerative colitis), pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, interstitial cystitis, atherosclerosis, allergies (type 1, 2, and 3 hypersensitivity, hay fever), inflammatory myopathies, as systemic sclerosis, and include dermatomyositis, polymyositis, inclusion body myositis, Chediak-Higashi syndrome, chronic granulomatous disease, Vitamin A
  • the inflammatory disease, disorder, or otherwise abnormal condition includes many autoimmune diseases or disorders that are associated with inflammation or have an inflammation component, e.g., corresponding to one or more types of hypersensitivity.
  • autoimmune diseases or disorders that correspond to one or more types of hypersensitivity include: atopic allergy, atopic dermatitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune polyendocrine syndrome, autoimmune urticaria, celiac disease, cold agglutinin disease, contact dermatitis, Crohn's disease, diabetes mellitus type 1, discoid lupus erythematosus, Erythroblastosis fetalis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's encephalopathy, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, autoimmune thrombocytopenic purpura, IgA n
  • Inflammatory disease, disorder, or otherwise abnormal condition in liver may include fatty liver disease, cirrhosis, liver cancer, and acute or chronic hepatitis caused by viral infection (e.g., by Hepatitis A, B, C, D and E), alcoholic hepatitis, drug or chemical intoxication (such as carbon-tetrachloride, amethopterin, tetracycline, acetaminophen, fenoprofen, and the like), mononucleosis, amebic dysentery, and other systematic infections by Epstein-Barr virus (EBV), cytomegalovirus (CMV), or bacteria.
  • EBV Epstein-Barr virus
  • CMV cytomegalovirus
  • Inflammatory disease, disorder, or otherwise abnormal condition in kidney may be associated with acute or chronic nephritis, interstitial nephritis, lupus nephritis, IgA nephropathy (Berger's disease), glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), autoimmune disorders related to chronic kidney disease (CKD) and inflammation, Goodpasture's syndrome, Wegener's granulomatosis, pyelonephritis, athletic nephritis, kidney stones, and gout.
  • IBD Inflammatory bowel disease
  • IBD is a group of inflammatory conditions of the colon and small intestine.
  • IBD Crohn's disease and ulcerative colitis.
  • Other forms of IBD which are not always classified as typical IBD, include collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's disease, and indeterminate colitis.
  • pancreatitis inflammatory disease, disorder, or otherwise abnormal condition in pancreas includes various forms of pancreatitis with a variety of causes and symptoms, including pancreatitis caused by alcohol, gallstone, medication (e.g., use of corticosteroids such as prednisolone, HIV drugs such as didanosine and pentamidine, diuretics, the anticonvulsant valproic acid, the chemotherapeutic agents L-asparaginase and azathioprine, estrogen by way of increased blood triglycerides, cholesterol-lowering statins, and the antihyperglycemic agents like metformin, vildagliptin, sitagliptin, and diabetes drug gliptins), trauma, mumps, autoimmune disease, scorpion stings, high blood calcium, high blood triglycerides, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), Pancreas divisum, pregnancy, diabetes mellitus type
  • the present invention provides, in some embodiments, methods and compositions for antagonizing vascular inflammation. Interfering or preventing such intercellular adhesion is useful both in the treatment of a variety of diseases and disorders, as well as for ameliorating one or more symptoms of such diseases or disorders.
  • the present invention provides methods of inhibiting vascular inflammation in a mammal, particularly where such vascular inflammation is associated with a disease, disorder, condition or undesired process in a mammal, comprising administering to the mammal an effective amount of a composition of the invention.
  • Diseases, disorders, conditions and undesired processes amendable to the methods of the invention include all those that are wholly or in part characterized by undesired inflammation, for example vascular inflammation, infection (for example mediated by a bacteria, a virus, or a parasite, including for example gingivitis, periodontitis, hemolytic uremic syndrome, and granulocyte transfusion associated syndrome), metastasis (for example associated with cancer), undesired immunological processes, and undesired thrombotic processes.
  • undesired inflammation for example vascular inflammation
  • infection for example mediated by a bacteria, a virus, or a parasite, including for example gingivitis, periodontitis, hemolytic uremic syndrome, and granulocyte transfusion associated syndrome
  • metastasis for example associated with cancer
  • undesired immunological processes for example associated with cancer
  • Non-limiting examples of the foregoing include atherosclerosis, restenosis, myocardial infarction, Reynauld's syndrome, inflammatory bowel disease, osteoarthritis, acute respiratory distress syndrome, asthma, emphysema, delayed type hypersensitivity reaction, thermal injury such as burns or frostbite, experimental allergic encephalomyelitis, multiple organ injury syndrome secondary to trauma, neutrophilic dermatosis (Sweet's disease), glomerulonephritis, ulcerative colitis, Crohn's disease, necrotizing enterocolitis, cytokine-induced toxicity, gingivitis, periodontitis, hemolytic uremic syndrome, psoriasis, systemic lupus erythematosus, autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis, Grave's disease, immunological-mediated side effects of treatment associated with hemodialysis or leukapheresis, granulocyte transfusion associated syndrome, deep vein
  • the infection process involves vascular inflammation.
  • the present invention also provides methods of treating or preventing an undesired infection process in a mammal, comprising administering to said mammal a composition of the invention.
  • the infection can be mediated by a bacteria, a virus, or a parasite, and examples of such infection processes include gingivitis, periodontitis, hemolytic uremic syndrome, and granulocyte transfusion associated syndrome.
  • diseases and disorders that involve vascular inflammation include metastasis in cancer, and diseases or disorders associated with an undesired immunological processes, for example psoriasis, systemic lupus erythematosus, autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis, Grave's disease and immunological- mediated side effects of treatment associated with hemodialysis or leukapheresis.
  • diseases or disorders associated with an undesired immunological processes for example psoriasis, systemic lupus erythematosus, autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis, Grave's disease and immunological- mediated side effects of treatment associated with hemodialysis or leukapheresis.
  • a further example is in organ transplantation, wherein patients generally receive immunosuppressive therapy to minimize the possibility of rejection of the organ.
  • Typical immunosuppressive agents used for such therapeutic regimes include cyclosporine, rapamycin and tacrolimus.
  • a composition of the invention can be administered to the patient to receive the organ transplant in conjunction with one or more such immunosuppressive agents.
  • the composition of the invention can be administered to an organ for transplant, by, for example, administering the composition to the patient prior to transplant, to the patient after transplant, or directly to the transplanted organ itself either before or after transplant (for example by perfusion), or in any combination.
  • the composition of the invention can be administered to an organ in conjunction with one or more immunosuppressive agents; i.e., the composition can be administered at the same time as an immunosuppressive agent, or at any time during which an immunosuppressive agent is present in effective amounts in the organ or patient.
  • FIG. 56 Further examples of processes involving vascular inflammation which are amenable to the methods of the invention include conditions associated with an undesired thrombotic process, for example deep vein thrombosis, unstable angina, transient ischemic attacks, peripheral vascular disease, or congestive heart failure.
  • an undesired thrombotic process for example deep vein thrombosis, unstable angina, transient ischemic attacks, peripheral vascular disease, or congestive heart failure.
  • compositions of the invention also find use in the treatment of sickle syndromes, for example sickle cell anemia, and in ameliorating one or more symptoms of such disorders.
  • the compositions of the invention find use in treatment of aforementioned diseases and/or disorders when administered in combination with other therapeutic agents.
  • the compositions of the invention can beneficially be administered to patients with vascular diseases, for example CAD (coronary artery disease, including but not limited to acute coronary syndrome (e.g., MI and stroke)), peripheral vascular disease including PAD (peripheral artery disease), and deep vein thrombosis, along with an anti-platelet agent, such as Plavix or aspirin, and/or lipid modulators such as, for example statins.
  • CAD coronary artery disease, including but not limited to acute coronary syndrome (e.g., MI and stroke)
  • peripheral vascular disease including PAD peripheral vascular disease
  • deep vein thrombosis deep vein thrombosis
  • an anti-platelet agent such as Plavix or aspirin
  • lipid modulators such as, for example statins.
  • Other suitable anti-platelet agents and lipid modulators will be apparent to those of skill in the
  • compositions of the invention further find use in the treatment of diseases and disorders implicated by biomarkers as are known in the art.
  • biomarkers include, for example, CD 40, CD 40 Ligand, MAC-1, TGF beta, ICAM, VCAM, IL-1, IL-6, IL-8, Eotaxin, RANTES, MCP-1, PIGF, CRP and SAA, as well as platelet monocyte aggregates.
  • the present invention provides a composition which includes one or more anti- apoptotic, pro-survival, and/or pro-regeneration factors, which are generally peptides.
  • the one or more factors include an inhibitor of Fas mediated apoptosis (i.e., soluble Fas (sFas)), Apo B, an activator of epidermal growth factor receptor (EGFR) mediated signal transduction (i.e., an EGFR agonist), a molecule that promotes a reducing environment thereby inhibiting oxidative stress-mediated apoptosis (i.e., glutathione), or any combination thereof.
  • the one or more factors are selected from those set forth in Table I or II, any may include any combination thereof.
  • Table I Factors of the disclosure (e.g., anti-apoptotic, pro-survival, and/or pro-regeneration factors).
  • Tissue Inhibitor of Metalloproteinse 1 (TIMP-1)
  • TGF Transforming Growth Factor alpha
  • TRR Transthyretin
  • VEGF Vascular Endothelial Growth Factor
  • VEGF-C Vascular Endothelial Growth Factor C
  • Factors of the disclosure e.g., anti-apoptotic, pro-survival, and/or pro- regeneration factors .
  • the one or more factors includes at least AR or sFAS.
  • the one or more factors includes both AR and sFAS and optionally one or more additional factors from Table I or II, such as a known mitogen, a factor that inhibits apoptosis related signal transduction in non-disease related cells, a factor that promotes apoptosis in disease related cells, and/or a factor that induces a phenotypic shift resulting in improved cellular functioning.
  • the one or more factors includes all of those set forth in Table I. In one embodiment, the one or more factors includes all of those set forth in Table II.
  • the one or more factors includes Apo B, AR, sFAS and one or more of Hepatocyte growth factor (HGF), Transforming growth factor alpha, Heparin binding epidermal growth factor, Platelet-derived growth factor BB, Vascular endothelial growth factor, Vascular endothelial growth factor C, Placental growth factor, Angiopoietin2, Erythropoietin, Stem cell factor or any combination thereof.
  • HGF Hepatocyte growth factor
  • Transforming growth factor alpha Heparin binding epidermal growth factor
  • Platelet-derived growth factor BB Platelet-derived growth factor BB
  • Vascular endothelial growth factor Vascular endothelial growth factor
  • Vascular endothelial growth factor C Placental growth factor
  • Angiopoietin2 Erythropoietin
  • Stem cell factor Stem cell factor
  • the one or more factors includes AR, sFAS, Hepatocyte growth factor (HGF), Transforming growth factor alpha, Heparin binding epidermal growth factor, Platelet-derived growth factor BB, Vascular endothelial growth factor, Vascular endothelial growth factor C, Placental growth factor, Angiopoietin2, Erythropoietin and Stem cell factor.
  • HGF Hepatocyte growth factor
  • HGF Hepatocyte growth factor
  • Transforming growth factor alpha Heparin binding epidermal growth factor
  • Platelet-derived growth factor BB vascular endothelial growth factor
  • Vascular endothelial growth factor C Placental growth factor
  • Angiopoietin2 Erythropoietin
  • Stem cell factor Stem cell factor
  • the one or more factors includes Apo B and one or more of AR, sFAS, gelsolin.
  • the one or more factors includes Apo B, AR, and sFAS.
  • the one or more factors includes AR, sFAS and one or more of AAT, A2Macro, Apo B, Apo A-I, Apo A-II, Apo C-I, Apo C-III, Apo H, ⁇ 2 ⁇ , Cancer Antigen 125 (CA-125), CD 40 antigen (CD40), CreatineKinase-MB (CK-MB), Eotaxin-1, Factor VII, Ferritin (FRTN), Fibrinogen, ICAM-1, IL-IRa, IL-7, IL-8, IL-17, Macrophage- Derived Chemokine (MDC), Neuron-Specific Enolase (NSE), Plasminogen Activator Inhibitor 1 (PAI-1), Serotransferrin (Transferrin), Sex Hormone-Binding Globulin (SHBG), Thyroxine-Binding Globulin (TBG), TIMP-1, Transthyretin (TTR), or any combination thereof
  • the one or more factors includes AR, sFAS, AAT, A2Macro, Apo A-I, Apo A-II, Apo C-I, Apo C-III, Apo H, ⁇ 2 ⁇ , Cancer Antigen 125 (CA-125), CD 40 antigen (CD40), CreatineKinase-MB (CK-MB), Eotaxin-1, Factor VII, Ferritin (FRTN), Fibrinogen, ICAM-1, IL-IRa, IL-7, IL-8, IL-17, Macrophage-Derived Chemokine (MDC), Neuron-Specific Enolase (NSE), Plasminogen Activator Inhibitor 1 (PAI-1), Serotransferrin (Transferrin), Sex Hormone-Binding Globulin (SHBG), Thyroxine-Binding Globulin (TBG), TDVIP-1 and Transthyretin (TTR).
  • CA-125 Cancer Antigen 125
  • CD40 CD 40
  • the one or more factors are polypeptides, such as those set forth in Table 1.
  • the composition is a pharmaceutical composition that includes one or more factors, such as a polypeptide and a pharmaceutically acceptable carrier.
  • polypeptide such as a polypeptide and a pharmaceutically acceptable carrier.
  • the composition includes a single type of factor from Table I, such as Apo B, AR or sFAS.
  • the pharmaceutical composition includes a combination of two or more factors from Table I, such as Apo B along with AR and/or sFas.
  • the composition is substantially free of blood proteins and/or metabolites found in the blood.
  • the composition includes serum albumin (e.g., human serum albumin).
  • any polypeptide factor present in the composition is recombinantly produced.
  • any polypeptide factor present in the composition is produced by a C3A cell in response to blood, or fraction thereof, from a subject.
  • the composition may further include one or more agents that increase expression or activity of one or more of the factors set forth in Table I.
  • An agent useful in the invention can be any type of molecule, for example, a polynucleotide, a peptide, a peptidomimetic, peptoids such as vinylogous peptoids, chemical compounds, such as organic molecules or small organic molecules, or the like.
  • expression or activity is increased by a factor of at least 2.0, 5.0, 10, 25, 50, 100, 250, 500, 1,000, 5,000 or greater as compared to expression or activity prior to contacting with the agent.
  • the agent is a polynucleotide, such as an antisense oligonucleotide or RNA molecule which increases expression and/or activity (directly or indirectly) in a cell of a factor set forth in Table I.
  • the agent may be a polynucleotide, such as an antisense oligonucleotide or RNA molecule, such as microRNA, dsRNA, siRNA, stRNA, and shRNA.
  • MicroRNAs are single-stranded RNA molecules, which regulate gene expression. miRNAs are encoded by genes from whose DNA they are transcribed but miRNAs are not translated into protein; instead each primary transcript (a pri-miRNA) is processed into a short stem-loop structure called a pre-miRNA and finally into a functional miRNA. Mature miRNA molecules are either fully or partially complementary to one or more messenger RNA (mRNA) molecules, and their main function is to down-regulate gene expression.
  • mRNA messenger RNA
  • MicroRNAs can be encoded by independent genes, but also be processed (via the enzyme Dicer) from a variety of different RNA species, including introns, 3' UTRs of mRNAs, long noncoding RNAs, snoRNAs and transposons.
  • microRNAs also include "mimic" microRNAs which are intended to mean a microRNA exogenously introduced into a cell that have the same or substantially the same function as their endogenous counterpart.
  • an agent may be an exogenously introduced RNA
  • an agent also includes a compound or the like that increase or decrease expression of microRNA in the cell.
  • small interfering RNA and "siRNA” also are used herein to refer to short interfering RNA or silencing RNA, which are a class of short double-stranded RNA molecules that play a variety of biological roles. Most notably, siRNA is involved in the RNA interference (RNAi) pathway where the siRNA interferes with the expression of a specific gene. In addition to their role in the RNAi pathway, siRNAs also act in RNAi- related pathways (e.g., as an antiviral mechanism or in shaping the chromatin structure of a genome).
  • RNAi RNA interference
  • polynucleotide or “nucleotide sequence” or “nucleic acid molecule” is used broadly herein to mean a sequence of two or more deoxyribonucleotides or ribonucleotides that are linked together by a phosphodiester bond.
  • the terms include RNA and DNA, which can be a gene or a portion thereof, a cDNA, a synthetic polydeoxyribonucleic acid sequence, or the like, and can be single stranded or double stranded, as well as a DNA/RNA hybrid.
  • nucleic acid molecules which can be isolated from a cell
  • synthetic polynucleotides which can be prepared, for example, by methods of chemical synthesis or by enzymatic methods such as by the polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • the composition of the disclosure can include a single factor set forth in Table I, or combinations thereof.
  • the composition can be substantially free of proteins other than those of Table I.
  • the composition can be substantially free of any proinflammatory molecules.
  • the term "substantially free of proteins other than those of Table I” means that less than 5% of the protein content of the composition is made up of proteins that are not set forth in Table I.
  • the term "substantially free of a pro-inflammatory molecule” means that less than 5% of the content of the composition is made up of pro-inflammatory molecules.
  • a composition that is substantially free of proteins other than those of Table I can have less than 4%, 3%, 2% , 1%, 0.5%, 0.1%, 0.05%, 0.01%, 0.001%, 0.0001%, or less (e.g., 0.0%) of proteins other than those of Table I.
  • a composition that is substantially free of a pro-inflammatory molecule can have less than 4%, 3%, 2% , 1%, 0.5%, 0.1%, 0.05%, 0.01%, 0.001%, 0.0001% or less of such molecules.
  • the composition can be substantially free of blood proteins, such as serum albumin, globulins, fibrinogen, and clotting factors.
  • the composition can include one or more of serum albumin, globulins, fibrinogen, and clotting factors.
  • the peptide factor of the composition is not naturally found in a human or other mammal or animal.
  • the factor may be synthetic, recombinant or the like.
  • a composition of the invention can include a peptide factor that is naturally found in a human or other mammal or animal.
  • the peptide factor may include a non-naturally occurring amino acid.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, .gamma.- carboxyglutamate, and O-phosphoserine.
  • amino acid analogs refers to compounds that have the same fundamental chemical structure as a naturally occurring amino acid, i.e., an alpha carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.
  • the composition includes one or more conservatively modified variants of a factor set forth in Table I.
  • the conservatively modified variant has at least 80% sequence similarity, often at least 85% sequence similarity, 90% sequence similarity, or at least 95%, 96%, 97%, 98%, or 99% sequence similarity at the amino acid level, with the naturally occurring polypeptide.
  • amino acid sequences With respect to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologues, and alleles of the invention.
  • substitutions may be made wherein an aliphatic amino acid (G, A, I, L, or V) is substituted with another member of the group, or substitution such as the substitution of one polar residue for another, such as arginine for lysine, glutamic for aspartic acid, or glutamine for asparagine.
  • Each of the following eight groups contains other exemplary amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W), 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M) (see, e.g., Creighton, Proteins (1984)).
  • identity in the context of two or more polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithm with default parameters, or by manual alignment and visual inspection.
  • the composition is substantially free of biological molecules (such as polypeptides, nucleic acids, lipids, carbohydrates, and metabolites) that are associated with the one or more factors of the invention in vivo or co-purify with the factors.
  • biological molecules such as polypeptides, nucleic acids, lipids, carbohydrates, and metabolites
  • the term "substantially free of biological molecules” means that less than 5% of the dry weight of the composition is made up of biological molecules not set forth in Table I.
  • a composition that is substantially free of such biological molecules can have less than 4%, 3%, 2% , 1%, 0.5%, 0.1%, 0.05%, 0.01%, or less of biological molecules that are not set forth in Table I.
  • the composition can be substantially free of biological molecules that are abundant in the blood, such as, fatty acids, cholesterol, non-protein clotting factors, metabolites, and the like.
  • the composition can be substantially free of cells, including red blood cells, white blood cells, platelets, and cell fragments.
  • the composition of the invention includes at least 1 mg (e.g., at least 5, 10, 20, 30, 40, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000 mg, or more) of one or more of the factors set forth in Table I.
  • the composition can include an amount of one or more factors equal to about 1 mg to about 1000 mg (e.g., about 5 mg to about 900 mg, about 5 mg to about 800 mg, about 5 mg to about 700 mg, about 5 mg to about 600 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg, about 75 mg to about 500 mg, about 75 mg to about 400 mg, about 75 mg to about 300 mg, about 75 mg to about 250 mg, about 75 mg to about 200 mg, about 75 mg to about 150 mg, about 75 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 75 mg
  • the composition of the invention can include a solution that contains at least 1 mg/ml (e.g., at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg/ml or more) of one or more of the factors set forth in Table I.
  • at least 1 mg/ml e.g., at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg/ml or more
  • the composition can include a solution having a concentration of one or more of the factors set forth in Table I of about 1 mg/ml to about 1000 mg/ml (e.g., about 5 mg/ml to about 900 mg/ml, about 5 mg/ml to about 800 mg/ml, about 5 mg/ml to about 700 mg/ml, about 5 mg/ml to about 600 mg/ml, about 5 mg/ml to about 500 mg/ml, about 10 mg/ml to about 500 mg/ml, about 10 mg/ml to about 400 mg/ml, about 10 mg/ml to about 300 mg/ml, about 10 mg/ml to about 250 mg/ml, about 10 mg/ml to about 200 mg/ml, about 10 mg/ml to about 150 mg/ml, about 10 mg/ml to about 100 mg/ml, about 50 mg/ml to about 500 mg/ml, about 50 mg/ml to about 400 mg/ml, about 50 mg/ml to about 300 mg
  • the composition of the invention includes at least 1 pg (e.g., at least 5, 10, 20, 30, 40, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000 pg, or more) of one or more of the factors set forth in Table I.
  • at least 1 pg e.g., at least 5, 10, 20, 30, 40, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000 pg, or more
  • the composition can include an amount of one or more factors of equal to about 1 pg to about 1000 pg (e.g., about 5 pg to about 900 pg, about 5 pg to about 800 pg, about 5 pg to about 700 pg, about 5 pg to about 600 pg, about 10 pg to about 500 pg, about 10 pg to about 400 pg, about 10 pg to about 300 pg, about 10 pg to about 250 pg, about 10 pg to about 200 pg, about 10 pg to about 150 pg, about 10 pg to about 100 pg, about 50 pg to about 500 pg, about 50 pg to about 400 pg, about 50 pg to about 300 pg, about 50 pg to about 250 pg, about 50 pg to about 200 pg, about 50 pg to about 150 pg, about 50 pg to about 100 pg, about 75
  • the composition of the invention can include a solution that contains at least 1 pg/ml (e.g., at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 pg/ml or more) of one or more of the factors set forth in Table I.
  • at least 1 pg/ml e.g., at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 pg/ml or more
  • the composition can include a solution having a concentration of one or more of the factors set forth in Table I of about 1 pg/ml to about 1000 pg/ml (e.g., about 5 pg/ml to about 900 pg/ml, about 5 pg/ml to about 800 pg/ml, about 5 pg/ml to about 700 pg/ml, about 5 pg/ml to about 600 pg/ml, about 5 pg/ml to about 500 pg/ml, about 10 pg/ml to about 500 pg/ml, about 10 pg/ml to about 400 pg/ml, about 10 pg/ml to about 300 pg/ml, about 10 pg/ml to about 250 pg/ml, about 10 pg/ml to about 200 pg/ml, about 10 pg/ml to about 150 pg/ml, about 10 pg/ml
  • the composition of the invention is typically a pharmaceutical composition.
  • a pharmaceutical composition can include one or more of the factors set forth in Table I or II and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition can further include a protein other than a factor as set forth in Table I or II.
  • the other protein can be a therapeutic agent, such as a therapeutic polypeptide.
  • the other protein can be a carrier protein.
  • the composition of the invention includes an anti-coagulant, such as heparin or citrate.
  • an anti-coagulant such as heparin or citrate.
  • citrate refers to a citrate anion, in any form, including citric acid (citrate anion complexed with three protons), salts containing citrate anion, and partial casters of citrate anion.
  • Citrate anion is an organic tricarboxylate.
  • Citric acid which has been assigned Chemical Abstracts Registry No. 77-92-2, has the molecular formula HOC(C0 2 H)(CH 2 C0 2 H)2 and a formula weight of 192.12 g/mol.
  • a citrate salt (i.e., a salt containing citrate anion) is composed of one or more citrate anions in association with one or more physiologically-acceptable cations.
  • physiologically-acceptable cations include, but are not limited to, protons, ammonium cations and metal cations.
  • metal cations include, but are not limited to, sodium, potassium, calcium, and magnesium, where sodium and potassium are preferred, and sodium is more preferred.
  • a composition containing citrate anion may contain a mixture of physiologically-acceptable cations.
  • the composition includes sodium citrate.
  • Sodium citrate may be in the form of a dry chemical powder, crystal, pellet or tablet. Any physiologically tolerable form of citric acid or sodium citrate may be used.
  • the citric acid or sodium citrate may be in the form of a hydrate, including a monohydrate.
  • the pharmaceutical composition of the invention may be prepared by mixing one or more of the factors set forth in Table I having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. Ed. (1980)).
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine,
  • the composition of the present invention may include live cells.
  • the composition includes a hepatocyte cell.
  • the composition includes HepG2 cells or C3A cells which are optionally recombinantly engineered.
  • composition of the invention provides powerful tools for inducing anti- apoptosis, survival, and/or proliferation of a target cell and/or treating a disease or disorder, such as an inflammatory disease.
  • the invention provides a method of inducing anti-apoptosis, anti- pyroptosis, anti-necroptosis, survival, protection, proliferation, and/or phenotypic modulation in a cell by contacting the cell with a composition of the disclosure.
  • proliferation of the contacted cell is increase by a factor of at least 1.1, 1.5, 2.0, 5.0, 10, 25, 50, 100 or greater as compared to proliferation of a comparable cell not contacted with the composition.
  • survival of the cell is increase by a factor of at least 1.1, 1.5, 2.0, 5.0, 10, 25, 50, 100 or greater as compared to survival of a comparable cell not contacted with the composition.
  • the invention also provides a method of treating a disease or disorder in a subject.
  • the method includes administering one or more factors set forth in Table I or II (or, for example, a pharmaceutical composition comprising one or more factors set forth in Table I or II) to the subject, or cell or tissue thereof.
  • the one or more factors induces anti-apoptosis, anti- pyroptosis, anti-necroptosis, survival, protection, proliferation, and/or phenotypic modulation in the contacted cell or tissue.
  • the contacted cell (also referred to as a target cell) is a eukaryotic cell, such as a mammalian cell.
  • the contacted cell is a hepatocyte.
  • the cell is a hepatoblastoma-derived cell.
  • the cell is a HepG2 cell or a C3A cell of a C3A cell line.
  • the cell is a clonal derivative from a parental C3A cell line. In one embodiment, the cell is a recombinantly engineered cell. In one embodiment the contacted cell is an endothelial cell. In one embodiment the contacted cell is a human aortic endothelial cell.
  • C3A cell line refers to a sub-clone of the human hepatoblastoma cell line HepG2.
  • the C3A cell line is a qualified cell line having been deposited at the American Type Culture Collection under ATCC No. CRL- 10741.
  • Administration of the composition may be performed in any suitable manner including, for example, intravenously, intraperitoneally, parenteral, orthotopically, subcutaneously, topically, nasally, orally, sublingually, intraocularly, by means of an implantable depot, using nanoparticle-based delivery systems, microneedle patch, microspheres, beads, osmotic or mechanical pumps, and/or other mechanical means.
  • a cell may be contacted by the composition in-vivo or in- vitro.
  • a cell or an organ is contacted ex-vivo, such as a removed liver, to regenerate the organ and prepare the organ for transplant or preserve the organ.
  • the organ may be a diseased organ, such as a diseased liver, which may be regenerated for transplantation into a donor.
  • the cell is contacted in-vivo, the contacted cell being within a subject being treated by an extracorporeal detoxification system, such as that described in U. S. Patent No. 8, 105,491 which is incorporated herein by reference in its entirety.
  • one more factors of the composition may be produced by a cell, such as a C3A cell, contained within an active cartridge (bioreactor) of the system.
  • the system may be fluidly coupled to a subject, or a cell or organ thereof, e.g., a liver.
  • the extracorporeal detoxification system 10 generally includes a blood circuit 100 configured to be coupled to a patient and operative to communicate blood from the patient, through an ultrafiltrate generator (UFG) 40, and back to the patient; a recirculation circuit 50 coupled to the UFG 40 and operative to draw ultrafiltrate from the UFG 40 and to treat ultrafiltrate independently of cellular components of the blood; and a conduit junction 15 operative to recombine the ultrafiltrate in the recirculation circuit 50 and the cellular components in the blood circuit 100 prior to reintroduction to the patient.
  • an active cartridge 70 and oxygenator 60 arranged within the recirculation circuit 50. The active cartridge 70 is utilized to treat the ultrafiltrate.
  • active cartridge refers to a hollow fiber based cartridge comprising cells (such as, for example, cells of the C3A cell line) having utility in therapeutic applications and detoxification processes.
  • the term "blood circuit” refers to a circuit of tubing connected to a double lumen catheter and operative to circulate blood from a patient to a blood control unit and back to the patient.
  • C3A cell line refers to a sub-clone of the human hepatoblastoma cell line HepG2. In embodiments, C3A cells are contained in the extracapillary space of one or more active cartridges. The C3A cell line has been deposited at the American Type Culture Collection under ATCC No. CRL- 10741.
  • detoxification device refers to a cartridge, canister, or other device that provides a means of removal of specific or non-specific molecules from a fluid stream. Examples would be a dialysis cartridge, an adsorption cartridge, or a filter.
  • ECS extracapillary space
  • ICS intracapillary space
  • the ICS is the flow path for whole blood or the ultrafiltrate fluid.
  • recirculation circuit refers to a circuit generally enabling filtration, detoxification, and treatment of ultrafiltrate fluid; in some implementations, a recirculation circuit generally encompasses a reservoir, an oxygenator, and one or more active cartridges.
  • UF ultrafiltrate
  • the term "ultrafiltrate generator” refers to a device comprising or embodied as a "blank” active cartridge (i.e., a hollow fiber cartridge which does not contain therapeutically active cells) and operative to separate plasma fluid (ultrafiltrate) from cellular blood components.
  • the hollow fibers may be composed of a semi-permeable membrane which has, for example, a nominal molecular weight cut-off of approximately 100,000 Daltons in some implementations.
  • blood may be circulated through the ICS of the hollow fibers; ultrafiltrate, comprising blood plasma and various macromolecules, passes through the membrane fiber walls into the recirculation circuit, where it is circulated through one or more active cartridges.
  • UF ultrafiltrate
  • ICS lumen
  • toxins, nutrients, glucose, and dissolved oxygen from the UF to diffuse across the membrane into the ECS, where the live cells may metabolize them.
  • Metabolites, along with albumin and other proteins produced by the cells may diffuse back across the membrane into the UF for return to the patient.
  • the C3A cell line is a subclone of the human hepatoblastoma cell line HepG2.
  • Some subclones of this parent cell line, such as C3A exhibit liver-specific functional capabilities such as high albumin production and a-fetoprotein (AFP) production as well as expression of anti-inflammatory mediator proteins a- 1 -antitrypsin (AAT) and IL-lRa in response to pro-inflammatory molecules of the present invention, including for example, cytokines IL-6 and IL- ⁇ .
  • Such cells are also capable of producing one or more factors set forth in Table I or II.
  • the system may be fluidly coupled to the subject, or a cell or organ thereof, e.g., a liver.
  • the composition of the present invention is introduced into the blood circuit of system 10.
  • the composition may be introduced into the circulatory of the subject, or introduced directly into the blood flow path of the system.
  • one or more of the factors set forth in Table I or II is generated by cells within the active cartridge 70 of system 10.
  • treated UF including factors of the composition is reintroduced into the subject wherein the factors of the composition contact cells of the subject, such as liver cells, thereby facilitating treatment of a disease or disorder.
  • the active cartridge may include any number of suitable cell types which are beneficial in treating any number of different diseases, such as inflammatory diseases as disclosed herein.
  • the active cartridge may include cells recombinantly engineered to produce one or more of the factors set forth in Table I or II, such as AR and/or sFas, in response to a stimuli, for example, a stimuli generated within the subject being treated, such as a pro-inflammatory molecule.
  • the composition can be administered daily (or every other day, or weekly), wherein the amount of one or more factors of Table I or II is between about 1 mg and about 1000 mg (e.g., about 5 mg to about 900 mg, about 5 mg to about 800 mg, about 5 mg to about 700 mg, about 5 mg to about 600 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg, about 75 mg to about 500 mg, about 75 mg to about 400 mg, about 75 mg to about 300 mg, about 75 mg to about 250 mg, about 75 mg to about 200 mg, about 75 mg to about 150 mg, about 75 mg,
  • the composition can be administered daily (or every other day, or weekly), wherein the amount of one or more factors of Table I or II is between about 1 pg and about 1000 pg (e.g., about 5 pg to about 900 pg, about 5 pg to about 800 pg, about 5 pg to about 700 pg, about 5 pg to about 600 pg, about 10 pg to about 500 pg, about 10 pg to about 400 pg, about 10 pg to about 300 pg, about 10 pg to about 250 pg, about 10 pg to about 200 pg, about 10 pg to about 150 pg, about 10 pg to about 100 pg, about 50 pg to about 500 pg, about 50 pg to about 400 pg, about 50 pg to about 300 pg, about 50 pg to about 250 pg, about 50 pg to about 200 pg
  • the composition can be administered in combination with a drug useful for treatment of the disease or disorder.
  • the composition is administered with an antibiotic.
  • antibiotics useful for synergistic therapy with the composition of the invention include aminoglycosides (e.g., tobramycin), penicillins (e.g., piperacillin), cephalosporins (e.g., ceftazidime), fluoroquinolones (e.g., ciprofloxacin), carbapenems (e.g., imipenem), tetracyclines and macrolides (e.g., erythromycin and clarithromycin).
  • aminoglycosides e.g., tobramycin
  • penicillins e.g., piperacillin
  • cephalosporins e.g., ceftazidime
  • fluoroquinolones e.g., ciprofloxacin
  • carbapenems e.g., imipenem
  • typical antibiotics include aminoglycosides (amikacin, gentamicin, kanamycin, netilmicin, tobramycin, streptomycin, azithromycin, clarithromycin, erythromycin, erythromycin estolate/ethylsuccinate/gluceptate/lactobionate/stearate), beta- lactams such as penicillins (e.g., penicillin G, penicillin V, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, ampicillin, amoxicillin, ticarcillin, carbenicillin, mezlocillin, azlocillin and piperacillin), or cephalosporins (e.g., cephalothin, cefazolin, cefaclor, cefamandole, cefoxitin, cefuroxime, cefonicid, cefmetazole, cefotetan, ce
  • antibiotics include carbapenems (e.g., imipenem), monobactams (e.g.,aztreonam), quinolones (e.g., fleroxacin, nalidixic acid, norfloxacin, ciprofloxacin, ofloxacin, enoxacin, lomefloxacin and cinoxacin), tetracyclines (e.g., doxycycline, minocycline, tetracycline), and glycopeptides (e.g., vancomycin, teicoplanin).
  • Other antibiotics include chloramphenicol, clindamycin, trimethoprim, sulfamethoxazole, nitrofurantoin, rifampin, mupirocin and the cationic peptides.
  • any of the foregoing methods of the invention further include a step of assessing the efficacy of the therapeutic treatment. Because the factors of the invention have a demonstrable ability to induce anti-apoptosis, survival, and/or proliferation of a target cell, the efficacy of the therapeutic treatment can be assessed by measuring aspects of the respective biological pathways, including measuring levels of factors (e.g., in the serum) that are associated with such pathways.
  • C3A cell cartridge spent media were assayed using chemiluminescent multiplex array detection (Aushon) and/or contracted immunoassay multiplex services (Myriad Rules Based Medicine) for known mitogens, angiogenesis factors, or other proteins demonstrated in the literature to be involved with liver regeneration.
  • System steady-state concentrations were converted into a "Dose” by multiplying the perfusion flow rates and time, then compared to literature values of normal healthy individuals, and a mass that a Dose may be expected to increase above those levels was determined.
  • HGF is the most widely known hepatocyte mitogen, but other mitogens include transforming growth factor alpha (TGFa), amphiregulin, heparin-binding EGF (HB-EGF), and platelet-derived growth factor BB (PDGF-BB). All of these growth factors were secreted in measurable amounts by C3A cells.
  • TGFa transforming growth factor alpha
  • HB-EGF amphiregulin
  • PDGF-BB platelet-derived growth factor BB
  • VEGF Vascular endothelial growth factor
  • VEGF-C vascular endothelial growth factor
  • PLGF placental growth factor
  • ANG2 angiopoiein2
  • SCF stem cell factor
  • EPO erythropoietin
  • proteins could act directly on hepatocyte populations or act indirectly on hepatocytes by stimulating other resident cell populations, such as endothelial cells, stellate cells, or immune cells to produce hepatocyte-beneficial factors.
  • C3A cells contribute to liver regeneration by providing an environment of pro-hepatocyte mediators as part of the multiple mechanisms for therapeutic benefit.
  • C3A cells are capable of producing a variety of secreted factors with known involvement in liver regeneration. This may facilitate liver regeneration, either directly through direct stimulation of hepatocytes, indirectly through interactions with other resident cell populations during treatment of liver failure patients with the system of the disclosure.
  • the present study demonstrates a potential role for C3A cell secreted factors in a subsequent stage of liver regeneration, that of promoting cell survival and proliferative capacity of various liver cell types.
  • the system of the disclosure is a human hepatic cell-based liver treatment comprised of four metabolically-active cell cartridges (C3A cells) with ancillary device components and support circuitry intended to continuously treat subjects with liver failure secondary to acute hepatocellular insult and alcohol use.
  • C3A cell cartridge spent media were assayed using contracted ELISA multiplex (Myriad) or chemiluminescent multiplex array detection (Aushon Ciraplex) assays for known mitogenic, angiogenic and other regenerative factors.
  • a primary human hepatocyte (PHH) apoptosis model was adapted from Berasain et al. ⁇ J Biol Chem. 280(19): 19012-20 (2005)).
  • Apoptosis was induced in PHH (Gibco) using anti-CD95 (Fas) antibody (EOS9.1, eBioscience) following a 3-h incubation with Williams E medium (w/supplements, w/o dexamethasone, [Gibco]) or system conditioned media (CM) prepared by static incubation of Williams E medium in a mature C3A cell cartridge.
  • Apoptosis was measured by Caspase-Glo 3/7 Assay (Promega), annexin V (Roche) and Western immunoblot (primary antibodies, Cell Signaling).
  • a human aortic endothelial cell (HAEC) angiogenic factor model was developed as a surrogate for liver sinusoidal EC (LSEC) by co-culture in Transwells with C3A cells or treated with CM prepared by static incubation of EGM-2 media (Lonza) in a mature cartridge. Cumulative expression of selected angiogenic factors was measured in supernatants at 24, 48 and 72 h by Aushon Ciraplex.
  • CM administered 3 h prior to challenge of PHH cultures with a Fas-agonist antibody significantly reduced Fas mediated apoptosis, as measured by caspase activity (FIG. 1).
  • CM also reduced spontaneous apoptosis in untreated hepatocytes.
  • CM-treated PHH maintained a more normal size and cobblestone morphology vs. Fas-agonist-treated PHH, as visualized by annexin V staining (data not shown).
  • Liver regeneration is a highly orchestrated event involving multiple pathways and cell types. Metabolically-active C3A cells offer the potential of contributing to liver regeneration by impacting these multiple cell types and pathways in ways that non-cell based therapies are unlikely to achieve.
  • CM was administered to PHH in culture. CM was found to promote survival in both untreated cells and those induced toward apoptosis by a Fas-agonist antibody (FIG. 1).
  • LSEC and bone marrow progenitor cells of LSEC have been shown to participate in liver regeneration by increased production of HGF in response to hepatic VEGF.
  • the effects of C3A cell secreted VEGF was evaluated in an HAEC co-culture surrogate model of LSEC (due to greater availability of HAEC).
  • HGF was not significantly increased (DNS)
  • secretion of PLGF increased 5-fold over untreated HAEC, 24 h after administration of CM.
  • the HAEC continued to produce increased PLGF in the presence of CM for the 72-h length of the model (FIG. 2).
  • PLGF is purported to recruit VEGFR1+ stem cells from bone marrow for organogenesis.
  • C3A cells of the disclosure produce a variety of secreted factors with well- established roles in cell growth, survival, regeneration, and hematopoiesis.
  • the cell-based models prevented PHH apoptosis and enhanced HAEC PLGF secretion. This may facilitate liver regeneration, directly by stimulation of hepatocytes, or indirectly by interactions with other resident cell populations during treatment.
  • Hallmarks of alcoholic hepatitis are increased hepatocellular death, increased liver dysfunction and further inflammatory responses if dying cells are ineffectively cleared.
  • the inventors are clinically evaluating the system of the disclosure using C3A cells of the disclosure in the treatment of severe acute AH (sAAH).
  • CM conditioned medium
  • EGFR epidermal growth factor receptor
  • Apoptosis was induced in PHH in vitro by an anti-Fas agonist antibody.
  • Fas agonist-treated PHH lysates showed increased cleavage products, whereas lysates from PHH treated with Fas agonist in the presence of CM showed a reduction of cleavage products compared to controls.
  • addition of the EGFR-inhibitor canertinib to Fas agonist/CM-treated PHH produced cleavage product levels similar to Fas agonist alone.
  • Phosphorylation of proteins known to be associated with EGFR activation were increased in lysates of CM-treated PHH and were decreased in samples treated with canertinib.
  • C3A cells were found to produce soluble Fas (sFas). Recombinant human sFas was effective in reducing apoptosis in PHH, supporting secretion of sFas by C3A cells as an additional and novel factor contributing to survival of PHH in this Fas-induced apoptosis model.
  • Hallmarks of alcoholic hepatitis are increased hepatocellular death, increased liver dysfunction and further inflammatory responses if dying cells are ineffectively cleared.
  • the inventors are clinically evaluating an investigational liver treatment (C3A cells present in an active cartridge of the system of the disclosure, system of the disclosure (FIG. 3)) using C3A cells in the treatment of severe acute AH (sAAH).
  • CM conditioned medium
  • HGF human hepatocyte
  • CM may offer hepatoprotective effects: (i) epidermal growth factor receptor (EGFR) activation; (ii) soluble Fas (sFas) competition for Fas ligand (FasL); and (iii) reducing oxidative stress.
  • EGFR epidermal growth factor receptor
  • sFas soluble Fas
  • FasL Fas ligand
  • ELAD System is an investigational extracorporeal human hepatic cell-based liver treatment comprised of four metabolically-active ELAD cartridges with ancillary device components and support circuitry intended to continuously treat subjects with liver failure secondary to acute hepatocellular insult and alcohol use for up to 5 days.
  • a primary human hepatocyte (PHH) apoptosis model was adapted from Berasain. Apoptosis was induced in PFIH (Gibco) using anti-CD95 (Fas) antibody (EOS9.1, eBioscience) following a 3-h incubation with Williams E medium (w/supplements, w/o dexamethasone [Gibco]) or ELAD CM prepared by static incubation of Williams E medium in a mature C3A cell cartridge. Recombinant human sFas and amphiregulin (R&D Systems), and EGFR-inhibitor (EGFR-I) canertinib (abeam) were also used as treatments to establish dependence of the model.
  • Fas agonist-treated PHH lysates showed increased caspase 8 and PARP cleavage products, whereas lysates from PHH treated with Fas agonist in the presence of CM showed a reduction of caspase 8 and PARP cleavage compared to controls (FIG. 6).
  • Phosphorylation of proteins known to be associated with EGFR activation were increased in lysates of CM-treated PHH and were decreased in samples treated with the EGFR-I, canertinib (FIG. 7).
  • VTL C3A cells were found to produce soluble Fas (sFas).
  • sFas soluble Fas
  • Recombinant human sFas was effective in reducing apoptosis in PHH (FIG. 9), supporting secretion of sFas by C3A cells as an additional and novel factor contributing to survival of PHH in this Fas- induced apoptosis model.
  • FIG. 5 ELAD CM Reduced Apoptotic Phenotypic Shift in PHH. Cobblestone morphology and minimal fluorescence of untreated controls (left). Morphology was maintained in ELAD CM-treated PHH cell cultures (right) relative to Fas agonist-treated cells (center). Agonist-treated cells also show greater annexin V fluorescent staining.
  • FIG. 6 ELAD CM Reduced Caspase 8 and PARP Cleavage. Fas agonist-treated PHH lysates showed both increased caspase 8 (p-18) and PARP cleavage products, whereas lysates from PHH treated with Fas agonist in the presence of CM showed a reduction of both cleavage products compared to controls. EGFR inhibition reversed the protective effect.
  • FIG. 7 ELAD CM Induced Phosphorylation of Molecules Associated with EGFR Signaling.
  • EGFR, MEK1/2, ERK1/2 and STAT3 were phosphorylated in lysates from ELAD CM-treated PHH.
  • EGFR-inhibitor canertinib reduced this signal, however, not completely.
  • FIG. 8 Amphiregulin Reduced Caspase Activity. Fas agonist-treated PHH lysates showed reduced apoptosis as measured by caspase activity in the presence of amphiregulin. Addition of the EGFR-inhibitor canertinib blocked the effects of amphiregulin. (ANOVA, Tukey 's post-hoc test)
  • FIG. 9 sFas Reduced Caspase Activity. Fas agonist-treated PHH lysates showed reduced apoptosis as measured by caspase activity in the presence of sFas. (ANOVA, Tukey 's post-hoc test)
  • FIG. 10 A Pattern of TCA Cycle Intermediate Downregulation in ELAD-Treated Subjects. Dark green shading highlights the greater degree of TCA cycle intermediates significantly down regulated in ELAD-treated subjects. This is consistent with increased glutathione synthesis. Glutathione, an important cellular antioxidant, is not directly measurable in plasma.
  • FIG. 1 1 ELAD CM Increased the Ratio of Reduced Glutathione to Oxidized Glutathione in Cultured PHH.
  • ELAD CM treatment increased the amount of reduced glutathione relative to oxidized glutathione over 5-fold above untreated cells, in both Fas- induced cells and non-induced (untreated) cells.
  • sFas also secreted by VTL C3A cells, serves to block Fas receptor activation. Oxidative stress further contributes to AH hepatocyte death. PHH treated with CM show higher ratios of GSH/GSSG (reduced oxidative stress). Although the exact mechanism has yet to be determined, CM contains several proteins reported in the literature and associated with reducing oxidative stress.
  • VTL C3A cells promote hepatocyte survival through multiple mechanisms including, but perhaps not limited to, (i) epidermal growth factor receptor (EGFR) activation; (ii) soluble Fas (sFas) competition for Fas ligand (FasL); and (iii) reducing oxidative stress.
  • EGFR epidermal growth factor receptor
  • sFas soluble Fas
  • FasL Fas ligand
  • Hallmarks of alcoholic hepatitis are increased hepatocellular death, increased liver dysfunction and further inflammatory responses if dying cells are ineffectively cleared.
  • the inventors are clinically evaluating an investigational liver treatment (ELAD System) using C3A cells in the treatment of severe acute AH (sAAH).
  • CM conditioned medium
  • CM may offer hepatoprotective effects: (i) epidermal growth factor receptor (EGFR) activation; (ii) soluble Fas (sFas) competition for Fas ligand (FasL); and (iii) reducing oxidative stress.
  • EGFR epidermal growth factor receptor
  • sFas soluble Fas
  • FasL Fas ligand
  • Apoptosis was induced in PFIH in vitro by an anti-Fas agonist antibody.
  • Fas agonist-treated PFIH lysates showed increased cleavage products, whereas lysates from PHH treated with Fas agonist in the presence of CM showed a reduction of cleavage products compared to controls.
  • addition of the EGFR-inhibitor canertinib to Fas agonist/CM-treated PFIH produced cleavage product levels similar to Fas agonist alone.
  • Phosphorylation of proteins known to be associated with EGFR activation were increased in lysates of CM-treated PHH and were decreased in samples treated with canertinib.
  • C3A cells were found to produce soluble Fas (sFas). Recombinant human sFas was effective in reducing apoptosis in PHH, supporting secretion of sFas by C3A cells as an additional and novel factor contributing to survival of PHH in this Fas-induced apoptosis model.

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Abstract

La présente invention porte sur une composition et sur un procédé permettant de provoquer une anti-apoptose, une anti-pyroptose, une anti-nécroptose, la survie, la protection, la prolifération et/ou la modulation phénotypique d'une cellule, ainsi que pour traiter une maladie chez un sujet.
PCT/US2017/051582 2016-09-14 2017-09-14 Composition et procédé permettant de provoquer une anti-apoptose, la survie ou la prolifération de la cellule WO2018053143A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021031893A1 (fr) * 2019-08-21 2021-02-25 National Institute Of Biological Sciences, Beijing Traitement de la prostatite

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US7807783B1 (en) * 1995-04-03 2010-10-05 The Regents Of The University Of Michigan Methods and compositions for regulating FAS-associated apoptosis
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US7807783B1 (en) * 1995-04-03 2010-10-05 The Regents Of The University Of Michigan Methods and compositions for regulating FAS-associated apoptosis
US20090035805A1 (en) * 1998-02-11 2009-02-05 Vital Therapies, Inc. C3A Serum-Free Clonal Cell Line and Methods of Use
US20010051628A1 (en) * 1998-05-04 2001-12-13 H.-J. Su Huang Methods to modulate the resistance of cells to apoptosis mediated by mutant epidermal growth factor receptors
WO2016205227A1 (fr) * 2015-06-15 2016-12-22 Vital Therapies, Inc. Composition et procédé permettant d'induire l'anti-apoptose, la survie ou la prolifération de cellule

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Publication number Priority date Publication date Assignee Title
WO2021031893A1 (fr) * 2019-08-21 2021-02-25 National Institute Of Biological Sciences, Beijing Traitement de la prostatite

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