WO2019215300A1 - Anticorps destinés à être utilisés en polythérapie - Google Patents

Anticorps destinés à être utilisés en polythérapie Download PDF

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WO2019215300A1
WO2019215300A1 PCT/EP2019/061976 EP2019061976W WO2019215300A1 WO 2019215300 A1 WO2019215300 A1 WO 2019215300A1 EP 2019061976 W EP2019061976 W EP 2019061976W WO 2019215300 A1 WO2019215300 A1 WO 2019215300A1
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cancer
diseases
arthritis
mammal
disease
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PCT/EP2019/061976
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English (en)
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Johan FROSTEGÅRD
Anquan LIU
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Medirista Biotechnologies Ab
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39583—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials not provided for elsewhere, e.g. haptens, coenzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to Phosphorylcholine or fragments thereof for use in active immunization to raise antibody levels against phosphorylcholine in a mammal in combination therapy with an HMG-CoA reductase inhibitor; to antibodies against phosphorylcholine or fragments thereof for use in combination therapy with an HMG- CoA reductase inhibitor;
  • the HMG-CoA reductase inhibitors include among others atorvastatin, f!uvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.
  • Said combinations are for use in preventing the development of or for treating a mammal having increased risk of or suffering from cardiovascular diseases (CVD), including Myocardial infarction, stroke, peripheral artery disease, chronic inflammatory conditions,; cancers; SLE or other autoimmune systemic diseases or uremia and kidney disease and dementia.
  • CVD cardiovascular diseases
  • the invention also relates to compositions such as a vaccine comprising phosphorylcholine or fragments thereof or antibodies against phosphorylcholine or fragments thereof and statin and to the use of such compositions.
  • Antibodies against danger associated molecular patterns (DAMP) and pathogen associated molecular patterns (PAMP) as PC are associated with protection in rheumatic disease, cardiovascular disease and atherosclerosis and also several other chronic inflammatory conditions including uremia 1 , but also a hematological cancerous disease, Chronic lymphatic leukemia. 2 Underlying mechanisms include protection against inflammatory and other effects of oxidized low density lipoprotein and related inflammatory phospholipids including decreased foam cell formation and an antiinflammatory effect. 1 , 3'5 Another mechanism is clearance of dead and damaged cells 6 and yet another promotion of T regulatory cell polarization. 7
  • DAMPs PAMPs where antibodies also have protective properties also include other compounds and antigens as malondialdehyde (MDA), oxidized cardiolipin and phosphatidylserine, oxLDL, apoptotic, necrotic and/or damaged cells, microvesicles, mitochondria.
  • MDA malondialdehyde
  • oxidized cardiolipin and phosphatidylserine oxidized cardiolipin and phosphatidylserine
  • oxLDL oxidized cardiolipin and phosphatidylserine
  • oxLDL oxidized cardiolipin and phosphatidylserine
  • oxLDL oxidized cardiolipin and phosphatidylserine
  • oxLDL oxidized cardiolipin and phosphatidylserine
  • oxLDL oxidized cardiolipin and phosphatidylserine
  • oxLDL oxidized cardiolipin and phosphat
  • HMG-CoA reductase catalyses the conversion of HMG-CoA to mevalonic acid and is essential for cholesterol synthesis.
  • Different statins have been developed, which all inhibit this enzyme. 12 Statins are now widely used to prevent cardiovascular disease, especially but not exclusively Ml, prevention of atherosclerosis complications have been much studied and are widely used 13 15 , Clinical studies have indicated that statin effects may also be related to inflammation 18 , a possibility supported by different experimental lines of evidence 17 .
  • statins Pleiotropic effects of statins have been much discussed, including anti-inflammatory 18 , and we recently reported that statins also have an immune modulatory effect, ameliorating the immune stimulatory effects of oxidixed LDL. 19 Still, of note, LDL- lowering by itself is believed to be a significant factor in reducing risk in acute coronary syndromes 20 .
  • Phosphoryl choline is the hydrophilic polar head group of some phospholipids, which is composed of a negatively charged phosphate bonded to a small, positively charged choline group.
  • Phosphorylcholine is part of platelet-activating factor; the phospholipid phosphatidylcholine as well as sphingomyelin. Treatment of cell membranes by certain enzymes renders the phosphorylcholine moiety exposed to the external aqueous phase, and thus accessible for recognition by the immune system.
  • Antibodies against phosphorylcholine are naturally occurring autoantibodies that are created by CD5+/B-1 B cells and are referred to as non-pathogenic autoantibodies.
  • Anti-PC are natural antibodies, which were described in early studies as being of major importance in the early response to lethal infections with PC-exposing Meningococcae in mice 10 , PC may play different roles in immune reactions, which may be both protective and deleterious 11 . It has been suggested that anti-PC are atheroprotective in humans, since anti-PC are negatively associated with atherosclerosis development 12 . Further, low anti-PC levels are independently associated with increased risk of CVD 1 3 ⁇ 14 . Also, it has previously been reported that individuals from Kitava, New Guinea, with a traditional life-style, have high anti-PC levels. Interestingly, these individuals do not seem to suffer from CVD and only to a very limited degree from rheumatic diseases 15 . In line with clinical studies, mice experiments indicate that both active and passive immunization with anti-PC lead to decreased development of atherosclerosis 16 ⁇ 17 .
  • Anti-PC would appear to have several effects in relation to preventing diseases. Firstly, anti-PC have anti-inflammatory and inhibiting effects on inflammatory phospholipids, such as platelet activating factor (PAF) 3 . Another mechanism seems to be inhibition of macrophage uptake of oxLDL by anti-PC 14 . Increased levels of anti-PC could in principle ameliorate disease manifestations through inhibition of PAF, with implications for chronic inflammatory diseases in general 18 . A third mechanism would appear to be prevention of plaque rupture by the inhibition of the cytotoxic effects of lysophosphatidylcholine, with implications for acute cardiovascular diseases in particular (WO201 1/107291 ).
  • PAF platelet activating factor
  • Oxidative stress is an imbalance between oxidants and antioxidants on a cellular or individual level and cold promote LDL-oxidation. Oxidative damage is one result of such an imbalance and includes oxidative modification of cellular macromolecules, induction of cel! death by apoptosis or necrosis, as well as structural tissue damage.
  • MDA and PC lipid epitopes
  • An antibody response is abundant in humans, and may have atheroprotective properties.
  • the antibodies could either be endogenously produced as a result of active immunization (vaccination), or exogenously administered (passive immunization).
  • Antibodies against OxLDL and related oxidized epitopes have previously been described in various connections with statins.
  • WO 2006/102395 relates to a method, for treatment of atherosclerosis and CVD for a wide variety of targets. Many targets are mentioned and include both cytokines and chemokines, and the use of these for treatment in combination with inter alia statins.
  • WO 2007/025781 and WO 2008/104194 relates to methods to raise immunity to oxidized LDL. Methods to combine immunization to raise OxLDL antibodies, with statins are mentioned.
  • WO 2011/025978 relates to methods for increasing insulin sensitivity by raising levels of antibodies to OxLDL. The focus is on the LDL protein apoB100-related epitopes.
  • W02006086288 relates to a method for inhibiting a disease response wherein dead or dying cells exposing an antigen such as a PC determinant and/or a MDA determinant are put into contact with an antibody that recognizes and binds said determinants thereby inhibiting the pathologic response.
  • the document also describes a kit useful for treating an autoimmune disease or inflammatory disease state comprising methotrexate as a possible second agent.
  • the patent application is not related to statins.
  • AU201 1223222 discloses the use of a combination of antibodies against phosphorylcholine or its conjugate, and biologic agents and/or stem cells for treating or preventing autoimmune diseases, chronic inflammatory diseases and cancerous diseases. Some of the patients investigated had been treated with DMARDs such as methotrexate prior to the study. The patent application is not related to statins.
  • Atherosclerosis is the main cause of cardiovascular disease (CVD), and is nowadays seen as an inflammatory process in the artery wall, where activated immune competent cells including T-cells, dendritic cells (DC), monocytes/macrophages are present, together with dead cells and oxidized lipids from Oxidized LDL (OxLDL) 1 ⁇ 22 .
  • CVD cardiovascular disease
  • DC dendritic cells
  • Oxidized LDL Oxidized LDL
  • DCs have been proposed to play an important role in atherosclerosis at different stages as specialized antigen-presenting cells 23 25 .
  • statins The enzyme 3-hydroxy-3-methylglutaryl co enzyme A (HMG-CoA) reductase catalyses the conversion of HMG-CoA to mevalonic acid and is essential for cholesterol synthesis.
  • Different statins act by inhibition of this enzyme 12 .
  • Statins are widely used for prevention of atherosclerosis complications and also in other conditions, including chronic inflammatory conditions 13 15 .
  • inflammation There is also an association with inflammation, as in the Jupiter study 18 , and also experimental evidence support the anti-inflammatory and pleiotropic effects of statins 17 .
  • statins We recently reported a specific mechanism by which statins can be immune modulatory, ameliorating OxLDL induced DC and T cell activation and even promoting an anti-inflammatory type of immune response. In previous study we had several markers of DC maturation, one important being CD80, 19
  • anti-PC in combination with statins provides a highly effective anti-inflammatory effect as disclosed in the examples. It has not previously been known that antibodies directed to an epitope such as phosphrylcholine, which is not oxidized, may provide such an effect when combined with statin, We have found that administering anti-PC in combination with statins will improve the effect of administering statin and the dosage of statin used in monotherapy may accordingly be lowered which will reduce unwanted side effects in patient of administering statins. Moreover, the level of anti-PC in a patient may be used as a marker to evaluate whether the patient will benefit from a combination of anti-PC (or PC) treatment if statin treatment is considered beneficial or if statin treatment is already ongoing,
  • the present invention relates to lipid-related antigens such PC and to antibodies against lipid-related antigens such as antibodies against phosphorylcholine (anti-PC) for use in combination therapy with an 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor such as statins in mammals such as humans in order to prevent the development of, or to treat a mammal suffering from or being at risk of developing various diseases including: cardiovascular disease such as Ml, stroke, PAD, rheumatic diseases, such as active rheumatoid arthritis, active juvenile idiopathic arthritis (JIA), psoriasis and severe psoriatic arthritis; esophageal, colorectal, gastric, hepatocellular, prostate, also lung, kidney, breast, pancreatic, bladder and also cancers in the hematological or lymphoid system, skin, head, neck, lung or bone-marrow cancer; SLE, other systemic autoimmune diseases.
  • the invention also relates to compositions such as a vaccine comprising lipid-related antigens or antibodies against phosphorylcholine and one or more 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor such as statin and to the use of such compositions.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin in combination with antibodies to phosphorylcholine (anti-PC) add to each others anti-inflammatory effects in an unexpected way
  • Statins are widely used to prevent CVD, which is a huge disease, and the major cause of mortality in the developed world and increasingly in the whole world.
  • statins Since response to statins varies, it is thus possible that the number of patients responding to statin treatment can be increased by increasing the level of lipid-related antibodies such as anti-PC prior to, during or simultaneously with treatment with an agent such as statin. Furthermore, since side-effects of statins have been much discussed, and include muscular symptoms and possibly also type II diabetes, treatment to raise anti-PC or related lipid-antibodies, could potentially reduce the statin dose needed, and thus decreasing dose-dependent side-effects.
  • the patients that will benefit from a combination therapy with lipid-related antibodies such as anti-PC and an HMG-CoA inhibiting agent such as statin may suffer from or have a history of or have an increased risk of cardiovascular diseases such as myocardial infarction (Ml), PAD, stroke, TIA, congestive heart failure, and also other chronic inflammatory conditions, including rheumatic diseases, such as active rheumatoid arthritis, active juvenile idiopathic arthritis (JIA), psoriasis and severe psoriatic arthritis or may suffer from cancer, but the beneficial therapeutic effect of administering lipid-related antibodies such as anti-PC in combination with therapy with an HMG-CoA inhibiting agent as statin may not be limited to these diseases since patients suffering from other anti-inflammatory diseases may also benefit from an increase in these antibodies prior to treatment with an HMG-CoA inhibiting agent.
  • cardiovascular diseases such as myocardial infarction (Ml), PAD, stroke, TIA, congestive heart failure, and also other chronic
  • Patients who have an increased risk of cardiovascular disease include those with hypertension, hyperlipidemia and dyslipidemia (including Lp(a), diabetes; smokers, heritability, previous CVD, inflammation as exemplified with increased C-reactive protein, and also low levels of anti-PC and other lipid related antibodies as described above.
  • the mammal that will benefit from administration of lipid-related antigens such as is a mammal that has a lower than average level of antibodies against the lipid-related antigens compared with the average level in a given population of the mammal.
  • any lipid-related antibodies of the 5 isotypes IgA, IgG, IgM, IgE and IgD and of any subclass thereof i.e. lgA1 , lgA2, lgG1 , lgG2, lgG3 or lgG4 would provide the same results.
  • the present invention provides lipid-related antigens for use in active immunization including subcutaneous, intramuscular, intranasal, oral or otherwise to raise antibody levels against PC also together with one or several of the mentioned antigens in a mammal in order to prevent the following conditions or in order to treat mammals already suffering from one or more of the following diseases: systemic autoimmune diseases, cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, peripheral artery disease (PAD), transient ischemic attack (TIA), congestive heart failure, claudication, angina pectoris; Hyperlipidemia; dyslipidemia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, active rheumatoid arthritis, osteoarthritis, active juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis, ankylosing spondylitis, Re
  • the present invention further provides compositions comprising such antigens and optionally an HMG-CoA inhibiting agent such as statin; use of such compositions for the prevention and/or treatment of rheumatic disease, cancer, psoriasis, SLE or CVD; a method for treating a human suffering from one or more of the above entioned diseases.
  • an HMG-CoA inhibiting agent such as statin
  • the present invention also provides antibodies against lipid-related antigens for use in combination therapy with HMG-CoA inhibitor as statin, in mammals; compositions comprising antibodies against lipid-related antigens and an HMG-CoA inhibitor as statin; use of such compositions for the prevention and/or treatment of rheumatic disease, cancer, psoriasis, SLE or CVD; a method for treating a human suffering from a rheumatic disease, cancer, psoriasis, SLE or CVD including one or more of the following diseases: systemic autoimmune diseases, cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, peripheral artery disease (PAD), transient ischemic attack (TIA), congestive heart failure, claudication, angina pectoris; Hyperlipidemia; dyslipidemia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, active r
  • Figure 1 Curve diagrams showing CD80 expression of human dendritic cells treated with Oxidized LDL or IgM anti-PC or combinations thereof .
  • Figure 2 Curve diagrams showing CD80 expression of human dendritic cells treated with Oxidized LDL or atorvastatin or IgM anti- PC or various combinations thereof.
  • Figure 3 Stable diagram showing CD80 expression of human dendritic cells treated with Oxidized LDL or IgM anti-PC or combinations thereof, Mean Fluorescence values are presented for each staple.
  • FIG. 4 Stable diagram showing CD80 expression of human dendritic cells treated with Oxidized LDL or atorvastatin or IgM anti-PC or various combinations thereof. Mean Fluorescence values are presented for each staple. Detailed description of the invention
  • OxLDL is a major compound and antigen in the plaques and is pro-inflammatory and activates immune competent cells induing also T cells 1 ⁇ 28 ⁇ 30 .
  • the statin effects we report could indicate that statin treatment is beneficial also through other mechanisms than lipid lowering and indeed, statins decrease inflammation in atherosclerotic plaques, 31 ⁇ 32
  • One specific mechanism by which oxLDL LDL induces immune activation is through heat shock protein 60 (HSP060), 33 ⁇ 34
  • IgM anti-PC extracted from human IgM, inhibits OxLDL-induced DC activation.
  • statin and increased anti-PC levels could have beneficial effects, including stronger inhibition of CVD and atherosclerosis (and other types of inflammation), and could In principle also be of interest to decrease statin side- effects by lowering dose and addition of increased anti-PC levels. It is also interesting that anti-PC could be a protection marker when statin treatment is indicated.
  • the present invention thus relates to lipid-related antigens for use in active immunization to raise antibody levels against said antigens in a mammal optionally in combination therapy with an HMG-CoA inhibitor as statin.
  • the present invention moreover relates to Phosphorylcholine or fragments thereof for use in active immunization to raise antibody levels against phosphorylcholine in a mammal in combination therapy with an HMG-CoA reductase inhibitor for preventing one or more of the following conditions or in order to treat a mammal already suffering from or being at increased risk of developing one or more of the following conditions: systemic autoimmune diseases, cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, peripheral artery disease (PAD), transient ischemic attack (TIA), congestive heart failure, claudication, angina pectoris; Hyperlipidemia; dyslipidemia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, active rheumatoid arthritis, osteoarthritis, active juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis,
  • the antigens may be antigens from apoptotic or necrotic cells or oxidized LDL and/or may be selected from one or more of the following: maiondialdehyde, malondia!dehyde- acetaldehyde (MMA), phosphorylcholine, oxidized cardio!ipin, oxidized phosphatidylserine, 4-hydroxynonenal.
  • the antigens may be carried by or linked to a compound which can be a protein or part thereof, a carbohydrate, a lipid, a micelle or a nanoparticle.
  • the antibodies against lipid-related antigens may be monoclonal or polyclonal and be of any of the five isotypes IgA, including the subclasses lgA1 and lgA2, IgD, IgE, IgG, including the subclasses lgG1 , lgG2, lgG3 and lgG4, and IgM antibodies hereunder conjugates and/or bioactive components and/or fragments thereof.
  • one aspect of the invention relates to antibodies against lipid-related antigens selected from the group comprising IgA, lgA1 , lgA2, IgD, IgE, IgG, lgG1 , lgG2, lgG3 and lgG4, and IgM and to conjugates and/or bioactive components and/or fragments thereof for use in combination and/or in combination therapy with an antineop!astic agent.
  • the antibodies against lipid-related antigens are IgM antibodies against MDA and/or IgM antibodies against PC; MDA and PC conjugates and/or bioactive components and/or fragments thereof for use in combination and/or in combination therapy with an lipid lowering drug as statin.
  • the antineoplastic agent is statin.
  • the antibodies against lipid-related antigens are IgM antibodies against DA and/or IgM antibodies against PC; MDA and PC conjugates and/or bioactive components and/or fragments thereof for use in combination and/or in combination therapy with HMG-CoA inhibitor as statin in a preferred embodiment of the invention the HMG-CoA inhibitor as statin is statin.
  • Another aspect of the present invention relates to antibodies against against phosphorylcholine or fragments thereof for use in combination therapy with an HMG- CoA reductase inhibitor in a mammal for preventing one or more of the following conditions or in order to treat a mammal already suffering from or being at increased risk of developing one or more of the following conditions
  • systemic autoimmune diseases cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, peripheral artery disease (PAD), transient ischemic attack (TIA), congestive heart failure, claudication, angina pectoris; Hyperlipidemia; dyslipide ia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, active rheumatoid arthritis, osteoarthritis, active juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus (SLE), dermatomyositis, Sjogren's syndrome, multiple sclerosis, myasthenia gravis, encephalitis, inflammatory bowel disease, arthritis, idiopathic inflammatory myopathies (MM), dermatomyo
  • Levels of IgM antibodies to PC can be determined by enzyme-linked immunosorbent assay (ELISA) essentially as described 44 45 . This can be done by use of an available ELISA kit 46 ⁇ 47 , or by in house methods 44 45 .
  • ELISA enzyme-linked immunosorbent assay
  • Example 1 One such in house method is described here in Example 1 , but the method can be varied in different ways, though the basics are the same, with PC, conjugated with a carrier protein, is coated onto ELISA plates, and exposed to serum, plasma or other material from a mammal, including a human, where anti-PC levels are to be determined.
  • This method can typically also be developed in different ways, either as the available kit, where levels of anti-PC are determined as Units or Arbitrary Units, or by a more formal quantification, determining anti-PC levels in for example pg/ml.
  • anti-PC are risk marker(s) in the prevention and/or treatment of systemic autoimmune diseases, cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, peripheral artery disease (PAD), transient ischemic attack (TIA), congestive heart failure, claudication, angina pectoris; Hyperlipidemia; dyslipidemia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, active rheumatoid arthritis, osteoarthritis, active juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus (SLE), dermatomyositis, Sjogren's syndrome, multiple sclerosis, myasthenia gravis, encephalitis, inflammatory bowel disease,
  • CVD cardiovascular
  • anti-PC are risk marker(s) in the prevention and/or treatment of systemic autoimmune diseases, cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, peripheral artery disease (PAD), transient ischemic attack (TIA), congestive heart failure, claudication, angina pectoris; Hyperlipidemia; dyslipidemia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, active rheumatoid arthritis, osteoarthritis, active juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus (SLE), dermatomyositis, Sjogren's syndrome, multiple sclerosis, myasthenia gravis, encephalitis, inflammatory bowel
  • anti-PC are used in the prevention and/or treatment of active rheumatoid arthritis, active juvenile idiopathic arthritis, psoriasis or severe psoriatic arthritis; wherein low antibody levels is a risk marker, and high levels as a protective marker, so individuals at risk of developing one or more of the above-mentioned diseases could be identified and be eligible for treatment with any of the above-mentioned lipid-related antigens or antibodies against lipid-related antigens prior to or together with treatment with statin.
  • antibodies against lipid-related antigens from the group comprising IgA, lgA1 , lgA2, IgD, IgE, IgG, lgG1 , lgG2, lgG3 and lgG4, and IgM such as anti-MDA and/or anti-PC are used as risk marker(s) prior to or simultaneous with the treatment of one or more of systemic autoimmune diseases, cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, peripheral artery disease (PAD), transient ischemic attack (TIA), congestive heart failure, claudication, angina pectoris; Hyperlipidemia; dyslipidemia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, active rheumatoid arthritis, osteoarthritis, active juvenile idiopathic arthritis (JIA), ps
  • IgM antibodies against PC are used as risk arker(s) prior to or simultaneous with the treatment of one or more of active rheumatoid arthritis, active juvenile idiopathic arthritis, psoriasis or severe psoriatic arthritis; where said antibody level is below the mean average, or below the median, or below the 33 rd percentile, such as or below a particular percentile value determined with reference to the wider population, such as below the 5th, 10th, 20th or 25th percentile, such as to a level, wherein the odds ratio is above one, the p-value is ⁇ 0.05 and the upper limit of the odd ratio confidence interval is less than one, indicating a statistically significant level of high risk.
  • Another aspect of the present invention is use of antibodies against lipid-related antigens selected from the group comprising IgA, lgA1 , lgA2, IgD, IgE, IgG, lgG1 , lgG2, IgG3 and lgG4, and IgM or bioactive components and/or parts thereof for the preparation of a pharmaceutical composition to be used in a treatment, prophylaxis and/or prevention of systemic autoimmune diseases, cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, peripheral artery disease (PAD), transient ischemic attack (TIA), congestive heart failure, claudication, angina pectoris; Hyperlipidemia; dyslipidemia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, active rheumatoid arthritis, osteoarthritis, active juvenile idiopathic arthritis (JI
  • a preferred aspect of the present invention is use of PC conjugates or PC or bioactive components and/or parts thereof for the preparation of a pharmaceutical composition to be used in a treatment, prophylaxis and/or prevention of systemic autoimmune diseases, cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, peripheral artery disease (PAD), transient ischemic attack (TIA), congestive heart failure, claudication, angina pectoris; Hyperlipidemia; dyslipide ia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, active rheumatoid arthritis, osteoarthritis, active juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus (SLE), dermatomyositis,
  • the treatment, prophylaxis and or prevention is related to active rheumatoid arthritis, active juvenile idiopathic arthritis, psoriasis, severe psoriatic arthritis antineoplastic.
  • the lipid-related antigens such as a PC conjugate can be linked to a pharmaceutically acceptable protein, carbohydrate, or polymer.
  • the pharmaceutical composition is preferably given by injection, but can in practice be administered by any suitable means that allows the DA conjugate and/or the PC conjugate to provoke an immune response in the subject to which it is administered such as via subcutaneous, intramuscular, intranasal or oral formulations or by other means to raise antibody levels against the mentioned antigens in a mammal.
  • active immunization will modulate the titre of the anti-PC antibodies (or other abovementioned antibodies against the abovementioned antigens), which in turn will have a positive effect on the development of autoimmune diseases, chronic inflammatory diseases, and cancerous diseases.
  • active immunization may be used to increase the titre of anti-PC antibodies to a level that, when assessed by the methods of diagnosis according to the present application, would not be said to be "iow” or indicative of an increased risk of development, or progression, of autoimmune diseases, chronic inflammatory diseases, and cancerous diseases.
  • a method of active immunization according to the present invention may be used to increase the levels of lipid-related antibodies such as the anti-MDA and/or anti-PC levels, such as IgM anti-MDA levels and/or anti-PC levels, in an individual to a level that is greater than the average baseline level in a representative group of patients when tested by the methods described in the Examples.
  • lipid-related antibodies such as the anti-MDA and/or anti-PC levels, such as IgM anti-MDA levels and/or anti-PC levels
  • the method of active immunization according to the present invention may be used to increase the anti-PC levels to a level that is above the mean average, or above the median, or above the 33 rd percentile, such as or above a particular percentile value determined with reference to the wider population, such as above the 5th, 10th, 20th or 25th percentile, such as to a level, wherein the odds ratio is below one, the p-value is ⁇ 0.05 and the upper limit of the odd ratio confidence interval is less than one, indicating a statistically significant level of iow risk.
  • Another embodiment of the invention concerns the use PC conjugates or PC or bioactive components and/or parts thereof for the preparation of a pharmaceutical composition to be used in a treatment, prophylaxis and/or prevention prior to treatment of a mammal with biologic agents for curing autoimmune diseases, chronic inflammatory diseases, and cancerous diseases.
  • Another embodiment of the invention concerns the use of an antibody preparation, comprising a combination of antibodies recognizing PC conjugates or PC or bioactive components and/or parts thereof for the preparation of a pharmaceutical composition to be used in a treatment, prophylaxis and/or prevention prior to treatment of a mammal with an agent such as statin for curing autoimmune diseases, chronic inflammatory diseases, and cancerous diseases such as systemic autoimmune diseases, cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, peripheral artery disease (PAD), transient ischemic attack (TIA), congestive heart failure, claudication, angina pectoris; Hyperlipidemia; dyslipidemia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, active rheumatoid arthritis, osteoarthritis, active juvenile idiopathic arthritis (J I A) , psoriasis, psoriatic arthritis
  • said treatment may be in the form of either passive immunization or active immunization or a combination of both.
  • Any form of administration that increases the antibody levels directly or indirectly (i.e.by inducing the immune response of the patient) known in the art may be applied such as injection, transdermal, oral or nasal administration which are increasingly used in other contexts.
  • oral immunization include polio and cholera 24 .
  • the monoclonal antibody can be produced using methods known in the art.
  • Other antibody preparations may be used, such as enriched preparations of antibodies against lipid-related antigens selected from the group comprising IgA, lgA1 , lgA2, IgD, IgE, IgG, lgG1 , lgG2, lgG3 and lgG4, and IgM or bioactive components and/or parts thereof obtained from intravenous immunoglobulin preparations, recombinantly produced antibodies and/or other artificially created antibody derivatives.
  • anti-PC enriched preparations may be obtained from intravenous immunoglobulin preparations, recombinantly produced anti-PC antibodies and/or other artificially created anti-PC antibody derivatives.
  • passive immunization may be used to increase the titre of antibodies against lipid-related antigens selected from the group comprising IgA, lgA1 , lgA2, IgD, IgE, IgG, lgG1 , IgG2, lgG3 and lgG4, and anti-PC antibodies in an individual to a level that, when assessed by the methods according to the present application, would not be said to be "low” or indicative of an increased risk of development, or progression, of autoimmune diseases, chronic inflammatory diseases, and cancerous diseases.
  • a method of passive immunization according to the present invention may be used to increase antibody levels such as anti-PC levels, such as IgM and/or IgM anti-PC levels, in an individual to a level that is greater the average baseline level in a representative group of patients when tested by the methods described in the examples. Further, a method of passive immunization according to the present invention may be used to increase anti-PC levels, such as IgM anti-PC levels, in an individual to a level that is greater than about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or 85 U/ml when tested by the methods described above. Moreover, a method of passive immunization according to the present invention may be used to increase anti-PC levels simultaneously to a level that is greater than the above-mentioned levels for each antibody, respectively.
  • anti-PC levels such as IgM and/or IgM anti-PC levels
  • the method of active immunization according to the present invention may be used to increase the !evel(s) of antibodies against lipid-related antigens selected from the group comprising IgA, lgA1 , lgA2, IgD, IgE, IgG, lgG1 , IgG2, lgG3 and lgG4, and IgM to a level that is above the mean average, or above the median, or above the 33 rd percentile, such as or above a particular percentile value determined with reference to the wider population, such as above the 5th, 10th, 20th or 25th percentile, such as to a level wherein the odds ratio is below one, the p-value is ⁇ 0.05 and the upper limit of the odd ratio confidence interval is less than one, indicating a statistically significant level of low risk.
  • the method of active immunization according to the present invention may be used to increase anti-PC levels to a level that is above the mean average, or above the median, or above the 33 rd percentile, such as or above a particular percentile value determined with reference to the wider population, such as above the 5th, 10th, 20th or 25th percentile, such as to a level wherein the odds ratio is below one, the p-value is ⁇ 0.05 and the upper limit of the odd ratio confidence interval is less than one, indicating a statistically significant level of low risk.
  • the antibodies can be used for curing, treating, preventing, and/or reducing the risk of developing autoimmune diseases, chronic inflammatory diseases, or cancerous diseases in a mammal, and can be monoclonal, polyclonal or chimeric antibodies of isotype IgA, IgD, IgE, IgG, IgM, optionally in combination with any suitable excipients or adjuvants.
  • Another embodiment according to the invention relates to antibodies against PC, PC conjugate or bioactive components and/or fragments thereof for immunization, treating, preventing, and/or reducing the risk of developing autoimmune diseases, chronic inflammatory diseases, and cancerous diseases in a mammal, said mammal being in therapy with one or more HMG-CoA inhibitor as statins.
  • Yet another embodiment according to the invention relates to compositions comprising antibodies against PC, PC conjugates or bioactive components and/or fragments thereof in combination with one or statin, particularly for use as a medicament, especially for curing, treating, preventing, and/or reducing the risk of developing autoimmune diseases, chronic inflammatory diseases, or cancerous diseases in a mammal.
  • Yet another embodiment according to the invention relates to PC conjugates, PC or bioactive components and/or parts/fragments thereof for use in activation immunotherapy prior to or in combination (combination therapy) with the treatment of a mammal with one or more HMG CoA inhibitor as statin for curing, treating, preventing, and/or reducing the risk of developing autoimmune diseases, chronic inflammatory diseases, and cancer diseases.
  • mammal means all known mammals, and in particular mice, rats, rabbits, dogs, cats, cattle, horses and humans.
  • the medicament may be administered by any suitable means known by the skilled person and be formulated with excipients and adjuvants normally employed for such medicaments and their corresponding formulations.
  • the medicament may be intended for administration by injection, optionally together with any suitable excipients and adjuvants employed for such formulations.
  • the medicament may be given in the form of a pill, tablet, capsule or spray.
  • the medicament may be administered in a way so as to be compatible with the dosage formulation and in such amount as will be therapeutically effective and/or immunogenic.
  • any agent that is suitable for increasing the antibody response towards lipid-related antigens such as anti-PC response, in particular PC conjugates, optionally in combination with any suitable adjuvants and PC or bioactive components and/or parts thereof, optionally in combination with any suitable adjuvants is to be considered as part of this invention.
  • Such lipid-related antigens including MDA in addition to PC which can be exposed on OxLDL and on apoptotic necrotic and damaged cells and/or PC-exposing compounds also include platelet activating factor (PAF), PAF-like lipids or lysophosphatidylcholine, which have pro- inflammatory effects where PC is an important mediator.
  • PAF platelet activating factor
  • PAF-like lipids or lysophosphatidylcholine
  • monoclonal, polyclonal or chimeric antibodies of isotype IgA, IgD, IgE, IgG, IgM, raised against MDA, MDA conjugate or bioactive components and/or fragments thereof or raised against PC, PC conjugate or bio active components and/or parts/fragments thereof refer to any monoclonal or polyclonal antibody produced by immunization of a suitable mammal, including, but not limited to, mouse, rabbit, goat, sheep, or horse.
  • the term "bodily fluid” means any natural bodily fluid or secretion of fluid including, but not limited to, plasma, serum, blood, urine, or saliva.
  • the term "combination therapy” means the individual or simultaneous administration of two or more medications to treat a single disease and/or diseases that may develop due to unwanted medical side- effects or lack of satisfactory positive pharmaceutical response from the administration of one of the medications, e.g. unwanted medical side-effects due to the administration of biologic agents to treat chronic inflammatory diseases, autoimmune disease and cancer diseases.
  • chronic inflammatory diseases, autoimmune and cancer diseases means any of - including, but not limited to - the following diseases;
  • systemic autoimmune diseases cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, peripheral artery disease (PAD), transient ischemic attack (TIA), congestive heart failure, claudication, angina pectoris; Hyperlipidemia; dyslipidemia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, active rheumatoid arthritis, osteoarthritis, active juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus (SLE), dermatomyositis, Sjogren's syndrome, multiple sclerosis, myasthenia gravis, encephalitis, inflammatory bowel disease, arthritis, idiopathic inflammatory myopathies (MM), dermatomyositis
  • Immunotherapy is normally defined within medicine as "treatment of disease by inducing, enhancing, or suppressing an immune response”. Passive immunity can be achieved through the transfer of ready-made antibodies into the affected individual or mammal.
  • Immunotherapies designed to elicit or amplify an immune response are normally termed “activation immunotherapies”, and include, for example, immunization.
  • Immunotherapies designed to reduce, suppress or more appropriately direct an existing immune response, as in cases of autoimmunity or allergy are normally termed “suppression immunotherapies”.
  • the active agents of immunotherapy are collectively called “immunomodulators", and include a wide variety of natural, synthetic and recombinant substances, many of which are biological agents as defined above. Examples of immunomodulators include medicinal mushrooms and herbs, various plant and microorganism extracts, vaccines, adjuvants, hormones, various drugs, interleukins, interferons and other cytokines.
  • a sub-fraction with anti-PC activity of a human immunoglobulin preparation can be prepared as described below by affinity purification using a PC conjugate.
  • intravenous immunoglobulin preparations e.g., IGIV; Baxter and others
  • IgG intravenous immunoglobulin preparations
  • Immunoglobulin preparations include those available from the following manufacturers: Baxter (US), e.g., Gammagard ®, Isiven (Antimo Naples, Italy), Omrix (Tel-Hashomer, Israel), Miles (Biological Products Division, West Heaven, CT), Sclavo (Lucca, Italy), Sandoz (Nonachis, Basel, Swizeriand), e.g., Sandoglobulin ®, Biotest Diagnostic Corporation (Deville, NJ)
  • Examples of immunoglobulin preparations are GammagardS/D ®, GammarlV ®, Gaimnar-PiV ®, Gammimune N®, Iveegam®, Panglobulin ®, Polygam S/D®, Sandoglobulin ®, Venoglobulin ®.
  • Immunoglobulin preparations typically contain some IgM as well as IgG, Trace amounts of IgM are present in Gammagard ®.
  • Pentaglobin Biotest
  • the subfraction with anti-PC activity may comprise both IgG and IgM, or may be selected to comprise mainly IgG (for example by starting with an IgG-rich preparation, such as Gammagard ® and/or by selecting for IgG); or mainly IgM (for example by starting with an IgM-rich preparation such as Pentaglobin and/or by selecting for IgM).
  • an antibody preparation with specificity to a PC conjugate binds to unconjugated PC and may also bind to PC present in PC-containing compounds, in which PC is exposed, for example in lysophosphatidylcholine (see for example, Kim et al, , 2002 J Exp Med. 196, 655-65).
  • an antibody preparation with specificity to a PC conjugate may also bind to lysophosphatidylcholine or other phospholipids or phospholipid-containing compounds as platelet activating factor (PAF) or PAF- like lipids which have PC as a major component
  • PAF platelet activating factor
  • Combination therapy comprises any kind of therapy wherein one or more antibodies against lipid-related antigens (such as anti-PC) is administered to a patient either prior to, simultaneous with or subsequent to administration of an HMG- CoA inhibitor as statins to the same patient.
  • Combination therapy also comprises any kind of therapy wherein one or more lipid-related antigens (such as PC) is administered to a patient either prior to, simultaneous with or subsequent to administration of an HMG-CoA inhibitor as statin to the same patient.
  • statins comprises statins, including including among others atorvastatin, fluvastatin, iovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, exert their blood lipid-lowering effect by inhibition of HMG- CoA reductase which is a pivotal step in the production of mevalonate, a precursor of cholesterol.
  • mevalonate reverts the effects on statin- induced inhibition of OxLDL induced DC-mediated activation of T cells which is an indication of specificity of these novel immune modulatory properties of statins.
  • atorvastatin had a striking, unexpeced and similar immune modulatory effect, inhibiting OxLDL induced DC-mediated activation of T cells, which is likely to be an important component in atherosclerosis and related inflammation.
  • the unexpected properties described herein are thus applicable to all inhibitors of HMG-CoA reductase including among others atorva statin, fluvastatin, lovastatsn, pitavastatin, pravastatin, rosuvastatin and simvastatin.
  • Phosphorylcholine or fragments thereof for use in active immunization to raise antibody levels against phosphorylcholine in a mammal in combination therapy with an HMG-CoA reductase inhibitor for preventing one or more of the following conditions or in order to treat a mammal already suffering from or being at increased risk of developing one or more of the following conditions: systemic autoimmune diseases, cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, peripheral artery disease (PAD), transient ischemic attack (TIA), congestive heart failure, claudication, angina pectoris; Hyperlipidemia; dyslipidemia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, active rheumatoid arthritis, osteoarthritis, active juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis, ankylosing spondy
  • Phosphorylcholine or fragments thereof for use according to any of aspects 1 to 2 wherein said Phosphorylcholine or fragments thereof are carried by or linked to a compound which can be a protein or part thereof, a carbohydrate, a iipid, a micelle or a nanoparticle.
  • HMG-CoA reductase inhibitor is selected from the group comprising atorvastatin, fluvastatm, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.
  • Phosphorylcholine or fragments thereof for use according to any of aspects 1 to 9 wherein said antibodies raised against said phosphorylcholine in said mammal boost the therapeutic effect of said HMG-CoA reductase inhibitor.
  • Phosphorylcholine or fragments thereof for use according to any of aspects 1 to 10 wherein the dose of said HMG-CoA reductase inhibitor is reduced compared to the dose that would be administered to the patient in monotherapy of said HMG-CoA reductase inhibitor.
  • Phosphorylcholine or fragments thereof for use according to any of aspects 1 to 1 1 wherein said mammal is a human.
  • Antibodies against phosphorylcholine or fragments thereof for use in combination therapy with an HMG-CoA reductase inhibitor in a mammal for preventing one or more of the following conditions or in order to treat a mammal already suffering from or being at increased risk of developing one or more of the following conditions: cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, transient ischemic attack (TIA), claudication, angina pectoris; Hyperlipidemia; dyslidide ia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, osteoarthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, multiple sclerosis, myasthenia gravis, ence
  • Antibodies against phosphorylcholine or fragments thereof for use according to aspect 13 wherein said antibodies are IgM antibodies.
  • HMG-CoA reductase inhibitor is selected from the group comprising atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.
  • composition according to aspect 25 wherein said antibodies phosphorylcholine or fragments thereof are selected from the group comprising IgA, including lgA1 and lgA1 , IgG, including lgG1 , lgG2, lgG3, lgG4, IgM, IgE and IgD.
  • composition according to aspect 26 wherein said antibodies are IgM antibodies.
  • said HMG-CoA reductase inhibitor is selected from the group comprising atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.
  • compositions according to any of aspects 25 to 30 in the prevention of development of or in the treatment of a mammal suffering from one or more of the following diseases: cardiovascular disease (CVD), atherosclerosis, atheromatous plaque rupture, myocardial infarction, acute coronary syndrome, stroke, transient ischemic attack (TIA), claudication, angina pectoris; Hyperlipidemia; dyslididemia including increased Lp(a); rheumatic diseases, acute and/or chronic inflammatory conditions, rheumatoid arthritis, osteoarthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, multiple sclerosis, myasthenia gravis, encephalitis, inflammatory bowel disease, arthritis, idiopathic inflammatory myopathies (MM), dermatomyositis (DM), poly
  • the level of anti-PC in said mammal is below the mean average, or below the median, or below the 33 rd percentile, such as below the 25th percentile, or such as below the 20 th percentile or below the 10 th percentile or even below the 5 th percentile, determined with reference to the wider population prior to treatment with a HMG-CoA reductase inhibitor.
  • CVD cardiovascular disease
  • TIA transient ischemic attack
  • CIA transient ischemic attack
  • claudication angina pectoris
  • Hyperlipidemia dyslididemia including increased Lp(a)
  • rheumatic diseases acute and/or chronic inflammatory conditions, rheumatoid arthritis, osteoarthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, multiple sclerosis, myasthenia gravis, encephalitis, inflammatory bowel disease, arthritis, idiopathic inflammatory myopathies (MM), dermatomyositis (DM), polymyositis (PM), inclusion body myositis, spondylopathies, va
  • HMG-CoA reductase inhibitor is selected from the group comprising atorva statin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin,
  • Method according to any of aspects 40 to 45 wherein said mammal is suffering from one or more of the following diseases: a rheumatic disease, cancer, psoriasis, SLE or CVD.
  • Method according to any of aspects 40 to 46 said mammal is suffering from active rheumatoid arthritis, active juvenile idiopathic arthritis, psoriasis or severe psoriatic arthritis.
  • the level of anti-PC in said mammal is below the mean average, or below the median, or below the 33 rd percentile, such as below the 25th percentile, or such as below the 20 th percentile or below the 10 th percentile or even below the 5 th percentile, determined with reference to the wider population prior to treatment with a HMG-CoA reductase inhibitor.
  • Method according to aspect 48 wherein the level of antibodies against PC is measured by use of a method comprising (a) contacting a sample of body fluid with phosphocholine and/or a derivative thereof, (b) assessing the presence and/or concentration of antibodies to phosphocholine and/or to said derivative in the sample by measuring antibodies bound to phosphocholine and/or derivative thereof (c) determining whether the level of anti-PC in said mammal is below the mean average, or below the median, or below the 33 rd percentile, such as below the 25th percentile, or such as below the 20 th percentile or below the 10 th percentile or even below the 5 th percentile, determined with reference to the wider population.
  • HMG-CoA reductase inhibitor is reduced compared to the dose that would be administered to the patient in monotherapy of said HMG-CoA reductase inhibitor. 52. Method according to any of aspects 40 to 51 wherein said mammal is a human.
  • PBMC Peripheral blood mononuclear cells
  • Monocytes were then differentiated to immature dendritic cells (DCs) 7 days with 50 ng/ml human recombinant GM-CSF and 25 ng/mi human recombinant IL-4 in RPMI 1640 supplemented with 2 mM glutamine, 10 mM HEPES, 1 % peniciilin/streptavidin.
  • DCs dendritic cells
  • Statin treatment of cells was performed essentially as described. 19 Briefly, immature DCs at day 5 were treated with the indicated concentrations of atorvastatin (Sigma- Aldrich, Germany) for 24h, then DCs were incubated with 2 mM atorvastatin, in the presence or absence of 10pg/ml oxLDL for another 24h Ceils were harvested and analyzed. Cell viability was above 90%.
  • atorvastatin Sigma- Aldrich, Germany
  • IgM Anti-PC were extracted essentially as described previously. 3 ⁇ 44 Briefly, according to previously described protocol, PC-HSA (Biosearch Technologies Inc. , CA, USA) was coupled to a HiTrap NHS column (GE Healthcare, Sweden).
  • DC prepared and studied by FACScan (flow cytometry) essentially as described. 19 ’ 34 Briefly, they were fixed with 500 pi BD Cytofix (BD Biosciences) for at 37 °C, 15 min, permeabilized with ice-cold Perm Buffer III (BD Biosciences) for 30 min on ice. Thereafter, cells were stained with Alexa Fluor® 647 or Alexa Fluor® 488 conjugated Mouse anti-Akt (pS473), Alexa Fluor® 488 or PerCP-CyTM5.5 conjugated Mouse anti- MEK1 (pS298). Isotype controls were used to establish positive expression limits. After 60 min incubation, cells were analyzed on LSRII FortessaTM cell analyzer. Statistical Analysis
  • PC is typically conjugated with a carrier protein such as albumin or Keyhole Limpet Hemocyanin (KLH) here albumin (bovine serium albumin, BSA) Donors serum diluted (1 :100) in 0.2% BSA in PBS and added at 10OmI/well is used as internal standard and tested on each plate. The plateau of IgM antibody binding was reached with the antigen concentration of 10 pg/ml which can vary depending on specific circumstances of experiment. 96-well ELISA plates are coated with PC conjugated with a carrier protein, here BSA and antigen concentration at 10 pg/ml. Coated plates were incubated overnight at 4°C.
  • a carrier protein such as albumin or Keyhole Limpet Hemocyanin (KLH) here albumin (bovine serium albumin, BSA) Donors serum diluted (1 :100) in 0.2% BSA in PBS and added at 10OmI/well is used as internal standard and tested on each plate. The plateau of IgM antibody binding was reached
  • Alkaline phosphatase conjugated goat anti-human IgM (Sigma Aldrich, MO, USA) diluted 1 :7000 in the sample buffer was added at 100pl/well and incubated for 2h at room temperature. After five washings, color was developed by adding the alkaline phosphatase substrate (PNPP) or other substrate, at 10OmI/well and incubating the plates for 30 min at room temperature in the dark. The plates were read in an ELISA Multiscan Plus (Spectra Max 250, Molecular Devices, CA, USA) at 405nm. All samples were measured in duplicates and the coefficient of variation was below 15%.
  • An arbitrary in house level of anti-PC can be determined by using control as standard, typically subtracting background value and then multiplying with 100.
  • IgM anti-PC and statins Combined inhibition of oxidized LDL-induced DC maturation by IgM anti-PC and statins
  • PC phosphorylcholine
  • AVA atorvastatin
  • OxLDL Oxidized LDL
  • FlowThr control IgM antibodies not binding PC.
  • Kang S, Wu Y and Li X Effects of statin therapy on the progression of carotid atherosclerosis: a systematic review and meta-analysis. Atherosclerosis. 2004;177:433-42.
  • Oxidized Low-Density Lipoprotein (OxLDL)-Treated Dendritic Cells Promote Activation of T Cells in Fluman Atherosclerotic Plaque and Blood, which Is Repressed by Statins: microRNA let-7c Is Integral to the Effect. JAm Heart Assoc. 2016;5.
  • the immunomodulatory parasitic worm product ES-62 reduces lupus-associated accelerated atherosclerosis in a mouse model.
  • Atheroprotective natural anti-phosphorylcholine antibodies of IgM subclass are decreased in Swedish controls as compared to non-westernized individuals from New Guinea. Nutr Metab (Land). 2007;4:7.

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Abstract

Les anticorps contre la phosphorylcholine sont associés à la protection dans plusieurs états inflammatoires chroniques. Le traitement de ce type d'états implique souvent l'administration d'inhibiteurs de la HMG-CoA réductase. On a découvert que l'augmentation active ou passive des taux d'anticorps contre la phosphorylcholine chez un mammifère en polythérapie avec un inhibiteur de la HMG-CoA réductase, tel que la statine, améliore la réponse au traitement par statines. L'augmentation du niveau anti-PC en combinaison avec l'administration d'inhibiteurs de la HMG-CoA réductase peut ainsi être utilisée pour le traitement d'un mammifère présentant un risque accru de souffrir ou souffrant d'états inflammatoires chroniques, de maladies systémiques auto-immunes et de cancers, ou pour la prévention du développement de ces maladies.
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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003006634A2 (fr) * 2001-07-09 2003-01-23 Biomerieux Utilisation de lipoproteines oxydees pour obtenir la differenciation de cellules precurseur en cellules dendritiques matures
WO2006086288A2 (fr) 2005-02-07 2006-08-17 The Regents Of The University Of California Methodes pour reduire les symptomes d'auto-immunite et d'inflammation au moyen de proteines de liaison dirigees contre des antigenes exposes sur des cellules mortes ou mourantes
WO2006102395A2 (fr) 2005-03-22 2006-09-28 Medstar Health Inc Systemes et methodes d'administration pour le diagnostic et le traitement de maladies cardio-vasculaires
WO2007025781A2 (fr) 2005-09-02 2007-03-08 Bioinvent International Ab Traitement immunotherapeutique
US20070122419A1 (en) * 2003-04-11 2007-05-31 The Regents Of The University Of California Methods and compositions for treating atherosclerosis
WO2008104194A1 (fr) 2007-02-28 2008-09-04 Bioinvent International Ab Lipoprotéines de basse densité oxyde et leurs anticorps pour le traitement de plaques d'athérosclérose
WO2010003602A1 (fr) 2008-07-07 2010-01-14 Athera Biotechnologies Ab Nouveaux procédés thérapeutiques et diagnostiques pour la maladie d'alzheimer
WO2011025978A2 (fr) 2009-08-28 2011-03-03 Stuart Bunting Méthodes de traitement faisant appel à des anticorps anti-ldl oxydées
WO2011107291A1 (fr) 2010-03-04 2011-09-09 Medirista Biotechnologies Ab Anticorps anti-phosphorylcholine en polythérapie doté des agents biologiques

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003006634A2 (fr) * 2001-07-09 2003-01-23 Biomerieux Utilisation de lipoproteines oxydees pour obtenir la differenciation de cellules precurseur en cellules dendritiques matures
US20070122419A1 (en) * 2003-04-11 2007-05-31 The Regents Of The University Of California Methods and compositions for treating atherosclerosis
WO2006086288A2 (fr) 2005-02-07 2006-08-17 The Regents Of The University Of California Methodes pour reduire les symptomes d'auto-immunite et d'inflammation au moyen de proteines de liaison dirigees contre des antigenes exposes sur des cellules mortes ou mourantes
WO2006102395A2 (fr) 2005-03-22 2006-09-28 Medstar Health Inc Systemes et methodes d'administration pour le diagnostic et le traitement de maladies cardio-vasculaires
WO2007025781A2 (fr) 2005-09-02 2007-03-08 Bioinvent International Ab Traitement immunotherapeutique
WO2008104194A1 (fr) 2007-02-28 2008-09-04 Bioinvent International Ab Lipoprotéines de basse densité oxyde et leurs anticorps pour le traitement de plaques d'athérosclérose
WO2010003602A1 (fr) 2008-07-07 2010-01-14 Athera Biotechnologies Ab Nouveaux procédés thérapeutiques et diagnostiques pour la maladie d'alzheimer
WO2011025978A2 (fr) 2009-08-28 2011-03-03 Stuart Bunting Méthodes de traitement faisant appel à des anticorps anti-ldl oxydées
WO2011107291A1 (fr) 2010-03-04 2011-09-09 Medirista Biotechnologies Ab Anticorps anti-phosphorylcholine en polythérapie doté des agents biologiques
AU2011223222A1 (en) 2010-03-04 2012-09-27 Athera Biotechnologies Ab Antibodies against phosphorylcholine in combination therapy with biologic agents

Non-Patent Citations (62)

* Cited by examiner, † Cited by third party
Title
ALDERMAN C J J ET AL: "Effects of oxidised low density lipoprotein on dendritic cells: A possible immunoregulatory component of the atherogenic micro-environment?", CARDIOVASCULAR RESEARCH, OXFORD UNIVERSITY PRESS, GB, vol. 55, no. 4, 1 September 2002 (2002-09-01), pages 806 - 819, XP002224603, ISSN: 0008-6363, DOI: 10.1016/S0008-6363(02)00447-9 *
APRAHAMIAN TRZHONG XAMIR SBINDER CJCHIANG LKAL-RIYAMI LGHARAKHANIAN RHARNETT MMHARNETT WRIFKIN IR: "The immunomodulatory parasitic worm product ES-62 reduces lupus-associated accelerated atherosclerosis in a mouse model", INTERNATIONAL JOURNAL FOR PARASITOLOGY, vol. 45, 2015, pages 203 - 7, XP029175943, DOI: doi:10.1016/j.ijpara.2014.12.006
ATILLA YILMAZ ET AL: "Differential effects of statins on relevant functions of human monocyte-derived dendritic cells", JOURNAL OF LEUKOCYTE BIOLOGY, vol. 79, no. 3, 1 March 2006 (2006-03-01), US, pages 529 - 538, XP055621325, ISSN: 0741-5400, DOI: 10.1189/jlb.0205064 *
ATILLA YILMAZ ET AL: "HMG-CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis", ATHEROSCLEROSIS, vol. 172, no. 1, 1 January 2004 (2004-01-01), AMSTERDAM, NL, pages 85 - 93, XP055621320, ISSN: 0021-9150, DOI: 10.1016/j.atherosclerosis.2003.10.002 *
ATOUT RKARABINA SADOLLET SCARRERAS MPAYRE CANDRE PLAMBEAU GLOTTEAU VNINIO EPERRIN-COCON L: "Human group X secreted phospholipase A2 induces dendritic cell maturation through lipoprotein-dependent and -independent mechanisms", ATHEROSCLEROSIS, vol. 222, 2012, pages 367 - 74, XP028507832, DOI: doi:10.1016/j.atherosclerosis.2012.03.014
BASHI TBLANK MBEN-AMI SHOR DFRIDKIN MVERSINI MGENDELMAN OVOLKOV ABARSHAK ISHOENFELD Y: "Successful modulation of murine lupus nephritis with tuftsin-phosphorylcholine", J AUTOIMMUN., vol. 59, 2015, pages 1 - 7, XP055315733, DOI: doi:10.1016/j.jaut.2015.03.001
BASHI TSHOVMAN 0FRIDKIN MVOLKOV ABARSHACK IBLANK MSHOENFELD Y: "Novel therapeutic compound tuftsin-phosphorylcholine attenuate collagen induced arthritis", CLIN EXP IMMUNAL, 2015
BRILES, J EXP MED, vol. 156, 1982, pages 1177 - 1185
CAIDAHL KHARTFORD MKARLSSON THERLITZ JPETTERSSON KDE FAIRE UFROSTEGARD J: "IgM-phosphorylcholine autoantibodies and outcome in acute coronary syndromes", LNT J CARDIOL., vol. 167, 2013, pages 464 - 9, XP028568698, DOI: doi:10.1016/j.ijcard.2012.01.018
CANNON CPBLAZING MAGIUGLIANO RPMCCAGG AWHITE JATHEROUX PDARIUS HLEWIS BSOPHUIS TOJUKEMA JW: "Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes", N ENGL J MED., vol. 372, 2015, pages 2387 - 97
CAROLINE GRÖNWALL ET AL: "Natural IgM: Beneficial Autoantibodies for the Control of Inflammatory and Autoimmune Disease", JOURNAL OF CLINICAL IMMUNOLOGY., vol. 34, no. S1, 2 April 2014 (2014-04-02), New York, pages 12 - 21, XP055617453, ISSN: 0271-9142, DOI: 10.1007/s10875-014-0025-4 *
CHEN XGUSTAFSSON SWHITINGTON TBORNE YLORENTZEN ESUN JALMGREN PSU JKARLSSON RSONG J: "A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relation to chronic lymphocytic leukemia", HUM MOL GENET., 2018
DE FAIRE USU JHUA XFROSTEGARD AHALLDIN MHELLENIUS MLWIKSTROM MDAHLBOM IGRONLUND HFROSTEGARD J: "Low levels of IgM antibodies to phosphorylcholine predict cardiovascular disease in 60-year old men: effects on uptake of oxidized LDL in macrophages as a potential mechanism", J AUTOIMMUN., vol. 34, 2010, pages 73 - 9, XP026886085, DOI: doi:10.1016/j.jaut.2009.05.003
DOWNS JRCLEARFIELD MWEIS SWHITNEY ESHAPIRO DRBEERE PALANGENDORFER ASTEIN EAKRUYER WGOTTO AM, JR.: "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study", JAMA, vol. 279, 1998, pages 1615 - 22
FISKESUND RSTEGMAYR BHALLMANS GVIKSTROM MWEINEHALL LFAIRE UFROSTEGARD J: "Low levels of antibodies against phosphorylcholine predict development of stroke in a population-based study from northern Sweden", STROKE, vol. 41, pages 607 - 12, XP002664275, DOI: doi:10.1161/STROKEAHA.109.558742
FISKESUND RSU JBULATOVIC IVIKSTROM MDE FAIRE UFROSTEGARD J: "IgM phosphorylcholine antibodies inhibit cell death and constitute a strong protection marker for atherosclerosis development, particularly in combination with other auto-antibodies against modified LDL", RESULTS IMMUNOL., vol. 2, 2012, pages 13 - 8
FROSTEGARD AGSU JHUA XVIKSTROM MDE FAIRE UFROSTEGARD J: "Antibodies against Native and Oxidized Cardiolipin and Phosphatidylserine and Phosphorylcholine in Atherosclerosis Development", PLOS ONE, vol. 9, 2014, pages elll764
FROSTEGARD J.: "Immunity, atherosclerosis and cardiovascular disease", BMC MED., vol. 11, 2013, pages 117, XP021151229, DOI: doi:10.1186/1741-7015-11-117
FROSTEGARD JSU JSING SHUA XVIKSTROM MLEANDER KGIGANTE BDE FAIRE UFROSTEGARD AG: "IgM antibodies to oxidized phosphatidylserine as protection markers in cardiovascular disease among 60-year olds", PLOS ONE, vol. 12, 2017, pages e0171195
FROSTEGARD JTAO WGEORGIADES ARASTAM LLINDBFAD ULINDEBERG S: "Atheroprotective natural anti-phosphorylcholine antibodies of IgM subclass are decreased in Swedish controls as compared to non-westernized individuals from New Guinea", NUTR METAB, vol. 4, 2007, pages 7, XP021025512, DOI: doi:10.1186/1743-7075-4-7
FROSTEGARD JTAO WRASTAM LLINDBLAD ULINDEBERG S: "Antibodies against Phosphorylcholine among New Guineans Compared to Swedes: An Aspect of the Hygiene/Missing Old Friends Hypothesis", IMMUNOL INVEST., vol. 46, 2017, pages 59 - 69
FROSTEGARD JULFGREN AKNYBERG PHEDIN USWEDENBORG JANDERSSON UHANSSON GK: "Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Thl) and macrophage-stimulating cytokines", ATHEROSCLEROSIS, vol. 145, 1999, pages 33 - 43, XP000994998, DOI: doi:10.1016/S0021-9150(99)00011-8
FROSTEGARD JWU RGISCOMBE RHOLM GLEFVERT AKNILSSON J: "Induction of T-cell activation by oxidized low density lipoprotein", ARTERIOSCLER THROMB., vol. 12, 1992, pages 461 - 7
FROSTEGARD JZHANG YSUN JYAN KLIU A: "Oxidized Low-Density Lipoprotein (OxLDL)-Treated Dendritic Cells Promote Activation of T Cells in Human Atherosclerotic Plaque and Blood, Which Is Repressed by Statins: microRNA let-7c Is Integral to the Effect", J AM HEART ASSOC., 2016, pages 5
GLEISSNER CAERBEL CHAEUSSLER JAKHAVANPOOR MDOMSCHKE GLINDEN FDOESCH AOCONRADSON GBUSS SJHOFMANN NP: "Low levels of natural igiv) antibodies against phosphorylcholine are independently associated with vascular remodeling in patients with coronary artery disease", CLINICAL RESEARCH IN CARDIOLOGY: OFFICIAL JOURNAL OF THE GERMAN CARDIAC SOCIETY, vol. 104, 2015, pages 13 - 22, XP035430903, DOI: doi:10.1007/s00392-014-0750-y
GRONWALL CVAS JSILVERMAN GJ: "Protective Roles of Natural IgM Antibodies", FRONT IMMUNOL., vol. 3, 2012, pages 1 - 10
HAFID AIT-OUFELLA ET AL: "Adaptive (T and B Cells) Immunity and Control by Dendritic Cells in Atherosclerosis", CIRCULATION RESEARCH, vol. 114, no. 10, 9 May 2014 (2014-05-09), US, pages 1640 - 1660, XP055621349, ISSN: 0009-7330, DOI: 10.1161/CIRCRESAHA.114.302761 *
HELEN S. GOODRIDGE ET AL: "In vivo exposure of murine dendritic cell and macrophage bone marrow progenitors to the phosphorylcholine-containing filarial nematode glycoprotein ES-62 polarizes their differentiation to an anti-inflammatory phenotype", IMMUNOLOGY, vol. 113, no. 4, 1 December 2004 (2004-12-01), GB, pages 491 - 498, XP055621334, ISSN: 0019-2805, DOI: 10.1111/j.1365-2567.2004.01993.x *
IMHOF AKOENIG WJAENSCH AMONS UBRENNER HROTHENBACHER D: "Long-term prognostic value of IgM antibodies against phosphoryl choline for adverse cardiovascular events in patients with stable coronary heart disease", ATHEROSCLEROSIS, vol. 243, 2015, pages 414 - 20
ISTVAN ESDEISENHOFER J: "Structural mechanism for statin inhibition of HMG-CoA reductase", SCIENCE, vol. 292, 2001, pages 1160 - 4, XP002609536
KANG SWU YLI X: "Effects of statin therapy on the progression of carotid atherosclerosis: a systematic review and meta-analysis", ATHEROSCLEROSIS, vol. 177, 2004, pages 433 - 42, XP004628503, DOI: doi:10.1016/j.atherosclerosis.2004.08.005
KIM ET AL., J EXP MED., vol. 196, 2002, pages 655 - 65
KOFLER ET AL: "Dual mode of HMG-CoA reductase inhibition on dendritic cell invasion", ATHEROSCLEROSIS, ELSEVIER, AMSTERDAM, NL, vol. 197, no. 1, 21 February 2008 (2008-02-21), pages 105 - 110, XP022493938, ISSN: 0021-9150, DOI: 10.1016/J.ATHEROSCLEROSIS.2007.08.005 *
LIU AFROSTEGARD J: "PCSK9 plays a novel immunological role in Oxidized LDL-induced dendritic cell maturation and T cell activation from human blood and atherosclerotic plaque", JOUNAL OF INTERNAL MEDICINE, 2018
LIU AMING JYFISKESUND RNINIO EKARABINA SABERGMARK CFROSTEGARD AGFROSTEGARD J: "Induction of dendritic cell-mediated T-cell activation by modified but not native low-density lipoprotein in humans and inhibition by annexin a5: involvement of heat shock proteins", ARTERIOSCLER THROMB VASE BIOI, vol. 35, 2015, pages 197 - 205
LIU AMINGJYFISKESUND RNINIO EKARABINA SABERGMARK CFROSTEGARD AGFROSTEGARD J: "Induction of dendritic cell-mediated T-cell activation by modified but not native low-density lipoprotein in humans and inhibition by annexin a5: involvement of heat shock proteins", ARTERIOSCLER THROMB VASE BIOL., vol. 35, 2015, pages 197 - 205
LIU PYU YRSPENCER JAJOHNSON AEVALLANAT CTFONG AMPATTERSON CPATEL DD: "CX3CR1 deficiency impairs dendritic cell accumulation in arterial intima and reduces atherosclerotic burden", ARTERIOSCLER THROMB VASE BIOL., vol. 28, 2008, pages 243 - 50
MILLONIG GNIEDEREGGER HRABL WHOCHLEITNER BWHOEFER DROMANI NWICKG: "Network of vascular-associated dendritic cells in intima of healthy young individuals", ARTERIOSCLER THROMB VASE BIOL., vol. 21, 2001, pages 503 - 8
PERRIN-COCON LCOUTANT FAGAUGUE SDEFORGES SANDRE PLOTTEAU V: "Oxidized low-density lipoprotein promotes mature dendritic cell transition from differentiating monocyte", J LMMUNOL., vol. 167, 2001, pages 3785 - 91, XP002196476
RAHMAN MSING SGOLABKESH ZFISKESUND RGUSTAFSSON TJOGESTRAND TFROSTEGARD AGHAFSTROM ILIU AFROSTEGARD J.: "IgM antibodies against malondialdehyde and phosphorylcholine are together strong protection markers for atherosclerosis in systemic lupus erythematosus: Regulation and underlying mechanisms", CLIN LMMUNOL., vol. 166-167, 2016, pages 27 - 37, XP029570863, DOI: doi:10.1016/j.clim.2016.04.007
RAHMAN MSING SGOLABKESH ZFISKESUND RGUSTAFSSON TJOGESTRAND TFROSTEGARD AGHAFSTROM ILIU AFROSTEGARD J: "IgM antibodies against malondialdehyde and phosphorylcholine are together strong protection markers for atherosclerosis in systemic lupus erythematosus: Regulation and underlying mechanisms", CLIN IMMUNOL., vol. 166-167, 2016, pages 27 - 37, XP029570863, DOI: doi:10.1016/j.clim.2016.04.007
RAHMAN MSTEUER JGILLGREN PHAYDERI ALIU AFROSTEGARD J: "Induction of Dendritic Cell-Mediated Activation of T Cells From Atherosclerotic Plaques by Human Heat Shock Protein 60", J AM HEART ASSOC., 2017, pages 6
RIDKER PMMOVING BEYOND JUPITER: "Will Inhibiting Inflammation Reduce Vascular Event Rates?", CURR ATHEROSCLER REP., vol. 15, 2013, pages 295
ROLAND FISKESUND ET AL: "IgM phosphorylcholine antibodies inhibit cell death and constitute a strong protection marker for atherosclerosis development, particularly in combination with other auto-antibodies against modified LDL", RESULTS IN IMMUNOLOGY, vol. 2, 1 January 2012 (2012-01-01), pages 13 - 18, XP055617577, ISSN: 2211-2839, DOI: 10.1016/j.rinim.2012.01.001 *
SHEPHERD JCOBBE SMFORD IISLES CGLORIMER ARMACFARLANE PWMCKILLOP JHPACKARD CJ: "Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group", N ENGF J MED., vol. 333, 1995, pages 1301 - 7
SOBEL MMORENO 1<1YAGI MKOHLER TRTANG GLCLOWES AWZHOU XHEUGENIO E: "Low levels of a natural IgM antibody are associated with vein graft stenosis and failure", J VASE SURG., vol. 58, 2013, pages 997 - 1005 el,2
SPIRA ET AL., J. IMMUNOLOGY, vol. 140, 1988, pages 2675 - 2680
STEPHEN J. NICHOLLS ET AL: "Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary Atherosclerosis", JAMA THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, vol. 297, no. 5, 7 February 2007 (2007-02-07), US, pages 499, XP055621322, ISSN: 0098-7484, DOI: 10.1001/jama.297.5.499 *
SU JGEORGIADES AWU RTHULIN TDE FAIRE UFROSTEGARD J: "Antibodies of IgM subclass to phosphorylcholine and oxidized LDL are protective factors for atherosclerosis in patients with hypertension", ATHEROSCLEROSIS, vol. 188, 2006, pages 160 - 6
SU JHUA XCONCHA HSVENUNGSSON ECEDERHOLM AFROSTEGARD J: "Natural antibodies against phosphorylcholine as potential protective factors in SLE", RHEUMATOLOGY, vol. 47, 2008, pages 1144 - 50, XP002653739, DOI: doi:10.1093/RHEUMATOLOGY/KEN120
SUN JITONG ET AL: "IgM antibodies against phosphorylcholine promote polarization of T regulatory cells from patients with atherosclerotic plaques, systemiclupus erythematosusand healthy donors", ATHEROSCLEROSIS, vol. 268, 16 November 2017 (2017-11-16), pages 36 - 48, XP085322075, ISSN: 0021-9150, DOI: 10.1016/J.ATHEROSCLEROSIS.2017.11.010 *
SUN JLUNDSTROM SLZHANG BZUBAREV RASTEUER JGILLGREN PRAHMAN MAJEGANOVA SLIU AFROSTEGARD J: "IgM antibodies against phosphorylcholine promote polarization of T regulatory cells from patients with atherosclerotic plaques, systemic lupus erythematosus and healthy donors", ATHEROSCLEROSIS, vol. 268, 2017, pages 36 - 48
TAHARA NKAI HISHIBASHI MNAKAURA HKAIDA HBABA KHAYABUCHI NIMAIZUMI T: "Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography", J AM COLL CARDIOL., vol. 48, 2006, pages 1825 - 31, XP029653859, DOI: doi:10.1016/j.jacc.2006.03.069
TAWAKOL AFAYAD ZAMOGG RALON AKIIMAS MTDANSKY HSUBRAMANIAN SSABDELBAKY ARUDD JHFARKOUH ME: "Nunes 10, Beals CR and Shankar SS. Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study", J AM COLL CARDIOL., vol. 62, 2013, pages 909 - 17
THIAGARAJAN DFROSTEGARD AGSINGH SRAHMAN MLIU AVIKSTROM MLEANDER KGIGANTE BHELLENIUS MLZHANG B: "Human IgM Antibodies to Malondialdehyde Conjugated With Albumin Are Negatively Associated With Cardiovascular Disease Among 60-Year-Oids", JAM HEART ASSOC., 2016, pages 5
TINA LEUENBERGER ET AL: "Modulation of Dendritic Cell Immunobiology via Inhibition of 3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) Reductase", PLOS ONE, vol. 9, no. 7, 11 July 2014 (2014-07-11), pages e100871, XP055621327, DOI: 10.1371/journal.pone.0100871 *
TOBERT JA: "Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors", NAT REV DRUG DISCOV., vol. 2, 2003, pages 517 - 26
TOUSOULIS DPSARROS CDEMOSTHENOUS MPATEL RANTONIADES CSTEFANADIS C: "Innate and adaptive inflammation as a therapeutic target in vascular disease: the emerging role of statins", J AM COLL CARDIOL., vol. 63, 2014, pages 2491 - 502, XP028865793, DOI: doi:10.1016/j.jacc.2014.01.054
VAS JGRONWALL CMARSHAK-ROTHSTEIN ASILVERMAN GJ: "Natural antibody to apoptotic cell membranes inhibits the proinflammatory properties of lupus autoantibody immune complexes", ARTHRITIS RHEUM., vol. 64, 2012, pages 3388 - 98
WANG CYLIU PYLIAO JK: "Pleiotropic effects of statin therapy: molecular mechanisms and clinical results", TRENDS MOL MED., vol. 14, 2008, pages 37 - 44, XP022420263, DOI: doi:10.1016/j.molmed.2007.11.004
WILDE BSLOT MVAN PAASSEN PTHEUNISSEN RKEMNA MWITZKE 0COHEN TERVAERT JW: "Phosphorylcholine antibodies are diminished in ANCA-associated vasculitis", FUR J CLIN INVEST., 2015
YILMAZ ALOCHNO MTRAEG FCICHA IREISS CSTUMPF CRAAZ DANGER TAMANN KPROBST T: "Emergence of dendritic cells in rupture-prone regions of vulnerable carotid plaques", ATHEROSCLEROSIS, vol. 176, 2004, pages 101 - 10

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