WO2008043725A1 - Biomarqueur utilisé dans des affections inflammatoires - Google Patents

Biomarqueur utilisé dans des affections inflammatoires Download PDF

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Publication number
WO2008043725A1
WO2008043725A1 PCT/EP2007/060637 EP2007060637W WO2008043725A1 WO 2008043725 A1 WO2008043725 A1 WO 2008043725A1 EP 2007060637 W EP2007060637 W EP 2007060637W WO 2008043725 A1 WO2008043725 A1 WO 2008043725A1
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Prior art keywords
sms2
level
activity
sample
individual
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PCT/EP2007/060637
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English (en)
Inventor
Thomas Baumruker
Andreas Billich
Diana Mechtcheriakova
Alexander Wlachos
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Novartis Ag
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Publication of WO2008043725A1 publication Critical patent/WO2008043725A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/25—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving enzymes not classifiable in groups C12Q1/26 - C12Q1/66
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/9015—Ligases (6)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/10—Musculoskeletal or connective tissue disorders
    • G01N2800/101—Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis
    • G01N2800/102—Arthritis; Rheumatoid arthritis, i.e. inflammation of peripheral joints
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/10—Musculoskeletal or connective tissue disorders
    • G01N2800/101—Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis
    • G01N2800/104—Lupus erythematosus [SLE]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/285—Demyelinating diseases; Multipel sclerosis

Definitions

  • the present invention relates to biomarkers in inflammatory disorders, e.g. to the expression of sphingomyelin synthase enzyme 2 as a player in autoimmune diseases.
  • SMS1 and SMS2 catalyse the interconversion of phosphatidylcholine and ceramide with sphingomyelin and diacylglycerol, see e.g. The Journal of Biological Chemistry VoI 281 , No. 40, pp. 29421-29425 (October 6, 2006).
  • SMS2 NM_152621 the sphingomyelin synthase enzyme 2
  • SES1 , NIVM47156 the sphingomyelin synthase enzyme 1
  • the present invention provides 1. SMS2 for use, e.g., or the use of SMS2, e.g. SMS2 in human CD3 + cells, 1.1 as a target in immune, e.g. autoimmune, disorders; such as immune disorders in humans;
  • MS Multiple Sclerosis
  • SLE Systemic Lupus Erythematosus
  • LA Lupus Anticoagulant
  • RA Rheumatoid Arthritis
  • IDP Idiopathic Thrombocytopenic Purpura
  • disorders according to the present invention are disorders mediated, e.g. associated with, e.g. driven by, elevated levels of SMS2.
  • Elevated levels of SMS2 include levels which are elevated at least 2-fold up to 30-fold and more, e.g. 3-fold to 30-fold, such as 3-fold to 20-fold. Since, according to the present invention it is shown that the amount of SMS2 in a sample from a patient suffering from an (auto) ⁇ mmune disorder is elevated, it reasonably may be concluded that also SMS2 activity plays a role in (auto) ⁇ mmune disorders, e g a higher amount of SMS2 is related with higher activity of SMS2
  • SMS2 as used herein is to be understood as sphingomyelin synthase enzyme 2 Disorders as used herein include diseases
  • disorders mediated, e g associated with, e g driven by , elevated levels of SMS2, e g or SMS2 activity include immune, such as autoimmune disorders, e g such as autoimmune disorders associated with inflammation, e g Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE), Lupus Anticoagulant (LA), Rheumatoid Arthritis (RA), Idiopathic Thrombocytopenic Purpura (ITP), inflammatory bowel disease (IBD), autoimmune hepatitis (AHI) and fibrosis, such as MS, SLE, LA, RA and/or ITP
  • MS Multiple Sclerosis
  • SLE Systemic Lupus Erythematosus
  • LA Lupus Anticoagulant
  • RA Rheumatoid Arthritis
  • ITP Idiopathic Thrombocytopenic Purpura
  • IBD inflammatory bowel disease
  • AHI autoimmune hepatitis
  • fibrosis such as MS, S
  • SMS2 for use, e g , or the use of SMS2, for diagnosing Multiple Sclerosis (MS),
  • SLE Systemic Lupus Erythematosus
  • LA Lupus Anticoagulant
  • RA Rheumatoid Arthritis
  • ITP Idiopathic Thrombocytopenic Purpura
  • IBD inflammatory bowel disease
  • AHI autoimmune hepatitis
  • MS MS, SLE, LA, RA and/or ITP
  • the present invention further provides
  • SMS2 e g or the use of SMS2, as a biomarker, for a use as indicated under 1 1 to 1 3 above, e g in a sample of an individual, e g in a sample of a body fluid or a tissue sample of an individual,
  • SMS2 as indicated under any of 1 or 2 above includes SMS2 in CD3 + cells
  • SMS2 as indicated herein includes SMS2 in any form, e.g. in the form of
  • nucleic acid encoding SMS2 e.g. including a nucleic acid encoding a derivative of SMS2,
  • SMS2 protein e.g. including protein which is SMS2 or a derivative thereof, or
  • SMS2 secreting cells e.g. or a derivative of SMS2 secreting cells.
  • a derivative of SMS2 nucleic acid or protein, e.g. in secreting cells, according to the present invention includes a fragment, a mutant, a variant, an homolog or a modification of a SMS2 protein, or of a nucleic acid encoding SMS2 which retains, e.g. essentially, the biological function of SMS2, e.g. which retains, e.g. essentially, the biological function of SMS2, e.g. in dendritic cells.
  • SMS2 containing cells e.g. including SMS2 producing cells, e.g. include CD3 + cells.
  • SMS2 for use as provided by the present invention includes splice variants encoded by mRNA generated by alternative splicing of a primary transcript, amino acid mutants, posttranslational modifications, such as glycosylation and phosphorylation variants, and modifications which are covalent derivatives of SMS2 and which retain the biological function of SMS2, e.g. in CD3 + cells.
  • exemplary SMS2 derivatives include modifications wherein the SMS2 protein is covalently modified by substitution, e.g. substitution originating from appropriate means, e.g. chemical or enzymatic means, by a moiety in the SMS2 protein.
  • a moiety e.g. includes one or more amino acids, e.g.
  • SMS2 derivatives further included naturally occurring variants of SMS2, e.g. provided within a particular species. Such a variant may be encoded by a related gene of the same gene family, by an allelic variant of a particular gene, or represent an alternative splicing variant of the SMS2 gene.
  • a SMS2 derivative as used herein also includes fragments of a nucleic acid encoding SMS2, or of the SMS2 protein, and comprises individual SMS2 domains and smaller polypeptides derived from SMS2 domains.
  • smaller polypeptides derived from SMS2 according to the invention define a single functional activity which is characteristic of SMS2. Fragments may in theory be of almost any size, as long as they retain the biological characteristic of SMS2. Preferably, fragments will be between 12 and 210 nucleic acids in length or between 4 and 70 amino acids, respectively. Longer fragments are regarded as truncations of the full- length SMS2.
  • Derivatives of SMS2 as used herein also comprise mutants thereof, which may contain amino acid deletions, additions or substitutions, subject to the requirement to retain the biological function of SMS2, e.g. in CD3 + cells.
  • Conservative amino acid substitutions may be made substantially without altering the nature of SMS2, e.g. by truncations from the 5' or 3' ends.
  • Deletions and substitutions also include deletions and substitutions in fragments of SMS2.
  • SMS2 mutants may be produced from a DNA encoding SMS2 which has been subjected to in vitro mutagenesis resulting e.g. in an addition, exchange and/or deletion of one or more amino acids in SMS2.
  • substitutional, deletional or insertional variants of SMS2 can be prepared by recombinant methods and screened for functional similarity to the native forms of SMS2.
  • SMS2 homologs preferably SMS2 homologs retain substantial homology with SMS2.
  • homology means that SMS2and a SMS2 homolog share sufficient characteristics to retain the biological function of SMS2, e.g. in CD3 + cells.
  • homology is used to refer to sequence identity.
  • the derivatives of SMS2 preferably retain substantial sequence identity with the nucleic acid sequence as given in
  • Substantial homology where homology indicates sequence identity, means more than 50% sequence identity, preferably more than 75% sequence identity and even more preferably a sequence identity of 80% and more, e.g. 90% and more, such as 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%.
  • SMS2 is originating from a mammal, e.g. a human.
  • the nucleic acid encoding SMS2 preferably has the nucleic acid sequence as disclosed in literature for SMS2, such as NM_152621.
  • the SMS2 protein preferably corresponds to the translated protein sequence of the above mentioned nucleic acid.
  • the present invention provides a method for diagnosing a disorder which is mediated, e g associated with, e g driven by, elevated levels of SMS2, e g or SMS2 activity, comprising a) providing a sample of an individual, b) determining the level of SMS2 in said sample, e g the level of mRNA of SMS2, e g in CD3 + cells, c) comparing the level of SMS2 as determined in step b) with a reference level from a sample of a healthy control individual, and d) diagnosing a disorder or disease which is mediated, e g associated with, e g driven by, elevated levels of SMS2, e g or SMS2 activity, by determination whether the level of
  • SMS2 as determined in step b) is, e g significantly, different from said reference level
  • the present invention provides a method for monitoring the therapeutic efficacy in the treatment of an individual with a substance which is expected to have an effect on reducing or curing a disorder or disease which is mediated, e g associated with, e g driven by, elevated levels of SMS2, e g or SMS2 activity, which method comprises determining the level of SMS2 in cells, e g CD3 + cells, in a sample of said individual and comparing that level with the level of SMS2 prior to administration of said substance
  • a sample of an individual according to a use or a method of the present invention includes a sample of a body fluid or a tissue sample
  • a body fluid may be derived e g from blood, e g including isolated mononuclear cells, or from a blood fraction, e g including plasma or serum, preferably serum
  • a tissue sample may be a biopsy, e g such as a skin biopsy
  • a sample is a body fluid or a tissue sample of an individual, e g a body fluid may be derived from blood, e g isolated cells, such as CD3 + cells, or from a blood fraction, e g plasma or serum, e g serum, e g the tissue sample may be a biopsy, e g such as a skin biopsy
  • Cells, e g CD3 + cells from a sample of an individual may be isolated as appropriate, e g according, e g analogously, to a a method as conventional
  • Detection means in cells for determining the level of SMS2 include means as conventional, e g immunoassays, such as an immunodiagnostic method, an enzyme linked immunoassay (ELISAs), a fluorescence based assay, such as dissociation enhanced lanthanide fluoroimmunoassay (DELFIA), an radiometric assay or by carrying out a SMS2 specific Polymerase Chain Reaction (PCR)
  • detection means include a molecule which specifically recognizes SMS2, e g a molecule which is directly or indirectly detectable, preferably comprising an antibody, including antibody derivatives or fragments thereof, e g an antibody which recognizes SMS2, e g a label bearing SMS2 recognizing antibody
  • Such label may be a conventional label, e g biotin or an enzyme such as alkaline phosphatase (AP), horse radish peroxidase (HRP) or peroxidase (POD) or a fluorescent molecule, e g a fluorescent dye,
  • An antibody fragment or antibody derivative includes a fragment or a derivative, e g chemically or enzymatically modified, of an antibody which still is capable of recognising SMS2
  • SMS2 -secreting cells in a sample of a body fluid of an individual, e g blood may be determined by a method as conventional, e g by the following method
  • Cells e g dendritic cells may be purified, e g separated by a density gradient, from the sample, e g blood, and the purified cells obtained are stained
  • Anti- SMS2 antibodies e g fluorescence labeled anti- SMS2 antibodies, are added to the stained cell preparation, optionally after stimulation of the cells, e g with ⁇ nterleuk ⁇ n-4, and the level of SMS2- secreting cells is determined
  • SMS2 comprised in the sample or the SMS2 recognizing, e g detectable, molecule comprised in the detection means is immobilized on a solid phase
  • An appropriate solid phase includes e g conventional solid phases used for immobilization, e g a plastic plate like a polystyrene or polyvinyl plate, especially a microtiter plate
  • microbeads can be used as a solid phase, e g coated microbeads
  • the solid phase can be coated with a coating material the nature of which depends e g on the label comprised in the detection means
  • the coating material should be able to bind to the label, e g if the label is biotin a coating material includes streptavidin, e g covalently bound to the solid phase
  • determination of SMS2 in cells, e g CD3 + cells is carried out by PCR
  • the present invention provides a method for diagnosing a disorder or disease which is mediated, e g associated with, e g driven
  • the present invention provides the a kit, comprising a) a molecule which recognizes SMS2, optionally in a labeled form, b) instructions how to use said kit, e g in CD 3 + cell isolates, c) optionally detection means, d) optionally a solid phase, for diagnosing a disorder which is mediated, e g associated with, e g driven, by elevated levels of SMS2, e g or SMS2 activity, in a sample of an individual
  • the present invention provides the use of a kit, comprising a) a molecule which recognizes SMS2, optionally in a labeled form, b) instructions how to use said kit, e g in CD 3 + cell isolates, c) optionally detection means, d) optionally a solid phase, for diagnosing a disorder or disease which is mediated, e g associated with, e g driven, by elevated levels of SMS2, e g or SMS2 activity, in a sample of an individual
  • kit may further comprise a substantial component, e g including an appropriate environment of a sample to be tested and, e g appropriate means to determine SMS2 in a sample to be tested
  • the present invention provides a method for the preparation of a kit by provision of a) a molecule which recognizes SMS2, optionally in a labeled form, b) instructions how to use said kit, e g in CD 3 + cell isolates, c) optionally detection means, d) optionally a solid phase, for diagnosing a disorder or disease which is mediated, e g associated with, e g driven, by elevated levels of SMS2, e g or SMS2 activity, in a sample of an individual
  • the present invention provides an assay for identifying an agent that mediates a disorder which is mediated by elevated SMS2 level, e g or SMS2 activity, comprising a) determining the level of SMS2, e g in CD3 + cells of a sample of an individual, in the absence and in the presence of a candidate compound which may be expected to modulate the level of SMS2, b) identifying a candidate compound which modulates the level of SMS2 as determined in step a) as an agent, e
  • a candidate compound identified decreases the level of SMS2
  • the level of SMS2 is determined as appropriate, e g as described herein
  • a candidate compound as described herein is a compound which may be expected to modulate the level of SMS2, or SMS2 activity or SMS2 secreting cells, and includes compound(s)(l ⁇ bra ⁇ es) from which its influence on SMS2 can be determined
  • Compound (libraries) include for example oligopeptides, polypeptides, proteins, antibodies, mimetics, small molecules, e g low molecular weight compounds (LMW ' s)
  • An agent is a candidate compound which modulates the level of the level of SMS2, or SMS2 activity or SMS2 secreting cells, e g in cells, such as CD3 + cells in a sample form a patient, e g a blood sample, such as serum, e g or a skin biopsy
  • An agent includes oligopeptides, polypeptides, proteins, antibodies, mimetics, small molecules, e g low molecular weight compounds (LMWs)
  • the present invention provides an agent identified by an assay or a method of the present invention
  • An agent of the present invention may exhibit pharmacological activity and is therefore useful as a pharmaceutical
  • An agent of the present invention may show therapeutic activity, e g in disorders or diseases mediated, e g associated with, e g driven by elevated levels of SMS2, or SMS2 activity
  • the present invention provides the use of an agent of the present invention as a pharmaceutical in disorders mediated, e g associated with, e g driven by elevated levels of SMS2, e g or SMS2 activity
  • an agent of the present invention for treatment includes one or more, preferably one, agent of the present invention, e g a combination of two or more agents of the present invention
  • the present invention provides the use of an agent of the present invention for the manufacture of a medicament for the treatment of disorders or diseases mediated, e g associated with, e g driven by SMS2 activity
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an agent of the present invention beside at least one pharmaceutical excipient, e g appropriate carrier and/or diluent, e g including fillers, binders, disintegrators, flow conditioners, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers
  • a pharmaceutical excipient e g appropriate carrier and/or diluent, e g including fillers, binders, disintegrators, flow conditioners, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers
  • the present invention provides a method for the treatment of disorders or diseases mediated, e g associated with, e g driven, by elevated SMS2 levels, e g or SMS2 activity, comprising administering an effective amount of an agent of the present invention to a subject in need of such treatment
  • an indicated daily dosage includes a range - from about 0 001 g to about 1 5 g, such as 0 001 g to 1 5 g,
  • An agent of the present invention may be administered by any conventional route, for example enterally, e g including nasal, buccal, rectal, oral, administration, parenterally, e g including intravenous, intramuscular, subcutanous administration, or topically, e g including epicutaneous, intranasal, intratracheal administration, via medical devices for local delivery, e g stents, e g in form of coated or uncoated tablets, capsules, (injectable) solutions, solid solutions, suspensions, dispersions, solid dispersions, e g in the form of ampoules, vials, in the form of creams, gels, pastes, inhaler powder, foams, tinctures, lip sticks, drops, sprays, or in the form of suppositories
  • enterally e g including nasal, buccal, rectal, oral, administration, parenterally, e g including intravenous, intramuscular, subcutanous administration, or topically, e g including epicutaneous,
  • An agent of the present invention may be administered in the form of a pharmaceutically acceptable salt, e g an acid addition salt or metal salt, or in free form, optionally in the form of a solvate
  • a pharmaceutically acceptable salt e g an acid addition salt or metal salt
  • An agent of the present invention in the form of a salt may exhibit the same order of activity as an agent of the present invention in free form, optionally in the form of a solvate
  • An agent of the present invention may be used for pharmaceutical treatment according to the present invention alone, or in combination with one or more other pharmaceutically active agents
  • Combinations include fixed combinations, in which two or more pharmaceutically active agents are in the same formulation, kits, in which two or more pharmaceutically active agents in separate formulations are sold in the same package, e g with instruction for coadministration, and free combinations in which the pharmaceutically active agents are packaged separately, but instruction for simultaneous or sequential administration are given
  • SMS2 mRNA Shows the relative expression of SMS2 mRNA in CD3 + cells of patients with autoimmune diseases compared with healthy donors (ND)
  • SMS2 mRNA expression but not SMS1 mRNA expression in cells, such as in CD3 + cells, has been found to be associated with autoimmune disorders

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Abstract

L'invention concerne l'utilisation de SMS2 comme cible dans des affections auto-immunes, notamment comme biomarqueur, p. ex. dans des affections auto-immunes associées à des inflammations, telles que la sclérose en plaques, le lupus érythémateux disséminé, le lupus anticoagulant, l'arthrite rhumatoïde, l'affection abdominale inflammatoire, le purpura thrombocytopénique idiopathique, l'hépathite auto-immune (AHI) ou fibrose; l'invention concerne également des kits de diagnostic contenant SMS2 ainsi qu'un procédé d'identification d'agents qui module les affections associées à des taux élevés de SMS2, ou l'activité des SMS2.
PCT/EP2007/060637 2006-10-10 2007-10-08 Biomarqueur utilisé dans des affections inflammatoires WO2008043725A1 (fr)

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EP06122039.8 2006-10-10

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US10295527B2 (en) 2016-03-14 2019-05-21 Bruce Yacyshyn Process and system for predicting responders and non-responders to mesalamine treatment of ulcerative colitis
US10494675B2 (en) 2013-03-09 2019-12-03 Cell Mdx, Llc Methods of detecting cancer
US10626464B2 (en) 2014-09-11 2020-04-21 Cell Mdx, Llc Methods of detecting prostate cancer
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US10934588B2 (en) 2008-01-18 2021-03-02 President And Fellows Of Harvard College Methods of detecting signatures of disease or conditions in bodily fluids
US10961578B2 (en) 2010-07-23 2021-03-30 President And Fellows Of Harvard College Methods of detecting prenatal or pregnancy-related diseases or conditions
US11111537B2 (en) 2010-07-23 2021-09-07 President And Fellows Of Harvard College Methods of detecting autoimmune or immune-related diseases or conditions
US11585814B2 (en) 2013-03-09 2023-02-21 Immunis.Ai, Inc. Methods of detecting prostate cancer
EP4303584A2 (fr) 2010-07-23 2024-01-10 President and Fellows of Harvard College Procédés de détection de signatures de maladies ou pathologies dans des liquides biologiques
US11946927B2 (en) 2016-03-14 2024-04-02 Musidora Biotechnology Llc Process and system for identifying individuals having a high risk of inflammatory bowel disease and a method of treatment

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10934588B2 (en) 2008-01-18 2021-03-02 President And Fellows Of Harvard College Methods of detecting signatures of disease or conditions in bodily fluids
US11001894B2 (en) 2008-01-18 2021-05-11 President And Fellows Of Harvard College Methods of detecting signatures of disease or conditions in bodily fluids
US10934589B2 (en) 2008-01-18 2021-03-02 President And Fellows Of Harvard College Methods of detecting signatures of disease or conditions in bodily fluids
US11111537B2 (en) 2010-07-23 2021-09-07 President And Fellows Of Harvard College Methods of detecting autoimmune or immune-related diseases or conditions
US10961578B2 (en) 2010-07-23 2021-03-30 President And Fellows Of Harvard College Methods of detecting prenatal or pregnancy-related diseases or conditions
WO2012012725A2 (fr) 2010-07-23 2012-01-26 President And Fellows Of Harvard College Méthodes de dépistage de maladies ou d'affections à l'aide de cellules phagocytaires
EP4303584A2 (fr) 2010-07-23 2024-01-10 President and Fellows of Harvard College Procédés de détection de signatures de maladies ou pathologies dans des liquides biologiques
US10494675B2 (en) 2013-03-09 2019-12-03 Cell Mdx, Llc Methods of detecting cancer
US11585814B2 (en) 2013-03-09 2023-02-21 Immunis.Ai, Inc. Methods of detecting prostate cancer
US10626464B2 (en) 2014-09-11 2020-04-21 Cell Mdx, Llc Methods of detecting prostate cancer
US10295527B2 (en) 2016-03-14 2019-05-21 Bruce Yacyshyn Process and system for predicting responders and non-responders to mesalamine treatment of ulcerative colitis
US11199534B2 (en) 2016-03-14 2021-12-14 Bruce Yacyshyn Process and system for predicting responders and non-responders to mesalamine treatment of ulcerative colitis
US11946927B2 (en) 2016-03-14 2024-04-02 Musidora Biotechnology Llc Process and system for identifying individuals having a high risk of inflammatory bowel disease and a method of treatment
CN111481548A (zh) * 2019-01-29 2020-08-04 复旦大学 4-(2,6-二氯苄氧基)-3-(3-氨基吡啶)苯并[d]异噁唑在制药中的用途

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