WO2013019896A1 - Plateforme pour identification et/ou caractérisation d'agents immunomodulateurs - Google Patents

Plateforme pour identification et/ou caractérisation d'agents immunomodulateurs Download PDF

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Publication number
WO2013019896A1
WO2013019896A1 PCT/US2012/049215 US2012049215W WO2013019896A1 WO 2013019896 A1 WO2013019896 A1 WO 2013019896A1 US 2012049215 W US2012049215 W US 2012049215W WO 2013019896 A1 WO2013019896 A1 WO 2013019896A1
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WIPO (PCT)
Prior art keywords
immunomodulatory
mice
free mice
agents
germ
Prior art date
Application number
PCT/US2012/049215
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English (en)
Inventor
Dennis L. Kasper
Sarkis K. Mazmanian
Lloyd KASPER
Original Assignee
Symbiotix Biotherapies, Inc.
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Publication date
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Publication of WO2013019896A1 publication Critical patent/WO2013019896A1/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
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/70—Mechanisms involved in disease identification
    • G01N2800/7095—Inflammation

Definitions

  • Figure 1 shows microbiome screening for probiotic strains and therapeutic molecules.
  • an activity or effect is “comparable” to a reference if it is in the same direction as the reference. In some embodiments, an activity or effect is “comparable” to a reference if it has a magnitude that is within about 0.25 fold, 0.5 fold, 1 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold of the reference. In some embodiments, an activity or effect is "comparable” to a reference if it has a magnitude within 1 or 2 standard deviations of the reference.
  • an activity or effect is "comparable" to a reference if it varies from the reference by not more than about 50%, 40%, 30%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less.
  • Immunomodulatory The present disclosure provides, among other things, methods and systems for screening microorganisms and/or agents they produce or comprise for
  • a microorganism or agent is considered to be “immunomodulatory” if its administration to an immune system (e.g., an organism or a collection of immune cells) elicits a detectable change in the immune system.
  • an immune system e.g., an organism or a collection of immune cells
  • a microorganism (or agent) is considered to be
  • immunomodulatory in accordance with the present disclosure if the detectable change observed when the microorganism is administered to the immune system is comparable to that observed when Bacteroides fragilis is administered to the immune system under experimentally comparable conditions.
  • the detectable change observed with the immunomodulatory microorganism (or agent) is at least as large as that observed with
  • immunomodulatory microorganism (or agent) has a magnitude that is at least 0.25 fold, 0.5 fold, 1 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold or more that observed with Bacteroides fragilis.
  • the detectable change observed with the immunomodulatory microorganism (or agent) is in the same direction (e.g., increase or decrease in particular detected activity or event) as that observed with Bacteroides fragilis.
  • a microorganism or agent is "immunomodulatory" if it has anti-inflammatory properties (i.e., an ability to promote a state associated with absence of an inflammatory response to delay onset or reduce severity of an inflammatory response after imposition of an expected inflammatory response trigger, and/or to reduce severity of one or more features of an existing inflammatory response.
  • a state of inflammation, or an inflammatory response can be assessed by detection of one or more cytokines (e.g., pro-inflammatory cytokines such as IL-1, IL-6, TNF-a, IL-17, IL21, IL23, and/or combinations thereof).
  • the present disclosure provides, among other things, methods and systems for screening microorganisms and/or agents they produce or comprise for immunomodulatory and, in particular, anti inflammatory properties.
  • methods and systems that in several embodiments allow identification and/or characterization of bacterial substances that, when administered to an organism, induce an immunomodulatory response in that organism; in some embodiments, such an induced immunomodulatory response is comparable to one induced by Bacteroides fragilis and/or its antigen polysaccharide A (PSA).
  • PSA antigen polysaccharide A
  • the human gut microflora acts as an immune system. At birth, an infant acquires its first microbial inhabitants through the mother's genital tract. Additional microbial residents are acquired upon further exposure to the outside world. Bacteria in the human body, whose numbers have been estimated at 100 trillion (tenfold the number of human cells), play a major role in modulating immunity to diseases.
  • the mammalian gastrointestinal tract is the largest reservoir of commensal microorganisms, possibly over a thousand distinct species many of which exist in a mutualistic or symbiotic relationship with one another and with the host whose intestines they inhabit. These microbes have a profound influence on human physiology and nutrition, and are considered to be crucial for human life.
  • the symbiotic host-microbial interaction has co-evolved to establish a delicate balance in which bacteria make important contributions to human metabolism and in turn benefit from their nutrient-rich intestinal-niche.
  • the host's immune system represents a strong force driving the evolution of bacterial species— whether commensals or pathogens— that utilize mammals as a host. It logically follows that microbes must have evolved to synthesize a variety of molecules that perturb or modulate the host's immune system.
  • the present disclosure builds upon and provides important technologies relating to work done by the present inventors demonstrating an association between the intestinal microbiota and protection against disease has recently been identified (see, for example, US Patent number 5,679,654, US Patent number 5700787, US Patent Application publication number US2009- 031427, US Patent Application publication number US2009-0124573, US Patent Application publication number US2011-0002965, and US Patent Application publication number
  • Bacteroides fragilis is a strictly anaerobic gram-negative bacterium whose primary known environmental reservoir is the human gastrointestinal tract. Its limited niche suggests a relationship that benefits both the microbe and its host.
  • PSA polysaccharide A
  • PSA confers multiple critical immunologic advantages. Most important of these functions is the ability of PSA to induce interleukin-10 (IL-10) production.
  • IL-10 is an anti-inflammatory cytokine that suppresses uncontrolled immune responses.
  • PSA promotes the production of IL-10 from a specialized subset of immune cells known as regulatory T cells (Tregs). By activating Tregs which are well known to dampen unwanted inflammation, we have shown that PSA confers protection against Inflammatory Bowel Disease (IBD) in preclinical animal models, and in an animal model of multiple sclerosis (MS). Oral administration of PSA is able to suppress disease in both the intestine and the central nervous system. Most impressively, PSA is able to treat existing disease in both preclinical models, emboldening its potential use as a therapy in human IBD and MS.
  • IBD Inflammatory Bowel Disease
  • MS multiple sclerosis
  • the present inventors propose that the vast reservoir of microbes in the gastrointestinal tract harbors a treasure trove of natural therapeutic molecules, many of which are not yet molecularly defined, with great potential both for probing immune system function and for therapeutic application in several disease contexts.
  • the present disclosure provides, among other things, systems, reagents, and
  • Such strains and/or agents are useful in treatment (whether therapeutic or prophylactic) of a wide variety of human diseases, disorders, and conditions.
  • mice will be on genetic backgrounds that are predisposed to immune-mediated diseases (T1D), such as the NOD mouse, a strain which develops symptoms of human type 1 diabetes mellitus or the Kbx/n mouse, a strain genetically predisposed to develop a disease very similar to rheumatoid arthritis (RA).
  • T1D immune-mediated diseases
  • NOD NOD
  • Kbx/n mouse a strain which develops symptoms of human type 1 diabetes mellitus or the Kbx/n mouse
  • RA rheumatoid arthritis
  • mice may be mono-colonized and analyzed using induced animal models of human disease.
  • mono-colonized mice may be challenged with aerosolized ovalbumin in an established model of asthma, or induced to develop colitis in one of several known models, including for example, chemically induced or microbially induced models.
  • mice mono-colonized with known bacterial species may be induced for EAE (an animal model for MS).
  • EAE an animal model for MS
  • our objective will be do identify and/or characterize specific bacterial strains that under conditions of mono-colonization, prevent the mouse from developing (e.g., retard or reduce the development of one or more symptoms or manifestations of) the anticipated disease, or materially ameliorate the anticipated course of disease.
  • Other diseases that could be studied by this approach include, but are not limited to, surgical adhesions, abscesses, enteric infections such as Salmonellosis, Shigelloisis, various types of infection due to Escherichia coli or sepsis.
  • SPF pathogen free mice
  • test bacterial strains which have a complete microbiota, rather than germ free mice
  • test bacterial strains would be colonized with test bacterial strains.
  • SPF pathogen free mice
  • Those of ordinary skill in the art will appreciate that the same animal models discussed above can be utilized to identify and/or characterize the test strains (and/or agents the strains comprise or produce), for example for the same protective or therapeutic endpoints. This approach will validate that identified therapeutic bacterial species are effective in a natural setting with a complex microbiota.
  • two or more different mouse strains e.g., C57B1/6, Balb/c and SJL germ-free mice
  • C57B1/6, Balb/c and SJL germ-free mice will be colonized and tested in appropriate animal models.
  • use of germ-free animals has a particular advantage in that it ensures that observed therapeutic properties of identified strains (and/or agents they comprise or produce) are specific and/or attributable to that strain (and/or agent(s)).
  • testing strains in SPF mice validates observed activities in conditions that mimic human disease where patients have a complex microbiota.
  • immunomodulatory microorganisms and/or agents comprise immunologic assessment of successfully treated mice.
  • one or more of various tissues including but not limited to spleen, lymph nodes, small-intestinal lamina basement (LP), Peyer's patches, large-intestinal LP, cecal patches, intestinal epithelium, pancreas, lungs, joints, central nervous system, and/or combinations thereof will be examined in individual mice (e.g., in 3-5 individual mice) from each group, preferably at about 6-8 weeks of age.
  • Single-cell suspensions will be prepared, labeled with monoclonal antibodies, and analyzed by polychromatic cytofluorometry.
  • immune-related cells such as but not limited to B-cells, CD4+ and CD8+T-cells, iNKT cells, dendritic cells, macrophages, neutrophils, mast cells, eosinophils and other immune cells, or combinations thereof. Proportions of each examined cell population will be determined. Various approaches will be used to determine surface and secreted molecules from each examined cell subset.
  • immunomodulatory microorganisms and/or agents includes genomic sequencing of active microorganisms.
  • genomic sequencing For example, in some embodiments, the genome of bacterial strains that are highly protective and for which no genome sequence is available will be determined using current sequencing technologies e.g., those available from Illumina, Inc (San Diego, CA). Each annotated genome will yield a catalog of genes that can be mined for candidate genes that encode immunomodulatory agents or entities (e.g., enzymes) that generate them. 4. Purification of Agents Comprised in or Produced by Active Microorganisms
  • immunomodulatory microorganisms and/or agents includes identifying individual agents comprised in or produced by immunomodulatory microbes. For example, in some embodiments, we will fractionate the contents of the potent microbes to identify individual agents found in bacterial strains which confer protection from disease in animal models. This biochemical approach may also be complemented by a genetic (mutagenesis) approach. It is likely that the effective molecules are polysaccharides, polynucleotides, proteins, lipids and/or small molecules. In some embodiments, chemical analysis at this step may include FPLC, HPLC, mass- spectrometry analysis, proton NMR spectroscopy, and/or combinations thereof.
  • immunomodulatory microorganisms and/or agents includes an assessment of impact of isolated agents comprised in or produced by microorganisms on immune systems or cells. For example, in some embodiments, we will treat various subsets of immune cells with purified compounds from the protective strains we have identified to determine and validate their sufficiency. We will employ standard assays to measure cellular responses known to be involved in protection from immune-mediate disease.
  • immunomodulatory microorganisms and/or agents includes an assessment of activities of agents comprised in and/or produced by microorganisms in one or more well-characterized mouse models of immunological disease (e.g., those mentioned above). For example, in some embodiments, we will measure relevant parameters of disease in each individual animal model. In some cases, we may test agents directly in animal models without the prior step of treating immune cell subsets (step #5 above). In some embodiments, these studies will integrate innovative structural carbohydrate-chemistry, microbiology, immunology, genetics,
  • bioinformatics and/or combinations thereof.
  • Immune-system-associated diseases, disorders and conditions of particular interest include inflammatory diseases, disorders, or conditions, including those associated with or involving either chronic or acute inflammation.
  • acute inflammation typically refers to a short-term process characterized by classic signs of inflammation (swelling, redness, pain, heat, and loss of function) due to infiltration of tissues by plasma and leukocytes.
  • An acute inflammation typically occurs as long as an injurious stimulus is present and ceases once the stimulus has been removed, broken down, or walled off by scarring (fibrosis).
  • chronic inflammation typically refers to a condition characterized by concurrent active inflammation, tissue destruction, and attempts at repair.
  • Chronic inflammation is usually not characterized by the classic signs of acute inflammation listed above. Instead, chronically inflamed tissue is characterized by the infiltration of mononuclear immune cells (monocytes, macrophages, lymphocytes, and plasma cells), tissue destruction, and attempts at healing, which include angiogenesis and fibrosis.
  • mononuclear immune cells mononuclear immune cells

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  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des microorganismes et/ou des agents qu'ils produisent ou comportent qui présentent des propriétés immunomodulatrices et, en particulier, anti-inflammatoires, et des systèmes et des procédés d'identification et/ou de caractérisation de ceux-ci.
PCT/US2012/049215 2011-08-01 2012-08-01 Plateforme pour identification et/ou caractérisation d'agents immunomodulateurs WO2013019896A1 (fr)

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Cited By (15)

* Cited by examiner, † Cited by third party
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US8906668B2 (en) 2012-11-23 2014-12-09 Seres Health, Inc. Synergistic bacterial compositions and methods of production and use thereof
US9011834B1 (en) 2013-02-04 2015-04-21 Seres Health, Inc. Compositions and methods
US9539281B2 (en) 2011-07-12 2017-01-10 The Brigham And Women's Hospital, Inc. Lipid-containing PSA compositions, methods of isolation and methods of use thereof
US9956282B2 (en) 2013-12-16 2018-05-01 Seres Therapeutics, Inc. Bacterial compositions and methods of use thereof for treatment of immune system disorders
US10076546B2 (en) 2013-03-15 2018-09-18 Seres Therapeutics, Inc. Network-based microbial compositions and methods
US10258655B2 (en) 2013-11-25 2019-04-16 Seres Therapeutics, Inc. Synergistic bacterial compositions and methods of production and use thereof
US10772918B2 (en) 2013-05-10 2020-09-15 California Institute Of Technology Probiotic prevention and treatment of colon cancer
US10857177B2 (en) 2015-08-19 2020-12-08 President And Fellows Of Harvard College Lipidated PSA compositions and methods
US10973861B2 (en) 2013-02-04 2021-04-13 Seres Therapeutics, Inc. Compositions and methods
US11103566B2 (en) 2010-05-20 2021-08-31 California Institute Of Technology Antigen specific Tregs and related compositions, methods and systems
US11331335B2 (en) 2015-06-10 2022-05-17 California Institute Of Technology Sepsis treatment and related compositions methods and systems
US11419887B2 (en) 2010-04-07 2022-08-23 California Institute Of Technology Vehicle for delivering a compound to a mucous membrane and related compositions, methods and systems
US11491181B2 (en) 2016-07-15 2022-11-08 President And Fellows Of Harvard College Glycolipid compositions and methods of use
US11622973B2 (en) 2007-11-09 2023-04-11 California Institute Of Technology Immunomodulating compounds and related compositions and methods
US11701394B2 (en) 2017-08-14 2023-07-18 Seres Therapeutics, Inc. Compositions and methods for treating cholestatic disease

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Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11622973B2 (en) 2007-11-09 2023-04-11 California Institute Of Technology Immunomodulating compounds and related compositions and methods
US11419887B2 (en) 2010-04-07 2022-08-23 California Institute Of Technology Vehicle for delivering a compound to a mucous membrane and related compositions, methods and systems
US11103566B2 (en) 2010-05-20 2021-08-31 California Institute Of Technology Antigen specific Tregs and related compositions, methods and systems
US9539281B2 (en) 2011-07-12 2017-01-10 The Brigham And Women's Hospital, Inc. Lipid-containing PSA compositions, methods of isolation and methods of use thereof
US11389490B2 (en) 2012-11-23 2022-07-19 Seres Therapeutics, Inc. Synergistic bacterial compositions and methods of production and use thereof
US10864235B2 (en) 2012-11-23 2020-12-15 Seres Therapeutics, Inc. Synergistic bacterial compositions and methods of production and use thereof
US11464812B2 (en) 2012-11-23 2022-10-11 Seres Therapeutics, Inc. Synergistic bacterial compositions and methods of production and use thereof
US11458173B2 (en) 2012-11-23 2022-10-04 Seres Therapeutics, Inc. Synergistic bacterial compositions and methods of production and use thereof
US11458174B2 (en) 2012-11-23 2022-10-04 Seres Therapeutics, Inc. Synergistic bacterial compositions and methods of production and use thereof
US9028841B2 (en) 2012-11-23 2015-05-12 Seres Health, Inc. Synergistic bacterial compositions and methods of production and use thereof
US8906668B2 (en) 2012-11-23 2014-12-09 Seres Health, Inc. Synergistic bacterial compositions and methods of production and use thereof
US9533014B2 (en) 2012-11-23 2017-01-03 Seres Therapeutics, Inc. Synergistic bacterial compositions and methods of production and use thereof
US10973861B2 (en) 2013-02-04 2021-04-13 Seres Therapeutics, Inc. Compositions and methods
US9446080B2 (en) 2013-02-04 2016-09-20 Seres Therapeutics, Inc. Compositions and methods
US11730775B2 (en) 2013-02-04 2023-08-22 Seres Therapeutics, Inc. Methods for treatment of Clostridium difficile infection or recurrence or symptoms thereof
US9011834B1 (en) 2013-02-04 2015-04-21 Seres Health, Inc. Compositions and methods
US9585921B2 (en) 2013-02-04 2017-03-07 Seres Therapeutics, Inc. Compositions and methods
US9855303B2 (en) 2013-02-04 2018-01-02 Seres Therapeutics, Inc. Compositions and methods
US10967011B2 (en) 2013-02-04 2021-04-06 Seres Therapeutics, Inc. Compositions and methods
US10064901B2 (en) 2013-02-04 2018-09-04 Seres Therapeutics, Inc. Compositions and methods
US9180147B2 (en) 2013-02-04 2015-11-10 Seres Therapeutics, Inc. Compositions and methods
US11185562B2 (en) 2013-02-04 2021-11-30 Seres Therapeutics, Inc. Compositions and methods for inhibition of pathogenic bacterial growth
US10064900B2 (en) 2013-02-04 2018-09-04 Seres Therapeutics, Inc. Methods of populating a gastrointestinal tract
US10881696B2 (en) 2013-03-15 2021-01-05 Seres Therapeutics, Inc. Network-based microbial compositions and methods
US10076546B2 (en) 2013-03-15 2018-09-18 Seres Therapeutics, Inc. Network-based microbial compositions and methods
US11666612B2 (en) 2013-03-15 2023-06-06 Seres Therapeutics, Inc Network-based microbial compositions and methods
US10772918B2 (en) 2013-05-10 2020-09-15 California Institute Of Technology Probiotic prevention and treatment of colon cancer
US11266699B2 (en) 2013-11-25 2022-03-08 Seres Therapeutics, Inc. Synergistic bacterial compositions and methods of production and use thereof
US10258655B2 (en) 2013-11-25 2019-04-16 Seres Therapeutics, Inc. Synergistic bacterial compositions and methods of production and use thereof
US11918612B2 (en) 2013-11-25 2024-03-05 Seres Therapeutics, Inc. Synergistic bacterial compositions and methods of production and use thereof
US9956282B2 (en) 2013-12-16 2018-05-01 Seres Therapeutics, Inc. Bacterial compositions and methods of use thereof for treatment of immune system disorders
US11331335B2 (en) 2015-06-10 2022-05-17 California Institute Of Technology Sepsis treatment and related compositions methods and systems
US10857177B2 (en) 2015-08-19 2020-12-08 President And Fellows Of Harvard College Lipidated PSA compositions and methods
US11491181B2 (en) 2016-07-15 2022-11-08 President And Fellows Of Harvard College Glycolipid compositions and methods of use
US11701394B2 (en) 2017-08-14 2023-07-18 Seres Therapeutics, Inc. Compositions and methods for treating cholestatic disease

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