WO2010059975A2 - Procédé pour moduler l'athérosclérose - Google Patents

Procédé pour moduler l'athérosclérose Download PDF

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Publication number
WO2010059975A2
WO2010059975A2 PCT/US2009/065387 US2009065387W WO2010059975A2 WO 2010059975 A2 WO2010059975 A2 WO 2010059975A2 US 2009065387 W US2009065387 W US 2009065387W WO 2010059975 A2 WO2010059975 A2 WO 2010059975A2
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collagen
individual
atherosclerosis
step comprises
mice
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PCT/US2009/065387
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English (en)
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WO2010059975A3 (fr
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Daniel S. Greenspan
William J. Burlingham
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Wisconsin Alumni Research Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Atherosclerosis is a chronic inflammatory disease characterized by flow- obstructing deposits on inner arterial linings.
  • the deposits, or plaques contain cellular waste products and substances such as cholesterol and calcium.
  • the plaques can rupture and set in motion a cascade that culminates in blood clots associated with gangrene, heart attack, and stroke.
  • Immune responses to autoantigens are important components of the pathogenesis of atherosclerosis as evident from proatherogenic adoptive transfer of CD4 + T cells from atherosclerotic donors and reduced atherosclerotic lesions in immunodeficient animals.
  • oxidized low-density lipoprotein oxLDL
  • HSP 60 heat shock protein-60
  • ⁇ l(V) chains form ⁇ l(V) 3 homotrimers (Haralson etal, PNAS 77:5206-5210 (1980). These homotrimers are excluded from the interior of type I collagen fibrils (Chanut-Delalande et at, J Biol. Chem. 276:24352- 24359 (2001)) and are instead exposed to the immune system, potentially initiating an immune cascade leading to obliterative bronchiolitis. Oral administration of collagen V reduced delayed type hypersensitivity to alloantigens in rats (WO 2007/120947). [0005] ⁇ l(V) chains are specifically up-regulated in atherosclerotic plaques
  • the present invention arises from the inventors' observation, disclosed herein for the first time, that human and non-human subjects having coronary artery disease, but not control subjects, exhibit antigen-specific cellular immunoreactivity to collagen V. From this observation, the inventors understand that incidence of atherosclerosis and its associated physiological symptoms can be modulated by inducing immunological tolerance towards collagen V or antigenic fragments thereof such that the immune system does not mount a specific anti-collagen V immune response. Relatedly, new methods for diagnosing atherosclerosis involve detecting collagen V in coronary arteries and/or collagen V-specific immunoreactivity.
  • the invention is summarized in that methods for modulating an effect of atherosclerosis in a human or non-human subject having, or at risk of developing, the disease include the step of inducing immunological tolerance in the subject.
  • the tolerance-inducing step includes the steps of administering to the subject collagen V, at least one antigenic fragment thereof or a polynucleotide encoding either of the foregoing, and observing a reduced atherosclerotic burden in the subject.
  • a therapeutically effective amount of type V collagen is administered to a patient having atherosclerosis.
  • Type V collagen, or fragment thereof can be administered, for example, orally, intravenously, intramuscularly, or via any other suitable route.
  • methods for determining risk of an individual for developing atherosclerotic cardiovascular disease includes the step of determining collagen V specific immunoreactivity.
  • the determining step comprises measuring the amount of collagen V-specific antibodies in a serum sample of an individual.
  • Methods for measuring amounts of specific antibodies are well known in the art and include enzyme-linked immunosorbent assay (ELISA) and flow cytometry.
  • collagen V fragments are immobilized on a bead and collagen V-specific antibodies binding to the immobilized collagen V are detected through secondary antibody staining.
  • the secondary antibody can be selective for antibody subclasses, e.g., the IgGl-4 subclasses, such that the progression of disease in an individual can be monitored by measuring different collagen V-specific antibody subclass amounts in samples taken at time intervals.
  • FIG. 1 illustrates trans vivo delayed type hypersensitivity (TV-DTH) responses using peripheral blood mononuclear cells (PBMCs) from individuals having coronary artery disease and from healthy, age-matched controls.
  • PBMCs peripheral blood mononuclear cells
  • FIG. 2 illustrates TV-DTH responses in the presence of neutralizing antibodies using cells from individuals with coronary artery disease and from healthy controls.
  • PBMCs from CAD patients that had exhibited swelling responses of at least 3O x IO "4 inches were coinjected into mouse footpads with 5 ⁇ g of neutralizing antibodies to human IFN- ⁇ , TNF- ⁇ (both from BD Biosciences, San Jose, CA), IL- l ⁇ (eBiosciences, San Diego, CA), or IL- 17 (R&D Systems, Minneapolis, MN).
  • FIG. 3 illustrates TV-DTH responses using peripheral blood mononuclear cells from an individual with coronary artery disease, either undepleted or depleted of CD14 + monocytes. Sham depleted cells were run through an immunomagnetic bead column but were not depleted of any cells.
  • FIG. 4 illustrates TV-DTH responses by splenocytes from ApoE-/-
  • FIG. 5 illustrates TV-DTH responses by splenocytes from ApoE-/- mice to collagen V alone, or in the presence of neutralizing antibodies.
  • FIG. 6A-B illustrate TV-DTH responses to collagen V (FIG. 6A) or tetanus toxoid/diphtheria-tetanus toxoids pediatric vaccine (TTfDT, FIG. 6B) by ApoE-/- mice splenocytes either undepleted or depleted of various cells.
  • FIG. 7 illustrates serum levels of antibodies specific for col(V) in ApoE-/-
  • FIG. 8 illustrates the percent lumen occlusion calculated from aortic root section of col(V) sensitized and untreated ApoE-/- mice.
  • the methods comprise administering to a subject a tolerance-inducing antigenic agent in an amount effective to induce tolerance to collagen V in the subject.
  • the subject is a human or non-human animal having the disease.
  • the goal is to prevent occurrence of the disease, the subject is a healthy human or non-human animal, where healthy is defined relative to this disease.
  • Suitable forms of tolerance-inducing antigenic agent can harbor a continuous- or discontinuous epitope and can include the collagen V protein (GenBank/eMBL Accession No. M76729 and J04478) and individual alpha chains of collagen V, as well as antigenic peptides of collagen V, another antigenic fragment of any of the foregoing, or a polynucleotide encoding any of the foregoing, including the collagen V gene or a portion thereof (GenBank Accession No. NM_000093).
  • the tolerance-inducing antigen is allogeneic, but can be xenogeneic, corresponding to a collagen V protein, a collagen V chain, an antigenic peptide or another antigenic fragment of any of the foregoing from other species.
  • Collagen V is highly conserved among human and non-human species, including mammalian and rodent species.
  • Suitable antigens referred to collectively herein as col(V), can be obtained from bacteria, plants or animals (prokaryotes and eukaryotes) that produce col(V), or fragments thereof, either natively or after being engineered to do so, or can be synthesized de novo.
  • Collagen V and fragments thereof can be obtained from a variety of commercial (e.g., Collaborative Biomedical Products/ Becton, Dickinson and Company, Franklin Lakes, NJ USA) and non-commercial sources and can be further purified or modified, if required.
  • the col(V) is administered to an individual in a manner that induces tolerance towards collagen V.
  • the administration can be parenteral (e.g. injection, infusion), topical (e.g. inhalation, intranasal administration), enteral (e.g. oral-, rectal administration) or in any other manner suitable to induce tolerance.
  • a polynucleotide encoding the tolerance-inducing antigen can be introduced to an individual such as to express the protein or peptide.
  • the composition inducing tolerance to collagen V can be administered once or a plurality of times. The skilled person is familiar with pharmaceutically acceptable formulations suitable for administering the tolerance-inducing antigen to a subject.
  • Collagen V polynucleotide and polypeptide sequences are known to the skilled person and are available in public databases.
  • a "polypeptide” refers to a molecule comprising a sequence of amino acids of any length and with or without post- translational modifications, such as glycosilation, both naturally occurring and artificially created. Polypeptides used in the described methods can span all or portions of a protein. In some embodiments, certain amino acids are substituted in the polypeptide compared to the respective naturally-occurring protein, such that the polypeptide has about 70% to about 100% sequence identity to the naturally occurring protein. Methods for effectuating amino acid substitutions are well known in the art and include site directed mutagenesis.
  • Polypeptides used in the described methods can also be modified to enhance stability or bioavailability using methods well known in the art, such as using alternative bases or peptide backbone linkages. Further, polypeptides can include leader sequences, tags, and/or linkers to direct polynucleotide transfer, facilitate synthesis, identification, and isolation of the polypeptide. Polypeptides used in the described methods can also be fusion polypeptides comprising amino acid sequences from more than one naturally occurring protein or variants thereof. [00027] In some embodiments, a polynucleotide encoding the tolerance-inducing col(V) antigen can be introduced to an individual such as to express the protein or peptide.
  • polynucleotide refers to a molecule comprising a sequence of nucleotides of any length and with or without modifications.
  • Polynucleotides used in the described methods can be obtained from a variety of sources well known in the art, such as through purification and/or amplification from cells or tissues or by artificial synthesis.
  • polynucleotides used in the described methods can comprise naturally occurring sequences or variants thereof, as well as artificial sequences and hybrids of naturally occurring and hybrid sequences.
  • the term "tolerance” refers to an unresponsiveness of an individuals' immune system to a specific antigen. Tolerance can be induced by administering an antigen to an individual through various routes, including administering the antigen intravenously, intramuscularly, subcutaneously, intradermally, orally, and nasally.
  • the antigen can be administered, for example, in form of a polypeptide, a precursor- or pre- polypeptide, a polynucleotide encoding the antigen.
  • Specifically contemplated is the induction of tolerance that results in prevention, suppression, or alleviation of cardiovascular disease, such as atherosclerosis.
  • col(V) administered to an individual can comprise the collagen V homotrimer or fragments thereof.
  • two or more collagen V fragments are administered to an individual, either concurrently as fusion protein or hybrid polynucleotide or sequentially.
  • Example 1 Cells from patients having coronary artery disease (CAD " ) are immunoreactive to CoI(V)
  • CAD coronary artery bypass grafting
  • CABG coronary artery bypass grafting
  • TV-DTH trans vivo delayed type hypersensitivity
  • PBMCs Peripheral blood mononuclear cells
  • TV-DTH Trans vivo delayed type hypersensitivity
  • Antigens were injected into the murine footpad (5 ⁇ g per injection).
  • Purified collagen V from human placenta was prepared as described by Yasufuku et al., Am. J. Resp. Cell MoI. Biol. 25:26-34 (2001), incorporated herein by reference as if set forth in its entirety.
  • Bovine collagen II (BD Biosciences) was a control antigen not found in the cardiovascular system.
  • Inactivated Epstein-Barr virus (EBV) (Viral Antigens Inc., Saco, ME) was a control antigen for adequate immune memory function.
  • EBV Epstein-Barr virus
  • neutralizing antibody against human IFN-gamma, IL- 17, IL-22, IL-lbeta (eBiosciences), and TNF-alpha were coinjected with the antigen.
  • DTH was assessed by measuring the footpad thickness prior to injection
  • Th-17 pathway Consistent with a role of the Th-17 pathway, neutralizing antibodies to IL- 17-induced monokines TNF- ⁇ and IL- l ⁇ consistently blocked the response, as did neutralizing antibodies to IL-22, another cytokine secreted by Th-17 CD4+ T cells. Immunoreactivity was also abolished by depleting CD14 + cells, such as monocytes, from the PBMCs using immunomagnetic beads (MACs beads; Miltenyi Biotec, Bergisch Gladbach, Germany) before conducting the TV-DTH assays (FIG. 3). This result is consistent with a role of the Th-17 pathway in the CAD anti-collagen V response.
  • MACs beads immunomagnetic beads
  • Example 2 Cellular immunity to collagen V in ApoE-/- mice on a high fat diet.
  • mice deficient in the plasma cholesterol-clearing apolipoprotein E have high plasma cholesterol levels and spontaneously develop atherosclerotic lesions, which dramatically increase on high cholesterol/high fat diets.
  • This widely accepted murine model has been demonstrated to be predictive of human atherosclerosis (Lichtman et al., Am. J. Pathol. 149:351-357 (1996); Zhang et al., Science 258:468-471 (1992); Plump et al.
  • mice (strain B6.129P2- ⁇ />oe'"" Wl 7J) and C57BL/6J (B6) control mice having the same genetic background were obtained from Jackson Laboratory (The Jackson Laboratory, Bar Harbor, ME).
  • mice were shifted from a normal diet (Harlan Teklad Rodent Diet 8604, Harlan Laboratories, Inc., Madison, WI) to a high-fat "Western" diet (TD.88137 Adjusted Calories Diet, 42% from fat, Harlan Teklad, Madison, WI). After 15 weeks on the high-fat diet, mice were sacrificed and spleens were collected for TV-DTH assays.
  • mice were immunized with 1 Lf TTfDT pediatric vaccine subcutaneously in the inguinal pouch two weeks prior to harvesting splenocytes.
  • the respective immunoreactivities were averaged from duplicate tests and are shown as individual data points (FIG. 4). Horizontal bars denote group means.
  • Serum samples were analyzed for col(V)-specific antibodies using a bead assay and flow cytometry (FIG. 7).
  • Streptavidin coated beads (5 ⁇ m, binding capacity 10-20 ⁇ g)/l x 10 7 beads - Polyscience, Warrington, PA) were washed in PBS, suspended in 100 ⁇ l of PBS with 40 ⁇ g/ml bovine collagen V (Immune Works, Inc., Indianapolis, IN), and incubated for 60 minutes at 40 0 C. The beads were washed in PBS containing 10% fetal calf serum (FCS) and stored at 40 0 C until use.
  • FCS fetal calf serum
  • Aortic roots from ApoE-/- mice fed a high fat diet displayed the prototypical lesions, while aortic roots from control B6 mice were free of such lesions.
  • the hearts were removed and washed in PBS. The heart was then cut transversely and embedded in O.C.T. Compound (Sakura Finetek USA). Serial sections were cut through the entire aortic sinus and sections were stained with hematoxylin and eosin. Percent vessel occlusion was measured using imaging system by measuring the ratio of the vessel intima area (without plaque) to the vessel lumen area (with plaque) and calculated as the mean of 3 section/sample, each at 50 ⁇ m apart spanning the aortic sinus.
  • ApoE-/- mice fed a high fat diet had a significantly higher percentage of vessel occlusion compared to the B6 control mice fed a high fat diet.
  • CoI(V) is expressed in atherosclerotic lesions of ApoE-/- mice on a high fat diet Collage V was strongly expressed in the intimal and medial layer regions of advanced lesions from ApoE-/- aortae, along with strong expression in some areas of the adventia, whereas B6 control aorta lacked detectable collagen V expression in the intimal and medial layers.
  • Example 4 Collagen V injection exacerbates atherosclerotic burden.
  • Aortic sinuses of ApoE-/- mice that were injected with collagen V had an increased plaque burden, compared to aortic sinuses from untreated ApoE-/- mice.
  • Collagen V-injected ApoE-/- mice also had a significant increase in percent vessel occlusion due to the increased plaque burden, compared to untreated ApoE-/- mice (FIG. 8).
  • collagen V-injected ApoE-/- mice had significantly higher titers of anti-collagen V antibodies in their serum than untreated ApoE-/- control mice.
  • collagen V-injected ApoE-/- mice had significantly greater TV-DTH swelling responses to collagen V.
  • Example 5 (prophetic " ): Reduction of atherosclerosis or effects thereof on subject having atherosclerosis
  • Collagen V a collagen V chain, or a peptide or fragment of any of the foregoing (collectively, "col(V)", or a polynucleotide encoding any of the foregoing is administered to a human or non-human subject having atherosclerosis in a pharmaceutically acceptable carrier such as physiological saline (see, e.g., Yasufuku et al, Am. J. Respir. Cell MoI. Biol. 25:26-342001)) or phosphate buffered saline through an acceptable delivery route (e.g., intra-nasal, oral, or the like) (see, e.g., Carbone et al, Arthritis Rheum.
  • physiological saline see, e.g., Yasufuku et al, Am. J. Respir. Cell MoI. Biol. 25:26-342001
  • phosphate buffered saline through an acceptable delivery route (e.g.,
  • the aforementioned tolerance inducing agent is administered in an amount sufficient to induce immunological tolerance to collagen V in the subject.
  • the status of the subject as having atherosclerosis can be assessed by conventional methods available to physicians.
  • Tolerance to collagen V is monitored by testing PBMCs in a TV-DTH assay essentially as described in Example 1.
  • Example 6 Prevention of atherosclerosis in a subject at risk for atherosclerosis.
  • Collagen V a collagen V chain, or a peptide or fragment of any of the foregoing (collectively referred to as "col(V)" is administered in a pharmaceutically acceptable carrier (e.g., a buffer) via an acceptable delivery route (e.g., parenterally, enterally, or topically, especially by intra-nasal, oral, or similar delivery route) to a human or non- human subject at risk of developing atherosclerosis in an amount sufficient to induce immunological tolerance to collagen V in the subject.
  • a pharmaceutically acceptable carrier e.g., a buffer
  • an acceptable delivery route e.g., parenterally, enterally, or topically, especially by intra-nasal, oral, or similar delivery route
  • the at-risk nature of the subject can be assessed using conventional measures, such as elevated LDL concentration in peripheral blood.
  • Tolerance to collagen V is monitored by testing PBMCs in a TV-DTH assay essentially as described in Example 1, or via a suitable ELISPOT assay. It is observed that the subject does not develop atherosclerosis at a rate that would be expected in the population of subjects sharing the same level of risk.
  • Example 7(prophetic) Anti-collagen V DTH as biomarker of atherosclerosis.
  • Immune system cells (such as PBMCs) from a subject are tested for immunoreactivity to collagen V using a TV-DTH assay, essentially as described in Example 1, or a suitable ELISPOT assay.
  • a subject's risk for developing atherosclerosis is evaluated whereby evidence of immunoreactivity (i.e., a lack of tolerance to collagen V) is associated with a higher risk than would be expected in a subject from whose PBMCs immunoreactivity is not observed.

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Abstract

L’immunoréactivité au collagène V est associée au développement de l’athérosclérose. Les procédés présentement décrits pour moduler l’athérosclérose et réduire un effet de celle-ci, mettent en œuvre l’induction d’une tolérance immunologique au collagène V. La présente invention concerne en outre des procédés pour évaluer le risque qu’un individu développe l’athérosclérose et des procédés pour diagnostiquer l’athérosclérose.
PCT/US2009/065387 2008-11-21 2009-11-20 Procédé pour moduler l'athérosclérose WO2010059975A2 (fr)

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WO2012094463A1 (fr) * 2011-01-05 2012-07-12 Wisconsin Alumni Research Foundation Immunosuppression de voisinage comme moyen de prévision d'une réponse à un vaccin

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EP1676602A1 (fr) * 2005-01-04 2006-07-05 Institut National De La Sante Et De La Recherche Medicale (Inserm) Administration continue d'épitopes derivés de protéinse présentes dans la plaque atèrosclérotique pour le traitement de l'athérosclérose

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012094463A1 (fr) * 2011-01-05 2012-07-12 Wisconsin Alumni Research Foundation Immunosuppression de voisinage comme moyen de prévision d'une réponse à un vaccin
US8603485B2 (en) 2011-01-05 2013-12-10 Wisconsin Alumni Research Foundation Bystander immune suppression as a predictor for response to a vaccine
US9339538B2 (en) 2011-01-05 2016-05-17 Wisconsin Alumni Research Foundation Bystander immune suppression as a predictor for response to a vaccine
US10350291B2 (en) 2011-01-05 2019-07-16 Wisconsin Alumni Research Foundation Bystander immune suppression as a predictor for response to a vaccine

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