WO2000002920A1 - Inhibition de la formation de lipoproteines - Google Patents

Inhibition de la formation de lipoproteines Download PDF

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Publication number
WO2000002920A1
WO2000002920A1 PCT/NZ1999/000109 NZ9900109W WO0002920A1 WO 2000002920 A1 WO2000002920 A1 WO 2000002920A1 NZ 9900109 W NZ9900109 W NZ 9900109W WO 0002920 A1 WO0002920 A1 WO 0002920A1
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Prior art keywords
peptide
lipoprotein
amino acid
sequence
formation
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PCT/NZ1999/000109
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English (en)
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Sally Priscilla Anna Mccormick
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University Of Otago
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Priority to AU52006/99A priority Critical patent/AU5200699A/en
Publication of WO2000002920A1 publication Critical patent/WO2000002920A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/775—Apolipopeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to inhibition of lipoprotein(a) formation.
  • it relates to peptides and antibodies which have the capability of at least partially inhibiting the formation of lipoprotein(a) .
  • Lipoprotein(a) is a cholesterol-rich lipoprotein formed in human plasma by the linkage of apolipoprotein (apo) B, on a low density lipoprotein (LDL) particle, to apo(a) (Utermann (1989), McLean et al (1987)). Elevated levels of lipoprotein (a) have recently been identified as an independent risk factor for developing atherosclerosis.
  • lipoprotein(a) The atherogenic nature of lipoprotein(a) is supported by its presence in human atherosclerotic tissue (Rath et al (1989), Cushing et al (1989)) and by many human studies that show a positive link between high plasma lipoprotein (a) levels and the risk of developing heart disease (Dahlen et al (1986), Kostner et al (1981), Berg et al
  • the general object of this invention is therefore to provide a molecule that will at least partially inhibit lipoprotein (a) formation and hence have the potential to be used as a lipoprotein (a) -lowering agent.
  • lipoprotein(a) is formed in circulation after independent secretion of LDL and apo(a) from the liver (Chiesa et al (1992), White (1995)). It is generally accepted that the linkage of apoB to apo(a) is a two-step process (Trieu et al (1995), Brunner et al (1993)). The first step is an initial noncovalent binding of apoB to apo (a), while the second step is the formation of a disulphide bridge between apo(a)Cys4057 and apoBCys4326.
  • the invention provides a peptide which at least partially inhibits lipoprotein(a) formation which comprises the following amino acid sequence:
  • Ri, R 2 , R3 and R 4 are each independently selected from lysine, arginine and histidine, and wherein each X is an amino acid other than lysine, arginine or histidine.
  • Ri, R 2 , R3 and R 4 are each lysine.
  • Ri, R 2 , R3 and R 4 are each arginine.
  • the invention provides a peptide which at least partially inhibits lipoprotein (a) formation which comprises the following amino acid sequence:
  • the invention provides a peptide which has an alpha- helical structure and which comprises the following amino acid sequence:
  • X is any amino acid other than lysine, and wherein said peptide is capable of at least partially inhibiting lipoprotein (a) formation.
  • the invention provides a peptide which is at least 21 amino acid residues in length, which forms an alpha- helical structure with four surface residues independently selected from lysine, arginine or histidine and which is capable of at least partially inhibiting lipoprotein(a) formation.
  • the peptide includes four surface lysine residues.
  • the peptide includes four surface arginine residues.
  • the invention provides a polynucleotide which encodes a peptide as defined above.
  • the invention provides antibodies which bind to a peptide as defined above and which at least partially inhibit lipoprotein (a) formation.
  • the invention provides antibodies which bind to the region spanning amino acids 4372 to 4392 of apoB.
  • the invention provides an anti-idiotypic antibody which mimics the conformation of the region spanning amino acids 4372 to 4392 of apoB.
  • the invention provides a medicament which comprises a peptide or antibody as defined above in a pharmaceutically acceptable form, said peptide or antibody being present in an amount sufficient to inhibit lipoprotein (a) formation.
  • the invention provides for the use of a peptide or antibody as defined above in the manufacture of a lipoprotein(a) lowering medicament.
  • the invention provides a method of lowering lipoprotein(a) levels in plasma in a patient comprising the step of administering to said patient an amount of a peptide, antibody or medicament as defined above which is effective to at least partially inhibit new lipoprotein(a) formation.
  • the invention provides a method of lowering lipoprotein (a) levels in a patient comprising the step of preventing or reducing the non-covalent binding of apoB region apoB 4372-4392 to apo(a).
  • Figure 1 shows a strategy to disrupt lipoprotein(a) formation using a synthetic apoB peptide.
  • the two step model of lipoprotein (a) assembly is shown.
  • surface lysine residues in the apoB4372-4392 region bind to lysine-binding sites on the apo(a) molecule bringing the apoBCys4326 and apo(a)Cys4057 residues in close proximity.
  • Lipoprotein (a) assembly is completed in the second step with the formation of a disulphide bond between the two cysteines.
  • the strategy followed in the present invention was to introduce a synthetic apoB peptide spanning apoB4372-4392 to compete with the apoB molecule for binding to apo (a) and therefore inhibit the first step of lipoprotein (a) assembly.
  • Figure 2 shows the predicted alpha helix formed by the apoB602 peptide.
  • Computer analysis of the apoB602 sequence using the HELICALWHEEL programme predicts an amphipathic alpha helix. Hydrophobic resides (shown boxed) are predicted to be buried in the lipid phase while the hydrophilic resides project into the aqueous phase. Two sets of paired lysine residues (K) are located on opposite sides of the lipid/ aqueous interface.
  • Figure 3 shows the Western blots of lipoprotein (a) formation in incubations containing apoB synthetic peptides.
  • Figure 4 shows inhibition of lipoprotein(a) formation by apoB peptides.
  • the ability of the apoB peptides to inhibit lipoprotein (a) formation in vitro was quantified using a sandwich enzyme-linked immunoassay (ELISA).
  • ELISA sandwich enzyme-linked immunoassay
  • Increasing amounts of peptide (from 0 to 200 ⁇ M) were added to incubations containing l ⁇ l of apo(a) and l ⁇ l of apoB transgenic mouse plasma.
  • the amount of lipoprotein (a) formed in each incubation was quantified in triplicate with a sandwich ELISA.
  • Sigmoidal curves were fitted to all data points for each peptide in the Microsoft Excel programme and IC50 values were derived for each peptide.
  • Figure 5 shows the half-life of peptide apoB602 in mice.
  • the half-life of radiolabelled apoB602 was calculated in wildtype and transgenic mice. 125 I-radiolabelled peptide was injected into mice and an initial total cpm was calculated from time zero plasma samples. Blood samples were then taken at set time points and the percent of the initial total cpm was calculated for each time point. These percentages were graphed on a logio scale against time. The decay lines were used to calculate the half-lives in wildtype and transgenic mice.
  • the primary focus of the invention is on proteins which are capable of at least partially inhibiting the formation of lipoprotein(a) .
  • This inhibitory function makes the proteins suitable for use in the lowering of lipoprotein(a) levels in plasma.
  • the proteins are peptides.
  • the peptides of the invention are generally at least 21 amino acid residues in length. They may have a number of amino acid sequences.
  • Ri, R 2 , R3 and R 4 are each independently selected from lysine, arginine and histidine, and each X is an amino acid other than lysine, arginine or histidine.
  • Another amino acid sequence is as follows:
  • each X can be any amino acid other than lysine, more preferably any amino acid other than lysine, arginine or histidine.
  • Still another such amino acid sequence is:
  • the peptide of this invention is believed to form an alpha-helical structure, usually with four lysine residues as paired surface residues.
  • One or more of the lysine residues can however be replaced by arginine or histidine residue(s).
  • the present invention also contemplates functional equivalents of the specific peptide sequences above.
  • Such functional equivalents are those in which individual amino acid residues from within the specific sequence are replaced by other individual amino acid residues without substantially affecting the functionality of the resulting peptide as an inhibitor of lipoprotein (a) formation.
  • lysine residues can be replaced by arginine residues.
  • a peptide in which all four lysine residues are replaced to give four arginine surface residues is a preferred (and functionally equivalent) variant.
  • This peptide has the sequence:
  • the peptide of the invention will not generally have less than 21 amino acid residues but can have more. Longer sequences (containing, for example, from 22 to 40 amino acids) which form stable alpha- helical structures are expressly contemplated.
  • the peptides can also be provided as dimers or trimers of smaller peptides, such as dimers or trimers of the 21 amino acid peptide above.
  • the peptides can be prepared using any conventional approach. Such methods include protein synthesis from individual amino acids as described by Stuart and Young in “Solid Phase Peptide Synthesis", Second Edition, Pierce Chemical Company (1984). This is the presently preferred preparative route given the short length of the peptides, although it is by no means intended that other synthetic routes (including recombinant expression if appropriate) are excluded. Should that be required, standard techniques can be employed as are generally described by Sambrook et al ( 1987) .
  • polynucleotides which encode the peptides are provided.
  • the precise nucleotide sequence of the polynucleotides will vary depending upon the amino acid sequence of the peptide to be expressed as well as the degeneracy of the nucleic acid code.
  • an exemplary polynucleotide according to the invention is the following:
  • the peptides of the invention can be formulated into medicaments.
  • medicaments can include solid dosage forms or liquid dosage forms, whichever is appropriate.
  • the medicament will contain pharmaceutically acceptable carriers, excipients, and be prepared by any conventional approach.
  • Injectable formulations are presently preferred, although many other formulations which provide for delivery of the peptides in an active form (such as oral formulations including microencapsulated peptides and transdermal patches and the like) are also applicable.
  • the dosage of peptide employed will be dependent upon the peptide and the selected route of administration. Determination of a specific dosage will be routine to the art-skilled worker in this field.
  • Antibodies to the apoB 4372-4392 region are also proteins provided by this invention.
  • Such antibodies can be polyclonal but will preferably be monoclonal antibodies.
  • Monoclonal antibodies with affinities of 10 8 M 1 or preferably 10 9 to 10- l o M-i or stronger will typically be made by standard procedures as described, eg. in Harlow & Lane (1988). Briefly, appropriate animals will be selected and the desired immunization protocol followed. After the appropriate period of time, the spleens of such animals are excised and individual spleen cells fused, typically, to immortalised myeloma cells under appropriate selection conditions. Thereafter, the cells are clonally separated and the supernatants of each clone tested for their production of an appropriate antibody specific for the desired region.
  • recombinant immunoglobulins may be produced using procedures known in the art (see, for example, US Patent 4,816,567 and Hodgson (1991)).
  • Anti-idiotypic antibodies raised against antibodies to the apoB 4372-4392 region are also contemplated. Such anti-idiotypic antibodies will mimic the conformation of the region. These antibodies have applications equivalent to the peptides discussed above in inhibiting lipoprotein (a) formation.
  • the apoB602 peptide corresponds to amino acids 4372-4392 in the apoB carboxyl- terminus. Arg 602 spans the same sequence, however includes replacement of all four lysines in the apoB602 sequence with arginine residues.
  • the Scram602 peptide is a scrambled version of the apoB602 sequence and apoB602L peptide is a longer version of the apoB602 peptide spanning the entire predicted alpha helix in this region (Segrest et al (1998). All four apoB peptides were chemically synthesised using the solid phase method (Valerio et al (1994)) by Chiron Technologies (Clayton, Australia).
  • the peptides were lyophilised and stored in the dark under vacuum until use. To prepare the peptides for the lipoprotein (a) formation assays all peptides were either dissolved in 0. 1% acetic acid or sterile saline.
  • the human apo(a) used for the in vitro lipoprotein(a) formation assays was obtained from the plasma of transgenic mice expressing human apo(a) (Chiesa et al (1992)).
  • the human apoB was obtained from the plasma of transgenic mice expressing human apoBlOO (Linton et al (1993)).
  • peptides were tested for their effect on lipoprotein(a) formation in a standard Western blot-based lipoprotein (a) formation assay (McCormick et al (1994)). An increasing amount of peptide (from 0 to 280 ⁇ M) was added to incubations containing human apo(a) from transgenic mouse plasma (1.0 ⁇ L) and human apoBlOO from transgenic mouse plasma (2.0 ⁇ L, equivalent to approximately l ⁇ g of apoB). Incubations were performed in duplicate in 0. 15M NaCl in a total volume of 40 ⁇ L for 3 hours at 37°C.
  • the incubations were subjected to electrophoresis on SDS-4% polyacrylamide gels under non-reducing conditions and the separated proteins transferred to nitrocellulose.
  • Western blot analysis was performed with the human apo (a) -specific monoclonal antibody al- 1 (Marcovina et al (1995)) conjugated to horse-radish peroxidase.
  • the amount of lipoprotein(a) formed in each incubation was visualised after detection with Enhanced Chemiluminesence reagents (Amersham Corp.).
  • apoB peptides to inhibit lipoprotein (a) formation in vitro was quantified using an sandwich enzyme-linked immunoassay (ELISA) performed in 96 well ELISA plates. Increasing amounts of peptide (from 0 to 200 ⁇ M) were added to incubations containing l ⁇ l of apo (a) and l ⁇ l of apoB transgenic mouse plasma. In separate incubations, increasing amounts of a lysine analogue, ⁇ -amino caproic acid (0- lOOmM) were added. Incubations were performed in PBS containing 2% BSA for 3 hours at 37°C.
  • ELISA sandwich enzyme-linked immunoassay
  • the amount of lipoprotein (a) formed in each incubation was quantified in triplicate with an sandwich ELISA which uses an apo(a)-specific 'capture' and an apoB-specific 'detection' monoclonal antibody. Plates were developed after incubation with an HRP-labelled anti-mouse IgG Antibody. Controls to quantify background binding included incubations containing apo (a) or apoB only, as well as apo(a)/apoB incubations containing 100 nM ⁇ -amino caproic acid which completely inhibits lipoprotein(a) formation (Chiesa et al (1992)). Sigmoidal curves were fitted to all data points for each peptide in the Microsoft Excel programme and IC50 values were derived for each peptide.
  • Lipoprotein(a) formation assays To test the peptides for their ability to inhibit lipoprotein (a) formation in vitro, the peptides were placed into a standard lipoprotein (a) formation assay and measured by two separate methods; a Western-blot based method which visualises the amount of lipoprotein (a) and free apo(a) in the incubations; and a sandwich ELISA which quantifies the amount of lipoprotein(a) formed in each incubation. Results from Western blot analysis (Figure 3) showed the arg 602 peptide to be the most effective inhibitor of lipoprotein(a) formation in vitro, showing almost complete inhibition of lipoprotein(a) formation at around 33 ⁇ M.
  • apoB4372-4392 The focus of the above work is a peptide which comprises a highly conserved stretch of 21 amino acids (apoB4372-4392). It is believed that the peptide mimics the natural apo (a) binding site on the apoB molecule and competes with native apoB for binding to apo (a).
  • apoB602 lipoprotein (a) formation was tested in a standard lipoprotein (a) formation assay. The results indicate that the apoB602 peptide is an effective inhibitor of lipoprotein (a) formation. Lipoprotein (a) formation was almost completely inhibited in incubations containing 70 ⁇ m of the apoB602 peptide. A control peptide (scram602) containing the same sequence, only scrambled, had no effect on lipoprotein (a) formation. Structural analysis of the apoB602 peptide predicts that the sequence forms an alpha helix.
  • This region of apoB is contained within apoB sequences previously found to form a class A alpha helix and constituting an important lipid-binding site (Segrest et al (1998)).
  • a striking feature of the alpha helix formed by the apo4372- 4392 sequence is the presence of paired lysine residues on opposite sides of the interface between the lipid and aqueous phases. Lysine residues have been implicated in the first step of lipoprotein(a) assembly since lysine analogues can block the formation of lipoprotein(a) in vitro. The results obtained suggest that the alpha helix containing paired surface ly sines forms an important binding motif that binds to the lysine binding sites in apo(a).
  • the alpha helix and presence of lysine residues in this putative apo(a) binding site are both important structural features.
  • the scram 602 peptide sequence disrupts both features and renders the peptide inactive as an lipoprotein (a) inhibitor.
  • the arg602 peptide proved to be an even more effective inhibitor than the apoB602 peptide in both the Western blot and ELISA assays. These results show clearly that replacement of one positively charged amino acid residue (lysine) with another (arginine) can be effected without substantially affecting functionality of the peptide.
  • the alpha helical structure is however expected to be retained in the arg602 peptide.
  • the in vivo stability of peptide 602 was measured in both wildtype and apo (a) transgenic mice.
  • Two C57/B16 male wild-type mice and two apo(a) transgenic male mice were injected via the tail vein with 125 I-radiolabelled peptide (5 x 10 5 counts per mouse) diluted in 0. 15M sterile NaCl.
  • Blood samples were collected from the mice at times 0, 10 min, 30 min, 1 hr, 2 hrs, 4 hrs, 8hrs and 24hrs. Aliquots (40 ⁇ l) of blood taken at each time point, were centrifuged, and the plasma was measured for radioactivity in a gamma counter. The percent of the initial total radioactivity (in cpm) was then calculated at each time point. The logio of the % total cpm was then plotted against time. The half-lives of peptide apoB602 in both wildtype and transgenic mice was then calculated from the slope of the decay line.
  • proteins having the capability of at least partially inhibiting the formation of lipoprotein(a).
  • This inhibitory function means that the peptides and antibodies of the invention and the medicaments containing them have utility as lipoprotein (a) lowering agents. In turn, this has important implications in the strategy for preventing or treating diseases such as atherosclerosis.

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Abstract

Protéines qui sont des inhibiteurs efficaces de la formation de lipoprotéine(s), généralement sous forme de peptides qui correspondent à la région apoB 4372 à 4392 ou d'anticorps qui se lient à cette région. Des médicaments qui contiennent ces peptides ou anticorps sont également décrits. Les protéines et médicaments selon la présente invention sont utiles en thérapie, dont le traitement de l'athérosclérose.
PCT/NZ1999/000109 1998-07-13 1999-07-13 Inhibition de la formation de lipoproteines WO2000002920A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1918300A2 (fr) * 2001-04-05 2008-05-07 Forskarpatent I Syd Ab Thérapie d'immunisation à base de peptide pour le traitement d'athérosclérose
US7785589B2 (en) 2001-04-05 2010-08-31 Forskarpatent I Syd Antibodies against a peptide epitope of apolipoprotein B
US8114966B2 (en) 2002-10-04 2012-02-14 Forskarpatent I Syd Ab Peptide-based passive immunization therapy for treatment of atherosclerosis
US8119590B2 (en) 2001-09-28 2012-02-21 Cedars-Sinai Medical Center Prevention and treatment of restenosis by local administration of drug
US8926958B2 (en) 2004-04-06 2015-01-06 Cedars-Sinai Medical Center Prevention and treatment of vascular disease with recombinant adeno-associated virus vectors encoding apolipoprotein A-I and apolipoprotein A-I milano
US9205141B2 (en) 2010-11-12 2015-12-08 Cardio Vax, Llc Immunomodulatory methods and systems for treatment and/or prevention of hypertension
US9205139B2 (en) 2010-11-12 2015-12-08 Cardiovax, Llc Immunomodulatory methods and systems for treatment and/or prevention of aneurysms

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WO1997043311A1 (fr) * 1996-05-09 1997-11-20 University College London Fragments peptidiques anticoagulants derives de l'apolipoproteine b-11
WO1998056938A1 (fr) * 1997-06-13 1998-12-17 Baylor College Of Medicine Lipoproteines utilisees comme vecteurs d'acide nucleique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997043311A1 (fr) * 1996-05-09 1997-11-20 University College London Fragments peptidiques anticoagulants derives de l'apolipoproteine b-11
WO1998056938A1 (fr) * 1997-06-13 1998-12-17 Baylor College Of Medicine Lipoproteines utilisees comme vecteurs d'acide nucleique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEN S.H. ET AL: "The complete cDNA and amino acid sequence of human apolipoprotein B-100", J. BIOL. CHEM., vol. 261, 1986, pages 12918 - 12921 *
KNOTT T.J. ET AL: "Human apolipoprotein B: structure of carboxyl-terminal domains, sites of gene expression and chromosomal localization", SCIENCE, vol. 230, 1985, pages 37 - 43 *
MAEDA N. ET AL: "Molecular genetics of the apolipoprotein B gene in pigs in relation to atherosclerosis", GENE, vol. 70, 1988, pages 213 - 229 *

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1918300A2 (fr) * 2001-04-05 2008-05-07 Forskarpatent I Syd Ab Thérapie d'immunisation à base de peptide pour le traitement d'athérosclérose
EP1918300A3 (fr) * 2001-04-05 2009-06-17 Forskarpatent I Syd Ab Thérapie d'immunisation à base de peptide pour le traitement d'athérosclérose
EP2147928A3 (fr) * 2001-04-05 2010-04-14 Forskarpatent I Syd Ab Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2147680A3 (fr) * 2001-04-05 2010-04-14 Forskarpatent i Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2147929A3 (fr) * 2001-04-05 2010-04-14 Forskarpatent i Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2147930A3 (fr) * 2001-04-05 2010-04-14 Forskarpatent i Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
US7785589B2 (en) 2001-04-05 2010-08-31 Forskarpatent I Syd Antibodies against a peptide epitope of apolipoprotein B
EP2289922A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289919A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289915A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I SYD AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289925A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289929A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289917A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I SYD AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289920A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289924A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289914A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289913A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289930A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289918A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I SYD AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289923A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289931A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289912A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289928A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289926A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289921A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289927A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289932A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289933A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289934A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289935A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2289916A1 (fr) * 2001-04-05 2011-03-02 Forskarpatent I SYD AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2295460A1 (fr) * 2001-04-05 2011-03-16 Forskarpatent I SYD AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2295461A1 (fr) * 2001-04-05 2011-03-16 Forskarpatent I SYD AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2295463A1 (fr) * 2001-04-05 2011-03-16 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2295458A1 (fr) * 2001-04-05 2011-03-16 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2295457A1 (fr) * 2001-04-05 2011-03-16 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2295459A1 (fr) * 2001-04-05 2011-03-16 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2295464A1 (fr) * 2001-04-05 2011-03-16 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2295462A1 (fr) * 2001-04-05 2011-03-16 Forskarpatent I SYD AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2305708A1 (fr) * 2001-04-05 2011-04-06 Forskarpatent I SYD AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2305706A1 (fr) * 2001-04-05 2011-04-06 Forskarpatent I SYD AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
EP2305707A1 (fr) * 2001-04-05 2011-04-06 Forskarpatent I Syd AB Thérapie d'immunisation à base de peptides pour le traitement de l'athérosclérose et développement d'un dosage à base de peptides pour la détermination des réponses immunes contre une lipoprotéine oxydée à basse densité
US8025876B2 (en) 2001-04-05 2011-09-27 Forskarpatent I Syd Antibodies against a peptide epitope of apolipoprotein B
US8029786B2 (en) 2001-04-05 2011-10-04 Forskarpatent I Syd Antibodies against a peptide epitope of apolipoprotein B
US8034336B2 (en) 2001-04-05 2011-10-11 Forskarpaten I SYD Antibodies against a peptide epitope of apoliprotein B
USRE43581E1 (en) 2001-04-05 2012-08-14 Forskarpatent I Syd Ab Peptide epitopes of apolipoprotein B
US8470768B2 (en) 2001-04-05 2013-06-25 Cedars-Sinai Medical Center Peptide epitopes of apolipoprotein B
US8642726B2 (en) 2001-04-05 2014-02-04 Cardiovax, Llc Peptide epitopes of apolipoprotein B
US8642043B2 (en) 2001-04-05 2014-02-04 Cardiovax, Llc Peptide epitopes of apolipoprotein B
US8647628B2 (en) 2001-04-05 2014-02-11 Cardiovax, Llc Peptide epitopes of apolipoprotein B
US8119590B2 (en) 2001-09-28 2012-02-21 Cedars-Sinai Medical Center Prevention and treatment of restenosis by local administration of drug
US8114966B2 (en) 2002-10-04 2012-02-14 Forskarpatent I Syd Ab Peptide-based passive immunization therapy for treatment of atherosclerosis
US8926958B2 (en) 2004-04-06 2015-01-06 Cedars-Sinai Medical Center Prevention and treatment of vascular disease with recombinant adeno-associated virus vectors encoding apolipoprotein A-I and apolipoprotein A-I milano
US9205141B2 (en) 2010-11-12 2015-12-08 Cardio Vax, Llc Immunomodulatory methods and systems for treatment and/or prevention of hypertension
US9205139B2 (en) 2010-11-12 2015-12-08 Cardiovax, Llc Immunomodulatory methods and systems for treatment and/or prevention of aneurysms

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