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WO2012116210A2 - Peptide pour l'induction d'une immunotolérance en tant que traitement pour le lupus érythémateux disséminé - Google Patents

Peptide pour l'induction d'une immunotolérance en tant que traitement pour le lupus érythémateux disséminé Download PDF

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Publication number
WO2012116210A2
WO2012116210A2 PCT/US2012/026364 US2012026364W WO2012116210A2 WO 2012116210 A2 WO2012116210 A2 WO 2012116210A2 US 2012026364 W US2012026364 W US 2012026364W WO 2012116210 A2 WO2012116210 A2 WO 2012116210A2
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WO
WIPO (PCT)
Prior art keywords
peptide
cells
pcons
amino acid
mammal
Prior art date
Application number
PCT/US2012/026364
Other languages
English (en)
Other versions
WO2012116210A3 (fr
Inventor
Bevra H. Hahn
Brian J. SKAGGS
Ram Raj Singh
Fanny M. Ebling
Antonio La Cava
Ram Pyare Singh
Original Assignee
The Regents Of The University Of California
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Regents Of The University Of California filed Critical The Regents Of The University Of California
Publication of WO2012116210A2 publication Critical patent/WO2012116210A2/fr
Publication of WO2012116210A3 publication Critical patent/WO2012116210A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/542—Mucosal route oral/gastrointestinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/64—Medicinal preparations containing antigens or antibodies characterised by the architecture of the carrier-antigen complex, e.g. repetition of carrier-antigen units
    • A61K2039/645—Dendrimers; Multiple antigen peptides

Definitions

  • At least one amino acid moiety in the peptide is a D-amino acid; and/ or the peptide is in a head-to-tail cyclic configuration; and/ or multiple copies of the peptide are coupled to a polymeric matrix; and the peptide is capable of binding a T lymphocyte and/or modulating the immune response of an animal to whom the peptide is administered.
  • Such embodiments can use the peptide as probe for example to identify the presence of a T lymphocyte in a biological sample as a CD4+CD25- helper T lymphocyte.
  • the peptides of this invention comprising D- form amino acids can be administered, even orally, without protection against proteolysis by stomach proteases, etc.
  • peptide delivery can be enhanced by the use of protective excipients. This is typically accomplished either by complexing the polypeptide with a composition to render it resistant to acidic and enzymatic hydrolysis or by packaging the polypeptide in an appropriately resistant carrier such as a liposome.
  • protective excipients is typically accomplished either by complexing the polypeptide with a composition to render it resistant to acidic and enzymatic hydrolysis or by packaging the polypeptide in an appropriately resistant carrier such as a liposome.
  • Means of protecting polypeptides for oral delivery are well known in the art (see, e.g., U.S. Pat. No. 5,391,377 describing lipid compositions for oral delivery of therapeutic agents).
  • Spleen cells were isolated from saline-treated, naive or tolerized, BWF1 mice one- week after administration of pCons after lysis of red blood cells with ACK lysing buffer (Sigma, St. Louis, MO). Cell subsets were purified by incubation with anti-CD4, anti- B and anti-CD8+, anti NKl.l, anti Mac-3, anti Gr-1, microbeads from (Miltenyi Biotech, Auburn, CA). A total of lx 2 x 10 6 freshly isolated spleen cells or CD8 + T cells were used for staining of cell surface molecules. Antibodies used to analyze the cells included anti-Thyl.2, Anti-CD4, Anti-B220, anti-CD8, anti-CD25 and anti-CD28 (all from BD Pharmingen, San Diego, CA).
  • Isolated cells were washed with FACS buffer and 1-2 million cells were used for surface staining and immunophenotyping. Before staining, cells were incubated with rat anti-mouse CD16/CD32 (FCy III/II receptor) monoclonal antibody to block- nonspecific binding.
  • Stimulatory control peptides B and D are wild peptides from human mAb anti-DNA; peptide A is a nonstimulatory negative control (see, e.g. Kalsi et al., Lupus 2004; 13:490-500).
  • addition of pCons or peptides B and D to cultures of SLE T cells expanded CD4+CD25hi populations in some patients (and in some controls: we have not found a stimulatory Ig peptide that is exclusively recognized by SLE patients).
  • the TGF l Quantikine ELISA kit (R&D Systems, MBIOOB) was utilized to determine serum TGFP levels. 5 ⁇ serum from individual animals in each treatment group at each timepoint were pooled (40 ⁇ total) and acid activated per the manufacturer's directions. Samples were diluted and assayed in duplicate exactly as described by the manufacturer. Prism was used to construct a TGF standard curve and identify unknown sample TGF concentrations. Cumulative TGF levels over all timepoints were graphed using Prism.
  • Prism 4 software (GraphPad) was used for all statistical determinations. Testing between two groups (unfed control or DMSO-fed control versus individual treatment groups) was performed using the Mann- Whitney U test for proteinuria, anti-dsDNA antibody titer, total serum IgG, and TGF concentration. Cox regression was performed for survival curves. R values ⁇ 0.05 were considered significant.
  • pCons peptide variants and feeding schedule We were initially concerned that linear pCons would be sensitive to gut peptidases and proteases, as it is constructed of L-amino acids (see, e.g. Navab et al., Circulation. 2002;105:290-2). Therefore, we utilized a version of pCons in which every amino acid (except for the glycine at position 12) is a D-amino acid (D-pCons). Cyclic peptides such as the immunosuppressant cyclosporine, where the N- and C-termini are linked via a standard peptide bond, are more stable to proteolytic degradation (see, e.g.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Rheumatology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des peptides d'acide aminé comprenant la séquence FIEWNKLRFRQGLEW et leur utilisation dans des procédés pour le diagnostic et/ou le traitement de troubles immunitaires tels que le lupus érythémateux disséminé. Typiquement, au moins un fragment d'acide aminé dans le peptide est un acide aminé D ; et/ou le peptide est dans une configuration cyclique tête à queue ; et/ou des copies multiples du peptide sont couplées à une matrice polymère non immunogène telle que la polylysine (en tant que peptide antigène multiple ou MAP). Typiquement, le peptide est capable d'inhiber la production d'auto-anticorps qui se lient à de l'ADN bicaténaire chez un mammifère ayant le lupus érythémateux disséminé (SLE).
PCT/US2012/026364 2011-02-23 2012-02-23 Peptide pour l'induction d'une immunotolérance en tant que traitement pour le lupus érythémateux disséminé WO2012116210A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161445769P 2011-02-23 2011-02-23
US61/445,769 2011-02-23

Publications (2)

Publication Number Publication Date
WO2012116210A2 true WO2012116210A2 (fr) 2012-08-30
WO2012116210A3 WO2012116210A3 (fr) 2013-01-31

Family

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Family Applications (1)

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PCT/US2012/026364 WO2012116210A2 (fr) 2011-02-23 2012-02-23 Peptide pour l'induction d'une immunotolérance en tant que traitement pour le lupus érythémateux disséminé

Country Status (1)

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WO (1) WO2012116210A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019174104A1 (fr) * 2018-03-13 2019-09-19 江苏浩欧博生物医药股份有限公司 Kit de mesure d'un anticorps anti-peptide citrulliné cyclique, son application et procédé de test

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7081242B1 (en) * 1999-11-28 2006-07-25 La Jolla Pharmaceutical Company Methods of treating lupus based on antibody affinity and screening methods and compositions for use thereof
US7501132B2 (en) * 1998-03-02 2009-03-10 The United States Of America As Represented By The Department Of Health And Human Services Multiple antigenic peptides immunogenic against Streptococcus pneumonia
US20100234302A1 (en) * 2007-10-17 2010-09-16 The Regents Of The University Of California Peptide for induction of immune tolerance as treatment for systemic lupus erythematosus
US20110028409A1 (en) * 2009-07-31 2011-02-03 Toscana Biomarkers S.R.L. Detection of anti-ribosomal p protein antibodies by means of synthetic peptides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7501132B2 (en) * 1998-03-02 2009-03-10 The United States Of America As Represented By The Department Of Health And Human Services Multiple antigenic peptides immunogenic against Streptococcus pneumonia
US7081242B1 (en) * 1999-11-28 2006-07-25 La Jolla Pharmaceutical Company Methods of treating lupus based on antibody affinity and screening methods and compositions for use thereof
US20100234302A1 (en) * 2007-10-17 2010-09-16 The Regents Of The University Of California Peptide for induction of immune tolerance as treatment for systemic lupus erythematosus
US20110028409A1 (en) * 2009-07-31 2011-02-03 Toscana Biomarkers S.R.L. Detection of anti-ribosomal p protein antibodies by means of synthetic peptides

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019174104A1 (fr) * 2018-03-13 2019-09-19 江苏浩欧博生物医药股份有限公司 Kit de mesure d'un anticorps anti-peptide citrulliné cyclique, son application et procédé de test

Also Published As

Publication number Publication date
WO2012116210A3 (fr) 2013-01-31

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