WO2011101870A1 - Protéines de fusion utilisées pour le traitement de la sclérose en plaques et d'autres maladies auto-immunes - Google Patents

Protéines de fusion utilisées pour le traitement de la sclérose en plaques et d'autres maladies auto-immunes Download PDF

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Publication number
WO2011101870A1
WO2011101870A1 PCT/IN2011/000105 IN2011000105W WO2011101870A1 WO 2011101870 A1 WO2011101870 A1 WO 2011101870A1 IN 2011000105 W IN2011000105 W IN 2011000105W WO 2011101870 A1 WO2011101870 A1 WO 2011101870A1
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WO
WIPO (PCT)
Prior art keywords
seq
myelin
specific antibodies
fusion protein
targeting
Prior art date
Application number
PCT/IN2011/000105
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English (en)
Inventor
Koteswara Rao Kollipara
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Transgene Biotek Ltd.
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Publication date
Application filed by Transgene Biotek Ltd. filed Critical Transgene Biotek Ltd.
Publication of WO2011101870A1 publication Critical patent/WO2011101870A1/fr

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Classifications

    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4713—Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • G01N33/5044—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 involving specific cell types
    • G01N33/5047—Cells of the immune system
    • G01N33/5052—Cells of the immune system involving B-cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/55—Fusion polypeptide containing a fusion with a toxin, e.g. diphteria toxin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/285—Demyelinating diseases; Multipel sclerosis

Definitions

  • the present invention generally relates to the field of immunotherapy, and more particularly to fusion proteins for the treatment of Multiple Sclerosis.
  • Antibody-secreting B lymphocytes are in the focus in relation to autoimmune diseases, because of their central role in the induction and maintenance of inflammatory reactions.
  • Multiple sclerosis is an inflammatory demyelinating autoimmune disease of the central nervous system. MS is triggered by the body's own immune system attacking the myelin sheath around the axons.
  • Auto reactive T cells CD8+ and CD4+ cells
  • CD8+ and CD4+ cells in genetically disposed persons initiate the inflammatory process and through their pro inflammatory cytokines secretion, activate the auto reactive B lymphocytes to secrete myelin specific antibodies.
  • the principal object of this invention is to provide a method of treatment for multiple sclerosis using the immunotoxin (or fusion protein) comprising Myelin Binding Protein fragment, Myelin Oligodendrocyte Glycoprotein fragment and a cytotoxic fragment, wherein the cytotoxic fragment may be a diphtheria toxin fragment or an Fc fragment of a IgG.
  • Another object of the invention is to provide a method of treatment for multiple sclerosis by targeting and killing B cells displaying myelin specific antibodies.
  • Another object of this invention is to provide a method for killing B cells displaying myelin specific antibodies by administering a fusion protein of SEQ ID NO:2 (TBLMS1 ) and/or fusion protein of SEQ ID NO:4 (TBLMS2) which comprises of Myelin Binding Protein fragment, Myelin Oligodendrocyte Glycoprotein fragment, and cytotoxic fragment.
  • TLMS1 fusion protein of SEQ ID NO:2
  • TLMS2 fusion protein of SEQ ID NO:4
  • the invention provides a fusion protein comprising Myelin Binding Protein fragment, a Myelin Oligodendrocyte Glycoprotein fragment and a cytotoxic fragment which is characterized in that to target and kill B cells displaying myelin specific antibodies, wherein the cytotoxic fragment may be AB chain of diphtheria toxin or Fc fragment of lgG.
  • TLMS1 polypeptide sequence of SEQ ID NO: 2
  • TLMS2 polypeptide sequence of SEQ ID NO: 4
  • the invention provides a vector comprising at least one polynucleotide sequence of SEQ ID NO: 1 and SEQ ID NO: 3.
  • the invention provides a pharmaceutical composition comprising at least one polypeptide sequence of SEQ ID NO: 2 and SEQ ID NO: 4, and a pharmaceutically acceptable carrier.
  • the invention provides a method of killing B cells displaying myelin specific antibodies comprising contacting said B cells with at least one polypeptide sequence selected from the group consisting of SEQ ID NO: 2 and SEQ ID NO: 4.
  • the invention provides a method of treating multiple sclerosis comprising administering to a patient therapeutically effective amount of at least one polypeptide sequence of SEQ ID NO: 2 and SEQ ID NO: 4.
  • the invention provides a diagnostic method for diagnosing the presence of myelin specific B cells in a sample, wherein the diagnostic method comprises of contacting the sample with at least one polypeptide sequence selected from the group consisting of SEQ ID NO: 2 and SEQ ID NO: 4 under conditions that allow for formation of a complex between said polypeptide sequence and B cell, and detecting the formation of the complex.
  • the invention provides a diagnostic kit for detecting the presence of myelin specific B cells in a sample, wherein said diagnostic kit comprises of at least one polypeptide sequence selected from the group consisting of SEQ ID NO: 2 and SEQ ID NO: 4.
  • Fig. 1A (also referred to as SEQ ID NO:l) is a diagram depicting the nucleotide sequence of the fusion protein, TBLMS1
  • Fig. IB (also referred to as SEQ ID NO:2) is a diagram depicting the amino acid sequence of the fusion protein, TBLMS1
  • Fig. 2A (also referred to as SEQ ID NO:3) is a diagram depicting the nucleotide sequence of the fusion protein, TBLMS2
  • Fig. 2B (also referred to as SEQ ID NO:4) is a diagram depicting the amino acid sequence of the fusion protein, TBLMS2
  • the focus of the disclosed embodiments is to bring down the myelin antigens specific humoral responses through removal of myelin specific B lymphocytes. Removal of these auto reactive B cells will have a dual impact on disease progression. The immediate effect would be lowering of Myelin specific B lymphocytes and the specific antibodies. As the myelin specific B lymphocytes support and maintain myelin specific CD4+ T lymphocyte functions, the removal of these B lymphocytes will lead to lowering of myelin specific CD4+ T lymphocytes as well. Therefore, eventually, there will be diminished humoral and cell mediated attack on the myelin sheath.
  • MS is being treated with general immune suppression drugs or drugs that prevent infiltration of circulating T and B cells into the CNS.
  • the former therapy can lead to general immune deficiency and the later on compromising of regular T and B cell surveillance of the CNS.
  • the embodiments disclosed herein provide selective removal of the myelin specific B cells without harming other cells of the immune system and therefore circumvent the problems associated with the current medical interventions.
  • the embodiments herein disclose designs of therapeutic molecules for the treatment of multiple sclerosis. It aims at removal of myelin antigen specific auto antibodies producing B cells only and thereby effectively brings down the auto reactive B cell and also the auto reactive T lymphocyte populations.
  • the unique design of the therapeutic molecules allow them to target all MBP, MOG reactive B cells without affecting other antibody producing B cells or any other cells of the immune system, thereby being highly target specific.
  • the fusion proteins described herein may also be used to treat autoimmune disease such as Crohn's disease, Rheumatoid arthritis, etc. Fusion proteins
  • the therapeutic molecule is a fusion protein referred to as TBLMS1.
  • TBLMS1 is a bi-specific immunotoxin molecule comprising a targeting domain and a cytotoxic fragment.
  • the targeting domain of TBLMS1 comprises of an MOG fragment and an MBP fragment
  • the cytotoxic fragment of TBLMS1 comprises of a truncated diphtheria toxin fragment.
  • the truncated diphtheria toxin may comprise of A chain, B chain or A and B chain of diphtheria toxin.
  • the diphtheria toxin fragment comprises of the A and B chain of Diphtheria toxin.
  • the therapeutic molecules described herein can be produced and isolated by various methods familiar to those skilled in the art, such as recombinant DNA methods.
  • the therapeutic molecule is a fusion protein referred to as TBLMS2.
  • TBLMS2 is a bi-specific immunotoxin molecule comprising a targeting domain and a cytotoxic fragment.
  • the targeting domain of TBLMS2 comprises of an MOG fragment and an MBP fragment
  • the cytotoxic fragment of TBLMS2 comprises of the Fc fragment of an immunoglobulin.
  • the cytotoxic fragment is Fc fragment of IgG.
  • the therapeutic molecules described herein can be produced and isolated by various methods familiar to those skilled in the art, such as recombinant DNA methods.
  • Fig. 1A (also referred to as SEQ ID NO: l) is the nucleotide sequence of TBLMS1 which is a design of the bi-specific immunotoxin molecule that can specifically target MBP as well as MOG antibody producing B cells.
  • the targeting domain is a fusion of extracellular domains of MOG and MBP that is linked to the diphtheria toxin by a linker sequence. This design is well suited for expression in E.coli, mammalian cells or yeast as a monomer.
  • the targeting domain (MOG+MBP) targets all MBP and MOG specific B lymphocytes, which are killed by the Diphtheria toxin after the target cells internalize the whole immunotoxin molecule.
  • Fig. IB (also referred to as SEQ ID NO:2) is the amino acid sequence of TBLMS1.
  • SEQ ID NO:2 is encoded by the nucleotide sequence of SEQ ID NO:l.
  • Fig. 2A (also referred to as SEQ ID NO:3) is the nucleotide sequence of TBLMS2 which is the design of the bi-specific immunotoxin molecule that can specifically target MBP as well as MOG antibody producing B cells.
  • the targeting domain (MOG+MBP) is linked to the Fc fragment of human IgG by a linker sequence.
  • This molecule can be expressed in mammalian system like CHO as a dimer with an IgG like structure.
  • the targeting domain of the immunotoxin molecule binds to the MOG and MBP specific B lymphocytes and via Fc portion of the immunotoxin, these B lymphocyte complexes are recognized and internalized by the macrophages which subsequently dispose them effectively.
  • Fig. 2B (also referred to as SEQ ID NO:4) is the amino acid sequence of TBLMS2.
  • SEQ ID NO:4 is encoded by the nucleotide sequence of SEQ ID NO:3.
  • a vector comprising the polynucleotide sequence of SEQ ID NO:l and/or SEQ ID NO:3 is provided.
  • a cell line comprising the vector, wherein the vector further comprises of polynucleotide sequence of SEQ ID NO:l and/or SEQ ID NO:3, is provided .
  • the cell line may be used to produce the fusion proteins TBLMSI and/or TBLMS2.
  • TBLMS2 may be administered to a subject with multiple sclerosis by way of a pharmaceutical composition.
  • the pharmaceutical composition may comprise of TBLMSI and/or TBLMS2, and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carriers in the pharmaceutical composition include generally used carriers well known in the art including water, salt solutions, gelatins, oils, alcohols, and other excipients and auxiliaries that facilitate processing of the active compounds into preparations that may be used pharmaceutically.
  • the pharmaceutical composition may also comprise of pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvant and/or other carriers well known in the art.
  • the disclosed embodiments of the fusion protein(s) may be used for the treatment of autoimmune disease including Multiple sclerosis, Crohn's disease and Rheumatoid arthritis.
  • the fusion protein(s) of the present invention may be used for the treatment of multiple sclerosis.
  • the method for treating multiple sclerosis comprises of administering a therapeutically effective amount of TBLMS1 and/or TBLMS2 to the subject.
  • terapéuticaally effective amount includes an amount of the composition having therapeutic effect on a subject upon administration of the composition to the subject.
  • the fusion protein(s) TBLMS1 and/or TBLMS2 are used to target B cells displaying myelin specific antibodies by contacting TBLMS1 and/or TBLMS2 with myelin specific B cells.
  • the targeted B cells are inactivated or killed by the cytotoxic fragments of fusion protein(s) TBLMSl and/or TBLMS2
  • the fusion protein(s) TBLMSl and/or TBLMS2 may be used to detect the presence of B cells displaying myelin specific antibodies in a sample.
  • the diagnostic method for detecting the presence of B cells displaying myelin specific antibodies in a sample comprises of: contacting the sample with the fusion protein(s) TBLMS l and/or TBLMS2, under conditions that allow for formation of a complex between the polypeptide sequence(s) of fusion protein(s) TBLMSl and /or TBLMS2 and B cell; and detecting the formation of the complex.
  • the complex formed between the fusion protein(s) TBLMSl and/or TBLMS2, and the B cells displaying myelin specific antibodies may further be detected by methods known in the art.
  • sample may originate from a mammal, and includes tissue or body fluids (such as bone marrow tissue, colon tissue, blood sample etc.) or an extract of any tissue suspected of having B cells displaying myelin specific antibodies.
  • the detection of the complex as described herein can be performed by apparatus capable of detecting specific signals emitted by detectable labels generally known in the art such as radiation emission, color change, fluorescence, etc.
  • the fusion protein(s) TBLMS 1 and/or TBLMS2 may be provided in a diagnostic kit for detecting the presence of B cells displaying myelin specific antibodies.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne des protéines de fusion utilisables dans le cadre du traitement de la sclérose en plaques et d'autres maladies auto-immunes. La sclérose en plaques est une maladie auto-immune démyélinisante inflammatoire du système nerveux central. La sclérose en plaques est déclenchée par le propre système immunitaire de l'organisme qui attaque la gaine de myéline entourant les axones. Les interventions médicales actuellement pratiquées en cas de sclérose en plaques comprennent la prévention de l'infiltration des lymphocytes T et B inflammatoires dans le SNC (natalizumab) ou la neutralisation des anticorps anti-MBP (copaxone) ou des méthodes plus générales d'immunosuppression (interférons). Les protéines de fusion décrites, TBLMS1 et TBLMS2, entraînent une diminution des réponses humorales spécifiques des antigènes de la myéline grâce à l'élimination des lymphocytes B spécifiques de la myéline.
PCT/IN2011/000105 2010-02-22 2011-02-22 Protéines de fusion utilisées pour le traitement de la sclérose en plaques et d'autres maladies auto-immunes WO2011101870A1 (fr)

Applications Claiming Priority (2)

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IN443/CHE/2010 2010-02-22
IN443CH2010 2010-02-22

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10662212B2 (en) 2014-03-13 2020-05-26 Universitat Basel Carbohydrate ligands that bind to IGM antibodies against myelin-associated glycoprotein
US11091591B2 (en) 2015-09-16 2021-08-17 Universität Basel Carbohydrate ligands that bind to antibodies against glycoepitopes of glycosphingolipids
CN114702595A (zh) * 2022-02-20 2022-07-05 黄凯旋 一种靶向杀伤特异性b淋巴细胞的融合蛋白及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019179A1 (fr) * 1995-11-17 1997-05-29 Yissum Research Development Company Of The Hebrew University Of Jerusalem Proteines chimeres a exotoxine de pseudomonas-proteine basique myelinique
WO2002016414A2 (fr) * 2000-08-22 2002-02-28 Micromet Ag Composition destinee a l'elimination des cellules b autoreactives
WO2003068822A2 (fr) * 2002-02-13 2003-08-21 Micromet Ag Constructions (poly)peptidiques desimmunisees

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019179A1 (fr) * 1995-11-17 1997-05-29 Yissum Research Development Company Of The Hebrew University Of Jerusalem Proteines chimeres a exotoxine de pseudomonas-proteine basique myelinique
WO2002016414A2 (fr) * 2000-08-22 2002-02-28 Micromet Ag Composition destinee a l'elimination des cellules b autoreactives
WO2003068822A2 (fr) * 2002-02-13 2003-08-21 Micromet Ag Constructions (poly)peptidiques desimmunisees

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRENNER, T. ET AL.: "A novel antigen-toxin chimeric protein: myelin basic protein-pseudomonas exotoxin (MBP-PE40) for treatment of experimental autoimmune encephalomyelitis.", IMMUNOLOGY LETTERS., vol. 68, no. 2-3, 1 June 1999 (1999-06-01), pages 403 - 410, XP001057134 *
NACHREINER, T. ET AL.: "Depletion of autoreactive B-lymphocytes by a recombinant myelin oligodendrocyte glycoprotein-based immunotoxin.", JOURNAL OF NEUROIMMUNOLOGY., vol. 195, no. 1-2, March 2008 (2008-03-01), pages 28 - 35, XP022612044 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10662212B2 (en) 2014-03-13 2020-05-26 Universitat Basel Carbohydrate ligands that bind to IGM antibodies against myelin-associated glycoprotein
US11220523B2 (en) 2014-03-13 2022-01-11 Universität Basel Carbohydrate ligands that bind to IgM antibodies against myelin-associated glycoprotein
US11091591B2 (en) 2015-09-16 2021-08-17 Universität Basel Carbohydrate ligands that bind to antibodies against glycoepitopes of glycosphingolipids
CN114702595A (zh) * 2022-02-20 2022-07-05 黄凯旋 一种靶向杀伤特异性b淋巴细胞的融合蛋白及其应用

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