WO1999048914A1 - Methodes d'utilisation des proteines de choc thermique - Google Patents

Methodes d'utilisation des proteines de choc thermique Download PDF

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Publication number
WO1999048914A1
WO1999048914A1 PCT/US1999/006432 US9906432W WO9948914A1 WO 1999048914 A1 WO1999048914 A1 WO 1999048914A1 US 9906432 W US9906432 W US 9906432W WO 9948914 A1 WO9948914 A1 WO 9948914A1
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WO
WIPO (PCT)
Prior art keywords
immunotoxin
heat shock
toxin
shock protein
fragment
Prior art date
Application number
PCT/US1999/006432
Other languages
English (en)
Inventor
Erik Wallen
Pope Mosley
Original Assignee
The University Of New Mexico
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 University Of New Mexico filed Critical The University Of New Mexico
Publication of WO1999048914A1 publication Critical patent/WO1999048914A1/fr

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Classifications

    • 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
    • A61K47/646—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 the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines

Definitions

  • the present invention relates generally to treating diseases with immunotoxins.
  • the present invention provides a heat shock protein immunotoxin comprising: at least a fragment of a heat shock protein, the fragment being capable of being bound by an immune cell; and a toxin bound to the fragment.
  • the present invention provides a method for reducing the number of at least one type of immune cells in an individual comprising the step of administering a heat shock protein immunotoxin to an individual in an amount sufficient to decrease the number of immune cells of at least one type in the individual, the heat shock protein immunotoxin comprising at least a fragment of a heat shock protein, the fragment being capable of being bound by an immune cell; and a toxin bound to the fragment.
  • the present invention provides a method for reducing the number of at least one type of immune cells in an organ comprising the step of administering a heat shock protein immunotoxin to at least a portion of an organ in an amount sufficient to decrease the number of immune cells of at least one type in the organ, the heat shock protein immunotoxin comprising at least a fragment of a heat shock protein, the fragment being capable of being bound by an immune cell; and a toxin bound to the fragment.
  • toxin refers to any chemical or substance which kills cells, renders them inactive or causes them to be unable to perform their normal functions.
  • examples of such toxins include ricin. saporin, Shiga toxin, Pseudomonas exotoxin, radioactive isotopes (either alone or as part of a molecule), etc.
  • Toxins suitable for use with the present invention may also include chemotherapeutic agents such as: bleomycin, methotrexate, cyclophosphamide. vinca alkaloids, adriamycin, cisplatin, etoposides, etc.
  • heat shock protein immunotoxin ' ' refers to heat shock protein-peptide complexes where the peptide is a toxin, immunotoxins in which a heat shock protein or a fragment of a heat shock protein is covalently bound to a toxin, and immunotoxins in which a heat shock protein or a fragment of a heat shock protein is combined with a toxin comprising a protein oligonucleotide sequence or molecule.
  • binding * and “binding" refer to both covalent and non-covalent binding.
  • fragment can refer to a portion of a heat shock protein or an entire heat shock protein.
  • oligonucleotide refers to any oligonucleotide, including double and single-stranded DNA, RNA, PNAs (peptide nucleic acids) and any sequence of nucleic acids, either natural or synthetic, derivatized or underivatized.
  • peptide refers to all types of peptides and conjugated peptides including: peptides, proteins, polypeptides, protein sequences, amino acid sequences, denatured proteins, antigens, oncogenes and portions of oncogenes.
  • the term "individual” refers to either an individual person or animal from whom a cell lysate, heat shock protein, or peptide is obtained or an individual patient who is treated according to a method of the present invention.
  • immune cells refers to B lymphocytes, T lymphocytes, antigen presenting cells, macrophages. monocytes. natural killer cells, and dendritic cells.
  • the term “antigen presenting cells” refers to B lymphocytes, macrophages, and dendritic cells.
  • organ is used in the broad sense of this term to include such organs as the skin, bone marrow, etc.
  • the present invention provides a method for specifically destroying or inhibiting cellular function of immune cells which bind heat shock proteins or portions of heat shock proteins.
  • HSPs Heat shock proteins
  • HSP-peptide complexes have been shown to be capable of inducing T-cell mediated responses to tumor antigens, see for example Udono et al. "Heat shock protein 70- associated peptides elicit specific cancer immunity” in Journal of Experimental Medicine (1993) 178: 1391-1396; and Tamura et al. "Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations” in Science (1997). 278: 1 17- 120.
  • HSP-peptide complexes have also been show to be capable of inducing T-cell mediated responses to viral antigens as described in Roman et al .
  • Synthetic peptides non-covalently bound to bacterial HSP 70 elicit peptide specific T-cell responses in vivo in mmunology (1996), 88:487-492.
  • HSPs covalently bound to antigens as fusion proteins have also be shown to elicit a T-cell specific response, see for example, Suzue, "Heat shock proteins as vehicles for antigen delivery into the major histocompatibility complex I presentation pathway " in Proceedings of the National Academy of Sciences ( 1997), 94 : 13146- 13151.
  • HSPs have also been shown to be important in the recognition structure for NK cells, see for example Multhoff et al , "Heat shock protein 72 on tumor cells: a recognition structure for NK cells” in The Journal of Immunology (1997), 158:4341 -4350 and gamma delta T-cells. see for example Wei et al, "Induction of autologous tumor killing by heat treatment of fresh human tumor cells: involvement of ⁇ T cells and heat shock protein 70, in Cancer Research (1996), 56: 1 104-1 1 10.
  • Toxins linked to antibodies have been used to specifically target cancer cells as described by Siegall et al, "Immunotoxins as cancer chemotherapeutic-agents " in Drug Development Research, v. 34(#2), (Feb. 1 95), pp. 210-219. Toxins have also been linked as a fusion protein to human granulocyte-macrophage colony-stimulating factor by Burbage et al . "Ricin fusion toxin targeted to human granulocyte-macrophage colony-stimulating factor-receptor is selectively toxi to acute myeloid-leukemia cells" in Leukemia Research, v. 21 (#7), (Jul. 1997). pp.
  • heat shock proteins as cell-specific carriers of toxins and agents capable of inhibiting the cellular function of immune cells. Since HSPs appear to be recognized by a variety of immune cells, toxin or cellular pathyway inhibitors linked to heat shock proteins may be a very useful tool.
  • the present invention relies on the fact that heat shock proteins are recognized by numerous cells in the immune system.
  • the cells that are known to respond in the presence of heat shock proteins include T-cells. macrophages, dendritic cells, and B- cells.
  • the toxin linked heat shock proteins of the present invention may provide a means to deplete these cells in circumstances where it is desirable to do so. Although it is not clearly understood at the present time which cells react to specific heat shock proteins, it is conceivable that individual heat shock proteins could be used to knock out specific sub-groups of immune cells.
  • Suitable heat shock proteins for the present invention include the heat shock proteins listed n U.S. Patent No. 5,747,332.
  • HSPs include: members of the hsp60 family, hsp70 family, hsp90 family and the hspl 04-105 family.
  • Members of the hsp60 family include hsp60, hsp65, rubisco binding protein, and TCP-1 in eukaryotes; and GroEl/GroES in prokaryotes; Mif4. and TCPlalpha and beta in yeast.
  • Members of the hsp70 family include DnaK proteins from prokaryotes, Ssa, Ssb, and Ssc from yeast.
  • hsp70, Grp75 and Grp78(Bip) from eukaryotes.
  • Members of the hsp90 family include hsp90, gp96 and grp94.
  • Members of the hspl04-105 family include hspl05 and hspl 10.
  • toxins which may be used in the complexes of the present invention include ricin, saporin, bryodin, Diptheria toxin and Pseudomonas exotoxin.
  • Immunotoxins which may be used in the present invention's cancer therapeutic-agents have been described in Siegall et al, Drug Development Research, v. 34(#2), pp. 210- 219 (Feb. 1995), the entire disclosure and contents of which is hereby incorporated by reference.
  • the heat shock proteins of the present invention may also be used to deliver toxins such as specific inhibitors of cellular processes such as inhibitors of signal transduction, ion channel function, etc.
  • Another use of the heat shock protein immunotoxins of the present invention is to deliver chemotherapeutic agents to target cells to treat conditions such as cancer, autoimmune diseases, asthma, etc.
  • One of the advantages using the heat shock protein immunotoxins of the present invention over prior chemotherapy treatments is that using the immunotoxins of the present invention allow for chemotherapeutic agents to be delivered to specific target cells. Because the immunotoxins of the present invention allow for the delivery of the chemotheropeutic agents to specific target cells, the amount of chemotherapeutic agent used in the methods of the present invention may be greatly decreased when compared to conventional chemotherapy treaments, thus avoiding the numerous systemic side effects associated with conventional chemotherapy treatments.
  • the toxins may be non-covalently linked to the heat shock proteins either as peptides (in the peptide binding grooves of individual HSPs), covalently linked to the HSPs, or by the construction of a fusion protein.
  • Methods which can used to covalently link toxins to HSP include methods such as those described in U.S. Patent Nos. 4,714,759 and 5,645,836, the entire disclosure and contents of which are hereby incorporated by reference.
  • heat shock protein DNA sequences or fragments of heat shock protein DNA sequences may be combined with toxic protein DNA sequences or molecules using techniques known in the art. Fusion proteins containing sequences of both heat shock proteins or heat shock protein fragments and toxins can then easily be created. Methods which can be used to link toxins to HSP as part of a fusion protein include methods such as those described in U.S. Patent No. 5,696,237, the entire disclosure and contents of which is hereby incorporated by reference.
  • the toxin-linked heat shock proteins complexes of the present invention are particularly useful for treating auto-immune diseases, diseases where the immune system attacks self proteins.
  • the complexes of the present invention may also be used to temporarily debilitate an individual's immune system before and after transplanting an organ.
  • the complexes of the present invention may be used to inhibit specific intracellular pathways of immune cells. In general, the present invention is useful to treat diseases where it is desirable to reduce the effectiveness of an individual ' s immune system.
  • the heat shock protein immunotoxins of the present invention may be used to kill antigen presenting cells (APCs) and other immune cells having receptors which bind at least a portion of a heat shock protein.
  • the immunotoxins of the present invention may also be useful in treating diseases such as psoriasis. Lupus, or other diseases and autoimmune diseases in which APCs. or other immune cells with receptors which bind at least a portion of a heat shock protein, mediate an inappropriate immune response.
  • the heat shock protein immunotoxins of the present invention are particularly useful for treating auto-immune diseases, diseases where the immune system attacks self proteins because the immune system mistakes self-proteins for bacterial proteins.
  • the immunotoxins of the present invention may also be used to temporarily debilitate an individual's immune system before and after transplanting an organ.
  • the heat shock protein immunotoxins of the present inveniton may also be useful in depleting APCs in transplanted organs to increase the chance that the organ will not be rejected, see Seminars in Immunology (1998), 10:399.
  • the complexes of the present invention may be used to inhibit specific intracellular pathways of immune cells.
  • the present invention is useful to treat diseases where it is desirable to reduce the effectiveness of an individual's immune system.
  • the immunotoxins of the present invention can be administered in any conventional way for treating individual with a drug such as by injecting a solution containing a immunotoxin of the present invention into an individual's bloodstream, topically applying a solution containing a immunotoxin of the present invention on a particular part of a tissue or organ.
  • a solution containing the immunotoxin may be applied to the skin of a patient suffering from psoriasis.
  • a immunotoxin of the present invention may be topically applied to the organ, the organ may be immersed in a solution of the immunotoxin. or the organ may be treated with perfusion techniques prior to the transplantation procedure. In perfusion, an organ is treated with a solution by using the blood vessels associated with the organ to administer the solution throughout the organ.
  • the organ Prior to liver transplantation, the organ is perfused with hsp70-ricin immunotoxin complex for 30 minutes on ice. Immediately prior to transplantation, the organ is perfused with saline or other appropriate buffer.
  • activated macrophages are killed by topical application of an hsp70-saporin immunotoxin containing ointment.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une immunotoxine de protéines de choc thermique comprenant : au moins un fragment de protéine de choc thermique, ledit fragment pouvant être lié par une cellule immunitaire ; et une toxine liée au fragment. La présente invention concerne également une méthode, qui utilise les immunotoxines des protéines de choc thermique de l'invention, et qui permet de réduire le nombre de cellules immunitaires chez un individu . En outre, la présente invention concerne une méthode, qui utilise les immunotoxines des protéines de choc thermique de l'invention, et qui permet de réduire le nombre de cellules immunitaires dans un organe.
PCT/US1999/006432 1998-03-26 1999-03-25 Methodes d'utilisation des proteines de choc thermique WO1999048914A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7942698P 1998-03-26 1998-03-26
US60/079,426 1998-03-26

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WO1999048914A1 true WO1999048914A1 (fr) 1999-09-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006020743A2 (fr) * 2004-08-13 2006-02-23 General Electric Company Proteine de choc thermique comme agent de ciblage pour la transduction specifique d'endothelium in vivo

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5830464A (en) * 1997-02-07 1998-11-03 Fordham University Compositions and methods for the treatment and growth inhibition of cancer using heat shock/stress protein-peptide complexes in combination with adoptive immunotherapy
US5837251A (en) * 1995-09-13 1998-11-17 Fordham University Compositions and methods using complexes of heat shock proteins and antigenic molecules for the treatment and prevention of neoplastic diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5837251A (en) * 1995-09-13 1998-11-17 Fordham University Compositions and methods using complexes of heat shock proteins and antigenic molecules for the treatment and prevention of neoplastic diseases
US5830464A (en) * 1997-02-07 1998-11-03 Fordham University Compositions and methods for the treatment and growth inhibition of cancer using heat shock/stress protein-peptide complexes in combination with adoptive immunotherapy

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BUCHNER J.: "SUPERVISING THE FOLD: FUNCTIONAL PRINCIPLES OF MOLECULAR CHAPERONES", THE FASEB JOURNAL, FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY, US, vol. 10., 1 January 1996 (1996-01-01), US, pages 10 - 19., XP002921181, ISSN: 0892-6638 *
PALLEROS D. R., ET AL.: "HSP70-PROTEIN COMPLEXES.", JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY, US, vol. 269., no. 18., 6 May 1994 (1994-05-06), US, pages 13107 - 13114., XP002921180, ISSN: 0021-9258 *
SRIVASTAVA P. K., UDONO H.: "HEAT SHOCK PROTEIN-PEPTIDE COMPLEXES IN CANCER IMMUNOTHERAPY.", CURRENT OPINION IN IMMUNOLOGY., ELSEVIER, OXFORD., GB, vol. 6, no. 5, 1 January 1994 (1994-01-01), GB, pages 728 - 732, XP002037578, ISSN: 0952-7915, DOI: 10.1016/0952-7915(94)90076-0 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006020743A2 (fr) * 2004-08-13 2006-02-23 General Electric Company Proteine de choc thermique comme agent de ciblage pour la transduction specifique d'endothelium in vivo
WO2006020743A3 (fr) * 2004-08-13 2006-07-20 Gen Electric Proteine de choc thermique comme agent de ciblage pour la transduction specifique d'endothelium in vivo
JP2008509921A (ja) * 2004-08-13 2008-04-03 ゼネラル・エレクトリック・カンパニイ 内皮特異的な生体内伝達のターゲティング剤としての熱ショックタンパク質

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