CA2223402A1 - Methods of inhibiting phagocytosis - Google Patents

Methods of inhibiting phagocytosis

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Publication number
CA2223402A1
CA2223402A1 CA002223402A CA2223402A CA2223402A1 CA 2223402 A1 CA2223402 A1 CA 2223402A1 CA 002223402 A CA002223402 A CA 002223402A CA 2223402 A CA2223402 A CA 2223402A CA 2223402 A1 CA2223402 A1 CA 2223402A1
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Prior art keywords
gamma
receptor
sequence
cell
mrna
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CA002223402A
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French (fr)
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CA2223402C (en
Inventor
Alan D. Schreiber
Jong-Gu Park
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University of Pennsylvania
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70535—Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C12N2310/111—Antisense spanning the whole gene, or a large part of it
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/50—Physical structure
    • C12N2310/53—Physical structure partially self-complementary or closed

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Zoology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Wood Science & Technology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Pulmonology (AREA)
  • Plant Pathology (AREA)
  • Toxicology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Virology (AREA)
  • Transplantation (AREA)
  • Physics & Mathematics (AREA)
  • Cell Biology (AREA)
  • Rheumatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Microbiology (AREA)
  • Pain & Pain Management (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

The present invention relates, in general, to methods of treating diseases resulting from interactions between immune complexes and Fc receptors. In particular, the present invention relates to methods of modulating the clearance of antibody-coated cells from the circulation by inhibiting phagocytosis and to methods of modulating the interaction of immune complexes with tissue Fc receptors. Further, the invention relates to methods of modulating the activation of immunological processes mediate by Fc receptor activation resulting from antibody-antigen/receptor interaction.

Claims (59)

1. A method of preventing phagocytosis of immune complexes in a mammal comprising introducing into phagocytic cells of said mammal that are in contact with said immune complexes an inhibitor of a kinase endogenous to said cells associated with an Fc receptor present at the membrane of said cells, said introduction being effected under conditions such that the phagocytic potential or said cells is inhibited.
2. The method according to claim 1 wherein said immune complexes are IgG-containing immune complexes.
3. The method according to claim 1 wherein said inhibitor is a peptide or mimetic.
4. The method according to claim 3 wherein said peptide is introduced directly into said cells.
5. The method according to claim 3 wherein said peptide is incorporated into a liposome prior to introduction into said cells.
6. The method according to claim 3 wherein a DNA
sequence encoding said peptide is introduced into said cells under conditions such that said DNA sequence is expressed and said peptide thereby produced.
7. The method according to claim 3 wherein said peptide comprises a sequence corresponding to the tyrosine-containing motif of the cytoplasmic domain Fc.gamma.RIIA or the .gamma. chain of Fc.gamma.RIIIA or of Fc~RI.
8. The method according to claim 3 wherein said peptide comprises the sequence Y-X2-L wherein X2 is any two amino acids.
9. The method according to claim 8 wherein X2 represents the amino acids or a Y-X2-L sequence of the cytoplasmic domain of Fc.gamma.RIIA or the .gamma. chain of Fc.gamma.RIIIA or of Fc~RI.
10. A method of preventing the clearance of immune complexes from a mammal comprising introducing into phagocytic cells of said mammal that are in contact with said immune complexes a molecule that specificially degrades transcripts encoding Fc receptors present at the membrane of said cells.
11. The method according to claim 10 wherein said immune complexes are IgG-containing immune complexes.
12. The method according to claim 10 wherein said molecule is a ribozyme.
13. A method of inhibiting the binding of immune complexes present in a mammal to membrane-bound Fc receptors comprising introducing into said mammal a soluble Fc receptor that competes with said membrane-bound Fc receptor for binding to said immune complexes, wherein said introduction is effected under conditions such that binding of said immune complexes to said membrane-bound Fc receptor is inhibited.
14. The method according to claim 13 wherein said immune complexes are IgG-containing immune complexes.
15. The method according to claim 13 wherein said soluble Fc receptor consists essentially of the extracellular domain of an Fc.gamma. receptor, or binding portion thereof.
16. The method according to claim 13 wherein said soluble Fc receptor comprises an extracellular domain from a first Fc.gamma. receptor type or an Fc~ receptor type and a cytoplasmic domain from a second Fc.gamma. receptor type wherein at least one of said first and second receptor types is Fc.gamma.RI or the .alpha. or .gamma. chain of Fc.gamma.RIII.
17. A method of inhibiting the phagocytic potential of a mammalian cell expressing an Fc receptor comprising introducing into said cell a construct comprising, in the 5'-3' direction of transcription:
i) a promoter functional in said cell, ii) a segment of double-stranded DNA the transcribed strand of which comprises a sequence complementary to endogenous mRNA encoding said Fc receptor, and iii) a termination sequence functional in said cell, wherein said construct is introduced under conditions such that said complementary strand is transcribed and binds to said endogenous mRNA thereby reducing expression or said Fc receptor and inhibiting the phagocytic potential of said cell.
18. The method according to claim 17 wherein said sequence complementary to endogenous mRNA is complementary to an untranslated region of said mRNA.
19. A method of inhibiting the phagocytic potential of a mammalian cell expressing an Fc receptor comprising introducing into said cell a construct comprising, in the 5'-3' direction of transcription:
i) a promoter functional in said cell, ii) a segment of double-stranded DNA the transcribed strand of which comprises a sequence complementary to endogenous mRNA encoding Syk kinase, and iii) a termination sequence functional in said cell, wherein said construct is introduced under conditions such that said complementary strand is transcribed and binds to said endogenous mRNA thereby reducing expression of Syk kinase and inhibiting the phagocytic and signaling potential of said cell.
20. The method according to claim 19 wherein said Fc receptor is Fc.gamma.RI, Fc.gamma.RIIA or Fc.gamma.RIIIA.
21. A method of inhibiting the phagocytic potential of a mammalian cell expressing an Fc receptor comprising introducing into said cell a nucleic acid complementary to an endogenous mRNA encoding Syk kinase, wherein said nucleic acid is introduced under conditions such that said nucleic acid binds to said mRNA and thereby inhibits translation of said mRNA into Syk kinase.
22. The method according to claim 21 wherein said Fc receptor is Fc.gamma.RI, Fc.gamma.RIIA or Fc.gamma.RIIIA.
23. The method according to claim 19 wherein said sequence is complementary to a region of said endogenous mRNA free of secondary structure.
24. The method according to claim 21 wherein said nucleic acid is complementary to a region of said mRNA
free of secondary structure.
25. The method according to claim 21 wherein said nucleic acid has a stem-loop structure.
26. The method according to claim 21 wherein said nucleic acid has the sequence shown in Figure 5 or Figure 6.
27. A method of inhibiting the phagocytic potential or a mammalian cell expressing an Fc receptor comprising introducing into said cell a nucleic acid complementary to an endogenous mRNA encoding said Fc receptor, wherein said nucleic acid is introduced under conditions such that said nucleic acid binds to said mRNA and thereby inhibits translation of said mRNA into said Fc receptor.
28. The method according to claim 27 wherein said nucleic acid is an RNA molecule.
29. The method according to claim 27 wherein said nucleic acid is complementary to an untranslated region of said mRNA.
30. A method of inhibiting the signal transduction of the y subunit of the IgE receptor Fc~RI
comprising introducing into cells bearing said receptor an inhibitor of a kinase endogenous to said cells that activates said signal transduction of said Fc~RI
receptor or the .gamma. subunit thereof, said introduction being effected under conditions such that said signal transduction is inhibited.
31. The method according to claim 30 wherein said inhibitor is a peptide or mimetic.
32. The method according to claim 31 wherein said peptide comprises the sequence Y-X2-L, wherein X2 represents any two amino acid.
33. The method according to claim 32 wherein X2 represents the amino acids of a Y-X2-L sequence of the cytoplasmic domain of the .gamma. chain Fc.epsilon.RI.
34. A construct comprising, in the 5'-3' direction of transcription:
i) a promoter, ii) a segment of double-stranded DNA the transcribed stand of which comprises a sequence complementary to Fc receptor mRNA, and iii) a termination sequence, wherein said promoter, double-stranded DNA and termination sequence are operably linked.
35. A cell comprising said construct according to claim 34, wherein said promoter and said termination sequence are functional in said cell.
36. A soluble Fc receptor consisting essentially of the extracellular domain of an Fc.gamma. or Fc.epsilon. receptor, or binding portion thereof.
37. A soluble Fc.gamma. receptor comprising an extracellular domain from a first Fc.gamma. receptor type and a cytoplasmic domain from a second Fc.gamma. receptor type, wherein at least one of said first and second receptor types is Fc.gamma.RI or the .alpha. or .gamma. chain of Fc.gamma.RIII.
38. A DNA molecule encoding the soluble receptor of claim 36.
39. A DNA molecule encoding the soluble receptor of claim 37.
40. A peptide consisting essentially of the tyrosine-containing motif of the cytoplasmic domain of Fc.gamma.RIIA or the .gamma. chain of Fc.gamma.RIIIA or Fc.epsilon.RI, or functional portion thereof
41. A DNA molecule encoding the peptide of claim 40.
42. A cell comprising the peptide according to claim 40.
43. A peptide that inhibits phagocytosis, or mediator release from mast cells, comprising a portion of the cytoplasmic domain of Fc.gamma.RIIA or of the .gamma. chain of Fc.gamma.RIIIA or of Fc.epsilon.RI that contains the sequence Y-X2-L, wherein X2 represents the two amino acids of the Y-X2-L sequence of the cytoplasmic domain of Fc.gamma.RIIA or the .gamma. chain of Fc.gamma.RIIIA or of Fc~RI.
44. The method according to claim 1 wherein said inhibition reduces or prevents regional tissue damage resulting from monocyte or neutrophil activation.
45. A method of inhibiting the phagocytic potential of a Syk-producing cell comprising introducing into said cell an antisense construct or ribozyme that targets Syk encoding sequences present in said cell under conditions such that production of Syk is inhibited.
46. A method of inhibiting the phagocytic potential of a cell comprising introducing into said cell Fc.gamma.RIIB under conditions such that said inhibition is effected.
47. The method according to claim 30 wherein said kinase is Syk kinase.
48. A method of inhibiting signal transduction of the .gamma. subunit of the IgE receptor Fc~RI comprising introducing into cells bearing said receptor an antisense construct that targets Syk encoding sequences present in said cell under conditions such that said signal transduction is inhibited.
49. The method of claim 48 wherein said cells are present in the lungs or an asthma patient.
50. The method according to claim 49 wherein said introduction is effected by administering said construct to the lungs of said patient via aerosol or systemic administration.
51. The method according to claim 47 wherein said inhibitor targets the interval region between the second SH2 domain and catalytic (kinase) domain of Syk kinase.
52. A method of screening a test compound for the ability to selectively inhibit signal transduction mediated by the interval region of Syk kinase comprising contacting said compound with a polypeptide that comprises the Syk interval sequence and a polypeptide comprising the ZAP70 interval sequence and determining whether said compound binds said Syk interval sequence or said Zap 70 interval sequence, compounds that bind said Syk interval sequence but not said ZAP70 interval sequence being capable of said selective inhibition.
53. A method of inhibiting the release of a mediator from a Syk-producing cell comprising introducing into said cell an antisense construct or ribozyme that targets Syk encoding sequences present in said cells or an agent that selectively inhibits signal transduction mediated by Syk interval region sequences under conditions such that said inhibition is effected.
54. The method according to claim 53 wherein said cell is present in a lung of an asthma patient.
55. A nucleic acid having the sequence set forth in Figure 5 or Figure 6.
56. An antisense construct comprising in the 5'-3' direction of transcription:
i) a promoter, and ii) a segment of double stranded DNA the transcribed strand of which comprises a sequence complementary to Syk kinase mRNA operably linked to said promoter.
57. The construct according to claim 56 wherein said sequence complementary to Syk kinase mRNA is complementary to a region of Syk kinase mRNA that surrounds or includes the translation initiation codon.
58. The construct according to claim 56 wherein said sequence complementary to Syk kinase mRNA is complementary to a region of Syk kinase mRNA that has minimum secondary structure.
59. A pharmaceutical composition comprising Syk kinase interval region, or portion thereof of at least 6 amino acids, or mimetic thereof, and a pharmaceutically acceptable carrier.
CA2223402A 1995-06-07 1996-06-07 Methods of inhibiting phagocytosis Expired - Fee Related CA2223402C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US48353095A 1995-06-07 1995-06-07
US08/483,530 1995-06-07
PCT/US1996/010494 WO1996040199A1 (en) 1995-06-07 1996-06-07 Methods of inhibiting phagocytosis

Publications (2)

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CA2223402A1 true CA2223402A1 (en) 1996-12-19
CA2223402C CA2223402C (en) 2012-07-31

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CA2223402A Expired - Fee Related CA2223402C (en) 1995-06-07 1996-06-07 Methods of inhibiting phagocytosis

Country Status (6)

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EP (1) EP0831875A4 (en)
JP (1) JPH11507824A (en)
AU (1) AU723595B2 (en)
CA (1) CA2223402C (en)
IL (1) IL122338A0 (en)
WO (1) WO1996040199A1 (en)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8039026B1 (en) 1997-07-28 2011-10-18 Johnson & Johnson Consumer Companies, Inc Methods for treating skin pigmentation
US8106094B2 (en) 1998-07-06 2012-01-31 Johnson & Johnson Consumer Companies, Inc. Compositions and methods for treating skin conditions
US8093293B2 (en) 1998-07-06 2012-01-10 Johnson & Johnson Consumer Companies, Inc. Methods for treating skin conditions
GB9822763D0 (en) * 1998-10-20 1998-12-16 Univ Sheffield Immunoglobin variant
EP1006183A1 (en) * 1998-12-03 2000-06-07 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Recombinant soluble Fc receptors
US7985404B1 (en) 1999-07-27 2011-07-26 Johnson & Johnson Consumer Companies, Inc. Reducing hair growth, hair follicle and hair shaft size and hair pigmentation
US7309688B2 (en) 2000-10-27 2007-12-18 Johnson & Johnson Consumer Companies Topical anti-cancer compositions and methods of use thereof
US8431550B2 (en) 2000-10-27 2013-04-30 Johnson & Johnson Consumer Companies, Inc. Topical anti-cancer compositions and methods of use thereof
US7192615B2 (en) 2001-02-28 2007-03-20 J&J Consumer Companies, Inc. Compositions containing legume products
JP2004536800A (en) * 2001-05-09 2004-12-09 アルカベロ アクチェセルスカプ Pharmaceutical composition for preventing or treating TH1 and TH2 cell-related diseases by modulating the TH1 / TH2 ratio
WO2005049838A2 (en) 2003-11-14 2005-06-02 Yale University Syk-targeted nucleic acid interference
TW200808360A (en) * 2006-04-13 2008-02-16 Alcon Mfg Ltd RNAi-mediated inhibition of spleen tyrosine kinase-related inflammatory conditions
GB201509413D0 (en) * 2015-06-01 2015-07-15 Ucl Business Plc Fusion protein

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL111105A (en) * 1993-09-30 2009-05-04 Univ Pennsylvania Use of a molecule capable of inhibiting the expression of syk kinase to prepare a pharmaceutical composition for inhibiting phagocytosis
US5641863A (en) * 1993-09-30 1997-06-24 University Of Pennsylvania Chimeric IgG Fc receptors
PL314522A1 (en) * 1993-11-23 1996-09-16 Ciba Corning Diagnostics Corp Application of antisense oligomers in a contamination controlling process during nucleic acids amplification reactions

Also Published As

Publication number Publication date
EP0831875A4 (en) 2002-07-31
CA2223402C (en) 2012-07-31
JPH11507824A (en) 1999-07-13
AU723595B2 (en) 2000-08-31
AU6386996A (en) 1996-12-30
IL122338A0 (en) 1998-04-05
EP0831875A1 (en) 1998-04-01
WO1996040199A1 (en) 1996-12-19

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