CA2454048A1 - Therapeutic agents comprising pro-apoptotic proteins - Google Patents

Therapeutic agents comprising pro-apoptotic proteins Download PDF

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Publication number
CA2454048A1
CA2454048A1 CA002454048A CA2454048A CA2454048A1 CA 2454048 A1 CA2454048 A1 CA 2454048A1 CA 002454048 A CA002454048 A CA 002454048A CA 2454048 A CA2454048 A CA 2454048A CA 2454048 A1 CA2454048 A1 CA 2454048A1
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granzyme
cell
polypeptide
seq
targeting moiety
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CA002454048A
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French (fr)
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CA2454048C (en
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Michael G. Rosenblum
Yuying Liu
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Research Development Foundation
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Research Development Foundation
Michael G. Rosenblum
Yuying Liu
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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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C12N9/6467—Granzymes, e.g. granzyme A (3.4.21.78); granzyme B (3.4.21.79)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07K14/4747—Apoptosis related proteins
    • 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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • 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
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • 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

Abstract

The present invention relates to targeted killing of a cell utilizing a chimeric polypeptide comprising a cell-specific targeting moiety and a signa l transduction pathway factor. In a preferred embodiment, the signal transduction pathway factor is an apoptosisinducing factor, such as granzyme B, granzyme A, or Bax.

Claims (61)

1. A chimeric polypeptide comprising a cell-specific targeting moiety and a signal transduction pathway factor.
2. A chimeric polypeptide comprising a cell-specific targeting moiety and an apoptosis-inducing factor, wherein said apoptosis-inducing factor is a granzyme.
3. The polypeptide of claim 2, wherein said granzyme is granzyme B.
4. The polypeptide of claim 3, wherein the amino acid sequence of said granzyme B is SEQ ID NO:60.
5. The polypeptide of claim 3, wherein the amino acid sequence of said granzyme B is at least 100 contiguous amino acids from SEQ ID NO:60.
6. The polypeptide of claim 3, wherein the amino acid sequence of said granzyme B is at least 75 contiguous amino acids from SEQ ID NO:60.
7. The polypeptide of claim 3, wherein the amino acid sequence of said granzyme B is at least 40 contiguous amino acids from SEQ ID NO:60.
8. The polypeptide of claim 4, wherein SEQ ID NO:60 further comprises an N-terminal extension comprising SEQ ID NO:61.
9. The polypeptide of claim 4, wherein the first twenty amino acids are absent from SEQ ID NO:60.
10. The polypeptide of claim 2, wherein said granzyme is granzyme A.
11. The polypeptide of claim 10, wherein the amino acid sequence of said granzyme A is SEQ ID NO:25.
12. The polypeptide of claim 10, wherein the amino acid sequence of said granzyme A is at least 100 contiguous amino acids from SEQ ID NO:25.
13. The polypeptide of claim 10, wherein the amino acid sequence of said granzyme A is at least 75 contiguous amino acids from SEQ ID NO:25.
14. The polypeptide of claim 10, wherein the amino acid sequence of said granzyme A is at least 40 contiguous amino acids from SEQ ID NO:25.
15. The polypeptide of claim 2, wherein said cell-specific targeting moiety is a cytokine, an antibody, a ligand, or a hormone.
16. The polypeptide of claim 15, wherein said ligand is VEGF.
17. The polypeptide of claim 16, wherein said VEGF is vegf121.
18. The polypeptide of claim 15, wherein said antibody is a single chain antibody.
19. The polypeptide of claim 18, wherein said single chain antibody is scFvMEL.
20. The polypeptide of claim 2, wherein said granzyme is granzyme B and said cell-specific targeting moiety is vegf121.
21. The polypeptide of claim 2, wherein said granzyme is granzyme B and said cell-specific targeting moiety is scFvMEL.
22. The polypeptide of claim 2, further comprising a linker.
23. The polypeptide of claim 22, wherein the linker comprises SEQ ID NO:50, SEQ ID NO:51, or SEQ ID NO:52.
24. The polypeptide of claim 2, wherein the polypeptide is encoded by a recombinant polynucleotide.
25. An expression cassette comprising a polynucleotide encoding a chimeric polypeptide comprising a cell-specific targeting moiety and an apoptosis-inducing factor, wherein said apoptosis-inducing factor is a granzyme, and wherein said polynucleotide is under control of a regulatory sequence operable in a host cell.
26. The expression cassette of claim 25, wherein said granzyme is granzyme A.
27. The expression cassette of claim 25, wherein said granzyme is granzyme B.
28. The expression cassette of claim 26, wherein said granzyme A is encoded by a polynucleotide of SEQ ID NO:26, SEQ ID NO:27, or SEQ ID NO:28.
29. The expression cassette of claim 27, wherein said granzyme B is encoded by a polynucleotide of SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ
ID
NO:21, or SEQ ID NO:22.
30. The expression cassette of claim 25, wherein the cassette is comprised in a recombinant viral vector.
31. The expression cassette of claim 30, wherein the viral vector is an adenoviral vector, an adeno-associated viral vector, or a retroviral vector.
32. A host cell comprising an expression cassette comprising a polynucleotide encoding a chimeric polypeptide comprising a cell-specific targeting moiety and an apoptosis-inducing factor, wherein said apoptosis-inducing factor is a granzyme.
33. The host cell of claim 32, further defined as a prokaryotic host cell.
34. The host cell of claim 32, further defined as an eukaryotic host cell.
35. A method of using a host cell comprising an expression cassette comprising a polynucleotide encoding a chimeric polypeptide comprising a cell-specific targeting moiety and an apoptosis-inducing factor, wherein said apoptosis-inducing factor is a granzyme, the method comprising culturing the host cell under conditions suitable for the expression of the chimeric polypeptide.
36. A method of inducing apoptosis in a cell, comprising administering to said cell an effective amount of a chimeric polypeptide comprising a cell-specific targeting moiety and a granzyme.
37. The method of claim 36, wherein said granzyme is granzyme A or granzyme B.
38. The method of claim 37, wherein said granzyme is granzyme B.
39. The method of claim 36, wherein said cell is in vivo.
40. The method of claim 39, wherein said cell is in a human.
41. A method of inducing apoptosis in a cell, comprising administering to said cell an effective amount of a chimeric polypeptide comprising a cell-specific targeting moiety and a granzyme, wherein said cell-specific targeting moiety is scFvMEL and said granzyme is granzyme B.
42. A method of inducing apoptosis in a cell, comprising administering to said cell an effective amount of a chimeric polypeptide comprising a cell-specific targeting moiety and a granzyme, wherein said cell-specific targeting moiety is vegf121 and said granzyme is granzyme B.
43. A method of inducing apoptosis in a cell, comprising administering to said cell an effective amount of a chimeric polypeptide comprising a cell-specific targeting moiety and a pro-apoptotic member of the Bcl-2 family.
44. The method of claim 43, wherein said pro-apoptotic member of the Bcl-2 family is Bax or a fragment thereof.
45. The method of claim 43, wherein said cell is in vivo.
46. The method of claim 45, wherein said cell is in a human.
47. The method of claim 44, wherein said fragment of Bax lacks at least part of a polypeptide encoded by exon 6 in a Bax polynucleotide sequence.
48. A method of inducing apoptosis in a cell, comprising administering to said cell an effective amount of a chimeric polypeptide comprising a cell-specific targeting moiety and a pro-apoptotic member of the Bcl-2 family, wherein said cell-specific targeting moiety is scFvMEL and said pro-apoptotic member of the Bcl-2 family is Bax or a fragment of Bax.
49. The method of claim 48, wherein said fragment of Bax lacks at least part of exon 6 in a Bax polynucleotide sequence.
50. A method of treating a disease in an individual, comprising the steps of administering to said individual a therapeutically effective amount of a composition comprising:

a) a chimeric polypeptide comprising an apoptosis-inducing moiety and a cell-specific targeting moiety; and b) a pharmaceutical carrier.
51. The method of claim 50, wherein said pharmaceutical carrier comprises a lipid.
52. The method of claim 50, wherein said disease is cancer, diabetes, arthritis, or inflammatory bowel disease, atherosclerosis, or diabetic retinopathy.
53. The method of claim 52, wherein said disease is cancer.
54. The method of claim 50, wherein said apoptosis-inducing moiety is a granzyme.
55. The method of claim 54, wherein said granzyme is granzyme B or a fragment thereof.
56. The method of claim 50, wherein said apoptosis-inducing moiety is a pro-apoptotic member of the Bcl-2 family.
57. The method of claim 56, wherein said pro-apoptotic member of the Bcl-2 family is Bax or a fragment thereof.
58. The method of claim 57, wherein said fragment of Bax lacks at least part of a polypeptide encoded by exon 6 in a Bax polynucleotide sequence.
59. The method of claim 57, wherein said fragment of Bax lacks at least part of a polypeptide encoded by exons 4, 5, or 6.
60. The method of claim 50, wherein said administration is intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intramuscularly, intraperitoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, topically, locally, by inhalation (e.g. aerosol inhalation), by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, via a catheter, via a lavage, in a creme, or in a lipid composition.
61. The method of claim 50, further comprising administering to said individual an anti-inflammatory composition, chemotherapy, surgery, radiation, hormone therapy, or gene therapy.
CA2454048A 2001-07-17 2002-07-17 Therapeutic agents comprising pro-apoptotic proteins Expired - Fee Related CA2454048C (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US30609101P 2001-07-17 2001-07-17
US60/306,091 2001-07-17
US33288601P 2001-11-06 2001-11-06
US60/332,886 2001-11-06
US36036102P 2002-02-28 2002-02-28
US60/360,361 2002-02-28
PCT/US2002/023378 WO2003007889A2 (en) 2001-07-17 2002-07-17 Therapeutic agents comprising pro-apoptotic proteins

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CA2454048A1 true CA2454048A1 (en) 2003-01-30
CA2454048C CA2454048C (en) 2011-05-03

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US (5) US7101977B2 (en)
EP (1) EP1414471B1 (en)
JP (1) JP2004535202A (en)
KR (1) KR100891272B1 (en)
CN (1) CN1555268B (en)
AU (1) AU2002327310B2 (en)
CA (1) CA2454048C (en)
DK (1) DK1414471T3 (en)
IL (2) IL159894A0 (en)
NZ (1) NZ530582A (en)
WO (1) WO2003007889A2 (en)

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