JP2013515731A - フューリンノックダウン及びgm−csf増強(fang)癌ワクチン - Google Patents
フューリンノックダウン及びgm−csf増強(fang)癌ワクチン Download PDFInfo
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001136—Cytokines
- A61K39/001139—Colony stimulating factors [CSF]
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- 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
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Abstract
Description
1. Murphy, K., Travers, P., Walport, M., ed. Janeway's Immunobiology. 7th ed. 2008, Garland Science: New York. 674-687
2. Fakhrai, H., et al., Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma. Cancer Gene Ther, 2006. 13(12): p. 1052-60
3. Nemunaitis, J., GVAX (GMCSF gene modified tumor vaccine) in advanced stage non small cell lung cancer. J Control Release, 2003. 91(1-2): p. 225-31
4. Nemunaitis, J., et al., Phase 1/2 trial of autologous tumor mixed with an allogeneic GVAX vaccine in advanced-stage non-small-cell lung cancer. Cancer Gene Ther, 2006. 13(6): p. 555-62
5. Nemunaitis, J. and J. Nemunaitis, A review of vaccine clinical trials for non-small cell lung cancer. Expert Opin Biol Ther, 2007. 7(1): p. 89-102
6. Ahmad, M., R.C. Rees, and S.A. Ali, Escape from immunotherapy: possible mechanisms that influence tumor regression/progression. Cancer Immunol Immunother, 2004. 53(10): p. 844-54
7. Hege, K.M., K. Jooss, and D. Pardoll, GM-CSF gene-modifed cancer cell immunotherapies: of mice and men. Int Rev Immunol, 2006. 25(5-6): p. 321-52
8. Dranoff, G., et al., Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A, 1993. 90(8): p. 3539-43
9. Hege, K.M. and D.P. Carbone, Lung cancer vaccines and gene therapy. Lung Cancer, 2003. 41 Suppl 1: p. S103-13
10. Huang, A.Y., et al., Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science, 1994. 264(5161): p. 961-5
11. Banchereau, J., et al., Immunobiology of dendritic cells. Annu Rev Immunol, 2000. 18: p. 767-811
12. Hodi, F.S., et al., Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A, 2008. 105(8): p. 3005-10
13. Wick, W., U. Naumann, and M. Weller, Transforming growth factor-beta: a molecular target for the future therapy of glioblastoma. Curr Pharm Des, 2006. 12(3): p. 341-9
14. Bierie, B. and H.L. Moses, Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer, 2006. 6(7): p. 506-20
15. Levy, L. and C.S. Hill, Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev, 2006. 17(1-2): p. 41-58
16. Sporn, M.B., et al., Transforming growth factor-beta: biological function and chemical structure. Science, 1986. 233(4763): p. 532-4
17. Massague, J., The TGF-beta family of growth and differentiation factors. Cell, 1987. 49(4): p. 437-8
18. Bodmer, S., et al., Immunosuppression and transforming growth factor-beta in glioblastoma. Preferential production of transforming growth factor-beta 2. J Immunol, 1989. 143(10): p. 3222-9
19. Border, W.A. and E. Ruoslahti, Transforming growth factor-beta in disease: the dark side of tissue repair. J Clin Invest, 1992. 90(1): p. 1-7
20. Chen, T.C., et al., TGF-B2 and soluble p55 TNFR modulate VCAM-1 expression in glioma cells and brain derived endothelial cells. J Neuroimmunol, 1997. 73(1-2): p. 155-61
21. Li, M.O., et al., Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol, 2006. 24: p. 99-146
22. Yamaguchi, Y., et al., Contrasting effects of TGF-beta 1 and TNF-alpha on the development of dendritic cells from progenitors in mouse bone marrow. Stem Cells, 1997. 15(2): p. 144-53
23. Geissmann, F., et al., TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells. J Immunol, 1999. 162(8): p. 4567-75
24. Ardeshna, K.M., et al., The PI3 kinase, p38 SAP kinase, and NF-kappaB signal transduction pathways are involved in the survival and maturation of lipopolysaccharide-stimulated human monocyte-derived dendritic cells. Blood, 2000. 96(3): p. 1039-46
25. Montenegro, D.E., et al., TGFbeta inhibits GM-CSF-induced phosphorylation of ERK and MEK in human myeloid leukaemia cell lines via inhibition of phosphatidylinositol 3-kinase (PI3-k). Cell Prolif, 2009. 42(1): p. 1-9
26. Steinman, R.M., et al., Dendritic cell function in vivo during the steady state: a role in peripheral tolerance. Ann N Y Acad Sci, 2003. 987: p. 15-25
27. Ashcroft, G.S., Bidirectional regulation of macrophage function by TGF-beta. Microbes Infect, 1999. 1(15): p. 1275-82
28. Du, C. and S. Sriram, Mechanism of inhibition of LPS-induced IL-12p40 production by IL-10 and TGF-beta in ANA-1 cells. J Leukoc Biol, 1998. 64(1): p. 92-7
29. Takeuchi, M., P. Alard, and J.W. Streilein, TGF-beta promotes immune deviation by altering accessory signals of antigen-presenting cells. J Immunol, 1998. 160(4): p. 1589-97
30. Ruffini, P.A., et al., Factors, including transforming growth factor beta, released in the glioblastoma residual cavity, impair activity of adherent lymphokine-activated killer cells. Cancer Immunol Immunother, 1993. 36(6): p. 409-16
31. Fakhrai, H., et al., Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy. Proc Natl Acad Sci U S A, 1996. 93(7): p. 2909-14
32. Fantini, M.C., et al., Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol, 2004. 172(9): p. 5149-53
33. Thomas, D.A. and J. Massague, TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell, 2005. 8(5): p. 369-80
34. Polak, M.E., et al., Mechanisms of local immunosuppression in cutaneous melanoma. Br J Cancer, 2007. 96(12): p. 1879-87
35. Rook, A.H., et al., Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. J Immunol, 1986. 136(10): p. 3916-20
36. Kasid, A., G.I. Bell, and E.P. Director, Effects of transforming growth factor-beta on human lymphokine-activated killer cell precursors. Autocrine inhibition of cellular proliferation and differentiation to immune killer cells. J Immunol, 1988. 141(2): p. 690-8
37. Tsunawaki, S., et al., Deactivation of macrophages by transforming growth factor-beta. Nature, 1988. 334(6179): p. 260-2
38. Hirte, H. and D.A. Clark, Generation of lymphokine-activated killer cells in human ovarian carcinoma ascitic fluid: identification of transforming growth factor-beta as a suppressive factor. Cancer Immunol Immunother, 1991. 32(5): p. 296-302
39. Naganuma, H., et al., Transforming growth factor-beta inhibits interferon-gamma secretion by lymphokine-activated killer cells stimulated with tumor cells. Neurol Med Chir (Tokyo), 1996. 36(11): p. 789-95
40. Penafuerte, C. and J. Galipeau, TGF beta secreted by B16 melanoma antagonizes cancer gene immunotherapy bystander effect. Cancer Immunol Immunother, 2008. 57(8): p. 1197-206
41. Nemunaitis, J., et al., Phase II trial of Belagenpumatucel-L, a TGF-beta2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients. Cancer Gene Ther, 2009. 16(8): p. 620-4
42. Maples PB, K.P., Oxendine I, Jay C, Yu Y, Kuhn J, Nemunaitis J, TAG Vaccine: Autologous Tumor Vaccine Genetically Modified to Express GM-CSF and Block Production of TGFB2. BioProcessing Journal, 2009. 8(2)
43. Nemunaitis, J., Kumar, P., Senzer, N., Yu, Y., Oxendine, I., Tong, A.W., Maples, P.B., A phase I trial of GMCSF gene-TGFbeta antisense gene autologous tumor cell (TAG) vaccine in advanced cancer. Mol Therapy, 2009. 17 (Suppl 1): p. S206
44. Maples, P.B., et al. Autologous Tumor Cell Vaccine Genetically Modified To Express GM-CSF and Block Expression of TGFb2 (Abstract # 553). in The Twelfth Annual Meeting of the American Society of Gene Therapy. 2009. San Diego, California
45. Page, R.E., et al., Increased expression of the pro-protein convertase furin predicts decreased survival in ovarian cancer. Cell Oncol, 2007. 29(4): p. 289-99
46. Schalken, J.A., et al., fur gene expression as a discriminating marker for small cell and nonsmall cell lung carcinomas. J Clin Invest, 1987. 80(6): p. 1545-9
47. Mbikay, M., et al., Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours. Br J Cancer, 1997. 75(10): p. 1509-14
48. Cheng, M., et al., Pro-protein convertase gene expression in human breast cancer. Int J Cancer, 1997. 71(6): p. 966-71
49. Bassi, D.E., H. Mahloogi, and A.J. Klein-Szanto, The proprotein convertases furin and PACE4 play a significant role in tumor progression. Mol Carcinog, 2000. 28(2): p. 63-9
50. Bassi, D.E., et al., Elevated furin expression in aggressive human head and neck tumors and tumor cell lines. Mol Carcinog, 2001. 31(4): p. 224-32
51. Lopez de Cicco, R., et al., Human carcinoma cell growth and invasiveness is impaired by the propeptide of the ubiquitous proprotein convertase furin. Cancer Res, 2005. 65(10): p. 4162-71
52. Khatib, A.M., et al., Proprotein convertases in tumor progression and malignancy: novel targets in cancer therapy. Am J Pathol, 2002. 160(6): p. 1921-35
53. Thomas, G., Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol, 2002. 3(10): p. 753-66
54. Pesu, M., et al., T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance. Nature, 2008. 455(7210): p. 246-50
55. Pesu, M., et al., Proprotein convertase furin is preferentially expressed in T helper 1 cells and regulates interferon gamma. Blood, 2006. 108(3): p. 983-5
56. Lu, J., et al., TAP-independent presentation of CTL epitopes by Trojan antigens. J Immunol, 2001. 166(12): p. 7063-71
57. Fogel-Petrovic, M., et al., Physiological concentrations of transforming growth factor beta1 selectively inhibit human dendritic cell function. Int Immunopharmacol, 2007. 7(14): p. 1924-33
58. Bommireddy, R. and T. Doetschman, TGFbeta1 and Treg cells: alliance for tolerance. Trends Mol Med, 2007. 13(11): p. 492-501
59. Henrich, S., et al., The crystal structure of the proprotein processing proteinase furin explains its stringent specificity. Nat Struct Biol, 2003. 10(7): p. 520-6
60. Pearton, D.J., et al., Proprotein convertase expression and localization in epidermis: evidence for multiple roles and substrates. Exp Dermatol, 2001. 10(3): p. 193-203
61. Rao, D., Maples, P.B., Senzer, N., Kumar, P., Wang, Z., papper, B.O., Yu, Y., Haddock, C., Tong, A., Nemunaitis, J., Bi-functional shRNA: A novel approach of RNA interference. (submitted), 2009
62. Matranga, C., et al., Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell, 2005. 123(4): p. 607-20
63. Leuschner, P.J., et al., Cleavage of the siRNA passenger strand during RISC assembly in human cells. EMBO Rep, 2006. 7(3): p. 314-20
64. Rana, S., et al., Stathmin 1: a novel therapeutic target for anticancer activity. Expert Rev Anticancer Ther, 2008. 8(9): p. 1461-70
65. Azuma-Mukai, A., et al., Characterization of endogenous human Argonautes and their miRNA partners in RNA silencing. Proc Natl Acad Sci U S A, 2008. 105(23): p. 7964-9
66. Jackson, S.A., S. Koduvayur, and S.A. Woodson, Self-splicing of a group I intron reveals partitioning of native and misfolded RNA populations in yeast. RNA, 2006. 12(12): p. 2149-59
67. Funston, G.M., et al., Expression of heterologous genes in oncolytic adenoviruses using picornaviral 2A sequences that trigger ribosome skipping. J Gen Virol, 2008. 89(Pt 2): p. 389-96
68. Tong, A.W., et al., Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients. Mol Ther, 2005. 11(1): p. 160-72
69. Hu, X., et al., Characterization of a unique factor-independent variant derived from human factor-dependent TF-1 cells: a transformed event. Leuk Res, 1998. 22(9): p. 817-26
70. Santoli, D., et al., Synergistic and antagonistic effects of recombinant human interleukin (IL) 3, IL-1 alpha, granulocyte and macrophage colony-stimulating factors (G-CSF and M-CSF) on the growth of GM-CSF-dependent leukemic cell lines. J Immunol, 1987. 139(10): p. 3348-54
71. Romero, P., Current state of vaccine therapies in non-small-cell lung cancer. Clin Lung Cancer, 2008. 9 Suppl 1: p. S28-36
72. Robinson, J., et al., The European searchable tumour line database. Cancer Immunol Immunother, 2009
73. http:jura.wi. mit.edu/bioc/ siRNAext
74. Kumar, P.J., C. Oxendine, I Nemunaitis, J. Maples, P., TAG Xenograft Vaccine: Xenograft-Expanded Autologous Tumor Vaccine Genetically Modified to Express GM-CSF and Block Production of TGFβ2. BioProcessing Journal, 2009(Spring 2009): p. 30-36
75. Burghardt, I., et al., Pirfenidone inhibits TGF-beta expression in malignant glioma cells. Biochem Biophys Res Commun, 2007. 354(2): p. 542-7
76. McMahon, S., M.H. Laprise, and C.M. Dubois, Alternative pathway for the role of furin in tumor cell invasion process. Enhanced MMP-2 levels through bioactive TGFbeta. Exp Cell Res, 2003. 291(2): p. 326-39
77. Arteaga, C.L., Inhibition of TGFbeta signaling in cancer therapy. Curr Opin Genet Dev, 2006. 16(1): p. 30-7
78. Constam, D.B., et al., Differential expression of transforming growth factor-beta 1, -beta 2, and -beta 3 by glioblastoma cells, astrocytes, and microglia. J Immunol, 1992. 148(5): p. 1404-10
79. Eastham, J.A., et al., Transforming growth factor-beta 1: comparative immunohistochemical localization in human primary and metastatic prostate cancer. Lab Invest, 1995. 73(5): p. 628-35
80. Friedman, E., et al., High levels of transforming growth factor beta 1 correlate with disease progression in human colon cancer. Cancer Epidemiol Biomarkers Prev, 1995. 4(5): p. 549-54
81. Jakowlew, S.B., et al., Expression of transforming growth factor beta ligand and receptor messenger RNAs in lung cancer cell lines. Cell Growth Differ, 1995. 6(4): p. 465-76
82. Kong, F.M., et al., Elevated plasma transforming growth factor-beta 1 levels in breast cancer patients decrease after surgical removal of the tumor. Ann Surg, 1995. 222(2): p. 155-62
83. Yamada, N., et al., Enhanced expression of transforming growth factor-beta and its type-I and type-II receptors in human glioblastoma. Int J Cancer, 1995. 62(4): p. 386-92
84. Eder, I.E., et al., Transforming growth factors-beta 1 and beta 2 in serum and urine from patients with bladder carcinoma. J Urol, 1996. 156(3): p. 953-7
Claims (76)
- 顆粒球マクロファージコロニー刺激因子(GM−CSF)cDNAをコードする、プロモーターに作動可能に連結した第一の核酸インサート及び
フューリンをコードするmRNA転写産物の領域とハイブリダイズして、これによりRNA干渉を介してフューリン発現を阻害できる1又は2以上の低分子ヘアピン型RNA(shRNA)をコードする、前記プロモーターに作動可能に連結した第二の核酸インサート
を含むbishRNAフューリン/GMCSF発現ベクタープラスミドと、
1又は2以上の必要に応じたワクチンアジュバントと
を含むワクチン組成物。 - GM−CSFがヒトのものである、請求項1に記載の組成物。
- shRNAが、siRNA(切断依存的)及びmiRNA(切断非依存的)モチーフを組み入れている、請求項1に記載の組成物。
- shRNAが、切断依存的及び切断非依存的の両方であるフューリン発現阻害因子である、請求項1に記載の組成物。
- shRNAが、二機能性shRNAとしてさらに定義される、請求項1に記載の組成物。
- ピコルナウイルス2Aリボソームスキップペプチドが、第一及び第二の核酸インサート間にインターカレートしている、請求項1に記載の組成物。
- プロモーターがCMV哺乳類プロモーターである、請求項1に記載の組成物。
- CMV哺乳類プロモーターが、CMV IE 5’UTRエンハンサー配列及びCMV IEイントロンAを含有する、請求項7に記載の組成物。
- shRNAの標的となる領域が、フューリンmRNA転写産物の3’UTR領域配列である、請求項1に記載の組成物。
- shRNAの標的となる領域が、フューリンmRNA転写産物のコード領域である、請求項1に記載の組成物。
- 癌の症状の予防、治療及び/又は寛解を必要とする患者を同定するステップと、
顆粒球マクロファージコロニー刺激因子(GM−CSF)cDNAをコードする、プロモーターに作動可能に連結した第一の核酸インサート及びフューリンをコードするmRNA転写産物の領域とハイブリダイズして、これによりRNA干渉を介してフューリン発現を阻害できる1又は2以上の低分子ヘアピン型RNA(shRNA)をコードする、前記プロモーターに作動可能に連結した第二の核酸インサートを含むbishRNAフューリン/GMCSF発現ベクタープラスミド、並びに1又は2以上の必要に応じたワクチンアジュバントを含む自家細胞ワクチンを投与するステップと
を含むことにより、患者における癌の症状を予防、治療及び/又は寛解させる方法。 - 1又は2以上の癌細胞におけるトランスフォーミング増殖因子ベータ(TGF−ベータ又はTGF−β)及びGM−CSFのレベルを測定することにより療法の進行をモニターするステップであって、TGF−βレベルの低下及びGM−CSFレベルの上昇が療法の成功を示すステップと、
前記TGF−β及びGM−CSFのレベルに基づき自家細胞ワクチンの投与を変更するステップと
をさらに含む、請求項11に記載の方法。 - TGF−βが、TGF−β1、TGF−β2及びTGF−β3のうち少なくとも1種類から選択される、請求項12に記載の方法。
- 癌が、メラノーマ、非小細胞肺癌、胆嚢癌、結腸直腸癌、乳癌、卵巣癌、肝癌、肝癌転移及びユーイング肉腫からなる群から選択される、請求項11に記載の方法。
- shRNAが、siRNA(切断依存的)及びmiRNA(切断非依存的)モチーフを組み入れている、請求項11に記載の方法。
- shRNAが、切断依存的及び切断非依存的両方のフューリン発現阻害因子である、請求項11に記載の方法。
- shRNAが、二機能性shRNAとしてさらに定義される、請求項11に記載の方法。
- GM−CSF cDNAをコードする、プロモーターに作動可能に連結した第一の核酸インサート及び
フューリンをコードするmRNA転写産物の領域とハイブリダイズして、これによりRNA干渉を介してフューリン発現を阻害できる1又は2以上の低分子ヘアピン型RNA(shRNA)をコードする、前記プロモーターに作動可能に連結した第二の核酸インサート
を含むbishRNAフューリン/GMCSF発現ベクタープラスミドと、
1又は2以上の必要に応じたワクチンアジュバントと
を含む、自家フューリンノックダウン及び顆粒球マクロファージコロニー刺激因子(GM−CSF)増強(FANG)癌ワクチン組成物。 - 組成物が、癌の症状の予防、治療及び/又は寛解に用いられ、前記癌が、メラノーマ、非小細胞肺癌、胆嚢癌、結腸直腸癌、乳癌、卵巣癌、肝癌、肝癌転移及びユーイング肉腫からなる群から選択される、請求項18に記載の組成物。
- NSCLCの症状の予防、治療及び/又は寛解を必要とする患者を同定するステップと、
GM−CSF cDNAをコードする、プロモーターに作動可能に連結した第一の核酸インサート、及びフューリンをコードするmRNA転写産物の領域とハイブリダイズして、これによりRNA干渉を介してフューリン発現を阻害できる1又は2以上の低分子ヘアピン型RNA(shRNA)をコードする、前記プロモーターに作動可能に連結した第二の核酸インサートを含むbishRNAフューリン/GMCSF発現ベクタープラスミド、並びに1又は2以上の必要に応じたワクチンアジュバントを含むFANGワクチンを投与するステップと
を含む、フューリンノックダウン及び顆粒球マクロファージコロニー刺激因子(GM−CSF)増強(FANG)癌ワクチンの投与により、患者における非小細胞肺癌(NSCLC)の症状を治療、予防及び/又は寛解させる方法。 - 1又は2以上のNSCLC細胞におけるトランスフォーミング増殖因子ベータ(TGF−ベータ又はTGF−β)及びGM−CSFのレベルを測定することにより療法の進行をモニターするステップであって、TGF−βレベルの低下及びGM−CSFレベルの上昇が療法の成功を示すステップと、
前記TGF−β及びGM−CSFのレベルに基づき自家細胞ワクチンの投与を変更するステップと
をさらに含む、請求項20に記載の方法。 - TGF−βが、ヒトTGF−β1、TGF−β2及びTGF−β3のうち少なくとも1種類から選択される、請求項21に記載の方法。
- 1又は2以上の癌細胞を患者から無菌的に収集するステップと、
前記収集した細胞を無菌容器内の抗生物質溶液中に置くステップと、
前記収集した溶液から細胞懸濁液を生成するステップであって、前記細胞懸濁液の生成が酵素による解体、機械的脱凝集又は両者によって達成されるステップと、
前記細胞懸濁液を電気穿孔することによって前記細胞を遺伝的に改変し、GM−CSF cDNAをコードする、プロモーターに作動可能に連結した第一の核酸インサート、及びフューリンをコードするmRNA転写産物の領域とハイブリダイズして、これによりRNA干渉を介してフューリン発現を阻害できる1又は2以上の低分子ヘアピン型RNA(shRNA)をコードする、前記プロモーターに作動可能に連結した第二の核酸インサートを含むbishRNAフューリン/GMCSF発現ベクタープラスミドを有するワクチンを作製するステップと、
前記ワクチンを収集するステップと、
前記ワクチンに放射線照射するステップと、
前記ワクチンを凍結するステップと
を含む、フューリンノックダウン及び顆粒球マクロファージコロニー刺激因子(GM−CSF)増強(FANG)癌ワクチンを作製する方法。 - 1又は2以上の癌細胞が、メラノーマ、非小細胞肺癌、胆嚢癌、結腸直腸癌、乳癌、卵巣癌、肝癌、肝癌転移及びユーイング肉腫からなる群から選択される癌を患う患者から収集される、請求項23に記載の方法。
- 遺伝的に改変された細胞が、放射線照射によって増殖能力のない状態にされている、請求項23に記載の方法。
- 遺伝的に改変された細胞が自家細胞である、請求項23に記載の方法。
- 遺伝的に改変された細胞が異種移植片増幅細胞である、請求項23に記載の方法。
- 遺伝的に改変された細胞が同種異系細胞である、請求項23に記載の方法。
- 同種異系細胞が樹立細胞系である、請求項28に記載の方法。
- 遺伝的に改変された細胞が、月に1回を最大12用量まで対象に投与される、請求項23に記載の方法。
- 対象に投与される遺伝的に改変された細胞の用量が、1×107細胞/注射〜5×107細胞/注射である、請求項23に記載の方法。
- 遺伝的に改変された細胞の投与が、追加的な治療薬との併用療法の一部である、請求項31に記載の方法。
- 併用療法に用いられる追加的な治療薬がγIFNである、請求項32に記載の方法。
- 併用療法において対象に投与されるγIFNの用量が、50又は100μg/m2である、請求項33に記載の方法。
- トランスフェクション後に、遺伝的に改変された細胞をγIFNとインキュベートするさらなるステップを含む、請求項23に記載の方法。
- トランスフェクション後に、遺伝的に改変された細胞に適用されるγIFNの用量が、約250U/mlである、請求項35に記載の方法。
- 標的細胞を選択するステップと、
前記標的細胞に、プロモーター及び前記プロモーターに作動可能に連結した核酸インサートを含む発現ベクターをトランスフェクトするステップであって、前記インサートが、フューリンをコードするmRNA転写産物の領域とハイブリダイズして、これによりRNA干渉を介してフューリン発現を阻害できる1又は2以上の低分子ヘアピン型RNA(shRNA)をコードする、ステップと
を含む、フューリンノックダウンを介してトランスフォーミング増殖因子ベータ(TGF−ベータ又はTGF−β)発現を阻害するためのsiRNAを介在した方法。 - shRNAが、siRNA(切断依存的)及びmiRNA(切断非依存的)モチーフを組み入れている、請求項37に記載の方法。
- shRNAが、切断依存的及び切断非依存的の両方であるフューリン発現阻害因子である、請求項37に記載の方法。
- shRNAが、二機能性shRNAとしてさらに定義される、請求項37に記載の方法。
- shRNAの標的となる領域が、フューリンmRNA転写産物の3’UTR領域配列である、請求項37に記載の方法。
- shRNAの標的となる領域が、フューリンmRNA転写産物のコード領域である、請求項37に記載の方法。
- 標的細胞を選択するステップと、
前記標的細胞に、GM−CSFをコードする、プロモーターに作動可能に連結した第一の核酸インサート、及びフューリンをコードするmRNA転写産物の領域とハイブリダイズして、これによりRNA干渉を介してフューリン発現を阻害できる1又は2以上の低分子ヘアピン型RNA(shRNA)をコードする、前記プロモーターに作動可能に連結した第二の核酸インサートを含む発現ベクターをトランスフェクトするステップと
を含む、標的細胞における抗原の発現、提示及びプロセシングを増強するため並びにトランスフォーミング増殖因子ベータ(TGF−ベータ又はTGF−β)の分泌性免疫抑制活性を減衰するための方法。 - 標的細胞が自家細胞である、請求項43に記載の方法。
- 標的細胞が同種異系細胞である、請求項43に記載の方法。
- 同種異系細胞が樹立ヒト細胞系である、請求項45に記載の方法。
- 標的細胞が、プラスミドベクター電気穿孔によりトランスフェクトされる、請求項43に記載の方法。
- TGF−βが、TGF−β1、TGF−β2及びTGF−β3のうち少なくとも1種類から選択される、請求項43に記載の方法。
- 治療を必要とする対象を同定するステップと、
前記対象から癌組織試料を収集するステップと、
前記収集された癌試料における癌細胞を、GM−CSFをコードする、プロモーターに作動可能に連結した第一の核酸インサート、及びフューリンをコードするmRNA転写産物の領域とハイブリダイズして、これによりRNA干渉を介してフューリン発現を阻害できる1又は2以上の低分子ヘアピン型RNA(shRNA)をコードする、前記プロモーターに作動可能に連結した第二の核酸インサートを含む発現ベクターを前記細胞にトランスフェクトすることによって、遺伝的に改変するステップと、
癌の症状の治療又は寛解に十分な量で、前記対象に治療上有効用量の前記遺伝的に改変された細胞を投与するステップと
を含む、癌を治療する方法。 - 癌が、メラノーマ、非小細胞肺癌、胆嚢癌、結腸直腸癌、乳癌、卵巣癌、肝癌、肝癌転移及びユーイング肉腫からなる癌の群から選ばれる、請求項49に記載の方法。
- 遺伝的に改変された細胞が、放射線照射により増殖能力のない状態にされている、請求項49に記載の方法。
- 遺伝的に改変された細胞が自家細胞である、請求項49に記載の方法。
- 遺伝的に改変された細胞が同種異系細胞である、請求項49に記載の方法。
- 同種異系細胞が樹立細胞系である、請求項53に記載の方法。
- 遺伝的に改変された細胞が異種移植片増幅細胞である、請求項49に記載の方法。
- 遺伝的に改変された細胞が、月に1回を最大12用量まで対象に投与される、請求項49に記載の方法。
- 対象に投与される遺伝的に改変された細胞の用量が、1×107細胞/注射〜5×107細胞/注射である、請求項49に記載の方法。
- 遺伝的に改変された細胞の投与が、追加的な治療薬との併用療法の一部である、請求項49に記載の方法。
- 併用療法に用いられる追加的な治療薬がγIFNである、請求項58に記載の方法。
- 併用療法において対象に投与されるγIFNの用量が、50又は100μg/m2である、請求項59に記載の方法。
- トランスフェクション後に、遺伝的に改変された細胞をγIFNとインキュベートするさらなるステップを含む、請求項49に記載の方法。
- トランスフェクション後に、遺伝的に改変された細胞に適用されるγIFNの用量が、約250U/mlである、請求項61に記載の方法。
- 顆粒球マクロファージコロニー刺激因子(GM−CSF)cDNAをコードする、プロモーターに作動可能に連結した第一の核酸インサート、並びに
RNA干渉の切断及び隔離機構両方のための単一の標的部位を提供する1又は2以上の二機能性低分子ヘアピン型RNA(shRNAフューリン)をコードする、前記プロモーターに作動可能に連結した第二の核酸インサートであって、二機能性shRNAフューリンが、フューリンをコードするmRNA転写産物の領域とハイブリダイズして、これによりRNA干渉を介してフューリン発現を阻害できる、完全に相補的なガイド鎖及びパッセンジャー鎖を含む第一のステム−ループ構造並びに前記パッセンジャー鎖の1又は2以上の塩基対ミスマッチを含む第二のステム−ループ構造を含む第二の核酸インサート
を含むbishRNAフューリン/GMCSF発現ベクタープラスミドと、
1又は2以上の必要に応じたワクチンアジュバントと
を含む、RNA干渉を介したフューリン発現の阻害による癌治療のための自家細胞ワクチン組成物。 - 第二のステム−ループ構造が、3塩基対ミスマッチを含む、請求項63に記載の組成物。
- 塩基対ミスマッチが、パッセンジャー鎖のポジション9〜11に位置する、請求項63に記載の組成物。
- 顆粒球マクロファージコロニー刺激因子(GM−CSF)cDNAをコードする、プロモーターに作動可能に連結した第一の核酸インサート、並びに
RNA干渉の切断及び隔離機構両方のための単一の標的部位を提供する1又は2以上の二機能性低分子ヘアピン型RNA(shRNAフューリン)をコードする、前記プロモーターに作動可能に連結した第二の核酸インサートであって、二機能性shRNAフューリンが、フューリンをコードするmRNA転写産物の領域とハイブリダイズして、これによりRNA干渉を介してフューリン発現を阻害できる、完全に相補的なガイド鎖及びパッセンジャー鎖を含む第一のステム−ループ構造並びに前記ガイド鎖の1又は2以上の塩基対ミスマッチを含む第二のステム−ループ構造を含む第二の核酸インサート
を含むbishRNAフューリン/GMCSF発現ベクタープラスミドと、
1又は2以上の必要に応じたワクチンアジュバントと
を含む、RNA干渉を介したフューリン発現の阻害による癌治療のための自家細胞ワクチン組成物。 - 第二のステム−ループ構造が、3塩基対ミスマッチを含む、請求項66に記載の組成物。
- 塩基対ミスマッチが、ガイド鎖のポジション9〜11に位置する、請求項66に記載の組成物。
- 標的細胞を選択するステップと、
前記標的細胞に、1又は2以上のGM−CSFと、完全に相補的なガイド鎖及びパッセンジャー鎖を含む第一のステム−ループ構造並びに前記パッセンジャー鎖の1又は2以上の塩基対ミスマッチを含む第二のステム−ループ構造を含み、フューリンをコードするmRNA転写産物の領域とハイブリダイズして、これによりRNA干渉を介してフューリン発現を阻害する二機能性低分子ヘアピン(shRNA)フューリンとを含むコンストラクトをトランスフェクトするステップと
を含む、標的細胞においてRNA干渉を介してフューリン発現を阻害する方法。 - 第二のステム−ループ構造が、3塩基対ミスマッチを含む、請求項69に記載の方法。
- 塩基対ミスマッチが、パッセンジャー鎖のポジション9〜11に位置する、請求項69に記載の方法。
- 塩基対ミスマッチが、Ago2介在性の切断を妨げることによってパッセンジャー鎖離脱を促す、請求項69に記載の方法。
- 塩基対ミスマッチがガイド鎖のポジションを占める、請求項69に記載の方法。
- 標的細胞を選択するステップと、
前記標的細胞に、1又は2以上のGM−CSFと、完全に相補的なガイド鎖及びパッセンジャー鎖を含む第一のステム−ループ構造並びに前記ガイド鎖の1又は2以上の塩基対ミスマッチを含む第二のステム−ループ構造を含み、フューリンをコードするmRNA転写産物の領域とハイブリダイズして、これによりRNA干渉を介してフューリン発現を阻害する二機能性低分子ヘアピン(shRNA)フューリンとを含むコンストラクトをトランスフェクトするステップと
を含む、標的細胞におけるRNA干渉を介してフューリン発現を阻害する方法。 - 第二のステム−ループ構造が、3塩基対ミスマッチを含む、請求項74に記載の方法。
- 塩基対ミスマッチが、ガイド鎖のポジション9〜11に位置する、請求項74に記載の方法。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017511128A (ja) * | 2014-03-26 | 2017-04-20 | トカジェン インコーポレーテッド | 免疫刺激活性を有するレトロウイルスベクター |
JP2021509253A (ja) * | 2017-10-10 | 2021-03-25 | ナントバイオ,インコーポレイテッド | ウイルス生成ペイロードに対して低い毒性を有する改変ec7細胞 |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8603991B2 (en) | 2005-11-18 | 2013-12-10 | Gradalis, Inc. | Individualized cancer therapy |
SG181881A1 (en) | 2009-12-23 | 2012-07-30 | Gradalis Inc | Furin-knockdown bi-functional rna |
CN102917709B (zh) | 2009-12-23 | 2018-04-24 | 格兰达利斯有限公司 | 弗林蛋白酶敲减和gm-csf增强的(fang)癌症疫苗 |
US20140141015A1 (en) | 2010-09-20 | 2014-05-22 | Douglas Lake | QSOX1 as an Anti-Neoplastic Drug Target |
US8946186B2 (en) | 2010-09-20 | 2015-02-03 | Arizona Board Of Regents, A Body Corporate Of The State Of Arizona Acting For And On Behalf Of Arizona State University | QSOX1 as an anti-neoplastic drug target |
WO2013115579A1 (ko) * | 2012-01-31 | 2013-08-08 | 연세대학교 산학협력단 | TGF-β2 발현을 억제하는 shRNA |
US9890215B2 (en) * | 2012-06-22 | 2018-02-13 | King's College London | Vista modulators for diagnosis and treatment of cancer |
US20160024600A1 (en) * | 2013-03-15 | 2016-01-28 | The United States of America, as represented by the Secretary, Department of Health and Human Ser | Coincidence reporter gene system |
US10640542B2 (en) * | 2013-07-18 | 2020-05-05 | Vib Vzw | Fusokines involving cytokines with strongly reduced receptor binding affinities |
WO2015152609A1 (ko) * | 2014-03-31 | 2015-10-08 | 연세대학교 산학협력단 | GM-CSF 유전자; 데코린 유전자; TGF-β2 발현을 억제하는 shRNA; 및 FoxP3 발현을 억제하는 shRNA를 포함하는 항종양 조성물 |
KR101713407B1 (ko) * | 2014-03-31 | 2017-03-07 | 연세대학교 산학협력단 | 아데노바이러스 감염 및 복제가 가능한 흑색종 세포주 |
EP3134528A4 (en) * | 2014-04-25 | 2017-12-06 | Strike Bio, Inc. | Multiple targeted rnai for the treatment of cancers |
ES2852002T3 (es) | 2015-07-30 | 2021-09-10 | Endor Tech S L | Factor estimulante de colonias para su uso en el tratamiento del cáncer de páncreas o de colon |
JP6898325B2 (ja) * | 2015-12-08 | 2021-07-07 | ユニバーシティ−インダストリー・ファンデーション・ヨンセイ・ユニバーシティ | GM−CSF遺伝子;Flt3L−TRAIL融合遺伝子;TGF−βの発現を抑制するshRNA;およびHSP発現を抑制するshRNAを含む抗腫瘍組成物 |
CN105734080A (zh) * | 2016-01-30 | 2016-07-06 | 山西大学 | 一种靶向抗癌基因-质粒及其构建方法和应用 |
WO2020048942A1 (en) * | 2018-09-04 | 2020-03-12 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for enhancing cytotoxic t lymphocyte-dependent immune responses |
CN109160888B (zh) * | 2018-10-09 | 2022-03-01 | 四川医立特生物医药有限公司 | 一种含脒基的对称化合物及其应用 |
JP7211139B2 (ja) * | 2019-02-14 | 2023-01-24 | 日本電信電話株式会社 | 校閲方法、情報処理装置および校閲プログラム |
CN110760477A (zh) * | 2019-10-10 | 2020-02-07 | 杭州广科安德生物科技有限公司 | 一种小鼠肝脏高转移肠癌细胞株的建立方法,细胞株和应用 |
CN115551537A (zh) | 2019-12-03 | 2022-12-30 | 纽沃进公司 | 肿瘤细胞疫苗 |
EP4090380A1 (en) * | 2020-01-13 | 2022-11-23 | Gradalis, Inc. | Methods for treating cancers using gm-csf encoding polynucleotide and additional agents |
WO2021146213A1 (en) * | 2020-01-13 | 2021-07-22 | Gradalis, Inc. | Methods for treating cancers using gm-csf encoding polynucleotide and additional agents |
EP4158025A1 (en) * | 2020-05-26 | 2023-04-05 | Gradalis, Inc. | Methods for the treatment of viral respiratory infections |
WO2022055817A1 (en) | 2020-09-09 | 2022-03-17 | Gradalis, Inc. | Composition formulated into inhalable dosage forms for the treatment of lung|tumors |
CN117136237A (zh) * | 2021-03-10 | 2023-11-28 | 格兰达利斯有限公司 | 用于治疗癌症的方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62164695A (ja) * | 1985-12-21 | 1987-07-21 | ヘキスト、アクチエンゲゼルシヤフト | Gm−csfタンパク質、その誘導体、このタイプのタンパク質の調製及びそれらの用途 |
US20070224194A1 (en) * | 2004-05-20 | 2007-09-27 | Ludwig Institute For Cancer Research | Methods for Inhibiting Angiogenesis and/or Lymphangiogenesis |
Family Cites Families (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6506559B1 (en) | 1997-12-23 | 2003-01-14 | Carnegie Institute Of Washington | Genetic inhibition by double-stranded RNA |
BR9908267A (pt) * | 1998-02-27 | 2000-10-24 | Univ Pennsylvania | Plasmìdeo, composição farmacêutica, processos para induzir uma resposta imunológica em um indivìduo contra um imunógeno, para imunizar um indivìduo contra uma infecção por vìrus de herpes simples e para tratar um indivìduo que tem uma doença autoimune, vacina recombinante, e, patógeno atenuado vivo |
US8791081B2 (en) | 1999-08-13 | 2014-07-29 | Case Western Reserve University | MGMT inhibitor combination for the treatment of neoplastic disorders |
JP4095895B2 (ja) | 2000-12-01 | 2008-06-04 | マックス−プランク−ゲゼルシャフト ツール フォーデルング デル ヴィッセンシャフテン エー.ヴェー. | Rna干渉を媒介する短鎖rna分子 |
JP2004519247A (ja) | 2001-03-20 | 2004-07-02 | オーソ・クリニカル・ダイアグノスティックス・インコーポレーテッド | 発現プロファイルおよび使用法 |
US20050143333A1 (en) | 2001-05-18 | 2005-06-30 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA) |
US20050080031A1 (en) | 2001-05-18 | 2005-04-14 | Sirna Therapeutics, Inc. | Nucleic acid treatment of diseases or conditions related to levels of Ras, HER2 and HIV |
BR0211111A (pt) | 2001-07-12 | 2004-06-22 | Univ Massachusetts | Molécula de ácido nucleico isolada, vetor, célula hospedeira, transgene, precursor de rna engenheirado, animal transgênico não humano, e, método de induzir a interferência de ácido ribonucleico de um gene alvo em uma célula |
US20030144823A1 (en) | 2001-11-01 | 2003-07-31 | Fox Jeffrey J. | Scale-free network inference methods |
JP2005508396A (ja) | 2001-11-02 | 2005-03-31 | イントラディグム、コーポレイション | 核酸送達ビヒクルのための治療方法 |
EP1474433A4 (en) | 2002-02-20 | 2005-02-23 | Sirna Therapeutics Inc | TARGET LOCALIZATION TARGETED BY RNA INTERFERENCE AND TARGET VALIDATION WITH SHORT INTERFERING NUCLEIC ACID (siNA) |
US20040241854A1 (en) | 2002-08-05 | 2004-12-02 | Davidson Beverly L. | siRNA-mediated gene silencing |
US20040023390A1 (en) | 2002-08-05 | 2004-02-05 | Davidson Beverly L. | SiRNA-mediated gene silencing with viral vectors |
DE60321689D1 (de) | 2002-08-29 | 2008-07-31 | Gene Network Sciences Inc | Systeme und verfahren zum schliessen auf biologische netzwerke |
CN1756568A (zh) | 2002-10-09 | 2006-04-05 | 衣阿华中央卫生系统 | 使用表达α(1,3)-半乳糖基转移酶的同种异型肿瘤细胞的抗肿瘤免疫 |
US20040088116A1 (en) | 2002-11-04 | 2004-05-06 | Gene Network Sciences, Inc. | Methods and systems for creating and using comprehensive and data-driven simulations of biological systems for pharmacological and industrial applications |
US7763722B2 (en) | 2003-01-17 | 2010-07-27 | University Of Florida Research Foundation, Inc. | Small interference RNA gene therapy |
WO2004087930A1 (en) | 2003-03-28 | 2004-10-14 | Saint Louis University | Adenovirus replication-competent vectors expressing trail |
CA2530125A1 (en) | 2003-06-27 | 2005-01-06 | Atugen Ag | Use of double-stranded ribonucleic acid for inducing cell lysis |
MXPA06008157A (es) | 2003-12-24 | 2007-09-07 | Johnson & Johnson | Tratamiento de gliomas malignos con inhibidores de factor de crecimiento transformante-beta. |
US20050146081A1 (en) | 2004-01-07 | 2005-07-07 | Maclean David | Needle protection device with gauge specific color coding and method for manufacturing thereof |
EP1765375A1 (en) | 2004-05-20 | 2007-03-28 | The Ludwig Institute for Cancer Research | Method for inhibiting angiogenesis and/or lymphangiogenesis |
US7615618B2 (en) | 2004-06-30 | 2009-11-10 | Alnylam Pharmaceuticals, Inc. | Oligonucleotides comprising a non-phosphate backbone linkage |
EP1797183B1 (en) | 2004-09-02 | 2012-08-01 | Yale University | Regulation of oncogenes by micrornas |
US20080152633A1 (en) | 2005-02-16 | 2008-06-26 | The University Of Queensland | Flavivirus Replicon Constructs for Tumor Therapy |
US20070179113A1 (en) * | 2005-05-19 | 2007-08-02 | Schering Aktiengesellachaft | GM-CSF gene therapy for Crohn's disease using an improved regulated expression system |
US8053183B2 (en) | 2005-07-27 | 2011-11-08 | Oncotherapy Science, Inc. | Method of diagnosing esophageal cancer |
US8603991B2 (en) | 2005-11-18 | 2013-12-10 | Gradalis, Inc. | Individualized cancer therapy |
US8916530B2 (en) | 2005-11-18 | 2014-12-23 | Gradalis, Inc. | Individualized cancer therapy |
US8906874B2 (en) | 2006-11-09 | 2014-12-09 | Gradalis, Inc. | Bi-functional shRNA targeting Stathmin 1 and uses thereof |
US8252526B2 (en) | 2006-11-09 | 2012-08-28 | Gradalis, Inc. | ShRNA molecules and methods of use thereof |
US8758998B2 (en) | 2006-11-09 | 2014-06-24 | Gradalis, Inc. | Construction of bifunctional short hairpin RNA |
WO2008101087A1 (en) | 2007-02-14 | 2008-08-21 | Ontherex Llc | Compositions and methods for modulation of pdx-1 |
WO2008144900A1 (en) * | 2007-05-25 | 2008-12-04 | Peel Sean A | A method of enhancing recombinant protein production |
US20090004668A1 (en) | 2007-06-22 | 2009-01-01 | The Board Of Trustees Of The Leland Stanford Junior University | Pre-miRNA loop-modulated target regulation |
WO2010008726A1 (en) | 2008-06-16 | 2010-01-21 | Immunogen Inc. | Novel synergistic effects |
US20110045534A1 (en) * | 2009-08-20 | 2011-02-24 | Cell Signaling Technology, Inc. | Nucleic Acid Cassette For Producing Recombinant Antibodies |
WO2011053660A2 (en) | 2009-10-30 | 2011-05-05 | Gradalis, Inc. | Novel therapeutic rna interference technology targeted to the pdx-1 oncogene in pdx-1 expressing neuroendocrine tumors |
CN102917709B (zh) | 2009-12-23 | 2018-04-24 | 格兰达利斯有限公司 | 弗林蛋白酶敲减和gm-csf增强的(fang)癌症疫苗 |
SG181881A1 (en) * | 2009-12-23 | 2012-07-30 | Gradalis Inc | Furin-knockdown bi-functional rna |
US20110286979A1 (en) | 2010-05-20 | 2011-11-24 | Gradalis, Inc. | CHEMOSENSITIZATION BY BI-FUNCTIONAL SMALL HAIRPIN RNA (bi-shRNA) |
SG11201407239SA (en) | 2012-05-09 | 2014-12-30 | Gradalis Inc | BI-FUNCTIONAL SHORT-HAIRPIN RNA (BI-SHRNA) SPECIFIC FOR SINGLE-NUCLEOTIDE <i>KRAS</i> MUTATIONS |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62164695A (ja) * | 1985-12-21 | 1987-07-21 | ヘキスト、アクチエンゲゼルシヤフト | Gm−csfタンパク質、その誘導体、このタイプのタンパク質の調製及びそれらの用途 |
US20070224194A1 (en) * | 2004-05-20 | 2007-09-27 | Ludwig Institute For Cancer Research | Methods for Inhibiting Angiogenesis and/or Lymphangiogenesis |
Non-Patent Citations (4)
Title |
---|
JPN6013063989; Advanced Drug Delivery Reviews Vol.61, 200904, Vol.746-759 * |
JPN6013063991; BioProcessing Journal Vol.8, No.1, 200902, p.30-36 * |
JPN6013063992; Nature Vol.455, 2008, p.246-251 * |
JPN6013063993; BioProcessing Journal Vol.8, No.4, 20100330, p.4-14 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017511128A (ja) * | 2014-03-26 | 2017-04-20 | トカジェン インコーポレーテッド | 免疫刺激活性を有するレトロウイルスベクター |
JP2021509253A (ja) * | 2017-10-10 | 2021-03-25 | ナントバイオ,インコーポレイテッド | ウイルス生成ペイロードに対して低い毒性を有する改変ec7細胞 |
US11485957B2 (en) | 2017-10-10 | 2022-11-01 | Nantbio, Inc. | Modified EC7 cells having low toxicity to viral production payloads |
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