Improving the therapeutic potential of human granzyme B for targeted cancer therapy

Antibodies

Volumn 2, Issue 1, 2013, Pages 19-49

  Hehmann Titt, Grit ^a   Schiffer, Sonja ^b,c   Berges, Nina ^b   Melmer, Georg ^a   Barth, Stefan ^b,c  

^a PharmedArtis GmbH   (Germany)

^b UNIVERSITY HOSPITAL RWTH AACHEN   (Germany)

^c FRAUNHOFER INSTITUTE FOR MOLECULAR BIOLOGY AND APPLIED ECOLOGY IME   (Germany)

Author keywords

Bio engineering; Endosomal release; Human cytolytic fusion protein; Immunotherapy; Immunotoxin; Serpin B9; Surface charge

Indexed keywords

CD30 LIGAND; EPIDERMAL GROWTH FACTOR; GRANZYME B; HUMAN CYTOLYTIC FUSION PROTEIN; HYBRID PROTEIN; IMMUNOTOXIN; INTERLEUKIN 2; INTERLEUKIN 4; SERINE PROTEINASE INHIBITOR; SERPIN B9; TRANSFORMING GROWTH FACTOR ALPHA; UNCLASSIFIED DRUG;

APOPTOSIS; BIOENGINEERING; CANCER CELL CULTURE; CANCER RESISTANCE; CELLULAR IMMUNITY; CYTOTOXICITY; ENZYME ACTIVITY; HETEROLOGOUS EXPRESSION; HUMAN; IMMUNOGENICITY; MOLECULARLY TARGETED THERAPY; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW;

EID: 84887153701     PISSN: 20734468     EISSN: None     Source Type: Journal    
DOI: 10.3390/antib2010019     Document Type: Review

References (199)

1. Klebanoff, C. A.; Acquavella, N.; Yu, Z. Y.; Restifo, N. P. Therapeutic cancer vaccines: Are we there yet? Immunol. Rev. 2011, 239, 27-44.
2. Kreitman, R. J. Immunotoxins for targeted cancer therapy. AAPS J. 2006, 8, E532-E551.
3. Vanneman, M.; Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 2012, 12, 237-251.
4. Waldmann, T. A. Immunotherapy: Past, present and future. Nat. Med. 2003, 9, 269-277.
5. Scott, A. M.; Allison, J. P.; Wolchok, J. D. Monoclonal antibodies in cancer therapy. Cancer Immun. 2012, 12, 14.
6. Reichert, J. M. Antibody-based therapeutics to watch in 2011. MAbs 2011, 3, 76-99.
7. Schrama, D.; Reisfeld, R. A.; Becker, J. C. Antibody targeted drugs as cancer therapeutics. Nat. Rev. Drug Discov. 2006, 5, 147-59.
8. Carter, P. Improving the efficacy of antibody-based cancer therapies. Nat. Rev. Cancer 2001, 1, 118-129.
9. Rybak, S. M.; Hoogenboom, H. R.; Meade, H. M.; Raus, J. C.; Schwartz, D.; Youle, R. J. Humanization of immunotoxins. Proc. Natl. Acad. Sci. USA 1992, 89, 3165-3169.
10. Natsume, A.; Niwa, R.; Satoh, M. Improving effector functions of antibodies for cancer treatment: Enhancing ADCC and CDC. Drug Des. Devel. Ther. 2009, 3, 7-16.
11. Carter, P. J.; Senter, P. D. Antibody-drug conjugates for cancer therapy. Cancer J. 2008, 14, 154-169.
12. Lambert, J. M. Drug-conjugated monoclonal antibodies for the treatment of cancer. Curr. Opin. Pharmacol. 2005, 5, 543-549.
13. Younes, A.; Yasothan, U.; Kirkpatrick, P. Brentuximab vedotin. Nat. Rev. Drug Discov. 2012, 11, 19-20.
14. Bross, P. F.; Beitz, J.; Chen, G.; Chen, X. H.; Duffy, E.; Kieffer, L.; Roy, S.; Sridhara, R.; Rahman, A.; Williams, G.; et al. Approval summary: Gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin. Cancer Res. 2001, 7, 1490-1496.
15. Kreitman, R. J. Recombinant toxins for the treatment of cancer. Curr. Opin. Mol. Ther. 2003, 5, 44-51.
16. Allen, T. M. Ligand-targeted therapeutics in anticancer therapy. Nat. Rev. Cancer 2002, 2, 750-763.
17. Pavlinkova, G.; Beresford, G. W.; Booth, B. J.; Batra, S. K.; Colcher, D. Pharmacokinetics and biodistribution of engineered single-chain antibody constructs of MAb CC49 in colon carcinoma xenografts. J. Nucl. Med. 1999, 40, 1536-1546.
18. Pirker, R.; FitzGerald, D. J.; Willingham, M. C.; Pastan, I. Enhancement of the activity of immunotoxins made with either ricin A chain or Pseudomonas exotoxin in human ovarian and epidermoid carcinoma cell lines. Cancer Res. 1988, 48, 3919-3923.
19. Barth, S.; Huhn, M.; Matthey, B.; Schnell, R.; Tawadros, S.; Schinkothe, T.; Lorenzen, J.; Diehl, V.; Engert, A. Recombinant anti-CD25 immunotoxin RFT5(SCFV)-ETA' demonstrates successful elimination of disseminated human Hodgkin lymphoma in SCID mice. Int. J. Cancer 2000, 86, 718-724.
20. Barth, S.; Huhn, M.; Matthey, B.; Tawadros, S.; Schnell, R.; Schinkothe, T.; Diehl, V.; Engert, A. Ki-4(scFv)-ETA', a new recombinant anti-CD30 immunotoxin with highly specific cytotoxic activity against disseminated Hodgkin tumors in SCID mice. Blood 2000, 95, 3909-3914.
21. Schnell, R.; Vitetta, E.; Schindler, J.; Borchmann, P.; Barth, S.; Ghetie, V.; Hell, K.; Drillich, S.; Diehl, V.; Engert, A. Treatment of refractory Hodgkin's lymphoma patients with an anti-CD25 ricin A-chain immunotoxin. Leukemia 2000, 14, 129-135.
22. Kreitman, R. J. Recombinant immunotoxins for the treatment of chemoresistant hematologic malignancies. Curr. Pharm. Des. 2009, 15, 2652-2664.
23. Kreitman, R. J.; Wilson, W. H.; Bergeron, K.; Raggio, M.; Stetler-Stevenson, M.; FitzGerald, D. J.; Pastan, I. Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N. Engl. J. Med. 2001, 345, 241-247.
24. Frankel, A. E.; Powell, B. L.; Hall, P. D.; Case, L. D.; Kreitman, R. J. Phase I trial of a novel diphtheria toxin/granulocyte macrophage colony-stimulating factor fusion protein (DT388GMCSF) for refractory or relapsed acute myeloid leukemia. Clin. Cancer Res. 2002, 8, 1004-1013.
25. Szatrowski, T. P.; Dodge, R. K.; Reynolds, C.; Westbrook, C. A.; Frankel, S. R.; Sklar, J.; Stewart, C. C.; Hurd, D. D.; Kolitz, J. E.; Velez-Garcia, E.; et al. Lineage specific treatment of adult patients with acute lymphoblastic leukemia in first remission with anti-B4-blocked ricin or high-dose cytarabine: Cancer and Leukemia Group B Study 9311. Cancer 2003, 97, 1471-1480.
26. Pai, L. H.; Pastan, I. Clinical trials with Pseudomonas exotoxin immunotoxins. Curr. Top. Microbiol. Immunol. 1998, 234, 83-96.
27. Pastan, I.; Hassan, R.; Fitzgerald, D. J.; Kreitman, R. J. Immunotoxin therapy of cancer. Nat. Rev. Cancer 2006, 6, 559-565.
28. Pastan, I.; Hassan, R.; FitzGerald, D. J.; Kreitman, R. J. Immunotoxin treatment of cancer. Annu. Rev. Med. 2007, 58, 221-237.
29. Madhumathi, J.; Verma, R. S. Therapeutic targets and recent advances in protein immunotoxins. Curr. Opin. Microbiol. 2012, 15, 300-309.
30. Becker, N.; Benhar, I. Antibody-Based Immunotoxins for the Treatment of Cancer. Antibodies 2012, 1, 39-69.
31. Dang, N. H.; Pro, B.; Hagemeister, F. B.; Samaniego, F.; Jones, D.; Samuels, B. I.; Rodriguez, M. A.; Goy, A.; Romaguera, J. E.; McLaughlin, P.; et al. Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma. Br. J. Haematol. 2007, 136, 439-447.
32. Mathew, M.; Verma, R. S. Humanized immunotoxins: A new generation of immunotoxins for targeted cancer therapy. Cancer Sci. 2009, 100, 1359-1365.
33. Tur, M. K.; Neef, I.; Jager, G.; Teubner, A.; Stocker, M.; Melmer, G.; Barth, S. Immunokinases, a novel class of immunotherapeutics for targeted cancer therapy. Curr. Pharm. Des. 2009, 15, 2693-2699.
34. Huhn, M.; Sasse, S.; Tur, M. K.; Matthey, B.; Schinkothe, T.; Rybak, S. M.; Barth, S.; Engert, A. Human angiogenin fused to human CD30 ligand (Ang-CD30L) exhibits specific cytotoxicity against CD30-positive lymphoma. Cancer Res. 2001, 61, 8737-8742.
35. Rosenblum, M. G.; Barth, S. Development of novel, highly cytotoxic fusion constructs containing granzyme B: Unique mechanisms and functions. Curr. Pharm. Des. 2009, 15, 2676-2692.
36. von Minckwitz, G.; Harder, S.; Hovelmann, S.; Jager, E.; Al-Batran, S. E.; Loibl, S.; Atmaca, A.; Cimpoiasu, C.; Neumann, A.; Abera, A.; et al. Phase I clinical study of the recombinant antibody toxin scFv(FRP5)-ETA specific for the ErbB2/HER2 receptor in patients with advanced solid malignomas. Breast Cancer Res. 2005, 7, R617-R626.
37. Engert, A.; Diehl, V.; Schnell, R.; Radszuhn, A.; Hatwig, M. T.; Drillich, S.; Schon, G.; Bohlen, H.; Tesch, H.; Hansmann, M. L.; et al. A phase-I study of an anti-CD25 ricin A-chain immunotoxin (RFT5-SMPT-dgA) in patients with refractory Hodgkin's lymphoma. Blood 1997, 89, 403-410.
38. Hall, P. D.; Virella, G.; Willoughby, T.; Atchley, D. H.; Kreitman, R. J.; Frankel, A. E. Antibody response to DT-GM, a novel fusion toxin consisting of a truncated diphtheria toxin (DT) linked to human granulocyte-macrophage colony stimulating factor (GM), during a phase I trial of patients with relapsed or refractory acute myeloid leukemia. Clin. Immunol. 2001, 100, 191-17.
39. Posey, J. A.; Khazaeli, M. B.; Bookman, M. A.; Nowrouzi, A.; Grizzle, W. E.; Thornton, J.; Carey, D. E.; Lorenz, J. M.; Sing, A. P.; Siegall, C. B.; et al. A phase I trial of the single-chain immunotoxin SGN-10 (BR96 sFv-PE40) in patients with advanced solid tumors. Clin. Cancer Res. 2002, 8, 3092-3099.
40. Scadden, D. T.; Schenkein, D. P.; Bernstein, Z.; Luskey, B.; Doweiko, J.; Tulpule, A.; Levine, A. M. Immunotoxin combined with chemotherapy for patients with AIDS-related non-Hodgkin's lymphoma. Cancer 1998, 83, 2580-2587.
41. Mischak, R. P.; Foxall, C.; Rosendorf, L. L.; Knebel, K.; Scannon, P. J.; Spitler, L. E. Human antibody responses to components of the monoclonal antimelanoma antibody ricin A chain immunotoxin XomaZyme-MEL. Mol. Biother. 1990, 2, 104-109.
42. Tur, M. K.; Neef, I.; Jost, E.; Galm, O.; Jager, G.; Stocker, M.; Ribbert, M.; Osieka, R.; Klinge, U.; Barth, S. Targeted restoration of down-regulated DAPK2 tumor suppressor activity induces apoptosis in Hodgkin lymphoma cells. J. Immunother. 2009, 32, 431-441.
43. Hwang, W. Y.; Foote, J. Immunogenicity of engineered antibodies. Methods 2005, 36, 3-10.
44. Boulianne, G. L.; Hozumi, N.; Shulman, M. J. Production of functional chimaeric mouse/human antibody. Nature 1984, 312, 643-646.
45. Morrison, S. L.; Johnson, M. J.; Herzenberg, L. A.; Oi, V. T. Chimeric human antibody molecules: Mouse antigen-binding domains with human constant region domains. Proc. Natl. Acad. Sci. USA 1984, 81, 6851-6855.
46. Jones, P. T.; Dear, P. H.; Foote, J.; Neuberger, M. S.; Winter, G. Replacing the complementaritydetermining regions in a human antibody with those from a mouse. Nature 1986, 321, 522-525.
47. Verhoeyen, M.; Milstein, C.; Winter, G. Reshaping human antibodies: Grafting an antilysozyme activity. Science 1988, 239, 1534-1536.
48. Hu, W. G.; Yin, J.; Chau, D.; Negrych, L. M.; Cherwonogrodzky, J. W. Humanization and characterization of an anti-ricin neutralization monoclonal antibody. PLoS One 2012, 7, e45595.
49. Lonberg, N. Fully human antibodies from transgenic mouse and phage display platforms. Curr. Opin. Immunol. 2008, 20, 450-459.
50. Menoret, S.; Iscache, A. L.; Tesson, L.; Remy, S.; Usal, C.; Osborn, M. J.; Cost, G. J.; Bruggemann, M.; Buelow, R.; Anegon, I. Characterization of immunoglobulin heavy chain knockout rats. Eur. J. Immunol. 2010, 40, 2932-2941.
51. Hansen, J. K.; Weldon, J. E.; Xiang, L.; Beers, R.; Onda, M.; Pastan, I. A recombinant immunotoxin targeting CD22 with low immunogenicity, low nonspecific toxicity, and high antitumor activity in mice. J. Immunother. 2010, 33, 297-304.
52. Liu, W.; Onda, M.; Lee, B.; Kreitman, R. J.; Hassan, R.; Xiang, L.; Pastan, I. Recombinant immunotoxin engineered for low immunogenicity and antigenicity by identifying and silencing human B-cell epitopes. Proc. Natl. Acad. Sci. USA 2012, 109, 11782-11787.
53. Tsutsumi, Y.; Onda, M.; Nagata, S.; Lee, B.; Kreitman, R. J.; Pastan, I. Site-specific chemical modification with polyethylene glycol of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) improves antitumor activity and reduces animal toxicity and immunogenicity. Proc. Natl. Acad. Sci. USA 2000, 97, 8548-8553.
54. Oratz, R.; Speyer, J. L.; Wernz, J. C.; Hochster, H.; Meyers, M.; Mischak, R.; Spitler, L. E. Antimelanoma monoclonal antibody-ricin A chain immunoconjugate (XMMME-001-RTA) plus cyclophosphamide in the treatment of metastatic malignant melanoma: Results of a phase II trial. J. Biol. Response Mod. 1990, 9, 345-354.
55. Siegall, C. B.; Haggerty, H. G.; Warner, G. L.; Chace, D.; Mixan, B.; Linsley, P. S.; Davidson, T. Prevention of immunotoxin-induced immunogenicity by coadministration with CTLA4Ig enhances antitumor efficacy. J. Immunol. 1997, 159, 5168-5173.
56. Igney, F. H.; Krammer, P. H. Immune escape of tumors: Apoptosis resistance and tumor counterattack. J. Leuk. Biol. 2002, 71, 907-920.
57. Vesely, M. D.; Kershaw, M. H.; Schreiber, R. D.; Smyth, M. J. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol. 2011, 29, 235-271.
58. Griffith, T. S.; Chin, W. A.; Jackson, G. C.; Lynch, D. H.; Kubin, M. Z. Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J. Immunol. 1998, 161, 2833-2840.
59. Sutton, V. R.; Wowk, M. E.; Cancilla, M.; Trapani, J. A. Caspase activation by granzyme B is indirect, and caspase autoprocessing requires the release of proapoptotic mitochondrial factors. Immunity 2003, 18, 319-329.
60. Campos, L.; Rouault, J. P.; Sabido, O.; Oriol, P.; Roubi, N.; Vasselon, C.; Archimbaud, E.; Magaud, J. P.; Guyotat, D. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 1993, 81, 3091-3096.
61. Ambrosini, G.; Adida, C.; Altieri, D. C. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat. Med. 1997, 3, 917-921.
62. Russell, J. H.; Ley, T. J. Lymphocyte-mediated cytotoxicity. Annu. Rev. Immunol. 2002, 20, 323-370.
63. Boivin, W. A.; Cooper, D. M.; Hiebert, P. R.; Granville, D. J. Intracellular versus extracellular granzyme B in immunity and disease: Challenging the dogma. Lab. Invest. 2009, 89, 1195-1220.
64. Raja, S. M.; Wang, B.; Dantuluri, M.; Desai, U. R.; Demeler, B.; Spiegel, K.; Metkar, S. S.; Froelich, C. J. Cytotoxic cell granule-mediated apoptosis. Characterization of the macromolecular complex of granzyme B with serglycin. J. Biol. Chem. 2002, 277, 49523-49530.
65. Grossman, W. J.; Revell, P. A.; Lu, Z. H.; Johnson, H.; Bredemeyer, A. J.; Ley, T. J. The orphan granzymes of humans and mice. Curr. Opin. Immunol. 2003, 15, 544-552.
66. Bots, M.; Medema, J. P. Granzymes at a glance. J. Cell Sci. 2006, 119, 5011-5014.
67. Galvin, J. P.; Spaeny-Dekking, L. H.; Wang, B.; Seth, P.; Hack, C. E.; Froelich, C. J. Apoptosis induced by granzyme B-glycosaminoglycan complexes: Implications for granule-mediated apoptosis in vivo. J. Immunol. 1999, 162, 5345-5350.
68. Grujic, M.; Braga, T.; Lukinius, A.; Eloranta, M. L.; Knight, S. D.; Pejler, G.; Abrink, M. Serglycin-deficient cytotoxic T lymphocytes display defective secretory granule maturation and granzyme B storage. J. Biol. Chem. 2005, 280, 33411-33418.
69. Lanier, L. L. NK cell recognition. Annu. Rev. Immunol. 2005, 23, 225-274.
70. Kurschus, F. C.; Jenne, D. E. Delivery and therapeutic potential of human granzyme B. Immunol. Rev. 2010, 235, 159-171.
71. Andrade, F.; Casciola-Rosen, L. A.; Rosen, A. Granzyme B-induced cell death. Acta Haematol. 2004, 111, 28-41.
72. Heibein, J. A.; Goping, I. S.; Barry, M.; Pinkoski, M. J.; Shore, G. C.; Green, D. R.; Bleackley, R. C. Granzyme B-mediated cytochrome c release is regulated by the Bcl-2 family members bid and Bax. J. Exp. Med. 2000, 192, 1391-1402.
73. Pinkoski, M. J.; Waterhouse, N. J.; Heibein, J. A.; Wolf, B. B.; Kuwana, T.; Goldstein, J. C.; Newmeyer, D. D.; Bleackley, R. C.; Green, D. R. Granzyme B-mediated apoptosis proceeds predominantly through a Bcl-2-inhibitable mitochondrial pathway. J. Biol. Chem. 2001, 276, 12060-12067.
74. Metkar, S. S.; Wang, B.; Ebbs, M. L.; Kim, J. H.; Lee, Y. J.; Raja, S. M.; Froelich, C. J. Granzyme B activates procaspase-3 which signals a mitochondrial amplification loop for maximal apoptosis. J. Cell Biol. 2003, 160, 875-885.
75. Talanian, R. V.; Yang, X.; Turbov, J.; Seth, P.; Ghayur, T.; Casiano, C. A.; Orth, K.; Froelich, C. J. Granule-mediated killing: Pathways for granzyme B-initiated apoptosis. J. Exp. Med. 1997, 186, 1323-1331.
76. Waterhouse, N. J.; Sedelies, K. A.; Trapani, J. A. Role of Bid-induced mitochondrial outer membrane permeabilization in granzyme B-induced apoptosis. Immunol. Cell Biol. 2006, 84, 72-78.
77. Hengartner, M. O. The biochemistry of apoptosis. Nature 2000, 407, 770-776.
78. Stahnke, B.; Thepen, T.; Stocker, M.; Rosinke, R.; Jost, E.; Fischer, R.; Tur, M. K.; Barth, S. Granzyme B-H22(scFv), a human immunotoxin targeting CD64 in acute myeloid leukemia of monocytic subtypes. Mol. Cancer Ther. 2008, 7, 2924-2932.
79. Schiffer, S. Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany. 2012, unpublished work.
80. Liu, Y.; Cheung, L. H.; Hittelman, W. N.; Rosenblum, M. G. Targeted delivery of human proapoptotic enzymes to tumor cells: In vitro studies describing a novel class of recombinant highly cytotoxic agents. Mol. Cancer Ther. 2003, 2, 1341-1350.
81. Liu, Y.; Zhang, W.; Niu, T.; Cheung, L. H.; Munshi, A.; Meyn, R. E., Jr.; Rosenblum, M. G. Targeted apoptosis activation with GrB/scFvMEL modulates melanoma growth, metastatic spread, chemosensitivity, and radiosensitivity. Neoplasia 2006, 8, 125-135.
82. Dalken, B.; Giesubel, U.; Knauer, S. K.; Wels, W. S. Targeted induction of apoptosis by chimeric granzyme B fusion proteins carrying antibody and growth factor domains for cell recognition. Cell Death Differ. 2006, 13, 576-585.
83. Medema, J. P.; de Jong, J.; Peltenburg, L. T.; Verdegaal, E. M.; Gorter, A.; Bres, S. A.; Franken, K. L.; Hahne, M.; Albar, J. P.; Melief, C. J.; et al. Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors. Proc. Natl. Acad. Sci. USA 2001, 98, 11515-11520.
84. Jiang, X.; Ellison, S. J.; Alarid, E. T.; Shapiro, D. J. Interplay between the levels of estrogen and estrogen receptor controls the level of the granzyme inhibitor, proteinase inhibitor 9 and susceptibility to immune surveillance by natural killer cells. Oncogene 2007, 26, 4106-4114.
85. Kurschus, F. C.; Kleinschmidt, M.; Fellows, E.; Dornmair, K.; Rudolph, R.; Lilie, H.; Jenne, D. E. Killing of target cells by redirected granzyme B in the absence of perforin. FEBS Lett. 2004, 562, 87-92.
86. Liu, Y.; Cheung, L. H.; Thorpe, P.; Rosenblum, M. G. Mechanistic studies of a novel human fusion toxin composed of vascular endothelial growth factor (VEGF)121 and the serine protease granzyme B: Directed apoptotic events in vascular endothelial cells. Mol. Cancer Ther. 2003, 2, 949-959.
87. Zhang, L.; Zhao, J.; Wang, T.; Yu, C. J.; Jia, L. T.; Duan, Y. Y.; Yao, L. B.; Chen, S. Y.; Yang, A. G. HER2-targeting recombinant protein with truncated pseudomonas exotoxin A translocation domain efficiently kills breast cancer cells. Cancer Biol. Ther. 2008, 7, 1226-1231.
88. Wang, T.; Zhao, J.; Ren, J. L.; Zhang, L.; Wen, W. H.; Zhang, R.; Qin, W. W.; Jia, L. T.; Yao, L. B.; Zhang, Y. Q.; et al. Recombinant immunoproapoptotic proteins with furin site can translocate and kill HER2-positive cancer cells. Cancer Res. 2007, 67, 11830-11839.
89. Kanatani, I.; Lin, X.; Yuan, X.; Manorek, G.; Shang, X.; Cheung, L. H.; Rosenblum, M. G.; Howell, S. B. Targeting granzyme B to tumor cells using a yoked human chorionic gonadotropin. Cancer Chemother. Pharmacol. 2011, 68, 979-990.
90. Hegde, R.; Srinivasula, S. M.; Zhang, Z.; Wassell, R.; Mukattash, R.; Cilenti, L.; DuBois, G.; Lazebnik, Y.; Zervos, A. S.; Fernandes-Alnemri, T.; et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J. Biol. Chem. 2002, 277, 432-438.
91. Liu, X.; Kim, C. N.; Yang, J.; Jemmerson, R.; Wang, X. Induction of apoptotic program in cellfree extracts: Requirement for dATP and cytochrome c. Cell 1996, 86, 147-157.
92. Han, J.; Goldstein, L. A.; Gastman, B. R.; Froelich, C. J.; Yin, X. M.; Rabinowich, H. Degradation of Mcl-1 by granzyme B: Implications for Bim-mediated mitochondrial apoptotic events. J. Biol. Chem. 2004, 279, 22020-22029.
93. Alimonti, J. B.; Shi, L.; Baijal, P. K.; Greenberg, A. H. Granzyme B induces BID-mediated cytochrome c release and mitochondrial permeability transition. J. Biol. Chem. 2001, 276, 6974-6982.
94. Waterhouse, N. J.; Sedelies, K. A.; Browne, K. A.; Wowk, M. E.; Newbold, A.; Sutton, V. R.; Clarke, C. J.; Oliaro, J.; Lindemann, R. K.; Bird, P. I.; et al. A central role for Bid in granzyme Binduced apoptosis. J. Biol. Chem. 2005, 280, 4476-4482.
95. Cullen, S. P.; Adrain, C.; Luthi, A. U.; Duriez, P. J.; Martin, S. J. Human and murine granzyme B exhibit divergent substrate preferences. J. Cell Biol. 2007, 176, 435-444.
96. Chowdhury, D.; Lieberman, J. Death by a thousand cuts: Granzyme pathways of programmed cell death. Annu. Rev. Immunol. 2008, 26, 389-420.
97. Trapani, J. A.; Sutton, V. R. Granzyme B: Pro-apoptotic, antiviral and antitumor functions. Curr. Opin. Immunol. 2003, 15, 533-543.
98. Bleackley, R. C. A molecular view of cytotoxic T lymphocyte induced killing. Biochem. Cell Biol. 2005, 83, 747-51.
99. Sun, J.; Bird, C. H.; Sutton, V.; McDonald, L.; Coughlin, P. B.; De Jong, T. A.; Trapani, J. A.; Bird, P. I. A cytosolic granzyme B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes. J. Biol. Chem. 1996, 271, 27802-27809.
100. Poe, M.; Blake, J. T.; Boulton, D. A.; Gammon, M.; Sigal, N. H.; Wu, J. K.; Zweerink, H. J. Human cytotoxic lymphocyte granzyme B. Its purification from granules and the characterization of substrate and inhibitor specificity. J. Biol. Chem. 1991, 266, 98-103.
101. Zhao, J.; Zhang, L. H.; Jia, L. T.; Zhang, L.; Xu, Y. M.; Wang, Z.; Yu, C. J.; Peng, W. D.; Wen, W. H.; Wang, C. J.; et al. Secreted antibody/granzyme B fusion protein stimulates selective killing of HER2-overexpressing tumor cells. J. Biol. Chem. 2004, 279, 21343-21348.
102. Caputo, A.; Garner, R. S.; Winkler, U.; Hudig, D.; Bleackley, R. C. Activation of recombinant murine cytotoxic cell proteinase-1 requires deletion of an amino-terminal dipeptide. J. Biol. Chem. 1993, 268, 17672-17675.
103. Dalken, B.; Jabulowsky, R. A.; Oberoi, P.; Benhar, I.; Wels, W. S. Maltose-binding protein enhances secretion of recombinant human granzyme B accompanied by in vivo processing of a precursor MBP fusion protein. PLoS One 2010, 5, e14404.
104. Kam, C. M.; Hudig, D.; Powers, J. C. Granzymes (lymphocyte serine proteases): Characterization with natural and synthetic substrates and inhibitors. Biochim. Biophys. Acta 2000, 1477, 307-323.
105. Griffiths, G. M.; Isaaz, S. Granzymes A and B are targeted to the lytic granules of lymphocytes by the mannose-6-phosphate receptor. J. Cell Biol. 1993, 120, 885-896.
106. Edwards, K. M.; Davis, J. E.; Browne, K. A.; Sutton, V. R.; Trapani, J. A. Anti-viral strategies of cytotoxic T lymphocytes are manifested through a variety of granule-bound pathways of apoptosis induction. Immunol. Cell Biol. 1999, 77, 76-89.
107. Giesubel, U.; Dalken, B.; Mahmud, F.; Wels, W. S. Cell binding, internalization and cytotoxic activity of human granzyme B expressed in the yeast Pichia pastoris. Biochem. J. 2006, 394, 563-573.
108. Xia, Z.; Kam, C. M.; Huang, C.; Powers, J. C.; Mandle, R. J.; Stevens, R. L.; Lieberman, J. Expression and purification of enzymatically active recombinant granzyme B in a baculovirus system. Biochem. Biophys. Res. Commun. 1998, 243, 384-389.
109. Smyth, M. J.; McGuire, M. J.; Thia, K. Y. Expression of recombinant human granzyme B. A processing and activation role for dipeptidyl peptidase I. J. Immunol. 1995, 154, 6299-6305.
110. Godal, R.; Keilholz, U.; Uharek, L.; Letsch, A.; Asemissen, A. M.; Busse, A.; Na, I. K.; Thiel, E.; Scheibenbogen, C. Lymphomas are sensitive to perforin-dependent cytotoxic pathways despite expression of PI-9 and overexpression of bcl-2. Blood 2006, 107, 3205-3211.
111. Soriano, C.; Mukaro, V.; Hodge, G.; Ahern, J.; Holmes, M.; Jersmann, H.; Moffat, D.; Meredith, D.; Jurisevic, C.; Reynolds, P. N.; et al. Increased proteinase inhibitor-9 (PI-9) and reduced granzyme B in lung cancer: Mechanism for immune evasion? Lung Cancer 2012, 77, 38-45.
112. Ray, M.; Hostetter, D. R.; Loeb, C. R.; Simko, J.; Craik, C. S. Inhibition of Granzyme B by PI-9 protects prostate cancer cells from apoptosis. Prostate 2012, 72, 846-855.
113. Rousalova, I.; Krepela, E.; Prochazka, J.; Cermak, J.; Benkova, K. Expression of proteinase inhibitor-9/serpinB9 in non-small cell lung carcinoma cells and tissues. Int. J. Oncol. 2010, 36, 275-283.
114. Jiang, X. G.; Patterson, N. M.; Ling, Y.; Xie, J. W.; Helferich, W. G.; Shapiro, D. J. Low Concentrations of the Soy Phytoestrogen Genistein Induce Proteinase Inhibitor 9 and Block Killing of Breast Cancer Cells by Immune Cells. Endocrinology 2008, 149, 5366-5373.
115. van Houdt, I. S.; Oudejans, J. J.; van den Eertwegh, A. J.; Baars, A.; Vos, W.; Bladergroen, B. A.; Rimoldi, D.; Muris, J. J.; Hooijberg, E.; Gundy, C. M.; et al. Expression of the apoptosis inhibitor protease inhibitor 9 predicts clinical outcome in vaccinated patients with stage III and IV melanoma. Clin. Cancer Res. 2005, 11, 6400-6407.
116. Oudejans, J. J.; Harijadi, H.; Kummer, J. A.; Tan, I. B.; Bloemena, E.; Middeldorp, J. M.; Bladergroen, B.; Dukers, D. F.; Vos, W.; Meijer, C. J. High numbers of granzyme B/CD8-positive tumour-infiltrating lymphocytes in nasopharyngeal carcinoma biopsies predict rapid fatal outcome in patients treated with curative intent. J. Pathol. 2002, 198, 468-475.
117. Bots, M.; Liesbeth, V. A. N. B.; Rademaker, M. T.; Offringa, R.; Medema, J. P. Serpins prevent granzyme-induced death in a species-specific manner. Immunol. Cell Biol. 2006, 84, 79-86.
118. Huntington, J. A.; Read, R. J.; Carrell, R. W. Structure of a serpin-protease complex shows inhibition by deformation. Nature 2000, 407, 923-926.
119. Bladergroen, B. A.; Strik, M. C.; Bovenschen, N.; van Berkum, O.; Scheffer, G. L.; Meijer, C. J.; Hack, C. E.; Kummer, J. A. The granzyme B inhibitor, protease inhibitor 9, is mainly expressed by dendritic cells and at immune-privileged sites. J. Immunol. 2001, 166, 3218-3225.
120. Buzza, M. S.; Hosking, P.; Bird, P. I. The granzyme B inhibitor, PI-9, is differentially expressed during placental development and up-regulated in hydatidiform moles. Placenta 2006, 27, 62-69.
121. Kannan-Thulasiraman, P.; Shapiro, D. J. Modulators of inflammation use nuclear factor-kappa B and activator protein-1 sites to induce the caspase-1 and granzyme B inhibitor, proteinase inhibitor 9. J. Biol. Chem. 2002, 277, 41230-41239.
122. El Haddad, N.; Moore, R.; Heathcote, D.; Mounayar, M.; Azzi, J.; Mfarrej, B.; Batal, I.; Ting, C.; Atkinson, M.; Sayegh, M. H.; et al. The novel role of SERPINB9 in cytotoxic protection of human mesenchymal stem cells. J. Immunol. 2011, 187, 2252-2260.
123. Heutinck, K. M.; Kassies, J.; Florquin, S.; Ten Berge, I. J.; Hamann, J.; Rowshani, A. T. SerpinB9 expression in human renal tubular epithelial cells is induced by triggering of the viral dsRNA sensors TLR3, MDA5 and RIG-I. Nephrol. Dial. Transplant. 2012, 27, 2746-2754.
124. Rowshani, A. T.; Strik, M. C.; Molenaar, R.; Yong, S. L.; Wolbink, A. M.; Bemelman, F. J.; Hack, C. E.; Ten Berge, I. J. The granzyme B inhibitor SERPINB9 (protease inhibitor 9) circulates in blood and increases on primary cytomegalovirus infection after renal transplantation. J. Infect. Dis. 2005, 192, 1908-1911.
125. Classen, C. F.; Bird, P. I.; Debatin, K. M. Modulation of the granzyme B inhibitor proteinase inhibitor 9 (PI-9) by activation of lymphocytes and monocytes in vitro and by Epstein-Barr virus and bacterial infection. Clin. Exp. Immunol. 2006, 143, 534-542.
126. Buzza, M. S.; Hirst, C. E.; Bird, C. H.; Hosking, P.; McKendrick, J.; Bird, P. I. The granzyme B inhibitor, PI-9, is present in endothelial and mesothelial cells, suggesting that it protects bystander cells during immune responses. Cell. Immunol. 2001, 210, 21-29.
127. Barrie, M. B.; Stout, H. W.; Abougergi, M. S.; Miller, B. C.; Thiele, D. L. Antiviral cytokines induce hepatic expression of the granzyme B inhibitors, proteinase inhibitor 9 and serine proteinase inhibitor 6. J. Immunol. 2004, 172, 6453-6459.
128. Horie, O.; Saigo, K.; Murayama, T.; Ryo, R. Differential expression of proteinase inhibitor-9 and granzyme B mRNAs in activated immunocompetent cells. Tohoku J. Exp. Med. 2005, 205, 103-113.
129. Hirst, C. E.; Buzza, M. S.; Bird, C. H.; Warren, H. S.; Cameron, P. U.; Zhang, M.; Ashton-Rickardt, P. G.; Bird, P. I. The intracellular granzyme B inhibitor, proteinase inhibitor 9, is up-regulated during accessory cell maturation and effector cell degranulation, and its overexpression enhances CTL potency. J. Immunol. 2003, 170, 805-815.
130. Rowshani, A. T.; Florquin, S.; Bemelman, F.; Kummer, J. A.; Hack, C. E.; Ten Berge, I. J. Hyperexpression of the granzyme B inhibitor PI-9 in human renal allografts: A potential mechanism for stable renal function in patients with subclinical rejection. Kidney Int. 2004, 66, 1417-1422.
131. Walker, P. R.; Saas, P.; Dietrich, P. Y. Role of Fas ligand (CD95L) in immune escape: The tumor cell strikes back. J. Immunol. 1997, 158, 4521-4524.
132. Buehring, G. C.; Eby, E. A.; Eby, M. J. Cell line cross-contamination: How aware are Mammalian cell culturists of the problem and how to monitor it? In Vitro Cell. Dev. Biol. Anim. 2004, 40, 211-215.
133. Bird, C. H.; Sutton, V. R.; Sun, J.; Hirst, C. E.; Novak, A.; Kumar, S.; Trapani, J. A.; Bird, P. I. Selective regulation of apoptosis: The cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway. Mol. Cell. Biol. 1998, 18, 6387-6398.
134. Schiffer, S. Efficacy of an adapted Granzyme B-based anti-CD30 cytolytic fusion protein against PI-9-positive classical Hodgkin lymphoma cells in a murine model. Blood Cancer J. 2012, submitted for publication.
135. ten Berge, R. L.; Meijer, C. J.; Dukers, D. F.; Kummer, J. A.; Bladergroen, B. A.; Vos, W.; Hack, C. E.; Ossenkoppele, G. J.; Oudejans, J. J. Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma. Blood 2002, 99, 4540-4546.
136. Tiacci, E.; Doring, C.; Brune, V.; van Noesel, C. J.; Klapper, W.; Mechtersheimer, G.; Falini, B.; Kuppers, R.; Hansmann, M. L. Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma. Blood 2012, 120, 4609-4620.
137. Fritsch, K. Die Bedeutung des Proteinase Inhibitor 9 für die Apoptoseresistenz in leukämischen Zelllinien, Ph. D. Thesis. Albert-Ludwigs-University, Freiburg im Breisgau.
138. Bossard, C.; Belhadj, K.; Reyes, F.; Martin-Garcia, N.; Berger, F.; Kummer, J. A.; Briere, J.; Baglin, A. C.; Cheze, S.; Bosq, J.; et al. Expression of the granzyme B inhibitor PI9 predicts outcome in nasal NK/T-cell lymphoma: Results of a Western series of 48 patients treated with first-line polychemotherapy within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials. Blood 2007, 109, 2183-2189.
139. Bladergroen, B. A.; Meijer, C. J.; ten Berge, R. L.; Hack, C. E.; Muris, J. J.; Dukers, D. F.; Chott, A.; Kazama, Y.; Oudejans, J. J.; van Berkum, O.; et al. Expression of the granzyme B inhibitor, protease inhibitor 9, by tumor cells in patients with non-Hodgkin and Hodgkin lymphoma: A novel protective mechanism for tumor cells to circumvent the immune system? Blood 2002, 99, 232-237.
140. Mahrus, S.; Kisiel, W.; Craik, C. S. Granzyme M is a regulatory protease that inactivates proteinase inhibitor 9, an endogenous inhibitor of granzyme B. J. Biol. Chem. 2004, 279, 54275-54282.
141. Madison, E. L.; Goldsmith, E. J.; Gerard, R. D.; Gething, M. J.; Sambrook, J. F. Serpin-resistant mutants of human tissue-type plasminogen activator. Nature 1989, 339, 721-724.
142. Potempa, J.; Korzus, E.; Travis, J. The serpin superfamily of proteinase inhibitors: Structure, function, and regulation. J. Biol. Chem. 1994, 269, 15957-15960.
143. Marszal, E.; Shrake, A. Serpin crystal structure and serpin polymer structure. Arch. Biochem. Biophys. 2006, 453, 123-129.
144. Silverman, G. A.; Bird, P. I.; Carrell, R. W.; Church, F. C.; Coughlin, P. B.; Gettins, P. G.; Irving, J. A.; Lomas, D. A.; Luke, C. J.; Moyer, R. W.; et al. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J. Biol. Chem. 2001, 276, 33293-33296.
145. Sun, J.; Whisstock, J. C.; Harriott, P.; Walker, B.; Novak, A.; Thompson, P. E.; Smith, A. I.; Bird, P. I. Importance of the P4' residue in human granzyme B inhibitors and substrates revealed by scanning mutagenesis of the proteinase inhibitor 9 reactive center loop. J. Biol. Chem. 2001, 276, 15177-15184.
146. Hedstrom, L. Serine protease mechanism and specificity. Chem. Rev. 2002, 102, 4501-4524.
147. Ye, S.; Cech, A. L.; Belmares, R.; Bergstrom, R. C.; Tong, Y.; Corey, D. R.; Kanost, M. R.; Goldsmith, E. J. The structure of a Michaelis serpin-protease complex. Nat. Struct. Biol. 2001, 8, 979-983.
148. Rotonda, J.; Garcia-Calvo, M.; Bull, H. G.; Geissler, W. M.; McKeever, B. M.; Willoughby, C. A.; Thornberry, N. A.; Becker, J. W. The three-dimensional structure of human granzyme B compared to caspase-3, key mediators of cell death with cleavage specificity for aspartic acid in P1. Chem. Biol. 2001, 8, 357-368.
149. Kortemme, T.; Baker, D. A simple physical model for binding energy hot spots in protein-protein complexes. Proc. Natl. Acad. Sci. USA 2002, 99, 14116-14121.
150. Losasso, V.; Schiffer, S.; Barth, S.; Carloni, P. Design of human granzyme B variants resistant to serpin B9. Proteins 2012, 80, 2514-2522.
151. Jabulowsky, R. A.; Oberoi, P.; Bahr-Mahmud, H.; Dalken, B.; Wels, W. S. Surface Charge-Modification Prevents Sequestration and Enhances Tumor-Cell Specificity of a Recombinant Granzyme B-TGF alpha Fusion Protein. Bioconjug. Chem. 2012, 23, 1567-1576.
152. Motyka, B.; Korbutt, G.; Pinkoski, M. J.; Heibein, J. A.; Caputo, A.; Hobman, M.; Barry, M.; Shostak, I.; Sawchuk, T.; Holmes, C. F.; et al. Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell 2000, 103, 491-500.
153. Veugelers, K.; Motyka, B.; Goping, I. S.; Shostak, I.; Sawchuk, T.; Bleackley, R. C. Granulemediated killing by granzyme B and perforin requires a mannose 6-phosphate receptor and is augmented by cell surface heparan sulfate. Mol. Biol. Cell 2006, 17, 623-633.
154. Kurschus, F. C.; Bruno, R.; Fellows, E.; Falk, C. S.; Jenne, D. E. Membrane receptors are not required to deliver granzyme B during killer cell attack. Blood 2005, 105, 2049-2058.
155. Trapani, J. A.; Sutton, V. R.; Thia, K. Y.; Li, Y. Q.; Froelich, C. J.; Jans, D. A.; Sandrin, M. S.; Browne, K. A. A clathrin/dynamin-and mannose-6-phosphate receptor-independent pathway for granzyme B-induced cell death. J. Cell Biol. 2003, 160, 223-233.
156. Bretthauer, R. K.; Castellino, F. J. Glycosylation of Pichia pastoris-derived proteins. Biotechnol. Appl. Biochem. 1999, 30, 193-200.
157. Raja, S. M.; Metkar, S. S.; Froelich, C. J. Cytotoxic granule-mediated apoptosis: Unraveling the complex mechanism. Curr. Opin. Immunol. 2003, 15, 528-532.
158. Gross, C.; Koelch, W.; DeMaio, A.; Arispe, N.; Multhoff, G. Cell surface-bound heat shock protein 70 (Hsp70) mediates perforin-independent apoptosis by specific binding and uptake of granzyme B. J. Biol. Chem. 2003, 278, 41173-41181.
159. Bird, C. H.; Sun, J.; Ung, K.; Karambalis, D.; Whisstock, J. C.; Trapani, J. A.; Bird, P. I. Cationic sites on granzyme B contribute to cytotoxicity by promoting its uptake into target cells. Mol. Cell. Biol. 2005, 25, 7854-7867.
160. Shi, L.; Keefe, D.; Durand, E.; Feng, H.; Zhang, D.; Lieberman, J. Granzyme B binds to target cells mostly by charge and must be added at the same time as perforin to trigger apoptosis. J. Immunol. 2005, 174, 5456-5461.
161. Metkar, S. S.; Wang, B.; Aguilar-Santelises, M.; Raja, S. M.; Uhlin-Hansen, L.; Podack, E.; Trapani, J. A.; Froelich, C. J. Cytotoxic cell granule-mediated apoptosis: Perforin delivers granzyme B-serglycin complexes into target cells without plasma membrane pore formation. Immunity 2002, 16, 417-428.
162. Onda, M.; Nagata, S.; Tsutsumi, Y.; Vincent, J. J.; Wang, Q.; Kreitman, R. J.; Lee, B.; Pastan, I. Lowering the isoelectric point of the Fv portion of recombinant immunotoxins leads to decreased nonspecific animal toxicity without affecting antitumor activity. Cancer Res. 2001, 61, 5070-5077.
163. Buzza, M. S.; Zamurs, L.; Sun, J.; Bird, C. H.; Smith, A. I.; Trapani, J. A.; Froelich, C. J.; Nice, E. C.; Bird, P. I. Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin. J. Biol. Chem. 2005, 280, 23549-23558.
164. Ronday, H. K.; van der Laan, W. H.; Tak, P. P.; de Roos, J. A.; Bank, R. A.; TeKoppele, J. M.; Froelich, C. J.; Hack, C. E.; Hogendoorn, P. C.; Breedveld, F. C.; et al. Human granzyme B mediates cartilage proteoglycan degradation and is expressed at the invasive front of the synovium in rheumatoid arthritis. Rheumatology (Oxford) 2001, 40, 55-61.
165. Tak, P. P.; Spaeny-Dekking, L.; Kraan, M. C.; Breedveld, F. C.; Froelich, C. J.; Hack, C. E. The levels of soluble granzyme A and B are elevated in plasma and synovial fluid of patients with rheumatoid arthritis (RA). Clin. Exp. Immunol. 1999, 116, 366-370.
166. Goldbach-Mansky, R.; Suson, S.; Wesley, R.; Hack, C. E.; El-Gabalawy, H. S.; Tak, P. P. Raised granzyme B levels are associated with erosions in patients with early rheumatoid factor positive rheumatoid arthritis. Ann. Rheum. Dis. 2005, 64, 715-721.
167. Chamberlain, C. M.; Ang, L. S.; Boivin, W. A.; Cooper, D. M.; Williams, S. J.; Zhao, H.; Hendel, A.; Folkesson, M.; Swedenborg, J.; Allard, M. F.; et al. Perforin-independent extracellular granzyme B activity contributes to abdominal aortic aneurysm. Am. J. Pathol. 2010, 176, 1038-1049.
168. Saito, Y.; Kondo, H.; Hojo, Y. Granzyme B as a novel factor involved in cardiovascular diseases. J. Cardiol. 2011, 57, 141-147.
169. Kurschus, F. C.; Fellows, E.; Stegmann, E.; Jenne, D. E. Granzyme B delivery via perforin is restricted by size, but not by heparan sulfate-dependent endocytosis. Proc. Natl. Acad. Sci. USA 2008, 105, 13799-13804.
170. Thomas, G. Furin at the cutting edge: From protein traffic to embryogenesis and disease. Nat. Rev. Mol. Cell Biol. 2002, 3, 753-766.
171. Molloy, S. S.; Anderson, E. D.; Jean, F.; Thomas, G. Bi-cycling the furin pathway: From TGN localization to pathogen activation and embryogenesis. Trends Cell Biol. 1999, 9, 28-35.
172. Ogata, M.; Fryling, C. M.; Pastan, I.; FitzGerald, D. J. Cell-mediated cleavage of Pseudomonas exotoxin between Arg279 and Gly280 generates the enzymatically active fragment which translocates to the cytosol. J. Biol. Chem. 1992, 267, 25396-25401.
173. Theuer, C. P.; FitzGerald, D.; Pastan, I. A recombinant form of Pseudomonas exotoxin directed at the epidermal growth factor receptor that is cytotoxic without requiring proteolytic processing. J. Biol. Chem. 1992, 267, 16872-16877.
174. Wolf, P.; Elsasser-Beile, U. Pseudomonas exotoxin A: From virulence factor to anti-cancer agent. Int. J. Med. Microbiol. 2009, 299, 161-176.
175. Collier, R. J. Understanding the mode of action of diphtheria toxin: A perspective on progress during the 20th century. Toxicon 2001, 39, 1793-1803.
176. Zhan, H.; Choe, S.; Huynh, P. D.; Finkelstein, A.; Eisenberg, D.; Collier, R. J. Dynamic transitions of the transmembrane domain of diphtheria toxin: Disulfide trapping and fluorescence proximity studies. Biochemistry 1994, 33, 11254-11263.
177. Plank, C.; Oberhauser, B.; Mechtler, K.; Koch, C.; Wagner, E. The influence of endosomedisruptive peptides on gene transfer using synthetic virus-like gene transfer systems. J. Biol. Chem. 1994, 269, 12918-12924.
178. Vives, E.; Brodin, P.; Lebleu, B. A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J. Biol. Chem. 1997, 272, 16010-16017.
179. Gius, D. R.; Ezhevsky, S. A.; Becker-Hapak, M.; Nagahara, H.; Wei, M. C.; Dowdy, S. F. Transduced p16INK4a peptides inhibit hypophosphorylation of the retinoblastoma protein and cell cycle progression prior to activation of Cdk2 complexes in late G1. Cancer Res. 1999, 59, 2577-2580.
180. Vocero-Akbani, A. M.; Heyden, N. V.; Lissy, N. A.; Ratner, L.; Dowdy, S. F. Killing HIV-infected cells by transduction with an HIV protease-activated caspase-3 protein. Nat. Med. 1999, 5, 29-33.
181. Falnes, P. O.; Wesche, J.; Olsnes, S. Ability of the Tat basic domain and VP22 to mediate cell binding, but not membrane translocation of the diphtheria toxin A-fragment. Biochemistry 2001, 40, 4349-4358.
182. Ziegler, A.; Seelig, J. Interaction of the protein transduction domain of HIV-1 TAT with heparan sulfate: Binding mechanism and thermodynamic parameters. Biophys. J. 2004, 86, 254-263.
183. Noguchi, H.; Ueda, M.; Matsumoto, S.; Kobayashi, N.; Hayashi, S. BETA2/NeuroD protein transduction requires cell surface heparan sulfate proteoglycans. Hum. Gene Ther. 2007, 18, 10-17.
184. Richard, J. P.; Melikov, K.; Brooks, H.; Prevot, P.; Lebleu, B.; Chernomordik, L. V. Cellular uptake of unconjugated TAT peptide involves clathrin-dependent endocytosis and heparan sulfate receptors. J. Biol. Chem. 2005, 280, 15300-15306.
185. Tilstra, J.; Rehman, K. K.; Hennon, T.; Plevy, S. E.; Clemens, P.; Robbins, P. D. Protein transduction: Identification, characterization and optimization. Biochem. Soc. Trans. 2007, 35, 811-815.
186. Zahid, M.; Lu, X.; Mi, Z.; Robbins, P. D. Cationic and tissue-specific protein transduction domains identification, characterization, and therapeutic application. Adv. Genet. 2010, 69, 83-95.
187. Fuchs, H.; Bachran, C.; Heisler, I.; Sutherland, M. A Closer Look at Protein Transduction Domains as a Tool in Drug Delivery. Curr. Nanosci. 2005, 1, 117-124.
188. Kabouridis, P. S. Biological applications of protein transduction technology. Trends Biotechnol. 2003, 21, 498-503.
189. van den Berg, A.; Dowdy, S. F. Protein transduction domain delivery of therapeutic macromolecules. Curr. Opin. Biotechnol. 2011, 22, 888-893.
190. Snyder, E. L.; Meade, B. R.; Dowdy, S. F. Anti-cancer protein transduction strategies: Reconstitution of p27 tumor suppressor function. J. Control Release 2003, 91, 45-51.
191. Plescia, J.; Salz, W.; Xia, F.; Pennati, M.; Zaffaroni, N.; Daidone, M. G.; Meli, M.; Dohi, T.; Fortugno, P.; Nefedova, Y.; et al. Rational design of shepherdin, a novel anticancer agent. Cancer Cell 2005, 7, 457-468.
192. Hong, F. D.; Clayman, G. L. Isolation of a peptide for targeted drug delivery into human head and neck solid tumors. Cancer Res. 2000, 60, 6551-6556.
193. Wang, J. L.; Zhang, Z. J.; Choksi, S.; Shan, S.; Lu, Z.; Croce, C. M.; Alnemri, E. S.; Korngold, R.; Huang, Z. Cell permeable Bcl-2 binding peptides: A chemical approach to apoptosis induction in tumor cells. Cancer Res. 2000, 60, 1498-1502.
194. Curnis, F.; Arrigoni, G.; Sacchi, A.; Fischetti, L.; Arap, W.; Pasqualini, R.; Corti, A. Differential binding of drugs containing the NGR motif to CD13 isoforms in tumor vessels, epithelia, and myeloid cells. Cancer Res. 2002, 62, 867-874.
195. Snyder, E. L.; Saenz, C. C.; Denicourt, C.; Meade, B. R.; Cui, X. S.; Kaplan, I. M.; Dowdy, S. F. Enhanced targeting and killing of tumor cells expressing the CXC chemokine receptor 4 by transducible anticancer peptides. Cancer Res. 2005, 65, 10646-10650.
196. Keller, J.; Heisler, I.; Tauber, R.; Fuchs, H. Development of a novel molecular adapter for the optimization of immunotoxins. J. Control Release 2001, 74, 259-261.
197. Heisler, I.; Keller, J.; Tauber, R.; Sutherland, M.; Fuchs, H. A cleavable adapter to reduce nonspecific cytotoxicity of recombinant immunotoxins. Int. J. Cancer 2003, 103, 277-282.
198. Hetzel, C.; Bachran, C.; Tur, M. K.; Fuchs, H.; Stocker, M. Improved immunotoxins with novel functional elements. Curr. Pharm Des. 2009, 15, 2700-2711.
199. Hetzel, C.; Bachran, C.; Fischer, R.; Fuchs, H.; Barth, S.; Stocker, M. Small cleavable adapters enhance the specific cytotoxicity of a humanized immunotoxin directed against CD64-positive cells. J. Immunother. 2008, 31, 370-376.