Giao hàng có chọn lọc siRNA bằng cách sử dụng lipoplex liên hợp transferrin tăng cường tính nhạy cảm của các tế bào ác tính có biểu hiện cao CD71 với sự tấn công bổ sung do kháng thể trung gian

Springer Science and Business Media LLC - Tập 10 - Trang 405-413 - 2014
Marc Cinci1, Srinivas Mamidi1, Wenhan Li1, Volker Fehring2, Michael Kirschfink1
1Institute of Immunology, University of Heidelberg, Heidelberg, Germany
2Silence Therapeutics AG, Berlin, Germany

Tóm tắt

Việc biểu hiện quá mức các protein điều hòa bổ sung liên kết với màng (mCRP; CD46, CD55, CD59) ngăn cản quá trình opson hóa và độc tính phụ thuộc vào bổ sung (CDC) được coi là một trở ngại lớn cho liệu pháp miễn dịch ung thư dựa trên kháng thể thành công. Để tránh tác động tiêu cực tiềm ẩn của việc trung hòa mCRP lên các tế bào mô bình thường, việc điều hòa bổ sung cần được nhắm mục tiêu một cách có chọn lọc vào các tế bào ác tính. Trong nghiên cứu này, các RNA nhỏ can thiệp (siRNA) chống mCRP đã được bao gói trong lipoplex liên hợp transferrin để cung cấp cụ thể đến các tế bào u có CD71 cao BT474, DU145 và SW480 cũng như các tế bào khối u CD71-gõ thấp tương ứng (CD71low). Việc giao hàng có chọn lọc bằng lipoplex transferrin-siRNA trở nên khả thi thông qua việc trung hòa điện tích và đạt được hiệu quả im lặng hóa tất cả ba mCRP lên đến 90%, tùy thuộc vào biểu hiện CD71 của chúng. Việc giảm mCRP dẫn đến sự gia tăng đáng kể của CDC trên các tế bào khối u CD71high với mức tăng 68% ở BT474, 58% ở DU145, và 40% ở SW480 nhưng chỉ tăng nhẹ ở các tế bào CD71low. Việc điều chỉnh giảm CD46 và CD55 đã làm tăng đáng kể quá trình opson hóa C3 chỉ trên các tế bào khối u CD71high. Kết quả của chúng tôi chứng minh lần đầu tiên rằng thông qua việc giao hàng cụ thể siRNA chống mCRP qua thụ thể transferrin, việc điều hòa bổ sung có thể được trung hòa một cách có chọn lọc, cho phép tiêu diệt tế bào khối u do kháng thể trung gian mà không ảnh hưởng đến các tế bào bình thường xung quanh, điều này dường như là một chiến lược phù hợp để cải thiện liệu pháp miễn dịch ung thư dựa trên kháng thể.

Từ khóa

#mCRP #siRNA #transferrin #tua cell #CDC #liệu pháp miễn dịch ung thư

Tài liệu tham khảo

Carroll MC (2004) The complement system in regulation of adaptive immunity. Nat Immunol 5:981–986 Walport MJ (2001) Complement. First of two parts. N Engl J Med 344:1058–1066 Ricklin D, Hajishengallis G, Yang K, Lambris JD (2010) Complement: a key system for immune surveillance and homeostasis. Nat Immunol 11:785–797 Gasque P, Morgan BP, Legoedec J, Chan P, Fontaine M (1996) Human skeletal myoblasts spontaneously activate allogeneic complement but are resistant to killing. J Immunol 156:3402–3411 Goldberger G, Arnaout MA, Aden D, Kay R, Rits M, Colten HR (1984) Biosynthesis and postsynthetic processing of human C3b/C4b inactivator (factor I) in three hepatoma cell lines. J Biol Chem 259:6492–6497 Jurianz K, Ziegler S, Donin N, Reiter Y, Fishelson Z, Kirschfink M (2001) K562 erythroleukemic cells are equipped with multiple mechanisms of resistance to lysis by complement. Int J Cancer J Int du Cancer 93:848–854 Li L, Spendlove I, Morgan J, Durrant LG (2001) CD55 is over-expressed in the tumour environment. Br J Cancer 84:80–86 Thomas A, Gasque P, Vaudry D, Gonzalez B, Fontaine M (2000) Expression of a complete and functional complement system by human neuronal cells in vitro. Int Immunol 12:1015–1023 Donin N, Jurianz K, Ziporen L, Schultz S, Kirschfink M, Fishelson Z (2003) Complement resistance of human carcinoma cells depends on membrane regulatory proteins, protein kinases and sialic acid. Clin Exp Immunol 131:254–263 Frade R (1999) Structure and functions of proteases which cleave human C3 and are expressed on normal or tumor human cells: some are involved in tumorigenic and metastatic properties of human melanoma cells. Immunopharmacology 42:39–45 Fishelson Z, Donin N, Zell S, Schultz S, Kirschfink M (2003) Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors. Mol Immunol 40:109–123 Gorter A, Meri S (1999) Immune evasion of tumor cells using membrane-bound complement regulatory proteins. Immunol Today 20:576–582 Czuczman MS, Olejniczak S, Gowda A, Kotowski A, Binder A, Kaur H, Knight J, Starostik P, Deans J, Hernandez-Ilizaliturri FJ (2008) Acquirement of rituximab resistance in lymphoma cell lines is associated with both global CD20 gene and protein down-regulation regulated at the pretranscriptional and posttranscriptional levels. Clin Cancer Res Off J Am Assoc Cancer Res 14:1561–1570 Ge X, Wu L, Hu W, Fernandes S, Wang C, Li X, Brown JR, Qin X (2011) rILYd4, a human CD59 inhibitor, enhances complement-dependent cytotoxicity of ofatumumab against rituximab-resistant B-cell lymphoma cells and chronic lymphocytic leukemia. Clin Cancer Res Off J Am Assoc Cancer Res 17:6702–6711 Golay J, Lazzari M, Facchinetti V, Bernasconi S, Borleri G, Barbui T, Rambaldi A, Introna M (2001) CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood 98:3383–3389 Macor P, Tripodo C, Zorzet S, Piovan E, Bossi F, Marzari R, Amadori A, Tedesco F (2007) In vivo targeting of human neutralizing antibodies against CD55 and CD59 to lymphoma cells increases the antitumor activity of rituximab. Cancer Res 67:10556–10563 Takei K, Yamazaki T, Sawada U, Ishizuka H, Aizawa S (2006) Analysis of changes in CD20, CD55, and CD59 expression on established rituximab-resistant B-lymphoma cell lines. Leuk Res 30:625–631 Zhao WP, Zhu B, Duan YZ, Chen ZT (2009) Neutralization of complement regulatory proteins CD55 and CD59 augments therapeutic effect of herceptin against lung carcinoma cells. Oncol Rep 21:1405–1411 Hu W, Ge X, You T, Xu T, Zhang J, Wu G, Peng Z, Chorev M, Aktas BH, Halperin JA, Brown JR, Qin X (2011) Human CD59 inhibitor sensitizes rituximab-resistant lymphoma cells to complement-mediated cytolysis. Cancer Res 71:2298–2307 Geis N, Zell S, Rutz R, Li W, Giese T, Mamidi S, Schultz S, Kirschfink M (2010) Inhibition of membrane complement inhibitor expression (CD46, CD55, CD59) by siRNA sensitizes tumor cells to complement attack in vitro. Curr Cancer Drug Targets 10:922–931 Mamidi S, Cinci M, Hasmann M, Fehring V, Kirschfink M (2013) Lipoplex mediated silencing of membrane regulators (CD46, CD55 and CD59) enhances complement-dependent anti-tumor activity of trastuzumab and pertuzumab. Molec Oncol 7:580–594 Zell S, Geis N, Rutz R, Schultz S, Giese T, Kirschfink M (2007) Down-regulation of CD55 and CD46 expression by anti-sense phosphorothioate oligonucleotides (S-ODNs) sensitizes tumour cells to complement attack. Clin Exp Immunol 150:576–584 Filleur S, Courtin A, Ait-Si-Ali S, Guglielmi J, Merle C, Harel-Bellan A, Clezardin P, Cabon F (2003) SiRNA-mediated inhibition of vascular endothelial growth factor severely limits tumor resistance to antiangiogenic thrombospondin-1 and slows tumor vascularization and growth. Cancer Res 63:3919–3922 Tolentino MJ, Brucker AJ, Fosnot J, Ying GS, Wu IH, Malik G, Wan S, Reich SJ (2004) Intravitreal injection of vascular endothelial growth factor small interfering RNA inhibits growth and leakage in a nonhuman primate, laser-induced model of choroidal neovascularization. Retina 24:132–138 Park JW, Benz CC, Martin FJ (2004) Future directions of liposome- and immunoliposome-based cancer therapeutics. Semin Oncol 31:196–205 Camp ER, Wang C, Little EC, Watson PM, Pirollo KF, Rait A, Cole DJ, Chang EH, Watson DK (2013) Transferrin receptor targeting nanomedicine delivering wild-type p53 gene sensitizes pancreatic cancer to gemcitabine therapy. Cancer Gene Ther 20:222–228 Cardoso AL, Simoes S, de Almeida LP, Plesnila N, Pedroso de Lima MC, Wagner E, Culmsee C (2008) Tf-lipoplexes for neuronal siRNA delivery: a promising system to mediate gene silencing in the CNS. J Cont Rel Off J Cont Rel Soc 132:113–123 Dufes C, Al Robaian M, Somani S (2013) Transferrin and the transferrin receptor for the targeted delivery of therapeutic agents to the brain and cancer cells. Ther Deliv 4:629–640 Li X, Ding L, Xu Y, Wang Y, Ping Q (2009) Targeted delivery of doxorubicin using stealth liposomes modified with transferrin. Int J Pharm 373:116–123 Liu Y, Tao J, Li Y, Yang J, Yu Y, Wang M, Xu X, Huang C, Huang W, Dong J, Li L, Liu J, Shen G, Tu Y (2009) Targeting hypoxia-inducible factor-1alpha with Tf-PEI-shRNA complex via transferrin receptor-mediated endocytosis inhibits melanoma growth. Molec Ther J Am Soc Gene Ther 17:269–277 Mendonca LS, Firmino F, Moreira JN, Pedroso de Lima MC, Simoes S (2010) Transferrin receptor-targeted liposomes encapsulating anti-BCR-ABL siRNA or asODN for chronic myeloid leukemia treatment. Bioconjug Chem 21:157–168 Santel A, Aleku M, Keil O, Endruschat J, Esche V, Fisch G, Dames S, Loffler K, Fechtner M, Arnold W, Giese K, Klippel A, Kaufmann J (2006) A novel siRNA-lipoplex technology for RNA interference in the mouse vascular endothelium. Gene Ther 13:1222–1234 Jurianz K, Maslak S, Garcia-Schuler H, Fishelson Z, Kirschfink M (1999) Neutralization of complement regulatory proteins augments lysis of breast carcinoma cells targeted with rhumAb anti-HER2. Immunopharmacology 42:209–218 Ben-Kasus T, Schechter B, Sela M, Yarden Y (2007) Cancer therapeutic antibodies come of age: targeting minimal residual disease. Molec Oncol 1:42–54 Gancz D, Fishelson Z (2009) Cancer resistance to complement-dependent cytotoxicity (CDC): problem-oriented research and development. Mol Immunol 46:2794–2800 Horl S, Banki Z, Huber G, Ejaz A, Mullauer B, Willenbacher E, Steurer M, Stoiber H (2013) Complement factor H-derived short consensus repeat 18-20 enhanced complement-dependent cytotoxicity of ofatumumab on chronic lymphocytic leukemia cells. Haematologica 98:1939–1947 Horl S, Banki Z, Huber G, Ejaz A, Windisch D, Muellauer B, Willenbacher E, Steurer M, Stoiber H (2013) Reduction of complement factor H binding to CLL cells improves the induction of rituximab-mediated complement-dependent cytotoxicity. Leukemia 27:2200–2208 Lindorfer MA, Beum PV, Taylor RP (2013) CD20 mAb-mediated complement dependent cytotoxicity of tumor cells is enhanced by blocking the action of factor I. Antibodies 2:598–616 Czauderna F, Fechtner M, Dames S, Aygun H, Klippel A, Pronk GJ, Giese K, Kaufmann J (2003) Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells. Nucleic Acids Res 31:2705–2716 Judge AD, Bola G, Lee AC, MacLachlan I (2006) Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Molec Ther J Am Soc Gene Ther 13:494–505 Carbognani P, Rusca M, Romani A, Spaggiari L, Cattelani L, Solli P, Bobbio P (1996) Transferrin receptor expression in nonsmall cell lung cancer: histopathologic and clinical correlates. Cancer 78:178–179 Daniels TR, Delgado T, Rodriguez JA, Helguera G, Penichet ML (2006) The transferrin receptor part I: biology and targeting with cytotoxic antibodies for the treatment of cancer. Clin Immunol 121:144–158 Ryschich E, Huszty G, Knaebel HP, Hartel M, Buchler MW, Schmidt J (2004) Transferrin receptor is a marker of malignant phenotype in human pancreatic cancer and in neuroendocrine carcinoma of the pancreas. Eur J Cancer 40:1418–1422 Smilevska T, Stamatopoulos K, Samara M, Belessi C, Tsompanakou A, Paterakis G, Stavroyianni N, Athanasiadou I, Chiotoglou I, Hadzidimitriou A, Athanasiadou A, Douka V, Saloum R, Laoutaris N, Anagnostopoulos A, Fassas A, Stathakis N, Kollia P (2006) Transferrin receptor-1 and 2 expression in chronic lymphocytic leukemia. Leuk Res 30:183–189 Qing Y, Shuo W, Zhihua W, Huifen Z, Ping L, Lijiang L, Xiaorong Z, Liming C, Daiwen X, Yu H, Wei X, Min F, Zuohua F, Guanxin S (2006) The in vitro antitumor effect and in vivo tumor-specificity distribution of human-mouse chimeric antibody against transferrin receptor. Cancer Immunol Immunother CII 55:1111–1121 Gatter KC, Brown G, Trowbridge IS, Woolston RE, Mason DY (1983) Transferrin receptors in human tissues: their distribution and possible clinical relevance. J Clin Pathol 36:539–545 Brooks D, Taylor C, Dos Santos B, Linden H, Houghton A, Hecht TT, Kornfeld S, Taetle R (1995) Phase Ia trial of murine immunoglobulin A antitransferrin receptor antibody 42/6. Clin Cancer Res Off J Am Assoc Cancer Res 1:1259–1265 Tros De Ilarduya C, Bunuales M, Qian C, Duzgunes N (2006) Antitumoral activity of transferrin-lipoplexes carrying the IL-12 gene in the treatment of colon cancer. J Drug Target 14:527–535