全部 标题 作者
关键词 摘要

OALib Journal期刊
ISSN: 2333-9721
费用:99美元

查看量下载量

相关文章

更多...

抗CD20单链抗体与力达霉素强化融合蛋白的制备及其抗肿瘤活性

, PP. 22-29

Keywords: 淋巴瘤,CD20,力达霉素,单链抗体,强化融合蛋白

Full-Text   Cite this paper   Add to My Lib

Abstract:

抗体融合蛋白是新一代抗肿瘤抗体药物.CD20在约95%的B细胞非霍奇金淋巴瘤表面过度表达,是治疗B细胞淋巴瘤的理想靶点.力达霉素(LDM)是强效烯二炔抗肿瘤抗生素,目前已进入Ⅱ期临床阶段.采用DNA重组技术,利用大肠杆菌表达体系,制备抗CD20单链抗体与力达霉素辅基蛋白LDP的基因工程融合蛋白scFv-LDP.经纯化和复性后,ELISA和间接免疫荧光实验测定其抗原结合活性,发现抗CD20scFv-LDP能够与表达CD20的肿瘤细胞特异性结合.将其与LDM的活性发色团AE进行分子组装,得到强化融合蛋白scFv-LDP-AE.MTT结果表明,和LDM一样,scFv-LDP-AE对肿瘤细胞有强烈的杀伤作用,CD20+的Raji细胞和Daudi细胞的IC50值分别为1.21×10-11和6.24×10-11mol/L.CD20+B细胞淋巴瘤裸鼠移植模型检测抗肿瘤活性.接种肿瘤后第14和21天分别尾静脉注射给药,共2次.发现scFv-LDP-AE能够显著抑制肿瘤生长,0.3mg/kg剂量组抑瘤率为79.3%,显著强于LDM可耐受剂量0.05mg/kg(68.6%)的抑瘤率.强化融合蛋白scFv-LDP-AE有发展成抗肿瘤抗体靶向药物的潜能.

References

[1]  17 张胜华, 陈静, 江敏, 等. 力达霉素诱导人胃癌BGC823细胞凋亡和抑制裸鼠移植瘤生长. 药学学报, 2008, 43: 601-604
[2]  1 Berinstein N L, Grillo-Lopez A J, White C A, et al. Association of serum Rituximab(IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin''s lymphoma. Ann Oncol, 1998, 9: 995-1001??
[3]  2 Van Meerten T, Claessen M J, Hagenbeek A. The CD20/a CD20''suicide''system: novel vectors with improved safety and expression profiles and efficient elimination of CD20-transgenic T cells. Gene Ther, 2006, 13: 789-797??
[4]  3 Maloney D G, Smith B, Rose A. Rituximab: mechanism of action and resistance. Semin Oncol, 2002, 29(suppl 2): 2-9
[5]  4 Gisselbrecht C. Use of rituximab in diffuse large B-cell lymphoma in the salvage setting. Br J Haematol, 2008, 143: 607-621??
[6]  5 Bonavida B. Rituximab-induced inhibition of antiapoptotic cell survival pathways: implications in chemo/immunoresistance, rituximab unresponsiveness, prognostic and novel therapeutic interventions. Oncogene, 2007, 26: 3629-3636??
[7]  6 Polido-Pereira J, Ferreira D, Rodrigues A M. Rituximab use in pediatric autoimmune diseases: four case reports. Ann N Y Acad Sci, 2009, 1173: 712-720??
[8]  7 Korhonen R, Moilanen E. Anti-CD20 antibody rituximab in the treatment of rheumatoid arthritis. Basic Clin Pharmacol Toxicol, 2010, 106: 13-21
[9]  8 Murray E, Perry M. Off-label use of rituximab in systemic lupus erythematosus: a systematic review. Clin Rheumatol, 2010, 29: 707-716??
[10]  9 Lui N L, Thumboo J, Fong K Y. A case of refractory vasculitic ulcers in a systemic lupus erythematosus patient responding to rituximab and hyperbaric oxygen therapy. Int J Rheum Dis, 2009, 12: 366-369??
[11]  10 Troiano M, Lotti T. Rituximab in dermatological diseases. G Ital Dermatol Venereol, 2009, 144: 495-499
[12]  11 杨希峰, 沈德诚, 金宇光, 等. HI47, 一种人成熟B细胞单克隆抗体制备, 鉴定及其生物特性研究. 上海免疫学杂志, 1990, 10: 65
[13]  12 Harrison J S, Gill A, Hoare M. Stability of a single-chain Fv antibody fragment when exposed to a high shear environment combined with air-liquid interfaces. Biotechnol Bioeng, 1998, 59: 517-519??
[14]  13 Zhen Y S, Ming X Y, Yu B, et al. A new macromolecular antitumor antibiotic, C-1027. Ⅲ. Antitumor activity. J Antibiot(Tokyo), 1989, 42: 1294-1298
[15]  14 Shao R G. Pharmacology and therapeutic applications of enediyne antitumor antibiotics. Curr Mol Pharmacol, 2008, 1: 50-60??
[16]  15 Shao R G, Zhen Y S. Enediyne anticancer antibiotic lidamycin: chemistry, biology and pharmacology. Anticancer Agents Med Chem, 2008, 8: 123-131??
[17]  16 Zhen Y Z, Lin Y J, Li Y, et al. Lidamycin shows highly potent cytotoxic to myeloma cells and inhibits tumor growth in mice. Acta Pharmacol Sin, 2009, 30: 1025-1032??
[18]  18 邵荣光, 甄永苏. 新烯二炔类大分子抗肿瘤抗生素C1027的分子构成与活性关系. 药学学报, 1995, 30: 336-342
[19]  19 刘秀筠, 戴垚, 商悦. 力达霉素对小鼠结肠癌生长及其肝转移的抑制作用. 癌症, 2005, 24: 641-645
[20]  20 Gao R J, Liang Y X, Li D D. Effect of lidamycin on telomerase activity in human hepatoma BEL-7402 cells. Biomed Environ Sci, 2007, 20: 189-197
[21]  21 Huang Y H, Shang B Y, Zhen Y S. Antitumor efficacy of lidamycin on hepatoma and active moiety of its molecule. World J Gastroenterol, 2005, 11: 3980-3984
[22]  22 Miao Q F, Liu X Y, Shang B Y, et al. An enediyne-energized single-domain antibody-containing fusion protein shows potent antitumor activity. Anticancer Drugs, 2007, 18: 127-137??
[23]  23 Fischer L, Penack O, Gentilini C, et al. The anti-lymphoma effect of antibody-mediated immunotherapy is based on an increased degranulation of peripheral blood natural killer (NK) cells. Exp Hematol, 2006, 34: 753-759??
[24]  24 Berdeja J G, Hess A, Lucas D M, et al. Systemic interleukin-2 and adoptive transfer of lymphokine-activated killer cells improves antibody-dependent cellular cytotoxicity in patients with relapsed B-cell lymphoma treated with rituximab. Clin Cancer Res, 2007, 13: 2392-2399??
[25]  25 Van de Loosdrecht A A, Huijgens P C, Ossenkoppele G J. Antibody-targeted therapy: a paradigm of innovative treatment strategies in indolent and aggressive B-cell non-Hodgkin''s lymphoma. Curr Opin Hematol, 2004, 11: 419-425??
[26]  26 Xu Y J, Li D D, Zhen Y S. Mode of action of C-1027, a new macromolecular antitumor antibiotic with highly potent cytotoxicity, on human hepatoma BEL-7402 cells. Cancer Chemoth Pharm, 1990, 27: 41-46
[27]  27 Sugimoto Y, Otani T, Oie S, et al. Mechanism of action of a new macromolecular antitumor antibiotic, C-1027. J Antibiot(Tokyo), 1990, 43: 417-421
[28]  28 Kennedy A D, Beum P V, Solga M D, et al. Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia. J Immunol, 2004, 172: 3280-3288
[29]  29 Dillman R O. Infusion reactions associated with the therapeutic use of monoclonal antibodies in the treatment of malignancy. Cancer Metastasis Rev, 1999, 18: 465-471??
[30]  30 Beerman T A, Gawron L S, Shin S, et al. C-1027, a radiomimetic enediyne anticancer drug, preferentially targets hypoxic cells. Cancer Res, 2009, 69: 593-598??

Full-Text

Contact Us

service@oalib.com

QQ:3279437679

WhatsApp +8615387084133