陈雪静;常亮;高健;

• 1:华北制药集团新药研究开发有限责任公司抗体药物研制国家重点实验室

摘要(Abstract)：

经过30多年的发展,抗肿瘤抗体药物已成为癌症治疗中最成功和最重要的策略之一。本文综述了已上市的抗肿瘤抗体药物,详细介绍了临床应用较成功的药物靶点,包括CD20、表皮生长因子受体(epithelial growth factor receptor,EGFR)、表皮生长因子受体2(HER2)、血管内皮生长因子(vascular endothelial growthfactor,VEGF),并总结了抗体偶联药物及癌症免疫疗法等新兴疗法的研究进展。

关键词(KeyWords)： 肿瘤;抗体药物;靶点;免疫治疗

Abstract:

Keywords:

基金项目(Foundation): 国家高技术研究发展计划(863计划)项目(2012AA02A306)

作者(Authors): 陈雪静;常亮;高健;

DOI: 10.13200/j.cnki.cjb.000733

参考文献(References)：

• [1]Mathas S,Rickers A,Bommert K,et al.Anti-CD20-and B-cell receptor]mediated apoptosis:evidence for shared intracellular signaling pathways[J].Cancer Res,2000,60(24):7170-7176.
• [2]Mendelsohn J,Baselga J.The EGF receptor family as targets for cancer therapy[J].Oncogene,2000,19(56):6550-6565.
• [3]Ferrara N,Hillan KJ,Gerber HP,et al.Discovery and development of bevacizumab,an anti-VEGF antibody for treating cancer[J].Nat Rev Drug Discov,2004,3(5):391-400.
• [4]Park S,Jiang Z,Mortenson ED,et al.The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity[J].Cancer Cell,2010,18(2):160-170.
• [5]Stagg J,Loi S,Divisekera U,et al.Anti-Erb B-2 m Ab therapy requires type I and II interferons and synergizes with anti-PD-1or anti-CD137 m Ab therapy[J].Proc Natl Acad Sci USA,2011,108(17):7142-7147.
• [6]Wilson NS,Yang B,Yang A,et al.An Fcγreceptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells[J].Cancer Cell,2011,19(1):101-113.
• [7]Olafsen T.Fc engineering:serum half-life modulation through Fc Rn binding[J].Methods Mol Biol,2012,907(7):537-556.
• [8]Scott AM,Wolchok JD,Old LJ.Antibody therapy of cancer[J].Nat Rev Cancer,2012,12(4):278-287.
• [9]Maloney DG.Anti-CD20 antibody therapy for B-cell lymphomas[J].N Engl J Med,2012,366(21):2008-2016.
• [10]Chen J,Li J.Rituximab-induced rare adverse reactions[J].Adv Drug React J,2010,12(5):321-324.(in Chinese)陈净,李剑.利妥昔单抗的罕见不良反应[J].药物不良反应杂志,2010,12(5):321-324.
• [11]Barth MJ,Czuczman MS.Ofatumumab:a novel,fully human anti-CD20 monoclonal antibody for the treatment of chronic lymphocytic leukemia[J].Future Oncol,2013,9(12):1829-1839.
• [12]Dalle S,Reslan L,Besseyre de Horts T,et al.Preclinical studies on the mechanism of action and the anti-lymphoma activity of the novel anti-CD20 antibody GA101[J].Mol Cancer Ther,2011,10(1):178-185.
• [13]Mendelsohn J,Baselga J.Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer[J].J Clin Oncol,2003,21(14):2787-2799.
• [14]Sliwkowski MX,Mellman I.Antibody therapeutics in cancer[J].Science,2013,341(6151):1192-1198.
• [15]Garrett CR,Eng C.Cetuximab in the treatment of patients with colorectal cancer[J].Expert Opin Biol Ther,2011,11(7):937-949.
• [16]Assenat E,Desseigne F,Thezenas S,et al.Cetuximab plus FOLFIRINOX(ERBIRINOX)as first-line treatment for unresec table metastatic colorectal cancer:a phase II trial[J].Oncologist,2011,16(11):1557-1564.
• [17]Bonner JA,Harari PM,Giralt J,et al.Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer:5-year survival data from a phase 3 randomised trial,and relation between cetuximab-induced rash and survival[J].Lancet Oncol,2010,11(1):21-28.
• [18]Douillard JY,Siena S,Cassidy J,et al.Randomized,phaseⅢtrial of panitumumab with infusional fluorouracil,leucovorin,and oxaliplatin(FOLFOX4)versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer:the PRIME study[J].J Clin Oncol,2010,28(31):4697-4705.
• [19]Schrag D,Chung KY,Flombaum C,et al.Cetuximab therapy and symptomatic hypomagnesemia[J].J Natl Cancer Inst,2005,97(16):1221-1224.
• [20]Cobleigh MA,Vogel CL,Tripathy D,et al.Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progreeed after chemotherapy for metastatic disease[J].J Clin Oncol,1999,17(9):2639-2648.
• [21]Mc Cormack PL.Pertuzumab:a review of its use for first-line combination treatment of HER2-positive metastatic breast cancer[J].Drugs,2013,73(13):1491-1502.
• [22]Wu YY,Li EX.Progression of VEGF in the malignant tumor[J].Mod Oncol,2005,13(5):S18-S21.(in Chinese)吴胤瑛,李恩孝.VEGF在恶性肿瘤中的研究进展[J].现代肿瘤医学,2005,13(5):附18-附21.
• [23]Giantonio BJ,Catalano PJ,Meropol NJ,et al.Bevacizumab in combination with oxaliplatin,fluorouracil,and leucovorin(FOLFOX4)for previously treated metastatic colorectal cancer:results from the Eastern Cooperative Oncology Group Study E3200[J].J Clin Oncol,2007,25(12):1539-1544.
• [24]Saltz LB,Clarke S,Daz-Rubio E,et al.Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer:a randomized phase III study[J].J Clin Oncol,2008,26(12):2013-2019.
• [25]Sandler A,Gray R,Perry MC,et al.Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer[J].N Engl J Med,2006,355(24):2542-2550.
• [26]Escudier B,Pluzanska A,Koralewski P,et al.Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma:a randomised,double-blind phase III trial[J].Lancet,2007,370(9605):2103-2111.
• [27]Zhu Z,Witte L.Inhibition of tumor growth and metastasis by targeting tumor-associated angiogenesis with antagonists to the receptors of vascular endothelial growth factor[J].Invest New Drugs,1999,17(3):195-212.
• [28]Adair JR,Howard PW,Hartley JA,et al.Antibody-drug conjugates-aperfect synergy[J].Expert Opin Biol Ther,2012,12(9):1191-1206.
• [29]Hollander I,Kunz A,Hamann PR,et al.Selection of reaction additives used in the preparation of monomeric antibodycalicheamicin conjugates[J].Bioconjug Chem,2008,19(1):358-361.
• [30]Robillard N,Wuillème S,LodéL,et al.CD33 is expressed on plasma cells of a significant number of myeloma patients,and may represent a therapeutic target[J].Leukemia,2005,19(11):2021-2022.
• [31]Okeley NM,Miyamoto JB,Zhang X,et al.Intracellular activation of SGN-35,a potent anti-CD30 antibody-drug conjugate[J].Clin Cancer Res,2010,16(3):888-897.
• [32]Katz J,Janik JE,Younes A.Brentuximab Vedotin(SGN-35)[J].Clin Cancer Res,2011,17(20):6428-6436.
• [33]Lewis Phillips GD,Li G,Dugger DL,et al.Targeting HER2-positive breast cancer with trastuzumab-DM1,an antibodycytotoxic drug conjugate[J].Cancer Res,2008,68(22):9280-9290.
• [34]Hurvitz SA,Dirix L,Kocsis J,et al.Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-postive metastatic breast cancer[J].J Clin Oncol,2013,31(9):1157-1163.
• [35]Verma S,Miles D,Gianni L,et al.Trastuzumab emtansine for HER2-positive advanced breast cancer[J].N Engl J Med,2012,367(19):1783-1791.
• [36]Chambers CA,Kuhns MS,Egen JG,et al.CTLA-4-mediated inhibition in regulation of T cell responses:mechanisms and manipulation in tumor immunotherapy[J].Annu Rev Immunol,2001,19(4):565-594.
• [37]Weber J.Overcoming immunologic tolerance to melanoma:targeting CTLA-4 with ipilimumab(MDX-010)[J].Oncologist,2008,13(Suppl 4):16-25.
• [38]Sherrill B,Wang J,Kotapati S,et al.Q-TWi ST analysis comparing ipilimumab/dacarbazine vs placebo/dacarbazine for patients with stage III/IVmelanoma[J].Br J Cancer,2013,109(1):8-13.
• [39]Topalian SL,Sznol M,Mc Dermott DF,et al.Survival,durable tumor remission,and long-term safety in patients with advanced melanoma receiving nivolumab[J].J Clin Oncol,2014,32(10):1020-1030.
• [40]Wolchok JD,Kluger H,Callahan MK,et al.Nivolumab plus ipilimumab in advanced melanoma[J].N Engl J Med,2013,369(2):122-133.
• [41]Hamid O,Robert C,Daud A,et al.Safety and tumor responses with lambrolizumab(anti-PD-1)in melanoma[J].N Engl J Med,2013,369(2):134-144.
• [42]Robert C,Soria JC,Eggermont AM,et al.Drug of the year:programmed death-1 receptor/programmed death-1 ligand-1receptor monoclonal antibodies[J].Eur J Cancer,2013,49(14):2968-2971.