徐晓竹;陈哲文;

• 1:上海生物制品研究所有限责任公司第一研究室

摘要(Abstract)：

目前以叶酸受体α(folate receptorα,FRα)为基础的靶向肿瘤药物正在积极研发中,据了解可能针对上皮性卵巢癌(ovarian cancer,OC)及非小细胞肺癌(non-small cell lung cancer,NSCLC)等癌症有良好的临床前研究进展及结果。FRα已逐渐成为肿瘤免疫疗法中引人注目的治疗靶点之一。本文介绍了目前研究开发的靶向FRα的抗体药物,主要包括单克隆抗体药物和抗体偶联药物(antibody-drug conjugate,ADC),并对这两类药物的临床研究进展作一综述。

关键词(KeyWords)： 叶酸受体α;肿瘤;单克隆抗体;抗体偶联药物;免疫治疗

Abstract:

Keywords:

基金项目(Foundation):

作者(Authors): 徐晓竹;陈哲文;

DOI: 10.13200/j.cnki.cjb.003206

参考文献(References)：

• [1]OMOTE S,TAKATA K,TANAKA T,et al.Overexpression of folate receptor alpha is an independent prognostic factor for outcomes of pancreatic cancer patients[J].Med Mol Morphol,2018,51(4):237-243.
• [2]A E M,N M C,DANIEL R,et al.Microbial metabolic capacity for intestinal folate production and modulation of host folate receptors[J].Frontiers Microbiol,2019,10.
• [3]FRIGERIO B,BIZZONI C,JANSEN G,et al.Folate receptors and transporters:biological role and diagnostic/therapeutic targets in cancer and other diseases[J].J Exp&Clin Cancer Res,2019,38(1）.
• [4]LEDERMANN J A,CANEVARI S,THIGPEN T.Targeting the folate receptor:diagnostic and therapeutic approaches to personalize cancer treatments[J].Ann Oncol,2015,26(10):2034-2043.
• [5]CHEN C,KE J,ZHOU X E,et al.Structural basis for molecular recognition of folic acid by folate receptors[J].Nature,2013,500(7463):486-489.
• [6]ASSARAF Y G,LEAMON C P,REDDY J A.The folate receptor as a rational therapeutic target for personalized cancer treatment[J].Drug Resistance Updates,2014,17(4-6):89-95.
• [7]VERGOTE I B,MARTH C,COLEMAN R L.Role of the folate receptor in ovarian cancer treatment:evidence,mechanism,and clinical implications[J].Cancer Metast Rev,2015,34(1):41-52.
• [8]RAMAEKERS V T,TH魻NY B,SEQUEIRA J M,et al.Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies[J].Mol Gen Metab,2014,113(4):307-314.
• [9]HANSEN M F,GREIBE E,SKOVBJERG S,et al.Folic acid mediates activation of the pro-oncogene STAT3 via the folate receptor alpha[J].Cell Signal,2015,27(7):1356-1368.
• [10]WALLS G,GORE M.Farletuzumab in the treatment of ovarian cancer[J].Expert Opin Orphan Drugs,2016,4(3):327-331.
• [11]WEN Y,GRAYBILL W S,PREVIS R A,et al.Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer[J].Clin Cancer Res,2015,21(2):448-459.
• [12]JELOVAC D,ARMSTRONG D K.Role of farletuzumab in epithelial ovarian carcinoma[J].Curr Pharm Design,2012,18(25):3812.
• [13]ARMSTRONG D K,WHITE A J,WEIL S C,et al.Farletuzumab(a monoclonal antibody against folate receptor alpha) in relapsed platinum-sensitive ovarian cancer[J].Gynecol Oncol,2013,129(3):452-458.
• [14]SATO S,ITAMOCHI H.Profile of farletuzumab and its potential in the treatment of solid tumors[J].Onco Targets Ther,2016(9):1181.
• [15]SASAKI Y,MIWA K,YAMASHITA K,et al.A phase I study of farletuzumab,a humanized anti-folate receptorαmonoclonal antibody,in patients with solid tumors[J].Investig New Drugs,2015,33(2):332-340.
• [16]LOBO ED,HANSEN R J,BALTHASAR J P.Antibody pharmacokinetics and pharmacodynamics[J].Pharm Sci,2004,93:2645-1668.
• [17]MORIYAMA T,KAKIUCHI D,GRASSO L,et al.Farletuzumab,a monoclonal antibody directed against folate receptor alpha,shows no evidence of teratogenicity in cynomolgus monkeys[J].Reprod Toxicol,2018,79:89-95.
• [18]BRONTE G,LO VULLO F,PERNICE G,et al.Farletuzumab for NSCLC:exploiting a well-known metabolic pathway for a new therapeutic strategy[J].Expert Opin Investig Drugs,2015,24(1):125-132.
• [19]CHEUNG A,BAX H J,JOSEPHS D H,et al.Targeting folate receptor alpha for cancer treatment[J].Oncotarget,2016,7(32):52553.
• [20]CHEUNG A,OPZOOMER J W,ILIEVA K M,et al.Antifolate receptor alpha-directed antibody therapies restrict the growth of triple negative breast cancer[J].Clin Cancer Res,2018,24(20):652-2018.
• [21]SUTTON B J,DAVIES A M,BAX H J,et al.IgE antibodies:From structure to function and clinical translation[J].Antibodies(Basel,Switzerland),2019,8(1):19.
• [22]JOSEPHS D H,BAX H J,LENTFER H,et al.Potential for monocyte recruitment by IgE immunotherapy for cancer in a rat model of tumour metastasis[J].Lancet (London,England),2015,385(Suppl 1):S53.
• [23]RUDMAN S M,JOSEPHS D H,CAMBROOK H,et al.Harnessing engineered antibodies of the IgE class to combat malignancy:initial assessment of FcvarepsilonRI-mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I hypersensitivity[J].Clin Exp Allergy,2011,41(10):1400-1413.
• [24]PONTE J F,AB O,LANIERI L,et al.Mirvetuximab soravtansine (IMGN853),a folate receptor alpha-Targeting antibodydrug conjugate,potentiates the activity of standard of care therapeutics in ovarian cancer models[J].Neoplasia,2016,18(12):775-784.
• [25]MOORE K N,BORGHAEI H,O'MALLEY D M,et al.Phase 1dose-escalation study of mirvetuximab soravtansine(IMGN853),a folate receptorα-targeting antibody-drug conjugate,in patients with solid tumors[J].Cancer,2017,123(16):3080-3087.
• [26]MATULONIS U A,BIRRER M J,O'MALLEY D M,et al.Evaluation of prophylactic corticosteroid eye drop use in the management of corneal abnormalities induced by the antibody-drug conjugate Mirvetuximab soravtansine[J].Clin Cancer Res,2019,25(6):1727-1736.
• [27]MOORE K N,MARTIN L P,O MALLEY D M,et al.Safety and activity of Mirvetuximab soravtansine(IMGN853),a folate receptor alpha-targeting antibody-drug conjugate,in platinumresistant ovarian,Fallopian tube,or primary peritoneal cancer:A phase I expansion study[J].J Clin Oncol,2017,35(10):1112-1118.
• [28]MOORE K N,O'MALLEY D M,VERGOTE I,et al.Safety and activity findings from a phase 1b escalation study of mirvetuximab soravtansine,a folate receptor alpha (FRα）-targeting antibody-drug conjugate (ADC),in combination with carboplatin in patients with platinum-sensitive ovarian cancer[J].Gynecol Oncol,2018,151(1):46-52.
• [29]MOORE K N,VERGOTE I,OAKNIN A,et al.FORWARD I:a Phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer[J].Future Oncol,2018,14(17):1669-1678.
• [30]BECK A,GOETSCH L,DUMONTET C,et al.Strategies and challenges for the next generation of antibody-drug conjugates[J].Nat Rev Drug Discov,2017,16(5):315-337.
• [31]DOODHI H,PROTA A E,RODRIGUEZ-GARCIA R,et al.Termination of protofilament elongation by eribulin induces lattice defects that promote microtubule catastrophes[J].Curr Biol,2016,26(13):1713-1721.
• [32]WILSON L,LOPUS M,MILLER H P,et al.Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the betaIII tubulin isotype[J].Biochemistry,2015,54(42):6482-6489.
• [33]CHANEZ B,GONCALVES A,BADACHE A,et al.Eribulin targets a ch-TOG-dependent directed migration of cancer cells[J].Oncotarget,2015,6(39):41667-41678.
• [34]FUNAHASHI Y,OKAMOTO K,ADACHI Y,et al.Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models[J].Cancer Sci,2014,105(10):1334-1342.
• [35]ISLAM B,LUSTBERG M,STAFF N P,et al.Vinca alkaloids,thalidomide and eribulin-induced peripheral neurotoxicity:From pathogenesis to treatment[J].J Peripheral Nervous Syst,2019,24(Suppl 2):S63-S73.
• [36]CHENG X,LI J,TANAKA K,et al.MORAb-202,an antibody-drug conjugate utilizing humanized anti-human FRαFarletuzumab and the microtubule-targeting agent Eribulin,has potent antitumor activity[J].Mol Cancer Ther,2018,17(12):2665-2675.
• [37]INC E.A study of MORAb-202 in participants with solid tumors[EB/OL].(2019-01-30)[2019-10-14].https：//www.clinicaltrials.gov/ct2/show/NCT03386942.
• [38]ANDO M,NAGATA K,NIHIRA K,et al.Potent therapeutic activity against peritoneal dissemination and malignant ascites by the novel anti-folate receptor alpha antibody KHK2805[J].Translat Oncol,2017,10(5):707-718.
• [39]SHIVANGE G,URBANEK K,PRZANOWSKI P,et al.Asingle-agent dual-specificity targeting of FOLR1 and DR5 as an effective strategy for ovarian cancer[J].Cancer Cell,2018,34(2):331-345.