靶向VEGFR2抗体研究进展
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摘要
恶性肿瘤是全球范围内严重危害人类健康的疾病,并且发病率逐年上升。血管生成是肿瘤发生发展最重要的过程之一,90%的实体瘤都依赖功能性的血管网络提供氧气和营养。血管生成主要由血管内皮生长因子(VEGFs)和血管内皮生长因子受体(VEGFRs)调节,而通过单克隆抗体阻断VEGF/VEGFR2相互作用能够显著抑制肿瘤生长,是一种非常有前景的抗肿瘤策略。雷莫芦作为目前惟一一款上市的靶向VEGFR2的抗体药物,在多种癌症中取得了良好的临床效果。然而单靶点的治疗方法易产生耐药性及不良反应,多功能、多靶点的治疗策略如联合用药等成为目前肿瘤治疗的主流。同时,VEGFR2由于其在肿瘤细胞及肿瘤血管高表达的特性也成为了双特异性抗体良好的靶标。因此文章就靶向VEGFR2抗体的研究现状、挑战及以其为基础的多靶点治疗策略进行综述,并对肿瘤治疗的未来发展趋势进行展望。
Malignant tumor is a kind of deadly disease that threatens human health severely,and its incidence is on rise year by year. Angiogenesis is one of the most pivotal progresses of tumor growth,and more than 90% of solid tumors are dependent on a functional vascular network for the supply of oxygen and nutrients. In addition,angiogenesis is regulated principally by interactions between vascular endothelial growth factors( VEGFs) and VEGF receptors( VEGFRs). The approach of blocking the interaction of VEGF and VEGFR2 significantly inhibits tumor growth and has become a promising anticancer strategy. Ramucirumab,a fully humanized monoclonal antibody,was the only drug that targeted to VEGFR2 approved by FDA for the treatment of human cancer and has achieved excellent clinical outcome. However,mono-target therapy may lead to drug resistance and side effects. As a result,mutifunction and muti-target therapeutic methods like combination therapy have become a major trend for the treatment of malignant tumor. Because of the high expression on tumor cell and tumor vascular but low expression on normal tissue,VEGFR2 becomes a great target applied in bi-specific antibody. Thus,this article reviews the progress,challenge of anti-VEGFR2 antibody as well as its application in the field of muti-target treatment,and also makes a prospect for the future tumor treatment.
Malignant tumor is a kind of deadly disease that threatens human health severely,and its incidence is on rise year by year. Angiogenesis is one of the most pivotal progresses of tumor growth,and more than 90% of solid tumors are dependent on a functional vascular network for the supply of oxygen and nutrients. In addition,angiogenesis is regulated principally by interactions between vascular endothelial growth factors( VEGFs) and VEGF receptors( VEGFRs). The approach of blocking the interaction of VEGF and VEGFR2 significantly inhibits tumor growth and has become a promising anticancer strategy. Ramucirumab,a fully humanized monoclonal antibody,was the only drug that targeted to VEGFR2 approved by FDA for the treatment of human cancer and has achieved excellent clinical outcome. However,mono-target therapy may lead to drug resistance and side effects. As a result,mutifunction and muti-target therapeutic methods like combination therapy have become a major trend for the treatment of malignant tumor. Because of the high expression on tumor cell and tumor vascular but low expression on normal tissue,VEGFR2 becomes a great target applied in bi-specific antibody. Thus,this article reviews the progress,challenge of anti-VEGFR2 antibody as well as its application in the field of muti-target treatment,and also makes a prospect for the future tumor treatment.
引文
[1] Folkman J. Tumor angiogenesis:therapeutic implications[J]. New Engl J Med,1971,285(21):1182.
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[3]李晓蕊,郭青龙,卢娜. VEGFA/VEGFR2作用于血管内皮细胞途径及其抑制剂研究进展[J].药物生物技术,2016,23(3):274-278.
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[8] Verdaguer H,Tabernero J,Macarulla T. Ramucirumab in metastatic colorectal cancer:evidence to date and place in therapy[J]. Therap Adv Med Oncol,2016,8(3):230.
[9] Tanimura K,Uchino J,Tamiya N,et al. Treatment rationale and design of the RAMNITA study:A phase II study of the efficacy of docetaxel+ramucirumab for non-small cell lung cancer with brain metastasis[J]. Med,2018,97(23):e11084.
[10] Bamias A,Heijden MVD,Wit RD,et al. 94-Healthcare resource utilization in RANGE:Ramucirumab plus docetaxel versus placebo plus docetaxel in platinum-refractory advanced or metastatic urothelial cancer[J]. Eur Urol Suppl,2018,17(2):e140-e141.
[11] Lee WS,Pyun BJ,Kim SW,et al. TTAC-0001,a human monoclonal antibody targeting VEGFR-2/KDR,blocks tumor angiogenesis[J]. m Abs,2015,7(5):957-968.
[12] Qasemi M,Behdani M,Shokrgozar MA,et al. Construction and expression of an anti-VEGFR2 Nanobody-Fc fusionbody in NS0host cell.[J]. Protein Expr Purif,2016,123:19-25.
[13] Xuan Z X,Li L N,Zhang Q,et al. Fully human VEGFR2 monoclonal antibody BC001 attenuates tumor angiogenesis and inhibits tumor growth.[J]. Int J Oncol,2014,45(6):2411-2420.
[14] Wang J,Wang Z,Zhao Y. Incidence and risk of hypertension with ramucirumab in cancer patients:a meta-analysis of published studies[J]. Clin Drug Investig,2015,35(4):221-228.
[15] Arnold D,Fuchs C,Tabernero J,et al. Meta-analysis of individual patient safety data from six randomized,placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab[J]. Ann Oncol,2017,28(12):2932-2942.
[16] Craven KE,Gore J,Korc M. Overview of pre-clinical and clinical studies targeting angiogenesis in pancreatic ductal adenocarcinoma[J]. Cancer Lett,2016,381(1):201-210.
[17] Penson RT,Moore KM,Fleming GF,et al. A phase II study of ramucirumab(IMC-1121B)in the treatment of persistent or recurrent epithelial ovarian,fallopian tube or primary peritoneal carcinoma[J]. Gynecol Oncol,2014,134(3):478-485.
[18] Yasuda S,Sho M,Yamato I,et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2(VEGFR2)induces synergistic anti-tumour effect in vivo[J].Clin Exp Immunol,2013,172(3):500-506.
[19] Chintharlapalli SR,Croy JE,Leung D,et al. Abstract 3259:LY3127804,a novel anti-Angiopoietin-2 antibody in combination with an anti-VEGFR2 antibody potently inhibits angiogenesis,tumor growth and metastasis[J]. Cancer Res,2016,76(14 Supplement):3259-3259.
[20] Choi HJ,Kim YJ,Lee S,et al. A heterodimeric Fc-based bispecific antibody simultaneously targeting VEGFR-2 and met exhibits potent antitumor activity[J]. Mol Cancer Ther,2013,12(12):2748-2759.
[21] Tetreault J,Chintharlapalli S,Leung D,et al. LY3207447,a tetravalent bispecific antibody targeting VEGFR2 and angiopoietin-2,provides a more efficient anti-angiogenic therapy and an alternative for combination[J]. Cancer Res,2017,77(13 Supplement):3090-3090.
[22] Lu D,Polonskaya Z,Zhang H,et al. A novel anti-PDL1 x antiVEGFR2 bispecific antibody for enhanced antitumor immunity[J]. Cancer Res,2016,76(14 Supplement):572-572.
[23] Dai LJ,Yan CW,Li SZ,et al. Expression and immunological activity of an anti-CD3×VEGFR2 bispecific single-chain antibody[J]. Cell Mol Immunol,2011,27(27):883-886.
[24] Xie W,Fang L,Wang Y,et al. VEGFR2 targeted antibody fused with MICA stimulates NKG2D mediated immunosurveillance and exhibits potent anti-tumor activity against breast cancer[J].Oncotarget,2016,7(13):16445-16461.
[25] Li Z,Zhu Y,Li C,et al. Anti-VEGFR2-interferon-α2 regulates the tumor microenvironment and exhibits potent antitumor efficacy against colorectal cancer[J]. OncoImmunology,2017,6(3):e1290038.
[26] Behdani M,Zeinali S,Karimipour M,et al. Development of VEGFR2-specific nanobody pseudomonas exotoxin a conjugated to provide efficient inhibition of tumor cell growth[J]. New Biotechnol,2013,30(2):205-209.
[27] Kulemzin SV,Gorchakov AA,Chikaev AN,et al. VEGFR2-specific Fn CAR effectively redirects the cytotoxic activity of T cells and YT NK cells[J]. Oncotarget,2018,9(10):9021-9029.
[28] Yip A,Webster RM. The market for chimeric antigen receptor T cell therapies[J]. Nat Rev Drug Discov,2018,17(3):161-162.
[29] Mackey JR,Ramosvazquez M,Lipatov O,et al. Primary results of ROSE/TRIO-12,a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer[J]. J Clin Onco,2015,33(2):141.
[30] Zhu AX,Baron AD,Malfertheiner P,et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma:analysis of REACH trial results by child-pugh score[J]. JAMA Oncol,2017,3(2):235-243.
[2] Ferrara N,Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells[J]. Biochem Bioph Res Co,1989,161(2):851-858.
[3]李晓蕊,郭青龙,卢娜. VEGFA/VEGFR2作用于血管内皮细胞途径及其抑制剂研究进展[J].药物生物技术,2016,23(3):274-278.
[4] Fu X,Yang Y,Li X,et al. RGD peptide-conjugated selenium nanoparticles:antiangiogenesis by suppressing VEGF-VEGFR2-ERK/AKT pathway[J]. Nanomed-Nanotechnol,2016,12(6):1627-1639.
[5] Holzer TR,Fulford AD,Nedderman DM,et al. Tumor cell expression of vascular endothelial growth factor receptor 2 is an adverse prognostic factor in patients with squamous cell carcinoma of the lung[J]. Plos One,2013,8(11):e80292.
[6] Liguigli W,Tomasello G,Toppo L,et al. Ramucirumab for metastatic gastric or gastroesophageal junction cancer:results and implications of the REGARD trial[J]. Future Oncol,2014,10(9):1549-1557.
[7] Reck M,Garon EB,Pazares L. Randomized,double-blind phase Ib/III study of erlotinib with ramucirumab or placebo in previously untreated EGFR-mutant metastatic Non-Small-Cell lung cancer(RELAY)phase Ib results[J]. Clin Lung Cancer,2017,19(3):213-220.
[8] Verdaguer H,Tabernero J,Macarulla T. Ramucirumab in metastatic colorectal cancer:evidence to date and place in therapy[J]. Therap Adv Med Oncol,2016,8(3):230.
[9] Tanimura K,Uchino J,Tamiya N,et al. Treatment rationale and design of the RAMNITA study:A phase II study of the efficacy of docetaxel+ramucirumab for non-small cell lung cancer with brain metastasis[J]. Med,2018,97(23):e11084.
[10] Bamias A,Heijden MVD,Wit RD,et al. 94-Healthcare resource utilization in RANGE:Ramucirumab plus docetaxel versus placebo plus docetaxel in platinum-refractory advanced or metastatic urothelial cancer[J]. Eur Urol Suppl,2018,17(2):e140-e141.
[11] Lee WS,Pyun BJ,Kim SW,et al. TTAC-0001,a human monoclonal antibody targeting VEGFR-2/KDR,blocks tumor angiogenesis[J]. m Abs,2015,7(5):957-968.
[12] Qasemi M,Behdani M,Shokrgozar MA,et al. Construction and expression of an anti-VEGFR2 Nanobody-Fc fusionbody in NS0host cell.[J]. Protein Expr Purif,2016,123:19-25.
[13] Xuan Z X,Li L N,Zhang Q,et al. Fully human VEGFR2 monoclonal antibody BC001 attenuates tumor angiogenesis and inhibits tumor growth.[J]. Int J Oncol,2014,45(6):2411-2420.
[14] Wang J,Wang Z,Zhao Y. Incidence and risk of hypertension with ramucirumab in cancer patients:a meta-analysis of published studies[J]. Clin Drug Investig,2015,35(4):221-228.
[15] Arnold D,Fuchs C,Tabernero J,et al. Meta-analysis of individual patient safety data from six randomized,placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab[J]. Ann Oncol,2017,28(12):2932-2942.
[16] Craven KE,Gore J,Korc M. Overview of pre-clinical and clinical studies targeting angiogenesis in pancreatic ductal adenocarcinoma[J]. Cancer Lett,2016,381(1):201-210.
[17] Penson RT,Moore KM,Fleming GF,et al. A phase II study of ramucirumab(IMC-1121B)in the treatment of persistent or recurrent epithelial ovarian,fallopian tube or primary peritoneal carcinoma[J]. Gynecol Oncol,2014,134(3):478-485.
[18] Yasuda S,Sho M,Yamato I,et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2(VEGFR2)induces synergistic anti-tumour effect in vivo[J].Clin Exp Immunol,2013,172(3):500-506.
[19] Chintharlapalli SR,Croy JE,Leung D,et al. Abstract 3259:LY3127804,a novel anti-Angiopoietin-2 antibody in combination with an anti-VEGFR2 antibody potently inhibits angiogenesis,tumor growth and metastasis[J]. Cancer Res,2016,76(14 Supplement):3259-3259.
[20] Choi HJ,Kim YJ,Lee S,et al. A heterodimeric Fc-based bispecific antibody simultaneously targeting VEGFR-2 and met exhibits potent antitumor activity[J]. Mol Cancer Ther,2013,12(12):2748-2759.
[21] Tetreault J,Chintharlapalli S,Leung D,et al. LY3207447,a tetravalent bispecific antibody targeting VEGFR2 and angiopoietin-2,provides a more efficient anti-angiogenic therapy and an alternative for combination[J]. Cancer Res,2017,77(13 Supplement):3090-3090.
[22] Lu D,Polonskaya Z,Zhang H,et al. A novel anti-PDL1 x antiVEGFR2 bispecific antibody for enhanced antitumor immunity[J]. Cancer Res,2016,76(14 Supplement):572-572.
[23] Dai LJ,Yan CW,Li SZ,et al. Expression and immunological activity of an anti-CD3×VEGFR2 bispecific single-chain antibody[J]. Cell Mol Immunol,2011,27(27):883-886.
[24] Xie W,Fang L,Wang Y,et al. VEGFR2 targeted antibody fused with MICA stimulates NKG2D mediated immunosurveillance and exhibits potent anti-tumor activity against breast cancer[J].Oncotarget,2016,7(13):16445-16461.
[25] Li Z,Zhu Y,Li C,et al. Anti-VEGFR2-interferon-α2 regulates the tumor microenvironment and exhibits potent antitumor efficacy against colorectal cancer[J]. OncoImmunology,2017,6(3):e1290038.
[26] Behdani M,Zeinali S,Karimipour M,et al. Development of VEGFR2-specific nanobody pseudomonas exotoxin a conjugated to provide efficient inhibition of tumor cell growth[J]. New Biotechnol,2013,30(2):205-209.
[27] Kulemzin SV,Gorchakov AA,Chikaev AN,et al. VEGFR2-specific Fn CAR effectively redirects the cytotoxic activity of T cells and YT NK cells[J]. Oncotarget,2018,9(10):9021-9029.
[28] Yip A,Webster RM. The market for chimeric antigen receptor T cell therapies[J]. Nat Rev Drug Discov,2018,17(3):161-162.
[29] Mackey JR,Ramosvazquez M,Lipatov O,et al. Primary results of ROSE/TRIO-12,a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer[J]. J Clin Onco,2015,33(2):141.
[30] Zhu AX,Baron AD,Malfertheiner P,et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma:analysis of REACH trial results by child-pugh score[J]. JAMA Oncol,2017,3(2):235-243.