肿瘤坏死因子家族及其相关药物的研究进展
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摘要
细胞凋亡是进化保守的重要生物学过程,具有重要的生理和病理作用,如在免疫系统的发育与稳态以及多种疾病(包括肿瘤)的发生、发展、预后及治疗等过程中起重要作用。因此,近年来参与细胞凋亡信号转导的肿瘤坏死因子(TNF)/TNF受体(TNFR)家族的重要成员TNFα/TNFR、Fas/Fas L和TRAIL/TRAILR成为重要的药物靶点,并开发出多个相关靶向药物,尤其是生物药物,其中有些在临床疗效和商业上获得巨大成功。简介参与细胞凋亡信号转导的TNF/TNFR家族重要成员,着重对其通过介导细胞凋亡而发挥的生物学作用及其相关药物研发作一综述,希望对我国的药物研发有所裨益。
Apoptosis is an evolutionarily conserved and primary biological event with crucial roles in physiological and pathological processes, including the development and homestasis of immune system as well as the pathogenesis, development, prognosis and treatment of several diseases such as cancer. Therefore, in recent years, the major tumor necrosis factor(TNF)/TNF receptor(TNFR) family members, TNFα/TNFR, Fas/Fas L and TRAIL/TRAILR, involved in apoptosis signal transduction have become important targets for drug development, and a number of the targeted drugs, especially biological pharmaceuticals, have been developed, in which some have achieved great success in clinical effi cacy and commercialization. These major TNF/TNFR family members involved in apoptosis signal transduction were introduced, and their biological functions by mediating apoptosis and the development of the related therapeutics were highlighted so as to promote new drug research and development in our country.
Apoptosis is an evolutionarily conserved and primary biological event with crucial roles in physiological and pathological processes, including the development and homestasis of immune system as well as the pathogenesis, development, prognosis and treatment of several diseases such as cancer. Therefore, in recent years, the major tumor necrosis factor(TNF)/TNF receptor(TNFR) family members, TNFα/TNFR, Fas/Fas L and TRAIL/TRAILR, involved in apoptosis signal transduction have become important targets for drug development, and a number of the targeted drugs, especially biological pharmaceuticals, have been developed, in which some have achieved great success in clinical effi cacy and commercialization. These major TNF/TNFR family members involved in apoptosis signal transduction were introduced, and their biological functions by mediating apoptosis and the development of the related therapeutics were highlighted so as to promote new drug research and development in our country.
引文
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[11]Goukassian D A,Qin G,Dolan C,et al.Tumor necrosis factor-alpha receptor p75 is required in ischemia-induced neovascularization[J].Circulation,2007,115(6):752-762.
[12]Chen X,Baumel M,Mannel D N,et al.Interaction of TNF with TNFreceptor type 2 promotes expansion and function of mouse CD4+CD25+T regulatory cells[J].J Immunol,2007,179(1):154-161.
[13]Zalevsky J,Secher T,Ezhevsky S A,et al.Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection[J].J Immunol,2007,179(3):1872-1883.
[14]Olleros M L,Vesin D,Lambou A F,et al.Dominant-negative tumor necrosis factor protects from Mycobacterium bovis Bacillus Calmette Guerin(BCG)and endotoxin-induced liver injury without compromising host immunity to BCG and Mycobacterium tuberculosis[J].J Infect Dis,2009,199(7):1053-1063.
[15]Mukai Y,Nakamura T,Yoshioka Y,et al.Fast binding kinetics and conserved 3D structure underlie the antagonistic activity of mutant TNF:useful information for designing artifi cial proteo-antagonists[J].JBiochem,2009,146(2):167-72.
[16]Gonzales P E,Galli J D,Milla M E.Identification of key sequence determinants for the inhibitory function of the prodomain of TACE[J].Biochemistry,2008,47(37):9911-9919.
[17]Chakrabandhu K,Herincs Z,Huault S,et al.Palmitoylation is required for effi cient Fas cell death signaling[J].EMBO J,2007,26(1):209-220.
[18]Feig C,Tchikov V,Schutze S,et al.Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signaling[J].EMBO J,2007,26(1):221-231.
[19]Lee K H,Feig C,Tchikov V,et al.The role of receptor internalization in CD95 signaling[J].EMBO J,2006,25(5):1009-1023.
[20]Bidere N,Su H C,Lenardo M J.Genetic disorders of programmed cell death in the immune system[J].Annu Rev Immunol,2006,24:321-352.
[21]O′Reilly LA,Tai L,Lee L,et al.Membrane-bound Fas ligand only is essential for Fas-induced apoptosis[J].Nature,2009,461(7264):659-663.
[22]Merino D,Lalaoui N,Morizot A,et al.Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2[J].Mol Cell Biol,2006,26(19):7046-7055.
[23]Riccioni R,Pasquini L,Mariani G,et al.TRAIL decoy receptors mediate resistance of acute myeloid leukemia cells to TRAIL[J].Haematologica,2005,90(5):612-624.
[24]Vitovski S,Phillips JS,Sayers J,et al.Investigating the interaction between osteoprotegerin and receptor activator of NF-kappa B or tumor necrosis factor-related apoptosis-inducing ligand:evidence for a pivotal role for osteoprotegerin in regulating two distinct pathways[J].J Biol Chem,2007,282(43):31601-31609.
[25]Finnberg N,Klein-Szanto A J,El-Deiry W S.TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis[J].J Clin Invest,2008,118(1):111-123.
[26]Janssen E M,Droin N M,Lemmens EE,et al.CD4+T-cell help controls CD8+T-cell memory via TRAIL-mediated activation-induced cell death[J].Nature,2005,434(7029):88-93.
[27]Koschny R,Walczak H,Ganten T M.The promise of TRAIL-potential and risks of a novel anticancer therapy[J].J Mol Med,2007,85(9):923-935.
[28]Horak P,Pils D,Haller G,et al.Contribution of epigenetic silencing of tumor necrosis factor-related apoptosis inducing ligand receptor 1(DR4)to TRAIL resistance and ovarian cancer[J].Mol Cancer Res,2005,3(6):335-343.
[29]Wagner K W,Punnoose E A,Januario T,et al.Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL[J].Nat Med,2007,13(9):1070-1077.
[30]Volkmann X,Fischer U,Bahr M J,et al.Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver[J].Hepatology,2007,46(5):1498-1508.
[31]Ashkenazi A,Holland P,Eckhardt S G.Ligand-based targeting of apoptosis in cancer:the potential of recombinant human apoptosis ligand2/tumor necrosis factor-related apoptosis-inducing ligand(rh Apo2L/TRAIL)[J].J Clin Oncol,2008,26(21):3621-3630.
[32]Hotte S J,Hirte H W,Chen E X,et al.A phase 1 study of mapatumumab(fully human monoclonal antibody to TRAIL-R1)in patients with advanced solid malignancies[J].Clin Cancer Res,2008,14(11):3450-3455.
[33]Wakelee H A,Patnaik A,Sikic B I,et al.Phase I and pharmacokinetic study of lexatumumab(HGS-ETR2)given every 2 weeks in patients with advanced solid tumors[J].Ann Oncol,2010,21(2):376-381.
[34]Trarbach T,Moehler M,Heinemann V,et al.Phase II trial of mapatumumab,a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1(TRAIL-R1),in patients with refractory colorectal cancer[J].Br J Cancer,2010,102(3):506-512.
[35]Koschny R,Holland H,Sykora J,et al.Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis[J].Clin Cancer Res,2007,13(11):3403-3412.
[36]Leong S,Cohen R B,Gustafson D L,et al.Mapatumumab,an antibody targeting TRAIL-R1,in combination with paclitaxel and carboplatin in patients with advanced solid malignancies:results of a phase I and pharmacokinetic study[J].J Clin Oncol,2009,27(26):4413-4421.
[37]Mom C H,Verweij J,Oldenhuis C N,et al.Mapatumumab,a fully human agonistic monoclonal antibody that targets TRAIL-R1,in combination with gemcitabine and cisplatin:a phase I study[J].Clin Cancer Res,2009,15(17):5584-5590.
[38]El-Zawahry A,Mc Killop J,Voelkel-Johnson C.Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts[J].BMC Cancer,2005,5(1):2.
[39]Marini P,Budach W,Niyazi M,et al.Combination of the pro-apoptotic TRAIL-receptor antibody mapatumumab with ionizing radiation strongly increases long-term tumor control under ambient and hypoxic conditions[J].Int J Radiat Oncol Biol Phys,2009,75(1):198-202.
[40]Stieglmaier J,Bremer E,Kellner C,et al.Selective induction of apoptosis in leukemic B-lymphoid cells by a CD19-specific TRAILfusion protein[J].Cancer Immunol Immunother,2008,57(2):233-246.
[41]Schneider B,Gerspach-Joner J,Wajant H,et al.Novel TRAIL variants for targeted cancer therapy[J].J Clin Oncol,2010,28(15suppl):e13592.
[42]Cao L,Du P,Jiang S H,et al.Enhancement of antitumor properties of TRAIL by targeted delivery to the tumor neovasculature[J].Mol Cancer Ther,2008,7(4):851-861.
[43]Holoch P A,Griffith T S.TNF-related apoptosis-inducing ligand(TRAIL):a new path to anti-cancer therapies[J].Eur J Pharmacol,2009,625(1/2/3):63-72.
[44]van der Sloot A M,Tur V,Szegezdi E,et al.Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the DR5 receptor[J].Proc Natl Acad Sci USA,2006,103(23):8634-8639.
[45]Tur V,van der Sloot A M,Reis C R,et al.DR4-selective tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)variants obtained by structure-based design[J].J Biol Chem,2008,283(29):20560-20568.
[46]Pavet V,Beyrath J,Pardin C,et al.Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity[J].Cancer Res,2010,70(3):1101-1110.
[2]Ea C K,Deng L,Xia Z P,et al.Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO[J].Mol Cell,2006,22(2):245-257.
[3]Guicciardi M E,Gores G J.Life and death by death receptors[J].FASEBJ,2009,23(6):1625-1637.
[4]La Merie Business Intelligence.R&D Pipeline News:Top 30 biologics2010[EB/OL].[2015-10-02].http://www.pipelinereview.com/freedownloads/TOP_30_Biologics_2010_RDPN_Special_Mar_2011.pdf.
[5]Alexopoulou L,Kranidioti K,Xanthoulea S,et al.Transmembrane TNFprotects mutant mice against intracellular bacterial infections,chronic infl ammation and autoimmunity[J].Eur J Immunol,2006,36(10):2768-2780.
[6]Torres D,Janot L,Quesniaux V F,et al.Membrane tumor necrosis factor confers partial protection to Listeria infection[J].Am J Pathol,2005,167(6):1677-1687.
[7]Allenbach C,Launois P,Mueller C,et al.An essential role for transmembrane TNF in the resolution of the inflammatory lesion induced by Leishmania major infection[J].Eur J Immunol,2008,38(3):720-731.
[8]Fremond C,Allie N,Dambuza I,et al.Membrane TNF confers protection to acute mycobacterial infection[J].Respir Res,2005,6(1):136.
[9]Olleros M L,Guler R,Vesin D,et al.Contribution of transmembrane tumor necrosis factor to host defense against Mycobacterium bovis bacillus Calmette-guerin and Mycobacterium tuberculosis infections[J].Am J Pathol,2005,166(4):1109-1120.
[10]Saunders B M,Tran S,Ruuls S,et al.Transmembrane TNF is suffi cient to initiate cell migration and granuloma formation and provide acute,but not long-term,control of Mycobacterium tuberculosis infection[J].JImmunol,2005,174(8):4852-4859.
[11]Goukassian D A,Qin G,Dolan C,et al.Tumor necrosis factor-alpha receptor p75 is required in ischemia-induced neovascularization[J].Circulation,2007,115(6):752-762.
[12]Chen X,Baumel M,Mannel D N,et al.Interaction of TNF with TNFreceptor type 2 promotes expansion and function of mouse CD4+CD25+T regulatory cells[J].J Immunol,2007,179(1):154-161.
[13]Zalevsky J,Secher T,Ezhevsky S A,et al.Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection[J].J Immunol,2007,179(3):1872-1883.
[14]Olleros M L,Vesin D,Lambou A F,et al.Dominant-negative tumor necrosis factor protects from Mycobacterium bovis Bacillus Calmette Guerin(BCG)and endotoxin-induced liver injury without compromising host immunity to BCG and Mycobacterium tuberculosis[J].J Infect Dis,2009,199(7):1053-1063.
[15]Mukai Y,Nakamura T,Yoshioka Y,et al.Fast binding kinetics and conserved 3D structure underlie the antagonistic activity of mutant TNF:useful information for designing artifi cial proteo-antagonists[J].JBiochem,2009,146(2):167-72.
[16]Gonzales P E,Galli J D,Milla M E.Identification of key sequence determinants for the inhibitory function of the prodomain of TACE[J].Biochemistry,2008,47(37):9911-9919.
[17]Chakrabandhu K,Herincs Z,Huault S,et al.Palmitoylation is required for effi cient Fas cell death signaling[J].EMBO J,2007,26(1):209-220.
[18]Feig C,Tchikov V,Schutze S,et al.Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signaling[J].EMBO J,2007,26(1):221-231.
[19]Lee K H,Feig C,Tchikov V,et al.The role of receptor internalization in CD95 signaling[J].EMBO J,2006,25(5):1009-1023.
[20]Bidere N,Su H C,Lenardo M J.Genetic disorders of programmed cell death in the immune system[J].Annu Rev Immunol,2006,24:321-352.
[21]O′Reilly LA,Tai L,Lee L,et al.Membrane-bound Fas ligand only is essential for Fas-induced apoptosis[J].Nature,2009,461(7264):659-663.
[22]Merino D,Lalaoui N,Morizot A,et al.Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2[J].Mol Cell Biol,2006,26(19):7046-7055.
[23]Riccioni R,Pasquini L,Mariani G,et al.TRAIL decoy receptors mediate resistance of acute myeloid leukemia cells to TRAIL[J].Haematologica,2005,90(5):612-624.
[24]Vitovski S,Phillips JS,Sayers J,et al.Investigating the interaction between osteoprotegerin and receptor activator of NF-kappa B or tumor necrosis factor-related apoptosis-inducing ligand:evidence for a pivotal role for osteoprotegerin in regulating two distinct pathways[J].J Biol Chem,2007,282(43):31601-31609.
[25]Finnberg N,Klein-Szanto A J,El-Deiry W S.TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis[J].J Clin Invest,2008,118(1):111-123.
[26]Janssen E M,Droin N M,Lemmens EE,et al.CD4+T-cell help controls CD8+T-cell memory via TRAIL-mediated activation-induced cell death[J].Nature,2005,434(7029):88-93.
[27]Koschny R,Walczak H,Ganten T M.The promise of TRAIL-potential and risks of a novel anticancer therapy[J].J Mol Med,2007,85(9):923-935.
[28]Horak P,Pils D,Haller G,et al.Contribution of epigenetic silencing of tumor necrosis factor-related apoptosis inducing ligand receptor 1(DR4)to TRAIL resistance and ovarian cancer[J].Mol Cancer Res,2005,3(6):335-343.
[29]Wagner K W,Punnoose E A,Januario T,et al.Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL[J].Nat Med,2007,13(9):1070-1077.
[30]Volkmann X,Fischer U,Bahr M J,et al.Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver[J].Hepatology,2007,46(5):1498-1508.
[31]Ashkenazi A,Holland P,Eckhardt S G.Ligand-based targeting of apoptosis in cancer:the potential of recombinant human apoptosis ligand2/tumor necrosis factor-related apoptosis-inducing ligand(rh Apo2L/TRAIL)[J].J Clin Oncol,2008,26(21):3621-3630.
[32]Hotte S J,Hirte H W,Chen E X,et al.A phase 1 study of mapatumumab(fully human monoclonal antibody to TRAIL-R1)in patients with advanced solid malignancies[J].Clin Cancer Res,2008,14(11):3450-3455.
[33]Wakelee H A,Patnaik A,Sikic B I,et al.Phase I and pharmacokinetic study of lexatumumab(HGS-ETR2)given every 2 weeks in patients with advanced solid tumors[J].Ann Oncol,2010,21(2):376-381.
[34]Trarbach T,Moehler M,Heinemann V,et al.Phase II trial of mapatumumab,a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1(TRAIL-R1),in patients with refractory colorectal cancer[J].Br J Cancer,2010,102(3):506-512.
[35]Koschny R,Holland H,Sykora J,et al.Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis[J].Clin Cancer Res,2007,13(11):3403-3412.
[36]Leong S,Cohen R B,Gustafson D L,et al.Mapatumumab,an antibody targeting TRAIL-R1,in combination with paclitaxel and carboplatin in patients with advanced solid malignancies:results of a phase I and pharmacokinetic study[J].J Clin Oncol,2009,27(26):4413-4421.
[37]Mom C H,Verweij J,Oldenhuis C N,et al.Mapatumumab,a fully human agonistic monoclonal antibody that targets TRAIL-R1,in combination with gemcitabine and cisplatin:a phase I study[J].Clin Cancer Res,2009,15(17):5584-5590.
[38]El-Zawahry A,Mc Killop J,Voelkel-Johnson C.Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts[J].BMC Cancer,2005,5(1):2.
[39]Marini P,Budach W,Niyazi M,et al.Combination of the pro-apoptotic TRAIL-receptor antibody mapatumumab with ionizing radiation strongly increases long-term tumor control under ambient and hypoxic conditions[J].Int J Radiat Oncol Biol Phys,2009,75(1):198-202.
[40]Stieglmaier J,Bremer E,Kellner C,et al.Selective induction of apoptosis in leukemic B-lymphoid cells by a CD19-specific TRAILfusion protein[J].Cancer Immunol Immunother,2008,57(2):233-246.
[41]Schneider B,Gerspach-Joner J,Wajant H,et al.Novel TRAIL variants for targeted cancer therapy[J].J Clin Oncol,2010,28(15suppl):e13592.
[42]Cao L,Du P,Jiang S H,et al.Enhancement of antitumor properties of TRAIL by targeted delivery to the tumor neovasculature[J].Mol Cancer Ther,2008,7(4):851-861.
[43]Holoch P A,Griffith T S.TNF-related apoptosis-inducing ligand(TRAIL):a new path to anti-cancer therapies[J].Eur J Pharmacol,2009,625(1/2/3):63-72.
[44]van der Sloot A M,Tur V,Szegezdi E,et al.Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the DR5 receptor[J].Proc Natl Acad Sci USA,2006,103(23):8634-8639.
[45]Tur V,van der Sloot A M,Reis C R,et al.DR4-selective tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)variants obtained by structure-based design[J].J Biol Chem,2008,283(29):20560-20568.
[46]Pavet V,Beyrath J,Pardin C,et al.Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity[J].Cancer Res,2010,70(3):1101-1110.