在肿瘤免疫治疗领域，PD-1抑制剂自首次露面以来就一直带着光环，临床试验、审批阶段都受到相关机构的加速批准待遇。自2014年全球首个该类药物获得批准以来，国外各企业高度聚焦，临床试验也是加紧进行。让人欣慰的是，国内企业也毫不示弱，截至2016年2月底，已经有4家本土企业积极投入到这场激烈战斗中。　　随着精准医疗概念的提出，有关免疫治疗与肿瘤基因突变关系的研究得到越来越多的关注。在卫计委重大新药创制2015年重点研究方向中，提出研发重点要针对恶性肿瘤等重大疾病，并进一步聚焦为靶向及免疫抗肿瘤药物，还提出了推荐的药物靶点，包括PD1、PD-L1靶点，明确范围无疑将使国内制药企业研发目标更准确。　　目前国外已上市的抗PD-1/PD-L1药物是百时美施贵宝(BMS)的Opdivo(Nivolumab)和默沙东的Keytruda(Pembrolizumab)，其他处于在研阶段的药物有Pidilizumab(CT-011，CureTech)、Avelumab(默克)、BMS-936559(MDX-1105，BMS)、Atezolizumab(MPDL3280A，罗氏)和MED14736(阿斯利康)。　　查询CDE数据发现，近两年，在国内PD-1/PD-L1市场中也出现一批领先“玩家”，包括君实生物、恒瑞医药、百济神州、嘉和生物等，泰州君实和江苏恒瑞先后获得了临床试验批件，目前没有在中国上市者。全球专利技术情况
从PD-1抗体专利技术布局来看，抗体专利申请量最多，其次是抗受体、抗肿瘤药、DNA重组技术、受体表面抗原等。　　从权利人来看，专利最多的公司是日本小野制药(ono pharmaceutical)和达纳法伯癌症研究机构(dana-farber cancer institute)。　　从PD-1抗体专利市场布局来看，美国是各大药企最重要的市场，各申请人在美国共布局了156件专利，基本覆盖全部技术类别；欧洲、日本和中国也是各大药企竞相追逐的市场；此外，奥地利、阿根廷、秘鲁、波兰等国均有专利布局。国外研发进展上市药物Opdivo(Nivolumab，纳武单抗)2020年销售额预计：88亿美元　　2014年7月，Opdivo(nivolumab)率先在日本获批用于治疗晚期黑色素瘤，成为全球首个批准上市的PD-1抑制剂。　　Nivolumab由BMS和小野制药共同开发。截至目前，Opdivo已经在46个国家获批上市(不含中国)。Opdivo因疗效显著而4次临床试验提前结束，因此FDA只用了4个工作日便批准其鳞状非小细胞肺癌适应症，创审批速度新纪录。　　BMS的2015年年报显示，Opdivo第四季度销售增长至4.7亿美元，全年贡献了9.42亿美元。　　据EvaluatePharma预测，Opdivo(Nivolumab)将成为PD-1/PD-L1领域最成功的免疫疗法，2020年销售额将达到88亿美元。Keytruda(Pembrolizumab，派姆单抗)2020年销售额预计：55亿美元　　默沙东的Keytruda通过企业收购获得。2014年，该药的上市申请启动，并获得突破性治疗药物资格，于日获FDA批准，比限期日提前50天，成为FDA批准的第一个PD-1抗体药物。默沙东就该药与辉瑞、安进及Incyte达成合作协议，将其与其他抗癌药合用以扩大适应症范围。　　默沙东2015年年报显示，Keytruda第四季度累计2.14亿美元，全年销售达5.66亿美元。　　据EvaluatePharma预测，Keytruda(pembrolizumab)2020年销售额将达到55亿美元。　　其他在研药物　　●Atezolizumab 2015年8月，罗氏宣布，其开发的PD-L1药物Atezolizumab(代号MPDL3280A)在一项治疗非细小性细胞肺癌的Ⅱ期临床研究中取得重大成功，公司将凭借这一结果向FDA寻求加速审批，以追上在前面的Opdivo(BMS)和Keytruda(默沙东)。　　●Avelumab 2015年11月，默克(Merck KGaA)和辉瑞合作开发的抗PD-L1免疫疗法Avelumab被FDA授予治疗既往已接受至少一种化疗方案的转移性Merkel细胞癌患者的突破性药物资格。2015年9月和10月，FDA已授予Avelumab孤儿药地位和快车道地位。目前，Avelumab的临床开发项目涉及超过15种肿瘤类型。　　●Durvalumab 阿斯利康的Durvalumab(代号MEDI4736)是一种PD-L1抑制剂，用于治疗非小细胞肺癌的研究处于Ⅲ期临床阶段；对黑色素瘤的研究处于Ⅰ期临床阶段。对结直肠癌的研究处于Ⅱ期临床阶段。目前，其他竞争对手尽管已将结直肠癌列为研究的一部分，但尚未针对结直肠癌开展专门研究。因此，阿斯利康推进其PD-L1抑制剂项目MEDI-4736至结直肠癌，将开启一个潜在的一鸣惊人的机会。　　●Pidilizumab CureTech公司的Pidilizumab(代号CT-011)是针对PD-1的重组单克隆抗体，目前处于Ⅱ期临床研究阶段，拟适应症包括大B细胞淋巴瘤、胶质细胞瘤和多发性骨髓瘤。　　临床客观缓解率　　2015年8月，期刊《Current Opinion in Pharmacology》汇总了PD-1/PD-L1的部分品种及部分临床，翻译后如表1所示。Opdivo对黑色素瘤的客观缓解率达到35%，对比来看，仍处于研究阶段的Pidilizumab就有些差强人意，仅有6%的客观缓解率。在2016年初，FDA暂停了Pidilizumab的部分临床试验。PD-1/PD-L1靶点研发火爆，但并非都是道路平坦。（点击图片可放大）　国内研发申报情况　　根据CFDA及CDE网站提供的数据，目前国内暂无抗PD-1单克隆抗体获批生产。但临床研发活跃，主要涉及4家国外企业和4家国内企业的8个产品。　　日，沃森生物子公司嘉和生物研发的抗PD-1单抗(杰诺单抗注射液)产品临床研究申请获得CDE的受理。至此，国内共有4个厂家参与到PD-1/PD-L1的激烈争夺战中，包括恒瑞、百济神州、泰州君实。默沙东、BMS、罗氏、阿斯利康也在积极开展该类药物中国的临床试验(见表2)。
（点击图片可放大）国外企业在国内的临床试验　　查询CDE药物临床试验与登记平台，数据显示，Nivolumab已在积极开展临床试验，BMS于日向CDE提出该药临床申请，是国外该类药物企业最早在国内申报临床的。CDE于日批准了该临床试验，其用于晚期或转移性非小细胞肺癌、晚期或复发性实体瘤的临床试验正在进行(见表3)。（点击图片可放大）　　CDE数据显示，罗氏的Atezolizumab(MPDL3280A)自2013年12月开始，截至目前一共提交了9个临床试验申请，其中一项于日获得临床批件。默沙东的Keytruda(pembrolizumab)于日获得临床批件。阿斯利康的Durvalumab(MEDI4736)在2015年12月提交了临床试验申请，CDE正在审核中。　　国内企业的临床试验开展　　3月2日，中山大学肿瘤防治中心贴出了招收国产人源化抗PD-1单抗患者的通知，临床试验使用的是泰州君实生产的国产重组人源化PD-1单克隆抗体注射液JS001。　　泰州君实的重组人源化抗PD-1单克隆抗体注射液在2015年12月获得CDE临床批件，成为国内首家PD-1单抗获批临床的企业，该药预计将在2020年上市销售。　　随后，在日，江苏恒瑞的SHR-1210获得临床批件。恒瑞与美国Incyte公司在2015年9月达成协议，恒瑞医药将具有自主知识产权的SHR-1210项目有偿许可转让给美国Incyte公司，交易额达7.95亿美元，这是中国企业首次实现了从进口美国医药技术变成出口创新药技术的转变。　　百济神州与嘉和生物的PD-1药物临川申请仍在受理中。2016年1月，百济神州的PD-1单抗BGB-A317通过FDA的新药研究申请审评，可在美国开展临床试验。嘉和生物的杰诺单抗注射液主要的潜在适应症包括各种血癌及黑色素瘤、非小细胞肺癌、肾癌等多种实体瘤，是目前最后申报的企业。　　组合疗法的利弊衡量　　PD-1单抗开发火爆，各大企业纷纷开展外部合作，火速推进各自的临床项目，设想并尝试与各种上市或没上市的药物联用，以彻底发掘该类药物的最大临床潜力。　　EvaluatePharma的报告显示，目前有多家企业在研究PD-1/PD-L1抗体与其他药物的组合，组合药物包括疫苗、小分子药物、化疗药物、免疫抑制剂等。从数据来看，与其他药物组合的研究占据了31%(见图1)。　　2015年10月，FDA批准Opdivo与Yervoy(ipilimumab，依匹木单抗)合并用于黑色素瘤患者治疗，Yervoy是CTLA-4抑制剂。这是首个也是唯一一个获FDA批准用于癌症的两联免疫肿瘤药物疗法。　　不过，目前生存期延长2.5~6个月才被认为具有临床意义，何种药物组合可达到这个新标准还有待研究。应深入开展多种临床试验，从而发现免疫治疗药物的最佳用药方案。　　此外，免疫疗法也显示出比较严重的副作用，尤其是复方组合。根据适应症的不同，免疫疗法与不同的化疗或靶向疗法组合，但有些组合毒性太大，疗效一般。所以，免疫疗法到底能对多少肿瘤起到重要作用还有待观察。　　2015下半年，FDA曾紧急叫停了一个临床试验。这个试验是PD-1抑制剂和靶向药物AZD9291的联合用药，同时使用这两个药物毒性增强，病人不能耐受。　　结语&&&　　据花旗预测，2020年PD-1/PD-L1抗体全球市场规模将达到350亿美元，年复合增长率达到惊人的61%。未来10年，将有超过60%的癌症患者接受免疫治疗。免疫治疗的良好疗效、广阔的市场空间，吸引着众多药企巨头投入其中。　　我们看到，在抗肿瘤领域，国内企业一直紧跟国际研发潮流，加上国家政策的支持，相信国内患者很快就能用上该类药物。　　医学的发展总会给我们带来希望，未满足的临床需求终会被满足。Programmed cell death protein 1Programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), is a protein that in humans is encoded by the PDCD1 gene.PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells.PD-1 binds two ligands, PD-L1 and PD-L2.PD-1, functioning as an immune checkpoint, plays an important role in down regulating the immune system by preventing the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance. The inhibitory effect of PD-1 is accomplished through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (suppressor T cells).A new class of drugs that block PD-1, the PD-1 inhibitors, activate the immune system to attack tumors and are therefore used with varying success to treat some types of cancer.Contents
1Structure2Ligands3Function4Clinical significance4.1Cancer4.2HIV5References6Further reading7External linksStructureProgrammed death 1 is a type I membrane protein of 268 amino acids. PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators.The protein's structure includes an extracellular IgV domain followed by a transmembrane region and an intracellular tail. The intracellular tail contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates TCR signals. This is consistent with binding of SHP-1 and SHP-2 phosphatases to the cytoplasmic tail of PD-1 upon ligand binding. In addition, PD-1 ligation up-regulates E3-ubiquitin ligases CBL-b and c-CBL that trigger T cell receptor down-modulation.PD-1 is expressed on the surface of activated T cells, B cells, and macrophages, suggesting that compared to CTLA-4, PD-1 more broadly negatively regulates immune responses.LigandsPD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family.PD-L1 protein is upregulated on macrophages and dendritic cells (DC) in response to LPS and GM-CSF treatment, and on T cells and B cells upon TCR and B cell receptor signaling, whereas in resting mice, PD-L1 mRNA can be detected in the heart, lung, thymus, spleen, and kidney. PD-L1 is expressed on almost all murine tumor cell lines, including PA1 myeloma, P815 mastocytoma, and B16 melanoma upon treatment with IFN-γ. PD-L2 expression is more restricted and is expressed mainly by DCs and a few tumor lines.FunctionSeveral lines of evidence suggest that PD-1 and its ligands negatively regulate immune responses. PD-1 knockout mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy on the C57BL/6 and BALB/c backgrounds, respectively.In vitro, treatment of anti-CD3 stimulated T cells with PD-L1-Ig results in reduced T cell proliferation and IFN-γ secretion. Reduced T cell proliferation correlated with attenuated IL-2 secretion, which can be rescued by addition of cross-linking anti-CD28 antibodies or exogenous IL-2.Together, these data suggest that PD-1 negatively regulates T cell responses. Experiments using PD-L1 transfected DCs and PD-1 expressing transgenic (Tg) CD4+ and CD8+ T cells suggest that CD8+ T cells are more susceptible to inhibition by PD-L1, although this could be dependent on the strength of TCR signaling. Consistent with a role in negatively regulating CD8+ T cell responses, using an LCMV model of chronic infection, Rafi Ahmed’s group showed that the PD-1-PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus specific CD8+ T cells, which can be reversed by blocking the PD-1-PD-L1 interaction.As CTLA-4 negatively regulates anti-tumor immune responses, the closely related molecule PD-1 has been independently explored as a target for immunotherapy. The 2C TCR recognizes the peptide SIYRYYGL in the context of H 2kb. 2C CD8 T cells incubated with IFN-γ treated B16 targets expressing SIYRYYGL peptide poorly lyse their targets and secrete low levels of IL-2.[14] However, PD-1 knockout 2C T cells have heightened cytolytic capacity and IL-2 secretion, suggesting that PD-1 negatively regulates anti-tumor CD8 T cell responses. Similarly, P815 mastocytoma, which does not express PD-L1 unless treated with IFN-γ, can be transduced to express PD-L1, resulting in inhibition of in vitro CD8-mediated cytotoxicity and enhanced in vivo tumor growth. In vitro cytotoxicity and in vivo inhibition of growth can be restored by anti-PD-L1 antibodies or by genetic ablation of PD-1[13][14] Together, these data suggest that expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells. Expression of PD-L1 on tumors is correlated with reduced survival in esophageal, pancreatic and other types of cancers, highlighting this pathway as a target for immunotherapy.[19] Said et al. showed that triggering PD-1, expressed on monocytes and up-regulated upon monocytes activation, by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function.Clinical significanceIn mice, expression of this gene is induced in the thymus when anti-CD3 antibodies are injected and large numbers of thymocytes undergo apoptosis. Mice deficient for this gene bred on a BALB/c background developed dilated cardiomyopathy and died from congestive heart failure. These studies suggest that this gene product may also be important in T cell function and contribute to the prevention of autoimmune diseases.CancerPD-L1 the ligand for PD1 is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established. (PMID , PMID , PMID
and PMID ) Monoclonal antibodies targeting PD-1 that boost the immune system are being developed for the treatment of cancer.[21] Many tumor cells express PD-L1, an immunosuppressive PD-1 inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumor activity. This is known as immune checkpoint blockade.It has been suggested that this section be split into an article. (Discuss) (August 2015)One such anti-PD-1 antibody drug, nivolumab, (Opdivo - Bristol Myers Squibb), produced complete or partial responses in non-small-cell lung cancer, melanoma, and renal-cell cancer, in a clinical trial with a total of 296 patients.[22] Colon and pancreatic cancer did not have a response.Nivolumab (Opdivo, Bristol-Myers Squibb), which also targets PD-1 receptors, was approved in Japan in July 2014 and by the US FDA in December 2014 to treat metastatic melanoma.Pembrolizumab (Keytruda, MK-3475, Merck), which also targets PD-1 receptors, was approved by the FDA in Sept 2014 to treat metastatic melanoma. Pembrolizumab has been made accessible to advanced melanoma patients in the UK via UK Early Access to Medicines Scheme (EAMS) in March 2015. It is being used in clinical trials in the US for lung cancer, lymphoma, and mesothelioma. It has had measured success, with little side effects.It is up to the manufacturer of the drug to submit application to the FDA for approval for use in these diseases. On October 2, 2015 Pembrolizumab was approved by FDA for advanced (metastatic) non-small cell lung cancer (NSCLC) patients whose disease has progressed after other treatments.[23] Other drugs in early stage development targeting PD-1 receptors (aka checkpoint inhibitors): Pidilizumab (CT-011, 单抗观察(mAb_observer)　
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京公网安备78来源：壹汽车现在买车一族请注意了，今天车妹就为大家这推荐10款2016年内即将上市的热销实惠性能高的SUV车型。凯迪拉克XT5延续了此前海外版的样式，在外型上还是采用了传统是钻石切割设计风格，车前的树直的LED大灯延伸到保险杠的两侧，设计比较前卫而且发动机还是采用ATS的，所以发动机的力量更强。马自达CX-4，这款鲜红的色调非常尊贵，格栅个灯组都十分和谐同时又变现出非凡的魄力，方向盘和中控的设计更加精致，性能提升了很多，油耗相对来说降低了很多。宝沃BX7，这款车的先祖是相当的大牌的，虽为新牌，但是历史和宝马差不多，我们期望着款2.0T的混合动力系统的SUV在年内上市。长安CX70，这款车在3月17下线，预计在4月底在北京车展上展示，新款将推出五座和七座SUV，空间更加充裕，我们更加期待。凯翼X3在2015年12月已经在安徽芜湖下线了，在2016年6月这款车将上市，这款车个进气格栅分为两处都是经过熏黑处理的，对于镀铬装饰的中网，可以更加看出这款车的动感所在。昌河Q25，昌河公司也开始从面包车走向SUV小型客车上了，这款车的设计比较精致，在去年12月份已经在景德镇下线了，价格比较亲民，售价为5.59-7.59万。吉利帝豪GS，这是吉利公司的收款跨界型SUV，造型比较犀利，而且采用LED大灯，我们期望着性能不错的行车上市。新款比亚迪S6，这款SUV将更具有运动型的特征，相比之下这款车的想能将大大提升，内饰将会提高更多。大迈X5 1.6L，这款小排量紧凑型SUV已经今年年内会实现量产上市，其七座的售价7.99-8.59万，我们很是期待。总结SUV市场竞争非常激烈，增配减价的事情多数发生在合资品牌上，希望国内品牌也能跟上脚步！版权归原创者所有，如有侵权请及时联系！【很准】下面五位美女，凭直觉谁转过身来最漂亮？准确分析您的性格与感情特点。我选3好，你呢？全球车迷会(qqchemihui)　
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