我国未来生物医药产业发展的思考

魏于全 四川大学华西医院肿瘤中心生物治疗全国重点实验室 加强生物医药产业的创新能力与创新体系建设 重点发展生物技术药物、化学药新品种、现代中药、先进医疗器械、新型药用辅料包装材料与制药设备等2.积极推进实现国产化替代，减少生物医药行业的“卡脖子”环节3.传统制药公司、生物技术公司等为创新主体，以高校和科研院所为技术支撑4.政府创新基金、风险投资公司、私人资本等投入，加速高端人才的聚集CRO和中介机构为创新载体，并与高水平临床研究机构合作等6创新监管政策环境，监管科学如何跟上生物医药创新步改革市场准入环节，医保谈判、集中采购、医保报销等加强知识产权保护，抢占世界生物医药行业的制高点加强国际合作，融入全球生物医药创新体系 生物技术药物 生物技术药物是指采用DNA重组技术或其它创新生物技术生产的治疗药物 抗体药物>疫苗细胞因子与重组蛋白药物基因治疗核酸类：反义核酸、RNA干扰等>其它 生物治疗 免疫治疗：包括抗体、免疫细胞、细胞因子与疫苗等治疗（Immunotherapy，includingvaccine,immunecell Therapy,cytokine,monoclonalantibodies). 基因治疗（GeneTherapy） 干细胞与组织工程等（StemCellTherapyandTissue Engineering) 其它：如纤溶酶原激活剂、重组血浆因子、生长因子、融合蛋白等。 基因组学、蛋白组学以及生物信息学为疫苗研发带来新机遇 细菌与病毒等病原基因组序列开发疫苗 Nature Geneties|VOL51JUNE 2019|923www.nature.com/naturegenetics “结构生物学指导疫苗设计”，将为新型疫苗的设计带来新的突破 辉瑞、GSK相继通过FDA委员会评审，最终结果将于5月揭晓 A prefusion-stabilized RSV F subunit vaccine elicits Bcell responses with greater breadth and potency than apostfusion Fvaccine Lauren A, Chang'+t, Emily Phung*+5, Midhelle C. Crank'll, Kaityn M, Morabito', Tonya Vllafana',Barney 5. Geaham'-, Tracy J. RuckwardtPs, Mark T. Esser, Bob C. Lin', Grace L Chen'** Sciencetransl Med,2022,Dec. 设计RSV疫苗 Structure of RSV Fusion GlycoproteinTrimerBoundtoa Prefusion-SpecificNeutralizing Antibody pingtane.Peter D. Kaong," Bamey S. Grahurherg Zheng"in 2hun,'singshao Xin, Science,2013,340:1113-1117 合成生物学是21世纪生物学的新兴学科，代表了生物系统设计的新趋势同样也是疫苗设计的新方向 SyntheticGenerationofInfluenzaVaccineVirusesforRapidResponsetoPandemics SyntheticbiologyspeedsvaccinedevelopmentNature, 28September2020 Timothy B, Stockwell," Mikkel A. Algire," Nina Alperovich," Mario Barro," David M., Brown," Nowartis公司采用这种技术，进行新型流感病毒快速测序，分析、克隆，表达，生产，已可将疫苗的研发和制备时间缩短至一周之内。 Sci.Traasl.Med,2013,5:185ra68 CAR基因递送系统的发展 病毒载体（Retrovirus，Lentivirus），非病毒载体（mRNA电转染CR/SPR/Cas9(ZhangJHuangH,Nature.2022) CAR-T在血液系统肿瘤治疗中获得成功 TICNEW ENGLAND JOUNALNEDICINE Chimeric Antigen ReceptorModified T Cellsfor Acute Lymphoid Leukemia Chimeric Antigen Receptor T Cellsfor Sustained Remissions in Leukemia Stephan A Grupp, M.D, Ph.D_, Michael Kalos, Ph.D., David Baret, M D., Ph.D.Richard Aolenc, M.D. Ph.D., Devd L Porter, M.D., Susan R. Rhengold, M.D.Dirid T. Teachey, M D., Anne Chew, Pa. D_ Bend Hiuck, Ph.D.L Fraser Wrigpht, Ph D., Michael C_ Milone, M.D_ Ph D.Bruce L Lesine, Ph.D., and Cal M. June, M.D. Article Cell GeneticInactivationofcD33inHematopoieticStemCellstoEnableCARTCell ImmunotherapyforAcuteMyeloidLeukemia Analysis of Factors Predicting Treatment Response of 254 Patients WhoReceived CD19-Targeted CAR-T Cell Therapy for Relapsed/Refractory(R/R) B-Cell Acute Lymphoblastic Leukemia (B-ALL) Suex6yu Li, Kui Y ACRcaseofCD19CARTtrialsforrelapsedrefractorypatient CAR-T在实体肿瘤也正在取得进展 肿瘤微环境响应的CAR-T细胞 抗体药物 1.单克隆抗体2.抗体偶联药物（antibody-drugconjugates，ADCs）3.双特异性抗体和多特异性抗体4.放射性同位素抗体偶联物（RDC)5.抗体-细胞因子融合蛋白6.抗体-免疫毒素融合蛋白 抗体药物市场不断扩大 截至2023年4月底，FDA累计批准了121款抗体新药，中国累计批准74款抗体药物，其中23款国产抗体药物在国内获批。 Melanomaantibody(ipilimumab)approved Anti-PD-lAntibodvActiveAgainstVariousCancers objectiveresponses28percentofpatientswithmelanoma,27percentwithrenalcellcancer,and18percentwithNSCLC.Manyoftheresponseswereongoingformorethanoneyear.Grade3or4drug-relatedadverseeventswereseen in14percentofpatients NewEnglandJournalofMedicineJune2,2012ASCO，Junelto5inChicago. 如何提高Anti-PD-1等免疫检测点的疗效？ Overcoming resistance to checkpoint blockadetherapy by targeting PI3K~ in myeloid cells PI3K抑制剂 IC500.7nm 保证HLA表达的多态性，提高向T细胞提呈抗原的能力，有望强化ICBs疗效。 CXCLi3asaNovelImmuneCheckpointforRegulatoryBCellsandItsRoleinTumorMetastasis CXCLi3deficiencvenhancedthemetastasisinhibitoryabilityofchemotherapy 竞争极为激烈抗体-化疗药物偶联药物（ADC）是当前研发的热点 2019年以来，ADC领域进入收获爆发期全球处于活跃状态的ADC药物共836个，大多处于早期研究阶段，I期以上共322个。 抗体药物的发展趋势 ·从鼠源性抗体、人源化抗体到全人源体 ·抗体多功能化和高效化 Antibody-drugconjugate（ADC)、Bispecificantibodies，Immunotoxin、ImmunocytokineAntibody-enzyme,Radioimmunoconjugates,Antibody-siRNAconjugates ·抗体小型化：VHH、scFv、Fab、Diabody ·抗体的适应症不断扩大：从肿瘤、自身免疫性疾病、感染性疾病等到疼痛、高血脂、老年性痴呆症等 Cancervaccines:thenextimmunotherapyfrontier Ignacio Melero7, Brian D. Brown @ and Joshua D. Brodyuas After several decades, therapeutic cancer vaccines now show slgns of efficacy and potential to help patients resistant to otherHere,we classify cancer vaccinesby what iskncwn of the included antigens, which tumors express thoseantigens and whereearly trials to acknowledge failures and advance the most promisi tion. Therapeutic vaccines designed to treat intections.into late-stage dinical trials with pnhas enaled more potemt vaccine onmulation, Treatint establishemalignancy with vaccines traces baxk to William Coley's injectionof tums with killed Nnpleooccus and Srraia the 1910s ar prime tumlor-neactive 1 cells. CencurrentFor esanle, when the sipaleuodl-T vaccine was approved sith aIsurvival benefir,enzalutamide(a oral therapy) demonstranedsurvival benefit in highcr-risk putients, Similesly, thenterleukin (lL)-2 demeestrated imgprewed survival the sameprotcin 100 (gp1o0) vaccine givea with inpstiert high-dos-tuap aoadde stx (ideiap Buagdino ut) qr