Glembatumumab vedotin

抗体偶联药物（ADC）是一类意义非凡的高效生物药，有望成为广泛应用的癌症治疗方法。ADC是由单克隆抗体与细胞毒性药物通过生物活性连接子偶联而成的化合物分子。与化疗不同，ADC的研究理念是仅标记并杀死癌细胞，因而成为靶向性较高的治疗方法。ADC在癌症领域发挥着举足轻重的作用，全球市场上约有12种ADC用于血液瘤和恶性实体瘤。辉瑞公司、基因泰克公司、吉利德科学公司以及许多其他药企都在大力投资ADC，市场竞争处于白热化状态。作为靶向肿瘤的生物治疗药物，ADC的治疗潜力非比寻常；ADC只有在内化到肿瘤细胞后才会启动其作用机制，然后释放细胞毒性有效载荷，从而选择性地杀死恶性肿瘤细胞。ADC无疑是近几年最火的领域之一，2022年全球销售规模超过70亿美元，去年前九个月主要产品销售额已超过70亿美元，全年有望突破百亿美元大关，目前全球已经有15个ADC获批上市，在中国获批的有7个。目前比较热门的靶点有CD22、HER2、EGFR、Trop-2、BCMA、Nectin-4等，常见适应症主要包括乳腺癌、肺癌、胃癌和血癌等肿瘤。ADC赛道席卷全球，在研的ADC药物多达几百款，国内外药企不惜重金纷纷布局ADC，如辉瑞斥资430亿美元收购Seagen，近期默沙东以高达220亿美元与第一三共达成合成协议，共同开发第一三共的三款ADC产品。国内也有通过自研、并购或License in等模式布局ADC管线的药企，其中科伦药业的HER2 ADC产品A166正在申报上市，科伦药业的SKB264、恒瑞医药的SHR-A1811、石药的DP303c和乐普生物的MRG002等都处于临床3期。越来越多的ADC的获批上市，截至目前，全球获批上市ADC药物有15个，在中国获批上市的产品有7个。也有多款药物进入临床阶段，其中靶向HER2的ADC研究最火热，其次是Trop-2等。图1. 获批上市的ADC药物（药时代整理）图2. 部分在研的临床3期ADC药物（药时代整理）图3. 部分临床2期在研的ADC药物（药时代整理）图4. 部分临床1期在研的ADC药物（药时代整理）值新书佳节之际，小编精选了ADC药物在研发、生产、注册、临床及市场的8本书籍和大家一起学习交流，有兴趣的老师可以扫码登记，符合要求方可加入我们学习行列。快快加入我们喔，一起过一个充实而又愉快的春节！Antibody-Drug Conjugates and Cellular Metabolic DynamicsThis book summarizes the related research achievements in Antibody-drug conjugates (ADCs) and their cell metabolism kinetics. The book has three main parts. The first part describes the basic theory of ADCs, including the basic concept and structure of ADCs, and the relationship between the targets of ADCs and their specific functions. The second part mainly introduces the endocytosis and intracellular metabolism of ADCs, including the relationship between endocytosis and ADC activity, the endocytosis and intracellular transport of ADCs, the distribution and metabolism of ADC in vivo. Then it discusses the new formats and research technology of ADCs, including the application of miniaturized antibodies in ADC synthesis, novel carriers for ADC design, the technology and application of site-specific conjugation, and approaches for analyzing the drug: antibody ratio (DAR), the study of pharmacokinetics of ADCs. This book combines the basic theory with the research technology. It can be used as a reference book for students, teachers and researchers of biomedical field.Chemical Linkers in Antibody-Drug Conjugates (ADCs) 2021The covalent conjugation of potent cytotoxic agents to monoclonal antibodies, known as antibody-drug conjugates (ADCs) is a powerful approach in the field of targeted treatment of cancer. Clearly, both monoclonal antibody and cytotoxic payload are crucial elements in determining the clinical value of an ADC and have receive ample attention. However, the structural element connecting the two –the chemical linker– also plays an essential role in mode-of-action, efficacy, pharmacokinetics and safety profile of an ADC, but is often underappreciated in considerations of ADC design.Chemical Linkers in Antibody–Drug Conjugatesaims to shine a detailed light on the various key attributes of chemical linkers in ADCs, for drug-to-antibody ratio, for stability, for release mechanism of payload, for pharmacokinetics, for stability determination, and for efficacy and safety. Ideal for postgraduate students and active researchers in drug discovery and development, this book provides a comprehensive description of linkers used in ADCs (clinical and late preclinical), insight into key quality attributes of linkers for ADCs, and aids the reader in understanding the role of linker chemistry and designing new ADCs.Antibody-Drug Conjugates: Methods and ProtocolsThis volume looks at key methodologies that are commonly used across antibody drug conjugates (ADCs) programs. The chapters in this book cover topics such as conjugations to endogenous cysteine residues; click chemistry conjugations; antibody conjugations via glycosyl remodeling; analysis of ADCs by native mass spectrometry; characterization of ADCs by capillary electrophoresis; LC/MS methods for studying lysosomal ADC catabolism; and determination of ADC concentration by ligand-binding assays. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Cutting-edge and practical, Antibody-Drug Conjugates: Methods and Protocols is a valuable resource that aims to lower the “activation barrier” when undertaking a new discipline, and provides a “toolbox” for the next generation of ADC scientists.Next Generation Antibody Drug Conjugates (ADCs) and ImmunotoxinsThis book describes the newest developments in antibody drug conjugates and immunotoxins, paving their way to clinical application. Lessons learned from the current state of the art are used to further improve our understanding of their mechanisms of action and off target activities.The book introduces scientists to all of the prerequisites that must be properly addressed, including identification of the right target, specific traits of target binding antibodies, proper selection of the toxic payload, internalization induced by binding, and next generation conjugation and linker technologies. These knowledge-based, revolutionary new drug principles will form the cornerstone of the future standard of care and will lead to major advances in application, as well as improved quality of life and patient survival rates. This book will be of interest to biotech companies and researchers working in the fields of immunology, pharmacology, and oncology.Antibody-Drug Conjugates: Fundamentals, Drug Development, and Clinical Outcomes to Target CancerProviding practical and proven solutions for antibody-drug conjugate (ADC) drug discovery success in oncology, this book helps readers improve the drug safety and therapeutic efficacy of ADCs to kill targeted tumor cells.• Discusses the basics, drug delivery strategies, pharmacology and toxicology, and regulatory approval strategies• Covers the conduct and design of oncology clinical trials and the use of ADCs for tumor imaging• Includes case studies of ADCs in oncology drug development• Features contributions from highly-regarded experts on the frontlines of ADC research and developmentAntibody-Drug Conjugates and Immunotoxins: From Pre-Clinical Development to Therapeutic ApplicationsThis volume gathers the leading research on antibody-drug conjugates and immunotoxins. Following a rigorous overview, the volume delves into focused sections on all aspects of ADCs and ITs from clinical development through to targeted therapeutic applications and the latest technologies.Antibody-Drug Conjugates: The 21st Century Magic Bullets for CancerThis authoritative volume provides a holistic picture of antibody-drug conjugates (ADCs). Fourteen comprehensive chapters are divided into six sections including an introduction to ADCs, the ADC construct, development issues, landscape, IP and pharmacoeconomics, case studies, and the future of the field. The book examines everything from the selection of the antibody, the drug, and the linker to a discussion of developmental issues such as formulations, bio-analysis, pharmacokinetic-pharmacodynamic relationships, and toxicological and regulatory challenges. It also explores pharmacoecomonics and intellectual properties, including recently issued patents and the cost analysis of drug therapy. Case studies are presented for the three ADCs that have received FDA approval: gemtuzumab ozogamicin (Mylotarg®), Brentuximab vedotin (Adcetris®), and ado-trastuzumab emtansine (Kadcyla®), as well as an ADC in late-stage clinical trials, glembatumumab vedotin (CDX-011). Finally, the volume presents a perspective by the editors on the future directions of ADC development and clinical applications.Antibody-Drug Conjugates is a practical and systematic resource for scientists, professors, and students interested in expanding their knowledge of cutting-edge research in this exciting field.Innovations for Next-Generation Antibody-Drug Conjugates Antibody-drug conjugates (ADCs) stand at the verge of a transformation.  Scores of clinical programs have yielded only a few regulatory approvals, but a wave of technological innovation now empowers us to overcome past technical challenges.  This volume focuses on the next generation of ADCs and the innovations that will enable them.  The book inspires the future by integrating the field’s history with novel strategies and cutting-edge technologies.  While the book primarily addresses ADCs for solid tumors, the last chapter explores the emerging interest in using ADCs to treat other diseases.The therapeutic rationale of ADCs is strong: to direct small molecules to the desired site of action (and away from normal tissues) by conjugation to antibodies or other targeting moieties.  However, the combination of small and large molecules imposes deep complexity to lead optimization, pharmacokinetics, toxicology, analytics and manufacturing.  The field has made significant advances in all of these areas by improving target selection, ADC design, manufacturing methods and clinical strategies.  These innovations will inspire and educate scientists who are designing next-generation ADCs with the potential to transform the lives of patients.识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

迄今为止，超过260款ADC已在临床中针对各种肿瘤适应症进行研究，其中92款已终止(图1)[1]，主要归因于以下三个原因中的一个或多个：1)由于无法耐受的毒性而导致治疗效果不足。2)由于疗效不足而导致治疗效果与当前护理标准相比无优势。3)商业考量/发展决策。 图1. 已终止临床研究的ADC简要概况(按Payload及临床进展分类)“ADC终止”系列将对已终止研究的ADC相关局限性进行分析，助力后续该系列药物的的设计与开发。第一期我们分析了Upifitamab Rilsodotin (2016→2023；Mersana公司)、Enapotamab vedotin (2016→2020；Genmab公司) 的结构设计、临床数据、终止原因。第二期分析了Glembatumumab Vedotin (2006→2018；Celldex Therapeutics公司)、Depatuxizumab Mafodotin (2013→2019；Abbvie公司) 的相关数据及终止开发原因。第三期分析了PF-06263507 (2013→2015；Pfizer公司)、SC-004/003/002/005/006/007 (AbbVie公司)的终止开发原因。本期我们将分享免疫刺激抗体偶联物(Immune-stimulating antibody conjugate, ISAC)的相关开发及终止原因：  01  NJH395[2]NJH395由Novartis开发，产品管线生存期为2018-2020年。NJH395属于免疫刺激抗体偶联物(ISAC)，靶向于HER2，用于非乳腺HER2+恶性肿瘤的治疗。NJH395由IgG1 MIW338与免疫刺激性TLR7激动剂组成。MIW338是一种结合HER2的人源化单克隆抗体，属于IgG1/κ同种型亚类，具有与曲妥珠单抗(Trastuzumab)相似的序列。经过基因工程化技术在MIW338中引入四个半胱氨酸(Cys)残基，所选位点避免破坏其与HER2和FcγR结合；通过马来酰亚胺与TLR7激动剂进行位点特异性偶联，采用非可裂解Linker以最大限度地降低在与HER2+肿瘤细胞结合之前Payload释放的风险来提供稳定性，降低全身暴露并最大程度地减少免疫相关毒性。NJH395可特异性结合人和食蟹猴的HER2 (Kd= 0.33/5.0 nmol/L），并且与T-DM1具有相似的结合亲和力，以此强调NJH395的临床相关性。 图2. NJH395结构及其相关代谢物活性利用NJH395及MIW338处理HER2+乳腺癌细胞HCC1954，实验数据表明二者可与靶细胞结合，而同型对照分子则不会；同时也可观察到NJH395在HCC1954细胞中的内化，但未观察到同种型对照ISAC (NJH397)的内化。NJH395与N87胃癌细胞的体外孵育可打开马来酰亚胺环，这表明NJH395在内化后被溶酶体加工产生活性分解代谢物，主要由MIM697 (Cys-Linker-Payload)和次要分解代谢物YFB712组成(图2B)。利用这些分解代谢物在体外测定TLR激活效果，该两种分解代谢物均在表达TLR7的HEK293T细胞中诱导NF-κB报告基因的表达，其最大激活程度与对照TLR7/8激动剂瑞喹莫德相当(图2C)。此外，MIM697在HEK-TLR8报告基因测定中没有表现出显着的活性，表明TLR7特异性。由于TLR7诱导促炎细胞因子(TNFα、IL6、IL8和IL1β)的转录，因此通过测定这些细胞因子评估TLR7的激活水平。MIM697和YFB712诱导IFNα和IL6分泌，表明人PBMC中TLR7的强烈激活(图3A)。来自健康供体的全血与NJH395或MIW338共孵育，qPCR显示NJH395处理组的TNFα、IL6和IL1β基因上调，但MIW338处理组则没有上调，表明这种效应是由TLR7激动作用所驱动的(图3B)，同时TLR7下游信号通路中的OAS1和OAS2也上调，进一步支持了这一点。通过HER2+ HCC1954肿瘤细胞和HER2- THP-1巨噬细胞的共培养进一步评估NJH395的药效活性，与NJH395或对照孵育后评估上清液的IL1β产量。与同种型NJH397相比，当表达TLR7+ THP-1巨噬细胞和HER2+ HCC1954共培养时，NJH395诱导更多的IL1β产生，而使用MIW338或同型对照人IgG1处理组未观察到IL1β的产生(图3C)，但NJH395在单独与HCC1954肿瘤细胞孵育后不会诱导IL1β的产生。此外，后续实验还表明FcγR的结合对其活性有一定影响，但不是主要驱动力。 图3. NJH395作用机制研究在HER2+异种移植模型(皮下人胃癌N87、原位人乳腺癌HCC1954和皮下人卵巢癌SKOV-3)中评估NJH395的体内活性。与对照相比，NJH395在所有三种模型中均能显著抑制肿瘤生长(图4A-C)。在N87和HCC1954肿瘤中，NJH395剂量≥3 mg/kg观察到完全缓解(图4A/B)。MIW338或NJH397没有观察到显着的抗肿瘤作用(图4B/C)，这表明HER2靶向和TLR7激动作用都有助于NJH395体内功效的发挥。图4. NJH395体内抗肿瘤活性为了评估骨髓细胞的活性贡献，使用含有氯膦酸盐的脂质体将吞噬细胞耗竭[3]。在携带N87肿瘤的SCID (severe combined immune deficency)小鼠中，单剂量静脉注射NJH395与每周两次腹膜内注射氯膦酸盐脂质体同时进行，并与对照组(未经治疗或用单一给药)进行比较。与未治疗的小鼠或用氯膦酸盐脂质体和NJH395治疗的小鼠相比，单独用NJH395治疗的小鼠在第28天的肿瘤明显更小(图4D)，这表明巨噬细胞在NJH395功效中发挥作用；单独使用一或两剂氯膦酸盐脂质体后，Iba-1+巨噬细胞的肿瘤浸润减少；但在NJH395治疗后增加，甚至NJH395与氯膦酸盐脂质体联合治疗也会引起浸润增加(图4E)；即使采用氯膦酸盐预处理，巨噬细胞浸润也会增加。NJH395在食蟹猴中进行单剂量和重复剂量毒理学研究。经NJH395治疗的食蟹猴细胞因子增加，NJH395、NJH397和MIM697诱导高细胞因子表达，与人全血中的TLR7激动作用一致。临床前PK数据表明，NJH395总ISAC (DAR≥1)与总抗体(DAR 0~4)的PK曲线具有可比性。当单次静脉推注剂量为30 mg/kg时出现神经炎症(一只)。炎症在辐射冠中最为明显，但也影响灰质(大脑皮层)和脑膜的血管。此外，NJH395会产生抗药抗体(Antidrug antibodies, ADA)。基于上述临床前实验数据，NJH395于2018年12月进行I期临床试验(NCT03696771)，用于非乳腺HER2+恶性肿瘤的治疗。作为第一个在人体中测试ISAC的临床试验，其结果不如人意。来自单次剂量递增的18名患者的数据表明，TLR7激动剂在HER2+肿瘤细胞中诱导I型IFN反应，这与肿瘤微环境中的免疫调节相关，但其在耐受剂量下疗效不足，客观缓解率(ORR)为0%。NJH395诱导快速而强大的全身免疫激活，细胞因子释放综合征(55.6%, Gr≥2)是常见的药物相关不良事件。高剂量给药会产生ADA和神经炎症，成为重大的临床挑战。ISAC概念的提出引起各大药企对免疫调节ADC的广泛关注，但ISAC究竟能不能解决TLR激动剂自身的副作用问题值得商榷。通俗一点讲，“加油门”远比“踩刹车”难得多。  02  SBT6050/6290除上述NJH395外，采用TLR8激动剂作为有效载荷的SBT6050/6290 (Silverback，DAR~4)也出师不利。SBT6050SBT6050在中/高HER2表达的情况下激活骨髓细胞，从而诱导多种抗肿瘤免疫机制，包括促炎细胞因子和趋化因子的产生、炎性体激活、树突状细胞(DC)的直接激活以及间接T细胞和自然杀伤细胞(NK)细胞的激活。SBT6050还可以诱导巨噬细胞杀死肿瘤细胞，诱导树突状细胞促进肿瘤特异性细胞毒性T淋巴细胞反应。SBT6050共进行两项临床试验(NCT05091528/NCT04460456)，用于HER2+实体瘤的治疗。NCT05091528 (Phase I/II)因投资组合优先级的考虑终止[4]。NCT04460456 (Phase I)旨在评估皮下注射SBT6050剂量递增的安全性、耐受性和活性，单独使用或与PD-1阻断剂(Pembrolizumab/Cemiplimab)联用治疗局部晚期(不可切除)和/或转移性HER2+实体瘤的成年患者，结果表明SBT6050在耐受剂量下治疗效果不佳，所有剂量水平的初步数据显示部分缓解(n=1)、疾病稳定(n=3)和疾病进展(n=10)，7%部分缓解(PR)[5]。SBT6290SBT6290靶向肿瘤相关抗原Nectin-4。Nectin-4作为细胞表面粘附分子在正常组织中很少表达，但在多种癌症类型中过度表达，包括膀胱癌、头颈癌、非小细胞肺癌、鳞状细胞癌和三阴性乳腺癌。SBT6290于2022年3月开展I/II临床试验(NCT05234606)，单用或联用Pembrolizumab治疗Nectin-4+晚期实体瘤，但因投资组合优先级的考虑终止，管线生存期极为短暂，可谓胎死腹中[6]。  03  XMT-2056除TLR受体激动剂构建的ISAC外，Sting激动剂构建的ISAC也前途坎坷。2023年3月13日，Mersana宣布其ISAC管线XMT-2056的Ⅰ期临床试验(NCT05514717)被FDA叫停，原因是XMT-2056在剂量爬坡试验的第一个剂量组中就出现5级(致命)严重不良事件；2023年11月1日，Mersana宣布美国FDA已经解除MT-2056的临床搁置，重新启动针对HER2+实体瘤的Ⅰ期剂量递增研究。XMT-2056由该公司Dolaflexin技术平台[7]开发，其DAR值能够精确为8，本次ISAC解除临床搁置的消息，使得Mersana公司股票上涨，但涨幅不大。Mersana能否走出自己的至暗时刻，让我们拭目以待。 图5 XMT-2056与BDC-1001 (根据CDDI数据绘制)  04  BDC-1001当然并非所有的ISAC都前途黯淡。由Bolt Biotherapeutics开发BDC-1001[8, 9]于2023年9月22日获得孤儿药资格(Orphan Drug Designation)，其由Trastuzumab生物类似物与TLR7/8激动剂通过不可裂解连接子(聚乙二醇链)偶联。BDC-1001于2020年2月进行Ⅰ/Ⅱ期临床试验(NCT04278144)，用于晚期HER2+实体瘤的治疗；于2023年8月开展Ⅱ期临床试验(NCT05954143)，单用或联用Pertuzumab用于既往接受ENHERTU®治疗的HER2+转移性乳腺癌患者。或许，BDC-1001所含TLR7/8激动剂经PEGylation后对其副作用的减少有一定帮助，“油门”不一定越大越好，当然这只是笔者的猜测。  05  改善ISAC疗效的可行性策略关于ISAC。在临床前研究中，显示出有希望的结果。在临床试验中，疗效不佳且存在全身毒性。一方面，药效提升的同时毒性也将增大，在保证安全性的前提下提高药效确实不易。另一方面，机体会产生抗药物抗体，加快代谢，影响药物的疗效。①使用基于嘌呤的 TLR7 激动剂来提高 ISAC 抗肿瘤功效。 在一项临床前研究中，将含有与曲妥珠单抗连接的基于嘌呤的 TLR7 激动剂的 ISAC 给予健康小鼠和患有胃癌的小鼠。该 ISAC 对患有胃癌的小鼠显示出功效，但不会导致健康小鼠体重减轻 。②TLR激动剂的选择影响ISAC的疗效。 CL264-ISAC在激活髓系抗原递呈细胞方面的功效大于T785-ISAC。T785 是 TLR7/8 激动剂，CL264 是 TLR7 特异性激动剂。可以研究其他免疫刺激剂以开发新的有效 ISAC。③ISAC 会导致抗药物抗体的产生，从而影响药物的功效。 抗药物抗体的产生取决于ISAC抗体的免疫原性。曲妥珠单抗的免疫原性率低于1%。其他免疫原性较低的单克隆抗体也可用于预防ISAC的这种不良反应。④基于免疫激动的特殊性，瘤内给药可以减少激动剂的全身渗漏，从而最大限度地减少脱靶毒性。该策略也需要较低的剂量来阻止肿瘤进展。然而，瘤内注射面临着技术挑战，包括尺寸、密度和可及性等。此外，目前尚不清楚在一个病变处给药是否可以产生全身保护[10]。  06  ISAC 还有未来吗？2021年9月至今，ISAC的一系列负面消息让制药企业和投资人都捏了一把冷汗。人们纷纷对ISAC的未来产生了担忧，ISAC真的是下一代ADC吗？就整体开发进度来看，ISAC的开发处于非常更早期的一个阶段，ISAC虽然理念清晰，但在临床试验中很难跨过剂量爬坡这一关。而TLRs、STING等激动剂本身开发常伴有治疗窗口窄、全身毒性的问题，在疗效提升的同时毒性也将增大，相较于ADC而言，ISAC的治疗窗口更难以把控。虽然ISAC临床试验接连败北，但我们不必对其过于失望，试想，ADC最早在1913年就由Paul Ehrlich首次提出，但受限于其合成需要较高的技术门槛和长期的脱靶、特异性抗原的发现等技术难题，进行了多年试验和不断迭代，直到近几年ADC药物才迎来快速发展。所以回归到那句制药行业的至理名句“新药的研发本就是九死一生”，也就释怀了。而且最近几个月也有一些好消息：2023年9月22日，由Bolt Biotherapeutics开发的BDC-1001获得孤儿药资格；2023年11月1日，Mersana宣布美国FDA已经解除MT-2056的临床搁置，重新启动针对HER2+实体瘤的Ⅰ期剂量递增研究，国内也有一些公司在积极布局ISAC管线，如恒瑞医药、百济神州、信达生物、启德医药等。ISAC之外，为了走出ADC的差异化竞争之路，各种偶联药物也在层出不穷。比如，多肽偶联药物（PDC）、抗体片段偶联药物（FDC）、抗体寡核苷酸偶联物（AOC）等。在这个万物皆可偶联的时代，总有一些设计方案可以或早或晚地带来如同ADC般的惊人效果，为数以百万计的病人带来治疗的希望。总体而言，ISAC道阻且长，但仍值得期待。免责声明：本文仅作信息交流之目的，文中观点不代表个人立场，亦不代表个人支持或反对文中观点。本文并非治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。欲有所明，终有所蔽。欢迎各位批评指正(dyc21@mails.tsinghua.edu.cn)，谢谢！ 主要参考文献 1. Maecker, H., et al., Exploration of the antibody–drug conjugate clinical landscape. mAbs, 2023. 15(1): p. 2229101.2. Janku, F., et al., Preclinical Characterization and Phase I Study of an Anti–HER2-TLR7 Immune-Stimulator Antibody Conjugate in Patients with HER2+ Malignancies. Cancer Immunology Research, 2022. 10(12): p. 1441-1461.3. Ackerman, S.E., et al., Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nature Cancer, 2021. 2(1): p. 18-33.4. Metz, H., et al., SBT6050, a HER2-directed TLR8 therapeutic, as a systemically administered, tumor-targeted human myeloid cell agonist. 2020, American Society of Clinical Oncology.5. Klempner, S.J., et al., 209P Interim results of a phase I/Ib study of SBT6050 monotherapy and pembrolizumab combination in patients with advanced HER2-expressing or amplified solid tumors. Annals of Oncology, 2021. 32: p. S450.6. Comeau, M.R., et al., SBT6290, a systemically administered Nectin4-directed TLR8 ImmunoTAC™ product candidate, is designed for tumor-localized activation of myeloid cells. Cancer Research, 2021. 81(13_Supplement): p. 1858-1858.7. Yurkovetskiy, A.V., et al., Dolaflexin: A Novel Antibody-Drug Conjugate Platform Featuring High Drug Loading and a Controlled Bystander Effect. Mol Cancer Ther, 2021. 20(5): p. 885-895.8. Li, B.T., et al., A phase 1/2 study of a first-in-human immune-stimulating antibody conjugate (ISAC) BDC-1001 in patients with advanced HER2-expressing solid tumors. Journal of Clinical Oncology, 2023. 41(16_suppl): p. 2538-2538.9. Sharma, M., et al., Preliminary results from a phase 1/2 study of BDC-1001, a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), in patients (pts) with advanced HER2-expressing solid tumors. J Clin Oncol, 2021. 39(15_suppl): p. 2549.10. Le Naour, J. and G. Kroemer, Trial watch: Toll-like receptor ligands in cancer therapy. Oncoimmunology, 2023. 12(1): p. 2180237.识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。