SYSA-1801

作者：唐立成美工：何国红 罗真真排版：马超抗体偶联药物（ADC）领域正经历着前所未有的繁荣与动荡。2025年，全球进入临床阶段的ADC药物已突破200个，涵盖50余个靶点，其中10个核心靶点集中了超40%的研发管线。截至当前，全球已获批ADC药物总数已达17款（详见表1）。中国药企在这一领域频频有精彩表现——百利天恒的EGFR/HER3双抗ADC在关键III期临床告捷，成为全球首个取得突破的双抗ADC；信诺维的Claudin18.2 ADC以15亿美元授权安斯泰来后快速推进至III期临床；而复宏汉霖的PD-L1 ADC则领跑全球，率先进入国际多中心II期研究。▲ 表1 全球ADC获批药物详情表01 全球ADC临床管线全景分析抗体偶联药物（ADC）的临床开发呈现指数级增长态势。截至2025年7月，全球处于临床阶段的ADC药物约230个，涵盖从I期到III期的全阶段布局。这些药物在靶点选择上呈现明显的“靶点聚集效应”：HER2、TROP2、EGFR、Claudin18.2四大靶点占据主导地位，合计占比超过50%。▲ 图1 全球ADC热门靶点热门靶点背后的科学逻辑驱动了这一分布格局：HER2：作为经典肿瘤驱动基因，在乳腺癌、胃癌等多种实体瘤中高表达，其内化效率高的特性使其成为ADC的理想靶标。目前已有三款HER2 ADC（T-DM1、DS-8201、RC48）获批上市，临床验证降低了研发风险。TROP2：在三阴性乳腺癌等缺乏有效治疗手段的癌种中广泛表达，成为解决未满足临床需求的突破口。吉利德的Trodelvy获批后，其市场表现证明了该靶点的商业价值。EGFR：在非小细胞肺癌、头颈癌等多种肿瘤中过表达，得利于百利天恒的EGFR/HER3双抗ADC药物BL-B01D1的推动，EGFR双抗ADC管线迎来大爆发。Claudin18.2：具有高度组织特异性（主要在胃黏膜），在70%-80%的胃癌患者中表达，被视为胃癌靶向治疗的“圣杯”。但其在正常组织中的低水平表达也为安全性埋下隐患。02 热门靶点的临床进展与技术迭代01HER2靶点：后DS-8201时代的破局尝试HER2 ADC领域目前正经历技术代际更替，作为一个已有三款ADC药物上市的成熟靶点，HER2仍有不少挖掘潜力。第三代ADC药物DS-8201在2024年全球年销突破40亿美元，涵盖乳腺癌、胃癌、肺癌等五大癌种，堪称ADC界的“天花板”。DS-8201凭借高DAR值（~8）和可裂解连接子技术，在乳腺癌治疗中取得突破，但其引发的间质性肺病（ILD）风险和耐药问题催生了新一代研发策略。▲ 图2 国内外HER2 ADC产品对比除了高歌猛进的好消息，也有坏消息传来。就在2025年5月，曾经视为HER2 ADC又一款明星潜力药物的BB-1701被百力司康的合作伙伴卫材宣布终止双方高达20亿美元的合作，原因是合作伙伴卫材主导的试验显示ORR仅14.3%，相比百力司康自主试验（206试验）的患者客观缓解率（ORR）21.4%，最佳缓解率（BRR）32.1%相差甚远。02Claudin18.2靶点：从折戟案例中寻找出路Claudin18.2 ADC的研发之路布满荆棘。全球12个进入临床阶段的该靶点ADC中，7个在Ⅱ期遭遇安全性问题，石药集团的SYSA1801（EO-3021）是最新折戟案例。但同时，也有不少管线表现出很大的潜力。信达生物的IBI343在2025年6月的ASCO报道了其治疗晚期胰腺癌的I期临床研究优异数据。确认的客观缓解率（cORR）为22.7%，疾病控制率（DCR）为81.8%，中位无进展生存期（PFS）为5.4个月，中位总生存期（OS）为9.1个月。≥3级恶心、呕吐的发生率均为0。信达生物在今年6月底刚刚开启了一项IBI343针对胰腺癌的III期临床试验。信诺维的XNW27011也展现出很好的安全性。在I期剂量递增研究中，4.8 mg/kg以下剂量未观察到≥3级治疗相关不良事件，未出现间质性肺病或神经毒性。其采用的可裂解连接子技术增强了肿瘤微环境中的药物释放效率，即使在CLDN18.2低表达患者中也观察到疗效。此外还有恒瑞医药的SHR-A1904、康诺亚的CMG-901、德琪医药的ATG022等多款已进入临床的CLDN18.2 ADC颇具潜力。03PD-L1靶点：免疫调节型ADC的崛起复宏汉霖的HLX43开创了免疫调节型ADC新赛道。该药物通过双重抗肿瘤机制发挥作用：一方面通过经典ADC途径精准杀伤肿瘤细胞；另一方面通过阻断PD-L1激活免疫应答。在2025年ASCO年会上公布的I期数据显示，其对不同PD-L1表达状态的NSCLC患者均有效，包括EGFR突变型、脑转移患者等难治人群。HLX43的高DAR值设计（≈8）突破了传统ADC的载荷限制，但同时也带来安全性挑战。其全球多中心II期研究将重点评估这一设计在更大患者群体中的风险获益比。03 ADC技术创新与新兴ADC靶点过去，ADC研发主要聚焦于靶点的选择、载荷和连接子的迭代以及偶联技术的优化。如今，这些技术日益成熟并催生出如德曲妥珠单抗、恩美曲妥珠单抗和维布妥昔单抗等年销售额数十亿美元的重磅ADC产品，ADC疗法的商业价值已被充分验证。当前，以双抗/多抗ADC、多载荷ADC等为代表的“高阶”创新形式正成为行业探索的新方向，并可能成为药企差异化竞争的关键所在。越来越多相关临床试验的成功，正为这一趋势写下生动注脚。百利天恒的BL-B01D1同时靶向EGFR和HER3，在经治的EGFR突变非小细胞肺癌患者中ORR达69%，外显子20插入突变患者ORR高达86%，中位无进展生存期（PFS）10.5个月。基石药业CS5007（EGFR/HER3）：临床前数据显示对双阳性肿瘤强效杀伤，稳定性优于传统ADC。优异的数据启发了大量药企布局双抗ADC赛道。科伦博泰Sac-TMT连接子：兼具pH依赖性和酶促裂解特性，优化旁观者效应并降低脱靶毒性。默克exatecan平台：采用新一代拓扑异构酶I抑制剂（TOPOi）载荷，开发中的CEACAM5靶向ADC（M9140）在结直肠癌I期试验ORR 31%，mPFS 6.9个月。各种连接子与毒素的创新赋予了ADC新的可能。在2025年的AACR中，也涌现了一批新颖ADC靶点，如CDH17、MLSN、PSMA以及CEACAM5等。01CDH17 ADCCDH17是钙粘蛋白超家族的成员，钙粘蛋白超家族是一组钙依赖性细胞粘附分子，对器官发育、组织完整性和癌症进展至关重要。▲ 图3 CDH17结构在正常组织中，CDH17高度局限于侧膜，隐藏在无法接近的肠道紧密连接处。相比之下，它在50%至90%的胃肠道癌症中过表达和重新分布，导致其暴露于癌细胞表面，因此变得更容易获得。这一独特功能使CDH17成为基于抗体的治疗的有前途的靶点。目前已布局CDH17的公司有：维立志博的LBL-054、华东医药的HDM2017、Tavotek Biotherapeutics的TAVO307、宜联生物的YL127、SOTIO Biotech的SOT109、博奥信生物的BSI-721、橙帆医药的VBC108、礼新医药的LM-350、先声药业的SCR-A008等。02MSLN ADCMSLN（Mesothelin，间皮素）是一种细胞表面分子，以成熟形式表达为通过糖基磷脂酰肌醇键固定在细胞膜上的40 kDa蛋白。MSLN的异常与很多疾病相关，在许多实体瘤中过表达，包括卵巢癌、胰腺癌、子宫内膜癌、肺癌和结直肠癌等。▲ 图4 MSLN相关信号通路自发现以来，MSLN一直是各种方式的抗肿瘤疗法开发的目标，有很多不同在研药物类型，包括抗体、CAR-T和多种ADC药物等。目前已布局MSLN的公司有：辉瑞与和铂医药合作开发的PF-08052666、荣昌生物的RC88等。03PSMA ADCPSMA（前列腺特异性膜抗原）是一种II型跨膜糖蛋白，包含跨膜结构域、细胞外结构域以及酶活性区域，PSMA具有N-乙酰基-α-氨基己糖苷酶（GluN）的酶活性，能够水解N-乙酰氨基己糖苷，这种酶活性在某些生理和病理过程中发挥作用。▲ 图5 PSMA的结构PSMA在绝大多数前列腺癌（PCa）细胞中高表达，因此是一个成熟的靶向前列腺癌的诊断和治疗领域的靶点。目前已布局PSMA的公司有：金赛药业开发的B7-H3 x PSMA双抗ADC GenSci143，Syndivia开发的SDV2102等。04CEACAM5 ADCCEACAM5（通常称为CEA）是癌胚抗原相关细胞黏附分子（CEACAM）家族的成员之一。▲ 图6 CEACAM家族成员结构CEACAM5在多种上皮肿瘤中高表达，包括结肠癌、胃癌、胰腺癌、卵巢癌和肺癌，靶向CEACAM5的治疗策略正在不断开发中，包括ADC药物、单域抗体药物偶联物（UdADC）、双特异性抗体以及CAR-T细胞疗法等目前已布局CEACAM5的公司有：百济神州开发的BG-C477，信达开发的新一代双载荷ADC IBI3020等。三优ADC药物研发系统解决方案针对ADC药物研发目前的4大痛点：▶ 1. 多次跨膜靶点的抗体开发困境，好分子一将难求▶ 2. ADC药物毒素元件研发面临安全性与疗效双重挑战▶ 3. 缺失参比品与Payload库▶ 4. 缺乏一体化研发服务三优生物皆可提供多种产品支持，并有专业的技术团队可提供完善的选型方案推荐，能够为客户带来“确定性”。三优生物建立的ADC偶联平台可以实现高通量和快速偶联。对于大多数偶联项目，可以实现一次性开发。下图显示了来自定期统计的平台偶联样品，其中8%在4天内完成，29%在7天内完成，63%在10天内完成。▲ 图7 平台交付周期（包括开发和偶联）更多三优ADC药物研发系统解决方案流程案例请见《三优ADC药物研发系统解决方案》Innovation Frontier｜Global ADC Drug Clinical Development in 2025: Key Targets and Technological InnovationsThe field of antibody-drug conjugates (ADCs) is undergoing unprecedented growth and volatility. As of 2025, over 200 ADC drugs have entered the clinical stage globally, targeting more than 50 different antigens. Notably, 10 core targets account for over 40% of the development pipeline. As of now, a total of 17 ADC drugs have been approved worldwide (see Table 1).Chinese pharmaceutical companies have made frequent breakthroughs in this area. Betta Pharmaceuticals’ EGFR/HER3 bispecific ADC achieved success in a pivotal Phase III trial, marking the first global breakthrough for a bispecific ADC. After licensing its Claudin18.2 ADC to Astellas for $1.5 billion, Syncell quickly advanced the asset into Phase III trials. Meanwhile, Henlius’ PD-L1 ADC leads globally, entering an international multicenter Phase II study ahead of competitors.▲ Table 1. Approved ADC Drugs Worldwide01 Global ADC Clinical Pipeline OverviewThe clinical development of ADCs has shown exponential growth. As of July 2025, approximately 230 ADC drugs are in clinical stages globally, spanning from Phase I to Phase III. Target selection shows a significant “target concentration effect,” with four major targets-HER2, TROP2, EGFR, and Claudin18.2-dominating the field and accounting for over 50% of clinical pipelines.▲ Figure 1. Popular ADC Targets GloballyScientific rationale underpins this distribution:HER2: A classic tumor driver gene, highly expressed in multiple solid tumors such as breast and gastric cancers. Its efficient internalization makes it ideal for ADCs. Three HER2 ADCs (T-DM1, DS-8201, RC48) have already been approved, reducing development risk.TROP2: Widely expressed in cancers with limited treatment options such as triple-negative breast cancer (TNBC), providing a breakthrough for unmet medical needs. The commercial success of Gilead’s Trodelvy validated this target’s market potential.EGFR: Overexpressed in several cancers, including non-small cell lung cancer (NSCLC) and head and neck cancers. The success of Betta Pharmaceuticals’ EGFR/HER3 bispecific ADC BL-B01D1 has sparked a surge in EGFR-targeting bispecific ADC pipelines.Claudin18.2: Highly tissue-specific (primarily in gastric mucosa) and expressed in 70%–80% of gastric cancer patients, making it the “Holy Grail” for targeted gastric cancer therapy. However, low-level expression in normal tissues poses potential safety risks.02 Clinical Progress and Technological Iteration of Popular Targets01HER2: Innovation in the Post-DS-8201 EraThe HER2 ADC field is undergoing a generational shift. Although three HER2 ADCs are already on the market, the target still holds substantial potential. The third-generation DS-8201 achieved global sales exceeding $4 billion in 2024 across five major cancers (breast, gastric, lung, etc.), setting a high benchmark in the ADC space.DS-8201’s success is attributed to its high drug-to-antibody ratio (DAR ~8) and cleavable linker technology, which contributed to breakthroughs in breast cancer treatment. However, the risk of interstitial lung disease (ILD) and resistance issues have prompted new development strategies.▲ Figure 2. Comparison of Domesticand International HER2 ADCsHowever, not all news is positive. In May 2025, Eisai terminated its up-to-$2 billion partnership with BioAtla on the HER2 ADC BB-1701 due to disappointing Phase I results-an objective response rate (ORR) of just 14.3%, compared to 21.4% ORR and 32.1% best response rate (BRR) from BioAtla’s own Study 206.02Claudin18.2: Learning from FailuresDevelopment of Claudin18.2-targeting ADCs has faced significant hurdles. Of the 12 Claudin18.2 ADCs in clinical development, 7 encountered safety issues in Phase II trials. The most recent failure was SYSA1801 (EO-3021) from CSPC Pharmaceutical.Nevertheless, some pipelines show promise. Innovent’s IBI343 reported outstanding Phase I results at ASCO 2025 for advanced pancreatic cancer: confirmed ORR of 22.7%, disease control rate (DCR) of 81.8%, median progression-free survival (PFS) of 5.4 months, and median overall survival (OS) of 9.1 months. Notably, no ≥ Grade 3 nausea or vomiting events occurred. Innovent launched a Phase III trial targeting pancreatic cancer in late June 2025.Syncell’s XNW27011 also demonstrated excellent safety. In the dose-escalation Phase I study, doses below 4.8 mg/kg showed no ≥ Grade 3 treatment-related adverse events, including no ILD or neurotoxicity. Its cleavable linker technology enhances drug release in the tumor microenvironment and showed efficacy even in low CLDN18.2 expressers.Other promising Claudin18.2 ADCs in clinical stages include SHR-A1904 (Hengrui), CMG-901 (Keymed Biosciences), and ATG022 (Antengene).03PD-L1: Rise of Immunomodulatory ADCsHenlius’ HLX43 pioneered the immunomodulatory ADC (iADC) concept. It leverages a dual anti-tumor mechanism: traditional ADC-mediated cytotoxicity and PD-L1 blockade-induced immune activation.Phase I data presented at ASCO 2025 showed efficacy across NSCLC patients with varying PD-L1 expression, including difficult-to-treat populations like EGFR-mutated and brain metastasis patients.Designed with a high DAR (~8), HLX43 pushes the payload boundary of ADCs, raising safety concerns. Its ongoing global Phase II trial will assess the benefit-risk balance in a broader population.03 ADC Technology Innovations and Emerging TargetsNow, advanced innovations-like bispecific/multispecific ADCs and multi-payload ADCs-are emerging as key differentiators. Successful trials are increasingly validating these next-gen strategies.BL-B01D1 (Betta Pharmaceuticals): Targets EGFR and HER3 simultaneously, achieving a 69% ORR in pretreated EGFR-mutant NSCLC patients and 86% in those with exon 20 insertions; median PFS of 10.5 months.CS5007 (CStone): Strong preclinical efficacy against EGFR/HER3 dual-positive tumors, with superior stability over traditional ADCs.Innovations in conjugation and payload chemistry include:Sac-TMT linker (Sichuan Kelun-Biotech): Combines pH sensitivity and enzymatic cleavage to optimize bystander effects and reduce off-target toxicity.Exatecan platform (Merck): A next-gen topoisomerase I inhibitor payload. M9140, a CEACAM5-targeting ADC, showed an ORR of 31% and median PFS of 6.9 months in Phase I colorectal cancer trials.The AACR 2025 conference spotlighted several novel ADC targets:01CDH17 ADCCDH17 is a cadherin superfamily member crucial for organ development, tissue integrity, and cancer progression.▲ Figure 3. CDH17 StructureIn normal tissues, CDH17 is restricted to the lateral membrane within intestinal tight junctions. In contrast, it is overexpressed and redistributed in 50%–90% of GI cancers, becoming exposed on the cell surface-making it highly accessible for antibody-based therapy.Companies with CDH17 ADC programs include: Leadsbiolabs’s LBL-054, Huadong Medicine’s HDM2017, Tavotek’s TAVO307, YL Biotech’s YL127, SOTIO Biotech’s SOT109, BioCeen’s BSI-721, Voronoi’s VBC108, Laekna’s LM-350, Simcere’s SCR-A008, among others.02MSLN ADCMesothelin (MSLN) is a GPI-anchored surface protein overexpressed in multiple solid tumors, including ovarian, pancreatic, endometrial, lung, and colorectal cancers.▲ Figure 4. MSLN-Associated Signaling PathwaysMSLN has long been a target for anti-tumor therapeutics, including monoclonal antibodies, CAR-Ts, and ADCs.Notable developers include: Pfizer and Harbour BioMed (PF-08052666), RemeGen (RC88).03PSMA ADCProstate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein with GluN enzymatic activity. It is highly expressed in most prostate cancer cells, making it an established target for prostate cancer diagnosis and treatment.▲ Figure 5. PSMA StructureCurrent developers include: GenSci’s GenSci143 (B7-H3 x PSMA bispecific ADC), Syndivia’s SDV2102, among others.04CEACAM5 ADCCEACAM5 (commonly known as CEA) is a member of the carcinoembryonic antigen-related cell adhesion molecule family.▲ Figure 6. CEACAM Family StructureHighly expressed in many epithelial cancers (e.g., colorectal, gastric, pancreatic, ovarian, lung), CEACAM5 is the target of multiple approaches including ADCs, UdADCs (single-domain antibody-drug conjugates), bispecific antibodies, and CAR-T cells.  Companies developing CEACAM5-targeting ADCs include: BeiGene (BG-C477), Innovent (dual-payload IBI3020).Sanyou ADC Drug Development SolutionsSanyou Bio offers comprehensive system solutions for ADC drug development, addressing four major challenges in the field:▶ 1. Difficulty in antibody discovery for multi-transmembrane targets—“one good molecule is hard to find.”▶ 2. Dual challenge of safety and efficacy in toxin development.▶ 3. Lack of reference standards and payload libraries.▶ 4. Need for integrated R&D services.Sanyou provides extensive product support and expert technical teams capable of delivering reliable target selection strategies, helping clients gain “development certainty.”Sanyou’s ADC conjugation platform supports high-throughput and rapid conjugation, with many projects achieving one-time development success. The chart below shows turnaround statistics: 8% of conjugates delivered within 4 days, 29% within 7 days, 63% within 10 days▲ Figure 7. Sanyou Platform Turnaround Time (Including Development and Conjugation)For more details, see “Sanyou’s System Solutions for ADC Drug Development.”推荐阅读三优十周年｜AI-STAL篇-千亿高等电点单域抗体库6类分子形式之环状多肽分子产生系统解决方案轻松玩转三优oneClick+线上9大云程序6类分子形式之mRNA分子产生系统解决方案三重好礼相送暨四种抗体制备解决方案全新上线三优生物单域抗体产生系统解决方案三优生物双抗参比品网站SY-BsAb正式上线三优ADC药物研发系统解决方案三优生物oneClick+平台再次上新三优磁阵列全人源小鼠抗体发现平台重磅发布三优超万亿全人单克隆抗体产生平台盘点三优磁阵列全人源小鼠抗体发现平台隆重上线共同轻链抗体产生之超万亿共轻库盘点三优生物73种全系列双抗参比品全新上线三优生物智能超万亿分子发现平台盘点及展望关于三优生物三优生物是一家以“让天下没有难做的创新生物药”为使命，以超万亿分子库和人工智能技术双驱的生物医药智能高新技术企业。公司以智能超万亿分子库为核心，打造了干湿结合、国际领先的创新生物药临床前智能化及一体化研发平台，通过“新药发现、临床前研究、智能化药物研发及前沿科学研究”等四个维度加速全球新药发现及靶标深度研究。公司总部位于中国上海，在美国、欧洲等地设有子公司，现有投产及布局的研发及GMP场地20000多平方米。公司为合作伙伴提供“差异化CRO、整合型CDO、协同型CPO、特色CRS”于一体的“创新生物药4C综合业务”。公司已建立全球营销网络，已与全球1200多家药企、生技公司等建立了良好的合作关系；已完成了1200多个新药发现及开发服务项目；已完成了50多个合作研发项目，其中9个合作项目已完成临床申报。公司已获得国家高新技术、上海市专精特新、上海市小巨人和上海“张江之星”企业认定。