ASN-004

▎药明康德内容团队编辑2024年2月，非同生物宣布其研发的新型5T4 x 4-1BB双特异性抗体FTL008.16获得美国FDA批准临床试验，拟开发用于治疗恶性实体肿瘤。2024年1月，爱科瑞思宣布其研发的靶向5T4的抗体偶联药物（ADC）ADC2154获得中国NMPA批准临床试验，拟开发用于治疗晚期实体瘤。在2023年，英百瑞生物也曾宣布其开发的靶向5T4的CAR-NK细胞疗法已获中国NMPA批准临床，拟开发用于实体肿瘤患者的治疗。那么，5T4是什么？从双特异性抗体、ADC到细胞疗法，5T4因何具有这么广的开发潜力？除了上述药物，当前还有哪些靶向5T4的创新疗法已进入到临床试验阶段？它们又有望惠及哪些肿瘤患者？本文将结合公开资料带大家来了解下。图片来源：123RF——✦5T4：肿瘤免疫治疗新星✦——5T4又称滋养层糖蛋白（Trophoblast glycoprotein, TPBG）、Wnt激活抑制因子 1（WAIF1），是由TPBG基因编码的脊椎动物特异性单次跨膜蛋白。5T4蛋白首次在人胎盘组织中发现[1]，是N端高度糖基化的跨膜蛋白。人类5T4全长蛋白的分子量约为72kDa，蛋白序列保守，由420个氨基酸组成。该蛋白在胞外结构域中包含一个细胞外区、一个跨膜区（356-376aa）和一个胞内区（如下图所示）[2,3]，其中胞内区含有PDZ结合基序（Ser-Asp-Val），该结合基序可以与位于细胞附近囊泡相关的细胞质蛋白膜TIP-2/GIPC互相作用，从而可参与细胞迁移和黏附信号转导过程的调控[4]。▲5T4结构（截图来源：Front Mol Neurosci [5]）研究发现，5T4广泛表达于胚胎发育期的各种滋养层细胞，其在成人正常组织中表达受限，只在几种上皮细胞中表达，但却在很多癌症细胞中有表达，包括子宫癌、结肠癌、胃癌、卵巢癌、口腔癌、前列腺癌、肺癌或肾癌等。这一特点使其成为了一种有吸引力的肿瘤免疫治疗新靶点。对于5T4影响肿瘤的作用机制，目前尚不十分清晰。但有相关研究发现，5T4具有阻断经典Wnt/β-catenin通路和非经典Wnt信号通路的双重作用：一方面，5T4会与Wnt共受体LRP6结合并抑制其与Wnt受体的内吞，从而阻断Wnt/β-catenin经典信号通路，继而抑制细胞黏附和细胞骨架的形成，促进肿瘤迁移和扩散；另一方面，5T4还可通过活化DKK1来激活非经典Wnt通路，促进细胞迁移和浸润[6]。此外，还有研究认为，5T4也可能是通过影响上皮间质转化（EMT）和CXCR4/CXCL12相关通路来影响肿瘤细胞的发生、发展、转移等。基于5T4肿瘤表达的选择性模式、与肿瘤起始表型的相关性以及其在癌症扩散中的作用，研究人员认为可以针对该靶点开发不同的免疫疗法[7]，包括疫苗、抗体偶联药物、细胞疗法等等，为患者带来潜在的治疗新选择。——✦多款5T4靶向疗法已迈入临床阶段✦——公开资料显示，目前全球尚无靶向5T4的药物获批上市，但已有很多5T4靶向疗法进入到临床试验阶段。这些在研药物包括双特异性抗体、ADC、细胞疗法、融合蛋白等多种药物类型，针对的适应症均为肿瘤。下面我们将介绍部分已进入临床阶段的在研产品，仅供读者参阅。Aptevo、Alligator：ALG.APV-527作用机制：5T4 x 4-1BB双抗Aptevo Therapeutics和Alligator Biosciences共同开发的ALG.APV-527是一款同时靶向5T4和共刺激受体4-1BB（CD137）的双特异性抗体。在第35届肿瘤免疫治疗学会年会（SITC 2020）上，Aptevo曾展示了ALG.APV-527的研究结果。数据显示，ALG.APV-527具有选择性刺激和增强肿瘤中T细胞反应的潜力，而不会刺激身体其他部位的免疫系统，并在体内动物模型中有效抑制了肿瘤。目前，该候选药正在开展针对实体瘤的1/2期临床研究。非同生物：FTL008.16作用机制：5T4 x 4-1BB双抗FTL008.16是非同生物研发的一款新型5T4 x 4-1BB双特异性抗体，拟开发用于治疗恶性实体肿瘤。该产品可通过5T4抗体引导药物分子聚集于表达5T4抗原的肿瘤部位，由共刺激分子4-1BB抗体诱导肿瘤特异性的免疫细胞激活，产生肿瘤杀伤作用，同时将作用限制在肿瘤部位以降低系统毒性。2024年2月，FTL008.16获美国FDA批准临床试验。NeoTX公司：NAP作用机制：靶向5T4的融合蛋白NeoTX Therapeutics开发的NAP（Naptumomab Estafenatox，ABR-217620）是一款靶向5T4的融合蛋白，该药已完成两项分别针对晚期肾细胞癌患者、晚期或转移性NSCLC受试者的2期临床试验。此外，NAP还正在开展多项1期临床试验，分别为：与阿斯利康（AstraZeneca）PD-L1抑制剂durvalumab联合治疗晚期或转移性实体瘤患者的1期临床；以及联合默沙东（MSD）PD-1抑制剂pembrolizumab治疗尿路上皮癌患者的1期临床。爱科瑞思：ADC2154作用机制：靶向5T4的ADCADC2154是爱科瑞思研发的一款靶向5T4的抗体偶联药物（ADC）。ADC2154结构采用全新结构的拓扑异构酶抑制剂为载荷和全新释放机制的连接子，具有循环系统稳定、靶向肿瘤组织和胞内释放的特点。2024年1月，该药已获中国NMPA批准临床，拟开发用于晚期实体瘤，包括但不限于食管癌、结直肠癌、非小细胞肺癌、前列腺癌、卵巢癌、宫颈癌、胰腺癌、肾癌、乳腺癌。Asana公司、Mersana公司：ASN004作用机制：靶向5T4的ADCASN004是Asana Biosciences与Mersana Therapeutics合作开发的一款靶向5T4的ADC，拟用于治疗实体瘤。根据Asana公司官网资料，ASN004结合了一种新型单链scFv-Fc抗体，该抗体与经过临床验证的auristatin F-羟丙基酰胺细胞毒性药物相连。在临床前癌症模型中，ASN004单次给药实现了完全和持久的肿瘤消退。目前该药正处于1期临床试验阶段。Byondis：SYD-1875作用机制：靶向5T4的ADCSYD-1875是Byondis公司开发的一款靶向5T4的ADC。临床前研究显示，在5T4低、中、高表达的多种肿瘤细胞系和人源性组织异种移植（PDX）模型中，SYD-1875不仅能够实现靶向杀伤，也能够诱导旁观者效应介导的抗肿瘤活性。食蟹猴GLP毒性研究显示，该候选药具有可接受的毒性和PK特征，游离毒素水平极低。目前该药已完成了一项1期临床试验。英百瑞：IBR854作用机制：靶向5T4的CAR-raNK细胞产品IBR854是英百瑞生物研发的一款针对实体肿瘤的非基因修饰的CAR-raNK细胞疗法。其核心构造是将靶向5T4的特异性抗体通过连接子与同种异体的NK细胞进行共价偶联，能够与表达5T4靶抗原的肿瘤细胞特异性结合，从而达到靶向识别和杀伤肿瘤细胞的目的。目前，IBR854正在中国开展一项1期临床试验，该研究旨在评价IBR854细胞注射液在不可切除的局部晚期或转移性实体肿瘤患者中的安全性、耐受性及初步疗效。Barinthus公司：VTP-800、VTP850作用机制：靶向5T4的免疫药物Barinthus Biotherapeutics公司开发了两款靶向5T4的免疫治疗候选药物VTP-800和VTP850，拟用于治疗前列腺癌。其中，VTP-800是Barinthus公司开发的一款靶向5T4的第一代免疫候选药物，其与PD-1抑制剂纳武利尤单抗的组合疗法已在针对前列腺癌的1期临床中取得积极效果。VTP-850是Barinthus公司基于VTP-800的1/2a期积极临床试验数据开发的一款下一代免疫候选药物，它可靶向多个与前列腺癌相关的抗原，包括5T4、PSA、PAP、STEAP等。根据Barinthus公司官网信息，该公司预计将于2025年获得VTP-850治疗前列腺癌的1/2期临床数据。当然，除了肿瘤，研究显示靶向5T4还有治疗更多疾病的可能。近年来，该靶点还被发现是帕金森病相关的新潜在基因、是先兆子痫预测和治疗的潜在遗传生物标志物、并在嗅觉和视觉系统的感觉处理中起着关键作用等[8-10]。期待5T4靶向疗法领域能够取得更多的突破，早日造福广大病患！参考资料：（可上下滑动查看） [1] Hole N, Stern PL. (1988) A 72 kD trophoblast glycoprotein defined by a monoclonal antibody. Br J Cancer. https://pubmed.ncbi.nlm.nih.gov/3355761/[2] Myers KA, Rahi-Saund V, Davison MD, et al. (1994) Isolation of a cDNA encoding 5T4 oncofetal trophoblast glycoprotein. An antigen associated with metastasis contains leucine-rich repeats. J Biol Chem. https://pubmed.ncbi.nlm.nih.gov/8132670/[3] Zhao Y, Malinauskas T, Harlos K, et al. (2014) Structural insights into the inhibition of Wnt signaling by cancer antigen 5T4/Wnt-activated inhibitory factor 1. Structure. https://pubmed.ncbi.nlm.nih.gov/24582434/[4] Awan A, Lucic MR, Shaw DM, et al. (2002) 5T4 interacts with TIP-2/GIPC, a PDZ protein, with implications for metastasis. Biochem Biophys Res Commun. https://pubmed.ncbi.nlm.nih.gov/11798178/[5] Tsuboi A. (2020) LRR-Containing Oncofetal Trophoblast Glycoprotein 5T4 Shapes Neural Circuits in Olfactory and Visual Systems. Front Mol Neurosci. https://pubmed.ncbi.nlm.nih.gov/33192298/[6] Kagermeier-Schenk B, Wehner D, Ozhan-Kizil G,  et al. (2011) Waif1/5T4 inhibits Wnt/β-catenin signaling and activates noncanonical Wnt pathways by modifying LRP6 subcellular localization. Dev Cell.  https://pubmed.ncbi.nlm.nih.gov/22100263/[7] Stern PL, Harrop R. (2017) 5T4 oncofoetal antigen: an attractive target for immune intervention in cancer. Cancer Immunol Immunother. https://pubmed.ncbi.nlm.nih.gov/27757559/[8] Wang Y, Li B, Zhao Y. (2022) Inflammation in Preeclampsia: Genetic Biomarkers, Mechanisms, and Therapeutic Strategies. Front Immunol. https://pubmed.ncbi.nlm.nih.gov/35880174/[9] Park S, Yoo JE, Yeon GB, et al. (2021) Trophoblast glycoprotein is a new candidate gene for Parkinson's disease. NPJ Parkinsons Dis. https://pubmed.ncbi.nlm.nih.gov/34876581/[10] Tsuboi A. (2020) LRR-Containing Oncofetal Trophoblast Glycoprotein 5T4 Shapes Neural Circuits in Olfactory and Visual Systems. Front Mol Neurosci. https://pubmed.ncbi.nlm.nih.gov/33192298/[11]各公司官网本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

Mersana Therapeutics, Inc. (NASDAQ: MRSN), a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody-drug conjugates (ADCs) targeting cancers in areas of high unmet medical need, today announced that the U.S. Food and Drug Administration (FDA) has issued a partial clinical hold pausing new patient enrollment in UP-NEXT and UPGRADE-A, the company’s ongoing clinical trials of UpRi in platinum-sensitive ovarian cancer. UPLIFT, Mersana’s ongoing clinical trial of UpRi in platinum-resistant ovarian cancer, completed enrollment in October 2022. Patients who are already enrolled in these trials may continue receiving UpRi. Mersana expects to lock its UPLIFT clinical trial database and disclose UPLIFT top-line data by early August. The partial clinical hold follows a submission by Mersana of a recent aggregate safety report of all patients dosed with UpRi (approximately 560 patients) evaluating bleeding events. As noted in FDA guidance, aggregate analyses generally become more informative as a drug progresses through development and accumulates data. Detection of a clinically meaningful risk, particularly in single-arm clinical trials, typically requires a large safety database to detect differences in rates of adverse events compared to those that are expected in the population being studied. Although data on the background rate of bleeding in platinum-resistant ovarian cancer are limited, Mersana’s recent assessment determined that serious bleeding events appear to occur at a higher rate than background. While most bleeding cases in this aggregate safety analysis were low-grade, five (<1%) Grade 5 (fatal) bleeding events were observed among the approximately 560 patients dosed to date. The causes of bleeding events remain under investigation. “Patient safety is always at the forefront for us, and work is now underway to compile further analyses that may inform FDA,” said Anna Protopapas, President and Chief Executive Officer of Mersana Therapeutics. “Additionally, with UPLIFT top-line data on the near-term horizon, we will soon have a much more complete assessment of both the efficacy and safety profile for UpRi in platinum-resistant ovarian cancer.” The company is awaiting the FDA’s written correspondence regarding the partial clinical hold and expects the FDA will request a comprehensive assessment of UpRi safety data, inclusive of bleeding events. In addition, Mersana plans to submit to the FDA the UPLIFT safety and efficacy data once available. The company plans to seek alignment with the FDA to lift the partial clinical hold and resume enrollment in UP-NEXT and UPGRADE-A. About Mersana Therapeutics Mersana Therapeutics is a clinical-stage biopharmaceutical company using its differentiated and proprietary ADC platforms to rapidly develop novel ADCs with optimal efficacy, safety and tolerability to meaningfully improve the lives of people fighting cancer. Mersana’s lead product candidate, upifitamab rilsodotin (UpRi), is a Dolaflexin ADC targeting NaPi2b that is being studied in UPLIFT, a single-arm registrational trial in patients with platinum-resistant ovarian cancer; UPGRADE-A, a Phase 1 clinical trial evaluating UpRi in combination with carboplatin; and UP-NEXT, a Phase 3 clinical trial of UpRi as monotherapy maintenance following treatment with platinum doublets in recurrent platinum-sensitive ovarian cancer. Mersana's pipeline also includes XMT-1660, a Dolasynthen ADC targeting B7-H4 in a Phase 1 clinical trial, and XMT-2056, an Immunosynthen ADC targeting a novel epitope of human epidermal growth factor receptor 2 (HER2), in addition to other earlier-stage assets. In addition, multiple partners are using Mersana’s platforms to advance their ADC pipelines. Mersana routinely posts information that may be useful to investors on the “Investors & Media” section of its website at www.mersana.com. The content above comes from the network. if any infringement, please contact us to modify.