Folate-Fluorescein

关键词索米妥昔单抗；FRα；研究进展近日，杭州中美华东制药有限公司引进的「索米妥昔单抗注射液」被CDE拟纳入优先审评，用于既往接受过1-3种系统治疗的叶酸受体α（FRα）阳性的铂类耐药的上皮性卵巢癌、输卵管癌或原发性腹膜癌成年患者。索米妥昔单抗(Mirvetuximab Soravtansine，MIRV)是一款抗体偶联药物（ADC），由叶酸受体α（FRα）结合抗体、可裂解连接子和美登木素生物碱DM4（一种强效的微管蛋白靶向剂）组成。2022年11月，该药被FDA加速批准用于曾经接受过1-3种全身治疗方案，且FRα阳性、铂类耐药的上皮性卵巢癌、输卵管癌或原发性腹膜癌的成人患者，商品名为Elahere。索米妥昔单抗是全球首个针对FRα阳性卵巢癌的ADC，最新公布的其在FRα高表达、既往接受过1-3线治疗（需要包括贝伐珠单抗）的铂耐药卵巢癌患者中开展的国际3期单臂临床试验SORAYA结果显示：疗效方面索米妥昔单抗的临床抗肿瘤能力不受限于既往治疗线数及PARPi使用，研究者评估的客观缓解率（ORR）为32.4%，包括5例完全缓解。中位持续缓解时间（mDOR）为6.9个月，51.4%的患者疾病得到控制，71.4的患者实现肿瘤缩小。安全性方面研究中最常见的不良反应是眼部事件和胃肠不适，且属于低级别、可逆的。严重（3级及以上）治疗相关不良事件发生率为9%。索米妥昔单抗获FDA批准正是基于SORAYA研究的积极数据。该药由ImmunoGen研发，2020年10月华东医药获得其在大中华区的独家临床开发及商业化权益。此次索米妥昔单抗在国内拟纳入优先申请，将进一步加速其在国内的上市进程，为FRα阳性、复发卵巢癌患者提供新选择。关于FRα叶酸是人体所必需的维生素之一，参与核酸、氨基酸、蛋白质和磷脂代谢，并与细胞分化、倍增及其功能密切相关。叶酸需要从外界摄取，经叶酸受体介导，通过内吞作用将叶酸运送到细胞质中。人体内转运叶酸的受体有三种，叶酸受体（FR）家族就是其中一种。FR家族是通过糖基磷脂酰肌醇（GPI）锚定于细胞膜的单链糖蛋白，能够结合叶酸并通过内吞作用转运叶酸进入细胞。FR有FRα、FRβ、FRγ和FRδ四种亚型，分别由FOLR1、FOLR2、FOLR3和FOLR4编码，家族同源性约为70%。FRɑ研究最为广泛，是一种分子量38-40kDa的位于细胞膜上的叶酸结合蛋白，其编码基因FOLR1由7个外显子和6个内含子组成。FRɑ主要在上皮来源的肿瘤组织中高表达，在正常组织中不表达或者表达量非常低，对叶酸具有高亲和力，而对还原型叶酸亲和力较低。据Nature Reviews Clinical Oncology 上的一篇综述，FRɑ在72-100%的间皮瘤患者、35-68%的三阴性乳腺癌癌患者、76-89%的卵巢癌患者和14-74%的非小细胞肺癌患者样本中高表达。研究发现，FRα通过以下作用机制参与肿瘤的浸润、转移、进展：（1）FRα通过内吞途径为癌细胞转运叶酸，内吞后的叶酸通过一碳单位代谢参与DNA的合成、损伤修复和甲基化；（2）FRα参与多种癌症相关信号通路的调控（ JAK-STAT3, ERK1/2 等）；（3）FRα高表达可以促进癌细胞的增殖，迁移和侵袭（2.3作用独立于叶酸）；（4）FRs还可能通过作为转录因子和信号分子直接支持肿瘤细胞的生长——将叶酸送进细胞后，FRα会转移到细胞核中并充当转录因子，与顺式调节元件结合，负责调控基因转录的部分关键DNA，直接调节癌细胞关键发育基因的表达。FRα靶向药研究进展FRα被认为是一个理想的抗肿瘤药研发靶点。然而，FRα靶向药的研发并不顺利，2013年卫材开发的FRα靶向单抗farletuzumab在一项3期临床试验中错失主要终点，2014年Endocyte研发的FRα靶向小分子偶联药物Vintafolide宣告失败。而默沙东曾以1.2亿美元的首付款和高达8.8亿美元的里程碑款从Endocyte获得Vintafolide的权利。直到2022年，首款且唯一一款FRα靶向药索米妥昔单抗加速获批，FRα靶向药的研发才算迎来曙光。目前，全球还有多款在研FRα靶向药，详见下表。全球部分FRα靶向药来源：药渡数据库目前，全球超10款FRα靶向药进入临床试验阶段，适应症多为Frα阳性卵巢癌。研发阶段上，Farletuzumab ecteribulin、AZD5335等6款进入2期临床，IMGN151、UB-TT170等5款进入1期临床。药物类型上在研FRα靶向药多为ADC。此外，在研FRα靶向药还涉及CAR-T、TIL疗法、双配体药物偶联药物。ITIL-306ITIL-306是Instil Bio的首个基因工程共刺激抗原受体TIL（CoStAR-TIL）疗法，采用新型专有共刺激抗原受体（CoStAR）设计，由FRα激活，以提供强大的共刺激信号。在具备天然TIL的优势的同时，ITIL-306又能够增强细胞因子释放、提升TIL在肿瘤微环境中的活性。在人异种移植小鼠实体瘤模型中，ITIL-306表现出良好的抗肿瘤活性和持久性，并且避免了由高剂量IL-2输注带来的风险，具有更低的毒副作用。2022年6月，ITIL-306在美国获批临床，用于治疗非小细胞肺癌（NSCLC）、肾细胞癌（RCC）和卵巢癌患者。普方生物、同宜医药等国内药企积极布局FRα靶点我国药企也积极布局FRα靶点，如普方生物、同宜医药、普众发现/联宁生物和百奥泰。其中同宜医药研发的CBP-1008是全球首创的双配体药物偶联药物，能同时靶向FRα和TRPV6，由优化过的特异靶向FRα/TRPV6的双配体连接子系统、可酶裂解的连接子和细胞毒素MMAE组成。2023年ASCO上公布的Ib期研究结果显示：疗效方面82例铂耐药复发卵巢癌（PROC）患者接受0.15mg/kg或以上剂量的CBP-1008治疗，ORR和DCR分别为25.6%和62.2%。中位PFS为3.7个月。在34例FRα表达≥25％且既往治疗线数≤3的卵巢癌患者中，ORR为32.4％，mPFS仍为3.7个月。安全性方面最常见的不良事件为中性粒细胞减少（80.9%），白细胞减少（77%），发热（71.3%）和AST升高（65.2%），其中47.8%出现≥3级的中性粒细胞减少，27.5%的患者出现≥3级的白细胞减少。AMT-151普众发现与联宁生物联合开发的AMT-151是一款靶向FRα的ADC，以普众发现自主研发的重组人源化抗体和新型毒素分子（DUO-5）为有效载荷，采用联宁K-lock定点偶联技术，极大的提高了临床开发的可靠性。2023年4月，该药在国内获批临床。多款FRα靶向药研究数据亮相AACR、ASCO据不完全统计，Farletuzumab ecteribulin、AZD5335、ELU001等多款药物相关研究亮相近年AACR、ASCO大会。Farletuzumab ecteribulinFarletuzumab ecteribulin是卫材开发的ADC，由卫材自主研发的靶向FRα的farletuzumab（一种人源化IgG1单克隆抗体）、酶可裂解的连接子和卫材自主研发的抗癌药艾立布林组成，被开发用于治疗FRα阳性实体瘤。不过，在临床前研究中，farletuzumab ecteribulin显示出旁观者效应，对FRα阳性癌细胞周围的FRα阴性癌细胞具有抗肿瘤活性。2021年AACR年会上公布的Farletuzumab ecteribulin治疗FRα阳性实体瘤患者的1期临床试验结果显示：Farletuzumab ecteribulin治疗对FRα阳性实体瘤患者（包括卵巢癌患者）具有抗肿瘤活性。同时，研究发现患者血清中的FRα水平与肿瘤缩小之间存在正相关关系。此外，已公布的1期研究扩展部分研究结果显示：对于铂耐药卵巢癌患者，0.9mg/kg（队列1）、1.2mg/kg（队列2）Farletuzumab ecteribulin治疗的ORR分别为25.0％和52.4%。对于高级别浆液性卵巢癌（HGSOC）患者，队列1和队列2中的ORR分别为31.6％和50.0％。对于FRα表达水平低于50.0％的患者，队列1和队列2中Farletuzumab ecteribulin治疗的ORR分别为33.3％和50.0％。对于FRα表达水平≥50.0％的患者，队列1和队列2中Farletuzumab ecteribulin治疗的ORR分别为22.2%和52.6%。安全性方面，最常见治疗相关不良事件（TEAE）是间质性肺疾病/肺部炎症，队列1、队列2的发生率分别为37.5％和66.7％。此外，常见TEAE还包括发热（队列1：33.3％；队列2：42.9％）、头痛（队列1：12.5％；队列2：47.6％）和恶心（队列1：25.0％；队列2 ：33.3％）。在队列1和队列2中分别有33.3％的患者和28.6％的患者发生≥3级TEAE。2021年6月，卫材和百时美施贵宝宣布就该药达成全球性合作。据协议，卫材将获得6.5亿美元的前期付款和可达24.5亿美元的里程碑付款。AZD5335AZD5335是阿斯利康自研的一款ADC，由FRα靶向抗体、AstraZeneca专有的拓扑异构酶1抑制剂（TOP1i）偶联而成，DAR值为8。2023年AACR上公布的AZD5335针对FRα阳性卵巢癌的临床前疗效数据显示：AZD5335（2.5 mg/kg, IV, SD）在卵巢癌细胞系异种移植（CDX）中肿瘤生长抑制（TGI）为75% - 94%；在评估的14/17（82%）卵巢癌患者的异种移植模型（PDX）中，中位最佳肿瘤皱缩>30%。相同或更高剂量下，在FRα低-中表达的两种PDX模型中，AZD5335比基于微管抑制剂（MTI）有效载荷的靶向FRα ADC具有更优秀的临床前活性。IMGN151IMGN151是ImmunoGen基于Elahere研发的一款FRα靶向ADC，目前其1期临床试验已完成首例患者给药。IMGN151具有多项改进：能够结合两个不同的FRα表位，并拥有下一代 payload和新型linker，具有更长的半衰期、更高的有效载荷递送量和更高的暴露量。临床前数据表明：IMGN151对 FRα 的亲和力是Elahere的两倍，其中一个结果是增强了旁观者效应。ELU001ELU001是基于Elucida公司 C'dot 技术的 ADC，该技术可生成“超小”结构，其靶向部分和有效载荷是传统ADC的10倍多，目前主要被开发用于治疗卵巢癌和原发性胶质瘤。2023年AACR上公布的关于脑转移的临床前数据显示：ELU001具有穿透被破坏的血脑屏障而治疗脑转移瘤的独特能力，具有解决危重病人治疗需求的潜力。Elucida首席科学官Gregory Adams表示，ELU001能够在避开大脑健康区域的同时，选择性地定位和治疗接种在小鼠大脑中的肺部肿瘤。ELU001介导试验动物的大脑中早期和晚期肿瘤的大小明显减少，并恢复由肿瘤生长而导致的体重下降。Luveltamab tazevibulinLuveltamab tazevibulin 是一种新型靶向FRα的ADC，具有稳定的可裂解接头和3-aminophenyl hemiasterlin弹头（DAR=4），可诱导细胞毒性和免疫细胞死亡。2023年ASCO大会上公布的1期剂量扩展研究的结果显示：Luveltamab tazevibulin治疗FRα阳性的晚期卵巢癌(定义为肿瘤比例评分>25%)患者的ORR为37.5%；无论起始剂量如何，Luveltamab tazevibulin诱导的mDOR为5.5个月，mPFS为6.1个月。而且，Luveltamab tazevibulin反应率呈现与FRα相关性：在FRα TPS≤25%的患者中，ORR为11.1%，mDOR为2.9个月，mPFS为3.8个月。ZW191ZW191是一款新型FRα靶向ADC，由人源化IgG1抗体与基于喜树碱的新型拓扑异构酶1抑制剂ZD06519通过可裂解的连接子偶联而成，DAR值为8。2023年AACR 上公布的临床前数据表明：与其他ADC中使用的FRα靶向抗体相比，ZW191具有更强的肿瘤球体穿透性、细胞内化和有效载荷传递性。在代表FRα表达范围的CDX和PDX模型中，ZW191显示出令人信服的抗肿瘤活性。总结从90年代发现至今，FRα靶向药的研发虽历经重重挫折，最终于2022年迎来首款药物Elahere。此外，目前全球还有多款在研FRα靶向药进入临床试验阶段，且多款药物取得不多进展，相关研究数据亮相近年AACR、ASCO大会。在研FRα靶向药目前大多被开发用于治疗FRα高表达的复发卵巢癌，药企在布局的时候要注意差异化开发，以免适应症扎堆。END👇关注药渡数据媒体矩阵

Looking at mice with xenografts of folate receptor-expressing tumor cells, researchers saw that UB-VV200 controlled solid tumor growth in a dose dependent manner—the more TagCAR T cells that were generated, the smaller the tumor volume. It’s a statistic that haunts David Fontana, Ph.D., chief operating officer of Umoja Biopharma: At a time when manufacturing space is hard to come by, as many patients die waiting for CAR-T cell therapy as are actually treated. “Physicians … are having to choose which patient [gets the therapy]. Do we go with the sick elderly one that has no hope, or the healthy one that can probably survive?” Fontana told Fierce Biotech at the American Society for Gene and Cell Therapy’s (ASGCT's) annual meeting. “I’ve started calling them the ‘Goldilocks patients’: The ones who aren’t too sick, not too well. You’re narrowly defining these patients simply because of these supply chain issues.” Umoja wants to offer a solution. The biotech is working on ways to confront all the major limitations of CAR T-cell therapy—the lengthy, pricey manufacturing process and the poor efficacy against solid tumors—with therapies that reengineer a patient’s T cells within their own body, rather than removing and redelivering them the way current autologous CAR T-cell therapy is administered today. It’s also in the process of establishing partnerships with Big Pharma companies that want to take their ex vivo therapies in vivo by pairing them with Umoja’s VivoVec gene delivery system, which the company is aiming to manufacture end-to-end at its forthcoming plant in Colorado. “We know we can manufacture 100% of our own supply chain, so that’s attractive to partners,” Fontana said, especially in light of the ongoing shortage of lentiviral vectors. Though no deals have been announced yet, Umoja is “actively pursuing” partnerships, he added. What the company has announced is new preclinical data validating its therapeutic approach in solid tumors. On May 17 at ASGCT, researcher Alyssa Sheih, Ph.D., showed how Umoja’s gene delivery platform UB-VV200, which uses the company’s VivoVec technology, combined with UB-TT170, a folate receptor-targeting version of its small-molecule adapter TumorTag technology, was able to generate CAR T cells in vivo and successfully control solid tumor growth in mice. A brief overview of how all the pieces work together: The scientists administer UB-VV200, an engineered lentiviral vector that encodes a universal CAR called a TagCAR along with the company’s synthetic cytokine system, RACR, which helps the CAR T cells expand and persist without the need for pre-treatment chemotherapy. UB-VV200 selectively binds, activates and transduces the T cells, resulting in TagCAR expression on their surface. The TagCAR-T cells will bind to the TumorTag coated folate receptor-expressing tumors—in this instance, the TumorTag UB-TT170, which binds to folate receptors. Looking at mice with xenografts of folate receptor-expressing tumor cells, the researchers saw that UB-VV200 controlled solid tumor growth in a dose-dependent manner. The more TagCAR T cells that were generated, the smaller the tumor volume. Umoja is conducting ongoing nonhuman primate studies, which the company described as “encouraging” so far. Details are to be presented at an upcoming medical conference, though Umoja declined to disclose which one.  The Seattle Children's Research Institute is currently testing Umoja's UB-TT170 in pediatric osteosarcoma, a folate receptor-expressing tumor type, with plans to expand into gynecological tumors. The company also intends to submit an investigational new drug application for human testing with the FDA for UB-VV200 by the second half of 2024. Other preclinical assets include UB-VV111, a CD-19 CAR T-cell therapy for hematological cancer. Meanwhile, the company is busy finishing up the manufacturing plant in Louisville, Colorado, dubbed The Colorado Laboratory & Innovative Manufacturing Building, or The CLIMB. The $70 million plant will span 77,000 square feet and is expected to open later this year. Producing an off-the-shelf, in vivo CAR T therapy rather than an ex vivo one allows the company to make more efficient use of its manufacturing space, Senior Vice President of Translational Sciences Ryan Larson explained. Autologous ex vivo CAR T cell therapies are produced for each individual patient, so each batch of CAR T cells must be produced one at a time. In contrast, “we can scale up—we don’t have to scale out,” Larson said. As demand for Umoja's therapies grows, along with the number of partners that want to use the VivoVec platform to convert their own CAR T cell therapies to in vivo products, “we can just increase the volume of our bioreactors.” Given the manufacturing challenges and other accessibility issues associated with autologous CAR T-cell therapies, it’s likely that the field more broadly is headed toward an in vivo approach, Larson said. There’s a precedent for this already in the gene therapy space. Gene therapies started out with genes being transduced into cells outside a patient’s body, then over time began to move in-patient as the technology improved. The same thing is happening with CAR T-cell therapies: As the treatment’s power has become clear, researchers are looking for ways to make it more accessible. “Now, to me, it’s an obvious next step if you can make a truly off-the-shelf product that engineers the patient’s own cells in vivo essentially an autologous product—it’s your T cells—and you bypass all the complexity of the ex vivo approach by going directly in vivo,” Larson said. “I would say yeah, it’s definitely the way of the future.”