IMC-C103C

关注并星标CPHI制药在线黑色素相关抗原A4（MAGE-A4）是一种肿瘤/睾丸组织中抗原，属于MAGE-As蛋白家族亚型。MAGE-As是一种肿瘤特异性抗原，家族成员包括MAGE-A1、MAGE-A2……等15个成员，研究发现人类许多其它组织来源的肿瘤都至少表达一种MAGE-A基因。MAGE-A在细胞内可被加工成抗原肽，与HLA-I类分子相结合形成复合物，通过MHC I类分子提呈给CD8+T细胞，在肿瘤患者体内诱发肿瘤特异性免疫应答。       关于MAGE-A4       MAGE-A4是MAGE-A亚家族的重要成员，具有很好的组织学特异性，广泛表达于滑膜肉瘤 (SS)、粘液样/圆形细胞脂肪肉瘤 (MRCLS)、非小细胞肺癌 (NSCLC)、头颈部鳞状细胞癌 (HNSCC) 以及卵巢癌、尿路上皮癌、黑色素瘤和胃食管癌等多种实体瘤组织，但在正常组织(睾丸、胎盘除外)中低表达。       MAGE-A4与肿瘤的发生、发展、转移及预后密切相关。研究发现，MAGE-A4与抑癌基因P53（p53可促使癌细胞凋亡并控制细胞周期）呈正相关，其C端107个氨基酸片段通过与Miz-1部分结合可诱导P53-依赖和P53-非依赖的独立机制，增强P53的转录活性，减少p21（Cip1）转录子和蛋白水平。       而且，研究发现MAGE-A4还可活化跨损伤DNA合成（TLS）途径的活化，抑制对正常细胞的损伤修复，选择性活化化疗细胞DNA损伤修复，造成肿瘤细胞损伤的修复，从而引起肿瘤细胞对化疗药的耐药。       MAGE-A4靶向药进展       MAGE-A4被认为是肿瘤治疗的潜力靶点，目前全球药企针对该靶点已开发出几款在研药物，详见下表。其中Adaptimmune Therapeutics的Afamitresgene Autoleucel (Afami-cel)进展最快，其治疗晚期滑膜肉瘤的BLA正在美国接受优先审查，PDUFA日期为2024年8月4日。       资料来源：公开资料       Adaptimmune Therapeutics领跑，Afami-cel即将出线       Afami-cel是一款针对MAGE-A4癌症抗原的TCR-T疗法，其从患者体内提取T细胞并使用慢病毒载体进行基因工程改造，表达靶向HLA-A*02呈递的MAGE-A4 230-239 GVYDGREHTV的高亲和力和特异性T细胞受体（TCR），该TCR引导T细胞靶向表达MAGE-A4的癌细胞并清除这些癌细胞。       滑膜肉瘤和粘液样/圆形细胞脂肪肉瘤（MRCLS）是两种极其罕见的恶性肿瘤，占所有软组织肉瘤的5%-10%，常规治疗后一旦发生复发转移，预后极差，临床上迫切需要有效的治疗方案。已公布的Afami-cel在晚期滑膜肉瘤或粘液样/圆形细胞脂肪肉瘤患者中开展的关键2期临床试验SPEARHEAD-1队列1数据显示：截至2022年8月29日，共52例（44例滑膜肉瘤，8例MRCLS）患者接受Afami-cel治疗，客观缓解率（ORR）为36.5%，疾病控制率（DCR）为88.4%。中位随访27.8个月时，中位持续反应时间（DOR）为11.6个月。       其中，Afami-cel在经过大量预先治疗的晚期滑膜肉瘤患者中的ORR为39%，中位生存期约为17个月。而且，接受Afami-cel治疗有缓解的晚期滑膜肉瘤患者中，70%的人在治疗两年后仍然存活。       安全性方面，与先前的研究结果一致，Afami-cel安全性可接受，最常见的副作用包括红细胞和白细胞计数低。       值得一提的是，若顺利，Afami-cel或成为首 个获批治疗实体瘤的TCR-T细胞疗法，也是十多年来首 个获批治疗滑膜肉瘤的新疗法。       此外，Adaptimmune Therapeutics还开了另外一款MAGE-A4靶向TCR-T细胞疗法ADP-A2M4CD8。该疗法经CD8α辅助受体修饰，用于治疗符合条件的患有不可切除/转移性实体瘤的人类白细胞抗原A*02患者。已公布的1期临床试验SURPASS结果显示：ADP-A2M4CD8单一疗法在晚期/转移性实体瘤患者中表现出可接受的获益风险比，以及令人鼓舞的抗肿瘤活性。因抑制免疫抑制途径可能会改善抗肿瘤反应，因此新的SURPASS队列包括ADP-A2M4CD8联合纳武利尤单抗或帕博利珠单抗。             罗氏进军MAGE-A4靶点，但进展不顺       IMC-C103C是基于Immunocore公司专有的ImmTAC®技术平台开发的一种新型双特异性蛋白，由亲和增强的TCR和一种靶向CD3的抗体片段组成，一端可以识别MAGE-A4，另一端可以激活T细胞表面的CD3受体，从而使T细胞重新定位以杀伤表达MAGE-A4的肿瘤细胞。       已公布的IMC-C103C治疗卵巢癌的1期临床试验扩展数据显示：在17例可评估的MAGE-A4阳性患者中，1例患者获得持久的PR，持续时间为12.7个月，6例患者为SD，其中1例在数据截止后转变为未确认的PR。而且，在超过一半（12/22）的ctDNA可评估的患者中观察到ctDNA水平的降低，其中7例降低≥50%。       2018年11月，罗氏与Immunocore签署新的研发合作协议，共同开发IMC-C103C（RG6290）。遗憾的是，RG6290于2023年从罗氏的研发管线中剔除。       不过，罗氏并没有放弃在MAGE-A4靶点布局，在推进RG6290的过程中开发了RG6129。RG6129是一款治疗实体肿瘤的双特异性抗体，靶向HLA-A2-MAGE-A4和CD3。该疗法的临床试验在2021年启动后，并未公布任何结果，随后在2023年被终止。       此外，目前罗氏手里还有一款MAGE-A4/CD3 TCR双抗药物RO7617991。今年4月，罗氏在clinical trails网站上，登记了一项RO7617991在MAGE-A4阳性(HLA)-A*02型患者中开展1期临床试验NCT06372574，计划总入组人数为210例。       我国药企布局MAGE-A4靶点，KSH01获批临床       我国药企科士华也积极布局MAGE-A4靶点，其开发的KSH01是我国首 个靶向MAGE-A4抗原的TCR-T疗法。KSH01的核心序列是依托科士华生物的核心技术平台TCR-XFinder™及TCR-XPlanet™ T细胞数据库，从患者体内快速筛选出的具有强效抗肿瘤活性的天然来源TCR序列。       KSH01也是我国首个针对消化道和泌尿系大癌种的TCR-T疗法，2023年3月被FDA授予孤儿药资格。今年4月该疗法在国内获批临床，治疗晚期实体瘤。       总结作为肿瘤药研发的潜力靶点，MAGE-A4靶点布局企业相对较少，而且进展并不顺利，罗氏的两款药物先后终止。Adaptimmune Therapeutics是MAGE-A4领域的领头羊，其开发的Afami-cel针对滑膜肉瘤的BLA正在美国接受优先审查。我国药企科士华在MAGE-A4领域也有布局，但相关产品进展较慢，近期才在国内获批临床。整体来看，MAGE-A4靶点还处于早期阶段，未来前景还充满不确定性，企业在布局的时候切忌盲目跟进。【企业推荐】【智药研习社近期线下课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

Roche used an update to reveal the disappearance of a geographic atrophy program from its pipeline. Roche no longer sees the magic in MAGE-A4. The Swiss drugmaker signaled a retreat from the TCR T-cell target in its first quarter results by putting a pair of phase 1 solid tumor programs out to pasture along with hopes of recouping the $490 million paid out for the assets. Genentech, a subsidiary of Roche, put down $100 million in upfront and near-term milestone payments to co-develop one of the candidates with Immunocore in 2018. The drug candidate, a bispecific T-cell engager targeting MAGE-A4, entered the clinic the following year, but both developers have walked away from the program since the release of phase 1 ovarian cancer data late last year. In February, Immunocore stopped funding the program, apart from the cost of winding down the phase 1 trial. The action left Roche’s Genentech with an exclusive worldwide license to the MAGE-A4 HLA-A02 soluble TCR bispecific therapeutic candidate compounds. It seems Roche doesn’t want the compounds, either. The Swiss drugmaker disclosed the axing of RG6290, a drug candidate based on Immunocore’s ImmTAC technology that is also known as IMC-C103C, alongside news of the removal of another MAGE-A4 asset from its pipeline. Roche took the other candidate, HLA-A2-MAGE-A4xCD3 bispecific antibody RG6129, into the clinic months after Immunocore began a phase 1 trial of IMC-C103C. Early this year, Roche said it had stopped enrolling patients in the study of RG6129, pulling the targeted completion date of the trial forward by more than two years in the process. The removal of the asset from the pipeline recasts the cessation of enrollment as the start of Roche’s retreat from the candidate. Roche invested in the programs in the belief a molecule that simultaneously binds to CD3 on cytotoxic T-lymphocytes and HLA-A2 MAGE-A4 on tumor cells could orchestrate an anti-cancer immune attack. As MAGE-A4 is overexpressed by a variety of cancer cell types, the mechanism is potentially applicable to a range of tumors. The attributes of MAGE-A4 have made it a popular target for TCR T-cell biotechs, with Immunocore and its sibling Adaptimmune among the companies to go after the protein. Adaptimmune is closing in (PDF) on a filing for FDA approval of its first-generation MAGE-A4 candidate. Roche disclosed the MAGE-A4 news as part of a pipeline update that saw it punt two other programs. The list of castoffs includes zinpentraxin alfa, also known as PRM-151 and RG6354. Roche previously stopped a phase 3 trial of the candidate in idiopathic pulmonary fibrosis early because the study looked on course to fail.  Now, the drugmaker has stopped work on myelofibrosis, too. Roche acquired the drug candidate in the 2019 takeover of Promedior, which cost it $390 million upfront. Removing the myelofibrosis program from the midphase pipeline leaves Roche without active clinical programs involving zinpentraxin alfa. Finally, Roche also used the update to disclose the removal of a geographic atrophy program RG6312 from its phase 1 pipeline. Since RG6312 entered the clinic in 2020, the Big Pharma has suffered setbacks in its pursuit of the eye indication, failing a phase 3 trial in 2017 and dropping galegenimab last year. But it still has two shots on goal, including a Lineage Cell Therapeutics candidate that recently entered phase 2.