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重生洪荒之有始有终:从本土到国际的跨越
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重生洪荒之有始有终:从本土到国际的跨越

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所有团队均经过专业培训、持证上岗,所用产品配件均为原厂直供,








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2020年底,美国FDA紧急批准了两种mRNA疫苗(辉瑞/BioNTech联合研发的BNT162b2和Moderna公司的mRNA-1273),为新冠疫情防控提供了革命性工具。

这两款疫苗的巨大成功,开启了mRNA技术的新纪元,也促进了mRNA疫苗在肿瘤等更多疾病领域的研发和应用。

1

mRNA疗法:癌症治疗新希望

疫苗是人类在医学领域里最伟大的发明之一,每当一款疫苗被研发出来,就意味着某些疾病将被击败,甚至永久性地从人类生活中消失。

而针对癌症的疫苗也被人们寄予了厚望。

癌症疫苗是指药物进入机体后,其中的肿瘤相关抗原(tumor-associatedantigen,TAA)或肿瘤特异性抗原(tumor-specificantigen,TSA)通过主要组织相容性复合体Ⅰ/Ⅱ提呈作用,激活细胞毒性T淋巴细胞、辅助T细胞等免疫细胞,增强人体免疫系统特异性识别抗原的能力,从而抑制肿瘤的生长、转移。

图片来源:参考资料1

事实上,癌症疫苗的研究已经历很多阶段,利用许多的技术和方法推动肿瘤疫苗的研发。目前用于肿瘤治疗的疫苗平台有以下四种:全细胞疫苗、多肽疫苗、病毒载体疫苗、DNA/mRNA疫苗。

但此前,除了HPV疫苗等少数预防性癌症疫苗,治疗性癌症疫苗发展并不顺利,虽有获批上市,但应用有限。

相比较而言,近期崛起的mRNA肿瘤疫苗具有众多优势:

①与病毒疫苗类似,mRNA肿瘤疫苗能够同时递送多种抗原,引发体液免疫和细胞免疫,增加了肿瘤细胞根除的可能性。

②与多肽疫苗相比,mRNA的分子量更小,并且mRNA疫苗可以将多种抗原同时编码进mRNA序列当中,并在细胞内翻译产生大量相关抗原。

③与DNA疫苗相比,mRNA疫苗是转录后的产物,是一条单链,不需要在细胞核中再进行转录,可以直接利用细胞中的原料,提高抗原产生效率,同时也避免外来信息整合进入宿主的DNA中。

④开发快速且灵活性高。mRNA疫苗的设计和生产过程相对简单,能够快速响应肿瘤抗原的变化。mRNA疫苗可以根据不同患者的肿瘤抗原进行快速设计和合成,具有个性化治疗的潜力。

⑤与其他疗法的协同作用。mRNA疫苗可以与免疫检查点抑制剂(如PD-1/PD-L1抑制剂)、化疗和放疗等传统疗法联合使用,进一步增强抗肿瘤效果。

mRNA肿瘤疫苗具有的这些优势,使其成为未来肿瘤免疫治疗的重要方向之一。

2

首个上市在即

药智数据显示,目前全球已有数十个mRNA肿瘤疫苗正在开发中,虽无上市产品,但Moderna与默沙东联合开发的mRNA-4157已进入临床3期,预计将在2027年上市,有望成为首款上市的mRNA肿瘤疫苗。

此外,德国生物技术公司BioNTech、国内瑞宏迪医药、云顶新耀、康方生物、思路迪医药等公司也有mRNA肿瘤疫苗管线在研。

表1全球在研mRNA肿瘤疫苗管线(部分)

数据来源:药智数据

Moderna和BioNTech两家生物技术公司在领跑mRNA新冠疫苗之后,继续领跑mRNA肿瘤疫苗。

mRNA-4157是Moderna公司开发的一款个体化mRNA肿瘤疫苗,其抗原为包含编码最多34种新抗原的单一合成mRNA分子,佐剂为脂质纳米颗粒(lipidnanoparticle,LNP)。该药目前已启动三项Ⅲ期研究,分别为一项针对黑色素瘤和两项针对非小细胞肺癌的研究。

图片来源:Moderna公司

在2024年ASCO年会上,Moderna公布了mRNA-4157联合Keytruda(帕博利珠单抗,pembrolizumab)治疗已切除黑色素瘤的Ⅱb期临床试验3年随访数据。结果显示,中位随访时间约34.9个月,与单独使用帕博利珠单抗相比,mRNA-4157与帕博利珠单抗联用可使黑色素瘤患者复发和死亡风险降低49%,远处转移的风险降低了62%。且与单独使用帕博利珠单抗相比,mRNA-4157联合帕博利珠单抗的总生存(overallsurvival,OS)时间的探索性终点更有利,2.5年OS率分别为96.0%和90.2%,其RFS时间显著延长,RFS率提高了19.2%。

值得一提的是,此前Moderna与默沙东就mRNA-4157已达成协议,共同开发和商业化mRNA-4157。Moderna预计2026年可能会公布mRNA-4157的关键数据,并有望拿下首款基于mRNA的个性化癌症疫苗。

除了mRNA-4157,Moderna公司的mRNA-4359也已进入临床Ⅱ期。

BioNTech公司则开发了两个mRNA癌症疫苗技术平台:个体化新抗原特异性免疫治疗平台iNeST和针对特定适应症的“现货”mRNA癌症疫苗平台FixVac。

图片来源:BioNTech公司

基于iNeST技术,BioNTech开发了BNT122(autogenecevumeran)。这是一种针对多种实体瘤的个体化癌症候选疫苗,编码多达20种患者特异性肿瘤新抗原,诱导针对患者个体肿瘤的免疫反应。其治疗胰腺癌的I期临床研究显示,50%(8/16)的患者检测显示诱导出新抗原特异性T细胞。在中位随访时间为18个月时,获得新抗原特异性免疫反应患者的无复发生存期(RFS)显著长于无疫苗激发免疫反应的患者。

BNT122目前正在各种实体瘤适应症中进行评估,包括肌层浸润性尿路上皮癌、结直肠癌、胰腺导管腺癌、黑色素瘤等。

基于FixVac技术,BioNTech开发了BNT111、BNT113、BNT116三款癌症疫苗,分别针对黑色素瘤、头颈鳞状细胞癌和非小细胞肺癌,目前皆已进入临床研究阶段。

3

国内多家Biotech已布局

目前国内mRNA肿瘤疫苗也已有多个产品处于临床及临床前研究阶段,如云顶新耀的EVM16、上海瑞宏迪医药的HRXG-K-1939、成都威斯津生物的WGc-043、北京臻知医学的IPM514、合肥阿法纳生物的AFN18等。

EVM16是云顶新耀通过AI辅助研发的首款新型mRNA个性化肿瘤治疗性疫苗。临床前研究显示,EVM16在小鼠模型中显著抑制了肿瘤生长,同时展现出良好的安全性。而且EVM16与PD-1抗体联用后具有协同抗肿瘤效果。目前该药已在北京大学肿瘤医院顺利完成首例患者给药。

另外,云顶新耀的通用型的现货肿瘤治疗性疫苗EVM14也已成功获得美国FDAIND批准,拟用于非小细胞肺癌、头颈癌等多种癌症的治疗。

HRXG-K-1939是上海瑞宏迪医药自主研发的个性化新抗原mRNA肿瘤疫苗,已在复旦大学附属肿瘤医院和中国人民解放军总医院分别开展实体瘤和胰腺癌的IIT研究。

WGc-043是成都威斯津生物研发的一款EB病毒阳性肿瘤mRNA疫苗,已先后获得美国食品药品监督管理局(FDA)和中国国家药品监督管理局(NMPA)IND许可,获准在两地开展临床试验,这也是全球首款针对EB病毒相关肿瘤获得IND批件的治疗性mRNA肿瘤疫苗。

IPM514是北京臻知医学研发的一种基于mRNA-LNP的现货通用型肿瘤治疗性疫苗候选药物,可通过肌肉注射递送一套经优化设计编码近20个食管鳞癌(ESCC)肿瘤相关抗原表位序列的纳米脂质体药物。目前一项开放、多中心、评估IPM514治疗食管鳞状细胞癌的安全性、耐受性、药代动力学和初步有效性的临床研究正在开展中。

AFN18是合肥阿法纳生物开发的一款个体化肿瘤新生抗原mRNA疫苗,已在肿瘤癌前病变和实体瘤两大领域分别获得国家药监局的两项临床批件。

此外,康方生物于近期注册了个体化mRNA疫苗单药或联合PD-1/CTLA-4双抗、PD-1/VEGF双抗辅助治疗胰腺癌的IIT临床试验。

思路迪医药基于mRNA-LNP平台开发的首个mRNA肿瘤疫苗3D124计划在今年向FDA及CDE递交IND申请。

4

结语

近年来,mRNA肿瘤疫苗在癌症治疗领域方面展现出巨大潜力,并取得了显著进展,但仍然面临递送、免疫反应调控、规模化生产等许多挑战,距离全面用于临床治疗仍需大量研究和系统性验证。不过,随着基础研究的深入和相关技术的进步,mRNA肿瘤疗法有望在未来几年取得更多突破,成为下一个肿瘤治疗爆发领域。

参考资料:

1.https://link.cnki.net/urlid/11.1784.N.20240402.1658.028

2.DOI:10.3969/j.issn.1672-4992.2024.09.029

3.DOI:10.12206/j.issn.2097-2024.202410034

4.医药领袖:后疫情时代BioNTech生存法则:进军mRNA癌症疫苗

5.阿法纳生物:阿法纳生物个体化肿瘤mRNA疫苗临床研究启动会顺利召开

6.医药笔记:康方生物:个体化mRNA疫苗启动胰腺癌IIT临床研究

7.云顶新耀:云顶新耀宣布通用型的现货肿瘤治疗性疫苗EVM14注射液的新药临床试验申请获美国FDA批准

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