iPSC-NK(CellOrigin Technology (Hangzhou) Co., Ltd.)

BOSTON & TOKYO--(BUSINESS WIRE)-- HebeCell Corp (HebeCell), a biotechnology company developing ProtoNK™ cell therapeutics based on its proprietary 3D PSC-NK manufacture platform, and Logomix Inc (Logomix), a Tokyo-based synthetic biology company, with a platform technology to engineer-in complex genomic messages of ~Mb-scale into human cells, today announced a strategic partnership to research and develop gene-edited NK cells and discover genetic modifications that can create next generation designer NK cells. Under the agreement, the companies enter a strategic partnership where Logomix first provides genome editing capabilities to HebeCell for development of next generation designer protoNK cells. The combination of PSC-based platform with genome editing capabilities will significantly broaden and accelerate new development for screening de novo genetic modifications that enhance the persistence and efficacy of protoNK cells against cancers. “We know our protoNK cells are strong cytotoxic cells. Our goal is to make PSC-derived protoNK more efficacious in vivo. This collaboration with Logomix will give us a very powerful toolbox to achieve that goal,” said John Lu, Ph.D., Chief Executive Officer at HebeCell Corp. “This collaboration expands our efforts to develop unique NK cell therapies, and has the potential to create something new and never seen before in the NK therapeutic field.” "Logomix’s proprietary technology, Geno-Writing™ is a genome-writing platform that grants cell therapy developers unprecedented freedom to screen, design and write-in large-scale genomic alterations in human cells. Because our technology allows Mb-scale and scarless modifications, applied to any sequences at either or both alleles, it is an ideal tool to create source of allogeneic cell therapy with desired gene edits,” said Taiki Ishikura, CEO at Logomix Inc. “This collaboration with HebeCell demonstrates how our genome engineering technologies can be applied to the field of immuno-oncology and develop the next generation of cell therapy modalities more efficacious and safe to cancer patients.” About HebeCell HebeCell Corp, founded in 2016, is primarily engaged in developing universal and cost-effective NK cell therapeutics based on its proprietary 3D pluripotent stem cell (PSC) platform, the off-the-shelf ProtoNK™ cell products will be readily available to all patients worldwide for the treatment of cancer, viral infection, and autoimmune diseases. HebeCell’s team includes multiple world-leading experts in stem cell biology, as well as experienced entrepreneurs and business developers. The company operates a fully equipped state-of-the-art R&D and GMP facility in Natick, MA, one of the world’s largest biotech hubs. For more please see: About Logomix Logomix is a Tokyo-based synthetic biology company, maximizing the potential of cells by its Mb-scale and ultra-accurate genome engineering. Using its proprietary genome engineering platform Geno-Writing™, Logomix has developed multiple iPS cell lines as universal donor cells available for licensing. Logomix is also participating in development collaboration with biotech companies and academia to enable accelerated development of next generation cell therapy modalities with augmented functionality. For more information, visit .

自然杀伤（NK）细胞是先天免疫的效应细胞，与 T 细胞一样具有识别并杀死癌细胞的能力。ClinicalTrials.gov 网站显示，NK 及 CAR-T 相关的研究达到免疫细胞疗法的 60%。CAR-T 细胞疗法是第一个进入临床转化和商业化的疗法。然而，CAR-T 要求患者以自体细胞为原材料并延长了「静脉到静脉的时间」，因此对于疾病快速进展、迫切需要治疗的患者来说是一个障碍。此外，在临床上，CAR-T 引起的细胞因子释放综合征（cytokine release syndrome，CRS）和神经毒性更是不可忽视的问题。鉴于这些限制，科学家们将目光放在了能克服 CAR-T 疗法局限性的 CAR-NK 细胞上面。图 1. 免疫细胞疗法及 CAR-NK 相关临床实验统计图A. 截止 2022 年 11 月 11 日，ClinicalTrials.gov 网站上显示与免疫细胞疗法相关的研究 B. CAR-NK 相关临床实验全球分布统计图极具前途的 CAR-NK 细胞疗法CAR-NK 细胞疗法越来越多地被用于评估和治疗多种恶性肿瘤，NK 细胞具有显著的肿瘤清除和招募其他免疫亚群的能力，且无需像T细胞或 B 细胞那样预先呈递抗原。循环中 CAR-NK 细胞的寿命有限，靶向非肿瘤或正常组织的风险相对较低。同种异体 CAR-NK 细胞输注可降低移植物抗宿主病（graft versus host disease，GVHD）的风险，CRS 和神经毒性也极少发生。由于这些潜在的优势，脐带血、外周血细胞、NK-92细胞系和诱导多能干细胞（induced pluripotent stem cells，iPSCs）来源的 NK 细胞均极具临床价值，以便用于 CAR 工程。由 iPSC 产生的 NK 细胞已成为一种极具潜力的策略，可以生产具有抗肿瘤活性的标准化现货型 NK 细胞。图 2. CAR-NK 细胞的来源[1]iPSC ：「现货」NK 细胞供应商目前大多数 CAR-NK 细胞的临床试验都使用 NK-92 细胞系，因其在体外具有无限的增殖能力、对重复冻融的敏感性较低的特点，并能根据 GMP 规范扩增大量临床用细胞。这些特性在制造临床的「现货」CAR-NK 产品时，占据了明显的优势。然而，NK-92 细胞作为肿瘤细胞系具有潜在的致瘤性风险，且输注前的辐照会导致体内扩增潜力丧失。iPSC-NK 不仅为 CAR-NK 细胞治疗提供了另一种途径, 而且它为「现货」的 CAR-NK 细胞产品提供了可再生资源。此外，来源于血液的具有自然异质性，使得过继转移前 NK 细胞功能和扩增潜力的验证更加复杂。与 PB-NK 或 UB-NK 相比，iPSC-NK 细胞具有克隆生长、高扩增及体外分化的能力，能生产出大量均质 NK 细胞。iPSC-NK 细胞结合了原代 NK 细胞和 NK-92 细胞系最具吸引力的优势，即高细胞毒性且冷冻保存后也能在体内持续扩增。图 3. iPSC-NK 细胞疗法制造示意图[1]尽管 iPSC-NK 还没有获得 FDA 批准临床转化的疗法，但临床研究的数量逐年增加。一些正在进行的临床实验显示，iPSC-NK 细胞疗法具有强烈的抗肿瘤反应。例如，iPSC-NK 细胞在体外对多种血液和实体瘤细胞系（包括卵巢癌、髓系白血病和黑色素瘤）表现出效应细胞毒性反应（表 1）。表 1. 研究 iPSC-NK 细胞治疗产品的临床研究[2, 3]iPSC-NK 的发展蓝图在原代 NK 细胞中，涉及许多细胞死亡的病毒整合是一个效率低下的工程。然而，iPSC 细胞非常适合这些病毒整合方法，允许直接敲入或敲除基因，iPSC-NK 细胞更容易以可靠和有效的方式进行基因工程改造。iPSC-NK 细胞经过基因工程改造，可克服与 NK 疗法相关的各种限制。可尝试的 iPSC-NK 修饰包括：1）CD16 受体的突变版本以抑制 ADAM17 蛋白酶的切割，从而增强 ADCC 和抗肿瘤能力；2）IL15/IL15r 融合受体以改善体内持久性；3）CARs 用于改善抗肿瘤细胞毒性；4）CD38 受体敲除以防止组合抗体治疗的相互干扰；5）重组 CD4/CD3 ζ 受体增加 NK 细胞毒性；6）删除 CISH 基因来靶向检查点抑制剂。iPSC 经过基因修饰大大提高了抗肿瘤活性及持久性。寻找一种方法使 CAR-NK 细胞更安全有效，这对于下一代细胞疗法至关重要。iPSC-CAR-NK 技术可能是未来更加优于 CAR-T 的免疫细胞疗法。图 4. 基因修饰 iPSC-NK 疗法[3]看过文章的朋友们，有没有对 iPSC-NK 细胞疗法产生浓厚的兴趣？Bio-Techne 能为您提供 iPSC-NK 细胞研究完整的解决方案。图 5. iPSC-NK 细胞产品解决方案iPSC 诱导分化常用蛋白或小分子：”如需了解更多信息，可致电 400-8213475 官方电话，或长按识别二维码联系当地经销商咨询～ 内容策划：邹礼平内容审核：陆雯芸题图来源：图虫创意参考文献[1] X Shankar K, Capitini CM, Saha K. Genome engineering of induced pluripotent stem cells to manufacture natural killer cell therapies. Stem Cell Res Ther. 2020 Jun 16;11(1):234. doi: 10.1186/s13287-020-01741-4. PMID: 32546200; PMCID: PMC7298853.[2] Zhang L, Meng Y, Feng X, Han Z. CAR-NK cells for cancer immunotherapy: from bench to bedside. Biomark Res. 2022 Mar 18;10(1):12. doi: 10.1186/s40364-022-00364-6. PMID: 35303962; PMCID: PMC8932134.[3] Laskowski TJ, Biederstädt A, Rezvani K. Natural killer cells in antitumour adoptive cell immunotherapy. Nat Rev Cancer. 2022 Oct;22(10):557-575. doi: 10.1038/s41568-022-00491-0. Epub 2022 Jul 25. PMID: 35879429; PMCID: PMC9309992.