IRG1

HANGZHOU, China, Dec. 20, 2023 /PRNewswire/ -- Recently, a CAR-macrophage therapy product (CAR-M) SY001 from CellOrigin Biotechnology (Hangzhou) Co., Ltd. was dosed to the first patient in a hospital in China. "A single center, single-arm, dose-escalation, exploratory clinical trial to examine the safety, tolerability, pharmacokinetics and preliminary efficacy of SY001 from CellOrigin Biotechnology in patients with advanced solid tumors" is the first investigator-initiated clinical study of CAR-M cell therapy product in China. The successful completion of the first patient dosing of SY001 demonstrates the advanced technology of the company's R&D platform and the maturity of the CMC platform. Currently, the clinical study is actively recruiting patients. SY001 was well tolerated and no dose-limiting toxicity (DLT) was observed (n=2). Only 2 grade 3 adverse events occurred; Common grade 1 - 2 adverse events included fever, elevated C-reactive protein, etc. No cytokine release syndrome or neurotoxicity related to cell infusion occurred in any patients. The clinical data of CAR-M products up to now suggest the excellent safety and certain clinical benefits of macrophage immunotherapy. CellOrigin expects that this innovative product will prove its safety and effectiveness in clinical trials, bringing new hope for the treatment of solid tumors, thereby improving patients' quality of life and prolonging their life span. Besides, in November 2023, CellOrigin collaborated with Zhejiang University to publish a paper entitled "A second generation M1-polarized CAR macrophage with antitumor efficacy" in Nature immunology, designing an exclusive CAR with antigen-dependent polarization and activation of macrophage function (TIR-CAR or M-CAR) by introducing the TIR signal transduction domain. Based on M-CAR, a functionally enhanced second generation CAR-iMAC has been developed to enhance the effectiveness of the therapy for solid tumors. The mechanism of antigen-dependent activation and polarization of the second generation CAR-iMAC and the mechanisms of solid tumor cell killing were also revealed. In November 2020, the team published a paper in J Hematol Oncol entitled "Pluripotent stem cell-derived CAR-macrophage cells with antigen-dependent anti-cancer cell functions." It opens the door for human iPSC-derived CAR-macrophage (CAR-iMAC) and its applications in targeted anti-tumor research. The first generation CAR-iMAC was designed, and was capable of carrying out the antigen-dependent killing of tumor cells. On September 11, 2023, the team collaborated with Dr. Wang Ben's Research Group of Zhejiang University to publish a paper entitled "Targeted glycan degradation potentials cellular immunotherapy for solid tumors" in Proceedings of the National Academy of Sciences (PNAS). The collaboration found that simultaneous deletion of sialidase-binding immune checkpoints Siglec-5 and Siglec-10 (DKO-CAR-iMac) on macrophages significantly enhanced CAR-iMAC's anti-solid tumor function. Almost the same time, the team published another paper entitled "Metabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophases in solid tumors" in Nature communications. A CRISPR Screen method was used to find the key metabolic genes related to CAR-iMAC polarization in tumor microenvironment. It was discovered that knockout of ACOD1 (or IRG1) could improve macrophage proinflammatory polarization, phagocytic capacity and tumor-killing activity. Furthermore, the study also found that the anti-tumor effect of ACOD1-/- MSLN-CAR-iMAC can be further enhanced by combining immune checkpoint inhibitors. These findings offer fresh concepts for remodeling macrophages based on metabolic reprogramming or editing the immune checkpoints. Based on these research results, CellOrigin is conducting a series of pre-clinical and clinical studies of CAR-macrophage therapies for solid tumors in an effort to provide patients with safe and effective treatment choices as soon as possible. About CellOrigin: CellOrigin is committed to the development and clinical translation of their proprietary CAR-expressing iPSC-derived immune cells such as CAR-iMAC. They have obtained engineered immune cells derived from iPSC using cutting-edge technologies including gene editing and synthetic biology. CellOrigin takes advantage of the unique characteristics of macrophages that can infiltrate the solid tumor microenvironment (TME), and is developing CAR-M products mainly for relapsed/refractory solid tumors. They have completed the establishment of a clinical-grade iPSC cell bank, independently developed the CMC process of CAR-iMAC cells that can be produced in large scale to meet the amount for off-the-shelf products, and established a complete GMP quality system and corresponding quality control methods. They are collaborating with domestic and international hospitals for clinical trials, and also seeking for opportunities of licensing of the technology platform and certain pipelines. For more information,please contact Yaoyao Li, [email protected]. SOURCE CellOrigin

转移是癌症死亡和发病的主要原因。免疫检查点阻断（ICB）药物atezolizumab和pembrolizumab联合化疗已被批准用于治疗PD-L1 转移是癌症死亡和发病的主要原因。免疫检查点阻断（ICB）药物atezolizumab和pembrolizumab联合化疗已被批准用于治疗PD-L1+转移性三阴乳腺癌（TNBC）患者。然而，免疫疗法耐药性仍然是一个巨大的挑战。 许多临床前研究支持TIN的促肿瘤和促转移功能，而TIN的抗肿瘤活性通常在早期疾病中发现。对于BC，富含TIN的肿瘤微环境（TME）对ICB具有耐药性。当与免疫疗法结合时，免疫抑制性TIN的耗竭或治疗靶向有望引发协同效应。尽管如此，中性粒细胞的治疗靶向必须解决选择性和安全性方面的挑战。 图片来源：https://doi.org/10.1016/j.cmet.2023.09.004 近日，来自美国圣母大学的研究者们在Cell Metab.杂志上发表了题为“Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1”的文章，该研究报道了附子酸脱羧酶1（Acod1）在肿瘤浸润性中性粒细胞（TINs）中的诱导及其在钝化脱铁性贫血和维持TINs生存能力中的关键作用。Acod1消融降低了TIN密度，抑制了乳腺癌症转移，增强了抗肿瘤T细胞免疫，并增强了免疫检查点阻断在小鼠中的抗转移效力。 转移导致乳腺癌相关死亡率。TINs引起免疫抑制并促进转移。TINs的治疗性衰弱可能会增强免疫治疗，但识别TINs中高表达和功能必需但在肿瘤外中性粒细胞中表达不足的治疗靶点仍然是一个挑战。 在这里，研究者使用单细胞RNA测序来比较小鼠乳腺肿瘤模型中的TINs和循环中性粒细胞，确定Acod1是小鼠TINs中最上调的代谢酶，并验证了Acod1在人类TINs中的高表达。Acod1通过GM-CSF-JAK/STAT5-C/EBPb途径激活，产生衣康酸盐，介导Nrf2依赖性防御脱铁性贫血，并维持TIN的持久性。 Acod1消融可减少TIN浸润，抑制转移（但不是原发性肿瘤），增强抗肿瘤T细胞免疫力，并提高免疫检查点阻断的疗效。该研究结果揭示了TIN如何通过Acod1依赖性免疫代谢转换从脱铁性贫血中逃逸，并将Acod1确立为抵消免疫抑制和改善免疫治疗以对抗转移的靶点。 中性粒细胞通过附子酸脱羧酶1抗脱铁作用促进乳腺癌症转移 图片来源：https://doi.org/10.1016/j.cmet.2023.09.004 综上所述， FIN和ICB结合具有协同抗肿瘤活性，并将脱铁性贫血识别为一种免疫原性细胞死亡形式，尽管如此，诱导脱铁性贫血的具体治疗靶点仍应仔细考虑。（生物谷 Bioon.com） 参考文献 Yun Zhao et al. Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab. 2023 Oct 3;35(10):1688-1703.e10. doi: 10.1016/j.cmet.2023.09.004.

导读：肝癌的发生是由反复的肝细胞死亡和肝损伤引发的，介导细胞死亡和随后的癌变的潜在机制仍有待充分研究。免疫应答基因1 (IRG1)及其酶促代谢物衣康酸(itaconate)已知可抑制髓细胞炎症，目前正在确定其在肝实质肝细胞中的表达。然而，IRG1在肝癌发生中的潜在作用仍然未知。9月22日，海军军医大学侯晋及曹雪涛共同通讯在《Cell Death & Disease》在线发表题为“Mitochondrial IRG1 traps MCL-1 to induce hepatocyte apoptosis and promote carcinogenesis”的研究论文，研究发现可诱导线粒体IRG1促进肝细胞凋亡和随后的肝癌发生，这为预防肝损伤和HCC提供了机制见解和潜在靶点。https://www.nature.com/articles/s41419-023-06155-7#Sec8研究背景 01 肝细胞癌（HCC）是最普遍的原发性肝恶性肿瘤，发病率和死亡率都在增加。乙型或丙型肝炎病毒感染、代谢性脂肪肝、黄曲霉毒素B1暴露和过量饮酒是HCC癌变的主要危险因素。HCC的病理生理学由多步骤过程组成，积累的证据支持细胞死亡与肝癌发生之间有着千丝万缕的联系。在健康的肝脏中，大多数肝细胞处于静息期，没有明显的细胞死亡。这种静息状态可能被病毒、代谢、毒性或免疫损伤破坏，从而诱导肝细胞死亡。反复的肝细胞死亡导致剩余肝细胞的代偿性增殖，最终可能引发肝癌发生。。因此，过度的肝细胞死亡被认为是急性和慢性肝病的关键驱动因素，也是疾病结局的重要决定因素。因此，细胞死亡、肝损伤和随后的肝癌发生的机制需要进一步深入研究。为了研究IRG1在肝癌发生中的潜在作用，我们采用化学致癌物二乙基亚硝胺（DEN）诱导的HCC小鼠模型，发现DEN给药显著增强了肝细胞中IRG1的表达，肝IRG1的敲除显著抑制了DEN诱导的HCC，表明IRG1在肝癌发生中的潜在肿瘤促进作用。因此，本研究重点探讨了肝IRG1在肝细胞癌致癌中的作用及其机制，以期为预防肝细胞癌提供机制见解和潜在靶点。研究进展 02 为了研究IRG1在肝癌发生中的潜在作用，我们使用DEN诱导的HCC小鼠模型，并检查了化学致癌物DEN给药时IRG1的表达。DEN在肝脏中mRNA和蛋白质水平上显著增强IRG1表达，在注射后约48小时达到峰值，表明DEN诱导的IRG1处于肝损伤期（图1A，B）。分离原代肝细胞，测定DEN诱导的肝实质细胞IRG1表达（图1C）。此外，使用肝毒性对乙酰氨基酚（APAP），经肝细胞色素P450系统代谢为DEN引起肝损伤，我们发现肝损伤期间肝脏IRG1表达也显著增强。因此，这些数据确定了DEN诱导的肝损伤期间增强的肝IRG1表达，并暗示IRG1在肝癌发生中的潜在作用。肝细胞中DEN诱导的IRG1促进肝癌发生然后，我们构建了肝细胞特异性IRG1敲除（Irg1hep-/-）小鼠，并确认了分离的原代肝细胞中耗尽的IRG1表达。使用DEN诱导的肝癌发生小鼠模型，我们发现DEN诱导的HCC被肝细胞特异性IRG1缺乏症显著抑制（图1D，E）。此外，使用STAM肝癌发生模型与链脲佐菌素和高脂肪饮食，这是现有肝癌发生小鼠模型中分子与人HCC最相似的，诱导的HCC在Irg1hep-/-小鼠中也受到显著抑制（图1F，G），并且在STAM诱导过程中肝脏Irg1表达增加。结合肝损伤期间增强的IRG1，我们确定诱导的肝IRG1表达促进了肝癌发生。研究结果 03 在与我们的发现相容的最简单的模型中，我们提出肝细胞中的IRG1表达在肝损伤期间显着增加，并且诱导的IRG1促进肝细胞的凋亡和随后的肝癌发生。在机制上，诱导线粒体IRG1捕获抗凋亡MCL-1以抑制MCL-1与促凋亡Bim之间的相互作用，进而促进Bim的激活和下游Bax的线粒体易位，从而释放细胞色素c以启动内在线粒体凋亡（图7）。总之，我们发现肝损伤期间线粒体中诱导的IRG1是促进肝细胞凋亡和随后肝癌发生的重要机制。化学致癌物诱导线粒体IRG1促进肝细胞凋亡及后续肝癌发生的工作模型。DEN诱导的线粒体IRG1捕获抗凋亡MCL-1以抑制MCL-1与促凋亡Bim之间的相互作用，进而促进Bim的激活和下游Bax的线粒体易位，从而释放细胞色素c以启动内在线粒体凋亡和随后的肝癌发生。参考资料：https://www.nature.com/articles/s41419-023-06155-7#Sec8抗体行业在过去几十年中经历了快速而显著的发展，成为生物医药领域中一个快速发展且备受关注的领域。自20世纪80年代第一种单克隆抗体药物（Muromonab-CD3）获得批准以来，许多抗体药物已经被批准用于各种疾病的治疗，包括肿瘤、免疫性疾病和感染性疾病等。市场上已经有数十种成功抗体药物，并且在临床开发和研究中有更多的候选药物，预计未来将有更多新药上市。如今，除了传统的单克隆抗体，越来越多的新型抗体技术被陆续开发出来，包括双特异性抗体、多克隆抗体、人源化抗体、重组抗体、抗体偶联药物等。这些新技术使得抗体药物具有更高的特异性、亲和力、稳定性和生产可行性，拓宽了抗体的应用范围。今年是COVID-19大流行趋于稳定后的第一年，人民生活逐渐走向正轨，经济也在缓慢但有力的复苏之中，而各抗体企业也依然在不断奋进、不断突破、不断超越，使抗体领域蓬勃发展，硕果累累。为促进抗体行业的交流与创新，2023年10月14-15日第六届金秋十月抗体产业发展大会如约而至。会议旨在为研究人员提供一个互动交流的平台，有助于推动抗体产业的进一步发展。会议内容时间：2023年10月14-15日地点：苏州（酒店定向通知）规模：600-800人主办单位：生物制品圈、抗体圈指导单位：康维讯生物、夏尔巴生物会议费用：免费FREE!（仅收取50元报名定金，含参会学习、茶歇、会议手册，定金概不退还），9月15日报名定金提高到100元，先到先得，报完即止，超过9月20日预登记将收取会议费！报名方式：扫描下方二维码或点击文章最底部“阅读原文”→ 填写表格 → 报名成功（报名志愿者，承担一定工作，请慎重考虑，免交定金）！组委会获得报名信息后，根据报名信息进行初筛，并进一步与报名者沟通确认，实现精准邀请。最终有机会进入大会微信群（严格审核通过）。日程安排更多嘉宾仍在邀请中。。。。。。识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。