CFLAR

最近备受科学家关注的是一种叫做JN.1 的SARS-CoV-2 新亚型，其进化来自于Omicron BA.2.86。BA.2.86毒株于 2023 年 7 月下旬在以色列和丹麦被首次发现，当时已经蔓延到全球各地，包括中国。相对于初始的Omicron亚型BA.2而言，BA.2.86有超过30个突变；而对照从年初到9月份占主流的XBB.1.5，也有35个突变。所以，人们担心一个比Omicron更能免疫逃避的毒株可能会使全球再次陷入2022年初的新冠全球爆发流行时期， 但庆幸的是，这种担心没有发生。为什么？研究 BA.2.86的生物学特性和免疫逃逸特性意义重大。2024年1月8日，俄亥俄州立大学刘善虑教授团队在Cell杂志上发表了题为Immune Evasion, Infectivity, and Fusogenicity of SARS-CoV-2 BA.2.86 and FLip Variants的研究论文，对以上问题进行了系统研究。该团队同时也研究了FLip 突变株；FLip来源于XBB.1.5, 但其刺突蛋白基因含有额外的两个非常有趣的L455F和F456L互换突变，比XBB1.5更能逃避中和抗体。该团队首先发现BA.2.86在感染性方面与之前的Omicron流行株明显不同: 在293T-ACE2细胞里，BA.2.86病毒滴度比所有 Omicron 变体（包括 XBB.1.5 和EG.5.1）低 1.8~2.1 倍，而在人的肺衍生的上皮CaLu-3细胞里， BA.2.86的病毒滴度比所有的Omicron都高， 比XBB.1.5、EG.5.1和FLip增加了1.9~2.8倍， 但还是大大低于D614G。该结果提示与其他Omicron相比，BA.2.86有可能 增加感染人肺上皮细胞毒力。有趣的是，作者通过细胞与细胞间融合实验还发现BA.2.86刺突蛋白在 293T-ACE2 细胞中具有低融合性，而在 CaLu-3 细胞中的膜融合性比其他任何Omicron 毒株包括XBB.1.5都明显增强。在免疫逃逸方面，研究者首先检测了14名接种过至少两剂单价mRNA疫苗和一剂双价mRNA加强针的健康医护工作者的血清对于D614G和包括BA.2.86在内的Omicron亚型的中和效果。作者吃惊地发现，尽管BA.2.86的中和抗体效价低于D614G 12.8倍和低于BA.2 约11.7倍， 但比近期流行的 XBB系列边变异株XBB.1.5、EG.5.1 和 FLip高出1.7～5.5倍 。该结果显示，相比XBB突变株， BA.2.86对于接种二价疫苗健康医护工作者的血清更敏感，而 FLip在这一队列的血清抗性最强。该结果与David Ho（Wang, Q., et al. Nature，2023），Dan Barouch (Lasrado, N. et al. Vaccine，2023) 和Xuping Xie/Ping Ren (Hu, Y., et al. Emerging Microbes & Infections (2023)) 的研究一致，也解释了为何BA.2.86没有像原始Omicron 那样引起全球大流行。作者还检测了15名接种过三剂单价mRNA疫苗的健康医护工作者的血清对于这些病毒的中和能力，显示BA.2.86 ，FLip 和其它XBB.1.5变异株几乎完全逃逸中和抗体。作者接着调查了BA.2.86和FLip对于XBB.1.5流行期间感染的11名患者的中和抗体抗性。结果显示， XBB.1.5感染诱导产生的中和抗体对 BA.2.86 和 FLip 几乎没有中和作用；但与XBB 突变株相比，BA.2.86 还是表现出了较低程度的免疫逃避。出乎意料的是，作者发现一种原来对所有Omicron亚型， 包括XBB.1.5，EG.5.1和FLip变异株，都有效的单克隆抗体S309对BA.2.86没有效果， 即在最高剂量12 g/ml的浓度下也不能中和BA.2.86。结构模拟显示，这可能是由于D339H 在BA.2.86上的突变导致。综上所述，该研究发现新近出现的Omicron变异株BA.2.86 和FLip在生物学和免疫逃避上有很大的区别。与 FLip 和其他 XBB 突变体相比，BA.2.86 的免疫逃避程度较低，与抗原距离结果一致：BA.2.86 在抗原性上与早期 Omicron 变体 BA.1、BA.2 和 BA.4/5 更为相似，而与 FLip 明显不同。重要也需要警惕的是，BA.2.86在人肺上皮传代细胞系的感染性和膜融合性比目前已知的Omicron都高。但是，这是否预示着新毒株在嗜肺性和毒力上增强，还有待于进一步研究。值得一提的是，该感染性和融合性的结果与同天Cell发表的来自德国一家实验室的结果一致。俄亥俄州立大学刘善虑教授团队博士研究生屈攀科（Panke Qu）是文章的第一作者，刘善虑教授是通讯作者。该研究得到了俄亥俄州立大学Richard J. Gumina等教授的大力合作和支持。原文链接：https://www.cell.com/cell/fulltext/S0092-8674(23)01400-9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。

8月17日，中国科学院上海免疫与感染研究所孟广勋组在学术期刊Cellular & Molecular Immunology在线发表了研究论文“cFLIPs regulates alternative NLRP3 inflammasome activation in human monocytes”。生理性炎症对机体免疫至关重要，但不受控制的炎症可能导致组织损伤和自身免疫性疾病。适当程度的免疫反应是宿主对微生物感染做出反应所必需的。负调控机制的存在可以避免过度的炎症反应对组织和整个机体造成不可逆转的损害。虽然目前对于经典型（Canonical）和非经典型（Non-canonical）NLRP3炎症小体激活的负调控机制已经有了较多的研究，但人单核细胞中非传统型（Alternative）NLRP3炎症小体激活强度的调控机制还没有报道。在LPS的作用下，人单核细胞通过TLR4-TRIF-caspase-8通路介导下游非传统型NLRP3炎症小体的激活。在本研究中，研究者发现非传统型NLRP3炎症小体的激活强度在几小时内就会达到最大值，后续阶段维持不变。在机制上，灭活革兰氏阴性菌刺激诱导单核细胞NF-kB通路的激活，这使细胞caspase-8样抑制蛋白（cFLIP）表达上调。上调的短亚型cFLIP (cFLIPs) 通过靶向caspase-8，并抑制caspase-8持续切割，从而阻止了下游NLRP3炎症小体的过度活化。实验数据表明，cFLIP编码基因（cFLAR）的缺失会导致过度炎症反应的发生。因此，cFLIPs的表达上调是人单核细胞维持非传统型NLRP3炎症小体有限性激活不可或缺的分子事件之一。图例 cFLIPs负调控单核细胞中非传统型（Alternative）炎症小体激活原文链接：https://pubmed.ncbi.nlm.nih.gov/37591930/ 会议推荐会议详情会议名称：2023（第14届）细胞与基因治疗研讨会暨抗体工程与创新免疫治疗技术论坛主办单位：生物谷、梅斯医学、同济大学附属同济医院、南京可缘大会时间：9月22-23日大会地点：上海 大会规模：1500人2010年至今，生物谷联合各合作单位已经顺利召开了13届细胞与基因治疗研讨会，与全球致力于细胞治疗行业同仁们一同成长沉淀，在提供行业信息交流平台的同时，也为基础研究提供了技术/产品等产业化的孵化平台。基于此，本届会议将继续以转化医学为切入点，以基础研究与临床应用相结合，针对细胞治疗的临床前沿研究、临床监管、治疗规范、细胞治疗安全性，免疫细胞新型疗法、实体瘤治疗、干细胞与癌症、抗体药物、核酸药物、基因编辑、肿瘤免疫治疗等热门议题进行讨论，诚邀国内外产学研医专家共聚，共绘产业发展新蓝图！长按识别二维码立即报名参会

bbT369, a dual-targeted (CD79a/CD20) and CBLB gene edited autologous CAR T for non-Hodgkin lymphoma, showed edit-driven enhanced T cell activity in multiple preclinical models RESET, a novel TCR coupled antigen receptor architecture, displayed markedly increased targeting sensitivity and pharmacologically controlled anti-tumor activity A novel TGFβ switch receptor drove enhanced MAGE-A4 TCR anti-tumor activity with a favorable safety pro > CAMBRIDGE, Mass.--(BUSINESS WIRE)-- 2seventy bio, Inc. (Nasdaq: TSVT), a leading immuno-oncology cell therapy company, today announced new data featuring novel approaches combining the company’s platform CAR T cell and T cell receptor technology and unique cell therapy engineering capabilities to potentially enhance treatment potency in a range of cancers. The data were shared in three presentations at this year’s American Society of Gene & Cell Therapy (ASGCT) Annual Meeting in Los Angeles, California. “We’re excited to present new data related to our programs in acute myeloid leukemia, non-Hodgkin lymphoma and solid tumors,” said Philip Gregory, D.Phil., chief scientific officer, 2seventy bio. “These presentations provide further evidence of our focus on generating potent and targeted anti-tumor activity while limiting toxicity through innovative approaches to controlling T cell responses. With this approach, we believe we can augment the tremendous potential of cell-based immunotherapy, with the goal of advancing next-generation treatments targeting a broad range of cancer types.” bbT369, a dual-targeted and CBLB gene edited autologous CAR T product for non-Hodgkin lymphoma, showed edit-driven enhanced activity in preclinical in vitro and in vivo models bbT369 is 2seventy’s novel investigational CD79a/CD20 dual-targeting CBLB gene edited CAR T cell therapy for the treatment of patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). This preclinical study evaluated the role of the CBLB edit across multiple aspects of CAR T cell function compared to unedited controls. In the study, in vitro assays were designed to model known challenges to maximal CAR T cell activity within the tumor, such as chronic activation, antigen downregulation, and immunosuppression. The data demonstrated that the CBLB gene edit significantly enhanced the activity of the bbT369 CAR T cells across each of the in vitro model systems tested. bbT369 T cells also drove greater T cell expansion and durable tumor control compared with unedited controls in vivo using a xenograft NSG mouse model. RESET, a novel TCR coupled antigen receptor architecture, showed targeting sensitivity and pharmacologically- controlled anti-tumor activity in models of acute myeloid leukemia For some tumors, available target antigens lack ideal expression, necessitating improvements in targeting sensitivity, potency, control, and/or exhaustion mitigation to achieve robust anti-tumor efficacy. While classical CAR T cells require high levels of target antigen for maximum activity, the endogenous T cell receptor (TCR) is significantly more sensitive to low target antigen abundance. To address this gap, a novel receptor architecture called RESET (rapamycin-enabled, switchable endogenous TCR) was developed to more closely mimic TCR activation, thus potentially improving T cell killing of low antigen expression tumor cells. RESET combines the antibody-based targeting of CARs, the drug-regulated activity of the DARIC (a rapamycin-regulated CAR) technology and the natural signaling proficiency and inherent sensitivity of TCRs. The RESET receptor comprises two functional units that are designed to enable toggling of RESET T cells between inert and activated states through rapamycin-induced dimerization: When challenged with low antigen density tumor cells in vitro, CD33-targeted RESET T cells (RESET33) were more potently reactive to CD33+ tumor cells after rapamycin dimerization, secreting approximately three times more cytokine than CD33-targeted regulated CAR T cells. This enhancement was also observed in preclinical NSG mouse models in vivo, where RESET33 T cells more deeply controlled systemic CD33+ AML tumor models, providing a significant survival benefit in comparison to DARIC33 T cells. A novel TGFβ switch receptor drove robust MAGE-A4 TCR anti-tumor activity with a favorable safety pro > Solid tumors frequently secrete TGFβ, a pleiotropic cytokine that suppresses T cell responses. To counteract the immunosuppressive effects of TGFβ within engineered T cells, a synthetic receptor (CTBR12) was developed to leverage an immunosuppressive cytokine to convert TGFβ binding into pro-inflammatory signaling events that enhance anti-tumor function: T cells co-expressing a pairing enhanced MAGE-A4 TCR with the CTBR12 switch receptor demonstrated robust antigen-dependent responses that were significantly enhanced upon exposure to TGFβ, whereas MAGE-A4 TCR controls lacking CTBR12 were suppressed by this anti-inflammatory cytokine. CTBR12 co-expression did not alter the safety pro the MAGE-A4 TCR. In two murine xenograft tumor models with abundant TGFβ, T cells co-expressing the MAGE-A4 TCR and CTBR12 both controlled tumors at T cell doses that elicited only minimal responses without CTBR12 co-expression and exhibited superior durability of response overall. About SC-DARIC33 SC-DARIC33 is an investigational CD33-specific cell therapy that utilizes 2seventy bio’s proprietary Dimerizing Agent Regulated Immunoreceptor Complex (DARIC) T cell platform. SC-DARIC33 is designed as a regulatable, potentially first-in-class autologous T cell therapy and is now being studied at Seattle Children’s in a Phase 1 trial, PLAT-08 (NCT05105152), as a first-in-human investigation of the DARIC T cell platform in relapsed/refractory pediatric and young adult AML. DARIC separates the antigen binding and signaling functions of a CAR, with the intent that these two components are brought together by the small molecule rapamycin, resulting in a functional CAR construct. In preclinical studies, SC-DARIC33 has shown robust drug-dependent anti-tumor activity (similar to CD19 CAR T controls). Importantly, SC-DARIC33 has been shown to be activated by low non-immunosuppressive concentrations of rapamycin in the blood and, when rapamycin is removed, DARIC returns to an inactive state. SC-DARIC33 tests the hypothesis that a pharmacologically regulated CAR can enable potent AML targeting while limiting toxicities associated with normal myeloid and myeloid progenitor cell targeting. The investigation of SC-DARIC33 in the Phase 1 PLAT-08 study of pediatric and young adult AML patients and the scientific translation of these data are intended to establish the safety pro SC-DARIC33 and evaluate feasibility of the reversable modulation (OFF-ON-OFF) of SC-DARIC33. SC-DARIC33 is not approved for any indication in any geography. About bbT369 bbT369 is an investigational dual-targeting CAR T cell therapy with a gene edit being evaluated for the treatment of patients with relapsed and/or refractory B-NHL currently being evaluated in a first-in-human Phase 1/2 trial (CRC-403 NCT05169489). bbT369 was purposely designed with three layers of innovation to address the potential mechanisms of anti-CD19 CAR T cell therapy failure, including dual targeting of CD79a/CD20, which is a novel combination of antigens highly expressed in B cell lymphomas, a split co-stimulation signaling technology intended to drive more robust T cell activation, and a gene edit to remove the function of CBLB, a known negative regulator of T cells. In the 3L+ relapsed and/or refractory B-NHL setting, 60-70% of patients treated with commercially available CAR T cell therapies do not achieve a long-term remission, highlighting a significant unmet clinical need. In December 2021, the FDA cleared the Investigational New Drug (IND) application for bbT369. The clinical development program for bbT369 includes the Phase 1/2 CRC-403 study (NCT05169489). Safety and potential efficacy of bbT369 in patients with specific subtypes of relapsed and/or refractory B-NHL will be assessed, including patients who relapsed after CD19 CAR T cell therapy as well as patients who are CAR-naïve. bbT369 is not approved for any indication in any geography. About the MAGE-A4 Program MAGE-A4 is a member of the MAGE family of cancer-testis antigens expressed in a number of solid tumor types. The program employs a highly potent TCR discovered in our MediGene collaboration that recognizes HLA-presented MAGE-A4 peptides and further enhances the potency of these re-directed T cells using our CTBR12 TGFβ “flip” receptor technology -- which converts the immunosuppressive effects of TGFβ into an activation signal for the T cells. Regeneron and 2seventy bio are co-developing the program under their collaboration entered into in 2018. About 2seventy bio Our name, 2seventy bio, reflects why we do what we do - TIME. Cancer rips time away, and our goal is to work at the maximum speed of translating human thought into action – 270 miles per hour – to give the people we serve more time. We are building the leading immuno-oncology cell therapy company, focused on discovering and developing new therapies that truly disrupt the cancer treatment landscape. With a deep understanding of the human body’s immune response to tumor cells and how to translate cell therapies into practice, we’re applying this knowledge to deliver next generation cellular therapies that focus on a broad range of hematologic malignancies, including the first FDA-approved CAR T cell therapy for multiple myeloma, as well as solid tumors. Our research and development is focused on delivering therapies that are designed with the goal to “think” smarter and faster than the disease. Importantly, we remain focused on accomplishing these goals by staying genuine and authentic to our “why” and keeping our people and culture top of mind every day. For more information, visit . Follow 2seventy bio on social media: Twitter and LinkedIn. 2seventy bio is a trademark of 2seventy bio, Inc. Cautionary Note Regarding Forward-Looking Statements of 2seventy bio This release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to: statements about our plans, strategies, timelines and expectations with respect to the research, development, manufacture or sale of our product candidates, including the results of ongoing and planned pre-clinical studies and clinical trials; statements about the efficacy and perceived therapeutic benefits of our product candidates and the potential indications, market opportunities and demand therefor; statements about the strategic plans for 2seventy bio and potential corporate development opportunities; and statements about our ability to execute our strategic priorities. 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Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect 2seventy bio’s business, particularly those identified in the risk factors discussion in 2seventy bio’s Annual Report on Form 10-K, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, 2seventy bio undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.