TLR3

导读：使用脂质纳米颗粒（LNP）递送mRNA是一项变革性技术，使全球数十亿剂COVID-19疫苗的快速开发和管理成为可能。然而，mRNA-LNP潜在的毒性风险包括IVT RNA的免疫原性、LNP脂质成分、工艺相关杂质等。如何避免mRNA药物和疫苗潜在的毒性仍是一种挑战。2024年1月，美国东北大学与mRNA领军企业Moderna、Intellia联合在Nature Reviews Drug Discovery（一区，影响因子120）发表重磅综述文章：《Strategies to reduce the risks of mRNA drug and vaccine toxicity》。该综述结合实际案例，探讨了mRNA-LNP的风险来源和降低毒性风险的有效策略，且覆盖了mRNA疫苗、mRNA蛋白替代疗法和基因编辑疗法等多领域。认知mRNA-LNP制剂的毒性风险是控制其风险的必需条件。本系列文章，菌菌将分期解析mRNA-LNP制剂的毒性风险来源和控制策略，包括IVT RNA免疫原性、LNP脂质毒性、以及如何借助下一代非临床模型研究mRNA毒理学。本篇我们将分享降低IVT RNA免疫原性的策略。01背景介绍与传统疫苗、药物开发相比，mRNA技术具有制备时间短，经简单序列变化实现应用多样性等优势。短期内针对新冠病毒原始毒株，以及联合变异株omicron B.1.1.529的二价疫苗的开发表明，mRNA技术在临床中的快速改进，且二价疫苗相较于原始菌株疫苗对omicron的中和抗体反应更强。几十款基于mRNA技术的预防性疫苗、治疗性疫苗、治疗性药物（蛋白替代疗法）和基因编辑疗法正在开展临床试验，用于呼吸道和潜伏病毒、癌症、自身免疫性疾病、基因缺陷等罕见病等。这里写个题外话，作者单位之二的Moderna和Intellia是mRNA行业的领军型企业，因此这篇文章的实用性很强。其中Moderna是mRNA疫苗的龙头企业，新冠疫苗mRNA-1273的快速获批使其名声大震，Moderna在研的mRNA管线还包括mRNA流感疫苗、mRNA呼吸道合胞病毒（RSV）疫苗、mRNA巨细胞病毒（CMV）疫苗、mRNA肿瘤治疗性疫苗和罕见病蛋白替代疗法等。而Intellia专注于以mRNA为基础的CRISPR体内基因编辑技术，通过LNP将Cas9 mRNA和向导RNA（gRNA）递送至体内，发挥靶基因编辑效应。Intellia的代表性管线包括NTLA-2001、NTLA-2002等，其中NTLA-2001特异性敲除人转甲状腺素蛋白（TTR）基因，目前处于后期临床阶段。02IVT mRNA 免疫原性确定蛋白质靶标后，其mRNA序列通过体外转录（IVT）合成：线性质粒DNA与核糖核苷酸通过噬菌体RNA聚合酶结合合成RNA，但未经修饰的IVT mRNA存在异常免疫原性和低效的细胞内递送。2.1 IVT mRNA免疫原性来源未修饰的IVT mRNA可能含有双链区域（如发夹结构），该区域可结合并调节TLR3的表达，激活NF-κB，增加树突状细胞（DCs）内TNFmRNA水平和IL-8分泌（HEK293细胞）。IVT mRNA激活DCs中的干扰素调节因子1（IRF1），并增加IL-1受体相关激酶M（IRAK-M或IRAK3）的mRNA水平。未修饰的IVT mRNA也可触发TLR7或TLR8并产生促炎细胞因子。从未修饰IVT mRNA的无启动子末端转录产生互补的反义RNA；产生的dsRNA刺激MDA5（胞质PRR），上调IFNβ。图1 对未修饰的IVT mRNA的先天免疫应答2.2 消除IVT mRNA的免疫原性降低IVT RNA的异常免疫原性对于其临床转化是必需的，目前的策略如下：（1）核苷甲基化和假尿苷掺入：可抑制IVT ssRNA的先天免疫识别，如ssRNA含假尿苷、N6-甲基腺苷、5-甲基胞苷或2-硫代尿苷时，DCs的TNF或IL-12分泌减少。（2）dsRNA去除：有报道显示，改造筛选的T7 RNA聚合酶突变体可减少IVT mRNA中的dsRNA，抑制体外免疫刺激。通过层析纯化去除IVT mRNA中的dsRNA，可抑制其免疫原性，提高安全性和蛋白翻译效率。耀海生物自主开发了mRNA层析纯化工艺，能够有效去除dsRNA至0.06%以下(ELISA方法)。详情可咨询菌菌：13380332910（微信同号）（3）其他修饰：在模板编码3′poly（A）的尾部添加120-150个腺嘌呤，促进翻译的启动并增强mRNA稳定性；与假尿苷相比，N1-甲基假尿苷（1mψ）增强转染效率并降低免疫原性，且经纤维素纯化后的dsRNA残留水平与RP-HPLC相当。（4）环状mRNA可延长细胞内半衰期。与线性mRNA相比，circRNA具有更好的稳定性和更低的免疫原性，并且可能改善药代动力学。目前circRNA面临解决的问题是环化率的提升与nicked RNA的去除。03总结今天的文章，菌菌汇总了mRNA毒性风险的来源和消除措施。简而言之，mRNA的免疫原性来源主要为mRNA自身的免疫原性、以及IVT RNA合成过程中产生的副产物dsRNA。其改善策略包括：核苷酸修饰、筛选T7 RNA聚合酶或优化IVT体系降低dsRNA的生成、利用层析等方法有效去除dsRNA等。参考文献 [1] Bitounis D, Jacquinet E, Rogers MA, Amiji MM. Strategies to reduce the risks of mRNA drug and vaccine toxicity. Nat Rev Drug Discov. 2024 Jan 23. doi: 10.1038/s41573-023-00859-3. 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。

SOUTH SAN FRANCISCO, Calif., March 27, 2024 (GLOBE NEWSWIRE) -- Vaxart, Inc. (Nasdaq: VXRT) today announced that Dr. Sean Tucker, Founder and Chief Scientific Officer, will present at the World Vaccine Congress Washington 2024 in Washington, D.C. on Wednesday, April 3, 2024. The Company has appeared repeatedly at the annual event in Washington, D.C. Presentation Information: Title: Moving the needle: Blocking transmission and boosting existing vaccines by oral tablet vaccinationSpeaker: Dr. Sean TuckerDate: Wednesday, April 3, 2024 Time: 3:10 p.m. ETRoom: 207A About VaxartVaxart is a clinical-stage biotechnology company developing a range of oral recombinant vaccines based on its proprietary delivery platform. Vaxart vaccines are designed to be administered using pills that can be stored and shipped without refrigeration and eliminate the risk of needle-stick injury. Vaxart believes that its proprietary pill vaccine delivery platform is suitable to deliver recombinant vaccines, positioning the company to develop oral versions of currently marketed vaccines and to design recombinant vaccines for new indications. Vaxart’s development programs currently include pill vaccines designed to protect against coronavirus, norovirus, and influenza, as well as a therapeutic vaccine for human papillomavirus (HPV), Vaxart’s first immune-oncology indication. Vaxart has filed broad domestic and international patent applications covering its proprietary technology and creations for oral vaccination using adenovirus and TLR3 agonists. Contacts  Vaxart Media Relations:Investor Relations:Mark HerrAndrew BlazierVaxart, Inc.FINN Partnersmherr@vaxart.comIR@Vaxart.com(203) 517-8957(646) 871-8486

SOUTH SAN FRANCISCO, Calif., March 20, 2024 (GLOBE NEWSWIRE) -- Vaxart, Inc. (Nasdaq: VXRT) (the “Company” or “Vaxart”) today announced that the Compensation Committee of the Board of Directors approved certain equity awards to the Company’s new President and Chief Executive Officer, Steven Lo, effective March 18, 2024. The awards were made pursuant to the Company’s previously disclosed offer letter with Mr. Lo, and as a material inducement to his joining the Company as President and Chief Executive Officer and a member of the Board of Directors. The awards made to Mr. Lo are as follows: (i) an option to purchase 1,000,000 shares of Vaxart’s common stock, which vests as to 1/4th of the total shares on the one-year anniversary of his start date, and as to 1/48th of the total shares on each month thereafter, and has a per share exercise price equal to the closing price of Vaxart’s common stock on the grant date; and (ii) a restricted stock unit award covering 250,000 shares of Vaxart’s common stock, which vests as to 25% of the shares underlying the award on the first, second, third and fourth anniversary of his start date. The awards were granted under the Vaxart, Inc. 2024 Inducement Award Plan as an employment “inducement award” pursuant to Nasdaq Listing Rule 5635(c)(4). The Inducement Plan is used exclusively for the grant of equity awards to individuals who were not previously employees of Vaxart (or following a bona fide period of non-employment) as an inducement material to entering into employment with Vaxart. About Vaxart Vaxart is a clinical-stage biotechnology company developing a range of oral recombinant vaccines based on its proprietary delivery platform. Vaxart vaccines are designed to be administered using pills that can be stored and shipped without refrigeration and to eliminate the risk of needle-stick injury. Vaxart believes that its proprietary pill vaccine delivery platform is suitable to deliver recombinant vaccines, positioning the company to develop oral versions of currently marketed vaccines and to design recombinant vaccines for new indications. Vaxart’s development programs currently include pill vaccines designed to protect against coronavirus, norovirus and influenza, as well as a therapeutic vaccine for human papillomavirus (HPV), Vaxart’s first immune-oncology indication. Vaxart has filed broad domestic and international patent applications covering its proprietary technology and creations for oral vaccination using adenovirus and TLR3 agonists. Note Regarding Forward-Looking Statements This press release contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, included in this press release regarding Vaxart’s strategy, prospects, plans and objectives, results from preclinical and clinical trials and the timing of such results, and beliefs and expectations of management are forward-looking statements. These forward-looking statements may be accompanied by such words as “should,” “believe,” “could,” “potential,” “will,” “expected,” “anticipate,” “plan,” and other words and terms of similar meaning. Examples of such statements include, but are not limited to, statements relating to Vaxart’s expectations with respect to the management transition; Vaxart’s ability to develop and commercialize its product candidates, including its vaccine booster products; Vaxart’s expectations regarding clinical results and trial data, and the timing of receiving and reporting such clinical results and trial data; and Vaxart’s expectations with respect to the effectiveness of its product candidates. Vaxart may not actually achieve the plans, carry out the intentions, or meet the expectations or projections disclosed in the forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions, expectations, and projections disclosed in the forward-looking statements. Various important factors could cause actual results or events to differ materially from the forward-looking statements that Vaxart makes, including uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement, and/or completion dates for clinical trials, regulatory submission dates, regulatory approval dates, and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from the clinical studies; decisions by regulatory authorities impacting labeling, manufacturing processes, and safety that could affect the availability or commercial potential of any product candidate, including the possibility that Vaxart’s product candidates may not be approved by the FDA or non-U.S. regulatory authorities; that, even if approved by the FDA or non-U.S. regulatory authorities, Vaxart’s product candidates may not achieve broad market acceptance; that a Vaxart collaborator may not attain development and commercial milestones; that Vaxart or its partners may experience manufacturing issues and delays due to events within, or outside of, Vaxart’s or its partners’ control; difficulties in production, particularly in scaling up initial production, including difficulties with production costs and yields, quality control, including stability of the product candidate and quality assurance testing, shortages of qualified personnel or key raw materials, and compliance with strictly enforced federal, state, and foreign regulations; that Vaxart may not be able to obtain, maintain, and enforce necessary patent and other intellectual property protection; that Vaxart’s capital resources may be inadequate; Vaxart’s ability to resolve pending legal matters; Vaxart’s ability to obtain sufficient capital to fund its operations on terms acceptable to Vaxart, if at all; the impact of government healthcare proposals and policies; competitive factors; and other risks described in the “Risk Factors” sections of Vaxart’s Quarterly and Annual Reports filed with the SEC. Vaxart does not assume any obligation to update any forward-looking statements, except as required by law. Contacts VaxartMedia Relations: Mark Herr Vaxart, Inc. mherr@vaxart.com (203) 517-8957 Investor Relations: Andrew Blazier FINN Partners IR@vaxart.com (646) 871-8486