Reactive amanitin for bioconjugation to antibodies**

用于与抗体生物缀合的反应性鹅膏蕈碱**

• 批准号: 536295-2018
• 负责人: Perrin, David
• 金额: $ 1.82万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Engage Grants Program
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=661987
• 关键词: Reactive; amanitin; bioconjugation; antibodies

This proposal addresses unmet needs in targeted therapy for cancer in collaboration with Iprogen, Inc. a biopharmaceutical company dedicated to the production of antibody-drug conjugates (ADCs). Iprogen is strategically positioned to create new targeted therapies from novel warheads. My lab is poised to provide Iprogen with new warheads based on amanitin. Targeted therapies for cancer represent a rapidly expanding class of anticancer agents that use a cancer-specific targeting agent (e.g. an antibody) to deliver a potent, but usually non-specific, cytotoxic agent to cancer cells. Antibodies or peptides alone are often ineffective but become effective against cancer when conjugated to a suitable toxin that otherwise would be too toxic. ADCs now offer definitive hope to cancer patients. Yet in terms of industrial translation, there is a significant unmet need for new toxic payloads that that can be targeted to cancer as well as a means of producing new ADCs for testing and clinical translation. ****My lab, which specializes in bioconjugation and natural product synthesis, has recently accomplished the first total synthesis of amanitin, a potent and validated payload toxin for ADC development. Iprogen, Inc. is an established biotechnology company in Richmond, B.C., with an interest in generating new antibody-drug conjugates for preclinical and clinical applications. This Engage Grant will forge a unique research synergy between my lab's research interest where we will develop new amanitin-based toxic payloads and Iprogen's commercial interests in applying these toxins to various therapeutic antibodies to create new IP based on their conjugation to diseased-mitigating antibodies. My lab will provide scientists at Iprogen with the needed payload toxins and novel linker-arm technologies. In turn, staff scientists at Iprogen will generate new ADCs and will test them in suitable toxicity assays**

该提案与Iprogen，Inc.合作解决了癌症靶向治疗中未满足的需求。一家生物制药公司，致力于生产抗体-药物偶联物（ADC）。Iprogen的战略定位是从新型弹头中创造新的靶向疗法。我的实验室准备为伊普罗金提供基于鹅膏蕈碱的新型弹头。癌症的靶向治疗代表了一类快速扩展的抗癌剂，其使用癌症特异性靶向剂（例如抗体）将有效但通常非特异性的细胞毒性剂递送至癌细胞。单独的抗体或肽通常是无效的，但当与合适的毒素缀合时，抗体或肽对癌症是有效的，否则毒素会毒性太大。ADC现在为癌症患者提供了明确的希望。然而，在工业转化方面，对于可以靶向癌症的新毒性有效载荷以及生产用于测试和临床转化的新ADC的方法存在显著未满足的需求。* 我的实验室专门从事生物缀合和天然产物合成，最近完成了鹅膏蕈碱的首次全合成，鹅膏蕈碱是一种有效且经验证的ADC开发有效载荷毒素。Iprogen，Inc.是一家位于不列颠哥伦比亚省里士满的老牌生物技术公司，对产生用于临床前和临床应用的新的抗体-药物缀合物感兴趣。这项参与补助金将在我的实验室的研究兴趣（我们将开发新的基于鹅膏蕈碱的有毒有效载荷）和Iprogen的商业利益（将这些毒素应用于各种治疗性抗体以基于其与疾病缓解抗体的结合来创建新的IP）之间形成独特的研究协同作用。我的实验室将为Iprogen的科学家提供所需的有效载荷毒素和新型连接臂技术。反过来，Iprogen的科学家将产生新的ADC，并将在合适的毒性试验中对其进行测试 **