Reactive amanitin for bioconjugation to antibodies**

这项建议与一家致力于生产抗体-药物结合物(ADC)的生物制药公司Iprogen，Inc.合作，解决了癌症靶向治疗中未得到满足的需求。Iprogen在战略上处于有利地位，可以利用新型弹头创造新的靶向疗法。我的实验室准备为依普罗根提供基于阿马尼丁的新型弹头。针对癌症的靶向治疗代表了一类迅速扩大的抗癌药物，它们使用癌症特异性靶向剂(例如抗体)将一种有效的、但通常是非特异性的细胞毒剂输送到癌细胞。抗体或多肽本身往往无效，但当与一种合适的毒素结合时，就能有效地对抗癌症，否则这种毒素就会太有毒。ADC现在给癌症患者带来了明确的希望。然而，在工业翻译方面，存在着对可针对癌症的新有毒有效载荷以及生产用于测试和临床翻译的新ADC的重大未得到满足的需求。*我的实验室专门从事生物偶联和天然产物合成，最近完成了第一次Amanitin的全合成，这是一种用于ADC开发的有效载荷毒素。Iprogen公司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，致力于为临床前和临床应用开发新的抗体-药物结合物。这项Engage Grant将在我的实验室的研究兴趣(我们将开发新的基于Amanitin的有毒有效载荷)和Iprogen将这些毒素应用于各种治疗性抗体以基于它们与疾病缓解抗体的结合来创建新IP的商业兴趣之间形成独特的研究协同。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颖的连接臂技术。反过来，Iprogen的工作人员科学家将产生新的ADC，并将在适当的毒性测试中对它们进行测试**

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**