Antibody venom conjugates

抗体药物结合物(ADC)是一类结合抗体和药物有效载荷的新型药物。该抗体将药物有效载荷靶向特定的靶细胞，提高了安全性和有效性。到目前为止，FDA批准的ADC药物有8种，全部用于肿瘤应用，使用小分子药物。虽然这些带有小分子的ADC比非靶向小分子药物具有更好的疗效和安全性，但越来越明显的是，它们屈服于癌细胞同样的多重耐药。在这个项目中，我们正在探索合成和评估更大分子的环肽毒素药物，这些药物将无法对癌细胞产生耐药性。这项提议融合了Perrin实验室关于新型毒液衍生多肽生物偶联抗体的独特化学培训成果，并与温哥华新兴生物制药公司iProgen建立了工业合作伙伴关系。在很短的时间内，我们已经找到了一位具有多肽经验并准备参与这一项目的合格博士后。传统上，由于各种全身毒性，这些环状多肽毒素很少用于肿瘤学应用；然而，通过利用ADC平台，我们假设这类新的毒素可能代表着一类重要的、尚未开发的抗癌药物有效载荷有待解锁。Perrin实验室在环肽和双环肽的合成和评估方面拥有丰富的经验，包括鬼臼毒素和双环肽的合成，展示了这一领域的技术诀窍，因为毒素代表着备用分子，因为我们推出了新的有毒支架作为ADC的有效载荷。结果将是一流的化学结合抗体的毒素成分，这将由我们的工业合作伙伴iProgen在体外进行验证。

Antibody Drug Conjugates (ADCs) are an emerging class of drugs that combines antibody and drug payload. The antibody targets the drug payload to specific targeted cells improving both safety and efficacy. To date that are 8 FDA approved ADC drugs all for oncology application using small molecule drugs. Although these ADCs with small molecules encompasses superior efficacy and safety than non-targeted small molecule drugs, it is increasingly evident that they succumb to the same multi-drug resistance by the cancer cells. In this project, we are exploring the synthesis and evaluation of larger molecule cyclical peptide toxin drugs that cancer cells will not be able to develop resistance to. This proposal merges unique chemical training outcomes in the Perrin lab on bioconjugation of novel venom-derived peptides to antibodies with an industrial partnership with iProgen, an emerging biopharmaceutical company in Vancouver. With a short time-frame, we have identified a qualified postdoctoral fellow who has experience in peptides and is prepared to engage in this project.Traditionally, these cyclic peptide toxins are rarely used for oncology application due to a variety of systemic toxicity; however, by utilizing an ADC platform, we hypothesize that this new class of toxins may represent an important and untapped class of anti-cancer drug payloads to be unlocked. The Perrin lab has extensive experience in the synthesis and evaluation of cyclic and bicyclic peptides including the synthesis of both phalloidins and amanitins, which showcase know-how in this domain and as toxins represent back-up molecules as we advance new toxic scaffolds as payloads for ADCs. Outcomes will be first-in-class compositions of chemically conjugated toxins to antibodies that will be validated in vitro by our industrial partner, iProgen.