A platform for engineering bi-specific antibody constructs

制药行业的全球趋势表明，单克隆抗体（mAb）将成为未来的重磅药物之一，到2020年，其全球销售额预计将达到1250亿美元。然而，单克隆抗体疗法可能非常昂贵（每位患者每年高达6万美元），这可能使它们难以使用——几乎与它们治疗疾病的功效无关。因此，迫切需要降低单克隆抗体治疗的成本。在过去的六年里，我们的团队为实现这一目标做出了贡献，例如，提高关键制造步骤的效率，克服阻碍注射的粘度挑战（管理成本低于输液）。为了实现这些发展，我们的项目将在未来五年内利用我们在这一主题上的专业知识开发一个平台，以促进和加速双特异性抗体（bsAb）的研发过程，bsAb是单克隆抗体的一种新兴变体，在癌症治疗中显示出前景。促进研发过程将为加拿大人带来更有效和更实惠的bsAb疗法。与只有一个靶点的传统单克隆抗体不同，bsAb可以结合两个不同的靶点。这可以用来将癌细胞和患者自身免疫系统的杀癌细胞结合在一起。然而，虽然bsAb有可能彻底改变癌症治疗，但目前尚不清楚bsAb的“最佳结构”应该是什么。本研究计划提出使用“DNA纳米技术”快速研究bsAb结构参数对t细胞接合和抗体依赖性细胞毒性的影响。DNA纳米技术以利用定制DNA链之间的精确碱基配对来组装令人难以置信的复杂3D纳米结构而闻名。这些结构对于在空间中精确定位抗体的两个不同的目标结合部分是理想的。因此，我们的项目将利用生物偶联、超分子和动态化学来开发和巩固一个平台技术，以促进未来针对各种疾病的bsAb的开发。

Global trends in the pharmaceutical sector indicate that monoclonal antibodies (mAb) will be among the blockbuster drugs of the future, and their worldwide sales are forecast to reach 125 B$ by 2020. However, mAb therapies can be very expensive (upwards to $60,000 per year per patient), which can be prohibitive to their use - almost irrespectively of their efficacy in treating disease. There is thus an immediate need to reduce the cost of mAb therapies. Over the past six years, our group has contributed to this goal by e.g., improving the efficiency of key manufacturing steps and overcoming viscosity challenges that prevent injection (less costly to administer than infusion). To pursue these developments, our program over the next five years will capitalize on our expertise on this topic to develop a platform to facilitate and accelerate the R&D process for bispecific antibodies (bsAb), an emerging variant of mAb that has shown promise in cancer treatment. Facilitating the R&D process will lead to more potent and more affordable bsAb therapies for Canadians. Unlike conventional mAb, which have one target, bsAb can bind two different targets. This can be exploited to bring together cancer cells and cancer-killing cells of the patient's own immune system. However, while bsAb have the potential to revolutionize cancer treatment, it is currently unknown what the `optimal structure' of a bsAb should be. This research program proposes to use `DNA nanotechnology' to rapidly study the effect of bsAb structural parameters on T-cell engagement and antibody-dependent cellular cytotoxicity. DNA nanotechnology is well known for exploiting the precise base-pairing between custom DNA strands in order to assemble 3D nanostructures of incredible complexity. These structures are ideal for precisely positioning the two different target-binding portions of antibodies in space. Our program will therefore use bioconjugate, supramolecular, and dynamic chemistry to develop and consolidate a platform technology to facilitate the development of future bsAb for a variety of diseases.