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）将成为未来的重磅炸弹药物，预计到2020年其全球销售额将达到125 B$。然而，mAb疗法可能非常昂贵（每位患者每年高达60，000美元），这可能使其无法使用-几乎与其治疗疾病的功效无关。因此，迫切需要降低mAb疗法的成本。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，提高关键生产步骤的效率，克服阻碍注射的粘度挑战（给药成本低于输注）。为了追求这些发展，我们的计划在未来五年将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，这是一种新兴的mAb变体，在癌症治疗中显示出了希望。促进研发过程将为加拿大人带来更有效和更负担得起的bsAb疗法。与具有一个靶标的常规mAb不同，bsAb可以结合两个不同的靶标。这可以用来将癌细胞和患者自身免疫系统的抗癌细胞聚集在一起。然而，虽然bsAb有可能彻底改变癌症治疗，但目前还不知道bsAb的“最佳结构”应该是什么。该研究计划建议使用“DNA纳米技术”来快速研究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而闻名，以组装令人难以置信的复杂性的3D纳米结构。这些结构对于在空间中精确定位抗体的两个不同靶结合部分是理想的。因此，我们的计划将使用生物缀合物，超分子和动态化学来开发和巩固平台技术，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.