Opening the door to novel antibody fragment-based therapeutics and diagnostics via a "dual click" strategy

将抗体用作治疗和诊断是新保健产品研究中最令人兴奋和最有前途的领域之一。抗体是增长最快的治疗药物类别，到目前为止已有20多种抗体被批准用于临床，超过150种正在进行临床开发。据估计，目前全球抗体疗法的市场规模约为400亿美元。抗体的威力在于它们高度特异地与靶抗原结合的能力。这可以被利用来产生直接的影响，就像乳腺癌药物赫赛汀(一种抗体)一样，它与某些癌细胞表面过度产生的蛋白质结合，抑制细胞增殖。然而，在许多情况下，仅有裸体抗体并不具有足够的效力。在这种情况下，抗体可以简单地用作一个高度选择性的靶向装置，将有效的药物输送到作用部位(例如癌细胞)。这种抗体-药物结合物(ADC)被称为“神奇子弹”，因为它们能够选择性地寻找和摧毁疾病细胞，从而极大地减少与不分青红皂白的细胞毒性化疗药物相关的副作用。药物与抗体的化学结合是该领域的关键技术挑战。目前的技术状况还远远不够理想，因为：(I)药物结合是非特异性的(导致具有不可预测的药理特性的结合物，如活性、稳定性、体内寿命和副作用，以及批次可变性；以及(Ii)它们仅限于完全抗体结合(导致重大成本问题(排除在NHS中的使用)和一定程度的异地毒性)。我们最近开发了一种非常有前途的新化学方法，允许将小分子连接到抗体中的特定位置，以产生高度明确、稳定和完全有效的结合物。在这个项目中，我们的目标是提供一个化学主导的平台，它将利用我们新的特定部位的化学方法学来引入多功能的正交手柄，使我们能够基于抗体片段构建ADC，与完全抗体相比，抗体片段在生产成本和时间方面要经济得多。结合位点特异性抗体片段修饰和特别通用的小分子，这种化学技术有能力克服ADC开发的许多现有障碍。此外，通过采用化学方法，还有可能利用我们的创新战略提供全新的基于抗体片段的双特异性和诊断学。我们将通过产生抗体-片段药物结合物(用于乳腺癌的预期治疗)、抗体片段-抗体片段结合物(作为一种潜在的新型抗癌治疗方法)和抗体片段-多模式成像结合物(用于改进的诊断方法)来举例说明这项技术。该项目对该领域的研究和下一代基于抗体的保健产品的开发具有潜在的变革性。

Using antibodies as therapeutics and diagnostics is one of the most exciting and promising areas of research into new healthcare products. Antibodies represent the fastest growing class of therapeutics, with over 20 approved for clinical use to date and over 150 in clinical development. It is estimated that the global market for antibody therapeutics is currently around $40 billion. The power of antibodies lies in their ability to highly specifically bind to a target antigen. This can be exploited to lead to a direct effect, as is the case for the breast cancer drug Herceptin (an antibody) which binds to a protein overproduced on the surface of certain cancer cells, inhibiting cell proliferation. However in many cases naked antibodies alone do not have enough potency. In such cases, the antibody can simply be used as a highly selective targeting device to deliver potent drugs to the site of action (e.g. the cancer cell). Such antibody-drug conjugates (ADCs) are referred to as "Magic-Bullets" due to their ability to seek and destroy diseased cells selectively, and thus greatly reduce the side-effects associated with indiscriminate cytotoxic chemotherapeutics. The chemical attachment of the drug to the antibody is a key technological challenge in the area. The current state of the art is far from ideal, as: (i) drug conjugation is unspecific (leading to very poorly defined conjugates that have unpredictable pharmacological properties such as activity, stability, in vivo lifetimes and side-effects, as well as batch variability; and (ii) they are limited to full antibody conjugation (resulting in major cost issues (precluding there use in the NHS) and a degree of off-site toxicity).We have recently developed a highly promising new chemical method that allows the attachment of small molecules to specific sites in antibodies, to produce highly defined, stable and fully active conjugates. In this project we aim to deliver a chemistry-led platform which will utilise of our new site-specific chemical methodology to introduce versatile orthogonal handles that will allow us to construct ADCs based on antibody fragments, which are far more economical compared with full antibodies in terms of productions costs and time. Combining site-specific antibody fragment modification with exceptionally versatile small molecules this chemical technology has the ability to overcome many of the existing barriers to ADC development. Moreover, by taking a chemistry approach, there is also the potential to deliver on entirely new antibody fragment-based bispecifics and diagnostics using our innovative strategy. We will exemplify the technology by generating antibody-fragment drug conjugates (for the prospective treatment of breast cancer), antibody fragment-antibody fragment conjugates (as a prospective novel anti-cancer treatment) and antibody fragment-multi-modal imaging conjugates (for improved diagnostic methods). This project has the potential to be transformative to research in the area and to the developments of next generation antibody-based healthcare products.