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

使用抗体作为治疗和诊断是研究新保健产品的最令人兴奋和最有前途的领域之一。抗体是增长最快的一类治疗药物，迄今已有超过20种被批准用于临床，超过150种正在临床开发中。据估计，抗体疗法的全球市场目前约为400亿美元。抗体的力量在于它们能够高度特异性地与目标抗原结合。这可以被利用来产生直接的效果，比如乳腺癌药物赫赛汀（一种抗体），它与某些癌细胞表面过量产生的蛋白质结合，抑制细胞增殖。然而，在许多情况下，裸抗体本身没有足够的效力。在这种情况下，抗体可以简单地用作高度选择性的靶向装置，将强效药物输送到作用部位（例如癌细胞）。这种抗体-药物偶联物（adc）被称为“神奇子弹”，因为它们有选择性地寻找和破坏病变细胞的能力，从而大大减少了与不加区分的细胞毒性化疗相关的副作用。药物与抗体的化学附着是该领域的一个关键技术挑战。目前的技术水平远非理想，因为：(i)药物偶联是非特异性的（导致非常不明确的偶联物具有不可预测的药理学性质，如活性、稳定性、体内寿命和副作用，以及批次可变性）；（ii）它们仅限于完全抗体偶联（导致主要的成本问题（排除在NHS中使用）和一定程度的非现场毒性）。我们最近开发了一种非常有前途的新化学方法，可以将小分子附着在抗体的特定位点上，从而产生高度明确、稳定和完全活性的偶联物。在这个项目中，我们的目标是提供一个化学主导的平台，该平台将利用我们新的位点特异性化学方法来引入多功能正交处理，这将使我们能够基于抗体片段构建adc，与生产成本和时间相比，这比全抗体更经济。结合位点特异性抗体片段修饰和异常通用的小分子，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，我们也有可能利用我们的创新策略提供全新的基于抗体片段的双特异性和诊断。我们将通过产生抗体-片段药物偶联物（用于乳腺癌的前瞻性治疗），抗体片段-抗体片段偶联物（作为一种前瞻性的新型抗癌治疗）和抗体片段-多模态成像偶联物（用于改进诊断方法）来举例说明该技术。该项目有可能对该领域的研究和下一代基于抗体的医疗保健产品的开发产生变革。

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.