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

通过“双击”策略打开基于抗体片段的新型治疗和诊断的大门

• 批准号: EP/M01732X/1
• 负责人: Stephen Caddick
• 金额: $ 71.87万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FM01732X%2F1
• 关键词: Opening; door; novel; antibody; fragment

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.

使用抗体作为治疗和诊断是研究新医疗保健产品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，迄今为止已有超过20种药物获批用于临床，超过150种药物正在临床开发中。据估计，全球抗体治疗市场目前约为400亿美元。抗体的力量在于它们高度特异性结合靶抗原的能力。这可以被利用来产生直接的效果，就像乳腺癌药物赫赛汀（一种抗体）的情况一样，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，单独的裸抗体不具有足够的效力。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，以将强效药物递送到作用部位（例如癌细胞）。此类抗体-药物缀合物（ADC）由于其选择性地寻找和破坏患病细胞的能力而被称为“魔术子弹”，并且因此大大降低了与不加选择的细胞毒性化疗剂相关的副作用。药物与抗体的化学连接是该领域的关键技术挑战。目前的技术水平远非理想，因为：（i）药物结合是非特异性的（导致非常不明确的缀合物，其具有不可预测的药理学性质，例如活性、稳定性、体内寿命和副作用以及批次可变性;和（ii）它们限于完全抗体缀合（导致主要的成本问题（排除在NHS中的使用）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，其允许将小分子连接到抗体中的特定位点，以产生高度确定的、稳定的和完全活性的缀合物。在这个项目中，我们的目标是提供一个化学主导的平台，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手柄，使我们能够基于抗体片段构建ADC，与完整抗体相比，在生产成本和时间方面更加经济。将位点特异性抗体片段修饰与特别通用的小分子相结合，这种化学技术能够克服ADC开发的许多现有障碍。此外，通过采用化学方法，也有可能使用我们的创新策略提供全新的基于抗体片段的双特异性抗体和诊断方法。我们将通过产生抗体-片段药物缀合物（用于乳腺癌的前瞻性治疗）、抗体片段-抗体片段缀合物（作为前瞻性的新型抗癌治疗）和抗体片段-多模态成像缀合物（用于改进的诊断方法）来验证该技术。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性影响。

项目成果

Enabling the controlled assembly of antibody conjugates with a loading of two modules without antibody engineering.

• DOI: 10.1039/c6sc03655d
• 发表时间: 2017-03-01
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Lee MTW;Maruani A;Richards DA;Baker JR;Caddick S;Chudasama V
• 通讯作者: Chudasama V

A plug-and-play approach to antibody-based therapeutics via a chemoselective dual click strategy.

• DOI: 10.1038/ncomms7645
• 发表时间: 2015-03-31
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Maruani, Antoine;Smith, Mark E. B.;Miranda, Enrique;Chester, Kerry A.;Chudasama, Vijay;Caddick, Stephen
• 通讯作者: Caddick, Stephen

A platform for efficient, thiol-stable conjugation to albumin's native single accessible cysteine.

与白蛋白的原生单一可访问半胱氨酸的高效，硫代结合的平台。

• DOI: 10.1039/c5ob01205h
• 发表时间: 2015-08-07
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Smith ME;Caspersen MB;Robinson E;Morais M;Maruani A;Nunes JP;Nicholls K;Saxton MJ;Caddick S;Baker JR;Chudasama V
• 通讯作者: Chudasama V

Pyridazinediones deliver potent, stable, targeted and efficacious antibody-drug conjugates (ADCs) with a controlled loading of 4 drugs per antibody

• DOI: 10.1039/c7ra00788d
• 发表时间: 2017-01-01
• 期刊: RSC ADVANCES
• 影响因子: 3.9
• 作者: Robinson, Eifion;Nunes, Joao P. M.;Chudasama, Vijay
• 通讯作者: Chudasama, Vijay

Next-generation disulfide stapling: reduction and functional re-bridging all in one.

• DOI: 10.1039/c5sc02666k
• 发表时间: 2016-01-01
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Lee MTW;Maruani A;Baker JR;Caddick S;Chudasama V
• 通讯作者: Chudasama V