Design and Synthesis of Novel Sequence-dependent Bioconjugation Linkers for Antibody-Drug Conjugates (ADCs)

布景主题：工业生物技术和生物能源新治疗剂的发现和开发最近进入了一个关键的新领域，寻求将两种不同类别的化学或生物制剂联合收割机结合成一个实体。将两种不同的试剂放在一起提供了协同效应的机会，最值得注意的是当其中一种组分充当靶向剂而另一种组分与所需的生物系统相互作用时。新型协同治疗模式的主要领域之一是抗体药物偶联物（ADC）。近年来，人们对ADC产生了极大的兴趣;两种ADC已经作为抗癌药物上市（罗氏的Kadcyla和西雅图遗传学公司的Adcetris），现在还有54种ADC正在进行临床试验。接头技术是ADC化学治疗剂的关键方面，并且可以分为两个方面：（1）“缀合化学”（接头与抗体和弹头连接的化学方法）和（2）“接头组合物”（接头的结构，以及因此接头的性质，包括弹头释放机制）。接头不仅提供用于弹头与抗体的有效缀合的功能柄（理想地不损害抗体结合或细胞毒性活性），而且其还显著影响所得ADC构建体的行为。接头的稳定性在调节弹头的释放中起关键作用，从而调节ADC的治疗指数。此外，接头的性质可以对整个ADC的物理化学和药代动力学性质产生深远的影响。本研究旨在开发能够克服当前缺点的增强接头技术。

Theme: Industrial Biotechnology and BioenergyThe discovery and development of new therapeutic agents has recently moved into a key new area, looking to combine two distinct classes of chemical or biological agents into a single entity. Bringing two different agents together provides the opportunity for synergistic effects, most notably when one of the components acts as a targeting agent and the other interacting with the desired biological system. One of the leading areas for new synergistic therapeutic modalities is Antibody Drug Conjugates (ADCs). Recent years have witnessed tremendous interest in ADCs; two are already on the market as anticancer agents (Roche's Kadcyla and Seattle Genetics' Adcetris) and there are now a further 54 ADCs in clinical trials. Linker technology is a crucial aspect of ADC chemotherapeutics and can be split into two aspects; (1) 'conjugation chemistry' (the chemical method of attachment of the linker to the antibody and to the warhead) and (2) 'linker composition' (the structure, and thus properties of the linker, including the warhead release mechanism). The linker not only provides a functional handle for efficient conjugation of the warhead to the antibody (ideally without compromising antibody binding or cytotoxic activity), but it also impacts significantly upon the behaviour of the resultant ADC construct. The stability of the linker plays a key role in regulating the release of the warhead and thus the therapeutic index of the ADC. In addition, the nature of the linker can have a profound effect on the physico-chemical and pharmacokinetic properties of the overall ADC.This research aims to develop enhanced linker technologies capable of overcoming current shortcomings.