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

用于抗体药物偶联物 (ADC) 的新型序列依赖性生物偶联连接子的设计和合成

• 批准号: 1800637
• 金额: --
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1800637
• 关键词: Design; Synthesis; Novel; Sequence; dependent

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.

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结合成一个单一的实体。将两种不同的药物结合在一起提供了协同作用的机会，最明显的是当其中一种成分作为靶向剂而另一种成分与所需的生物系统相互作用时。新的协同治疗方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已经作为抗癌药物进入市场（罗氏公司的Kadcyla和西雅图基因公司的Adcetris），现在还有54种adc正在临床试验中。链接器技术是ADC化疗的一个关键方面，可分为两个方面；(1)“偶联化学”（连接体与抗体和战斗部连接的化学方法）和(2)“连接体组成”（连接体的结构和性质，包括战斗部释放机制）。连接体不仅为弹头与抗体的有效结合提供了一个功能手柄（理想情况下，不影响抗体结合或细胞毒性活性），而且还显著影响了最终ADC结构的行为。连接体的稳定性在调节战斗部的释放和ADC的治疗指标方面起着关键作用。此外，连接物的性质会对整个ADC的理化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连接技术。

项目成果

The development of functionalised stapled peptides as chemical tools to modulate biological processes in platelets and as novel antimicrobial therapeutics targeting Pseudomonas aeruginosa

功能化钉合肽的开发作为调节血小板生物过程的化学工具和针对铜绿假单胞菌的新型抗菌疗法

• DOI: 10.17863/cam.59572
• 发表时间: 2020
• 作者: Gaynord J

Stapled peptides as a new technology to investigate protein-protein interactions in human platelets.

• DOI: 10.1039/c8sc00284c
• 发表时间: 2018-05-28
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Iegre J;Ahmed NS;Gaynord JS;Wu Y;Herlihy KM;Tan YS;Lopes-Pires ME;Jha R;Lau YH;Sore HF;Verma C;O' Donovan DH;Pugh N;Spring DR
• 通讯作者: Spring DR

Two-Component Stapling of Biologically Active and Conformationally Constrained Peptides: Past, Present, and Future

• DOI: 10.1002/adtp.201800052
• 发表时间: 2018-11-01
• 期刊: ADVANCED THERAPEUTICS
• 影响因子: 4.6
• 作者: Iegre, Jessica;Gaynord, Josephine S.;Spring, David R.
• 通讯作者: Spring, David R.