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Antibody engineering to identify optimal expression systems and glycoforms of IgE class antibodies for cancer therapy

抗体工程以确定用于癌症治疗的 IgE 类抗体的最佳表达系统和糖型

基本信息

批准号：
2468071
负责人：
金额：
--
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2468071
关键词：
Antibody engineering identify optimal expression

项目摘要

Design strategies for cancer therapy have largely focused on one of nine human antibody classes, IgG1. We have designed an alternative approach by engineering anti-cancer antibodies bearing IgE Fc class regions. IgE antibodies are known to support immune defences against parasites and to be associated with allergies. These activities may be harnessed against cancer as a novel cancer immunotherapy strategy, exemplified by our first-in-class IgE antibody recognising a tumour-associated antigen undergoing a Phase I clinical trial at Guy's Hospital. IgEs are highly glycosylated antibodies, yet the precise effects of IgE glycan moieties on the potency and immune cell-activating mechanisms of IgE against cancer remain unclear. In this study, we aim to explore optimal engineering and glycoengineering strategies for the generation of anti-tumour IgE class antibodies in order to identify optimised antibodies for immuno-oncology. We will generate IgEs of the same specificity expressed in different mammalian expression systems and we will characterise their carbohydrate profiles in relation to function. Furthermore, we will generate different IgE glycoforms by administering inhibitors of glycan biosynthesis (Wagner). Antibody variant generation and pharmacological evaluations will be conducted in Year 1. Years 2-3 will focus on elucidating antibody biological functions, potency and ex vivo safety studies in patient blood and sera. Furthermore, glycoprofiling analyses (Ludger Ltd) will be conducted and correlated with antibody functional profiles. The study is designed to aid the identification of IgE antibodies and glycovariants with defined functional profiles and harbours considerable potentialto deliver optimised antibody immunotherapies for clinical testing in oncology.Project Aims: We will apply our established expression cloning methodologies to produce anti-tumour IgE antibody clones in different mammalian expression systems and as different glycoforms using glycosyltransferase inhibitors. We will interrogate the functional and glycosylation profiles of antibody variants. A panel of characterised antibodies with defined attributes will be selected for downstream translation and clinical testing.

癌症治疗的设计策略主要集中在九种人类抗体中的一种，IgG 1。我们已经设计了一种替代方法，通过工程化携带IgE Fc类区域的抗癌抗体。已知IgE抗体支持针对寄生虫的免疫防御，并且与过敏相关。这些活性可以作为一种新的癌症免疫治疗策略来对抗癌症，例如我们的一流IgE抗体识别肿瘤相关抗原，正在盖伊医院进行I期临床试验。IgE是高度糖基化的抗体，但IgE聚糖部分对IgE抗癌症的效力和免疫细胞激活机制的精确作用仍不清楚。在这项研究中，我们的目标是探索最佳的工程和糖工程策略，以产生抗肿瘤IgE类抗体，以确定优化的抗体免疫肿瘤学。我们将产生在不同哺乳动物表达系统中表达的相同特异性的IgE，并且我们将分析它们的碳水化合物谱与功能的关系。此外，我们将通过给予聚糖生物合成抑制剂产生不同的IgE糖型（瓦格纳）。抗体变体生成和药理学评价将在第1年进行。第2-3年将专注于阐明抗体生物学功能，效力和患者血液和血清中的离体安全性研究。此外，将进行糖谱分析（Ludger Ltd），并与抗体功能谱相关。该研究的目的是帮助识别IgE抗体和糖变体与定义的功能概况和harbours相当大的potentialto提供优化的抗体免疫疗法的临床测试在oncology.Project目的：我们将应用我们建立的表达克隆方法，生产抗肿瘤IgE抗体克隆在不同的哺乳动物表达系统和不同的糖基转移酶抑制剂。我们将研究抗体变体的功能和糖基化特征。将选择一组具有定义属性的表征抗体用于下游翻译和临床检测。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Insights from IgE Immune Surveillance in Allergy and Cancer for Anti-Tumour IgE Treatments.

DOI：
10.3390/cancers13174460
发表时间：
2021-09-04
期刊：
Cancers
影响因子：
5.2
作者：
McCraw AJ;Chauhan J;Bax HJ;Stavraka C;Osborn G;Grandits M;López-Abente J;Josephs DH;Spicer J;Wagner GK;Karagiannis SN;Chenoweth A;Crescioli S
通讯作者：
Crescioli S

IgE Antibodies against Cancer: Efficacy and Safety.

抗癌的IgE抗体：功效和安全性。

DOI：
10.3390/antib9040055
发表时间：
2020-10-16
期刊：
Antibodies (Basel, Switzerland)
影响因子：
0
作者：
Chauhan J;McCraw AJ;Nakamura M;Osborn G;Sow HS;Cox VF;Stavraka C;Josephs DH;Spicer JF;Karagiannis SN;Bax HJ
通讯作者：
Bax HJ

Generation and Characterization of Native and Sialic Acid-Deficient IgE.