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Improving the functional affinity of human anti-glycan monoclonal antibodies (mabs) for cancer therapy

提高人类抗聚糖单克隆抗体 (mab) 的功能亲和力用于癌症治疗

基本信息

批准号：
MR/M015564/1
负责人：
Lindy Durrant
金额：
$ 113.96万
依托单位：
University of Nottingham
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FM015564%2F1
关键词：
Improving functional affinity human anti

项目摘要

Over the last decade, antibodies have become one of the major growth areas in the Pharmaceutical industry. They combine a high level of specificity for their target (the 'antigen') with the ability to recruit powerful immune system-mediated effects. Indeed, antibodies are one of the main mechanisms by which the immune system normally eliminates infectious agents.. We have a proven track record in the production of clinically valuable anti-cancer antibodies (two of our antibodies are currently in clinical trials) and we are striving to produce more. However, we have observed that during the molecular procedures necessary to allow an antibody to be used in patients, they often lose a substantial fraction of their potency. We believe that we now have an explanation for why this might be occurring, and we are seeking the funding to make the changes necessary to avoid this loss of potency.Antibodies are typically produced by immunising mice with a target 'antigen'. Antibody-producing cells are isolated from responding mice and the cells immortalised. The antibodies being produced are then screened for reactivity and clinical applicability, and the genes encoding the antibodies are cloned. The areas of the antibody that are not responsible for the target specificity (the 'constant regions') are then replaced with their human equivalent, in a process referred to as the 'humanisation' of the antibody. This is essential to create a clinically useful reagent; if the majority of the mouse areas remain, an immune response can develop in patients that negates the effectiveness of the antibody. We have observed that after this 'humanisation' process, the antibodies bind less strongly to their target and that many of the clinically beneficial effects of the antibodies are lost. We believe that this reduced potency is due to the replacement of the original mouse 'subclass' of the antibody, called mouse IgG3, as we do not observe it when other mouse subclasses are involved. Previous investigators have suggested that mouse IgG3 antibodies might combine together once bound to their target, in a way that other antibody subclasses do not. This stabilises binding and amplifies the clinical potency of the antibody. Our proposal is to confirm the areas of mouse IgG3s that are having this effect, and to transfer these areas to human IgG1, the most common human subclass used clinically. This is feasible because, although the antibodies are very similar in sequence, they nevertheless have unique differences. Rather than investigate these numerous differences individually, we propose to alter whole patches of the surface of human IgG1 to resemble mouse IgG3. In this way, we will cover the differences in a more time- and cost-efficient way, and also pick up any changes where multiple simultaneous differences are necessary for the effect. Once we have isolated which overall area is responsible for the effect, we will investigate the area change by change to identify exactly which changes are important. We have two candidate antibodies in which we have shown a hundred-fold and ten-fold reduction in potency, respectively, introduced by the change from mouse IgG3 to human IgG1. These make ideal candidates to test which alterations in the human IgG1 re-introduce this lost potency. We believe that this work will result in a number of very exciting prospects. It will permit the use of antibodies against clinically useful targets that would otherwise have failed at the 'humanisation' stage; it will allow the use of lower doses of antibody, with a lower risk of side-effects; and it will increase the potency of currently available antibodies, increasing their clinical effectiveness. We therefore consider that the proposed project is an excellent use of resources with patient and economic benefits encompassing our antibodies and many other therapeutic antibodies.

在过去的十年中，抗体已成为制药行业的主要增长领域之一。它们结合了联合收割机对其靶点（“抗原”）的高水平特异性和招募强大的免疫系统介导效应的能力。事实上，抗体是免疫系统通常消除感染因子的主要机制之一。我们在生产具有临床价值的抗癌抗体方面有着良好的记录（我们的两种抗体目前正在进行临床试验），我们正在努力生产更多。然而，我们已经观察到，在允许抗体用于患者所必需的分子程序期间，它们通常会失去相当大一部分效力。我们相信，我们现在有了一个解释，为什么会发生这种情况，我们正在寻求资金进行必要的改变，以避免这种效力的损失。抗体通常是通过用靶向“抗原”免疫小鼠来产生的。从应答小鼠中分离抗体产生细胞，并使细胞永生化。然后筛选产生的抗体的反应性和临床适用性，并克隆编码抗体的基因。然后将不负责靶特异性的抗体区域（“恒定区”）替换为其人等效物，该过程称为抗体的“人源化”。这对于创建临床有用的试剂至关重要;如果大部分小鼠区域仍然存在，则可以在患者中产生免疫反应，从而否定抗体的有效性。我们已经观察到，在这种“人源化”过程之后，抗体与其靶标的结合强度降低，并且抗体的许多临床有益效果丧失。我们认为，这种效力降低是由于抗体的原始小鼠“亚类”（称为小鼠IgG 3）被替换，因为当涉及其他小鼠亚类时，我们没有观察到它。以前的研究人员认为，小鼠IgG 3抗体一旦与其靶标结合，可能会以其他抗体亚类所不具备的方式联合收割机在一起。这稳定了结合并放大了抗体的临床效力。我们的建议是确认小鼠IgG 3具有这种作用的区域，并将这些区域转移到临床上最常见的人IgG 1亚类。这是可行的，因为尽管抗体的序列非常相似，但它们仍具有独特的差异。而不是单独研究这些众多的差异，我们建议改变整个补丁的表面的人IgG 1类似于小鼠IgG 3。通过这种方式，我们将以一种更节省时间和成本的方式来覆盖差异，并且还可以选择需要多个同时差异才能实现效果的任何更改。一旦我们分离出哪个整体区域对效果负责，我们将逐个调查区域变化，以准确识别哪些变化是重要的。我们有两种候选抗体，其中我们已经显示出效力分别降低了100倍和10倍，这是由小鼠IgG 3变为人IgG 1引起的。这些使得理想的候选人来测试在人IgG 1中的哪些改变重新引入这种失去的效力。我们相信，这项工作将带来一些非常令人兴奋的前景。它将允许使用针对临床上有用的靶点的抗体，否则这些靶点在“人源化”阶段会失败;它将允许使用较低剂量的抗体，具有较低的副作用风险;并且它将增加目前可用的抗体的效力，增加其临床有效性。因此，我们认为，拟议的项目是对资源的一种很好的利用，具有患者和经济效益，包括我们的抗体和许多其他治疗性抗体。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting Glycans and Heavily Glycosylated Proteins for Tumor Imaging.

DOI：
10.3390/cancers12123870
发表时间：
2020-12-21
期刊：
Cancers
影响因子：
5.2
作者：
Houvast RD;Vankemmelbeke M;Durrant LG;Wuhrer M;Baart VM;Kuppen PJK;de Geus-Oei LF;Vahrmeijer AL;Sier CFM
通讯作者：
Sier CFM

Engineering the Human Fc Region Enables Direct Cell Killing by Cancer Glycan-Targeting Antibodies without the Need for Immune Effector Cells or Complement.

DOI：
10.1158/0008-5472.can-19-3599
发表时间：
2020-08-15
期刊：
Cancer research
影响因子：
11.2
作者：
Vankemmelbeke M;McIntosh RS;Chua JX;Kirk T;Daniels I;Patsalidou M;Moss R;Parsons T;Scott D;Harris G;Ramage JM;Spendlove I;Durrant LG
通讯作者：
Durrant LG

The terminal sialic acid of stage-specific embryonic antigen-4 has a crucial role in binding to a cancer-targeting antibody.

阶段特异性胚胎抗原 4 的末端唾液酸在与癌症靶向抗体的结合中起着至关重要的作用。