Dissecting the regulation of antibody immunotherapy by Fc gamma receptor IIB

剖析 Fc γ 受体 IIB 对抗体免疫治疗的调节

• 批准号: 1943869
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1943869
• 关键词: Dissecting; regulation; antibody; immunotherapy; Fc

Biological therapies are one of the fastest growing sectors of the pharmaceutical industry, driven in large part by the success of monoclonal antibodies (mAbs). Since the approval of rituximab in 1997, mAbs are now successfully employed in the treatment of multiple diseases, ranging from cancer to autoimmunity. These diseases are rapidly increasing in number due to our aging population and so new and more effective treatments are required. To maintain this growth in mAb-based treatments and increase their effectiveness we need to better understand their mechanisms of action and develop new antibody formats to overcome any limitations. Amongst these new formats are multi-specific antibodies which have the ability to engage targets simultaneously to drive unique biological responses.mAb depend on their Fc region for function, triggering immune responses following engagement of Fc receptors on immune effector cells. Typically, therapeutic mAbs are of the IfG isotype and so Fc gamma Receptors (FcyRs) are centrally involved in their regulation and mode of action. In humans there are 6 FcyRs; 5 which typically trigger activation of the effector cell and a single inhibitory receptor FcyRIIB, with a similar situation in the mouse.Our recent work has demonstrated that this inhibitory receptor can in fact have very differing effects on mAb immunotherapy, according to the antibody target and/or the specific mAb. Principally, this appears to be related to the ability of FcyRIIB to facilitate higher order clustering of receptors, leading to more potent signalling, however this has not been demonstrated formally. We have also made a surprising observation indicating that FcyRIIB regulates the half-life of mAb and mAb-like reagents such as multi-specifics. The aim of the proposed project is to explore these basic properties of FcyRIIB, to fully elucidate if and how it regulates mAb clustering, whether simple competition with activatory FcyR is involved and how it contributes to mAb half-life. A secondary aim is to develop strategies to potentially overcome these inhibitory aspects to boost mAb immunotherapy. Specifically, using a panel of existing and novel mouse models, lacking FcyRIIB and expressing modified versions of the receptor (eg signalling defective) we will explore how mAb half-life and activity is regulated. This will be achieved using a variety of established and novel mAb formats, designed to understand the molecular basis of the interactions driving the biology. As the FcyR repertoire varies with cell type, location and disease status, these technologies will require careful assessment. For example, the ratio of activatory: inhibitory FcyR may well influence the biology and will be assessed through careful measurement and also the use of mice lacking one or all of the activatory FcyR and/or mice expressing human FcyR. The research outcomes will foster basic understanding of how FcyRIIB regulates mAb half-life and activity, serving to inform the development of more effective mAb therapies and so improve the health of those with diseases such as cancer and autoimmunity. In addition, the tools generated will yield better basic understanding of mAb regulation by FcyRIIB assisting all researchers working with mAb (basic scientists, small biotechs, large pharma developing/producing these reagents).

生物疗法是制药行业增长最快的领域之一，这在很大程度上是由单克隆抗体（mAb）的成功推动的。自1997年利妥昔单抗获批以来，mAb现已成功用于治疗多种疾病，从癌症到自身免疫。由于人口老龄化，这些疾病的数量正在迅速增加，因此需要新的和更有效的治疗方法。为了保持基于mAb的治疗的这种增长并提高其有效性，我们需要更好地了解其作用机制并开发新的抗体形式以克服任何限制。在这些新形式中，多特异性抗体具有同时接合靶点以驱动独特生物学应答的能力。mAb依赖于其Fc区发挥功能，在免疫效应细胞上的Fc受体接合后触发免疫应答。通常，治疗性mAb是IfG同种型的，因此Fc γ受体（Fc γ R）主要参与其调节和作用模式。在人类中，有6个Fc γ R; 5，其通常触发效应细胞的活化和单个抑制性受体Fc γ RIIB，在小鼠中具有类似的情况。我们最近的工作已经证明，根据抗体靶标和/或特异性mAb，这种抑制性受体实际上可以对mAb免疫疗法具有非常不同的作用。主要地，这似乎与Fc γ RIIB促进受体的更高阶聚集的能力有关，导致更有效的信号传导，然而这尚未正式证明。我们还进行了令人惊讶的观察，表明Fc γ RIIB调节mAb和mAb样试剂如多特异性的半衰期。该项目的目的是探索Fc γ RIIB的这些基本性质，以充分阐明其是否以及如何调节mAb聚类，是否涉及与活化Fc γ R的简单竞争以及其如何有助于mAb半衰期。第二个目的是开发可能克服这些抑制方面的策略，以促进mAb免疫治疗。具体而言，使用一组现有的和新的小鼠模型，缺乏Fc γ RIIB并表达受体的修饰形式（例如信号传导缺陷），我们将探索mAb半衰期和活性是如何调节的。这将使用各种已建立和新型mAb形式来实现，旨在了解驱动生物学的相互作用的分子基础。由于Fc γ R库随细胞类型、位置和疾病状态而变化，这些技术将需要仔细评估。例如，活化性：抑制性Fc γ R的比率可以很好地影响生物学，并且将通过仔细测量以及使用缺乏一种或所有活化性Fc γ R的小鼠和/或表达人Fc γ R的小鼠来评估。研究结果将促进对Fc γ RIIB如何调节mAb半衰期和活性的基本理解，有助于开发更有效的mAb疗法，从而改善癌症和自身免疫等疾病患者的健康状况。此外，生成的工具将产生对Fc γ RIIB的mAb调节的更好的基本理解，帮助所有使用mAb的研究人员（基础科学家，小型生物技术公司，开发/生产这些试剂的大型制药公司）。