A chemistry-driven approach to Senolytic Bispecific T-Cell Engagers

化学驱动的 Senolytic 双特异性 T 细胞接合剂方法

• 批准号: EP/Y024699/1
• 负责人: Gonçalo Bernardes
• 金额: $ 25.55万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY024699%2F1
• 关键词: chemistry; driven; approach; Senolytic; Bispecific

Cellular senescence involves the stress-induced, durable cell-cycle arrest of previously replication-competent cells and has been associated with a plethora of age-related pathologies, such as liver and lung fibrosis, atherosclerosis, diabetes, and osteoarthritis.Since most small molecules with senolytic activity lack potency and produce substantial side effects, there is growing interest in the development of senolytic agents that selectively eliminate senescent over healthy cells. The present project will tackle this problem by establishing a new, chemistry-driven approach for the assembly of unique Bispecific T-Cell Engagers (BiTEs) with senolytic activity.This will be achieved by designing two orthogonal reactions that are specific to cysteine (one of them exclusively targeting N-terminal Cys and therefore allowing asymmetric ligation), for the assembly of a library of bispecific antibodies (bsAbs) from individual Cys-tagged monoclonal antibodies (mAbs) and avoiding the need to clone, express, purify and test each bsAbs one by one. The approach will then consist on expressing two sets of Cys-tagged antibodies, one targeting cell-surface antigens on hematopoietic and immune cells, and the other targeting senescent cells, which will be ligated to each other through designed linkers into bsAbs specific to senescent and T-cells antigens, and therefore capable to trigger an immune cytotoxic response towards senescent cells. To profile this library in vitro, the immunomodulatory properties of the senolytic BiTEs will be inferred from cell lysis and viability assays from cocultures of senescent cells and peripheral blood mononuclear cells. Following this, the immunomodulatory effects of selected bsAbs with senolytic activity will be elucidated using -omics and immunological tools. The technology developed will not be limited to bsAbs but will allow being extended to the ligation of any type of proteins, enabling future applications in protein-based drug discovery.

细胞衰老涉及与先前复制能力的细胞所诱导的压力诱导的耐用细胞周期停滞，并且与多种与年龄相关的病理学（例如肝脏和肺纤维化，动脉粥样硬化，糖尿病，糖尿病和糖尿病和肺炎的疾病）相关，因此在骨质疾病中产生了多大的影响，因此在其上产生了多大的分子，因此具有促进性的影响，而存在于此。有选择地消除对健康细胞的衰老。 The present project will tackle this problem by establishing a new, chemistry-driven approach for the assembly of unique Bispecific T-Cell Engagers (BiTEs) with senolytic activity.This will be achieved by designing two orthogonal reactions that are specific to cysteine (one of them exclusively targeting N-terminal Cys and therefore allowing asymmetric ligation), for the assembly of a library of bispecific antibodies （BSABS）来自单个Cys标记的单克隆抗体（mAb），并避免需要克隆，表达，净化和测试每个BSABS一个一个。然后，该方法将包括表达两组Cys标记的抗体，一种靶向造血和免疫细胞上的细胞表面抗原，另一个靶向细胞，另一个靶向衰老细胞，它们将通过特定于BSABS的粘液蛋白和T-Cells抗原的BSABS互相连接，从而触发毒素cytot cytot cytot cytotic cytotic cytot cytot cytot cytot cytot cytot cytot cy毒素。为了在体外介绍该文库，将从细胞裂解和衰老细胞和周围血液单核细胞共培养的细胞裂解和生存力测定中推断出鼻溶液的免疫调节特性。之后，将使用 - 词和免疫学工具阐明具有鼻溶性活性的选定BSAB的免疫调节作用。开发的技术将不仅限于BSABS，但将允许扩展到任何类型的蛋白质的连接，从而在基于蛋白质的药物发现中实现未来的应用。