从重组IgG1抗体产生T细胞依赖的双特异性构建体的模块化半合成方法
Modular Semisynthetic Approach to Generate T Cell-Dependent Bispecific Constructs from Recombinant IgG1 Antibodies
影响因子:3.90000
分区:化学2区 / 生化研究方法2区 有机化学2区 生化与分子生物学3区 化学：综合3区
发表日期:2024 Sep 16
作者:
Irene Shajan, Léa N C Rochet, Shannon R Tracey, Rania Benazza, Bianka Jackowska, Oscar Hernandez-Alba, Sarah Cianférani, Christopher J Scott, Floris L van Delft, Vijay Chudasama, Bauke Albada
摘要
双特异性抗体将T细胞重定向到肿瘤细胞是治疗癌症的有效方法，而T细胞依赖性双特异性抗体（TDBA）是一类新兴的有效免疫治疗剂。通过同时将抗原靶向肿瘤细胞和T细胞，T细胞被激活以杀死肿瘤细胞。在本文中，我们报告了一个平台，以生成新型类别的2：1 T细胞依赖性双特异性抗体的结构，其对HER2受体的双相度在肿瘤细胞上的双相度以及T细胞上CD3受体的单价。为此，我们使用遗传编码的酪氨酸残基对遗传编码的酪氨酸残基的反应使用生物逆电子需求alder（IEDDA）在治疗批准的抗体曲妥珠单抗上安装一个TCO手柄。随后的TCO-四嗪用四嗪官能化的CD3结合晶面接收到2：1 HER2×CD3 TDBA，在皮莫尔浓度下表现出肿瘤的功能。对T细胞上CD3受体的一致性可以降低细胞因子释放综合征的机会，这是这种药物的常见副作用。我们的半合成方法可以在一些化学酶和合成步骤中产生高度有效的TDBA构建体。
Abstract
Redirecting T cells to tumor cells by bispecific antibodies is an effective approach to treat cancer, and T cell-dependent bispecific antibodies (TDBAs) are an emerging class of potent immunotherapeutic agents. By simultaneously targeting antigens on tumor cells and T cells, T cells are activated to kill tumor cells. Herein, we report a platform to generate a novel class of 2:1 structure of T cell-dependent bispecific antibody with bivalency for HER2 receptors on tumor cells and monovalency for CD3 receptors on T cells. For this, we use a biogenic inverse electron-demand Diels-Alder (IEDDA) click reaction on genetically encoded tyrosine residues to install one TCO handle on therapeutically approved antibody trastuzumab. Subsequent TCO-tetrazine click with a tetrazine-functionalized CD3-binding Fab yields a 2:1 HER2 × CD3 TDBA that exhibits a tumor-killing capability at picomolar concentrations. Monovalency toward the CD3 receptor on T cells can lower the chances of cytokine release syndrome, which is a common side effect of such agents. Our semisynthetic approach can generate highly potent TDBA constructs in a few chemoenzymatic and synthetic steps.