Chemical generation of checkpoint inhibitory T cell engagers for the treatment of cancer.
Chemical generation of checkpoint inhibitory T cell engagers for the treatment of cancer.
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DOI：
10.1038/s41557-023-01280-4
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发表时间：
2023-11
期刊：
影响因子：
21.8
通讯作者：
Chudasama, Vijay
中科院分区：
文献类型：
--
作者：
Szijj, Peter A.;Gray, Melissa A.;Ribi, Mikaela K.;Bahou, Calise;Nogueira, Joao C. F.;Bertozzi, Carolyn R.;Chudasama, Vijay
双特异性T细胞接合物（BiTEs）是双特异性抗体（bsAbs）的一个子集，它可以通过使目标癌细胞靠近细胞毒性T细胞来促进其死亡。检查点抑制性T细胞接合物（CiTEs）包括一个BiTE核心和一个额外的免疫调节蛋白，用于逆转癌细胞免疫抑制策略，提高疗效。到目前为止，蛋白质工程一直是生成bsab和CiTEs的主要方法，但最近开发了改进的化学方法来生成它们。利用点击化学可以生成基于片段抗原结合区（fab）的均匀片段bsab。在这里，我们描述了一种化学方法来生成生物素功能化的三蛋白偶联物，其中包括两个CiTE分子，一个含有抗pd -1 Fab，另一个含有免疫调节酶，鼠伤寒沙门菌唾液酸酶。结果表明，CiTEs的效果优于简单的BiTE支架，含有唾液酸酶的CiTE在体外诱导T细胞介导的细胞毒性显著增强。这里描述的化学方法，更普遍地，能够产生具有进一步生物学应用的多蛋白结构。到目前为止，三蛋白偶联物是用蛋白质工程策略生产的，现在可以用一种化学方法来生产，这种方法可以增加小分子的功能。与传统的T细胞接合物相比，检查点抑制性T细胞接合物（CiTEs）组装并显示具有增强的体外效力。
Bispecific T cell engagers (BiTEs), a subset of bispecific antibodies (bsAbs), can promote a targeted cancer cell’s death by bringing it close to a cytotoxic T cell. Checkpoint inhibitory T cell engagers (CiTEs) comprise a BiTE core with an added immunomodulatory protein, which serves to reverse cancer-cell immune-dampening strategies, improving efficacy. So far, protein engineering has been the main approach to generate bsAbs and CiTEs, but improved chemical methods for their generation have recently been developed. Homogeneous fragment-based bsAbs constructed from fragment antigen-binding regions (Fabs) can be generated using click chemistry. Here we describe a chemical method to generate biotin-functionalized three-protein conjugates, which include two CiTE molecules, one containing an anti-PD-1 Fab and the other containing an immunomodulatory enzyme, Salmonella typhimurium sialidase. The CiTEs’ efficacy was shown to be superior to that of the simpler BiTE scaffold, with the sialidase-containing CiTE inducing substantially enhanced T cell-mediated cytotoxicity in vitro. The chemical method described here, more generally, enables the generation of multi-protein constructs with further biological applications. Three-protein conjugates, which have so far been produced using protein-engineering strategies, can now be generated using a chemical approach that enables the addition of small-molecule functionality. Checkpoint inhibitory T cell engagers (CiTEs) were assembled and shown to have enhanced in vitro potency compared to a traditional T cell engager.
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影响因子：
4.7
作者：
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