T cell activation is initiated upon binding of the T cell receptor (TCR)/CD3 complex to peptide-major histocompatibility complexes ("signal 1"); activation is enhanced by engagement of a second "costimulatory" receptor, such as the CD28 receptor on T cells binding to its cognate ligand(s) on the target cell ("signal 2"). CD3-based bispecific antibodies act by replacing conventional signal 1, linking T cells to tumor cells by binding a tumor-specific antigen (TSA) with one arm of the bispecific and bridging to TCR/CD3 with the other. Although some of these so-called TSAxCD3 bispecifics have demonstrated promising antitumor efficacy in patients with cancer, their activity remains to be optimized. Here, we introduce a class of bispecific antibodies that mimic signal 2 by bridging TSA to the costimulatory CD28 receptor on T cells. We term these TSAxCD28 bispecifics and describe two such bispecific antibodies: one specific for ovarian and the other for prostate cancer antigens. Unlike CD28 superagonists, which broadly activate T cells and resulted in profound toxicity in early clinical trials, these TSAxCD28 bispecifics show limited activity and no toxicity when used alone in genetically humanized immunocompetent mouse models or in primates. However, when combined with TSAxCD3 bispecifics, they enhance the artificial synapse between a T cell and its target cell, potentiate T cell activation, and markedly improve antitumor activity of CD3 bispecifics in a variety of xenogeneic and syngeneic tumor models. Combining this class of CD28-costimulatory bispecific antibodies with the emerging class of TSAxCD3 bispecifics may provide well-tolerated, off-the-shelf antibody therapies with robust antitumor efficacy.

中文翻译：

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一类共刺激性CD28双特异性抗体，可增强CD3双特异性抗体的抗肿瘤活性。

当T细胞受体（TCR）/ CD3复合物与肽-主要组织相容性复合物（“信号1”）结合后，开始T细胞活化。通过第二个“共刺激”受体（例如T细胞上的CD28受体）与其靶细胞上其同源配体结合（“信号2”）的结合，增强了活化。基于CD3的双特异性抗体通过替换常规信号1发挥作用，通过将双特异性抗体的一个臂与肿瘤特异性抗原（TSA）结合，将T细胞与肿瘤细胞连接，并与TCR / CD3的另一臂桥接。尽管其中一些所谓的TSAxCD3双特异性抗体已显示出对癌症患者有希望的抗肿瘤功效，但其活性仍有待优化。这里，我们引入了一类双特异性抗体，通过将TSA桥接到T细胞上的共刺激CD28受体来模拟信号2。我们将这些术语称为TSAxCD28双特异性抗体，并描述了两种此类双特异性抗体：一种对卵巢特异性，另一种对前列腺癌抗原具有特异性。与CD28超激动剂广泛活化T细胞并在早期临床试验中产生深远的毒性不同，这些TSAxCD28双特异性抗体在基因人源化免疫功能小鼠模型或灵长类动物中单独使用时，显示出有限的活性且无毒性。但是，当与TSAxCD3双特异性抗体结合时，它们可以增强T细胞与其靶细胞之间的人工突触，增强T细胞活化，并在各种异种和同基因肿瘤模型中显着提高CD3双特异性抗体的抗肿瘤活性。