Activation of the programmed cell death protein 1 and programmed cell death ligand 1 (PD-1/PD-L1) signaling axis plays important roles in intrinsic or acquired resistance to human epidermal growth factor receptor 2 (HER2)-directed therapies in the clinic. Therefore, therapies simultaneously targeting both HER2 and PD-1/PD-L1 signaling pathways are of great significance. Here, aiming to direct the anti-PD-L1 responses toward HER2-expressing tumor cells, we constructed a humanized bispecific IgG1 subclass antibody targeting both HER2 and PD-L1 (HER2/PD-L1; BsAb), which displayed satisfactory purity, thermostability, and serum stability. We found that BsAb showed enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity in vitro. In the late phase of peripheral blood mononuclear cell (PBMC)-humanized HER2+ tumor xenograft models, BsAb showed superior therapeutic efficacies as compared with monoclonal antibodies (mAbs) or combination treatment strategies. In cynomolgus monkeys, BsAb showed favorable pharmacokinetics and toxicity profiles when administered at a 10 mg/kg dosage. Thus, HER2/PD-L1 BsAb was demonstrated as a potentially effective option for managing HER2+ and trastuzumab-resistant tumors in the clinic. We propose that the enhanced antitumor activities of BsAb in vivo may be due to direct inhibition of HER2 signaling or activation of T cells.

中文翻译：

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一种靶向 HER2 和 PD-L1 的双特异性抗体以卓越的疗效抑制肿瘤生长。

程序性细胞死亡蛋白 1 和程序性细胞死亡配体 1 (PD-1/PD-L1) 信号轴的激活在临床对人表皮生长因子受体 2 (HER2) 导向疗法的内在或获得性耐药中起重要作用。因此，同时针对 HER2 和 PD-1/PD-L1 信号通路的治疗具有重要意义。在这里，为了将抗 PD-L1 反应引导至表达 HER2 的肿瘤细胞，我们构建了一种靶向 HER2 和 PD-L1 的人源化双特异性 IgG1 亚类抗体（HER2/PD-L1；BsAb），该抗体显示出令人满意的纯度和热稳定性和血清稳定性。我们发现 BsAb 在体外显示出增强的抗体依赖性细胞介导的细胞毒性 (ADCC) 活性。在外周血单个核细胞 (PBMC)-人源化 HER2+ 肿瘤异种移植模型的晚期，与单克隆抗体 (mAb) 或联合治疗策略相比，BsAb 显示出更好的治疗效果。在食蟹猴中，当以 10 mg/kg 剂量给药时，BsAb 显示出良好的药代动力学和毒性特征。因此，HER2/PD-L1 BsAb 被证明是临床治疗 HER2+ 和曲妥珠单抗耐药肿瘤的潜在有效选择。我们认为 BsAb 在体内增强的抗肿瘤活性可能是由于直接抑制 HER2 信号传导或激活 T 细胞。HER2/PD-L1 BsAb 被证明是临床治疗 HER2+ 和曲妥珠单抗耐药肿瘤的潜在有效选择。我们认为 BsAb 在体内增强的抗肿瘤活性可能是由于直接抑制 HER2 信号传导或激活 T 细胞。HER2/PD-L1 BsAb 被证明是临床治疗 HER2+ 和曲妥珠单抗耐药肿瘤的潜在有效选择。我们认为 BsAb 在体内增强的抗肿瘤活性可能是由于直接抑制 HER2 信号传导或激活 T 细胞。