Purpose: To overcome the limited efficacy of immune checkpoint blockade, there is a need to find novel cancer immunotherapeutic strategies for the optimal treatment of cancer. The novel anti-4-1BB×PD-L1 bispecific antibody—ABL503 (also known as TJ-L14B)—was designed to simultaneously target PD-L1 and 4-1BB, and demonstrated strong antitumor T-cell responses without considerable toxicity. Here, we investigated how the combination of ABL503 and anti-PD-1 blockade affected the reinvigoration of exhausted tumor-infiltrating CD8+ T cells (CD8+ TILs) and anti-tumor efficacy. Experimental Design: Single cell suspensions of hepatocellular carcinoma and ovarian cancer from treatment-naive patients were used for immunophenotyping of CD8+ TILs and in vitro functional assays. Humanized hPD-1/hPD-L1/h4-1BB triple knock-in mice were used to evaluate the effects of ABL503 and anti-PD-1 blockade in vivo. Results: We observed that ABL503 successfully restored the functions of 4-1BB+ exhausted CD8+ TILs, which were enriched for tumor-specific T cells but unresponsive to anti-PD-1 blockade. Importantly, compared to anti-PD-1 blockade alone, the combination of ABL503 and anti-PD-1 blockade further enhanced the functional restoration of human CD8+ TILs in vitro. Consistently, the combination of ABL503 with anti-PD-1 in vivo significantly alleviated tumor growth, and induced enhanced infiltration and activation of CD8+ TILs. Conclusions: ABL503—a PD-L1 and 4-1BB dual-targeting bispecific antibody—elicits pronounced additive tumor growth inhibition, with increased infiltration and functionality of exhausted CD8+ T cells, which in turn enhances the anti-cancer effects of anti-PD-1 blockade. These promising findings suggest that ABL503 (TJ-L14B) in combination with PD-1 inhibitors will likely further enhance therapeutic benefit in clinical trials.

中文翻译：

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Anti-4-1BB×PD-L1 双特异性抗体可重振肿瘤特异性耗尽的 CD8+ T 细胞并增强抗 PD-1 阻断的功效

目的：为了克服免疫检查点阻断的有限功效，需要寻找新的癌症免疫治疗策略来实现癌症的最佳治疗。新型抗 4-1BB×PD-L1 双特异性抗体 ABL503（也称为 TJ-L14B）旨在同时靶向 PD-L1 和 4-1BB，并表现出强大的抗肿瘤 T 细胞反应，且没有相当大的毒性。在这里，我们研究了 ABL503 和抗 PD-1 阻断剂的组合如何影响耗尽的肿瘤浸润 CD8+ T 细胞 (CD8+ TIL) 的恢复和抗肿瘤功效。实验设计：使用来自初治患者的肝细胞癌和卵巢癌的单细胞悬液进行 CD8+ TIL 的免疫表型分析和体外功能测定。使用人源化 hPD-1/hPD-L1/h4-1BB 三重敲入小鼠来评估 ABL503 和抗 PD-1 阻断的体内效果。结果：我们观察到 ABL503 成功恢复了 4-1BB+ 耗尽的 CD8+ TIL 的功能，这些 TIL 富含肿瘤特异性 T 细胞，但对抗 PD-1 阻断无反应。重要的是，与单独的抗PD-1阻断相比，ABL503和抗PD-1阻断的组合进一步增强了人CD8+TIL的体外功能恢复。一致的是，ABL503 与抗 PD-1 体内组合显着减轻了肿瘤生长，并诱导 CD8+ TIL 的浸润和激活增强。结论：ABL503——一种 PD-L1 和 4-1BB 双靶向双特异性抗体——可引起显着的附加肿瘤生长抑制，增加耗尽的 CD8+ T 细胞的浸润和功能，从而增强抗 PD- 1封锁。这些有希望的发现表明，ABL503 (TJ-L14B) 与 PD-1 抑制剂联合使用可能会进一步增强临床试验中的治疗效果。