Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
ABL Bio Inc, Seongnam, Korea.
J Immunother Cancer. 2021 Jul;9(7). doi: 10.1136/jitc-2021-002428.
Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells.
To avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed "ABL503") uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling.
Functional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8 T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys.
The novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.
激动型抗 4-1BB 抗体与免疫检查点抑制剂（ICI）联合使用是一种很有前途的策略，可以提高免疫检查点抑制剂的疗效，或克服对免疫检查点抑制剂的耐药性。然而，由于 4-1BB 信号在肝驻留的库普弗细胞中被激活，临床研究中使用单克隆抗 4-1BB 激动型抗体导致了剂量依赖性肝毒性。
为了避免这种针对肝脏的毒性，我们开发了一种新型双特异性抗体（4-1BB×PD-L1 双特异性抗体，称为“ABL503”），该抗体独特地设计为仅在 PD-L1 背景下激活 4-1BB 信号，同时阻断 PD-1/PD-L1 信号。
使用表达 4-1BB 和 PD-1 的效应细胞进行功能评估显示，ABL503 的生物学活性优于每种单克隆抗体的组合。ABL503 还增强了体外试验中 T 细胞的激活，并进一步增强了抗 PD-L1 介导的肿瘤浸润 CD8 T 细胞的再激活。此外，在接受过表达 huPD-L1 的肿瘤细胞挑战的 PD-L1/4-1BB 转基因人源化小鼠中，ABL503 诱导了更强的抗肿瘤活性，并保持了对肿瘤再挑战的抗肿瘤反应。ABL503 具有良好的耐受性，猴子的肝功能正常。
新型抗 4-1BB×PD-L1 双特异性抗体可能通过限制肿瘤中 4-1BB 的刺激，发挥强大的抗肿瘤治疗效果，同时降低肝脏毒性的风险。
