Bifunctional small molecules targeting PD-L1/CXCL12 as dual immunotherapy for cancer treatment
Binbin Cheng, Wei Wang, Ting Liu, Hao Cao, Wei Pan, Yao Xiao, Shuwen Liu, Jianjun Chen
Abstract
Inhibiting PD-1/PD-L1 interaction is a highly promising therapeutic modality. 1 However, due to the low overall response rate in patients, researchers have attempted to combine PD-L1 inhibitors with other antitumor agents for cancer therapy. Studies have shown that combination immunotherapy of PD-L1 antibodies with CXCL12 inhibitors exhibited synergistic and better antitumor efficacy than monotherapy, indicating the potential clinical utility of targeting both PD-L1 and CXCL12 as dual immunotherapy to treat cancer. 2 , 3 However, there are several disadvantages for combination therapy, including unpredictable PK/PD and overlapping toxicities. A potential alternative to combination therapy would be to use a single molecule with dual or multi-targeting capability, as the PK/PD of a single molecule is easily predictable. For example, dual-targeting bispecific antibodies (bsAbs) have gained significant attention in the field of anticancer drug discovery in recent years. Many PD-1/PD-L1-based bsAbs (e.g., anti-PD-L1/TGF-β, anti-PD-1/CTLA-4, and anti-PD-1/LAG-3) have entered clinical trials as dual immunotherapy for treating cancer. However, bsAbs-based dual immunotherapies also suffer from the common drawbacks (e.g., immunogenicity, poor pharmacokinetics) as antibodies, thus it would be of high significance to develop small molecule PD-L1 inhibitor-based dual immunotherapy, as small molecules may overcome the above drawbacks of antibodies.