PD‐L1/TIGIT bispecific antibody showed survival advantage in animal model

Dear Editor, Although PD-1 and PD-L1 (programmed cell death1/ligand 1) antibody therapies have provided persistent benefits in various cancers, their clinical applications have been limited by relatively low response rates and the occurrence of drug resistance.1 Thus, they have been extensively investigated in combination with a variety of antitumor therapies, such as inhibitors to other immune checkpoints in combinational or bispecific antibody (BsAb) therapeutical strategies, to improve the response rates or efficacies in the clinic.2 TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains) is an inhibitory T-cell immunoreceptor discovered in 2009,3 which is expressed mainly on regulatory T cells (Tregs), memory T-cells, and NK cells. Combination therapies that block both PD-L1 and TIGIT pathways have superior clinical benefits to PD-L1 monotherapy.4 BsAbs simultaneously targeting both pathways are also entering clinical trials (NCT05102214), but whether BsAbs are superior to combinational approaches has not been elucidated yet. We reported here a novel bispecific anti-PD-L1/TIGIT antibodywith potent effects in enhancing human IL-2 production by primary human T cells in vitro and in increasing the overall survival in a transgenic mouse model in vivo.More importantly, we compared the tetravalent bispecific anti-PD-L1/TIGIT antibody to mAb and combination therapies head-to-head systematically, and our data supported the the advantage of taking bispecific approach over mAb and combination therapies experimentally. First, hybridomas were established5 and humanization was carried out through "framework shuffling6,7 on both anti-PD-L1 and anti-TIGIT antibodies. Both chimeric (antiPD-L1-8A1 and anti-TIGIT-31C3) and humanized (antiPD-L1-#77, anti-TIGIT-T26 and T87) antibodies showed binding and blocking capabilities comparable to corresponding positive controls (Figure 1A–D), i.e., atezolizumab (Tencentriq) for anti-PD-L1 and tiragolumab for