Discovery of a novel anti PD-L1 X TIGIT bispecific antibody for the treatment of solid tumors.
Yang Xiao, Peiran Chen, Cheng Luo, Ziyang Xu, Xue Li, Liqiong Liu, Liwen Zhao
Abstract
The emergence of immune checkpoint inhibitors (ICIs), mainly based on PD-1/PD-L1 blockade has revolutionized the therapeutic landscape of cancer. Despite the huge clinical success ICIs have achieved, about 70% of patients still showed de novo and adaptive resistance. Exploring novel and complementary immune checkpoint molecules in addition to PD-1/PD-L1 is in great urgency. T cell immunoglobulin and ITIM domain (TIGIT) is a co-inhibitory molecule containing an immunoreceptor tyrosine-based inhibition motif (ITIM) within its cytoplasmic tail, and is highly expressed on regulatory T cells and activated CD4+ T, CD8+ T, and NK cells. We generated a novel single chain Fab heterodimeric bispecific IgG antibody format targeting PD-L1 and TIGIT with one binding site for each target antigen. The bispecifc antibody BiAb-1 is based on "knob-into-hole" technology for heavy chain heterodimerization with a glycine serine linker connecting the 3' end of Cκand the 5' end of VH to prevent wrong pairing of light chains. BiAb-1 was produced with high expression yields and show simultaneous binding to PD-L1 and TIGIT with high affinity. Importantly, cytokine production was enhanced by BiAb-1 from staphylococcal enterotoxin B (SEB) stimulated PBMCs. BiAb-1 also demonstrated potent anti-tumor efficacy in multiple tumor models and superior activity to PD-1/PD-L1 blockade molecules. In conclusion, we have applied rational antibody engineering technology to develop a monovalent heterodimeric bispecifc antibody, which combines the blockade of both PD-1/PD-L1 and TIGIT/CD155 pathways simultaneously and results in superior anti-tumor efficacy in multiple tumor models over existing anti PD-1/PD-L1 molecules.