Development of a bispecific antibody targeting PD-L1 and TIGIT with optimal cytotoxicity

• Published in: Scientific reports 2022-10, Vol.12 (1), p.18011-18011, Article 18011
• Main Authors: Zhong, Zhenwei, Zhang, Mengyao, Ning, Yanan, Mao, Guanchao, Li, Xiaopei, Deng, Qi, Chen, Xiaorui, Zuo, Dongliang, Zhao, Xiangyu, Xie, Ermin, Wang, Huajing, Guo, Lina, Li, Bohua, Xiao, Kai, He, Xiaowen
• Format: Article
• Language: English
• Subjects: 631/154; 631/250; 631/45; 631/61; 631/67; Antibodies; Antibodies, Bispecific; Apoptosis; B7-H1 Antigen; Bispecific antibodies; Cancer immunotherapy; CD11b antigen; Cytotoxicity; Humanities and Social Sciences; Humans; Immunoglobulin G; Immunoglobulin G - therapeutic use; Immunoreceptor tyrosine-based inhibition motif; Immunoregulation; Immunotherapy; Lymphocytes; Lymphocytes T; Metastases; multidisciplinary; Natural killer cells; Neoplasms - drug therapy; Neoplasms - metabolism; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - metabolism; Receptors, Immunologic; Science; Science (multidisciplinary); Tumor cells; Tumor Microenvironment; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-22975-7

Programmed death-ligand 1 (PD-L1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) are two potential targets for cancer immunotherapy, early clinical studies showed the combination therapy of anti-PD-L1 and anti-TIGIT had synergistic efficacy both in the terms of overall response rate (ORR) and overall survival (OS). It is rational to construct bispecific antibodies targeting PD-L1 and TIGIT, besides retaining the efficacy of the combination therapy, bispecific antibodies (BsAbs) can provide a new mechanism of action, such as bridging between tumor cells and T/NK cells. Here, we developed an IgG1-type bispecific antibody with optimal cytotoxicity. In this study, we thoroughly investigated 16 IgG-VHH formats with variable orientations and linker lengths, the results demonstrated that (G4S)2 linker not only properly separated two binding domains but also had the highest protein yield. Moreover, VHH-HC orientation perfectly maintained the binding and cytotoxicity activity of the variable domain of the heavy chain of heavy‐chain‐only antibody (VHH) and immunoglobulin G (IgG). Following treatment with BiPT-23, tumor growth was significantly suppressed in vivo, with more cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells infiltration, and selective depletion of Regulatory T cells (Tregs). BiPT-23 represents novel immunotherapy engineered to prevent hyperprogression of cancer with PD-1 blockade, and preferentially killed PD-L1 + tumor cells, and TIGIT + Tregs but maintained CD11b + F4/80 + immune cells within the tumor microenvironment (TME).