A novel anti-LAG-3/TIGIT bispecific antibody exhibits potent anti-tumor efficacy in mouse models as monotherapy or in combination with PD-1 antibody

• Published in: Scientific reports Vol. 14; no. 1; p. 10661
• Main Authors: Dai, Tongcheng, Sun, Hao, Liban, Tyler, Vicente-Suarez, Ildefonso, Zhang, Bin, Song, Yongping, Jiang, Zhongxing, Yu, Jifeng, Sheng, Jackie, Lv, Binhua
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 692/308/153; 692/308/2778; Animal models; Animals; Antibodies; Antibodies, Bispecific - pharmacology; Antibodies, Bispecific - therapeutic use; Antigens, CD - immunology; Antigens, CD - metabolism; Bispecific antibodies; Bispecific monoclonal antibody; Cancer immunotherapy; CD223 antigen; Cell Line, Tumor; CHO Cells; Cricetulus; Cytokines; Disease Models, Animal; Female; Humanities and Social Sciences; Humans; Immune checkpoint inhibitor; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunoglobulin G; Lymphocyte Activation Gene 3 Protein; Lymphocyte-activation gene 3 (LAG-3); Mice; multidisciplinary; PD-1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - immunology; Receptors, Immunologic - metabolism; Science; Science (multidisciplinary); Synergistic effect; T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT); Tumors; Xenograft Model Antitumor Assays; Lymphocyte-activation gene 3 (LAG-3); Bispecific monoclonal antibody; Immune checkpoint inhibitor; Cancer immunotherapy; T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-61477-6

We report the generation of a novel anti-LAG-3/TIGIT bispecific IgG4 antibody, ZGGS15, and evaluated its anti-tumor efficacy in mouse models as monotherapy or in combination with a PD-1 antibody. ZGGS15 exhibited strong affinities for human LAG-3 and TIGIT, with KDs of 3.05 nM and 2.65 nM, respectively. ZGGS15 has EC50s of 0.69 nM and 1.87 nM for binding to human LAG-3 and TIGIT on CHO-K1 cells, respectively. ZGGS15 competitively inhibited the binding of LAG-3 to MHC-II (IC50 = 0.77 nM) and the binding of TIGIT to CD155 (IC50 = 0.24 nM). ZGGS15 does not induce ADCC, CDC, or obvious cytokine production. In vivo results showed that ZGGS15 had better anti-tumor inhibition than single anti-LAG-3 or anti-TIGIT agents and demonstrated a synergistic effect when combined with nivolumab, with a significantly higher tumor growth inhibition of 95.80% ( p  = 0.001). The tumor volume inhibition rate for ZGGS15 at 2 mg/kg was 69.70%, and for ZGGS15 at 5 mg/kg plus nivolumab at 1 mg/kg, it was 94.03% ( p  < 0.001). Our data reveal that ZGGS15 exhibits potent anti-tumor efficacy without eliciting ADCC or CDC or causing cytokine production, therefore having a safe profile.