Sung and Ko et al. developed a bispecific antibody, ABL501, that co-targets PD-L1 and LAG3. In vitro, ABL501 enhanced the proliferation, activation, and effector functions of CD4+ and CD8+ T cells through blockade of inhibitory LAG3 and PD-1 signaling in T cells; through blockade of PD-L1 signaling on DCs, leading to improved DC maturation; and through promotion of T cell conjugation with tumor cells. In humanized mouse models, BL501 enhanced antigen-specific T cell responses and improved antitumor efficacy compared to combined monotherapy. LAG3hiPD-1hi memory CD4+ T cell signatures predicted responses in patients with cholangiocarcinoma.
Contributed by Lauren Hitchings
ABSTRACT: Several preclinical studies demonstrate that antitumor efficacy of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade can be improved by combination with other checkpoint inhibitors. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory checkpoint receptor involved in T cell exhaustion and tumor immune escape. Here, we describe ABL501, a bispecific antibody targeting LAG-3 and PD-L1 in modulating immune cell responses against tumors. ABL501 that efficiently inhibits both LAG-3 and PD-L1 pathways enhances the activation of effector CD4(+) and CD8(+) T cells with a higher degree than a combination of single anti-LAG-3 and anti-PD-L1. The augmented effector T cell responses by ABL501 resulted in mitigating regulatory-T-cell-mediated immunosuppression. Mechanistically, the simultaneous binding of ABL501 to LAG-3 and PD-L1 promotes dendritic cell (DC) activation and tumor cell conjugation with T cells that subsequently mounts effective CD8(+) T cell responses. ABL501 demonstrates its potent in vivo antitumor efficacy in a humanized xenograft model and with knockin mice expressing human orthologs. The immune profiling analysis of peripheral blood reveals an increased abundance of LAG-3(hi)PD-1(hi) memory CD4(+) T cell subset in relapsed cholangiocarcinoma patients after gemcitabine plus cisplatin therapy, which are more responsive to ABL501. This study supports the clinical evaluation of ABL501 as a novel cancer immunotherapeutic, and a first-in-human trial has started (NCT05101109).
Author Info: (1) ABL Bio Inc., Seongnam 13488, South Korea. (2) Theragnosis Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, South Korea. (3
Author Info: (1) ABL Bio Inc., Seongnam 13488, South Korea. (2) Theragnosis Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, South Korea. (3) Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea. (4) Theragnosis Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, South Korea; Department of Life Sciences, Korea University, Seoul 02481, South Korea. (5) ABL Bio Inc., Seongnam 13488, South Korea. (6) ABL Bio Inc., Seongnam 13488, South Korea. (7) Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea. (8) ABL Bio Inc., Seongnam 13488, South Korea. (9) ABL Bio Inc., Seongnam 13488, South Korea. (10) ABL Bio Inc., Seongnam 13488, South Korea. (11) Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea. (12) Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea. (13) Theragnosis Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, South Korea. (14) ABL Bio Inc., Seongnam 13488, South Korea. (15) ABL Bio Inc., Seongnam 13488, South Korea. (16) ABL Bio Inc., Seongnam 13488, South Korea. (17) ABL Bio Inc., Seongnam 13488, South Korea. (18) ABL Bio Inc., Seongnam 13488, South Korea. (19) ABL Bio Inc., Seongnam 13488, South Korea. (20) Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea. (21) Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea. (22) Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea. (23) Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea. (24) Department of Life Sciences, Korea University, Seoul 02481, South Korea. (25) Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea. Electronic address: hsjin@amc.seoul.kr. (26) ABL Bio Inc., Seongnam 13488, South Korea. Electronic address: jaeho.jung@ablbio.com. (27) Theragnosis Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, South Korea. Electronic address: ypark@kist.re.kr.
