LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation.

Autor:	Sung E; ABL Bio Inc., Seongnam 13488, South Korea., Ko M; Theragnosis Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, South Korea., Won JY; Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea., Jo Y; 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., Park E; ABL Bio Inc., Seongnam 13488, South Korea., Kim H; ABL Bio Inc., Seongnam 13488, South Korea., Choi E; Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea., Jung UJ; ABL Bio Inc., Seongnam 13488, South Korea., Jeon J; ABL Bio Inc., Seongnam 13488, South Korea., Kim Y; ABL Bio Inc., Seongnam 13488, South Korea., Ahn H; Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea., Choi DS; Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea., Choi S; Theragnosis Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, South Korea., Hong Y; ABL Bio Inc., Seongnam 13488, South Korea., Park H; ABL Bio Inc., Seongnam 13488, South Korea., Lee H; ABL Bio Inc., Seongnam 13488, South Korea., Son YG; ABL Bio Inc., Seongnam 13488, South Korea., Park K; ABL Bio Inc., Seongnam 13488, South Korea., Won J; ABL Bio Inc., Seongnam 13488, South Korea., Oh SJ; Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea., Lee S; Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea., Kim KP; Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea., Yoo C; Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea., Song HK; Department of Life Sciences, Korea University, Seoul 02481, South Korea., Jin HS; 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., Jung J; ABL Bio Inc., Seongnam 13488, South Korea. Electronic address: jaeho.jung@ablbio.com., Park Y; Theragnosis Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, South Korea. Electronic address: ypark@kist.re.kr.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2022 Aug 03; Vol. 30 (8), pp. 2800-2816. Date of Electronic Publication: 2022 May 06.
DOI:	10.1016/j.ymthe.2022.05.003
Abstrakt:	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). Competing Interests: Declaration of interests E.S., E.P., H.K., U.J., J. Jeon, Y.K., Y.H., H.P., H.L., Y.-G.S., K.P., Jonghwa Won, and J. Jung are employees of ABL Bio Inc. The other authors declare no competing interests. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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