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

Eunsil Sung, Minkyung Ko, Ju young Won, Yunju Jo, Eunyoung Park, Hyunjoo Kim, Eunji Choi, Ui jung Jung, Jaehyoung Jeon, Youngkwang Kim, Hyejin Ahn, Da som Choi, Seunghyun Choi, Youngeun Hong, Hyeyoung Park, Hanbyul Lee, Yong Gyu Son, Kyeongsu Park, Jonghwa Won, Soo Jin OhSeonmin Lee, Kyu pyo Kim, Changhoon Yoo, Hyun Kyu Song, Hyung seung Jin, Jaeho Jung, Yoon Park

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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-3hiPD-1hi 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).

Original languageEnglish
Pages (from-to)2800-2816
Number of pages17
JournalMolecular Therapy
Volume30
Issue number8
DOIs
Publication statusPublished - 2022 Aug 3

Keywords

  • LAG-3
  • PD-L1
  • bispecific antibody
  • cancer immunotherapy
  • cholangiocarcinoma
  • immune checkpoint inhibitor

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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