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).
