LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation
Eunsil Sung1, Minkyung Ko2, Ju-Young Won3
1ABL Bio Inc., Seongnam 13488, South Korea.
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).
Insights
A novel bispecific antibody, ABL501, targets both Lymphocyte-activation gene 3 (LAG-3) and Programmed death-ligand 1 (PD-L1) to enhance anti-tumor immune responses. This approach shows potent efficacy by boosting T-cell activation and overcoming immunosuppression, supporting its clinical evaluation.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint inhibitors like PD-1/PD-L1 blockade are crucial in cancer therapy.
- Combining checkpoint inhibitors can improve antitumor efficacy.
- LAG-3 is an inhibitory receptor implicated in T-cell exhaustion and immune evasion.
Purpose of the Study:
- To introduce ABL501, a bispecific antibody targeting LAG-3 and PD-L1.
- To evaluate the immune-modulating effects and antitumor efficacy of ABL501.
- To identify patient populations potentially responsive to ABL501.
Main Methods:
- Development of a bispecific antibody (ABL501) targeting LAG-3 and PD-L1.
- Assessment of T-cell activation (CD4+, CD8+) and regulatory T-cell suppression.
- In vivo studies using humanized xenograft and knockin mouse models.
- Analysis of peripheral blood immune cells in cholangiocarcinoma patients.
Main Results:
- ABL501 enhanced effector T-cell activation more effectively than combined single inhibitors.
- ABL501 mitigated regulatory T-cell-mediated immunosuppression.
- The antibody promoted dendritic cell activation and T-cell tumor cell conjugation.
- ABL501 demonstrated potent in vivo antitumor efficacy.
- A specific T-cell subset (LAG-3hiPD-1hi memory CD4+) in cholangiocarcinoma patients showed responsiveness to ABL501.
Conclusions:
- ABL501 is a promising novel bispecific antibody for cancer immunotherapy.
- The simultaneous blockade of LAG-3 and PD-L1 pathways enhances anti-tumor immunity.
- ABL501 warrants further clinical investigation, with a first-in-human trial initiated.
