Ontology highlight
ABSTRACT: Background
Therapeutic antibodies targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis induce potent and durable anti-tumor responses in multiple types of cancers. However, only a subset of patients benefits from anti-PD-1/PD-L1 therapies. As a negative regulator of anti-tumor immunity, TGF-? impairs the efficacy of anti-PD-1/PD-L1 and induces drug resistance. Developing a novel treatment strategy to simultaneously block PD-1/PD-L1 and TGF-? would be valuable to enhance the effect of anti-PD-1/PD-L1 and relieve drug resistance.Methods
Based on the Check-BODY™ technology platform, we developed an anti-TGF-?/PD-L1 bispecific antibody YM101. The bioactivity of the anti-TGF-? moiety was determined by Smad-luciferase reporter assay, transwell assay, western blotting, CCK-8, and flow cytometry. The bioactivity of the anti-PD-L1 moiety was measured by T cell activation assays. EMT-6, CT26, and 3LL tumor models were used to investigate the anti-tumor activity of YM101 in vivo. RNA-seq, immunohistochemical staining, and flow cytometry were utilized to analyze the effect of YM101 on the tumor microenvironment.Results
YM101 could bind to TGF-? and PD-L1 specifically. In vitro experiments showed that YM101 effectively counteracted the biological effects of TGF-? and PD-1/PD-L1 pathway, including activating Smad signaling, inducing epithelial-mesenchymal transition, and immunosuppression. Besides, in vivo experiments indicated the anti-tumor activity of YM101 was superior to anti-TGF-? and anti-PD-L1 monotherapies. Mechanistically, YM101 promoted the formation of 'hot tumor': increasing the numbers of tumor infiltrating lymphocytes and dendritic cells, elevating the ratio of M1/M2, and enhancing cytokine production in T cells. This normalized tumor immune microenvironment and enhanced anti-tumor immune response might contribute to the robust anti-tumor effect of YM101.Conclusion
Our results demonstrated that YM101 could simultaneously block TGF-? and PD-L1 pathways and had a superior anti-tumor effect compared to the monotherapies.
SUBMITTER: Yi M
PROVIDER: S-EPMC7885589 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
Journal of hematology & oncology 20210216 1
<h4>Background</h4>Therapeutic antibodies targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis induce potent and durable anti-tumor responses in multiple types of cancers. However, only a subset of patients benefits from anti-PD-1/PD-L1 therapies. As a negative regulator of anti-tumor immunity, TGF-β impairs the efficacy of anti-PD-1/PD-L1 and induces drug resistance. Developing a novel treatment strategy to simultaneously block PD-1/PD-L1 and TGF-β would be va ...[more]