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The construction, expression, and enhanced anti-tumor activity of YM101: a bispecific antibody simultaneously targeting TGF-? and PD-L1.


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

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Publications

The construction, expression, and enhanced anti-tumor activity of YM101: a bispecific antibody simultaneously targeting TGF-β and PD-L1.

Yi Ming M   Zhang Jing J   Li Anping A   Niu Mengke M   Yan Yongxiang Y   Jiao Ying Y   Luo Suxia S   Zhou Pengfei P   Wu Kongming K  

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]

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