Anti-TGF-β/PD-L1 bispecific antibody promotes T cell infiltration and exhibits enhanced antitumor activity in triple-negative breast cancer

Abstract

BackgroundAgents blocking programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) have been approved for triple-negative breast cancer (TNBC). However, the response rate of anti-PD-1/PD-L1 is still unsatisfactory, partly due to immunosuppressive factors such as transforming growth factor-beta (TGF-β). In our previous pilot study, the bispecific antibody targeting TGF-β and murine PD-L1 (termed YM101) showed potent antitumor effect. In this work, we constructed a bispecific antibody targeting TGF-β and human PD-L1 (termed BiTP) and explored the antitumor effect of BiTP in TNBC.MethodsBiTP was developed using Check-BODYTMbispecific platform. The binding affinity of BiTP was measured by surface plasmon resonance, ELISA, and flow cytometry. The bioactivity was assessed by Smad and NFAT luciferase reporter assays, immunofluorescence, western blotting, and superantigen stimulation assays. The antitumor activity of BiTP was explored in humanized epithelial-mesenchymal transition-6-hPDL1 and 4T1-hPDL1 murine TNBC models. Immunohistochemical staining, flow cytometry, and bulk RNA-seq were used to investigate the effect of BiTP on immune cell infiltration.ResultsBiTP exhibited high binding affinity to dual targets. In vitro experiments verified that BiTP effectively counteracted TGF-β-Smad and PD-L1-PD-1-NFAT signaling. In vivo animal experiments demonstrated that BiTP had superior antitumor activity relative to anti-PD-L1 and anti-TGF-β monotherapy. Mechanistically, BiTP decreased collagen deposition, enhanced CD8+T cell penetration, and increased tumor-infiltrating lymphocytes. This improved tumor microenvironment contributed to the potent antitumor activity of BiTP.ConclusionBiTP retains parent antibodies’ binding affinity and bioactivity, with superior antitumor activity to parent antibodies in TNBC. Our data suggest that BiTP might be a promising agent for TNBC treatment.

Identification of MTHFD2 as a prognostic biomarker and ferroptosis regulator in triple-negative breast cancer

“…In this context, findings from studies suggest that the expression level of immune checkpoints strongly affects immunotherapy efficacy ( 39 ). Hence, immune checkpoint inhibitors are promising therapies for MTHFD2-mediated triple-negative breast cancer ( 40 ).…”

Cardiotoxicity of lung cancer-related immunotherapy versus chemotherapy: a systematic review and network meta-analysis of randomized controlled trials

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Immune Checkpoint Inhibitors in Breast Cancer: A Narrative Review

“…Recent studies show that depending on the cell and cytokine configuration present in the TME, cancer cells are more or less responsive to immunotherapy, leading to the definitions of ''hot'' and ''cold'' tumors [26]. There are many targets directed toward tumor-associated immune and stromal compartments and of these, we highlight tumor growth factor (TGF)-beta, which has many immunosuppressive effects in the TME, by affecting the activities of tumor-infiltrating lymphocytes, macrophages, and regulatory T and dendritic cells and bispecific antibodies (targeting TGF-beta and PD-L1), such as YM101, BiTP, and M7824 [27][28][29].…”