Anti-HER2×CCR4 bispecific antibody enhances antitumor immunity in advanced HER2-positive tumors by chemotaxis blockade and depletion of tumor-associated Tregs, without inducing systemic toxicity.

ABSTRACT:

Background

CCR4⁺ regulatory T cells (Tregs), which are widely present in peripheral circulation and tumor microenvironment (TME), promote tumor immune evasion by infiltrating human epidermal growth factor receptor 2-positive (HER2⁺) tumors in a chemokine-driven manner. However, therapies targeting CCR4 (eg, mogamulizumab) for systemic Treg depletion risk significant toxicity and have far been confined to hematological malignancies. Notably, tumor-chemotactic peripheral Tregs-key precursors to tumor-infiltrating Tregs (tumor-infiltrating lymphocyte (TIL)-Tregs)-remain overlooked.

Methods

We designed and expressed four candidate anti-HER2×CCR4 DVD-Ig bispecific antibodies with varying degrees of anti-CCR4 domain masking, while leaving anti-HER2 domains fu

SUBMITTER: Wang C 

PROVIDER: S-EPMC12719890 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature