Recombinant anti-PD-L1/TGF-β bispecific antibody (Wuhan YZY Biopharma)

In the previous studies, anti‐TGF‐β/PD‐L1 bispecific antibody YM101 is demonstrated, with superior efficacy to anti‐PD‐L1 monotherapy in multiple tumor models. However, YM101 therapy can not achieve complete regression in most tumor‐bearing mice, suggesting the presence of other immunosuppressive elements in the tumor microenvironment (TME) beyond TGF‐β and PD‐L1. Thoroughly exploring the TME is imperative to pave the way for the successful translation of anti‐TGF‐β/PD‐L1 BsAb into clinical practice. In this work, scRNA‐seq is employed to comprehensively profile the TME changes induced by YM101. The scRNA‐seq analysis reveals an increase in immune cell populations associated with antitumor immunity and enhances cell‐killing pathways. However, the analysis also uncovers the presence of immunosuppressive CCR5+ T cells in the TME after YM101 treatment. To overcome this hurdle, YM101 is combined with Maraviroc, a widely used CCR5 antagonist for treating HIV infection, suppressing CCR5+ T cell accumulation, and optimizing the immune response. Mechanistically, YM101‐induced neutrophil activation recruits immunosuppressive CCR5+ T cells via CCR5 ligand secretion, creating a feedback loop that diminishes the antitumor response. Maraviroc then cleared these infiltrating cells and offset YM101‐mediated immunosuppressive effects, further unleashing the antitumor immunity. These findings suggest selectively targeting CCR5 signaling with Maraviroc represents a promising and strategic approach to enhance YM101 efficacy.