Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGF beta enhance the efficacy of cancer immunotherapy

A majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express transforming growth factor-beta (TGF beta), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8(+) and T(H)1 cells. To address this therapeutic challenge, we invent bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGF beta receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGF beta in the target cell microenvironment (alpha-CTLA4-TGF beta RIIecd and alpha-PDL1-TGF beta RIIecd). alpha-CTLA4-TGF beta RIIecd is more effective in reducing tumor-infiltrating Tregs and inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab). Likewise, alpha-PDL1-TGF beta RIIecd exhibits superior antitumor efficacy compared with PD-L1 antibodies (Atezolizumab or Avelumab). Our data demonstrate that Y-traps counteract TGF beta-mediated differentiation of Tregs and immune tolerance, thereby providing a potentially more effective immunotherapeutic strategy against cancers that are resistant to current immune checkpoint inhibitors.