Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events

Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra-or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)-super-affinity peptide derived from placenta growth factor-2 (PlGF-(2123-144)). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-(2123-144) conjugation, reducing systemic side effects such as the risk of autoimmune diabetes. Peritumoral injections of PlGF-(2123-144)-anti-CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-(2123-144)-anti-PD-L1 (programmed death ligand 1) Abs delayed tumor growth and prolonged survival compared to the unmodified Abs in genetically engineered murine tumor models of melanoma and breast cancer. The PlGF-(2123-144)-Abs increased tumor-infiltrating activated CD8(+) and CD4(+) T cells, resulting in a delay of distant tumor growth as well. This simple and translatable approach of engineered ECM-binding Abs may present a viable and safer approach in checkpoint blockade.