Ishihara et al. conjugated the heparin-binding domain of placenta growth factor-2 (PlGF-2123-144) to αCTLA-4 and αPD-L1 antibodies and demonstrated that peritumoral injection of PlGF-2123-144-αCTLA-4 + PlGF-2123-144-αPD-L1 into mice with melanoma or breast cancer enhanced local and systemic antitumor immunity, prolonged survival, and reduced the risk of systemic side effects compared with unconjugated antibodies by binding to the extracellular matrix and retaining antibodies within the tumor.
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.