Bispecific antibody approach for improved melanoma-selective PD-L1 immune checkpoint blockade

Abstract Reactivation of functionally-impaired anticancer T cells by PD-1/PD-L1-blocking antibodies shows prominent therapeutic benefit in advanced melanoma and NCSLC patients. However, current PD-L1-blocking antibodies lack intrinsic tumor-selectively. Therefore, efficacy may be reduced due to ‘on-target/off-tumor’ binding to PD-L1-expressing normal cells. This may lead to indiscriminate activation of antigen-experienced T cells, including those implicated in autoimmune-related adverse events. To direct PD-L1-blockade to CSPG4-expressing cancers and to reactivate anticancer T cells more selectively we constructed bispecific antibody (bsAb) PD-L1xCSPG4. CSPG4 is an established target antigen that is selectively overexpressed on malignant melanoma and various other difficult-to-treat cancers. PD-L1xCSPG4 showed enhanced capacity for CSPG4-directed blockade of PD-L1 on cancer cells. Importantly, treatment of mixed-cultures containing primary patient-derived CSPG4-expressing melanoma cells and autologous tumor-infiltrating lymphocytes with PD-L1xCSPG4 significantly enhanced activation status, IFN-γ production, and cytolytic activity of anticancer T cells. In conclusion, tumor-directed blockade of PD-L1 by PD-L1xCSPG4 may improve efficacy and safety of PD-1/PD-L1 checkpoint blockade for treatment of melanoma and other CSPG4-overexpressing malignancies.