Development and Preliminary Clinical Activity of PD-1-Guided CTLA-4 Blocking Bispecific DART® Molecule

Combination immunotherapy with antibodies directed against PD-1 and CTLA-4 has shown improved clinical benefit across cancer indications compared to single agents, albeit with increased toxicity. Leveraging the observation that PD-1 and CTLA-4 are co-expressed by tumor-infiltrating lymphocytes, an investigational PD-1 x CTLA-4 bispecific DART® molecule, MGD019, was developed to maximize checkpoint blockade in the tumor microenvironment via enhanced CTLA-4 blockade in a PD-1-binding dependent manner. In vitro, MGD019 mediates combinatorial blockade of PD-1 and CTLA-4 confirming dual inhibition via a single molecule. MGD019 was well tolerated in non-human primates, with evidence of both PD-1 and CTLA-4 blockade including increases in Ki67+CD8 and ICOS+CD4 T cells respectively. In the ongoing MGD019 first-in-human study enrolling patients with advanced solid tumors (NCT03761017), an analysis undertaken following the dose escalation phase revealed acceptable safety, pharmacodynamic evidence of combinatorial blockade, and objective responses in multiple tumor types typically unresponsive to checkpoint inhibitor therapy.