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

• Published in: Cell reports. Medicine 2020-12, Vol.1 (9), p.100163, Article 100163
• Main Authors: Berezhnoy, Alexey, Sumrow, Bradley J., Stahl, Kurt, Shah, Kalpana, Liu, Daorong, Li, Jonathan, Hao, Su-Shin, De Costa, Anushka, Kaul, Sanjeev, Bendell, Johanna, Cote, Gregory M., Luke, Jason J., Sanborn, Rachel E., Sharma, Manish R., Chen, Francine, Li, Hua, Diedrich, Gundo, Bonvini, Ezio, Moore, Paul A.
• Format: Article
• Language: English
• Subjects: Antibodies - therapeutic use; bispecific; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; checkpoint; combinatorial; CTLA-4; CTLA-4 Antigen - drug effects; CTLA-4 Antigen - immunology; Humans; Immune Checkpoint Inhibitors - therapeutic use; immunotherapy; Immunotherapy - methods; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; PD-1; pharmacodynamics; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2020.100163

Combination immunotherapy with antibodies directed against PD-1 and CTLA-4 shows 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, is engineered to maximize checkpoint blockade in the tumor microenvironment via enhanced CTLA-4 blockade in a PD-1-binding-dependent manner. In vitro, MGD019 mediates the combinatorial blockade of PD-1 and CTLA-4, confirming dual inhibition via a single molecule. MGD019 is 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. [Display omitted] PD-1 and CTLA-4 are co-expressed by TILs but not healthy lymphocytesMGD019 is designed to block PD-1 and deliver enhanced CTLA-4 blockade in TMEMGD019 is safe in NHP while demonstrating biomarkers of PD-1 and CTLA-4 inhibitionEncouraging activity in tumors traditionally unresponsive to checkpoint blockade Co-blockade of PD-1 and CTLA-4 increases benefits in cancer immunotherapy but also its toxicity. Berezhnoy et al. constructed a bispecific DART molecule to deliver safer and potentially more effective co-blockade by targeting CTLA-4 inhibition to tumors. MGD019 demonstrates encouraging activity in tumors traditionally unresponsive to checkpoint blockade.