Development and Preliminary Clinical Activity of PD-1-Guided CTLA-4 Blocking Bispecific DART Molecule
| Autor: | Kurt Stahl, Gregory M. Cote, Anushka De Costa, Kalpana Shah, Daorong Liu, Johanna C. Bendell, Sanjeev Kaul, Alexey Berezhnoy, Hua Li, Su-Shin Hao, Ezio Bonvini, Manish R. Sharma, Francine Chen, Jason J. Luke, Rachel E. Sanborn, Jonathan C. Li, Paul A. Moore, Bradley James Sumrow, Gundo Diedrich |
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| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_treatment
Programmed Cell Death 1 Receptor CD8-Positive T-Lymphocytes bispecific Antibodies Article General Biochemistry Genetics and Molecular Biology Lymphocytes Tumor-Infiltrating checkpoint PD-1 Tumor Microenvironment pharmacodynamics Humans Medicine CTLA-4 Antigen Immune Checkpoint Inhibitors Tumor microenvironment biology business.industry Cancer Immunotherapy medicine.disease combinatorial In vitro Blockade CTLA-4 Toxicity biology.protein Cancer research immunotherapy Antibody business CD8 |
| Zdroj: | Cell Reports Medicine |
| ISSN: | 2666-3791 |
| DOI: | 10.1016/j.xcrm.2020.100163 |
| Popis: | Summary 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. Graphical Abstract Highlights PD-1 and CTLA-4 are co-expressed by TILs but not healthy lymphocytes MGD019 is designed to block PD-1 and deliver enhanced CTLA-4 blockade in TME MGD019 is safe in NHP while demonstrating biomarkers of PD-1 and CTLA-4 inhibition Encouraging 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. |
| Databáze: | OpenAIRE |
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