Development and Preliminary Clinical Activity of PD-1-Guided CTLA-4 Blocking Bispecific DART Molecule
Open accessAbstract
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.
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Numerous bispecific antibodies have been developed, including CTLA-4 × PD-L1 (KN046), CTLA-4 × PD-1 (MGD019 and MEDI5752), LAG-3 × PD-L1 (IBI323), LAG-3 × PD-1 (Tebotelimab), TIM-3 × PD-L1 (LY3415244), TIM-3 × PD-1, and TIGIT×PD-L1.
“Numerous bispecific antibodies have been developed, including CTLA-4 × PD-L1 (KN046) [281], CTLA-4 × PD-1 (MGD019 and MEDI5752) [282, 283], LAG-3 × PD-L1 (IBI323) [284], LAG-3 × PD-1 (Tebotelimab) [285], TIM-3 × PD-L1 (LY3415244) [286], TIM-3 × PD-1 [305], TIGIT×PD-L1 [287].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [282]
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Self-citation
- Authors
- Berezhnoy, A., Sumrow, B. J., Stahl, K., Shah, K., Liu, D., Li, J., Hao, S.-S., De Costa, A., Kaul, S., Bendell, J., Cote, G. M., Luke, J. J., Sanborn, R. E., Sharma, M. R., Chen, F., Li, H., Diedrich, G., Bonvini, E., & Moore, P. A.
- Affiliations
- MacroGenics (United States) (US)
- Cranberry Institute (US)
- Sarah Cannon (US)
- Massachusetts General Hospital (US)
- UPMC Hillman Cancer Center (US)
- Providence Portland Medical Center (US)
- Corresponding author
- Moore, Paul A.
- ORCID
- Venue
- Cell Reports Medicine
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 1
- Issue
- 9
- Pages
- 100163
- ISSN
- 2666-3791 (ISSN-L)
- PMC
- PMC7762776
- OpenAlex
- W3115547163
- Cited by
- 56
- References
- 42
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 13 · 2023: 14 · 2022: 9 · 2021: 8
- FWCI
- 2.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports Medicine (publishedVersion, cc-by-nc-nd)
- SSRN Electronic Journal (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- MacroGenics
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- PD-1, CTLA-4, immune checkpoint blockade, combination immunotherapy, tumor-infiltrating lymphocytes, non-human primate toxicity, dose escalation, solid tumors, CD8+ T cells
- MeSH terms
- Immune Checkpoint Inhibitors, Antibodies, Humans, Immunotherapy, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Tumor Microenvironment, CTLA-4 Antigen, Programmed Cell Death 1 Receptor
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