Development and Preliminary Clinical Activity of PD-1-Guided CTLA-4 Blocking Bispecific DART Molecule
Alexey Berezhnoy1, Bradley J Sumrow1, Kurt Stahl1
1MacroGenics, Rockville, MD, USA.
Cell Reports. Medicine
|December 30, 2020
Summary
A novel bispecific antibody, MGD019, targeting PD-1 and CTLA-4, demonstrates effective dual immune checkpoint blockade in preclinical models and early human trials for advanced cancers.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Combination immunotherapy using PD-1 and CTLA-4 inhibitors improves cancer treatment outcomes.
- Increased toxicity is a concern with combined checkpoint blockade.
- Tumor-infiltrating lymphocytes co-express PD-1 and CTLA-4.
Purpose of the Study:
- To evaluate MGD019, a bispecific DART molecule engineered for enhanced PD-1 and CTLA-4 blockade in the tumor microenvironment.
- To assess the in vitro and in vivo efficacy and safety of MGD019.
Main Methods:
- In vitro studies confirmed MGD019's ability to block both PD-1 and CTLA-4.
- Non-human primate studies assessed MGD019 tolerability and pharmacodynamic effects.
- A first-in-human Phase 1 study (NCT03761017) evaluated MGD019 in patients with advanced solid tumors.
Main Results:
- MGD019 demonstrated dual PD-1 and CTLA-4 blockade in vitro.
- MGD019 was well-tolerated in non-human primates, showing increased CD8+ T cells (Ki67+) and CD4+ T cells (ICOS+).
- Early human trial data showed acceptable safety, pharmacodynamic evidence of blockade, and objective responses in refractory tumors.
Conclusions:
- MGD019 effectively achieves combined PD-1 and CTLA-4 blockade with a single molecule.
- The bispecific DART molecule shows promise as a novel immunotherapy for advanced solid tumors.
- MGD019 warrants further investigation in larger clinical trials.
