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.
Abstract:
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.
Insights
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.
