2. Academic Validation
  3. Development and Preliminary Clinical Activity of PD-1-Guided CTLA-4 Blocking Bispecific DART Molecule

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

  • Cell Rep Med. 2020 Dec 22;1(9):100163. doi: 10.1016/j.xcrm.2020.100163.
Alexey Berezhnoy 1,  Bradley J Sumrow 1,  Kurt Stahl 1,  Kalpana Shah 1,  Daorong Liu 1,  Jonathan Li 2,  Su-Shin Hao 1,  Anushka De Costa 2,  Sanjeev Kaul 3,  Johanna Bendell 4,  Gregory M Cote 5,  Jason J Luke 6,  Rachel E Sanborn 7,  Manish R Sharma 8,  Francine Chen 2,  Hua Li 1,  Gundo Diedrich 1,  Ezio Bonvini 1,  Paul A Moore 1
Affiliations

Affiliations

  • 1 MacroGenics, Rockville, MD, USA.
  • 2 MacroGenics, Brisbane, CA, USA.
  • 3 Bio-ClinPharm Consulting, Cranbury, NJ, USA.
  • 4 Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA.
  • 5 Massachusetts General Hospital Cancer Center, Boston, MA, USA.
  • 6 UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
  • 7 Earle A. Chiles Research Institute at Providence Cancer Institute, Portland, OR, USA.
  • 8 START-Midwest, Grand Rapids, MI, USA.
PMID: 33377134 DOI: 10.1016/j.xcrm.2020.100163
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.

Keywords

CTLA-4; PD-1; bispecific; checkpoint; combinatorial; immunotherapy; pharmacodynamics.

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