A CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: preclinical activity and safety in nonhuman primates.

Abstract

Current therapies for acute myeloid leukemia (AML) are largely ineffective, and AML patients may benefit from targeted immunotherapy approaches. MGD006 is a bispecific CD3xCD123 dual-affinity re-targeting (DART) molecule that binds T lymphocytes and cells expressing CD123, an antigen up-regulated in several hematological malignancies including AML. MGD006 mediates blast killing in AML samples, together with concomitant activation and expansion of residual T cells. MGD006 is designed to be rapidly cleared, and therefore requires continuous delivery. In a mouse model of continuous administration, MGD006 eliminated engrafted KG-1a cells (an AML-M0 line) in human PBMC (peripheral blood mononuclear cell)-reconstituted NSG/β2m(-/-) mice at doses as low as 0.5 μg/kg per day for ~7 days. MGD006 binds to human and cynomolgus monkey antigens with similar affinities and redirects T cells from either species to kill CD123-expressing target cells. MGD006 was well tolerated in monkeys continuously infused with 0.1 μg/kg per day escalated weekly to up to 1 μg/kg per day during a 4-week period. Depletion of circulating CD123-positive cells was observed as early as 72 hours after treatment initiation and persisted throughout the infusion period. Cytokine release, observed after the first infusion, was reduced after subsequent administrations, even when the dose was escalated. T cells from animals with prolonged in vivo exposure exhibited unperturbed target cell lysis ex vivo, indicating no exhaustion. A transient decrease in red cell mass was observed, with no neutropenia or thrombocytopenia. These studies support clinical testing of MGD006 in hematological malignancies, including AML.

• Authors: Gurunadh R Chichili, Ling Huang, Hua Li, Steve Burke, Leilei He, Qin Tang, Linda Jin, Sergey Gorlatov, Valentina Ciccarone, Francine Chen, Scott Koenig, Michele Shannon, Ralph Alderson, Paul A Moore, Syd Johnson, Ezio Bonvini
• Journal: Science translational medicine (Sci Transl Med) Vol. 7 Issue 289 Pg. 289ra82 (May 27 2015) ISSN: 1946-6242 [Electronic] United States
• PMID: 26019218 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Antigens, CD
• CD3 Complex
• Cytokines
• Interleukin-3 Receptor alpha Subunit

Topics

• Animals
• Antigens, CD
• Bone Marrow (pathology)
• CD3 Complex (metabolism)
• Cell Death
• Cell Proliferation
• Cytokines (metabolism)
• Dose-Response Relationship, Immunologic
• Female
• Hematopoiesis
• Humans
• Interleukin-3 Receptor alpha Subunit (metabolism)
• Leukemia, Myeloid, Acute (immunology, pathology)
• Lymphocyte Activation (immunology)
• Lymphocyte Count
• Macaca fascicularis
• Male
• Mice
• Protein Binding
• Protein Engineering
• T-Lymphocytes (immunology)