Targeting CD123 in acute myeloid leukemia using a T-cCell-Directed dual-Affinity retargeting platform

Muneera Al-Hussaini, Michael P. Rettig, Julie K. Ritchey, Darja Karpova, Geoffrey L. Uy, Linda G. Eissenberg, Feng Gao, William C. Eades, Ezio Bonvini, Gurunadh R. Chichili, Paul A. Moore, Syd Johnson, Lynne Collins, John F. Dipersio

Research output: Contribution to journalArticlepeer-review

110 Scopus citations

Abstract

T-cell-directed killing of tumor cells using bispecific antibodies is a promising approach for the treatment of hematologic malignancies. Here we describe our preclinical work with a dual-affinity retargeting (DART) molecule generated from antibodies to CD3 and CD123, designed to redirect T cells against acute myeloid leukemia blasts. The CD33CD123 DART (also referred to as MGD006/S80880) consists of 2 independent polypeptides, each composed of the VH of 1 antibody in tandem with the VL of the other antibody. The target antigen CD123 (interleukin 3RA) is highly and differentially expressed in acute myeloid leukemia (AML) blasts compared with normal hematopoietic stem and progenitor cells. In this study we demonstrate that the CD33CD123 DART binds to both human CD3 and CD123 to mediate target-effector cell association, T-cell activation, proliferation, and receptor diversification. The CD33CD123 DART also induces a dose-dependent killing of AML cell lines and primary AML blasts in vitro and in vivo. These results provide the basis for testing the CD33CD123 DART in the treatment of patients with CD123+ AML.

Original languageEnglish
Pages (from-to)122-131
Number of pages10
JournalBlood
Volume127
Issue number1
DOIs
StatePublished - Jan 7 2016

Keywords

  • A novel CD33CD123 dart agent induces t-cell-target-specific association
  • Activation
  • And proliferation
  • The CD33CD123 dart induces a dose-Dependent killing of AML cell lines and primary AML blasts in vitro and in vivo

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