TY - JOUR
T1 - Targeting CD123 in acute myeloid leukemia using a T-cCell-Directed dual-Affinity retargeting platform
AU - Al-Hussaini, Muneera
AU - Rettig, Michael P.
AU - Ritchey, Julie K.
AU - Karpova, Darja
AU - Uy, Geoffrey L.
AU - Eissenberg, Linda G.
AU - Gao, Feng
AU - Eades, William C.
AU - Bonvini, Ezio
AU - Chichili, Gurunadh R.
AU - Moore, Paul A.
AU - Johnson, Syd
AU - Collins, Lynne
AU - Dipersio, John F.
N1 - Publisher Copyright:
© 2016 by The American Society of Hematology.
PY - 2016/1/7
Y1 - 2016/1/7
N2 - 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.
AB - 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.
KW - A novel CD33CD123 dart agent induces t-cell-target-specific association
KW - Activation
KW - And proliferation
KW - The CD33CD123 dart induces a dose-Dependent killing of AML cell lines and primary AML blasts in vitro and in vivo
UR - http://www.scopus.com/inward/record.url?scp=84955453336&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-05-575704
DO - 10.1182/blood-2014-05-575704
M3 - Article
C2 - 26531164
AN - SCOPUS:84955453336
SN - 0006-4971
VL - 127
SP - 122
EP - 131
JO - Blood
JF - Blood
IS - 1
ER -