Targeting CD123 in acute myeloid leukemia using a T-cell–directed dual-affinity retargeting platform

Abstract

Key Points• A novel CD33CD123DART 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.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 V H of 1 antibody in tandem with the V L 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 1 AML. (Blood.2016;127(1):122-131)

Antibody darts on target for acute myelogenous leukemia

“…Subsequently this group further explored the therapeutic potential of the CD123/ DART. They studied the interaction between T cells, antibody and primary human AML targets and cell lines in vitro and in vivo in non-obese diabetic immune deficient (NSG) mice (18). They confirmed that the CD123 DART binds to both human CD3 and CD123 to mediate targeteffector cell association, T-cell activation, proliferation, and receptor diversification.…”

“…Recombinant technology is used to link the variable heavy and light domains of two antibodies as a single 55 kDa polypeptide chain. In clinical (12); (II) chimeric antigen receptor T cell using anti CD123 to target myeloid cells (13,14) (not yet in clinical trial); (III) single polypeptide chain bispecific engager antibodies (BiTE) recognizing CD3 and CD3 (15) or CD123 (16); (IV) double polypeptide chain dual affinity retargeting antibodies (DART) recognizing CD3 and CD123 (17,18). AML, acute myelogenous leukemia; VL, light chain; VH, heavy chain; CD3z, zeta chain of CD3; Co-stim, costimulatory molecules.…”

An anti-CD3/anti–CLL-1 bispecific antibody for the treatment of acute myeloid leukemia

“…7,8 Our in vitro HSC/progenitor CFU assay suggests minimal impact on hematopoiesis by a CLL-1 TDB, whereas it is ambiguous for a CD123-directed molecule given the reports of marked impairment of human hematopoiesis by a CAR-T-CD123, but none with a CD123-DART. [18][19][20] Rather than using an antibody-fragmentbased format like the CD33 BiTE 21 or CD123 DART, 19 a fulllength IgG was used for improving PK and potentially lowering immunogenicity. We hypothesized that CD3 affinity would be a key driver of both efficacy and safety.…”

Characterization of SGN-CD123A, A Potent CD123-Directed Antibody–Drug Conjugate for Acute Myeloid Leukemia

“…Examples include unconjugated monoclonal antibodies, T-cell engaging bispecific antibodies, immunotoxins, and chimeric antigen receptor (CAR)-modified T cells (36)(37)(38)(39)(40)(41). Although each of the modality has its own advantages, our study shows that SGN-CD123A is highly active against AML models regardless of cytogenetic profiles and MDR status, and can be effectively combined with quizartinib.…”