Here we describe the generation and characterization of a fully-human monoclonal antibody specific to CD123, a surface marker which is overexpressed in a variety of hematological disorders, including acute myeloid leukemia.
In conclusion, these recent studies strongly support CD123 as an important therapeutic target for the treatment of BPDCN, while a possible in the treatment of AML and other hematological malignancies will have to be evaluated by in the ongoing clinical studies.
CARs comprised of these D domains mediate potent T cell activation and cytolysis of CD123-expressing target cells and induce complete durable remission in two AML xenograft models.
The addition of interferon (IFN)-γ and tumor necrosis factor (TNF)-α neutralizing antibodies can effectively reverse the upregulation of CD123 on the endothelial cells caused by CART123, while the cytotoxicity of CART123 in AML cell lines was not affected in vitro.
Clinical trials are underway investigating non-HLA matched T cells expressing anti-CD19 CARs for the treatment of B cell acute lymphoblastic leukemia (B-ALL) and anti-CD123 CAR for acute myeloid leukemia (AML).
The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN).
We studied the CD34+CD38-CD123+ fraction in AML blasts at diagnosis, and its utility as a unique phenotype for minimal residual disease (MRD) of AML patients.
Importantly, SL-401 was highly active even in cells expressing low levels of CD123, with minimal effect on modulation of the CD123 target in acute myeloid leukemia.
Approaches to harness the body's own T cells against AML include antibodies that recruit and induce cytotoxicity of tumor cells by T cells (bispecific T-cell engager [BiTE] such as CD33 x CD3 (e.g.AMG 330) or CD123 x CD3 (e.g. flotetuzumab, JNJ-63709178) or antibodies that block immune checkpoint receptors CTLA4 (e.g. ipilimumab) or PD1/PD-L1 (e.g. nivolumab, pembrolizumab, avelumab) on T cells, unleashing the patients' T cells against leukemic cells.
IL3 receptor alpha (IL3Rα, or CD123) is expressed on the majority of AML blasts, and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy.
<b>Purpose:</b> Flotetuzumab (MGD006 or S80880) is a bispecific molecule that recognizes CD3 and CD123 membrane proteins, redirecting T cells to kill CD123-expressing cells for the treatment of acute myeloid leukemia.
In a patient-derived xenograft model using NSG mice, the repopulating capacity of LSCs pretreated with SL-101 <i>in vitro</i> was significantly impaired.<b>Conclusions:</b> Our data define the mechanisms by which SL-101 targets AML and warrant further investigation of the clinical application of SL-101 and other CD123-targeting strategies in AML.<i></i>.
Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen receptor (CAR)-engineered T-cells (CAR-T-cells), a therapy that has been highly successful in the treatment of B-cell leukemia and lymphoma.
These suggest that CD123 aptamer and CD123 aptamer-mediated targeted drug delivery system may have potential applications for selective delivery cytotoxic agents to CD123-expressing tumors in AML theranostics.
This observation raises concern for potential myeloablation in patients with AML treated with CD123-redirected CAR T cells and mandates novel approaches for toxicity mitigation.
We first validated the expression of CD123 by 100% (52/52) of patient samples and the correlation of NPM1 and FLT3-ITD mutations with the high frequency of CD123 in AML.
CLL-1 is prevalent in AML and, unlike other targets such as CD33 and CD123, is not expressed on hematopoietic stem cells providing potential hematopoietic recovery.