CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies

Testa, Ugo; Pelosi, Elvira; Frankel, Arthur E.

doi:10.1186/2050-7771-2-4

Cited by 220 publications

(152 citation statements)

References 77 publications

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“…(34), which is thought to be responsible for the relapse of AML. Importantly, CD123 was discovered as a marker of LSC and high CD123 expression on the CD34 þ CD38 À population is associated with poor prognosis (6,9). CSL362, a CD123 antibody, was shown to reduce the LSC population in xenograft studies (10).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that high CD123 levels on blasts is associated with increased resistance to apoptotic cell death and activation of the signal transducer and activator of transcription 5 pathway (8). In addition, clinical studies showed that increased CD123 expression was associated with higher blast counts at presentation and reduced responses to chemotherapy (9).…”

Section: Introductionmentioning

confidence: 99%

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

Sutherland

et al. 2018

Molecular Cancer Therapeutics

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Treatment choices for acute myelogenous leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. IL3 receptor alpha (IL3Ra, 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. Here, we report the generation and preclinical characterization of SGN-CD123A, an antibody-drug conjugate using the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation. Mechanistically, SGN-CD123A induces activation of DNA damage response pathways, cell-cycle changes, and apoptosis in AML cells. In vitro, SGN-CD123A-mediated potent cytotoxicity of 11/12 CD123 þ AML cell lines and 20/23 primary samples from AML patients, including those with unfavorable cytogenetic profiles or FLT3 mutations. In vivo, SGN-CD123A treatment led to AML eradication in a disseminated disease model, remission in a subcutaneous xenograft model, and significant growth delay in a multidrug resistance xenograft model. Moreover, SGN-CD123A also resulted in durable complete remission of a patient-derived xenograft AML model. When combined with a FLT3 inhibitor quizartinib, SGN-CD123A enhanced the activity of quizartinib against two FLT3-mutated xenograft models. Overall, these data demonstrate that SGN-CD123A is a potent antileukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients (NCT02848248). Mol Cancer Ther; 17(2); 554-64. Ó2017 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sutherland

et al. 2018

Molecular Cancer Therapeutics

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“…27 Finally, CD123 is also expressed on cells from other hematologic malignancies including Acute Lymphoblastic Leukemia (ALL), Chronic Myeloid Leukemia (CML), Myelo-Dysplastic Syndromes (MDS), Hodgkin Lymphoma (HL), Hairy Cell Leukemia (HCL) and others. 44,45 …”

Section: Introductionmentioning

confidence: 99%

Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells

et al. 2018

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A number of agents designed for immunotherapy of Acute Myeloid Leukemia (AML) are in preclinical and early clinical development. Most of them target a single antigen on the surface of AML cells. Here we describe the development and key biological properties of a tri-specific agent, the dual-targeting triplebody SPM-2, with binding sites for target antigens CD33 and CD123, and for CD16 to engage NK cells as cytolytic effectors. Primary blasts of nearly all AML patients carry at least one of these target antigens and the pair is particularly promising for the elimination of blasts and leukemia stem cells (LSCs) from a majority of AML patients by dual-targeting agents. The cytolytic activity of NK cells mediated by SPM-2 was analyzed in vitro for primary leukemic cells from 29 patients with a broad range of AML-subtypes. Blasts from all 29 patients, including patients with genomic alterations associated with an unfavorable genetic subtype, were lysed at nanomolar concentrations of SPM-2. Maximum susceptibility was observed for cells with a combined density of CD33 and CD123 above 10,000 copies/cell. Cell populations enriched for AML-LSCs (CD34pos and CD34pos CD38neg cells) from 2 AML patients carried an increased combined antigen density and were lysed at correspondingly lower concentrations of SPM-2 than unsorted blasts. These initial findings raise the expectation that SPM-2 may also be capable of eliminating AML-LSCs and thus of prolonging survival. In the future, patients with a broad range of AML subtypes may benefit from treatment with SPM-2.

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“…IL3R is a heterodimeric cytokine receptor comprised of the alpha unit and beta unit, which is activated by the ligand binding and necessary of IL-3 activity [23] . IL-3 is one of the prominent cytokines that controls proliferation, growth and differentiation of hematopoietic cells [24] .…”

Section: Cd123mentioning

confidence: 99%

Identification and targeting leukemia stem cells: The path to the cure for acute myeloid leukemia

Zhou

Chng

2014

WJSC

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Accumulating evidence support the notion that acute myeloid leukemia (AML) is organized in a hierarchical system, originating from a special proportion of leukemia stem cells (LSC). Similar to their normal counterpart, hematopoietic stem cells (HSC), LSC possess selfrenewal capacity and are responsible for the continued growth and proliferation of the bulk of leukemia cells in the blood and bone marrow. It is believed that LSC are also the root cause for the treatment failure and relapse of AML because LSC are often resistant to chemotherapy. In the past decade, we have made significant advancement in identification and understanding the molecular biology of LSC, but it remains a daunting task to specifically targeting LSC, while sparing normal HSC. In this review, we will first provide a historical overview of the discovery of LSC, followed by a summary of identification and separation of LSC by either cell surface markers or functional assays. Next, the review will focus on the current, various strategies for eradicating LSC. Finally, we will highlight future directions and challenges ahead of our ultimate goal for the cure of AML by targeting LSC.

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CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies

Cited by 220 publications

References 77 publications

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

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

Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells

Identification and targeting leukemia stem cells: The path to the cure for acute myeloid leukemia

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