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

Braciak, Todd A.; Roskopf, Claudia C.; Wildenhain, Sarah; Fenn, Nadja C.; Schiller, Christian; Schubert, Ingo; Jacob, Uwe; Honegger, Annemarie; Krupka, Christina; Subklewe, Marion; Spiekermann, Karsten; Hopfner, Karl‐Peter; Fey, Georg H.; Aigner, Michael; Krause, Stefan W.; Mackensen, Andréas; Oduncu, Fuat

doi:10.1080/2162402x.2018.1472195

Cited by 24 publications

(14 citation statements)

References 76 publications

(113 reference statements)

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“…Interestingly, the combination of CD33 and CD123 was found unsuitable ( 370 ). Approaches that already implement combinatorial targeting of AML LSCs include tri-specific killer engagers against CD33 and CD123 ( 373 ), compound CAR T-cells against CD33 and CD123 ( 374 ) or CLL-1 and CD33 (i.e., NCT03795779), universal CAR T-cells against CD33 and CD123 ( 375 ), and CAR CIK-cells against CD33 and CD123 ( 376 ).…”

Section: Next Generation Cars and Targeting Of Cscs In Combinational mentioning

confidence: 99%

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

et al. 2020

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The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.

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Section: Next Generation Cars and Targeting Of Cscs In Combinational mentioning

confidence: 99%

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

et al. 2020

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“…Recently, the development of a dual-targeting triplebody 33-16-123 (SPM-2) agent, with binding sites for target antigens CD33 and CD123, and for CD16 to engage NK as cytolytic effectors was reported [146]. Primary blasts of most AMLs carry at least one of these antigens; blasts from 29 AML patients were lysed at nanomolar concentrations of SPM-2, the optimal lytic effect being observed for leukemic cells with a combined density of CD33 and CD123 above 10,000 molecules/cell [146]. Cell populations phenotypically enriched in leukemic stem cells (CD34 + CD38 − ) carry increased CD33 and CD123 expression and were lysed even at low SPM-2 concentrations [146].…”

Section: Therapeutic Cd123 Targetingmentioning

confidence: 99%

CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

Testa

Pelosi

Castelli

2019

Cancers

102

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The interleukin-3 receptor alpha chain (IL-3Rα), more commonly referred to as CD123, is widely overexpressed in various hematological malignancies, including acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia, hairy cell leukemia, Hodgkin lymphoma and particularly, blastic plasmacytoid dendritic neoplasm (BPDCN). Importantly, CD123 is expressed at both the level of leukemic stem cells (LSCs) and more differentiated leukemic blasts, which makes CD123 an attractive therapeutic target. Various agents have been developed as drugs able to target CD123 on malignant leukemic cells and on the normal counterpart. Tagraxofusp (SL401, Stemline Therapeutics), a recombinant protein composed of a truncated diphtheria toxin payload fused to IL-3, was approved for use in patients with BPDCN in December of 2018 and showed some clinical activity in AML. Different monoclonal antibodies directed against CD123 are under evaluation as antileukemic drugs, showing promising results either for the treatment of AML minimal residual disease or of relapsing/refractory AML or BPDCN. Finally, recent studies are exploring T cell expressing CD123 chimeric antigen receptor-modified T-cells (CAR T) as a new immunotherapy for the treatment of refractory/relapsing AML and BPDCN. In December of 2018, MB-102 CD123 CAR T developed by Mustang Bio Inc. received the Orphan Drug Designation for the treatment of BPDCN. 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.

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“…Braciak and colleagues developed SPM-2, which is a triplebody molecule with binding sites for CD33, CD123, and CD16. Large clusters of CD33 and CD123 on the surface of leukemic cells were needed to achieve the maximum efficiency of this drug [ 108 ].…”

Section: Cd123-targeted Therapiesmentioning

confidence: 99%

CD123 as a Biomarker in Hematolymphoid Malignancies: Principles of Detection and Targeted Therapies

Achi¹,

Dupont

Stolzmann

et al. 2020

Cancers

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CD123, the α chain of the interleukin 3 receptor, is a cytokine receptor that is overexpressed in multiple hematolymphoid neoplasms, including acute myeloid leukemia, blastic plasmacytoid dendritic cell neoplasm, acute lymphoblastic leukemia, hairy cell leukemia, and systemic mastocytosis. Importantly, CD123 expression is upregulated in leukemic stem cells relative to non-neoplastic hematopoietic stem cells, which makes it a useful diagnostic and therapeutic biomarker in hematologic malignancies. Varying levels of evidence have shown that CD123-targeted therapy represents a promising therapeutic approach in several cancers. Tagraxofusp, an anti-CD123 antibody conjugated to a diphtheria toxin, has been approved for use in patients with blastic plasmacytoid dendritic cell neoplasm. Multiple clinical trials are investigating the use of various CD123-targeting agents, including chimeric antigen receptor-modified T cells (expressing CD123, monoclonal antibodies, combined CD3-CD123 dual-affinity retargeting antibody therapy, recombinant fusion proteins, and CD123-engager T cells. In this review, we provide an overview of laboratory techniques used to evaluate and monitor CD123 expression, describe the strengths and limitations of detecting this biomarker in guiding therapy decisions, and provide an overview of the pharmacologic principles and strategies used in CD123-targeted therapies.

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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

Cited by 24 publications

References 76 publications

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

CD123 as a Biomarker in Hematolymphoid Malignancies: Principles of Detection and Targeted Therapies

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