CD123 expression patterns and selective targeting with a CD123-targeted antibody-drug conjugate (IMGN632) in acute lymphoblastic leukemia

Angelova, Evgeniya; Audette, Charlene A.; Kovtun, Yelena; Daver, Naval; Wang, Sa A.; Pierce, Sherry; Konoplev, Sergej; Khogeer, Haitham; Jorgensen, Jeffrey L.; Konopleva, Marina; Zweidler‐McKay, Patrick A.; Medeiros, L. Jeffrey; Kantarjian, Hagop M.; Khoury, Joseph D.

doi:10.3324/haematol.2018.205252

Cited by 54 publications

(40 citation statements)

References 31 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Sreejesh et al 26 reported 1 case of B-ALL with CD5 expression, indicating that CD5 expression is a poor prognostic marker in patients below 18 years of age. Angelova et al 27 reported on 183 patients with B acute lymphoblastic leukemia/lymphoma. The expression of CD123 in B acute lymphoblastic leukemia/lymphoma is prevalent (164/183; (89.6%).…”

Section: Discussionmentioning

confidence: 99%

Study on the Prognostic Value of Aberrant Antigen in Patients With Acute B Lymphocytic Leukemia

Tan

et al. 2019

Clinical Lymphoma Myeloma and Leukemia

View full text Add to dashboard Cite

Chimeric antigen receptors redirected T cell (CAR-T cell) therapy is an effective means of treating relapsed/ refractory acute B-lymphocytic leukemia, and new targets are needed to solve the recurrence after CART cell treatment. A retrospective analysis of 194 patients with acute B-lymphocytic leukemia showed a poor prognosis for CD123 expression. To improve efficacy, CAR19 can be considered to bind to aberrant antigens such as CD123 to form a bispecific or multispecific antigen in CART cell construction. Background: Approximately 30% to 60% of patients with acute B-lymphocytic leukemia (B-ALL) show as refractory or relapsed, which is one of the major causes of death in patients with BALL , but the methods of the treatment for relapsed/refractory BALL (R/R BALL) are limited. The chimeric antigen receptors redirected T cells (CAR-T cells) have showed a strong anti-leukemia role for BALL. About 90% of patients with R/R BALL treated with CD19-CART cells achieved complete remission. However, 60% to 70% of patients relapsed after CART cells treatment, which may be related to target antigen reduction or escape. New products are urgently needed to prevent and treat antigenic escapes causing recurrence. Patients and Methods: In this article, we retrospectively analyzed the immunophenotype of patients with BALL initially diagnosed in our center from January 2010 to December 2015 to determine whether aberrant antigen expression was associated with the prognosis of patients in order to find new targets for immunotherapy. Results: The results show that disease-free and overall survival in patients without aberrant antigen expression were better than patients with aberrant antigen expression. The most common abnormal antigens were CD123, CD13, and CD56. Correlation analysis showed a negative correlation between aberrant CD123 expression and both disease-free and overall survival. Conclusion: Therefore, in the construction of CART cells in patients with R/R BALL , conventional CD19 can be combined with aberrant antigens such as CD123 to form CARs with bi-specific antigens or multi-specific antigens may achieve the purpose of improving efficacy. However, more clinical trials are needed.

show abstract

Section: Discussionmentioning

confidence: 99%

Study on the Prognostic Value of Aberrant Antigen in Patients With Acute B Lymphocytic Leukemia

Tan

et al. 2019

Clinical Lymphoma Myeloma and Leukemia

View full text Add to dashboard Cite

show abstract

“…This finding was confirmed in subsequent studies, showing also that CD123 overexpression in B-ALL associates with hyperdiploid genotype [84]; furthermore, CD123 is clearly expressed at higher levels in B-ALL blasts than in normal B-lymphoid progenitors/precursors [85,86]. More recently, Angelova et al have performed a large screening of CD123 expression on a large set of ALLs, showing that CD123 expression was more prevalent in Philadelphia chromosome-positive patients than in Philadelphia chromosome-negative patients [87]. Importantly, Liu et al reported the existence of a negative correlation between CD123 expression on B-ALL blasts and both disease-free and overall survival [88].…”

Section: Introductionmentioning

confidence: 99%

CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

Testa

Pelosi

Castelli

2019

Cancers

108

View full text Add to dashboard Cite

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.

show abstract

“…The number of CD123 molecules expressed on various cell populations are indirectly reflected in the intensity of fluorescence detected, which is typically expressed as median fluorescence intensity (MFI). Such intensity is normalized against background fluorescence and/or control cell populations [ 22 ]. Furthermore, by employing carefully selected lineage and maturation-associated markers, CD123 expression on neoplastic cells can be clearly distinguished from that on other cell populations within a given sample.…”

Section: Principles Of Laboratory Evaluation Of Cd123mentioning

confidence: 99%

“…CD123 is frequently overexpressed in B-ALL. Angelova and colleagues [ 22 ] conducted a large study in which CD123 expression was evaluated by FC in various subsets of B-ALL and T-ALL. They demonstrated CD123 overexpression in 96.6% of Ph-positive and 86.3% of Ph-negative B-ALL.…”

Section: Cd123 Expression In Hematologic Malignanciesmentioning

confidence: 99%

“…Angelova and colleagues showed that IMGN632 therapy in vitro was effective against B-ALL cell lines and primary B-ALL cells expressing CD123, with no effect on normal lymphocytes [ 22 ]. Currently, IMGN632 monotherapy is being investigated in relapsed/refracotry AML, BPDCN, ALL, and other CD123+ myeloproliferative neoplasms (NCT03386513).…”

Section: Cd123-targeted Therapiesmentioning

confidence: 99%

See 1 more Smart Citation

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

Achi¹,

Dupont

Stolzmann

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

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.

show abstract

CD123 expression patterns and selective targeting with a CD123-targeted antibody-drug conjugate (IMGN632) in acute lymphoblastic leukemia

Cited by 54 publications

References 31 publications

Study on the Prognostic Value of Aberrant Antigen in Patients With Acute B Lymphocytic Leukemia

Study on the Prognostic Value of Aberrant Antigen in Patients With Acute B Lymphocytic Leukemia

CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

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

Contact Info

Product

Resources

About