Dual-Targeting CD33/CD123 NANOBODY ® T Cell Engager Targeting Leukemia Blasts and Stem/Progenitor Cells in Relapsed AML
Zhihong ZengAnnelies RoobrouckGeert DeschampsHélène BonnevauxS. GuérifVeronique De BrabandereAmara CélineEline JonckheereAngéla Virone-OddosMarielle ChironMélissa DullaersMarina Konopleva
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Interleukin-3 receptor
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Owing to the more recent positive results with the anti-CD33 immunotoxin gemtuzumab ozogamicin, therapy against acute myeloid leukemias (AMLs) targeting CD33 holds many promises. Here, CD33 and CD123 expression on AML blasts was studied by flow cytometry in a cohort of 319 patients with detailed information on French-American-British/World Health Organization (FAB/WHO) classification, cytogenetics and molecular aberrations. AMLs of 87.8% express CD33 and would therefore be targetable with anti-CD33 therapies. Additionally, 9.4% of AMLs express CD123 without concomitant CD33 expression. Thus, nearly all AMLs could be either targeted via CD33 or CD123. Simultaneous presence of both antigens was observed in 69.5% of patients. Most importantly, even AMLs with adverse cytogenetics express CD33 and CD123 levels comparable to those with favorable and intermediate subtypes. Some patient groups with unfavorable alterations, such as FMS-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations, high FLT3-ITD mutant/wild-type ratios and monosomy 5 are even characterized by high expression of CD33 and CD123. In addition, blasts of patients with mutant nucleophosmin (NPM1) revealed significantly higher CD33 and CD123 expression pointing toward the possibility of minimal residual disease-guided interventions in mutated NPM1-positive AMLs. These results stimulate the development of novel concepts to redirect immune effector cells toward CD33- and CD123-expressing blasts using bi-specific antibodies or engineered T cells expressing chimeric antigen receptors.
Gemtuzumab ozogamicin
Interleukin-3 receptor
NPM1
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Interleukin-3 receptor
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Objective:To explore the possibility of secondary neoplasia following long term combined chemotherapy.Methods:Sister chromatid exchanges(SCE)were investigated in 44 patients with adult leukemia.Rusults:Frequencies of SCE in patients with de novo leukemia,relapsed leukemia and chronic myeloid leukemia(CML)were significant higher than health controls.The five patients(5/16)with complete remission showed higher SCE frequencies,those were mainly the patients received more than nine courses of combined chemotherapeutic regimens received more than nine courses of combined chemotherapeutic regimens.Conclusion:The patients with de novo leukemia,relapsed leukemia and CML have DNA damage in diagnosis,long term combined chemotherapy may cause the DNA instability in partial patients.
Sister chromatid exchange
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Monoclonal antibody therapy for patients with acute myeloid leukemia is currently based on targeting cell surface receptors selectively expressed on myeloid cells. These include primarily CD33 and CD45. Antibodies are unlabeled or have been conjugated to various radioisotopes or DNA-damaging cytotoxic agents. The safety of this approach has been determined, and antibody-related infusional events are common. Other toxicity is primarily dependent on the conjugate to which the antibody has been linked. Efficacy of this approach is still to be determined. Phase II studies have demonstrated antileukemic responses with all agents, although less so with unlabeled antibodies. Whether the use of these antibodies in combination with, or as a substitute for, currently available therapy will lead to improved outcomes for patients with acute myeloid leukemia has not been demonstrated to date.
Gemtuzumab ozogamicin
Monoclonal antibody therapy
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In the January/February 2013 edition, Maio et al describe a patient with CD4/CD56/CD123 ascribed as blastic plasmacytoid dendritic cell neoplasia (BDCN). However, since CD4/CD56/CD123 neoplasms are highly heterogeneous, the precise diagnosis requires an extensive immunophenotypic panel. 3 Although highly suggestive, the cytochemical positivity for CD4, CD56 together with CD123 in the absence of myeloperoxidase, CD3, CD2, CD5, and CD7, is not sufficient to determine the BDCN malignant nature. Despite the expression of CD123, the aforementioned phenotype could also correspond to acute myeloid dendritic cell leukemia or acute myeloid leukemia (myeloid leukemia cutis), especially with monocytic differentiation. The diagnostic work-up of these entities relies on a comprehensive antibody panel that should also include CD13, CD33, CD15, CD14, CD64, CD16, CD34, CD117, BDCA-2 (CD303), BDCA-4 (CD304), BDCA-3 (CD141) and TCL1. BDCN are phenotypically recognized by expression of specific plasmacytoid dendritic cell proteins (CD303 and CD304) in the absence or dim expression of myeloid markers. Conversely, acute myeloid dendritic cell leukemias specifically express CD141 along with some myeloid markers. By exclusion, the absence of CD303, CD304 and CD141, along with the presence of myeloid and monocytic markers, supports the diagnosis of myelomonocytic leukemia. Additional molecular tests targeting well-characterized abnormalities could serve as ancillary diagnostic tools. Although the panel herein proposed could not be entirely performed on skin biopsies, it could be easily applied by flow cytometry on circulating cells during the disseminated phase. It is clear that strong collaborative efforts are required to improve diagnosis and management of these rare diseases.
Interleukin-3 receptor
Plasmacytoid dendritic cell
Immunophenotyping
CD117
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Interleukin-3 receptor
Plasmacytoid dendritic cell
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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of acute leukemia that typically follows a highly aggressive clinical course in adults, whereas experience in children with this disease is very limited. We report cases of two children in whom bone marrow showed infiltration by large atypical monocytoid 'blast-like' cells which on immunophenotyping expressed CD4, CD56, HLA-DR and CD33 while were negative for CD34 other T-cell, B-cell and myeloid markers. The differential diagnoses considered were AML, T/NK-cell leukemia and acute undifferentiated leukemia. Additional markers CD303/BDCA-2 and CD123 which are recently validated plasmacytoid dendritic cell markers were done which helped us clinch the diagnosis of this rare neoplasm. An accurate diagnosis of BPDCN is essential in order to provide prompt treatment. Due to its rarity and only recent recognition as a distinct clinicopathological entity, no standardized therapeutic approach has been established for BPDCN.
Interleukin-3 receptor
Immunophenotyping
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Plasmacytoid dendritic cell
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