The Experts below are selected from a list of 170082 Experts worldwide ranked by ideXlab platform
Fatih M. Uckun - One of the best experts on this subject based on the ideXlab platform.
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Dual Targeting of Multiple Myeloma Stem Cells and Myeloid-Derived Suppressor Cells for Treatment of Chemotherapy-Resistant Multiple Myeloma
'Frontiers Media SA', 2021Co-Authors: Fatih M. UckunAbstract:Here we review the insights and lessons learned from early clinical trials of T-cell engaging bispecific antibodies (BsABs) as a new class of biotherapeutic drug candidates with clinical impact potential for the treatment of multiple myeloma (MM). BsABs are capable of redirecting host T-cell cytotoxicity in an MHC-independent manner to malignant MM clones as well as immunosuppressive myeloid-derived suppressor cells (MDSC). T-cell engaging BsAB targeting the BCMA Antigen may help delay disease progression in MM by destroying the MM cells. T-cell engaging BsAB targeting the CD38 Antigen may help delay disease progression in MM by depleting both the malignant MM clones and the MDSC in the bone marrow microenvironment (BMME). BsABs may facilitate the development of a new therapeutic paradigm for achieving improved survival in MM by altering the immunosuppressive BMME. T-cell engaging BsiABs targeting the CD123 Antigen may help delay disease progression in MM by depleting the MDSC in the BMME and destroying the MM stem cells that also carry the CD123 Antigen on their surface
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CD123-Directed Bispecific Antibodies for Targeting MDS Clones and Immunosuppressive Myeloid-Derived Suppressor Cells (MDSC) in High-Risk Adult MDS Patients
'Frontiers Media SA', 2021Co-Authors: Fatih M. Uckun, Justin WattsAbstract:There is an urgent need to identify effective strategies to prevent leukemic transformation and induce sustained deep remissions in adult high-risk myelodysplastic syndrome (MDS) patients. This article discusses the clinical impact potential of bispecific antibodies (BiAB) capable of redirecting host T-cell cytotoxicity in an MHC-independent manner to malignant clones as well as immunosuppressive myeloid-derived suppressor cells (MDSC) as a new class of anti-MDS drug candidates. T-cell engaging BiAB targeting the CD123 Antigen may help delay disease progression in high-risk adult MDS and potentially reduce the risk of transformation to secondary AML
Stefan O Ciurea - One of the best experts on this subject based on the ideXlab platform.
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antileukemia efficacy and mechanisms of action of sl 101 a novel anti CD123 antibody conjugate in acute myeloid leukemia
Clinical Cancer Research, 2017Co-Authors: Jeffrey L Jorgensen, Antonio Cavazos, Gheath Aiatrash, Graciela Nogueras M Gonzalez, Christopher Brooks, Sa A. Wang, Hong Mu, Jin Zhou, Qi Zhang, Stefan O CiureaAbstract:Purpose: The persistence of leukemia stem cells (LSC)-containing cells after induction therapy may contribute to minimal residual disease (MRD) and relapse in acute myeloid leukemia (AML). We investigated the clinical relevance of CD34 + CD123 + LSC-containing cells and antileukemia potency of a novel antibody conjugate SL-101 in targeting CD123 + LSCs. Experimental Methods and Results: In a retrospective study on 86 newly diagnosed AML patients, we demonstrated that a higher proportion of CD34 + CD123 + LSC-containing cells in remission was associated with persistent MRD and predicted shorter relapse-free survival in patients with poor-risk cytogenetics. Using flow cytometry, we explored the potential benefit of therapeutic targeting of CD34 + CD38 − CD123 + cells by SL-101, a novel antibody conjugate comprising an anti-CD123 single-chain Fv fused to Pseudomonas exotoxin A . The antileukemia potency of SL-101 was determined by the expression levels of CD123 Antigen in a panel of AML cell lines. Colony-forming assay established that SL-101 strongly and selectively suppressed the function of leukemic progenitors while sparing normal counterparts. The internalization, protein synthesis inhibition, and flow cytometry assays revealed the mechanisms underlying the cytotoxic activities of SL-101 involved rapid and efficient internalization of antibody, sustained inhibition of protein synthesis, induction of apoptosis, and blockade of IL3-induced p-STAT5 and p-AKT signaling pathways. In a patient-derived xenograft model using NSG mice, the repopulating capacity of LSCs pretreated with SL-101 in vitro was significantly impaired. Conclusions: 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. Clin Cancer Res; 23(13); 3385–95. ©2017 AACR .
Jeffrey L Jorgensen - One of the best experts on this subject based on the ideXlab platform.
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antileukemia efficacy and mechanisms of action of sl 101 a novel anti CD123 antibody conjugate in acute myeloid leukemia
Clinical Cancer Research, 2017Co-Authors: Jeffrey L Jorgensen, Antonio Cavazos, Gheath Aiatrash, Graciela Nogueras M Gonzalez, Christopher Brooks, Sa A. Wang, Hong Mu, Jin Zhou, Qi Zhang, Stefan O CiureaAbstract:Purpose: The persistence of leukemia stem cells (LSC)-containing cells after induction therapy may contribute to minimal residual disease (MRD) and relapse in acute myeloid leukemia (AML). We investigated the clinical relevance of CD34 + CD123 + LSC-containing cells and antileukemia potency of a novel antibody conjugate SL-101 in targeting CD123 + LSCs. Experimental Methods and Results: In a retrospective study on 86 newly diagnosed AML patients, we demonstrated that a higher proportion of CD34 + CD123 + LSC-containing cells in remission was associated with persistent MRD and predicted shorter relapse-free survival in patients with poor-risk cytogenetics. Using flow cytometry, we explored the potential benefit of therapeutic targeting of CD34 + CD38 − CD123 + cells by SL-101, a novel antibody conjugate comprising an anti-CD123 single-chain Fv fused to Pseudomonas exotoxin A . The antileukemia potency of SL-101 was determined by the expression levels of CD123 Antigen in a panel of AML cell lines. Colony-forming assay established that SL-101 strongly and selectively suppressed the function of leukemic progenitors while sparing normal counterparts. The internalization, protein synthesis inhibition, and flow cytometry assays revealed the mechanisms underlying the cytotoxic activities of SL-101 involved rapid and efficient internalization of antibody, sustained inhibition of protein synthesis, induction of apoptosis, and blockade of IL3-induced p-STAT5 and p-AKT signaling pathways. In a patient-derived xenograft model using NSG mice, the repopulating capacity of LSCs pretreated with SL-101 in vitro was significantly impaired. Conclusions: 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. Clin Cancer Res; 23(13); 3385–95. ©2017 AACR .
Da Rizzieri - One of the best experts on this subject based on the ideXlab platform.
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The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells
Leukemia, 2000Co-Authors: Ct Jordan, D Upchurch, Sj Szilvassy, Ml Guzman, Ds Howard, Al Pettigrew, T Meyerrose, R Rossi, B Grimes, Da RizzieriAbstract:Recent studies suggest that the population of malignant cells found in human acute myelogenous leukemia (AML) arises from a rare population of leukemic stem cells (LSCs). LSCs have been documented for nearly all AML subtypes and have been phenotypically described as CD34^+/CD38^− or CD34^+/HLA-DR^−. Given the potentially critical role of these primitive cells in perpetuating leukemic disease, we sought to further investigate their molecular and cellular characteristics. Flow cytometric studies using primary AML tissue showed that the interleukin-3 receptor alpha chain (IL-3Rα or CD123) was strongly expressed in CD34^+/CD38^− cells (98 ± 2% positive) from 16 of 18 primary specimens. Conversely, normal bone marrow derived CD34^+/CD38^− cells showed virtually no detectable expression of the CD123 Antigen. To assess the functional role of IL-3Rα positive cells, purified CD34^+/CD123^+ leukemia cells were transplanted into immune deficient NOD/SCID mice. These experiments showed that CD123^+ cells were competent to establish and maintain leukemic populations in vivo . To begin to elucidate a biological role for CD123 in leukemia, primary AML samples were analyzed with respect to signal transduction activity in the MAPK, Akt, and Stat5 pathways. Phosphorylation was not detected in response to IL-3 stimulation, thereby suggesting CD123 is not active in conventional IL-3-mediated signaling. Collectively, these data indicate that CD123 represents a unique marker for primitive leukemic stem cells. Given the strong expression of this receptor on LSCs, we propose that targeting of CD123 may be a promising strategy for the preferential ablation of AML cells.
Mohsen Abolhassani - One of the best experts on this subject based on the ideXlab platform.
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development of a new anti CD123 monoclonal antibody to target the human CD123 Antigen as an acute myeloid leukemia cancer stem cell biomarker
Biotechnology and Applied Biochemistry, 2018Co-Authors: Meghdad Abdollahpouralitappeh, Sepand Razavivakhshourpour, Mohsen AbolhassaniAbstract:Acute myeloid leukemia (AML) is a clonal hematologic malignancy arising from a small population of leukemic cells initiating the disease. CD123 is differentially expressed in AML blasts compared with normal hematopoietic stem and progenitor cells. The aim of this study was to develop specific monoclonal antibodies (mAbs) directed against AML. Three BALB/c mice were immunized with the human CD123 Antigen, and the immune spleen cells were fused with the SP2/0 myeloma cell line. Hybridomas were screened by indirect enzyme-linked immunosorbent assay (ELISA), and the positive hybrids were cloned by limiting dilution. The mAb isotype was determined, ascitic fluids were produced, and antibodies were purified using Fast protein liquid chromatography (Sephacryl S-200). The specificity of the hybridomas was examined by ELISA, cell-based ELISA, and flow cytometry. After three rounds of cell cloning, four anti-CD123 secreting hybridomas were obtained with the IgM isotype. Among them, one stable hybrid, designated sC1, exhibited the higher ability to recognize the CD123 Antigen, as compared with the other hybridomas. Our results showed that sC1 has the ability to bind specifically to the CD123 Antigen (41.36%) on the cell surface. The anti-CD123 mAb produced in this study may be useful for the development of both diagnostic and therapeutic purposes for AML.