Immunophenotypic Markers
Wojciech Gorczyca in Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
The pan-myeloid antigens, CD13 and CD33, are expressed by AML and 10%–20% of ALL. CD13 is expressed by the majority of AML. The CD33 molecule is a cell surface differentiation protein that is expressed on normal progenitor and myeloid cells, as well as on >80% of AML blasts. It belongs to the family of the sialic acid-binding immunoglobulin-like lectin (Siglec). With the availability of immunotherapy targeted for CD33, the analysis of CD33 expression is becoming very important for patients with acute leukemias. Jilani et al. [74] showed that CD33 intensity in the total BM CD33+ cells differed significantly with the type of disease: The median number of CD33 molecules per cell was highest in AML, followed by myelodysplastic syndrome (MDS), CML, and control subjects, and lowest in chronic myeloproliferative neoplasms. CD33 antigen is rapidly internalized upon binding to Gemtuzumab ozogamicin (Mylotarg), delivering the drug (calicheamycin) into the cell, with subsequent double-stranded DNA breaks. Mylotarg is currently approved for relapsed AML in patients older than 65 years, but is being evaluated in combination with chemotherapy. Mylotarg is highly effective as a single treatment for patients with molecularly relapsed APL including those with very advanced disease.
Precision medicine in acute myeloid leukemia
Debmalya Barh in Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Immunotherapies, which have shown promise in the treatment of hematologic malignancies, have the potential to target AML through pathways that are distinct and complementary to current approaches (Lichtenegger et al., 2015). A second-generation CD33-specific chimeric antigen receptor capable of redirecting cytolytic effector T cells against leukemic cells was prepared. CD33 is expressed in approximately 90% of AML cases and has demonstrated utility as a target of therapeutic antibodies. Chimeric antigen receptor (CAR)-modified T cells efficiently killed leukemia cell lines and primary tumor cells in vitro. The antileukemia effect was CD33-specific, mediated through T-cell effector functions, and displayed tumor lysis at effector:target ratios as low as 1:20. Furthermore, the CD33-redirected T cells were effective in vivo, preventing the development of leukemia after prophylactic administration and delaying the progression of established disease in mice. These data provide preclinical validation of the effectiveness of a second-generation anti-CD33 chimeric antigen receptor therapy for AML, and support its continued development as a clinical therapeutic (O'Hear et al., 2015; Minagawa et al., 2016). An alternative antibody-based immunotherapeutic strategy is a novel class of bispecific T-cell-engaging antibodies (BiTEs) targeting CD33 antigen on AML cells and the CD3e component of the T-cell receptor complex (AMG 330) (Lichtenegger et al., 2015).
Marrow Purging And Stem Cell Preparation
Siegfried Matzku, Rolf A. Stahel in Antibodies in Diagnosis and Therapy, 2019
CD33 is a surface glycoprotein of 67 kd, member of the immunoglobulin superfamily, and homologous to sialoadhesin, myelin-associated glycoprotein and CD22 antigen, and a particularly appealing antigen to target AML cells (Simmons and Seed, 1988; Freeman et al., 1995; Griffin et al., 1984; Takahashi et al., 1992). Indeed, greater than 80% of AML cells express this sialic acid-dependent cell adhesion molecule (Freeman et al., 1995; Griffin et al., 1984; 1986). Moreover, it is found on the majority of leukemia progenitor cells (L-CFC) in almost all AML patients evaluated (95%) (Griffin and Lowenberg, 1986). MY9, a mAb with reactivity against CD33, in combination with C is capable of eliminating 3.6 logarithms (logs) of clonogenic HL-60 cells (Griffin et al., 1984; Roy et al., 1991). When its effect was measured against normal hematopoietic progenitors, MY9+C inhibited the growth of 99% of day 7 and 14 CFU-GM and 53% of CFU-GEMM (Roy et al., 1991; Griffin et al., 1984; Griffin and Lowenberg, 1986). Following purging, hematologic reconstitution would thus probably originate from CFU-GEMM progenitors, which were only partially eliminated by such treatment, and from the hematopoietic progenitor cells that do not express CD33 (Griffin, 1987). With these results, Robertson et al. used CD33+C to treat marrow grafts from 12 patients with AML in CR2 (10 pts), CR1 (1 pt) and CR3 (1 pt). Neutrophil engraftment* was achieved at a median interval of 43 days, and platelet engraftment* at 92 days following autologous PCT. The DFS at 3 to 4 years was estimated at 33% with 4 patients in continuous CR at 3 to 5 years post PCT. These results clearly demonstrate that it is possible to target AML clonogenic cells for purging, and that radical eradication of CFU-GM and even partial elimination of CFU-GEMM do not irreversibly impair engraftment.
Evaluation of a 10color protocol as part of a 2tube screening panel for flow cytometric assessment of peripheral blood leukocytic subsets
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2019
Evdoxia Gounari, Vasiliki Tsavdaridou, Aliki Ioakeimidou, Anna-Bettina Haidich, Lemonia Skoura
CD33 is a myeloid antigen which is expressed at the highest intensity on classical monocytes and dimmer on CD14+/CD16+ monocytes, basophils, neutrophils, and eosinophils. It is often expressed intensely by blasts in acute myeloid leukemias [20]. To take advantage of its variable expression profile by myeloid subsets, this marker was included in our protocol conjugated to a bright fluorochrome. According to established knowledge and tests performed in our lab, CD33 outweighs CD64 and CD14 as a gating marker, due to the upregulation of CD64 on granulocytes during infection and diminished or negative expression of CD14 in non-classical monocytes, although not all CD33 antibodies behave in the same way, rendering the selection of clone important in some cases [20]. To our knowledge, CD33 is not included in the majority of PB multicolor screening protocols, some of which are commercially available in ready for use combinations [3,4,6,8,11–15]. Correia et al. have used it in a customized 10-color tube with dried antibody reagents for screening hematologic malignancies, but the benefits from its application or the gating strategy are not presented [21]. CD33 is not included in the suggested panel for chronic myelomonocytic leukemia (CMML) by Selimoglou-Buet et al. [22], where an exclusion gating strategy is preferred for the detection of monocytes. Cherian et al. distinguish monocytes by the simultaneous evaluation of CD33/CD64, HLADR, and CD16/CD19 [7]; in our protocol, CD64 and HLADR were considered redundant for discriminating monocytes in PB, after preliminary evaluation.
Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC
Published in mAbs, 2018
Isabel Figueroa, Doug Leipold, Steve Leong, Bing Zheng, Montserrat Triguero-Carrasco, Aimee Fourie-O'Donohue, Katherine R. Kozak, Keyang Xu, Melissa Schutten, Hong Wang, Andrew G. Polson, Amrita V. Kamath
An anti-CD33 ADC with dose-limiting neutropenia in monkeys was used as a case study to illustrate our approach. CD33, a glycoprotein expressed on most myeloid leukemia cells as well as on normal myeloid and monocytic precursors, has been pursued clinically as a target for drugs intended as treatments for acute myeloid leukemia (AML).27 A non-linear 2-compartment model incorporating non-specific and specific (target-mediated) clearances, where the latter is a function of RO, was used to describe the PK. We tested our model by comparing PK predictions based on the unconjugated antibody (referred to here as anti-CD33 mAb) to observed conjugated antibody (referred to here as anti-CD33 ADC) PK data that was not utilized for model development, and subsequently translated the model to predict human PK. Additionally, we used this approach to compare model predictions for other previously tested anti-CD33 molecules with published clinical data.
Identifying effective drug combinations for patients with acute myeloid leukemia
Published in Expert Review of Anticancer Therapy, 2020
Musa Yilmaz, Tapan Kadia, Farhad Ravandi
The CD33 surface antigen is expressed on the majority of AML cells and represents an important target for AML therapy [65]. Gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody conjugated to calicheamicin, was approved by the FDA in 2000 for older AML patients who are ineligible for intensive chemotherapy. However, in 2010, it was removed from the market when the confirmatory trial performed by the Southwest Oncology Group (SWOG) demonstrated no OS benefit and increased incidence of induction death [66]. However, when evaluated at lower and/or fractionated dosages, adding gemtuzumab to chemotherapy has shown superior survival in multiple other randomized studies [67–71]. Hills and colleagues performed a meta-analysis of data from five randomized clinical studies and showed that using gemtuzumab in combination with standard intensive chemotherapy reduces the relapse risk and improves OS; however, this benefit is limited to the patients without adverse risk cytogenetics. In 2017, FDA reapproved gemtuzumab based on ALFA-0701 clinical study, which showed an improvement in event-free survival (EFS) and OS (Table 3). Persistent cytopenias were more common in gemtuzumab arm, but lower gemtuzumab dose was not associated with increased induction death.
Related Knowledge Centers
- Immunoglobulin Domain
- Lectin
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- Lymphatic System
- Cell Surface Receptor
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