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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Tagraxofusp (Elzonris™) is a fusion protein consisting of interleukin 3 (IL-3) fused to diphtheria toxin that is used for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). It gained FDA approval in 2018 and it is considered to be a first-in-class medication. Elzonris™ is a novel targeted therapy directed to CD123 of the tumor cells. The IL-3 binds to the CD123-expressing tumor cells and delivers the cytotoxic diphtheria toxin to the cells. This causes the blockage of protein synthesis in the cell and causing cell death. The approval of Elzonris™ was based on the positive results of two multi-center, open-label, single-arm clinical trials, which were performed in two groups of patients. The rate of complete response was the primary endpoint of the trial. The primary endpoint was reached by approximately 54% of the patients. One of the patients achieved a complete response and one clinical complete response in the study. Most common adverse events include capillary leak syndrome, nausea, weight gain, fatigue, peripheral edema, and an increase in body temperature.
Blastic Plasmacytoid Dendritic Cell Neoplasms (BPDCN)
Published in Dongyou Liu, Tumors and Cancers, 2017
In flow cytometry, BPDCN display a high-intensity expression of CD123 and positivity for HLA-DR, CD4, CD45RA, and CD56 but negativity for lineage-associated antigens. This immunophenotype is considered unique and virtually pathognomonic for BPDCN.
Immunophenotypic Markers
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
CD123 antigen is an antibody that binds to the α-subunit of the interleukin-3 receptor. CD123 is expressed in AML, ALL, NK cell tumors, and dendritic cell neoplasms [88,89]. CD123+ AML are often positive for FLT3-ITD or NPM1 mutations. It can also be expressed in mature B-cell disorders, such as HCL [88,90]. The expression of CD123 in HCL is bright. The subset of HCL-Vs (~40%) and rare cases of other mature B-cell disorders (including SMLZ, CLL, MCL, and FL) may express CD123, but the expression is usually partial and/or dim [90].
A review of treatment options employed in relapsed/refractory AML
Published in Hematology, 2023
Mohamed Zakee Mohamed Jiffry, Robert Kloss, Mohammad Ahmed-khan, Felipe Carmona-Pires, Nkechi Okam, Prabasha Weeraddana, Dinusha Dharmaratna, Mehndi Dandwani, Kayvon Moin
CD33 directed CAR-T therapy was evaluated for r/r AML in a clinical trial involving a 41-year-old male patient with a marked decrease in blast fraction two weeks after the therapy from >50% to <6%. However, cytokine release syndrome subsequently developed, and the patient died of disease progression 12 weeks later [89]. CD123 is also being explored as a highly desirable target and may potentially be superior to CD33 directed therapy owing to their lower toxicity profile [88]. A number of phase I/II studies are ongoing to investigate the efficacy of CD33 and CD123 directed CAR-T therapy as a potential target (e.g. NCT01864902, NCT03795779, NCT03190278). First results from a phase I clinical study evaluating CYAD-02, an NKG2D ligand-directed CAR-T therapy in 6 r/r AML patients demonstrated safety and tolerability with no dose-limiting toxicities being observed [90].
Targeting CD123 in BPDCN: an emerging field
Published in Expert Review of Hematology, 2021
Adam J DiPippo, Nathaniel R Wilson, Naveen Pemmaraju
The concept of utilizing the target of CD123 to direct the natural immune response toward malignant BPDCN cells is also being explored [87]. Bispecific T-cell engager therapy (BiTE) was first developed in ALL therapy targeted toward CD19 and has been utilized with great success [88]. This approach is being built upon and is now under development for several tumor cell targets, including CD123. BiTE or the newly designed dual-affinity retargeting antibodies (DART) consist of two main peptides with a CD3 variable heavy chain and light chain region linked via disulfide bond to a target variable heavy chain and light chain region, in this case CD123. The CD3 portion is designed to bind and activate T lymphocytes, while the targeting domain recognizes cancer cells and helps form an immunologic synapse with activated T lymphocytes [87,89–91].
Combining phage display with SMRTbell next-generation sequencing for the rapid discovery of functional scFv fragments
Published in mAbs, 2021
Francesco Nannini, Lenart Senicar, Farhaan Parekh, Khai J. Kong, Alexander Kinna, Reyisa Bughda, James Sillibourne, Xihao Hu, Biao Ma, Yuchen Bai, Mathieu Ferrari, Martin A. Pule, Shimobi C. Onuoha
We applied PacBio sequencing technology to a second library generated from rats immunized with the target antigen CD123. CD123 is a cell surface receptor that transmits signal from the cytokine interleukin 3 and has been identified as a possible target in the treatment of acute myeloid leukemia.22,23 The library was chosen for analysis because the generation of antibodies using standard clone selection and expression had yielded few unique hits. Of 200 screened clones, only 6 unique clones that showed specificity toward CD123-positive SupT1s by flow cytometry were identified. We analyzed the clonal distribution of the CD123 library after three rounds of selection. A total of 5193 IGH and 1361 IGK clonotypes were identified. IGHV1 and IGHV5 were observed to be the most abundant v-genes, with pairing to IGHJ3 and IGHJ2 predominantly favored. Again, V gene utilization for IGK was more diverse, with IGKV4 (20%), IGKV22 (13%), IGKV3 (11%), IGKV10 (11%), IGKV12 (9%), IGKV14 (8%), IGKV8 (7%), IGKV6 (6%) and IGKV2 (4%) all present within the library. IGKJ1 (44%) was the most abundant, closely followed by IGKJ5 (36%) and IGKJ2 (20%) (Supplementary Figure 5a). Analysis of IGHV-IGKV pairing showed that IGHV1 appeared to favor pairing with IGKV12 (60%), while IGHV5 favored pairing with IGKV4 (50%) following enrichment.