CD300f epitopes are specific targets for acute myeloid leukemia with monocytic differentiation

Autor: P. Joy Ho, Kenneth F. Bradstock, Tsun-Ho Lo, Phillip D. Fromm, Harry J. Iland, Derek N.J. Hart, Adelina Romano, Fiona Kupresanin, Marina L. Kennerson, Kaitao Lai, Robin Gasiorowski, Georgina J. Clark, Edward Abadir, Pablo A. Silveira, P. Mark Hogarth
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Myeloid
medicine.drug_class
CD34
acute myeloid leukemia
Biology
Monoclonal antibody
lcsh:RC254-282
Monocytes
Epitope
Epitopes
03 medical and health sciences
Antineoplastic Agents
Immunological
0302 clinical medicine
Cell Line
Tumor
hemic and lymphatic diseases
Genetics
medicine
Humans
Molecular Targeted Therapy
Receptors
Immunologic
isoform expression
Research Articles
antibody epitopes
Antibodies
Monoclonal
Myeloid leukemia
General Medicine
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
3. Good health
Leukemia
Myeloid
Acute
Haematopoiesis
Leukemia
cell surface targeting
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Cancer research
Molecular Medicine
monoclonal antibodies
Stem cell
Research Article
CD300f
Zdroj: Molecular Oncology
Molecular Oncology, Vol 13, Iss 10, Pp 2107-2120 (2019)
ISSN: 1878-0261
1574-7891
Popis: Antibody‐based therapy in acute myeloid leukemia (AML) has been marred by significant hematologic toxicity due to targeting of both hematopoietic stem and progenitor cells (HSPCs). Achieving greater success with therapeutic antibodies requires careful characterization of the potential target molecules on AML. One potential target is CD300f, which is an immunoregulatory molecule expressed predominantly on myeloid lineage cells. To confirm the value of CD300f as a leukemic target, we showed that CD300f antibodies bind to AML from 85% of patient samples. While one CD300f monoclonal antibody (mAb) reportedly did not bind healthy hematopoietic stem cells, transcriptomic analysis found that CD300f transcripts are expressed by healthy HSPC. Several CD300f protein isoforms exist as a result of alternative splicing. Importantly for antibody targeting, the extracellular region of CD300f can be present with or without the exon 4‐encoded sequence. This results in CD300f isoforms that are differentially bound by CD300f‐specific antibodies. Furthermore, binding of one mAb, DCR‐2, to CD300f exposes a structural epitope recognized by a second CD300f mAb, UP‐D2. Detailed analysis of publicly available transcriptomic data indicated that CD34+ HSPC expressed fewer CD300f transcripts that lacked exon 4 compared to AML with monocytic differentiation. Analysis of a small cohort of AML cells revealed that the UP‐D2 conformational binding site could be induced in cells from AML patients with monocytic differentiation but not those from other AML or HSPC. This provides the opportunity to develop an antibody‐based strategy to target AMLs with monocytic differentiation but not healthy CD34+ HSPCs. This would be a major step forward in developing effective anti‐AML therapeutic antibodies with reduced hematologic toxicity.
Databáze: OpenAIRE
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