SIRPα-αCD123 fusion antibodies targeting CD123 in conjunction with CD47 blockade enhance the clearance of AML-initiating cells.
Adult
Aged
Aged, 80 and over
Antigens, Differentiation
/ immunology
Antineoplastic Agents, Immunological
/ therapeutic use
CD47 Antigen
/ immunology
Cell Line, Tumor
Female
Humans
Interleukin-3 Receptor alpha Subunit
/ immunology
Leukemia, Myeloid, Acute
/ drug therapy
Male
Middle Aged
Neoplastic Stem Cells
/ drug effects
Receptors, Immunologic
/ immunology
Acute myeloid leukaemia
CD123
CD47
Immunotherapy
Leukemic stem cells
Phagocytosis
Journal
Journal of hematology & oncology
ISSN: 1756-8722
Titre abrégé: J Hematol Oncol
Pays: England
ID NLM: 101468937
Informations de publication
Date de publication:
27 09 2021
27 09 2021
Historique:
received:
05
03
2021
accepted:
07
09
2021
entrez:
28
9
2021
pubmed:
29
9
2021
medline:
23
11
2021
Statut:
epublish
Résumé
Acute myeloid leukaemia (AML) stem cells (LSCs) cause disease relapse. The CD47 "don't eat me signal" is upregulated on LSCs and contributes to immune evasion by inhibiting phagocytosis through interacting with myeloid-specific signal regulatory protein alpha (SIRPα). Activation of macrophages by blocking CD47 has been successful, but the ubiquitous expression of CD47 on healthy cells poses potential limitations for such therapies. In contrast, CD123 is a well-known LSC-specific surface marker utilized as a therapeutic target. Here, we report the development of SIRPα-αCD123 fusion antibodies that localize the disruption of CD47/SIRPα signalling to AML while specifically enhancing LSC clearance. SIRPα-αCD123 antibodies were generated by fusing the extracellular domain of SIRPα to an αCD123 antibody. The binding properties of the antibodies were analysed by flow cytometry and surface plasmon resonance. The functional characteristics of the fusion antibodies were determined by antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity assays using primary AML patient cells. Finally, an in vivo engraftment assay was utilized to assess LSC targeting. SIRPα-αCD123 fusion antibodies exhibited increased binding and preferential targeting of CD123 SIRPα-αCD123 antibodies combine local CD47 blockade with specific LSC targeting in a single molecule, minimize the risk of targeting healthy cells and efficiently eliminate AML LSCs. These results validate SIRPα-αCD123 antibodies as promising therapeutic interventions for AML.
Sections du résumé
BACKGROUND
Acute myeloid leukaemia (AML) stem cells (LSCs) cause disease relapse. The CD47 "don't eat me signal" is upregulated on LSCs and contributes to immune evasion by inhibiting phagocytosis through interacting with myeloid-specific signal regulatory protein alpha (SIRPα). Activation of macrophages by blocking CD47 has been successful, but the ubiquitous expression of CD47 on healthy cells poses potential limitations for such therapies. In contrast, CD123 is a well-known LSC-specific surface marker utilized as a therapeutic target. Here, we report the development of SIRPα-αCD123 fusion antibodies that localize the disruption of CD47/SIRPα signalling to AML while specifically enhancing LSC clearance.
METHODS
SIRPα-αCD123 antibodies were generated by fusing the extracellular domain of SIRPα to an αCD123 antibody. The binding properties of the antibodies were analysed by flow cytometry and surface plasmon resonance. The functional characteristics of the fusion antibodies were determined by antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity assays using primary AML patient cells. Finally, an in vivo engraftment assay was utilized to assess LSC targeting.
RESULTS
SIRPα-αCD123 fusion antibodies exhibited increased binding and preferential targeting of CD123
CONCLUSIONS
SIRPα-αCD123 antibodies combine local CD47 blockade with specific LSC targeting in a single molecule, minimize the risk of targeting healthy cells and efficiently eliminate AML LSCs. These results validate SIRPα-αCD123 antibodies as promising therapeutic interventions for AML.
Identifiants
pubmed: 34579739
doi: 10.1186/s13045-021-01163-6
pii: 10.1186/s13045-021-01163-6
pmc: PMC8477557
doi:
Substances chimiques
Antigens, Differentiation
0
Antineoplastic Agents, Immunological
0
CD47 Antigen
0
CD47 protein, human
0
IL3RA protein, human
0
Interleukin-3 Receptor alpha Subunit
0
Receptors, Immunologic
0
SIRPA protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
155Subventions
Organisme : Marie Curie
ID : 641549
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
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