Epitope-engineered human hematopoietic stem cells are shielded from CD123-targeted immunotherapy

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Abstract: Targeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody–drug conjugates (ADC), T cell engagers (TCE), or chimeric antigen receptor (CAR) cells is very effective for hematologic diseases. Unlike the breakthrough progress achieved for B cell malignancies, there is a pressing need to find suitable antigens for myeloid malignancies. CD123, the interleukin-3 (IL-3) receptor alpha-chain, is highly expressed in various hematological malignancies, including acute myeloid leukemia (AML). However, shared CD123 expression on healthy hematopoietic stem and progenitor cells (HSPCs) bears the risk for myelotoxicity. We demonstrate that epitope-engineered HSPCs were shielded from CD123-targeted immunotherapy but remained functional, while CD123-deficient HSPCs displayed a competitive disadvantage. Transplantation of genome-edited HSPCs could enable tumor-selective targeted immunotherapy while rebuilding a fully functional hematopoietic system. We envision that this approach is broadly applicable to other targets and cells, could render hitherto undruggable targets accessible to immunotherapy, and will allow continued posttransplant therapy, for instance, to treat minimal residual disease (MRD)

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Notes: Journal of experimental medicine. - 220, 12 (2023) , e20231235, ISSN: 1540-9538

Classification: Medizin, Gesundheit

Event: Veröffentlichung

(where): Freiburg

(who): Universität

(when): 2023

Creator: Marone, Romina
Landmann, Emmanuelle
Devaux, Anna
Lepore, Rosalba
Rositzka, Julia
Rhiel, Manuel
Geoffroy, Andrieux
Cathomen, Anton
Cornu, Tatjana I.
Jeker, Lukas T.

DOI: 10.1084/jem.20231235

URN: urn:nbn:de:bsz:25-freidok-2402564

Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 14.08.2025, 10:57 AM CEST

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Associated

Marone, Romina
Landmann, Emmanuelle
Devaux, Anna
Lepore, Rosalba
Rositzka, Julia
Rhiel, Manuel
Geoffroy, Andrieux
Cathomen, Anton
Cornu, Tatjana I.
Jeker, Lukas T.
Universität

Time of origin

2023

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Epitope-engineered human hematopoietic stem cells are shielded from CD123-targeted immunotherapy

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Other Objects (12)

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