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1.
Nature ; 630(8017): 728-735, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38778101

ABSTRACT

Haematopoietic stem cell (HSC) transplantation (HSCT) is the only curative treatment for a broad range of haematological malignancies, but the standard of care relies on untargeted chemotherapies and limited possibilities to treat malignant cells after HSCT without affecting the transplanted healthy cells1. Antigen-specific cell-depleting therapies hold the promise of much more targeted elimination of diseased cells, as witnessed in the past decade by the revolution of clinical practice for B cell malignancies2. However, target selection is complex and limited to antigens expressed on subsets of haematopoietic cells, resulting in a fragmented therapy landscape with high development costs2-5. Here we demonstrate that an antibody-drug conjugate (ADC) targeting the pan-haematopoietic marker CD45 enables the antigen-specific depletion of the entire haematopoietic system, including HSCs. Pairing this ADC with the transplantation of human HSCs engineered to be shielded from the CD45-targeting ADC enables the selective eradication of leukaemic cells with preserved haematopoiesis. The combination of CD45-targeting ADCs and engineered HSCs creates an almost universal strategy to replace a diseased haematopoietic system, irrespective of disease aetiology or originating cell type. We propose that this approach could have broad implications beyond haematological malignancies.


Subject(s)
Hematologic Neoplasms , Hematopoiesis , Immunoconjugates , Leukocyte Common Antigens , Animals , Female , Humans , Male , Mice , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/therapy , Hematologic Neoplasms/immunology , Hematopoiesis/drug effects , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Leukocyte Common Antigens/immunology , Leukocyte Common Antigens/metabolism , Cell Line, Tumor , Antibody Specificity
2.
J Exp Med ; 220(12)2023 12 04.
Article in English | MEDLINE | ID: mdl-37773046

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).


Subject(s)
Interleukin-3 Receptor alpha Subunit , Leukemia, Myeloid, Acute , Humans , Interleukin-3 Receptor alpha Subunit/metabolism , Epitopes , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Immunotherapy , Hematopoietic Stem Cells/metabolism , Immunotherapy, Adoptive
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