(original) (raw)

TY - JOUR AU - Garaudé, Simon AU - Marone, Romina AU - Lepore, Rosalba AU - Devaux, Anna AU - Beerlage, Astrid AU - Seyres, Denis AU - Dell’ Aglio, Alessandro AU - Juskevicius, Darius AU - Zuin, Jessica AU - Burgold, Thomas AU - Wang, Sisi AU - Katta, Varun AU - Manquen, Garret AU - Li, Yichao AU - Larrue, Clément AU - Camus, Anna AU - Durzynska, Izabela AU - Wellinger, Lisa C. AU - Kirby, Ian AU - Van Berkel, Patrick H. AU - Kunz, Christian AU - Tamburini, Jérôme AU - Bertoni, Francesco AU - Widmer, Corinne C. AU - Tsai, Shengdar Q. AU - Simonetta, Federico AU - Urlinger, Stefanie AU - Jeker, Lukas T. PY - 2024 DA - 2024/06/01 TI - Selective haematological cancer eradication with preserved haematopoiesis JO - Nature SP - 728 EP - 735 VL - 630 IS - 8017 AB - 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. SN - 1476-4687 UR - https://doi.org/10.1038/s41586-024-07456-3 DO - 10.1038/s41586-024-07456-3 ID - Garaudé2024 ER -