학술논문
Selective haematological cancer eradication with preserved haematopoiesis
Document Type
Article
Author
Garaudé, Simon; Marone, Romina; Lepore, Rosalba; Devaux, Anna; Beerlage, Astrid; Seyres, Denis; Dell’ Aglio, Alessandro; Juskevicius, Darius; Zuin, Jessica; Burgold, Thomas; Wang, Sisi; Katta, Varun; Manquen, Garret; Li, Yichao; Larrue, Clément; Camus, Anna; Durzynska, Izabela; Wellinger, Lisa C.; Kirby, Ian; Van Berkel, Patrick H.; Kunz, Christian; Tamburini, Jérôme; Bertoni, Francesco; Widmer, Corinne C.; Tsai, Shengdar Q.; Simonetta, Federico; Urlinger, Stefanie; Jeker, Lukas T.
Source
Nature; June 2024, Vol. 630 Issue: 8017 p728-735, 8p
Subject
Language
ISSN
00280836; 14764687
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.