Selective haematological cancer eradication with preserved haematopoiesis

• 成果类型: Article
• 署名作者: Garaude, 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, Clement; Camus, Anna; Durzynska, Izabela; Wellinger, Lisa C.; Kirby, Ian; Van Berkel, Patrick H.; Kunz, Christian; Tamburini, Jerome; Bertoni, Francesco; Widmer, Corinne C.; Tsai, Shengdar Q.; Simonetta, Federico; Urlinger, Stefanie; Jeker, Lukas T.
• 署名单位: University of Basel; University of Basel; University of Basel; University of Basel; University of Basel; University of Geneva; St Jude Children's Research Hospital; University of Geneva; Institute of Oncology Research (IOR); Universita della Svizzera Italiana; Institute of Oncology Research (IOR); University of Basel; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); Universite de Toulouse; Universite Toulouse III - Paul Sabatier
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3717
• DOI: 10.1038/s41586-024-07456-3
• 发表日期: 2024-06-20
• 页码: 728-+
• 关键词: stem-cell transplantation; cd45; gene; immunotherapy; leukemia; therapy; cas9

摘要

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 cells(1). 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 malignancies(2). However, target selection is complex and limited to antigens expressed on subsets of haematopoietic cells, resulting in a fragmented therapy landscape with high development costs(2-5). 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.