Selective haematological cancer eradication with preserved haematopoiesis

Simon Garaudé, Romina Marone, Rosalba Lepore, Anna Devaux, Astrid Beerlage, Denis Seyres, Alessandro Dell’ Aglio, Darius Juskevicius, Jessica Zuin, Thomas Burgold, Sisi Wang, Varun Katta, Garret Manquen, Yichao Li, Clément Larrue, Anna Camus, Izabela Durzynska, Lisa C. Wellinger, Ian Kirby, Patrick H. Berkel, Christian Kunz, Jérôme Tamburini, Francesco Bertoni, Corinne C. Widmer, Shengdar Q. Tsai, Federico Simonetta, Stefanie Urlinger and Lukas T. Jeker ()
Additional contact information
Simon Garaudé: Basel University Hospital and University of Basel
Romina Marone: Basel University Hospital and University of Basel
Rosalba Lepore: Basel University Hospital and University of Basel
Anna Devaux: Basel University Hospital and University of Basel
Astrid Beerlage: Basel University Hospital and University of Basel
Denis Seyres: Basel University Hospital and University of Basel
Alessandro Dell’ Aglio: Basel University Hospital and University of Basel
Darius Juskevicius: Diagnostic Hematology, Basel University Hospital
Jessica Zuin: Basel University Hospital and University of Basel
Thomas Burgold: Basel University Hospital and University of Basel
Sisi Wang: Geneva University Hospitals
Varun Katta: St. Jude Children’s Research Hospital
Garret Manquen: St. Jude Children’s Research Hospital
Yichao Li: St. Jude Children’s Research Hospital
Clément Larrue: University of Geneva
Anna Camus: Cimeio Therapeutics
Izabela Durzynska: Ridgeline Discovery
Lisa C. Wellinger: Ridgeline Discovery
Ian Kirby: ADC Therapeutics (UK)
Patrick H. Berkel: ADC Therapeutics (UK)
Christian Kunz: Ridgeline Discovery
Jérôme Tamburini: University of Geneva
Francesco Bertoni: USI
Corinne C. Widmer: Basel University Hospital
Shengdar Q. Tsai: St. Jude Children’s Research Hospital
Federico Simonetta: Geneva University Hospitals
Stefanie Urlinger: Cimeio Therapeutics
Lukas T. Jeker: Basel University Hospital and University of Basel

Nature, 2024, vol. 630, issue 8017, 728-735

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07456-3

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