A single‐chain variable fragment‐based bispecific T‐cell activating antibody against CD117 enables T‐cell mediated lysis of acute myeloid leukemia and hematopoietic stem and progenitor cells
Laura Volta,
Renier Myburgh,
Mara Hofstetter,
Christian Koch,
Jonathan D. Kiefer,
Celeste Gobbi,
Francesco Manfredi,
Kathrin Zimmermann,
Philipp Kaufmann,
Serena Fazio,
Christian Pellegrino,
Norman F. Russkamp,
Danielle Villars,
Mattia Matasci,
Monique Maurer,
Jan Mueller,
Florin Schneiter,
Paul Büschl,
Niclas Harrer,
Jacqueline Mock,
Stefan Balabanov,
César Nombela‐Arrieta,
Timm Schroeder,
Dario Neri,
Markus G. Manz
Affiliations
Laura Volta
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Renier Myburgh
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Mara Hofstetter
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Christian Koch
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Jonathan D. Kiefer
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences Swiss Federal Institute of Technology (ETH Zürich) Zürich Switzerland
Celeste Gobbi
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Francesco Manfredi
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Kathrin Zimmermann
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Philipp Kaufmann
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Serena Fazio
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Christian Pellegrino
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Norman F. Russkamp
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Danielle Villars
Phire/ATLyphe, Wyss Zurich Translational Center ETH Zürich/University of Zürich Zürich Switzerland
Mattia Matasci
Philochem AG Otelfingen Switzerland
Monique Maurer
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Jan Mueller
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Florin Schneiter
Department of Biosystems Science and Engineering ETH Zurich Basel Switzerland
Paul Büschl
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Niclas Harrer
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Jacqueline Mock
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences Swiss Federal Institute of Technology (ETH Zürich) Zürich Switzerland
Stefan Balabanov
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
César Nombela‐Arrieta
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Timm Schroeder
Department of Biosystems Science and Engineering ETH Zurich Basel Switzerland
Dario Neri
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences Swiss Federal Institute of Technology (ETH Zürich) Zürich Switzerland
Markus G. Manz
Department of Medical Oncology and Hematology University and University Hospital Zürich Zürich Switzerland
Abstract Acute myeloid leukemia (AML) derives from hematopoietic stem and progenitor cells (HSPCs). To date, no AML‐exclusive, non‐HSPC‐expressed cell‐surface target molecules for AML selective immunotherapy have been identified. Therefore, to still apply surface‐directed immunotherapy in this disease setting, time‐limited combined immune‐targeting of AML cells and healthy HSPCs, followed by hematopoietic stem cell transplantation (HSCT), might be a viable therapeutic approach. To explore this, we generated a recombinant single‐chain variable fragment‐based bispecific T‐cell engaging and activating antibody directed against CD3 on T‐cells and CD117, the surface receptor for stem cell factor, expressed by both AML cells and healthy HSPCs. Bispecific CD117xCD3 targeting induced lysis of CD117‐positive healthy human HSPCs, AML cell lines and patient‐derived AML blasts in the presence of T‐cells at subnanomolar concentrations in vitro. Furthermore, in immunocompromised mice, engrafted with human CD117‐expressing leukemia cells and human T‐cells, the bispecific molecule efficiently prevented leukemia growth in vivo. Additionally, in immunodeficient mice transplanted with healthy human HSPCs, the molecule decreased the number of CD117‐positive cells in vivo. Therefore, bispecific CD117xCD3 targeting might be developed clinically in order to reduce CD117‐expressing leukemia cells and HSPCs prior to HSCT.
