The glycosaminoglycan oncofetal chondroitin sulfate is a novel target for antibody-drug conjugate therapy for AML
Abstract
Abstract Antibody-drug conjugates (ADCs) have emerged as promising targeted therapies for acute myeloid leukemia (AML). However, most ADCs exhibit off-target binding to normal hematopoietic stem and myeloid progenitor cells, resulting in adverse hematotoxicity and narrow therapeutic windows, thereby limiting their clinical application to young and fit patients with AML who are eligible for intensive curative therapies. Proteoglycans with high levels of the glycosaminoglycan oncofetal chondroitin sulfate (ofCS) are abundantly expressed in solid cancers but are absent or expressed at low levels in normal adult tissues. Here, we report high ofCS levels on bone marrow (BM) cells from patients with AML and patient-derived xenografts (PDXs) from these patients, whereas BM cells from healthy individuals showed low or undetectable ofCS levels. Consistently, an anti-ofCS antibody demonstrated binding to and internalization into AML cells, and anti-ofCS ADCs effectively killed AML cells in vitro. Moreover, anti-ofCS ADC treatment significantly prolonged survival of AML PDXs compared with controls and was associated with low toxicity. Thus, anti-ofCS ADCs could represent an effective therapy with acceptable toxicity for patients with AML, including those who are ineligible for or unresponsive to current intensive curative therapies. In conclusion, this study demonstrates, to our knowledge for the first time, that a glycosaminoglycan-like ofCS is a druggable target for the development of effective antibody-based AML therapies.
Article Details
Authors (22)
Joana Mujollari
1Centre for translational Medicine and Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Montserrat Estruch
4Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Priya Khadgawat
4Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Swati Choudhary
1Centre for translational Medicine and Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Tobias Gustavsson
1Centre for translational Medicine and Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Robert Dagil
1Centre for translational Medicine and Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Norbert Redlinger
6Institute of Molecular Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
Caroline Løppke
1Centre for translational Medicine and Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Elena Ethel Vidal-Calvo
1Centre for translational Medicine and Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Mie Anemone Nordmaj
1Centre for translational Medicine and Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Thor Grundtvig Theander
Olaf Heidenreich
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Yen Nguyen
4Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Shuyu Qin
4Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Anne Louise Tølbøll Sørensen
10Department of Haematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
Kirsten Grønbæk
4Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Bo Torben Porse
4Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Brigitte Kircher
7Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
Jan Mueller
6Institute of Molecular Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
Mette Ørskov Agerbæk
Ali Salanti
Kim Theilgaard-Mönch
4Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark