Preprint Epublish
PubMed: 38405731 DOI: 10.1101/2024.02.12.579199
Streptavidin-drug conjugates streamline optimization of antibody-based conditioning for hematopoietic stem cell transplantation.
bioRxiv
Authors: Aditya R Yelamali, Ezhilarasi Chendamarai, Julie K Ritchey, Michael P Rettig, John F DiPersio, Stephen P Persaud
Affiliations
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110 USA.
- Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110 USA.
Abstract
Hematopoietic stem cell transplantation (HSCT) conditioning using antibody-drug conjugates (ADC) is a promising alternative to conventional chemotherapy- and irradiation-based conditioning regimens. The drug payload bound to an ADC is a key contributor to its efficacy and potential toxicities; however, a comparison of HSCT conditioning ADCs produced with different toxic payloads has not been performed. Indeed, ADC optimization studies in general are hampered by the inability to produce and screen multiple combinations of antibody and drug payload in a rapid, cost-effective manner. Herein, we used Click chemistry to covalently conjugate four different small molecule payloads to streptavidin; these streptavidin-drug conjugates can then be joined to any biotinylated antibody to produce stable, indirectly conjugated ADCs. Evaluating CD45-targeted ADCs produced with this system, we found the pyrrolobenzodiazepine (PBD) dimer SGD-1882 was the most effective payload for targeting mouse and human hematopoietic stem cells (HSCs) and acute myeloid leukemia cells. In murine syngeneic HSCT studies, a single dose of CD45-PBD enabled near-complete conversion to donor hematopoiesis. Finally, human CD45-PBD provided significant antitumor benefit in a patient-derived xenograft model of acute myeloid leukemia. As our streptavidin-drug conjugates were generated in-house with readily accessible equipment, reagents, and routine molecular biology techniques, we anticipate this flexible platform will facilitate the evaluation and optimization of ADCs for myriad targeting applications.
MeSH
Cells, Microscopy, Electron, Scanning Transmission, Hematopoietic Stem Cell Transplantation, Pharmaceutical Preparations, Leukemia, Stem Cells, Leukemia, Myeloid, Acute, Leukemia, Myeloid, Streptavidin, Cell Transplantation, Conditioning, Psychological, Stem Cell Transplantation, Hematopoietic Stem Cells, Transplantation