Alloengraftment without significant toxicity or GVHD in CD45 antibody-drug conjugate–conditioned Fanconi anemia mice
Year: 2024
Type: article
Abstract: ABSTRACT: Fanconi anemia (FA) is an inherited DNA repair disorder characterized by bone marrow (BM) failure, developmental abnormalities, myelodysplasia, leukemia, and solid tumor predisposition. Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a mainstay treatment, is limited by conditioning regimen-related toxicity and graft-versus-host disease (GVHD). Antibody-drug conjugates (ADCs) targeting hematopoietic stem cells (HSCs) can open marrow niches permitting donor stem cell alloengraftment. Here, we report that single dose anti-mouse CD45-targeted ADC (CD45-ADC) facilitated stable, multilineage chimerism in 3 distinct FA mouse models representing 90% of FA complementation groups. CD45-ADC profoundly depleted host stem cell enriched Lineage-Sca1+cKit+ cells within 48 hours. Fanca-/- recipients of minor-mismatched BM and single dose CD45-ADC had peripheral blood (PB) mean donor chimerism >90%; donor HSCs alloengraftment was verified in secondary recipients. In Fancc-/- and Fancg-/- recipients of fully allogeneic grafts, PB mean donor chimerism was 60% to 80% and 70% to 80%, respectively. The mean percent donor chimerism in BM and spleen mirrored PB results. CD45-ADC-conditioned mice did not have clinical toxicity. A transient <2.5-fold increase in hepatocellular enzymes and mild-to-moderate histopathological changes were seen. Under GVHD allo-HSCT conditions, wild-type and Fanca-/- recipients of CD45-ADC had markedly reduced GVHD lethality compared with lethal irradiation. Moreover, single dose anti-human CD45-ADC given to rhesus macaque nonhuman primates on days -6 or -10 was at least as myeloablative as lethal irradiation. These data suggest that CD45-ADC can potently promote donor alloengraftment and hematopoiesis without significant toxicity or severe GVHD, as seen with lethal irradiation, providing strong support for clinical trial considerations in highly vulnerable patients with FA.
Source: Blood
Authors: Asim Saha, Rahul Palchaudhuri, Leanne Lanieri, Sharon Hyzy, Megan J. Riddle, Jamie Panthera, Cindy R. Eide, Jakub Tolar, Angela Panoskaltsis-Mortari, Lev Gorfinkel, Victor Tkachev, Ulrike Gerdemann, Francesca Alvarez-Calderon, Elisa Rojas Palato, Margaret L. MacMillan, John E. Wagner, Leslie S. Kean, Mark J. Osborn, Hans-Peter Kiem, David T. Scadden, Lisa M. Olson, Bruce R. Blazar
Institutions: University of Minnesota, Masonic Cancer Center, Dana-Farber Cancer Institute, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Massachusetts General Hospital, Mass General Brigham, Boston Children's Hospital, Harvard University, University of Washington, Fred Hutch Cancer Center, Harvard Stem Cell Institute
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: T-Cell Targeting for GVHD, In vivo Prevention of Murine GVHD, Post Graduate Training in Pediatric Oncology, Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia, Novel hematopoietic stem cell engineering and transplantation approaches for HIV cure, Transplant Tolerance in Non-Human Primates, Washington National Primate Research Center, New Approaches to Inducing Cardiac Allograft Tolerance, Hematopoiesis in Cardiovascular Disease, In Vivo Prevention of Murine GVHD, Mechanisms and Therapy of Chronic Graft-vs.-Host Disease, Novel Approaches to Inducing Lung Allograft Tolerance in NHPs, Off-the-Shelf Immune Effector Cells for Hematological Malignancies, Novel Biologic Therapies for GVHD
OpenAlex ID: W4392503580