Alloengraftment without significant toxicity or GVHD in CD45 antibody-drug conjugate-conditioned Fanconi anemia mice.

Autor:	Saha A; Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Palchaudhuri R; Magenta Therapeutics, Cambridge, MA., Lanieri L; Magenta Therapeutics, Cambridge, MA., Hyzy S; Magenta Therapeutics, Cambridge, MA., Riddle MJ; Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Panthera J; Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Eide CR; Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Tolar J; Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Panoskaltsis-Mortari A; Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Gorfinkel L; Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA., Tkachev V; Massachusetts General Hospital Center for Transplantation Sciences, Mass General Brigham and Massachusetts General Hospital, Boston, MA., Gerdemann U; Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA., Alvarez-Calderon F; Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA., Palato ER; Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA., MacMillan ML; Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Wagner JE; Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Kean LS; Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA., Osborn MJ; Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Kiem HP; Department of Medicine, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA., Scadden DT; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.; Harvard Stem Cell Institute, Cambridge, MA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA., Olson LM; Magenta Therapeutics, Cambridge, MA., Blazar BR; Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 May 23; Vol. 143 (21), pp. 2201-2216.
DOI:	10.1182/blood.2023023549
Abstrakt:	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. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
Databáze:	MEDLINE
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