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

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. ScaddenLisa M. Olson, Bruce R. Blazar

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 LineageSca1+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.

Original languageEnglish (US)
Pages (from-to)2201-2216
Number of pages16
JournalBlood
Volume143
Issue number21
DOIs
StatePublished - May 23 2024

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© 2024 American Society of Hematology

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