Hematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation

Zhanzhuo Li, Agnieszka Czechowicz (), Amelia Scheck, Derrick J. Rossi () and Philip M. Murphy ()
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Zhanzhuo Li: National Institutes of Health
Agnieszka Czechowicz: Boston Children’s Hospital
Amelia Scheck: Boston Children’s Hospital
Derrick J. Rossi: Boston Children’s Hospital
Philip M. Murphy: National Institutes of Health

Nature Communications, 2019, vol. 10, issue 1, 1-7

Abstract: Abstract Hematopoietic chimerism after allogeneic bone marrow transplantation may establish a state of donor antigen-specific tolerance. However, current allotransplantation protocols involve genotoxic conditioning which has harmful side-effects and predisposes to infection and cancer. Here we describe a non-genotoxic conditioning protocol for fully MHC-mismatched bone marrow allotransplantation in mice involving transient immunosuppression and selective depletion of recipient hematopoietic stem cells with a CD117-antibody-drug-conjugate (ADC). This protocol resulted in multilineage, high level (up to 50%), durable, donor-derived hematopoietic chimerism after transplantation of 20 million total bone marrow cells, compared with ≤ 2.1% hematopoietic chimerism from 50 million total bone marrow cells without conditioning. Moreover, long-term survival of bone marrow donor-type but not third party skin allografts is achieved in CD117-ADC-conditioned chimeric mice without chronic immunosuppression. The only observed adverse event is transient elevation of liver enzymes in the first week after conditioning. These results provide proof-of-principle for CD117-ADC as a non−genotoxic, highly-targeted conditioning agent in allotransplantation and tolerance protocols.

Date: 2019
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DOI: 10.1038/s41467-018-08202-w

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