Abstract
Abstract Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curative therapy for hematologic diseases. However, toxicities from chemotherapy- or irradiation-based transplant conditioning, as well as graft-versus-host disease (GvHD), limit the use of alloHSCT to the most severe diseases. Novel conditioning regimens able to achieve donor engraftment with minimal adverse effects for the patient could greatly expand the safe applicability of alloHSCT to a wider variety of diseases. Antibody-drug conjugates targeting CD45 (CD45-ADC) have been shown previously to permit engraftment in murine syngeneic HSCT models. We set out to extend this approach to the allogeneic setting, developing CD45-ADC-based regimens able to both make marrow space for donor stem cells and overcome immune barriers to their engraftment. CD45-ADC combined with CD4+ and CD8+ T cell depletion was sufficient for engraftment in MHC-matched (BALB to DBA/2) and MHC-mismatched (CB6F1 to B6) murine alloHSCT models. The selective Janus kinase inhibitor baricitinib, shown by our lab to prevent GvHD, also inhibited host-versus-graft responses and allowed allogeneic engraftment when combined with CD45-ADC. In our alloHSCT models, up to 90% donor chimerism was achieved in over 70% of mice treated with CD45-ADC plus baricitinib. Finally, unlike mice conditioned with irradiation, mice treated with CD45-ADC did not develop GvHD when infused with allogeneic splenocytes. In conclusion, CD45-ADC plus baricitinib provides a safe, effective approach to alloHSCT conditioning in mice. These studies demonstrate the promise of immunotherapeutic strategies to achieve transplant tolerance while minimizing treatment-related morbidity and mortality.
Published Version
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