Bone marrow or stem cell transplantation
Targeted antibody drug conjugates (ADCs) to mouse antigens have been shown to effectively prepare immunocompetent mice for congenic whole bone marrow (WBM) transplants (Palchaudhuri et al. Nature Biotech 2016 34:738; Czechowicz et al. Blood 2016 128:493). Targeted ablation of host hematopoietic cells via CD45-targeted ADCs has the potential to effectively condition for both autologous and allogeneic transplantation. If this novel approach can be successfully translated to humans, it has the potential to expand the utility of transplantation. We developed a short half-life ADC targeting murine CD45 coupled to saporin (SAP), a ribosome-inhibiting toxin, to model broad hematopoietic depletion as a conditioning agent for allogeneic transplant in immunocompetent mice. Administration of a single dose of the ADC at 1.9 mg/kg effectively depleted murine hematopoietic stem cells (HSCs). To determine if the ADC could enable allogeneic transplant as part of a reduced intensity conditioning regimen, we transplanted recipient DBA-2 mice (H-2d, CD45.2+) with congenically-marked Balb/c (H-2d, CD45.1+) WBM 5 days after single dose administration of a myeloablative dose of our ADC in combination with post-transplant Cytoxan or additional T-cell depletion. CD45-SAP in combination with post-transplant Cytoxan enabled >85% peripheral donor chimerism at 12 weeks post-transplantation with multilineage reconstitution observed in the T-, B- and myeloid cell compartments ( >80%, >90% and >90% donor chimerism, respectively). These results demonstrate that anti-CD45 ADCs used in combination with immunosuppression enable highly efficient allogeneic transplantation in a murine minor mismatch model and suggest that a similar approach may be effective in humans.