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.
Highlights
Hematopoietic chimerism after allogeneic bone marrow transplantation may establish a state of donor antigen-specific tolerance
Monoclonal antibody-based approaches for depleting recipient hematopoietic stem cells (HSCs) have shown promise as non-genotoxic conditioning agents in bone marrow (BM)/HSC transplantation (BMT/HSCT)1–6. mAb targeting of CD117 (c-Kit)[7], a receptor tyrosine kinase that is highly expressed on HSCs and that binds the cytokine stem cell factor (SCF), was first shown to enhance HSC engraftment after syngeneic HSCT in immunodeficient mice; this stand-alone approach was unsuccessful in adult wild-type, immunocompetent mice[2]
Without pre-transplant conditioning, ≥ 5 × 107 donor BM cells are required in this model to establish de minimis hematopoietic chimerism (1–2%), which reliably establishes donor-specific skin allograft tolerance[12,13]
Summary
Hematopoietic chimerism after allogeneic bone marrow transplantation may establish a state of donor antigen-specific tolerance. 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). Given the limitations with prior methods, we have developed a novel saporin−based CD117 antibody-drug-conjugate (CD117ADC) that as a single-agent potently and selectively depletes recipient HSCs without immune or hematopoietic ablation and supports robust (~99%) and long-term (>1 year) hematopoietic chimerism after syngeneic BMT and HSCT in adult, immunocompetent mice without limiting morbidity or mortality[8] This approach has obvious advantages for syngeneic applications in the clinic where preservation of immunity is desired, such as autologous gene therapy and gene editing. The strong cell-sparing effect, lack of genotoxicity and robust donor-specific tolerance associated with the protocol establish a pre-clinical proof-of-principle for the use of HSC-depleting antibodies such CD117-ADC as safe and effective conditioning agents for allotransplantation
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