Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin

Abstract

Hematopoietic stem cell transplantation (HSCT) offers curative therapy for patients with hemoglobinopathies, congenital immunodeficiencies, and other conditions, possibly including AIDS. Autologous HSCT using genetically corrected cells would avoid the risk of graft-versus-host disease (GVHD), but the genotoxicity of conditioning remains a substantial barrier to the development of this approach. Here we report an internalizing immunotoxin targeting the hematopoietic-cell-restricted CD45 receptor that effectively conditions immunocompetent mice. A single dose of the immunotoxin, CD45–saporin (SAP), enabled efficient (>90%) engraftment of donor cells and full correction of a sickle-cell anemia model. In contrast to irradiation, CD45–SAP completely avoided neutropenia and anemia, spared bone marrow and thymic niches, enabling rapid recovery of T and B cells, preserved anti-fungal immunity, and had minimal overall toxicity. This non-genotoxic conditioning method may provide an attractive alternative to current conditioning regimens for HSCT in the treatment of non-malignant blood diseases.

Modulating host immune responses to fight invasive fungal infections

“…Similar clinical deteriorations have also been observed in solid organ transplant recipients with cryptococcal meningitis who undergo rapid reductions in immune suppressive medications [16], and in patients with chronic disseminated candidiasis following neutrophil recovery [17]. Given the problems with infection following haematopoietic stem cell transplantation (HSCT), there are now efforts to explore novel conditioning strategies using haematopoetic cell-specific immunotoxins that avoid such profound immune suppression [18]. …”

Transplantation of gene-modified haematopoietic stem cells: Application and clinical considerations

“…Novel approaches in this regard include the use of immunotoxins and monoclonal antibodies directed to markers expressed on HSCs, such as c-Kit, [29] c-Kit and CD47, [30] and RESEARCH CD45. [31] Impressive HSC depletion in pre-clinical models of up to 99% has been reported. [30] More recently, CAR T cells against the c-Kit antigen on HSCs have also been reported as a promising approach.…”

Umbilical Cord Blood Hematopoietic Stem and Progenitor Cell Expansion for Therapeutic Use

“…However, the use of myeloablative conditioning creates a substantial risk. Recently, studies in mice suggest that the risk of myeloablative conditioning can be greatly reduced by using CD45-saporin toxin conjugated antibody treatment to make space in the bone marrow for transplanted cells to treat sickle cell disease in the autologous seting without signiicant adverse efects on graft recovery [39], but this has not been conducted in the human. However, earlier studies using rat CD45 antibodies produced in Cambridge, UK [40,41] have demonstrated the safety and eicacy of an 111 In-labeled CD45 conjugate in bone marrow transplant patients with acute leukemia [42].…”