Imlifidase and EndoS Enables Haploidentical Bone Marrow Engraftment in Sensitized Mice Under Reduced Intensity...

Patients in need of a hematopoietic stem cell transplant frequently have pre-existing donor-specific antibodies (DSA) which can impair engraftment. These patients often require more complex conditioning regimens, even in the setting of partially matched (haploidentical) donors. Reducing the complexity and toxicity of conditioning and desensitization protocols is therefore a major goal. We previously showed that enzymatic desensitization of donor-specific IgG using imlifidase and endoglycosidase (EndoS) from S. pyogenes improved murine bone marrow engraftment in donor sensitized, autoimmune-prone recipient mice. Conditioning included a 6 Gy total body irradiation, cyclophosphamide, bortezomib, and T cell depletion. In non-autoimmune prone haploidentical recipients sensitized to the donor, we demonstrate that desensitization with single dose imlifidase and EndoS permits donor bone marrow engraftment in all recipients and long-term chimerism in the majority, under a 3 Gy irradiation protocol. Long-term chimeras were tolerant to subsequent donor skin grafts. Enzymatic inactivation of DSA facilitates donor hematopoietic stem cell engraftment in allo-sensitized haploidentical recipients in a reduced intensity conditioning protocol.