Fucosylation with fucosyltransferase VI or fucosyltransferase VII improves cord blood engraftment

Abstract

Background Advantages associated with the use of cord blood (CB) transplantation include the availability of cryopreserved units, ethnic diversity and lower incidence of graft-versus-host disease when compared to bone marrow or mobilized peripheral blood. However, poor engraftment remains a major obstacle. We and others have found that ex vivo fucosylation can enhance engraftment in murine models and thus ex vivo treatment of CB with fucosyltransferase (FT)-VI prior to transplantation is under clinical evaluation (NCT01471067). However, FT-VII appears to be more relevant to hematopoietic cells and may alter acceptor substrate diversity. In this study, we compare the ability of FT-VI and FT-VII to improve the rapidity, magnitude, multi-lineage and multi-tissue engraftment of human CB hematopoietic stem and progenitor cells (HSPC) in vivo. Methods CD34-selected CB HSPC were treated with recombinant FT-VI, FT-VI or mock control, then injected into immunodeficient mice and monitored for multi-lineage and multi-tissue engraftment. Results Both FT-VI and FT-VII fucosylated CB CD34+ cells in vitro, and both led to enhanced rates and magnitudes of engraftment when compared to untreated CB CD34+ cells in vivo. Engraftment following treatment with either fucosyltransferase was robust at multiple timepoints, and in multiple tissues, with similar multi-lineage potential. In contrast, only FT-VII was able to fucosylate T- and B-lymphocytes. Discussion While we found that FT-VI and FT-VII were similarly able to fucosylate and enhance the engraftment of CB CD34+ cells, differences in their ability to fucosylate lymphocytes cells may modulate graft-versus-tumor and/or graft-versus-host effects and may allow further optimization of CB transplantation.

mRNA-mediated glycoengineering ameliorates deficient homing of human stem cell–derived hematopoietic progenitors

“…We anticipate that strategies to increase E-selectin ligand expression could be applicable as part of a multifaceted approach to optimize the production of HSPCs from human PSCs. As an example of the power of glycoengineering to enforce E-selectin ligand expression, fucosylation of human cord blood using recombinant fucosyltransferase has recently been reported to accelerate engraftment in xenotransplant models (15,16) and has also shown promising results in early-stage clinical trials (17).…”

Umbilical cord blood donation: public or private?

“…[35][36][37] Additional strategies to increase homing and migration of cord blood cells are also under development using prostaglandin E2, CD 26/dipeptidyl peptidase (DPP-IV) and Fucosylation. [38][39][40] All of these approaches are in early clinical trials and are showing promising results. 41 Strategies to support immune reconstitution are more challenging but the emergence of new antivirals (Chimerix CMX001) and third-party cytotoxic T lymphocytes appear to have benefit in pilot clinical trials.…”

Modalities to Improve Cord Blood Engraftment

“…FTVI and FTVII fucosylated CB CD34+ cells in vitro, and both led to enhanced rates and magnitudes of engraftment compared with untreated CB CD34+ cells in vivo. In contrast, only FTVII was able to fucosylate T and B lymphocytes as indicated by Robinson and colleagues [71].…”