Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

Abstract

Allograft rejection and immunosuppression are two major issues in transplantation medicine. The specific targeting of alloreactive T cells, the initiators and promoters of allograft rejection, would be a promising strategy to reduce unwanted T-cell responses and side effects of lifelong immunosuppression. The novel humanized monoclonal antibody GZ-αβTCR, specific for the human αβT-cell receptor, was tested in vitro and in vivo for its specificity and efficacy to modulate the αβT-cell compartment. GZ-αβTCR moderately induced apoptosis in resting αβT cells in vitro, an effect considerably amplified in activated T cells. A single dose of GZ-αβTCR significantly reduced human CD45 + CD3 + T cells in vivo, with a preferential modulation of CD4 + αβT cells. Importantly, naive T cells, the T-cell subset from which alloreactivity emanates, were significantly reduced. Simultaneously, a significant, compensatory increase of γδ T cells was observed in vitro and in vivo in both humanized mouse models examined. GZ-αβTCR did not induce cytokines and was well tolerated. Thus, specificity and high efficacy make GZ-αβTCR a powerful tool to selectively eliminate putatively detrimental T-cell subsets, a major goal in transplantation medicine. At the same time, GZ-αβTCR spares γδ and natural killer cells, thus leaving the recipient's immune system competent for cell-mediated immunoregulation and cell-mediated immunity.

Selective Depletion of αβ T Cells and B Cells for Human Leukocyte Antigen–Haploidentical Hematopoietic Stem Cell Transplantation. A Three-Year Follow-Up of Procedure Efficiency

“…The technical staff must also be aware that even apparently negligible volumes of unlabeled cells may severely affect cell-depletion efficiency and, thus, they must ensure that cells are thoroughly dislodged from all bag recesses during the labeling step. The αβ T cell-depletion procedure performed in a single center with commercial reagents and supplies proved to be robust and reproducible, since our results are in agreement with the figures reported by other centers in studies based on smaller numbers of cases [10,11,40,43,44].…”

“…It was also demonstrated that the clonogenic potential of CD34 + HSC after depletion remained unaffected [10]. New developments are now in sight following the reports that a novel humanized anti-αβ TCR antibody, endowed with an improved capacity to target CD4 + T cells for GVHD prevention both in vitro and in vivo in a mouse-human model of HSCT [39,40], may become available for clinical use.…”