Preemptive administration of human alpha beta T cell receptor-targeting monoclonal antibody GZ-alpha beta TCR potently abrogates aggressive graft-versus-host disease in vivo

摘要

GVHD, both acute and chronic, remains the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Thus, there is still a great need for therapeutic tools for the prevention and treatment of GVHD. Several biologics have shown promising results in salvage therapies but are attendant on an increased risk for opportunistic infections, lymphoproliferative disorders, and relapse. This is partly due to efficient T cell elimination that neither dissects alloreactive from non-alloreactive T cells nor considers functional and structural distinctiveness of pathogen- and malignancy-reactive gamma delta and iNKT T cells. A novel, humanized monoclonal antibody, GZ-alpha beta TCR, specific for the human alpha beta T cell receptor, was evaluated in a xenogeneic GVHD model for its potential to prevent or ameliorate GVHD and prolong survival. We could show that GZ-alpha beta TCR significantly attenuated clinical signs of GVHD and prolonged survival by preferential depletion of CD4 cells and the na < ve T cell compartment, the trigger and driver of GVHD. In a regimen that included a preemptive dose, GZ-alpha beta TCR treatment sufficiently abrogated GVHD. Importantly, GZ-alpha beta TCR's specificity spared host cell-mediated immune competence of cell types other than alpha beta T cells: namely gamma delta T cells. GZ-alpha beta TCR's outstanding capacity to prevent GVHD and ameliorate an ongoing GVHD while sparing immune cells other than alpha beta T cells strongly recommends GZ-alpha beta TCR for the prevention and treatment of acute GVHD in clinical settings.