Preemptive administration of human αβ T cell receptor-targeting monoclonal antibody GZ-αβTCR potently abrogates aggressive graft-versus-host disease in vivo.
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 γδ and iNKT T cells. A novel, humanized monoclonal antibody, GZ-αβTCR, specific for the human αβ 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-αβTCR significantly attenuated clinical signs of GVHD and prolonged survival by preferential depletion of CD4 cells and the naïve T cell compartment, the trigger and driver of GVHD. In a regimen that included a preemptive dose, GZ-αβTCR treatment sufficiently abrogated GVHD. Importantly, GZ-αβTCR's specificity spared host cell-mediated immune competence of cell types other than αβT cells: namely γδT cells. GZ-αβTCR's outstanding capacity to prevent GVHD and ameliorate an ongoing GVHD while sparing immune cells other than αβT cells strongly recommends GZ-αβTCR for the prevention and treatment of acute GVHD in clinical settings.
Department of General, Visceral and Transplantation Surgery, University Hospital Tübingen, Tübingen, Germany.|Department of Pediatric Hematology and Oncology, University Children's Hospital Tübingen, Hoppe-Seyler Street 1, 72076, Tübingen, Germany.
Gregor
G
Blank
Department of Pediatric Hematology and Oncology, University Children's Hospital Tübingen, Hoppe-Seyler Street 1, 72076, Tübingen, Germany.
Christian
C
Welker
Department of Pathology, University Hospital Tübingen, Tübingen, Germany.
Bence
B
Sipos
Department of Pediatric Hematology and Oncology, University Children's Hospital Tübingen, Hoppe-Seyler Street 1, 72076, Tübingen, Germany.
Katja
K
Sonntag
Department of Pediatric Hematology and Oncology, University Children's Hospital Tübingen, Hoppe-Seyler Street 1, 72076, Tübingen, Germany.
Friederike
F
Müller
Department of Radiation Oncology, University Hospital Tübingen, Tübingen, Germany.
Franziska
F
Eckert
Department of Pediatric Hematology and Oncology, University Children's Hospital Tübingen, Hoppe-Seyler Street 1, 72076, Tübingen, Germany.
Christian
C
Seitz
Department of General, Visceral and Transplantation Surgery, University Hospital Tübingen, Tübingen, Germany.
Silvio
S
Nadalin
Genzyme, Sanofi, Framingham, MA, USA.
Gina
G
LaCorcia
Department of General, Visceral and Transplantation Surgery, University Hospital Tübingen, Tübingen, Germany.
Alfred
A
Königsrainer
Genzyme, Sanofi, Framingham, MA, USA.
Daniel
D
Snell
Department of Pediatric Hematology and Oncology, University Children's Hospital Tübingen, Hoppe-Seyler Street 1, 72076, Tübingen, Germany.
Rupert
R
Handgretinger
Department of Pediatric Hematology and Oncology, University Children's Hospital Tübingen, Hoppe-Seyler Street 1, 72076, Tübingen, Germany. karin.schilbach@med.uni-tuebingen.de.
Karin
K
Schilbach
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D002478:Cells, Cultured; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods*; D014611:Vaccination / Q000379:methods*
D061067:Antibodies, Monoclonal, Humanized; D016693:Receptors, Antigen, T-Cell, alpha-beta
Antibody therapy; Prevention of GVHD; Stem cell transplantation; αβ-T cell depletion; γδT cells