Anti-CD4 Antibody-modulated Transplants for GVHD Prevention in Hematopoietic Cell Transplantation

Graft-versus-host disease (GvHD) remains one of the major complications following allogeneic haematopoietic cell transplantation. Currently, immunosuppressants are used for GvHD prophylaxis and treatment in the majority of transplant recipients. Due to their systemic, non-specific mode of action, this treatment regimen is frequently associated with severe toxic side effects, opportunistic infections as well as cancer relapse when treating haematologic malignancies. By using short-term ex vivo modulation of haematopoietic cell transplants with the anti-human CD4 antibody MAX.16H5, we have developed a novel immune tolerance-inducing strategy enabling potent GvHD prevention. Functional in vitro assays and transcriptome profiling data suggest impaired TCR signalling and a shift towards an IL-10-dependent regulatory phenotype as the primary mechanism of action of anti-human CD4 antibody treatment, leading to a significantly reduced activation and proliferation of CD4+ and CD8+ T cells. A one-time incubation of haematopoietic transplants with MAX.16H5 prolongs survival of NSG mice and reduces signs of GvHD manifestation as effectively as repeated application with clinically applied immunosuppressants - making it a safe and effective immunotherapy for GvHD prevention.