A single dose of a CD137 antibody–drug conjugate protects rhesus macaque allogeneic HCT recipients against acute GVHD Available to Purchase

• In NHPs, a single CD137-ADC dose after HCT eliminates PD-1⁺ effector T cells, enabling reconstitution of nonpathogenic T-cell subsets.

• The CD137-ADC offers long-term aGVHD-free survival but increases the risk of rhesus homolog of Epstein-Barr virus reactivation and disease.

Rapid CD137 upregulation on alloreactive T cells upon allogeneic stimulation suggests that their selective elimination could prevent acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HCT). Here, we developed a novel aGVHD prophylactic regimen consisting of a single dose of an anti-CD137 antibody–drug conjugate (CD137-ADC) administered on the day of transplant without additional immunosuppression. The CD137-ADC depleted both human and nonhuman primate (NHP) activated T cells and proved highly effective in preventing xenogeneic aGVHD in mice receiving human peripheral blood mononuclear cells, as well as in NHP undergoing major histocompatibility complex (MHC)-haploidentical HCT. Flow cytometry analysis of NHP T cells indicated specific depletion of activated PD-1⁺ CD4 and CD8 T cells, while sparing naïve and PD-1⁻OX40⁺ memory T-cell subsets during the first week after HCT. CD137-ADC–treated NHP recipients demonstrated robust hematopoietic and immune reconstitution. Hallmarks of T-cell recovery after CD137-ADC, which were associated with long-term aGVHD-free survival, included reconstitution of CD4 memory T cells expressing TRAIL, terminally differentiated CD8 T cells expressing CX3CR1, and CD4 FoxP3⁺ regulatory T cells, cell types not expected to be involved in aGVHD pathogenesis. CD137-ADC–treated recipients demonstrated a higher risk of reactivation of rhesus lymphocryptovirus (the rhesus macaque Epstein-Barr virus analog), which was associated with reconstitution of follicular helper T cells, interferon signaling–associated memory, and γδT-cell subsets. This reactivation was controllable with rituximab administration. These results document effective depletion of alloreactive T cells and prevention of aGVHD after a single dose of CD137-ADC, suggesting that clinical translation should be carefully explored.