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

作者：Ulrike Gerdemann, Kyle Kimler, Matthew R. Warren, Connor McGuckin, Ryan A. Fleming, Matthew R. D’Ambra, Alal Eran, Alexandre Albanese, Edward Chen, Marlana Winschel, Lorenzo Cagnin, Jennifer Lane, Lev Gorfinkel, Bartley Adams, Jean Kwun, Leanne Lanieri, Megan D. Hoban, Tahirih L. Lamothe, Sharon L. Hyzy, Lisa Olson, Angela Panoskaltsis‐Mortari, Susan E. Prockop, Bruce R. Blazar, Leslie S. Kean, Victor Tkachev · 发表于：Blood · 年份：2025 · DOI：10.1182/blood.2024027239 · 被引用次数：5 · 研究领域：Monoclonal and Polyclonal Antibodies Research、T-cell and B-cell Immunology、Receptor Mechanisms and Signaling

ABSTRACT: 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 ana...