Preclinical Testing of Antihuman CD28 Fab′ Antibody in a Novel Nonhuman Primate Small Animal Rodent Model of Xenogenic Graft-Versus-Host Disease

Abstract : Background-Graft-versus-host disease (GVHD) is a severe complication of hematopoietic stem cell transplantation. Current therapies to prevent alloreactive T cell activation largely cause generalized immunosuppression and may result in adverse drug, anti-leukemia and anti-pathogen responses. Recently, several immunomodulatory therapeutics have been developed that show efficacy in maintaining anti-leukemia responses while inhibiting GVHD in murine models. To analyze efficacy and better understand immunological tolerance, escape mechanisms, and side effects of clinical reagents, testing of species-cross-reactive human agents in large animal GVHD models is critical. Methods—We have previously developed and refined a NHP large animal GVHD model. However, this model is not readily amenable to semi-high throughput screening of candidate clinical reagents. Results—Here, we report a novel, optimized NHP xenogeneic GVHD (xeno-GVHD) small animal model that recapitulates many aspects of NHP and human GVHD. This model was validated using a clinically available blocking, monovalent anti-CD28 antibody (FR104) whose effects in a human xeno-GVHD rodent model are known. Conclusions—Since human-reactive reagents may not be fully cross-reactive or effective in vivo on NHP immune cells, this NHP xeno-GVHD model provides immunological insights and direct testing on NHP-induced GVHD prior to committing to the intensive NHP studies that are being increasingly used for detailed evaluation of new immune therapeutic strategies prior to human trials.