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.

Advances in targeting co‐inhibitory and co‐stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy

“…FR104 has been shown to have biologic activity in a number of autoimmune and alloimmune settings, including in prolonging renal allograft survival in NHP and in preventing xenoGVHD in a NHP-→→ mouse model recently developed by our group. [75][76][77][78][79][80][81] Importantly, FR104 performed superiorly to belatacept in NHP models of renal transplant 80 and human xeno-GVHD. 76 The mechanisms that were critical for this improved activity have not been determined, although experiments in both systems suggest that both CTLA-4-and Treg-mediated mechanisms may be operative.…”

“…Led by Dr. Bernard Vanhove, Effimune independently developed a pegylated anti‐CD28 Fab, ‘FR104’, which has now been licensed to Janssen Biotech. FR104 has been shown to have biologic activity in a number of autoimmune and alloimmune settings, including in prolonging renal allograft survival in NHP and in preventing xenoGVHD in a NHP‐→→ mouse model recently developed by our group . Importantly, FR104 performed superiorly to belatacept in NHP models of renal transplant and human xeno‐GVHD .…”

“…[325][326][327] Vanhove et al 328 have subsequently shown that baboons represent a much more predictive NHP model for testing the toxicity of reagents targeting CD28, and used this model to provide compelling data for the safety of their single-chain anti-CD28 reagent, FR104. They have gone on to demonstrate the potential efficacy of this therapeutic (originally developed by Effimune, now licensed to Janssen) in a number of NHP models of transplantation, [76][77][78][79][80][81]328 and it has now completed Phase I trials in RA (Clinialtrials.gov # NCT02800811). BMS has also developed a similar single-chain anti-CD28 antibody, 'Lulizumab', which has also been moved into early-phase clinical trials for Sjogrens syndrome and lupus (Clinicaltrials.gov # NCT02843659 and NCT02265744).…”

Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis

“…This work has been driven by detailed flow cytometric evaluation of the T-and B-cell subpopulations driving both acute and chronic disease, [86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102] as well as increasing use of systems-based transcriptomic approaches to identifying the pathways associated with GVHD, both in preclinical models and clinical samples. 50, [103][104][105][106][107] This work is identifying a new cohort of targetable pathways for GVHD control, many of which are amenable for clinical translation.…”

Impact of infection on transplantation tolerance

“…152,153 Compared with belatacept, these selective CD28 blocking agents have been shown to preserve negative signaling through CTLA-4 and promote superior graft survival. 125,126,154 In addition, another CD28 domain-specific antibody, lulizumab, has also moved to a phase I/II clinical trial in kidney transplantation (clini caltr ials.gov). 125,126,154 In addition, another CD28 domain-specific antibody, lulizumab, has also moved to a phase I/II clinical trial in kidney transplantation (clini caltr ials.gov).…”