Date: Tuesday, May 5, 2015
Session Time: 4:00pm-5:30pm
Presentation Time: 4:00pm-4:12pm
Location: Room 119-A
Introduction. Costimulation blockade using belatacept has the potential to improve long-term renal function and reduce cardiovascular risk by avoiding calcineurin inhibitors, yet higher rates and grades of rejection have prevented its widespread clinical adoption. Treatment with belatacept, which binds CD80/86 on APCs, blocks both positive (CD28) and negative (CTLA-4) T cell signaling. CD28-selective therapies may offer improved potency by blocking CD28-mediated costimulation while allowing CTLA-4 coinhibitory signals. We test a novel domain antibody directed at CD28 (αCD28 dAb, BMS-931699-01) in a non-human primate kidney transplant model.
Methods. Rhesus macaques underwent bilateral nephrectomy and life-sustaining renal transplantation using a kidney from an MHC-mismatched donor. Animals were treated with belatacept monotherapy, αCD28 dAb monotherapy, belatacept plus conventional (MMF, steroids, and basiliximab), or αCD28 dAb plus conventional. Weekly serum chemistries assessed graft function post-transplant. Rejection was defined as serum creatinine >5mg/dL or BUN >100mg/dL on two consecutive measurements.
Results. Treatment with belatacept monotherapy significantly prolonged survival compared to control animals (MST=29 days; n=5; 53, 47, 29, 12, & 8 days). αCD28 treatment extended survival compared to belatacept monotherapy (MST >110.5 days, p=0.07; n=6; >168, >160, >119, 53, 35, & 9 days). Addition of conventional therapy to either drug further prolonged survival (bela+conventional MST=118 days [n=10] 306, 287, 197, 196, 183, 53, 35, 34, 29, & 7 days; versus αCD28 dAb+conventional [n=5] >140, >139, >103, >97, & 92 days). Protective immunity was maintained with no significant CMV viremia in belatacept or αCD28 dAb monotherapy regimens. One animal receiving αCD28 dAb + conventional (1/5, 20%) and two animals treated with belatacept + conventional (2/11, 18.2%) required CMV antiviral therapy (p=0.94). Peripheral blood analysis by flow cytometry revealed no gross T cell depletion or gross changes in T cell subsets in any treatment arm.
Conclusions. αCD28 dAb (BMS-931699-01) therapy alone or in combination with conventional immunosuppression prolongs renal allograft survival in non-human primates. CD28-directed therapy is a safe and efficacious immunosuppressant with the presumed benefit of permitting intact CTLA-4 coinhibitory signaling.
To cite this abstract in AMA style:Higginbotham L, Mathews D, Breeden C, Wakwe W, Larsen C, Nadler S, Adams A. CD28-Directed Therapy Prolongs Survival in a Non-Human Primate Kidney Transplant Model [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/cd28-directed-therapy-prolongs-survival-in-a-non-human-primate-kidney-transplant-model/. Accessed November 29, 2020.
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