CD28-Selective Inhibition Prolongs Non-Human Primate Kidney Transplant Survival

Lovasik, B. P.; Kim, S. C.; Higginbotham, L.; Wakwe, W.; Mathews, D. V.; Breeden, C. P.; Farris, A. B.; Larsen, C. P.; Ford, M. L.; Nadler, S.; Adams, A. B.

doi:10.1101/2023.05.03.539333

bioRxiv · 10.1101/2023.05.03.539333

CD28-Selective Inhibition Prolongs Non-Human Primate Kidney Transplant Survival

Lovasik, B. P.·Kim, S. C.·Higginbotham, L.·Wakwe, W.·Mathews, D. V.·Breeden, C. P.·Farris, A. B.·Larsen, C. P.·Ford, M. L.·Nadler, S.·Adams, A. B.

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Abstract

Costimulation blockade using belatacept results in improved renal function after kidney transplant as well as decreased likelihood of death/graft loss and reduced cardiovascular risk; however, higher rates and grades of acute rejection have prevented its widespread clinical adoption. Treatment with belatacept blocks both positive (CD28) and negative (CTLA-4) T cell signaling. CD28-selective therapies may offer improved potency by blocking CD28-mediated costimulation while leaving CTLA-4 mediated coinhibitory signals intact. Here we test a novel domain antibody directed at CD28 (anti-CD28 dAb (BMS-931699)) in a non-human primate kidney transplant model. Sixteen macaques underwent native nephrectomy and received life-sustaining renal allotransplantation from an MHC-mismatched donor. Animals were treated with belatacept alone, anti-CD28 dAb alone, or anti-CD28 dAb plus clinically relevant maintenance (MMF, Steroids) and induction therapy with either anti-IL-2R or T cell depletion. Treatment with anti-CD28 dAb extended survival compared to belatacept monotherapy (MST 187 vs. 29 days, p=0.07). The combination of anti-CD28 dAb and conventional immunosuppression further prolonged survival to MST [~]270 days. Animals maintained protective immunity with no significant infectious issues. These data demonstrate CD28-directed therapy is a safe and effective next-generation costimulatory blockade strategy with a demonstrated survival benefit and presumed advantage over belatacept by maintaining intact CTLA-4 coinhibitory signaling.

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Lovasik, B. P., Kim, S. C., Higginbotham, L., Wakwe, W., Mathews, D. V., Breeden, C. P., Farris, A. B., Larsen, C. P., Ford, M. L., Nadler, S., Adams, A. B.. 2023-05-05. CD28-Selective Inhibition Prolongs Non-Human Primate Kidney Transplant Survival. https://doi.org/10.1101/2023.05.03.539333

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