Siplizumab combination therapy with belatacept or abatacept broadly inhibits human T cell alloreactivity in vitro.

Combined antigen-specific T cell receptor stimulation and costimulation are needed for complete T cell activation. Belatacept and abatacept are nondepleting fusion proteins blocking CD28/B7 costimulation, whereas siplizumab is a depleting antiCD2 immunoglobulin G1 monoclonal antibody targeting CD2/CD58 costimulation. Herein, the effect of siplizumab combination therapy with abatacept or belatacept on T cell alloreactivity in mixed lymphocyte reactions was investigated. In contrast to monotherapy, the combination of siplizumab with belatacept or abatacept induced near-complete suppression of T cell proliferation and increased the potency of siplizumab-mediated T cell inhibition. Furthermore, dual targeting of CD2 and CD28 costimulation enhanced the selective depletion of memory T cells compared with monotherapy. Although siplizumab monotherapy leads to significant regulatory T cell enrichment, high doses of cytotoxic T-lymphocyte-associated antigen 4 and a human IgG1 Fc fragment in the combination therapy reduced this effect. These results support the clinical evaluation of dual costimulation blockade, combining siplizumab with abatacept or belatacept, for the prophylaxis of organ transplant rejection and improvement of long-term outcomes following transplantation. Ongoing investigative research will elucidate when other forms of siplizumab-based dual costimulatory blockade may be able to induce similarly strong inhibition of T cell activation although still allowing for enrichment of regulatory T cells.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David Berglund reports financial support was provided by ITB-MED. David Berglund reports a relationship with ITB-MED that includes: employment, equity or stocks, and funding grants. David Berglund has patent pending to ITB-MED.Erik Berglund reports financial support was provided by ITB-MED. Erik Berglund reports a relationship with ITB-MED that includes: employment and equity or stocks. Erik Berglund has patent pending to ITB-MED. Filip Cvetkovski reports financial support was provided by ITB-MED. Filip Cvetkovski reports a relationship with ITB-MED that includes: employment. Filip Cvetkovski has patent pending to ITB-MED. The other authors have nothing to declare. The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. F. Cvetkovski, R. Razavi, E. Berglund, and D. Berglund are employees of ITB-MED. E. Berglund and D. Berglund own shares in ITB-MED. F. Sellberg is a former employee of ITB-MED. The ITB-MED Group has applied for patent protection for the use of siplizumab in combination with CTLA4-Ig treatment.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)