Siplizumab combination therapy with belatacept or abatacept broadly inhibits human T cell alloreactivity in vitro
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
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| Enthalten in: |
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons - 23(2023), 10 vom: 15. Okt., Seite 1603-1611 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cvetkovski, Filip [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 23.10.2023 Date Revised 07.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ajt.2023.05.032 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Sellberg, Felix |e verfasserin |4 aut | |
| 700 | 1 | |a Berglund, Erik |e verfasserin |4 aut | |
| 700 | 1 | |a Berglund, David |e verfasserin |4 aut | |
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