Combination of Anti-CD40 and Anti-CD40L Antibodies as Co-Stimulation Blockade in Preclinical Cardiac Xenotransplantation
(2024) In Biomedicines 12(8).- Abstract
The blockade of the CD40/CD40L immune checkpoint is considered essential for cardiac xenotransplantation. However, it is still unclear which single antibody directed against CD40 or CD40L (CD154), or which combination of antibodies, is better at preventing organ rejection. For example, the high doses of antibody administered in previous experiments might not be feasible for the treatment of humans, while thrombotic side effects were described for first-generation anti-CD40L antibodies. To address these issues, we conducted six orthotopic pig-to-baboon cardiac xenotransplantation experiments, combining a chimeric anti-CD40 antibody with an investigational long-acting PASylated anti-CD40L Fab fragment. The combination therapy effectively... (More)
The blockade of the CD40/CD40L immune checkpoint is considered essential for cardiac xenotransplantation. However, it is still unclear which single antibody directed against CD40 or CD40L (CD154), or which combination of antibodies, is better at preventing organ rejection. For example, the high doses of antibody administered in previous experiments might not be feasible for the treatment of humans, while thrombotic side effects were described for first-generation anti-CD40L antibodies. To address these issues, we conducted six orthotopic pig-to-baboon cardiac xenotransplantation experiments, combining a chimeric anti-CD40 antibody with an investigational long-acting PASylated anti-CD40L Fab fragment. The combination therapy effectively resulted in animal survival with a rate comparable to a previous study that utilized anti-CD40 monotherapy. Importantly, no incidence of thromboembolic events associated with the administration of the anti-CD40L PAS-Fab was observed. Two experiments failed early because of technical reasons, two were terminated deliberately after 90 days with the baboons in excellent condition and two were extended to 120 and 170 days, respectively. Unexpectedly, and despite the absence of any clinical signs, histopathology revealed fungal infections in all four recipients. This study provides, for the first time, insights into a combination therapy with anti-CD40/anti-CD40L antibodies to block this immune checkpoint.
(Less)
- author
- organization
- publishing date
- 2024-08
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- CD40/CD40L, co-stimulation blockade, heart, orthotopic heart transplantation, xenotransplantation
- in
- Biomedicines
- volume
- 12
- issue
- 8
- article number
- 1927
- publisher
- MDPI AG
- external identifiers
-
- pmid:39200391
- scopus:85202628385
- ISSN
- 2227-9059
- DOI
- 10.3390/biomedicines12081927
- language
- English
- LU publication?
- yes
- id
- 95259b98-1a53-4e64-9fa7-e0843bb21385
- date added to LUP
- 2025-01-09 15:18:09
- date last changed
- 2025-07-11 19:58:23
@article{95259b98-1a53-4e64-9fa7-e0843bb21385,
abstract = {{<p>The blockade of the CD40/CD40L immune checkpoint is considered essential for cardiac xenotransplantation. However, it is still unclear which single antibody directed against CD40 or CD40L (CD154), or which combination of antibodies, is better at preventing organ rejection. For example, the high doses of antibody administered in previous experiments might not be feasible for the treatment of humans, while thrombotic side effects were described for first-generation anti-CD40L antibodies. To address these issues, we conducted six orthotopic pig-to-baboon cardiac xenotransplantation experiments, combining a chimeric anti-CD40 antibody with an investigational long-acting PASylated anti-CD40L Fab fragment. The combination therapy effectively resulted in animal survival with a rate comparable to a previous study that utilized anti-CD40 monotherapy. Importantly, no incidence of thromboembolic events associated with the administration of the anti-CD40L PAS-Fab was observed. Two experiments failed early because of technical reasons, two were terminated deliberately after 90 days with the baboons in excellent condition and two were extended to 120 and 170 days, respectively. Unexpectedly, and despite the absence of any clinical signs, histopathology revealed fungal infections in all four recipients. This study provides, for the first time, insights into a combination therapy with anti-CD40/anti-CD40L antibodies to block this immune checkpoint.</p>}},
author = {{Bender, Martin and Abicht, Jan Michael and Reichart, Bruno and Neumann, Elisabeth and Radan, Julia and Mokelke, Maren and Buttgereit, Ines and Leuschen, Maria and Wall, Felicia and Michel, Sebastian and Ellgass, Reinhard and Steen, Stig and Paskevicius, Audrius and Lange, Andreas and Kessler, Barbara and Kemter, Elisabeth and Klymiuk, Nikolai and Denner, Joachim and Godehardt, Antonia W. and Tönjes, Ralf R. and Burgmann, Jonathan M. and Figueiredo, Constança and Milusev, Anastasia and Zollet, Valentina and Salimi-Afjani, Neda and Despont, Alain and Rieben, Robert and Ledderose, Stephan and Walz, Christoph and Hagl, Christian and Ayares, David and Wolf, Eckhard and Schmoeckel, Michael and Brenner, Paolo and Binder, Uli and Gebauer, Michaela and Skerra, Arne and Längin, Matthias}},
issn = {{2227-9059}},
keywords = {{CD40/CD40L; co-stimulation blockade; heart; orthotopic heart transplantation; xenotransplantation}},
language = {{eng}},
number = {{8}},
publisher = {{MDPI AG}},
series = {{Biomedicines}},
title = {{Combination of Anti-CD40 and Anti-CD40L Antibodies as Co-Stimulation Blockade in Preclinical Cardiac Xenotransplantation}},
url = {{http://dx.doi.org/10.3390/biomedicines12081927}},
doi = {{10.3390/biomedicines12081927}},
volume = {{12}},
year = {{2024}},
}