Combination of Anti-CD40 and Anti-CD40L Antibodies as Co-Stimulation Blockade in Preclinical Cardiac Xenotransplantation

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.

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Publication Details

Journal
Biomedicines
Published
2024-08-22
DOI
https://doi.org/10.3390/biomedicines12081927
Citations
9
Primary Topic
Xenotransplantation and immune response
Type
article
Field-Weighted Citation Impact
5.15

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article

Combination of Anti-CD40 and Anti-CD40L Antibodies as Co-Stimulation Blockade in Preclinical Cardiac Xenotransplantation

Christian M. Hagl, David Ayares, Michaela Gebauer, Ines Buttgereit et al.
9 citations
Biomedicines
Xenotransplantation and immune response
5.15
article

Combination of Anti-CD40 and Anti-CD40L Antibodies as Co-Stimulation Blockade in Preclinical Cardiac Xenotransplantation

Christian M. Hagl, David Ayares, Michaela Gebauer, Ines Buttgereit, Antonia W. Godehardt, Andreas Lange, M. Patricia Leuschen, Felicia Wall, Algimantas Paškevičius, Stephan Ledderose, Eckhard Wolf, Arne Skerra, Robert Rieben, Elisabeth Kemter, Julia Radan, Ralf R. Tönjes, Paolo Brenner, Martin Bender, Matthias Längin, Michael Schmoeckel, Constança Figueiredo, Jan‐Michael Abicht, Bruno Reichart, Reinhard Ellgass, Alain Despont, Anastasia Milusev, Uli Binder, Elisabeth Neumann, Maren Mokelke, Joachim Denner, Barbara Keßler, Christoph Walz, Jonathan M. Burgmann, Valentina Zollet, Nikolai Klymiuk, Sebastian G. Michel, Neda Salimi‐Afjani, Stig Steen
article en
9 citations

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 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.

BiomedicinesVol. 12(8)
University of Bern (CH), Lund University (SE), LMU Klinikum (DE), Medizinische Hochschule Hannover (DE), German Centre for Cardiovascular Research (DE), Skåne University Hospital (SE), Technical University of Munich (DE), Freie Universität Berlin (DE), Ludwig-Maximilians-Universität München (DE), Paul Ehrlich Institut (DE)
Deutsche Forschungsgemeinschaft, Fondation Leducq, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Deutsches Primatenzentrum
Good health and well-being
Openalex Percentile: Top 4%
Xenotransplantation and immune response
5.15
DOIOpen Access PDFOpenAlex
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