Publikationsdatenbank

Combination of anti-CD40 and anti-CD40L antibodies as co-stimulation blockade in preclinical cardiac xenotransplantation (2024)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Bender, Martin

Abicht, Jan-Michael

Reichart, Bruno

Neumann, Elisabeth

Radan, Julia

Mokelke, Maren

Buttgereit, Ines

Leuschen, Maria

Wall, Felicia

Michel, Sebastian

Ellgass, Reinhard

Steen, Stig

Paskevicius, Audrius

Lange, Andreas

Kessler, Barbara

Kemter, Elisabeth

Klymiuk, Nikolai

Denner, Joachim (WE 5)

Godehardt, Antonia W.

Tönjes, Ralf R.

Burgmann, Jonathan M.

Figueiredo, Constança

Milusev, Anastasia

Zollet, Valentina

Salimi-Afjani, Neda

Despont, Alain

Rieben, Robert

Ledderose, Stephan

Walz, Christoph

Hagl, Christian

Ayares, David

Wolf, Eckhard

Schmoeckel, Michael

Brenner, Paolo

Binder, Uli

Gebauer, Michaela

Skerra, Arne

Längin, Matthias

Quelle

Biomedicines : open access journal

Bandzählung: 12

Heftzählung: 8

Seiten: 1927

ISSN: 2227-9059

Sprache

Englisch

Verweise

URL (Volltext): https://www.mdpi.com/2227-9059/12/8/1927

DOI: 10.3390/biomedicines12081927

Pubmed: 39200391

Kontakt

Institut für Virologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51833
virologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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.