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

Area of Science:

• Immunology
• Transplantation Biology
• Xenotransplantation Research

Background:

• The CD40/CD40L pathway is a critical immune checkpoint for xenotransplantation.
• Optimal antibody blockade strategy (single vs. combination) and potential side effects remain unclear.
• Previous studies faced challenges with high antibody doses and thrombotic events from anti-CD40L therapies.

Purpose of the Study:

• To evaluate a novel combination therapy blocking CD40 and CD40L (CD154) in pig-to-baboon cardiac xenotransplantation.
• To assess the efficacy and safety of a chimeric anti-CD40 antibody combined with a long-acting PASylated anti-CD40L Fab fragment.
• To investigate the impact of this combination therapy on organ rejection and potential adverse events.

Main Methods:

• Six orthotopic pig-to-baboon cardiac xenotransplantation experiments were performed.
• A combination therapy involving a chimeric anti-CD40 antibody and a PASylated anti-CD40L Fab fragment was administered.
• Animal survival, thromboembolic events, and post-transplant histopathology were analyzed.

Main Results:

• The combination therapy achieved survival rates comparable to anti-CD40 monotherapy.
• No thromboembolic events were observed with the anti-CD40L PAS-Fab fragment.
• All surviving recipients developed unexpected fungal infections despite the absence of clinical signs.

Conclusions:

• Combination therapy with anti-CD40 and anti-CD40L antibodies is effective in cardiac xenotransplantation, offering comparable survival to monotherapy.
• This approach avoids thrombotic side effects associated with earlier anti-CD40L antibodies.
• The study highlights the need to monitor for opportunistic infections, such as fungal infections, in xenotransplantation recipients under immunosuppression.