Introduction: Xenotransplantation research has relied on agents like anti-C10, which lacks clinical approval, and Cobra Venom Factor (CVF), which is unsuitable for human use. These drugs remain significant barriers to clinical translation. Therefore, revising immunomodulatory strategies and identifying clinically viable alternatives are essential steps toward clinical xenotransplantation.
Methods: To address the limitations of non-approved drugs, two approaches are possible: using regimens based on already approved agents, or developing new drugs suitable for clinical application. We have chosen to focus on the development of novel immunomodulatory agents that could gain clinical approval, rather than relying on drugs currently used in allotransplantation protocols.
Results: Recent studies have evaluated PG-405 as a substitute for the non-approved antibody C10. PG-405 contains the same Fab fragment as C10, conjugated to interleukin-10 (IL-10), an immunosuppressive cytokine expected to enhance regulatory T-cell activity and suppress immune responses. MD-3 (anti-ICAM-1) is a new agent that modulates immune suppression by inhibiting T-cell differentiation and affecting dendritic cells. Crovalimab, a complement 5 (C5) inhibitor, has been used as an alternative to CVF and functions by blocking C5 activity. In three recent studies using transgenic pigs, kidneys treated with PG-405, MD-3, and Crovalimab demonstrated graft survival periods of 61 and 44 days. Additional therapies under development include anti-CD154/CD28 bispecific antibodies and CAR-Treg cell therapy, which aim to overcome side effects such as thrombosis.
Conclusions: The development and clinical approval of new immunotherapeutic agents will facilitate clinical trials in xenotransplantation and may also lead to innovative immunomodulation protocols applicable to allotransplantation, ultimately advancing the field of transplantation medicine.