Complement Blockade Improves Renal Xenograft Survival in Primates in the Absence of Transgenic Complement Regulatory Proteins
1Surgery, Emory University School of Medicine, Atlanta, GA, 2Pathology, Emory University School of Medicine, Atlanta, GA, 3Surgery, University of Miami, Miami, FL, 4Surgery, University of Minnesota, Minneapolis, MN
Meeting: 2021 American Transplant Congress
Abstract number: 460
Keywords: Immunosuppression, Kidney transplantation, Pig, Preclinical trails
Topic: Basic Science » Xenotransplantation
Session Information
Session Time: 7:30pm-8:30pm
Presentation Time: 7:30pm-7:40pm
Location: Virtual
*Purpose: Complement activation is a major contributor to xenograft rejection. To minimize xenograft injury, complement suppression via insertion of human complement-regulatory transgenes into the donor pig genome has been previously evaluated; however, genome modification is of undefined efficacy and risk. As such, pharmacologic complement regulation is a viable option to suppress complement activity in the absence of transgene insertion in the donor pig. The aim of this study was to assess the efficacy of terminal complement blockade using a novel, clinically relevant anti-C5 mAb (tesidolumab, LFG316) in a pig-to-NHP renal xenotransplant model using non-transgenic pig donors.
*Methods: Porcine donors were engineered without GGTA1/B4GALNT2 (DKO) or GGTA1/B4GALNT2/Class I SLA (TKO). In vitro assays were performed combining xenoreactive rhesus macaque serum with porcine peripheral blood mononuclear cells (PBMCs) in the presence of complement and tesidolumab. Kidney xenotransplants were then performed from porcine donors to rhesus macaques (n=17). Recipients received T-cell depletion plus either anti-CD154 (clone 5C8) and tesidolumab (n=7), or anti-CD154 alone (n=10).
*Results: Incubation of tesidolumab with porcine PBMCs and xenoreactive NHP serum impaired complement-mediated cytotoxicity in a dose-dependent manner. Anti-C5 therapy significantly prolonged xenograft survival (MST >350 days) compared to treatment with anti-CD154 alone (MST 9 days, p=0.0118). The combination of xenoantigen knockout and treatment with anti-CD154 prevented the formation of de-novo anti-pig antibody.
*Conclusions: Transient terminal complement blockade using tesidolumab significantly prolongs graft survival and prevents early antibody-mediated xenograft rejection in a pig-to-NHP renal transplant model using porcine donors without transgenes. Selective knockout of GGTA1/B4Gal/SLA-I xenoreactive antigens on the cell surface allows for long-term graft survival and prevents development of xenoreactive DSA. These data suggest that therapeutic terminal complement blockade permits successful xenotransplantation without the need for multiple complement regulatory transgenes.
To cite this abstract in AMA style:
Faber DA, Lovasik B, Matar A, Breeden C, Farris AB, Tector M, Tector A, Adams A. Complement Blockade Improves Renal Xenograft Survival in Primates in the Absence of Transgenic Complement Regulatory Proteins [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/complement-blockade-improves-renal-xenograft-survival-in-primates-in-the-absence-of-transgenic-complement-regulatory-proteins/. Accessed May 6, 2025.« Back to 2021 American Transplant Congress