Successful Long-Term TMA- and Rejection- Free Survival of a Kidney Xenograft with Triple Xenoantigen Knockout Plus Insertion of Multiple Human Transgenes

D. H. Ma¹, H. Sasaki¹, T. Hirose¹, I. Rosales¹, A. Dehnadi¹, R. Colvin¹, J. F. Markmann¹, W. Win², Y. Kan², J. Layer², M. Youd², W. Westlin², L. Yang², T. Kawai¹

¹Surgery, MGH, Boston, MA, ²eGenesis Inc., Cambridge, MA

Meeting: 2020 American Transplant Congress

Abstract number: A-267

Keywords: Primates, Xenoreactive antibodies

Session Information

Session Name: Poster Session A: Xenotransplantation

Session Type: Poster Session

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:00pm

Presentation Time: 3:30pm-4:00pm

Location: Virtual

*Purpose: Recent advances in genome engineering technology allow for the generation of porcine organ donors with multiplex gene edits. Here we evaluated survival of kidneys from triple xenoantigen knockout pigs that contain multiple human transgenes (Pig 2.0) in a life-sustaining non-human primate renal xenotransplant model.

*Methods: Cynomolgus macaques received kidneys from either GTKO.hCD55 pigs (n=2; reference group) or Pig 2.0 (n=7) followed by bilateral native nephrectomy. All Pig 2.0 donors were triple antigen knockout and expressed human complement, coagulation, and immune regulatory transgenes at different levels in three variations (Pig 2.5, 2.9, 2.10). Recipients were treated with anti-rhesus ATG and anti-CD20 mAb as induction, followed by weekly anti-CD154 (hu5C8), daily mycophenolate mofetil (MMF) and, in the reference and 2.9 groups, methylprednisolone and sirolimus. Animals were followed clinically with lab tests, serial ultrasound and protocol biopsies.

*Results: Regardless of gene modifications, graft survival clustered into three patterns – rapid rejection within two weeks (n=4), delayed rejection at two months (n=3), and longer-term surviving where the animals were euthanized for non-rejection related complications (n=2). The longest survivor (Pig 2.9) had no evidence of rejection on biopsy at Day 237 and intractable anemia secondary to parvovirus resulted in sacrifice at day 265. Overall, graft rejection was associated with thrombotic microangiopathy (TMA), chronic antibody-mediated rejection (AMR) and borderline T-cell Mediated Rejection (TCMR). Recipients were not screened for preformed anti-pig antibodies. Retrospective analysis showed longer-term survivors had lower IgM and IgG (MFI<500 and <2000, respectively) pre-transplant antibody levels against donor endothelial cells than delayed (MFI >3000 and >8500) or rapid rejection groups (MFI >4500 and >8500).

*Conclusions: Genetic modification with with depletion of xenoantigens and addition of human transgenes allowed kidney graft survival up to 265 days in the Pig 2.0 group. Lower pre-transplant donor specific antibody titers were generally associated with better post-transplant outcomes.

To cite this abstract in AMA style:

Ma DH, Sasaki H, Hirose T, Rosales I, Dehnadi A, Colvin R, Markmann JF, Win W, Kan Y, Layer J, Youd M, Westlin W, Yang L, Kawai T. Successful Long-Term TMA- and Rejection- Free Survival of a Kidney Xenograft with Triple Xenoantigen Knockout Plus Insertion of Multiple Human Transgenes [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/successful-long-term-tma-and-rejection-free-survival-of-a-kidney-xenograft-with-triple-xenoantigen-knockout-plus-insertion-of-multiple-human-transgenes/. Accessed November 22, 2024.

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