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An IgM Cleaving Enzyme for Clearance of Anti-Pig Xenoreactive Antibodies in a Nonhuman Primate Model.

Publication ,  Journal Article
Martinino, A; Smith, TJ; Elmore, ZC; Yoon, J; Ladowski, J; Schiliro, D; Hull, JA; Schwalb, A; Hu, M; Spangler, R; Lee, KW; Kim, MJ; Asokan, A ...
Published in: Xenotransplantation
2025

BACKGROUND: The removal of preformed antibodies with cleaving enzyme like IdeS (Imlifidase) has demonstrated therapeutic potential in organ transplantation for sensitized recipients. However, preformed xenoreactive antibodies (XAbs) against porcine glycans are predominantly IgM and considered detrimental in pig-to-human xenotransplantation. METHODS: Recombinant IceM, an endopeptidase cleaving IgM, was generated in Escherichia coli. Four maximally MHC-mismatched rhesus macaques underwent two serial skin transplantations to model allosensitized patients awaiting xenotransplantation. IceM was administered IV in allosensitized animals at 28 and 56 days after the first skin transplantation to assess in vivo IgM cleavage. Total IgG and IgM were quantified with western blot, and anti-pig (xenoreactive) IgG/IgM were evaluated using flowcrossmatch. B cell and its subpopulations were assessed using flow cytometry. RESULTS: IceM selectively cleaved human IgM, while showing no cleavage activity toward other isotypes including IgG, IgA, IgD, and IgE. Additionally, IceM cleaves only human and non-human primate IgM in vitro, but not in sera from other species. At a dose of 0.5 mg/kg, IceM reduced xenoreactive IgM levels to 13.76% ± 4.98% of baseline (B cell flow crossmatch) at 24 h post-administration, with baseline levels restored approximately 2 weeks after treatment. Additionally, animals showed similar kinetics of xenoreative IgM degradation with the repeated dose of IceM. CONCLUSION: In this study, we report a recombinant bacterial enzyme that selectively cleaves IgM in human and non-human primate sera. Repeat administration of IceM in macaques enables selective, robust clearance of circulating xenoreactive IgM. This approach will be useful in treating preformed natural and rebound IgM in xenotransplantation.

Duke Scholars

Published In

Xenotransplantation

DOI

EISSN

1399-3089

Publication Date

2025

Volume

32

Issue

1

Start / End Page

e70015

Location

Denmark

Related Subject Headings

  • Transplantation, Heterologous
  • Swine
  • Surgery
  • Skin Transplantation
  • Macaca mulatta
  • Immunoglobulin M
  • Immunoglobulin G
  • Humans
  • Graft Rejection
  • Bacterial Proteins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Martinino, A., Smith, T. J., Elmore, Z. C., Yoon, J., Ladowski, J., Schiliro, D., … Kwun, J. (2025). An IgM Cleaving Enzyme for Clearance of Anti-Pig Xenoreactive Antibodies in a Nonhuman Primate Model. Xenotransplantation, 32(1), e70015. https://doi.org/10.1111/xen.70015
Martinino, Alessandro, Timothy J. Smith, Zachary C. Elmore, Janghoon Yoon, Joseph Ladowski, Davide Schiliro, Joshua A. Hull, et al. “An IgM Cleaving Enzyme for Clearance of Anti-Pig Xenoreactive Antibodies in a Nonhuman Primate Model.Xenotransplantation 32, no. 1 (2025): e70015. https://doi.org/10.1111/xen.70015.
Martinino A, Smith TJ, Elmore ZC, Yoon J, Ladowski J, Schiliro D, et al. An IgM Cleaving Enzyme for Clearance of Anti-Pig Xenoreactive Antibodies in a Nonhuman Primate Model. Xenotransplantation. 2025;32(1):e70015.
Martinino, Alessandro, et al. “An IgM Cleaving Enzyme for Clearance of Anti-Pig Xenoreactive Antibodies in a Nonhuman Primate Model.Xenotransplantation, vol. 32, no. 1, 2025, p. e70015. Pubmed, doi:10.1111/xen.70015.
Martinino A, Smith TJ, Elmore ZC, Yoon J, Ladowski J, Schiliro D, Hull JA, Schwalb A, Hu M, Spangler R, Lee KW, Kim MJ, Williams K, Jackson A, Knechtle SJ, Asokan A, Kwun J. An IgM Cleaving Enzyme for Clearance of Anti-Pig Xenoreactive Antibodies in a Nonhuman Primate Model. Xenotransplantation. 2025;32(1):e70015.
Journal cover image

Published In

Xenotransplantation

DOI

EISSN

1399-3089

Publication Date

2025

Volume

32

Issue

1

Start / End Page

e70015

Location

Denmark

Related Subject Headings

  • Transplantation, Heterologous
  • Swine
  • Surgery
  • Skin Transplantation
  • Macaca mulatta
  • Immunoglobulin M
  • Immunoglobulin G
  • Humans
  • Graft Rejection
  • Bacterial Proteins