Anti-non-Gal-specific combination treatment with an anti-idiotypic Ab and an inhibitory small molecule mitigates the xenoantibody response

John M. Stewart, Alice F Tarantal, Yan Chen, Nancy C. Appleby, Tania I. Fuentes, Charles C Lee, Evelyn J. Salvaris, Anthony J F D'Apice, Peter J. Cowan, Mary Kearns-Jonker

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background B-cell depletion significantly extends survival of α-1,3-galactosyltranferase knockout (GTKO) porcine organs in pig-to-primate models. Our previous work demonstrated that the anti-non-Gal xenoantibody response is structurally restricted. Selective inhibition of xenoantigen/xenoantibody interactions could prolong xenograft survival while preserving B-cell-mediated immune surveillance. Methods The anti-idiotypic antibody, B4N190, was selected from a synthetic human phage display library after enrichment against a recombinant anti-non-Gal xenoantibody followed by functional testing in vitro. The inhibitory small molecule, JMS022, was selected from the NCI diversity set III using virtual screening based on predicted xenoantibody structure. Three rhesus monkeys were pre-treated with anti-non-Gal-specific single-chain anti-idiotypic antibody, B4N190. A total of five monkeys, including two untreated controls, were then immunized with GTKO porcine endothelial cells to initiate an anti-non-α-1,3-Gal (non-Gal) xenoantibody response. The efficacy of the inhibitory small molecule specific for anti-non-Gal xenoantibody, JMS022, was tested in vitro. Results After the combination of in vivo anti-id and in vitro small molecule treatments, IgM xenoantibody binding to GTKO cells was reduced to pre-immunization levels in two-thirds of animals; however, some xenoantibodies remained in the third animal. Furthermore, when treated with anti-id alone, all three experimental animals displayed a lower anti-non-Gal IgG xenoantibody response compared with controls. Treatment with anti-idiotypic antibody alone reduced IgM xenoantibody response intensity in only one of three monkeys injected with GTKO pig endothelial cells. In the one experimental animal, which displayed reduced IgM and IgG responses, select B-cell subsets were also reduced by anti-id therapy alone. Furthermore, natural antibody responses, including anti-laminin, anti-ssDNA, and anti-thyroglobulin antibodies were intact despite targeted depletion of anti-non-Gal xenoantibodies in vivo indicating that selective reduction of xenoantibodies can be accomplished without total B-cell depletion. Conclusions This preliminary study demonstrates the strength of approaches designed to selectively inhibit anti-non-Gal xenoantibody. Both anti-non-Gal-specific anti-idiotypic antibody and small molecules can be used to selectively limit xenoantibody responses.

Original languageEnglish (US)
Pages (from-to)254-266
Number of pages13
JournalXenotransplantation
Volume21
Issue number3
DOIs
StatePublished - 2014

Fingerprint

Heterophile Antibodies
Therapeutics
Anti-Idiotypic Antibodies
Swine
Immunoglobulin M
B-Lymphocytes
Haplorhini
Endothelial Cells
Immunoglobulin G
Heterophile Antigens
B-Lymphocyte Subsets
Single-Chain Antibodies
Laminin
Macaca mulatta
Heterografts

Keywords

  • anti-idiotypic antibody
  • B cell
  • natural antibody
  • phage display library
  • small molecule
  • xenotransplantation

ASJC Scopus subject areas

  • Transplantation
  • Immunology
  • Medicine(all)

Cite this

Anti-non-Gal-specific combination treatment with an anti-idiotypic Ab and an inhibitory small molecule mitigates the xenoantibody response. / Stewart, John M.; Tarantal, Alice F; Chen, Yan; Appleby, Nancy C.; Fuentes, Tania I.; Lee, Charles C; Salvaris, Evelyn J.; D'Apice, Anthony J F; Cowan, Peter J.; Kearns-Jonker, Mary.

In: Xenotransplantation, Vol. 21, No. 3, 2014, p. 254-266.

Research output: Contribution to journalArticle

Stewart, JM, Tarantal, AF, Chen, Y, Appleby, NC, Fuentes, TI, Lee, CC, Salvaris, EJ, D'Apice, AJF, Cowan, PJ & Kearns-Jonker, M 2014, 'Anti-non-Gal-specific combination treatment with an anti-idiotypic Ab and an inhibitory small molecule mitigates the xenoantibody response', Xenotransplantation, vol. 21, no. 3, pp. 254-266. https://doi.org/10.1111/xen.12096
Stewart, John M. ; Tarantal, Alice F ; Chen, Yan ; Appleby, Nancy C. ; Fuentes, Tania I. ; Lee, Charles C ; Salvaris, Evelyn J. ; D'Apice, Anthony J F ; Cowan, Peter J. ; Kearns-Jonker, Mary. / Anti-non-Gal-specific combination treatment with an anti-idiotypic Ab and an inhibitory small molecule mitigates the xenoantibody response. In: Xenotransplantation. 2014 ; Vol. 21, No. 3. pp. 254-266.
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abstract = "Background B-cell depletion significantly extends survival of α-1,3-galactosyltranferase knockout (GTKO) porcine organs in pig-to-primate models. Our previous work demonstrated that the anti-non-Gal xenoantibody response is structurally restricted. Selective inhibition of xenoantigen/xenoantibody interactions could prolong xenograft survival while preserving B-cell-mediated immune surveillance. Methods The anti-idiotypic antibody, B4N190, was selected from a synthetic human phage display library after enrichment against a recombinant anti-non-Gal xenoantibody followed by functional testing in vitro. The inhibitory small molecule, JMS022, was selected from the NCI diversity set III using virtual screening based on predicted xenoantibody structure. Three rhesus monkeys were pre-treated with anti-non-Gal-specific single-chain anti-idiotypic antibody, B4N190. A total of five monkeys, including two untreated controls, were then immunized with GTKO porcine endothelial cells to initiate an anti-non-α-1,3-Gal (non-Gal) xenoantibody response. The efficacy of the inhibitory small molecule specific for anti-non-Gal xenoantibody, JMS022, was tested in vitro. Results After the combination of in vivo anti-id and in vitro small molecule treatments, IgM xenoantibody binding to GTKO cells was reduced to pre-immunization levels in two-thirds of animals; however, some xenoantibodies remained in the third animal. Furthermore, when treated with anti-id alone, all three experimental animals displayed a lower anti-non-Gal IgG xenoantibody response compared with controls. Treatment with anti-idiotypic antibody alone reduced IgM xenoantibody response intensity in only one of three monkeys injected with GTKO pig endothelial cells. In the one experimental animal, which displayed reduced IgM and IgG responses, select B-cell subsets were also reduced by anti-id therapy alone. Furthermore, natural antibody responses, including anti-laminin, anti-ssDNA, and anti-thyroglobulin antibodies were intact despite targeted depletion of anti-non-Gal xenoantibodies in vivo indicating that selective reduction of xenoantibodies can be accomplished without total B-cell depletion. Conclusions This preliminary study demonstrates the strength of approaches designed to selectively inhibit anti-non-Gal xenoantibody. Both anti-non-Gal-specific anti-idiotypic antibody and small molecules can be used to selectively limit xenoantibody responses.",
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AU - Chen, Yan

AU - Appleby, Nancy C.

AU - Fuentes, Tania I.

AU - Lee, Charles C

AU - Salvaris, Evelyn J.

AU - D'Apice, Anthony J F

AU - Cowan, Peter J.

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N2 - Background B-cell depletion significantly extends survival of α-1,3-galactosyltranferase knockout (GTKO) porcine organs in pig-to-primate models. Our previous work demonstrated that the anti-non-Gal xenoantibody response is structurally restricted. Selective inhibition of xenoantigen/xenoantibody interactions could prolong xenograft survival while preserving B-cell-mediated immune surveillance. Methods The anti-idiotypic antibody, B4N190, was selected from a synthetic human phage display library after enrichment against a recombinant anti-non-Gal xenoantibody followed by functional testing in vitro. The inhibitory small molecule, JMS022, was selected from the NCI diversity set III using virtual screening based on predicted xenoantibody structure. Three rhesus monkeys were pre-treated with anti-non-Gal-specific single-chain anti-idiotypic antibody, B4N190. A total of five monkeys, including two untreated controls, were then immunized with GTKO porcine endothelial cells to initiate an anti-non-α-1,3-Gal (non-Gal) xenoantibody response. The efficacy of the inhibitory small molecule specific for anti-non-Gal xenoantibody, JMS022, was tested in vitro. Results After the combination of in vivo anti-id and in vitro small molecule treatments, IgM xenoantibody binding to GTKO cells was reduced to pre-immunization levels in two-thirds of animals; however, some xenoantibodies remained in the third animal. Furthermore, when treated with anti-id alone, all three experimental animals displayed a lower anti-non-Gal IgG xenoantibody response compared with controls. Treatment with anti-idiotypic antibody alone reduced IgM xenoantibody response intensity in only one of three monkeys injected with GTKO pig endothelial cells. In the one experimental animal, which displayed reduced IgM and IgG responses, select B-cell subsets were also reduced by anti-id therapy alone. Furthermore, natural antibody responses, including anti-laminin, anti-ssDNA, and anti-thyroglobulin antibodies were intact despite targeted depletion of anti-non-Gal xenoantibodies in vivo indicating that selective reduction of xenoantibodies can be accomplished without total B-cell depletion. Conclusions This preliminary study demonstrates the strength of approaches designed to selectively inhibit anti-non-Gal xenoantibody. Both anti-non-Gal-specific anti-idiotypic antibody and small molecules can be used to selectively limit xenoantibody responses.

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