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Synthetic HLA-G proteins for therapeutic use in transplantation.

ABSTRACT: The human leukocyte antigen (HLA)-G is a tolerogenic molecule, whose expression by allografts is associated with better acceptance. An increasing interest in producing HLA-G as a clinical-grade molecule for therapy use is impaired by its complexity and limited stability. Our purpose was to engineer simpler and more stable HLA-G-derived molecules than the full-length HLA-G trimolecular complex that are also tolerogenic, functional as soluble molecules, and compatible with good manufacturing practice (GMP) production conditions. We present two synthetic molecules: (?3-L)x2 and (?1-?3)x2 polypeptides. We show their capability to bind the HLA-G receptor LILRB2 and their functions in vitro and in vivo. The (?1-?3)x2 polypeptide proved to be a potent tolerogenic molecule in vivo: One treatment of skin allograft recipient mice with (?1-?3)x2 was sufficient to significantly prolong graft survival, and four weekly treatments induced complete tolerance. Furthermore, (?1-?3)x2 was active as a soluble molecule and capable of inhibiting the proliferation of tumor cell lines, as does the full length HLA-G trimolecular complex. Thus, the synthetic (?1-?3)x2 polypeptide is a stable and simpler alternative to the full-length HLA-G molecule. It can be produced under GMP conditions, it functions as a soluble molecule, and it is at least as tolerogenic as HLA-G in vivo.

SUBMITTER: LeMaoult J

PROVIDER: S-EPMC3752534 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Synthetic HLA-G proteins for therapeutic use in transplantation.

LeMaoult Joel J Daouya Marina M Wu Juan J Loustau Maria M Horuzsko Anatolij A Carosella Edgardo D ED

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20130610 9

The human leukocyte antigen (HLA)-G is a tolerogenic molecule, whose expression by allografts is associated with better acceptance. An increasing interest in producing HLA-G as a clinical-grade molecule for therapy use is impaired by its complexity and limited stability. Our purpose was to engineer simpler and more stable HLA-G-derived molecules than the full-length HLA-G trimolecular complex that are also tolerogenic, functional as soluble molecules, and compatible with good manufacturing pract ...[more]

PMID: 23752205

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Project description:Composite endpoints that not only encompass mortality and relapse, but other critical post-transplant events such as graft-versus-host disease, are being increasingly utilized to quantify survival without significant morbidity after allogeneic blood or marrow transplantation. High-dose, post-transplantation cyclophosphamide reduces severe graft-versus-host disease with allogeneic marrow transplantation, making composite endpoints after this management particularly interesting. We retrospectively analyzed 684 adults with hematologic malignancies who received T-cell-replete bone marrow grafts and cyclophosphamide after myeloablative HLA-matched related (n=192) or unrelated (n=120), or non-myeloablative HLA-haploidentical (n=372) donor transplantation. The median follow up was 4 (range, 0.02-11.4) years. Graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without grade III-IV acute graft-versus-host disease, chronic graft-versus-host disease requiring systemic treatment, relapse, or death. Chronic graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without moderate or severe chronic graft-versus-host disease, relapse, or death. One-year graft-versus-host disease-free, relapse-free survival and chronic graft-versus-host disease-free, relapse-free survival estimates were, respectively, 47% (95% CI: 41-55%) and 53% (95% CI: 46-61%) after myeloablative HLA-matched related, 42% (95% CI: 34-52%) and 52% (95% CI: 44-62%) after myeloablative HLA-matched unrelated, and 45% (95% CI: 40-50%) and 50% (95% CI: 45-55%) after non-myeloablative HLA-haploidentical donor transplantation. In multivariable models, there were no differences in graft-versus-host disease-free, or chronic graft-versus-host disease-free, relapse-free survival after either myeloablative HLA-matched unrelated or non-myeloablative HLA-haploidentical, compared with myeloablative HLA-matched related donor transplantation. Although limited by inclusion of dissimilar cohorts, we found that post-transplantation cyclophosphamide-based platforms yield comparable composite endpoints across conditioning intensity, donor type, and HLA match.

Project description:BackgroundAllogeneic therapeutic cells may be rejected if they express HLA alleles not found in the recipient. As finding cell donors with a full HLA match to a recipient requires vast donor pools, the use of HLA homozygous cells has been suggested as an alternative. HLA homozygous cells should be well tolerated by those who carry at least one copy of donor HLA alleles. HLA-A-B homozygotes could be valuable for HLA-matched thrombocyte products. We evaluated the feasibility of blood donor biobank and HLA imputation for the identification of potential cell donors homozygous for HLA alleles.MethodsWe imputed HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and -DPB1 alleles from genotypes of 20,737 Finnish blood donors in the Blood Service Biobank. We confirmed homozygosity by sequencing HLA alleles in 30 samples and by examining 36,161 MHC-located polymorphic DNA markers.ResultsThree hundred and seventeen individuals (1.5%), representing 41 different haplotypes, were found to be homozygous for HLA-A, -B, -C, -DRB1, -DQA1 and -DQB1 alleles. Ten most frequent haplotypes homozygous for HLA-A to -DQB1 were HLA-compatible with 49.5%, and three most frequent homozygotes to 30.4% of the Finnish population. Ten most frequent HLA-A-B homozygotes were compatible with 75.3%, and three most frequent haplotypes to 42.6% of the Finnish population. HLA homozygotes had a low level of heterozygosity in MHC-located DNA markers, in particular in HLA haplotypes enriched in Finland.ConclusionsThe present study shows that HLA imputation in a blood donor biobank of reasonable size can be used to identify HLA homozygous blood donors suitable for cell therapy, HLA-typed thrombocytes and research. The homozygotes were HLA-compatible with a large fraction of the Finnish population. Regular blood donors reported to have positive attitude to research donation appear a good option for these purposes. Differences in population frequencies of HLA haplotypes emphasize the need for population-specific collections of HLA homozygous samples.

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Synthetic HLA-G proteins for therapeutic use in transplantation.

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Synthetic HLA-G proteins for therapeutic use in transplantation.

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