title: 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: (α3-L)x2 and (α1-α3)x2 polypeptides. We show their capability to bind the HLA-G receptor LILRB2 and their functions in vitro and in vivo. The (α1-α3)x2 polypeptide proved to be a potent tolerogenic molecule in vivo: One treatment of skin allograft recipient mice with (α1-α3)x2 was sufficient to significantly prolong graft survival, and four weekly treatments induced complete tolerance. Furthermore, (α1-α3)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 (α1-α3)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.
authors.affiliation: Commissariat à l'Énergie Atomique et aux Énergies Alternatives (CEA), Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Paris, France. joel.lemaoult@cea.fr
authors.forename: Joel
authors.initials: J
authors.lastname: LeMaoult
authors.forename: Marina
authors.initials: M
authors.lastname: Daouya
authors.forename: Juan
authors.initials: J
authors.lastname: Wu
authors.forename: Maria
authors.initials: M
authors.lastname: Loustau
authors.forename: Anatolij
authors.initials: A
authors.lastname: Horuzsko
authors.forename: Edgardo D
authors.initials: ED
authors.lastname: Carosella
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006085:Graft Survival / Q000187:drug effects; D059951:HLA-G Antigens / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014184:Transplantation, Homologous
chemical_list: D059951:HLA-G Antigens; D010455:Peptides
keywords: engineered molecules; immune regulation; therapy; tolerance