Synthetic HLA-G proteins for therapeutic use in transplantation

• Published in: The FASEB journal Vol. 27; no. 9; p. 3643
• Main Authors: LeMaoult, Joel, Daouya, Marina, Wu, Juan, Loustau, Maria, Horuzsko, Anatolij, Carosella, Edgardo D
• Format: Journal Article
• Language: English
• Published: United States 01.09.2013
• Subjects: Animals; Cell Line; Cell Proliferation - drug effects; Flow Cytometry; Graft Survival - drug effects; HLA-G Antigens - chemistry; HLA-G Antigens - pharmacology; HLA-G Antigens - therapeutic use; Humans; Mice; Peptides - chemistry; Peptides - pharmacology; Peptides - therapeutic use; Transplantation, Homologous; engineered molecules; therapy; immune regulation; tolerance
• ISSN: 1530-6860
• DOI: 10.1096/fj.13-228247

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.