Synthetic HLA‐G proteins for therapeutic use in transplantation

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: (α 3 ‐L) x2 and (α 1 ‐α 3 ) x2 polypeptides. We show their capability to bind the HLA‐G receptor LILRB2 and their functions in vitro and in vivo. The (α 1 ‐α 3 ) x2 polypeptide proved to be a potent tolerogenic molecule in vivo: One treatment of skin allograft recipient mice with (α 1 ‐α 3 ) x2 was sufficient to significantly prolong graft survival, and four weekly treatments induced complete tolerance. Furthermore, (α 1 ‐α 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 (α 1 ‐α 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. —LeMaoult, J., Daouya, M., Wu, J., Loustau, M., Horuzsko, A. , Carosella, E. D. Synthetic HLA‐G proteins for therapeutic use in transplantation. FASEB J. 27, 3643–3651 (2013). www.fasebj.org