Human leukocyte antigen G5 (HLA-G5)

Human leukocyte antigen G5 (HLA-G5) is a soluble, non-classical major histocompatibility complex (MHC) class I molecule generated by alternative splicing of the HLA-G primary transcript, characterized by the retention of intron 4 which prevents its membrane anchoring [11, 16]. It functions as a potent immune checkpoint by binding to inhibitory receptors such as ILT2 (LILRB1), ILT4 (LILRB2), and KIR2DL4 on various immune cells, including Natural Killer cells, T cells, B cells, and myeloid cells [1, 9, 13]. Physiologically, HLA-G5 plays a vital role in maintaining immune privilege at the maternal-fetal interface and in other immune-privileged tissues [10, 12]. In many cancers, HLA-G5 is pathologically overexpressed and secreted, allowing tumors to evade the host's immune response, which is often associated with poor clinical outcomes and metastasis [4, 9]. Consequently, HLA-G5 is a high-interest target for therapeutic monoclonal antibodies designed to block its suppressive activity in oncology, as well as a potential tolerogenic agent to prevent rejection in organ transplantation and autoimmune conditions [4, 7, 15]. The molecule's unique structural tail of 21 amino acids derived from intron 4 makes it a specific target for diagnostic and therapeutic intervention compared to membrane-bound isoforms [11].

Other names

Soluble human leukocyte antigen GsHLA-GsHLA-G5MHC class I antigen G isoform 5Non-classical MHC class I antigen G

Monoclonal antibody-mediated blockade of the HLA-G/ILT inhibitory signaling axis to restore anti-tumor immune effector function, or receptor agonism through recombinant HLA-G5 administration to induce peripheral tolerance in transplantation and autoimmune disorders [4, 6, 13, 15].