Human endogenous retrovirus-H long terminal repeat-associating 2 (HHLA2) (HHLA2)

Human endogenous retrovirus-H long terminal repeat-associating 2 (HHLA2), also known as B7-H7, is a member of the B7 family of immune checkpoint ligands that plays a significant role in modulating the human immune response (UniProt Consortium, 2023). It is uniquely expressed in humans and certain primates, lacking a direct ortholog in rodents, which distinguishes it from other well-characterized checkpoints like PD-L1 (Janakiram et al., 2015). HHLA2 exerts its effects through interaction with two distinct receptors: TMIGD2 (CD28H), which primarily mediates costimulatory signals in naive T cells, and KIR3DL3, which delivers potent coinhibitory signals to activated T cells and natural killer (NK) cells (Zhu et al., 2013; Bhatt et al., 2021). In various malignancies, including lung, breast, and pancreatic cancers, HHLA2 is frequently overexpressed and serves as a mechanism for tumor immune evasion by suppressing T-cell proliferation and cytokine production. Because HHLA2 expression is often independent of PD-L1, it represents a promising therapeutic target for patients who are refractory to existing anti-PD-1/PD-L1 therapies. Current drug development efforts, such as the monoclonal antibody NGM438, aim to block the inhibitory HHLA2-KIR3DL3 pathway to reinvigorate anti-tumor immunity (NGM Biopharmaceuticals, 2024).

Other names

B7-H7B7yHERV-H LTR-associating 2B7 homolog 7HERV-H LTR-associating protein 2

Antagonist monoclonal antibody that blocks the interaction of HHLA2 with its inhibitory receptor KIR3DL3, thereby preventing immune suppression and enhancing anti-tumor T-cell and NK-cell activity (Bhatt et al., 2021; NGM Biopharmaceuticals, 2024).