B7H4, V-set domain-containing inhibitor of T-cell activation 1 (VTCN1), also known as B7x, is a member of the B7 family and an inhibitory immune checkpoint. It negatively regulates T cell-mediated immune responses by inhibiting T cell activation, proliferation, cytokine production, and the development of cytotoxicity. When expressed on the surface of tumor macrophages, it plays a crucial role in suppressing tumor-associated antigen-specific T cell immunity alongside regulatory T cells (Tregs).
Expression distribution of B7H4
B7H4 is mainly expressed in duct cells, luminal cells, secretory cells, mucous gland cells, mammary gland cells, collecting duct cells, and salivary gland duct cells.
(Data source: Uniprot)
Structure of B7H4
B7H4 gene is located on chromosome 1, p12–13.1. B7H4 is a type I transmembrane protein composed of 282 amino acids, including a signal peptide, an extracellular structure , a continuous stem region, a transmembrane domain, and a very short cytoplasmic tail without a signal motif. The B7x extracellular domain consists of an Ig variable (IgV) domain and an Ig constant (IgC) domain, similar to other B7 family ligands. The B7x IgV adopts a β-sandwich fold consisting of a back (AA-BED) strand and a front (CC-C-FG) strand, stabilized by disulfide bonds between the B and F strands.
(Data source: John P, et al. Trends Pharmacol Sci. 2019)
Functions of B7H4
B7x mediates multiple immunosuppressive mechanisms by regulating T cell function. B7x blocks the inflammatory functions of effector CD4 and CD8 T cells, reduces the production of cytokines such as IFNγ, and inhibits their proliferation. Conversely, B7x promotes Treg function, including the secretion of immunosuppressive factors such as IL-10. B7x also regulates T cell differentiation, inhibiting their polarization into effector T cells and their differentiation into Tregs.
B7x is expressed in various cancer types, including ovarian, breast, and endometrial cancers. Tumor-expressed B7x is associated with advanced disease progression and poor prognosis. B7x is expressed by both tumor cells and tumor-associated macrophages, mediating tumor immune evasion. Tumor-expressed B7x suppresses the activity of anti-tumor T cells and promotes their exhaustion and dysfunction. Furthermore, B7x promotes the production of tumor-associated neutrophils (myeloid-derived suppressor cells). In ovarian cancer and glioma, tumor cells secrete cytokines such as IL-6 and IL-10, which drive B7x expression in tumor-associated macrophages.
(Data source: John P, et al. Trends Pharmacol Sci. 2019)
Targeted therapy for B7H4
Immunotherapy targeting B7-H4 in ovarian cancer (OC) and other cancers focuses on ICI, adoptive cell therapy (ACT) and antibody-drug conjugates (ADCs), bispecific antibodies, with many drugs in clinical development.
(Data source: Zhou L, et al. Front Immunol. 2024)
HS-20089, an antibody-drug conjugate targeting B7H4 developed by Shanghai Hansoh Biomedical Co., Ltd, is currently in Phase 2 clinical trials. HS-20089 has demonstrated promising anti-tumor activity in OC, with an objective response rate (ORR) of 66.7% and a disease control rate (DCR) of 100% in platinum-resistant ovarian cancer (PROC).
ABL103 is a novel T cell engagement bispecific antibody designed to simultaneously target B7-H4 and 4-1BB. ABL103 works through a dual mechanism, enhancing T cell function by inhibiting B7-H4 and simultaneously activating 4-1BB. This novel approach achieves potent in vitro and in vivo anti-tumor activity through B7-H4-dependent 4-1BB activation in the tumor necrosis factor (TCM) membrane (TME) of OC, with a favorable safety profile.
(Data source: Zhou L, et al. Front Immunol. 2024)
