B7-H4 Immune Checkpoint Molecule for Drug Development

Introduction to B7-H4

B7-H4, also known as B7S1, B7x, and VTCN1, is a member of the B7 family of immune modulators. B7-H4 is a transmembrane protein that binds an unknown receptor on activated T cells resulting in inhibition of T-cell effector function via cell cycle arrest, reduced IL-2 production, and decreased proliferation. The B7-H4 protein possesses 282 amino acid residues containing an amino-terminal extracellular domain, a large hydrophobic transmembrane domain, and a very short intracellular domain with only two amino acids. B7-H4 possesses a pair of Ig-like regions and seven potential N-glycosylation sites in its extracellular domain.

Fig.1 The mechanistic action of B7-H4 in tumor immunity. (Wang, 2016)

Expression and Function of B7-H4

In healthy individuals, B7-H4 mRNA is detected at low levels in many non-lymphoid tissues. However, B7-H4 protein expression seems to be limited due to tight translational control in peripheral tissues in humans. B7-H4 is up-regulated on the surface of cancer cells and immunosuppressive tumor-associated macrophages in a variety of human cancers. The expression of B7-H4 is up-regulated by IL10 and IL6 and is inhibited by IL4 and GM-CSF on antigen-presenting cells (APCs).

Soluble sB7-H4

Besides being present on the cell surface, B7-H4 can also be cleaved from the surface of cells via the metalloproteinase nardilysin (NRD1). Levels of soluble serum B7-H4 (sB7-H4) correlate with tumor stage, poor prognosis, and pathological types. sB7-H4 is highly expressed in inflammation, tumors, autoimmune diseases, and pregnancy. Measurement of sB7-H4 levels may provide helpful information for the unique diagnosis of different types of hematological malignancies.

B7-H4 in Signal Pathways

Studies have shown that B7-H4 is involved in mitochondrial signal transduction, IL6/JAK/STAT3 signal pathway, IL6/JAK/STAT3 signal pathway, and CXCL12/CXCR4 signal pathway. Key elements in these signaling pathways could serve as research points for the development of therapeutic strategies.

Therapeutics Targeting B7-H4

B7-H4 plays a role in immune evasion and tumorigenesis; eliminating or diminishing the effects of B7-H4 may positively affect the host immune response and negatively affect tumor cell survival simultaneously. Potential methods targeting B7-H4 include siRNA, immunotoxins, blocking antibodies, T-cell-based immunotherapy, antibody-drug conjugate (ADC), and vaccine. For instance, locking the putative B7-H4 receptor on T cells from engaging with B7-H4 on the surface of tumor cells or macrophages could be achieved using an anti-B7-H4 antibody. An anti-B7-H4-specific CAR could be generated by combining an anti-B7-H4 single-chain variable fragment (scFv) with optimal T cell co-stimulation domains.

Fig.2 Anti-B7-H4 treatment modalities. (Smith, 2014)

Creative Biolabs is competent to provide B7-H4-based immunotherapy agents, including mAbs, ADC, bispecific antibody, and CAR-T cells, with acceptable efficacy. A comprehensive set of immune checkpoint molecule research services are available for you to support your project. For any questions, please do not hesitate to contact us for more information.

References

1. Wang, L.; et al. Could B7-H4 serve as a target to activate anti-cancer immunity? International immunopharmacology. 2016, 38: 97-103.
2. Smith, J. B.; et al. B7-H4 as a potential target for immunotherapy for gynecologic cancers: a closer look. Gynecologic oncology. 2014, 134(1): 181-189.

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