Axon guidance agent 4D (SEMA4D), also known as CD100, belongs to the semaphorin IV subfamily. It is a cell surface receptor for PLXNB1 and PLXNB2 and plays an important role in intercellular signaling. It is a transmembrane glycoprotein that regulates neurogenesis, immunomodulation, and angiogenesis.

(Data source: Jiang J, et al. Front Oncol. 2022)

Expression distribution of SEMA4D

CD100 is widely expressed in various tissues and cell types. SEMA4D is primarily expressed in oligodendrocytes, NK cells, T cells, and monocytes, with small amounts also expressed in granulocytes, macrophages, Hofbauer cells, Kupffer cells, and dendritic cells.

(Data source: Uniprot)

Structure of SEMA4D and its receptor

CD100 is a transmembrane glycoprotein with a molecular weight of 150 kDa and composed of 862 amino acids. Its structure comprises three major domains: a cytoplasmic region containing serine phosphorylation sites, a transmembrane domain, and a large extracellular region composed of multiple conserved structural motifs. The extracellular region contains a SEMA domain (approximately 500 amino acid residues in length), a hallmark of the semaphorin family responsible for receptor binding, as well as an immunoglobulin (Ig)-like structure and a conserved PSI domain. The transmembrane domain anchors the extracellular region to the cell membrane. The relatively short intracellular region suggests that it primarily transmits signals through interactions with other signaling molecules. Proteolytic cleavage of the extracellular region by enzymes such as ADAM10 and matrix metalloproteinases (MMP2/9) produces a soluble 120 kDa form (sCD100), which acts as a ligand to mediate immunomodulatory functions.

CD100 binds to two major classes of receptors: the high-affinity Plexin family members (Plexin-B1 and Plexin-B2) and the low-affinity CD72.

(Data source: Zhao M, et al. Int J Mol Sci. 2025)

(Data source: AlphaFold)

The role of SEMA4D in immune cells

CD100 has diverse functions in various immune cells. It enhances T cell activation through both direct mechanisms and indirect pathways involving DC-mediated regulation. CD100 promotes DC activation and maturation by binding to CD72 and inhibits their migration through interaction with Plexin-B1. CD100's interaction with CD72 prevents SHP-1 recruitment to ITIMs, promoting B cell proliferation and antibody production. mCD100 binding to CD72/Plexin-B1/B2 on target cells enhances NK cell adhesion, degranulation (CD107a), and IFN-γ secretion. mCD100's interaction with Plexin-B2 inhibits Rac1-dependent ROS generation and NET formation. CD100's interaction with CD72 enhances macrophage phagocytosis of parasites, while its interaction with Plexin-B2 downregulates CD36 expression and inhibits oxLDL uptake. CD100 also promotes M2-like polarization.

(Data source: Zhao M, et al. Int J Mol Sci. 2025)

SEMA4D signaling in cancer

Membrane-bound SEMA4D is cleaved by MT1-MMP into a soluble form , which may then bind to PlexinB1 , a major receptor expressed on the surface of various cell types in the tumor microenvironment, including cancer cells, endothelial cells, and immune cells. This leads to transactivation of the tyrosine kinase receptors Met and ErbB2, and activation of the GTPase RhoA, leading to phosphorylation of the MAPK and Akt effector cascades. Furthermore, Sema4D has been found to mediate RhoA phosphorylation, a mechanism currently under investigation for regulating invasion and metastasis. Sema4D/PlexinB1 signaling enhances cell invasiveness by activating the RhoA, MAPK, and Akt pathways.

(Data source: Mastrantonio R, et al. Theranostics. 2021)

Targeted therapy of SEMA4D

Pepinemab (VX15/2503), a monoclonal antibody targeting SEMA4D, is Vaccinex's most advanced clinical candidate. It is currently in clinical trials for head and neck cancer (R/M HNSCC), Huntington's disease (HD), and Alzheimer's disease (AD). In addition to the recently completed Phase 2 trials for HD and non-small cell lung cancer (NSCLC), Vaccinex is actively planning a Phase 3 trial for HD. Pepinemab also has potential as a treatment for other cancers and neurodegenerative diseases, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Rett syndrome.

(Data source: Vaccinex official website)