CD80 Immune Checkpoint Molecule for Drug Development

Introduction to Immune Checkpoint CD80

The cluster of differentiation 80, also named CD80 and B7-1, is the type I membrane protein in the immunoglobulin superfamily. It is composed of an extracellular immunoglobulin constant-like domain and a variable-like domain for receptor binding. It is closely related to CD86 and often acts synergistically. The genes are located in the 3q13.3~q21 and 3q21 regions of human chromosomes, respectively. They have 25% amino acid homology, and the extracellular domains are both IgV+IgC.

Table.1 Immune checkpoint CD80.

Checkpoint receptor Alternate name Extracellular domain Ligand Function of ligand-receptor interaction Expression
CD80 B7-1; B7
IgV+IgC CD28
CTLA-4 (CD152)
PD-L1 (CD274)
Co-stimulatory Monocytes, activated B cells, activated T cells, macrophages, and antigen-presenting cells (APCs)
  • Expression of CD80
  • As the receptor of both CD28 and CTLA-4, CD80 can be found on the surface of various immune cells, which include monocytes, activated B cells, activated T cells, macrophages, and antigen-presenting cells (APCs). For most human malignancies, the expression of CD80 is downregulated, which results in immune surveillance evasion and the failure of immune recognition.

  • Function of CD80
  • CD80 is the receptor for both CD28 and CTLA-4 protein. In general, CD80 binds to CD28/CTLA-4 with lower affinity and fast binding kinetics. As an important costimulatory signal, this interaction results in T and B cell activation, proliferation, and differentiation. Besides, CD80 is efficient for cytotoxic T cell activation and dendritic cell licensing. Recent studies have shown that CD80 also interacts with a different ligand on Natural Killer cells, which results in cell death. The activation of the CD80 signal can increase the expression of pro-apoptotic molecules and decrease the expression of anti-apoptotic proteins, thereby inducing tumor cell apoptosis and inhibiting their growth.

Structure of CD80 Fig.1 Structure of CD80.

Preclinical and Clinical Development of Drugs Targeting CD80

Studies have shown that a variety of hematological malignancies have low or no expression of CD80 molecules. The transfer of CD80 molecules into tumor cells enhances their immunogenicity and promotes the activation of anti-tumor T cells. Clinical trials have shown that blocking CD28-CD80/CD86 signaling can sensitize chemotherapy drugs and significantly reduce tumor burden. In this case, CD80 has been served as a potential target for drug discovery against various tumors. Now, several CD80-targeting therapeutics have been discovered for tumor treatment.

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