CD48 Immune Checkpoint Molecule for Drug Development
Overview of Immune Checkpoint Molecule CD48
CD48, a CD2-like molecule, is a glycosyl-phosphatidyl-inositol (GPI)-anchored protein referred to as human Blast-1 or BCM1 in mice and OX45 in rats. CD48 was first discovered in 1982 as a viral-induced differentiation antigen on human transformed B lymphoblasts. Since then, the 40-45 kDa protein has been found on the surface of several hematopoietic cells yet also exists insoluble form. CD48 is a ligand for the immunoreceptors CD2 and CD244 (2B4). Its activation involves signaling molecules such as Src kinases and caveolin. Over the years, CD48 has been defined as an adhesion protein and a costimulatory factor, and its role extends from innate responses to bacteria to allergic inflammation.
Like other CD2 molecules, the CD48 structure combines a distal V-like domain with a C2-like domain containing conserved cysteine residues that form disulfide bonds. A unique feature of CD48 within the CD2 group, shared only by CD58, is the lack of a transmembrane domain. Instead, CD48 is attached to the cell surface by a glycolipid, GPI, restricted to the outer leaflet of the membrane bilayer. The C-terminus of the polypeptide is covalently bound to ethanolamine, linked to an oligosaccharide containing mannose and glucosamine. The oligosaccharide binds the inositol head of GPI in the membrane. GPI molecules cluster in lipid rafts; thus, CD48 is highly active and aggregates in large microdomains involving signaling protein complexes. Due to its GPI structure, CD48 may be cleaved after activation, explaining soluble CD48 in circulation.
Fig.1 Structure and signaling cascade of CD48. (Elishmereni, 2011)
CD48 exists on the surface of B and T lymphocytes, natural killer cells (NK), dendritic cells (DC), monocytes, neutrophils, mast cells (MC), and eosinophils (Eos). Endothelial cells (EC) are also a source of CD48.
Together with CD40, IL-4, and/or IL-10 stimuli, CD48 cross-linking by antibodies causes B cells to aggregate, proliferate, differentiate and/or release Ig. In neutrophils, similar CD48 activation leads to increased cytoplasmic calcium levels. The co-stimulatory effect of the molecule was more extensively investigated in T lymphocytes: CD48 crosslinking increased intracellular calcium in human T cells and proliferation of mouse CD3-stimulated CD8+ T cells. Concomitantly, CD48 blockade by soluble and immobilized Abs impaired T cell proliferation, IL-2 synthesis and receptor expression, and T cell receptor and cytoskeleton rearrangement. Cytotoxic T lymphocyte activity can be reduced upon CD48 Ab administration in vitro and in vivo.
Clinical Applications and Targeted Therapeutics of CD48
CD48 may be an important biomarker of infectious and allergic disorders. Monocytes, neutrophils, and lymphocytes of patients with infections, and Eos of the allergic donors, display elevated CD48 levels. Soluble CD48 is detected in the plasma of patients suffering from arthritis, infectious diseases, and lymphoid leukemia, supporting its diagnostic potential. The high CD48 level is probably a sign that immune protection against infection occurs. However, in tandem, a pathophysiological role for CD48 in inflammatory and autoimmune disorders may have been assumed. Accordingly, CD48-antagonistic therapies (blocking Abs, recombinant decoy molecules, gene targeting, etc.) may be helpful in treating allergy, inflammation, and autoimmune syndromes.
Services at Creative Biolabs
Creative Biolabs has focused on the drug development of immune checkpoint for years and thus accumulated extensive experience from practice. We provide a series of customer services for CD48 immune checkpoint, including but not limited to: