Targeting of Tetraspanin CD81 with Monoclonal Antibodies and Small Molecules to Combat Cancers and Viral Diseases

Abstract

Tetraspanin CD81 plays major roles in cell-cell interactions and the regulation of cellular trafficking. This cholesterol-embarking transmembrane protein is a co-receptor for several viruses, including HCV, HIV-1 and Chikungunya virus, which exploits the large extracellular loop EC2 for cell entry. CD81 is also an anticancer target implicated in cancer cell proliferation and mobility, and in tumor metastasis. CD81 signaling contributes to the development of solid tumors (notably colorectal, liver and gastric cancers) and has been implicated in the aggressivity of B-cell lymphomas. A variety of protein partners can interact with CD81, either to regulate attachment and uptake of viruses (HCV E2, claudin-1, IFIM1) or to contribute to tumor growth and dissemination (CD19, CD44, EWI-2). CD81-protein interactions can be modulated with molecules targeting the extracellular domain of CD81, investigated as antiviral and/or anticancer agents. Several monoclonal antibodies anti-CD81 have been developed, notably mAb 5A6 active against invasion and metastasis of triple-negative breast cancer cells. CD81-EC2 can also be targeted with natural products (trachelogenin and harzianoic acids A-B) and synthetic compounds (such as benzothiazole-quinoline derivatives). They are weak CD81 binders but offer templates for the design of new compounds targeting the open EC2 loop. There is no anti-CD81 compound in clinical development at present, but this structurally well-characterized tetraspanin warrants more substantial considerations as a drug target.

Immunoassays for Extracellular Vesicle Detection via Transmembrane Proteins Using Surface Plasmon Resonance Biosensors

“…In contrast, mAbs originate from the same B cell in a host animal, and it recognizes only one binding epitope or binding site on a protein , (Figure B). Previous reports suggest that mAbs target the open EC2 loop in CD81 . It has been shown that the EC2 loop in CD81 possesses sites that are crucial for recognition and cell interaction whereas the EC1 loop plays a less important role .…”

Alterations in N-glycosylation of HCV E2 Protein in Children Patients with IFN-RBV Therapy Failure

“…The next step in the functional analysis of E1E2 heterodimers was the study of their affinity to the recombinant large extracellular loop (LEL) of the human CD81 receptor fused to Glutathione S-transferase (GST). Tetraspanin CD81 is one of the main HCV entry receptors and a key player in the HCV lifecycle [ 19 ]. In this experiment, ELISA plates were coated with recombinant purified GST-CD81-LEL and incubated with the lysates of cells expressing E1E2 proteins.…”

CD71: Role in permafrost immunity

“…It is possible and even probable that PPV and other yet to be uncovered novel and ancient viruses emerging from permafrost thaw may also manifest affinities for CD71 receptor and for CD81 co-receptor. It follows that, whereas there is no anti-CD81 compound in clinical development at present, the current knowledge-base about the role of CD71 and CD81 in viral infections and immunopathology warrants more substantial considerations as a drug target [ 37 ].…”