Targeting the Tetraspanins with Monoclonal Antibodies in Oncology: Focus on Tspan8/Co-029

Abstract

Tetraspanins are exposed at the surface of cellular membranes, which allows for the fixation of cognate antibodies. Developing specific antibodies in conjunction with genetic data would largely contribute to deciphering their biological behavior. In this short review, we summarize the main functions of Tspan8/Co-029 and its role in the biology of tumor cells. Based on data collected from recently reported studies, the possibilities of using antibodies to target Tspan8 in immunotherapy or radioimmunotherapy approaches are also discussed.

Keywords: Tspan8; cancer; immunotherapy; radioimmunotherapy; tetraspanins.

Figure 1

Homology tree between human tetraspanins. Protein sequences have been aligned to generate this distance tree. Bolded names correspond to commonly used ones. The number of cysteines in the extracellular loop EC2 is given when they are different from six cysteines.

Figure 2

Schematic representation of Tspan8 in membrane. The transmembrane (TM) domains inserted in the phospholipid bilayer are palmitoylated with a cholesterol molecule in between these domains (by analogy with CD81 structure [13]). Among the two extracellular (EC) regions, the larger region contains six cysteines involved in disulfide bonds. EC1 and EC2 = extracellular domains 1 and 2; Ch = cholesterol; and PL = phospholipid.

Figure 3

In-vivo selection of [¹¹¹In]DOTA-Ts29 antibodies for imaging and therapy in mice with HT29 colon carcinoma xenografts. Nude NMRI mice with HT-29 tumors were injected (i.v.) with 3.7 MBq of [¹¹¹In]DOTA-Ts29.1 (upper images) or [¹¹¹In]DOTA-Ts29.2 (lower images), which were imaged with a planar γ-camera at 4 h, 24 h, 72 h, 120 h and 168 h post injection (A). Biodistribution was performed after euthanasia and expressed as the percentage of activity injected per gram of tissue (%AI/g) of [¹¹¹In]DOTA-Ts29.1 (orange) or [¹¹¹In]DOTA-Ts29.2 (purple) (B). Radioactivity was measured using a γ-counter. Results are presented as the average percentage of injected dose/gram of tissue of three animals for each time point. The error bars represent the standard deviation. Biodistribution difference between the two mAbs: * p < 0.05 Fisher test.

Figure 4

In-vivo specificity of [¹¹¹In]DOTA-Ts29.2 for Tspan8-expressing tumors. Nude NMRI mice with Isreco-1 (left shoulder) and Is1-Co29 (right shoulder) were injected (i.v.) with 3.7 MBq of [¹¹¹In]DOTA-Ts29.2 and imaged with a planar γ-camera at 4 h, 24 h, 72 h and 120 h post injection (A). Ex-vivo biodistribution study (%AI/g) of [¹¹¹In]DOTA-Ts29.2 (B) was determined on the same mice with the same protocol as Figure 3B. Biodistribution difference between the two tumors: * p < 0.05. Fisher test.