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Abstract
The anti-mesothelioma mAb SKM9-2 recognizes the sialylated protein HEG homolog 1 (HEG1). HEG1 is a 400 kDa mucin-like membrane protein found on mesothelioma. SKM9-2 can detect mesothelioma more specifically and sensitively than other antibodies against current mesothelioma markers; therefore, SKM9-2 would be likely useful for the precise detection and diagnosis of malignant mesothelioma. In the present study, we investigated the epitope of SKM9-2. We analyzed the binding of SKM9-2 to truncated HEG1 and candidate epitope-fused glycosylphosphatidylinositol-anchor proteins. The epitope of SKM9-2 was identified as an O-glycosylated region, 893-SKSPSLVSLPT-903, in HEG1. An alanine scanning assay of the epitope showed that SKM9-2 bound to a simple epitope in HEG1, and the SKxPSxVS sequence within the epitope was essential for SKM9-2 recognition. Mass spectrometry analysis and lectin binding analysis of soluble epitope peptides indicated that the SKM9-2 epitope, in which Ser897 was not glycosylated, contained two disialylated core 1 O-linked glycan-modified serine residues, Ser893 and Ser900. Neuraminidase treatment analysis also confirmed that the epitope in mesothelioma cells contained a similar glycan modification. The specific detection of mesothelioma with SKM9-2 can thus be performed by the recognition of sialylated glycan modification in the specific region of HEG1.
Highlights
A glycoprotein containing many O-linked glycans, such as those of the mucin family and a mucin-like protein, can be a good cancer-related marker[1,2,3]
We have shown in the previous study that the anti-HEG1 monoclonal antibody (mAb) SKM9-2 recognizes the glycopeptide sequence and can detect mesothelioma (99%) and sensitively (92%) than other mAbs against current mesothelioma markers
MAb SKM9-2 recognizes an extracellular region of the sialylated HEG115
Summary
A glycoprotein containing many O-linked glycans, such as those of the mucin family and a mucin-like protein, can be a good cancer-related marker[1,2,3]. In conjunction with the results of alanine substitution, as shown in Figs 3, 5, SKM9-2 binding requires the O-linked glycan modification of Ser[893] and Ser[900] and non-glycosylated Ser[897].
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