Abstract
Ontuxizumab (MORAb-004) is a humanized recombinant antibody targeting endosialin (TEM-1, CD248). We conducted an analysis of endosialin expression in metastatic melanoma specimens using the anti-endosialin rat anti- MAb 9G5, in order to determine the potential of endosialin as a therapeutic target within the tumor microenvironment vasculature. Endosialin expression in paraffin-embedded archival tissue block (PEAT) melanoma tissues was assessed using immunohistochemistry (IHC) with the anti-endosialin, MAb 9G5, in the vessels of American Joint Commission on Cancer (AJCC) Stage III (n = 18) and Stage IV (n = 48) specimens. IHC for endosialin expression was further performed on a TMA that included 136 Stage IV and 33 paired Stage III melanoma specimens. BRAF mutation (mt) was also evaluated in individual melanoma specimens and as well as the TMA. Analysis showed 70 % of melanoma specimens (n = 46) were positive for endosialin expression. There was no significant difference in endosialin and BRAFmt expression between stages III vs. IV specimens. Endosialin expression was detected in 86 % (n = 117) of stage IV TMA specimens, while no expression was detected in 29 normal tissue controls. MAb 9G5 detects the presence of endosialin in the microenvironment tumor vasculature of most metastatic melanoma tissues, regardless of clinical stage and presence of BRAFmt. Endosialin may be a potential therapeutic target by virtue of its selective expression in metastatic melanoma relative to normal tissues.Electronic supplementary materialThe online version of this article (doi:10.1007/s12307-015-0168-8) contains supplementary material, which is available to authorized users.
Highlights
Ontuxizumab (MORAb-004) is a humanized recombinant mouse antibody (Ab) targeting endosialin (TEM-1, CD248) [1]
Endosialin expression was significantly upregulated within tumor vessels and stromal region of the melanoma specimens, while none was observed in the vascular regions of the normal controls
BRAF V600E mutation (BRAFmt) was detected in 38 % (n=3) of American Joint Commission on Cancer (AJCC) Stage III and 35 % (n=6) of AJCC Stage IV melanoma specimens (Table 1b)
Summary
Ontuxizumab (MORAb-004) is a humanized recombinant mouse antibody (Ab) targeting endosialin (TEM-1, CD248) [1]. Endosialin is predominantly expressed in tumor blood vessels [4]. Endosialin expression has previously been detected in tumor pericytes and stromal cells by immunohistochemistry (IHC) [9]. Tumorassociated fibroblasts in the stroma contribute to migration and invasion by producing extracellular matrix proteins, matrix metalloproteinases (MMPs) and growth factors [10, 11]. These factors can recruit endothelial precursor cells that initiate angiogenesis. Platelet-derived growth factor-B (PDGF-B), which is secreted from cancer cells, recruits pericytes that express PDGF receptor-β (PDGFR-β) on tumor vessels [12, 13]. Endosialin seems to be primarily expressed on pericytes as opposed to endothelial cells in the tumor vasculature
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