A novel human anti-syndecan-1 antibody inhibits vascular maturation and tumour growth in melanoma.
BACKGROUND
Syndecan-1 is a cell membrane protein that, after its shedding by heparanase enzymes, is accumulated in the extracellular matrix of some tumours, e.g. myeloma and lung carcinoma, where it modulates several key processes of tumourigenesis such as cancer cell proliferation and apoptosis, angiogenesis and metastasis. Few studies have focused on syndecan-1 in malignant melanoma, a tumour for which new therapeutic targets are desperately needed. We aimed to investigate the role of syndecan-1 in melanoma and to evaluate the potential therapeutic efficacy of a novel fully human anti-syndecan-1 recombinant antibody in this deadly disease.


METHODS
The OC-46F2 recombinant antibody was generated by selecting a human antibody phage display library on human melanoma cells and by its expression in mammalian cells. The specific antigen recognised by the antibody was identified by mass spectrometry. Murine models of human melanoma and ovarian carcinoma were used in the pre-clinical in vivo experiments.


RESULTS
The fully human antibody OC-46F2, specific for the extracellular domain of syndecan-1, inhibited vascular maturation and tumour growth in an experimental human melanoma model. The therapeutic efficacy of this antibody was also demonstrated in an experimental ovarian carcinoma model. A co-distribution of syndecan-1 with vascular endothelial growth factor receptor 2 (VEGFR2) observed in the intratumour melanoma microenvironment was absent in the tumours from mice treated with OC-46F2 scFv.


CONCLUSIONS
These findings highlight the role of syndecan-1 as a potential therapeutic target in melanoma and ovarian carcinoma and provide a new tool able to block vessel maturation, one of the mechanisms that underpin the angiogenic process essential for solid tumour growth.
Laboratory of Immunology, IRCCS AOU San Martino-IST, Genoa, Italy.
Paola
P
Orecchia
Romana
R
Conte
Enrica
E
Balza
Andrea
A
Petretto
PierLuigi
P
Mauri
Maria Cristina
MC
Mingari
Barbara
B
Carnemolla
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D019151:Peptide Library; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D053668:Syndecan-1 / Q000276:immunology / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D019151:Peptide Library; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; D053668:Syndecan-1; D040301:Vascular Endothelial Growth Factor Receptor-2