Fully human antibodies to MCAM/MUC18 inhibit tumor growth and metastasis of human melanoma.
MCAM/MUC18 expression correlates with tumor thickness and metastatic potential of human melanoma cells in nude mice. Moreover, ectopic expression of MUC18 in primary cutaneous melanoma cells leads to increased tumor growth and metastasis in vivo. Here we tested the effect of a fully human anti-MUC18 antibody, ABX-MA1, on angiogenesis, tumor growth, and metastasis. ABX-MA1 had no effect on melanoma cell proliferation rate in vitro. However, when cells of the metastatic melanoma lines A375SM and WM2664 (which express high levels of MUC18) were injected s.c. into nude mice and treated with ABX-MA1 (100 micro g, weekly, i.p. for 5 weeks), tumor growth was significantly inhibited compared with control IgG-treated mice. ABX-MA1 treatment also suppressed experimental lung metastasis of these melanoma cells. ABX-MA1 disrupted spheroid formation by melanoma cells expressing MUC18 (homotypic interaction) and the ability of these cells to attach to human vascular endothelial cells [HUVECs (MUC18 positive)] in vitro. ABX-MA1 treatment of melanoma cells in vitro significantly inhibited the promoter and collagenase activity of matrix metalloproteinase 2, resulting in decreased invasion through Matrigel-coated filters. Decreased expression of matrix metalloproteinase 2 was also observed in the implanted tumors in vivo. Moreover, because HUVECs also express MUC18, ABX-MA1 directly disrupted the tube-like formation by HUVECs in an in vitro vessel formation assay. Collectively, these results point to usefulness of ABX-MA1 as a modality to treat melanoma either alone or in combination with conventional chemotherapy or other antitumor agents.
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Lisa
L
Mills
Carmen
C
Tellez
Suyun
S
Huang
Cheryl
C
Baker
Marya
M
McCarty
Larry
L
Green
Jean M
JM
Gudas
X
X
Feng
Menashe
M
Bar-Eli
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000918:Antibody Specificity; D015703:Antigens, CD; D000954:Antigens, Surface / Q000276:immunology / Q000502:physiology*; D051929:CD146 Antigen; D002448:Cell Adhesion / Q000502:physiology; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008545:Melanoma / Q000276:immunology / Q000473:pathology* / Q000556:secondary / Q000628:therapy; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology / Q000628:therapy; D019006:Neural Cell Adhesion Molecules; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000954:Antigens, Surface; D051929:CD146 Antigen; D007074:Immunoglobulin G; C497902:MCAM protein, human; D061965:Matrix Metalloproteinase Inhibitors; C497903:Mcam protein, mouse; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules; D020778:Matrix Metalloproteinase 2