title: Anti-tumor activity of an anti-endoglin monoclonal antibody is enhanced in immunocompetent mice.
abstract: In the present study, we investigated the mechanisms by which anti-endoglin (EDG; CD105) monoclonal antibodies (mAbs) suppress angiogenesis and tumor growth. Antihuman EDG mAb SN6j specifically bound to murine endothelial cells and was internalized into the cells in vitro. SN6j effectively suppressed angiogenesis in mice in the Matrigel plug assay. We found that SN6j is more effective for tumor suppression in immunocompetent mice than in SCID mice. We hypothesized that T cell immunity is important for effective antitumor efficacy of SN6j in vivo. To test this hypothesis, we investigated effects of CpG oligodeoxynucleotides (ODN) and depletion of CD4(+) T cells and/or CD8(+) T cells on antitumor efficacy of SN6j in mice. Systemic (i.v.) administration of a relatively small dose (0.6 mug/g body weight/dose) of SN6j suppressed growth of established s.c. tumors of colon-26 in BALB/c mice and improved survival of the tumor-bearing mice. Addition of CpG ODN to SN6j synergistically enhanced antitumor efficacy of SN6j. In contrast, such enhancing effects of CpG ODN were not detected in SCID mice. Antitumor efficacy of SN6j in BALB/c mice was abrogated when CD4(+) T cells and/or CD8(+) T cells were depleted; effect of CD8(+) T cell depletion was stronger. Interestingly, CD4-depletion decreased tumor growth while CD8-depletion enhanced tumor growth in the absence of SN6j. SN6j induced apoptosis in human umbilical vein endothelial cells in a dose-dependent manner which indicates an additional mechanism of antiangiogenesis by SN6j. (c) 2008 Wiley-Liss, Inc.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, NY, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tsujie
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tsujie
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Toi
authors.forename: Shima
authors.initials: S
authors.lastname: Uneda
authors.forename: Ken
authors.initials: K
authors.lastname: Shiozaki
authors.forename: Hilda
authors.initials: H
authors.lastname: Tsai
authors.forename: Ben K
authors.initials: BK
authors.lastname: Seon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000276:immunology / Q000628:therapy*; D004247:DNA / Q000627:therapeutic use; D004338:Drug Combinations; D004357:Drug Synergism; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008212:Lymphocyte Depletion; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D009389:Neovascularization, Pathologic; D009838:Oligodeoxyribonucleotides; D011509:Proteoglycans / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology*; D013683:Telangiectasia, Hereditary Hemorrhagic; D014471:Umbilical Veins / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C423449:CpG ODN 1826; D004338:Drug Combinations; C064206:ENG protein, human; D000071063:Endoglin; D007797:Laminin; D009838:Oligodeoxyribonucleotides; D011509:Proteoglycans; D011956:Receptors, Cell Surface; C059485:matrigel; D003094:Collagen; D004247:DNA