Supraagonistic, bispecific single-chain antibody purified from the serum of cloned, transgenic cows induces T-cell-mediated killing of glioblastoma cells in vitro and in vivo.
Here we characterize the antitumor activity of a recombinant bispecific single-chain antibody isolated from the serum of cloned transgenic cows. The antibody, termed r28M, is directed to a melanoma-associated proteoglycan, also expressed on glioblastoma cells, and to human CD28. Bound to tumor cells, r28M induced exceedingly efficient supraagonistic T-cell activation via the CD28 molecule without an additional stimulus via the TCR/CD3 complex. In vitro, T cells and NK cells contributed to tumor cell killing after r28M-mediated activation of peripheral blood mononuclear cells. However, NK activity depended on T-cell-derived cytokines. In vivo, r28M markedly inhibited the growth of human glioblastoma cells in nude mice. The serum half-life of the protein after i.v. injection was approximately 6 hr. Thus, r28M is unique not only in inducing supraagonistic CD28-mediated T-cell activation against tumor cells in vitro and in vivo, it also meets 2 additional requirements that are critical for clinical application: a relatively long serum half-life and the possibility of obtaining large amounts of active material from cloned transgenic livestock.
Grosse-Hovest
Ludger
L
Institute for Cell Biology, Department of Immunology, Eberhard Karls University Tübingen, Tübingen, Germany.
Wick
Wolfgang
W
Minoia
Rosa
R
Weller
Michael
M
Rammensee
Hans-Georg
HG
Brem
Gottfried
G
Jung
Gundram
G
D000818:Animals; D030801:Animals, Genetically Modified / Q000276:immunology*; D018033:Antibodies, Bispecific / Q000097:blood*; D000951:Antigens, Neoplasm / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D002417:Cattle; D002455:Cell Division / Q000276:immunology; D005909:Glioblastoma / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011509:Proteoglycans / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D011509:Proteoglycans; C069150:melanoma-associated proteoglycan antigen, human