title: MT110: a novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors.
abstract: We have developed a novel single-chain Ep-CAM-/CD3-bispecific single-chain antibody construct designated MT110. MT110 redirected unstimulated human peripheral T cells to induce the specific lysis of every Ep-CAM-expressing tumor cell line tested. MT110 induced a costimulation independent polyclonal activation of CD4- and CD8-positive T cells as seen by de novo expression of CD69 and CD25, and secretion of interferon gamma, tumor necrosis factor alpha, and interleukins 2, 4 and 10. CD8-positive T cells made the major contribution to redirected tumor cell lysis by MT110. With a delay, CD4-positive cells could also contribute presumably as consequence of a dramatic upregulation of granzyme B expression. MT110 was highly efficacious in a NOD/SCID mouse model with subcutaneously growing SW480 human colon cancer cells. Five daily doses of 1 microg MT110 on days 0-4 completely prevented tumor outgrowth in all mice treated. The bispecific antibody construct also led to a durable eradication of established tumors in all mice treated with 1 microg doses of MT110 on days 8-12 after tumor inoculation. Finally, MT110 could eradicate patient-derived metastatic ovarian cancer tissue growing under the skin of NOD/SCID mice. MT110 appears as an attractive bispecific antibody candidate for treatment of human Ep-CAM-overexpressing carcinomas.
authors.affiliation: Micromet AG, Staffelseestr. 2, 81477 Munich, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Brischwein
authors.forename: Bernd
authors.initials: B
authors.lastname: Schlereth
authors.forename: Benjamin
authors.initials: B
authors.lastname: Guller
authors.forename: Carola
authors.initials: C
authors.lastname: Steiger
authors.forename: Andreas
authors.initials: A
authors.lastname: Wolf
authors.forename: Ralf
authors.initials: R
authors.lastname: Lutterbuese
authors.forename: Sonja
authors.initials: S
authors.lastname: Offner
authors.forename: Mathias
authors.initials: M
authors.lastname: Locher
authors.forename: Thomas
authors.initials: T
authors.lastname: Urbig
authors.forename: Tobias
authors.initials: T
authors.lastname: Raum
authors.forename: Petra
authors.initials: P
authors.lastname: Kleindienst
authors.forename: Pauline
authors.initials: P
authors.lastname: Wimberger
authors.forename: Rainer
authors.initials: R
authors.lastname: Kimmig
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
authors.forename: Peter
authors.initials: P
authors.lastname: Kufer
authors.forename: Robert
authors.initials: R
authors.lastname: Hofmeister
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: da Silva
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Baeuerle
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D000918:Antibody Specificity; D018941:Antigens, CD19 / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011994:Recombinant Proteins / Q000302:isolation & purification; D057127:Single-Chain Antibodies
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D017252:CD3 Complex; C509173:MT110 monoclonal antibody; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies