MT110: a novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors.
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.
Brischwein
Klaus
K
Micromet AG, Staffelseestr. 2, 81477 Munich, Germany.
Schlereth
Bernd
B
Guller
Benjamin
B
Steiger
Carola
C
Wolf
Andreas
A
Lutterbuese
Ralf
R
Offner
Sonja
S
Locher
Mathias
M
Urbig
Thomas
T
Raum
Tobias
T
Kleindienst
Petra
P
Wimberger
Pauline
P
Kimmig
Rainer
R
Fichtner
Iduna
I
Kufer
Peter
P
Hofmeister
Robert
R
da Silva
Antonio J
AJ
Baeuerle
Patrick A
PA
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
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D017252:CD3 Complex; C509173:MT110 monoclonal antibody; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies