MUC1-specific targeting immunotherapy with bispecific antibodies: inhibition of xenografted human bile duct carcinoma growth.
For the purpose of establishing a new adoptive immunotherapy for bile duct carcinoma (BDC), we synthesized two bispecific antibodies (BsAbs), MUC1 x CD3 BsAb constructed with MUSE11 (anti-MUC1 tumor antigen) and OKT-3 (anti-CD3), and MUC1 x CD28 BsAb constructed with MUSE11 and 15E8 (anti-CD28) antibodies. These two BsAbs reacted well with both MUC1-positive target tumor cells and effector lymphokine-activated killer (LAK) cells. Investigation of in vitro cytotoxicity [3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide assay] revealed that the MUC1 x CD3 BsAb could antigen-specifically enhance the cytotoxicity of LAK cells. Addition of the two BsAbs (MUC1 x CD3 BsAb plus MUC1 x CD28 BsAb) in vitro resulted in a 60% cytotoxicity, similar to that obtained with BsAb (MUC1 x CD3) alone. Interleukin 12-induced LAK cells demonstrated far greater cytotoxicity (50%) than their interleukin 2-induced counterparts (LAK cells), and this was also enhanced by the BsAbs. When 2 x 10(7) LAK cells sensitized with both kinds of BsAbs were administered four times i.v. to BDC-grafted severe combined immunodeficient mice (tumor size 5 mm in diameter), inhibition of tumor growth was observed. Thus, BsAb-LAK therapy for control of BDC warrants clinical trials.
Katayose
Y
Y
First Department of Surgery, Tohoku University School of Medicine, Sendai, Japan.
Kudo
T
T
Suzuki
M
M
Shinoda
M
M
Saijyo
S
S
Sakurai
N
N
Saeki
H
H
Fukuhara
K
K
Imai
K
K
Matsuno
S
S
D000818:Animals; D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D001650:Bile Duct Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D017252:CD3 Complex / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D018664:Interleukin-12 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D018396:Mucin-1 / Q000276:immunology*; D016853:Muromonab-CD3 / Q000276:immunology; D013997:Time Factors; D014183:Transplantation, Heterologous
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D017252:CD3 Complex; D007376:Interleukin-2; D018396:Mucin-1; D016853:Muromonab-CD3; D018664:Interleukin-12