A mutated superantigen SEA D227A fusion diabody specific to MUC1 and CD3 in targeted cancer immunotherapy for bile duct carcinoma.
In cancer immunotherapy research, many bispecific antibodies (BsAbs) have been developed for directing T cells toward tumor cells. Recent advances in genetic engineering have made it possible to prepare immunoglobulin fragments consisting of variable domains using bacterial expression systems. Therefore, recombinant BsAbs, termed diabodies, have attracted particular attention. We have previously produced an anti-MUC1 x anti-CD3 diabody (Mx3 diabody) in an Escherichia coli ( E. coli) expression system. In order to reinforce the antitumor effects of the Mx3 diabody, mutated superantigen staphylococcal enterotoxin A (SEA) D227A was genetically fused to the Mx3 diabody. The SEA D227A fusion Mx3 diabody (SEA D227A-Mx3 diabody) thus constructed showed remarkable MUC1-specific antitumor effects when used with effector cells (lymphokine-activated killer cells with T-cell phenotype [T-LAK] and peripheral blood mononuclear cells [PBMCs]). In the bile duct carcinoma (BDC)-xenografted severe combined immunodeficient (SCID) mouse model, it also demonstrated strong antitumor activity when administered i.v. together with T-LAK cells and interleukin-2 (IL-2). In this experiment, the complete disappearance of tumors was observed in 3 out of 6 mice, and the other 3 showed marked retardation of tumor growth. Therefore, the SEA D227A-Mx3 diabody is considered to be a promising reagent in specific targeted immunotherapy for BDC and other MUC1-positive carcinomas. This is the first report on a diabody that is effective in treating human solid cancers in the xenografted SCID mouse experimental model.
Takemura
Shin-ichi
S
First Department of Surgery, Tohoku University School of Medicine, Sendai 980-8574, Japan.
Kudo
Toshio
T
Asano
Ryutaro
R
Suzuki
Masanori
M
Tsumoto
Kouhei
K
Sakurai
Naoki
N
Katayose
Yu
Y
Kodama
Hideaki
H
Yoshida
Hiroshi
H
Ebara
Shinji
S
Saeki
Hisaaki
H
Imai
Kohzoh
K
Matsuno
Seiki
S
Kumagai
Izumi
I
D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology*; D001650:Bile Duct Neoplasms / Q000276:immunology / Q000628:therapy*; D017252:CD3 Complex / Q000276:immunology*; D002277:Carcinoma / Q000276:immunology / Q000628:therapy*; D004768:Enterotoxins / Q000235:genetics / Q000276:immunology; D004926:Escherichia coli; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D007167:Immunotherapy; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D008970:Molecular Weight; D018396:Mucin-1 / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology*; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D018089:Superantigens / Q000276:immunology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D017252:CD3 Complex; D004768:Enterotoxins; D018396:Mucin-1; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal