Specific and effective targeting cancer immunotherapy with a combination of three bispecific antibodies.
For the purpose of establishing a new adoptive immunotherapy for bile duct carcinoma (BDC), we previously constructed two kinds of bispecific antibodies (bsAbs), anti-MUC1 x anti-CD3 (M x 3) and anti-MUC1 x anti-CD28 (M x 28), which activate T cells and form bridges between them and MUC1-expressing tumor cells. In our previous studies [Cancer Res. 56 (1996) 4205] specific targeting therapy (STT) consisting of i.v. administration of lymphokine activated killer cells with a T cell phenotype (T-LAK) sensitized with two kinds of bsAbs to human BDC-grafted severe combined immunodeficient (SCID) mice demonstrated remarkable inhibition of tumor growth. However, complete cures could not be obtained. In order to improve antitumor efficacy, we have paid attention to anti-CD2 monoclonal antibodies (mAbs), thought to play an important roles in signal transduction in T cell activation or control of T cell receptor (TCR)-driven activation. Therefore, we developed another bsAb, anti-MUC1 x anti-CD2 (M x 2), in order to examine if this would show synergism with the two previously described bsAbs. The combination of the three bsAbs (M x 3, M x 28 and M x 2 bsAbs) showed highest cytotoxicity against MUC1-expressing BDC cells when given simultaneously with peripheral blood mononuclear cells (PBMCs) or T-LAK cells in vitro. When 2 x 10(7) T-LAK cells sensitized with different combinations of bsAbs were administered four times i.v. to BDC-grafted SCID mice, the best therapeutic result was obtained with a combination of all three bsAbs. These results indicate usefulness of combination of three bsAbs for targeting cancer immunotherapy.
Kodama
Hideaki
H
First Department of Surgery, Tohoku University School of Medicine, Tohoku University, Seiryomachi 1-1, Aoba-ku, Sendai, Japan.
Suzuki
Masanori
M
Katayose
Yu
Y
Shinoda
Masao
M
Sakurai
Naoki
N
Takemura
Shin-ichi
S
Yoshida
Hiroshi
H
Saeki
Hisaaki
H
Asano
Ryutaro
R
Ichiyama
Masahiko
M
Imai
Kohzoh
K
Hinoda
Yuji
Y
Matsuno
Seiki
S
Kudo
Toshio
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology / Q000627:therapeutic use*; D000918:Antibody Specificity; D001650:Bile Duct Neoplasms / Q000628:therapy*; D018801:CD2 Antigens / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007962:Leukocytes / Q000166:cytology / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D018396:Mucin-1 / Q000276:immunology*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D018801:CD2 Antigens; D018106:CD28 Antigens; D017252:CD3 Complex; D018396:Mucin-1; D007371:Interferon-gamma