Tumor growth suppression by a mouse/human chimeric anti-CEA antibody and lymphokine-activated killer cells in vitro and in SCID mouse xenograft model.
The mouse/human chimeric antibody Ch F11-39, recently generated by ourselves, shows the same high specificity and affinity for carcinoembryonic antigen (CEA) as those of its parental mouse monoclonal antibody. Ch F11-39 is capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) with human peripheral blood lymphocytes (PBL). Interleukin-2 (IL-2) modulates the function of immunocytes, in particular inducing lymphokine-activated killer (LAK) cells and enhancing ADCC. In the present study, we therefore tested the combination immunotherapy of Ch F11-39 with LAK cells in vitro and in severe combined immunodeficiency (SCID) mice bearing human CEA-producing tumors. In vitro experiments using human gastric tumor cell lines, Ch F11-39 effectively mediated ADCC against CEA-positive MKN-45 cells, but not against CEA-negative cells. The specificity of ADCC for Ch F11-39 was demonstrated by experiments with irrelevant target cells or irrelevant antibody. ADCC activity of PBL with Ch F11-39 was enhanced by double after preincubation with IL-2 at 10 U/ml. The concentration of Ch F11-39 required for 50% maximal cell killing was about 0.25 microgram/ml at 10 U/ml of IL-2. Increasing ADCC was triggered by IL-2 earlier (1 day) than the generation of LAK cells (3 days). Control human IgG blocked the ADCC, suggesting that the enhancement of ADCC by IL-2 may be caused by activation of effector cells expressing Fc receptors. In vivo anti-tumor activity of combined immunotherapy was estimated using SCID mice inoculated s.c. with 1 x 10(7) MKN-45 cells. The i.v. administration of LAK cells and i.p. administration of Ch F11-39 and IL-2 produced a marked growth inhibition of MKN-45 tumors in SCID mice (about 50% reduction in tumor size as compared to the control untreated group, measured 15 days after treatment). In summary, the enhanced antitumor activity of Ch F11-39 with LAK cells suggests that it might be a useful immunotherapeutic reagent for CEA-expressing tumors.
Senba
T
T
First Department of Biochemistry, School of Medicine Fukuoka University, Japan.
Kuroki
M
M
Arakawa
F
F
Yamamoto
T
T
Kuwahara
M
M
Haruno
M
M
Ikeda
S
S
Matsuoka
Y
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000008:administration & dosage; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins; D013274:Stomach Neoplasms / Q000628:therapy*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D002272:Carcinoembryonic Antigen; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins