Synergetic effect of interleukin-2 and cellular cytotoxicity against a novel tumor-associated carbohydrate antigen Le(a)/Le(a) (dimeric Le(a)) mediated by monoclonal antibody NCC-ST-421 in adoptive immunization using SCID mice.
The murine IgG3 monoclonal antibody NCC-ST-421, raised against a human gastric cancer, shows strong reactivity with dimeric Le(a) (Le(a)/Le(a); V4FucIII4FucLc6Cer) expressed on gastrointestinal cancer cells. ST-421 reacted minimally with non-dimeric or simple Le(a) expressed on normal tissues. ST-421 is capable of mediating both antibody-dependent cellular cytotoxicity (ADCC) with human peripheral blood lymphocytes, and complement-dependent cytotoxicity with human complement. Interleukin-2 (IL-2) modulates the function of immunocytes, in particular inducing lymphokine-activated killer (LAK) cell activity and enhancing ADCC. We therefore employed combination immunotherapy with IL-2, LAK, and ST-421-induced ADCC in vitro and in mice with severe combined immunodeficiency (SCID), using target tumor cells expressing Le(a)/Le(a) antigen. ADCC against human colon cancer cell lines in vitro was enhanced three to four times after preincubation with IL-2. Addition of IL-2 reduced the amount of ST-421 required for efficient ADCC 10- to 100-fold. ADCC was activated by IL-2 earlier (1 day) than the generation of LAK cells (3-4 days), and at lower concentration of IL-2. These effects were specific for ST-421, as demonstrated by experiments with irrelevant antibody or irrelevant target cells. An anti-(Fc receptor) antibody blocked the ADCC but not the LAK activity in vitro. The enhancement of ADCC by IL-2 may be caused by activation of effector cells expressing Fc receptors. In vivo experiments using SCID mice inoculated with human colon cancer showed a significant tumor-growth-suppressive effect after combined therapy using human peripheral blood lymphocytes, LAK, IL-2, and ST-421. In summary, adoptive immunization with human lymphocytes activated by IL-2 and ST-421 effectively suppressed growth of gastrointestinal cancer cells expressing Le(a)/Le(a).
Watanabe
M
M
Biomembrane Institute, Seattle, WA 98119.
Kubota
T
T
Kitajima
M
M
Hakomori
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology*; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D003131:Combined Modality Therapy; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D015979:Killer Cells, Lymphokine-Activated / Q000637:transplantation*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation
D000911:Antibodies, Monoclonal; D015295:Antigens, Tumor-Associated, Carbohydrate; D005732:Gangliosides; D007376:Interleukin-2; C082657:dimeric Le(a) antigen, human