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. 1993 Jul;37(4):245–250. doi: 10.1007/BF01518518

Synergetic effect of interleukin-2 and cellular cytotoxicity against a novel tumor-associated carbohydrate antigen Lea/Lea (dimeric Lea) mediated by monoclonal antibody NCC-ST-421 in adoptive immunization using SCID mice

Masahiko Watanabe 1,2,3,✉, Tetsuro Kubota 3, Masaki Kitajima 3, Sen-itiroh Hakomori 1,2,✉
PMCID: PMC11038915  PMID: 8348564

Abstract

The murine IgG3 monoclonal antibody NCC-ST-421, raised against a human gastric cancer, shows strong reactivity with dimeric Lea (Lea/Lea; V4FucIII4FucLe6Cer) expressed on gastrointestinal cancer cells. ST-421 reacted minimally with non-dimeric or simple Lea 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 Lea/Lea antigen. ADCC against human colon cancer cell lines in vitro was enhanced three to four times after preicubation 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 enhacement 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 Lea/Lea.

Key words: Interleukin-2, Extended α1→4-fucosylated type-1 chain antigen, Lymphokine-activated killer cell, Antibody-dependent cytotoxicity

Footnotes

This study was supported by the grant Ten Year Strategy for Control of Cancer from the Ministry of Health and Welfare, Japan, and funds from The Biomembrane Institute, in part under a research contract with Otsuka Pharmaceutical Co. S.H. is supported by National Cancer Institute Outstanding Investigator Grant CA42505.

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