TARGETING OF T-LYMPHOCYTES AGAINST EGF-RECEPTOR(+) TUMOR-CELLS BY BISPECIFIC MONOCLONAL-ANTIBODIES - REQUIREMENT OF CD3 MOLECULE CROSS-LINKING FOR T-CELL ACTIVATION

被引:20
作者
FERRINI, S
CAMBIAGGI, A
SFORZINI, S
MARCIANO, S
CANEVARI, S
MEZZANZANICA, D
COLNAGHI, MI
GROSSI, CE
MORETTA, L
机构
[1] IST NAZL TUMORI, I-20133 MILAN, ITALY
[2] UNIV GENOA, IST ANAT UMANA, I-16126 GENOA, ITALY
关键词
D O I
10.1002/ijc.2910550610
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Targeting of T lymphocytes against epidermal growth-factor-receptor (EGF-R)+ tumor cells was achieved by constructing a hybrid hybridoma which secretes an anti-EGF-R/anti-CD3 bispecific monoclonal antibody (biMAb) of hybrid isotype (IgG1/IgG2a). Purification of biMAb molecules from parental anti-EGF-R and anti-CD3 MAbs was performed by protein-A chromatography. The purified biMAb was able to trigger the lysis of EGF-R+ tumor cell lines (A431, IGROV-1, MDA-468 and U-87) and of NIH-3T3 transfectants expressing human EGF-R by cytolytic T lymphocytes, but it was ineffective in the case of EGF-R-negative tumor targets. Normal EGF-R+ cells (keratinocytes and endometrial cells) were also susceptible to biMAb-targeted cytolysis. However, the amount of biMAb required to induce half-maximal cytolysis of tumor cells over-expressing the EGF-R molecule (A43 1) was considerably lower than that required to induce lysis of EGF-R+ tumor or normal cells which express EGF-R at considerably lower density. The ability of such biMAbs to deliver activation signals to T cells was evaluated by Ca++ mobilization and lymphokine production experiments. The soluble anti-EGF-R/anti-CD3 biMAb failed to induce intracellular Ca++ increases, which occurred only after cross-linking induced by an anti-mouse IgG antibody. Secretion of lymphokines (IFN-gamma, TNF-alpha and GM-CSF) was induced by contact of the biMAb-coated effector cells with the relevant tumor target, whereas the soluble biMAb was virtually ineffective. In addition, biMAb-coated effector cells retained the ability to recognize and to lyse EGF-R+ tumor cells for a prolonged period of time. Our data indicate that activation of effector cells targeted by biMAbs can only occur at the tumor site, where cross-linking of surface CD3 molecules is induced by contact with the tumor cells. (C) 1993 Wiley-Liss, Inc.
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页码:931 / 937
页数:7
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