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Targeting of T lymphocytes against EGF-receptor+ tumor cells by bispecific monoclonal antibodies: requirement of CD3 molecule cross-linking for T-cell activation.

Abstract：

: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 (A431) 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.

journal_name

Int J Cancer

journal_title

International journal of cancer

authors

Ferrini S,Cambiaggi A,Sforzini S,Marciano S,Canevari S,Mezzanzanica D,Colnaghi MI,Grossi CE,Moretta L

doi

10.1002/ijc.2910550610

subject

Has Abstract

pub_date

1993-12-02 00:00:00

pages

931-7

issue

eissn

0020-7136

issn

1097-0215

journal_volume

pub_type

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Targeting of T lymphocytes against EGF-receptor+ tumor cells by bispecific monoclonal antibodies: requirement of CD3 molecule cross-linking for T-cell activation.