Targeting of cytotoxic cells against tumors with heterocrosslinked, bispecific antibodies.
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abstract
Cytotoxic cells express specific receptors on their surfaces by which they distinguish altered or foreign cells from normal autologous cells. Recently, a method has been developed by which the natural recognition system of cytotoxic cells can be artificially manipulated, giving rise to cytotoxic cells of any desired specificity, including specificity against tumor and virally infected cells. The method for retargeting cytotoxic cells employs heterocrosslinked antibodies, in which one antibody is directed against the cytotoxic cell receptor (CCR) involved in lysis, while the second antibody is directed against a target cell structure, for example a tumor or viral antigen. By linking the CCR directly to the target cell, the heterocrosslinked antibodies promote the formation of effector: target conjugates and signal the cytotoxic cell to deliver a lethal hit. T cells can be targeted by heteroconjugates containing antibodies against components of the T cell receptor complex, e.g., Ti or CD3, while several types of antibody-dependent cellular cytotoxicity (ADCC) effector cells, including K/NK cells, macrophages, and neutrophils, are targeted using heteroconjugates containing antibodies against Fc gamma receptors. In peripheral blood from normal donors at least six types of targetable activities have been identified in vitro. In Winn type tumor neutralization assays in nude mice, targeted T and K cells can prevent the establishment of subcutaneous tumor at low effector: tumor ratios. Moreover, targeted human peripheral blood T cells cause the eradication of established intraperitoneal human ovarian carcinoma in nude mouse models. Targeted cytotoxic cells therefore hold great promise as a novel form of cancer immunotherapy in humans.
