Heteroantibody duplexes target cells for lysis by cytotoxic T lymphocytes

Antibodies to the clonally unique variable-region determinants (idiotype) of the antigen-specific αβ heterodimeric receptor of a clone of cytotoxic T cells (CTLs) were shown previously to render diverse cells, regardless of their own surface antigens, susceptible to lysis by that clone of CTLs. To extend these findings, we have sought to develop a general means for targeting cells for destruction by any CTL, without regard to its αβ idiotype and specificity for antigen. We explored the use of heteroantibody duplexes formed by joining covalently an antibody to the T3 complex (anti-T3), which is associated with the αβ receptors on all human mature T cells, and a second antibody, specific for an antigen on the intended target cell. The second antibody selected in this study was specific for the idiotype (Id) of the surface immunoglobulin of a human B-lymphoma (anti-Ig Id). In the presence of the anti-T3/anti-Ig Id heteroantibody duplex the B-lymphoma cells were lysed by a clone of human T8⁺ CTLs (of unrelated specificity) but not by a noncytotoxic clone of human T4⁺ helper T cells, and lysis by the CTLs was specifically blocked by the uncoupled anti-T3 or the uncoupled anti-Ig Id antibodies. The extent of the heteroantibody-dependent cytolysis depended both on the heteroantibody concentration and on whether the intended target cells or the CTL effectors were initially preincubated with the heteroantibody. Under optimal conditions, heteroantibody-dependent lysis of the surrogate target (B-lymphoma) cells by the CTLs compared favorably with lysis of their natural target cells by the same CTLs. Overall, our findings suggest that heteroantibody duplexes containing anti-T3 antibody may be capable of targeting selected cells, such as tumor cells, for destruction in vivo by the body's CTLs.