Bispecific molecules produced by genetic engineering

The development of molecular biology techniques provided a new approach which permits the insertion, within or adjacent to the genes encoding an immunoglobulin molecule, of oligonucleotides encoding another immunoglobulin, a desired immunogenic epitope or an epitope responsible for interaction with a viral antigen. For example, it is possible to create a bispecific molecule in which the coding sequence for the V region of a CD3-specific antibody is combined with the sequence for the CD4 molecule which is able to bind HIVgpl20. Such a bispecific molecule could activate a CTL and bring it into intimate contact with an HIV-infected cell.

Bispecific antibodies and heteroconjugates have a potential application in antitumor therapy and in the treatment of infectious diseases caused by bacteria or viruses in which the microbial antigen is expressed on the surface of infected cells. In the case of anti-tumour therapy, a bispecific antibody could be constructed using a monoclonal antibody specific for the TCR-CD3 complex (i.e. anti-CD3, anti-idiotype or anti-allotype) and a monoclonal antibody specific for a tumor-associated antigen. Bispecific antibodies have also been used to deliver isotopes or toxins to tumors which are difficult to remove by surgery or to tag remaining tumor cells after surgery. The efficiency of bispecific antibodies as antitumor immunotherapeutic agents are currently being evaluated in clinical trials in humans.

In the case of the treatment of infectious diseases the heteroconjugates or bispecific antibodies can be constructed using monoclonal antibodies against the TCR-CD3 complex of CTL and monoclonal antibody specific for a viral antigen. Evidence has been presented in a number of viral diseases that viral-specific CTLs reduce viral replication and dissemination. Therefore, the focusing of CTLs on virally infected cells by bispecific antibodies can prevent viral replication and spreading. It has already been shown that heteroconjugates or bispecific antibodies can redirect CTL activity against cells infected with viruses such as human immunodeficiency virus (HIV), herpes or influenza.

Thus, it appears that bispecific antibodies have the potential to become a new category of immunotherapeutic reagents.

See also: Antigen-binding site; Cytotoxic T lymphocytes; Hybridomas, B cell; Monoclonal antibodies (mAbs).

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