Bispecific antibodies that mediate killing of cells infected with human immunodeficiency virus of any strain.

Abstract

Although AIDS patients lose human immunodeficiency virus (HIV)-specific cytotoxic T cells, their remaining CD8-positive T lymphocytes maintain cytotoxic function. To exploit this fact we have constructed bispecific antibodies that direct cytotoxic T lymphocytes of any specificity to cells that express gpl20 of HIV. These bispecific antibodies comprise one heavy/light chain pair from an antibody to CD3, linked to a heavy chain whose variable region has been replaced with sequences from CD4 plus a second light chain. CD3 is part of the antigen receptor on T cells and is responsible for signal transduction. In the presence of these bispecific antibodies, T cells of irrelevant specificity effectively lyse HIV-infected cells in vitro.

Engineering Antibodies for the Treatment of Infectious Diseases

“…Now BiS4αPa is in clinical candidate for the treatment of P. aeruginosa [39]. Berg et al constructed a bispecific antibody by linking one heavy/light chain pair from an antibody against CD3 on cytotoxic T cells to a heavy chain whose variable region was replaced by sequence from CD4 [6]. The constructed antibody has dual binding specificity with one arm binding to CD3 on cytotoxic T cells and the other arm which contained sequences from CD4 binding to viral envelope protein gp120 of HIV [6].…”

Engineering broadly neutralizing antibodies for HIV prevention and therapy

“…Historically, bispecific molecules to target HIV latent reservoir cells paired soluble versions of the CD4 receptor to anti-CD3 T cell engaging antibody fragments in a variety of formats [283–285]. Previous attempts to employ anti-HIV mAb specificities in bispecific formats with anti-CD3 demonstrated limited efficacy, likely due to limited breadth [284–286].…”

The maturation of antibody technology for the HIV epidemic

“…Early approaches produced modified antibodies that, although are not bispecifics, exploit a similar principle. Examples are ‘immunoadhesins’ and ‘janusins’, which bind gp120 via recombinant CD4 domains attached to an anti‐CD3 that targets CD3 + cytotoxic cells to kill HIV‐infected cells with gp120 on their surface 69 , 70 , 71 . No HIV immunoadhesins or janusins have been approved for use in the clinic to date.…”