Abstract
We have constructed bispecific immunoglobulin-like immunoadhesins that bind to both the HIV-envelope glycoproteins: gp120 and gp41. These immunoadhesins have N terminal domains of human CD4 engrafted onto the N-terminus of the heavy chain of human anti-gp41 mAb 7B2. Binding of these constructs to recombinant Env and their antiviral activities were compared to that of the parental mAbs and CD4, as well as to control mAbs. The CD4/7B2 constructs bind to both gp41 and gp140, as well as to native Env expressed on the surface of infected cells. These constructs deliver cytotoxic immunoconjugates to HIV-infected cells, but not as well as a mixture of 7B2 and sCD4, and opsonize for antibody-mediated phagocytosis. Most surprisingly, given that 7B2 neutralizes weakly, if at all, is that the chimeric CD4/7B2 immunoadhesins exhibit broad and potent neutralization of HIV, comparable to that of well-known neutralizing mAbs. These data add to the growing evidence that enhanced neutralizing activity can be obtained with bifunctional mAbs/immunoadhesins. The enhanced neutralization activity of the CD4/7B2 chimeras may result from cross-linking of the two Env subunits with subsequent inhibition of the pre-fusion conformational events that are necessary for entry.
Highlights
The HIV envelope (Env) glycoproteins, precursor, surface, and transmembrane, are the sole virus-encoded proteins expressed on the surface of virions and HIV-infected cells
We have previously described a panel of double variable domain (DVD) Abs that bind to both gp120 and gp41 using variable domains derived from monoclonal Abs (mAbs) to the CD4-binding site of gp120 and to the gp41 external loop region [24]
The H and L chains were expressed from different plasmids by cotransfection into 293T cells, creating CD4/7B2 chimeric Ig-like immunoadhesins with various CD4-Ab conformations and linkers joining
Summary
The HIV envelope (Env) glycoproteins, precursor (gp160), surface (gp120), and transmembrane (gp41), are the sole virus-encoded proteins expressed on the surface of virions and HIV-infected cells. Env is the only viral target of HIV-neutralizing antibodies (Abs). The anti-Env Ab response is the subject of intense investigation, both for the development of an HIV vaccine [1,2,3,4,5,6] and for the administration of therapeutic Abs [2,3,7,8,9,10,11,12,13,14,15]. Well-defined regions of Env have been described as targets of patient-derived neutralizing monoclonal Abs (mAbs), including the gp120 CD4 binding site, variable loops, glycan shield, interface of gp120/gp, and the gp membrane proximal external region.
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