Biological properties of a CD4 immunoadhesin

Abstract

Molecular fusions of CD4, the receptor for human immunodeficiency virus (HIV), with immunoglobulin (termed CD4 immunoadhesins) possess both the gp120-binding and HIV-blocking properties of recombinant soluble CD4, and certain properties of IgG, notably long plasma half-life and Fc receptor binding. Here we show that a CD4 immunoadhesin can mediate antibody-dependent cell-mediated cytotoxicity (ADCC) towards HIV-infected cells, although, unlike natural anti-gp120 antibodies, it does not allow ADCC towards uninfected CD4-expressing cells that have bound soluble gp120 to the CD4 on their surface. In addition, CD4 immunoadhesin, like natural IgG molecules, is efficiently transferred across the placenta of a primate. These observations have implications for the therapeutic application of CD4 immunoadhesins, particularly in the area of perinatal transmission of HIV infection.

Quantification and Modeling of Tripartite CD2-, CD58FC Chimera (Alefacept)-, and CD16-mediated Cell Adhesion

“…3 We use the following notation: L is the alefacept concentration, e T is the total surface concentration of CD2 when CD2 is uniformly distributed on the T cell; e is the surface concentration of free CD2; e 1 and e 2 are the surface concentrations of alefacept with its Fc portion unbound and with one CD58 site bound and both CD58 sites bound respectively; r T is the total surface concentration of the CD16B when they are uniformly 3 K b1 , equilibrium constant for binding of alefacept Fc to FcR in planar bilayer when one of alefacept's CD58s is bound to CD2 on the T cell; K b2 , equilibrium constant for binding of alefacept Fc to FcR in planar bilayer when both of the alefacept CD58s are bound to CD2; K E , equilibrium constant for binding of first Alefacept CD58 Ig domain to CD2 on T cell while its Fc site is free; K R , solution equilibrium constant for binding of Fc to FcR in planar bilayer; K X , equilibrium constant for binding of second alefacept CD58 Ig domain to CD2 on T cell while its Fc is free; L, alefacept concentration; L min , the minimum concentration of alefacept at which adhesion is observed; L max , the maximum concentration of alefacept at which adhesion is observed; N T , total number of CD2 per cell. 2 , and the adhesion as a function of the ligand concentration. The first two equations arise from the assumption that binding is at equilibrium so that the total numbers of CD2 and CD16B are constant.…”

“…Alefacept is approved for treatment of psoriasis. Alefacept mediates reduction of circulating memory T cells in patients and mediates Fc receptor (FcR) 2 -dependent cell-mediated killing of T cells in vitro (3,4). It is hypothesized that alefacept both reduces deleterious effector functions of activated T cells by blocking interaction of CD2 with CD58 and deletes autoaggressive T cells through FcR-dependent killing.…”

“…Immunoadhesins are biopharmaceuticals that take the basic framework of antibodies and replace the antigen-binding domain with the ectodomain of adhesion molecules (1,2). The common fragment of IgG (Fc) portion is thought to link to immune effector mechanisms to destroy cancer cells and or over-reactive immune cells.…”

Expression of the extracellular domain of OB-cadherin as an Fc fusion protein using bicistronic retroviral expression vector

“…The positive clones were then cut with BglII and BamHI and subcloned into BamHI-digested pBMN-Fc-I-GFP. The resulting plasmid, pBMN-(OB-CAD-Fc)-I-GFP, contains the extracellular domain of OB-cadherin linked to glutamic acid residue 211 of the human IgG1 Fc region [19] through an artificial BamHI adapter, which creates a junction sequence, "GSEPKSCD," with the amino acids GS (glycine and serine) encoded from the restriction-site sequence of BamHI.…”

Monoclonal antibodies in drug targeting

“…It has a long plasma half-life and is capable of binding to Fc receptors. Recombinant CD4 immunoadhesin modulates antibody-dependent cell-mediated cytotoxicity towards HIV infected cells (130,131). In addition, CD4 immunoadhesin permeates efficiently through the placenta (113) thereby making possible perinatal treatment of HIV infection.…”