Infliximab is a monoclonal antibody that neutralizes the cytokine tumor necrosis factor (TNF)-a by binding selectively and with high affinity to soluble and membrane-bound TNF-a. Infliximab does not bind to TNF-
(lymphotoxin ), a related cytokine that utilizes the same receptors as TNF-a. Thus infliximab was developed as a therapeutic agent for various inflammatory chronic diseases that are believed to be driven by the pro-inflammatory cytokine TNF- .
Infliximab was developed by fusing the TNF-a binding site of the murine antibody A2 to the constant region of human IgG1 k immunoglobulin. This created a chimeric antibody with an acceptable immunogenic and pharmacokinetic profile (Knight et al. 1993).
Infliximab binds the trimeric form of soluble TNF-a with an affinity of Kd 100 pM but also binds to its monomeric form (Scallon et al. 1995,2002). Although the tri-meric form of TNF- is the bioactive form, binding of TNF- monomers might be clinically important by slowing down or even preventing the formation of tri-meric TNF- .
When testing the binding affinity of infliximab on a cell line that expresses only membrane-bound recombinant human TNF- , the affinity of the antibody to TNF- was about twofold higher when compared to the affinity to soluble TNF-a (Kd 46 pM) (Scallon et al. 1995). In addition, the binding affinities of the dimeric F(ab')2 fragment were 50-fold higher than that of the monomeric FAB fragment (Scallon et al. 1995). This verified that the strong avidity of the antibody binding to TNF- is in part based on the bivalent interaction of the antibody with its ligand.
The stability of the infliximab-TNF-a complex was confirmed by its slow dissociation rate. In fact, no dissociation of infliximab was observed within 4 h from soluble or within 2 h from membrane-bound TNF-a in an in vitro assay (Scallon et al. 2002).
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