Exploring avidity: understanding the potential gains in functional affinity and target residence time of bivalent and heterobivalent ligands

Georges Vauquelin, Steven Charlton

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    147 Citaten (Scopus)

    Samenvatting

    Bivalent ligands are increasingly important therapeutic agents. Although the naturally occurring antibodies prevail, it is becoming more common to combine different antibody fragments or even low molecular weight compounds to generate heterobivalent ligands. Those experience markedly increased affinity (i.e avidity) and target residence time when both pharmacophores can bind simultaneously to their target sites. This is because binding of one pharmacophore forces the second, tethered one to stay close to its corresponding site. This "forced proximity" incites its binding and rebinding (once dissociated) to that site. Yet, rebinding will also take place when the diffusion of freshly dissociated ligands is merely slowed-down. The present differential equation- based simulations explore the way both situations affect ligand binding. Both delay the attainment of binding equilibrium (resulting in steep saturation curves) and also increase the target residence time. Competitive ligands are able to interfere in a concentration-dependent manner, although much higher concentrations are required in the "forced proximity" situation. Also, it is only in that situation that the ligand shows increased affinity. These simulations shed light on two practical consequences. Depending upon the pharmacokinetic half-life of the bivalent ligand in the body, it may not have sufficient time to achieve equilibrium with the target. This will result in lower potency than expected, although it would have significant advantages in terms of residence time. In in vitro experiments, the manifestation of steep saturation curves and of accelerated dissociation in presence of competitive ligands could inadvertently be interpreted as evidence for non-competitive, allosteric interactions.
    Originele taal-2English
    Pagina's (van-tot)1771-1785
    Aantal pagina's15
    TijdschriftBritish Journal of Pharmacology
    Volume168
    StatusPublished - 2013

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