Model and Simulation of Multivalent Binding to Fixed Ligands

Müller, Kristian M.; Arndt, Katja M.; Plückthun, Andreas

doi:10.1006/abio.1998.2725

Cited by 135 publications

(115 citation statements)

References 21 publications

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“…Although expressed in the periplasm, the dimer A10-AP bound HER2 with a K D in the lower nanomolar range, a log worse than the A10-Fc construct produced in the cytoplasm ( Figure 5). This result confirms that functional binding capacity is not a simple matter of active domain number [29].…”

Section: Resultssupporting

confidence: 83%

Bacterial cytoplasm as an effective cell compartment for producing functional VHH-based affinity reagents and Camelidae IgG-like recombinant antibodies

et al. 2014

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Background: The isolation of recombinant antibody fragments from displayed libraries represents a powerful alternative to the generation of IgGs using hybridoma technology. The selected antibody fragments can then be easily engineered into (multi)-tagged constructs of variable mass and complexity as well as reconstituted into Camelidae IgG-like molecules when expressed fused to Fc domains. Nevertheless, all antibody constructs depend on an oxidizing environment for correct folding and consequently still belong to the proteins difficult to express in bacteria. In such organisms they are mostly produced at low yields in the periplasmic space.

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Section: Resultssupporting

confidence: 83%

Bacterial cytoplasm as an effective cell compartment for producing functional VHH-based affinity reagents and Camelidae IgG-like recombinant antibodies

et al. 2014

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“…micro-compartments with little convective stirring, such as synapses and other interstitial spaces -and (C) interactions with membrane components that promote the 2D diffusion of drugs at the surface or deeper within the hydrocarbon core of the membrane. (D) The most extreme form of rebinding applies to bivalent ligands because binding of one of their domains/pharmacophores (red circles) to the target 'forces' the second, tethered pharmacophore to remain close to its cognate binding pocket at the target for bivalent ligand-target interactions [61][62][63] is that, as long as one of the ligand's binding domains/pharmacophores is bound, the second, tethered pharmacophore is forced to remain close to its cognate target site ( Figure 3D). The resultant high 'local' concentration of this second pharmacophore will boost its association rate and, as a result, both pharmacophores will experience multiple unbinding and rebinding events before the bivalent ligand drifts away [64].…”

Section: Figurementioning

confidence: 99%

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

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The time course of the beneficial pharmacological effect of a drug has long been considered to depend merely on the temporal fluctuation of its free concentration. Only in the last decade has it become widely accepted that target-binding kinetics can also affect in vivo pharmacological activity. Although current reviews still essentially focus on genuine dissociation rates, evidence is accumulating that additional micro-pharmacokinetic (PK) and -pharmacodynamic (PD) mechanisms, in which the cell membrane plays a central role, may also increase the residence time of a drug on its target. The present review provides a compilation of otherwise widely dispersed information on this topic. The cell membrane can intervene in drug binding via the following three major mechanisms: (i) by acting as a sink/repository for the drug; (ii) by modulating the conformation of the drug and even by participating in the binding process; and (iii) by facilitating the approach (and rebinding) of the drug to the target. To highlight these mechanisms, we focus on drugs that are currently used in clinical therapy, such as the antihypertensive angiotensin II type 1 receptor antagonist candesartan, the atypical antipsychotic agent clozapine and the bronchodilator salmeterol. Although the role of cell membranes in PK-PD modelling is gaining increasing interest, many issues remain unresolved. It is likely that novel biophysical and computational approaches will provide improved insights in the near future. IntroductionThe pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug are determinants of its efficacy and the duration of its clinical action [1]. PK and PD have long been considered to be separate disciplines, and the time course of the pharmacological effect of a drug has essentially been considered in terms of the temporal fluctuation of its free concentration [2]. In accordance with this principle, the frequently observed time lag between the concentration of a drug in the systemic circulation and its effect was initially attributed to slow equilibration between the plasma and a hypothetical target-surrounding 'effect compartment' [3]. By contrast, preclinical screening studies traditionally aim to optimize drug candidates in terms of only their efficacy and potency (i.e. PD properties). Inherent to this practice is the proposal that drug-target interactions are adequately described by equilibrium equations and, hence, that association and dissociation rates play only subordinate roles. In addition to a few noteworthy exceptions [4,5], it is only in the last decade that it has become fashionable to include binding kinetics as an additional criterion for clinical efficacy. This insight was largely sparked by the seminal articles by Swinney [6] and Copeland et al. [7]. The numerous review articles that have been published subsequently have focused mainly on long residence times. This property is now recognized to play a key role with respect to the clinical British Journal of Clinical Pharmacology Br J Clin Pharmacol (2016...

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“…Clearly, the bivalent model used in this study is too simplistic to describe all of the components of the true interaction (63). This is particularly evident when observing the higher k off2 value estimated for IgD⌬h1 as opposed to the observed dissociation kinetics.…”

Section: Discrepancies Between Intrinsic and Functional Affinitymentioning

confidence: 88%

“…This is particularly evident when observing the higher k off2 value estimated for IgD⌬h1 as opposed to the observed dissociation kinetics. To give a more complete kinetic description, parameters such as the functional difference between the two binding sites on the analyte, ligand density, and steric hindrance must be incorporated in the model (63,64). Furthermore, even a lower epitope density would have been necessary to minimize rebinding of Fab arms of IgD, where the flexibility and reach is great.…”

Section: Discrepancies Between Intrinsic and Functional Affinitymentioning

confidence: 99%

Differential Segmental Flexibility and Reach Dictate the Antigen Binding Mode of Chimeric IgD and IgM: Implications for the Function of the B Cell Receptor

Løset

Roux

Zhu

et al. 2004

The Journal of Immunology

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Mature, naive B cells coexpress IgD and IgM with identical binding sites. In this study, the binding properties of such IgM and IgD are compared to determine how size and shape may influence their ability to bind Ag and thus function as receptors. To dissect their intrinsic binding properties, recombinant IgM and IgD were produced in soluble form as monomers of the basic H2L2 Ab architecture, each with two Ag binding sites. Since these sites are connected with a hinge region in IgD and structural Ig domains in IgM, the two molecules differ significantly in this region. The results show that IgD exhibited the larger angle and longer distance between its binding sites, as well as having the greater flexibility. Relative functional affinity was assessed on two antigenic surfaces with high or low epitope density, respectively. At high epitope density, IgM had a higher functional affinity for the Ag compared with IgD. The order was reversed at low epitope density due to a decrease in the functional affinity of IgM. Studies of binding kinetics showed similar association rates for both molecules. The dissociation rate, however, was slower for IgM at high epitope density and for IgD at low epitope density. Taken together, the results show that IgM and IgD with identical Ag binding regions have different Ag binding properties.

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Model and Simulation of Multivalent Binding to Fixed Ligands

Cited by 135 publications

References 21 publications

Bacterial cytoplasm as an effective cell compartment for producing functional VHH-based affinity reagents and Camelidae IgG-like recombinant antibodies

Bacterial cytoplasm as an effective cell compartment for producing functional VHH-based affinity reagents and Camelidae IgG-like recombinant antibodies

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Differential Segmental Flexibility and Reach Dictate the Antigen Binding Mode of Chimeric IgD and IgM: Implications for the Function of the B Cell Receptor

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