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A biophysical model of cell adhesion mediated by immunoadhesin drugs and antibodies.

Gutenkunst RN, Coombs D, Starr T, Dustin ML, Goldstein B - PLoS ONE (2011)

Bottom Line: Monoclonal antibodies and drugs designed to elicit this effect typically bind cell-surface epitopes that are overexpressed on target cells but also present on other cells.We also quantitatively describe the parameter space in which binding occurs.Our model elaborates substantially on previous work, and our results offer guidance for the refinement of therapeutic immunoadhesins.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, United States of America.

ABSTRACT
A promising direction in drug development is to exploit the ability of natural killer cells to kill antibody-labeled target cells. Monoclonal antibodies and drugs designed to elicit this effect typically bind cell-surface epitopes that are overexpressed on target cells but also present on other cells. Thus it is important to understand adhesion of cells by antibodies and similar molecules. We present an equilibrium model of such adhesion, incorporating heterogeneity in target cell epitope density, nonspecific adhesion forces, and epitope immobility. We compare with experiments on the adhesion of Jurkat T cells to bilayers containing the relevant natural killer cell receptor, with adhesion mediated by the drug alefacept. We show that a model in which all target cell epitopes are mobile and available is inconsistent with the data, suggesting that more complex mechanisms are at work. We hypothesize that the immobile epitope fraction may change with cell adhesion, and we find that such a model is more consistent with the data, although discrepancies remain. We also quantitatively describe the parameter space in which binding occurs. Our model elaborates substantially on previous work, and our results offer guidance for the refinement of therapeutic immunoadhesins. Furthermore, our comparison with data from Jurkat T cells also points toward mechanisms relating epitope immobility to cell adhesion.

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Related in: MedlinePlus

Model reaction network.All molecular species and reactions are labeled. All reactions are reversible; the arrow in the figure denotes the forward direction for defining the equilibrium constant, which labels the arrow. Underlined rate constants are eliminated using detailed balance.
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pone-0019701-g001: Model reaction network.All molecular species and reactions are labeled. All reactions are reversible; the arrow in the figure denotes the forward direction for defining the equilibrium constant, which labels the arrow. Underlined rate constants are eliminated using detailed balance.

Mentions: The potential reactions among mobile and immobile epitopes, ligand, receptor, and nonspecific antibody are illustrated in Fig. 1. Each molecular complex is labeled by our mathematical notation for its surface concentration. All species except those involving a bridging bond (, , , and ) exist both inside and outside the contact region, and the subscript ‘in’ denotes species inside the contact region. Detailed balance places six constraints on the equilibrium constants, which we use to eliminate the underlined constants in Fig. 1 (Text S1). To find the equilibrium state of this system for any given bulk ligand concentration , we solve five algebraic equations for five unknowns: the free immobile epitope concentrations outside and inside the contact region, the free mobile epitope and receptor concentrations outside the contact region, and the fraction of the target cell surface comprising the contact region. To make our analysis tractable, we make several simplifying assumptions regarding the equilibrium configuration of receptors and epitopes.


A biophysical model of cell adhesion mediated by immunoadhesin drugs and antibodies.

Gutenkunst RN, Coombs D, Starr T, Dustin ML, Goldstein B - PLoS ONE (2011)

Model reaction network.All molecular species and reactions are labeled. All reactions are reversible; the arrow in the figure denotes the forward direction for defining the equilibrium constant, which labels the arrow. Underlined rate constants are eliminated using detailed balance.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3100730&req=5

pone-0019701-g001: Model reaction network.All molecular species and reactions are labeled. All reactions are reversible; the arrow in the figure denotes the forward direction for defining the equilibrium constant, which labels the arrow. Underlined rate constants are eliminated using detailed balance.
Mentions: The potential reactions among mobile and immobile epitopes, ligand, receptor, and nonspecific antibody are illustrated in Fig. 1. Each molecular complex is labeled by our mathematical notation for its surface concentration. All species except those involving a bridging bond (, , , and ) exist both inside and outside the contact region, and the subscript ‘in’ denotes species inside the contact region. Detailed balance places six constraints on the equilibrium constants, which we use to eliminate the underlined constants in Fig. 1 (Text S1). To find the equilibrium state of this system for any given bulk ligand concentration , we solve five algebraic equations for five unknowns: the free immobile epitope concentrations outside and inside the contact region, the free mobile epitope and receptor concentrations outside the contact region, and the fraction of the target cell surface comprising the contact region. To make our analysis tractable, we make several simplifying assumptions regarding the equilibrium configuration of receptors and epitopes.

Bottom Line: Monoclonal antibodies and drugs designed to elicit this effect typically bind cell-surface epitopes that are overexpressed on target cells but also present on other cells.We also quantitatively describe the parameter space in which binding occurs.Our model elaborates substantially on previous work, and our results offer guidance for the refinement of therapeutic immunoadhesins.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, United States of America.

ABSTRACT
A promising direction in drug development is to exploit the ability of natural killer cells to kill antibody-labeled target cells. Monoclonal antibodies and drugs designed to elicit this effect typically bind cell-surface epitopes that are overexpressed on target cells but also present on other cells. Thus it is important to understand adhesion of cells by antibodies and similar molecules. We present an equilibrium model of such adhesion, incorporating heterogeneity in target cell epitope density, nonspecific adhesion forces, and epitope immobility. We compare with experiments on the adhesion of Jurkat T cells to bilayers containing the relevant natural killer cell receptor, with adhesion mediated by the drug alefacept. We show that a model in which all target cell epitopes are mobile and available is inconsistent with the data, suggesting that more complex mechanisms are at work. We hypothesize that the immobile epitope fraction may change with cell adhesion, and we find that such a model is more consistent with the data, although discrepancies remain. We also quantitatively describe the parameter space in which binding occurs. Our model elaborates substantially on previous work, and our results offer guidance for the refinement of therapeutic immunoadhesins. Furthermore, our comparison with data from Jurkat T cells also points toward mechanisms relating epitope immobility to cell adhesion.

Show MeSH
Related in: MedlinePlus