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

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 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. We also quantitatively describe the parameter space in which binding occurs. Our results point toward mechanisms relating epitope immobility to cell adhesion and offer insight into the activity of an important class of drugs.

💡 Research Summary

This paper addresses a fundamental problem in immunotherapy: how antibodies or immunoadhesin drugs mediate the adhesion of target cells to natural killer (NK) cells, a prerequisite for NK‑mediated cytotoxicity. While many therapeutic antibodies bind antigens that are over‑expressed on diseased cells, those antigens are often also present at lower levels on healthy cells, and the physical state of the antigen on the cell surface (mobile versus immobilized) can dramatically affect the formation of stable cell‑cell contacts. The authors therefore develop a quantitative equilibrium model that explicitly incorporates two realistic sources of heterogeneity: (1) cell‑to‑cell variation in epitope (antigen) density and (2) a fraction of epitopes that are immobilized on the plasma membrane and cannot freely diffuse.

Model formulation
The system is described as a two‑step binding process. First, an immunoadhesin (ale‑facept) binds to its target epitope (CD2) on the surface of a Jurkat T cell with dissociation constant K_d^1. Second, the same immunoadhesin simultaneously engages an NK‑cell receptor (CD58) presented on a supported lipid bilayer, with dissociation constant K_d^2. For a given cell i with epitope density ρ_i, the fraction of bound immunoadhesin in the first step follows a Langmuir‑type expression: θ(ρ_i)=