Selective tumor cell targeting using low-affinity, multivalent interactions.

This report highlights the advantages of low-affinity, multivalent interactions to recognize one cell type over another. Our goal was to devise a strategy to mediate selective killing of tumor cells, which are often distinguished from normal cells by their higher levels of particular cell surface receptors. To test whether multivalent interactions could lead to highly specific cell targeting, we used a chemically synthesized small-molecule ligand composed of two distinct motifs: (1) an Arg-Gly-Asp (RGD) peptidomimetic that binds tightly (Kd ≈ 10–9 M) to αvβ3 integrins and (2) the galactosyl-α(1–3)galactose (α-Gal epitope), which is recognized by human anti-α-galactosyl antibodies (anti-Gal). Importantly, anti-Gal binding requires a multivalent presentation of carbohydrate residues; anti-Gal antibodies interact weakly with the monovalent oligosaccharide (Kd ≈ 10–5 M) but bind tightly (Kd ≈ 10–11 M) to multivalent displays of α-Gal epitopes. Such a display is generated when the bifunctional conjugate decora...