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Receptor Modulation by FcRI-Specific Fusion Proteins Is Dependent on Receptor Number and Modified by IgG¹

Cheryl A. Guyre^*, Tibor Keler, Sharon L. Swink, Laura A. Vitale, Robert F. Graziano and Michael W. Fanger^2,

Departments of ^* Physiology and Microbiology, Dartmouth Medical School, Lebanon, NH 03756; and Medarex, Bloomsbury, NJ 08804

The high-affinity IgG receptor, FcRI (CD64), is constitutively expressed exclusively on professional APCs. Human FcRI binds monomeric IgG with high affinity and is, therefore, saturated in vivo. The binding of IgG to FcRI causes receptor recycling, while Abs that cross-link FcRI cause rapid down-modulation of surface FcRI. Because studies performed in the absence of ligand may not be representative of FcRI modulation in vivo, we investigated the ability of FcRI-cross-linking Abs and non-cross-linking derivatives to modulate FcRI in the presence and absence of ligand. In the absence of ligand mAb H22 and wH22xeGFP, an enhanced green fluorescent protein (eGFP)-labeled fusion protein of H22, cross-linked and rapidly down-modulated surface FcRI on the human myeloid cell line, U937, and its high FcRI-expressing subclone, 10.6. This effect was dependent on the concentration of fusion protein and the level of FcRI expression and correlated with internalization of both wH22xeGFP and FcRI, itself, as assessed by confocal microscopy. A single-chain Fv version, sFv22xeGFP, which does not cross-link FcRI, was unable to modulate FcRI in the absence of IgG. However, if ligand was present, treatment with either monovalent or cross-linking fusion protein led to intracellular receptor accumulation. These findings suggest at least two alternate mechanisms of internalization that are influenced by ligand and demonstrate the physiologic potential of FcRI to transport a large antigenic load into APCs for processing. These studies may lead to the development of better FcRI-targeted vaccines, as well as therapies to down-modulate FcR involved in autoimmune diseases.

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