Redirected targeting of LDL to human monocyte Fc gamma receptors with bispecific antibodies.

Abstract

Recent studies indicate that low density lipoprotein (LDL)-immune complexes consisting of anti-LDL antibodies bound to LDL may contribute to macrophage foam cell development by uptake through immunoglobulin G (IgG) Fc receptors. As human mononuclear phagocytes possess three structurally and functionally distinct classes of IgG Fc receptors, we developed a system whereby the effects of LDL-immune complexes could be studied with respect to each type of IgG Fc receptor. Novel bispecific antibodies consisting of anti-Fc gamma receptor antibodies linked to anti-LDL antibodies were used to prepare bispecific LDL-immune complexes for targeting to specific Fc gamma receptors. In this report, the effects of bispecific LDL-immune complexes directed to Fc gamma receptor types I, II, and III were studied primarily with monocytes and were compared with the effects of similarly prepared bispecific complexes that targeted LDL to human leukocyte antigen (HLA) class I antigens. Each type of bispecific antibody was effective in targeting 125I-LDL to its respective site on the cell surface. Using fluorophore-labeled LDL and flow cytometry, bispecific complexes directed to Fc gamma receptor types I or II but not to HLA class I antigens caused a two- to sevenfold increase in cell-associated fluorescence relative to control cells treated with LDL in the absence of bispecific antibody. Uptake occurred in the presence of excess unlabeled LDL, acetylated LDL, and antioxidants. That the bispecific complexes triggered metabolic uptake was supported by studies of kinetics and temperature dependence. Using 125I-labeled complexes, metabolic degradation of LDL was demonstrated in association with each of the three types of Fc gamma receptors.(ABSTRACT TRUNCATED AT 250 WORDS)