Harnessing receptor clustering in lipid rafts to tailor the inhibitory effects of monoclonal antibodies to specific cell types

Abstract

Certain cell signaling pharmaceutical targets have the potential to provide substantial clinical benefit when inhibited on some cell types yet elicit unwanted collateral damage when impeded on others. Thus, the appropriate therapeutic strategy for this situation would be to block preferentially receptor activation on the desired cell set. Taking advantage of the clustering within lipid rafts of toll-like receptor 4 (TLR4) and Fc gamma receptors (Fc?R) during TLR4 activation, we have identified a mechanism that allows an antibody to block more favorably signaling on leukocytes, cells that underlie acute and chronic inflammatory processes. The anti-TLR4 monoclonal antibody (mAb), Hu 15C1, co-engages TLR4 and Fc?Rs to enhance its inhibitory potency via an avidity effect on Fc?R-bearing cells. This novel mechanism of action allows the mAb to block efficiently TLR4 activation on Fc?R-bearing inflammatory cells, while limiting the duration of effect on cells lacking Fc?Rs. As receptor clustering in lipid rafts is a common phenomenon, this mechanism could be exploited to anchor similar receptor-targeting mAbs or formats bearing an antibody Fc domain to desired cell types.