A Novel Strategy for Etiologic Factor Removal: Drug-Navigated Clearance System (DNCS)

Abstract

Here, we propose a novel therapeutic concept named drugnavigated clearance system (DNCS), in which a "navigator" decreases the concentration of a target etiologic factor in the blood by steering it to an unusual metabolic pathway. The navigator is composed of protein A (ProA) and dextran sulfate (DexS) and it successfully navigated antibodies (ABs), a model etiologic factor of dilated cardiomyopathy, to hepatocytes in vitro in the presence of low-density lipoprotein (LDL). ProA captured the Fc region of the target antibody while the DexS bound to LDL via the well-known electrostatic interaction. The hepatocytes simultaneously took up LDL via the LDL-receptor and internalized the AB/ProA-DexS complex that was bound to LDL. Therefore, this process demonstrates our attempt to navigate the etiologic factor to an alternate target pathway such as the LDL salvage.Key words metabolic abnormality; navigator; low-density lipoprotein; low-density lipoprotein receptor Increase in blood concentration of various etiologic factors has been known to cause different diseases. An effective and direct clinical strategy for reducing the blood concentration of these factors is apheresis. Furthermore, the removal of pathological autoantibodies in the blood has demonstrated therapeutic effects in diseases such as rheumatoid arthritis (RA) and dilated cardiomyopathy (DCM). Many groups reported that DCM is caused by accumulation of several autoantibodies including cardiac myosin and tropoin-I.1,2) The use of an absorption column in the extracorporeal circulation for the treatment of DCM is currently attracting considerable attention. 3,4) Recently, immunoadsorption therapy for DCM is evaluated in clinical trials, and improvement of the dilated cardiomyopathy was confirmed. 5,6) Protein A conjugated column is also used in the immunoadsorption therapy. 5) However, the patients are required to spend a significant amount of time weekly, the lifetime treatment costs are substantial, and there are associated QOL problems.Therefore, we attempted to develop a less invasive alternative strategy for apheresis and, here, are proposing a novel therapeutic concept called drug-navigated clearance system (DNCS). This strategy involves steering a target etiologic factor in the blood to an unusual metabolic path by the action of a "navigator," resulting in a reduction of the concentration of that factor in the blood. In the present study, we focused on an antibody as a model etiologic factor, while the low-density lipoprotein receptor (LDLR)-mediated LDL salvage pathway of the hepatocytes was selected as the eliminating route on account of its high capacity for LDL removal. 7,8) The LDLR binds not only LDL but also apolipoprotein E (apoE)-containing remnants of chylomicrons and very low-density lipoproteins (VLDLs).9) These receptors mediate cellular uptake and lysosomal hydrolysis.10-12) Therefore, LDLR-mediated uptake represented an attractive pathway for effective removal and hydrolysis of target molecules.The navigator, composed of protein A (ProA) ...

Enhanced β2-microglobulin binding of a “navigator” molecule bearing a single-chain variable fragment antibody for artificial switching of metabolic processing pathways

“…The drug-navigated clearance system (DNCS) is a novel therapeutic concept, in which the levels of an etiologic factor of a metabolic disease are decreased by artificially switching its metabolic processing pathways. 1,2 A "navigator" drug is critical for this switching: these navigator molecules capture the etiologic factor of interest in the blood and steer it toward another metabolic processing pathway. To achieve this, a typical navigator molecule consists of a capturing part and a steering part; for a highly efficient switching, the former needs to bind strongly to the etiologic factor, while the latter should exhibit a high affinity to surface receptors on a designated metabolic organ.…”