A system to remove b2-microglobulin from blood

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DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop a blood detoxification system that is specific for b2-microglobulin (b2m), an amyloidgenic protein that has been implicated in dialysis-related amyloidosis (DRA). DRA is an incapacitating, potentially fatal, and unavoidable consequence of long-term renal failure and the inability of current medical technology to replace all aspects of kidney function. The lack of b2m-clearance by the kidneys results in elevated plasma concentrations of this protein, followed by b2m-amyloid deposition in tissues via mechanisms that are not fully understood. Although several attempts have been made to reduce b2m plasma concentrations, the incidence and complications of this disease remain a significant problem. It is proposed to investigate an extracorporeal, immunoadsorptive approach that uses immobilized recombinant single-chain antibody fragments to remove b2m. Single-chain variable region antibody fragments (scFv) against human b2m will be produced using molecular biology and fermentation techniques, characterized and immobilized onto a porous support for use in a novel adsorber design. The efficacy of the adsorber will be tested in blood in vitro and its biocompatibility will be tested ex vivo in sheep. The results of the proposed research could potentially lead to the following: 1) use of a recombinant antibody fragment immunoadsorber as a therapy to slow the progression of DRA while avoiding the indiscriminate loss of needed proteins and 2) use of specifically designed immunoadsorbers as tool to help elucidate the role of suspected middle molecular weight soluble factors in the morbidity of end stage renal disease. Achieving proof of principle using DRA as a model disease would support the tailored application of this technology for the removal of target molecules that cause other pathologic states.