A novel immunoadsorption device for removing β2-microglobulin from whole blood

Grovender, Eric A.; Ploegh, Hidde L.; Ting, David T.; Owen, William F.; Rupnick, Maria A.; Langer, Robert

doi:10.1046/j.1523-1755.2001.0590041544.x

Cited by 29 publications

(21 citation statements)

References 30 publications

(2 reference statements)

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“…As an alternative approach, we have developed an anti-human ␤ 2 m scFv for the engineering of a novel immunoadsorbent that could address effi ciency, stability and operating conditions associated with clinical implementation [33] . This immunoadsorbent media could then be used within a novel bioreactor referred to as vortex fl ow plasmapheretic reactor (VFPR) [50] to remove ␤ 2 m from whole blood. The VFPR has been shown to be effective for the enzymatic neutralization of heparin in a sheep animal model [51] .…”

Section: Discussionmentioning

confidence: 99%

“…The value obtained for the ␤ 2 m adsorption site density was approximately 44% higher than what was reported by Vallar et al [22] (they used whole monoclonal antibodies) and approximately 220% higher than that reported by Grovender et al [33] . The ␤ 2 m binding capacity that was obtained is promising and suffi cient to remove clinically relevant amounts of ␤ 2 m assuming the use of 250-350 ml of gel beads, a gel volume that is typical of other systems used in the clinical setting [50] . Nevertheless, other immobilization strategies are currently under investigation to increase the adsorption site density to at least 2 mg ␤ 2 m/ml scFv settled gel.…”

Section: Discussionmentioning

confidence: 99%

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Assessment of the Stability of an Immunoadsorbent for the Extracorporeal Removal of Beta-2-Microglobulin from Blood

2005

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Background: Dialysis-related amyloidosis (DRA) is a devastating and costly condition that affects patients with end stage kidney disease. A key feature of DRA is the formation of amyloid fibrils, consisting primarily of β₂-microglobulin. Except for kidney transplantation, conventional kidney replacement therapies, which are based on nonspecific mechanisms, do not adequately address β₂-microglobulin removal. An antihuman β₂-microglobulin single-chain variable region antibody fragment (scFv) was developed to confer specificity to β₂-microglobulin removal during hemodialysis. Methods: The scFv was immobilized onto agarose and characterized for β₂m binding capacity, thermal stability at 37°C, regeneration capacity, storage conditions, and sterility. Results: The β₂-microglobulin binding capacity was 1.3 mg/ml scFv gel. The immunoadsorbent is thermally stable, can be regenerated, stored short-term in 20% ethanol, lyophilized for long-term storage, and withstand process conditions similar to that of a patient’s hemodialysis therapy. Conclusions: The results support further investigation of immobilized scFvs as a novel tool to remove β₂-microglobulin from blood.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Assessment of the Stability of an Immunoadsorbent for the Extracorporeal Removal of Beta-2-Microglobulin from Blood

2005

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“…It has equivalent affinity to both free-form and HLA-I associated b2m and binds only to cells of humans, chimpanzees, and gorillas (Brodsky and Parham, 1982a;Brodsky and Parham, 1982b). Biochemical and cell biological data have shown that BBM.1 and its derived single chain antibodies can effectively eliminate b2m from blood and have promising therapeutic benefits (Ameer et al, 2001;Grovender et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Structural modeling and biochemical studies reveal insights into the molecular basis of the recognition of β‐2‐microglobulin by antibody BBM.1

Peng

et al. 2009

J of Molecular Recognition

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Human beta-2-microglobulin (beta2m) is the light chain of human leucocyte antigen-I (HLA-I). It can disassociate from HLA-I and accumulate to cause serious dialysis-related amyloidosis (DRA) in long-term hemodialysis patients. Monoclonal antibody (mAb) BBM.1 can recognize both free-form and HLA-I associated beta2m. It can be used for specific elimination of beta2m from serum and can induce apoptosis of several types of tumor cells, and thus has great therapeutic potential. In this study, we constructed structural models of the BBM.1 Fv (fragment of the variable domain) and the BBM.1 Fv-beta2m complex, followed by biochemical evaluation. Analysis of the optimal complex model reveals that the previously identified immunodominant residues Glu(44) and Arg(45) of beta2m have direct interactions with BBM.1, while Asp(38) exerts its function mainly via stabilization of Arg(45). In addition, Arg(81) of beta2m is a newly identified immunodominant residue to have direct interaction with BBM.1. Further modeling study shows no steric conflict between the antibody and the HLA-I heavy chain. These results provide insights into the molecular basis of the recognition of beta2m by BBM.1 and explain why BBM.1 can bind both free-form and HLA-1 associated beta2m. This information could be exploited in the engineering and improvement of BBM.1 and the development of other beta2m-targeting mAbs for therapeutic purposes.

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“…Also, the application of immunoadsorption principles to the treatment of DRA has attracted many research interests during the past decades, and a variety of techniques and ingenuity have been combined with the inherent unique advantages of immunoadsorption to create useful, promising materials and modalities for the removal of β‐2M. For example, remarkable advances include production of monoclonal antibodies specific to β‐2M (18), regenerated cellulose‐based hemodialyzers with immobilized proteins (19), and an immunoaffinity‐based extracorporeal vortex flow plasmapheretic reactor (20). These achievements suggest the future potentials of reducing abnormally high levels of β‐2M in uremic blood by immunoadsorption.…”

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confidence: 99%

In Vitro Removal of Beta‐2‐Microglobulin From Uremic Blood With an Immunoadsorption Wall

Yang

Lin

et al. 2011

Artificial Organs

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Dialysis-related amyloidosis (DRA), caused by the accumulation of beta-2-microglobulin (β-2M), remains a major concern in long-term renal replacement therapies. For years, we have developed an immunoadsorption wall (iWall) for the removal of β-2M. In this study, we employed a new approach taking advantage of the melting of a buffer ice rod to improve the conditions associated with the manufacturing of an iWall and tested its performance with uremic serum and blood. The preliminary results reveal that the present iWalls thus prepared not only possess the superior properties of affinity and specificity but also show structural stability and acceptable hemocompatibility. We believe that this breakthrough might provide a promising path to successful treatment of DRA as well as establish a useful platform for studying removal of certain pathological toxins accumulated in the blood.

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A novel immunoadsorption device for removing β2-microglobulin from whole blood

Abstract: The adsorptive kinetics of the VFPR are optimal for the conditions used and support the use of immunoadsorption for the removal of beta2m.

Cited by 29 publications

References 30 publications

Assessment of the Stability of an Immunoadsorbent for the Extracorporeal Removal of Beta-2-Microglobulin from Blood

Assessment of the Stability of an Immunoadsorbent for the Extracorporeal Removal of Beta-2-Microglobulin from Blood

Structural modeling and biochemical studies reveal insights into the molecular basis of the recognition of β‐2‐microglobulin by antibody BBM.1

In Vitro Removal of Beta‐2‐Microglobulin From Uremic Blood With an Immunoadsorption Wall

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