Antibody-Mediated Resolution of Light Chain-Associated Amyloid Deposits

Hrncic, Rudi; Wall, Jonathan S.; Wolfenbarger, D; Murphy, Charles L.; Schell, Maria; Weiss, Deborah; Solomon, Alan

doi:10.1016/s0002-9440(10)64639-1

Cited by 183 publications

(139 citation statements)

References 39 publications

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“…These antibodies do not, however, bind to the soluble precursors of these fibrils, nor do they bind to other forms of protein aggregates such as bovine collagen, elastin or gelatin. In addition, a monoclonal antibody raised against amyloid proteins extracted from spleens and livers of patients with immunoglobulin light chain-associated amyloidosis, has been reported to recognise ex vivo amyloid fibrils composed of the light chain variable domain, Ab, and other amyloidogenic proteins [71].…”

Section: Probes Of Structural Features Of Mature Fibrilsmentioning

confidence: 99%

“…If a similar phenomenon is observed in humans, such an antibody may be useful for quantifying brain amyloid burden in patients who have been diagnosed with Alzheimer's disease, or even known to be at risk of developing it. Finally, antibodies that bind to the generic epitope(s) of oligomeric aggregates or fibrils such as those described above [61,70,71], may prove to be reagents able to diagnose the whole family of amyloid diseases.…”

Section: Diagnostic Reagentsmentioning

confidence: 99%

“…Recent studies report the success of both active and passive vaccination approaches to slowing and/or reversing the aggregation process, and its pathological consequences, in mouse models of light chain amyloidosis [71], Alzheimer's disease [77,79,80,[86][87][88][89][90] and mammalian prion diseases [76,[91][92][93]. The molecular mechanisms by which antibodies act in a therapeutic manner are just beginning to be understood (for recent reviews see [94][95][96][97][98][99]) (Textbox 3).…”

Section: Therapeutic Reagentsmentioning

confidence: 99%

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Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Dumoulin

Dobson

2004

Biochimie

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The deposition of proteins in the form of amyloid fibrils is the characteristic feature of more than 20 medical conditions affecting the central nervous system or a variety of peripheral tissues. These disorders, which include Alzheimer's disease, the prion diseases and type II diabetes, are of enormous importance in the context of present-day human health and welfare. Extensive research is therefore being carried out to define the molecular details of the mechanism of the pathological conversion of amyloidogenic proteins from their soluble forms into fibrillar structures. This review focuses on recent studies that demonstrate the power of using antibodies or antibody fragments to probe the process of fibril formation, and discusses the emerging potential of these species as diagnostic and therapeutic agents.

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Section: Probes Of Structural Features Of Mature Fibrilsmentioning

confidence: 99%

Section: Diagnostic Reagentsmentioning

confidence: 99%

Section: Therapeutic Reagentsmentioning

confidence: 99%

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Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Dumoulin

Dobson

2004

Biochimie

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“…In this regard, we had previously reported that the IgG1 mAb 11-1F4, generated by immunizing mice with a thermally denatured variable region fragment of the human Igκ4 Bence Jones protein Len, reacted specifically with light chain (LC) fibrils, irrespective of κ or λ isotype but, notably, did not with native molecules (Hrncic, R. et al (2000) Am. J. Pathol.…”

mentioning

confidence: 99%

Localization of a Conformational Epitope Common to Non-Native and Fibrillar Immunoglobulin Light Chains

et al. 2007

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Amyloid fibrils and partially unfolded intermediates may be distinguished serologically from native amyloidogenic precursor proteins or peptides. In this regard, we had previously reported that the IgG1 mAb 11-1F4, generated by immunizing mice with a thermally denatured variable region fragment of the human Igκ4 Bence Jones protein Len, reacted specifically with light chain (LC) fibrils, irrespective of κ or λ isotype but, notably, did not with native molecules (Hrncic, R. et al. (2000) Am. J. Pathol. 157, 1239Pathol. 157, -1246. To elucidate the molecular basis of this specificity, we have used a europium-linked fluorescent immunoassay, where it was demonstrated through epitope mapping that mAb 11-1F4 recognizes a conformational determinant contained within the first (Nterminal) 18 amino acids of misfolded LCs. The nature of this epitope was evidenced in competition studies where the peptide Len (1-18), but not the intact protein or other LCs, inhibited the binding of the antibody to fibrils. This unique reactivity was dependent on the structural integrity of this portion of the molecule, particularly the presence of a highly conserved prolyl residue at position 8. On the basis of our experimental data, we posit that the mAb 11-1F4 binding site found on partially denatured and fibrillar LCs involves an inducible N-terminal main chain reversal that results in the formation of a proline anchored β-turn. Our delineation of this LC fibril-associated epitope provides the rationale for the design of novel amyloid-reactive antibodies with diagnostic and therapeutic potential for patients with LC-associated and other forms of amyloidosis. Amyloidogenesis involves a process by which normally soluble proteins or peptides form nonnative intermediates that eventually assemble into fibrils (1). All types of amyloid, regardless of amino acid sequence, share common tertiary structural features, that is, they are comprised of extended β-sheets oriented perpendicularly to the long fibril axis (2,3) and possess sites that bind the dyes thioflavin T (ThT1) and Congo red (4,5). Additionally, these components and their assembly precursors, irrespective of primary structure, contain generic conformational epitopes not present on native molecules (6-12), further indicating their physical homogeneity.The common epitopes present on amyloid fibrils and their intermediates offer targets for the design of novel diagnostic and therapeutic reagents. In this regard, we have generated a murine monoclonal antibody (mAb), designated 11-1F4 (13), which reacts specifically with light chain (LC) fibrils, but not soluble proteins, and has been shown in an experimental in vivo model to accelerate the removal of amyloidomas composed of human LC fibrils, an effect independent of the κ or λ isotype or the V L subgroup (9). This mAb was generated using as immunogen a heat-aggregated suspension of the human κ4 variable domain (V L ) Len (13,14) To localize and determine the nature of the neo-antigen recognized on conformationally altered LCs by...

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“…The process then can be accelerated by passive administration of an apparently conformation specific antibody. 93,94 In contrast to the systemic amyloidoses, it has been well recognized that glial activation is common, if not universal, in the neighborhood of Ab plaques in the Alzheimers Disease brain. 95 It has been experimentally shown that Ab fibrils can activate glia and this may be mediated by the nuclear factor kappa B pathway triggered via RAGE or CD36.…”

Section: Interfaces Between the Amyloidoses And The Immune Systemmentioning

confidence: 99%

The genetics of the amyloidoses: interactions with immunity and inflammation

Buxbaum

2006

Genes Immun

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Historically, the amyloidoses have been associated with inflammation and the immune response. From Virchow's original description in human pathologic inflammatory states through their identification in horses used to produce antitoxin to their frequent occurrence in the course of multiple myeloma and a somewhat abortive designation as 'gammaloid', the disorders were felt to have an inflammatory origin. These presumptive associations antedated the availability of a reliable method for tissue extraction that would allow chemical analysis of the major deposited molecules. With the identification of the multiple precursors and the realization that most were not intrinsic elements of immune/inflammatory pathways, the investigative emphasis shifted to the analysis of the biophysical events involved in aggregation and fibril formation. As more in vivo models and better tools for examination of tissues have become available, it appears as if inflammation may participate as both a response to, and an amplifier of, the effects of the fibrillar aggregates. Hence, while only a limited number of amyloid protein precursors are involved in immunity and inflammation per se, host defense, in its broadest sense, is likely to be involved in the clinically relevant amyloidoses. Further it now appears that harnessing the immune respone in an appropriate fashion may be able to play a role in treatment.

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Antibody-Mediated Resolution of Light Chain-Associated Amyloid Deposits

Cited by 183 publications

References 39 publications

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Localization of a Conformational Epitope Common to Non-Native and Fibrillar Immunoglobulin Light Chains

The genetics of the amyloidoses: interactions with immunity and inflammation

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