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Proc Natl Acad Sci U S A. 2018 Nov 13;115(46):E10839-E10848. doi: 10.1073/pnas.1805515115. Epub 2018 Oct 30.

Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy.

Author information

1
Department of Medicine, University of Tennessee Medical Center, Knoxville, TN 37920; jwall@utmck.edu.
2
Department of Radiology, University of Tennessee Medical Center, Knoxville, TN 37920.
3
Department of Medicine, University of Tennessee Medical Center, Knoxville, TN 37920.
4
Department of Chemistry, University of Tennessee, Knoxville, TN 37916.
5
Biological Small Molecule Mass Spectrometry Core, University of Tennessee, Knoxville, TN 37916.
6
Department of Surgery, University of Tennessee Medical Center, Knoxville, TN 37920.

Abstract

Amyloidosis is a malignant pathology associated with the formation of proteinaceous amyloid fibrils that deposit in organs and tissues, leading to dysfunction and severe morbidity. More than 25 proteins have been identified as components of amyloid, but the most common form of systemic amyloidosis is associated with the deposition of amyloid composed of Ig light chains (AL). Clinical management of amyloidosis focuses on reducing synthesis of the amyloid precursor protein. However, recently, passive immunotherapy using amyloid fibril-reactive antibodies, such as 11-1F4, to remove amyloid from organs has been shown to be effective at restoring organ function in patients with AL amyloidosis. However, 11-1F4 does not bind amyloid in all AL patients, as evidenced by PET/CT imaging, nor does it efficiently bind the many other forms of amyloid. To enhance the reactivity and expand the utility of the 11-1F4 mAb as an amyloid immunotherapeutic, we have developed a pretargeting "peptope" comprising a multiamyloid-reactive peptide, p5+14, fused to a high-affinity peptide epitope recognized by 11-1F4. The peptope, known as p66, bound the 11-1F4 mAb in vitro with subnanomolar efficiency, exhibited multiamyloid reactivity in vitro and, using tissue biodistribution and SPECT imaging, colocalized with amyloid deposits in a mouse model of systemic serum amyloid A amyloidosis. Pretreatment with the peptope induced 11-1F4 mAb accumulation in serum amyloid A deposits in vivo and enhanced 11-1F4-mediated dissolution of a human AL amyloid extract implanted in mice.

KEYWORDS:

11-1F4; amyloidosis; immunotherapy; p5+14 peptide; peptope

PMID:
30377267
PMCID:
PMC6243252
[Available on 2019-05-13]
DOI:
10.1073/pnas.1805515115
[Indexed for MEDLINE]

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