Novel Antibody for the Treatment of Transthyretin Amyloidosis

Familial amyloidotic polyneuropathy (FAP) is a systemic amyloidosis mainly caused by amyloidogenic transthyretin (ATTR). This incurable disease causes death ∼10 years after onset. Although it has been widely accepted that conformational change of the monomeric form of transthyretin (TTR) is very imp...

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Published inThe Journal of biological chemistry Vol. 291; no. 48; pp. 25096 - 25105
Main Authors Hosoi, Akihiko, Su, Yu, Torikai, Masaharu, Jono, Hirofumi, Ishikawa, Daisuke, Soejima, Kenji, Higuchi, Hirofumi, Guo, Jianying, Ueda, Mitsuharu, Suenaga, Genki, Motokawa, Hiroaki, Ikeda, Tokunori, Senju, Satoru, Nakashima, Toshihiro, Ando, Yukio
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 25.11.2016
American Society for Biochemistry and Molecular Biology
Subjects
amyloid
Amyloid Neuropathies, Familial - drug therapy
Amyloid Neuropathies, Familial - immunology
Amyloid Neuropathies, Familial - pathology
Animals
Antibodies, Monoclonal, Murine-Derived - immunology
Antibodies, Monoclonal, Murine-Derived - therapeutic use
antibody
antibody engineering
drug design
FAP
Female
fibril
Humans
Macrophages - immunology
Macrophages - pathology
Male
Mice
Neurobiology
Phagocytosis - drug effects
Prealbumin - immunology
Rats
transthyretin
antibody engineering
fibril
amyloid
antibody
FAP
drug design
transthyretin
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Summary:Familial amyloidotic polyneuropathy (FAP) is a systemic amyloidosis mainly caused by amyloidogenic transthyretin (ATTR). This incurable disease causes death ∼10 years after onset. Although it has been widely accepted that conformational change of the monomeric form of transthyretin (TTR) is very important for amyloid formation and deposition in the organs, no effective therapy targeting this step is available. In this study, we generated a mouse monoclonal antibody, T24, that recognized the cryptic epitope of conformationally changed TTR. T24 inhibited TTR accumulation in FAP model rats, which expressed human ATTR V30M in various tissues and exhibited non-fibrillar deposits of ATTR in the gastrointestinal tracts. Additionally, humanized T24 (RT24) inhibited TTR fibrillation and promoted macrophage phagocytosis of aggregated TTR. This antibody did not recognize normal serum TTR functioning properly in the blood. These results demonstrate that RT24 would be an effective novel therapeutic antibody for FAP.
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Edited by Paul Fraser
Both authors contributed equally to this work.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M116.738138