Top > Search of International Patents > ANTIBODY FRAGMENT DEGRADING AND REMOVING ABNORMAL TDP-43

ANTIBODY FRAGMENT DEGRADING AND REMOVING ABNORMAL TDP-43 NEW_EN

Foreign code F190009978
File No. (S2018-0474-N0)
Posted date Oct 28, 2019
Country WIPO
International application number 2019JP010771
International publication number WO 2019177138
Date of international filing Mar 15, 2019
Date of international publication Sep 19, 2019
Priority data
  • P2018-049752 (Mar 16, 2018) JP
Title ANTIBODY FRAGMENT DEGRADING AND REMOVING ABNORMAL TDP-43 NEW_EN
Abstract Disclosed is a modified antibody fragment consisting of an antibody fragment capable of binding to misfolded TDP-43 and a chaperone-mediated autophagy transit signal peptide, wherein: the antibody fragment includes a heavy-chain variable region that comprises heavy chain CDR1 comprising the amino acid sequence GFNIKDYY (SEQ ID NO: 1), heavy chain CDR2 comprising the amino acid sequence IDPEDGET (SEQ ID NO: 2) and heavy chain CDR3 comprising the amino acid sequence TIIYYYGSRYVDY (SEQ ID NO: 3), each sequence optionally having not more than 3 amino acid substitutions, and/or a light-chain variable region that comprises light chain CDR1 comprising the amino acid sequence SSISSSY(SEQ ID NO: 4), light chain CDR2 comprising the amino acid sequence RTS and light chain CDR3 comprising the amino acid sequence QQGSSIPLT (SEQ ID NO: 5), each sequence optionally having not more than 3 amino acid substitutions; and the antibody fragment is scFv, VH or VL.
Outline of related art and contending technology BACKGROUND ART
Is the most refractory nerve injuries Amyotrophic Lateral Sclerosis (ALS) amyotrophic lateral sclerosis and dementia has a prevalence of 2 in the second fronto-temporal dementia (FTD) is a nuclear protein protein TDP-43 (TAR DNA-binding protein of 43kDa) causes have been identified. FTD is in ALS and TDP-43 escape from the nucleus, the cytoplasm is the mechanism to form an aggregation condition is unknown.
TDP-43 is, in the ALS FTD and ubiquitination is observed a very high in the enclosure is known. Current, exhibits an abnormal pathology findings TDP-43 is a disease, a disease group and referred to as TDP-43 positioned puroteinopachi, the functions of the various reports from the abnormal condition of the TDP-43 ALS be increasingly essential.
In this way the physiological and pathological TDP-43 to elucidate the function of the ALS could lead to overcome, such as the world has been studied energetically. Of the TDP-43 puroteinopachi pathological findings are important and most clearly, and a decrease in the nuclear staining of the TDP-43 body formation in the cytoplasm. To elucidate the function of the localization of the ectopic the ALS disease is essential for the understanding of the present invention.
TDP-43 may have a molecular structure, RNA-binding region (RRM) 2 and one end of the region C and glycine-rich, nuclear localization signal (NLS), and nuclear export signal (NES) has. TDP-43 into somatic cells of all constant and expressed, mainly localized to the nucleus. In the ALS and FTD in normal tissues from the nuclear localization without exception, ectopic TDP-43 influence on the localization conditions have been noted. TDP-43 positive cell enclosure, a high frequency which have been fragmented and contains a TDP-43.
Also, in addition to the ALS and FTD TDP-43 as ectopic exhibits localized disease, syndrome Perry, low-grade glioma, Alzheimer's disease, Huntington's disease, Pick's disease, Parkinson's disease, Lewy body disease, corticobasal degeneration, inclusion body myositis, B-cell lymphoma (M phase) and the like have been reported.
The inventors of the present invention, (1) which is independent of the TDP-43 disease pathogenesis of toxic normal structure is how to structure the transformation structure, and (2) how abnormal structures from the viewpoint that the capture has been studied. As a result, the cysteine residues of the TDP-43 RRM1 is important to maintain a normal structure, the modification of the abnormality found in the brain of the ALS and FTD abnormal aggregates can reproduce in vitro (Patent Document 1) are demonstrated. In addition, such abnormal aggregation and abnormally to the localized exposed to the outside in the TDP-43 molecules to identify the sequence, the sequence in the target, accumulate the aggregate of the TDP-43 risk of the onset of the disease can be predicted and reported (Patent Document 2).
In addition, in Patent Document 3 and 4, the detection antibody TDP-43 is reported, the antibody recognizes the aggregate of these, an advanced stage in a state in which a structural change of the earlier as a therapeutic target is obtained.
Scope of claims (In Japanese)[請求項1]
 ミスフォールドしたTDP-43に結合性を有する抗体断片と、シャペロン介在性オートファジー移行シグナルペプチドとから構成される修飾抗体断片であって、
 該抗体断片が、3以下のアミノ酸置換をしてもよい、GFNIKDYY (配列番号1)のアミノ酸配列からなる重鎖CDR1、IDPEDGET (配列番号2)のアミノ酸配列からなる重鎖CDR2、及びTIIYYYGSRYVDY (配列番号3)のアミノ酸配列からなる重鎖CDR3を含む重鎖可変領域、並びに/又は
 3以下のアミノ酸置換をしてもよい、SSISSSY (配列番号4)のアミノ酸配列からなる軽鎖CDR1、RTSのアミノ酸配列からなる軽鎖CDR2、及びQQGSSIPLT (配列番号5)のアミノ酸配列からなる軽鎖CDR3を含む軽鎖可変領域を含み、
 該抗体断片が、scFv、VH又はVLである、
修飾抗体断片。

[請求項2]
 前記抗体断片がscFvである、請求項1に記載の修飾抗体断片。

[請求項3]
 前記抗体断片がヒト化抗体断片である、請求項1又は2に記載の修飾抗体断片。

[請求項4]
 請求項1~3のいずれか一項に記載の修飾抗体断片をコードする核酸。

[請求項5]
 請求項4に記載の核酸を含む発現ベクター。

[請求項6]
 請求項4に記載の核酸を含む遺伝子治療剤。

[請求項7]
 TDP-43の凝集体が蓄積する疾患の治療用である、請求項6に記載の治療剤。

[請求項8]
 前記TDP-43の凝集体が蓄積する疾患が筋萎縮性側索硬化症、前頭側頭型認知症、又はPerry症候群である、請求項7に記載の治療剤。

[請求項9]
 熱ショックタンパク質を誘導させるために用いられる、請求項6に記載の治療剤。

[請求項10]
 前記熱ショックタンパク質がHsp70である、請求項9に記載の治療剤。

[請求項11]
 請求項4に記載の核酸の有効量を哺乳動物に投与する工程を含む、TDP-43の凝集体が蓄積する疾患の治療方法。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • SHIGA UNIVERSITY OF MEDICAL SCIENCE
  • Inventor
  • URUSHITANI, Makoto
  • TAMAKI, Yoshitaka
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DJ DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JO JP KE KG KH KN KP KR KW KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG

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