Antibodies recognizing alpha-synuclein

A technology of synuclein and antibody, applied in the direction of antibody, immunoglobulin, antibody medical components, etc., can solve problems such as poisoning nerves

Active Publication Date: 2015-08-05
PROTHENA BIOSCI LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, it has been shown that soluble synuclein oligomers may be neurotoxic (see Conway et al., Proc. Natl. Acad. Sci. USA (2000) 97:571-576; Volles et al., J. Biochemistry (2003) 42:7871–7878)

Method used

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  • Antibodies recognizing alpha-synuclein
  • Antibodies recognizing alpha-synuclein
  • Antibodies recognizing alpha-synuclein

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0237] Example 1: Isolation of mouse 5C1

[0238] The mouse 5C1 antibody was produced in mice injected with a polypeptide conjugate containing the polypeptide immunogen VDPDNEAYEGGC (SEQ ID NO: 14) coupled with a goat anti-mouse antibody. The polypeptide contains residues 118 to 126 of α-synuclein fused to the C-terminal end of the GGC polypeptide, and is coupled to the goat antibody through a maleimide linker that binds to the C-terminal cysteine ​​residue. Mouse antibodies.

Embodiment 2

[0239] Example 2: Passive immunization of α-synuclein antibody

[0240] In order to test the effect of α-synuclein antibodies in Lewy body disease animal models, a variety of α-synuclein antibodies were used to passively immunize mice. Wild-type, α-synuclein knock-out and α-synuclein transgenic (line 61, line 61) female mice aged 3 to 4 months were used. The antibodies tested include:

[0241] 9E4 (IgG1, epitope: amino acids 118-126 of α-synuclein);

[0242] 5C1 (IgG1, immunogen: amino acids 118-126 of α-synuclein, cys-linker);

[0243] 5D12 (IgG2, immunogen: amino acids 118-126 of α-synuclein, n-linker);

[0244] 1H7 (IgG1, epitope: amino acids 91-99 of α-synuclein); and

[0245] 27-1 (IgG1 control antibody).

[0246] The mice received a dose of 10 mg / kg of antibody over a period of 5 months, for a total of 21 injections. In addition, the mouse was injected with a lentiviral vector (LV) expressing human α-synuclein (wt), unilaterally introducing human α-synuclein (wt) into the hippoca...

Embodiment 3

[0252] Example 3: 5C1 variable domain sequencing

[0253] use The mRNA kit is used to extract and purify mRNA from 5C1 hybridoma cells. Then use oligo dT antisense primers and The II kit transcribes purified mRNA into cDNA. By PCR, degenerate VH and VL forward primers and gene-specific (CH / CL) antisense primers were used to amplify the nucleic acid sequences encoding the 5C1 heavy chain and light chain variable regions from cDNA. PCR products designed to include sequences of signal peptide, variable domain and constant region (depending on the antisense primer) are gel purified, cloned into blunt vector or TA vector, and then sequenced. The sequence was deduced from the analysis of at least 3 independent clones with an open reading frame starting from methionine and extending from the variable region to the constant region.

[0254] The nucleic acid sequence encoding the 5C1 heavy chain variable region is shown in SEQ ID NO: 5, and its corresponding protein sequence ( figure ...

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Abstract

The invention provides monoclonal antibody 5C1 and related antibodies. The 5C1 antibody binds to an epitope within residues 118-126 of α-synuclein. The antibodies of the invention are useful, for example, for treating and/or diagnosing disorders associated with α-synuclein, particularly accumulation of α-synuclein deposits. Such disorders include Lewy body diseases, such as Parkinson's disease, Diffuse Lewy Body Disease (DLBD), Lewy body variant of Alzheimer's disease (LBV), Combined Alzheimer's and Parkinson disease, pure autonomic failure and multiple system atrophy (MSA).

Description

[0001] Cross references to related applications [0002] In accordance with the provisions of Article 119 of Title 35 of the United States Code, this application requires U.S. Patent Application No. 61 / 711,204 filed on October 8, 2012 and U.S. Patent Application No. 61 / 719,281 filed on October 26, 2012. , Priority of U.S. Patent Application No. 61 / 840,432 filed on June 27, 2013 and U.S. Patent Application No. 61 / 872,366 filed on August 30, 2013. For all purposes, the above four patent applications The entire content of is incorporated into this application by reference. [0003] Sequence Listing [0004] A sequence listing including SEQ ID NOs: 1-40 is attached herein, and all contents of the sequence listing are incorporated herein by reference. The sequence table is in ASCII format, generated by _______, named _______.txt, with a total of _______ bytes. Background technique [0005] Synucleinopathies, also known as Lewy body diseases (Lewy body diseases, LBDs), are characterized...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395C07K16/18G01N33/53
CPCC07K16/18C07K2317/92C07K2317/24C07K2317/567G01N33/6896A61K2039/505A61K2039/6056C07K2317/565A61K49/0004C07K2317/14C07K2317/34C07K2317/52C07K2317/55C07K2317/56A61P25/00A61P25/14A61P25/16A61P25/20A61P25/28A61K39/00
Inventor 罗宾·巴伯尔凯特 多拉·盖姆斯 蒂尔塔洛陈·S.·尼扎
Owner PROTHENA BIOSCI LTD
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