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Humanized tau antibody

A technology of humanized antibodies and antibodies, applied in chemical instruments and methods, anti-animal/human immunoglobulins, instruments, etc.

Active Publication Date: 2015-04-15
AC IMMUNE SA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although rodent antibodies share a large degree of sequence conservation with human antibodies, there are many sequence differences between rodent and human antibodies that are sufficient to render rodent antibodies immunogenic in humans

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0363] Example 1. Binding of hACI-36-2B6-Ab1 and hACI-36-3A8-Ab1 to T4 peptide detected by ELISA

[0364] 1.1. method

[0365] 1.1.1 Phosphorylated Tau binding assay

[0366] Antibody binding to pTau was tested using an ELISA assay. Nunc MaxiSorp 96-well plates (Nunc, Denmark) were coated with 10 μg / mL of Tau-derived peptides Tau401 to 418 (phosphorylated (T4.5) or unphosphorylated (T4.6) at serine at position 409). Coatings were left overnight at 4°C in phosphate buffered saline (PBS; Sigma-Aldrich, Switzerland). Plates were washed extensively with 0.05% Tween20 / PBS and then blocked with 1% bovine serum albumin (BSA; Sigma-Aldrich) in 0.05% Tween20 / PBS for 1 hour at 37°C. Antibody-containing supernatants to be tested were then added in 8 two-fold dilutions (starting at 0.5 μg / mL) and incubated at 37°C for 2 hours. Plates were then washed as previously described, and alkaline phosphatase (AP)-conjugated goat anti-human IgG (Jackson ImmunoResearch Laboratories, England)...

Embodiment 2

[0369] Example 2. Staining of pTau in the brains of 20-month-old transgenic tauopathic (biGT) mice using hACI-36-2B6-Ab1 and hACI-36-3A8-Ab1 by TAUPIR

[0370] 2.1. method

[0371] 2.1.1 Binding of anti-Tau antibody to Tau tangles on brain slices from Tau transgenic animals (TAUPIR)

[0372] Small tau lesions using aged (>18 months old) bigenic transgenic biGT (GSK-3β transgenic mice crossed with TPLH mice containing the longest isoform (441 aa) of human Tau with the P301L mutation) Rat brain slices. Brain slices were washed in PBS for 5 min and then incubated in 1.5% HO in PBS:MeOH (1:1) at ambient temperature. 2 o 2 Incubate for 15 min to block endogenous peroxidase activity. After sections were washed 3 times in PBST (PBS / 0.1% TritonX100), they were incubated in PBST+10% FCS (fetal calf serum) blocking solution for 30 min at room temperature. Sections were then incubated overnight at 4°C with undiluted supernatant containing the antibody to be tested. Sections wer...

Embodiment 3

[0375] Example 3. Binding Study II: Detection of Antibody Affinity by Biacore / SPR

[0376] 3.1 Method

[0377] 3.1.1 SPR binding assay

[0378] To assess the binding interaction between hACI-36-2B6-Ab1 and peptide T4.5, the antibody hACI-36-2B6-Ab1 was immobilized on the sensor chip, and T4.5 was then injected as an analyte.

[0379] SPR experiments were performed on a Biacore T100 instrument (GE Healthcare). Reagents for immobilization (EDC, NHS and ethanolamine) and sensor chip CM7 (carboxymethyl dextran) were purchased from GE Healthcare. The running buffer was PBS (Dulbecco's PBS, Sigma). To properly orient the antibody for binding to peptide T4.5, the antibody was coupled to the sensor surface via protein G. For this, recombinant protein G (Sigma) was diluted to 50 μg / mL from a stock solution (2 mg / mL) in water with 10 mM sodium acetate, pH 4.0 (GE Healthcare). This protein solution was then coupled to the flow cell (fc)2 of a CM7 sensor chip pre-activated with EDC...

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Abstract

The present invention provides, methods end composites for the therapeutic and diagnostic use in the treatment of diseases and disorders which are caused by or associated with neurofibrillary tangles. In particular,, the Invention relates to humanized antibodies, which specifically recognize and bind to phosphorylated pathological protein tau-conformers to rnethods and compositions involving antibodies for the therapeutic and diagnostic use In the treatment of tauopathies including Alzheimer's Disease (AD).

Description

field of invention [0001] The present invention relates to methods and compositions for therapeutic and diagnostic use in the treatment of diseases and conditions caused by or associated with neurofibrillary tangles. In particular, the present invention relates to a humanized antibody that specifically recognizes and binds to a phosphorylated pathological tau protein-conformer and the use of said antibody in tauopathies, including Alzheimer's disease (AD) Methods and compositions for therapeutic and diagnostic use in therapy. Background of the invention [0002] Neurofibrillary tangles and neuropil threads (NT) are the main neuropathological hallmarks of Alzheimer's disease (AD). It consists of microtubule-associated tau proteins that undergo post-translational modifications on asparaginyl or asparaginyl residues, including phosphorylation, deamidation, and isomerization. It arises from the aggregation of hyperphosphorylated tau protein and its conformers. AD shares this ...

Claims

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Application Information

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IPC IPC(8): C07K16/18
CPCC07K16/18C07K2317/565C07K2317/92C07K2317/24A61P21/02A61P25/00A61P25/16A61P25/28G01N33/6896G01N2800/28G01N2333/4703G01N2800/52
Inventor A·普法伊费尔A·穆斯M·皮尔格伦O·阿道夫松F·V·勒文G·阿亚隆D·M·迪卡拉I·霍策尔
Owner AC IMMUNE SA
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