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Anti-abeta antibodies and uses thereof

A technology of antibody and β protein, applied in the direction of antibody, anti-animal/human immunoglobulin, immunoglobulin, etc., can solve the problem of lack of effective treatment for AD

Pending Publication Date: 2021-04-02
NAT INST OF HEALTH REPRESENTED BY THE SEC OF THE DEPT OF HEALTH & HUMAN SERVICES NAT INST OF HEALTH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is currently no method for early diagnosis of AD in the preclinical stage, and there is also a lack of effective treatment for AD

Method used

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  • Anti-abeta antibodies and uses thereof
  • Anti-abeta antibodies and uses thereof
  • Anti-abeta antibodies and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1: Generation of seven antibody clones against Aβ from fusion tumors.

[0041] To generate fusionomas, mice were immunized with oligomeric Aβ (oAβ). synthesized Aβ 1–42 Dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and evaporated. Dried membranes were redissolved in 1XPBS, followed by centrifugation to remove fibrillar and aggregated A[beta]. The prepared oAβ was characterized by western blotting using a commercially available Aβ antibody 6E10. The results showed that the prepared oAβ oligomer constituted a mixture of Aβ, including monomer, dimer and oAβ in various structural orders, with a molecular weight range of 37-250kDa. The prepared oAβ oligomers were stored at -80°C until submitted to LTK Biolaboratories for immunization to generate single fusion tumors. By ELISA ( figure 1 A) Antibodies were analyzed for Aβ binding affinity by immunohistochemistry (data not shown). Create an epitope map of your antibody. please see figure 1 b. Seven dif...

Embodiment 2

[0042] Example 2: Production of Chimeric Antibodies

[0043] The mouse IgG variable regions were inserted into the human IgG1 backbone to generate chimeric antibodies. The Aβ-binding affinities of the seven chimeric antibodies were evaluated by surface plasmon resonance (SPR) with Biacore. please see figure 2 a. In vitro experiments were performed to test the effect of the antibody on enhancing the phagocytosis of Aβ by microglia. The data indicated that all antibodies enhanced Aβ uptake by microglia, with the lead antibody appearing to perform best in the assay. please see figure 2 b.

Embodiment 3

[0044] Example 3: Humanization of mAβ-10

[0045] A humanized version of the lead antibody (hzAβ-10) was constructed from a chimeric antibody using a human IgG1 framework. Analysis of protein solubility using fast protein liquid chromatography (FPLC) ( image 3 A), and by performing immunofluorescence histochemistry on APP / PS1 mouse brain sections (data not shown), ELISA ( image 3 B) and SPR ( image 3 C) Detection of A binding features. The data show that hzAβ-10 exhibits the special properties of excellent Aβ binding affinity and extremely high protein solubility, which is suitable for cell line development.

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Abstract

An isolated antibody structurally comprises a light chain CDR1, a light chain CDR2, a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3, and the antibody has specific binding capacity to A beta 142 or N-terminal modified A beta 142. The antibody can be used for treating AD and early detecting the content of brain A beta. N-terminal modified pyroglutamic acid A [beta] (pE-A[beta] 3-42) isvery easy to aggregate and may be very important for A [beta] plaque formation.

Description

technical field [0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 678,080, filed May 30, 2018, which is incorporated herein by reference in its entirety. Background technique [0002] Alzheimer's disease (AD) is clinically characterized by progressive memory loss and cognitive impairment. One of its pathological features is the deposition of extracellular senile amyloid plaques mainly composed of Aβ. See Nat Rev Neurol. 2017, 13(10):612-623 by Wang et al. Most cases of AD are sporadic, and the etiology of AD remains poorly understood because of the diversity of disease origins. The drugs currently used clinically can only temporarily relieve the symptoms and do not cure the disease. [0003] In AD, Aβ deposition in the brain promotes the activation of glial cells and tends to pro-inflammatory mode, and the continuous accumulation of Aβ exacerbates the ensuing neuroinflammation and increases the hyperphosphorylation of Tau protein, which...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P25/28C07K16/18C07K16/46
CPCA61P25/28C07K16/18C07K2317/565C07K2317/76C07K2317/92A61K2039/505C07K2317/24C07K2317/34G01N33/6896G01N2333/4709G01N33/58G01N33/60
Inventor 谢奉勋徐祖安石全沈三泰
Owner NAT INST OF HEALTH REPRESENTED BY THE SEC OF THE DEPT OF HEALTH & HUMAN SERVICES NAT INST OF HEALTH
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