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Humanized antibody that recognizes α-synuclein

An antibody, human technology, applied in the direction of antibodies, immunoglobulins, anti-animal/human immunoglobulins, etc., can solve problems such as poisoning nerves

Inactive Publication Date: 2018-05-04
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 oligomerization 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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  • Humanized antibody that recognizes α-synuclein
  • Humanized antibody that recognizes α-synuclein
  • Humanized antibody that recognizes α-synuclein

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0180] Example 1. Design of Humanized 1H7 Antibody

[0181] The starting point of the humanized donor antibody is the murine antibody 1H7 produced by the hybridoma with ATCC deposit No. PTA-8220, which is described in US Patent Application No. 11 / 710248 and Publication No. US2009 / 0208487. The complete amino acid and nucleic acid sequences of the heavy chain variable region of m1H7 are shown in SEQ ID NO: 4 and 5, respectively. The complete light chain variable region amino acid and nucleic acid sequences of m1H7 are shown in SEQ ID NO: 6 and 7, respectively. The amino acid and nucleic acid sequences of the heavy chain variable region of mature m1H7 are shown in SEQ ID NO: 8 and 9, respectively. The amino acid and nucleic acid sequences of the light chain variable region of mature m1H7 are shown in SEQ ID NOS: 10 and 11, respectively. The amino acid sequences of heavy chain CDR1, CDR2 and CDR3 are shown in SEQ ID NO: 12, 13 and 14, respectively. The amino acid sequences of...

Embodiment 2

[0224] Example 2. Binding Kinetic Analysis of Murine, Chimeric and Humanized 1H7 Antibodies

[0225] The binding kinetics of humanized 1H7 antibodies comprising a heavy chain selected from Hu1H7VHv1-5 and a light chain selected from Hu1H7VLv1-4 were characterized.

[0226] Antibodies were analyzed using Biacore for full Biacore binding kinetics. For mouse 1H7 (such as Figure 3A shown), chimeric 1H7 (as shown Figure 3B shown) and humanized 1H7 (Hu1H7VHv3-Hu1H7VLv3, Hu1H7VHv3-Hu1H7VLv1, Hu1H7VHv4-Hu1H7VLv1) antibodies (such as Figure 3C The detailed binding kinetic parameters (association rate constant Ka, dissociation rate constant Kd and affinity constant KD) were determined. The binding kinetic parameters of humanized 1H7, especially Hu1H7VHv3-Hu1H7VLv3, were comparable to those of murine 1H7.

[0227] Table 3. Binding Kinetic Parameters of Murine 1H7, Chimeric 1H7 and Humanized 1H7

[0228] (Hu1H7VHv3-Hu1H7VLv3, Hu1H7VHv3-Hu1H7VLv1, Hu1H7VHv4-Hu1H7VLv1)

[0229] ...

Embodiment II

[0240] Example II. Passive immunization of α-synuclein antibodies

[0241]The purpose of this experiment was to determine the effectiveness of α-synuclein antibodies in in vitro and in vivo studies and behavioral assays. We used α-synuclein transgenic (row 61), α-synuclein knockout and wild-type female mice, initially 3-4 months old and n=14 / group. Antibodies detected include 9E4 (IgG1, epitope: amino acids 118-126 of α-synuclein), 5C1 (IgG1, epitope: amino acids 118-126 of α-synuclein , C-linker), 5D12, IgG2 (SN118-126), 1H7, IgG1 (SN91-99) and IgG1 control antibody 27-1. Mice received a dose of 10 mg / kg for a total of 21 injections over a period of 5 months. In addition, animals were injected with a lentiviral vector (LV) expressing human α-synuclein via unilateral introduction of human α-synuclein (wt) to the hippocampus.

[0242] Readout antibodies included those from Chemicon (epitope: full-length α-synuclein), Millipore (epitope: full-length α-synuclein) and Neotope, ...

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Abstract

The present application discloses humanized 1H7 antibodies. The antibody binds to human α-synuclein and can be used for the treatment and diagnosis of Lewy body disease.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application No. 61 / 591,835, filed January 27, 2012, and U.S. Provisional Patent Application No. 61 / 711,207, filed August 8, 2012, for all purposes, above The entire contents of both provisional patent applications are incorporated by reference into this application. Background technique [0003] Synucleinopathies, including Lewy body diseases (LBDs), are characterized by degeneration of the dopaminergic nervous system, altered mobility, cognitive impairment, and Lewy bodies (LBs) and / or Lewy neurites (Lewy bodies). neurites) formation (cf. McKeith et al., Neurology (1996) 47:1113-24). Synucleinopathies include Parkinson's disease (including idiopathic Parkinson's disease), diffuse Lewy body disease (DLBD) also known as dementia with Lewy bodies (DLB), Alzheimer's disease Lewy body variant, Combination of Alzheimer's disease and Parkinson's disease, isolated a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K16/00C12P21/08A61K39/395
CPCA61K2039/505C07K2317/24C07K2317/565C07K2317/567C07K16/18A61P25/00A61P25/16A61P25/28A61P43/00A61K49/0004A61K49/0058A61K49/16A61K51/1018C07K2317/55C07K2317/56C07K2317/64C07K2317/71C07K2317/76C07K2317/92
Inventor 约瑟·萨尔丹哈塔洛陈·S.·尼扎
Owner PROTHENA BIOSCI LTD