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Antibodies recognizing tau

一种抗体、人源化抗体的技术，应用在抗体、非有效成分的医用配制品、抗动物/人类的免疫球蛋白等方向，能够解决干扰微管组装、神经元网络破坏等问题

Active Publication Date: 2019-03-01
PROTHENA BIOSCI LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has also been reported that hyperphosphorylated tau interferes with microtubule assembly, which may promote disruption of neuronal networks

Method used

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  • Antibodies recognizing tau
  • Antibodies recognizing tau
  • Antibodies recognizing tau

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0350] Example 1. Identification of tau monoclonal antibody

[0351] Monoclonal antibody 16G7 was prepared according to a modification of the method of Kohler and Milstein (G. Kohler and C. Milstein (1975) Nature 256:495-497). Human tau containing all four microtubule-binding repeats and lacking the N-terminal splice variant (4RON tau, 383 amino acids) was used in all injection and screening assays. Tau was purified from SF9 cells infected with a tau-containing baculovirus construct (J. Knops et al. (1991) J Cell Biol 115(5):725-33). Six-week-old A / J mice were injected with 100 μg of purified tau at two-week intervals. Tau was emulsified in complete Freund's adjuvant for the first immunization and in incomplete Freund's adjuvant for all subsequent immunizations. Serum samples were taken three days after the third injection to assess titers in these animals. The mouse with the highest titer was injected intravenously with 100 μg tau in 500 μL PBS two weeks after receiving it...

Embodiment 2

[0352] Example 2. Epitope mapping of antibody 16G7

[0353] A series of overlapping biotinylated peptides spanning the entire 383aa 4RON human tau protein was used to map the murine 16G7 antibody. Additional peptides were used to model potential post-translational modifications of the protein's C- and N-termini.

[0354] Biotinylated peptides were bound to individual wells of streptavidin-coated ELISA plates. Plates were blocked and treated with murine 16G7, followed by incubation with horseradish peroxidase-conjugated anti-mouse antibody. After thorough washing, OPD was applied to the plate and allowed to develop. Read the absorbance of the plate at 450 nm. Absorbance values ​​of wells without primary antibody were used for background subtraction and a threshold of 0.2 absorbance units was set for positive binding.

[0355] Positive binding was detected for the peptide spanning amino acid residues 55-69 of SEQ ID NO:3, and minor binding was detected for the peptide spanni...

Embodiment 3

[0356] Example 3. Design of Humanized 16G7 Antibody

[0357] The starting or donor antibody for humanization was mouse antibody 16G7. The heavy chain variable amino acid sequence of mature m16G7 is provided as SEQ ID NO:7. The light chain variable amino acid sequence of mature m16G7 is provided as SEQ ID NO:11. The heavy chain Kabat / Chothia complex CDR1, CDR2 and CDR3 amino acid sequences are provided as SEQ ID NOs: 8-10, respectively. The light chain Kabat CDR1, CDR2 and CDR3 amino acid sequences are provided as SEQ ID NOs 12-14, respectively. Always use Kabat numbers.

[0358] The variable kappa (Vk) of 16G7 belongs to mouse Kabat subgroup 1, which corresponds to human Kabat subgroup 4, and the variable heavy chain (Vh) belongs to mouse Kabat subgroup 2b, which corresponds to human Kabat subgroup 4. 1 Subgroup [Kabat E.A. et al., (1991), Sequences of Proteins of Immunological Interest, Fifth Edition NIH Publication No. 91-3242]. In Vk, the 17-residue Chothia CDR-L1 belo...

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Abstract

The invention provides antibodies that specifically bind tau. The antibodies inhibit or delay tau-associated pathologies and associated symptomatic deterioration.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit under 35 USC 119(e) of US Provisional Application No. 62 / 330,800, filed May 2, 2016, which is incorporated by reference in its entirety for all purposes. [0003] References to Sequence Listings [0004] The Sequence Listing written in file 497448SEQLIST.txt is 59 kilobytes, created on May 2, 2017, and incorporated herein by reference. Background technique [0005] Tau is a well-known human protein that can exist in a phosphorylated form (see, e.g., Goedert, Proc. ; Lee, Neuron 2: 1615-1624 (1989); Goedert, Neuron 3: 519-526 (1989); Andreadis, Biochemistry 31: 10626-10633 (1992). It is reported that Tau plays a role in stabilizing microtubules, especially is in the central nervous system. Total tau (t-tau, i.e. phosphorylated and non-phosphorylated forms) and phosphorylated-tau (p-tau, i.e. phosphorylated tau) are produced by the brain in response to neuronal injury and neurodegenera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/18G01N33/68
CPCC07K16/18A61K2039/505C07K2317/92C07K2317/76C07K2317/34C07K2317/24C07K2317/55C07K2317/567C07K2317/565G01N33/6896A61P25/00A61P25/16A61P25/28A61P43/00A61K47/6843C07K2317/14C07K2317/33C07K2317/52
Inventor R·巴布尔P·J·多兰刘跃
Owner PROTHENA BIOSCI LTD
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