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Humanized antibodies that recognize beta amyloid peptide

Inactive Publication Date: 2008-02-28
WYETH LLC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010] The present invention features new immunological reagents, in particular, therapeutic antibody reagents for the prevention and treatment of amyloidogenic disease (e.g., Alzheimer's disease). The invention is based, at least in part, on the identification and characterization of two monoclonal antibodies that specifically bind to Aβ peptide and are effective at reducing plaque burden and / or reducing the neuritic dystrophy associated with amyloidogenic disorders. Structural and functional analysis of these antibodies leads to the design of various humanized antibodies for prophylactic and / or therapeutic use. In particular, the invention features humanization of the variable regions of these antibodies and, accordingly provides for humanized immunoglobulin or antibody chains, intact humanized immunoglobulins or antibodies, and functional immunoglobulin or antibody fragments, in particular, antigen binding fragments, of the featured antibodies.

Problems solved by technology

Accumulation of amyloid plaques in the brain eventually leads to neuronal cell death.
Because EP 526,511's proposed dosage would barely alter the level of endogenous circulating Aβ and because EP 526,511 does not recommend use of an adjuvant, as an immunostimulant, it seems implausible that any therapeutic benefit would result.

Method used

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  • Humanized antibodies that recognize beta amyloid peptide
  • Humanized antibodies that recognize beta amyloid peptide
  • Humanized antibodies that recognize beta amyloid peptide

Examples

Experimental program
Comparison scheme
Effect test

example i

Therapeutic Efficacy of Anti-Aβ Antibodies

mAb 2H3, mAb 10D5, mAb 266, mAb 21F12 and pAb Aβ1-42

[0255] This example tests the capacity of various monoclonal and polyclonal antibodies to Aβ to inhibit accumulation of Aβ in the brain of heterozygotic transgenic mice.

[0256] A. Study Design

[0257] Sixty male and female, heterozygous PDAPP transgenic mice, 8.5 to 10.5 months of age were obtained from Charles River Laboratory. The mice were sorted into six groups to be treated with various antibodies directed to Aβ. Animals were distributed to match the gender, age, parentage and source of the animals within the groups as closely as possible. Table 2 depicts the Experimental design.

TABLE 2Experimental DesignTreatmentTreatmentAntibodyAntibodyGroupNaAntibodySpecificityIsotype19noneNAbNA(PBS alone)210PolyclonalAβ1-42mixed30mAbd 2H3Aβ1-12IgG148mAb 10D5Aβ3-7IgG156mAb 266Aβ13-28IgG168mAb 21F12Aβ33-42IgG2a

aNumber of mice in group at termination of the experiment. All groups started with 10 an...

example ii

Therapeutic Efficacy of Anti-Aβ Antibodies

mAb 2H3, mAb 10D5, mAb 266, mAb 21F12, mAb 3D6, mAb 16C11 and pAb Aβ1-42

[0279] In a second study, treatment with 10D5 was repeated and two additional anti-Aβ antibodies were tested, monoclonals 3D6 (Aβ1-5) and 16C11 (Aβ33-42). Control groups received either PBS or an irrelevant isotype-matched antibody (TM2a). The mice were older (11.5-12 month old heterozygotes) than in the previous study, otherwise the experimental design was the same. Once again, after six months of treatment, 10D5 reduced plaque burden by greater than 80% relative to either the PBS or isotype-matched antibody controls (p=0.003). One of the other antibodies against Aβ, 3D6, was equally effective, producing an 86% reduction (p=0.003). In contrast, the third antibody against the peptide, 16C11, failed to have any effect on plaque burden. Similar findings were obtained with Aβ42 ELISA measurements.

[0280] These results demonstrate that an antibody response against Aβ pepti...

example iii

Monitoring of Antibody Binding in the CNS

[0281] This Example demonstrates that when held at modest serum concentrations (25-70 μg / ml), the antibodies gained access to the CNS at levels sufficient to decorate β-amyloid plaques.

[0282] To determine whether antibodies against Aβ could be acting directly within the CNS, brains taken from saline-perfused mice at the end of the Example II, were examined for the presence of the peripherally-administered antibodies. Unfixed cryostat brain sections were exposed to a fluorescent reagent against mouse immunoglobulin (goat anti-mouse IgG-Cy3). Plaques within brains of the 10D5 and 3D6 groups were strongly decorated with antibody, while there was no staining in the 16C11 group. To reveal the full extent of plaque deposition, serial sections of each brain were first immunoreacted with an anti-Aβ antibody, and then with the secondary reagent. 10D5 and 3D6, following peripheral administration, gained access to most plaques within the CNS. The plaq...

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Abstract

The invention provides improved agents and methods for treatment of diseases associated with amyloid deposits of Aβ in the brain of a patient. Preferred agents include humanized antibodies.

Description

RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10 / 703,713, filed on Nov. 7, 2003. This application is also a continuation of U.S. application Ser. No. 11 / 413,638, filed on Apr. 28, 2006, which is a continuation of U.S. application Ser. No. 10 / 388,389, filed Mar. 12, 2003, which is a continuation-in-part of U.S. application Ser. No. 10 / 010,942, filed Dec. 6, 2001, U.S. Publication No. 20030165496 A1, which is a an application claiming the benefit under 35 U.S.C. 119(e) of U.S. Application No. 60 / 251,892, filed Dec. 6, 2000. [0002] This application is also a continuation-in-part of U.S. application Ser. No. 10 / 232,030, filed on Aug. 30, 2002, which is a continuation of U.S. application Ser. No. 10 / 010,942, filed on Dec. 6, 2001, which claims the benefit under 35 U.S.C. 119(e) of U.S. Application No. 60 / 251,892, filed Dec. 6, 2000. [0003] This application is also a continuation-in-part of U.S. application Ser. No. 11 / 058,757, filed Feb. 14, ...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P25/00A61P25/28C07K16/18C12N15/13C12N15/63C12N5/10
CPCA61K9/0019A61K39/3955A61K9/2031A61K9/2054A61K9/4866A61K9/7023A61K31/00A61K31/739A61K38/193A61K39/00A61K39/0007A61K47/4833A61K2039/505A61K2039/53A61K2039/55505A61K2039/55555A61K2039/55566A61K2039/55572A61K2039/55577A61K2039/6037A61K2039/605C07K14/4711C07K16/18C07K2317/24C07K2317/34C07K2317/565C07K2317/567C07K2317/77C07K2317/92C07K2319/00A61K9/2009A61K2300/00A61K47/646A61P25/00A61P25/28
Inventor BASI, GURIQSALDANHA, JOSE WILLIAMSCHENK, DALE B.
Owner WYETH LLC
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