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Method of Providing Disease-Specific Binding Molecules and Targets

a technology of specific binding molecules and targets, applied in the direction of peptides, drug compositions, fused cells, etc., can solve the problems of inconvenient production of antibodies with characteristics, insufficient specificity of antibodies, and hampered therapeutic utility of murine based antibodies in human patients

Inactive Publication Date: 2013-10-10
UNIV ZURICH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]Known is the fact that, in case of autoimmune diseases, antibodies are directed against autologous cells and proteins or other compounds such as glycolipids expressed by said cells while evading the known tolerance mechanisms. Also known is the fact that, in case of endogenous neoplastic developments, a cellular and humoral immunity to the neoplastic cells can develop and can thus effect an endogenous immunological protection mechanism against neoplastic tissue degeneration.

Problems solved by technology

However, the therapeutic utility of murine based antibodies in human is hampered by the human anti-mouse antibody (HAMA) response in view of their non-human origin.
However, the methods hitherto available suffer from the drawback that they are not suitable to produce antibodies with the characteristics of those produced in the course of a physiological human immune response.
Furthermore, such antibodies may not be specific enough because of cross-reactivity with other proteins and / or the target protein in context with normal physiological function.
On the other hand, active immunization with pathological relevant antigens bears the considerable risk of patients developing antibodies and T cell responses which also recognize physiological variants of such proteins and in consequence lead to a dangerous and uncontrollable autoimmune response.

Method used

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  • Method of Providing Disease-Specific Binding Molecules and Targets
  • Method of Providing Disease-Specific Binding Molecules and Targets
  • Method of Providing Disease-Specific Binding Molecules and Targets

Examples

Experimental program
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Effect test

example 1

Detection of Human Antibodies Against Abnormal Structures Prevalent in Human Brain Diseases

[0320]Antibodies from phenotypically healthy subjects, or clinically unusually stable patients with Alzheimer's disease were tested by immunohistochemistry on brain sections obtained from patients with pathologically confirmed Alzheimer's disease. FIG. 1A demonstrates the presence of antibodies in a clinically unusually stable patient that bind to beta-amyloid plaques as was confirmed by co-staining with a known antibody against human beta-amyloid (antibody 4G8; FIG. 1B). The presence in a healthy human subject of antibodies to neurofibrillary tangles in a tissue section obtained from a patient with Alzheimer's disease is shown in FIG. 2A. This result was confirmed by co-staining with a known antibody against human tau (HT7). FIG. 3A reveals the presence in a healthy human subject of antibodies against dystrophic neurites in a tissue section obtained from a patient with Alzheimer's disease. Co...

example 2

Recombinant Human Antibodies Maintain Specificity to Abnormal Structure In Vivo and Recognize Conformational Epitope of Disease-Associated Beta-Amyloid Protein in Brain Amyloid Plaques but not the Physiological Precursor or Non-Pathogenic Derivative Thereof

[0321]Antibodies NI-101.11, NI-101.12, NI-101.13A and NI-101.13B were obtained from clinically unusually stable Alzheimer's disease patients with a significantly reduced rate of cognitive decline. Antibody isolation and recombinant production was performed as specified in supplementary methods.

NI-101.11

[0322]Recombinant NI-101.11 was tested for binding to brain beta-amyloid plaques (FIG. 4). Brain sections obtained from a patient with neuropathologically confirmed Alzheimer's disease were stained at the indicated concentrations. Antibody binding to beta-amyloid plaques with concentrations of 50 μM suggest high affinity binding. The binding of antibody NI-101.11 to beta-amyloid plaques at a concentration of 0.5 nM cannot be compete...

example 3

Recombinant Human Antibody Against Brain Beta-Amyloid Crosses the Blood Brain Barrier in a Transgenic Mouse Model of Alzheimer's Disease, and Binds to Brain Beta-Amyloid Plaques In vivo

[0331]To determine whether recombinant human NI-101.11 antibody crosses the blood brain barrier and binds to brain beta-amyloid plaques in vivo transgenic PS-1 / APPswe Alzheimer's disease model mice received two peripheral injections of 150 μg NI-101.11 at day 1 and day 3. Mice were sacrificed 24 h after the second injection and perfused with PBS. Brains were harvested and brain sections were stained with FITC-labeled antibodies against human IgG or with the mouse monoclonal Abeta antibody 6E10 followed by a FITC-labeled antibody against mouse IgG to confirm the presence of brain beta-amyloid plaques. Intense staining of amyloid plaques with anti-human IgG indicated that the recombinant human NI-101.11 antibody can cross the blood-brain barrier of transgenic mice and bind to brain beta-amyloid plaques ...

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Abstract

Provided are novel specific binding molecules, particularly human antibodies as well as fragments, derivatives and variants thereof that recognize neoepitopes of disease-associated proteins which derive from native endogenous proteins but are prevalent in the body of a patient in a variant form and / or out of their normal physiological context. In addition, pharmaceutical compositions comprising such binding molecules, antibodies and mimics thereof and methods of screening for novel binding molecules, which may or may not be antibodies as well as targets in the treatment of neurological disorders such as Alzheimer's disease are described.

Description

RELATED APPLICATIONS[0001]U.S. patent application Ser. No. 12 / 522,031, which is the National Stage of International Application No. PCT / EP2008 / 000053, filed Jan. 7, 2008, U.S. Provisional Application No. 60 / 934,291, filed Jun. 11, 2007, U.S. Provisional Application No. 60 / 878,831, filed Jan. 5, 2007, European Application No. 07020341.9, filed Oct. 17, 2007, and European Application No. 07000211.8, filed Jan. 5, 2007 are incorporated herein by reference in their entireties.[0002]The content of the electronically submitted sequence listing (Name: 21591900004_sequencelisting_ascii.txt, Size: 46,754 bytes; and Date of Creation: Mar. 13, 2013) is herein incorporated by reference in its entirety.FIELD OF THE INVENTION[0003]The present invention relates to novel specific binding molecules, particularly human antibodies as well as fragments, derivatives and variants thereof that recognize disease-associated epitopes, including neoepitopes, of proteins which derive from native endogenous pro...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/00A61K39/395A61K45/06A61K39/00
CPCA61K2039/505C07K2317/21C07K2317/30C07K16/18A61K39/3955A61K45/06C07K16/00C07K2317/76A61P25/00A61P25/08A61P25/14A61P25/16A61P25/22A61P25/24A61P25/28A61P9/00G01N33/6896G01N2800/2821A61K51/1018C07K2317/34C07K2317/51C07K2317/515C07K2317/55C07K2317/56C07K2317/565C07K2317/73G01N2800/52C07K2317/33G01N33/6854G01N2333/4709
Inventor NITSCH, ROGERHOCK, CHRISTOPHESSLINGER, CHRISTOPHKNOBLOCH, MARLENTISSOT, KATHRINGRIMM, JAN
Owner UNIV ZURICH
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