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Affinity regions

A technology of affinity region and protein, applied in the fields of biochemistry, molecular biology, structural biology and medicine, can solve problems such as harmful side effects, achieve the effects of preventing harmful side effects, improving therapeutic effect, and improving performance

Inactive Publication Date: 2009-04-29
CROSSBETA BIOSCIENCES BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Administration of large amounts of IgIV involves risk of harmful side effects

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0201] Example 1: IgIV (human immunoglobulin IgG antibody) binds misfolded proteins comprising a cross-beta structural conformation

[0202] Non-enzymatic modification of proteins by carbohydrates (hydrocarbons), a process called glycation, induces protein misfolding with formation of amyloid cross-beta structures ((Bouma et al., 2003). IgIV on immobilized The combination of glycated protein Hb-AGE and BSA-AGE and non-glycated Hb and BSA was constructed by ELISA device ( figure 1 A-C). IgIV binding was detected using alkaline phosphatase-labeled anti-human IgG or IgM antibodies. Both IgIV(I) and IgIV(II) bind with high affinity to glycated proteins containing cross-beta structures, whereas they bind weakly to immobilized native albumin and native hemoglobin ( figure 1 A-C). IgIV(I) has a higher affinity for immobilized proteins than IgIV(II). IgIV(I) has a higher affinity for Hb-AGE than for BSA-AGE. Depending on the albumin or hemoglobin preparation, slightly different...

Embodiment 2

[0206] Example 2: Platelet aggregation is induced by amyloid misfolded protein and inhibited by human IgIV and mouse monoclonal antibodies

[0207] Platelets isolated from freshly citrated blood of apparently healthy human volunteers were prone to aggregate when exposed to misfolded glycosylated proteins, as from three different individuals with Hb-AGE (for "A", "B", "C") platelet confirmed ( figure 2 ). When the misfolded protein Hb-AGE or BSA-AGE was pre-incubated with IgIV(I) ( figure 2 A, C) or incubation with a mixture of 5 monoclonal antibodies (2E2B3D12, 7H2H2, 7H1C6A7, 7H9B9, 8F2G7H7) with affinity for misfolded proteins containing cross-beta conformation ( figure 2 E, F), platelet aggregation was inhibited. Induction of platelet aggregation by collagen or TRAP was poorly affected by IgIV(I) or mixed monoclonal antibodies ( figure 2 B, D), showing that these monoclonal antibodies are specifically known to be mediated by proteins containing cross-[beta] structur...

Embodiment 3

[0210] Example 3: Enhancement of binding of IgIV and tPA to misfolded proteins by Thioflavin T and Thioflavin S

[0211] Two amyloid-specific dyes, Thioflavin T and Thioflavin S, somewhat inhibit the IgIV-glycosylated protein interaction at relatively low dye concentrations, while at relatively high dye concentrations, both dyes appear to promote IgIV Binding to immobilized misfolded proteins ( Figure 4 B, C). This is explained by the fact that the binding of amyloid-specific dyes to misfolded proteins facilitates the subsequent binding of proteins that have binding affinity to misfolded proteins. Thioflavin T and Thioflavin S binding stabilize surrounding molecules or portions of molecules with a cross-beta structural conformation in a relatively fixed state representing the binding site for IgIV. At low dye concentrations, these forces were too weak to trigger immobilization into the IgIV binding sites of the more uniform exposed cross-[beta] structures. Now, dye binding...

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Abstract

The present invention provides a method for selecting from a collection of IgIV molecules, at least one IgIV molecule comprising an affinity region that is capable of interacting with a misfolded protein and / or with an epitope of a cross-ss structure and / or with an epitope of a protein comprising a cross-beta structure, said method comprising contacting a collection of IgIV molecules with a misfolded protein and / or with a cross-ss structure and / or with a protein comprising a cross-beta structure and collecting at least one IgIV molecule comprising an affinity region interacting with said misfolded protein and / or epitope.

Description

technical field [0001] The invention relates to the fields of biochemistry, molecular biology, structural biology and medicine. Background technique [0002] Intravenous immunoglobulins (IgIV) are immunoglobulins from healthy-appearing animals or humans that are collected from serum or blood. IgIV is considered to be antibody-deficient for both animals and humans. The lack of antibodies may be due to a disease affecting the immune system such as AIDS, or a congenital defect causing complete or partial a-gammaglobulinaemia or hypogammaglobulinaemia such as primary Immunodeficiency Syndrome (SCIDS). Immunoglobulin collected from human serum or blood is commercially available under a number of different names such as "human immunoglobulin intravenously" (IgIV, or IVIg). Since IgIVs were first introduced in 1981 as immunoglobulin replacement therapy for immunocompromised humans as described above, they have also been used off label in patients with a wide variety of diseases,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/18C07K1/22A61K39/395G01N33/68A61P25/28
CPCC07K16/18C07K2317/21A61K2039/505C07K16/065A61P7/02A61P25/28A61P31/00
Inventor 马蒂杰恩·弗兰斯·本·赫拉德·格比宾克巴伦德·鲍马
Owner CROSSBETA BIOSCIENCES BV
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