Anti-Adrenomedullin (ADM) antibody or anti-ADM antibody fragment or an anti-ADM non-Ig protein scaffold for use in therapy

A technology of adrenomedullin and antibody fragments, applied in the direction of antibodies, antibody medical components, anti-hormone immunoglobulin, etc., can solve harmful and other problems

Active Publication Date: 2014-11-12
ADRENOMED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ADM can also be harmful if it is completely neutralized, as certain amounts of ADM may be necessary for some physiological functions

Method used

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  • Anti-Adrenomedullin (ADM) antibody or anti-ADM antibody fragment or an anti-ADM non-Ig protein scaffold for use in therapy
  • Anti-Adrenomedullin (ADM) antibody or anti-ADM antibody fragment or an anti-ADM non-Ig protein scaffold for use in therapy
  • Anti-Adrenomedullin (ADM) antibody or anti-ADM antibody fragment or an anti-ADM non-Ig protein scaffold for use in therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0568] Production of Antibodies and Determination of Their Affinity Constants

[0569] Several human and murine antibodies were produced and their affinity constants determined (see Tables 1 and 2).

[0570] Peptides / conjugates used for immunization:

[0571] Peptides for immunization were synthesized, see Table 1 (JPT Technologies, Berlin, Germany), with an additional N-terminal cysteine ​​(if there is no cysteine ​​in the selected ADM sequence) residue The peptide is conjugated to bovine serum albumin (BSA). Peptides were linked to BSA by using Sulfolink coupling gels (Perbio-science, Bonn, Germany). The coupling protocol was performed according to the Perbio manual.

[0572] Raise mouse antibodies as follows:

[0573] 100 μg peptide-BSA-conjugate (emulsified in 100 μl Freund’s complete adjuvant) on days 0 and 14 and 50 μg peptide-BSA-conjugate (in 100 μl Freund’s adjuvant) on days 21 and 28 in complete adjuvant) to immunize Balb / c mice. Three days before fusion experi...

Embodiment 2

[0630] Effect of selected anti-ADM antibodies on anti-ADM biological activity

[0631] The effect of selected anti-ADM antibodies on ADM biological activity was tested in a human recombinant adrenomedullin receptor cAMP functional assay (adrenomedullin bioassay).

[0632] Testing of Antibodies Targeting Human or Mouse Adrenomedullin in the Human Recombinant Adrenomedullin Receptor cAMP Functional Assay (Adrenomedullin Bioassay)

[0633] Material:

[0634] Cell line: CHO-K1

[0635] Receptor: Adrenomedullin (CRLR+RAMP3)

[0636] Receptor accession number cell line: CRLR: U17473; RAMP3: AJ001016

[0637] Before testing, CHO-K1 cells expressing human recombinant adrenomedullin receptor (FAST-027C) grown in antibiotic-free medium were isolated by gently washing with PBS-EDTA (5 mM EDTA) and recovered by centrifugation , and resuspended in assay buffer (KRH: 5mM KCl, 1.25mM MgSO 4 , 124mM NaCl, 25mM HEPES, 13.3mM Glucose, 1.25mM KH 2 PO 4 ,1.45mM CaCl 2 ,0.5g / l BSA).

[06...

Embodiment 3

[0648] Stabilization of hADM data by anti-ADM antibody

[0649] The hADM immunoassay was used to test the stabilizing effect of human ADM antibodies on human ADM.

[0650] Immunoassay for quantification of human adrenomedullin

[0651] The technique used is a luminescent immunoassay based on acridinium ester-labeled sandwich-coated tubes.

[0652] Labeled compound (tracer): mix 100μg (100ul) CT-H (1mg / ml in PBS, pH7.4, AdrenoMed AGGermany) with 10μl acridinium NHS-ester (Acridinium NHS-ester) (1mg / ml in Acetonitrile, InVent GmbH, Germany) (EP0353971) was mixed and incubated at room temperature for 20 min. exist Labeled CT-H was purified by gel filtration HPLC on SEC400-5 (Bio-Rad Laboratories, Inc., USA). The purified CT-H was diluted in (300mmol / L potassium phosphate, 100mmol / L NaCl, 10mmol / L Na-EDTA, 5g / L bovine serum albumin, pH 7.0). The final concentration is about 800.000 relative light units (RLU) of labeled compound (about 20 ng of labeled antibody) per 200 μL. ...

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Abstract

Subject matter of the present disclosure is an anti-adrenomedullin antibody or an anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold wherein said antibody or said fragment or scaffold is a non-neutralizing antibody, antibody fragment or non-Ig scaffold, respectively. Subject matter of the present disclosure is also an anti-adrenomedullin antibody or an anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in a treatment of a chronic or acute disease wherein said antibody or fragment or scaffold is: —� an ADM stabilizing antibody or an adrenomedullin stabilizing antibody fragment or an ADM stabilizing non-Ig scaffold that enhances the t 1/2 half retention time of adrenomedullin in serum, blood, plasma at least 10 %, preferably at least, 50 %, more preferably >50 %, most preferably 100 % and/or —� wherein said anti-ADM antibody or an anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold blocks the bioactivity of ADM to not more than 80 %, or not more than 50 %.

Description

field of invention [0001] The subject of the present invention is an anti-adrenomedullin antibody or an anti-adrenomedullin antibody fragment or an anti-ADM non-Ig backbone, wherein said antibody or fragment or backbone is a non-neutralizing antibody. [0002] The subject of the present invention is an anti-adrenomedullin antibody or an anti-adrenomedullin antibody fragment or an anti-ADM non-Ig backbone, wherein said antibody or fragment or backbone is [0003] Make the half-life of adrenomedullin in serum, blood and plasma (t 1 / 2 ADM-stabilized antibody or ADM-stabilized antibody fragment or ADM-stabilized non-Ig backbone, and / or [0004] • Wherein the ADM-stabilized antibody or adrenomedullin-stabilized antibody fragment or ADM-stabilized non-Ig backbone blocks less than 80%, preferably less than 50%, of the biological activity of ADM. [0005] The above-mentioned meaning is to block not more than 80% or not more than 50% of the biological activity of ADM, respectively, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/26A61K39/395A61P31/00A61P9/00A61P13/12
CPCC07K2317/24C07K2317/55G01N2800/7095C07K2317/34C07K2317/622C07K2317/54C07K16/26G01N2800/52C07K2317/21C07K2317/76A61K2039/505G01N33/6893C07K2317/92A61P1/16A61P13/12A61P17/02A61P29/00A61P31/00A61P31/04A61P35/00A61P39/02A61P7/10A61P9/00A61P9/04A61P9/10A61P3/10A61K39/00
Inventor 安德里亚斯·伯格曼
Owner ADRENOMED
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