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Antibodies specific for MMP9

一种MMP9、特异性的技术，应用在抗体、抗炎剂、特定肽等方向，能够解决严重的副作用、毒性、缺乏MMP靶选择性等问题

Pending Publication Date: 2017-04-19
CALYPSO BIOTECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This approach has so far failed to translate into expected clinical benefits, in part due to dose-limiting toxicities and serious side effects such as musculoskeletal syndromes
Because the structure of the MMP9 catalytic site is highly conserved in the MMP family, this contraindication may be attributed to the lack of MMP target selectivity at therapeutic doses

Method used

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  • Antibodies specific for MMP9
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  • Antibodies specific for MMP9

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0658] Example 1: Production and isolation of the anti-MMP9 antibody of the present invention

[0659] The anti-MMP9 antibody of the present invention is obtained by performing the following steps:

[0660] 1 / Phage display hit discovery (Hit Discovery, HD)

[0661] A ScFv library was used as a source of ScFv fragments. The library is of natural origin (i.e., constructed using PBMCs from unimmunized healthy human donors), medium in size (approximately 2.5 × 10 9 VH / VL combinations) and contain VH domains derived from the IgM profiles of clones not selected and not class switched. Using this library, ScFv candidates were first selected by phage display based on their binding to human or mouse MMP9 (full-length, pro-form and activated form), the ScFv was reconstituted as IgG1, and screened for functional neutralization of MMP9 activity (specifically IC 50 , species-selective, neutralizing form (proMMP9 or MMP9).

[0662] This step allowed the identification of 10 candidate ...

Embodiment 2

[0671] Example 2: Potency and efficacy of some anti-MMP9 antibodies of the present invention in human MMP3 / MMP9 and human MMP9 activity assays

[0672] Some antibodies of the invention were evaluated for functional neutralization of the MMP9 catalytic activity of the fluorescent polymer substrate DQ-gelatin.

[0673] A characteristic activity of MMP9 (and MMP2) is gelatin degradation. Gelatin is essentially derived from irreversibly denatured forms of various collagens, several of which are considered key physiological substrates of MMP9. Unlike small peptide substrates, binding and recognition of gelatin (like collagen) by MMP9 is complex and known to be mediated by regions of the molecule beyond the active site, including fibronectin and PEX domains. To preserve these physiologically relevant "exosite" interactions and facilitate the isolation of potential "non-canonical" allosteric neutralizer classes, a fluorine-quenched soluble gelatin polymer (DQ-gelatin) was chosen for...

Embodiment 3

[0682] Example 3: Species Specificity of Certain Anti-MMP9 Antibodies of the Invention in MMP3 / MMP9 Assays

[0683] The species specificity of the enzyme inhibitory activity of the anti-MMP9 antibodies was evaluated using the "MMP3 / MMP9 assay" described in Example 2. The enzyme used was cyno monkey (cyno), rat or mouse proMMP9.

[0684] Some antibodies of the invention tested were able to effectively block the activation and / or downstream catalytic activity of proMMP9 in cynomolgus monkey (cyno), rat and mouse (Tables 5, 6 and 7, respectively).

[0685] Table 5. Potency and efficacy of anti-MMP9 antibodies in neutralizing cynomolgus proMMP9 in the MMP3 / MMP9 gelatin assay

[0686]

[0687] Table 6. Potency and efficacy of anti-MMP9 antibodies in neutralizing rat proMMP9 in the MMP3 / MMP9 gelatin assay

[0688]

[0689] Table 7. Potency and efficacy of anti-MMP9 antibodies in neutralizing mouse proMMP9 or active MMP9 in MMP3 / MMP9 and MMP9 gelatin assays, respectively

[...

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Abstract

The present invention relates to new proteins that bind to MMP9 and comprise at least one fragment of a heavy chain variable region and / or at least one fragment of a light chain variable region of an antibody. In particular, the MMP9 binding proteins according to the invention are able to neutralize MMP9 activity and are useful in the prevention and / or treatment of inflammatory and / or autoimmune diseases or cancers.In particular, the MMP9 binding proteins according to the invention are useful in diagnosis of MMP9-related disorders.

Description

technical field [0001] The present invention relates to antibodies and fragments thereof that specifically bind to and neutralize the activity of said proteins, and their use as therapeutic or diagnostic agents. Background technique [0002] The matrix metalloproteinase (MMP) family consists of at least 23 structurally related, soluble or membrane-bound zinc-dependent endopeptidases that are broadly involved in the remodeling of the extracellular matrix (ECM) and the functional regulation of various bioactive molecules . [0003] All MMPs have a prototypical structure that includes a prodomain that maintains the MMP in an inactive form and a catalytic domain that acts on a broad spectrum of extracellular matrix components. [0004] Matrix metallopeptidase 9 (MMP9), also known as 92kDa type IV collagenase or gelatinase B (GELB), is a member of the MMP family of enzymes responsible for degrading denatured and basement membrane collagen (Agrawal et al., 2006 J.Exp.Med 203, 10...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/40C12N15/13C12P21/00A61K39/395A61P29/00A61P37/02A61P1/00A61P35/00A61P9/00A61P25/00A61P27/02G01N33/573
CPCA61K2039/505C07K16/40C07K2317/33C07K2317/34C07K2317/565C07K2317/76C07K2317/90G01N33/573G01N2333/96494A61P1/00A61P9/00A61P11/00A61P25/00A61P27/02A61P29/00A61P35/00A61P37/00A61P37/02A61P37/06C12Y304/24035C07K2317/92
Inventor 约兰德·赫瓦特奇科·米索顿劳伦斯·戈芬奥利维尔·莱格尔史蒂文·M·邓恩克莉丝汀·鲍尔金赛·孟德雷尔
Owner CALYPSO BIOTECH
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