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14-3-3 Antagonists for the Prevention and Treatment of Arthritis

a technology of 1433 proteins and antagonists, applied in the field of arthritis prevention and treatment, can solve the problems of permanent structural damage, swelling of the joint area, and substantial loss of mobility, and achieve the effect of reducing the effectors of arthritis

Inactive Publication Date: 2011-02-03
THE UNVERSITY OF BRITISH OFFICE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]The invention stems in part from the findings that (1) 14-3-3 protein is aberrantly localized in the extracellular synovial space in arthritis, (ii) such extracellular 14-3-3 protein can induce effectors of arthritis, and (iii) 14-3-3 antagonists directed to such extracellular 14-3-3 proteins can reduce the effectors of arthritis.

Problems solved by technology

It is a disabling and painful inflammatory condition which can lead to substantial loss of mobility due to pain and joint destruction.
The consequences of such insults include excessive production and release of synovial fluid into the joint, thereby causing swelling within and about the joint area.
However, the physiological events associated with progression of the disease, from prolonged periods of swelling and inflammation caused by excessive synovial fluid accumulation in the joints, through degradation and deterioration of the cartilage and underlying bone tissues by degradative enzyme activities, and the accompanying FLS cell proliferation into bone which results in permanent structural damage, are known.

Method used

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  • 14-3-3 Antagonists for the Prevention and Treatment of Arthritis
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  • 14-3-3 Antagonists for the Prevention and Treatment of Arthritis

Examples

Experimental program
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Effect test

example 1

14-3-3 Eta Immunogen Sequences and Anti-14-3-3 Eta Antibodies

[0238]To prepare monospecific anti-14-3-3 eta antibodies, various peptides, 8 to 15 amino acids in length, were selected based on our own criteria. These peptides, as well as full-length recombinant native (untagged) 14-3-3 eta were used as immunogens in the production of monoclonal antibodies. A protein sequence alignment for the 7 isoforms of 14-3-3 is shown in FIG. 4 (14-3-3 gamma (SEQ ID NO: 64, 14-3-3 eta (SEQ ID NO:63), 14-3-3 alpha / beta (SEQ ID NO: 71), 14-3-3 zeta (SEQ ID NO:72), 14-3-3 theta (SEQ ID NO:73), 14-3-3 sigma (SEQ ID NO:74), and 14-3-3 epsilon (SEQ ID NO:75)).

[0239]Immunogen #1: C-LDKFLIKNSNDF (SEQ ID NO:76) (Amino Acid Sequence 104-115; “AUG1-CLDK”). A peptide corresponding to a segment of human 14-3-3 eta residues 104-115 was modified by addition of an N-terminal cysteine moiety for conjugation to carrier, and replacement of internal cysteine-112 moiety to avoid formation of internal disulphide bonds....

example 2

Testing the Cross-Reactivity of Tissue Culture (TC) Supernatants from Hybridoma Clones Using Biotinylated 14-3-3 Isoforms as Bait in a Capture ELISA

[0250]We have utilized a custom capture ELISA using the seven 14-3-3 isoforms as “bait” to determine whether any of the hybridoma clones that we have produced cross-react or recognize any of the six isoforms other than 14-3-3 Eta (η). As is evidenced by the representative data presented in Table 4, four of the selected hybridoma clones (AUG3-CKNS-2D5, AUG3-CKNS-7F8, AUG3-CKNS-7H8, AUG4-ETA-8F10) bind to and recognize 14-3-3 Eta at two serial dilutions, but do not bind with or cross-react with any of the other 14-3-3 isoforms, even at the lower dilution tested. This data clearly demonstrates that these clones are highly specific for 14-3-3 Eta (η). By contrast, one clone, AUG3-CKNS-4F10, binds with or cross-reacts with three other 14-3-3 isoforms, mainly 14-3-3 gamma, beta and zeta respectively. Taken together, these data indicate that ou...

example 3

14-3-3 Expression in Synovial Fluid and Serum of RA Affected Patients

[0252]The levels of the different isoforms of 14-3-3 proteins—β, γ, ε, η, τσ and ξ—in pooled patient synovial fluid (SF) and serum (PS) samples were analyzed by western analysis using keratinocyte cell lysate (K) as a positive control. Only the η and γ isoforms were detected in SF samples, and stained with greater intensity compared to PS. Articular joint synovial fluid samples from 17 RA patients who presented with active synovitis, but had not yet received anti-TNF therapies also exhibited consistent expression of the η isoform of 14-3-3 (data not shown). All patients had a disease activity score (DAS) greater than 6.0.

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Abstract

Methods for treating arthritis comprising 14-3-3 antagonists that are capable of specifically binding to extracellularly localized 14-3-3 eta and / or 14-3-3 gamma protein isoforms are provided. In preferred embodiments, the 14-3-3 antagonist is an inhibitory peptide or an anti-14-3-3 antibody. The 14-3-3 antagonists are also formulated in a pharmaceutical composition and used in a method for reducing matrix metalloprotease (MMP) expression in the synovial fluid of a patient, wherein the MMP is MMP-1 or MMP-3.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60 / 990,520, filed 27 Nov. 2007, and U.S. Provisional Patent Application Ser. No. 61 / 077,123, filed 30 Jun. 2008, which are expressly incorporated herein in their entirety by reference.FIELD OF THE INVENTION[0002]The invention relates to the involvement of 14-3-3 proteins in arthritis, and compositions and methods for the prevention and treatment of arthritis.BACKGROUND OF THE INVENTION[0003]Arthritis, or arthralgia, generally refers to inflammatory disorders of the joints of the body, and is usually accompanied by pain, swelling and stiffness. Arthritis may result from any of several causes including infection, trauma, degenerative disorders, metabolic disorders or disturbances or other unknown etiologies. Osteoarthritis (OA) is a common form of arthritis that may occur following trauma to a joint, following an infection of a joint or simply as a result of...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/18A61K38/02C12N5/16C07K2/00A61P19/02A61P29/00
CPCA61K2039/505G01N2800/102C07K16/18G01N33/6893C07K2317/34C07K2317/33C07K2317/24C07K2317/76G01N2333/47A61K39/001163A61K39/001162A61P19/02A61P29/00A61P37/06A61P43/00A61K39/395G01N33/53G01N33/564A61K2039/515
Inventor MARROTTA, ANTHONYGHAHARY, AZIZMAKSY MOWYCH, WALTER WOLODMYR PETERKILANI, RUHANGIZ
Owner THE UNVERSITY OF BRITISH OFFICE
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