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Antibodies that recognize cutting edge within the TGF-β activation controlling region UPDATE_EN achieved

Foreign code F190009899
File No. 06315-US-2
Posted date Aug 26, 2019
Country United States of America
Application number 85619510
Gazette No. 20110071278
Gazette No. 8198412
Date of filing Aug 13, 2010
Gazette Date Mar 24, 2011
Gazette Date Jun 12, 2012
Priority data
  • P2003-313014 (Sep 4, 2003) JP
  • 2004JP13189 (Sep 3, 2004) WO
  • 200611570606 (Oct 24, 2006) US
Title Antibodies that recognize cutting edge within the TGF-β activation controlling region UPDATE_EN achieved
Abstract It is an object of the present invention to provide antibodies capable of detecting an active TGF-&bgr; generation reaction that is specific to pathogenesis, tissues, or isoforms. The present invention provides antibodies against an LAP fragment (or latent TGF-&bgr;) generated as a result of generation of active form of human TGF-&bgr;1, human TGF-&bgr;2 and human TGF-&bgr;3. The antibodies are able to specifically recognize respective cutting edges within protease cleavage sites existing in the region from the amino acid residue glycine at position 51 to the amino acid residue arginine at position 110 of human TGF-&bgr;1, and corresponding regions of human TGF-&bgr;2 and human TGF-&bgr;3.
Outline of related art and contending technology BACKGROUND ART
Transforming growth factor (TGF)-β strongly promotes generation of the extracellular matrices of mesenchymal cells, and at the same time, it suppresses the growth of epithelial cells, so as to promote pathogenesis of sclerotic diseases such as hepatic fibrosis/cirrhosis, atherosclerosis, lung fibrosis, scleroderma, or renal failure. On the other hand, TGF-β suppresses the action of immune cells. TGF-β is a multifunctional cytokine acting as a homodimer with a molecular weight of 25 kD, which exhibits various biological activities. As a result of studies using a combination of the neutralizing antibody to TGF-β and animal models, it has been revealed that sclerotic diseases can be prevented or cured by suppressing the action of TGF-β. For example, Okuno et al. Gastroenterology 120: 18784-1800, 2001 describes the prevention or treatment of hepatic fibrosis/cirrhosis by suppressing a TGF-β activation reaction using a protease inhibitor. Moreover, Akita et al. Gastroenterology 123: 352-364, 2002 using an antibody to protease. In addition, there are several review articles on TGF-β activation reaction, such as Kondo et al., Journal of the Japanese Society on Thrombosis and Hemostasis, 14 (3): 210-219, 2003, and Annes et al. J Cell Sci 116: 217-224, 2003.
On the other hand, TGF-β also plays an important role to maintain our health. For example, TGF-β suppresses excessive generation of proteases in lung and prevents lung tissue from destruction leading to emphysema. It also suppresses the growth of cancer cells. Furthermore, TGF-β has three isoforms, β1, β2 and β3, which exhibit almost the same biological activities. Thus, it has been desired to develop the technique, useful for treatment of diseases and prediction of prognosis, which detect and suppress pathogenesis-, tissues- or isoforms-specific TGF-β generation reactions, so as to block aberrant generation of a certain TGF-β isoform during the progression of pathogenesis. However, it has been difficult to detect such specific TGF-β generation reactions using the hitherto reported techniques.
Although there are established techniques to determine the isoform types of generated TGF-β in a certain lesion during pathogenesis process in animal models or patients utilizing antibodies (manufactured by R & D, or Sant Cruz) or gene probes (Bissell et al. J Clin Invest 96: 447-455, 1995) specific to each TGF-β isoform, since pathogenesis-, tissue-, or isoform-specific TGF-β generation reaction can not be detected by these techniques, these techniques have not allowed to develop a specific method for therapy or prevention of the diseases.
Scope of claims [claim1]
1. An antibody against a latency-associated peptide (LAP) fragment of a human TGF-β selected from the group consisting of human TGF-β1, human TGF-β2 and human TGF-β3, which is able to specifically recognize a cutting edge within protease cleavage sites existing in the region from the amino acid residue glycine at position 51 to the amino acid residue arginine at position 110 of human TGF-β1 as shown in SEQ ID NO: 1, and corresponding regions of human TGF-β2 and human TGF-β3.

[claim2]
2. The antibody of claim 1 which is a polyclonal antibody.

[claim3]
3. The antibody of claim 1 which is a monoclonal antibody.

[claim4]
4. The antibody of claim 1 which is selected from the group consisting of the following (a) to (l)
(a) an antibody specifically recognizing the cutting edge ending at the leucine residue at position 59, wherein a protease cleavage site is between the arginine residue at position 58 and the leucine residue at position 59;
(b) an antibody specifically recognizing the cutting edge ending at the arginine residue at position 58, wherein a protease cleavage site is between the arginine residue at position 58 and the leucine residue at position 59;
(c) an antibody specifically recognizing the cutting edge ending at the leucine residue at position 57, wherein a protease cleavage site is between the lysine residue at position 56 and the leucine residue at position 57;
(d) an antibody specifically recognizing the cutting edge ending at the lysine residue at position 56, wherein a protease cleavage site is between the lysine residue at position 56 and the leucine residue at position 57;
(e) an antibody specifically recognizing the cutting edge ending at the leucine residue at position 80, wherein a protease cleavage site is between the alanine residue at position 79 and the leucine residue at position 80;
(f) an antibody specifically recognizing the cutting edge ending at the alanine residue at position 79, wherein a protease cleavage site is between the alanine residue at position 79 and the leucine residue at position 80;
(g) an antibody specifically recognizing the cutting edge ending at the aspartic acid residue at position 86, wherein a protease cleavage site is between the arginine residue at position 85 and the aspartic acid residue at position 86;
(h) an antibody specifically recognizing the cutting edge ending at the arginine residue at position 85, wherein a protease cleavage site is between the arginine residue at position 85 and the aspartic acid residue at position 86;
(i) an antibody specifically recognizing the cutting edge ending at the glutamic acid residue at position 107, wherein a protease cleavage site is between the lysine residue at position 106 and the glutamic acid residue at position 107;
(j) an antibody specifically recognizing the cutting edge ending at the lysine residue at position 106, wherein a protease cleavage site is between the lysine residue at position 106 and the glutamic acid residue at position 107;
(k) an antibody specifically recognizing the cutting edge ending at the valine residue at position 77, wherein a protease cleavage site is between the alanine residue at position 76 and the valine residue at position 77; and
(l) an antibody specifically recognizing the cutting edge ending at the alanine residue at position 76, wherein a protease cleavage site is between the alanine residue at position 76 and the valine residue at position 77.

[claim5]
5. A diagnostic agent composition for TGF-β-associated diseases, which comprises the antibody of claim 1.
  • Inventor, and Inventor/Applicant
  • KOJIMA Soichi
  • DOHMAE Naoshi
  • KONDO Wakako
  • RIKEN
IPC(International Patent Classification)

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