Joint destruction biomarkers for anti-il-17a therapy of inflammatory joint disease

A biomarker, inflammatory joint technology, applied in biological testing, biological material analysis, antibodies, etc., can solve problems such as not seen

Inactive Publication Date: 2010-12-29
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] However, the inventors of the present invention have not seen from all published studies that blocking IL-17A in severely arthritic animals inhibits bone erosion and modulates serum levels of any of the above proteins

Method used

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  • Joint destruction biomarkers for anti-il-17a therapy of inflammatory joint disease
  • Joint destruction biomarkers for anti-il-17a therapy of inflammatory joint disease
  • Joint destruction biomarkers for anti-il-17a therapy of inflammatory joint disease

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Experimental program
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preparation example Construction

[0120] Antibody antagonists for use in the present invention can be prepared by any method known in the art for preparing antibodies. Preparation of monoclonal antibodies, polyclonal antibodies and humanized antibodies can be found in Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New York, NY; Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer -Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 139-243; Carpenter et al. (2000) J. Immunol. 165:6205; He et al (1998) J. Immunol. 160: 1029; Tang et al. (1999) J. Biol. Chem. 274: 27371-27378; Baca et al. (1997) J. Biol. Chem. 272: 10678-10684; Chothia et al. Nature 342:877-883; Foote and Winter (1992) J. Mol. Biol. 224:487-499; and US Patent No. 6,329,511 (to Vasquez et al.).

[0121] Any antigenic form of the desired target can be used to generate antibodies against which antibodies can be screened for...

Embodiment 1

[0145] NHDF assay for anti-IL-17A antibody

[0146] Blocking of IL-17A biological activity by anti-IL-17A antibodies used in the invention was determined by monitoring rhIL-17A-induced IL-6 expression in a normal human (adult) dermal fibroblast (NHDF) primary cell line ability. Briefly, different concentrations of anti-IL-17A antibodies to be tested were incubated with rhIL-17A, and the resulting mixture was added to NHDF cell cultures. IL-6 production was then assayed as a measure of the antibody's ability to inhibit IL-17A activity. A more detailed scheme is as follows.

[0147]A series of 2-fold dilutions of the anti-IL-17A antibody of interest (in duplicate) was prepared starting with a 40 μg / ml stock solution. A 120 ng / ml rhIL-17A stock solution was prepared. 70 μl rhIL-17A stock solution was mixed with 70 μl anti-IL-17A antibody dilution in wells of a microtiter plate and incubated at room temperature for 20 minutes. 100 μl of each of these mixtures was then added t...

Embodiment 2

[0151] Anti-IL-17A antibody assay in foreskin fibroblasts

[0152] The ability of the anti-IL-17A antibodies used in the present invention to block the biological activity of IL-17A was determined by monitoring the rhIL-17A-induced IL-6 expression in the HS68 foreskin fibroblast cell line. Reduced IL-6 production in response to rhIL-17A can be used as a measure of the blocking activity of the anti-IL-17A antibodies used in the invention.

[0153] IL-17RC (IL-17A receptor) expression was analyzed in a panel of fibroblast cell lines identified as potential IL-17A responsive cell lines in the human foreskin fibroblast cell line HS68 (ATCC CRL1635). This was confirmed by the following experiments: by using polyclonal goat anti-human IL-17R antibody (R&D Systems, Gaithersburg, Maryland, USA), followed by phycoerythrin (PE)-F(ab') 2 Indirect immunofluorescence staining of donkey anti-goat IgG (Jackson Immunoresearch, Inc., WestGrove, Pennsylvania, USA) and analysis of PE immunofluo...

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Abstract

Novel methods and drug products for treating inflammatory joint diseases such as rheumatoid arthritis and associated arthritides are disclosed. The methods and products employ various serum markers of bone and cartilage metabolism or destruction, including cartilage oligomer matrix protein (COMP) and Receptor activator of NFB ligand (RANKL), as biomarkers to assess the effect of IL-17A antagonists on joint destruction in inflammatory joint diseases.

Description

[0001] This application claims the benefit of US Provisional Patent Application 60 / 945,239, filed June 20, 2007. field of invention [0002] In general, the present invention relates to the treatment of inflammatory joint diseases with interleukin-17A (IL-17A) antagonists. More specifically, the present invention relates to biomarkers associated with the inhibitory efficacy of IL-17A antagonists on joint destruction in rheumatoid arthritis and related arthritic rashes. Background of the invention [0003] Rheumatoid arthritis (RA) is an inflammatory disease caused by a dysregulation of the immune system that results in inflammation of the joints, causing joint pain, discomfort, swelling and stiffness with progressive bone and cartilage erosion. Inflammation and structural joint damage combine to cause loss of function that can lead to permanent disability. [0004] IL-17A, formerly known as cytotoxic T lymphocyte-associated antigen 8 (CTLA8), is a homodimeric cytokine that ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/50
CPCG01N33/564C07K16/244A61K2039/505G01N2800/52G01N33/6887C07K2316/96A61P19/02A61P29/00A61P43/00C07K2317/73C07K2317/76
Inventor E·P·鲍曼C·朝S·-J·陈
Owner MERCK & CO INC
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