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Methods of inhibiting osteoclastogenesis

a technology of osteoclastogenesis and inhibition, which is applied in the field of cytokine receptor protein/ligand pair, can solve problems such as the effect of fading, and achieve the effect of meliorating the effect of osteoclastogenesis

Inactive Publication Date: 2005-04-28
IMMUNEX CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006] Soluble forms of the receptor can be prepared and used to interfere with signal transduction through membrane-bound RANK. Inhibition of RANKL-mediated signal transduction will be useful in ameliorating the effects of osteoclastogenesis and osteoclast activity in disease conditions in which there is excess bone break down. Examples of such

Problems solved by technology

However, OPG is also known to bind other ligands in the TNF family, which may have a deleterious effect on the activities of such ligands in vivo.

Method used

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  • Methods of inhibiting osteoclastogenesis

Examples

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example 1

[0035] This example describes a plate binding assay useful in comparing the ability of various ligands to bind receptors. The assay is performed essentially as described in Smith et al., Virology 236:316 (1997). Briefly, 96-well microtiter plates are coated with an antibody to human Fc (i.e., polyclonal goat anti human Fc). Receptor / Fc fusion proteins are then added, and after incubation, the plates are washed. Serial dilutions of the ligands are then added. The ligands may be directly labeled (i.e., with 125I), or a detecting reagent that is radioactively labeled may be used. After incubation, the plates are washed, specifically bound ligands are released, and the amount of ligand bound quantified.

[0036] Using this method, RANK / Fc and OPG / Fc were bound to 96-well plates. In an indirect method, a RANKL / zipper fusion is detected using a labeled antibody to the zipper moiety. It was found that human OPG / Fc binds mRANKL at 0.05 nM, and human RANK / Fc binds mRANKL at 0.1 nM. These value...

example 2

[0037] The following describes the formation of osteoclast like cells from bone marrow cell cultures using a soluble RANKL in the form of soluble RANKL / leucine zipper fusion protein (RANKL LZ).

[0038] Using RANKL LZ at 1 μg / ml, osteoclasts were generated from murine bone marrow (BM) in the presence of CSF-1. These osteoclasts are formed by the fusion of macrophage-like cells and are characterized by their TRAP (tartrate-resistant acid phosphatase) positivity. No TRAP+ cells were seen in cultures containing CSF-1 alone or in cultures containing CSF-1 and TRAIL LZ (a control for the soluble RANKL LZ). Even though human and monkey bone marrow contains more contaminating fibroblasts than murine bone marrow, osteoclasts were generated from murine and monkey bone marrow with the combination of CSF-1 and soluble RANKL LZ. In a dose-response study using murine bone marrow and suboptimal amounts of CSF-1 (40ng / ml), the effects of soluble RANKL LZ plateaued at about 100 ng / ml.

[0039] The effe...

example 3

[0042] In order to determine RANKL expression by either of two different squamous cell carcinomas, standard Western blot and RT-PCR studies were performed on MH-85 and OKK cells. One of these carcinoma cells, the MH-85 cells, is associated with hypercalcemia.

[0043] The results confirmed that MH-85 and OKK squamous cells express RANKL. MH-85 cells, in addition to being linked with hypercalcemia in patients inflicted with this carcinoma, also express M-CSF (CSF-1). It was also determined that CSF-1 upregulates RANK expression on osteoclast precursors. The enhanced amount of CSF-1 in MH-85 type squamous cell cancer patients can lead to an upregulation of RANK and increased RANK interaction with RANKL. Signals transduced by RANK and RANKL interaction result in increased numbers of mature osteoclasts and bone breakdown. Since soluble forms of RANK can inhibit the RAKNK L interaction, administering a soluble form of RANK (e.g. the extracellular region of RANK fused to an Fc) to a squamou...

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Abstract

Provided here are methods of inhibiting RANKL-induced osteoclastogenesis in patients suffering from specific types of cancer.

Description

[0001] This application is a continuation of U.S. patent application 09 / 705,985, filed Nov. 3, 2000, which is a continuation of international patent application PCT / US99 / 10588, filed May 13, 1999, which claims benefit of U.S. provisional patent applications 60 / 110,836, filed Dec. 3, 1998 and 60 / 085,487 filed May 14, 1998. The entire disclosures of these applications are relied upon and incorporated by reference herein.TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates generally to the field of cytokine receptors, and more specifically to cytokine receptor protein / ligand pairs having osteoclast regulatory activity. BACKGROUND OF THE INVENTION [0003] RANK (Receptor Activator of NF-κB) and its ligand (RANKL) are a recently-described receptor / ligand pair that play an important role in an immune response. The cloning of RANK and RANKL is described in U.S. Ser. No. 08 / 996,139 and U.S. Ser. No. 08 / 995,659, respectively. It has recently been found that RANKL binds to a pr...

Claims

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Application Information

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IPC IPC(8): A61K38/00C12N15/09A61P19/08A61P19/10A61P43/00C07K14/705C12N15/12
CPCA61K38/00A61K2039/505C07K14/70575Y10S530/866C07K2319/00C07K2319/30C07K2319/73C07K14/70578A61P19/08A61P19/10A61P35/04A61P43/00
Inventor ANDERSON, DIRKGALIBERT, LAURENT
Owner IMMUNEX CORP
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