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APRIL receptor (BCMA) and uses thereof

A variant, amino acid technology, applied in the direction of cytokine/lymphokine/interferon receptor, receptor/cell surface antigen/cell surface determinant, antibody, etc., can solve the problem of little curative effect and multiple existing treatments Insufficient types of tumors and other issues

Inactive Publication Date: 2003-02-26
BIOGEN MA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Existing treatments for cancer are inadequate for many types of tumors due to little efficacy, minimal impact on survival status, toxicity with serious side effects, or a combination

Method used

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  • APRIL receptor (BCMA) and uses thereof
  • APRIL receptor (BCMA) and uses thereof
  • APRIL receptor (BCMA) and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] Embodiment 1: Detect the combination of APRIL and APRIL-R with plate test

[0116] In this example, the binding of BCMA to April was tested.

[0117] To test whether BCMA binds April, we performed a co-immunoprecipitation assay. Two soluble proteins, hBCMA-Fc and myc-mApril, were used in this assay.

[0118] HBCMA-Fc and LTbR-Fc and the following different TNF ligands were added to medium containing 10% FBS: myc-mApril; myc-CD40L and myc-RANKL and incubated for 1 / 2 hour at room temperature. Fc protein was combined with protein A beads for 1-2 hours, washed 3 times with 1ml PBS, immunoblot analysis was performed with mouse monoclonal antibody 9E10 (anti-myc), and color development was performed with enhanced chemiluminescence.

[0119] The detection of myc-APRIL in hBCMA-Fc immunoprecipitate showed that the interaction between BCMA and April was specific because other TNF ligands myc-CD40L and myc-RANKL could not bind to BCMA. Myc-April does not bind LTbR-Fc.

[0120...

Embodiment 2

[0122] This example describes the interaction between hBCMA-Fc and FLAG-hAPRIL.

[0123] ELISA test: Coat the plate with pH 9.6 carbonate solution (1 ug / ml) of receptor-Fc fusion protein (hBCMA-Fc739 or hTNFR2-Fc-492), overnight at 4°C. Block with PBS / 5% skim milk powder / 0.5% Tween-20 for 2 hours at room temperature. Use 100 μl blocking solution to make 2-fold serial dilutions of the ligand (TNFa-197 starts from 1000ng / ml, muAPRIL-657 starts from 1000ng / ml, hApril-507 starts from 2000ng / ml (inactive), hApril-429 starts from 5x concentrated culture medium starts). After incubation with ligand, the plates were washed with PBS containing 0.5% Tween-20 and then hybridized with anti-FLAG mAb M2 in dilution buffer at a concentration of 0.5 μg / ml. The antibody was then detected with anti-mouse-PO 1 / 2000 and enzymatic color development (OPD).

[0124] Immunoprecipitation assay: 293T cells were transfected with the indicated expression plasmids (Rec-Fc or flag ligand) in a 9cm plate...

Embodiment 3

[0126]This example describes the binding of myc-mAPRIL, hKayL-440(hAPRIL) and Flag-mAPRIL to hBCMA-Ig, hLT-R-Ig or hp80 TNFR-Ig. The conditions for all experiments were: 25°C, flow rate of 10 μl / ml min.

[0127] All experiments used HBS buffer (10 mM HEPES, 150 mM NaCl, 0.005% P20 surfactant, pH 7.4). This solution is also used as running buffer and sample diluent. .

[0128] First, the surface of a CM5 chip (BIAcore, Inc.) was activated with N-hydroxysuccinimide / N-ethyl-N'-(3-diethylaminopropyl)-carbodiimide hydrochloride (BIAcore). Dilute hBCMA-Ig, hLT-R05-Ig, hp80-TNFR with 10mM acetic acid to 30g / ml, take 20μl, 15μl and 10μl of these three solutions respectively, then use 30μl and then 15μl ethanolamine-HCl (pH8.5) closed. This results in a surface density of 1600-3700 resonance units (RU). Chips were regenerated with 20 μl 1 mM formic acid. These were repeated 5 times to establish a repeatable stable baseline.

[0129] In the experiment, 100 μl each of myc-mApril, ...

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Abstract

A receptor in the TNF family is provided: APRIL-R. Chimeric molecules and antibodies to APRIL-R and methods of use thereof are also provided.

Description

field of invention [0001] The present invention broadly relates to methods of treating cancer. The method involves the administration of specific tumor necrosis factor (TNF) antagonists. Background of the invention [0002] Tumor necrosis factor (TNF) family members of cytokines participate in more and more biological functions. Each member of the TNF family plays its role by binding to one or more members of its receptor protein matching family. In turn, these receptors send signals into the cell mediating various physiological or developmental responses. Most of these receptor signals determine cell fate and often trigger terminal differentiation. Examples of cell differentiation include proliferation, maturation, migration and death. [0003] Members of the TNF family are type II membrane-bound proteins with a short intramembrane N-terminal domain, a transmembrane domain, and a C-terminal receptor-binding domain that protrudes from the cell surf...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/09A61KA61K38/00A61K38/17A61K39/395A61P35/00C07K14/705C07K14/715C07K16/28C07K19/00
CPCA61K38/00A61K2039/505C07K14/70575C07K2319/30A61P35/00A61P43/00A61K38/16
Inventor 帕斯卡尔·施耐德杰弗里·汤普森特里萨·卡切罗克里斯廷·安布罗斯保罗·伦纳特
Owner BIOGEN MA INC
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