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Npp1 fusion proteins

a fusion protein and protein technology, applied in the field of npp1 fusion proteins, can solve the problems of no treatment available in the art for those affected by diseases, and achieve the effects of enhancing the efficiency of targeting the npp1 fusion protein, enhancing the formation of pyrophosphate (ppi), and inhibiting calcification

Inactive Publication Date: 2014-06-05
ALEXION PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The NPP1 fusion proteins effectively target and inhibit calcification, providing a potential treatment for conditions like IIAC, insulin resistance, and ossification of the posterior longitudinal ligament of the spine by enhancing pyrophosphate formation and solubilizing phosphate, thereby reducing or preventing calcification structures.

Problems solved by technology

Although defects in the NPP1 protein have been implicated in such serious disease as IIAC, there is no treatment available in the art for those who are affected by the disease.

Method used

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Examples

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examples

[0105]The present invention is further exemplified by the following examples. The examples are for illustrative purpose only and are not intended, nor should they be construed as limiting the invention in any manner.

example i

[0106]The TAGsNNP1 construct containing the targeting moiety having eight consecutive aspartic acids fused to sNPP1 was ligated into pTT22 vector using EcoRI and HindIII sites (pTT22-sNPP1.D8; FIG. 19). pTT22-sNPP1.D8 was transfected into HEK203E cells and the transformants were cultured to express TAGsNNP 1. TAGsNNP 1 was isolated from the culture media and partially purified as well known in the art. Following the purification, the pyrophosphase / phosphodiesterase activity of TAGsNPP1 was measured for its ability to hydrolyze thymmidine 5′ monophosphate p-nitrophenyl ester. Briefly, TAGsNPP1 was diluted to 1 ng / μL in 50 mM Tris, 250 mM NaCl, pH 9.5. In a plate containing 50 μL of 1 ng / μL TAGsNPP1, 50 μL of 10 mM thymmidine 5′ monophosphate p-nitrophenyl ester (Sigma™, Catalog #T4510) substrate was added. The enzyme activity of TAGsNPP1 was measured at 405 nm (absobance) in kinetic mode for 5 minutes. As shown in FIG. 21, the activity of TAGsNPP1 was detected above the level observe...

example ii

[0107]This non-limiting prophetic example describes how to treat idiopathic infantile arterial calcification by administering a formulation comprising a TAGNPP1 fusion protein.

[0108]A clinician uses a diagnostic test to verify that a patient has high levels of calcification in the artery. A genetic test can be also performed for NPP1 defects as described in Rutsch et al. (2003), Nature Genetics 34:379-81.

[0109]The pharmaceutical compositions of the present invention are preferably administered intravenously, although interadermal, intramuscular or oral administration are employed in certain circumstances.

[0110]The clinician determines a dose which may vary depending on the gender, age, health, and weight of the patient. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary physician.

[0111]The formulation containing TAGNPP1 can be infused, between about 10 mg / kg and about 1000 mg / kg per week weekly. 10-30 mg / kg can be administe...

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Abstract

The present invention provides a novel fusion polypeptide containing a catalytic domain of NPP1 fused to a targeting moiety, nucleic acids encoding the fusion polypeptide, a vector containing the nucleic acid integrated thereinto, a host cell transformed with the vector and pharmaceutical compositions comprising the fusion polypeptide.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of PCT / US2011 / 028233, filed Mar. 11, 2011, which claims the benefit of U.S. Provisional Application No. 61 / 340,066, filed on Mar. 12, 2010. The entire teachings of the above application are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Ectonucleotide pyrophosphatase / phosphodiesterase 1 (NPP1 / ENPP1 / PC-1) is a type II transmembrane glycoprotein that forms a homodimer. The protein cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. NPP1 protein functions to hydrolyze nucleoside 5′ triphosphtase to either corresponding monophosphates and also hydrolyzes diadenosine polyphosphates. Mutations in the NPP1 gene have been associated with idiopathic infantile arterial calcification (IIAC), insulin resistance, hypophosphatemic rickets, and ossification of the posterior longitudinal ligament of the spine....

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N9/96C12N9/14
CPCC07K2319/02C07K2319/33C12N9/22C07K2319/01C12N9/00C07K2319/30A61K38/00C12N15/625Y10S530/827C12N9/16C12Y301/04001C12N9/96A61P19/02A61P19/08A61P21/00A61P7/00A61P9/00A61P9/10A61P3/10C07K2319/00C07K7/06C12N15/8509C12N15/86C12N2840/007
Inventor QUINN, ANTHONYHARVEY, ALEX J.XIA, ZHINAN
Owner ALEXION PHARMA INC
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