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Researchers Submit Patent Application, "Cell for Use in Immunotherapy Which Contains Modified Nucleic Acid Construct Encoding Wilms Tumor Gene...

July 14, 2014



Researchers Submit Patent Application, "Cell for Use in Immunotherapy Which Contains Modified Nucleic Acid Construct Encoding Wilms Tumor Gene Product Or Fragment Thereof, Method for Producing Said Ce

By a News Reporter-Staff News Editor at Cancer Gene Therapy Week -- From Washington, D.C., NewsRx journalists report that a patent application by the inventors Fujii, Shin-ichiro (Yokohama-shi, JP); Shimizu, Kanako (Yokohama-shi, JP); Shinga, Jun (Yokohama-shi, JP), filed on July 30, 2012, was made available online on July 3, 2014 (see also Riken).

The patent's assignee is Riken.

News editors obtained the following quote from the background information supplied by the inventors: "Antitumor effects of an NKT cell which have been known so far include (i) a direct effect on a tumor and (ii) an indirect effect on a tumor via maturation of a dendritic cell (adjuvant effect). As an immunotherapy using the NKT cell, an immunotherapy involving administration of a dendritic cell presenting a tumor antigen has been known, and studies for clinical application of such the immunotherapy have been conducted (Non-Patent Literatures 1 through 7). Further, an antigen-specific immunotherapy using a dendritic cell into which mRNA encoding a tumor antigen is introduced has been already established and clinically applied (Non-Patent Literatures 8 through 15). In order to introduce, into a cell material to be used, an antigen for immune induction in such immunotherapies, it is simple and easy to use an expression vector or the like. However, in a case where the expression vector is introduced into the cell in such an immunotherapy, that immunotherapy may be regarded as a gene therapy and application range thereof may be limited due to regulations. As a measure for avoiding this, introduction of RNA into a dendritic cell has been considered. However, this involves problems of a low introduction efficiency of RNA and a low expression level of a tumor antigen in the dendritic cell. In order to improve therapeutic effects of these immunotherapies, attempts to try various combinations with adjuvants have been made.

"Another immunotherapy for a tumor is a peptide therapy involving use of a plurality of epitopes contained in a WT1 protein encoded by a Wilms tumor gene (Wilms tumor 1: WT1).

"Meanwhile, the inventors of the subject application have developed unique immunotherapies (Patent Literatures 1, 2, etc.). Disclosed in Patent Literature 1 are (i) an abnormal cell which is isolated from a patient and has, on its surface, CD1d presenting an NKT cell ligand and (ii) a method for producing the cell (Patent Literature 1). This cell is capable of inducing both activation of NKT cells and tumor-specific immune response of T-cells. Disclosed in Patent Literature 2 are (i) an allo-cell which is not derived from a patient and has, on its surface, CD1d presenting an NKT cell ligand and in which a disease-specific antigen is expressed and (ii) a method for producing the cell. This allo-cell is capable of exhibiting immune inducibility similar to that of the cell disclosed in Patent Literature 1 without being isolated from a patient. Such the immunotherapies are expected to be applied to various antitumor immunotherapies for leukemia etc."

As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventors' summary information for this patent application: "Technical Problem

"The immunotherapies developed by the inventors of the subject application can improve therapeutic effect in combination with an adjuvant, as with the conventional immunotherapies. However, the inventors of the present invention found that, according to the immunotherapies, a cell itself to be administered is a target to be attacked by an immune system of a patient and accordingly an increase in an expression level of the tumor antigen protein therein greatly contributes to an increase in efficiency of the immune induction. The expression level of the tumor antigen protein is improved by increasing an amount of RNA to be introduced. The improvement in the expression level of the tumor antigen protein in this case is almost proportional to the amount of the RNA to be introduced. However, a total amount of RNA which can be introduced into a cell is limited. Therefore, in a case where, for example, another RNA (such as RNA encoding CD1d) is further introduced into the cell, the expression level of the tumor antigen protein may not be improved to a desired level. In view of this, it is desirable to remarkably enhance the expression level of the tumor antigen protein while suppressing the amount of the RNA to be introduced as much as possible.

"In view of the above problem found by the inventors of the present application, an object of the present invention is to remarkably enhance an expression level of a WT1 protein in a cell independently of an expression regulating element contained in an expression vector or the like, in a case where the WT1 protein is selected as a tumor-specific antigenic protein. That is, the object of the present invention is to provide (i) a cell which contains a modified WT1 nucleic acid construct so that an expression level of a WT1-derived polypeptide is enhanced therein independently of DNA and (ii) a modified WT1 nucleic acid construct to be introduced into the cell.

"Solution to Problem

"The inventors of the present invention found that an expression level of a WT1-derived polypeptide is enhanced far beyond expectations by introducing a mutation into a publicly-known nucleic acid sequence of WT1. Such modified WT1 has not been known so far that allows the remarkable increase in the expression level of the polypeptide. The inventors of the present invention accomplished the present invention as a result of studies based on this finding. Specifically, in order to attain the above object, the present invention includes the following features:

"A cell for immunotherapy, including: a nucleic acid construct encoding a Wilms tumor gene product or a fragment of the Wilms tumor gene product, the nucleic acid construct including (i) a region encoding a fragment of the Wilms tumor gene product, the fragment being indicated by positions 194 to 493 of SEQ ID NO: 1 or by positions corresponding to the positions 194 to 493 of a sequence corresponding to SEQ ID NO: 1 and (ii) only one AUG as a functional start codon, connected to a 5' terminal side of the region via 3m (m is 0 or a positive integer) bases intervening between the 5' terminal side of the region and the AUG as the functional start codon.

"Advantageous Effects of Invention

"According to the present invention, it is possible to provide (i) a cell for immunotherapy into which a nucleic acid construct is introduced so that an expression level of a WT1 gene product or a fragment of the WT1 gene product is enhanced therein independently of an expression regulating element contained in an expression vector or the like and (ii) the nucleic acid construct. Such the cell and nucleic acid construct are applicable to an effective immunotherapy independent of a gene therapy.

BRIEF DESCRIPTION OF DRAWINGS

"FIG. 1 is a view illustrating results of assay of proteins from a nucleic acid construct of the present invention for expression levels."

For additional information on this patent application, see: Fujii, Shin-ichiro; Shimizu, Kanako; Shinga, Jun. Cell for Use in Immunotherapy Which Contains Modified Nucleic Acid Construct Encoding Wilms Tumor Gene Product Or Fragment Thereof, Method for Producing Said Cell, and Said Nucleic Acid Construct. Filed July 30, 2012 and posted July 3, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=3034&p=61&f=G&l=50&d=PG01&S1=20140626.PD.&OS=PD/20140626&RS=PD/20140626

Keywords for this news article include: Antigen-Presenting Cells, Biotechnology, Riken, Immunology, Gene Therapy, Immunotherapy, Bioengineering, Dendritic Cells, Immunomodulation, Mononuclear Phagocyte System.

Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2014, NewsRx LLC


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Source: Cancer Gene Therapy Week


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