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Method of modulating the activity of functional immune molecules

a functional immune and molecule technology, applied in the field of immunologically functional molecule activity control, can solve the problems of insufficient anti-tumor effect of an antibody alone in many current cases, and achieve the effects of reducing dependence on chemotherapy, increasing adcc activity, and increasing the therapeutic

Inactive Publication Date: 2005-12-08
KYOWA HAKKO KIRIN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] An object of the present invention is to specify a sugar chain which increases the ADCC activity, by analyzing sugar chains of human IgG1 subclass antibodies produced by various animal cells, and to thereby also provide a method for controlling the activity of an immunologically functional molecule. Since the ADCC activity is improved in such antibodies, increase in the therapeutic effect for various human diseases can be expected by use of not only anti-tumor antibodies but also anti-other diseases antibodies, as well as proteins or peptides against various diseases. Particularly, in the clinical application of anti-tumor antibodies, the anti-tumor effect of an antibody alone is insufficient in many of current cases. The insufficiencies of known antibodies have required the concomitant use of chemotherapy (Science, 280, 1197, 1998). The dependency on chemotherapy however will be reduced, with a reduction of side effects, if a stronger anti-tumor effect of an antibody alone is provided by the improvement of ADCC activity. The present inventors have evaluated in vitro activity of various humanized antibodies of human IgG1 subclass produced by two kinds of Chinese hamster ovary cells, CHO / dhFr cell (ATCC CRL 9096) and CHO / DG44 cell (Somatic Cell and Molecular Genetics, 12, 555 (1986)), mouse myeloma NS0 cell (RCB 0213, BIO / TECHNOLOGY, 10, 169 (1992)), mouse myelbma SP2 / 0-Ag14 cell (hereinafter referred to as “SP2 / 0 cell”; ATCC CRL 1581) and rat myeloma YB2 / 3HL.P2.G11.16Ag.20 cell (hereinafter referred to as “YB2 / 0 / cell”; ATCC CRL 1662) and have discovered, as a result, that the ADCC activity of a humanized antibody produced by the rat myeloma YB2 / 0 cell is considerably higher than that of the humanized antibodies produced by other cells. Further, as a result of an in vivo activity evaluation using Macaca faseicularis, it has been discovered that the humanized antibody produced by YB2 / 0 cell shows the greatest effect, suggesting the utility of an antibody having elevated ADCC activity in a human clinical application. In addition, a sugar chain having the ability to increase the ADCC activity has been identified by analyzing and comparing structures of the sugar chains of humanized antibodies produced by various animal cells in detail, and the present invention has been accomplished.

Problems solved by technology

Particularly, in the clinical application of anti-tumor antibodies, the anti-tumor effect of an antibody alone is insufficient in many of current cases.

Method used

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  • Method of modulating the activity of functional immune molecules
  • Method of modulating the activity of functional immune molecules
  • Method of modulating the activity of functional immune molecules

Examples

Experimental program
Comparison scheme
Effect test

example 1

Production of Anti-Ganglioside GD3 Human Chimeric Antibody:

1. Construction of Tandem Expression Vector, pChiLHGM4, for anti-ganglioside GD3 human chimeric antibody

[0217] A plasmid, pChi641LGM40, was constructed by ligating a fragment of about 4.03 kb containing an L chain cDNA, obtained by digesting an L chain expression vector, pChi641LGM4 (J. Immunol. Methods, 167, 271 (1994)) for anti-ganglioside GD3 human chimeric antibody (hereinafter referred to as “anti-GD3 chimeric antibody”) with restriction enzymes, MulI (manufactured by Takara Shuzo) and SalI (manufactured by Takara Shuzo), with a fragment of about 3.40 kb containing a G418-resistant gene and a splicing signal, obtained by digesting an expression vector pAGE107 (Cytotechnology, 3, 133 (1990)) for animal cell with restriction enzymes, MulI (manufactured by Takara Shuzo) and SalI (manufactured by Takara Shuzo), using DNA Ligation Kit (manufactured by Takara Shuzo), and then transforming E. coli HB101 (Molecular Cloning:...

example 2

Activity Evaluation of Anti-GD3 Chimeric Antibody:

1. Binding Activity of Anti-GD3 Chimeric Antibodies to GD3 (ELISA)

[0234] The activity of the five purified anti-GD3 chimeric antibodies obtained in the above item 4 of Example 1 to bind to GD3 (manufactured by Snow Brand Milk Products) was measured by the ELISA shown in the item 3 of Example 1. FIG. 2 shows a result of the examination of the binding activity measured by changing the concentration of the anti-GD3 chimeric antibody to be added. AS shown in FIG. 2, the five anti-GD3 chimeric antibodies showed almost the same binding activity to GD3. This result shows that antigen binding activities of these antibodies are constant independently of the antibody producing animal cells and their culturing methods. Also, it was suggested from the comparison of the NS0-GD3 chimeric antibody (302) with the NS0-GD3 chimeric antibody (GIT) that the antigen binding activities are constant independently of the media used in the culturing.

2....

example 3

Production of Anti-Human Interleukin 5 Receptor a Chain Human CDR-Grafted Antibody:

1. Production of Cells Stably Producing Anti-Human Interleukin 5 Receptor α Chain Human CDR-Grafted Antibody

(1) Production of Producer Cell Using Rat Myeloma YB2 / 0 Cell

[0240] Using the anti-human interleukin 5 receptor α chain human CDR-grafted antibody (hereinafter referred to as “anti-hIL-5R α CDR-grafted antibody”) expression vector, pKANTEX1259HV3LV0, described in WO 97 / 10354, cells capable of stably producing anti-hIL-5R α CDR-grafted antibody were prepared as described below.

[0241] After introducing 5 μg of the anti-hIL-5R α CDR-grafted antibody expression vector, pKANTEX1259HV3LV0, into 4×106 cells of rat myeloma YB2 / 0 by electroporation (Cytotechnology, 3, 133 (1990)), the cells were suspended in 40 ml of RPMI1640-FBS(10) and dispensed in 200 μl / well into a 96 well culture plate (manufactured by Sumitomo Bakelite). Twenty-four hours after culturing at 37° C. in a 5% CO2 incubator, G418 ...

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Abstract

The invention relates to a method for controlling the activity of an immunologically functional molecule, such as an antibody, a protein, a peptide or the like, an agent of promoting the activity of an immunologically functional molecule, and an immunologically functional molecule having the promoted activity.

Description

[0001] The present application is a divisional of U.S. Ser. No. 09 / 958,307, filed Oct. 9, 2001 (pending), which is a 371 U.S. national phase of PCT / JP00 / 02260, filed Apr. 7, 2000, which claims benefit of JP 11.103158, filed Apr. 9, 1999, the entire the entire contents of each of which is hereby incorporated by reference.TECHNICAL FIELD [0002] The present invention relates to a method for controlling the activity of an immunologically functional molecule, such as an antibody, a protein, a peptide or the like, an agent of promoting the activity of an immunologically functional molecule, and an immunologically functional molecule having the promoted activity. BACKGROUND ART [0003] Since antibodies have high binding activity, binding specificity and high stability in blood, their applications to the diagnosis, prevention and treatment of various human diseases have been attempted (Monoclonal Antibodies: Principles and Applications, Wiley-Liss, Inc., Chapter 2.1 (1995)). However, an anti...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07K16/28C07K16/30C07K16/46C12P21/08G01N33/53
CPCA61K2039/505C07K16/2866C07K16/30C07K16/3084C07K2317/24C07K2317/41C12P21/005C07K2317/732C07K2319/00G01N33/53C07K2317/52C07K2317/21C07K2317/565C07K2317/73A61P29/00A61P31/00A61P35/00A61P37/00A61P37/06A61P37/08A61P9/00
Inventor HANAI, NOBUONAKAMURA, KAZUYASUHOSAKA, EMIYAMASAKI, MOTOOUCHIDA, KAZUHISASHINKAWA, TOYOHIDEIMABEPPU, SUSUMUKANDA, YUTAKAYAMANE, NAOKOANAZAWA, HIDEHARU
Owner KYOWA HAKKO KIRIN CO LTD
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