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new anti-dr5 antibody

A technology of antibodies and chimeric antibodies, applied in the direction of antibodies, antibody medical components, antibody mimics/stents, etc., can solve problems such as no correlation

Active Publication Date: 2017-06-09
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order for such antibodies to have an antitumor effect, it is necessary that the cells express DR5, however, it has been revealed in preclinical tests that there is no correlation between the effect and the expression level of DR5 (Non-Patent Document 4)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0394] [Example 1] Production of mouse antibody B273

[0395] 1)-1 Production of human DR5 protein (human DR5 extracellular domain / human Fc fusion protein)

[0396] 1)-1-1 Production of human DR5 extracellular domain expression vector

[0397] A vector expressing human DR5 protein (isoform 2: NP_671716) was constructed by inserting a gene in which the extracellular domain of human DR5 was fused to the human IgG1 / Fc region downstream of the CMV promoter.

[0398] 1)-1-2 Production of human DR5 protein

[0399] Introduction of the expression vector into 293 FreeStyle cells and collection of the culture supernatant were performed by Invitrogen Corporation (now Life Technologies Japan Ltd.).

[0400] 1)-1-3 Purification of human DR5 protein

[0401] The culture supernatant obtained in b) above was purified using protein A affinity column chromatography. 5 L of the culture supernatant was applied to "HiTrap Protein AFF" (GE Healthcare Bio-Sciences Co., Ltd., catalog number 17-5...

Embodiment 2

[0428] [Example 2] Cloning of mouse antibody B273 gene and production of human chimeric antibody gene

[0429] 2)-1 Cloning and sequence determination of mouse antibody B273 cDNA

[0430] 2)-1-1 Determination of N-terminal amino acid sequences of heavy chain and light chain of mouse antibody B273

[0431]In order to determine the N-terminal amino acid sequences of the heavy and light chains of the mouse antibody B273, the mouse antibody B273 purified in Examples 1-8 was separated by SDS-PAGE. After separation, the protein in the gel was transferred from the gel to a PVDF membrane (pore size: 0.45 μm, manufactured by Invitrogen Corporation). The membrane was washed with wash buffer (25 mM NaCl, 10 mM sodium borate buffer, pH 8.0) and thereafter stained by immersion in dye solution (50% methanol, 20% acetic acid, 0.05% Coomassie brilliant blue) for 5 minutes, followed by 90% Methanol decolorizes. The band corresponding to the heavy chain (band with smaller mobility) and the b...

Embodiment 3

[0472] [Example 3] Measurement of human chimeric B273 (cB273) antibody activity (in vitro)

[0473] 3) Study on the selective binding properties of -1 cB273 antibody to the extracellular domain of human DR5

[0474] The binding properties of cB273 to human TRAIL R1-R4 and mouse TRAIL R2 extracellular domain proteins (manufactured by R&D Systems, Inc.) were investigated by the direct ELISA method described below. First, each of the ectodomain proteins of TRAIL R was diluted to 1 μg / ml with PBS, and the diluted solution was distributed in an immunoplate (manufactured by Nunc, Inc., #442404) at 50 μl / well, and the plate was incubated at 4 The protein was thus adsorbed to the plate by standing overnight at ℃. The next day, the liquid in each well was removed, and each well was washed once with PBS. Thereafter, in order to suppress non-specific adsorption of proteins, 200 μl / well of PBS containing 3% fetal bovine serum was dispensed, and the plate was allowed to stand at room tem...

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Abstract

The present invention relates to antibodies having a therapeutic effect on cancer, autoimmune or inflammatory diseases. That is, the present invention relates to an antibody that exhibits apoptosis-mediated cytotoxicity against cells expressing a death domain-containing receptor. The present invention solves the problem of providing a medicament having a therapeutic effect on cancer. The present invention elucidates a novel anti-DR5 antibody, which is capable of inducing apoptosis in cells, and has significant cytotoxic activity compared with conventional anti-DR5 antibodies.

Description

[technical field] [0001] The present invention relates to an antibody that binds to a cell surface receptor involved in the induction of apoptosis and can be used as a tumor therapeutic and / or preventive agent, and also relates to the use of the antibody for the treatment and / or prevention of cancer, autoimmune disease or inflammatory disease method. [Background technique] [0002] Apoptosis is a phenomenon essential to the physiological process of removing unnecessary or damaged cells in the body while maintaining normal cell numbers. New cells that can be used for the treatment of cancer or immune diseases due to the elucidation of the fact that the regulatory mechanisms of apoptosis are often impaired in cancer or immune diseases, and also the elucidation of the regulatory pathways of apoptosis The development of apoptosis inducers has also been facilitated. Antibodies with binding affinity for ligands of cell surface receptors involved in the induction of apoptosis (ch...

Claims

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Application Information

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IPC IPC(8): C12N15/09A61K31/337A61K31/475A61K39/395A61P35/00A61P43/00C07K16/28C12N1/15C12N1/19C12N1/21C12N5/10C12P21/08
CPCA61K31/337A61K31/439A61K31/4545A61K31/4745A61K31/475A61K31/513A61K31/555A61K39/3955A61K39/39558A61K45/06C07K16/2878C07K16/30A61K2039/505A61K2300/00C07K2299/00C07K2317/92C07K2319/30C07K2317/24C07K2317/55C07K2317/515C07K2317/51C07K2317/34C07K2317/73C07K14/70578A61P35/00A61P43/00A61K38/17A61K38/18A61K39/395A61K48/00C07K14/435C07K14/475C07K16/18C07K16/22C07K16/24C07K16/28C07K19/00
Inventor 大塚敏明泷泽刚小国晶子松冈达司好田宏子松井由美
Owner DAIICHI SANKYO CO LTD
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