Anti-TRAIL-R antibody

a technology of anti-trail receptor and antibody, which is applied in the field of anti-trail receptor (trailr) antibodies, can solve the problems of insufficient theoretical support of selectivity, inability to obtain agonistic antibodies with no toxicity, and inability to demonstrate whether or not agonistic antibodies having no toxicity can be obtained

Inactive Publication Date: 2005-11-10
KIRIN BREWERY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0034] A first purpose of the present invention is to provide a novel antibody or a molecule analogous thereto, which is capable of binding to human TRAIL-R1 and / or human TRAIL-R2 and induces apoptosis specifically in carcinoma cells, without inducing damage to normal human hepatocytes to which a recombinant human TRAIL protein can cause damages. The novel antibody or a molecule analogous thereto also includes an antibody or a molecule analogous thereto which is capable of inducing apoptosis independently of exogenous factors and as a monomer in carcinoma cells. A second purpose of the present invention is to provide a prophylactic or therapeutic agent comprising the above antibody or a molecule analogous thereto as an active ingredient against various malignant tumors including solid tumors that are currently difficult to treat.

Problems solved by technology

It is thought that when cells which should originally be eliminated by apoptosis are not removed, this may cause cancer, lupus, herpes virus infection, hepatitis and other problems.
However, such selectivity has not yet been supported theoretically since TRAIL receptors are also expressed in normal cells.
Because agonistic anti-Fas antibodies, which induce apoptosis in hepatocytes, induce fulminant hepatitis in a very short time and thus cause death in mice and chimpanzees, cell death induction by TRAIL on hepatocytes has attracted attention as a particularly significant issue.
For example, in the case of a different antigen such as TRAIL, it has not been demonstrated whether or not agonistic antibodies having no toxicity can be obtained.
Furthermore, no research has been done based on the idea of whether hepatotoxicity can be avoided by adding TRAIL-R1 / R2 selectivity to agonistic antibodies.
A drug whose action mechanism is apoptosis induction by the recombinant human TRAIL may cause damages to normal tissues, particularly the liver and the brain, even if it is able to remove carcinoma cells.
In addition, if antibodies are those against TRAIL receptors, antibodies that may be obtained can avoid causing damage to the liver, which is unable to avoid with the recombinant human TRAIL, and have equivalent apoptosis-inducing activity against carcinoma cells.
Since a polymer antibody induces the formation of aggregates and may possibly cause adverse side effects, a polymer antibody is generally removed as much as possible.
Thus, in case where a polymer alone possesses the activity, the activity is lost by the increase of the purity of a monomer antibody.
Under these circumstances, an antibody which needs exogenous factors to exert its activity cannot always take anti-tumor effects.
However, since these antibodies have problems that include a shortening of a half life in blood, antigenicity and the like, and the usefulness as a pharmaceutical antibody may be lost, there are many problems to be solved.

Method used

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  • Anti-TRAIL-R antibody
  • Anti-TRAIL-R antibody
  • Anti-TRAIL-R antibody

Examples

Experimental program
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Effect test

example 1

Preparation of antigen

[0188] To obtain cells excessively expressing human TRAIL-R1 and R2 on the cell membrane, plasmid vectors for the expression of human TRAIL R1 and human TRAIL-R2 (which had been prepared by removing the death domain and the amino acids on the C-terminal side from the death domain in the intracellular regions from the full-length amino acids of the human TRAIL-R1 and R2, hereinafter referred to as TRAIL-R1 and R2delta,) were prepared. DNAs encoding TRAIL-R1 and R2delta were prepared by the PCR method.

a) Construction of Full-Length Human TRAIL-R1 and R2 Expression Vectors

[0189] To perform template PCR, plasmid vectors, pcDNA3-TRAIL-R1 and pcDNA3-TRAIL-R2, retaining cDNAs encoding human TRAIL-R1 and R2 were used as templates. pcDNA3-TRAIL-R1 and pcDNA3-TRAIL-R2 were constructed by the following method. The full-length human TRAIL-R1 DNA and TRAIL-R2 DNA were modified by polymerase chain reaction (PCR) to add an EcoR I sequence to the 5′ end, and a Not I sequen...

example 2

Generation of Human Antibody-Producing Mice

[0193] The mice used for immunization had a genetic background whereby they were homozygotes for both disrupted endogenous Ig heavy chain and κ light chain, and the mice harbored at the same time chromosome 14 fragment (SC20) containing a human Ig heavy chain locus, and a human Igκ chain transgene (KCo5). These mice were generated by crossing mice of a line A having a human Ig heavy chain locus with mice of a line B having a human Igκ chain transgene. The mice of line A are homozygotes for both disrupted endogenous Ig heavy chain and κ light chain, and harbor chromosome 14 fragment (SC20), which is transmittable to progeny, as is described, for example, in the report of Tomizuka et al. (Tomizuka. et al., Proc Natl Acad Sci USA., 2000 Vol 97: 722). Furthermore, the mice of line B (transgenic mice) are homozygotes for both disrupted endogenous Ig heavy chain and κ light chain, and harbor a human Igκ chain transgene (KCo5), as described, for ...

example 3

Preparation of Human Monoclonal Antibodies Against Human TRAIL-R1 and R2

[0195] In this example, monoclonal antibodies were prepared according to general methods as described in, for example, Introduction of Experimental Protocols for Monoclonal Antibody (Monoclonal Antibody Jikken Sosa Nyumon, written by Tamie ANDO et al., KODANSHA, 1991). As immunogens, the TRAIL-R1 and R2delta-expressing L929 cell prepared in Example 1 or a fusion protein of the extracellular regions of human TRAIL-R1 and R2 and the Fc region of human IgG1 was used. Animals used for immunization were the human antibody (human immunoglobulin)-producing mice generated in Example 2.

[0196] To prepare human monoclonal antibodies against human TRAIL-R1, human antibody-producing mice were initially immunized via the right foot pad with the TRAIL-R1delta-expressing L929 cells (3×106 cells / mouse) prepared in Example 1. After the initial immunization, immunization with the L929 cells was performed 10 times every 3 days vi...

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Abstract

Anti-TRAIL-R1 and R2 antibodies or functional fragments thereof, having at least one property selected from the following (a) to (c) of: (a) having activity to induce apoptosis in carcinoma cells expressing TRAIL-R1 and/or TRAIL-R2; (b) not having effect on normal human cells expressing TRAIL-R1 and/or TRAIL-R2; and (c) not inducing human hepatocyte toxicity, and an anti-TRAIL-R1 and R2 antibodies or functional fragments thereof, having the following properties: having activity to induce apoptosis in carcinoma cells independently of exogenous factors and as a monomer of an antibody.

Description

[0001] This a Continuation-In-Part Application of PCT / JP02 / 04816 filed May 17, 2002, and is incorporated herein in its entirety by reference.FIELD OF THE INVENTION [0002] The present invention relates to an anti-TRAIL receptor (TRAIL-R) antibody recognizing a TRAIL receptor 1 (TRAIL-R1) or a TRAIL receptor 2 (TRAIL-R2), which are cell membrane molecules involved in apoptosis. [0003] Furthermore, the present invention relates to a prophylactic or therapeutic agent, which contains anti-TRAIL-R antibody as an active ingredient and is used against diseases caused by cells expressing TRAIL-R, and in particular relates to a therapeutic agent used against malignant tumors. [0004] Furthermore, the present invention relates to a prophylactic or therapeutic agent, which contains anti-TRAIL-R antibody having the activity to induce apoptosis as a monomer independently of exogenous factors as an active ingredient and is used against diseases caused by cells expressing TRAIL-R, and in particular ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/28C12N1/19C12N1/21C12N15/13C12P21/08
CPCA61K2039/505C07K2317/73C07K16/2878A61P35/00A61P35/02A61P43/00C07K16/28
Inventor MORI, EIJIMOTOKI, KAZUHIROKATAOKA, SHIRO
Owner KIRIN BREWERY CO LTD
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