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Monoclonal antibodies against claudin-18 for treatment of cancer

A technology of antibodies and cancer cells, applied in the direction of anti-animal/human immunoglobulins, antibodies, immunoglobulins, etc., can solve problems such as inaccessibility of antibodies

Active Publication Date: 2014-01-15
ASTELLAS PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is possible that in healthy epithelium the binding epitope of claudin is shielded in tight junctions, making it inaccessible to these antibodies

Method used

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  • Monoclonal antibodies against claudin-18 for treatment of cancer
  • Monoclonal antibodies against claudin-18 for treatment of cancer
  • Monoclonal antibodies against claudin-18 for treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0501] 1. Generation of mouse antibodies against CLD18

[0502] a. Immunity:

[0503] Balb / c or C57 / BL6 mice were immunized with eukaryotic expression vectors encoding human CLD18 fragments (SEQ ID NO: 15, 16, 17, 18). In the presence of an adjuvant (such as CpG), 50 μg or 25 μg of plasmid DNA was injected into the quadriceps muscle (intramuscular, i.m.) on days 1 and 10 for the production of group 1 monoclonal antibodies, or on day 1 Day 1 and day 9, day 1 and day 11 or day 1, day 16 and day 36 for generation of a second set of antibodies (see Table 1b for details). CpG was injected intramuscularly along with cells transfected with CLD18A2 (SEQ ID NO: 1 ) alone or co-transfected with CLD18A2 and mouse soluble CD40L encoding RNA, PEI-Man was injected intramuscularly or intraperitoneally. Depending on the specific immunization protocol used, mouse sera were monitored for the presence of antibodies against human CLD18 by immunofluorescence microscopy between days 16 and 43. I...

example

[0551] The binding specificity of the identified mAbs to the CLD18A2 isoform was analyzed by flow cytometry. HEK293 cells stably expressing human CLD18A2 (HEK293-CLD18A2) and HEK293 cells stably expressing human CLD18A1 (SEQ ID NO: 7, 8) (HEK293-CLD18A1) were incubated with hybridoma supernatants containing monoclonal antibodies at 4°C After 30 minutes incubation with Alexa647-conjugated anti-mouse IgG secondary antibody and cells fixed or left unfixed and counterstained with PI. Binding was assessed by flow cytometry using a BD FACSArray. Figure 6 shows the Examples of two groups of mAbs identified in 175D10: (i) mAbs 43A11, 45C1 and 163E12 specifically bind human CLD18A2, but not human CLD18A1 ( Figure 6A , B), and (ii) mAb 37H8 binds to both human isoforms ( Figure 6A ).

[0552] e. Comparison of antibody binding to human CLD18A1 and CLD18A2 transfectants by immunofluorescence microscopy:

[0553]HEK293 cells were transiently transfected with an expression vector enc...

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Abstract

The present invention provides antibodies useful as therapeutics for treating and / or preventing diseases associated with cells expressing CLD18, including tumor-related diseases such as gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, and cancer of the gallbladder.

Description

[0001] This application is a divisional application of a Chinese patent application with application number 200680043664.X, and the original application is a Chinese national phase application of the international application PCT / EP2006 / 011302. technical field [0002] Antibody-based cancer therapies have the potential for higher specificity and lower side effect profiles than conventional drugs. This is due to the antibody's precise distinction between normal and neoplastic cells and the fact that its mode of action relies on less toxic immunological anti-tumor mechanisms, such as complement activation and recruitment of cytotoxic immune cells. [0003] Targets for antibody-based therapies must have specific properties, which form the basis for the correct distinction between normal and neoplastic cells. Clearly, targets that are exclusively localized in tumor cells and completely undetectable in normal tissues are ideal for the development of highly effective and safe antibo...

Claims

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Application Information

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IPC IPC(8): C07K16/28C12N5/20C12N5/07A61K39/395A61P35/00C12R1/91
CPCA61K47/48407A61K51/1063A61K47/48384A61K47/48615C07K2317/734C07K2317/732A61K47/48484A61K47/48453A61K47/48461C07K16/3046A61K47/48423C07K2317/73A61K47/6813A61K47/6821A61K47/6823A61K47/6829A61K47/6863A61K47/6809A61P35/00A61P35/04A61P43/00A61K39/395C07K16/30A61K47/50A61K47/6803A61K47/6851A61K47/6807A61K47/6859A61K39/3955A61K45/06A61K2039/505C07K16/18C07K2317/14C07K2317/24C07K2317/56C07K2317/51C07K2317/515C07K2317/565C07K16/28C07K2317/76A61K47/6869
Inventor 乌尔·沙欣厄兹莱姆·图雷奇迪尔克·乌泽纳斯特凡·弗里茨克里斯托夫·乌赫雷克贡达·勃兰登堡哈拉尔德-格哈德·格佩特安雅·克里斯蒂娜·施罗德菲利普·蒂尔
Owner ASTELLAS PHARMA INC
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