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Compounds and methods for the treatment of erb b2/neu positive diseases

a technology of erb b2/neu positive disease and compounds, which is applied in the field of compounds and methods for the treatment of erb b2/neu positive diseases, can solve the problems of high and often unacceptable toxicity, and achieve the effects of reducing the undesirable side effects of maytansinoid, preventing recurrence, and reducing the number of side effects

Inactive Publication Date: 2014-06-26
BIO THERA SOLUTIONS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a new treatment for breast cancers that targets a specific protein called Erb B2 / neu. The treatment involves using an antibody that is attached to a toxic drug called maytansinoid. The antibody specifically targets the cancer cells and the toxic drug works to kill or inhibit their growth. The new technology ensures that the toxic drug is only released once inside the cancer cells, minimizing its toxic effects on other cells in the body. This approach increases the effectiveness and reduces the toxicity of the treatment. The antibody is connected to the drug using a stable linker that does not release the drug during circulation. The resulting treatment has a high drug load and remains stable for targeted delivery to cancer cells.

Problems solved by technology

Otherwise, the highly toxic maytansinoid will become systemically bound to unintended targets which results in very high and often unacceptable toxicity.

Method used

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  • Compounds and methods for the treatment of erb b2/neu positive diseases
  • Compounds and methods for the treatment of erb b2/neu positive diseases
  • Compounds and methods for the treatment of erb b2/neu positive diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Esterification of Maytansinol with Fmoc-N-methyl-L-alanine (Fmoc-N-Me-D / L-Ala-MDC)

[0144]

[0145]A mixture of maytansinol (0.600 g, 1.062 mmol), Fmoc-N-Me-L-Ala (6.911 g, 21.24 mmol), Sc(OTf)3 (0.314 g, 0.637 mmol) and DMAP (0.389 g, 3.186 mmol) in CH2Cl2 (100 mL) was stirred for 0.5 h at −8° C. DIC (2.949 g, 23.37 mmol) was added dropwise, stirred for 0.5 h, warmed to r.t. slowly, filtered to recover the Lewis acid catalyst, the filtrate was quenched with diluted HCl and extracted with CH2Cl2. The combined organic phase was washed with NaHCO3 aq, brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. Chromatography (silica gel, CH2Cl2 / MeOH 30:1) gave the desired product as a mixture of diastereomer Fmoc-N-Me-D / L-Ala-MDC: white solid (0.8385 g, 90.5%). Further column chromatography (silica gel, CH2Cl2 / MeOH 100:1 to 20:1) gave two fractions as pure diastereomer. The higher Rf fraction was determined to be the D-aminoacyl ester diastereomer (Fmoc-N-Me-D-Ala-M...

example 2

Deprotection of Fmoc-N-Me-D / L-Ala-MDC (N-Me-D / L-Ala-MDC)

[0146]

[0147]Into Fmoc-N-Me-D / L-Ala-MDC (0.463 g, 0.5307 mmol) in ACN (200 mL) was added piperidine (0.865 g, 10.15 mmol). The mixture was stirred at r.t. for 4 h, quenched with water and extracted with CH2Cl2. The combined organic phase was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to give the crude product, which was used in the next step without further purification. LC-MS (M+H+) calc.: 650.3, found: 650.3. Rt: 3.96 min.

example 3

Deprotection of Fmoc-N-Me-L-Ala-MDC (N-Me-L-Ala-MDC)

[0148]

[0149]Into Fmoc-N-Me-L-Ala-MDC (0.463 g, 0.5307 mmol) in ACN (200 mL) was added piperidine (0.865 g, 10.15 mmol). The mixture was stirred at r.t. for 4 h, quenched with water and extracted with CH2Cl2. The combined organic phase was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to give the crude product, which was used in the next step without further purification. LC-MS (M+H+) calc.: 650.3, found: 650.3. Rt: 3.96 min.

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Abstract

Disclosed herein are anti-ERB B2 / NEU antibodies conjugated with maytansinoid drugs for targeted delivery to disease tissues. Methods relating to the preparation and uses of such drug conjugates to treat ERB B2 / NEU positive cells in cancers are provided.

Description

FIELD OF INVENTION[0001]The present invention generally relates to compounds comprising antibodies, antigen-binding fragments thereof, polypeptides, and immunoconjugates that bind to ERB B2 / NEU (HER2). The present invention also relates to methods of using such ERB B2 / NEU-binding molecules for diagnosing and treating diseases, such as malignancies.BACKGROUND OF INVENTION[0002]The ErbB2 / NEU (HER2) receptor is amplified and overexpressed in 20% to 25% of human breast cancer and also predictive of poor clinical outcome, ErbB2 / NEU (HER2) receptor was recognized and validated for targeted antibody therapy. Trastuzumab (Herceptin), a humanized anti-ErbB2 / NEU receptor antibody was approved by the Food and Drug Administration in 1998 for use in metastatic breast cancer and later on for gastric cancer. Despite the clinical benefits, a significant proportion of patients treated with trastuzumab either do not respond initially or relapse after experiencing a period of clinical response. There ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/48
CPCA61K47/48723A61K47/6889A61K47/6809A61K47/6849A61K31/537A61K47/6855A61P1/00A61P19/02A61P29/00A61P35/00A61P35/02A61P37/00A61P37/06A61P3/10A61K47/68033C07K16/32A61K47/6899A61K47/6851
Inventor TANG, WEIJIALI, SHENGFENGYU, JIN-CHENDENG, XIAOBIN
Owner BIO THERA SOLUTIONS LTD
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