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

[0008]The present invention provides an anti-Erb B2 / neu antibody that is conjugated with maytansinoid molecules, thus targeting disease cells or tissues. The anti-Erb B2 / neu antibody binds to an antigen in the disease cells or tissues. A drug conjugated to the antibody exerts a cytotoxic, cytostatic, or immunosuppressive effect on the antigen-expressing cells to treat or prevent recurrence of ERB B2 / NEU-positive cancers. The high affinity of the antibody drug conjugate ensure that the cytotoxic maytansinoid targets the tumor cells. Otherwise, the highly toxic maytansinoid will become systemically bound to unintended targets which results in very high and often unacceptable toxicity. The present technology provides a method to treat cancers by exerting cellular inhibitory or killing effect of maytansinoid on the ERB B2 / NEU positive cells, while minimizing the undesirable side effects of maytansinoid, such as bystander killing effects on antigen negative cells.
[0009]In one aspect, provided is an anti-Erb B2 / neu antibody conjugated with a maytansinoid compound, wherein the maytansinoid compound is d linked to an anti-Erb B2 / neu antibody via a linker that is not acid labile, not peptidase cathepsin sensitive, and does not contain a disulfide bond and provides stability during circulation while being able to release the drug once inside the cells. Such linkers are contemplated to provide stability to the conjugated molecule prior to endocytosis, such as during circulation, to prevent premature degradation of the linker and release of the toxic drug, thus minimize the toxic effect of the drug. In some embodiments, the maytansinoid-linker portion of the conjugate is N2′-deacetyl-N2′-(6-maleimido-1-oxo-hexyl)-maytansine (3AA-MDC or batansine), or a derivative thereof. In some embodiments, the conjugate has a high drug load of at least 3 drug molecules per antibody for improved activity. Surprisingly, the antibody remain sufficiently stable for targeted delivery of the drug to target cells despite the high drug load.

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
CPCA61K47/48723A61K47/6889A61K47/6809A61K47/6849A61K31/537A61K47/6803A61K47/6855A61P1/00A61P19/02A61P29/00A61P35/00A61P35/02A61P37/00A61P37/06A61P3/10C07K16/32A61K47/6899A61K47/6851
Inventor TANG, WEIJIALI, SHENGFENGYU, JIN-CHENDENG, XIAOBIN
Owner BIO THERA SOLUTIONS LTD
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