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Compositions and methods for diagnosing and treating cancer

A therapeutic agent, antibody technology, applied in the field of oncology, can solve problems such as failure of treatment methods

Inactive Publication Date: 2012-11-21
ONCOMED PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Indeed, mutations in the long-lived stem cell population can trigger the formation of cancer stem cells that form the basis for tumor growth and maintenance, and whose presence contributes to the failure of current therapies

Method used

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  • Compositions and methods for diagnosing and treating cancer
  • Compositions and methods for diagnosing and treating cancer
  • Compositions and methods for diagnosing and treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] Example 1 Preparation of monoclonal DLL4 antibody and humanized DLL4 antibody

[0184] Antigen preparation

[0185] The recombinant polypeptide fragment of the extracellular domain of human DLL4 was prepared as an antigen for antibody preparation. The polynucleotide encoding amino acids 1-522 of DLL4 (SEQ ID NO: 25) was isolated using standard recombinant DNA techniques. The polynucleotide is N-terminally linked in frame to a human Fc tag or a histidine tag and cloned into a transfer plasmid vector for baculovirus-mediated expression in insect cells. Standard transfection, infection, and cell culture procedures are used to generate recombinant insect cells expressing the corresponding DLL4 polypeptides (O'Reilley et al., Baculovirus expression vectors: A Laboratory Manual, Oxford: Oxford University Press (1994)).

[0186] Cleavage of the endogenous signal sequence of human DLL4 was simulated using the cleavage prediction software SignalP 3.0, but the actual in vivo ...

Embodiment 2

[0211] Example 2: In vitro assays to evaluate antibodies against DLL4

[0212] This example describes a representative in vitro assay for testing the activity of antibodies raised against DLL4 on cell proliferation, Notch pathway activation, and cytotoxicity.

[0213] Proliferation assay

[0214] Taqman analysis was used to quantify the expression of DLL4 in different cancer cell lines. In 96-well tissue culture microplates, 10 4 The density of cells / well will be identified as the DLL4-expressing cell line is plated and allowed to expand for 24 hours. Cells were then cultured for a further 12 hours in fresh DMEM containing 2% FCS, at which time antibodies against DLL4 and control antibodies were added to the medium in the presence of 10 μmol / LBrdU. After BrdU labeling, the medium was removed, cells were fixed in ethanol for 30 minutes at room temperature, and reacted with peroxidase-conjugated anti-BrdU monoclonal antibody (BMG 6H8 clone, Fab fragment) for 90 minutes. Th...

Embodiment 3

[0223] Example 3: Prevention of tumor growth in vivo using antibodies against DLL4

[0224] This example describes the use of anti-DLL4 antibodies to prevent tumor growth in a xenograft model. In certain embodiments, tumor cells that have been passaged in mice as xenografts from patient samples (eg, solid tumor biopsies or pleural effusions) are prepared for passage into experimental animals. Tumor tissue was removed under sterile conditions, cut into small pieces, completely minced with a sterile blade, and single-cell suspension was obtained by enzymatic digestion and mechanical disruption. Specifically, pleural effusion cells or the resulting tumor mass were mixed with ultrapure collagenase III in culture medium (200-250 units collagenase / mL) and incubated at 37°C for 1-4 hours, every 15-20 minutes Pipette up and down through a 10 mL pipette. Digested cells were filtered through 40 [mu]M nylon mesh and washed with Hank's buffered saline solution (HBSS) (pH 7.4) containing...

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Abstract

An isolated antibody that specifically binds to an extracellular domain of human DLL4 and affects growth of a tumor comprising cancer stem cells is described. Also described is a method of treating cancer comprising administering a therapeutically effective amount of an anti-DLL4 antibody.

Description

technical field [0001] The present invention relates to the field of oncology and provides novel compositions and methods for the diagnosis and treatment of cancer. The present invention provides an anti-cancer stem cell marker antibody for diagnosing and treating solid tumors. Background technique [0002] Cancer is one of the leading causes of death in the developed world, with more than one million people diagnosed with cancer and 500,000 dying each year in the United States alone. Overall, it is estimated that more than 1 in 3 people will develop some form of cancer during their lifetime. There are more than 200 different types of cancer, four of which - breast, lung, colorectal and prostate - account for more than half of all new cases (Jemal et al., 2003, Cancer J. Clin. 53: 5-26) . [0003] Breast cancer is the most common cancer in women, with an estimated 12% of women at risk of developing the disease in their lifetime. Although mortality rates have decreased du...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K16/00C12P21/08C07H21/04C12N15/00
Inventor 奥斯丁·格尼蒂莫西·霍伊桑吉维·萨蒂亚尔富米考·阿克塞尔罗德
Owner ONCOMED PHARMA
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