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NOTCH1 receptor binding agents and methods of use thereof

A receptor, antibody technology, used in the characterization, diagnosis and treatment of cancer and other diseases, the field of treatment of cancer, can solve problems such as loss of heterozygosity

Inactive Publication Date: 2011-06-29
ONCOMED PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, homozygous null mutations of Notch1 / 4 and Jagged1 and heterozygous loss of DLL4 lead to severe but variable defects in arterial development and yolk sac vascularization

Method used

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  • NOTCH1 receptor binding agents and methods of use thereof
  • NOTCH1 receptor binding agents and methods of use thereof
  • NOTCH1 receptor binding agents and methods of use thereof

Examples

Experimental program
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Embodiment approach

[0102] The present invention provides compositions and methods for the study, diagnosis, characterization and treatment of cancer. In particular, in certain embodiments, the present invention provides agents (including antagonists) that bind Notch receptors and methods of using the agents or antagonists to inhibit tumor growth and treat cancer and other diseases in human patients. In a specific embodiment, the antagonist is an antibody that specifically binds to the non-ligand binding region of the extracellular domain of the human Notch receptor.

[0103] In one aspect, the invention provides antibodies that specifically bind to the non-ligand-binding membrane-proximal region of the extracellular domain of the human Notchl receptor. In certain embodiments, the antibody binds a region of human Notch1 comprising about amino acid 1427 to about amino acid 1732. In certain embodiments, the antibody binds to a region comprising SEQ ID NO:2. In specific embodiments, the antibody s...

Embodiment 1

[0228] Antibodies were raised against the non-ligand-binding region of Notch1, particularly against the non-ligand-binding membrane-proximal region of the ectodomain. In a specific embodiment, recombinant polypeptide fragments of the extracellular domain of human Notchl are produced as antigens for antibody production. The polynucleotide (SEQ ID NO. 1) encoding the membrane-proximal region of the extracellular domain of human Notchl amino acid sequence 1427-1732 was isolated using standard recombinant DNA techniques. These polynucleotides were individually linked in N-terminal frame to human Fc and histidine tags and cloned into transfer plasmid vectors for baculovirus-mediated expression in insect cells. Standard transfection, infection, and cell culture protocols were used to generate recombinant insect cells expressing the corresponding Notch1 polypeptide (SEQ ID NO: 2) corresponding to the membrane-proximal region comprising amino acids 1427-1732 (O'Reilly et al., 1994, Ba...

Embodiment 2

[0243] Humanized antibodies were raised against the membrane-proximal region of the extracellular domain of human Notchl. Degenerate PCR was used to hybridize The variable domains of the murine monoclonal antibody 52M51 were isolated from tumor lines and sequenced. Human heavy and light chain variable framework regions, which may be structurally similar to the parental 52M51 antibody amino acid sequence, were then considered reference human framework regions to help guide the design of novel synthetic frameworks. To identify human framework regions similar to the 52M51 murine framework, the predicted protein sequences encoded by the VH and VL murine variable domains of 52M51 were compared with those encoded by the expressed human cDNA using BLAST searches of human sequences deposited in Genbank. Comparison of human antibody sequences. Using this approach, expressed human cDNA sequences (eg genbank DA975021, DB242412) and germline Vh domains (eg IGHV1-24) were selected for fu...

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Abstract

The present invention discloses means and methods for the diagnosis, characterization, prognosis and treatment of cancer and specifically targeting cancer stem cells. The present invention provides an antibody that specifically binds to a non-hgand binding membrane proximal region of the extracellular domain of a human Notch receptor and inhibits tumor growth, and a method of treating cancer, wherein the method comprises administering the antibody for study subjects.

Description

technical field [0001] The present invention relates to compositions comprising agents that bind human Notch receptors and methods of using the compositions to characterize, diagnose and treat cancer and other diseases. In particular, the present invention provides an antibody that specifically binds to the non-ligand-binding membrane-adjacent region of the extracellular domain of human Notch1 receptor and inhibits tumor growth. The present invention also provides a method of treating cancer comprising administering a therapeutically effective amount of an antibody that specifically binds to the non-ligand-binding membrane-proximal region of the extracellular domain of human Notch1 receptor protein and inhibits tumor growth. Background technique [0002] Cancer is a leading cause of death in the developed world, causing more than 500,000 deaths per year in the United States alone. More than 1 million people are diagnosed with cancer in the United States each year, and overa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61K39/395
CPCC07K16/462C07K16/464C12N15/63A61K45/06C07K2317/56C07K2317/734C12N5/12C07H21/04C07K2316/96C07K14/71C07K2317/732A61K39/39558A61K2039/505A61K39/3955C07K14/435C07K16/22C12N15/79C07K16/28C07K16/30C07K2317/73C07K2317/34C07K2317/76A61K31/337A61P35/00A61P35/04A61P43/00A61P9/00C07K7/18C07K7/22C07K7/23C12N5/0693C12N2501/998C07K2317/24A61N5/10C07K16/3046C07K2317/565C07K2317/92C07K2317/21
Inventor 奥斯丁·L·格尼蒂莫西·查尔斯·霍伊莫林·菲奇·布鲁恩斯富米考·塔卡达·阿克塞尔罗德
Owner ONCOMED PHARMA INC
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