IgE antibodies for the inhibition of tumor metastasis

A tumor-associated antigen and antibody technology, applied in the direction of antibodies, anti-tumor drugs, drug combinations, etc., can solve short-term problems

Active Publication Date: 2016-03-23
斯坦福大学董事会
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Mouse IgE30.6 inhibits the growth of established human colorectal carcinoma COLO205 cells grown subcutaneously in severe combined immunodeficiency (SCID) mice, but the effect is transient

Method used

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  • IgE antibodies for the inhibition of tumor metastasis
  • IgE antibodies for the inhibition of tumor metastasis
  • IgE antibodies for the inhibition of tumor metastasis

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preparation example Construction

[0053] For the production of monoclonal antibodies, any technique for producing antibody molecules by passaged cell lines in culture can be used (see, e.g., Antibodies--A Laboratory Manual, Harlow and Lane, eds., Cold Spring Harbor Laboratory Press: Cold Spring Harbor, New York, 1988). These include, but are not limited to, hybridoma technology originally developed by Kohler and Milstein (1975, Nature 256:495-497), and trioma (trioma) technology, human B cell hybridoma technology (Kozbor et al., 1983, Immunology Today, 4:72 ) and EBV-hybridoma technology to produce human monoclonal antibodies (Cole et al., 1985, in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). In an additional embodiment of the invention, monoclonal antibodies can be produced in germ-free animals using state-of-the-art technology (PCT / US90 / 02545). According to the present invention, a human antibody can be used, and the human antibody can be obtained by transforming human B Cells (...

Embodiment 1

[0100] Example 1: Formation of chimeric IgE gene carrier

[0101] Hybridomas VU-3C6 and VU-4H5 were generated against two different isoforms of human mucin 1 (hMUC-1 ), a mucin overexpressed on tumors derived from glandular epithelium. Antibody variable gene segments were cloned from each hybridoma and sequenced, then grafted onto human kappa light chain and epsilon heavy chain gene segments using standard procedures. For kcDNA clones obtained from human peripheral lymphocytes the sequence was then compared with database sequences (eg GenBank: J00241.1). The ε constant region cDNA was cloned from an IgE-expressing hybridoma (SKO-007, ATCCCRL8033-1), and then compared with the genome sequence in a database (eg GenBank: J00222.1). The final IgE mouse-human chimeric antibodies were named 3C6.hlgE and 4H5.hlgE. The final plasmid is in figure 1 Shown in A.

[0102] The 1F5 hybridoma targets human CD20 (hCD20), a pan-B cell marker and an important therapeutic target for the trea...

Embodiment 2

[0105] Example 2: IgE produced by 1F5.hIgE (anti-hCD20) mediates tumor cytotoxicity

[0106] To determine whether the anti-hCD20 chimeric antibody 1F5.hIgE possesses a functional IgEFc region, we investigated its ability to activate cord blood-derived mast cells (CBMCs). Using interleukin-8 (IL-8) production as a measure of CBMC activation, we observed that: CBMCs precoated with 1F5.hIgE were in the presence of hCD20-transfected mouse B cells (A20.hCD20) but not untransfected cells produced IL-8. Similarly, only CBMCs coated with anti-hCD20 IgE (1F5.hIgE) were sensitive to hCD20 + Human B cells OCI-Ly8 responded, whereas CBMCs coated with control IgE (SKO) did not produce IL-8 under these conditions. These data suggest that 1F5.hIgE activates mast cells in an antigen-dependent and antigen-specific manner.

[0107] Mast cell and IgE-mediated tumor cytotoxicity

[0108] To test potential tumor-specific IgE-mediated cytotoxic effects, we focused on effector cells known to exp...

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Abstract

The present invention provides novel IgE antibodies useful for inhibiting or preventing metastatic cancer. Also provided are methods to inhibit tumor metastasis by modulating the activity of at least one non-tumor cell, treating a patient to inhibit or prevent the appearance of tumor metastases derived from a primary solid tumor, treating established metastatic carcinoma, reducing metastasis of carcinoma cells, and reducing the growth kinetics of a primary solid tumor or a metastasized cell or tumor.

Description

[0001] related application [0002] This application claims the benefit of US Provisional Application No. 61 / 834,169, filed June 12, 2013, and US Patent Application No. 13 / 939,781, filed July 11, 2013. The entire teachings of the above applications are incorporated herein by reference in their entirety. [0003] governmental support [0004] This invention was made with government support, specifically Contract No. CA111639 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] IgE antibodies mediate allergic and asthmatic responses characterized by immediate-type hypersensitivity and inflammatory delayed-type responses requiring recruitment of effector cells. IgE antibodies are transported from the peripheral circulation into tissues where they can bind to allergic effector cells such as mast cells, basophils, eosinophils, dendritic cells, Langerhans Hans cells, monocytes and macrophages: FcεRI (or ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P35/04
CPCA61K2039/505C07K2317/52C07K2317/70C07K2317/73C07K16/2887C07K16/3092A61P35/00A61P35/04C07K2317/24C07K2317/56C07K2317/76
Inventor 约瑟夫·A·莫利克张珀琳保罗·J·乌茨
Owner 斯坦福大学董事会
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