Antibodies directed to the deletion mutants of epidermal growth factor receptor and uses thereof

A technology of antibody and monoclonal antibody, applied in growth factors/growth regulators, antibodies, receptors/cell surface antigens/cell surface determinants, etc.

Inactive Publication Date: 2007-03-14
AMGEN FREMONT INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The presence of these murine-derived proteins can lead to rapid clearance of antibodies or can lead to the development of an immune response against antibodies in the patient

Method used

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  • Antibodies directed to the deletion mutants of epidermal growth factor receptor and uses thereof
  • Antibodies directed to the deletion mutants of epidermal growth factor receptor and uses thereof
  • Antibodies directed to the deletion mutants of epidermal growth factor receptor and uses thereof

Examples

Experimental program
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preparation example Construction

[0214] Antibody preparation

[0215] As described herein, antibodies can be prepared using the XenoMouse(R) technology as described below. The mice are then capable of producing human immunoglobulin molecules and antibodies, but are insufficient to produce murine immunoglobulin molecules and antibodies. Techniques for accomplishing the same purpose are disclosed in the patents, applications and references disclosed herein. However, one example, inter alia, of transgenically produced mice and antibodies produced therefrom is disclosed in U.S. Patent Application Serial No. 08 / 759,620, filed December 3, 1996, and International Patent Publication June 11, 1998. The disclosures of applications WO 98 / 24893 and WO 00 / 76310 published on December 21, 2000 are incorporated herein by reference. See also Mendez et al. Nature Genetics 15:146-156 (1997).

[0216] Using this technique, fully human monoclonal antibodies can be produced against a variety of antibodies. In one example, a Xe...

example

[0223] The following examples, including experiments performed and results obtained, are provided for illustrative purposes only and are not to be construed as limiting the invention.

[0224] The initial strategy to generate EGFRvIII-specific antibodies involved immunizing XenoMouse mice with complex antigens (peptides, multiple soluble proteins, and antigen-expressing cells), followed by generation of hybrid cells by fusion or by XenoMax TM / SLAM TM The technique isolates B cells while isolating antibody producing cells. Antibody producing cells are presented to primary screening by ELISA for specificity and secondary screening by FMAT and / or FACS for cell surface binding. Internalization assays were then performed to identify antibodies that might be useful for drug delivery. The affinities of these antibodies were measured. Select specific antibodies for epitope mapping. In addition, specific antibodies are selected for in vivo and in vitro testing to analyze the effic...

example 1

[0225] Example 1' Antigen Preparation

[0226] A. Preparation of EGFRvIII PEP3-KLH antigen

[0227] Along with Example 2, the 14-mer human EGFRvIII PEP3 (LE E K K G N Y V V T D H C (SEQ ID NO: 56)) peptide was routinely synthesized by the R&D system. The PEP3 peptide was then conjugated to keyhole limpet hemocyanin (KLH) as follows: EGFRvIII PEP3 (200 meg) (R&D) was mixed with 50 meg of keyhole limpet hemocyanin (KLH; Pierce, Rockford, IL) and brought up to 165 mecl with distilled water. Add 250mcl binding buffer (0.1M MES, 0.9M NaCl, pH 4.7) and by adding 25mcl of 10mg / ml 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride Stock solutions of compounds (EDC, Pierce, Rockford, IL) crosslinked EGFRvIII PEP3 and KLH. Binding was incubated at room temperature for 2 hours, and unreacted EDC was removed by centrifugation through a 1 kDa filter (centrifugal filter, Millipore, Bedford, MA) using PBS pH 7.4.

[0228] Along with Example 3, the 14-mer human EGFRvIII PEP3 (LE E...

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Abstract

The present invention relates to novel antibodies, in particular to antibodies against deletion mutants of the epidermal growth factor receptor, and in particular to the type III deletion mutant EGFRvIII. The present invention also relates to human monoclonal antibodies directed against deletion mutants of the epidermal growth factor receptor, and in particular EGFRvIII. The invention also provides diagnostic and therapeutic formulations of these antibodies, and immunoconjugates thereof.

Description

technical field [0001] This example relates to novel antibodies, in particular to antibodies against deletion mutants of the epidermal growth factor receptor, and in particular to the type III deletion mutant EGFRvIII. This example also relates to human monoclonal antibodies directed against deletion mutants of the epidermal growth factor receptor, and in particular EGFRvIII. This example also relates to variants of these antibodies. The invention also provides diagnostic and therapeutic formulations of these antibodies, and immunoconjugates thereof. Background technique [0002] Since the last century, tumor-specific molecules that contribute to better diagnosis and treatment of human and animal cancers have been sought. In most types of human cancer, except those based on virus-induced cancers and containing molecular structures dictated by viral genes, it is difficult to provide definitive evidence for tumor-specific substances based on molecular structure data. There ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/42C07K14/71C12P21/08A61K39/44A61K39/395C07H21/04C12N5/12G01N33/53G01N33/552G01N33/577
Inventor 理查德·韦伯冯晓奥里特·福德拉里·格林琼·古达斯布鲁斯·基特刘颖帕拉尼·拉塔纳斯瓦米罗伯特·拉亚杨晓东乔斯·克尔瓦兰伊恩·福尔茨贾小池贾斯帕·康查德威克·T·金斯科特·L·克拉坎普巧娟·简·苏
Owner AMGEN FREMONT INC
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