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Humanized EGFR antibodies

A humanized antibody and antibody technology, applied in the direction of antibodies, antineoplastic drugs, chemical instruments and methods, etc., can solve the problems of low HAMA response and low immunogenicity of humanized antibodies

Inactive Publication Date: 2013-04-03
GLYCOTOPE GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Humanized antibodies are less immunogenic (i.e., elicit a lower HAMA response) because more murine sequences are replaced by human sequences

Method used

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  • Humanized EGFR antibodies
  • Humanized EGFR antibodies
  • Humanized EGFR antibodies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0122] Example 1: Humanization of the Murine Heavy and Light Chain Variable Regions of Anti-EGFR Antibodies

[0123] The coding nucleic acid sequences of the heavy chain and light chain variable regions (VH, SEQ ID NO:4 and VL, SEQ ID NO:8) of the monoclonal antibody targeting the epitope in the extracellular ligand binding domain of human EGFR1 The genomic sequences of the human constant γ1 region (CH) and the human constant κ region (CL) are each linked.

[0124] Based on these chimeric clones, humanized antibodies were constructed. To this end, point mutations were introduced into the nucleic acid sequences of the murine framework regions of VH and VL to generate the corresponding human framework regions. The human framework regions of interest are selected from human germline antibody libraries. In particular, the most related framework regions were selected from the library based on their overall sequence similarity and CDR loop classification. Considering all the data...

Embodiment 2

[0129] Example 2: Binding of humanized antibody variants to immobilized EGFR

[0130] After expression of the different constructs in COS cells, the titers of the humanized antibody variants were determined and their concentrations adjusted. Then, humanized antibodies were screened in antigen ELISA. Exemplary results of one round of screening are shown in figure 1 middle. All variants showed significant binding to the antigen. Good antigen binding was observed for humanized antibody variants comprising a heavy chain variable region selected from VH2, VH3, VH5 and VH6. In particular, the variant VH3 / VL3 showed good results. In addition, antibodies comprising heavy chain variable regions VH7 or VH8 also showed good antigen binding. figure 2 A direct comparison of the chimeric antibody and the humanized antibody variant hVH3 / hVL3 in antigen ELISA is shown in .

Embodiment 3

[0131] Example 3: Binding of humanized antibody variants to different EGFR expressing cells

[0132] Using IgG antibodies containing these humanized heavy and light chain variable regions at different concentrations, FACS experiments using HT-29 cells, LS174.T cells or DU145 cells were performed. Figures 3 to 7 Binding of selected antibody variants is shown in . It was demonstrated that the humanized antibodies, in particular the humanized antibody variant VH3 / VL3, have comparable antigen binding properties to those of the chimeric antibodies from which they were generated. In addition, VH7 and VH8 antibody variants also showed good binding to these cells.

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Abstract

The present invention pertains to humanized anti-EGFR antibodies having antigen binding properties similar to those of the murine or chimeric anti-EGFR antibody from which they are derived. In particular, the present invention is directed to humanized anti-EGFR antibodies which are useful in the treatment of cancer.

Description

field of invention [0001] The present invention relates to the field of antibodies. In particular, humanized anti-EGFR antibodies exhibiting improved antigen binding and / or recognition are provided. In specific embodiments, the invention relates to humanized anti-EGFR antibodies useful in the treatment of cancer. Background of the invention [0002] Today, antibodies are widely used substances in medicine and research. In medicine, they find application in many different fields. For example, antibodies are used as labeling reagents for the detection of certain markers, which allow the diagnosis and / or prognosis of diseases or the determination of specific bodily parameters, such as, for example, the presence or concentration of certain hormones. [0003] In addition, antibodies are also used as therapeutic agents in the treatment and prevention of various diseases such as cancer, cardiovascular diseases, inflammatory diseases, macular degeneration, transplant rejection, m...

Claims

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Application Information

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IPC IPC(8): C07K16/28C07K16/46A61P35/00
CPCC07K16/2863C07K2317/732C07K2317/94A61K2039/505C07K2317/41C07K2317/73C07K2317/24A61P35/00
Inventor S·戈莱茨A·丹尼尔奇克
Owner GLYCOTOPE GMBH
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