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Bispecific antibody or antibody mixture having common light chain

A bispecific antibody and common light chain technology, applied in the direction of antibodies, translation products of oncogenes, anti-receptors/cell surface antigens/cell surface determinant immunoglobulins, etc.

Active Publication Date: 2016-08-03
JIANGSU ALPHAMAB BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This may partly explain why Pertuzumab inhibits the growth of tumors with low HER-2 expression, while Trastuzumab binds to the extracellular IV domain of the HER-2 receptor, and dimer formation does not involve the IV domain, so Trastuzumab only effective in breast cancer patients with HER-2 overexpression

Method used

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  • Bispecific antibody or antibody mixture having common light chain
  • Bispecific antibody or antibody mixture having common light chain
  • Bispecific antibody or antibody mixture having common light chain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0157] Embodiment 1 Acquisition of common light chain

[0158] 1. Sequence and structure acquisition

[0159] Obtain the complex crystal structure of Trastuzumab and Pertuzumab from the Protein Data Bank (PDB, www.pdb.org), the PDB number of Trastuzumab is 1N8Z, and the PDB number of Pertuzumab is 1S78 . Two screening strategies can be used to identify amino acid contacts between CH3-CH3: (i) distance of amino acid interactions (ii) solvent accessible region analysis. Here, screening is performed based on the interaction distance of amino acids.

[0160] 2. Monoclonal antibody light chain and antigen HER2 interface amino acid acquisition

[0161] According to the amino acid contact rule, interfacial amino acids refer to those amino acids whose distance between the heavy atoms of the side chain and the heavy atoms of any amino acid of another chain is less than a threshold value. Here the threshold is chosen as In some literature it is also possible to choose (Bahar and...

Embodiment 2

[0190] Example 2 Preparation and functional verification of antigenic protein HER2 variant protein

[0191] 1. Design of HER2 variant protein that only binds Pertuzumab

[0192] RobertF.Kelley'andMarkP.O'Connell announced in 1993 the kinetic parameters of the binding of trastuzumab and corresponding mutations to the extracellular domain (ECD) of HER2. Among them, H91A, R50A, W95A, and Y100aA have a significant impact on the binding of trastuzumab to the extracellular domain of HER2. The Hyun-SooCho team crystallized the complex of trastuzumab Fab fragment and HER2 extracellular domain (ECD) in 2003 (PDB number: 1N8Z), and the results were published in Nature. By analyzing the structure of the complex of trastuzumab Fab fragment and HER2 extracellular domain (ECD) (its sequence is shown in SEQ ID NO: 18), we obtained the trastuzumab Fab fragment and HER2 extracellular domain (ECD ) interface with amino acids, as shown in Table 5.

[0193] Focus on the analysis of the amino a...

Embodiment 4

[0238] Example 4 Replace the original light chains of Tmab and Pmab with common light chains, and verify the effect of common light chains

[0239] 1. Construction of Tmab and Pmab monoclonal antibody eukaryotic expression vectors carrying a common light chain

[0240] Amino acid sequences of Trastuzumab and Pertuzumab full antibodies searched according to patent US2009 / 0285837A1 (patent in figure 2 and Figure 16 ), using the DNAworks online tool (http: / / helixweb.nih.gov / dnaworks / ) to design the corresponding coding DNA sequence, and obtain the heavy chain gene of Trastuzumab (SEQ ID NO: 16) and the heavy chain gene of Pertuzumab ( SEQ ID NO: 17). According to the amino acid sequence (SEQIDNO:1~6) of a group of common light chains obtained in Example 1, utilize DNAworks online tool (http: / / helixweb.nih.gov / dnaworks / ) to design the corresponding coding DNA sequence, and pass The common light chain genes CLC1 (SEQ ID NO: 7) and CLC5 (SEQ NO: 11) of the Pmab-Tmab bispecific ...

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Abstract

The invention relates to a bispecific antibody or antibody mixture, and more specifically relates to the bispecific antibody or the antibody mixture having a common light chain, and a preparation method of the bispecific antibody or the antibody mixture. The invention also relates to nucleic acid molecules for coding the bispecific antibody or the antibody mixture, a recombinant vector containing the nucleic acid molecules and recombinant cells, and a detection and quantification method for the bispecific antibody or the antibody mixture. The bispecific antibody or the antibody mixture is prepared by a common light chain technology, the preparation method is simple and controllable, mismatching of the light chains in the bispecific antibody can be avoided, the antibody mixture can be expressed in same host cell, difficulty for culturing the mixed cell groups is reduced, and the amplification production is easily achieved.

Description

technical field [0001] The present invention relates to a bispecific antibody or antibody mixture, and a method for preparing the bispecific antibody or antibody mixture. The present invention also relates to nucleic acid molecules encoding the bispecific antibodies or antibody mixtures, recombinant vectors and recombinant cells containing the nucleic acid molecules, and detection and quantification methods for the bispecific antibodies or antibody mixtures. Background technique [0002] Monoclonal antibody drugs have grown rapidly in the past fifteen years and have become a growth point in the pharmaceutical industry. Since 1996, a total of about 30 monoclonal antibody drugs have been approved for marketing. Among them, nine monoclonal antibody drugs have annual sales exceeding one billion US dollars. In 2010, the total sales of monoclonal antibody drugs exceeded 30 billion US dollars, and the annual growth rate exceeded 10%. Due to the strong target specificity of monoc...

Claims

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Application Information

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IPC IPC(8): C07K16/46C07K16/32C07K14/82C07K14/71C12N15/12C12N15/85C12N15/13G01N33/68G01N33/574A61K39/395A61P35/00
CPCC07K14/71C12N15/63G01N33/577C07K16/32A61K2039/505A61K2039/507C07K2317/31C07K2317/515C07K2317/565C07K2317/73C07K2317/94A61P35/00C07K16/28A61K39/395C07K16/468C07K2317/52
Inventor 徐霆须涛汪皛皛李倩逄敏洁张慧敏韩莉张庆青
Owner JIANGSU ALPHAMAB BIOPHARMACEUTICALS CO LTD
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