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Method of manufacturing human antibody possessing bioreceptor synergist, antagonist and/or inverse synergist

A synergist and antagonist technology, applied in the field of manufacturing fully human antibodies, can solve problems such as clinical application limitations

Inactive Publication Date: 2009-05-27
金立德 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The existing anti-human CD152 human monoclonal antibody can only be used as an antagonistic blocker, which has its limitations in clinical application

Method used

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  • Method of manufacturing human antibody possessing bioreceptor synergist, antagonist and/or inverse synergist
  • Method of manufacturing human antibody possessing bioreceptor synergist, antagonist and/or inverse synergist
  • Method of manufacturing human antibody possessing bioreceptor synergist, antagonist and/or inverse synergist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1, the preparation of polypeptide antigen

[0051] The overall structure of the human CD152 receptor is drawn in Figure 1A . The amino acid sequence corresponding to human CD152 is shown in Figure 1B. From the integration of information obtained from the scientific literature, an important relationship between the CDR3 region and native CD80 and CD86 ligands was thus established. Additional evidence suggests that amino acids located in the CDR1 region play a role in the interaction with CD80 / CD86. However, the synergist binding mechanism of CDR2 has not been fully explored so far.

[0052] To elicit antibodies that bind to the native protein, the polypeptides of the protein used must have properties similar to their conformation. Therefore, the complete sequences of CDR1, CDR2 and CDR3 regions were preserved for the design of synthetic immunogens. In addition, each CDR polypeptide portion was extended to conform to the aforementioned epitope pattern. To...

Embodiment 2

[0054] Example 2, Production of Anti-CD152 Human Antibody

[0055] Healthy blood donors were screened negative for HIV-1 / 2, HTLV-I / II, HCV, and HbsAg, and contained a normal amount of alanine transferase (ALT). The blood was from the Tainan Blood Donation Center of the Chinese Blood Foundation (Tainan, Taiwan). Peripheral blood mononuclear cells (PBMC) were separated in Ficoll-Paque (Amersham Biosiences) by density centrifugation (400xg); cells were then washed twice with PBS and collected by centrifugation at 100xg.

[0056] The obtained PBMCs were first magnetically labeled with CD45RO MACS microbeads (Miltenyi Biotec), and then separated with VarioMACS (Miltenyi Biotec). After magnetic calibration, cells are passed through a separation column, which is placed on a powerful permanent magnet. The matrix of the magnetic column can generate high-order magnetic field. Magnetically labeled cells remain in the column and unlabeled cells are filtered out. After the magnetic fie...

Embodiment 3

[0062] Example 3. Altering the ability of anti-CD152 antibody to induce apoptosis and cell differentiation and comparing with natural synergists

[0063] The binding sites of the different anti-CD152 human antibodies were identified by aligning synthetic polypeptides to primary alkylamine derivatized cellulose membranes (Rapp Polymere GmbH). In order to further evaluate the pharmacological effects of different anti-CD152 antibodies and a better natural synergist CD80, cell growth and PBMC culture of human peripheral lymphocytes stimulated with phytohemagglutinin in vitro were carried out. Briefly, prepare a flat-bottomed 96-well microtiter plate and add 50 μl of the cell suspension (10 5cells), 60 μl of PHA-containing medium (the final concentration of culture is 1.25 μg / ml, Amersham Biosciences AB), 40 μl of autologous plasma and 50 μl of RPMI-1640 medium containing anti-CD152 antibody or monomeric human CD80-muIg The concentration of fusion protein (Ancell) ranged from 0.2 ...

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Abstract

A method for developing the synergist, antagon and reverse synergist of a particular bioreceptor includes using computer to design and synthesize the immunogen and externally acting on human lymphocyte cluster. Said receptor is human CD 152, especially the CDR1, CDR2 and CDR3 regions able to respectively trigger the antibody to play the role of synergist, antagon and reverse synergist. A method for determining their pharmacologic efficacy is also disclosed.

Description

technical field [0001] The present invention relates to a method for producing a fully human antibody having the properties of synergist, antagonist and / or inverse synergist of the receptor. Background technique [0002] Generally speaking, the drug must reach the cell surface receptor in the body before it can interact with the drug molecule. The result of interaction or binding between drugs and receptors may activate receptors or block receptors, so in pharmacokinetics, a group of drugs or ligands with the same or similar physiological effects is called synergist (agonist). Similarly, when the effect of a drug is opposite to that of other drugs or ligands, it is called an antagonist (antagonist). When the effect of a ligand on the same receptor is opposite to that of a synergist, the ligand is called an antagonist. To the synergist (inverse agonist). [0003] Human antibodies have been successfully used as therapeutic drugs for various diseases, especially traditional i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K16/18A61K39/395A61P35/00C12N5/08G01N33/53
Inventor 金立德许淑菁
Owner 金立德
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