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Hutnfr1 selective antagonists

A selective and ligand-based technology, applied in anti-inflammatory agents, antiviral agents, non-central analgesics, etc., can solve problems such as inability to evaluate the therapeutic effect

Active Publication Date: 2010-03-24
UNIV STUTTGART
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is impossible to evaluate the therapeutic effect of antibody H398 in TNF-dependent chronic diseases in clinical trials, because the antibody is of mouse origin, and it is necessary to suffer acute adverse reactions to mouse origin antibodies and / or undergo repeated treatment cycles quickly risk of developing an immune response

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Example 1 : Electronic (in silico) generation of anti-TNF receptor 1 antagonist based on mouse monoclonal antibody H398 sequence and human germline IgV gene sequence

[0098] Utilize H398 heavy chain variable region (V H ) And the light chain variable region (V L ) (Moosmayer et al., Ther. Immunol., 1995, No. 2, p. 31-40) amino acid sequence, in the V base database (http: / / vbase.mrc-cpe.cam.ac.uk / ) and IgBlast Search for similar human germline V segments. The search identified several V with 61.2-62.2% full similarity H Germline sequence (DP75, DP8, DP88) and several V with 80.0-81.0% similarity L Germline sequence (DPK15, DPK13, DPK27, DPK28). Compare the identified sequence with the V of H398 H And V L For comparison, the critical amino acids of CDR structure, V H / V L The critical part and the cursor area are identified as described (O'Brien S., Jones T., Antibody engineering, a lab manual, Springer, 2001, p.567-590; Lo BKC, Antibody engineering, methods and protocols,...

Embodiment 2

[0099] Example 2 : Synthesis of the DNA sequence of IZI-06.1VH and IZI-06.1VL

[0100] The codon optimized DNA encoding the two humanized variable regions (IZI-06.1VH, (SEQ ID NO.: 7), IZI-06.1VL (SEQ ID NO.: 8)) was synthesized by GeneArt (Regensburg, Germany), And add the appropriate cloning site ( figure 2 ).

Embodiment 3

[0101] Example 3 : Model structure of H398 and IZI-06.1Fv fragment

[0102] A Web Antibody Modelling server (WAM) (Whitelegg N.R.J., Rees A.R., Web.Prot.Eng., 2000, No. 13, p.819-824) was used to generate the model structures of H398 and IZI-06.1Fv. The comparison of the two model structures showed a high degree of consistency between the protein backbone and the side chain structures including CDRs, except that CDRH3 showed a slight distortion ( image 3 ). In this way, the Asp96 on the top of CDRH3 of the H398 model and IZI-06.1 model has been removed from the antigen binding pocket (pocket) by about 0.38 nm.

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Abstract

The present invention relates to a ligand which specifically binds to the human tumor necrosis factor type 1 receptor (huTNFR1 ), the ligand comprising one or more amino acid sequences of human origincapable of reducing the immunogenic response of the ligand in human beings and one or more amino acid sequences capable of selectively binding to huTNFR1. The present invention further relates to a nucleic acid encoding said ligand and to a pharmaceutical composition for the treatment of disorders connected to huTNFR1.

Description

Technical field [0001] The present invention relates to a ligand that specifically binds to human tumor necrosis factor type 1 receptor (huTNFR1), the ligand comprising one or more human amino acid sequences capable of reducing the immunogenic response of the ligand in humans, and a One or more amino acid sequences capable of selectively binding to huTNFR1. The present invention further relates to a nucleic acid encoding the ligand and a pharmaceutical composition for treating diseases related to huTNFR1. Background technique [0002] TNF is a key cytokine that regulates inflammation and apoptosis. Depending on the cell type and the surrounding environment, TNF can have the opposite effect, immunostimulation or immunosuppression. TNF can mediate and resist apoptosis (Locksley et al., Cell, 2001, No.104, p.487-501; Aggarwal BB, Nat. Rev. Immunol., 2003, No. 3, p745-756J). In humans, TNF is an essential cytokine that regulates the innate immune system and inflammatory response a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28
CPCC07K16/2878C07K16/241C07K2317/92A61K38/00C07K2317/55C07K2317/56C07K2316/96C07K2317/24C07K2317/76A61P1/04A61P17/06A61P19/02A61P25/00A61P25/16A61P25/28A61P29/00A61P3/00A61P31/04A61P31/12A61P35/00A61P37/00A61P37/06
Inventor 克劳斯·普菲岑迈尔彼得·谢里奇罗兰德·康特曼赛宾·明克尔
Owner UNIV STUTTGART
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