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Novel antibody binding to tfpi and composition comprising the same

An antibody and carrier technology, applied in the field of pharmaceutical compositions for the treatment of hemophilia, can solve problems such as inconvenience

Active Publication Date: 2017-12-01
MOGAM INST FOR BIOMEDICAL RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The above-mentioned recombinant proteins are administered to hemophiliacs by intravenous injection two or more times per week, but there is a persistent problem of inconvenience caused by repeated administration of the recombinant proteins

Method used

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  • Novel antibody binding to tfpi and composition comprising the same
  • Novel antibody binding to tfpi and composition comprising the same
  • Novel antibody binding to tfpi and composition comprising the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Embodiment 1: Preparation anti-TFPI antibody

[0106] As an anti-TFPI antibody (tissue factor channel inhibitor) that inhibits the activity of factor X, an antibody that prevents inhibition of blood coagulation is prepared, which is useful for treating or preventing hemophilia.

[0107] 1-1: Selection of Antibody

[0108] Mice were immunized with recombinant human TFPI, and spleens were excised from the mice. Total RNA was isolated from B lymphocytes extracted from the spleen and then synthesized into cDNA. From the synthesized cDNA, various mouse antibody genes were cloned by PCR (polymerase chain reaction), and inserted into pComb3X phagemid, thereby constructing an antibody library showing antibody fragments having various sequences. To select human TFPI-specific antibodies from the antibody library, TFPI-immobilized magnetic beads and the antibody library were mixed with each other, and clones binding to the target antigen were isolated and cultured. Then, cl...

Embodiment 2

[0124] Example 2: Construction of humanized antibody by CDR grafting to stable framework

[0125] When the quantitative binding affinity of TFPI antigen (full-length human TFPI protein) (Cat. No. TFPI-875H; Creative Biomart, USA) to T417 and T308 cloned antibodies was evaluated, the cloned T417 antibody showed the best effect (see Figure 8 and Example 6). Therefore, clone T417 was humanized to clone 308.

[0126] To humanize the cloned T417 antibody of mouse origin, the most widely used CDR grafts for humanization were selected. Specifically, the structure of clone T417 was determined by the sample showing the highest QMEAN, GMQE and homology values ​​among 50 samples obtained from the structure prediction website, namely Swiss-Model (http: / / swissmodel.expasy.org / ). CDRs that bound antigen and framework in addition to CDRs were predicted and identified using the Kabat and Chothia numbering scheme. Then, human frameworks with the highest homology were searched using IgBLA...

Embodiment 3

[0133] Example 3: Mapping the clone 308 antibody by computer modeling (in Silico Modeling)

[0134] The binding between clone 308 constructed in Example 2 and TFPI KPI-2 (Kunitz domain 2) was predicted by computer modeling, and the positions (heavy chain-52a, heavy chain-64 and light chain 27d) (see Figure 5 and Table 6 below).

[0135] The structure of the TFPI-binding clone 308 antibody was generated using homology modeling, the BioLuminate module (Schrodinger, USA). To generate the structure, a template search was performed through the PDB database using the sequence of clone 308. Therefore, 3QOS (PDB number) structures with similar structures and high combination scores were selected. It can be seen that the 3QOS and clone 308 sequences are similar except for the HV CDR H3 region which has the antigen-specific structure and are suitable templates for generating the structure. All clone 308 models were produced and compared with the structure of 3QOS, and the most si...

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Abstract

The invention discloses a novel antibody binding to TFPI and a composition comprising the same. The present invention relates to an antibody that binds specifically to a tissue factor pathway inhibitor (TFPI), a nucleic acid encoding the antibody, a vector comprising the nucleic acid, a host cell transformed with the vector, a method for producing the antibody, and a pharmaceutical composition for treating hemophilia, which comprises the antibody as an active ingredient. The antibody of the present invention, which binds specifically to TFPI, can activate the extrinsic pathway of blood coagulation by inhibiting TFPI. Thus, the antibody of the present invention can be effectively used for the treatment of antibody-induced hemophilia patients and for the prevention of blood coagulation disease in hemophilia-A or hemophilia-B patients.

Description

technical field [0001] The present invention relates to an antibody specifically binding to tissue factor channel inhibitor (TFPI), a nucleic acid encoding the antibody, a vector comprising the nucleic acid, a host cell comprising the vector, a method for producing the antibody, As well as a pharmaceutical composition for treating hemophilia comprising said antibody as an active ingredient. Background technique [0002] It is known that in about 30% of hemophilia A and B patients, antibodies are developed against the FVIII (factor VIII) or FIX (factor IX) protein used for therapy, thereby significantly reducing the therapeutic effect of the protein. As a protein replacement, activated factor Vila or aPCC (plasma-derived activated prothrombin complex concentrate) has been administered. [0003] The above-mentioned recombinant proteins are administered to hemophiliacs by intravenous injection two or more times per week, but there continues to be a problem of inconvenience cau...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/38C12N15/13A61K39/395C12N15/63A61P7/04
CPCC07K16/38C07K2317/565A61K2039/505C07K2317/24C07K2317/622C07K2317/92C07K2317/72C07K2317/34A61P7/00A61P7/04
Inventor 金董植李美祯朴在灿李秀珉郭曦天黄成虎李滢权金基洙朴荣燮丁俊弘赵基俊
Owner MOGAM INST FOR BIOMEDICAL RES
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