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Neutralizing Anti-tl1a monoclonal antibodies

A technology of antibodies and antigens, applied in the direction of antibodies, antibody medical components, anti-inflammatory agents, etc., can solve the problems that hinder the development of new treatments and the limited number of treatments

Pending Publication Date: 2019-08-13
CEDARS SINAI MEDICAL CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, the number of therapies available to IBD patients is limited, and poor results in clinical trials have hampered the development of new treatments

Method used

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  • Neutralizing Anti-tl1a monoclonal antibodies
  • Neutralizing Anti-tl1a monoclonal antibodies
  • Neutralizing Anti-tl1a monoclonal antibodies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0165] Generation of immunogens and immunization protocols for hybridoma generation

[0166] The recombinant TL1A protein with the point mutation C66S (counted from the leading methionine in the full-length protein) and lacking the leading 57 amino acids was expressed in E. coli. 重组TL1A序列由SEQ ID NO:33(QLRAQGEASVQFQALKGQEFAPSHQQVYAPLRADGDKPRAHLTVVRQTPTQHFKNQFPALHWEHELGLAFTKNRMNYTNKFLLIPESGDYFIYSQVTFRGMTSECSEIRQAGRPNKPDSITVVITKVTDSYPEPTQLLMGTKSVCEVGSNWFQPIYLGAMFSLQEGDKLMVNVSDISLVDYTKEDKTFFGAFLL)表示。

[0167] HEK293 cell lines expressing TL1A were generated by transduction with a lentiviral construct containing the full-length TL1A protein sequence. This cell line expresses the membrane-bound and secreted forms of the protein (as determined by flow cytometry and ELISA-based methods, respectively). 由HEK293细胞系表达的TL1A的序列由SEQ ID NO:34(MAEDLGLSFGETASVEMLPEHGSCRPKARSSSARWALTCCLVLLPFLAGLTTYLLVSQLRAQGEACVQFQALKGQEFAPSHQQVYAPLRADGDKPRAHLTVVRQTPTQHFKNQFPALHWEHELGLAFTKNRMNYTNKFLLIPESGDYFIYS...

Embodiment 2

[0211] The heavy chain variable region (Table 4) and light chain variable region (Table 5) of the two antibody sequences were compared using BLASTP 2.2.32+ alignment.

[0212] Table 4: BLAST analysis of the heavy chain variable region

[0213]

[0214]

[0215] table 5 : BLAST analysis of light chain variable regions

[0216]

Embodiment 3

[0218] Anti-human TL1A monoclonal antibodies 9E12E5 and 5C3D11 neutralized the activity of human TL1A in vitro. The effect of TL1A antibodies on IFN-γ production was assessed, and both TL1A antibodies showed inhibition of TL1A-induced IFN-γ production as Figure 5 shown. MSD plates were coated with murine TL1A and incubated with various concentrations of 5C3D11 or 9E12E5 to assess the ability of the antibody to recognize murine TL1A as Figure 6 shown. Human TL1A was included as a positive control. 5C3D11 recognizes murine TL1A in a concentration-dependent manner. The binding profiles of the 5C3D11 and 9E12E5 antibodies were assessed using TL1A-transfected HEK293 cell lines and compared to the untransfected parental HEK293 cell lines. Fluorescent staining of anti-TL1A antibodies in TL1A-expressing HEK293 cells was compared to untransfected parental HEK293 cells, as Figure 7 shown. The binding affinity of the anti-TL1A antibody was measured by Biacore, and the dissociati...

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Abstract

Described herein are methods and pharmaceutical compositions for the treatment of inflammatory bowel disease (IBD), Crohns Disease (CD), ulcerative colitis (UC) and medically refractive-ulcerative colitis (MR-UC). In particular, disclosed are anti-TL1A antibodies useful for the treatment of IBD.

Description

[0001] cross reference [0002] This application claims priority to US Provisional Application 62 / 413,188, filed October 26, 2016, which is hereby incorporated by reference in its entirety. [0003] sequence listing [0004] This application contains a Sequence Listing that has been filed electronically in ASCII format, and is hereby incorporated by reference in its entirety. Said ASCII copy, created on October 23, 2017, is named 52388-728_601_SL.txt and is 33,920 bytes in size. Background technique [0005] Inflammatory bowel disease (IBD) refers to a collection of intestinal disorders that cause an inflammatory condition in the gastrointestinal tract. The main types of IBD are ulcerative colitis (UC) and Crohn's disease (CD). These diseases are prevalent, with approximately 1.86 billion people diagnosed with UC worldwide and approximately 1.3 million people diagnosed with CD worldwide. Unfortunately, the number of therapies available to IBD patients is limited, and po...

Claims

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Application Information

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IPC IPC(8): C07K16/28A61K39/395A61P1/00A61P29/00A61P37/00
CPCC07K16/2875C07K2317/33C07K2317/92A61P37/00A61P1/02A61P29/00C07K2317/24C07K2317/76A61K2039/545C07K16/241C07K16/2809A61K39/39533A61K39/3955A61K48/005C07K2317/56C07K2317/565C07K2317/90A61K2039/505
Inventor J·比尔斯伯勒斯蒂芬·塔尔干布拉德利·亨克尔
Owner CEDARS SINAI MEDICAL CENT
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