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TOLL like receptor 3 antagonists, methods and uses

An antagonist and receptor technology, applied in the field of Toll-like receptor 3 antagonists

Active Publication Date: 2009-04-22
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, since these therapeutic agents only reduce the risk of developing exacerbations and are associated with significant side effects, there is a need for alternative therapeutic modalities to prevent and treat exacerbations of lung disease

Method used

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  • TOLL like receptor 3 antagonists, methods and uses
  • TOLL like receptor 3 antagonists, methods and uses
  • TOLL like receptor 3 antagonists, methods and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0226] Identification of anti-hTLR3 antagonist mAbs

[0227] Anti-hTLR3 antagonist mAbs that block signaling through the hTLR3 receptor are identified by cell-based screening assays. A library of hybridomas producing anti-hTLR3 mAb was generated in BALB / C mice using standard techniques (Kohler et al., 1976). Mice were immunized with hTLR3 by intradermal injection of plasmid DNA encoding amino acids 1-703 of hTLR3 (SEQ ID NO: 3). Amino acids 1-703 correspond to the predicted extracellular domain of hTLR3 (SEQ ID NO: 4). Initially, mice were injected with 10 μg of plasmid DNA, followed by a second 10 μg DNA injection 2 weeks later. Two weeks after the second 10 μg plasmid DNA injection, a booster injection of 15 μg DNA was administered to each mouse. Three days before B cell fusion, mice were injected intravenously with 15 μg of hTLR3 protein dissolved in phosphate buffered saline (PBS; 10 mM phosphate, 150 mM NaCl, pH 7.4). Spleens from immunized mice were then harvested ...

Embodiment 2

[0233] Effects of hTLR3 antagonists on IL-6, IL-8 and RANTES cytokines in human lung-derived cells Inhibition of child production

[0234] Such as image 3 , Figure 4 and Figure 5 As indicated, IL-6, TLR3 cells were detected by incubating A549-hTLR3 cells with 1068 mAb or TLR3.7 mAb at 37°C for 30 minutes, followed by the addition of 5 μg / ml poly(I:C) (Amersham Biosciences Corp., Piscataway, NJ). Cytokine assays specific for IL-8 and RANTES. After 24 hours, use Cytokine levels in cell culture supernatants were measured using the instrument (Luminex Corp., Austin, TX) and mAb-conjugated beads specific for IL-6, IL-8 or RANTES as appropriate. Follow the manufacturer's instructions for each cytokine Determination.

[0235] The results showed that the hTLR3 antagonist mAb 1068 inhibited hTLR3-mediated IL-6( image 3 ), IL-8 ( Figure 4 ) and RANTES ( Figure 5 ) cytokine production. However, hTLR3-specific murine mAb TLR3.7 (eBioscience, San Diego, CA) did not inhi...

Embodiment 3

[0237] Effect of hTLR3 antagonist on MIP1-α and IL-6 cells in primary human bronchial-epithelial cells Inhibition of factor production

[0238] hTLR3 antagonist mAb 1068 inhibits hTLR3-mediated MIP1-α( Figure 6 ) and IL-6 ( Figure 7 ) cytokine production. Such as Figure 6 or Figure 7 As indicated, primary human bronchial-epithelial cells were incubated with 1068mAb or non-specific polyclonal mouse IgG preparations at 37°C for 30 minutes, followed by the addition of 5 μg / ml poly(I:C) (Amersham Biosciences Corp., Piscataway, NJ). , MIP1-α and IL-6 specific cytokine assays were performed. After 24 hours, use Cytokine levels in cell culture supernatants were measured using the instrument (Luminex Corp., Austin, TX) and appropriate mAb-conjugated beads specific for MIP1-[alpha] or IL-6. Follow the manufacturer's instructions for each cytokine Determination. Primary human bronchio-epithelial cells were isolated from human tissue samples and cultured using standard ...

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Abstract

TOLL Like Receptor 3 (TLR3) antagonists, polynucleotides encoding TLR3 antagonists or fragments thereof, and methods of making and using the foregoing are disclosed.

Description

field of invention [0001] The present invention relates to Toll-like receptor 3 (TLR3) antagonists, polynucleotides encoding TLR3 antagonists or fragments thereof, and methods of making and using them. Background of the invention [0002] Pathology associated with inflammatory conditions represents a major challenge in healthcare and can be painful, debilitating and fatal. For example, sepsis and sepsis-related conditions affect more than 750,000 people per year in the United States with a mortality rate of 28-50%, resulting in 215,000 deaths per year (Natanson et al., Crit. Care Med. 26:1927-1931 (1998) ; Angus et al., Crit. Care Med. 29: 1303-1310 (2001 )). Other inflammatory conditions such as inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis affect more than 1 million people annually in the United States (Hanauer et al., Rev. Gastroenterol. Disord. 3:81-92 (2003)). [0003] Inflammatory lung conditions such as chronic obstructive pulmonary disea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395C07K16/28
Inventor J·卡顿M·坎宁安A·达斯K·杜菲D·M·奈特R·兰布M·L·姆鲍夫G·拉亨纳坦L·桑马特奥R·T·萨里斯基N·斯托威尔R·斯维特S·赵S·陈J·吉尔斯-科马K·皮查V·斯托亚诺维克-苏苏利克T·J·戈尔茨
Owner CENTOCOR
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