Development of an inflammatory tissue-selective chimeric TNF receptor

Area of Science:

• Biochemistry
• Immunology
• Drug Development

Background:

• Tumor Necrosis Factor-alpha (TNF-α) inhibition is a key therapy for inflammatory conditions like rheumatoid arthritis.
• Systemic neutralization of TNF-α can lead to significant adverse effects due to its widespread role in the body.

Purpose of the Study:

• To engineer a chimeric TNF receptor with controllable binding activity.
• To develop a method for tissue-selective neutralization of TNF-α, thereby minimizing side effects.

Main Methods:

• Constructed a trimeric chimeric TNF receptor (Acrp-MMP-TNFR-Tn) incorporating Acrp30 trimerization and tetranectin domains with MMP substrate sequences.
• Investigated the effect of the Acrp30 domain on TNF receptor binding and the impact of MMP cleavage on restoring binding activity.
• Developed a humanized version using MMP-13 substrate for human TNF receptor 2.

Main Results:

• The Acrp30 trimerization domain initially inhibited TNF receptor binding, potentially by altering the receptor's conformation.
• Matrix metalloproteinase (MMP)-9 (in mouse model) and MMP-13 (in human construct) efficiently cleaved the substrate sequence, restoring TNF-α binding.
• The engineered human chimeric receptor demonstrated reduced basal binding, which was recovered upon MMP-13 digestion.

Conclusions:

• Acrp-masked chimeric TNF receptors offer a potential strategy for localized TNF-α neutralization in inflammatory tissues.
• This approach may significantly reduce the adverse effects associated with current systemic anti-TNF therapies.