Development of New IL-1R Antagonists with Improved Anti-inflammatory Efficacy

Area of Science:

• Biochemistry and Molecular Biology
• Neuroscience
• Immunology

Background:

• Anakinra (hIL-1Ra) is an anti-inflammatory biologic with limitations in potency and side effects.
• Existing therapies necessitate the development of more effective interleukin-1 receptor (IL-1R) antagonists.
• Targeting IL-1R signaling is crucial for managing inflammatory and neurological conditions.

Purpose of the Study:

• To engineer novel human interleukin-1 receptor antagonist (hIL-1Ra) variants with enhanced binding stability and anti-inflammatory potency.
• To evaluate the efficacy of these variants in preclinical models of inflammation and neuroinflammation.
• To identify a next-generation therapeutic candidate for IL-1R-mediated diseases.

Main Methods:

• Structure-guided mutagenesis was employed to design six hIL-1Ra variants.
• Molecular dynamics simulations predicted enhanced binding free energy for the variants.
• Functional assays in cell cultures and in vivo studies in Nlrp3 ^D301N mice assessed anti-inflammatory and neuroprotective effects.

Main Results:

• All six engineered hIL-1Ra variants exhibited improved anti-inflammatory activity, suppressing IL-1β and IL-6 mRNA.
• The E127Q variant demonstrated superior efficacy, effectively inhibiting IL-1β-induced NMDAR hyperactivation in neurons.
• In vivo administration of hIL-1Ra E127Q reversed elevated NMDAR activity in a mouse model of chronic neuroinflammation.

Conclusions:

• Next-generation hIL-1Ra variants with superior receptor binding and anti-inflammatory properties were successfully developed.
• The E127Q variant represents a promising therapeutic candidate for attenuating inflammatory and neuroinflammatory responses.
• Engineered IL-1R antagonists hold significant potential for treating a range of systemic and neurological disorders.