Increased CD74 binding and EAE treatment efficacy of a modified DRα1 molecular construct

Area of Science:

• Neuroimmunology
• Molecular Medicine

Background:

• Multiple sclerosis (MS) is a CNS disease characterized by inflammation, demyelination, and degeneration.
• Macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT) exacerbate MS inflammation via CD74 receptor interaction.
• Targeting the MIF-CD74 interaction is crucial for developing novel MS therapeutics.

Purpose of the Study:

• To investigate the therapeutic potential of a modified DRα1-MOG-35-55 construct with enhanced CD74 binding.
• To evaluate the efficacy of the modified construct in blocking inflammatory factor interaction and signaling pathways.
• To assess the therapeutic activity of the modified construct in a mouse model of MS.

Main Methods:

• Engineered DRα1-MOG-35-55 constructs with a single amino acid substitution (L50Q), creating DRhQ (human) and DRmQ (mouse).
• Assessed binding affinity of DRhQ to CD74 and its capacity to inhibit MIF and D-DT binding.
• Evaluated the inhibition of pERK1/2 signaling pathway activation.
• Tested the therapeutic efficacy of DRhQ in a mouse model of experimental autoimmune encephalomyelitis (EAE).

Main Results:

• The L50Q substitution in DRhQ significantly increased affinity for CD74 compared to the original construct.
• DRhQ demonstrated a greater ability to block MIF binding and inhibit pERK1/2 signaling.
• DRhQ exhibited enhanced therapeutic activity in mice with EAE, reducing disease severity.
• Increased binding affinity to CD74 correlated with improved biological potency.

Conclusions:

• The modified DRhQ construct offers a promising therapeutic strategy for MS by enhancing CD74 binding and blocking key inflammatory mediators.
• Binding affinity to CD74 serves as a reliable indicator of the biological potency of DRhQ.
• DRhQ holds potential for clinical application in MS and other inflammatory diseases driven by MIF and D-DT.