A novel CRIg-targeted complement inhibitor protects cells from complement damage.

Area of Science:

• Immunology
• Biochemistry
• Drug Discovery

Background:

• Inappropriate complement system activation contributes to immune diseases.
• The alternative pathway (AP) is a key pathway in complement activation.
• Factor H (FH) and complement receptor of the immunoglobulin superfamily (CRIg) are crucial regulators.

Purpose of the Study:

• To develop novel CRIg-targeted complement inhibitors by fusing CRIg and FH functional domains.
• To evaluate the efficacy of these inhibitors in preclinical models of complement-mediated diseases.

Main Methods:

• Construction and characterization of CRIg-FH and CRIg-L-FH fusion proteins.
• Assessment of AP- and classical pathway (CP)-mediated hemolysis inhibition.
• Evaluation of C3b/iC3b deposition reduction.
• Kinetic analysis of binding affinity.
• Testing in paroxysmal nocturnal hemoglobinuria (PNH) erythrocyte models and a mesangioproliferative glomerulonephritis (MPGN) rat model.

Main Results:

• CRIg-L-FH demonstrated potent inhibition of both AP- and CP-mediated hemolysis and C3b/iC3b deposition.
• The fusion proteins exhibited a micromolar binding affinity (KD) to complement-attacked cells.
• CRIg-L-FH protected PNH erythrocytes from complement damage with low nanomolar IC50 values.
• In vivo studies showed CRIg-L-FH inhibited complement activation in an MPGN rat model, protecting glomerular mesangial cells (GMCs).

Conclusions:

• CRIg/FH fusion proteins represent promising therapeutic candidates for complement-mediated diseases.
• CRIg-L-FH effectively inhibits complement activation and protects cells from damage in various disease models.
• Further development of CRIg/FH-based therapeutics is warranted for treating a spectrum of immune disorders.