Blockade of autoantibody-initiated tissue damage by using recombinant fab antibody fragments against pathogenic...

Area of Science:

• Immunology
• Autoimmune Diseases
• Molecular Biology

Background:

• Autoantibody-mediated diseases often involve complement cascade activation, leading to tissue injury.
• Blocking autoantibody binding to pathogenic autoantigens is a potential therapeutic strategy.
• Bullous pemphigoid (BP) serves as a model autoimmune disease for this investigation.

Purpose of the Study:

• To develop targeted Fab antibody fragments to inhibit autoantibody binding to pathogenic autoantigens.
• To evaluate the efficacy of these Fabs in preventing complement activation and disease development in a BP model.

Main Methods:

• Recombinant Fabs targeting the non-collagenous 16th-A domain of type XVII collagen were generated using phage display from BP patient antibody repertoires.
• In vitro assays assessed the ability of Fabs to inhibit autoantibody binding and complement activation.
• In vivo studies utilized a humanized BP mouse model to evaluate Fab efficacy against autoantibody-induced blistering.

Main Results:

• Two Fabs, Fab-B4 and Fab-19, demonstrated significant inhibition of BP autoantibody binding and subsequent complement activation in vitro.
• These Fabs successfully protected mice in a humanized BP model from autoantibody-induced blistering disease in vivo.

Conclusions:

• Engineered Fabs targeting pathogenic epitopes are effective in blocking autoantibody binding and complement activation.
• This strategy shows potential for developing disease-specific treatments for antibody-mediated autoimmune diseases.