Blockade of Autoantibody-Initiated Tissue Damage by Using Recombinant Fab Antibody Fragments against Pathogenic Autoantigen

Abstract

Activation of the complement cascade via the classical pathway is required for the development of tissue injury in many autoantibody-mediated diseases. It therefore makes sense to block the pathological action of autoantibodies by preventing complement activation through inhibition of autoantibody binding to the corresponding pathogenic autoantigen using targeted Fab antibody fragments. To achieve this, we use bullous pemphigoid (BP) as an example of a typical autoimmune disease. Recombinant Fabs against the non-collagenous 16th-A domain of type XVII collagen , the main pathogenic epitope for autoantibodies in BP , were generated from antibody repertoires of BP patients by phage display. Two Fabs , Fab-B4 and Fab-19 , showed marked ability to inhibit the binding of BP autoantibodies and subsequent complement activation in vitro. In the in vivo experiments using type XVII collagen humanized BP model mice , these Fabs protected mice against BP autoantibody-induced blistering disease. Thus , the blocking of pathogenic epitopes using engineered Fabs appears to demonstrate efficacy and may lead to disease-specific treatments for antibody-mediated autoimmune diseases.

Antibodies to Pathogenic Epitopes on Type XVII Collagen Cause Skin Fragility in a Complement-Dependent and -Independent Manner

“…Most recently, treatment with Fab mAb fragments in a passive-transfer model using COL17-humanized mice has proved that inhibition of the complement pathway can ameliorate skin detachment (41). Moreover, IgG1 mAb with mutations at C1q binding sites, reacting against NC16A, had less potential for blister formation (42).…”

Human IgG1 Monoclonal Antibody against Human Collagen 17 Noncollagenous 16A Domain Induces Blisters via Complement Activation in Experimental Bullous Pemphigoid Model

“…This concept is further supported by a previous report by Mihai et al (41) in which the pathogenicity of BP IgG1 and IgG4 autoantibodies was amplified by the additional recruitment of neutrophils and mast cells via Fc-FcgR interaction. Recently, our group has used a phage display technique to develop a monoclonal Fab Ab against hCOL17 NC16A from BP patients (51). The monoclonal Fab Ab lacked pathogenic activity when administrated to neonatal COL17-humanized (COL17 m2/2, h+ ) mice.…”

What’s new in bullous pemphigoid

“…In addition, we recently developed a novel therapeutic strategy of treating BP by using the recombinant Fab fraction of IgG monoclonal antibodies to block the complement activation that would otherwise be induced by pathogenic autoantibodies. 36 In BP, complement activation is considered to be critical to blister formation. 30 To block autoantibody-induced complement activation A passive-transfer bullous pemphigoid model using the type XVII collagen (COL17)-humanized mouse.…”