Figure 4.

Antibody engineering strategies to reduce endogenous IgG levels.

A. In the presence of an inhibitor of FcRn such as an Abdeg that binds to FcRn with increased affinity at both near neutral and acidic pH, the inhibitor is internalized by receptor (FcRn)-mediated processes and competes with endogenous IgGs for FcRn binding in acidic endosomes. Consequently, endogenous IgG molecules are driven into lysosomes and are degraded. The inhibitor shown binds through its Fc region to FcRn, whereas other classes of inhibitors can be peptide-based inhibitors or antibodies that bind through their variable domains [33,84–89,92]. B. A specific class of engineered proteins comprising antibody Fc regions fused to an antigen (one antigen molecule per Fc fragment) can be used to deplete antigen-specific antibodies. This fusion protein, named a Seldeg (for selective degradation of antigen-specific antibodies), is engineered to bind to FcRn via its Fc region with increased affinity at both near neutral and acidic pH. Seldeg-antibody complexes are internalized into FcRn-expressing cells by receptor-mediated uptake, and subsequently follow the constitutive degradation pathway of FcRn into lysosomes [83], leading to the breakdown of the targeted antibody. Due to their different mechanism of action, Seldegs can be used at lower doses than Abdegs and do not affect the levels of antibodies that are not specific for antigen.