Analyses of the pharmacokinetic behaviour of MOG- and HER2-Seldeg revealed relatively short -phase half-lives (MOG-Seldeg, 47.01.4h (s.d.); HER2-Seldeg, 38.33.1h;n=5 for both groups) that were similar to those of the Abdeg (37.82.5h;n=5;Supplementary Fig. imaging. The knowledge that the neonatal Fc receptor, FcRn, maintains immunoglobulin G (IgG) levels and transport in the body has prompted the development of antibody- or peptide-based inhibitors to reduce IgG levels1,2,3,4,5. However, these inhibitors block the interaction of the Fc region of IgG with FcRn and decrease levels of IgGs of all specificities, including protective antibodies. To overcome these off-target effects, here we have designed a novel class of engineered antibodies that selectively clear antigen-specific antibodies without modulating the levels of antibodies of other specificities. We have named these agents Seldegs’ to indicate their ability to selectively degrade antibodies of defined specificities. The design of clearing agents for antigen-specific antibodies presents several challenges: first, antigen-specific antibody levels are typically very low compared with those of antibodies of irrelevant specificities, and these two antibody pools are similar with shared constant regions but distinct variable domains. Second, since the antibodies being targeted are bivalent, crosslinking could result in inflammatory immune complexes. Seldegs were therefore designed to display recombinant antigen as a monomer linked to a dimeric, human IgG1-derived Fc fragment using a similar approach to that described previously for monomeric erythropoietin (Epo)-Fc fusions6. Mutations to ablate interactions with human FcRs7and enhance binding to FcRn in the pH range 6.07.4 (ref.1) were inserted. Naturally occurring IgGs have substantially higher affinity for FcRn at acidic pH than at near neutral pH, and this property is essential for the recycling and transcytosis of IgG within FcRn-expressing cells8. By contrast, gain of binding affinity of an Fc (or IgG) for FcRn at pH 7.4 results in receptor-mediated internalization into cells and lysosomal STMN1 delivery1,9,10. In the current study, we demonstrate that Fc-antigen fusions, or Seldegs, containing such affinity-enhanced Fc fragments selectively capture antigen-specific antibodies and direct them into degradative lysosomal compartments in FcRn-expressing cells. == Results == == Clearance of antigen-specific antibodies by Seldegs == To demonstrate the generality of the Seldeg approach, antibodies specific for two antigens were targeted (Fig. 1a): first, the extracellular domain (ECD) of Cyanidin chloride myelin oligodendrocyte glycoprotein (MOG-Seldeg), which is recognized by autoreactive antibodies in Cyanidin chloride both animal models of multiple sclerosis and multiple sclerosis in humans11,12,13. Second, the ECD of HER2 (HER2-Seldeg), a well-defined target for therapy and diagnostic imaging of HER2-overexpressing tumours with HER2-specific antibodies such as trastuzumab (TZB)14. Both MOG- and HER2-Seldegs have the expected binding properties for FcRn, MOG-specific antibody (8-18C5 (ref.15)) and TZB (Fig. 1b;Supplementary Fig. 1;Supplementary Table 1). The expression yields of the Seldegs are 50 mg l1(MOG-Seldeg) and 15 mg l1(HER2-Seldeg). SDSpolyacrylamide gel electrophoresis and high-performance liquid chromatography analyses also indicate that these Fc fusion proteins have favourable biophysical properties following storage at 4 C (30 days) or 37 C (5 days) in PBS or human serum (Supplementary Fig. 2). In addition, the Seldegs retain their affinity for binding to 8-18C5 (KD=33.0 nM; MOG-Seldeg) and TZB (KD=14.3 nM; HER2-Seldeg) following incubation for 5 days at 37 C. == Figure 1. TZB and 8-18C5 are rapidly cleared by Seldegs in transgenic mice expressing huFcRs. == (a) Schematic representation of Seldeg design. (b) A concentration of 100 nM MOG-Seldeg or MOG-WT was injected over immobilized mouse FcRn at the indicated pH. (c) Mice were Cyanidin chloride intravenously injected with radiolabelled (125I) 8-18C5 (15 g) and 24 h later PBS, MOG-WT (31 g) or MOG-Seldeg (4-fold (31 g) or 16-fold (125 g) molar excess; low or high dose, respectively) was delivered intravenously. Radioactivity levels were determined at the indicated times. Whole body or blood levels obtained immediately before Seldeg or control delivery were taken as 100%. (d,e) The same methodology as incwas used, except that radiolabelled TZB (15 g) injection was followed 24 h later by intravenous delivery of PBS, HER2-WT (51 g), HER2-Seldeg (51 g), MOG-Seldeg (31 g) or Abdeg (MST-HN; 60 g), each at fourfold molar excess. Error bars indicate s.d. and statistically significant differences are indicated for MOG-WT versus MOG-Seldeg (low) (c) HER2-Seldeg versus MOG-Seldeg (d) and HER2-Seldeg versus Abdeg (e) by *(P<0.05, two-way analysis of variance with Tukey's multiple comparisons;n=6 mice per group). Data shown are representative of two independent experiments. We first investigated the ability of Seldegs to clear antigen-specific antibodies in transgenic mice that express human FcRs (huFcR mice)16. These mice were used since Seldegs have human IgG1-derived Fc regions. Mice were injected with125I-labelled, MOG-specific antibody 8-18C5 (ref.15)..