Background/Purpose: Novel extracellular IgG degraders (BHV-1300/-1310) from the innovative molecular degraders of extracellular protein (MoDE) drug platform are being developed for the treatment of IgG-mediated autoimmune diseases, including rheumatoid arthritis (RA) and myasthenia gravis. IgG MoDEs have the potential to target IgG and IgG-immune complexes, both in the circulation and in disease-relevant tissues. Thus, this new modality offers a therapeutic strategy for targeting pathogenic autoantibodies and immune complexes.

IgG MoDEs are bifunctional molecules engineered to bind simultaneously to IgG molecules and to hepatic asialoglycoprotein (ASGPR) receptors, leading to internalization and endo-lysosomal degradation of IgG in the liver. They have previously shown the ability to decrease serum IgG levels in a rapid, robust, and selective manner. The current studies evaluated the ability of IgG MoDEs to also remove interstitial IgG and disease-relevant IgG-immune complexes.

Methods: Large, multimeric human IgG-immune complexes (i.e., IgG-IgM, and IgG-IgA) were generated in vitro. The ability of BHV-1300/-1310 to mediate cellular uptake and degradation of these IgG-immune complexes was assessed in vitro utilizing an endocytosis assay with human ASGPR expressing HEK-293T cells. The ability to remove interstitial IgG and disease relevant IgG-immune complexes in tissues was examined in vivo in mice by a combination of methods (e.g., MSD and immunofluorescence). Specificity of this mechanism of action was confirmed by conducting studies in mice lacking the expression of ASGPR.

Results: In the endocytosis assay, IgG MoDEs (BHV-1300/-1310) mediated robust cellular uptake of human IgG-immune complexes with EC50s in the single to double digit nanomolar range in HEK cells expressing ASGPR. In mice, complete clearance of IgG from liver, spleen, kidney, bone marrow, fat, meninges, and neuromuscular junction was observed within 48 hrs of dosing; and immune complex uptake and degradation in the liver was noted within 1-2 hrs of dosing. IgG signal was colocalized with a lysosomal marker. Studies in mice lacking ASGPR expression confirmed that Ig uptake and degradation in the liver following treatment with IgG degraders was specifically mediated by ASGPR.

Conclusion: In these in vitro and in vivo studies, extracellular IgG degraders (BHV-1300/-1310) from the MoDE drug platform demonstrated the ability to remove interstitial IgG and disease-relevant immune complexes through endo-lysosomal degradation in the liver. This new modality offers an attractive and differentiated therapeutic strategy for treating a spectrum of autoimmune conditions by targeting pathogenic autoantibodies and immune complexes that play a critical role in disease onset, progression and end organ damage.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/molecular-degraders-of-extracellular-protein-modestm-rapidly-and-effectively-remove-interstitial-igg-and-disease-relevant-immune-complexes-through-endo-lysosomal-degradation-in-the-liver/