To investigate BHV-1310  clearance of human IgG through ASGPR mediated hepatic degradation in a murine mouse model. 

Up to 10% of the population is affected by autoimmune diseases, many of which are associated with pathogenic autoantibodies. IgG targeting therapeutics are now approved for a variety of neurological disorders. However, available IgG reducing therapeutics have suboptimal pharmacology and pharmacodynamic effects, cannot be co-administered with antibody therapeutics and have mechanism-based tolerability challenges. BHV-1310 is a bispecific extracellular degrader engineered to rapidly deplete IgG via ASGPR-mediated hepatic lysosomal degradation. BHV-1310 offers mechanistic advantages including fast IgG-lowering; short time to maximal effect; brief exposure period; potential for reduced immunogenicity and immunosuppression given selectivity against IgG3, and co-administration with biologics. 

Athymic nude mice, pre-exposed to human IgG, received vehicle control or BHV-1310 IV or SC up to 10 mg/kg. Plasma and tissues were harvested at various time points up to 48 hrs after dosing and IgG levels were evaluated by MSD or immunofluorescence respectively. Anti-human IgG, phalloidin, DAPI, LAMP-1, CD31, and 𝛼-bungarotoxin were used for immunofluorescence studies.

Immunofluorescence showed IgG within hepatocyte cytosol, colocalized with the lysosomal compartment marker, LAMP-1. Immunofluorescent assessment of interstitial IgG showed effective BHV-1310 mediated clearance of IgG from liver (sinusoids and within hepatocytes), spleen (red and white pulp), kidney (tubules and glomeruli), brain (meninges and microvascular areas), muscle and neuromuscular junctions, spinal cord (meninges and white matter), bone marrow and adipose tissue. The kinetics of IgG reduction varied depending on the tissue, and spanned 1-48 hrs.

In this murine model, BHV-1310 mediated effective clearance of human IgG through ASGPR mediated hepatic degradation across several tissues and anatomical structures within 48 hours of administration. These findings underscore the therapeutic potential of BHV-1310 for both systemic and organ-specific autoimmune diseases.