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Preprint WatchModerateSeptember 17th, 2026

A bispecific antibody targeting a membrane-proximal ASGPR1 region promotes TNF-α recruitment and uptake

Song, X.; Li, S.; HaShan, A.; Du, J.; Sun, Y.; Jiang, X. T.; Liu, X.

A bispecific antibody linking TNF-alpha recognition to a membrane-proximal epitope on ASGPR1 recruits soluble TNF-alpha into hepatocyte-like cells and lysosomal compartments, reducing supernatant TNF-alpha by roughly 60 percent over 90 minutes, which proposes receptor-mediated cytokine clearance as an alternative to neutralization.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The proposal is a modality change rather than a target change: instead of neutralizing soluble TNF-alpha, the bispecific redirects it to an endocytic receptor for degradation. The single TNF entry in the Claidex graph is a soluble TNF selective agent stopped for futility in COVID-19 acute respiratory distress syndrome (inb03-soluble-tnf-covid19-ards-futility), where the limiting problem was indication and timing rather than incomplete ligand removal. Deeper clearance of a cytokine that was not driving the outcome would not have changed that trial. The flag is a reminder that a clearance advantage over neutralization needs to be demonstrated in a disease where soluble TNF-alpha is established as causal, and that the cell culture readout here is not yet a pharmacodynamic claim in vivo.

Abstract excerpt

Abstract Recruiting an endocytic receptor through an antibody offers a route to redirect extracellular cytokines into cells. Here, we developed BiAb J31, an IgG like bispecific antibody linking TNF recognition to a membrane-proximal region of asialoglycoprotein receptor 1 (ASGPR1). J31 was isolated by immunization with an engineered ASGPR1 extracellular domain followed by screening against wild-type ASGPR1 and HepG2 cells. Its variable domains were combined with unmodified adalimumab variable regions using knobs into holes and CrossMab engineering, with L234A/L235A/P329G Fc substitutions. BiAb J31 retained HepG2 binding and engaged both antigens in bridging assays. Sequential binding experiments demonstrated recruitment of TNF to BiAb J31 treated cells. Live cell imaging showed uptake of fluorescent antibody-containing complexes and overlap with LysoTracker-positive compartments. In HepG2 cultures containing BiAb J31, TNF and a PE conjugated detection antibody, supernatant PE fluorescence fell by approximately 60% over 90 minutes. Truncation and synthetic-peptide assays localized J31 recognition to ASGPR1 residues 62~100, outside the carbohydrate-recognition domain, and AlphaFold 3 modeling proposed an Fv peptide interface. These findings identify a membrane-proximal ASGPR1 binding antibody that is compatible with bispecific engineering and supports cellular recruitment and

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.