Background/Purpose: Pathological elevation of type I interferon (IFN-I) , B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) has been robustly documented across multiple autoimmune diseases. But blocking these pathways individually only demonstrates limited efficacy with a considerable proportion of patients exhibiting inadequate therapeutic responses, which may be attributed to pathogenic heterogenicity of disease and population. IFN-I is required for B cell activation and differentiation as well as other multiple immune cells, while BAFF and APRIL synergistically sustain plasma cell survival and clonal expansion. We developed a fusion protein (vTACI-aIFNAR) by covalently linking a BAFF/APRIL-neutralizing TACI variant to an IFN-I-blocking anti-IFNAR antibody. This multi-pathway blocker is designed to achieve greater therapeutic effect, thereby improving outcomes across heterogeneous patient populations.

Methods: Single-cell RNA sequencing data of PBMCs from 175 systemic lupus erythematosus (SLE) patients and 99 healthy controls were obtained from the cellxgene database and analyzed. Binding affinity was evaluated by surface plasmon resonance. The B cell proliferation, STAT-1 phosphorylation and plasma cell generation were measured in function related cellular assays. In vivo efficacy was evaluated using two distinct murine models: an allogeneic salivary gland protein-induced Sjögren’s syndrome (SS) model and the NZBWF1/J spontaneous SLE model. Safety profiling was performed through a 4-week repeated-dose Good Laboratory Practice (GLP) toxicology study in cynomolgus monkeys.

Results: Pseudobulk RNA-seq analyses revealed elevated BAFF, APRIL, and IFN-I expression in SLE patients compared to healthy controls, with 82.3% exhibiting concurrent overexpression of IFN gene signature (IFGS) and BAFF, 40.6% of IFGS and APRIL, 37.7% of BAFF and APRIL, and 37.5% of all three factors, which indicates pathogenic heterogeneities of SLE patients. The vTACI-aIFNAR displayed robust BAFF/APRIL binding and potent suppression of B cell proliferation driven by these factors, while its IFN-I binding and STAT-1 phosphorylation inhibition were similar to that of anti-IFNAR antibody. Notably, vTACI-aIFNAR surpassed TACI-Fc and anti-IFNAR in blocking IFN-α/BAFF/APRIL-induced plasma cell generation in vitro. In murine SS models, the murine surrogate of vTACI-aIFNAR restored salivary flow rates in a dose-dependent manner, outperforming both TACI-Fc and anti-IFNAR antibody at equimolar doses. SLE models demonstrated marked alleviation in proteinuria, anti-dsDNA IgG/IgM level, and renal histopathology following treatment. GLP-compliant primate toxicity studies confirmed favorable tolerability with a 43× safety margin relative to projected clinical exposure.

Conclusion: Collectively, our findings demonstrate that the multi-pathway blocker, vTACI-aIFNAR, shows greater therapeutic effect with favorable tolerability profiles, implying enhanced therapeutic efficacy across diverse autoimmune patient subsets. These preclinical advantages substantiate its clinical translation potential for autoimmune disorders.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-fusion-of-taci-variant-and-anti-ifnar-antibody-with-greater-therapeutic-effect-on-related-autoimmune-disease-models/