Background: The development of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (bDMARDs and tsDMARDs) has improved rheumatoid arthritis (RA) patient care by providing additional therapeutic options for achieving disease remission or low disease activity. However, there is continued unmet need for safe and effective agents with improved convenience. TNF-like protein 1A (TL1A) is a pro-inflammatory cytokine that is upregulated in the blood and synovial fluid of RA patients and has been implicated in RA pathogenesis. Spyre Therapeutics is developing half-life extended antibodies targeting TL1A (SPY002) for the treatment of patients with autoimmune diseases, such as inflammatory bowel disease and rheumatoid arthritis.

Objectives: To compare the biological activity of an anti-TL1A antibody in a rodent model of rheumatoid arthritis (collagen-induced arthritis (CIA) model) to etanercept, a clinically validated TNF inhibitor.

Methods: To induce arthritis, 6–8-week-old female Wistar rats were injected with a bovine type II collagen emulsion in Freund’s incomplete adjuvant on study days 0 and 7. In the semi-preventative CIA model, test article dosing was started on day 6 prior to disease onset. In the therapeutic CIA model, test article dosing was started on day 13 after onset of disease. Anti-TL1A and isotype control (BioXCell) antibodies were injected intravenously once weekly. Etanercept was injected intraperitoneally every three days. Body weight, hind paw volume and observational arthritic scoring were measured twice per week until the end of the study. At study conclusion, X-ray images were taken for the left and right hind paws and scored. The left hind paw was placed in formalin for histopathological scoring. Following decalcification, paraffin embedding and sectioning, slides were stained with hematoxylin and eosin (H&E) or Safranin O. H&E slides were scored for cell infiltration and pannus severity and Safranin O slides were scored for cartilage lesion severity and bone resorption severity by a blinded pathologist.

Results: In the semi-preventative CIA model, treatment with anti-TL1A resulted in significantly improved disease activity score and hind paw volume compared to etanercept treatment from day 16 until the end of the study (day 25). Treatment with anti-TL1A or etanercept resulted in improved hind paw X-ray scores relative to control groups, and the magnitude of improvement was significantly greater for animals treated with anti-TL1A than with etanercept. Anti-TL1A treatment, but not etanercept treatment, resulted in improvement across all histopathology scores compared to the vehicle control group. In the therapeutic CIA model, treatment with anti-TL1A or etanercept resulted in comparable improvement in disease activity score, hind paw volume, and hind paw X-ray score relative to the vehicle control group.

Conclusion: Anti-TL1A antibody treatment reduced disease symptoms and macroscopic and microscopic pathology in the semi-preventative and therapeutic rat CIA models. Treatment with anti-TL1A resulted in superior efficacy relative to etanercept treatment in the semi-preventative CIA model, and the treatments showed comparable efficacy in the therapeutic CIA model. These data support the clinical development of SPY002 in RA patients.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Matthew Siegel Spyre Therapeutics, Current employee of Spyre Therapeutics, Emily Lewis Spyre Therapeutics, Current employee of Spyre Therapeutics, David Giles Spyre Therapeutics, Spyre Therapeutics, Justin LaFountaine Spyre Therapeutics, Spyre Therapeutics, Joshua R. Friedman Spyre Therapeutics, Johnson & Johnson, Current employee of Spyre Therapeutics, Andy Spencer Spyre Therapeutics, Spyre Therapeutics.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.