Background: Rheumatoid arthritis (RA) is one of the most prevalent joint diseases with no cure. Despite advancements in treatment, RA patients often require lifelong therapy, and a substantial proportion fails to respond to existing therapies. We previously engineered a recombinant monoclonal antibody (R69-4) [1] targeting the F4 epitope on type-II collagen (COL2), which demonstrated promising therapeutic potential in experimental arthritis. Concurrently, we developed humanized mouse models incorporating human alleles such as HLA_DRB1*0401 [2], closely mimicking seropositive RA in Caucasians.

Objectives: This study aimed to evaluate the efficacy of R69-4 in humanized arthritis models.

Methods: Humanized mice carrying RA-associated HLA-DRB1*0401 allele were immunized with citrullinated COL2 on day 0 and boosted with the same autoantigen on day 21. Recombinant R69-4 antibody (1 mg) or control was administrated on day 28. Arthritis severity was assessed on a 60-point scale over seven weeks. COL2-specific antibody responses were measured via ELISA, and immune cell profiles were analyzed using flow cytometry.

Results: R69-4 significantly reduced arthritis severity in citrullinated COL2-induced arthritis, particularly during the onset phase. COL2-specific antibody levels were slightly decreased one-week post-immunization. Immunophenotyping revealed reduced expression of the activating Fc gamma receptor 3 (FCGR3) on both neutrophils and synovial macrophages.

Conclusion: R69-4 exhibited significant efficacy in humanized arthritis models, highlighting its potential as a therapeutic candidate for RA, especially during early disease stages.

REFERENCES: [1] Xu Z, Xu B, Lundström SL, Moreno-Giró À, Zhao D, Martin M et al. A subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils. Nature Communications 2023; 14 (1): 5949.

[2] Romero-Castillo L, Li T, Do N-N, Sareila O, Xu B, Hennings V et al. Human MHC Class II and Invariant Chain Knock-in Mice Mimic Rheumatoid Arthritis with Allele Restriction in Immune Response and Arthritis Association. Advanced Science 2024; 11 (23): 2401513.

Acknowledgements: This study was funded by Karolinska Institutet Rheumatology Foundation (2024-03940).

Disclosure of Interests: Zhongwei Xu is partially employed by Vacara AB, Rajan Kumar Pandey: None declared , Laura Romero Castillo: None declared , Alex Moreno-Giro: None declared , Rikard Holmdahl is the founder of Vacara AB.

© 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.