Background/Purpose: Although the management of rheumatoid arthritis (RA) has been remarkably improved, there are still patients who have not responded to existing targeted drugs that mainly suppresses inflammatory cytokines. We hypothesize that the pathophysiology mediated by activated neutrophils is responsible for non-response to existing drugs, and inhibiting peptidyl arginine deiminase type 4 (PAD4), which are released by activated neutrophils and plays a key role in the development and progression of RA, could be a new therapy for difficult-to-treat RA. Based on this concept, we have developed MT-3534, a humanized monoclonal antibody that binds to human, mouse, and cynomolgus monkey PAD4, but not to other human PAD family proteins. Non-clinical safety studies in animals have shown no notable adverse events, and a Phase 1 clinical trial is currently ongoing. The objectives of this study were to provide evidence that PAD4-related pathophysiology is the cause of non-response to existing bDMARDs and to profile the anti-arthritic effects of MT-3534 in mouse arthritis models.

Methods: Human plasma PAD4 levels were measured in samples obtained from 29 RA patients treated with TNF inhibitors, IL-6 receptor inhibitors, or abatacept, and 25 healthy controls. Patients were categorized as responders (R) or inadequate responders (IR) to bDMARDs based on their treatment history and disease activity, and plasma PAD4 levels were compared between them. Next, MT-3534 was administered to collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA) models in mice. Arthritis progression was monitored by scoring the swelling of digits and paws. Various biomarkers in mouse sera and joint homogenates were measured using ELISA. PAD4 in mouse joints was detected using standard immunostaining techniques.

Results: Pre-treatment plasma PAD4 levels in bDMARD-IR patients were higher than that in healthy controls and bDMARD-R patients. After bDMARD treatment, the decrease in plasma PAD4 levels were less in bDMARD-IR patients compared with bDMARD-R patients. In CAIA models, while prophylactic etanercept administration prevented arthritis development but therapeutic etanercept administration did not improve arthritis after arthritis development, MT-3534 suppressed arthritis development and improved developed arthritis equally with prophylactic and therapeutic usage, respectively. Time-course immunostaining of PAD4 in the joints of CIA model mice revealed that MT-3534 worked after neutrophil infiltrated and PAD4 expression increased with arthritis onset. MT-3534 significantly suppressed related biomarkers in the CIA model. Furthermore, it was confirmed that the administration of MT-3534 to mice in which arthritis progressed despite etanercept treatment inhibited the progression of arthritis compared to mice that continued etanercept treatment alone.

Conclusion: MT-3534 inhibited arthritis in mice through a mechanism distinct. The unique mechanism of action of MT-3534 has the potential to fill an unmet medical need in the treatment of RA.AcknowledgementsMT-3534 was produced in collaboration with Pharma Foods International Co., Ltd.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/profiling-of-mt-3534-a-humanized-monoclonal-antibody-targeting-peptidylarginine-deiminase-4-as-a-candidate-drug-for-the-treatment-of-ra/