Targeting pathogenic T Cells: Rosnilimab shows promise in rheumatoid arthritis

Despite the availability of biologic and targeted synthetic DMARDs for rheumatoid arthritis (RA), many patients experience loss of therapeutic response over time, often due to anti-drug antibodies or disease chronicity. Rosnilimab, a humanized monoclonal antibody targeting PD-1, selectively binds and depletes PD-1–high pathogenic T cells, while sparing regulatory T cells. This mechanism offers a novel, cell-targeted approach aimed at restoring immune balance in RA.

In this Q&A, Professor Paul Emery (University of Leeds, UK) explores the factors driving the loss of therapeutic response in RA, how this affects disease management, and the mechanism of action of rosnilimab. Prof. Emery also highlights the methodology, findings and clinical implications of the phase 2b study investigating rosnilimab for the treatment of RA, which he presented at this year’s ACR meeting.

The abstract “LB19: Rosnilimab, a Selective and Potent Depleter of Pathogenic T Cells, Demonstrates Efficacy, Safety, and Translational Proof of Mechanism in a Rheumatoid Arthritis Phase 2B Trial” was presented at the ACR Convergence 2025, October 24–29, Chicago, Illinois, USA.

touchIMMUNOLOGY coverage of ACR 2025: 

I’m a Consultant Rheumatologist, and Arthritis UK Professor of Rheumatology at the University of Leeds, where I’ve been for nearly 30 years. Before that I was senior lecturer in Birmingham and before that at the Walter and Eliza Hall Institute of Medical Research (WEHI), Melbourne. In Leeds, we have a large population that we provide a rheumatology service for, with specialist professors in most areas. We’ve been involved in virtually all the new drugs that have been developed for rheumatoid arthritis, lupus, etc. We have a very large group of academic clinical researchers, and we try and put as many patients as we can through the research protocols with the idea of improving on state-of-the-art treatment.

What factors drive loss of therapeutic response in rheumatoid arthritis and how does this affect disease management?

A major factor in determining loss of response is late treatment, because, as we’ve shown, if patients are left exposed to inflammation, the number of dysregulated pathways increases exponentially with time. If they are treated early, there’s much less loss of response. But if treated late, patients rarely achieve deep remission and often gradually lose their response to conventional synthetic DMARDs over time.

For advanced therapies, largely cytokine inhibitors (particularly anti-TNF alpha), a major reason patients lose response is that they develop anti-drug antibodies. This means they get a good response initially, which they gradually lose over time, associated with a shortened duration of response. This results in patients having to cycle through different therapies. Patients who have had one or more advanced therapies are less responsive for a variety of reasons; they have longer duration of disease, they have more damage, and they are less responsive to purely anti-inflammatory treatment.

What is the mechanism of action of rosnilimab?

Rosnilimab binds to PD-1, and PD-1 is expressed at high levels on pathogenic T cells, which include T peripheral helper cells, T follicular helper cells and effector T cells. It wasn’t known until this study just how powerful rosnilimab was at depleting these pathogenic cells. Pathogenic T cells make up over 80% of the T-cells in the synovium of patients with rheumatoid arthritis (RA), and they’re increased threefold over controls in the peripheral blood. They are not normally found in large numbers and even in RA, they represent only about 5% of the circulating T cells. This study showed that rosnilimab is a very potent depleter of the pathogenic T cell subsets.

Could you describe the methodology of the phase 2B trial you presented at ACR?

The details of the study were determined by the FDA, it was placebo-controlled with 3 different active drug doses, 1:1:1:1, and the primary endpoint was at 12 weeks. At 14 weeks, participants had to have reached a Clinical Disease Activity Index (CDAI)  score of less than 10, which requires quite a big improvement, and those that hadn’t were removed from the study. This removed 14 ACR50 improvement criteria responders and some ACR70 responders. Placebo patients were also removed from the study at that time as well. If those on active treatment achieved the target CDAI response, they could continue for the rest of the study, which was initially to week 28, followed by a period of 3 months off drug.

What were the primary and secondary endpoints and how well were they met?

The primary endpoint, which was an improvement in the Disease Activity Score 28 (DAS-28-CRP) was met by all the doses compared to placebo. Secondary endpoints consisted of the usual measures, ACR20, ACR50, ACR70, CDAI, low disease activity, and C-reactive protein (CRP). What was interesting was all doses had a significant improvement in CRP, as early as week 2, whilst the CRP was not affected by placebo.

For the secondary endpoints, the ACR20 improvement criteria were met by all doses and the others numerically improved with some improvements significant compared to placebo. What was striking was the further improvement participants had between week 12 and week 28. There was improvement in all endpoints measured, including clinical and patient reported outcomes. This improvement seemed to be genuine as it was seen less at the low dose and more dramatically at the high doses.

Finally, the improvement in the outcomes occurred irrespective of what patients had been treated with previously. Off drug, the patients who had good responses maintained them over 3 months in approximately 75% of cases.

What were the findings in terms of depletion of pathogenic T cells?

One of the strengths of the study was the translational medicine data. There was flow cytometry studying the PD-1 high cells, the total T cell numbers, and regulatory T cells. At the higher doses, there was over 90% reduction in the PD-1 high cells (with >90% reduction in TpH cells), very little change in T cells overall, and unchanged or improved regulatory T cell numbers, with the last continuing to improve in the off-drug period.

Gene expression was also looked at pooled, because of smaller numbers (n=24 patients) dose level, T-cell activation, B-cell activation and myeloid activation all dramatically improved in patients, consistent with the clinical effectiveness.

Could you outline the safety profile of rosnilimab?

The safety profile was remarkably good, with very few dropouts, no malignancies, and no deaths. There was one major adverse cardiovascular event (MACE), a stroke, but this was in the lowest dose, in a patient with pre-existing carotid artery stenosis. There were relatively few serious treatment emergent adverse events. Safety was re-assuring, especially in a population which included a mixture of failure of conventional synthetic and advanced therapies, (failure of up to two biologic drugs, or bio-targeted synthetic drugs was permitted).