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A phase 1 experimental medicine study of anti-CD3 monoclonal antibody in rheumatoid arthritis
Catherine A Lawson1,2, Rachel Harry3, Bridget Griffiths1,4
1Academic Unit of Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom.
Introduction:
An Fc-mutated chimeric aglycosyl anti-CD3 monoclonal antibody (mAb), otelixizumab, has been used successfully to treat renal transplant rejection and type 1 diabetes, with reduced toxicity compared with traditional anti-CD3 therapies such as OKT3. The aim of this study was to seek preliminary safety data for otelixizumab in rheumatoid arthritis (RA).
Methods:
A small Phase 1 experimental medicine study was performed in six participants with RA. The primary outcome measure was safety, with a focus on first-dose cytokine release reactions and extent of CD3+ lymphopenia. Cytokine release was quantified using ELISA, and lymphocyte subsets by flow cytometry. In vitro whole blood assays were used to interrogate the mechanisms underlying the first-dose cytokine release reaction. Clinical progress following therapy was monitored as an exploratory outcome.
Results:
All participants experienced a moderate first-dose cytokine release reaction. There was transient lymphopenia but no T-cell depletion, and a temporary CD8+ T-cell lymphocytosis occurred in all participants. In those who completed therapy, a sustained reduction in CRP following treatment was noted. In an in vitro whole blood assay, designed to mirror in vivo cytokine release, there was a trend for reduced cytokine production in seropositive RA compared with seronegative RA, psoriatic arthritis, or healthy controls.
Conclusions:
At the dosing regimen used, otelixizumab was associated with an unexpected and significant first-dose reaction in participants with RA.
Insights
Otelixizumab, an anti-CD3 monoclonal antibody, caused significant first-dose reactions in rheumatoid arthritis patients. While generally safe, further study is needed to manage these cytokine release reactions in RA treatment.
Area of Science:
- Immunology
- Rheumatology
- Pharmacology
Background:
- Otelixizumab is an Fc-mutated, aglycosyl anti-CD3 monoclonal antibody (mAb) with a history of successful use in renal transplant rejection and type 1 diabetes.
- Compared to traditional anti-CD3 therapies like OKT3, otelixizumab offers reduced toxicity.
- This study aimed to evaluate the preliminary safety of otelixizumab in rheumatoid arthritis (RA) patients.
Purpose of the Study:
- To assess the safety profile of otelixizumab in individuals with rheumatoid arthritis.
- To investigate first-dose cytokine release reactions and CD3+ lymphopenia.
- To explore potential mechanisms behind the observed reactions.
Main Methods:
- A Phase 1 experimental medicine study involving six RA participants.
- Primary safety outcomes included first-dose cytokine release and CD3+ lymphopenia.
- Cytokine levels were measured by ELISA, lymphocyte subsets by flow cytometry, and in vitro whole blood assays were used to explore reaction mechanisms.
Main Results:
- All participants experienced a moderate first-dose cytokine release reaction.
- Transient lymphopenia was observed, but no T-cell depletion occurred.
- A temporary CD8+ T-cell lymphocytosis was noted in all participants; sustained CRP reduction was observed in those completing therapy.
Conclusions:
- Otelixizumab administration at the studied regimen resulted in an unexpected and significant first-dose reaction in RA patients.
- The findings highlight the need for careful monitoring and potential management strategies for cytokine release syndrome in RA patients receiving otelixizumab.
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