A recent study published in Modern Rheumatology found that the development of anti-drug antibodies (ADAs) during treatment with ozoralizumab did not appear to affect treatment continuation or safety in patients with rheumatoid arthritis (RA). Neutralising antibodies (NAbs) were associated with reduced efficacy in some patients, particularly when ozoralizumab was administered without methotrexate.
Ozoralizumab is a novel tumour necrosis factor (TNF) inhibitor and was first approved in Japan in September 2022 as a treatment for RA. The drug inhibits TNF activity through two human TNFα-binding domains and contains a human serum albumin-binding domain that extends its plasma half-life, allowing administration at 4-week intervals.
With a molecular weight of approximately 38 kDa, ozoralizumab is about one-fourth the size of conventional immunoglobulin G molecules. Preclinical studies in mice have demonstrated rapid distribution of ozoralizumab to inflamed joint tissues, potentially owing to its small molecular size and albumin-binding properties. Previous clinical studies have shown that ozoralizumab can produce early improvements in clinical symptoms and patient-reported outcomes. In particular, administration of 30 mg ozoralizumab by subcutaneous injection with concomitant methotrexate was associated with improvements as early as 2 days after treatment. Its efficacy and tolerability have also been demonstrated for up to 52 weeks, both in combination with methotrexate and as monotherapy.
The investigators evaluated the immunogenicity of ozoralizumab using data from two clinical trials. The phase II/III OHZORA trial assessed ozoralizumab administered in combination with methotrexate, while the phase III NATSUZORA trial evaluated ozoralizumab without concomitant methotrexate. Participants in both trials were classified according to their ADA and NAb status, and safety, treatment continuation, and efficacy outcomes were compared between antibody-positive and antibody-negative participants.
ADA development occurred in 29.2% of participants in the OHZORA trial and 44.3% of participants in the NATSUZORA trial. NAbs were detected in 7.5% and 19.3% of participants, respectively. Importantly, ADA development was not associated with differences in treatment continuation or safety outcomes in either study. These findings suggest that the emergence of ADAs during ozoralizumab therapy may not necessarily compromise treatment tolerability or continuation.
The impact of NAbs on treatment efficacy differed between the two trials. In the NATSUZORA trial, patients who developed NAbs generally demonstrated lower treatment efficacy than NAb-negative participants. However, approximately half of the NAb-positive patients continued to maintain low disease activity through week 52. In contrast, NAb development did not appear to significantly affect efficacy in the OHZORA trial, in which patients received concomitant methotrexate.
Furthermore, several NAb-positive patients from both clinical trials maintained disease control during the long-term extension study, HOSHIZORA. These findings suggest that the presence of NAbs does not invariably lead to loss of clinical response.
The differences observed between the OHZORA and NATSUZORA trials suggest that concomitant methotrexate may influence the immunogenicity of ozoralizumab. The lower frequency of NAb development among patients receiving methotrexate, together with the absence of a significant impact on efficacy in the OHZORA trial, raises the possibility that methotrexate may help preserve the therapeutic response to ozoralizumab.
The current study found that ADA development had no discernible effect on safety or treatment continuation. Although NAbs were associated with reduced efficacy in some patients, their overall impact appeared limited, particularly among patients receiving ozoralizumab with methotrexate. The findings support the continued evaluation of ozoralizumab as a treatment option for RA, particularly given its subcutaneous administration at 4-week intervals, early clinical response, and demonstrated efficacy with or without methotrexate. Further research may help clarify the long-term clinical significance of NAb development and the potential role of methotrexate in reducing immunogenicity.
References
- Kawanishi M, Takeuchi T, Horiuchi N, Yamasaki H, Okamoto S, Miyazaki Y, et al. Impact of anti-drug antibodies and neutralising antibodies on safety and efficacy of ozoralizumab in rheumatoid arthritis. Mod Rheumatol. 2026 Aug 31;36(5):737-746.
- Tanaka Y. Ozoralizumab: first Nanobody® therapeutic for rheumatoid arthritis. Expert Opin Biol Ther. 2023 Jul-Dec;23(7):579-587.