Anti-Tocilizumab (TCZ) antibodies developed among patients treated with TCZ-Subcutaneous (SC) and TCZ Intravenous (IV) approach, either as a monotherapy or in combination with conventional synthetic Disease Modiffying Anti-rheumatic Drugs (csDMARDs), had no evident impact on the pharmacokinetics, efficacy or safety.  Therefore, routine anti-drug antibodies (ADA) testing is not required for the clinical use of TCZ in treating rheumatoid arthritis (RA) in adults.

Biologic DMARDs (bDMARDs) are first-line treatment agents for RA patients not responding to or intolerant to csDMARDs. The currently approved bDMARDs include anti-tumor necrosis factor-α agents (aTNFs), Anti-interleukin 6 receptor (IL-6R) therapy, Anti-CD20 B cell targeted therapy and T cell co-stimulation inhibition. One of the major safety concerns associated with bDMARDs use is the development of ADAs. Anti-drug antibodies or ADAs can lead to a loss of efficacy and/or immune-mediated adverse reactions, including IgE-mediated or non-IgE-mediated events. Many factors may contribute to ADA development including structure and idiotype, route of administration, mechanism of action, concomitant csDMARD use, disease activity, genetic status, patient immunocompetence, treatment duration, the disease itself and drug dose/frequency.

Tocilizumab (TCZ) is a humanized monoclonal antibody (mAb) of the IgG1subclass that has been approved for adult RA (as intravenous or subcutaneous formulations) and as IV for systemic-course and polyarticular-course juvenile idiopathic arthritis and Castleman disease (Japan only). It inhibits IL-6 activity by blocking IL-6 binding to the membrane-bound and soluble IL-6R. Its efficacy and safety profile are well characterized as a monotherapy or in combination with csDMARDs

Based on the effectiveness and safety, the SC and IV formulations of TCZ are available for the treatment of RA. The present study evaluated the development of Anti-TCZ antibody and its effect on safety and effectiveness in adult patients with RA treated with intravenous TCZ (TCZ-IV) or TCZ-SC as a monotherapy or in combination with csDMARDs).

Rationale behind the research:

• There is lack of studies evaluating the immunogenicity of TCZ in different clinical settings.  

Objective:

• To develop Anti-TCZ antibody and to evaluate its effect on safety and effectiveness in RA patients treated with TCZ-IV or TCZ-SC as monotherapy or in combination with csDMARDs.

Study outcomes:

• Evaluation of immunogenicity rates, safety and efficacy rates in patients who developed anti -TCZ antibodies following TCZ-SC or TCZ-IV treatment
• Evaluation of safety, immunogenicity and effect of ADAs on safety and efficacy following TCZ as monotherapy or in combination with csDMARDs
• Assessment of correlation of ADAs with clinical response, adverse events or pharmacokinetics

Time Points: Not described

Study outcomes:

• The percentage of patients who developed ADAs following TCZ-SC (99.8%) or TCZ-IV (98.8%) treatment was 1.5% and 1.2%, respectively (Fig 1)

• The overall incidence of ADA development was low in the 1360 patients treated with TCZ monotherapy (intravenous: 0.7%; SC: 2.0%) and the 7540 patients treated with TCZ + csDMARDs (intravenous: 1.3%; SC: 1.4%), regardless of formulation (Fig 2)

• ADA development did not correlate with pharmacokinetic or safety events, including anaphylaxis, hypersensitivity or injection-site reactions, and no patients who developed ADAs had loss of efficacy
  

The study indicates that out of 8974 patients treated with TCZ, the rate of ADA development was low, despite IV or SC formulation and whether it was administered as a monotherapy or in combination with csDMARDs. In patients who did develop ADAs, it was mostly transient, and had no correlation to pharmacokinectics, safety events or loss of efficacy was observed.

The proposed mechanism of the observed low immunogenicity in patients treated with TCZ has not been fully elucidated. However, immunogenicity assays are challenged and complicated by various factors like molecule-related factors (e.g., mechanisms of action, molecular structure, and manufacturing process) and patient characteristics. Immunogenicity assays, controlled by drug interference, also affects ADA incidence and immunogenicity. To minimize the effect of assays on immunogenicity, the drug (TCZ) interference rates were controlled by collecting and evaluating TCZ-washout samples.

One possible mechanism of the observed low immunogenicity of TCZ was thought to be related with the downregulation of B cell activities due to the blocking of IL-6 signaling (a different mechanism of action from that of aTNFs).

In general, it is not clear whether a humanized mAb treatment is more immunogenic than a fully human mAb. It has been reported that a fully human mAbs (e.g., adalimumab and golimumab) may account for ADA development. ADAs developed against the fully human adalimumab induces a neutralizing response that may vary by disease and therapy (5–89%).