The Association between Clinical Response to Ustekinumab and Immunogenicity to Ustekinumab and Prior Adalimumab

Abstract

BackgroundImmunogenicity due to antidrug antibodies (ADA) to tumor necrosis factor (TNF)-α antagonists is known to decrease treatment response. However, few studies have investigated ADA in ustekinumab, an interleukin-12 and -23 antagonist, in a clinical setting. This study aimed to investigate the immunogenicity of ustekinumab and its clinical consequences in psoriasis.MethodsThis prospective observational study enrolled 76 patients with plaque psoriasis who were treated with ustekinumab for a minimum of 7 months. Blood samples were drawn just prior to scheduled ustekinumab injection during clinic visits. Levels of anti-ustekinumab antibody (AUA) and serum ustekinumab concentration were measured respectively by radioimmunoassays and enzyme-linked immunoassays respectively, and correlated to clinical data and Psoriasis Area and Severity Index (PASI).ResultsAUA was detected in 6.5% of patients after a mean of 13 months of treatment. Patients with positive AUA had significantly lower serum ustekinumab concentrations (0.01 vs. 0.2 mg/L, p<0.001) and lower PASI 50 response than patients without AUA (0% vs. 69%, p = 0.004).The percentage of AUA formation was comparable between patients who had failed previous adalimumab with or without anti-adalimumab antibodies (AAA) (14.3% vs. 12.5%, p = 1.00). However, a higher proportion of switchers without AAA obtaining PASI50 (71.4% vs. 37.5%) and PASI75 response (42.9% vs.12.5%) within 7 months of ustekinumab treatment than with AAA though this difference did not reach statistical significance.ConclusionsOur results suggest that presence of AUA was significantly associated with treatment failure for ustekinumab, though limited by a small sample size. Also, determining the presence of ADA to antecedent TNF-α antagonists may assist in choosing an optimized subsequent treatment modality achieving treatment success.

Using Real‐World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic‐Pharmacodynamic Study

“…Initially developed for psoriasis (where it remains first‐line), it is now also licensed for use in psoriatic arthritis and inflammatory bowel disease . Studies investigating the relationship between ustekinumab exposure and outcome are few, generally limited to descriptive or empirical analyses, and report mixed results . Understanding exposure‐response is complicated by the fact that some patients’ disease may not respond to IL‐23‐Th17 therapies, and furthermore, some may receive subtherapeutic drug exposure due to PK variability.…”

Immunogenicity assay development and validation for biological therapy as exemplified by ustekinumab

“…We found the least non-specific binding using ELISA for UST and ADA determination, allowing less dilution (1:5 in ELISA versus 1:10 in SPR) of serum samples and more precise and accurate quantitation at lower analyte concentrations compared to the SPR approach. In both assays, the linear range for UST detection covered the concentration range expected in serum samples from treated patients [6]. This is due probably to the multiple washing steps included in the ELISA.…”

“…An SPR assay was developed to enable detection of UST in serum samples from UST-treated patients. Patients with plaque psoriasis who underwent an UST treatment regimen (45 mg; application interval = 12 weeks) have a median trough level of 0·20 mg/l (interquartile range = 0·023-0·4) when UST was measured just prior to UST injection [6]. 1).…”

“…UST at a constant concentration of 0·08 µg/ml, a concentration expected in patients treated with UST [6], was incubated with varying concentrations of nADA. In this case, the binding sites of both antibodies would be covered and thus unable to bind to the assay target and induce a signal.…”

“…Regulatory agencies recommend that the linear range of the analyte should cover 80-120% of the expected clinical concentration. Patients with plaque psoriasis who underwent an UST treatment regimen (45 mg; application interval = 12 weeks) have a median trough level of 0·20 mg/l (interquartile range = 0·023-0·4) when UST was measured just prior to UST injection [6]. Therefore, an UST concentration range between 0·008 and 0·45 µg/ml led to a linear assay response with high precision and accuracy ( Fig.…”