Objective: To evaluate baseline prevalence and post-baseline incidence of anti-drug antibodies (ADAs) in ocrelizumab-treated patients from two identical Phase III, randomized, double-blind, double-dummy, IFNβ-1a-controlled trials of ocrelizumab in relapsing MS (OPERA I and OPERA II).
Background: Ocrelizumab is a humanized monoclonal antibody (mAb) that selectively targets CD20+ B cells. Humanization is believed to potentially reduce mAb immunogenicity, a measure of which is the formation of ADAs. Theoretically, a lower immunogenicity risk is expected with humanized antibodies like ocrelizumab (85-90% human protein) compared with chimeric antibodies (typically 65-75% human protein), which could potentially improve tolerability and efficacy with long-term treatment of chronic diseases. In the treatment period of a Phase II study of ocrelizumab in relapsing-remitting MS, no treatment-emergent ADAs were detected.
Methods: Patient serum samples were evaluated for ADAs at baseline and every 24 weeks throughout the treatment period. ADAs were detected in a validated bridging ELISA-based screening assay with appropriate sensitivity and drug tolerance. Screened positive samples were confirmed for specificity by competition with ocrelizumab and further titered. Confirmed positive samples were tested in an antibody-mediated cellular cytotoxicity-based neutralizing antibody (NAb) assay to determine the neutralizing capabilities of ADAs.
Results: Overall, >96% of ocrelizumab-treated patients were evaluable for baseline prevalence and post-baseline incidence of ADAs in OPERA I and OPERA II. Baseline prevalence of ADAs among evaluable ocrelizumab-treated patients, but prior to ocrelizumab infusion, was 0.3% (1/396) in OPERA I and 1.0% (4/402) in OPERA II, which is expected based on assay specificity. Incidence of treatment-emergent ADAs post-baseline was 0.2% (1/402) and 0.5% (2/405) in OPERA I and OPERA II, respectively. Among these ADA-positive patients, one tested positive for NAbs.
Conclusions: There was a low incidence of immunogenicity in the ocrelizumab groups in the OPERA I and OPERA II studies. Supported by F. Hoffmann-La Roche.