#ResearchSpeak & #NeuroSpeak: the great differentiator

Anti-drug antibodies are a major problem in clinical practice and are important for safety and efficacy reasons. #ResearchSpeak #ClinicSpeak #MSBlog

How important are anti-drug antibodies in relation to biological therapies, in particular neutralising antibodies to the monoclonal therapies used to treat MS? 

This issue became a defining issue in rheumatology amongst the monoclonal antibodies targeting TNF-alpha. Infliximab the initial anti-TNF monoclonal is so immunogenic that it has to be used in combination with another immunosuppressive, typically methotrexate or azathioprine, to try and prevent NABs. In comparison, the incidence of NABs on the newer generation anti-TNFs, for example adalimumab, is much lower. 

It will be interesting to speculate how important anti-drug antibodies (ADA), in particular neutralising antibodies (NABs), will become with the anti-CD20 monoclonals in MS. The incidence of NABs to rituximab is in the range of 6-9% compared to 0.2-0.5% for ocrelizumab and ~0% on ofatumumab (Phase 2 trial). We know that NABs are a major problem with biologicals in terms of both efficacy and safety. I would therefore predict that as in other areas, such as the anti-TNF-alphas, NABs will be a major differentiator amongst the anti-CD20s; this won't be simply for marketing reasons, but it will be driven by efficacy and patient safety concerns. NABs blunt efficacy and are a common cause of treatment failure, and are also responsible for infusion reactions. Just ask any pwMS who has been unfortunate enough to develop anti-natalizumab antibodies. 

We also think NABs are a major problem with alemtuzumab as well (please watch this space). We have just set-up an anti-alemtuzmab antibody assay and will soon be using this assay in clinical practice and will make it available for other groups to use. We plan to extend our panel of NAB testing from anti-natalizumab and anti-alemtuzumab antibodies to include anti-rituximab and anti-ocrelizumab binding and neutralising antibodies. Knowing who has NABs affects clinical practice. 

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, IFN╬▓-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.

CoI: multiple

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