How important are anti-drug antibodies in relation to biological therapies, in particular neutralising antibodies to the monoclonal therapies used to treat MS?
This problem was defined in rheumatology with 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.
Anti-drug antibodies (ADA), in particular neutralising antibodies (NABs), to the anti-CD20 monoclonals will become increasingly important. In the Swedish study below the incidence of ADAs to rituximab was between 26-37% with some evidence that at least a proportion are neutralizing. The NAb rate to rituximab is known to be 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 have evidence that NABs are a major problem with alemtuzumab as well. We are setting-up an anti-alemtuzumab antibody assay and will soon be using this assay in clinical practice and will make it available for other groups to use. We hope 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, in particular patient safety.
Dunn et al. Rituximab in multiple sclerosis: Frequency and clinical relevance of anti-drug antibodies. Mult Scler. 2017 Jul 1:1352458517720044.
BACKGROUND: Rituximab is a chimeric monoclonal anti-CD20 B-cell-depleting antibody increasingly used off-label in multiple sclerosis (MS). The clinical relevance of anti-drug antibodies (ADAs) against rituximab in MS is unknown.
OBJECTIVE: To determine frequency of ADA in relation to B-cell counts, allergic reactions and clinical efficacy in a large cohort of MS-treated patients.
METHODS: Cross-sectional study with collection of serum samples from 339 MS patients immediately before a scheduled rituximab infusion. ADAs were detected using an in-house-validated electrochemiluminescent immunoassay and a commercial enzyme-linked immunosorbent assay (ELISA) to compare methods. Data on patient demographics and clinical outcomes were retrieved from the Swedish MS Registry and patient records.
RESULTS: ADAs were detected in 37% of relapsing-remitting MS and 26% in progressive forms of MS. Presence of ADAs decreased with increasing number of rituximab infusions. There was a significant association between both presence and titres of ADAs and incomplete B-cell depletion, but not with infusion/adverse reactions or clinical outcomes at the group level. Only five patients terminated rituximab during follow-up, four of which were ADA positive.
CONCLUSION: Rituximab treatment is associated with a high degree of ADAs, which correlates with efficacy of B-cell depletion; however, the clinical relevance of ADAs remains uncertain.