Saturday, 5 August 2017

Anti-drug antibodies following rituximab

Rituximab in multiple sclerosis: Frequency and clinical relevance of anti-drug antibodies.Dunn N, Juto A, Ryner M, Manouchehrinia A, Piccoli L, Fink K, Piehl F, Fogdell-Hahn A. Mult Scler. 2017 :1352458517720044. doi: 10.1177/1352458517720044. [Epub ahead of print]


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

I know ProfG posted on this yesterday, but I had already written this so you may as well have my nuggets.


You may have thought that this paper was written by Roche as this is going to be a battle ground in a bid to convince you that ocrelizumab is better. Ocrelizumab is humanized so is mostly human with abit of mouse compared to rituximab which is chimeric that is human with a lot more mouse and so should cause more anti-drug responses. Novartis has a variant that is completely human. 
However are the rodent parts important? 
In this study they report that about 40% of people make an anti-rituximab antibody response, this is way more that the 1% of less of people making neutralizing antibodies reported for ocrelizumab. 
But this is still chicken feed compared to alemtuzumab, which was the first humanised antibody, designed to reduce immunogenicity, which it did, but it still caused binding anti-drug responses in about 60% of people with MS within the first month of infusion and the vast majority of people within 2 years. We have suggested that alemtuzumab blocks tolerance-induction and this why you get secondary autoimmunity and anti-drug responses
I suspect the anti-drug response is one of the reasons alemtuzumab is given at yearly intervals (it depletes CD4 T cells for longer than a year, CD19 cells for 6 months) and not less, such that when you have disease breakthrough you don't get the treatment immediately, but you have to wait for the 12 months to be up. This allows the anti-drug response to subside.
In contrast to alemtuzumab where antibody levels increase with more doses, with rituximab these drop with time. This is interesting as you may think that they would increase with time as you are boosting by the six-monthly dosing. So repeated depletion of B cells must impact on the plasma cell function or maybe high-zone immune tolerance is occurring. 
However, it is clear that there is some impact and this is seen in by an effect on B cell depletion and so if you have a lot of the anti-rituximab antibody it can block depletion. 
Now they say that this does not impact on adverse reactions, which you get because the drug is exploding cells, nor efficacy. This has been said for people taking alemtuzumab also.
Whilst I think this is true at the population level, at the individual level there are certainly people where anti-drug antibodies impact on efficacy. The question one poses is how common is this?. 
COI. None relevant

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