Anti-Drug Antibodies. Don’t SH1 on yourself when you have a problem…hatchet the others!

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Rule #1 of “Pharma club” is Don’t admit you have a problem! Rule #2 of “Pharma Club” is “Don’t admit you have a problem”, Rule#3….Don’t admit…

As you know. We have been looking at anti-drug antibody responses because they are important to the individuals who fail treatments as their drugs stop working.

You can now get our latest paper online go to

A cell-based assay for the detection of neutralizing antibodies against alemtuzumab. Ali L, Saxena G, Jones M, Leisegang GR, Gammon L, Gnanapavan S, Giovannoni G, Schmierer K, Baker D, Kang AS.Biotechniques. 2020 Feb 25. doi: 10.2144/btn-2019-0122. [Epub ahead of print]

You can get a smashing new PDF here (click) https://www.future-science.com/doi/pdf/10.2144/btn-2019-0122

This rounds off the Valentine’s trilogy by Dr Angry

Saxena GK, Theocharopoulos I, Aziz NT, Jones M, Gnanapavan S, Giovannoni G, Schmierer K, Garnett JA, Baker D, Kang AS. GloBody Technology: Detecting Anti-Drug Antibody against VH/VL domains.Sci Rep. 2020 Feb 5;10(1):1860

Baker et al. The Irony of Humanization: Alemtuzumab, the First, But One of the Most Immunogenic, Humanized Monoclonal Antibodies Front. Immunol., 14 February 2020 | https://doi.org/10.3389/fimmu.2020.00124 Click here

As you can see from the papers above, and the other in the pipeline (Oh Yes more to come!), alemtuzumab, sadly is the the star when it comes to making anti-drug responses. Therefore, it is interesting that the folks from Sanofi-Genzyme have done as DrAngry says “a hatchet job on Biogen’s natalizumab”, rather than look in the mirror and spend considerable effort on their own drug, they report other people’s problems.

A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients.Cassotta A, Mikol V, Bertrand T, Pouzieux S, Le Parc J, Ferrari P, Dumas J, Auer M, Deisenhammer F, Gastaldi M, Franciotta D, Silacci-Fregni C, Fernandez Rodriguez B, Giacchetto-Sasselli I, Foglierini M, Jarrossay D, Geiger R, Sallusto F, Lanzavecchia A, Piccoli L.Nat Med. 2019;25(9):1402-1407.

Natalizumab (NZM), a humanized monoclonal IgG4 antibody to α4 integrins, is used to treat patients with relapsing-remitting multiple sclerosis (MS)1,2, but in about 6% of the cases persistent neutralizing anti-drug antibodies (ADAs) are induced leading to therapy discontinuation3,4. To understand the basis of the ADA response and the mechanism of ADA-mediated neutralization, we performed an in-depth analysis of the B and T cell responses in two patients. By characterizing a large panel of NZM-specific monoclonal antibodies, we found that, in both patients, the response was polyclonal and targeted different epitopes of the NZM idiotype. The neutralizing activity was acquired through somatic mutations and correlated with a slow dissociation rate, a finding that was supported by structural data. Interestingly, in both patients, the analysis of the CD4+ T cell response, combined with mass spectrometry-based peptidomics, revealed a single immunodominant T cell epitope spanning the FR2-CDR2 region of the NZM light chain. Moreover, a CDR2-modified version of NZM was not recognized by T cells, while retaining binding to α4 integrins. Collectively, our integrated analysis identifies the basis of T-B collaboration that leads to ADA-mediated therapeutic resistance and delineates an approach to design novel deimmunized antibodies for autoimmune disease and cancer treatment.

I guess you don’t SH1 in your own backyard and do your own drug that has a problem, you look at the problems of others….or maybe they have done it and have kept it all quiet…..but’s lot of effort not to report it.

This study asks if there is a difference between binding and neutralizing antibody responses. The answer is surprising.

At first you would think the neutralizing antibodies bind to the active antibody binding sites,and you may think that the binding antibodies that don’t stop the drug working, would bind somewhere outside these regions on a different bit.

Is the hole important for not blocking function NAA32 is a blocker NAA84 is a neutralizer

Surprising in this study they suggest that the binding antibodies bind to more or less the same sites, but with much less strength than the blocking antibodies, so they fall off easier rather than bind tightly.

This is related to the observation that the sequence of the antibody has not been re arranged and mutated as normally happens. B cells do this so that the antibodies they produce become more sticky to their targets and bind with more strength.

They go further and show that the T cells that recognise these antibodies and so help the B cells to make them, seem to recognise a common bit of the anti-drug antibody. Importantly they make a new variant of natalizumab that still binds to CD49d but does not get recognised by the T cells and so does not, they think, make anti-drug antibodies.

Therefore, has Biogen got a new competitor?.

Does this give insight for the boys and girls at Sanofi to make a new alemtuzumab that does not make anti-drug responses….I suspect the answer to that question is no.

Have a read of the paper (below) as it gives an opinion why this probably won’t happen.

Baker et al. The Irony of Humanization: Alemtuzumab, the First, But One of the Most Immunogenic, Humanized Monoclonal Antibodies Front. Immunol., 14 February 2020 | https://doi.org/10.3389/fimmu.2020.00124 Click here

Importantly the issue for alemtuzumab is the generation of secondary autoimmunity. However if you read our.paper on the Irony of Humanisation I think it won’t.matter what you do to fiddle with the antibody to make it less immunogenic, the problem is inherent in the target it binds to. It makes the perfect storm when it comes to making anti-drug responses. However, within the paper there is a potential solution to both the anti-drug antibodies and the secondary autoimmunity, if you follow our logic.

We couldn’t get any interest, when we pitched the idea for our approach many years ago. Maybe we were before our time as there was no competition then and no need to do anything, now there is competition, it is probably too late. However,get rid of autoimmunity and alemtuzumab looks a lot more attractive again. Maybe we will have to wait before some other neurologists gives it a go, after all the idea has been out there for over two years.

You may say that you can’t get rid of anti-drug antibodies! But I say em, I think we can. Hopefully, this will surface later in the year as it could tell you how to get rid of MS….if only we knew the autoantigen(s)….if there is one:-(.

Any way DrAngry is chirping and says “thanks very much”, more useful info for the next student project. We have a neutralizing and a binding antibody for natalizumab, without having to make a monoclonal or immortalise any B cells, I bet the Globodies have been designed already.

Dr Angry looking at his new antibody test

COI : None relevant. However Dr Angry has patent protection on the testss Give him a call and do a deal:-)

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MouseDoctor

5 comments

    • You wont make anti-drug antibodies before the first treatment, they can be there for the second treatment and more so for the third treatment. In our cohort (submitted) we had 6/32 people who needed three or more courses who had high enough levels for the drug to stop working, two of them had stopped working on the second cycle, they could have been switched and this is the reason to monitor. Most people will get complete or partial effect, it is the few that fail that we need to look out for, a test on £100 (not the real cost) verses £22,000 drug costs, the costs of dealing with a relapse after futile treatment and the cost of increased disability after futile treatment. We had one person in the CARE-MS trial with 4 futile treatments (£90,000 wasted drug), 4 disease episodes that may have been preventatable and and increase in 3 points on the EDSS (1/3 of their life). You may be able to measure and predict these failures, but simply looking at the lymphocyte levels (these would have been could have been hidden during the trial as it would afffect blinding) this could have been spotted. Neuros do not have the time and they have been educated against the relevance of looking a white cell counts..but if it is not depleting it is not working. Therefore this is something that everyone on a depleting drug should do and ask to see your own blood counts after infusion so you can check it has worked. If it hasn’t let your MS nurse know and they can have a check.

  • Are the antibodies there for good or do they “expire” after a period of time (years) allowing for effective use of offending mab again?

    • For alemtuzumab most people make them but they go before a year hence the reason possibly for waiting a year, but once they reach high levels the inhibiting level can last for years over 3 years.

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