Talk:Theralizumab

Introduction

Shouldn't there be a brief mention of the drug trial incident in the opener, seeing as that's why the drug is particularly notable? Amo 18:04, 17 May 2006 (UTC)

I agree. Added. Carcharoth 11:12, 23 May 2006 (UTC)

New development, needing proper source

An article of this type should try to avoid the sloppy use of the word "receptor" that is unfortunately endemic in the field of immunology. For instance, immunologists use the phrase "T cell receptor" when referring to particular receptor molecules that are located on T cells, but they also use the phrase "Fc receptor" when referring to a receptor whose ligand is an antibody's Fc region . These are two mutually contradictory definitions of the same word (with the second being the accepted usage in other branches of cell biology). Even though this sort of woolly thinking pervades the scientific literature, there are really no excuses for forcing it upon a lay readership. The ubiquity of these opposing definitions of "receptor" means that they can't be completely circumvented, but contributors to this article should at least try to warn their readers of the semantic quicksand. Blithely using both opposing definitions of "receptor" in the same sentence, however, does an disservice to the reading public and reinforces the culture of intellectual sloppiness among immunologists. Could it be that this same woolly thinking blinded the designers of the clinical trial to the consequences of their actions? — Preceding unsigned comment added by 86.4.181.49 (talk) 00:36, 12 March 2013 (UTC)

Translated from a Danish web news page, [1]:

Swollen men victims of "fusk" (fraud?).

20-05-06: 11:02

When six Brittish men suffered from a medical test going wrong in England, they were victims of serious errors from the medical company, writes Politiken [2].

...

A standard analysis in a computer model shows that the medical experiment never should have been approved.

This revelation comes from two associate professors in biomedicine from University of Southern Denmark, Søren Hansen and Graham Q. Leslie, who have published this explanation in the latest issue of the scientific periodical Nature [3].

The problem even has been known since 2001.

The substance, which the German biotech company TeGenero ensured could fit like a Lego block in a protein in the six human bodies, did not fit anyway.

But that was what the company claimed in their application to the Brittish medical authorities.

As the original story was a featured news article, this new development should be featured too, if someone can check the original source. (I am not competent to do so myself.)--Niels Ø 09:11, 21 May 2006 (UTC)

Here's the Nature article: [4]. Chl 13:53, 21 May 2006 (UTC)

It's a letter to Nature from 2 Danish academics- not an actual article. Secretlondon 22:42, 21 May 2006 (UTC)

Yes however I still think we should mention it. One of the most interesting bits was not the difference between the human and rhesus monkey CD28 but this bit

"Furthermore, preclinical studies should also include comparative measurements of the binding affinities for both human antigen and primate antigen, to control for unforeseen variations in protein structure.".

I'm still very surprised, as I mentioned a while back (I guess in the archive) that binding affinity tests were not performed. I would have thought they would be basic preclinical tests for any drug and a large difference between the binding affinity of the drug with the target (well preferbly any known targets, perhaps identified via a library screening) between human and animal models would be enough to require serious further investigation.

Nil Einne 13:37, 17 June 2006 (UTC)

"Elephant man" to loose all fingers on hands and feet

This is terrible: http://www.mirror.co.uk/news/topstories/tm_objectid=17292803%26method=full%26siteid=94762-name_page.html%22 —Preceding unsigned comment added by 195.70.32.136 (talk • contribs)

http://news.bbc.co.uk/1/hi/health/5121824.stm says parts of three fingers - not all his fingers. Secretlondon 18:09, 27 June 2006 (UTC)

Could this be misused? In a bigger way?

Other than direct dosing....

Could a virus or a bacteria be developed to spread this?

I don't want this or even suggest that this be pursued. I don't know enough medical technology to know the implications...

Reminds me of some SCI-FI literature "Andromeda Strain" http://www.crichton-official.com/strain/index.html and one of Stephen King's book "The Stand" I think...

Signed curious. —Preceding unsigned comment added by 70.29.188.133 (talk • contribs)

I'm sure there are more efficent ways to kill people than by inducing a cytokine storm. Issue here is that everybody knew this drug was likely dangerous but they did the tests quickly, makes you wonder if learning something 'else' about the immune system from the tests wasn't the real goal. —Preceding unsigned comment added by 134.214.102.33 (talk • contribs)

Its useful as a weapon since a cytokine storm leaves many peeople requiring healthcare. Americans might, for example, choose to use sucha weapon while fighting an Islamic countr, such as Iran, since producing thousands of cripple soldiers wouldn't have the same religious impact, i.e. no martyers, big visible costs for fighting, etc. —Preceding unsigned comment added by 69.61.125.42 (talk • contribs)

Conspiracy theories are great fun - if an organisation claims that they were tests for non-lethal weapons or something then we can add that to the article - but quoting them. Ie - "Political party X stated that it believes that the tests were funded by the United Nations secret anti-Christian warfare department [ref]" Secretlondon 18:32, 1 August 2006 (UTC)

Bacteria lack mechanisms required to make a functional antibody, which is why they are prepared using mammalian cell cultures (usually NS/0 or CHO). I'm sure there is some way you could abuse this compound to do harm but there are far easier ways to harm people and bacteria that naturally make far more deadly compounds than this. —Preceding unsigned comment added by Austringer (talk • contribs) 12:48, December 11, 2006

Isn't all of this mildly ghoulish? 82.44.64.173

When bacteria are transfected with the genetic sequences for antibody construction (no mean feat, the different chains are coded on separate chunks of disparate chromosomes in their native hosts), bacteria can indeed synthesize these proteins- but their folding and glycosylation mechanisms usually fail to make a functional mammalian-type molecule. NS/0 is a tenable hybridoma parent; CHO is readily transfected and with its mammalian folding and glycosylation propensities is far more likely to produce a functional protein. 70.16.187.30 00:59, 30 August 2007 (UTC) Shannon

More information

I just published another editorial on this:

Changing the culture of research

See this week’s BMJ (August 5): http://bmj.bmjjournals.com/

Editorial Further lessons from the TGN1412 tragedy New guidelines call for a change in the culture of research BMJ 2006;333:270-271 (5 August), doi:10.1136/bmj.38929.647662.80

“As eight young men assembled at a London hospital on 13 March this year, they had no idea that within an hour their lives would be changed irrevocably and they would have contributed to a fundamental rethinking of the development and testing of new drugs. The first trial of TeGenero's TGN1412 (a T cell agonist) in humans took place at Parexel's clinical pharmacology research unit at Northwick Park Hospital, London. The events that followed fuelled speculation not only into the conduct of the trial and the nature of the drug, but also into aspects of research as diverse as comparative molecular biology, bioethics, and health economics.

The Medicines and Healthcare Products Regulatory Agency initiated an investigation, but the BMJ and other journals called for a more far reaching inquiry independent of the regulatory agency that had approved the trial. On 5 April the agency released its interim report, and the government announced that an independent Expert Scientific Group, chaired by Professor Gordon Duff, would be appointed "to learn from the Parexel clinical trials incident." On 25 July this group released their interim report and recommendations. …..”

http://bmj.bmjjournals.com/cgi/content/full/333/7562/270?ijkey=whP3FyWKdYWdMvy&keytype=ref

Dose

The dose given to the men, was just 1/500th the dose that exhibited observable effects in Animals. It is an important point to include in the article. Diamond Dave 14/08/2006 14:05

As has been pointed out before, the dose given to the human volunteers (1/500th of the lowest dose showing effects in animals) contained enough antibody molecules to bind every T cell in the bloodstream ten times over. Neither a mouse nor a monkey is a man; a response (or absence of a response) in animals is no guarantee of the same in humans. 198.140.178.11

Not true - the dose would have activated around 45-80% CD28 occupancy (Waibler). Even so, such large scale activation can have dramatic effects. — Preceding unsigned comment added by 78.105.76.223 (talk) 23:58, 9 January 2012 (UTC)

Yes, it simply gives a false impression of safety. Diamond Dave 15/08/2006 16:40

Which is precisely why we have clinical trials. If we could predict the effects in man with 100% accuracy following in-vitro and non human in-vivo work, we wouldn't need trials. As awful as it may sound, this trial did its job - i.e identified that this treatment at this dose in healthy patients is not safe.

It is absolutely right and proper to examine whether the battery of tests conducted by Tegenero was sufficient to proceed to the clinic - however, other than the comments about binding affinity (or lack of) we don't seem to have much in the way of valid discussion on this. Quoting sensationalist newspaper headlines or vulture lawyer soundbites isn't the same as proper scientific discussion or specific references to informed and educated sources. —Preceding unsigned comment added by 81.98.19.20 (talk) 20:13, 14 May 2009 (UTC)

ESG's Final Report

The Expert Scientific Group has issued it's final report. I'm very much a newbie at the whole wikipedia thing so I'm going to let someone more adept do the page edit. Information on the report available here:

[5]

Of interest is the dificulty involved in simulating the cytokine storm in vitro. Austringer 17:00, 11 December 2006 (UTC)

Just published in the Journal of Immunology, August 2007 is an article illuminating an in vitro model duplicating/simulating the observed in vivo cytokine storm. 70.16.187.30 00:51, 30 August 2007 (UTC) Shannon

GA review

A good article has the following attributes.

1. It is well written.

Mechanism of action section does not explain what CD28 actually is and would benefit from a one or two sentence lead summarizing the section for non-specialist readers.

2. It is factually accurate and verifiable.

Has references, however not all refs are in the same format, but this a minor point.

3. It is broad in its coverage.

It covers the subject well.

4. It follows the neutral point of view policy.

I don't think it is biased either for or against the company.

5. It is stable, i.e. it does not change significantly from day to day and is not the subject of ongoing edit wars.

it is stable.

6. It contains images, where possible, to illustrate the topic.

The image Image:T cell activation.jpg might help improve the "Mechanism of action" section.

Actioned —The preceding unsigned comment was added by SeanMack (talk • contribs) 16:18, 2 January 2007 (UTC).

Overall very good, I'll put this on hold until the point in section 1 is dealt with. Drop me a note on my talk page when you're done. TimVickers 00:26, 28 December 2006 (UTC)

I still can't work out from reading the article what CD28 does. Passed the 1 week hold limit so it fails. Sorry.TimVickers 17:34, 2 January 2007 (UTC)

hope thats a joke. This article is completely innacurate from start to finish. Below a biomed student alluded to some changes required, but none have been implemented. — Preceding unsigned comment added by 129.31.120.3 (talk) 16:53, 25 October 2011 (UTC)

References

Reference 4 is wrong.

Dr Marelli-Berg works on lymphocyte migration not memory B cells. In the article she states that binding (and stimulation) of CD28 could alter lymphocyte migration so they exit the blood stream and enter the tissues.

Do you have a reference for the memory B cell theory?82.69.51.149 (talk) 22:01, 20 August 2008 (UTC)

The claim that a single "patient in Northampton" had been given a similar drug and had had similar symptoms desperately needs a reference (or else should be omitted altogether). Why and when was that patient given exactly which drug and why wasn't the outcome reported before the trial began?

Update needed

The final report by the Expert Scientific Group on Clinical trials was published in November 2006 (http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_063117)

Also See http://www.sciencebase.com/science-blog/critical-trials-tgn1412.html —Preceding unsigned comment added by 192.211.24.142 (talk) 22:11, 14 September 2009 (UTC)

I came here to copy edit the one marked section

....but don't see anything wrong with it, in terms of grammar, etc.--LeValley 21:11, 6 March 2010 (UTC)

My Dissertation

I have just completed my undergraduate dissertation exploring this subject in great detail. I think this article is quite old and needs updating as brand new research has been brought to light, and this disaster can now be explained in three main ways: 1) Treg cell activation protects rodents from a CRS 2) Monkeys do not express CD28 on effector memory cells, hence thye tolerated the drug. 3) Human PBMC cells did not respond in vitro in pre-clinical trials because it was found this year that the TCR whilst doesn't need to be engaged for this reaction, it does need to be signalling in a very small way dubbed 'tonic' signalling.

I cannot be bothered to write an article on TGN1412 and change, add everything I have found out on wiki, but Im happy to send a copy of the 6000 words to the person who wrote this so they can make a 'better' article using latest data. If interested just reply with an email. —Preceding unsigned comment added by 139.184.30.134 (talk) 17:41, 15 March 2011 (UTC)

"The person who wrote this"? This is Wikipedia, where articles are written and changed by anyone. Few articles have a clear author of most of the content. If you don't like the article as-is -- and are willing to back it up with references -- make the changes yourself. You don't have to (and in fact shouldn't) do it all at once. -- tooki (talk) 12:22, 16 April 2011 (UTC)

Im just trying to be helpful as this article is largely inaccurate, and not well written. It's main problem is the lack of scientific sources, so it focuses on the wrong things. For example the intro talks suggests animals who were used in 'sterile' conditions may cause the tria, but idea was debunked in 2008. The monkeys dont respond because their effector memory cells dont express CD28, as well as this they have siglecs on their cells which lower the response. Mice didnt respond because 5.11A1 (mouse version of TGN1412) activates their regulatory T-Cells. Too many newspapers (such as the infamous Daily Mail) are used as references to science. These are not credible scientific sources. My conclusions are based on the latest data (some unpublished). I've got the protein sequences of all the animals involved and the binding affinities (as someone else asked for). All in all I have 133 references and as I said I'm happy to hand all I have over to someone else who wants to use some of it to improve this poor article.

The only thing I lack is the will to sort the article out. I spent 4 months of my life looking into this full-time and I just want to see the back of it. Its sad the number one hit for TGN1412 is so badly put together. People will likely come here first, and largely be misinformed. —Preceding unsigned comment added by Mark gg daniels (talk • contribs) 03:24, 12 May 2011 (UTC)

i guess no-one took up my offer... but heres a very recent reasearch paper with more answers I alluded to in my previous comments when talking of unpublished work. 'Preculture of PBMC at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412.'. I really want to press the issue that this article is completely innacurate. It deosnt explain the biology of this event in any factual way whatsoever. — Preceding unsigned comment added by 129.31.120.10 (talk) 13:36, 21 October 2011 (UTC)

The article "Preculture of PBMC ..." is by none other than Hunig et al , Tomas Hunig being the very dude who precipitated the debacle of SuperMAB. Clever name, eh? Like calling your new ocean liner "unsinkable". It's an interesting article though, and the real take home lesson is that tweaking the immune system is definitely playing with fire. I'm currently marketing some stuff that I call SuperMannan; I just found out a little while ago (it's now 2014) about TeGenero using the name SuperMAB in 2006. When you get right down to it they were just unlucky; sure, they were hubristic and all that, but who knew? Nobody. Wikipedia really needs an update on the volunteers of the SuperMAB trial; I read that this one young fellow was the Elephant Man and he lost all his digits, eventually; and really can't get around, with all the problems. Richard8081 (talk) 06:11, 24 February 2014 (UTC)

Update

The same drug (named TAB08) is under phase II clinical trials since January 2014 ( http://theramab.ru/en/news/phase_II ). According wikipedia (see TeGenero), Theramab has acquired the assets of TeGenero.79.43.237.29 (talk) 10:56, 18 September 2014 (UTC)

Interesting. here is some of what they've been up to.LeadSongDog come howl! 18:38, 18 September 2014 (UTC)

Molar mass reported incorrectly

The chemical/physical properties listed the molecular weight as "~148g/mol" which seems highly improbable given that antibodies generally have a mass in the kilodalton range. I removed that molecular weight but didn't look for the real number. — Preceding unsigned comment added by 204.28.125.102 (talk) 01:17, 17 February 2017 (UTC)

possible additional reference

I came across this article via this. I don't understand much of it but it looks relevant and doesn't seem to be already cited. I'd rather someone more literate in the topic than me decide whether to add it. 173.228.123.166 (talk) 14:45, 1 September 2018 (UTC)