Talk:Theralizumab

The whole approach of giving anti-cd28 is a bit naive. If someone believes CD28 is only stimulating T-cells they haven't bothered to do their science. AntiCD28 can be used to release Neurotoxins from Eosinophils which is definitively not what I would want to do. The reason that biology avoids regulation via a single pathway but uses "logical and gating" is to avoid disasters like this. User:Gerne1

The media are saying it's an anti inflammatory drug. All of the official sources say it's a monoclonal antibody. The article currently has both terms in but they appear to be contradictory. Secretlondon 18:35, 15 March 2006 (UTC)

They're not contradictory because the anti-body works as an anti-inflammatory.--Wikipediatastic 10:23, 16 March 2006 (UTC)

CD28 is the major co-stimulatory receptor on T-cells. This drug is a humanized monoclonal antibody which not only binds to CD28 but also activates this receptor, transmitting a very potent co-stimulatory signal to the T-cell. How this can be described as anti-inflammatory doesn't make any sense. Bizarre drug - not sure why anyone would want to do this - crudely put it massively activates every single T-cell in your body - not a good idea (evidently). Not sure what therapeutic potential it would have. It got orphan drug status in the EU so they must have some good data somewhere - wow. 16th March 13:10 GMT User:mxpule.

Fascinating - I have found the only academic reference to this anywhere. It was presented as a poster in the American Society of Haematology meeting in 2004. Here is the abstract for you (I don't know how to do nice formatting):

[2519] Superagonistic Anti-CD28 Antibody TGN1412 as a Potential Immunotherapeutic for the Treatment of B Cell Chronic Lymphocytic Leukemia. Session Type: Poster Session 732-II

Chia-Huey Lin, Thomas Kerkau, Christine Guntermann, Martin Trischler, Niklas Beyersdorf, Yvonne Scheuring, Hans-Peter Tony, Christian Kneitz, Martin Wilhelm, Peter Mueller, Thomas Huenig, Thomas Hanke. Non-clinical development, TeGenero AG, Wuerzburg, Germany; Institut for Virology und Immunbiology, University Wuerzburg, Wuerzburg, Germany; Medizinische Poliklinik, University of Wuerzburg, Wuerzburg, Germany

B cell chronic lymphocytic leukemia (B-CLL) is characterised by an accumulation of malignant B cells, and impaired humoral and cellular immune responses. Evasion strategies of leukemic cells appear to involve down-regulation of co-stimulatory molecules as well as increased resistance to apoptosis. Here we provide data supporting a novel concept to treat B-CLL with a humanized, superagonistic monoclonal antibody specific for CD28 (TGN1412). Superagonistic anti-CD28 antibodies have been shown to activate human T cells in vitro without requirement for engagement of the T cell antigen receptor (Luhder et al., J. Exp. Med. 2003. 197(8):955-66). Indicative of their activation, TGN1412-triggered T cells from healthy donors upregulate, among other activation markers, CD40L, that has been reported to promote anti-leukemic effects when ectopically expressed on B-CLL cells (Wierda et al., Blood. 2000. 96 (9): 2917-2924). In this report, the responses of PBMCs from B-CLL patients to soluble TGN1412 were examined. We show that in a dose-dependent fashion, polyclonal T cell activation was induced by TGN1412 including proliferation, cytokine production and induction of activation markers such as CD25, CD71, CD134 (Ox40), CTLA-4 (CD152) and CD154 (CD40L). Significantly, modulation of malignant B-CLL cells was also observed. MHC class II molecules (HLA-DR), CD95 and the co-stimulatory molecules CD80 and CD86, but not the proliferation marker Ki-67, were strongly up-regulated upon TGN1412 stimulation. These data suggested that improved antigen-presenting functions of B-CLL cells were induced by TGN1412. Accordingly, preliminary data indicate that B-CLL cells isolated from TGN1412 stimulated cultures induced enhanced proliferation of both allogeneic and autologous T cells, and importantly, TGN1412 activated T cells exhibited enhanced CTL-activity against B-CLL cells. In conclusion, our data suggest that TGN1412 induces polyclonal T cell expansion and activation as well as increased APC function of B-CLL cells. They imply that TGN1412 may have future therapeutic benefit for B-CLL patients. Abstract #2519 appears in Blood, Volume 104, issue 11, November 16, 2004 Keywords: T cell expansion|T cell costimulation|Non-Hodgkin's lymphoma

Not only was this agonistic but superagonist - not requiring even signal one to activate the T-cells. Basically this will fully activate every single T-cell in your body. Why someone would think this was a good idea is beyond me. User:mxpule

They thought that it would lead to a release of IL-10, this was supposed to mitigate the immune system rather than stimulate it. This is from their website (they have since pulled this information) "A pronounced T-cell activation and expansion mediated by CD28-SuperMAB® in animal models is accompanied by the expression of anti-inflammatory cytokines, like IL-10, rather than by the toxic cytokine storm of pro-inflammatory mediators induced by other agents that address the TCR complex. CD28-SuperMAB® over-proportionately expand regulatory T cells, a specialized T-cell subset that suppresses auto-aggressive T-cells present in the body and which has only recently been appreciated as important guardians of immune tolerance. Based on their functional potency in suppression of organ-specific as well as systemic autoimmune diseases, regulatory T-cells have been widely accepted as attractive targets for immunotherapeutic intervention. However, attempts to expand and activate this subset of CD4 T-cells in vivo and, ultimately, in autoimmune/inflammatory diseases have been hampered so far by the lack of therapeutic agents."-- Wikipediatastic 14:37, 16 March 2006 (UTC)

While of course easy to say now, with my limited biochemical knowledge, I seem to agree that the rationale behind this drug seems srtange. If you look at the primary mechanism of action it would appear to be a strong immune stimulant - not an anti-inflammatory drugs. Not because of the fact that it is an antibody (after all, there are other monoclonal antibody drugs that DO suppress the immune system) but because it is superagonistic to CD28. It seems like too much of a risk to rely on this expected massive immune stimulation to go away due to subsequent events. At least, it doesn't seem very surprising that a drug like this could trigger the reactions described (even though the doctors that have spoken to the media appear very surprised). Apparently, animal models showed different behaviour but as has been shown many times before, that does not guarantee the same behaviour in human beings, especially not in relation to the immune system. For instance, HIV causes AIDS in humans whereas it appears to cause no such things in monkeys. I really hope that the company made every effort to test the drug in vitro on human blood / tissues before this trial.

BTW, in the patent application for the drug (http://www.freshpatents.com/Use-of-a-cd28-binding-pharmaceutical-substance-for-making-a-pharmaceutical-composition-with-dose-dependent-effect-dt20060112ptan20060009382.php) it is noted that "In the rat animal model, it could be shown that a novel monoclonal antibody (MAB) with specificity for the CD28 molecule--JJ316--efficiently activates T lymphocytes in vitro as well as in vivo without TCR stimulation (Tacke et al., 1997), i.e. acts "superagonistically". This antibody--in spite of its strong T cell-stimulatory properties--is very well tolerated in vivo, in contrast to all other known T cellactivating substances (Rodriguez-Palmero et al., 1999; Tacke et al., 1997). Maybe it was too good to be true (in humans at least). It is probably too early to tell as it could also be a dosing issue. BTW, this is pure speculation but from reading biochemistry texts it seems the immune system can choose between two types of responses, TH1 and TH2. This choice is made early in the process and is reinforced. It seems that only TH2 responses yield IL10. Could it be that humans respond with a TH1 reaction instead of TH2 in monkeys? Even between individual humans there can be differences in which response is chosen to a given disease due to genetic differences. Could someone with knowledge in this area comment on this? —This unsigned comment was added by Para82 (talk • contribs) .

OK, I've found another scientific reference to the parent antibody (before humanization). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12707299 user:mxpule. Incidentally, the patent describes experimentation in non-human primates. I wonder how different human CD28 is from rhesus CD28. - just looked exactly the same.

Has anyone seen any media coverage discussing how this drug works (or was supposed to work) or references to the patent application? I think this is a "Wikipedia first" thing because I haven't found it anywhere. I really hope we can create a good article here that may generate more attention to the case. While I don't know if there is someone to blame yet, from the wording of the patent application etc. I can't help getting a feeling no-one really understood how the drug worked in detail, in particular why it exhibited immuno-surpressive effects rather than the opposite. While in vivo data demonstrating the effect of a drug in practice is of course important I think it would be reasonable to demand that the theoretical rationale for a drug's claimed effect is well-understood before it goes to market - particularly when it is opposite of what one would intuitively expect. Am I the only one feeling this way? Para82 21:26, 16 March 2006 (UTC)

I believe this is the most definitive public description anywhere - can we get it onto the front page of wikipedia? Does anyone know how to do that - I can't seem to edit that page. Mxpule 21:37, 16 March 2006 (UTC)

As an admin I can edit the main page but I'm just looking up the criteria. Secretlondon 21:41, 16 March 2006 (UTC)

I've added it to the main page In the news section. It may get swapped out again by someone else. It's pretty rare that science stories get in there and it may not be obvious why it belongs there. Secretlondon 21:53, 16 March 2006 (UTC)

Sorry, I'm not science literate. Could this article be dumbed down a bit for the non-science crowd.? After reading this I'm still not sure what this drug does, what diseases it was designed to fight, the implications etc. — Preceding unsigned comment added by 129.173.96.99 (talk • contribs)

Well we need both - we need a general para for the non-science literate. Secretlondon 22:33, 16 March 2006 (UTC)

I'm not an immunologist and I've only looked at a few scanty accounts for 15 minutes, but one thing glares at me: according to this, they tested an antibody against human CD28 in monkeys, then guessed the antibody would have roughly the same potency in the human? It would stand to reason that the antibody might bind the human protein that it was raised against much better than the related monkey protein. Now, they might have done an in vitro test to address this issue that I don't know about, but the whole thing is pretty creepy. They combine this uncertainty with the uncertainties of antibody treatments, the assumptions that the relative susceptibilities of each class of T cells will be the same in different species, and the inescapable fact that (even as they themselves admitted when they said that other T cell activating agents had problems) indiscriminately activating T cells is a gloriously bad idea. Even if the volunteers had come out perfectly fine I'd be left wondering if they'd suffer some kind of autoimmune problem later on in life because the wrong T cells had been activated. Now I'm not saying that dire diseases couldn't justify such risk - in patients - but if they truly just took the maximum safe monkey dose and divided by 500, that seems outrageous.Mike Serfas 23:35, 16 March 2006 (UTC)

Rhesus monkey CD28 is 100% similar to human CD28 (primate/human genome data), hence I would have thought binding would have been similar - this is crucial. Monkeys are expensive animals to experiment on - in the patent they mention monkey (singular) rather than monkeys - so I don't know how many they tested. Data from rodents would be largely meaningless with this agent since their CD28 are significantly different to result in much less binding of this antibody. Hence going 1/500th of murine LD50 would have been a big mistake - I don't imagine these investigators would have made this mistake. I am thinking more and more that this must be a dosing error - they gave much more of the drug than intended. They would have needed to submit their data to the MHRA (equivalent to the FDA in the US), we should be able to get this under freedom of information act at some point.Mxpule 10:43, 17 March 2006 (UTC)

It could be a dosing error, but if that's the case I would have expected them to know these symptoms very well from the animal trials where they also give high doses of the drugs. However, a reason why they seem so puzzeled over the symptoms could be that they would face a great liability risk if they gave the impression they kind of expected that this could happen. Another thing to keep in mind is that the drug was humanized so that it wouldn't be rejected by the human immune system. Thus, it is not as surprising that it gives a different reaction in humans than in animals. As I understand the humanization process they replace part of the animal antibody with a part of the human body. Couldn't this mean that the resulting antibodies would be able to send a signal 1 to other human T-cells (in addition to also being able to signal 2 via binding to CD28) leading to an even stronger immune response. Perhaps that could explain why the same reaction wasn't seen in monkeys even if they have identical CD28. 14:40, 17 March 2006 (UTC)

Media etc.

How much is the media playing up the "we have no clue how to treat this" "we're totally in the dark" angle of the doctors in this case? It would seem that if they know that this isn't a case of overdosing then they have general reason to believe that the drug really did 'hyperstimulate' the immune system to attack it's own body. Knowing that, wouldn't it be reasonable to turn to immunosuppressants such as Cyclosporine as a next course of action? Not knowing much about how clinical trials for pharmaceuticals like these go, I have to say it is rather shocking that they are allowed to tinker so freely with something as horrendously complex as the immune system. You would think that one would be more careful about not conjuring demons which one doesn't know how to cage. scary.--Deglr6328 04:11, 17 March 2006 (UTC)

Correction to article

..then delete this comment. I just don't have time to be "bold". original: "Criticism has been raised that 6 participants were given the drug in such a short time, which is against the recommendations of some standard literature."

correct: "Criticism has been raised that 6 participants were given the drug simultaneosly or in VERY short time, which is against anything even healthy brain and no SOME literature. I've read it in some serious newspaper yesterday that it is against all the odds to give such EXPERIMENTAL NON-CHEMICAL(I mean genetical here, e.g. not similar to 99.999% of the common drugs) DRUG to 6 patient at once. No some "standart literature" are we fuc"£ing joking here?

And also: "The initial dose, he said, was one five-hundredth of that which the animal studies indicated was the maximum safe amount.[11]." This is FUC£"ING lie, just delete it. I've read 4 newspapers on this subject yesterday(Times, FT, Guardian and ES) and I can't recall some of them said it. Maybe some Tabloid but I REALLY doubt it was 1/500 of the maximum animal dose. This is satan's first line of defence to say it. —This unsigned comment was added by 80.2.38.195 (talk • contribs) 10:15, 17 March 2006 (UTC).

It was on the Channel 4 news last night. It was a spokesman from the MHRA (I think). It wasn't a lie. That is standard procedure. They build up the doses over time. --Wikipediatastic 10:46, 17 March 2006 (UTC)

The statement about "one five-hundredth" on C4 news is unfortunately not verifiable online. The C4 web site has not been updated to include this interview. If the edit had been done by an anon, then it would probably have to be deleted. Since it was done by a logged-in user, with whom I have corresponded, I would like to assume good faith and leave it for now. Obviously, once better information is available, this section is likely to be rewritten. Colin Harkness°^Talk 11:34, 17 March 2006 (UTC)

No, it's not verifiable online. But that isn't a requirement, else we wouldnt be able to cite any book not released into the public domain. GeeJo _{(t) (c)} • 16:08, 17 March 2006 (UTC)

Lots of references on Wikipedia are not easily verifiable. They are, however, still verifiable. However, "I saw/heard on the news last night" is not verifiable unless someone has subsequently transcribed the interview and made it publicly available, or has otherwise written about it.

It is amusing that one primary source for this scientific article is The Sun. Colin Harkness°^Talk 17:07, 17 March 2006 (UTC)

Daily Mail.co.uk Article Okay its online now. I have read the 500 number elsewhere. The original question remains however: 500th of what. --ParticleBry 16:34, 17 March 2006

I would advise, as the original poster did, against the use of tabloids as sources of information. --Oldak Quill 22:33, 17 March 2006 (UTC)

Conjecture

Any conjecture in this article must be made by a third party otherwise it is Original Research. We can report facts (such as the difference between rodent and primate biology, etc) but postulating as to the cause of error must be attributable to some other source, preferrably with a citation/reference to online material that can be verified.

Also, this talk page is for discussion regarding this article, and how to improve it. It is not a forum for general discussion/speculation about this drug and the clinical trial. Colin Harkness°^Talk 11:34, 17 March 2006 (UTC)

That rule only applies to the article itself. Talk pages can and do contain whatever people want to talk about regarding the subject. With a story like this one, especially since it's still ongoing, it is only natural that this page will be full of conjecture like so many others. --Deglr6328 13:39, 17 March 2006 (UTC)

See What may talk pages be used for?. Whilst talk pages have relaxed some rules (e.g. you can express a POV), they are not a substitute for an Internet forum or blog. This is just a Guideline, not a Rule. I'm not trying to stop any discussion here, just to keep it focussed on the article. Colin Harkness°^Talk 14:40, 17 March 2006 (UTC)

Only academic reference?

The article presently states something like "this is the only academic reference" in connection with an abstract. What about the articles returned from Google Scholar: [1], e.g., [2] Sorry Dude #1 isn't academic (i.e) peer reviewed #2 is about the antibody before it got humanized.Mxpule 15:38, 17 March 2006 (UTC) If you can find a peer reviewed paper or abstract about the humanized antibody that would be fab.

Since when is LD50 "safe"???

"The critical point here is whether investigators gave 1/500th of the murinae LD50 or a safe dose in primates."

LD50 is the dose that has a 50% chance of having death as a side effect. LD50 is an unsafe dose. Don't talk about it like it's a safe dose. It isn't, the whole point of labelling it such is that it isn't.

Er did you actually read the sentence? What it is trying to say is we don't know whether it is 1/500th of the murinae LD50 which would be a very serious mistake OR 1/500th of the safe dose in primates. I believe the original quote is something like 1/500th of the maximal dose in animals. We cannot conclude from this quote what exactly they mean by 1/500th of the maximal dose in animals, it could be the LD50, it could be the safe dose... A number of people including me find it unlikely that anyone would be stupid enough to give 1/500th of the LD50 in murines as the starting dose given that the people administring this trial were dumb enough to give it to 6 people in a short space of time, who knows? Nil Einne 17:10, 17 March 2006 (UTC)

Multicentre trial

This article links to multicentre trial. Was this intended to be a multicentre trial and were there other centres going to test the drug in a few days or hours time? If so, I would guess the people recruited in the other centres must be thanking their lucky stars that they weren't the first Nil Einne 17:10, 17 March 2006 (UTC)

Time frame

Does anyone have any idea what the time frame is like? This article supports what I think many of us not knowledgable in clinical testing thought, that it is not standard practice to give the drug to 8 different people (although 2 received the placebo of course) in such a short space of time but what kind of time frame are we talking about. Did they administer doses within minutes? Hours? How long is it normal to wait? Nil Einne 17:16, 17 March 2006 (UTC)

Diagram

I think what this article needs is a diagram on the mechanism of action - even if it is just a molecule binding to a T Cell. Do we know enough about the mechanism to be able to pull it off? Secretlondon 21:09, 17 March 2006 (UTC)

• Agreed. 4.232.195.49 01:19, 18 March 2006 (UTC)

MOST importantly...

What sort of compo are they looking at if they make it? Presumably they took part in these trials to earn a bit of extra dosh. They should be able to sue after this. Probably never need to work again. ;-).

Sounds like some of these subjects will be lucky to make it out of ICU alive, probably won't be able to ever work again. Mxpule 11:20, 18 March 2006 (UTC)

Mistake comparing CD28

Sorry I made a mistake, I thought why tested in Pan troglodytes not Macaca mulatta. The Macaca's CD28 is slightly different - a few amino acids. You can look at the links below - the sequence starts "MLRLLLALNLLP...." with each letter representing a different amino acid. If there are some protein chemists out there they might tell us if the small differences could effect where the antibody binds. This is probably explains what happened. http://feb2006.archive.ensembl.org/Macaca_mulatta/protview?transcript=ENSMMUT00000008414;db=core http://feb2006.archive.ensembl.org/Homo_sapiens/protview?transcript=ENST00000340642;db=core http://feb2006.archive.ensembl.org/Mus_musculus/protview?transcript=ENSMUST00000027165;db=core

Mxpule 14:47, 18 March 2006 (UTC)