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Study reveals risks of interfering with immune system.
Researchers are trying to explain how a prototype drug that manipulates the immune system triggered devastating side effects in a British clinical trial.
Read the story here.
Posted by Nicola Jones on March 17, 2006 05:17 PM | Permalink
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» Follow-Up on the British Trial of TGN1412 from circle.10
A British clinical trial of the antibody, TGN1412, made headlines last week when six healthy men who were involved in the early phases of testing developed multiple organ failure. Two of the six men remain in critical condition. The other four have i... [Read More]
Tracked on March 20, 2006 06:51 AM
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If TGN1412 were to bind to human CD28 much more strongly than to the CD28 of the animal species tested, would that not go some way to explaining what happened?
Posted by: John Rokos | March 17, 2006 07:33 PM
The drug being tested, TGN1412, has now entered Phase I in the drug testing procedure. It apparently passed its preclinical phase and entered the clinical phase giving raise to these surprising and horrible side-effects. One must hope, the development of this drug is discontinued. This is a very unfortunate course of events. God bless these poor students in UK!
Sincerely yours, christer sundqvist PhD
Posted by: christer sundqvist | March 18, 2006 12:47 PM
Antibodies to human CD28 have been tested on human peripheral blood mononuclear cells in the lab, which contains the majority of cells involved in adaptive immunity. However, this antibody alone has never led to massive T cell stimulation and cytokine release as seen in these human subjects. Therefore, it suggests another component of the immune system is at play here....and that component may be uniquely senstive in humans in comparison to other species. We need to know why this has occured as it will be crucial to development of several future immune therapies.
Posted by: Keith Dredge | March 18, 2006 09:50 PM
If anyone is interested, Dr Thomas Hanke was issued with a patent for TGN1412 (SuperMAB) titled: "Use of an active substance binding to CD28 for producing a pharmaceutical composition for the treatment of B-CLL". It was published on 12 Jan 2006. The full pdf can be found at http://gb.espacenet.com/search97cgi/s97_cgi.exe?Action=FormGen&Template=gb/en/quick.hts
Posted by: Chamiel | March 19, 2006 03:30 AM
This is a unfortunate cours of events indeed. But we may not forget to keep a neutral attitude. Cancelling the development of this drug would be tragical as well.
Posted by: DR. Dutré | March 19, 2006 11:08 AM
The symptoms described, such as headache, backache, are those normal for severe immune ractions? Or does this point to parts of the immune system that we currently are not aware of?
Posted by: Carl Olme | March 19, 2006 01:36 PM
I hope everybody maintains a scientific outlook regarding this unfortunate event. We do not yet know what caused the severe reaction in all study participants who received the drug. Was it contaminated? Was the dose incorrectly prepared? Regardless of the answer, these events do seem to suggest that for all Phase I human trials drug doses be very slowly and carefully titrated.
Posted by: Irene Fricker | March 20, 2006 02:33 PM
it is absolutely not surprising. CD28 is not at all good therapeutic target. It is fine to use antibodies to CD28 to activate T cells in vitrio. I am surprised that somebody wanted to give it in vivo!!
Did they give the same antibody to mice!! That is not the same thing since these antibodies and proteins will be sensitive to minor sequence variation. I would never have given anti-CD28 to a human. There is gross oversight in the approval process and the authorities should have taken opinion from a wider group of Immunologists who could have anticipated the disaster.
Able Lawrence MD, DM (Clinical Immunology)
Posted by: Able Lawrence | March 21, 2006 08:18 AM
Thinking about why odds against these poor youths should be this drug, as anti-CD28 molecules clustering of CD28 molecules and activate numbers of T cells. The consequence just likes that of superantigens, seen might be in birds flu and other acute infections also. Before had reported that anti-CD3 could activate high percent T cells like T cell mitogens. … Ask do I be clever than God before prescription may be clever.
Posted by: Du, Xiasntang | March 21, 2006 08:44 AM
Maybe it is time to stop thinking that we have clear understanding of the signaling pathway in the immune system and before going into clinical trial question whether are read outs are correct.
Posted by: Badrichani | March 21, 2006 01:23 PM
The reason that "such an extreme reaction among so many trial participants is extremely rare" is that good practice dictates that trials are not run on several test subjects simultaneously. If this trial had been run properly, there would have been one adverse reaction of this nature and the trial would have been discontinued.
Additionally, until contamination and dosage issues are ruled out, speculation regarding the effects of TGN1412 are superflous.
So far, the available data allow only conclusions that can be applied to how drug trials are managed. Speculation about the effects of TGN1412 need to wait until we can attribute these nighmarish responses to the drug itself.
Posted by: Carmen Reznik | March 21, 2006 01:44 PM
Common sense would require healthy subjects to enter a phase I trial one at a time. How fast were these 6 subjects recruited into the study ?
Posted by: Catherine Hill | March 21, 2006 01:50 PM
Could be posible that massive T cell stimulation by antibodies to CD28 consecuentely produce a severe and acute inmunodeficiency?This cuold be generate by apoptotic events after massive stimulation of immune system then fatal evolution in endotoxic shock with multiorganic failure
Posted by: Alvarez Gianni Maria | March 21, 2006 02:13 PM
Beyond the human tragedy it is a setback for biotech pharma research. A clear indication that preclinical safety may say nothing concerning human safety in case of a biotech approach. Tightening of regulatory measures is inevitable.
Posted by: Karoly Tihanyi | March 21, 2006 02:17 PM
As a former patient of arthertic damage; a digested thumb tendon, I can refer to myself as some level of expert. After tendon replacement I was informed that I needed to take a medication that would suppress my immune system; which was rated as very high and bordering on being out of control.
I lasted one dose of medication and opted out of the treatment.
My family is drug free and in good health. An aspirin is a high intake for us.
I also noticed that when I incur an injury my immune system activity tones down while it protects from infection. It is when I am in perfect health tht I must monitor for self imposed damage.
R. Tostado
Posted by: RAMON TOSTADO | March 21, 2006 04:03 PM
On considering this event, studies on Human Interactomics can be boosted for further explorations and developments.
Posted by: Jayakar Johnson Joseph | March 21, 2006 05:04 PM
It appears from Dr Hanke’s patent that TGN1412 was raised against human CD28 or a sequence from it and then tested on non-humans (including monkeys). This approach relies on inter-species cross-reaction. Had the animals been tested with antibody raised against their own receptor (which with previous drugs may have been done as part of the initial feasibility study, thus inadvertently avoiding a disaster like this one), similar effects to those found in the human subjects might have been observed. And a more realistic initial dosage might have been arrived at. Do the “standard clinical research guidelines” perhaps need to be revised when it comes to such molecules that are tailor-made to a particular species, like antibodies and genome-related sequences? Or is the situation so complicated that an independent ethics committee should be set up for developing this kind of therapeutic agent?
Posted by: John Rokos | March 21, 2006 06:20 PM
Existence of species-specific-antigens apart from CD28 and CTLA-4; may be one of the causatives for regulating the T cells. Hence the antigenic factors for these antigens to be explored for assigning them and to proceed with the study on the, superagonist of the CD28 receptors, in specific.
Posted by: Jayakar Johnson Joseph | March 21, 2006 08:10 PM
It is difficult to tell from the news posts but it sounds as if the individuals were responding to a hypersensitive /anaphylactic response. In the mouse, CD28 is expressed by mast cells. If this is also true for humans (and perhaps basophils) then injecting this antibody might have the same response to injecting anti-IgE receptor: wholesale degranulation and mast cell responses. It is not hard to kill a mouse doing this. Is this what happended here? Mouse and monkey trials would likley NOT produce such a response if this were the case.
Posted by: john weis | March 21, 2006 11:11 PM
Why were the investigators using placebo controls in a Phase I trial which is, by definition, purely a human safety study? Testing efficacy & tolerability (where placebos might be relevant) should have waited for Phase II, once safety was established.
Were commercial imperatives driving acceleration of the early phases to get into phase III more quickly? Was the ethics committee awake to this possibility? The high payments offered to subjects were arguably an undue inducement. These issues raise disturbing questions about the ethical integrity of the sponsoring biotech company, the CRO, the researchers, and the institutional oversight of this study.
Posted by: Robert H Loblay | March 21, 2006 11:33 PM
Dr Hanke's patent also mentioned that genetically humanized antibodies might be used. There is then the danger that a human handle might induce the entire immune system to "get in on the act". If TGN1412 is one of such, antibodies used in valid testing on monkeys would have to be genetically simianized, as well as raised against simian CD28 (and similarly for other animals tested).
Posted by: John Rokos | March 22, 2006 08:03 PM
On the difference between theory and practice:
In theory there is no difference between theory and practice, but in practice there is. (Jan LA van de Snepscheut)
This is even more relevant if the theory is based on selective observations as in the case of the CD28 superagonistic antibody. Not for no reason biology avoids non-specific stimulation of large cell cohorts but fine tunes responses locally by concentration or by very clever "logical gating" in form of cell surface rafting and multiple pathways.
There are two general questions that need to be answered:
Does TGN1412 have only one reactive site?
CD28 ligation is normally achieved by a cell surface molecule anchored in another cell – e.g. the ligand got it's tail covered in another cell. What is supposed to happen if the other end of the ligand is suddenly carries a serious message on its own, e.g. a functional antibody tail - if TGN1412 is really just a humanised anti-cd28 antibody. Thus in an animal study you need cd28 similarity and homology of the humoral response.
Which cells are stimulated by CD28
This blog is the only place other than Wikipedia were I found the suggestion that cd28 binds to something other than a T-cell (unfortunately w/o link). If one searches the literature or just looks in entrez gene you find that cd28 directly interacts with eosinophils in humans. As most scientists these days only look at PBMC's they probably never consider expression on places other than Lymphocytes, let alone that our idea of expression in most cases is limited to "expression high enough to cluster above negative cells as seen by flow cytometry".
It would be nice to get clarification on these points and how they were dealt with in a risk assessment that clearly must have been done.
Posted by: Gerhard Nebe-von-Caron | April 2, 2006 04:19 PM
All that is only preinvestigations and nobody has sounded the result yet.
Posted by: drug counselor | April 17, 2006 07:42 AM
Check out this introduction article on Multiple organ failure:
Multiple organ failure
Content:
1.Causes
2.Hepatorenal syndrome
3.Cardiopulmonary Failure
4.Shock
Posted by: Multiple organ failure | June 7, 2006 10:38 PM
(English is not my first language)
AS a prosessional in Physics (hold a MSc degree) I have to wander if medical science is ready to admit how little it knows about it's own business.
It is just not OK to learn at the cost of human health. Period.
How to learn? Maybe this is the first question that was never solved by medical science. Maybe the entire biotech "idea" has to be re-considered.
Posted by: Miranda cros | November 27, 2006 12:12 PM
Scientists who work in the field say there are several possible ways that the drug could have triggered multiple organ failure. It may have stimulated T cells so much that they released an overwhelming flood of inflammatory molecules called cytokines.
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