TeGenero fallout will be minor

By Steve Mitchell Mar 24, 2006, WASHINGTON, DC, United States (UPI) -- TeGenero`s disastrous phase 1 trial of TGN1412 -- in which six men became seriously ill hours after receiving the drug -- has stirred up questions about the clinical trial process, but experts said the fallout for industry and the regulation of clinical trials is likely to be minimal.

'I don`t think it will have much implication for the biopharmaceutical industry,' Eric Schmidt, an analyst with S.G. Cowen, told United Press International. 'Anytime a foreign substance is tested in humans, it carries risk,' Schmidt said. 'This seemed to be an unfortunate occurrence, but also an isolated example.'

In the trial, which was being conducted at Northwick Park Hospital in London, six volunteers who received TGN1412 on March 13 developed a severe inflammatory reaction and multi-organ failure. The men were admitted to intensive care and two remain critically ill.

Jerome Yates, a medical oncologist and senior vice president for research at the American Cancer Society, told UPI he didn`t think the study indicated there was a problem with the clinical-trial process in the United States. 'Generally speaking, the way clinical trials are conducted in this country, particularly phase 1 trials, are much, much more careful,' Yates said. He added that the study design should have raised red flags before the trial was ever initiated. The warnings included that the study participants were paid approximately $3,500. 'Most institutional review boards in this country would not approve something like that because it`s a form of financial coercion,' Yates said. In addition, phase 1 trials of this type generally call for treating one patient at a time, not six simultaneously as apparently happened in this study. Healthy volunteers also are generally not included in phase 1 trials of potential cancer treatments, he said.

Still, Yates thought it was likely that regulatory authorities would review the clinical trial process. 'I think everybody will review the situation,' he said. 'You can`t take healthy people and put them in life-threatening jeopardy.'

The industry and regulatory authorities are apparently not eager to discuss the matter. The Pharmaceutical Research and Manufacturers of America, the Biotechnology Industry Organization and the Food and Drug Administration did not respond to requests from UPI for comment.

The Medicines and Healthcare products Regulatory Agency and the local ethics board approved the trial design.

TeGenero, which was developing the monoclonal antibody drug for treatment of leukemia, rheumatoid arthritis and multiple sclerosis, subsequently acknowledged that monkeys given the drug during preclinical studies developed swollen glands but insisted there was no indication the compound would cause serious problems in humans.

'We are shocked about the symptoms we have seen in the volunteers,' said Thomas Hanke, TeGenero`s chief scientific officer. 'Extensive pre-clinical tests showed no sign of any risk,' Hanke added.

Despite these assurances, The Lancet, in an editorial in the March 25 issue of the journal, called for independent scrutiny of the trial. 'Although most first-in-man trials are not associated with such dreadful events, the fact that they have occurred should lead to maximum transparency to reaffirm trust in clinical trials and their regulation,' the Lancet stated in the editorial.

The Lancet raised the issue of whether the trial protocol was followed to the letter. The protocol approved by the MHRA specified the drug should be given at two-hour intervals, but TeGenero`s Hanke said the protocol left the order and timing of administration to the discretion of the principal investigator at Parexel, a contract research organization that was conducting the trial for TeGenero.

The Lancet said both MHRA and TeGenero denied its request to see the protocol on the grounds that it was 'commercially sensitive.' The Lancet objected to this rationale, stating, 'Commercial confidentiality should not obstruct independent scrutiny of the TGN1412 protocol and trial conduct.'

The editorial added, 'Until the MHRA and police investigations are complete, it is unclear whether there was a fault with the quality of the drug, contamination, a deviation from the protocol, or whether this was an unpredicted adverse event.'

Parexel said in a statement issued this week that a preliminary audit conducted by its internal quality-assurance department supports the notion that the protocol 'was adhered to properly, and that best practices and policies and procedures were correctly followed.' The firm also noted that so far MHRA, which is investigating, 'has found no reason to recommend the discontinuation of trials at Parexel`s phase 1 unit.'

Boehringer Ingelheim, which manufactured the compound used in the clinical trial, said it conducted 'an additional review of the manufacturing documentation and the pharmaceutical release procedure' and confirmed that the material it supplied 'complied with all pharmaceutical and legal requirements.' - via monstersandcritics.com

Monoclonal Antibody Technology - The Basics

(BIO). "What is Biotechnology?" Washington, D.C.: Biotechnology Industry Organization, 1989.

Substances foreign to the body, such as disease-causing bacteria and viruses and other infectious agents, known as antigens, are recognized by the body's immune system as invaders. Our natural defenses against these infectious agents are antibodies, proteins that seek out the antigens and help destroy them.

Antibodies have two very useful characteristics. First, they are extremely specific; that is, each antibody binds to and attacks one particular antigen. Second, some antibodies, once activated by the occurrence of a disease, continue to confer resistance against that disease; classic examples are the antibodies to the childhood diseases chickenpox and measles.

The second characteristic of antibodies makes it possible to develop vaccines. A vaccine is a preparation of killed or weakened bacteria or viruses that, when introduced into the body, stimulates the production of antibodies against the antigens it contains.

It is the first trait of antibodies, their specificity, that makes monoclonal antibody technology so valuable. Not only can antibodies be used therapeutically, to protect against disease; they can also help to diagnose a wide variety of illnesses, and can detect the presence of drugs, viral and bacterial products, and other unusual or abnormal substances in the blood.

Given such a diversity of uses for these disease-fighting substances, their production in pure quantities has long been the focus of scientific investigation. The conventional method was to inject a laboratory animal with an antigen and then, after antibodies had been formed, collect those antibodies from the blood serum (antibody-containing blood serum is called antiserum). There are two problems with this method: It yields antiserum that contains undesired substances, and it provides a very small amount of usable antibody.

Monoclonal antibody technology allows us to produce large amounts of pure antibodies in the following way: We can obtain cells that produce antibodies naturally; we also have available a class of cells that can grow continually in cell culture. If we form a hybrid that combines the characteristic of "immortality" with the ability to produce the desired substance, we would have, in effect, a factory to produce antibodies that worked around the clock.

In monoclonal antibody technology, tumor cells that can replicate endlessly are fused with mammalian cells that produce an antibody. The result of this cell fusion is a "hybridoma," which will continually produce antibodies. These antibodies are called monoclonal because they come from only one type of cell, the hybridoma cell; antibodies produced by conventional methods, on the other hand, are derived from preparations containing many kinds of cells, and hence are called polyclonal. An example of how monoclonal antibodies are derived is described below.

A myeloma is a tumor of the bone marrow that can be adapted to grow permanently in cell culture. When myeloma cells were fused with antibody-producing mammalian spleen cells, it was found that the resulting hybrid cells, or hybridomas, produced large amounts of monoclonal antibody. This product of cell fusion combined the desired qualities of the two different types of cells: the ability to grow continually, and the ability to produce large amounts of pure antibody.

Because selected hybrid cells produce only one specific antibody, they are more pure than the polyclonal antibodies produced by conventional techniques. They are potentially more effective than conventional drugs in fighting disease, since drugs attack not only the foreign substance but the body's own cells as well, sometimes producing undesirable side effects such as nausea and allergic reactions. Monoclonal antibodies attack the target molecule and only the target molecule, with no or greatly diminished side effects. - accessexcellence.org

CROPS IN SECRET LOCATIONS USE GM DRUG THAT LEFT SIX CRITICALLY ILL

notopharmaceuticalexperiments on IndyMediaUk

original source

Independent scientists have raised the alarm after media reports ommitted to mention that drugs, which left six people critically ill after a trial, are genetically modified and are being used in crops planted in secret locations across the UK.

Drug Trial Catastrophe & Safety of Secretly Tested Pharm Crops

A monoclonal antibody drug tested in a clinical trial made all six healthy volunteers violently ill, yet transgenic crop plants with similar drugs are being tested in secret locations and the unsuspecting public are being exposed without their knowledge or consent. Prof. Joe Cummins and Dr. Mae-Wan Ho

A fully referenced version of this article is posted on ISIS members' website. Details here

Drug trial reactions attest to the deadly nature of MAB drugs

The London drug trial that left six healthy volunteers dangerously ill has raised awkward questions on the science and ethics involved in all stages of drug research and development ("Drug trial catastrophe – collapse of science and ethics", this series). The drug, code named TGN1412, is a genetically engineered humanized monoclonal antibody (MAB) aimed at treating leukaemia and autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Hundreds of MAB drugs are under development, 18 of which have already been approved by the US FDA, with warnings posted on each and every one of them ("Warnings over FDA approved monoclonal antibody drugs", this series).

The violent reactions of all six human volunteers injected with TGN1412 serves as a graphic demonstration on how deadly such drugs can be.

In the aftershock of the episode, bioethicists and others have called for tighter regulation of human drug trials and a more cautious protocol. However, no one has raised the alarm over the distinct possibility that the general public might be exposed without informed consent to transgenic crops producing such drugs.

Secret pharm crops with MABs

Currently, the MAB drugs approved have mainly been prepared from cell cultures. The cost to the patients would be at least $20 000 to $50 000 per year; the colon cancer drug Erbitux costs $17 000 per month [1]. So, only the wealthy could benefit from such drugs, if at all. Producing the drugs in transgenic farm animals or in crop plants, therefore, promises to greatly reduce the cost of MAB drugs. And plans are afoot to do just that, with reckless disregard for the safety of the general public.

Laboratory mice have already been modified to produce human antibodies and there are efforts to create farm animals producing human antibodies [2]. Human monoclonal antibodies have been produced at relatively high levels in chicken eggs [3]. And humanized MABs have been produced using the yeast Pichia pastoris, ‘glycoengineered' to express human patterns of glycosylation (carbohydrate chains on proteins) to avoid immunological problems arising from non-human glycosylation [4].

Plant-based production of recombinant antibodies has been discussed extensively. A review published in 2003 [5] reported that six plant-derived antibodies have been developed as human therapeutics. The drug, Avicidin, developed by NeoRx and Monsanto, had some anticancer effect on colon cancer; but it caused severe diarrhoea and was withdrawn. A plant-derived antibody CaroRx produced in tobacco claims to reduce tooth decay by preventing adhesion of the bacterium Streptococcus mutans. A MAB targeting the cancer-antigen CEA was produced in tobacco, pea, rice and wheat. A humanized MAB recognizing herpes simples virus 2 was produced in soybean. Tobacco plants were transformed with a viral vector to produce antibodies targeting non-Hodgkin's lymphoma. Finally, a MAB produced in tobacco targeted human chorionic gonadotropin, and was intended for use in contraception, pregnancy detection and therapy of tumours [6]. Plants have been transformed to produce prophylactic antibodies against rabies and other disease conditions [7].

We have drawn attention to the hazards of producing genetically modified vaccines and therapeutic antibodies. The main threat is the genetic pollution of major food crops resulting in food that is toxic [8]. Humanized MABs structured to attack herpes virus or regulate the human immune system were to be produced by transgenic strains of the green alga Chlamydomonas in large plastic tubes near a beach in Hawaii Chlamydomonas is a common soil microbe so the nature and location of the production facility would risk spreading the transgenic strains and the human genes also to soil microbes [9].

Molecular pharming (producing pharmaceuticals in transgenic crops) is turning into a new battlefront in the struggle of the global civil society against transgenic crops. Too many governments of industrialised countries appear to be prepared to allow biotech corporations to contaminate our food supply with un- prescribed and dangerous drugs [10].

The precise MABs in pharm crops deemed confidential business information

There have been at least 29 field tests of transgenic crops known to be producing antibodies, but the actual genes have been deemed confidential business information (CBI). The crops modified include maize and soybean; and the companies testing the transgenic crops are Prodigene, Monsanto and Agracetus, among others. The field releases were in Hawaii, Nebraska, Wisconsin, Iowa, Indiana Minnesota, Puerto Rico, Texas and other states [1]. Other crops and MABs may have been tested, but designated CBI, as are the actual locations of such tests, and no effort has been made to notify bystanders and neighbours that are likely to be directly exposed to the drugs. People may be exposed to MABs from transgenic crops by pollen, dust debris from leaves, stems and flowers, and from polluted surface and groundwater. Once the MAB genes escape to fertilize neighbouring crops, they will persist within the contaminated crops, by virtue of simple Hardy-Weinberg equilibrium in elementary population genetics!

There is no case for using crop plants in the open field to produce these drugs, as they could easily be produced in plant cell culture under fully contained conditions.

The secretive field trials should never have been allowed, as they are exposing people, without their knowledge or consent, to drugs that could become life- threatening, as the London drug trial so vividly demonstrated.

The location and nature of current and previous field trials should be made public now before any more damage is done, and all further field trials should be banned.