The hypothesis, raised by Nature reporter Michael Hopkin, is that the way TGN1412 was constructed may have meant that human safety issues went undetected in animal studies. Hopkin posits that the "tail" of the antibody may be different in humans and monkeys, in which TGN1412 was tested prior to the clinical trial.

A process called crosslinking can result in antibody "tails" amplifying an immune response and could explain the serious adverse events seen in the phase 1 study, a possibility that Hopkin reported was acknowledged by TeGenero co-founder Thomas H�nig, an immunologist at the University of W�rzburg.

In the trial, which was being conducted at Northwick Park Hospital in London, six volunteers who received TGN1412 last month developed a severe inflammatory reaction and multi-organ failure. The men were admitted to intensive care, but five have been discharged from the hospital and the remaining man appears to be recovering as well.

The hypothesis also suggests some superantibodies may pose serious safety concerns.

Eric Coldwell, an analyst with Robert Baird, told United Press International contract research organizations have traditionally stayed away from monoclonal antibody studies and the TGN1412 fiasco certainly won't persuade them to reconsider.

"CROs tend to shy away from those studies because they're incredibly complex and can pose safety issues," Coldwell said, adding that he went back to some of the bigger CROs after the TGN1412 catastrophe and some of them said zero percent of their work is in this field.

"This is not the focus for the vast majority of companies that I follow," he said.

As for Parexel, the CRO that was conducting the research for TeGenero, "as a therapeutic class, this is not likely a very big area for them," Coldwell said.

"What's more unfortunate is the impact it's going to have on how the world is going to see the drug industry," he said. "The European press has done a real butcher job on this, calling it a failed study. It wasn't a failed study, it was a failed drug. The study did exactly what it was supposed to do," he added.

TeGenero itself, which was developing TGN1412 for treatment of leukemia, rheumatoid arthritis and multiple sclerosis, is concerned how the superantibody field will proceed in light of a recent recommendation from the United Kingdom's Medicines and Healthcare products Regulatory Agency, but the company appears intent on moving forward.

The MHRA, which investigated the circumstances surrounding the clinical trial, said in an announcement issued last week that it found no evidence of wrongdoing by either Parexel or TeGenero and concluded "that an unpredicted biological action of the drug in humans is the most likely cause of the adverse reactions in the trial participants."

The MHRA, noting that the situation could affect the regulation of clinical trials worldwide, recommended a group of leading international experts be established to review the trial and determine whether changes should be made to the regulation of similar future studies.

TeGenero, which did not respond to UPI's request for comment, said in a statement issued in response to the MHRA recommendation, "The announcement of a new expert commission to supervise future trials of monoclonal antibodies challenges all of us in the biotechnology industry to think again about the safest way to develop new medicines in the future."

Nature reported TeGenero gave a more upbeat perspective about superantibody development. "Dangers can possibly be reduced by very careful assessment of pharmacological as well as safety characteristics," the company said in a statement to the journal.

Trials involving monoclonal antibodies will likely find it very difficult to proceed in the United Kingdom, at least for the next three months, when the expert group's report is due.

"Until the Expert Group has completed its work, the MHRA will take a precautionary approach for all further clinical trial applications involving first-in-man trials of any monoclonal antibody (regardless of intended target) or other novel molecules targeting the immune system, acting via a novel mechanism," the MHRA stated. "Such trials will be not be authorised without having had additional expert opinion on whether the effects seen in the TGN1412 case may be repeated in relation to those substances."

The cautious approach of the MHRA may be wise because problems similar to those proposed in Hopkin's hypothesis had previously been seen with another monoclonal antibody: PDL Biopharma's Nuvion. That drug, which is in phase 2 and phase 3 trials, targets a different receptor than TGN1412, but it produced an uncontrolled immune response in immunocompromised mice until researchers resolved the problem by modifying the antibody's tail to prevent crosslinking.

The Food and Drug Administration did not return a phone call from UPI requesting comment, so it is uncertain if they are considering similar steps as their UK counterparts that could hold up trials in the United States.

Dr. Peter Lurie, deputy director of Public Citizen's Health Research Group, said the TGN1412 situation highlights the problems that could be created if the FDA proceeds with its proposal issued in January to relax Good Manufacturing Practice standards for compounds going into phase 1 studies.

Authorities were able to quickly determine the TGN1412 adverse events were due to the drug and not due to a contaminant because the companies involved adhered to GMP requirements, Lurie told UPI. "If the new proposal (by the FDA) was implemented, it would greatly diminish the FDA's ability to investigate something like this," he added.

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