NEWS - Follow-up on the TGN1412 trial: Can super-antibody drugs be tamed?

[Guest guest]

News

Nature 440, 855-856 (13 April 2006)

Can super-antibody drugs be tamed?

As it becomes clear that the London clinical trial disaster was indeed the

fault of the drug itself, Hopkin looks at what went wrong, and

whether there is any future for 'superagonist' antibody therapies.

There was no warning from animal tests, but last month the experimental

antibody drug TGN1412 put six British men in intensive care. The resulting

investigation ruled out any failure of experimental and regulatory

procedures - a relief for those involved, but a damaging blow for the field.

Immunologists are now left asking what went so badly wrong in the trial, and

whether the fearsome potency of 'superagonist' antibody therapies will

outweigh their promise.

The six volunteers at London's Northwick Park Hospital were probably struck

by a huge immune reaction called a cytokine storm - a flood of inflammatory

molecules released by cells called helper T cells, which shut down their

organs in hours. The UK Medical and Healthcare products Regulatory Agency,

which approved the trial, announced last week that it has found no evidence

of contamination in the treatments, which means the devastating effects were

almost certainly caused by TGN1412 itself.

With hindsight, it might be no surprise that the compound, dubbed a

'superagonist' antibody by its creators, could run amok in the immune

system. Around 20 antibody therapies are currently approved or nearing

approval, most of which mimic natural human antibodies against specific

viruses or cancer-cell types. But TGN1412 is different. It was designed to

circumvent the usual checks and balances that prevent T cells from

overreacting in the course of their normal duties.

Usually, T cells respond to specific enemies, or antigens, recognized by the

immune system. After the antigen is first encountered, an

'antigen-presenting cell' binds to a T cell at two sites on its surface: the

T-cell receptor (TCR) and the CD28 receptor. TCR binding is specific to the

antigen in question, whereas CD28 binding acts more like a 'go' switch for

the T cell; both are normally required (see graphic, below). But the makers

of TGN1412 found a way to switch on the CD28 green light without TCR

binding, activating T cells across the board.

T cells fall into three broad categories: killers, which destroy specific

target cells; helpers, which boost other parts of the immune system and are

the most likely source of a cytokine storm; and regulatory T cells, which

suppress other elements of the immune system. Roughly half of killer T

cells, and virtually all helper and regulatory T cells, express the CD28

receptor.

When Hünig, an immunologist at the University of Würzburg and

researchers at TeGenero, the spin-off company he co-founded to develop

TGN1412, began testing the antibody on animals, they found that the drug

seemed only to activate regulatory T cells (Beyersdorf, N. et al. J. Exp.

Med. 202, 445-455; 2005). This made it an enticing candidate for treating

autoimmune diseases such as rheumatoid arthritis and type-1 diabetes. The

researchers hoped that TGN1412 could make immunosuppressive cells soothe

sites of overinflammation, while the rest of the immune system carried on as

usual.

It is still not clear why, when TGN1412 affected only regulatory T cells in

animals, the same almost certainly did not occur in the human trial. It is

likely that in humans the super-antibody activated helper T cells en masse,

triggering a cytokine storm.

" We were shocked and surprised to see what happened in humans, " Hünig told

Nature. In preclinical trials, monkeys got a dose 500 times that given to

the human volunteers, and the monkey CD28 receptor is identical to the human

one, says Hünig. This means that the effects in the monkey trial should have

been comparable.

One possible source of the difference between the animal and human trials is

that the 'tail' of the antibody molecule at the opposite end from the

CD28-binding site may not be the same in humans and monkeys. Antibody tails

can undergo a process called crosslinking, which amplifies an immune

response by recruiting more immune cells or antibodies. Therapeutic

antibodies are modified so that they have the same overall structure as a

generic human antibody, but doing this may also have prevented the full

extent of TGN1412's activity from showing up in animal tests. Hünig admits

that this could have happened.

Hünig's team should have known of previous research on this region, says

Camilo Colaco of ImmunoBiology, an immunological research company in

Cambridge, UK. Similar work has been done on CD3 receptors, which are

crucial for the TCR component of T-cell activation, he says. Researchers

were hoping that a superagonist antibody directed at this receptor could

boost general T-cell activity, helping transplant patients restore their

immune systems after taking immunosuppressive drugs.

But in tests of the antibody in mice, researchers found that uncontrolled

cytokine release was a problem - albeit not a large one because the mice

were already immunodepleted (L. Chatenoud et al. Transplantation 49,

697-702; 1990). Tweaks to the antibody's tail to prevent crosslinking

resulted in an antibody that did not have the same problem and could enter

clinical trials (P. A. Carpenter et al. Biol. Blood Marrow Transplant. 11,

465-471; 2005); the drug has now been approved under the name visilizumab.

But using unmodified superagonists in a healthy volunteer with an intact

immune system is playing with fire, says Colaco: " It would go bananas. "

Another, more controversial, theory is that, in humans, CD28 receptors are

found in the immune system beyond just T cells. Dorothy , an

immunologist at Baylor College of Medicine in Houston, Texas, says that the

receptor may be present on granulocytes, the most numerous white blood cells

in the body, which have a range of cell-killing tricks. Alternatively,

killer T cells might have been triggered to release a cell-destroying

molecule called granzyme B. These processes could theoretically produce the

effect seen in the TGN1412 trial, says . She also suggests that a

cytokine storm might come on too slowly to account for the reaction seen in

the trial volunteers, all of whom suffered severe effects within minutes and

collapsed within 12 hours of being injected with TGN1412. " When you trigger

T cells it takes a while to get up to speed, " she says. " But granulocytes

are good to go. "

Hünig doesn't buy her theory, however. After the trial went wrong, he says

he went over the literature to see if CD28 receptors might be more common

than he had imagined. He says that only one group has ever claimed to have

spotted them on granulocytes (K. Venuprasad et al. Eur. J. Immunol. 31,

1536-1543; 2001), and he is confident that the idea can be ruled out. Hünig

remains convinced that overactivation of helper T cells was to blame: " It

was not too fast to be cytokines. "

Some, such as Steve Anderton, an immunologist at the University of

Edinburgh, UK, who is studying the use of antibodies to overcome cancers

that evade the immune system, are concerned at the haste with which TGN1412

was tried out in humans - barely a year after the structure of the CD28

receptor was deduced (E. J. et al. Nature Immunol. 6, 271-279; 2005).

" It is flabbergasting that this approach was tried, " he says. " It takes away

all the rules of the immune response. " Jim Riley of the University of

Pennsylvania in Philadelphia, who works on the CD28 pathway, feels

similarly. " My first reaction was 'how did they get that through the

regulatory body?' " he says.

A major question now is how the field can move forward. Instead of risking

further work with superantibodies, some favour turning to other approaches.

One option is to culture a patient's regulatory T cells in the lab, then

inject them into the bloodstream. Another is to target processes such as the

binding of antigen-presenting cells to T cells using blocking antibodies.

This method allows autoimmune disease to be treated without activating

regulatory T cells, and has already been tested on a mouse model of multiple

sclerosis (H. D. Lum et al. Leukocyte Biol.; in the press).

But others feel that superantibody therapy does have a future. The CD3

superantibody visilizumab suggests that such drugs can be safe. And Anderton

says that the CD25 receptor, which is expressed mainly by regulatory T

cells, and by other T cells only once they are activated, may be a safer

target than CD28.

TeGenero's future is unclear - it has a staff of just 15 people, and TGN1412

was its only product. The company seems hopeful that the technology can be

tamed: " It is too early to give definitive answers on how superagonistic

antibodies must be developed in the future, " TeGenero said in a statement to

Nature. " Dangers can possibly be reduced by very careful assessment of

pharmacological as well as safety characteristics. "

But the idea of using superantibodies to activate the CD28 receptor is

almost certainly dead. " In its current form I wouldn't want to have anything

to do with it, " says Riley.

http://www.nature.com/nature/journal/v440/n7086/full/440855a.html

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org