2003 Lasker Award goes to RA researchers

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http://www.laskerfoundation.org/media/press/2003_pr20030919.html

NEW YORK, NY, September 19, 2003 — THE 2003 ALBERT LASKER MEDICAL

RESEARCH AWARDS WERE ANNOUNCED TODAY. THE NATION'S MOST DISTINGUISHED

HONOR FOR OUTSTANDING CONTRIBUTIONS TO BASIC AND CLINICAL MEDICAL

RESEARCH, THE LASKER AWARDS WILL BE PRESENTED TO TWO SCIENTISTS WHO

DISCOVERED AND DEVELOPED THE USE OF ANTI-TNF THERAPY FOR RHEUMATOID

ARTHRITIS AND OTHER AUTOIMMUNE DISEASES, WHICH HAS RESTORED VITALITY

AND WELL-BEING TO HUNDREDS OF THOUSANDS OF PEOPLE, AND TO A PIONEER

IN THE UNDERSTANDING OF EUKARYOTIC TRANSCRIPTION, THE PROCESS BY

WHICH NUCLEATED CELLS READ OUT GENETIC INFORMATION. ACTOR-ACTIVIST

CHRISTOPHER REEVE WILL BE HONORED FOR HIS TIRELESS AND EFFECTIVE

PUBLIC ADVOCACY IN SUPPORT OF EXPANDED MEDICAL RESEARCH.

The Awards will be presented at a luncheon ceremony on Friday,

September 19th at the Pierre Hotel in New York City. Guest speakers

at the ceremony include Dr. Mark B. McClellan, Commissioner of the

U.S. Food and Drug Administration, and Lemann, the new Dean

of the Columbia School of Journalism.

Often called " America's Nobels, " the Lasker Award has been given to

66 scientists who subsequently received the Nobel Prize, including 15

in the last 11 years.

http://www.laskerfoundation.org/awards/library/2003c_cit.shtml

Albert Lasker Award for Clinical Medical Research, 2003

Press release

Marc Feldmann and Sir Ravinder N. Maini

The 2003 Albert Lasker Award for Clinical Medical Research honors two

scientists who discovered anti-TNF therapy as an effective treatment

for rheumatoid arthritis and other autoimmune diseases. Despite

initial skepticism from the research community about their idea, Marc

Feldmann and Ravinder N. Maini transformed their findings in the

laboratory into a powerful treatment. The therapy they developed has

brought relief and vitality to hundreds of thousands of people

worldwide, and promises to better the lives of even more individuals

as it proves effective in additional debilitating illnesses.

All autoimmune diseases - conditions in which the body turns against

itself - arise from multiple causes and involve a large number of

misbehaving molecules. In particular, proteins called cytokines,

which carry signals between cells to orchestrate the fight against

invading microorganisms, act up and provoke ferocious inflammation.

When Feldmann and Maini began their work in 1984, most scientists

doubted that neutralizing a single molecule would quiet such

complicated multifactorial systems. Yet the researchers discovered

that crippling one of the cytokines - TNF - pacified the entire

inflammatory entourage.

They made their breakthroughs by studying rheumatoid arthritis, a

chronic autoimmune disease that afflicts approximately 0.5% to 1% of

the population. The illness attacks the joints; inflammation and

progressive damage to cartilage and bone causes pain and stiffness,

makes movement difficult, and leads to serious disability.

Conventionally, patients took aspirin or other nonsteroidal anti-

inflammatory drugs to soothe their discomfort, but these drugs didn't

halt disease progression. Agents such as corticosteroids and so-

called disease-modifying anti-rheumatoid drugs posed problems because

they helped only half of the patients and caused side effects. No

treatment healed the joints or completely impeded damage to cartilage

and bone.

In the early 1980s, Feldmann, a medically trained immunologist from

Australia, was working at University College, London, and had begun

studying a different autoimmune condition called Graves' disease,

which causes the thyroid to become overactive. In this illness,

particular non-immune thyroid cells take on unusual properties,

acquiring molecules (such as HLA class II proteins) that allow them

to stimulate an immune reaction that leads to inflammation.

Scientists knew that these same molecules cropped up inappropriately

in other autoimmune diseases as well, and that cytokines stimulate

production of them.

Feldmann proposed that cytokines stir up autoimmune disease. He

decided to test this idea; as a first step, he would check whether

tissue afflicted with an autoimmune illness contained excess

cytokines. He chose rheumatoid arthritis, because it would provide

the opportunity to study tissue at the height of inflammation, which

was not possible in Graves' disease: Doctors routinely remove

diseased tissue from rheumatoid arthritis patients to relieve

symptoms.

A mutual acquaintance recommended that Feldmann meet Maini, a leading

rheumatologist and researcher at the Arthritis Research Campaign's

Kennedy Institute of Rheumatology at Imperial College in London. With

one foot in the lab and one foot in the clinic, Maini had good access

to the human tissue that would be needed for the investigations. The

notion that deranged cytokine behavior fostered rheumatoid arthritis

had snagged his attention as well, and the two scientists teamed up,

hoping eventually to harness the chaos.

By the early 1980s, scientists were developing new research tools

that could identify individual cytokines - an important advance

because these chemical messengers often show up in groups. The

ability to catalog which cytokines were present - and to foil them

separately - would prove crucial to Feldmann and Maini's analysis.

The two researchers, as well as others, showed that the joints of

people with rheumatoid arthritis teem with proinflammatory cytokines.

Furthermore, Feldmann and Maini found that the diseased joint cells

themselves produced these cytokines in an uncontrolled fashion. When

the researchers grew the cells from afflicted knee joint tissue in

culture dishes, the mixture churned out cytokines continuously for

six days; during a healthy inflammatory response, the signaling

molecules appear only briefly. The observation that arthritic cells

gush cytokines implied that the normal means of tempering the immune

response had gone awry.

The identity of the cytokines hinted at the underpinnings of specific

disease features. For example, one of the cytokines in the joints

recruits immune cells to sites of tissue injury, an observation that

could explain the local inflammation; another activates antibody-

producing cells, and might thus spur the output of antibodies that

ravage the body's own tissues. Despite these potential windows into

the molecular mechanisms of the disease, the results vexed

scientists. Many of the cytokines present in the joints perform

overlapping duties. A treatment that disarmed one cytokine could prod

another to work overtime, experts reasoned, and wouldn't quell the

disease.

Maini and Feldmann, however, suspected that a single cytokine might

act as a fire alarm to jolt the entire system into action. Studies

had shown that a cytokine called IL-1 causes joint damage in animal

tissue. Furthermore, mice suffering from a condition that mimics some

aspects of rheumatoid arthritis produced IL-1 in their inflamed

joints. These observations pointed to IL-1 as a rheumatoid arthritis

suspect. The researchers wanted to know whether they could find a

cytokine that would kick-start the disease - and in particular, IL-1

production.

As a first step, Feldmann and Maini tested whether several cytokines

emitted by joint cells in culture dishes influenced the manufacture

of IL-1. To accomplish this task, they added antibodies that knocked

the cytokines out of commission. Most antibodies had no effect, but

one that foiled TNF quashed IL-1 output. Feldmann and Maini then

conducted the converse experiment, adding instead antibody that

disabled IL-1; TNF quantities remained unchanged. Additional work

showed that the anti-TNF antibodies also squelched the manufacture of

other proinflammatory cytokines. These results and those from other

groups indicated that TNF played a key role in governing the creation

of cytokines and other inflammatory molecules: Blocking this single

molecule could apparently turn down the entire inflammatory response.

To move toward their goal of treating humans, the researchers wanted

to test whether similar events occurred in mice with arthritis.

Injecting collagen - a component of connective tissue, which includes

cartilage and bone - into a particular strain of susceptible mice

sparks a condition that shares some key features with rheumatoid

arthritis. In particular, a comparable immune response erupts in the

joint and a related type of tissue damage develops. Using collagen,

the researchers induced rheumatoid arthritis-like symptoms in mice

and then injected anti-TNF antibody. This treatment reduced swelling

and joint destruction. Several other groups - in New York City,

Geneva, and Athens - independently generated similar results,

supporting the idea that an excess of TNF can incite the whole

disease.

This success in animals gave the researchers confidence to attempt

therapy in patients. But the antibody they had used in the rodent

studies wouldn't suffice because it inactivated mouse, but not human,

TNF. The researchers had antibody that bound human TNF, but it had

been made in mice and would likely cause dangerous side effects as

the human immune system mounted a response against it; furthermore,

this immune response would expel the antibody. Feldmann and Maini

wanted instead a molecule that bound human TNF and contained a large

portion of a human antibody. A person's body would treat the

resulting antibody more normally and wouldn't reject it.

In attempts to fight sepsis, a number of companies had developed such

chimeric human-mouse antibodies as well as other compounds that

knocked TNF out of commission. However, at the time (early 1990s),

the conventional wisdom in the pharmaceutical industry was that

therapeutic antibodies wouldn't thwart chronic diseases. Humans

wouldn't tolerate antibodies that were part human and part mouse over

the long term, the thinking went; the immune system would notice the

portion from mouse and attack it, limiting the benefit and inducing

dangerous side effects. Furthermore, many experts thought that

disrupting the cytokine system would spur it to reorganize;

inflammation would flare up again and patients would wind up back

where they started. Finally, given the number of cytokines in

diseased joints, scientists were still skeptical that hobbling a

single cytokine would relieve symptoms. Although the strategy had

triumphed in mice, rodent and human physiology differ and many

apparently promising therapies had failed to transfer from animals to

people. Even Feldmann and Maini didn't think that an antibody-based

therapy would prove ideal in the long run. Producing these molecules

is very costly and thus, therapeutic antibodies - even if they

worked - wouldn't flourish in the marketplace.

However, if Feldmann and Maini could remedy disease in humans by

blocking their target molecule, they figured they could eventually

develop a less expensive drug that would mimic the antibody.

Therefore, they were eager to know whether their novel scheme would

work.

Fortunately, one of Feldmann's former visiting scientists named

Woody had taken a position as research director at a company called

Centocor Inc. in Malvern, Pennsylvania, which had created a chimeric

anti-TNF antibody for use against sepsis. Woody was amenable to

Feldmann and Maini's idea, and Centocor agreed to provide material

for a preliminary test in humans.

In 1992, Feldmann and Maini, working together at the Kennedy

Institute by this time, performed the first clinical trial of anti-

TNF therapy for rheumatoid arthritis. Because no one knew whether it

would trigger harmful side effects in patients who were already ill,

the researchers recruited only patients who had not responded to

other therapies and had no other treatment options. They injected the

antibody, called cA2 at the time, subsequently known as infliximab,

and now Remicade®, into the bloodstream.

Within a few hours, the patients reported dramatic symptomatic

relief; they felt more energetic and their joints had loosened up.

Within several weeks, previously incapacitated people were playing

golf and climbing stairs. Maini and Feldmann were thrilled - but they

worried about the placebo effect - a phenomenon in which people feel

better even when they're receiving a fake drug. Objective measures,

however, indicated that the disease was retreating. Quantities of a

blood-borne protein that accompanies inflammation dove and joint

swelling subsided.

Between 6 and 12 weeks after finishing the two-week treatment,

symptoms recurred. The researchers re-administered the antibody to

eight of the 20 patients, which again considerably benefited them.

Eventually disease returned, indicating that blocking TNF temporarily

did not permanently cure individuals with resistant disease. However,

the antibody seemed safe and the results justified further trials.

Feldmann and Maini presented their findings at a meeting in 1992,

drawing the attention of other companies, which started brushing up

their own anti-TNF agents for possible use in combating rheumatoid

arthritis.

The striking initial success persuaded Centocor to support the first

multi-center clinical trial of TNF blockade in four European cities.

To generate formal proof that the treatment helps patients, the

researchers set up a rigorous experiment in which two groups of

patients would receive the active drug in different doses and another

would receive a placebo; neither doctors nor patients would know who

was in which group. The researchers injected the agent of choice once

into 72 people and then tracked disease over a period of four weeks.

Again, joints became less tender and swollen, and amounts of the

blood-borne inflammatory marker plummeted.

These results heartened Feldmann and Maini, but rheumatoid arthritis

is a long-term disease, and their patients eventually relapsed. To

test whether re-treatment might further fend off the disease, they

conducted another study in which they administered five infusions

over a period of 14 weeks and observed patients for six months. This

tactic kept the disease on hold, indicating not only that people

could tolerate the antibody over the long term, but also that it

continued to exert a therapeutic effect. In this study, the

researchers also assessed whether another drug enhanced the anti-TNF

regimen. Feldmann and Maini knew from their work in animals that

depleting a particular class of immune cells amplified the effects of

the anti-TNF antibody. A compound called methotrexate, the most

commonly used anti-rheumatic drug, hinders the activity of these same

immune cells, so the researchers administered methotrexate along with

the antibody to half of the patients. Their predictions panned out:

Methotrexate magnified the positive effects of anti-TNF, and

combination therapy is currently used for the majority of rheumatoid

arthritis patients who undergo long-term anti-TNF therapy.

The treatment was clearly performing well by every yardstick they had

used so far, but Maini and Feldmann, joined by Lipsky in Dallas

and several other North American and European groups, wanted to

measure structural joint damage per se, which they could track over a

long period of time with X-rays. A year of treatment with anti-TNF

antibodies and methotrexate every eight weeks arrested cartilage and

bone devastation in about half of 428 patients. Not only did joint

destruction stall in these individuals, but the results hinted that

the body managed to repair previous injury. These results gave

Centocor sufficient results to apply for FDA approval of their

antibody. Even after two years on the combination regimen, the

patients continued to do well.

Although Centocor was the first company to sign on to anti-TNF

antibody trials for rheumatoid arthritis, Feldmann and Maini's 1992

disclosure of their results prompted other companies to compete

vigorously and test their own anti-TNF agents. Wyeth/Immunex's

etanercept (Enbrel®) was approved in November 1998, a year before

Centocor's drug was approved for use in combination with methotrexate

for rheumatoid arthritis. Three drugs that restrain TNF - Remicade®,

Enbrel®, and Abbott's adalimumab (Humira®) - are now licensed in the

U. S. and in Europe. Patients inject themselves under the skin from

twice a week (Enbrel) to once every 2 weeks (Humira), or come to the

clinic every eight weeks for an infusion into a vein (Remicade®). All

of these agents pack an effective punch; for many patients, they are

continuing to keep the disease in check even after five years of

treatment. Several more TNF blockers have been tested and appear

promising in clinical studies, but have not yet been approved.

The clinical trials established that the treatment helps many people -

but they also revealed a gap. Approximately 60% of the individuals

studied responded to anti-TNF therapy. Because these patients

included only those with severe disease whose illness defied other

therapies, that statistic is impressive - but it leaves room for

improvement. In an attempt to help people who derive no benefit from

treatment and to better understand the molecular mechanism of the

disease, Feldmann and Maini have dug deeper into how anti-TNF therapy

works. As predicted, amounts of particular cytokines in the blood and

joints ramp down after treatment and, presumably as a consequence,

inflammatory cells stop gravitating toward the ailing joints.

Furthermore, new blood vessels - which normally nourish the

congregating immune cells - no longer form. Together, these

observations suggest that the treatment scrambles signals that would

otherwise draw troublemaking cells to the joints and minimizes their

ability to gather. Additional experiments hint at how the anti-TNF

agents deter - and possibly even heal - joint damage. The treatment,

for example, depletes a particular type of tissue-destroying enzyme.

Such information might provide information that could goad

researchers toward the development of alternative treatments for

patients with recalcitrant disease.

The success of anti-TNF-based therapy for rheumatoid arthritis led to

clinical trials to assess these agents' ability to curb other chronic

illnesses in which cytokines become unruly. The first was Crohn's

disease, an inflammatory condition of the bowel. Anti-TNF antibody

ameliorated the illness, and Remicade® is now approved for the

treatment of severe Crohn's disease. More recently, scientists have

conducted successful trials of agents that foil TNF in other chronic

diseases of excess inflammation, and the drugs are now licensed to

treat juvenile rheumatoid arthritis, ankylosing spondylitis, and

psoriatic arthritis.

All in all, therapies that muzzle TNF have benefited approximately

400,000 people, approximately 70% of whom suffer from rheumatoid

arthritis. By pursuing their vision, Feldmann and Maini turned a

speculative hypothesis into a potent discovery that will aid myriad

patients for years to come.

Citation text by Strauss, Ph.D.