New Potential For Interferon

Pestka’s Advice For Young Scientists

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This article by Barbara Fox was prepared for the August 28, 2002 edition of U.S. 1 Newspaper. All rights reserved.

New Attacks on the Big C

Nearly every American family has lost a loved one to

the Big C: cancer. Unlike other diseases, which come in just one or

two virulent versions, cancer can strike dozens of different ways

— through the blood, through a body organ like the breast, lung,

pancreas, colon, or prostate, or even through the skin. And although

researchers have come up with dozens of different ways to prevent

and treat it, to the tune of $60 billion a year, more than one-third

of the people in the United States will be diagnosed with cancer in

their lifetimes. Cancer remains the second leading cause of death

in the United States, exceeded only by heart disease.

Surgery, radiation, and chemotherapy are the traditional ways to stop

cancer cells from growing, but the chemical and radiation poisons

that kill cancer also kill normal cells and cause bad side effects.

News of the latest cancer cures are therefore sure-fire headline grabbers.

Among them:

Anti-angiogenesis. Still in the research stage, this method

aims to cut off the blood supply to starve the cancer cell. Not yet

approved by the FDA.

Apoptosis. This method uses a receptor to talk to the

cancer cell and convince it to commit suicide. Normal cells know when

to stop living, but cancer cells do not. No approvals yet from the

FDA.

Genetic approaches, such as using a virus to deliver a

gene to a cancer cell which will alter the properties of the cell.

Or antisense therapy — designing a strand of nucleic acid to block

the tumor’s production of harmful protein. No approvals yet from the

FDA.

Vaccines. Using proteins or viruses to mount an immune

response to proteins found on tumor cells. In cancer, this is a therapeutic

approach to prevent the cancer from spreading. No approvals from the

FDA.

Interferons. A group of compounds approved by the FDA

for use in certain leukemias, such as hairy cell leukemia, and certain

forms of melanoma.

Monoclonal antibodies. This method sends antibodies, like

guided missiles, to attach a "bomb" to cancer cells and destroy

them — or to convince the cell to act more like a normal cell.

Two antibody therapies have been approved by the FDA for cancer, one

for lymphoma, the other for breast cancer.

In the shadow of those screaming headlines, scientists in biotech

companies and big pharmas keep on plugging away in their labs. On

Wednesday, September 4, at 3 p.m., at the Merrill Lynch conference

center, those who attend the Princeton Chamber trade fair and U.S.

1 technology showcase will have the opportunity to hear about progress

being made by two of those companies. Lisa Drakeman, CEO of Genmab,

and Sidney Pestka, founder of PBL Biomedical Laboratories, will talk

about what their firms are doing to move toward a better cancer cure.

Genmab’s technology, monoclonal antibodies produced by genetically

engineered mice, is one of the trend favorites for 2002. In contrast,

PBL’s technology focuses on a method, interferon research, that had

its heyday 15 years ago but still holds promise today.

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New Potential For Interferon

Insulin was the first important biological product produced

by genetic engineering, and interferon was the second. Interferons

are among the proteins — some of the human body’s 30,000 to 50,000

different proteins — that regulate the immune system.

In the early 1990s, when drug companies discovered that interferon-based

drugs could successfully treat AIDS, interferons made the headlines.

Now these biotherapeutics are still being used for hepatitis, multiple

sclerosis, AIDS, and some forms of cancer, but interferon research

is seldom touted. Attention has moved on to trendier areas, such as

gene therapy, yet some researchers cling to their interferon work.

They insist this could lead to a much better understanding of how

the cells communicate with each other, which could lead to important

new drugs.

Sidney Pestka remains loyal to the interferon cause. "I believe

that interferon has the potential to treat cancer like no other pharmaceutical

agent I know," says Pestka. "Interferon has been disappointing

as an anti-cancer agent — not because it isn’t powerful enough,

but because it is too powerful. We simply need to figure out how to

harness its potential."

This year Pestka received two significant honors, one of five National

Medals of Technology awarded by President George W. Bush and a Fleet

Bank prize for entrepreneurs that garnered $20,000 split between the

scientist and a charity (U.S. 1, June 26). These honors — one

for scientific exploits, the other for business achievements —

represent Pestka’s unusual status. Not only does he lead an academic

team to do important research on interferons, but he also founded

a profit-making business that is run by his son, Robert.

Rare is the scientist whose work generates a biotech business, let

alone one that is profitable in its early years. Rarer still in the

biotech world is a father-son combination like this.

Pestka Biomedical Laboratories (PBL) is 12 years old, has 25 employees,

and is the world’s largest maker of interferon products for research

laboratory use. It has generated $5 million in profits that have been

injected back into the business. This week CEO Robert Pestka will

triple the company’s space with a move from incubator quarters at

100 Jersey Avenue in New Brunswick to 10,000 square feet in Piscataway.

Sidney Pestka, founder and chief scientific officer, will keep his

12-person laboratory at UMDNJ.

Interferons, produced in the body by white blood cells, are the infection

fighters of your body. When you suffer from headache, fever, muscle

aches, and chills of a viral cold, interferons are at work and the

"symptoms" are interferons’ side effects. For tumors, interferons

can "blow the whistle" by stopping the tumor’s growh, restoring

normal intra-cellular communication, and mustering the immune system’s

apt response. But current delivery methods are way too strong and

cause too many side effects to be useful for any but the most dire

cases.

Big pharmas sell nearly $5 billion of interferon drugs annually, say

the Pestkas. Roche holds the patents for 12 forms of alpha interferon

and one beta species, and these patents protect a worldwide market

that includes licenses to the major companies for such ills as Kaposi’s

sarcoma (a tumor associated with AIDS), hepatitis B and C, and multiple

sclerosis. These FDA-approved drugs, prepared as injectable fluids,

are based partly on work that Pestka did at Hoffman LaRoche in the

1980s, and the earliest of these patents has just expired.

In contrast to Roche, PBL makes reagents (chemicals used for research

purposes), and it sells small quantities of these interferon products

in a very pure form — specks in vials, shipped with dry ice, to

laboratory scientists. This income helps to fund PBL’s own drug discovery

operation.

In its inventory PBL has 20 types of human interferons and another

15 animal interferons, all sold in nanogram quantities at prices ranging

up to $200. It makes large initial batches of each product and rarely

has to repeat that process. These 100 products are sold in 25 countries

around the world, directly to laboratories and through some of the

larger biochemical companies. PBL’s exclusive products are its assay

kits that enable scientists to easily measure their own interferon

samples without having to create a test themselves.

"We started the way most businesses don’t, with a viable product

line that gives us income, versus raising $.5 million to do some initial

work. Outside investors don’t really know how to look on us,"

says Robert Pestka, who is considering separating the cash cow side

of the business from the new drug side. He wants to clarify the firm’s

financial position in order to attract the investment needed for clinical

trials.

Sidney Pestka is the son of a Polish steelworker, tavern

owner, and ingenious inventor. He carries on his father’s trait of

being able to think outside the box. Living first in Brooklyn and

then in Trenton, he graduated from Trenton High and majored in chemistry

at Princeton University, Class of 1957. After graduating from the

University of Pennsylvania medical school he did research at the National

Institutes of Health and the Roche Institute of Molecular Biology.

He was a pioneer in purifying many of the human interferon alpha and

interferon beta species in the late 1970s and early 1980s.

Pestka was department chair at Robert Wood Johnson University Medical

School when the university asked him to start a company. "The

university had suggested that Sid set up a business of his own, mainly

to show that the university was helping to stimulate commercial development,"

says son Robert. Sidney and his wife Joan started the company in their

basement and were employing two part-time scientists when Robert joined

the firm.

Though Robert’s training is as a civil engineer, he had been working

in his father’s laboratory since ninth grade and entered Princeton

University as a molecular biology major, so he knows the basics of

this technology. "After two years, I had to rebel," says Robert,

telling of his switch to architecture and civil engineering. Graduating

in 1988, he spent four years doing CAD design, construction, and project

management for a Japanese company. When he joined PBL he moved it

out of the basement and into the Rutgers incubator on Jersey Avenue.

Now Robert drives to work from Manhattan, where his wife, Kazumi,

works as a translator and interpreter. He has even had a chance to

dust off his architectural skills. At the time of a telephone interview

he was managing a renovation of the new facilities. "One thing

I can guarantee is our employees will be very happy. Now we have old

laboratory desks scattered around the building and had maxed out our

space. These new facilities are first class," he says.

"We have grown one step beyond the family business," says

Robert. "We have a CFO, a general manager with a PhD who runs

the reagents business, a research director who interfaces with Sid

and runs the drug development program on a day to day business, and

Joan, my mother, who is currently office manager and HR officer."

Interferons were boosted as possible cancer cures in the early 1980s,

and when it became obvious that they weren’t the cure for cancer

there was some skepticism, says Robert Friedman, chairman of the pathology

department at the Uniform Services Medical School in Bethesda, Maryland.

"Interferon may not be the final answer to cancer, but understanding

how it works may lead to some very effective therapies."

"There may be a `lull’ in terms of interferons as a therapy unto

themselves, but interferons have an enormous biological modifier potential.

They alter the biology of the cancer cell and the expression of different

genes in the cancer cell," says Jeffrey Schlom, chief of the laboratory

of tumor immunology and biology at the Center for Cancer Research

at the National Cancer Institute. "Pestka has been leading in

making new interferons that have different properties and making genetically

modified interferons."

Sidney Pestka would argue that interferon alpha uses several of the

currently known ways of fighting cancer, including apoptosis, anti-angiogenesis,

and metastatic control. "Interferon has a powerful anti-proliferative

impact that slows the reproduction of tumor cells and destroys metastatic

cancer cells dispersed throughout the body," he says. "As

the most powerful anti-angiogenic agent known, interferon also inhibits

the growth of blood vessels necessary to feed a tumor. Finally, interferon

stimulates apoptosis — the death of tumor cells."

Nevertheless, interferon is most well known for acting as a vaccine

that helps the immune system recognize the diseased cell as a cell

to be attacked. It activates the immune system’s cells — cytotoxic

lymphocytes, natural killer cells, macrophages and dendritic cells

— to attack the cancer cells. What results is not only a direct

attack on the primary tumor, but also the "education" of the

immune system, which is now equipped to find and destroy the metastatic

cells that have escaped from the primary tumor.

Interferon is supposed to be the best late stage treatment for melanoma,

so PBL is working on that. "We ask the question, why didn’t

interferon make the impact that everyone was hoping for. We think

it was because of how it was administered to cancer patients then

and today — too much at once injected in the blood stream, producing

side effects that make patients sick," says Robert.

PBL is also working on a way to inject the interferon directly into

the tumor to stimulate the immune system, as well as on a sustained

release system to reduce the number of injections needed. Patents

have been applied for.

Another new research area is monoclonal radioactive isotopes, funded

by a $1.2 million two-year grant from the NIH. "Our technology

offers a gentle way to label the antibodies with radioisotopes in

a way much more effective than current chemical methods that can deactivate

or denature the antibody and cause toxicity problems," says Robert,

who believes the potential market for this could be as much as $10

billion.

Perhaps the most far-reaching of PBL’s technology involves what the

Pestkas call "ultra" interferons. Son Robert says that 10

years ago his father hypothesized that disease cells mutate all of

their proteins, and that this enormous resource of unique, naturally

occurring proteins in cancer cells could be harnessed to treat the

disease. These proteins use the natural pathways of the body’s immune

system. "We looked in cancer cells, starting with interferons,

for new variants of interferons, and we found them, theoretically

an unlimited number. Some of these new proteins, which we call ultra

interferons or ultra human growth hormones, are 15, 25, or even 85

percent better than those currently used," says Robert.

The ultra interferons could be particularly useful to patients who

are getting allergic reactions from the interferons they are currently

using. And because ultra interferon material has been selected to

be effective against a particular disease, less is needed for treatment,

which means the drug is less expensive and has fewer side effects.

Another cost-cutter is that the ultra interferons can get very useful

initial testing on mice.

PBL has already purified 23 ultra interferon alphas. Three were chosen

for further research and preclinical trials, and PBL hopes to partner

with larger companies to develop some of the other ultra interferons

for additional diseases.

"Since my father founded PBL 12 years ago, we have built three,

maybe four technology platforms that have great potential," says

Robert Pestka. "He developed interferon for human use. He bridged

the gap between discovering interferon and making it practical to

treat people in large groups. Many of his groundbreaking discoveries

came about because he went against the prevailing thinking of the

time."

Sidney Pestka agrees. "I have been doing that all my life. You

have to do what you think makes sense. Now my early work is being

listed as dogma. No one was interested in my work on interferon at

the Roche Institute. I went ahead anyway, and it made an impact. There

have been advances by other companies, but our goal is to make a real

dent in cancer."

"Cancer research has gone through all sorts of fads," says

Sidney. "We had the genomic fad, and right now we have the proteomic

fad. They are very important but I don’t think they should be oversold.

I don’t want to downplay proteomics and genomics because I use them

— they can add additional knowledge about how interferons work.

Just studying genomics and proteomics is not going to lead us to a

cancer cure. To understand the biology of cancer, you have to integrate

everything."

PBL Biomedical Laboratories, 131 Ethel Road West,

Piscataway 08854. Robert Pestka, president and CEO. 732-777-9123;

fax, 732-777-9141. Www.pblbio.com

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Pestka’s Advice For Young Scientists

Persevere. Good scientists (and good science) will always

be funded.

Focus on important problems. It takes no more effort to

concentrate on important problems than on trivial ones, and the rewards

are far greater with the former.

Enjoy the effort.

Collaborate. Pestka cites the establishment of excellent

collaborations as a key to much of his success.

Be good mentors. Nurture the next generation of scientists.

Focus on personal responsibilities and keep a balance

in life.

These comments are from Patricia Fitzgerald-Bocarsly’s 1995

interview with Sidney Pestka, who was then president of the International

Society for Interferon and Cytokine Research.


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