The chimera that roared: Remicade royalties to fund $105 million biomedical research, education at NYU

Janis Kelly

August 18, 2005

August 18, 2005

New York, NY - Although many prizes have been awarded to the doctors who worked out how to use tumor-necrosis-factor (TNF) inhibition to treat rheumatoid arthritis (RA), the antibody they tested, now known as infliximab (Remicade, Centocor), was developed by a relatively low-profile team of researchers at New York University (NYU) and Centocor. The university had taken a chance on a young ¿migr¿ doctor in 1965 and will soon reap the fruits of that good deed, to the tune of about $105 million. Dr Jan T Vilcek, a professor of microbiology at NYU School of Medicine, is donating a percentage of his royalties from inventing infliximab to that institution, where the money will support both research and education programs [ 1 ].

Vilcek discussed with rheumawire his role in the development of infliximab, more recent work by his group on another promising new approach, and his hopes for what this generous gift, one of the largest ever given to a US university, might make possible at NYU.


"They took a risk . . . "



Dr Jan T Vilcek



Vilcek, who was born in Bratislava, in then-Czechoslovakia, wound up at NYU after surviving the Nazi Holocaust as a child and communism as a young doctor. He and his wife, Marica F Vilcek, defected to the West in 1964, after being allowed, "probably by mistake," he says, to visit Austria. He joined the New York University medical school faculty in 1965.

NYU gave me a faculty position when I came to this country. I was 31 and had no prior experience anywhere outside communist Czechoslovakia.

"NYU gave me a faculty position when I came to this country. I was 31 and had no prior experience anywhere outside communist Czechoslovakia. It was a courageous thing for NYU to do. They took a risk, and I think it worked out," Vilcek has said .

Infliximab was the product of Vilcek's long-standing interest in interferons (IFNs).

"Interferons were among the earliest identified members of the large family of cytokines that also includes TNF. In the early 1980s, my colleagues and I were producing IFN-  in mitogen-stimulated mononuclear cells from human peripheral blood. We noticed that IFN-  preparations were cytotoxic for some cells, but that much of the cytotoxicity was lost when IFN-  was purified. Eventually we figured out that there were other cytokines produced by the mononuclear cells along with IFN- , including TNF. We became interested in TNF mainly because we realized that IFN-  and TNF were not only produced together but also acted in concert and often had synergistic activity," Vilcek tells rheumawire.

As early as 1983, Vilcek and his colleague Dr Junming Le had begun to wonder whether monoclonal antibodies to cytokines, especially to interferons and TNF, could be medically useful.

We proposed to collaborate on the development of such antibodies with the then-fledgling biotechnology company, Centocor.

"We proposed to collaborate on the development of such antibodies with the then-fledgling biotechnology company, Centocor. Thanks to the foresight of Centocor principals Michael Wall and Dr Hubert Schoemaker, Centocor funded our work at NYU. However, initially we did not have enough purified TNF to successfully immunize mice. The situation changed in about 1986 when the human TNF gene was cloned by Genentech scientists, and pure recombinant TNF protein became available," Vilcek recalls.

Producing a mouse antibody to human TNF with desirable characteristics was an arduous process, and even more time went into creating a human-mouse chimeric antibody, labeled cA2. They completed preclinical evaluation of that antibody, now known as infliximab, in collaboration with Centocor scientists in 1991.

"Soon thereafter, Drs Marc Feldmann and Ravinder Maini in London convinced Centocor to let them try the cA2 antibody in patients with rheumatoid arthritis. Their trial marked the first successful application of an anti-TNF agent in humans. Then followed the demonstration, by Dr Sander van Deventer in Holland, that cA2 is effective in patients with Crohn's disease. The rest, as they say, is history," said Vilcek, who is coholder of infliximab patents with Le and others.

TSG-6: The next big thing?

Vilcek's group subsequently did a lot of work and filed a batch of patents on TNF-stimulated gene 6 ( TSG-6). Is TSG-6, rheumawire wondered, the next big thing?

In addition to its anti-inflammatory activity, TSG-6 also shows chondroprotective action, raising the possibility that it might be effective not only in RA but also in osteoarthritis.

"TSG-6 was discovered in my laboratory by a talented former graduate student, Dr Tae-Ho Lee. We were trying to understand the growth-stimulatory action of TNF in normal human fibroblasts. Toward this end, we decided to see what genes were activated in fibroblasts under the influence of TNF. One of the new genes identified was TSG-6. It turned out that TSG-6 is not important for the mitogenic action of TNF, but, to our surprise, my colleague Dr Hans-Georg Wisniewski and others found that the TSG-6 protein has potent anti-inflammatory activity," Vilcek says.

Specifically, TSG-6 protects mice from collagen-induced arthritis and other forms of experimental arthritis. "In addition to its anti-inflammatory activity, TSG-6 also shows chondroprotective action, raising the possibility that it might be effective not only in RA but also in osteoarthritis," Vilcek says. "Its mechanism of action seems quite different from that of the anti-TNF agents, and we are therefore working toward a possible clinical application of TSG-6 protein."

Meanwhile, Remicade royalties will fund biomedical research

Vilcek says that his gift will be used for a variety of programs, mainly in the basic sciences. "A portion will pay for the establishment of two endowed professorships in the department of microbiology, of which I have been a member for over 40 years," he says. "Another portion will be used to establish an endowment that will generate funds for fellowships for graduate students and postdoctoral fellows. There are also plans to use the money for the hiring of new scientists, for the purchase of major equipment, and for the renovation of existing research laboratory space. My hope is that the gift will significantly strengthen the basic sciences at NYU School of Medicine and help to secure its position as a premier biomedical research center for years to come."

Source

  1. New York University School of Medicine. Remicade coinventor and NYU professor of microbiology Jan Vilcek, MD, PhD, pledges $105 million to NYU School of Medicine [press release]. August 12, 2005. Available at: http://www.med.nyu.edu/communications/news/pr_118.html.


 

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