The twisting journey from cA2 to infliximab

The path of scientific discovery from the first glimmerings of an idea to approved treatment is long, twisted, and filled with false starts. Just ask Jan T. Vilcek, MD, PhD, whose lab developed infliximab, the first TNF inhibitor approved for clinical use.

“Most people, including health care professionals, believe there is a very straightforward path from original idea to all the important accolades,” said Dr. Vilcek, professor emeritus at the New York University Langone Medical Center. “The path to infliximab was considerably less than straight.”

In fact, the biologic almost didn’t happen. Dr. Vilcek’s lab developed an inhibitor of tumor necrosis factor — cA2 — in the 1980s. The agent was intended to treat sepsis and failed clinical trials in 1991.

It wasn’t until other researchers unexpectedly stumbled across the ability of cA2 to dramatically reduce symptoms and improve function in rheumatoid arthritis and Crohn’s disease that TNF inhibition became anything more than a biological curiosity.

Dr. Vilcek received the 2018 Eugene J. Van Scott Award for Innovative Therapy of the Skin for his co-discovery of the molecule that became infliximab. He traced the twists and turns in that discovery during the Phillip Frost Leadership Lecture during the Plenary session (P151) on Sunday.

Tumor necrosis factor — TNF — was first described from rodent experiments in 1975. It took another decade of painstaking laboratory work to purify human TNF and work out the genetic sequence that produces the cytokine.

That initial characterization of human TNF and the TNF gene sparked scientific research into the molecule, Dr. Vilcek continued. In 1984, an early genetic engineering company, Centocor, licensed development rights for interferon, TNF, and other cytokines developed by the Vilcek lab. Centocor is now Janssen Biotech.

Researchers soon realized that TNF was responsible for far more than inducing apoptosis in tumors for which it was named. TNF receptors are ubiquitous throughout the body with different effects in different tissue types.

In macrophages and dendritic cells, TNF promotes inflammation. In endothelial cells, it promotes leucocyte infiltration and angiogenesis. In synoviocytes, it promotes cartilage depletion. In osteoclasts, it promotes joint and bone erosion.

“It is easier to list biologic functions in which TNF does not play a role than to list those in which it is active,” said Dr. Vilcek. “One of my students renamed it ‘Too Numerous Functions.’”

His lab identified two TNF receptor types. Type 1 is involved both in cell death and in gene expression, while type 2 is active in gene expression and regulation.

“TNF receptors can regulate antagonistic effects between cell death and gene expression,” Dr. Vilcek explained. “Many of the genes activated by TNF actively inhibit cell death while other pathways lead to apoptosis.”

Blocking the activity of TNF seemed a logical approach to a variety of diseases, he continued. His lab developed a chimeric monoclonal antibody — the human TNF — 70% human and 30% mouse. It was this cA2 antibody that became infliximab.

Initially approved by the FDA for Crohn’s disease, it was not clear that anti-TNF would become a successful strategy. There were concerns that modifying the immune system might open the way for opportunistic infection. There were no data on long-term treatment, or even whether long-term use was possible. The agent was clearly antigenic, raising more worries about use in the real world.

“I have stopped counting how many TNF inhibitors have been approved,” Dr. Vilcek said. “These drugs do not cure the underlying disease. Patients have to continue taking them for perhaps the rest of their lives. But even though they do not cure disease, they alleviate symptoms, induce clinical remission, improve physical function, and allow patients to live normal lives.”


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