Serotonin, Repurposed

From bench to business

Roth completed his PhD in biology at Case Western Reserve University in 1968. He did a two-year postdoc at Johns Hopkins studying complex carbohydrates and enzymology, then took a faculty position in the biology department. In 1982 Roth moved to Philadelphia and became the head of the University of Pennsylvania's biology department. He spent 10 years working on a group of enzymes responsible for assembling sugar chains, called glycosyltransferases. Roth's group figured out a way to isolate the enzymes required for assembling particular sugar groups, something that had eluded the field until then.

In 1990, the venture capital group Paramount Capital approached Roth with an interest to license the group's technology and use it to make sugars commercially. "I said 'why do you care?''' Roth recalls. "It turns out there were a million reasons, that I had no idea about." Up until then "I was a professor all the way, I had no commercial interest, zero desire about being a business man."

Paramount was looking to start up a company that manufactured infant formula containing human milk oligosaccharides - sugars found in breast milk that are known to boost infant immune response. Roth thought it was a great idea, and in 1990 took a leave of absence from UPenn to join the new company, called Neose Technologies, as its chief scientific officer.

After two years, Roth resigned his professorship at UPenn (although he's still an adjunct professor) and joined Neose permanently, becoming its new CEO in 1994. During his tenure he accrued numerous prizes for his contribution to the company, and the glass and wooden awards now line the broad window sills of his corner office at Immune Control, in a West Conshohocken office building. Neose grew quickly to more than 100 employees and raised nearly $200 million for research, all the while creating partnerships with pharmaceuticals such as Wyeth and Abbott Laboratories. In 1996 Neose went public and at one point, says Roth, the company had a market capitalization near $800 million.

"A lot of people don't understand the difference between a public and private company," Roth says. With a public company "you have quarterly reports, SEC documents and filings; if anything unusual happens, and it's material, you have to write a press release - and figure out what's worth writing a press release for." In addition, shares fluctuate daily and as CEO of the publically traded Neose, Roth's office was routinely flooded with phone calls from disgruntled shareholders. "It just stopped being fun."

The serotonin surprise

In 2002, shortly before Roth was set to retire from Neose, he got a call from Katherine Doyle, a patent attorney at the law firm Drinker Biddle, asking him to hear a presentation by a group of venture capitalists and Drexel University scientists led by Brad Jameson. In the meeting, Jameson explained that while designing drugs to block autoimmune response, he had created a molecule that was highly efficient at killing T cells. But when the structure of the molecule was compared to that of other known drugs, the group found it was homologous to a serotonin antagonist - suggesting serotonin played some unknown role in immunity. At first, the researchers were as shocked as Roth was on hearing this. "How could serotonin be involved in immune response and nobody knows?" Jameson recalls of his first reaction to the discovery.

During the meeting, Roth recalled other interesting ways that immune response is altered in the human body, including one of the classic problems in mammalian embryology: why the female body doesn't reject its fetus, even though every baby has a different major histocompatability complex from its mother and should, by definition, trigger an immune response. In 1998, a group at the Medical College of Georgia showed that an enzyme called IDO is upregulated and catabolizes tryptophan - an essential amino acid for protein synthesis. Without tryptophan, the mother's T cells can't survive and mount an immune response. "So this is kind of stuff going through my mind when I'm hearing this presentation," says Roth, and he mentioned it to the group. Jameson's eyes lit up and he told Roth that tryptophan is an immediate precursor to serotonin. "Then it started to fall into place, and I started thinking maybe there is something going on here," says Roth. If the scientists' assumptions were right, serotonin also played a key role in activating immune response.

After the meeting Roth read a pile of unrelated literature that linked serotonin to immune function. About a month later he paid a visit to Leigh Thompson - former chief scientific officer of Eli Lilly when Prozac was being developed. According to Roth, Thompson said he'd always thought that Prozac played some kind of role in the immune system, rather than working solely in the brain as a selective serotonin reuptake inhibitor. Roth was convinced, and told the group he would be the CEO of the new company.

Jameson continued to work on serotonin and immune response. He followed up a few years later by evaluating the effect of blocking each of the 14 known serotonin receptors in the central nervous system and observing the effect on human T cells.3 Blocking one receptor in particular, called 5-HT1B, stopped T cells in their tracks, causing their nuclei to condense in the fashion of classic programmed cell death.

As a virtual company, the skeleton crew of four employees at Immune Control handles the outsourcing of all the lab and clinical research. Although there was volumes' worth of literature on serotonin, and serotonin antagonists had been created, they all shared the same flaw: they crossed the blood-brain barrier. This is a good thing if manipulating serotonin in the brain, a bad thing if you're trying to block lymphocyte formation in autoimmune disease and don't want to cause neurological side effects. Scientists working with Immune Control - mostly based at commercial labs, but some also at academic labs such as Tufts University and the University of Medicine and Dentistry at Newark - have designed molecules that solve this problem. So far, the results are surprising.

One molecule that Immune Control developed, called C-027, acts on one of the serotonin 5-HT receptors in an asthma rodent model. "We found that the [C-027] is as effective or near effective as steroids in not only blocking the inflammation but in attenuating the bronchial constriction as well," says Reynold Panettieri, professor of medicine and director of clinical care of asthma patients at UPenn, and a contract researcher for Immune Control. Inflammation in asthma is caused, in part, by T cell localization to lung tissue. By blocking the serotonin receptor, Panettieri and his group have unpublished results showing that C-027 derails T cell proliferation in the lungs, both in human lung tissue and in vivo rodent models. In addition, C-027 is effective at a dose 30-times smaller than steroids, the classic treatment for asthma, he adds.

A group at the Dana Farber Cancer Institute demonstrated in vivo and in vitro that two of Immune Control's compounds (ICI-735 and ICI-685) target multiple myeloma cell lines, and were toxic to cells by inducing apoptosis.4 A Phase Ia safety trial of fluphenazine hydrochloride - a known serotonin antagonist - in patients with multiple myeloma was well tolerated and the high dose patients achieved disease stability.

Roth has told his investors that by the end of this year the company will chose one of his three lead compounds and develop an IND application. So far, he's done a good job of convincing investors that the serotonin-immune theory is legitimate; Immune Control has raised close to $25 million and is in discussions with two pharmaceutical companies to continue developing the technology. But winning over fellow scientists could be another story. "I believe I could convince any scientist in the world, if they take time to read the papers, that the serotonin hypothesis is true in vitro," says Roth. "There's no way you can read those papers and walk away saying it's not true."

The serotonin-immune hypothesis holds promise, admits Randy Blakely, director of the Center for Molecular Neuroscience at Vanderbilt University. "Serotonin has a somewhat still ill-defined role in normal immune system function," he says in an E-mail. "But serotonin transporter and receptor proteins are expressed on different classes of lymphocytes, so a biological role such as [what Immune Control is pursuing] is not outside the realm of possibility."

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