Molecular makeover

Molecular makeover By Tia Ghose Illustration of Lodamin 3-D structure When postdoc Don Ingber noticed strange fuzz contaminating one of his endothelial cell cultures in 1985, his first instinct was to hide it from his advisor, Judah Folkman. Ingber was studying the role of blood vessel cell shape in growth and survival at Harvard Medical School and Children's Hospital in Boston, Mass. He noticed that cells under the fungus died, while those a

Tia Ghose
May 1, 2009

Molecular makeover

By Tia Ghose

Illustration of Lodamin 3-D structure

When postdoc Don Ingber noticed strange fuzz contaminating one of his endothelial cell cultures in 1985, his first instinct was to hide it from his advisor, Judah Folkman. Ingber was studying the role of blood vessel cell shape in growth and survival at Harvard Medical School and Children's Hospital in Boston, Mass. He noticed that cells under the fungus died, while those a little further away were round—a sign of sickly cells. Cells at the edge of the dish looked flat and healthy.

Though he was curious, the overloaded postdoc already "had about 40 million projects. The last thing I wanted [was] to have another project," he says. He knew Folkman was "the type of person who would get really excited," and convince him to look into it, so he scooped the fungus into a test tube, locked the sample...

Now a cell biologist and bioengineer at the same institutions, Ingber finally cultured the fungus several months after he first discovered it, and found that the fungus consistently prevented new capillaries from forming. In the 1970s, Folkman had pioneered the idea that inhibiting angiogenesis, or new blood vessel formation, could slow cancer's progression, so the mystery compound presented an exciting way to verify Folkman's hypothesis.

Folkman's group created a more potent version of the active ingredient, which they called TNP-470, and handed off development to TAP Pharmaceuticals, a joint venture between Takeda Pharmaceuticals and Abbott Laboratories. TNP-470 blocks methionyl aminopeptidase 2 function, disrupting the cell cycle and halting angiogenesis.

In phase II trials, TNP-470 shrunk tumors by 25–30%, says Roy Herbst, a thoracic medical oncologist at M. D. Anderson Cancer Center in Houston, Tex., who was involved in the trials (J Clin Oncol, 20:4440–47). In a few cases patients went into complete remission, Herbst says. But the drug crossed the blood-brain barrier and caused neurological problems: altered gait, slurred speech, and impaired memory.

What ultimately killed the drug, however, wasn't the neurotoxicity, but problems with formulation. "The drug was crystallizing in the tubing that was used for the continuous infusion," Herbst says. Rather than improve the delivery method, TAP dropped TNP-470 development.

Folkman, however, was "incredibly persistent" in pursuing ideas that he believed in, says Ofra Benny-Ratsaby, a polymer chemist at Children's Hospital in Boston, Mass. And Folkman wasn't ready to give up on TNP-470. So in 2001, he recruited polymer chemist Ronit Satchi-Fainaro to formulate a new drug. It tethered TNP-470 to a larger polymer, making it too bulky to enter the brain and cause neurological problems. Though promising, the new version still had to be given intravenously.

In 2004, Benny-Ratsaby began developing an oral formulation of TNP-470. The drug, called Lodamin, binds TNP-470 into the hydrophobic core of a polymer. In last year's Nature Biotechnology, they showed that Lodamin makes it through the stomach intact. Its small size—between 10 and 100 nm—enables it to be absorbed through the intestine. Yet it was still too big to enter the brain, which prevented neurotoxicity, Benny-Ratsaby says.

In mice, Lodamin halted blood vessel growth and shrunk both lung and melanoma tumors, Benny-Ratsaby says. It's too early to say whether it will be as effective in humans, since a key element of conjugated drugs is how much is actually absorbed, says Bob Langer, a bioengineer at the Massachusetts Institute of Technology who was not involved in the studies. If successful, Lodamin will use a different mechanism than existing angiogenesis inhibitors, "so there's a whole pathway that could be targeted," says Craig Crews, a Yale cell biologist who studies TNP-470 but was not involved in the research. A company called SyndevRx has licensed the compound and is moving towards clinical trials.

In January of 2008, Folkman died of a heart attack, the weekend after they submitted the Nature Biotechnology paper for review (it was published six months later). But his vision and enthusiasm are still motivating the lab, Benny-Ratsaby says. At every lab meeting he wrote new ideas out on the board, and some of them are still there. "When we want to have some good idea [we] just come to the board."


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