By David N. Leff
A newborn infant enters a world fraught with mortal danger.
From the first few hours of life to about five days, he (slightly more often than she) may be stricken with early-onset neonatal sepsis. This often takes the form of group B streptococcal (GBS) pneumonia. That life-threatening pulmonic infection is the work of Streptococcus agalactiae, which also infects the udders of cows with mastitis.
The bacterial toxin secreted by GBS kills from 50 percent to 85 percent of new babies who contract it within hours after birth, with preemies getting the worst of these odds. A child infected between one week and three months of life is more likely to contract late-onset GBS bacterial meningitis, for which mortality is only 20 percent.
After thus taking it out on the youngest of the young, GBS continues to inhabit human tissues and cells, but harmlessly. Now its lethal carbohydrate toxin is trying out for a career in community service.
Back in 1981, at Vanderbilt University, in Nashville, Tenn., a group of pediatricians -- and one biochemist named Carl Hellerqvist -- were examining a number of GBS pneumonia cases in children. Its toxin, they perceived, attacked newly formed blood vessels in the lungs. The research clinicians isolated and purified the active, virulent compounds in the GBS-toxin, which now bears the name CM101.
CM stands for CarboMed Inc., of Brentwood, Tenn., a company Hellerqvist co-founded in 1990 to diagnose and treat infectious diseases and cancer. He serves as a scientific consultant to the company, which holds licenses to his CM101 patents from Vanderbilt and funds his research.
Product Targets Cancer-Feeding Angiogenesis
The product owes its anticancer credentials to its antiangiogenic activity. Angiogenesis promotes the infiltration of inflammatory cells into tumor tissue, and thereby the formation of granulation tissue, which produces scarring.
Hellerqvist and his CM101 laboratory colleagues hypothesized that this scar-stopping property might well serve to limit or correct injury to the spinal cord.
"Since we had done some research on mice with tumors and wounds on the skin," biochemist Barbara Wamil told BioWorld Today, "we discovered that CM101 can accelerate wound-healing, and reduce the amount of formation of granulation tissue, which forms scars. That gave us the idea to try it on injured spinal cords, to reduce the scarring between axons." Wamil is a member of Hellerqvist's lab.
"The key to preventing serious damage in spinal cord injury," he said, "appears to be blocking the inflammatory process, which is the body's effort to clean up the damaged tissue, but which becomes self-destructive." CM101 can block that process, he added, "and then the body has a tremendous ability to recover."
Concretely, Hellerqvist and his associates reasoned that CM101's ability to inhibit formation of new blood vessels might thus prevent scar tissue from forming on the spinal cord after injury, and thus might allow severed nerve cells to reconnect.
Putting this concept to the test, they mounted in vivo and in vitro trials, reported in Tuesday's Proceedings of the National Academy of Sciences, dated Oct. 27, 1998. Their paper, of which Hellerqvist is senior author, bears the title, "CM101-mediated recovery of walking ability in adult mice paralyzed by spinal cord injury." Barbara Wamil and her surgeon-husband Artur are co-lead authors.
First, they divided their muster of 40 mice into 26 designated to receive CM101 therapy after experimental spinal-cord injury, and 14 controls, assigned the injury only. Next, all 40 had their spinal cords randomly crushed, such that 15 "monoplegic" mice lost the use of both legs on one side, and 25 "paraplegics," all four limbs on both sides. They induced this paralysis under anesthetic by the standard research method of crushing the spinal cord so as to sever selected neuronal axons within it.
"Most accidents that damage the spinal cord are crush injuries," Wamil noted. "That's why we used the crushed model. A cut is very seldom."
Within one hour of the cord-crushing surgery, the co-authors injected doses of CM101 systemically into the tail veins of the 26 treatment cohorts, and repeated this therapy on five alternate days. Controls got placebo injections.
Within the first 24 hours after their spinal cords were crushed, eight of the 15 control mice had died, but all 26 treated animals survived. Three more controls died during the next 28 days, as did two of the 26 CM101-treated animals.
Of this group, 24 were able to walk again within two to 12 days, and 17 retained this ability through 120 days, when the researchers sacrificed them for histology studies.
Translating these preclinical in vivo results into human victims of spinal cord injury is problematical, Wamil pointed out. "It's very difficult to know what will happen in humans," she said, "because spinal cord drugs that work in mouse models never work in humans.
"In fact," she added, "CM101 doesn't work with many species. It's a bacterial derivative related to mice, sheep, bovines and humans. But it doesn't work in rats, for example."
Zeneca Holds License For CM101 For Cancer
In July 1997, CarboMed licensed CM101 as an anticancer agent to Zeneca Ltd., of Wilmington, Del., a subsidiary of London-based Zeneca Group plc.
"We have completed a Phase I study of CM101 with 27 patients here at Vanderbilt," Wamil said. They were of differing tumor types, including a few adenocarcinomas. There were some indications of tumor responses, including tumor shrinkage in three patients, and stabilization in two."
She added that "Zeneca is working with CarboMed now on developing CM101 for a Phase II clinical trial, probably in 1999." *