By David N. Leff

Most infectious diseases are relatively straightforward.

A specific pathogen - be it virus, bacterium, fungus or parasite - causes its own characteristic infection. A specific disease targets one or a few organ systems, from skin to liver to brain. It answers to a particular array of symptoms, responds to defined therapies, proceeds fairly predictably to either recovery or death.

Not so, septic shock syndrome.

A score or more Gram-negative bacteria share the guilt for this grim reaper of a massive infection, which takes 100,000 lives a year in the U.S. alone.

Besides its lethality, septic shock is multiply paradoxical, with many contradictory features:

Septic shock (SS) is a nosocomial infection - that is, it's hospital-born and bred. Far more of its victims die in intensive care than in their own beds at home. In fact, numerous hospitals are known for the particular species of Gram-negative bacilli they harbor.

But it isn't just the local presence of a known germ. Hospitals propagate SS infection by the very life-saving procedures they practice, notably: in-dwelling catheters; tracheotomies; immunity-depressing cancer chemotherapy; and corticosteroids, to name a few.

Among the early symptoms of SS, besides confusion and altered alertness, is hypotension, brought on by acute circulatory failure. This drop in blood pressure should, by rights, leave the hands and feet chilly. Actually, they become unaccountably warm.

A new and perhaps most striking paradox has just surfaced, in the current Proceedings of the National Academy of Sciences (PNAS), dated Nov, 10, 1998. To wit: "The presence of endotoxin from Gram-negative bacteria signals the innate immune system to upregulate bacterial clearance and/or killing mechanisms. Paradoxically, such responses also contribute to septic shock ..."

The paper reporting this provocative finding bears the title, "Anti-CD14 mAb treatment provides therapeutic benefit after in vivo exposure to endotoxin."

Its senior author is biochemist Richard Ulevitch, chairman of immunology at the Scripps Research Institute, in La Jolla, Calif.

"Our over-all rationale in combating septic shock," he told BioWorld Today, "is that if you could somehow control the cellular responses to the causative agent - endotoxin - at the receptor level, then you could perhaps thwart some of the injurious inflammatory responses, without focusing on one of the body's immune systems versus the other."

That common-denominator causative agent is the bacterium's outer double-membrane coat, consisting of a sugar-plus-fat molecule called lipopolysaccharide (LPS).

Innate Immune Troops Forward To The Front

Well before the body's traditional adaptive defenses - humoral (antibody-secreting) and cellular (T-lymphocyte killer cells) - perceive the toxic LPS, an advance guard - cells of the less-familiar innate immune system - unleash pro-inflammatory mediators against the enemy. Best known of these cytokines is tumor necrosis factor (TNF), which, Ulevitch observed, "is important in up-regulating the host defense, but which can become pathogenic in itself, for reasons nobody really understands."

Those innate immune cells have evolved a cell surface receptor called CD14, which recognizes a pathogen's LPS for what it is, binds to it, and calls in the innate reinforcements. Ulevitch and his co-authors have developed and patented an antibody to CD14, which prevents it from binding LPS in the first place.

In preclinical studies involving 108 test rabbits plus 15 control animals, they found that the CD14 antibody could save 100 percent of the rabbits, while 70 percent of untreated controls died. In one study, they first injected an initial aliquot of LPS into the ear veins of test rabbits at ground-zero time, with follow-up shots at five and 24 hours.

That endotoxin challenge set off a large cytokine response as expected, but did not lead to organ injury or death.

The second, five hours later, apparently lay low, waiting to potentiate the third LPS dose at 24 hours. This did induce lethality by 48 hours in 10 of 31 animals untreated prophylactically with CD14 antibody.

In contrast, all 39 rabbits that got the antibody pre-treatment survived.

ICOS Corp. Planning Human Trials

Scripps has licensed Ulevitch's CD14 antibody to ICOS Corp., of Bothell, Wash. ICOS spokeswoman Lacy Fitzpatrick said the company has "some additional preclinical studies under way, testing the concept in models where the challenge is bacteria, not endotoxin. And these look promising. Then, we expect to go into a Phase I clinical trial by the end of this year."

But what about the adaptive immune system, waiting in the rear until after the innate forces have fired the first round of cytokines? Can a rabbit, or a patient, withstand failure of those follow-on defenses?

"It's not an issue," Ulevitch said, "because the time frame is very different. When you have an infection, the response of the innate immune system is rapid, just hours; it's immediate. On the other hand, in antibody production, or other adaptive immune responses, it takes days or longer. Moreover, the antibody production against endotoxin is generally not neutralizing." That is, it doesn't always block LPS.

Ever since the first fledgling biotech firms started up in the early 1980s, septic shock syndrome has been the therapeutic and marketing target of choice for many. So it remains, but repeated setbacks have made their quest seem like hunting an unholy grail. (See BioWorld Today, March 30, 1998, p. 1.)

Ulevitch explained this succession of dry holes, and his apparent preclinical in vivo success. "Ours is a completely different approach," he said, "because it's not focused on one pro-inflammatory mediator, but on the endotoxin that might be responsible for triggering those inflammatory responses.

"To be sure," he concluded, "there have been lots of disappointments, but whether it's this one of ours or some other strategy based on new information, there's some reason to be optimistic - cautiously optimistic - about doing something for this disease." n