Making resistance futile

“Our job”, says Jan Kemper, “is to make cells happy.” Ms Kemper works at MedImmune, a subsidiary of AstraZeneca based in Gaithersburg, Maryland. Her laboratory contains 40 bioreactors—fluid-filled tanks of about three litres’ capacity. Paddles within them whirl around a mixture of nutrient broth and specially engineered hamster cells that are busy making human antibodies.

It is, indeed, cell heaven in one of these reactors. It is also part of a new front in the ancient war between man and microbe, for the antibodies Ms Kemper’s cells produce are designed to attack bacteria, and thus back up conventional antibiotics, some of which are failing in the face of rising bacterial resistance.

In America alone, at least 2m illnesses a year—and 23,000 deaths—are caused by antibiotic-resistant bacteria. Besides the human suffering this inflicts, it adds $20 billion to the annual cost of health care. The toll is such that, in September, Barack Obama directed federal agencies to take action against antibiotic-resistant bacteria. A task-force, ordered to report in February, has been appointed. And the Department of Health and Human Services is putting up a $20m prize for a rapid, diagnostic test for such bacteria. But a diagnosis is of little value without a treatment. Which is where antibodies come in.

Horse sense

Antibodies are proteins that have special sites on them which can vary in shape in myriad ways. Each variation is tailored to stick to one or a handful of specific other molecules, known as antigens, and neutralise them. If an antigen is part of a bacterium or virus, that gets neutralised too.

Using antibodies to treat infections is not a new idea. The first Nobel prize in medicine, awarded in 1901, went to Emil von Behring for discovering how to employ antitoxins, as he called them, to treat diphtheria. Von Behring found he could transfer them from infected horses to sick people by injecting those people with horse-blood serum. In the wake of this discovery, serum therapy became, until the invention of antibiotics, the main way of treating not only diphtheria but also tetanus, scarlet fever and meningitis. It faded into the background after the invention of antibiotics, but is still employed for neutralising snake venom and—albeit experimentally—for treating Ebola fever. However, now that biotechnology allows particular antibodies to be created in laboratories like Ms Kemper’s, the technique is poised to return to wider use, albeit in a slightly different guise.

Merck, a large American drug company, is testing a combination of two antibodies against toxins made by Clostridium difficile, a bacterium that plagues hospitals and which can be hard to treat with conventional antibiotics. The past few years have seen a particularly virulent strain of this bug emerge, and death rates have increased. Early trials of Merck’s treatment suggest that, when used alongside conventional antibiotics, antibody therapy reduces the recurrence of infection.

MedImmune’s antibodies, known for the moment as MEDI3902 and MEDI4893, are aimed respectively at Pseudomonas aeruginosa and Staphylococcus aureus and bind, in the former case, to bugs themselves and in the latter to human cells, shielding them from bacterial toxins. Pseudomonas and Staphylococcus are bacteria that particularly plague intensive-care units, sometimes causing stays in hospital to be five to eight times longer than they need be. For that reason, and the lack of alternative therapies, America’s Food and Drug Administration has recently agreed to expedite the review process for these two potential treatments.

Unlike most antibodies, MEDI3902 is bi-specific—meaning it has been engineered to bind to two different targets. One of these is on Pseudomonas’s tip, the site that injects toxins into an infected individual’s body cells. When the tip is plastered with antibodies, this cannot happen. The other target is on the bacterium’s surface. Here, the antibody does two things. It stops bacteria it is attached to interacting with, and thus harming, body cells. It also brings the bugs in question to the notice of the body’s defences, such as white blood cells called macrophages, which then eat them.

MEDI4893 also has more than one function. It stops the toxin produced by Staphylococcus binding to body cells. It also prevents the bug rupturing those cells’ membranes and killing them. And Merck and MedImmune are not the only companies involved in this area. Sanofi, a French firm, is also working on an antibody that kills Staphylococcus by attracting it to the attention of macrophages.

All these new treatments will, if they work, be useful in hospitals—particularly to treat infections that are resistant to antibiotics and thus hard to get rid of. But they might also be used prophylactically, as conventional antibiotics already sometimes are, before someone undergoes surgery. They may, indeed, prove to be a way of sparing the routine use of antibiotics, thus reducing the selective pressure on bacteria to evolve resistance to those drugs—for the reason resistance is such a problem in hospitals is that there are an awful lot of antibiotics sloshing around in them.

Evolution being what it is, bacteria will no doubt find ways around antibodies, as they have with antibiotics. But the wider the range of weapons available for deployment in the conflict, the harder life will be for them. As Steve Projan, who oversees MedImmune’s antibody project, eloquently puts it, “I’ve been working on staph for 34 years. I’m ready to beat the bastard.”