It's not really intuitive that you should be able to fight autoimmunity by inducing an immune response. But that's what French company Neovacs SA intends to do.

In the Dec. 19, 2006 issue of the Proceedings of the National Academy of Sciences, researchers from Paris-based Neovacs, the University of Paris and Avicenne Hospital in Bobigny, France, and the University of Maryland in Baltimore, report that inducing an immune response to human TNF-alpha protected transgenic mice from several diseases driven by the overproduction of TNF-alpha and other cytokines.

Usually, the body will not produce antibodies to cytokines. "If you vaccinate humans with the cytokine alone you cannot induce an immune response as this is a self molecule and it is thus invisible' to the immune system," Neovacs scientist Elena Ritsou told BioWorld Today.

Neutralizing cytokines via monoclonal antibodies, though, has been an effective therapeutic strategy. And because pathological levels of cytokines are found mainly extracellularly, while cytokines doing their jobs are by and large inside cells, such blocking does not interfere too much with normal cytokine functions.

In fact, anti-TNF monoclonal antibodies - Amgen's etanercept (Enbrel), Centocor's infliximab (Remicade) and Abbott Laboratories' adalimumab (Humira) - have "radically transformed treatment in severe immune disorders," Ritsou said.

Nevertheless, they have drawbacks, the biggest of which is probably that with repeated administration, they can be immunogenic. In other words, up to a third of patients end up making antibodies to the antibodies.

Neovacs hopes to get around that by inducing an active immune response to cytokines. To that end, the company links nontoxic but immunogenic cytokine derivatives to KLH - a carrier protein from the keyhole limpet.

The day job of the marine invertebrate is to delight scuba divers and confuse evolutionary biologists with its odd shape. Science writer Carl Zimmer describes evolutionary tradeoffs in the February, 2001 issue of Natural History that make the limpet's shell "a long way from perfection" for the job of staying glued to rocks underwater. And a commenter on Zimmer's blog notes that "Keyhole limpet design' is really like a welcome mat" for predators.

Keyhole limpet hemocyanin, or KLH, is being used as either an immunostimulant or carrier protein in nearly a dozen clinical trials in all phases. Neovacs calls the KLH-cytokine conjugates "kinoids." Neovacs also has a toxoid program using the same principle with viral toxins.

In the work reported in Proceedings of the National Academy of Sciences, the scientists made transgenic mice that overproduced human TNF-alpha, and thus rapidly develop the mouse equivalent of rheumatoid arthritis. Vaccination with the TNF-alpha kinoid reversed the signs of arthritis in one experiment, and in another, prevented mice from dying of septic shock after administration of high doses of TNF-alpha. While the mice produced antibodies to the cytokines, there was no T-cell response.

Ritsou said that with its kinoid program, "Neovacs intends to focus on diseases where the overproduction of TNF-alpha is well documented . . . , such as cancer-related cachexia, rheumatoid arthritis or Crohn's disease." The company expects to enter the clinic within the next 18 months, but she declined to give specifics on time or indication.

Because it is an active response by the immune system itself, which makes polyclonal antibodies against epitopes on both the carrier protein and the cytokine fragment, immunogenicity should be less of a problem with active vaccination than it has been with monoclonal antibodies. "Neovacs technology should significantly reduce the risk of drug resistance and severe allergic reactions compared with monoclonal antibodies and markedly improve long-term efficacy," Ritsou said.

Furthermore, because the kinoid vaccination induces an antibody response that lasts for several months, the kinoid approach, if it pans out, has appealing practical features. "It should require a very limited number of administrations a year, improving patient compliance in chronic diseases," Ritsou said.