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Roundtable on Innate Immunity: A Lot Done, a Lot More to Do

By Cormac Sheridan
Staff Writer

PARIS – Despite managing to put together a star-studded lineup for a roundtable on innate immunity, which included two current Nobel prizewinners, Bristol-Myers Squibb Co. (BMS) and Innate Pharma SA found their best-laid plans were upstaged Tuesday by the French presidential inauguration at the Elysée Palace.

One of the speakers, 2011 Nobel laureate Jules Hoffmann, of the University of Strasbourg, France, was a little late arriving at the roundtable due to his attendance at the inauguration of the new leader of the fifth republic, Francois Hollande. Others were caught up in the snarl of traffic created by the citywide road closures that are now a salient feature of any high-profile political event.

But those in the audience who gathered at the Oceanographic Institute, across town in the fifth arondissement, were less concerned with politics than with the new scientific horizons opened up by Hoffmann and his fellow laureate Bruce Beutler, of the University of Texas.

Both scientists were recognized by the Swedish Academy for their work in nonhuman systems, which was subsequently extended by others into human biology. Hoffmann identified the molecular components underpinning Drosophila's defense against fungal and bacterial infection, and Beutler elucidated the role of Toll-like receptor 4 (TLR-4) in mice.

Notwithstanding the emergence of powerful new analytical tools, notably high-throughput genome sequencing, which make some problems in human biology more tractable, each remains firmly committed to exploring biological phenomena in nonhuman systems as a means of understanding immune system functioning and identifying new targets for therapeutic intervention.

The IMD signaling pathway in Drosophila, which is analogous to the TNF-alpha pathway in mammals, has 11 members and, Hoffmann told BioWorld International, an "interactome" comprising 345 proteins. Some 80 percent of those are conserved in humans, he said. "About a half of them give a phenotype if we knock them out," he said. That alone will provide plenty of target discovery work for human biologists.

Bruce Beutler advocates a greater focus on mouse rather than human genome sequencing. "It's not a bad tool to use for humans, but it's a perfect tool for the mouse," he told BioWorld International. Beutler's lab is continuing its mouse genetic studies, by generating random mutations and screening for immune-associated phenotypes.

The pace at which that work can be done is orders of magnitude ahead of what Beutler was able to do in the mid-1990s, when he performed the work on lipopolysaccharide (LPS) signal transduction in mice that led to the 2011 Nobel. "It took us five years to find the LPS mutation," he said, "and in a good year, 50 mutations can be turned around now in the mouse."

The advantage of working in murine rather than human systems is that researchers avoid the complexity of having to deconvolute the enormous genetic variation between human individuals and the great genetic diversity of human tumors. "It's still much easier to start with a defined genetic background," he told the roundtable audience.

Nils Lonberg, vice president in charge of R&D for biological drugs at BMS (and the scientist who led the development of the UltiMab antibody platform at Genpharm International and subsequently Medarex), expressed his support for continuing mouse work, too. "I understand the criticism of mouse models, but maybe the way around that is not to call them models but in vivo assays," he told the roundtable.

And academic scientists remain best equipped to discover new biological targets, one at a time. "A lot of companies spent a lot of money doing target searches. I don't think a lot came out of it," he said. "It's really the academic community you have to rely on to understand the biology."

Notwithstanding the progress in basic research on innate immunity that has been made since the mid- and late-1990s, when Hoffmann and Beutler made their discoveries, progress in converting that knowledge into useful therapeutics has been slow. "It seems to me to be going slower than I would have hoped," Beutler said. "But that is the nature of the business."

New York-based BMS has licensed from Marseille, France-based Innate a Phase I antibody called IPH2102, which blocks several inhibitory natural killer cell receptors, which are known as killer-cell immunoglobulin-like receptors. That compound is being developed for cancer applications.

The pharma company has, however, so far steered clear of molecules that act on TLRs, a target category that has so far attracted the greatest attention but which also has led to the greatest disappointment in the emerging field of therapeutics based on innate immunity.

"I think one of the difficulties of translating the PAMP (pathogen-associated molecular pattern) receptors into medicines – what they are really doing is locally marking sites of inflammation. It's hard to give a drug systemically that is acting only locally," Lonberg told BioWorld International.

Innate Pharma CEO Hervé Brailly told BioWorld International that this week's news from Berlin-based Mologen AG may represent "a second coming" for TLR modulators. (See BioWorld Today, May 15, 2011.)

Even so, the basic research agenda – never mind the drug development agenda – is far from complete, although the participants were optimistic about current progress. "In five to 10 years, we'll have a full understanding of the way mosquitoes get rid of the parasites," Hoffmann said. Although all insects are able to reduce the burden of parasite infection significantly, some are able to eradicate it completely. Understanding the difference between the two could yield new insights into the biology of malaria.

"It should be a golden age for big pharma in taking advantage of what has been learned already," Beutler said.

"Ten years from now people are going to view cancer and cancer therapy differently from how we view it now," Lonberg added.

The panel moderator, Philippe Kourlisky, of the Ecole Polytechnique in Paris, sounded a cautionary note in his concluding remarks, however. "Too much trust and confidence in the current knowledge is not justified, because even if we know a lot, we don't know enough," he said.

Privately, Beutler echoed that view when applied to the aberrant immune signaling associated with rheumatoid arthritis. "What's at the top of the apex?" he asked. "What causes RA?"