CHIRON IN LINE FOR EXCLUSIVE LICENSE TOINTERLEUKIN-2 PATENT

Editor's note: Science Scan is a round-up of recentlypublished biotechnology related research.

Unless other firms enter timely objections, Chiron Corp.,of Emeryville, Calif., will gain an exclusive, world-wide,royalty-bearing license to U.S. patent number 5,419,900,titled "Immunologic enhancement with intermittentinterleukin-2 therapy," issued May 30, 1995. Its principalinventor is Clifford Lane, clinical director of the NationalInstitute of Allergy and Infectious Diseases.

Notice of the proposed license appeared in the FederalRegister on Aug. 15, 1995 triggering a 60-day graceperiod for possible objections before definitive grant ofthe license to Chiron.

The rights covered by the prospective license cover "alltherapeutic applications, including treatment of HIVinfection and AIDS, as well as for the attendantopportunistic infections that occur in AIDS patients."

Lane's invention describes "the continuous intermittentinfusion of interleukin-2, alone or in combination withretroviral therapy, as a means of enhancing the patient'simmune system."

In particular, interleukin-2 is a growth factor thatincreases the number of T cells, which are prime moversin the immune system's cellular arm.

NOTE: Interested parties should address inquiriesconcerning the proposed license to the National Institutesof Health technology licensing specialist Steven Fergusonat (301) 496-7735, extension 266.

Turning Platinum Anti-Tumor Agent On, Off

On world metals markets, platinum is more precious thangold, but to cancer victims its price is above rubies.

Oncologists treat testicular, ovarian and bladder tumors inparticular with cis-platin, a chloride that releases metallicplatinum. It's thought to work by binding and cross-linking DNA.

At the Massachusetts Institute of Technology (MIT),organic chemist Stephen Buchwald and his students havedesigned a very simple analog of very complicated anti-tumor agents, which damage DNA when they bind to it.

In chemists' jargon, Buchwald told BioWorld Today,"these highly cytotoxic compounds, called enediyneantibiotics, form very reactive species upon binding toDNA. That is, they cleave and damage its strands with ahigh degree of activity.

"Such an analog as this," he observed, "had never beenmade before."

"What we were trying to do was find a way to turn thisreactivity on or off selectively, by adding a very simplechemical species."

The enediyene antibiotic analog they designed "could getthat reaction to occur much more readily by adding aspecific metal ion," namely, platinum chloride. "Whereas,in the absence of that ion," he added, "it wouldn't react atall."

Buchwald and his co-authors report their unique chemicaltoggle switch in the current issue of Science, dated Aug.11, 1995. Their paper bears the title: "Controlledacceleration and inhibition of Bergman cyclization [achemical transformation] by metal chlorides."

To create their simple-is-beautiful molecule, they"stripped away all of an enediyene antibiotic'ssuperfluous part," Buchwald said, "and kept the businessend. We wanted a way to control it, because one of theproblems with anti-cancer drugs is that they are often tootoxic, too reactive."

He explained: "What you need is something that will goand bind specifically to cells, either tumor cells or AIDSvirus or something like that, and be able to add our co-drug, so that you are activating it only when it's in thearea of the bad actor rather than the healthy cell."

Although this project, Buchwald observed, "is certainlynot therapeutic at this point, we have been talking withbiochemists and toxicologists in our department, and withpotential collaborators."

A Surprise Bacterial Resistance To Solvents

Drop a colony of E. coli into tetralin, an industrialsolvent, and the bacteria drop dead. All except the luckyfew mutants that carry a resistance factor to 1,2,3,4-tetrahydronaphthalene, which is tetralin's chemical name.

Finding out the secret weapon those mutants wield toward off death by solvents would give a big boost to thechemical industry. "Combining the biochemicalversatility of microorganisms with the ability to survivein high concentrations of organic solvents is essential forfurther development of industrial biocatalysis."

This observation leads off a paper in the currentProceedings of the National Academy of Sciences,(PNAS), dated Aug. 15. Its title: "Cloning of an organicsolvent-resistant gene in Escherichia coli: Theunexpected role of alkylhydroperoxide reductase[AHPR]."

When the article's senior author, Massachusetts Instituteof Technology biochemist Alexander Klibanov, and hisco-authors isolated the resistant E. coli strain, they foundthat it shrugged off not only tetralin but half a dozen otherwidely used solvents, which lay wild-type E. coli low,notably cyclohexane and propylbenzene.

When Klibanov and colleagues isolated the genomicsequence of the mutant bacterium that conferred thisresistance, they found _ to their surprise _ that themutated gene, a valine-for-glycine substitution,identically matched the gene that encodes the catalyticsubunit of the enzyme alkylhydroperoxide reductase.

"The surprising finding of AHPR involvement suggestedan unexpected hypothesis for the nature of tetralintoxicity and resistance to it," Klibanov concluded,"whereby tetralin by itself is not toxic to E. coli but formsa toxic hydroperoxide in the cell. AHPR confersresistance by reducing the hydroperoxides."

_ Compiled By Science Editor David N. Leff

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