NEWS OF THE WEEK

CATALYTIC ANTIBODIES Enzymes cleave cocaine, block the <high'

Catalytic antibodies that promote the breakdown of cocaine before it reaches the brain have been de­

veloped by researchers at Columbia University. Although further work is needed, the artificial enzymes represent a new concept in antiaddictive medicine, and the first potential medical applica­tion of catalytic antibodies.

"If s a very pretty study," says Rich­ard A. Lerner, president of Scripps Re­search Institute in La Jolla, Calif., and one of the pioneers of catalytic antibody technology. "The significance is you could actually inject passive antibodies into people, and if they took cocaine it wouldn't do them any good—they wouldn't get any high from it. The anti­bodies also could possibly be used to treat overdoses."

The anticocaine antibodies were de­veloped by Donald W. Landry and co­workers in the department of medicine at Columbia University's College of Physicians & Surgeons, who reported the work in last week's Science [259,1899 (1993)]. The work was funded by the Counterdrug Technology Assessment Center (CTAC), part of President Bill Clinton's Office of National Drug Con­trol Policy.

In the study, Landry and coworkers immunized mice with a phosphonate ester whose structure is analogous to that of the putative transition state in the ben­zoyl ester hydrolysis of cocaine. Immu­nizing mice with an immunogenic ver­sion of this transition-state analog caus­es the animals to develop antibodies that bind and stabilize the transition state, thus catalyzing the hydrolysis reaction.

The researchers found that two mono­clonal antibodies derived from the anti­bodies produced by the immunized ani­mals can speed up cocaine hydrolysis by a factor of 100 to 1000. The hydrolysis yields two products—ecgonine methyl ester and benzoic acid, which lack co­caine's stimulant activity.

In addition to an M.D. degree, Landry has a Ph.D. in organic chemistry from

Harvard University—where he was the last graduate student of the late Nobel Laureate Robert B. Woodward—and his training in both chemistry and medicine was key to the project's success, he stresses. For example, synthesizing the immunogen necessitated developing a new method for phosphonate ester syn­thesis—an unusual feat for an assistant professor of medicine.

Currently, there are no direct antago­nists of cocaine (drugs that block uptake of cocaine at brain receptors). Hence, drug treatment of cocaine addiction has focused, up to now, on antidepressants like desipramine. Desipramine can help recovering addicts abstain, but it takes several weeks to work, and during that time there is a high relapse rate.

Hydrolysis cleaves cocaine into inactive products

o. H 3 C - N N ^ ^ O C H 3

Cocaine

H3C—Ν V O C H 3

cv:°x ,OH

Transition state

ι Ο C02H

H3C—Ν ^ - O C H 3

&y Ecgonine

methyl ester

ΌΗ +

Benzoic acid

Typical crack cocaine addicts "utilize all their resources taking the drug for several days," Landry explains. "At that point, resources and drug supply ex­hausted, they crash, present themselves [for treatment], and may sleep for 24 continuous hours. They wake and for a couple of days they would like to quit, but around the third or fourth day there's an overwhelming urge to resume using the drug. These cravings are al­most insurmountable."

It's during this craving period that something needs to be done. "You can start a patient on desipramine," he says, but because it takes so long to work "they're likely to binge again and stop taking desipramine. So they'll be back to square one."

However, if an addict in treatment were willing to take an anticocaine cat­alytic antibody, the medication would act immediately to negate the effects of any cocaine taken later. The medication would not eliminate the craving for the drug, but would make it impossible to alleviate it.

However, Landry points out, the cata­lytic antibodies his group developed have a long way to go before they can be used in humans. The main problem is that they would have to be administered in very large quantities because of their low potency. "We hope we can develop more active agents, since the ones we have in hand, in and of themselves, are not appropriate for human use," he says.

Ideally, the catalytic antibodies would be sufficiently potent so that a single dose, administered after a binge, would retain significant activity against cocaine for two weeks or more. "If you can pro­tect someone for several weeks, that might be enough time for desipramine, psychotherapy, group therapy, and all the rest to exert some positive effect," says Landry. "And the strongest crav­ings actually occur earliest on. So even protecting someone for a week or two after they come off a binge could make a significant dent in the relapse rate."

4 MARCH 29,1993 C&EN

To improve the enzymes, Landry, in collaboration with Columbia biochemis­try and molecular biophysics professor Wayne A. Hendrickson, is currently try­ing to obtain their x-ray crystal struc­tures. The structural data will help pro­vide a basis for site-directed mutagenesis to enhance the enzymes' activity. "In ad­dition," Landry says, "we want to inves­tigate the effect of these artificial en­zymes in an animal model for cocaine addiction—to see, for example, if we can induce extinction of cocaine self-admin­istration in a monkey model."

The ultimate goal, says Landry, "is to develop a completely new class of medications. There's nothing like this on the market now. We're looking ahead perhaps five years to the first human trials, and possibly 10 years to the first agent for treatment. That's a reasonable time frame—assuming ev­erything works out in between."

Stu Borman

OSHA won't appeal toxics exposure ruling The Occupational Safety & Health Ad­ministration has decided to wait for Congress to change the law rather than appeal a federal court decision last July that struck down OSHA's permissible exposure limit (PEL) regulations gov­erning hundreds of workplace chemi­cals (C&EN, July 13,1992, page 7).

The court granted a stay of its ruling until March 22 to allow filing of an Ad­ministration appeal. However, Secretary of Labor Robert B. Reich allowed the PEL standards to lapse. The Occupation­al Safety & Health Act is very specific about how the agency is supposed to regulate chemicals, so it is likely any fur­ther appeal would have been lost.

OSHA took a bold step in 1989 by set­ting new exposure limits in a single reg­ulation for 428 workplace chemicals, based in part on voluntary industry guidelines. This regulation updated and expanded PELs for toxic substances that the agency originally had adopted in 1971, shortly after its inception, also based on voluntary industry guidelines. In all, the 1989 regulation set more pro­tective limits for 212 chemicals, covered 164 new chemicals, and left 52 standards unchanged.

This "generic standard" was viewed as a way to cover a large amount of

complex material—and improve work­ers' health protection—as quickly as possible, replacing a slow case-by-case approach. But the appeals court in At­lanta, responding to a challenge to the rule made by labor unions and trade associations, vacated the new standard, claiming OSHA had not provided the scientific and economic data required for each of the individual changes.

Reich is looking forward to passage of legislation revising the current law. Bills were introduced in both the House and Senate this month that strive to streamline the process for regulating workplace haz­ards. Rep. William D. Ford (D.-Mich.), chairman of the House Committee on Ed­ucation & Labor, who introduced a simi­lar bill two years ago, explains that his bill did not pass in the last Congress because of opposition from the Bush Administra­tion. He does not expect similar opposi­tion from the Clinton Administration.

One provision of Ford's bill specifical­ly addresses the PEL standards. It would codify into law the 428 exposure limits set in 1989. It also would order OSHA to update the PELs every three years, and require three more generic standards from the agency: exposure monitoring of toxic substances, medical surveillance of exposed employees, and ergonomie haz­ards.

Many companies already had imple­mented the more protective 1989 PELs. OSHA officials are optimistic that few employers will roll them back, even though the limits are no longer legally enforceable.

The Chemical Manufacturers Associa­tion (CMA) is a little disappointed that OSHA did not appeal. The industry gen­erally has supported the higher stan­dards, and believes the generic rule pro­cess is a way for the agency to do its job with its limited resources. A CMA spokesman notes the proposed legislation is one way to make the PELs enforceable, but CMA is concerned this will just con­tribute to the movement by Congress to micromanage agency programs.

A representative of the health and safety office of the Oil, Chemical & Atomic Workers International Union is more skeptical about the decision not to appeal. She says the exposure limits are difficult to monitor at plant level, and that unless there are specific health standards in place, such as for benzene or lead exposure, most plants do not do much to monitor for PELs.

David Hanson

NSF, EPA spur research to prevent pollution Research on design of environmentally benign pathways for chemical syn­theses will be spurred under an agree­ment between the National Science Foundation's chemistry division and the Environmental Protection Agency's Office of Pollution Prevention & Toxics (OPPT).

The agreement, signed Jan. 28, but disclosed only last week, is intended to improve coordination between the two agencies' programs of basic research related to pollution prevention. Both have ongoing research grant programs aimed at limiting production of un­wanted by-products and pollution by U.S. industries that use and produce chemicals, thereby reducing potential pollutants at the source. The agreement outlines ways the two agencies can help "foster a new environmental con­sciousness in the community of syn­thetic chemists," including joint review of research projects, exchange of scien­tific information and personnel, and joint outreach and education efforts in pollution prevention.

The collaboration will stress research in several areas of organic synthesis and chemical processing—use of less toxic chemical and synthetic feedstocks, use of photochemical processes instead of tra­ditional ones that employ toxic reagents, use of recyclable catalysts to cut down on metal contaminants, and use of natu­ral feedstocks when synthesizing chemi­cals in large quantities. Cooperative re­search also wùl focus on alternatives to using large quantities of solvents as reac­tion media, and on alternative methods to avoid generating greenhouse gases.

"What we're really talking about here is rewriting Morrison and Boyd for the 21st century," says Joseph J. Breen, chief of the industrial chemistry branch at OPPT, referring to the well-known introductory organic chemistry textbook. Paul T. Anastas, chief of OPPT's new chemicals section, ex­plains that new research is needed to generate a set of fundamental synthetic tools in chemistry that can be applied in different ways and that are designed to be environmentally benign. EPA's Design for the Environment Program supports six academic research projects toward this end.

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