A NEW class of highly reactive antibodies could be turned into drugs with an extra punch. Unlike ordinary antibodies, which cling to their target molecules temporarily, these superantibodies react with them, either breaking the molecules apart or forming a permanent chemical bond.
Kim Janda, Richard Lerner and their colleagues at the Scripps Research Institute in La Jolla, California, are turning their new weaponry on HIV. They hope to develop superantibodies that will react with key viral proteins. Conventional antibodies have already been used as experimental drugs. They home in on cancer cells or microorganisms but can only cripple their target with the help of an accompanying 鈥渨arhead鈥� 鈥� usually a toxin or a radioactive isotope. In theory, the superantibodies being developed at Scripps could do the job without this extra help.
Immunologists produce antibodies to a specific chemical by injecting mice with the target molecule. After collecting immune system B cells from the animals鈥� spleens, they screen them for antibodies that bind strongly to the target. These antibodies can then be mass produced in cell cultures. The Scripps team used the same procedure, but injected the mice with reactive organic compounds. The aim was to produce antibodies that were themselves unusually reactive.
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The search for the right compounds was painstaking. If the chemical was too reactive, it would break down in the bloodstream before contacting the B cells. And if it was not reactive enough, ordinary antibodies were produced. 鈥淢ost molecules we tried were either too 鈥榟ot鈥� or too 鈥榗old鈥�,鈥� says Janda.
Eventually, the researchers found that chemicals called organophosphonate esters fitted the bill. These molecules carry two reactive ester groups, organic groups derived from acids. In all, the Scripps team injected mice with around two dozen organophosphonate ester variants, and screened 19 reactive antibodies from the animals鈥� B cells.
The antibodies and the organophosphonate esters reacted with one another in a variety of ways. Sometimes, ester groups were knocked off the organophosphonate, leaving behind reactive ions. These ions could be used as chemical catalysts. Most commonly, one ester group was chopped off as the chemical and antibody reacted to form a stable covalent bond. 鈥淣ormally, the antibody goes on and off [its target],鈥� says Janda, 鈥渂ut these ones stayed on permanently.鈥�
Janda, Lerner and their team say that superantibodies should also react with compounds that resemble their target molecule. They are now trying to raise superantibodies against gp120, a protein found on HIV鈥檚 outer coat that enables the virus to slip into human cells. 鈥淸Strongly-bound] antibodies are valuable because they would work for longer in the body and bind much more effectively,鈥� says Ivan Riott, an immunologist at University College London.
The researchers are altering parts of the gp120 molecule with the aim of making it as reactive as the organophosphonate esters they used in their earlier experiments. If they can make superantibodies that form permanent covalent bonds with natural gp120 protein, these antibodies could be used as drugs to block HIV鈥檚 entry into human cells. 鈥淚f you have an [ordinary] antibody on gp120, the virus can still infect a cell,鈥� says Riott. 鈥淏ut if they can attach one covalently, it may not.鈥� Nevertheless, Janda warns that trials in humans are at least five years away.
