Neutralizing HIV

NCI researchers seek commercial partner after identifying first human domain antibody that potently inhibits HIV

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BETHESDA, Md.—Researchers at the National Cancer Institute (NCI) have identified a novel type of antibody that is highly effective in neutralizing the human immunodeficiency virus (HIV). Believing the finding could lead to the development of new treatments against HIV and other viruses, the researchers say they are actively seeking a commercial partner to realize that goal sooner rather than later.

In an earlier study, the researchers identified a unique antibody, called m0, while screening a large library of antibodies directed against the HIV protein, Env (also known as gp140). The library contained the variable portions of antibodies that can bind to Env antigens.

In this most recent study, published online Oct. 28 in the Proceedings of the National Academy of Sciences (PNAS), the researchers constructed a library of 25 billion different domain antibodies (dAbs), screened it against Env proteins from two different strains of HIV and identified m36, a dAb that bound strongly to different Env and blocked the infectivity of a broad range of HIV strains.

The researchers believe that m36 represents the first human dAb against HIV reported, according to the study.

"There are a number of experiments with monkeys suggesting that antibodies can effectively prevent infection if administered before the virus, but if applied about one day or longer after the virus infection, they are generally not effective," says Dr. Dimiter S. Dimitrov, a scientist at the NCI's Center for Cancer Research and one of the study's co-authors. "We thought that because the virus has evolved strategies to evade neutralization by naturally occurring antibodies which are relatively large molecules, we can use much smaller molecules based on portions of the antibodies called domains against which the virus has not evolved protective strategies."

These domain antibodies target highly conserved regions of the virus, so it is less likely the virus can develop resistance—the fundamental problem of currently available therapies—and they have fewer side effects, Dimitrov says.

"The reason is that these domain antibodies are part of our bodies and part of the full-size antibodies which have evolved to be safe, even at the very high concentration in our blood," he says.

The research team is working to test various combinations of m36 with other inhibitors that may be effective against HIV and is seeking a commercial partner to speed the ability to evaluate m36 as a potential treatment for the more than 40 million people living with HIV worldwide, Dimitrov says.

"In such cases as the USA, which probably has a majority of the HIV-infected individuals, one needs to add new drugs to fight resistance. We are looking for a commercial partner, and there are several companies which have expressed interest," he adds.

The team is also using its dAb libraries to identify and characterize domain antibodies that could be useful against other infectious diseases, Dimitrov adds.

"Such antibodies can be useful against any disease including infectious diseases, cancer and immune diseases," he says.

The study, Human domain antibodies to conserved sterically restricted regions on gp120 as exceptionally potent cross-reactive HIV-1 neutralizers, was co-authored by Weizao Chen, Zhongyu Zhu and Yang Feng. DDN

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