A small antibody fragment that is highly effective in neutralizing the human immunodeficiency virus (HIV) by preventing the virus from entering cells has been identified by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH). This finding may provide insight into the development of new treatments against HIV and other viruses, hopefully in the not too distant future. The study appears online Oct. 20, 2008, in Proceedings of the National Academy of Sciences.
Treating HIV-infected individuals is difficult because the virus is able to mutate and become resistant to antiretroviral drugs. "In the United States, it is estimated that more than 50 percent of patients who are receiving antiretroviral therapy for their HIV infection carry strains of the virus that are resistant to treatment with at least one of the currently available antiretroviral drugs," said NCI director John E. Niederhuber, MD. "The development of new drugs against HIV is an urgent public health need."
Antibodies are large proteins naturally produced by the immune system to help fight disease-causing foreign invaders, such as viruses and bacteria. Although the general structure of all antibodies is very similar, a small region at the tip of the protein is extremely variable, allowing millions of antibodies, characterized by slightly different tip structures, to exist and bind to different targets, known as antigens. Previous research has shown that reducing antibodies to the smallest independently functional fragment, known as a variable domain, can extend their utility as therapeutic agents. These fragments, called domain antibodies (dAbs), retain the variable tip structure and, therefore, the antigen-binding specificity of the parent antibody. Because of their small size, they are able to access targets that cannot be reached by much larger, whole antibodies.
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 gp120). The library contained the variable portions of antibodies that can bind to Env antigens. "We found an antibody fragment that exhibited the ability to neutralize HIV and had properties that allowed us to construct a novel library containing dAbs directed against HIV," said Dimiter S. Dimitrov, PhD, of NCI’s Center for Cancer Research.
Based on m0’s framework, the leading author of the study, Weizao Chen, PhD, constructed a very large library of dAbs (25 billion different dAbs), screened it against Env proteins from two different strains of HIV, and identified a dAb, m36, that bound strongly to different Env proteins and blocked the infectivity of a broad range of HIV strains. The researchers believe that m36 represents the first human dAb against HIV reported.
"The antibody fragment that we identified, m36, could have potential in the development of a therapeutic drug that inhibits HIV," said Dimitrov. "Further research with this molecule also could offer insight about how the virus infects cells and how it evades neutralization by the immune system."
The research team is working to test various combinations of m36 with other inhibitors that may be effective against HIV. The team is also attempting to construct more potent versions of m36. Partnership with industry could speed the ability to evaluate m36 as a potential treatment for HIV. Dimitrov’s team is also using this approach to identify dAbs against cancer and other disease-related antigens.
Source: National Institutes of Health (NIH)
Reference: Chen, W, Zhu Z, Feng Y, Dimitrov DS. Human domain antibodies to conserved sterically restricted regions on gp120 as exceptionally potent cross-reactive HIV-1 neutralizers. Proceedings of the National Academy of Sciences. Online October 20, 2008.