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October 3, 2017
Engineered antibody protects monkeys from HIV-like virus
At a Glance
- A “three-in-one” antibody made in the laboratory protected monkeys from infection with an HIV-related virus better than the natural antibodies from which it was derived.
- Plans are under way to test the antibody in people in the hope that it could eventually be used for long-acting HIV prevention and treatment.
HIV, the virus that causes AIDS, attacks the body’s immune system, making people vulnerable to other infections and diseases. Treatments can control HIV infection, but the virus persists in the body for a lifetime. An effective vaccine has been elusive, in part because of the diversity of HIV strains.
Researchers have isolated antibodies from people living with HIV that can neutralize multiple strains of HIV. By studying these broadly neutralizing antibodies, they’ve gained important insights into how the antibodies bind to the virus and why they’re effective. Investigators from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and the pharmaceutical company Sanofi set out to create more potent broadly neutralizing HIV antibodies. The team was led by Dr. John R. Mascola, director of the NIAID Vaccine Research Center, and Dr. Gary J. Nabel, Sanofi chief scientific officer and senior vice president. The work appeared online in Science on September 20, 2017.
The researchers combined portions of individual broadly neutralizing antibodies to engineer a series of antibodies in the laboratory. They created dozens of “bispecific” (binding to two different sites on the virus) and “trispecific” (binding to three different sites) antibodies. Testing revealed the most successful to be a trispecific antibody that combined parts of the broadly neutralizing HIV antibodies VRC01, PGDM1400, and 10E8v4. This single engineered molecule interacts with three independent parts of the HIV surface.
Infusions of the three-pronged antibody completely protected eight monkeys from infection with two strains of SHIV, a monkey form of HIV. In contrast, infusions of the individual antibodies from which the engineered antibody was derived were only partially protective. The trispecific antibody also prevented a broader range of HIV strains from infecting cells in the laboratory.
Sanofi is manufacturing the trispecific antibody for use in a Phase 1 clinical trial that NIAID is planning to conduct. The trial will test the antibody’s safety and effects in healthy people beginning in late 2018. Discussions also are under way for a separate Phase 1 clinical trial of the antibody in people living with HIV.
“Combinations of antibodies that each bind to a distinct site on HIV may best overcome the defenses of the virus in the effort to achieve effective antibody-based treatment and prevention,” says NIAID Director Dr. Anthony S. Fauci. “The concept of having a single antibody that binds to three unique sites on HIV is certainly an intriguing approach for investigators to pursue.”
The ability of trispecific antibodies to bind to three independent targets could make them useful for other types of treatments as well. Other potential targets include infectious diseases and cancers.
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References: Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques. Xu L, Pegu A, Rao E, Doria-Rose N, Beninga J, McKee K, Lord DM, Wei RR, Deng G, Louder M, Schmidt SD, Mankoff Z, Wu L, Asokan M, Beil C, Lange C, Leuschner WD, Kruip J, Sendak R, Do Kwon Y, Zhou T, Chen X, Bailer RT, Wang K, Choe M, Tartaglia LJ, Barouch DH, O'Dell S, Todd JP, Burton DR, Roederer M, Connors M, Koup RA, Kwong PD, Yang ZY, Mascola JR, Nabel GJ. Science. 2017 Sep 20. pii: eaan8630. doi: 10.1126/science.aan8630. [Epub ahead of print]. PMID: 28931639.
Funding: NIH’s National Institute of Allergy and Infectious Diseases (NIAID); Sanofi; and International AIDS Vaccine Initiative (IAVI).