October 2, 2017Infectious Disease
According to an article published in Science (20 September 2017), a three-pronged antibody made in the laboratory protected monkeys from infection with two strains of SHIV, a monkey form of HIV, better than individual natural antibodies from which the engineered antibody is derived. The three-pronged antibody was created by investigators from the National Institutes of Health (NIH) and the Paris-based pharmaceutical company Sanofi, also stopped a greater number of HIV strains from infecting cells in the laboratory more potently than natural, single antibodies. This new broadly neutralizing antibody binds to three different critical sites on HIV. According to the NIH, 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, and that the concept of having a single antibody that binds to three unique sites on HIV is certainly an intriguing approach.
For the study, the authors tested dozens of bispecific and trispecific antibodies in the laboratory to find the best-performing combination. Individual antibodies were combined into trispecific antibodies using technology proprietary to Sanofi. The most successful formula combines the unique structures of the broadly neutralizing HIV antibodies called VRC01, PGDM1400, and 10E8v4. The authors then tested this trispecific antibody in an experiment involving monkeys and two strains of SHIV. One SHIV strain is sensitive to neutralization by VRC01 and the trispecific antibody, but resistant to neutralization by PGDM1400. The other SHIV strain is sensitive to neutralization by PGDM1400 and the trispecific antibody, but resistant to neutralization by VRC01. Twenty four monkeys were treated: 8 with VRC01, 8 with PGDM1400, and 8 with the trispecific antibody. Five days later, the all of the 24 monkeys were exposed to both SHIV strains. Results showed that 5/8 of the monkeys that received PGDM1400 and 6/8 of the monkeys that received VRC01 became infected with SHIV, but 0/8 of the monkeys that received the trispecific antibody became infected.
Sanofi is manufacturing the trispecific antibody for use in a Phase 1 clinical trial that will be conducted by NIAID to test the antibody's safety and pharmacokinetics in healthy people beginning in late 2018. Discussions also are under way with the NIAID-funded AIDS Clinical Trials Group to conduct a separate Phase 1 clinical trial of the antibody in people living with HIV. By binding to three different sites on the virus, the new antibody should be harder for HIV to dodge than natural, single antibodies.
According to the authors, the ability of trispecific antibodies to bind to three independent targets at once could make them a useful prototype for treatments developed not only for HIV but also for other infectious diseases, autoimmune diseases and cancers.