New trispecific, broadly neutralizing antibodies target 99% of HIV strains

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New research has reported a trispecific antibody thought to target 99% of HIV strains. The antibody has been demonstrated to prevent SHIV infection in primate, and have higher potency and breadth than naturally occurring antibodies.

Development of a HIV vaccine has been challenging due to viral genetic diversity, making it difficult to generate broadly neutralizing antibodies. These antibodies have been observed in some patients and researchers have long been trying to harness these as a way to treat HIV.

This study, published recently in Science, was a result of collaboration between the National Institutes of Health (MD, USA) and the pharmaceutical company Sanofi (Paris, France). The team engineered a novel, trispecific antibody targeting three separate sites on the HIV virus; the CD4 binding site, the membrane proximal external region and the V1V2 glycan site.

The antibody is based on three naturally-occurring antibodies, each of which can neutralize many strains of HIV and had previously been isolated from HIV+ individuals. The researchers tested many combinations of antibodies in preliminary studies to isolate the best-performing combination – settling on the structures of three antibodies termed VRC01, PGDM1400, and 10E8v4.

The trispecific antibody was then tested in animal models and compared with naturally-occurring counterparts, exhibiting higher potency and breadth. The team assessed a group of 24 non-human primates – eight received VRC01, eight received PGDM1400 and the trispecific antibody was administered to a third group of eight monkeys before they underwent viral challenge with two strains of SHIV.

The researchers observed that while the previously-defined antibodies targeted 90% of strains, the novel antibody appeared to be effective against 99% of HIV strains. Moreover, five of the eight PGDM1400 primates and six of the eight VRC01 primates became infected with SHIV, however, none of the primates treated with the trispecific antibody developed SHIV when challenged with the virus.

Anthony Fauci, Director of the National Institutes of Allergy and Infectious Disease (MD, USA), commented: “Combinations of antibodies that each bind to a distinct site on HIV may best overcome the defences of the virus in the effort to achieve effective antibody-based treatment and prevention.”

The team hope that early-Phase clinical trials will begin in late 2018, testing the antibody’s safety and pharmacokinetic profile in healthy volunteers. They have suggested that this novel antibody could eventually be used for long-lasting HIV prevention and treatment, in addition to being an applicable approach for other diseases including cancer, infections and autoimmune conditions.

Linda-Gail Bekker, President of the International Aids Society, concluded: “This paper reports an exciting breakthrough. These super-engineered antibodies seem to go beyond the natural and could have more applications than we have imagined to date.

“It’s early days yet, and as a scientist I look forward to seeing the first trials get off the ground in 2018. “

Sources: Xu L, Pegu A, Rao E et al. Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaquesScience. doi:10.1126/science.aan8630 (Epub ahead of print) (2017); www.nih.gov/news-events/news-releases/three-one-antibody-protects-monkeys-hiv-virus

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