The Human Immunodeficiency Virus-1 (HIV-1) has the intrinsic capability to rapidly mutate, and generate a daunting diversity of viral strains. This severely impedes our body’s efforts to mount an effective immune response against HIV infections.
Yet, a small number of patients with many years of infection produce antibodies that can neutralize several different strains of the HIV virus.
These antibodies are termed ‘broadly neutralizing antibodies’ (bnAbs). Efforts have been made by many research teams to combine different bnAbs to treat HIV. This multi-pronged approach has greater potential to effectively rout out more viral strains in an infected patient, than single broadly neutralising antibodies.
Now, in a breakthrough paper, researchers from the US have engineered a trispecific antibody against HIV that attacks a sweeping 99% of viral strains in monkeys. The research was published in the journal Science.
The engineered trispecific antibodies recognise three regions specific to the virus. The study demonstrates that the trispecific molecules combine advantages of both broad recognition of several viral strains, and increased neutralisation potency against HIV infection.
The paper is the result of work from Sanofi, National Institute of Allergy and Infectious Diseases (NIAID), Harvard Medical School, The Scripps Research Institute, and the Ragon Institute of MGH, MIT and Harvard.
The pre-clinical results showed unprecedented potency against diverse viral strains.
“We’re getting 99% coverage, and getting coverage at very low concentrations of the antibody,” said lead co-author and Sanofi Senior Vice President and Chief Scientific Officer Dr. Nabel.
The study compared the trispecific antibodies against other bispecific and trispecific designs. One of the trispecific antibodies completely protected 24 monkeys against infection from a mixture of viruses, that were resistant to single-epitope specific bnAbs. The combination antibody recognized the CD4 binding site, the membrane proximal external region (MPER), and the V1V2 glycan site of HIV.
“Combination therapy has already demonstrated its value in HIV and cancer therapy. Trispecific antibodies represent a potential new class of therapeutics that can block multiple targets with a single agent,” said Dr. Nabel.
A single antibody, which combines the effects of multiple broadly neutralising antibodies, presents a simpler design that can be taken into clinical trials faster than a cocktail mix approach. Clinical trials are anticipated to begin in the next year.
The antibody design may also be adopted to treat other infections and diseases, and even protect against them.
Prof Linda-Gail Bekker, the president of the International Aids Society, told the BBC,“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.”