When it comes to combating HIV, three virus-killing antibodies should be better than one, scientists at French pharma giant Sanofi have long believed. That’s why they’ve been working with investigators at the National Institutes of Health (NIH) to develop a “trispecific” antibody—a three-pronged protein that binds to three different sites on the virus in order to neutralize it.
Now they have compelling preclinical evidence that the approach might work, not only to prevent infection with the virus that causes AIDS in healthy people, but also to treat patients facing the risk of developing resistance to current antiretroviral treatments. The researchers announced today that their trispecific antibody protected monkeys against SHIV, a similar virus, and that it outperformed the individual antibodies from which their engineered compound originated. Their research was published in the journal Science.
Sanofi is manufacturing the antibody for a phase 1 trial to be conducted by the NIH’s National Institute of Allergy and Infectious Diseases next year in healthy people. The company also hopes to contribute to a second phase 1 trial in people living with HIV, said Gary Nabel, M.D., Ph.D., the company’s chief scientific officer, in an interview with Fierce.
“When you target HIV with any single agent alone, the virus quickly becomes resistant. The ability to create a three-in-one engineered antibody was really a defining step for us,” Nabel said. “These antibodies are potent, so they work at lower concentrations, and they provide broader coverage than any single naturally occurring antibody. It allows us to get better coverage of the virus.”
In fact, the trispecific antibody was able to neutralize 99% of more than 200 HIV-1 strains, vs. 50% or less with bispecific antibodies tested in the past, according to the researchers.
Sanofi has had the technological know-how to combine antibodies for several years, but when the company’s scientists tried to make a two-part antibody against HIV it didn’t work, Nabel said. When they added a third antibody and tested it in HIV-infected cells, they saw that it stopped more strains of the virus than any single antibody could. They have since refined the three-part compound and figured out how to manufacture it efficiently, Nabel added.
The effort to develop a vaccine against HIV has been challenging because the virus is genetically diverse. And once patients are infected, they can become resistant to antiretroviral treatments because the virus mutates over time. The approach taken by Sanofi and the NIH aims to get around those problems by targeting three different HIV “envelope determinants,” which are sites on the virus that allow it to infect cells. The compound they developed targets all three sites with a single molecule.
The same approach could prove useful in treating patients who are already infected, Nabel said. “Once somebody is already infected they’re continuing to make the virus all the time. So we would probably be inclined to try this in combination with antiretroviral drugs. That way you knock the virus down, you limit the number of mutations it acquires, and then you get that additional coverage.”
Although some progress has been reported recently in the development of HIV vaccines, most of the approaches are still unable to target a large percentage of virus strains. For example, the experimental shot RV144, which was tested eight years ago in Thailand, was just 31% effective. In June of this year, scientists at Duke University reported that they improved upon that success rate with a five-part vaccine they developed. It provides 55% protection against HIV, they said.
“This field has made a lot of progress,” Nabel said, “but it has a long way to go.” Given the early evidence that the Sanofi compound may offer 99% protection, “we have to give this a try at least,” he added.
Sanofi’s interest in trispecific antibodies extends beyond HIV, Nabel said. He envisions using the same technology to develop multipronged treatments for cancer, autoimmune diseases and other viruses, he said. In cancer, for example, it might be possible to develop an immunotherapy treatment that contains three antibodies—one that recognizes cancer cells, another that recruits immune cells to tumors and third that activates them to fight the disease.
“This is a tool that allows us to transform cells more specifically,” Nabel said. “It’s a fundamental approach of multi-targeting that really allows us to be more discriminating in how we protect against different diseases.”