April 9, 2015
The past decade has seen a boom in the identification of antibodies capable of potently neutralizing a broad array of different HIV isolates (broadly neutralizing antibodies or bNAbs). New technologies that allow antibodies to be fished from huge numbers of individual B cells and tested for activity have spurred this rapid acceleration of discovery. There is now intense interest in learning whether the blossoming array of bNAbs can be put to therapeutic and preventive use. A paper published yesterday in Nature describes encouraging results from a phase I trial involving the bNAb 3BNC117. Reflecting the level of interest in the topic, the paper has attracted extensive press coverage.
Led by Marina Caskey from Rockefeller University, the study enrolled 12 HIV-negative and 17 HIV-positive individuals (including two on ART) who received a single infusion of 3BNC117 at various doses (1, 3, 10 or 30 mg kg-1). The infusions were well tolerated; there were no grade 3 or greater adverse events and no laboratory abnormalities. HIV-positive participants receiving the two highest doses showed significant declines in viral load, with the exception of one individual whose virus turned out to be resistant to 3BNC117 at baseline. The eight recipients of the 30 mg kg-1 dose experienced reductions in viral load ranging from 0.8 to 2.5 logs, with four remaining below baseline at the last reported follow-up (day 56 post-infusion). Evidence of HIV evolving resistance to 3BNC117 was documented, particularly in the lowest dose groups. Assessments of whether anti-3BNC117 immune responses were invoked in any participants are not yet complete, but will be reported in the near future.
The study confirms that bNAbs are active against HIV in humans, consistent with humanized mice and macaque experiments. A number of pathways toward the therapeutic and preventive use of bNAbs can now be explored, but could still prove challenging to navigate. As the authors of the paper note, bNAbs will likely need to be used in combination to maximize activity and prevent resistance; they may also benefit from additional modifications to enhance their potency and persistence in the body.
On the preventive side, there is interest in evaluating the efficacy of passive immunization (either intravenous or subcutaneous) with bNAbs in both high risk adults and infants exposed to HIV via breastfeeding (see the webcast of Barney Graham's presentation at the 2014 R4P conference for additional information).
While this research is likely to move forward, there are many lingering uncertainties regarding passive immunization: the need for repeated injections raises the concern of practicality (particularly in the prevention context), and another issue that has to be considered is the complexity and cost of bNAb manufacture (for an informative excursion into the industry of bNAb production, see Michael Dumiak's 2014 IAVI Report article, "Making it to Manufacturing"). As has been covered previously on the blog, there is at least one alternative, potentially simpler method of bNAb delivery: gene transfer with adeno-associated virus (AAV), which is being tested in an ongoing phase I trial in the UK. But it is not yet known if AAV can deliver bNAb levels high enough to be efficacious.
To discuss the prospects for passive immunization against HIV, AVAC is hosting a webinar on Tuesday, April 21 at 11am EDT with Dr. Sarah Schlesinger from Rockefeller University.
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.
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