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 therapeutic side, there is the potential to combine bNAbs with latency-reversing agents with the aim of promoting clearance of the viral reservoir via antibody-mediated cellular cytotoxicity (ADCC). Another approach is to test whether combination bNAbs could provide a long-acting alternative or supplement to daily ART. A trial involving the combination of the bNAb VRC01 plus ART is due to start later this year in individuals with acute HIV infection in Thailand (see Jintanat Ananworanich’s presentation at last year’s Forum for Collaborative HIV Research cure research meeting for background). Dan Barouch has plans to study the bNAb PGT121 in several different populations, as outlined in his talk at CROI 2015.
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 (click here to register).
Nature (2015) doi:10.1038/nature14411
Marina Caskey, Florian Klein, Julio C. C. Lorenzi, Michael S. Seaman, Anthony P. West Jr, Noreen Buckley, Gisela Kremer, Lilian Nogueira, Malte Braunschweig, Johannes F. Scheid, Joshua A. Horwitz, Irina Shimeliovich, Sivan Ben-Avraham, Maggi Witmer-Pack, Martin Platten, Clara Lehmann, Leah A. Burke, Thomas Hawthorne, Robert J. Gorelick, Bruce D. Walker, Tibor Keler, Roy M. Gulick, Gerd Fätkenheuer, Sarah J. Schlesinger & Michel C. Nussenzweig
HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned. However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1. These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30 mg kg−1 infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8–2.5 log10 and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.
Erika Check Hayden