Broadly neutralising antibody suppresses HIV in clinical trial

1 June 2015. Related: Basic science and immunology.

Richard Jefferys, TAG

The past decade has seen a boom in the identification of antibodies capable of potently neutralising a broad array of different HIV isolates (broadly neutralising 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. [1] 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 group.

The study confirms that bNAbs are active against HIV in humans, consistent with experiments in humanised mice [2] and macaques [3, 4]. 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 maximise 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) [5].

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). [6]

Dan Barouch has plans to study the bNAb PGT121 in several different populations, as outlined in his talk at CROI 2015. [7]

On the preventive side, there is interest in evaluating the efficacy of passive immunisation (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). [8]

While this research is likely to move forward, there are many lingering uncertainties regarding passive immunisation: 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 [9]. As has been covered previously, 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.

Source:

TAG Basic Science blog (09 April 2015)
http://tagbasicscienceproject.typepad.com

References:

1. Caskey M et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralising antibody 3BNC117. Nature (2015) doi:10.1038/nature14411.
   http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature14411.pdf (PDF)
2. Klein F et al. HIV therapy by a combination of broadly neutralising antibodies in humanised mice. Nature. 2012 Dec 6; 492(7427): 10.1038/nature11604. doi: 10.1038/nature11604.
   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809838
3. Barouch DH et al. Therapeutic efficacy of potent neutralising HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature (2013) doi:10.1038/nature12744.
   http://www.nature.com/nature/journal/v503/n7475/abs/nature12744.html
4. Shingai M et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature (2013) doi:10.1038/nature12746.
   http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature12746.html
5. http://en.wikipedia.org/wiki/Antibody-dependent_cell-mediated_cytotoxicity
6. Ananworanich J. RV397: Therapeutic efficacy of broadly neutralising HIV-1 specific monoclonal antibodies in Thai patients who initiated antiretroviral therapy during early acute HIV infection. Forum for Collaborative HIV Research cure research meeting, 2014.
   http://www.hivforum.org/storage/documents/2014/HIVCure/case_study_rv397_ja.pdf (PDF)
7. Barouch D. Harnessing antibodies for prevention and therapeutics. 22nd CROI, 23-26 February 2015, Seattle.
   http://www.croiwebcasts.org/console/player/25642
8. Graham B. Differential use of antibodies in prevention. R4P conference, 28-31 October 2014, Cape Town.
   http://webcasts.hivr4p.org/console/player/25262
9. Dumiak M. Making it to manufacturing. IAVI Report 18(2):2014.
   http://www.iavireport.org/Back-Issues/Pages/Making-it-to-Manufacturing.aspx
10. A Phase 1, randomised, blinded, dose-escalation study of rAAV1-PG9DP recombinant AAV vector coding for PG9 antibody in healthy male adults.
    https://clinicaltrials.gov/ct2/show/NCT01937455