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Long-term Delivery of Anti-HIV Monoclonal Antibodies with Gene Therapy Approach in Monkeys
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Reported by Jules Levin
HIVR4P - HIV Research for Prevention (HIVR4P), October 21-25, 2018, Madrid
program abstract
OA13.05 - Long-term Delivery of Anti-HIV Monoclonal Antibodies
Jose M. Martinez-Navio1, Sebastian P. Fuchs1,2, Shara N. Pantry1, Natasha N. Duggan1, William A. Lauer1, Eva G. Rakasz3, Brandon F. Keele4, Jeffrey D. Lifson4, Guangping Gao5, Ronald C. Desrosiers1 1University of Miami, Miller School of Medicine, United States, 2Friedrich-Alexander-Universität Erlangen-Nürnberg, Institut für Klinische und Molekulare Virologie, Germany, 3University of Wisconsin, Wisconsin National Primate Research Center, United States, 4Frederick National Laboratory for Cancer Research - AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., United States, 5University of Massachusetts Medical School, Gene Therapy Center, United States
Background: Delivery of potent neutralizing antibodies using recombinant adeno-associated virus (AAV) vectors is a promising approach for the prevention and/or treatment of HIV infection since it circumvents the difficulties of generating a successful immunogen or vaccine. AAV vectors have an outstanding safety record in clinical trials and, as long as the delivered protein is viewed as self, it can result in continuous durable expression of the transgene product for years.
Methods: Four rhesus monkeys were infected with SHIV-AD8 for 86 weeks before receiving recombinant AAV vectors expressing rhesusized IgG1 versions of anti-HIV monoclonal antibodies 10-1074 (which binds the V3 glycan supersite), 3BNC117 (which targets the CD4 binding site of HIV-1 envelope) and 10E8 (which binds the membrane proximal external region).
Results: Host anti-antibody responses hampered the deliverability of 10-1074 in one animal, of 3BNC117 in three, and of 10E8 in all four. However, SHIV-infected monkey rh2438 consistently maintained serum concentrations of 3BNC117 and 10-1074 of 50-200 µg/ml for 30 months following the AAV administration. The chronic phase viral load set point in rh2438 was consistently measured at 10,000-20,000 viral RNA copies per ml of plasma for the prolonged period leading up to the time of AAV administration. Following the initial decline in viremia in rh2438 after AAV administration, viral loads have remained suppressed to below the limit of detection for 32 successive measurements over a 30-month period. Monkey rh2438 never received antiviral drugs at any time and therefore appears functionally cured.
Conclusions: Sustained and prolonged virological control is achievable with AAV-mediated delivery of broadly neutralizing antibodies. These findings highlight the enormous potential of AAV-directed antibody expression for impacting HIV-1 infections worldwide.
WEBCAST:
http://webcasts.hivr4p.org/console/player/40411?mediaType=slideVideo&&crd_fl=1&ssmsrq=1540573007200&ctms=5000&csmsrq=797
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