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New HIV Functional Cure: Lifelong Delivery of anti-HIV Monoclonal Antibodies
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These data ae impressive, we look forward to further developments & research. Jules Levin, NATAP
Abstract
Monoclonal antibody (mAb) strategies against HIV have been made possible by the identification and characterization of an incredible array of mAbs with potent neutralizing activity against a broad range of HIV isolates. My laboratory has been investigating use of AAV vectors for delivery of such antibodies to rhesus monkeys. Unfortunately, 80-90% of our delivery attempts have resulted in anti-drug antibody (ADA) responses that have negated continuous delivery. When ADA responses are absent, mAb delivery proceeds for years following AAV administration to muscle. We now have three examples where continuous delivery of two mAbs to a SHIVinfected monkey has resulted in impressive virological control for 3-8 years. No ART: not before, not during, not after the AAV administration. Essentially, three "functionally cured" SHIV-infected monkeys. These results illustrate the extreme promise of this approach when ADA responses can be avoided and long-term delivery achieved.
My laboratory has invested considerable effort over the last several years investigating approaches to creating antigen-specific tolerance in monkeys to the AAV-delivered mAbs. These approaches include but are not limited to: CpG depletion; liver targeting; RBC targeting; inclusion of microRNA binding sequences. These investigations have yielded little or no success. A few years ago, we teamed with Dr Anjie Zhen of UCLA to start doing exploratory experiments in less expensive mice. Voila. We found that transient treatment with an FDA-approved immune modulatory agent allowed consistent long-term delivery of the 3BNC117 mAb. Control mice that did not receive the immune modulatory agent behaved like the monkeys. We then proceeded to a five monkey study with three mAbs: 3BNC117, 10-1074 and PGT145. 5 monkeys x 3 mAbs = 15 delivery attempts. Despite some shortcomings in maintaining appropriate concentrations of the immune modulatory agent, continuous long-term delivery at therapeutic levels was observed in 12 of the 15 attempts for more than 6 months after discontinuation of the therapeutic agent.
link to slide presentation at HIV DART Dec 2024
HIV-DART: Ron Desrosier
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