C-102 Long-term delivery of antiviral monoclonal antibodies

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The current availability of an incredible array of monoclonal antibodies (mAbs) with potent neutralizing activity against a broad range of HIV-1 isolates creates attractive possibilities for treatment and prevention. An ability to achieve stable levels of protective mAb concentrations long-term via vector delivery has a number of distinct advantages over repeated passive administrations. These include cost, issues relating to adherence, and convenience. Using AAV as vector, we have achieved stable concentrations of authentic IgG mAb in monkeys in excess of 100 ug per ml of serum for as long as 3.5 years, the longest we have measured. In the one SHIV-infected monkey to which we have successfully delivered two anti-HIV mAbs, viral loads have been impressively suppressed from 11,000 at the time of AAV administration to below the limit of detection for more than 22 months in the absence any antiviral drug treatment. The main obstacle hindering development of this approach for use in humans is anti-drug antibodies, i.e. the development of an antibody response to the delivered antibody that can severely impair the concentrations of delivered antibody that can be achieved. These anti-antibodies are predominantly or exclusively directed to the variable domains, i.e. they are anti-idiotype. This is especially a problem because the mAbs with potent neutralizing activity that we want to deliver for the most part are highly divergent from germline and have unusually long CDR3 regions. We now appear to have found vector design and vector delivery conditions that allow consistent delivery of problematic anti-SIV/anti-HIV mAbs. Nonetheless, continued work is needed to effectively realize the full potential of this approach.

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