Optimizing SIV reservoir depletion by Tendel bsAb-98 - We are developing an HIV reservoir-depletion agent that targets CCR5+ cells for elimination and achieved remission of over 3 months in more than half of treated infant macaques. The agent is a bispecific antibody (bsAb) with one arm directed against CD3 and the other against CCR5, which approximates cytotoxic T cells to CCR5-expressing cells. These cells form a key part of the HIV reservoir and have been eliminated in all cases of HIV cures. Our preclinical studies revealed >50% remission in simian immunodeficiency virus (SIV)-infected infant rhesus macaques after bsAb-98 treatment. Mathematical modeling suggested that the agent achieved an effect equivalent to depletion of >99.9% of reservoir cells, probably through a combination of true reservoir depletion and removal of SIV target cells required for rebound. This agent may therefore have a unique role to play in HIV cure strategies. In this R44 application, we propose tasks that will improve the manufacturing process for bsAb-98 and test its efficacy in adult animals—both needed to support first-in-human testing of the agent alone and in combination regimens. We will test the value of an enhanced purification process for this bsAb. We will then rigorously test the reservoir depletion that is achievable using bsAb-98 in adult rhesus macaques. Finally, we will evaluate bsAb-98 in combination with a vaccine strategy. The result will be a complete data package supporting safety and efficacy of the agent and supporting the rationale for human clinical trials. Hypothesis: bsAb-98 can safely deplete CCR5+ cells from the blood and tissues of adult macaques, significantly deplete the acute or later SIV reservoir, and achieve instances of long-term remission. Aim 1. Optimize the purification process for bsAb-98 to minimize residual monospecific antibody. Despite the ability of cFAE to produce nearly 100% bispecific product, bsAb-98 preparations that were curative in our experiments were likely contaminated with small amounts of parental anti-CD3, which are unacceptable in a clinical product. Here we will develop strategies to eliminate any such contaminants. Aim 2. Quantify the SIV reservoir depletion achievable in adult macaques when CCR5/CD3 bsAb-98 is administered either (i) 30 days or (ii) 6 months after SIV infection. Surprisingly, our results in infant macaques resembled temporary CCR5 knockout, which could affect both the CCR5+ reservoir and the potential for viral outgrowth after ART withdrawal. In this aim we will rigorously evaluate both mechanistic possibilities in adult animals by testing (i) depletion of CCR5+ cells from blood and tissues, (ii) depletion of the SIV reservoir, and (iii) delayed rebound or SIV remission. Aim 3. Test the contribution of therapeutic vaccination to delayed rebound or remission in adults receiving bsAb-98. Tendel believes that bsAb-98 will most likely be used in combination regimens. The experiments of this Aim will provide proof-of-concept support for combining bsAb-98 with vaccines.
