Control of HIV-1 infection can be achieved in most patients with combination anti-retroviral therapy (ART). Even with a prolonged period of completely suppressive ART, the viral load increases within weeks to months after discontinuation. The source of re-emergent HIV-1 is found mainly in memory CD4+ T cells which harbor replication-competent but transcriptionally silent pro-viral DNA. Elimination of this latent HIV-1 reservoir is the major impediment to achieving a cure of HIV-1 infection. Strategies to eradicate the latent reservoir by stimulating HIV-1 replication in latently infected cells, either through drug-induced activation of viral transcription or cytokine-induced acceleration of CD4+ cell turnover, have met with limited success. An alternative strategy is to directly target and kill latently infected cells. We hypothesize that memory CD4+ cells can be targeted by monoclonal antibodies (MAb) and killed by radiation in the form of an alpha-emitter without undue toxicity to the patient. We furthr hypothesize that radiolabeled MAb depletion of memory CD4+ cells, followed by measures to protect CD4+ cells during rebound proliferation, would considerably shorten the duration of ART and accomplish a sterilizing cure. Here, we propose to develop the radiolabeled MAb and to study efficacy and toxicity in nonhuman primates. We propose two targeting strategies, one to deplete CD4+ cells that include all memory CD4+ subsets, and a second to broadly target CD3+ cells, which would likely result in a greater depletion of CD4+ cells and for which we have already shown in a canine model to be safe (nontoxic). In the R21 phase, we will produce the radiolabeled MAbs that target macaque and human T cells and characterize binding to target antigen.
In Aim 1 we will conjugate 211At to both anti-CD4 and anti-CD3 MAb using a novel method for radiolabeling and validate binding specificity.
In Aim 2 we will characterize the radiolabeled MAb in vivo, using a human T-cell xenograft mouse model to ascertain stability of the conjugation and binding to target antigens. The R33 phase will proceed only after the radiolabeled MAb(s) have been validated. Here, we will test the radiolabeled MAbs in rhesus macaques to determine the optimal dose for use in depletion of memory CD4+ T cell subsets.
In Aim 3 we will conduct bio distribution studies to determine the dose of radiolabeled MAb that will result in >50% saturation of the target antigens. Then, in Aim 4 we will investigate the toxicity profile of the radiolabeled MAbs and their effects on CD4+ cell subsets in peripheral blood and lymphoid tissues. Finally, we will consider results of the toxicity and efficacy studies to arrive t the optimal dose of each radiolabeled MAb. The immediate goal of our proposal is to develop a highly effective agent to deplete memory CD4+ cells, to be tested further in NHP models of HIV-1 latency. The ultimate goal is to develop a non-toxic agent capable of depleting latently infected cells to a level that, when combined with fully suppressive ART and ongoing reservoir decay, would allow for HIV eradiation within years rather than decades.
Cure of human immunodeficiency virus-1 (HIV-1) is made difficult because the virus persists in a resting state in very small numbers of immune (CD4+) cells. Eradication of the virus is not possible with the current anti-retroviral drugs. This projec is focused on developing a safe therapy that targets and kills the cells harboring HIV-1.
|Li, Yawen; Hamlin, Donald K; Chyan, Ming-Kuan et al. (2018) cGMP production of astatine-211-labeled anti-CD45 antibodies for use in allogeneic hematopoietic cell transplantation for treatment of advanced hematopoietic malignancies. PLoS One 13:e0205135|