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Bispecific Biologics That Target and Activate the HIV Latent Reservoir Ex Vivo and In Vivo
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CROI 2026 Feb 22-25 Denver
Yaoxing Huang1, Jian Yu1, Manoj S. Nair1, Hiroshi Mohri1, Sue Chong1, Carlo Sacdalan2,3, Somchai Sriplienchan3, Lydie Trautmann4,5, Sandhya Vasan4,5 and David D. Ho1
1Aaron Diamond AIDS Center, Columbia University Medical Center, New York, NY 10032, 2SEARCH Research Foundation, Bangkok, Thailand, 3Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, 4U.S. Military HIV Research Program, CIDR, Walter Reed Army Institute of
Research, Silver Spring, MD, USA, 5Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA
Science Mag, Jon Cohen: New HIV cure approach forces hidden virus into tripping immune sensor
Now, studies in the lab and in a few patients, presented last week at an HIV/AIDS conference here, bolster an ingenious new cure approach.....a class called targeted activator of cell kill (TACK) molecules....David Ho is testing a one-two punch strategy that combines a related TACK with an established—but so far unsuccessful—approach to depleting those reservoirs......"The cure field right now is thinking about TACKs as strategies to reduce the reservoir load, but I see these molecules as potentially having a more direct, earlier effect on inflammation," Peter Hunt says. "It could be very important."
Program abstract
Background: IL-15 induces activation of memory CD4 (mCD4) and CD8 T cells as well as NK cells. It could also reactivate latent HIV-1 hiding in resting mCD4 T cells ex vivo. N-803 (IL15RaFc, Anktiva) is an IL-15 superagonist approved for cancer therapy, and its utility in activating latent HIV-1 is being studied. We posited that targeted delivery of IL-15 to mCD4 T cells will lead to better HIV-1 latency reversal and minimize off-target activation of CD8 and NK cells.
Methods: We made two bispecific antibody-like constructs. First, T4IL15 has one arm bearing the Fab of ibalizumab (approved anti-CD4 mAb) and another arm bearing a complex of IL-15 and IL-15 receptor alpha chain (IL15Ra) that can bind IL2/IL15 receptor beta and common gamma chain. Second, T4IL15Δ has an identical structure except for a mutation in IL-15 that reduces the receptor beta/gamma binding affinity. We tested the activity of T4IL15 and T4IL15Δ by assessing CD69 activation in healthy donor PBMCs, as well as looking for
evidence of ex vivo HIV-1 reactivation in PBMCs obtained from patients who initiated suppressive ART in the Thai RV254 study during acute infection. We also evaluated their efficacy on latency reversal as manifested by plasma viral blips in HIV-1-infected, ART-suppressed humanized mice.
Results: T4IL15 was more effective than N-803 in activating mCD4 T cells, but it also activated memory CD8 and NK cells. T4IL15Δ retained activity in activating mCD4 T cells, while abrogating stimulation of CD8 and NK cells. The exquisite selectivity of T4IL15Δ is likely due to an avidity effect of anchoring the low-affinity IL15Ra on CD4 molecules. Ex vivo studies on PBMCs from 12 RV254 participants failed to show release of HIV-1 particles when treated with N-803 (0.1 μg/mL), like PBMCs treated with a negative control, 10E8.4/iMab. PMA/Ionomycin led to viral particle release in 4/12 samples, whereas T4IL15 and T4IL15Δ (0.1 μg/mL) showed evidence of HIV-1 reactivation in 11/12 samples and 9/12 samples, respectively (Fig. A in oster below its 12/12). Furthermore, in HIV-1-infected humanized mice on suppressive ART, T4IL15 or T4IL15Δ (3μg) induced detectable plasma viremia within 2 days in 9/16 or 12/16 mice, respectively, whereas N-803 (3μg) failed to do so (0/9) (Fig. B).
Conclusions: Both T4IL15 and T4IL15Δ can activate mCD4 T cells, with the latter being highly specific. Both constructs demonstrate an unprecedented propensity to activate latent HIV-1 in PBMCs ex vivo and infected humanized mice in vivo.
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