N-803 IL-15 Superagonist Complex and HIV Clinical Trials, Dosage, News, Side Effects, Usage
ImmunityBio N-803 is a novel investigational IL-15 superagonist complex (Anktiva®) consisting of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. Its proposed mechanism of action is direct specific stimulation of CD8+ T cells and NK cells through beta gamma T-cell receptor binding with a generation of memory T-cells while avoiding T-reg stimulation. N-803 (ALT-803) is designed to have improved pharmacokinetic properties, longer persistence in lymphoid tissues, and enhanced anti-tumor activity compared to native, non-complexed IL-15 in vivo.
Natural killer (NK) cells are dysfunctional in chronic human immunodeficiency virus (HIV) infection as they cannot clear the virus. Researchers hypothesized that an infusion of NK cells, supported by interleukin 2 (IL-2) or IL-15, could decrease virus-producing cells in the lymphatic tissues. A phase 1 clinical study detected a moderate decrease in HIV-producing cells in lymph nodes. All participants in this Phase 1 study experienced a significant reduction in infection levels following treatment with N-803. The approach was well tolerated, with no unexpected adverse events. Tim Schacker, MD, senior author of this paper, and colleagues at the University of Minnesota Medical School are planning a follow-up study with additional participants to investigate these immunotherapies further in HIV-infected individuals. In addition to this study, three clinical trials are underway involving N-803 in HIV Cure-related strategies.
Patrick Soon-Shiong, M.D., Chairman and Global Chief Scientific and Medical Officer at ImmunityBio, commented in a press release, "These data preliminarily appear to validate what we know about the benefit of enhancing NK cell function and the potential utility of N-803 in infectious diseases."
On March 6, 2024, ImmunityBio announced the recent publication of preclinical data in Science, First Release, indicating that combination therapy with N-803 and broadly neutralizing antibodies may potentially enable the immune system to manage HIV without the need for antiretroviral treatment.
Over the last two decades, ImmunityBio's Dr. Patrick Soon-Shiong, M.D., has investigated mechanisms to activate the immune system to attack tumors that can otherwise evade and escape the body's defense mechanisms. To learn more about these studies, please visit our website.
N-803 in HIV Indication
HIV affects tens of millions of people globally and currently has no known cure. One strategy for curing HIV is known as the "kick and kill" approach. The "kick" is to induce HIV out of its latent resting state in T cells, and the "kill" is to remove or kill the infected cells via an immune response or immunotherapy. "The viral reservoir in people with HIV is established within the first few days of infection and cannot be eliminated by the body's immune system or currently available treatments, representing a significant obstacle in curing an established HIV infection," said James B. Whitney, M.D. HIV can disable NK cells—a frontline defense against viral infections—making it difficult to clear the infection.
A research article published on February 29, 2024, titled' Induction of durable remission by dual immunotherapy in SHIV-infected ART-suppressed macaques' stated, 'complete eradication of the replication-competent viral reservoir is likely not a prerequisite for the induction of sustained remission after discontinuation of ART.'
A peer-reviewed Research Article published in March 2020, The human IL-15 superagonist N-803 promotes migration of virus-specific CD8+ T and NK cells to B cell follicles but does not reverse latency in ART-suppressed, SHIV-infected macaques, substantiates N-803 as a potent immunotherapeutic candidate capable of activating and directing effector CD8+ T and NK cells to the B cell follicle durincompletell ART suppression, and suggest N-803 must be paired with a bona fide latency-reversing agent in vivo to facilitate immune-mediated modulation of the latent viral reservoir.
In January 2020, a study, 'Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells' results, advanced the understanding of the mechanisms responsible for latency reversal and lentivirus reactivation during ART-suppressed infection.
N-803 in HIV News
March 6, 2024 - James B. Whitney, M.D., study author and researcher at the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and Harvard Medical School, commented, "When combined with broadly neutralizing antibodies, N-803 has the potential to provide viral control without significant reduction in the viral reservoir, which further suggests that the complete eradication of this reservoir may not be required to induce sustained remission after discontinuing antiretroviral therapy."
March 5, 2024 - ImmunityBio announced data from a Phase 1 pilot study showed N-803 combined with natural killer cells could have the potential to reduce viral load in people living with HIV.
September 12, 2023 - The journal Viruses published: IL-15 and N-803 for HIV Cure Approaches.
N-803 in HIV Clinical Trials
All participants in the Phase 1 pilot study (NCT03346499, NCT03899480) experienced a marked decrease in the burden of infection, and the procedures were found to be safe and well-tolerated.
Two Phase 1 clinical trials are investigating N-803 in combination with bNAbs in HIV-infected individuals (ACTG A5386, NCT04340596, and NCT05245292 at Rockefeller University), and a Phase 2 study, sponsored by the Thai Red Cross and the U.S. Military HIV Research Program, is also underway to investigate the effect of combining N-803 with ART during acute HIV infection.
