Background:
A stable reservoir of replication-competent HIV proviruses that persist in CD4+ T cells is the main barrier to functional cure. Safe and effective strategies for immune clearance of the HIV reservoir are needed. Immune-mobilising monoclonal T cell receptors (TCR) against viruses (ImmTAV®) are unique bispecific soluble proteins comprising an affinity-enhanced TCR fused to an anti-CD3 scFv T cell activating moiety that redirects polyclonal T cells of any specificity to kill virus-infected cells. IMC-M113V is an HIV-specific ImmTAV® (GAGxCD3) that redirects effector T cells to eliminate HIV-infected cells presenting a specific HLA-bound Gag-derived peptide. Induction of systemic cytokines is an expected on-target pharmacodynamic (PD) effect, based on clinical studies with TCR bispecifics with a similar mechanism of action, against cancer and hepatitis B.
Methods:
STRIVE (Soluble T cell Receptors In Virus Eradication) is an open-label Phase 1/2 study evaluating IMC-M113V in HLA-A*02:01 positive PLWH receiving suppressive antiretroviral therapy (ART) (EudraCT: 2021-002008-11). PLWH on ART for ≤7 years were enrolled in a single ascending dose study to identify a safe and biologically active dose. Secondary objectives were to characterize pharmacokinetic and PD profiles, including serum cytokines (IL2, IL6, IL8, IL10, IFNγ, TNFα, and IP10) pre- and ≤24 hours post-dosing. A ≥4-fold rise in IL6 was prespecified as indicative of PD activity.
Results:
Three dose levels of IMC-M113V, given as a single IV infusion, were evaluated: a starting dose of 1.6 mcg, based on the minimum anticipated biological effect level (n=1), 5 mcg (n=1) and 15 mcg (n=10). Doses were well tolerated and were not associated with cytokine release syndrome or neurotoxicity of any grade. There were no serious adverse events, nor significant changes in hematology or chemistry. One subject reported moderate fatigue of < 24 hours’ duration. Plasma viral load remained suppressed throughout dosing and follow-up. Transient, dose-dependent increases in serum IL6 occurred 8-24 hours post-infusion, with 5/10 subjects showing a >4-fold rise after receiving the 15 mcg dose. Further cytokine quantification is ongoing.
Conclusions:
A single infusion of IMC-M113V was associated with biological activity consistent with the mechanism of action and was well tolerated at doses ≤15 mcg. This study provides the first human safety and PD impact of this novel agent to inform the design of a multiple ascending dose study.
