Background
ImmTAV® are soluble bispecific T cell engagers that kill virus-infected cells presenting extremely low target peptide-HLA levels. IMC-M113V (GAGxCD3) is the first HIV ImmTAV in the clinic; a single dose study demonstrated safety and biological activity in antiretroviral therapy (ART)-suppressed PLWH. We investigated the effect of multiple ascending doses of IMC-M113V on HIV reservoir size and post-treatment viral control off ART.
Methods
HLA-A*02:01 positive PLWH on ART ≤7 years were enrolled in this open-label Phase 1/2 trial (EudraCT: 2021-002008-11). After step dosing during weeks (W) 1-2, escalating target IMC-M113V doses were administered IV Q1W to sequential cohorts during W3-12. Participants paused ART (analytical therapy interruption, ATI) during W13-W24. ART was resumed at W24 or earlier if plasma viral load (pVL) copies/ml exceeded 103 for >4 weeks or 105 x2 weeks, or CD4 count fell <350 cells/μl. Primary objectives were safety and tolerability; secondary and exploratory analyses include quantification of serum cytokines and cell-associated HIV RNA (CA-RNA), duration of pVL <103 during ATI and time to ART resumption. Change in CA-RNA from baseline to W13 was analysed by mixed effects models.
Results
Sixteen males were enrolled to 3 target dose cohorts of IMC-M113V: 60 μg, n=5; 120 μg, n=5; 300 μg, n=6. Doses were well tolerated and there were no serious adverse events or treatment-related discontinuations. Transient (<24 h duration) fever ≥38 oC was observed in 5/6 PLWH only after the first 300 μg dose, in tandem with a rise in serum IL-6, IFN-γ and CXCL10 (peak 16-, 4- and 264-fold respectively). At W13, IMC-M113V was not detectable in serum. During ATI (n = 13), post-rebound viremia control was observed in 3/13 PLWH: 0 at 60 µg; 1 at 120 μg (pVL <103 x7/12 weeks); 2 at 300 μg (1 with pVL <103 x10 weeks, enabling ATI extension to W28; 1 with rebound at W17, followed by a 3-log decline in pVL at W18-21). Of the remaining 3 at 300 mcg dose, 2 are due to start ATI and 1 withdrew prior to ATI. HIV CA-RNA (mean ±SD copies/106 TBP) was significantly reduced from baseline (2374 ±2733) to W13 (1175 ±1809), p = 0.019.
Conclusions
IMC-M113V was well tolerated with initial evidence of post-rebound viral control off-ART. We observed a reduction in the active reservoir (CA-RNA) during treatment, the most substantial reported to date. This study provides the first evidence of antiviral efficacy for this novel mechanism of action. Doses >300 μg and longer ATI duration will be evaluated.