Background
Eradication of the latent reservoir is a key objective for an HIV cure. Bispecific T-cell engagers (BsTCEs) offer a promising approach by redirecting cytotoxic T cells to eliminate HIV-infected cells. Amtabafusp alfa (ABF) is a novel BsTCE consisting of an Env-targeting engineered CD4 D1 domain paired with an anti-CD3 T-cell engaging Fab, which enables T-cell activation and redirection against HIV-infected cells. We evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ABF in people with HIV-1 (PWH).
Methods
We conducted a randomized, blinded, placebo-controlled, phase 1 study in virologically suppressed PWH (HIV-1 RNA <50 copies/mL, on ART ≥6 months). Participants were randomized to receive ABF or placebo via IV administration in single ascending doses (SAD; 0.3 mg up to 300 mg) or multiple ascending doses (MAD; 30 mg up to 300 mg every 2 weeks [Q2W] for 5 doses). Participants remained on ART throughout the study. Safety, PK, and PD (measured by CD3 T-cell receptor occupancy [CD3RO]) were evaluated.
Results
In total, 54 participants were enrolled (SAD, n=37; MAD, n=17) (Table). Treatment-emergent adverse events (TEAEs) occurred in 47/54 (87%) participants, mostly mild/moderate. Six (11%) experienced grade 3 TEAEs considered related to study drug by investigator: pyrexia (n=4), nausea (n=1), vomiting (n=1), and a transient decrease in CD4 lymphocytes (n=1). Cytokine release syndrome (CRS; all grade 1) occurred in 13/54 (24%) and reversible dermatologic TEAEs (grade 1-2) in 24/54 (44%) (Table); both were dose-dependent (up to 150 mg, the highest SAD tested) and did not worsen with multiple doses (≤75 mg Q2W, the highest MAD tested). There were no serious adverse events related to study drug. ABF showed linear PK (10-150 mg), 6-10 day terminal half-life, and minimal accumulation with multiple Q2W dosing. CD3RO peaked at 1-2 hours post-infusion, returned to baseline between days 15-57 (depending on dose), with no accumulation found after multiple dosing. Peak CD3RO ranged from 52% (10 mg) to 90% (150 mg), indicating T-cell engagement.
Conclusions
ABF was generally safe in virologically suppressed PWH, with manageable CRS and mild-to-moderate reversible dermatologic events. T-cell engagement was demonstrated through dose-dependent CD3RO, consistent with ABF’s mechanism of action. Forthcoming immune activation and reservoir data will further elucidate the mechanism of action of ABF and the risk/benefit profile of BsTCEs for HIV cure.
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