Dose-dependent effects of neutralizing anti-HBs monoclonal antibody VIR-3434 on hepatitis B surface antigen composition

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Introduction: Tobevibart (VIR-3434) is an investigational Fc-engineered human monoclonal antibody (mAb) targeting the conserved antigenic loop of HBsAg in development for the treatment of chronic hepatitis B (CHB). Recently, a decrease in large (L) and medium (M) HBsAg components during treatment with nucleos(t)ide analogues (NA) was found to be associated with subsequent HBsAg loss, indicating a likely association of MHBs and LHBs with cccDNA transcriptional activity. Aim: We analyzed the effect of tobevibart, alone or in combination with NA, on the composition of HBsAg in the serum of patients with chronic hepatitis B. Methods: Sera of 69 mostly HBeAg-negative patients from the prospective randomized VIR-3434-1002 phase I trial were retrospectively analyzed. Patients were divided in 3 cohorts: Part B (n=30; NA treatment≥2 months prior to study+BL HBsAg levels<3000 IU/mL), Part C (n=23; NA treatment≥2 months prior to study+BL HBsAg levels≥3000 IU/mL) and Part D (n=16; not on NA, BL HBV DNA≥1000 IU/mL, any HBsAg level) and received a single dose subcutaneous injection of either 6, 18, 75, or 300 mg of tobevibart at day 1 (BL). Serum HBsAg components were quantified on an automated platform (DiaSorin) with well-defined mAbs (LHBs [Ma18/7]; MHBs [Q19/10]; total HBsAg: [DiaSorin, Enzygnost HBsAg 6.0]) in sera of days 1, 8 and 57. Results: At BL, levels of total HBsAg, MHBs, and LHBs were significantly lower in Part B compared to Part C or D, respectively ( p <0.001). At day 8, levels of LHBs and MHBs decreased in all groups independent of the tobevibart dose, with Part B showing the strongest decline. However, the ratio of MHBs only decreased significantly in Part B from 3.8% at BL to 0% at day 8 ( p <0.001) and slightly re-increased to 0.7% at day 57. In Part C and D, MHBs also decreased from 3.9 and 3.4% at BL to 1.4 and 2.1% after 8 days but re-increased to 4.3 and 6.1% at day 57 ( p =n.s.). Moreover, treatment in Part B showed a dose-dependent effect on the decrease of LHBs and MHBs levels, with a single dose of 300 mg causing the strongest decrease in ratios of LHBs and MHBs. Conclusion: A single dose of tobevibart added to NA treatment significantly suppressed LHBs and MHBs components in patients with baseline HBsAg levels below 3.000 IU/mL. Further investigation is needed to determine if this suppression indicates reduced cccDNA transcriptional activity, potentially predicting a functional cure with long-term tobevibart treatment. Publication History Article published online: 04 September 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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