Bispecific 10E8.4/iMab broadly neutralizing antibody in people with or without HIV-1: a partially randomized phase 1 trial.

Broadly neutralizing antibodies (bnAbs) are a promising tool for HIV prevention and treatment. Here we conducted a first-in-human, phase 1 trial of the bispecific 10E8.4/iMab antibody, which consists of a 10E8.4 arm binding the HIV-1 envelope glycoprotein membrane-proximal external region and an ibalizumab (iMab) arm binding the human CD4 molecule. 10E8.4/iMab was administered intravenously (IV) or subcutaneously (SC). Safety/tolerability within 2 weeks of 10E8.4/iMab administration (primary outcome) and the pharmacokinetics (PK), antiviral activity, induction of anti-10E8.4/iMab antibodies, longitudinal CD4+ and CD8+ T cell counts and long-term safety (secondary outcomes) were evaluated. 54 participants living with HIV (PLWH) or without HIV (PLWoH) received 10E8.4/iMab or placebo. In arm 1, PLWoH received 10E8.4/iMab 0.3 mg kg-1 IV, 1 mg kg-1 SC, or 1 mg kg-1 IV (n = 3 each). In arm 2, PLWoH received 10E8.4/iMab 3 mg kg-1 IV, 10 mg kg-1 IV or 30 mg kg-1 IV (n = 6 each). In arms 3/3a, PLWH received 10E8.4/iMab 10 mg kg-1 IV (n = 3) or 30 mg kg-1 IV (n = 6). In arm 4, PLWoH were randomized to receive 10E8.4/iMab or placebo 2.5 mg kg-1 SC or 10 mg kg-1 SC (n = 9 each). Participants in arms 1-3 were not randomized. No treatment-related serious adverse events (AEs) or AEs ≥ grade 3 were reported. The most common solicited AEs were tenderness (10/54, 18.5%), fatigue (18/54, 33.3%) and headache (12/54, 22.2%). Related grade 2 local and systemic solicited AEs occurred in one and six participants, respectively. Three of nine PLWH developed a generalized rash 8-12 days after infusion that resolved within 9-16 days. The primary objective of the study to evaluate the safety/tolerability of 10E8.4/iMab was met. These data support further study of 10E8.4/iMab to expand HIV treatment and prevention options. ClinicalTrials.gov: NCT03875209 .