Infectious Disease · Medical Literature
Bispecific 10E8.4/iMab broadly neutralizing antibody in people with or without HIV-1: a partially randomized phase 1 trial.
Abstract
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 .
Clinical relevance
Is the bispecific broadly neutralizing antibody 10E8.4/iMab safe, tolerable, and pharmacokinetically active when administered intravenously or subcutaneously across a range of doses in adults living with or without HIV-1? __SNAPSHOT__ {"studyDesign":"First-in-human, partially randomized, placebo-controlled, dose-escalation Phase 1 trial (arms 1–3 non-randomized; arm 4 randomized)","setting":"Multi-center; Columbia University Medical Center (New York City) and Orlando Immunology Center (Orlando, Florida), USA; conducted partially during the COVID-19 pandemic","sampleSize":"n=54 total (10E8.4/iMab active recipients across multiple dose cohorts plus placebo recipients in arm 4; exact per-arm placebo n not fully reported in abstract)","population":"Adults living with HIV (PLWH; arms 3/3a: viremic with HIV-1 RNA 1,000–100,000 copies/mL and CD4 >350 cells/mm³, or ART-suppressed) and adults living without HIV (PLWoH; arms 1, 2, 4); CD4 nadir >250 cells/mm³ required for PLWH","intervention":"Single-dose 10E8.4/iMab bispecific antibody administered IV or SC across dose levels: 0.3, 1, 3, 10, 30 mg/kg IV; 1, 2.5, 10 mg/kg SC","comparator":"Placebo (arm 4 only, PLWoH randomized to 10E8.4/iMab 2.5 mg/kg SC or 10 mg/kg SC vs. placebo, n=9 per group)","primaryOutcome":"Rate of signs, symptoms, and laboratory abnormalities (including solicited local and systemic adverse events) within 2 weeks of 10E8.4/iMab administration","followUp":"Long-term safety follow-up duration not reported in abstract; 2-week primary safety window specified","fundingSource":"Not reported in abstract; study registered under NCT03875209 with Columbia University as sponsor"}
Key findings
The primary safety outcome was met: no treatment-related serious adverse events (SAEs) and no adverse events of Grade ≥3 severity were reported across all arms, doses (0.3–30 mg/kg IV; 1–10 mg/kg SC), and both populations (PLWH and PLWoH). Absolute risk of Grade ≥3 or serious treatment-related AEs was 0% (0/54 active recipients); NNH is not calculable. The pharmacokinetic profile was notably non-linear due to target-mediated drug disposition driven by the iMab arm's interaction with host CD4 receptors, making elimination half-life dose- and context-dependent rather than constant. Population PK modeling predicted a maximal elimination half-life of approximately 21.3 days (under conditions of negligible free CD4 receptor or very high serum concentrations). At the 10 mg/kg IV level (group E), an approximate half-life of 3.4 days was estimated between days 3–10; at 30 mg/kg IV (group F), approximately 8.7 days between days 6–13—both representing transient quasi-linear phases during high CD4 receptor occupancy. Anti-drug antibodies (ADAs) developed in a subset of participants once drug concentrations declined; the rate of ADA detection, multi-epitope targeting, and evidence that some ADAs could inhibit drug function indicate significant immunogenicity potential. Critically, no ADA-related adverse events and no CD4+ T cell depletion were observed among ADA-positive participants. Antiviral activity data were limited: enrollment of viremic PLWH was curtailed due to COVID-19 pandemic-related protocol amendments, and the abstract does not report quantitative viral load decline figures. No specific p-values, confidence intervals, or NNT/NNH for efficacy endpoints are reported in the abstract.
Practice implications
This first-in-human trial established that 10E8.4/iMab is safe and well tolerated across a broad dose range (0.3–30 mg/kg IV; up to 10 mg/kg SC) in both PLWH and PLWoH, with no treatment-emergent SAEs or Grade ≥3 events — a particularly meaningful finding given that the iMab arm targets host CD4 receptors, raising theoretical concerns about immunosuppression and CD4 depletion. The absence of CD4+ T cell depletion even among ADA-positive participants provides reassurance regarding this host-targeting mechanism. The trial did NOT establish antiviral efficacy: viremic PLWH enrollment was reduced during the COVID-19 pandemic, and quantitative antiviral conclusions are explicitly limited. The non-linear, target-mediated PK driven by CD4 receptor engagement represents a clinically important distinguishing feature from conventional monoclonal antibodies and will complicate dose selection and interval planning for future studies. The high immunogenicity signal (ADA development, multi-epitope coverage, functional inhibition by some ADAs) is a notable concern that will require careful monitoring and potential mitigation strategies in later-phase trials. Findings apply most directly to ART-naive or suppressed adults with preserved CD4 counts; broadly diverse populations (pediatrics, advanced immunosuppression, diverse HIV-1 subtypes including high-prevalence clade C) were not adequately represented. Results should be considered hypothesis-generating; practice should not change on the basis of this Phase 1 safety trial alone. Only the abstract was available for review, which limits granular assessment of subgroup outcomes, full ADA characterization, and the complete antiviral dataset. __LIMITATIONS__ Small sample sizes within each dose cohort (n=3–9), limiting statistical power to detect uncommon adverse events or dose-response relationships.,COVID-19 pandemic disrupted enrollment of viremic PLWH, critically limiting the antiviral activity dataset — the investigators explicitly acknowledge this precluded firm conclusions about antiviral properties.,Arms 1–3 were non-randomized (open-label dose escalation), introducing allocation and assessment bias; only arm 4 (PLWoH, SC dosing) was randomized and placebo-controlled.,Single-dose administration only: repeat-dosing safety, cumulative immunogenicity, and sustained antiviral activity cannot be assessed.,Non-linear, target-mediated PK makes half-life estimation complex and dose-dependent, complicating comparisons with other bnAbs and inference about prophylactic or therapeutic dosing intervals.,High ADA immunogenicity rate raises concern for loss of efficacy with repeat dosing in future trials; functional impact not fully characterized from the abstract.,Geographic and demographic homogeneity (two US sites); limited representation of populations most affected by HIV globally (sub-Saharan Africa, clade C-predominant settings).,Surrogate pharmacokinetic and immunogenicity endpoints — no clinical outcomes (HIV acquisition, virologic suppression durability) evaluated.,Funding source not reported in the abstract, limiting assessment of potential industry influence.,Only the abstract was available; full data tables, individual participant-level outcomes, and complete ADA immunogenicity data could not be independently reviewed. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ 10E8.4/iMab, a dual-mechanism bispecific bnAb targeting both HIV-1 gp41 MPER and host CD4, was safe and well tolerated at all tested IV and SC doses in adults with and without HIV-1, with no treatment-related serious or Grade ≥3 adverse events and no CD4+ T cell depletion even among participants who developed anti-drug antibodies. The trial did not establish antiviral efficacy due to pandemic-related enrollment limitations, and notable immunogenicity signals require vigilance in future dosing studies. This is a promising safety proof-of-concept for a novel bispecific bnAb platform; larger, repeat-dose trials with viremic participants across diverse HIV-1 subtypes are needed before any clinical application can be considered.