Safety, tolerability, and Plasmodium falciparum transmission-reducing activity of monoclonal antibody TB31F: a single-centre, open-label, first-in-human, dose-escalation, phase 1 trial in healthy malaria-naive adults

Abstract

Background: Malaria elimination requires interruption of the highly efficient transmission of Plasmodium parasites by mosquitoes. TB31F is a humanised monoclonal antibody that binds the gamete surface protein Pfs48/45 and inhibits fertilisation, thereby preventing further parasite development in the mosquito midgut and onward transmission. We aimed to evaluate the safety and efficacy of TB31F in malaria-naive participants.

Methods: In this open-label, first-in-human, dose-escalation, phase 1 clinical trial, healthy, malaria-naive, adult participants were administered a single intravenous dose of 0·1, 1, 3, or 10 mg/kg TB31F or a subcutaneous dose of 100 mg TB31F, and monitored until day 84 after administration at a single centre in the Netherlands. The primary outcome was the frequency and magnitude of adverse events. Additionally, TB31F serum concentrations were measured by ELISA. Transmission-reducing activity (TRA) of participant sera was assessed by standard membrane feeding assays with Anopheles stephensi mosquitoes and cultured Plasmodium falciparum gametocytes. The trial is registered with Clinicaltrials.gov, NCT04238689.

Findings: Between Feb 17 and Dec 10, 2020, 25 participants were enrolled and sequentially assigned to each dose (n=5 per group). No serious or severe adverse events occurred. In total, 33 grade 1 and six grade 2 related adverse events occurred in 20 (80%) of 25 participants across all groups. Serum of all participants administered 1 mg/kg, 3 mg/kg, or 10 mg/kg TB31F intravenously had more than 80% TRA for 28 days or more, 56 days or more, and 84 days or more, respectively. The TB31F serum concentration reaching 80% TRA was 2·1 μg/mL (95% CI 1·9-2·3). Extrapolating the duration of TRA from antibody kinetics suggests more than 80% TRA is maintained for 160 days (95% CI 136-193) following a single intravenous 10 mg/kg dose.

Interpretation: TB31F is a well tolerated and highly potent monoclonal antibody capable of completely blocking transmission of P falciparum parasites from humans to mosquitoes. In areas of seasonal transmission, a single dose might cover an entire malaria season.

Funding: PATH's Malaria Vaccine Initiative.

Conflict of interest statement

Declaration of interests We declare no competing interests.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Study profile PK–PD analysis=pharmacokinetic and pharmacodynamic analysis.

Figure 2

TB31F concentrations per dose group over time (A) Groups 1–4 (intravenous infusion, n=5 per group). (B) Group 5 (subcutaneous administration, n=4). Datapoints and error bars represent group mean and standard deviation, respectively. For group 1, serum TB31F concentrations were unavailable for one participant at day 28 and all five participants at day 56. One participant in group 5 had no detectable or very low concentrations of TB31F at any timepoint (appendix p 6).

Figure 3

TRA of TB31F per dose group over time (A) Group 2 (1 mg/kg intravenously). (B) Group 3 (3 mg/kg intravenously). (C) Group 4 (10 mg/kg intravenously). (D) Group 5 (100 mg subcutaneously). TRA was calculated by comparing the reduction of oocyst counts of participant sera compared with pooled naive serum in standard membrane feeding assay. Each line represents a participant. The horizontal dashed lines represent the 100% and 80% TRA threshold. No participants in the lowest dose group (group 1, 0·1 mg/kg) showed TRA >80% at any time point (data not shown). One participant in group 5 had no detectable or very low concentrations of TB31F, and TRA data are shown in the appendix (p 6). TRA=transmission-reducing activity.

Figure 4

Estimation of IC80 and predicted time of more than 80% TRA (A) TB31F concentration in serum at which 80% TRA (horizontal dashed line) is expected (IC80) was calculated by linear regression to be 2·1 μg/mL (vertical dashed line). Datapoints represent measured serum TB31F concentrations and respective TRA values for individual participants in groups 1 to 5, including only those timepoints where TRA was less than 99·5%. Shaded areas represent the pointwise 95% CI for the linear association. Given that all group 4 volunteers had TRA values of more than 99·5%, no points were included in this analysis. (B) The observed TB31F concentrations of individuals (circles) were used to extrapolate TB31F concentrations over time. For each individual in group 4 (10 mg/kg), the observed concentrations in samples from day 7 to day 84 were used to extrapolate concentrations up to month 6 via linear regression. The solid line represents the geometric mean of the observed data and the dashed line represents the extrapolated linear regressions. The coloured band represents the 95% CI for the extrapolated data. The horizontal dashed black line represents the IC80 of 2·1 μg/mL, which is crossed on day 160 (95% CI 136–193). The confidence intervals were calculated with the geometric standard deviation assuming lognormality. TRA=transmission-reducing activity.