Safety and serum distribution of anti-SARS-CoV-2 monoclonal antibody MAD0004J08 after intramuscular injection

Abstract

The emerging threat represented by SARS-CoV-2 variants, demands the development of therapies for better clinical management of COVID-19. MAD0004J08 is a potent Fc-engineered monoclonal antibody (mAb) able to neutralize in vitro all current SARS-CoV-2 variants of concern (VoCs) including the omicron variant even if with significantly reduced potency. Here we evaluated data obtained from the first 30 days of a phase 1 clinical study (EudraCT N.: 2020-005469-15 and ClinicalTrials.gov Identifier: NCT04932850). The primary endpoint evaluated the percentage of severe adverse events. Secondary endpoints evaluated pharmacokinetic and serum neutralization titers. A single dose administration of MAD0004J08 via intramuscular (i.m.) route is safe and well tolerated, resulting in rapid serum distribution and sera neutralizing titers higher than COVID-19 convalescent and vaccinated subjects. A single dose administration of MAD0004J08 is also sufficient to effectively neutralize major SARS-CoV-2 variants of concern (alpha, beta, gamma and delta). MAD0004J08 can be a major advancement in the prophylaxis and clinical management of COVID-19.

Fig. 1. CONSORT diagram phase 1 trial.

The graph shows the enrollment of subjects and their allocation to treatment and analysis.

Fig. 2. MAD0004J08 pharmacokinetics.

SARS-CoV-2 spike (S) protein IgG mean titers in (ng/mL) pre and post MAD0004J08 injection in three cohorts. Dots indicate the individual antibody titers for Cohort 1 (48mg-light blue; n = 8), Cohort 2 (100mg-blue; n = 8) and Cohort 3 (400mg-dark blue; n = 8). Only p values for statistically significant differences are shown in the figure. A nonparametric Mann–Whitney t test was used to evaluate statistical significance between groups. Two-tailed p value significances are shown as *p ≤ 0.05, **p ≤ 0.01, and ***p ≤ 0.001. Data are presented as geometric mean ± standard deviation. Subjects from the placebo group (2/group) were excluded from the analyses.

Fig. 3. Serum neutralization activity against SARS-CoV-2 Wuhan virus.

The graph shows the neutralization reported as 100% inhibitory dilution (ID₁₀₀) of sera collected from COVID-19 convalescent patients (n = 20; red), average samples collection 10 days post-hospitalization, vaccinees not exposed (seronegative; n = 5; light gray), average samples collection 48 days post-vaccination, or previously exposed (seropositive; n = 5; dark gray), average samples collection 21 days post-vaccination, to SARS-CoV-2 and subjects that received MAD0004J08 at 48 (n = 8; light blue), 100 (n = 8; blue), and 400 mg (n = 8; dark blue) at day 8. Only p values for statistically significant differences are shown in the figure. A nonparametric Mann–Whitney t test was used to evaluate statistical significance between groups. Two-tailed p value significances are shown as *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, and ****p ≤ 0.0001. Data are presented as geometric mean ± standard deviation.

Fig. 4. Serum neutralization activity against SARS-CoV-2 variants of concern.

a–d Graphs show the neutralization activity reported as 100% inhibitory dilution (ID₁₀₀) of sera collected from subjects who received MAD0004J08 at 48 (cohort 1; n = 8; light blue), 100 (cohort 2; n = 8; blue) and 400 (cohort 3; n = 8; dark blue) mg against SARS-CoV-2 B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), and B.1.617.2 (delta) variants at day 8. Data are presented as geometric mean ± standard deviation. e–g Graphs show values of serum neutralization activity against the different SARS-CoV-2 VoCs tested in this study for Cohort 1 (n = 8), Cohort 2 (n = 8), and Cohort 3 (n = 8). Fold changes relative to Wuhan virus are reported for each VoCs. A nonparametric Mann–Whitney t test was used to evaluate statistical significances between groups and tested viruses. Two-tailed p value significances are shown as *p ≤ 0.05, **p ≤ 0.01, and ***p ≤ 0.001. Data are presented as geometric mean ± standard deviation. Data are presented as geometric mean.