Summary
Background: The emerging threat represented by SARS–CoV–2 variants, demands the development of therapies for better clinical management of COVID–19. MAD0004J08 is an extremely potent Fc-engineered monoclonal antibody (mAb) able to neutralise in vitro all current SARS–CoV–2 variants of concern (VoCs). This ongoing study, evaluates safety, pharmacokinetics and SARS–CoV–2 sera neutralization effect of MAD0004J08 when administered as single dose intramuscularly in healthy adults.
Method: We conducted a dose escalation study with sequential enrolment of three cohorts, each with an increasing dose level of MAD0004J08 (48mg, 100mg and 400mg). Within each cohort, 10 young healthy adults were randomized with 4:1 ratio to a single intramuscular (i.m.) injection of MAD0004J08 or placebo. The primary endpoint is the proportion of subjects with severe and/or serious treatment emergent adverse events (TEAEs) within 7 days post–treatment. Secondary endpoints reported in this paper are the proportion of subjects with solicited TEAEs up 7 days post dosing, MAD0004J08 serum concentrations and neutralising activity versus the original SARS-COV-2 Wuhan virus at different timepoints post-dosing. As post-hoc analyses, we compared the sera neutralising titres of subjects who received MAD0004J08 with those of people that had received the COVID–19 BNT162b2 mRNA vaccine in the previous sixty days (n=10) and COVID-19 convalescent patients (n=20), and assessed serum neutralisation activity against the B.1.1.7 (alpha), B.1.351 (beta) and B.1.1.248 (gamma) SARS–CoV–2 variants of concern.
Findings: A total of 30 subjects, 10 per cohort, were enrolled and randomized. Data up to 30 days were available and analysed in this report. No severe TEAEs were reported in any of the cohorts in the 7 days post-treatment. MAD0004J08 was detected in the sera of treated subjects within few hours post-administration and reached almost maximal levels on day 8. The geometric mean neutralising titres (GMT) assessed against the original Wuhan virus peaked on day 8 and ranged 226 – 905, 905 – 2,560, and 1,280 – 5,120 for cohort 1, 2 and 3 respectively. The sera neutralising GMT in MAD0004J08 treated subjects in all the three cohorts were found to be 1·5– 54·5–fold higher compared to sera from convalescent patients and 1·83– 76·4–fold higher compared to sera from COVID-19 vaccinees. Finally, GMT in MAD0004J08 treated subjects showed high neutralising titres versus the B.1.1.7 (alpha), B.1.351 (beta) and B.1.1.248 (gamma) SARS-CoV-2 VoCs.
Interpretation: A single dose administration of MAD0004J08 via i.m. route is safe and well tolerated and results in a rapid systemic distribution of the MAD0004J08 and sera neutralising titres higher than COVID–19 convalescent and vaccinated subjects. A single dose administration of MAD0004J08 is also sufficient to effectively neutralise major SARS–CoV–2 variants of concern. Based on these results, a Phase 2-3 trial is ongoing to further assess the safety, dosage, and efficacy of MAD0004J08 in asymptomatic or mild-moderate symptomatic COVID–19 patients.
Funding: EU Malaria Fund, Ministero dello Sviluppo Economico, Ministero della Salute, Regione Toscana, Toscana Life Sciences Sviluppo and European Research Council.
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