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.
Evidence before this study We searched PUBMED, MEDLINE and MedRxiv for clinical trials, meta-analyses and randomized controlled trials evaluating the antibody neutralization titres vs. different SARS-CoV-2 variants of concern obtained from subjects who received monoclonal antibodies for the treatment of COVID-19 using the following search terms: (“COVID-19” OR “SARS-CoV-2”) AND (“monoclonal antibody” OR “neutralising antibody”) AND (“variants” OR “variants of concern”). No relevant studies were identified.
Added value of this study This is the first human study assessing safety, PK and neutralising potential of MAD0004J08, a monoclonal antibody against SARS-CoV-2 wild type Wuhan virus and variants of concern, administered intramuscularly at low dosages (48, 100 and 400 mg). MAD0004J08 showed to be safe and well tolerated in the tested dose range. Anti-spike antibodies were detected in the sera of tested SARS-CoV-2 negative healthy adults few hours post-injection. In addition, the sera obtained from MAD0004J08treated subjects, showed to have high neutralisation titres against the Wuhan virus, the B.1.1.7 (alpha), B.1.351 (beta) and B.1.1.248 (gamma) variants of concern.
Implications of all the available evidence A potent monoclonal antibody such as MAD0004J08, capable of neutralising multiple variants of concern of SARS-CoV-2 rapidly and long lastingly when given as a single intramuscular injection. The antibody, presently tested in a phase 2-3 efficacy trial, can be a major advancement in the prophylaxis and clinical management of COVID-19, because of its broad spectrum, ease of use in non-hospital settings and economic sustainability.
Competing Interest Statement
Rino Rappuoli is an employee of GSK group of companies. Emanuele Andreano, Ida Paciello and Rino Rappuoli are listed as inventors of full-length human monoclonal antibodies described in Italian patent applications n. 102020000015754 filed on June 30th 2020, 102020000018955 filed on August 3rd 2020 and 102020000029969 filed on 4th of December 2020, and the international patent system number PCT/IB2021/055755 filed on the 28th of June 2021.
Clinical Trial
NCT04932850
Funding Statement
This study was supported by the EU Malaria Fund, inaugurated on the 3rd of June 2020 and initiated by the kENUP Foundation. This publication was supported by the COVID-2020-12371817 project, which has received funding from the Italian Ministry of Health (Ministero della Salute), from the Italian Ministry of Economic (Ministero dello Sviluppo Economico) through the Contratti di Sviluppo funding program, and from Regione Toscana. This work was funded by the European Research Council (ERC) advanced grant agreement number 787552 (vAMRes). This publication was supported by the European Virus Archive goes Global (EVAg) project, which has received funding from the European Union Horizon 2020 research and innovation program under grant agreement No 653316.
https://www.medrxiv.org/content/10.1101/2021.08.03.21261441v1
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