A single intramuscular injection of monoclonal antibody MAD0004J08 induces in healthy adults SARS-CoV-2 neutralising antibody titres exceeding those induced by infection and vaccination

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.

Salbutamol Residue in Plasma and Urine of Balinese Calves after Single-Dose Administration

Salbutamol, a short-acting β2-adrenergic receptor agonist, due to illegal use in animal feed, is very dangerous for the safety of animal origin products. The purpose of this study is to determine the residue of salbutamol in plasma and urine of balinese calf after a single-dose administration. Three calves were given of feed fortification of salbutamol (10 mg/kg body weight). The salbutamol concentrations were measured in the plasma and urine. Samples were extracted with perchloric acid and purified by cation exchange solid phase extraction (SPE), then analyzed by High-Performance Liquid Chromatography (HPLC) with a photodiode array detector using an RP C18 column with a mixed mobile phase of purified water pH 3.0 (adjusted with phosphoric acid) and acetonitrile (90:10, v/v). The highest salbutamol concentration in the plasma sample was 0.28±0.15 μg/mL at 12 hours and decreased after 24 hours after feeding. The highest concentration of salbutamol in urine was 15.85±4.42 μg/mL at 18 hours and decreased gradually starting at 24 hours. This result concluded that salbutamol residues mostly excreted in the urine, and the highest salbutamol residues in plasma samples formed faster but also decreased more rapidly than residues formed in urine. The residue formed in plasma is lower than that in the urine.

A NEW BACTERIAL TRANSFER THERAPY FOR IBD: ENDOSCOPIC BIFIDOBACTERIUM AND XYLOGLUCAN ADMINISTRATION

Ulcerative colitis (UC) pathogenesis includes the altered gut microbiota, environmental factors, and human immune and genetic predisposition. Recently, its association with reduced bifidobacteria quantity in the microbiota is reported.Xyloglucan, a plant based prebiotic oligosaccharide, causes increase in bifidobacteria quantity. In this article we share the results of our UC cases treated by intracolonic single dose administration of Bifidobacterium animalis subsp. Lactis and xyloglucan combination. Intracolonic single dose administration of 200 billion CFUs of Bifidobacterium animalis subsp. lactis and 4 gr of xyloglucan combination was administrated to ten severe UC patients, who were either unresponsive or had inadequate response to treatment. All patients continued treatment after the procedure. Treatment responses were evaluated by colonoscopic, laboratory and clinical examination after 6 weeks. Intracolonic single dose administration of Bifidobacterium animalis subsp. lactis and xyloglucan was found effective in the mucosal healing and resolution of colonic symptoms in ulcerative colitis patients. Intracolonic administration of Bifidobacterium animalis subsp. lactis and xyloglucan in UC is a new single strain and strain specific prebiotic combination method. It is easy to apply and has no observable side effect. Its effectiveness on mucosal healing could be attributed to the enhancement of non-stimulatory status and biodiversity in colonic mucosa. Nonetheless, it is still necessary to develop diagnostic strategies to determine the patients to whom this method would be the most applicable.