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Background: Glenzocimab is a novel antithrombotic agent which targets platelet glycoprotein VI (GPVI) and does not induce haemorrhage. SARS-CoV-2 triggers a prothrombotic state and lung injury whose mechanisms include coagulopathy, endothelial dysfunction, and inflammation with dysregulated platelets., Methods and Patients: GARDEN was a randomised double-blind, exploratory phase II study of glenzocimab in SARS-CoV-2 respiratory failure (NCT04659109). PCR+ adults in Brazil and France (7 centres) were randomized to standard-of-care (SOC) plus glenzocimab (1000 mg/dayx3 days) or placebo, followed for 40 days. Primary efficacy endpoint was clinical progression at Day 4. All analyses concerned the intention-to-treat population., Results: Between December 2020 and August 2021, 61 patients received at least one dose (30 glenzocimab vs 32 placebo) and 58 completed the study (29 vs 29). Clinical progression of COVID-19 ARDS was not statistically different between glenzocimab and placebo arms (43.3% and 29.0%, respectively; p = 0.245). Decrease in the NEWS-2 category at D4 was statistically significant (p = 0.0290) in the glenzocimab arm vs placebo. No Serious Adverse Event (SAE) was deemed related to study drug; bleeding related events were reported in 6 patients (7 events) and 4 patients (4 events) in glenzocimab and placebo arms, respectively., Conclusions: Therapeutic GPVI inhibition assessment during COVID-19 was conducted in response to a Public Health emergency. Glenzocimab in coagulopathic patients under therapeutic heparin was neither associated with increased bleeding, nor SAE. Clinical impact of glenzocimab on COVID-19 ARDS was not demonstrated. A potential role for GPVI inhibition in other types of ARDS deserves further experimentation. Glenzocimab is currently studied in stroke (ACTISAVE: NCT05070260) and cardiovascular indications., Competing Interests: The authors are declaring the following links of interest. JP was a part of GARDEN study scientific committee and worked as a consultant for Acticor Biotech, he also has link with AOP Orphan, Baxter, Edwards Lifseciences, Masimo, LFB, RDS and Takeda outside the scope of this work. FR has consultancy agreement with Astra Zeneca, Gilead, MSD, Roche and ViiV Healthcare. MJP is a scientific co-founder, consultant and shareholder of Acticor-Biotech. GA is a co-founder, CEO and shareholder of Acticor-Biotech. SB is the CSO and GM of Acticor Biotech. YP is the CMO and GM of Acticor Biotech as a consultant and has stock interest in Acticor Biotech. SB, AC, DF, ML, AM and ET are employees and have stock interest in Acticor Biotech. SG, VDH and GA are consultant for Acticor Biotech. Other authors have no links to disclose. Acticor Biotech is a commercial company currently developing GARDEN study drug, glenzocimab, and holds several related patents/rights. GARDEN study was an industry sponsored trial, and Acticor Biotech was involved, or provided support, for study design, data collection and analysis, decision to publish, and preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials. , (Copyright: © 2024 Pottecher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Antagonists of glycoprotein VI-triggered platelet activation used in combination with recanalisation therapies are a promising therapeutic approach in acute ischaemic stroke. Glenzocimab is an antibody fragment that inhibits the action of platelet glycoprotein VI. We aimed to determine and assess the safety and efficacy of the optimal dose of glenzocimab in patients with acute ischaemic stroke eligible to receive alteplase with or without mechanical thrombectomy., Methods: This randomised, double-blind, placebo-controlled study with dose-escalation (1b) and dose-confirmation (2a) phases (ACTIMIS) was done in 26 stroke centres in six European countries. Participants were adults (≥18 years) with disabling acute ischaemic stroke with a National Institutes of Health Stroke Scale score of 6 or higher before alteplase administration. Patients were randomly assigned treatment using a central electronic procedure. Total administered dose at the end of the intravenous administration was 125 mg, 250 mg, 500 mg, and 1000 mg of glenzocimab or placebo in phase 1b and 1000 mg of glenzocimab or placebo in phase 2a. Treatment was initiated 4·5 h or earlier from stroke symptom onset in patients treated with alteplase with or without mechanical thrombectomy. The sponsor, study investigator and study staff, patients, and central laboratories were all masked to study treatment until database lock. Primary endpoints across both phases were safety, mortality, and intracranial haemorrhage (symptomatic, total, and fatal), assessed in all patients who received at least a partial dose of study medication (safety set). The trial is registered on ClinicalTrials.gov, NCT03803007, and is complete., Findings: Between March 6, 2019, and June 27, 2021, 60 recruited patients were randomly assigned to 125 mg, 250 mg, 500 mg, or 1000 mg glenzocimab, or to placebo in phase 1b (n=12 per group) and were included in the safety analysis. Glenzocimab 1000 mg was well tolerated and selected as the phase 2a recommended dose; from Oct 2, 2020, to June 27, 2021, 106 patients were randomly assigned to glenzocimab 1000 mg (n=53) or placebo (n=53). One patient in the placebo group received glenzocimab in error and therefore 54 and 52, respectively, were included in the safety set. In phase 2a, the most frequent treatment-emergent adverse event was non-symptomatic haemorrhagic transformation, which occurred in 17 (31%) of 54 patients treated with glenzocimab and 26 (50%) of 52 patients treated with placebo. Symptomatic intracranial haemorrhage occurred in no patients treated with glenzocimab compared with five (10%) patients in the placebo group. All-cause deaths were lower with glenzocimab 1000 mg (four [7%] patients) than with placebo (11 [21%] patients)., Interpretation: Glenzocimab 1000 mg in addition to alteplase, with or without mechanical thrombectomy, was well tolerated, and might reduce serious adverse events, intracranial haemorrhage, and mortality. These findings support the need for future research into the potential therapeutic inhibition of glycoprotein VI with glenzocimab plus alteplase in patients with acute ischaemic stroke., Funding: Acticor Biotech., Competing Interests: Declaration of interests MM reports consulting fees from Acticor Biotech, Novonordisk, Novartis, and Boehringer Ingelheim. He is a member of the data safety monitoring board for OPTIMIL and MIVAR studies. MK has received speaker's honoraria or compensation for advisory board participation from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Pfizer, Bristol Myers Squibb, AstraZeneca, Sanofi, Novartis, Biogen, and Acticor. MK is member of the supervisory board of CompuGroup Medical. RL reports institutional fees for consultancy from Boehringer Ingelheim and Genentech. PAL has received honoraria for contribution to advisory boards from Boehringer Ingelheim, Bristol Myers Squibb, Bayer, Pfizer, Daiichi Sankyo, and Ricordati; research compensations from Bayer, Sanofi, Acticor; and research grants from the Swiss Heart Foundation, Swiss National Foundation, and the University Hospital Basel Foundation (propatient). SR reports consulting fees from Acticor Biotech and Boerhinger Ingelheim; has received support for attending meetings from Acticor; and is a member of the data safety monitoring board for Pfizer and Bristol Myers Squibb. DT received honoraria from Alexion, AstraZeneca, Pfizer, and Medtronic, and is a member of the advisory board for Alexion and AstraZeneca. JCG is a consultant and a data safety monitoring board member for Acticor, Prolong Pharmaceuticals, and Haemonetics, and an advisory board member for Acticor, Prolong Pharma, and Haemonetics. GA and MJ-P are co-founders of Acticor. GA, SB, and YP are respectively chief executive officer, chief strategy officer, and chief marketing officer of Acticor Biotech. AC, AM, AS, GA, J-MG, MJ-P, SB, and YP are employees or consultants for Acticor. AC, AM, AS, GA, MJ-P, SB, and YP have stock interest in Acticor Biotech. CAM declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective- ACT017 is a novel, first in class, therapeutic antibody to platelet GPVI (glycoprotein VI) with potent and selective antiplatelet effects. This first-in-human, randomized, placebo-controlled phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT017 in healthy subjects. Approach and Results- Six cohorts of 8 healthy male and female subjects each received ascending single doses of ACT017 (n=6) or placebo (n=2) as a 6-hour intravenous infusion, with ¼ of the total dose administered within 15 minutes and the rest of the dose (¾ of the total dose) administered within 5 hours and 45 minutes. The 6 investigated doses ranged from 62.5 to 2000 mg. All doses of ACT017 were well tolerated, and no serious adverse events occurred during the study. None of the subjects reported an infusion site reaction. Template bleeding time was not affected in a clinically significant manner by any of the ACT017 doses. Plasma concentrations, determined by liquid chromatography-tandem mass spectrometry, increased linearly with the dose received as were the established pharmacokinetics values. There was no change in the platelet count, platelet GPVI expression assessed by flow cytometry, or plasma levels of soluble GPVI assessed by ELISA. In contrast, administration of ACT017 inhibited collagen-induced platelet aggregation measured by light transmission aggregometry on platelet-rich plasma, and the extent and duration of the effect were dose-dependent. Conclusions- The novel antiplatelet agent ACT017 has consistent pharmacokinetic/pharmacodynamic properties and favorable safety and tolerability profiles warranting further clinical development.

Monoclonal antibody fragments (Fab) are a promising class of therapeutic agents. Fabs are aglycosylated proteins and so many expression platforms have been developed including prokaryotic, yeast and mammalian cells. However, these platforms are not equivalent in terms of cell line development and culture time, product quality and possibly cost of production that greatly influence the success of a drug candidate's pharmaceutical development. This study is an assessment of the humanized Fab fragment ACT017 produced from two microorganisms (Escherichia coli and Pichia pastoris) and one mammalian cell host (CHO). Following low scale production and Protein L-affinity purification under generic conditions, physico-chemical and functional quality assessments were carried out prior to economic analysis of industrial scale production using a specialized software (Biosolve, Biopharm Services, UK). Results show higher titer production when using E. coli but associated with high heterogeneity of the protein content recovered in the supernatant. We also observed glycoforms of the Fab produced from P. pastoris, while Fab secreted from CHO was the most homogeneous despite a much longer culture time and slightly higher estimated cost of goods. This study may help inform future pharmaceutical development of this class of therapeutic proteins., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Glycoprotein VI is a platelet-specific collagen receptor critical for in vivo formation of arterial thrombosis. It is also considered as an attractive target for the development of anti-thrombotic drugs because blocking glycoprotein (GP)VI inhibits platelet aggregation without inducing detrimental effects on physiologic hemostasis. Here, we present data on the identification, in vitro and ex vivo pharmacology of a humanized Fab fragment designated as ACT017. ACT017 was selected out of 15 humanized variants based upon structural and functional properties. It was produced under GMP-like conditions followed by detailed physico-chemical analysis and functional characterization indicating high antigen-binding specificity and affinity. In addition, we demonstrate, in a dose-escalation study, that ACT017 has a high capacity to specifically inhibit collagen-induced platelet aggregation ex vivo after injection to the macaque without inducing thrombocytopenia, GPVI depletion or bleeding side effects as is the case for conventional anti-platelets. Therefore, ACT017 is a promising therapeutic candidate for the development of a new generation of safe and efficient anti-thrombotic drugs.

Comparison between 157 children treated with defibrinated convalescent plasma and 257 children treated with specific immunoglobulins revealed the improved effectiveness of the latter treatment in the prevention of chickenpox. Specific Herpes Zoster-Chickenpox immunoglobulins are prepared by caprylic acid fractionation of convalescent plasma. The prevention obtained in more than 90% of cases would appear to be clinically and biologically total as shown by serological surveillance of certain children with particularly severe immune depression.

The human serum of about twenty years old men, recently vaccinated has been tested by Laurell's method (Mesnier and Piquet variant). Purified antitetanic equine serum from Pasteur Institute (P.I.) has been taken as reference. With 5 Lf tetanic toxoid from P.I. concentration we can trust in the results until 50 antitetanics I.U. For richer serum, a 10 Lf toxoid concentration must be used. Correspondance between Pasteur Institute serum and gamma TS (human specific immunoglobulins) is indicated. Technics of Laurell, latex and electroimmunodiffusion are compared. The way to obtain plasma pool with higher antitetanic titre than 8 I.U. from poor and rich plasma is mentionned. The highest rate of titre antibody after the first typhoid diphteria tetanic vaccinal injection is observed between the 11th and 21th day.

The screening of zoster's antibodies has been performed in blood donors population and persons convalescing from herpes zoster. The results show that 25% of blood donors and 83,5% of convalescents have respectively a titer of CF antibody of 8. Plasma units were pooled and the pool had a final titer of CF antibody of 16. Varicella zoster immunoglobulin prepared by alcohol fractionation had a fluorescent antibody titer of 1 024 and a CF antibody of 512. These results are discussed and compared with those of literature.

The saline-adenine-glucose-mannitol (SAGM) solution for resuspension of red cells was evaluated on 30 blood units tested over 42 days and compared to 5 red cell concentrates collected on the conventional CPD medium. Total and extra-cellular hemoglobin, potassium, pH, ATP and DPG concentrations, osmotic fragility, schizocyte formation, and red cell antigenicity were studied through the storage period. Chromium survival studies of autologous donated red cells were performed in 10 donors. Red cell concentrates resuspended in SAGM solution showed at the 35th day of conservation at 4 degrees C, a mean storage hemolysis of only 0.66%, an ATP concentration of 67% of the initial value, a schizocyte proportion of less than 1.5%, a mean 24 hour posttransfusion viability of 88.33% and a mean red cell T 1/2 survival of 25 days 10 hours. No alteration of common blood group antigens could be found after storage of red cells for 42 days.

The comparison of two skin antiseptics (70 degrees alcohol and 0,5% alcoholic chlorhexidine solution) was carried out by the method of in vivo impressions. The study used 45 healthy volonteers from whom a bacteriological sample was taken from both bends of the elbow, without use of an antiseptic, and after the application of one according to usual sample taking methods. The subjects were divided into two sets according to the antiseptic being tested. The results of the cultures after 24 and 48 hours are expressed in the number of germs per cm2, which thus permits us to calculate a reduction in percentage or log 10 form, and to appreciate the efficiency of the antiseptic studied. Routine bacteriological inspection of labile blood products was carried out on products picked at random every week during 18 months of exclusive use of 70 degrees alcohol by the sample taking services. The results show a comparable in vivo effectiveness of the two antiseptics on the superficial aerobic flora of the bend of the elbow, and the ease of use of 70 degrees alcohol has led to its choice. This choice is confronted with the results of the inspection of blood products: out of 1 293 inspections, only one slight contamination (cocci gram+) was found on a unit of whole blood. These data as a whole can be compared with the work of various authors.