Certolizumab

Certolizumab is a Fab fragment of a humanized monoclonal antibody against tumor necrosis factor-alpha (TNF-alpha). Differing from the other TNF-alpha inhibitors due to the absence of Fc fragment and pegylation, it binds to both the soluble and transmembrane forms of TNF-alpha, creating a strong TNF-alpha blockage. Previously approved for psoriatic arthritis, certolizumab received another approval from FDA in 2018 for the treatment of moderate to severe chronic plaque psoriasis that does not respond to conventional systemic treatments or for which these treatments are contraindicated. Administered via subcutaneous injections, certolizumab also has a low-dose option for patients weighing less than 90 kg. Certolizumab is considered a safe biological drug that can be preferred during pregnancy and lactation.Copyright © 2022 by Turkish Society of Dermatology and Venereology.

Potential of Interferon Lambda as an Inhibitor of SARS-CoV-2.

This study provides an overview of scientific results on the feasibility of using type III interferons against SARS-CoV-2. We have analyzed data obtained from the PubMed electronic database for the period 2020-2022. The results of our own studies of pharmacological substances based on recombinant IFN-lambda1 and its pegylated form are also presented. Completed and ongoing investigations allow us to position IFN-lambda as an effective therapeutic agent against SARS-CoV-2.

Severe allergy to polyethylene glycol: The importance of allergy work-up testing with PEG 1500 extract in the scope of SARS-CoV- 2 vaccination

Background: Polyethylene glycol (PEG) is being used for the first time as an excipient in mRNA vaccines against SARS-CoV- 2 containing PEG 2000, highlighting it as a potential cause of anaphylaxis. We aim to report clinical cases of severe allergy to PEG and furthermore to assess the usefulness of skin tests (ST) performed with the commercial extract PEG 1500 for the allergy work-up of patients with suspected allergy to SARS-CoV- 2 vaccines. Method(s): We evaluated 126 patients with moderate to high risk of allergy to SARS-CoV- 2 vaccination referred to our Allergy Department from March to December 2021. ST were performed with extract PEG 1500 (Roxall), using the following methodology: prick tests with 0.1%, 1% and 10% concentrations, with readings at 30 minutes (according to manufacturer's instructions);if negative, intradermal tests (IDT) were performed with the 1/10 dilution (0.01%), except in cases of anaphylaxis, where dilutions 1/1000 and 1/100 were used (adapted from previous publication using PEG 20000). Immediate IDT readings were made at 30 minutes and delayed readings at 24 hours. The same protocol was applied to 5 healthy controls who received PEGylated vaccines. Result(s): We present 6 cases of severe PEG allergy: one near-fatal anaphylaxis after glucocorticoid injection containing PEG 3350 and five systemic allergic reactions after mRNA vaccine containing PEG 2000 (Pfizer-BioNTech or Moderna). All patients had positive immediate IDT using PEG 1500 allowing the diagnosis and the selection of vaccine without PEG. All of them were negative to polysorbate 80. One patient developed anaphylaxis following IDT 0.01%. In the remaining 120 patients, the ST using PEG 1500 were negative in immediate and delayed reading of IDT. Seven patients were positive to polysorbate 80. All healthy controls had negative ST using PEG 1500. Conclusion(s): To our knowledge this is the first case series describing the allergy work-up testing with commercial extract PEG 1500 in the scope of SARS-CoV- 2 vaccination. ST using extract PEG 1500 revealed to be a useful tool for the diagnosis of PEG allergy, since it allowed confirming six cases of severe PEG allergy, contraindicating the further administration of PEGylated vaccines. It also allowed allergy exclusion in one hundred cases that took afterwards SARS-CoV- 2 vaccines containing PEG 2000. Moreover, healthy controls had negative IDT demonstrating the reliability of the proposed procedure. Investigation should only be conducted in a specialized drug allergy centre.

Recent Progress of Lipid Nanoparticles-Based Lipophilic Drug Delivery: Focus on Surface Modifications.

Numerous drugs have emerged to treat various diseases, such as COVID-19, cancer, and protect human health. Approximately 40% of them are lipophilic and are used for treating diseases through various delivery routes, including skin absorption, oral administration, and injection. However, as lipophilic drugs have a low solubility in the human body, drug delivery systems (DDSs) are being actively developed to increase drug bioavailability. Liposomes, micro-sponges, and polymer-based nanoparticles have been proposed as DDS carriers for lipophilic drugs. However, their instability, cytotoxicity, and lack of targeting ability limit their commercialization. Lipid nanoparticles (LNPs) have fewer side effects, excellent biocompatibility, and high physical stability. LNPs are considered efficient vehicles of lipophilic drugs owing to their lipid-based internal structure. In addition, recent LNP studies suggest that the bioavailability of LNP can be increased through surface modifications, such as PEGylation, chitosan, and surfactant protein coating. Thus, their combinations have an abundant utilization potential in the fields of DDSs for carrying lipophilic drugs. In this review, the functions and efficiencies of various types of LNPs and surface modifications developed to optimize lipophilic drug delivery are discussed.

Controlled release nanomedicine (CRNM) of aspirin using "biomimetic niosomal nanoparticles (BNNs)”for Covid-19 and cardiovascular treatment: DOE based optimization

Biomimetic strategies can be adopted to improve biopharmaceutical aspects. Subsequently, Biomimetic reconstitutable pegylated amphiphilic lipid nanocarriers have high translational potential for systemic controlled drug delivery;however, such an improvised system for systemic aspirin delivery exploring nanotechnology is not available. Systemic administration of aspirin and its controlled delivery can significantly control blood clotting events, leading to stroke, which has immediate applications in cardiovascular diseases and Covid-19. In this work, we are developing aspirin sustained release pegylated amphiphilic self-assembling nanoparticles to develop reconstitutable aspirin injections by solvent-based co-precipitation method with phase inversion technique that leads to novel "biomimetic niosomal nanoparticles (BNNs).” DOE led optimization is done to develop Design of space for optimized particles. Upon reconstitution of solid powder, the particle size was 144.8 ± 12.90 nm with a surface charge of -29.2 ± 2.24 mV. The entrapment efficiency was found to be 49 ± 0.15%, wherein 96.99 ± 1.57% of the drug was released in 24hr showing super case II transport-based drug release mechanism. The formulation has the least hemolysis while showing significant suppression of platelet aggregation. MTT assay does not show any significant cytotoxicity. This is a potential nanoparticle that can be explored for developing aspirin injection, which is not available.

Could Celastrol Nanosystem be Suitable for the Treatment of COVID-19?

The COVID-19 pandemic occurred over two years and has not yet been finished. There are some possible Chinese medicines formulations used to prevent and treat COVID-19. Single pure herbal such as curcumin is the most common to combat SARS-CoV-2 with antioxidant, anti-inflammatory, antibacterial, antiviral, antitumor, and hepatoprotective properties. This short communication describes another single pure herbal, "Celastrol", research progress and its nanosystem for the treatment of COVID-19.

PEGylation Prolongs the Half-Life of Equine Anti-SARS-CoV-2 Specific F(ab')2.

Therapeutic antibodies-F(ab')2 obtained from hyperimmune equine plasma could treat emerging infectious diseases rapidly because of their high neutralization activity and high output. However, the small-sized F(ab')2 is rapidly eliminated by blood circulation. This study explored PEGylation strategies to maximize the half-life of equine anti-SARS-CoV-2 specific F(ab')2. Equine anti-SARS-CoV-2 specific F(ab')2 were combined with 10 KDa MAL-PEG-MAL in optimum conditions. Specifically, there were two strategies: Fab-PEG and Fab-PEG-Fab, F(ab')2 bind to a PEG or two PEG, respectively. A single ion exchange chromatography step accomplished the purification of the products. Finally, the affinity and neutralizing activity was evaluated by ELISA and pseudovirus neutralization assay, and ELISA detected the pharmacokinetic parameters. The results displayed that equine anti-SARS-CoV-2 specific F(ab')2 has high specificity. Furthermore, PEGylation F(ab')2-Fab-PEG-Fab had a longer half-life than specific F(ab')2. The serum half-life of Fab-PEG-Fab, Fab-PEG, and specific F(ab')2 were 71.41 h, 26.73 h, and 38.32 h, respectively. The half-life of Fab-PEG-Fab was approximately two times as long as the specific F(ab')2. Thus far, PEGylated F(ab')2 has been prepared with high safety, high specificity, and a longer half-life, which could be used as a potential treatment for COVID-19.

Characterization of adenovirus interactions with PF4 using a novel ELISA-qPCR technology

The COVID vaccines Janssen and AstraZeneca, based respectively on adenovirus (AdV) serotypes AdV26 and ChAdOx1, have been associated with rare cases of vaccine-induced thrombotic thrombocytopenia (VITT). It was recently demonstrated that the AdVs of the vaccines can bind to the blood protein platelet factor 4 (PF4), an interaction very likely to be involved in VITT. Since there are hundreds of known AdV serotypes, we hypothesized that certain serotypes have a lower affinity for PF4. We therefore aimed to screen a library comprising dozens of serotypes from different AdV species. For this purpose, we established the ELISA-qPCR technology. Like in standard ELISA, AdV viral particles are allowed to specifically interact with PF4 proteins coated on a plate. However, the revelation is not performed by antibody staining, but by qPCR after the genomes of bound AdVs are released through alkaline heat lysis. This technology enables fast, accurate and unbiased assessment of virus molecular interactions. Unlike most tested serotypes, the species D AdV37, AdV69 and AdV70 did not bind to PF4. Even though the ELISA-qPCR technique is not sensitive enough to detect potential low-affinity interactions, these serotypes may avoid or decrease the risk of VITT and represent safer candidates for vaccine or gene therapy vector development. In order to gain deeper insights into the mechanism of virion binding to PF4, we tested how AdV5 affinity for PF4 was affected by genetic removal or PEGylation of different hypervariable regions (HVR) of the hexon protein of the capsid.

Structural and dynamical properties of Palmitoyl-Oleoyl phosphatidylserine lipid nanotubes containing cholesterols and PEGylated dioleoyl Phosphatidylethanolamine: A Coarse-Grained molecular dynamics simulation

Lipid nanotubes (LNTs) are a class of lipid-based drug delivery systems (LBDDSs). Reports indicate that LBDDSs are effective systems in drug delivery to deal with COVID-19. The rational design of LNTs requires a deeper understanding of their structural properties in various influential factors such as lipid composition and PEGylation. This work uses coarse-grained molecular dynamics simulation to study the structural/dynamical properties of palmitoyl-Oleoyl phosphatidylserine (POPS) LNTs. To this end, the density distribution profiles are examined to evaluate of diameters and thicknesses of LNTs. The results show that adding cholesterol to LNT leads to lipid tail regularity, increasing the bilayer thickness and LNT diameter. PEGylation tends to increase irregularities of lipid chains, reduce the molecular packing and increase lipids dynamics. Our calculations predicted that manipulating LNT composition can be used to obtain favorable structural/dynamical properties and desired dimensions.

Clinical Relevance of Pre-Existing and Treatment-Induced Anti-Poly(Ethylene Glycol) Antibodies.

Abstract: Poly(ethylene glycol) (PEG) is a nontoxic, hydrophilic polymer that is often covalently attached to proteins, drugs, tissues, or materials; a procedure commonly referred to as PEGylation. PEGylation improves solubility, circulation time, and reduces immunogenicity of therapeutic molecules. Currently, there are 21 PEGylated drugs approved by the Food and Drug Administration (FDA), and more in the developmental stage. In addition to the polymer's applications in the clinic, PEG is widely used as a solvent and emulsifying agent in the formulation of cosmetics, cleaning, and personal care products. Due to the ubiquitous presence of the polymer in everyday products, patients can develop antibodies against PEG (αPEG Abs) that can be problematic when a PEGylated drug is administered. These αPEG Abs can provoke hypersensitivity reactions, accelerated drug clearance, and decreased therapeutic efficacy. Herein, we review how the prevalence of PEG in everyday products has induced αPEG Abs within the general public as well as the effect of these Abs on the performance of PEGylated therapeutics. We will focus on clinical manifestations following the administration of PEGylated drugs. Lay Summary: Poly(ethylene glycol) (PEG) is a polymer found in products including cosmetics, personal care products, cleaning agents, medicine, and food. Due to the prevalence of PEG, people can develop antibodies (αPEG Abs) against the polymer, which recognize PEG as foreign. Of note, PEG is frequently incorporated into drug formulations to improve therapeutic efficacy. Complications can arise when a patient receiving a PEGylated drug has previously developed αPEG Abs from interactions with PEG in everyday products. The presence of high concentrations of αPEG Abs in blood can result in decreased treatment efficacy and allergic reactions to a wide range of therapeutics.

The Pharmaceutical Industry in 2021. An Analysis of FDA Drug Approvals from the Perspective of Molecules.

Similar to last year, 2021 will be remembered for the COVID-19 pandemic. Although five vaccines have been approved by the two most important drug regulatory agencies, namely the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the pandemic has still not been brought under control. However, despite the context of a global pandemic, 2021 has been an excellent year with respect to drug approvals by the FDA. In 2021, 50 drugs have been authorized, making it the fourth-best year after 2018 (59 drugs) and 1996 and 2020 (53 each). Regarding biologics, 2021 has been the third-best year to date, with 14 approvals, and it has also witnessed the authorization of 36 small molecules. Of note, nine peptides, eight monoclonal antibodies, two antibody-drug conjugates, and two oligonucleotides have been approved this year. From them, five of the molecules are pegylated and three of them highly pegylated. The presence of nitrogen aromatic heterocycles and/or fluorine atoms are once again predominant among the so-called small molecules. This report analyzes the 50 new drugs approved in 2021 from a chemical perspective, as it did for those authorized in the previous five years. On the basis of chemical structure alone, the drugs that received approval in 2021 are classified as the following: biologics (antibodies, antibody-drug conjugates, enzymes, and pegylated proteins); TIDES (peptide and oligonucleotides); combined drugs; natural products; nitrogen aromatic heterocycles; fluorine-containing molecules; and other small molecules.

The Research of Toxicity and Sensitization Potential of PEGylated Silver and Gold Nanomaterials.

Polyethylene glycol (PEG) is a polymer used for surface modification of important substances in the modern pharmaceutical industry and biopharmaceutical fields. Despite the many benefits of PEGylation, there is also the possibility that the application and exposure of the substance may cause adverse effects in the body, such as an immune response. Therefore, we aimed to evaluate the sensitization responses that could be induced through the intercomparison of nanomaterials of the PEG-coated group with the original group. We selected gold/silver nanomaterials (NMs) for original group and PEGylated silver/gold NMs in this study. First, we measured the physicochemical properties of the four NMs, such as size and zeta potential under various conditions. Additionally, we performed the test of the NM's sensitization potential using the KeratinoSens™ assay for in vitro test method and the LLNA: 5-bromo-2-deoxyuridine (BrdU)-FCM for in vivo test method. The results showed that PEGylated-NMs did not lead to skin sensitization according to OECD TG 442 (alternative test for skin sensitization). In addition, gold nanomaterial showed that cytotoxicity of PEGylated-AuNMs was lower than AuNMs. These results suggest the possibility that PEG coating does not induce an immune response in the skin tissue and can lower the cytotoxicity of nanomaterials.

A Randomised Evaluation of Low-Dose Ara-C Plus BCT-100 Versus Low Dose Ara-C in Older Patients with Acute Myeloid Leukaemia: Results from the LI-1 Trial

Background: Among patients with Acute Myeloid Leukaemia (AML) over the age of 60, a considerable number are not considered suitable for intensive remission-induction chemotherapy. Survival in these patients is poor, whether they are treated using hypomethylating agents or low-dose ara-C (LDAC). The possibility of combination therapy with additional agents represents an attractive option. Arginine metabolism plays a key role in AML pathogenesis (Mussai et al. Blood 2013);BCT-100 is a pegylated recombinant human arginase that leads to a rapid depletion in extracellular and intracellular arginine concentrations resulting in G0/G1 arrest, and subsequent death by necrosis. BCT-100 demonstrates significant activity as single-agent against AML cell lines, AML xenografts and primary AML blasts from newly diagnosed or relapsed patients (Mussai et al. Blood 2015). Importantly BCT-100 is synergistic in combination with cytarabine. Aims: To assess the efficacy of LDAC+BCT100 versus LDAC alone in patients aged 60+ unsuitable for intensive therapy, in a “pick a winner” design. This design allows several treatments to be assessed simultaneously in a randomised fashion, with the aim of doubling 2-year survival from 11% to 22% (HR 0.69), with interim assessments after 50 and 100 patients per arm are recruited. Methods: LDAC was given at 20mg BD SC on days 1-10 of each course. Patients randomised to the combination received LDAC as above with BCT-100 1600U/kg on Days 1, 8, 15 and 22 as a 1-hour intravenous infusion. Courses occurred at 4-6 week intervals. Toxicities were recorded using CTCAE version 3. Pharmacokinetic and biomarker samples were assessed in BCT-100 patients. Results here are based upon median follow-up of 3.8 months (range: 0.1 - 20.6 months) Results: Between September 2018 and December 2020, 83 patients were randomised. The trial was prematurely closed due to the COVID pandemic and did not reach the pre-planned first evaluation. Median age was 76.7 years (range 62-88). Overall, 65% were male;70% de novo AML, 23% secondary AML, and 6% high risk MDS;2% favourable, 59% intermediate, 23% adverse and 15% unknown/unreported cytogenetics. Median of 2 courses was delivered in either arm (mean 2 LDAC, 2 LDAC+BCT, range for both: 1-12). BCT-100 leads to a depletion of arginine from baseline in the majority of patients. Overall response (CR/CRi) was achieved in 12/81 patients (15%), (LDAC+BCT-100 15%, LDAC 15%, R 1.03 (0.30, 3.51),P=0.963). Thirty-day mortality was not significantly increased (18% vs 11%, HR 1.71 (0.50, 5.84), P=0.393;and 1-year survival showed no evidence of a difference (31% vs 30%, HR 1.28 (0.72, 2.25). Median overall survival time was 3.8 vs 6.4months;overall survival HR 1.11 (0.64, 1.90), P=0.715. The most common cause of death was resistant/recurrent disease: 12(46%) vs 16(59%). BCT-100 was not associated with any haematological toxicity;although rare grade 3/4 cardiac and hepatic events were reported, these were not significantly increased with BCT-100. Summary: The addition of BCT-100 to LDAC did not improve response rate or survival. BCT-100 was well tolerated with an acceptable toxicity profile. Further clinical evaluation of BCT-100 induced arginase depletion continues in a variety of malignancies. Acknowledgements: We are grateful to Blood Cancer UK for funding the trial and Bio-Cancer Treatment International for providing drug and additional support for this Investigator Initiated Study. Figure 1. OS All patients [Formula presented] Disclosures: Knapper: Jazz: Consultancy, Speakers Bureau;Pfizer: Consultancy, Speakers Bureau;Astellas: Ended employment in the past 24 months, Speakers Bureau;Novartis: Consultancy, Research Funding, Speakers Bureau. McMullin: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial support, Research Funding;Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abb ie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AOP Orphan: Research Funding, Speakers Bureau. Copland: Incyte: Honoraria, Research Funding, Speakers Bureau;Novartis: Honoraria, Speakers Bureau;Pfizer: Honoraria, Speakers Bureau;Cyclacel Ltd: Research Funding;Astellas: Honoraria, Speakers Bureau;Jazz: Honoraria, Speakers Bureau. Russell: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis: Speakers Bureau;Astellas: Membership on an entity's Board of Directors or advisory committees;Jazz: Research Funding, Speakers Bureau.

Polyethylene Glycol Immunogenicity: Theoretical, Clinical, and Practical Aspects of Anti-Polyethylene Glycol Antibodies.

Polyethylene glycol (PEG) is a flexible, hydrophilic simple polymer that is physically attached to peptides, proteins, nucleic acids, liposomes, and nanoparticles to reduce renal clearance, block antibody and protein binding sites, and enhance the half-life and efficacy of therapeutic molecules. Some naïve individuals have pre-existing antibodies that can bind to PEG, and some PEG-modified compounds induce additional antibodies against PEG, which can adversely impact drug efficacy and safety. Here we provide a framework to better understand PEG immunogenicity and how antibodies against PEG affect pegylated drug and nanoparticles. Analysis of published studies reveals rules for predicting accelerated blood clearance of pegylated medicine and therapeutic liposomes. Experimental studies of anti-PEG antibody binding to different forms, sizes, and immobilization states of PEG are also provided. The widespread use of SARS-CoV-2 RNA vaccines that incorporate PEG in lipid nanoparticles make understanding possible effects of anti-PEG antibodies on pegylated medicines even more critical.

Genetic and Chemical Capsid Modifications of Adenovirus Vectors to Modulate Vector-Host Interactions.

Adenovirus-based vectors are playing an important role as efficacious genetic vaccines to fight the current COVID-19 pandemic. Furthermore, they have an enormous potential as oncolytic vectors for virotherapy and as vectors for classic gene therapy. However, numerous vector-host interactions on a cellular and noncellular level, including specific components of the immune system, must be modulated in order to generate safe and efficacious vectors for virotherapy or classic gene therapy. Importantly, the current widespread use of Ad vectors as vaccines against COVID-19 will induce antivector immunity in many humans. This requires the development of strategies and techniques to enable Ad-based vectors to evade pre-existing immunity. In this review article, we discuss the current status of genetic and chemical capsid modifications as means to modulate the vector-host interactions of Ad-based vectors.

Capsid and Genome Modification Strategies to Reduce the Immunogenicity of Adenoviral Vectors.

Adenovirus-based gene transfer vectors are the most frequently used vector type in gene therapy clinical trials to date, and they play an important role as genetic vaccine candidates during the ongoing SARS-CoV-2 pandemic. Immediately upon delivery, adenovirus-based vectors exhibit multiple complex vector-host interactions and induce innate and adaptive immune responses. This can severely limit their safety and efficacy, particularly after delivery through the blood stream. In this review article we summarize two strategies to modulate Ad vector-induced immune responses: extensive genomic and chemical capsid modifications. Both strategies have shown beneficial effects in a number of preclinical studies while potential synergistic effects warrant further investigations.