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REVIEW
Yang Li, Kai-di Yang, Hao-Yu Duan, Ya-Nan Du, Jun-Feng Ye
Pancreatic cancer is a devastating disease with a high mortality rate and a lack of effective therapies. The challenges associated with early detection and the highly aggressive nature of pancreatic cancer have limited treatment options, underscoring the urgent need for better disease-modifying therapies. Peptide-based biotherapeutics have become an attractive area of research due to their favorable properties such as high selectivity and affinity, chemical modifiability, good tissue permeability, and easy metabolism and excretion...
2023: Frontiers in Microbiology
#22
JOURNAL ARTICLE
Kylie S Chew, Robert C Wells, Arash Moshkforoush, Darren Chan, Kendra J Lechtenberg, Hai L Tran, Johann Chow, Do Jin Kim, Yaneth Robles-Colmenares, Devendra B Srivastava, Raymond K Tong, Mabel Tong, Kaitlin Xa, Alexander Yang, Yinhan Zhou, Padma Akkapeddi, Lakshman Annamalai, Kaja Bajc, Marie Blanchette, Gerald Maxwell Cherf, Timothy K Earr, Audrey Gill, David Huynh, David Joy, Kristen N Knight, Diana Lac, Amy Wing-Sze Leung, Katrina W Lexa, Nicholas P D Liau, Isabel Becerra, Mario Malfavon, Joseph McInnes, Hoang N Nguyen, Edwin I Lozano, Michelle E Pizzo, Elysia Roche, Patricia Sacayon, Meredith E K Calvert, Richard Daneman, Mark S Dennis, Joseph Duque, Kapil Gadkar, Joseph W Lewcock, Cathal S Mahon, René Meisner, Hilda Solanoy, Robert G Thorne, Ryan J Watts, Y Joy Yu Zuchero, Mihalis S Kariolis
Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TVCD98hc ). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc ) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties...
August 19, 2023: Nature Communications
#23
REVIEW
Yue Wang, Minah Kim, Chantal Buckley, Heather D Maynard, Ries J Langley, Jo K Perry
Recombinant human growth hormone (rhGH) and GH receptor antagonists (GHAs) are used clinically to treat a range of disorders associated with GH deficiency or hypersecretion, respectively. However, these biotherapeutics can be difficult and expensive to manufacture with multiple challenges from recombinant protein generation through to the development of long-acting formulations required to improve the circulating half-life of the drug. In this review, we summarize methodologies and approaches used for making and purifying recombinant GH and GHA proteins, and strategies to improve pharmacokinetic and pharmacodynamic properties, including PEGylation and fusion proteins...
September 2023: Protein Science
#24
REVIEW
Myung Jin Oh, Unyong Kim, Sol Kim, Dae Sik Cho, Jung-A Seo, Nari Seo, Hyun Joo An
Glycosylation is a crucial attribute for biotherapeutics with significant impacts on quality, stability, safety, immunogenicity, pharmacokinetics, and efficacy. Therefore, to ensure consistent glycosylation, a systematic review of biotherapeutics is absolutely required including the variable glycan structure (micro-heterogeneity) and different occupancy at individual site (macro-heterogeneity) from drug design to upstream and downstream bioprocesses. Various methods have been used for glyco-characterization of biotherapeutics at the glycan, glycopeptide, and intact protein levels...
June 28, 2023: Journal of Pharmaceutical and Biomedical Analysis
#25
REVIEW
Lisa Benedetta De Martini, Claudia Sulmona, Liliana Brambilla, Daniela Rossi
Due to their high specificity toward the target and their low toxicity, biological drugs have been successfully employed in a wide range of therapeutic areas. It is yet to be mentioned that biologics exhibit unfavorable pharmacokinetic properties, are susceptible to degradation by endogenous enzymes, and cannot penetrate biological barriers such as the blood-brain barrier (i.e., the major impediment to reaching the central nervous system (CNS)). Attempts to overcome these issues have been made by exploiting the intracerebroventricular and intrathecal routes of administration...
June 16, 2023: Cells
#26
REVIEW
Biswajita Pradhan, Prajna Paramita Bhuyan, Jang-Seu Ki
Cancer is one of the most worldwide spread diseases and causes maximum death. Treatment of cancer depends on the host immune system and the type of drugs. The inefficiency of conventional cancer treatments as a result of drug resistance, nontargeted delivery, and chemotherapy-related negative side effects has caused bioactive phytochemicals to come into focus. As a result, recent years have seen an increase in research into screening and identifying natural compounds with anticancer properties. Recent studies on the isolation and use of polysaccharides derived from various marine algal species have revealed a variety of biological activities, including antioxidant and anticancer properties...
May 16, 2023: Marine Drugs
#27
REVIEW
Bahareh Farasati Far, Maryam Safaei, Fatemeh Mokhtari, Mohammad Sadegh Fallahi, Mohammad Reza Naimi-Jamal
Current treatment regimens in cancer cases cause significant side effects and cannot effectively eradicate the advanced disease. Hence, much effort has been expended over the past years to understand how cancer grows and responds to therapies. Meanwhile, proteins as a type of biopolymers have been under commercial development for over three decades and have been proven to improve the healthcare system as effective medicines for treating many types of progressive disease, such as cancer. Following approving the first recombinant protein therapeutics by FDA (Humulin), there have been a revolution for drawing attention toward protein-based therapeutics (PTs)...
May 5, 2023: Medical Oncology
#28
JOURNAL ARTICLE
Alok Rathi, Sherri Rinker, Hongmei Niu, Carina Carter, Seema Kumar, Kyra Cowan
Neutralizing anti-drug antibodies (ADAs) may affect safety, efficacy, and pharmacokinetic profile of a biotherapeutic drug and thus their assessment is of particular importance during immunogenicity testing. Neutralizing antibody (NAb) assays typically rely on NAbs ability to block the drug-target interaction. Higher NAb concentration and/or higher binding affinity of NAb to the drug, lowers the drug-target binding interaction. However, in the presence of high concentrations of residual circulating drug, as often seen for drugs with longer half-lives or in repeat-dose studies, NAbs may exist as drug bound complexes...
April 26, 2023: Journal of Immunological Methods
#29
REVIEW
Sean Chia, Shi Jie Tay, Zhiwei Song, Yuansheng Yang, Ian Walsh, Kuin Tian Pang
The circulatory half-life of recombinant therapeutic proteins is an important pharmacokinetic attribute because it determines the dosing frequency of these drugs, translating directly to treatment cost. Thus, recombinant therapeutic glycoproteins such as monoclonal antibodies have been chemically modified by various means to enhance their circulatory half-life. One approach is to manipulate the N-glycan composition of these agents. Among the many glycan constituents, sialic acid (specifically, N-acetylneuraminic acid) plays a critical role in extending circulatory half-life by masking the terminal galactose that would otherwise be recognised by the hepatic asialoglycoprotein receptor (ASGPR), resulting in clearance of the biotherapeutic from the circulation...
April 21, 2023: Biomedicine & Pharmacotherapy
#30
JOURNAL ARTICLE
Shiyu Dong, Linzhi Chen, Achim Sauer, Lars Dittus
Many biotherapeutics such as monoclonal antibodies (mAbs) consist of various glycoforms, which can have different PK properties upon administration to animals and human. As a result, it is necessary to monitor the abundance of glycoforms and limit lot-to-lot variability during the manufacturing process. However, limited information is known about the clearance of mAb glycoforms in ocular space upon intravitreal injection. We present here an assessment of glycoform clearance of a biotherapeutic mAb (IgG1) in rabbit vitreous humor, aqueous humor and retina tissue using LC/MS...
April 14, 2023: Journal of Pharmaceutical Sciences
#31
REVIEW
Joshuaine Grant, Fei Hua, Joshua F Apgar, John M Burke, Diana H Marcantonio
Early assessment of dosing requirements should be an integral part of developability assessments for a discovery program. If a very high dose is required to achieve the desired pharmacological effect, it may not be clinically feasible or commercially desirable to develop the biotherapeutic for the selected target unless extra measures are taken to develop a high concentration formulation or maximize yield during manufacturing. A quantitative understanding of the impact of target selection, biotherapeutic format, and optimal drug properties on potential dosing requirements to achieve efficacy can affect many early decisions...
2023: MAbs
#32
REVIEW
Hetal Sarvaiya, Shuai Niu, Daniel T Ladror, Yuting Wang, Dolonchampa Maji, Malerie Wolke, Paramasivam Natarajan, Gary J Jenkins
Over the past two decades, we have seen an increase in the complexity and diversity of biotherapeutic modalities pursued by biopharmaceutical companies. These biologics are multifaceted and susceptible to post-translational modifications and in vivo biotransformation that could impose challenges for bioanalysis. It is vital to characterize the functionality, stability and biotransformation products of these molecules to enable screening, identify potential liabilities at an early stage and devise a bioanalytical strategy...
February 2023: Bioanalysis
#33
REVIEW
Monica L Fernández-Quintero, Anne Ljungars, Franz Waibl, Victor Greiff, Jan Terje Andersen, Torelif T Gjølberg, Timothy P Jenkins, Bjørn Gunnar Voldborg, Lise Marie Grav, Sandeep Kumar, Guy Georges, Hubert Kettenberger, Klaus R Liedl, Peter M Tessier, John McCafferty, Andreas H Laustsen
Beyond potency, a good developability profile is a key attribute of a biological drug. Selecting and screening for such attributes early in the drug development process can save resources and avoid costly late-stage failures. Here, we review some of the most important developability properties that can be assessed early on for biologics. These include the influence of the source of the biologic, its biophysical and pharmacokinetic properties, and how well it can be expressed recombinantly. We furthermore present in silico, in vitro , and in vivo methods and techniques that can be exploited at different stages of the discovery process to identify molecules with liabilities and thereby facilitate the selection of the most optimal drug leads...
2023: MAbs
#34
JOURNAL ARTICLE
Johan Engström
Gyrolab® is an open immunoassay platform that automates the complete immunoassay protocol in a microfluidic disc. The column profiles generated with Gyrolab immunoassays are used to gain more information about biomolecular interactions that can be useful in assay development or quantify analytes in samples. Gyrolab immunoassays can be used to cover a broad concentration range and diversity of matrices in applications ranging from biomarker monitoring, pharmacodynamics and pharmacokinetics studies, to bioprocess development in many areas, including therapeutic antibodies, vaccines, and cell and gene therapy...
2023: Methods in Molecular Biology
#35
JOURNAL ARTICLE
Nathalie Mignet, Daniel Scherman
Vector biodistribution is a requirement prior pharmaceutical development. Radioactive tracers allow the most sensitive and quantitative assessment of biodistribution, and conventional fluorophores are widely used in academic laboratories. We propose here to use europium complexes as a label for nanoparticles or biotherapeutics taking liposomes as models. Time-resolved fluorimetry (TRF) has the tremendous advantage of taking into accounts the fluorescence decay time of the lanthanide chelates, resulting in an improved sensitivity in biological media...
2023: Methods in Molecular Biology
#36
JOURNAL ARTICLE
Toan D Nguyen, Brandon M Bordeau, Yu Zhang, Anna G Mattle, Joseph P Balthasar
Small therapeutic proteins are receiving increased interest as therapeutic drugs; however, their clinical success has been limited due to their rapid elimination. Here, we report a half-life extension strategy via strategy via red blood cell red blood cell (RBC) hitch-hiking. This manuscript details the development and characterization of novel anti-RBC single-domain antibodies (sdAbs), their genetic fusion to therapeutic antibody fragments (TAF) as bispecific fusion constructs, and their influence on TAF pharmacokinetics and biodistribution...
December 28, 2022: International Journal of Molecular Sciences
#37
JOURNAL ARTICLE
David B Ascher, Lisa M Kaminskas, Yoochan Myung, Douglas E V Pires
Antibodies are essential experimental and diagnostic tools and as biotherapeutics have significantly advanced our ability to treat a range of diseases. With recent innovations in computational tools to guide protein engineering, we can now rationally design better antibodies with improved efficacy, stability, and pharmacokinetics. Here, we describe the use of the mCSM web-based in silico suite, which uses graph-based signatures to rapidly identify the structural and functional consequences of mutations, to guide rational antibody engineering to improve stability, affinity, and specificity...
2023: Methods in Molecular Biology
#38
JOURNAL ARTICLE
Suzanne Edavettal, Pilar Cejudo-Martin, Bidisha Dasgupta, Danlin Yang, Matthew D Buschman, Derrick Domingo, Kristof Van Kolen, Pharavee Jaiprasat, Renata Gordon, Keith Schutsky, Brian Geist, Natalie Taylor, Camille Helene Soubrane, Elisabeth Van Der Helm, Ann LaCombe, Zemeda Ainekulu, Eilyn Lacy, Jason Aligo, Jason Ho, Yingbo He, Peter F Lebowitz, James T Patterson, Justin M Scheer, Sanjaya Singh
BACKGROUND: The near impermeability of the blood-brain barrier (BBB) and the unique neuroimmune environment of the CNS prevents the effective use of antibodies in neurological diseases. Delivery of biotherapeutics to the brain can be enabled through receptor-mediated transcytosis via proteins such as the transferrin receptor, although limitations such as the ability to use Fc-mediated effector function to clear pathogenic targets can introduce safety liabilities. Hence, novel delivery approaches with alternative clearance mechanisms are warranted...
October 12, 2022: Med
#39
JOURNAL ARTICLE
Hasan Afzaal, Shahiq-Uz-Zaman, Adil Saeed, Syed Damin Abbas Hamdani, Amir Raza, Alvina Gul, Mustafeez Mujtaba Babar, Jayakumar Rajadas
Purpose: Alternate formulation strategies need to be devised for improving the absorption and bioavailability of drug molecules administered through the intravaginal route. Enhancing the coating of vaginal mucosa can aid the achievement of this goal. The aim of the current study is to develop a mucoadhesive formulation having adequate adhesiveness, spreading, and viscosity profiles that can ensure good tissue absorption of adapalene upon intravaginal application. Method: A combination of mucoadhesive agents has been employed, including Carbopol-934, HPMC K-15M, and xanthan gum, in varying ratios to formulate five different gels...
2022: Frontiers in Pharmacology
#40
REVIEW
Qiuping Qin, Likun Gong
Antibody-drug conjugates (ADCs) are a new class of biotherapeutics, consisting of a cytotoxic payload covalently bound to an antibody by a linker. Ligand-binding assay (LBA) and liquid chromatography-mass spectrometry (LC-MS) are the favored techniques for the analysis of ADCs in biomatrices. The goal of our review is to provide current strategies related to a series of bioanalytical assays for pharmacokinetics (PK) and anti-drug antibody (ADA) assessments. Furthermore, the strengths and limitations of LBA and LC-MS platforms are compared...
September 24, 2022: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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