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Pharmacokinetics of biotherapeutics

Viswanath Devanarayan, Wendell C Smith, Rocco L Brunelle, Mary E Seger, Kim Krug, Ronald R Bowsher
Today, the assessment of immunogenicity is integral in nonclinical and clinical testing of new biotherapeutics and biosimilars. A key component in the risk-based evaluation of immunogenicity involves the detection and characterization of anti-drug antibodies (ADA). Over the past couple of decades, much progress has been made in standardizing the generalized approach for ADA testing with a three-tiered testing paradigm involving screening, confirmation, and quasi-quantitative titer assessment representing the typical harmonized scheme...
July 21, 2017: AAPS Journal
Frederick J Krambeck, Sandra V Bennun, Mikael R Andersen, Michael J Betenbaugh
The Chinese hamster ovary (CHO) cell is the gold standard for manufacturing of glycosylated recombinant proteins for production of biotherapeutics. The similarity of its glycosylation patterns to the human versions enable the products of this cell line favorable pharmacokinetic properties and lower likelihood of causing immunogenic responses. Because glycan structures are the product of the concerted action of intracellular enzymes, it is difficult to predict a priori how the effects of genetic manipulations alter glycan structures of cells and therapeutic properties...
2017: PloS One
Sari Latvala, Bjoern Jacobsen, Michael B Otteneder, Annika Herrmann, Sven Kronenberg
The neonatal Fc receptor (FcRn) is a major histocompatibility complex class I type molecule that binds to, transports, and recycles immunoglobulin G (IgG) and albumin, thereby protecting them from lysosomal degradation. Therefore, besides the knowledge of FcRn affinity, FcRn protein expression is critical in understanding the pharmacokinetic behavior of Fc-containing biotherapeutics such as monoclonal antibodies. The goal of this investigation was to achieve for the first time a comparative assessment of FcRn distribution across a variety of tissues and species...
June 2017: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
Joseph C Marini, Michael Anderson, Xiao-Yan Cai, John Chappell, Todd Coffey, Dominique Gouty, Aparna Kasinath, Vera Koppenburg, Philip Oldfield, Shannon Rebarchak, Ronald R Bowsher
No abstract text is available yet for this article.
April 3, 2017: AAPS Journal
Christian Lanshoeft, Sarah Cianférani, Olivier Heudi
The quantitative analysis of human immunoglobulin G1 (hIgG1) by mass spectrometry is commonly performed using surrogate peptides after enzymatic digestion. Since some limitations are associated with this approach, a novel workflow is presented by hybridizing ligand binding assay (LBA) with liquid chromatography-high-resolution mass spectrometry (LC-HRMS) for hIgG1 quantification directly at the intact protein level. Different hIgG1s, including a [(13)C]-labeled version used as internal standard, were immuno-enriched from rat serum with a fully automated platform based on streptavidin coated tips and a biotinylated mouse anti-hIgG capture antibody targeting the fragment crystallizable region followed by overnight deglycosylation prior to LC-HRMS analysis...
February 21, 2017: Analytical Chemistry
Lorna Ashton, Victoria L Brewster, Elon Correa, Royston Goodacre
In this study we demonstrate the use of Raman spectroscopy to determine protein modifications as a result of glycosylation and iron binding. Most proteins undergo some modifications after translation which can directly affect protein function. Identifying these modifications is particularly important in the production of biotherapeutic agents as they can affect stability, immunogenicity and pharmacokinetics. However, post-translational modifications can often be difficult to detect with regard to the subtle structural changes they induce in proteins...
February 8, 2017: Analyst
Jonathan Herskovitz, Josiah Ryman, Theingi Thway, Stephanie Lee, Lei Zhou, Narendra Chirmule, Bernd Meibohm, Vibha Jawa
In the clinical setting, anti-drug antibodies (ADA) against biotherapeutics can influence patient safety and interfere with product efficacy. High immunogenicity has been addressed in clinic by concomitant immune suppression, such as co-administration of methotrexate with enzyme replacement therapy (ERT) and combination tacrolimus/sirolimus treatment for prophylaxis against organ transplant rejection. This study investigates the use of such immune suppressants in mitigating ADA responses to a fully human monoclonal antibody (mAb1) in preclinical animal studies...
March 2017: AAPS Journal
Rong Liu, Brian Hoffpauir, Shannon D Chilewski, Janice Gamberdella, Uma Kavita, Jia Duo, Carol Gleason, Yan Zhang, Renuka Pillutla, Binodh DeSilva, Lora Hamuro
The Gyrolab™ xP is a microfluidic platform for conducting ligand binding assays (LBAs) and is recognized for its utility in discovery bioanalysis. However, few reports have focused on the technology for regulated bioanalysis. This technology has the advantage of low reagent consumption, low sample volume, and automated ligand binding methods. To improve bioanalysis testing timelines and increase the speed at which biotherapeutics are delivered to patients, we evaluated the technology for its potential to deliver high-quality data at reduced testing timelines for regulated bioanalysis...
January 2017: AAPS Journal
Carlos H Villa, Douglas B Cines, Don L Siegel, Vladimir Muzykantov
Red blood cells (RBCs) are innate carriers that can also be engineered to improve the pharmacokinetics and pharmacodynamics of many drugs, particularly biotherapeutics. Successful loading of drugs, both internally and on the external surface of RBCs, has been demonstrated for many drugs including anti-inflammatory, antimicrobial, and antithrombotic agents. Methods for internal loading of drugs within RBCs are now entering clinical use. Although internal loading can result in membrane disruption that may compromise biocompatibility, surface loading using either affinity or chemical ligands offers a diverse set of approaches for the production of RBC drug carriers...
January 2017: Transfusion Medicine Reviews
Alison Smith, Hugh Manoli, Stacey Jaw, Kimberley Frutoz, Alan L Epstein, Leslie A Khawli, Frank-Peter Theil
Biologics have emerged as a powerful and diverse class of molecular and cell-based therapies that are capable of replacing enzymes, editing genomes, targeting tumors, and more. As this complex array of tools arises a distinct set of challenges is rarely encountered in the development of small molecule therapies. Biotherapeutics tend to be big, bulky, polar molecules comprised of protein and/or nucleic acids. Compared to their small molecule counterparts, they are fragile, labile, and heterogeneous. Their biodistribution is often limited by hydrophobic barriers which often restrict their administration to either intravenous or subcutaneous entry routes...
2016: Journal of Immunology Research
Michael A Partridge, Shobha Purushothama, Chinnasamy Elango, Yanmei Lu
Anti-drug antibodies induced by biologic therapeutics often impact drug pharmacokinetics, pharmacodynamics response, clinical efficacy, and patient safety. It is critical to assess the immunogenicity risk of potential biotherapeutics in producing neutralizing and nonneutralizing anti-drug antibodies, especially in clinical phases of drug development. Different assay methodologies have been used to detect all anti-drug antibodies, including ELISA, radioimmunoassay, surface plasmon resonance, and electrochemiluminescence-based technologies...
2016: Journal of Immunology Research
Mary E Spilker, Xiaoying Chen, Ravi Visswanathan, Chandra Vage, Shinji Yamazaki, Gang Li, Judy Lucas, Erica L Bradshaw-Pierce, Paolo Vicini
PURPOSE: The translation of nonclinical oncology studies is a subject of continuous debate. We propose that translational oncology studies need to optimize both pharmacokinetic (drug exposure) and pharmacodynamic (xenograft model) aspects. While improvements in pharmacodynamic translatability can be obtained by choosing cell lines or patient-derived xenograft models closer to the clinical indication, significant ambiguity and variability exists when optimizing the pharmacokinetic translation of small molecule and biotherapeutic agents...
August 22, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Takashi K Kishimoto, Joseph D Ferrari, Robert A LaMothe, Pallavi N Kolte, Aaron P Griset, Conlin O'Neil, Victor Chan, Erica Browning, Aditi Chalishazar, William Kuhlman, Fen-Ni Fu, Nelly Viseux, David H Altreuter, Lloyd Johnston, Roberto A Maldonado
The development of antidrug antibodies (ADAs) is a common cause for the failure of biotherapeutic treatments and adverse hypersensitivity reactions. Here we demonstrate that poly(lactic-co-glycolic acid) (PLGA) nanoparticles carrying rapamycin, but not free rapamycin, are capable of inducing durable immunological tolerance to co-administered proteins that is characterized by the induction of tolerogenic dendritic cells, an increase in regulatory T cells, a reduction in B cell activation and germinal centre formation, and the inhibition of antigen-specific hypersensitivity reactions...
October 2016: Nature Nanotechnology
Surinder Kaur, Luna Liu, Diego F Cortes, Junlong Shao, Rand Jenkins, William R Mylott, Keyang Xu
BACKGROUND: Biotherapeutics development requires validated assays in biological matrices for pharmacokinetic assessment. Historically, ligand-binding assays have been the predominant platform available. Recently, alternative hybrid methods, combining ligand-binding analyte enrichment with LC-MS detection have emerged. Methodology & results: The validation of an immunoaffinity (IA)-LC-MS/MS method to quantify a monoclonal antibody biotherapeutic in cynomolgus monkey serum is described...
August 2016: Bioanalysis
Karl E Griswold, Chris Bailey-Kellogg
Therapeutic proteins are powerful next-generation drugs able to effectively treat diverse and devastating diseases, but the development and use of biotherapeutics entails unique challenges and risks. In particular, protein drugs are subject to immune surveillance in the human body, and ensuing antidrug immune responses can cause a wide range of problems including altered pharmacokinetics, loss of efficacy, and even life-threating complications. Here we review recent progress in technologies for engineering deimmunized biotherapeutics, placing particular emphasis on deletion of immunogenic antibody and T cell epitopes via experimentally or computationally guided mutagenesis...
August 2016: Current Opinion in Structural Biology
Yao-Yun Fan, Lindsay B Avery, Mengmeng Wang, Denise M O'Hara, Sheldon Leung, Hendrik Neubert
The neonatal Fc receptor (FcRn) is a homeostatic receptor responsible for prolonging immunoglobulin G (IgG) half-life by protecting it from lysosomal degradation and recycling it to systemic circulation. Tissue-specific FcRn expression is a critical parameter in physiologically-based pharmacokinetic (PBPK) modeling for translational pharmacokinetics of Fc-containing biotherapeutics. Using online peptide immuno-affinity chromatography coupled with high resolution mass spectrometry, we established a quantitative FcRn tissue protein expression profile in human FcRn (hFcRn) transgenic mice, Tg32 homozygous and hemizygous strains...
July 2016: MAbs
Montserrat Carrasco-Triguero, Helen Davis, Yuda Zhu, Daniel Coleman, Denise Nazzal, Paul Vu, Surinder Kaur
Immunogenicity assessment during early stages of nonclinical biotherapeutic development is not always warranted. It is rarely predictive for clinical studies and evidence for the presence of anti-drug antibodies (ADAs) may be inferred from the pharmacokinetic (PK) profile. However, collecting and banking samples during the course of the study are prudent for confirmation and a deeper understanding of the impact on PK and safety. Biotherapeutic-specific ADA assays commonly developed can require considerable time and resources...
2016: Journal of Immunology Research
Yao-Yun Fan, Hendrik Neubert
Neonatal Fc receptor (FcRn) is the homeostatic receptor responsible for the long half-life of endogenous IgG by protecting it from lysosomal degradation. Understanding systemic FcRn tissue expression is important to predict and design the half-life of therapeutic antibodies and Fc-coupled biotherapeutics. To this end, we measured human FcRn (hFcRn) tissue expression in Tg32, a human FcRn knock-in transgenic mouse model, for which a strong correlation of drug clearance to humans has been demonstrated. Building an hFcRn tissue expression profile in Tg32 was enabled by the development of a tissue preparation procedure composed of bead-based protein extraction and protein precipitation using acetone followed by pellet digestion with trypsin...
April 19, 2016: Analytical Chemistry
Roland E Kontermann
INTRODUCTION: Many of the biotherapeutics approved or under development suffer from a short half-life necessitating frequent applications in order to maintain a therapeutic concentration over an extended period of time. The implementation of half-life extension strategies allows the generation of long-lasting therapeutics with improved pharmacokinetic and pharmacodynamic properties. AREAS COVERED: This review gives an overview of the different half-life extension strategies developed over the past years and their application to generate next-generation biotherapeutics...
July 2016: Expert Opinion on Biological Therapy
Justin Daller
Biosimilars are defined as biological products that are highly similar to a reference product, notwithstanding minor differences in clinically inactive components. Biosimilars show no clinically meaningful differences in safety, purity, and potency of the product in comparison to the reference product. With the ever looming patent expiry of some major high cost biologics, biosimilar production is becoming ever more lucrative to companies. Europe (EU) set the precedent, followed by the United States (US) in early 2012, for the approval process for biosimilars...
April 2016: Regulatory Toxicology and Pharmacology: RTP
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