Article
Pharmacology & Pharmacy
Michel Siegel, Guido Steiner, Linnea C. C. Franssen, Francesca Carratu, James Herron, Katharina Hartman, Cary M. M. Looney, Axel Ducret, Katharine Bray-French, Olivier Rohr, Timothy P. P. Hickling, Noel Smith, Celine Marban-Doran
Summary: In this article, a new in vitro assay method for evaluating the risk of drug-specific T cell responses is described and validated. By testing a panel of biotherapeutics, it was found that this assay method could effectively identify compounds with high immunogenicity rates and characterize the main sources of assay variability.
Review
Biochemistry & Molecular Biology
Yanis Ramdani, Juliette Lamamy, Herve Watier, Valerie Gouilleux-Gruart
Summary: This review discusses the mutations that regulate FcRn binding and the application of anti-FcRn monoclonal antibodies. Mutations near and outside the FcRn binding site can enhance affinity for FcRn, leading to prolonged half-life and improved biodistribution of monoclonal antibodies. Blocking FcRn binding can result in degradation of endogenous IgG. Anti-FcRn monoclonal antibodies have the potential to deplete endogenous IgG and show promising biological and clinical applications.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Gastroenterology & Hepatology
Emily Ef Fekete, Daniel Figeys, Xu Zhang
Summary: Mounting evidence suggests that the gut microbiome plays a causative or correlative role in various diseases, such as gastrointestinal diseases, metabolic diseases, neurological disorders, and cancers. Therefore, there have been efforts to develop and apply therapies that target the gut microbiota for disease treatment and wellness maintenance. This review summarizes the current development of gut microbiota-directed therapeutics, emphasizes the importance of advanced -omics approaches for evaluating microbiota-type therapies, and discusses the clinical and regulatory challenges. It also explores the development and potential application of ex vivo microbiome assays and in vitro intestinal cellular models. Overall, this review provides a comprehensive view of the promises and challenges in the emerging field of microbiome-directed human healthcare.
Article
Biochemical Research Methods
Jack Wade, Charlotte Rimbault, Hanif Ali, Line Ledsgaard, Esperanza Rivera-de-Torre, Maher Abou Hachem, Kim Boddum, Nadia Mirza, Markus-Frederik Bohn, Siri A. Sakya, Fulgencio Ruso-Julve, Jan Terje Andersen, Andreas H. Laustsen
Summary: This study presents a protein engineering approach to increase the valence of neutralizing nanobodies against snake toxins. The engineered nanobody fusion proteins, called Quads, showed improved blocking potency in vitro compared to the monomeric format. This technology offers a means of tailoring therapeutic properties for improved neutralization of soluble targets such as snake toxins.
BIOCONJUGATE CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Rozaleen Dash, Sumit Kumar Singh, Narendra Chirmule, Anurag S. Rathore
Summary: The development of monoclonal antibody (mAb) biosimilars is a complex process that requires a deep understanding of key product attributes affecting safety and efficacy, as well as strategies to control them. Establishing a relevant and robust functional assay for mAb comparability demands an interdisciplinary approach and flexibility. However, current advanced tools often have major shortcomings limiting their routine use, highlighting the need for multiple orthogonal state-of-the-art techniques to address these challenges.
Article
Multidisciplinary Sciences
Lucky Ahmed, Priyanka Gupta, Kyle P. Martin, Justin M. Scheer, Andrew E. Nixon, Sandeep Kumar
Summary: By analyzing the physicochemical descriptors of Fv regions in marketed antibody-based biotherapeutics, this study derived a set of descriptors that can help guide hit selection, lead identification, and optimization of biotherapeutic candidates. The research found that 33% of CST antibodies deviate in physicochemical properties from currently marketed biotherapeutics, providing valuable information for risk assessment and collaborations.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Chemistry, Multidisciplinary
Corentin Gauthier, Julie Mariot, Morgane Daurat, Christine Dhommee, Khaled El Cheikh, Elodie Morere, Geoffrey Depaepe, Magali Gary-Bobo, Alain Morere, Marcel Garcia, Ilaria Basile, Valerie Gouilleux-Gruart, Marie Maynadier
Summary: The grafting of AMFA on therapeutic proteins improves enzyme delivery by increasing cellular uptake via the M6PR receptor. In this study, the impact of AMFA grafting on the cell uptake and recycling of a monoclonal antibody was investigated. AMFA grafting increased drug release in cells and had no effect on antibody recycling mediated by the FcRn receptor. AMFA grafting did not impair the pharmacokinetics and showed high stability.
JOURNAL OF CONTROLLED RELEASE
(2023)
Article
Biology
Ole A. Mandrup, Sui Ching Ong, Simon Lykkemark, Anders Dinesen, Imke Rudnik-Jansen, Niels Frederik Dagnaes-Hansen, Jan Terje Andersen, Luis Alvarez-Vallina, Kenneth A. Howard
Summary: This study introduces a programmable serum half-life extension platform based on human albumin sequences fused with bispecific T-cell engagers, offering potential long-lasting effects, better patient compliance, and the ability to tailor pharmacokinetics to maximize therapeutic efficacy and safety of immuno-oncology targeted biologics.
COMMUNICATIONS BIOLOGY
(2021)
Article
Chemistry, Medicinal
Qianmeng Lin, Xuan Xia, Jun Li, Zhan Zhou, Yongheng Chen
Summary: The study developed a site-specific N-terminal PEGylation method and successfully constructed two homogeneous mPEG-GLP-1 peptides. After PEGylation, degradation decreased, pharmacokinetic performance improved, and hypoglycemic effects were enhanced. This method achieved better pharmacological and therapeutic properties through site-specific modification.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Fudan Zheng, Peng Hou, Clairissa D. Corpstein, Kinam Park, Tonglei Li
Summary: A multiscale pharmacokinetic model was developed to study the absorption kinetics of subcutaneously injected biological products, providing insights into the presystemic clearance by the lymphatic system. The local absorption rate was found to be influential on the systemic exposure of albumin and nineteen monoclonal antibodies, suggesting a correlation between stability propensities and presystemic clearance, as well as the influence of electrostatic charges on local absorption rates. The study emphasizes the importance of experimentally determining biophysical characteristics of large molecules and biomechanical properties of human skin tissues.
JOURNAL OF CONTROLLED RELEASE
(2021)
Article
Chemistry, Multidisciplinary
Fudan Zheng, Peng Hou, Clairissa D. Corpstein, Lei Xing, Tonglei Li
Summary: A bottom-up method was developed to simulate drug transport and absorption of protein solutions in skin tissue based on physical principles. The results appear to match experimental observations.
PHARMACEUTICAL RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Joschka Bauer, Nandhini Rajagopal, Priyanka Gupta, Pankaj Gupta, Andrew E. Nixon, Sandeep Kumar
Summary: Antibody-based biotherapeutics have encountered significant challenges and risks in their discovery and development, but have still emerged as successful pharmaceuticals. This review proposes the use of biopharmaceutical informatics, a conceptual framework that integrates computation and experimentation throughout the entire drug discovery process. The advancements in computational methods allow for better disease conceptualization, target identification, antibody design, and lead drug candidate optimization. By adopting biopharmaceutical informatics, affordable and effective biotherapeutics can be brought to patients more quickly.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2023)
Article
Multidisciplinary Sciences
Jeffrey Y. K. Wong, Arunika I. Ekanayake, Serhii Kharchenko, Steven E. Kirberger, Ryan Qiu, Payam Kelich, Susmita Sarkar, Jianqian Li, Kleinberg X. Fernandez, Edgar R. Alvizo-Paez, Jiayuan Miao, Shiva Kalhor-Monfared, J. Dwyer John, Hongsuk Kang, Hwanho Choi, John M. Nuss, John C. Vederas, Yu-Shan Lin, Matthew S. Macauley, Lela Vukovic, William C. K. Pomerantz, Ratmir Derda
Summary: Peptide-based therapeutics with poor circulation half-life have been a challenge. In this study, researchers successfully selected albumin-binding macrocyclic peptides from genetically encoded libraries modified by specific chemistry. The selected peptides showed high affinity for human serum albumin and demonstrated longer in vivo circulation half-life, which is a promising starting point for developing compact macrocycles with extended half-life.
NATURE COMMUNICATIONS
(2023)
Review
Medicine, Research & Experimental
Kyle P. P. Martin, Christine Grimaldi, Rolf Grempler, Steven Hansel, Sandeep Kumar
Summary: There is significant interest in antibody-based biotherapeutics due to their selectivity and desirable pharmacology. This study analyzed characteristics of 89 marketed antibody-based biotherapeutics approved between 1986 and mid-2020. The findings reveal major trends in their emergence as best-selling pharmaceuticals and provide insights for better drug discovery and development strategies.
Article
Biochemical Research Methods
Yakai Song, Xiaojie Deng, Wei Shi, Feng Tang, Wei Huang, Likun Gong, Qiuping Qin
Summary: The study developed a homogeneous time-resolved fluorometric energy transfer assay for assessing human neonatal Fc receptor binding activity with IgG antibodies. The assay showed good accuracy, precision, linearity, and specificity, and was further validated in a rat pharmacokinetics study. This assay has the potential for identifying antibodies with appropriate binding ability to human Fc receptors through modifications.
JOURNAL OF IMMUNOLOGICAL METHODS
(2021)
Article
Biochemical Research Methods
Shan Chung, Van Nguyen, Yuwen Linda Lin, Lynn Kamen, An Song
JOURNAL OF IMMUNOLOGICAL METHODS
(2017)
Article
Biochemical Research Methods
Shan Chung, Yuwen Linda Lin, Van Nguyen, Lynn Kamen, Kai Zheng, Bianca Vora, An Song
JOURNAL OF IMMUNOLOGICAL METHODS
(2018)
Article
Biochemical Research Methods
Shan Chung, Yuwen L. Lin, Chae Reed, Carl Ng, Zhijie Jey Cheng, Fabio Malavasi, Jihong Yang, Valerie Quarmby, An Song
JOURNAL OF IMMUNOLOGICAL METHODS
(2014)
Article
Biochemical Research Methods
Lynn Kamen, Tara Thakurta, Srividya Myneni, Kai Zheng, Shan Chung
JOURNAL OF IMMUNOLOGICAL METHODS
(2019)
Article
Biochemical Research Methods
Lynn Kamen, Srividya Myneni, Chris Langsdorf, Elviza Kho, Benjamin Ordonia, Tara Thakurta, Kai Zheng, An Song, Shan Chung
JOURNAL OF IMMUNOLOGICAL METHODS
(2019)
Article
Medicine, Research & Experimental
Shan Chung, Van Nguyen, Yuwen Linda Lin, Julien Lafrance-Vanasse, Suzie J. Scales, Kevin Lin, Rong Deng, Kathi Williams, Gizette Sperinde, Juan Jenny Li, Kai Zheng, Siddharth Sukumaran, Devin Tesar, James A. Ernst, Saloumeh Fischer, Greg A. Lazar, Saileta Prabhu, An Song
Review
Biochemical Research Methods
Sivan Cohen, Shan Chung
Summary: This review emphasizes the role of innate and adaptive immune cells in immunogenicity and summarizes their use in predicting clinical ADAs.
Article
Biochemical Research Methods
Rachel Melendez, Benjamin Ordonia, Joyce Guerrero, Azadeh Hassanzadeh, Peter Tran, Justin Low, Manda Wong, Jochen Brumm, Shan Chung, Lynn Kamen
Summary: This study developed a novel assay to predict the immunogenicity of biotherapeutics by measuring the degree of antibody internalization. The results demonstrated that biotherapeutics with higher clinical immunogenicity had a higher degree of internalization.
Article
Medicine, Research & Experimental
Sivan Cohen, Shan Chung, Christoph Spiess, Victor Lundin, Eric Stefanich, Steven T. Laing, Vanessa Clark, Jochen Brumm, Ying Zhou, Catherine Huang, Joyce Guerrero, Srividya Myneni, Rajbharan Yadav, Ketevan Siradze, Kun Peng
Summary: BsAbs, which recognize and bind two different targets or epitopes, require more engineering and manufacturing compared to conventional antibodies, potentially leading to increased immunogenic risk. The bsAb Anti-A/B showed unexpectedly high immunogenicity in preclinical and clinical studies, leading to early termination of clinical development.
Article
Medicine, Research & Experimental
Sivan Cohen, Srividya Myneni, Anna Batt, Joyce Guerrero, Jochen Brumm, Shan Chung
Summary: Biotherapeutics, natural or bioengineered products of living cells, have transformed the treatment of diseases but continue to face challenges from unwanted immune responses. A method for assessing the immunogenic risk of biotherapeutics has been described, showing a correlation between clinical immunogenicity and the stimulation of certain cell surface markers on CD4(+) T cells. This approach allows for the rapid evaluation of potential immunogenicity in early stages of biotherapeutic development, leading to the elimination of candidates with high risk of adverse events related to anti-drug antibodies.
