11 results on '"biotherapeutics"'
Search Results
2. Pulmonary Inhalation of Biotherapeutics: A Systematic Approach to Understanding the Effects of Atomisation Gas Flow Rate on Particle Physiochemical Properties and Retained Bioactivity
- Author
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Laura Foley, Ahmad Ziaee, Gavin Walker, and Emmet O’Reilly
- Subjects
biotherapeutics ,spray-drying ,atomisation gas flow rate ,enzymatic activity ,particle engineering ,pulmonary delivery ,Pharmacy and materia medica ,RS1-441 - Abstract
The identification of spray-drying processing parameters capable of producing particles suitable for pulmonary inhalation with retained bioactivity underpins the development of inhalable biotherapeutics. Effective delivery of biopharmaceuticals via pulmonary delivery routes such as dry powder inhalation (DPI) requires developing techniques that engineer particles to well-defined target profiles while simultaneously minimising protein denaturation. This study examines the simultaneous effects of atomisation gas flow rate on particle properties and retained bioactivity for the model biopharmaceutical lysozyme. The results show that optimising the interplay between atomisation gas flow rate and excipient concentration enables the production of free-flowing powder with retained bioactivity approaching 100%, moisture content below 4%, and D50 < 4 µm, at yields exceeding 50%. The developed methodologies inform the future design of protein-specific spray-drying parameters for inhalable biotherapeutics.
- Published
- 2024
- Full Text
- View/download PDF
3. Enhancing Oral Delivery of Biologics: A Non-Competitive and Cross-Reactive Anti-Leptin Receptor Nanofitin Demonstrates a Gut-Crossing Capacity in an Ex Vivo Porcine Intestinal Model.
- Author
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Masloh, Solene, Chevrel, Anne, Culot, Maxime, Perrocheau, Anaëlle, Kalia, Yogeshvar N., Frehel, Samuel, Gaussin, Rémi, Gosselet, Fabien, Huet, Simon, Zeisser Labouebe, Magali, and Scapozza, Leonardo
- Subjects
- *
LEPTIN receptors , *INTESTINAL barrier function , *INTESTINES , *INTESTINAL absorption , *BIOLOGICALS , *LEPTIN - Abstract
Biotherapeutics exhibit high efficacy in targeted therapy, but their oral delivery is impeded by the harsh conditions of the gastrointestinal (GI) tract and limited intestinal absorption. This article presents a strategy to overcome the challenges of poor intestinal permeability by using a protein shuttle that specifically binds to an intestinal target, the leptin receptor (LepR), and exploiting its capacity to perform a receptor-mediated transport. Our proof-of-concept study focuses on the characterization and transport of robust affinity proteins, known as Nanofitins, across an ex vivo porcine intestinal model. We describe the potential to deliver biologically active molecules across the mucosa by fusing them with the Nanofitin 1-F08 targeting the LepR. This particular Nanofitin was selected for its absence of competition with leptin, its cross-reactivity with LepR from human, mouse, and pig hosts, and its shuttle capability associated with its ability to induce a receptor-mediated transport. This study paves the way for future in vivo demonstration of a safe and efficient oral-to-systemic delivery of targeted therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
4. Enhancing Oral Delivery of Biologics: A Non-Competitive and Cross-Reactive Anti-Leptin Receptor Nanofitin Demonstrates a Gut-Crossing Capacity in an Ex Vivo Porcine Intestinal Model
- Author
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Solene Masloh, Anne Chevrel, Maxime Culot, Anaëlle Perrocheau, Yogeshvar N. Kalia, Samuel Frehel, Rémi Gaussin, Fabien Gosselet, Simon Huet, Magali Zeisser Labouebe, and Leonardo Scapozza
- Subjects
biotherapeutics ,permeability ,shuttle ,leptin receptor ,Nanofitins ,ex vivo ,Pharmacy and materia medica ,RS1-441 - Abstract
Biotherapeutics exhibit high efficacy in targeted therapy, but their oral delivery is impeded by the harsh conditions of the gastrointestinal (GI) tract and limited intestinal absorption. This article presents a strategy to overcome the challenges of poor intestinal permeability by using a protein shuttle that specifically binds to an intestinal target, the leptin receptor (LepR), and exploiting its capacity to perform a receptor-mediated transport. Our proof-of-concept study focuses on the characterization and transport of robust affinity proteins, known as Nanofitins, across an ex vivo porcine intestinal model. We describe the potential to deliver biologically active molecules across the mucosa by fusing them with the Nanofitin 1-F08 targeting the LepR. This particular Nanofitin was selected for its absence of competition with leptin, its cross-reactivity with LepR from human, mouse, and pig hosts, and its shuttle capability associated with its ability to induce a receptor-mediated transport. This study paves the way for future in vivo demonstration of a safe and efficient oral-to-systemic delivery of targeted therapies.
- Published
- 2024
- Full Text
- View/download PDF
5. Validation of a Dendritic Cell and CD4+ T Cell Restimulation Assay Contributing to the Immunogenicity Risk Evaluation of Biotherapeutics.
- Author
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Siegel, Michel, Steiner, Guido, Franssen, Linnea C., Carratu, Francesca, Herron, James, Hartman, Katharina, Looney, Cary M., Ducret, Axel, Bray-French, Katharine, Rohr, Olivier, Hickling, Timothy P., Smith, Noel, and Marban-Doran, Céline
- Subjects
- *
IMMUNE response , *DENDRITIC cells , *RISK assessment , *T cells , *ANTIBODY formation , *PEPTIDES - Abstract
Immunogenicity, defined as the ability to provoke an immune response, can be either wanted (i.e., vaccines) or unwanted. The latter refers to an immune response to protein or peptide therapeutics, characterized by the production of anti-drug antibodies, which may affect the efficacy and/or the safety profiles of these drugs. Consequently, evaluation of the risk of immunogenicity early in the development of biotherapeutics is of critical importance for defining their efficacy and safety profiles. Here, we describe and validate a fit-for-purpose FluoroSpot-based in vitro assay for the evaluation of drug-specific T cell responses. A panel of 24 biotherapeutics with a wide range of clinical anti-drug antibody response rates were tested in this assay. We demonstrated that using suitable cutoffs and donor cohort sizes, this assay could identify most of the compounds with high clinical immunogenicity rates (71% and 78% for sensitivity and specificity, respectively) while we characterized the main sources of assay variability. Overall, these data indicate that the dendritic cell and CD4+ T cell restimulation assay published herein could be a valuable tool to assess the risk of drug-specific T cell responses and contribute to the selection of clinical candidates in early development. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
6. Pre-Clinical In-Vitro Studies on Parameters Governing Immune Complex Formation.
- Author
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Fichter, Marie, Richter, Gesa, Bepperling, Alexander, and Wassmann, Paul
- Subjects
- *
IMMUNE complexes , *IMMUNE response , *ANTIBODY formation , *PHOTOMETRY - Abstract
The success of biotherapeutics is often challenged by the undesirable events of immunogenicity in patients, characterized by the formation of anti-drug antibodies (ADA). Under specific conditions, the ADAs recognizing the biotherapeutic can trigger the formation of immune complexes (ICs), followed by cascades of subsequent effects on various cell types. Hereby, the connection between the characteristics of ICs and their downstream impact is still not well understood. Factors governing the formation of ICs and the characteristics of these IC species were assessed systematically in vitro. Classic analytical methodologies such as SEC-MALS and SV-AUC, and the state-of-the-art technology mass photometry were applied for the characterization. The study demonstrates a clear interplay between (1) the absolute concentration of the involved components, (2) their molar ratios, (3) structural features of the biologic, (4) and of its endogenous target. This surrogate study design and the associated analytical tool-box is readily applicable to most biotherapeutics and provides valuable insights into mechanisms of IC formation prior to FIH studies. The applicability is versatile—from the detection of candidates with immunogenicity risks during developability assessment to evaluation of the impact of degraded or post-translationally modified biotherapeutics on the formation of ICs. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
7. Validation of a Dendritic Cell and CD4+ T Cell Restimulation Assay Contributing to the Immunogenicity Risk Evaluation of Biotherapeutics
- Author
-
Michel Siegel, Guido Steiner, Linnea C. Franssen, Francesca Carratu, James Herron, Katharina Hartman, Cary M. Looney, Axel Ducret, Katharine Bray-French, Olivier Rohr, Timothy P. Hickling, Noel Smith, and Céline Marban-Doran
- Subjects
immunogenicity ,immunomodulation ,biotherapeutics ,in vitro T cell assay ,assay validation ,Pharmacy and materia medica ,RS1-441 - Abstract
Immunogenicity, defined as the ability to provoke an immune response, can be either wanted (i.e., vaccines) or unwanted. The latter refers to an immune response to protein or peptide therapeutics, characterized by the production of anti-drug antibodies, which may affect the efficacy and/or the safety profiles of these drugs. Consequently, evaluation of the risk of immunogenicity early in the development of biotherapeutics is of critical importance for defining their efficacy and safety profiles. Here, we describe and validate a fit-for-purpose FluoroSpot-based in vitro assay for the evaluation of drug-specific T cell responses. A panel of 24 biotherapeutics with a wide range of clinical anti-drug antibody response rates were tested in this assay. We demonstrated that using suitable cutoffs and donor cohort sizes, this assay could identify most of the compounds with high clinical immunogenicity rates (71% and 78% for sensitivity and specificity, respectively) while we characterized the main sources of assay variability. Overall, these data indicate that the dendritic cell and CD4+ T cell restimulation assay published herein could be a valuable tool to assess the risk of drug-specific T cell responses and contribute to the selection of clinical candidates in early development.
- Published
- 2022
- Full Text
- View/download PDF
8. Pre-Clinical In-Vitro Studies on Parameters Governing Immune Complex Formation
- Author
-
Marie Fichter, Gesa Richter, Alexander Bepperling, and Paul Wassmann
- Subjects
immune complexes ,protein complexes ,anti-drug antibodies ,immunogenicity ,biotherapeutics ,analytical assessment ,Pharmacy and materia medica ,RS1-441 - Abstract
The success of biotherapeutics is often challenged by the undesirable events of immunogenicity in patients, characterized by the formation of anti-drug antibodies (ADA). Under specific conditions, the ADAs recognizing the biotherapeutic can trigger the formation of immune complexes (ICs), followed by cascades of subsequent effects on various cell types. Hereby, the connection between the characteristics of ICs and their downstream impact is still not well understood. Factors governing the formation of ICs and the characteristics of these IC species were assessed systematically in vitro. Classic analytical methodologies such as SEC-MALS and SV-AUC, and the state-of-the-art technology mass photometry were applied for the characterization. The study demonstrates a clear interplay between (1) the absolute concentration of the involved components, (2) their molar ratios, (3) structural features of the biologic, (4) and of its endogenous target. This surrogate study design and the associated analytical tool-box is readily applicable to most biotherapeutics and provides valuable insights into mechanisms of IC formation prior to FIH studies. The applicability is versatile—from the detection of candidates with immunogenicity risks during developability assessment to evaluation of the impact of degraded or post-translationally modified biotherapeutics on the formation of ICs.
- Published
- 2022
- Full Text
- View/download PDF
9. Current and Emerging Strategies for Enhancing Antibody Delivery to the Brain
- Author
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Rinie Bajracharya, Alayna C. Caruso, Laura J. Vella, and Rebecca M. Nisbet
- Subjects
blood–brain barrier ,neurological disease ,antibodies ,monoclonal antibodies ,biotherapeutics ,focused ultrasound ,Pharmacy and materia medica ,RS1-441 - Abstract
For the treatment of neurological diseases, achieving sufficient exposure to the brain parenchyma is a critical determinant of drug efficacy. The blood–brain barrier (BBB) functions to tightly control the passage of substances between the bloodstream and the central nervous system, and as such poses a major obstacle that must be overcome for therapeutics to enter the brain. Monoclonal antibodies have emerged as one of the best-selling treatment modalities available in the pharmaceutical market owing to their high target specificity. However, it has been estimated that only 0.1% of peripherally administered antibodies can cross the BBB, contributing to the low success rate of immunotherapy seen in clinical trials for the treatment of neurological diseases. The development of new strategies for antibody delivery across the BBB is thereby crucial to improve immunotherapeutic efficacy. Here, we discuss the current strategies that have been employed to enhance antibody delivery across the BBB. These include (i) focused ultrasound in combination with microbubbles, (ii) engineered bi-specific antibodies, and (iii) nanoparticles. Furthermore, we discuss emerging strategies such as extracellular vesicles with BBB-crossing properties and vectored antibody genes capable of being encapsulated within a BBB delivery vehicle.
- Published
- 2021
- Full Text
- View/download PDF
10. Current and Emerging Strategies for Enhancing Antibody Delivery to the Brain
- Author
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Laura J Vella, Rinie Bajracharya, Rebecca M. Nisbet, and Alayna C. Caruso
- Subjects
medicine.drug_class ,medicine.medical_treatment ,Central nervous system ,Pharmaceutical Science ,Review ,exosomes ,Pharmacology ,blood–brain barrier ,Blood–brain barrier ,Monoclonal antibody ,bi-specific antibodies ,Efficacy ,Pharmacy and materia medica ,medicine ,antibodies ,biotherapeutics ,neurological disease ,biology ,business.industry ,Immunotherapy ,Microvesicles ,RS1-441 ,medicine.anatomical_structure ,biology.protein ,Microbubbles ,focused ultrasound ,nanoparticles ,monoclonal antibodies ,Antibody ,business - Abstract
For the treatment of neurological diseases, achieving sufficient exposure to the brain parenchyma is a critical determinant of drug efficacy. The blood–brain barrier (BBB) functions to tightly control the passage of substances between the bloodstream and the central nervous system, and as such poses a major obstacle that must be overcome for therapeutics to enter the brain. Monoclonal antibodies have emerged as one of the best-selling treatment modalities available in the pharmaceutical market owing to their high target specificity. However, it has been estimated that only 0.1% of peripherally administered antibodies can cross the BBB, contributing to the low success rate of immunotherapy seen in clinical trials for the treatment of neurological diseases. The development of new strategies for antibody delivery across the BBB is thereby crucial to improve immunotherapeutic efficacy. Here, we discuss the current strategies that have been employed to enhance antibody delivery across the BBB. These include (i) focused ultrasound in combination with microbubbles, (ii) engineered bi-specific antibodies, and (iii) nanoparticles. Furthermore, we discuss emerging strategies such as extracellular vesicles with BBB-crossing properties and vectored antibody genes capable of being encapsulated within a BBB delivery vehicle.
- Published
- 2021
11. Current and Emerging Strategies for Enhancing Antibody Delivery to the Brain.
- Author
-
Bajracharya R, Caruso AC, Vella LJ, and Nisbet RM
- Abstract
For the treatment of neurological diseases, achieving sufficient exposure to the brain parenchyma is a critical determinant of drug efficacy. The blood-brain barrier (BBB) functions to tightly control the passage of substances between the bloodstream and the central nervous system, and as such poses a major obstacle that must be overcome for therapeutics to enter the brain. Monoclonal antibodies have emerged as one of the best-selling treatment modalities available in the pharmaceutical market owing to their high target specificity. However, it has been estimated that only 0.1% of peripherally administered antibodies can cross the BBB, contributing to the low success rate of immunotherapy seen in clinical trials for the treatment of neurological diseases. The development of new strategies for antibody delivery across the BBB is thereby crucial to improve immunotherapeutic efficacy. Here, we discuss the current strategies that have been employed to enhance antibody delivery across the BBB. These include (i) focused ultrasound in combination with microbubbles, (ii) engineered bi-specific antibodies, and (iii) nanoparticles. Furthermore, we discuss emerging strategies such as extracellular vesicles with BBB-crossing properties and vectored antibody genes capable of being encapsulated within a BBB delivery vehicle.
- Published
- 2021
- Full Text
- View/download PDF
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