Advances in the design of new types of inhaled medicines

Czechtizky, Werngard; Su, Wu Chou; Ripa, Lena; Schießer, Stefan; Höijer, Andreas; Cox, Rhona J.

doi:10.1016/bs.pmch.2022.04.001

Cited by 4 publications

(4 citation statements)

References 237 publications

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“…Fc-mediated active transepithelial uptake might therefore have additionally enhanced the in vivo activity of intranasally administered IF8-Fc and compensated for the fact that IF8-Fc was administered at a four times lower molar concentration during equimass treatment compared to scFv V2D7. Further studies are needed to assess the suitability of anti-ALCAM mAbs upon delivery by inhalation, i.e., the most suitable route of topical administration for therapeutic proteins in human asthma [ 72 ]. At this point, our study confirms ALCAM as a therapeutic target for asthma and demonstrates the in vivo activity of both IF8-Fc and scFv V2D7 upon intranasal administration.…”

Section: Discussionmentioning

confidence: 99%

Optimization and Characterization of Novel ALCAM-Targeting Antibody Fragments for Transepithelial Delivery

Bauer,

Klassa,

Herbst

et al. 2023

Pharmaceutics

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Activated leukocyte cell adhesion molecule (ALCAM) is a cell adhesion molecule that supports T cell activation, leukocyte migration, and (lymph)angiogenesis and has been shown to contribute to the pathology of various immune-mediated disorders, including asthma and corneal graft rejection. In contrast to monoclonal antibodies (mAbs) targeting ALCAM’s T cell expressed binding partner CD6, no ALCAM-targeting mAbs have thus far entered clinical development. This is likely linked with the broad expression of ALCAM on many different cell types, which increases the risk of eliciting unwanted treatment-induced side effects upon systemic mAb application. Targeting ALCAM in surface-exposed tissues, such as the lungs or the cornea, by a topical application could circumvent this issue. Here, we report the development of various stability- and affinity-improved anti-ALCAM mAb fragments with cross-species reactivity towards mouse, rat, monkey, and human ALCAM. Fragments generated in either mono- or bivalent formats potently blocked ALCAM–CD6 interactions in a competition ELISA, but only bivalent fragments efficiently inhibited ALCAM–ALCAM interactions in a leukocyte transmigration assay. The different fragments displayed a clear size-dependence in their ability to penetrate the human corneal epithelium. Furthermore, intranasal delivery of anti-ALCAM fragments reduced leukocyte infiltration in a mouse model of asthma, confirming ALCAM as a target for topical application in the lungs.

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Section: Discussionmentioning

confidence: 99%

Optimization and Characterization of Novel ALCAM-Targeting Antibody Fragments for Transepithelial Delivery

Bauer,

Klassa,

Herbst

et al. 2023

Pharmaceutics

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“…Glucuronosyltransferases are responsible for the glucuronidation process, a primary and most important part of phase II metabolism [71]. The UGT enzyme [15] catalyzes the addition of a glucuronic acid moiety to xenobiotics, which is the primary method through which the human body eliminates the most frequently prescribed medications.…”

Section: Ugts Predictionmentioning

confidence: 99%

Artificial Intelligence in Drug Metabolism and Excretion Prediction: Recent Advances, Challenges, and Future Perspectives

2023

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Drug metabolism and excretion play crucial roles in determining the efficacy and safety of drug candidates, and predicting these processes is an essential part of drug discovery and development. In recent years, artificial intelligence (AI) has emerged as a powerful tool for predicting drug metabolism and excretion, offering the potential to speed up drug development and improve clinical success rates. This review highlights recent advances in AI-based drug metabolism and excretion prediction, including deep learning and machine learning algorithms. We provide a list of public data sources and free prediction tools for the research community. We also discuss the challenges associated with the development of AI models for drug metabolism and excretion prediction and explore future perspectives in the field. We hope this will be a helpful resource for anyone who is researching in silico drug metabolism, excretion, and pharmacokinetic properties.

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“…With broad and flattened cytoplasm, alveolar type I cells make up approximately 90% of the alveolar surface area, with a thickness of 0.2–0.7 µm, providing a structural lining with very short diffusion distances for gas exchange between the alveolar space and the capillary blood perfusion (~5 L/min). The alveolar surface is lined with 0.07–0.3 µm thick pulmonary surfactant produced by alveolar type II cells, which is composed of 80% phospholipids (roughly half of them being dipalmitoylphosphatidylcholine (DPPC)), 5–10% neutral lipids (mainly cholesterol), and 5–10% surfactant proteins [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Systemic Protein Delivery via Inhalable Liposomes: Formulation and Pharmacokinetics

2023

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The enormous and thin alveolar epithelium is an attractive site for systemic protein delivery. Considering the excellent biocompatibility of phospholipids with endogenous pulmonary surfactant, we engineered dimyristoylphosphatidylcholine (DMPC)-based liposomes for pulmonary administration, using Cy5.5-labeled bovine serum albumin (BSA-Cy5.5) as a model protein payload. The level of cholesterol (Chol) and surface modification with PEG in inhalable liposomes were optimized iteratively based on the encapsulation efficiency, the release kinetics in the simulated lung fluid, and the uptake in murine RAW 264.7 macrophages. The plasma pharmacokinetics of BSA-Cy5.5-encapsulated liposomes with the composition of DMPC/Chol/PEG at 85:10:5 (molar ratio) was studied in mice following intratracheal aerosolization, in comparison with that of free BSA-Cy5.5 solution. The biodisposition of BSA-Cy5.5 was continuously monitored using whole-body near-infrared (NIR) fluorescence imaging for 10 days. We found that the systemic bioavailability of BSA-Cy5.5 from inhaled liposomes was 22%, which was notably higher than that of inhaled free BSA-Cy5.5. The mean residence time of BSA-Cy5.5 was markedly prolonged in mice administered intratracheally with liposomal BSA-Cy5.5, which is in agreement with the NIR imaging results. Our work demonstrates the great promise of inhalable DMPC-based liposomes to achieve non-invasive systemic protein delivery.

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Advances in the design of new types of inhaled medicines

Cited by 4 publications

References 237 publications

Optimization and Characterization of Novel ALCAM-Targeting Antibody Fragments for Transepithelial Delivery

Optimization and Characterization of Novel ALCAM-Targeting Antibody Fragments for Transepithelial Delivery

Artificial Intelligence in Drug Metabolism and Excretion Prediction: Recent Advances, Challenges, and Future Perspectives

Systemic Protein Delivery via Inhalable Liposomes: Formulation and Pharmacokinetics

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