Recent advances in (therapeutic protein) drug development

Lagassé, H. A. Daniel; Alexaki, Aikaterini; Simhadri, Vijaya L.; Hamasaki-Katagiri, Nobuko; Jankowski, Wojciech; Sauna, Zuben E.; Kimchi-Sarfaty, Chava

doi:10.12688/f1000research.9970.1

Cited by 388 publications

(259 citation statements)

References 57 publications

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“…Delivery efficiency depends on multiple factors, including cargo and cell type, and if done poorly can induce cell death . Exciting new gene, protein, and peptide therapies have the potential to tackle complex conditions, such as inherited human diseases, but rely upon the ability to simultaneously deliver biomolecules or transfect large numbers of cells in tissues, hence the demand for delivery technologies.…”

Section: Biochemical Deliverymentioning

confidence: 99%

High‐Aspect‐Ratio Nanostructured Surfaces as Biological Metamaterials

et al. 2020

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Materials patterned with high‐aspect‐ratio nanostructures have features on similar length scales to cellular components. These surfaces are an extreme topography on the cellular level and have become useful tools for perturbing and sensing the cellular environment. Motivation comes from the ability of high‐aspect‐ratio nanostructures to deliver cargoes into cells and tissues, access the intracellular environment, and control cell behavior. These structures directly perturb cells' ability to sense and respond to external forces, influencing cell fate, and enabling new mechanistic studies. Through careful design of their nanoscale structure, these systems act as biological metamaterials, eliciting unusual biological responses. While predominantly used to interface eukaryotic cells, there is growing interest in nonanimal and prokaryotic cell interfacing. Both experimental and theoretical studies have attempted to develop a mechanistic understanding for the observed behaviors, predominantly focusing on the cell–nanostructure interface. This review considers how high‐aspect‐ratio nanostructured surfaces are used to both stimulate and sense biological systems.

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Section: Biochemical Deliverymentioning

confidence: 99%

High‐Aspect‐Ratio Nanostructured Surfaces as Biological Metamaterials

et al. 2020

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“…The first recombinant therapeutic protein, insulin, was approved in 1982. This class of drugs now represents an essential and rapidly growing sector of clinical therapeutics used to treat a wide variety of clinical indications including autoimmune disease, cancer, infectious diseases and genetic disorders . Over the years, advances in protein engineering have permitted alterations in the structure of protein therapeutics to enhance desirable functional characteristics and thus, product efficacy and safety .…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity assessment during the development of protein therapeutics

Rosenberg

Sauna

2018

Journal of Pharmacy and Pharmacology

106

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Objective Here we provide a critical review of the state of the art with respect to non-clinical assessments of immunogenicity for therapeutic proteins. Key findings The number of studies on immunogenicity published annually has more than doubled in the last 5 years. The science and technology, which have reached a critical mass, provide multiple of non-clinical approaches (computational, in vitro, ex vivo and animal models) to first predict and then to modify or eliminate T-cell or B-cell epitopes via de-immunization strategies. We discuss how these may be used in the context of drug development in assigning the immunogenicity risk of new and marketed therapeutic proteins. Summary Protein therapeutics represents a large share of the pharma market and provide medical interventions for some of the most complex and intractable diseases. Immunogenicity (the development of antibodies to therapeutic proteins) is an important concern for both the safety and efficacy of protein therapeutics as immune responses may neutralize the activity of life-saving and highly effective protein therapeutics and induce hypersensitivity responses including anaphylaxis. The non-clinical computational tools and experimental technologies that offer a comprehensive and increasingly accurate estimation of immunogenic potential are surveyed here. This critical review also discusses technologies which are promising but are not as yet ready for routine use.

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“…cell-penetrating peptides | peptidomimetics | enzyme replacement therapy | endocytosis | protein therapeutics P rotein and peptide therapeutics-biologics-comprise a rapidly growing sector of the modern pharmacopeia (1). Seven of the top 10 highest grossing therapeutic agents in 2017 were biologics used to treat cancer, diabetes, and autoimmune inflammatory disorders, such as rheumatoid arthritis and Crohn's disease.…”

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confidence: 99%

HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins

Steinauer

LaRochelle

Knox

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Protein therapeutics represent a significant and growing component of the modern pharmacopeia, but their potential to treat human disease is limited because most proteins fail to traffic across biological membranes. Recently, we discovered a class of cell-permeant miniature proteins (CPMPs) containing a precisely defined, penta-arginine (penta-Arg) motif that traffics readily to the cytosol and nucleus of mammalian cells with efficiencies that rival those of hydrocarbon-stapled peptides active in animals and man. Like many cell-penetrating peptides (CPPs), CPMPs enter the endocytic pathway; the difference is that CPMPs containing a penta-Arg motif are released efficiently from endosomes, while other CPPs are not. Here, we seek to understand how CPMPs traffic from endosomes into the cytosol and what factors contribute to the efficiency of endosomal release. First, using two complementary cellbased assays, we exclude endosomal rupture as the primary means of endosomal escape. Next, using an RNA interference screen, fluorescence correlation spectroscopy, and confocal imaging, we identify VPS39-a gene encoding a subunit of the homotypic fusion and protein-sorting (HOPS) complex-as a critical determinant in the trafficking of CPMPs and hydrocarbon-stapled peptides to the cytosol. Although CPMPs neither inhibit nor activate HOPS function, HOPS activity is essential to efficiently deliver CPMPs to the cytosol. CPMPs localize within the lumen of Rab7 + and Lamp1 + endosomes and their transport requires HOPS activity. Overall, our results identify Lamp1 + late endosomes and lysosomes as portals for passing proteins into the cytosol and suggest that this environment is prerequisite for endosomal escape.cell-penetrating peptides | peptidomimetics | enzyme replacement therapy | endocytosis | protein therapeutics

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Recent advances in (therapeutic protein) drug development

Cited by 388 publications

References 57 publications

High‐Aspect‐Ratio Nanostructured Surfaces as Biological Metamaterials

High‐Aspect‐Ratio Nanostructured Surfaces as Biological Metamaterials

Immunogenicity assessment during the development of protein therapeutics

HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins

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