Current strategies in extending half-lives of therapeutic proteins

Zaman, Rahela; Islam, Rowshan Ara; Ibnat, Nabilah; Othman, Iekhsan; Zaini, Azriyanti Anuar; Lee, Chooi Yeng; Chowdhury, Ezharul Hoque

doi:10.1016/j.jconrel.2019.02.016

Cited by 195 publications

(143 citation statements)

References 87 publications

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“…For most of the therapeutic peptides, a short half-life in the systemic circulation is one of the key challenges in their clinical applications [2,21,22]. In the present study, to extend the duration of the pharmacological action of sCT, PLGA was selected as a biodegradable sustained-release carrier for preparing sCT/SR.…”

Section: Preparation Of Sct/sr By the Fdd Processmentioning

confidence: 99%

“…In this study, salmon calcitonin (sCT) was selected as a model peptide, consisting of 32-amino acids, with a short half-life in the body [20,21]. Poly (lactic-co-glycolic) acid (PLGA) with an average molecular weight of 12 kDa (Resomer ® RG502H) was used as a carrier polymer for preparing sustained-release particles of sCT (sCT/SR) with a prolonged systemic biological action.…”

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confidence: 99%

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Design and Characterizations of Inhalable Poly(lactic-co-glycolic acid) Microspheres Prepared by the Fine Droplet Drying Process for a Sustained Effect of Salmon Calcitonin

et al. 2020

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The present study aimed to develop inhalable poly (lactic-co-glycolic acid) (PLGA)-based microparticles of salmon calcitonin (sCT) for sustained pharmacological action by the fine droplet drying (FDD) process, a novel powderization technique employing printing technologies. PLGA was selected as a biodegradable carrier polymer for sustained-release particles of sCT (sCT/SR), and physicochemical characterizations of sCT/SR were conducted. To estimate the in vivo efficacy of the sCT/SR respirable powder (sCT/SR-RP), plasma calcium levels were measured after intratracheal administration in rats. The particle size of sCT/SR was 3.6 µm, and the SPAN factor, one of the parameters to present the uniformity of particle size distribution, was calculated to be 0.65. In the evaluation of the conformational structure of sCT, no significant changes were observed in sCT/SR even after the FDD process. The drug release from sCT/SR showed a biphasic pattern with an initial burst and slow diffusion in simulated lung fluid. sCT/SR-RP showed fine inhalation performance, as evidenced by a fine particle fraction value of 28% in the cascade impactor analysis. After the insufflation of sCT samples (40 µg-sCT/kg) in rats, sCT/SR-RP could enhance and prolong the hypocalcemic action of sCT possibly due to the sustained release and pulmonary absorption of sCT. From these observations, the strategic application of the FDD process could be efficacious to provide PLGA-based inhalable formulations of sCT, as well as other therapeutic peptides, to enhance their biopharmaceutical potentials.

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Section: Preparation Of Sct/sr By the Fdd Processmentioning

confidence: 99%

mentioning

confidence: 99%

Design and Characterizations of Inhalable Poly(lactic-co-glycolic acid) Microspheres Prepared by the Fine Droplet Drying Process for a Sustained Effect of Salmon Calcitonin

et al. 2020

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“…As alternatives to PEGylation, several strategies were developed [19,24]. First, in order to increase hydrodynamic volumes, therapeutic peptides/proteins were fused to recombinant PEG mimetics such as XTEN and PAS sequences or conjugated to carbohydrates such as hydroxyethyl starch and polysialic acid.…”

Section: Introductionmentioning

confidence: 99%

Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide

et al. 2020

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The number of therapeutic peptides for human treatment is growing rapidly. However, their development faces two major issues: the poor yield of large peptides from conventional solid-phase synthesis, and the intrinsically short serum half-life of peptides. To address these issues, we investigated a platform for the production of a recombinant therapeutic peptide with an extended serum half-life involving the site-specific conjugation of human serum albumin (HSA). HSA has an exceptionally long serum half-life and can be used to extend the serum half-lives of therapeutic proteins and peptides. We used glucagon-like-peptide 1 (GLP-1) as a model peptide in the present study. A “clickable” non-natural amino acid—p-azido-l-phenylalanine (AzF)—was incorporated into three specific sites (V16, Y19, and F28) of a GLP-1 variant, followed by conjugation with HSA through strain-promoted azide–alkyne cycloaddition. All three HSA-conjugated GLP-1 variants (GLP1_16HSA, GLP1_19HSA, and GLP1_28HSA) exhibited comparable serum half-lives in vivo. However, the three GLP1_HSA variants had different in vitro biological activities and in vivo glucose-lowering effects, demonstrating the importance of site-specific HSA conjugation. The platform described herein could be used to develop other therapeutic peptides with extended serum half-lives.

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“…This component has been commonly used to extend the blood half‐life of externally injected drugs or biomolecules in vivo by increasing the complex size and stability mediated by albumin binding. [ 24 ]…”

Section: Resultsmentioning

confidence: 99%

Selective and Effective Cancer Treatments using Target‐Switchable Intracellular Bacterial Toxin Delivery Systems

Park

Choi

Bae

et al. 2020

Advanced Therapeutics

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Targeted cancer therapies have been extensively tested with the purpose to selectively suppress tumor growth and to avoid harming healthy tissue. However, failure to escape endosomes upon receptor‐mediated endocytosis is a major obstacle limiting the efficacy of targeted cancer therapeutics. Here, novel target‐switchable intracellular toxin delivery systems (TiTDS) are presented which use the catalytic and translocation domain of diphtheria toxin (dtA‐T) as an intracellular toxin delivery platform and affibody molecules targeting human epidermal growth factor receptor 2 or epidermal growth factor receptor (HER2Afb or EGFRAfb) as target‐specific ligands. The intracellular toxin delivery platform and the affibody molecules are genetically fused with SpyCatcher (SC) protein and SpyTag (ST) peptide, respectively, to generate dtA‐T‐SC and ST‐HER2Afb or ST‐EGFRAfb modules. These modules can be individually purified and post‐translationally ligated to produce dtA‐T/HER2Afb or dtA‐T/EGFRAf. dtA‐T/HER2Afb and dtA‐T/EGFRAfb can selectively bind to their corresponding target cancer cells, efficiently enter the cells through receptor‐mediated endocytosis, successfully escape endosomes, and release toxins into the cytosol. They exhibit high target‐specific cytotoxicity in vitro and can significantly reduce tumor masses in vivo. TiTDS is a promising targeted cancer therapy platform because of its high target specificity, effective intracellular delivery of active toxins with improved therapeutic efficacy, and target switchability.

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Current strategies in extending half-lives of therapeutic proteins

Cited by 195 publications

References 87 publications

Design and Characterizations of Inhalable Poly(lactic-co-glycolic acid) Microspheres Prepared by the Fine Droplet Drying Process for a Sustained Effect of Salmon Calcitonin

Design and Characterizations of Inhalable Poly(lactic-co-glycolic acid) Microspheres Prepared by the Fine Droplet Drying Process for a Sustained Effect of Salmon Calcitonin

Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide

Selective and Effective Cancer Treatments using Target‐Switchable Intracellular Bacterial Toxin Delivery Systems

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