Challenges for the pharmaceutical technical development of protein coformulations

Mueller, Claudia; Altenburger, Ulrike; Mohl, Silke

doi:10.1111/jphp.12731

Cited by 33 publications

(22 citation statements)

References 63 publications

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“…The manufacturing, formulation, storage, transport, handling, administration, and stability of a single protein‐based drug is already cumbersome and costly. The idea of combining two or more protein therapeutics into a single dosage form will pose daunting new challenges for manufacturers, distributors, healthcare providers, and patients . Second, as previously discussed, the PK/PD of monoclonal antibodies are often exaggerated due to their prolonged residence time in the body.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Yang

2018

Medicinal Research Reviews

146

121

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Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity. However, antibodies do have their flaws including immune-related toxicities, inadequate pharmacokinetics and tumor penetration, and high cost burden to manufacturers and consumers. These limitations hinder broader clinical applications of the antibodies and have heightened interests in developing the alternative small molecule platform that includes peptidomimetics and peptides to target the PD-1/PD-L1 immune checkpoint system. The progress on these small molecule alternatives has been relatively slow compared to that of the antibodies. Fortunately, recent structural studies of the interactions among PD-1, PD-L1, and their respective antibodies have revealed key hotspots on PD-1 and PD-L1 that may facilitate drug discovery efforts for small molecule immunotherapeutics. This review is intended to discuss key concepts in immuno-oncology, describe the successes and shortcomings of PD-1/PD-L1 antibody-based therapies, and to highlight the recent development of small molecule inhibitors of the PD-1/PD-L1 protein-protein interaction.

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Section: Discussionmentioning

confidence: 99%

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Yang

2018

Medicinal Research Reviews

146

121

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“…One desirable property of therapeutic proteins is the ability to tolerate temperatures during formulation, manufacture, storage, transport, handling and patient administration [42]. In this study, we evaluated stability of the proteins at −20 °C, 4 °C and 37 °C for 60 days.…”

Section: Discussionmentioning

confidence: 99%

Production and Characterization of Recombinant Wild Type Uricase from Indonesian Coelacanth (L. menadoensis) and Improvement of Its Thermostability by In Silico Rational Design and Disulphide Bridges Engineering

Yainoy

Phuadraksa

Wichit

et al. 2019

IJMS

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The ideal therapeutic uricase (UOX) is expected to have the following properties; high expression level, high activity, high thermostability, high solubility and low immunogenicity. The latter property is believed to depend largely on sequence identity to the deduced human UOX (dH-UOX). Herein, we explored L. menadoensis uricase (LM-UOX) and found that it has 65% sequence identity to dH-UOX, 68% to the therapeutic chimeric porcine-baboon UOX (PBC) and 70% to the resurrected ancient mammal UOX. To study its biochemical properties, recombinant LM-UOX was produced in E. coli and purified to more than 95% homogeneity. The enzyme had specific activity up to 10.45 unit/mg, which was about 2-fold higher than that of the PBC. One-litre culture yielded purified protein up to 132 mg. Based on homology modelling, we successfully engineered I27C/N289C mutant, which was proven to contain inter-subunit disulphide bridges. The mutant had similar specific activity and production yield to that of wild type (WT) but its thermostability was dramatically improved. Up on storage at −20 °C and 4 °C, the mutant retained ~100% activity for at least 60 days. By keeping at 37 °C, the mutant retained ~100% activity for 15 days, which was 120-fold longer than that of the wild type. Thus, the I27C/N289C mutant has potential to be developed for treatment of hyperuricemia.

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“…As a result, the overall cost of IV administered medicines can be high [ 174 ]. Sterility is another crucial parameter to consider prior to administration, which in turn can increase the cost of manufacture, and steps, such as sterile filtration of a polypeptide can alter its stability [ 175 ].…”

Section: Polypeptide Deliverymentioning

confidence: 99%

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

et al. 2020

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Proteins and peptides have emerged in recent years to treat a wide range of multifaceted diseases such as cancer, diabetes and inflammation. The emergence of polypeptides has yielded advancements in the fields of biopharmaceutical production and formulation. Polypeptides often display poor pharmacokinetics, limited permeability across biological barriers, suboptimal biodistribution, and some proclivity for immunogenicity. Frequent administration of polypeptides is generally required to maintain adequate therapeutic levels, which can limit efficacy and compliance while increasing adverse reactions. Many strategies to increase the duration of action of therapeutic polypeptides have been described with many clinical products having been developed. This review describes approaches to optimise polypeptide delivery organised by the commonly used routes of administration. Future innovations in formulation may hold the key to the continued successful development of proteins and peptides with optimal clinical properties.

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Challenges for the pharmaceutical technical development of protein coformulations

Cited by 33 publications

References 63 publications

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Production and Characterization of Recombinant Wild Type Uricase from Indonesian Coelacanth (L. menadoensis) and Improvement of Its Thermostability by In Silico Rational Design and Disulphide Bridges Engineering

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

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